CN101137370B - Liquid formulations for treatment of diseases or conditions - Google Patents

Abstract

Diseases and conditions associated with tissues of the body, including tissues in the eye, can be effectively treated by administering therapeutic agents to those tissues. Described herein are self-emulsifying formulations and methods for delivering therapeutic agents to such tissues. A self-emulsifying formulation may be delivered to an aqueous medium of a subject, including but not limited to the vitreous. A method may, for instance, be used to administer rapamycin or related compounds to treat or prevent choroidal neovascularization associated with age-related macular degeneration, or to treat dry AMD. A self-emulsifying formulation may also be administered systernically, such as orally, to treat transplant rejection in a subject. A self-emulsifying formulation may comprise rapamycin, related compounds, or other therapeutic agents.

Description

The liquid preparation that is used for the treatment of disease or disease

Technical field

This paper describes by experimenter's (including but are not limited to people experimenter) delivering therapeutic agents is treated, prevents, suppressed disease or disease, postpones its generation or makes its liquid preparation disappearing, include but are not limited to by experimenter's (including but are not limited to people experimenter) eyes being sent to the degeneration of macula (AMD) of the liquid preparation treatment age-dependent that comprises therapeutic agent.The limiting examples of described liquid preparation comprises solution, suspensoid and in-situ gelling preparation.

With the mutual reference of related application

" the Liquid Formulations ForTreatment Of Diseases Or Conditions by name submitting in the application and on March 21st, 2005, " U.S. Provisional Patent Application serial number 60/664, 040, " the In Situ Gelling Formulations AndLiquid Formulations For Treatment of Diseases Or Conditions by name submitting on March 21st, 2005, " U.S. Provisional Patent Application serial number 60/664, 306, " the FormulationsFor Ocular Treatment by name submitting on February 9th, 2005, " U.S. Provisional Patent Application serial number 60/651, 790 are correlated with and require their priority, each data is complete the quoting as a reference for all objects of this paper.

Technical background

The cone cell that the retina of eyes comprises sensitization and rod cell.Retinal centre is macula retinae, and its diameter is approximately 1/3 to 1/2cm.Macula lutea provides detailed vision (particularly in central authorities' (central fovea)), because cone cell density is higher.Blood vessel, ganglionic cell, inner nuclear layer and cell and plexiform layers all move to a side (rather than being still on cone cell), thereby make light arrive cone cell with more direct path.

Under retina, be choroid, comprise the one group of blood vessel embedding in fibrous tissue and the dark pigment epithelium that covers choroid layer.Choroidal artery provides nutrition to retina (particularly its visual cell).

There is multiple cannot treat at present or current therapy is not best retinal diseases.Retinal diseases is as uveitis (uvea: sclera, corpus ciliare and choroidal inflammation), central retinal vein occlusion sick (CRVO), branch retinal vein occlusion (BRVO), degeneration of macula, macular edema, proliferative diabetic retinopathy change and the normally all retinal diseasess that are difficult to Routine Treatment Therapy For Instability of detachment of retina.

Relevant degeneration of macula (AMD) of age is the main cause that the U.S. is greater than individual severe visual forfeiture in 60 years old the age.AMD occurs with atrophic or more not general exudative form.The AMD of atrophic form is also referred to as " dry AMD ", and Exudative AMD is also referred to as " moist AMD ".

In Exudative AMD, blood vessel passes the defect growth Bruch's membrane (retinal pigment epithelium below being in some cases) from choriocapillary layer.The tissue of the serosity of overflowing from these vasculars or blood exudate cause subsidiary degeneration, the retinal pigment epithelium of macular area fiber blood vessel cicatrization and neuroretina come off and tear, vitreous hemorrhage and central vision permanent loss.This process occupies remarkable the more than 80% of visual loss case in the experimenter who suffers from AMD.Treatment current or that soon occur comprises laser photocoagulation, photodynamic therapy, with VEGF antibody fragment, treats, uses the aptamer therapeutics of Pegylation and treat with some micromolecule agent.

Some Recent Researchs have been described purposes (Macular Photocoagulation Study Groups (1991) inArch.Ophthal.109:1220 of laser photocoagulation in the treatment constitutional relevant to AMD or the damage of recidivity neovascularity; Arch.Ophthal 109:1232; Arch.Ophthal.109:1242).Unfortunately, carry out AMD patient that having of laser therapy damage under central fovea and in the tracing study of 3 months, experienced visual acuity very rapidly decline (average 3 row).In addition, treat latter 2 years, the eyes through treating only have a small amount of eyesight improving (being respectively average 20/320 and 20/400) compared with their untreated eyes.Another shortcoming of the method is postoperative vision variation at once.

Photodynamic therapy (PDT) is a kind of optical treatment---comprises and makes to use up all treatments that experimenter produced to useful reaction.Best is that PDT destroys unwanted tissue and lets slip normal structure.Generally experimenter is used to the compound that is called photosensitizer.Conventionally photosensitizer self has a little or does not affect experimenter.When light (conventionally from laser instrument) directive contains organizing of photosensitizer, photosensitizer is activated and starts to destroy target tissue.Because directive experimenter's light is limited in specific target region, can use optionally targeting abnormal structure of PDT, therefore let slip health tissues around.Use at present PDT treatment retinal diseases as AMD.PDT is the Main Means (Photodynamic Therapy for SubfovealChoroidal Neovascularization in Age Related Macular Degeneration withVerteporfin (TAP research group) Arch Ophthalmol.1999 117:1329-1345) that is used for the treatment of choroid neovascularization under AMD patient's central fovea at present.

It is that opposing is treated that choroid neovascularization (CNV) is proved to be in majority of cases.Conventional laser therapy is in the situation that relate to the selection of foveal region of retina and can excise CNV and help to keep vision, but this only limits in approximately 10% case.Unfortunately, even if carried out the solidifying art of successful conventional laser light, also recurrence in the eyes of 50%-70% of neovascularization (3 years be 50%, and 5 years time > 60%).(Macular?Photocoagulation?Study?Group，Arch.Ophthalmol.204：694-701(1986))。In addition, the experimenter of many CNV of suffering from is not the good candidate of laser therapy, because CNV is too large for laser therapy, or can not determine position so the doctor laser that can not take accurate aim.Although photodynamic therapy is applied in nearly under 50% central fovea in CNV new case, it only has a small amount of benefit to natural medical history, and conventionally postpones the progress of visual loss rather than improve the vision having reduced after damage under central fovea.PDT is not preventative, neither be deterministic.Each experimenter needs some PDT treatments conventionally, and in addition, the progress ground that the CNV of some hypotype is not so good as other is good.

Therefore, still exist for a long time can be used for preventing best or significantly suppressing choroid neovascularization and for preventing and treat the needs of method, compositions and the preparation of moist AMD.

Except AMD, choroid neovascularization is relevant to this class retinal diseases, as ocular tissue's endochylema bacterium syndrome, myopic degeneration, angioid streaks, ICSC, retina and/or choroid inflammatory disease and the ocular injury of supposition.The angiogenesis damage relevant to neovascularization occurs in various diseases, comprises diabetic retinopathy, venous occlusion, sickle cell retinopathy, retinopathy of prematurity, detachment of retina, eye ischemia and wound.

Uveitis is to have proved another retinal disorder that uses existing therapy to be difficult to treatment.Uveitis is for indicating the general term of any assembly inflammation of tunica uvea.The tunica uvea of eyes is comprised of sclera, corpus ciliare and choroid.On the amphiblestroid inflammation (being called retinitis) covered or the inflammation (being called optic neuritis) of optic nerve can follow or do not follow uveitis and occur.

Before, during and after uveitis is divided into by anatomy the most at large or diversity.Rear uveitis represents in retinitis, choroiditis or the optic neuritis of various ways any.Diversity uveitis refers to and relates to all parts of the eyes inflammation of (comprising front portion, middle part and rear structure).

Uveitic symptom and symptom can be slight, and significantly change according to the position of inflammation and seriousness.With regard to rear uveitis, the most general symptom comprises that the existence of float and vision reduce.Suffer from also can exist in rear uveitic experimenter and in vitreous humor, have white or yellow-white damage, exudative detachment of retina, retinal vasculitis and optic nerve edema in cell, retina and/or choroid below.

Uveitic ophthalmic complications can produce great and irreversible visual loss, particularly when not recognizing or during by inappropriate treatment.The most general complication of rear uveitis comprises the neovascularization of detachment of retina, retina, optic nerve or sclera, and cystoid macular edema.

If be recorded to swelling, seepage and hard exudate in macula lutea (retina of the most key central authorities 5% to vision) in background diabetic retinopathy (BDR), macular edema (ME) occur.Background diabetic retinopathy (BDR) is comprised of retina microaneurysm conventionally, and this microaneurysm is changed and caused by retinal microcirculation.The visual variation the earliest of the retinopathy that these microaneurysms are seen during normally with ophthalmofundoscopy, it is shown as the red point disperseing in retina, wherein small expansion of the blood vessel weakening.In background diabetic retinopathy process, visual discovery develops into cotton-wool patches, inter-retinal hemorrhage, liquid and from retinal capillary, oozes out and retinal exudates.The vascular permeability improving also relates to the local growth factor that level improves, as VEGF.Macula lutea is rich in cone cell, and it is to experience the teleneuron that color and day mesopic vision rely on.When the retinal capillary permeability improving affects macula lutea, the avris of central authorities or only central vision field occurs fuzzy, just as seeing through cellophane.Visual loss can develop within the time of several months, and can owing to can not knowing focusing, make very much people worried.ME is some VI common reasons.

Once had and make to heal with medicine CNV and relevant disease and disease, and other diseases are as the trial of macular edema and chronic inflammatory disease.For example, use rapamycin inhibition CNV and moist AMD to be described in U. S. application No.10/665,203, its integral body is quoted as a reference herein.Use rapamycin treatment eyes inflammatory diseases to be described in U.S. Patent number 5,387,589, its title is Method of Treating Ocular Inflammation, invention people is Prassad Kulkarni, transfer University of Louisville Research Foundation, its content is quoted in this paper integral body.

Especially for chronic disease (comprising chronic disease as herein described), be starved of for for example, the long-acting method to eyes (be delivered to back segment with treatment as the CNV of this class disease of AMD, macular edema, proliferative retinopathy and chronic inflammatory disease) by therapeutic agent delivery.The preparation that extends delivering therapeutic agents is more comfortable and convenient for experimenter, because the frequency of ocular injection therapeutic agent reduces.

To eyes delivering therapeutic agents rather than systemic administration, can be directly favourable, because with respect to concentration for the treatment of agent in experimenter's blood circulation, the concentration for the treatment of agent of action site improves.In addition, systemic delivery therapeutic agent can have less desirable side effect with treatment posterior segment disease.Therefore, localized drug delivery can be raised the efficiency, and reduces side effect and general toxicity simultaneously.

Summary of the invention

Methods described herein, compositions and liquid preparation allow the eyes delivering therapeutic agents to experimenter's (including but are not limited to people experimenter) or experimenter.This paper describes method, compositions and the liquid preparation of for time expand, sending multiple therapeutic agent, described therapeutic agent can be used for treatment, prevention, suppresses various disease conditions or disease, postpones its generation or cause that it disappears, described disease or disease include but not limited to ophthalmic or disease.Liquid preparation include but not limited to solution, suspensoid and in-situ gelling preparation.

This paper describes that the amount of described rapamycin can effectively treat, prevents, suppresses moist AMD, postpones its generation or cause that it disappears for use method, compositions and the liquid preparation of rapamycin to people experimenter.

As " detailed Description Of The Invention " part describes in further detail, also can use described method, compositions and liquid preparation for being used for the treatment of, preventing, suppressing moist AMD, postpone its generation or cause that it disappears to experimenter's (including but are not limited to people experimenter) or to the rapamycin of people experimenter's eyes delivery treatments effective dose.In some modification, use described method, compositions and liquid preparation to treat moist AMD.In some modification, use described method, compositions and liquid preparation for pre-moisture resistance AMD.In some modification, use methods described herein and preparation to be used for preventing dryness AMD to change moist AMD into.Described method, compositions and liquid preparation also can be used for being used for the treatment of, preventing, suppressing CNV, postpone its generation or cause that it disappears to experimenter's (including but are not limited to people experimenter) or to the rapamycin of experimenter's eyes delivery treatments effective dose.In some modification, use described method, compositions and liquid preparation treatment CNV.Described method, compositions and liquid preparation also can be used for to experimenter's (including but are not limited to people experimenter) or are used for the treatment of, prevent, suppress eye medium vessels to the rapamycin of experimenter's eyes delivery treatments effective dose occurring, postponing its generation or cause that it disappears.In some modification, use described method, compositions and liquid preparation to be used for the treatment of blood vessel and occur.Can use rapamycin treatment, prevention, inhibition, postpone its generation or cause that other diseases and disease that it disappears are described in " disease and the disease " part of " detailed Description Of The Invention ".

As " detailed Description Of The Invention " part describes in further detail, also can use described method, compositions and liquid preparation for being used for the treatment of, preventing, suppressing moist AMD, postpone its generation or cause that it disappears to experimenter's (including but are not limited to people experimenter) or to the therapeutic agent except rapamycin of experimenter's eyes delivery treatments effective dose.In some modification, use described method, compositions and liquid preparation to be used for the treatment of moist AMD.Operable therapeutic agent is described in detail in " therapeutic agent " part.But this class therapeutic agent includes but are not limited in conjunction with the compound of exempting from albumen.But operable combination is exempted from the compound of albumen and is included but are not limited to the limus family compound that " therapeutic agent " part further describes herein, comprises rapamycin, SDZ-RAD, tacrolimus (tacrolimus), everolimus (everolimus), pimecrolimus (pimecrolimus), CCI-779, AP23841, ABT-578 and derivant, analog, prodrug, salt and ester.Also can use described method, compositions and liquid preparation for being used for the treatment of, preventing, suppressing CNV, postpone its generation or cause that it disappears to experimenter's (including but are not limited to people experimenter) or to the therapeutic agent of experimenter's eyes delivery treatments effective dose.In some modification, use described method, compositions and liquid preparation to be used for the treatment of CNV.Also can use described method, compositions and liquid preparation for to experimenter's (including but are not limited to people experimenter) or be used for the treatment of, prevent, suppress eye medium vessels to the therapeutic agent of experimenter's eyes delivery treatments effective dose and occur, postpone its generation or cause that it disappears.In some modification, use described method, compositions and liquid preparation to be used for the treatment of blood vessel and occur.The therapeutic agent of use except rapamycin can be treated, prevent, suppress, postpone its generation or be caused that other diseases and disease that it disappears are described in " disease and disease " part in " detailed Description Of The Invention ".

A kind of liquid preparation described herein comprises a kind of solution, and described solution contains the therapeutic agent being dissolved in solvent.Conventionally can use any solvent with required effect, the eyes that therapeutic agent is dissolved in wherein and it can be administered to experimenter's (including but are not limited to people experimenter) or be administered to experimenter.Conventionally can use the therapeutic agent of any concentration with required effect.In some modification, preparation is undersaturated, saturated or oversaturated solution.Solvent can be that neat solvent can be maybe the mixture of liquid flux composition.In some modification, the solution of formation is in-situ gelling preparation.Operable solvent and solution type are that this type of drug delivery technical field technical staff is known.

When being placed in lagophthalmos (including but are not limited to lagophthalmos vitreous body), liquid preparation described herein can form the agglomerate of non-diversity.In some modification, described nondispersive agglomerate comprises gel.In some modification, liquid preparation comprises therapeutic agent and multiple polymers.In some modification, one of polymer is polyacrylate or polymethacrylates.In some modification, one of polymer is polyvinylpyrrolidone.

In some modification, non-diversity agglomerate comprises depot formulation.In some modification, non-diversity agglomerate is comprised of depot formulation.

For the liquid preparation of the non-diversity agglomerate of formation, non-diversity agglomerate can be any geometry or shape conventionally.When being placed in vitreous body, the liquid preparation that forms non-diversity agglomerate can for example be shown as fine and close spherical agglomerate.In some modification, when liquid preparation described herein is placed in vitreous body, the medium being placed with respect to it forms semicontinuous or semi-solid non-diversity agglomerate milky white or white.

Liquid preparation can be used to have any volume of required effect conventionally.In one approach, to vitreous body, use the liquid preparation of a volume, and liquid preparation is less than vitreous body volume half.

The route of administration of operable applicating liquid preparation comprises, but be not limited only to (1) and settle liquid preparation by settling (comprising injection) to enter medium (including but are not limited to the aqueous medium in body), include but are not limited to ophthalmic or periocular injections; Or (2) oral liquid.Liquid preparation can systemic administration, includes but are not limited to following route of administration: rectum, vagina, inculcate, in intramuscular, intraperitoneal, intra-arterial, sheath, in bronchus, in pond, in epidermis, subcutaneous, Intradermal, percutaneous, intravenous, cervical canal, in abdomen, intracranial, lung is interior, intrathoracic, trachea interior, nose, suck, the aerosolization of Sublingual, per os, parenteral or spraying or the agent of use aerosol spray.In some modification, under liquid preparation conjunctiva, use.In some modification, liquid preparation intravitreal administration.

Liquid preparation described herein can be delivered to any medium (including but are not limited to experimenter's aqueous medium) of experimenter's (including but are not limited to people experimenter).

The liquid preparation that a kind of liquid preparation described herein comprises rapamycin or other treatment agent.Liquid preparation can comprise solution, suspensoid, in-situ gelling preparation or Emulsion.Microdroplet in Emulsion can be generally any size, include but are not limited to large to approximately 5,000nm.

In preparations more described herein, liquid preparation can comprise therapeutic agent (including but are not limited to rapamycin) and one or more solubilizing agents or solvent.In some modification, solubilizing agent or solvent are the Polyethylene Glycol (including but are not limited to PEG 300 and PEG 400) of glycerol, DMSO, DMA, N-Methyl pyrrolidone, ethanol, benzyl alcohol, isopropyl alcohol, various molecular weights, or the mixture of propylene glycol or one or more these materials.

In preparations more described herein, liquid preparation comprises hyaluronic acid.

Liquid preparation described herein can be with the time period delivering therapeutic agents extending.The limiting examples that this class extends release delivery system is the system that the time period to extend therapeutic agent is delivered to experimenter's (including but are not limited to people experimenter) or is delivered to experimenter's eyes can maintain the q.s of effective dose, and described effective dose can in experimenter, treat, prevent, suppress, postpone disease or disease occurs or causes that it disappears.In some modification, liquid preparation is used for the treatment of experimenter's's (including but are not limited to people experimenter) disease or disease.In some modification, liquid preparation delivering therapeutic agents continues at least about one month, approximately two months, approximately three months, approximately six months, approximately nine months or approximately 12 months.

The time period that liquid preparation described herein can extend is sent rapamycin or other treatment agent.The limiting examples that this class extends release delivery system is the eyes that the time period to extend rapamycin are delivered to experimenter's (including but are not limited to people experimenter) or are delivered to experimenter can maintain the q.s of effective dose, and described effective dose can be treated, prevent, suppresses, postpones the generation of relevant degeneration of macula of moist age or be caused that it disappears in experimenter.In some modification, the time period internal therapy moist age relevant degeneration of macula of liquid preparation for extending.In some modification, use liquid preparation pre-relevant degeneration of macula of moisture resistance age within the time period extending.In some modification, use liquid preparation to prevent dryness AMD to change moist AMD within the time period extending.In a nonrestrictive example, liquid preparation can be treated rapamycin, prevent, suppress, postpone the relevant degeneration of macula generation of moist age or cause that its amount disappearing is delivered in the vitreous body of experimenter's (including but are not limited to people experimenter), sclera, retina, choroid, macula lutea or its hetero-organization at least about three months, approximately six months, approximately nine months or approximately 12 months with enough.In some modification, the level of rapamycin is enough treated AMD.In some modification, the level of rapamycin is the generation of pre-moisture resistance AMD enough.

Other time expands, discharge and are described in " detailed Description Of The Invention ".

Summary of drawings

Figure 1A-1C illustrates the formation of nondispersive agglomerate after injecting fluid preparation in vitreum, as it is considered to occur in some modification.

Fig. 2 has described the level of rapamycin in vitreous body (ng/ml), retina choroid (ng/ml) and the sclera (ng/ml) of 20,40,67 and 90 days lagophthalmos after rapamycin water, ethanol and F127 (Lutrol) solution of subconjunctival injection 1.256%.

Fig. 3 has described the level of rapamycin in 14,35,62 and 85 Lepus vitreums (ng/ml) after the rapamycin PEG 400 of subconjunctival injection 5% and alcoholic solution, retina choroid (ng/ml) and sclera (ng/ml).

Fig. 4 has described the level of rapamycin in 14,35,62 and 90 Lepus vitreums (ng/ml) after the rapamycin PEG 400 of intravitreal injection 5% and alcoholic solution, retina choroid (ng/ml) and sclera (ng/ml).Also shown and injected the rapamycin levels (ng/ml) existing in latter 2 days vitreous body.

Fig. 5 has described 8 Lepus eye pattern pictures after the PEG400 suspension of intravitreal injection 10 μ l (Fig. 4 A), 20 μ l (Fig. 4 B) and 40 μ l (Fig. 4 C), 6% rapamycin.

Fig. 6 describes the level of rapamycin in 7,32,45 and 90 Lepus vitreums (ng/ml) after ethanol, PVP K90, PEG 400 and Eudragit RL 100 solution of subconjunctival injection 4.2% rapamycin, retina tela chorioidea (ng/mg) and sclera (ng/ml).

Fig. 7 describes the level of rapamycin in 14,42,63 and 91 Lepus vitreums (ng/ml) after PEG 400 suspensions of subconjunctival injection 3% rapamycin, retina tela chorioidea (ng/mg) and sclera (ng/mg).

Fig. 8 describes in 14,42,63 and 91 Lepus vitreums (ng/ml) after PEG 400 suspensions of intravitreal injection 3% rapamycin, retina tela chorioidea (ng/mg) and sclera (ng/mg) and after injection the level of horizontal rapamycin in 63 and 91 days vitreous body.

Fig. 9 describes the level of rapamycin in 14,42,63 and 91 Lepus vitreums (ng/ml) after subconjunctival injection 2% rapamycin ethanol and PEG 400 solution, retina tela chorioidea (ng/mg) and sclera (ng/mg).

Figure 10 describes after intravitreal injection 2% rapamycin ethanol and PEG 400 solution 14,42, the level of rapamycin in 63He91Tian retina in rabbits tela chorioidea (ng/mg) and sclera (ng/mg).

Figure 11 describes after intravitreal injection 2% rapamycin ethanol and PEG 400 solution the level (ng/ml) of rapamycin in 63 and 91 Lepus vitreums.

Figure 12 describes the level of the interior rapamycin of 5,30,60,90 and 120 Lepus vitreum (ng/ml) after the ethanol of 2% rapamycin of subconjunctival injection 20 μ l, 40 μ l and 60 μ l dosage and PEG 400 solution.

Figure 13 describes the level of 5,30,60,90 and 120 days interior rapamycins of retina in rabbits choroid (ng/mg) after the ethanol of 2% rapamycin of subconjunctival injection 20 μ l, 40 μ l and 60 μ l dosage and PEG 400 solution.

Figure 14 describes the level of the interior rapamycin of 5,30,60,90 and 120 Lepus vitreum (ng/ml) after the ethanol of 2% rapamycin of intravitreal injection 20 μ l and 40 μ l dosage and the ethanol of 0.4% rapamycin of PEG 400 solution and 100 μ l dosage and PEG 400 solution.

Figure 15 describes after the ethanol of 2% rapamycin of intravitreal injection 20 μ l and 40 μ l dosage and the ethanol of 0.4% rapamycin of PEG 400 solution and 100 μ l dosage and PEG 400 solution 5,30,60, the level of the interior rapamycin of 90He120Tian retina in rabbits tela chorioidea (ng/mg).

Figure 16 describes the level of the interior rapamycin of 5 and 14 Lepus vitreum (ng/ml) after the ethanol of 2% rapamycin of single part of 10 μ l dosage of subconjunctival injection, single part of 60 μ l dosage, twice 30 μ l dosage and three 30 μ l dosage and PEG 400 solution.

Figure 17 describes the level of the 5 interior rapamycins of He14Tian retina in rabbits tela chorioidea (ng/mg) after the ethanol of 2% rapamycin of subconjunctival injection single 10 μ l dosage, single 60 μ l dosage, twice 30 μ l dosage and three 30 μ l dosage and PEG 400 solution.

Figure 18 describes the level of the interior rapamycin of 5,14 and 30 Lepus vitreum (ng/ml) after PEG 400 suspensions of 3% rapamycin of subconjunctival injection single 10 μ l dosage, single 30 μ l dosage and three 30 μ l dosage.

Figure 19 describes after PEG 400 suspensions of 3% rapamycin of subconjunctival injection single 10 μ l dosage, single 30 μ l dosage and three 30 μ l dosage 5, the level of the interior rapamycin of 14He30Tian retina in rabbits tela chorioidea (ng/mg).

Figure 20 describes after the ethanol of intravitreal injection 10 μ l 0.2% rapamycins and PEG 400 solution, the ethanol of injection 10 μ l 0.6% rapamycins and the ethanol of PEG 400 solution and injection 10 μ l 2% rapamycins and PEG 400 solution 5, the level of the interior rapamycin of 30He90Tian retina in rabbits tela chorioidea (ng/mg).

Figure 21 describes the level of the interior rapamycin of 5,30 and 90 Lepus vitreum (ng/ml) after the ethanol of intravitreal injection 10 μ l 0.2% rapamycins and PEG 400 solution, the ethanol of injection 10 μ l 0.6% rapamycins and the ethanol of PEG 400 solution and injection 10 μ l 2% rapamycins and PEG 400 solution.

Figure 22 describes after the ethanol of subconjunctival injection 40 μ l 2% rapamycins and PEG 400 solution after 1,4,7,11,14,21,28,35,54 and 56 day the level of rapamycin in rabbit aqueous humor (ng/ml), cornea (ng/mg) and retina tela chorioidea (ng/mg).

Detailed Description Of The Invention

This paper describes and relate to compositions, liquid preparation and the method to experimenter's (including but are not limited to people experimenter) or experimenter's eye by therapeutic agent delivery.These compositionss, liquid preparation and method can be used for treatment, prevention, suppress, postpone ophthalmic and disease generation or it is disappeared, described ophthalmic and disease include but are not limited to posterior segment disease or disease, include but are not limited to choroid neovascularization, degeneration of macula, relevant degeneration of macula (comprising moist AMD and dryness AMD), retinal vessel generation, uveitis and other retina hypertrophy diseases of age.In some modification, described compositions, liquid preparation and method are used for the treatment of above-mentioned ophthalmic or disease.

This paper describes that (1) can be used compositions described herein, liquid preparation and method to be delivered to the therapeutic agent of experimenter's (including but are not limited to people experimenter) or experimenter's eye; (2) can treat by delivering therapeutic agents, prevent, suppress, postpone to occur or make its disease disappearing and disease; (3) can be used for the liquid preparation of delivering therapeutic agents; (4) route of administration of delivering liquid preparation; (5) therapeutic agent delivery extending, described therapeutic agent includes but are not limited to rapamycin; (6) describe the treatment of CNV and moist AMD, described treatment is undertaken by using described compositions and liquid preparation to send rapamycin with time period of prolongation to experimenter's (including but are not limited to people experimenter) or experimenter's eye.

Term " about " used herein refers to the level of accuracy obtaining while using methods described herein (as the method in embodiment).Yet, determine that the formulation components of amount refers to the 90-110% of described amount by " approximately ".

Therapeutic agent

Generally speaking, known or still to be found so far can be used for treating, preventing, suppress, postpone disease described herein and disease occurs or causes that any compound and compositions that it disappears can be the therapeutic agents for compositions described herein, liquid preparation and method.

But operable therapeutic agent comprises by exempt from the compound that protein family member is worked in conjunction with cell protein.This compounds is known as " but in conjunction with the compound of exempting from albumen ".But include but are not limited in conjunction with the compound of exempting from albumen " limus " compound family.The example of operable limus compound includes but are not limited to cyclophilin and FKBPL (FKBPs), comprises sirolimus (sirolimus) (rapamycin) and water-soluble analogues SDZ-RAD (Novartis) thereof, TAFA-93 (Isotechnika), tacrolimus, everolimus, RAD-001 (Novartis), pimecrolimus, temsirolimus, CCI-779 (Wyeth), AP23841 (Ariad), AP23573 (Ariad) and ABT-578 (Abbott Laboratories).Operable Limus compound analog and derivant include but not limited to be described in United States Patent (USP) 5,527,907; 6,376,517 and 6,329,386 and the compound of U.S. Patent Application No. 09/950,307, each data is quoted as a reference in this paper integral body.Therapeutic agent also comprises analog, prodrug, salt and the ester of limus compound.

Term rapamycin, rapa and sirolimus are used interchangeably herein.

Other spendable rapamycin derivatives include but are not limited to the monoesters of 7-table-rapamycin, 7-sulfidomethyl-rapamycin, 7-table-trimethoxyphenyl-rapamycin, 7-table-sulfidomethyl-rapamycin, 7-demethoxylation-rapamycin, 32-demethoxylation-rapamycin, 2-demethylation-rapamycin, rapamycin and diester deriv, rapamycin 27-oxime; The 42-oxo analog of rapamycin; Bicyclo-rapamycin; Rapamycin dimer; Rapamycin monosilane ether; Rapamycin aromatic yl sulphonate and sulfamate, the monoesters of 31 and 42 and diester, 30-demethoxylation rapamycin, and Vezina etc., " Rapamycin (AY-22; 989), A New Antifungal Antibiotic.I.Taxonomy Of The Producing Streptomycete And Isolation Of The ActivePrinciple " J.Antibiot. (Tokyo) 28:721-726 (1975); Sehgal etc., " Rapamycin (AY-22,989), A New Antifungal Antibiotic.II.Fermentation, Isolation AndCharacterization " J.Antibiot. (Tokyo) 28:727-732 (1975); Sehgal etc., Demethoxyrapamycin (AY-24,668), A New Antifungal Antibiotic " J.Antibiot. (Tokyo) 36:351-354 (1983); With Paiva etc., " Incorporation Of Acetate; Propionate; And Methionine Into Rapamycin By Streptomyceteshygroscopicus " J Nat Prod 54:167-177 (1991), WO 92/05179, and EP 467606, Caufield etc., " Hydrogenated Rapamycin Derivatives " U.S. Patent number No.5,023,262; Kao etc., " Bicyclic Rapamycins " U.S. Patent number No.5,120,725; Kao etc., " Rapamycin Dimers " U.S. Patent number No.5,120,727; Failli etc., " SilylEthers Of Rapamycin " U.S. Patent number No.5,120,842; Failli etc., " Rapamycin42-Sulfonates And 42-(N-carboalkoxy) Sulfamates Useful AsImmunosuppressive Agents " U.S. Patent number 5,177,203; Nicolaou etc., " TotalSynthesis Of Rapamycin " J.Am.Chem.Soc.115:4419-4420 (1993); Romo etc., " Total Synthesis Of (-) Rapamycin Using An Evans-TishchenkoFragment Coupling " J.Am.Chem.Soc.115:7906-7907 (1993); With Hayward etc., " Total Synthesis Of Rapamycin Via A NovelTitanium-Mediated Aldol Macrocyclization Reaction " J.Am.Chem.Soc., other derivants that 115:9345-9346 (1993) is described, each data is quoted as a reference in this paper integral body.

Ophthalmic and disease (comprising choroid neovascularization) that Limus family compound can be used for treatment, prevention, inhibition, delay blood vessel generation mediation occur or make in its compositions disappearing, liquid preparation and method.Limus compound family can be used for preventing, treats, suppresses, postpones AMD (comprising moist AMD) and occurs or it is disappeared.Ophthalmic and disease (comprising choroid neovascularization) that rapamycin and rapamycin derivative and analog can be used for prevention, treatment, inhibition, delay blood vessel generation mediation occur or it are disappeared.Rapamycin can be used for preventing, treats, suppresses, postpones AMD (comprising moist AMD) and occurs or it is disappeared.In some modification, the member of limus compound family or rapamycin are used for the treatment of moist AMD or the ophthalmic and the disease that mediate occur blood vessel, comprises choroid neovascularization.

Operable other treatment agent is included in disclosed therapeutic agent in following patent and publication, each data is quoted its integral body as a reference herein: the open WO 2004/027027 of PCT, on April 1st, 2004 is open, be entitled as Method of inhibiting choroidal neovascularization, transfer Trustees of the University of Pennsylvania; U.S. Patent number 5,387,589, announce February 7 nineteen ninety-five, is entitled as Method of Treating Ocular Inflammation, and invention people is Prassad Kulkarni, authorizes University of Louisville Research Foundation; U.S. Patent number 6,376, on April 23rd, 517,2003 announces, and is entitled as Pipecolic acid derivativesfor vision and memory disorders, transfers GPI NIL Holdings, Inc; The open WO 2004/028477 of PCT, on April 8th, 2004 is open, is entitled as Method subretinaladministration of therapeutics including steroids:method for localizingpharmadynamic action at the choroid and retina; And related methods fortreatment and or prevention of retinal diseases, assigned to Innorx, Inc; U.S. Patent number 6,416, on July 9th, 777,2002 submits to, is entitled as Ophthalmic drug deliverydevice, transfers Alcon Universal Ltd; U.S. Patent number 6, on March 30th, 713,081,2004 announces, be entitled as Ocular therapeutic agent delivery device and methods formaking and using such devices, transfer Department of Health and HumanServices; U.S. Patent number 5,100, on March 31st, 899,1992 announces, and is entitled as Methods ofinhibiting transplant rej ection in mammals using rapamycin andderivatives and prodrugs thereof.

Spendable other treatment agent comprises pyrrolidine, dithiocar-bamate (NF kB inhibitor); Squalamine; TPN 470 analog and Amebacilin; PKC (Protein kinase C) inhibitor; Tie-1 and Tie-2 inhibitors of kinases; Vegf receptor kinase inhibitor; Albuminous body inhibitor is as the Velcade for injecting ^tM(bortezomib); Ranibuzumab (Lucentis ^tM) and other antibody for identical target; Pegaptanib (Macugen ^tM); Vitronectic receptor antagonist, as the cyclic peptide antagonist of Vitronectic receptor type integrin; α-v/ β-3 integrin antagonists; α-v/ β-1 integrin antagonists; Thiazolidinediones, as rosiglitazone (rosiglitazone) or troglitazone (troglitazone); Interferon, comprises gamma interferon or by using the interferon of glucosan and metal-complexing targeting CNV; Pigment epidermal derived factors (PEDF); Endostatin; Angiostatin; Tumistatin; Canstatin; NSC 24345 (anecortave acetate); Acetonide; Omcilon (triamcinolone); Tetrathiomolybdate; The RNA silence of angiogenesis factor or RNA disturb (RNAi), comprise the ribozyme of targeting vegf expression; Accutane ^tM(Accutane); ACE inhibitor, includes but are not limited to quinopril, captopril (captopril) and perindozril; MTOR inhibitors (target of rapamycin in mammal); The amino Thalidomide (3-aminothalidomide) of 3-; Pentoxifylline (pentoxifylline); Methoxyestradiol (2-methoxyestradiol); Colchicine; AMG-1470; Cyclooxygenase-2 inhibitor, as nepafenac (nepafenac), rofecoxib (rofecoxib), diclofenac (diclofenac), rofecoxib, NS398, celecoxib (celecoxib), Vioxx (vioxx) and (E)-2-alkyl-2 (4-methyl sulphonyl phenyl)-1-styrene; T-RNA synthase regulator; MMP-13 inhibitor; Acetylcholinesteraseinhibitors inhibitors; Potassium channel antagonists; Endorepellin; The purine analogue of 6-thioguanine; Cyclic peroxide decomposition ANO-2; (restructuring) arginine desimidase (deiminase); Epigallocatechin-3-epicatechol gallate (epigallocatechin-3-gallate); Cerivastatin (cerivastatin); Suramin (suramin) analog; VEGFR1R2-Fc DELTA C1(a) molecule; Apoptosis inhibitor; Visudyne ^tM, snET2 and other photosensitizer, it can be used for photodynamic therapy (PDT); Hepatocyte growth factor inhibitor (clipped form of HGF is as HK4 for growth factor antibodies or its receptor, the micromolecular inhibitor of c-met tyrosine kinase).

Spendable other treatment agent comprises antiinflammatory, includes but are not limited to on-steroidal antiinflammatory and steroid antiinflammatory.In some modification, can use the activating agent in liquid preparation is ace-inhibitor, the endogenous cell factor, the activating agent that affects basement membrane, the activating agent that affects endothelial cell growth, 2-adrenergic agonist components or blocker, cholinergic agonist or blocker, aldose reductase inhibitor, analgesic, anesthetis, anti-allergy agent, antibacterium medicine, antihypertensive, supercharging medicine (pressor), antiprotozoan agent, antiviral agent, antifungal, anti-infective, antitumor agent, antimetabolite and anti-angiogenic agent.

Spendable steroid therapy agent includes but are not limited to 21-acetoxypregnenolone, alclometasone (alclometasone), algestone (algestone), amcinonide (amcinonide), beclometasone (beclomethasone), betamethasone (betamethasone), budesonide (budesonide), chloroprednisone (chloroprednisone), clobetasol (clobetasol), clobetasone (clobetasone), clocortolone (clocortolone), cloprednol (cloprednol), corticosterone (corticosterone), cortisone (cortisone), cortivazol (cortivazol), deflazacort (deflazacort), desonide (desonide), desoximetasone (desoximetasone), dexamethasone (dexamethasone), dichloro draws pine (diflorasone), diflucortolone (diflucortolone), difluprednate (difluprednate), enoxolone (enoxolone), chlorine Zha Kete (fluazacort), flucloronide (flucloronide), aniprime (flumethasone), flunisolide (flunisolide), fluocinolone acetonide (fluocinolone acetonide), fluocinonide (fluocinonide), fluocortin butyl (fluocortin butyl), fluocortolone (fluocortolone), fluorometholone (fluorometholone), fluperolone acetate (fluperolone acetate), fluprednylidene acetate (fluprednidene acetate), fluprednisolone (fluprednisolone), Cordran (flurandrenolide), Fluticasone Propionate (fluticasone propionate), fluderma (formocortal), halcinonide (halcinonide), clobetasol propionate (halobetasolpropionate), halometasone (halometasone), halopredone acetate (halopredoneacetate), hydrocortamate (hydrocortamate), hydrocortisone (hydrocortisone), loteprednol etabonate (loteprednol etabonate), mazipredone (mazipredone), medrysone (medrysone), methyl prednisone (meprednisone), radiosone (methylprednisolone), Mometasone Furoate (mometasone furoate), paramethasone (paramethasone), prednicarbate (prednicarbate), prednisolone (prednisolone), prednisolone-25-lignocaine-acetate (prednisolone 25-diethylamino-acetate), prednisolone phosphate sodium (prednisolone sodium phosphate), prednisone (prednisone), W-4869 (prednival), methylene prednisolone (prednylidene), rimexolone (rimexolone), tixocortol (tixocortol), omcilon (triamcinolone), triamcinolone acetonide (triamcinolone acetonide), triamcinolone benetonide (triamcinolone benetonide), triamcinolone hexacetonide (triamcinolone hexacetonide) and any derivant thereof.

In some modification, can use cortisone, dexamethasone, fluocinolone acetonide, hydrocortisone, methylprednisolone, prednisolone, prednisone and omcilon and derivant thereof.Liquid preparation can comprise the combination of two or more steroid therapy agent.

In a nonrestrictive example, steroid therapy agent can form liquid preparation by weight approximately 0.05% to approximately 50%.In another nonrestrictive example, steroid forms liquid preparation by weight approximately 0.05% to approximately 10%, and approximately between 10% to 20%, approximately 30% to approximately between 40%, or approximately 40% arrives approximately between 50%.

Other limiting examples of operable therapeutic agent include but are not limited to anesthetis, analgesics, cell traffic/migration inhibitor, as Colchicine, vincristine vincristine, cytochalasin B and related compound, carbonic anhydrase inhibitors, if acetazolamide (acetazolamide), methazolamide (methazolamide), daranide (dichlorphenamide), acetazolamide (diamox) and neuroprotective are as nimodipine and related compound, antibiotic is as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, Gramicidin, cefalexin, oxytetracycline, chloromycetin, rifampicin, ciprofloxacin, aminoglycoside, gentamycin, erythromycin and penicillin, quinolinones, ceftazidime, vancomycin imines penem (vancomycine imipeneme), antifungal is as amphotericin B, croconazole, ketoconazole and miconazole (miconazole), antibacterial agent is as different in sulfonamides (sulfonamides), sulfadiazine (sulfadiazine), sulfacetamide (sulfacetamide), sulfamethizole (sulfamethizole) and sulfanilamide azoles (sulfisoxazole), nitrofural (nitrofurazone) and sodium propionate, antiviral agent is as idoxuridine (idoxuridine), trifluorothymidine (trifluorothymidine), trifluridine (trifluorouridine), acyclovir (acyclovir), ganciclovir (ganciclovir), cidofovir (cidofovir), interferon, DDI, AZT, Foscanet (foscamet), vidarabine (vidarabine), irbavirin, protease inhibitor and anti-cytomegalovirus agent, anti-allergy agent is as sodium cromoglicate (sodium cromoglycate), antazoline (antazoline), methapyriline, chlorphenamine (chlorpheniramine), cetirizine (cetirizine), neo-antergan (pyrilamine) and pheniramine (prophenpyridamine), synthetic glucocorticoid and mineralocorticoid and the more general hormone form (DHEA, Progesterone, estrogen) of coming from cholesterol metabolism, nonsteroidal anti-inflammatory agent, for example Salicylate, indomethacin (indomethacin), ibuprofen (ibuprofen), diclofenac, flurbiprofen (flurbiprofen), piroxicam (piroxicam) and COX2 inhibitor, antitumor agent is as carmustine (carmustine), cisplatin (cisplatin), fluorouracil, amycin, asparaginase, azacitidine (azacitidine), azathioprine (azathioprine), bleomycin, busulfan (busulfan), carboplatin (carboplatin), carmustine, chlorambucil (chlorambucil), cyclophosphamide (cyclophosphamide), cyclosporin, cytosine arabinoside, dacarbazine (dacarbazine), actinomycin D (dactinomycin), daunorubicin (daunorubicin), doxorubicin (doxorubicin), estramustine (estramustine), etoposide (etoposide), etretinate (etretinate), filgrastin (filgrastin), fluorodeoxyuridine (floxuridine), fludarabine (fludarabine), fluorouracil, florxymesterone, flutamide (flutamide), goserelin (goserelin), hydroxyurea (hydroxyurea), ifosfamide (ifosfamide), leuprorelin acetate (leuprolide), levamisole (levamisole), limustine, chlormethine (nitrogenmustard), melphalan (melphalan), mercaptopurine (mercaptopurine), methotrexate (methotrexate), mitomycin (mitomycin), mitotane (mitotane), pentostatin (pentostatin), group's pool bromine alkane (pipobroman), plicamycin (plicamycin), procarbazine (procarbazine), leulkine (sargramostin), streptozotocin (streptozocin), tamoxifen (tamoxifen), paclitaxel (taxol), teniposide (teniposide), thioguanine, uracil mustard (uracil mustard), vinblastine (vinblastine), vincristine (vincristine) and vindesine (vindesine), immune drug is as vaccine and immunostimulant, insulin, calcitonin, parathyroid hormone and peptide and vassopressin hypothalamic releasing factor, beta-adrenergic blocking agent is as timolol (timolol), levobunolol (levobunolol) and betaxolol (betaxolol), cytokine, interleukin and somatomedin, epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor β, ciliary nerve nutrition somatomedin, glial cell line-derived neurotrophic, NGF, EPO, PLGF, nerve growth factor (BNGF), VEGF (VEGF) and for monoclonal antibody or its fragment of this class somatomedin, antiinflammatory is as hydrocortisone, dexamethasone, fluocinolone acetonide, prednisone, prednisolone, methylprednisolone, fluorometholone, betamethasone and omcilon, Decongestant is as phenylephrine (phenylephrine), naphazoline (naphazoline) and tetrahydrazoline, miotic and anticholinergic are as pilocarpine (pilocarpine), carbachol (carbachol), diisopropyl fluorophosphate (DFP) (di-isopropylfluorophosphates), iodate diethoxyphosphinylthiocholine (phospholine iodine) and demecarium bromide (demecarium bromide), iridodilator is as atropine sulfate, cyclopentolate (cyclopentolate), melyltropeine (homatropine), scopolamine (scopolamine), tropicamide (tropicamide), eucatropine (eucatropine), sympathomimetic is as epinephrine and vasoconstrictor and vasodilation, anticoagulant (anticlotting agents) is as heparin, antifibrin is former, plasmin (fibrinolysin), anticoagulant kinase (anticlotting activase), antidiabetic comprises acetohexamide (acetohexamide), chlorpropamide (chlorpropamide), glipizide (glipizide), glibenclamide (glyburide), tolazamide (tolazamide), tolbutamide (tolbutamide), insulin and aldose reductase inhibitor, hormone, peptide, nucleic acid, sugar, lipid, glycolipid, glycoprotein and other macromole, comprise that endocrine hormone is as pituitrin, insulin, the insulin relative growth factor, thyroxine, growth hormone, heat shock protein, immunne response dressing agent as muramyldipeptide, cyclosporin, interferon (comprise α-, β-and gamma interferon), interleukin-22, cytokine, FK506 (a kind of epoxy-pyrido-oxa-azacyclo-tricosene-tetraketone, is also known as tacrolimus), tumor necrosis factor, pentostatin, Thymopentin (thymopentin), transforming factor β 2, erythropoietin (erythropoetin), anti-new raw albumen (such as anti-VEGF, interferon), antibody (monoclonal, polyclone, humanization etc.) or antibody fragment, oligomerization is fit, fit and genetic fragment (oligonucleotide, plasmid, ribozyme, siRNA (SiRNA), nucleic acid fragment, peptide), immunomodulator be as endoxan (endoxan), Thalidomide, zitazonium, antithrombotic and vasodilation are as rtPA, urokinase, fibrinolysin, nitric oxide donors, nucleic acid, dexamethasone, cyclosporin A, azathioprine, brequinar (brequinar), gusperimus (gusperimus), Ismipur, mizoribine (mizoribine), rapamycin, tacrolimus (FK-506), folacin (for example 9,10-dimethylpteroylglutamic acid, edatrexate (edatrexate), methotrexate, piritrexim (piritrexim), Pteropterin (pteropterin), Tomudex , trimetrexate (trimetrexate)), purine analogue (cladribine (cladribine) for example, fludarabine (fludarabine), Ismipur, ITG (thiamiprine), thiaguanine), pyrimidine analogue (ancitabine (ancitabine) for example, azacitidine, 6-azauridine, carmofur (carmofur), cytosine arabinoside, doxifluridine (doxifluridine), emitefur (emitefur), Shan Yu arabinose pyridine (enocitabine), fluorodeoxyuridine, fluorouracil, gemcitabine, tegafur (tegafur)), fluocinolone acetonide, triaminolone, NSC 24345, fluorometholone, medrysone (medrysone) and prednisolone.In some modification, immunosuppressant is dexamethasone.In some modification, immunosuppressant is cyclosporin A.

In some modification, the combination that preparation comprises one or more therapeutic agents.

In preparation described herein, other limiting examples of spendable therapeutic agent comprise antibacterial antibiotic, aminoglycoside (for example amikacin (amikacin), apramycin (apramycin), Arbekacin (arbekacin), bambermycin (bambermycins), Butirosin (butirosin), dibekacin (dibekacin), dihydrostreptomycin (dihydrostreptomycin), astromicin (fortimicin (s)), gentamicin, Isepamicin (isepamicin), kanamycins, Micronomicin (micronomicin), neomycin, neodecyllin (neomycin undecylenate), Netilmicin (netilmicin), paromomycin (paromomycin), ribostamycin (ribostamycin), sisomicin (sisomicin), spectinomycin (spectinomycin), streptomysin, TOB (tobramycin), Trospectomycin (trospectomycin)), amphenicols (for example azidamfenicol (azidamfenicol), chloramphenicol, Florfenicol (florfenicol), Thiamphenicol), ansamycins (for example Rifamide (rifamide), rifampin, rifamicina (rifamycin sv), Rifapentine (rifapentine), rifaximin (rifaximin)), P-lactams (for example carbacephems (carbacephems) (for example Loracarbef (loracarbef), Carbapenems (for example Biapenem (biapenem), Imipenem (imipenem), Meropenem (meropenem), Panipenem (panipenem)), cephalosporins (for example Cefaclor (cefaclor), cefadroxil (cefadroxil), Cefamandole (cefamandole), cefatrizine (cefatrizine), Cefazedone (cefazedone), Cefazolin (cefazolin), Cefcapene (cefcapene pivoxil), Cefclidin (cefclidin), Cefdinir (cefdinir), Cefditoren (cefditoren), Cefepime (cefepime), cefetamet (cefetamet), Cefixime (cefixime), cefinenoxime, cefodizime (cefodizime), cefonicid (cefonicid), cefoperazone (cefoperazone), ceforanide (ceforanide), CTX (cefotaxime),Cefotiam (cefotiam), Cefozopran (cefozopran), Cefpimizole (cefpimizole), cefpiramide (cefpiramide), Cefpirome (cefpirome), Cefpodoxime (cefpodoxime proxetil), Cefprozil (cefprozil), cefroxadine (cefroxadine), Cefsulodin (cefsulodin), cefotaxime (ceftazidime), Cefteram (cefteram), ceftezole (ceftezole), Ceftibuten (ceftibuten), Ceftizoxime (ceftizoxime), ceftriaxone (ceftriaxone), cefuroxime (cefuroxime), Cefuzonam (cefuzonam), celospor (cephacetrile sodium), cefalexin (cephalexin), cephaloglycin (cephaloglycin), cefaloridine (cephaloridine), cynnematin (cephalosporin), cefoxitin (cephalothin), cefapirin sodium (cephapirinsodium), cephradine (cephradine), pivcefalexin), cephamycin (for example cefbuperazone (cefbuperazone), cefinetazole, Cefminox (cefminox), cefotetan (cefotetan), Cefoxitin), monobactam class (for example AZT (aztreonam), Ka Lumonan (carumonam), Tigemonam (tigemonam)), oxacephems (oxacephems) (Flomoxef (flomoxef), latamoxef (moxalactam)), PCs (for example nitrogen amidine penicillin (amdinocillin), nitrogen an amidine penicillin ester (amdinocillin pivoxil), Amoxicillin, ampicillin,Apalcillin (apalcillin), aspoxicillin (aspoxicillin), Azidocillin (azidocillin), azlocillin (azlocillin), Bacampicillin (bacampicillin), benzyl penicillinic acid (benzylpenicillinic acid), sodium benzylpenicillin (benzylpenicillin sodium), Carbenicillin (carbenicillin), carindacillin (carindacillin), clometocillin (clometocillin), Cloxacillin (cloxacillin), cyclacillin (cyclacillin), dicloxacillin (dicloxacillin), Epicillin (epicillin), fenbenicillin (fenbenicillin), flucloxacillin (floxacillin), hetacillin (hetacillin), Lenampicillin (lenampicillin), metampicillin (metampicillin), methicillin (methicillin sodium), mezlocillin (mezlocillin), sodium nafcillin (nafcillin sodium), OXA (oxacillin), penamecillin (penamecillin), penethamate hydriodide (penethamate hydriodide), penicillin g benethamine, benzathine penicillin G (penicillin g benzathine), penicillin g benzhydrylamine, penicillin g calcium, Hydrabeamine Penicillin penicillin g, scotcil (penicillin g potassium), neoproc (penicillin g procaine), (penicillin n) for penicillin N, (penicillin o) for penicillin, (penicillin v) for ospen, penicillin V benzathine (penicillin v benzathine), hydrabamine penicillin V (penicillin v hydrabamine), penimepicycline (penimepicycline), phenethicillin potassium (phenethicillin potassium), Piperacillin (piperacillin), Pivampicillin (pivampicillin), propicillin (propicillin), quinacillin (quinacillin), sulbenicillin (sulbenicillin), Sultamicillin (sultamicillin), Talampicillin (talampicillin), temocillin (temocillin),Ticarcillin (ticarcillin)), vertical for training south (ritipenem), lincosamide class (lincosamides) (for example clindamycin (clindamycin), lincomycin), macrolides (for example azithromycin (azithromycin), carbomycin (carbomycin), CLA (clarithromycin), Dirithromycin (dirithromycin), erythromycin (erythromycin), Erythromycin Acistrate (erythromycin acistrate), Erythromycin Estolate (erythromycin estolate), erythromycin gluceptate (erythromycin glucoheptonate), Erythromycin Lactobionate (erythromycinlactobionate), erythromycin propionate (erythromycin propionate), bristamycin (erythromycin stearate), josamycin (josamycin), kitasamycin (leucomycins), medecamycin, mikamycin (miokamycin), oleandomycin (oleandomycin), Primycin (primycin), rokitamycin (rokitamycin), rosamicin (rosaramicin), ROX (roxithromycin), spiramvcin (spiramycin), troleandomycin (troleandomycin)), polypeptide (for example amfomycin, bacitracin (bacitracin), capreomycin, colistin (colistin), enduracidin (enduracidin), Enviomycin (enviomycin), Fusafungine (fusafungine), (gramicidin s) for gramicidin S, gramicidins, mikamycin, polymyxins, Pristinamycin (pristinamycin), ristocetin (ristocetin), teicoplanin (teicoplanin), bryamycin (thiostrepton), tuberactin (tuberactinomycin), tyrocidine, tyrothricin, vancomycin, viomycin, VIRGINIAMYCIN (virginiamycin), Bacitracin Zinc (zinc bacitracin)), Tetracyclines (for example apicycline (apicycline), aureomycin (chlortetracycline), clomocycline (clomocycline), demeclocycline (demeclocycline), Doxycycline (doxycycline), guamecycline (guamecycline), lymecycline (lymecycline),Meclocycline (meclocycline), metacycline (methacycline), minocycline (minocycline), terramycin, penimepicycline, Pipacycline (pipacycline), rolitetracycline (rolitetracycline), Sancycline (sancycline), tetracycline) and other (for example seromycin (cycloserine), mupirocin (mupirocin), antitubercular agents (tuberin)), synthetic antibacterium medicine, 2,4-di-amino-pyrimidine (for example brodimoprim (brodimoprim), Tetroxoprim (tetroxoprim), TMP (trimethoprim)), itrofurans (for example furaltadone (furaltadone), fluorine azoles oronain (furazolium chloride), Nifuradene (nifuradene), nitre furan La Er (nifuratel), nifurfoline (nifurfoline), nifurpirinol (nifurpirinol), Nifurprazine (nifurprazine), nifurtoinol (nifurtoinol), Nifuran (nitrofurantoin)), quinolones and analog (for example cinoxacin (cinoxacin), Ciprofloxacin, Clinafloxacin (clinafloxacin), Difloxacin (difloxacin), Enoxacin (enoxacin), fleraxacin (fleroxacin), flumequine (flumequine), Grepafloxacin (grepafloxacin), Lomefloxacin, Miloxacin (miloxacin), Nadifloxacin (nadifloxacin), acidum nalidixicum (nalidixic acid), Norfloxacin, Ofloxacin, Oxolinic Acid (oxolinic acid), Pazufloxacin (pazufloxacin), Pefloxacin (pefloxacin), pipemidic acid (pipemidic acid), piromidic acid (piromidic acid), Rosoxacin (rosoxacin), Rufloxacin (rufloxacin), Sparfloxacin (sparfloxacin), Temafloxacin (temafloxacin), Tosufloxacin (tosufloxacin), trovafloxacin (trovafloxacin)), sulfamido (for example acetyl group sulfalene (acetylsulfamethoxypyrazine), benzylsulfamide (benzylsulfamide), chloramine B (chloramine-b), toluene-sodium-sulfonchloramide (chloramine-t), (dichloramine t) for Dichloramine,N2-Formylsulfamethine (n2-formylsulfisomidine), n4-beta-d-glucose-base sulfanilamide (SN), mafenide (mafenide), 4 '-(methyl sulfamoyl) sulfanilanilide, noprylsulfamide (noprylsulfamide), sterathal (phthalylsulfacetamide), phthalylsulfathiazol (phthalylsulfathiazole), Salazosulfadimidine (salazosulfadimidine), succinylsulfathiazole (succinylsulfathiazole), sulfabenzamide (sulfabenzamide), sulfacetamide (sulfacetamide), sulfachlorpyridazine (sulfachlorpyridazine), prontosil (sulfachrysoidine), renoquid (sulfacytine), sulphadiazine (sulfadiazine), sulfadicramide (sulfadicramide), sulfadimethoxine (sulfadimethoxine), sulfadoxine (sulfadoxine), sulfaethidole (sulfaethidole), sulphoamidine (sulfaguanidine), sulfaguanole (sulfaguanol), sulfalene (sulfalene), sulfaloxic acid (sulfaloxic acid), sulfamerazine (sulfamerazine), 5-methoxysulfadiazine (sulfameter), sulfamethazine (sulfamethazine), sulfamethizole (sulfamethizole), deposulf (sulfamethomidine), sulfalene azoles (sulfamethoxazole), kynix (sulfamethoxypyridazine), sulfametrole (sulfametrole), Sulfamidochrysoidine (sulfamidochrysoidine),Sulfanilamide (SN) azoles (sulfamoxole), sulfanilamide (SN) (sulfanilamide), 4-sulfanilamidosalicylic acid (4-sulfanilamidosalicylicacid), N4-sulfanilyl sulfanilamide (n4-sulfanilylsulfanilamide), euvernyl (sulfanilylurea), n-sulfanilyl-3, 4-the third paddy ammonia, sulfanitran (sulfanitran), sulfatreis (sulfaperine), sulfaphenazolum (sulfaphenazole), sulfaproxyline (sulfaproxyline), sulfapyrazine (sulfapyrazine), sulfapryidine (sulfapyridine), sulfasomizole (sulfasomizole), sulfasymazine (sulfasymazine), sulphathiazole (sulfathiazole), badional (sulfathiourea), sulfatolamide (sulfatolamide), sulfisomidine (sulfisomidine), sulfanilamide (SN) is different azoles (sulfisoxazole)), sulfone (for example acedapsone (acedapsone), acediasulfone (acediasulfone), acetosulphone (acetosulfone sodium), dapsone (dapsone), Diathymosulfone (diathymosulfone), angeli's sulfone (glucosulfone sodium), solasulfone (solasulfone), succisulfone (succisulfone), sulfanilic acid (sulfanilic acid), sulfanilyl radical benzylamine, sulfoxone sodium (sulfoxone sodium), thiazolsulfone (thiazolsulfone)) and other (for example clofoctols (clofoctol), hexedine (hexedine), methenamine (methenamine),Methenamine anhydromethylene citrate (methenamineanhydromethylene-citrate), methenamine hippu (methenamine hippurate), methenamine mandelate (methenamine mandelate), methenamine sulfosalicylate (methenamine sulfosalicylate), nitroxoline (nitroxoline), Taurolidine (taurolidine), xibornol (xibomol)), antifungal antibiotic, (for example (amphotericin b) for amphotericin B for polyenoid class, cannitracin (candicidin), dermostatin (dermostatin), filipin (filipin), fungichromin (fungichromin), trichomycin (hachimycin), Hamycin (hamycin), lucimycin (lucensomycin), mepartricin (mepartricin), Natamycin (natamycin), nystatin (nystatin), pecilocin (pecilocin, perimycin)), azaserine (azaserine), griseofulvin (griseofulvin), oligomycin (oligomycins), neodecyllin (neomycin undecylenate), pyrrolnitrin (pyrrolnitrin), siccanin (siccanin), tubercidin (tubercidin), viridin (viridin), synthetic antifungal, allylamine (for example Butenafine (butenafine), Naftifine (naftifine), Terbinafine (terbinafine)), imidazoles (for example bifonazole (bifonazole), butoconazole (butoconazole), clodantoin (chlordantoin), Chlormidazole (chlormidazole), croconazole (cloconazole), clotrimazole (clotrimazole), econazole (econazole), enilconazole (enilconazole), Fenticonazole (fenticonazole), Flutrimazole (flutrimazole), Isoconazole (isoconazole), ketoconazole (ketoconazole), lanoconazole (lanoconazole), Miconazole (miconazole), Omoconazole (omoconazole), Oxiconazole Nitrate (oxiconazole nitrate), Sertaconazole (sertaconazole), sulconazole (sulconazole), tioconazole (tioconazole)),Thiocarbamate (for example tolciclate (tolciclate), tolindate (tolindate), Tolnaftate (tolnaftate)), triazole (for example Fluconazole (fluconazole), Itraconazole (itraconazole), Saperconazole (saperconazole), terconazole (terconazole)), acrisorcin (acrisorcin), Amorolfine (amorolfine), xenysalate (biphenamine), Bromosalicylchloranilide (bromosalicylchloranilide), buclosamide (buclosamide), calcium propionate (calciumpropionate), Chlorphenesin (chlorphenesin), Ciclopirox (ciclopirox), cloxiquine (cloxyquin), Coparaffinate (coparaffinate), diamthazole dihydrochloride (diamthazoledihydrochloride), exalarnide, Flucytosine (flucytosine), haletazole (halethazole), Hexetidine (hexetidine), loflucarban (loflucarban), Nifuratel (nifuratel), KI, propionic acid, PTO (pyrithione), salicylanilide (salicylanilide), sodium propionate, sulbentine (sulbentine), tenonitrozole (tenonitrozole), triacetin (triacetin), ujothion (ujothion), undecenoic acid, zinc propionate, antineoplastic, antibiotic and analog (for example aclacinomycin (aclacinomycins), actinomycin F1 (actinomycin f1), Anthramycin (anthramycin), azaserine (azaserine), bleomycin (bleomycins), act-C (cactinomycin), Carubicin (carubicin), cardinophyllin (carzinophilin), chromomycin (chromomycins), actinomycin D (dactinomycin), daunorubicin (daunorubicin), 6-diazo-5-oxygen-L-nor-leucine, Doxorubicin, epirubicin (epirubicin), idarubicin (idarubicin), menogaril (menogaril), mitomycin (mitomycins), Mycophenolic Acid (mycophenolic acid), nogalamycin (nogalamycin), olivomycin (olivomycines), Peplomycin (peplomycin),THP (pirarubicin), plicamycin (plicamycin), porfiromycin (porfiromycin), Puromycin (puromycin), streptonigrin (streptonigrin), streptozotocin (streptozocin), tubercidin (tubercidin), Zinostatin (zinostatin), zorubicin (zorubicin)), antimetabolite (for example folacin (for example denopterin (denopterin), Edatrexate (edatrexate), methotrexate (MTX) (methotrexate), piritrexim (piritrexim), pteropterin (pteropterin), Tomudex , Trimetrexate (trimetrexate)), purine analogue (for example Cladribine, fludarabine (fludarabine), 6-MP, ITG (thiamiprine), thioguanine (thioguanine)), pyrimidine analogue (for example ancitabine, azacitidine, 6-azauridine, Carmofur (carmofur), cytarabine, doxifluridine (doxifluridine), Emitefur (emitefur), enocitabine (enocitabine), floxuridine (floxuridine), fluorouracil (fluorouracil), gemcitabine (gemcitabine), tagafur), antiinflammatory, steroid antiinflammatory, acetoxypregnenolone (acetoxypregnenolone), alclometasone (alclometasone), Algestone (algestone), Amcinonide, beclomethasone, betamethasone, budesonide, Chloroprednisone, clobetasol, clobetasone, clocortolone, Cloprednol, cortisone, cortisone, cortivazol, deflazacort (deflazacort), desonide, Desoximetasone, dexamethasone, diflorasone, diflucortolone, Difluprednate, enoxolone, fluazacort (fluazacort), flucloronide, aniprime, flunisolide, FA, Fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednylidene acetate, fluprednisolone, Cordran, Fluticasone Propionate, fluderma, Halcinonide, halobetasol propionate, Halometasone, halopredone acetate, Hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone,Mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-lignocaine-acetate, prednisolone phosphate sodium, metacortandracin, prednisolone valerate, Prednylidene, Rimexolone (rimexolone), Tixocortol (tixocortol), triamcinolone, Triamcinolone acetonide, Triamcinolone Benetonide and Triamcinolone Hexacetonide (triamcinolone hexacetonide), non-steroid antiinflammatory, aminoaryl carboxylic acid derivates (for example enfenamic acid, etofenamate (etofenamate), Flufenamic acid (flufenamic acid), Isonixin (isonixin), Meclofenamic Acid (meclofenamicacid), mefenamic acid (mefenamic acid), Niflumic Acid (niflumic acid), Talniflumate (talniflumate), Terofenamate (terofenamate), Tolfenamic Acid (tolfenamic acid)), aryl acetic acid derivatives (for example Aceclofenac (aceclofenac), acemetacin (acemetacin), alclofenac (alclofenac), the fragrant acid of ammonia (amfenac), Amtolmetin Guacil (amtolmetin guacil), the fragrant acid of bromine (bromfenac), bufexamac (bufexamac), cinmetacin (cinmetacin), Clopirac (clopirac), diclofenac (diclofenac sodium), Etodolac (etodolac), felbinac (felbinac), fenclozic acid (fenclozic acid), Fentiazac (fentiazac), glucametacin (glucametacin), ibufenac (ibufenac), Indomethacin (indomethacin), isofezolac (isofezolac), Isoxepac (isoxepac), lonazolac (lonazolac), metiazinic acid (metiazinic acid), Mofezolac (mofezolac), oxametacine, pirazolac (pirazolac), proglumetacin (proglumetacin), sulindac (sulindac), tiaramide (tiaramide), tolmetin (tolmetin), tropesin, the U.S. acid of assistant (zomepirac)), arylbutyric acid derivatives (for example bumadizon (bumadizon), butibufen (butibufen), fenbufen (fenbufen), xenbucine (xenbucin)), aryl carboxylic acid (for example clidanac (clidanac), ketorolac (ketorolac), Tinoridine (tinoridine)),Aryl propionic acid derivatives (for example alminoprofen (alminoprofen), benzene Luo Fen (benoxaprofen), bermoprofen (bermoprofen), bucloxic acid (bucloxic acid), Carprofen (carprofen), fenoprofen (fenoprofen), Flunoxaprofen (flunoxaprofen), Flurbiprofen (flurbiprofen), brufen (ibuprofen), ibuproxam (ibuproxam), indoprofen (indoprofen), Ketoprofen (ketoprofen), loxoprofen (loxoprofen), naproxen (naproxen), olsapozine (oxaprozin), piketoprolen, pirprofen (pirprofen), pranoprofen (pranoprofen), protizinic acid (protizinic acid), suprofen (suprofen), Tiaprofenic Acid (tiaprofenic acid), ximoprofen (ximoprofen), Zaltoprofen (zaltoprofen)), pyrazoles (for example difenamizole (difenamizole), epirizole (epirizole)), pyrazolone (for example apazone (apazone), Benzpiperylone (benzpiperylon), feprazone (feprazone), Mofebutazone (mofebutazone), morazone (morazone), Oxyphenbutazone (oxyphenbutazone), phenylbutazone (phenylbutazone), pipebuzone (pipebuzone), propyphenazone (propyphenazone), ramifenazone (ramifenazone), Suxibuzone (suxibuzone), thiazolinobutazone), salicyclic acid derivatives (for example Acetaminosalol (acetaminosalol), aspirin, benorylate (benorylate), bromosaligenin (bromosaligenin), calcium acetylsalicylate (calcium acetylsalicylate), Diflunisal (diflunisal), Etersalate (etersalate), fendosal (fendosal), gentianic acid (gentisic acid),Spirosal (glycol salicylate), imidazole salicylate (imidazole salicylate), lysine acetylsalicylate (lysine acetylsalicylate), Mesalazine (mesalamine), morophine salicylate (morpholine salicylate), 1-Naphthyl Salicylate (1-naphthyl salicylate), Olsalazine (olsalazine), Parsalmide (parsalmide), acetylphenyl salicylate (phenyl acetylsalicylate), phenyl salicytate (phenyl salicylate), salacetamide (salacetamide), salicylamide o-acetic acid (salicylamide o-acetic acid), Salicylsulfuric Acid (salicylsulfuric acid), salsalate (salsalate), SASP (sulfasalazine)), thiazinecarboxamides (for example Ampiroxicam (ampiroxicam), bend former times health (droxicam), isoxicam (isoxicam), lomoxicam, piroxicam (piroxicam), tenoxicam (tenoxicam)), ε-ether aminocaproic acid, s-adenosylmethionine, 3-amino-4-hydroxybutyric acid, Amixetrine (amixetrine), Bendazac (bendazac), benzydamine (benzydamine), bisabol (a-bisabolol), bucolome (bucolome), Difenpiramide (difenpiramide), ditazole (ditazol), Emorfazone (emorfazone), fepradinol (fepradinol), guaiazulene (guaiazulene), Nabumetone (nabumetone), aulin (nimesulide), Oxaceprol (oxaceprol), paranyline (paranyline), perisoxal (perisoxal), proquazone (proquazone), superoxide dismutase, Tenidap (tenidap) and Zileuton (zileuton).

Described therapeutic agent also can be used in combination with other treatment agent and therapy, includes but are not limited to and is used for the treatment of, prevents, suppresses, postpones blood vessel generation or neovascularization (particularly CNV) or make its therapeutic agent disappearing and therapy.In some modification, use extra therapeutic agent or the generation of therapy for treating blood vessel or neovascularization (particularly CNV) or it is disappeared.The therapeutic agent that this class is extra and the limiting examples of therapy comprise pyrrolidine, dithiocar-bamate (dithiocarbamate) (NF kB inhibitor); Squalamine; TPN 470 analog and Amebacilin; PKC (Protein kinase C) inhibitor; Tie-1 and Tie-2 inhibitors of kinases; Vegf receptor kinase inhibitor; Albuminous body inhibitor is as Velcade ^tM(bortezomib is for injection; Ranibuzumab (Lucentis ^tM) and for other antibody of identical target; Pegaptanib (Macugen ^tM); Vitronectic receptor antagonist, as the cyclic peptide antagonist of Vitronectic receptor type integrin; α-v/ β-3 integrin antagonists; α-v/ β-1 integrin antagonists; Thiazolidinediones is as rosiglitazone or troglitazone; Interferon, comprises gamma interferon or by using the interferon of glucosan and metal-complexing targeting CNV; Pigment epidermal derived factors (PEDF); Endostatin; Angiostatin; Tumistatin; Canstatin; NSC 24345; Acetonide; Omcilon; Tetrathiomolybdate (tetrathiomolybdate); The RNA silence of angiogenesis factor or RNA disturb (RNAi), comprise the ribozyme of targeting vegf expression; Accutane ^tM(Accutane); ACE inhibitor, includes but are not limited to quinidine (quinopril), captopril and perindozril; MTOR inhibitors (the mammal target of rapamycin); The amino Thalidomide (3-aminothalidomide) of 3-; Pentoxifylline (pentoxifylline); Methoxyestradiol (2-methoxyestradiol); Colchicine; AMG-1470; Cyclooxygenase-2 inhibitor, as nepafenac (nepafenac), rofecoxib (rofecoxib), diclofenac (diclofenac), rofecoxib, NS398, celecoxib (celecoxib), Vioxx (vioxx) and (E)-2-alkyl-2 (4-methyl sulphonyl phenyl)-1-styrene; T-RNA synthase regulator; MMP-13 inhibitor; Acetylcholinesteraseinhibitors inhibitors; Potassium channel antagonists; Endorepellin; The purine analogue of 6-thioguanine; Cyclic peroxide decomposition ANO-2; (restructuring) arginine desimidase; Epigallocatechin-3-epicatechol gallate (epigallocatechin-3-gallate); Cerivastatin (cerivastatin); Suramin (suramin) analog; VEGFR1R2-Fc DELTA C1(a) molecule; Hepatocyte growth factor inhibitor (clipped form of HGF is as HK4 for growth factor antibodies or its receptor, the micromolecular inhibitor of c-met tyrosine kinase); Apoptosis inhibitor; Visudyne ^tM, snET2 and other photodynamic therapies (PDT) photosensitizer; And laser photocoagulation.

Can be treated, prevent, suppress, postpone its generation or make its disease disappearing and disease

This paper describes and can use therapeutic agent described herein and preparation, liquid preparation and method to treat, prevent, suppress, postpone its generation or make its disease disappearing and disease.In some modification, use therapeutic agent described herein and preparation, liquid preparation and method to treat described disease and disease.Unless otherwise indicated herein, be considered as the experimenter that all Therapeutic Method carries out and include but are not limited to people experimenter.

Generally speaking, to using therapeutic agent described herein and preparation, liquid preparation and method treatment, prevention, suppress, postpone to occur or causing that disappear responsive any ophthalmic or disease can be treated, prevent, suppress, postpone to occur or cause to disappear.The example of ophthalmic or disease includes but are not limited to disease or the disease relevant to neovascularization (comprising retina and/or choroid neovascularization).

Use preparation described herein, liquid preparation and method can be treated, prevention, suppress, postpone occur or cause that disease or the disease relevant to retina and/or choroid neovascularization that disappear comprise (but being not limited only to) diabetic retinopathy, degeneration of macula, moist and dryness AMD, retinopathy of prematurity (Terry's sign disease), cause retinitis or uvaeformis infection, the ocular histoplasmosis of inferring, myopic degeneration, angioid streaks (angioid streaks) and ocular injury.Use preparation described herein, liquid preparation and method can be treated, prevention, suppress, postpone to occur or cause that the ophthalmic that disappears and other limiting examples of disease comprise (but being not limited only to) pseudoxanthoma elasticum (pseudoxanthoma elasticum), vein obstruction (vein occlusion), obstruction of artery (artery occlusion), carotid artery obstruction sick (carotid obstructive disease), sicklemia (Sickle Cell anemia), eales disease (Eales disease), myopia (myopia), chronic detachment of retina (chronic retinal detachment), hyperviscosity syndrome (hyperviscosity syndromes), toxoplasmosis (toxoplasmosis), wound (trauma), polypoid (the sick polypoidal choroidal of choroidal artery vasculopathy), laser therapy infectious-related complication (post-laser complications), the complication of ICSC (complications of idiopathic central serous chorioretinopathy), choroid inflammation complication (complications of choroidal inflammatory conditions), rubescent (rubeosis), to rubescent relevant disease (canthus neovascularization), neovascular glaucoma (neovascular glaucoma), uveitis and chronic eye uveitis, macular edema, whether proliferating retinopathy and the disease or the disease that by fiber blood vessel or fibrous tissue paraplasm, are caused, comprise the proliferative vitreoretinopathy (comprising postoperative proliferative vitreoretinopathy) of form of ownership, no matter relevant to diabetes.

In some modification, preparation described herein and pharmaceutical preparation are for preventing or postpone the generation of ophthalmic or disease, wherein under the risk of raising of experimenter's (including but are not limited to people experimenter) in there is ophthalmic or disease.The experimenter with the risk that disease or disease raising occur is the experimenter with one or more signs, and this disease or disease probably occur in this particular subject.In some modification, having the high risk experimenter that carries of the moist AMD of generation is the experimenter that at least one eye suffers from dryness AMD.In some modification, Second eye has the high risk experimenter that carries that moist AMD occurs to suffer from the experimenter of moist AMD for another.In some modification, preparation described herein and pharmaceutical preparation occur for the experimenter CNV preventing or postpone under the risk of raising in there is CNV, include but are not limited to prevention or postpone the generation of CNV in experimenter's (including but are not limited to the people experimenter that an eye suffers from AMD) Second eye.In some modification, preparation described herein and pharmaceutical preparation are used for preventing or postponing the generation that an eye suffers from patient's Second eye CNV of moist AMD.In some modification, preparation and pharmaceutical preparation comprise limus compound, include but are not limited to rapamycin.In some modification, preparation and pharmaceutical preparation (include but are not limited under conjunctiva) to be administered near the eyes has 20/40 or the people experimenter of better vision.In some modification, preparation and pharmaceutical preparation (include but are not limited under conjunctiva) eye that is administered to people experimenter near the eyes, and the eye of wherein using said preparation has 20/40 or better vision.

In some modification, preparation described herein and pharmaceutical preparation are used for the treatment of, prevent or postpone AMD and occurs.In some modification, preparation described herein and pharmaceutical preparation are used for the treatment of, prevent or postpone dryness AMD and occurs.In some modification, to suffering from experimenter's (including but are not limited to people experimenter) of non-central geographical atrophy (non-centralgeographic atrophy), use preparation described herein or pharmaceutical preparation with the generation of the geographical atrophy in treatment, prevention or delay center.In some modification, preparation and pharmaceutical preparation contain limus compound, include but are not limited to rapamycin.In some modification, preparation and pharmaceutical preparation (include but are not limited under conjunctiva) to be administered near the eyes has 20/40 or the people experimenter of better vision.In some modification, preparation described herein and pharmaceutical preparation are applied, and experimenter's (including but are not limited to people experimenter) is also used for the treatment of the therapy for treating of disease or disease with another.In some modification, preparation described herein and pharmaceutical preparation are used for the treatment of, prevent or postpone generation moist or dryness AMD, and before treating with preparation described herein and pharmaceutical preparation, in treatment or after treatment, experimenter's (including but are not limited to people experimenter) also uses laser therapy (as photodynamics laser therapy) treatment.

In some modification, preparation described herein and pharmaceutical preparation are used for the treatment of one or more uveitiss, anaphylaxis conjunctivitis, macular edema, glaucoma or xerophthalmia.

In some modification, preparation or pharmaceutical preparation comprise limus compound as rapamycin, and are applied in order to treatment, prevention or postpone xerophthalmia generation.In some modification, preparation or pharmaceutical preparation comprise limus compound as rapamycin, and are applied in order to treatment, prevention or postpone the generation of anaphylaxis conjunctivitis.

In some modification, preparation described herein and pharmaceutical preparation are used for the treatment of glaucoma.In some modification, be described hereinly used for the treatment of glaucomatous preparation and pharmaceutical preparation comprises limus compound as rapamycin, and as prevention, the surgery adjuvant that alleviates or postpone postoperative complication.In some modification, be described hereinly used for the treatment of glaucomatous preparation and pharmaceutical preparation contains limus compound as rapamycin, and in order to improve or to extend surgical implant success.In some modification, be described hereinly used for the treatment of glaucomatous preparation and pharmaceutical preparation contains limus compound as rapamycin, and for promoting or extend the success of argon laser trabecular resection or other glaucoma related surgicals.In some modification, preparation described herein and pharmaceutical preparation have neuroprotective, and in order to treat glaucoma.

In some modification, preparation described herein and pharmaceutical preparation are used for the treatment of retinitis pigmentosa.In some modification, be described hereinly used for the treatment of glaucomatous preparation and pharmaceutical preparation comprises limus compound as rapamycin, and be used for the treatment of, prevent or postpone the generation of retinitis pigmentosa.In some modification, preparation described herein and pharmaceutical preparation have neuroprotective, and are used for the treatment of retinitis pigmentosa.

In some modification, preparation described herein and pharmaceutical preparation are used for the treatment of one or more central retinal vein occlusions sick (CRVO), branch retinal vein occlusion (BRVO), retinal vascular disease and disease, macular edema, diabetic macular edema, sclera neovascularization, diabetic retinopathy or corneal graft rejection.In some modification, preparation and pharmaceutical preparation contain limus compound as rapamycin, and are applied to treat, prevent or postpone the generation of one or more these class diseases or disease.In some modification, preparation described herein and pharmaceutical preparation are administered under conjunctiva has 20/40 or the eye of better vision.

When being used for the treatment of, preventing, suppressing, postponing uveitis generation or it is disappeared, preparation described herein and liquid preparation can be used by number of ways known in the art, include but are not limited to by eye or oral administration.Other administration route is known in the art and conventional.In some modification, preparation described herein comprises rapamycin and is used for the treatment of uveitis.

Using preparation described herein, liquid preparation and method can treat, suppress, postpone its generation or make its a kind of disease disappearing is moist AMD.In some modification, use preparation described herein, liquid preparation and method to treat moist AMD.Moist AMD is characterized as blood vessel, and from them, the common position choroid grows into less desirable position under retina.These neovascularity seepages and hemorrhagely cause that vision reduces, and may be blind.

Preparation described herein, liquid preparation and method also can be used for prevention or delay the conversion of dryness AMD (wherein retinal pigment epithelium or RPE degenerate and cause that the yellow deposit that is called drusen (drusen) under photoreceptor cell death and retina forms) hygrotropism AMD.

" degeneration of macula " is characterized as fibrous deposit in macula lutea and retina and excessively produces and retinal pigment epithelium atrophy.Eye by degeneration of macula " torment " used herein is interpreted as at least one detectable physiological feature relevant to macular degeneration disease of this demonstration.Using rapamycin shows restriction angiogenesis (for example, choroid neovascularization in the age related macular degeneration (AMD) that just can occur without treatment) and it is disappeared.Term used herein " angiogenesis " refers to the generation (" neovascularization ") of neovascularity in tissue or organ.Eye or amphiblestroid " disease of angiogenesis-mediated or disease " are such disease or diseases: neovascularity forms in eye or retina in the mode of causing a disease therein, cause vision reduction or forfeiture or other problems, for example the choroid neovascularization relevant to AMD.

Preparation described herein and liquid preparation (including but are not limited to preparation and liquid preparation containing rapamycin) also can be used for treatment, prevention, suppress, postpone the generation of disease that panimmunity is relevant and disease or it is disappeared, and described disease and disease include but are not limited to organ-graft refection in host, graft versus host disease, autoimmune disease, inflammatory diseases, super hypertrophy angiopathy, solid tumor and fungal infection.In some modification, preparation described herein is used for the treatment of with liquid preparation (including but are not limited to preparation and liquid preparation containing rapamycin) disease and disease that panimmunity is relevant, and described disease and disease include but are not limited to organ-graft refection in host, graft versus host disease, autoimmune disease, inflammatory diseases, super hypertrophy angiopathy, solid tumor and fungal infection.Preparation described herein and liquid preparation (including but are not limited to preparation and liquid preparation containing rapamycin) useful as immunosuppressants.Preparation described herein and liquid preparation (including but are not limited to preparation and liquid preparation containing rapamycin) can be used for treatment, prevention, suppress or generation that the organ or tissue of Delayed grafting repels or it is disappeared, and the organ or tissue of described transplanting includes but are not limited to the heart of transplanting, liver,kidney,spleen, lung, small intestinal, pancreas and bone marrow.In some modification, preparation described herein and liquid preparation are used for the treatment of the generation of organ or tissue's repulsion of transplanting, and the organ or tissue of described transplanting includes but are not limited to the heart of transplanting, liver,kidney,spleen, lung, small intestinal, pancreas and bone marrow.When being used for the treatment of, preventing, suppressing, postponing immune correlated disease (including but are not limited to transplant rejection) when occurring or it being disappeared, preparation described herein and liquid preparation can be used by number of ways known in the art, include but are not limited to by Orally administered.

General is used and can be completed by oral liquid.The approach that other generals are used is this area routine techniques.Some of them example is listed in detailed Description Of The Invention part.

Used hereinly by administering therapeutic agent " inhibition " disease or disease, refer to after administering therapeutic agent, with do not use the disease of this therapeutic agent or the progress of disease is compared, this disease or at least one detected physiological feature of disease or the development of symptom are delayed or stop.

Used herein by administering therapeutic agent " prevention " disease or disease be after administering therapeutic agent development refer to detected physiological feature or the symptom of this disease or disease.

" generation " by administering therapeutic agent " delay " disease or disease used herein refers to after administering therapeutic agent, with do not use the disease of this therapeutic agent or the progress of disease is compared, at least one detected physiological feature of this disease or disease or the more late development of symptom.

Use and refer to after administering therapeutic agent by administering therapeutic agent " treatment " disease or disease herein, with do not use the disease of this therapeutic agent or the progress of disease is compared, this disease or at least one detected physiological feature of disease or the progress of symptom are delayed, stop or reversing.

Used hereinly by administering therapeutic agent, " cause " that disease or disease " disappear " and refer to that after administering therapeutic agent this disease or at least one detected physiological feature of disease or the progress of symptom are reversed to a certain extent.

Having procatarxis maybe needs experimenter's (including but are not limited to people experimenter) of prevention by the definite method in this area and standard, according to instruction herein, to be determined by skilled doctor.Skilled doctor also can for the identification of blood vessel, occur according to this area and/or definite standard of neovascularization is easily diagnosed the individuality that needs inhibition or treatment according to instruction herein.

" experimenter " used herein can benefit from any animal of using therapeutic agent described herein.In some modification, therapeutic agent is administered to mammalian subject.In some modification, therapeutic agent is administered to people experimenter.In some modification, therapeutic agent can be administered to veterinary animal experimenter.In some modification, therapeutic agent can be administered to model experiment animal subjects.

Use methods described herein can treat, prevent, suppress, postpone its generation or make its other diseases disappearing and disease comprise disclosed disease and disease in following patent and publication, the content of each data is quoted its integral body as a reference herein: the open WO 2004/027027 of PCT, on April 1st, 2004 is open, be entitled as Method of inhibiting choroidal neovascularization, transfer Trustees of the University of Pennsylvania; U.S. Patent number 5,387,589, announce February 7 nineteen ninety-five, is entitled as Method of Treating Ocular Inflammation, and invention people is Prassad Kulkarni, transfers University of Louisville Research Foundation; U.S. Patent number 6,376, on April 23rd, 517,2003 announces, and is entitled as Pipecolic acidderivatives for vision and memory disorders, transfers GPI NIL Holdings, Inc; The open WO 2004/028477 of PCT, on April 8th, 2004 is open, is entitled as Methodsubretinal administration of therapeutics including steroids:method forlocalizing pharmadynamic action at the choroid and retina; And relatedmethods for treatment and or prevention of retinal diseases, transfers Innorx, Inc; U.S. Patent number 6,416, on July 9th, 777,2002 announces, and is entitled as Ophthalmic drugdelivery device, transfers Alcon Universal Ltd; U.S. Patent number 6, on March 30th, 713,081,2004 announces, be entitled as Ocular therapeutic agent delivery device andmethods for making and using such devices, transfer Department of Healthand Human Services; With U.S. Patent number 5,536,729, on July 16th, 1996 submits to, is entitled as Rapamycin Formulations for Oral Administration, transfers AmericanHome Products Corp., with U.S. Patent Application No. 60/503,840 and 10/945,682.

Liquid preparation

Liquid preparation described herein contains therapeutic agent and can be any liquid preparation conventionally, includes but are not limited to solution, suspensoid and Emulsion.In some modification, liquid preparation forms the nondispersive agglomerate with respect to surrounding medium while being placed in lagophthalmos vitreous body.

When using the liquid preparation of certain volume, there is certain inaccuracy in the accuracy that should understand the plurality of devices that can be used for applicating liquid preparation.When being appointed as certain volume, should understand that it is object volume.Yet some equipment is greater than 10% as insulin syringe inaccuracy, and inaccuracy is greater than 20% or more sometimes.Hamilton HPLC type syringe it is generally acknowledged that degree of accuracy is in 10%, and recommends for being less than the volume to be injected of 10 μ l.

In some modification, be administered to the volume of the Vitrea liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) for being less than approximately 500 μ l, being less than approximately 400 μ l, being less than approximately 300 μ l, being less than approximately 200 μ l, being less than approximately 100 μ l, being less than approximately 90 μ l, being less than approximately 80 μ l, being less than approximately 70 μ l, being less than approximately 60 μ l, being less than approximately 50 μ l, being less than approximately 40 μ l, being less than approximately 30 μ l, being less than approximately 20 μ l, being less than approximately 10 μ l, being less than approximately 5 μ l, being less than approximately 3 μ l or being less than approximately 1 μ l.In some modification, the volume that is administered to the Vitrea liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) is less than approximately 20 μ l.In some modification, the volume that is administered to the Vitrea liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) is less than approximately 10 μ l.In some modification, the volume that is administered to the Vitrea liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) is between approximately 0.1 μ l and approximately 200 μ l, between approximately 50 μ l and approximately 200 μ l, between approximately 50 μ l and approximately 150 μ l, between approximately 0.1 μ l and approximately 100 μ l, between approximately 0.1 μ l and approximately 50 μ l, between approximately 1 μ l and approximately 40 μ l, between approximately 1 μ l and approximately 30 μ l, between approximately 1 μ l and approximately 20 μ l, at approximately 1 μ l and approximately 10 μ l or between approximately 1 μ l and approximately 5 μ l.In some modification, be administered to the volume of the intravitreous liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) between approximately 1 μ l and approximately 10 μ l.In some modification, be administered to the volume of the intravitreous liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) between approximately 1 μ l and approximately 5 μ l.In some modification, be administered to the volume of the intravitreous liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) between approximately 1 μ l and approximately 5 μ l.In some modification, be administered to the volume of the liquid preparation described herein in lagophthalmos or experimenter's vitreum between approximately 0.1 μ l and approximately 200 μ l.

In some modification, under conjunctiva, be administered to the cumulative volume of liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) for being less than approximately 1000 μ l, be less than approximately 900 μ l, be less than approximately 800 μ l, be less than approximately 700 μ l, be less than approximately 600 μ l, be less than approximately 500 μ l, be less than approximately 400 μ l, be less than approximately 300 μ l, be less than approximately 200 μ l, be less than approximately 100 μ l, be less than approximately 90 μ l, be less than approximately 80 μ l, be less than approximately 70 μ l, be less than approximately 60 μ l, be less than approximately 50 μ l, be less than approximately 40 μ l, be less than approximately 30 μ l, be less than approximately 20 μ l, be less than approximately 10 μ l, be less than approximately 5 μ l, be less than approximately 3 μ l or be less than approximately 1 μ l.In some modification, the volume that is administered to the liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) under conjunctiva is less than approximately 20 μ l.In some modification, the volume that is administered to the liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) under conjunctiva is less than approximately 10 μ l.In some modification, the volume that is administered to the liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) under conjunctiva arrives between approximately 200 μ l at approximately 0.1 μ l, between approximately 50 μ l and approximately 200 μ l, between approximately 200 μ l and approximately 300 μ l, between approximately 300 μ l and approximately 400 μ l, between approximately 400 μ l and approximately 500 μ l, between approximately 600 μ l and approximately 700 μ l, between approximately 700 μ l and approximately 800 μ l, between approximately 800 μ l and approximately 900 μ l, between approximately 900 μ l and approximately 1000 μ l, between approximately 50 μ l and approximately 150 μ l, between approximately 0.1 μ l and approximately 100 μ l, between approximately 0.1 μ l and approximately 50 μ l, between approximately 1 μ l and approximately 40 μ l, between approximately 1 μ l and approximately 30 μ l, between approximately 1 μ l and approximately 20 μ l, between approximately 1 μ l and approximately 10 μ l or between approximately 1 μ l and approximately 5 μ l.In some modification, under conjunctiva, be administered to the volume of liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) between approximately 1 μ l and approximately 10 μ l.In some modification, under conjunctiva, be administered to the volume of liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) between approximately 1 μ l and approximately 5 μ l.In some modification, under conjunctiva, be administered to the volume of liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) between approximately 1 μ l and approximately 5 μ l.In some modification, under conjunctiva, be administered to the volume of liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) between approximately 0.1 μ l and approximately 200 μ l.

In some modification, liquid preparation described herein (includes but are not limited to each other in one hour) and is applied in a plurality of conjunctiva upper/lower positions within a period of time.Not bound by theory, think that this class repeatedly uses (for example multiple injection) and allow to compare with single dose under conjunctiva and use larger accumulated dose, possible limited because topical ophthalmic tissue absorbs the ability of larger volume.

A kind of liquid preparation described herein is in-situ gelling preparation.In-situ gelling preparation comprises therapeutic agent and multiple polymers as described herein, and it provides the preparation that forms gel or gel-like substance while being placed in aqueous medium (including but are not limited to the aqueous medium of eye).

In some modification of liquid preparation described herein, therapeutic agent is solution or the suspension of rapamycin in liquid medium.Liquid medium includes but are not limited to solvent, and described solvent includes but are not limited to the solvent of " therapeutic agent solubilising " part.

Liquid preparation described herein can comprise solubilizing agent composition.In some modification, solubilizing agent composition is surfactant.Attention exists overlapping between the composition that can be solvent and solubilizing agent, and therefore identical composition can be used as solvent or solubilizing agent in some systems.Liquid preparation contains therapeutic agent and composition, and described composition can be considered to solvent or solubilizing agent or surfactant, if this composition plays solvent action, thinks solvent; If this composition does not play solvent action, this composition can be considered to solubilizing agent or surfactant.

Liquid preparation also optionally comprises stabilizing agent, excipient, gellant, adjuvant, antioxidant and/or other compositions described herein.

In some modification, all the components in liquid preparation except therapeutic agent is at room temperature liquid.

In some modification, liquid preparation comprises release dressing agent.In some modification, discharging dressing agent is film forming polymer composition.Film forming polymer composition can comprise one or more film forming polymers.Any film forming polymer can be used in excipient composition.In some modification, film forming polymer composition contains the polymer that forms water-fast film.In some modification, discharge dressing agent composition and comprise acrylate polymer, include but are not limited to polymethacrylates, include but are not limited to Eudragit RL.

This paper describes for sending compositions and the liquid preparation of the therapeutic agent of " therapeutic agent " part description.Use compositions described herein and liquid preparation delivering therapeutic agents to can be used for treatment, prevention, suppress, postpone the generation of the described disease of " disease and disease " part and disease or it is disappeared.Compositions described herein and liquid preparation can contain any therapeutic agent that " therapeutic agent " part is described, and include but are not limited to rapamycin.It is a kind of or more than a kind of therapeutic agent that compositions as herein described and liquid preparation can comprise.Can use compositions and the compositions liquid preparation and the liquid preparation except herein, clearly described.

When therapeutic agent is rapamycin, compositions and liquid preparation are used in vitreous body and keep a certain amount of rapamycin, and described amount can effectively be treated moist AMD.In a limiting examples, believe that the following liquid preparation of sending rapamycin can be used for treating moist AMD, described preparation can maintain about 10pg/ml in vitreous body to the rapamycin concentrations of approximately 2 μ g/ml within a period of time.When rapamycin is contained in the liquid preparation that forms nondispersive agglomerate, the rapamycin concentrations of stating has represented the amount of effective treatment ophthalmic or disease, but not only exists only in nondispersive agglomerate form.In another limiting examples, believe that the following delivery system of sending rapamycin can be used for treating moist AMD, described delivery system can maintain about 0.01pg/mg in retina tela chorioidea to the rapamycin concentrations of about 10ng/mg within a period of time.The therapeutic agent of other treatment effective dose is also possible, and can according to instruction herein, easily be determined by those skilled in the art.

When therapeutic agent is rapamycin, compositions described herein and liquid preparation can be used for sending to experimenter's (including but are not limited to people experimenter) or experimenter's eye the rapamycin of doses.In a limiting examples, believe containing the liquid preparation of 20 μ g to about 4mg dosage of having an appointment and can be used for treating moist AMD.

In some modification, the therapeutic agent in liquid preparation account for composition total weight approximately 0.01% and approximately between 30%; Approximately 0.05% and approximately between 15%; Approximately 0.1% and approximately between 10%; Approximately 1% and approximately between 5%; Or approximately 5% and approximately between 15%; Approximately 8% and approximately between 10%; Approximately 0.01% and approximately between 1%; Approximately 0.05% and approximately between 5%; Approximately 0.1% and approximately between 0.2%; Approximately 0.2% and approximately between 0.3%; Approximately 0.3% and approximately between 0.4%; Approximately 0.4% and approximately between 0.5%; Approximately 0.5% and approximately between 0.6%; Approximately 0.6% and approximately between 0.7%; Approximately 0.7% and approximately between 1%; Approximately 1% and approximately between 5%; Approximately 5% and approximately between 10%; Approximately 15% and approximately 30%, approximately 20% and approximately 30%; Or approximately 25% and approximately between 30%.

Those skilled in the art can determine that based on instruction herein the given therapeutic agent of which kind of amount or concentration is equal to the rapamycin of a certain amount of or concentration, for example, for example, by therapeutic agent being applied to in disease model system (in body or external model system) and in comparison model system result with respect to the result of the rapamycin of multiple amount or concentration with not commensurability or concentration.Those skilled in the art also can determine that the given therapeutic agent of which kind of amount or concentration is equal to the rapamycin of a certain amount of or concentration by looking back the comparison rapamycin that carries out in scientific literature and the experiment of other treatment agent based on instruction herein.Should understand when for example assessing different diseases or disease, or while using dissimilar preparation, even if identical therapeutic agent also can have the different same levels such as rapamycin.For the limiting examples of the scientific literature of ophthalmic comparative study rapamycin and other treatment agent, be Ohia etc., Effects of steroids andimmunosuppressive drugs on endotoxin-uveitis in rabbits, J.Ocul.Pharmacol.8 (4): 295-307 (1992); Kulkarni, Steroidal and nonsteroidal drugsin endotoxin-induced uveitis, J.Ocul.Pharmacol.10 (1): 329-34 (1994); Hafizi etc., Differential effects of rapamycin, cyclosporine A, and FK506 onhuman coronary artery smooth muscle cell proliferation and signaling, Vascul Pharmacol.41 (4-5): 167-76 (2004); With US 2005/0187241.

For example, in moist AMD model, if find that therapeutic agent is lower 10 times than rapamycin effect or effect when the moist AMD for the treatment of, the concentration for the treatment of agent of 10ng/ml should be equal to the rapamycin concentrations of 1ng/ml.If or find that therapeutic agent is lower 10 times than rapamycin effect or effect, should use the therapeutic agent with respect to 10 times of amounts of amount of rapamycin when the moist AMD for the treatment of.

Solvent composition for example can form composition total weight approximately 0.01% and approximately between 99.9%; Approximately 0.1% and approximately between 99%; Approximately 25% and approximately between 55%; Approximately 30% and approximately between 50%; Or approximately 35% and approximately between 45%; Approximately 0.1% and approximately between 10%; Approximately 10% and approximately between 20%; Approximately 20% and approximately between 30%; Approximately 30% and approximately between 40%; Approximately 40% and approximately between 45%; Approximately 40% and approximately between 45%; Approximately 45% and approximately between 50%; Approximately 50% and approximately between 60%; Approximately 50% and approximately between 70%; Approximately 70% and approximately between 80%; Approximately 80% and approximately between 90%; Or approximately 90% and approximately between 100%.

Solubilizing agent composition for example can form composition total weight approximately 0.01% and approximately between 30%; Approximately 0.1% and approximately between 20%; Approximately 2.5% and approximately between 15%; Approximately 10% and approximately between 15%; Or approximately 5% and approximately between 10%; Approximately 8% and approximately between 12%; Approximately 10% and approximately between 20%; Approximately 20% and approximately between 30%.

In some modification, liquid preparation described herein has the viscosity between 40% and 120% centipoise.In some modification, liquid preparation described herein has the viscosity between 60% and 80% centipoise.

In some modification, liquid preparation described herein contains therapeutic agent and solvent composition.Solvent composition can contain the combination of single solvent or solvent.Therapeutic agent component can contain the combination of single therapy agent or therapeutic agent.In some modification, solvent is glycerol, dimethyl sulfoxide, N-Methyl pyrrolidone, dimethyl acetylamide (DMA), dimethyl formamide, glyceryl formal, ethoxydiglycol, TRIGLYME, glyceryl triacetate, Glycerine 1,3-diacetate, Semen Maydis oil, CitroflexA-2 (ATC), ethyl lactate, the caprylin of Pegylation, gamma butyrolactone, dimethyl isosorbide, benzyl alcohol, ethanol, isopropyl alcohol, the Polyethylene Glycol of various molecular weights (including but are not limited to PEG 300 and PEG 400) or propylene glycol, or one of them or more mixture.

In some modification, liquid preparation described herein is solution, and comprises therapeutic agent and solvent composition.In some modification, solvent composition comprises ethanol.In some modification, solvent composition comprises ethanol and Polyethylene Glycol, includes but are not limited to liquid macrogol (include but are not limited to one or more in PEG 300 or PEG 400).

In some modification, the Polyethylene Glycol that liquid preparation described herein contains no more than approximately 250 μ l.In some modification, the Polyethylene Glycol that liquid preparation described herein contains no more than approximately 250 μ l, no more than approximately 200 μ l, no more than approximately 150 μ l, no more than approximately 125 μ l, no more than approximately 100 μ l, no more than approximately 75 μ l, no more than approximately 50 μ l, no more than approximately 25 μ l, no more than approximately 20 μ l, no more than approximately 15 μ l, no more than approximately 10 μ l, no more than approximately 7.5 μ l, no more than approximately 5 μ l, no more than approximately 2.5 μ l, no more than approximately 1.0 μ l or no more than approximately 0.5 μ l.The preparation that contains Polyethylene Glycol can contain for example PEG 300 or PEG 400.

In some modification, liquid preparation described herein is suspensoid and comprises therapeutic agent and diluent components.In some modification, diluent components contains one or more compositions of listing as solvent or solubilizing agent herein, and the mixture wherein obtaining is suspension.

In some modification, liquid preparation is partly that solution and part are suspension.

In some modification, liquid preparation is in-situ gelling preparation, and comprises therapeutic agent and component of polymer, and wherein component of polymer can contain multiple polymers.In some modification, liquid preparation contains polymethacrylate polymer.In some modification, liquid preparation contains polyvinyl pyrrolidone polymers.

Some modification of liquid preparation contain and account for gross weight approximately 0.01% and the about therapeutic agent between 20% (for example but be not limited only to rapamycin), account for gross weight approximately 5% and approximately the solvent between 15%, account for gross weight approximately 5% and the approximately solubilizing agent between 15% (including but are not limited to surfactant), with as the main water that keeps composition.In some modification, preparation also comprises and accounts for gross weight approximately 0 and the approximately stabilizing agent between 40%, excipient, adjuvant or antioxidant.

In some modification, liquid preparation contains and accounts for gross weight approximately 5% therapeutic agent (including but are not limited to rapamycin) at the most; With account for gross weight approximately 99.9% solvent composition at the most.In some modification, liquid preparation contains and accounts for gross weight approximately 5% therapeutic agent (including but are not limited to rapamycin) at the most; Approximately 99.9% diluent components at the most.

In some modification, liquid preparation contains and accounts for gross weight approximately 5% therapeutic agent (including but are not limited to rapamycin) at the most; Account for gross weight approximately 10% solvent composition at the most; With account for gross weight approximately 85% solubilising composition at the most.In some modification, the aqueous solution that solubilising composition is surfactant.

Multiple polymers composition for example can form composition total weight approximately 0.01% and approximately between 30%; Approximately 0.1% and approximately between 20%; Approximately 2.5% and approximately between 15%; Approximately 10% and approximately between 15%; Approximately 3% and approximately between 5%; Approximately 5% and approximately between 10%; Approximately 8% and approximately between 12%; Approximately 10% and approximately between 20%; Or approximately 20% and approximately between 30%.

Some modification of liquid preparation contain account for gross weight approximately 0.01% and approximately the therapeutic agent between 20% (including but are not limited to rapamycin), account for gross weight approximately 60% and the about solvent composition between 98%, and multiple polymers, the percentage ratio of its combination account for gross weight approximately 0.1% and approximately between 15%.In some modification, preparation also comprises and accounts for gross weight approximately 0 and the approximately stabilizing agent between 40%, excipient, adjuvant or antioxidant.

In some modification, liquid preparation can contain the therapeutic agent (including but are not limited to rapamycin) that accounts for gross weight approximately 4%; Account for the solvent of gross weight approximately 91%; With the component of polymer that accounts for gross weight approximately 5%.

Some examples of liquid preparation described herein and modification are produced and are listed in table 1.According to their type, the preparation of listing is called to one or more solutions (" S "), suspensoid (" SP "), Emulsion (" E ") or situ-gel (" ISG ").Some suspensoids are listed granular size intermediate value.As described herein, some liquid preparations form nondispersive agglomerate after being for example injected into aqueous environments (as the vitreous body of eye).For being injected into Vitrea these preparations of lagophthalmos, the right-hand column of table 1 indicates after designated volume is injected into lagophthalmos vitreous body, whether to form nondispersive agglomerate (NDM).

Below with reference to data, show one or more preparations (including but are not limited to rapamycin preparation), it has been incorporated herein and has been described the rapamycin of various dose and the purposes that other treatment agent is used for the treatment of various diseases or disease with its integral body: US 60/651,790,2/9/2005 submits to, be entitled as FORMULATIONS FOR OCULAR TREATMENT, application attorney docket (attorneydocket number) 57796-30002.00; US 60/664,040, and 2/9/2005 submits to, and application attorney docket 57796-30004.00, is entitled as LIQUID FORMULATIONS FOR TREATMENTOF DISEASES OR CONDITIONS; US 60/664,119, and 3/21/2005 submits to, and application attorney docket 57796-30005.00, is entitled as DRUG DELIVERY SYSTEMS FOR TREATMENT OF DISEASES OR CONDITIONS; US 60/664,306, and 3/21/2005 submits to, and application attorney docket 57796-30006.00, is entitled as IN SITU GELLINGFORMULATIONS AND LIQUID FORMULATIONS FOR TREATMENTOF DISEASES OR CONDITIONS; US_/_, 2/9/2006 submits to, is entitled as FORMULATIONS FOR OCULAR TREATMENT, application attorney docket 57796-20002.00; _/_, 2/9/2006 submits to, and application attorney docket 57796-20004.00, is entitled as LIQUID FORMULATIONS FOR TREATMENT OF DISEASES ORCONDITIONS; US 2005/0187241 and US 2005/0064010.

Form the liquid preparation of nondispersive agglomerate

A class I liquid I preparation described herein forms nondispersive agglomerate when being placed in aqueous medium.Use " nondispersive agglomerate " to refer to when liquid preparation is placed in environment herein, the structure that the environment being placed into respect to it forms or the shape presenting.Generally speaking, the nondispersive agglomerate of liquid preparation is any situation except liquid preparation is evenly distributed in surrounding medium.The liquid preparation that nondispersive agglomerate can for example be applied by observation also characterizes its outward appearance with respect to surrounding and points out.

In some modification, aqueous medium is water.In some modification, aqueous medium is de-ionized water, distilled water, sterilized water or tap water (including but are not limited to the City at MacuSight in Union, obtainable tap water in the scope of offical duty of California).

In some modification, the aqueous medium that aqueous medium is experimenter.In some modification, aqueous medium is the aqueous medium of experimenter's eye, includes but are not limited to the vitreous body of experimenter's eye.In some modification, the experimenter experimenter that behaves.In some modification, experimenter is rabbit.

In some modification, liquid preparation in being exposed to certain temperature or temperature range (include but are not limited to be about room temperature, be about ambient temperature, be about 30 ℃, be about 37 ℃ or be about the temperature of experimenter's aqueous medium) time form nondispersive agglomerate.

In some modification, liquid preparation forms nondispersive agglomerate when (include but are not limited to approximately 6 and approximately the pH between 8) within the scope of being exposed to certain pH or pH.

In some modification, nondispersive agglomerate comprises gel or gel-like substance.

In some modification, nondispersive agglomerate comprises polymeric matrix.In some modification, nondispersive agglomerate comprises that therapeutic agent is dispersed in polymeric matrix wherein.

Liquid preparation described herein can be generally any geometry or shape after being administered to experimenter or experimenter's eye (including but are not limited to people experimenter).In some modification, nondispersive agglomerate is between about 0.1mm and about 5mm.In some modification, nondispersive agglomerate is between about 1mm and about 3mm.The liquid preparation that forms nondispersive agglomerate can be shown as for example fine and close spherical agglomerate while being administered to vitreous body.In some cases, liquid preparation can be rendered as nondispersive agglomerate with respect to surrounding medium, and wherein said nondispersive agglomerate definition is more indefinite, and with spherical to compare its geometry more unsetting.

The liquid preparation of the nondispersive agglomerate of formation described herein can form at once nondispersive agglomerate when being placed in medium, or nondispersive agglomerate can a period of time formation after placing liquid preparation.In some modification, nondispersive agglomerate formed in approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days or approximately 7 days.In some modification, nondispersive agglomerate formed in approximately 1 week, approximately 2 weeks or approximately 3 weeks.

In some modification, the medium that the liquid preparation of the nondispersive agglomerate of formation described herein is placed with respect to it is shown as milky or the albescent semicontinuous or nondispersive agglomerate of semisolid.

A kind of liquid preparation as herein described forms following nondispersive agglomerate, and described nondispersive agglomerate forms solid reservoir when preparation is injected in any or all water (between lagophthalmos vitreous body or lagophthalmos CSC).A kind of liquid preparation as herein described forms following nondispersive agglomerate, and described nondispersive agglomerate forms semisolid when preparation is injected in any or all water (between lagophthalmos vitreous body or lagophthalmos CSC).A kind of liquid preparation as herein described forms following nondispersive agglomerate, and described nondispersive agglomerate forms polymeric matrix when preparation is injected in any or all water (between lagophthalmos vitreous body or lagophthalmos CSC).A kind of liquid preparation as herein described forms following nondispersive agglomerate, and described nondispersive agglomerate has the form of gel, hydrogel or gel-like substance when preparation is injected in any or all water (between lagophthalmos vitreous body or lagophthalmos CSC).

In modification more as herein described, when surrounding medium is aqueous, liquid preparation forms nondispersive agglomerate with respect to surrounding medium." aqueous medium " or " aqueous environments " is medium or the environment containing at least about 50% water.The example of aqueous medium includes but are not limited between water, vitreous body, extracellular fluid, conjunctiva, sclera, CSC, aqueous humor, gastric juice and comprise any tissue or the body fluid at least about 50% water.Aqueous medium includes but are not limited to gel structure, includes but are not limited to the gel structure of conjunctivae and selerae.

In some modification, liquid preparation described herein forms nondispersive agglomerate when the liquid preparation of test volume is placed in lagophthalmos vitreous body.In some modification, test volume is applied to lagophthalmos, and test volume equals to be administered to the volume of experimenter's's (including but are not limited to people experimenter's eye) liquid preparation.

In some modification, the volume that the test volume that is administered to lagophthalmos equals to be administered to experimenter's eye is multiplied by scale factor, and scale factor equals lagophthalmos average external volume divided by the average external volume of experimenter's eye." average external volume " of eye used herein generally refers to the similar age member's of considered species average eye volume, and the average external volume of any concrete individual eye is relative.

In some modification, the test volume that is administered to lagophthalmos is between approximately 10 μ l and approximately 50 μ l.In some modification, the test volume that is administered to lagophthalmos is between approximately 1 μ l and approximately 30 μ l.In some modification, the test volume that is administered to lagophthalmos is between approximately 50 μ l and approximately 100 μ l.In some modification, the test volume that is administered to lagophthalmos is between approximately 25 μ l and approximately 75 μ l.In some modification, the test volume that is administered to lagophthalmos is approximately 30 μ l.

In some modification, the liquid preparation that forms nondispersive agglomerate when being placed in medium comprises and accounts for gross weight approximately 0.01% and about one or more therapeutic agents of concentration between 10%, and accounts for gross weight approximately 10% and the about solvent between 99%.In some modification, liquid preparation also comprises solubilizing agent, includes but are not limited to surfactant.In some modification, liquid preparation also contains and accounts for gross weight approximately 0 and the approximately stabilizing agent between 40%, excipient, adjuvant or antioxidant etc.In some modification, therapeutic agent accounts for approximately 5% of gross weight, and solvent composition accounts for gross weight approximately 95%.

In the time of can being present in experimenter's (including but are not limited to people experimenter) or experimenter's eye by following method is definite, whether liquid preparation shows nondispersive agglomerate with respect to surrounding medium: by therapeutic agent and solvent, be administered to vitreous body comparative liquid preparation and the surrounding medium of experimenter's (including but are not limited to people experimenter) eye.

Can be used for treatment, prevention, suppressing, postpone the generation of experimenter's (including but are not limited to people experimenter) disease and disease or make its a kind of liquid preparation disappearing is while being placed in lagophthalmos vitreous body, to form the liquid preparation of nondispersive agglomerate.When being used for the treatment of, preventing, suppressing, postponing experimenter's disease or disease generation or it is disappeared, liquid preparation is administered to experimenter.Liquid preparation can form or not form nondispersive agglomerate in experimenter.A kind of liquid preparation described herein forms nondispersive agglomerate while being applied to experimenter, and forms nondispersive agglomerate while being applied to lagophthalmos.

Not bound by theory, believe that rapamycin contributes to the rapamycin liquid preparation that contains more as herein described to form nondispersive agglomerate at intravitreous low solubility.Vitreous body is the classifying gel being substantially comprised of water (up to 99%) completely.Not bound by theory, believe that rapamycin in the preparation through injection is when contact with vitreous body, rapamycin precipitates.

Not bound by theory, believe that the nondispersive agglomerate of impact forms and the factor of shape comprises the concentration of rapamycin in preparation, the ethanol content of the viscosity of preparation, preparation and volume injected.Believe that the rapamycin that maintains higher concentration after ejection preparation facilitates the formation of nondispersive agglomerate, lower contrary with rapamycin local concentration after ejection preparation.When the volume of given dose increases, be not more conducive to form nondispersive agglomerate.When improving rapamycin concentrations and/or improving viscosity, can more be conducive to form nondispersive agglomerate.Ethanol content affects the dissolubility of rapamycin and the viscosity of preparation in preparation.

One relatively in, the solution of 0.4% rapamycin of 100 μ l, 4.0% ethanol and 95.6%PEG 400 (400 μ g dosage) does not form nondispersive agglomerate after being injected into lagophthalmos.On the contrary, the solution of 2.00% rapamycin of 20 μ l, 4.0% ethanol and 94%PEG 400 (being also 400 μ g dosage) forms fine and close spherical nondispersive agglomerate after being injected into lagophthalmos.

Not bound by theory, in a rear example, suppose that the formation of nondispersive agglomerate is as Figure 1A-1C and hereinafter described generation.During injection, liquid preparation is because its viscosity has formed spheroid 100 in vitreous body 110.Then ethanol spreads from this bead, forms the localized precipitation 120 of rapamycin in bead.Finally, Polyethylene Glycol also spreads from bead, obtains solid-state, the fine and close nondispersive agglomerate 130 of rapamycin.

In some modification, nondispersive agglomerate described herein by by volume at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or therapeutic agent at least about in 95% injection lagophthalmos vitreous body time form.

In some modification, while forming the nondispersive agglomerate that contains rapamycin, with roughly constant speed, within the time period extending, continue to send.Be not bound by any theory, believe that in vitreous body, from nondispersive agglomerate, sending rapamycin depends on that rapamycin is in intravitreous dissolving, this depends on again the clearance rate of medicine from vitreous body to its hetero-organization.Be not bound by any theory, believe that this dispose procedure maintains the Css of rapamycin in vitreous body.

In some modification, to compare with the dosage that is equal to that does not form nondispersive agglomerate, the formation of nondispersive agglomerate has reduced the toxicity of the liquid preparation of injection.Do not form in the modification of nondispersive agglomerate being injected into intravitreous liquid preparation, medicine (for example rapamycin) shows and is dispersed in vitreous body.In some modification, this can disturb vision.

In some modification, for the liquid preparation of suspension forms nondispersive agglomerate after being injected into vitreous body.When suspension particle size increases, from the suspension of injecting, forming nondispersive agglomerate can be more favourable.

In some modification, believe be injected into experimenter's (including but are not limited to people experimenter) at the moment liquid preparation can form the visible nondispersive agglomerate of vision.

In some modification, while believing subconjunctival injection, liquid preparation can form nondispersive agglomerate.In some modification, believe under conjunctiva and form reservoir in applicating liquid preparation Hui scleral tissue.Believe that therapeutic agent is absorbed into approaching the sclera of injection site and form medicine local concentration in sclera.

In-situ gelling preparation

This paper describes the liquid preparation of the nondispersive agglomerate of following formation, described preparation forms gel or gel-like substance while being placed in aqueous medium.In some modification, nondispersive agglomerate comprises gel; In some modification, gel is hydrogel.

Use " in-situ gelling preparation " to refer to the liquid preparation that forms the nondispersive agglomerate of gel sample when liquid preparation is placed in aqueous medium (including but are not limited to as the aqueous medium between water, lagophthalmos vitreous body and lagophthalmos CSC) herein.In some modification, when being placed in tap water, in-situ gelling preparation forms the nondispersive agglomerate of gel sample.

In some modification, in-situ gelling preparation was suspension before being placed in aqueous medium, and when being placed in aqueous medium, formed gel.In some modification, in-situ gelling preparation is solution before being placed in aqueous medium, and original position forms gel when being placed in aqueous medium.In some modification, in-situ gelling preparation is Emulsion before being placed in aqueous medium, and when being placed in aqueous medium, forms gel.In some modification, after being placed in to aqueous medium (include but are not limited between water, vitreous body or eye sclera and conjunctiva any or whole), in-situ gelling preparation forms the nondispersive agglomerate of gel sample.In some modification, situ-gel is formed by polymeric matrix.In some modification, therapeutic agent is dispersed in polymeric matrix.

This paper describes and can be used for treatment, prevention, inhibition, delay experimenter's (including but are not limited to people experimenter) disease and the generation of disease or the in-situ gelling preparation that it is disappeared.When being used for the treatment of, preventing, suppressing, postponing the generation of experimenter's disease or disease or it is disappeared, to experimenter, use in-situ gelling preparation.A kind of liquid preparation described herein comprises in-situ gelling preparation, and described in-situ gelling preparation forms nondispersive agglomerate while being applied to experimenter, and when being applied to lagophthalmos, forms nondispersive agglomerate.

In some modification, in-situ gelling preparation comprises one or more polymer.This paper describes polytype polymer, be included as the polymer of solvent, is the polymer of solubilizing agent, be to discharge the polymer of dressing agent, for the polymer of stabilizing agent etc.In some modification, use any combination of polymer, wherein, when being placed in aqueous medium (include but are not limited between water, vitreous body or CSC any or all), when polymer and therapeutic combination, form any or whole of nondispersive agglomerate, gel, hydrogel or polymeric matrix.

In some modification, when in-situ gelling preparation is applied to experimenter, to experimenter, sends and extend the therapeutic agent discharging.

In some modification, liquid preparation comprises therapeutic agent and multiple polymers, and wherein one of polymer is polymethacrylates.Polymethacrylates is known as multiple title and can derives from several formulations, include but are not limited to polymethacrylates, methacrylic acid-ethyl propylene acid ester copolymer (1: 1), methacrylic acid-ethyl propylene acid ester copolymer (1: 1) of dispersion 30%, methacrylic acid-methyl methacrylate ester copolymer (1: 2), methacrylic acid-methyl methacrylate ester copolymer (1: 1), acidum methacrylicum et ethylis acrylas polymerisatum 1: 1, 1: 1 dispersio 30 percentum of acidummethacrylicum et ethylis acrylas polymerisatum, acidum methacrylicum et methylis methacrylas polymerisatum1: 1, acidum methacrylicum et methylis methacrylas polymerisatum 1: 2, USPNF: ammonio methacrylate copolymer, methacrylic acid copolymer, methacrylic acid copolymer dispersion.

In some modification, one of polymer is polyvinylpyrrolidone.Polyvinylpyrrolidone is known as multiple title and can in several formulations, obtains, and includes but are not limited to polyvidone, povidonum, kollidon; Plasdone; Poly-[1-(2-oxygen-1-pyrrolidinyl) ethylene]; Polyvidone; PVP; 1-vinyl-2-pyrrolidinyl polymer and 1 vinyl 2 pyrrolidone homopolymer.

A kind of liquid preparation as herein described comprises therapeutic agent and solvent composition.Described solvent composition can comprise the combination of single solvent or solvent.

In some modification, solvent is Polyethylene Glycol (including but are not limited to PEG 300 and PEG 400) or the propylene glycol of glycerol, dimethyl sulfoxide, N-Methyl pyrrolidone, ethanol, isopropyl alcohol, various molecular weights, or one of them or multiple mixture.

In some modification, solvent is Polyethylene Glycol.Polyethylene Glycol is known as multiple title and can in several formulations, obtains, and includes but are not limited to Polyethylene Glycol, PEG400, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000, PEG 20000, macrogola, breox PEG; Carbowax; Carbowax sentry; Hodag PEG; Lipo; Lipoxol; Lutrol E; PEG; Pluriol E; Polyethylene Glycol and alpha-hydro-omega-hydroxy-poly (Oxy-1,2-second two bases).

Compositions and liquid preparation for delivering therapeutic agents

Compositions described herein and liquid preparation can be used for sending a certain amount of therapeutic agent, and described amount can effectively treat, prevent, suppresses, postpones the generation of the described disease of " disease and disease " part and disease or it is disappeared.In some modification, compositions described herein and liquid preparation are sent one or more therapeutic agents in the time period extending.

For " effective dose " (it is in this article also referred to as " treatment effective dose ") of the therapeutic agent of using described herein, refer to while being administered to experimenter's (including but are not limited to people experimenter), seek to provide the amount of the therapeutic agent of therapeutic effect.The realization of different treatment effects can need the different effective dose of therapeutic agent.For example for the treatment effective dose of the therapeutic agent of prevent disease or disease can from be used for the treatment of, suppress, postpone disease or disease and occur or make its treatment effective dose disappearing different.In addition, treatment effective dose can be depending on the described disease of age, body weight and processing or known other health status of disease those skilled in the art of experimenter.Therefore, treatment effective dose therapeutic agent be applied to each experimenter in can be different.

Being used for the treatment of, preventing, suppressing, postponing specified disease or disease occurs or makes the therapeutic agent of its effective dose disappearing also refer to that in this article the amount of its therapeutic agent disappearing occurs or makes for effective treatment, prevention, inhibition, delay disease or disease.

In order to determine whether the level of therapeutic agent is " the treatment effective dose " that treatment, prevention, inhibition, the delay described disease of " disease and disease " part and disease occur or it is disappeared, can be to the animal model applicating liquid preparation of object disease or disease, and observing effect.In addition, can carry out dosage within the scope of people's clinical trial to determine the treatment effective dose of therapeutic agent.

Usually, therapeutic agent can following any compositions or liquid preparation preparation, described compositions or liquid preparation can be to experimenter or experimenter's eye the therapeutic agent with required Delivery time delivery treatments effective dose.Compositions comprises liquid preparation.

The solubilising of therapeutic agent

Operable a kind of compositions or liquid preparation are that therapeutic agent is dissolved in compositions or the liquid preparation in solvent composition.Usually, any solvent with required effect can be used, and therapeutic agent is dissolved in wherein.In some modification, solvent is aqueous.In some modification, solvent is nonaqueous." aqueous solvent " is for containing the solvent at least about 50% water.

Usually, can use the dissolved therapeutic agent of any concentration with required effect.Solvent composition can be the mixture of single solvent or solvent.The type of solvent and solution is that in drug delivery technology, technical staff is known.Consult for example Remington:The Science and Practice ofPharmacy, the 20th edition, Lippincott Williams & Wilkins; The 20th edition (on December 15th, 2000); Ansel ' s Pharmaceutical Dosage Forms and Drug DeliverySystems, the 8th edition, Lippincott Williams & Wilkins (in August, 2004); HandbookOf Pharmaceutical Excipients 2003, American Pharmaceutical Association, Washington, DC, USA and Pharmaceutical Press, London, UK; And Strickley, solubilizing Excipients in Oral and Injectable Formulations, Pharmaceutical Research, the 21st volume, No.2, in February, 2004.

As discussed previously, some solvents also can be used as solubilizing agent.

Spendable solvent includes but are not limited to DMSO, ethanol, methanol, isopropyl alcohol, Oleum Ricini, propylene glycol, glycerol, polyoxyethylene sorbitan monoleate, benzyl alcohol, dimethyl acetylamide (DMA), dimethyl formamide (DMF), glyceryl triacetate, Glycerine 1,3-diacetate, Semen Maydis oil, CitroflexA-2 (ATC), ethyl lactate, glyceryl formal, ethoxydiglycol (Transcutol, Gattefosse), triethylene glycol dimethyl ether. (Triglyme), dimethyl isosorbide (DMI), gamma-butyrolacton, METHYLPYRROLIDONE (NMP), caprylin (the Labrasol of the Polyethylene Glycol of various molecular weights (including but are not limited to PEG 300 and PEG 400) and Pegylation, Gattefosse), aforementioned any one or more combination, or aforementioned any one or more analog or derivant.

In some modification, solvent is Polyethylene Glycol.Polyethylene Glycol is known as multiple title and can in several formulations, obtains, and includes but are not limited to Polyethylene Glycol, PEG400, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000, PEG 20000, macrogola, breox PEG; Carbowax; Carbowax sentry; Hodag PEG; Lipo; Lipoxol; Lutrol E; PEG; Pluriol E; Polyethylene Glycol and alpha-hydro-omega-hydroxy-poly (Oxy-1,2-second two bases).

In some modification, Polyethylene Glycol is liquid PEG, and is PEG 300 or PEG 400 one or more.

Other solvents comprise a certain amount of C ₆-C ₂₄fatty acid, the enough solubilising therapeutic agents of described amount.

Also can use phospholipid solvent, for example the mixture of lecithin, phosphatidylcholine or the multiple diglyceride (diglyceride of stearic acid, Palmic acid and oleic acid) that is connected with phosphocholine ester; The S-PC of hydrogenation (HSPC), DSPG (DSPG), L-α-dimyristoyl phosphatidyl choline (DMPC), L-α-GLYCEROL,DIMYRISTOYL PHOSPHATIDYL (DMPG).

Other examples of solvent comprise such as following composition: the Polyethylene Glycol of alcohol, propylene glycol, different molecular weight, propylene glycol ester, use fatty acid are as the propylene glycol of the esterifications such as oleic acid, stearic acid, Palmic acid, capric acid, linoleic acid; Single, double or three acid esters of the glycerol of medium chain, long-chain fatty acid, naturally occurring oil and composition thereof.The oil component of dicyandiamide solution comprises the commercially available oil of business and naturally occurring oil.Described oil can also be vegetable oil or mineral oil.Described oil can be characterized by on-surface-active oil, and it does not have Lipophilicity equilibrium valve conventionally.The business that comprises heavy chain triglyceride can be buied material and be included but are not limited to Captex 100, Captex 300, Captex 355, Miglyol 810, Miglyol 812, Miglyol 818, Miglyol 829 and Dynacerin 660.The commercially available propylene glycol ester compositions of business comprises Captex 200 and Miglyol 840 etc.Commercially available prod Capmul MCM comprises one of many possible medium chain mixture containing monoglyceride and diglyceride.

Other solvents comprise naturally occurring oil, as Oleum menthae and seed oil.Exemplary natural oil comprises oleic acid, Oleum Ricini, Semen Carthami oil, soybean oil, olive oil, Oleum Helianthi, Oleum sesami and Oleum Arachidis hypogaeae semen.Also can use soya bean fatty acid.The example of completely saturated non-aqueous solvent comprises that (C for example has an appointment to the ester of long-chain fatty acid during load is not limited only to ₆to about C ₂₄the fatty acid triglycercide of chain length).Also can use oil with hydrogenated soybean and other plant oil.The mixture of fatty acid can for example, from natural oil (Oleum Cocois, palm-kernel oil, babassu wet goods) separated and refine.In some embodiments, can use medium chain (the about C from Oleum Cocois or Petiolus Trachycarpi seed oil ₈to about C ₁₂) triglyceride is as caprylic/capric triglyceride.Also can use medium chain monoglyceride or diglyceride.Other completely saturated non-aqueous solvents comprise that load is not limited only to saturated Oleum Cocois (it generally includes the mixture of lauric acid, myristic acid, Palmic acid, capric acid and caproic acid), comprise from Huls with trade mark Miglyol ^tMsell and there are those of trade name 810,812,829 and 840.The NeoBee being sold by Drew Chemicals ^tMproduct is also mentioned.Non-aqueous solvent comprises isopropyl myristate.The example of artificial oil comprises triglyceride and the propylene glycol ester of the saturated or unsaturated fatty acid with 6 to 24 carbon atoms, and described fatty acid is such as caproic acid, sad (caprylic acid), n-nonanoic acid (n-nonanoic acid), capric acid (capric acid), hendecanoic acid, dodecylic acid, tridecanoic acid, tetradecanoic acid (myristic acid), pentadecanoic acid, hexadecanoic acid (Palmic acid), heptadecanoic acid, octadecanoid acid (stearic acid), nonadecylic acid, heptadecanoic acid, arachic acid, heneicosanoic acid, behenic acid and tetracosanoic acid etc.The example of unsaturated carboxylic acid comprises oleic acid, linoleic acid plus linolenic acid etc.Non-aqueous solvent can comprise monoglyceride, diglyceride and the triglyceride of fatty acid or the glyceride of mixing and/or propylene glycol monoester or diester, and wherein at least one glycerol molecule is had the fatty acid esterification of different carbon atom length.A limiting examples that is used as " the non-oil " of solvent is Polyethylene Glycol.

Exemplary vegetable oil comprises Oleum Gossypii semen, Semen Maydis oil, Oleum sesami, soybean oil, olive oil, fractionated coconut oil, Oleum Arachidis hypogaeae semen, Oleum Helianthi, safflower oil, almond oil, American Avocado Tree oil, Petiolus Trachycarpi oil, palm-kernel oil, babassu oil, beech nut oil, Semen Lini oil, Semen Allii Tuberosi wet goods.Also can use monoglyceride, diglyceride and the triglyceride of plant (including but are not limited to Semen Maydis) oil.

Also can use crosslinked or uncrosslinked polyvinylpyrrolidone (PVP) as solvent.Other solvent includes but are not limited to C ₆-C ₂₄fatty acid, oleic acid, Imwitor 742, Capmul, F68, F68 (Lutrol), PLURONICS (include but are not limited to PLURONICS F108, F127 and F68, poloxamer, Jeffamines), Tetronics, F127; Cyclodextrin is as alpha-cyclodextrin, beta-schardinger dextrin-, HP-β-CD, sulfo group butyl ether-beta-schardinger dextrin-(Captisol); The Polyethylene Glycol of CMC, polysorbitan 20, Cavitron, various molecular weights, includes but are not limited to PEG300 and PEG 400.

Also can use Cera Flava and d-alpha-tocopherol (vitamin E) as solvent.

Solvent for liquid preparation can be definite by several different methods known in the art, and described method includes but are not limited to the solvent that (1) is used this area standard equation to estimate in theory their solubility parameter value and select to mate with therapeutic agent; (2) to test, determine the saturation solubility of therapeutic agent in solvent, and select to show the solvent of required dissolubility.

The solubilising of rapamycin

When therapeutic agent is rapamycin, the solvent that can be used for preparing rapamycin solution or suspensoid includes but are not limited to any solvent described herein, includes but are not limited to DMSO, glycerol, ethanol, methanol, isopropyl alcohol; Oleum Ricini, propylene glycol, polyethylene propylene, glycerol, polyoxyethylene sorbitan monoleate, benzyl alcohol, dimethyl acetylamide (DMA), dimethyl formamide (DMF), glyceryl formal, ethoxydiglycol (Transcutol, Gattefosse), any one or more of the caprylin (Labrasol, Gattefosse) of the Polyethylene Glycol of triethylene glycol dimethyl ether. (Triglyme), dimethyl isosorbide (DMI), gamma-butyrolacton, METHYLPYRROLIDONE (NMP), various molecular weights (including but are not limited to PEG 300 and PEG 400) and Pegylation.

Other solvents include but are not limited to C ₆-C ₂₄fatty acid, oleic acid, Imwitor 742, Capmul, F68, F68 (Lutrol), PLURONICS (include but are not limited to PLURONICS F108, F127 and F68, poloxamer, Jeffamines), Tetronics, F127, beta-schardinger dextrin-, CMC, polysorbitan 20, Cavitron, softigen 767, captisol and Oleum sesami.

The additive method that can be used for dissolving rapamycin is described in Solubilization of Rapamycin, Int ' l J.Pharma 213 (2001) 25-29 such as P.Simamora, and its whole content is quoted as a reference herein.

As nonrestrictive example, rapamycin dissolves in the saline solution that balance crosses in 5%DMSO or methanol.Rapamycin solution can be undersaturated, saturated or oversaturated rapamycin solution.Rapamycin solution can contact with solid rapamycin.In a nonrestrictive example, rapamycin can be dissolved as the concentration up to about 400mg/ml.Rapamycin also can for example be dissolved in in fatty acid-esterified propylene glycol, and described fatty acid is such as oleic acid, stearic acid, Palmic acid, capric acid, linoleic acid etc.

Many other solvents are possible.This area routine techniques personnel can find to identify that according to instruction herein the solvent for rapamycin is conventional.

Solubilizing agent

Usually, the combination of any solubilizing agent or solubilizing agent can be used for liquid preparation described herein.

In some modification, solubilizing agent is the combination of surfactant or surfactant.Many surfactants are possible.Also can use the combination of surfactant, comprise the combination of polytype surfactant.For example, can use non-ionic, anion (as soap, sulfonate), cation (as CTAB), zwitterionic, polymerization or amphoteric surfactant.

Can be by therapeutic interest agent and the solvent of inferring and the surfactant of inferring are mixed, and observe and be exposed to the character of said preparation after medium and determine spendable surfactant.

The example of surfactant includes but are not limited to fatty acid ester or amide or ether analogs thing, or its hydrophilic derivant; Monoesters or diester, or its hydrophilic derivant; Or its mixture; Monoglyceride or diglyceride, or its hydrophilic derivant; Or its mixture; There is the monoglyceride of enrichment or/and the mixture of diglyceride, or its hydrophilic derivant; The derivative surfactant of hydrophilic segment for part; The monoesters of other alcohol, polyhydric alcohol, sugar or oligosaccharide or polysaccharide or diester or polyester, its oxyalkylene oligomer or polymer or block polymer, or its hydrophilic derivant, or its amide analogue; The derivative of fatty acid of amine, polyamines, many imines, amino alcohol, amino sugar, hydroxyalkyl amine, hydroxy polyamine, peptide, polypeptide or its ether analogs thing.

Hydrophilic-lipophilic balance (" HLB ") presentation surface activating agent attracts water and the relative of oil (or to described Emulsion system biphase) simultaneously.

Surfactant characterizes according to the balance between the hydrophilic and lipophilic portion of their molecules.Hydrophil lipophil balance (HLB) number is pointed out the molecular polarity in any range of 1-40, and the emulsifying agent the most often using has the value between 1-20.HLB increases with hydrophilic.

Operable surfactant includes but are not limited to have and is greater than 10,11,12,13 or the surfactant of 14HLB.The example of surfactant comprises polyoxyethylene product, the Oleum Ricini of polyethoxylated or the castor oil hydrogenated of polyethoxylated, polyoxyethylene-sorbitan fatty acid esters, castor oil derivatives of hydrogenated vegetable oil etc., for example Nikkol HCO-50, NikkolHCO-35, Nikkol HCO-40, Nikkol HCO-60 (from Nikko Chemicals Co.Ltd.); Cremophor (from BASF) is as Cremophor RH40, Cremophor RH60, Cremophor EL, TWEENs (from ICI Chemicals), such as polysorbas20, tween 21, polysorbate40, polysorbate60, Tween 80, sorbimacrogol oleate100, Cremophor RH 410, Cremophor RH455 etc.

Surfactant component can be selected to be had at least one and has the compound at least about the aliphatic alcohol chain of 12 to approximately 22 carbon atoms from the ether that forms at least about 1 to 100 ethylene oxide unit(s) and at least one; There is at least one and there is the compound at least about the fatty acid chain of 12 to 22 carbon atoms from the ester forming at least about 1 to 100 ethylene oxide unit(s) with at least one; There is at least one from ether, ester or amide at least about 1 to 100 ethylene oxide unit(s) formation and the compound of at least one vitamin or vitamin derivative; With it by no more than two kinds of combinations that surfactant forms.

Other examples of surfactant comprise Lumulse GRH-40, TGPS, Tween-80 (tween 80), Tween-20 (tween 20), polyoxyethylene (20) sorbitan monooleate, glyceryl glycol ester, macrogol ester, polyglycolyzed glyceride (polyglycolyzedglycerides) etc. or its mixture; Polyethylene sorbitan fatty acid ester, polyoxyethylene glyceride are as Tagat TO, Tagat L, Tagat I, tagat I2 and Tagat 0 (can business purchased from Goldschmidt Chemical Co., Essen, Germany); Glycol ester, as glycol stearate and diglycol stearate; Propylene glycol ester, as tetradecylic acid propylene glycol ester; Fatty glyceride, as tristerin and glyceryl monostearate; Sorbitan ester, as spans and Tweens; Polyglycerin ester, as polyglyceryl 4-oleate; Alcohol ethoxylate, as Brij type emulsifying agent; The propenoxylated block copolymer of ethoxylation, as poloxamer; The macrogol ester of fatty acid, as PEG 300 glyceryl linoleates or Labrafil 2125 CS, PEG 300 oleins or Labrafil M 1944 CS, PEG 400 caprylic/capric glyceride or Labrasol and PEG 300 caprylic/capric glyceride or Softigen 767; Cremophors, as Cremophor E, CREMOPHORE EL or Cremophor EL, Cremophor EL-P, Cremophor RH 4OP, polyoxyl 40 hydrogenated castor oil, Cremophor RH40; Cremophor RH60 or Cremophor RH 60, single caprylic/capric glyceride, as Campmul CM 10; Polyoxyethylene fatty acid (PEG-stearate, PED-laurate, Brij ), the ethylating fatty glyceride of polyoxy, the ethylating fatty acid glyceride of polyoxy, as Solutol HS-15; PEG-ether (Mirj ), dehydrated sorbitol derivative (tween), dehydrated sorbitol mono-fatty acid ester or Span 20, aromatic (Tritons ), PEG-glyceride (PECEOL ^tM), PEG-PPG (polypropylene glycol) copolymer (PLURONICS includes but are not limited to PLURONICS F108, F127 and F68, poloxamer, Jeffamines), Tetronics, polyglycereol, PEG-tocopherol, PEG-LICOL 6-oleate; The alkyl of propanediol derivative, sugar and polysaccharide and acyl derivative (octyl group sucrose, sucrose stearate, lauroyl glucosan etc.) and/or its mixture; Based on polyhydric alcohol and the oleic acid of oxirane copolymerization or the surfactant of laurate; Labrasol Gelucire 44/14; Myrj 45; Saturated polyglycolyzed glyceride; Or poloxamer; They are all can business buy.Polyoxyethylene dehydration sorbitol fatty acid ester can comprise Polysorbate, for example polysorbate 20, polysorbate 40, polysorbate 60 and polyoxyethylene sorbitan monoleate.Myrj 45 can comprise polyoxyethylene 6 stearates, Myrj 45, polyoxyethylene 12 stearates and polyoxyethylene 20 stearates.Saturated polyglycolyzed glyceride is for example GELUCIRE 44/14 or GELUCIRE ^tM50/13 (Gattefosse, Westwood, N.J., U.S.A.).Poloxamer used herein comprises Pluronic/Lutrol F 44 and PLURONICS F87.

Surfactant comprises d-alpha-tocopherol base cetomacrogol 1000 succinate (TPGS), Myrj 45 (PEG 400 monostearates), Myrj 52 (PEG 1750 monostearates) and Oleum menthae.

In some modification, use the surfactant have lower than 10 HLB.This class surfactant optionally with as other surfactant combinations of cosurfactant is used.Some have the surfactant, mixture of the HLB that is less than or equal to 10 and other, and to be equal to compositions be propylene glycol, glyceryl fatty acid, glycerin fatty acid ester, macrogol ester, glyceryl glycol ester, polyglycolyzed glyceride and polyoxyethylene sterol base ether.Propylene glycol ester or part ester form commercial product as the Lauroglycol FCC component of (it contains lauric acid propylene glycol ester).The commercially available excipient Maisine of business 35-1 comprises long-chain fatty acid, for example glyceryl linoleate.Also can use the product that comprises polyoxyethylene 8 stearate ether, as Acconon E.Labrafil M 1944 CS are examples for surfactant, the mixture that wherein said composition contains glyceryl glycol ester and macrogol ester.

The solubilizing agent of rapamycin

Many solubilizing agents can be used for rapamycin, include but are not limited to above the described solubilizing agent of " solubilizing agent " part.

In some modification, solubilizing agent is surfactant.The limiting examples that can be used for the surfactant of rapamycin includes but are not limited to has the surfactant that is greater than 10,11,12,13 or 14 HLB.A nonrestrictive example is Cremophor EL.In some modification, surfactant can be the surfactant of polymerization, includes but are not limited to PLURONICS F108, F127 and F68 and Tetronics.Solvents more used herein are useful as surfactants also.This area routine techniques personnel can find to identify that according to instruction herein it is conventional which kind of solubilizing agent and surfactant can be used for rapamycin.

Viscosity dressing agent

Viscosity dressing agent can be used or also contain to liquid preparation described herein together with viscosity dressing agent.

Spendable a kind of exemplary viscosity dressing agent is hyaluronic acid.Hyaluronic acid is glycosaminoglycans.Its repetitive sequence by glucuronic acid and glycosamine forms.Hyaluronic acid is present in many tissues and organ of health, and contributes to viscosity and the denseness of this class tissue and organ.Hyaluronic acid is present in eye (vitreous body that comprises eye) and contributes to its viscosity together with collagen.Liquid preparation described herein can also comprise hyaluronic acid or therewith use.

Other limiting examples of viscosity dressing agent comprise polyalkylene oxide, glycerol, carboxymethyl cellulose, sodium alginate, chitosan, glucosan, dextran sulfate and collagen.These viscosity dressing agents can be by chemical modification.

Operable other viscosity dressing agents include but are not limited to carrageenan, cellulose gel, silicon dioxide colloid, gelatin, propylene carbonate, carbonic acid, alginic acid, agar, CVP Carbopol ETD2050 or carbomer and polyacrylamide, arabic gum, ester gum, guar gum, arabic gum, ghatti, karaya gum, tragakanta, terra, pectin, tamarind, larch arabinogalactan, alginate, Semen sophorae, xanthan gum, starch, aluminium-magnesium silicate, tragakanta, polyvinyl alcohol, gellan gum, hydrocolloid admixture and polyvidone.Also other viscosity dressing agents known in the art be can use, sodium carboxymethyl cellulose, sodium alginate, antler glue, galactomannan, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, Polyethylene Glycol, polyvinylpyrrolidone, carboxymethyl chitosan sodium, Sensor Chip CM 5 sodium, carboxymethyl starch sodium, xanthan gum and zein included but are not limited to.

Other compositions of liquid preparation

Preparation described herein also can comprise multiple other compositions, for example stabilizing agent.The stabilizing agent that can be used for preparation described herein comprises but the meeting of being not limited only to (1) improves excipient and cover material as the compatibility of gelatin, (2) for example improve therapeutic agent, as the stability of rapamycin and/or rapamycin derivative (prophylactic treatment agent is as the crystal growth of rapamycin), and/or (3) improve the reagent of preparation stability.Attention is overlapping for existing between the composition of stabilizing agent and the composition for solvent, solubilizing agent or surfactant, and identical composition can be brought into play more than a kind of effect.

Stabilizing agent can be selected from hydrophilic derivant, polyvinylpyrrolidone, polyvinylether, polyvinyl alcohol, hydrocarbon, hydrophobic polymer, absorbent polymer and the combination thereof of fatty acid, fatty alcohol, alcohol, long-chain fatty acid ester, long chain ether, fatty acid.Also can use the amide analogue of aforementioned stable agent.Selected stabilizing agent can change the hydrophobicity (for example oleic acid, wax) of preparation or promote the mobility of the mixing (as ethanol) of Multiple components in preparation, the level of wetness (for example PVP) of controlling preparation, control phase (to have the material higher than the fusing point of room temperature, such as long-chain fatty acid, alcohol, ester, ether, amide etc. or its mixture; Wax) and/or promote the compatibility (for example oleic acid or wax) of preparation and cover material.Some of these stabilizing agents can be used as solvent/co-solvent (for example ethanol).Can there is for example, crystallization with suppression therapy agent (rapamycin) with q.s in stabilizing agent.

That the example of stabilizing agent includes but are not limited to is saturated, monoene, polyenoid, branch, containing the fatty acid of He Han ring, alkynes, dicarboxyl functional group as oleic acid, sad, capric acid, caproic acid, lauric acid, myristic acid, Palmic acid, stearic acid, behenic acid, linoleic acid, linolenic acid, eicosapentaenoic acid (EPA), DHA; Fatty alcohol is as hard ester alcohol, hexadecanol, ceteryl alcohol; Other alcohol are as ethanol, isopropyl alcohol, butanols; Long-chain fatty acid ester, ether or amide, as tristerin, stearic acid hexadecyl ester, oleyl ether, hard ester acyl ether, cetyl ether, oil base amide, hard esteramides; The hydrophilic derivant of fatty acid, as polyglyceryl fatty acid, cithrol; Polyvinylpyrrolidone, polyvinyl alcohol (PVA), wax, docosahexenoic acid and dehydroabietic acid etc.

Described preparation also can contain by gellant, and it changes the quality of final preparation by forming gel.

Therapeutic agent (as rapamycin) can carry out conventional pharmaceutical operation (for example sterilizing) as described herein, and the compositions that contains therapeutic agent also can contain conventional adjuvant, as antiseptic, stabilizing agent, wetting agent, emulsifying agent, buffer agent etc.Therapeutic agent also can be prepared with the pharmaceutical acceptable excipient of clinical use, for the manufacture of pharmaceutical composition.The preparation of using for eye can exist for the explant of solution, suspension, solid material particle, solid material, the form of mixing polymeric matrix, liquid preparation or other any ocular administrations.Therapeutic agent can be used for for the preparation of the medicine for the treatment of, preventing, suppressing, postponing the generation of arbitrary disease described herein or it being disappeared.In some modification, therapeutic agent can be used for the medicine of preparation treatment arbitrary disease described herein.

The compositions that contains therapeutic agent (as rapamycin) can contain the adjuvant that one or more are applicable to the route of administration of appointment.The adjuvant that therapeutic agent can mix with it includes but are not limited to sodium salt and calcium salt, arabic gum, gelatin, sodium alginate, polyvinylpyrrolidine and/or the polyvinyl alcohol of lactose, glucose, starch powder, alkanoic acid cellulose esters, stearic acid, Talcum, magnesium stearate, magnesium oxide, phosphoric acid and sulphuric acid.When needing the preparation of solubilising, therapeutic agent can be in following solvents, and described solvent includes but are not limited to Polyethylene Glycol, propylene glycol, carboxymethyl cellulose gum liquid solution, methanol, ethanol, DMSO, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, Oleum sesami, Tragacanth and/or the multiple buffer of different molecular weight.Other adjuvants and method of application are that pharmaceutical field is known, and can be used in the practice of methods described herein, compositions and liquid preparation.Carrier or diluent can comprise time delay material (as glyceryl monostearate or the distearin separately or together with wax) or other materials well known in the art.Preparation for purposes described herein also can comprise gel preparation, polymer, microsphere and liposome that easily lose and that be difficult for erosion.

Spendable other adjuvants and excipient include but are not limited to C ₈-C ₁₀fatty acid ester is as softigen 767, polyoxyethylene sorbitan monoleate, PLURONICS, Tetronics, Miglyol and Transcutol.

At the normally used additive of pharmaceutical field and diluent, be optionally added in pharmaceutical composition and liquid preparation.These additives and diluent comprise thickening agent, granulating agent, dispersant, flavoring agent, sweeting agent, coloring agent and stabilizing agent (comprising pH stabilizing agent), other excipient, antioxidant (such as tocopherol, BHA, BHT, TBHQ, tocopherol acetate, ascorbic palmitate, ascorbic acid propyl gallate etc.), antiseptic (as p-Hydroxybenzoate) etc.Exemplary antiseptic include but not limited to benzyl alcohol, ethanol, benzalkonium chloride, phenol, chlorobutanol etc.Some useful antioxidants provide oxygen or peroxide inhibitor for preparation, and include but are not limited to butylated hydroxytoluene, butylated hydroxyanisole (BHA), propyl gallate, ascorbic palmitate, alpha-tocopherol etc.Thickening agent can improve the quality of preparation as lecithin, hydroxypropyl cellulose, aluminium stearate etc.

In some modification, therapeutic agent is rapamycin, and rapamycin is formulated as the rapamycin of solid or liquid form.In some modification, rapamycin is formulated as oral dose.

In addition, can be to the polymer that adds thickness in suspension, auxiliary positioning and easily place and process.In some purposes of liquid preparation, can in sclera, form by surgical operation bag, so that the injection of acceptable solution body preparation.The hydrogel structure of sclera can be used as the film of speed control.The therapeutic agent material grains that is used to form suspension can be manufactured by known method, and described method includes but are not limited to for example uses ceramic bead to manufacture by ball milling.For example, Cole Parmer ball mill can be used with together with 0.8mm YTZ ceramic bead from Tosoh or Norstone Inc as Labmill 8000.

Preparation can be present in expediently in unit dosage forms and can prepare by conventional pharmaceutical technology.This class technology comprises the step of therapeutic agent and pharmaceutical carrier or excipient combination.Can, by solid carrier or the evenly also combination nearly together with the two with liquid-carrier or segmentation by active component, then when needed product molding be prepared to preparation.

In some modification, preparation described herein provides with one or more unit dosage forms, and wherein said unit dosage forms comprises a certain amount of liquid preparation described herein, and its disease being applied or disease can effectively be treated or prevent to described amount.In some modification, preparation described herein provides with one or more unit dosage forms, and wherein said unit dosage forms comprises a certain amount of liquid rapamycin preparation described herein, and its disease being applied or disease can effectively be treated or prevent to described amount.

In some embodiments, unit dosage forms is prepared with it concentration being applied.In some modification, unit dosage forms was diluted before being administered to experimenter.In some modification, liquid preparation described herein was diluted in aqueous medium before being administered to experimenter.In some modification, aqueous medium oozes medium for waiting.In some modification, liquid preparation described herein was diluted in non-aqueous media before being administered to experimenter.

The medicine box that comprises one or more unit dosage forms described herein is provided herein on the other hand.In some embodiments, described medicine box comprises one or more packings and the description that is used for the treatment of one or more diseases or disease.In some embodiments, described medicine box comprises the diluent physically not contacting with preparation or pharmaceutical formulations.In some embodiments, described medicine box comprises the described herein any or multiple unit dosage forms in one or more sealed tubes.In some embodiments, described medicine box comprises any or multiple sterile unit dosage form.

In some modification, unit dosage forms is container, includes but are not limited to the container of sterile sealing.In some modification, container is bottle, ampoule or small size applicator (applicator), includes but are not limited to syringe.In some modification, small size applicator is filled with the rapamycin that is used for the treatment of ophthalmic diseases or disease in advance, includes but are not limited to the limus compound that is used for the treatment of relevant degeneration of macula of age.This paper describes the prepackage small size applicator being equipped with in advance containing the preparation of therapeutic agent (including but are not limited to rapamycin).In some modification, small size applicator is equipped with the solution containing therapeutic agent (including but are not limited to rapamycin) and Polyethylene Glycol in advance, and optionally also comprises one or more extra compositions, includes but are not limited to ethanol.In some modification, the small size applicator of prepackage is equipped with the solution containing approximately 2% rapamycin, about 94%PEG-400, approximately 4% ethanol in advance.

This paper describes the medicine box that comprises one or more containers.In some modification, the medicine box that comprises one or more small size applicators is equipped with the preparation that contains therapeutic agent as herein described in advance, includes but are not limited to the preparation that comprises rapamycin, comprises rapamycin and Polyethylene Glycol and the preparation of the liquid form that optionally also comprises the preparation (described extra composition includes but are not limited to ethanol) of one or more extra compositions and comprise approximately 2% rapamycin, about 94%PEG-400, approximately 4% ethanol.In some modification, medicine box comprises one or more containers (including but are not limited to prepackage small size applicator) and operation instruction thereof.In another modification, medicine box comprises one or more small size applicators that rapamycin is housed in advance, and is used for the treatment of the operation instruction of ophthalmic or disease.In some modification, container described herein is in secondary package.

Route of administration

Compositions described herein, method and liquid preparation by one or more therapeutic agent delivery to experimenter (including but are not limited to people experimenter).

In some modification, compositions described herein, method and liquid preparation are by one or more therapeutic agent delivery the pure man experimenters' aqueous medium.

In some modification, compositions described herein, method and liquid preparation extremely will be treated one or more therapeutic agent delivery, prevent, suppress, postpone its generation or make near the aqueous medium in its disease disappearing or disease region or it.

In some modification, compositions described herein, method and liquid preparation are delivered to one or more therapeutic agents experimenter's eye with a certain amount of and persistent period, comprise macula lutea and retina tela chorioidea, described amount and persistent period can effectively treat, prevent, suppress, postpone the generation of the described disease of " disease and disease " part and disease or it is disappeared.

Using " retina choroid " and " retina tela chorioidea " is herein synonym, and refers to retina and the tela chorioidea of the combination of eye.

As limiting examples, compositions described herein, liquid preparation and method can occur or make its amount disappearing and persistent period effectively to treat, prevent, to postpone CNV and moist AMD, directly or by approach are near the eyes applied to following tissue: between vitreous body, aqueous humor, sclera, conjunctiva, CSC, retina tela chorioidea, macula lutea or near other regions in experimenter's eye or eye.Effective dose and persistent period occur or it is disappeared for each treatment, prevention, inhibition CNV and moist AMD can be different, and can be different for variant site of delivery.

Intravitreal administration has more invasive than the eye operation of some other types.Because the risk of possible ill effect, intravitreal administration is not best to the relatively healthy eye for the treatment of.Compare, use near the eyes (as under conjunctiva, using) more much smaller than intravitreal administration invasive.When therapeutic agent is when approach is sent near the eyes, can treat the patient compared with healthy eyes, rather than can use the patient of intravitreal administration treatment.In some modification, use subconjunctival injection prevention or postpone the disease of eye or the generation of disease, wherein experimenter's eye has 20/40 or better visual acuity.

" under conjunctiva " used herein places or injection refers to placement or injection between CSC.Under conjunctiva, herein, being sometimes referred to as " sub-conj " uses.

The route of administration that can be used for applicating liquid preparation includes but are not limited to (for example, by injection) and liquid preparation is placed in to experimenter's aqueous medium, includes but are not limited to and is placed in (including but are not limited to by injection) experimenter's (including but are not limited to people experimenter) eye.Liquid preparation can general be used, and includes but are not limited to following route of delivery: rectum, vagina, inculcate, in intramuscular, intraperitoneal, intra-arterial, sheath, in bronchus, in pond, in epidermis, subcutaneous, Intradermal, percutaneous, intravenous, neck, in abdomen, in interior, intrathoracic, the trachea of intracranial, ophthalmic, lung, per nasal, cheek, Sublingual, mouth, parenteral or use aerosol propellant is sprayed or atomization.

The compositions that comprises therapeutic agent and liquid preparation can be used multiple programs to be applied directly to eye, include but are not limited to following program, in described program, (1) therapeutic agent is by being used syringe and hypodermic needle injection to use, (2) use the agent of specially designed equipment injection for curing, (3) before injection for curing agent, in sclera, operation forms bag, as the container of therapeutic agent or therapeutic agent compositions.For example, at one, use in program, surgeon forms bag in the sclera of eye, then the solution that contains therapeutic agent or liquid preparation is injected in bag.

Other are used program and include but are not limited to following program, in described program, (1) therapeutic drug formulation is injected by specially designed bend cannula, therapeutic agent is directly placed the part of eye, (2) therapeutic agent of compressed format is directly placed the part of eye, (3) by specially designed syringe or inserter, therapeutic agent is inserted in sclera, (4) liquid preparation that comprises therapeutic agent mixes in polymer, (5) surgeon produces little conjunctival incision, stitching thread and any therapeutic agent delivery structure are through this otch, thereby this structure is adjacent with sclera fixing, (6) use pin to enter the vitreous body of eye or enter any other described position for direct injection.

Liquid preparation described herein can (for example, by injection) directly be used, as elixir, be used for local application (include but are not limited to and pass through eye drop), or is used in soft or glutoid or starch capsule.Capsule can be tied with anti-leak.

Pass through injected delivery

A kind of method that can be used for sending compositions described herein and liquid preparation is for passing through injected delivery.In the method, compositions and liquid preparation injectable enter experimenter's (including but are not limited to people experimenter), or are injected near the position in experimenter's eye or eye, for delivery to experimenter or experimenter's eye.Injection includes but are not limited to ophthalmic and periocular injections.The limiting examples of position is as follows in experimenter's eye or near eye.

Injection of therapeutic agent enters in vitreous body can provide the high local concentrations of therapeutic agent in vitreous body and retina.In addition, found to increase with molecular weight in the removing half-life of glass drug disposition.

Also can use intracameral injection or be injected into anterior chamber.In an example, can intracameral injection 100 μ l at the most.

The approach near the eyes of sending can not have therapeutic agent delivery some risks of sending in vitreous body to retina.Near the eyes approach include but are not limited under conjunctiva, after subtenon, eyeball, send after eyeball week and juxtascleral." near the eyes " route of delivery refer to be placed in eye near or around.Periocular routes for retinal drugdelivery is consulted in the exemplary description of the approach near the eyes of retina drug delivery, Raghava etc. (2004), Expert Opin.Drug Deliv.1 (1): 99-114, its integral body is quoted as a reference herein.

In some modification, liquid preparation ophthalmic described herein is used.Ophthalmic use comprise be placed in or be injected into eye (including but are not limited to vitreous body).

Subconjunctival injection can be by injection of therapeutic agent is entered under conjunctiva, or between CSC.In an example, can subconjunctival injection approximately 500 μ l at the most.As a nonrestrictive example, can use the long syringe needle of approximately 25 to 30 specifications and about 30mm.Under the conjunctiva that therapeutic agent is used, the local pressure in site can improve therapeutic agent sending to back segment by reducing local Choroidal blood flow.

Subtenon injection can be by injection of therapeutic agent being entered in tenon ' the s capsule around of a top, and be injected in superior rectus " abdomen ".In an example, can be injected to how about 4ml by subtenon.As a limiting examples, can use the long blunt intubation of about 2.5cm.

Retrobulbar injection refers to that to be injected into after eyeball the conical area of four rectus and intermuscular septum film thereof indoor.In an example, can retrobulbar injection about 5ml at the most.As a limiting examples, can use the blunt nosed pin of approximately 25 or approximately 27 specifications.

Eyeball week injection can be the position of four rectus and intermuscular septum diaphragm area thereof outer (being that muscle cone is outer).Can eyeball week injection for example up to about the volume of 10ml.As a limiting examples, can use the blunt intubation of approximately 1.25 inches long and approximately 25 specifications.

After Juxtascleral, send and refer to therapeutic agent is placed near macula lutea or on macula lutea, directly contact with the outer surface of sclera, and the eyeball that do not puncture.In an example, can after juxtascleral, inject the about 500ml of as many as.As a nonrestrictive example, use blunt nosed bend cannula (being particularly designed to 56 °) that therapeutic agent is placed in to scleral incision.

In some modification, liquid preparation intraocular injection described herein.Intraocular injection comprises and is injected into ophthalmic.

The site that compositions and liquid preparation can be used includes but are not limited between vitreous body, aqueous humor, sclera, conjunctiva, CSC, near in retina tela chorioidea, macula lutea or experimenter's eye or other regions.The method that can be used for placing compositions and liquid preparation includes but are not limited to injection.

In a spendable method, therapeutic agent is dissolved in solvent or solvent mixture, then according to above-mentioned arbitrary program injection enter between experimenter's vitreous body, aqueous humor, sclera, conjunctiva, CSC, in retina tela chorioidea, macula lutea or eye or in other media of near other regions or experimenter or injection in its vicinity.In spendable these class methods, therapeutic agent is the rapamycin in liquid preparation.

When therapeutic agent is rapamycin, compositions and liquid preparation can be used for sending or maintain a certain amount of rapamycin in ocular tissue, and described ocular tissue includes but are not limited to retina, choroid or vitreous body, and described amount can effectively be treated AMD.In a nonrestrictive example, the liquid preparation of believing to send a certain amount of rapamycin can be used for treating moist AMD, and described amount can provide in vitreous body about 0.1pg/ml to the rapamycin concentrations of approximately 2 μ g/ml.In some nonrestrictive examples, believe that sending about 0.1pg/mg in retina tela chorioidea can be used for treating moist AMD to the liquid preparation of approximately 1 μ g/mg rapamycin concentrations.Other valid density can easily be determined based on instruction described herein by those skilled in the art.

The method of preparing liquid preparation

The non-limiting method that can be used for preparing liquid preparation described herein (including but are not limited to the liquid preparation containing rapamycin) is for by by solvent and therapeutic agent at room temperature or mix at the temperature slightly improving together with (optionally using ultrasonoscope) until acquisition solution or suspension, then cooling preparation.Then other compositions (including but are not limited to mentioned component) can be mixed with preparation.Spendable other preparation methoies are described herein, in comprising embodiment, and those skilled in the art can select other preparation methoies according to instruction herein.

Extend delivering therapeutic agents

This paper describes and show compositions and the liquid preparation of sending or remove spectrum in the body with following one or more features.Send or remove spectrum for the removing spectrum of therapeutic agent by compositions or liquid preparation subconjunctival injection or after being injected in lagophthalmos vitreous body.In some modification, send or remove spectrum and be by compositions or liquid preparation subconjunctival injection or after being injected into lagophthalmos vitreous body the removing of rapamycin spectrum in body.The approximately 30-40% of the Vitrea volume behaviour of rabbit vitreous body volume.The amount of therapeutic agent is used commercial measurement as described in Example 2, but is not subject to the restriction of preparation described in embodiment 2 and therapeutic agent.

In some modification, there is the therapeutic agent of sending or remove spectrum in body described herein and include but are not limited to and be described in those in " therapeutic agent " part.In some modification, therapeutic agent is rapamycin.In some modification, liquid preparation described herein is for the concentration delivering therapeutic agents to be equal to rapamycin.Liquid preparation described herein can comprise (including but are not limited to the concentration described herein that embodiment comprises) the arbitrary therapeutic agent being equal to rapamycin, includes but are not limited to the described therapeutic agent of " therapeutic agent " part.

" body in average percent " level refers to for select preset time from the mean concentration of the therapeutic agent of a plurality of lagophthalmos acquisitions, and by the therapeutic agent mean concentration of a time point therapeutic agent mean concentration divided by another time point.In some modification of average percent level, therapeutic agent is rapamycin in vivo.

Use containing after the preparation of therapeutic agent during preset time in rabbit eyes the mean concentration of therapeutic agent can measure according to following methods.When injection is less than the volume of 10 μ l, use Hamilton syringe.

Before using, liquid preparation is stored at 2-8 ℃ of temperature.

Laboratory animal is the New Zealand white rabbit (New Zealand Whiterabbits) of SFF (SPF).Use approximately 50% male, approximately 50% female population mixture.During administration, rabbit is at least 12 ages in week, conventionally at least 14 ages in week.The heavy at least 2.2kg of each rabbit during administration, conventionally 2.5kg at least.Front quarantine at least one week of animal of research also checks general health parameter.In research, do not use any unsound animal.For one preset time point, at least measure 6 eyes average.

According to the standardization program of using in industry, settle and sanitized.Offer the high fiber rabbit grain (Teklad Certified Hi-Fiber Rabbit Diet) of approximately 150 grams of Teklad checks of animal every day, and tap water is unrestrictedly provided.In known water, there is not pollution, not except local water community provide additional analysis.Monitoring environment condition.

Ophthalmologic examination before the treatment that veterinary's ophthalmologists that each animal stands to be authenticated by committee carries out (slit lamp and ophthalmoscopy).According to Dermatoxicology, F.N.Marzulli and H.I.Maibach, McDonald and Shadduck score-system described in 1977 " Eye Irritation, " T.O.McDonald and J.A.Shadduck (579-582 page) are marked to eye examination result.Use standardized data collection table record observed result.As follows for the Acceptable criterion of studying: conjunctival congestion and swelling score value≤1; Every other observation variable score value is 0.

Medication the previous day, the medication same day (the 1st day) and medication one day after (the 2nd day) in two eyes of each animal every day administered twice eyedrops of garamycin.Medication was carried out with two stages, and the first stage comprises a treated animal, and second stage comprises other animals.Before each medication stage, according to the Latin square of revising, animal is randomized in the treatment group of sheltering.At least fasting 8 hours of animal before injection.Record initial time and the inject time of fasting.

The animal of weighing is also used ketamine/xylazine mixture (87mg/mL ketamine, 13mg/mL xylazine) anesthetized animal of intravenous injection 0.1-0.2mL/kg volume.The following preparation for injection of eyes of each animal: injection precontract 5 minutes, with the moistening eye of povidone-iodine (Betadine) for eye.After five minutes, with Sterile Saline, povidone-iodine is washed out from eye.Each is sent to the proparacaine hydrochloride (Proparacaine hydrochloride) of 0.5% (1-2 drips).For by the eye of intravitreal injection, to each, send 1% tropicamide (Tropicamide) (1).

The 1st day, eyes ejection testing product or the reference substance of each animal.Animal in selected group was administration for the second time in 90th ± 1 day.Under conjunctiva or glass vivo medicine-feeding.Actual therapeutic, injection site and dose volume are sheltered, and disclose when research finishes.

Use insulin syringe and 30 specification x1/2 inch syringe needles to carry out subconjunctival injection.Use the bulbar conjunctiva in tweezers rising dorsotemporal quadrant.Test article is injected into space under conjunctiva.

Use insulin syringe and 30 specification x1/2 inch pins to carry out intravitreal injection.For each injection, by pin through abdomen-nose quadrant, limbus of corneae of eye after 2-3mm introduce, make the inclined-plane of pin point to lower and rear to, to avoid crystalline lens.In single bolus infusion mode, detection product are injected near retina in vitreous body.

Observe the mortality rate/sickness rate of animal twice every day.Be defined as the commercially available euthanasia solution of intravenous injection euthanasia for dying animal.Win eyes freezing being stored in-70 ℃ in the future possible assessment.If find animal dead before postmortem rigidity, win eyes freezing being stored in-70 ℃ in the future possible assessment.Occur to find that dead animal does not carry out necropsy after postmortem rigidity.

The animal of weighing at random before medication in the 1st day and before euthanasia.

In the time of 5th ± 1,30 ± 1,60 ± 1,90 ± 1 day, (in some modification on the more late date) carry out ophthalmology observation (slit lamp and an eye microscopy indirect review method) to all animals.Veterinary's ophthalmologists that observation You Jing committee authenticates carries out.For will, the animal of medication in 90th ± 1 day, carrying out ophthalmology observation before medication.According to Dermatoxicology, F.N.Marzulli and H.I.Maibach, 1977 " Eye Irritation; " McDonald described in T.O.McDonald and J.A.Shadduck (579-582 page) and Shadduck score-system are marked to ophthalmologic examination result, and use standardized data collection table record observed result.

Before necropsy, from each animal, whole blood sample (each sample 1-3mL) is collected in the vacutainer pipe containing EDTA.Each pipe is full of at least 2/3, and thoroughly mixes at least 30 seconds.Pipe freezing until transport on dry ice.

With the commercially available euthanasia solution of intravenous injection, make animal euthanasia.According to the standardization program of using in industry, carry out euthanasia.

For using the treatment group of placebo in vitreous body or under conjunctiva, all eyes of organizing each group from these are placed in Davidsons solution approximately 24 hours.After 24 hours, eye is transferred in 70% ethanol; The pathology that the veterinary pathologist that these eyeballs are authenticated by committee is sheltered are assessed.Record eye is placed in the time of Davidsons and the time of taking-up.

To with in test article vitreous body or the treatment group of medication under conjunctiva, freezing and carry out pharmacokinetics analysis at-70 ℃ from some eyes of each group.Residue eye from each group is placed in Davidsons solution approximately 24 hours.After 24 hours, eye is transferred in 70% ethanol; The histopathological evaluation that the veterinary pathologist that these eyeballs are authenticated by committee is sheltered.Record eye is placed in the time of Davidsons and the time of taking-up.

Carrying out the freezing sample of pharmacokinetics analysis dissects with disposable instrument.Every is used one group of instrument, then abandons.Sample thaws 1 to 2 minute to guarantee that tissue frost is around removed in room temperature.It is 4 quadrants that sclera is dissected, and takes out vitreous body.If high-visible nondispersive agglomerate (NDM) in vitreous body, is separated to vitreous body in two sections.Section with NDM is about Vitrea 2/3rds.The section with NDM is not apart from NDM Vitrea part farthest.Separated aqueous humor, crystalline lens, iris and cornea.Use tweezers to take out retina tela chorioidea and collect for analyzing.Conjunctiva is separated with sclera.

Various Tissues type is collected in the separated bottle of weighing in advance, then cover and manage and weigh.Organize bottle to be stored in-80 ℃ until analyze.

Use 32-O-de-methoxy rapamycin as interior mark, by high pressure liquid chromatography/tandem mass spectrum (HPLC/MS/MS), determine the sirolimus content of retina choroid, sclera, vitreous humor and anticoagulated whole blood.While observing NDM in vitreous body, containing vitreous body section and the vitreous body section that does not contain NDM of NDM, analyze respectively.

The mean treatment agent concentration of a period of time is for the representative time point of this time period of finger, the mean concentration of each time point.For example, if the time cycle is 30 days, mean concentration can be with the interval measurement of 5 days: for the mean concentration of the 5th day, should calculate the 5th day repeatedly average of measurement of concetration; For the mean concentration of the 10th day, should calculate the 10th day repeatedly average of measurement of concetration, etc.

In some modification, liquid preparation described herein can have have a feature hereinafter described in Vitrea body, send spectrum, wherein send spectrum for after liquid preparation being injected between lagophthalmos CSC, delivering therapeutic agents in body.To a non-limiting modification of sending spectrum in Vitrea body, be shown in Fig. 2.

After injection the 40th day time, in body, level can be approximately 70% with approximately between 100% the 20th day time after with respect to injection for average percent vitreous body level, and more through being everlasting approximately 80% and approximately between 90%.After injection the 40th day time, in body average percent vitreous body level with respect to injection after the 20th day time level can be greater than approximately 70%, and be more often greater than approximately 80%.

After injection the 67th day time, in body average percent vitreous body level with respect to injection after level the 20th day time can be approximately 75% with approximately between 115%, and more through being everlasting approximately 85% and approximately between 105%.Injection is in the time of latter the 67th day, and in body, with respect to injection, the level in the time of latter the 20th day can be greater than approximately 75% to average percent vitreous body level, and is more often greater than approximately 85%.

After injection the 90th day time, in body average percent vitreous body level with respect to injection after level the 20th day time can be approximately 20% with approximately between 50%, and more through being everlasting approximately 30% and approximately between 40%.Injection is in the time of latter the 90th day, and in body, with respect to injection, the level in the time of latter the 20th day can be greater than approximately 20% to average percent vitreous body level, and is more often greater than approximately 30%.

In some modification, in body average percent vitreous body level with respect to injection after the 20th day performance level there is following characteristics: after injection the 40th day, it was less than approximately 100%; After injection the 67th day its be less than approximately 115%; With injection after the 90th day its be less than approximately 50%.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, cause after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 0.01ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 0.1ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 1ng/mL.

In some modification, liquid preparation described herein can have have a following characteristics in retinochoroid body, send spectrum, while wherein sending spectrum, after liquid preparation being injected between lagophthalmos CSC, in body, delivering therapeutic agents sends spectrum.

After injection the 40th day time, in body, performance level can be approximately 350% with approximately between 410% the 20th day time after with respect to injection for average percent retina choroid level, and more through being everlasting approximately 360% and approximately between 400%.After injection the 40th day time, in body average percent retina choroid level with respect to injection after the 20th day time performance level can be greater than approximately 350%, and be more often greater than approximately 360%.

After injection the 67th day time, in body, performance level can be approximately 125% with approximately between 165% the 20th day time after with respect to injection for average percent retina choroid level, and more through being everlasting approximately 135% and approximately between 155%.After injection the 67th day time, in body average percent retina choroid level with respect to injection after the 20th day time performance level can be greater than approximately 125%, and be more often greater than approximately 135%.

After injection the 90th day time, in body, performance level can be approximately 10% with approximately between 50% the 20th day time after with respect to injection for average percent retina choroid level, and more through being everlasting approximately 20% and approximately between 40%.After injection the 90th day time, in body average percent retina choroid level with respect to injection after the 20th day time performance level can be greater than approximately 10%, and be more often greater than approximately 20%.

In some modification, in body average percent retina choroid level with respect to injection after the 20th day performance level there is following characteristics: after injection the 40th day, it was less than approximately 410%; After injection the 67th day its be less than approximately 165%; With injection after the 90th day its be less than approximately 50%.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in 90Tian Nei retina in rabbits tela chorioidea at least about the therapeutic agent mean concentration of 0.001ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos glass retina tela chorioidea in 90 days at least about the therapeutic agent mean concentration of 0.01ng/mL.

In some modification, first the level for the treatment of agent existing in retina tela chorioidea rises, and then reaches peak value and reduces.Peak value can for example occur for the approximately the 40th day after injection.

In some modification, liquid preparation described herein can have has sclera in the body of following characteristics to remove spectrum, and wherein removing spectrum is the removing spectrum of removing in the body of therapeutic agent after liquid preparation is injected between lagophthalmos CSC.While being injected between CSC, think that sclera level comprises injected liquid preparation.

After injection the 40th day time, in body, performance level can be approximately 150% with approximately between 230% the 20th day time after with respect to injection for average percent sclera level, and more through being everlasting approximately 170% and approximately between 210%.After injection the 40th day time, in body average percent sclera level with respect to injection after the 20th day time performance level can be greater than approximately 150%, and be more often greater than approximately 170%.

After injection the 67th day time, in body, performance level can be approximately 30% with approximately between 70% the 20th day time after with respect to injection for average percent sclera level, and more through being everlasting approximately 40% and approximately between 60%.After injection the 67th day time, in body average percent sclera level with respect to injection after the 20th day time performance level can be greater than approximately 30%, and be more often greater than approximately 40%.

After injection the 90th day time, in body, performance level can be approximately 110% with approximately between 160% the 20th day time after with respect to injection for average percent sclera level, and more through being everlasting approximately 125% and approximately between 145%.After injection the 90th day time, in body average percent sclera level with respect to injection after the 20th day time performance level can be greater than approximately 110%, and be more often greater than approximately 125%.

In some modification, in body average percent sclera level with respect to injection after the 20th day performance level there is following characteristics: after injection the 40th day, it was less than approximately 230%; After injection the 67th day its be less than approximately 70%; With injection after the 90th day its be less than approximately 160%.

In some modification, first the level for the treatment of agent existing in sclera rises, and then reaches peak value and reduces.Peak value can for example occur for the approximately the 40th day after injection.

In some modification, liquid preparation described herein can have have a following characteristics in Vitrea body, send spectrum, wherein sending spectrum is after liquid preparation being injected between lagophthalmos CSC, in body, delivering therapeutic agents sends spectrum.

After injection the 14th day time, in body, performance level can be approximately 1350% with approximately between 1650% the 2nd day time after with respect to injection for average percent vitreous body level, and more through being everlasting approximately 1450% and approximately between 1550%.After injection the 14th day time, in body average percent vitreous body level with respect to injection after the 2nd day time performance level can be greater than approximately 1350%, and be more often greater than approximately 1450%.

After injection the 35th day time, in body, performance level can be approximately 200% with approximately between 300% the 2nd day time after with respect to injection for average percent vitreous body level, and more through being everlasting approximately 225% and approximately between 275%.After injection the 35th day time, in body average percent vitreous body level with respect to injection after the 2nd day time performance level can be greater than approximately 200%, and be more often greater than approximately 225%.

After injection the 62nd day time, in body, performance level can be approximately 100% with approximately between 160% the 2nd day time after with respect to injection for average percent vitreous body level, and more through being everlasting approximately 115% and approximately between 145%.After injection the 62nd day time, in body average percent vitreous body level with respect to injection after the 2nd day time performance level can be greater than approximately 100%, and be more often greater than approximately 115%.

After injection the 85th day time, in body, performance level can be approximately 5% with approximately between 30% the 2nd day time after with respect to injection for average percent vitreous body level, and more through being everlasting approximately 10% and approximately between 25%.After injection the 85th day time, in body average percent vitreous body level with respect to injection after the 2nd day time performance level can be greater than approximately 5%, and be more often greater than approximately 10%.

In some modification, in body average percent vitreous body level with respect to injection after the 2nd day performance level there is following characteristics: after injection the 14th day, it was less than approximately 1600%; After injection the 35th day its be less than approximately 300%; After injection the 62nd day its be less than approximately 160% and injection after the 85th day its be less than approximately 30%.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos vitreous body in 85 days at least about the therapeutic agent mean concentration of 0.01ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos vitreous body in 85 days at least about the therapeutic agent mean concentration of 0.1ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about in lagophthalmos vitreous body in 60 days at least about the therapeutic agent mean concentration of 1ng/mL.

In some modification, first the level for the treatment of agent existing in vitreous body rises, and then reaches peak value and reduces.Peak value can for example occur for the approximately the 14th day after injection.

In some modification, liquid preparation described herein can have have a following characteristics in retinochoroid body, send spectrum, wherein sending spectrum is after liquid preparation being injected between lagophthalmos CSC, in body, delivering therapeutic agents sends spectrum.

After injection the 35th day time, in body, performance level can be approximately 320% with approximately between 400% the 14th day time after with respect to injection for average percent retina choroid level, and more through being everlasting approximately 340% and approximately between 380%.After injection the 35th day time, in body average percent retina choroid level with respect to injection after the 14th day time performance level can be greater than approximately 320%, and be more often greater than approximately 340%.

After injection the 62nd day time, in body, performance level can be approximately 3% with approximately between 25% the 14th day time after with respect to injection for average percent retina choroid level, and more through being everlasting approximately 6% and approximately between 20%.After injection the 62nd day time, in body average percent retina choroid level with respect to injection after the 14th day time performance level can be greater than approximately 3%, and be more often greater than approximately 6%.

After injection the 85th day time, in body, performance level can be approximately 0.1% with approximately between 6% the 14th day time after with respect to injection for average percent retina choroid level, and more through being everlasting approximately 0.5% and approximately between 4%.After injection the 85th day time, in body average percent retina choroid level with respect to injection after the 14th day time performance level can be greater than approximately 0.1%, and be more often greater than approximately 0.5%.

In some modification, in body average percent retina choroid level with respect to injection after the 14th day performance level there is following characteristics: after injection the 35th day, it was less than approximately 400%; After injection the 62nd day its be less than approximately 25%; With injection after the 85th day its be less than approximately 6%.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in 85Tian Nei retina in rabbits tela chorioidea at least about the therapeutic agent mean concentration of 0.001ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in 85Tian Nei retina in rabbits tela chorioidea at least about the therapeutic agent mean concentration of 0.01ng/mL.

In some modification, liquid preparation described herein can have has sclera in the body of following characteristics to remove spectrum, and wherein removing spectrum is the removing spectrum of removing in the body of therapeutic agent after liquid preparation is injected between lagophthalmos CSC.While being injected between CSC, think that sclera level comprises injected liquid preparation.

After injection the 35th day time, in body, performance level can be approximately 0.1% with approximately between 0.7% the 14th day time after with respect to injection for average percent sclera level, and more through being everlasting approximately 0.2% and approximately between 0.6%.After injection the 35th day time, in body average percent sclera level with respect to injection after the 14th day time performance level can be greater than approximately 0.1%, and be more often greater than approximately 0.2%.

After injection the 62nd day time, in body, performance level can be approximately 0.05% with approximately between 0.35% the 14th day time after with respect to injection for average percent sclera level, and more through being everlasting approximately 0.07% and approximately between 0.3%.After injection the 62nd day time, in body average percent sclera level with respect to injection after the 14th day time performance level can be greater than approximately 0.05%, and be more often greater than approximately 0.07%.

After injection the 85th day time, in body, performance level can be approximately 0.1% with approximately between 0.9% the 14th day time after with respect to injection for average percent sclera level, and more through being everlasting approximately 0.3% and approximately between 0.7%.After injection the 85th day time, in body average percent sclera level with respect to injection after the 14th day time performance level can be greater than approximately 0.1%, and be more often greater than approximately 0.3%.

In some modification, in body average percent sclera level with respect to injection after the 14th day time performance level there is following characteristics: after injection the 35th day, it was less than approximately 0.7%; After injection the 62nd day its be less than approximately 0.35%; With injection latter 85 days its be less than approximately 0.9%.

In some modification, liquid preparation described herein can have has vitreous body in the body of following characteristics to remove spectrum, wherein removes the removing spectrum of removing in the body of spectrum for therapeutic agent after liquid preparation is injected in lagophthalmos vitreous body.While being injected in vitreous body, think that measured vitreous body level comprises injected preparation.

After injection the 35th day time, in body, performance level can be approximately 1% with approximately between 40% the 14th day time after with respect to injection for average percent vitreous body level, and more through being everlasting approximately 1% and approximately between 10%.After injection the 35th day time, in body average percent vitreous body level with respect to injection after the 14th day time performance level can be greater than approximately 1%.

After injection the 62nd day time, in body, performance level can be approximately 1% with approximately between 40% the 14th day time after with respect to injection for average percent vitreous body level, and more through being everlasting approximately 5% and approximately between 25%.After injection the 62nd day time, in body average percent vitreous body level with respect to injection after the 14th day time performance level can be greater than approximately 1%, and more often with respect to after injection the 14th day time performance level be greater than approximately 5%.

After injection the 90th day time, in body, performance level can be approximately 1% with approximately between 40% the 14th day time after with respect to injection for average percent vitreous body level, and more through being everlasting approximately 10% and approximately between 30%.After injection the 90th day time, in body average percent vitreous body level with respect to injection after the 14th day time performance level can be greater than approximately 1%, and more often with respect to after injection the 14th day time performance level be greater than approximately 10%.

In some modification, first the level for the treatment of agent existing in vitreous body rises, and then reaches peak value and reduces.Peak value can for example occur for the approximately the 14th day after injection.

In some modification, liquid preparation described herein can have have a following characteristics in retinochoroid body, send spectrum, wherein sending spectrum is liquid preparation to be injected into after lagophthalmos vitreous body, in body, delivering therapeutic agents sends spectrum.

After injection the 35th day time, in body, performance level can be approximately 3400% with approximately between 5100% the 14th day time after with respect to injection for average percent retina choroid level, and more through being everlasting approximately 3750% and approximately between 4750%.After injection the 35th day time, in body average percent retina choroid level with respect to injection after the 14th day time performance level can be greater than approximately 3400%, and be more often greater than approximately 3750%.

While injecting latter 62 days, performance level can be approximately 0.1% with approximately between 5% the 14th day time after with respect to injection for average percent retina choroid level in body, and more through being everlasting approximately 1% and approximately between 3%.After injection the 62nd day time, in body average percent retina choroid level with respect to injection after the 14th day time performance level can be greater than approximately 0.1%, and be more often greater than approximately 1%.

While injecting latter 90 days, performance level can be approximately 10% with approximately between 50% the 14th day time after with respect to injection for average percent retina choroid level in body, and more through being everlasting approximately 20% and approximately between 40%.After injection the 90th day time, in body average percent retina choroid level with respect to injection after the 14th day time performance level can be greater than approximately 10%, and be more often greater than approximately 20%.

In some modification, in body average percent retina choroid level with respect to injection after the 14th day performance level there is following characteristics: after injection the 35th day, it was less than approximately 5100%; After injection the 62nd day its be less than approximately 5%; With injection after the 90th day its be less than approximately 50%.

In some modification, liquid preparation described herein can have have a following characteristics in the body of sclera, send spectrum, wherein send spectrum for after liquid preparation being injected in lagophthalmos vitreous body, in body, delivering therapeutic agents sends spectrum.

After injection the 35th day time, in body, performance level can be approximately 1700% with approximately between 2600% the 14th day time after with respect to injection for average percent sclera level, and more through being everlasting approximately 1900% and approximately between 2400%.After injection the 35th day time, in body average percent sclera level with respect to injection after the 14th day time performance level can be greater than approximately 1700%, and be more often greater than approximately 1900%.

After injection the 62nd day time, in body, performance level can be approximately 120% with approximately between 180% the 14th day time after with respect to injection for average percent sclera level, and more through being everlasting approximately 140% and approximately between 160%.After injection the 62nd day time, in body average percent sclera level with respect to injection after the 14th day time performance level can be greater than approximately 120%, and be more often greater than approximately 140%.

After injection the 90th day time, in body, performance level can be approximately 95% with approximately between 155% the 14th day time after with respect to injection for average percent sclera level, and more through being everlasting approximately 115% and approximately between 135%.After injection the 90th day time, in body average percent sclera level with respect to injection after the 14th day time performance level can be greater than approximately 95%, and be more often greater than approximately 115%.

In some modification, in body average percent sclera level with respect to injection after the 14th day time performance level there is following characteristics: after injection the 35th day, it was less than approximately 2600%; After injection the 62nd day its be less than approximately 180%; With injection latter 90 days its be less than approximately 155%.

In some modification, delivering therapeutic agents when liquid preparation is injected into lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos sclera in 90 days at least about the therapeutic agent mean concentration of 0.001ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected into lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos sclera in 90 days at least about the therapeutic agent mean concentration of 0.01ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected into lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos sclera in 90 days at least about the therapeutic agent mean concentration of 0.1ng/mL.

In some modification, first the level for the treatment of agent existing in vitreous body rises, and then reaches peak value and reduces.Peak value can for example occur for the approximately the 35th day after injection.

In some modification, in-situ gelling preparation described herein can have have a following characteristics in Vitrea body, send spectrum, wherein send spectrum for after liquid preparation being injected between lagophthalmos CSC, in body, delivering therapeutic agents sends spectrum.

After injection the 32nd day time, in body, performance level can be approximately 25% with approximately between 85% the 7th day time after with respect to injection for average percent vitreous body level, and more through being everlasting approximately 45% and approximately between 65%.After injection the 40th day time, in body average percent vitreous body level with respect to injection after the 7th day time performance level can be greater than approximately 25%, and be more often greater than approximately 45%.

After injection the 45th day time, in body, performance level can be approximately 2% with approximately between 50% the 7th day time after with respect to injection for average percent vitreous body level, and more through being everlasting approximately 8% and approximately between 20%.After injection the 67th day time, in body average percent vitreous body level with respect to injection after the 7th day time performance level can be greater than approximately 2%, and be more often greater than approximately 5%.

After injection the 90th day time, in body, performance level can be approximately 40% with approximately between 100% the 7th day time after with respect to injection for average percent vitreous body level, and more through being everlasting approximately 60% and approximately between 80%.After injection the 90th day time, in body average percent vitreous body level with respect to injection after the 7th day time performance level can be greater than approximately 40%, and be more often greater than approximately 60%.

In some modification, in body average percent vitreous body level with respect to injection after the 7th day performance level there is following characteristics: after injection the 32nd day, it was less than approximately 80%; After injection the 45th day its be less than approximately 30%; With injection after the 90th day its be less than approximately 100%.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 0.1pg/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 0.01ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 0.1ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 1ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 10ng/mL.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtains after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days in lagophthalmos vitreous body at least therapeutic agent mean concentration of 0.001ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days, at least about 90 days or at least about the therapeutic agent mean concentration of 0.01ng/mL at least in lagophthalmos vitreous body in 120 days.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtains after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days in lagophthalmos vitreous body at least therapeutic agent mean concentration of 0.1ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtains after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days in lagophthalmos vitreous body at least therapeutic agent mean concentration of 0.5ng/mL.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtains after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration between 0.001ng/mL and 10.0ng/mL in lagophthalmos vitreous body.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtains after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration between 0.01ng/mL and 10.0ng/mL in lagophthalmos vitreous body.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtains after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration between 0.1ng/mL and 10ng/mL in lagophthalmos vitreous body.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtains after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration between 0.5ng/mL and 10.0ng/mL in lagophthalmos vitreous body.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of the maximum mean concentration of lagophthalmos vitreous body internal therapy agent and lagophthalmos vitreous body internal therapy agent minimum average B configuration concentration is less than 100.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of the maximum mean concentration of lagophthalmos vitreous body internal therapy agent and lagophthalmos vitreous body internal therapy agent minimum average B configuration concentration is less than 50.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of the maximum mean concentration of lagophthalmos vitreous body internal therapy agent and lagophthalmos vitreous body internal therapy agent minimum average B configuration concentration is less than 10.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of the maximum mean concentration of lagophthalmos vitreous body internal therapy agent and lagophthalmos vitreous body internal therapy agent minimum average B configuration concentration is less than 5.

" roughly constant " used herein is to say that in the time period extending average level is not greater than the change of a magnitude, and mean concentration maximum and the difference between minima that in correlation time section, different time is measured are less than 10 times.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after solution is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos vitreous body internal therapy agent is roughly constant at the numerical value place that is greater than 0.001ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos vitreous body internal therapy agent is roughly constant at the numerical value place that is greater than 0.01ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after solution is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos vitreous body internal therapy agent is roughly constant at the numerical value place that is greater than 0.1ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos vitreous body internal therapy agent is roughly constant at the numerical value place of 1.0ng/mL.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration of 0.001ng/mg at least in retina in rabbits tela chorioidea.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration of 0.005ng/mg at least in retina in rabbits tela chorioidea.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration of 0.01ng/mg at least in retina in rabbits tela chorioidea.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.001ng/mg and 1.0ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.001ng/mg and 0.50ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.001ng/mg and 0.15ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.001ng/mg and 0.1ng/mg.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.005ng/mg and 1.0ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.005ng/mg and 0.50ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.005ng/mg and 0.15ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.005ng/mg and 0.1ng/mg.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.01ng/mg and 1.0ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.01ng/mg and 0.50ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.01ng/mg and 0.15ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.01ng/mg and 0.1ng/mg.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of the maximum mean concentration of retina in rabbits tela chorioidea internal therapy agent and retina in rabbits tela chorioidea internal therapy agent minimum average B configuration concentration is less than 100.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of the maximum mean concentration of retina in rabbits tela chorioidea internal therapy agent and retina in rabbits tela chorioidea internal therapy agent minimum average B configuration concentration is less than 50.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of the maximum mean concentration of retina in rabbits tela chorioidea internal therapy agent and retina in rabbits tela chorioidea internal therapy agent minimum average B configuration concentration is less than 10.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of the maximum mean concentration of retina in rabbits tela chorioidea internal therapy agent and retina in rabbits tela chorioidea internal therapy agent minimum average B configuration concentration is less than 5.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of retina in rabbits tela chorioidea internal therapy agent is roughly constant at the numerical value place that is greater than 0.001ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of retina in rabbits tela chorioidea internal therapy agent is roughly constant at the numerical value place that is greater than 0.005ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of retina in rabbits tela chorioidea internal therapy agent is roughly constant at the numerical value place that is greater than 0.01ng/mg.

In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration of 100ng/mL at least in lagophthalmos vitreous body.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration of 1000ng/mL at least in lagophthalmos vitreous body.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days, in lagophthalmos vitreous body at least 10, the therapeutic agent mean concentration of 000ng/mL.

In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in lagophthalmos vitreous body between 100ng/mL and 100,000ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in lagophthalmos vitreous body between 100ng/mL and 50,000ng/mL.

In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in lagophthalmos vitreous body between 1000ng/mL and 100,000ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in lagophthalmos vitreous body between 1000ng/mL and 50,000ng/mL.

In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of the maximum mean concentration of lagophthalmos vitreous body internal therapy agent and lagophthalmos vitreous body internal therapy agent minimum average B configuration concentration is less than 100.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of the maximum mean concentration of lagophthalmos vitreous body internal therapy agent and lagophthalmos vitreous body internal therapy agent minimum average B configuration concentration is less than 50.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of the maximum mean concentration of lagophthalmos vitreous body internal therapy agent and lagophthalmos vitreous body internal therapy agent minimum average B configuration concentration is less than 10.

In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos vitreous body internal therapy agent is roughly constant at the numerical value place that is greater than 100ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos vitreous body internal therapy agent is roughly constant at the numerical value place that is greater than 1000ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos vitreous body internal therapy agent is roughly constant at the numerical value place that is greater than 10,000ng/mL.

In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration of 0.001ng/mg at least in retina in rabbits tela chorioidea.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration of 0.01ng/mg at least in retina in rabbits tela chorioidea.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration of 0.05ng/mg at least in retina in rabbits tela chorioidea.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration of 0.10ng/mg at least in retina in rabbits tela chorioidea.

In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.001ng/mg and 10.00ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.001ng/mg and 5.00ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.001ng/mg and 1.00ng/mg.

In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.01ng/mg and 10.00ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.01ng/mg and 5.00ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.01ng/mg and 1.00ng/mg.

In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.05ng/mg and 10.00ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.05ng/mg and 5.00ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.05ng/mg and 1.00ng/mg.

In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.10ng/mg and 10.00ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.10ng/mg and 5.00ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days the therapeutic agent mean concentration in retina in rabbits tela chorioidea between 0.10ng/mg and 1.00ng/mg.

In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of the maximum mean concentration of retina in rabbits tela chorioidea internal therapy agent and retina in rabbits tela chorioidea internal therapy agent minimum average B configuration concentration is less than 100.In some modification, delivering therapeutic agents when liquid preparation is injected in lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of the maximum mean concentration of retina in rabbits tela chorioidea internal therapy agent and retina in rabbits tela chorioidea internal therapy agent minimum average B configuration concentration is less than 50.

In some modification, in-situ gelling preparation described herein can have have a following characteristics in the body of retina tela chorioidea, send spectrum, wherein send spectrum for after liquid preparation being injected between lagophthalmos CSC, in body, delivering therapeutic agents sends spectrum.

After injection the 32nd day time, in body, performance level can be approximately 20% with approximately between 80% the 7th day time after with respect to injection for percentage ratio vitreous body level, and more through being everlasting approximately 40% and approximately between 60%.After injection the 40th day time, in body percentage ratio vitreous body level with respect to injection after the 7th day time performance level can be greater than approximately 20%, and be more often greater than approximately 40%.

After injection the 45th day time, in body, performance level can be approximately 15% with approximately between 55% the 7th day time after with respect to injection for percentage ratio vitreous body level, and more through being everlasting approximately 25% and approximately between 45%.After injection the 67th day time, in body percentage ratio vitreous body level with respect to injection after the 7th day time performance level can be greater than approximately 15%, and be more often greater than approximately 25%.

After injection the 90th day time, in body, performance level can be approximately 60% with approximately between 100% the 7th day time after with respect to injection for percentage ratio vitreous body level, and more through being everlasting approximately 70% and approximately between 90%.After injection the 90th day time, in body percentage ratio vitreous body level with respect to injection after the 7th day time performance level can be greater than approximately 60%, and be more often greater than approximately 70%.

In some modification, in body percentage ratio vitreous body level with respect to injection after the 7th day performance level there is following characteristics: after injection the 32nd day, it was less than approximately 80%; After injection the 45th day its be less than approximately 60%; With injection after the 90th day its be less than approximately 100%.

In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in 90Tian Nei retina in rabbits tela chorioidea at least about the therapeutic agent mean concentration of 0.1pg/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 0.01ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 0.1ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 1ng/mg.

In some modification, by in-situ gelling preparation be placed in eye or eye near after, the average level of retina tela chorioidea, sclera and Vitrea two or more middle therapeutic agents take ten ratios as end logarithm prolongation time period in roughly constant.In some modification, by in-situ gelling preparation be placed in eye CSC between after, in two or more retina tela chorioideas, sclera and vitreous body the average level of therapeutic agent take ten ratios as end logarithm prolongation time period in roughly constant.In some modification, after in-situ gelling preparation is placed between eye sclera and conjunctiva, in vitreous body and sclera, to take ten ratios as end logarithm roughly constant in the time period extending for the average level of therapeutic agent.

In some modification, in vitreous body and retina tela chorioidea, to take ten ratios as end logarithm roughly constant in the time period extending for the average level of therapeutic agent.In other words, while considering with logarithmic scale, when vitreous body internal therapy agent level rises, in retina tela chorioidea, the level of therapeutic agent rises to similar degree, and vice versa.

In some modification, in vitreous body contrast retina tela chorioidea, to take ten ratios as end logarithm roughly constant in the time period of the prolongation of approximately 7 days, approximately 30 days, approximately 60 days or approximately 90 days for the average level of therapeutic agent.In some modification, after in-situ gelling preparation is placed between eye sclera and conjunctiva, vitreous body internal therapy agent average level is constant at the 7th day with respect to the ratio of therapeutic agent average level in retina tela chorioidea is approximately 37: 1, the 32nd day approximately 40: 1, the 45th day approximately 10: 1 and the 90th day approximately 34: 1.

In some modification, vitreous body internal therapy agent average level is constant when approximately 7 days, approximately 32 days, approximately 45 days or approximately 90 days with respect to the ratio of therapeutic agent average level in retina tela chorioidea is approximately 40: 1.

In some modification, after in-situ gelling preparation is placed near ophthalmic or eye, in retina tela chorioidea, sclera and vitreous body, any or all of middle therapeutic agent average level is roughly constant in the time period extending.

In some modification, after in-situ gelling preparation is placed between CSC, the average level of vitreous body internal therapy agent is roughly constant at about 8.1ng/ml.In some modification, after in-situ gelling preparation is placed between CSC, the average level of retina tela chorioidea internal therapy agent is roughly constant at about 0.25ng/mg.In some modification, after in-situ gelling preparation is placed between CSC, the mean concentration of sclera internal therapy agent is roughly constant at about 1930ng/mg.

In some modification, while being injected between lagophthalmos CSC in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.1pg/mL place at least about the average level that maintains the agent of lagophthalmos vitreous body internal therapy for 90 days.In some modification, while being injected between lagophthalmos CSC in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.001ng/mL place at least about the average level that maintains the agent of lagophthalmos vitreous body internal therapy for 90 days.In some modification, while being injected between lagophthalmos CSC in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.01ng/mL place at least about the average level that maintains the agent of lagophthalmos vitreous body internal therapy for 90 days.In some modification, while being injected between lagophthalmos CSC in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.1ng/mL place at least about the average level that maintains the agent of lagophthalmos vitreous body internal therapy for 90 days.In some modification, while being injected between lagophthalmos CSC in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 1ng/mL place at least about the average level that maintains the agent of lagophthalmos vitreous body internal therapy for 90 days.In some modification, while being injected between lagophthalmos CSC in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 10ng/mL place at least about the average level that maintains the agent of lagophthalmos vitreous body internal therapy for 90 days.In some modification, while being injected between lagophthalmos CSC in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 100ng/mL place at least about the average level that maintains the agent of lagophthalmos vitreous body internal therapy for 90 days.

In some modification, while being injected between lagophthalmos CSC, in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.1pg/mg place at least about the average level that maintains the internal therapy agent of retina tela chorioidea for 90 days.In some modification, while being injected between lagophthalmos CSC, in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.001ng/mg place at least about the average level that maintains the internal therapy agent of retina tela chorioidea for 90 days.In some modification, while being injected between lagophthalmos CSC, in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.01ng/mg place at least about the average level that maintains the internal therapy agent of retina tela chorioidea for 90 days.In some modification, while being injected between lagophthalmos CSC, in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.1ng/mg place at least about the average level that maintains the internal therapy agent of retina tela chorioidea for 90 days.In some modification, while being injected between lagophthalmos CSC, in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 1ng/mg place at least about the average level that maintains the internal therapy agent of retina tela chorioidea for 90 days.In some modification, while being injected between lagophthalmos CSC, in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 10ng/mg place at least about the average level that maintains the internal therapy agent of retina tela chorioidea for 90 days.

In some modification, while being injected between lagophthalmos CSC, in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.1pg/mg place at least about the average level that maintains the agent of sclera internal therapy for 90 days.In some modification, while being injected between lagophthalmos CSC, in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.001ng/mg place at least about the average level that maintains the agent of sclera internal therapy for 90 days.In some modification, while being injected between lagophthalmos CSC, in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.01ng/mg place at least about the average level that maintains the agent of sclera internal therapy for 90 days.In some modification, while being injected between lagophthalmos CSC, in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.1ng/mg place at least about the average level that maintains the agent of sclera internal therapy for 90 days.In some modification, while being injected between lagophthalmos CSC, in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 1ng/mg place at least about the average level that maintains the agent of sclera internal therapy for 90 days.In some modification, while being injected between lagophthalmos CSC, in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 10ng/mg place at least about the average level that maintains the agent of sclera internal therapy for 90 days.In some modification, while being injected between lagophthalmos CSC, in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 100ng/mg place at least about the average level that maintains the agent of sclera internal therapy for 90 days.In some modification, while being injected between lagophthalmos CSC, in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at approximately 1 μ g/mg place at least about the average level that maintains the agent of sclera internal therapy for 90 days.In some modification, while being injected between lagophthalmos CSC, in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at approximately 10 μ g/mg places at least about the average level that maintains the agent of sclera internal therapy for 90 days.

In order to treat, prevent, suppress, to postpone the generation of some disease or disease or it being disappeared, can be desirably in the therapeutic agent that maintains delivery treatments effective dose in time period of prolongation.Based on treating, prevent, suppress, postpone its generation or making its disease disappearing or disease, the time period of this prolongation can be at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 3 months, at least about 6 months, at least about 9 months or at least about 1 year.Yet the Delivery time of common any prolongation can be possible.The therapeutic agent for the treatment of effective dose can be sent the time of prolongation by liquid preparation or compositions, described liquid preparation or compositions within the time extending, maintain experimenter or experimenter's eye in the concentration of therapeutic agent, described concentration is the therapeutic agent of delivery treatments effective dose within the time extending enough.

Within the time extending, the therapeutic agent of delivery treatments effective dose can pass through to place a kind of compositions or liquid preparation, or completes by applying compositions or the liquid preparation of two or more dosage.The limiting examples of repeatedly applying as this class, the therapeutic dose of rapamycin is maintained and within three months, be used for the treatment of, prevent, suppress, postpone the generation of moist AMD or it is disappeared to pass through application delivery treatments amount a kind of liquid preparation or the compositions of 3 months, or complete by order application plurality of liquid preparation or compositions.Optimal dose strategy will depend on the therapeutic dose of the therapeutic agent that need to be delivered, and its time that need to be delivered.The technical staff that administration field is sent in extended treatment agent can understand how based on instruction herein, to determine spendable administration strategy.

When using some therapeutic agent or being used for the treatment of, preventing, suppressing, postponing the generation of some disease or it is disappeared, in the time of can expecting liquid preparation or compositions to be placed in a region, sending of therapeutic agent do not get started, but starts after some delay to send.For example (but not limiting), when therapeutic agent suppresses or postpones wound healing, and the release that need to be delayed produce while making to place liquid preparation or compositions any wound healing time, the release that this class is delayed can be useful.According to the therapeutic agent being delivered and/or be treated, prevent, suppress, postpone its generation or make its disease disappearing and disease, it can be approximately 1 hour, approximately 6 hours, approximately 12 hours, approximately 18 hours, approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, approximately 7 days, approximately 8 days, approximately 9 days, approximately 10 days, approximately 11 days, approximately 12 days, approximately 13 days, approximately 14 days, approximately 21 days, approximately 28 days, approximately 35 days or approximately 42 days that therapeutic agent delivery starts front period of delay.Also can be possible other period of delay.Spendable delayed release preparation is that to be proficient in the personnel of this technology known.

In vitreous body and under conjunctiva, sending rapamycin is used for the treatment of, prevents, suppresses, postpones AMD generation or it is disappeared

In a kind of method described herein, by sending or send under the liquid preparation conjunctiva that comprises rapamycin in vitreum, with treatment, prevention, inhibition, delay eye medium vessels, occur or it is disappeared, include but are not limited to treatment as the CNV observing in AMD.In some modification, use liquid preparation treatment eye medium vessels to occur, the CNV that includes but are not limited to treatment as observe in AMD.Rapamycin has been presented in rabbit and mouse model and has suppressed CNV, described in U. S. application number 10/665,203, quotes its integral body as a reference herein.Observed and when rapamycin is used under systemic administration and retina, suppressed Matrigel ^tMcNV with induced with laser.In addition, periocular injections rapamycin suppresses the CNV of induced with laser.

Can be delivered to eye (particularly vitreum) and be used for the treatment of, prevent, suppress, postpone the generation of eye angiogenesis (as CNV) or make its other therapeutic agent disappearing for the limus family compound except rapamycin, include but are not limited to everolimus and tacrolimus (FK-506).

As described herein, the dosage of therapeutic agent depends on handled disease (no matter this disease will be treated, and prevent, suppresses, postpones its generation or it is disappeared), concrete therapeutic agent and other clinical factor, as the approach of experimenter's body weight and situation and administering therapeutic agent.Should understand that methods described herein, liquid preparation and compositions can be used for people and veterinary purpose and for other possible animal.As described herein, the tissue concentration of the therapeutic agent of expressing with the unit of mass/volume typically refers to the tissue that is essentially aqueous, as vitreous body.The tissue concentration of the therapeutic agent of expressing with mass/mass unit typically refers to other tissue, for example sclera or retina tela chorioidea.

Can be used for a kind of rapamycin concentrations of methods described herein for providing about 0.01pg/ml or pg/mg or more rapamycins to organize the concentration of level.Operable another concentration is for providing about 0.1pg/ml or ng/mg or more concentration organizing in level.Operable another concentration is for organizing the concentration that about 1pg/ml or ng/mg or more rapamycins are provided in level.Operable another concentration is for providing about 0.01ng/ml or ng/mg or more concentration organizing in level.Operable another concentration is for providing about 0.1ng/ml or ng/mg or more concentration organizing in level.Operable another concentration is for providing about 0.5ng/ml or ng/mg or more concentration organizing in level.Operable another concentration is for providing about 1ng/ml or more concentration organizing in level.Operable another concentration is for providing about 2ng/ml or more concentration organizing in level.Operable another concentration is for providing about 3ng/ml or more concentration organizing in level.Operable another concentration is for providing about 5ng/ml or more concentration organizing in level.Operable another concentration is for providing about 10ng/ml or more concentration organizing in level.Operable another concentration is for providing about 15ng/ml or more concentration organizing in level.Operable another concentration is for providing about 20ng/ml or more concentration organizing in level.Operable another concentration is for providing about 30ng/ml or more concentration organizing in level.Operable another concentration is for providing about 50ng/ml or more concentration organizing in level.Those skilled in the art can know how according to used route of administration and persistent period, to reach suitable concentration according to instruction herein.

The amount of the rapamycin of usually, using in liquid preparation is in required time quantum, enough to treat, prevent, suppress, postpone the amount that ophthalmic or disease occur or it is disappeared.In some modification, the amount of the rapamycin of using in liquid preparation is the amount of ophthalmic or disease of enough treating in required time quantum.

In some modification, under conjunctiva, use the rapamycin that is less than about 5mg total amount.In some modification, under conjunctiva, use the rapamycin that is less than about 5.0mg total amount.In some modification, under conjunctiva, use the rapamycin that is less than about 4.5mg total amount.In some modification, under conjunctiva, use the rapamycin that is less than about 4.0mg total amount.In some modification, under conjunctiva, use the rapamycin that is less than about 3.5mg total amount.In some modification, under conjunctiva, use the rapamycin that is less than about 3.0mg total amount.In some modification, under conjunctiva, use the rapamycin that is less than about 2.5mg total amount.In some modification, under conjunctiva, use the rapamycin that is less than about 2mg total amount.In some modification, under conjunctiva, use the rapamycin that is less than about 1.2mg total amount.In some modification, under conjunctiva, use the rapamycin that is less than about 1.0mg total amount.In some modification, under conjunctiva, use the rapamycin that is less than about 0.8mg total amount.In some modification, under conjunctiva, use the rapamycin that is less than about 0.6mg total amount.In some modification, under conjunctiva, use the rapamycin that is less than about 0.4mg total amount.In some modification, use the volumes of formulation that comprises rapamycin amount described herein.

In some modification, by using between approximately 0.1 μ l and approximately 200 μ l liquid preparation described herein to using under people experimenter's conjunctiva containing accounting for by weight gross weight approximately 0.5% and the about liquid preparation of rapamycin concentrations between 6%.In some modification, by using between approximately 1 μ l and approximately 50 μ l liquid preparation described herein to using under people experimenter's conjunctiva containing accounting for by weight gross weight approximately 0.5% and the about liquid preparation of rapamycin concentrations between 4%.In some modification, by using between approximately 1 μ l and approximately 15 μ l liquid preparation described herein to using under people experimenter's conjunctiva containing accounting for by weight gross weight approximately 1.5% and the about liquid preparation of rapamycin concentrations between 3.5%.In some modification, by using liquid preparation described herein between approximately 1 μ l and approximately 15 μ l, under people experimenter's conjunctiva, use containing accounting for by weight the liquid preparation of gross weight approximately 2% rapamycin concentrations.

In some modification, by using liquid preparation described herein between approximately 0.1 μ l and approximately 200 μ l, under people experimenter's conjunctiva, use containing measuring the liquid preparation of rapamycin between approximately 0.2 μ g and about 4mg.In some modification, by using liquid preparation described herein between approximately 0.1 μ l and approximately 100 μ l, under people experimenter's conjunctiva, use containing measuring the liquid preparation of rapamycin between approximately 20 μ g and about 2mg.In some modification, by using liquid preparation described herein between approximately 1 μ l and approximately 50 μ l, under people experimenter's conjunctiva, use containing measuring the liquid preparation of rapamycin between approximately 20 μ g and about 1mg.In some modification, by using liquid preparation described herein between approximately 1 μ l and approximately 25 μ l, under people experimenter's conjunctiva, use containing measuring the liquid preparation of rapamycin between approximately 20 μ g and approximately 500 μ g.In some modification, by using liquid preparation described herein between approximately 1 μ l and approximately 15 μ l, under people experimenter's conjunctiva, use containing measuring the liquid preparation of rapamycin between approximately 20 μ g and approximately 300 μ g.

In some modification, intravitreal administration is less than the rapamycin of approximately 200 μ g total amounts.In some modification, intravitreal administration is less than the rapamycin of approximately 200 μ g total amounts.In some modification, intravitreal administration is less than the rapamycin of approximately 300 μ g total amounts.In some modification, intravitreal administration is less than the rapamycin of approximately 400 μ g total amounts.In some modification, intravitreal administration is less than the rapamycin of approximately 500 μ g total amounts.In some modification, intravitreal administration is less than the rapamycin of approximately 600 μ g total amounts.In some modification, intravitreal administration is less than the rapamycin of approximately 800 μ g total amounts.In some modification, intravitreal administration is less than the rapamycin of about 1mg total amount.In some modification, intravitreal administration is less than the rapamycin of about 2mg total amount.In some modification, intravitreal administration is less than the rapamycin of about 2.5mg total amount.In some modification, intravitreal administration is less than the rapamycin of about 3mg total amount.In some modification, intravitreal administration is less than the rapamycin of about 3.5mg total amount.In some modification, intravitreal administration is less than the rapamycin of about 4mg total amount.In some modification, use the volumes of formulation that contains amount rapamycin described herein.

In some modification, by use between approximately 0.1 μ l and approximately 200 μ l liquid preparation described herein to people experimenter's intravitreal administration containing accounting for by weight gross weight approximately 0.5% and the about liquid preparation of rapamycin concentrations between 6%.In some modification, by use between approximately 1 μ l and approximately 50 μ l liquid preparation described herein to people experimenter's intravitreal administration containing accounting for by weight gross weight approximately 0.5% and the about liquid preparation of rapamycin concentrations between 4%.In some modification, by use between approximately 1 μ l and approximately 15 μ l liquid preparation described herein to people experimenter's intravitreal administration containing accounting for by weight gross weight approximately 1.5% and the about liquid preparation of rapamycin concentrations between 3.5%.In some modification, by using liquid preparation described herein between approximately 1 μ l and approximately 15 μ l, to people experimenter's intravitreal administration, contain and account for by weight the liquid preparation of gross weight approximately 2% rapamycin concentrations.

In some modification, by using liquid preparation described herein between approximately 0.1 μ l and approximately 200 μ l, to people experimenter's intravitreal administration, contain the liquid preparation of measuring rapamycin between approximately 0.2 μ g and about 4mg.In some modification, by using liquid preparation described herein between approximately 1 μ l and approximately 100 μ l, to people experimenter's intravitreal administration, contain the liquid preparation of measuring rapamycin between approximately 20 μ g and about 2mg.In some modification, by using liquid preparation described herein between approximately 1 μ l and approximately 50 μ l, to people experimenter's intravitreal administration, contain the liquid preparation of measuring rapamycin between approximately 20 μ g and about 1mg.In some modification, by using liquid preparation described herein between approximately 1 μ l and approximately 25 μ l, to people experimenter's intravitreal administration, contain the liquid preparation of measuring rapamycin between approximately 20 μ g and approximately 500 μ g.In some modification, by using liquid preparation described herein between approximately 1 μ l and approximately 15 μ l, to people experimenter's intravitreal administration, contain the liquid preparation of measuring rapamycin between approximately 20 μ g and approximately 300 μ g.

In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 1 μ g and about 5mg, be used for the treatment of moist AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 20 μ g and about 4mg, be used for the treatment of moist AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 20 μ g and about 1.2mg, be used for the treatment of moist AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 10 μ g and about 0.5mg, be used for the treatment of moist AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 10 μ g and approximately 90 μ g, be used for the treatment of moist AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 60 μ g and approximately 120 μ g, be used for the treatment of moist AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 100 μ g and approximately 400 μ g, be used for the treatment of moist AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 400 μ g and about 1mg, be used for the treatment of moist AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between about 1mg and about 5mg, be used for the treatment of moist AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between about 3mg and about 7mg, be used for the treatment of moist AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between about 5mg and about 10mg, be used for the treatment of moist AMD.

In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 1 μ g and about 5mg, for pre-moisture resistance AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 20 μ g and about 4mg, for pre-moisture resistance AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 20 μ g and about 1.2mg, for pre-moisture resistance AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 10 μ g and about 0.5mg, for pre-moisture resistance AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 10 μ g and approximately 90 μ g, for pre-moisture resistance AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 60 μ g and approximately 120 μ g, for pre-moisture resistance AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 100 μ g and approximately 400 μ g, for pre-moisture resistance AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 400 μ g and about 1mg, for pre-moisture resistance AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between about 1mg and about 5mg, for pre-moisture resistance AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between about 3mg and about 7mg, for pre-moisture resistance AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between about 5mg and about 10mg, for pre-moisture resistance AMD.

In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 1 μ g and about 5mg, be used for the treatment of dryness AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 20 μ g and about 4mg, be used for the treatment of dryness AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 20 μ g and about 1.2mg, be used for the treatment of dryness AMD.In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 10 μ g and about 0.5mg, be used for the treatment of dryness AMD.In some modification, to people experimenter, use containing measuring rapamycin between approximately 10 μ g and approximately 90 μ g, be used for the treatment of dryness AMD.In some modification, to people experimenter, use containing measuring rapamycin between approximately 60 μ g and approximately 120 μ g, be used for the treatment of dryness AMD.In some modification, to people experimenter, use containing measuring rapamycin between approximately 100 μ g and approximately 400 μ g, be used for the treatment of dryness AMD.In some modification, to people experimenter, use containing measuring rapamycin between approximately 400 μ g and about 1mg, be used for the treatment of dryness AMD.In some modification, to people experimenter, use containing measuring rapamycin between about 1mg and about 5mg, be used for the treatment of dryness AMD.In some modification, to people experimenter, use containing measuring rapamycin between about 3mg and about 7mg, be used for the treatment of dryness AMD.In some modification, to people experimenter, use containing measuring rapamycin between about 5mg and about 10mg, be used for the treatment of dryness AMD.

In some modification, to people experimenter, use containing measuring the liquid preparation described herein of rapamycin between approximately 1 μ g and about 5mg, be used for the treatment of blood vessel and occur, include but are not limited to choroid neovascularization.In some modification, to people experimenter, use the rapamycin of measuring between approximately 20 μ g and about 4mg; Between approximately 20 μ g and about 1.2mg; To people experimenter, use the rapamycin of measuring between approximately 10 μ g and about 0.5mg and be used for the treatment of moist AMD, to people experimenter use between approximately 10 μ g and 90 μ g, between approximately 60 μ g and 120 μ g; To people experimenter use between approximately 100 μ g and 400 μ g, between approximately 400 μ g and 1mg; In some modification, to people experimenter, use the rapamycin of measuring between about 1mg and 5mg; In some modification, to people experimenter, use the rapamycin of measuring between about 3mg and 7mg; In some modification, to people experimenter, use the rapamycin of measuring between about 5mg and 10mg and be used for the treatment of blood vessel generation, include but are not limited to choroid neovascularization.

In one approach, liquid preparation described herein contains a certain amount of therapeutic agent being equal to a certain amount of rapamycin.

In one approach, to people experimenter use containing and approximately 1 μ g and about 5mg between measure the liquid preparation described herein of the amount of the therapeutic agent that rapamycin is equal to, be used for the treatment of moist AMD.In some modification, to people experimenter use and approximately 1 μ g and about 5mg between the amount of the therapeutic agent that is equal to of rapamycin; Between approximately 20 μ g and about 1.2mg; To people experimenter, use between approximately 10 μ g and about 0.5mg and be used for the treatment of moist AMD, to people experimenter use between approximately 10 μ g and 90 μ g, between approximately 60 μ g and 120 μ g; To people experimenter use between approximately 100 μ g and 400 μ g, between approximately 400 μ g and 1mg; In some modification, to people experimenter use and about 1mg and 5mg between measure the amount of the therapeutic agent that rapamycin is equal to; In some modification, to people experimenter use and about 3mg and 7mg between measure the amount of the therapeutic agent that rapamycin is equal to; In some modification, to people experimenter use and about 5mg and 10mg between measure the amount of the therapeutic agent that rapamycin is equal to.

In some modification, to people experimenter use containing and approximately 1 μ g and about 5mg between measure the liquid preparation described herein of the amount of the therapeutic agent that rapamycin is equal to, be used for the treatment of dryness AMD.In some modification, to people experimenter use and approximately 20 μ g and about 4mg between the amount of the therapeutic agent that is equal to of rapamycin; Between approximately 20 μ g and about 1.2mg; To people experimenter, use between approximately 10 μ g and about 0.5mg and be used for the treatment of moist AMD, to people experimenter use between approximately 10 μ g and 90 μ g, between approximately 60 μ g and 120 μ g; To people experimenter use between approximately 100 μ g and 400 μ g, between approximately 400 μ g and 1mg; In some modification, to people experimenter use and approximately 400 μ g and 1mg between measure the amount of the therapeutic agent that rapamycin is equal to; In some modification, to people experimenter use and about 1mg and 5mg between measure the amount of the therapeutic agent that rapamycin is equal to; In some modification, to people experimenter use and about 3mg and 7mg between measure the amount of the therapeutic agent that rapamycin is equal to; In some modification, to people experimenter use and about 5mg and 10mg between measure the therapeutic agent that rapamycin is equal to amount treat dryness AMD.

In some modification, to people experimenter use containing and approximately 1 μ g and about 5mg between measure the liquid preparation described herein of the amount of the therapeutic agent that rapamycin is equal to, for pre-moisture resistance AMD.In some modification, to people experimenter use and approximately 20 μ g and approximately 4 μ g between the amount of the therapeutic agent that is equal to of rapamycin; Between approximately 20 μ g and about 1.2mg; To people experimenter, use between approximately 10 μ g and about 0.5mg for pre-moisture resistance AMD, to people experimenter use between approximately 10 μ g and 90 μ g, between approximately 60 μ g and 120 μ g; To people experimenter use between approximately 100 μ g and 400 μ g, between approximately 400 μ g and 1mg; In some modification, to people experimenter use and approximately 400 μ g and 1mg between measure the amount of the therapeutic agent that rapamycin is equal to; In some modification, to people experimenter use and about 1mg and 5mg between measure the amount of the therapeutic agent that rapamycin is equal to; In some modification, to people experimenter use and about 3mg and 7mg between measure the amount of the therapeutic agent that rapamycin is equal to; In some modification, to people experimenter use and about 5mg and 10mg between measure the therapeutic agent that rapamycin is equal to amount for pre-moisture resistance AMD.

In some modification, every 3 or more months, every 6 or more months, every 9 or more months or every 12 or more months or longer time intravitreal administration any one or more preparation described herein, in order to treat in choroid neovascularization, moist AMD, dryness AMD one or more, in order to pre-moisture resistance AMD or for preventing the development of dryness AMD hygrotropism AMD.In some modification, under every 3 or more months, every 6 or more months, every 9 or more months or every 12 or more months or longer time conjunctiva, use any one or more preparation described herein, in order to treat in choroid neovascularization, moist AMD, dryness AMD one or more, or for pre-moisture resistance AMD.

In some modification, every 3 or more months, every 6 or more months, every 9 or more months or every 12 or more months or longer time intravitreal administration any one or more rapamycin preparation described herein, in order to treat in choroid neovascularization, moist AMD, dryness AMD one or more, in order to pre-moisture resistance AMD or for preventing the development of dryness AMD hygrotropism AMD.In some modification, under every 3 or more months, every 6 or more months, every 9 or more months or every 12 or more months or longer time conjunctiva, use any one or more rapamycin preparation described herein, in order to treat in choroid neovascularization, moist AMD, dryness AMD one or more, or for pre-moisture resistance AMD.In some modification, the effect of rapamycin continue to its be present in ocular tissue during beyond.

Therapeutic agent described herein send can be for example with the dosage range between about 1ng/ days and approximately 100 μ g/ days, or with higher or lower than this scope dosage send, depend on approach and the persistent period of using.In some modification of the liquid preparation using in methods described herein or compositions, therapeutic agent can be sent with the dosage range between approximately 0.1 μ g/ days and approximately 10 μ g/ days.In some modification of the liquid preparation using in methods described herein or compositions, therapeutic agent can be sent with the dosage range between approximately 1 μ g/ days and approximately 5 μ g/ days.Being used for the treatment of, preventing, suppressing, postponing various diseases described herein and disease occurs or the dosage of its multiple therapeutic agent disappearing can be optimized by use clinical trial.

The liquid preparation and the compositions as herein described that include but are not limited to solution, suspensoid, Emulsion and in-situ gelling preparation can be used for the rapamycin for the treatment of effective dose within the time period extending, to be delivered to eye (as a kind of limiting examples, by eye, use or use near the eyes), therefore be used for the treatment of, prevent, suppress, postpone the generation of CNV or it is disappeared, and can be used for the treatment of, prevent, suppress, postpone the generation of moist AMD or it be disappeared or the conversion of dryness AMD hygrotropism AMD.Believe that (including but are not limited to the composition of liquid preparation, described liquid preparation is delivered into the position in eye for some feature by changing liquid preparation described herein, include but are not limited under conjunctiva or in vitreous body and put), described liquid preparation can be used for by treatment effective dose rapamycin within the time period of multiple prolongation, be delivered to eye, comprise by treatment effective dose send more than approximately 1 week, more than approximately 2 weeks, more than approximately 3 weeks, more than approximately 1 month, more than approximately 3 months, more than approximately 6 months, more than approximately 9 months, more than approximately 1 year.

When the rapamycin for the treatment of effective dose is administered to the experimenter who suffers from moist AMD, rapamycin can treat, suppress moist AMD or it is disappeared.Treat, suppress or it is disappeared to need different treatment effective doses.The experimenter who suffers from moist AMD can have CNV damage, and believes that the rapamycin of administering therapeutic effective dose can have multi-effect, includes but are not limited to and causes that CNV damages the development of disappearing, stablizing CNV damage and prophylactic activity CNV damage.

When suffering from the rapamycin of experimenter's administering therapeutic effective dose of dryness AMD, believe that rapamycin can prevent or delay dryness AMD to the development of moist AMD.

Embodiment

Unless context is otherwise noted, the error line in chart shows a standard deviation.While using ethanol, it is from Gold Shield Distributors, Hayward, the 200 proof ethanol of CA.While using rapamycin, it is from LC laboratories, Woburn, MA or Chunghwa ChemicalSynthesis & Biotech Co., LTD (CCSB), Taipei Hsien, Taiwan, ROC.While using PEG 400, it is from The Dow Chemical Company, New Milford, CT.Some figure refer to respectively μ L or μ L with the expression of " uL " or " ug ".When using 10 μ L or more during small size, using Hamilton HPLC syringe.

Embodiment 1-Preparation and characterization is containing the solution of rapamycin

1.256% rapamycin (percentage ratio of gross weight) is dissolved in 9.676% ethanol (percentage ratio of gross weight).At the sterilized water aqueous solution that continues slowly to add under stirring 15%F127 (Lutrol).Final concentration is approximately 78.57% sterilized water (percentage ratio of gross weight) and about 10.50%F127 (Lutrol) (percentage ratio of gross weight).This solution is listed as preparation #32 in table 1.This solution is placed in 2 ℃ until use.

Embodiment 2-subconjunctival injection is containing the solution of rapamycin

The injection of solution that 50 μ l embodiment 1 are described is entered between New Zealand white rabbit CSC.

Fig. 2 has described within 20,40,67 and 90 days, to be present in after injection the mean concentration of the rapamycin logarithmic scale in vitreous body (ng/ml), retina choroid (ng/mg) and sclera (ng/mg).

In using, mark is analyzed by liquid chromatography-mass spectrometry (LCMS).

At each time point, by the rapamycin concentrations of every the eye of each rabbit obtaining is added, and use analyzed eye number divided by total amount, to calculate the mean concentration of rapamycin.In this experiment, each time point represents two rabbits meansigma methods (two eyes of described time point) of the meansigma methods of eyes (four eyes of described time point) or rabbit eyes separately.

The whole vitreous body of homogenate is also analyzed.By the rapamycin quality with measured, divided by analyzed vitreous body volume, calculate Vitrea mean concentration.Sample does not comprise site of administration; Therefore, this measurement is pointed out to send into Vitrea rapamycin levels by solution.

After subconjunctival injection, in 20,40,67 and 90 days vitreous body, the average level of rapamycin is respectively approximately 4.425,3.800,4.100 and 1.500ng/ml.

The whole retina choroid of homogenate to its analysis.By the rapamycin quality with measured, divided by analyzed retina choroid quality, calculate retinochoroid mean concentration.Sample does not comprise uses site; Therefore, this measurement is pointed out to send into retinochoroid rapamycin levels by solution.

After subconjunctival injection, in 20,40,67 and 90 days retina choroid, the average level of rapamycin is respectively approximately 0.055,0.209,0.080 and 0.017ng/mg.

In the mode identical with retina choroid, analyze sclera.Sclera sample comprises injection site; Therefore, this measurement points out that rapamycin is from the clearance rate of sclera.

After subconjunctival injection, in 20,40,67 and 90 days scleras, the average level of rapamycin is respectively approximately 0.141,0.271,0.067 and 0.192ng/ml.

Embodiment 3-Preparation and characterization is containing the solution of rapamycin

5.233% rapamycin (adding the percentage ratio that accounts for total formulation weight amount after all the components) is dissolved in 0.4177g EtOH; The amount of EtOH by forced evaporation (heating) reduce to 0.1296g (6.344%, w/w).Continuing to add PEG 400 under stirring.As the final concentration of total weight percent for approximately: rapamycin 5.233%, ethanol 6.344% and PEG 400 88.424%.While contacting with vitreous body, preparation forms the nondispersive agglomerate with respect to surrounding medium.This solution is listed as preparation #34 in table 1.

Embodiment 4-subconjunctival injection is containing the solution of rapamycin

The injection of solution that 25 μ l embodiment 3 are described is entered between New Zealand white rabbit CSC.

Fig. 3 has described within 14,35,62 and 85 days, to be present in after injection the rapamycin levels of logarithmic scale in vitreous body (ng/ml), retina choroid (ng/mg) and sclera (ng/mg).

By vitreous body homogenate analysis as described in example 2 above, just single the eye of every in the 2nd day analyzes three rabbits; The eyes of every in the 14th day analyzes two rabbits; At the 35th day, analyze the eyes of a rabbit; At the 62nd day, analyze the eyes of a rabbit; And at the 85th day, analyze from the simple eye of a rabbit with from the eyes of another rabbit.

Vitreous body sample does not comprise uses site; Therefore, this measurement is pointed out to send into Vitrea rapamycin levels by solution.After subconjunctival injection, in 2,14,35 and 85 days vitreous body, the average level of rapamycin is respectively approximately 3.57,53.65,9.00,4.700 and 0.600ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above about the date described in vitreous body, sampling.Do not carry out analyzing for the 2nd day.Retina choroid sample does not comprise uses site; Therefore, this measurement is pointed out to send into retinochoroid rapamycin levels by solution.After subconjunctival injection, in 14,35,62 and 85 days retina choroid, the average level of rapamycin is respectively approximately 0.4815,1.725,0.057 and 0.009ng/mg.

Sclera sample is analyzed as described in example 2 above, in the date sampling as described in about retina choroid.Sclera sample comprises uses site; Therefore, this measurement points out that rapamycin is from the clearance rate of sclera.After subconjunctival injection, in 14,35,62 and 85 days scleras, the average level of rapamycin is respectively approximately 34.5815,0.135,0.042 and 0.163666667ng/mg.

Embodiment 5-intravitreal injection is containing the solution of rapamycin

The injection of solution that 25 μ l embodiment 3 are described is entered in the vitreous body of New Zealand white rabbit eye.Fig. 4 has described within 14,35,62 and 90 days, to be present in after injection the level of the rapamycin logarithmic scale in vitreous body (ng/ml), retina choroid (ng/mg) and sclera (ng/mg).Also show the rapamycin levels that injection is present in vitreous body (ng/ml) for latter 2 days.

By vitreous body homogenate analyze as described in example 2 above, every simple eye in the 2nd day analyzes tri-rabbits of approximately 1 μ l just; Each that analyzed two rabbits at the 14th day eyes only; At the 35th day, analyze the eyes of a rabbit; At the 62nd day, analyze the eyes of a rabbit; And in the 90th day analyzes from two rabbits the eyes of every.

Except the 2nd day sample, vitreous body sample comprises uses site.When possible, avoid the solution of using as far as possible.Yet the accuracy of measured rapamycin levels may be owing to having comprised because of carelessness the solution of using and be subject to the impact of sampling error.

After intravitreal injection, in 2,14,35,62 and 90 days vitreous body, the average level of rapamycin is respectively approximately 11.4,136538,2850.3,21820.35 and 27142.75ng/ml.

By the homogenate analyze as described in example 2 above of retina choroid, as above-mentioned for Vitrea date sampling.Do not carry out analyzing for the 2nd day.Retina choroid sample does not comprise uses site; Therefore, this measurement is pointed out to send into retinochoroid rapamycin levels by solution.After intravitreal injection, in 14,35,62 and 90 days retina choroid, the average level of rapamycin is respectively approximately 5.78975,244.485,0.105 and 1.782ng/mg.

Sclera sample is analyzed as described in example 2 above, as above-mentioned for the sampling of retinochoroid date.Sclera sample does not comprise injection site; Therefore, this measurement points out that rapamycin is from the clearance rate of sclera.After intravitreal injection, in 14,35,62 and 90 days scleras, the average level of rapamycin is respectively approximately 0.5695,12.34,0.8505 and 0.71175ng/mg.

Embodiment 6-Preparation and characterization is containing the suspension of rapamycin

6% rapamycin (percentage ratio of gross weight) is scattered in 94%PEG400 (percentage ratio of gross weight).This suspension is classified preparation #55 as in table 1.

Embodiment 7-intravitreal injection is containing the suspension of rapamycin

The solution intravitreal injection of preparation in embodiment 6 is entered to New Zealand white rabbit ophthalmic.Fig. 5 has described the image that intravitreal injection 10 μ l (Fig. 5 A), 20 μ l (Fig. 5 B) and 40 μ l (Fig. 5 C) are suspended in the 6% rapamycin lagophthalmos of PEG400.This causes approximately 0.6, approximately 1.2 and the injected dose of about 2.4mg.Image focusing is on used suspension.These images show that suspensions form nondispersive agglomerate with respect to vitreous body medium around.

Embodiment 8-Preparation and characterization is containing the in-situ gelling preparation of rapamycin

4.2% rapamycin (derives from LC laboratories in Woburn, MA and ChunghwaChemical Synthesis & BioTech.Co, Ltd in Taiwan), 4.3% ethanol (derives from GoldShield Chemical in Hayward, CA), the liquid preparation of 2.2%PVP K90 (deriving from BASF), 87.1%PEG 400 (deriving from DOW Chemical) and 2.2%Eudragit RL 100 (deriving from RohmPharma Polymers), wherein all percentage ratio is the percentage ratio that accounts for gross weight.

Eudragit RL 100 is dissolved in to ethanol.This step can need sonication and heating.Ethanol-Eudragit is added in PEG 400.In Eudragit-ethanol-PEG solution, slowly add PVP, obtain the solution that homogeneous mixes.This step can need abundant mixing.

Add rapamycin and it is dissolved in Eudragit-ethanol-PEG-PVP mixture.Can use heating and sonication.Preparation thoroughly mixes (using vortice or blender) and reaches homogeneous.Said preparation is classified #37 as in table 1.

While being placed in deionized water or tap water, liquid preparation forms nondispersive agglomerate.This nondispersive agglomerate is shown as gel-like substance.

Embodiment 9-subconjunctival injection is containing the preparation of the nondispersive agglomerate of one-tenth of rapamycin

The injection of solution that 50 μ l embodiment 8 are described is entered between New Zealand white rabbit CSC.

Fig. 6 has described within 7,32,45 and 90 days, to be present in after injection in-situ gelling preparation the mean concentration of rapamycin in vitreous body (ng/ml), retina choroid (ng/mg) and sclera (ng/mg).

By LCMS (liquid chromatography (LC)-mass spectrography), analyze.

When analyzing when simple eye, by the rapamycin concentrations that derives from each each eye of rabbit is added, and by total amount the mean concentration divided by analyzed eye number calculating rapamycin.In this experiment, with respect to average level, vitreous body the 7th day and the 7th, 32 and 45 days time points of sclera represent simple eye.Remaining the 7th, 32 and 45 days time points represent the meansigma methods of rabbit eyes, and the 90th day time point represents the meansigma methods (totally four eyes) of each eyes in two rabbits.

The whole vitreous body of homogenate is also analyzed.By the rapamycin quality with measured, divided by analyzed vitreous body volume, calculate Vitrea mean concentration.Sample does not comprise uses site; Therefore, this measurement is pointed out to enter Vitrea rapamycin levels by in-situ gelling formulation delivered.

After subconjunctival injection 7,32,45 and 90 days, in vitreous body, the average level of rapamycin was respectively approximately 13.9, approximately 7.4, approximately 1.35 and about 9.9ng/ml.

The whole retina choroid of homogenate to its analysis.By the rapamycin quality with measured divided by the analyzed retinochoroid mean concentration of retina tela chorioidea Mass Calculation.Sample does not comprise uses site; Therefore, this measurement points out to enter by in-situ gelling formulation delivered the rapamycin levels of retina tela chorioidea.

After subconjunctival injection 7,32, in 45He90Tian retina tela chorioidea, the average level of rapamycin is respectively approximately 0.376, approximately 0.1875, approximately 0.136 and about 0.29ng/mg.

The identical mode of Yi Yu retina tela chorioidea is analyzed sclera.Sclera sample can comprise the liquid preparation of injection; Therefore, this measurement points out that rapamycin is from the clearance rate of sclera.

After subconjunctival injection, in 7,32,45 and 90 days scleras, the average level of rapamycin is respectively approximately 2033, approximately 1653, approximately 3626 and about 420.5ng/mg.

Embodiment 10-Preparation and characterization is containing the suspension of rapamycin

By 150.5mg rapamycin (by weight 3.004%) being scattered in 4860.3mg PEG400 (by weight 96.996%) to preparation containing the suspension of rapamycin.Said preparation is classified #49 as in table 1.150.5 mg rapamycins (by weight 3.004%) and 4860.3mg PEG 400 (by weight 96.996%) are placed in to succinum colour tube.Add the high abrasion zirconium oxide of the 3mm diameter culture medium (High Wear Resistant Zirconia Grinding Media) (pearl) of milling, be at most 3/4ths of cumulative volume.Sealed tube is also placed in Cole-Parmer milling device 48 hours.Rapamycin granular size intermediate value is 2.8386mm, and average is 3.1275mm.Said preparation is kept at 4 ℃ until use.While being placed in lagophthalmos vitreous body, the volume of 20 μ l and 40 μ l respectively forms nondispersive agglomerate.

Embodiment 11-subconjunctival injection is containing the suspension of rapamycin

The suspension that 40 μ l embodiment 10 are described is injected between New Zealand white rabbit CSC.Fig. 7 has described the level of the rapamycin logarithmic scale in 14,42,63 and 91 days vitreous body (ng/ml), retina choroid (ng/mg) and scleras (ng/mg) after injection.

By vitreous body homogenate analysis as described in example 2 above.Except the 91st beyond the highest heavens, each time point is analyzed from each eyes of two rabbits, the eyes of analyzing from a rabbit at the 91st day.Vitreous body sample does not comprise uses site; Therefore, this measurement is pointed out to send into Vitrea rapamycin levels.After subconjunctival injection, in 14,42,63 and 91 days vitreous body, the average level of rapamycin is respectively approximately 4.031,23.11,53.27 and 13.94ng/ml.

By the homogenate analyze as described in example 2 above of retina choroid, as above-mentioned for Vitrea date sampling.Retina choroid does not comprise uses site; Therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After subconjunctival injection, in 14,42,63 and 91 days retina choroid, the average level of rapamycin is respectively approximately 0.1577,4.965,0.385 and 0.05ng/mg.

By homogenate the analysis as described in example 2 above of sclera sample, as above-mentioned, for Vitrea mode, sample.Sclera sample comprises injection site.After subconjunctival injection, in 14,42,63 and 91 days scleras, the average level of rapamycin is respectively approximately 1283,476.3,854.2 and 168.5ng/mg.

Embodiment 12-intravitreal injection is containing the suspension of rapamycin

The suspension that 20 μ l embodiment 10 are described is injected in the vitreous body of New Zealand white rabbit eye.Injected suspension forms nondispersive agglomerate with respect to surrounding medium.Fig. 8 has described after injection the rapamycin levels of 63 and 91 days middle logarithmic scales of vitreous body (ng/ml) after 14,42,63 and 91 days retina choroid (ng/mg) and sclera (ng/mg) neutralization injection.

By vitreous body homogenate analysis as described in example 2 above.At each time point, analyze from each eyes of two rabbits.Vitreous body sample can comprise uses site.After intravitreal injection, in 63 and 91 days vitreous body, the average level of rapamycin is respectively approximately 381,600 and 150,400ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid.At each time point, analyze from each eyes of two rabbits.Retina choroid does not comprise uses site, so this measurement is pointed out to send into retinochoroid rapamycin levels.After intravitreal injection, in 14,42,63 and 91 days retina choroid, the average level of rapamycin is respectively approximately 2.588,4.249,21.42 and 0.922ng/mg.

By homogenate the analysis as described in example 2 above of sclera sample, as above-mentioned, for retinochoroid mode, sample.Sclera sample does not comprise injection site; Therefore, this measurement points out to be delivered to the level of the rapamycin of sclera.After intravitreal injection, in 14,42,63 and 91 days scleras, the average level of rapamycin is respectively approximately 0.7327,6.053,1.373 and 17.49ng/mg.

Embodiment 13-Preparation and characterization is containing the solution of rapamycin

By 116.6mg rapamycin being placed in to ethanol and mixture being stored to the solution forming containing rapamycin for 6 hours at 4 ℃.Then this solution and 4647.5mg PEG 400 are mixed to get to following solution, described solution has the final concentration of 2.29% rapamycin, 6.05% ethanol and 91.66%PEG400 by weight.This solution is classified preparation #51 as in table 1.While being placed in lagophthalmos vitreous body, the volume of 30 μ l forms nondispersive agglomerate.

Embodiment 14-subconjunctival injection is containing the solution of rapamycin

The injection of solution that 40 μ l embodiment 13 are described is entered between the CSC of New Zealand white rabbit eye.Fig. 9 has described the rapamycin levels of the linear-scale in 14,42,63 and 91 days vitreous body (ng/ml), retina choroid (ng/mg) and scleras (ng/mg) after injection.

By vitreous body homogenate analysis as described in example 2 above.Except the 91st beyond the highest heavens, each time point is analyzed from each eyes of two rabbits, the eyes of analyzing from a rabbit at the 91st day.Vitreous body sample does not comprise uses site; Therefore, this measurement is pointed out to send into Vitrea rapamycin levels.After subconjunctival injection, in 14,42,63 and 91 days vitreous body, the average level of rapamycin is respectively approximately 1.804,1.854,1.785 and 1.255ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample.Retina choroid does not comprise uses site; Therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After subconjunctival injection, in 14,42,63 and 91 days retina choroid, the average level of rapamycin is respectively approximately 1.221,4.697,0.1075 and 0.02ng/mg.

By homogenate the analysis as described in example 2 above of sclera sample, as above-mentioned, for Vitrea mode, sample.Sclera sample comprises injection site.After subconjunctival injection, in 14,42,63 and 91 days scleras, the average level of rapamycin is respectively approximately 1.987,1.884,0.56 and 10.84ng/mg.

Embodiment 15-intravitreal injection is containing the solution of rapamycin

The injection of solution that 30 μ l embodiment 13 are described is entered in the vitreous body of New Zealand white rabbit eye.Injected solution phase forms nondispersive agglomerate for surrounding medium.Figure 10 has described after injection the rapamycin levels of 14,42,63 and 91 days retina choroid (ng/mg) and sclera (ng/mg) neutral line yardstick.

By homogenate the analysis as described in example 2 above of retina choroid.At each time point, analyze from each eyes of two rabbits.Retina choroid does not comprise uses site, so this measurement is pointed out to send into retinochoroid rapamycin levels.After intravitreal injection, in 14,42,63 and 91 days retina choroid, the average level of rapamycin is respectively approximately 5.515,5.388,0.3833 and 11.52ng/mg.

By homogenate the analysis as described in example 2 above of sclera sample, as above-mentioned, for retinochoroid mode, sample.Sclera sample does not comprise injection site, so this measurement points out to send the rapamycin levels into sclera.After intravitreal injection, in 14,42,63 and 91 days scleras, the average level of rapamycin is respectively approximately 1.077,0.9239,0.0975 and 2.0825ng/mg.

Figure 11 has described the rapamycin levels of 63 and 91 days vitreous body (ng/ml) neutral line yardsticks after injection.By vitreous body homogenate analysis as described in example 2 above.At each time point, analyze from each eyes of two rabbits.Vitreous body sample can comprise uses site.After intravitreal injection, in 63 and 91 days vitreous body, the average level of rapamycin is respectively approximately 299,900 and 196,600ng/ml.

Embodiment 16-Preparation and characterization is containing the solution of rapamycin

About 320g ethanol N ₂rinse approximately 10 minutes, then in ethanol, add about 40g sirolimus.Mixture sonication approximately 20 minutes, sirolimuss all during end have entered solution, form sirolimus storage liquid.By about 1880g PEG 400 sonications are prepared to retarder thinner for approximately 60 minutes, then with this solvent of nitrogen wash approximately 10 minutes.

Then in rotary evaporator, sirolimus storage solutions and PEG 400 are rotated approximately 10 minutes under about room temperature, so that storage solutions and retarder thinner are mixed.After mixing, by nitrogen wash approximately 10 minutes for solution, and cover approximately 5 minutes with nitrogen.When solution is with nitrogen wash and after being full of, by improving solution temperature, keeping being no more than the temperature of 40 ℃ and continue rotation solution approximately 2.5 hours within the time period extending, the unnecessary alcohol of about 240g is evaporated from solution.

The solution obtaining comprises about 40g sirolimus (by weight approximately 2%), about 80g ethanol (by weight approximately 4%) and about 1880g PEG 400 (by weight approximately 94%).By this solution with nitrogen wash approximately 10 minutes and cover approximately 5 minutes with nitrogen.Then solution is filtered by 0.2 micron of filter.With 2ml, respectively cross filtered solution and pack in HPLC bottle, in each container, leave the headroom of approximately 400 μ l.This headroom is full of with nitrogen and closes the lid.

Embodiment 17-Preparation and characterization is containing the solution of rapamycin

Rapamycin, ethanol and PEG 400 are placed in to container and obtain the final concentration of approximately 2.00% rapamycin, approximately 4.00% ethanol and about 94.00%PEG 400 by weight.This mixture cover lid sonication 1-2 hour.Sonication produces heat, and temperature is up to approximately 40 or 50 ℃.This solution is classified preparation #100 as in table 1.1 μ l, 3 μ l, 20 μ l and 40 μ l volumes form nondispersive agglomerate in lagophthalmos vitreous body.

Embodiment 18-subconjunctival injection is containing the solution of rapamycin

The injection of solution that 20 μ l embodiment 17 are described is entered between New Zealand white rabbit eye sclera and conjunctiva.Figure 12 has described within 5,30,60,90 and 120 days, to be present in after injection the rapamycin levels of logarithmic scale in vitreous body.Figure 13 has described the rapamycin levels of logarithmic scale in same time point retina choroid.For relatively, Figure 12 and Figure 13 have also described the result of the similar research carried out with 40 μ l and 60 μ l injection, description in embodiment 19 and embodiment 20 hereinafter.

In Figure 12-15 of discussing in the present embodiment and following examples, some exceptional values are omitted.At same time point, from the number of individuals strong point of identical research, compare mutually.When the arithmetic mean of instantaneous value of data point is during lower than their standard deviation, higher or lower than the data point of an order of magnitude, be considered to exceptional value.

By vitreous body homogenate analysis as described in example 2 above.Each time point is analyzed two to five lagophthalmos.Vitreous body sample does not comprise uses site; Therefore, this measurement is pointed out to send into Vitrea rapamycin levels.After subconjunctival injection, in 5,30,60,90 and 120 days vitreous body, the average level of rapamycin is respectively approximately 1.81,0.45,0.39,1.85 and 1.49ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample.Retina choroid does not comprise uses site; Therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After subconjunctival injection, in 5,30,60,90 and 120 days retina choroid, the average level of rapamycin is respectively approximately 0.14,0.03,0.02,0.02 and 0.01ng/mg.

Embodiment 19-subconjunctival injection is containing the solution of rapamycin

The injection of solution that 40 μ l embodiment 17 are described is entered between New Zealand white rabbit eye sclera and conjunctiva.Figure 12 has described within 5,30,60,90 and 120 days, to be present in after injection the rapamycin levels of logarithmic scale in vitreous body.Figure 13 has described the rapamycin levels of logarithmic scale in same time point retina choroid.

By vitreous body homogenate analysis as described in example 2 above.Each time point is analyzed two to five lagophthalmos.Vitreous body sample does not comprise uses site; Therefore, this measurement is pointed out to send into Vitrea rapamycin levels.After subconjunctival injection, in 5,30,60,90 and 120 days vitreous body, the average level of rapamycin is respectively approximately 2.39,0.65,0.54,2.07 and 1.92ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample.Retina choroid does not comprise uses site; Therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After subconjunctival injection, in 5,30,60,90 and 120 days retina choroid, the average level of rapamycin is respectively approximately 0.47,0.04,0.01,0.05 and 0.0ng/mg.

Embodiment 20-subconjunctival injection is containing the solution of rapamycin

The injection of solution that 60 μ l embodiment 17 are described is entered between New Zealand white rabbit eye sclera and conjunctiva.Figure 12 has described within 5,30,60,90 and 120 days, to be present in after injection the rapamycin levels of logarithmic scale in vitreous body.Figure 13 has described the rapamycin levels of logarithmic scale in same time point retina choroid.

By vitreous body homogenate analysis as described in example 2 above.Each time point is analyzed two to five lagophthalmos.Vitreous body sample does not comprise uses site; Therefore, this measurement is pointed out to send into Vitrea rapamycin levels.After subconjunctival injection in 5,30,60,90 and 120 days vitreous body the average level of rapamycin be respectively approximately 8.65,0.29,0.18,2.00,1.41ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample.Retina choroid does not comprise uses site; Therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After subconjunctival injection, in 5,30,60,90 and 120 days retina choroid, the average level of rapamycin is respectively approximately 0.63,0.02,0.02,0.06 and 0.01ng/mg.

Embodiment 21-intravitreal injection is containing the solution of rapamycin

The injection of solution that 20 μ l embodiment 17 are described is entered in the vitreous body of New Zealand white rabbit eye.Injected solution phase forms nondispersive agglomerate for surrounding medium.Figure 14 has described the rapamycin levels of 5,30,60,90 and 120 days interior logarithmic scales of vitreous body after injection.Figure 15 has described the rapamycin levels of logarithmic scale in same time point retina choroid.For relatively, Figure 14 and Figure 15 have also described the below result of other research described in embodiment 22 and embodiment 24.

By vitreous body homogenate analysis as described in example 2 above.Each time point is analyzed two to five lagophthalmos.Vitreous body sample can comprise uses site.After intravitreal injection, in 5,30,60,90 and 120 days vitreous body, the average level of rapamycin is respectively approximately 162,100; 18,780; 57,830; 94,040 and 13,150ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample.Retina choroid sample does not comprise uses site; Therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After intravitreal injection, in 5,30,60,90 and 120 days retina choroid, the average level of rapamycin is respectively approximately 2.84,2.26,0.17,0.22 and 0.05ng/mg.

Embodiment 22-intravitreal injection is containing the solution of rapamycin

The injection of solution that 40 μ l embodiment 17 are described is entered in the vitreous body of New Zealand white rabbit eye.Injected solution phase forms nondispersive agglomerate for surrounding medium.Figure 14 has described the rapamycin levels of 5,30,60,90 and 120 days interior logarithmic scales of vitreous body after injection.Figure 15 has described the rapamycin levels of logarithmic scale in same time point retina choroid.

By vitreous body homogenate analysis as described in example 2 above.Each time point is analyzed two to five lagophthalmos.Vitreous body sample can comprise uses site.After intravitreal injection, in 5,30,60,90 and 120 days vitreous body, the average level of rapamycin is respectively approximately 415,600; 4,830; 74,510; 301,300 and 7,854ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample.Retina choroid sample does not comprise uses site; Therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After intravitreal injection, in 5,30,60,90 and 120 days retina choroid, the average level of rapamycin is respectively approximately 5.36,0.23,1.27,1.08 and 0.08ng/mg.

Embodiment 23-Preparation and characterization is containing the solution of rapamycin.

Rapamycin, ethanol and PEG400 are placed in to container and obtain the final concentration of approximately 0.4% rapamycin, approximately 4.0% ethanol and about 95.6%PEG400 by weight.This mixture sonication 1-2 hour.Sonication causes that temperature raises paramount approximately 40 to 50 ℃.This solution is classified preparation #99 as in table 1.

Embodiment 24-intravitreal injection is containing the solution of rapamycin

The injection of solution that 100 μ l embodiment 23 are described is entered in the vitreous body of New Zealand white rabbit eye.Injected solution phase does not form nondispersive agglomerate for surrounding medium.Figure 14 has described the rapamycin levels of 5,30,60 and 90 days interior logarithmic scales of vitreous body after injection.Figure 15 has described the rapamycin levels of logarithmic scale in same time point retina choroid.

By vitreous body homogenate analysis as described in example 2 above.Each time point is analyzed two to five lagophthalmos.Vitreous body sample can comprise uses site.After intravitreal injection, in 5,30,60 and 90 days vitreous body, the average level of rapamycin is respectively approximately 151,000; 14,890; 4,743 and 1620ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample.Retina choroid sample does not comprise uses site; Therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After intravitreal injection, in 5,30,60 and 90 days retina choroid, the average level of rapamycin is respectively approximately 1.21,1.84,0.04 and 0.71ng/mg.

Embodiment 25 Preparation and characterizations are containing the solution of rapamycin.

By 102.4mg rapamycin is placed in to ethanol, add 4719.3mg PEG400 vortex, form the solution containing rapamycin.The solution producing has the final concentration of 2.036% rapamycin, 4.154% ethanol and 93.81%PEG400 by weight.This solution is classified preparation #139 as in table 1.

Embodiment 26 subconjunctival injections are containing the solution of rapamycin

The solution that 10 μ l embodiment 25 are described is injected between New Zealand white rabbit eye sclera and conjunctiva as single dose.Figure 16 has described within 5 and 14 days, to be present in after injection the rapamycin levels of logarithmic scale in vitreous body.Figure 17 has described the rapamycin levels of logarithmic scale in same time point retina choroid.In order to compare, Figure 16 and Figure 17 have also described the below result of other research described in embodiment 27-29.

By vitreous body homogenate analysis as described in example 2 above.Each time point is analyzed four lagophthalmos.Vitreous body sample does not comprise uses site, and therefore, this measurement is pointed out to send into Vitrea rapamycin levels.After subconjunctival injection, in 5 and 14 days vitreous body, the average level of rapamycin is respectively approximately 2.45 and 20.13ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample.Retina choroid does not comprise uses site, and therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After subconjunctival injection, in 5 and 14 days retina choroid, the average level of rapamycin is respectively approximately 0.13 and 0.19ng/mg.

Embodiment 27-subconjunctival injection is containing the solution of rapamycin

The solution that 60 μ l embodiment 25 are described is injected between New Zealand white rabbit eye sclera and conjunctiva as single dose.Figure 16 has described within 5 and 14 days, to be present in after injection the rapamycin levels of logarithmic scale in vitreous body.Figure 17 has described the rapamycin levels of logarithmic scale in same time point retina choroid.

By vitreous body homogenate analysis as described in example 2 above.Each time point is analyzed four lagophthalmos.Vitreous body sample does not comprise uses site, and therefore, this measurement is pointed out to send into Vitrea rapamycin levels.After subconjunctival injection, in 5 and 14 days vitreous body, the average level of rapamycin is respectively approximately 17.98 and 87.03ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample.Retina choroid does not comprise uses site, and therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After subconjunctival injection, in 5 and 14 days retina choroid, the average level of rapamycin is respectively approximately 0.27 and 0.21ng/mg.

Embodiment 28-subconjunctival injection is containing the solution of rapamycin

The solution that 60 μ l embodiment 25 are described is injected into two sites between New Zealand white rabbit eye sclera and conjunctiva as two 30 μ l dosage.Figure 16 has described within 5 and 14 days, to be present in after injection the rapamycin levels of logarithmic scale in vitreous body.Figure 17 has described the rapamycin levels of logarithmic scale in same time point retina choroid.

By vitreous body homogenate analysis as described in example 2 above.Each time point is analyzed four lagophthalmos.Vitreous body sample does not comprise uses site, and therefore, this measurement is pointed out to send into Vitrea rapamycin levels.After subconjunctival injection, in 5 and 14 days vitreous body, the average level of rapamycin is respectively approximately 502.2 and 31.80ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample.Retina choroid does not comprise uses site, and therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After subconjunctival injection, in 5 and 14 days retina choroid, the average level of rapamycin is respectively approximately 0.80 and 0.15ng/mg.

Embodiment 29-subconjunctival injection is containing the solution of rapamycin

The solution that 90 μ l embodiment 25 are described is injected into three sites between New Zealand white rabbit eye sclera and conjunctiva as three 30 μ l dosage.Figure 16 has described within 5 and 14 days, to be present in after injection the rapamycin levels of logarithmic scale in vitreous body.Figure 17 has described the rapamycin levels of logarithmic scale in same time point retina choroid.

By vitreous body homogenate analysis as described in example 2 above.Each time point is analyzed four lagophthalmos.Vitreous body sample does not comprise uses site, and therefore, this measurement is pointed out to send into Vitrea rapamycin levels.After subconjunctival injection, in 5 and 14 days vitreous body, the average level of rapamycin is respectively approximately 39.05 and 13.63ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample.Retina choroid does not comprise uses site, and therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After subconjunctival injection, in 5 and 14 days retina choroid, the average level of rapamycin is respectively approximately 0.83 and 0.10ng/mg.

Embodiment 30 – Preparation and characterizations are containing the suspension of rapamycin

By 1201.6mg rapamycin (by weight 3.000%) being placed in to 6518.8mg PEG400(by weight 97.000%) and vortex preparation containing the suspension of rapamycin.The granular size obtaining is not quantitative, but very large, estimates to have an appointment 10 μ m.This suspension is classified preparation #147 as in table 1.

Embodiment 31 – subconjunctival injections are containing the suspension of rapamycin

The suspension that 10 μ l embodiment 30 are described is injected between New Zealand white rabbit eye sclera and conjunctiva as single dose.Figure 18 has described within 5,14 and 30 days, to be present in after injection the rapamycin levels of logarithmic scale in vitreous body.Figure 19 has described the rapamycin levels of logarithmic scale in same time point retina choroid.For relatively, Figure 18 and Figure 19 have also described the below result of other research described in embodiment 32 and embodiment 33.

By vitreous body homogenate analysis as described in example 2 above.Each time point is analyzed the eye of the rabbit of four.Vitreous body sample does not comprise uses site, and therefore, this measurement is pointed out to send into Vitrea rapamycin levels.After subconjunctival injection, in 5,14 and 30 days vitreous body, the average level of rapamycin is respectively approximately 2.68,0.90 and 5.43ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample.Retina choroid sample does not comprise uses site, and therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After subconjunctival injection, in 5,14 and 30 days retina choroid, the average level of rapamycin is respectively approximately 0.20,0.06 and 1.23ng/mg.

Embodiment 32 – subconjunctival injections are containing the suspension of rapamycin

The solution that 30 μ l embodiment 30 are described is injected between New Zealand white rabbit eye sclera and conjunctiva as single dose.Figure 18 has described within 5,14 and 30 days, to be present in after injection the rapamycin levels of logarithmic scale in vitreous body.Figure 19 has described the rapamycin levels of logarithmic scale in same time point retina choroid.

By vitreous body homogenate analysis as described in example 2 above.Each time point is analyzed the eye of the rabbit of four.Vitreous body sample does not comprise uses site, and therefore, this measurement is pointed out to send into Vitrea rapamycin levels.After subconjunctival injection, in 5,14 and 30 days vitreous body, the average level of rapamycin is respectively approximately 84.55,11.23 and 66.35ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample.Retina choroid sample does not comprise uses site, and therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After subconjunctival injection, in 5,14 and 30 days retina choroid, the average level of rapamycin is respectively approximately 1.09,0.19 and 1.02ng/mg.

Embodiment 33 – subconjunctival injections are containing the suspension of rapamycin

The solution that 90 μ l embodiment 30 are described is injected into three sites between New Zealand white rabbit eye sclera and conjunctiva as three 30 μ l dosage.Figure 18 has described within 5,14 and 30 days, to be present in after injection the rapamycin levels of logarithmic scale in vitreous body.Figure 19 has described the rapamycin levels of logarithmic scale in same time point retina choroid.

By vitreous body homogenate analysis as described in example 2 above.Each time point is analyzed the eye of the rabbit of four.Vitreous body sample does not comprise uses site, and therefore, this measurement is pointed out to send into Vitrea rapamycin levels.After subconjunctival injection, in 5,14 and 30 days vitreous body, the average level of rapamycin is respectively approximately 29.95,15.30 and 49.20ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample.Retina choroid sample does not comprise uses site, and therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After subconjunctival injection, in 5,14 and 30 days retina choroid, the average level of rapamycin is respectively approximately 0.55,1.31 and 5.74ng/mg.

Embodiment 34 Preparation and characterizations are containing the solution of rapamycin.

10.3mg rapamycin is placed in to ethanol, adds 4995.8mg PEG400, and mixture vortex is obtained having the solution of 0.205% rapamycin, 0.544% ethanol and 99.251%PEG 400 final concentrations by weight.This solution is classified preparation #140 as in table 1.While being placed in lagophthalmos vitreous body, this solution of 10 μ l volumes forms nondispersive agglomerate.

Embodiment 35-intravitreal injection is containing the solution of rapamycin

The injection of solution that 10 μ l embodiment 34 are described is entered in the vitreous body of New Zealand white rabbit eye.Injected solution phase forms nondispersive agglomerate for surrounding medium.Figure 20 has described the rapamycin levels of logarithmic scale in the rear 5 and 30 days retina choroid of injection.Figure 21 has described the rapamycin levels of logarithmic scale in same time point vitreous body.For relatively, Figure 20 and Figure 21 have also described the below result of other research described in embodiment 37 and embodiment 39.

By vitreous body homogenate analysis as described in example 2 above.Each time point is analyzed five lagophthalmos.Vitreous body sample can comprise uses site.After intravitreal injection, in 5 and 30 days vitreous body, the average level of rapamycin is respectively approximately 12.02 and 0.92ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample.Retina choroid does not comprise uses site, and therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After intravitreal injection, in 5 and 30 days retina choroid, the average level of rapamycin is respectively approximately 0.08 and 0.02ng/mg.

Embodiment 36 Preparation and characterizations are containing the solution of rapamycin

31.5mg rapamycin is placed in to ethanol, adds 4918.9mg PEG400, and by solution vortex.Final concentration is by weight 0.628% rapamycin, 1.337% ethanol and 98.035%PEG400.Said preparation is saved backup at 4 ℃.This solution is classified preparation #142 as in table 1.While being placed in lagophthalmos vitreous body, this solution of 10 μ l volumes forms nondispersive agglomerate.

Embodiment 37-intravitreal injection is containing the solution of rapamycin

The injection of solution that 10 μ l embodiment 36 are described is entered in the vitreous body of New Zealand white rabbit eye.Injected solution phase forms nondispersive agglomerate for surrounding medium.Figure 20 has described the rapamycin levels of logarithmic scale in the rear 5 and 30 days retina choroid of injection.Figure 21 has described the rapamycin levels of logarithmic scale in same time point vitreous body.

By vitreous body homogenate analysis as described in example 2 above.Each time point is analyzed five lagophthalmos.Vitreous body sample can comprise uses site.After intravitreal injection, in 5 and 30 days vitreous body, the average level of rapamycin is respectively approximately 87.46 and 44.34ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample.Retina choroid does not comprise uses site, and therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After intravitreal injection, in 5 and 30 days retina choroid, the average level of rapamycin is respectively approximately 1.40 and 0.01ng/mg.

Embodiment 38 Preparation and characterizations are containing the solution of rapamycin

103.5mg rapamycin is placed in to ethanol, adds 4720.8mg PEG 400, and mixture vortex is obtained having the solution of 2.057% rapamycin, 4.116% ethanol and 93.827%PEG 400 final concentrations by weight.This solution is classified preparation #144 as in table 1.This solution of 10 μ l volumes forms nondispersive agglomerate in lagophthalmos vitreous body.

Embodiment 39-intravitreal injection is containing the solution of rapamycin

The injection of solution that 10 μ l embodiment 38 are described is entered in the vitreous body of New Zealand white rabbit eye.Injected solution phase forms nondispersive agglomerate for surrounding medium.Figure 20 has described the rapamycin levels of logarithmic scale in rear 5, the 30 and 90 days retina choroid of injection.Figure 21 has described the rapamycin levels of logarithmic scale in same time point vitreous body.

By vitreous body homogenate analysis as described in example 2 above.Each time point is analyzed four lagophthalmos.Vitreous body sample can comprise uses site.After intravitreal injection, in 5,30 and 90 days vitreous body, the average level of rapamycin is respectively approximately 120,500; 55,160 and 0.55ng/ml.

By homogenate the analysis as described in example 2 above of retina choroid, as above-mentioned, for Vitrea mode, sample, be that described five lagophthalmos were 5 days and time point analysis in 30 days.Retina choroid sample does not comprise uses site, and therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After intravitreal injection, in 5,30 and 90 days retina choroid, the average level of rapamycin is respectively approximately 4.75,0.17 and 0.01ng/mg.

Embodiment 40-subconjunctival injection is containing the solution of rapamycin

The injection of solution that 40 μ l embodiment 17 are described is entered between New Zealand white rabbit eye sclera and conjunctiva.Figure 22 has described after injection the rapamycin levels (ng/ml) of logarithmic scale in 1,4,7,11,14,21,28,35,54 and 56 day aqueous humor, and the level of 4,14,21 and 35 days corneas (ng/mg) and the middle rapamycin of retina choroid (ng/mg) after injection.Retina choroid level is labeled as " R/ choroid " in Figure 22.

By aqueous humor homogenate then by liquid chromatography (LC) and analytical reagent composition.Each time point is analyzed four lagophthalmos.Aqueous humor does not comprise injection site, so this measurement points out to send the rapamycin levels into aqueous humor.After injection, rapamycin average level is respectively approximately 0.875,1.0,7.0,0.725,0.5,0.525,0.0,0.125,0.014 and 0.0485ng/ml in 1,4,7,11,14,21,28,35,54 and 56 day aqueous humor.

By cornea homogenate then by liquid chromatography (LC) and analytical reagent composition.Cornea does not comprise injection site, so this measurement points out to send the rapamycin levels into cornea.Each time point is analyzed four lagophthalmos.After injection, rapamycin average level is respectively approximately 0.3225,0.1,0.0275 and 0.0125ng/mg in 4,14,21 and 35 days corneas.

By the homogenate of retina choroid analysis as described in Example 2, as above-mentioned, for Vitrea mode, sample.Retina choroid does not comprise uses site, and therefore, this measurement is pointed out to send into retinochoroid rapamycin levels.After injection, in 4,14,21 and 35 days retina choroid, the average level of rapamycin is respectively approximately 11.61,0.2,0.0275 and 2.655ng/mg.

Embodiment 41-intravitreal injection is containing the solution of rapamycin

The injection of solution that 1.0 μ l embodiment 17 are described is entered in New Zealand white rabbit vitreum.Injected solution phase forms nondispersive agglomerate for surrounding medium.Table 2 has been reported the average level of injecting rapamycin in aqueous humor one day after.In order to compare, table 2 has also been reported the result of the research that below embodiment 42-45 describes.

By aqueous humor homogenate analysis as described in example 40 above.Analyze two lagophthalmos.Aqueous humor does not comprise injection site, so this measurement points out to send the rapamycin levels into aqueous humor.Injecting one day after rapamycin average level in aqueous humor is about 0.438ng/ml, and standard deviation is about 0.141ng/ml.

Embodiment 42-intravitreal injection is containing the solution of rapamycin

The injection of solution that 3.0 μ l embodiment 17 are described is entered in New Zealand white rabbit vitreum.Injected solution phase forms nondispersive agglomerate for surrounding medium.Table 2 has been reported the average level of injecting rapamycin in aqueous humor one day after.

By aqueous humor homogenate analysis as described in example 40 above.Analyze two lagophthalmos.Aqueous humor does not comprise injection site, so this measurement points out to send the rapamycin levels into aqueous humor.Injecting one day after rapamycin average level in aqueous humor is about 0.355ng/ml, and standard deviation is about 0.234mg/ml.

Embodiment 43-subconjunctival injection is containing the solution of rapamycin

The injection of solution that 3.0 μ l embodiment 17 are described is entered between New Zealand white rabbit eye sclera and conjunctiva.Injected solution phase forms nondispersive agglomerate for surrounding medium.Table 2 has been reported the average level of injecting rapamycin in aqueous humor one day after.

By aqueous humor homogenate analysis as described in example 40 above.Analyze two lagophthalmos.Aqueous humor does not comprise injection site, so this measurement points out to send the rapamycin levels into aqueous humor.Injecting one day after rapamycin average level in aqueous humor is about 0.338ng/ml, and standard deviation is about 0.122ng/ml.

Embodiment 44-anterior chamber uses the solution containing rapamycin

The solution that 5.0 μ l embodiment 17 are described is injected in New Zealand white rabbit camera oculi anterior by being expelled to the front end of eye.Use syringe to extract aqueous humor.Table 2 has been reported the average level of injecting rapamycin in latter 14 days aqueous humors.

By aqueous humor homogenate analysis as described in example 40 above.Analyze two lagophthalmos.Aqueous humor does not comprise injection site, so this measurement points out to send the rapamycin levels into aqueous humor.Injecting rapamycin average level in latter 14 days aqueous humors is about 0.166ng/ml, and standard deviation is about 0.183ng/ml.

Embodiment 45-anterior chamber uses the solution containing rapamycin

The injection of solution that 10 μ l embodiment 17 are described is entered in New Zealand white rabbit camera oculi anterior.Table 2 has been reported the average level of injecting rapamycin in latter 14 days aqueous humors.

By aqueous humor homogenate analysis as described in example 40 above.Analyze two lagophthalmos.Aqueous humor does not comprise injection site, so this measurement points out to send the rapamycin levels into aqueous humor.Injecting rapamycin average level in latter 14 days aqueous humors is about 0.004ng/ml, and standard deviation is about 0.006ng/ml.

All lists of references of quoting herein (comprising patent, patent application and publication) are quoted as a reference with its integral body herein, no matter before specific reference whether.

table 1 liquid preparation

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table 2 aqueous humor rapamycin concentrations

Claims (1)

1. liquid preparation, it comprises by weight 2% rapamycin altogether, 4% ethanol and 94% PEG400, forms nondispersive agglomerate when wherein this liquid preparation is in the vitreous body that is expelled to experimenter's eye.