CN101437478A - Ocular delivery of polymeric delivery formulations - Google Patents

Abstract

The present invention provides a flowable composition suitable for use as a controlled release implant. The flowable composition can be administered into the ocular region of a mammal. The composition includes: (a) a biodegradable, biocompatible thermoplastic polymer that is at least substantially insoluble in aqueous medium, water or body fluid; (b) a biological agent, a metabolite thereof, a biological agently acceptable salt thereof, or a prodrug thereof; and (c) a biocompatible organic liquid, at standard temperature and pressure, in which the thermoplastic polymer is soluble. The present invention also provides methods of medical treatment that include administering the flowable composition into the ocular region of a mammal.

Description

Polymerization is sent the eye of delivery formulations to send and is passed

Background technology

The treatment of ophthalmic and/or eye wound requires specific biological agent to keep effective a period of time in the treatment site.Because for example the natural fluid of tear has the tendency of the biological agent composition of rapid flushing local application, thus the topical ophthalmic therapy or with conjunctiva as general route of administration existing problems always just.

The eye insert is used for the medicine part and send the purposes of passing that description (referring to for example Ness, United States Patent (USP) 3,416,530 and Cheng, United States Patent (USP) 4,053,580) was just arranged before more than 30 years.These initial inserts are included in the tear insoluble or can not bioerodible material.

Other disclosures have been described in a period of time the eye that distributes medicine and final erosion fully to separate and have been sent and pass insert, but all do not have suitable bioadhesion ability in these lists of references.Referring to people's (United States Patent (USP)s 4 such as people such as for example Whitaker (United States Patent (USP) 3,963,025), Miyata, 164,559), people's (United States Patent (USP) 4,179 such as Cohen, 497), people (United States Patent (USP) 4,346,709 and 4 such as Heller, 249,431), people's (United States Patent (USP) 6,264 such as Darougar, 971), people (United States Patent (USP) 6,331,313) and Masters (United States Patent (USP) 6 such as Wong, 342,250).

But the fluent solution of bioadhesion polymeric blends increases also existing description of the holdup time of eye drop (people's such as Bowman United States Patent (USP) 6,372, the 245 and United States Patent (USP) 5,283,236 of Chiou)., these solution realize promptly beginning to bring into play therapeutic effect yet can not keeping contacting closely with conjunctiva.

Eye is a very complicated organ on the anatomy, and this part for biological agent is sent to pass to send to pass with whole body all its special advantages and inferior position.The superficial epithelium tissue of eye is that conjunctiva or cornea are the moistening tissue that continues to be dipped in the tear.This normally stable liquid stream is expelled in the nasolacrimal duct at endocanthion.

Eye is the increase of shedding tears to first reaction of external source object, allogenic material can be flushed out eye like this, perhaps can be with drug irrigation to hole for the biological agent in the eye drop.The inner surface of eyelid or palpebral conjunctiva are moistening height blood vessel tissue.When the most of biological agent in the eye drop when hole is expelled to the rear portion of throat, some biological agents will be brought into vascular system and become general, and some will penetrate the anterior chamber that bulbar conjunctiva enters eye.

Though it is very fast to be transported to the speed of systemic circulation, from eye drop, send the efficient of passing very low, and because the local leading portion that uses medicine can enter eye easily, thereby always have genotoxic potential.

But some lists of references have been described the flow composition that is suitable for use as the controlled release implant, that is send delivery system as lasting release biodegradable and can bioerodible implant; But wherein should send delivery system to comprise with continuing to discharge by flow composition: (a) biodegradable, biocompatible polymer; (b) biological agent; (c) biocompatibility organic liquid; And wherein the gained implant of original position formation comprises (a) biodegradable, biocompatible polymer; (b) biological agent.Referring to for example, United States Patent (USP) 6,565,874,6,528,080, RE37,950,6,461,631,6,395,293,6,355,657,6,261,583,6,143,314,5,990,194,5,945,115,5,792,469,5,780,044,5,759,563,5,744,153,5,739,176,5,736,152,5,733,950,5,702,716,5,681,873,5,599,552,5,487,897,5,340,849,5,324,519,5,278,202 and 5,278,201.But these lists of references are not described this eye that is applicable to as the controlled release implant and are sent the flow composition of passing.

Therefore, needed is to be used for whole body or topical therapeutic and to send the biological agent of passing biological agent carrier to eye (for example stride conjunctiva or stride cornea) in the variable time section, and the described time period is for example sent and passed several minutes or a few hours.

Summary of the invention

Continue release with other parenterals and send delivery system to compare, preparation of the present invention provides many significant advantages.For example, microsphere must use the aseptic method that may comprise with halogenated solvent to produce.In addition, the ratio of medicine and microsphere is by encapsulated control from view of profit, and encapsulated method can cause losing 25% to 50% API irretrievablely in the drug products production process.By contrast, preparation of the present invention is made of biocompatible composition, and it is to prepare by suitable biodegradable polymers is dissolved in biocompatible solvent.Different with microsphere, preparation of the present invention can use the routine techniques sterilization that comprises γ irradiation at last.Production method that this is unique and proprietary product structure have overcome the drug loss in the production process substantially.And give with big volume injected with microsphere and to pass smaller dose and compare, preparation of the present invention can send with less volume injected and pass heavy dose of API.The most important thing is, can protect responsive bio-pharmaceutical in order to avoid be degraded in vivo and the enzyme inactivation with the bank (depot) that preparation of the present invention obtained.

Or storage device implantable with other compared, and preparation of the present invention is for to pass platform to sending of patient close friend.The implant of subcutaneous injection preparation gained of the present invention discharges medicine in the preset time interval.Usually, the biodegradable speed of implant is identical with rate of drug release; Therefore injection site can be recovered during an infra shot basically in time.By contrast, the mechanicalness implant must remove by surgical operation, and must be replaced after the medicine storage depletion or load.

Be used for when eye gives biological agent, but flow composition as herein described uses effective and an amount of material to reduce stimulation or toxic incidence rate and/or the seriousness to eye and surrounding tissue.This class stimulates or toxicity can be caused by a large amount of relatively organic solvents such as for example acetone or the N-N-methyl-2-2-pyrrolidone N-that for example exist.

But the invention provides a kind of flow composition that is suitable for use as the controlled release implant, described compositions comprises: (a) biodegradable, biocompatible thermoplastic polymer, and this polymer is insoluble to aqueous medium, water or body fluid at least basically; (b) acceptable salt or its prodrug on biological agent, its metabolite, its biopharmaceutics; (c) biocompatibility organic liquid, under standard temperature and pressure, described thermoplastic polymer dissolves in wherein; Wherein said compositions is suitable for eye and send and pass.

The present invention also provides a kind of method for the treatment of mammiferous disease or disease, gives the flow composition of the present invention of effective dose but described method comprises the mammal ocular to this treatment of needs.

The present invention also provides a kind of and send the method for passing biological agent through mammal ocular part, but described method comprises the mammal ocular is contacted with flow composition of the present invention.

The present invention also provides a kind of and send the method for passing biological agent through mammal ocular whole body, but described method comprises the mammal ocular is contacted with flow composition of the present invention.

The present invention also provides a kind of implant, and it comprises: (a) biodegradable, biocompatible thermoplastic polymer, and this polymer is insoluble to aqueous medium, water or body fluid at least basically; (b) acceptable salt or its prodrug on biological agent, its metabolite, its biopharmaceutics; (c) biocompatibility organic liquid, under standard temperature and pressure, described thermoplastic polymer dissolves in wherein; Wherein this implant places the mammal ocular, and this implant has solid or gel pore substrate, the core of this substrate for holding by epidermis, and wherein this implant is surrounded by bodily tissue.

The present invention also provides a kind of implant, and it comprises: (a) biodegradable, biocompatible thermoplastic polymer, and this polymer is insoluble to aqueous medium, water or body fluid at least basically; (b) acceptable salt or its prodrug on biological agent, its metabolite, its biopharmaceutics; Wherein this implant is placed in mammiferous ocular, and this implant has solid or gel micropore substrate, the core of this substrate for holding by epidermis, and wherein this implant is surrounded by bodily tissue.

The present invention also provide a kind of in the live body ocular original position form the method for implant, this method comprises: but (a) inject flowable composition in patient's ocular is any one flow composition of the present invention; (b) make the dissipation of biocompatibility organic liquid to produce the solid biodegradable implant.

The present invention also provides a kind of biological agent test kit that is suitable for forming in the ocular original position Biodegradable implants, this test kit comprises: but (a) comprise and be suitable for sending first container of passing to the flow composition of ocular, said composition comprises: (i) biodegradable, biocompatible thermoplastic polymer, and this polymer is insoluble in aqueous medium, water or the body fluid at least basically; (ii) biocompatibility organic liquid, under standard temperature and pressure, described thermoplastic polymer dissolves in wherein; (b) comprise second container of acceptable salt on biological agent, its metabolite, its biopharmaceutics or its prodrug.

Description of drawings

Embodiment of the present invention can be by obtaining best understanding with reference to following description and the accompanying drawing that illustrates these embodiments.The method for numbering serial of the contained figure of this paper makes that the leading number of given reference numerals is associated with the numbering of this figure among the figure.For components identical among the different figure, reference numerals is identical for those.For example, can make ocular and eye surface for example lacrimal ductule (110) be arranged in Fig. 1.Yet for components identical among the different figure, reference numerals is identical for those.In the drawings:

Fig. 1 diagram is used for ocular of the present invention and eye surface.

Fig. 2 diagram is used for ocular of the present invention and eye surface.

Fig. 3 diagram is used for ocular of the present invention and eye surface.

Fig. 4 diagram is used for mucosa of the present invention zone and mucous membrane surface.

The specific embodiment

Pass but the eye that the present invention relates to flow composition send, said composition is suitable for use as the controlled release implant.Said composition comprises: (a) biodegradable, biocompatible thermoplastic polymer, and this polymer is insoluble in aqueous medium, water or the body fluid at least basically; (b) acceptable salt or its prodrug on biological agent, its metabolite, its biopharmaceutics; (c) biocompatibility organic liquid, under standard temperature and pressure, described thermoplastic polymer dissolves in wherein.This thermoplastic polymer preferably dissolves in the organic solvent at least basically substantially fully, and at least basically, preferably is insoluble to aqueous medium, body fluid and water fully.Organic solvent is slightly soluble in water at least, and preferably moderate is solvable in water, preferred especially basic water soluble.But flow composition is suitable for injection into body from biopharmaceutics, and it can form acceptable solid matrix on the biopharmaceutics in body, and it is generally monomer implant or drug delivery system.Implant can discharge acceptable salt or its prodrug on biological agent, its metabolite, its biopharmaceutics with controlled speed.Can change rate of release and make it faster or slower by comprising the rate adaptation agent.

" embodiment " " embodiment " " the example embodiment " in description, mentioned etc., be meant that described embodiment can comprise concrete feature, structure or characteristic, but each embodiment must not comprise concrete feature, structure or characteristic.And this term might not refer to same embodiment.In addition, when having described concrete feature, structure or characteristic, should think that it is in those skilled in the art's limit of power that these features, structure or characteristic are applied to other embodiment that may clearly not describe about an embodiment.

" eye " used herein or " ocular " (550) are meant the body fluid in eye, circumocular tissue and the eye zone.Particularly, this term comprises cornea (350) or (250), sclera (310) or (210), tunica uvea (320), conjunctiva (330) (for example bulbar conjunctiva (220), palpebral conjunctiva (230) and tarsal conjunctiva (270)), anterior chamber (340), lachrymal sac, tear stains (130), lacrimal ductule (110), endocanthion (120), nasolacrimal duct (150) and eyelid (for example upper eyelid (240) and palpebra inferior (260)).In addition, this term comprises the inner surface (overlaying on the conjunctiva of sclera (310) or (210) and eyelid inner surface (palpebral conjunctiva)) of eye.

" conjunctiva " used herein is meant the forward mucosa of lining in eyelid inner surface and sclera (310) or (210)." palpebral conjunctiva " serves as a contrast the inner surface at eyelid, thicker, opaque and height vascularization." bulbar conjunctiva " is loose and connects, and be thin and transparent, covers preocular 1/3rd sclera (310) or (210).

" sclera " used herein is meant the transparent preocular of protrusion, comprises eyeball outermost layer 1/6 tunicle.It can make light by and reach crystalline lens.Cornea (350) or (250) are fibrous structure, have five layers: cornea epithelium, continued access conjunctiva; Anterior limiting lamina (Bowman film); Intrinsic substrate (substantial propria); Posterior limiting lamina (Descemet film) and anterior chamber's (340) (cornea (keratoderma)) endotheliocyte.Its densification, thickness is even and do not have blood vessel, and protrudes just as the dome on sclera (310) or (210), and the outermost layer of sclera formation eye is 5/6 tunicle in addition.The degree of curvature difference of cornea between different individualities, and also different for the degree of curvature of same individual cornea when the different ages; The people's that youthful ratio of curvature is aged curvature is more obvious.

" eye " used herein is meant in a pair of visual organ, and it is contained in the forward bone socket of the eye of skull, and embedding in the orbital fat and being subjected to four kinds of cranial nerves is the innervation of optic nerve, oculomotorius, trochlear nerve and abducent nerve.What be connected with eye is some supplementary structure, for example muscle, fascia, eyebrow, eyelid, conjunctiva (330) and lachrymal gland.The bulb of eye has the approximate spherical calotte that parallels to the axis by two to be formed, and this sphere has constituted one of outer tunicle and three layers of fibrous layer, and these three layers of fibrous layers surround two inner chambers being separated by crystalline lens.Crystalline lens the place ahead be divided into two chambers than loculus by iris, two Room all are full of aqueous humor.Back cavity is bigger than ante-chamber, contains the gluey vitreous body of being demarcated by vitreous canal.The outer tunicle in bulb is made of the opaque sclera at forward transparency cornea and rear portion, and anterior cornea accounts for 1/5 of tunicle, and the rear portion sclera accounts for 5/6 of tunicle.Middle level blood vessel pigment tunicle is made of choroid, corpus ciliare and iris.Internal layer nervous tissue tunicle is a retina., get excited thereby produce to amphiblestroid layer of rods and cones by lenticular light wave projection, this impulsion passes to brain by optic nerve again.The transverse diameter of eyeball portion and anteroposterior diameter are bigger slightly than vertical diameter, and women's bulb is littler than male usually.The motion of eye is to be subjected to six kinds of muscle controls, i.e. superior obliquus and inferior obliquus and superior rectus, inferior retcus, medial rectus and lateral rectus.Eyeball is also referred to as Bulbus oculi.

" eyelid " used herein is meant mobilizable thin one-tenth pleat skin of eye top, and it has eyelashes and along its periphery ciliation and tarsal glands.It is made of the loose connective tissue that contains the thin slice fibrous tissue that is lined with mucosa (conjunctiva).By opening of orbicularis oculi and oculomotorius control eyelid with closed.Upper eyelid and palpebra inferior separate by fissura palpebrae.Eyelid also is known as palpebra.

" corner of the eyes " used herein is meant the canthus, just is in the angle of eyelid medial border and lateral border.Endocanthion (120) is opened on dacryocanalicular less crack opening towards containing.Also be known as palpebral commissure (palpebral commissure).

The wet and slippery secretions of stickiness that " mucus " used herein is meant mucosa and body of gland, the cell that contains mucoprotein, leukocyte, water, inorganic salt and come off.

" nasal sinuses " used herein is meant any one in numerous lacunas between each bone of skull, and is lined with the band cilium mucosa with the nasal cavity continued access.This film is very responsive; Easily stimulated, thereby can cause swelling and block nasal sinuses.Nasal sinuses can comprise for example sinus frontalis (410) and sphenoid sinus (420).

" tear " used herein is meant tear.

" lacrimal ductule " used herein is to instigate one of tear pair of channels from cus lacrimalis to each tear capsule.

" palpebral conjunctiva " used herein is meant the mucosa that is lining in eyelid inner surface and sclera (310) or (210) forward part." palpebral conjunctiva " is lining in the inner surface of eyelid, thicker, opaque and height vascularization." bulbar conjunctiva " is loose and connects, and be thin and transparent, covers preocular 1/3rd sclera (310) or (210).

" retina " used herein is meant that branch has the meticulous nervous tissue of the eye film of 10 layers of structure, and it is mutually continuous with optic nerve, can receive the image of exterior object and by optic nerve the vision impulsion be transferred to brain.Retina is softer, is translucent, and contains rhodopsin.It is made of outside uvea and the retina inherent structure that is divided into nine layers.From innermost layer, above-mentioned nine layers for internal limiting membrane, look layer, ganglion cell layer, inner plexiform layer, inner nuclear layer, outer plexiform layer, outer nuclear layer, outer limiting membrane and layer of rods and cones.The retina outer surface contacts with choroid, and inner surface contacts with vitreous body.The retina front portion is thinner, and it almost is extensible to corpus ciliare like this; And the rear portion is thicker, only is thin point at the positive center of posterior face, is best focal point herein.Photoreceptor the place ahead ends at capsulociliary zigzag ora serrata, but amphiblestroid film can prolong and the back of ciliary processes and iris.If retina is exposed under the direct sunlight, it will thicken, opaque.Also considerable bacillary layer, macula lutea, the optic disc examined.

" retina choroid " used herein is meant the inflammation of eyes retina and choroid layer.

" sclera " used herein is meant the harder nonelastic opaque coating that covers back 5/6 eyeball.It keeps the size and the shape of eyeball, links to each other with the muscle that makes ocular movemeut.At its rear portion, it is penetrated by optic nerve, and forms the outermost layer of three layers of tunicle that cover eyeball jointly with transparent cornea.

" hole " used herein is a kind of chamber or passage, for example bone cavity, expansible venous blood passage or make effusive chamber of purulent material or passage.

" tarsal glands " used herein is meant any of many sebaceous gland that changed of being positioned at the eyelid inner surface.The acute localized bacterial infection of tarsal glands may cause hordeolum or chalazion.

" tear " used herein are meant by saliferous or the alkaliferous water sample fluid of lacrimal secretion with moistening conjunctiva.

" tunica uvea " used herein is meant sclera (310) or (210) following fibrous coat, comprises an iris, corpus ciliare and choroid.

" vascular system " used herein is meant the vascularity in the organ or tissue.

Biological agent

Biological agent should be applicable to that the eye part is sent and pass.Perhaps, described biological agent should be suitable for carrying out the whole body administration through eye.

Biological agent can comprise the combination of single biological agent or biological agent.The biological agent examples of types that is used singly or in combination comprises: beta adrenergic agent (adrenergic agent); adrenocortical steroid (adrenocortical steroid); adrenal cortex depressant (adrenocortical suppressant); alcohol inhibitor (alcohol deterrent); aldosterone antagonists (aldosterone antagonist); aminoacid (amino acid); ammonia detoxicant (ammonia detoxicant); anabolic agent (anabolic); analeptic (analeptic); analgesic (analgesic); androgen (androgen); angiogenesis inhibitor medicine (anti-angiogenic); anesthesia accessory drugs (anesthesia; adjunt to); anesthetics (anesthesic); fenisorex (anorectic); antagonist (antagonist); antepituitary depressant (anterior pituitary suppressant); anthelmintic (anthelmintic); anti-acne drug (antiacne agent); antiadrenergic (anti-adrenergic); resistance is answered medicine (anti-allergic); anti-amebic (anti-amebic); antiandrogen (antiandrogen); anti-anemic drug (anti-anemic) anti-anginal drug (antianginal); antianxiety drugs (anti-anxiety); anti-arthritic (anti-arthritic); antasthmatic (anti-asthmatic); antiatherosclerotic (antiatherosclerotic); antibacterial (antibacterial); anti-cholelithiasis medicine (anticholelithic); anti-cholelithiasis forms medicine (anticholelithogenic); anticholinergic (anticholinergic); anticoagulant (anticoagulant); anticoccidial drug (anticoccidal); anticonvulsant (anticonvulsant); antidepressants (antidepressant); antidiabetic drug (antidiabetic); diarrhea (antidiarrheal); antidiuretic (antidiurietic); antidote (antidote); Bendectin (anti-emetic); antuepileptic (anti-epileptic); antiestrogen (anti-estrogen); antifibrinolytics (antifibronolytic); antifungal agent (antifungal); Betimol (antiglaucoma agent); antihemophilic (antihemophilic); antihemorrhagic (antihermorrhagic); antihistaminic (antihistamine); antihyperlipidemic (antihyperlipidemia); antihyperlipoproteinemic (antihyperlipoproteinemic); antihypertensive (antihypertensive); antihypotensive (antihypotensive); anti-infective (antlinfective); local anti-infective agent (anti-infective, topical); anti-inflammatory agent (anti-inflammatory); antikeratinizing agent (antikeratinizing agent); antimalarial (antimalarial); antimicrobial drug (antimicrobial); antimigraine (antimigraine); antifungal (antimycotic); antinauseant (antinausant); antineoplastic agent (antineoplastic); antineutropenic (antineutropenic); antiadipositas drug (antiobessional agent); antiparasitic (antiparasitic); antiparkinsonian drug (antiparkinsonian); anti-wriggling medicine (antiperistaltic); anti-lung sac worm medicine (antipneumocystic); antiproliferative (antiproliferative); anti-prostate hyperplasia medicine (antiprostatic hypertrophy); antiprotozoal drug (antiprotozoal); antipruritic (antipruritic); psychosis (antipsychotic); antirheumatic (antirheumatic); antischistosomal drug (antischistosomal); antiseborrhoic (antiseborrheic); antisecretory drug (antisecretory); spasmolytic (antispasmodic); antithrombotic (antithrombotic); cough medicine (antitussive); antiulcerative (anti-ulcerative); anti-urolithic (antiurolithic); antiviral agents (antiviral); appetite suppressant (appetite suppressant); treatment of benign prostate hyperplasia agent (benign prostatic hyperplasia therapy agent); blood sugar regulator (blood glucose regulator); bone resorption inhibitor (bone resorptioninhibitor); bronchodilator (bronchodilator); carbonic anhydrase inhibitors (carbonic anhydrase inhibitor); cardiac depressant (cardiac depressant); cardioprotectant (cardioprotectant); cardiac tonic (cardiotonic); cardiovascular drug (cardiovascular agent); choleretic (choleretic); cholinergic agent (cholinergic); cholinergic diagnostic aid (cholinergie diagnostic aid); diuretic (diuretic); dopaminergic (dopaminergic agent); ectoparasiticide (ectoparasiticide); emetic (emetic); enzyme inhibitor (enxzymeinhibitor); estrogen (estrogen); fibrinolytic (fibrinolytic); fluorescent agent (flourescent agent); oxygen free radical scavenger (free oxygen radicalscavenger); gastrointestinal peristalsis effector (gastrointestinal motility effector); glucocorticoid (glucocorticoid); gonadotrope (gonad-stimulatingprinciple); hair growth stimulus object (hair growth stimulant); hemorrhage (hemostatic); histamine H2 receptor antagonist (histamine H2 receptorantagonist); hormone (hormone); pravastatin (hypocholesterolemic); blood sugar lowering (hypoglycemic); hypolipidemic (hypolipidemic); hypotensor (hypotensive); developer (imaging agent); immunizing agent (immunizing agent); imnlune modulator (immunomodulator); immunomodulator (immunoregulator); immunostimulant (immunostimulant); immunosuppressant (immunosuppressant); impotence treatment agent (impotence therapy); inhibitor (inhibitor); keratolytic (keratolytic); LNRN agonist (LNRN agonist); hepatopathy therapeutic agent (liverdisorder treatment); luteolysin (luteolysin); memory accessory drugs (memoryadjuvant); psychology performance reinforcing agent (mental performance enhancer); mood regulation agent (mood regulator); mucolytic (mucolytic); mucosa protective agent (mucosalprotective agent); mydriatic (mydriatic); the congested medicine (nasaldecongestant) of eliminating of nasal mucosa; neuromuscular blocking agents (neuromuscular blocking agent); neuroprotective (neuroprotective); nmda antagonist (NMDA antagonist); non-hormone sterol derivative (non-hormonal sterol derivative); oxytocic (oxytocic); plasminogen activator (plasminogen activator); platelet activating factor antagonist (platelet activating factor antagonist); anticoagulant (platelet aggregaton inhibitor); after the apoplexy and head trauma after therapeutic agent (post-stroke and post-head trauma treatment); intensifier (potentiator); Progesterone (progestin); prostaglandin (prostaglandin); prostate growth inhibitor (prostate growth inhibitor); thyrotropin former (prothyrotropin); psychotropic drugs (psychotropic); radiopharmaceutical (radioactive agent); regulator (regulator); relaxant (relaxant); heavy partitioning agent (repartitioning agent); Scabicide (scabicide); sclerosing agent (sclerosing agent); tranquilizer (sedative); sedative hypnotic (sedative-hypnotic); selective adenosine A1 antagonist (selective adenosineA1 antagonist); 5-hydroxytryptamine antagonist (serotonin antagonist); serotonin antagonist (serotinin inhibitor); 5-hydroxytryptamine receptor antagonist (serotininreceptor antagonist); steroid (steroid); stimulus object (stimulant); depressant (suppressant); symptomatic multiple sclerosis (symptomatic multiplesclerosis); synergist (synergist); thyroxin (thyroid hormone); thyroid imhibitor (thyroid inhibitor); thyromimetic (thyromimetic); tranquilizer (tranquilizer); amyotrophic lateral sclerosis therapeutic agent (treatmentof amyotrophic lat erial sclerosis); cerebral ischemia therapeutic agent (treatment ofcerebral ischemia); Paget therapeutic agent (treatment of Paget ' s disease); unstable angina pectoris therapeutic agent (treatment of unstable angina); uricosuric (uricosuric); vasoconstrictor (vasoconstrictor); vasodilator (vasodilator); vulnerary (vulnerary); wound healing medicine (wound healingagent) and xanthine oxidase inhibitor (zxanthine oxidase inhibitor).

Concrete biological agent as the example of above disclosed different kind organism medicament includes but not limited to: acebutolol (Acebutolol); Acebutolol (Acebutolol); ACV (Acyclovir); Salbutamol (Albuterol); Alfentanil (Alfentanil); Almotriptan (Almotriptan); Alprazolam (Alprazlam); Amiodarone (Amiodarone); Amlexanox (Amlexanox); Amphotericin B (Amphotericin B); NSC 24345 (Anecortave Acetate); Atorvastatin (Atorvastatin); Atropine (Atropine); Anranofin (Auranofin); Aurothioglucose (Aurothioglucose); Benazepil (Benazepril); Bicalutamide (Bicalutamide); Bretylium tosylate (Bretylium); Brifentanil (Brifentanil); Bromocriptine (Bromocriptine); Buprenorphine (Buprenorphine); Butorphanol (Butorphanol); Buspirone (Buspirone); Calcitonin (Calcitonin); Candesartan (Candesartan); Carfentanil (Carfentanil); Carvedilol (Carvedilol); Chlorphenamine (Chlorpheniramine); Chlorothiazide (Chlorothiazide); Chlorphentermine (Chlorphentermine); Chlorpromazine (Chlorpromazine); Clindamycin (Clindamycin); Clonidine (Clonidine); Codeine (Codeine); Cyclosporin (Cyclosporine); Desipramine (Desipramine); Minirin (Desmopressin); Dexamethasone (Dexamethasone); Diazepam (Diazepam); Diclofenac (Diclofenac); Digoxin (Digoxin); Dihydrocodeine (Digydrocodeine); Dolasetron (Dolasetron); Dopamine (Dopamine); Doxepin (Doxepin); Doxycycline (Doxycycline); Dronabinol (Dronabinol); Droperidol (Droperidol); Dyclonine (Dyclonine); Eletriptan (Eletriptan); Enalapril (Enalapril); Enoxaparin (Enoxaparin); Ephedrine (Ephedrine); Adrenaline (Epinephrine); Ergotamine (Ergotamine); Etomidate (Etomidate); Famotidine (Famotidine); Felodipine (Felodipine); Fentanyl (Fentanyl); Fexofenadine (Fexofenadine); Fluconazole (Fluconazole); Prozac (Fluoxetine); Fluphenazinum (Fluphenazine); Flurbiprofen (Flurbiprofen); Fluvastatin (Fluvastatin); Fluvoxamine (Fluvoxamine); Frovatriptan (Frovatriptan); Frusemide (Furosemide); GCV (Ganciclovir); Sodium aurothiomalate (Gold sodium thiomalate); Granisetron (Granisetron); Griseofulvin (Griseofulvin); Haloperole (Haloperidol); Hepatitis B virus vaccine (Hepatitis B Virus Vaccine); Hydrolazine (Hydralazine); Hydromorphone (Hydromorphone); Insulin (Insulin); Ipratropium (Ipratropium); Isradipine (Isradipine); ISDN (Isosorbide Dinitrate); Ketamine (Ketamine); Ketorolac (Ketorolac); Labetalol (Labetalol); Levorphanol (Levorphanol); Lisinopril (Lisinopril); Loratadine (Loratadine); Lorazepam (Lorazepam); Losartan (Losartan); Lovastatin (Lovastatin); Melatonin (Melatonin); Ethyldopa (Methyldopa); Methylphenidate (Methylphenidate); Metoprolol (Metoprolol); Midazolam (Midazolam); Mirtazapine (Mirtazapine); Morphine (Morhpine); Nadolol (Nadolol); Nalbuphine (Nalbuphine); Naloxone (Naloxone); Naltrexone (Naltrexone); Naratriptan (Naratriptan); Neostigmine (Neostigmine); Nicardipine (Nicardipine); Nifedipine (Nifedipine); Norepinephrine (Norepinephrine); Nortriptyline (Nortriptyline); Octreotide (Octreotide) and analog thereof; Olanzapine (Olanzapine); Omeprazole (Omeprazole); Ondansetron (Ondansetron); Oxybutynin (Oxybutynin); Oxycodone (Oxycodone); Oxymorphone (Oxymorphone); Oxytocin (Oxytocin); Neo-synephrine (Phenylephrine); Phenylpropanolamine (Phenylpropanolaimine); Phenytoinum naticum (Phenytoin); Pimozide (Pimozide); Pioglitazone (Pioglitazone); Piroxicam (Piroxicam); Pravastatin (Pravastatin); Prazosin (Prazosin); Prochlorperazine (Prochlorperazine); Propafenone (Propafenone); Prochlorperazine (Prochlorperazine); Propiomazine (Propiomazine); Propofol (Propofol); Propranolol (Propranolol); Pseudoephedrine (Pseudoephedrine); This bright (Pyridostigmine) of pyrrole; Quetiapine (Quetiapine); Raloxifene (Raloxifene); Remifentanil (Remifentanil); Recombinant human Fab V2 (rhuFab V2); Rofecoxib (Rofecoxib); Repaglinide (Repaglinide); Risperidone (Risperidone); Rizatriptan (Rizatriptan); Ropinirole (Ropinirole); Growth hormone release inhibiting hormone (Somatostatin) and analog thereof; Hyoscine (Scopolamine); Selegiline (Selegiline); Sertraline (Sertraline); Silaenafil (Sildenafil); Simvastatin (Simvastatin); Sirolimus (Sirolimus); Spirolactone (Spironolactone); Sufentanil (Sufentanil); Sumatriptan (Sumatriptan); Tacrolimus (Tacrolimus); TAM (Tamoxifen); Terbinafine (Terbinafine); Terbutaline (Terbutaline); Testosterone (Testosterone); Tetanus toxoid (Tetanus toxoid); THC Tolterodine (THC Tolterodine); Triamterene (Triamterene); Triazolam (Triazolam); Trimeglamide (Tricetamide); Valsartan (Valsartan); Venlafaxine (Venlafaxine); Verapamil (Verapamil); Tie up fast Da Er (Visudyne); Zaleplon (Zaleplon); Zanamivir (Zanamivir); Zafirlukast (Zafirlukast); Zolmitriptan (Zolmitriptan) and zolpidem (Zolpidem).

The amount of the biological agent that provides with compositions is decided according to the required therapeutic dose of administration, but but the biological agent component that usually exists be flow composition weight about 0.001% to about 50%, but more particularly be about 0.005% to about 35% of flow composition weight.

In one embodiment, but flow composition of the present invention can comprise the antimigraine as biological agent.Antimigraine can comprise for example naratriptan, Zolmitriptan, rizatriptan, frovatriptan, octreotide, sumatriptan or other " Qu Putan class " biological agents.

In another embodiment, but flow composition of the present invention can comprise the angiogenesis inhibitor medicine as biological agent.But can sending the angiogenesis inhibitor medicine, passs this flow composition, with effective treatment diabetic retinopathy patient or patients with macular degeneration to the retina choroid.

In another embodiment, but flow composition of the present invention can comprise the immunosuppressant as biological agent, with effective treatment uveitis patient.

In another embodiment, but flow composition of the present invention can comprise immunosuppressant or the anti-inflammatory agent as biological agent.Pass to tarsal conjunctiva (270) but should flow composition immunosuppressant or anti-inflammatory agent part can be sent, with effective treatment vernal keratoconjunctivitis.

In another embodiment, but flow composition of the present invention can comprise the wound healing medicine as biological agent.But this flow composition can effectively be kept this biological agent and contact with the direct of corneal wound.

In another embodiment, but flow composition of the present invention can comprise antiviral agents, antibiotic, antifungal or its combination.But should can effectively treat infectious disease (for example antibacterial, virus or fungus) by flow composition.

In another embodiment, but flow composition of the present invention can comprise antiviral agents.Pass to cornea (350) or (250) but this flow composition can send antiviral agents, suffer from the patient of phlyctenular conjunctivitis or blepharitis with effective treatment.

" treatment " used herein or " processing " are meant that (i) prevents generation (for example prevention) or its related symptoms of pathologic illness; (ii) suppress the pathologic illness or stop its development or suppress its related symptoms; Perhaps (iii) alleviate pathologic illness or its related symptoms.

Should be understood that, those skilled in the art will know that term " solvable " and " insoluble " are the terms of relative meaning.For example, dissolubility is about 1 * 10 in the water ^-45The material of mg/L is water-fast relatively.But it still has dissolubility in certain (promptly discrete and limited) water.Because this terminology imprecision, the applicant has used the term of " from arbitrary portion complete insoluble to the completely soluble dissolubility of all parts ", " to the small part water solublity " and " complete water solublity " to describe organic solvent/liquid.

It is to be further understood that to those skilled in the art will know that the dissolubility of organic solvent/liquid in body fluid can change, for example for concrete body fluid and can be different for concrete individuality.Because the applicant does not know any generally accepted parameter that defines organic liquid/solvent with the dissolubility in body fluid, so the applicant describes organic liquid/solvent according to the dissolubility in water.Therefore, when mentioning the dissolubility of organic liquid/solvent in water, be interpreted as those skilled in the art will know that this has provided and instruct and guide for have equal deliquescent organic liquid/solvent in body fluid.Although know, the dissolubility in the body fluid, not every organic liquid/solvent all has identical water solublity, and this has still provided and has instructed and guide.

Term " ester bond " is meant-OC (=O)-or-C (=O) O-; Term " thioester bond " is meant-SC (=O)-or-C (=O) S-; Term " amido link " is meant-N (R) C (=O)-or-C (=O) N (R)-; Term " phosphate ester " is meant-OP (=O) ₂O-; The term sulphonic acid ester is meant-SO ₂O-or-OSO ₂-, wherein each R is suitable organic group, for example hydrogen, (C ₁-C ₂₀) alkyl, (C ₃-C ₆) cycloalkyl, (C ₃-C ₆) cycloalkyl (C ₁-C ₂₀) alkyl, aryl, heteroaryl, aryl (C ₁-C ₂₀) alkyl or heteroaryl (C ₁-C ₂₀) alkyl.

Term " aminoacid " comprises the natural amino acid (Ala for example of D or L shaped formula, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val) residue and alpha-non-natural amino acid (phosphoserine for example, phosphothreonine, phosphotyrosine, hydroxyproline, γ-carboxyl glutamine, hippuric acid, the octahydro indole-2-carboxylic acid, statine (statine), 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, citrulline, Alpha-Methyl-alanine, to the benzoyl phenylalanine, phenylglycine, PGIY, sarcosine and tert-butyl group glycine) residue.This term also comprises have common amido protecting the group natural and alpha-non-natural amino acid of (for example acyl group or benzyloxycarbonyl group), and c-terminus is (for example as (C ₁-C ₆) alkyl, phenyl or benzyl ester or amide; Perhaps as the α-Jia Jibianji amide) protected natural and alpha-non-natural amino acid.Known other suitable amino of those skilled in the art and carboxy protective group are (referring to for example Greene, T.W.; Wutz, P.G.M. ＂ Protecting Groups In Organic Synthesis ＂ second edition, 1991, New York, John Wiley ﹠amp; Sons, Inc., and quote the document).

What term " peptide " was described is the sequence with 2-35 aminoacid (for example, defining as mentioned) or peptidyl residue.This sequence can be linearity or cyclic.For example cyclic peptide can prepare or obtain by formation disulphide bridges between two cysteine of sequence.Preferably, peptide comprises 3 to 20 or 5 to 15 aminoacid.Peptide derivant can be by United States Patent (USP) 4,612, and 302,4,853,371 and 4,684,620 disclosed content preparations perhaps prepare described in this paper embodiment hereinafter.The concrete described peptide sequence of this paper with aminoterminal in the left side, c-terminus writes in the mode on right side.

Term " sugar " is meant sugar or other carbohydrates arbitrarily, especially refers to better simply sugar or carbohydrate.Sugar is the basic structure component of living cells, also is the basic energy source of animal.This term comprises micromolecular simple sugars, also comprises macromolecular substances.Can come sugar is classified according to monosaccharide group number contained in the sugar.

The class that is meant term " polysaccharide " contains the carbohydrate of the glycan molecule that promptly links together by glycosidic bond with chemical mode.This term is meant any one of a class carbohydrate kind, and this class carbohydrate is the carbohydrate that is made of the formed chain of simple sugar.Polysaccharide is the polymer that is made of a plurality of monosaccharide (simple sugar) unit.

Term " fatty acid " " be meant a class aliphatic monocarboxylic acid, they constitute the part of lipid molecular, and can obtain by hydrolyzed fat.This term is meant and is present in many long-chain fat carboxylic acids that fat, coil neutralization exists as the component of the phospholipid of animal cell membrane and glycolipid any one.

Term " many alcohol " is meant the hydrocarbon that contains one or more (for example 2,3,4 or 5) hydroxyl.

Term " carbohydrate " refers to the basic structure component of living cells and the basic energy source of animal; It comprises micromolecular simple sugar and macromolecular substances; Can classify according to the number of their contained monosaccharide groups.This term refers to one of following chemical compound, described chemical compound comprises sugar, starch and natural gum, and it contains six (or multiple of six) carbon atoms, and carbon atom combines with number could vary hydrogen atom and oxygen atom, but but hydrogen atom and oxygen atom always exist with the ratio that forms water, as glucose { C ₆H ₁₂O ₆.This term is meant that by ratio be chemical compound and the molecule that hydrogen, carbon and the oxygen of 2H:1C:1O is formed.Carbohydrate can be for example sucrose and a fructose of simple sugar, or complicated polysaccharide polymer chitin for example.

" starch " used herein be meant be present in the plant, repeat the complicated polysaccharide that subunit and α-(1,6)-glycosidic bond form by α-(1,4)-D-glucose.

" dextrin " used herein is meant the glucose polymer of the medium chain that starch is partly degraded produce by heat, acid, enzyme or its combination.

" maltodextrin " used herein or " glucose polymer " be meant by the main D-glucose unit that connects by α-1,4 key form and DE (glucose equivalent) less than 20 no sweet taste trophism glycopolymers.Referring to for example FDA (Food and Drug Adminstration) (21C.C.R.184.1444 chapters and sections).Maltodextrin is the starch partial hydrolysate.Starch hydrolysate characterizes with its hydrolysis degree usually, and (DE) represents with glucose equivalent, and DE is counted as the percentage ratio that the sugar of glucose is reduced by dry weight basis.

" cyclodextrin " used herein be meant naturally occurring clathrate and act on the product that starch gets by bacillus macerans amylase (Bacillus macerans amylase), for example α-, β-and gamma-cyclodextrin.

But flow composition

According to the present invention, but a kind of flow composition is provided, and acceptable salt or its prodrug are dissolved in or are scattered in the biocompatibility organic solvent on wherein biocompatible, biodegradable thermoplastic polymer and biological agent, its metabolite, its biopharmaceutics.

After aqueous medium, body fluid or water contact, but be somebody's turn to do the flow composition solidification to form implant or implantable material.Be used to control drug release by formed implant of flowable polymer compositions of the present invention and implantable material.When but flow composition carried out to implant or the conversion of implantable material, acceptable salt or its prodrug were comprised in the cured polymer substrate on biological agent, its metabolite, its biopharmaceutics.When this implant is present in the body, acceptable salt or its prodrug on its metabolite, its biopharmaceutics, by separating, pass polymeric matrix and discharge in the mode that continues through diffusion in the direct stripping of implant surface with by the degraded and the erosion of thermoplastic polymer.

Polymer

Used according to the invention, biocompatible, biodegradable thermoplastic polymer can make by the multiple monomer that forms polymer chain or by the monomeric unit that linking group links together.These polymer comprise having the polymer chain that contains following linking group and the polymer of main polymer chain, described linking group is ester, amide, carbamate, anhydride, carbonic ester, urea, esteramides, acetal, ketal and orthocarbonic ester group for example, and other can be by enzymatic reaction or hydrolysis (promptly biodegradable by this hydrolysis) and the organo-functional group of hydrolysis arbitrarily.These polymer normally reaction of the initial monomers by containing reactant group form, and described reactive group can form these main chain linking groups.For example, alcohol and carboxylic acid can form the ester linking group.Carbimide. and amine or alcohol can form urea or carbamate linking group respectively.

According to the present invention, certain part of one of these initial monomers is at least trifunctional, is preferably polyfunctional.The polymer chain that this multifunctional feature can be gained provides at least some branches.For example, when selected polymer when this main polymer chain contains the ester linking group, initial monomers can be the cyclic dimer of hydroxyl carboxylic acid, hydroxyl carboxylic acid, cyclic trimer, glycol or the dicarboxylic acids of hydroxyl carboxylic acid usually.Polymer of the present invention can be included by certain part with initial monomers and be obtained, and described initial monomers is polyfunctional at least.In addition, polymer of the present invention, each polymer molecule can comprise more than one multifunctional unit, generally include a plurality of multifunctional unit, and this stoichiometry according to polyreaction is decided.Preferably, polymer of the present invention, each polymer molecule comprise at least one multifunctional unit.So-called star polymer or branched polymer when all including a multifunctional unit in each polymer molecule, have just been formed.Biodegradable, biocompatible thermoplastic polymer of the present invention can be a linear polymer, and biodegradable, biocompatible thermoplastic polymer perhaps of the present invention can be a branched polymer.

For example, for above-mentioned ester linking group polymer, first kind of initial monomers can comprise dihydroxy carboxylic acids, and perhaps second kind of initial monomers can comprise triol and/or tricarboxylic acids.Similarly, first kind of initial monomers can comprise triol, tetrol, pentol or six alcohol for example Sorbitol or glucose.For the applicable same principle of polyamide.Diamidogen and dicarboxylic acids initial monomers can comprise triamine and/or ternary acid.Second kind of initial monomers aminoacid can comprise diamino dicarboxylic acid, diamino monocarboxylic acid or triamine.According to the present invention, any aliphatic, aryl or aralkyl initial monomers with concrete functional group can be used to prepare branched thermoplastic polymer of the present invention, and prerequisite is that this polymer and their catabolites are biocompatible.Biocompatibility technical specification to this class initial monomers is known in this area.

Particularly, the monomer that is used to prepare the branched polymer of biocompatible thermoplasticity of the present invention can be produced biocompatible and biodegradable polymer or copolymer.Be suitable for use as the biocompatible of the branched polymer of biocompatible thermoplasticity of the present invention, the example of biodegradable polymer comprises polyester, polylactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, polycaprolactone, polyanhydride, polyamide, polyurethanes, polyesteramide, poly-to dioxanone, polyacetals, polyketals, Merlon, poly-orthocarbonic ester, poe, poly phosphate, polyphosphazene, the poly hydroxybutyric acid ester, poly-hydroxyvaline ester, poly-oxalic acid alkylene ester (polyalkylene oxalate), poly-succinic acid alkylene ester (polyalkylene succinate), polymalic acid, the copolymer of polyamino acid and above-mentioned substance, terpolymer or its compositions or mixture.

Polymer composition of the present invention also can comprise the admixture of polymer of the present invention and other biological compatible polymer, and condition is that they do not produce bad interference to the biodegradable feature of said composition.The admixture of polymer of the present invention and described other polymer send and pass required accurate release profiles at the design targeted drug, or the required biodegradable accurate speed of structure implant (for example being used for orthopedics's purposes) has more motility.

Preferred biocompatible thermoplastic polymer of the present invention or copolymer have than low-crystallinity and than high hydrophobicity.Compare with for example poly-Acetic acid, hydroxy-, bimol. cyclic ester of high crystallinity polymer or chitin, these polymer and copolymer more are soluble in biocompatible organic solvent, and described high crystallinity polymer has the hydrogen bond of higher degree.Preferred substance with desirable solubility parameter is the copolymer of branched polylactide, polycaprolactone and they and Acetic acid, hydroxy-, bimol. cyclic ester, thereby has more amorphous areas to strengthen dissolubility in these materials.Generally speaking, be dissolved in organic solvent on biocompatible, biodegradable thermoplastic polymer based, so that the mixture that can prepare contains the solid of 50-60 weight % at most.Preferably, polymer used according to the invention is dissolved in organic solvent substantially fully, so that the mixture that can prepare contains the solid of 85-98 weight % at most.This polymer is also water insoluble at least substantially, makes in every ml water dissolving or dispersive polymer be less than 0.1g.Preferably, polymer used according to the invention is gone up water insoluble fully substantially, makes in every ml water dissolving or dispersive polymer be less than 0.001g.On this preferred level, but the flow composition that contains complete water-miscible solvent almost can be converted into solid polymer.

Solvent/liquid

But the liquid that is applicable to flow composition is biocompatible, and is slightly soluble in aqueous medium, body fluid or water at least.Organic liquid preferably at least in aqueous medium, body fluid or water moderate solvable, more preferably very easily molten, most preferably all solvable with any concentration.At least the organic liquid that is slightly soluble in aqueous medium or body fluid can make water infiltrate in the polymer solution in time several seconds to several weeks, it is solidified or solidifies.But slightly soluble liquid can diffuse out lentamente from flow composition, makes usually for example to transform to several weeks at about one day in the time period of a few days to several weeks.But the solvable extremely fairly soluble organic liquor cognition of moderate diffused out from flow composition to the time of a few days at several minutes, thereby transformed rapidly, but the operation after enough aperture times carry out flexible implant placement is arranged during this.But can diffusing out from flow composition in the several seconds to a few hours, highly soluble organic liquid almost just transforms immediately.Preferred organic liquid is polar non-proton organic solvent or polar protic organic solvent.Preferably, the molecular weight of organic solvent is about 30 to about 1000.

But though but but flow composition to solid transformation be considered to organic liquid from the flow composition loss to around aqueous medium or the body fluid and water immerse the result the organic liquid in the flow composition from aqueous medium or body fluid on every side, this does not mean it is limitation of the present invention.In transition process, but think that thermoplastic polymer and organic liquid in the flow composition have been assigned to the zone of enrichment polymer and have lacked the zone of polymer.The zone that lacks polymer is immersed by water gradually, thereby forms the porous character of gained solid structure.

The example that can be used for forming the biocompatibility organic liquid of the present composition is included in room temperature and physiological temp and is liquid or flowable at least and contain aliphatic, aryl and aralkyl linearity, ring-type and the branched organic compound of following functional group down, and described functional group is as alcohol, ketone, ether, amide, ester, carbonic ester, sulfoxide, sulfone and other functional groups compatible with living tissue.

At least the preferred biocompatibility organic liquid that is slightly soluble in aqueous medium or body fluid comprises: N-N-methyl-2-2-pyrrolidone N-, 2-Pyrrolidone; C ₁-C ₁₅Alcohol, glycol, three pure and mild tetrols, for example ethanol, glycerol, propylene glycol, butanols; C ₃-C ₁₅Alkyl ketone, for example acetone, diethyl ketone and methyl ethyl ketone; C ₃-C ₁₅Ester, for example methyl acetate, ethyl acetate, ethyl lactate; C ₁-C ₁₅Amide, for example dimethyl formamide, dimethyl acetylamide and caprolactam; C ₃-C ₂₀Ether, for example oxolane or the acetone glycerol (solketal) that contracts; Tweens, glyceryl triacetate, propylene carbonate, decyl methyl sulfoxide, dimethyl sulfoxide, oleic acid and 1-dodecyl-aza-cycloheptane-2-ketone.Other preferred organic liquids are benzyl alcohol, benzyl benzoate, dipropylene glycol, tributyorin, ethyl oleate, glycerol, Tetrahydrofurfuryl polyethylene glycol ether (glycofural), isopropyl myristate, isopropyl palmitate, oleic acid, Polyethylene Glycol, Allyl carbonate and triethyl citrate.In view of its solvability and their compatibility, most preferred solvent is N-N-methyl-2-2-pyrrolidone N-, 2-Pyrrolidone, dimethyl sulfoxide, glyceryl triacetate and Allyl carbonate.

Biodegradable thermoplastic polymer is according to their crystallinity, their hydrophilic, hydrogen bonded and molecular weight, the dissolubility difference in different organic liquid agent.The polymer that molecular weight is lower more is soluble in organic liquid than high molecular weight polymers usually.Therefore, according to the type and the molecular weight thereof of polymer, the concentration difference of polymer dissolution in different organic liquids.And, to compare with the material of lower molecular weight, the polymer of higher molecular weight easily produces higher solution viscosity.

Usually, according to the present invention, the concentration range of polymer in organic liquid is that about 0.01g/ml organic liquid is to saturated concentration.In general, saturated concentration is the solid of 80-95 weight % or for every milliliter of organic liquid 4 to about 5gm (supposing the heavily about 1gm/ml of solvent) is arranged.

For the polymer that is difficult for rapid solidification, can use solvent mixture to increase setting rate.Basically, a kind of component of solvent mixture is the good solvent of polymer, and the another kind of component of solvent mixture is relatively poor solvent or is non-solvent.Two kinds of liquid are with a kind of like this mixed, and described ratio can make polymer still solvable, but precipitate when the amount of non-solvent (for example water in the physiological environment) increases a little.This solvent system is necessary can be all miscible with polymer and water, and this point is inevitable.An example of this binary solvent system is N-Methyl pyrrolidone and ethanol.In the NMP/ polymer solution, add ethanol and then increase its setting rate.

If when using the organic liquid subgroup of compositions, then can keep the flexibility of compositions substantially as the whole life period of implant in compositions.This organic liquid also can be used as the plasticizer of thermoplastic polymer, and has at least part can remain in the compositions rather than be scattered in the body fluid, and is especially all the more so when dissolubility in organic liquid water hangs down.Except the organic liquid of highly-water-soluble, also can comprise this organic liquid that has dissolubility in the described low water and have plasticising character in the compositions.For a kind of situation in back, first kind of organic liquid preferably is scattered in the body fluid fast.

The organic liquid of low aqueous solubility promptly is formed on the organic liquid of the aqueous solution that is no more than 5 weight % in the water, also can be used as the organic liquid of implant composition.This class organic liquid also can be used as the plasticizer of thermoplastic polymer.When organic liquid had these character, it just became the member who is called the organic solvent subgroup of " plasticizer organic liquid " by this paper.The plasticizer organic solvent is influential to the flexibility and the moldability of implant composition, thereby can make the patient feel more comfortable when it is implanted.And the plasticizer organic liquid can influence the lasting rate of release of bioactive agent, thereby can speed be increased or reduces according to the characteristic of mixing the plasticizer organic liquid in the implant composition.Though the organic liquid with low aqueous solubility and plasticization capacity can be used alone as the organic liquid of implant composition, preferably is used in combination as follows.When selecting the highly-water-soluble organic liquid when being mainly used in the implant composition, can realize the plasticizer effect by second kind of organic liquid that use has low aqueous solubility and a plasticization capacity.In this case, second kind of organic liquid is the member of organic liquid subgroup, and some maintains in the implant composition in one period persistent period at least.Usually, the organic liquid as plasticizer is considered to can promote molecular motion in solid thermoplastic substrate.Plasticity can make the polymer molecule of substrate relative to each other move, thereby flexibility and the performance that is easy to mold pressing are provided.Plasticity also can make bioactive agent more easily move, thereby in some cases, can influence the speed that continues release positive or negatively.

Highly-water-soluble organic liquid/solvent

Usually the highly-water-soluble organic liquid can be used in the implant composition, when especially not having flexible problem after implant composition is implanted.But but use the highly-water-soluble organic liquid can produce the implant of physical characteristic and the implant of finishing by direct insertion flow composition with flow composition.But this class implant and precursor flow composition for example are described in the United States Patent (USP) 4,938,763 and 5,278,201, and its disclosure mode is by reference included this paper in.

Available highly-water-soluble organic liquid comprises, for example, and the heterocyclic compound of replacement, for example N-N-methyl-2-2-pyrrolidone N-(NMP) and 2-Pyrrolidone; C ₂To C ₁₀Alkanoic acid, for example acetic acid and lactic acid; Carboxylic esters, for example methyl lactate, ethyl lactate, citric acid Arrcostab etc.; The monoesters of polybasic carboxylic acid, for example monomethyl succinate, citric acid mono-methyl etc.; Ether alcohol, for example Tetrahydrofurfuryl polyethylene glycol ether (glycofurol), glycerol formal (glycerol formal), isopropylidene glycol, 2,2-dimethyl-1,3-dioxolone-4-methanol; The acetone glycerol that contracts; Dialkyl amide, for example dimethyl formamide, dimethyl acetylamide; Dimethyl sulfoxide (DMSO) and dimethylsulfone; Lactone, for example 6-caprolactone and butyrolactone; Cyclic alkyl amide, for example caprolactam; And their mixture and compositions.Preferred organic liquid comprises N-N-methyl-2-2-pyrrolidone N-, 2-Pyrrolidone, dimethyl sulfoxide, ethyl lactate, Tetrahydrofurfuryl polyethylene glycol ether, glycerol formal and isopropylidene glycol.

Low aqueous solubility organic liquid/solvent

As mentioned above, low aqueous solubility liquid also can be used in the implant composition.Preferably, keep flexible and use low aqueous solubility liquid during the implant that can be extruded when needs.And, by using the low aqueous solubility organic liquid, can influence the rate of release of bioactive agent in some cases.Usually, this class situation comprise organic liquid in the implant product when sluggish and it play the time spent of doing of plasticizer.

The example of low aqueous solubility organic liquid comprises the ester of carbonic acid and aryl alcohol, for example benzyl benzoate; C ₄-C ₁₀Alkylol; C ₂-C ₆Alkanoic acid C ₁-C ₆Arrcostab; The ester of carbonic acid and alkylol, for example propyl carbonate, ethylene carbonate and DMC dimethyl carbonate; Monocarboxylic acid, dicarboxylic acids and tricarboxylic Arrcostab, for example acetic acid-2-ethoxy-ethyl ester, ethyl acetate, methyl acetate, ethyl n-butyrate., diethyl malonate, glutamate diethyl ester, tributyl citrate, diethyl succinate, tributyorin, isopropyl myristate, dimethyl adipate, dimethyl succinate, dimethyl oxalate., citric acid dimethyl ester, triethyl citrate, citric acid acetyl tributyl, glyceryl triacetate; Alkyl ketone, for example butanone; And other have the to a certain degree water miscible liquid organic compound that contains other carbonyls, ether, carboxylate, amide and hydroxyl.In view of its biocompatibility with to the acceptance of biological agent, preferred propyl carbonate, ethyl acetate, triethyl citrate, isopropyl myristate and glyceryl triacetate.

In addition, for providing the mixture of the aforementioned highly-water-soluble of different solubilities and low aqueous solubility organic liquid, the material that forms substrate can be used for changing the setting rate of implant composition.Example comprises the combination of N-Methyl pyrrolidone and propyl carbonate, can provide than independent N-Methyl pyrrolidone to have more hydrophobic solvent; And the combination of N-Methyl pyrrolidone and Polyethylene Glycol, can provide than independent N-Methyl pyrrolidone to have more hydrophilic solvent.

Prodrug comprises hydroxyl well known to those skilled in the art and aminoderivative, the ester that is made by parent hydroxy chemical compound and suitable carboxylic acid reaction for example, or the amide that is made by parent amino-compound and suitable carboxylic acid reaction.Simple fatty ester or the aromatic ester that obtains from chemical compound hydroxyl side chain used in the present invention is preferred prodrug.Need to prepare the prodrug of dibasic acid esters type in some cases, for example (acyloxy) Arrcostab or ((alkoxy carbonyl group) oxygen) Arrcostab.Suitable concrete ester as prodrug comprises methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, the tert-butyl group and morpholino ethyl ester.

Hydrolysis in Drug and Prodrug Metabolism:Chemistry, Biochemistry, and Enzymology, by Bernard Testa and Joachim Mayer; Vch Verlagsgesellschaft Mbh (August 2003) has made comprehensive summary to the metabolic response and the enzyme that relate in medicine and the prodrug hydrolysis.This article has also been described the meaning of biotransformation and the hydrolysis of hydrolytic enzyme, amide has been discussed and the physiological action of the hydrolysis of lactams.Other lists of references that can be used for designing prodrug used in the present invention comprise, for example, Biological Approaches to theControlled Delivery of Drugs (Annals of the New York Academy ofSciences, Vol.507), R.L.Juliano (editor) (February 1988); Designof Biobiological agent Properties through Prodrugs and Analogs, Edward B.Roche (editor), Amer Biological agent Assn (MacK) is (June1977); Prodrugs:Topical and Ocular Drug Delivery (Drugs and theBiological agent Sciences, Vol.53), Kenneth B.Sloan (editor), Marcel Dekker (March17,1992); Enzyme-Prodrug Strategies forCancer Therapy, Roger G.Melton (editor), Richard J.Knox (editor), Plenum Press (February 1999); Design of Prodrugs, Hans Bundgaard (editor), Elsevier Science (February 1986); Textbook of DrugDesign and Development, Povl Krogsgaard-Larsen, Hans Bundgaard (editor), Hardwood Academic Pub (May 1991); Conversion ofNon-Toxic Prodrugs to Active, Anti-Neoplastic Drugs Selectivelyin Breast Cancer Metastases, Basse, Per H. (September 2000) and Marine lipids for prodrugs, of compounds and other biological agentapplications, M.M á sson, T.Loftsson and is à raldsson G.30G.H, Die Pharmazie, 55 (3), 172-177 (2000).

Prodrug used in the present invention comprise can by lyolysis or under physiological condition with the functional group of chemical mode or the cracked any appropriate of metabolic way, thereby bioactive compound is provided.Suitable functional group comprises for example carboxylate, amide and thioester.According to the reactive functional groups of bioactive compound, the corresponding functional group of suitable junctional complex precursor can be selected from the functional group in the following table, to form for example ester bond, thioester bond or the amido link in the prodrug.

Functional group on the bioactive compound	Functional group on the junctional complex precursor	The key of gained in the prodrug
			-COOH	-OH	Ester
-COOH	-NHR	Amide
			-COOH	-SH	Thioester
-OH	-COOH	Carboxylate
			-SH	-COOH	Thioester
-NHR	-COOH	Amide
			-OH	-OP(＝O)(OH) 2	Phosphate ester
-OH	-OP(＝O)(OR) 2	Phosphate ester
			-OH	-SO 2OH	Sulphonic acid ester

Junctional complex precursor and linking group

Bioactive compound can link to each other so that prodrug to be provided with suitable junctional complex precursor.As implied above, the reactive functional groups that exists on the bioactive compound usually can be influential to the functional group that need are present on the junctional complex precursor.The character of junctional complex precursor is not crucial, and condition is mechanical property and the release dynamics that prodrug used in the present invention has selected treatment application need.It is that about 25 dalton are to about 400 daltonian bivalence organic radicals that the junctional complex precursor is generally molecular weight.More preferably, junctional complex precursor molecule amount is that about 40 dalton are to about 200 dalton.

The gained linking group that is present on the prodrug can be that inanimate object is active, perhaps it self biologically active.Linking group also can comprise other functional groups (comprising hydroxyl, sulfydryl, amido, carboxylic acid etc.) of the character that can be used for changing prodrug (additional other molecules on prodrug for example change the dissolubility of prodrug or influence the bio distribution of prodrug).

Particularly; linking group can be the bivalence with 1-50 carbon atom; branch or unbranched; saturated or undersaturated hydrocarbon chain; wherein one or more are (for example 1 years old; 2; 3 or 4) carbon atom is optional by (O-) or (NR-) replace; wherein R can be a hydrogen; alkyl; cycloalkyl or aralkyl; wherein this chain is chosen wantonly on carbon by one or more (for example 1; 2; 3 or 4) the substituent group replacement; described substituent group is selected from alkoxyl; the alkoxyl that replaces; cycloalkyl; the cycloalkyl that replaces; alkanoyl; alkanoyloxy; alkoxy carbonyl group; alkyl sulfide; the alkyl sulfide that replaces; hydroxycarbonyl group; azido; cyano group; nitro; halo; hydroxyl; oxo; carboxyl; aryl; the aryl that replaces; aryloxy; the aryloxy that replaces; heteroaryl; the heteroaryl that replaces; heteroaryl oxygen base; the heteroaryl oxygen base that replaces; COOR or NRR, wherein each R can be a hydrogen independently; alkyl; cycloalkyl aryl or aryl alkyl.

Term " alkyl " be meant preferably have 1 to 40 carbon atom, more preferably 1 to 10 carbon atom, the more preferably branch of the unit price root of 1 to 6 carbon atom or not branch's saturated hydrocarbon chain again.Illustrate this term with following groups, for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, n-hexyl, positive decyl, myristyl etc.

Alkyl can be chosen wantonly by one or more following groups and replace: alkoxyl, halo, haloalkyl, hydroxyl, hydroxy alkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxy carbonyl group, amino, alkyl amino, acyl amino, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, carboxyalkyl, ketone group, sulfo-, alkylthio, alkyl sulphinyl, alkyl sulphonyl and cyano group.

Term " alkylidene " be meant preferably have 1 to 40 carbon atom, more preferably have 1 to 10 carbon atom, the more preferably branch of the bivalence root of 1 to 6 carbon atom or unbranched saturated hydrocarbon chain again.Illustrate this term with following groups, for example methylene, ethylidene, positive propylidene, isopropylidene, positive butylidene, isobutylene, sec-butylidene, positive hexylidene, positive inferior decyl, inferior myristyl etc.

Alkylidene can be chosen wantonly by one or more following groups and replace: alkoxyl, halo, haloalkyl, hydroxyl, hydroxy alkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxy carbonyl group, amino, alkyl amino, acyl amino, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, carboxyalkyl, ketone group, sulfo-, alkylthio, alkyl sulphinyl, alkyl sulphonyl and cyano group.

Term " alkoxyl " is meant alkyl-O-, and wherein alkyl is an alkyl defined herein.Preferred alkoxyl comprises, for example methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, positive hexyloxy, 1,2-dimethyl butoxy etc.

Alkoxyl can be chosen wantonly by one or more following groups and replace: halo, haloalkyl, hydroxyl, hydroxy alkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxy carbonyl group, amino, alkyl amino, acyl amino, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, carboxyalkyl, ketone group, sulfo-, alkylthio, alkyl sulphinyl, alkyl sulphonyl and cyano group.

Term " aryl " is meant the unsaturated aromatic carbon cyclic group of monocycle (for example phenyl) with 6 to 20 carbon atoms or polycondensation (condensing) ring, and wherein at least one ring is aromatic (for example naphthyl, dihydrophenanthrenyl (dihydrophenanthrenyl), fluorenyl or anthryl).Preferred aryl groups comprises phenyl, naphthyl etc.

Aryl can be chosen wantonly by one or more following groups and replace: alkyl, alkoxyl, halo, haloalkyl, hydroxyl, hydroxy alkyl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxy carbonyl group, amino, alkyl amino, acyl amino, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, carboxyalkyl, ketone group, sulfo-, alkylthio, alkyl sulphinyl, alkyl sulphonyl and cyano group.

Term " cycloalkyl " is meant the monocycle with 3-20 carbon atom or the cyclic alkyl of polycondensation ring.This class cycloalkyl comprises, for example, and such as the single ring architecture of cyclopropyl, cyclobutyl, cyclopenta, ring octyl group etc., perhaps such as the multiring structure of adamantyl (adamantanyl) etc.

Cycloalkyl can be chosen wantonly by one or more following groups and replace: alkyl, alkoxyl, halo, haloalkyl, hydroxyl, hydroxy alkyl, aryl, heteroaryl, heterocycle, alkanoyl, alkoxy carbonyl group, amino, alkyl amino, acyl amino, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, carboxyalkyl, ketone group, sulfo-, alkylthio, alkyl sulphinyl, alkyl sulphonyl and cyano group.

Term " halo " is meant fluoro, chloro, bromo and iodo.Equally, term " halogen " is meant fluorine, chlorine, bromine and iodine.

" haloalkyl " is meant the alkyl defined herein that is replaced by 1-4 halo group defined herein, and described halo group can be identical, also can be different.Representational haloalkyl comprises, for example trifluoromethyl, 3-fluorine dodecyl, 12,12,12-trifluoro dodecyl, 2-bromine octyl group, 3-bromo-6-chlorine heptyl etc.

Term " heteroaryl " is defined as containing one, two or three aromatic ring and monocyclic, bicyclic or tricyclic system contain at least one nitrogen, oxygen or sulphur atom in aromatic ring at this paper; it can be unsubstituted or replace; for example; have one or more substituent groups; especially has one to three substituent group, for example halo, alkyl, hydroxyl, hydroxy alkyl, alkoxyl, alkoxyalkyl, haloalkyl, nitro, amino, alkyl amino, acyl amino, alkylthio, alkyl sulphinyl and alkyl sulphonyl.The example of heteroaryl comprises for being not limited to: 2H-pyrrole radicals (2H-pyrrolyl), 3H-indyl (3H-indolyl), 4H-quinolizinyl (4H-quinolizinyl), 4nH-carbazyl (4nH-carbazolyl), acridinyl (acridinyl), benzo [b] thienyl (benzo[b] thienyl), benzothiazolyl (benzothiazolyl),-carbolinyl (-carbolinyl), carbazyl (carbazolyl), benzopyranyl (chromenyl), cinnolines base (cinnaolinyl), dibenzo [b, d] furyl (dibenzo[b, d] furanyl), furazan base (furazanyl), furyl (furyl), imidazole radicals (imidazolyl), imide (imidizolyl), indazolyl (indazolyl), indolizine base (indolisinyl), indyl (indolyl), isobenzofuran-base (isobenzofuranyl), isoindolyl (isoindolyl), isoquinolyl (isoquinolyl), isothiazolyl (isothiazolyl) isoxazolyl (isoxazolyl), naphthyridinyl (naphthyridinyl), naphtho-[2,3-b] oxazolyl (naptho[2,3-b] oxazolyl), phenodiazine between the naphthalene embedding (mixing) phenyl (perimidinyl), phenanthridinyl (phenanthridinyl), phenanthroline base (phenanthrolinyl), phenarsazine base (phenarsazinyl), phenazinyl (phenazinyl), phenothiazinyl (phenothiazinyl) phenoxathiin group (phenoxathiinyl) Sai oxazinyl (phenoxazinyl), 2 base (phthalazinyl), pteridyl (pteridinyl), purine radicals (purinyl), pyranose (pyranyl), pyrazinyl (pyrazinyl), pyrazolyl (pyrazolyl), pyridazinyl (pyridazinyl), pyridine radicals (pyridyl), pyrimidine radicals (pyrimidinyl), pyrimidine radicals (pyrimidinyl), pyrrole radicals (pyrrolyl), quinazolyl (quinazolinyl), quinolyl (quinolyl), quinoxalinyl (quinoxalinyl), thiadiazolyl group (thiadiazolyl), thianthrene group (thianthrenyl), thiazolyl (thiazolyl), thienyl (thienyl), triazolyl (triazolyl) and xanthyl (xanthenyl).In one embodiment, term " heteroaryl " is meant and contains the monocycle aromatic rings that comprises carbon and 1,2,3 or 4 heteroatomic 5 or 6 annular atoms, described hetero atom is independently selected from oxygen, sulfur and the N (Z) of non-peroxidating form, and wherein Z does not exist or is H, O, alkyl, phenyl or benzyl.In another embodiment, heteroaryl is meant the monolateral condensed bicyclic heterocycles of about 8 to 10 annular atomses, and this heterocycle is derived by benzene derivative especially or obtained by itself and propylidene or tetramethylene bivalence root are condensed.

Heteroaryl can be chosen wantonly by one or more following groups and replace: alkyl, alkoxyl, halo, haloalkyl, hydroxyl, hydroxy alkyl, aryl, heterocycle, cycloalkyl, alkanoyl, alkoxy carbonyl group, amino, alkyl amino, acyl amino, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, carboxyalkyl, ketone group, sulfo-, alkylthio, alkyl sulphinyl, alkyl sulphonyl and cyano group.

The undersaturated loop systems of saturated or part that term " heterocycle " is meant, this loop systems contains at least one hetero atom that is selected from oxygen, nitrogen and sulfur, this loop systems optional by alkyl or C (=O) ORb replaces, wherein Rb is a hydrogen or alkyl.Usually, heterocycle is to contain one or more heteroatomic monocyclic, bicyclic or tricyclic groups that are selected from oxygen, nitrogen and sulfur.Heterocyclic group also can comprise the oxo group that is connected on the ring (=O).The non exhaustive example of heterocyclic group comprises: 1,3-Dihydrobenzofuranes, 1,3-dioxolanes, 1,4-diox, 1,4-dithiane, 2H-pyrans, 2-pyrazoline, 4H-pyrans, chromanyl, imidazolidinyl, imidazolinyl, indolinyl, isochroman base, different dihydro nitrogen (mixing) indenyl, morpholine, piperazinyl, piperidines, piperidyl, pyrazolidine, pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrrolin, quinuclidine and sulfur morphine quinoline.

Heterocycle can be chosen wantonly by one or more following groups and replace: alkyl, alkoxyl, halo, haloalkyl, hydroxyl, hydroxy alkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyloxy, alkoxy carbonyl group, amino, alkyl amino, acyl amino, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, carboxyalkyl, ketone group, sulfo-, alkylthio, alkyl sulphinyl, alkyl sulphonyl and cyano group.

The example of azacyclo-and azepine aryl includes but not limited to: pyrroles, imidazoles, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, iso-indoles, indole, indazole, purine, quinolizine, isoquinolin, quinoline, 2, naphthopyridine, quinoxaline, quinazoline, cinnolines, pteridine, carbazole, carboline, phenanthridines, acridine, phenanthroline, isothiazole, azophenlyene, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidines, piperazine, indoline, morpholino, piperidyl, oxolane glycosyl etc. and the heterocycle that contains N-alkoxyl-nitrogen.

Known another kind of heterocycle is " crown compound ", promptly refers to have one or more formula [(CH ₂) _aA-] heterocyclic compound of special category of repetitive, wherein a is more than or equal to 2, and A can be O, N, S or P when independent each time occurs.The example of crown compound comprises, for example: [(CH ₂) ₃-NH-] ₃, [((CH ₂) ₂-O) ₄-((CH ₂) ₂-NH) ₂] etc.Usually this class crown compound can have 4 to 10 hetero atoms and 8 to 40 carbon atoms.

Term " alkanoyloxy " is meant that (=O) R, wherein R is the alkyl as the preamble definition to C.

Term " alkoxy carbonyl group " is meant that (=O) OR, wherein R is the alkyl as the preamble definition to C.

Term " amino " is meant-NH ₂, term " alkyl amino " is meant-NR ₂, wherein at least one R is an alkyl, second R is alkyl or hydrogen.Term " acyl amino " is meant that (=O) N, wherein R is an alkyl or aryl to RC.

Term " nitro " is meant-NO ₂

Term " trifluoromethyl " is meant-CF ₃

Term " trifluoromethoxy " is meant-OCF ₃

Term " cyano group " is meant-CN.

Term " hydroxyl " is meant-OH.

" replacement " is intended to refer to that the one or more hydrogen on the indication atom are selected from following expression group in using " replacement " statement replaces, and condition is the common rate that does not exceed the indication atom, and to replace what obtain be stable chemical compound.Suitable expression group comprises; for example, alkyl, alkoxyl, halo, haloalkyl, hydroxyl, hydroxy alkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyloxy, alkoxy carbonyl group, amino, alkyl amino, acyl amino, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, carboxyalkyl, ketone group, sulfo-, alkylthio, alkyl sulphinyl, alkyl sulphonyl and cyano group.When substituent group is that ketone group (promptly=O) or during thio group, then has two hydrogen to be substituted on this atom.

For containing one or more substituent any above-mentioned groups, it should be understood that then this class group does not comprise impracticable and/or synthetic infeasible any replacement or the replacement form of on the spatial chemistry in the nature of things.In addition, chemical compound of the present invention comprises all three-dimensional chemical isomers that got by the replacement of these chemical compounds.

Especially, linking group can be bivalence peptide, aminoacid, fatty acid, sugar, polysaccharide, polyhydric alcohol (for example PEG or PVA), starch, dextrin, maltodextrin, cyclodextrin or carbohydrate.For example, linking group can be bivalence peptide, aminoacid, sugar, polysaccharide or polyhydric alcohol.

In a specific embodiments of the present invention, linking group self can biologically active.For example, linking group can be the bivalence biologically active peptide, growth hormone-releasing peptide (GHRP) for example, lutropin release peptide (LHRH), leuprorelin acetate, somatostatin, bombesin, gastrin releasing peptide (GRP), calcitonin, Kallidin I, galanin, melanotropin (MSH), somatotropin releasing factor (GRF), amylopectin, tachykinin, secretin, parathyroid hormone (PTH), enkephalin, endothelin, calcitonin gene release peptide (CGRP), neuromedin, parathyroid hormone-related protein (PTHrP), glucagon, neurotensin, thyroliberin (ACTH), peptide YY (PYY), glucagon release peptide (GLP), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating peptide (PACAP), motilin, the P material, neuropeptide tyrosine (NPY), TSH, and their analog and fragment.Referring to for example, United States Patent (USP) 6,221,958,6,113,943 and 5,863,985.

In a specific embodiments of the present invention, linking group can be lipophilic.In another specific embodiments of the present invention, linking group can be hydrophilic.

A suitable class prodrug comprises the chemical compound of formula (I):

D-X ¹-L ¹ (I)

Wherein,

D is the unit price root of bioactive compound disclosed herein;

X ¹Be carboxylic acid ester bond, amido link, thioester bond, phosphoric acid ester bond or sulfonic acid ester bond; And

L ¹Be linking group.

Another kind of suitable prodrug comprises the chemical compound of formula (II):

Wherein,

Each D is the unit price root or the bivalence root of bioactive compound disclosed herein independently;

Each X ¹Be carboxylic acid ester bond, amido link, thioester bond, phosphoric acid ester bond or sulfonic acid ester bond independently;

Each L ¹Be a linking group independently.

X ²Be carboxylate, amide, thioesters, phosphate ester or sulphonic acid ester; And

N is about 1 to about 10,000.

As implied above, suitable prodrug type comprises the polymerization prodrug of bioactive compound disclosed herein.According to the reactive functional groups of bioactive compound, can select one or more positions of bioactive compound to be used for the junctional complex precursor is connected in multiple mode with bioactive compound, the polymerization prodrug is provided thus.

Dosage

But flow composition is to be suitable for liquid or gel combination that patient's ocular is injected.But the amount that gives flow composition is decided according to the character of required controlled release implant usually.For example, but the amount of flow composition can influence the time length that biological agent, its metabolite or its prodrug discharge from the controlled release implant.In addition, but the amount that gives flow composition usually decide according to concrete purpose purposes (for example, the character of disease or disease or by stages/process).In addition, but the amount that gives flow composition usually decide according to the number (but number of the flow composition that promptly gives) of formed controlled release implant.Particularly, can give that as many as is about 200, but as many as is about 100, as many as is about 50, as many as about 25 or about 10 flow compositions of as many as, but can form by giving those flow compositions that as many as is about 200, as many as is about 100, as many as is about 50, as many as about 25 or about 10 the controlled release implants of as many as.Usually, but increase when the number of the flow composition that gives, but the amount of the flow composition that then gives can reduce.Similarly, but when the decreased number of the flow composition that gives, but the amount of the flow composition that then gives can increase.

Especially, compositions can be used for making acceptable salt on biological agent, its metabolite, its biopharmaceutics or its prodrug 1 year and send delivery system.Send delivery system the half a year that compositions also can be used for making acceptable salt on biological agent, its metabolite, its biopharmaceutics or its prodrug.Compositions also can be used for making acceptable salt on biological agent, its metabolite, its biopharmaceutics or its prodrug three months and send delivery system.Compositions also can be used for making acceptable salt on biological agent, its metabolite, its biopharmaceutics or its prodrug two months and send delivery system.Compositions also can be used for making acceptable salt on biological agent, its metabolite, its biopharmaceutics or its prodrug one month and send delivery system.

Especially, but can give flow composition up to about 10mL.More particularly, but can give up to about 5mL, up to about 1mL or up to about the 0.5mL flow composition.

As mentioned above, when forming a plurality of controlled release implant (but giving a plurality of flow compositions), but each flow composition can comprise acceptable salt or its prodrug on the biological agent, its metabolite, its biopharmaceutics of same amount.Perhaps, when forming a plurality of controlled release implants (but promptly giving a plurality of flow compositions) as mentioned above, but each flow composition can comprise acceptable salt or its prodrug on not commensurability biological agent, its metabolite, its biopharmaceutics.But can give each flow composition of any suitable amount.Especially, but each flow composition administered dose up to about 10mL, up to about 5mL, up to about 1mL, up to about 0.5mL or up to about 0.1mL.

Acceptable salt or its prodrug can exist with effective, suitable, appropriate amount arbitrarily on biological agent, its metabolite, its biopharmaceutics.But but but but on the biological agent that for example exists, its metabolite, its biopharmaceutics acceptable salt or its prodrug can account for flow composition up to about 70 weight % flow compositions up to about 60 weight % flow compositions up to about 40 weight % or flow composition up to about 20 weight %.Especially, but but but but on the biological agent of existence, its metabolite, its biopharmaceutics acceptable salt or its prodrug can account for flow composition up to about 10 weight % flow compositions up to about 5 weight % flow compositions up to about 1 weight % or flow composition up to about 0.1 weight %.

As mentioned above, when forming a plurality of controlled release implants (but promptly giving a plurality of flow compositions), but the flow composition that gives can comprise acceptable salt or its prodrug on the biological agent, its metabolite, its biopharmaceutics of same amount.Perhaps, when forming a plurality of controlled release implant (but giving a plurality of flow compositions), but but each flow composition that gives can comprise acceptable salt or its prodrug on not commensurability flow composition, its metabolite, its biopharmaceutics.In any case, but the biological agent that each flow composition that gives comprises, its metabolite, its biological acceptable salt or its prodrug, but but but but can account for about 10 weight % of flow composition the most nearly, the most about 5 weight %, the most about 1 weight % or the most about 0.1 weight % of flow composition of flow composition of flow composition independently.

Especially, but the volume of flow composition greater than about 0.001mL.In addition, but the volume of flow composition can maximum reach about 20.0mL.Especially, but the volume of flow composition can be about 0.01 to about 10mL, and about 0.05mL is to about 1.5mL, and about 0.1mL is about 1.0mL or about 0.2mL about 0.8mL. extremely extremely

Especially, but flow composition can be configured to the administration that is used to be less than approximately once a day.More particularly, but flow composition can be configured to and be used to be less than weekly approximately administration, be less than approximately every month once more than annual approximately administration, weekly approximately to annual approximately administration, perhaps once extremely annual approximately administration in every month approximately.

But flow composition can send acceptable salt or its prodrug on biological agent, its metabolite, its biopharmaceutics effectively and pass to mammalian tissues with suitable, effective, safe and appropriate dosage.For example, but flow composition effectively send the dosage of acceptable salt on the biological agent passed, its metabolite, its biopharmaceutics or its prodrug greater than about 0.001pg/kg/ day, greater than about 0.01pg/kg/ day, greater than about 0.1pg/kg/ day or greater than about 1pg/kg/ day to mammalian tissues.Perhaps, but flow composition can effectively send the dosage of acceptable salt on the biological agent passed, its metabolite, its biopharmaceutics or its prodrug to be up to about 100mg/kg/ day, to be up to about 50mg/kg/ day, to be up to about 10mg/kg/ day or to be up to about 1mg/kg/ day to mammalian tissues.

More particularly, but the dosage that flow composition can effectively send acceptable salt on the biological agent passed, its metabolite, its biopharmaceutics or its prodrug to mammal is about 100mg/kg/ day extremely about 0.001pg/kg/ day; About 0.01pg/kg/ day to about 50mg/kg/ day; About 0.1pg/kg/ day to about 10mg/kg/ day; About 1pg/kg/ day to about 1mg/kg/ day.

Acceptable salt or its prodrug can discharge from the controlled release implant in any suitable manner on biological agent, its metabolite, its biopharmaceutics.For example, acceptable salt or its prodrug can discharge from the controlled release implant linearly or with the first order kinetics pattern on biological agent, its metabolite, its biopharmaceutics.Perhaps, acceptable salt or its prodrug can discharge from the controlled release implant to continue zero mode on biological agent, its metabolite, its biopharmaceutics.In addition, acceptable salt or its prodrug can be followed few medicine burst release or not have medicine burst release on biological agent, its metabolite, its biopharmaceutics when discharging from the controlled release implant.

With acceptable salt or its prodrug on biological agent, its metabolite, its biopharmaceutics to sending of mammalian tissues pass can be general and/or locality.Especially, can the part send and pass dosage.More particularly, can local send and pass dosage and reach about 1 year time most.More particularly, can local send and pass dosage and reach about 1 month most, reach an about week most or greater than about one day time.

On biological agent, its metabolite, its biopharmaceutics acceptable salt or its prodrug, but flow composition of the present invention and/or implant can be chosen wantonly and contain at least a analgesic, anesthetics, anti-infective, antimigraine, muscle relaxant or sedative hypnotic.Analgesic, anesthetics, anti-infective, gastrointestinal drug, antimigraine, muscle relaxant or sedative hypnotic can exist with any suitable amount.Referring to for example Physician ' s Desk Reference, 55 ^ThEdition (2001).

Suitable analgesic comprises, for example: acetaminophen (acetaminophen), phenylpropanolamine HC1 (phenylpropanolamine HCl), chlorphenamine maleate (chlorpheniramine maleate), Hycodan (hydrocodonebitartrate), acetaminophen elixir (acetaminophen elixir), diphhydramine hydrochloride (diphenhydramine HCl), pseudoephedrine hydrochloride (pseudoephedrine HCl), dextromethorphan hydrobromide (dextromethorphan HBr), guaifenesin (guaifenesin), doxylamine succinate (doxylamine succinate), pamabrom (pamabron), clonidine hydrochloride (clonidine hydrochloride), tramadol hydrochloride (tramadolhydrochloride), carbamazepine (carbamazepine), hyaluronate sodium (sodiumhyaluronate), lignocaine (lidocaine), hyaluronic acid (hylan), Montana arnica montana (Arnica Montana), root (radix) (arnica montana (mountain arnica)), Calendula officinalis (Calendula officinalis) (Calendula officinalis (marigold)), Hamamelis virginiana (Hamamelis (witch hazel)), achillea millefolium (Millefolium (milfoil)), Semen daturae (Belladonna (deadly nightshade)), Aconitum carmichjaelii Debx. (Aconitum napellus (monkshood)), Flos Chrysanthemi (Chamomilla (chamomile))), comfrey (Symphytumofficinale (comfrey)), Bellis perennis (Bellis perennis (daisy)), narrow leaf Echinacea Species (Echinacea angustifolia) (narrow leaf taper flower), Herba Hyperici perforati (Hypericumperforatum) (Radix Hyperici Monogyni (Herba Hyperici Monogyni) (St.John ' s wort)), calcium Potassium monosulfide. (Hepar sulphuriscalcareum) (calcium sulfide), buprenorphin hydrochloride (buprenorphine hydrochloride), nalbuphlne hydrochloride (nalbuphine hydrochloride), pentazocine hydrochloride (pentazocinehydrochloride), aspirin (acetylsalicylic acid), salicylic acid (salicylicacid), naloxone hydrochloride (naloxone hydrochloride), oral per mucous membrane fentanyl citrate (oral ransmucosal fentanyl citrate), morphine sulfate (morphinesulfate), propoxyphene napsylate (propoxyphene napsylate), regretol (propoxyphene hydrochloride), pethidine hydrochloride (meperidinehydrochloride), dihydromorphinone hydrochloride (hydromorphone hydrochloride), fentanyl is through dermal system (fentanyl transdermal system), levorphanol tartrate (levorphanol tartrate), promethazine hydrochloride (promethazine HCl), oxymorphone hydrochloride (oxymorphone hydrochloride), levomethadyl acetate hydrochloride (levomethadylacetate hydrochloride), oxycodone hydrochloride (oxycodone HCl), oxycodone (oxycodone), codeine phosphate (codeine phosphate), isometheptene mucate (isometheptene mucate), dichloralphenazone (dichloralphenazone), butalbital (butalbital), naproxen sodium (naproxen sodium), diclofenac sodium (diclofenac sodium), misoprostol (misoprostol), diclofenac potassium (diclofenac potassium), celecoxib (celecoxib), sulindac (sulindac), oxaprozin (oxaprozin), salsalate (salsalate), diflunisal (diflunisal), naproxen (naproxen), piroxicam (piroxicam), indomethacin (indomethacin), three hydration Indomethacin sodiums (indomethacin sodium trihydrate), etodolac (etodolac), meloxicam (meloxicam), ibuprofen (ibuprofen), Fenoprofen (fenoprofen calcium), ketoprofen (ketoprofen), mefenamic acid (mefenamic acid), nabumetone (nabumetone), tolmetin sodium (tolmetinsodium), ketorolac tromethamine (ketorolac tromethamine), Choline magnesium trisalicylate (choline magnesium trisalicylate) and rofecoxib (rofecoxib).

Suitable anesthetics comprises: propofol (propofol), halothane (halothane), desflurane (desflurane), midazolam hydrochloride (midazolam HCl), epinephrine (epinephrine), chirocaine (levobupivacaine), etidocaine hydrochloride (etidocaine hydrochloride), Ropivacaine HCL (ropivacaine HCl), chloroprocaine hydrochloride (chloroprocaine HCl), bupivacaine hydrochloride (bupivacaineHCl) and lidocaine hydrochloride (lidocaine HCl).

Suitable anti-infective comprises, for example: trimethoprim (trimethoprim), Sulfamethoxazole (sulfamethoxazole), clarithromycin (clarithromycin), ganciclovir sodium (ganciclovir sodium), ganciclovir (ganciclovir), DaunoXome (daunorubicin citrate liposome), fluconazol (fluconazole), Doxil (doxorubicin HCl liposome), foscarnet sodium (foscarnetsodium), Interferon Alpha-2b (interferon alfa-2b), atovaquone (atovaquone), rifabutin (rifabutun), gluconic acid trimetrexate (trimetrexate glucoronate), itraconazole (itraconazole), cidofovir (ciclofovir), azithromycin (azithromycin), delavirdine mesilate (delavirdine mesylate), efavirenz (efavirenz), nevirapine (nevirapine), lamivudine (lamivudine)/zidovudine (zidovudine), zalcitabine (zalcitabine), didanosine (didanosine), stavudine (stavudine), abacavir sulfate (abacavirsulfate), amprenavir (amprenavir), indinavir sulfate (indinavir sulfate), Saquinavir (saquinavir), saquinavir mesilate (saquinavir mesylate), ritonavir (ritonavir), viracept see nelfinaivr (nelfinavir), chloroquine hydrochloride (chloroquinehydrochloride), metronidazole,clotrimazole and chlorhexidine acetate suppositories (metronidazole), hydrochloric acid metronidazole,clotrimazole and chlorhexidine acetate suppositories (metronidazole hydrochloride), diiodohydroxyquinoline (Iodoquinol) (iodoquinol), albendazole (albendazole), praziquantel (praziquantel), thiabendazole (thiabendazole), ivermectin (ivermectin), sulphuric acid mebendazole (mebendazole sulfate), tobramycin sulfate (tobramycin sulfate), tobramycin (tobramycin), aztreonam (azetreonam), Cefotetan Disodium (cefotetan disodium), cefotetan (cefotetan), Loracarbef (loracarbef), cefoxitin (cefoxitin), meropenem (meropenem), imipenem cilastatin (imipenemand cilastatin), cefazolin (cefazolin), cefaclor (cefaclor), ceftibuten (ceftibuten), ceftizoxime (ceftizoxime), cefoperazone (cefoperazone), cefuroxumeaxetil, cefprozil (cefprozil), ceftazidime (ceftazidime), cefotaxime sodium (cefotaxime sodium), cefadroxil monohydrate (cefadroxilmonohydrate), cefalexin (cephalexin), cefalexin hydrochloride (cephalexinhydrochloride), cefuroxime (cefuroxime), cefazolin (cefazolin), cefamandole nafate (cefamandole nafate), hydrochloric acid cefapirin (cefapimehydrochloride), cefdinir (cefdinir), ceftriaxone sodium (ceftriaxonesodium), cefixime (cefixme), Cefpodoxime Proxetil (cefpodoxime proxetil), dirithromycin (dirithromycin), erythromycin (erythromycin), erythromycin ethylsuccinate (erythromycin ethylsuccinate), bristamycin (erythromycinstearate), erythromycin (erythromycin), acetyl-sulfisoxazole (sulfisoxazoleacetyl), triacetyloleandomycin (troleandomycin), azithromycin (azithromycin), clindamycin (clindamycin), Clindamycin Hydrochloride (clindamycin hydrochloride), colistimethate sodium (colistimethate sodium), quinupristin (quinupristin)/dalfopristin (dalfopristin), Lyphocin (Fujisawa) (vancomycinhydrochloride), amoxicillin (amoxicillin), amoxicillin (amoxicillin)/clavulanate potassium (calvulanate potassium), benzathine penicillin G (penicillin Gbenzathine), neoproc (penicillin G procaine), scotcil (penicillin G potassium), carindacillin sodium (carbenicillin indanylsodium), avocin (piperacillin sodium), ticarcillin disodium (ticarcillin disodium), clavulanate potassium (clavulanate potassium), ampicillin (ampicillin sodium)/Sulbactam Sodium (sulbactam sodium), tazobactam sodium (tazobactam sodium), quadracycline (tetracycline HCl), demeclocycline hydrochloride (demeclocycline hydrochloride), Doryx (doxycycline hyclate), minocycline hydrochloride (minocycline HCl), doxycycline monohydrate (doxycycline monohydrate), tetramycin hydrochloride (oxytetracycline HCl), cellulose acetate hydrogen cortisone (hydrocortisone acetate), doxycycline calcium (doxycycline calcium), amphotericin B lipid (amphotericinB lipid), flucytosine (flucytosine), griseofulvin (griseofulvin), terbinafine HCl (terbinafine hydrochloride), ketoconazole (ketoconazole), chloroquine hydrochloride (chloroquine hydrochloride), Arechin (Polfa) (chloroquinephosphate), pyrimethamine (pyrimethamine), Mefloquine Hydrochloride (mefloquinehydrochloride), atovaquone and proguanil hydrochlorate (atovaquone and proguanilhydrochloride), hydroxychloroquine sulfate (hydroxychloroquine sulfate), ebutol (ethambutol hydrochloride), aminosalicylic acid (aminosalicylicacid), rifapentine (rifapentine), rifampicin (rifampin), isoniazid (isoniazid), pyrazinamide (pyrazinamide), ethionamide (ethionamide), Alferon N (interferon alfa-n3), famciclovir (famciclovir), rimantadine hydrochloride (rimantadine hydrochloride), foscarnet sodium (foscarnetsodium), Alfacon-1 (interferon alfacon-1), ribavirin (ribavirin), zanamivir (zanamivir), Amantadine Hydrochloride (amantadine hydrochloride), palivizumab (palivizumab), oseltamivir phosphate (oseltamivir phosphate), valaciclovir hydrochlordide (valacyclovir hydrochloride), nelfinavir mesilate (nelfinavir mesylate), stavudine (stavudine), acyclovir (acyclovir), Acycloguanosine sodium (acyclovir sodium), rifabutin (rifabutin), gluconic acid trimetrexate (trimetrexate glucuronate), Linezolid (linezolid), Moxifloxacin (moxifloxacin), moxifloxacin hydrochloride (moxifloxacin hydrochloride), ciprofloxacin (ciprofloxacin), ciprofloxacin (ciprofloxacinhydrochloride), ofloxacin (ofloxacin), levofloxacin (levofloxacin), lomefloxacin hydrochloride (lomefloxacin hydrochloride), nalidixan (nalidixicacid), norfloxacin (norfloxacin), enoxacin (enoxacin), Gatifloxacin (gatifloxacin), trovafloxacin mesilate (trovafloxacin mesylate), Alatrofloxacin. (alatrofloxacin), Sparfloxacin (sparfloxacin), aztreonam (aztreonam), nitrofirantoin monohydrate/ macrocrystalline, cefepime hydrochloride (cefepime hydrochloride), fosfomycin trometamol (fosfomycintromethamine), polygynax (neomycin sulfate)-aerosporin (polymyxin B sulfate), imipenum (imipenem), cilastatin (cilastatin), hexamethylenamine (methenamine), hexamine mandelate (methenamine mandelate), phenyl salicytate (phenyl salicylate), atropine sulfate (atropine sulfate), hyoscyamine sulfate (hyoscyamine sulfate), benzoic acid (benzoic acid), tetramycin hydrochloride (oxytetracycline hydrochloride), sulfamethizole (sulfamethizole), phenazopyridine hydrochloride (phenazopyridine hydrochloride) and biphosphate sodium-hydrate (sodium acid phosphate, monohydrate).

The suitable curative of taking advantage of a situation comprises, for example: fish berry (cocculus indicus), hemlock (conium maculatum), Ambra Grisea (ambra grisea) and oil (petroleum).

Suitable antimigraine comprises, for example: timolol maleate (timololmaleate), propranolol hydrochloride (propranolol hydrochloride), agit (dihydroergotamine mesylate), gynergen (ergotaminetartrate), caffeine (caffeine), divalproex sodium (divalproex sodium), acetaminophen (acetaminophen), aspirin (acetylsalicylic acid), salicylic acid (salicylic acid), naratriptan hydrochloride (naratriptan hydrochloride), Sumatriptan Succinate (sumatriptan succinate), sumatriptan (sumatriptan), Lizakuputan benzoate (rizatriptan benzoate) and Zolmitriptan (zolmitriptan).

Suitable muscle relaxant comprises, for example: succinylcholine chloride (succinylcholine chloride), vecuronium bromide (vecuronium bromide), Lei Paku bromine ammonium (rapacuronium bromide), Rocuronium Bromide (rocuronium bromide), dantamacrin (dantrolene sodium), cyclobenzaprine hydrochloride (cyclobanzaprine HCl), orphenadrine citrate (or phenadrinecitrate) chlorzoxazone (chlorzoxazone), methocarbamol (methocarbamol), aspirin (acetylsalicylic acid), salicylic acid (salicylic acid), metaxalone (metaxalone), carisoprodol (carisoprodol), codeine phosphate (codeinephosphate), diazepam (diazepam) and tizanidine hydrochloride (tizanidinehydrochloride).

Suitable sedative hypnotic comprises, for example: enphenemal (mephobarbital), pentobarbital sodium (pentobarbital sodium), lorazepam (lorazepam), triazolam (triazolam), estazolam (estazolam), diazepam (diazepam), midazolam hydrochloride (midazolam HCl), Tartaric acid zolpidem (zolpidem tartrate), melatonin (melatonin), vitamin B12 (vitamin B 12), folic acid (folic acid), propofol (propofol), pethidine hydrochloride (meperidine HCl), promethazine hydrochloride (promethazine HCl), diphhydramine hydrochloride (diphenhydramine HCl), Zaleplon (zaleplon) and doxylamine succinate (doxylamine succinate).

The disease or the disease of eye

But flow composition of the present invention can be through the ocular topical to treat one or more ophthalmics or disease.Ophthalmic that is applicable to or disease for example comprise: the invisible outer retina pathological changes of acute band shape (Acute Zonal Occult Outer Retinopathy), Adie syndrome (Adie Syndrome), relevant degeneration of macula of age (Age Related MacularDegeneration, AMD), albinism (Albinism), blackout (AmaurosisFugax), amblyopia (Amblyopia), aniridia (Aniridia), anisocoria (Anisocoria), anophthalmia (Anophthalmos), aphakia (Aphakia), obstruction of artery (ArteryOcclusion), astigmatism (Astigmatism), basal cell carcinoma (Basal Cell Carcinoma), blepharitis (Blepharitis), branch's retinal artery occlusion (Branch Retinal ArteryOcclusion), branch's retinal vein occlusion (Branch Retinal Vein Occlusion), blepharoptosis (Blepharoptosis), blepharospasm (Blepharospasm), blind (Blindness), cataract (Cataract), glass pattern retinopathy (Cellophane Retinopathy), central retinal vein occlusion (Central Retinal Vein Occlusion), central serous chorioretinopathy (Central Serous Chorioretinopathy), chalazion (Chalazion), chemical burn (Chemical Burn), choroidal neovascularization film (Choroidal Neovascular Membrane), choroid nevus (Choroidal Nevus), the Cogan malnutrition (Cogan ' s Dystrophy), achromatopsia (Color Blindness), computer vision syndrome (Computer Vision Syndrome), conjunctivitis (Conjunctivitis), cerneal dystrophy (Corneal Dystrophy), corneal edema (Corneal Edema), corneal ulcer (Corneal Ulcer), cystoid macular edema (Cystoid Macular Edema), cytomegalovirus (Cytomegalovirus), chorioretinitis (Chorioretinitis), choroideremia (Choroideremia), damaged (Coloboma), dacryocystisis (Dacryocystitis), diabetic retinopathy (Diabetic Retinopathy), blepharoptosis (Droopy Eyelid), xerophthalmia (Dry Eye), diplopia (Diplopia), distichiasis (Distichiasis), duane syndrome (Duane Retraction Syndrome), ectropion (Ectropion), entropion (Entropion), preretinal membrane (Epiretinal membrane), episcleritis (Episcleritis), esotropia (Esotropia), exfoliation syndrome (Exfoliation Syndrome), exotropia (Exotropia), ophthalmorrhagia (EyeHemorrhage), eye neoplasms (Eye Neoplasms), hypermetropia (Farsightedness), flash of light and float (Flashes ﹠amp; Floaters), foreign body (Foreign Body), Fuchs (Fuchs ' Dystrophy), giant cell arteritis (Giant CellArteritis), glaucoma (Glaucoma), extensive fibrosis syndrome (General FibrosisSyndrome), gyrate atrophy (Gyrate Atrophy), headache (Headache), herpes simplex (Herpes Simplex), herpes zoster (Herpes Zoster), ocular hypertension (HighPressure in the Eye), (eye) histoplasmosis ((Histoplasmosis (Ocular)), latent hypermetropia (Hyperopia), hyphema (Hyphema), hemianopsia (Hemianopsia), the Hermanski-Pudlak syndrome, hordeolum (Hordeolum), the Homer syndrome, entropion (Inward Turned Eyelid), the iris new vessels forms (Iris Neovascularization), iris nevus (Iris Nevus), iritis (Iritis), keratoconus (Keratoconus), the Kearns-Sayer syndrome, keratitis (Keratitis), lacrimal apparatus disease (Lacrimal Apparatus Disease), lacrimal ductule obturation (Lacrimal DuctObstruction), degeneration of macula (Macular Degeneration), macular edema (MacularEdema), macular hole (Macular Hole), macular pucker (Macular Pucker), blepharitis (Marginal Blepharitis), myopia (Myopia), ommatidium (Microphthalmos), myopia (Myopia), nystagmus (Nystagmus), myopia (Nearsightedness), cornea rebirth blood vessel forms (Neovascularization of the Cornea), the papilla of optic nerve new vessels forms (Neovascularization of the Optic Nerve Head), nevus (choroid) (Nevus (Choroidal)), nevus (iris) (Nevus (Iris)), ocular histoplasmosis (Ocular Histoplasmosis), ocular rosacea (Ocular Rosacea), optic neuritis (Optic Neuritis), ectropion of lid (Outward Turned Eyelid), ophthalmoplegia (Ophthalmoplegia), optic atrophy (Optic Atrophies), optic neuropathy (Optic Neuropathy), orbital cellulitis (Orbital Cellulitis), pinguecula (Pinguecula), pink eye disease (Pink Eye), back capsule muddiness (Posterior CapsularOpacification), presbyopia (Presbyopia), pterygium (Pterygium), the ptosis (Ptosis), papilloedema (Papilledema), Peter unusual (Peter ' sAnomaly), recurrent corneal erosion (Recurrent Corneal Erosion), blood-shot eye illness disease (Red Eye), tears retinal (Retinal Tear), detachment of retina (RetinalDetachment), retinitis pigmentosa (Retinitis Pigmentosa), retinopathy of prematurity (Retinopathy of Prematurity), Terry's sign disease (Retrolental Fibroplasia, ROP), rubescent (Rubeosis), retinal vein occlusion (Retinal Vein Occlusion), retinoschisis (Retinoschisis), scleritis (Scleritis), stravismus (Strabismus), hordeolum (Stye), subconjunctival hemorrhage (Subconjunctival Hemorrhage), dim spot (Scotoma), stravismus (Strabismus), temporal arteritis (Temporal Arteritis), Thygeson superficial punctate keratitis (Thygeson ' sSuperficial Punctate Keratitis), trachoma, uveitis, vein obstruction (VeinOcclusion) and detachment of vitreous (Vitreous Detachment).But when through ocular topical administration flow composition as herein described when treating one or more ophthalmics or disease, but should generally comprise one or more known biological agents for the treatment of this class ophthalmic or disease by flow composition.The biological agent that this class is suitable comprises, for example: the acetylcholine blocker (for example, the neurotoxin complex of botox purification), adrenergic agonist (for example, Alphagan P (alphaganp), that element reaches (naphcon-a)), antibiotic (for example, Polytrim (polytrim), Tobradex (tobradex)), Betimol (for example, betimol, Betoptic (betoptic), cosopt, timoptic in ocudose, Timolol (timoptic), Timoptic-XE (timoptic-xe), Pai Liming (azopt), cosopt, daranide, TruSopt (trusopt), lumigan, travatan, Xalatan (xalatan), Alphagan P, that element reaches, rev-eyes), the compositions of antihistaminic and mast cell stabilizers (for example, elesat, patanol, zaditor), antihistaminic and compositions are (for example, that element reaches, optivar), anti-infective (for example, polytrim, Tobradex, Ciloxan (ciloxan), quixin, vigamox, zymar, Blephamide (blephamide)), anti-inflammatory agent (for example, Acular (acular)), Acular ls (acular ls), Acular pf (acular pf), Voltaren (voltaren), Blephamide (blephamide), Tobradex), artificial tears/lubricant and compositions are (for example, bion tears, Lacrisert (lacrisert), restasis, tears naturale forte, tears naturalefree), the Beta-3 adrenergic blocker (for example, betimol, betoptic s, cosopt, timoptic in ocudose, Timolol, Timoptic-XE), Beta-3 adrenergic blocker and carbonic anhydrase inhibitor compositions (for example cosopt), carbonic anhydrase inhibitor (azopt for example, cosopt, daranide, trusopt), decongestant drug (for example, Alphagan P, that element reaches), (for example be used for glaucomatous medicament, betimol, Betoptic, cosopt, timoptic in ocudose, Timolol, Timoptic-XE, Pai Liming, cosopt, daranide, TruSopt, lumigan, travatan, Xalatan, Alphagan P, that element reaches, rev-eyes), lubricant (for example, bion tears, Lacrisert, restasis, tears naturale forte, tears naturale free), mast cell stabilizers (for example, alamast), the photodynamic therapy agent (for example, visudyne), prostaglandins (for example, lumigan, travatan, Xalatan), sympathomimetic and compositions are (for example, Alphagan P, that element reaches), vasoconstrictor (for example, Alphagan P, that element reaches), vitamin and compositions (catasod-ocuxtra/optigold/macutein for example, visutein), antibiotic and compositions are (for example, polytrim, Tobradex), quinolones (for example, Ciloxan, quixin, vigamox, zymar), sulfonamides and compositions are (for example, Blephamide), miotic (for example, rev-eyes), NSAID (non-steroidal anti-inflammatory drug) (for example, Acular, Acular ls, Acular pf, Voltaren) and steroidal anti-inflammatory medicine and compositions (for example, Blephamide, Tobradex).

It is at least a that but flow composition of the present invention and/or implant also can comprise: the release rate modifier (modification agent) that the control biological agent discharges from implant substrate in vivo, pore former, biodegradable crystal controlling agent, plasticizer, leaching agent, penetration enhancer, absorption change agent, opacifier and coloring agent.

Release rate modifier

But rate adaptation agent, plasticizer and leaching agent can be included, with the release speed of control bioactive agent RateFlexibility with substrate.The same with leaching agent with the soft readjustment thing, the known plasticizers and the organic compound that are suitable for the false bonding of secondary (pseudobongding) in the polymer system are acceptable.Ester, dihydroxylic alcohols and the polyhydric alcohol that common these materials are monobasic, binary and ternary acid, polyester, nonionic surfactant, fatty acid, oil is the plant wet goods for example.The concentration range of this class material in solid matrix preferably is up to 30 weight % for be up to the amount of 60 weight % with respect to the substrate gross weight, more preferably is up to 15 weight %.Usually, these leaching agents, plasticizer and soft readjustment thing and they be applied in United States Patent (USP) 5,702,716 and 5,447, describe to some extent in 725, disclosed content mode is by reference included this paper in these documents, and prerequisite is that employed polymer is biocompatible, biodegradable a, thermoplastic polymer of the present invention.

But also can comprise in the flow composition and discharge speed RateRegulator, the speed that from implant substrate, discharges in vivo with the decomposition rate and/or the bioactive agent of control implant substrate.The rate adaptation agent can increase or slow down the speed of release, and this decides according to being included in according to the character of the rate adaptation agent in the solid matrix of the present invention.The example as the suitable substance of rate adaptation agent that is comprised comprises citric acid dimethyl ester, triethyl citrate, cognac oil, glycerol, hexanediol etc.

Polymer solution can comprise release speed RateRegulator is to provide the release controlled, that continue of bioactive agent from implant substrate.Though and be not intended to the application's disclosure limited, think, discharge speed RateRegulator can change the speed that bioactive agent discharges by the hydrophobicity that changes polymeric implant from implant substrate.

Discharge speed with nothing RateThe release of bioactive agent during regulator from solid matrix is compared, and uses to discharge speed RateRegulator can reduce or increase the release of bioactive agent, the change that preferred up is ten times in a plurality of orders of magnitude (promptly 1 to 10 to 100) scope.For example the hydrophilic of Polyethylene Glycol discharges speed RateRegulator can increase the release of bioactive agent.By fast to polymer molecular weight and release RateThe appropriate selection of regulator effective dose can change the release speed that bioactive agent discharges from implant substrate RateAnd releasing degree, for example can be from very fast to relatively slow relatively.

Available release speed RateRegulator comprises for example water solublity, water organic substance that dissolve each other or water-insoluble (promptly not dissolving each other with water), preferred water insoluble substance.

Discharge speed RateRegulator is preferably such organic compound, the alternative additional molecule of this organic compound as the secondary chemical valence bonding between polymer molecule, and strengthen elasticity and the ability that polymer molecule slides to each other.This class organic compound preferably includes hydrophobic and hydrophilic region to influence secondary chemical valence bonding.Preferably, discharge speed RateRegulator is compatible with the polymer and the solvent that are used to be mixed with polymer solution.More preferably, discharge speed RateRegulator is an acceptable material on the biopharmaceutics.

Available release speed RateRegulator comprises, for example: fatty acid, triglyceride, other similar hydrophobic compounds, organic solvent, plasticized compound and hydrophilic compounds.Suitable release speed RateRegulator comprises, for example: the ester of monoacid, binary acid and ternary acid, for example acetic acid 2-ethoxy ethyl ester, methyl acetate, ethyl acetate, diethyl phthalate, dimethyl phthalate, dibutyl phthalate, dimethyl adipate, dimethyl succinate, dimethyl oxalate., citric acid dimethyl ester, triethyl citrate, tributyl 2-acetylcitrate, acetyl triethyl citrate, glyceryl triacetate, n-butyl sebacate etc.; Polyhydroxy-alcohol, for example propylene glycol, Polyethylene Glycol, glycerol, Sorbitol etc.; Fatty acid; Three esters of glycerol, for example triglyceride, epoxidised soybean oil and other epoxidized vegetable oils; The vegetable oil that from seed, flower, water reality, leaf or the stem of plant or tree, obtains, for example Oleum sesami, soybean oil, Oleum Gossypii semen, almond oil, sunflower oil and Oleum Arachidis hypogaeae semen; Sterol, for example cholesterol; Alcohol, for example C6-C12 alkanol, 2-ethoxy ethanol etc.Discharge speed RateRegulator can single use or is used in combination with other similar substances.Discharge speed RateThe appropriate combination of regulator for example comprises: glycerin/propylene glycol, Sorbitol/glycerol, ethylene oxide/propylene oxide, adipate butanediol etc.The preferred speed that discharges RateRegulator comprises citric acid dimethyl ester, triethyl citrate, cognac oil, glycerol and hexanediol.

The release speed that comprises in the polymer solution RateThe amount of regulator can discharge speed according to required bioactive agent from polymeric matrix RateAnd change.Preferably, polymer solution contains about 0.5-15%, the preferred release speed of about 5-10% RateRegulator.

Pore former/additive

But flow composition of the present invention can be used for intactly or partly being placed in the body with implantation, injection or other modes.A kind of bioactive substance and the polymer of the present invention of compositions can form homogenizing substrate, and perhaps a kind of bioactive substance can be encapsulated in the polymer in some way.For example, a kind of bioactive substance can at first be encapsulated in the microsphere, then mode and the combination of polymers can be maintained until the small part micro-sphere structure.Perhaps, a kind of bioactive substance and polymer of the present invention are not gone up substantially and are dissolved each other, to such an extent as to it can be scattered in small droplet form rather than be dissolved in the polymer of the present invention.More than any of two kinds of forms all can be accepted, but preferably, no matter the homogeneity of compositions how, bioactive substance release speed in vivo RateAll keep controlled, to the make a living exercising result of thing when degraded polymer ester bond hydrolysis of small part.

Additive can be used for helping further to control the size in the hole in the solid matrix, and this can influence the structure of substrate and the release speed of bioactive agent RateOr the diffusion rate of body fluid.For example, if but flow composition for aqueous medium, water or tissue ingrowth thing, can't see through, can add pore former in substrate, to produce extra hole.Biocompatible arbitrarily water-soluble substances all can serve as macroporous additive.But these additives can dissolve in the flow composition, also can be merely to be dispersed in wherein.They can dissolve, spread or disperse to have produced thereon outside two kinds of solidified polymeric substrate of hole and micro channel.But become the size and the number of the direct impact polymer substrate mesopore of amount (with the size (if appropriate) of this class pore-forming agent discrete particles) of macroporous additive in the flow composition.

The pore-forming additive comprises on the miscible any biopharmaceutics of basic and water and body fluid can accept Organic substance or inorganic matter, and these additives Ying Kecong forming with established substrate in dissipate in aqueous medium or the body fluid or dissipate to the water not in the intersolubility material that can be degraded into water-soluble substances rapidly.More preferably, become macroporous additive in organic solvent, can misciblely maybe can be scattered in wherein to form the mixture of homogeneous.Suitable pore former comprises, for example: sugar is sucrose and glucose, salt for example hydroxypropyl cellulose, carboxymethyl cellulose, Polyethylene Glycol and polyvinylpyrrolidone of sodium chloride and sodium carbonate and polymer for example for example.But be contained in the molecular weight and the percentage ratio of the one-tenth macroporous additive in the flow composition by change, the size in hole and scope can change in the larger context.

As described herein, with after body fluid contacts, solvent and optional hole form additive and dissipate to and organizes in the liquid.This just makes and form micro channel in the polymeric matrix that solidifies.Randomly, the speed that hole formation additive can be slower than solvent dissipation dissipates to from substrate in the surrounding tissue liquid, perhaps separates by the biodegradation or the biological erosion of substrate, discharges from substrate in time.Preferably, the hole form additive in the short time after implantation from the implant substrate of solidifying dissipation go out, have the substrate of certain voidage and pore structure with formation, thereby effectively realize the specific purposes of implant as the barrier system in for example tissue regeneration site, the substrate that timing discharges medicine or medicament etc.

The concentration of the composition that the voidage of solid polymer substrate can be dissolved each other with water solublity or water changes, and described composition is solvent in polymer composition and/or pore-forming agent for example.For example, but the high concentration of water-soluble substances in flow composition can produce the polymeric matrix with high-voidage.Can change in the compositions pore-forming agent with respect to the concentration of polymer, to obtain in the substrate hole formation rate or voidage in various degree.Usually, polymer composition can contain the pore-forming agent of every gram polymer 0.01-1g that has an appointment.

The size in the hole that forms in the implant substrate and diameter can change according to the size and/or the distribution of pore-forming agent in the polymeric matrix.For example, can the pore-forming agent that be insoluble to polymeric blends relatively optionally be included in the polymer composition, with the corresponding hole of the size that produces bore dia and pore-forming agent according to granular size.By pore-forming agent is distributed and/or accumulate in the polymeric blends and solidify or solid polymer substrate in mode, can will be dissolved in hole size and the voidage that pore-forming agent in the polymeric blends is used to change implant.

Can be for example measure bore dia and distribution in the polymeric matrix of implant by the crosslink part that detects polymeric matrix according to the method for scanning electron microscope.Can measure the voidage of polymeric matrix according to suitable method known in the art, for example hydrargyrum invade porosimetry, proportion or density relative method, from the method for the image calculation of scanning electron microscope etc.In addition, can recently calculate voidage according to the ratio or the percentage of the water-soluble substances that comprises in the polymer composition.For example, the polymer composition that contains have an appointment 30% polymer and about 70% solvent and/or other water-soluble components can generate the implant with about 70% voidage polymeric matrix.

The bioactive substance of compositions and polymer of the present invention can form the substrate of homogenizing, and perhaps bioactive substance can be encapsulated in the polymer in some way.For example, bioactive substance can at first be encapsulated in the microsphere, then mode and the combination of polymers can be maintained until the small part micro-sphere structure.Perhaps, a kind of bioactive substance and polymer of the present invention are not gone up substantially and are dissolved each other, to such an extent as to it can be scattered in small droplet form rather than be dissolved in the polymer.More than any of two kinds of forms all can be accepted, but preferably, no matter the homogeneity of compositions how, bioactive substance release speed in vivo RateAll keep controlled, to the make a living exercising result of thing when degraded polymer ester bond hydrolysis of small part.

Object of the present invention is for being implanted into or injecting and design to mammiferous body.The particularly important is, when implanted or when being injected in the tissue of vascularization, the tissue stimulation minimum that this class object causes.As the structure medical treatment device, polymer composition of the present invention provides the physical form with specific chemistry, physics and engineering properties, and described character is enough for above-mentioned application becomes non-toxicity residue with degradation in vivo compositions.

The implant that forms in the Injectable polymer solution should slowly be degraded in vivo, makes natural tissues to grow when implant fades away and also can make its influence up.The implant that forms from the injectable system should discharge the medicine that is contained in its substrate with controlled speed, has been released until medicine.For some drugs, polymer will discharge the back degraded fully at medicine.For other drug for example for peptide or the protein, have only when depolymerization to the medicine that has made non-diffusion during with degree that body fluid contacts, medicine just can be discharged fully.

Biodegradable crystal controlling agent

Crystal controlling agent can choose wantonly with combination of polymers to obtain the polymer blocks of homogenizing, that is the polymer crystallization part of basic homogeneous distribution, the homogeneous thing piece of required moldability, cohesion and stable physical features when being effective to bone and its hetero-organization to obtain having.Crystallization control can be the form of the dispersion solid particle in the compositions, for example, and inorganic salt such as calcium carbonate or calcium phosphate, polymer for example poly-(vinyl alcohol), starch or glucosan and other similar substances.Other available crystal controlling agents or be in mixed process with fused those materials of polymer, perhaps for dissolving in those materials in the melted polymer.The example of these materials comprises for example for example poly-(ethylene glycol) or poly-(lactide-altogether-caprolactone) and other similar substances of tripalmitin or ethyl lactate, polymer of low molecular weight organic compound.The composition prepared that contains crystal controlling agent comprises about 40-95 weight % polymer, the preferred crystal controlling agent of about 60-90 weight % and about 5-60 weight %, preferably about 10-40 weight %.

The crystal controlling agent that is applicable to the present composition mainly can be divided into two classes, and a class is to be present in solids form in the compositions of thawing, and a class is the form that is melted in or is dissolved in the melted polymer compositions.

The crystal controlling agent that is present in the compositions with solid particle or implant form comprises inorganic or organic salt and polymer.Suitable organic salt comprises, for example: calcium carbonate, hydroxyapatite, calcium phosphate, apatite calcium, calcium sulfate, calcium bicarbonate, calcium chloride, sodium carbonate, sodium bicarbonate, sodium chloride and other similar salts.Suitable organic salt comprises, for example: calcium stearate, calcium palmitate, sodium stearate, C ₁₀-C ₅₀Other slaines of derivative of fatty acid and other similar salts.In compositions, exist with dispersed particles form or implant form, be applicable to that the polymer in the compositions comprises, for example: polysaccharide, cellulose derivative and poly-(vinyl alcohol).The example of suitable polysaccharide comprises that for example: glucosan, maltodextrin, the starch that derives from corn, Semen Tritici aestivi, rice etc. and starch derivatives be sodium starch glycollate for example.The example of suitable cellulose derivative for example comprises: sodium carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose, carboxymethyl cellulose, hydroxylated cellulose etc.The molecular weight of suitable poly-(vinyl alcohol) is about 5,000 to 20,000, and is preferred about 10,000-15, and 000, and percent hydrolysis is about 80-100%.

Fused or be dissolved in that crystal controlling agent also can be used in the polymer composition of the present invention in the melted polymer with polymer in mixed process.Being separated to a certain degree may take place or can not take place in these compositionss in cooling procedure.The crystal controlling agent of this type comprises low molecular weight organic compound or polymer.Suitable low molecular weight compound comprises, for example: tripalmitin, tristerin and other similar glycerol derivatives, triethyl citrate and other similar citric acid derivants, ethyl lactate and other similar esters or the like.

The amount of the crystal controlling agent that comprises in the compositions can effectively make polymer softening to denseness moldable and/or that can smear.Preferably, crystal controlling agent is the non-solvent solid matter.A kind of crystal controlling agent can be contained in the compositions individually or in the mode with another kind of crystal controlling agent combination.The example of the preferred compositions of this class material is poly-(lactide-be total to-caprolactone) and calcium stearate.

Penetration enhancer

Compositions also can comprise and can effectively promote biological agent to infiltrate through for the compositions that lacks penetration enhancer and spread all over systemic penetration enhancer.Penetration enhancer can be penetration enhancer arbitrarily usually, is preferably oleic acid, oleyl alcohol, ethyoxyl diethylene glycol, laurocapram, alkanoic acid, dimethyl sulfoxide, polar lipid or N-N-methyl-2-2-pyrrolidone N-, more preferably oleic acid or oleyl alcohol.Penetration enhancer can any appropriate and appropriate amount (for example between about 1 weight % and about 10 weight %) but be present in the flow composition.

Absorb and change agent

Can use absorption any appropriate and appropriate to change agent among the present invention.For example, absorb the change agent and can be selected from propylene glycol, glycerol, urea, diethyl decanedioic acid sodium, lauryl sulfate, sodium lauryl sulphate, sorbitan ethoxylate, oleic acid, 2-pyrrolidone-5-carboxylic acid's ester, N-Methyl pyrrolidone, N, the N-diethyl--toluamide (tolumide), dimethyl sulfoxide, alkyl methyl sulfoxide, and their combination.

Opacifier

Can use any appropriate and appropriate opacifier among the present invention.For example, opacifier can be selected from barium, iodine, calcium and their mixture.

Coloring agent

Also can in fluid composition, add the coloring agent of effective dose, so that can monitor the biological degradability or the bioerodible of microporous membrane effectively in time.Suitable and appropriate coloring agent answer avirulence, nonirritant and with fluid composition in the solvent anergy.The coloring agent that is used for cosmetics, food and medicine by FDA approval comprises: D ﹠amp; C Yellow No.7; D ﹠amp; C Red No.17; D ﹠amp; C Red No.7,9 and 34; FD ﹠amp; C Red No.4; Orange D ﹠amp; C No.4; FD ﹠amp; C Blue2; FD ﹠amp; C Green No.3 etc.

Moldable implant precursor

According to U.S. Patent No. 5,487,897 disclosed technology, but by with flow composition and aqueous medium water or saline contacts or for example serum, lymph etc. contact with body fluid for example, can be so that but flow composition forms moldable implant precursor, the disclosure of the described document mode of its description is by reference included this paper in, and the thermoplastic polymer of ' 897 patent is biocompatible, a biodegradable thermoplastic polymer as herein described in this description.

In brief, the compositions that will contain or not contain bioactive agent of the technology by ' 897 patent disclosure is transformed into the two-part structure that comprises the external capsule with the content that can flow.This technology is applied to limited amount aqueous medium etc. in some biological agent systems, only system's outer surface is changed into solid, has therefore formed inner capsule with the content that can flow.The denseness of the flowable content of body weight can be in the extremely heavy-gravity scope of water sample before the implant.The denseness of external capsule can be at gel to the scope of mouldable, moldable and wax sample.Then can be with device or implant precursor applications and the implantation site that obtains.After the implantation, solvent diffuses to the surrounding tissue body fluid from implant precursor, has the implant of solid polymer substrate with formation.Preferably, the implant precursor implant in 0.5-4 hour, preferably in about 1-3 hour, preferably in about 2 hours, be solid polymer substrate at in-situ solidifying.Like this, when placing body to be implanted into the site implant precursor, the implant precursor finally is frozen into the matrix structure of solid micropore.

Loose structure

The loose structure of solid matrix (implant, implant, implantable object, biodegradable object and device that original position for example of the present invention forms), be subjected to the influence of the character of organic solvent and thermoplastic polymer, be subjected to their influences at water, aqueous medium or body fluid (may be different in every kind of medium) dissolubility, and the influence of other materials that existed (for example becoming bore portion).Loose structure is considered to form by several mechanism and their combination.But the flow composition dissipation of solvent from solidify, run off or diffuse in the contiguous liquid and can in polymeric matrix, form the hole, comprise hole path.But aqueous medium, water or body fluid also can be invaded in the flow composition, and this has also partly caused the formation in hole.It is generally acknowledged, but pore structure is to form in the process of conversions such as implant, object at flow composition.Explain as above, in this process, but think that organic solvent and thermoplastic polymer have distributed the zone of enrichment or shortage thermoplastic polymer in flow composition.The result of the dynamic interaction that is considered to water immersion and solvent dissipation of this distribution.But immersion comprises the motion in flow composition of aqueous medium, water or body fluid, but dissipation comprises the motion of organic liquid dissipation in the flow composition surrounding medium.But flow composition lacks the zone of thermoplastic polymer to be impregnated by the mixture of organic solvent and water, aqueous matrix or body fluid gradually.These zones are considered to finally form the holey system of implant, object etc.

Usually the macrostructure of solid matrix comprises nuclear and epidermis.Usually nuclear and epidermis are micro porous, but except use as mentioned below independently the pore-forming agent, the size in epidermis hole is less than the size of nucleopore.Preferably, the diameter in the hole of the external skins of solid matrix part is significantly less than the diameter in the hole of inner core part.The hole of nuclear is preferably basically identical, compares epidermis with the porous of nuclear and is generally functional atresia.The magnitude range in the hole of implant, object, device etc. is at about 4-1000 micron, and the size in the hole of preferred epidermal area is about 1-500 micron.The porosity of this class substrate is at United States Patent (USP) 5,324, describes to some extent in 519, and its disclosure mode is by reference included this paper in.

The scope of the porosity of solid micropore implant, object, device etc. should be at about 5-95%, and this percentage ratio is to record by the percentage of solids of measuring solid volume.The porosity that forms should be subjected to controlling to small part of dissolubility in the water of organic solvent and thermoplastic polymer.If dissolubility is higher in the water of organic solvent, and dissolubility is extremely low or do not exist in the water of polymer, then can form quite high porosity, is generally the rank of 30-95%.If dissolubility is lower in the water of organic solvent, and polymer have lower to the non-existent water dissolubility, then form lower porosity, be generally the rank of 5-40%.Think that but porosity is subjected to polymer-solvent assigned portions control when flow composition contact aqueous medium etc.Control to porosity helps producing different types of biodegradable object of the present invention, implant and device.For example, when the intensity to this object, implant or device etc. had requirement, it was favourable having lower porosity.

The solid biodegradable object

Biodegradable medicine send pass product can be by making water or aqueous medium or body fluid to cause the conversion process preparation of solidification.Usually these products are the solid matrix that exsomatizes.Solid matrix has given shape if exsomatize, but then can obtain this substrate by flow composition is converted in suitable mould according to body technique before the above-mentioned mold pressing implant.After forming precursor, it can contact to finish conversion with other aqueous mediums.Perhaps, but flow composition can be placed the closed die that can allow aqueous medium permeate, the mould that compositions is housed be contacted with aqueous matrix it is immersed in the water-bath.Preferably, but flow composition in this case should have moderate to the height viscosity.

Microcapsule and microgranule can form by technology known in the art.In brief, but the microcapsule preparation is included in the micellar emulsion of formation bioactive agent carrier in the flow composition, and wherein this carrier is non-solvent for biocompatible, biodegradable, the branched thermoplastic polymer of the present invention.Filter micelle, then it is suspended from the aqueous medium.Afterwards, but the bag tegillum of the flow composition of micellar surface be cured to form porous microcapsule.Form microgranule with similar method.But but the mixture of flow composition and bioactive agent is dropwise added in the non-solvent for flow composition by spraying, instillation, aerosolization mode or by other similar techniques.The size and the shape of control microdroplet are to produce the small porous particle of required form and size.Can produce lamella, film, thin film by but flow composition being added on the suitable non-solvent and making to be converted.Similarly, but can regulate, to form silk thread but not microdroplet in spraying or during aerosolization to the viscosity of flow composition.But these silk threads can be added on the non-solvent for flow composition to produce thread support or film.Suture material or other similar materials also can form by but flow composition being squeezed in the non-solvent bath.Extrusion answers may command to be extruded the size and the shape of product.The technology that forms these stripped solid matrixs is at United States Patent (USP) 4,652, and 441,4,917,893,4,954,298,5,061,492,5,330,767,5,476,663,5,575,987,5,480,656,5,643,607,5,631,020,5,631,021,5, state in 651,990, its disclosure can mode by reference be included this paper in, and condition is that employed polymer is biocompatible, biodegradable a, thermoplastic polymer disclosed in this invention.

Can use them according to the known function of these stripped solid matrixs.In addition, can use technology known in the art for example implant and other solid articles to be inserted in the body by otch or with trocar.

The present invention can provide a kind of implant, and this implant comprises biodegradable, the biocompatible thermoplastic polymer that is insoluble at least substantially in aqueous medium, water or the body fluid; And acceptable salt or its prodrug on the biological agent, its metabolite, its biopharmaceutics.Implant has solid or gel micropore substrate, and its mesostroma is the nuclear that has epidermis to surround.Implant can further comprise the biocompatibility organic liquid, and under standard temperature and pressure, described thermoplastic polymer dissolves in wherein.If there is the biocompatibility organic liquid, its amount is preferably less, and the about 0 weight % that for example accounts for compositions is to about 20 weight %.In addition, the amount of biocompatibility organic liquid preferably reduces gradually along with the time.It is about 1 to about 1000 microns hole that described nuclear preferably comprises diameter.Described epidermis preferably comprises the hole of diameter less than nucleopore.In addition, the size in epidermis hole preferably make epidermis with nuclear comparatively speaking for functional atresia.Implant can have the shape of any appropriate, can have the form of any appropriate.For example, implant can be solid, semisolid, the wax sample, heavy-gravity, and perhaps implant can be gelatinous.

" processing " used herein or " treatment " comprise that (i) prevents the generation (for example prevention) of pathologic illness (for example solid tumor); (ii) suppress pathologic illness (for example solid tumor) or stop its development; And (iii) alleviate pathologic illness (for example alleviate relevant symptom) with solid tumor.

" metabolite " is meant the arbitrary substance that obtains through Biochemical processes, when active parent drug or other preparations or compositions of the present invention were given mammalian subject, living cells interacted by described Biochemical processes and this class active parent drug or other preparations or compositions of the present invention in vivo.Metabolite comprises product or the intermediate that is got by any metabolic pathway.

" metabolic pathway " is meant the continuous a series of enzyme mediated responses that a kind of chemical compound are converted into another kind of chemical compound and intermediate and energy are provided for cell function.Metabolic pathway can be linear, or circulation.

" treatment effective dose " is intended to comprise for example for treating or prevent potential disease or disease, perhaps be treatment and host's the potential disease or the symptom of disease association, and can be used for acceptable salt or its prodrug on a certain amount of biological agent of the present invention, its metabolite, its biopharmaceutics, the compositions of acceptable salt or its prodrug on perhaps a certain amount of biological agent, its metabolite, its biopharmaceutics.The compositions of acceptable salt or its prodrug is preferably Synergistic compositions on biological agent, its metabolite, its biopharmaceutics.As for example Chou and Talalay, described in the Adv.EnzymeRegul.22:27-55 (1984), when unite give acceptable salt on biological agent, its metabolite, its biopharmaceutics or its prodrug effect greater than biological agent, its metabolite, its biopharmaceutics on the effect that gives separately as single medicament of acceptable salt or its prodrug add and the time, just produced synergism.Usually, synergism obtains the clearest and the most definite confirmation by acceptable salt or its prodrug on biological agent, its metabolite, its biopharmaceutics inferior to optium concentration.Synergism is compared the aspect of active or some other beneficial effect that may be embodied in lower toxicity, increase with independent component.

" acceptable salt on the biopharmaceutics " used herein is meant that wherein parent compound is by its acid of preparation or the adorned derivant of alkali salt.Acceptable salt includes but not limited on the biopharmaceutics: alkaline residue is the mineral salt or the organic salt of amine for example; Acidic residues is the alkali salt of carboxylic acid or organic salt etc. for example.Acceptable salt for example comprises common non-toxic salts or the quaternary ammonium salt by nontoxic mineral acid or the formed parent compound of organic acid on the biopharmaceutics.For example, the common nontoxic salts of this class comprises: derive from for example salt of hydrochloric acid, hydrobromic acid, sulphuric acid, sulfamic acid, phosphoric acid, nitric acid etc. of mineral acid; With the salt that is got by following organic acid preparation, described organic acid is acetic acid, propanoic acid, succinic acid, hydroxyacetic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-anilinesulfonic acid., 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethyl sulfonic acid, oxalic acid, isethionic acid etc. for example.Especially, acceptable salt can comprise the natural intravital salt of mammal that is present on the biopharmaceutics.

Can be used for acceptable salt on the biopharmaceutics of the present invention can obtain from the parent compound that contains alkalescence or acidic moiety is synthetic by the conventional chemical method.Generally speaking, this class salt can be by in water or in organic solvent, perhaps in both mixture, the appropriate alkali of the free acid of these chemical compounds or alkali form and stoichiometric amount or acid reaction is prepared; Usually preferred non-aqueous media, for example ether, ethyl acetate, ethanol, isopropyl alcohol or acetonitrile.The tabulation of suitable salt can be at Remington ' s Biological agent Sciences, 17th ed., and Mack PublishingCompany, Easton, PA, 1985, to find in p.1418, its disclosure mode is by reference included this paper in.

Term " acceptable on the biopharmaceutics " is used in reference in the scope of rational medical judgment at this paper, be applicable to human or animal's tissue to contact, and those chemical compounds (for example chemotherapeutic agent) the many toxicity of no mistake in treatment, stimulation, atopic reaction or other problems or complication, that adapt with rational benefit/risk ratio.

The biological agent test kit

The invention provides the biological agent test kit.This class test kit is suitable in vivo, and original position forms biodegradable implant.But test kit can comprise first container that contains flow composition.Described compositions comprises biodegradable, the biocompatible thermoplastic polymer that is insoluble at least substantially in aqueous medium, water or the body fluid; With the biocompatibility organic liquid, under standard temperature and pressure, described thermoplastic polymer dissolves in wherein.This test kit also can comprise second container that contains acceptable salt in biological agent, its metabolism, its crude drug agent or its prodrug.This biological agent test kit can randomly also comprise description and the marking that is used to assemble and/or use this biological agent test kit.

Especially, first container can comprise syringe or conduit; Second container can comprise syringe or conduit independently.In addition, first container can comprise syringe, and second container can comprise syringe, and two syringes fitted to be directly connected to each other.

Concrete scope, value and embodiment

In a specific embodiments of the present invention, biodegradable, biocompatible thermoplastic polymer can have and comprises the structural formula that is selected from following monomeric unit, described monomeric unit is selected from lactide, Acetic acid, hydroxy-, bimol. cyclic ester, caprolactone, glyceride, anhydride, amide, carbamate, esteramides, ortho esters, to dioxanone, acetal, ketal, carbonic ester, phosphonitrile, hydroxy butyrate, hydroxyl valerate, alkylidene oxalate, alkylidene succinate, aminoacid, and their combination in any; This structural formula comprises the monomeric unit of random order or block order.

In another specific embodiments of the present invention, biodegradable, biocompatible thermoplastic polymer can be the polymer or the copolymer of lactide monomer unit, caprolactone monomer unit, glycolide monomer unit or their combination in any.

In another specific embodiments of the present invention, biodegradable, biocompatible thermoplastic polymer can comprise and be selected from following polymer that described polymer is selected from: polylactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, polycaprolactone, poly-to dioxanone, Merlon, the poly hydroxybutyric acid ester, the polyalkylene oxalate, polyanhydride, polyamide, polyesteramide, polyurethanes, polyacetals, polyketals, poly-orthocarbonic ester, polyphosphazene, polyoxyvalerate, the polyalkylene succinate, poly-(malic acid), poly-(aminoacid), chitin, chitosan, poe, poly-(methyl vinyl ether), polyester, poly-alkyl diol, their copolymer, their block copolymer, their terpolymer, their compositions or mixture.

In another specific embodiments of the present invention, biodegradable, biocompatible thermoplastic polymer can comprise at least a polyester.

In another specific embodiments of the present invention, biodegradable, biocompatible thermoplastic polymer can be polylactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, polycaprolactone, they copolymer, they terpolymer or their combination in any at least a.

In another specific embodiments of the present invention, biodegradable, biocompatible thermoplastic polymer can be poly-(DL-lactide-co-glycolide).In another specific embodiments of the present invention, biodegradable, biocompatible thermoplastic polymer can be poly-(the DL-lactide-co-glycolide) with carboxyl end groups.In another specific embodiments of the present invention, biodegradable, biocompatible thermoplastic polymer can be poly-(the DL-lactide-co-glycolide) of no carboxyl end groups.In another specific embodiments of the present invention, biodegradable, biocompatible thermoplastic polymer can be 50/50 poly-(a DL-lactide-co-glycolide) with carboxyl end groups.In another specific embodiments of the present invention, biodegradable, biocompatible thermoplastic polymer can be 75/25 poly-(a DL-lactide-co-glycolide) of no carboxyl end groups.

In another specific embodiments of the present invention, biodegradable, biocompatible thermoplastic polymer can exist with the about 80 weight % that are up to compositions.In another specific embodiments of the present invention, biodegradable, biocompatible thermoplastic polymer can exist with the about 10 weight % that surpass compositions.In another specific embodiments of the present invention, biodegradable, biocompatible thermoplastic polymer can exist to about 80 weight % with about 10 weight % of compositions.In another specific embodiments of the present invention, biodegradable, biocompatible thermoplastic polymer can exist to about 50 weight % with about 30 weight % of compositions.

In another specific embodiments of the present invention, mean molecule quantity biodegradable, biocompatible thermoplastic polymer can surpass about 15,000.In another specific embodiments of the present invention, mean molecule quantity biodegradable, biocompatible thermoplastic polymer can be up to about 45,000.In another specific embodiments of the present invention, mean molecule quantity biodegradable, biocompatible thermoplastic polymer can be about 15,000 to about 45,000.

In one embodiment of the invention, the water solublity of biocompatibility organic liquid can be from insoluble fully to solvable fully with all proportions with arbitrary proportion.In another embodiment of the invention, the biocompatibility organic liquid can be insoluble fully in water but can be diffused in people's body fluid.In another embodiment of the invention, the biocompatibility organic liquid can be to small part water miscible.In another embodiment of the invention, the biocompatibility organic liquid can be water miscible fully.In another embodiment of the invention, the biocompatibility organic liquid can be scattered in aqueous medium, water or the body fluid.

In another embodiment of the invention, the biocompatibility organic liquid can be polar protic liquids.In another specific embodiments of the present invention, the biocompatibility organic liquid can be aprotic, polar liquid.

In another embodiment of the invention, the biocompatibility organic liquid can be annular aliphatic, linear aliphatic family, branched aliphatic or aromatics organic compound, it is a liquid when room temperature and physiological temp, and contain at least a following functional group, described functional group is selected from alcohol, ketone, ether, amide, amine, alkylamine, ester, carbonic acid, sulfoxide, sulfone and sulfonic acid.

In another embodiment of the invention, the biocompatibility organic liquid can be selected from: the heterocyclic compound of replacement, the ester of carbonic acid and alkylol, monocarboxylic Arrcostab, monocarboxylic aryl ester, monocarboxylic aralkyl ester, the Arrcostab of dicarboxylic acids, the aryl ester of dicarboxylic acids, the aralkyl ester of dicarboxylic acids, the Arrcostab of tricarboxylic acid, the aryl ester of tricarboxylic acid, the aralkyl ester of tricarboxylic acid, alkyl ketone, aryl ketones, aralkyl ketone, alcohol, polyhydric alcohol, alkylamide, dialkyl amide, alkyl sulfoxide, dialkyl sulphoxide, the alkyl sulfone, dialkyl sulfone, lactone, the cyclic alkyl amide, cyclic alkyl amine, aromatic amides, aromatic amine, their mixture or their compositions.

In another embodiment of the invention, the biocompatibility organic liquid can be selected from: N-N-methyl-2-2-pyrrolidone N-, 2-Pyrrolidone, (C ₂-C ₈) aliphatic alcohol, glycerol, tetraethylene glycol (TEG), glycerol formal, 2,2-dimethyl-1,3-dioxolone-4-methanol, ethyl acetate, ethyl lactate, ethyl n-butyrate., malonic acid di-tert-butyl ester, tributyl citrate, the just own ester of acetyl tributyl citrate three, diethyl succinate, ethyl glutarate, diethyl malonate, triethyl citrate, glyceryl triacetate, tributyorin, diethyl carbonate, Allyl carbonate, acetone, butanone, dimethyl acetylamide, dimethyl formamide, caprolactam, dimethyl sulfoxide, dimethyl sulfone, oxolane, caprolactam, N, the N-diethyl--toluamide, 1-dodecyl-aza-cycloheptane-2-ketone, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2-(1H)-pyrimidone, benzyl benzoate, and their compositions.

In another embodiment of the invention, biocompatibility organic liquid molecular weight ranges can be about 30 to about 500.

In another embodiment of the invention, the biocompatibility organic liquid can be N-N-methyl-2-2-pyrrolidone N-, 2-Pyrrolidone, N, dinethylformamide, dimethyl sulfoxide, Allyl carbonate, caprolactam, glyceryl triacetate or their arbitrary composition.In another embodiment of the invention, the biocompatibility organic liquid can be the N-N-methyl-2-2-pyrrolidone N-.

In another embodiment of the invention, biocompatible liquid can exist with the about 40 weight % that surpass compositions.In another embodiment of the invention, biocompatible liquid can exist with the about 80 weight % that are up to compositions.In another embodiment of the invention, biocompatible liquid can exist to about 70 weight % with about 50 weight % of compositions.

Embodiment

Utilize

Send of the lasting release of the medicine of delivery system to eye

Medicine send the introduction of the technology of passing

The QLT USA of subsidiary of QLT Phototherapeutics Inc. has developed a kind of be used for continuing to discharge micromolecule, peptide and the biodegradable delivery system that send of proteinic liquid

This send delivery system to comprise to be dissolved in the biodegradable polymers in the biocompatible solvent, for example poly (lactide-co-glycolide).Comprise medicine in this solution, can use the mixture of standard syringe and syringe needle subcutaneous injection gained.After body fluid contacts, Send delivery system to solidify and with drug limits in solid implant.When implant was degraded, medicine discharged with predetermined speed.

Utilize

Send delivery system, Atrix send the multiple medicine of having passed from micromolecule to reorganization of bio-pharmaceutical, and medicine send the persistent period scope of passing from 1 thoughtful 6 months.At present, Atrix has had multiple application

Send the listing product of the FDA approval of delivery system, comprise dental product (

With

) and drug products (

7.5mg, 22.5mg and 30mg) and be in several prods in the clinical trial.

Send the advantage of delivery system

Send delivery system to provide some to be better than other parenterals and continue to discharge the significant advantage that send delivery system.For example, microsphere must be with comprising the aseptic method production of using halogenated solvent.And the ratio of medicine and microsphere is by the control from view of profit of encapsulation, and this method can cause can't losing the API of 25-50% with remedying in the process of producing drug products.By contrast,

Send delivery system to be made of biocompatible composition, it is to prepare by appropriate biodegradable polymers is dissolved in the biocompatible solvent.Different with microsphere is,

Send delivery system can adopt the conventional method that comprises γ irradiation to sterilize at last.The production method of this uniqueness and proprietary product structure have been eliminated drug loss in process of production basically.And, send than the bigger volume injected of the usefulness of microsphere and to pass smaller dose,

Send delivery system to send the API that passs bigger metering with less volume injected.The most important,

Bank can protect responsive bio-pharmaceutical to avoid vivo degradation and enzyme-deactivating.

Compare with implantable or storage facility,

Technology is that sending of patient close friend passed platform. Drug products is a subcutaneous injection, and the implant of gained discharges medicine in the preset time interval.Usually, biodegradable speed of implant and drug release speed RateIdentical; Therefore, injection site can be recovered during an infra shot basically in time.Comparatively speaking, the mechanicalness implant must remove by operating mode, and must be replaced or recharge after medicine storage exhausts.When being used for when eye gives biological agent,

Sending delivery system to use effective and an amount of material reduces the incidence rate of the stimulation of eye and surrounding tissue and/or reduces its seriousness.

Embodiment 1

Right behind the execution intraocular injection

Send the toleration of delivery system

For right behind the mensuration eye drops

Send the toleration of delivery system, carried out a series of preclinical studies.In these researchs, to three kinds of New Zealand white rabbit injections

A kind of in the carrier.Directly within the eye (intravitreal injection), in (subconjunctival injection) under the conjunctiva or pass the eyeball back and be covered in muscle and supraneural film ((subtenon) injection under the fascial bursa) and inject.Local response of routine observation rabbit and eye visual acuity were observed 28 days.In addition, carry out the vitreous humor sampling to estimate each

The cytopathology influence of carrier.

Desired the same with any eye drops mode, for all

Solution has all been observed slight conjunctival congestion; Yet this temporary transient being reflected in 72 hours just eliminated.In whole research, intraocular pressure and visual acuity remain unchanged.The rational evaluation of the cytopathy of the 3rd day, 14 days and 28 days shows that numeration of leukocyte (WBC) and protein level are all normal after the administration.In addition, any time, the eye for any treatment does not observe inflammatory cell or teratocyte or infectious substance after administration.

These results show

Send the well-tolerated of delivery system, it is seemingly inert after the injection within the eye.In fact, Drug products can weaken the local response of some drugs.For example, in research subsequently, will by

Carrier and known eye stimulant (benzethonium chloride) mix and the toleration of the aqueous solution of the toleration of the preparation of preparation and same substance compares.The overall observation and cytopathology evaluation confirmation, the stimulant of single usefulness has produced significant conjunctiva swelling at intravitreal injection after one day, serious aqueous humor and cell glitters (cellular flare) and almost completely lose corneal transparency.Yet,

/ stimulant preparation only shows slight conjunctiva swelling to moderate in identical administration time, moderate aqueous humor and cell glitter and do not lose corneal transparency.Therefore

The feature that bank slowly discharges makes that the stimulus object level of responsive part tissue of eye contact is lower, and the probability that local untoward reaction is taken place drops to minimum thus.In sum,

Send delivery system to be very suitable for therapeutic agent continued to send passing to eye.

Embodiment 2

Utilize lagophthalmos, in three days, pass through in the vitreous body or subconjunctival mode, estimated and contained the several of PEG300, mPEG350, PEG400, NMP, glyceryl triacetate, DMSO and pure DMSO

Preparation and BEC aqueous solution.Adopt any route of administration in above-mentioned two kinds, find several at short notice Preparation is acceptable for eye is implanted, and particularly, these preparations comprise the preparation that contains PEG300, mPEG350, PEG400 and NMP.Therefore, with containing PEG300, mPEG350 and NMP

Preparation adopts two kinds of route of administration to carry out long-time stimulus effect research.The result who studies for a long period of time shows that polymer as expection degraded has taken place, and does not observe the stimulation of prolongation.Therefore, can think and contain PEG300, mPEG350 and NMP Preparation is in the vitreous body or conjunctiva implants down and medicine subsequently send the acceptable carrier of passing.

The target of this project plan is to inciting somebody to action

Send delivery system to estimate as the feasibility of ocular drug slow-released carrier.For the final purpose of this plan,

Carrier will be injected to ophthalmic and circumocular each position, to determine clinically acceptable carrier and injection technique and to form the function of not disturbing eye or do not cause the implant of serious tissue reaction.If the elementary step of this research work achieves success, the scheme that then can produce is subsequently sent and is passed to estimate medicine to eye.

A series of preclinical studies to rabbit can be right Various injection techniques and position in the carrier scope are studied.The tissue reaction of each organizational structure of injection site and eye also will obtain estimating.Injection site can comprise the subconjunctival injection of having the outside in mind and pass the intravitreal injection of eye sclera (hard outer side form).Be hopeful to obtain a kind of implant that is fixed in sclera and forms the thromboembolism that prevents the vitreous humor loss thus.The implant of intravitreal injection has the advantage that directly contacts with intraccular part, can send drug delivery most effectively thus.Yet this route of administration has the probability of obviously higher generation ill effect.

Studying the preliminary study at these injection techniques and position can carry out on a small amount of rabbit, and these rabbits were condemned to death after 72 hours.After finishing preliminary study, can identify acceptable

Preparation just can carry out long-time stimulus research.In all research, the untoward reaction of close observation rabbit; If suitably, can carry out euthanasia to rabbit.Can utilize improved McDonald-Shadduck marking system that the slit lamp observation result who estimates anterior chamber's feature is carried out many grade scorings.Also can estimate the cytopathology of injection site and especially amphiblestroid histology of vital tissue and vitreous humor.The cytopathology report can comprise numeration of leukocyte, protein counting and rate of specific gravity.

In view of the sensitivity of ocular tissue, in preliminary study, only use

Carrier and the solvent that has biocompatibility most.The initial solvent of being studied comprises Liquid Macrogol (PEG 300), PEG400, Polyethylene Glycol monomethyl ether 350 (mPEG350), n-methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO) and glyceryl triacetate (glyceryl triacetate).In addition, known eye stimulus object benzethonium chloride (BEC) is estimated observed positive reaction.In the overall process of research, uses intrinsic viscosity to gather (lactide-Acetic acid, hydroxy-, bimol. cyclic ester) (PLGH), also used the syringe needle of 5/8 inch of the constant volume injected of 50 μ L and No. 25 as the single polymers 50/50 of 0.18dL/g.

4.1 ATRS917

Studied in the first term rabbit body on June 19th, 2003 and finish, it is to 6 kinds The intravitreal injection approach of carrier formulation is estimated.Use the biodegradable stitching thread of Vicryl to test article in contrast.

Preparation is listed in the table below:

PEG400 preparation (group E and F) is thickness the most, and hard for having a few by No. 25 needle injection, yet all injection all can have no carrying out smoothly of difficulty.Inject after 24 hours, do not see that for group A-D stimulation or the eye relevant with the treatment eye are unusual.In group E and F, 1/3rd treatment eye shows conjunctival secretion and increases (conjunctival discharge), and other are unusual but do not observe.Injected back 72 hours, and do not see that for group A, D and E stimulation or eye were unusual, yet group B, C and F demonstrate that 1/3rd eye has slight aqueous humor and cell glitters, other are unusual but do not observe.Do not observe pupillary reaction in animal, this is owing to the pharmacology's blocking effect that is caused by N-ethyl-N-(.gamma.-picolyl)tropamide (tropicamide) mydriasis solution, and described solution is used for helping the eye rear portion is carried out classification.In the research in all future, also can predict this result, and lack pupillary reaction with

Implant and onrelevant.

Intraocular pressure, proportion, leukocyte and proteinometer number average are normal level, and all do not observe inflammation, teratocyte or infectious substance in all treatment eyes.This intravitreal injection is very neat and tidy, when syringe needle has when eye shifts out

Puncturing hole can seal automatically.Postmortem demonstration implant is attached to the inner surface of eye rather than swims in the vitreous humor.

This result of study shows PEG and mPEG preparation be injected into well-tolerated at the moment.All do not observe eye/tissue stimulation effect for all test article.What make that the ophthalmologists of Biological Test Center (BTC) Labs of this research only worries a bit is that the injection size is a bit big for solid bank implant.They think, adopt this volume injected can damage the vision of rabbit.Because what this research was concerned about is the size of eye and tissue stimulation rather than implant, thereby we are not optimized volume injected.This problem will obtain paying close attention in the research that further continues.

4.2 ATRS929

Research was finished on August 20th, 2003 in second rabbit body.Four kinds have been estimated through intravitreal injection

Preparation and two kinds of preparations through subconjunctival injection.Reuse the biodegradable stitching thread of 7-0Vicryl and test article in contrast.

Preparation is listed in the table below:

Group A-D is an intravitreal injection, and group E and F are subconjunctival injection.According to the breadboard report of BTC, all injections are all carried out without difficulty smoothly (annotate: group E and F preparation have also carried out vitreous body inner evaluation (being used for reference) in ATRS917).

Injected back 24 hours, the treatment eye (left eye) of most of animals shows slightly to moderate conjunctival congestion and swelling.In three treatment eyes (A organizes two eyes, and C organizes an eye), observe aqueous humor and cell glitters.In three treatment eyes (C organizes two eyes, and D organizes an eye), observe nuclear cataract.At group C and D (glyceryl triacetate Preparation) in, test article is forwardly sealed crystalline lens with the rear portion, and migrates to nucleus lentis.Observe three treatment eyes and a contrast eye (organizing an A) has the opaque body that some are dispersed at vitreous chamber.Do not see other unusual eye observation phenomenons.

Inject after 72 hours, only have the treatment eye of an animal (group A) to show conjunctival congestion.Do not see after 72 hours that aqueous humor or cell glitter, only treatment eye of observing group C animal has nuclear cataract.Test article in two treatment eyes of group C animal is positioned back segment eyeball bottom.Test article is shaped as taper shape.In an animal, 1 to the 2mm less sections of test article migrates to the peripheral region of papilla of optic nerve.Observe a treatment eye (group D) and have slight choroid/retina inflammation.

With preliminary eye

Research (ATRS917) is the same, and these injections are very neat and tidy, and has when eye shifts out when syringe needle Puncturing hole can seal automatically.Postmortem demonstration group A and B implant are attached to the inner surface of eye rather than swim in the vitreous humor.Discovery group C links to each other with crystalline lens with the D implant and demonstrates very thin thin film sample form.Discovery group E and F implant are attached to the outer surface of eye.The proportion of all preparations in the research, intraocular pressure, leukocyte and proteinometer number average are normal level.But the animal of discovery group C has the inflammatory cell than low number.

The result of this research shows that glyceryl triacetate is not an eye The carrier solvent accepted of implant.Yet the NMP preparation has shown acceptable result, and the PEG300 of the intravitreal injection that (ATRS917) studied in estimating in this result and the first term body and 400 suitable promptly observes similar cytopathology and eye observation phenomenon.Lower eye/tissue stimulation the effect of PEG300 and 400 implants also promotes and provides

System is as the additional flexibility of ocular drug delivery device, and PEG300 and 400 implants are subconjunctival injection and the outer surface that is attached to eye.

4.3 ATRS939

Research is finished in JIUYUE in 2003 23 days in the 3rd rabbit body.Four kinds have been estimated through intravitreal injection

Preparation and through two kinds of preparations of subconjunctival injection.Identical with research in preceding two bodies, use the biodegradable stitching thread of 7-0 Vicryl to test article in contrast.

Preparation is listed in the table below:

Group A-D is an intravitreal injection, and group E and F are subconjunctival injection.(annotate: in ATRS929, also estimated group E and F preparation (being used for reference).) according to the breadboard report of BTC, all injections are all carried out without difficulty smoothly.

Injected back 24 hours, the animal of group A and E demonstrates slight conjunctival congestion.All animals of group C, D and F show conjunctival congestion at least, and the conjunctival congestion color follows limbus of corneae week congested for bright red, and have covered at least 75% periphery in limbus of corneae week zone.The conjunctiva swelling of group C is slight and organize F also clearly.Except above-mentioned unusual, also to have observed the transparency of cornea among the group C and almost completely lost, this relates to the surface of about 76-100%.Group C also shows serious aqueous humor and cell glitters.Group C and D demonstrate iris third level vascular pole slightly to moderate hyperemia, and with the slight swelling of stroma iridis, in addition, it is obviously fuzzy to observe many opaque bodies and substrate fine structure in vitreous body, and slight choroid/retina inflammation to moderate.Injected back 24 hours, group A, B, E and F do not see other observation phenomenons.

Inject after 72 hours, all animals do not demonstrate other unusual eye observation phenomenons except lacking pupillary reaction among group B, E and the F, are among expecting and lack pupillary reaction yet.The animal of group A shows slight retinal hemorrhage and inflammation.The animal of group C and D still shows slight conjunctival congestion to moderate, and group C animal also shows secretions increase and swelling.Group C animal also demonstrates corneal transparency forfeiture, iris disease (iris involvement), nuclearity and mature cataract and causes the significantly fuzzy opaque body of substrate fine structure.In group C and D, detachment of retina, hemorrhage and inflammation are not estimated.

The cytopathology result of study that the vitreous humor of group among the A-D carried out shows among group C and the D that proportion and the protein level of 2/3 animal raise.All observed remarkable inflammation in an animal among all animals of group C and D and the group A.Find that all retina cell outward appearances are normal, do not observe teratocyte or infectious substance.

With preliminary eye

Research (ATRS917 and 939) is the same, and these injections are very neat and tidy, when syringe needle has when eye shifts out

Puncturing hole can seal automatically.Postmortem shows that the group B that contains 40% polymer is more much bigger than only containing the implant that comprises among the group D of 25% polymer.This part ground is owing to expansion and the polymer concentration itself of polymer after curing, and people can estimate that higher polymer concentration can produce bigger implant.Find these intravitreal injections

Implant links to each other with the eye side, but not clear they whether be that " grappling " is in eye.Discovery group E and F implant are attached to the outer surface of eye, and compare with the intravitreal injection implant of spherical form and to have flat, discoid form.

The result of this research shows that BEC causes significant eye stimulation really as expected, and BEC exists Preparation in (group D) has alleviated really that cell glitters, conjunctiva swelling, secretions increase and hyperemia, but can not alleviate inflammation actual in the vitreous humor.In the research test article of whole series, the stimulation minimum that the NMP preparation demonstrates, and glyceryl triacetate has caused significant conjunctival congestion.Find that DMSO preparation and neat solvent do not show its inflammation more than the test article of being studied in the research (ATRS917 and 929) in first and second bodies.

5. 28 days

Feasibility study, ATRS948

Research started on October 28th, 2003 in the 4th the rabbit body.This research evaluation in 28 day time three kinds Interior and the subconjunctival injection approach of the vitreous body of carrier formulation.For estimating

The long-time stimulus effect of implant and for research implant degradation kinetics carried out this research.

Be listed in the table below:

Group A-B, E-F and I-J are intravitreal injection, and group C-D, G-H and K-L are subconjunctival injection.According to the breadboard report of BTC, all injections are all carried out without difficulty smoothly.

Injected back 24 hours, group A, C, D, E, H and K demonstrate slight conjunctival congestion, and also observe slight conjunctiva swelling in group C, D and E.In addition, an animal among the group D shows a large amount of conjunctiva secretions.Observe aqueous flare in the animal in group C, observe cell in the animal in group A and C and glitter.In the animal of group A, observe the iris disease.Do not see other unusual eye observation phenomenons.

Implant one week of back, only observe the unusual eye phenomenon of an example.This comprises that a horn film transparency organizing D is slightly damaged.Though obvious some muddiness relates to the 1-25% of cornea, the intraccular part structure is still high-visible.Find that this unusual observation phenomenon is because animal is scratched eyes no thanks to

Test article causes.

The review time in 2,3 and 4 weeks puts and does not observe any unusual observation phenomenon after implantation.As if yet the crystalline lens of the animal of group J is pushed ahead slightly.In addition, the cytopathology result of study to the vitreous humor of group A-B, E-F and I-J shows that for the preparation of these intravitreal injections, proportion, intraocular pressure, leukocyte and proteinometer number average are normal level.In addition, do not observe deformity or inflammatory cell.

Selected eye is performed an autopsy on sb, to be evaluated at the depolymerization and the implant form of the 14th day and the 28th day.At the 14th day, group A, E and I implant presented the translucent structure of soft gel-shaped.Find these intravitreal injections

Implant links to each other with the side of eye, but not clear they whether " grappling " is in eye.Discovery group C, G and K implant are attached to the outside of eye, are rendered as the sign that has integrity but show degraded.By the 28th day, only there is a kind of implant corresponding to group B, this implant is very soft, be translucent and obvious degradation.Do not find other implants at the 28th day, and do not observe the sign that preexist is crossed implant.

The result of this research shows and at first three items short-term eye

Observation phenomenon in the evaluation study is the same, observes similar 24 hours observation phenomenons.These observation phenomenons are limited to conjunctival congestion mostly, and this is in the vitreous body or the type reaction of subconjunctival injection.Implant prolongation was not seen in the back yet up to the 28th day stimulation or abnormal cell pathology.Postmortem shows that the implant of finding in the 14th day is obvious degradation, has only found a kind of implant at the 28th day time point.This result is very encouraging because wish be at this moment between the boundary interpolymer degrade fully.In addition, have no stimulation in whole 28 days, show

Catabolite does not cause stimulation and is eliminated from eye.

5.2 ATRS1012

Research started on August 18th, 2004 in the 5th the rabbit body.This research evaluation in 28 day time three kinds

Injecting pathway under the fascial bursa of carrier formulation.For estimating eye

The long-time stimulus effect of implant and carried out this research for the degradation kinetics of studying implant. Preparation is listed in the table below:

At the 1st day and/or the 3rd day, there are 17 to show conjunctival congestion in 36 eyes.With 6 in 12 eyes that contain 25% 50/50 PLGH, 0.18 administration among the PEG300, with 7 in 12 eyes that contain 30% 50/50 PLGH, 0.18 administration among the mPEG350, show conjunctival congestion with 4 in 12 eyes that contain 45% 50/50PLGH 0.18 administration among the NMP.Also showed conjunctiva swelling at the 1st day to contain in these of 25% 50/50 PLGH, 0.18 administration one among the PEG300.There to be one to show conjunctival secretion at the 3rd day and increase in the eye that contains 30% 50/50PLGH 0.18 administration among the mPEG350; In research process, do not observe this eye conjunctival congestion is arranged.There to be near two corneal transparencies the position that shows conjunctival congestion that to a certain degree forfeiture is arranged in the eye that contains 45% 50/50 PLGH, 0.18 administration among the NMP; This observation phenomenon only a day after injection (the 1st day) takes place.

At the 1st day, the 3rd day, the 7th day and/or the 14th day, in 36 eyes 9 were observed test article and spill or be shifted from injection site.With 1 in 12 eyes that contain 25% 50/50 PLGH0.18 administration among the PEG300, with 3 in 12 eyes that contain 30% 50/50 PLGH, 0.18 administration among the mPEG350, all be observed test article with 5 in 12 eyes that contain 45% 50/50 PLGH, 0.18 administration among the NMP and spill or be shifted.For these eyes, test article is present in conjunctiva zone, anterior corneal surface and/or nictitating membrance.

At the 21st day, observe the test article that only has trace in all residue eyes that give one of two kinds of PEG object preparations; In giving all residue eyes of NMP preparation, test article obviously exists and in these sites normal vascular reaction is arranged.

The cytopathology result of study that the vitreous humor of all groups is carried out shows that for these ejection preparations, proportion, intraocular pressure, leukocyte and proteinometer number average are normal level.In addition, do not observe deformity or inflammatory cell.Consultant pathologist thinks that the cytological result of study of liquid is consistent with the normal glass body.

Be the form of assessment depolymerization and implant, carried out the postmortem of selected eye at the 3rd day, the 14th day and the 28th day.At the 3rd day, find that implant is attached to eye sclera and very firm.At the 14th day, find that implant is attached to the outside of eye, is rendered as the sign (soft) that has integrity but show degraded.Do not find implant at the 28th day, and do not observe the sign that preexist is crossed implant.

The result of this research shows and four of pro-are estimated in the vitreous body and the eye of route of administration under the conjunctiva

Observation phenomenon in the evaluation study is the same, observes similar 24 hours observation phenomenons.These observation phenomenons are limited to conjunctival congestion mostly, this be in the vitreous body, conjunctiva down or the fascial bursa type reaction of injection down.Implant prolongation was not seen in the back yet up to the 28th day stimulation or abnormal cell pathology.Postmortem shows that the implant that existed in the 14th day has hydrolysis slightly, and as estimating, does not find implant at the 28th day time point.Have no stimulation in whole 28 days, show that the position can be accepted and tolerate under the fascial bursa

Implant.

6. discuss

The result of eye feasibility study shows that PEG300, PEG400, mPEG350 and NMP are in the vitreous body or subconjunctival in the first three items short-term body

Implanting all is suitable carriers solvents.Adopt any of this two kinds of injecting pathways, these carrier solvents show minimum eye and tissue stimulation effect in 3 day time.

Preparation does not show the stimulation greater than the aforementioned test article of having carried out the vitreous body inner evaluation, and may tolerate for conjunctiva is following, yet the biocompatibility of DMSO also has problem.In addition, glyceryl triacetate just is found can not be compatible with the eye implantation, and this constitutes problem of relatively poor and stimulation owing to implant.Known in 3 days PEG300, mPEG350 and NMP After preparation and ocular implants are compatible, use these

Carrier has been finished two long-time stimulus researchs.The result of long-time stimulus research shows, for vitreous body in, conjunctiva down or fascial bursa down for the implant of injection, in 28 day time period, do not have the significant stimulation effect.And, do not exist when finishing research

Shown

Degraded carry out as scheduled, the eye catabolite is not retained yet.

Result of study shows that also the implant of intravitreal injection is attached to the inner surface of eye rather than swims in the vitreous humor.The postmortem of the eye of intravitreal injection shows have The automatic sealing of injection orifice cause remaining implant to be anchored to the ophthalmic surface, it is movable in vitreous humor that this can limit implant, this activity can cause vision impairment.Similarly, because

The tackness of implant, conjunctiva implant following and that fascial bursa is injected down is attached to the outer surface of eye.This shows, because implant contacts with the surface of eye, can increase a large amount of transhipments that medicine passes outer side form.Because in order to satisfy the longer needs that send the time of passing, volume injected, polymer concentration or medicine carrying capacity may increase, thus conjunctiva down and the acceptability that injecting pathway showed under the fascial bursa also increased

Send the motility of delivery system.

Sum up: for determining and after enclosing injection near the eyes at eye

Send the toleration of delivery system, carried out a series of zooscopies.In these researchs, several to the rabbit injection

One of solution.Can carry out direct injection (intravitreal injection) to eye, or under conjunctiva (subconjunctival injection) or pass the covering muscle at eyeball back and neural film (injecting fascial bursa under) is injected.Routine observation local response and vision loss or the damage of rabbit.In addition, any index of damaging in the ophthalmic liquid is analyzed.

Pleasing to the eye the same with expectation with the arbitrary substance injection, for all

Solution is all observed seldom rubescent; Yet this rubescent disappearance in 72 hours.Intraocular pressure remains unchanged in whole research process.The more important thing is the vision unimpaired.The ophthalmic liquid evaluation of microscopically shows that numeration of leukocyte (WBC) keeps normal in whole research process.This normal WBC counting shows a not damaged, infection and/or inflammation.And chemical analysis shows that the amount of substance that is dissolved in the liquid keeps normal.Random time at research process is being treated the appearance that does not all observe the sign or the infectious substance of infection in the eye arbitrarily.

These results of study proof after being injected to eye and enclosing near the eyes,

Send the delivery system well-tolerated and appear as biologically inert.In fact, Drug products can alleviate the toxic action of some drugs.For example in research subsequently, will be by will Send the delivery system and the preparation of the compound preparation that eye is produced stimulation to compare with the influence that is dissolved in the same compound of water.Direct observation shows that the stimulus object that is dissolved in water produces remarkable swelling, seriously rubescent and eye has watery secretion.In addition, preocular cover layer (cornea) is from the transparent muddiness that becomes.This variation of cornea causes vision partly to lose or completely lose.Yet injection contains stimulus object

Send delivery system only to show to slightly to moderate swelling, the rubescent and eye cover layer of moderate keeps transparent.Be exposed under the aqueous solution middle and high concentration stimulus object comparatively speaking with eye is instantaneous, alleviating of this stimulation is

Send delivery system result to the slow release of irritants of ophthalmic in long-time.This slow release has alleviated the toxic action of stimulus object, and the probability of permanent damage is reduced to minimum.

In a word, contain PEG300, mPEG350 and NMP

Preparation is in the vitreous body or conjunctiva is implanted acceptable carrier down.

All publications, patent and the patent document mode by reference that this paper quoted from is included this paper in, is included into as by reference mode individually.By invention has been described with reference to various concrete and embodiment preferred and technology.Yet, it should be understood that and can make many conversion and modification without departing from the spirit and scope of the present invention.

Some feature of the present invention that should be understood that for the sake of clarity and describe in dividing other embodiment also can combine in an independent embodiment.Say it on the contrary, for for the purpose of concise and to the point and the of the present invention various features of describing also can separately be used or use in the mode of subclass combination arbitrarily in an independent embodiment.

Claims (103)

1. But 1. flow composition that is suitable for use as the controlled release implant, described compositions comprises:

   (a) biodegradable, biocompatible thermoplastic polymer, this polymer is insoluble to aqueous medium, water or body fluid at least basically;

   (b) acceptable salt or its prodrug on biological agent, its metabolite, its biopharmaceutics; With

   (c) biocompatibility organic liquid, under standard temperature and pressure, described thermoplastic polymer dissolves in wherein;

   Wherein said composition is applicable to that eye send and passs.
2. 2. the compositions of claim 1, wherein said biodegradable, biocompatible thermoplastic polymer is a linear polymer.
3. 3. the compositions of claim 1, wherein said biodegradable, biocompatible thermoplastic polymer is a branched polymer.
4. 4. the compositions of claim 1, wherein said biodegradable, biocompatible thermoplastic polymer has the structural formula that comprises following monomer units, and described monomeric unit is selected from lactide, Acetic acid, hydroxy-, bimol. cyclic ester, caprolactone, glyceride, anhydride, amide, carbamate, esteramides, ortho esters, to dioxanone, acetal, ketal, carbonic ester, phosphonitrile, hydroxy butyrate, hydroxyl valerate, alkylidene oxalate, alkylidene succinate, aminoacid and their combination in any; This structural formula comprises the monomeric unit of random order or block order.
5. 5. the compositions of claim 1, wherein said biodegradable, biocompatible thermoplastic polymer is the polymer or the copolymer of lactide monomer unit, caprolactone monomer unit, glycolide monomer unit or their combination in any.
6. 6. the compositions of claim 1 is wherein said biodegradable, biocompatible thermoplastic polymer comprises and is selected from following polymer: polylactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, polycaprolactone, poly-to dioxanone, Merlon, the poly hydroxybutyric acid ester, the polyalkylene oxalate, polyanhydride, polyamide, polyesteramide, polyurethanes, polyacetals, polyketals, poly-orthocarbonic ester, polyphosphazene, polyoxyvalerate, the polyalkylene succinate, poly-(malic acid), poly-(aminoacid), chitin, chitosan, poe, poly-(methyl vinyl ether), polyester, poly-alkyl diol, their copolymer, their block copolymer, their terpolymer, their compositions and their mixture.
7. 7. the compositions of claim 1, wherein said biodegradable, biocompatible thermoplastic polymer comprises at least a polyester.
8. 8. the compositions of claim 1, wherein said biodegradable, biocompatible thermoplastic polymer be polylactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, polycaprolactone, they copolymer, they terpolymer or their combination in any at least a.
9. 9. the compositions of claim 1, wherein said biodegradable, biocompatible thermoplastic polymer is poly-(DL-lactide-co-glycolide).
10. 10. the compositions of claim 1, wherein said biodegradable, biocompatible thermoplastic polymer are poly-(the DL-lactide-co-glycolide) with carboxyl end groups.
11. 11. the compositions of claim 1, wherein said biodegradable, biocompatible thermoplastic polymer is poly-(the DL-lactide-co-glycolide) of no carboxyl end groups.
12. 12. the compositions of claim 1, wherein said biodegradable, biocompatible thermoplastic polymer are 50/50 poly-(DL-lactide-co-glycolide) with carboxyl end groups.
13. 13. the compositions of claim 1, wherein said biodegradable, biocompatible thermoplastic polymer is 75/25 poly-(DL-lactide-co-glycolide) of no carboxyl end groups.
14. 14. the compositions of claim 1, wherein said biodegradable, biocompatible thermoplastic polymer exists with the about 80 weight % that are up to compositions.
15. 15. the compositions of claim 1, wherein said biodegradable, biocompatible thermoplastic polymer exists with the about 10 weight % more than compositions.
16. 16. the compositions of claim 1, wherein said biodegradable, biocompatible thermoplastic polymer exists to about 80 weight % with about 10 weight % of compositions.
17. 17. the compositions of claim 1, wherein said biodegradable, biocompatible thermoplastic polymer exists to about 50 weight % with about 30 weight % of compositions.
18. 18. the compositions of claim 1, wherein said mean molecule quantity biodegradable, biocompatible thermoplastic polymer surpasses about 15,000.
19. 19. the compositions of claim 1, wherein said mean molecule quantity biodegradable, biocompatible thermoplastic polymer is up to about 45,000.
20. 20. the compositions of claim 1, wherein said mean molecule quantity biodegradable, biocompatible thermoplastic polymer is about 15,000 to about 45,000.
21. 21. the compositions of claim 1, the water solublity of wherein said biocompatibility organic liquid are from insoluble fully to solvable fully with all proportions with arbitrary proportion.
22. 22. the compositions of claim 1, wherein said biocompatibility organic liquid are fully insoluble but can diffuse in people's body fluid in water.
23. 23. the compositions of claim 1, it is water miscible that wherein said biocompatibility organic liquid is at least part.
24. 24. the compositions of claim 1, wherein said biocompatibility organic liquid is for water miscible fully.
25. 25. the compositions of claim 1, wherein said biocompatibility organic liquid is a polar protic liquids.
26. 26. the compositions of claim 1, wherein said biocompatibility organic liquid is an aprotic, polar liquid.
27. 27. the compositions of claim 1, wherein said biocompatibility organic liquid is annular aliphatic, linear aliphatic family, branched aliphatic or aromatics organic compound, it is a liquid when room temperature and physiological temp, and contain at least a following functional group, described functional group is selected from alcohol, ketone, ether, amide, amine, alkylamine, ester, carbonic acid, sulfoxide, sulfone and sulfonic acid.
28. 28. the compositions of claim 1, wherein said biocompatibility organic liquid is selected from: the heterocyclic compound of replacement, the ester of carbonic acid and alkylol, monocarboxylic Arrcostab, monocarboxylic aryl ester, monocarboxylic aralkyl ester, the Arrcostab of dicarboxylic acids, the aryl ester of dicarboxylic acids, the aralkyl ester of dicarboxylic acids, the Arrcostab of tricarboxylic acid, the aryl ester of tricarboxylic acid, the aralkyl ester of tricarboxylic acid, alkyl ketone, aryl ketones, aralkyl ketone, alcohol, polyhydric alcohol, alkylamide, dialkyl amide, alkyl sulfoxide, dialkyl sulphoxide, the alkyl sulfone, dialkyl sulfone, lactone, the cyclic alkyl amide, cyclic alkyl amine, aromatic amides, aromatic amine, their mixture and their compositions.
29. 29. the compositions of claim 1, wherein said biocompatibility organic liquid is selected from: N-N-methyl-2-2-pyrrolidone N-, 2-Pyrrolidone, (C ₂-C ₈) aliphatic alcohol, glycerol, tetraethylene glycol (TEG), glycerol formal, 2,2-dimethyl-1,3-dioxolone-4-methanol, ethyl acetate, ethyl lactate, ethyl n-butyrate., malonic acid di-tert-butyl ester, tributyl citrate, the just own ester of acetyl tributyl citrate three, diethyl succinate, ethyl glutarate, diethyl malonate, triethyl citrate, glyceryl triacetate, tributyorin, diethyl carbonate, Allyl carbonate, acetone, butanone, dimethyl acetylamide, dimethyl formamide, caprolactam, dimethyl sulfoxide, dimethyl sulfone, oxolane, caprolactam, N, the N-diethyl--toluamide, 1-dodecyl-aza-cycloheptane-2-ketone, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2-(1H)-pyrimidone, benzyl benzoate and their compositions.
30. 30. the compositions of claim 1, wherein said biocompatibility organic liquid molecular weight ranges is about 30 to about 500.
31. 31. the compositions of claim 1, wherein said biocompatibility organic liquid is N-N-methyl-2-2-pyrrolidone N-, 2-Pyrrolidone, N, dinethylformamide, dimethyl sulfoxide, Allyl carbonate, caprolactam, glyceryl triacetate or their arbitrary composition.
32. 32. the compositions of claim 1, wherein said biocompatibility organic liquid is the N-N-methyl-2-2-pyrrolidone N-.
33. 33. the compositions of claim 1, wherein said biocompatible liquid exists with the about 40 weight % that surpass compositions.
34. 34. the compositions of claim 1, wherein said biocompatible liquid exists with the about 80 weight % that are up to compositions.
35. 35. the compositions of claim 1, wherein said biocompatible liquid exists to about 70 weight % with about 50 weight % of compositions.
36. 36. the compositions of claim 1, wherein said biocompatible liquid can be scattered in aqueous medium, water or the body fluid.
37. 37. the compositions of claim 1, wherein said biological agent is independently selected from: beta adrenergic agent; adrenocortical steroid; the adrenal cortex depressant; the alcohol inhibitor; aldosterone antagonists; aminoacid; ammonia detoxicant; anabolic agent; analeptic; analgesic; androgen; the anesthesia accessory drugs; anesthetics; fenisorex; antagonist; the antepituitary depressant; anthelmintic; anti-acne drug; antiadrenergic; resistance is answered medicine; anti-amebic; antiandrogen; the anti-anemic drug anti-anginal drug; antianxiety drugs; anti-arthritic; antasthmatic; antiatherosclerotic; antibacterial; anti-cholelithiasis forms medicine; anticholelithogenic; anticholinergic; anticoagulant; anticoccidial drug; anticonvulsant; antidepressants; antidiabetic drug; diarrhea; antidiuretic; antidote; Bendectin; antuepileptic; antiestrogen; antifibrinolytics; antifungal agent; Betimol; antihemophilic; antihemorrhagic; antihistaminic; antihyperlipidemic; antihyperlipoproteinemic; antihypertensive; antihypotensive; anti-infective; local anti-infective agent; anti-inflammatory agent; antikeratinizing agent; antimalarial; antimicrobial drug; antimigraine; antifungal; antinauseant; antineoplastic agent; antineutropenic; antiadipositas drug; antiparasitic; antiparkinsonian drug; anti-wriggling medicine; anti-lung sac worm medicine; antiproliferative; anti-prostate hyperplasia medicine; antiprotozoal drug; antipruritic; psychosis; antirheumatic; antischistosomal drug; antiseborrhoic; antisecretory drug; spasmolytic; antithrombotic; cough medicine; antiulcerative; anti-urolithic; antiviral agents; appetite suppressant; the treatment of benign prostate hyperplasia agent; blood sugar regulator; bone resorption inhibitor; bronchodilator; carbonic anhydrase inhibitors; cardiac depressant; cardioprotectant; cardiac tonic; cardiovascular drug; choleretic; cholinergic agent; the cholinergic diagnostic aid; diuretic; dopaminergic; ectoparasiticide; emetic; enzyme inhibitor; estrogen; fibrinolytic; fluorescent agent; oxygen free radical scavenger; the gastrointestinal peristalsis effector; glucocorticoid; gonadotrope; the hair growth stimulus object; hemorrhage; histamine H2 receptor antagonist; hormone; pravastatin; blood sugar lowering; hypolipidemic; hypotensor; developer; immunizing agent; imnlune modulator; immunomodulator; immunostimulant; immunosuppressant; the impotence treatment agent; inhibitor; keratolytic; the LNRN agonist; remedies for liver diseases; luteolysin; the memory accessory drugs; psychology performance reinforcing agent; the mood regulation agent; mucolytic; the mucosa protective agent; mydriatic; the congested medicine of eliminating of nasal mucosa; neuromuscular blocking agents; neuroprotective; nmda antagonist; non-hormone sterol derivative; oxytocic; plasminogen activator; platelet activating factor antagonist; anticoagulant; after the apoplexy and head trauma after therapeutic agent; intensifier; Progesterone; prostaglandin; the prostate growth inhibitor; thyrotropin is former; psychotropic drugs; radiopharmaceutical; regulator; relaxant; heavy partitioning agent; Scabicide; sclerosing agent; tranquilizer; the sedative hypnotic; selective adenosine A1 antagonist; 5-hydroxytryptamine antagonist; serotonin antagonist; the 5-hydroxytryptamine receptor antagonist; steroid; stimulus object; depressant; symptomatic multiple sclerosis; synergist; thyroxin; thyroid imhibitor; thyromimetic; tranquilizer; the amyotrophic lateral sclerosis therapeutic agent; the cerebral ischemia therapeutic agent; the Paget therapeutic agent; the unstable angina pectoris therapeutic agent; uricosuric; vasoconstrictor; vasodilator; vulnerary; the wound healing medicine; xanthine oxidase inhibitor; and their compositions.
38. 38. the composition of claim 1; Wherein said biological agent is independently selected from acebutolol; Acebutolol; ACV; Salbutamol; Alfentanil; Almotriptan; Alprazolam; Amiodarone; Amlexanox; Amphotericin B; Atorvastatin; Atropine; Anranofin; Aurothioglucose; Benazepil; Bicalutamide; Bretylium tosylate; Brifentanil; Bromocriptine; Buprenorphine; Butorphanol; Buspirone; Calcitonin; Candesartan; Carfentanil; Carvedilol; Chlorphenamine; Chlorothiazide; Chlorphentermine; Chlorpromazine; Clindamycin; Clonidine; Codeine; Cyclosporin; Desipramine; Minirin; Dexamethasone; Diazepam; Diclofenac; Digoxin; Dihydrocodeine; Dolasetron; Dopamine; Doxepin; Doxycycline; Dronabinol; Droperidol; Dyclonine; Eletriptan; Enalapril; Enoxaparin; Ephedrine; Adrenaline; Ergotamine; Etomidate; Famotidine; Felodipine; Fentanyl; Fexofenadine; Fluconazole; Prozac; Fluphenazinum; Flurbiprofen; Fluvastatin; Fluvoxamine; Frovatriptan; Frusemide; GCV; Sodium aurothiomalate; Granisetron; Griseofulvin; Haloperole; Hepatitis B virus vaccine; Hydrolazine; Hydromorphone; Insulin; Ipratropium; Isradipine; ISDN; Ketamine; Ketorolac; Labetalol; Levorphanol; Lisinopril; Loratadine; Lorazepam; Losartan; Lovastatin; Melatonin; Ethyldopa; Methylphenidate; Metoprolol; Midazolam; Mirtazapine; Morphine; Nadolol; Nalbuphine; Naloxone; Naltrexone; Naratriptan; Neostigmine; Nicardipine; Nifedipine; Norepinephrine; Nortriptyline; Octreotide; Olanzapine; Omeprazole; Ondansetron; Oxybutynin; Oxycodone; Oxymorphone; Oxytocin; Neo-synephrine; Phenylpropanolamine; Phenytoinum naticum; Pimozide; Pioglitazone; Piroxicam; Pravastatin; Prazosin; Prochlorperazine; Propafenone; Prochlorperazine; Propiomazine; Propofol; Propranolol; Pseudoephedrine; This bright of pyrrole; Quetiapine; Raloxifene; Remifentanil; Rofecoxib; Repaglinide; Risperidone; Rizatriptan; Ropinirole; Hyoscine; Selegiline; Sertraline; Silaenafil; Simvastatin; Sirolimus; Spirolactone; Sufentanil; Sumatriptan; Tacrolimus; TAM; Terbinafine; Terbutaline; Testosterone; Tetanus toxoid; The THC Tolterodine; Triamterene; Triazolam; Trimeglamide; Valsartan; Venlafaxine; Verapamil; Zaleplon; Zanamivir; Zafirlukast; Zolmitriptan; Zolpidem, and their composition.
39. 39. the compositions of claim 1, wherein on the cell cycle biological agent of Cun Zaiing, time dependence biological agent, its metabolite, its biopharmaceutics acceptable salt or its prodrug more than about 0.00001 weight % of said composition.
40. 40. the compositions of claim 1, wherein acceptable salt or its prodrug are up to about 20 weight % of said composition on the cell cycle biological agent of Cun Zaiing, time dependence biological agent, its metabolite, its biopharmaceutics.
41. 41. the compositions of claim 1, wherein acceptable salt or its prodrug are that about 0.00001 weight % of said composition is to about 10 weight % on the cell cycle biological agent of Cun Zaiing, time dependence biological agent, its metabolite, its biopharmaceutics.
42. 42. the compositions of claim 1, but people's maximum tolerated dose (MTD) of the cell cycle biological agent, time dependence biological agent, its metabolite or its prodrug that exist in wherein should flow composition is littler than people's maximum tolerated dose (MTD) of the cell cycle biological agent that exists in the solution, time dependence biological agent, its metabolite or its prodrug.
43. 43. the compositions of claim 1, but wherein be somebody's turn to do the people maximum tolerated dose (MTD) little at least 50% of people's maximum tolerated dose (MTD) of the cell cycle biological agent, time dependence biological agent, its metabolite or its prodrug that exist in the flow composition than the cell cycle biological agent that exists in the solution, time dependence biological agent, its metabolite or its prodrug.
44. 44. the compositions of claim 1 also comprises one of following at least:

    Be used for controlling the release rate modifier of the speed that biological agent discharges from implant substrate in vivo;

    Pore former;

    Biodegradable crystal controlling agent;

    Plasticizer;

    Leaching agent;

    Penetration enhancer;

    Absorb and change agent;

    Opacifier; With

    Coloring agent.
45. 45. the compositions of claim 44, wherein said release rate modifier is selected from: monocarboxylate, dicarboxylic ester, tricarboxylic ester, polyhydroxy-alcohol, fatty acid, triglyceride, sterol, alcohol, and their combination in any.
46. 46. the compositions of claim 44, wherein said release rate modifier is selected from: acetic acid 2-ethoxy ethyl ester; methyl acetate; ethyl acetate; diethyl phthalate; dimethyl phthalate; dibutyl phthalate; dimethyl adipate; dimethyl succinate; dimethyl oxalate.; the citric acid dimethyl ester; triethyl citrate; citroflex A-4; CitroflexA-2; triacetin; decanedioic acid two (positive fourth) ester; propylene glycol; Polyethylene Glycol; glycerol; Sorbitol; triglyceride; epoxidized soybean oil; cholesterol; (C ₆-C ₁₂) alkanol, 2-ethoxy ethanol and their arbitrary composition.
47. 47. the compositions of claim 44, wherein said pore former are sugar, salt, water-soluble polymer or water-soluble organic liquid.
48. 48. the compositions of claim 44, wherein said biodegradable crystal controlling agent is selected from: calcium carbonate, hydroxyapatite, calcium phosphate, apatite calcium, calcium sulfate, calcium bicarbonate, calcium chloride, sodium carbonate, sodium bicarbonate, sodium chloride, calcium stearate, calcium palmitate, sodium stearate, glucosan, starch, sodium carboxymethyl cellulose, carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, crosslinked sodium carboxymethyl cellulose, poly-(vinyl alcohol), tripalmitin, tristerin, triethyl citrate, ethyl lactate, poly-(ethylene glycol), poly-(vinyl pyrrolidone), poly-(lactide-be total to-caprolactone) and their compositions.
49. 49. the compositions of claim 44, wherein said regulator is selected from: benzyl benzoate, phthalic acid ester, benzyl phthalate, benzoic acid second diester, inclined to one side benzoate, adipate ester, azelate, sebacate, aliphatic and aromatic dicarboxylic acid ester and tricarboxylic ester, organophosphorus ester, Oleum sesami, Oleum Glycines, Oleum Gossypii semen, almond oil, sunflower oil, Oleum Arachidis hypogaeae semen and their compositions.
50. 50. the compositions of claim 44, wherein absorb changing agent is selected from: propylene glycol, glycerol, urea, diethyl decanedioic acid sodium, lauryl sulfate, sodium lauryl sulphate, sorbitan ethoxylate, oleic acid, 2-pyrrolidone-5-carboxylic acid's ester, N-Methyl pyrrolidone, N, and the N-diethyl--toluamide, dimethyl sulfoxide, alkyl methyl sulfoxide and their compositions.
51. 51. the compositions of claim 44, wherein said rate adaptation agent is the water-insoluble organic substance.
52. 52. the compositions of claim 51, wherein said water-insoluble organic substance is monocarboxylate, dicarboxylic ester or tricarboxylic ester.
53. 53. the compositions of claim 44, wherein said opacifier comprises barium, iodine or calcium.
54. 54. the compositions of claim 1, acceptable salt or its prodrug are comprised to particulate or encapsulated release components on wherein said biological agent, its metabolite, its biopharmaceutics.
55. 55. the compositions of claim 54, wherein said granular controlled release component comprise wherein acceptable salt or its prodrug and the covalently bound conjugate of carrier molecule on biological agent, its metabolite, its biopharmaceutics.
56. 56. the compositions of claim 54, wherein said granular controlled release component is the micro structure that is selected from microcapsule, nano-particle, cyclodextrin, liposome and micelle.
57. 57. the compositions of claim 54, wherein said granular controlled release component is less than about 500 microns micro structure.
58. 58. the compositions of claim 54, wherein said granular controlled release component macrostructure is selected from fiber, thin film, rod, disk and cylinder.
59. 59. the compositions of claim 54, wherein said granular controlled release component macrostructure is at least about 500 microns.
60. 60. the compositions of claim 1, described compositions can form solid micropore substrate, the core of described substrate for being held by epidermis, this core contain diameter be about 1 micron to about 1000 microns hole.
61. 61. the compositions of claim 60, the diameter of its mesocuticle contained hole are less than the diameter of cored hole, so that epidermis and core are in a ratio of functional atresia.
62. 62. the compositions of claim 1, described compositions has the volume greater than about 0.001mL.
63. 63. the compositions of claim 1, described compositions have maximum volume to about 20.0mL.
64. 64. the compositions of claim 1, described compositions have the volume of about 0.01mL to about 10.0mL.
65. 65. the compositions of claim 1, described compositions are configured to the administration that is used for being less than weekly approximately once.
66. 66. being configured to, the compositions of claim 1, described compositions be used for every year more than about administration once.
67. 67. being configured to, the compositions of claim 1, described compositions be used for weekly about once extremely annual administration approximately once.
68. 68. the compositions of claim 1, described compositions are sent to mammalian tissues with about 1 pik/kilogram/day to the dosage of about 1 mg/kg/day and are passed acceptable salt or its prodrug on described biological agent, its metabolite, its biopharmaceutics.
69. 69. the compositions of claim 68, wherein said send to pass be systemic delivery.
70. 70. the compositions of claim 68, wherein said send to pass to send for the part pass.
71. 71. the compositions of claim 68, wherein the part is sent and is passed this dosage and reach about 1 year most.
72. 72. the compositions of claim 68, wherein local sending passed this dosage and reached about 1 month time most.
73. 73. the compositions of claim 68, wherein the part is sent and is passed this dosage and reach about 1 time-of-week most.
74. 74. the compositions of claim 68, wherein the part is sent and is passed this dosage above about 1 day time.
75. 75. the compositions of claim 1, described compositions also comprise second kind of biological agent.
76. 76. a method for the treatment of mammalian diseases or disease gives each the flow composition of the claim 1-75 of effective dose but described method comprises mammiferous ocular to this treatment of needs.
77. 77. the method for claim 76, wherein said mammal is behaved.
78. 78. the method for claim 76, but wherein be somebody's turn to do flow composition at a plurality of positions of mammiferous ocular.
79. 79. one kind is sent the method for passing biological agent through mammal ocular part, contacts but described method comprises each the flow composition that makes mammiferous ocular and claim 1-75.
80. 80. one kind is sent the method for passing biological agent through mammal ocular whole body, contacts but described method comprises each the flow composition that makes mammiferous ocular and claim 1-75.
81. 81. an implant comprises:

    (a) biodegradable, biocompatible thermoplastic polymer, this polymer is insoluble to aqueous medium, water or body fluid at least basically;

    (b) acceptable salt or its prodrug on biological agent, its metabolite, its biopharmaceutics; With

    (c) biocompatibility organic liquid, under standard temperature and pressure, described thermoplastic polymer dissolves in wherein;

    Wherein said implant is placed in mammiferous ocular, and this implant has solid or gel micropore substrate, the core of this substrate for holding by epidermis, and wherein this implant is surrounded by bodily tissue.
82. 82. the implant of claim 81, described implant are what solidify fully.
83. 83. the implant of claim 81, described implant are solidified.
84. 84. the implant of claim 81, the amount of wherein said biocompatibility organic liquid reduces in time.
85. 85. the implant of claim 81, wherein said core contain diameter be about 1 micron to about 1000 microns hole.
86. 86. the implant of claim 81, the diameter of wherein said epidermis contained hole is less than the diameter of cored hole.
87. 87. the implant of claim 81, the big I in wherein said epidermis hole makes epidermis and core be in a ratio of functional atresia.
88. 88. an implant comprises:

    (a) biodegradable, biocompatible thermoplastic polymer, this polymer is insoluble to aqueous medium, water or body fluid at least basically;

    (b) acceptable salt or its prodrug on biological agent, its metabolite, its biopharmaceutics;

    Wherein said implant is placed in mammiferous ocular and this implant has solid or gel micropore substrate, the core of this substrate for holding by epidermis, and wherein this implant is surrounded by bodily tissue.
89. 89. the implant of claim 88, wherein said core contain diameter be about 1 micron to about 1000 microns hole.
90. 90. the implant of claim 88, the diameter of wherein said epidermis contained hole is less than the diameter of cored hole.
91. 91. the implant of claim 88, the big I in wherein said epidermis hole makes epidermis and core be in a ratio of functional atresia.
92. 92. the method for an original position formation implant in the live body ocular, described method comprises:

    (a) in patient's ocular, inject each the flowable composition that flowable composition is claim 1-75; With

    (b) make the dissipation of biocompatibility organic liquid to produce the solid biodegradable implant.
93. 93. a biological agent test kit that is suitable for forming in the ocular original position Biodegradable implants, described test kit comprises:

    (a) but comprise and be suitable for sending first container of passing to the flow composition of ocular, described compositions comprises:

    (i) biodegradable, biocompatible thermoplastic polymer, this polymer is insoluble to aqueous medium, water or body fluid at least basically; With

    (ii) biocompatibility organic liquid, under standard temperature and pressure, described thermoplastic polymer dissolves in wherein;

    (b) comprise second container of acceptable salt on biological agent, its metabolite, its biopharmaceutics or its prodrug.
94. 94. the test kit of claim 93, wherein said first container is a syringe.
95. 95. the test kit of claim 93, wherein said second container is a syringe.
96. 96. the test kit of claim 93, wherein said first container is a syringe, and second container is a syringe, and two syringes fitted to be directly connected to each other.
97. 97. the test kit of claim 93, described test kit also comprises description.
98. 98. the disease that the mammiferous ocular of treatment is relevant or the method for disease give each the flow composition of the claim 1-75 of effective dose but described method comprises mammiferous ocular to this treatment of needs.
99. 99. the method for claim 98, wherein said disease relevant with ocular or disease are degeneration of macula.
100. 100. the method for claim 98, wherein said disease relevant with ocular or disease are cancer.
101. But the flow composition of each of claim 1-75 is in the purposes that is used for preparing the medicine for the treatment of disease relevant with the mammal ocular or disease.
102. But the purposes of the flow composition of claim 101, wherein said disease relevant with ocular or disease are degeneration of macula.
103. But the purposes of the flow composition of claim 101, wherein said disease relevant with ocular or disease are cancer.

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