WO2010125416A1 - Administration de médicaments dans le segment antérieur et le segment postérieur de l'oeil - Google Patents

Administration de médicaments dans le segment antérieur et le segment postérieur de l'oeil Download PDF

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Publication number
WO2010125416A1
WO2010125416A1 PCT/IB2009/005397 IB2009005397W WO2010125416A1 WO 2010125416 A1 WO2010125416 A1 WO 2010125416A1 IB 2009005397 W IB2009005397 W IB 2009005397W WO 2010125416 A1 WO2010125416 A1 WO 2010125416A1
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agents
eye
mixtures
agent
group
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PCT/IB2009/005397
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English (en)
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Raouf Rekik
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Raouf Rekik
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Priority to PCT/IB2009/005397 priority Critical patent/WO2010125416A1/fr
Publication of WO2010125416A1 publication Critical patent/WO2010125416A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention relates to a method to deliver drugs to the anterior and posterior segments of the eye and to compositions and to a kit for such a delivery.
  • the present invention relates to a method, to compositions and to a kit wherein at least one drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof or mixtures thereof, and optionally, at least another drug delivery agent which is an adrenergic agent is (are) administered with an effective amount of a drug that can treat chorio-retinal and/or optic nerve head disorders.
  • the present invention also relates to such drug delivery agent(s) or to compositions comprising such drug delivery agent(s), for use for the transfer, to the posterior segment of one or both eye(s), of at least one second drug that treats disorders and/or diseases of the eyes.
  • the anterior segment of the eye is the front third of the eye that includes the structures in front of the vitreous humor such as the cornea, iris, ciliary body and lens.
  • Ophthalmic disorders associated with the anterior segment of the eye include glaucoma, cataract, congenital and developmental abnormalities, inflammatory and infectious diseases, hereditary and degenerative diseases and ocular manifestations of systemic diseases, tumors, injury and trauma.
  • the posterior segment of the eye is the back two-thirds of the eye that includes the anterior hyaloid membrane and all of the structures behind it such as the vitreous humor, the retina, the choroid and the optic nerve.
  • Opthalmic disorders resulting in the posterior segment of the eye include age-related macular degeneration, diabetic retinopathy, retinal vein occlusions, retinal arterial occlusions, macular edema, post-operative inflammation, uveitis, retinitis, proliferative vitreoretinopathy, glaucoma neuropathy, high myopia and macular degeneration.
  • Administering drugs for treatment of various disorders of the eye can be performed by a variety of methods known in the art such as by topical administration, administration of eye drops, intraocular injection and systemic administration.
  • ranibizumab (Lucentis®) injection is known for treating wet age-related macular degeneration.
  • Ranibizumab is a vascular endothelial growth factor (VEGF) antagonist that blocks abnormal blood vessel growth and leakage in the eye. It must be administered once a month by a physician.
  • VEGF vascular endothelial growth factor
  • Pegatanib Macugen®
  • bevacizumab Avastin®
  • Pegatanib Macugen®
  • bevacizumab Avastin®
  • drugs can enter the eye through three distinct routes; i.e., (1 ) the corneal route which is through the anterior chamber and then through the lens, the pupil or the iris; (2) the conjunctival route which either is directly across the sclera, choroid, choriocapillaries and retinal pigment epithelium to the retina or indirectly into the retrobulbar space and then the optic nerve head; and (3) from the systemic circulation after topical, parental, oral or intranasal or any other route that delivers the drug to the blood circulation.
  • eye drops is generally a route of delivering drugs into the posterior segment of the eyes which is considered quite ineffective due to the lack of therapeutic amounts of the drugs that can be effective in this area of the eye. See, for example Myles et al Adv. Drug Del Rev. 57(14):2063-79). Due to this ineffectiveness, several attempts have been made to overcome this problem in the art.
  • U.S. Patent publication No. 2007/0020336 A1 describes the use of cyclodextrin nanotechnology for delivery to the posterior segment of the eye.
  • This ophthalmic composition contains a drug, cyclodextrin and water in which about 0.1 % to 90% (w/v) of the drug is dissolved in the solution and a solid phase consisting of particles which have a size of 10 nm to 1 mm.
  • This composition can be in the form of eye drops.
  • U.S. publication No. 2005/0009910 A1 describes a method and composition which uses an effective concentration of an ester prodrug of the active drug.
  • This composition is a sustained release composition in which a polymeric microparticle system enhances the release of the drug.
  • the prodrug is administered via injection or implantation.
  • WO 2007/075720 A2 describes topical mecamylamine formulations for ocular administrations for the treatment of neovascularization, abnormal angiogenesis, vascular permeability or combinations thereof of posterior and/or anterior tissues and fluids of the eye.
  • Yet another object of the present invention is to provide a non-invasive treatment for delivering drugs to treat ophthalmic disorders or diseases which is simple and less expensive.
  • Another object of the present invention is to provide an ophthalmic composition
  • an ophthalmic composition comprising an effective amount of a drug to treat the ophthalmic disorder and/or disease and at least one drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof, and optionally, at least another drug delivery agent which is an adrenergic agent, in an effective amount such that the drug used to treat the ophthalmic disorders and/or diseases of the eye is delivered to the posterior segment of the eye.
  • Said adrenergic agent(s) can be selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta-blocking agents and mixtures thereof.
  • the present invention provides a method to deliver drugs to the chorio-retina and optic nerve head of the eye.
  • Drug delivery agent(s) selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof, for use to deliver drugs to treat ophthalmic disorders and/or diseases are also part of the present invention.
  • the present invention relates to a method for treating eye disorders and/or diseases of the eye comprising: contacting the surface of the eye with an effective amount of a cholinergic agent, in particular with pilocarpine, or with a derivative thereof or mixtures thereof.
  • the present invention relates to a method for delivering drugs to the posterior and anterior segments of the eyes comprising: contacting the surface of the eye with an effective amount of a drug for treating eye disorders and/or diseases of the eye and a physiologically acceptable amount of at least one (i.e., one or several) drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof, in an ophtalmologically acceptable carrier.
  • a drug for treating eye disorders and/or diseases of the eye and a physiologically acceptable amount of at least one (i.e., one or several) drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof, in an ophtalmologically acceptable carrier.
  • Said drug delivery agent(s) can be used in conjunction with at least another delivery agent (i.e., one or several delivery agent(s)) which is an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta-blocking agents and mixtures thereof.
  • another delivery agent i.e., one or several delivery agent(s)
  • an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta-blocking agents and mixtures thereof.
  • the present invention relates to a method of treating a eye disorders and/or diseases of the eye by delivering drugs to the chorio-retina and optic nerve head of an eye comprising administering to a person or an animal in need of such treatment an effective amount of a drug for treatment of the chorio- retina and optic nerve head and a physiologically acceptable amount of at least one drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof, and, optionally at least another drug delivery agent which is an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta-blocking agents and mixtures thereof .
  • the present invention provides a composition
  • a composition comprising, consisting of or consisting essentially of a) at least one drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof, and b) a drug for treating eye disorders and/or diseases of the eye, and , c) optionally, at least another delivery agent which is an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta-blocking agents and mixtures thereof.
  • the present invention provides a method for increasing the transfer of a drug to the posterior segment of the eye, and in particular into the eye orbit, the posterior sclera and then into chorio-retina and optic nerve head to treat disorders and/or diseases of the eye comprising contacting the surface of an eye or both eye(s) with at least one drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof, and a second drug that treats disorders and/or diseases of the eyes.
  • Said drug delivery agent(s) can be used in conjunction with at least another drug delivery agent which is an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta- blocking agents, derivatives of the beta-blocking agents and mixtures thereof.
  • an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta- blocking agents, derivatives of the beta-blocking agents and mixtures thereof.
  • physiologically acceptable amounts of drug delivery agent(s) and/or of the second drug that treats disorders and/or diseases of the eyes are used.
  • Drug delivery agent(s) selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof, for use for treating diseases and/or disorders of the eye and in particular for use for the transfer, to the posterior segment of one or both eye(s), of a second drug that treats disorders and/or diseases of the eyes, to treat diseases and/or disorders of the eye is another aspect of the present invention.
  • the present invention provides a kit comprising or consisting of: a) drug delivery agent(s) as defined herein or a composition comprising, consisting of or consisting essentially of said drug delivery agent(s); and b) a drug that treats disorders and/or diseases of the eyes, and , c) optionally, at least another delivery agent which is an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta-blocking agents and mixtures thereof.
  • an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta-blocking agents and mixtures thereof.
  • the present invention also provides use of a) at least one drug delivery agent ; and b) a pharmaceutically acceptable amount of a second drug that treats disorders and/or diseases of the eyes, and , c) optionally, at least another delivery agent which is an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta-blocking agents and mixtures thereof, for the manufacture of a medicament to treat disorders and/or diseases of the eye.
  • an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta-blocking agents and mixtures thereof, for the manufacture of a medicament to treat disorders and/or diseases of the eye.
  • Figure 1 is an optical coherence tomography scan (O. CT.) of a patient having diabetic retinopathy (patient HJ.) prior to treatment (A), and two months after treatment (topical administration) (B) with a cholinergic agent (pilocarpine).
  • Figure 2 is an optical coherence tomography scan (O. CT.) of a patient having diabetic retinopathy (patient F.K.) prior to treatment (A), and two months after treatment (topical administration) (B) with a cholinergic agent (pilocarpine).
  • Figure 3 is an optical coherence tomography scan (O. CT.) of a patient having diabetic retinopathy (patient ZA.) prior to treatment (A), and six months after treatment (topical administration) (B) with a composition comprising pilocarpine (1% w/v), ramipril (2% w/v), dexamethasone (Tobradex®; 0.1% w/v) and indomethacin
  • Figure 4 is an optical coherence tomography scan (O. CT.) of a patient having diabetic retinopathy (patient S. H.) prior to treatment (A), and two months after treatment (topical administration) (B) with a cholinergic agent (pilocarpine), a corticosteroid (dexamethazone), a non steroidal anti-inflammatory agent (indomethacin (Indocollyre ⁇ )), a beta-blocking agent (timolol) and an alpha adrenergic agonist agent (brimonidin).
  • a cholinergic agent prilocarpine
  • corticosteroid diosteroid
  • non steroidal anti-inflammatory agent indomethacin (Indocollyre ⁇ )
  • beta-blocking agent timolol
  • an alpha adrenergic agonist agent brimonidin
  • Figure 5 is an optical coherence tomography scan (O.C.T.) of a patient with a central vein occlusion (patient A.M.) prior to treatment (A), and two months after treatment (topical administration) (B) with a cholinergic agent (pilocarpine).
  • O.C.T. optical coherence tomography scan
  • Figure 6 is an optical coherence tomography scan (O.C.T.) of a patient with a central vein occlusion in the right eye (patient R. S.) prior to treatment (A), and three months after treatment (topical administration) (B) with a composition comprising pilocarpine (1% w/v), ramipril (2% w/v), dexamethasone (Tobradex®; 0.1 % w/v) and indomethacin (Indocollyre ®; 0.1% w/v).
  • O.C.T. optical coherence tomography scan
  • Figure 7 is an optical coherence tomography scan (O.C.T.) of a patient with a central vein occlusion (patient B.R.N.) prior to treatment (A), and two months after treatment (topical administration) (B) with a cholinergic agent (pilocarpine 1 %), a corticosteroid (dexamethazone), a non steroidal anti-inflammatory agent (indomethacin (Indocollyre ⁇ )), a beta-blocking agent (timolol) and an alpha adrenergic agonist agent (brimonidin).
  • O.C.T. optical coherence tomography scan
  • Figure 8 is a vertical scan of an optical coherence tomography scan (O.C.T.) of a patient presenting a reduction of visual acuity of the left eye due to a macular degeneration (patient G.N.) prior to treatment (A), and three months after treatment (topical administration) (B) with a cholinergic agent (pilocarpine).
  • O.C.T. optical coherence tomography scan
  • Figure 9 is a vertical scan of an optical coherence tomography scan (O.C.T.) of a patient with a history of decreased vision in the right eye due to ARMD (patient H. M.) prior to treatment (A), and one month after treatment (topical administration) (B) with a composition comprising pilocarpine (1% w/v), ramipril (2% w/v), dexamethasone (Tobradex®; 0.1 % w/v) and indomethacin (Indocollyre ®; 0.1% w/v).
  • O.C.T. optical coherence tomography scan
  • Figure 10 is an optical coherence tomography scan (O.C.T.) of a patient having a history of deceased vision in the left eye (patient G.N.) prior to treatment (A) and three months after treatment (topical administration) (B) with a cholinergic agent (pilocarpine), a corticosteroid (dexamethazone), a non steroidal antiinflammatory agent (indomethacin (Indocollyre ⁇ )), timolol and brimonidin.
  • O.C.T. optical coherence tomography scan
  • anterior segment of the eye means the front third of the eye that includes the structures in front of the vitreous humor such as the cornea, iris, ciliary body and lens.
  • anterior segments of the eye means the back two-thirds of the eye that includes the anterior hyaloid membrane and the optical structures behind it such as the vitreous humor, retina, choroid, optic nerve and optic nerve head.
  • optical nerve head means the circular area in the back (posterior segment) of the eye where the optic nerve connects to the retina.
  • chorio-retina refers to the posterior segments of the eye in which the retina contacts the choroid, which is the middle membrane of the eye.
  • treating and “treatment” mean that the eye disorder and/or eye disease is improved.
  • Eye disorders encompasses changes in vision, in the appearance of the eye or having abnormal sensations in the eye. Eye disorders include optic nerve disorders, chorio-retinal disorders, visual degradation (of near and/or far visual acuity or of visual field), and trauma such as injuries to the eye.
  • eye diseases means any disease of the eye such as of glaucomatous neuropathy, central serous chorio retinopathy (CSCR), high myopia chorioretinopathy, pigmentosa retinopathy, diabetic retinopathy, proliferative vitreoretinopathy, retinal vein occlusion, (in particular central retinal vein occlusion or branch retinal vein occlusion), retinal arterial occlusions (in particular central retinal artery occlusion), myopia (in particular high myopia), presbyopia, age related vision degradation, macular degeneration and in particular age-related macular degeneration, exsudative macular degeneration, macular edema, uveitis (in particular anterior uveitis and/or posterior uveitis), papillitis, retinitis, endophthalmitis and post-operative inflammation of the eye.
  • This terminology also encompasses at least one of the above diseases and thus two or more diseases of the above diseases
  • eye diseases refer to diseases that affect the posterior segment of the eye, and in particular, eye diseases selected from the group consisting of macular edema, macular degeneration and in particular age- related macular degeneration, high myopia or macular degeneration, in particular age-related macular degeneration), retinal vein occlusion (in particular central retinal vein occlusion or branch retinal vein occlusion), retinal arterial occlusions, in particular central retinal artery occlusion, diabetic retinopathy, central serous chorio retinopathy, high myopia chorio-retinopathy, pigmentosa retinopathy, proliferative vitreoretinopathy, myopia (in particular high myopia), presbyopia, posterior uveitis, retinitis, papillitis, endophthalmitis, optic nerve head inflammation, choroidal new vessels (in particular those associated with high myopia or macular degeneration, in particular age-related macular degeneration), and exsudative
  • animal includes mammalians, in particular humans and non human mammalians.
  • mammal encompasses any of various warm- blooded vertebrate animals of the class Mammalia, including humans and non human mammalians, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
  • ophthalmologically acceptable carrier means any carrier that has substantially no long term or permanent detrimental effect on the eye to which it is administered, in particular any carrier that can be placed in the eye and that does not cause eye irritation.
  • Opthamologically acceptable carriers include water (distilled or deionized water), saline solutions, phosphate buffered saline solutions, and other aqueous media.
  • Consisting essentially of it is meant herein that minor ingredients can be added without having a major effect.
  • At least one agent as used herein means one or several agent(s), in particular one, two three, four, five, or six agents.
  • drug delivery agent an agent which is able to reach the posterior segment of the eye after it is delivered to the ocular surface of a patient or an animal in need thereof.
  • this agent When this agent is used in conjunction with a second drug for treating the eye, it enables this second drug to reach the posterior segment of the eye or at least enhances the amount of this second drug that reaches the posterior segment of the eye (drug delivery-enhancing agent).
  • a drug delivery agent as used herein increases delivery of a second drug for treating eye disorders and/or diseases of the eye into the ocular tissue and in particular into the posterior segment of the eye, compared to delivery of the same second drug in the absence of this drug delivery agent.
  • drug delivery agents When several drug delivery agents are used in the invention, they can be used as separate compounds or be present in the same composition.
  • the drug delivery agents or at least some of the drug delivery agents used are present in a composition, in combination with one or several drugs for treating eye disorders and/or diseases of the eye.
  • These compositions are appropriate for topical administration, i.e., adapted to be applied to the surface of the eye, and in particular in the form of eye drops.
  • cholinergic agent or "cholinergic drug” it is meant herein a compound that produces the same effects as acetylcholine (the most common neurohormone of the parasympathetic nervous system, i.e., the part of the peripheral nervous system responsible for the every day work of the body (e.g., salivation, digestion, and muscle relaxation)).
  • Cholinergic agents as used herein can either directly mimic the effect of acetylcholine, or block the effects of acetylcholinesterase (an enzyme that destroys naturally occurring acetylcholine, and thus enhance the effects mediated by acetylcholine).
  • acetylcholine's precursors and cofactors include acetylcholine's precursors and cofactors, acetylcholine receptor agonists (for example pilocarpine, muscarine, nicotine, suxamethonium) and cholinergic enzymes (i.e., cholinesterase inhibitors such as physostigmine, neostigmine or mintacol).
  • acetylcholine's precursors and cofactors for example pilocarpine, muscarine, nicotine, suxamethonium
  • cholinergic enzymes i.e., cholinesterase inhibitors such as physostigmine, neostigmine or mintacol.
  • cholinergic agent derivative it is meant herein a compound obtained via a chemical modification of a cholinergic agent as defined herein, and which retains the ability to either mimic the effect of acetylcholine, or block the effects of acetylcholinesterase.
  • cholinergic agent derivative it is meant herein a compound obtained via a chemical modification of a cholinergic agent as defined herein, and which retains the ability to either mimic the effect of acetylcholine, or block the effects of acetylcholinesterase.
  • These properties can be shown, for example, by applying, to one eye of a mouse, a rat or a monkey, few drops (one, two or three) of said derivative in solution in an ophthalmologically acceptable carrier, and applying, to the other eye of the same animal, the same volume of the ophthalmologically acceptable carrier alone, and measuring and comparing pupil constriction (myosis) of both eyes.
  • adrenergic agent encompasses an alpha adrenergic agonist agent, a derivative of an alpha adrenergic agonist agent, a beta- blocking agent, a derivative of a beta-blocking agents and mixtures thereof.
  • an "alpha adrenergic agonist agent” is a drug which has effects similar to, or the same as, epinephrine (adrenaline) or which is susceptible to epinephrine, or similar substances, such as biological receptors. This term includes alpha 1 agonists, and alpha 2 agonists.
  • Alpha 1 agonists stimulate phospholipase C activity in a human and an animal body, which results in vasoconstriction and mydriasis (excessive dilation of the pupil).
  • Alpha 2 agonists are able to inhibit adenyl cyclase activity in a human and an animal body and are used notably as antihypertensives, sedatives, to reduce eye's aqueous humor secretions and to facilitate aqueous humor outflow via the uveoscleral route.
  • alpha 1 agonist include neosynephrine.
  • alpha 2 agonists include brimonidine, aprachlonidine and clonidine.
  • alpha adrenergic agonist agents that can be used in the present methods and compounds of the present invention include methoxamine, methylnorepinephrine, oxymetazoline, phenylephrine, neosynephrine pivalat, beta-methylepinephrine, guanfacine, guanabenz, guanoxabenz, guanethidine, tizanidine, and mixtures thereof.
  • an alpha adrenergic agonist agent a compound obtained via a chemical modification of an alpha 1 agonist or an alpha 2 agonist, and which retains respectively the ability to stimulate phospholipase C activity or the ability to inhibit adenyl cyclase activity in an animal model such as a mouse, a rat or a monkey.
  • Said derivatives are preferably amine-containing compounds, which more preferably have pKa's of greater than 7, preferably about 7.5 to 9.
  • the alpha 1 or alpha 2 activity of a derivative of an adrenergic agonist agent can be shown for example, by applying, to one eye of a mouse, a rat or a monkey, few drops (one, two or three) of said derivative in solution in an ophthalmologically acceptable carrier, and applying, to the other eye of the same animal, the same volume of the ophthalmologically acceptable carrier alone, and comparing dilation of the pupil (in the case of an alpha 1 agonist derivative) or aqueous humor secretions (in the case of an alpha 2 agonist derivative) of both eyes.
  • Derivatives of an alpha adrenergic agonist agent include imidazoline derivatives such as oxymetazoline, xylometazoline, tetrahydrozoline and the like. Also those derivatives defined in U.S. Patent Nos. 7,345,077 and 7,335,803 can also be used as derivatives in the methods, compositions and kits of the present invention.
  • beta-blocking agent or beta-adrenergic antagonist agent
  • a drug which blocks the action of epinephrine (adrenaline) and/or norepinephrine (noradrenaline) in a human and an animal body. These compounds are used notably to lower intraocular tension and/or to reduce eye's aqueous humor secretions. This term encompasses antagonists of the beta 1 , beta 2 and beta 3 adrenergic receptors.
  • beta-blocking agents that can be used in the methods, the compositions and the kits of the present invention include timolol, sotalol, propranolol, penbutolol, nadolol, metoprolol, labetalol, esmolol, carteolol, bisoprolol, betaxolol, atenolol, acebutolol, levobunolol, metipranolol and mixtures thereof.
  • Beta-blocking agent derivative it is meant herein a compound obtained via a chemical modification of a beta-blocking agent as defined above, and which retains the ability to lower intraocular tension and/or to reduce eye's aqueous humor secretions in an animal model such as a mouse, a rat or a monkey.
  • Beta-blocking agent derivatives include guaiacoxy propanolamine derivatives such as those described in U.S. Patent 5,804,603.
  • x "percent weight by volume" (or "% w/v") of a given drug means x percent weight by volume of the entire formulation comprising said drug.
  • the present invention relates to a method for delivering drugs to the posterior and anterior segments of the eyes (of one or both eye(s)) comprising contacting the surface of the eye with an effective amount of a drug for treating eye disorders and/or diseases of the eye and a physiologically acceptable amount of at least one drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof, in an opthalmologically acceptable carrier.
  • Said drug delivery agent(s) can be used in conjunction with at least another (i.e., one or several) drug delivery agent which is an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta-blocking agents and mixtures thereof.
  • an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta-blocking agents and mixtures thereof.
  • the methods, compositions and kits of the present invention provide for the treatment of many eye disorders and/or diseases of the eye, including the ones mentioned above.
  • the methods, compositions and kits of the invention disclosed herein can be used for the treatment of eye disorders and/or diseases of the eye that affect the posterior segment of the eye, and in particular, eye disorders and/or diseases selected from the group consisting of diabetic retinopathy, choroidal new vessels (in particular those associated with high myopia or macular degeneration, in particular age-related macular degeneration), posterior uveitis, papillitis, endophthalmitis, retinitis, optic nerve head inflammation, retinal vein occlusion (in particular central retinal vein occlusion or branch retinal vein occlusion), retinal arterial occlusion (in particular central retinal artery occlusion), central serous chorio-retinopathy (CSCR), pigmentosa retinopathy, myopia (in particular high myopia), presbyopia, macular
  • CSCR central serous chor
  • the methods, compositions and kits of the invention can be used for the treatment or the prevention of visual degradation (of near and/or far visual acuity or of visual field), in particular age related visual degradation (of near and/or far visual acuity or of visual field), uveitis (in particular anterior uveitis and/or posterior uveitis), post-operative inflammation, and eye infections or inflammation.
  • visual degradation of near and/or far visual acuity or of visual field
  • age related visual degradation of near and/or far visual acuity or of visual field
  • uveitis in particular anterior uveitis and/or posterior uveitis
  • post-operative inflammation in particular anterior uveitis and/or posterior uveitis
  • the methods, compositions and kits of the present invention can also be used for the treatment of glaucoma and/or glaucomatous neuropathy.
  • the methods, compositions and kits of the present invention can in particular be used for improving vision of one or both eyes, and more particularly for improving distance vision and/or near vision.
  • the methods, compositions and kits of the invention disclosed herein can be used to perform topic anaesthesia as a prelude to surgery.
  • At least one eye disorder and/or disease of the eye can be treated with the methods and compositions of the present invention and more than one or several eye disorders and/or diseases can also be treated.
  • the drug to treat the disorders and/or diseases of the eyes is administered topically in the form of suspensions, gels or ointments or in the form of eye drops or solutions along with a physiologically acceptable amount of at least one drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof, and, optionally, along with at least one other drug delivery agent which is an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta-blocking agents and mixtures thereof.
  • active compounds are administered in accordance with the present invention to the eye admixed with an ophthalmically acceptable carrier.
  • an ophthalmically acceptable carrier Any suitable, e.g., conventional, ophthalmically acceptable carrier as defined herein may be employed.
  • compositions and the kits of the present invention may contain the active ingredient in a concentration range of approximately 0.001% to 20% weight by volume (w/v), preferably from 0.01 % to 10% (w/v) or 0.05% to 10% (w/v), and more preferably from 0.1 to 3% or 0.5% to 3% (w/v).
  • the composition itself may include, in addition to the active ingredient, excipients which are per se well know in the art for preparing ophthalmic compositions, particularly ophthalmic solutions.
  • compositions that contain the drug delivery agent(s) as defined herein (i.e., the cholinergic agent(s) and, optionally, the adrenergic agent(s), and/or the drug(s) for treating disorders and/or diseases of the eyes may be administered to the mammalian eye as often as necessary to obtain an improvement of the eye disorder and/or eye disease.
  • the drug delivery agent(s) as defined herein i.e., the cholinergic agent(s) and, optionally, the adrenergic agent(s), and/or the drug(s) for treating disorders and/or diseases of the eyes
  • the drug delivery agent(s) as defined herein i.e., the cholinergic agent(s) and, optionally, the adrenergic agent(s), and/or the drug(s) for treating disorders and/or diseases of the eyes may be administered to the mammalian eye as often as necessary to obtain an improvement of the eye disorder and/or eye disease.
  • the frequency of administration and duration of treatment depends on the precise nature of the active ingredient(s) and its concentration in the ophthalmic formulation, and various factors such as the type and severity of the eye disorder and/or eye disease, the age and weight of the patient or animal, the patient's or animal's general physical condition and the cause of the eye disorder and/or eye disease.
  • the ophthalmic formulations (preferably ophthalmic solutions) of the present invention will be administered topically to the mammalian eye approximately once, twice or three times daily.
  • the duration of treatment administered in accordance with the present invention may range, for example, from few weeks (at least one week) to few months (at least one month), in particular from 1 week to 6 months, preferably at least 2 weeks and less than 4 months and more preferably at least 3 weeks and less than 3 months.
  • a prolonged treatment may be required.
  • the treatment may last for life, for example in case of recurrence of the eye disorder and/or eye disease.
  • the physiologically acceptable amount of the drug delivery agent(s) is administered prior to administering the effective amount of the drug(s) for treating disorders and/or diseases of the eyes; hence, in this case, the drug delivery agent(s) contact(s) the eye prior to the drug(s) for treating disorders and/or diseases of the eyes.
  • Cholinergic agents that can be used in the methods, the compositions and the kits of the present invention can be selected from the group consisting of pilocarpine, aceclidine, carbachol (also known as carbamylcholine), diflupyl (or diisopropyl fluorophosphate (DFP), also known as diflurophate), mintacol, phospholine or phospholine iodide (also known as echothiophate iodide) and mixtures thereof.
  • pilocarpine also known as carbamylcholine
  • DFP diisopropyl fluorophosphate
  • mintacol phospholine or phospholine iodide (also known as echothiophate iodide) and mixtures thereof.
  • Alpha adrenergic agonist agents that can be used in the methods, the compositions and the kits of the present invention can be selected from the group consisting of methoxamine, methylnorepinephrine, oxymetazoline, phenylephrine, neosynephrine, in particular neosynephrine pivalat, beta-methylepinephrine, brimonidine, apraclonidine, clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, tizanidine, and mixtures thereof.
  • Beta-blocking agents that can be used in the methods, the compositions and the kits of the present invention can be selected from the group consisting of timolol, sotalol, propranolol, penbutolol, nadolol, metoprolol, labetalol, esmolol, carteolol, bisoprolol, betaxolol, bisoprolol, atenolol, acebutolol, levobunolol, metipranolol and mixtures thereof.
  • the actual amount of the drug delivery agent(s) and the drug(s) for treating eye disorders and/or diseases of the eye to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the type and severity of the eye disorder and/or eye disease, the age and weight of the patient or animal, the patient's or animal's general physical condition and the cause of the eye disorder and/or eye disease.
  • physiologically acceptable amounts of each of the drug delivery agent(s) that are generally administered to a person or an animal in need thereof are ranging from 0.01 % to 20% (w/v), preferably from 0.1 % to 15% (w/v) and more preferably from 0.1% to 3% (w/v), for example from 0.1% to 2% (w/v) or 0.2% to 1 % (w/v) if eyedrops are used and from 0.1 % to 2% (w/v) in the case of other types of topical administration.
  • the effective amount of a drug for treating eye disorders and/or diseases of the eye is generally administered to a person or an animal in need thereof in a concentration ranging from 0.001 to 15% (w/v), preferably from 0.05 to 10% (w/v), and more preferably from 0.1 to 3% (w/v).
  • the substances or drugs used for treating disorders of the eyes and/or eye diseases can be selected from the group of calcium antagonists, angiotensin converting enzyme inhibitors, nitrates or nitric oxide generators, beta adrenergic agonists, antioxidants and radical scavengers, dopaminergic and serotoninergic agents, monoamine oxidase inhibitors, anti-inflammatory agents, growth factors, neuroprotective agents, growth factor vasoactive agents, neuropeptides, antiinflammatory mediators, anti-infective agents, anti-ischemic association agents, non-steroidal anti-inflammatory agents, anti-growth factor agents, immunosuppressive agents, and mixtures thereof.
  • At least one drug or substance for treating eye disorders and/or diseases of the eye can be used in the methods, the compositions and the kits of the present invention.
  • a person or an animal has more than one eye disorder and/or eye disease, several drugs can be administered at the same time providing that these drugs do not interact with themselves to provide adverse side effects.
  • one can administer at least one anti-inflammatory and at least one angiotensin converting enzyme inhibitor.
  • the drugs or combinations of drugs can be administered at room temperature.
  • Examples of calcium antagonists that can be used in the methods, the compositions and the kits of the present invention can selected from the group comprising verapamil, nifedipine, nimadipine, diltiazem, nicardipine, felodipine, amlodipine, isradipine and mixtures thereof.
  • Examples of angiotensin converting enzyme inhibitors that can be used in the methods, the compositions and the kits of the present invention are selected from the group comprising captopril, enalapril, usinopril, ramipril, kinapril, benazepril, cilazapril and mixtures thereof.
  • Nitrates, isorbide dinitrate, isorbide mononitrate, linsidomine and mixtures thereof are examples of nitrates or nitric oxide generators that can be used in the methods, the compositions and the kits of the present invention.
  • Beta adrenergic agonists that can be used in the methods, the compositions and the kits of the present invention can be selected from the group comprising salbutamol, terbutalin, isoprenalin and mixtures thereof while antioxidants and radical scavengers that can be used in the present invention can be selected from the group comprising ascorbic acid, glutathione catalases and their derivatives and mixtures thereof.
  • Dopaminergic and serotoninergic agent that can be used in the methods, the compositions and the kits of the present invention can be selected from the group comprising: levodopa, amantadine, bromocriptine, serotonine and mixtures thereof.
  • Amitryptiline, nortriptyline, selegiline and mixtures thereof are monoamine oxidase inhibitors that can be used in the methods, the compositions and the kits of the present invention.
  • anti-inflammatory agents examples include non-steroidal antiinflammatory agents or steroidal anti-inflammatory agents, in particular corticosteroids, or mixtures thereof.
  • non-steroidal anti-inflammatory drugs that can be used in the methods, the compositions and the kits of the present invention can be selected from the group comprising or consisting of aspirin, arylalkanoic acids such as bromfenac, indometacin, oxameticin, 2-arylpropionic acids such as fenbufen, pirprofen, ketoprofen, ibuprofen, oxaprozin, and ketorolac, femamic acids, pyrazolidine derivatives such as clofezonem kebuzone and phenazone, ocicams such as droxicam and meloxicam, and COX-2 inhibitors, such as celecoxib and rofecoxib.
  • arylalkanoic acids such as bromfenac, indometacin, oxameticin
  • 2-arylpropionic acids such as fenbufen, pirprofen, ketoprofen, i
  • corticosteroids that can be used in the methods, the compositions and the kits of the present invention can be selected from the group consisting of cortisone, hydrocortisone, deltacortisone or prednisolone, prednisone, deltahydrocortisone or prednisolone, methylprednisolone or medrocortisone, fluorohydrocortisone or fluorocortisone, fluoromethylprednisolone or dexamethazone, fluoromethyldeltahydrocortisone or betamethazone and paramethazone.
  • Growth factors such as nerve growth factors (NGF), epidermal growth factor (EGF), platelet derived growth factor (PDGF), transforming growth factor (TGF) and mixtures thereof can be used in the methods, the compositions and the kits of the present invention.
  • Anti-growth factor agents that can be used in the methods, the compositions and the kits of the present invention include anti-vascular endothelial growth factor (anti-VEGF) agents, anti-insulin like growth factor (anti-IGF) agents, anti-fibroblast growth factor (anti-FGF) agents, anti-platelet derived growth factor (anti-PDGF) agents, anti-placenta growth factor agents and mixtures thereof.
  • anti-VEGF anti-vascular endothelial growth factor
  • anti-IGF anti-insulin like growth factor
  • anti-FGF anti-fibroblast growth factor
  • anti-PDGF anti-platelet derived growth factor
  • Anti-VEGF agents that can be used in the methods, the compositions and the kits of the present invention can be selected from the group comprising bevacizumab (Avastin®), ranibizumab (Lucentis®), pegaptanib (Macugen®), and mixtures thereof.
  • Anti-inflammatory mediators that can be used in the methods, the compositions and the kits of the present invention can be selected from the group comprising cytokines, bradikinine, histamine, serotonin, thrombin, ADP, acetylcholine, adrenalin and derivatives and mixtures thereof.
  • Anti-infective agents that can be used in the methods, the compositions and the kits of the present invention can be selected from the group comprising antibiotics, antifungal agents, antiviral agents and mixtures thereof.
  • Anti-ischemic association compounds selected from the group comprising angiotensin converting enzyme inhibitors, non-steroidal anti-inflammatory agents and mixtures thereof, can also be used in the methods, the compositions and the kits of the present invention.
  • Immunosuppressive agents that can be used in the methods, the compositions and the kits of the present invention can be selected from the group consisting of general immunosuppressive agents, specific immunosuppressive agents and mixtures thereof.
  • General immunosuppressive agents include azathioprin, cyclophosphamide, methotrexate, cyclosporine AFK 506, rapamycin and mixtures thereof.
  • Specific immunosuppressive agents include monoclonal antibodies directed against T-lymphocytes or cytokines.
  • a combination of drugs as set forth in table 1 or a combination of drugs comprising, consisting essentially of or consisting of a combination of drugs as set forth in Table 1 is used.
  • the drugs i.e., the drug delivery agent(s) and the drug(s) to for treating disorders and/or diseases of the eyes
  • the drugs are delivered to the posterior segment of the eye.
  • Said drugs can be in particular delivered to the chorio-retina and optic nerve head of the eyes.
  • the present invention relates to a method of treating eye disorders and/or diseases of the eye by delivering drugs to the chorio-retina and optic nerve head of an eye comprising administering to a person or an animal (in particular a mammal) in need of such treatment
  • a drug for treatment of the chorio-retina and/or optic nerve head and - a physiologically acceptable amount of at least one drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof.
  • the above mentioned drugs are administered topically into the eye, in particular in the form of eye drops. They can be administered separately or in the same composition.
  • Said method can further comprise administering to the person or the animal (in particular a mammal) in need of such treatment at least another drug delivery agent which is an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta- blocking agents, derivatives of the beta-blocking agents and mixtures thereof.
  • adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta- blocking agents, derivatives of the beta-blocking agents and mixtures thereof.
  • Cholinergic agents that can be used in the methods, the compositions and the kits of the present invention can be selected from the group consisting of pilocarpine, aceclidine, carbachol, diflupyl, mintacol, phospholine iodide and mixtures thereof.
  • the effective amount of the drug for treating chorio-retina and optic nerve head can be selected from the group comprising calcium antagonists, angiotensin converting enzyme inhibitors, nitrates or nitric oxide generators, beta-adrenergic agonists, antioxidants and radical scavengers, dopaminergic and serotoninergic agents, monoamine oxidase inhibitors, anti- inflammatory agents, growth factors, neuropeptides, anti-inflammatory mediators, anti-infective agents, non-steroidal anti-inflammatory agents, anti-ischemic association agents (non-steroidal anti-inflammatory agents and angiotensin converting enzyme inhibitors), neuroprotective agents, growth factor vasoactive agents, anti-growth factor agents, in particular anti-vascular endothelial growth factor (anti-VEGF) agents, anti-insulin like growth factor (anti-lGF) agents, anti- fibroblast growth factor (anti-FGF) agents, anti-platelet derived growth factor (anti- PDGF) agents,
  • alpha adrenergic agonist agents are used in the methods, the compositions and the kits of the present invention, they can be selected from the group consisting of methoxamine, methylnorepinephrine, oxymetazoline, phenylephrine, neosynephrine pivalat, beta-methylepinephrine, brimonidine, apraclonidine, clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, tizanidine, and mixtures thereof.
  • beta-blocking agents are used in the methods, the compositions and the kits of the present invention, they can be selected from the group consisting of timolol, sotalol, propranolol, penbutolol, nadolol, metoprolol, labetalol, esmolol, carteolol, bisoprolol, betaxolol, bisoprolol, atenolol, acebutolol, levobunolol, metipranolol and mixtures thereof.
  • the effective amount of a drug for treatment of the chorio-retina and/or optic nerve head is administered in a concentration ranging from 0.001 to 15% (w/v), preferably from 0.05 to 10% (w/v), and more preferably from 0.1 to 3% (w/v).
  • physiologically acceptable amounts of cholinergic agents, alpha adrenergic agonist agent, beta-blocking agent, derivatives thereof and of mixtures thereof that are generally administered are ranging from 0.01% to 20% (w/v), preferably from 0.1% to 15% (w/v), and more preferably from 0.1 % to 3% (w/v), for example from 0.1% to 2% (w/v) or 0.2% to 1% (w/v) if eyedrops are used and from 0.1% to 2% (w/v) in the case of other types of topical administration.
  • physiologically acceptable amounts of cholinergic agents (or derivatives or mixtures thereof) that are generally administered vary from 0.01% to 5% (w/v), preferably from 0.1 to 2% (w/v) and more preferably from 0.1% to 1 % (w/v) or 0.2% to 0.5% (w/v) (e.g.
  • alpha adrenergic agonist agent(s) or derivatives or mixtures thereof
  • physiologically acceptable amounts of beta-blocking agent(s) or derivatives or mixtures thereof
  • the physiologically acceptable amounts of beta-blocking agent(s) or derivatives or mixtures thereof
  • 0.05% to 2% preferably 0.1 % to 1 % (w/v)
  • w/v physiologically acceptable amounts of beta-blocking agent(s) (or derivatives or mixtures thereof)
  • the drug(s) and the physiologically acceptable amounts of drug delivery agent(s) can be administered simultaneously or the drug delivery agent(s) or at least some of the delivery agents can be administered prior to the drug(s) which are used to treat the at least one eye disorder and/or eye disease.
  • the drug delivery agent(s), some of the drug delivery agent(s) or the drug delivery composition is(are) administered before the drug(s), usually it (they) is (are) administered from 1 second to 3 hours, preferably from 5 to 60 minutes, prior to the administration of the treating drug(s).
  • the present invention provides a composition
  • a composition comprising, consisting or consisting essentially of a) at least one drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof, and b) at least one drug that treats eye disorders and/or diseases of the eye.
  • said composition further comprises at least one drug delivery agent which is an adrenergic agent chosen among alpha adrenergic agonist agents and derivatives of alpha adrenergic agonist agents, beta-blocking agents and derivatives of beta-blocking agents.
  • adrenergic agent chosen among alpha adrenergic agonist agents and derivatives of alpha adrenergic agonist agents, beta-blocking agents and derivatives of beta-blocking agents.
  • the drug(s) for treating eye disorders and/or diseases of the eye can be selected from the group comprising calcium antagonists, angiotensin converting enzyme inhibitors, nitrates or nitric oxide generators, beta-adrenergic agonists, antioxidants and radical scavengers, dopaminergic and serotoninergic agents, monoamine oxidase inhibitors, anti-inflammatory agents, growth factors, neuropeptides, anti-inflammatory mediators, anti-infective agents, non-steroidal anti-inflammatory agents, anti-ischemic association agents (non-steroidal antiinflammatory agents and angiotensin converting enzyme inhibitors), anti-growth factor agents, in particular anti-vascular endothelial growth factor (anti-VEGF) agents, anti-insulin like growth factor (anti-IGF) agents, anti-fibroblast growth factor (anti-FGF) agents, anti-platelet derived growth factor (anti-PDGF) agents, anti- placenta growth factor agents, immunosuppressive agents and mixtures thereof.
  • said drug for treating eye disorders and/or diseases of the eye is selected from the group consisting of angiotensin converting enzyme inhibitors, non-steroidal anti-inflammatory agents, anti-growth factor agents, steroidal anti-inflammatory agents, in particular corticosteroids, immunosuppressive agents and mixtures thereof. Said drug(s) are as set forth above.
  • said drug for treating eye disorders and/or diseases of the eye is an anti-growth factor agent as defined herein, in particular an anti-vascular endothelial growth factor agent (anti-VEGF agent), a corticosteroid as set forth above or mixtures thereof.
  • anti-VEGF agent anti-vascular endothelial growth factor agent
  • said drug for treating eye disorders and/or diseases of the eye is an angiotensin converting enzyme inhibitor and/or a nonsteroidal inflammatory agent (anti-ischemic complex).
  • the adrenergic agent is generally selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents and mixtures thereof. Said drug(s) are as set forth above.
  • said drug for treating disorders and/or diseases of the eyes is a corticosteroid and/or an antt-VEGF agent.
  • Said drug(s) are as set forth above.
  • the compositions of the invention can be used as a medicament.
  • said composition are suitable for the treatment of one or several disorders and/or diseases of the eye as defined herein and in particular one or several disorders and/or diseases of the eye selected from the group comprising or consisting of diabetic retinopathy, retinal vein occlusion (in particular central retinal vein occlusion or branch retinal vein occlusion), retinal arterial occlusions, (in particular central retinal artery occlusion), age related visual degradation (near and far visual acuity; visual field), visual degradation of visual acuity and visual field, myopia, presbyopia, macular oedema, central serious chorio-retinopathy, exsudative macular degeneration (age related macular degeneration, high myopia; macular degeneration) u
  • compositions of the invention can be administered topically to a person or an animal in need thereof, for example, in the form of eye drops.
  • compositions of the invention can be used in the methods disclosed herein, to treat the posterior segment of the eye and in particular to treat chorioretinal and/or optic nerve head disorders in a person or an animal.
  • compositions of the invention are administered topically (for example in the form of eye drops) to a person or an animal in need thereof, for increasing the transfer (or delivery), into the posterior segment of the eye, and in particular into the eye orbit, the posterior sclera and then into chorio-retina and optic nerve head, of at least one drug to treat disorders and/or diseases of the eye.
  • Cholinergic agents that can be used in the methods, the compositions and the kits of the present invention can be selected from the group consisting of pilocarpine, aceclidine, carbachol, diflupyl, mintacol, phospholine iodide and mixtures thereof.
  • alpha adrenergic agonist agents are used in the methods, the compositions and the kits of the present invention, they can be selected from the group comprising or consisting of methoxamine, methylnorepinephrine, oxymetazoline, phenylephrine, neosynephrine pivalat, beta-methylepinephrine, brimonidine, apraclonidine, clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, tizanidine, and mixtures thereof.
  • beta-blocking agents are used in the methods, the compositions and the kits of the present invention, they can be selected from the group comprising or consisting of timolol, sotalol, propranolol, penbutolol, nadolol, metoprolol, labetalol, esmolol, carteolol, bisoprolol, betaxolol, atenolol, acebutolol, levobunolol, metipranolol and mixtures thereof.
  • the angiotensin converting enzyme inhibitors that can be used can be selected from the group comprising or consisting of captopril, enalapril, usinopril, ramipril, kinapril, benazepril, cilazapril and mixtures thereof.
  • the non-steroidal anti-inflammatory agents that can be used in the composition can be selected from the group comprising or consisting of aspirin, arylalkanoic acids such as bromfenac, indometacin, oxameticin, 2-arylpropionic acids such as fenbufen, pirprofen, ketoprofen, ibuprofen, oxaprozin, and ketorolac, femamic acids, pyrazolidine derivatives such as clofezonem kebuzone and phenazone, ocicams such as droxicam and meloxicam, and COX-2 inhibitors, such as celecoxib and rofecoxib.
  • arylalkanoic acids such as bromfenac, indometacin, oxameticin
  • 2-arylpropionic acids such as fenbufen, pirprofen, ketoprofen, ibuprofen, oxapro
  • the drug delivery agent(s) are generally present in amounts ranging from 0.01% to 20% (w/v), preferably from 0.1% to 15% (w/v), and more preferably from 0.1 % to 3% (w/v), for example from 0.1% to 3% (w/v), 0.1 % to 2% (w/v) or 0.1 % to 0.5% (w/v).
  • the amounts of cholinergic agents (or derivatives or mixtures thereof) that are generally administered vary from 0.01 % to 5% (w/v), preferably from 0.1 to 2% (w/v) and more preferably from 0.1 % to 1 % (w/v) or 0.2% to 0.5% (w/v) (e.g., 0.2% or 0.5%), while the amounts of alpha adrenergic agonist agent(s) (or derivatives or mixtures thereof) that are present in the compositions of the invention generally vary from 0.01 % to 20% (w/v), preferably from 0.1 % to 3% (w/v) and the amounts of beta- blocking agent(s) (or derivatives or mixtures thereof) that are present in the compositions of the invention generally vary from in the amounts of 0.05% to 2% (w/v), preferably 0.1% to 1% (w/v), and more preferably from 0.1% to 0.5% (w/v).
  • the drug for treating eye disorders and/or diseases of the eye is generally present in amounts ranging from
  • compositions of the invention comprise,, consist essentially of, or consist of a combination of drugs (i.e., a combination of drug delivery agent(s) and of drugs that treats eye disorders and/or diseases) as set forth in Table 1.
  • said composition further comprises at least one drug delivery agent which is an adrenergic agent chosen among alpha adrenergic agonist agents and derivatives of alpha adrenergic agonist agents, beta-blocking agents and derivatives of beta-blocking agents.
  • adrenergic agent chosen among alpha adrenergic agonist agents and derivatives of alpha adrenergic agonist agents, beta-blocking agents and derivatives of beta-blocking agents.
  • Cholinergic agents that can be used in the methods, the compositions and the kits of the present invention can be selected from the group consisting of pilocarpine, aceclidine, carbachol, diflupyl, mintacol, phospholine iodide and mixtures thereof.
  • alpha adrenergic agonist agents are used in the methods, the compositions and the kits of the present invention, they can be selected from the group comprising or consisting of methoxamine, methylnorepinephrine, oxymetazoline, phenylephrine, neosynephrine, in particular neosynephrine pivalat, beta- methylepinephrine, brimonidine, apraclonidine, clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, tizanidine, and mixtures thereof.
  • beta-blocking agents are used in the methods, the compositions and the kits of the present invention, they can be selected from the group comprising or consisting of timolol, sotalol, propranolol, penbutolol, nadolol, metoprolol, labetalol, esmolol, carteolol, bisoprolol, betaxolol, atenolol, acebutolol, levobunolol, metipranolol and mixtures thereof.
  • the anti-VEGF is selected from the group comprising or consisting of bevacizumab (Avastin®), ranibizumab (Lucentis®), pegaptanib (Macugen®) and mixtures thereof.
  • the corticosteroids can be selected from the group consisting of cortisone, hydrocortisone, deltacortisone or prednisolone, prednisone, deltahydrocortisone or prednisolone, methylprednisolone or medrocortisone, fluorohydrocortisone or fluorocortisone, fluoromethylprednisolone or dexamethazone, fluoromethyldeltahydrocortisone or betamethazone and paramethazone.
  • cholinergic agents alpha adrenergic agent(s), beta-blocking agent(s), derivative(s) thereof or mixtures thereof that can be used are as set forth above.
  • the amounts of anti-VEGF and/or corticosteroids that can be used are generally ranging from 0.001% to 15% (w/v), preferably from 0.05% to 10% (w/v), and more preferably from 0.1 % to 3% (w/v).
  • the present invention provides a composition for the topical treatment of disorders and/or diseases of the eye as defined herein, and in particular for the topical treatment of diabetic retinopathy, macular oedema, exudative macular degeneration, retinal vein occlusion (in particular central retinal vein occlusion or branch retinal vein occlusion), uveitis, papillitis, or endophtalmitis comprising, consisting or consisting essentially of a) at least one drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof, and b) angiotensin converting enzyme inhibitor(s) and/or non steroidal antiinflammatory agent(s) and/or steroidal anti-inflammatory agent(s), in particular corticosteroid(s), or mixtures thereof.
  • said composition further comprises at least one drug delivery agent which is an adrenergic agent chosen among alpha adrenergic agonist agents and derivatives of alpha adrenergic agonist agents, beta-blocking agents and derivatives of beta-blocking agents.
  • the drug delivery agent(s), angiotensin converting enzyme inhibitor(s), non steroidal anti-inflammatory agent(s) and corticosteroid(s) used in this composition can be any drug set forth above with respect to the other methods and compositions.
  • the amounts of drug delivery agent(s) that can be used are as set forth above.
  • angiotensin converting enzyme inhibitor(s), non steroidal anti-inflammatory agent(s) and/or corticosteroid(s) that can be used are generally ranging from 0.001 % to 15% (w/v), preferably from 0.05% to 10% (w/v), and more preferably from 0.1 % to 3% (w/v).
  • the present invention provides a composition for the topical treatment of disorders and/or diseases of the eye as defined herein, and in particular of age related vision degradation and presbyopia comprising or consisting of: a) at least one drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof, and b) an angiotensin converting enzyme inhibitor and/or a non steroidal antiinflammatory agent and/or an anti vascular endothelial growth factor agent (anti- VEGF agent) selected from the group comprising bevacizumab (Avastin®), ranibizumab (lucentis®), pegaptanib (Macugen®) and mixtures thereof.
  • anti- VEGF agent anti vascular endothelial growth factor agent
  • said composition further comprises at least one drug delivery agent which is an adrenergic agent chosen among alpha adrenergic agonist agents and derivatives of alpha adrenergic agonist agents, beta-blocking agents and derivatives of beta-blocking agents, preferably an alpha adrenergic agonist agent and/or a derivative of an alpha adrenergic agonist agent.
  • an adrenergic agent chosen among alpha adrenergic agonist agents and derivatives of alpha adrenergic agonist agents, beta-blocking agents and derivatives of beta-blocking agents, preferably an alpha adrenergic agonist agent and/or a derivative of an alpha adrenergic agonist agent.
  • the drug delivery agent(s), angiotensin converting enzyme inhibitor and non steroidal anti-inflammatory agent and corticosteroid(s) used in this composition can be any drug set forth above with respect to the other methods and compositions.
  • drug delivery agent(s), derivative(s) thereof or mixtures thereof that can be used are as set forth above.
  • angiotensin converting enzyme inhibitor(s), non steroidal anti-inflammatory agent(s) and/or anti-VEGF agent(s) that can be used are generally ranging from 0.001 % to 15% (w/v), preferably from 0.05% to 10% (w/v), and more preferably from 0.1 % to 3% (w/v).
  • the present invention provides a method for increasing the transfer (or delivery), of a drug into the posterior segment of the eye and in particular into the eye orbit, the posterior sclera and then into chorio-retina and optic nerve head to treat disorders and/or diseases of the eye as defined herein, said method comprising contacting the surface of an eye or both eyes with a) a physiologically acceptable at least one drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof and b) a pharmaceutically acceptable amount of a second drug that treats disorders and/or diseases of the eyes, and , c) optionally, at least another delivery agent which is an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta-blocking agents and mixtures thereof.
  • a physiologically acceptable at least one drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof
  • Cholinergic agents that can be used in the methods, the compositions and the kits of the present invention can be selected from the group consisting of pilocarpine, aceclidine, carbachol, diflupyl, mintacol, phospholine iodide and mixtures thereof.
  • alpha adrenergic agonist agents are used in the methods, the compositions and the kits of the present invention, they can be selected from the group comprising or consisting of methoxamine, methylnorepinephrine, oxymetazoline, phenylephrine, neosynephrine pivalat, beta- methylepinephrine, brimonidine, apraclonidine, clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, tizanidine, and mixtures thereof.
  • beta-blocking agents are used in the methods, the compositions and the kits of the present invention, they can be selected from the group comprising or consisting of timolol, sotalol, propranolol, penbutolol, nadolol, metoprolol, labetalol, esmolol, carteolol, bisoprolol, betaxolol, atenolol, acebutolol, levobunolol, metipranolol and mixtures thereof.
  • the amounts of drug delivery agent(s), derivative(s) thereof or mixtures thereof that can be used are as set forth above.
  • the pharmaceutically acceptable amount of a second drug that treats disorders and/or diseases of the eyes that can be used is as set forth above.
  • the combination of drugs contacting the surface of one or both eye(s) is a combination of drugs as set forth in table 1 , or a combination of drugs comprising, consisting essentially of or consisting of the drugs of a combination as set forth in Table 1.
  • Another aspect of the invention relates to drug delivery agent(s) as defined herein (i.e., cholinergic agent(s) or derivative(s) thereof as defined herein, and optionally, adrenergic agent(s) or derivative(s) thereof as defined herein), or mixture thereof, or a composition comprising, consisting of or consisting essentially of said drug delivery agent(s), for use for the transfer (or delivery),, to the posterior segment of the eyes, of a second drug that treats disorders and/or diseases of the eyes, for use in the treatment of diseases and/or disorders of the eye.
  • drug delivery agent(s) as defined herein i.e., cholinergic agent(s) or derivative(s) thereof as defined herein, and optionally, adrenergic agent(s) or derivative(s) thereof as defined herein
  • a composition comprising, consisting of or consisting essentially of said drug delivery agent(s), for use for the transfer (or delivery),, to the posterior segment of the eyes, of a second drug that treats
  • Cholinergic agents that can be used in the methods, the compositions and the kits of the present invention can be selected from the group consisting of pilocarpine, aceclidine, carbachol, diflupyl, mintacol, phospholine iodide and mixtures thereof.
  • alpha adrenergic agonist agents are used in the methods, the compositions and the kits of the present invention, they can be selected from the group consisting of methoxamine, methylnorepinephrine, oxymetazoline, phenylephrine, neosynephhne pivalat, beta-methylepinephrine, brimonidine, apraclonidine, clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, tizanidine, and mixtures thereof.
  • beta-blocking agents are used in the methods, the compositions and the kits of the present invention, they can be selected from the group consisting of timolol, sotalol, propranolol, penbutolol, nadolol, metoprolol, labetalol, esmolol, carteolol, bisoprolol, betaxolol, atenolol, acebutolol, levobunolol, metipranolol and mixtures thereof.
  • drug delivery agent(s), derivative(s) thereof or mixtures thereof that can be used are as set forth above.
  • the second drug that treats disorders and/or diseases of the eyes can be selected from the group consisting of a calcium antagonists, nitrates or nitric oxide generators, beta adrenergic agonists, antioxidants and radical scavengers, dopaminergic and serotonergic agents, monoamine oxidase inhibitors, antiinflammatory agents, growth factors, neuropeptides, anti-inflammatory mediators, anti-infective agents, anti-ischemic association agents (non-steroidal antiinflammatory agents and angiotensin converting enzyme inhibitors), anti-growth factor agents, in particular anti-vascular endothelial growth factor (anti-VEGF) agents, anti-insulin like growth factor (anti-IGF) agents, anti-fibroblast growth factor (anti-FGF) agents, anti-platelet derived growth factor (anti-PDGF) agents, anti- placenta growth factor agents, immunosuppressive agents and mixtures thereof.
  • a calcium antagonists nitrates or nitric oxide generators
  • the specific drugs that can also be used in this method are set forth above.
  • the specific drugs that are used to treat eye disorders and/or diseases can be any drug set forth above with respect to the other methods.
  • the pharmaceutically acceptable amount of the second drug depends upon which drug is being used. Examples of pharmaceutically acceptable amounts include amounts ranging from 0.1 to 15% (w/v), preferably from 0.5 to 10%, and more preferably from 0.5 to 3% (w/v).
  • a combination of drugs as set forth in table 1 or a combination of drugs comprising, consisting essentially of or consisting of the drugs of a combination as set forth in Table 1 is used.
  • the present invention also provides use of a) at least one drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof, in combination with b) a pharmaceutically acceptable amount of a second drug that treats disorders and/or diseases of the eyes, and, optionally, c) at least another drug delivery agent which is an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta- blocking agents and mixtures thereof, for use for the treatment of disorders and/or diseases of the eye or for the manufacture of a medicament to treat disorders and/or diseases of the eye.
  • a drug delivery agent selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof
  • a pharmaceutically acceptable amount of a second drug that treats disorders and/or diseases of the eyes and, optionally, c) at least another drug delivery agent which is an adrenergic agent selected from the group
  • cholinergic agents that can be used in the methods, the compositions and the kits of the present invention can be selected from the group consisting of pilocarpine, aceclidine, carbachol, diflupyl, mintacol, phospholine iodide and mixtures thereof.
  • alpha adrenergic agonist agents are used in the methods, the compositions and the kits of the present invention, they can be selected from the group comprising or consisting of methoxamine, methylnorepinephrine, oxymetazoline, phenylephrine, neosynephrine pivalat, beta-methylepinephrine, brimonidine, apraclonidine, clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, tizanidine, and mixtures thereof.
  • beta-blocking agents are used in the methods, the compositions and the kits of the present invention, they can be selected from the group comprising or consisting of timolol, sotalol, propranolol, penbutolol, nadolol, metoprolol, labetalol, esmolol, carteolol, bisoprolol, betaxolol, atenolol, acebutolol, levobunolol, metipranolol and mixtures thereof.
  • the amounts of drug delivery agent(s) that are present in this medicament are as set forth above.
  • the pharmaceutically acceptable amount of a second drug that treats disorders and/or diseases of the eyes that can be used is as set forth above.
  • a combination of drugs as set forth in table 1 or a combination of drugs comprising, consisting essentially of or consisting of a combination of drugs as set forth in Table 1 is used.
  • the present invention provides a kit comprising, consisting or consisting essentially of:
  • At least another drug delivery agent which is an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta-blocking agents and mixtures thereof.
  • an adrenergic agent selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta-blocking agents and mixtures thereof.
  • the drug delivery agent(s) and the derivatives thereof, as well as the drug for treating disorders and/or diseases of the eyes are as set forth above.
  • the amounts of drug delivery agent(s) and said drug for treating disorders and/or diseases of the eyes that can be used are as set forth above.
  • kits can be used in the methods of the present invention, to treat chorio-retinal and/or optic nerve head disorders in a person or an animal.
  • said drug for treating disorders and/or diseases of the eyes is selected from the group consisting of angiotensin converting enzyme inhibitors, non-steroidal anti-inflammatory agents, anti-growth factor agents, steroidal anti-inflammatory agents, in particular corticosteroids, immunosuppressive agents and mixtures thereof.
  • angiotensin converting enzyme inhibitors non-steroidal anti-inflammatory agents, anti-growth factor agents, steroidal anti-inflammatory agents, in particular corticosteroids, immunosuppressive agents and mixtures thereof.
  • said drug for treating disorders and/or diseases of the eyes is an angiotensin converting enzyme inhibitor and/or a non-steroidal anti-inflammatory agent (anti-ischemic complex).
  • the adrenergic agent if present is generally selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents and mixtures thereof. Said drug(s) are as set forth above.
  • drug for treating disorders and/or diseases of the eyes is a corticosteroid and/or an anti-VEGF agent. Said drug(s) are as set forth above.
  • the kit of the invention comprises or consists of the drugs of a combination of drugs as set forth in Table 1.
  • both (i) drug delivery agent(s) selected from the group consisting of cholinergic agents, derivatives thereof and mixtures thereof (for example pilocarpine) and (ii) drug delivery agent(s) selected from the group consisting of alpha adrenergic agonist agents, derivatives of the alpha adrenergic agonist agents, beta-blocking agents, derivatives of the beta-blocking agents and mixtures thereof are used (in particular administered topically to a person or an animal in need thereof).
  • the drug delivery agent(s) used in the methods, the compositions and the kits of the present invention can comprise, consist essentially of, or consist of:
  • combinations of at least two or three drug delivery agents are in particular useful for use for the transfer (or delivery),, to the posterior segment of one or both eye(s), of at least one second drug that treats disorders and/or diseases of the eyes as disclosed herein, and in particular at least one second drug which is selected from the group consisting of corticosteroids (for example dexamethazone), non steroidal anti-inflammatroy agents (for example indomethacin (Indocollyre ⁇ )) and angiotensin converting enzyme inhibitors.
  • corticosteroids for example dexamethazone
  • non steroidal anti-inflammatroy agents for example indomethacin (Indocollyre ⁇ )
  • angiotensin converting enzyme inhibitors angiotensin converting enzyme inhibitors.
  • the combination of drugs used comprises or consists of at least a cholinergic agent or a derivative thereof (for example pilocarpine), and:
  • alpha adrenergic agonist agent or a derivative thereof for example neosynephrine, brimonidine, apraclonidine or mixtures thereof;
  • beta-blocking agent at least a beta-blocking agent, or a derivative thereof (for example timolol);
  • an anti-VEGF agent for example bevacizumab (Avastin®), ranibizumab (lucentis®), pegaptanib (Macugen®) or mixtures thereof; and/or
  • non-steroidal anti-inflammatory agent for example Indomethacin
  • corticosteroid for example Dexamethasone
  • an immunosuppressive agent for example azathioprin, cyclophosphamide, methotrexate, cyclosporine AFK 506, rapamycin, or mixtures thereof.
  • an immunosuppressive agent for example azathioprin, cyclophosphamide, methotrexate, cyclosporine AFK 506, rapamycin, or mixtures thereof.
  • These drugs can be used as separate compounds or be present in the same composition.
  • the amounts of drug delivery agent(s) and of the other drug(s) for treating disorders and/or diseases of the eyes that can be used are as set forth herein. Examples of such combinations of drugs are shown in Table 1.
  • the cholinergic agent(s) used increase(s) the effects of or even act(s) in synergy with the other drug delivery agent(s) and/or the other drug(s) for treating eye disorders and/or diseases of the eye used in the invention.
  • the use of cholinergic agent(s) allows to achieve a stronger therapeutic effect than the one that is obtained if no cholinergic agent(s) are used.
  • lower concentrations of drug(s) for treating eye disorders and/or diseases of the eye can be administered and/or the frequency of drug administration can be decreased.
  • cholinergic agent(s) when cholinergic agent(s) are used, administrating the treatment three or four times a day is usually sufficient for treating an eye disease or disorder, whereas in case no cholinergic agent(s) are used, it is usually necessary to administer the treatment every hour during the day to a person or an animal in need thereof.
  • cholinergic agents and in particular pilocarpine, are particularly useful for treating eye disorders and/or diseases.
  • another aspect of the invention relates to a method for treating eye disorders and/or diseases of the eye comprising: contacting the surface of the eye with an effective amount of a cholinergic agent as defined herein, in particular with pilocarpine, or with a derivative thereof or mixtures thereof.
  • the cholinergic agent(s), and in particular pilocarpine is (are) the only drug delivery agent(s) or even the only drug to treat eye disorders and/or diseases that is used in the above-mentioned method.
  • the eye disorders and/or diseases that can be treated using the above- mentioned method are as disclosed herein and can be selected in particular from the group consisting of macular edema, age-related macular degeneration, choroidal new vessels (in particular those associated with high myopia or macular degeneration, in particular age-related macular degeneration), exsudative macular degeneration (in particular the one that is associated with high myopia or macular degeneration, in particular age-related macular degeneration), retinal vein occlusion, in particular central retinal vein occlusion or branch retinal vein occlusion, retinal arterial occlusions, in particular central retinal artery occlusion, central serous chorio retinopathy (CSCR), diabetic retinopathy, high myopia chorioretinopathy, pigmentosa retinopathy, proliferative vitreoretinopathy, myopia (in particular high myopia), presbyopia, uveitis (in particular anterior uveitis or posterior uveitis),
  • the opthalmic disorders and/or diseases only affect(s) the posterior segment of the eye, and are in particular, selected from the group consisting of macular edema, age-related macular degeneration, choroidal new vessels (in particular those associated with high myopia or macular degeneration, in particular age-related macular degeneration), exsudative macular degeneration (in particular the one that is associated with high myopia or macular degeneration, in particular age-related macular degeneration), retinal vein occlusion, in particular central retinal vein occlusion or branch retinal vein occlusion, retinal arterial occlusions, in particular central retinal artery occlusion, central serous chorio retinopathy (CSCR), diabetic retinopathy, high myopia chorio-retinopathy, pigmentosa retinopathy, proliferative vitreoretinopathy, myopia (in particular high myopia), presbyopia, posterior uveitis, retinitis,
  • the above-mentioned method is used for treating diabetic retinopathy, retinal vein occlusion (in particular central retinal vein occlusion or branch retinal vein occlusion), or age - related macular degeneration.
  • cholinergic agent that can be used in this method are as set forth above.
  • the invention also relates to one or several cholinergic agent(s) as defined herein, in particular to pilocarpine, or to derivative(s) thereof or mixtures thereof, or to a composition comprising, consisting essentially or consisting of this (these) drug(s), or to a kit comprising or consisting of this (these) drug(s), for use in the treatment of eye disorders and/or diseases as disclosed herein and in particular for use in the method disclosed above, or for the manufacture of a medicament to treat disorders and/or diseases of the eye as disclosed herein.
  • the cholinergic agent(s), derivative(s) or mixtures thereof can administered topically to one or both eye of a patient or an animal in need thereof.
  • Corneal into the anterior chamber, and then through the lens, the pupil or the iris.
  • the fluid When a large drop is allowed to flood the interpalpebal space, the fluid could fall under gravity and distend the cul-de-sac. In that case, the drug would have the opportunity to penetrate into the posterior sclera and orbit.
  • the penetration from a drop to the posterior segment is increased by using an alpha adrenergic agonist agent or a beta-blocking agent as the drug carrier.
  • each treated eye received daily, four times per day, of one or several drops of treatment (either one drop of each drug when these drugs where administered separately, or one drop of a composition comprising a mixture of the different drugs to be administered).
  • An OTC scan was performed before treatment and after several months of treatment (in general after one to six months of treatment).
  • Example 1 DIABETIC RETINOPATHY
  • Diabetic retinopathy is the leading cause of new blindness in individuals under 65 years of age. Diabetic retinopathy can be classified into non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR).
  • NPDR non-proliferative diabetic retinopathy
  • PDR proliferative diabetic retinopathy
  • the clinical features of NPDR include microaneurysms, intraretinal hemorrhages, hard exudates, nerve fiber layer infarcts or cotton wool exudates and intra retinal microvascular abnormalities (IRMA).
  • IRMA intra retinal microvascular abnormalities
  • the clinical picture of PDR includes the features from NPDR in addition to proliferating new vessels on the optic nerve head, retina or iris.
  • Diabetic macular oedema is a principal cause of visual loss in diabetic patients. Two examination techniques are very useful in evaluating diabetic retinopathy: fluorescein angiography and
  • Fluorescein angiography is used to detect several of the retinal vascular abnormalities.
  • the dye delineates structural vascular alterations, such as aneurysms or neovascularization, changes in blood flow such as ischemia and vascular occlusion are seen as an interruption of the normal perfusion pattern.
  • Abnormal vascular permeability is seen as a leaking cloud of dye-stained oedema fluid increasing overtime.
  • Optical coherence tomography may be more sensitive in evaluating diabetic macular oedema than slit-lamp examination.
  • central macular thickness correlates with visual acuity even better than fluorescein leakage.
  • macular oedema The response of macular oedema to the administration of one drug such as an anti-VEGF agent or an anti-inflammatory treatment such as topical corticosteroids, non-steroidal anti-inflammatory agents or angiotensin converting enzyme inhibitors, can be documented accurately by OCT imaging.
  • one drug such as an anti-VEGF agent or an anti-inflammatory treatment such as topical corticosteroids, non-steroidal anti-inflammatory agents or angiotensin converting enzyme inhibitors
  • Diabetic patients were treated with the following drugs given topically: a corticosteroid (dexamethasone (Tobradex®)) and non steroidal anti-inflammatory agent (indomethacin (Indocollyre ⁇ )).
  • a corticosteroid diexamethasone (Tobradex®)
  • non steroidal anti-inflammatory agent indomethacin (Indocollyre ⁇ )
  • a cholinergic agent prilocarpine
  • a cholinergic agent prilocarpine
  • a cholinergic agent prilocarpine
  • a beta- blocking agent timolol
  • an alpha adrenergic agonist agent brimonidin
  • Patient F.K. presented with a bilateral decrease of his visual acuity because of a serious macular oedema caused by a diabetic retinopathy.
  • An OCT scan was performed prior to treatment and the results are shown in Figure 2A.
  • Patient Z.A. is a diabetic patient who presented with a diabetic retinopathy. He received topically a composition comprising pilocarpine (1% w/v), ramipril (2% (w/v), dexamethasone (Tobradex®; 0.1 % w/v) and indomethacin (Indocollyre ®; 0.1 % w/v).
  • An OCT exam shown in Figure 3A was performed before the patient received the treatment. After six months of treatment, a follow up OCT scan showed that the total macula volume had decreased explaining visual improvement (see Figure 3B).
  • Patient S. H. presented with a diabetic retinopathy. He received topically: a cholinergic agent (pilocarpine), an alpha adrenergic agonist agent (brimonidin), a beta-blocking agent (timolol), a corticosteroid (dexamethazone) and a non steroidal anti-inflammatroy agent (indomethacin (Indocollyre ⁇ )).
  • a cholinergic agent prilocarpine
  • brimonidin alpha adrenergic agonist agent
  • beta-blocking agent timolol
  • corticosteroid dexamethazone
  • non steroidal anti-inflammatroy agent indomethacin (Indocollyre ⁇ )
  • Patient J. D. has diabetic retinopathy. During two months, she receives topically, every hour during the day:
  • composition comprising an angiotensin converting enzyme inhibitor (ramipril; 2% (w/v); a corticosteroid (dexamethazone; 0.1% w/v) and a non steroidal anti-inflammatroy agent
  • Example 2 RETINAL VEIN OCCLUSION
  • Central retinal vein occlusion is a common retinal vascular condition usually affecting people older than 50 years. Patients typically experience visual loss and present with dilated tortuous retinal veins and scattered intra-retinal hemorrhage in all four quadrants, cotton wool spots, optic disc swelling, and macular oedema can occur. Intra veinous fluorescein angiography shows areas of blocked fluorescence from the intra-retinal blood, staining of the vessel walls, a delayed arteriovenous phase, and nonperfused areas, and perifoveal leakage.
  • a corticosteroid (dexamethasone (Tobradex®)) and a non steroidal anti-inflammatory agent (indomethacin (Indocollyre ⁇ )), associated with one or sevral delivery drug enhancers: either a cholinergic agent (pilocarpine), or a cholinergic agent (pilocarpine) in combination with a beta-blocking agent (timolol) and an alpha adrenergic agonist agent (brimonidin).
  • a corticosteroid diexamethasone (Tobradex®)
  • an indomethacin Indocollyre ⁇
  • sevral delivery drug enhancers either a cholinergic agent (pilocarpine), or a cholinergic agent (pilocarpine) in combination with a beta-blocking agent (timolol) and an alpha adrenergic agonist agent (brimonidin).
  • Patient A.M. presented with a retinal central vein occlusion associated with a dramatic decrease of his visual acuity. He received topically a cholinergic agent (pilocarpine). Prior to receiving the treatment, an OCT scan was taken, which is shown in Figure 5A. After three months of treatment, his visual acuity improved. In addition, an OCT scan (shown in Figure 5B) demonstrated a decrease in macular oedema.
  • Patient R. S. presented with a central retinal vein occlusion in the right eye. He received topically a composition comprising pilocarpine (1% w/v), ramipril (2% (w/v), dexamethasone (Tobradex®; 0.1 % w/v) and indomethacin (Indocollyre ®; 0.1% w/v).
  • a composition comprising pilocarpine (1% w/v), ramipril (2% (w/v), dexamethasone (Tobradex®; 0.1 % w/v) and indomethacin (Indocollyre ®; 0.1% w/v).
  • OCT scan shown in Figure 6A
  • a follow up OCT scan shown in Figure 6B
  • Patient B.R.N presented with a central vein occlusion.
  • a cholinergic agent prilocarpine 1%
  • an alpha adrenergic agonist agent brimonidin
  • a beta-blocking agent timolol
  • corticosteroid dexamethazone
  • non steroidal anti-inflammatroy agent indomethacin (Indocollyre ⁇ )
  • Example 3 age - related macular degeneration (ARMD)
  • Age related macular degeneration (ARMD) is the leading cause of severe vision loss among the elderly. The cause of ARMD remains elusive and complex, with both environmental and genetic contributions. ARMD has two distinct forms known as “dry” or non-neovascular ARMD and “wet", or neovascular ARMD. Most the severe vision loss in ARMD is caused by neovascular ARMD.
  • the best proven therapies for ARMD treat the neovascular form of the disease and include photocoagulation triamcinolone intraocular injection and anti- VEGF intraocular injection (Avastin®; Lucentis®; Macugen®).
  • OCT optical coherence tomography
  • a corticosteroid (dexamethasone (Tobradex®)) and a non steroidal anti-inflammatory agent (indomethacin (Indocollyre ®)
  • a corticosteroid such as a corticosteroid (dexamethasone (Tobradex®)
  • a non steroidal anti-inflammatory agent such asdomethacin (Indocollyre ®)
  • delivery drug enhancers either a cholinergic agent (pilocarpine), or a cholinergic agent (pilocarpine) in combination with a beta-blocking agent (timolol) and an alpha adrenergic agonist agent (brimonidin).
  • Patient G.N presented with a reduction of visual acuity of the left eye due to a macular degeneration.
  • an OCT scan was taken, which is shown in Figure 8A.
  • This OCT scan revealed a macular thickening associated with this pathology.
  • the patient was treated topically with a cholinergic agent (pilocarpine). After three months later, both his fisual acuity and the OCT scan were improved; a decrease in macular thickening can be seen on the OTC scan shown in Figure 8B).
  • Patient H. M. presented with a history of decreased vision in the right eye due to ARMD. This decreased vision was related to a choroid occult new vessel.
  • An OCT exam revealed a macular thickening and a pigmentary epithelium detachment. He was treated with a composition comprising pilocarpine (1% w/v), ramipril (2% (w/v), dexamethasone (Tobradex®; 0.1 % w/v) and indomethacin (Indocollyre ®; 0.1% w/v). After one month of treatment, the patient's vision improved.
  • a follow up OCT shown in Figure 9B) scan demonstrated a complete regression of macular thickening and recovery of foveal contour.
  • Patient G.N. presented with a history of decreased vision in the left eye. As mentioned above, he had previously been treated with pilocarpine, which improved his visual acuity but after few months, his vision decreased again. A fluoro- angiographic image showed choroid occult new vessel (C.N.V.). Prior to receiving a new treatment, an OCT scan was taken, which is shown in Figure 1OA.
  • a cholinergic agent pentipeptide 1%
  • an alpha adrenergic agonist agent brimonidin
  • a beta-blocking agent timolol
  • a corticosteroid dexamethazone
  • a non steroidal anti-inflammatroy agent indomethacin (Indocollyre ⁇ )
  • Cholinergic agents and especially pilocarpine are useful as drug delivery agents. They enable delivery, to the posterior segment of the eye, of drugs for treating the eye (for example anti-inflammatory agents, corticoids, angiotensin converting enzyme inhibitors, neuroprotective agents, immunosuppressive agents) that have been administered topically in one or both eyes of a patient.
  • drugs for treating the eye for example anti-inflammatory agents, corticoids, angiotensin converting enzyme inhibitors, neuroprotective agents, immunosuppressive agents
  • Topical administration of a cholinergic agent, and in particular of pilocarpine, in conjunction with a second drug to a patient in need thereof allows to lower the concentration of the second drug which is administered and/or to lower the frequency of administration of the treatment.
  • cholinergic agents, especially pilocarpine act in synergy with other drug delivery agents, for example alpha adrenergic agonist agents and/or beta- blocking agents.

Abstract

Cette invention concerne une méthode et un système, en particulier un ou plusieurs agents d'administration de médicaments, un kit et des compositions, pour la délivrance de médicaments dans la choroïde-rétine et la tête du nerf optique. La méthode consiste à mettre en contact la surface de l'œil avec une quantité efficace de médicament pour traiter la choroïde-rétine et la tête du nerf optique et avec une quantité physiologiquement acceptable d'au moins un agent d'administration de médicaments pour augmenter la délivrance du médicament dans ces tissus dans un excipient acceptable du point de vue ophtalmologique, ledit agent d'administration étant choisi dans le groupe constitué par les agents cholinergiques, leurs dérivés ou leurs mélanges. L'invention concerne également le(s)dit(s) agent(s) d'administration de médicaments ou les compositions comprenant cet agent ou ces agents utilisé(s) pour introduire, dans le segment postérieur d'un œil ou des deux yeux, au moins un second médicament qui traite les affections et/ou les maladies oculaires. L'agent/Les agents d'administration de médicaments peu(ven)t être utilisé(s) en même temps qu'au moins un autre agent d'administration qui est un agent adrénergique choisi dans le groupe constitué par les agonistes alpha‑adrénergiques, les dérivés des agonistes alpha‑adrénergiques, les bêtabloquants, les dérivés des bêtabloquants et leurs mélanges.
PCT/IB2009/005397 2009-04-27 2009-04-27 Administration de médicaments dans le segment antérieur et le segment postérieur de l'oeil WO2010125416A1 (fr)

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US9474756B2 (en) 2014-08-08 2016-10-25 Forsight Vision4, Inc. Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof
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