sign in sign up
<<
Home , Fluazacort

(19) TZZ _Z _T

(11) EP 2 216 026 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/573 (2006.01) A61P 27/02 (2006.01) 20.04.2016 Bulletin 2016/16 A61K 9/10 (2006.01) A61K 47/30 (2006.01) A61K 9/00 (2006.01) (21) Application number: 10154221.5

(22) Date of filing: 11.07.2005

(54) Ophthalmic compositions and uses for treating ophthalmic conditions Ophthalmologische Zusammensetzungen und deren Verwendung zur Behandlung von Augenkrankheiten Compositions ophthalmologiques et leur utilisation pour le traitement des maladies oculaires.

(84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR EP-A- 0 488 401 US-A- 4 052 505 HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI US-A- 4 144 317 US-A- 4 997 652 SK TR US-A- 5 869 079 US-A1- 2003 211 123

(30) Priority: 12.07.2004 US 587092 • RECHTMAN E ET AL: "Intravitreal with photodynamic therapy for subfoveal (43) Date of publication of application: choroidal neovascularisation in age related 11.08.2010 Bulletin 2010/32 macular degeneration" BRITISH JOURNAL OF OPHTHALMOLOGY, LONDON, GB, vol. 88, no. 3, (62) Document number(s) of the earlier application(s) in March 2004 (2004-03), pages 344-347, accordance with Art. 76 EPC: XP002338290 ISSN: 0007-1161 05772211.8 / 1 773 350 • MCGHEE CHARLES N J ET AL: "Locally administered ocular : Benefits (73) Proprietor: ALLERGAN, INC. and risks" DRUG SAFETY, vol. 25, no. 1, 2002, Irvine, CA 92612 (US) pages 33-55, XP009059939 ISSN: 0114-5916

(72) Inventor: Whitcup, Scott M. Remarks: Laguna Hills, CA 92653 (US) Ophthalmic compositions and uses for treating ophthalmic conditions. (74) Representative: Hoffmann Eitle Patent- und Rechtsanwälte PartmbB Arabellastraße 30 81925 München (DE)

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 216 026 B1

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 216 026 B1 2

Description have a prolonged duration of action by virtue of their own intrinsic dissolution rates. For example, triamcinolone ac- CROSS-REFERENCE TO RELATED APPLICATIONS etonide has been successfully administered by direct in- travitreal injection in an aqueous composition due to its [0001] The present application claims the benefit of 5 slow dissolution rate and tolerability. Unfortunately, side U.S. Application No. 60/587,092, filed July 12, 2004. effects from the existing formu- lation often include endophthalmitis as well as retinal tox- BACKGROUND icity from the benzyl alcohol preservative. Glaucoma and cataract are also observed. [0002] The present invention relates to ophthalmic10 [0008] Reducing the lens concentration of a corticos- compositions that are delivered to the interior of an eye teroid may help mitigate the cataractogenic potential of of a human or animal. More particularly, the invention these drugs. Additionally, reducing the anterior segment relates to ophthalmically acceptable compositions in- concentration of the corticosteroids relative to the poste- cluding one or more therapeutic agents. Such composi- rior concentrations may reduce the chance of elevating tions are advantageously intraocularly placed into the in- 15 the TIGR (MYOC, GLC1A) gene activity in the trabecular terior of an eye and form solid or semi-solid drug delivery meshwork thought to be associated with induced elements in situ that are effective in providing extended glaucoma. or delayed release of the therapeutic agent or agents into [0009] Some extended release compositions contain- the eye. ing therapeutic agents have been described. For exam- [0003] , for example corticosteroids, among 20 ple,U.S. Patent No. 5,077,049 discloses a biodegradable other agents, are utilized to treat a wide variety of oph- system for regenerating the periodontium. U.S. Patent thalmic diseases that affect the posterior segment of an No. 5,324,519 discloses a biodegradable polymer com- eye. Examples of some diseases treated with corticos- position. U.S. Patent Nos. 5,487,897 and 6,395,293 dis- teroids include: central retinal vein occlusion (CRVO), close a biodegradable implant precursor. U.S. Patent No. branch retinal vein occlusion (BRVO), choroidal macular 25 5,702,716 discloses polymeric compositions useful as edema (CME), diabetic macular edema (DME), diabetic controlled release implants. U.S. Patent No. 5,717,030 macular retinopathy, uveitis, telangitis, and age related discloses an adjunctive polymer system for use with med- macular degeneration (ARMD) as well as other diseases ical device. U.S. Patent No. 5,780,044 discloses liquid or conditions of the eye, for example of the posterior seg- delivery compositions. U.S. Patent No. 6,143,314 dis- ment of the eye. 30 closes controlled release liquid delivery compositions [0004] In treating ocular diseases or disorders, ster- with low initial drug burst. U.S. Patent No. 6,261,583 dis- oids can be administered systemically. However, sys- closes a moldable solid delivery system. U.S. Patent No. temic administration of steroids is often associated with 6,461,631 discloses a biodegradable polymer composi- side effects that are often too substantial for ophthalmic tion. U.S. Patent No. 6,565,874 discloses polymeric de- use. Thus, topical, suprachoroidal, subconjunctival, ret- 35 livery formulations of leuprolide with improved efficacy. robulbar, and intravitreal administration have also been [0010] Thus, there is a need for new ophthalmic com- studied. These administration techniques typically em- positions for injection into the interior of eyes of humans ploy aqueous compositions containing a steroid. or animals and methods for providing desired therapeutic [0005] The desired site of action for therapeutic agents effects of ophthalmic conditions of eyes of humans or administered to the posterior segment of an eye gener- 40 animals. ally, and corticosteroids in particular, is the retinal pig- mented epithelium (RPE). The RPE is a single cell layer SUMMARY OF THE INVENTION responsible for maintenance of the blood-retinal barrier as well as subretinal fluid volume and composition. The [0011] New compositions and uses for treating oph- cells of the RPE comprise the outer blood retinal barrier 45 thalmic conditions of eyes of humans or animals are pro- and are joined by zonulae occludente tight junctions. As vided. The present compositions are highly suitable for such, permeation of compounds into the RPE is quite intraocular administration into the interior of an eye and limited. Thus, regardless of the administration route, pen- provide therapeutic effects to the eye, which may be ef- etration of a therapeutic agent through the outer blood- fective in stabilizing, enhancing or improving a patient’s retinal barrier is limited. To overcome these limitations 50 vision. extremely high and potentially toxic doses of drugs are [0012] In one broad embodiment, an ophthalmic com- frequently used. position comprises a therapeutic component, a biocom- [0006] In certain situations, drugs are administered by patible polymeric component, and a solvent component controlled or sustained release technologies to attempt as set out in the present claims. The solvent component to increase their duration of action or reduce the toxicity 55 is effective in maintaining the polymeric component in a of transient high general concentrations. fluid state. For example, the composition may be a liquid. [0007] Some poorly soluble therapeutic agents, such The liquid may be a suspension or a solution, that is, the as corticosteroids, however, are well tolerated locally and therapeutic component may be provided as particles in

2 3 EP 2 216 026 B1 4 suspension, or the therapeutic component may be solu- comes a solid, a semi-solid, or a moldable drug-releasing bilized in a solution. The fluid composition when placed element when placed in the eye. The element is effective in the interior of an eye becomes less fluid and forms a in providing prolonged delivery of a therapeutic agent or solid or semi-solid drug delivery element, which is effec- agents to the eye, for example, to a posterior segment tive in releasing the therapeutic component for extended 5 of the eye, or an anterior segment of the eye. The element periods of time. The composition may be used in a meth- is biodegraded and/or bioeroded as the implant element od to enhance or improve vision of a patient by treating is releasing the therapeutic agent or agents. The com- one or more ophthalmic conditions. ponents of the element are absorbed by the patient’s [0013] In one embodiment, a composition useful for body thereby reducing, and preferably eliminating, the intraocular placement in an eye of a human or animal 10 need to surgically remove the element after the thera- comprises a component present in a ther- peutic agent or agents have been released. apeutically effective amount; a biocompatible polymeric [0018] In general, the present compositions comprise component in an amount effective to delay release of the a therapeutic component, a biocompatible polymeric corticosteroid component into the interior of the eye after component, and an ophthalmically compatible solvent the composition is placed in the eye; and an ophthalmi- 15 component as specified in the claims. The composition cally compatible solvent component in an amount effec- is effective, after being placed into the interior of an eye tive to solubilize the polymeric component, as specified of a patient, to form a delayed release composition, such in the claims. as a drug delivery element, effective in delaying the re- [0014] The composition is effective, after being placed lease of the therapeutic component in the eye. The delay into the interior of the eye, to form a delayed release20 of release is relative to intraocular placement of a sub- composition, such as a drug delivery element, effective stantially identical composition without the polymeric to delay or extend the release of the corticosteriod com- component. ponent in the eye relative to intraocular placement of a [0019] As used herein, a "therapeutic component" re- substantially identical composition without the polymeric fersto a portion of theophthalmic composition ora portion component. 25 of the drug delivery element that is formed in the eye of [0015] Also disclosed are ophthalmic compositions for a patient, which comprises one or more therapeutic use in a method of treating a condition of the interior of agents or substances used to treat a medical ophthalmic the eye of a human or animal, comprising administering, disease or condition of the eye and/or to otherwise ben- e.g. injecting a composition in accordance with the eficially affect a patient’s vision. The therapeutic compo- present intention, into the interior of an eye of a human 30 nent may be provided in a discrete region of drug delivery or animal. Such administering is effective in providing a element, or it may be homogenously distributed through- desired therapeutic effect. The administering step advan- out the drug delivery element. The therapeutic agents of tageously comprises at least one of intravitreal injecting, the therapeutic component are typically ophthalmically subconjunctival injecting, sub-tenon injecting, retrobul- acceptable, and are provided in a form that does not bar injecting, suprachoroidal injecting and the like. The 35 cause adverse reactions when the composition is placed liquid composition forms a solid or semi-solid drug deliv- in an eye. ery element when the liquid composition is placed in the [0020] In one embodiment of the present composi- eye. The administration of the composition into the eye tions, the therapeutic component may comprise one or typically occurs without placing the composition in the more anti-inflammatory agents. For example, the thera- cul-de-sac of the eye. 40 peutic component of the composition may comprise at [0016] These and other aspects and advantages of the least one steroidal anti-inflammatory agent, at least one present invention are apparent in the following detailed non-steroidal anti-inflammatory agent, or combinations description, examples and claims. thereof. The anti-inflammatory agent may be soluble in the ophthalmic composition or it may be insoluble in the DETAILED DESCRIPTION 45 ophthalmic composition. [0021] Examples of poorly soluble therapeutic agents [0017] The presentinvention involves ophthalmiccom- include ophthalmically acceptable therapeutic agents positions, that provide therapy to a patient. In accordance that have a limited solubility in a fluid, such as water, for with the disclosure herein, compositions are disclosed example, at 25°C or at 37°C. For example, the therapeu- that are useful for placement, preferably by injection, into 50 tic agent may have a solubility in water at 25°C or at 37°C the interior of an eye of a human or animal, and preferably of less than 10 mg/ml. a living human or animal. Such compositions are admin- [0022] Examples of steroidal anti-inflammatory agents istered into an eye of a patient in a fluid form, such as a include corticosteroids. In view of the above, the ophthal- liquid. By administering the compositions as a fluid, the mic compositions may comprise a corticosteroid compo- administration may occur without forming an incision in 55 nent. For example, the corticosteroid component may the eye. The liquid composition becomes less fluid when comprise one or more corticosteroids. The corticosteroid placed in the eye, thereby forming an extended release component is provided in a therapeutically effective drug delivery element. For example, the composition be- amount, such as an amount which is effective in providing

3 5 EP 2 216 026 B1 6 a therapeutic effect when the corticosteroid component [0026] As used herein, a "biocompatible polymeric is released from the drug delivery element in the eye. component" refers to a portion of the ophthalmic compo- The corticosteroid component may be soluble or insolu- sition or drug delivery element which comprises one or ble in the composition. The corticosteroid component more biocompatible polymers, such as polymers that do may include without limitation, one or more corticoster- 5 not cause an adverse reaction when placed in an eye, oids selected from the group consisting of that is, the polymers should have substantially no signif- dipropionate, , amcinafel, , bec- icant or undue detrimental effect of the eye structures or lamethasone, , betamethasone dipropi- tissues.. The biocompatible polymer or polymers may be onate, , propion- cross-linked together, or may be associated with each ate, , clocortelone, , , 10 other in a matrix or network of polymers. cortodoxone, difluorosone diacetate, , des- [0027] The biocompatible polymeric component is pro- onide, defluprednate, dihydroxycortisone, desoximeta- vided in an amount in the composition that is effective in sone, , , , diflora- delaying release of the therapeutic component into the sone diacetate, , esters of betamethasone, interior of the eye after the composition is placed in the fluazacort, flucetonide, flucloronide, fludrotisone, fluoro- 15 eye. When the therapeutic component is a corticosteroid cortisone, flumethasone, , , fluoc- component, the biocompatible polymeric component is inolone, acetonide, flucortolone, fluperolo- effectivein delaying therelease ofthe corticosteroid com- ne, , fluroandrenolone acetonide, fluoci- ponent into the interior of the eye after the composition nolone acetonide, flurandrenolide, fluorametholone, flu- is placed in the eye. ticasone propionate, , hydrocortisone bu- 20 [0028] The biocompatible polymeric component of the tyrate, , , lote- ophthalmic composition may be effective, after the com- prendol, , , methylprednisone, position is placed in the eye, to be included in a solid or , furoate, parametha- gelatinous polymer matrix. In certain embodiments, the sone, acetate, , prednisolo- polymer matrix may be porous, for example, micropo- ne, prednidone, triamcinolone acetonide, triamcinolone 25 rous. hexacatonide, and triamcinolone, salts thereof, and mix- [0029] The biocompatible polymeric component may tures thereof. In one embodiment of the present ophthal- comprise a water coagulable polymeric material. For ex- mic composition, the corticosteroid component compris- ample, the polymeric component may comprise one or es, consists essentially of, or consists only of triamcinolo- more thermoplastic polymers or thermosetting, as dis- ne acetonide. 30 closed in U.S. Patent Nos. 5,077,049; 5,324,519; [0023] Other steroids which may be useful in the 5,487,897; 6,395,293; 5,702,716; 5,717,030; 5,780,044; present compositions include, without limitation, gluco- 6,143,314; 6,261,583; 6,461,631; and 6,565,874. The corticoids, androgenic steroids, estrogenic steroids, and polymers may comprise thermoplastic or thermosetting non-estrogenic steroids. polymers. Thermoplastic polymers comprises a biode- [0024] In certain embodiments, the composition com- 35 gradable polymer or copolymer dissolved in a solvent, prises a therapeutically effective amount of the therapeu- such as pharmaceutically acceptable solvents and or- tic agent or agents before the composition is adminis- ganic solvents. tered to an eye. In other embodiments, the composition [0030] In certain compositions, the polymeric compo- may comprise a sub-therapeutically effective amount of nent is selected from the group consisting of polylactides, the therapeutic agent before it is administered to the eye. 40 polyglycolides, polycaprolactones, polyanhydrides, The dissipation of the solvent when the composition is polyamides, polyurethanes, polyesteramides, poly- placed in the interior of the eye may be effective to form orthoesters, polydioxanones, polyacetals, polyketals, a drug delivery element comprising a relatively more con- polycarbonates, polyorthoesters, polyphosphazenes, centrated amount of the therapeutic agent or agents. polyhydroxybutyrates, polyhydroxyvalerates, poly- Thus, the drug delivery element that is formed in the in- 45 alkylene oxalates, polyalkylene succinates, poly(malic terior of the eye may have a therapeutically effective acid), poly(amino acids), poly(methyl vinyl ether), po- amount of a therapeutic,agent or agents although the ly(maleic anhydride), chitin, chitosan, and copolymers, initial composition had a sub-therapeutically effective terpolymers, derivatives thereof and mixtures thereof. amount of the agent or agents. [0031] For example, the biocompatible polymeric com- [0025] The therapeutic component of the compositions 50 ponent of the present compositions may be selected from may be present in an amount in the range of 1 % or less the group consisting of poly lactic acid, poly glycolic acid, to 5% or 10% or 20% or 25% or 30% or more (w/v) of poly lactic acid/glycolic acid (PLGA) and copolymers and the composition. In accordance with the disclosure here- mixtures thereof. in, reduced amounts of the composition may be required [0032] The polymers of the biocompatible polymeric to be placed or injected into the interior of the eye in order 55 component may be crosslinked or blended or used as to provide the same amount or more of the therapeutic copolymers in this invention. agent in the interior of the eye relative to existing com- [0033] As used herein, an "ophthalmically compatible positions, such as Kenalog®-40. solvent component" refers to a portion of the composition

4 7 EP 2 216 026 B1 8 which comprises one or more solvents, including organic tissues in the interior of the eye into which the composi- solvents which, when placed into the interior of the eye, tion is placed than benzyl alcohol. Examples of such pre- has no substantial or undue or significant deterimental servative components include, without limitation, benza- effect on the eye. Of course, such solvents should func- lkonium, chloride, methyl and ethyl parabens, hexetidine, tion in accordance with the present invention, as dis- 5 chlorite components, such as stabilized chlorine dioxide, closed elsewhere herein. metal chlorites and the like, other ophthalmically accept- [0034] The ophthalmically compatible solvent compo- able preservatives and the like and mixtures thereof. The nentof the presentcompositions is provided inan amount concentration of the preservative component, if any, in effective to solubilize the polymeric component, for ex- the present compositions is a concentration effective to ample, before the composition is placed in the interior of 10 preserve the composition, and is often in a range of an eye. Thus, the solvent component is effective in main- 0.00001% to 0.05% or 0.1% (w/v) of the composition. taining the therapeutic component, such as the corticos- [0040] The present compositions may also comprise teroid component, and the polymeric component in a fluid one or more pore-forming agents. The pore-forming form, such as a liquid. The solvent is preferably non-toxic agents are effective in forming pores in the composition and water miscible and enables the biodegradable pol- 15 as the composition becomes less fluid or solidifies. Pores ymer or copolymer to be provided in solution before may be formed in the drug delivery element by incorpo- placement in an eye. rating water-soluble materials into the polymer solution. [0035] In certain embodiments of the present compo- Examples of pore-forming agents include sugars, salts, sitions, the solvent component is effective in dissipating and polymers, such as polymers that are not soluble in or passively or actively being removed from the compo- 20 the biodegradable polymeric component or its carrier sol- sition after the composition is placed into the interior of vent. For example, the pore-forming agents may include the eye. For example, the solvent component is effective one or more of sucrose, dextrose, sodium chloride, so- in dissipating from the liquid composition when the com- dium carbonate, hydroxypropylcellulose, carboxymeth- position is placed in the interior of the eye. The dissipation ylcellulose, polyethylene glycol, and polyvinylpyrol- is effective in permitting the composition to form a less 25 lidone. The pores may have a diameter from 3 mm to 500 fluid drug releasing composition, such as a solid, or semi- mm. For example, the pores may have a diameter from solid drug delivery implant. The drug delivery implant may 10 mm to 250 mm. In certain drug delivery implants, the be formed by a coagulation or other solidification proc- pores have a diameter from 75 mm to 150 mm. ess. [0041] The therapeutic component may also act as a [0036] The solvent component of the present ophthal- 30 pore forming agent for the drug delivery element. For mic compositions may be non-aqueous. Alternatively or example, dissolution of the therapeutic component from in addition, the solvent component may be water-misci- the solid or semi-solid drug delivery element may be ef- ble. In certain compositions, the solvent component may fective in forming pores in the drug delivery element. be organic. The solvent component may also be a liquid [0042] The present intraocular drug delivery implants in the ophthalmic compositions. 35 which are formed in the interior of the eye are effective [0037] The solvent component of the present compo- in releasing the therapeutic component for a prolonged sitions may be selected from the group consisting of period of time. For example, the therapeutic component dimethyl sulfoxide, methyl-2-pyrrolidone, 2-pyrrolidone, may be released for at least about one week. In certain C2 to C 6 alkanols, propylene glycol, acetone, alkyl esters embodiments, the therapeutic component may be re- such as methyl acetate, ethyl acetate, ethyl lactate, alkyl 40 leased for at least six months, such as for nine months ketones such as methyl ethyl ketone, dialkylamides such or more. Typically, a major portion of the therapeutic com- as dimethylformamide, dimethyl sulfoxide, dimethyl sul- ponent will be released within about three years from fone, tetrahydrofuran, cyclic alkyl amides such as capro- when the ophthalmic fluid composition is placed into the lactam, decylmethylsulfoxide, oleic acid, propylene car- interior of the eye. Thus, the present compositions may bonate, aromatic amides such as N,N-diethyl-m-tolua- 45 be effective in providing a prolonged therapeutic effect mide, 1-dodecylazacycloheptan-2-one, and the like. Pre- to one or more intraocular structures of a patient. For ferred solvents according to the invention include N-me- example, the intraocular drug delivery elements that are thyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, formed in situ may provide a prolonged therapeutic effect ethyllactate, propylene carbonate and mixtures thereof. to the retinal pigment epithelium, or other posterior ocular [0038] In certain of the present ophthalmic composi- 50 structure, of an eye. tions, the solvent component comprises dimethyl sulfox- [0043] The present compositions may also include one ide. or more controlled release components, such as one or [0039] The present ophthalmic compositions may also more agents were are effective in controlling the release be provided with or without a preservative component. rate of the therapeutic component from the drug delivery Or, stated differently, the present compositions may in- 55 element. Thus, it is possible to provide pulsatile or con- clude a preservative component, or may include no pre- tinuous or substantially constant release profiles of the servative component. Such preservative components therapeutic component into the interior of the eye. In ad- are preferably more compatible with or friendly to the dition, the release profile may be controlled by the rate

5 9 EP 2 216 026 B1 10 at which pores are formed in the drug delivery element. ergic agonists, cholinergic agonists, carbonic anhydrase For example, a relatively higher rate of pore formation inhibitors, guanylate cyclase activators, cannabinoids, may result in a more rapid rate of release of the thera- endothelin, adenosine agonists, antianagiogenic com- peutic component due to enhanced diffusion effects and pounds, angiostatic compounds, neuroprotectants, and the like. 5 the like and mixtures thereof. The therapeutic component [0044] Advantageously, it has been found that in cer- may also include, analgesics, or antipyretics; antihista- tain situations, the drug delivery element that is formed mines, antibiotics, beta blockers, antineoplastic agents, in the interior of the eye is formed before the polymeric immunosupressive agents, antiviral agents, antioxidants component of the fluid composition adheres to a surface and the like and mixtures thereof. or structure of the eye. For example, the liquid ophthalmic 10 [0049] Non-limiting examples of non-steroidal anti-in- composition may form a drug delivery element in the in- flarnmants, analgesics, and antipyretics, include aspirin, terior of the eye without contacting or being dispensed acetaminophen, ibuprofen, naproxen, diclofenac, etodol- onto a substrate, such as an ocular substrate. For exam- ac, fenoprofen, indomethacin, ketoprofen, oxaprozin, ple, the liquid composition may form an implant when the piroxicam, sulindac, diflunisal, mefenamic acid, deriva- composition is injected into a cavity located in the eye, 15 tives thereof, and the like and mixtures thereof. such as the posterior chamber or the anterior chamber [0050] Examplesof antihistamines include,and are not of the eye. limited to, loradatine, hydroxyzine, diphenhydramine, [0045] In other situations, the drug delivery element chlorpheniramine, brompheniramine, cyproheptadine, may be formed upon contacting an intraocular substrate, terfenadine, clemastine, triprolidine, carbinoxamine, such as a posterior intraocular substrate, of the eye. This 20 diphenylpyraline, phenindamine, azatadine, tripelen- substrate-induced formation of the drug delivery element namine, dexchlorpheniramine, dexbrompheniramine, may be effective in providing enhanced localized delivery methdilazine, and trimprazine doxylamine, pheniramine, of the therapeutic component to the eye of the patient. pyrilamine, chiorcyclizine, thonzylamine, derivatives [0046] In one embodiment, an ophthalmic composition thereof, and the like and mixtures thereof. suitable for forming an in situ solid implant in an animal 25 [0051] Examples of antibiotics include without limita- comprises a liquid formulation of a biodegradable, tion, cefazolin,cephradine, cefaclor, cephapirin, ceftizox- bioerodible, biocompatible thermoplastic polymer that is ime, cefoperazone, cefotetan, cefutoxime, cefotaxime, insoluble in aqueous or body fluid, and a biocompatible cefadroxil, ceftazidime, cephalexin, cephalothin,, cefa- organic solvent that is miscible or dispersible in aqueous mandole, cefoxitin, cefonicid, ceforanide, ceftriaxone, or body fluid and dissolves the thermoplastic polymer. 30 cefidroxil, cephradine, cefuroxime, ampicillin, amoxicil- The composition is capable of coagulating or solidifying lin, cyclacillin, ampicillin, penicillin G, penicillin V potas- or hardening to form a solid or gelatinous microporous sium, piperacillin, oxacillin, bacampicillin, cloxacillin, matrix upon its contact with aqueous or body fluid. The ticarcillin, azlocillin, carbenicillin, methicillin, nafcillin, matrix may be a core surrounded by a an outer layer, the erythromycin, tetracycline, doxycycline, minocycline, az- core containing pores of diameters from 1 to 1000 mi- 35 treonam, chloramphenicol, ciprofloxacin hydrochloride, crons, and the outer layer containing pores of smaller clindamycin, metronidazole, gentamicin, lincomycin, to- diameters than those of the core pores. bramycin, vancomycin, polymyxin B sulfate, colistimeth- [0047] The fluid ophthalmic compositions may be man- ate, colistin, azithromycin, augmentin, sulfamethoxa- ufactured by adding one or more therapeutic agents to zole, trimethoprim, derivatives thereof, and the like and the polymer solution to form a homogenous solution, or 40 mixtures thereof. a suspension, or a dispersion of the agent. The polymer [0052] Examples of beta blockers include without lim- solution is formed by combining the biocompatible poly- itation acebutolol, atenolol, labetalot, metoprolol, pro- meric component with the solvent component. The com- pranolol, derivatives thereof, and the like and mixtures ponents are mixed, blended, or otherwise processed us- thereof. ing conventional techniques. The composition may be 45 [0053] Examples of antineoplastic agents include with- stored for long term use in sterile conditions, such as in out limitation adtiamycin, cyclophosphamide, actinomy- sterile packages. The preparation processing should be cin, bleomycin, duanorubicin, doxombicin, epirubicin, mi- chosen to provide the present compositions in forms tomycin, methotrexate, fluorouracil, carboplatin, carmus- which are useful for placement or injection into the interior tine (BCNU), methyl-CCNU, cisplatin, etoposide, inter- of eyes of humans or animals. The ingredients may be 50 ferons, camptothecin and derivatives thereof, phenester- mixed to disperse the therapeutic component and then ine, taxol and derivatives thereof, taxotere and deriva- may be autoclaved to sterilize the composition. tives thereof, vinblastine, vincristine, tamoxifen, etopo- [0048] Reference is made to ophthalmic compositions side, piposulfan, cyclophosphamide, and flutamide, de- comprising other therapeutic agents instead of or in ad- rivatives thereof, and the like and mixtures thereof. dition to the anti-inflammatory agents disclosed herein. 55 [0054] Examples of immunosuppressive agents in- For example, therapeutic agents may include without lim- clude without limitation cyclosporine, azathioprine, tac- itation retinoids, prostaglandins, tyrosine kinase inhibi- rolimus, derivatives thereof, and the like and mixtures tors, adrenoreceptor agonists or antagonists, dopamin- thereof.

6 11 EP 2 216 026 B1 12

[0055] Examples of antiviral agents include without drome. limitation interferon gamma, zidovudine, amantadine hy- VASCULAR DISEASES/EXUDATIVE DISEASES: drochloride, ribavirin, acyclovir, valciclovir, dideoxycyti- Retinal Arterial Occlusive Disease, Central Retinal dine, derivatives thereof, and the like and mixtures there- Vein Occlusion, Disseminated Intravascular Coag- of. 5 ulopathy, Branch Retinal Vein Occlusion, Hyperten- [0056] Examples of antioxidant agents include without sive Fundus Changes, Ocular Ischemic Syndrome, limitation ascorbate, alpha-tocopherol, mannitol, re- Retinal Arterial Microaneurysms, Coat’s Disease, duced glutathione, various carotenoids, cysteine, uric ac- Parafoveal Telangiectasis, Hemi-Retinal Vein Oc- id, taurine, tyrosine, superoxide dismutase, lutein, zeax- clusion, Papillophlebitis, Central Retinal Artery Oc- anthin, cryotpxanthin, astazanthin, lycopene, N-acetyl- 10 clusion, Branch Retinal Artery Occlusion, Carotid Ar- cysteine, carnosine, gamma-glutamylcysteine, quercitin, tery Disease (CAD), Frosted Branch Angitis, Sickle lactoferrin, dihydrolipoic acid, citrate, Ginkgo Biloba ex- Cell Retinopathy and other Hemoglobinopathies, tract, tea catechins, bilberry extract, vitamins E or esters Angioid Streaks, Familial Exudative Vitreoretinopa- of vitamin E, retinyl palmitate, derivatives thereof, and thy, Eales Disease.. the like and mixtures thereof. 15 TRAUMATIC/SURGICAL: Sympathetic Ophthal- [0057] Other therapeutic agents include without limita- mia, Uveitic Retinal Disease, Retinal Detachment, tion squalamine, carbonic anhydrase inhibitors, alpha Trauma, Laser, PDT, Photocoagulation, Hypoper- agonists, prostamides, prostaglandins, antiparasitics, fusion During Surgery, Radiation Retinopathy, Bone antifungals, derivatives thereof, and the like and mixtures Marrow Transplant Retinopathy. thereof. Further examples include aminosterols other 20 PROLIFERATIVE DISORDERS: Proliferative Vit- than squalamine that have antiangiogenic activity. An- real Retinopathy and Epiretinal Membranes, Prolif- other therapeutic agent may be anecortave acetate, or erative Diabetic Retinopathy. similar agents or compounds which have antiangiogenic INFECTIOUS DISORDERS: Ocular Histoplasmo- properties without substantial undesirable effects. sis, Ocular Toxocariasis, Presumed Ocular Histo- [0058] The therapeutic agent of the present composi- 25 plasmosis Syndrome (POHS), Endophthalmitis, tions may include any and all salts, and prodrugs or pre- Toxoplasmosis, Retinal Diseases Associated with cursors of the therapeutic agents, including those spe- HIV Infection, Choroidal Disease Associated with cifically identified herein. HIV Infection, Uveitic Disease Associated with HIV [0059] The present compositions may be, and are pref- Infection, Viral Retinitis, Acute Retina! Necrosis, Pro- erably, sterile, for example, prior to being used in the eye. 30 gressive Outer Retinal Necrosis, Fungal Retinal Dis- [0060] Such a composition may be marketed in pre- eases, Ocular Syphilis, Ocular Tuberculosis, Diffuse filled syringes to facilitate administration of the composi- Unilateral Subacute Neuroretinitis, Myiasis. tion into the interior of the eye of a patient. GENETIC DISORDERS: Retinitis Pigmentosa, Sys- [0061] The present compositions may be administered temic Disorders with Accosiated Retinal Dystro- to a patient to provide a treatment to a patient. For ex- 35 phies, Congenital Stationary Night Blindness, Cone ample, the composition may be administered to a human Dystrophies, Stargardt’s Disease and Fundus Flavi- or animal patient to treat an ocular condition or disease. maculatus, Best’s Disease, Pattern Dystrophy of the [0062] Among the diseases/conditions which can be Retinal Pigmented Epithelium, X-Linked Retino- treated or addressed in accordance with the present in- schisis, Sorsby’s Fundus Dystrophy, Benign Con- vention include, without limitation, the following: 40 centric Maculopathy, Bietti’s Crystalline Dystrophy, pseudoxanthoma elasticum. MACULOPATHIES/RETINAL DEGENERATION: RETINAL TEARS/HOLES: Retinal Detachment, Non-Exudative Age Related Macular Degeneration Macular Hole, Giant Retinal Tear. (ARMD), Exudative Age Related Macular Degener- TUMORS: Retinal Disease Associated with Tumors, ation (ARMD), wet macular degeneration, Choroidal 45 Congenital Hypertrophy of the RPE, Posterior Uveal Neovascularization, Diabetic Retinopathy, Acute Melanoma, Choroidal Hemangioma, Choroidal Os- Macular Neuroretinopathy, Central Serous Chori- teoma, Choroidal Metastasis, Combined Hamarto- oretinopathy, Cystoid Macular Edema, Diabetic ma of the Retina and Retinal Pigmented Epithelium, Macular Edema. Retinoblastoma, Vasoproliferative Tumors of the UVEITIS/RETINITIS/CHOROIDITIS: Acute Multifo- 50 Ocular Fundus, Retinal Astrocytoma, Intraocular cal Placoid Pigment Epitheliopathy, Behcet’s Dis- Lymphoid Tumors. ease, Birdshot Retinochoroidopathy, Infectious MISCELLANEOUS: Punctate Inner Choroidopathy, (Syphilis, Lyme, Tuberculosis, Toxoplasmosis), In- Acute Posterior Multifocal Placoid Pigment Epitheli- termediate Uveitis (Pars Planitis), Multifocal opathy, Myopic Retinal Degeneration, Acute Retinal Choroiditis, Multiple Evanescent White Dot Syn-55 Pigment Epithelitis and the like. drome (MEWDS), Ocular Sarcoidosis, Posterior Scleritis, Serpignous Choroiditis, Subretinal Fibrosis [0063] The present compositions may be placed into and Uveitis Syndrome, Vogt-Koyanagi-Harada Syn- the interior of an eye using a syringe, a needle, a cannula,

7 13 EP 2 216 026 B1 14 a catheter, a pressure applicator, and the like. Claims [0064] In one embodiment a composition disclosed herein, is administered to a posterior segment of an eye 1. An ophthalmic composition in fluid form useful for of a human or animal patient, and preferably, a living intraocular placement in an eye of a human or animal human or animal. In at least one embodiment, said com- 5 comprising: position is administered without accessing the subretinal space of the eye. For example, a use in a method of a corticosteroid component present in a thera- treating a patient may include injecting the composition peutically effective amount, wherein the corti- directly into the posterior chamber of the eye. In other costeroid component is selected from the group embodiments, a use in a method of treating a patient may 10 consisting of alclometasone dipropionate, am- comprise administering the composition to the patient by cinonide, amcinafel, amcinafide, beclametha- at least one of intravitreal injection, subconjuctival injec- sone, betamethasone, betamethasone dipropi- tion, sub-tenon injections, retrobulbar injection, and su- onate, betamethasone valerate, clobetasone prachoroidal injection. In certain situations, the use may propionate, chloroprednisone, clocortelone, comprise a step of applying an anesthetic to the patient, 15 cortisol, cortisone, cortodoxone, difluorosone such as to the eye of the patient, before the composition diacetate, descinolone, , deflupred- is placed into the interior of the eye. nate, dihydroxycortisone, , [0065] A syringe apparatus including an appropriately dexamethasone, deflazacort, diflorasone, diflo- sized needle, for example, a 27 gauge needle or a 30 rasone diacetate, dichlorisone, esters of betam- gauge needle, can be effectively used to inject the com- 20 ethasone, fluazacort, flucetonide, flucloronide, position with the posterior segment of an eye of a human fludrotisone, fluorocortisone, flumethasone, flu- or animal. The present methods may comprise a single nisolide,fluocinonide, fluocinolone,fluocinolone injection into the posterior segment of an eye or may acetonide, flucortolone, , flupred- involve repeated injections, for example over periods of nisolone, fluroandrenolone acetonide, fluoci- time ranging from about one week or about 1 month or 25 nolone acetonide, flurandrenolide, fluorameth- about 3 months to about 6 months or about 1 year or olone, propionate, hydrocortisone, longer. , hydrocortisone valer- [0066] The compositions of the present invention may ate, hydrocortamate, loteprendol, medrysone, be placed into the eye, for example the vitreous chamber meprednisone, methylprednisone, methylpred- of the eye, by a variety of methods, without making an 30 nisolone, mometasone furoate, parametha- incision in the eye. The method of placement may influ- sone, , prednisone, ence the therapeutic component or drug release kinetics. , prednidone, triamcinolone aceto- The location of the implant may influence the concentra- nide, triamcinolone hexacatonide, and triamci- tion gradients of therapeutic component or drug sur- nolone, salts thereof, and mixtures thereof; rounding the element, and thus influence the release35 a biocompatible polymeric component in an rates (e.g., an element placed closer to the edge of the amount effective to delay release of the corti- vitreous may result in a slower release rate). costeroid component into the interior of the eye [0067] In one embodiment, the liquid ophthalmic com- after the composition is intraocularly placed in position, disclosed herein, is administered to a posterior the eye; and segment of an eye of a human or animal patient, and 40 an ophthalmically compatible solvent compo- preferably, a living human or animal. In at least one em- nent in an amount effective to solubilize the pol- bodiment, the composition is administered without ac- ymeric component, the composition being effec- cessing the subretinal space of the eye. For example, a tive, after being intraocularly placed into the in- use in a method of treating a patient may include placing terior of the eye, to form a solid or semi-solid the composition directly into the posterior chamber of the 45 delayed release composition effective to delay eye. In other embodiments, said use may comprise ad- the release of the corticosteriod component in ministering the present composition to the patient by at the eye relative to intraocular placement of a least one of intravitreal injection, subconjuctival injection, substantially identical composition without the sub-tenon injections, retrobulbar injection, and supra- polymeric component wherein the solvent com- choroidalinjection. Incertain situations, the compositions 50 ponent is selected from the group consisting of are administered to the interior of the eye without placing dimethyl sulfoxide, methyl-2-pyrrolidone, 2-pyr- the composition in the cul-de-sac of the eye. rolidone, C 2 to C 6 alkanols, propylene glycol, ac- [0068] In another aspect of the present invention, the etone, alkyl esters such as methyl acetate, ethyl present compositions are used in the manufacture of a acetate, ethyl lactate, alkyl ketones such as me- medicament that is effective to treat one or more ocular 55 thyl ethyl ketone, dialkylamides such as dimeth- conditions, such as an ocular condition affecting the pos- ylformamide, dimethyl sulfoxide, dimethyl sul- terior segment of an eye of a patient, and including the fone, tetrahydrofuran, cyclic alkyl amides such conditions identified herein. as caprolactam, decylmethylsulfoxide, oleic ac-

8 15 EP 2 216 026 B1 16

id, propylene carbonate, aromatic amides such Patentansprüche as N,N-diethyl-m-toluamide, 1-dodecylazacy- cloheptan 2-one, N-methyl-2-pyrrolidone, and 1. Ophthalmische Zusammensetzung in flüssiger mixtures thereof. Form, die zur Plazierung im Auge eines Menschen 5 oder Tieres nützlich ist, umfassend: 2. The composition of claim 1 wherein the solvent com- ponent is effective to dissipate after the composition eine Corticosteroid-Komponente, die in einer is placed into the eye. therapeutisch wirksamen Menge vorhanden ist, wobei die Corticosteroid-Komponente aus der 3. The composition of claim 1 wherein the corticoster- 10 Gruppe bestehend aus Alclometasondipropio- oid component is soluble in the composition. nat, Amcinonid, Amcinafel, Amcinafid, Becla- methason, Betamethason, Betamethasondi- 4. The composition of claim 1 wherein the corticoster- propionat, Betamethasonvalerat, Clobetason- oid component is insoluble in the composition. propionat, Chlorprednison, Clocortelon, Corti- 15 sol, Cortison, Cortodoxon, Difluorsondiacetat, 5. The composition of claim 1 wherein the corticoster- Descinolon, Desonid, Defluprednat, Dihydroxy- oid component is triamcinolone acetonide. cortison, Desoximetason, Dexamethason, De- flazacort, Diflorason,Diflorasondiacetat, Dichlo- 6. The composition of claim 1 wherein the polymeric rison, Estern von Betamethason, Fluazacort, component is effective, after the composition is20 Flucetonid, Flucloronid, Fludrotison, Fluorcorti- placed in the eye, to be included in a solid or gelat- son, Flumethason, Flunisolid, Fluocinonid, Flu- inous polymer matrix. ocinolon, Fluocinolonacetonid, Flucortolon, Flu- perolon, Fluprednisolon, Fluroandrenolonace- 7. The composition of claim 1 wherein the polymeric tonid, Fluocinolonacetonid, Flurandrenolid, Flu- component comprises a water coagulable polymer 25 orametholon, Fluticasonpropionat, Hydrocorti- material. son, Hydrocortisonbutyrat, Hydrocortisonvale- rat, Hydrocortamat, Loteprendol, Medryson, 8. The composition of claim 7 wherein the polymer ma- Meprednison, Methylprednison, Methylpredni- terial is a thermoplastic polymer material. solon, Mometasonfuroat, Paramethason, Para- 30 methasonacetat, Prednison, Prednisolon, Pred- 9. The composition of Claim 1 wherein the polymeric nidon, Triamcinolonacetonid, Triamcinolonhe- component is selected from the group consisting of xacatonid und Triamcinolon, Salzen davon und polylactides, polyglycolides, polycaprolactones, Mischungen davon ausgewählt ist; polyanhydrides, polyamides, polyurethanes, polyes- eine biokompatible polymere Komponente in ei- teramides, polyorthoesters, polydioxanones, polya- 35 ner Menge, die zur verzögerten Freisetzung der cetals, polyketals, polycarbonates, polyorthoesters, Corticosteroid-Komponente in das Innere des polyphosphazenes, polyhydroxybutyrates, polyhy- Auges wirksam ist, nachdem die Zusammenset- droxyvalerates, polyalkylene oxalates, polyalkylene zung intraokular im Auge platziert worden ist; succinates, poly(malic acid), poly(amino acids), po- und ly(methyl vinyl ether), poly(maleic anhydride), chitin, 40 eine ophthalmisch kompatible Lösungsmittel- chitosan, copolymers thereof, combinations thereof komponente in einer wirksamen Menge, um die and mixtures thereof. Polymerkomponente zu solubilisieren, wobei die Zusammensetzung nach der intraokularen 10. The composition of claim 1 wherein the polymeric Plazierung in das Innere des Auges zur Bildung component is selected from the group consisting of 45 einerfesten oderhalbfesten Zusammensetzung poly lactic acid, poly glycolic acid, poly lactic acid/gly- mit verzögerter Freisetzung wirksam ist, die zur colic acid and mixtures thereof. verzögerten Freisetzung der Corticosteroid- Komponente in das Auge relativ zur intraokula- 11. The composition of claim 1 wherein the solvent com- ren Plazierung einer im wesentlichen identi- ponent comprises dimethyl sulfoxide. 50 schen Zusammensetzung ohne die polymere Komponente wirksam ist, wobei die Lösungs- 12. The composition of any of claims 1 to 11 for use in mittelkomponente aus der Gruppe bestehend a method of treating a condition of the interior of the aus Dimethylsulfoxid, Methyl-2-pyrrolidon, 2-

eye of the human or animal. Pyrrolidon, 2 C-6-Alkanolen, Propylenglykol, 55 Aceton, Alkylestern, wie Methylacetat, Ethyla- cetat, Ethyllactat, Alkylketonen, wie Methyle- thylketon, Dialkylamiden, wie Dimethylforma- mid, Dimethylsulfoxid, Dimethylsulfon, Tetrahy-

9 17 EP 2 216 026 B1 18

drofuran, cyclischen Alkylamiden, wie Capro- 11. Zusammensetzung gemäss Anspruch 1, wobei die lactam, Decylmethylsulfoxid, Ölsäure, Propy- Lösungsmittelkomponente Dimethylsulfoxid um- lencarbonat, aromatischen Amiden, wie N,N- fasst. Diethyl-m-toluamid, 1-Dodecylazacycloheptan- 2-on, N-Methyl-2-pyrrolidon, und Mischungen 5 12. Zusammensetzung gemäss einem der Ansprüche 1 davon ausgewählt ist. bis 11 zur Verwendung in einem Verfahren zur Be- handlung eines Leidens im Inneren des Auges eines 2. Zusammensetzung gemäss Anspruch 1, wobei die Menschen oder Tieres. Lösungsmittelkomponente wirksam ist, sich zu ver- teilen, nachdem die Zusammensetzung in das Auge 10 plaziert worden ist. Revendications

3. Zusammensetzung gemäss Anspruch 1, wobei die 1. Composition ophtalmique sous forme fluide utile Corticosteroid-Komponente in der Zusammenset- pour la mise en place intraoculaire dans un oeil d’un zung löslich ist. 15 humain ou d’un animal comprenant :

4. Zusammensetzung gemäss Anspruch 1, wobei die un composant corticostéroïde présent en une Corticosteroid-Komponente in der Zusammenset- quantité thérapeutiquement efficace, où le com- zung unlöslich ist. posant corticostéroïde est choisi dans le groupe 20 consistant en alclométasone dipropionate, am- 5. Zusammensetzung gemäss Anspruch 1, wobei die cinonide, amcinatel, amcinafide, béclaméthaso- Corticosteroid-Komponente Triamcinolonacetonid ne, bêtaméthasone, bêtaméthasone dipropio- ist. nate, bêtaméthasone valérate, clobetasone propionate, chloroprednisone, clocortelone, 6. Zusammensetzung gemäss Anspruch 1, wobei die 25 cortisol, cortisone, cortodoxone, difluorosone polymereKomponente wirksam ist,nachdem dieZu- diacétate, descinolone, désonide, deflupredna- sammensetzung in das Auge plaziert worden ist, in te, dihydroxycortisone, désoxymétasone, dexa- eine feste oder gelatineartige Polymermatrix aufge- méthasone, deflazacort, diflorasone, difloraso- nommen zu werden. nediacétate, dichlorisone, esters de bêtamétha- 30 sone, fluazacort, flucétonide, flucloronide, flu- 7. Zusammensetzung gemäss Anspruch 1, wobei die drotisone, fluorocortisone, fluméthasone, fluni- polymere Komponente ein Wasser-koagulierbares solide, fluocinonide, fluocinolone, fluocinolone Polymermaterial umfasst. acétonide, flucortolone, fluperolone, flupredni- solone, fluroandrénolone acétonide, fluocinolo- 8. Zusammensetzung gemäss Anspruch 7, wobei das 35 ne acétonide, flurandrénolide, fluoramétholone, Polymermaterial ein thermoplastisches Polymerma- , hydrocortisone, hydro- terial ist. cortisone butyrate, hydrocortisone valérate, hy- drocortamate, loteprendol, médrysone, me- 9. Zusammensetzung gemäss Anspruch 1, wobei die prednisone, méthylprednisone, méthylpredni- polymere Komponente aus der Gruppe bestehend 40 solone, mométasone furoate, paraméthasone, aus Polylactiden, Polyglykoliden, Polycaprolacto- paraméthasone acétate, prednisone, predniso- nen, Polyanhydriden, Polyamiden, Polyurethanen, lone, prednidone, triamcinolone acétonide, Polyesteramiden, Polyorthoestern, Polydioxano- triamcinolone hexacatonide et triamcinolone, nen, Polyacetalen, Polyketalen, Polycarbonaten, leurs sels, leurs dérivés et leurs mélanges ; Polyorthoestern, Polyphosphazenen, Polyhydroxy- 45 un composant polymère biocompatible en une butyraten, Polyhydroxyvaleraten, Polyalkylenoxala- quantité efficace pour retarder la libération du ten, Polyalkylensuccinaten, Poly(äpfelsäure), Po- composant corticostéroïde dans l’intérieur de ly(aminosäuren), Poly(methylvinylether), Poly(ma- l’oeil après que la composition soit placée de leinsäureanhydrid), Chitin, Chitosan, Copolymeren manière intraoculaire dans l’oeil; et davon, Kombinationen davon und Mischungen da- 50 un composant solvant ophtalmiquement com- von ausgewählt ist. patible en une quantité efficace pour solubiliser le composant polymère, la composition étant ef- 10. Zusammensetzung gemäss Anspruch 1, wobei die ficace, après avoir été placée de manière intrao- polymere Komponente aus der Gruppe bestehend culaire dans l’intérieur de l’oeil pour former une aus Polymilchsäure, Polyglykolsäure, Poly-Milch- 55 composition à libération retardée semi ou semi- säure/Glykolsäure und Mischungen davon ausge- solide efficace pour retarder la libération du wählt ist. composant corticostéroïde dans l’oeil par rap- port à la mise en place intraoculaire d’une com-

10 19 EP 2 216 026 B1 20

position sensiblement identique sans le compo- 10. Composition selon la revendication 1, où le compo- sant polymère, où le composant solvant est sant polymère est choisi dans le groupe consistant choisi dans le groupe consistant en le diméthyl- en polyacide lactique, polyacide glycolique, polyaci- sulfoxyde, la méthyl-2-pyrrolidone, la 2-pyrroli- de lactique/acide glycolique et leurs mélanges. done, les C2 à C6 alcanols, le propylèneglycol, 5 l’acétone, les esters d’alkyle comme l’acétate 11. Composition selon la revendication 1, où le compo- de méthyle, l’acétate d’éthyle, le lactate d’éthyle, sant solvant comprend du diméthylsulfoxyde. les alkylcétones comme la méthyléthylcétone, les dialkylamides comme le diméthylformamide, 12. composition selon l’une quelconque des revendica- le diméthylsulfoxyde, la diméthylsulfone, le té- 10 tions 1 à 11, pour son utilisation dans un procédé de trahydrofurane, les alkylamides cycliques com- traitement d’une affection de l’intérieur de l’oeil de me le caprolactame, le décylméthylsulfoxyde, l’humain ou de l’animal. l’acide oléique, le carbonate de propylène, les amides aromatiques comme le N,N-diéthyl-m- toluamide, la 1-dodécylazacycloheptan-2-one, 15 la N-méthyl-2-pyrrolidone, et leurs mélanges.

2. Composition selon la revendication 1, où le compo- sant solvant est efficace pour se dissiper après que la composition soit placée dans l’oeil. 20

3. Composition selon la revendication 1, où le compo- sant corticostéroïde est soluble dans la composition.

4. Composition selon la revendication 1, où le compo- 25 sant corticostéroïde est insoluble dans la composi- tion.

5. Composition selon la revendication 1, où le compo- sant corticostéroïde est le triamcinolone acétonide. 30

6. Composition selon la revendication 1, où le compo- sant polymère est efficace, après que la composition soit placée dans l’oeil, pour être inclus dans une ma- trice polymère solide ou gélatineuse. 35

7. Composition selon la revendication 1, où le compo- sant polymère comprend une matière polymère pou- vant coaguler dans l’eau. 40 8. Composition selon la revendication 7, où la matière polymère est une matière polymère thermoplasti- que.

9. Composition selon la revendication 1, où le compo- 45 sant polymère est choisi dans le groupe consistant en les polylactides, les polyglycolides, les polyca- prolactones, les polyanhydrides, les polyamides, les polyuréthanes, les polyesteramides, les polyor- thoesters, les polydioxanones, les polyacétals, les 50 polycétals, les polycarbonates, les polyorthoesters, les polyphosphazènes, les polyhydroxybutyrates, les polyhydroxyvalérates, les poly(oxalates d’alkylè- ne), les poly(succinates d’alkylène), le poly(acide malique), les poly(aminoacides), le poly(méthylviny- 55 léther), le poly(anhydride maléique), la chitine, le chi- tosane, leurs copolymères, leurs combinaisons et leurs mélanges.

11 EP 2 216 026 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 58709204 P [0001] • US 5717030 A [0009] [0029] • US 5077049 A [0009] [0029] • US 5780044 A [0009] [0029] • US 5324519 A [0009] [0029] • US 6143314 A [0009] [0029] • US 5487897 A [0009] [0029] • US 6261583 B [0009] [0029] • US 6395293 B [0009] [0029] • US 6461631 B [0009] [0029] • US 5702716 A [0009] [0029] • US 6565874 B [0009] [0029]

12