(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 triamcinolone 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 corticosteroids: 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 triamcinolone acetonide 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 steroid 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] Steroids, 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 corticosteroid 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.