(19) TZZ ¥___T (11) EP 2 319 517 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) A61K 47/48 (2006.01) 11.09.2013 Bulletin 2013/37 A61P 27/00 (2006.01) (21) Application number: 10177382.8 (22) Date of filing: 01.06.2006 (54) Use of prodrugs for ocular intravitreous administration Verwendung von Arzneimittelpräkursor für okuläre intravitreale Verabreichung Utilisation des promédicaments pour une administration oculaire intrvitréenne (84) Designated Contracting States: • CHENG LINGYUN ET AL: "Characterization of a AT BE BG CH CY CZ DE DK EE ES FI FR GB GR novel intraocular drug-delivery system using HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI crystalline lipid antiviral prodrugs of ganciclovir SK TR and cyclic cidofovir.", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE. NOV (30) Priority: 01.06.2006 EP 06290902 2004, vol. 45, no. 11, November 2004 (2004-11), pages 4138-4144, XP002409157, ISSN: 0146-0404 (43) Date of publication of application: • CHENG LINGYUN ET AL: "Treatment or 11.05.2011 Bulletin 2011/19 prevention of herpes simplex virus retinitis with intravitreally injectable crystalline 1-O- (62) Document number(s) of the earlier application(s) in hexadecylpropanediol-3-phospho- ganciclovir.", accordance with Art. 76 EPC: INVESTIGATIVE OPHTHALMOLOGY & VISUAL 06290902.3 / 1 864 668 SCIENCE. FEB 2002, vol. 43, no. 2, February 2002 (2002-02), pages 515-521, XP002409158, ISSN: (73) Proprietor: Novagali Pharma S.A. 0146-0404 91000 Evry (FR) • TASKINTUNA I ET AL: "Evaluation of a novel lipid prodrug for intraocular drug delivery: effect of (72) Inventors: acyclovir diphosphate dimyristoylglycerol in a • Rabinovich-Guilatt, Laura rabbit model with herpes simplex virus-1 60920 Kadima (IL) retinitis.", RETINA (PHILADELPHIA, PA.) 1997, • Lambert, Grégory vol. 17, no. 1, 1997, pages 57-64, XP009074806, 92290 Châtenay-Malabry (FR) ISSN: 0275-004X • SCHMIDT LAUGESEN CAROLINE ET AL: (74) Representative: Icosa "Pharmacokinetics of intravitreal 5-fluorouracil 83 avenue Denfert-Rochereau prodrugs in silicone oil: experimental studies in 75014 Paris (FR) pigs.", ACTA OPHTHALMOLOGICA SCANDINAVICA. APR 2005, vol. 83, no. 2, April (56) References cited: 2005 (2005-04), pages 184-190, XP002409159, WO-A-99/11270 WO-A-2004/058272 ISSN: 1395-3907 WO-A1-2005/107727 WO-A2-2005/011741 • YANG C-S ET AL: "AN INTRAVITREAL US-A1- 2006 094 700 SUSTAINED-RELEASE TRIAMCINOLONE AND 5- FLUOROURACIL CODRUG IN THE TREATMENT OF EXPERIMENTAL PROLIFERATIVE VITREORETINOPATHY", ARCHIVES OF OPHTHALMOLOGY, vol. 116, no. 1, January 1998 (1998-01), pages 69-77, XP008001871, ISSN: 0003-9950 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 2 319 517 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 319 517 B1 • MACHA SREERAJ ET AL: "Ocular disposition of • "Intraocular Sustained-Release Fluocinolone for ganciclovirand its monoester prodrugs following Uveitis", OPTOMETRY - JOURNAL OF THE intravitreal administration using microdialysis.", AMERICAN OPTOMETRIC ASSOCIATION, DRUG METABOLISM AND DISPOSITION: THE ELSEVIER, NL, vol. 76, no. 10, 1 October 2005 BIOLOGICAL FATE OF CHEMICALS. JUN 2002, (2005-10-01), page 566, XP025342157, ISSN: vol. 30, no. 6, June 2002 (2002-06), pages 670-675, 1529-1839, DOI: DOI:10.1016/J.OPTM. XP002409160, ISSN: 0090-9556 2005.07.005 [retrieved on 2005-10-01] 2 EP 2 319 517 B1 Description [0001] The present invention relates to the field of the treatment of the ophthalmic diseases, in particular of the intraocular diseases of a human being or an animal, by at least one steroid, and in particular by at least one corticosteroid. 5 [0002] The invention particularly focuses on ophthalmic compositions or devices, preferably ophthalmic emulsions, comprising at least one steroid, preferably a corticosteroid. The invention also relates to the administration of such ophthalmic compositions, and in particular to their intravitreal administration . The invention relates also to the controlled release of therapeutic active agents, in particular of corticosteroids intraocularly, in particular in the posterior segment of the eye. 10 [0003] A posterior ocular condition is a disease which primarily affects a posterior ocular site such as choroid or sclera, vitreous, vitreous chamber, retina, optic nerve, and blood vessels and nerves which vascularize or innervate a posterior ocular site [0004] Steroids are already largely used to treat ophthalmic diseases affecting the posterior chamber of the eye, in particular central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), choroidal macular edema (CME), 15 diabetic macular edema (DME), diabetic macular retinopathy, uveitis, and age related macular degeneration (ARMD). These treatments generally imply their systemic administration, causing known side effects, which are significant, re- garding the ophthalmic diseases to treat. These side effects singularly decrease the interest of the treatment of these ophthalmic diseases by systemic administration of steroids. [0005] Other modes of administration, topic, suprachoroidal, subconjunctival, retrobulbar, and intravitreal were 20 searched. Regarding topical application, dexamethasone penetration into the vitreous humour after repeated topical application is negligible (less than 2 ng/ml after 1 drop of 0.1% dexamethasone phosphate drops hourly for 10 hours) (Weijtens, Ophthalmology, 2002). In comparison, serum and vitreous levels of 60 and 5 ng/ml respectively are observed following a single oral administration of 7.5 mg dexamethasone (Weijtens, Am J Ophthalmol, 1998). [0006] It was also shown that the subretinals concentrations of dexamethasone after subconjunctival or peribulbar 25 injection were 120 and 13-fold more elevated than after oral administration (Weijtens et al Ophthalmology, 2000). The local intraocular administration is thus highly preferred. [0007] However, the injection of steroids in significant amounts in the eye, implies a sudden and massive increase in their concentration in all ocular structures, and can also lead to undesirable and consequent local ocular side effects, in particular a significant increase in the intraocular pressure possibly leading to the development of glaucoma, or to the 30 appearance or the development of cataracts. [0008] It was notably noticed that the presence of corticosteroids in the anterior segment of the eye was in particular related to the appearance of these side effects, and was thus undesirable. [0009] The need to administrate the corticosteroids the most locally possible, therefore selectively in the disease site, in effective quantities, was then clear. 35 [0010] The effectiveness of the treatment is in particular related to the presence of the active compound and hence to thehalf life of thedrug. A known corticosteroid,the dexamethasone has ahalf life of3.5 hours when injected intraocularl y (Kwak, Arch Ophthalmol, 1992). Thus, the injections must be repeated to maintain a therapeutic effect. [0011] However, repeated injections are difficult to cope with for the patients suffering of long or chronic diseases. Moreover, repeated injections are likely to increase harmful side effects such as retina detachment, endophtalmy, and 40 cataracts. [0012] In view of the additional side effects caused by repeated injections, intraocular implants of steroids have been developed: RETISERT™ (fluocinolone acetonide intravitreal implant, Bausch & Lomb) 0.59 mg is a sterile implant designed to 45 release fluocinolone acetonide locally to the posterior segment of the eye. RETISERT™ was recently approved by the FDA and is indicated for the treatment of chronic noninfectious uveitis affecting the posterior segment of the eye. However, clinical trials of this implant systematically results in a raise of the intraocular pressure (IOP) and cataracts as main adverse effects. Holekamp et al. found that after long- term follow-up, high-dose intraocular fluo- cinolone acetonide results in significant complications rate, with 100% of the eyes developing elevated IOP and 50 30% showing nonischemic central retinal vein occlusion. These complications required the implant removal in almost 60% of the eyes (Am J Ophthalmol 2005). Implantation of 0.59 mg or 2.1 mg fluocinolone acetonide in noninfectious posterior uveitis patients results in a 5- fold augmentation of the need of IOP lowering agents (Jaffe, Ophthalmology, 2005). In a randomized clinical trial of 0.59 mg fluocinolone acetonide intravitreal implant in patients with diabetic macular edema, the most common adverse included serious cataract progression (43.1%) and a serious intraocular 55 pressure rise (8.6%) (Pearson, ISOPT communication, Berlin, 2006). Based on clinical trials with RETISERT, within 34weeks post- implantation,approximately 60% ofpatients will requireIOP lowering medications to control intraocular pressure. Within an average postimplantation period of approximately 2 years, approximately 32% of patients are expectedto require filtering proceduresto control intraocular pressure.Moreover, within an average post- implantation 3 EP 2 319 517 B1 period of approximately 2 years, nearly all phakic