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Home , Fluazacort, Fluocinolone, Paramethasone acetate

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(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 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 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]

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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 , and in particular by at least one . 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 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] 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, 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™ ( 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

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period of approximately 2 years, nearly all phakic eyes are expected to develop cataracts and require cataract surgery (source Bausch & Lomb).

[0013] Posurdex is another intraocular device being developed by Allergan containing 700 micrograms of dexameth- 5 asone which are released during the first month post implantation. Its efficacy has been evaluated among others in cases of persistant macular edema (Williams, ISOPT communication, 2006) and for anti-inflammatory effects after cataract surgery (Tan, Ophthalmology, 2004). However, a safety and efficacy clinical study of 700 micrograms dexam- ethasone implant for the treatment of macular edema showed significant increases in IOP (to≥ 25 mm Hg) in 15% of patients (Williams, ISOPT communication, Berlin, 2006). 10 [0014] The off-label use of (Kenalog 40™, Bristol Myers Squib) intraocularly results indirectly in the slow-release of the drug, as the insoluble steroid precipitates following injection in the vitreous cavity and is only gradually solubilized. Therefore, it can be considered as well as a sustained release steroidal formulation. However, this formulation which was not originally developed for intraocular use can cause serious complications such as infectious endophthalmitis and sterile endophthalmitis, retinal toxicity and crystalline retinal deposits. Nevertheless, it has been 15 used intravitreally to treat ocular inflammation as well as macular edema due to numerous causes. In addition, retro- spective analysis of subtenon triamcinolone acetonide cases also reveals intraocular pressure rise in 21% of the patients (Bui Quoc, J Fr Ophtalmol, 2002). [0015] Other steroid-containing devices being developed in research are triamcinolone acetonide/polycaprolactone implants (Beeley, J Biomed Mater Res A, 2005), triamcinolone/ polyvinyl alcohol implants (Ciulla, Br J Ophthalmol, 2003), 20 polymeric implants (Kato, IOVS, 2004 and Okabe, IOVS, 2003) steroid- biodegradable polymeric implants (WO 2005/107727), and others. [0016] This analysis of the intraocular corticosteroid-containing implants shows that the long lasting presence of cor- ticosteroid in the posterior segment of the eye causes undesirable side effects, eventhough the therapeutic effect is undoubtful. 25 [0017] There is need therefore for an ophthalmic device or composition which will succeed in delivering the active compound not only for a sustained period in the eye, but more specifically in the disease site. [0018] From this assumption, the inventors searched alternative therapeutic pathways for an efficient administration of corticosteroids inside the eye : this invention relates to the use of prodrugs of steroids, especially corticosteroids, for the preparation of a medicament or an ophthalmic composition intended for the treatment of an ocular condition or 30 disease of a human being or an animal, said medicament or ophthalmic composition being administered by invasive means, preferably by intraocular injection, more preferably by intravitreal injection, for in- situ sustained release of ther- apeutic effective agents. [0019] Studies relative to intraocular administration of prodrugs, especially prodrugs of antivirals, have been reported in the art, as in the following references: 35 - Cheng Lingyun et al., "Characterization of a novel intraocular drug-delivery system using crystalline lipid antiviral prodrugs of ganciclovir and cyclic cidofovir", IOVS, 2004, 45(11), 4138-4144; - Cheng Lingyuneet al.,"Treatment or prevention of herpes simplexvirus retinitis with intravitreally injectablecrystalline 1- 0- hexadecylgrapadeniol- 3- phospho- ganciclovir", IOVS, 2002, 43 (2) , 515- 521; 40 - Taskintuna I et al., "Evaluation of a novel lipid prodrug for intraocular drug delivery: effect of acyclovir diphosphate dimyristoylglycerol in a rabbit model with herpes simplex virus- 1 retinitis", Retina, 1997, 17, 57-64; - Schmidt Laugesen Caroline et al., "Pharmacokinetics of intravitreal 5-fluorouracil prodrugs in silicone oil: experi- mental studies in pigs", Acta Ophthalm. Scandinavia, 2005, 83 (2), 184-190; - Yang et al., "An intravitreal sustained- release triamcinolone and 5- fluororacil codrug in the treatment of experimental 45 proliferative vitreoretinopathy", Archives of Ophthalmol., 1998, 116 (1), 69-77; - Macha Sreeraj et al., "Ocular disposition of ganciclovir and its monoester prodrugs following intravitreal administration using microdialysis", Drug metabolism and disposition: the biological fate of chemicals, 2002, 30(6), 670-675; - US 2006/094700; - WO 2004/058272; 50 - WO 2005/011741.

[0020] Topical administration of the prodrug dexamethasone palmitate was reported in WO 99/11270. In this patent application, repeated instillations at few hours of interval were needed to observe an effect on experimental uveitis. [0021] The inventors observed that intravitreal, injections of a corticosteroid prodrug, the dexamethasone palmitate, 55 resulted in the in-situ release of dexamethasone. [0022] Without wanting to being linked by this theory, the Inventors suppose that there might be a selective uptake of the steroid prodrug, preferably a lipophilic ester of a steroid, by the ocular inflammatory cells (macrophages). The increased macrophage activity at the inflamed sites may result in a targeted cleavage of the active moiety only in the

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disease location, with no unspecific release. Therefore, fewer side effects occasioned by the therapeutic agent are expected to be observed. The drug would be release at the very location of the disease, resulting in a decrease of unwanted adverse effects in other ocular structures where the prodrug is not hydrolyzed. The invention also allows to maintain the desired effect in the ocular condition for an extended period of time during which an amount of the prodrug 5 is present at the ocular site such that it allows the release of an effective amount of the active drug for an extended period of time, which is preferably at least one month By prodrug in the invention is meant a lipophilic long-chain prodrug ester of steroid, preferably of corticosteroid, said ester group comprising an alkyl group of more than 10 carbons preferentially of more than 14 carbons, even more preferentially of 16 carbons. According to a preferred embodiment of the invention, the prodrug does not have any direct 10 therapeutic and/or physiologic effect, and is therefore called "inactive", whereas the drug released by hydrolysis of the prodrug does have a physiological therapeutic effect. [0023] The invention is directed to the use of a composition comprising at least one prodrug of a steroid, preferably of a corticosteroid, for the preparation of an ophthalmic composition intended for the treatment of an ocular condition or disease of a human being or an animal. 15 [0024] The composition according to the invention comprises at least one prodrug of corticosteroid, which is preferably selected from: dipropionate, , amcinafel, , beclamethasone, betamethasone, bet- amethasone dipropionate, , propionate, , clocortelone, , , cortodoxone, difluorosone diacetate, , , defluprednate, dihydroxycortisone, desoximeta- sone, dexamethasone, , , , , esters of betamethasone, , 20 flucetonide, flucloronide, fludrotisone, fluorocortisone, flumethasone, , , fluocinolone, fluocinolone acetonide, flucortolone, , , fluroandrenolone acetonide, fluocinolone acetonide, flurandreno- lide, fluorametholone, propionate, , , , hydro- cortamate, loteprendol, , , methylprednisone, , furoate, , paramethasone , , , prednidone, triamcinolone acetonide, triamcinolone 25 hexacatonide, and triamcinolone, salts, derivatives, and a mixture thereof. [0025] More preferably, the corticosteroid is selected from: cortisone, dexamethasone, fluocinolone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone. [0026] In the most preferred embodiment of the invention, the composition comprises a prodrug of dexamethasone, more preferably dexamethasone palmitate. 30 [0027] Preferably, the prodrug is comprised in the emulsion in an amount of about 0.01% to about 10% w/w of the composition. According to an embodiment, the prodrug is comprised in the amount of about 0.5% to about 3% w/w of the composition. In a preferred embodiment, the prodrug is comprised in a amount of about 2% w/w of the composition. In another preferred embodiment of the present invention, the prodrug is comprised in an amount of about 1% w/w of the composition. 35 [0028] According to the invention, the composition of the invention includes at least one steroid prodrug dissolved in a ophthalmologically acceptable oil. [0029] According to another embodiment of the invention, the composition of the invention includes at least one steroid prodrug dissolved in a physiologically acceptable oil which is emulsified into a oil- in-water emulsion by different techniques such as high shear and high pressure homogenization with suitable emulsifiers; final preparation can be sterilized by 40 filtration or by autoclave. [0030] According to an embodiment of the invention, the composition comprises at least one prodrug as above- defined, in combination with any ophtalmologically acceptable excipient or carrier. The carrier may be selected from an ophtal- mologically acceptable oil, or oil-in-water emulsion or water-in-oil emulsion or any other suitable carrier about 20, at least about 30 or at least about 40 weight percent of the composition/emulsion, preferably 10 % of the emulsion. 45 [0031] Excipient characteristics that are considered include, but are not limited to, the biocompatibility and biodegrad- ability at the site of implantation, compatibility with the prodrug of interest, and processing temperatures. [0032] When the excipient or the carrier is an emulsion, according to an embodiment of the invention, the oil phase comprises at least about 1, at least about 5, at least about 10, at least about 20, at least about 30 or at least about 40 weight percent of the composition. In a preferred embodiment, the oil represents 10 weight percent of the composition. 50 [0033] In the meaning of this invention the term "about" means approximately or nearly and in the context of a numerical value or range set forth herein means .+/-.10% of the numerical value or range recited or claimed. [0034] According to an embodiment of the invention, the composition of the invention is administered through one intraocular injection, more preferably through one intravitreal injection. [0035] According to another embodiment of the invention, the composition of the invention is administered through 55 the placement of an intraocular implant containing or combined with the composition of the invention. [0036] According to another embodiment of the invention, the composition further comprises an active agent selected from cyclosporine, anti-VEGF, and/or an antibiotic. [0037] According to another embodiment of the invention, wherein the composition comprises dexamethasone palmi-

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tate and at least one active agent selected from the group consisting of cyclosporine, anti- VEGF, and an antibiotic. [0038] The invention also relates to a method of treatment of a human or animal ophthalmic condition or disease comprising the intraocular administration of the composition of the invention. [0039] According to an embodiment, the method of the invention includes the administration of a steroid prodrug into 5 an ocular site of a patient suffering from an ocular condition or disease. The prodrug can be administered alone or in an ophtalmologically carrier suitable for intraocular administration. The carrier may be an oil, phospholipid vesicles or oil-in-water emulsion, or any other suitable carrier. [0040] The administrated prodrug will gradually release through its hydrolysis by endogenous enzymes in situ, to generate therapeutic levels of the active drug. This results in the improvement of ocular conditions by the action of the 10 active drug in the very site of inflammation due to the ocular condition or disease. [0041] According to an embodiment of the invention, the frequency of administration of the composition of the invention trough injection is once a month, preferably once every two months, more preferably once every six months. It is an advantage of this invention to provide a less frequent need for repeated administration. [0042] According to an embodiment of the invention, the amount of the composition of the invention administered is 15 such that, after one month, the molar ratio drug/prodrug in the target tissue, preferably in choroid or in retina, is equal or less than 1, preferentially of 0.5, more preferentially of 0.1. [0043] The improvement of the ocular condition obtained by a method within the scope of the present invention can be determined by observing: an improved visual acuity, an improved visual contrast sensitivity, a decreased retinal or choroidal blood vessel leakage, a decreased retinal or macular thickness, or a reduced number of cells in the aqueous 20 or vitreous humor or by determining a reduced flare. [0044] According to an embodiment of the invention, the administration of the composition of the invention is invasive. More preferably, the composition of the invention is administered through an implant or through intraocular, preferably intravitreal injection. [0045] The compositions of the invention are useful for the treatment of conditions or diseases affecting the interior 25 of the eye, preferably of the back of the eye. These compositions are especially useful for the treatment of the following conditions or diseases: uveitis, macular edema, macular degeneration, retinal detachment, ocular tumors, bacterial, fungal but viral infections, multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic opthalmia, Vogt Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion, and vascular occlusion. [0046] In a preferred embodiment, the composition of the invention is within an implantable device and then used for 30 the treatment of uveitis, macular edema, vascular occlusive conditions, proliferative vitreoretinopathy (PVR), and various other retinopathies. [0047] The invention is further illustrated by the following example, which should not be considered in any way as a limitation the scope of the protection.

35 Example

1. Analytical methods for simultaneous determination of dexamethasone and dexamethasone palmitate in ocular tissues

[0048] A liquid chromatographic-mass spectrometric method for the simultaneous determination of dexamethasone 40 and dexamethasone palmitate in ocular tissues was developed. Analytes and internal standard (roxithromycine) were extracted from the tissues using acetonitrile and separated by reverse phase liquid chromatography with a C8 column and a gradient mobile phase. The compounds were detected by mass spectrometric detection (atmospheric pressure ionization) with selected ion monitoring (SIM) (393.0 for dexamethasone and 631.5 for dexamethasone palmitate). The method was selective for both compounds and the limits of quantification were 32.7 ng/g of retina and 71.6 ng/g choroid. 45 The unweighed linear model was applied.

2. Intraocular pharmacokinetics of Dexamethasone Palmitate and Dexamethasone following intravitreal administration

Methods: 50 [0049] One single unilateral intravitreal injection of a 0.8% (8 mg/ml) dexamethasone palmitate emulsion to rabbits (100 mL). Sacrifice at days 1, 7, 14, 21, 28 or 60 days (n=4/timepoint). Dexamethasone (D) and dexamethasone palmitate (DP) in tissues were determined. All concentrations are expressed in nmol/g tissue

55 Results:

[0050]

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Day 1 Day 7 Day 14 Day 28 Day 60 Mean sd Mean sd Mean sd Mean sd Mean sd 5 DP 106 74 93 38 136 19 146 109 55 37 (nmol/g) D 721146441 22 Retina (nmol/g)

10 D/DP 0.660 0.118 0.044 0.027 0.036 DP 191 69 103 77 22 11 143 61 52 22 (nmol/g) D 1261279 4 4 1 32 15 Choroid (nmol/g) D/DP 0.063 0.117 0.409 0.028 0.057 DP ND ND ND ND ND ND ND ND 0 0 (nmol/g) 20 Aqueous D ND ND ND ND ND ND ND ND 0 1 humor (nmol/g) ND: Not determined.

25 Following IVT injection of a dose of 800 mg of prodrug, dexamethasone of more than 800 ng/g (higher than therapeutic levels) were maintained for at least 2 months in the target tissues. Moreover, considerable amounts of the prodrug dexapalmitate remained in both retina and choroid, indicating an even more long- lasting release. At the same time, the amounts of steroid in the aqueous humor was undetectable, suggesting fewer (if any) side effects in adjacent sites. This last fact was corroborated by IOP measurements, which were normal 2 months following the 30 injection.

Claims

35 1. Composition comprising at least one prodrug of a steroid, for use in a method for the treatment of an ocular condition or disease of a human being or an animal, said composition being administered by intravitreal injection, wherein said prodrug is a lipophilic long-chain ester of steroid, said ester group comprising an alkyl group, of more than 10 carbons wherein said prodrug is dissolved in an ophthalmologically acceptably oil and wherein said steroid selected from the group consisting of alclometasone dipropionate, amcinonide, amcinafel, amcinafide, beclomethasone, 40 betamethasone, betamthasone dipropionate, batamethasone valerate, clobetasone propionate, chloroprednisone, clocortelone, cortisol, cortisone, cortodoxone, difluorosone diacetate, descinolone, desonide, , dihy- droxycortisone, , dexamethasone, deflazacort, diflorasone, diflorasone diacetate, dichlorisone, es- ters of betamethasone, fluazacort, flucetonide, flucloronide, fludrotisone, fluorocortisone, flumethasone, flunisolide, fluocinonide, fluocinolone, fluocinolone acetonide, flucortolone, fluperolone, fluprednisolone, fluroandrenolone ac- 45 etonide, fluocinolone acetonide, flurandrenolide, , , hydrocortisone, hydro- cortisone butyrate, hydrocortisone valerate, , , medrysone, meprednisone, methylpred- nisone, methylprednisolone, mometasone furoate, paramethasone, , prednisone, pred- nisolone, prédnidone, triamcinolone acetonide, triamcinolone hexacetonide, and triamcinolone, salts, and a mixture thereof. 50 2. Composition according to claim 1, wherein said ester group comprises an alkyl group of more than 14 carbons, even more preferentially of 16 carbons.

3. Composition according to any one of claim 1 or 2 wherein the steroid is selected from the group consisting of 55 cortisone, dexamethasone, fluocinolone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triam- cinolone.

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4. Composition according to claim 3, wherein the prodrug is dexamethasone palmitate.

5. Composition according to any one of claim 1 to 4, wherein the prodrug is comprised in the composition in an amount of 0,01% to 10% w/w, preferably of 0.5% to 3% w/w, more preferably 2% w/w of 1% w/w of the composition. 5 6. Composition according to any one of claim 1 to 5, wherein said prodrug is in combination with any ophthalmically acceptable excipient or carrier.

7. Composition according to claim 6, wherein the carrier is selected from an ophthalmic acceptable oil, or oil- in-water 10 emulsion or water-in-oil emulsion or any other suitable carrier.

8. Composition according to claim 7, wherein the oil phase comprises at least 1, at least 5, at least 10, at least 20, at least 30 or at least 40 weight percent of the composition/ emulsion, preferably 10 % of the emulsion.

15 9. Composition according to any one of claim 1 to 8, wherein the administrated prodrug will gradually release through its hydrolysis by endogenous enzymes in situ, to generate therapeutic levels of the active drug.

10. Composition according to any one of claim 1 to 9, wherein said prodrug is administered through one intraocular injection every one, two or six months. 20 11. Composition according to any one of claim 1 to 10, wherein the amount of the composition of the invention admin- istered is such that, after one month, the molar ratio drug/ prodrug in the retina or in the choroid is equal or less than 1, preferentially of 0.5, more preferentially of 0.1.

25 12. Composition according to any one of claim 1 to 11, wherein the disease is a condition or disease of the interior of the eye, preferably of the back of the eye.

13. Composition according to claim 12, characterized in that said diseases are:

30 uveitis, macular edema, macular degeneration, retinal detachment, ocular tumors, bacterial, fungal but viral infections, multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic opthol- mia, Vogt Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion, and vascular occlusion.

14. Composition according to any one of claim1 to 13, wherein the composition further comprises an active agent 35 selected from cyclosporine, anti-VEGF, and/or an antibiotic.

15. Composition according to any one of claim 1 to 14, wherein the composition comprises dexamethasone palmitate and at least one active agent selected from the group consisting of cyclosporine, anti- VEGF, and an antibiotic.

40 Patentansprüche

1. Zusammensetzung, umfassend mindestens einen Arzneimittelpräkursor eines Steroids zur Verwendung in einem Verfahren zur Behandlung eines Augenleidens oder einer Augenkrankheit eines Menschen oder eines Tiers, wobei 45 die besagte Zusammensetzung durch intravitreale Injektion verabreicht wird, wobei der besagte Arzneimittelprä- kursor eine lipophile langkettige Ester von Steroid ist, die besagte Estergruppe eine Alkylgruppe mit mehr als 10 Kohlenstoffatome umfassend, wobei der besagte Zusammensetzung in einem ophthalmischem verträglichem Öl aufgelöst ist, und wobei gesagtes Steroid ausgewählt ist aus der Gruppe bestehend aus Alclometasondipropionat, Amcinonid, Amcinafel, Amcinafide, Beclomethason, Betamethason, Betamethasondipropionat, Betamethasonva- 50 lerat, Clobetasonpropionat, Chloroprednison, Clocortelon, Cortisol, Cortison, Cortodoxon, Difluorosondiacetat, De- scinolon, Desonid, Difluprednat, Dihydroxycortison, Desoximetason, Dexamethason, Deflazacort, Diflorason, Diflo- rasondiacetat, Dichlorison, Esters von Betamethason, Fluazacort, Flucetonid, Flucloronid, Fludrotison, Fluorcorti- son, Flumethason, Flunisolid, Fluocinonid, Fluocinolon, Fluocinolonacetonid, Flucortolon, Fluperolon, Flupredniso- lon, Fluroandrenolonacetonid, Fluocinolonacetonid, Flurandrenolid, Fluorometholon, Fluticasonpropionat, Hydro- 55 cortison, Hydrocortisonbutyrat, Hydrocortisonvalerat, Hydrocortamat, Loteprednol, Medryson, Meprednison, Me- thylprednison,Methylprednisolon, Mometasonfuroat, Paramethason, Paramethasonacetat, Prednison, Prednisolon, Prednidon, Triamcinolonacetonid, Triamcinolonhexacetonid und Triamcinolon, Salzen davon und einem Gemisch davon.

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2. Zusammensetzung nach Anspruch 1, wobei die besagte Estergruppe eine Alkylgruppe umfassend mit mehr als 14 Kohlenstoffatomen, besonders bevorzugt von 16 Kohlenstoffatomen,.

3. Zusammensetzung nach einem der Ansprüche 1 bis 2, wobei das Steroid aus der Gruppe bestehend aus Cortison, 5 Dexamethason, Fluocinolon, Hydrocortison, Methylprednisolon, Prednisolon, Prednison und Triamcinolon ausge- wählt ist.

4. Zusammensetzung nach Anspruch 3, wobei der Arzneimittelpräkursor Dexamethasonpalmitat ist.

10 5. Zusammensetzung nach einem der Ansprüche 1 bis 4, wobei der Arzneimittelpräkursor in der Zusammensetzung in einer Menge von 0,01% bis 10 Gew.%, vorzugweise 0,5% bis 3 Gew.%, besonders bevorzugt 2 Gew.% oder 1 Gew.% der Zusammensetzung vorhanden ist.

6. Zusammensetzung nach einem der Ansprüche 1 bis 5, wobei der besagte Arzneimittelpräkursor in Kombination mit 15 jedem ophthalmisch verträglichen Füllstoff oder Träger vorliegt.

7. Zusammensetzung nach Anspruch 6, wobei der Träger aus einem ophthalmisch verträglichen Öl, oder einer Öl- in- Wasser-Emulsion oder Wasser-in-Öl-Emulsion oder jedem anderen geeigneten Träger ausgewählt ist.

20 8. Zusammensetzung nach Anspruch 7, wobei die Ölphase mindestens 1, mindestens 5, mindestens 10, mindestens 20, mindestens 30 oder mindestens 40 Gew.% der Zusammensetzung / Emulsion darstellt, vorzugweise 10 % der Emulsion.

9. Zusammensetzung nach einem der Ansprüche 1 bis 8, wobei der verabreichte Arzneimittelpräkursor schrittweise 25 durch seine Hydrolyse durch endogene Enzyme in situ freisetzt wird, um therapeutische Niveaus des aktiven Arz- neimittels zu erzeugen.

10. Zusammensetzung nach einem der Ansprüche 1 bis 9, wobei der besagte Arzneimittelpräkursor durch eine intra- okulare Injektion jeden Monat, alle zwei oder sechs Monate verabreicht wird. 30 11. Zusammensetzung nach einem der Ansprüche 1 bis 10, wobei die verabreichte Menge der Zusammensetzung der Erfindung derart ist, dass nach einem Monat das Molverhältnis zwischen Arzneimittel und Arzneimittelpräkursor in der Retina oder in der Choroidea gleich oder weniger als 1 ist, vorzugweise 0,5 und besonders bevorzugt 0,1.

35 12. Zusammensetzung nach einem der Ansprüche 1 bis 11, wobei die Krankheit ein Leiden oder eine Krankheit des Inneren des Auges ist, vorzugweise der Rückseite des Auges.

13. Zusammensetzung nach Anspruch 12, dadurch gekennzeichnet, dass die besagten Krankheiten die Folgenden sind: Uveitis, Makulaödem, Makuladegeneration, Retinaablösung, Augentumore, Bakterien-, Pilz- aber keine Virus- 40 infektionen, multifokale Choroiditis, diabetische Retinopatie, proliferative Vitreoretinopathie (PVR), sympathetische Ophthalmie, Vogt-Koyanagi-Harada (VKH)-Syndrom, Histoplasmosis, uveale Diffusion und Gefäßverschluss.

14. Zusammensetzung nach einem der Ansprüche 1 bis 13, wobeidie Zusammensetzung weitereinen Wirkstoff umfasst, ausgewählt aus Cyclosporin, Anti-VEGF und/oder einem Antibiotikum. 45 15. Zusammensetzung nach einem der Ansprüche 1 bis 14, wobei die Zusammensetzung Dexamethasonpalmitat und mindestens einen Wirkstoff aus der Gruppe bestehend aus Cyclosporin, anti- VEGF und einem Antibiotikum umfasst.

50 Revendications

1. Composition comprenant au moins un promédicament d’un stéroïde, pour une utilisation dans un procédé de trai- tement d’une affection ou d’une maladie oculaire d’un être humain ou d’un animal, ladite composition étant admi- nistrée par injection intravitréenne, dans laquelle ledit promédicament est un ester à longue chaîne lipophile de 55 stéroïde, ledit groupe ester comprenant un groupe alkyle de plus de 10 carbones, dans laquelle ledit promédicament est dissous dans une huile ophtalmologiquement acceptable et dans laquelle ledit stéroïde est choisi dans le groupe constitué par dipropionate d’alclométasone, amcinonide, amcinafel, amcinafide, béclométhasone, bétaméthasone, dipropionate de bétaméthasone, valérate de bétaméthasone, propionate de clobétasone, chloroprednisone, clo-

9 EP 2 319 517 B1

cortélone, Cortisol, cortisone, cortodoxone, diacétate de difluorosone, descinolone, désonide, difluprednate, dihy- droxycortisone, désoximétasone, dexaméthasone, déflazacort, diflorasone, diacétate de diflorasone, dichlorisone, esters de bétaméthasone, fluazacort, flucétonide, flucloronide, fludrotisone, fluorocortisone, fluméthasone, fluniso- lide, fluocinonide, fluocinolone, fluocinolone acétonide, flucortolone, flupérolone, fluprednisolone, fluroandrénolone 5 acétonide, fluocinolone acétonide, flurandrénolide, fluorométholone, propionate de fluticasone, hydrocortisone, bu- tyrate d’hydrocortisone, valérate d’hydrocortisone, hydrocortamate, loteprednol, médrysone, méprednisone, mé- thylprednisone, méthylprednisolone, furoate de mométasone, paraméthasone, acétate de paraméthasone, predni- sone, prednisolone, prednidone, triamcinolone acétonide, triamcinolone hexacétonide, et triamcinolone, leurs sels, et leurs mélanges. 10 2. Composition selon la revendication 1, dans laquelle ledit groupe ester comprend un groupe alkyle de plus de 14 carbones, de manière davantage préférée de 16 carbones.

3. Composition selon l’une quelconque des revendications 1 à 2, dans laquelle le stéroïde est sélectionné parmi le 15 groupe constitué par la cortisone, dexaméthasone, fluocinolone, hydrocortisone, méthylprednisolone, prednisolone, prednisone, et triamcinolone.

4. Composition selon la revendication 3, dans laquelle le promédicament est la dexaméthasone palmitate.

20 5. Composition selon l’une quelconque des revendications 1 à 4, dans laquelle le promédicament est compris dans la composition dans une quantité de 0,01 % à 10 % p/p, de préférence de 0,5 % à 3 % p/p, de manière davantage préférée de 2 % p/p ou de 1 % p/p de la composition.

6. Composition selon l’une quelconque des revendications 1 à 5, dans laquelle ledit promédicament est en combinaison 25 avec n’importe quel excipient ou support acceptable sur le plan ophtalmique.

7. Composition selon la revendication 6, dans laquelle le support est choisi parmi une huile ophtalmique acceptable, ou une émulsion huile-dans-eau ou une émulsion eau-dans-huile ou n’importe quel autre support approprié.

30 8. Composition selon la revendication 7, dans laquelle la phase huileuse représente au moins 1, au moins 5, au moins 10, au moins 20, au moins 30 ou au moins 40 pour cent en poids de la composition / de l’émulsion, de préférence 10 % de l’émulsion.

9. Composition selon l’une quelconque des revendications 1 à 8, dans laquelle le promédicament administré se libérera 35 graduellement via son hydrolyse par des enzymes endogènesin situ, pour générer des taux thérapeutiques du médicament actif.

10. Composition selon l’une quelconque des revendications 1 à 9, dans laquelle ledit promédicament est administré par une injection intraoculaire tous les un, deux ou six mois. 40 11. Composition selon l’une quelconque des revendications1 à 10, dans laquelle la quantité de la composition de l’invention administrée est telle que, après un mois, le rapport molaire médicament/promédicament dans la rétine ou dans la choroïde est égal ou inférieur à 1, de manière préférentielle de 0,5, de manière davantage préférentielle de 0,1. 45 12. Composition selon l’une quelconque des revendications 1 à 11, dans laquelle la maladie est une affection ou une maladie de l’intérieur de l’oeil, de préférence de l’arrière de l’oeil.

13. Composition selon la revendication 12, caractérisée en ce que lesdites maladies sont : une uvéite, un oedème 50 maculaire, une dégénérescence maculaire, un décollement de la rétine, des tumeurs oculaires, des infections bactériennes, fongiques mais pas virales, une choroïdite multifocale, une rétinopathie diabétique, une vitréorétino- pathie proliférative (PVR), une ophtalmie sympathique, le syndrome de Vogt Koyanagi-Harada (VKH), une histo- plasmose, une diffusion uvéale et une occlusion vasculaire.

55 14. Composition selon l’une quelconque des revendications 1 à 13, dans laquelle la composition comprend en outre un agent actif choisi parmi la cyclosporine, un anti- VEGF et/ou un antibiotique.

15. Composition selon l’une quelconque des revendications 1 à 14, dans laquelle la composition comprend de la dexa-

10 EP 2 319 517 B1

méthasone palmitate et au moins un agent actif choisi dans le groupe constitué par la cyclosporine, anti- VEGF, et un antibiotique.

5

10

15

20

25

30

35

40

45

50

55

11 EP 2 319 517 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.

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