(19) TZZ 56485¥_T (11) EP 2 564 853 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 06.03.2013 Bulletin 2013/10 A61K 31/573 (2006.01) A61K 38/13 (2006.01) A61P 27/00 (2006.01) (21) Application number: 12193075.4 (22) Date of filing: 03.12.2008 (84) Designated Contracting States: • Lambert, Grégory AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 92290 Châtenay-Malabry (FR) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT • Lallemand, Frédéric RO SE SI SK TR 94260 Fresnes (FR) •Philips,Betty (30) Priority: 04.12.2007 US 992160 P 92160 Antony (FR) (62) Document number(s) of the earlier application(s) in (74) Representative: Icosa accordance with Art. 76 EPC: 83 avenue Denfert-Rochereau 08858069.1 / 2 229 174 75014 Paris (FR) (71) Applicant: Novagali Pharma S.A. Remarks: 91000 Evry (FR) This application was filed on 16-11-2012 as a divisional application to the application mentioned (72) Inventors: under INID code 62. • Rabinovich-Guilatt, Laura 60920 Kadima (IL) (54) Compositions comprising corticosteroid prodrug such as dexamethasone palmitate for the treatment of eye disorders (57) The present invention relates to a new thera- vides methods of treatment involving the administration peutic approach for the treatment of eye diseases or con- of a corticosteroid prodrug, such as dexamethasone ditions that allows for the delivery of corticosteroids to palmitate, to the surface of the eye. Also provided are the eye’s surface but does not cause any of the usual pharmaceutical compositions and kits for carrying out side effects associated with topical administration of cor- such methods of treatment. ticosteroids. More specifically, the present invention pro- EP 2 564 853 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 564 853 A1 Description Background of the Invention 5 [0001] In the past 50 years or so, corticosteroids have been used in a broad spectrum of inflammatory conditions of the eye. In fact, corticosteroids belong to the class of therapeutics the most frequently prescribed in ophthalmology. In particular, topical corticosteroids have revolutionized the practice of ophthalmology and ophthalmic care when it comes to preventing or treating ocular inflammation due to trauma, chemical, infective, allergic or other causes. The most commonly used corticosteroids for topical ocular administration are prednisolone, fluorometholone, dexamethasone, 10 rimexolone, and medrysone. [0002] Corticosteroids are synthetic drugs that mimic steroid hormones naturally produced by the body. These steroid hormones have a wide variety of actions and control functions and are involved in a number of important physiological systems including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism and blood electrolyte levels. In addition to regulating inflammation, corticosteroids also have the ability to 15 affect these other physiological systems, resulting in many potential risks and side effects. [0003] As with most therapeutic drugs, the majority of side effects of corticosteroids are more pronounced with systemic therapy. However, they may occur with all routes of administration. For example, there are several potentially severe ocular side effects that can result from topical corticosteroid use. In particular, topical corticosteroid therapy can cause an increase in intra-ocular pressure (IOP). If IOP remains elevated for a length of time, glaucoma can occur with corre- 20 sponding optic nerve damage and visual field loss. IOP elevation can generally be reversed by discontinuation of the treatment. Another potential side effect that can result from topical corticosteroid use is the development of posterior subcapsular cataracts, which can be visually debilitating and require surgical removal. Topical corticosteroid use can also lead to an increase in corneal thickness, mydriasis (an excessive dilation of the pupil) and ptosis (dropping of the upper eyelid). 25 [0004] Side effects of topical corticosteroid therapy are generally directly related to the dosage and duration of treatment and are more often observed with the use of potent corticosteroids, such as dexamethasone. These side effects are believed to result, at least in part, from penetration of the corticosteroid in internal ocular tissues, such as the aqueous humor. The effectiveness of topical corticosteroid therapy is thus severely limited by these unwanted effects since it is often administered for a shorter period of time than necessary, and/or utilizes a less potent agent than necessary. 30 [0005] Therefore, there is still a need in the art for improved approaches to eliminate or reduce side effects associated with topical administration of corticosteroids in the treatment of eye diseases or conditions. Summary of the Invention 35 [0006] The present invention provides an improved strategy for the delivery of corticosteroids to the eye that does not result in undesirable side effects generally observed in topical corticosteroid therapy. The inventive approach is partic- ularly useful in the treatment of eye diseases and conditions affecting the surface of the eye, such as ocular inflammatory conditions. [0007] In particular, the present invention provides methods and compositions that include topical ocular administration 40 of a corticosteroid prodrug, i.e., a pharmaceutically inactive compound that is converted to and/or releases a pharma- ceutically active corticosteroid via a chemical or physiological process at the eye surface. Preferred corticosteroid pro- drugs according to the present invention are compounds that do not significantly penetrate into internal ocular tissues after delivery to the eye surface, in particular that do not traverse the stroma, thereby not reaching the aqueous humor. Systems of the present invention thus limit or reduce the risk of increase in IOP, formation of glaucoma, formation of 45 cataracts, and other unwanted side effects that can result from the presence of corticosteroids inside the eye. Conse- quently, therapeutic methods according to the present invention do not suffer from the limitations generally associated with topical corticosteroid administration, in that they can be administered for longer periods of time and can employ prodrugs of any suitable corticosteroid including the most potent corticosteroids. [0008] More specifically, in one aspect, the present invention provides pharmaceutical compositions of corticosteroid 50 prodrugs that are formulated for topical administration to the eye. An inventive pharmaceutical composition generally comprises an effective amount of at least one corticosteroid prodrug, or a physiologically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. [0009] Corticosteroids that may be released from corticosteroid prodrugs may be any corticosteroid suitable for use in the treatment of an eye disease or condition, in particular inflammatory conditions of the eye. In certain embodiments, 55 a prodrug may be converted to and/or release a corticosteroid selected from the group consisting of prednisolone, fluorometholone, dexamethasone, rimexolone, medrysone, physiologically acceptable salts thereof, derivatives thereof, and any combinations thereof. In certain preferred embodiments, a prodrug is converted to and/or releases dexameth- asone, a physiologically acceptable salt thereof or a derivative thereof. More preferably, a prodrug according to the 2 EP 2 564 853 A1 present invention is converted to and/or releases dexamethasone. [0010] In certain preferred embodiments of the present invention, release of a corticosteroid from a prodrug occurs via an enzymatic process at the surface of the eye. Thus, preferably, a corticosteroid prodrug comprises a chemical group or function that can be cleaved by an enzyme present at the eye surface. Such enzymes include any of a wide 5 variety of enzymes including, but not limited to, esterases (e.g., pseudocholinesterase, acetylcholine esterase), oxidore- ductases, transferases, lyases, isomerases, ligases, hydrolases, phosphatases, proteases and peptidases. In certain preferred embodiments, release of a corticosteroid from a prodrug occurs via the action of one or more esterases. [0011] Preferred corticosteroid prodrugs are lipophilic derivatives of corticosteroids, in particular lipoph ilic derivatives of corticosteroids having a log P (partition coefficient) comprised between 1 and 12, preferably higher than or equal to 10 5 and lower than 12. [0012] According to the present invention, the partition coefficient P of a compound is the ratio of concentration of said compound in water to the concentration in octanol, as the neutral molecule. [0013] The logarithm of said ratio is called log P. It can be determined with a suitable HPLC method according to published procedures (Caron, J.C., and Shroot, B., J. Pharm. Sci., 1984). 15 [0014] In particular, the present invention relates to the use of lipophilic long chain esters of corticosteroids. Lipophilic long chains may be selected from the group consisting of linear alkyls, linear alkenyls, branched alkyls, and branched alkenyls, wherein alkyl and alkenyl groups comprise 12, 14, 16, 18 or more than 18 carbon atoms. Preferably, the lipophilic long chains are selected among linear or branched alkyls comprising 12, 14, 16, 18 or more than 18 carbon atoms. In one embodiment, the lipophilic long chains are selected among linear alkyls comprising 12 or 14 carbon atoms. 20 [0015] In certain preferred embodiments, a pharmaceutical