sign in sign up
<<
Home , Chloroprednisone, Fluazacort, Hydrocortamate, Meprednisone, Paramethasone acetate

US 20070280995A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0280995 A1 Rabinovich-Guilatt et al. (43) Pub. Date: Dec. 6, 2007

(54) USE OF A PRODRUG FOR THE Related U.S. Application Data TREATMENT OF DISEASE OF THE POSTERIOR SEGMENT OF THE EYE (62) Division of application No. 1 1/444,337, filed on Jun. 1, 2006. (75) Inventors: Laura Rabinovich-Guilatt, (30) Foreign Application Priority Data Kadima (IL); Gregory Lambert, Chatenay-Malabry (FR) Jun. 1, 2006 (EP) ...... O629O902.3 Publication Classification Correspondence Address: YOUNG & THOMPSON (51) Int. Cl. A 6LX 3/57 (2006.01) 745 SOUTH 23RD STREET, 2ND FLOOR A6IR 9/00 (2006.01) ARLINGTON, VA 22202 A6IP27/02 (2006.01) (73) Assignee: NOVAGALI PHARMA SA, (52) U.S. Cl...... 424/427: 514/169; 514/177 EVRY (FR) (57) ABSTRACT Use of a composition comprising at least one prodrug of a (21) Appl. No.: 11/806,554 steroid, preferably of a , for the preparation of an ophthalmic composition intended for the treatment of an (22) Filed: Jun. 1, 2007 ocular condition or disease of a human being or an animal. US 2007/0280995 A1 Dec. 6, 2007

USE OF A STEROID PRODRUG FOR THE 0009. The need to administrate the the TREATMENT OF DISEASE OF THE most locally possible, therefore selectively in the disease POSTERIOR SEGMENT OF THE EYE site, in effective quantities, was then clear. 0010. The effectiveness of the treatment is in particular related to the presence of the active compound and hence to the half life of the drug. A known corticosteroid, the dex 0001. The present invention relates to the field of the amethasone has a half life of 3.5 hours when injected treatment of the ophthalmic diseases, in particular of the intraocularly (Kwak, Arch Opthalmol, 1992). Thus, the intraocular diseases of a human being or an animal, by at injections must be repeated to maintain a therapeutic effect. least one steroid, and in particular by at least one corticos 0011. However, repeated injections are difficult to cope teroid. with for the patients Suffering of long or chronic diseases. 0002 The invention particularly focuses on ophthalmic Moreover, repeated injections are likely to increase harmful compositions or devices, preferably ophthalmic emulsions, side effects such as retina detachment, endophtalmy, and comprising at least one steroid, preferably a corticosteroid. Cataracts. The invention also relates to the administration of such 0012. In view of the additional side effects caused by ophthalmic compositions, and in particular to their admin repeated injections, intraocular implants of have istration intraocularly. The invention relates also to the been developed: controlled release of therapeutic active agents, in particular (0013 RETISERTTM ( acetonide intravitreal of corticosteroids intraocularly, in particular in the posterior implant, Bausch & Lomb) 0.59 mg is a sterile implant segment of the eye. designed to release locally to the 0003) A posterior ocular condition is a disease which posterior segment of the eye. RETISERTTM was recently primarily affects a posterior ocular site Such as choroid or approved by the FDA and is indicated for the treatment of Sclera, vitreous, vitreous chamber, retina, optic nerve, and chronic non-infectious uveitis affecting the posterior seg blood vessels and nerves which vascularize or innervate a ment of the eye. However, clinical trials of this implant posterior ocular site. systematically results in a raise of the intraocular pressure 0004 Steroids are already largely used to treat oph (IOP) and cataracts as main adverse effects. Holekamp et al. thalmic diseases affecting the posterior chamber of the eye, found that after long-term follow-up, high-dose intraocular in particular central retinal vein occlusion (CRVO), branch fluocinolone acetonide results in significant complications retinal vein occlusion (BRVO), choroidal macular edema rate, with 100% of the eyes developing elevated IOP and (CME), diabetic macular edema (DME), diabetic macular 30% showing nonischemic central retinal vein occlusion. retinopathy, uveitis, and age related macular degeneration These complications required the implant removal in almost (ARMD). These treatments generally imply their systemic 60% of the eyes (Am J Opthalmol 2005). Implantation of administration, causing known side effects, which are sig 0.59 mg or 2.1 mg fluocinolone acetonide in noninfectious nificant, regarding the ophthalmic diseases to treat. These posterior uveitis patients results in a 5-fold augmentation of side effects singularly decrease the interest of the treatment the need of IOP lowering agents (Jaffe, Opthalmology, of these ophthalmic diseases by Systemic administration of 2005). In a randomized clinical trial of 0.59 mg fluocinolone steroids. acetonide intravitreal implant in patients with diabetic macu lar edema, the most common adverse included serious 0005. Other modes of administration, topic, suprachoroi cataract progression (43.1%) and a serious intraocular pres dal, subconjunctival, retrobulbar, and intravitreal were sure rise (8.6%) (Pearson, ISOPT communication, Berlin, searched. Regarding topical application, 2006). Based on clinical trials with RETISERT, within 34 penetration into the vitreous humour after repeated topical weeks post-implantation, approximately 60% of patients application is negligible (less than 2 ng/ml after 1 drop of will require IOP lowering medications to control intraocular 0.1% dexamethasone phosphate drops hourly for 10 hours) pressure. Within an average postimplantation period of (Weitens, Opthalmology, 2002). In comparison, serum and approximately 2 years, approximately 32% of patients are vitreous levels of 60 and 5 ng/ml respectively are observed expected to require filtering procedures to control intraocu following a single oral administration of 7.5 mg dexametha lar pressure. Moreover, within an average post-implantation sone (Weitens, Am J Opthalmol, 1998). period of approximately 2 years, nearly all phakic eyes are 0006. It was also shown that the subretinals concentra expected to develop cataracts and require cataract Surgery tions of dexamethasone after subconjunctival or peribulbar (source Bausch & Lomb). injection were 120 and 13-fold more elevated than after oral 0014 Posurdex is another intraocular device being devel administration (Weitens et al. Opthalmology, 2000). The oped by Allergan containing 700 micrograms of dexametha local intraocular administration is thus highly preferred. Sone which are released during the first month post implan 0007. However, the injection of steroids in significant tation. Its efficacy has been evaluated among others in cases amounts in the eye, implies a Sudden and massive increase of persistent macular edema (Williams, ISOPT communi in their concentration in all ocular structures, and can also cation, 2006) and for anti-inflammatory effects after cataract lead to undesirable and consequent local ocular side effects, surgery (Tan, Opthalmology, 2004). However, a safety and in particular a significant increase in the intraocular pressure efficacy clinical study of 700 micrograms dexamethasone possibly leading to the development of glaucoma, or to the implant for the treatment of macular edema showed signifi appearance or the development of cataracts. cant increases in IOP (to 225 mm Hg) in 15% of patients 0008. It was notably noticed that the presence of corti (Williams, ISOPT communication, Berlin, 2006). costeroids in the anterior segment of the eye was in particu 0015 The off-label use of acetonide (Ke lar related to the appearance of these side effects, and was nalog 40TM, Bristol Myers Squib) intraocularly results indi thus undesirable. rectly in the slow-release of the drug, as the insoluble steroid US 2007/0280995 A1 Dec. 6, 2007 precipitates following injection in the vitreous cavity and is fewer side effects occasioned by the therapeutic agent are only gradually solubilized. Therefore, it can be considered expected to be observed. The drug would be release at the as well as a Sustained release steroidal formulation. How very location of the disease, resulting in a decrease of ever, this formulation which was not originally developed unwanted adverse effects in other ocular structures where for intraocular use can cause serious complications such as the prodrug is not hydrolyzed. The invention also permits infectious endophthalmitis and sterile endophthalmitis, reti maintaining the desired effect in the ocular condition for an nal toxicity and crystalline retinal deposits. Nevertheless, it extended period of time during which an amount of the has been used intravitreally to treat ocular inflammation as prodrug is present at the ocular site such that it allows the well as macular edema due to numerous causes. In addition, retrospective analysis of Subtenon release of an effective amount of the active drug for an cases also reveals intraocular pressure rise in 21% of the extended period of time, which is preferably at least one patients (Bui Quoc, J. Fr Ophtalmol, 2002). month. Thus, the present invention also relates to a method 0016 Other steroid-containing devices being developed of personalized treatment of a patient in need of a steroid in research are triamcinolone acetonide/polycaprolactone intraocular treatment: each patient, as of he/she is adminis implants (Beeley, J Biomed Mater Res A, 2005), triamci tered with prodrug of the invention, may intraocularly nolone/polyvinyl alcohol implants (Ciulla, Br J Opthalmol, release the exact amount of needed active steroid according 2003), polymeric implants (Kato, IOVS. to his stage of development of his/her pathology, thus 2004 and Okabe, IOVS, 2003) and others. avoiding side effects due to extra and unneeded amounts of 0017. This analysis of the intraocular corticosteroid-con active steroids in the vitreous body. taining implants shows that the long lasting presence of 0023. A further advantage of this invention is that no corticosteroid in the posterior segment of the eye causes systemic side effect was observed when intraocularly admin undesirable side effects, even though the therapeutic effect is istering the ester of steroid of the invention. Moreover, the undoubtful. usual side effect linked to the presence of high amounts of 0018. There is need therefore for an ophthalmic device or steroids in the vitreous body, i.e. intraocular pressure, was composition which will Succeed in delivering a therapeutic not observed when administering high amounts of the pro amount of active steroid in a satisfactory manner for the drug, i.e. ester of steroid, of the invention. Another advan patient, i.e. ensuring safety and avoiding any toxic effect, tage of this invention is that the prodrug of the invention, especially avoiding undesirable systemic side effect of the when administered, may remain in the vitreous body as intraocularly administered steroid. such, resulting in the vitreous body being a storage of 0019. One goal of this invention is to provide a compo ready-to-be-released inactive prodrug. A further advantage sition, delivering a therapeutic amount of active steroid for of the invention is that, due to absence of side effects of the a sustained period in the eye. Preferably, the composition of inactive prodrug and due to the Sustained released of the the invention delivers a therapeutic amount of steroid in the steroid from the prodrug, the amount of prodrug to be disease site. More preferably, the composition of the inven possibly administered into the eye may be much more tion delivers the therapeutic amount of steroid needed to important than the amount of active (and toxic) drug. treat the very pathology of the patient. According to this Accordingly, the number of injections may be decreased. embodiment, the composition of the invention is of great According to an embodiment, the frequency of injection is interest for personalized methods of treatment. Another goal of once a month or less, preferably equal or less than once of this invention is to increase the comfort of the patient by every 2 months, more preferably equal or less than once reducing the number of needed injections. As intraocular every three months, most preferably equal or less than once injections are particularly uncomfortable, this further goal is every four, five or six months. of importance for the patient. 0024. By “prodrug in the invention is meant an ester of 0020. From this assumption, the inventors searched alter steroid, preferably a lipophilic long-chain ester of steroid, native therapeutic pathways for an efficient administration of preferably of corticosteroid, said ester group comprising an steroids, preferably corticosteroids inside the eye: this alkyl group of more than 10 carbons preferentially of more invention relates to the use of prodrugs of steroids, espe than 14 carbons, even more preferentially of 16 carbons cially corticosteroids, for the preparation of a medicament or being preferably directly linked to a function of the steroid. an ophthalmic composition intended for the treatment of an According to an embodiment, the ester of steroid of the ocular condition or disease of a human being or an animal, invention does not include a phosphate group. According to said medicament or ophthalmic composition being admin the invention, the ester group is of formula – COOR or istered by invasive means, preferably by intraocular injec —OC(O)R, wherein R is a long alkyl or alkenyl chain, tion, more preferably by intravitreal injection, for in-situ preferably a C4-C16 alkyl chain, even more preferably C12, Sustained release of therapeutic effective agents. C14, C16, C18, C20 saturated or unsaturated chain, more 0021. The inventors observed that intraocular, more espe preferably any suitable lipophilic chain. cially intravitreal, injections of a corticosteroid prodrug, the 0025. According to a preferred embodiment of the inven dexamethasone palmitate, resulted in the in-situ release of tion, the prodrug does not have any direct therapeutic and/or dexamethasone. physiologic effect, and is therefore called “inactive'. 0022. Without wanting to being linked by a theory, the whereas the drug released by hydrolysis of the prodrug does Inventors Suppose that there might be a selective uptake of have a physiological therapeutic effect. On the contrary, by the steroid prodrug, preferably a lipophilic ester of a steroid, “active' steroid, in the meaning of this invention, is meant by the ocular inflammatory cells (macrophages). The a steroid that has a direct therapeutic and/or physiologic increased macrophage activity at the inflamed sites may effect. Thus, a difference has to be made between steroids or result in a targeted cleavage of the active moiety only in the steroid derivatives that are therapeutically directly effective, disease location, with no unspecific release. Therefore, and are “active' steroids or steroid derivatives in the mean US 2007/0280995 A1 Dec. 6, 2007

ing of this invention, versus “inactive' esters of steroid, i.e. 0033. In a further embodiment the molar amount of ester the prodrugs of the invention. of steroid administered is higher than the highest non-toxic 0026. The invention is directed to the use of a composi molar amount of said steroid injected by the same admin tion comprising at least one prodrug of a steroid, preferably istration mode. of a corticosteroid, for the preparation of an ophthalmic 0034. In a preferred embodiment of the invention, the composition intended for the treatment of an ocular condi amount of prodrug to be administrated is an amount thera tion or disease of a human being or an animal. peutically equivalent to 0.1 to 2.5 mg of Dexamethasone. 0027. The composition according to the invention com 0035. In another preferred embodiment, the amount of prises at least one prodrug of corticosteroid, which is pref Dexamethasone Palmitate to be administrated is in the range erably selected from: dipropionate, amcino of 0.1 to 3.2 mg, preferentially 0.2 to 1 mg and most nide, amcinafel, , beclamethasone, preferentially 0.4 to 0.8 mg. betamethasone, betamethasone dipropionate, betamethasone 0036. According to an embodiment, the aqueous solubil Valerate, propionate, , clo ity of the prodrug of the invention is of less than 120 ug/mL, cortelone, , , cortodoxone, difluorosone preferably of less than 50 ug/mL and more preferably of less diacetate, , , defluprednate, dihydroxy than 10 g/mL. cortisone, , dexamethasone, , 0037 According to the invention, the composition of the , , , esters of invention includes at least one steroid prodrug dissolved in betamethasone, , flucetonide, flucloronide, fludro a opthalmologically acceptable oil. tisone, fluorocortisone, flumethasone, , fluocino 0038 According to an embodiment of the invention, the nide, fluocinolone, fluocinolone acetonide, flucortolone, flu carrier is selected from (1) an oil; examples of suitable oily perolone, , fluoroandrenolone acetonide, carrier are mineral oils such as silicone, paraffin or vegetal fluocinolone acetonide, flurandrenolide, fluorametholone, oils such as medium chain triglycerides, soybean castor oil, propionate, , hydrocortisone olive oil, corn oil, palm oil or any other oil suitable for butyrate, , , lotepren intraocular injection, preferably selected from MCT, castor dol, , , methylprednisone, methyl oil and soybean oil, or from (2) an emulsion where the oil , furoate, , phase preferably is selected from mineral oils such as paramethasone , , prednisolone, predni silicone, paraffin or vegetal oils such as medium chain done, triamcinolone acetonide, triamcinolone hexacatonide, triglycerides, soybean castor oil, olive oil, corn oil, palm oil and triamcinolone, salts, derivatives, and a mixture thereof. or any other oil suitable for intraocular injection 0028 More preferably, the corticosteroid is selected 0039. According to an embodiment of the invention, the from: cortisone, dexamethasone, fluocinolone, hydrocorti weight ratio prodrug/oil is 0.04 to 0.3. Sone, , prednisolone, prednisone, and 0040. According to a preferred embodiment of the inven triamcinolone. In this embodiment, the composition of the tion, the ratio Dexamethasone Palmitate/Soya bean oil is invention comprises a prodrug of cortisone, dexamethasone, O.04 to O.3. fluocinolone, hydrocortisone, methylprednisolone, pred 0041 According to another embodiment of the invention, nisolone, prednisone, and triamcinolone. the composition of the invention includes at least one steroid 0029. In the most preferred embodiment of the invention, prodrug dissolved in a physiologically acceptable oil which the composition comprises a prodrug of dexamethasone, is emulsified into a oil-in-water emulsion by different tech more preferably dexamethasone palmitate. niques such as high shear and high pressure homogenization 0030. In another preferred embodiment, the composition with suitable emulsifiers; final preparation can be sterilized comprises a long-chain ester of steroid, preferably a C12 by filtration or by autoclave. C18 ester of steroid, more preferably dexamethasone stear 0042. According to an embodiment of the invention, the ate, dexamethasone laurate, triamcinolone palmitate, triam composition comprises at least one prodrug as above-de cinolone Stearate, triamcinolone laurate, triamcinolone fined, in combination with any ophtalmologically acceptable acetonide palmitate, triamcinolone acetonide Stearate, triam excipient or carrier. The carrier may be selected from an cinolone acetonide laurate. ophtalmologically acceptable oil, phospholipid vesicles or 0031 Preferably, the prodrug is comprised in the emul oil-in-water emulsion or water-in-oil emulsion or any other sion in an amount of about 0.01% to about 10% w/w of the suitable carrier about 20, at least about 30 or at least about emulsion, preferably 0.05% to 5% w/w, more preferably 0.1 40 weight percent of the composition/emulsion, preferably to 1% w/w. According to an embodiment, the prodrug is 10% of the emulsion. comprised in the amount of about 0.5% to about 3% w/w of 0043. Excipient characteristics that are considered the composition, which preferably is an emulsion. In a include, but are not limited to, the biocompatibility and preferred embodiment, the prodrug is comprised in a amount biodegradability at the site of implantation, compatibility of about 2% w/w of the composition, which preferably is an with the prodrug of interest, and processing temperatures. emulsion. In another preferred embodiment of the present 0044) When the excipient or the carrier is an emulsion, invention, the prodrug is comprised in an amount of about according to an embodiment of the invention, the oil phase 1% w/w of the composition, which preferably is an emul represents at least about 1, at least about 5, at least about 10, S1O. at least about 20, at least about 30 or at least about 40 weight 0032. In an embodiment of the invention, the amount of percent of the composition. In a preferred embodiment, the prodrug to be administrated is an amount therapeutically oil represents 10 weight percent of the composition. In this equivalent to 0.01-6 Limol of steroid, preferably Dexametha embodiment, the composition includes at least one surfac sone, preferentially equivalent to 0.1 to 2.5umol of steroid, tant, preferably in an amount of 0.1-10% w/w of the com preferably Dexamethasone, and most preferentially equiva position. According to an embodiment, the Surfactant is lent to 0.15-1.3 umol of steroid, preferably Dexamethasone. selected from phospholipids, poloxamers, tyloxapol, US 2007/0280995 A1 Dec. 6, 2007

polysorbate, and polyoxyethylene fatty acid esters. In this the action of the active drug in the very site of inflammation embodiment, the composition preferably includes at least due to the ocular condition or disease. one isotonicity agent, preferably in an amount of 0.1-10% 0055 According to an embodiment of the invention, the W/w of the composition. According to an embodiment, the release of the steroid is in amount dependant from the istonicity agent is glycerol. condition of the patient: the more serious the condition is, 0045 Preferably, the composition of the invention is as the more the release of the steroid occurs. This means that follows: a more serious condition leads to the release of a bigger amount of steroid: thus, the treatment is adapted to the severity of the condition of the patient. This invention thus relates to a method for administering the exact amount of Role Amount (ww) steroid necessary to treat his specific condition. Prodrug O.O1-10% 0056. According to an embodiment of the invention, the Oil 1-40% frequency of administration of the composition of the inven Surfactant O.1-10% tion trough injection is once a month, preferably once every Tonicity agent O.1-10% two months, more preferably once every six months. It is an Dispersing medium Up to 100% advantage of this invention to provide a less frequent need for repeated administration. 0046 According to an embodiment, the composition of 0057 According to an embodiment of the invention, the the invention is as follows: amount of the composition of the invention administered is 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 Role Amount (ww) O.1. Prodrug O. 1-5% 0.058 According to one embodiment of the invention, the Oil 8-12% composition of the invention is in the form of a solution, an Surfactant O.S.-2% emulsion, a Suspension. Examples of the composition of the Tonicity agent 1-3% invention are the following: Dispersing medium Up to 100% Composition A 0047. In the meaning of this invention the term “about 0059 means approximately or nearly and in the context of a numerical value or range set forth herein means ..+/-0.10% of the numerical value or range recited or claimed. Role Component Amount (ww) 0048. According to an embodiment of the invention, the Active agent Dexamethasone O.8% composition of the invention is administered through one palmitate intraocular injection, more preferably through one intravit Oil MCT 10% real injection. Surfactant Lipoid E-80 1.5% 0049 According to another embodiment of the invention, Tonicity agent Glycerol 2.2% the composition of the invention is administered through the Dispersing medium Water Up to 100% placement of an intraocular implant containing or combined with the composition of the invention. Composition B 0050. According to another embodiment of the invention, the composition further comprises an active agent selected 0060 from cyclosporine, anti-VEGF, and/or an antibiotic. 0051. According to another embodiment of the invention, wherein the composition comprises dexamethasone palmi Role Component Amount (ww) tate and at least one active agent selected from the group Active agent Dexamethasone O.4% consisting of cyclosporine, anti-VEGF, and an antibiotic. palmitate 0.052 The invention also relates to a method of treatment Oil Soybean oil 10% of a human or animal ophthalmic condition or disease Surfactant Lipoid E-80 1.5% comprising the intraocular administration of the composi Tonicity agent Glycerol 2.2% tion of the invention. Dispersing medium Water Up to 100% 0053 According to an embodiment, the method of the invention includes the administration of a steroid prodrug Composition C into an ocular site of a patient Suffering from an ocular condition or disease. The prodrug can be administered alone 0061 or in an ophtalmologically carrier Suitable for intraocular administration. The carrier may be a surfactant solution, oil, phospholipid vesicles or oil-in-water emulsion, or any other Role Component Amount (ww) suitable carrier. Active agent Triamcinolone 59% 0054 The administrated prodrug will gradually release palmitate through its hydrolysis by endogenous enzymes in situ, to Oil MCT 10% generate therapeutic levels of the active drug in the disease Surfactant Lipoid E-80 1.5% site. This results in the improvement of ocular conditions by US 2007/0280995 A1 Dec. 6, 2007

0066. The invention is further illustrated by the following -continued example, which should not be considered in any way as a limitation the scope of the protection. Role Component Amount (ww) Tonicity agent Glycerol 2.2% EXAMPLES Dispersing medium Water Up to 100% Active agent Dexamethasone O.S9/o palmitate 1. Analytical Methods for Simultaneous Determination of Solubilizing agent PEG200 Up to 100% Dexamethasone and Dexamethasone Palmitate in Ocular Tissues 0067. A liquid chromatographic-mass spectrometric 0062. The improvement of the ocular condition obtained method for the simultaneous determination of dexametha by a method within the scope of the present invention can be Sone and dexamethasone palmitate in ocular tissues was determined by observing: an improved visual acuity, an developed. Analytes and internal standard (roXithromycine) improved visual contrast sensitivity, a decreased retinal or were extracted from the tissues using acetonitrile and sepa choroidal blood vessel leakage, a decreased retinal or macu rated by reverse phase liquid chromatography with a C8 lar thickness, or a reduced number of cells in the aqueous or column and a gradient mobile phase. The compounds were vitreous humor or by determining a reduced flare. detected by mass spectrometric detection (atmospheric pres 0063. According to an embodiment of the invention, the sure ionization) with selected ion monitoring (SIM) (393.0 administration of the composition of the invention is inva for dexamethasone and 631.5 for dexamethasone palmitate). sive. More preferably, the composition of the invention is The method was selective for both compounds and the limits administered through an implant or through intraocular, of quantification were 32.7 ng/g of retina and 71.6 ng/g preferably intravitreal injection. choroid. The unweighed linear model was applied. 0064. The compositions of the invention are useful for 2. Intraocular Pharmacokinetics of Dexamethasone Palmi the treatment of conditions or diseases affecting the interior tate and Dexamethasone Following Intravitreal Administra of the eye, preferably of the back of the eye. These com tion positions are especially useful for the treatment of the following conditions or diseases: uveitis, macular edema, Methods: macular degeneration, retinal detachment, ocular tumors, 0068. One single unilateral intravitreal injection of a bacterial, fungal but viral infections, multifocal choroiditis, 0.8% (8 mg/ml) dexamethasone palmitate emulsion to rab diabetic retinopathy, proliferative vitreoretinopathy (PVR), bits (100 LL). Sacrifice at days 1, 7, 14, 21, 28 or 60 days sympathetic opthalmia, Vogt Koyanagi-Harada (VKH) Syn (n=4/timepoint). Dexamethasone (D) and dexamethasone drome, histoplasmosis, uveal diffusion, and vascular occlu palmitate (DP) in tissues were determined. All concentra S1O. tions are expressed in nmol/g tissue. 0065. In a preferred embodiment, the composition of the invention is within an implantable device and then used for Results: the treatment of uveitis, macular oedema, Vascular occlusive conditions, proliferative vitreoretinopathy (PVR), and vari 0069

Day 1 Day 7 Day 14 Day 28 Day 60

Mean sd Mean sd Mean sd Mean sd Mean sc

Retina DP 106 74 93 38 136 19 146 109 55 37 (nmol/g) D 2 11 4 6 4 4 1 2 2 (nmol/g) DDP O660 O.118 O.044 O.O27 O.036 Choroid DP 191 69 103 77 22 11 143 61 S2 22 (nmol/g) D 6 12 7 9 4 4 1 3 2 (nmol/g) DDP O.O63 O. 117 O.409 O.O28 0.057 Aqueous DP ND ND ND ND ND ND ND O O humor (nmol/g) D ND ND ND ND ND ND ND O 1 (nmol/g)

ND: Not determined. ous other retinopathies. In view of the advantages of the Following IVT injection of a dose of 800 ug of prodrug, present invention for the patient, in term of lack of toxicity, dexamethasone of more than 800 ng/g (higher than thera comfort of limited number of injection, storage of ready-to peutic levels) were maintained for at least 2 months in the be released drug, it should be considered in the future of very target tissues. Moreover, considerable amounts of the pro limited interest to directly administering toxic steroid. drug dexapalmitate remained in both retina and choroid, US 2007/0280995 A1 Dec. 6, 2007

indicating an even more long-lasting release. At the same at least about 20, at least about 30 or at least about 40 weight time, the amount of Steroid in the aqueous humor was percent of the composition/emulsion, preferably 10% of the undetectable, Suggesting fewer (if any) side effects in adja emulsion. cent sites. This last fact was corroborated by IOP measure 11. Use according to claim 1 wherein the administrated ments, which were normal 2 months following the injection. ester of steroid will gradually release through its hydrolysis by endogenous enzymes in situ, to generate therapeutic 1. Use of a composition comprising at least one ester of levels of steroid. steroid, preferably of a corticosteroid, for the preparation of 12. Use according to claim 1, wherein said ester of steroid a medicament oran ophthalmic composition intended for the is administered through one intraocular injection every one, treatment of an ocular condition or disease of a human being two or six months. or an animal, said medicament or ophthalmic composition 13. Use according to claim 1, wherein the amount of the being administered by invasive means, preferably by composition of the invention administered is such that, after intraocular injection. one month, the molar ratio steroidfester of steroid in the 2. Use according to the claim 1, wherein the ester of retina or in the choroid is equal or less than 1, preferentially steroid is a long chain ester of steroid, preferably of corti of 0.5, more preferentially of 0.1. costeroid, said ester group comprising an alkyl group of 14. Use according to claim 1, wherein the disease is a more than 10 carbons preferentially of more than 14 car condition or disease of the interior of the eye, preferably of bons, even more preferentially of 16 carbons. the back of the eye. 3. Use according to claim 1, wherein the steroid is 15. Use according to claim 14, characterized in that said selected from the group consisting of alclometasone dipro diseases are: uveitis, macular edema, macular degeneration, pionate, , amcinafel, amcinafide, beclametha retinal detachment, ocular tumors, bacterial, fungal but viral Sone, betamethasone, betamethasone dipropionate, infections, multifocal choroiditis, diabetic retinopathy, pro , clobetaSone propionate, chloro liferative vitreoretinopathy (PVR), sympathetic opthalmia, prednisone, clocortelone, Cortisol, cortisone, cortodoxone, Vogt Koyanagi-Harada (VKH) syndrome, histoplasmosis, difluorosone diacetate, descinolone, desonide, deflupred uveal diffusion, and vascular occlusion. nate, dihydroxycortisone, desoximetaSone, dexamethasone, 16. Use according to claim 1, wherein the composition deflazacort, diflorasone, diflorasone diacetate, dichlorisone, further comprises an active agent selected from cyclospo esters of betamethasone, fluazacort, flucetonide, flucloron rine, anti-VEGF, and/or an antibiotic. ide, fluidrotisone, fluorocortisone, flumethasone, flunisolide, 17. Use according to claim 1, wherein the composition , fluocinolone, fluocinolone acetonide, flucor comprises dexamethasone palmitate and at least one active tolone, , fluprednisolone, fluoroandrenolone agent selected from the group consisting of cyclosporine, acetonide, fluocinolone acetonide, flurandrenolide, fluo anti-VEGF, and an antibiotic. rametholone, , hydrocortisone, hydro 18. Use according to claim 2, wherein the steroid is cortisone butyrate, hydrocortisone Valerate, hydrocortamate, selected from the group consisting of alclometasone dipro loteprendol, medrysone, meprednisone, methylprednisone, pionate, amcinonide, amcinafel, amcinafide, beclametha methylprednisolone, mometasone furoate, paramethasone, Sone, betamethasone, betamethasone dipropionate, , prednisone, prednisolone, predni betamethasone Valerate, clobetaSone propionate, chloro done, triamcinolone acetonide, triamcinolone hexacatonide, prednisone, clocortelone, Cortisol, cortisone, cortodoxone, and triamcinolone, salts, derivatives, and a mixture thereof. difluorosone diacetate, descinolone, desonide, deflupred 4. Use according to claim 1, wherein the steroid is nate, dihydroxycortisone, desoximetaSone, dexamethasone, selected from the group consisting of cortisone, dexametha deflazacort, diflorasone, diflorasone diacetate, dichlorisone, Sone, fluocinolone, hydrocortisone, methylprednisolone, esters of betamethasone, fluazacort, flucetonide, flucloron prednisolone, prednisone, and triamcinolone. ide, fluidrotisone, fluorocortisone, flumethasone, flunisolide, 5. Use according to claim 1, wherein the ester of steroid fluocinonide, fluocinolone, fluocinolone acetonide, flucor is dexamethasone palmitate. tolone, fluperolone, fluprednisolone, fluoroandrenolone 6. Use according to claim 1, wherein the ester of steroid acetonide, fluocinolone acetonide, flurandrenolide, fluo is comprised in the composition in an amount of about rametholone, fluticasone propionate, hydrocortisone, hydro 0.01% to about 10% w/w preferably about 0.5% to about 3% cortisone butyrate, hydrocortisone Valerate, hydrocortamate, w/w, more preferably about 2% w/w or about 1% w/w of the loteprendol, medrysone, meprednisone, methylprednisone, composition. methylprednisolone, mometasone furoate, paramethasone, 7. Use according to claim 1, wherein said ester of steroid paramethasone acetate, prednisone, prednisolone, predni is in combination with any ophthalmically acceptable done, triamcinolone acetonide, triamcinolone hexacatonide, excipient or carrier, or within an implant. and triamcinolone, salts, derivatives, and a mixture thereof. 8. Use according to claim 7, wherein the carrier is selected 19. Use according to claim 2, wherein the steroid is from an ophthalmic acceptable oil, a phospholipid vesicles selected from the group consisting of cortisone, dexametha or oil-in-water emulsion or water-in-oil emulsion or any Sone, fluocinolone, hydrocortisone, methylprednisolone, other suitable carrier. prednisolone, prednisone, and triamcinolone. 9. Use according to claim 1, wherein the carrier is selected 20. Use according to claim 3, wherein the steroid is from an oil selected from MCT, castor oil and soybean oil, selected from the group consisting of cortisone, dexametha or from an emulsion where the oil phase is selected from Sone, fluocinolone, hydrocortisone, methylprednisolone, MCT, castor oil and soybean oil. prednisolone, prednisone, and triamcinolone. 10. Use according to claim 8 wherein the oil phase comprises at least about 1, at least about 5, at least about 10, k k k k k