KR101541416B1 - Use of a Steroid Prodrug for the Treatment of Disease of the Posterior Segment of the Eye - Google Patents

Abstract

There is provided a use of a composition for preparing an ophthalmic composition for treating a symptom or a disease of a human or animal eye. The composition contains at least one prodrug of a steroid prodrug, preferably a prodrug of a corticosteroid.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to the use of a steroid prodrug for the treatment of posterior segment disease,

The present invention relates to the field of treating ophthalmic diseases, in particular human or animal eye diseases, with at least one steroid, especially at least one corticosteroid.

The present invention particularly focuses on the inclusion of at least one steroid, preferably a corticosteroid, as an ophthalmic composition or device, preferably as an ophthalmic emulsion. The present invention also relates to the administration of such ophthalmic compositions, in particular intraocular administration. The present invention also relates to the controlled release of a pharmacologically active agent, in particular a corticosteroid, in the eye, especially in the posterior segment of the eye.

Posterior respiratory disease is a disease that mainly affects the choroid, sclera, vitreous body, vitreous chamber, retina, eye nerves and the posterior part of the eye such as the blood vessels or nerves connected to the posterior ocular site.

 Steroids are used to treat ophthalmic diseases that damage the posterior chamber of the eye, especially retinal vein occlusion (CRVO), retinal vein occlusion (BRVO), choroidal macular edema (CME), diabetic macular edema (DME) , Diabetic macular retinopathy (DMR), uveitis and old age macular degeneration (ARMD). These treatments usually involve systemic administration and are therefore subject to known side effects, and the side effects are considerable given the ophthalmic conditions to be treated. This side effect significantly reduces the importance of using systemic administration of steroids for these eye diseases.

There have been attempts with other methods of administration, such as topical administration, suprachoroidal administration, subconjuctival administration, retrobulbar administration, and intravitreal administration. In the case of topical application, dexamethasone permeation into the vitreous body is insignificant even after repetitive topical application (Weijtens, Ophthalmology 2002), even when 1 drop of 0.1% dexamethasone phosphate solution is added every hour for 10 hours . In contrast, when oral dexamethasone 7.5 mg was administered orally, serum and vitreous concentrations were observed at 60 and 5 ng / mL, respectively (Weijtens, Am J Ophthalmol, 1998).

On the other hand, after administration of dexamethasone under the conjunctiva or peribulbar, retinal submucosal level was 120 times and 13 times higher than oral administration, respectively (Weijtens et al., Ophthalmolgy 2000). Local intraocular administration is therefore highly desirable.

However, injecting a significant amount of steroids into the eye means that the concentration of steroids in all the structures of the eye is rapidly increased to a large value, which can lead to local side effects of the undesired eye, especially when the intraocular pressure is significantly increased and can progress to glaucoma Or appearance of the cataract or appearance of cataract.

The presence of corticosteroids in the anterior segment of the eye has attracted attention because it is associated with these adverse effects. It has thus become clear that an effective amount of a corticosteroid should be administered as topically as possible, and thus, to the lesion selectively.

The effectiveness of the treatment is particularly related to the presence of the active compound, and thus to the half-life of the drug. The known corticosteroid, dexamethasone, has a half-life of 3.5 hours when injected into the eye (Kwak, Arch Ophthalmol, 1992). However, it is difficult to tolerate repeated injections for patients who have been ill for many years or are suffering from chronic diseases. Moreover, repeated injections may cause adverse side effects such as retinal detachment, endophthalmitis, and cataracts.

An intraocular implant of steroids has been developed because of the additional side effects of repeated injections. 0.59 mg of RETISERT (a trademark of Bausch & Lomb, a vitreous body of fluorocinolone acetonide) is a sterile insert designed for local release of fluocinolone acetonide in the posterior segment. RETISERT has recently been approved by the US Food and Drug Administration and applies to the treatment of chronic noninfectious uveitis in the posterior segment. However, in clinical trials using this insert, increased intraocular pressure and cataracts were the main adverse effects. Holekamp et al. Found that the incidence of complications after prolonged high doses of fluorocinolone acetonide was significant, with elevated intraocular pressure in 100% of eyes treated with nonischemic retinal vein occlusion in 30% of treated eyes. This complication necessitated removal of the implant from nearly 60% of the treated eyes (Am J Ophthalmol., 2005). The use of 0.59 mg or 2.1 mg fluorocinone acetonide insertions in patients with non-infective posterior uveitis leads to a 5-fold increase in the number of patients requiring intraocular pressure reductions (Jaffe, Ophthalmology, 2005). Randomized clinical trials of diabetic macular edema patients with 0.59 mg fluorocinolone acetonide in the vitreous showed that the most common side effects were severe cataract progression (43.1%) and severe intraocular pressure elevation (8.6%) (Pearson, ISOPT Communication , Berlin 2006). According to the results of the RETISERT clinical trial, about 34% of the treated patients require about 60% of the IOP regulator to control the IOP. Approximately 32% of physicians will need to perform filtration for intraocular pressure control within about 2 years after insertion. Furthermore, it is expected that cataracts will occur in almost all phakic eyes within approximately 2 years after insertion and cataract surgery will be required (provided by Bausch & Lomb).

 Posurdex is another ophthalmic device developed by Allergan that contains 700 μg of dexamethasone, which is released in the first month after insertion. The efficacy of Posurdex has been evaluated for efficacy including persistent macular edema (Williams, ISOPT Communication, 2006) and anti-inflammatory effects after cataract surgery (Tan, Ophthalmology, 2004). However, in a clinical trial of the safety and efficacy of 700 ug dexamethasone used in the treatment of macular edema, 15% of patients showed a significant increase in intraocular pressure (25 mmHg) (Williams, ISOPT Communication, Berlin 2006)

The use of triamcinolone acetonide (a trademark of Kenalog 40 (Bristol Myers Squib)) in ophthalmic applications results in a slow release of this drug in a circular fashion, since this insoluble steroid is injected into the vitreous cavity and precipitates, Is only progressing gradually. It may therefore be regarded as a sustained release steroid formulation. However, this formulation, which was not originally developed for ophthalmic use, can lead to serious complications such as infectious endophthalmitis, sterile endophthalmitis, retinal toxicity, and crystalline retinal deposits. Nevertheless, this formulation has been administered into the vitreous to treat eye inflammation and a number of etiologic macular edema. In a retrospective analysis of subtenon administration of triamcinolone acetonide, 21% of patients reported increased intraocular pressure (Bui Quoc, J Fr Ophtalmol, 2002)

Other steroid-containing devices developed in this field include triamcinolone acetonide / polycaprolactone inserts (Beeley, J Biomed Mater A, 2005), triamcinolone / polyvinyl alcohol inserts (Ciulla, Br J Ophthalmol, 20030, Inserts (Kato, IOVS, 2004 and Okabe, IOVS, 2003).

Examination of such corticosteroid-containing intraocular lens implants revealed that long-term presence of corticosteroids in the posterior segment resulted in undesirable side effects, but nevertheless the therapeutic effect is uncertain.

Thus, an ophthalmic device or composition capable of satisfactorily delivering active steroids to a patient in a therapeutic dose, that is, to ensure safety, to have no toxic effects, and in particular to avoid unwanted systemic side effects by steroids administered in the eye .

One of the objects of the present invention is to provide a composition which is capable of delivering therapeutic doses of active steroids into the eye over an extended period of time. Such a composition of the present invention preferably delivers a therapeutic dose of steroid to the lesion. More preferably, the compositions of the present invention deliver the amount of steroid needed to treat the pathology of the patient. According to this embodiment, the compositions of the present invention are of great relevance in the field of personalized methods of treatment. Another object of the present invention is to improve the well-being of a patient by reducing the number of necessary injections. This is very important for the patient because the intraocular injection is very uncomfortable.

Under these preconditions, the inventors have found alternatives to treatments for the effective administration of steroids, preferably to administer corticosteroids in the eye. The present invention relates to the use of steroids, in particular prodrugs of corticosteroids, for the preparation of medicaments or ophthalmic compositions for the treatment of eye conditions or diseases in humans or animals. Such a drug or ophthalmic composition may be administered by invasive means, preferably by intraocular injection, more preferably by intravitreal injection, in order to continuously release the in situ substance of the pharmacological effect do.

The present inventors have found that dexamethasone palmitate, a corticosteroid precursor drug, is injected in situ , especially when injected intravenously in the vitreous.

While not wishing to be bound to any particular theory, the present inventors suspect that inflammatory cells (proliferating cells) of the eye selectively absorb lipophilic esters of such steroid prodrugs, preferably steroids. If the activity of the proliferating cells in the inflammation site is increased, the active site of the prodrug will be able to be targeted only in the lesion, thereby avoiding the unspecific release. Therefore, we anticipate that the side effects caused by the therapeutic agent will be less observed. Since this drug will be released at the site of the lesion, it may reduce undesirable harmful effects in other eye structures where this prodrug is not hydrolyzed. The present invention also allows the prodrug to maintain a desired action effect on the eye symptoms over a prolonged period of time in which the prodrug is at a certain position in the eye, wherein the effective amount of the active agent is maintained for a prolonged period of time, It can be released over the month. The present invention therefore also relates to customized therapies for patients who need steroid treatment of the eye. The necessary active steroids may be released into the eye according to the developmental stage of the patient's own pathology from the time of administration of the prodrug of the present invention to each patient so that an excessive and useless amount of active steroid in the vitreous body may be avoided .

Another advantage of the present invention is that the inventive steroid esters have not been able to show a wide range of side effects when administered orally. Furthermore, when the prodrug of the present invention, that is, the ester of steroid, was administered at a high concentration, it was impossible to observe a usual side effect, that is, an increase in intraocular pressure, which occurs when a steroid is present in a high concentration in the vitreous body. Another advantage of the present invention is that the prodrug of the present invention remains in the vitreous when administered, so that the vitreous is a reservoir of the inactive prodrug drug waiting to be released. Furthermore, the advantage of the present invention is that the amount of prodrug that is thought to be administered to the eye due to the sustained release of steroids from the side effects of the inactive prodrug and the prodrug is much greater than the amount of active (and toxic) It will do. Therefore, the number of times of scanning can be reduced. In one embodiment, the frequency of injection is once or less per month, preferably once every two months or less, more preferably once every three months or less, most preferably four, five, six Once a month or less.

In the present invention, the term " prodrug " refers to an ester of a steroid and is preferably a lipophilic long chain ester of a steroid, preferably a corticosteroid, which has more than 10 carbon atoms, preferably 14 More preferably 16, and the alkyl group is preferably directly linked to one functional group of the steroid. In one embodiment, the ester of the steroid of the present invention does not comprise a phosphate group. In one embodiment of the present invention, the ester group has the structure of -COOR or -OC (O) R, wherein R is a long chain alkyl or long chain alkenyl group, preferably a C4 to C16 alkyl group, more preferably C12, C14, C16, C18, C20, or, more preferably, all suitable lipophilic chains.

In one preferred embodiment of the present invention, the prodrug has no direct therapeutic and / or physiological effects and thus will be referred to as "inactive ", but the drug released by hydrolysis of the prodrug has a physiological therapeutic effect. Conversely, in the present invention, "active" steroids are steroids with direct therapeutic and / or physiological effects. Therefore, it is necessary to distinguish between a steroid or steroid derivative that is therapeutically direct and "active" and an ester of "inert" steroid, ie, a prodrug of the present invention, in accordance with the predefined meaning of the present invention.

The present invention relates to the use of a composition containing at least one steroid, preferably a prodrug of a corticosteroid, to produce an ophthalmic composition for treating ophthalmologic symptoms or diseases in humans or animals.

The composition of the present invention contains at least one prodrug of a corticosteroid, which is preferably selected from the following drug classes: alclometasone dipropionate, amcinonide, amoxicillin, amcinafel, amcinafide, beclamethasone, betamethasone, betamethasone dipropionate, betamethasone valerate, clobetasone propionate, chloroprednisone, clocortelone, , Cortisol, cortisone, cortodoxone, di-fluorosone diacetate, descinolone, desonide, defluprednate, dihydroxy-cortisone, Dexamethasone, deflazacort, diflorasone, diacetate di-flasone, dichloro- e), an ester of betamethasone, fluazacort, flucetonide, flucloronide, fludrotisone, fluorocortisone, flumethasone, flunisolid, fluosinol, A fluconolone acetonide, fluconolone, fluperolone, fluprednisolone, fluroandrenolone acetonide, fluocinolone acetonide, fluconolone acetonide, (S) selected from the group consisting of hydrochlorothiazide, nitrate, flurandrenolide, fluorametholone, fluticasone propionate, hydrocortisone, hydrocortisone butyrate, hydrocortisone valerate, hydrocortamate, such as loteprendol, medrysone, meprednisone, methylprednisone, methylprednisolone, mofrednisone, etameric furoate, paramethasone, paramethasone acetate, prednisone, prednisone, prednidone, triamcinolone acetonide, triamcinolone hexacatonide, triamcinolone and salts, derivatives or mixtures thereof.

More preferably, the corticosteroid is selected from the following drug classes: cortisone, dexamethasone, fluocinolone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone. In this embodiment, the composition of the present invention contains a prodrug of cortisone, dexamethasone, fluorocinone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone.

In a most preferred embodiment of the invention, the composition contains a prodrug of dexamethasone, more preferably dexamethasone palmitate.

In another preferred embodiment, the composition comprises a long chain ester of a steroid, preferably a C 12 -C 18 ester of a steroid, more preferably a dexamethasone laurate stearate, dexamethasone laurate stearate, triamcinolone palmitate, Triamcinolone palmitate acetonide, stearic acid triamcinolone acetonide, and lauric acid triamcinolone acetonide.

The content of the prodrug is preferably contained in the emulsion in an amount of about 0.01 to about 10% (w / w), preferably 0.05 to 5% (w / w) of the emulsion, more preferably 0.1 to 1 % (w / w). In one embodiment, the prodrug is preferably contained in the composition as an emulsion at about 0.5% to about 3% (w / w). In another preferred embodiment, the prodrug is contained at about 2% (w / w) in the composition, which is preferably an emulsion. In another preferred embodiment of the present invention, the prodrug is preferably contained in an amount of about 1% (w / w) in the composition which is an emulsion.

In one embodiment of the invention, the amount of prodrug to be administered is from 0.1 to 2.5 [ mu] mol of steroid, preferably equivalent to dexamethasone, in an amount equivalent to 0.01 to 6 [ mu] mol steroid steroid, preferably dexamethasone, , And most preferably 0.15 to 1.3 mu mol of steroid, preferably equivalent amount of dexamethasone.

In another embodiment, the molar amount of the ester of the steroid to be administered is higher than the non-toxic molar maximum of the steroid to be injected by the same administration method.

In one preferred embodiment of the invention, the amount of prodrug to be administered is the amount equivalent to 0.1 to 2.5 mg of dexamethasone therapeutically equivalent.

In another preferred embodiment, the amount of dexamethasone palmitate to be administered is in the range of 0.1 to 3.2 mg, preferably 0.2 to 1 mg, most preferably 0.4 to 0.8 mg.

In one embodiment, the solubility of the prodrug of the invention in water is less than 120 ug / mL, preferably less than 50 ug / mL, more preferably less than 10 ug / mL.

According to the present invention, the composition of the present invention comprises at least one steroidal prodrug dissolved in an ophthalmically acceptable oil.

In one embodiment of the invention, the carrier is selected from the group consisting of (1) oils, suitable oil carriers such as mineral oils such as silicone, paraffin, medium chain triglycerides, soybean oil, castor oil, olive oil, corn oil, Vegetable oil or any other oil suitable for intraocular injection, preferably MCT, castor oil and soybean oil, or (2) as an emulsion, the oil phase is selected from mineral oils such as silicone, paraffin, medium chain triglycerides, Vegetable oils such as soybean oil, castor oil, olive oil, corn oil, palm oil, or all other oils suitable for intraocular injection.

In one embodiment of the invention, the weight ratio of prodrug / oil is 0.04 to 0.3. In one preferred embodiment of the present invention, the ratio of dexamethasone palmitate / soybean oil is 0.04 to 0.3.

In another embodiment of the present invention, the composition of the present invention contains at least one steroid prodrug, which is dissolved in a physiologically acceptable oil and is subjected to various methods such as high shear force high pressure homogenization by an appropriate emulsifying device, (oil-in-water) emulsion. The final formulation of the prodrug may be sterilized by filtration or sterilized.

In one embodiment of the invention, the composition contains at least one prodrug as defined above, and any of the ophthalmologically acceptable excipients or carriers may be used in combination. The carrier may be selected from oils acceptable for ophthalmic use, phospholipid vesicles or oil-in-water emulsions or water-in-oil emulsions or other suitable carriers, which contain at least about 20% of the total composition / About 30%, or at least about 40%, preferably about 10% of the emulsion.

Properties to be considered in the excipient include, but are not limited to, biocompatibility, biodegradability at the site of insertion, compatibility with the prodrug and the processing temperature.

When such excipient or carrier is an emulsion, in one embodiment of the invention, the oil phase is present in an amount of at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30% %. In a preferred embodiment, the oil accounts for 10% of the weight of the composition. In this embodiment, the composition contains at least one surfactant, preferably 0.1-10% (w / w) by weight of the composition. In one embodiment, the surfactant is selected from phospholipids, poloxamers, tyloxapol, polysorbates and polyoxyethylene fatty acid esters. In this embodiment, the composition preferably contains at least one isotonic agent, preferably 0.1 to 10% (w / w) of the total composition. In one embodiment, the isotrope is glycerol.

Preferred compositions of the present invention are as follows.

  Role Amount (w / w)   Prodrug drug      0.01 to 10%   oil      1 to 40%   Surfactants      0.1 to 10%   An emerging topic      0.1 to 10%   Dispersant      Up to 100%

In one embodiment, the composition of the present invention is as follows.

  Role Amount (w / w)   Prodrug drug      0.1 to 5%   oil      8-12%   Surfactants      0.5 to 2%   An emerging topic      1 to 3%   Dispersant      Up to 100%

The term "approximately" or " about, "in the present invention means almost or" close ", and refers to the numerical value or numerical range of the numerical value or numerical value within the range of 10%

In one aspect of the invention, the composition of the invention is administered via intraocular injection, more preferably through a vitrectomized injection. In another aspect of the present invention, the composition of the present invention is administered by providing an intraocular lens implant containing or containing a composition of the present invention.

In another embodiment of the invention, the composition further comprises an active agent selected from a cyclosporin, an anti-VEGF antibody and / or an antibiotic.

In another aspect of the invention, the composition comprises at least one active agent selected from the group consisting of dexamethasone palmitate and cyclosporin, anti-VEGF antibodies and antibiotics.

The present invention also relates to a method for treating an ophthalmologic condition or disease of a person or an animal, comprising the step of administering the composition of the present invention in the eye.

In one embodiment, the methods of the invention comprise administering a steroid prodrug at a location in the eye of a patient suffering from a symptom or disease of the eye. The prodrug may be administered alone or in combination with an ophthalmic carrier suitable for ophthalmic administration. The carrier is a surfactant solution, oil, phospholipid vesicle or oil-in-water emulsion or other suitable carrier.

The administered prodrug is gradually released through hydrolysis of the enzyme in situ, resulting in a therapeutically effective amount of the active drug in the lesion. Therefore, the active drug acts on the inflammation site due to the ophthalmologic symptom or the disease, and the symptom is accompanied by the symptom.

The amount of steroid released in one embodiment of the invention depends on the condition of the patient. If the patient's condition is more severe, more steroids are released. This means that the more intense the condition, the greater the amount of steroid release. Thus, this treatment can be tailored to the severity of the patient's condition. The present invention thus relates to a method of intimately adhering to the amount of steroid needed to treat the precise condition of the patient.

In one aspect of the invention, the frequency of injecting the composition of the invention is once a month, preferably once every two months, more preferably once every six months. It is an advantage of the present invention that the need for repeated administration can be reduced.

In one aspect of the invention, the amount of drug / prodrug in the target tissue, preferably choroid or retina, is less than 1, preferably 0.5, more preferably 0.1, after one month.

In one aspect of the invention, the compositions of the invention are in the form of solutions, emulsions, suspensions. Examples of the composition of the present invention are as follows.

Composition A   Role   ingredient Amount (w / w)   Active agent   Dexamethasone palmitate      0.8%   oil   MCT      10%   Surfactants   Lipoid E-80      1.5%   An emerging topic   Glycerol      2.2%   Dispersant   water      Up to 100%

Composition B   Role   ingredient Amount (w / w)   Active agent   Dexamethasone palmitate      0.4%   oil   Soybean oil      10%   Surfactants   Lipoid E-80      1.5%   An emerging topic   Glycerol      2.2%   Dispersant   water      Up to 100%

Improvement of eye symptoms according to methods within the scope of the present invention can be confirmed by observing the following effects: improvement of visual acuity, improvement of visual contrast sensitivity, reduction of retinal or choroidal vascular leakage, retinal or macular thickness decrease in macular thickness or decreased number of cells in the aqueous humor or vitreous humor and flare.

In one embodiment of the invention, invasive means are used for administration of the composition. More preferably, the composition of the present invention is administered via an implant or intraocular injection, preferably via a vitrectomized injection.

The composition of the present invention is useful for the treatment of symptoms or diseases which are harmful to the inside of the eye, preferably the back of the eye. The composition of the present invention is particularly useful for the treatment of the following conditions or diseases: uveitis, macular edema, macular degeneration, retinal detachment, ocular tumor, bacterial / fungal infections other than viral, polyglossal choroiditis, diabetic retinopathy, proliferative vitreous Retinopathy (PVR), sympathetic eye inflammation, Vogt-Koyanagi-Harada syndrome, histoplasmosis, uveal diffusion and vascular occlusion.

In a preferred embodiment, the compositions of the invention are placed in an implantable device and are used for the treatment of uveitis, macular edema, vascular occlusion, proliferative vitreoretinopathy and various other retinopathies. Considering the advantages of the present invention to the patient in terms of the lack of toxicity, the convenience from the restriction of the number of injections, the storage of medication in the waiting for release, etc., the importance of direct administration of toxic steroids will be very limited in the future.

The present invention will be described in more detail with reference to the following examples. These embodiments are not to be construed as limiting the scope of the present invention in any way.

1. Analysis method for the simultaneous determination of dexamethasone and dexamethasone palmitate in the eye tissue

Liquid chromatography - mass spectrometry was developed for the simultaneous determination of dexamethasone and dexamethasone palmitate in eye tissue. The analytes and internal standard (roxithromycine) were extracted from the tissue using acetonitrile and separated by reversed phase liquid chromatography using a C8 column and concentration gradient mobile phase. These compounds were detected by mass spectrometry (atmospheric pressure ionization) using selective ion monitoring (SIM) (393.0 for dexamethasone and 631.5 for palmitic dexamethasone). This assay was selective for both compounds and the detection limit was 32.7 ng per gram of retina and 71.6 ng per choroid. And analyzed by applying an unweighed linear model.

2. Pharmacokinetic methods of palmitate dexamethasone and dexamethasone after vitrectomy

100 μL of 0.8% palmitic dexamethasone emulsion (8 mg / mL) was injected once into the unilateral intravitreal injection of the rabbit. Rabbits were sacrificed on days 1, 7, 14, 21, 28 or 60 (4 data per point of view). The amounts of dexamethasone (D) and dexamethasone palmitate (DP) in the tissues were measured. All concentrations are expressed in nmol per gram of tissue.

When 800 μg of the prodrug was injected into the vitreous, dexamethasone above 800 ng / g (greater than the therapeutic concentration) was maintained in the target tissue for at least two months. Furthermore, a significant amount of this prodrug palmitic dexamethasone remained on both the retina and choroid, indicating more sustained release.

At the same time, the amount of steroid in the aqueous humor could not be detected, suggesting that the surrounding tissues would have no side effects or even fewer. The final result was confirmed by intraocular pressure measurement, and the intraocular pressure was normal 2 months after injection.

Claims (24)

At least one ester of steroid selected from palmitic acid dexamethasone or palmitic acid triamcinolone,
Wherein the surfactant is selected from a phospholipid, a poloxamer, a tyloxapol, a polysorbate or a polyoxyethylene fatty acid ester,
An ophthalmic composition for treating an ophthalmic condition or disease in a human or animal, which is administered by intravitreal injection of the eye. The method according to claim 1,
Wherein said composition comprises from 0.01% to 10% (w / w) of an ester of steroid selected from palmitic acid dexamethasone or palmitic acid triamcinolone. The method according to claim 1,
Wherein the ester of steroid selected from palmitic dexamethasone or palmitic triamcinolone is combined with an ophthalmically acceptable excipient or carrier or is located within an implant. The method of claim 3,
Wherein said carrier is selected from the group consisting of ophthalmically acceptable oils, phospholipid vesicles, oil-in-water emulsions and water-in-oil emulsions. The ophthalmic composition according to claim 3, wherein said carrier is selected from the group consisting of:
(a1) mineral oil selected from the group consisting of silicon and paraffin, or (a2) vegetable oil selected from the group consisting of MCT, castor oil, olive oil, corn oil or soybean oil; or
Oil phase (b1) mineral oil selected from the group consisting of silicon or paraffin, or (b1) a vegetable oil selected from the group consisting of MCT, castor oil, olive oil, corn oil, palm oil or soybean oil. The method according to claim 4 or 5,
Wherein the oily phase of the emulsion comprises at least 1% by weight of the composition. The method according to claim 4 or 5,
Wherein the weight ratio of ester / oil of steroid is 0.04 to 0.3, and the ester of said steroid is selected from palmitic dexamethasone or palmitic triamcinolone. delete The ophthalmic composition of claim 1, wherein the surfactant is 0.1-10% w / w of the weight of the composition. The ophthalmic composition of claim 1, further comprising at least one isotonic agent. 11. An ophthalmic composition according to claim 10, wherein said isotonic agent is 0.1-10% w / w of the composition weight. 11. The ophthalmic composition of claim 10, wherein the isotonicity agent is glycerol. The composition according to claim 1, which comprises 0.01 to 10% w / w of an ester of steroid selected from palmitic acid dexamethasone or palmitic triamcinolone, 1 to 40% w / w of an oil, 0.1 to 10% w / w of a surfactant and 0.1 To 10% w / w of the composition. The composition of claim 1 wherein 0.01 to 5% w / w of an ester of steroid selected from palmitic acid dexamethasone or palmitic triamcinolone, 8-12% w / w of an oil, 0.5-2% w / w of a surfactant and 1 To 3% w / w of the composition. The ophthalmic composition according to claim 1, comprising dexamethasone palmitate 0.8% w / w, MCT 10% w / w, Lipoid E-80 1.5% w / w, glycerol 2.2% w / . The ophthalmic composition according to claim 1, characterized in that it comprises 0.4% w / w dexamethasone palmitate, 10% w / w soybean oil, 1.5% w / w Lipofectin E-80, 2.2% w / w glycerol, . The ophthalmic composition according to claim 1, characterized in that it comprises 5% w / w of palmitic acid triamcinolone, 10% w / w of MCT, 1.5% w / w of Lipoid E-80, 2.2% w / w of glycerol, . The method according to claim 1,
Wherein the administered palmitate dexamethasone or palmitate triamcinolone is gradually released upon hydrolysis of the enzyme in situ in situ to produce the corresponding steroid at a therapeutic concentration. The method according to claim 1,
Wherein the palmitic acid dexamethasone or palmitic acid triamcinolone is administered once every two months. The method according to claim 1,
Wherein the amount of the composition to be administered is such that the molar ratio of dexamethasone / palmitate dexamethasone or triamcinolone / palmitate triamcinolone is 1 or less in the retina or choroid after one month. The method according to claim 1,
Wherein the disease is an intra-ocular symptom or disease. 22. The method of claim 21,
Wherein the disease is selected from the group consisting of uveitis, macular edema, macular degeneration, retinal detachment, ocular tumors, viral or bacterial / fungal infections, multifocal choroiditis, diabetic retinas, (PVR), sympathetic eye inflammation, Vogt-Koyanagi-Harada syndrome, histoplasmosis, uveal diffusion and vascular occlusion. The method according to claim 1,
Wherein said composition further comprises an active agent selected from the group consisting of cyclosporin, anti-VEGF antibody and / or antibiotic. delete