Compositions and methods for treating a posterior segment of an eye

European).

15/23853

EP 1682185

The invention relates to compositions and methods for treating posterior portions of the human or animal eye. More specifically, the invention relates to compositions containing corticosteroid components that can be effectively injected into the posterior portions of the eye, and methods of using such compositions to provide the desired therapeutic effects.

Among the therapies currently used to treat diseases of the posterior parts of the eye, such as uveitis, macular degeneration, macular edema, and the like, is intravitreal injection of a corticosteroid such as triamcinolone acetonide (TA). See, for example, US Patent No. 5,770,589 Billson et al.

One of the commonly used drugs in the treatment of eyes is Kenalog 40. Each milliliter (ml) of the composition Kenalog 40 contains 40 milligrams (mg) TA (triamcinolone acetonide), sodium chloride as a phonic agent, 10 mg of benzyl alcohol as a preservative, 7.5 mg carboxymethyl cellulose, and o, 4 mg polysorbate 80 as an aid in re-suspension. Although widely used by ophthalmologists, these commercially available formulations have many significant limitations.

For example, the presence of benzyl alcohol as a preservative and polysorbate 80 as a surfactant leads to unnecessary and / or pulsating cellular damage or other toxicity in sensitive ocular tissues. And while some doctors routinely "wash" TA sedimentation with saline many times to reduce the concentration of unwanted materials, such washing is inconvenient, time consuming, and most importantly, increases the possibility of microbial or endotoxin contamination that can lead to ocular infections and inflammation.

In addition, TA in the Kenalog 40 formulation tends to quickly separate and precipitate as a residue from the remaining composition. For example, if such a composition is left for 1 to 2 hours, TA precipitate will separate from the remaining composition. Therefore, if the composition is injected into the eye, it must be well shaken and used immediately after that shake to deliver a substantially homogeneous suspension to the eye. In addition, the suspension reconstitution process requires the use of the above-mentioned suspension reconstitution aids, at least one of which is less than completely desirable for sensitive ocular tissue.

Patent publication EP 0 244 178 A2 relates to an ophthalmic composition containing an aqueous solution of a pharmaceutical compound and a polysaccharide such as hyaluric acid.

Publication WO 2005/032510 A1 is the prior art according to art. 54 (3) EPC and discloses injectable suspension compositions containing triamcinolone acetonide or anecortave acetate for injection in posterior parts of the eye for the treatment of ocular diseases. These compositions contain polyvinylpyrrolidone in an amount sufficient to increase the physical stability of the suspension composition.

Publication WO 2004/073607 A2 is prior art according to art. 54 (3) EPC and discloses methods and compositions for the treatment of retinal edema and NPDR (nonproliferative diabetic retinopathy).

There is a need for new compositions for injection into the posterior parts of the human or animal eye, and methods for providing the desired therapeutic effects in the posterior parts of the human or animal eye.

Summary of the Invention

New compositions and methods have been found for treatment of posterior portions of the human or animal eye. The subject compositions are very suitable for administration through an effective body, for example, manually, injected into the vitreous to the posterior parts of the eye, without any of the required "washing steps", providing a reduction in ocular damage, e.g. retina, when applied to the eye. The present composition contains no preservatives, for example, no preservative benzyl alcohol. In addition, the present composition preferably does not require suspending agents or auxiliaries. In addition, the subject composition is capable of being easily and effectively injected into the posterior portions of the human or animal eye, and can be maintained as a substantially homogeneous suspension for a long period of time, namely for at least one week, without a resuspension process, for example, without having to agitation or other agitation of the composition to obtain a substantially uniform suspension. Briefly, the subject compositions and methods provide improvements and benefits, for example, relative to the prior art Kenalog® 40 composition, and methods for applying such a prior art composition to the posterior portions of the human or animal eye.

In a broad aspect of the present invention, compositions useful for injection into the posterior portions of the human or animal eye are provided. Such compositions include a corticosteroid component that has a water solubility at 25 ° C less than 10 mg / mL, a viscosity inducing component, and an aqueous carrier component. The corticosteroid component is present in a therapeutically effective amount. The corticosteroid component is present in the composition in a large number of particles.

The subject compositions may contain up to about 25% (w / v) or more of the corticosteroid component. In one very useful embodiment of the invention, the corticosteroid component is present in an amount of at least about 80 mg / mL of the composition. Preferably, the corticosteroid component is present in an amount ranging from about 1% to about 10% or 20% (w / v) of the composition.

In one very useful embodiment of the invention, the corticosteroid component is triamcinolone acetonide.

The viscosity inducing component is present in an amount effective to increase the viscosity of the composition.

A suitable, preferably ophthalmically acceptable, viscosity inducing component is used in accordance with the present invention as defined below.

Many such viscosity inducing ingredients have been proposed and / or used in ophthalmic ophthalmic compositions. Preferably, the viscosity-inducing component is present in the range of from about 0.5% to about 20% (w / v) of the composition. In a particularly preferred embodiment of the invention, the viscosity-inducing component is hyaluric acid, such as sodium hyaluronate.

In one embodiment of the invention, the compositions have a viscosity of at least about 10 mPas (cps) or at least about 100 mPa-s (cps), preferably at least about 1,000 mPa-s "(cps), more preferably at least about 10,000 mPas s (cps), even more preferably at least about 7,000 mPa-s (cps), e.g. up to about 250,000 mPa-s (cps), or about 300,000 mPa-s (cps), at a shear rate of 0.1 / second. The subject compositions are made or prepared to be effectively, for example, manually injected into the posterior portions of the human or animal eye, preferably by puncture with a needle, more preferably by 29 or 30 with a needle.

Without intending to limit the invention to any theory of operation, we believe that the use of high viscosity compositions as described herein leads to effective, and preferably substantially uniform suspension of particles of the steroid component, at the same time being capable of being injected into the posterior fragments eye through conventional or even less conventional needles.

According to the invention, the corticosteroid component is present in the composition in a variety of particles that are substantially uniformly suspended in the composition and remain substantially uniformly suspended in the composition for at least one week, preferably for at least two weeks, or at least about 1 month, even more preferably for at least 6 months, or at least about 1 year, or at least about 2 years, without having to reconstitute the suspension, that is, without the need for agitation or other agitation of the composition to keep the particles of the corticosteroid component substantially uniformly suspended in the composition.

Compositions containing such a substantially uniform suspension of particles of the corticosteroid component have significant advantages over prior art compositions. In particular, the subject composition can be prepared, transported and stored for a substantial period of time without precipitation of the corticosteroid component particles from the remaining composition. When the particles of the corticosteroid component are suspended evenly throughout the composition, this allows for a quick and effective treatment of the posterior fragments of the human or animal eye without anxiety due to re-suspension of these particles.

The aqueous carrier component is preferably ophthalmologically acceptable and may include one or more conventional preferred agents useful in ophthalmic compositions.

For example, the carrier component may include an effective amount of at least one preservative, tonicity component and buffer component.

The subject compositions do not contain an additional preservative ingredient. This feature reduces or minimizes or even substantially eliminates the adverse reactions in the eye that may be induced or associated with the presence of a preservative component.

Although the suspension reconstitution component may be used in accordance with the present invention, in many cases due to the ability of the subject composition to remain in a substantially homogeneous suspension for a long period of time without the necessary suspension reconstitution process, the compositions preferably do not contain additional suspension reconstitution components.

Methods for treating the posterior portions of the human or animal eye are described below. In general, such methods include administration, e.g., injection, of a composition comprising a corticosteroid component, for example, of the composition of the invention, posterior fragments of the human or animal eye. Such administration is effective in providing the desired therapeutic effect. The administration step preferably includes at least one intravitreal injection, subconjunctival injection, intraocular injection, extra-ocular injection, supra-epidural injection, and the like.

Each and all features described herein, and each and all combinations of two or more such features are within the scope of the present invention, provided that the features included in this combination are not incompatible with each other.

These and other aspects and advantages of the present invention are apparent in the following detailed description, examples and claims.

Detailed description

The present invention provides compositions useful for placement, preferably by injection, into the posterior fragment of a human or animal eye. Such compositions for the posterior fragment of the eye, e.g. for the vitreous of the eye, are therapeutically effective with respect to the conditions and / or diseases of the posterior fragment of the eye, and / or one or more symptoms of such conditions and / or diseases of the posterior fragment of the eye.

In general, the subject compositions comprise a corticosteroid component; viscosity inducing component; and an aqueous carrier component. The compositions are preferably ophthalmologically acceptable.

One important advantage of the present compositions is that they are friendly or compatible with the tissues of the posterior fragment of the eye, for example, the retina of the eye, compared to compositions of the prior art proposed for injection into the posterior fragment of the eye, for example, the composition sold under the trade name Kenalog ®-40. In particular, the subject compositions do not contain additional preservative ingredients such as benzyl alcohol, which is included in the Kenalog®-40 composition as a preservative ingredient.

In addition, the subject compositions do not contain an additional suspending or re-suspending component that is more friendly or compatible with the tissues of the posterior fragment of the eye, e.g. the retina of the eye, compared to polysorbate-80 which is included in the Kenalog® composition 40. Many other features of the subject compositions as described herein also make the subject compositions more friendly or compatible with the tissues of the posterior fragment of the eye into which the compositions are incorporated, compared to prior art compositions such as Kenalog®-40.

As stated above, the subject compositions contain a corticosteroid component. Such a corticosteroid component is included in the composition in a therapeutically effective amount, which is an amount effective to provide the desired therapeutic effect in the eye in which the composition is placed. The corticosteroid component is contained in the composition in a large number of particles.

According to the invention, any corticosteroid component may be used. Such a corticosteroid component has limited solubility in water, namely at 25 ° C. This means that the corticosteroid component has a water solubility at 25 ° C lower than 10 mg / ml.

Of course, the corticosteroid component should be ophthalmologically acceptable, that is, it should generally have little or no harmful effect on the structure of the eye or tissue. One particularly useful characteristic of the subject useful corticosteroid component is the ability of such a component to reduce the inflammation of the posterior fragment of the eye to which the composition is delivered caused by the action of one or more diseases and / or conditions in the posterior fragment of the eye.

Examples of useful corticosteroid components include, but are not limited to, cortisone, prednisolone, triamcinolone, triamcinolone acetonide, fluorometholone, medrison, loteprenol, derivatives thereof, and mixtures thereof. The term "derivatives" as used herein refers to any substance that is structurally sufficiently similar to a material that identifies itself as a derivative that has essentially the same functionality or activity, for example, therapeutic efficacy as the material, when the substance is used as a substitute material.

In one preferred embodiment of the invention, the corticosteroid component is triamcinolone acetonide.

The corticosteroid component is preferably present in an amount of at least 10 mg per ml of composition. One preferred feature of the invention is the effective ability of the present composition to incorporate a relatively large amount or concentration of the corticosteroid component. Therefore, the corticosteroid component may be present in the present composition in an amount in the range of about 1% or less, to about 5% or about 10%, or about 20%, about 30% or more (w / v) of the composition. Providing a relatively high concentration or amount of the corticosteroid component in the composition of the invention is an advantageous feature because it reduces the amount of composition required to be inserted or injected into the posterior fragment of the eye to deliver the same or more corticosteroid component to the posterior fragment of the eye, relative to other compositions. such as Kenalog®-40, which contains less than 4% (w / v) of the corticosteroid component. Therefore, in one very preferred embodiment of the invention, the subject compositions contain more than about 4% (w / v), for example at least about 5% (w / v), to about 10% (w / v) or about 20% (w / v) or about 30% (w / v) corticosteroid component.

The viscosity inducing component is present in an amount effective to increase, preferably substantially increase, the viscosity of the composition. Without intending to limit the invention to any particular theory of operations, we believe that increasing the viscosity of the composition to a value much greater than that of water, for example, at least about 100 cps at a shear rate of 0.1 / second, provides compositions that are highly effective to be placed, e.g. by injection in the back of the human or animal eye. Due to the beneficial introduction or injection of the subject compositions into the posterior portions of the eye, we believe that the relative high viscosity of the composition increases the ability of the composition to keep particles of the corticosteroid component in a substantially uniform suspension in the compositions for a prolonged period of time, for example for at least about one week, without having to suspension reconstitution process. The relatively high viscosity of the subject compositions may also have an additional benefit by at least helping the composition to have the ability to have an increased amount or concentration of the corticosteroid component, as discussed herein, for example, while maintaining such a corticosteroid component in a substantially uniform suspension for an extended period of time.

Preferably, the present compositions have a viscosity of at least about 10 cps or at least about 100 cps, or at least about 1000 cps, more preferably at least about 10,000 cps, even more preferably at least about 70,000 cps or more, e.g. up to 200 000 cps or about 250,000 cps, or about 300,000 cps or more, at a shear rate of 0.1 / second. The subject compositions not only have a relatively high viscosity as above, but also have the ability or are constructed or made to be effectively positioned, e.g., by injection, into the posterior portion of the human or animal eye, preferably through 27 punctures with a needle or even puncture with a needle.

Useful viscosity-inducing components are preferably slip-thinning components such that the present composition containing such a viscosity-reducing component is passed or injected into the posterior fragment of the eye, for example, through narrow areas such as through puncture with a needle, where under high shear the viscosity of the composition is substantially reduced during such transition. After such passage, the composition substantially regains its previous viscosity prior to injection, thereby keeping the corticosteroid component particles suspended in the eye.

Any component that produces a suitable viscosity, for example, an ophthalmically acceptable component that produces a viscosity, can be used in accordance with the present invention. Many such viscosity-inducing ingredients have been proposed or used in ophthalmic compositions for use in the eye or in the eye. The viscosity inducing component is present in the composition in an amount effective to provide the desired viscosity. Preferably, the viscosity-inducing component is present in an amount in the range of about 0.5% or about 1% to about 5% or about 10%, or about 20% (w / v) of the composition. The specific amount of viscosity-inducing component used depends on the amount of certain factors including, for example, but not limited to, the specific viscosity-inducing component used, the molecular weight of the viscosity-inducing component used, the viscosity required for the subject composition produced / or used, and the like. The viscosity inducing component is selected to provide at least one advantage, preferably many advantages of the present composition, for example, the ability to inject into the posterior fragment of the eye, viscosity, the ability to suspend the particles of the corticosteroid component in suspension, for example in a substantially homogeneous suspension for a prolonged period of time. without reconstruction of the suspension, compatibility with the tissues of the posterior eye fragment into which the composition is introduced, and the like. More preferably, the selected viscosity inducing component is effective to provide two or more of the above-mentioned advantages, and even more preferably to provide all of the above-mentioned advantages.

The viscosity inducing component preferably comprises a polymer component and / or at least one viscoplastic agent, such as those materials that are useful in ophthalmic surgical procedures.

The viscosity inducing component is selected from the group consisting of hyaluric acid, metal hyaluronate, carbomers, polyacrylic acid, cellulose derivatives, polycarbophil, gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl acetate, and mixtures thereof.

The molecular weight of useful viscosity-inducing components may be in the range of about 10,000 Dalton or less to about 2 million Dalton or more. In one preferred embodiment of the invention, the molecular weight of the viscosity inducing component ranges from about 100,000 Dalton or about 200,000 Dalton, to about 1 million Dalton or about 1.5 million Dalton. Again, the molecular weight of the useful viscosity-inducing components of the invention can be varied to a substantial extent based on the type of viscosity-inducing component used, and the desired final viscosity of the present composition, as well as possible one or more factors.

In one very preferred embodiment of the invention, the viscosity-inducing component is a hyaluronan component, for example, a metal hyaluronate, preferably selected from alkali metal hyaluronates, alkaline earth metal hyaluronates, and mixtures thereof, even more preferably selected from sodium hyaluronates and mixtures thereof. The molecular weight of such a hyaluronan component is preferably in the range of from about 50,000 Dalton or about 100,000 Dalton, to about 1.3 million Dalton or about 2 million Dalton. In one embodiment of the invention, the subject compositions comprise a hyaluronan component in an amount of from about 0.05% to about 0.5% (w / v). In another preferred embodiment of the invention, the hyaluronan component is present in an amount ranging from about 1% to about 4% (w / v) composition. In the latter case, very high polymeric viscosity forms a gel which slows down the settling of the particles extending the time so that there is often no need to reconstitute the suspension for the evaluated shelf life of the composition on the shelf, for example, for at least about 2 years. Such a composition can be sold in pre-filled syringes because the gel cannot be easily removed by the needle and syringe from the contents of the container.

The aqueous carrier component is preferably ophthalmologically acceptable and may include one or more conventional carriers useful in ophthalmic compositions.

In the present compositions, the majority is preferably liquid water. The subject compositions may be and preferably are sterile, for example, prior to being applied to the eye.

The subject compositions preferably contain at least one buffer component in an amount effective to control the pH of the composition and / or at least one component of the tonicity or osmolality of the composition. More preferably, the subject compositions contain both components, i.e. the buffer component and the tonicity component.

The buffer component and tonicity component may be selected from those that are conventional and well known in ophthalmology.

Examples of such buffer ingredients include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, borate buffers and the like, and mixtures thereof. Phosphate buffers are particularly useful. Useful tonicity components include, but are not limited to, salts, especially sodium chloride, potassium chloride, and any suitable ophthalmologically acceptable tonicity component, and mixtures thereof.

The amount of buffer component used is preferably sufficient to maintain the pH of the composition in the range of from about 6 to about 8, more preferably from about 7 to about 7.5. The amount of tonicity component used is preferably sufficient to provide osmolality of the present composition in the range of from about 200 to about 400, more preferably from about 250 to about 350 mosmol / kg, respectively. Preferably, the subject compositions are substantially isotonic.

The subject compositions may contain one or more other ingredients in an amount effective to provide one or more beneficial properties and / or benefits to the present compositions.

In addition, the subject composition may contain an effective amount of the component to re-suspend, effective to facilitate suspension or reconstitution of the particle suspension of the corticosteroid component in the present compositions. As noted above, in some embodiments, the subject compositions do not contain components for re-suspension. In other embodiments, the subject compositions contain ingredients for re-suspension, for example to increase the confidence that the particles of the corticosteroid component will remain in suspension, if required and / or the re-suspension in the present composition can be relatively easily formed, such re-formation suspensions are needed. Preferably, the re-suspension component used in accordance with the invention, if present, is selected to be more compatible or tissue-friendly in the posterior segment of the eye into which the composition is introduced, than polysorbate 80.

Any suitable component for re-suspension may be used in accordance with the invention. Examples of such re-suspension components include, but are not limited to, surfactants such as polyoxanes, for example, sold under the trade name Pluronic®; tyloxapol; sarcosinates; polyethoxylated castor oils, other surfactants, and similar types, and mixtures thereof.

Compounds selected from vitamin derivatives are a very useful class of ingredients for re-suspension. Although such materials have previously been suggested as surfactants for use in ophthalmic compositions, they have been found to be effective in the compositions of the invention as ingredients for re-suspension. Examples of useful vitamin derivatives include, but are not limited to, vitamin E tocopheryl polyethylene glycol succinates, such as vitamin E tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS). Other useful vitamin derivatives include, but are not limited to, vitamin E tocopheryl polyethylene glycol succinamides, such as vitamin E tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGSA), where the ester bond between polyethylene glycol and succinic acid is replaced by an amide group.

Currently, useful ingredients for re-suspending are, if any, in the compositions of the invention in amounts effective to facilitate particle suspension and after or after the manufacturing process. The specific amount of the suspension reconstitution component can be used in a very wide range depending on, for example, the specificity of the suspension reconstitution component used, the specificity of the composition into which the suspension reconstitution component used is incorporated, and the like. A suitable concentration of the reconstituting component often ranges from about 0.01% to about 5%, for example, from about 0.02% or about 0.05% to about 1% (w / v) of the composition.

The availability of minimally soluble corticosteroid components, such as triamcinolone acetonide, to ocular tissues may be limited by the degree of solubility of these substances. Slow dissolution is both good and bad for the patient. 2 on the one hand, after a single intravitreal injection of the present composition, the average half-life of triamcinolone acetonide is preferably quite long, for example about 19 days in patients injected intravitreal, and measurable drug levels are detected up to about 3 months . On the other hand, the therapeutic level of the drug in the vitreous portion (range) of the eye may not be achievable for about 1 to about 3 days, due to the slow solubility of the particles of the corticosteroid component.

In one embodiment of the invention, an effective amount of the solubilizing component is provided in the composition for solubilizing a smaller amount that is less than 50%, for example in the range of 1% or about 5% to about 10% or about 20% of the corticosteroid component. For example, inclusions of a cyclodextrin component such as β-cyclodextrin, sulfo-butyl ether β-cyclodextrin (SBE), other cyclodextrins and the like and mixtures thereof, at a level of 0.5% or about 5.0% (w / v) , solubilizes about 1 to about 10% of the initial dose of triamcinolone acetonide. This pre-solubilized fraction provides an easily bioavailable loading dose, thereby avoiding any time delay in the effectiveness of the therapy.

The use of such a solubilizer is advantageous in providing relatively rapid release of the corticosteroid component into the eye for therapeutic efficacy. Such a solubilizer, of course, should be ophthalmologically acceptable or at least compatible enough with the posterior fragment of the eye into which the composition is introduced to avoid tissue damage in that fragment of the eye.

The pharmacokinetics of the corticosteroid component, e.g. triamcinolone acetonide, following "" intravitreal administration may induce a degree of drug dissolution rate and a degree of efflux rate through the previous route. For example, after a single intravitreal injection of a composition containing 4% (w / v) triamcinolone acetonide (TA), the peak (peak) TA concentration (monitored in the aqueous humor) after several days was thousands of nanograms per mL. This peak (C_max) follows a sharp decline lasting about 200 hours, and ends in a slow secretion phase with a half-life of about 19 days. Patients generally require a repeat dosing, for example about every three months.

In one embodiment of the present invention, the compositions may further contain release retarding ingredients, for example polymers such as poly (D, L-lactide) or poly (D, Llactide co-glycolide), in an amount effective to reduce the local degree of diffusion and / or degree of solubility of the corticosteroid particles. The result is a flattened secretion profile (active substance) with reduced value (C_max) and a more prolonged period of therapeutic effect, and thus a longer time between the required injections for many patients.

Any component which is preferably acceptable under the given conditions can be used for release. Useful examples are presented above. The slow release component is preferably metabolizable or bioabsorbable in the eye so that there is no residue for a long period of time. The amount of delayed release component may be within a relatively wide range depending, for example, on the specificity of the slow release component used, the required release profile, and the like. A typical amount of delayed release component, if present in the composition, ranges from about 0.05% to 0.1% to about 0.5 or about 1 or more percent (w / v) of the composition.

The subject compositions can be prepared using appropriate mixing / operations techniques, or techniques, for example, one or more conventional mixing methods. The method of manufacture should be selected to provide the composition in forms that are useful for insertion or injection into the posterior fragment of the human or animal eye. In one preferred embodiment of the invention, the dispersion of the concentrated corticosteroid component is obtained by combining the corticosteroid component with water, and adding an excipient (other than the viscosity-inducing component) to the final composition. The ingredients are mixed to form a dispersion of the corticosteroid component and placed in an autoclave and heated. Alternatively, the steroid powder may be exposed to γ ​​rays prior to addition to the sterile vehicle. The viscosity inducing component may already be purchased sterile or may be sterilized by conventional methods, for example, by lyophilization to obtain a sterile powder. The viscous sterile component is combined with water to form an aqueous concentrate. Under aseptic conditions, the dispersion of the concentrate of the corticosteroid component is mixed and added as a suspension to the concentrate of the viscosity-inducing component. Water is added in sufficient amount (qs) to obtain the desired composition, and the composition is mixed until it becomes uniform.

The present invention provides a method of using the present composition and is included within the scope of the present invention. Generally, such methods involve administering the compositions of the present invention to the posterior fragment of the human or animal eye, thereby obtaining the desired therapeutic effect. The administration step preferably includes at least one intravitreal injection, subconjunctival injection, intra-spinal injection, extra-ocular injection, supra-epidural injection, and the like. A syringe apparatus comprising a suitable size needle, for example up to 27 or 30 punctures with a needle, can be effectively used to inject the composition into the posterior portion of the human or animal eye.

Diseases / conditions that can be treated or treated in accordance with the invention include, but are not limited to, the following;

SLOT ENVIRONMENT / MESH VOLTAGE; Non-exudative Age Related Macular Degeneration (ARMD), Exudative Age Related Macular Degeneration (ARMD), Follicular Neovascularization, Diabetic Retinopathy, Acute Macular Neurorethinopathy, Intracranial Diastole.

VISCULATION OF THE EYE VEHICLE / MIRRID LIGHTING / VASCIDitis; Acute Multifocal Plaque Dye Epiteliopathy, Behcet's Disease, Birdshot Retinochoroidopathy (Non-Inflammatory Vasodegeneration), Infectious (Syphilis, Lyme, Tuberculosis, Toxoplasmosis), Indirect Vasculitis, Vascular Focal Sclerosis (MEWDS), Ophthalmic Sarcoidosis, Posterior Scleritis, Creeping Uveitis, Sub Retinal Fibrosis, and Uveitis. VogtKoyanagi-Harada team.

VASCULAR DISEASES / EXTREME DISEASES; Retinal Occlusive Disease, Retinal Vein Thrombosis, Generalized Intravascular Coagulation, Retinal Vein Branching Thrombosis, Ocular Hypertension Changes, Ocular Ischemic Syndrome, Retinal Artery Tear, Coats' Disease, Reticulitis, Reticulitis, Reticulitis, Reticulitis Thrombotic Branching Thrombosis, Carotid Artery Disease (CAD), Defrosted Branched Vascular Disease, Sickle Cell Retinopathy, and Other Hemoglobinopathies, Retinal Vasodilation, Family Exudative Vitreretinopathy, Eales Disease.

TRAUMATIC / SURGICAL Sympathetic Aromatitis, Retinal Uveitis, Retinal Detachment, Trauma, Laser, PDT, Photocoagulation, Surgery During

Hypoperfusion, Radial Retinopathy, Transplanted Bone Marrow.

PROLIFERATION DISEASES; Vitreous and Retinal Proliferative Retinopathy, Diabetic Proliferative Retinopathy.

INFECTIOUS DISEASES; Ophthalmic Histoplasmosis, Ophthalmic Toxocarosis, Receptive Ophthalmic Histoplasmosis Syndrome (POHS), Acute Intraocular Infectious Inflammation, Toxoplasmosis, Retinoid Diseases Associated With HIV Infection, Endovascular Diseases Associated With HIV Infection, HIV Endovascular Disease, Retinal Vascular Infection Infection Retinas, External Progressive Retinal Necrosis, Retinal Diseases associated with Fungi, Ocular Syphilis, Ocular Tuberculosis, Expanding Unilateral Subacute Retinitis and Optic Nerve, Mycosis.

GENETIC DISEASES; Retinitis pigmentosa, systemic disorders related to retinal dystrophy, night blindness, congenital permanent night blindness, retinal suppository dystrophy, stargardt disease and bilateral fundus inflammation, best disease, model retinal retinal pigment epithelium,,-retina , Sorsby Eye Bottom Dystrophy, Mild Macular Concentric Degeneration, Eietti Crystal Dystrophy, elastic pseudo yellow tuft.

MESH OPENING / HOLE IN MESH; Retinal Detachment, Macular Hole, Huge Retinal Tear,

CANCER; Tumor-related Retinal Diseases, RPE Congenital Hypertrophy, Posterior Uveal Melanoma, Hemangioma, Follicular Hemangioma, Follicular Metastasis, Retinoid and Malignant Tumor (Hamartoma), Retinal and Dye Epithelium, Retinoblastoma, Retinovascular, Vascular Neoplasm lymphoid.

DIFFERENT; Internal Puncture Choroidopathy, Acute Posterior Multifocal Plaque Dye Epiteliopathy, Acute Retinal Dye Epitelitis, and the like.

The subject methods may include a single injection into the posterior segment of the eye, or multiple injection, for example, a period of time from about one week, or about one month, or about three months, to about 6 months or about 1 year or more.

The following examples illustrate some aspects of the invention.

EXAMPLES 1-4

Four compositions having the following composition;

<td>Ingredient</td><td>Example 1</td><td>Example 2</td><td>Example 3</td><td>Example 4</td>

<td>acetonide triamcinolone</td><td>2% (w / v)</td><td>2% (w / v)</td><td>4% (w / v)</td><td>4% (w / v)</td>

<td>Sodium Hyalurane (0,6x10® Dalton)</td><td>0.05% (w / v)</td><td>0.5% (w / v)</td><td>0.05% (w / v)</td><td>0.5% (w / v)</td>

<td>Sodium phosphate</td><td>0.4% (w / v)</td><td>0.4% (w / v)</td><td>0.4% (w / v)</td><td>0.4% (w / v)</td>

<td>Vitamin E-TPGS</td><td>0.5% (w / v)</td><td>0.5% (w / v)</td><td> 0,0</td><td> 0, 0</td>

<td>8-cyclodextrin</td><td>0.5% (w / v)</td><td>0.5% (w / v)</td><td> 0,0</td><td> 0,0</td>

<td>Water to injections</td><td>qs</td><td>qs</td><td>q.'s.</td><td>qs</td>

<td>Viscosity at extent shear 0.1 / second</td><td>20 cps</td><td>500 cps</td><td>20 cps</td><td>500 cps</td>

(w / v) means (w / vol)

qs means as much as needed

Each of these compositions is prepared as follows.

The triamcinolone acetonide concentrate dispersion is made by combining triamcinolone acetonide with water, vitamin E-TPGS and 8-cyclodextrin, if any. The ingredients are mixed to form a triamcinolone acetonide dispersion and autoclaved. Sodium hyalurane may already be purchased as a sterile powder, or it may be sterilized by conventional methods by draining the diluted solution, for example, by lyophilization to obtain a sterile powder. Sterile sodium hyaluronate was dissolved in water to form an aqueous concentrate. The triamcinolone acetonide concentrate dispersion was mixed and added as a suspension to the sodium hyaluronate concentrate. Water was added in a quantity of qs and mixed until a homogeneous mixture was obtained.

Each of these compositions produces a weak fluctuation of triamcinolone acetonide, which is easily reproduced again by gentle inversion. These compositions can be sold in glass bottles with a low pharmaceutical grade volume, and have been found to be therapeutically effective against macular edema following intra vitreous injection of the human eye.

EXAMPLES 5-7

<td colspan="3">Three compositions having the following sk3</td><td>: Ad;</td>

<td>Ingredient</td><td>Example 5</td><td>Example 6</td><td>Example 7</td>

<td>acetonide triamcinolone</td><td>2.0% (w / v)</td><td>4.0 (w / v)</td><td>8.0% (w / v)</td>

<td>Sodium Hyalurane</td><td>3.0% (w / v)</td><td>2.5% (w / v)</td><td>2.0% (w / v)</td>

<td>Sodium phosphate</td><td>0.4% (w / v)</td><td>0.4% (w / v)</td><td>0.4% (w / v)</td>

<td>Water for injections</td><td>qs</td><td>qs</td><td>qs</td>

<td>Viscosity at shear rate 0.1 / second</td><td>180,000 cps</td><td>120,000 cps</td><td>80,000 cps</td>

These compositions are prepared in a manner substantially analogous to those described in Example 1.

The high viscosity of the composition essentially slows the sedimentation of the particles by extending it over time, so that no suspension reconstitution process or requirement for the composition to last beyond the estimated half-life, e.g. about 2 years, is needed. These compositions can be sold in pre-filled syringes because they are not easily removed through the needle and syringe from the container. However, the composition of pre-filled syringes can be effectively injected into the posterior portion of the human eye using 27 or 30 needle punctures to deliver the desired therapeutic effect in the human eye.

The compositions of Examples 5-7 use or contain a concentration of high molecular weight sodium hyiuronate sufficient to form a gelatin plug or drug depot for injection into the vitreous body of the human eye. Triamcinolone acetonide particles are, in effect, trapped or retained by a sticky plug, also no undesirable "pluming" occurs, and the risk of adverse settling of particles directly on the ocular tissue is substantially reduced, for example compared to a known composition with a water-like viscosity, such like Kenalog®40. Since sodium hyiauronate solutions are the object of sharp shear and thinning, these preparations are easily injected through 27 or even 30 punctures with a needle.

EXAMPLES 8-9

Two compositions having the following composition;

<td>Ingredient</td><td>Example 8</td><td>Example 9</td>

<td>triamcinolone acetonide</td><td>2.0% (w / v)</td><td>8.0 (w / v)</td>

<td>Sodium hyalurate</td><td>2.5% (w / v)</td><td>2.3% (w / v)</td>

<td>Sodium chloride</td><td>0.63% (w / v)</td><td>0.6% (w / v)</td>

<td>Dibasic sodium phosphate pentahydrate</td><td>0.30% (w / v)</td><td>0.30% (w / v)</td>

<td>Monobasic sodium phosphate monohydrate</td><td>0.04% (w / v)</td><td>0.04% (w / v)</td>

<td>Water for injections</td><td>qs</td><td>qs</td>

<td>Viscosity at shear rate 0.1 / second</td><td>170,000 ± 25% cps</td><td>200,000 ± 25% cps</td>

These compositions are prepared in a substantially analogous manner as outlined in Example 1.

The high viscosity of the composition essentially slows down the sedimentation of the particles by extending it over time, so that no suspension reconstitution process or requirement for the composition to last beyond the estimated half-life, e.g. about 2 years, is needed. These compositions can be sold in pre-filled syringes because they are not easily removed through the needle and syringe from the container. However, the composition of pre-filled syringes can be effectively injected into the posterior portion of the human eye using 27 or 30 punctures with a needle to provide the desired therapeutic effect in the human eye.

The sodium hyaluronate powder used in these compositions (as well as other compositions as defined in the Examples herein) contains water in the range of from about 4% to about 20%, preferably from about 1% to about 8% by weight. The water content of the powder, and in particular the variable water content of the powders, may result from different viscosities of one or more compositions according to the invention, and which are produced using the same "nominal" chemical method. Therefore, the viscosities given herein should be understood as target viscosities, with the composition being acceptable for use if the current viscosity of the composition is in the plus or minus (±) range of about 25%, or about 30%, or about 35% of the target viscosity.

Since each of the compositions shown in the examples has a density of about 1 gm / ml, the percentage given here based on weight per volume (w / v), can also be considered based on weight per weight (w / w).

The compositions of Examples 8 and 9 use or contain a sufficient concentration of high molecular weight sodium hyaluronate to form a gelatinous plug or drug depot for injection into the vitreous humor of the human eye. Triamcinolone acetonide particles are, in effect, trapped or retained by a sticky plug, also no undesirable "pluming" occurs, and the risk of adverse settling of particles directly on the ocular tissue is substantially reduced, for example compared to a known composition with a water-like viscosity, such like Kenalog®40. Since sodium hyaluronate solutions are the object of sharp shearing and thinning, these preparations are easily injected through 27 or even 30 punctures with a needle.

Since the present invention is described by respecting various specific examples and embodiments, it should be understood that the invention can be widely used within the scope of the claims.