Compositions and methods for treating a posterior segment of an eye

The present invention relates to a pharmaceutical composition useful for injection into the posterior segment of the eye of a human or animal and the use of the corticosteroid component of the triamcinolone component. More particularly, the invention provides corticosteroid compositions that can be efficiently incorporated into the posterior segment to achieve the desired therapeutic effects.

The use of eye drops is known to treat disorders of the posterior segment of the eye. US Patent 5,106,615 discloses isotonic humectant eye drops having non-Newtonian rheological properties that mimic the rheological properties of tears. These types of drops are useful in the treatment of various eye disorders including, for example, dry eye syndrome. Among the currently practiced treatments for posterior segment disorders such as uveitis, macular degeneration, macular edema and the like, an intravitreal administered corticosteroid such as triamcinolone acetonide (TA) is used as an active ingredient. See, for example, Billson et al., US Patent No. US-5,770,589, the disclosure of which is hereby incorporated by reference. It is known from US 5,166,331 and WO 02/100437 to use such a triamcinolone corticosteroid component for the preparation of a composition for the treatment of ocular disorders.

One commonly used drug of this type in the treatment of the eyes is Kenalog © 40. Each milliliter (ml) of Kenalog © 40 contains 40 milligrams (mg) of TA, and sodium chloride as a tonic, 10 mg of benzyl alcohol as a preservative, and 7, 5 mg of carboxymethyl cellulose and 0.4 mg of polysorbate 80 as a suspension aid. Although widely used by ophthalmologists, this commercially available formulation is not devoid of numerous important limitations.

For example, the presence of the benzyl alcohol preservative and the polysorbate 80 surfactant leads to^-cell damage or other signs of toxicity within the sensitive eye tissue. Although many clinicians routinely wash the precipitate with TA saline several times to reduce the concentration of these undesirable materials, such washing is inconvenient, time consuming, and most importantly, increases the likelihood of microbial contamination or endotoxin being present, which can lead to intraocular infection and inflammation.

In addition, the TA in Kenalog® 40 tends to rapidly separate and precipitate from the remainder of the composition. For example, such a composition, if left for 1 to 2 hours, undergoes substantial separation of the TA precipitate from the residual composition. Thus, if the composition is to be injected into the eye, it must be shaken vigorously and used immediately after shaking to deliver a substantially uniform suspension to the eye. In addition, re-suspending requires the use of the aforementioned re-suspending aids, at least one of which is less than fully desirable for sensitive ocular tissue.

Also known from EP 0244178 are compositions for intraocular administration containing an aqueous solution of a pharmaceutical compound and a polysaccharide such as hyaluronic acid.

However, there is still a need for new compositions for injection into the posterior segment of the eye of a human or animal and for methods that deliver the desired therapeutic effect on the posterior segment of the eye of a human or animal.

The present inventors have developed a novel pharmaceutical composition useful for injection into the posterior segment of the eye of humans or animals, and the use of the corticosteroid component triamcinolone for the preparation of such a composition. The composition of the present invention is highly suitable for intravitreal administration to the posterior segments of the eye without requiring any washing step during administration to minimize damage to the eye, for example the retina, when applied to the eye. The present composition preferably is substantially free of added preservatives, for example it does not contain the above-mentioned benzyl alcohol as a preservative. Moreover, it is preferred that such a composition does not require the presence of a re-suspending agent or agents. In summary, the present composition is easily and efficiently injected into the posterior segment of the eye of humans or animals, and can be kept as a substantially uniform suspension for long periods of time, for example, for at least one

One week or more without re-suspending and without requiring shaking or other agitation of the composition, for example, to obtain a substantially homogeneous suspension.

Briefly, the compositions and methods of the invention provide substantial improvements and advantages, for example, with respect to the art-recognized Kenalog 40 composition and methods using such a prior art composition for administration to the posterior segment of the eye of humans or animals.

In one aspect, the present invention provides compositions useful for injection into the posterior segment of the eye of a human or animal. Such compositions include:

a. a corticosteroid active ingredient triamcinolone acetonide present in the composition in a therapeutically effective amount between 2% and 8% by weight, wherein the corticosteroid component has a water solubility at 25 ° C of less than 10 mg / ml; and auxiliary substances

b. a viscosity inducing component in an amount sufficient to increase the viscosity of the composition; and

c. a component of an aqueous carrier.

The corticosteroid component particles are suspended in the composition of the invention and remain suspended in the composition for at least 1 week without needing to be resuspended, and the viscosity inducing component is selected from the group consisting of hyaluronic acid and metal hyaluronates. It is of utmost importance that the composition be free of any additional preservative ingredient.

Preferably, the particles of the corticosteroid component remain suspended in the composition for at least 2 weeks without requiring re-suspension, more preferably remaining suspended in the composition for at least 1 month without requiring re-suspension, even more preferably remaining suspended in the composition for at least 6 months without requiring re-suspension. particularly preferably they remain suspended in the composition for at least 1 year without requiring re-suspension, and most preferably remain suspended in the composition for at least 2 years with substantially homogeneously suspended particles of the corticosteroid component in the composition without requiring re-suspending, and thus without requiring shaking or subjecting to them. different mixing.

According to a preferred embodiment, the corticosteroid component is present in the composition in an amount of at least 10 mg per ml of the composition.

Preferably, the carrier component comprises an effective amount of at least one of a toning component and a buffering component.

According to a further preferred embodiment, the composition according to the invention is free of an additional re-suspend aid component.

Preferably, the viscosity inducing component is present in the composition in an amount ranging from 0.05% to 20% (w / v) of the composition.

According to a preferred embodiment of the invention, the hyaluronan component comprises sodium hyaluronate.

Any suitable, preferably ophthalmically acceptable, viscosity inducing component may be used in the practice of the present invention. Many such viscosity inducing ingredients have been proposed and / or used in ophthalmic or ophthalmic compositions. Preferably, the viscosity inducing component is present in an amount ranging from 0.5% to 20% (w / v) of the composition. In one particularly useful embodiment, the viscosity inducing component is indicated above as the preferred polymeric hyaluronic acid component, such as sodium hyaluronate.

In one embodiment, the compositions have a viscosity of at least 10 cps or at least 100 cps, preferably at least about 1,000 cps, more preferably at least 10,000 cps and even more preferably at least 70,000 cps, for example up to 250,000 cps, or 300,000 cps. , at a shear rate of 0.1 / second. The present compositions are structured or composed such that they can be effectively introduced, for example by hand, into the posterior segment of the eye of a human or animal, preferably through a 27 gauge needle, more preferably through a 29 or 30 gauge needle.

Without wishing to limit the invention to any particular theory of operation, it is believed that the use of a relatively high viscosity composition as described herein results in an effective, and preferably substantially homogeneous, suspension of the steroid component capable of being simultaneously injected into the posterior segment of the eye using conventional, or even smaller than conventionally used needles.

PL 213 709 B1

Compositions characterized by such a substantially homogeneous suspension of the corticosteroid component particles provide significant advantages over the prior art. In particular, the present compositions can be manufactured, shipped, and stored for substantial periods of time without the corticosteroid component particles precipitating from the remainder of the composition. Due to the substantially uniformly suspended particles of the corticosteroid component in the composition, it is possible to apply the composition quickly and efficiently, providing a method of treating the posterior segment of the eye of humans or animals without the need to care for the resuspension of such particles.

The aqueous carrier component of the pharmaceutical composition is ophthalmically acceptable and may include one or more conventional excipients suitable for ophthalmic compositions.

For example, the carrier component can include an effective amount of at least one preservative component, a tonic component and a buffering component.

As indicated above in a preferred embodiment, the compositions do not contain an added preservative component. This property reduces or minimizes or even substantially eliminates adverse reactions in the eye that may be induced or associated with the presence of the preservative component.

Although a re-suspend aid may be present in the composition in accordance with the invention, in many cases, due to the ability of the composition to maintain substantially uniform suspend- ment over long periods without requiring re-suspendability, the compositions preferably do not contain added re-suspend aid components.

As already mentioned, the composition according to the invention may be useful in the treatment of the posterior segment of the eye of humans or animals. In general, such methods include administering, e.g., injecting, a composition comprising a corticosteroid component, e.g., a composition of the invention, to the posterior segment of the eye of a human or animal. Such administration is effective to deliver the desired therapeutic effect. The administering step preferably comprises at least one of intravitreal injection, subconjunctival injection, subocular injection, retrobulbar injection, supravascular injection, and the like.

Thus, according to a further aspect, the present invention relates to the use of a corticosteroid component of a triamcinolone component having a water solubility at 25 ° C of less than 10 mg / ml for the preparation of a composition of the invention useful for treating disorders of the posterior segment of the eye by injecting it into the posterior segment of the eye. people or animals. Preferably, the composition is injected directly into the vitreous body of the eye subconjunctivally, subconjunctivally, retrobulbar and choroid.

The objects and advantages of the present invention will become more apparent from the following detailed description of the invention, and especially its embodiments.

The invention relates to compositions useful for administration, preferably by injection, to the posterior segment of the eye of humans or animals. Such compositions in the posterior segment of the eye, e.g., the vitreous, are therapeutically effective against one or more conditions and / or diseases of the posterior segment of the eye, and / or one or more symptoms of such conditions and / or diseases of the posterior segment of the eye.

As noted above, the compositions of the invention include a corticosteroid component, a viscosity inducing component, and an aqueous carrier component.

One of the significant advantages of the present compositions of the invention is that, compared to previously proposed compositions for injection directly into the vitreous into the posterior segment of the eye, for example, compared to the compositions sold under the trademark Kenalog © 40, they are more compatible or friendly. for tissues in the posterior segment of the eye, for example, in the retina of the eye. In particular, the present compositions are preferably substantially free of added preservative ingredients or contain effective preservative ingredients which, compared to the benzyl alcohol present as a preservative in the Kenalog®-40 formulation, are more compatible with or friendly to the posterior segment of the eye, e.g. the retina.

Furthermore, the present compositions preferably contain no added re-suspend aid component or contain a re-suspend aid component which, compared to the polysorbate-80 present in Kenalog © -40, is more compatible or friendly to the posterior segment of the eye, e.g., the retina. Many other features of the present compositions, described elsewhere, also make such compositions more compatible or friendly to the posterior segments of the eye to which the compositions are administered, compared to prior art compositions such as Kenalog © -40.

PL 213 709 B1

As noted above, the present compositions contain a corticosteroid component. Such a corticosteroid component is present in the compositions in a therapeutically effective amount that is an amount effective to achieve the desired therapeutic effect in the eye to which the composition is administered. The corticosteroid component is present in the composition as a plurality of particles.

According to the present invention, the corticosteroid component used is triamcinolone acetonide, which has limited solubility in water, for example at 25 ° C less than 10 mg / ml. Obviously, the corticosteroid component triamcinolone acetonide is ophthalmically acceptable, meaning that it is generally characterized by the absence of significant or inappropriate deleterious effects on the structure or tissues of the eye. One particularly useful property of currently useful corticosteroid components is the ability of such a component to reduce inflammation in the posterior segment of the eye to which the composition is administered, which condition is the result of one or more diseases and / or conditions of the posterior segment of the eye.

Examples of other useful corticosteroid components include, without limitation, cortisone, prednisolone, triamcinolone, triamcinolone acetonide, fluorometolone, dexamethasone, medryson, loteprednol, and derivatives and mixtures thereof. As used herein, the term derivative refers to any substance that is sufficiently similar in structure to the material to which it is derived and, when used in place of a material, has substantially similar functionality or activity, for example, therapeutic efficacy like material.

The corticosteroid component triamcinolone acetonide is preferably present in an amount of at least 10 mg per ml of the composition. One significant benefit of the present invention is the effective ability of the compositions to contain relatively high amounts or concentrations of the corticosteroid component. Thus, the corticosteroid component may be present in the present composition in an amount ranging from 1% or less to 5% or 10% or 20% or 30% or more (w / v) of the composition. Providing relatively high concentrations or amounts of the corticosteroid component in the present compositions is advantageous in that to deliver to the posterior segment of the eye the same amount or more of the corticosteroid component as compared to compositions such as Kenalog® 40 which contain less than 4% ( (w / v) of the corticosteroid component may require less of the composition to be applied or injected into the posterior segment of the eye.

Thus, in one embodiment, the compositions herein may contain greater than 4% (w / v), for example at least 5% (w / v), up to 10% (w / v) or 20% (w / v). ) or 30% (w / v) of a corticosteroid component.

The viscosity inducing component is present in amounts effective to increase, preferably substantially increase, the viscosity of the composition. Without limiting the invention to any particular theory of operation, it is believed that by increasing the viscosity of the composition to values ​​well above the viscosities of water, e.g., at least 100 cps at a shear rate of 0.1 / second, compositions are obtained that are highly effective for administration. , for example, by injection into the posterior segment of the eye of humans or animals. Along with the more advantageous administration or injection of the compositions into the posterior segment of the eye, it is believed that the relatively high viscosity of the present compositions increases the ability of the composition to keep the corticosteroid component particles substantially uniformly suspended in the composition for extended periods of time, for example, for at least about one week. , without requiring a re-suspend. The relatively high viscosity of the present compositions may also provide additional benefits such as, at a minimum, assisting the compositions to exhibit the ability to contain an increased amount or concentration of a corticosteroid component, as discussed elsewhere herein, for example, by keeping such a corticosteroid component in a substantially uniform suspension for extended periods of time.

Preferably the present compositions have viscosities of at least 10 cps or at least 100 cps or at least 1000 cps, more preferably at least 10,000 cps and even more preferably at least 70,000 cps or more, for example up to 200,000 cps or 250,000 cps, or 300,000 cps or more, with a shear rate of 0.1 / second. The compositions are not only relatively highly viscous, as noted above, but also have the ability or structure or composition to be effectively administered, e.g., by injection, into the posterior segment of the eye of humans or animals, preferably through a 27 gauge needle, or even through a 30 gauge needle.

Viscosity inducing ingredients useful herein are preferably viscosity-lowering with increasing shear rate, such that when the present compositions contain

Such a viscosity inducing component of decreasing viscosity with increasing shear rate is applied to or injected into the posterior segment of the eye, for example, through a narrow opening such as a 27 gauge needle, under high shear viscosity conditions of the composition. it is substantially reduced during such passage through the lumen of the needle. After such passage through the lumen of the needle, the composition substantially recovers its pre-injection viscosity so as to keep the particles of the corticosteroid component in suspension in the eye.

Any suitable viscosity inducing component may be used in accordance with the present invention, for example an ophthalmically acceptable viscosity inducing component. Many such viscosity inducing ingredients have been proposed and / or used in ophthalmic compositions for use on or within the eye. The viscosity inducing component is present in an amount effective to provide the desired viscosity to the composition.

Preferably, the viscosity inducing component is present in an amount in the range of 0.5% or 1.0% to 5% or 10% or 20% (w / v) of the composition. The specific amount of viscosity inducing component used is dependent upon a number of factors including, for example, and not limited to, the particular viscosity inducing component used, the molecular weight of the viscosity inducing component used, the desired viscosity of the composition being prepared and / or used, and the like. The viscosity inducing component is selected so as to provide the compositions with at least one benefit, and preferably multiple benefits, e.g. no additional re-suspension process for an extended period of time, tissue compatibility of the posterior segment of the eye to which the composition is administered, and the like. More preferably, the selected viscosity inducing component is effective to provide two or more of the above-mentioned benefits, and even more preferably to provide all of the above-mentioned benefits.

The viscosity inducing component preferably comprises a polymeric component and / or at least one viscoelastic agent such as those materials which are useful in eye surgery.

Examples of useful viscosity inducing ingredients include, but are not limited to, hyaluronic acid, carbomers, polyacrylic acid, cellulose derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl acetate, and derivatives and mixtures thereof.

The molecular weight of the viscosity inducing components useful herein can range from about 10,000 Daltons or less to about 2 million Daltons or greater. In one particularly preferred embodiment, the molecular weight of the viscosity inducing component is in the range of 100,000 Daltons or 200,000 Daltons to 1 million Daltons or 1.5 million Daltons. Again, the molecular weight of the viscosity inducing component useful in the present invention may vary considerably depending on the type of viscosity inducing component used and the desired final viscosity of said composition as well as, optionally, one or more other factors.

The viscosity inducing component is, according to the invention, a polymeric hyaluronate component, for example a metal hyaluronate component, preferably selected from alkali metal hyaluronate, alkaline earth metal hyaluronate and mixtures thereof, more preferably selected from sodium hyaluronates and mixtures thereof. The molecular weight of such hyaluronan component is preferably in the range of 50,000 Daltons or 100,000 Daltons to 1.3 million Daltons or 2 million Daltons. In one embodiment, the present compositions contain the polymeric hyaluronan component in an amount in the range of 0.05% to 0.5% (w / v). In a further useful embodiment, the hyaluronan component is present in an amount ranging from 1% to 4% (w / v) of the composition. In the latter case, the ultra-high viscosity polymer forms a gel that slows the deposition rate of the particles to such an extent that a re-suspension process is often not needed for an indicative shelf life of the composition, for example, for at least 2 years. Such a composition may be distributed in the form of pre-filled syringes as the gel cannot be easily removed through the needle and syringe from the multipack.

The aqueous carrier component is typically ophthalmically acceptable, and may include one or more conventional excipients useful in ophthalmic compositions.

PL 213 709 B1

The present compositions preferably contain significant amounts of liquid water. The compositions can be, and in the practice of the invention typically, sterilized, for example, before being applied to the eye.

The present compositions preferably contain at least one buffering component in an amount effective to control the pH of the composition and / or at least one tonic component in an amount effective to control the tonicity or osmolarity of the composition. It is evident that even more preferably the compositions contain both a buffering component and a tonic component.

The buffering component and the toning component may be selected from those that are conventionally and well known in the eye formulation art.

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

The amount of buffering component used is preferably sufficient to maintain the pH of the composition in the range of 6 to 8, more preferably 7 to 7.5. The amount of toning agent used is preferably sufficient to provide an osmolality of the composition in the range of 200 to 400, more preferably 250 to 350, mOsmol / kg, respectively. Preferably, the compositions are substantially isotonic.

The present compositions may contain one or more other ingredients in an amount effective to provide the present compositions with one or more useful properties and / or benefits. For example, while the present compositions may be substantially free of added preservative ingredients, in other embodiments, the present compositions contain effective amounts of preservative ingredients, preferably ingredients that are more compatible with or friendly to the posterior tissue tissue than benzyl alcohol. the eye to which the composition is administered.

Examples of such preservative ingredients include, but are not limited to, benzalkonium chloride, chlorhexidine, PHMB (polyhexamethylene biguanide), methyl and ethyl parabens, hexetidine, chlorate components such as stabilized chlorine dioxide, metallic chlorates and the like, others acceptable for use with the eyes preservatives and the like, and mixtures thereof. In the present compositions, the concentration of the preservative component, if present at all, is an effective concentration to preserve the composition, and is often in the range of 0.00001% to 0.05% or 0.1% (w / v) of the composition.

In addition, the present composition may contain an effective amount of a re-suspend aid component effective to facilitate the suspension or resuspension of the corticosteroid component particles in the compositions. As noted above, in certain embodiments, the compositions are free of added re-suspend aid ingredient. In another embodiment, effective amounts of re-suspending aid components are used in the compositions, for example, to provide additional security that how the desired corticosteroid component particles remain in suspension and / or can be re-suspended relatively easily in the compositions when such resuspension is in place. required.

The resuspension aid component of the invention, if any, is selected to be more compatible or compatible with the tissue of the posterior segment of the eye into which the composition is administered than polysorbate 80.

Any suitable resuspension aid ingredient may be used in accordance with the present invention. Examples of such re-suspend aid ingredients include, but are not limited to, surfactants such as polyoxanes, for example, sold under the trademark Pluronic ©; tyloxapol; sarcosinates; polyoxyethylene castor oils, other surfactants and the like, and mixtures thereof.

One very useful class of resuspension aid ingredients are those selected from vitamin derivatives. While such materials have previously been proposed for use as surfactants in ophthalmic compositions, they have been found to be effective in the present compositions as re-suspending aid ingredients. Examples of useful vitamin derivatives include, but are not limited to, Vitamin E tocopherol polyethyleneglycol succinates, such as Vitamin E Tocopherol 1000 Polyethyleneglycol succinate (Vitamin E TPGS). Other useful vitamin derivatives include, again but not limited to, polyethyleneglycol tocopherol succinamides, Vitamin E, such as polyethyleneglycol succinamide.

Tocopherol 1000 Vitamin E (TPGSA Vitamin E) in which the ester bond between the polyethylene glycol and succinic acid is replaced with an amide group.

Herein, useful resuspension aid ingredients are present, if any, in amounts effective to facilitate the suspension of the particles in the compositions, for example, during or after preparation of the compositions. The specific amounts of the re-suspend aid component used can vary widely depending, for example, on the particular re-suspend aid component used, the particular composition in which the re-suspend aid component is used, and other factors. Suitable concentrations of the re-suspend aid component, if used at all, in the present compositions are often in the range of 0.01% to 5%, for example, 0.02% or 0.05% to 1.0% (w / v). ) composition.

The availability of minimally soluble corticosteroid components such as triamcinolone acetonide to intraocular tissues may be limited by the dissolution rate of these substances. Slow dissolution is both beneficial and disadvantageous to the patient. On the one hand, following a single injection directly into the vitreous body of the present composition, the mean half-life for triamcinolone acetonide is preferably quite long, for example, 19 days in unvitrectomized patients and measurable drug levels are detected for up to 3 months. On the other hand, due to the slow dissolution rates of the corticosteroid component particles, therapeutic drug levels in the vitreous segment of the eye may not be achieved for 1 to 3 days.

In one embodiment of the invention, effective amounts of a solubiliser component are incorporated into the composition to dissolve a minor amount that is less than 50%, such as from 1% or 5% to 10% or 20% of the corticosteroid component. For example, the inclusion of a cyclodextrin component such as β-cyclodextrins, β-cyclodextrin sulfobutyl ether (SBE), other cyclodextrins and the like, and mixtures thereof in an amount of 0.5 to 5.0% (w / v) facilitates dissolution 1 up to 10% of the initial dose of triamcinolone acetonide. This pre-dissolved fraction makes the loading dose more bioavailable, thus avoiding a delay in therapeutic efficacy.

The use of such a solubilizing component is useful for therapeutic efficacy providing a relatively rapid release of the corticosteroid component in the eye. Of course, to avoid undesirable damage to the tissue of such posterior segment, such a dissolution aid component should be ophthalmically acceptable or at least sufficiently compatible with the posterior segment of the eye to which the composition is administered.

The pharmacokinetics of a corticosteroid component, for example, triamcinolone acetonide, when administered directly to the vitreous body of the eye can include both the rate of drug dissolution and the rate of drug efflux through the anterior pathway. For example, after a single injection of a composition containing 4% (w / v) triamcinolone acetonide directly into the vitreous body of the eye, the concentration peaks of TA (recorded in an aqueous liquid) after a few days are thousands of nanograms per milliliter. Thereafter, this peak (C max) declines sharply within 200 hours, and the slow elimination phase ends with a half-life of 19 days. Typically patients require repeated dosing, for example every three months.

In one embodiment of the present invention, the compositions additionally contain sustained release ingredients, for example polymers such as poly (D, L, -lactide) or poly (D, L-lactide-co-glycolide), in amounts effective to reduce the local diffusion rate and / or dissolution rate of the corticosteroid particles. The result is a flattened elimination rate profile with a lower Cmax and a prolonged treatment window, resulting in longer injection times in many patients.

Any suitable, preferably conditionally acceptable, release component may be used. Useful examples are listed above. The sustained release component is preferably biodegradable or bioadsorbable in the eye so that no residue remains for a long time. The amount of the delay-release component included may vary within a relatively wide range depending, for example, on the particular sustained-release component used, the particular release profile desired, and the like. Typical amounts of delayed release components, if any, included in the present composition range from 0.05 to 0.1 to 0.5 or 1 or more percent (w / v) of the composition.

PL 213 709 B1

The present compositions can be prepared using suitable mixing / processing techniques or techniques such as, for example, one or more conventional mixing techniques. The manufacturing process should be selected to provide the compositions herein in forms which are suitable for application to or injection into the posterior segments of the eye of humans or animals. In one preferred embodiment, by combining a corticosteroid component with water, and an excipient (other than the viscosity inducing component), a concentrated dispersion of the corticosteroid component is prepared for inclusion in the final composition. The ingredients are mixed to disperse the corticosteroid component and then autoclaved. Alternatively, the steroid powder may be irradiated with γ-irradiation prior to addition to the sterile vehicle. The viscosity inducing component may be sterile or sterilized by conventional processing, for example, filtering the diluted solution followed by lyophilization to obtain a sterile powder. The sterile viscosity inducing component is combined with water to form an aqueous concentrate. Under aseptic conditions, the concentrated dispersion of the corticosteroid component is mixed and added as a suspension to the viscosity inducing component concentrate. The water is added in a quantity (qs) sufficient to produce the desired composition, and the composition is mixed until it becomes homogeneous.

The compositions of the present invention may be administered to the posterior segment of the eye of humans or animals, thereby providing the desired therapeutic effect. The administering step preferably comprises at least one of direct intravitreal injection, subconjunctival injection, subocular injection, retrobulbar injection, supravascular injection, and the like. The syringe kits include appropriately sized needles, for example, they can be effectively used to inject the composition into the posterior segment of the eye of a human or animal with 27 gauge needles or 30 gauge needles.

Among the diseases / conditions in which the compositions of the invention may be administered include:

YELLOW DEGENERATION Retina DEGENERATION: non-exudative senile macular degeneration (ARMD ANG. Non-Exudative Age Related Macular Degeneration), exudative age-related macular degeneration (ARMD), macular neovascular disease, macular neovascularization, macular neovascularization , vasospastic inflammation, small cystic edema, macular edema due to diabetic retinopathy.

EYE VASCULITIS / VOLCANISIS / CHEVALS: Acute Multifocal Pigmentary Pigmental Epitheliopathy, Behcet's Disease, Birdshot Retinopathy, Infections (Syphilis, Lyme Lyme disease, Tuberculosis, Multivasculitis, Multivasculitis syndrome) multiple disappearance of the white spot (ang. Multiple Evanescent White Dot Syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, acute uveitis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-Harada syndrome.

VASCULAR DISEASES / EXRESSIVE DISEASES: retinal arterial occlusive disease, central retinal vein thrombus, disseminated intravascular coagulation, retinal branched vein thrombus, hypertensive fundus changes, ophthalmic ischemic syndrome, retinal microturosis, coagulopapular retinal thrombosis, retinal thrombocytopenic retinal thrombosis central retinal artery thrombosis, retinal branched artery thrombus, carotid artery disease (CAD) Carotid Artery Disease), branched vessel hypertrophy, sickle cell retinopathy and other hemoglobinopathies, retinal vascular strands, familial exudative vitreoretinopathy, Eales' disease.

TRAUMA / SURGICAL: sympathetic ophthalmia, uveitis, retinal detachment, retinal trauma, laser, PDT, photocoagulation, hypoperfusion during surgery, radiation retinopathy, bone marrow transplant retinopathy.

PROLIFERATION DISORDERS: proliferative retinopathy of the vitreous body and epretinal membranes, proliferative diabetic retinopathy.

INFECTIVE DISORDERS: ocular histoplasmosis, ocular toxocaryosis, hypothetical ocular histoplasmosis syndrome Presumed Ocular Histoplasmosis Syndrome (POHS), endogenous endophthalmitis, toxoplasmosis, HIV-related retinal disease, HIV-related choroidal disease, HIV-related uveal disease, viral retinitis, acute retinal necrosis , progressive external retinal necrosis, fungal diseases of the retina, syphilis

Ophthalmic disease, ocular tuberculosis, unilateral diffuse subacute optic retinitis, myiasis.

GENETIC DISORDERS: Retinal pigment degeneration, systemic disorders accompanied by retinal dystrophy, congenital nonprogressive night blindness, retinal cone dystrophies, Stargardt's disease and progressive yolk degeneration around the macula (Latin Fundus Flavimaculatus), Best's disease, patterned reticular dystrophy of the pigment epithelium, X-linked retinoschiza, Sorsby fundus dystrophy, concentric Benign macular degeneration, Bietti's crystalline dystrophy, elastic tissue disorder of the Latin tissue. Pseudoksanthoma Elasticum.

Tears / holes in the retina: detachment of the retina, full-walled macular hole, giant retinal holes.

CANCER: neoplastic diseases of the retina, congenital retinal pigment hyperplasia, malignant melanoma of the posterior segment of the eye, choroidal hemangioma, choroidal osteoma, choroidal metastasis, mixed retinal hamartoma and patterned reticular dystrophy of the pigment epithelium, retinal glioma, lymphoproliferative lymphoma intraocular tumors.

MISCELLANEOUS: punctate internal choroidopathy, acute posterior multifocal pigmented plaque epitheliopathy, myopic retinal degeneration, acute retinal pigment epithelial disorder and the like.

The compositions of the invention may be administered by single injections into the posterior segment of the eye, or repeated injection may be required to achieve the desired therapeutic effect, for example over a specified period of time ranging from about one week or 1 month, or 3 months to 6 months or 1 year, or longer.

Certain aspects of the invention are illustrated by the following non-limiting Examples.

EXAMPLES 1 to 4

Four compositions were prepared as follows:

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

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

<td>Sodium hyaluronate</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 for injection</td><td>qs</td><td>qs</td><td>qs</td><td>qs</td>

<td>Viscosity at a shear rate of 0.1 / second</td><td>20 cps</td><td>500 cps</td><td>20 cps</td><td>500 cps</td>

Each of these compositions was prepared as follows.

A concentrated triamcinolone acetonide dispersion was prepared by combining triamcinolone acetonide with water, and if used with Vitamin E-TPGS and 8-cyclodextrin. These ingredients were mixed to disperse triamcinolone acetonide and then autoclaved. Sodium hyaluronate can be used as a sterile powder or sterilized by filtering the diluted solution followed by lyophilization to obtain a sterile powder. The sterile sodium hyaluronate was dissolved in water to form an aqueous concentrate. The concentrated triamcinolone acetonide dispersion was mixed and added as a slurry to the sodium hyaluronate concentrate. Thereafter, sufficient water (qs) was added and the mixture was stirred until it became homogeneous.

Each of these compositions shows slight variations in the content of triamcinolone acetonide, which can easily be re-suspended by gentle shaking. These compositions can be easily distributed in small pharmaceutical grade glass bottles, and it has been found that when administered directly into the vitreous body of the eye of humans, they are effective in treating macular edema.

EXAMPLES 5 to 7

Four compositions were prepared as follows:

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

<td>Acetonide triamcinolone</td><td>2% (w / v)</td><td>4.0% (w / v)</td><td>8.0% (w / v)</td>

<td>Sodium hyaluronate</td><td>3.05% (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 injection</td><td>qs</td><td>qs</td><td>qs</td>

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

These compositions were prepared in a manner substantially analogous to that described in Example 1.

The high viscosities of the compositions substantially slow down the sedimentation rate to the extent that no re-suspending process is necessary or required for the estimated shelf life of the composition, for example, at least about 2 years. These compositions can be easily distributed as pre-filled syringes as they cannot be readily removed by the needle and syringe from the multipack. Moreover, in the case of compositions in pre-filled syringes, these compositions can be effectively introduced into the posterior segment of the human eye using a 27 gauge or 30 gauge needle to achieve the desired therapeutic effect in the human eye.

The compositions of Examples 5 to 7 use or contain a sufficient concentration of high molecular weight sodium hyaluronate to form a gelatin suppository or depot when directly injected into the vitreous body of the human eye. The triamcinolone acetonide particles are, as a result, trapped or held in such a sticky suppository so that undesirable spotting does not occur, and the risk that drug particles adversely deposit directly onto the retinal tissue is substantially reduced, for example, with respect to the use of the composition. with a viscosity like water such as Kenalog © 40. Due to the fact that the viscosity of sodium hyaluronate solutions decreases significantly with increasing shear rate, these preparations are easily injected through 27 gauge or even 30 gauge needles.

EXAMPLES 8 and 9

Two compositions were prepared as follows:

<td>Ingredients</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 hyaluronate</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</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 injection</td><td>qs</td><td>qs</td>

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

PL 213 709 B1

These compositions were prepared in a manner substantially analogous to that described in Example 1.

The high viscosities of the compositions substantially slow down the sedimentation rate to the extent that no re-suspending process is necessary or required for the estimated shelf life of the composition, for example, at least about 2 years. These compositions can be easily distributed as pre-filled syringes as they cannot be readily removed by the needle and syringe from the multipack. Moreover, in the case of compositions in pre-filled syringes, these compositions can be effectively introduced into the posterior segment of the human eye using a 27 gauge or 30 gauge needle to achieve the desired therapeutic effect in the human eye.

The sodium hyaluronate powders used in these compositions (as well as in the other compositions discussed herein in the Examples) had a water content ranging from 4% to 20%, preferably from 4% to 8% by weight. The water content of a powder, and in particular a change in the water content of one powder relative to another powder, may result in changes in the viscosity of two or more compositions of the invention that are nominally of the same chemical composition. Thus, the viscosities indicated herein should be considered as target viscosities, with the composition considered acceptable for use if the actual viscosity of the composition is within the range of plus or minus (±) 25% or 30% or 35% of the target viscosity.

Since all compositions discussed in the Examples have a density of 1 g / ml, weight to volume percentages (w / v) indicated herein can also be taken as weight to weight (w / w) percentages.

The compositions of Examples 8 and 9 use or contain a sufficient concentration of high molecular weight sodium hyaluronate to form a gelatin suppository or depot when directly injected into the vitreous body of the human eye. The triamcinolone acetonide particles are, as a result, trapped or held in such a sticky suppository so that undesirable spotting does not occur, and the risk that drug particles adversely deposit directly onto the retinal tissue is substantially reduced, for example, with respect to the use of the composition. with a viscosity like water such as Kenalog® 40. Due to the fact that the viscosity of sodium hyaluronate solutions decreases significantly with increasing shear rate, these preparations are easily injected through 27 gauge or even 30 gauge needles.