HK1116399A - Compositions and methods for treating a posterior segment of an eye - Google Patents

Description

Compositions and methods for treating posterior segment of the eye

The present invention relates to compositions and methods for treating the posterior segment of the eye of humans or animals. More particularly, the present invention relates to compositions comprising a corticosteroid component that are effective for injection into the posterior segment of the eye, and to methods of using such compositions to provide a desired therapeutic effect.

One of the current therapies routinely used to treat posterior segment ophthalmic conditions, such as uveitis, macular degeneration, macular edema, etc., is the intravitreal injection of a corticosteroid, such as Triamcinolone Acetonide (TA). See, for example, U.S. patent No. 5,770,589 to Billson et al, the disclosure of which is incorporated herein by reference in its entirety.

One drug commonly used in the above ophthalmic therapies is Kenalog ® 40. Kenalog ® 40 composition contained 40 milligrams (mg) TA, sodium chloride as a tonicity agent (tonification agent), 10mg benzyl alcohol as a preservative, and 7.5mg carboxymethylcellulose and 0.4mg polysorbate 80 as a resuspension aid per milliliter (ml). Although widely used by ophthalmologists, this commercial formulation has a number of important limitations.

For example, the presence of benzyl alcohol preservatives and polysorbate 80 surfactants are susceptible to causing unwanted and/or excessive cellular damage or other toxicity in sensitive ocular tissues. Even though some clinicians routinely "wash" the TA precipitate several times with saline to reduce the concentration of such undesirable substances, such washing is inconvenient and time consuming, and most importantly, increases the potential for microbial or endotoxin contamination, resulting in intraocular infection and inflammation.

Furthermore, TA in Kenalog ® 40 also readily separated and precipitated from the composition residue. For example, the composition, if left for 1 to 2 hours, can cause substantial separation of the TA precipitate from the composition residue. Thus, if the composition is injected into the eye, it must be vigorously shaken and used immediately after shaking to provide a generally uniform suspension in the eye. In addition, the resuspension process requires the use of resuspension aids as described above, at least one of which is not completely required for sensitive ocular tissues.

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

Disclosure of Invention

Novel compositions and methods for treating the posterior segment of the human or animal eye have now been discovered. The compositions of the present invention are well suited for intravitreal administration to the posterior segment of the eye without any "washing step" while still providing reduced intraocular damage, such as retinal damage, during intraocular use. Advantageously, the compositions of the present invention are substantially free of added preservative ingredients, e.g., are free of benzyl alcohol preservatives. Advantageously, the compositions of the present invention also do not require a resuspension aid. In summary, the compositions of the invention can be simply and effectively injected into the posterior segment of a human or animal eye and can be maintained in a substantially uniform suspension state for an extended period of time, e.g., for at least about one week or more, without resuspension, e.g., without shaking or agitating the composition to achieve substantial suspension uniformity. Briefly, the compositions and methods of the present invention provide significant improvements and advantages in the posterior segment of the human or animal eye, for example, over prior art Kenalog ® 40 compositions and methods of using the prior art compositions.

In one broad aspect of the invention, there is provided a composition for injection into the posterior segment of a human or animal eye. The composition includes a corticosteroid component, a visco-inducing component, and an aqueous carrier component. The corticosteroid component is in a therapeutically effective amount. The corticosteroid component is present in the composition in the form of a plurality of particles.

The compositions of the present invention may include up to about 25% (w/v) or more of the corticosteroid component of the composition. In a very advantageous embodiment, the amount of corticosteroid component is at least about 80mg/ml of composition. Preferably, the corticosteroid component is present in an amount of about 1% to about 10% or about 20% (w/v) of the composition.

In a very advantageous embodiment, the corticosteroid component comprises triamcinolone acetonide.

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

Any suitable viscosity inducing component, preferably an ophthalmically acceptable viscosity inducing component, may be used in accordance with the present invention. Most of the viscosity inducing components have been proposed for use in ophthalmic compositions for on-eye or intraocular use, and/or have been used in the above ophthalmic compositions. Advantageously, the viscosity inducing component is present in an amount of from about 0.5% to about 20% (w/v) of the composition. In a particularly advantageous embodiment, the viscosity inducing component is a hyaluronic acid polymer component, such as sodium hyaluronate.

In one embodiment, the viscosity of the composition of the invention is at least about 10cps or at least about 100cps, preferably at least about 1,000cps, more preferably at least about 10,000cps, even more preferably at least about 70,000cps, for example up to about 250,000cps, or about 300,000cps at a shear rate of 0.1/second. The compositions of the present invention are adapted or configured to be effective, e.g., manually, for injection into the posterior segment of a human or animal eye, preferably through a 27 gauge needle cannula, more preferably through a 29 gauge or 30 gauge needle cannula.

Without wishing to limit the invention to any particular theory of action, it is believed that the use of a relatively high viscosity composition as described herein provides an effective, preferably substantially uniform suspension of particles of the steroid component, while still allowing injection into the posterior segment of the eye through a conventional needle cannula or a needle cannula smaller than a conventional needle cannula.

In one embodiment of the invention, the corticosteroid component is present in the form of a plurality of particles that are substantially uniformly suspended in the composition and that maintain a substantially uniform suspension in the composition for at least about 1 week, preferably at least about 2 weeks or at least about 1 month, and even more preferably at least about 6 months or at least about 1 year or at least about 2 years, without resuspension, i.e., without shaking or agitation, to maintain the corticosteroid component particles in a substantially uniform suspension in the composition.

Compositions having particles of the corticosteroid component suspended substantially uniformly provide significant advantages over the prior art. In particular, the compositions of the present invention can be manufactured, transported and stored for extended periods of time without the corticosteroid component particles precipitating from the remainder of the composition. Having particles of the corticosteroid component suspended substantially uniformly in the composition allows the composition to be used quickly and effectively to provide treatment of the posterior segment of a human or animal eye without having to consider resuspending the particles.

The aqueous carrier component is advantageously ophthalmically acceptable and may include one or more conventional excipients for ophthalmic compositions.

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

In an advantageous embodiment, the composition of the invention is free of added preservative ingredients. This feature reduces or minimizes, or even substantially eliminates, intraocular adverse effects that may be caused by or associated with the presence of preservative ingredients.

Although resuspension components can be used in accordance with the invention, it is advantageous in most cases that no resuspension components are added to the composition, since the composition of the invention maintains a substantially uniform suspension state for a long period of time without the need for a resuspension process.

Also disclosed are methods of treating the posterior segment of a human or animal eye, which methods are included within the scope of the invention. In general, the methods comprise administering, e.g., injecting, a composition comprising a corticosteroid component, e.g., a composition of the present invention, to the posterior segment of the eye of a human or animal. The administration is effective to provide the desired therapeutic effect. The step of administering advantageously comprises at least one of the following: intravitreal injection, subconjunctival injection, sub-tenon injection, retrobulbar injection, suprachoroidal injection, and the like.

Each feature described in this application, and each combination of two or more such features, is included within the scope of the present invention provided that the features included in such a combination are not mutually inconsistent.

The above and other aspects and advantages of the invention are apparent from the following detailed description, examples and claims.

Detailed Description

The present invention relates to a composition for placement, preferably by injection, in the posterior segment of the eye of a human or animal. The compositions, e.g., intravitreal compositions, in the posterior segment of the eye are therapeutically effective for one or more posterior segment conditions and/or diseases, and/or one or more symptoms of the posterior segment conditions and/or diseases.

In general, the compositions of the present invention comprise a corticosteroid component; a viscosity inducing component; and an aqueous carrier component. The composition is advantageously ophthalmically acceptable.

An important advantage of the compositions of the present invention is that they are more compatible or friendly to tissues in the posterior segment of the eye, such as the retina, than previously proposed compositions for intravitreal injection into the posterior segment of the eye, for example, as compared to commercially available compositions sold under the trademark Kenalog ® -40. In particular, the compositions of the present invention advantageously have substantially no added preservative component, or include an effective preservative component that is more compatible or friendly in the posterior segment of the eye (e.g., retina) than the benzyl alcohol preservative included in the Kenalog ® -40 composition.

In addition, the compositions of the present invention preferably do not include added resuspension components, or preferably include resuspension components that are more compatible or more friendly in the posterior segment of the eye (e.g., retina) than polysorbate 80 included in the Kenalog ® -40 composition. Many of the other features of the invention, as described elsewhere in this application, also make the compositions of the invention more compatible or more friendly to the posterior segment of the eye in which they are placed than prior art compositions, e.g., Kenalog ® -40.

As mentioned above, the compositions of the present invention include a corticosteroid component. The corticosteroid component is present in the composition in a therapeutically effective amount, i.e., an amount effective to provide the desired therapeutic effect in the eye in which the composition is placed. The corticosteroid component is present in the composition in the form of a plurality of particles.

Any suitable corticosteroid component can be used in accordance with the present invention. The corticosteroid component advantageously has limited solubility in, for example, 25EC water. For example, the corticosteroid component preferably has a solubility in 25EC water of less than 10 mg/ml. The corticosteroid component should naturally be ophthalmically acceptable, i.e., should not substantially have a significant or excessive deleterious effect on ocular structures or tissues. A particularly beneficial feature of the beneficial corticosteroid component of the present invention is that the component is capable of reducing inflammation caused by one or more diseases and/or conditions of the posterior segment of the eye in which the composition is placed.

Examples of beneficial corticosteroid components include, but are not limited to: cortisone, prednisolone, triamcinolone acetonide, fluocinolone acetonide, dexamethasone, medroxypsone, loteprednol etabonate, derivatives thereof, and mixtures thereof. As used herein, the term "derivative" refers to any substance that is structurally similar enough, e.g., therapeutically effective, to the substance identified as a derivative such that the function or activity, e.g., therapeutic effectiveness, is substantially similar when used in place of the substance.

In a very advantageous embodiment, the corticosteroid component comprises triamcinolone acetonide.

The amount of corticosteroid component is advantageously at least about 10mg per ml of composition. An important advantage of the present invention is that the compositions of the present invention can effectively include a corticosteroid in relatively large amounts or concentrations. Thus, the amount of corticosteroid in the compositions of the present invention may be from about 1% or less to about 5% or about 10% or about 20% or about 30% or more (w/v) of the composition. The provision of a relatively higher concentration or greater amount of corticosteroid component in the compositions of the present invention is beneficial to reduce the amount of composition that needs to be placed or injected into the posterior segment of the eye, thereby providing the same amount or greater of corticosteroid component in the posterior segment of the eye relative to compositions that include less than 4% (w/v) corticosteroid component, e.g., relative to Kenalog ® -40. Thus, in a very advantageous embodiment, the composition of the invention comprises a corticosteroid component in an amount greater than about 4% (w/v), such as at least about 5% (w/v), to about 10% (w/v) or about 20% (w/v) or about 30% (w/v).

The viscosity inducing component is present in an amount effective to increase the viscosity of the composition, advantageously in an amount effective to substantially increase the viscosity of the composition. Without wishing to limit the invention to any particular theory of action, it is believed that when the viscosity of the composition is increased above that of water, for example at least about 100cps at a shear rate of 0.1/second, the resulting composition is capable of being placed very effectively, for example, for injection into the posterior segment of a human or animal eye. The relatively high viscosity of the compositions of the present invention, in addition to enabling the compositions of the present invention to be advantageously placed or injected into the posterior segment, is believed to enhance the ability of the compositions of the present invention to maintain particles of the corticosteroid component in a substantially homogeneous suspension in the composition for an extended period of time without the need for re-suspension treatment, e.g., for at least about one week. A further benefit of the relatively higher viscosity of the compositions of the present invention is that the compositions can be at least helped to have a greater amount or concentration of the corticosteroid component, for example, while maintaining the corticosteroid component in a substantially homogeneous suspension for an extended period of time, as described elsewhere herein.

Advantageously, the viscosity of the present compositions at a shear rate of 0.1/second is at least about 10cps or at least about 100cps or at least about 1000cps, more preferably at least about 10,000cps, and even more preferably at least about 70,000cps or higher, for example up to about 200,000cps or about 250,000cps, or about 300,000cps or higher. The compositions of the present invention not only have the relatively high viscosities described above, but can also be effectively placed, or adapted to be, into a configuration or structure for effective placement, for example, for injection into the posterior segment of a human or animal eye, preferably through a 27 gauge needle, or even a 30 gauge needle.

The beneficial viscosity inducing component of the present invention is preferably a shear thinning component, since when the composition of the present invention containing the shear thinning viscosity inducing component is delivered or injected into the posterior segment of the eye through a narrow space, such as through a 27 gauge needle cannula, the viscosity of the composition decreases significantly under high shear conditions during the delivery process. After such delivery, the composition substantially returns to its pre-injection viscosity to maintain the corticosteroid composition particles in suspension in the eye.

Any suitable viscosity inducing component, such as an ophthalmically acceptable viscosity inducing component, can be used in accordance with the present invention. Most of the viscosity inducing components have been proposed for use in ophthalmic compositions for on-eye or intraocular use, and/or have been used in the above ophthalmic compositions. The amount of viscosity inducing component is an amount effective to provide the desired viscosity to the composition. Advantageously, the amount of viscosity inducing component is from about 0.5% or about 1.0% to about 5% or about 10% or about 20% (w/v) of the composition. The precise amount of viscosity inducing component used will depend on a number of factors including, for example, but not limited to, the particular viscosity inducing component used, the molecular weight of the viscosity inducing component used, the desired viscosity of the composition of the invention being prepared and/or used, and the like. The viscosity inducing component is selected such that the composition of the present invention has at least one advantage, preferably a plurality of advantages, such as: injectable into the posterior segment of the eye, viscous, maintenance of the corticosteroid particles in suspension for extended periods of time without resuspension, e.g., maintenance of a substantially uniform suspension, compatibility with the posterior segment tissue in which the composition is placed, and the like. The selected viscosity inducing component is more preferably effective to provide two or more of the above benefits, and even more preferably all of the above benefits.

The viscosity inducing component preferably comprises a polymeric component and/or at least one visco-elastic agent (visco-elastic agent), such as a material used in ophthalmic surgical procedures.

Examples of beneficial viscosity inducing components include, but are not limited to: hyaluronic acid, carbomer, polyacrylic acid, cellulose derivatives, polyacrylic resins, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl acetate, derivatives thereof, and mixtures thereof.

The molecular weight of the beneficial viscosity inducing components of the present invention can range from about 10,000 daltons or less to about 2,000,000 daltons or more. In a particularly advantageous embodiment, the viscosity inducing component has a molecular weight of from about 100,000 daltons or from about 200,000 daltons to about 1,000,000 daltons or about 1,500,000 daltons. In addition, the molecular weight of the viscosity inducing component used in the present invention may vary within a relatively wide range depending on the following factors: the type of viscosity inducing component used, the desired final viscosity of the composition of the present invention, and one or more other possible factors.

In a very advantageous embodiment, the viscosity inducing component is a polymeric hyaluronate component, such as a metal hyaluronate component, preferably selected from alkali metal salts of hyaluronic acid, alkaline earth metal salts of hyaluronic acid and mixtures thereof, and further more preferably selected from sodium hyaluronate and mixtures thereof. The molecular weight of the hyaluronate component is preferably from about 50,000 daltons or from about 100,000 daltons to about 1,300,000 daltons or about 2,000,000 daltons. In one embodiment, the compositions of the present invention comprise from about 0.05% to about 0.5% (w/v) of a polymeric hyaluronate component. In another beneficial embodiment, the amount of the hyaluronate component is from about 1% to about 4% (w/v) of the composition. In the latter case, the extremely high polymer viscosity enables the formation of a gel that reduces the rate of particle settling to the point where re-suspension treatment is not necessary for the expected shelf life of the composition, for example, for at least about 2 years. Since the gel is not easily transferred from a bulk container (bulk container) using a syringe and syringe, the composition can be sold pre-filled in the syringe.

The aqueous carrier component is advantageously ophthalmically acceptable and may include one or more conventional excipients for ophthalmic compositions.

The compositions of the present invention preferably include a large amount of liquid water. The compositions of the invention may be sterile, and are preferably sterile, for example prior to use in the eye.

The compositions of the present invention preferably include at least one buffer component in an amount effective to control the pH of the composition, and/or at least one tonicity adjusting component in an amount effective to control the tonicity or osmotic pressure of the composition. More preferably, the compositions of the present invention include both a buffer component and a tonicity modifier component.

The buffer component and the tonicity modifier component may be selected from the corresponding components that are conventional and known in the ophthalmic art.

Examples of such buffer components include, but are not limited to: acetate buffers, citrate buffers, phosphate buffers, borate buffers, and the like, and mixtures thereof. Particularly advantageous are phosphate buffers. Beneficial tonicity modifier components include, but are not limited to: salts, particularly sodium chloride, potassium chloride, any suitable other ophthalmically acceptable tonicity modifier component and mixtures thereof.

The buffer component is preferably used in an amount sufficient to provide a pH of the composition in the range of about 6 to about 8, more preferably about 7 to about 7.5. The tonicity modifier component is preferably used in an amount sufficient to provide an osmolality of the present composition in the range of about 200 to about 400mOsmol/kg, respectively, more preferably in the range of about 250 to about 350 mOsmol/kg. Advantageously, the compositions of the present invention are substantially isotonic.

The compositions of the present invention may include one or more additional ingredients in amounts effective to provide one or more beneficial properties and/or benefits to the compositions of the present invention. For example, while the compositions of the present invention may be substantially free of added preservative ingredients, in other embodiments, the compositions of the present invention include an effective amount of a preservative ingredient that is preferably more compatible or friendly than benzyl alcohol with respect to the tissue in the posterior segment of the eye in which the composition is placed. Examples of such preservative ingredients include, but are not limited to: benzalkonium chloride, chlorhexidine, PHMB (polyhexamethylene biguanide), methyl and ethyl parabens, hexetidine, chlorite components such as stabilized chlorine dioxide, metal chlorite salts and the like, other ophthalmically acceptable preservatives and the like and mixtures thereof. The concentration of preservative ingredients, if any, in the compositions of the present invention is typically from about 0.00001% to about 0.05% or about 0.1% (w/v) of the composition in order to effectively preserve the composition.

In addition, the compositions of the present invention may also include an effective amount of a resuspension ingredient that is effective to facilitate the suspension or resuspension of the corticosteroid ingredient particles in the compositions of the present invention. As noted above, in certain embodiments, the compositions of the present invention do not have added resuspension components. Other embodiments of the compositions of the present invention employ an effective amount of the resuspension component, e.g., to further ensure that the corticosteroid component particles are in suspension as desired, and/or to further ensure that the corticosteroid component particles can be relatively easily resuspended in the compositions of the present invention, where such a resuspended state is desired. Advantageously, the resuspension component used in the present invention, if any, is selected to be more compatible or friendly than polysorbate 80 with respect to the tissue in the posterior segment of the eye in which the composition is placed.

Any suitable resuspension component can be used in accordance with the invention. Examples of such re-suspended components include, but are not limited to: surfactants such as poloxamers (poloxames), for example the commercially available poloxamer under the trade name Pluronic ®; tetrabutyl phenol; a sarcosinate salt; polyoxyethylated castor oil, other surfactants, and the like, and mixtures thereof.

One very advantageous class of resuspension components is selected from vitamin derivatives. Although the above materials have long been suggested for use as surfactants in ophthalmic compositions, they have been found to be effective as resuspension components in the compositions of the present invention. Examples of beneficial vitamin derivatives include, but are not limited to: vitamin E tocopheryl polyethylene glycol succinate, such as vitamin E tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS). Other beneficial vitamin derivatives include, but are not limited to: vitamin E tocopheryl polyethylene glycol succinamide (vitamin E tocopheryl succinamide), such as vitamin E tocopheryl polyethylene glycol 1000 succinamide (vitamin E TPGSA), wherein the ester linkage between the polyethylene glycol and the succinic acid is substituted with an amide group.

The amount of the beneficial resuspension component of the invention in the composition of the invention, if any, is an amount effective to facilitate suspension of the particles in the composition of the invention, e.g., during or after preparation of the composition. The exact amount of the resuspension component can vary over a wide range depending on, for example, the following factors: the particular resuspension component used, the particular composition in which the resuspension component is used, and the like. Suitable concentrations of the resuspension component in the compositions of the invention, if any, are generally from about 0.01% to about 5%, for example from about 0.02% or from about 0.05% to about 1.0% (w/v) of the composition.

For corticosteroid components that are sparingly soluble in intraocular tissue, such as triamcinolone acetonide, the rate of dissolution may limit the availability of the substance. Slower dissolution is both beneficial and detrimental to the patient. In one aspect, following intravitreal injection of a composition of the invention alone, it is advantageous in patients who have not undergone vitrectomy (nonvitrectomy) that the mean elimination half-life of triamcinolone acetonide is relatively long, e.g., about 19 days, and that measurable drug levels are detectable for up to about 3 months. On the other hand, due to the slow dissolution rate of the corticosteroid component particles, the vitreous cavity of the eye may not reach therapeutic drug levels in about 1 to about 3 days.

In one embodiment of the invention, a solubilizing component is provided in the composition in an amount effective to solubilize a minor amount of the corticosteroid component, i.e., less than 50%, e.g., from 1% or about 5% to about 10% or about 20% of the corticosteroid component. For example, inclusion of a cyclodextrin component, such as beta-cyclodextrin, sulfobutylether beta-cyclodextrin (SBE), other cyclodextrins, and the like, and mixtures thereof, from about 0.5 to about 5.0% (w/v) can solubilize from about 1 to about 10% of the initial dose of triamcinolone acetonide. This portion of the pre-dissolution provides a loading dose that is readily bioavailable, thereby avoiding a delay in the effectiveness of the treatment.

The use of the solubilized component facilitates rapid release of the corticosteroid component into the eye for therapeutic effectiveness. The solubilized components should naturally be ophthalmically acceptable, or at least sufficiently compatible with the posterior segment of the eye in which the composition is placed, to avoid excessive damage to the tissues of the posterior segment of the eye.

The pharmacokinetics of intravitreal administration of a corticosteroid component (e.g., triamcinolone acetonide) can relate to both the rate of dissolution of the drug and the rate of drug efflux via the anterior ocular route (antigen route). For example, after intravitreal injection of a composition containing 4% (w/v) triamcinolone acetonide alone, the TA concentration reaches a maximum (monitored in aqueous humor) after several days, i.e., thousands of nanograms per mL. The highest value (C)_max) This is followed by a rapid decline lasting about 200 hours, and finally a slower elimination phase with a half-life of about 19 days. Patients typically require repeated dosing, e.g., about once every three months.

In one embodiment of the invention, the composition further comprises a sustained release ingredient, such as a polymer, for example poly (D, L-lactide) or poly (D, L-lactide-co-glycolide), in an amount effective to reduce the local diffusion rate and/or the dissolution rate of the corticosteroid particles. As a result, C was obtained_maxA lower flatter (flat) elimination rate curve and a longer treatment window, thereby extending the time interval during which most patients require injections.

Any suitable sustained release composition, preferably a conditionally acceptable (conditionally acceptable) sustained release composition, may be used. Advantageous examples are described above. The sustained release component is preferably biodegradable or bioabsorbable in the eye to achieve a residue free time. The amount of the included slow-release component may vary over a relatively wide range depending on, for example, the following factors: the particular sustained release component used, the particular release profile desired, and the like. The sustained release ingredients included in the compositions of the present invention are generally used in amounts of about 0.05% to 0.1% to about 0.5% or about 1% (w/v) or more of the composition, if any.

The compositions of the present invention may be prepared by suitable mixing/processing techniques or techniques, for example by one or more conventional mixing techniques. The method of processing and preparation should be selected so that the composition of the present invention is in a form that can be placed or injected into the posterior segment of a human or animal eye. In an advantageous embodiment, the corticosteroid component is combined with water to produce a concentrated dispersion of the corticosteroid component in which excipients (instead of viscosity inducing components) are included in the final composition. Mixing the above components, dispersing the corticosteroid component, and autoclaving. Alternatively, the steroid powder may be gamma-activated prior to addition to the sterile vehicle. The viscosity inducing component can be purchased as a commercially sterile product or can be sterilized by conventional methods, such as filtration of a dilute solution followed by low pressure sublimation drying to obtain a sterile powder. Combining the sterile viscosity inducing component with water to produce an aqueous concentrate. The concentrated dispersion of corticosteroid component is mixed under aseptic conditions and added as a slurry to the viscosity inducing component concentrate. Sufficient (moderate) water is added to provide the desired composition, and the composition is then mixed until homogeneous.

Also provided are methods of using the compositions of the invention, which methods are included within the scope of the invention. Generally, the method comprises administering a composition of the invention to the posterior segment of the eye of a human or animal to achieve a desired therapeutic effect. The step of administering advantageously comprises at least one of the following: intravitreal injection, subconjunctival injection, sub-tenon's injection, retrobulbar injection, suprachoroidal injection, and the like. An injection device comprising a suitably sized needle cannula, such as a 27 gauge needle cannula or a 30 gauge needle cannula, may be effectively used to inject the composition into the posterior segment of a human or animal eye.

Diseases/disorders that may be treated or treated according to the present invention include, but are not limited to:

macular degeneration/retinal degeneration: non-exudative age-related macular degeneration (ARMD), choroidal neovascularization, diabetic retinopathy, acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, diabetic macular edema;

uveitis/retinitis/choroiditis: acute multifocal squamous pigment epithelial lesions, Behcet's Disease, shotgun shell-like retinal choroidopathy, infectious diseases (syphilis, Lyme Disease (Lyme), tuberculosis, toxoplasmosis), intermediate uveitis ((pars plana inflammation), multifocal choroiditis, multiple transient White spot Syndrome (medds), ocular sarcoidosis (ocular sarcoidosis), posterior scleritis, paranoid uveitis (serogiogenic choroides), subretinal fibrosis and uveitis Syndrome, vogue-small willow-primordial Syndrome;

vascular/exudative disorders: retinal arterial occlusive Disease, central retinal vein Occlusion, disseminated intravascular coagulopathy, Branch retinal Occlusion, hypertensive fundus alteration, ocular ischemic syndrome, retinal arterial microaneurysms, chronic exudative retinopathy (Coat's Disease), juxtarfoveal telangiectasia, retinal hemilateral vein Occlusion (Hemi-retinal Occlusion), papillary phlebitis (papiilphlebetis), central retinal artery Occlusion, Branch retinal artery Occlusion, Carotid Artery Disease (CAD), frost-like dendritic vasculitis (Frosted Branch Angitis), sickle cell retinopathy and other hemoglobinopathies (hemoglobinopathies), vascular streaks, familial exudative vitreoretinopathy, illipe Disease (eaves Disease);

traumatic/surgical: sympathetic ophthalmia, uveitis retinopathy, retinal detachment, trauma, laser, PDT, photocoagulation, blood perfusion deficiency during surgery, radiation retinopathy, bone marrow transplantation retinopathy;

proliferative disorders: proliferative vitreoretinopathy and epiretinal membranes (epiretinalmermane), proliferative diabetic retinopathy;

infectious disorders: ocular histoplasmosis, ocular toxocariasis, pseudoocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal diseases associated with HIV infection, uveal diseases associated with HIV infection, viral retinitis, acute retinal Necrosis, Progressive outer retinal Necrosis (Progressive external retinitis), fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute retinitis, myiasis;

genetic disorders: retinitis pigmentosa, systemic disorders associated with retinal Dystrophy, congenital quiescent night blindness, pyramidal Dystrophy, Stargardt's Disease and Fundus macular Disease, Best's Disease, retinal pigment epithelial pattern Dystrophy (pattern Dystrophy), X-complicated (X-linked) retinoschisis, Sorsby's Fundus Dystrophy, Benign Concentric Maculopathy (Benign Concentric macular), biett's crystalloid Dystrophy, pseudoxanthoma elasticum;

retinal tears/holes: retinal detachment, macular hole, giant retinal hole;

tumor: retinal diseases associated with tumors, congenital hypertrophy of the RPE, Posterior Uveal Melanoma (posteror uval Melanoma), choroidal hemangioma, choroidal osteoma, choroidal metastasis, mixed hamartoma of the retina and retinal pigment epithelium, retinoblastoma, ocular fundus vascular proliferative tumors, retinal astrocytoma, intraocular lymphoma;

and others: punctate choroidopathy, acute posterior multifocal squamous pigment epithelial lesion, myopic retinal degeneration, acute retinal pigment epitheliosis, etc.

The methods of the invention may include injection into the posterior segment of the eye alone, and may also include repeated injections over a period of time, for example, over a period of about one week or about 1 month or about 3 months to about 6 months or about 1 year or more.

The following non-limiting examples illustrate certain aspects of the invention.

Examples 1 to 4

The four compositions are as follows:

components	Example 1	Example 2	Example 3	Example 4
					Triamcinolone acetonide	2％(w/v)	2％(w/v)	4％(w/v)	4％(w/v)
Sodium hyaluronate (0.6X 10)6Dalton)	0.05％(w/v)	0.5％(w/v)	0.05％(w/v)	0.5％(w/v)
					Sodium phosphate	0.4％(w/v)	0.4％(w/v)	0.4％(w/v)	0.4％(w/v)
Vitamin E-TPGS	0.5％(w/v)	0.5％(w/v)	0.0	0.0
					8-Cyclodextrin	0.5％(w/v)	0.5％(w/v)	0.0	0.0
Water for injection	Proper amount of	Proper amount of	Proper amount of	Proper amount of
					Viscosity at 0.1/sec shear rate	20cps	500cps	20cps	500cps

Each of the above compositions was prepared as follows.

Triamcinolone acetonide is combined with water, if any, with vitamin E-TPGS and 8-cyclodextrin to produce a concentrated triamcinolone acetonide dispersion. The above components are mixed, the triamcinolone acetonide is dispersed, and then autoclaved. Sodium hyaluronate can be purchased as a commercially sterile powder, or sterilized by the following method: the diluted solution was filtered and then dried by sublimation under low pressure to give a sterile powder. Sterile sodium hyaluronate is dissolved in water to prepare aqueous concentrated solution. The concentrated triamcinolone acetonide dispersion was mixed and added to the sodium hyaluronate concentrate as a slurry. Add the appropriate amount of water and mix the mixture until homogeneous.

Each of the above compositions loosens the aggregation (flocculation) of triamcinolone acetonide and is therefore easily re-suspendable by moderate inversion. The composition may be sold in small volume pharmaceutical grade glass vials and has been found to be effective in the treatment of macular edema when intravitreally injected into a human eye.

Examples 5 to 7

The three compositions were as follows:

components	Example 5	Example 6	Example 7
				Triamcinolone acetonide	2.0％(w/v)	4.0％(w/v)	8.0％(w/v)
Hyaluronic acid sodium salt	3.0％(w/v)	2.5％(w/v)	2.0％(w/v)
				Sodium phosphate	0.4％(w/v)	0.4％(w/v)	0.4％(w/v)
Water for injection	Proper amount of	Proper amount of	Proper amount of
				Viscosity at 0.1/sec shear rate	180,000cps	120,000cps	80,000cps

The above composition was prepared in a substantially similar manner as described in example 1.

The higher viscosity of the composition significantly reduces the settling rate of the particles to the point where no resuspension treatment is necessary or desirable over the expected shelf life of the composition, e.g., about 2 years. The composition can be sold pre-filled in a syringe because it is not easily transferred from the container using a needle and syringe. However, the composition, pre-filled in the syringe, can still be effectively injected into the posterior segment of the eye through a 27 gauge or 30 gauge needle cannula to provide the desired therapeutic effect in the eye.

The compositions of examples 5 to 7 employ or include high molecular weight sodium hyaluronate in a concentration sufficiently high to form a gelatinous plug or drug depot upon intravitreal injection into the human eye. In contrast to, for example, the use of a composition with a viscosity similar to water, such as Kenalog ® 40, triamcinolone acetonide particles are effectively trapped or preserved in the above-described viscous plug, thereby avoiding the occurrence of deleterious "tumbling" and also significantly reducing the risk of unwanted direct deposition of drug particles on the retinal tissue. The above formulations are easily injected through 27 gauge or even 30 gauge needle cannula because of the extremely strong shear thinning effect to which the sodium hyaluronate solution is subjected.

Examples 8 and 9

The two compositions were as follows:

components	Example 8	Example 9
			Triamcinolone acetonide	2.0％(w/v)	8.0％(w/v)
Hyaluronic acid sodium salt	2.5％(w/v)	2.3％(w/v)
			Sodium chloride	0.63％(w/v)	0.6％(w/v)
Disodium hydrogen phosphate, heptahydrate	0.30％(w/v)	0.30％(w/v)
			Sodium dihydrogen phosphate, monohydrate	0.04％(w/v)	0.04％(w/v)
Water for injection	Proper amount of	Proper amount of
			Viscosity at 0.1/sec shear rate	170,000±25％cps	200,000±25％cps

The above composition was prepared in a substantially similar manner as described in example 1.

The higher viscosity of the composition significantly reduces the settling rate of the particles to the point where no resuspension treatment is necessary or desirable over the expected shelf life of the composition, e.g., about 2 years. The composition can be sold pre-filled in a syringe because it is not easily transferred from the container using a needle and syringe. However, the composition, pre-filled in the syringe, can still be effectively injected into the posterior segment of the eye through a 27 gauge or 30 gauge needle cannula to provide the desired therapeutic effect in the eye.

The sodium hyaluronate powder used in the above compositions (and in other compositions identified in the examples herein) has a water content of from about 4% to about 20% by weight, preferably from about 4% to about 8% by weight. The moisture content of the powders, and in particular the variation in moisture content from powder to powder, can result in two or more compositions of the invention having the same "nominal" chemical composition having different viscosities. Thus, references herein to viscosity are to be understood as reference to target viscosity, and the composition may be used when its actual viscosity is above or below about 25% or about 30% or about 35% of the (+/-) target viscosity.

Since the density of each of the compositions described in the examples is about 1mg/ml, the weight-to-volume (w/v) based percentages described herein may also be considered weight-to-weight (w/w) based percentages.

The compositions of examples 8 and 9 employ or include high molecular weight sodium hyaluronate in a concentration high enough to form a gelatinous plug or drug depot upon intravitreal injection into the human eye. In contrast to, for example, the use of a composition having a viscosity similar to water, such as Kenalog ® 40, triamcinolone acetonide particles are effectively trapped or preserved in the above-described viscous plug, thereby avoiding the occurrence of deleterious "plume" and also significantly reducing the risk of unwanted direct deposition of drug particles onto retinal tissue. The above formulations are easily injected through 27 gauge or even 30 gauge needle cannula because of the extremely strong shear thinning effect to which the sodium hyaluronate solution is subjected.

While the invention has been described in terms of various specific examples and embodiments, it is to be understood that the invention is not so limited, but may be practiced otherwise than as specifically described within the scope of the following claims.

Claims (62)

1. A composition for injection into the posterior segment of a human or animal eye, the composition comprising:

a therapeutically effective amount of a corticosteroid component, the corticosteroid component being present in the form of a plurality of particles;

a viscosity inducing component in an amount effective to increase the viscosity of the composition; and

an aqueous carrier component, said composition having a viscosity of at least about 10cps at 0.1/sec shear rate and said composition being effective for injection into the posterior segment of a human or animal eye.

2. The composition of claim 1 having a viscosity of at least 100cps at 0.1/sec shear.

3. The composition of claim 1 having a viscosity of at least 10,000cps at 0.1/sec shear rate.

4. The composition of claim 1 having a viscosity of from about 140,000cps to about 300,000cps at 0.1/second shear rate.

5. The composition of claim 1, which is effective for injection into the posterior segment of a human or animal eye through a 27 gauge needle cannula.

6. The composition of claim 1, which is effective for injection into the posterior segment of a human or animal eye through a 30 gauge needle cannula.

7. The composition of claim 1, wherein the particles are substantially uniformly suspended in the composition.

8. The composition of claim 7, wherein the particles are substantially uniformly suspended in the composition without resuspension treatment for at least about 1 week.

9. The composition of claim 7, wherein the particles are substantially uniformly suspended in the composition without resuspension treatment for at least about 1 month.

10. The composition of claim 7, wherein the particles are substantially uniformly suspended in the composition without resuspension treatment for at least about 6 months.

11. The composition of claim 7, wherein the particles are substantially uniformly suspended in the composition for at least about 1 year without a resuspension process.

12. The composition of claim 7, wherein the particles are substantially uniformly suspended in the composition for at least about 2 years without a resuspension process.

13. The composition of claim 1, wherein the corticosteroid component is present in an amount up to about 25% (w/v) of the composition.

14. The composition of claim 1, wherein the corticosteroid component is present in an amount of at least about 10mg/ml of composition.

15. The composition of claim 1, wherein the corticosteroid component is present in an amount of about 1% to about 20% (w/v) of the composition.

16. The composition of claim 1, wherein the corticosteroid component is present in an amount of about 1% to about 10% (w/v) of the composition.

17. The composition of claim 1, wherein the corticosteroid component has a solubility in 25EC water of less than 10 mg/ml.

18. The composition of claim 1, wherein the corticosteroid component is selected from the group consisting of cortisone, prednisolone, triamcinolone, fluocinolone acetonide, dexamethasone, medrysone, loteprednol etabonate, derivatives thereof, and mixtures thereof.

19. The composition of claim 1, wherein the corticosteroid component is triamcinolone acetonide.

20. The composition of claim 1, wherein the carrier component comprises an effective amount of at least one of a preservative component, a tonicity modifier component and a buffer component.

21. The composition of claim 1, wherein no preservative component is added to the composition.

22. The composition of claim 1, wherein no resuspension component is added to the composition.

23. The composition of claim 1, wherein the viscosity inducing component is present in an amount from about 0.05% to about 20% (w/v) of the composition.

24. The composition of claim 1, wherein the viscosity inducing component comprises a polymeric component.

25. The composition of claim 1, wherein the viscosity inducing component comprises at least one viscoelastic agent.

26. The composition of claim 1, wherein the viscosity inducing component is selected from the group consisting of polymeric hyaluronic acid, carbomers, polyacrylic acid, cellulose derivatives, polyacrylic resins, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl acetate, derivatives thereof, and mixtures thereof.

27. The composition of claim 1, wherein the viscosity inducing component comprises a hyaluronate component.

28. The composition of claim 27 wherein the hyaluronate component comprises sodium hyaluronate.

29. A method of treatment comprising administering a composition according to claim 1 to the posterior segment of the eye of a human or animal, whereby a desired therapeutic effect is achieved.

30. The method of claim 29, wherein the administering step comprises intravitreal injection.

31. The method of claim 29, wherein the administering step comprises subconjunctival injection.

32. The method of claim 29 wherein the administering step comprises sub-tenon's injection.

33. The method of claim 29, wherein the administering step comprises retrobulbar injection.

34. The method of claim 29, wherein the administering step comprises suprachoroidal injection.

35. A composition for injection into the posterior segment of a human or animal eye, the composition comprising:

a therapeutically effective amount of a corticosteroid component, the corticosteroid component being present in the form of a plurality of particles;

a viscosity inducing component in an amount effective to increase the viscosity of the composition; and

an aqueous carrier component, said particles being substantially uniformly suspended in said composition and substantially uniformly suspended in said composition for at least about 1 week without a resuspension process.

36. The composition of claim 35, wherein the particles are substantially uniformly suspended in the composition without resuspension treatment for at least about 2 weeks.

37. The composition of claim 35, wherein the particles are substantially uniformly suspended in the composition without resuspension treatment for at least about 1 month.

38. The composition of claim 35, wherein the particles are substantially uniformly suspended in the composition without resuspension treatment for at least about 6 months.

39. The composition of claim 35, wherein the particles are substantially uniformly suspended in the composition for at least about 1 year without a resuspension process.

40. The composition of claim 35, wherein the particles are substantially uniformly suspended in the composition for at least about 2 years without a resuspension process.

41. The composition of claim 35, wherein the corticosteroid component is present in an amount up to about 25% (w/v) of the composition.

42. The composition of claim 35, wherein the corticosteroid component is present in an amount of at least about 10mg/ml of composition.

43. The composition of claim 35, wherein the corticosteroid component is present in an amount of about 1% to about 20% (w/v) of the composition.

44. The composition of claim 35, wherein the corticosteroid component is present in an amount of about 1% to about 10% (w/v) of the composition.

45. The composition of claim 35, wherein the corticosteroid component has a solubility in 25EC water of less than 10 mg/ml.

46. The composition of claim 35, wherein the corticosteroid component is selected from the group consisting of cortisone, prednisolone, triamcinolone, fluocinolone acetonide, dexamethasone, medrysone, loteprednol etabonate, derivatives thereof, and mixtures thereof.

47. The composition of claim 35, wherein the corticosteroid component is triamcinolone acetonide.

48. The composition of claim 35, wherein the carrier component comprises an effective amount of at least one of a preservative component, a tonicity modifier component and a buffer component.

49. The composition of claim 35, wherein no preservative component is added to the composition.

50. The composition of claim 35, wherein no resuspension component is added.

51. The composition of claim 35, wherein the viscosity inducing component is present in an amount from about 0.05% to about 20% (w/v) of the composition.

52. The composition of claim 35, wherein the viscosity inducing component comprises a polymeric component.

53. The composition of claim 35, wherein the viscosity inducing component comprises at least one viscoelastic agent.

54. The composition of claim 35, wherein the viscosity inducing component is selected from the group consisting of polymeric hyaluronic acid, carbomers, polyacrylic acid, cellulose derivatives, polyacrylic resins, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl acetate, derivatives thereof, and mixtures thereof.

55. The composition of claim 35, wherein the viscosity inducing component comprises a hyaluronate component.

56. The composition of claim 55 wherein the hyaluronate component comprises sodium hyaluronate.

57. A method of treatment comprising administering a composition according to claim 35 to the posterior segment of the human or animal eye, whereby a desired therapeutic effect is achieved.

58. The method of claim 57, wherein the administering step comprises intravitreal injection.

59. The method of claim 57, wherein the administering step comprises subconjunctival injection.

60. The method of claim 57 wherein the administering step comprises sub-tenon's injection.

61. The method of claim 57, wherein the administering step comprises retrobulbar injection.

62. The method of claim 57, wherein the administering step comprises suprachoroidal injection.