MXPA06005146A - Compositions and methods for treating a posterior segment of an eye - Google Patents

Abstract

Compositions, and methods of using such compositions, useful for injection into the posterior segments of human or animal eyes are provided. Such Compositions include corticosteroid component -containing particles present in a therapeutically effective amount, a viscosity inducing component, and an aqueous carrier component. The compositions have viscosities of at least about 10 cps or about 100 cps at a shear rate of 0.1/second. In a preferred embodiment, the viscosity is in the range of from about 140,000 cps to about 300,000 cps. The compositions advantageously suspend the particles for prolonged periods of time.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF THE POSTERIOR SEGMENT OF AN EYE FIELD OF THE INVENTION This invention relates to compositions and methods for the treatment of posterior segments of the eyes of humans or animals. More particularly, the invention relates to compositions that include corticosteroid components that can be effectively injected into the posterior segments of such eyes and methods of using such compositions to provide the desired therapeutic effects. BACKGROUND OF THE INVENTION Among the therapies that are commonly practiced to treat disorders of the posterior ocular segments, such as uveitis, macular degeneration, macular edema and the like, is the intravitreal injection of a corticosteroid, such as triamcinolone acetonide (TA) . See, for example, Billson et al., In U.S. Patent No. 5,770,589, the disclosure of which is incorporated herein in its entirety for reference. One medication commonly used for this ophthalmologic therapy is Kenalog® 40. Each milliliter (mi) of the Composition Kenalog® 40 includes 40 milligrams (mg) of TA, sodium chloride as a tonicity agent, 10 mg of benzyl alcohol as a preservative, and 7.5 mg of Ref.172408 carboxymethylcellulose and 0.4 mg of polysorbate 80 as resuspension aids. Although widely used by ophthalmologists, this commercially available formulation suffers from several important limitations. For example, the presence of the benzyl alcohol preservative and the polysorbate 80 surfactant tends to lead to unnecessary and / or undue cellular damage, or to other toxicities in sensitive ocular tissues. Although some clinical specialists routinely "wash" the TA precipitate several times with a saline solution to reduce the concentration of these undesirable materials, such washing is inconvenient, time-consuming, and most importantly, increases the likelihood of microbial contamination or endotoxins that could lead to inflammation or intraocular infection. In addition, the TA in Kenalog® 40 tends to separate and precipitate quickly from the rest of the composition. For example, this composition, if left to stand for 1 to 2 hours, leads to a substantial separation of a TA precipitate from the remainder of the composition. Accordingly, if the composition is to be injected into the eye, it must be vigorously shaken and used quickly after being shaken in this way, to provide a substantially uniform suspension in the eye. In addition, the resuspension processing requires the use of the resuspension aids noted above, at least one of which is less than totally desirable for sensitive ocular tissues. There is a need for new compositions for injection into the posterior segments of the eyes of humans or animals, and of methods for providing desirable therapeutic effects in the posterior segments of the eyes of humans or animals. Brief description of the invention New compositions and methods have been discovered for the treatment of the posterior segments of the eyes of humans or animals. The present compositions are highly suitable for intravitreal administration in the posterior segments of the eyes without requiring any "washing step", while providing reduced eye damage, for example, of the retina, when used in one eye . The present compositions are advantageously substantially free of added preservative components, for example, they do not contain a preservative of benzyl alcohol. In addition, the present compositions advantageously do not require an adjuvant or resuspension aids. In general, the present compositions are easily and effectively injectable in the posterior segment of an eye of a human or animal., and can be maintained as a substantially uniform suspension for extended periods of time, for example, at least about a week or more, without resuspension processing, for example, without agitation being required or otherwise having to be moved. composition to obtain a substantial uniformity of the suspension. In summary, the present compositions and methods provide substantial improvements and advantages, for example, in relation to the Kenalog® 40 composition of the prior art and methods of using such prior art composition, in the posterior segments of the eyes of the art. human beings or animals. In a broad aspect of the present invention, compositions useful for injection into a posterior segment of an eye of a human or animal are provided. Such compositions comprise a corticosteroid component, a viscosity-inducing component, and an aqueous carrier component. The corticosteroid component is present in a therapeutically effective amount. The corticosteroid component is present in the compositions in a plurality of particles. The present compositions may include a corticosteroid component in an amount of up to about 25% (w / v) or more of the composition. In a very useful embodiment, the corticosteroid component is present in an amount of at least about 80 mg / ml of the composition. Preferably, the corticosteroid component is present in an amount ranging from about 1% to about 10%, or about 20% (w / v) of the composition. In a very useful 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, optically acceptable, ophthalmically acceptable viscosity-inducing component can be employed according to the present invention. Many such viscosity-inducing components have been proposed and / or used in ophthalmic compositions used on or in the eye. Advantageously, the viscosity-inducing component is present in an amount in a range from about 0.5% to about 20% (p / v) of the composition. In a particularly useful embodiment, the viscosity-inducing component is a polymeric component of hyaluronic acid, such as sodium hyaluronate. In one embodiment, the present compositions have a viscosity of at least about 10 cps or at least about 100 cps, preferably at least about 1,000 cps, more preferably at least about 10,000 cps and still more preferably at least about 70,000 cps, for example, up to approximately 250,000 cps, or approximately 300,000 cps, at a shear rate of 0.1 / second. The present compositions are structured or have compositions to be injected effectively, for example, manually, into a posterior segment of an eye of a human or animal, preferably by means of a 27 gauge needle, more preferably by means of a needle of size 29 or 30. Without wishing to limit the invention to any particular theory of operation, it is believed that the use of compositions of relatively high viscosity, as described herein, provides an effective, and preferably substantially uniform, suspension of the particles of the spheroidal component while, at the same time, they are injectable in the posterior segment of an eye by means of conventionally used needles, or even smaller than those conventionally used. In one embodiment of the invention, the corticosteroid component is present in a plurality of particles that are suspended substantially uniformly in the composition and remain substantially uniformly suspended in the composition for at least about 1 week, preferably at least about 2 weeks or at least about one month, and still more preferably at least about 6 months or at least about 1 year or at least about 2 years, without requiring resuspension processing, that is, without requiring it to be agitated or moved from another way to maintain the corticosteroid component particles suspended substantially uniformly in the composition. Compositions having such a substantially uniform suspension of the corticosteroid component particles provide substantial advantages, relative to the prior art. In particular, the present compositions can be manufactured, shipped and stored for substantial periods of time without the particles of the corticosteroid component precipitating from the rest of the composition. By having the particles of the corticosteroid component held suspended substantially uniformly in the composition, the composition is allowed to be used quickly and effectively to provide treatment to the posterior segment of an eye of a human or animal without the interest that have to resuspend such particles. The aqueous carrier component is advantageously ophthalmicly acceptable and may include one or more conventional resources useful in the ophthalmic compositions.

For example, the carrier component can include an effective amount of at least one of a preservative component, a tonicity component and a buffering component. In an advantageous embodiment, the present compositions do not include an added preservative component. This feature reduces or minimizes, or even substantially eliminates, adverse reactions in the eye that may be caused by, or may be related to, the presence of a preservative component. Although a resuspension component can be employed in accordance with the present invention, in many cases, because of the ability of the present composition to remain as a substantially uniform suspension for a prolonged period of time without requiring resuspension processing, the compositions advantageously do not contain aggregate resuspension components. Methods of treating the posterior segments of the eyes of humans or animals are also described and are included within the scope of the present invention. In general, such methods comprise administration, i.e., injection of a composition containing the corticosteroid component, for example, a composition according to the present invention, to a posterior segment of an eye of a human or animal. Such administration is effective to provide a therapeutically desired effect. The administration step advantageously comprises at least one of the intravitreal injection, subconjunctival injection, injection into the sub-Tenon, retrobulbar injection, suprachoroidal injection and the like. Each feature described herein, and each combination of two or more such features, are included within the scope of the present invention so long as the features included in such a combination are not mutually inconsistent. These and other aspects and advantages of the present invention are apparent in the following detailed description, examples and claims. DETAILED DESCRIPTION OF THE INVENTION The present invention involves compositions useful for placement, preferably by injection, in a posterior segment of an eye of a human or animal. Such compositions in the back, for example, the vitreous humor of the eye, are therapeutically effective against one or more conditions and / or diseases of the back of the eye, and / or one or more symptoms of such conditions and / or diseases of the eye. the back of the eye. In general, the present compositions comprise a corticosteroid component; a component that induces viscosity; and an aqueous carrier component. Advantageously, the compositions are ophthalmically acceptable. One of the important advantages of the present compositions is that they are more compatible with, or more favorable for, tissues in the posterior segment of the eye, for example, the retina of the eye, relative to the compositions previously proposed for intravitreal injection. in a posterior segment of an eye, for example, a composition sold under the trademark Kenalog® 40. In particular, the present compositions are advantageously substantially free of added preservative components or include effective preservative components that are more compatible with, or favorable for, the posterior segment of the eye, for example, the retina, relative to benzyl alcohol, which is included in the composition of Kenalog® 40 as a preservative. In addition, the present compositions preferably do not include an added resuspension component or a resuspension component that is more compatible with, or favorable to, the posterior segment of the eye, eg, the retina, relative to polysorbate-80, which is included in the composition of Kenalog® 40. Many of the other features of the present compositions, as described herein in another "art, also make the present compositions more compatible with, or favorable to, the posterior segments of the eyes within which the compositions are placed in relation to prior art compositions, such as Kenalog® 40. As noted above, the present compositions include a corticosteroid component.Such corticosteroid component is present in the compositions in a therapeutically effective amount, ie in a effective amount to provide a desired therapeutic effect in the o jo within which the composition is placed. The corticosteroid component is present in the composition in a plurality of particles. Any suitable corticosteroid component can be employed in accordance with the present invention. Such a corticosteroid component advantageously has a limited solubility in water, for example, in 25EC. For example, the corticosteroid component preferably has a solubility in water at 25EC of less than 10 mg / ml. Of course, the corticosteroid component must be ophthalmically acceptable, that is, it must have substantially no significant or undue effect on the structures or tissues of the eye. A particularly useful feature of currently useful corticosteroid components is the ability of such a component to reduce inflammation in the posterior segment of the eye within which the composition is placed, caused as a result of one or more diseases and / or conditions in the posterior segment of the eye. Examples of useful corticosteroid components include, without limitation, cortisone, prednisolone, triamcinolone, triamcinolone acetonide, fluorometholone, dexamethasone, medrisone, loteprednol, derivatives thereof, and mixtures thereof. When used here, the term "derivative" refers to any substance that is structurally sufficiently similar to the material from which it is identified as a derivative to have a substantially similar functionality or activity, for example, therapeutic effectiveness, such as the material when the substance is used instead of the material. In a very useful embodiment, the corticosteroid component comprises triamcinolone acetonide. The corticosteroid component is advantageously present in an amount of at least about 10 mg per ml of the composition. An important advantage of the present invention is the effective ability of the present compositions to include relatively large amounts or concentrations of the corticosteroid component. Accordingly, the corticosteroid component may be present in the present compositions in an amount in the range of about 1% or less to about 5% or about 10% or about 20% or about 30% or greater (w / v) of the composition. The provision of relatively high concentrations or amounts of the corticosteroid component in the present compositions is beneficial because it may be required that small amounts of the composition be placed or injected into the posterior segment of the eye to provide the same or greater amount of the corticosteroid component in the segment. posterior of the eye, relative to the compositions, such as Kenalog®-40, which includes less than 4% (w / v) of the corticosteroid component. Accordingly, in a very useful embodiment, the present compositions include more than about 4% (w / v), for example at least about 5% (w / v), up to about 10% (w / v) or about 20% (w / v) or approximately 30% (w / v) of the corticosteroid component. The viscosity-inducing component is present in an amount effective to increase, or substantially substantially increase, the viscosity of the composition. Without wishing to limit the invention to any particular theory of operation, it is believed that increasing the viscosity of the compositions to values in excess of the viscosity of the water, for example at least about 100 cps at a shear rate of 0.1 / second, compositions are obtained that are highly effective for placement, for example, by injection, in the posterior segment of an eye of a human or animal. In the company of the advantageous positioning or the injectability of the present compositions in the posterior segment, the relatively high viscosity of the present compositions is believed to improve the ability of the present compositions to maintain the particles of the corticosteroid component in a substantially uniform suspension, in the compositions for extended periods of time, for example, for at least about a week, without the resuspension processing being required. The relatively high viscosity of the present compositions may also have an additional benefit of at least helping the compositions have the ability to have an increased amount or concentration of the corticosteroid component, as described herein elsewhere, for example, while maintains such a corticosteroid component in a substantially uniform suspension for prolonged periods of time. Advantageously, the present compositions have viscosities of at least about 10 cps or at least about 100 cps, or at least about 1000 cps, more preferably at least about 10,000 cps and still more preferably at least about 70,000 cps or more, for example up to about 200,000 cps or approximately 250,000 cps, or approximately 300,000 cps or greater, at a shear rate of 0.1 / second. The present compositions not only have a relatively high viscosity as noted above, but also have the capacity or are structured or composed so that they can be placed effectively, for example, in injectable manner, in a posterior segment of an eye of a human or animal, preferably by means of a gauge needle 27, or even by means of a 30 gauge needle. The currently useful viscosity-inducing components are preferably shear thinning components because the present composition containing such viscosity-inducing component that reduces shear is passed or injected in the posterior segment of an eye, for example, through a narrow space, such as a 27-gauge needle, under high shear conditions, the viscosity of the composition is substantially reduced during such a pass. After such passage, the composition substantially regains its pre-injection viscosity to maintain the particles of the corticosteroid component in suspension in the eye. Any suitable viscosity-inducing component, for example, an ophthalmically acceptable viscosity-inducing component, can be employed in accordance with the present invention. Many such viscosity-inducing components have been proposed and / or used in the ophthalmic compositions used on or in the eye. The viscosity-inducing component is present in an amount effective to provide the desired viscosity to the composition. Advantageously, the viscosity-inducing component is present in an amount in a range of about 0.5% or about 1.0% to about 5% or about 10% or about 20% (w / v) of the composition. The specific amount of the inductor component of the employed rate depends on a number of several factors including, for example - and without limitation, the inductor component of the specific viscosity that is employed, the molecular weight of the velocity-inducing component that is employed , the viscosity desired for the present composition that is produced and / or used and similar factors. The viscosity-inducing component is chosen to provide at least one advantage, and preferably multiple advantages, to the present compositions, for example, in terms of each of the injectability in the posterior segment of the eye, the viscosity, the holding capacity of the particles of the corticosteroid component in suspension, for example, in a substantially uniform suspension, for a prolonged period of time without resuspension processing, compatibility with tissues in the posterior segment of the eye within which the composition is to be placed and the similar advantages. More preferably, the inducing component of the selected viscosity is effective to provide two or more benefits noted above, and still more preferably to provide all of the benefits noted above. The viscosity-inducing component preferably comprises a polymeric component and / or at least one viscoelastic agent, such as those materials that are useful in ophthalmic surgical procedures. Examples of the useful viscosity-inducing components include, but are not limited to, hyaluronic acid, carbomers, polyacrylic acid, cellulose derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl acetate, derivatives of them and mixtures thereof. The molecular weight of the currently useful viscosity-inducing components may be in a range of about 10,000 Daltons or less to about 2 million Daltons or greater. In a particularly useful embodiment, the molecular weight of the viscosity-inducing component is in a range of about 10,000 Daltons or about 200,000 Daltons to about 1 million Daltons or about 1.5 million Daltons. Again, the molecular weight of the viscosity-inducing component, useful, according to the present invention, can vary over a substantial range based on the type of the viscosity-inducing component employed, and the desired final viscosity of the present composition in question, as well as, possibly one or more of other factors. In a very useful embodiment, a viscosity-inducing component is a polymeric hyaluronate component, for example, a metallic hyaluronate component, preferably selected from alkali metal hyaluronates, alkaline earth metal hyaluronates and mixtures thereof, and further preferably selected from the sodium hyaluronates, and mixtures thereof. The molecular weight of such a hyaluronate component is preferably in the range of about 50,000 Daltons or about 10,000 Daltons to about 1.3 million Daltons or about 2 million Daltons. In one embodiment, the present compositions include a polymeric hyaluronate component in an amount in a range of about 0.05% to about 0.5% (w / v). In a further useful embodiment, the hyaluronate component is present in an amount in a range of about 1% to about 4% (w / v) of the composition. In the latter case, the viscosity of the very high polymer forms a gel which slows down the rate of sedimentation of the particle to the extent that frequently no resuspension process is necessary for the estimated storage duration, for example, at least about 2 years , of the composition. Such a composition can be marketed in pre-filled syringes since the gel can not be easily removed by a needle and syringe from a volumetric container. The aqueous carrier component is advantageously ophthalmically acceptable and may include one or more conventional excipients useful in ophthalmic compositions. The present compositions preferably include a larger amount of liquid water. The present compositions can be, and are preferably, sterile, for example, prior to being used in the eye. The present compositions preferably include at least one buffer component in an amount effective to control the pH of the composition and / or at least one tonicity component in an amount effective to control the tonicity or osmolality of the compositions. More preferably, the present compositions include both a buffering component and a tonicity component. The buffering component and the tonicity component can be chosen from those which are conventional and well known in the ophthalmic 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 particularly useful. Useful tonicity components include, but are not limited to, salts, particularly sodium chloride, potassium chloride, any other ophthalmically acceptable tonicity component, and mixtures thereof. The amount of the buffer component employed preferably is sufficient to maintain the pH of the composition in a range of from about 6 to about 8, more preferably from about 7 to about 7.5. The amount of the tonicity component employed is preferably sufficient to provide an osmolality for the present compositions in a range from about 200 to about 400, more preferably from about 250 to about 350, mOsmol / g respectively.

Advantageously, the present compositions are substantially isotonic. The present compositions may include one or more other components in effective amounts to provide one or more properties and / or benefits useful to the present compositions. For example, although the present compositions may be substantially free of the added preservative components, in other embodiments, the present compositions include effective amounts of preservative components, preferably such components are more compatible with, or favorable for, tissue in the posterior segment of the eye. within which the composition is placed, that the benzyl alcohol. Examples of such preservative components include, without limitation, benzalkonium chloride, chlorhexidine, PHMB (polyhexamethylene biguanide), methyl and ethyl parabens, hexetidine, chlorite components, such as stabilized chlorine dioxide, metal chlorites and the like, other ophthalmically acceptable preservatives and the like, and mixtures thereof. The concentration of the preservative component, if any, in the present compositions is at an effective concentration to preserve the composition, and is frequently in a range of about 0.00001% to about 0.05% or about 0.1% (w / v) of the composition.

In addition, the present composition may include an effective amount of the resuspension component effective to facilitate suspension or resuspension of the corticosteroid component particles in the present compositions. As noted above, in certain embodiments, the present compositions are free of aggregate resuspension components. In other embodiments of the present compositions effective amounts of resuspension components are employed, for example, to provide an additional degree of assurance that the particles of the corticosteroid component remain in suspension, as is desirable and / or that they can be resuspended relatively easy in the present compositions, in the event that such resuspension is desired. Advantageously, the resuspension component used in accordance with the present invention, if any, is chosen to be more compatible with, or favorable for, the tissue in the posterior segment of the eye within which the composition is placed, than the polysorbate 80. Any suitable resuspension component can be employed in accordance with the present invention. Examples of such resuspension components include, without limitation, surfactants such as poloxanes, for example, sold under the trademark Pluronic®; Tyloxapol; sarcosinates; polyethoxylated castor oils; other surfactants and the like and mixtures thereof. A very useful class of resuspension components are those selected from the vitamin derivatives. Although such materials have been previously suggested for use as surfactants in ophthalmic compositions, it has been found that they will be effective in the present compositions as resuspension components. Examples of useful vitamin derivatives include, without limitation, polyethylene glycol tocopheryl vitamin E succinates, such as polyethylene glycol 1000 tocopheryl vitamin E succinate (vitamin E T.PGS). Other useful vitamin derivatives include, again without limitation, vitamin E tocopheryl polyethylene glycol succinamides, such as vitamin E tocopheryl polyethylene glycol 1000 succinamide (vitamin E TPGSA) wherein the ester bond between polyethylene glycol and succinic acid is replaced by an amide group . Currently useful resuspension components are present, if any, in the compositions according to the present invention in an amount effective to facilitate suspension of the particles in the present compositions., for example, during the manufacture of the compositions or after that. The specific amount of the resuspension component employed can vary over a wide range depending, for example, on the specific resuspension component that is employed, the specific composition in which the resuspension component is being employed and the like factors. Suitable concentrations of the resuspension component, if any, in the present compositions are frequently in a range of from about 0.01% to about 5%, for example, about 0.02% or about 0.05% to about 1.0% (w / v) ) of the composition. The availability of minimally soluble corticosteroid components, such as triamcinolone acetonide, to infra-ocular tissues may be limited by the rate of dissolution for these substances. Slow dissolution is both good and bad for the patient. On the one hand, after a single intravitreal injection of the present composition, the average elimination half-life for the triamcinolone acetonide is advantageously very long, for example, of about 19 days in patients who are not submitted to the vitreous operation and where Measurable drug levels are detected for up to about 3 months. On the other hand, the levels of the therapeutic drug in the vitreous compartment of the eye may not be achieved for about 1 to about 3 days, due to the slow dissolution rate of the corticosteroid component particles. In one embodiment of the present invention, an effective amount of a solubilizing component is provided in the composition to solubilize a minor amount, i.e., less than 50%, for example in a range of 1% or about 5% to about 10% or approximately 20% of the corticosteroid component. For example, the inclusion of a cyclodextrin component, such as β-cyclodextrin, ß-cyclodextrin sulfo-butyl ether (SBE), other cyclodextrins and the like and mixtures thereof, about 0.5 to about 5.0% (w / v), solubilizes approximately 1 to approximately 10 % of the initial dose of triamcinolone acetonide. This presolubilized fraction provides * an easily bioavailable loading dose, thereby avoiding any time delay in therapeutic effectiveness. The use of such a solubilization component is advantageous to provide any relatively rapid release of the corticosteroid component in the eye for therapeutic effectiveness. Such a solubilizing component, of course, must be ophthalmically acceptable or at least sufficiently compatible with the posterior segment of the eye within which the composition is positioned to avoid undue tissue damage in such a posterior segment. The pharmacokinetic characteristics of the corticosteroid component, eg, triamcinolone acetonide, after intravitreal administration, may involve both the rate of drug dissolution and the rate of drug flow through the above route. For example, after a single intravitreal injection of a composition containing 4% (w / v) of triamcinolone acetonide, the TA concentration takes maximum values (verified in the aqueous humor) after several days to thousands of nanograms per ml. . This maximum value (Cmax) is followed by a rapid reduction that lasts approximately 200 hours, and ends in a slow elimination phase with a half-life of approximately 19 days. Patients typically require a repeat dose, for example approximately every three months. In one embodiment of the present invention, the compositions further contain sustained release components, for example, polymers, such as poly (D, L-lactide) or poly (D, L-lactide co-glycolide), in effective amounts to reduce local diffusion rates and / or dissolution rates of corticosteroid particles. The result is a smoother removal rate profile with lower Cmax and a longer therapeutic window, which extends the time between injections required for many patients. Any suitable release component, preferably acceptable in a conditional manner, can be employed. Useful examples are described above. The sustained release component is preferably biodegradable or bioabsorbable in the eye so that no residue remains on it in the long term. The amount of the delayed release component included can vary over a relatively broad range depending, for example, on the specific sustained release component that is employed, the specific release profile desired and the like factors. Typical amounts of the delayed release components, if any, included in the present compositions are in a range of about 0.05 to 0.1 to about 0.5 or about 1 or more in percent (w / v) of the composition. The present compositions can be prepared using suitable processing / combination techniques, or techniques, for example, one or more conventional combination techniques. The processing of the preparation should be chosen to provide the present compositions in forms that are useful for placement or injection into the posterior segments of the eyes of humans or animals. In a useful embodiment, a dispersion of the concentrated corticosteroid component is made by combining the corticosteroid component with water, and the excipient (as opposed to the viscosity-inducing component) is to be included in the final composition. The ingredients are mixed to disperse the corticosteroid component and then subjected to autoclaving. Alternatively, the spheroid powder can be irradiated with lightning? before the addition to the sterile carrier. The viscosity-inducing component can be purchased sterile or sterilized by conventional processing, for example, by filtering a diluted solution followed by lyophilization to give a sterile powder. The sterile, viscosity-inducing component is combined with water to make an aqueous concentrate. Under aseptic conditions, the dispersion of the concentrated corticosteroid component is mixed and added as a suspension to the concentrate of the viscosity-inducing component. Water is added in a sufficient amount (c. S.) To provide the desired composition and the composition is mixed until it becomes homogeneous. The methods of use of the present composition are provided and are included within the scope of the present invention. In general, such methods comprise administering a composition according to the present invention to a posterior segment of an eye of a human or animal, whereby a desired therapeutic effect is obtained. The administration step advantageously comprises at least one of intravitreal injection, subconjunctival injection, sub-Tenon injection, retrobulbar injection, suprachoroidal injection and the like. A syringe apparatus including an appropriately sized needle, for example, a 27 gauge needle or a 30 gauge needle, can be effectively used to inject the composition into the posterior segment of an eye of a human or animal. Among the diseases / conditions that can be treated or resolved according to the present invention, the following are included, without limitation: MACULOPATHIES / DEGENERATION - RETINAL: Macular degeneration related to age, non-exudative (ARMD), macular degeneration related to age, exudative (ARMD), choroidal neovascularization, diabetic retinopathy, acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, diabetic macular edema. UVEITIS / RETINITIS / CHOLOIDITIS: Acute multifocal placoid pigment epitheliopathy, Behcet's disease, Birdshot retinochoroidopathy, infectious diseases (syphilis, Lyme disease, tuberculosis, toxoplasmosis), intermediate uveitis (Pars planitis), multifocal choroiditis, multiple evanescent white spots syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, serpignous choroiditis, subrretinal fibrosis and uveitis syndrome, syndrome of Vogt-Koyanagi-Harada. VASCULAR DISEASES / EXUDATIVE DISEASES: Retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branched retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat disease, parafoveal telangiectasia, hemi-retinal vein occlusion , papilloflebitis, occlusion of the central retinal artery, occlusion of the branched retinal artery, carotid artery disease (CAD), frozen branching angiitis, retinopathy for sickle cell anemia and other hemoglobinopathies, formation of angioid clefts, familial exudative vitreous retinopathy, Eales disease. TRAUMATIC / SURGICAL: Sympathetic system ophthalmia, uveitic retinal disease, retinal detachment, trauma, application of laser beam, PDT, photocoagulation, hypoperfusion during surgery, radiation retinopathy, retinopathy by bone marrow transplantation. PROLIFERATIVE DISEASES: Proliferative vitreous retinopathy and epirrebral membranes, proliferative diabetic retinopathy. INFECTIOUS DISEASES: Ocular histoplasmosis, ocular toxocariosis, presumed ocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associated with HIV infection, uveitis associated with HIV infection, viral retinitis, acute retinal necrosis, progressive external retinal necrosis, retinal diseases caused by fungi, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, myiasis. GENETIC DISORDERS: Retinitis pigmentosa, systemic disorders with associated retinal dystrophies, congenital stationary night blindness, conic dystrophies, Stargardt disease and Flavi aculatus fundus, Best's disease, retinal pigmented epithelium configuration dystrophy, retinochromosis related to X-rays, dystrophy of the Sorsby fundus, benign concentric maculopathy, Bietti's crystal dystrophy, pseudoxanthoma elasticum. REMOVAL / RETINAL HOLES: Detachment of the retina, macular orifice, giant retinal tear. TUMORS: Retinal disease associated with tumors, congenital RPE hypertrophy, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined retinal and retinal pigmented epithelium hamartoma, retinoblast a, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, lymphoid tumors infraocular. MISCEL NEOS: Punctate internal choroidopathy, epitheliopathy of posterior multifocal placoid pigments, acute, myopic retinal degeneration, acute retinal pigment epitheliitis and the like. The present methods may comprise a single injection in the posterior segment of an eye or may involve repeated injections, for example, for periods of time ranging from about a week or about 1 month or about 3 months to about 6 months or about 1 year or a longer period. The following non-limiting examples illustrate certain aspects of the present invention. Examples 1 to 4 Four compositions are as follows: Each of these compositions is prepared as follows. A dispersion of concentrated triamcinolone acetonide is made by combining the triamcinolone acetonide with water, vitamin E-TPGS and 8-cyclodextrin, if any. These ingredients are mixed to disperse the triamcinolone acetonide and - then autoclaved. Sodium hyaluronate can be purchased as a sterile powder or sterilized by filtering a diluted solution, followed by lyophilization to give a sterile powder. The sterile sodium hyaluronate is dissolved in water to make an aqueous concentrate. The dispersion of concentrated triamcinolone acetonide is mixed and added as a suspension to the concentrate of sodium hyaluronate. Water is added in a c. s. and the mixture is mixed until it becomes homogeneous. Each of these compositions produced a slight fluctuation of the triamcinolone acetonide which is easily resuspended by gentle inversion. These compositions can be marketed in small volume pharmaceutical grade glass bottles, and were found to be therapeutically effective against macular edema when injected intravitreally into human eyes. Examples 5 to 7 Three compositions are as follows: These compositions are prepared in a manner substantially analogous to that described in Example 1. The high viscosities of the compositions substantially slow down the sedimentation rate of the particle to a degree where no resuspension processing is necessary or required over the duration in estimated storage, for example, about 2 years, of the compositions. These compositions can be marketed in prefilled syringes since they can not be easily removed by a needle and syringe from a container. However, with compositions in prefilled syringes, the compositions can be effectively injected into the posterior segment of an eye of a human using a 27 gauge needle or a 30 gauge needle to provide a desired therapeutic effect in the human eye. The compositions of Examples 5 to 7 employ or contain a sufficient concentration of sodium hyaluronate, of high molecular weight, to form a gelatinous plug or drug reservoir during intravitreal injection in a human eye. The triamcinolone acetonide particles, in effect, are entrapped or held within this viscous plug, so that undesirable "plucking" does not occur, and the risk that the drug particles sediment disadvantageously directly on the tissue. retinal is substantially reduced, for example, in relation to the use of a composition with a viscosity similar to that of water, such as Kenalog® 40. Since sodium hyaluronate solutions are subjected to a dramatic shear thinning, these formulations are easily injected through 27-gauge needles or even 30-gauge needles. Examples 8 and 9 Two compositions are as follows: Cont. Of the table These compositions are prepared in a manner substantially analogous to that described in Example 1. The high viscosities of the compositions substantially slow down the rate of sedimentation of the particle to the extent that no resuspension processing is necessary or required for the duration of time. estimated storage, for example, approximately 2 years, of the compositions. These compositions can be marketed in pre-filled syringes since they can not be easily removed by a syringe and needle from a container. However, with compositions in prefilled syringes, the compositions can be effectively injected into the posterior segment of an eye of a human using a 27 gauge needle or a 30 gauge needle to provide a desired therapeutic effect in the human eye.

The sodium hyaluronate powders used in these compositions (as well as in the other compositions identified in the examples herein) have water contents in a range from about 4% to about 20%, preferably from about 4% to about 8% , in weigh. The water content of the powder, and in particular the variation in the water contents for the powder with respect to the powder, can lead to variations in the viscosities of two or more compositions according to the present invention, which have the same chemical compositions "nominal". Accordingly, the viscosities indicated herein should be understood as going to be target viscosities, with the composition being acceptable for use if the actual viscosity of the composition is within plus or minus (+) about 25% or about 30% or about 35% of the total viscosity. Because each of the compositions described in the examples has a density of about 1 g / ml, the percentages described herein that are based on weight per volume (w / v) can also be considered to be based on weight per weight (p / p). The compositions of Examples 8 and 9 employ or contain a sufficient concentration of sodium hyaluronate, of high molecular weight, to form a gelatinous cap or drug reservoir during intravitreal injection in a human eye. The triamcinolone acetonide particles, in effect, are trapped or held within this viscous plug, so that undesirable "flushing" does not occur, and the risk that the drug particles sediment disadvantageously directly on the tissue retinal is substantially reduced, for example, in relation to using a composition with a viscosity similar to that of water, such as Kenalog® 40. Since sodium hyaluronate solutions are subjected to a dramatic shear thinning, these formulations are injected easily through 27-gauge or even 30-gauge needles. Although this invention has been described with respect to several specific examples and embodiments, it is to be understood that the invention is not limited thereto and that it can be practiced differently. within the scope of the following claims. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (62)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property. A composition useful for injection into a posterior segment of an eye of a human or animal, characterized in that it comprises: a corticosteroid component present in a therapeutically effective amount, the corticosteroid component is present in a plurality of particles; a viscosity-inducing component in an amount effective to increase the viscosity of the composition; and ^ an aqueous carrier component, the composition has a viscosity of at least about 10 cps at a shear rate of 0.1 / second and is effectively injectable in a posterior segment of an eye of a human or animal.
2. 2. The composition according to claim 1, characterized in that it has a viscosity of at least 100 cps at a shear rate of 0.1 / second.
3. 3. The composition according to claim 1, characterized in that it has a viscosity of at least 10,000 cps at a shear rate of 0.1 / second.
4. The composition according to claim 1, characterized in that it has a viscosity from about 140,000 cps - about 300,000 cps at a shear rate of 0.1 / second.
5. The composition according to claim 1, characterized in that it is effectively injectable through a 27 gauge needle in a posterior segment of an eye of a human or animal.
6. The composition according to claim 1, characterized in that it is effectively injectable through a 30 gauge needle in the posterior segment of an eye of a human or animal.
7. 7. The composition according to claim 1, characterized in that the particles are suspended in a substantially uniform manner in the composition.
8. The composition according to claim 7, characterized in that the particles remain suspended substantially uniformly in the composition for at least about 1 week without requiring resuspension processing.
9. The composition according to claim 7, characterized in that the particles remain suspended substantially uniformly in the composition for at least about 1 month without requiring resuspension processing.
10. The composition according to claim 7, characterized in that the particles remain suspended substantially uniformly in the composition for at least about 6 months without requiring resuspension processing.
11. The composition according to claim 7, characterized in that the particles remain suspended substantially uniformly in the composition for at least about 1 year without requiring resuspension processing.
12. The composition according to claim 7, characterized in that the particles remain suspended substantially uniformly in the composition for at least about 2 years without requiring resuspension processing.
13. The composition according to claim 1, characterized in that the corticosteroid component is present in an amount of up to about 25% (w / v) of the composition.
14. The composition according to claim 1, characterized in that the corticosteroid component is present in an amount of at least about 10 mg per ml of the composition.
15. 15. The composition according to claim 1, characterized in that the corticosteroid component is present in an amount in a range from about 1% to about 20% (w / v) of the composition.
16. 16. The composition according to claim 1, characterized in that the corticosteroid component is present in an amount in a range from about 1% to about 10% (w / v) of the composition.
17. 17. The composition according to claim 1, characterized in that the corticosteroid component has a solubility in water at 25EC of less than 10 mg / ml.
18. 18. The composition according to claim 1, characterized in that the corticosteroid component is selected from the group consisting of cortisone, prednisolone, triamcinolone, fluorometholone, dexamethasone, medrisone, loteprednol, derivatives thereof and mixtures thereof.
19. 19. The composition according to claim 1, characterized in that the corticosteroid component is triamcinolone acetonide.
20. The composition according to claim 1, characterized in that the carrier component includes an effective amount of at least one of a preservative component, a tonicity component and a buffering component.
21. 21. The composition according to claim 1, characterized in that it does not include an added preservative component.
22. 22. The composition according to claim 1, characterized in that it does not include an aggregate resuspension component.
23. 23. The composition according to claim 1, characterized in that the viscosity-inducing component is present in an amount in a range from about 0.05% to about 20% (w / v) of the composition.
24. 24. The composition according to claim 1, characterized in that the viscous inducing component comprises a polymeric component.
25. 25. The composition according to claim 1, characterized in that the viscosity-inducing component comprises at least one viscoelastic agent.
26. 26. The composition according to claim 1, characterized in that the viscosity-inducing component is selected from the group consisting of polymeric hyaluronic acid, carbomers, polyacrylic acid, cellulose derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl acetate, derivatives thereof and mixtures thereof.
27. 27. The composition according to claim 1, characterized in that the viscosity-inducing component comprises a hyaluronate component.
28. 28. The composition according to claim 27, characterized in that the hyaluronate component comprises sodium hyaluronate.
29. 29. A method of treatment, characterized in that it comprises administering the composition according to claim 1 to a posterior segment of an eye of a human or animal, whereby a desired therapeutic effect is obtained.
30. 30. The method according to claim 29, characterized in that the administration step comprises intravitreal injection.
31. 31. The method according to claim 29, characterized in that the administration step comprises subconjunctival injection.
32. 32. The method according to claim 29, characterized in that the administration step comprises the injection in the sub-Tenon.
33. 33. The method according to claim 29, characterized in that the administration step comprises the retrobulbar injection.
34. 34. The method according to claim 29, characterized in that the administration step comprises the suprachoroidal injection.
35. 35. A composition useful for injection into the posterior segment of an eye of a human or animal being, characterized in that it comprises: a corticosteroid component present in an amount having a therapeutic effect, the corticosteroid component is present in a plurality of particles; a viscosity-inducing component in an amount effective to increase the viscosity of the composition; and an aqueous carrier component, the particles are suspended substantially uniformly in the composition and remain suspended substantially uniformly in the composition for at least about 1 week without requiring resuspension processing.
36. 36. The composition according to claim 35, characterized in that the particles remain suspended substantially uniformly in the composition for at least about 2 weeks without the resuspension processing being required.
37. 37. The composition according to claim 35, characterized in that the particles remain suspended substantially uniformly in the composition for at least about 1 month without requiring resuspension processing.
38. 38. The composition according to claim 35, characterized in that the particles remain suspended substantially uniformly in the composition for at least about 6 months without requiring resuspension processing.
39. 39. The composition according to claim 35, characterized in that the particles remain suspended substantially uniformly in the composition for at least about 1 year without requiring resuspension processing.
40. 40. The composition according to claim 35, characterized in that the particles remain suspended substantially uniformly in the composition for at least about 2 years without requiring resuspension processing.
41. 41. The composition according to claim 35, characterized in that the corticosteroid component is present in an amount of up to about 25% (w / v) of the composition.
42. 42. The composition according to claim 35, characterized in that the corticosteroid component is present in an amount of at least about 10 mg per ml of the composition.
43. 43. The composition according to claim 35, characterized in that the corticosteroid component is present in an amount in a range from about 1% to about 20% (w / v) of the composition.
44. 44. The composition according to claim 35, characterized in that the corticosteroid component is present in an amount in a range from about 1% to about 10% (w / v) of the composition.
45. 45. The composition according to claim 35, characterized in that the corticosteroid component has a solubility in water at 25EC of less than 10 mg / ml.
46. 46. The composition according to claim 35, characterized in that the corticosteroid component is selected from the group consisting of cortisone, prednisolone, triamcinolone, fluorometholone, dexamethasone, medrisone, loteprednol, derivatives thereof and mixtures thereof.
47. 47. The composition according to claim 35, characterized in that the corticosteroid component is triamcinolone acetonide.
48. 48. The composition according to claim 35, characterized in that the carrier component includes an effective amount of at least one of a preservative component, a tonicity component and a buffering component.
49. 49. The composition according to claim 35, characterized in that it does not include an added preservative component.
50. 50. The composition according to claim 35, characterized in that it does not include an aggregate resuspension component.
51. 51. The composition of conformity. with claim 35, characterized in that the viscosity-inducing component is present in an amount in a range from about 0.05% to about 20% (w / v) of the composition.
52. 52. The composition according to claim 35, characterized in that the viscosity-inducing component comprises a polymeric component.
53. 53. The composition according to claim 35, characterized in that the viscosity-inducing component comprises at least one viscoelastic agent.
54. 54. The composition according to claim 35, characterized in that the viscosity-inducing component is selected from the group consisting of polymeric hyaluronic acid, carbomers, polyacrylic acid, cellulose derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide, alcohol polyvinyl acetate, polyvinyl acetate, derivatives thereof and mixtures thereof.
55. 55. The composition according to claim 35, characterized in that the viscosity-inducing component comprises a hyaluronate component.
56. 56. The composition according to claim 55, characterized in that the hyaluronate component comprises sodium hyaluronate.
57. 57. A method of treatment, characterized in that it comprises administering the composition according to claim 35 to a posterior segment of an eye of a human or animal, whereby a desired therapeutic effect is obtained.
58. 58. The method according to claim 57, characterized in that the administration step comprises an intravitreal injection.
59. 59. The method according to claim 57, characterized in that the administration step comprises subconjunctival injection.
60. 60. The method according to claim 57, characterized in that the administration step comprises the injection in the sub-Tenon.
61. 61. The method of compliance with the claim 57, characterized in that the administration step comprises retrobulbar injection.
62. 62. The method according to claim 57, characterized in that the administration step comprises the suprachoroidal injection.