Compositions and methods of treatment of posterior ocular segment

FIELD: medicine; ophthalmology.

SUBSTANCE: invention is characterised by compositions and methods of application of such compositions applicable for injection in posterior ocular segment of people and animals. These compositions include particles containing corticosteroid component of water-soluble factor less than 10 mg/ml at 25°C presented in therapeutically effective amount, thickener and aqueous carrier. Viscosity of compositions is at least about 10 centipoises or about 100 centipoises at shear rate 0.1 c-1. Preferable version of invention implies that viscosity is within the range 140000 centipoises to 300000 centipoises. Particles in compositions mainly remain suspended during continuous period of time.

EFFECT: invention provides stability of composition d during continuous period of time without resuspending.

57 cl, 9 ex

 

The invention relates to compositions and methods for treating posterior segment of people and animals. More specifically, the invention relates to compositions comprising a corticosteroid components that can be efficiently injected into the posterior segment of the eye, and to methods of applying such compositions to provide the desired therapeutic effect.

In those practiced in the present methods of treatment of disorders of the posterior segment of the eye such as uveitis, macular degeneration, edema yellow spots, etc. is injected into the vitreous body of the corticosteroid, such as triamcinolone acetonide (TA) (see, for example, Billson et al, U.S. patent No. 5770589, the description of which is incorporated herein by reference).

One of the drugs commonly used to treat these eye diseases, is Kenalog®40. 1 milliliter (ml) of the composition Kenalog®40 contains 40 mg of THE sodium chloride as an agent, determining toychest, 10 mg benzyl alcohol as preservative, 7.5 mg of carboxymethylcellulose and 0.4 mg of Polysorbate 80 as an auxiliary resuspending funds. Although this commercially available product is widely used by ophthalmologists, its use has some significant limitations.

For example, the presence of benzyl alcohol as it is servant and surfactant Polysorbate 80 may lead to unnecessary and/or excessive cell damage or other toxic effects in the sensitive eye tissues. Although some clinicians standard several times, "washed" precipitate THE saline solution to reduce the concentration of these undesirable substances, such washing is inconvenient, requires time and, most importantly, increases the likelihood of microbial or endotoxin contamination, which can lead to eye infections and inflammation.

In addition, THE Kenalog®40 tends quickly to separate and precipitate from the remaining portion of the composition. For example, in this song, if you let it stand for one to two hours, resulting in a significant separation of the precipitate from THE remaining portion of the composition. Thus, if the composition need to be injected into the eye, it should before this vigorously shake well and use immediately after shaking for suspension in the eye turned out to be essentially uniform. In addition to resuspendable you want to apply auxiliary resuspending tools mentioned above, at least one of which is not entirely desirable for sensitive eye tissues.

Thus, there is a need for new compositions for injection into a posterior segment of an eye of people and animals and how to ensure the desired therapeutic effect in the posterior segment of the eye of humans and animals.

Brief and the Appendix of the invention

New compositions and methods of treatment of the posterior segment of people and animals. Compositions in accordance with the present invention are well suited for insertion through the vitreous body in the posterior segment of the eye, without having any "stage of leaching, and at the same time, resulting in reduced damage to the eye such as the retina, when applied to the eye. Compositions in accordance with the present invention mainly practically do not contain additional components, for example they do not contain benzyl alcohol as preservative. Moreover, the compositions in accordance with the present invention mainly do not require auxiliary resuspending vehicle or vehicles. In General, compositions in accordance with the present invention may be easily and efficiently injected into the posterior segment of the eye of a human or animal and can be supported in the form of a practically uniform suspension for a long period of time, such as within at least about one week or more, without resuspendable, in particular without the need to stir or otherwise mix the composition to obtain almost uniform suspension. Briefly, the compositions and methods in accordance with the present invention provide significant improvements and pre is the property, for example, compared with the composition Kenalog®40 in accordance with the prior art and methods of use of such compositions in accordance with the prior art in the posterior segment of an eye of a human or animal.

In one broad aspect of the present invention proposed a composition suitable for injection into a posterior segment of an eye of a human or animal. These compositions include corticosteroid component, a thickener and water media. Corticosteroid component is present in therapeutically effective amounts. Corticosteroid component is introduced into the compositions in the form of a set of particles.

Compositions in accordance with the present invention may include corticosteroid component in an amount up to about 25% (wt./about.) or more by volume of the composition. In one particularly preferred method of the invention, the corticosteroid component is present in an amount constituting at least about 80 mg per 1 ml of the composition. Preferably corticosteroid component is present in an amount in the range from about 1% to 10% or 20% (wt./about.) from the volume of the composition.

In one particularly preferred methods of the invention, the corticosteroid component is triazines is on acetonide.

The thickener is present in a quantity effective to increase the viscosity of the composition.

In accordance with the present invention may be used any suitable, preferably ophthalmologist acceptable thickening agent. Many of these thickeners proposed and/or used in ophthalmic compositions to be applied on the surface or inside the eye. Preferably the thickener is present in an amount in the range from about 0.5% to 20% (wt./about.) from the volume of the composition. In one particularly preferred method of carrying out the invention, the thickener is a polymer of hyaluronic acid, such as sodium hyaluronate.

One of the ways of making the viscosity of the compositions in accordance with the present invention is at least about 10 centipoise, or at least about 100 centipoise, preferably at least about 1000 centipoise, more preferably at least about 10,000 centipoise, and even more preferably at least about 70,000 centipoise, for example, to approximately 250,000 in CP, or about 300,000 centipoise at a shear rate of 0.1 s-1. The compositions of the present invention are structured or have such a composition that they can be effectively injected, the particular manually in the posterior segment of an eye of a human or animal, preferably through a needle 27 gauge (0,360 mm), preferably through a needle 29 or 30 gauge (0,286 or 0,255 mm).

Without wishing to limit the invention to any specific methodology, we hypothesized that the use of compositions having relatively high viscosity, as described in this application, allows to obtain an effective and preferably almost uniform particle suspension steroid component, which at the same time, can be injected into the posterior segment of the eye through a commonly used, or even smaller needles.

In one of the methods of the invention, the corticosteroid component is present in the form of a set of particles, which are almost uniformly suspended in the composition and remain almost uniformly suspended in the composition, at least for about one week, preferably at least about two weeks or at least about one month, and more preferably at least about six months or at least about one year, or at least about two years without resuspendable, i.e. without the need to stir or otherwise mix the composition to maintain the particles corticosteroid component in the composition in almost uniformly suspended status is I.

Compositions containing such almost uniform particle suspension corticosteroid component, provide significant advantages over prior art. In particular, the compositions of the present invention can be produced, transported and stored for a considerable period of time, and there is no precipitation of particles of the corticosteroid component of the remaining part of the composition. Maintaining the particles corticosteroid component is almost uniformly suspended in the composition allows for quick and effective use composition for the treatment of posterior segment eye of a human or animal without worrying about having to resuspendable these particles.

The water carrier is mainly ophthalmologist acceptable and may include one or more conventional excipients used in ophthalmic compositions.

For example, the carrier may include at least one of the following components: a preservative agent that defines toychest, or buffer in an effective amount.

In one of the preferred ways of making the composition in accordance with the present invention is not added preservative. This feature reduces or minimizes, or even virtually eliminates adverse reactions in the eye, the cat who that may be caused or associated with the presence of a preservative.

Although in accordance with the present invention can be used resuspendable component, in many cases, because of the ability of the composition in accordance with the present invention can be in the form of a practically uniform suspension for a long period of time without the need of resuspendable, composition mainly not contain resuspending components.

Methods of treatment of the posterior segment of people or animals are also described and included in the scope of the present invention. Typically, such methods include the introduction, for example an injection of a composition containing a corticosteroid component, for example, compositions in accordance with the present invention, in the posterior segment of the eye of a human or animal. This introduction effectively provides the desired therapeutic effect. Stage introduction mainly includes at least one of the following methods: subconjunctival injection, an injection under the tenon capsule, retro-bulbar injection, suprachoroidal injection, etc.

Each is described here, the characteristic and each combination of two or more of these signs included in the scope of the present invention, provided that the topics included in this combination are not vzaimoneobhodimy.

These and other aspects and advantages of the present invention is onati from the following detailed description, examples and claims.

Detailed description of the invention

The present invention includes compositions suitable for administration, preferably by injection, in the posterior segment of the eye of a human or animal. Such compositions in the back of the eye, for example in the vitreous body, a therapeutically effective against one or more conditions and/or diseases of the posterior segment and/or one or more symptoms of such conditions and/or diseases of the posterior segment.

Typically, the compositions in accordance with the present invention include corticosteroid component, a thickener and water media. The songs are mostly ophthalmologist acceptable.

One of the important advantages of the compositions in accordance with the present invention lies in the fact that they are more compatible with the tissues in the posterior segment of the eye such as the retina, or harmless against them compared to compositions previously proposed for injection through the vitreous body in the posterior segment of the eye, for example, compared with the composition supplied to the market under the trademark Kenalog®40. In particular, compositions in accordance with the present invention mainly practically do not contain preservatives or include effective preservatives that are more compatible with adnim segment, for example, retina, or less harmful compared to benzyl alcohol, which is included in the composition Kenalog®40 as preservative.

Additionally, compositions in accordance with the present invention preferably do not include resuspendable component or include resuspendable component that is more compatible with a rear segment, for example, retina, or less harmful in comparison with Polysorbate 80, which is included in the composition Kenalog®40. Many other properties of the composition in accordance with the present invention described here also make compositions in accordance with the present invention are more compatible with the posterior segment of the eye, in which they are administered, or less harmful in comparison with the compositions in accordance with the prior art, such as Kenalog®40.

As indicated above, the compositions in accordance with the present invention include corticosteroid component. This corticosteroid component is present in the composition in a therapeutically effective amount, that is, the number, effectively providing the desired therapeutic effect in the eye, which is injected composition. Corticosteroid component is introduced in the composition in the form of a set of particles.

In accordance with the present which m invention may be used any suitable corticosteroid component. This corticosteroid component preferably should have limited solubility in water, for example, at 25°C. for Example, the solubility of the corticosteroid component in water is preferably at 25°With less than 10 mg/ml. of Course, corticosteroid component must be ophthalmologist acceptable, i.e. it should not have a significant or very harmful effect on the structure or fabric of the eye. One particularly useful property is suitable corticosteroid component in accordance with the present invention is the ability of these components to reduce inflammation in the posterior segment of the eye, which introduced the composition caused by one or more of the disease and/or condition in the posterior segment of the eye.

Examples of suitable corticosteroid components include cortisone, prednisolone, triamcinolone, triamcinolone acetonide, formation, dexamethason, Madison, loteprednol, their derivatives, but not limited to. Used herein, the term "derivative" refers to any substance that is quite similar in structure to the connection on which it identifies as a derivative, in order to have a function or activity, for example, therapeutic efficacy, substantially similar to the corresponding function or activity : the underwater connection when using this substance instead of the original connection.

In one particularly preferred way of implementation of the corticosteroid component is triamcinolone acetonide.

The amount of the corticosteroid component is preferably at least about 10 mg per 1 ml of the composition. One of the important advantages of the present invention is of considerable ability of compositions in accordance with the present invention include a relatively large number or concentration of the corticosteroid component. Thus, corticosteroid component may be present in the composition in accordance with the present invention in amounts in the range from approximately 1% or less up to 5% or 10%, or 20%, or 30% or more (wt./about.) from the volume of the composition. Obtaining a relatively high concentration or amount of a corticosteroid component in the compositions in accordance with the present invention is desirable since it can require a smaller amount of the composition was introduced or injected into the posterior segment of the eye with getting in the rear segment of the eye the same or more corticosteroid component in comparison with such compositions, as Kenalog®40, which comprise less than 4% (wt./about.) corticosteroid component. Thus, in one particularly preferred the methods of the invention, the compositions in accordance with the present invention include corticosteroid component in the quantity greater than approximately 4% (wt./vol.), for example, at least about 5% (wt./about.) up to 10% (wt./vol.), or 20% (wt./vol.), or 30% (wt./vol.).

The thickener is present in such quantity that it is effectively increased, preferably substantially increased the viscosity of the composition. Without limiting the invention to any specific methodology, suggest that increasing the viscosity of the composition to a value sufficiently greater than the viscosity of water, for example at least 100 centipoise at a shear rate of 0.1 s-1get composition, highly effective for the introduction of, for example, by injection into a posterior segment of an eye of a human or animal. I believe that the relatively high viscosity of the composition in accordance with the present invention is not only conducive to the introduction or facilitates the injection of the composition in accordance with the present invention in the posterior segment of the eye, but also enhances the ability of the compositions in accordance with the present invention to maintain the particles of the corticosteroid component in the form of a practically uniform suspension in the composition for a long period of time, for example at least about one week, without resuspendable. The relatively high viscosity of the composition in accordance with the present invention may also be updat the additional benefit encouraging, at least, the ability of the composition to contain an increased amount or concentration of the corticosteroid component, as described here, and while maintaining this corticosteroid component in the form of a practically uniform suspension for a long period of time.

Preferably the viscosity of the compositions in accordance with the present invention is at least about 10 centipoise, or at least about 100 centipoise, or at least about 1000 centipoise, preferably at least about 10,000 centipoise, even more preferably at least about 70,000 centipoise or more, e.g. up to about 200,000 centipoise or almost 250,000 CP, or about 300,000 centipoise or greater at a shear rate of 0.1 s-1. Compositions in accordance with the present invention not only have a relatively high viscosity as described above, but also have the following capacity or as structured or prepared so that they could effectively introduce, for example, by injection into a posterior segment of an eye of a human or animal, preferably through a needle 27 gauge (0,321 mm), or even through a needle 30 gauge (0,255 mm).

Thickeners suitable in accordance with the present invention, preferably are components that razzhizhayuschiesya at which the motor so when the composition in accordance with the present invention containing such razzhizhayuschiesya shear component, injected or injected into the posterior segment of the eye, for example, through the narrow lumen, in particular through the needle 27 gauge (0,360 mm), with a large shearing force, the viscosity of the composition, the noise is thus significantly reduced. Being introduced thus, the composition restores almost the same viscosity before injection, thus supporting particles corticosteroid component in the eye in the form of a suspension.

In accordance with the present invention may be used any suitable thickener, for example ophthalmologist acceptable thickening agent. Many of these thickeners been proposed and/or used in ophthalmic compositions to be applied on the surface or inside the eye. The thickener is present in an amount effective to impart to the composition the desired viscosity. Mainly the thickener is present in an amount in the range from about 0.5% or 1.0% to 5% or 10%, or 20% (wt./about.) from the volume of the composition. The specific amount of the thickener depends on many factors, including, for example, what specifically thickener is used, the molecular weight of thickener used, what viscosity trebuet is manufactured and/or used in the composition, but not limited to them. The thickener is chosen so as to give a composition in accordance with the present invention at least one, and preferably many advantages, for example, in relation to the possibility of injection in the posterior segment of the eye, viscosity, stability of the suspended state particles corticosteroid component, in particular almost evenly suspended state for a long period of time without resuspendable, compatibility with the tissues in the posterior segment of the eye, which will enter the composition, and similar benefits. More preferably, the selected thickener effectively provided two or more of the above advantages, and even more preferably, it is ensured that all the aforementioned advantages.

Preferably, the thickener include a polymeric component and/or at least one viscoelastic agent, such as materials suitable for ophthalmic surgical procedures.

Examples of suitable thickening agents include hyaluronic acid, carbomer, polyacrylic acid, cellulose derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl acetate, derivatives thereof and mixtures, but are not limited to.

Molecular weight of prigodin the x in accordance with the present invention thickeners may be in the range of about 10,000 daltons or less to 2 megadalton or more. In one particularly preferred embodiments of the invention the molecular weight of the thickener is in the range of about 100,000 daltons or 200000 daltons up to 1 megadalton or 1.5 megadalton. In addition, the molecular weight of the thickener used in accordance with the present invention, may vary within a wide range depending on the type of thickener and what eventually viscosity requires consideration of the composition in accordance with the present invention, as well as possibly one or more other factors.

In one particularly preferred embodiments, the thickener is a polymer gialuronatnye component, such as component, representing hyaluronate metal, preferably selected from alkali metal hyaluronates, hyaluronates alkaline earth metals and mixtures thereof, more preferably selected from sodium hyaluronates and mixtures thereof. The molecular mass of this gialuronatnye component preferably is in the range of about 50,000 daltons or 100000 daltons to 1.3 megadalton or 2 megadalton. In one of the embodiments of the invention compositions in accordance with the present invention vklyuchayuschimisya gialuronatnye component number, in the range of about from 0.05% to 0.5% (wt./vol.). In another preferred embodiment, gialuronatnye component is present in amounts in the range from approximately 1% to 4% (wt./about.) from the volume of the composition. In the latter case, a very high polymer viscosity leads to the formation of a gel that slows the rate of sedimentation of particles to such an extent that during the expected shelf life of the composition, for example at least about two years, re-suspension is often not required. Such a composition can be sold in pre-filled syringes, because the gel is difficult to remove from the reservoir through the needle and syringe.

The aqueous medium preferably is ophthalmologist acceptable and may include one or more standard excipient suitable for ophthalmic compositions.

Preferably, the compositions in accordance with the present invention included a significant amount of liquid water. Compositions in accordance with the present invention can be and preferably are sterilized, for example, sterilized prior to use in the eye.

Compositions in accordance with the present invention preferably include at least one buffer component in an amount to effectively monitor the performance of the pH of the composition, and/or at least one agent that defines toychest, in an amount to effectively monitor toychest or osmollnosti compositions. More preferably the compositions in accordance with the present invention include a buffer component, and the agent that defines toychest.

The buffer component and the agent that defines toychest, can be selected from components that are conventional and well known in ophthalmology.

Examples of such buffer components include acetate buffers, citrate buffers, phosphate buffers, borate buffers, etc. and mixtures thereof, but are not limited to. Particularly preferred phosphate buffers. Suitable agents that determine toychest include the salts, in particular sodium chloride, potassium chloride, any other suitable ophthalmologist acceptable to the agent specifying toychest, and mixtures thereof, but are not limited to.

The used amount of the buffer component preferably should be sufficient to maintain the pH of the composition in the range of about 6 to 8, more preferably from about 7 to 7.5. The amount of agent that defines toychest, preferably should be sufficient to make the composition in accordance with the present invention, the osmolality in the range approx the tion from 200 to 400 mosmol/kg, more preferably from about 250 to 350 mosmol/kg. Preferably, the compositions in accordance with the present invention were nearly isotonic.

Compositions in accordance with the present invention can include one or more of the other components in amounts effective to impart to the compositions in accordance with the present invention one or more useful properties and/or benefits. For example, although the arrangement in accordance with the present invention basically can not contain preservatives, in some embodiments of the invention compositions in accordance with the present invention include an effective amount of preservatives, it is preferable that the components are more compatible with the tissue posterior segment of the eye, into which enter the composition, or less harmful compared to benzyl alcohol. Examples of such preservatives include benzalkonium chloride, chlorhexidine, polyhexamethylene biguanide (RNPS), methyl - and ethylparaben, hexetidine, chlorite components, such as stabilized chlorine dioxide, chlorite metals and the like, other ophthalmologist acceptable preservatives, etc. and mixtures thereof, but are not limited to. The concentration of preservative, if present in the composition in accordance with the present invention should effectively sposobstvo the th storage of the composition and is often in the range of from about 0.00001% to 0.05% or 0.1% (wt./about.) from the volume of the composition.

Additionally, the composition in accordance with the present invention may include the number resuspending component to effectively facilitate the suspension or re-suspension of particles corticosteroid component in the compositions in accordance with the present invention. As indicated above, in some embodiments, implementation of the present invention compositions in accordance with this agreement, do not contain resuspending components. In other embodiments, the implementation in the compositions in accordance with the present invention are effective amount resuspending components, for example, to provide additional assurance that the particles corticosteroid component will remain in suspension as described above, and/or can be relatively easily resuspendable in the compositions in accordance with the present invention, and such re-suspension is desirable. Preferably used in accordance with the present invention resuspendable component, if present, was selected more compatible with the tissue in the posterior segment of the eye, into which enter the composition, or less harmful, than Polysorbate 80.

In accordance with the present invention may be used any suitable resuspendable component. Examples takegreatpictures components include surfactants, such as proxeny, for example, supplied to the market under the trademark Pluronic®tyloxapol, sarcosinate, polyethoxysiloxane castor oil, other surfactants, etc. and mixtures thereof, but are not limited to.

One particularly preferred class resuspending components are components selected from derivatives of vitamins. Although these substances have been previously proposed for use as surfactants in ophthalmic compositions, it was found that they are effective in the compositions in accordance with the present invention as resuspending components. Examples of suitable derivatives of vitamins include derivatives of vitamin E tocopherolacetate succinate, such as vitamin E tocopherolacetate 1000 succinate (vitamin E TPGS), but are not limited to. Other preferred derivatives of vitamins include derivatives of vitamin E tocopherolacetate succinamide, such as vitamin E tocopherolacetate 1000 succinate (vitamin E TPGSA), where the ester linkage between the polyethylene glycol and succinic acid substituted amide group, but are not limited to.

Suitable for use in accordance with the present invention resuspending components, if they are present in the composition is x in accordance with the present invention, present in the amount in which they effectively facilitate the suspension of the particles in these compositions, for example, in the preparation of compositions or after that. The specific number used resuspending component can vary within a wide range depending, for example, what specifically resuspendable component is used, the specific composition, which is used resuspendable component, and similar factors. The proper concentration resuspending component, if present in the composition in accordance with the present invention, is often in the range from approximately 0.01% to 5%, for example approximately from 0.02% or 0.05% to 1.0% (wt./about.) from the volume of the composition.

The availability of the least soluble corticosteroid components, such as triamcinolone acetonide, to intraocular tissues may be limited by the dissolution rate of these substances. Slow dissolution simultaneously good and bad for the patient. On the one hand, after a single injection into the vitreous body composition in accordance with the present invention the average half-life of triamcinolone acetonide mainly is sufficiently long, for example about 19 days in patients with no remote vitreous body, and for up to about three months in the Le of this patients detected detected levels of drugs. On the other hand, therapeutic level of drug in the vitreous of the eye Department may not be achieved during the period from approximately one to three days due to the slow dissolution rate of the particles corticosteroid component.

In one of the embodiments of the present invention in the composition is added solubilizers component in an amount effective to solubilisate minor amount, i.e. an amount of less than 50%, for example from approximately 1% or 5% to 10% or 20%, corticosteroid component. For example, the inclusion of cyclodextrines component, such as β-cyclodextrin, sulphobutylether β-cyclodextrin (SBE), other cyclodextrins and the like, and mixtures thereof, at a concentration of from about 0.5 to about 5.0 percent (wt./about.) solubilities from about 1% to 10% of the initial dose of triamcinolone acetonide. This pre-solubilization fraction provides biologically easily accessible loading dose, thus eliminating any time lag therapeutic effect.

The use of such solubilizing component is preferred to provide a relatively quick release of the corticosteroid component in the eye to get therapeutic effect. This solubilizers comp the element, of course, should be ophthalmologist acceptable or at least compatible enough with the posterior segment of the eye, into which enter the composition, to avoid excessive tissue damage in the specified rear segment.

Pharmacokinetics corticosteroid component, for example, triamcinolone acetonide, after injection into the vitreous body may include both the dissolution rate of the drug, and the rate of outflow of medicines through the front path. For example, after a single injection into the vitreous body composition, containing 4% (wt./about.) triamcinolone acetonide, the peak concentration of THE (registered in intraocular fluid) in a few days amount to thousands of nanograms per ml. For this peak (Cmaxshould a rapid decrease, which lasts for approximately 200 hours, which ends with the slow phase of elimination with a half-life of approximately 19 days. Patients usually require a second dose of, for example approximately every three months.

In one of the embodiments of the present invention compositions additionally contain components that provide extended release of, for example, polymers, such as poly(D,L-lactide) or poly(D,L-lactide coglycolide), in quantities to effectively reduce the rate of local diffusion and/or speed races is of its corticosteroid particles. Because of this, the excretion profile becomes smoother with lessmaxand a longer therapeutic window, resulting in the time between required injections, many patients increases.

Can be used any suitable, preferably conditionally acceptable, disposable component. Preferred examples presented above. A component with a long release should preferably be biodegradable or biologically absorbable in the eye, so that over a long period of time were not formed any residue. The number included component with a slow release may be varied within a relatively wide range depending, for example, what specific component of the delayed release is used, a particular desired release profile, and similar factors. Typically, the number of components with a long release, if they are to be included in the compositions in accordance with the present invention, is in the range of about from 0.05% to 0.1%, 0.5% or 1% or more (wt./about.) from the volume of the composition.

Compositions in accordance with the present invention can be obtained by using appropriate methods of mixing/processing, such as one or more standard ways Pach the project. The processing method of the drug should be selected so that there is the possibility to obtain compositions in accordance with the present invention in a form suitable for injection or injection into the posterior segment of the eyes of people or animals. In one of the preferred embodiments of the invention a concentrated dispersion of the corticosteroid component is prepared by combining a corticosteroid component with water, and in the final composition include excipient (different from the thickener). The ingredients are mixed to disperse different corticosteroid component, and then autoclave. Or steroid powder is subjected to γ-irradiation before adding to sterile media. Thickener become sterile or sterilized using conventional processing, such as filtering the diluted solution, followed by lyophilization and obtaining sterile powder. Sterile thickener is combined with water to form a water concentrate. A concentrated dispersion of the corticosteroid component mix and add the suspension to the concentrate thickener in aseptic conditions. Add water in sufficient quantity (D.K.) to obtain the desired composition, and the composition is stirred until a homogeneous state.

In the scope of the present invention is proposed and included in the str the ordinary use of the composition in accordance with the present invention. Typically, such methods include the introduction of a composition in accordance with the present invention in the posterior segment of the eye of a human or animal, thus providing the desired therapeutic effect. Stage management preferably includes at least one of the following routes of administration: injection into the vitreous body, subconjunctival injection, an injection under the tenon capsule, retro-bulbar injection, suprachoroidal injection, etc. For injection of the composition into the posterior segment of the eye of a human or animal can effectively use a syringe with a needle of suitable size, for example a needle 27 gauge (0,360 mm) or needle 30 gauge (0,255 mm).

Diseases/conditions that can be treated or to refer to them in accordance with the present invention include the following:

MACULOPATHY/RETINAL DEGENERATION: exudative age-related macular degeneration (AMD), exudative age-related macular degeneration (AMD), choroidal neovascularization, diabetic retinopathy, acute macular neuromyopathy, Central serous homeopatia, racemose swelling yellow spots, diabetic edema yellow spots;

UVEITIS/RETINITIS/CHORIOIDEA: acute multifocal Placida pigment epitheliopathy, Behcet's disease, horioretinopatia "shot" (Birdshot), infectious ill the of (syphilis, limska disease, tuberculosis, toxoplasmosis), intermediary uveitis (Pars Planitis), multifocal chorioidea, multiple syndrome endangered white spots (SIBP), ocular sarcoidosis, posterior scleritis, serpiginosa chorioidea, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-Harada;

VASCULAR DISEASES/EXUDATIVE DISEASES: occlusive disease of the retinal arteries, occlusion of the Central retinal vein, disseminated intravascular coagulopathy, occlusion of branches of the Central retinal vein, hypertensive changes in the fundus of the eye, ocular ischemic syndrome, microaneurysms retinal artery disease Coates, parvovirinae telangiectasia, occlusion half of the retinal vein, papillovirus, occlusion of the Central retinal artery, occlusion of branches of the Central retinal artery, carotid artery disease, angia frosted branches (frosted branch), sickle cell retinopathy and hemoglobinopathy, angioini strip retinal hereditary the exudative vitreoretinopathy, disease ILSA;

TRAUMATIC/SURGICAL: sympathetic ophthalmia, uveitis, retinal detachment, trauma, laser, pulsating DC voltage (PPN), photocoagulation; hypoperfusion during surgery, radiation retinopathy, retinopathy after bone marrow transplantation;

DISORDERS PROLIF THE RADIO: proliferative vitreal retinopathy and epiretinal membranes, proliferative diabetic retinopathy;

INFECTIOUS DISORDERS: ocular histoplasmosis, ocular toxocariasis, presumed syndrome ocular histoplasmosis (PCGG), endophthalmitis, toxoplasmosis, retinal disease associated with infection by human immunodeficiency virus (HIV)infection, choroidal disease associate with HIV infection, uveitis associated with HIV infection, viral retinitis, acute retinal necrosis, progressive necrosis of the outer layer of the retina, fungal diseases of the retina, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, MIAS;

GENETIC DISORDERS: pigmentary retinal degeneration, systemic disorders associated with retinal dystrophies, congenital stationary night blindness, cone dystrophies, disease Stargardt and getpathdata abiotrophy retinal disease best, patterned dystrophy of the pigmented epithelium of the retina, X-chromosomal retinoschisis, dystrophy, fundus, Sorsby, benign concentric maculopathy, degeneration of the lens Bietti, elastic, pseudoxanthoma;

BREAKS/BREAKS RETINA: retinal detachment, the gap yellow spots, giant retinal rupture;

TUMOR: a disease of the retina associated with tumors, congenital hypertrophy of the pigment is petelia retina, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and pigment epithelium of the retina, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, intraocular lymphoma;

DIFFERENT point internal choroidopathy, acute posterior multifocal Placida pigment epitheliopathy, the myopic retinal atrophy, acute retinal pigment epitheli etc.,

but not limited to.

Methods in accordance with the present invention may include either only one injection in the posterior segment of the eye, or more, and repeated injections, for example, during the time period in the range of approximately one week, one month or three months to six months or one year or more.

The following not limiting the scope of invention Examples illustrate some aspects of the present invention.

EXAMPLES 1-4

Four compositions are as follows:

Sodium hyaluronate (0,6×106daltons)
IngredientExample 1Example 2Example 3Example 4
Triamcinolone acetonide2% (wt./about.)2% (wt./about.)4% (wt./about.)4% (wt./about.)
of 0.05% (wt./about.)of 0.5% (wt./about.)of 0.05% (wt./about.)of 0.5% (wt./about.)
Sodium phosphateof 0.4% (wt./about.)of 0.4% (wt./about.)of 0.4% (wt./about.)of 0.4% (wt./about.)
Vitamin E-TPGSof 0.5% (wt./about.)of 0.5% (wt./about.)0,00,0
β-Cyclodextrinof 0.5% (wt./about.)of 0.5% (wt./about.)0,00,0
Water for injectionsD.K. (enough)D.K.D.K.D.K.
The viscosity at the shear rate of 0.1 s-120 centipoise500 centipoise20 centipoise500 centipoise

Each of these compositions was prepared as follows.

A concentrated dispersion of triamcinolone acetonide is prepared by combination of triamcinolone acetonide water, vitamin E-TPGS and β-cyclodextrin, if present. These ingredients are mixed to disperse different triamcinolone acetonide, and then autoclave. Sodium hyaluronate acquire in the form of a sterile powder or sterilized by filtering a dilute solution followed by lyophilization is obtaining sterile powder. Sterile sodium hyaluronate dissolved in water to obtain an aqueous concentrate. A concentrated dispersion of triamcinolone acetonide mix and add in the form of a suspension concentrate of sodium hyaluronate. Add water in sufficient quantity (D.K.) and stirred the mixture until a homogeneous state.

Each of these compositions provides for the free flow of triamcinolone acetonide, which is easily resuspended quietly turning. These compositions can be sold in vials, small volume, made of glass pharmaceutical quality, and, as it turned out, they are therapeutically effective against macular edema when injected into the vitreous body of the human eye.

EXAMPLES 5-7

Three tracks are as follows:

IngredientExample 5Example 6Example 7
Triamcinolone acetonide2,0% (wt./about.)4,0% (wt./about.)8,0% (wt./about.)
Sodium hyaluronate3,0% (wt./about.)a 2.5% (wt./about.)2,0% (wt./about.)
Sodium phosphateof 0.4% (wt./about.)of 0.4% (wt./about.)of 0.4% (wt./about.)
Water for injectionsD.K.D. is. D.K.
The viscosity at the shear rate of 0.1 s-1180000 CP120000 CP80000 CP

These compositions are prepared by the way, is almost the same as specified in Example 1.

High viscosity compositions, essentially slows down the rate of sedimentation of particles to such an extent that the need for resuspending over the expected shelf life of the compositions, for example approximately two years, is missing. These compositions can be sold in pre-filled syringes, because they cannot easily be removed from the tank using a needle and syringe. However, the use of compositions in pre-filled syringes they can be effectively injected into the posterior segment of the human eye through the needle 27 gauge (0,360 mm) or 30 gauge (0,255 mm), providing the desired therapeutic effect in the human eye.

In the compositions according to Examples 5-7 use or they contain high molecular weight sodium hyaluronate in sufficient concentration for the formation of a gel tube or depot medication by injection into the vitreous body of the human eye. Particles of triamcinolone acetonide is actually captured and held in this viscous tube without forming thus undesirable "swelling", and the risk of Megilat the high deposition of particles medication directly on the retinal tissue is significantly reduced, compared to, for example, with the use of a composition, such as Kenalog®40, with a viscosity similar to the viscosity of water. Since solutions of sodium hyaluronate is exposed to a substantial decrease in viscosity when the shear, these drugs can easily be injected through the needle 27 gauge (0,360 mm) or even 30 gage (0,255 mm).

EXAMPLES 8 and 9

Two compositions are the following:

IngredientExample 8Example 9
Triamcinolone acetonide2,0% (wt./about.)8,0% (wt./about.)
Sodium hyaluronatea 2.5% (wt./about.)2,3% (wt./about.)
Sodium chloride0,63% (wt./about.)of 0.6% (wt./about.)
Dibasic phosphate

sodium heptahydrate
0,30% (wt./about.)0,30% (wt./about.)
Monobasic sodium phosphate, monohydrate0,04% (wt./about.)0,04% (wt./about.)
Water for injectionsD.K.D.K.
The viscosity at the shear rate of 0.1 s-1170000±25% CP200000±25% CP

These compositions are prepared by the way, is almost the same as specified in Example 1.

High viscosity compositions, there is TSS slows the rate of sedimentation of particles to such an extent that the need for resuspending over the expected shelf life of the compositions, for example approximately two years, is missing. These compositions can be sold in pre-filled syringes, because they cannot easily be removed from the tank using a needle and syringe. However, the use of compositions in pre-filled syringes they can be effectively injected into the posterior segment of the human eye through the needle 27 gauge (0,360 mm) or 30 gauge (0,255 mm), providing the desired therapeutic effect in the human eye.

Powder of sodium hyaluronate used in these compositions (as well as in other compositions, identified here in the Examples), contains water in an amount from about 4 wt.% up to 20 wt.%, preferably from about 4 wt.% up to 8 wt.%. The water content in the concrete powder and, in particular, fluctuations in water content between the different powders can result in variations in viscosity between two or more compositions in accordance with the present invention, which nominally have the same chemical composition. Thus, it should be understood that the above viscosity values are target values, and composition are acceptable for use, if the real wask the industry composition is within plus or minus (± approximately 25% or about 30%or about 35% relative to the target viscosity.

Since each of the compositions shown in the Examples, has a viscosity of approximately 1 g/ml, represented here by the percent concentration, expressed as the ratio of mass to volume (mass./vol.), can also be regarded as a percent concentration, expressed as the ratio of the mass of the weight (mass./mass.).

In the compositions in accordance with Examples 8 and 9 use or they contain high molecular weight sodium hyaluronate in sufficient concentration for the formation of a gel tube or depot medication by injection into the vitreous body of the human eye. Particles of triamcinolone acetonide is actually captured and held in this viscous tube without forming thus undesirable "swelling", and the risk of unwanted deposition of particles medication directly on the retinal tissue is significantly reduced, compared to, for example, with the use of a composition, such as Kenalog® 40 having a viscosity similar to the viscosity of water. Since solutions of sodium hyaluronate is exposed to a substantial decrease in viscosity when the shear, these drugs can easily be injected through the needle 27 gauge (0,360 mm) or even 30 gage (0,255 mm).

Although this invention is described about various specific examples and embodiments, it is clear, Chesapeake not limited to, and that in practice they may vary in the scope of the following claims.

1. The composition is suitable for injection into a posterior segment of an eye of a human or animal, comprising the corticosteroid component is present in therapeutically effective amounts, and corticosteroid component has a solubility in water at 25°With less than 10 mg/ml and corticosteroid component is presented in the form of a set of particles; the thickener is present in a quantity effective to increase the viscosity of the composition; a water carrier, and the particles suspended in the composition and the composition has a viscosity of at least about 10 CPS (at shear rate of 0.1 s-1and it can be effectively injected into the posterior segment of the eye of a human or animal; and g represents at least one viscoelastic agent.

2. The composition according to claim 1, the viscosity of which is at least 100 CPS (at shear rate of 0.1 s-1.

3. The composition according to claim 1, the viscosity of which is at least 10000 CPS at a shear rate of 0.1 s-1.

4. The composition according to claim 1, the viscosity is approximately 140000-300000 JV at the shear rate of 0.1 s-1.

5. The composition according to claim 1, which can be efficiently injected through the needle 27 gauge (0,360 mm) in the posterior segment of the eye of a human or animal.

6. Comp the position according to claim 1, which can be effectively injected through a needle 30 gauge (0,255 mm) in the posterior segment of the eye of a human or animal.

7. The composition according to claim 1 where the particles remain uniformly suspended in the composition, at least for about one week without resuspendable.

8. The composition according to claim 1 where the particles remain suspended in the composition, at least for about one month without resuspendable.

9. The composition according to claim 1 where the particles remain suspended in the composition, at least for about six months without resuspendable.

10. The composition according to claim 7, where the particles remain suspended in the composition, at least for about one year without resuspendable.

11. The composition according to claim 1 where the particles remain evenly suspended in the composition, at least for about two years without resuspendable.

12. The composition according to claim 1, where the corticosteroid component is present in amounts of up to about 25% (wt./about.) from the volume of the composition.

13. The composition according to claim 1, where the corticosteroid component is present in an amount constituting at least about 10 mg per milliliter of composition.

14. The composition according to claim 1, where Corti is asteroidy component is present in a quantity in the range from approximately 1 to 20% (wt./about.) from the volume of the composition.

15. The composition according to claim 1, where the corticosteroid component is present in an amount in the range from about 1 to 10% (wt./about.) from the volume of the composition.

16. The composition according to claim 1, where the corticosteroid component is selected from the group consisting of cortisone, prednisolone, triamcinolone, permetrina, medrysone, loteprednol, their derivatives and mixtures.

17. The composition according to claim 1, where the corticosteroid component is triamcinolone acetonide.

18. The composition according to claim 1, where the carrier includes an effective amount of at least one of the following components: a preservative agent that defines toychest, and buffer.

19. The composition according to claim 1, which contains no preservative.

20. The composition according to claim 1, which contains no resuspendable component.

21. The composition according to claim 1, where the thickener is present in an amount in the range from about 0.05 to 20% (wt./about.) from the volume of the composition.

22. The composition according to claim 1, where the thickening agent includes a polymer component.

23. The composition according to claim 1, where the thickener is selected from the group consisting of polymeric hyaluronic acid, carbomer, polyacrylic acid, cellulose derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide,polyvinyl alcohol, polyvinyl acetate, derivatives thereof and mixtures.

24. The composition according to paragraph 24, where the thickener is a polymer gialuronatnye component.

25. The composition according to paragraph 24, where gialuronatnye component is a sodium hyaluronate.

26. The method of treatment, wherein the composition according to claim 1 is introduced into the posterior segment of the eye of a human or animal, thereby providing the desired therapeutic effect.

27. The method according to p, where stage injection is an injection into the vitreous body.

28. The method according to p, where stage injection is a subconjunctival injection.

29. The method according to p, where stage injection is an injection under the tenon's capsule.

30. The method according to p, where stage injection is a retro-bulbar injection.

31. The method according to p, where stage injection is suprachoroidal injection.

32. The composition is suitable for injection into a posterior segment of an eye of a human or animal, comprising the corticosteroid component is present in therapeutically effective amounts, and corticosteroid component has a solubility in water at 25°With less than 10 mg/ml and corticosteroid component is presented in the form of a set of particles; the thickener is present in a quantity effective to increase the viscosity of the composition; odniesien, moreover, the particles suspended in the composition and remain suspended in the composition, at least for about one week without resuspendable; and g represents at least one viscoelastic agent.

33. The composition according to p where the particles remain suspended in the composition, at least for about two weeks without resuspendable.

34. The composition according to p where the particles remain suspended in the composition, at least for about one month without resuspendable.

35. The composition according to p where the particles remain suspended in the composition, at least for about six months without resuspendable.

36. The composition according to p where the particles remain suspended in the composition, at least for about one year without resuspendable.

37. The composition according to p where the particles remain suspended in the composition, at least for about two years without resuspendable.

38. The composition according to p where the corticosteroid component is present in amounts of up to about 25% (wt./about.) from the volume of the composition.

39. The composition according to p where corticosteroid component prisutstvuet is in the quantity comprising at least about 10 mg per milliliter of composition.

40. The composition according to p where the corticosteroid component is present in an amount in the range from about 1 to 20% (wt./about.) from the volume of the composition.

41. The composition according to p where the corticosteroid component is present in an amount in the range from about 1 to 10% (wt./about.) from the volume of the composition.

42. The composition according to p where the corticosteroid component is selected from the group consisting of cortisone, prednisolone, triamcinolone, permetrina, medrysone, loteprednol, their derivatives and mixtures.

43. The composition according to p where the corticosteroid component is triamcinolone acetonide.

44. The composition according to p where the medium includes an effective amount of at least one of the following components: a preservative agent that defines toychest, and buffer.

45. The composition according to p, which contains no preservative.

46. The composition according to p, which does not contain resuspendable component.

47. The composition according to p, where the thickener is present in an amount in the range from about 0.05 to 20% (wt./about.) from the volume of the composition.

48. The composition according to p, where the thickening agent includes a polymer component.

49. The composition according to p, where the thickener is selected from the group consisting of polymeric hyaluronic sour is s, carbonero, polyacrylic acid, cellulose derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl acetate, derivatives thereof and mixtures.

50. The composition according to p, where the thickener includes gialuronatnye component.

51. The composition according to item 50, where gialuronatnye component is a sodium hyaluronate.

52. The method of treatment, wherein the composition p injected into the posterior segment of the eye of a human or animal, thus providing the desired therapeutic effect.

53. The method according to paragraph 52, where stage injection is an injection into the vitreous body.

54. The method according to paragraph 52, where the stage of introduction is a subconjunctival injection.

55. The method according to paragraph 52, where stage injection is an injection under the tenon's capsule.

56. The method according to paragraph 52, where the stage of introduction is a retro-bulbar injection.

57. The method according to paragraph 52, where the stage of introduction is a

suprachoroidal injection.



 

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