Pharmaceutical compositions containing s1p receptor modulator

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and describes a solid pharmaceutical composition applicable for oral administration and containing: S1P receptor modulator which represents 2-amino-2-[2-(4-octylphenylethyl)]propane-1,3-diol in the free form or in the form of a pharmaceutically acceptable salt or a phosphate thereof and monocrystalline cellulose in the absence of a sugar alcohol.

EFFECT: invention provides higher storage stability of the composition.

9 cl, 40 ex, 11 tbl

 

The present invention relates to pharmaceutical compositions comprising a modulator of the receptor for sphingosine-1 phosphate, first of all, the agonist of the receptor for sphingosine-1 phosphate.

Sphingosine-1 phosphate (S1P) is a natural serum lipid. At the present time famous eight S1P receptors, namely S1P1-S1P8. Agonists of the receptor S1P accelerate homing lymphocytes.

Agonists of the receptor S1P are immunomodulators, causing lymphopenia due to the redistribution, preferably reversible, lymphocytes from blood flow in the secondary lymphatic tissue, and do not cause this generalized immunodepressants actions. Naive cells sequestered and stimulated the migration of T cells CD4 and CD8 and b cells from blood to lymph nodes (LU) and pierogie plaques (SP), thus, suppressed the infiltration of cells in transplanted organs.

Various known S1P receptor modulators are characterized by a similar structure, which leads to similar problems in obtaining suitable composition. There is a need to develop a composition that contains a modulator of the receptor S1P suitable for oral administration in solid form, for example, tablets or capsules. In addition, the oral method is usually the most appropriate for the introduction of medicines, who, however, unfortunately many patients have problems if swallowed, for example, due to the unpleasant taste of drugs or lack of water while taking the drug. Thus, there is a need to develop a modulator of the receptor S1P in the form of oral composition, which is easily eaten, for example, children or elderly patients. Moreover, there is a need to develop a simple method of obtaining the dosage forms modulator of S1P receptor containing different doses.

The present invention provides various pharmaceutical composition comprising a modulator of the receptor S1P and matching the given criteria. The composition allows you to enter simple systematic way agonist of S1P receptor and other modulators, thus eliminated the disadvantages of liquid compositions for injection or oral administration. The compositions of the present invention are characterized by improved physical-chemical properties and storage stability. First of all, the composition of the present invention are characterized by a high degree of uniformity of distribution of the modulator of the receptor S1P in compositions, as well as high stability. The compositions of the present invention obtained using automatic equipment with high cdigo is, doesn't require encapsulation manually.

Some of the objects of the present invention offers fast dispergirujutsja dosage forms, which rapidly disintegrate in the oral cavity and thus do not require the use of sweeteners or flavoring agents, taste masking, as well as the presence of fluid for flushing dosage forms. These dosage forms can disintegrate in the oral cavity, primarily in the saliva. Preferably the dosage form is characterized by a pleasant taste sensation and thus excluded premature release of the drug in the oral cavity. Quick raspadaemost solid pharmaceutical composition increases the solubility of the active ingredient(s). First of all, this raspadaemost leads to increased solubility of the drug in saliva compared to the solubility in the small intestine.

The pharmaceutical compositions of the present invention is obtained using standard methods, for example, a standard mixing, granulation, dissolution or lyophilization. Used methods known in the art and described, for example, in the book L.Lachman and others, theory and Practice of Industrial Pharmacy, 3rd ed. (1986), H.Sucker and others, Pharmazeutische Technologie, Thieme (1991), Hagers Handbuch der pharmazeutischen Praxis, 4th ed., Springer Verlag (1971 and Remington's Pharmaceutical Sciences, 13th ed., Mack Publ., Co. (1970) or in the later editions.

The compositions of the present invention may have a sufficiently high stability, according to the standard stability testing, for example, the retention period is up to one, two or three years or even more. Preferably the composition is stable for at least six months in CT. Stability can be defined, for example, when evaluating the products of decomposition of the active agent by a method GHUR after storage for a certain time at a certain temperature, for example, 20°, 40° or 60°C.

Compositions containing coating

The pharmaceutical compositions will be easier to proglatavetsa, if the core of tablets, pellets or the surface of the capsule coating, thus increasing the degree of agreement of patients with treatment as reduced or masking an unpleasant taste.

One object of the present invention features an oral pharmaceutical composition comprising a modulator of the S1P receptor, for example, the agonist of S1P receptor, the composition includes a coating consisting of the following components:

(a) one or more polymer resins

(b) one or more metal oxides.

Solid compositions in the form of pellets of various sizes, with the coating applied to each pellet, the plural is which is, for example, in a capsule or sachet.

Solid compositions obtained from powdered ingredients, which are not necessarily finely pulverized and pressed into compositions which are characterized by different hardness.

In one variant, the powder components are molded of the composition before extrusion coated.

In another embodiment, on the pressed composition coated after pressing.

In yet another embodiment, the coating is applied before pressing and after it.

Liquid oral compositions include capsules filled with a liquid composition, the capsule is coated.

In another embodiment, the coating applied on the outer part of the capsule.

In yet another embodiment, the coating is dispersed in the external phase capsules.

However, capsules are not limited to capsules with liquid content and also homogeneous liquid contents may contain solid composition in the form of powders, pellets or heterogeneous suspensions.

If a solid composition is in the form of pellets or granules, after coating, as described above, it is used by itself or before the introduction of the fill mixture of capsules, for example, hard gelatin capsules or other containers for storing, for example, the bags.

Pellets and granules are characterized by a diameter of from 2 to 0.3 mm, for example, "standard pellets are characterized by a size of from 1 to 0.6 mm, and the "granular" pellets are characterized by a size of from 0.4 to 0.8 mm

Composition for coating according to the present invention is primarily suitable for application to tablets, as described in this context, for example, on the core tablets.

In one embodiment, the composition for a coating to be applied on the extruded tablets, including S1P modulator, for example, agonist S1P.

The core tablet is any solid composition intended for oral administration.

The term "core" includes, in a broad sense not only tablets, pellets or granules, and capsules, such as soft or hard gelatin or starch capsules. Kernel get by known methods.

When using kernels tablets they preferably are characterized by a hardness of from about 10 to 70 N. The tensile strength of the core tablet is less than 38 N/cm2for example, less than 22 N/cm2.

The hardness of the core tablets, including S1P modulator, for example, S1P agonist, can be improved in the coating, as described in this context. The coating provides a tablet, characterized by a high structural integrity of the nuclei, the tensile strength which is less than 38 N/cm2(2.5 kPa), i.e. engines that otherwise sitouts is too fragile for practical use. The tensile strength of the cores may be less than 30 N/cm2(2.0 kPa), preferably less than 22 N/cm2(1,5 kPa).

Kernel get when pressing with a low compression ratio that allows the use of components with coating and fragile components, such as capsules, the composition of the mixture for extrusion with minimal damage or no damage.

The core tablet may contain adjuvant and S1P modulator, for example, agonist S1P.

The core tablet may contain suitable ingredient for tabletting, including thinners, dezintegriruetsja agents, oiling agents, wetting agents, glidant, surfactants, agents, accelerating the release, colouring agents, effervescent agents, etc.

The core tablets can be obtained with the use of any composition known to specialists in this field.

Core tablets may include, without limitation, fillers, such as polyols, for example, powdered mannitol, or other sugars or sugar, aridity, and the like, for example, lactose, sucrose, dextrose, mannitol and starch.

The composition of the core tablet may also include, or alternatively include a binder such as PVP, for example, cellulose, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, starch paste, Arabian gum, Aleynikova acid, carboxymethylcellulose, hydroxie icellulse, hydroxypropylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hypromellose, maniamerica, maltodextrin, methylcellulose, polyethylene oxide, povidone, sodium alginate and hydrogenated vegetable oil.

Composition for core tablets may also include, or alternatively include dezintegriruetsja agents (whether or not containing effervescent agents), for example, crosslinked sodium carboxymethyl cellulose (crosscarmelose), crospovidone or sodium salt starch glycolate.

Composition for core tablets may also include, or alternatively include oil, for example, magnesium stearate, calcium stearate, sodium fumarate, colloidal silicon hydroxide or talc.

In one embodiment, the core tablet comprises from 1.5% to 2% of a lubricant, such as magnesium stearate or calcium.

Composition for core tablets may also include, or alternatively include glidant, for example, silicon dioxide.

Composition for core tablets may also include, or alternatively include surfactants, for example, sodium lauryl sulfate or sodium docusinate.

Composition for core tablets may also include, or alternatively include flavorings.

Composition for core tablets may also include, or alternatively include effervescent is e agents, for example, sodium bicarbonate or citric acid.

Composition for core tablets may also or alternatively include sweeteners.

Composition for core tablets may also include, or alternatively include regulating pH agents, for example, citric or fumaric acid.

Composition for core tablets may also include, or alternatively include additives for controlled release. For example, the drug is included in a hydrophobic polymer matrix, which provides a gradual release of the active agent from it in contact with the liquid media of the organism.

In another embodiment, the drug is included in a hydrophilic matrix, which gradually or quickly dissolves in the presence of liquid media of the body. Tablet core may include two or more layers with different rates of release. Layers can be hydrophilic, hydrophobic or a mixture of hydrophilic and hydrophobic layers. Adjacent layers in the multilayered core tablet can be separated from each other using insoluble protective layer or the hydrophilic layer. Insoluble protective layer may consist of materials used to form the insoluble shell. Hydrophilic separating layer can be formed from materials that obl is giving greater solubility compared with other segments of the core tablet and thus, the first soluble separating layer, then display layers, releasing the drug.

Suitable speed control release polymers include, polymethacrylates, ethylcellulose, hypromellose, methylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, a polymer of acrylic acid, polyethylene glycol, polyethylene oxide, carrageenan, cellulose acetate, Zein, etc.

The core tablet may also include materials that swelling in contact with aqueous solutions, and which can be incorporated into the composition, including polymeric materials, for example, crosslinked sodium carboxymethyl cellulose, crosslinked hydroxypropylcellulose, macromolecular hydroxypropylcellulose, carboxymethylated, potassium salt of a copolymer of methacrylate and polystyrene, polymethyl methacrylate, crosslinked polyvinylpyrrolidone and high molecular weight polyvinyl alcohols.

Core tablets may include additional pharmaceutically active ingredients, along with S1P modulator, for example, an agonist of S1P.

In one embodiment, if the composition of the core tablet is a standard dosage form, each standard dose comprises from 0.5 to 10 mg of receptor modulator SP, for example, agonist S1P.

Suitable methods of obtaining cores tablet include mixing of all ingredients and pressed into pellets, and, in addition, granulation and compressing the granules into tablets.

In one embodiment, the proposed composition of a core tablet comprising aldit. An example of the composition of core tablet comprising a modulator of the S1P receptor, for example, agonist S1P described in patent WO 2004/089341, which describes a composition comprising an S1P modulator and aldith.

Aldit can be used as a diluent, carrier, excipient or lash thickening agent, and therefore it represents mannitol, ▫ maltitol, Inositol, xylitol or lactic, preferably mainly the hygroscopic aldith, for example, mannitol (D-mannitol). Use one aldet or a mixture of two or more alditol, for example, a mixture of mannitol and xylitol, for example, in a ratio of from 1:1 to 4:1.

In one embodiment, the proposed composition of a core comprising microcrystalline cellulose and a modulator of the S1P receptor, for example, agonist S1P in the absence of Aldata.

Preferably the components of the core and coating tablets finely chopped.

In another embodiment, the solid composition is characterized by high speed raspadaemosti.

Preferably the amount of active ingredient is from 0 to 1000 mg.

Floor get on powdered or liquid basis.

The coating can be characterized by a suitable electrical properties and melt at a temperature suitable for its use as a material for coating in the coating on the cores of pharmaceutical tablets.

Examples of polymer resins include, without limitation, polymethacrylates, for example, methacrylate ammonium cellulose and its derivatives, ethers and esters of cellulose and phthalate-cellulose acetate.

Preferably the polymer resin does not have conductive properties.

Compositions for coating may include polyethylene glycol or aldith, for example, xylitol.

Compositions for coating may also, or alternatively, in addition, include other suitable materials, including waxes and oils or alcoholate of waxes and oils, poloxamer, alkylphenate, for example, diethylphthalate, citric acid, or esters.

Compositions for coating may also include, or in another embodiment, in addition, include one or more polymers or copolymers of acrylic acid and derivatives thereof, for example, polymethylacrylate, polyalkene and derivatives thereof, including esters and arrowie esters and their derivatives, polyvinyl alcohols and esters, cellulose and its derivatives, for example, ethers and esters of cellulose (stitched or unstitched), for example, ethylcellulose, and one who does more intersolubility polymers, for example, phthalate-cellulose acetate, phthalate of hydroxypropylmethylcellulose, hydroxypropylcellulose, one or more biodegradable polymers, for example, one or more of polylactide, polyglycolides, polyhydroxybutyrates, polyhydroxyvalerate, copolymers of ethylene and vinyl acetate and polyanhydride (Homo - or heteropolymer) or polyethylene oxide.

Compositions for coating may also include, or in another embodiment, in addition, include a dispersing agent, for example, sodium lauryl sulfate, sodium docusinate, twins (esters of sorbitol and fatty acids), poloxamer and cetosteatil alcohol.

Compositions for coating may also include, or in another embodiment, in addition, to enable the air flow for reducing friction and/or other forces acting between the particles of the powdery coating material, to improve the fluidity of the powder, for example, titanium dioxide, colloidal silicon dioxide, talc, or combinations thereof.

Compositions for coating may also include, or alternatively include disintegrity agent, for example, sodium salt starch glycolate (custom made), sodium carboxymethyl cellulose (custom made), natural starch, crosslinked polyvinylpyrrolidone (crospovidone), sodium carbonate, sodium bicarbonate or glycinate sodium.

Compositions for coating may also include Il is in another variant, in addition, include dyes, for example, metal oxides or pigments (for example, pigments based on aluminum), iron oxide or other dyes.

Compositions for coating may also include, or in another embodiment, in addition, include the taste modifiers, for example, aspartame, Acesulfame K, cyclamate, saccharin, sugar or validity.

Compositions for coating may also include flavorings.

In one embodiment, the composition for coating includes:

(a) a copolymer of methacrylic acid

(b) cellulose

(C) one or more metal oxides.

The present invention also proposes a method of obtaining pharmaceutical compositions coated for oral administration, which is

(a) obtain core tablets comprising a modulator of the receptor S1P and

(b) coating as described above.

In one embodiment, the method is:

(a) mixing agonist of S1P receptor or other modulator with alditol,

(b) grinding and/or granulation of the mixture obtained in paragraph (a) and

(C) mixing the powdered mixture obtained in paragraph (b) sizing

(d) optional mixing with other solvent, flavoring or preservative in propylene glycol and adding glycerol and

(d) applying the composition for coating according to the present invention.

If IP is the use of this method get the song characterized by a high content and homogeneity (e.g., largely homogeneous distribution of the modulator of the receptor S1P in the composition, the time of dissolution and stability.

In the case of the composition of core tablet comprising an agonist of S1P receptor, for example, hydrochloride 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, before stage (a) to remove large aggregates composition optional finely pulverized and/or pre-screened, for example, through a sieve with cell diameter of from 400 to 500 μm. The mixing stage (a) may include mixing agonist of S1P receptor and alditha, for example, mannitol in a suitable mixer or blender, for example, at a speed of from 100 to 400 rpm.

The method can be performed by mixing the dry components. In this embodiment, the grinding stage (b) may include the transmission obtained at stage (a) of the mixture through a sieve preferably with a cell diameter of from 400 to 500 μm. Stage (a) may include mixing the entire amount of the agonist S1P receptor or other modulator, first with a small amount of alditha, for example, from 5 to 25 wt.% calculated on the total weight of alditha, you get a pre-mixture. Then in the preliminary mixture add the remaining alditha. Stage (a) may further include adding to the mixture of binder solution, for example, m is etilzellulozy and/or xylitol, for example, a water solution.

Powdered mixture obtained in stage (b), you can re-stir before adding lubricant. Lubricant, e.g. magnesium stearate, before mixing preferably pre-screened, for example, through a sieve with cell diameter of from 800 to 900 microns.

In another embodiment, applying the wet granulation. In this embodiment, the modulator of the receptor S1P preferably pre-mixed in a dry state with the required alditol, for example, mannitol, and the resulting mixture of Aldata with a modulator of the receptor S1P then mixed in the dry state with a binder such as hydroxypropylcellulose or hypromellose. Then add water and mix granularit, for example, in automatic pellet mill. The granulate is dried and pulverized.

If necessary, obtained in stage (b) a mixture of stage (C) add a further quantity of the binder.

The method may include the stage of tableting or encapsulating the mixture obtained in stage (b), for example, hard gelatin capsules using automatic machines for encapsulation. Capsules optional painted or marked to give an individual appearance and be easily recognized. To improve the appearance and recognition of capsules used dyes. Suitable PlaysForSure in pharmaceuticals, dyes include carotenoids, the oxides of iron and chlorophyll. Preferably the capsules are marked using the code.

First of all, in the case of core tablets with a coating mixture for coating can be obtained by extrusion from the melt of the mixture of polymer, colorant and other additives if necessary, with subsequent fine grinding the obtained extrudate (from 7 to 10 microns). Powders for coating is stable in suitable packaging and can be used for drawing on the product for at least one year after their receipt.

The coating on the tablet core is applied by electrostatic deposition of a powder containing fusible particles.

This method allows to obtain a thin continuous film on the surface of the core tablet. In General, the film covers from 25 to 100%, preferably from 50 to 100% of the surface of the core tablet. The tensile strength of the core tablet comprises at least 50 N/cm2, 60 N/cm2most preferably at least 70 N/cm2.

In one embodiment, use the following method of coating.

First, the kernel fix (in vacuum) of the rotating disk, give the core charge is passed through the chamber for coating, with oppositely charged powder coating is deposited on the surface of the nucleus. The kernel then covered with a layer of powder, move the disk to the infrared is the lamp, the coating melts. The kernel then transferred to a second rotating disk and the method is repeated for the lower part of the core tablets.

Film thickness: 20-50 microns.

Typically, the coating weight is 3-4% based on the mass of the nucleus, for example, the coating weight of 6 mg put on a biconvex tablets with a diameter of 10 mm, a Maximum coating weight for a round nucleus with a diameter of 12 mm is 20 mg. Coating preferably is vysokopatogennym and is characterized by a uniform thickness.

Stage of heating includes heating the tablets from CT to the temperature of the surface of the tablet at approximately 100°C and the temperature of the core tablet is approximately 70°C for about 20 C. the Total time of exposure to temperatures significantly less than standard coating film (60 to 70°C for 1-2 h).

Preferably, the composition for coating does not have conductive properties and is characterized by a melting temperature below 103°C, for example, melts within 5 s at 130°C.

Preferably the core has conductive properties. If the engine is not conductive, it preferably contains from 3 to 5% salt, for example NaCl, KCl, lactate or citric acid.

One object of the S1P modulator attached conductive properties of the core tablets.

Thus, it is proposed a method of obtaining compositions with a coating comprising an S1P modulator, which is:

(a) obtaining a composition comprising an S1P modulator, for example, agonist S1P,

(b) applying an electrostatic coating composition,

(in) secure the cover.

In one preferred variant of the method, the content of S1P modulator is at least 50% per weight of the conductive component of the composition of the nucleus, for example, at least 60%, typically more than 75%.

The S1P modulator is not necessarily the only conductive component of the composition engine.

The coating also can be applied by sputtering technique. The kernel can be treated with CT or before spraying heated up to 40°C, for example, in a stream of warm air at a temperature of from 40°-70°C. to prevent coalescence of the nuclei dispersion is preferably interrupted at intervals and kernel again heated. However, you can spray it without interruption, for example, using automatic regulation of the quantity of the sprayed substance with respect to temperature of exhaust air and/or cores.

To give a final product with a coating of a certain appearance use different variants of design, printing, forms, etc

Pressure spraying may vary within wide limits, in General satisfactory results are obtained when spraying at a pressure of from approx is Ino 1 to about 1.5 bar.

Compositions containing disintegrity agent

To simplify swallowed you when using the fast disintegrating dosage forms, for example, rapidly disintegrating tablets.

Another object of the present invention offers a quickly disintegrating solid pharmaceutical composition comprising

(a) an S1P modulator, for example, agonist S1P

(b) silicate alkaline earth metal

(C) disintegrity agent

where the ratio of silicate/disintegrity agent is from 2:1 to 10:1.

Silicate alkaline earth metal includes calcium silicate or magnesium.

Disintegrity agent may in addition contain effervescent agents.

Examples dezintegriruetsja agents include, without limitation, croscarmellose, cellulose, crospovidone and sodium salt starch glycolate.

The composition can also contain fillers selected from the group including, for example, gelatin, allday, for example, mannitol, sorbitol, dextrose, sucrose, lactose, maltose, sorbitol, maltodextrins, solid corn syrup or other sugars or sugar, trehalose, polyvinylpyrrolidone, polyelectrolyte gel chondroitin sulphate A, cellulose, derivatives of starch, pullulan, glycine, docusinate Na, polyvinyl alcohol, HPC-SL, mannitol & glycerin, xanthan gum/carrageenan/Arabian is kind of gum/guar gum/tragakant, mannitol, Polysorbate 60, sodium dodecyl sulphate, fatty acids, bile salts, methylhydroxybenzoate sodium, propylhydroxybenzoate sodium and starch.

Compositions also include, or in another embodiment, in addition, may contain oil, for example, magnesium stearate, calcium stearate, sodium fumarate, colloidal silicon dioxide or talc.

The composition, in addition, may further include a binder such as PVP, for example, cellulose, polyethylene glycol, polyvinylpyrrolidone, starch paste, Arabian gum, alginine acid, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hypromellose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hypromellose, maniamerica, maltodextrin, methylcellulose, polyethylene oxide, povidone, sodium alginate or hydrogenated vegetable oil.

The composition also includes, or in another embodiment may include surfactants, for example, sodium lauryl sulfate or sodium docusinate.

The composition also includes, or in another embodiment may include effervescent agents, such as sodium bicarbonate or citric acid.

The composition also includes, or in another embodiment may include flavoring agents.

The composition, in addition, also the before or in another embodiment may include glidant, for example, silicon dioxide.

The composition also includes, or in another embodiment may include sweeteners.

The composition also includes, or in another embodiment may include agents that regulate pH, for example, citric or fumaric acid.

In one variant, the composition including:

from 0.1 to 1% of S1P modulator, for example, agonist S1P,

from 60 to 90% filler, for example, alditha,

from 20 to 45% silicate and

from 4 to 10% dezintegriruetsja agent.

The compositions of the present invention are, for example, tablets, capsules, microtablets, tortillas, pillule, minitablets, pellets, beads or granules.

If a solid composition is in the form of pellets or granules, such a composition can be used by itself or for filling capsules, for example, hard gelatin capsules, or other containers for storage before the introduction of, for example, bags.

Pellets and granules are characterized by a diameter of from 2 to 0.3 mm, for example, "standard pellets" is characterized by a size of from 1 to 0.6 mm, and "granular pellets" is characterized by a size of from 0.4 to 0.8 mm

The composition optionally include a hydrophilic matrix, which gradually or quickly dissolves in the presence of physiological fluids.

The composition may also include materials, is a hoot in contact with aqueous solutions, which is included in the composition, including polymeric materials selected from the group comprising crosslinked sodium carboxymethyl cellulose, crosslinked hydroxypropylcellulose, macromolecular hydroxypropylcellulose, carboxymethylated, potassium salt of a copolymer of methacrylate and polystyrene, polymethyl methacrylate, crosslinked polyvinylpyrrolidone and high molecular weight polyvinyl alcohols.

Preferably the time raspadaemosti (BP) of the composition is less than 60 in contact with liquid, such as water or saliva.

Preferably BP is 30 C.

The hardness of the tablets can be modified to the specific composition characterized by a particular value of BP. The compositions of the present invention may have a different hardness.

Accordingly, compositions of the present invention may be characterized, for example, tensile strength of 30 N/cm2up to 80 N/cm2.

Preferably after the collapse of the compositions of the formed particle size of from 1 nm to 10 mm, for example, from 50 nm to 200 nm, which can dissolve or form a thin slurry.

To ensure fast raspadaemosti ratio of silicate, for example, calcium silicate and dezintegriruetsja agent is from 2:1 to 10:1, for example from 3:1 to 7:1, typically 6:1, 5:1 or 4:1.

In one embodiment of sootnosheniyami calcium and dezintegriruetsja agent is 5:1. For example, the ratio of calcium silicate and crosspovidone or croscarmellose may be 5:1.

In another variant capsule containing many pellets characterized by a rapid raspadaemost of the present invention.

Quick raspadaemost or improving the efficiency raspadaemosti can provide a higher solubility of the active agent. Increased solubility of drug compounds can lead to a higher bioavailability, as it reduces the risk of sedimentation in the liquid environment of the organism.

Bioavailability of S1P receptor modulators, primarily agonist of S1P receptor, can be improved by adding section buccal absorption of a section of oral absorption, which reduces presystemic metabolism. If the S1P receptor modulators are absorbed through the buccal area of the sublingual method, through the mucous membrane of the mouth, esophagus and/or tonsils, the bioavailability increases as buccal absorption occurs earlier than the absorption in the gastrointestinal tract and reduces the effect presystemic metabolism in the liver. The increase in bioavailability can reduce the dose that leads to improved safety profile.

Pharmaceutical dosage forms intended for use in medicine for insertion into the mouth of the first cavity for buccal, sublingual or gingival absorption, can be used in the presence or absence of enhancers of absorption, such as, without limitation, as described in the Examples.

Examples of these dosage forms include, without limitation, buccal spray, effervescent tablets, granules, oral disintegrating tablets, thin films or plates and mucoadhesive disks or patches.

Preferably, the dose of active ingredient is from 0 to 1000 mg, for example, from 0 to 500 mg.

Compositions comprising freeze-dried dosage forms

Another object of the present invention serves a rapidly disintegrating pharmaceutical composition comprising a lyophilized dosage form of S1P modulator, for example, agonist S1P.

In one embodiment, the compositions contain a lyophilized dosage form, containing one or more modulators of S1P, for example, agonist S1P, particles which are not deposited or coated with a polymer or lipid material that provides minimal release of the drug in the oral cavity.

This effect is achieved, for example, when using large particles of the medicinal product with the coating and the viscosity of the suspension by lowering the temperature during processing of the suspension to minimize the deposition of particles without changing the physical properties of the dried particles.

Received dosage form is characterized by a slow release of the drug in a period of time sufficient at least to mask the taste in the mouth before swallowing, and usually over a longer period of time to provide a controlled or slow release of the drug after swallowing.

The material of the carrier, forming a grid or matrix containing S1P modulator, for example, agonist S1P, after freeze drying, is any pharmaceutically acceptable water-soluble or dispersible in water material, inert in relation to pharmaceutically active compounds, which are capable of forming a rapidly decaying grid, i.e. able to disintegrate in the mouth within, for example, 10 or less.

Action lyophilized dosage forms is that such a dosage form quickly dispersed and as a result are able to quickly disintegrate. Thus, the composition can form a thin slurry or solution in contact with the saliva in the oral cavity.

The preferred material of the carrier is a gelatin, usually pure pharmaceutical grade gelatin. Other substances that can be used as carriers include, n is the sample, gidralizovanny dextrose, dextran, dextrin, maltodextrin, alginates, hydroxyethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, solid corn syrup, pectin, carrageenan, agar, chitosan, resin carob, xanthan gum, guar gum, Arabia gum, tragakant, flour konjac, rice powder, wheat gluten, sodium salt starch glycolate, soy protein fibers, potato protein, papain, horseradish peroxidase, glycine and mannitol.

The composition can also contain additional excipients, for example, cellulose or aldit.

You can use additional excipients that are not used as carriers, they are chosen, for example, from the group including validity, for example, mannitol, sorbitol, dextrose, sucrose, lactose, maltose, sorbitol, maltodextrins, solid corn syrup, trehalose, polyvinylpyrrolidone, polyelectrolyte gel chondroitin sulphate A, cellulose, derivatives of starch, pullulan, glycine, sodium docusinate, PVA, HPC-SL, mannitol & glycerin, xanthan gum/carrageenan/Arabian gum/guar gum/tragakant, mannitol, Polysorbate 60, sodium dodecyl sulphate, fatty acids, bile salts, sodium, methylhydroxybenzoate sodium, propylhydroxybenzoate sodium, polyols and starch.

The composition is optional is tion include hydrophilic matrix, which gradually or quickly dissolves in the presence of the liquid environment of the body.

The composition can also include materials that swell upon contact with aqueous solutions, and which are included in the composition, including polymeric materials selected from the group comprising crosslinked sodium carboxymethyl cellulose, crosslinked hydroxypropylcellulose, macromolecular hydroxypropylcellulose, carboxymethylated, potassium salt of a copolymer of methacrylate and polystyrene, polymethyl methacrylate, crosslinked polyvinylpyrrolidone and high molecular weight polyvinyl alcohol.

In one embodiment, the composition comprises gelatin and a polysaccharide, e.g., pullulan, or aldith, and lyophilized dosage form agonist of S1P receptor or other modulator.

In another embodiment, aldith serves as a structuring agent.

In yet another embodiment, the gelatin and aldith contained in a ratio of from 3:1 to 1:3, for example, from 2:1 to 1:2, usually 1:1.

In another embodiment, the gelatin is contained in an amount of from 2 to 10%, for example, from 2 to 4%, and aldith is contained in an amount of from 0.1 to 15%, for example, from 0.5 to 8%.

The composition also includes, or in another embodiment, in addition, may contain a binder such as PVP, for example, cellulose, polyethylene glycol, polyvinylpyrrolidone, starch paste, Arabian gum, alginin the new acid, the carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose,

the hypromellose, dextrin, ethylcellulose, gelatin, glucose, guar gum, magnesium aluminosilicate, maltodextrin, methylcellulose, polyethylene oxide, povidone, sodium alginate or hydrogenated vegetable oil.

The composition may also include, or alternatively include dezintegriruetsja agents (in the presence or in the absence of effervescent agents), for example, crosslinked carboxymethylcellulose (croscarmellose), crospovidone or sodium salt starch glycolate.

The composition may also include, or alternatively include oil, for example, stearic acid, magnesium stearate, calcium stearate, zinc stearate, glycerylmonostearate, fumarate, sodium, canola oil, hydrogenated vegetable oil, such as gidrirovannoe castor oil (for example, Cutina® or Lubriwax® 101), mineral oil, sodium lauryl sulfate, magnesium oxide, colloidal silicon dioxide, polyethylene glycol, polyvinyl alcohol, sodium benzoate, talc, poloxamer or a mixture of any such compounds.

The composition can also include, or alternatively, contain surfactants, such as lauryl sulfate, sodium docusinate.

The composition can also include, or alternatively, contain glidant, nab is emer, silicon dioxide.

The composition can also include, or alternatively, contain flavorings.

The composition can also include, or alternatively, contain effervescent agents, for example, sodium bicarbonate or citric acid.

The composition can also include, or alternatively, contain sweeteners.

The composition can also include, or alternatively, contain regulatory pH agents, for example, citric or fumaric acid.

The composition, in addition, may also or alternatively contain increasing viscosity agents.

The composition according to the present invention can be, for example, in the form of tablets, capsules, microtablets, cakes, pillule, minitablets, pellets, beads or granules.

If a solid composition is in the form of pellets or granules, after coating, as described above, prior to the introduction they can be used as themselves, and for filling capsules, for example, hard gelatin capsules or other containers for storing, for example, bags.

The pellets or granules are characterized by a diameter from 2 mm to 0.3 mm, for example, "standard pellets" is characterized by a size of from 1 to 0.6 mm, and "granular pellets" is characterized by a size of from 0.4 to 0.8 mm

In one variant, the capsule containing the centre is in pellets, characterized by a rapid raspadaemost of the present invention.

Quick raspadaemost or higher efficiency can provide a higher solubility of the active compound. The higher the solubility of the drug leads to increased bioavailability, as it reduces the risk of sedimentation in physiological fluids.

The term "fast raspadaemost"used in this context, means that the solid dosage form disintegrates in water at 37°C for 60 s or less. Dosage form usually fall within 5 to 20, usually from 5 to 10 or less, according to the definition raspadaemosti according to the standard Disintegration Test for Tablets, Brit, pharmacology (1973), described in UK patent No. 1548022.

Bioavailability of S1P receptor modulators, primarily agonist of S1P receptor, can be increased by adding buccal area to oral absorption area absorption, resulting in reduced presystemic metabolism. If the S1P receptor modulators absorbed by the buccal sublingual way through the mucous membrane of the mouth, esophagus and/or tonsils, the bioavailability increases as buccal absorption occurs earlier than the absorption in the gastrointestinal tract and reduces the effect presystemic metabolism in the liver. Led the increase bioavailability can reduce the dose, that leads to improved safety profile.

Pharmaceutical dosage forms intended for use in medicine for introduction into the oral cavity for buccal, sublingual or gingival absorption, can be used in the presence or absence of enhancers adsorption, such as, without limitation, as described in the Examples.

Examples of these dosage forms include, without limitation, buccal spray, effervescent tablets, granules, oral disintegrating tablets, thin films or plates and mucoadhesive disks or patches.

Preferably, the dose of active ingredient is from 0 to 1000 mg, for example, from 0 to 500 mg.

Dosage forms get by known methods, you get a suspension, etc. of the Liquid suspension is then divided into doses, for example, is poured into cavities formed in a suitable mold. In another embodiment, the suspension is in the form of solid particles, for example, the frozen particles or gel-like particles, and the material of the carrier easily forms a gel. Typically, each dosage form includes up to 250 mg medicines, for example, from 10 to 100 mg Standard dosage form of a medicinal product in a rapidly decaying form included in the scope of the present invention.

Suspension h the CI in the material of the carrier is preferably divided into separate forms, which form when the distribution of the suspension in the many recesses of the required shape and size, thus receive oral dosage form. Form to get dosage forms preferably includes a number of recesses in the sheet-forming material, such material, which is usually used in the pharmaceutical industry to obtain blister.

Other methods of forming the suspension in the form of individual or frozen gel forms include curing mixtures drip method. For example, the suspension is passed through one or more apertures for forming drops, spheres or spray of fine particles, which utverjdayut by passing in a stream of cold gas or liquid, for example, in the flow of liquid nitrogen. In another embodiment, drops, spheres or spray utverjdayut in contact with a cold liquid, immiscible with the solution or suspension, and which is characterized by a density sufficient for curing the droplets in the deposition process in immiscible liquid or in the process of floating on the surface of the immiscible liquid.

Removing the continuous phase of the suspension of discrete particles comprising a pharmaceutically active substance, carried out by the method known in the art. For example, if discrete particles between which are in liquid form, before drying them usually freeze or heliroute. Suspension, in cell suitable form, frozen, for example, by passing a gaseous cooling medium such as liquid nitrogen, through the form or when the form is in the camera to freeze when spraying liquid nitrogen. In another embodiment, the form is cooled while moving over a cold surface. After dosage form frozen form before drying can be stored in the refrigerator.

Frozen discrete particles can be freeze dried by known methods. Continuous phase, for example, water, sublimate in the process of freeze drying under reduced pressure, the solvent in the solid phase (ice) is converted directly into steam. The process of freeze drying is usually carried out in lyophilized in a vacuum from 0.1 to 1.0 mbar in the course of from 180 to 500 minutes

In the present invention, it is also proposed a method of obtaining a pharmaceutical composition, which is:

(a) mixing the lyophilized dosage forms agonist of S1P receptor or other modulator with a structuring agent,

(b) aqueous suspension containing less than 50% solids and

(C) is not necessary in the conduct of freeze drying.

In one embodiment, the suspension before the stage of lyophilization is cooled to a temperature which s from 10 to 20°C, for example, 15°C.

The composition obtained in the absence of Aldata

Another object of the present invention offers a solid pharmaceutical composition for oral administration, including:

(a) a modulator of the S1P receptor, for example, the agonist of S1P receptor and

(b) microcrystalline cellulose

and the composition does not include aldit.

The composition may contain a lubricant.

Suitable oiling agents include stearic acid, magnesium stearate, calcium stearate, zinc stearate, glycerylmonostearate, fumarate, sodium, canola oil, gidrirovannoe vegetable oil, for example, gidrirovannoe castor oil (for example Cutina® or Lubriwax® 101), mineral oil, sodium lauryl sulfate, magnesium oxide, colloidal silicon dioxide, polyethylene glycol, polyvinyl alcohol, sodium benzoate, talc, poloxamer or a mixture of any such compounds.

The preferred sizing means stearate or gidrirovannoe vegetable oil.

The composition preferably comprises from 0.01 to 5 wt.% sizing, more preferably from 1 to 3 wt.%, for example, about 2 wt.% calculated on the total weight of the composition.

The composition may contain one or more other excipients, such as carriers, binders or diluents.

The composition may further include a binder is e, for example, methylcellulose, hydroxypropylcellulose, hypromellose, dicalcium phosphate, PVP, for example, cellulose, polyethylene glycol, polyvinylpyrrolidone, starch paste, Arabian gum, alginine acid, carboxymethyl cellulose, hydroxyethyl cellulose, dextrin, ethylcellulose, gelatin, guar gum, hypromellose, magnesium aluminosilicate, maltodextrin, methylcellulose, polyethylene oxide, povidone, sodium alginate or hydrogenated vegetable oil.

The composition can also include, or alternatively, contain glidant, for example, silicon dioxide.

The composition may be a powder, granules or pellets or standard dosage form, e.g. tablet or capsule. Compositions suitable for filling capsules for oral administration, first of all, hard gelatin capsules. In another embodiment, the composition is pressed into tablets.

The tablets can be coated, for example, talc or polysaccharides (e.g. cellulose) or hypromellose.

The composition may also contain disintegrity agent. Examples dezintegriruetsja agents include, for example, croscarmellose, cellulose, crospovidone and sodium salt starch glycolate.

The composition may also include, or in another embodiment, the content is to be surfactants, for example, sodium lauryl sulfate or sodium docusinate.

The composition may also include, or alternatively, contain effervescent agents, for example, sodium bicarbonate or citric acid.

The composition may also contain additives that control the release of drugs. For example, the drug can be included in a hydrophobic polymer matrix and, thus, the drug is gradually released from it in contact with the liquid media of the organism.

In another embodiment, the drug is included in a hydrophilic matrix, which gradually or quickly dissolves in the presence of liquid media of the body. The core tablet may contain two or more layers with different velocities release. Layers are hydrophilic, hydrophobic or a mixture of hydrophilic and hydrophobic layers. Adjacent layers in the multilayered core tablet can be divided insoluble protective layer or the hydrophilic separating layer. Insoluble protective layer consists of materials used to obtain the insoluble shell. Hydrophilic separating layer consists of a material which is characterized by greater solubility compared with other segments of the core tablet and, therefore, upon the dissolution of the separating layer exhibited slo the core tablet, releasing the drug.

Suitable controlling the release of drugs polymers include polymethacrylates, ethylcellulose, hypromellose, methylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polymers of acrylic acid, polyethylene glycol, polyethylene oxide, carrageenan, cellulose acetate, Zein, etc.

The composition also may contain material that is swellable upon contact with aqueous solutions, and which can be incorporated into the composition, including polymeric materials selected from the group comprising crosslinked sodium carboxymethyl cellulose, crosslinked hydroxypropylcellulose, macromolecular hydroxypropylcellulose, carboxymethylated, potassium salt of a copolymer of methacrylate and polystyrene, polymethyl methacrylate, crosslinked polyvinylpyrrolidone and high molecular weight polyvinyl alcohols.

In one embodiment, the composition includes silicon dioxide.

Microcrystalline cellulose can serve as a diluent, carrier, filler or lash thickening agent, and may consist of Avicel®.

The particle size of the microcrystalline cellulose can be modified.

The use of microcrystalline cellulose in the composition may FPIC is bestoweth more uniform distribution of the modulator of the receptor S1P in microcrystalline cellulose, contained in the composition. The surface area can be increased when receiving drugs microcrystalline cellulose containing particles with a smaller average size and/or particle with a rough surface.

It was found that the use of micronized microcrystalline cellulose, for example, with an average particle size of 30 μm or less, furthermore, increases the ability to compaction and hardness of the tablets obtained on the basis of the composition.

The composition preferably comprises from 75 to 99.99 wt.% microcrystalline cellulose, for example, from 85 to 99.9%, for example, from 90 to 99.5 wt.% calculated on the total weight of the composition.

Usually aldit include lactose, sucrose, dextrose, mannitol or sorbitol.

The compositions of the present invention are, for example, tablets, capsules, microtablets, tortillas, pillule, minitablets, pellets, beads or granules.

If a solid composition is in the form of pellets or granules, after coating, as described in this context, they can be filled capsules, for example, hard gelatin capsules, or other containers for storage before the introduction of, for example, the bags.

Pellets and granules may have a diameter of from 2 to 0.3 mm, for example, "standard pellets" is characterized by sizes from 1 to 0.6 mm, and "granular pellets" x is specified sizes from 0.4 to 0.8 mm

In the present invention, it is also proposed a method of obtaining a pharmaceutical composition, which is:

(a) mixing agonist of S1P receptor or other modulator with microcrystalline cellulose, for example, Avicel®,

(b) grinding and/or granulation obtained in stage (a) mixture and

(C) optionally mixing the crushed mixture obtained in stage (b), with sizing.

When using this method get the composition is characterized by a high content of the active agent and the homogeneity of the mixture (i.e. a sufficiently homogeneous distribution of the modulator of the receptor S1P in the composition), a sufficiently low time of dissolution and high stability.

The modulator of the S1P receptor, for example, hydrochloride 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or another agonist of S1P receptor, can be finely comminuted and/or pre-sift, for example, through a sieve with cell diameter of from 400 to 500 μm, before carrying out stage (a) to remove large aggregates. Stage of mixing (a) may include the mixing of S1P receptor antagonist and microcrystalline cellulose, for example, Avicel®, in any suitable blender or mixer, for example, at speeds from 100 to 400 rpm.

The method can be performed by mixing the dry components. In this case, the stage of grinding (b) can the t to enable transmission of the mixture, obtained in stage (a), through a sieve, preferably with a cell diameter of from 400 to 500 μm. Stage (a) may include mixing the total number of receptor agonist S1P first with a small amount of microcrystalline cellulose, for example, Avicel®, for example, from 5 to 25 wt.% calculated on the total weight of microcrystalline cellulose, for example, Avicel®, you get an intermediate mixture. Accordingly, the remaining amount of microcrystalline cellulose, for example, Avicel®, added to the intermediate mixture. Stage (a), in addition, may include adding to the mixture of binder solution, for example, methylcellulose and/or xylitol, for example, a water solution.

Powdered mixture obtained in stage (b)can optionally be milled before mixing with the lubricant. Lubricant, e.g. magnesium stearate, before mixing preferably pre-screened, for example, through a sieve with cell diameter of from 800 to 900 microns.

In another embodiment, applying the wet granulation. In this embodiment, the modulator of the receptor S1P preferably pre-mixed in dry form with the required amount of microcrystalline cellulose, for example, Avicel®, and the resulting mixture is, for example, microcrystalline cellulose Avicel®/modulator receptor S1P then mixed in dry form with a binder, for example, hydroxypropyl what osoi or hypromellose. Then add water and mix granularit, for example, in automatic pellet mill. The granulate is dried and pulverized.

Optionally, the mixture obtained in stage (b)at the stage (C) add a further quantity of the binder.

The method may include the additional step tableting or encapsulating the mixture obtained in stage (b), for example, hard gelatin capsules in an automatic machine for encapsulation. Capsules can be painted or they are marked to give an individual appearance and to improve recognizability. To improve the appearance and identification of capsules used dyes. Suitable for use in pharmaceuticals, dyes include carotenoids, oxides of iron and chlorophyll. Preferred capsules labeled code.

Compositions comprising a coating containing receptor agonist S1P

When applied to the pharmaceutical composition coating comprising a modulator of the receptor S1P, you can get products containing different doses or combinations.

Accordingly, another object of the present invention features a pharmaceutical composition comprising a coating containing a modulator of the S1P receptor, for example, the agonist of S1P receptor.

The pharmaceutical composition typically includes a core with a coating containing the module the tor receptor S1P, for example, the agonist of S1P receptor.

The kernel can be any solid composition for oral administration.

The term "core" in a broad sense includes not only tablets, pellets or granules, and capsules, such as soft or hard gelatin or starch capsules. First of all, the core may consist of granules, pellets, tablet or minitablets. These nuclei receive by known methods.

In some embodiments, the core also includes a modulator of the S1P receptor, for example, the agonist of S1P receptor. In other embodiments, the agonist of S1P receptor in the nucleus is absent.

Solid compositions receive in the form of pellets of various sizes, the coating thus applied to each pellet, which is placed, for example, in a capsule or sachet.

Solid compositions can be obtained from powdered ingredients, which can finely grind and press in the composition of different hardness.

In one variant, the powder components are molded of the composition before extrusion coated.

In another embodiment, on the pressed composition coated after pressing.

In yet another embodiment, the coating is applied as before pressing and after it.

Liquid oral compositions include capsules containing liquid composition, the capsule includes the opening.

In one embodiment, the coating applied to the external surface of the capsule.

In another embodiment, the coating is dispersed in the external phase capsules.

Capsules are not limited to capsules with liquid content and in homogeneous liquids may contain solid composition in the form of powders, pellets or heterogeneous suspensions.

If a solid composition is in the form of pellets or granules, after coating, as described in this context, it can be used by itself or it is filled capsules, for example, hard gelatin capsules or other containers for storage before the introduction of, for example, the bags.

Pellets and granules are characterized by a diameter of from 2 to 0.3 mm, for example, "standard pellets" is characterized by a size of from 1 to 0.6 mm, and "granular pellets" is characterized by a size of from 0.4 to 0.8 mm

Composition for coating according to the present invention is suitable for use in the form of tablets described in this context, for example, nuclei of the tablets.

In one embodiment, the composition for coating is used for coating extruded core tablet containing a modulator of the S1P receptor, for example, agonist S1P.

If you use kernel tablets, they preferably are characterized by a hardness of from about 10 to 70 N. The core tablet is characterized by the value of strength p is sriv less than 38 N/cm 2for example, less than 22 N/cm2.

The kernel can be obtained by pressing with a low compression ratio that allows the use of components with coating and fragile components, such as capsules, the composition of the mixture for extrusion with minimal damage or no damage.

The core may contain adjuvant and modulator of the S1P receptor, for example, the agonist of S1P receptor.

The core may contain suitable for tableting ingredients, including solvents, dezintegriruetsja agents, oiling agents, wetting agents, glidant, surfactants, accelerating the release agents, coloring agents, effervescent agents, etc.

The core obtained from any of the compounds known to specialists in this field.

The core may contain, without limitation, fillers, such as polyols, for example, powdered mannitol or other polysaccharides or sugar, allday, for example, lactose, sucrose, dextrose, mannitol and starch.

The composition of the nuclei, in addition, can contain or in another embodiment, include a binder such as PVP, for example, cellulose, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, starch paste, Arabian gum, alginine acid, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxyprop is illiterate, the magnesium aluminosilicate, maltodextrin, methylcellulose, polyethylene oxide, povidone, sodium alginate and hydrogenated vegetable oil.

The composition of the nuclei, in addition, may include, or in another embodiment to contain dezintegriruetsja agents (in the presence or in the absence of effervescent agents), for example, crosslinked sodium carboxymethyl cellulose (croscarmellose), crosspovidone or sodium salt starch glycolate.

The composition of the nuclei, in addition, may include, or in another embodiment to contain the oil, for example, magnesium stearate, calcium stearate, sodium salt of fumarate, colloidal silicon dioxide or talc.

In one embodiment, the core comprises from 1.5% to 2% of a lubricant, such as magnesium stearate or calcium.

The composition of the nuclei, in addition, may include, or in another embodiment to contain glidant, for example, silicon dioxide.

The composition of the nuclei, in addition, may include, or in another embodiment to contain a surfactant, for example, sodium lauryl sulfate or sodium docusinate.

The composition of the nuclei, in addition, may include, or in another embodiment to contain flavorings.

The composition of the nuclei, in addition, may include, or in another embodiment to contain effervescent agents, for example, sodium bicarbonate or citric acid.

The composition of the nuclei, in addition, may include, or in another embodiment to contain sweeteners.

The composition of the nuclei, in addition, may include, or in another embodiment to contain regulatory pH agents, for example, citric acid or fumaric acid.

The core may contain additives that control the rate of release. For example, the drug may be contained in the hydrophobic polymer matrix and gradually be washed away from her in contact with bodily uids.

In another embodiment, the drug is incorporated in a hydrophilic polymer matrix, gradually or rapidly dissolving in the presence of liquid media of the body. The core may contain two or more layers, with different rates of release. Layers are hydrophilic, hydrophobic or a mixture of hydrophilic and hydrophobic layers. Adjacent layers in the multilayered core divided insoluble protective layer or the hydrophilic separating layer. Insoluble protective layer can consist of a material used for forming the insoluble shell. Hydrophilic separating layer may consist of a material with higher solubility compared with other segments of the core tablet, and thus, by dissolving the separating layer exhibited releasing the drug layers of the core tablets.

Suitable controlling the rate of release of poly is a career include polymethacrylates, ethylcellulose, hypromellose, methylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polymers of acrylic acid, polyethylene glycol, polyethylene oxide, carrageenan, cellulose acetate, Zein, etc.

The core may also contain material that is swellable upon contact with aqueous solutions, and is included in the composition, including polymers, such as sodium salt, cross-linked carboxymethylcellulose, crosslinked hydroxypropylcellulose, high molecular weight hydroxypropylcellulose, carboxymethylated, potassium salt of a copolymer of methacrylate and divinylbenzene, polymethylmethacrylat, crosslinked polyvinylpyrrolidone and Vysokomolekulyarnye polyvinyl alcohols.

The core may contain additional pharmaceutically active ingredients, along with the modulator of the S1P receptor, for example, an agonist of S1P.

In one embodiment, if the composition of the core is in the form of standard dosage forms, each standard dose comprises from 0.5 to 10 mg of the modulator of the S1P receptor, for example, agonist S1P.

Suitable methods of obtaining cores tablet include mixing of all ingredients, followed by pressing into tablets and granulation with subsequent pressing of the granules into tablets.

In one variant kompoziciata, containing aldit. An example of the composition of core tablet comprising a modulator of the S1P receptor, for example, S1P agonist, as described in the application WO 2004/089341, which describes a composition comprising an S1P modulator in a mixture with alditol.

Aldit can serve as a diluent, carrier, filler or increasing the amount of agent comprises mannitol, ▫ maltitol, Inositol, xylitol or lactic, preferably substantially non-hygroscopic aldith, for example, mannitol (D-mannitol). Use one aldet or a mixture of two or more alditol, for example, a mixture of mannitol and xylitol, for example, in a ratio of from 1:1 to 4:1.

In another variant, the composition of the nucleus, containing microcrystalline cellulose, and the modulator of the S1P receptor, for example, agonist S1P in the absence of Aldata.

Preferably the components of the core and coating finely chopped.

In one embodiment, the solid composition is characterized by rapid raspadaemost.

Preferably the amount of active ingredient is from 0 to 1000 mg.

Composition for coating is a powder or a liquid.

Composition for coating may include a polymer resin.

Examples of polymer resins include, without limitation, polymethacrylates, for example, methacrylate ammonium cellulose and its derivatives, ethers and esters of cellulose and phthalate-cellulose acetate.

Composition for coating can contain polyethylene glycol or aldith, for example, xylitol.

Composition for coating may also include, or alternatively include other materials, including waxes and oils or alcoholate of waxes and oils, poloxamer, alkylphenate, for example, diethylphthalate, citric acid, or esters.

Composition for coating may also include, or alternatively contain one or more of the following components: acrylic acid, polymers and copolymers of acrylic acid and their derivatives, for example, polymethylacrylate, polyalkene and derivatives thereof, including esters and arrowie esters and their derivatives, polyvinyl alcohols and esters, cellulose and its derivatives, for example, ethers and esters of cellulose (crosslinked or not crosslinked), for example, ethylcellulose, and one or more intersolubility polymers, for example, phthalate-cellulose acetate, phthalate of hydroxypropylmethylcellulose, hydroxypropylcellulose, one or more biodegradable polymers, for example, one or more of polylactide, polyglycolides, polyhydroxybutyrates, polyhydroxyvalerate, copolymers of ethylene and vinyl acetate and polyanhydride (Homo - or heteropolymer) or polyethylene oxide.

Composition for coating may also include, or alternatively, contain a dispersing agent, for example, La is resultat sodium, the sodium docusinate, twins (esters of sorbitol and fatty acids), poloxamer and cetosteatil alcohol.

Composition for coating may also include, or alternatively, contain anti-friction component to reduce friction and/or other forces acting between particles of the powder material to cover, and to increase the fluidity of the powder, for example, titanium dioxide, colloidal silicon dioxide, talc or starch, or a combination of these compounds.

Composition for coating may also include, or alternatively, contain disintegrity agent, for example, sodium salt starch glycolate (custom made), sodium carboxymethyl cellulose (custom made), natural starch, crosslinked polyvinylpyrrolidone (crosspovidone, sodium carbonate, sodium bicarbonate or glycinate sodium.

Composition for coating may also include, or alternatively, contain dyes, for example, metal oxides or pigments (for example, pigments based on aluminum), iron oxides or dyes.

Composition for coating may also include, or alternatively, contain taste modifiers, for example, aspartame, Acesulfame K, cyclamate, saccharin, sugar or validity.

Composition for coating may also include, or alternatively, contain flavorings.

The composition may contain one or more of the openings. The composition can be separated from the containing drug coating a protective layer. In another embodiment, the containing drug coating can be applied exterior coating. Each coating may contain a polymeric material, for example, hypromellose or hydroxypropylcellulose. These coatings are produced and applied to the composition using known methods.

The present invention also proposes a method of obtaining pharmaceutical compositions with a coating that is:

(a) obtaining a composition engine and

(b) coating the core coating containing a modulator of the receptor S1P.

The composition of the core is obtained using any of the techniques described in this context.

The coating can be applied to the core using known in the art methods, for example, a fluidized bed method.

Modulators of S1P

Each of the various compositions described in this context, includes an S1P modulator. In the embodiment, each composition described in this context, the S1P modulator means agonist S1P.

Agonists of the receptor SIP usually means the analogues of sphingosine, such as 2-substituted 2-aminopropan-1,3-diol or derivatives of 2-aminopropanol. Examples of suitable agonist of S1P receptor include, for example,

link is, as described in the application EP 627406 A1, for example, the compound of formula I

where

R1means (C12-C22)hydrocarbons with straight or branched chain,

containing in the chain link or a heteroatom selected from the group including a double bond, a triple bond, O, S, NR6where R6means H, alkyl, aralkyl, acyl or alkoxycarbonyl and carbonyl, and/or

containing a Deputy selected from the group comprising alkoxygroup, alkenylacyl, alkyloxy, aralkylated, acyl, alkylamino, allylthiourea, allmenalp, alkoxycarbonyl, alkoxycarbonylmethyl, alloctype, allylcarbamate, a nitrogroup, halogen, amino, hydroxyimino, the hydroxy-group or carboxypropyl, or

R1means phenylalkyl, where the alkyl means a (C6-C20)hydrocarbons with straight or branched chain, or

phenylalkyl, where the alkyl means a (C1-C30)hydrocarbons with straight or branched chain, where the specified phenylalkyl includes as Deputy

(C6-C20)hydrocarbons with straight or branched chain, optionally substituted by a halogen atom,

(C6-C20)alkoxygroup, optionally substituted by a halogen atom,

(C6-C20)alkenylacyl,

fenilalanina, halogenfree is alkoxygroup, generalkonsulat, phenoxyethoxy or phenoxyethyl,

cycloalkyl containing as substituent (C6-C20)alkyl straight or branched chain,

heteroaromatic containing as substituent (C6-C20)hydrocarbons with straight or branched chain,

heterocyclic alkyl, where the specified alkyl means a (C6-C20)hydrocarbons with straight or branched chain, or

heterocyclic alkyl containing as substituent (C2-C20)hydrocarbons with straight or branched chain,

and where the alkyl residue may contain hydrocarbon chain link or a heteroatom selected from the group including a double bond, a triple bond, O, S, sulfinil, sulfonyl or NR6where R6defined above,

and as Deputy alkoxygroup, alkenylacyl, alkyloxy, aralkylated, acyl, alkylamino, allylthiourea, allmenalp, alkoxycarbonyl, alkoxycarbonylmethyl, alloctype, allylcarbamate, the nitro-group, a halogen, an amino group, a hydroxy-group or carboxypropyl, and

each R2, R3, R4and R5independently mean H, C1-C4alkyl or acyl,

or their pharmaceutically acceptable salt,

compounds described in EP 1002792 A, for example, the compound of formula II

where

m is from 1 to 9, and

each R2, R3, R4and R5independently mean H, alkyl or acyl, or its pharmaceutically acceptable salt,

compounds described in the application EP 0778263 A1, for example, the compound of formula III

where

W denotes H, (C1-C6)alkyl straight or branched chain, (C2-C6)alkenyl or (C2-C6)quinil, unsubstituted or substituted by an OH group phenyl, R4O(CH2)nor (C1-C6)alkyl straight or branched chain, containing from 1 to 3 substituents selected from the group comprising halogen, cycloalkyl, phenyl and substituted by an OH group phenyl,

X is H or unsubstituted or substituted alkyl group with a straight chain containing p carbon atoms, or unsubstituted or substituted alkoxygroup straight chain, containing (p-1) of carbon atoms, for example, containing from 1 to 3 substituents selected from the group comprising alkyl, OH, alkoxygroup, alloctype, amino group, alkylamino, allmenalp, oxoprop, halogen, unsubstituted phenyl or phenyl containing from 1 to 3 substituents selected from the group comprising alkyl, OH, alkoxygroup, acyl, alloctype, amino group, alkylamino, alluminare halogenated or halogen,

Y represents H, alkyl, OH, alkoxygroup, and the sludge, alloctype, amino group, alkylamino, allmenalp, halogenated or halogen,

Z means a simple link or alkylene straight chain containing q carbon atoms,

p and q each independently is an integer from 1 to 20, provided that 6≤p+q≤23,

m is 1, 2 or 3,

n is 2 or 3,

each R1, R2, R3and R4independently mean H, alkyl or acyl,

or their pharmaceutically acceptable salt,

compounds described in the application WO 02/18395, for example, compounds of formula IVa or IVb

where

X represents O, S, NR1or a group -(CH2)n-, unsubstituted or containing as a substituent of 1 to 4 atoms of halogen,

n is 1 or 2,

R1means H or C1-C4alkyl, unsubstituted or substituted with halogen,

R1ameans H, OH, C1-C4alkyl or O(C1-C4)alkyl, where the alkyl unsubstituted or substituted by 1-3 halogen atoms,

R1bdenotes H, OH or C1-C4alkyl, where the alkyl unsubstituted or substituted with halogen,

each R2independently selected from the group comprising H or C1-C4alkyl, where the alkyl unsubstituted or substituted with halogen,

R3in the case of the compounds of formula IVa means H, OH, halogen or O(C1-C4)alkyl, where the alkyl unsubstituted or substituted with halogen,

R3in case the compounds of the formula IVb means H, OH, halogen, C1-C4alkyl, where the alkyl unsubstituted or substituted by a hydroxy-group, or means O(C1-C4)alkyl, where the alkyl unsubstituted or substituted with halogen,

Y represents-CH2-, -C(O)-, -CH(OH)-, -C(=NOH)-, O or S,

R4means (C4-C14)alkyl or (C4-C14)alkenyl,

or its pharmaceutically acceptable salt or hydrate

compounds described in the application WO 02/06268 or JP-14316985, for example, the compound of formula VII

where

each R1and R2independently denotes H or aminosidine group,

R3means hydrogen or hydroxyamino group,

R4means C1-C6alkyl,

n is an integer from 1 to 6,

X is ethylene, vinile, ethynylene, a group of formula-D-CH2- (where D means a carbonyl), a group of the formula-CH(OH)-, O, S or N), aryl or aryl containing up to three substituents selected from the group described below

Y represents a simple bond, C1-C10alkylene, C1-C10alkylene, substituted by 1-3 substituents selected from groups a and b, C1-C10alkylene containing atoms are O or S in the Central or terminal fragment of the hydrocarbon chain, or C1-C10alkylene containing atoms are O or S in the Central or terminal fragment of hydrocarbon chains, which, in turn substituted by 1-3 Deputy is mi, selected from groups a and b,

R5means hydrogen, cycloalkyl, aryl, heterocyclic group, cycloalkyl, substituted by 1-3 substituents selected from groups a and b, aryl, substituted by 1-3 substituents selected from groups a and b, or heterocyclic group substituted by 1-3 substituents selected from groups a or b, and

each R6and R7independently denote H or Deputy, selected from group a,

<a> means halogen, (ness.)alkyl, halogen(ness.)alkyl, (ness.)alkoxygroup, (ness.)allylthiourea, carboxyl, (ness.)alkoxycarbonyl, the hydroxy-group, (ness.)aliphatic acyl, amino, mono(ness.)alkylamino, di(ness.)alkylamino, (ness.)the aliphatic allmenalp, cyano and nitro-group,

<group b> means cycloalkyl, aryl, heterocycle, each of which optionally includes up to three substituents selected from group a,

provided that if R5means hydrogen, Y represents a simple bond or a C1-C10alkylen straight chain, for example, (2R)-2-amino-4-[3-(4-cyclohexylmethyl)benzo[b]Tien-6-yl]-2-methyl-butane-1-ol,

or a pharmacologically acceptable salt or ester specified connection.

If in the compounds of formula I of the hydrocarbon chain R1includes Deputy, the Deputy preferably selected from the group including g the lågen, the nitro-group, an amino group, a hydroxy-group or carboxypropyl. If the hydrocarbon chain is interrupted by optionally substituted phenylene, chain, preferably unsubstituted. If the rest of the phenylene includes the Deputy, the Deputy preferably means a halogen, a nitro-group, an amino group, a methoxy group, a hydroxy-group or carboxypropyl. Acyl means the remainder R is-CO-, where R is C1-C6alkyl, C3-C6cycloalkyl, phenyl or phenyl(C1-C4)alkyl.

Preferred compounds of formula I include compounds in which R1means alkyl straight or branched chain, preferably straight chain, containing from 13 to 20 carbon atoms, optionally substituted by a nitro-group, a halogen, an amino group, a hydroxy-group or carboxypropyl, more preferably R1means phenylalkyl, substituted C6-C14the alkyl straight or branched chain, optionally substituted with halogen, and the alkyl residue means C1-C6alkyl, optionally substituted hydroxy-group. More preferably R1means phenyl(C1-C6)alkyl, substituted C6-C14the alkyl straight or branched chain, preferably straight chain. C6-C14alkyl is in the ortho-, meta - or para-position, preferably in the para-position the AI.

Preferably each R2-R5means H.

The preferred compound of formula I is 2-amino-2-tetradecyl-1,3-propandiol. First of all, the preferred receptor agonist SIP of formula I is 2-amino-2-[2-(4-octylphenyl)]propane-1,3-diol in free form or in the form of pharmaceutically acceptable salts (in this context, the compound (A), for example, hydrochloride, i.e. FTY720:

The preferred compound of formula II is a compound where each of R2-R5means H, a m is equal to 4, i.e. the 2-amino-2-{2-[4-(1-oxo-5-fenilpentil)phenyl]ethyl}propane-1,3-diol (in this context, connection) in free form or in the form of a pharmaceutically acceptable salt, e.g. the hydrochloride.

The preferred compound of formula IVa is a phosphate compound A (R2means H, R3means OH, X is O, R1aand R1bmean OH). The preferred compound of formula V is a phosphate compound (R1means CH2OH, R3means H, X is O, m is 1, R2mean phosphate, and R is 2-[4-(1-oxo-5-fenilpentil)phenyl]ethyl.

If the compounds of formulas I-VII contain in the molecule one or more asymmetric centers, refers to various optical isomers and the racemates, the diastereomers and the mixtures thereof.

Examples of pharmaceutically acceptable with the representatives of compounds of formula I-VII include salts of inorganic acids, such as hydrochloride, hydrobromide and sulfate, salts of organic acids such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate, or where appropriate, salts of metals such as sodium, potassium, calcium and aluminium, salts of amines, such as triethylamine and salts of dibasic amino acids, such as lysine. The compounds and salts according to the present invention include hydrates and solvate.

The composition of the present invention may contain one or more salts and/or free acid modulators of S1P.

The composition according to the present invention preferably contains from 0.01 to 20 wt.% modulators of S1P receptor, more preferably from 0.1 to 10 wt.%, for example, from 0.5 to 5 wt.% calculated on the total weight of the composition.

If the standard dosage form is a capsule, each standard form may contain from 0.5 to 10 mg of the modulator of the S1P receptor.

Application

The pharmaceutical compositions of the present invention are used alone or in combination with other active agents intended for the treatment or prevention of conditions are described, for example, in applications US 5604229, WO 97/24112, WO 01/01978, US 6004565, US 6274629 and JP-14316985, the contents of which are incorporated in the present description as a reference.

The compositions described in this context, can accelerate the absorption and pronica is the necessity of S1P modulator through the blood-brain barrier into the brain. First of all, the pharmaceutical composition is used:

a) for the treatment and prevention of rejection of transplants of organs or tissues, for example, for the treatment of recipients after transplantation of heart, lung, heart-lung, liver, kidney, pancreatic, skin or corneal, and for the prevention of disease graft-versus-host, which sometimes develops after bone marrow transplantation, primarily for the treatment of acute or chronic rejection of ALLO - and xenografts, or after transplantation insulinproducing cells, for example, islet cells of the pancreas,

b) for the treatment and prevention of autoimmune diseases or inflammatory conditions such as multiple sclerosis, arthritis (e.g. rheumatoid arthritis), inflammation of colon, hepatitis, etc.

C) for the treatment and prevention of viral myocarditis and viral diseases induced by viral myocarditis, including hepatitis and AIDS.

In one embodiment, the present invention features the treatment of inflammatory conditions. For example, the present invention relates to compositions for controlling and/or suppressing activation of mast cells and secretion to reduce the intensity of inflammatory conditions such as brain in multiple sclerosis.

In addition, we offer a way to protect the subjects of the spread is lerose from neurodegenerative inflammation of the brain, and this method is the introduction of these subjects are described in the context of the composition, for example, compositions comprising an agonist of S1P receptor or other modulator.

The compositions of the present invention and any concentrate intended for dilution, and received from him the pharmaceutical solution is administered in a therapeutically effective amount for treatment of a disease or condition which is treatable with the introduction of the modulator of the S1P receptor.

The exact amount of the modulator of the S1P receptor or its pharmaceutically acceptable salt for injection can be changed in a wide range. The dose depends on the specific compound, the course of treatment, method of administration, the concentration of a specific concentrate or applied pharmaceutical solution, the nature of the disease or condition to be treated, sex, age and body weight of the patient. The dose also depends on the development, nature and severity of any negative side effects that occur with the introduction of the concentrate or pharmaceutical compositions. Usually children can get a dose of from 0.5 to 5 mg of the modulator of the S1P receptor, such as compounds A.

The composition of the present invention and any concentrate intended for dilution, and received from him the pharmaceutical solution can be introduced in combination with other IMM is depressant(s), steroid(s), such as prednisolone, methylprednisolone, dexamethasone, hydrocortisone and the like, or non-steroidal anti-inflammatory agent. The combination of active agents can be administered simultaneously or sequentially, with first enter one of the active agents. The dosage of active agent in the combined treatment depends on the efficiency and area of each active agent, and from the synergy of agents used for the combined treatment.

The present invention is illustrated by the following examples.

Example 1

Finely ground connection: the hydrochloride of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720) was sieved and mixed with microcrystalline cellulose, for example, Avicel PH 102. The mixture was crushed in a shredder Frewitt MGI (Key International Inc., USA) when using a 30 mesh sieve. Magnesium stearate was screened through a 20 mesh and mixed with a mixture of FTY720/cellulose. To obtain the finished composition was added to croscarmelose.

An example of the structure of the nucleus round tablets with a diameter of 6 mm, weight 80 mg, obtained by direct pressing, shown below.

IngredientDose mg
The FTY720 hydrochloride1,40
Mi is recrystallizes cellulose, for example, Avicel PH 10273,80
Magnesium stearate0,80
Crosscarmellose4,00

In another embodiment, the core tablet was received in the sealing composition in the press for tabletting using punch size 7 mm, and the received tablet weight of 120 mg, for example, as described below.

IngredientDose mg
The FTY720 hydrochloride1,40
Mannitol M200116,20
Magnesium stearate2,40

1 mg FTY720 in free form corresponds to 1.12 mg FTY720 hydrochloride.

Example 2

This example used the method described in example 1, but instead of magnesium stearate was added to the product Cutina® (gidrirovannoe castor oil).

Example 3

In this example, tablets were obtained as described in examples 1 and 2, but instead of FTY720 in each case used the hydrochloride of 2-amino-2-{2-[4-(1-oxo-5-fenilpentil)phenyl]ethyl}propane-1,3-diol.

Examples 4-7

Received tablets containing the following ingredients (mg):

Example 4Example 5Example 6Example 7
FTY7201111
D-mannitol62,362,362,062,0
Xylitol*26,7(5,4)26,7(5,4)26,626,6
The methylcellulose--0,40,4
Microcrystalline cellulose24,0-24,0-
Hydroxypropylcellulose with a low degree of substitution-24,0-24,0
Gidrirovannoe oil6,06,06,06,0
The total number of120,0120,0120,0120,0
* The amount of xylitol that is specified in brackets, used as a bonding agent.

FTY720, D-mannitol and xylitol were placed in a granulator fluidized bed (model MP-01, Powrex), was stirred for 5 min, was granulated while spraying a binder solution and dried to a temperature of exhaust air 40°C. the granulation Conditions below. The dry powder was passed through a sieve of 24 mesh, was added to a specific amount of filler and sizing and mixed in the mixer (tubular mixer, WAB) for 3 min, were obtained powder for pressing.

The resulting powder was extruded in a car for tabletting (Cleanpress correct 12 HUK, Kikushui Seisakusho) with a punch with an inner diameter of 7 mm × radius of 7.5 mm, the compression force 9800 N.

The granulation conditions:

Value
Download1170
The amount of intake air50 m3/min
Temperature sasivimol the air 75°C
The flow rate of the sprayed15 ml/min
solution
The air pressure when spraying15 N/cm2
The volume of air when spraying30 l/min
The amount of binder solution351 ml

Example 8

The sample powder composition for coating

Components are pre-mixed at high shear, then granulated in a wet state, mixing with water at high shear. The granulated mixture is dried in a fluidized bed dryer to a residual moisture content less than 3 wt.%. The dried pellets were crushed and received powder.

IngredientComposition (wt.%)
The copolymer ammoniojarosite, for example, Eudragit RS46,5
Hydroxypropylcellulose, for example, Klucel28,0
Titanium dioxide15,0
Pigment-based aluminum 5,0
Polyethylene glycol 60005,0
Colloidal silicon dioxide, for example, Aerosil 2000,5

Example 9

The sample powder composition for coating

IngredientComposition (wt.%)
The copolymer ammoniojarosite, for example, Eudragit RS39,75
Hydroxypropylcellulose, for example, Klucel39,75
Titanium dioxide15,0
Pigment-based aluminum5,0
Colloidal silicon dioxide, for example, Aerosil0,5

Example 10

An example of a liquid composition for coating (aqueous dispersion)

At the stages of melting or drying the surface of the kernel, you must exert energy to melt the powder or dry the liquid, you get a uniform coating on the exposed surface of the core. Power supply provide focused radiation, preferably in the infrared region, the energy required opredelaetsa the material of the coating. After melting or drying floor utverjdayut cooling using a fan.

IngredientComposition (wt.%)
The hypromellose70
Glycerin7
Iron oxide yellow23

Example 10

Example round tablets weighing 127 mg, a diameter of 7 mm with quick raspadaemost according to the present invention

Ingredientmg/dose
The FTY720 hydrochloride0,56
Compressible mannitol, for example, Parteck M20082,54
The calcium silicate36,00
Magnesium stearate0,90
Crosspovidone7,00

Tablets were obtained by known methods. For example, a tablet was obtained by mixing all ingredients and pressed into pellets and/or granulation and/or grinding, followed by pressing the grain is in the pill.

Example 11

Received composition characterized by a rapid raspadaemost containing gelatin (3%), mannitol as a structuring agent (1-5%), sweeteners, flavorings.

Gelatin and mannitol were added to water and heated to 40°C. for dissolution. A solution of gelatin/mannitol was cooled to 23°C and mixed with the active ingredient, for example, an agonist or other S1P modulator. The total solids content is less than 50%. Before freeze-drying a suspension of (coated or uncoated) was cooled to 15°C to prevent precipitation.

Example 12

The composition was obtained as described in example 11, but instead of mannitol used sorbitol.

Example 13

Crushed hydrochloride 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720) was sieved and mixed with microcrystalline cellulose, for example, Avicel PH 102. The mixture is then crushed in a shredder Frewitt MGI (Key International Inc. USA) and the sieve with cell diameter of 30 mesh. Magnesium stearate was screened through a 20 mesh and mixed with a mixture of FTY720/cellulose. To obtain the finished composition was added crosscarmelose.

The example kernel round tablets weighing 80 mg and a diameter of 6 mm, obtained by direct pressing is shown below.

Ingredientmg/dose
The FTY720 hydrochloride1,40
Microcrystalline cellulose, for example, Avicel PH 10273,80
Magnesium stearate0,80
Crosscarmelose4,00

Example 14

Ground connection And, for example, hydrochloride 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720), screened and of 116.7 g of sifted compounds were mixed with 9683,3 g microcrystalline cellulose. The mixture was ground using a grinder Frewitt MGI (Key International Inc., USA), the cell diameter of 30 mesh. Magnesium stearate was sieved using a sieve with a cell diameter of 20 mesh and 200 g of sifted compounds were mixed with FTY720, when it received the finished composition.

The composition is then condensed on the press for tabletting using punch 7 mm, and the received tablet weight of 120 mg, each of which contains:

The connection And, for example, FTY720*1.4 mg
Microcrystalline cellulose, for example, Avicel PH 102to 116.2 mg
Magnesium stearate2.4 mg
The total number of 120 mg
*1 mg compounds And free-form corresponds to 1.12 mg FTY720

Example 15

In the following example, repeated the procedure described in example 14, but instead of magnesium stearate used the product Cutina® (gidrirovannoe castor oil).

Example 16

The connection And, for example, FTY720, and microcrystalline cellulose, for example, Avicel PH 102,each individually Sieved using sieves with a diameter of cells 18 mesh. 1.9 grams sifted FTY720 was mixed with 40 g of sifted microcrystalline cellulose (120 spins in a blender at a speed of 32 rpm). A mixture of FTY720 then proseware through a sieve 35 mesh.

The sifted mixture of FTY720 were placed in a granulator and was added 340,1 g microcrystalline cellulose, for example, Avicel PH 102 and 12 g of hydroxypropylcellulose. The mixture was stirred for 3 minutes Then add the water at a rate of 100 ml/min and the mixture was granulated for 2 minutes Granulate was transferred to a tray drying, and was dried at 50°C for 150 minutes

The mixture was then crushed in a shredder Frewitt MGI using sieves with a cell diameter of 35 mesh. Magnesium stearate was sifted and 6 g of sifted compounds were mixed with FTY720 (90 spins at a speed of 32 rpm), it was obtained a composition characterized by a homogeneous distribution of agonist S1P receptor in a mixture with microke the metallic cellulose, for example, Avicel PH 102.

The finished composition was filled in hard gelatin capsules of size 3 in the car to encapsulate H&K 400. Each capsule was placed 120 mg of the composition. Thus, each capsule includes:

FTY720*0.56 mg
Microcrystalline cellulose114,04 mg
Hydroxypropylcellulose3.6 mg
Magnesium stearate1.8 mg
The total number of120 mg

Example 17

In this example the composition was obtained as described in example 16, but instead of magnesium stearate used the product Cutina® (gidrirovannoe castor oil).

Example 18

In this example the composition was obtained as described in example 16, but instead of hydroxypropylcellulose used hypromellose.

Example 19

Ground connection And, for example, FTY720, sieved through a sieve with cell diameter of 425 microns (40 mesh). 58,35 g sifted compounds were mixed with 4841,65 g microcrystalline cellulose, for example, Avicel PH 102, in bunker mixer 25L Bohle for 240 cycles of rotation. The mixture was ground in Frewitt MGI, using a sieve with a cell diameter of 425 μm and powdered mixture again stirred. Magnesium stearate was sifted and 100 g of sifted compounds were mixed with a mixture of FTY720, when it received the finished composition, characterized by a homogeneous distribution of the receptor agonist S1P in the mixture.

The obtained composition was filled in hard gelatin capsules of size 3 in the car to encapsulate H&K 400. Each capsule was placed 120 mg of the composition. Thus, each capsule includes:

FTY720*1.4 mg
Microcrystalline celluloseto 116.2 mg
Magnesium stearate2.4 mg
The total number of120 mg

Examples 20 and 21

In these examples, the composition was obtained as described in example 19, but each capsule contains the following quantities of components:

Example 20Example 21
FTY720*2.8 mg5.6 mg
Microcrys allicesia cellulose 114,8 mg112 mg
Magnesium stearate2.4 mg2.4 mg
The total number of120 mg120 mg

Examples 22-24

In these examples, the composition was obtained as described in examples 19-21, but instead of stearate in each case used the product Cutina® (gidrirovannoe castor oil).

Examples 25-35

In these examples, the composition was obtained as described in examples 13-23, but instead of FTY720 in each case used the hydrochloride of 2-amino-2-{2-[4-(1-oxo-5-fenilpentil)phenyl]ethyl}propane-1,3-diol.

Examples 36-38

Received the pharmaceutical composition containing the following ingredients:

Example 36Example 37Example 38
FTY720*5 mg10 g100 g
Microcrystalline cellulose991 g986 g897 g
Matically the oz SM-25 4 g4 g3 g
The total number of1000 g1000 mg1000 g

FTY720 and part of microcrystalline cellulose, for example, Avicel PH 102, equivalent to twice the weight of FTY720, mixed in the mixer Microspeed Mixer type MS-5 (Palmer, USA) for 2 min at a speed of 1200 R/min. the mixture was added the rest of microcrystalline cellulose and was stirred for a further 2 minutes 80 or 60 ml of 5% solution of methylcellulose SM-25 was added from the hopper and was granulated under the same conditions. The mixture was extrudible through a sieve with cell diameter of 0.4 mm for the extruder type RG-5. The extrudate was dried at 65°C in the granulator, fluidized bed type STREA I (Patheon, Canada) and sieved through sieves with a diameter of cells 24 mesh. Small particles passing through a sieve of 60 mesh, were separated. The obtained fine granules were filled in capsules in the car to encapsulate Zuma (100 mg in each capsule).

Example 39

An example of the composition to obtain tablets containing 1.25 mg FTY720, obtained by wet granulation.

Composition for wet granulation.

Ingredientmg tablet %
Hydrochloride FTY1,491,49
GPMC 3 SP3,003,00
Water liquid for granulationThe required numberThe required number
Mannitol46,2546,25
Avicel PH 10146,2546,25
Aerosil 2003,013,01
Crosscarmellose5,005,00
Magnesium stearate1,001,00
The total number of100,00100,00

Microcrystalline cellulose was granulated by wet granulation with an aqueous solution FTY720 and HPMC. After drying, the mixture was sieved and mixed with mannitol, silicon dioxide, croscarmellose and magnesium stearate, the mixture was extruded into round tablets with a weight of 100 mg and a diameter of 6 mm

In another embodiment, the composition is received in the absence of alditol, such as mannitol, which was replaced by microcrystalline cellulose.

Ingredientmg tablet%
Hydrochloride FTY1,491,49
GPMC 3 SP3,003,00
Water liquid for granulationThe required numberThe required number
Avicel PH 10192,5092,50
Aerosil 2003,013,01
Crosscarmellose5,005,00
Magnesium stearate1,001,00
The total number of100,00100,00

Example 40

Example compositions for coatings containing FTY720.

Composition for coating pellets, minitablets and small tablets.

And gradient mg tablet%
GPMC 3 SP1,6211,60
Hydrochloride FTY0,040,25
Equivalent0,010,05
Triethylcitrate0,070,50
Acetone6,1243,81
Ethanol6,1243,81
The total amount of dry matter1,74KZT 12.39
The total number of100,00100,00

The polymer HPMC can be replaced, for example, the GOC or other similar polymer. The coating containing FTY720, can be applied to the pellets containing the active ingredient, or pellets-placebo minitablets or small tablets that are separated, for example, a protective coating (e.g., MPC) and/or containing additional coverage (for example, HPMC). Specified dosage form can be filled capsules (in the example, from GPMC or hard gelatin capsules) or other packing, so you can get any song containing different dose of active agent, or various combinations of agents.

1. Solid pharmaceutical composition suitable for oral administration, including:
(a) a modulator of the receptor S1P, which is 2-amino-2-[2-(4-octylphenyl)]propane-1,3-diol in free form or in the form of a pharmaceutically acceptable salt or phosphate and
b) microcrystalline cellulose in the absence of sugar alcohol.

2. The composition according to claim 1, comprising from 90 to 99.5 wt.% microcrystalline cellulose.

3. The composition according to claim 1 or 2, where the microcrystalline cellulose comprises Avicel®.

4. The composition according to claim 1 or 2, further comprising sizing.

5. The composition according to claim 3, further comprising sizing.

6. The composition according to any one of claims 1 or 2 in the form of granules, tablets or capsules.

7. The composition according to claim 3 in the form of granules, tablets or capsules.

8. The composition according to any one of claims 1 or 2, in which the modulator of the receptor S1P is a hydrochloride of 2-amino-2-[2-(4-octylphenyl)]propane-1,3-diol.

9. The composition according to claim 7, in which the modulator of the receptor S1P is a hydrochloride of 2-amino-2-[2-(4-octylphenyl)]propane-1,3-diol.



 

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SUBSTANCE: method of batch crystallisation is provided for crystallising the antibody against hTNFα, comprising combining an aqueous solution of the antibody, salt of inorganic phosphate and acetate buffer, and incubating the resulting mixture. The crystalline antibody is considered, in particular the antibody D2E7 obtained by the method according to the invention, the pharmaceutical compositions including injectable liquid compositions comprising the antibody crystal, the crystal suspension, and also the methods of treatment the hTNFα-related disorder connected with, and application of the antibody crystals for obtaining the pharmaceutical composition for treatment such diseases.

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FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to novel crystalline forms of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrol-2,5-dione acetate salt, their use for the treating the diseases mediated by T-lymphocytes or PKC, to a pharmaceutical compositions thereof, and a method for preparing them. The presented crystalline forms have: a strong diffraction peak at the angle of 2θ making 21.5° for the A form, or a strong diffraction peak at the angle of 2θ making 9.7° for the B form. The mentioned crystalline forms can be prepared by dissolving 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrol-2,5-dione in 2-propanol at higher temperature, and then cooling after salt formation for preparing the A form, or dissolving 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrol-2,5-dione in ethyl acetate at higher temperature and then cooling after salt formation for preparing the B form.

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11 cl, 8 ex, 11 dwg

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EFFECT: preparing the pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

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FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new 1H-pyrrolo[3,4-b]quinoline-3,9(2H, 4H)-dione derivatives of general formula 1

wherein R1=Alk, Ar; R2=H, Alk, halogen; R3=H, Alk, halogen; R4=H, Alk, halogen; R5=H, Alk, halogen; R6=CH2Ar, R7=Ar, Also, the invention refers to a method for preparing them.

EFFECT: there are prepared new 1H-pyrrolo[3,4-b]quinoline-3,9(2H, 4H)-dione derivatives possessing anti-tuberculosis activity.

3 cl, 1 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to pharmaceutical industry and deals with solid pharmaceutical composition, possessing high physical strength. Claimed invention also presents method of manufacturing solid pharmaceutical composition. Claimed pharmaceutical composition contains 7 varicoloured types of granules in form of capsule. Granules contain, wt %: nikotinamide 1-35; pyridoxine 0.1-8; calcium pantitenate 0.1-15, thiamin 0.1-30; tryptophan 1-30; tocoferol 0.5-5; ascorbic acid 0.1-50; 5-hydroxyanthranyl acid 0.01-10; Riboflavin 0.1-10; folic acid 0.1-6; cyanocobalomin 0.001-6; isoleucin 0.5-10; leucin 0.5-15; lysine 0.5-20; phenylalanine 0.1-5; threonine 0.1-5.0; valin 0.1-8.0; methionine 0.1-15; lactose 1-4.0; ergocalcioferol 1-95.0 and auxiliary substances for obtaining granules.

EFFECT: claimed composition possesses excellent properties of medication release and digectionin application composition possesses hepatoprotective hypolipidemic immunostimulating and normalising kidney activity action.

2 cl. 2 ex. 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for the correction of cerebrovascular disease accompanying cardiovascular diseases which contains the active ingredients presented by atorvastating or pharmaceutically acceptable salt thereof and nicergolin in the therapeutically effective amounts.

EFFECT: pharmaceutical composition is characterised by high stability and bioavailability.

8 cl, 8 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, and represents an oral dosage form in the form of capsule, containing: 1) pomalidomide in the amount of 0.1 to 3 wt % of total weight; 2) a binding agent or an excipient in the amount of 90 to 99 wt % of total weight wherein the binding agent or the excipient represent starch, mannitol or their mixture.

EFFECT: invention provides stability of the declared dosage form.

22 cl, 7 ex, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to chemical-pharmaceutical industry and represents a pharmaceutical composition containing: {1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3;4-difluorophenyl)cyclopropyl]amino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol; an excipient representing mixed mannitol and dibasic calcium phosphate dihydrate; a binding agent representing hydroxypropyl cellulose; a disintegrant representing sodium starch glycolate; and one or more lubricating agents.

EFFECT: invention provides preparing the composition of the active compound possessing high stability and high bioavailability of the active agent.

12 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, namely a stable pharmaceutical composition of a water-soluble salt of vinorelbine. The composition contains approximately 56 wt % of a diluent, approximately 2.5 wt % of a binding agent, approximately 5 wt % of a disintegrant, approximately 0.25 wt % of a flow agent and approximately 0.5 wt % of a lubrication agent. The water-soluble salt of vinorelbine is preferentially vinorelbine ditartrate.

EFFECT: pharmaceutical composition is preferentially presented in the form of a gelatine capsule or a tablet.

5 cl, 6 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition applicable for oral administration contains an S1P receptor agonist and mannitol with the composition representing a solid dosage form. Mannitol has a particle specific surface area 1 to 7 m2/g, and the S1P receptor agonist is specified from 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720), its pharmaceutically acceptable salt and FTY720-phosphate.

EFFECT: compositions under the invention are characterised by a high level of distribution uniformity of said S1P receptor agonist, and applicable for oral administration in the solid dosage form, eg in the form of a tablet or a capsule.

14 cl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: method for preparing a pharmaceutical composition consists in mixing an S1P receptor agonist - 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt with sugar alcohols; the mixture is milled and/or granulated, and then mixed with an oil agent. The method under invention is implemented on high-speed automated equipment and enables producing the compositions with high-level distribution uniformity of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

EFFECT: preparing the pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

15 cl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for treating and/or preventing depressions. The pharmaceutical composition contains an active substance presented by a selective serotonin reuptake inhibitor (SSRI) specified in a group of fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine differing by the fact that as an active substance, it additionally contains N-acetyl-5-methoxytryptamine (melatonin) in the following proportions, mg: selective serotonin reuptake inhibitor (SSRI) - 10-30 mg, melatonin - 3-8 mg. The pharmaceutical composition may be presented by a solid dosage form - a tablet, a film-coated tablet, a capsule, by a soft dosage form - a rectal suppository.

EFFECT: pharmaceutical composition provides treating depressions and has a number of additional therapeutic properties: easing falling asleep and relieving sleeping disorders, recovering circadian rhythm and seasonal rhythm with reducing a risk of side effects of SSRI.

3 cl, 14 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention describes a method for stabilising a sensitive ingredient for biological absorption in the oral intake in a therapeutic composition involving the stages of combining pregelatinised starch with at least one sensitive ingredient, and mixing the sensitive ingredient with pregelatinised starch. Pregelatinised starch is used in the amount of 5% to 80% of composition weight. The sensitive ingredient is specified in vitamin C, phenylephrine and their combinations. The sensitive ingredient is used in the amount of 0.1% to 20% of composition weight. Said sensitive ingredient is uniformly distributed in pregelatinised starch and adsorbed on pregelatinised starch.

EFFECT: stability of said sensitive ingredients and maintenance of their activity and availability for biological absorption in the oral intake of the therapeutic composition.

17 cl, 15 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and concerns a pharmaceutical composition containing cholest-4-en-3-one oxime and oil specified in sesame oil, olive oil, soya oil, cottonseed oil or mixed medium-chain triglycerides (ESTASAN®, MYGLIOL®) or mixed oils, preferentially sesame oil, olive oil and soya oil, more preferentially sesame oil.

EFFECT: invention ensures chemical stability of the dosage form, higher concentration of the solubilised active ingredients, higher biological availability of the active ingredient.

6 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition in form of solid dosage form for treatment or prevention of diabetes, which contains therapeutically efficient quantity of metformin, polyvinylpyrrolodone, stearic acid and/or its salt, starch, silicon dioxide, characterised by the fact that as polyvinylpyrrolidone it contains polyvinylpirrolidone with molecular weight from 1000000 to 1500000 and additionally glycerol and/or basic finely dispersed magnesium carbonate.

EFFECT: pharmaceutical composition possesses high strength and ensures high degree of active substance release.

10 cl, 1 tbl, 5 ex

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