Pharmaceutical composition 271

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical compositions containing (2-hydroxyethoxy)amide 6-(4-brom-2-chlorophenylamino)-7-fluor-3-methyl-3H-benzoimidazole-5-carboxylic acid hydrosulphate and solvates, crystalline forms and amorphous forms thereof, to using the above compositions as a drug; and to methods for preparing the above compositions.

EFFECT: preparing the new pharmaceutical compositions.

20 cl, 7 tbl, 7 ex, 5 dwg

 

This invention relates to pharmaceutical compositions that contain an acidic sulphate salt (2 hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid (hereinafter referred to in this application referred to as "Agent"), in particular to compositions that are delivered orally, containing the Agent; the use of these compositions as medicaments, to methods of producing these compositions.

Agent disclosed in international patent application WO 2007/076245 and is a powerful inhibitor of MEK. The agent is an acidic sulfate salt of the compound with structure of formula I:

The agent possesses antiproliferative activity and, as you might expect, will be useful in treating diseases or medical conditions that are completely or partially mediated by MEK, and, in particular, different types of cancer such as cancer of the brain, lung, squamous cell, or gall bladder, stomach, pancreas, breast, head, neck, renal cancer, kidney cancer, ovarian cancer, prostate cancer, colorectal cancer, esophageal cancer, testicular, gynecological cancer, thyroid cancer or malignant melanoma. The agent can also be used in the treatment of non-cancer hyperproliferative diseases the project, such as benign hyperplasia of the skin (e.g. psoriasis), restenosis, or prostate hypertrophy (e.g., benign prostatic hypertrophy (national Department of standardization)), and for treatment of other mediated MEK diseases, including diseases of the pancreas or kidney disease (including proliferative glomerulonephritis and induced diabetes renal disease), or for the treatment of pain in a mammal. It is also assumed that the Agent would also be useful to prevent blastocyte implantation in a mammal or for the treatment of diseases associated with vasculogenesis or angiogenesis in a mammal. Such diseases may include tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retrolental fibroplasia, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and cancer of the ovary, breast, lung, pancreas, prostate, colon and epidermoid cancer.

The form of the free base of the Agent (i.e. (2-hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid) was classifica avana as the connection class 4 BCS (in accordance with the Pharmaceutical Classification System as defined in the Guidance for industry: Exception in vivo studies of bioavailability and bioequivalence studies for solid dosage oral forms immediate release based on the Biopharmaceutical Classification System), which suggests that it has a low rate of solubilization/solubility and low permeability. Such compounds typically have low and/or variable bioavailability and, in addition, the bioavailability of the free base form of the Agent from a traditional composition for tablets is relatively weak (~18% in dogs).

Applicants previously identified a specific form of salt (2 hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid, which demonstrates the unique pharmaceutical properties, making it particularly well-suited for use as a drug. This particular form of salts, in particular acid sulfate salt (1:1 remedy: H2SO4) (2 hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid (above and below in this application referred to as "Agent"), was disclosed in WO 2007/076245. This salt is crystalline and suddenly was revealed this, which has improved pharmaceutical properties PR is compared with the form of the free base of the Agent and other salts (2-hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid. In particular, the rate of dissolution of this salt, as well as its bioavailability have been identified as particularly high in comparison with the form of the free base of the Agent and other salts (2-hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid.

In order to receptivity pharmaceutically active compound, such as an Agent, in form acceptable dosage forms, the active compound must possess acceptable biopharmaceutical properties, such as the ability to solubilize and properties of dissolution, and, accordingly, to have acceptable stability and properties that make it acceptable for processing. In this regard, a special problem arises with the Agent. The form of the free base of the Agent is weakly basic compound and has two main groups with values ofpKand'approximately 2.7 and 8.2. The value of the PKandexpressing the strength of acids and bases, i.e. the tendency of the acid to lose a proton or a tendency of the base to accept a proton (Bronsted J.N. Rec. trav. Chim. (47), 718, 1923). The agent (i.e. sulfuric acid salt) is such that, in particular, is capable of dissociation with the formation of its free base form during the process the owls of receptione and/or storage. This conversion is undesirable, since the form of the free base of the Agent has a lower pharmacological properties, in particular, in terms of speed solubilization and dissolution. In addition, you must avoid this conversion, since it can be expected that this may cause a decrease in the bioavailability and/or lead to increased variability of the concentrations in plasma between different patients and that of the patient, these two causes can lead to a decrease in the optimal level of patient care.

Thus, there is a need in the pharmaceutical composition that contains an Agent (i.e. an acidic sulphate salt), in particular in compositions in which the stability of the Agent is maintained during processing and storage, to ensure acceptable absorption and/or bioavailability of the Agent is achieved during dosing.

According to the first aspect of the present invention is provided a pharmaceutical composition that includes an Agent and matrix media matrix where the carrier essentially consists of one or more pharmaceutically acceptable carriers selected from the following:

(a) d-alpha-tocopherylacetate 1000 succinate;

(b) poliglecaprone glycerides;

(c) polyethylene glycol (Page); and

(d) TV is rdye fats;

and where the Agent is dispersed in the matrix medium.

We unexpectedly found that the stability of the Agent can be maintained in the compositions of the present invention. Many materials that are acceptable for the formation of matrix media, are traditionally known in the art such as, for example, emulsifiers, solubilizing agents and enhancers of absorption, and are used to improve the kinetics of dissolution and bioavailability of poorly soluble drugs. However, applicants unexpectedly discovered that such fillers can also be used as inert matrix carriers for the stabilizing Agent in the form of acid sulphate during pharmaceutical processing and long term storage.

According to the compositions of this invention provide a means of stabilizing Agent in the form of its acid, sulfuric acid forms during processing of the composition and further long-term storage and, consequently, provide the fact that acceptable absorption and/or bioavailability of the Agent is achieved during dosing.

An additional advantage of the present invention relates to the production process, which is used to obtain an acceptable compositions in accordance with this invention. While most of the traditional p is acesso receptionarea, such as those used for receptionarea dosage forms as tablets, can involve a large number of lengthy and complex stages, which may lead to instability of the Agent, the compositions of this invention can be obtained by relatively simple and capable of change processes.

Matrix media

Matrix medium comprises one or more pharmaceutically acceptable carriers mentioned above. Matrix media may include only one pharmaceutically acceptable carrier selected from the groups defined above, or, alternatively, it may include a mixture. Pharmaceutically acceptable carrier is selected from any one of the following groups:

(a) d-alpha-Tocopheryl polyethylene glycol 1000 succinate;

(b) poliglecaprone glycerides;

(c) glycols; and

(d) solid fats.

D-alpha-Tocopheryl polyethylene glycol 1000 succinate (which is also known as vitamin E TPGS) is a water-soluble derivative of natural vitamin E and has a dual nature, such amphiphiles, hydrophilicity and lipophilicity. Vitamin E TPGS is obtained by esterification of crystalline succinate, d-α-tokoferolov acid using poly (ethylene glycol) (see USP 25 - national Formulary 20). Vitamin E TPGS also known for its use in pharmaceutical assignments as emulsifier, solubilizing agent and absorption enhancer, while WO 96/36316, US 5891845 and WO 00/76482 can be given as examples. Cm. also "Eastman Vitamin E TPGS" Eastman Brochure, Eastman Chemical Co., Kingsport, Tenn. (November 2002) for additional information on the use of vitamin E TPGS in such assignments.

Poliglecaprone glycerides are mixtures of glycerides, fatty acid esters of polyoxyethylene and fatty acids. In these mixtures of fatty acids are saturated or unsaturated, and glycerides is mono-, di - or triglycerides or mixtures thereof in any ratio. Examples of acceptable poliglecaprone of glycerides include, but are not limited to, capillary macrogolglycerol (for example, Lubrizol), oleoyl macrogolglycerol (for example, Labrafil M1944 CS), linoleoyl macrogolglycerol (for example, Labrafil M CS), lauroyl macrogolglycerol (for example, lauroyl macrogol-32 glycerides), stearoyl macrogolglycerol, for example, Gelucire 50/13 (see Pheur 6thedition, 2008, for additional details regarding these poliglecaprone of glycerides). Special group compositions poliglecaprone glycerides contained in the matrix media, have value hydrophilic/lipophilic balance (HLB) greater than 10. In additional particular group of compositions poliglecaprone glycerides contained in matrixmania, are capable of dispersing in water. In additional particular group of compositions poliglecaprone glycerides are lauroyl macrogolglycerol or stearoyl macrogolglycerol. In another more particular group of compositions poliglecaprone glycerides are lauroyl macrogolglycerol. In another more particular group of compositions poliglecaprone glycerides are lauroyl macrogol-32 glycerides or Gelucire 50/13. In another more particular group of compositions poliglecaprone glycerides are lauroyl macrogol-32 glycerides. Lauroyl macrogol-32 glycerides (commercially provided as Gelucire 44/14 or Ukkonen®C-44, EP) are saturated poliglecaprone the glycerides, which consists of mono-, di - or triglycerides and mono - and di-fatty acid polyethylene glycol (PEG). Lauroyl macrogol-32 glycerides are semi-solid/solid at room temperature and have a melting point at 44°C, they are obtained by reaction hydrogenerating kernel oil coconut with polyethylene glycol 1500.

The polyethylene glycol USP (Page)that alternative is known as macrogol (see Pheur 6thpublished 2008), are hydrophilic polymers oxyethylene. Page that have environments the s molecular weight of more than 900 daltons, in the General case are semi-solid or solid at room temperature. Acceptable interval average molecular weight for Pegov in this invention ranges from 900 to 35,000 daltons. Acceptable commercially available products include, but are not limited to, PEG 900, PEG 1000, PEG 1450, PEG 2000, PEG 6000 and PEG 20000. Special group compositions PEG(s) (s) is(are) in matrix media has interval average molecular weight from 900 to 25,000 daltons. In additional particular group of compositions of this embodiment the PEG has an average molecular weight of about 6000 daltons. In another additional group of compositions of this embodiment, the PEG has an average molecular weight of approximately 20,000 daltons.

Solid fats are solid mixtures of monoglycerides, diglycerides and triglycerides, which is practically insoluble in water. Examples of acceptable solid fats include, but are not limited to, Gelucire 33/01 (see USP-NF 'tallow'), Gelucire 39/01 (see USP-NF and EP 'tallow') and Gelucire 43/01 (see EP 3eedition and USP24/NF19 'tallow').

In accordance with one embodiment of the invention the matrix medium comprises one or more pharmaceutically acceptable carriers selected from the following:

(a) d-alpha-Tocopheryl polyethylene glycol 1000 succinate;

(b) poliglecaprone the glycerides is; and

(c) polyethylene glycol (Page);

where the Agent is dispersed in the matrix medium.

In an additional embodiment of the invention matrix media is a vitamin E TPGS.

In another additional embodiment of the invention matrix media is poliglecaprone the glycerides. Is acceptable when poliglecaprone the glycerides is lauroyl macrogol-32 glycerides or Gelucire 50/13, in particular lauroyl macrogol-32 glycerides.

In an additional embodiment of the invention the matrix medium comprises a mixture of vitamin E TPGS and at least one poliglecaprone glycerides. Is acceptable when at least one poliglecaprone the glycerides present in this embodiment, represents lauroyl macrogol-32 glycerides, is also acceptable when lauroyl macrogol-32 glycerides are present in an amount which is 1-60% by weight of the component matrix carrier composition, and acceptable way approximately 30-55%, and even more acceptable about 50% by weight of the component matrix carrier composition. Preferably, when lauroyl macrogol-32 glycerides are the only poliglecaprone the glycerides present in this incarnation.

In an additional embodiment of the image is to be placed matrix medium comprises a mixture of vitamin E TPGS and at least one Page. Is acceptable when at least one PEG, which is present in this embodiment, has an average molecular weight of from 900 to 25,000 daltons, and is acceptable when the PEG is present in an amount which is 1-30% by weight of the component matrix carrier composition in an acceptable manner approximately 5-15%, and even more acceptable about 10% by weight of the component matrix carrier composition. Preferably, when only one PEG is present in this embodiment. In a special group of compositions of this embodiment of this PEG has an average molecular weight of 6000 daltons. In another additional group of compositions of this embodiment, the PEG has an average molecular weight of 20,000 daltons. In another additional group of compositions of this embodiment, the PEG has an average molecular weight of 1000 daltons.

It is clear that the term 'approximately'as used in this application above for the ratio of fillers, such as lauroyl macrogol-32 glycerides or PEG, the matrix carrier composition, refers to ±2% by weight of the component matrix of the media.

Is acceptable when the composition comprises from 40 to 99% by weight, in particular from about 60 to 95% by weight, in particular from about 65 to 95% by weight of the matrix medium.

In CCA the Oh group of compositions of the present invention, the composition contains about 90-95% by weight of matrix media in particular, approximately 95% by weight of the matrix medium.

Special additional group of compositions of the present invention the composition comprises from about 85 to 90% by weight of matrix media, and in particular, approximately 90% by weight of the matrix medium.

In another more particular group of compositions of the present invention the composition comprises from about 75 to 85% by weight of matrix media, and in particular approximately 80% by weight of the matrix medium.

In another more particular group of compositions of the present invention the composition comprises from about 65 to 80% by weight of matrix media, and in particular about 70% by weight of the matrix medium.

It is clear that the term 'approximately'when it touches the correlation matrix of the medium composition, refers to ±2% of the total weight of the composition. As an example, if say that the composition contains about 70% by weight of matrix media, it will cover compositions which contain from 68 to 72% by weight of the matrix medium.

In another more particular group of compositions of the present invention the composition comprises 79-81%, for example 79,83%, by weight of the matrix medium.

Agent

Typically the Agent will be present in an amount which ranges from 1%to 0%, acceptable image from about 1 to 35% and especially from about 5 to 30% by weight of the composition. In a special group of compositions, the Agent will be present in amounts of about 5% by weight of the final composition. In additional particular group of compositions, the Agent will be present in amounts of about 10% by weight of the final composition. In another more particular group of compositions, the Agent will be present in amounts of about 20% by weight of the final composition. In another more particular group of compositions, the Agent will be present in amounts of about 30% by weight of the final composition. In another more particular group of compositions, the Agent will be present in the amount of 19-21%, for example 20,17%, by weight of the final composition.

It is clear that the term 'approximately', when it comes to the relation of the Agent present in the composition, refers to ±2% of the total weight of the composition.

Is acceptable when a single dose of the composition in accordance with the invention may contain from 0.01 mg to 500 mg of the Agent. Is acceptable when each therapeutic dose of the composition will contain a sufficient amount of the Agent to provide the daily dose of the Agent in one or more units. Acceptable number Agent e is innych doses in various embodiments include, for example, approximately 6,05, 12,1, 18,15, 30,25, 60,5, 72,6, 78,65, 84,7, 90,75, 96,8, 102,85, 108,9, 114,95, 121, 151,25, 181,5, 242, 302,5, 363, 423,5, 484 mg or more, depending on the dose, which is required, and the specific form of the pharmaceutical composition. In a separate embodiment the unit dose of the composition contains from 1 mg to 150 mg of the Agent, and in particular from 50 mg to 130 mg of the Agent, for example approximately 72,6, 78,65, 84,7, 90,75, 96,8, 102,85, 108,9, 114,95 or 121 mg of the Agent, and especially to 72.6, 78,65, 84,7, 90,75 or 96.8 mg of the Agent. The term 'approximately'as used immediately above in this application, is defined as +/- 2 mg from the specified weight quantities. In a separate embodiment the unit dose of the composition contains 90,75 or of 60.5 mg of the Agent. In a separate embodiment the unit dose of the composition contains 90,75 mg of the Agent. In a separate embodiment the unit dose of the composition contains of 60.5 mg of the Agent.

The agent can be used in a variety of forms, all of which are included in the scope of this invention. These include amorphous or crystalline forms, anhydrous forms, as well as a solvate and hydrate. In a special group of compositions, the Agent is crystalline and is in anhydrous form.

We found that the Agent can be stabilized to acceptable matrix media of the present invention. As used in this application, the term "stable" means that the active ingredient ((2-what hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid), which is present in the composition after processing and/or storage, is present substantially in the form of a sulfuric acid salt, i.e., as Agent, in contrast to the forms of the free base of the Agent. Specialist in the art can easily appreciate that the quantity of free base form of the Agent and the number of Agent (i.e., forms sulfuric acid salt) in the composition may be obtained using techniques such as, for example, XRPD and19F NMR spectroscopy of solids, and may also be subject to monitoring by analysis of dissolution.

As used in this application, the term "dispersed" refers to a two-phase system where one phase consists of the Agent, which is distributed in the second phase, which includes a matrix carrier, the Agent is dispergirovannoyj phase and matrix media, which includes this phase is the continuous phase. Special group compositions an Agent that forms a "dispergirovannoyj phase, is in the form of finely ground particles which are distributed in the "second phase", which includes the matrix media. In a special group of songs more than 60% by weight of the total amount of Agent that is present in the composition, are dispergirovannom. In one particular group of compositions b is over 90% and preferably more than 95% by weight of the total amount of Agent, which is present in the composition, are dispergirovannom. Specialist in the art will appreciate that the order of the ratio of the medicinal product, which is present in the form of a solid dispersion can be determined using techniques such as differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), differential scanning calorimetry and19F NMR spectroscopy solid. A qualified specialist in the art will appreciate that the crystalline structure of the drug in the composition can be determined using techniques such as, for example, diffraction of x-rays.

In a special group of compositions of the present invention the particle size of the dispersed Agent can vary from about 1 to 20 microns. It is desirable, when dispersed Agent has a grain size distribution such that 90% of the particles have a diameter less than 15 microns.

In one embodiment of the invention, the Agent is dispersed in the matrix medium and contains no additional solvents or auxiliary agents. Compositions of this embodiment can be obtained with particularly high loading of the Agent, and this is desirable because the additional comp the components often have disadvantages, such as the potential for increased toxicity and increased the size of the dosage form. Both of these deficiency may contribute to the poor adherence of the patient and the acceptability of treatment.

According to an additional aspect of the present invention is provided a pharmaceutical composition, which includes:

(i) the Agent; and

(ii) the matrix carrier;

where the matrix carrier has any of the definitions given above;

and where the Agent is dispersed in the matrix medium, and the composition is semi-solid or solid at room temperature.

As used in this application, the term "semi-solid" refers to a component or composition, which have a rigidity and viscosity, which are intermediate between solid and liquid. Semi-solid substances do not have such fluidity as powder and not a liquid at room temperature (that is, they have a melting point higher than room temperature). As used in this application, the term "hardening" refers to the formation of a solid or semi-solid substances. Under room temperature see temperature value in the range from 18 to 23°C.

In accordance with an additional aspect of the present invention is provided a pharmaceutical composition, which includes:

(i) And the UNT; and

(ii) matrix media, which essentially consists of vitamin E TPGS;

where the Agent is dispersed in the vitamin E TPGS, and the composition is semi-solid or solid at room temperature.

In accordance with an additional aspect of the present invention is provided a pharmaceutical composition, which includes:

(i) the Agent; and

(ii) matrix media, which essentially consists of poliglecaprone glycerides;

where the Agent is dispersed in poliglecaprone the glycerides, and the composition is semi-solid or solid at room temperature.

In accordance with an additional aspect of the present invention is provided a pharmaceutical composition, which includes:

(i) the Agent; and

(ii) matrix media, which essentially consists of vitamin E TPGS and lauroyl macrogol-32 glycerides;

where the Agent is dispersed in the matrix medium, and the composition is semi-solid or solid at room temperature.

In accordance with an additional aspect of the present invention is provided a pharmaceutical composition, which includes:

(i) the Agent; and

(ii) matrix media, which essentially consists of vitamin E TPGS and PEG;

where the Agent is dispersed in the matrix medium, and the composition is polut what Erdei or solid at room temperature.

In a separate embodiment provides the pharmaceutical composition, which includes:

(i) from 15 to 30 (in particular, from 15 to 25) parts of the Agent; and

(ii) from 70 to 85 (in particular from 75 to 85) parts of the matrix carrier;

where both parts are by weight, and the sum of the parts (i)+(ii)=100, matrix media has any of the values defined in the application above, and the Agent is dispersed in the matrix medium, and the composition is semi-solid or solid at room temperature.

In a separate embodiment provides the pharmaceutical composition, which includes:

(i) from 15 to 25 (in particular, from 18 to 22) parts of the Agent; and

(ii) 75 to 85 (in particular, from 78 to 82) parts of the matrix carrier;

where both parts are by weight, and the sum of the parts (i)+(ii)=100, matrix media has any of the values defined in the application above, and the Agent is dispersed in the matrix medium, and the composition is semi-solid or solid at room temperature.

In a separate embodiment provides the pharmaceutical composition, which includes:

(i) from 25 to 40 (in particular from 25 to 35) parts of the Agent; and

(ii) from 60 to 75 (in particular from 65 to 75) parts of the matrix carrier;

where both parts are by weight, and the sum of the parts (i)+(ii)=100, matrix media has any of the values defined in this is avce above, and the Agent is dispersed in the matrix medium, and the composition is semi-solid or solid at room temperature.

In a separate embodiment provides the pharmaceutical composition, which includes:

(i) from 25 to 35 (in particular, from 28 to 32) parts of the Agent; and

(ii) from 65 to 75 (in particular, from 68 to 72) parts of the matrix carrier;

where both parts are by weight, and the sum of the parts (i)+(ii)=100, matrix media has any of the values defined in the application above, and the Agent is dispersed in the matrix medium, and the composition is semi-solid or solid at room temperature.

In a separate embodiment provides the pharmaceutical composition, which includes:

(i) from 15 to 25 (in particular, from 18 to 22) parts of the Agent; and

(ii) 75 to 85 (in particular, from 78 to 82) parts of vitamin E TPGS;

where both parts are by weight, and the sum of the parts (i)+(ii)=100;

and where the Agent is dispersed in the vitamin E TPGS, and the composition is semi-solid or solid at room temperature.

In a separate embodiment provides the pharmaceutical composition, which includes:

(i) from 25 to 35 (in particular, from 28 to 32) parts of the Agent; and

(ii) from 65 to 75 (in particular, from 68 to 72) parts of vitamin E TPGS;

where both parts are by weight, and the sum of the parts (i)+(ii)=100;

and where the Agent is var is Giovanni in vitamin E TPGS, and the composition is semi-solid or solid at room temperature.

In a separate embodiment provides the pharmaceutical composition, which includes:

(i) 19-21, for example, 20,17, parts of the Agent; and

(ii) 79-81, for example, 79,83, parts of vitamin E TPGS;

where both parts are by weight, and the sum of the parts (i)+(ii)=100;

and where the Agent is dispersed in the vitamin E TPGS, and the composition is semi-solid or solid at room temperature.

In a separate embodiment provides the pharmaceutical composition, which includes:

(i) from 25 to 35 (in particular, from 28 to 32) parts of the Agent; and

(ii) from 65 to 75 (in particular, from 68 to 72) parts of the matrix carrier, which consists of a mixture of vitamin E TPGS and at least one poliglecaprone glycerides;

where both parts are by weight, and the sum of the parts (i)+(ii)=100;

and where the Agent is dispersed in the vitamin E TPGS and at least one poliglecaprone the glycerides, and the composition is semi-solid or solid at room temperature.

Composition

Optionally, the composition in accordance with this invention may include additional fillers, provided that inclusion of such fillers will not adversely affect the stability of the salt form of the Agent in the composition. In accordance with this any qualified is economony specialist in the art will appreciate, in some embodiments of the invention, the Agent that is present in the composition in accordance with the invention may be dispersed in the mixture, which consists of a matrix of media and additional fillers such as those described in certain specific examples, which are given in this application below. Additional additives that may be present include, for example, preservatives, stabilizers, emulsifiers, antioxidants, sweeteners, flavoring agents, agents for adjusting the pH value, the agents that contribute to the dispersion (for example, surface-active compounds such as, for example, ethoxylated castor oil (Cremophor EL), ethoxylated hydrogenated castor oil (Cremophor RH40) or Polysorbate 80) and a viscosity modifier. Such additional fillers is a well-known specialist in the art and are described, for example, Guide for pharmaceutical excipients, 4eedition, American pharmaceutical Association; theory and practice of industrial pharmacy, 3eedition, Lachman and others 1986; Pharmaceutical dosage forms: Tablets, volume 1, 2eedition, Lieberman, A. Hebert, and others, 1989; Modern pharmaceutics, Banker, Gilbert and Rhodes, Christopher T, 3eedition, 1995; and Remington's Pharmaceutical Sciences, 20e edition, 2000.

Is acceptable, when the composition in accordance with this invention is in the form adapted for oral administration, for example in the form of a capsule composition or liquid dispersion, acceptable for oral administration. Acceptable composition for capsules is well known and include, for example, solid, liquid or semi-solid compositions, which are contained in soft or hard gelatin capsules; capsules of the water-soluble etherow pulp (for example, hypromellose) or starch capsules.

In accordance with this additional aspect of the invention is a pharmaceutical composition adapted for oral administration, which includes the Agent and matrix media matrix where the carrier has any value, as defined in this application above; and where the Agent is dispersed in the matrix medium.

One additional aspect of the invention is a pharmaceutical capsule composition, which includes Agent and matrix media matrix where the carrier has any value, as defined in this application above; and where the Agent is dispersed in the matrix medium.

Compositions in accordance with this invention can be obtained by using traditional methods, notariaalsed well known in the pharmaceutical field. For example, in one particular embodiment, the component(s) of the matrix medium is heated to melting, and the Agent, the particle size can be reduced, for example, by grinding or micronization, is gradually introduced into the molten mixture with constant shaking/stirring to ensure a homogeneous distribution. The molten mixture may then be made in hard or soft capsules, then leave to cool with the formation of a viscous liquid, solid or semi-solid mass inside the capsule. Then the capsule is closed with conventional methods known in the art, such as, for example, merging with the edges.

Alternatively, the compositions in accordance with this invention can be obtained by using other known methods, such as, for example, melt extrusion or granulation of the melt (see A. Royce, J, Drug Dev. Ind. Pharm. 22 (1996) 9 IP 924, G. Verreck, Bull. tech. Gattefosse (2004) 85-95 and J. Breitenbach, Eur. J. Pharm. Biopharm. 54 (2002) 107-117 for details of acceptable methods of production).

The agent possesses antiproliferative activity, and accordingly the compositions of this invention are useful for treating conditions such as those described in international patent application WO 2007/076245, which reveals the Agent (i.e. an acidic sulphate salt), and also in WO 03/077914, where representatives of the Lena form of the free base of the Agent. For example, the composition in accordance with this invention is useful for treatment of many common types of human cancer, such as malignant melanoma, brain cancer, lung, squamous cell, bladder and gall bladder, stomach, pancreas, breast, head and neck cancer, renal cancer, kidney cancer, ovarian cancer, prostate cancer, kolorektalni cancer, esophageal cancer, testicular cancer, gynecological cancer, and thyroid cancer. Additionally, you can expect that compositions in accordance with this invention will be useful for the treatment of diseases that involve excessive cell proliferation, such as benign hyperplasia of the skin, for example psoriasis, restenosis or benign prostate hypertrophy (national Department of standardization). Other examples mediated MEK diseases which can be treated using Agent include diseases of the pancreas or kidney disease (including proliferative glomerulonephritis and induced diabetes renal disease) or treatment of pain in a mammal. In addition. The agent can also be used to prevent blastocyte implantation in a mammal or for the treatment of diseases associated with vasculogenesis or angiogenesis in a mammal. Such diseases may include tumor angiogenesis, chronic is splitline disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retrolental fibroplasia, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and cancer of the ovary, breast, lung, pancreas, prostate, colon and epidermoid cancer.

An additional aspect of the present invention provides a pharmaceutical composition in accordance with the invention, as defined in this application above, for use as pharmaceuticals.

The agent, which is present in the compositions in accordance with this invention possess anti-proliferative properties such as anti-cancer properties, which are supposed to derive from its activity against inhibition of MEK. In accordance with this composition of the present invention is assumed to be useful in treating diseases or medical conditions mediated fully or partially MEK, i.e. a composition in accordance with this invention can be used to obtain inhibitory effect on MEK warm-blooded animal that is in need of such treatment. Thus, the composition according to Dr. who authorized the invention provides a method for treating the proliferation of malignant tumors, which is characterized by inhibition of MEK, i.e. a composition in accordance with this invention can be used to obtain anti-proliferative effect mediated fully or partially by inhibition of MEK. In accordance with this composition of the present invention, as can be expected, will be useful in the treatment of cancer by providing an anti-proliferative effect, particularly in the treatment of sensitive to MEK types of cancer, such as cancers, described in the application above.

In one embodiment in accordance with this invention is provided a pharmaceutical composition in accordance with the invention, as defined in this application above, for use in obtaining anti-proliferative effect in a warm-blooded animal (mostly humans). In another embodiment is provided a pharmaceutical composition in accordance with the invention, as defined in this application above, for use in the treatment of cancer. In another additional embodiment provides a pharmaceutical composition in accordance with the invention for use in the prevention or treatment of tumours which are sensitive to MEK inhibition.

An additional aspect of the present invention provides use of a composition in accordance with the invention, as defined in this application to enter the, in the manufacture of a medicinal product for use in obtaining anti-proliferative effect in a warm-blooded animal (preferably a human).

An additional aspect of the present invention provides use of a composition in accordance with the invention, as defined in this application above, in the manufacture of a medicinal product for use in the treatment of cancer.

An additional aspect of the present invention provides a method of preventing unacceptable reduction of the bioavailability of the Agent in a patient, which requires the use of an Agent which comprises oral administration of the indicated patient a pharmaceutical composition in accordance with this invention, as defined in this application above.

An additional aspect of the present invention provides the use of pharmaceutical compositions in accordance with this invention, as defined in this application above, in the production of medicines to prevent unacceptable reduction of the bioavailability of the Agent.

Pharmaceutical compositions in accordance with this invention can be administered alone as basic therapy or can be additional to one or more other therapeutic agents and/or treatments. Such joint treatment may be achieved by simultaneous, the placenta is consistent or separate introduction of the individual components of treatment. In the field of medical Oncology is a common practice to use a combination of different forms of treatment for each patient with cancer. In medical Oncology the other(other) component(s) such joint treatment in addition to the compositions of this invention may be represented as: surgery, radiotherapy or chemotherapy. Such chemotherapy may include different categories of therapeutic agents, such as:

(i) other antiangiogenic agents such as those which inhibit the effects of growth factor vascular endothelium (e.g., antibody to factor a vascular endothelial growth bevacizumab [Avastin™]), and such that work by different mechanisms from those defined in the application above (for example, linomide, inhibitors of the function of integrin αvβ3, angiostatin, retuxin, thalidomide, an inhibitor of MMP-2 (matrix metalloproteinase 2)inhibitors, MMP-9 (matrix metalloproteinase 9), and inhibitors of COX-II (cyclooxygenase II)), and including agents targeting vessels (for example, complestatin phosphate and compounds disclosed in international patent applications WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213, and agents which damage the vessels described in the published international patent applications WO 99/02166, full disclosure of the specified document is entered into this application by reference (for example, aceti colchisol-O-phosphate));

(ii) cytostatic agents such as antiestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene, idoxifene), agents that detect lower regulation of the estrogen receptor (e.g., fulvestrant), POCs (for example, megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, varsol, exemestane), antiprogestogens, antiandrogens (for example flutamide, nilutamide, bikalutamid, carteron acetate), LHRH agonists and antagonists (for example goserelin acetate, leuprolide, buserelin), inhibitors of 5α-reductase inhibitors (e.g. finasteride), antiinvasive agents (for example, inhibitors of metalloproteinases, such marimastat, and inhibitors of receptor function urokinase plasminogen activator) and inhibitors of the function of a growth factor (such growth factors include for example platelet growth factor and a growth factor for hepatocytes), such inhibitors include antibodies to the growth factor, antibodies to the receptor of the growth factor, (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab [S]), inhibitors farnesyltransferase, tyrosine kinase inhibitors, for example inhibitors of the family of epidermal growth factor (for example EGFR family tyrosine kinase inhibitors such as N-(4-forfinal)-methoxy-6-(3-morpholinopropan)hinzelin-4-amine (gefitinib), N-(3-ethynylphenyl)-6,7-bis(2-Metacritic and)hinzelin-4-amine (erlotinib, OSI-774) and 6-acrylamide-(4-forfinal)-7-(3-morpholinopropan)hinzelin-4-amine (CI 1033) and inhibitors of serine/trionychinae; and

(iii) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical Oncology, such as antimetabolites (for example antifolates like methotrexate, ftorpirimidinu similar to 5-fluorouracil, tegafur, purine and analogues of adenosine, cytosine arabinoside); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin and idarubitsina, mitomycin C, dactinomycin, mithramycin); platinum derivatives (for example cisplatin, carboplatin); alkylating agents (for example nitrogen mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosamine, thiotepa); antimitoticescoe agents (for example Vinca alkaloids like vincristine, vinblastine, vindesine, vinorelbine, and taxoid, like Taxol, Taxotere); topoisomerase inhibitors (for example, epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, camptothecin, and irinotecan); as well as enzymes (for example asparaginase); and inhibitors timedilation (for example, raltitrexed);

and additional types of chemotherapeutic agents include:

(iv) biological response modifiers (for example the EP, interferon);

(v) antibodies (for example, edrecolomab);

(vi) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, antisense anti-ras;

(vii) gene therapy approaches, including for example approaches to replace abberant genes such as aberrant p53 or aberrantly BRCA1 or BRCA2, GDEPT (based therapy aimed at gene enzymatic procarcinogen funds) approaches such as those that use sitoindosides, timedancing or bacterial enzyme nitroreductase, as well as approaches to increase tolerantly patient to chemotherapy or radiotherapy such as gene therapy multilocational resistance; and

(viii) immunotherapy approaches, including for example ex vivo and in vivo approaches to increase the immunogenicity of tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or factor stimulation of colonies of granulocytes-macrophages, approaches to reduce the immunological tolerance of T cells, approaches using transfected immune cells such as transfetsirovannyh cytokines dendritic cells, approaches using transfected cytokines tumor cell lines and approaches using antiidiotypic antibodies.

(ix) mitotic inhibitors, for the example vinblastine;

(x) alkylating agents, such as cisplatin, carboplatin and cyclophosphane;

(xi) antimetabolites, such as 5-fluorouracil, cytosine arabinoside and hydroxyurea, or, for example, one of the dominant antimetabolites which are disclosed in the European patent EP 0239362 B1 (published April 12, 1991), such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoindole-6-ylmethyl)-N-methylamino-2-thenoyl)-L-glutamic acid;

(xii) inhibitors of growth factors; inhibitors of the cell cycle;

intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for example interferon; and antihormones such as antiestrogens such as Nolvadex™ (tamoxifen)or, for example anti-androgens such as Casodex™ (4'-cyano-3-(4-perpenicular)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide).

In particular, pharmaceutical compositions in accordance with this invention are used in combination with an effective amount of one or more substances selected from angiogenic agents, inhibitors of signal transduction and antiproliferative agents.

In a separate embodiment of antiangiogenic agents, such as inhibitors of MMP-2 (matrix metalloproteinase 2)inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, COX-II (collagenase II), can be used in combination with the pharmaceutical composition according to data from what Britanie. Examples of useful inhibitors of COX-II include CELEBREX™ (elecoxib), valdecoxib and alcoxyl. Examples of useful inhibitors of matrix metalloproteinases are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), the publication of the European patent EP 0818442 A2 (published January 14, 1998), European patent EP 1004578 B1 (issued February 25, 2004), WO 98/07697 (published 26 February 1998), WO 98/03516 (published January 29, 1998), WO 98/34918 (published August 13, 1998), WO 98/34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998), the publication of the European patent 606,046 (published 13 July 1994), the publication of the European patent 931,788 (published July 28, 1999), WO 90/05719 (published may 31, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (published 17 June 1999), international PCT application WO 99/07675 (published February 18, 1999), the European patent EP 0952148 B1 (issued may 12, 2004), a patent application in the UK No. 9912961,1 (filed June 3, 1999), time the application U.S. No. 60/148,464 (filed August 12, 1999), U.S. patent No. 5,863,949 (issued January 26, 1999), U.S. patent No. 5,861,510 (issued January 19, 1999) and the publication of the European patent 780,386 (published June 25, 1997), which are all put into this application in its entirety by reference. Desirable inhibitors of MMP-2 and MMP-9 is such which have a sky is Lishou inhibitory activity or no inhibitory activity against MMP-1. More desirable is those that selectively inhibit MMP-2 and/or MMP-9 relative to the other the matrix metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, Mmp-12 and Mmp-13).

Some specific examples of MMP inhibitors useful in this invention are AG-3340, RO 32-3555, RS 13-0830.

The dose of the Agent, which is required in the compositions in accordance with this invention for therapeutic or prophylactic treatment of a particular disease or medical condition (e.g., proliferative diseases), will need to vary depending on, for example, from the owner, which they were treated, and the severity of the disease, which is subjected to treatment. The number of active connections that you enter will depend on the subject, which they were treated, the severity of the disorder or condition, rate of administration, the nature of the connection and from the perspective of a doctor who prescribes a drug. However, the effective dose is in the range from about 0.01 to about 100 mg per kg of body weight per day, preferably from about 1 to about 35 mg/kg/day, in single or divided doses. For a person weighing 70 kg, this amount will be from about 0.7 to 7000 mg per day, preferably from about 70 to arr is siteline 2500 mg/day. In some cases, equal to doses that are lower than the lower bound of the specified interval will be more than adequate, while in other cases, higher doses can be used without any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day. A single dose of the composition, of course, will contain, for example, 1-500 mg of the active ingredient and preferably 5-150 mg of the active ingredient. It is assumed that the desired daily dose is in the range of 0.03 to 6 mg/kg

The invention is illustrated by the following non-limiting examples, where, if not specified otherwise, the "Agent" represents an acidic sulphate salt (2 hydroxyethoxy)amide-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid.

Brief description of figures

Figure 1 shows the results of x-ray powder diffraction for compositions that contain different amounts of the free base form of the Agent and the Agent (i.e. acidic sulphate salt), where the X-axis shows the 2-theta value and the Y-axis shows Lin (pulses). The data provide an indication of the level of definition of the form of the free base of the Agent in the composition using x-ray powder diffraction.

Figure 2 demo is helpful the x ray powder patterns for the compositions of the present invention, obtained after production, where the X-axis shows the 2-theta value and the Y-axis shows Lin (pulses). The data show that only the Agent (i.e. the form of the acid sulfate salt) is defined in the compositions.

Figure 3 shows the19F SS-NMR spectra, which are used to determine the approximate boundaries of the definition in the compositions of the free base form of the Agent in the vitamin E TPGS when using19F SS-NMR.

Figure 4 shows19F SS-NMR spectra of the composition of Example 1.2. The spectra show the absence of capable of determining the level of free base form of the Agent in the composition.

Figure 5 shows19F SS-NMR spectra of the composition of Example 1.3. The spectra demonstrate the absence of capable of determining the level of free base form of the Agent in the composition.

Example 1: Obtaining compositions in accordance tendered invention

Compositions presented in Table 1, was obtained by heating the matrix carrier to a temperature of 60-70°C using a thermostat. The temperature was maintained for approximately 2 hours to ensure complete melting of the material. Then gradually Agent was added and mechanically stirred at matrix media using a magnetic stirrer or homogenizer high add the ha The system is maintained at a sufficiently high temperature in order to maintain the mixture in the molten state during the stirring, which was continued to obtain a visually homogeneous mixture. Mixing time was varied depending on the particular composition, but in General ranged from 3 to 35 minutes. The resulting mixture is then brought to a receiver array capsules and left to cool to room temperature. The capsules were sealed and kept frozen until use.

Table 1
ExampleAgent (mg / capsule)Matrix media (mg / capsule)
1.112,10Vitamin E TPGS 107,90
1.230,25Vitamin E TPGS 119,75
1.36,05Vitamin E TPGS 113,95
1.460,36Vitamin E TPGS (71,06)
Gelucire 44/14 (71,49)
1.530,25 Vitamin E TPGS (107,78)
PEG 20000 (11,98)
1.630,25Vitamin E TPGS (107,78)
PEG 6000 (11,98)
1.730,25Gelucire 44/14 (119,75)

Example 2: Study of the stability of the compositions of the present invention by x-ray powder diffraction (XRPD)

The determination of the stability of the Agent (i.e. sulfuric acid salt) in the composition may be provided by XRPD. This technique is capable of simultaneous determination of the crystalline form of the free base of the Agent and the crystalline form of the acid sulfate salt Agent in the composition. Samples of the compositions were placed on a silicon base plate and analyzed using x-ray diffractometer Siemen''s D5000. The samples were subjected to scanning for 4 seconds 0.02° θ when using interval from 2° to 40° 2θ in continuous theta-theta mode.

Approximate limit of detection of crystalline forms of the free base of the Agent in the compositions in accordance with this invention was determined by obtaining compositions with different ratios of the number of crystalline forms of the free base of the Agent and the crystalline Agent (i.e. forms sulfuric acid which salt). These compositions were analyzed using XRPD. Figure 1 demonstrates that the form of the free base of the Agent is determined to 2.5% wt./weight. free base in vitamin E TPGS based on the composition, which nominally contains 21.2% of the weight./weight. Agent.

XRPD powder radiographs were obtained for each composition described in Examples 1.1, 1.2 and 1.3, directly after their production. These x-rays (shown in Figure 2) showed only the presence of the Agent (i.e. forms sulfuric acid salt).

Example 3: a Study of the stability of the compositions of this invention using NMR spectroscopy solid

The determination of the stability of the Agent in the compositions in accordance with this invention can be achieved when using19F NMR spectroscopy of solids (19F SS-NMR). This technique is capable of simultaneous determination of the crystalline form of the free base of the Agent and the crystalline form of the acid sulfate salt Agent in the composition. The form of the free base of the Agent and the Agent (i.e. the acid sulfate salt) provides an excellent and characteristic peaks of fluorine in the spectrum. These peaks can be integrated in the normal way for the NMR signals, and the ratio of the peaks is proportional to the ratio of the two present forms a solid status is status, that is, the form of the free base of the Agent and the Agent (i.e. forms sulfuric acid salt). Analysis of the compositions was carried out by placing the sample material 4 mm MAS (sample rotation under magic angle) of the rotor.19F NMR [376 MHz] spectrum with1N splitting of the composite pulse [TRM] were recorded on an Avance 400 spectrometer using 4 mm HFX (Bruker Biospin) probe. All samples were subjected to treatment at 12 kHz using pulse program "aringdec" (anti-ring cleavage). It should be noted that the friction force associated with the methodology of rotation of the sample under magic angle, can lead to heating of the sample by approximately 10°C-20°C above the temperature of the surrounding environment.

Approximate limit of detection of crystalline forms of the free base of the Agent in the compositions in accordance with this invention was determined by obtaining compositions with different ratios of the number of crystalline forms of the free base of the Agent and the crystalline Agent (i.e. forms sulfuric acid salt). These compositions were then subjected to analysis using the19F SS-NMR. NMR spectra are depicted in Figure 3, show that the form of the free base of the Agent is determined to the level of 1% wt./weight. free base in vitamin E TPGS based on the composition, which also contained 8.9% of the weight./weight. Agent (i.e. forms sulfuric acid salt).

The compositions described in Examples 1.2 and 1.3, were analyzed using19F SS-NMR after production, while there was no indication confirm the presence of the free base form of the Agent, see Figure 4 and Figure 5. Watched some heating of the samples in their analysis, which may lead to the appearance of the isotropic peak at -129,5 frequent. on million Without intent to associate it with any theory, we can say that the peak can be associated with (2 hydroxyethoxy)amidon 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid, dissolved in vitamin E TPGS, which is melted by heating of the sample.

Example 4. The stability of the compositions during storage

Study of the stability of the compositions described in Examples 1.2 and 1.3, for a period of time up to 12 months showed that they are stable at elevated temperatures and high humidity, if they are contained in white bottles made of high density polyethylene (HDPE) (induction sealed and contain a desiccant). No significant changes in data, relative stability for the compositions of Example 1.2 and 1.3 were not observed after 12 months of storage in HDPE bottles at 25°C/60% relative humidity (RH) and 30°C/65% 0 V, see data in Table 1 and Table 2.

Table 1
The composition of Example 1.3, which was kept in induction sealed HDPE bottles that contain a desiccant at 25°C/60% RH and 30°C/65% RH
AnalysisFirstAfter 12 months
25°C/60% RH
After 12 months
30°C/65% RH
DescriptionFlat, white capsules with edgeUnchangedUnchanged
Remedya 4.94,84,8
The composition ofand
The total number of organic pollutants identified by HPLC (% surface)0,64 (4)0,68 (4)0,67 (5)
DissolutionIn accordance with USPIn accordance with USPIn accordance with USP
Average 45 minutes (%)1079699
The relative standard deviation of 45 minutes (%)3,64,02,4
Water content (% wt./weight.)1,20,40,4
Polymorphic identity is determined using XRPDNot determined the form of the free base of the AgentNot determined the form of the free base of the AgentNot determined the form of the free base of the Agent
andWere expressed as mg equivalent of free base. Were analyzed using liquid chromatography with a gradient reverse phase and UV determining, using a column YMC-Pack ODS-AQ, 3 μm, 150×4, 6 mm (inner diameter), the diluent for sample 10% HS, 90% methanol.
Mobile phase A: 0.01% OF HFBA/1% IPA/Water (vol./about./vol.). Mobile phase b: 0.01% OF HFBA/1% IPA/ACN (about./about./vol.). Gradient: 0 min = 30%, 7,5 min = 30%, and 10.5 min = 36%, 16,5 min = 36%, 30,5 min = 90%, 33 min = 90%, 34 min = 30% B, 40 min = 30 C. The HPLC parameters: flow rate = 1.2 ml/min, column temperature = 40°C, wave length = 258 nm, the volume that is injected = 10 ml.

bThe total organic pollution included organic pollutants ≥0,05. Numbers given in parentheses refer to the number of organic pollutants, as defined in ≥0,05.

Table 2
The composition of Example 1.2, which was kept in induction sealed HDPE bottles that contain a desiccant at 25°C/60% RH and 30°C/65% RH
AnalysisFirstAfter 12 months
25°C/60% RH
After 12 months
30°C/65% RH
DescriptionFlat, white capsules with edgeUnchangedUnchanged
Remedy24,724,524,6
The composition ofand
The total number org. pollutants identified by HPLC (% surface)0,66 (4)0,74 (6)0,72 (6)
DissolutionIn accordance with USPIn accordance with USPIn accordance with USP
Average 45 minutes (%)1039798
The relative standard deviation of 45 minutes (%)2,13,6a 4.9
Water content (% wt./weight.)1,00,30,3
Polymorphic identity is determined using XRPDNot determined the form of the free base of the AgentNot determined the form of the free base of the AgentNot determined the form of the free base of the Agent
andExpr is whether in the form of mg equivalent to the free base. Were analyzed using liquid chromatography with a gradient reverse phase and UV determining, using a column YMC-Pack ODS-AQ, 3 μm, 150×4, 6 mm (inner diameter), the diluent for sample 10% HS, 90% methanol.
Mobile phase A: 0.01% OF HFBA/1% IPA/Water (vol./about./vol.). Mobile phase b: 0.01% OF HFBA/1% IPA/ACN (about./about./vol.). Gradient: 0 min = 30%, 7,5 min
= 30%, and 10.5 min = 36%, 16,5 min = 36%, 30,5 min = 90%, 33 min = 90%, 34 min = 30% B, 40 min = 30% C. the HPLC Parameters: flow rate = 1.2 ml/min, column temperature = 40°C, wave length = 258 nm, the volume that is injected = 10 ml.
bThe total organic pollution included organic pollutants ≥0,05. Numbers given in parentheses refer to the number of organic pollutants, as defined in ≥0,05%.

Example 5. The dissolution of the compositions in accordance with this invention

The way of dissolution in vitro was developed to analyze the behavior of the compositions contained in the receiver array capsules. The dissolution was carried out using the compositions shown below in Table 3.

The dissolution of the capsules was performed according to the General procedure using apparatus II United States Pharmacopeia (unit with mixer). Samples environment for dissolution were collected at different time points after EXT is the means of capsules and quantitatively evaluated concentrations (2-hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid by comparing their peak area response HPLC with such standard the solution, which was prepared at a level equivalent to 100% release of the connection. In this way used vessels made of transparent glass with a pointed end for dissolution, and spiral holders stainless steel used to strengthen capsules. Used 900 ml of pH 2.0 735 mosmol/l buffer solution phosphate based at 27°C and a stirring speed of 100 rpm./minute.

Table 3
The results of dissolution
TrackDissolve in 50 minutes (%)TrackDissolve in 50 minutes (%)
Example 1.1100The composition of comparison 1 (2% wt./weight. free base, 21.9% of Vah./weight. Agent (i.e. acidic sulfate salt))73 (45 min)
Example 1.299Composition comparison 2 (5% wt./weight. free base, 18.2% of the VAG./the weights. Agent (i.e. acidic sulfate salt))56 (40 min)
Example 1.3 (part 1)99 Composition comparison 3 (20% wt./weight. free base)41
Example 1.3 (part 2)95
Example 1.596
Example 1.6101
Example 1.795

In addition to the compositions described in Examples 1.1-1.3 and 1.5-1.7, made a few more songs for comparison when using mixtures of crystalline free base agent and a crystalline Agent (i.e. acidic sulfate salt). The mixture of these two forms was dispersible in vitamin E TPGS in accordance with methods similar to those described in Example 1, and made them into a receiver array capsules.

Data regarding the dissolution of the compositions of the comparison show that the dissolution decreases with increasing number of forms of the free base of the Agent in the composition. The decrease in dissolution to 17% after 50 minutes was observed in the composition containing the 2% wt./weight. the form of the free base of the Agent. Data obtained by analysis of the free base, which is contained in the composition for comparison showed that the dissolution method provides receiving of the indication of the level of the free base form of the Agent, which is present in the compositions. The results of dissolution for the compositions described in Examples 1.1-1.3 and 1.5-1.7, showed that it reached the dissolution rates of 95% or more, this suggests that in these compositions, the compound is substantially present in the form of its acid sulfate salt (i.e., an Agent).

Example 6. Additional compositions in accordance with this invention

Compositions presented in Table 4, were obtained by heating the matrix carrier in thermostat set to 70°C, for at least one hour. Gradually Agent was added and mechanically stirred at matrix media when using a mechanical stirrer or homogenizer, high shear. The system is maintained at a sufficiently high temperature in order to maintain the mixture in the molten state during mixing. Mixing was carried out to obtain a visually homogeneous mixture. Mixing time was varied depending on the composition, however, was at least 10 minute could be up to 60 minutes. The total weight of the system was varied from 3.75 g up to 75 g (as shown in Table 4). The resulting mixture was injected into a receiver array capsules and left to cool to room temperature and hardening. Capsules were stored or at room temperature, or frozen prior to use.

td align="center"> 15
Table 4
ExampleAgent (mg / capsule)Matrix media (mg / capsule)The total weight of the received party (g)
6.130,25Vitamin E TPGS (89,75)
Tween 80 (30,00)
3,75
6.230,25Vitamin E TPGS (89,75)
Cremophor EL (30,00)
3,75
6.330,25Vitamin E TPGS (89,75)
Pluronic-68 (30,00)
3,75
6.430,25Vitamin E TPGS (89,75)
PEG 1000 (30,00)
3,75
6.530,25Vitamin E TPGS (97,25)
PEG 1000 (22,50)
3,75
6.630,25Vitamin E TPGS (104,75)
PEG 1000 (15,00)
3,75
6.730,25Vitamin E TPGS (112,25)
PEG 1000 (7,50)
3,75
6.830,25 (API part 1)Vitamin E TPGS (119,75)3,75
6.930,25 API (part 2)Vitamin E TPGS (119,75)3,75
6.1030,25 API (part 3)Vitamin E TPGS (119,75)3,75
6.1130,25Vitamin E TPGS (269,75)7,5
6.1230,25Vitamin E TPGS (119,75)75
6.1315,12Vitamin E TPGS (134,88)75
6.14of 60.5Vitamin E TPGS (239,5)
6.1590,75Vitamin E TPGS (359,25)15

Example 7. The dissolution of the compositions in the environment for dissolution from pH 6.5

In vitro dissolution method, which uses the environment for dissolution with a pH of 6.5, was used to analyze the behavior of the compositions contained in the receiver array capsules. The method of dissolution at pH 6.5 was provided superior establishing differences in the presence of the free base form of the Agent in the compositions in comparison with the method described in Example 5. Dissolution in two-and three repetitions were performed on the compositions shown in Table 4, and the composition of Example 1.7.

The dissolution of the capsules was performed in accordance with the General procedure when using apparatus II United States Pharmacopeia (unit with mixer). Samples environment for dissolution were collected at different time points after addition of the capsules and quantitatively evaluated concentrations (2-hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid by comparing their peak area response HPLC with such a standard solution, which was prepared at a level equivalent to 100% release of the connection. In this way used vessels made of transparent glass with a pointed end for dissolution, and pyralinae holders stainless steel used to secure capsules. Used 1000 ml of medium for dissolution from pH 6.5 at 37°C and the stirring speed of 50 rpm./minute.

Environment for dissolution with a pH of 6.5 was prepared by adding 1.7 g of pellets of sodium hydroxide, 19,77 g of aqueous sodium dihydrophosphate (or 17,19 g anhydrous sodium dihydrophosphate) and 30,93 g of sodium chloride to 5 liters of deionized water. The pH was then brought to 6.5 with 1 M hydrochloric acid or 1 M sodium hydroxide.

In addition to the compositions described in Table 4, have produced a few more songs for comparison when using mixtures of crystalline free base agent and a crystalline Agent (i.e. acidic sulfate salt). The mixture of these two forms was dispersible in vitamin E TPGS in accordance with the method similar to that described in Example 6, and made them into a receiver array capsules. The specific formulations of the compositions for comparison shown in Table 5.

C1
Table 5
Comparative composition
ExampleAgent, the form of the free base/mg (% wt./weight.)The agent (i.e. the acid sulfate salt)/mg (% wt./weight.)Matrix media (mg)
0,605 mg (0.4% wt./weight.)29,645 mg (19,76% wt./weight.)Vitamin E TPGS (119,75)
C20.15 mg (0.1% wt./weight.)30,09 mg (grade of 20.06% wt./weight.)Vitamin E TPGS (119,76)
C30.075 mg (0.05% wt./weight.)30,165 mg (20,11% wt./weight.)Vitamin E TPGS (119,76)
C40,03 mg (0.02% wt./weight.)30,21 mg (20,14% wt./weight.)Vitamin E TPGS (119,76)

Data on dissolution for the comparative compositions (table 6) show that the dissolution decreases with increasing number of forms of the free base of the Agent in the composition. The reduction of dilution to 90% after 60 minutes was observed for compositions containing 0.4% wt./weight. the form of the free base of the Agent. In addition, the presence of 0.02 wt%./weight. the free base of the Agent caused a 13% decrease in dissolved after 60 minutes. Data obtained by analysis of the free base, which is contained in the comparative compositions showed that the method of dissolution at pH 6.5 provides a good indicator of the level of free-forms based what I Agent, which is present in the compositions.

Table 6
The results of dissolution for the comparative compositions in the environment for dissolution from pH 6.5
TrackDissolution in 60 minutes (%)
C110
C243
C378
C487

The results of dissolution for the compositions described in Example 6, as well as for the composition of Example 1.7 is presented in Table 7. A value greater than 96% dissolution in 60 minutes was achieved for all the compositions, this suggests that in these compositions, the Agent is present substantially in the form of its acid sulfate salt.

Table 7
The results of dissolution in the environment for dissolution at pH 6.5
The composition of ExampleDissolution in 60 minutes (%)HDMI is tion Dissolution in 60 minutes (%)
1.7996.8101
6.1986.9101
6.2986.10100
6.3966.1198
6.4976.1299
6.51026.1399
6.61006.1497
6.71016.1597

1. Pharmaceutical composition that includes an acidic sulphate salt (2 hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid and matrix media matrix where the carrier essentially consists of one is more pharmaceutically acceptable carriers, selected from the following groups:
(a) d-alpha-Tocopheryl polyethylene glycol 1000 succinate;
(b) poliglecaprone glycerides;
(c) polyethylene glycol (Page); and
(d) solid fats;
and where acid sulphate salt (2 hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid is dispersed in the matrix medium.

2. The pharmaceutical composition according to claim 1, where the matrix carrier essentially consists of one or more groups selected from the following groups:
A. d-alpha-tocopherylacetate 1000 succinate;
b. poliglecaprone glycerides; and
C. the glycol.

3. The pharmaceutical composition according to claim 1 or 2, where the matrix carrier essentially consists of one or both components:
A. d-alpha-Tocopheryl polyethylene glycol 1000 succinate; and
b. poliglecaprone of glycerides.

4. The pharmaceutical composition according to claim 1, where the matrix media is a d-alpha-Tocopheryl polyethylene glycol 1000 succinate or lauroyl macrogol-32 glycerides.

5. The pharmaceutical composition according to claim 1, where the matrix carrier is a mixture of d-alpha-Tocopheryl polyethylene glycol 1000 succinate and lauroyl macrogol-32 glycerides, and where lauroyl macrogol-32 glycerides are present in an amount which is approximately 30-55 wt.% component is trixera media composition.

6. The pharmaceutical composition according to claim 1, where the matrix media is a d-alpha-Tocopheryl polyethylene glycol 1000 succinate.

7. The pharmaceutical composition according to claim 6, where d-alpha-Tocopheryl polyethylene glycol 1000 succinate is present in an amount that is from about 65 to 95% by weight of the composition.

8. The pharmaceutical composition according to claim 1, where more than 90% of the total weight amount of acid sulphate salt (2 hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid, which is present in the composition is dispersed in the matrix medium.

9. The pharmaceutical composition according to claim 1, where the composition comprises from 5 to 30 wt.% acid sulphate salt (2 hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid.

10. The pharmaceutical composition according to claim 1, where the composition is semi-solid or solid at room temperature.

11. The pharmaceutical composition according to claim 1, where the acid sulfate salt (2 hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid is dispersed in the form of finely ground particles which are distributed in phase, which includes the matrix media.

12. The pharmaceutical composition according to claim 1, in which the cancel:
(i) from 15 to 25 parts of acid sulphate salt (2 hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid; and
(ii) 75 to 85 parts of vitamin E TPGS;
where both parts are by weight, and the sum of the parts (i)+(ii)=100;
and where acid sulphate salt (2 hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid is dispersed in the vitamin E TPGS, and the composition is semi-solid or solid at room temperature.

13. The pharmaceutical composition according to claim 1, which includes:
(i) from 18 to 22 parts of acid sulphate salt (2 hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid; and
(ii) from 78 to 82 parts of vitamin E TPGS;
where both parts are by weight, and the sum of the parts (i)+(ii)=100;
and where acid sulphate salt (2 hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid is dispersed in the vitamin E TPGS, and the composition is semi-solid or solid at room temperature.

14. The pharmaceutical composition according to claim 1, which includes:
(i) 19-21 parts of acid sulphate salt (2 hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid; and
(ii) 79-81 parts of vitamin E TPGS;
where both parts are by weight, and the amount of net assets the TEI (i)+(ii)=100; and where acid sulphate salt (2 hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid is dispersed in the vitamin E TPGS, and the composition is semi-solid or solid at room temperature.

15. The pharmaceutical composition according to claim 1, where the composition is a composition for oral capsules.

16. A method of obtaining a pharmaceutical composition according to claim 1, which includes the steps:
A. mixing and melting the components of the matrix carrier;
b. mixing the agent with the matrix carrier to obtain a homogeneous mixture; and
C. the making of the product of stage (b) in the capsule and cooling the mixture with the formation of a thick liquid, semisolid, or solid mass in the capsule.

17. A method of treating a warm-blooded animal (preferably a human), which suffers from a condition which may be subjected to treatment with sulfuric acid salt (2 hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid, which includes the introduction of the pharmaceutical composition according to any one of claims 1 to 15.

18. A method of treating cancer in warm-blooded animals (preferably in humans), which includes the introduction of the pharmaceutical composition according to any one of claims 1 to 15.

19. The pharmaceutical composition according to claim 1 for use as a medicinal product in which icenii state, which may be subjected to treatment with sulfuric acid salt (2 hydroxyethoxy)amide 6-(4-bromo-2-chlorpheniramine)-7-fluoro-3-methyl-3H-benzoimidazol-5-carboxylic acid.

20. The pharmaceutical composition according to claim 1 for use as a drug in the treatment of cancer.



 

Same patents:

Nanoemulsion // 2491917

FIELD: medicine.

SUBSTANCE: group of inventions refers to a nanoemulsion for active agent delivery, a method for preparing it, compositions containing it, and to using a nanoemulsion for preparing pharmaceutical compositions for local application and cosmetic compositions for skin application. The declared nanoemulstion contains a water ingredient and a carrier which contains a lipophilic ingredient in the amount of 0.1-15 wt %, a surfactant and isopropyl and/or 1-propyl alcohol. The average emulsified particle diameter makes less than 100 nm. The method for preparing the nanoemulsion involves mixing the water ingredient and carrier containing the lipophilic ingredient, surfactant and isopropyl and/or 1-propyl alcohol, for preparing the nanoemulsion at temperature 50-60°C. The invention also refers to the composition for photodynamic therapy containing the above nanoemulsion and the active agent representing 5-aminolevulinic acid, a derivative, a precursor and/or a metabolite thereof. The above composition is applied to prepare the drug substance for photodynamic therapy and to treat senile keratosis. What is also declared is a diagnostic composition for detecting the dividing cells which contains the nanoemulsion and 5-aminolevulinic acid. The invention also refers to a kit for photodynamic therapy which comprises the composition for photodynamic therapy and one ingredient specified in a photoresist coating, an agent for attaching the above coating or an agent for applying the composition.

EFFECT: invention provides better stability and intensified cell and tissue penetration of the nanoemulsion.

25 cl, 6 dwg, 9 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to immunology. What is presented is a low-immunogenicity anti-CD40 monoclonal antibody prepared of a chimeric 5D12 (ch5D12) antibody. There are also described: a nucleic acid, a cell and a cell culture for preparing the antibody according to the invention, a method for preparing it, a pharmaceutical composition, using the antibody for preparing a drug and a method for administering the antibody according to the invention to an individual for the purpose of relieving the symptoms of an autoimmune disease, an inflammatory disease, for the purpose of suppressing a graft rejection reaction and/or treating CD40-positive cancer.

EFFECT: what is described is a method for selecting the high-expression human anti-CD40 antibodies containing insertion, deletion, inversion and/or replacement of 1 to 5 amino acids as compared to the antibody according to the invention, and the antibody prepared by the above method for selecting.

31 cl, 21 dwg, 14 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to field of biotechnology and immunology. Claimed is antibody, specifically binding with form A FcγRIII (CD16) (FcγRIIIA, CD16A) and not-binding specifically with form B (FcγRIIIB, CD16B), its antigen-binding fragment and multi-specific antibody, which includes antigen-binding fragment of antibody by invention. Compositions, which contain antibody by invention or its antigen-binding fragment, and their application in treatment of autoimmune, inflammatory, inflectious diseases, allergy and cancer, as well as set for detection of FcγRIIIA are described. Polynucleotides, vectors and host cells and method of obtaining antibody by invention or its antigen-binding fragment are described.

EFFECT: claimed invention provides novel antibodies to FcγRIIIA and, in that way, can find further application in therapy of FcγRIIIA-mediated diseases.

51 cl, 24 ex, 8 dwg, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to polymorphous form of compound

,

which is characterised by picture of X-ray diffraction, including discriminatory peaks approximately 7.269, 9.120, 11.038, 13.704, 14.481, 15.483, 15.870, 16.718, 17.087, 17.473, 18.224, 19.248, 19.441, 19.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.681, 25.754, 26.777, 28.975, 29.609, 30.073 degree 2Θ. Invention also relates to method of obtaining polymorphous form of compound (IX), which includes processing of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-ylthiazol-2-ylamino)phenyl]benzamide with methanesulfonic acid at temperature from 20 to 80°C in solvent, selected from group, which includes methanol, ethanol, acetone, diethyl ether, dioxane and their mixtures.

EFFECT: obtaining polymorphous form of compound (IX), which remains dry at 80% relative humidity and thermodynamically stable at temperatures lower than 200°C.

7 cl, 3 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method of treating cancer in a patient, wherein the method involves administering a cancer-inhibiting amount of a compound of formula I into a patient's body. The method of treating cancer in the patient, including a human, wherein the method involves administering the cancer-inhibiting amount of a first compound of formula I or a physiologically acceptable salt thereof into the patient's body, wherein X represents CH or N, each R1 independently represents hydrogen or -CH2COR5; R5 represents hydroxy, optionally hydroxylated alkoxy, amino or alkylamino; each R2 independently represents the group ZYR6; Z represents a bond or the C1-3 alkylene or oxoalkylene group optionally substituted by the group R7; Y represents a bond, an oxygen atom or the group NR6; R6 is a hydrogen atom, the group COOR8, the alkyl, alkenyl, cycloalkyl, aryl or aralalkyl group optionally substituted by one or more groups COOR8, CONR82, NR82, OR8, =NR8, =O, OP(O)(OR8)R7 and OSO3M; R7 is hydroxy, the optionally alkoxylated or aminoalkyl group; R8 is a hydrogen atom or the optionally hydroxylated, optionally alkoxylated alkyl group; M is a hydrogen atom or one equivalent of a physiologically acceptable cation; R3 represents the C1-8 alkylene group, 1,2-cycloalkylene group or 1,2-arylene group, optionally substituted by R7; and each R4 independently represents hydrogen or C1-3 alkyl.

EFFECT: invention refers to a pharmaceutical composition for treating cancer in the patient, containing the compound of formula I, as well as to a kit for treating cancer.

23 cl, 3 ex, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new alkylthiopyrimidines of formula III or pharmaceutically acceptable salts thereof: In the compound III X represents a direct bond; R2 means hydrogen, halogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, -NR8aR8b or the group -SR3; each R3 independently represents (C1-C6)alkyl, optionally mono-, di- or trisubstituted by halogen; or (C3-C7)cycloalkyl; R4a and R4b represent hydrogen; R6 represents aryl; or heteroaryl; wherein aryl and heteroaryl are optionally substituted in a substituted position by one or more substitutes specified in a group consisting of (a) halogen; (b) cyano; (c) nitro; (a) hydroxy; (e) guanidino; (f) heteroaryl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy (k) -NR8aR8b; (1) -C(O)R9; (m)-C(O)NR8aR8b, (n) - OC(O)NR8aR8b; (o) -C(O)OR9; (p) -NR7C(O)0R9; (q) -NR7C(O)R9; (r) sulphamoyl; (s) (C1-C6) alkylsulphonyl; (t) (C1-C6)alkylaminosulphonyl; (i) di(C1-C6)alkylaminosulphonyl; (v) (C1-C6)alkyl, optionally mono-, di- or trisubstituted by halogen; (w) (C1-C6) alkoxy, optionally mono-, di- or trisubstituted by halogen; and (x)(C1-C6)alkylthio, optionally mono-, di- or trisubstituted by halogen R7 represents hydrogen. The other radical values are specified in the patent claim.

EFFECT: compounds possess CRTH2 (G-protein related chemoattractant receptor expressed on Th2 cells) antagonist activity and are applicable for treating and preventing the diseases related to CRTH2, including treating allergic diseases, eosinophil and basophile related diseases.

14 cl, 6 dwg, 1 tbl

Iap inhibitors // 2491276

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula: U1-M-U2, where U1 and U2 have general formula (I), where: G stands for: IVb IVd ive, and values M, X1, X2, R2, R3, R3', R4, R4', R5, R5', R6, R6', R7, Z7, Z2, Z3, Z4, Q2 are given in item 1 of the formula.

EFFECT: compounds can be applied for induction of apoptosis in cell.

37 cl, 13 dwg, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, and concerns using anti-CD40-antibodies in a combination with CHOP for treating diseases or conditions associated with neoplastic B cell growth, wherein the above disease or condition is resistant to a therapy using (i) CHOP, (ii) a chimeric monoclonal anti-CD20-antibody of rituximab or (iii) CHOP and rituximab in the form of the combination therapy, or a patient has shown recurrence following the therapy using (i) CHOP, (ii) the chimeric monoclonal anti-CD20-antibody of rituximab or (iii) CHOP and rituximab in the form of the combination therapy.

EFFECT: group of inventions provides synergistic therapeutic action ensured by using the combination according to the invention.

26 cl, 4 ex, 6 dwg, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method of increasing the therapeutic efficacy of curcuminoids and analogues thereof. The cosmetic method for uniform skin tanning for patients suffering psoriasis without hyperpigmentation comprising administering curcumine or its derivatives orally in a combination with exposure to ultraviolet under certain conditions. The cosmetic method for uniform skin tanning for patients suffering vitiligo without hyperpigmentation comprising administering curcumine or its derivatives orally in a combination with exposure to ultraviolet under certain conditions. Using the pharmaceutical composition comprising curcumin and its analogues applicable in treating psoriasis of a moderate to severe degree of severity in a combination with visible exposure under certain conditions.

EFFECT: methods are effective for uniform skin tanning and psoriasis treatment.

6 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely oncology and concerns treating lung cancer. That is ensured by 6 therapeutic sessions every 21 day according to the scheme: the patient is exposed to hyperbaric oxygenation at pressure 1.3 atm, 30 min daily for 5 days; and then chemotherapeutic preparations are administered as follows: on the 6th day, kemoplat dissolved in 0.9% sodium chloride is administered in a dose of 75 mg/m2 of the patient's body; on the 6th, 8th and 10th days, phytoside 120 mg/m2 of the patient's body dissolved in 0.9% sodium chloride is administered.

EFFECT: dose schedule of the chemopreparations in a combination with the hyperbaric oxygenation provides reducing such side effects of the chemotherapy as leukopenia and anaemia that in turn enables the following sessions of chemotherapy in the prescribed time and thereby increasing the clinical effectiveness in lung cancer.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a method of sublimation dehydration of high-disperse biologically active materials found in a microdrop state characterised by the fact that the microdrop powder is frozen at temperature -35°C to -45°C for 1.5 to 8 h, and then dehydrated.

EFFECT: invention provides reduced duration of the dehydration process of biologically active materials.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and represents a method for producing fine-grained biologically active materials containing active substances, characterised by the fact that the liquid with biologically active substances is dispersed to the microdrop state in a layer of dry fine-grained inert hydrophobic aerosil in the proportion 10:1.5 to 10:6, to form thereby liquid microdrops surrounded by hydrophobic aerosil particles and powdered which, if necessary, are dried by a technologically acceptable method.

EFFECT: invention provides increasing dispersion of biologically active materials.

11 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a method for making slow-release microspheres containing a biodegradable polymer as a carrier and a drug, and to the drug-loaded microspheres made by the specified method. The method provides spraying in the dry chamber of a solution, suspension or emulsion containing the biodegradable polymer, a drug and a solvent, and air-drying of the solvent to prepare the spray-dried microspheres. The prepared microspheres are dispersed in an aqueous solution containing polyvinyl alcohol to remove a residual solvent and to improve the dispersibility of the microspheres, and the dried microspheres are removed from the aqueous solution.

EFFECT: method allows to make microspheres with high effective drug encapsulation without residual toxic solvent and the improved syringe needle permeability.

11 cl, 3 dwg, 5 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, and concerns an oral drug delivery system including biliquid foam containing continuous hydrophilic phase 1 to 20 wt %, pharmaceutically acceptable oil 70 to 98 wt % producing discontinuous phase. A slightly water-soluble drug 0.1 to 20 wt % is dissolved or dispersed in said pharmaceutically acceptable oil. The drug delivery system also contains biliquid foam with included surface-active substance 0.5 to 10 wt % to produce stable biliquid foam with all the amounts specified in percentage of total composition.

EFFECT: drug delivery system ensures high bioavailability of slightly water-soluble oral drugs.

22 cl, 16 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: agent for prevention and alcoholism treatment contains admixture of amidocyanogen and polylactide in the ratio (wt) from 10:90 till 40:60. The method of prevention and alcoholism treatment consists that to the patient, as a rule, enter intramusculary a solution containing an admixture amidocyanogen and polylactide in a single dose of 0.5-1.5 g once a month.

EFFECT: appreciable effect of delay and slow liberation of the operating beginning.

4 cl, 3 dwg, 2 tbl, 3 ex

FIELD: medicine; ophthalmology.

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

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

57 cl, 9 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with peroral liquid compositions which could be designed into gelatinous capsules. The suggested pharmaceutical composition includes a pharmaceutically active agent, a solubilizing agent and, not obligatory, a surface-active substance and a plastifying agent. The pharmaceutically active agent has got, at least, one acidic fragment, preferrably, that of carbonic acid being chosen out of the group of non steroid antiphlogistic preparations being acid-soluble at acid : dissolved substance ratio being from 3:1 to 10000:1. New compositions provide increased rates and degrees of absorption of pharmaceutically active agent and minimize side effects caused by such active substances.

EFFECT: higher efficiency of application.

42 cl, 39 ex

The invention relates to the field of molecular biology

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for outpatient treatment and prevention of the cardiovascular diseases, containing therapeutic amounts of a vasodilator, a renin-angiotensin system inhibitor, a thrombocyte aggregation inhibitor, a cholesterol-lowering agent, and an antihypoxic agent. As a vasodilator, the declared composition contains an agent possessing α-adrenergic receptor antagonist action, and a thrombocyte aggregation inhibitor is presented by an ADP-dependent thrombocyte activation mechanism blocking agent.

EFFECT: invention provides the integrated therapeutic effect on the cardiovascular system after acute administration that improves the compliance with treatment regimen by the patient.

20 cl, 1 tbl, 15 ex

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