Composition with fast medication release, including granules of moisture-sensitive medication, obtained by granulation from melt, and method of obtaining it

FIELD: medicine.

SUBSTANCE: pharmaceutical composition of fast release includes granules obtained by granulation from melt. Granules contain DPP-IV inhibitor and meltable hydrophobic component with ratio from 1:1 to 1:10 (per dry weight). At least 90% of granule surface are covered with meltable hydrophobic component. Granules release approximately 50% of DPP-IV inhibitor during 30 minutes after peroral introduction of medication. DPP-IV inhibitor is N-(substituted glicyl)-2-cyanopyrrolodin or its pharmaceutically acceptable salt. Preferably DPP-IV is (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyanopyrrolidin.

EFFECT: composition for fast release according to invention possesses improved stability in presence of moisture in comparison with known compositions for controlled or prolonged release.

20 cl, 9 tbl, 10 ex

 

The technical field

The present invention relates to pharmaceutical compositions with quick release medicines, including moisture-sensitive therapeutic agent and fusible hydrophobic component. The present invention also relates to methods of producing such pharmaceutical compositions quick release of the drug.

Background of invention

The sensitivity to moisture of therapeutic connection limits its commercial value. The inclusion of hygroscopic moisture sensitive therapeutic compounds in pharmaceutically acceptable compositions intended for oral administration leads to significant problems, such as therapeutic compounds are characterized by chemical instability. This chemical instability is most evident in the application of moisture-sensitive therapeutic compound in the composition of the dosage form, including excipient with a high equilibrium moisture content. In this case, the moisture migrates from such excipients and can cause hydrolysis of moisture-sensitive therapeutic compound.

To minimize chemical instability, moisture-sensitive therapeutic compound is subjected to granulation of rspl the VA, the so-called thermoplasty. Granulation of the melt process includes mixing and heating of a solid and/or semi-solid material in the presence of therapeutic compounds, thus obtain granules containing particles of therapeutic compounds covered by solid and/or semi-solid material.

However, the method of granulation of the melt is also used to obtain pharmaceutical compositions with a slow or controlled release of the drug. Currently, there is a need in the pharmaceutical composition, which comprises granules obtained by granulating the melt, but have the property of rapid release of the drug. The present invention relates to such pharmaceutical compositions.

Summary of the invention

The present invention relates to pharmaceutical compositions intended for oral administration of moisture-sensitive therapeutic compound. The composition comprises granules of moisture-sensitive therapeutic compound and fusible hydrophobic component, obtained from the melt. Such pharmaceutical compositions allow to increase the chemical stability of therapeutic compounds, primarily, in the presence of moisture or water. In addition, the pharmacist is ical composition of the present invention are compositions with quick release medicines and do not have the properties of compositions with delayed or controlled-release of drug tools.

Another object of the present invention includes a method of producing granules of therapeutic compounds and fusible hydrophobic component obtained by granulation of the melt. This method mainly includes the following stages:

(a) obtaining a mixture of moisture-sensitive therapeutic compound with at least one fusible hydrophobic component,

(b) heating the resulting mixture at a temperature of above, near or substantially equal to the melting point of the specified fusible hydrophobic component or melting range of the specified component,

(C) granulating the obtained mixture under stirring with a high shear with the formation of granules and

(g) cooling the obtained pellets to room temperature. Another object of the present invention relates to pharmaceutical compositions comprising particles of moisture-sensitive therapeutic compound, completely or substantially completely coated with fusible hydrophobic component. Moisture-sensitive therapeutic compound is, for example, the inhibitor of DPP-IV.

Detailed description of embodiments of the invention

The present invention relates to a method for producing dosage forms of moisture-sensitive therapeutic compound with quick release drug what about the tools, which include granules moisture-sensitive therapeutic compound and fusible hydrophobic component obtained by granulation of the melt.

The term "pharmaceutical composition", as used in the present description, means a mixture or solution containing moisture-sensitive therapeutic compound intended for administration to a mammal such as a human, for the prevention or treatment of a specific disease or pathological condition in a mammal.

The term "therapeutic compound"as used in the present description, refers to any compound, substance, drug product, drug or active ingredient which has a therapeutic or pharmacological properties and is suitable for administration to a mammal, such as man, in the composition, which is primarily suitable for oral administration.

Examples of classes of therapeutic compounds include, but are not limited to, antihypertensives, antianxiety agents, anticoagulants, anti-convulsants, agents that reduce the levels of blood glucose, anti-inflammatory remedies, antihistamines, antitussives, anti-cancer drugs, beta-blockers, anti-inflammatories, antipsychotics what their agents, amplifiers cognitive function, antiatherosclerotic agents, agents that reduce cholesterol, anti-obesity agents against autoimmune disorders, anti impotence, antibacterial and antifungal agents, sleeping pills, antibiotics, antidepressants, antiviral agents, and combinations thereof.

The pharmaceutical compositions of the present invention include a therapeutic compound(I) in a therapeutically effective amount or concentration. The term "therapeutically effective amount or concentration known in the art, refers to the amount or concentration of therapeutic compound, which depends on the nature of therapeutic compound and disease, designed for treatment. For example, the number of therapeutic compounds of the present invention in the pharmaceutical composition is up to about 20 wt.%, for example, from about 0.05 wt.% based on the weight of the pharmaceutical composition. The amount of therapeutic compound in the pharmaceutical composition may also comprise from about 0.5 wt.% up to 15 wt.% based on the weight of the pharmaceutical composition, for example, from about 1.5 wt.% to about 5 wt.%.

The term "moisture-sensitive therapeutic connect the tion", used in the present description, refers to a therapeutic compound that undergoes spontaneous decomposition, for example, is hydrolyzed in the amount of at least 1 wt.% when interacting with water. Thus, the moisture-sensitive therapeutic compound in most cases are decomposed by direct interaction with eccipienti high or high equilibrium water content. Accipient high or high equilibrium water content of the present invention contains more than 5% moisture at 25°C and 75% relative humidity (OB). For example, such eccipienti include, without limitation, microcrystalline cellulose, pre-gelatinizing starch, corn starch, and povidone.

The most important therapeutic compounds of the present invention are inhibitors of dipeptidylpeptidase IV (DPP-IV), above all, N-(substituted glycyl)-2-cyanopyrrolidine, as described in U.S. patent No. 6011155 and 6166063 (patent '063), which are included in this description as a reference. These compounds and their corresponding pharmaceutically acceptable acid salt additive is used to treat disorders such as non-insulin-dependent diabetes mellitus, arthritis, obesity, allograft transplantation and calcitonin-osteoporosis. In addition to t the th, it is assumed that in connection with the properties glucagonomas peptides, such as GLP-1 and GLP-2, and their participation in the process of inhibiting DPP-IV, the compounds of the present invention can be, for example, sedative or anxiolytic properties, or to reduce postoperative catabolic changes and hormonal responses to stress, or to reduce mortality and morbidity after myocardial infarction, or they can be used for the treatment of diseases associated with these disorders mediated by altering the levels of GLP-1 and/or GLP-2.

In more detail, for example, compounds that are inhibitors of DPP-IV, according to the present invention, and their corresponding pharmaceutically acceptable acid additive salts accelerate the production of insulin at an early stage in response to oral glucose and, thus, are suitable for the treatment of non-insulin-dependent diabetes mellitus.

An example of such a compound includes monohydrochloride [S]-1-[2-(5-cyano-2-pyridinylamino)ethylamino]acetyl-2-carbonitrile formula (I)

The specified monohydrochloride formula (I) (in the present description "compound I") is described in scheme 2 in the article Villhauer, etc., J. Med. Chem., Vol.45, No. 12, SC-2365 (2002), which is incorporated in this description by reference. Compound I is sensitive to the lag of therapeutic compound. When the humidity is above 75% connection I absorbs water and begins to dissolve in the absorbed water, in addition, compound I is decomposed in acidic and basic medium with formation of a cyclic product amidation of cycloimide ("CI"), which is the main product of decomposition of the compounds I.

Another example is N-(substituted glycyl)-2-cyanopyrrolidines of the present invention includes compounds of formula (II)

where

R is substituted and substituted

n is from 0 to 3,

in free form or in the form of an acid additive salt.

The term "substituted substituted"used in the present description, refers to 1 - or 2-substituted, substituted by one or more substituents, for example, the two substituents selected from the group comprising alkyl, -OR1or-NR2R3where R1, R2and R3independently mean hydrogen, alkyl, C1-C8alkanoyl, carbamyl or-CO-NR4R5where R4and R5independently signify alkyl, unsubstituted or substituted aryl, and one of R4and R5in addition, means hydrogen, or R4and R5together mean With2-C7alkylen.

The term "aryl", as used in the present description, means phenyl. Substituted phenyl, first of all, means phenyl, substituted by one or more for what estately, for example, the two substituents selected from the group comprising alkyl, alkoxy, halogen and trifluoromethyl.

The term "alkoxy"used in the present description, means alkyl-O-.

The term "halogen", as used in the present description, means fluorine, chlorine, bromine and iodine.

The term "alkylene"used in the present description, means a straight hydrocarbon chain containing from 2 to 7 carbon atoms, for example, from 3 to 6 carbon atoms, or in another embodiment, a 5 carbon atoms.

One group of compounds of the present invention includes compounds of formula (II), in which the substituent in the composition Adamantine groups attached to the main chain or fragment to the methylene adjacent to the main part of the circuit. The compounds of formula (P), where the remainder of glycyl-2-cyanopyrrolidine attached to the main piece of chain, contain substituent R' in structure adamantly group, which means, first of all, 3-hydroxy. The compounds of formula (II), where the remainder of glycyl-2-cyanopyrrolidine attached to the methylene adjacent to the main part of the chain, contain substituent R' in structure adamantly group, which means, first of all, 5-hydroxy.

The present invention primarily relates to the compound of formula (IIA) (in the present description "connection IIA) or formula (RO) (in the present description "connection IIB"),

or

where

R' represents hydroxy, C1-C7aloxi,1-C8alkanoyloxy or R5R4N-CO-O-, where R4and R5independently mean C1-C7alkyl or phenyl, which is unsubstituted or substituted by a Deputy selected from the group comprising From1-C7aklil,1-C7aloxi, halogen and trifluoromethyl, and R4in addition, means hydrogen, or R4and R5together mean With2-C7alkylen and

R ' means hydrogen or

R' and R" independently denote With1-C7aklil,

in free form or in the form of a pharmaceutically acceptable acid additive salt.

These compounds of formula (II), (IIA) or (IIB), which are inhibitors of DPP-IV, known in the art and described in the patent '063. These compounds are in free form or in the form of an acid additive salt. Pharmaceutically acceptable, i.e. non-toxic and physiologically acceptable salts are primarily suitable for use, with other salts are also suitable for use, for example, in the process of separation or purification of the compounds of the present invention. Acid additive salts include hydrochloride, and salt methansulfonate, sulfuric, phosphoric, citric, lactic and MC is usnei acids are also suitable for use.

First of all, the compounds of formula (II), (IIA) or (IIB), suitable for use, include (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine formula (in the present description "connection IIC")

and not necessarily its pharmaceutically acceptable salt.

The amount of the daily dose of the compounds of PS is, for example, in the range from about 10 mg to about 150 mg, about 24 mg to 100 mg, and from about 50 mg to 100 mg of the Amount of waste dose oral administration of a medicinal product is, for example, 25 mg, 30 mg, 35 mg, 45 mg, 50 mg, 55 mg, 60 mg, 80 mg or 100 mg Therapeutic compound is administered up to three times per day or once or twice per day.

Inhibitors of DPP-IV, suitable for use, as described in the Examples in U.S. patent No. 6124305 and No. 6107317 and in PCT applications WO 98/19998, WO 95/15309 and WO 98/18763, which are included in this description as a reference. These examples include 1-[2-[(5-cyano-2-yl)aminoethylamino]acetyl-2-cyano-(S)-pyrrolidine and (2S)-1-[(2S)-2-amino-3,3-dimethylbutanol]-2-pyrrolidinecarbonyl.

In yet another embodiment, the present invention proposes an inhibitor of DPP-IV according to the present invention, which is N-peptidyl-O-aroylhydrazines or its pharmaceutically acceptable salt. Aroyl means, for example, afterburner or benzoyl, the cat is which is unsubstituted or mono - or disubstituted, for example, groups (ness.)alkoxy, (ness.)alkyl, halogen or preferably nitro. The remainder of the peptidyl preferably includes two α-amino acids, e.g. glycine, alanine, leucine, phenylalanine, lysine, or Proline, one of which is attached directly to the nitrogen atom of the hydroxylamine, and is primarily a Proline.

For example, N-peptidyl-O-aroylhydrazines is a compound of formula (IV)

where

j is 0, 1 or 2,

Rε1means a side chain of natural amino acids and

Rε2means (ness.)alkoxy, (ness.)alkyl, halogen or nitro,

or its pharmaceutically acceptable salt.

In another embodiment, the present invention features N-peptidyl-O-aroylhydrazines, which is a compound of formula (IVA)

or its pharmaceutically acceptable salt.

N-Peptidyl-O-aroylhydrazines, for example, formula (IV) or (IVA) and obtaining them are described in the article Demuth, etc., J. Enzyme Inhibition, vol. 2, her. 192-142 (1988), which is incorporated in this description by reference.

In other embodiments, implementation of the present invention provides inhibitors of DPP-IV, which include N-substituted adamantylamine-2-cyanopyrrolidines, N-(substituted glycyl)-4-cyanopyrrolidine, N-(N'-substituted glycyl)-2-cyanopyrrolidines, N-aminoazo thiazolidine, N-AMINOETHYLPIPERAZINE, L-ALLO-solicitation, L-threo-isolatin1encoding and L-ALLO-isolatin1encoding, 1-[2-[(5-cyano-2-yl)amino]ethylamino]acetyl-2-cyano-(8)-pyrrolidin and their pharmaceutically acceptable salts.

In yet another embodiment, the present invention also provides inhibitors of DPP-IV according to the present invention, which include inhibitors of DPP-IV, described in the article by Patel and others, Exp.Opin. Invest. Drugs, vol.12, No. 4, SS. 623-633 (2003), paragraph 5, which is incorporated in this description by reference, first of all, such as R/98, 364, FE-999011, BDPX, NVP-DDP-728 and other

Connection FE-999011 also described in PCT application WO 95/15309 as connection No. 18.

Connection R/98 or R (CAS number: 251572-86-8), also known as 3-[(2S,3S)-2-amino-3-methyl-1-oxobutyl]thiazolidin described in PCT application WO 99/61431 called Probiodrug, can be used in the form of a mixture, 2:1, two compounds, 3-[(28,38)-2-amino-3-methyl-1-oxobutyl]thiazolidine and (2E)-2-butenedioate shown below

In another embodiment, the present invention provides inhibitors of DPP-IV according to the present invention, which include inhibitors of DPP-IV, described in PCT applications WO 04/037169 in examples 1-48, WO 02/062764 in the examples 1-293 and WO 04/024184, which are included in this description as a reference. The examples described in the above post is forged applications include 3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-ethanolinduced and 2-{[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-ethanolic]oxy}acetamide", she described on page 7.

Other inhibitors of DPP-IV are described in PCT application WO 03/004498 in examples 1-33. In yet another embodiment, the present invention features a compound of formula (V), example 7, known as MK-0431.

Inhibitors of DPP-IV according to the present invention are also described in the article Ashton, Bioorg. Med. Chem. Lett., t, s-863 (2004), especially suitable are the connection 1 or connection e (see table 1) and the compounds listed in tables 1 and 2. Suitable for use with inhibitors of DPP-IV is also described in PCT application WO 04/037181, which is incorporated in this description by reference, especially suitable are compounds presented in examples 1-33, and most preferably the compounds described in the claims in p-5.

The term "rapid release of drugs"used in this description, means the rapid release of the principal amount of therapeutic compound, for example, more than about 50%, about 60%, about 70%, about 80% or about 90% within a relatively short period of time, for example, within 1 h, 40 min, 30 min or 20 min, the donkey oral administration of the drug. First of all, most preferably the speed of release of the drug is release at least about 80% of therapeutic compound within 30 minutes after oral administration of the drug. The speed of release of drugs for a specific therapeutic compounds known to specialists in this field of technology.

The term "controlled release of drugs"used in the present description, means a gradual, but continuous or delayed release of therapeutic compound after oral administration of a medicinal product for a relatively long period of time that begins after hitting a pharmaceutical composition in the stomach, in which the pharmaceutical composition begins to disintegrate into its constituent components. The release of drug can continue both before and after exposure of the pharmaceutical composition in the intestine. The term "controlled release of drugs" also means slow release of drugs, in which the release of therapeutic compound does not begin directly after hitting a pharmaceutical composition in the stomach, and nachine is camping after a certain period of time, for example, after exposure of the pharmaceutical composition in the intestine, in which the increase of pH contributes to the release of therapeutic compounds of the pharmaceutical composition.

The term "hydrophobic"as used in this description in connection with the term "fusible component"means that the fusible component is more comparable with oils, not water. A substance having a hydrophobic properties, is insoluble or practically insoluble in water, but readily soluble in oil or other non-polar solvents.

The term "fusible component used in the present description, means a substance or mixture of substances which are solid or semi-solid substances at room temperature (approximately 25°C) and have a relatively low melting point, for example, from approximately 30°to approximately 100°C. or from about 50°to about 80°C. Such fusible components when heated approximately at a temperature of about or equal to the melting temperature or temperature range of the melting transition from solid to liquid. The term "range melting point"used in the present description, means a temperature range from low temperature at which it begins to form the first to the Plage liquid from solids, to a higher temperature at which the solid is completely in the liquid state.

Examples of hydrophobic fusible component include, without limitation, esters, hydrogenated oils, natural waxes, synthetic waxes, hydrocarbons, fatty alcohols, fatty acids, monoglycerides, diglycerides, triglycerides and mixtures thereof. Examples of esters, such as glyceriae esters include, without limitation, glycerylmonostearate, for example, the product CAPMUL GMS firm Abitec (Columbus, OH), glycerylmonostearate, acetylated glycerylmonostearate, servicemonitor, for example, the product ARLACEL 60 by Uniqema (New Castle, DE), and cetylpalmitate, for example, the product CUTINA CF company Cognis Corp.(Dsseldorf, Germany). Examples of hydrogenated oils include, without limitation, gidrirovannoe castor oil, for example, the product CUTINA HR company Cognis Corp, gidrirovannoe cottonseed oil, gidrirovannoe soybean oil and gidrirovannoe palm oil. Examples of waxes include, but are not limited to, Carnauba wax, beeswax and spermaceti wax. Examples of hydrocarbons include, without limitation, microcrystalline wax and paraffin. Examples of fatty alcohols, i.e. non-volatile alcohols with higher molecular weight, containing from about 14 to about 31 atomo the carbon include, but are not limited to, cetyl alcohol, for example, the product CRODACOL C-70 firms Corp Croda.(Edison, NJ), stearyl alcohol, for example, the product CRODACOL S-95 company Croda Corp., lauric alcohol and ministerului alcohol. Examples of fatty acids which contain from about 10 to about 22 carbon atoms, include, without limitation, stearic acid, for example, the product HYSTRENE 5016 company Crompton Corp.(Middlebury, CT), dekanovu acid, palmitic acid, lauric acid and myristic acid.

The number of fusible hydrophobic component is, for example, from about 1 wt.% to about 70 wt.% based on the weight of the pharmaceutical composition, from about 10 wt.% to about 60 wt.% and from about 20 wt.% to about 40 wt.%.

The term "granulation of the melt used in the present description, comprises the following stages:

(a) obtaining a mixture of moisture-sensitive therapeutic compound and at least one fusible hydrophobic component,

(b) heating the resulting mixture at a temperature of above, near, almost near the melting point of the hydrophobic fusible component or in the range of the melting temperature, i.e. in the range of 10°C, while stirring with a high shear formed granules, and

(C) cooling the product is s granules with a controlled rate to room temperature.

The heating and mixing of moisture-sensitive therapeutic compound and fusible hydrophobic component with the formation of pellets from the melt is carried out, for example, using a granulator with a fluidized bed or reactor with a high speed shear mixing. The amount of the hydrophobic component is, for example, from about 40 wt.% to about 95 wt.% based on the weight of the composition of the granules, from about 50 wt.% to about 80 wt.% and from about 60 wt.% to about 75 wt.%. Similarly, the number of moisture-sensitive therapeutic compound is, for example, from about 5 wt.% to about 60 wt.% based on the weight of the composition of the granules obtained by granulating the melt, from about 20 wt.% to about 50 wt.% and from about 35 wt.% to approximately 40%.

Obtained from melt granules include, for example, particles of moisture-sensitive therapeutic compound, covered or substantially covered (for example, at least 90% of the surface area of the particles) fusible hydrophobic component. The resulting coating is, for example, continuous or intermittent, and homogeneous or inhomogeneous barrier covering the particles of therapeutic connection.

In addition, in another in which the approaches of the present invention offers received from melt granules, which include particles of moisture-sensitive therapeutic compound encapsulated or substantially encapsulated in a fusible hydrophobic component. Such encapsulated granules comprise particles of a therapeutic compound that is compatible with other particles of moisture-sensitive therapeutic compound, covered with fusible hydrophobic component.

Examples of the mixer with a high shear include, without limitation, a mixer with a high shear, high speed mixer, high speed pellet mill or extruder for pelletization of the melt. The method of granulation of the melt granules described in more detail below.

After the formation of pellets from the melt them processed into dosage forms suitable for oral administration, for example, conventional solid dosage forms for oral administration such as tablets, pills, lozenges, microtablets, capsules or sachets. Such a standard dosage forms for oral administration include standard eccipienti used in the pharmaceutical industry. Examples of such excipients include, without limitation, dezintegriruetsja agents, binders, sizing, glidant, stabilizers, fillers and diluents. Specialists in the art can select the ü one or more of the above excipients depending on the desired properties of the conventional solid dosage forms for oral administration after routine experimentation. The amount of each used excipient is in the range known in the art. Methods and eccipienti used to obtain a standard dosage forms for oral administration described in the books The Handbook of Pharmaceutical Excipients, 4th edition, ed Rowe and others, American Pharmaceuticals Association (2003) and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro ed, Lippincott Williams & Wilkins (2003).

Examples of pharmaceutically acceptable dezintegriruetsja agents include, without limitation, starches, clays, cellulose, alginates, gums, crosslinked polymers, for example, crosslinked polyvinylpyrrolidone or crosspovidone, e.g., POLYPLASDONE XL firms International Specialty Products (Wayne, NJ), sodium salt of cross-linked carboxymethylcellulose, or sodium salt of cross-linked croscarmellose, for example, the product AC-DI-SOL company FMC, and calcium salt of cross-linked carboxymethyl cellulose, polysaccharides of soybean and guar gum. The number dezintegriruetsja agent is, for example, from about 1 wt.% to about 20 wt.% based on the weight of the composition, from about 5 wt.% to about 10 wt.%, for example, about 5 wt.%.

Examples of pharmaceutically acceptable binding agents include, without limitation, starches, cellulose and derivatives thereof, for example, microcrystalline cellulose, product AVICEL PH company FMC (Philadelphia, PA), hydroxyprop is cellulose, hydroxyethyl cellulose and hypromellose, product METHOCEL from Dow Chemical Corp.(Midland, MI), sucrose, dextrose, corn syrup, polysaccharides and gelatin. The amount of coupling agent is, for example, from about 5 wt.% to about 50 wt.% based on the weight of the composition, for example, from about 10 wt.% up to 40 wt.%.

Examples of pharmaceutically acceptable oil and pharmaceutically acceptable glidants include, without limitation, colloidal silica, magnesium trisilicate, starch, talc, trehzameshchenny calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered and microcrystalline cellulose. The amount of the lubricant is, for example, from about 0.1 wt.% to about 5 wt.% based on the weight of the composition, the number of glidant is, for example, from about 0.1% to about 10 wt.% based on the weight of the composition.

Examples of pharmaceutically acceptable excipients and pharmaceutically acceptable diluents include, without limitation, powdered sugar, pressed sugar, dextrans, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc. The number of napolnitelei/or diluent in the composition is, for example, from about 15 wt.% to about 40 wt.% based on the weight of the composition.

For solid dosage forms for oral administration with rapid release of drug from the granules obtained by granulating the melt, first receive moisture-sensitive therapeutic compound and fusible hydrophobic component, which in a mixture or separately sieved, thus receive the particles of each material of the maximum size. The required size of the particles of each material are determined by experts in the art depending on the specific pharmaceutical composition. For example, suitable particle sizes are less than 1000 microns, 750 microns, 500 microns or 250 microns.

Moisture-sensitive therapeutic compound and fusible hydrophobic component are mixed in a ratio in the range from 1:0.25 to 1:1 or 1:10 (based on the weight in dry state), or more preferably in the range of from 1:1 to 1:4 (calculated as weight in the dry state) in the reactor with jacket, equipped with, for example, a mixer with high shear. The mixture is heated, for example, when the supply of steam to the jacket to a temperature near, almost near or equal to the melting temperature fusible hydrophobic component or above the range of the melting temperature fusible hydrophobic component. the received mixture is maintained at elevated temperature and is stirred for a certain period of time, sufficient to obtain a substantially homogeneous granular product. After the formation of the substantially homogeneous granular product granulated mixture is cooled, for example, when the supply of cold water in the jacket, before solidification of the mixture. Hardened granulated mixture is slowly cooled in the reactor jacket to room temperature or immediately removed from the reactor jacketed and cooled in an aluminum foil (for slow cooling of the mixture).

After cooling, the pellets are crushed and sieved, and then the obtained granules are mixed with eccipienti standard for solid dosage forms, i.e. fillers, binding agents, dezinfeciruyuhimi agents and sizing. The resulting mixture is stirred, for example, using a V-mixer and then pressed or molded, you get a tablet, or a mixture of filled capsules.

The suitability of all the pharmaceutical compositions of the present invention evaluated using standard clinical tests in, for example, when determining the dosage standard dosage forms, sufficient to achieve therapeutically effective levels of therapeutic compounds in the blood, for example, with the introduction of the drug in the dosage range from 2.5 mg to 1000 mg/day mlekopitayushchie is the mass of 75 kg, for example, an adult, or a standard animal model.

The number of therapeutic compounds in pharmaceutical compositions, for example, in the form of tablets or powder, suitable for tablets, ranging from 0.1 mg to 100 mg, for example, 0.1 mg, 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 50 mg or 100 mg standard dosage forms are suitable for administration of a medicinal product from 1 to 5 times per day depending on the assigned treatment, stage of treatment, etc.

The present invention relates to a method of treatment of a disease, condition or disorder of a subject with the use of moisture-sensitive therapeutic compound, which includes the introduction of a therapeutically effective amount of the pharmaceutical composition of the present invention to a subject requiring such treatment. In addition, the present invention relates to the use of a composition according to the present invention includes an inhibitor of DPP-IV, for obtaining a medicinal product intended for the treatment and/or prevention of diseases, such as non-insulin-dependent diabetes mellitus, arthritis, obesity, allograft transplantation and calcitonin-osteoporosis, or disorders mediated by altering the levels of GLP-1 and/or GLP-2.

The following examples are given to illustrate this izobreteny and do not limit its scope. Examples are provided only to describe the application of the method according to the present invention in practice.

The number of ingredients used in each example presented in mass percent based on the weight of the composition and is listed in the respective tables after proper description.

Example 1

Solid dosage form for oral administration obtained by dry mixing

The first connection I sifted through a sieve (25 mesh)was obtained 11.2 g of compound I. In a V-mixer capacity of 1 quart was added compound I and 100 g of lactose, was intensively stirred for 5 minutes the mixture was removed, sieved through a sieve (25 mesh) and was again added in a V-mixer, and then in the V-mixer was added talc, crosspovidone and the remaining portion of the lactose, the mixture was intensively stirred for another 10 minutes Gidrirovannoe castor oil was selling through a sieve (60 mesh), then added to the V-mixer and the resulting the mixture was intensively stirred for 5 minutes the mixture is Then extruded on a tablet press Manesty B3B using standard round cutter with a concave and beveled edge. The device is pre-polished to prevent the formation of the film. In this description of the obtained tablets weighing 150 mg containing approximately 5 mg of compound I as the exemplary is 1. Sample 1 does not contain particles of compound I, covered or substantially covered gidrirovanny castor oil.

Example 2

Solid dosage form for oral administration obtained by granulation of the melt with the addition of hydrogenated castor oil

For comparison with sample 1 solid dosage form for oral administration were obtained from granulated from a melt of compound I. Compound I and fusible hydrophobic component, i.e. gidrirovannoe castor oil, each material separately sieved through a sieve (25 mesh) and a sieve (60 mesh), respectively, then the ingredients were added to the pellet in a volume of 1 l with high shear Key company International (Englishtown, NJ), model KG5.

The capacity of the granulator is equipped with a heating jacket, the rheostat is set at 80°C, the pellet mill equipped with a paddle stirrer without cutting elements, which is included for mixing therapeutic compounds and fusible hydrophobic component.

After mixing the granules were removed from the granulator and uniformly distributed on aluminum foil to cool, then granules were sifted through a sieve using a vibrator Frewitt.

The obtained granules, microcrystalline cellulose and crosspovidone was added to the V-mixer and the mixture was intensively stirred for approximately 10 min, then up to allali gidrirovannoe castor oil and intensively stirred for a further 5 minutes

Then the resulting mixture was extruded on a tablet press Manesty B3B using standard round cutter with a concave and beveled edge. The device is pre-polished to prevent the formation of a film.

The tablets obtained as described in example 2, called sample 2.

Example 3

Solid dosage form for oral administration obtained by granulation of the melt with the addition of stearic acid

For comparison with sample 1 and sample 2 other solid dosage form for oral administration were obtained from granulated from the melt of compound I in the same way as described in example 2, but replacing hydrogenated castor oil stearic acid. In this case, stearic acid used as a fusible hydrophobic component in the composition obtained from melt granules and lubricant in the composition of the obtained tablets. In the present description thus obtained tablets are called sample 3.

Table 1 shows the composition of samples obtained as described in examples 1, 2 and 3.

Table 1
SampleSample 1 (mg)Sample 2 (mg) Sample 3 (mg)
The connection I3,7%3,7%3,7%
Gidrirovannoe castor oil as a hot melt component013,3%0
Stearic acid as a fusible component0013,3%
Dried spray lactose as filler86,3%76,3%76,3%
Crosspovidone as dezintegriruetsja agent4,7%4,7%4,7%
Talc as antiadhesive3,3%00
Gidrirovannoe castor oil as lubricant2%2%0
Stearic acid as lubricant00 2%

Each of the samples were placed in vials of HDPE, sealed induction, and maintained for 4 weeks in real-aging, i.e. at 25°C and relative humidity (OB) 75% and by accelerated aging, i.e. at 40°C and OB 75%. After 4 weeks was measured by the content of cyclic imidate as a decomposition product of the compound I. the test Results are presented below in table 2.

Table 2
TimeTest conditionsThe content of compound I (in percentage specified on the label of contents)The content of cyclic imidate (%)
Sample 1To test92,4%0,12
4 weeks25°C/60% OBof 92.7%0,18
4 weeks40°C/75% OB93,0%0,81
Sample 2 To test96,1%0,09
4 weeks25°C/60% OB92,3%0,12
4 weeks40°C/75% OB93,0%0,31
Sample 3To test86,8%0,09
4 weeks25°C/60% OB87,4%0,13
4 weeks40°C/75% OB84,8%0,34

After the test sample 1 (tablets, obtained by dry mixing) using accelerated aging for 4 weeks was observed the highest degree of decomposition of therapeutic compounds. Thus, therapeutic compound in the sample 1 is characterized by very high chemical instability and is the most sensitive to moisture. the La samples 2 and 3 obtained comparable results, which show improved chemical stability compared to sample 1.

In addition to stability testing for these three samples was determined solubility. For all the three samples was observed almost complete release of drug after 10 minutes the Sample 1, as expected, were characterized by a rapid release of the drug, because tablets were obtained by dry mixing and pressing. However, unexpectedly, it was found that pellets of samples 2 and 3, in which therapeutic compound is covered or substantially covered with fusible hydrophobic component, quickly and effectively dissolve and can be used for rapid release of the drug.

Example 4

Solid dosage form for oral administration obtained by granulation of the melt containing compound I in a dose of 5 mg and 20 mg

Standard solid form containing compound I in an amount of 5 mg and 20 mg, was obtained by granulation of the melt. Tablets weighing 125 mg and 250 mg, respectively, were obtained in the same way as described in example 2. The ratio of compounds 1 and hydrogenated castor oil in the obtained granules was approximately 1:4.

The obtained tablets weighing 125 mg, containing 5 mg of compound I and lactose, called clicks Scam 4A, and tablets weighing 250 mg, containing 20 mg of compound I and lactose, called sample 4B.

Example 5

Solid dosage form for oral administration obtained by granulation of the melt containing compound I in a dose of 50 mg and 100 mg

Dosage form containing compound I in a dose of 50 mg and 100 mg, was obtained by granulation of the melt. Tablets weighing 250 mg was obtained in the same way as described in example 2. The ratio of compound I and hydrogenated castor oil in the obtained granules was approximately 1:1.

The obtained tablets weighing 250 mg, containing 50 mg of compound I and lactose, called sample 5A and tablets weighing 250 mg containing 100 mg of compound I and lactose, called sample 5B.

Table 3 presents the composition of samples obtained as described in examples 4 and 5. The ingredients in bold are components of the granules obtained by granulating the melt.

Table 3
The sample (ratio of compound I and hydrogenated castor oil)Sample 4A (1:4)Sample 4B (1:4)Sample 5A (1:1)Sample 5B (1:1)
Connected to the e I 4,6% (wt.%)4,6%11,5%23,0%
Gidrirovannoe castor oil16,0%16,0%10,0%20,0%
Lactose73,4%73,4%72,5%51,0%
Crosspovidone5,0%5,0%5,0%5,0%
Gidrirovannoe castor oil1,0%1,0%1,0%1,0%

Example 6

Solid dosage form for oral administration obtained by granulation of the melt containing compound I in a dose of 20 mg, 55 mg and 100 mg) and microcrystalline cellulose

Samples 4B, 5A and 5B were used to produce dosage forms, containing microcrystalline cellulose or product AVICEL PH company FMC Corporation (Philadelphia, PA). Samples 4B, 5A and 5B were obtained in the same way as described above, but the replacement of half of the amount of lactose in microcrystalline Zell is RAM. Samples 4B, 5A and 5B, containing microcrystalline cellulose are examples 6A, 6B and 6C, respectively.

Table 4 presents the composition of samples 6A, 6B and 6C.

Table 4
The sample (ratio of compound I and hydrogenated castor oil)Sample 6A (1:4)Sample 6B (1:1)Sample 6B (1:1)
The connection I4,6%11,5%23,0%
Gidrirovannoe castor oil16,0%10,0%20,0%
Lactose36,7%36,3%25,0%
Microcrystalline cellulose36,7%36,2%25,0%
Crosspovidone5,0%5,0%5,0%
Gidrirovannoe castor oil1,0%1,% 1,0%

Table 5 presents data on the stability of samples 4A, 4B, 5A, 5B, 6A, 6B, and 6B, obtained by curing for 4 weeks at 25°C and OB 60%.

0,11%
Table 5
TimeTest conditionsThe content of compound I (in percentage specified on the label of contents)The content of cyclic imidate (%)
Sample 4A
Obtained from melt granules containing 5 mg of compound I andTo test 4 weeks25°C/60% OB98,6%0,27%
gidrirovannoe castor oil and does not contain microcrystalline cellulose99%0,25%
Sample 4BObtained from melt granules containing 20 mg of compound I andTo test 4 weeks25°C/60% RH94,1%0,31%
gidrirovannoe castor oil and does not contain microcrystalline cellulose98,8%0,30%
Sample 5A
Obtained from melt granules containing 50 mg of compound I andTo test 4 weeks25°C/60% OB101,0%0,11%
gidrirovannoe castor oil and does not contain microcrystalline cellulose102,7%0,21%
Sample 5B
Obtained from melt granules containing 100 mg of compound I and
To test 4 weeks25°C/60% OB100,2%
gidrirovannoe castor oil and does not contain microcrystalline cellulose100,4%0,14%
Sample 6A
Obtained from melt granules containing 20 mg of compound I,To test 4 weeks25°C/60% RHfor 95.30,28
gidrirovannoe castor oil and microcrystalline cellulose98,10,38
Sample 6B
Obtained from melt granules containing 50 mg of compound I,
To test 4 weeks25°C/60% RH101,10,15
gidrirovannoe castor oil and microcrystalline cellulose100,10,42
Sample 6V
Obtained from melt granules containing 100 mg of compound I,
To test 4 weeks25°C/60% RH99,50,13
gidrirovannoe castor oil and microcrystalline cellulose99,60,29

Table 6 presents data on the solubility of each sample 4A, 4B, 5A, 5B, 6A, 6B and 6C for 10 min, 20 min and 30 min after the start of testing. Each sample was dissolved in 0.1 G. of hydrochloric acid while stirring with a paddle stirrer (apparatus 2) at 37°C.

Table 6
The content of compounds in the percentage specified on the label content
0 min10 min20 min30 min
Sample 4A
Obtained from melt granules containing 5 mg of compound I and gidrirovannoe castor oil, not containing microcrystalline cellulose
073,7%87,9%91.3%of
Sample 4B
Obtained from melt granules containing 20 mg of compound I and gidrirovannoe castor oil, not containing microcrystalline cellulose
079,1%86,0%89,4%
Sample 5A
Obtained from melt granules containing 50 mg of compound I and gidrirovannoe castor oil, containing microcrystalline cellulose
0100,0%101,7%101,7%
Sample 5B
Obtained from melt granules containing 100 mg of compound I and gidrirovannoe castor oil, not containing microcrystalline cellulose
034,8%79,4%100,9%
Sample 6A
Obtained from melt granules containing 20 mg of compound I, gidrirovannoe castor oil and microcrystalline CE is lulose 072,1%78,5%81,9%
Sample 6B
Obtained from melt granules containing 50 mg of compound I, gidrirovannoe castor oil and microcrystalline cellulose
088,2%93,7%94,4%

When testing each sample 4A, 4B, 5A, 5B, 6A and 6B there is a dissolution more than 80% of the amount of compound I, calculated from the specified label content, in less than 30 min, which indicates the suitability of these samples for the rapid release of the drug.

Other experiments (examples 7 and 8) was performed to determine the effect of excipient high equilibrium water content in the compound I in the presence of the fusible hydrophobic component in various concentrations. As the main excipient used microcrystalline cellulose. The following samples are characterized by the following ratio x:y:z, where x represents the concentration of compound 1, the mean concentration of hydrogenated castor oil, and z means the concentration of microcrystalline cellulose.

Example 7

Obtained from the melt pellets containing microcrystalline cellulose/p>

Obtained from melt granules containing compound I and gidrirovannoe castor oil, obtained as described in example 2, were obtained for five samples. All of these samples, except for sample 7A, contained obtained from melt granules were mixed with microcrystalline cellulose in a ratio of connection 1/microcrystalline cellulose 1:1. However, each sample differed in the content of hydrogenated castor oil. Table 7 presents the composition of each sample.

Table 7
The sample (x:y:z)Sample
7A
(1:0:1)
Sample
7B
(1:0.5:1
Sample 7V
(1:1:1)
Sample
7G
(1:2:1)
Sample
7D
(1:4:1)
The connection I50%40%33,3%25%16,7%
Gidrirovannoe castor oil0%20%33,3%50%66,6%
Microcrystallin the definition cellulose 50%40%33,3%25%16,7%

Table 8 presents data on the stability of each sample, obtained as described in example 7, while keeping the sample at 40°C and at 40°C and OB 75%. Tablets of each sample was kept in bottles made of high density polyethylene (HDPE), sealed induction method.

Table 8
The ratio x:y:zTimeConditionsThe content of compounds (%)The content of cyclic imidate (%)
Sample 7ATo test98,890,06
4 weeks40°C97,721,05
4 weeks40°C/75% OB93,793.04 from
Sample 7B To test99,640,07
4 weeks40°C93,671,37
4 weeks40°C/75% OB95,991,80
Sample 7BTo test98,160,07
4 weeks40°C96,901,50
4 weeks40°C/75% OBto 96.651,56
Sample 7GTo test101,540,07
4 weeks40°C102,741,11
4 weeks/td> 40°C/75% OB101,791,45
Sample 7DTo test95,220,07
4 weeks40°C95,050,65
4 weeks40°C/75% OB92,871,13

The data presented in table 8, indicate a reduction in the content of cyclic imidate, resulting from the decomposition of compound I, the content of fusible hydrophobic component and hydrogenated castor oil increases. Unexpectedly, it was found that the presence of hydrogenated castor oil reduces the sensitivity of the compound I to moisture even in the presence of excipient with a high equilibrium moisture content, i.e. microcrystalline cellulose.

Example 9

Solid dosage form for oral administration containing compound PS

Tablets weighing 10 mg containing compound IIC, was obtained by the following method. Compound IIC, microcrystallites the Yu cellulose, lactose and sodium salt starch glycolate were mixed in the mixer volume 4 quarts to a complete mixing of the ingredients. Magnesium stearate was separately screened through a sieve (25 mesh) and then added to the mixer in the mixture. A mixture obtained by dry mixing, was removed from the mixer and extruded on a rotary tablet press, it was given a sample of 9.

Example 10

Solid dosage form for oral administration obtained by granulation of the melt containing compound IIC

For comparison with example 9 the composition containing 10 mg of compound IIC, was obtained by granulation of the melt according to the following procedure. 10 mg of compound IIC and 15 mg stearyl alcohol each material separately sieved through a sieve (18 mesh) and added to a Hobart mixer. The mixer is equipped with a heating jacket, the rheostat is set at 100°C. the Mixture was stirred until the formation of the granules for about 10-15 min, then the granules were removed from the mixer and placed on aluminum foil to cool to room temperature. After cooling, the granules were sifted through a sieve (20 mesh). Half the number of the obtained granules used for other purposes, and the other half of the obtained granules were mixed with microcrystalline cellulose (128 g), lactose (64 g), sodium salt starch glycolate (12 g) and magnesium stearate (3 g)in the turbula mixer and stirred for 10 min, the resulting mixture was extruded on a rotary tablet press, it was given a sample of 10.

Each sample 9 and 10 were placed in induction sealed bottles of HDPE and tested for stability for 3 weeks at 40°C and OB 75%, for 6 weeks at 30°C and OB 60% and for 6 weeks at 40°C and OB 75%. Table 9 presents data on the content of the product, the complete decomposition in percent, after a certain stability tests.

Table 9
Sample 9Sample 10
To testnot definednot defined
3 weeks: 40°C/75% OB0,08%not defined
6 weeks: 30°C/60% OB0,06%not defined
6 weeks: 40°C/75% OB0,23%not defined

The data presented in table 9, indicate that the solid dosage form for oral administration, containing obtained by granulation of the melt granules is (example 10), characterized by increased chemical stability of therapeutic compounds in comparison with a composition obtained by dry mixing (example 9).

In addition, we determined the solubility of the tablets prepared as described in example 10, in water at a rotation speed of 50 rpm After rotation for 30 min was observed release more than 90% of therapeutic compounds were dissolved in the water.

It should be understood that the present invention is described for illustration and does not limit the scope of the present invention, which is defined in the claims. Other objects, advantages, and modifications are also included in the scope of the invention.

1. The pharmaceutical composition of immediate release oral administration of an inhibitor of DPP-IV, comprising granules that contain the specified inhibitor of DPP-IV, at least 90% of the surface covered with fusible hydrophobic component, and these granules include an inhibitor of DPP-IV and the specified fusible hydrophobic component at a ratio of from 1:1 to 1:10 (dry weight) and obtained by granulation of the melt.

2. The pharmaceutical composition according to claim 1, whereby the mentioned pharmaceutical composition is released at least approximately 50% of the inhibitor of DPP-IV within 30 min after oral administration of the drug.

3. Pharmaceutical what I composition according to claim 2, moreover, the mentioned pharmaceutical composition is released at least approximately 80% of the inhibitor of DPP-IV within 30 min after oral administration of the drug.

4. The pharmaceutical composition according to claim 1, in which the aforementioned ratio is from 1:1 to 1:4.

5. The pharmaceutical composition according to claim 1, and specified the pharmaceutical composition also includes disintegrity agent, the content of which ranges from approximately 1 to 20% based on the weight of the specified composition.

6. The pharmaceutical composition according to claim 1, in which the inhibitor of DPP-IV is N-(substituted glycyl)-2-cyanopyrrolidine or its pharmaceutically acceptable salt.

7. The pharmaceutical composition according to claim 6, in which the specified N-(substituted glycyl)-2-cyanopyrrolidine characterized by formula (II)

where R is substituted and substituted
n is from 0 to 3.

8. The pharmaceutical composition according to any one of claims 1 to 6, in which the inhibitor of DPP-IV is (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine.

9. The pharmaceutical composition of claim 8, comprising (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine in the amount of from 50 to 100 mg.

10. A method of producing granules of at least 90% of the surface covered with fusible hydrophobic component, which includes stages:
a) the doctrine of the mixture of the inhibitor of DPP-IV and at least one fusible hydrophobic component, where the ratio of inhibitor of DPP-IV and the fusible hydrophobic component is from 1:1 to 1:10 (dry weight);
(b) heating this mixture at a temperature close to the melting point of the specified fusible hydrophobic component,
(C) granulating the obtained mixture under stirring with a high shear with the formation of granules and
(g) cooling of these pellets to room temperature.

11. The method according to claim 10, in which said mixture mainly includes an inhibitor of DPP-IV and at least one specified fusible hydrophobic component.

12. The method according to claim 10, in which the fusible hydrophobic component selected from the group comprising esters, waxes, hydrocarbons, fatty alcohols, fatty acids, monoglycerides, diglycerides, triglycerides and mixtures thereof.

13. The method according to claim 10, in which the inhibitor of DPP-IV is N-(substituted glycyl)-2-cyanopyrrolidine or its pharmaceutically acceptable salt.

14. The method according to item 13, in which the specified N-(substituted glycyl)-2-cyanopyrrolidine is (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine.

15. Pharmaceutical composition comprising granules obtained by the method according to claim 10.

16. The pharmaceutical composition of immediate release oral dosage forms, including granules, which essentially contain the inhibitor of DPP-IV and at least one fuse is hydrophoby component, at least 90% of the surface covered with fusible hydrophobic component, and these granules include an inhibitor of DPP-IV and the specified fusible hydrophobic component at a ratio of from 1:1 to 1:10 (dry weight) and obtained by granulation of the melt.

17. The pharmaceutical composition according to item 16, and the mentioned pharmaceutical composition is released at least approximately 50% of the indicated inhibitor of DPP-IV within 30 min after oral administration of the drug.

18. The pharmaceutical composition according to item 16, and the mentioned pharmaceutical composition is released at least approximately 80% of the specified inhibitor of DPP-IV within 30 min after oral administration of the drug.

19. The pharmaceutical composition according to any one of p-18, in which the specified inhibitor of DPP-IV is (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine.

20. The pharmaceutical composition according to claim 19, comprising (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine in the amount of from 50 to 100 mg.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula : in which R1 represents a hydrogen atom or alkyl optionally substituted with (1) aralkyloxy group, (2) aroyl, (3) isoquinolinyl or (4) aryl, optionally substituted with an alkoxy group; the solid line and the dashed line between A1 and A2 represent a double bond (A1=A2) or a single bond (A1-A2); A1 is a group of formula C(R4), and A2 is a nitrogen atom when the solid line and the dashed line between A1 and A2 represents a double bond (A1=A2); A1 is a group of formula C=O, and A2 is a group of formula N(R5) when the solid line or the dashed line between A1 and A2 represent a single bond (A1-A2); R2 represents alkyl optionally substituted with a cyano group, aryl optionally substituted with an alkoxy group, aralkyl optionally substituted with a halogen atom, a cyano group, an alkoxy group, an alkyl or carbamoyl or alkynyl; R3 represents a hydrogen atom, a halogen atom, cyano, formyl, carboxyl, alkyl optionally substituted with (1) amino group optionally substituted with alkyl, or (2) alkoxy group, aryl optionally substituted with an alkoxy group, tetrazolyl, alkylcarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, where heteroaryl is a 4-6-member monocyclic radical containing 1-2 heteroatoms selected from a nitrogen atom or oxygen atom, alkoxycarbonyl, carbamoyl optionally substituted with alkyl, cycloalkyl or cycloalkylalkyl, hydroxyl, alkoxy group or a group of formula: -Rd-C(O)O-Re, where Rd represents a single bond, and Re represents a group of formula: -CH(R4a)OC(O)R4b, where R4a represents alkyl or R4b represents cycloalkyloxy or aryloxy; R represents a hydrogen atom, hydroxyl, cyano, alkyl, carbamoyl, carboxyl, aryloxy optionally substituted with an alkoxy group or carbamoyl, alkylsulfonyl, alkylcarbonyl or alkoxycarbonyl; R5 represents a hydrogen atom or alkyl; -Y represents a group of formula (A) given below: in which m1 equals 2, and R6 is absent, or to pharmaceutically acceptable salts of the said compounds. The invention also relates to compounds of formula (VI), to pharmaceutical compositions, to a dipeptidyl peptidase IV inhibitor, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds with dipeptidyl peptidase IV inhibition properties.

20 cl, 76 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) which are protein tyrosine kinase 1B(PTP-1B) inhibitors and can be used in medicinal preparations for treating and preventing diseases related to high concentration of glucose in blood, for example diabetes and obesity. In formula (I) X is a X-1 group or X-2: , where R1 and R2 are each independently selected from a group consisting of hydrogen, lower alkyl, alkoxy-lower alkyl and hydroxyl-lower alkyl, under the condition that, R1 and R2 both represent hydrogen; R3, R4, R6 and R7 are each independently selected from a group consisting of hydrogen, lower alkyl; lower alkyl substituted with halogen or hydroxy; lower alkoxy; lower alkoxy substituted with halogen, hydroxy or lower alkoxy; hydroxyl, halogen, lower alkylthio, lower alkylsufanyl, lower alkylsufanyl, aminosufonyl, cyano, nitro, carbamoyl, lower mono- or dialkylcarbamoyl, lower alkanoyl, benzoyl, phenyl, phenyl substituted with halogen, phenyloxy, lower mono- or dialkylamino, hydroxy-substituted lower alkylamino, lower alkanoylamino, lower alkylsulfonylamino, heterocycloalkyl, hydroxy-substituted heterocycloalkyl, heterocyclyloxy, heterocyclylcarbonyl; where each heterocycloalkyl in the said values represents a 5-6-membr ring containing 1-2 heteroatoms selected from nitrogen and oxygen, and which can be substituted with lower alkyl or phenyl-lower alkyl; carboxyl, lower alkoxycarbonyl and a substitute of formula: ; R8 is selected from a group consisting of hydrogen, lower alkylthio, halogen, alkoxy-lower alkoxy, lower alkoxy, halogen-lower alkyl, hydroxy-lower alkyl; represents a 5-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of hydrogen, sulphur and nitrogen; R8 and R9 each independently represents hydrogen or lower alkyl.

EFFECT: novel compounds have useful biological properties.

31 cl, 7 dwg, 152 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexafluoroisopropanol substituted derivatives of cyclohexane of formula (I) with LXRα- and/or LXRβ agonist modulation properties, as well as to their pharmaceutically acceptable salts. In formula (I) R1 denotes hydrogen, lower alkyl, fluoro-lower alkyl, lower alkyl-carbonyl, fluoro-lower alkyl-carbonyl, phenyl-lower alkyl, C3-C6-cycloalkyl-lower alkyl, C3-C6-cycloalkylcarbonyl or C3-C6-cycloalkyl-lower alkyl-carbonyl; R2 denotes hydrogen or lower alkyl; R3 denotes lower alkyl, phenyl-lower alkyl, where phenyl is possibly substituted with lower alkoxycarbonyl, lower alkoxycarbonyl, or if X represents a single bond and m is not equal to 0, R3 can also denote a hydroxy group; R4 denotes phenyl or heterocyclyl, where heterocyclyl is a five-member aromatic heterocyclic ring containing two heteroatoms selected from nitrogen and sulphur, optionally substituted with 1-3 substitutes independently selected from a group which includes lower alkyl and halogen; X denotes a single bond, SO2, CO or C(O)O; m equals 0, 1, 2 or 3; n equals 0 or 1. The invention also relates to a pharmaceutical composition containing formula (I) compounds.

EFFECT: novel compounds have useful biological properties.

20 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: small peptides of formula X1-X2-X3-X4-X5-X6-X7-R1, containing 7-12 amino acid residues are proposed.

EFFECT: said peptides are MC4 receptor agonists and are therefore useful in treating obesity and related diseases.

31 cl, 2 tbl, 82 ex

Pyrazoles // 2381217

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where one of R1 and R2 is hydrogen or alkyl, and the other is (CH2)PY, where p=0 or 1, Y is a saturated mono-, bi- or tricyclic 5-10-member cycloalkyl ring optionally substituted with alkyl, or R1 and R2 together with N form a 7-10-member saturated bicyclic ring Z, optionally substituted with halogen, or a 5-7-member monocyclic ring Z, optionally substituted with alkyl, phenyl, phenylalkyl or pyridinyl; R3 is [2,2']bithiophenyl, 1-methylindole, 2,3-dihydrobenzo[1,4]dioxin, benzo[1,3]dioxole, benzothiophene, dibenzofuran, furan, naphthalene, quinoline, thianthrene, thiophene or pyrrole, or biphenyl substituted with halogen, or phenyl optionally substituted with one or more amino, cyano, formyls, halogens, hydroxyl, hydroxymethyls, acyls, acylamino, alkoxy, nitro, trifluoromethoxy, trifluoromethyls, phenoxy or benzyloxy, or R3 is a group, where Ar is phenyl substituted with halogen; and R4 is alkyl; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition with inhibitory activity towards the 11β-hydroxysteroid dehydrogenase1 (11(β-HSD1) enzyme.

EFFECT: pyrazole composition is disclosed.

22 cl, 1 tbl, 116 ex

FIELD: medicine.

SUBSTANCE: combined preparation containing thioctic acid in amount 100 to 1000 mg and dalargin in amount 0.1 to 4 mg is applied. The method of treating vascular complications of diabetes and diabetic polyneuropathy implies application of intravenous infusion of thioctic acid and dalargin in a pharmaceutically acceptable solvent within 2 courses of 10 days with a two-week interval. The preferential version of the composition is that one containing thioctic acid (300-600 mg), dalargin 3 mg and physiologic saline (250 ml). Application of the invention allows for prompt reduction or complete elimination of morbidity of vascular complications of diabetes and diabetic polyneuropathy.

EFFECT: development of the effective drug combination, improved life quality of the patients, reduced frequency of invalidisation, extended range of drug products for treating complications of pancreatic diabetes.

5 cl, 1 ex, 1 tbl

FIELD: food industry.

SUBSTANCE: food product is characterised by a low content of glucose - up to 5% or an utter absence of it, balanced content of fat of less than 10%. The product includes a mixture of phytosterol ethers and/or phytostanol ethers (PS-E) with 1,3-diglycerides (DAG), not necessarily disperse or dissolved in food oil or fat. Moreover, content of PS-E exceeds that of DAG.

EFFECT: invention enables to produce a product controlling glucose exchange and insulin secretion suitable for prevention and treatment of conditions caused by diabetes to patients suffering from diabetes or in people predisposed to it.

18 cl, 12 dwg, 4 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to solid unit dosage form for pancreatic diabetes. The solid unit dosage form for pancreatic diabetes contains as an active substance a combination of taurine, butadion, metformin, Riboxinum, arginine and gliclazide, as well as targeted additives in the certain ratio.

EFFECT: drug is effective for pancreatic diabetes.

4 cl, 2 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to inhibitors of enzymes cleaving protein after proline, such as depeptidyl peptidase IV inhibitors, as well as to their pharmaceutical compositions, and methods of application of such inhibitors. Particularly, inhibitors under this invention are improved in comparison with those currently in use in the present art by selecting special classes of side chains in P1 and/or P2 positions of inhibitor which contains carboxylic acid grouping.

EFFECT: compounds of specified formulas I, II and III can have the improved therapeutic index, partially owing to reduced toxicity and improved specificity in relation to target protease.

15 cl, 2 dwg, 6 ex

FIELD: food products.

SUBSTANCE: edible composition that contains at least one facility for conditioning with covering layer, which consists of agent that imparts hydrophobic properties and inorganic particles and at least one material that has been selected from the group that consists of pharmaceutically active agent, powdered food components and their combinations. At that agent that imparts hydrophobic properties directly covers mentioned inorganic particles and is available in mentioned facility for conditioning in amount of approximately from 1 weight % to 10 weight %, in conversion to total mass of facility for conditioning. Facility for conditioning with covering layer is used in pharmaceutical products, such as acetaminophen.

EFFECT: prepared composition expresses better fluidity properties.

25 cl, 11 tbl, 29 ex

FIELD: chemical-and-pharmaceutical industry, in particular solid pharmaceutical formulation coated with enterosoluble coating.

SUBSTANCE: claimed coating has four layers wherein the first and the third layers comprise of hydroxypropyl cellulose, and the second and the fourth ones comprise of acetatephthalate cellulose, bee wax and twin 0-20 in specific component ratio in coating.

EFFECT: enhanced assortment of drug active ingredients coatable with claimed coating, including thermolabile immunobiological medicines.

4 cl, 7 ex

FIELD: chemical-pharmaceutical industry.

SUBSTANCE: it has been suggested to apply a solid composition for manufacturing a pharmaceutical tablet or a suppository, its melting point being 25°C or higher and it contains an uninterrupted lipid component that contains either one or more than one galactolipids, one or more glyceride ether of fatty acids, possibly one or several out of the following: water and mono-triatomic alcohol at the quantity being up to 15 weight% against the weight of composition, and one or more agent chosen among pharmacologically active agent. The method for manufacturing the composition mentioned includes mixing galactolipids and glyceride ethers of fatty acids followed by dissolving pharmacologically active agents in a liquid phase, cooling up to a solid state and forming a tablet or a filled capsule. Pharmaceutical tablet or suppository are depicted that include uninterrupted lipid phase possibly containing an inert nucleus and, also, food tablets or suppositories of similar composition that include food agents instead of pharmacologically active agent and, possibly, having got one or more submembranes consisting of food excipients. The innovation provides economy and increased comfort in usage.

EFFECT: higher efficiency.

42 cl, 13 ex, 10 tbl

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and concerns preparation of a solid dosage form for treating respiratory allergosis and arresting nasopharynx edema. There is offered a tableted medical product containing mixed active substance and excipient. As an active substance, it contains a corticosteroid preparation, and according to the invention, additionally contains an active substance presented with adrenaline or noradrenaline. The inside of a tablet contains the corticosteroid preparation, while the exterior contains adrenaline. As a corticosteroid preparation it contains dexamethasone, prednisolone or celestone. Also there is offered a tableted medical product that contains mixed active substance and excipient. As an active substance, it contains a corticosteroid preparation, and additionally contains active substances presented with adrenaline or noradrenaline, and also aminophylline and mesatone. The tablet is multilayered, its inside contains mesatone, the layer containing aminophylline adjoins the inside, then the layer containing the corticosteroid preparation is executed, and the exterior contains adrenaline or noradrenaline.

EFFECT: there is offered a tableted medical product.

4 cl, 3 ex

FIELD: medicine.

SUBSTANCE: solid unit dosage form with enterosoluble coating contains pharmacologically effective amount of mycophenolic acid or mycophenolate and pharmaceutically acceptable additives, where mycophenolic acid or mycophenolate are found practically in an anhydrous form in amount approximately 20 to approximately 95% on total basis of solid unit dosage form with the enterosoluble coating. There is also offered method for preparing the solid unit dosage form containing practically anhydrous mycophenolic acid or its salt.

EFFECT: high efficiency and improved storage-stability of the composition.

12 cl, 4 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical unit dosage form for treatment or prevention of cardiovascular episodes contains therapeutic amount of: antagonist of β-adrenergic receptor, diuretic or both; an agent lowering cholesterol level; an inhibitor of renin-angiotensin system; and aspirin. The pharmaceutical unit dosage form can be made in a two-layered tableted form. The first layer thereof contains simvastatin and aspirin, the second layer contains athenolol and lisinopril, or the second layer contains hydrichlorothiazide and lisinopril.

EFFECT: according to the invention pharmaceutical unit dosage form combines a number of drugs for oral intake once a day that improves compliance by the patient with prescribed regimen due to elimination of inconveniences related to intake of several doses of drugs during the day, and reduces probability of missing the dose.

24 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medical products and concerns method for making solid oral pharmaceutical composition containing a hydrophilised form of 5-chlor-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidine-5-yl}-methyl)-2-thiophencarboxaime (I), differing that at first by spraying granulation, a granulated material is prepared. It contains a hydrophilised form of active substance (I). Then said granulated material if necessary is transformed into a pharmaceutical composition with pharmaceutically acceptable additives added.

EFFECT: method allows improving biological availability of the active substance.

6 cl, 2 tbl, 5 ex

Solid dosage form // 2377987

FIELD: medicine.

SUBSTANCE: present invention refers to medical products, particularly to a solid dosage form, containing an active substance from the group of inhibitor monoamine neurotransmitter uptake inhibitors with 2 3-two-substituted tropane skeleton of formula (1) which is produced by spaying a solution of the active substance over the carrier and containing the following components: 0.01-5.00 wt % of the active substance, 80.00-95.00 wt % of one or more carriers chosen from the group including carbohydrates and binding agents, providing binding of the components in a dry state, 1.00-10.00 wt % of one or more adjuvants chosen from the group, including cellulose derivative and salts of fatty acids, 0-10.00 wt % of a film coating mainly containing one or more filming agents, one or more elasticity improving substances, one or more pigments and optionally one or more dyes. Besides the inventions concern the method for making said dosage form and application thereof.

EFFECT: said dosage form expresses improved uniformity of the active substance, stability and biocompatibility.

17 cl, 2 dwg, 6 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: there is offered application of L-tryptophan and L-tryptophan peripheral decomposition inhibitor (preferentially, carbidopa or Benserazide) for making a medicinal agent for prevention or treatment of pain, depression, somnipathy and other serotonin-dependent diseases of central nervous system (CNS) with L-tryptophan being presented by a slow-release drug, and L-tryptophan peripheral decomposition inhibitor - by a fast-release drug.

EFFECT: there is assured constant high concentration of tryptophan in the patient's blood plasma with the real absence of by-effects following administration of the declared combination.

5 cl, 2 dwg, 2 ex

FIELD: food industry.

SUBSTANCE: invention refers to confectionary industry. Chewing confectionary composition contains from 0.1 to 3 % of weight of enzyme, solid material of base, sweetener not provoking caries, substance stabilising enzymes and water below 5% of weight. Enzyme is chosen from proteases extracted from fruit products and is introduced into solid material of composition base at temperature 80°C, also enzyme activity of proteases is maintained in the composition at least for 4 weeks at 23°C.

EFFECT: introduction of enzyme into composition facilitates destructing of dental deposit, prevents its formation and adhesion on teeth surface at product consumption.

13 cl, 7 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: present invention concerns medical products, particularly a tableted solid veterinary-medical compound containing a pharmaceutical active raw material (particularly enrofloxacin, pradofloxacin) 0.001 to 90 wt %, a flavouring and/or aromatic substance representing Bayopal and Artificial Beef Flavor, in amount 5% to 15% in terms of total mass of ready compound and at least 1.5 wt %, and no more than 15 wt % of fine-grained silicon dioxide in terms of total mass of ready compound, and one or more adjuvants.

EFFECT: such qualitative and quantitative composition of tablets provides comprehensible flavouring properties thereof with preserving pharmaceutical properties (particularly solidity).

3 cl, 10 dwg, 9 tbl, 5 ex

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