Revaprazan-containing solid dispersion and method for preparing it

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a solid dispersion wherein revaprazan particles are surface-modified by a water-soluble polymer, a water-soluble saccharide, a surfactant or their mixture wherein the water-soluble polymer is specified in a group consisting of polyvinylpyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, a water-soluble polyacrylic acid copolymer, polyvinyl alcohol or their mixture, and wherein the water-soluble saccharide is specified in a group consisting of lactose, white sugar, saccharose, mannitol, sorbitol, xylitol, trehalose, maltitol, dulcitol, inositol, dextrin, cyclodextrin and their mixture. The invention also refers to a method for preparing said solid dispersion. The present invention also presents a pharmaceutical composition containing the solid dispersion, and the method for producing the pharmaceutical composition.

EFFECT: invention provides improved solubility of revaprazan and reduced adhesion and agglutination properties.

16 cl, 4 dwg, 7 tbl, 55 ex

 

The technical field

The invention relates to a solid dispersion in which particles revaprazan surface-modified water-soluble polymer with water-soluble saccharide, a surface-active substance or mixtures thereof, and method of reception. The present invention also relates to a pharmaceutical composition containing a solid dispersion, and to a method for producing the pharmaceutical composition.

The level of technology

Revaprazan, the chemical name of which is 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-pyrimidine represented by the following formula 1. Revaprazan can be used in the form of an acid additive salt, including HCl-salt (see international publication number WO 1996/05177).

Formula 1

Revaprazan or its salt bind reversibly to N+/K+exchange site proton pump (H+/K+ANPase)existing in the gastric parietal cell, so that the secretion of H+into the gastric lumen is completely inhibited. Revaprazan or its salt is also associated with specific customers N+/K+ANPase, resulting in inhibited the transport of H+and suppressed the secretion of acid in the gastric lumen, which leads to the increase of pH of the stomach. Unlike irreversible inhibitors promonova what about the pump, for example omeprazole, revaprazan or its salt does not depend on the acid activation of the drug in the stomach or status secretion proton pump. Therefore, based on the mechanism that is different from the irreversible proton pump inhibitor such as omeprazole, revaprazan or its salt is classified as an antagonist of acid pump (ARA).

Meanwhile, revaprazan has a very low solubility in water, i.e. less than 0.2 mg/ml, and due to the low solubility of its dissolution in the gastrointestinal tract is low. Therefore, when revaprazan administered orally, its rate of absorption is relatively low. Revaprazan also has strong adhesion and agglutination properties, and therefore, when revaprazan prepared in the form of capsules or tablets, it may stick to the piston or form, manifesting as a result, lower the ability to process the drug.

The technical problem

The applicants of the present invention conducted a study with the aim of improving the physico-chemical properties revaprazan, i.e. low dissolution rate and low capacity for processing in the drug. In the result, found that when the particles revaprazan surface-modified water-soluble polymer with water-soluble saccharide and/or surface-active agent with obtaining the firmness of the DOI dispersion, the solubility and dissolution rate revaprazan significantly improved, resulting in significantly improved its bioavailability. In addition, it was found that the adhesive power and the agglutination characteristics revaprazan can be improved, resulting in improved ability to recycle the product.

Therefore, the aim of the present invention is to develop a containing revaprazan solid dispersion.

Another objective of the present invention is to develop a pharmaceutical composition, which comprises containing revaprazan solid dispersion and a pharmaceutically acceptable carrier.

Another objective of the present invention is to develop a method of obtaining containing revaprazan solid dispersion.

Another objective of the present invention is to develop a method of producing the pharmaceutical composition.

Technical solution

In accordance with one aspect of the present invention proposed a solid dispersion in which particles revaprazan surface-modified using the water-soluble polymer, the water-soluble saccharide, a surfactant, or a mixture thereof.

In accordance with another aspect of the present invention proposed a pharmaceutical composition containing a solid dispersion and farmatsevticheskiy media.

In accordance with another aspect of the present invention, a method for obtaining solid dispersion, and this method includes the suspension revaprazan and one component of the water-soluble polymer, the water-soluble saccharide, a surfactant and mixtures thereof in water to obtain a slurry, and drying the suspension.

In accordance with another aspect of the present invention, a method for obtaining granules, and this method includes the suspension revaprazan and one component of the water-soluble polymer, the water-soluble saccharide, a surfactant and mixtures thereof in water to obtain a slurry and spray drying the suspension in pharmaceutically acceptable carrier.

In accordance with another aspect of the present invention, a method for obtaining granules, and this method comprises granulating by adding a binder solution to a mixture of solid dispersion and a pharmaceutically acceptable carrier.

In accordance with another aspect of the present invention, a method for receiving tablets, and this method includes compressing the mixture of the solid dispersion and a pharmaceutically acceptable carrier or compressing the mixture of pellets, derived from the solid dispersion and a pharmaceutically acceptable carrier.

In accordance with another TSA the drive of the present invention, a method for receiving capsules, this method involves filling capsules with a mixture of solid dispersion and a pharmaceutically acceptable carrier or filling capsules with a mixture of pellets, derived from the solid dispersion and a pharmaceutically acceptable carrier.

POSITIVE EFFECTS

In accordance with the present invention, the particles revaprazan surface-modified water-soluble polymer with water-soluble saccharide and/or surface-active substance with a transfer in the form of a solid dispersion; as a result of increased penetration characteristics and solubility of the drug (i.e revaprazan), which leads to a significant increase solubility and/or extent of dissolution revaprazan, improving in the end its bioavailability. In addition, the adhesiveness and the agglutination characteristics revaprazan can be reduced, thus improving the ability to process the drug. In addition, the solid dispersion can be obtained using water as the medium and, consequently, the potential problems caused by the use of organic solvents, such as security issues associated with the residual amount of solvent, can be excluded.

Description of the DRAWINGS

Fig. 1 shows the results of a comparative test on the dissolution of the preparations obtained according the present invention, and conventional drug [capsule containing a solid dispersion obtained in accordance with example 3the tablet obtained in accordance with example 3and the capsule filled with powder revaprazan

Fig. 2 shows the results of pharmacokinetic studies using dogs breed Beagle preparation obtained in accordance with the present invention, and conventional drug [tablet obtained in example 36and the capsule filled with powder revaprazan

Fig. 3 represents the image in a scanning electron microscope solid dispersion (example 6)obtained in accordance with the present invention.

Fig. 4 represents the image in a scanning electron microscope solid dispersion (example 11), obtained in accordance with the present invention.

Fig. 5 is an image of particles revaprazan in the polarization microscope.

The BEST WAY of carrying out the INVENTION

Throughout the present description of the definition of "surface modified" refers to a coating or attaching a water-soluble polymer, the water-soluble saccharide, a surfactant or other particles or particles is m revaprazan.

The definition of "revaprazan" relates to 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-pyrimidine, including its pharmaceutically acceptable salt, such revaprazan hydrochloride revaprazan-sulfate, revaprazan-nitrate, revaprazan-camphorsulfonate (i.e. revaprazan-Kamelot), revaprazan-thiocyanate, revaprazan-phosphate, revaprazan-carbonate, etc. Preferably the definition of "revaprazan includes revaprazan hydrochloride.

In accordance with the present invention, the particles revaprazan surface-modified water-soluble polymer with water-soluble saccharide and/or surface-active substance with a transfer in the form of a solid dispersion, resulting in increased penetration characteristics and solubility of the drug (i.e revaprazan); this leads to a significant increase solubility and/or extent of dissolution revaprazan, increasing thus its bioavailability. In addition, the adhesiveness and the agglutination characteristics revaprazan can be reduced, thus improving the ability to process the drug. In addition, the solid dispersion can be obtained using water as the medium and, consequently, the potential problems caused by the use of organic solvents, such as security issues associated with the residual amount of solvent, can be excluded.

The present invention provides a solid dispersion in which particles revaprazan surface-modified water-soluble polymer with water-soluble saccharide, a surface-active substance or mixtures thereof.

Water-soluble polymer may be selected from the group comprising polyvinylpyrrolidone, hypromellose, hydroxypropylcellulose, polyethylene glycol, water-soluble copolymer of polyacrylic acid (e.g., Eudragit E or carbomer), polyvinyl alcohol and their mixture, and preferably selected from the group comprising polyvinylpyrrolidone, hypromellose, polyethylene glycol and a mixture thereof. More preferably the water-soluble polymer can be a polyvinylpyrrolidone.

Water-soluble saccharide may be selected from the group comprising lactose, white sugar, sucrose, mannitol, sorbitol, xylitol, trehalose, ▫ maltitol, dulcet, Inositol, dextrin, cyclodextrin (e.g., α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or hydroxypropyl-β-cyclodextrin and in particular hydroxypropyl-β-cyclodextrin) and their mixture. Preferably the water-soluble saccharide may be selected from the group comprising lactose, mannitol, cyclodextrin and their mixture.

Surfactant can be selected from the group including from bichenovii ether or polyoxyethylene-arbitarily ether fatty acids (for example, polysorbate 80TM), sucrose esters and fatty acids (Ryoto Ester L1695TM), polyethylene glycol-15-hydroxystearate (e.g., Solutol HS 15TM), polyoxyethylenesorbitan natural or gidrirovannoe castor oil (e.g., Cremophor RH 40TM, Cremophor RH 60TM), polyoxyethylene-polyoxypropylene copolymer (for example, Poloxamer 407TM, Poloxamer 118TM), a derivative of synthetic vitamin E (e.g., vitamin E TPGSTM), polyoxyethyleneglycol ether (for example, Brij 52TM), the glycerides microgel-fatty acids (e.g., Gelucire 44/14TM), polyglyceryl ether fatty acids (for example, Plurol oleiqueTM), bile acid (e.g., human beings need it to acid), sodium lauryl sulfate, lecithin, gliterry ether fatty acids (for example, glycerylmonostearate), polyoxyethylenated and their mixture. Preferably the surfactant may be selected from the group comprising arbitarily ether or polyoxyethylenesorbitan ester of fatty acids, sucrose esters and fatty acids, polyethylene glycol-15-hydroxystearate, polyoxyethylenesorbitan natural or gidrirovannoe castor oil, polyoxyethylene-polyoxypropylene copolymer derived synthetic vitamin E, the glycerides macrogol fatty acids and their mixture. More preferably the surface-active substance can be broadcast sakh the roses and fatty acids, polyoxyethylenesorbitan natural or gidrirovannoe castor oil, polyethylene glycol-15-hydroxystearate, polyoxyethylene-polyoxypropylene copolymer or their mixture.

Solid dispersion in accordance with the present invention can be obtained using one of the components, or a combination of the water-soluble polymer, the water-soluble saccharide and surfactants. For example, the solid dispersion can be obtained by surface modification of the particles revaprazan using polyvinylpyrrolidone, fatty acid ester and sucrose and polyoxyethylenesorbitan natural or hydrogenated castor oil.

The number revaprazan entered as the active ingredient in the solid dispersion in accordance with the present invention, depends on the dosage form, administered to achieve a therapeutic effect, for example for the treatment of ulcers. For example, the dosage form may contain revaprazan in the range from 10 to 600 mg, in particular from 50 to 400 mg Although the average particle size revaprazan is not limited, the average particle size may be approximately 50 micrograms or less.

The amount of the water-soluble polymer, the water-soluble saccharide or a surfactant which is solid is th dispersion in accordance with the present invention, can be adjusted based on the properties of the resulting solid dispersion. Preferably the particles revaprazan can be surface modified one component from among the water-soluble polymer, the water-soluble saccharide, a surfactant and mixtures thereof in amounts of from about 5 to 900 parts by weight, preferably from 20 to 200 parts by weight based on 100 parts by weight of revaprazan. More preferably, the particles revaprazan superficially modify 5-30 parts by weight of polyvinylpyrrolidone, 20-100 parts by weight of fatty acid ester and sucrose and 10-100 parts by weight of polyoxyethyleneglycol natural or hydrogenated castor oil based on 100 parts by weight of revaprazan.

The present invention includes in its scope a pharmaceutical composition comprising a solid dispersion and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carrier composition in accordance with the present invention is any conventional diluents, dispersing agents, lubricants, etc. are Examples of diluents are lactose, xylitol, ▫ maltitol, cellulose, microcrystalline cellulose, white sugar, silicon dioxide, dextrin, dextran, dihydrophosphate calcium, xanthan gum, polyvinylpyrrolidone, carboxymethylcellulose, cellulose, glucose, Polydextrose, starch, piglatin zeerovannyy starch, corn starch, ProsolvTM, MicroceLacTM, hydroxypropylcellulose, hypromellose, mixtures thereof, etc. are Examples of dispersing agents are croscarmellose sodium, nizkozameshhennoj the hypromellose and other Examples of lubricants include sodium fumarate, magnesium stearate, calcium stearate, zinc stearate, magnesium trisilicate, talc and other Composition in accordance with the present invention also includes additives such as sodium bicarbonate, sodium salt glycolate starch, fatty acid ester and sucrose and other Type of pharmaceutically acceptable carrier can be appropriately selected by a person skilled in the technical field in accordance with the drug that you want to retrieve.

The pharmaceutical composition can be prepared in various forms, such as granule, tablet, capsule, dry syrup or powder, preferably in the form of granules, tablets or capsules. Such preparations can be prepared using conventional methods known in the pharmaceutical field. For example, the pharmaceutical composition may be prepared in the form of tablets by mixing the surface-modified solid dispersion with a diluent, dispersing agent, lubricant, etc. and compressing the mixture. On the other hand, the farm is citiesa the composition may be prepared in the form of tablets by granulating surface-modified solid dispersion with a diluent, etc., mixing the resulting granules with a diluent, dispersing agent, lubricant, etc. and pressing the mixture. The pharmaceutical composition can also be prepared in the form of capsules by filling capsules with the mixture. In addition, can be performed film coating or enteric coating for improved stability, taking the medicine and its appearance.

The present invention includes in its scope a method of obtaining a solid dispersion. The method includes: the suspension revaprazan and one component from among the water-soluble polymer, the water-soluble saccharide, a surfactant, or a mixture thereof in water to obtain a slurry, and drying the suspension.

As described above, the use of water as a medium makes it possible exception of the potential problems caused by the use of organic solvents, such as security problems associated with residual amounts of solvent.

In the method of obtaining a solid dispersion slurry may be obtained by adding revaprazan to aqueous solution containing water-soluble polymer, water-soluble saccharide, a surfactant or a mixture, with vigorous stirring an aqueous solution. On the other hand, the suspension can also be obtained by way of the addition as revaprazan, and one component from among the water-soluble polymer, the water-soluble saccharide, a surfactant and a mixture thereof to water and then by intensive mixing of the mixture. Mixing (dispersion) can be carried out using any conventional methods known in the pharmaceutical field. For example, the mixing may be carried out using a mixer equipped with a mixing blade, ultrasonic generator, microfluidizer, homogenizer, high pressure, propeller stirrer or homogenizer. A homogeneous suspension can be obtained by using a stirrer equipped with a stirring blade, and, in addition, a homogeneous suspension can be obtained by using a homogenizer or microfluidizer.

In the method of obtaining a solid dispersion drying can be carried out using conventional drying methods known in the pharmaceutical field, such as spray drying, freeze drying or vacuum drying. Preferably, the drying can be performed by spray drying. Spray drying is performed using any conventional methods using a granulator with a fluidized bed or spray dryers.

The present invention includes in its scope a method of receiving the Oia pharmaceutical composition, containing a solid dispersion.

For example, in accordance with the embodiment of the present invention, the granule can be obtained by a method that includes the suspension revaprazan and one component from among the water-soluble polymer, the water-soluble saccharide, a surfactant, or a mixture thereof in water to obtain a slurry and spray drying the suspension in pharmaceutically acceptable carrier. Suspension can be obtained in the same way as in the method of obtaining a solid dispersion.

Spray drying can be carried out by any conventional methods using a granulator with a fluidized bed, a cylindrical granulator, high speed granulator, etc. Pharmaceutically acceptable carrier used at the stage spray drying, may be a diluent, such as microcrystalline cellulose, lactose, corn starch, mannitol, potato starch, pregelatinized starch, cellulose, MicroceLacTM, ProsolvTM, dextran, dextrin, dihydrophosphate calcium, citric acid, succinic acid, etc.; dispersing agent, such as crosspovidone, sodium salt glycolate starch, croscarmellose sodium, sodium bicarbonate or nizkozameshhennoj hydroxypropylcellulose and others; lubricating substance, so is e as magnesium stearate, silicon dioxide, etc.; and solid surface-active substance, such as sucrose esters and fatty acids (Ryoto EsterTM, Mitsubishi Co.), sodium lauryl sulfate, etc.

In addition, in accordance with another variant of the present invention, the granule can be obtained by a method which comprises granulating by adding a binder solution to a mixture of solid dispersion and a pharmaceutically acceptable carrier.

The binder solution may be a water; C1-4-alcohol (e.g. ethanol); a mixture of water and C1-4-alcohol (e.g. ethanol solution) or a solution obtained by adding any conventional binders used in the pharmaceutical field, to the water, With1-4-alcohol (e.g. ethanol) or a mixture of water and C1-4-alcohol (e.g. ethanol solution). The binder is at least one substance selected from the group comprising polyvinyl alcohol, xanthan gum, Arabic gum, alginic acid or its salts, polyvinylpyrrolidone, gelatin, hypromellose, carbomer, hydroxypropylcellulose, ethylcellulose and their mixture. The amount of binder is not limited, and may be about 10% wt. from the total mass of the granular pharmaceutical composition. When the amount of binder exceed the AET 10% wt. from the total mass of the granular pharmaceutical composition, the pellet can be cured and, therefore, its disintegration can be prolonged. When necessary, the binder may also include polyoxyethylenesorbitan natural or gidrirovannoe castor oil (e.g., Cremophor RH 40TM).

In addition, in accordance with another variant of the present invention, the tablet can be obtained by a method which comprises pressing a mixture of solid dispersion and a pharmaceutically acceptable carrier or compressing the mixture of pellets, derived from the solid dispersion and a pharmaceutically acceptable carrier (e.g., lubricants such as magnesium stearate).

In addition, in accordance with another variant of the present invention, the capsule can be obtained by a method which comprises filling capsules with a mixture of solid dispersion and a pharmaceutically acceptable carrier or filling capsules with a mixture of pellets, derived from the solid dispersion and a pharmaceutically acceptable carrier.

Further, the present invention is described in more detail with reference to the following examples. These examples serve to illustrate the invention and are not intended to limit its scope.

Example 1: Preparation of solid dispersion

In 2000 ml of purified water was dissolved 20 g of irrigation is of solerrain and 80 g of fatty acid ester and sucrose (Ryoto Ester L1695 TM, Mitsubishi Co., Japan). When mixing the resulting solution with a mechanical stirrer was added 100 g revaprazan receive a suspension. The resulting suspension is subjected to spray drying using a spray minissale (Buchi 190) under the conditions: temperature input 120-130°C and outlet temperature of 80-90°C; get a solid dispersion.

Examples 2-19: Preparation of solid dispersion

Solid dispersions get analogously to example 1 in accordance with the components and amounts shown in table 1. The amount of purified water is 10 ml per 1 g of the total quantity of components used.

Table 1
Etc.RevaprazanPolyvinyl-pyrrolidoneThe sucrose esters and fatty acidsGelucire 44/14TMSolutol HS 15TMPolysorbate 80TMCremophor RH 40TMPoloxamer 407TM
2100 g150 g
3100 g100 g
4100 g50 g
5100 g5 g
6100 g100 g
7100 g 50 g
810 g50 g
9100 g10 g30 g
1010 g90 g
11100 g10 g70 g15 g
12100 g20 g60 g20 g
13100 g20 g15 g40 g
14100 g15 g120 g20 g
15100 g15 g11,25 g26,25 g
16100 g20 g10 g10 g50 g
17100 g20 g15 g 60 g
18100 g10 g60 g20 g20 g
1910 g50 g10 g10 g

Example 20: Preparation of solid dispersion

In 2000 ml of purified water was dissolved 20 g of β-cyclodextrin and 80 g of lactose. When mixing the resulting solution with a mechanical stirrer was added 100 g revaprazan receive a suspension. The resulting suspension is homogenized by passing three times through microfluidizer at a pressure of 10000-15000 psi (68,95-103,4 MPa). The resulting suspension is subjected to spray drying using a spray minissale (Buchi 190) under the conditions: temperature input 120-130aboutC and outlet temperature of 80-90aboutWith; get a solid dispersion.

Examples 21-32: Preparation of solid dispersion

Solid dispersions get analogously to example 20 in accordance with the component of the AMI and quantities presented in table 2. The amount of purified water is 10 ml per 1 g of the total quantity of components used.

Table 2
Etc.RevaprazanHydroxy-propyl-β-cyclo-dextrinLactoseMannitolHydroxy-propeller-celluloseVitamin E TPGSTMPolyvinyl-pyrrolidonePolyethylene glycol 6000Poloxamer 407TM
21100 g100 g20 g
22100 g60 g
23 100 g100 g
2410 g60 g20 g20 g
25100 g20 g60 g
26100 g50 g
27100 g100 gthe
28100 g50 g50 g
29100 g150 g50 g
30100 g10 g10 g
31100 g60 g50 g
32 60 g50 g50 g

Example 33: Preparation of solid dispersion

To 110 ml of purified water add 10 g polyvinylpyrrolidone, 15 g of Cremophor RH 40TM(produced by BASF Co.) and 70 g of sucrose esters and fatty acids (Ryoto Ester L1695TM, Mitsubishi Co., Japan). When mixing the resulting solution with a mechanical stirrer slowly add 100 g revaprazan receive a suspension. The resulting suspension is homogenized using a homogenizer at a speed of 10,000 to 15,000 rpm for ten minutes. The resulting suspension is subjected to spray drying using a granulator fluidized bed (manufactured by Glatt Co.) in the conditions: temperature input 110-130aboutC and the pressure input from 1.0 to 2.0 bar, get a surface-modified solid dispersion.

Example 34: Obtain granules containing a solid dispersion

To 110 ml of purified water add 10 g polyvinylpyrrolidone, 15 g of Cremophor RH 40TM(produced by BASF Co.) and 50 g of sucrose esters and fatty acids (Ryoto Ester L1695TM, Mitsubishi Co., Japan). When mixing the resulting solution with a mechanical stirrer slowly on billaut 100 g revaprazan, receive a suspension. The resulting suspension is homogenized by stirring at a speed of 300 rpm or more within 2 hours, get gomogenizirovannogo suspension.

Using a sieve of 20 mesh sieved to 67.5 g of microcrystalline cellulose, 20 g of crosspovidone, 10 g of sodium bicarbonate, 10 g of sodium salt glycolate starch, 20 g of sucrose esters and fatty acids (Ryoto Ester L1695TM, Mitsubishi Co., Japan) and mixed together, get the media for the production of pellets.

When the fluidization medium for the production of granules in the granulator, fluidized bed (manufactured by Glatt Co.) obtained above gomogenizirovannogo suspension is subjected to spray drying under the conditions: temperature input 50-60°C, outlet temperature of 35-45°C and the pressure input 1.5 bar, get a solid dispersion in a granular form.

Examples 35-40: Obtain granules containing a solid dispersion

Solid dispersion in granular form is prepared analogously to example 34 in accordance with the components and amounts shown in table 3. The amount of purified water is 1.5 ml per 1 g of the total quantity of components used.

Example 41: Obtain granules containing a solid dispersion

The mixture 481,5 g microcrystalline cellulose, 360 g of sucrose esters and fatty the acid (Ryoto Ester L1695 TM, Mitsubishi Co., Japan), 90 g of crosspovidone and 90 g of sodium bicarbonate sieved using a sieve of 20 mesh and then add 1260 g of the solid dispersion obtained in accordance with example 9. The resulting mixture is stirred at high speed granulator for 1 minute. A binder solution is prepared by dissolving 135 g Cremophor RH 40TMin 90 ml of 50% (vol./about.) ethanol solution. While stirring the mixture at high speed granulator at a speed of 300 rpm for 3 minutes to the mixture of the binder solution to obtain granules containing a solid dispersion.

Examples 42-44: Obtain granules containing a solid dispersion

Granules containing a solid dispersion is prepared analogously to example 41 in accordance with the components and amounts shown in table 4.

Table 4
Example 42Example 43Example 44
Solid dispersion of example 11200 g
Solid dispersion of example 51260 g
Solid dispersion of example 111170
Microcrystalline cellulose700 g700 g
Lactose200 g
Crosspovidone100 g100 g
Sodium bicarbonate100 g100 g
The sucrose esters and fatty acids300 g
Cremophor RH 40TM300 g300 g100 g

Examples 45-48: Obtain granules containing surface-modified solid dispersion

In accordance with the components and amounts shown in table 5, are prepared containing a solid dispersion granules in a manner analogous to the method of example 41, except that Cremophor RH 40TMdo not use, and ka is este binder solution using 90 ml of 50% (vol./about.) ethanol solution.

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Table 5
Example 45Example 46Example 47Example 48
Solid dispersion of example 31200 g
Solid dispersion of example 61200 g
Solid dispersion of example 141530
Solid dispersion of example 171170
Microcrystalline cellulose500 g500 g700 g700 g
Lactose300 g
Corn starch300 g200 g
Crosspovidone90 g100 g100 g100 g
Sodium bicarbonate90 g100 g
Glycolate starch, Na-salt100 g100 g
The sucrose esters and fatty acids200 g

Example 49: Obtain granules containing a solid dispersion

A mixture of 500 g of microcrystalline cellulose, 360 g of sucrose esters and fatty acids (Ryoto Ester L1695TM, Mitsubishi Co., Japan), 90 g of crosspovidone and 90 g of sodium bicarbonate sieved using a sieve of 20 mesh and then add 1300 g of the solid dispersion obtained in accordance with example 9. The resulting mixture is stirred at high speed granulator for 1 minute. The binder solution preparing is by dissolving 20 g of hydroxypropylmethylcellulose in 100 ml of 80% (vol./about.) ethanol solution. While stirring the mixture at high speed granulator at a speed of 300 rpm for 3 minutes to the mixture of the binder solution to obtain granules containing a solid dispersion.

Example 50: Getting tablets

Mix 200 g of the solid dispersion obtained in accordance with example 1, 150 g of microcrystalline cellulose, 20 g of sodium salt of glycolate starch, 20 g of crosspovidone and 10 g of magnesium stearate and then compressed using tabletiruemogo press, get the pills (the weight of one tablet: 800 mg; number revaprazan in one tablet: 200 mg).

Experimental example 1: A test for dissolution

Solubility containing revaprazan solid dispersion measured in purified water. Solid dispersion containing 1 g revaprazan add in chemical beaker containing 50 ml of purified water, which is then intensively stirred using a magnetic stirrer at 25°C on a water bath for 6 hours. 1, 2 and 6 hours, each sample is withdrawn and filtered using 0.45 µm filter. The filtrate is diluted with methanol in an amount such that the absorption of the effluent was in the range of from 0.2 to 1.0. Then measure the absorption of the diluted filtrate at 270 nm using UV spectrophotometer (Agilent 8453, Agilent technologies, USA). From the obtained absorption values determine the concentration is of revaprazan using the standard curve.

Approximately 20 g of standard revaprazan dissolved in methanol, while the total volume of the solution reaches 10 ml In a 100 ml flask was added 1 ml of the resulting solution and then add purified water to obtain a standard reference solution. Standard original solution was diluted with purified water to obtain a standard solution of 2 μg/ml, 5 μg/ml, 8 μg/ml and 10 μg/ml to Measure the absorption of each of standard solutions with a maximum length of absorption at 270 nm, to obtain a standard curve. A standard curve medium is almost linearly up to (0,0) (correlation coefficient r2>0,98). The results are presented in table 6.

Table 6
Solubility (µg/ml)
Revaprazan powder173
Example 2905
Example 3505
Example 4237
Example 6303
Example 7240
Example 18 803

As for the data of table 6, we can see that the solubility of the surface-modified dispersion in accordance with the present invention is significantly improved.

Experimental example 2: A test for adhesiveness and agglutination

Measured bulk density and apparent density of the powder revaprazan and surface-modified solid dispersions obtained in accordance with examples 3 and 6, and determine the coefficients Carr to measure their fluidity. Approximately 3 g of the solid dispersion carefully add in a plastic measuring cylinder and measure the volume to get the density. Then the cylinder tap 3000 times using densimeter bulk density to measure the volume, and determine bulk density. From the obtained bulk density and the bulk density calculated coefficient Carr to evaluate fluidity. The results are presented in table 7.

Table 7
The coefficient Carr
Revaprazan powder41,2
Example 3of 21.9
Example 6 17,6

ρ: bulk density

ρt: bulk density

The coefficient Carr = (ρ-ρt)/ρt·100

As for the data of table 7, the powder revaprazan having high adhesion and agglutination properties, has a coefficient of Carr 40% or more and has a very low turnover. On the other hand, surface-modified solid dispersion has a high fluidity and its characteristics improved compression.

Experimental example 3: The study of the surface of the particles using a scanning electron microscope

The surface of the particles containing revaprazan solid dispersion is studied using scanning electron microscope (SEM). The samples prepared in accordance with examples 6 and 11, fixed on the metal rack, attached double-sided tape and then coated with platinum using an ion-napylyaemogo device (JFC-1100E, Jeol Co., Japan) in an argon atmosphere. Each coated sample is placed in a SEM (JSM 5410LV, Jeol Co., Japan). To study the surface of the particles increase set at a voltage of 15 kV. As a reference example of the shape of the particles revaprazan also studied using polarizing microscope for comparison with particles of surface-modified solid dispersions described above. Revaprazan pomeshaetsa glass slide and then drip a few drops of mineral oil for distribution. Sample cover covering the glass and placed on a movable table polarizing microscope (Nikon eklipse E600 POL, Nikon Co., Japan) to study the shape of the crystal, and the angle of polarization regulate.

As for the data of Fig. 3 and 4, revaprazan gives no images of crystals. However, containing revaprazan dispersions exhibit a crystalline form, covered with modifying the surface of the material.

Experimental example 4Comparative test for dissolution

Comparative test for dissolution is carried out for the evaluation of dissolution profiles of surface-modified solid dispersions in accordance with the present invention. As a comparative sample prepared containing revaprazan capsule. In particular, 50 mg powder revaprazan mixed with 10% (wt./wt.) sodium salt glycolate starch as a dispersing agent. The mixture is filled hard gelatin capsule. Solid dispersion obtained in accordance with example 3 is mixed with 10% (wt./wt.) sodium salt glycolate starch and then the obtained mixture is filled hard gelatin capsule. The test for dissolution is carried out with the use of tablets obtained according to example 36, and the above-described samples in 900 ml of 0.1 n HCl solution at a temperature of 37±0.5°C and the stirring speed of 50 rpm every 15, 30, 45, 6, and 90 minutes select a sample volume of 3 ml and immediately selected number of offsetting the same amount of protection. From selected samples of the dissolution measure the degree of dissolution by quantitative determination of the concentration revaprazan using UV spectrophotometer at 270 nm. The results are presented in Fig. 1.

As for the data of Fig. 1, the powdered drug revaprazan has a dilution of 30% or less, while the preparations in accordance with the present invention have a degree of dissolution up to 95 % or more for 30 minutes.

Experimental example 5: Pharmacokinetic studies

Choose a dog breed Beagle weighing approximately 10 kg, determine their weight and examined with the naked eye whether or not they have any wounds. Before the introduction of the materials tested dogs breed Beagle does not give any food except water for 15 hours. Then the tablet revaprazan (comparative product)obtained from a mixture revaprazan, lactose, sodium salt glycolate starch and magnesium stearate, and the tablet obtained in accordance with example 36, administered orally with 20-40 ml of water. Entered the dosage is 200 mg revaprazan on the subject. Before the introduction and after 0,25, 0,5, 1, 1,5, 2, 3, 4, 6 and 8 hours after administration select approximately 1.0 ml of blood using treated heparin syringe. Selected blood is centrifuged at a speed of 3000 rpm for 5 minutes, separated the second serum is loaded into the tube effendorf and leave at -20°C. Then selected frozen blood is thawed and using HPLC to measure the amount of revaprazan in serum.

Measure the maximum concentration (Cmaxand the time required to reach the maximum concentration (Tmax), using values obtained from curve (concentration in serum, and determine the area under the curve (concentration in serum)from time 0 to 8 hours (AUC0-8 h) using the trapezoid rule. The area under the curve AUC0-∞measured using extrapolation rules of the line. The area under the curve (concentration in serum)is the time from the end result to ∞ is determined by dividing the final concentration in serum at a constant removal. The concentration of drugs in blood and pharmacokinetic parameters represented by the values (mean ± standard error), and the statistical significance of the results of the experiment in vivo test using mnogotranshevogo Duncan test in accordance with the analysis of authenticity.

The area under the curve AUC0-8 h(ng·h/ml) tablets prepared according to example 36, is 1401±332, which is five times higher than the AUC0-8 h(ng·h/ml), i.e. 261±52, conventional tablets revaprazan (p<0,05). As for Cmaxobtained from the curve (concentration in the blood)-BP is me, example 36 has a value of 652 ng/ml, and normal tablet revaprazan - 165 ng/ml.

1. Solid dispersion to obtain a pharmaceutical composition in which particles revaprazan surface-modified water-soluble polymer with water-soluble saccharide, a surface-active substance or mixtures thereof,
where water-soluble polymer selected from the group comprising polyvinylpyrrolidone, hypromellose, hydroxypropylcellulose, polyethylene glycol, water-soluble copolymer of polyacrylic acid, polyvinyl alcohol and their mixture,
and where the water-soluble saccharide selected from the group comprising lactose, white sugar, sucrose, mannitol, sorbitol, xylitol, trehalose, ▫ maltitol, dulcet, Inositol, dextrin, cyclodextrin and their mixture.

2. Solid dispersion according to claim 1, where the surfactant is selected from the group comprising arbitarily ether or polyoxyethylenesorbitan ester of fatty acids, sucrose esters and fatty acids, polyethylene glycol-15-hydroxystearate, polyoxyethylenesorbitan natural or gidrirovannoe castor oil, polyoxyethylene-polyoxypropylene copolymer derived synthetic vitamin E, polyoxyethyleneglycol ester, glycerides of microgel-fatty acids, polyglycerol ester of fatty acid, bile acid, sodium lauryl sulfate, lecithin, literally a fatty acid ester, polyoxyethylenated and their mixture.

3. Solid dispersion according to claim 1 where the particles revaprazan surface modified polyvinylpyrrolidone, sucrose esters and fatty acids and polyoxyethylenesorbitan natural or gidrirovanny castor oil.

4. Solid dispersion according to claim 1 where the particles revaprazan surface modified using one component from among the water-soluble polymer, the water-soluble saccharide, a surfactant and mixtures thereof in an amount of 5 to 900 parts by weight based on 100 parts by weight of revaprazan.

5. Solid dispersion according to claim 4, where the particles revaprazan surface modified using one component of a number of water-soluble polymer, the water-soluble saccharide, a surfactant and mixtures thereof in an amount of from 20 to 200 parts by weight based on 100 parts by weight of revaprazan.

6. Solid dispersion according to claim 1 where the particles revaprazan surface modified using 5-30 parts by weight of polyvinylpyrrolidone, 20-100 parts by weight of sucrose esters and fatty acids and 10-100 parts by weight of polyoxyethyleneglycol natural or hydrogenated castor oil based on 100 parts by weight of revaprazan.

7. Pharmaceutical composition containing a solid dispersion according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, where f is rmaceuticals composition is in the form of pellets, tablets, capsules, dry syrup or powder.

9. A method of obtaining a solid dispersion according to any one of claims 1 to 6, where the method comprises adding revaprazan to aqueous solution of one of the water-soluble polymer, the water-soluble saccharide, a surfactant, or a mixture thereof to obtain a suspension; and drying the suspension.

10. The method according to claim 9, where the drying is carried out using spray drying.

11. The way to obtain pellets, which comprises a solid dispersion according to claims 1-6, where the method comprises adding revaprazan to aqueous solution of one of the water-soluble polymer, the water-soluble saccharide, a surfactant, or a mixture thereof to obtain a slurry; and spray drying the suspension in pharmaceutically acceptable carrier.

12. The way to obtain granules, where the method comprises granulating by adding a binder solution to a mixture of solid dispersion according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

13. The method according to item 12, where the binder solution is a water; C1-4-alcohol; a mixture of water and C1-4-alcohol, or a solution obtained by adding at least one binder selected from the group comprising polyvinyl alcohol, xanthan gum, Arabic gum, alginic acid or its salts, polyvinylpyrrolidone, gelatin, hydroxy what mobilecellular, carbomer, hydroxypropylcellulose, ethylcellulose and their mixture to water, C1-4-alcohol or a mixture of water and C1-4-alcohol.

14. The method according to item 13, where the binder solution further includes polyoxyethylenesorbitan natural or gidrirovannoe castor oil.

15. The method of producing tablets, where the method includes compressing the mixture of the solid dispersion according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier or compressing the mixture of pellets, derived from the solid dispersion according to any one of claims 1 to 6, and a pharmaceutically acceptable carrier.

16. A method of obtaining a capsule, where the method includes filling the capsules with a mixture of solid dispersion according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier or filling capsules with a mixture of pellets, derived from the solid dispersion according to any one of claims 1 to 6, and a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention concerns medicine, particularly gastoenterology, and concerns treating ulcerative colitis and Crohn's disease. That is ensured by the oral introduction of the probiotic Bifiform in dose 2-3 capcules. It is followed by the 4-5-fold introduction of mesenchymal stem cells in number 150-200 mil. cells in 0.5 to 1.5 ml into a mucous membrane of changed intestinal segments. Further, Bifiform is introduced in dose 1 capsule 3 times a day for 3 weeks.

EFFECT: method provides higher clinical effectiveness in said diseases.

3 ex

FIELD: medicine.

SUBSTANCE: invention refers to a pharmaceutical composition, particularly a composition for treating and/or preventing mucositis. The composition containing an effective amount of sanguinarine or chelerythrine in the form of a luteic acid salt mixed with appropriate carriers and/or excipients for treating and/or preventing mucositis. The chelerythrine and luteic acid salt. The sanguinarine and luteic acid salt. The use of sanguinarine or chelerythrine in the form of their lutec acid salts for preparing drugs for treating and/or preventing mucositis.

EFFECT: composition described above of sanguinarine or chelerythrine in the form of the lutec acid salts is effective for treating and/or preventing mucositis.

10 cl, 8 ex

FIELD: medicine.

SUBSTANCE: declared invention refers to an agent for treating ulcer including as an effective ingredient composite hydrotalcite in the form of particles, which contains zinc in the form of a solid solution and presented by formula (MgaZnb)1-xAlx(OH)2(An-1)x/n·H2O, wherein An-1 means CO32-, SO42- or Cl-, n is equal to 1 or 2, and x, a, b and m have the values fulfils the following conditions 0.18≤x≤0.4, 0.1≤a≤1, 0≤b≤0,5, 0≤m<1. Said agent may be presented in the granular or fine-grained form, suspension form or tableted form. The invention also refers to a method of treating peptic ulcer by the oral introduction of an effective amount of said hydrotalcite.

EFFECT: declared invention has an effective effect in treating peptic ulcer in an individual or a mammal, nor damaging a mucous membrane of internal walls of stomach, and possesses low probability of side effects.

17 cl, 6 tbl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzimidazole derivatives of general formula I wherein: R1 = CN, halogen or C(=O)CH3; R2 means methyl or H; R3=H or halogen; R4 and R5 independently mean methyl or ethyl, or R4 and R5 together with a carbon atom whereto attached form C3-6cycloalkyl or 5-6-member heterocycloalkyl; R6 and R7 independently mean H, halogen, methyl or ethyl; or their pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, and their application in therapy.

EFFECT: compounds may be used in treating osteoarthritis, chronic tendinitis, pelvic pain and peripheral neuropathy, gastroesophageal reflux disease, irritable bowel syndrome and overactive bladder.

39 cl, 34 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new benzimidazole derivatives of general formula (I) or to its pharmacologically acceptable salts wherein R1 represents a C6-aryl group which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), or a heterocyclic group which represents pyridyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, tetrahydropyranyl, tetrahydrofuranyl which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), R2 represents a C1-C6 alkyl group, R3 represents a C6-aryl group which can be substituted by 1-2 groups optionally specified in a group of substitutes (a), Q represents a group represented by formula =CH-, or a nitrogen atom and a group of substitutes (a) represents a group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a carboxyl group, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, an amino group, a 4-morpholinyl group and a di-C1-C6 alkyl)amino group. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I), to a PPARγ activator/modulator based on the compound of formula (I), to using the compound of formula (I), to a method of reducing blood glucose, to a method of activating PPARγ, a method of treating and/or preventing said pathological conditions.

EFFECT: there are produced new benzimidazole derivatives showing PPARγ modulatory activity.

41 cl, 2 dwg, 6 tbl, 76 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine and is intended for prevention of ulcer formation in stomach, caused by application of non-steroid anti-inflammatory medications. Solution of taurine is applied in dose range from 3.5 to 14.3 mg/kg before meal. It is administered for 7 days before application of non-steroid anti-inflammatory medications.

EFFECT: method makes it possible to increase resistance of stomach mucosa to injury by non-steroid anti-inflammatory medications.

FIELD: medicine.

SUBSTANCE: what is offered is a solid dosage pharmaceutical composition containing a combination of acetylsalicylic acid and ethylmethyl hydroxypyridine malate and ethylmethyl hydroxypyridine succinate possessing antiaggregant, lipid-regulating and gastroprotective activities. What is shown is substantial prolongation of shelf life of the solid dosage form.

EFFECT: pharmacological and pharmacokinetic findings of the new composition make perspective in manufacturing of the solid dosage drugs for preventing and treating obesity, pathological conditions of the cardiovascular system, preventing ischemic disorders with manifested atherosclerosis, old infarction, ischemic stroke; peripheral artery disease.

10 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, and aims at treating chronic gastritis with chronic erosions. If observing endothelial proliferation and angiomatosis of mucosal stroma vessels within chronic erosion, the latter is endoscopically coagulated by monopolar diathermocoagulation or silver nitrate chemical coagulation. It is followed by prescribing bismuth salts orally for impregnation of a coagulation crust.

EFFECT: method enables higher clinical effectiveness.

2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyridine derivatives of formula (I), where R denotes a linear alkyl with 4-8 carbon atoms. The invention also relates to a pharmaceutical composition based on a compound of formula (I), use of the compound of formula (I), a method of preventing or treating diseases caused by Helicobacter pyroli bacteria and/or diseases associated with secretion of gastric juice, and a method of producing a pyridine derivative of formula (I).

EFFECT: novel pyridine derivatives of formula (I), having useful biological properties, are obtained.

9 cl, 2 dwg, 8 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and aims at treating erosions and ulcers of gastric mucosa. Esomeprazole 20 mg is prescribed once a day before meals. It is added with prescribing a mixture of lyophilised culture Lactobacterium plantarum 8P -A3 4×109 in 1 ml of suspension and almagel in ratio 1:1. The mixture is prepared before use. The dose is 25 ml 3 times a day 30-40 minutes after meal. The course is 21 days.

EFFECT: method provides epithelised defects, reduced inflammations and dystrophic changes of the mucosa.

3 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and medicine. A composition represents a powder of a substance containing a consortium of immunoglobulins IgA, IgG and IgM and target additives able to form a stable foam structure, specified in: polyethylene glycol, albumin, gelatine, pectin, casein, caseinate, casein hydrolysate, hydroxypropyl cellulose, polyglucin, dextrin, tragacanth, aerosil, glycine, L-lysine monohydrochloride, L-arginine monohydrochloride, glucose, maltose, mannitol, lactose or their mixtures; it is characterised by porous structure and fragility, has a relative disintegration shrinkage at least 10 %, equivalent pore diameter 10-110 mcm at particle size no more than 100 mcm and a resting angle less than 50° and represented in the form of a solid capsule in the following proportions in 1.0 g of the composition: the consortium of immunoglobulins IgA, IgG and IgM 0.05-0.95 g; target additives - the rest with the capsule coated with a layer of a enterosoluble substance specified in: shellac, oleic acid, hydroxypropyl cellulose, cellulose acetate phthalate, bee wax, Tween-20, Tween-80, castor oil, polyethylene oxide or their mixture.

EFFECT: invention provides the isotropic filling of the 100% preset volume of the solid capsules that exceeds the effect of a similar composition by 5%, the maximum isotropic filling of the solid capsules ensures precise dosages of the consortium of immunoglobulins.

4 cl, 4 ex

FIELD: process engineering.

SUBSTANCE: invention relates to capsule comprising hollow tubular case 2 and cap 3. Said case and cap define volume there between and are furnished with complementary latches 12, 21 to lock cap 3 on case 2 in completely closed position. Said latches 12, 21 comprises lock ring 12 arranged on case 2 and ledge 21 arranged on cap 3. There is, at least one air vent hole 14 made up of axial recess on case outer surface to allow communication of fluids between inner volume and atmosphere. Capsule is used for dispensing fluids.

EFFECT: fluids communicated between inner volume and atmosphere.

10 cl, 8 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, particularly a technology of a new dosage form of 3,31-diindolylmethane. A method consists in mixing 3,31-diindolylmethane and a liquid fatty excipient and adding a wedding agent. In mixing, the prepared mixture is heated to 35-45°C to prepare a solution. Then the prepared solution is cooled to 21-23°C to fill gelatine capsules in the following proportions, g/capsule: 3,31-diindolylmethane - 0.01-0.1, the liquid fatty excipient - 0.05-0.1, the wedding agent 0.4-0.45. The prepared drug in the form of soft gelatine capsules containing 3,31-diindolylmethane in the form of the solution enables higher bioavailability of the active substance.

EFFECT: prepared drug is non-toxic, safe in prolonged introduction, has no local irritant action, no toxic effect on the immune and reproductive systems.

4 cl, 4 dwg, 7 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to a medicine for treating depression. The oral medicine for treating depression prepared from a jujuba extract containing jujube cyclic adenosine monophosphate (jujuba cAMP) and an additional ingredient taken from a group consisting of a pharmaceutically acceptable carrier, an additive, an adjuvant and combination thereof. A method for preparing jujube cyclic adenosine monophosphate (jujuba cAMP) taken as an ingredient of the medicine for treating depression, involving the stages: (a) jujube extraction in water and alcohol to produce a primary extract, (b) primary extract purification to produce a secondary extract wherein the jujuba cAMP concentration in the secondary extract is higher than that in the primary extract wherein the stage (b) is performed by jujuba cAMP chromatography of the primary extract with the use of macroporous resins bound with an aldehyde group.

EFFECT: medicine is effective for treating depression, has no side effects.

16 cl, 7 dwg, 2 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, oncology, and is applicable for photodynamic therapy of malignant growths. That is ensured by introducing a photosensitiser and conducting light illumination of the new growth at wave length corresponding to a maximum absorption of chlorine derivatives. The photosensitiser is presented by a gelatinous capsule with powder microparticles of chlorine derivatives mixed with lyophilised spirulina platensis. Each powder microparticle is coated with a protective acid-resistant film. The gelatinous capsule is introduced orally. Each gelatinous capsule contains the ingredients in the following proportions (Mg): chlorine derivatives - 1-1.5; spirulina platensis - 100-150; protective acid-resistant film - 50-75; calcium stearate - 0.5-0.75.

EFFECT: method enables providing higher clinical and preventative effectiveness in malignant new growths.

8 cl, 1 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, in particular - to composition of a medication possessing antiviral action and manufactured in the form of solid gelatine capsules as well as to such medication production method. The antiviral medication contains granules the active substance represented by sodium salt of 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazin-7-on, a dehydrate and physiologically acceptable accessory substances: starch as filler and disintegrant and talc as the anti-friction substance. The granules size is within the range of 0.5-0.63 mm. The gelatine capsules weight is from 0.290 to 0.300 g. The method for production of the antiviral medication in the form of granules contained in gelatine capsules is implemented by way of wet granulation.

EFFECT: according to the invention, the medication is noted for a pronounced virus-inhibiting action, satisfactory organoleptic properties and pharmacological safety and extends the arsenal of antiviral medications.

12 cl, 3 dwg, 7 tbl, 3 ex

Forming of capsules // 2450798

FIELD: process engineering.

SUBSTANCE: invention relates to chemistry and pharmaceutics, particularly, to method and device for producing capsule with solid shell wherein capsule components are formed from material to be gelled after heating, for example, HPMC. Drying conditions after dipping are accurately controlled for controlling drying rate.

EFFECT: heater for multiple dies.

21 cl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, and concerns a pharmaceutical composition in the form of capsules, containing as active substances 3,31-diindolylmethane and epicatechin-3-gallate, and a method for making this composition. A method consists in mixing 3,31-diindolylmethane and epicatechin-3-gallate with a liquid fatty excipient and adding a wedding agent. In mixing, the prepared mixture is heated to 35-45°C to prepare a solution. Then the prepared solution is cooled to 22-25°C to fill gelatine capsules in the following proportions, g/capsule: 3,3'-diindolylmethane - 0.01-0.1, epicatechin-3-gallate - 0.02-0.04, liquid fatty excipient - 0.05-0.1, wedding agent - 0.4-0.45. The prepared drug in the form of soft gelatine capsules containing 3,31-diindolylmethane and epicatechin-3-gallate in the form of a solution, enables increasing bioavailability of the active substances.

EFFECT: prepared drug is non-toxic, safe in prolonged introduction, has no local irritant action, no toxic effect on the immune and reproductive systems.

5 cl, 6 ex, 7 tbl, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, more specifically to an antiviral and interferonogenic amison preparation. The offered drug preparation is presented in the form of a capsule and contains the active substance amison (55.0-85.0 wt %) and target additives: lactose (11.0-44.0 wt %), aerosil (0.1-1.0 wt %), magnesium or calcium stearate (0.5-1.2 wt %) and talc (0-3.0 wt %).

EFFECT: invention provides the oral dosage form of amison for the first time presented in the form of capsules, storage-stable and enabling fast and complete release of the active substance.

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology and medicine, and represents a composition for treating and preventing a disorder related to digestive enzyme insufficiency, containing a set of coated particles; each said particle comprises a enteric-coated core wherein the core contains pancrelipase and the enteric coating contains 10-20 wt % of at least one enteric-coated polymer and 4-10 wt % of talc wherein said wt % are calculated from total weight of the coated particles and wherein the coated particles show pancrelipase enzymatic activity loss by no more than approximately 25% after 6 months of accelerated stability test.

EFFECT: invention provides enzyme activity stability.

47 cl, 14 ex, 35 tbl

FIELD: food industry.

SUBSTANCE: present invention relates to food additives composition. The composition of a poly-vitamin and mineral food additive includes at least one polyvalent metal, at least one oxidable vitamin and waterless dicalcium phosphate; weakly-coupled water is essentially absent from the said composition. One proposes a method for production of the said composition as well as methods for reduction of spots occurrence (caused by oxidation) on the poly-vitamin and mineral pill and stabilisation of decomposition characteristics of pills containing the said composition. Alternatively, one proposes the composition of a poly-vitamin and mineral additive containing the daily dose of at least one vitamin chosen from the group including 15 - 600 mg of vitamin C, 20 - 200 ME of vitamin E, at least one ion of polyvalent metal, chosen from the group including 0 - 400 mg of magnesium, 0 - 50 mg of zinc, 0 -12 mg of manganese, 0 - 4 mg of cuprum, 0 -300 mkg of chrome, 0 - 18 mg of ferrum and 100 - 1500 mg of calcium. In the said additive at least a part of calcium is in the form of waterless dicalcium phosphate; the additive essentially is free of weakly-coupled water.

EFFECT: invention allows to reduce the process of decomposition of vitamin and mineral additives and enhance their stability.

29 cl, 4 tbl, 2 ex

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