Controlled release solid drug

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, and concerns a controlled release drug exceeding an active ingredient in stability. The drug may show pharmacological effects stably and immediately after the introduction, and provides a prolonged pharmacological effect for a long period of time.

EFFECT: controlled release solid drug contains a combination of (1) antacid, (2) an immediate release portion containing an acid and base unstable compound, and (3) a prolonged release portion containing an acid and base unstable compound, and having a film which is dissolved at pH 6,5 and higher.

14 cl, 12 ex, 8 tbl

 

The technical field to which the invention relates

The present invention relates to solid dosage facility. In particular, the present invention relates to solid drug controlled release, which is excellent in stability of the active ingredient, may be pharmacological effects steadily and rapidly after the introduction and steady pharmacological effect over a long period of time.

The level of technology

As a proton pump inhibitor (hereinafter sometimes referred to as PPI (IIT)), such as compounds of benzimidazole (e.g., lansoprazole, omeprazole, rabeprazole, pantoprazole, ilaprazole and the like)have inhibitory effect on the secretion of gastric acid, a protective effect on the mucous membrane of the stomach and the like, they are widely used as therapeutic agents for peptic ulcer disease.

However, these compounds have low stability and unstable to moisture, temperature, light, acid and the like. These compounds are particularly unstable to acid and become extremely unstable when the pH of an aqueous solution or suspension becomes low. When administered orally, therefore, these compounds may not be sufficient and the efficiency, as they are destroyed by gastric acid, etc.

The stability of these compounds in dosage forms such as tablet, powder, fine granules, capsules and the like, may be lower than the stability of the compounds themselves, due to strong interactions with the other ingredients of the components in the medicinal product. As a result, the color change and the destruction can be observed during the production and storage.

Various attempts have been made in the pharmaceutical medicines containing these compounds as active ingredients, in order to overcome the instability of the compounds. For example, have been disclosed to the tablet, granule or fine granule containing particles of a kernel, containing the pit or its salt, or its optically active form, as active ingredient, and, in particular, pH-dependent soluble controlling the release film (enteric film) (reference patent 1). Thanks enteric film these drugs can suppress the destruction of the active ingredient of gastric acid, etc. But as for the dissolution of the enteric film in the gastrointestinal tract and absorption of medicines require some time, rapid demonstration of the pharmacological effect of early introduction hardly expected.

At the same time revealed disintegrating in the stomach hard drug-free enteric film, which contains an active ingredient unstable to acid, and at least one kind of component selected from metal oxides and metal hydroxides (reference patent 2). In addition, disclosed chewable tablet, free from enteric film, which contains an active ingredient unstable to acid, and at least one kind of component selected from carbonates of alkaline earth metals, metal oxides and metal hydroxides (reference to patent 3). These drugs can suppress the destruction of the active ingredient of gastric acid, etc. after the introduction and are suitable for rapid manifestation of pharmacological effects after injection. However, the pharmacological effect over a long period of time difficult for these medicines.

In addition, it is disclosed the application of the basic inorganic salt stabilizing the active ingredient upon receipt (refer to patent 4-6, the reference to non-patent is 1).

Also disclosed are various drugs having multiple different control systems release in combination for rapid manifestation of pharmacological effect poslesvecheniya and save pharmacological effect over a long period of time (reference to patent 7-11).

reference patent 1: JP-A-2004-292427

reference patent 2: JP-A-2003-327533

link to patent 3: JP-A-2005-154431

reference to the patent 4: JP-A-62-277322

reference to the patent 5: JP-A-2000-281564

reference to the patent 6: JP-A-2000-103731

reference to the patent 7: JP-A-2004-292442

reference to the patent 8: JP-A-2004-300149

reference to the patent 9: U.S. patent No. 6610323

reference to the patent 10: WO 01/51050

reference to the patent 11: WO 03/61584

reference to non-patent 1: "DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, 18 (13), 1437-1447 (1992)

Disclosure of inventions

Problems that are solved in the invention

There is a demand for improvement of solid medicinal product comprising an active ingredient having a high stability, in which the active ingredient is stable and fast exerts its pharmacological effect after the introduction, and pharmacological effect persists for a long period of time.

The authors of the present invention have conducted intensive studies and found that the solid drug, including (1) antacid, (2) the part of the immediate release, containing a compound unstable to acid and base, and (3) the part of a slow-release, containing a compound unstable to acid and base, and having a film that dissolves at pH 6.5 or above in combination, demonstrates the high stability of the active ingredient, the times, the t pharmacological effect of the active ingredient stably and quickly after the introduction and retains pharmacological effect over a long period of time, which led to completion of the present invention.

The ways to solve problems

Accordingly, the present invention provides [1] a solid drug controlled release, including (1) antacid, (2) the part of the immediate release, containing a compound unstable to acid and base, and (3) the part of a slow-release, containing a compound unstable to acid and base, and having a film that dissolves at pH 6.5 or above in combination;

[2] the drug of the above-mentioned [1], in which the film, which dissolves at pH 6.5 or above, contains one kind or a mixture of two or more kinds selected from the group consisting of a phthalate of hydroxypropylmethylcellulose, phthalate cellulose acetate, karboksimetiltselljulozy, copolymer of methyl methacrylate-methacrylic acid, copolymer of methacrylic acid-acrylate, copolymer of methacrylic acid-methyl acrylate-methyl methacrylate, succinate acetate hydroxypropylmethylcellulose, polyvinyl acetate phthalate and shellac;

[3] the drug of the above-mentioned [1], which is part of a slow-release includes a particle core containing a compound unstable to acid and base, an intermediate layer formed on the surface of the core particles, and a film that dissolves at a pH of 65 or higher formed through the intermediate layer;

[4] the drug of the above-mentioned [1], in which the compound unstable to acid, is an inhibitor of the proton pump (IIT);

[5] the drug of the above-mentioned [4], in which IIT is a compound represented by the formula (I):

where ring a is a benzene ring optionally having substituent(s), R1represents a hydrogen atom, aracelio group optionally having substituent(s), acyl group, or alloctype, R2, R3and R4are the same or different and each represents a hydrogen atom, alkyl group optionally having substituent(s), alkoxygroup, optionally having substituent(s)or amino group, optionally having substituent(s), and Y represents a nitrogen atom or CH, or its optically active form or its salt;

[6] the drug of the above-mentioned [4], where IIT represents lansoprazole, omeprazole, rabeprazole, pantoprazole, ilaprazole or its optically active form or its salt;

[7] the drug of the above-mentioned [1], in which the antacid represents at least one component selected from a metal oxide, metal hydroxide and carbó the ATA alkaline earth metal;

[8] the drug of the above-mentioned [1], in which a 1% aqueous solution or 1% water slurry of antacid has a pH less than 8,0;

[9] the drug of the above-mentioned [7], in which the oxide of the metal is at least one kind selected from the group consisting of magnesium oxide, magnesium silicate, dry gel of aluminum hydroxide and alumosilicate magnesium;

[10] the drug of the above-mentioned [7], in which the hydroxide of the metal is at least one kind selected from the group consisting of magnesium hydroxide, aluminum hydroxide, synthetic hydrotalcite, joint precipitate of aluminum hydroxide and magnesium hydroxide, joint precipitate of aluminum hydroxide, magnesium carbonate and calcium carbonate and joint precipitate of aluminum hydroxide and sodium bicarbonate;

[11] the drug of the above-mentioned [7], in which the carbonate of the alkaline earth metal is calcium carbonate or magnesium carbonate;

[12] the drug of the above-mentioned [1], in which the content of antacid is 5 mEq 50 mEq;

[13] the drug of the above-mentioned [1], in which the weight ratio of the content of the compound unstable to acid, part of the immediate-release and part of the slow release is 10:1-1:10;

[14] drug is redtwo the above-mentioned [1], which demonstrates the increase in intragastric medium pH to 4 or higher after 0.5 hours after oral administration to a mammal and time saving pH 4 or above not less than 14 hours per day; and

[15] solid drug, demonstrating the increase in intragastric medium pH to 4 or higher after 0.5 hours after oral administration to a mammal and time saving pH 4 or above not less than 14 hours a day.

The present invention is explained in detail in the following.

Solid drug controlled release according to the present invention includes (1) antacid, (2) the part of the immediate release, containing a compound unstable to acid and base, and (3) the part of a slow-release, containing a compound unstable to acid and base, and having a film that dissolves at pH 6.5 or above in combination.

In the present description, the terms "solid drug controlled release of the present invention" and "hard drug of the present invention" are used interchangeably, unless otherwise specified.

(1) Antacid

Solid drug of the present invention contains an antacid. Antacid will neutralize intragastric pH to release the connection is unstable to acid which is the active ingredient in the stomach, whereby the residual ratio of the compound is increased and sustained rapid pharmacological effect of the compounds may be shown. As antacid, which is used in the present invention, at least one kind of component selected from the group consisting of metal oxide, metal hydroxide or carbonate of the alkaline earth metal is preferred.

As the above-mentioned metal oxide is preferably used at least one kind selected from the group consisting of magnesium oxide, magnesium silicate (2MgO·3SiO2·xH2O), a dry gel of aluminum hydroxide (Al2O3·xH2O) and alumosilicate magnesium (Al2O3·MgO·2SiO2·xH2O), for all pharmaceutical agents.

Of these magnesium oxide is more preferred. Magnesium oxide for medical use, which is superior in acid reactivity and has neutralizing ability is preferred. As magnesium oxide, it is possible to apply the General method of production and commercially available product. What is called easily burned magnesium oxide, which is obtained by calcination at a low temperature, is preferred. Magnesium oxide obtained by calcination at a temperature of about 500°C to about 1000°C is about is a rule preferred and from the aspect of neutralizing the ability of magnesium oxide obtained by calcination at a temperature of about 600°C to about 900°C is preferable, and magnesium oxide obtained by calcination at about 800°C, is most preferred. Of these magnesium oxide magnesium oxide having a specific surface area according to the method of RESPONSE is typically 10-50 m2/g, preferably 20-50 m2/g is preferable.

In the present description, the specific surface area according to the method of RESPONSE is the specific surface area, measured by adsorption of nitrogen gas, where the specific surface area is measured based on the amount of nitrogen gas adsorbed a certain amount of surface of magnesium oxide and fine pores which receives gaseous nitrogen.

Examples of magnesium oxide include commercially available heavy magnesium oxide (manufactured by Kyowa chemical Industries Ltd.), heavy magnesium oxide (manufactured by Tomita Pharmaceutical Co., Ltd.), heavy N-magnesium oxide (manufactured by Kyowa chemical Industries Ltd.), light magnesium oxide (manufactured by Kyowa chemical Industries Ltd.) and similar. In particular, the heavy N-magnesium oxide (manufactured by Kyowa chemical Industries Ltd.) etc. is preferred.

As the metal hydroxide is at least one kind selected from the group consisting of hydroc the IDA magnesium, aluminum hydroxide, synthetic hydrotalcite (Mg6Al2(OH)16CO3·4H2O), joint precipitate of aluminum hydroxide and magnesium hydroxide, joint precipitate of aluminum hydroxide, magnesium carbonate and calcium carbonate and joint precipitate of aluminum hydroxide and sodium bicarbonate, all for the pharmaceutical agents is preferred. Of these magnesium hydroxide is preferred because of the disintegration properties of the medicinal product, the properties of solubility compounds are unstable to acid, etc.

As the above-mentioned carbonate, alkaline earth metal can be used calcium carbonate and magnesium carbonate for pharmaceutical agents, etc.

The above-mentioned metal oxide, metal hydroxide and a carbonate of the alkaline earth metal can be used alone or two or more kinds of them may be combined.

Some of the metal oxides and metal hydroxides polished surface of the device to obtain compositions in the production process of obtaining tablets with a fully or partially dark surface or dark area, line, or plane, or stick to press for tableting.

These properties significantly reduce performance. Thus, it was found that, when must be selected metal oxide sludge is the hydroxide of the metal, having the property of abrasion and adhesion to the press, the metal oxide and metal hydroxide, available from such properties can be used in combination, or they may be subjected to wet or dry granulation together with the additive, suitable for pharmaceutical products (for example, excipient, a binder, disintegrant and the like, described in the following (4)), whereby the polishing step and the adhesion property to the press can be suppressed.

The above antacid preferably has a pH not less than an 8.0, more preferably within the range of 8.0 to 12.0 when it was made in 1% aqueous solution or 1% water suspension.

The above antacid type in the number, allowing rapid dissolution of antacid to neutralize stomach acid, together with gastric disintegration of hard drugs and it is preferable to dissolve the compound unstable to acid, to prevent the destruction of unstable to acid compounds due to exposure to stomach acid. Although the number varies depending on the ability of each antacid to neutralize stomach acid in the solid medicinal product according to the present invention it is preferably 5 mEq 50 mEq, more preferably 10 IEC is - 50 mEq.

2) part of the immediate release

Part of immediate release solid dosage means of the present invention contains a compound unstable to acid and base.

In part of the immediate-release property of the release of the connection is unstable to acid, which is an active ingredient that is immediate release. In this description immediate release means the ratio of the extraction of the active ingredient within 30 minutes after the start of the test is not less than 85%, when the Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method) is performed using a suitable test solution (500 ml or 900 ml) under the conditions of rotation of the stirrer at 100 rpm. As the test solution of the compound unstable to acid, part of the immediate-release is used, for example, the test solution having the concentration of active ingredient is not more than 1/3 of the limit of solubility of the compounds are unstable to acid, after 100% dissolution in the test solution. Preferably use a 2nd fluid of the Japanese Pharmacopoeia Dissolution Test Method or water.

(2-1) the Compound unstable to acid

The above compound unstable to acid, is not particularly limited and may be any compound that becomes unstable as the result alongside the effects of gastric acid. As such a connection is unstable to acid, can be used, for example, anti-enzymatic agents such as IIT, eritromicina antibacterial compounds, serrapeptase, proselochnaya proteinase and the like, IIT is preferred.

As IIT, for example, a compound represented by the following formula (I) [hereinafter sometimes referred to simply as compound (I)]is preferred.

Examples of compound (I) include the compound represented by formula (I):

where ring A is a benzene ring optionally having substituent(s), R1represents a hydrogen atom, aracelio group optionally having substituent(s), acyl group, or alloctype, R2, R3and R4are the same or different and each represents a hydrogen atom, alkyl group optionally having substituent(s), alkoxygroup, optionally having substituent(s)or amino group, optionally having substituent(s), and Y represents a nitrogen atom or CH, or its optically active form or its salt.

In the above-mentioned compound (I), examples of the "substituent" of the "benzene ring optionally having substituent(s)" for ring A include a halogen atom, teenagr the PPU, the nitro-group, alkyl group optionally having substituent(s), a hydroxy-group, alkoxygroup, optionally having substituent(s), aryl group, alloctype, carboxypropyl, acyl group, alloctype, 5-10-membered heterocyclic group and the like. The benzene ring may be substituted by about 1 to 3 of these substituents. When the number of substituents is two or more, each Deputy may be the same or different. Of these substituents, halogen atom, alkyl group optionally having substituent(s), alkoxygroup, optionally having substituent(s), and the like are preferred.

Examples of the halogen atom include fluorine atom, chlorine, bromine and the like. Among them, the fluorine atom is preferred.

Examples of "alkyl group" of the "alkyl group optionally having substituent(s)"include C1-7alkyl group (e.g. methyl, ethyl, sawn, ISO-propyl, bucilina, isobutylene, second-bucilina, tert-bucilina, pentilla, hexeline, heptylene group etc) and the like. Examples of the "substituent" of the "alkyl group optionally having substituent(s)"include a halogen atom, a hydroxy-group, C1-6alkoxygroup (for example, methoxy, ethoxy, propoxy, butoxy etc.), C1-6alkoxycarbonyl group (the example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl etc), karbamoilnuyu group and the like, and the number of these substituents may be about 1-3. When the number of substituents is two or more, each Deputy may be the same or different.

Examples of "alkoxygroup" "alkoxygroup, optionally having substituent(s)"include C1-6alkoxygroup (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, intoxi etc) and the like. Examples of the "substituent" of the "alkoxygroup, optionally having substituent(s)"include Deputy similar to the "Deputy" of the above-mentioned "alkyl group optionally having substituent(s)", and the number of the substituents is the same.

Examples of "aryl group" include C6-14aryl group (e.g. phenyl, 1-naphthyl, 2-naphthyl, biphenyl, 2-antrel etc) and the like.

Examples of "alloctype" include C6-14alloctype (for example, phenyloxy, 1 naphthyloxy, 2-naphthyloxy etc) and the like.

Examples of the "acyl group" include formyl, alkylsulphonyl, alkoxycarbonyl, carbarnoyl, allylcarbamate, alkylsulfanyl, alkylsulfonyl and the like.

Examples of "alkylcarboxylic group" include C1-6alkylcarboxylic group (for example, acetyl, propionyl etc) and the like.

Examples of "alkoxycarbonyl the group" include C 1-6alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl etc) and the like.

Examples of "alkylcarboxylic groups include N-C1-6alkylcarboxylic group (for example, methylcarbamoyl, ethylcarbazole group and so on), N,N-di-C1-6alkylcarboxylic group (for example, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl etc) and the like.

Examples of "alkylsulfonyl group" include C1-7alkylsulfonyl group (for example, methylsulfinyl, ethylsulfinyl, propylsulfonyl, isopropylphenyl etc) and the like.

Examples of "alkylsulfonyl group" include C1-7alkylsulfonyl group (for example, methylsulphonyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl etc) and the like.

Examples of "alloctype" include alkylcarboxylic, alkoxycarbonyl, carbamoylated, alkylcarboxylic, alkylsulfonate, alkylsulfonate and the like.

Examples of "alkylcarboxylic" include C1-6alkylcarboxylic (for example, atomic charges, propionyloxy etc) and the like.

Examples of "alkoxycarbonyl" include C1-6alkoxycarbonylmethyl (for example, methoxycarbonylamino, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl etc) and the like.

Examples of "alkylcarboxylic is gruppy" include C 1-6alkylcarboxylic (for example, methylcarbamoyl, ethylcarbamate etc) and the like.

Examples of "alkylsulfonate" include C1-7alkylsulfonates (for example, methylsulfonylamino, ethylsulfinyl, propylsulfonyl, isopropylphenoxy etc) and the like.

Examples of "alkylsulfonate" include C1-7alkylsulfonates (for example, methylsulfonylamino, ethylsulfonyl, propylsulfonyl, isopropylphenoxy etc) and the like.

Examples of "5-to 10-membered heterocyclic group" include 5-to 10-membered (preferably 5 - or 6-membered) heterocyclic group containing, besides carbon atom, one or more (e.g., 1 to 3) heteroatoms selected from a nitrogen atom, sulfur atom and oxygen atom, and the like. Specific examples include 2 - or 3-thienyl group, 2-, 3 - or 4-pyridyloxy group, 2 - or 3-follow group, 1-, 2 - or 3-pyrrolidinyl group, 2-, 3-, 4-, 5 - or 8-pinolillo group, 1-, 3-, 4 - or 5-izohinolinove group, 1-, 2 - or 3-indolering group and the like. Of them, preferred is a 5 - or 6-membered heterocyclic group such as 1-, 2 - or 3-pyrrolidine group and the like.

Preferably, the ring A represents a benzene ring, optionally having 1 or 2 substituent selected from a halogen atom, a long is the super halogenated C 1-4alkyl group, optionally halogenated C1-4alkoxygroup and 5 - or 6-membered heterocyclic group.

Examples of "Uralkaliy group" "Uralkaliy group optionally having substituent(s)" for R1include C7-16aracelio group (for example, C6-10arils1-6alkyl group, such as benzyl, phenethyl etc., etc.) and the like. Examples of the "substituent" of the "Uralkaliy group optionally having substituent(s)"include substituents similar to the "Deputy" of the above-mentioned "alkyl group optionally having substituent(s)", and the number of the substituents represents approximately 1-4. When the number of substituents is two or more, each Deputy may be the same or different.

Examples of the "acyl group" for R1include "acyl group"described as the substituent for the above-mentioned ring A, etc.

Examples of "alloctype for R1include "alloctype"described as the substituent for the above-mentioned ring A, etc.

Preferred R1represents a hydrogen atom.

Examples of the "alkyl group optionally having substituent(s)" for R2, R3or R4include "alkyl group optionally having substituent(s)"described as the substituent for videopom the situation rings A, etc.

Examples of "alkoxygroup, optionally having substituent(s)" for R2, R3or R4include "alkoxygroup, optionally having substituent(s)"described as the substituent for the above-mentioned ring A, etc.

Examples of "amino group, optionally having substituent(s)" for R2, R3or R4include amino, mono-C1-6alkylamino (for example, methylamino, ethylamino etc), mono-C6-14killingray (for example, phenylamino, 1 naphthylamine, 2-naphthylamine and so on), di-C1-6alkylamino (for example, dimethylamino, diethylamino and so on), di-C6-14killingray (for example, diphenylamino etc) and the like.

Preferred R2represents a C1-6alkyl group, a C1-6alkoxygroup, C1-6alkoxy-C1-6alkoxygroup or di-C1-6alkylamino. More preferred R2represents a C1-3alkyl group or a C1-3alkoxygroup.

Preferred R3represents a hydrogen atom, a C1-6alkoxy-C1-6alkoxygroup or optionally halogenated C1-6alkoxygroup. More preferred R3represents a C1-3alkoxygroup, which is optionally halogenated or substituted C1-3alkoxygroup.

Predpochtite the local R 4represents a hydrogen atom or a C1-6alkyl group. More preferred R4represents a hydrogen atom or a C1-3alkyl group (particularly, a hydrogen atom).

Preferred Y is a nitrogen atom.

A preferred compound of formula (I) is a compound in which ring A is a benzene ring optionally having substituent(s)selected from halogen atom, optionally halogenated C1-4alkyl group, optionally halogenated C1-4alkoxygroup and 5 - or 6-membered heterocyclic group, R1represents a hydrogen atom, R2represents a C1-6alkyl group, a C1-6alkoxygroup, C1-6alkoxy-C1-6alkoxygroup or di-C1-6alkylamino, R3represents a hydrogen atom, a C1-6alkoxy-C1-6alkoxygroup or optionally halogenated C1-6alkoxygroup, R4represents a hydrogen atom or a C1-6alkyl group, and Y represents a nitrogen atom.

Of the compounds (I), the compound represented by formula (Ia):

where R1represents a hydrogen atom, R2represents a C1-3alkyl group or a C1-3alkoxygroup, R3is the tsya C 1-3alkoxygroup, optionally halogenated or substituted C1-3alkoxygroup, R4represents a hydrogen atom or a C1-3alkyl group, and R5represents a hydrogen atom, optionally halogenated C1-3alkoxygroup or pyrrolidino group (for example, 1-, 2 - or 3-pyrrolidinyl group).

In the formula (Ia) compound, where R1represents a hydrogen atom, R2represents a C1-3alkyl group, R3represents optionally halogenated C1-3alkoxygroup, R4represents a hydrogen atom, and R5represents a hydrogen atom or an optionally halogenated C1-3alkoxygroup, is preferable.

Specific examples of the compound (I) include the following compounds:

2-[[[3-methyl-4-(2,2,2-triptoreline)-2-pyridinyl]methyl]sulfinil]-1H-benzimidazole, 2-[[(3,5-dimethyl-4-methoxy-2-pyridinyl)methyl]sulfinil]-5-methoxy-1H-benzimidazole, 2-[[[4-(3-methoxypropane)-3-methyl-2-pyridinyl]methyl]sulfinil]-1H-benzimidazole sodium salt, 5-deformedarse-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole and the like.

Of these compounds, 2-[[[3-methyl-4-(2,2,2-triptoreline)-2-pyridinyl]methyl]sulfinil]-1H-benzimidazole (lansoprazole) is preferred.

The compound (I) may be what asamata or optically active form, such as R-form, S-form and the like. For example, the compound (I) may be optically active form, such as (R)-2-[[[3-methyl-4-(2,2,2-triptoreline)-2-pyridinyl]methyl]sulfinil]-1H-benzimidazole (sometimes referred to as lansoprazole R form) and the like. In addition, optically active form is preferred.

As the salt of compound (I) or its optically active forms of the pharmaceutically acceptable salt is preferred. For example, there can be mentioned salts of compound (I) or its optically active forms with inorganic base, organic base and a basic amino acid, etc.

Preferred examples of the salt with inorganic base include alkali metal salt such as sodium salt, potassium salt and the like; salts of alkaline earth metal such as calcium salt, magnesium salt and the like; ammonium salt and the like.

Preferred examples of the salt with organic base include salts with alkylamino (trimethylamine, triethylamine, etc.), heterocyclic amines (pyridine, picoline etc), alkanolamines (ethanolamine, diethanolamine, triethanolamine, etc.), dicyclohexylamine, N,N'-dibenziletilendiaminom and the like.

Preferred examples of salts with basic amino acid include salts with arginine, lysine, ornithine and the fact is such.

Of them, preferred is a salt of an alkali metal or alkaline earth salt of the metal. Especially the sodium salt is preferred.

The compound (I) can be obtained by a method known in essence, for example, a method described in JP-A-61-50978, US-B-4628098, JP-A-10-195068, WO98/21201 and the like, or a method similar to this.

Optically active form of compound (I) can be obtained by means such as a method of optical resolution (fractional recrystallization, chiral method column, diastereomeric method, a method using a microorganism or enzyme, and so on), asymmetric oxidation and the like. For example, lansoprazole R form can be obtained according to the methods described in WO00/78745, WO01/83473, WO01/87874 and WO02/44167.

IIT, which is used in the present invention, preferably selected from benzimidazole compounds with antiulcer activity, such as lansoprazole, omeprazole, rabeprazole, pantoprazole and ilaprazole, and their optically active forms and their pharmaceutically acceptable salts. Most preferred are lansoprazole, omeprazole, rabeprazole or pantoprazole.

(2-2) Base

In the present invention, the base is added to part of the immediate release to stabilize the above-mentioned compounds are unstable to acid, Lekarstvo the m tool.

Examples of the above-mentioned bases include carbonates, alkaline earth metal (e.g. calcium carbonate, magnesium carbonate for the pharmaceutical agent and so on), trometamol, disodium succinate, secondary, acidic sodium phosphate, sodium orthophosphate, secondary acid potassium phosphate, L-arginine, and the like. Preferred carbonate is alkaline earth metal, and more preferred is calcium carbonate. These bases can be used alone, or two or more kinds of them may be used in combination.

The amount of substrate that will be added is not particularly limited, as long as it is sufficient for stabilization of the above-mentioned substances, unstable to acid. It usually is 1.0 wt.% - 60 wt.%, preferably 3.0 wt.% - 50 wt.% relative to the total number of parts for immediate release.

The above basis should be distinguished from antacid described in the above (1). For example, the substance used as the above-mentioned reasons, can also be used as antacid the above (1) (for example, the aforementioned "carbonate of alkaline earth metal"). When this substance is used as antacid, it will neutralize intragastric pH. On the other hand, when it is added to part of the immediate visw is bogdania as the basis, it stabilizes the compound unstable to acid in medicine.

Form the above-mentioned part of the immediate-release can be any. In order to achieve immediate release, granules, fine granules and the like are preferred.

The above part of the immediate-release can be obtained by way of the known substance. For example, it can be obtained by combining sufficient quantities of compounds that are unstable to acid and base, and, where necessary, additives such as excipient, binder, dezintegriruetsja substance, lubricant, modifier drugs, dye, flavor and the like, and granulating the mixture.

The above-mentioned granulation is preferably carried out by wet granulation. The wet granulation comprises dispersing or dissolving a mixture of the active ingredient and other components, such as excipient and the like, in water, binding the substance or solvent, granulating dispersion or solution and drying the same to obtain a granulation product, such as granules, fine granules, and the like. The wet granulation can be carried out according to the method known in the pharmaceutical field. In the when asked mechanism of granulation can be used, for example, known methods such as extrusion, liquefaction, tumbling, centrifugation, mixing, spraying and the like.

(3) Part of a slow-release

Part of a slow-release solid pharmaceutical agent of the present invention contains a compound unstable to acid and base, and has a film that dissolves at pH 6.5 or above.

In part sustained release property of the release of the connection is unstable to acid, which is the active ingredient, is a slow release. Slow release means the ratio of the extraction of the active ingredient within 30 minutes after the start of the test is not less than 85%, when the Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method) is performed using a suitable test solution (500 ml or 900 ml) under the conditions of rotation of the stirrer at 100 rpm. As the test solution in this description can be used a solution similar to the above in the explanation of the above (2) parts for immediate release.

(3-1) the Compound unstable to acid

As the above-mentioned compounds are not stable to acid, can be used compounds, such compounds are not stable to acid, given in explanation of the above (2-1), preference, taking into account the FE is. The compound unstable to acid contained in part sustained release, can be the same or different from the compounds which are not resistant to acid, contained in part immediate release.

(3-2) Base

In the present invention, the base is added to part of a slow-release, in order to stabilize the compound unstable to acid in medicine.

As the above-mentioned reasons can be mentioned reasons similar to the reasons listed in the above (2-2), and magnesium carbonate is preferred. The base, which is contained in part of a slow-release, may be the same or different from the substrate, which is contained in part immediate release.

(3-3) the Film that dissolves at a pH of 6.5 or above

Part of a slow-release solid pharmaceutical agent of the present invention has a film that dissolves at a pH of 6.5 or higher.

The film, which dissolves at a pH of 6.5 or higher is not particularly limited, while it dissolves at a pH of 6.5 or above, preferably at a pH not less than 6.5 and not more than 7.5, more preferably at a pH not less than 6.5 and not more than 7,0. It preferably contains a mixture of one or more kinds selected from the group consisting of phthalate hydroxy is mobiletechnology, phthalate cellulose acetate, karboksimetiltselljulozy, copolymer of methyl methacrylate-methacrylic acid, copolymer of methacrylic acid-acrylate, copolymer of methacrylic acid-methyl acrylate-methyl methacrylate, succinate acetate hydroxypropylmethylcellulose, polyvinyl acetate phthalate and shellac.

Examples of phthalate hydroxypropylmethylcellulose include HPMCP (HP-55) (trademark, manufacture of Shin-Etsu Chemical Co., Ltd.), HPMCP (HP-50) (trademark, manufacture of Shin-Etsu Chemical Co., Ltd.) and the like.

Examples of karboksimetiltselljulozy include CMEC (trademark, production Freund Corporation) and the like.

Examples of the copolymer of methyl methacrylate-methacrylic acid include Eudragit L100 (trademark, manufacture of Rohm), Eudragit S100 (trademark, manufacture of Rohm) and the like.

Examples of the copolymer of methacrylic acid-acrylate include Eudragit L100-55 (trademark, manufacture of Rohm), Eudragit L30D-55 (trade mark, the manufacture of Rohm) and the like.

Examples of the copolymer of methacrylic acid-methyl acrylate-methyl methacrylate include Eudragit FS30D (trademark, manufacture of Rohm) and the like.

Examples of succinate acetate hydroxypropylmethylcellulose include AQOAT AS-L (trade mark, the production of Shin-Etsu Chemical Co., Ltd.), AQOAT AS-M (trade mark, the production of Shin-Etsu Chemical Co., Ltd.), AQOAT AS-H (trade mark, the production of Shin-Etsu ChemicalCo., Ltd.) and the like.

In the above-mentioned material film using one or a combination of two or more kinds so that the obtained film was dissolved at a pH of 6.5 or above, preferably at a pH not less than 6.5 and not more than 7.5, more preferably at a pH of not less than pH 6.5 and not more than 7,0. Alternatively, two or more kinds of materials may be used sequentially to obtain films having a multilayer structure.

Alternatively, a polymer which dissolves at a pH of 6.0 or above and a polymer that dissolves at pH 7.0 or above can accordingly be combined so that the obtained film was dissolved at pH 6.5 or higher, preferably at a pH not less than 6.5 and not more than 7.5, more preferably at a pH of not less than pH 6.5 and not more than 7,0. In this case, the polymer which dissolves at a pH of 6.0 or above and a polymer that dissolves at pH 7.0 or above, preferably combined in a ratio of 1:0.5 to 1:5 and use.

The above-mentioned film may contain, if necessary, a plasticizer, a stabilizer and the like, such as polyethylene glycol, dibutylsebacate, ethylphthalate, triacetin, triethylcitrate and the like.

Although the number of the above-mentioned materials for the film is not particularly limited, it is preferably 5%-200%, more preferably 20%-100%, most before occhialino 30%-60% relative to the particle core.

The above-mentioned "having" the film includes not only such film coating, but the coating with a higher thickness, and additionally not only covering film on the entire surface of the core particles containing a compound unstable to acid and base, but also covering film on the side surface of the core particles (for example, covering film on the greater part of the surface (not less than 80%) of the particles of the nucleus, although partially uncovered).

Although the form of the above-mentioned part of the slow release is not particularly limited, it preferably has a shape that includes a particle core containing a compound unstable to acid and base, and a film that dissolves at pH 6.5 or higher, which is formed on the surface of the particles.

As the core of this part of the slow release can be used in tablets, granules or fine granules containing inactive media [e.g., Nonpareil (Nonpareil-101 (particle size 850-710, 710-500, 500-355), Nonpareil 103 (particle size 850-710, 710-500, 500-355), Nonpareil 105 (particle size 300-180), production Freund Industry Co., Ltd.), Celphere CP-507 (particle size 500-710), CP-305 (particle size 300-500), CF-203 (particle size 150-300), CF-102 (particle size 106-212), SCP-100 (particle size 75-212), production of Asahi Kasei Chemicals Co., Ltd.) etc.] as the core, and covering the liquid containing the substance, unsustainable is stable to acid, and the base, which is applied to the surface of the core; tablet produced using granules or fine granules; particles obtained by granulating the active ingredient, and excipient, usually used to obtain medicines, etc.

The particle cores may be obtained, for example, a method described in JP-A-63-301816. For example, when the particle cores should be obtained by applying the above coating solution on the inactive core of the carrier particle core containing a substance unstable to acid and base, can be obtained by wet granulation using a rotating installation for coating fluidized bed (SPIR-A-FLOW, production Freund Industry Co., Ltd.), centrifugal granulator, fluidized bed (CF-mini, CF-360, production Freund Industry Co., Ltd.), rotating granulator, fluidized bed (POWREX Mr-10), and the like. Alternatively, the above-mentioned covering solution may be sprayed with the formation of the coating by spraying the solution containing the binder and the like on the core of an inactive carrier. In this case, the apparatus for receiving is not limited. However, preferably use a centrifugal granulator fluidized bed and the like. Alternatively, the coating process using the aforementioned is x two types of devices can be combined, and substance unstable to acid and base, can be applied in two stages.

Alternatively, the particle cores can be obtained by dry granulation using a skating rink, and the like.

On the other hand, when the core is inactive carrier is not used, the particle core containing a compound unstable to acid and base, can be obtained by adding compounds are unstable to acid and base, and, where necessary, excipient, such as lactose, sucrose, mannitol, corn starch, crystalline cellulose and the like, and binders, such as hypromellose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, macrogol, pluronic F68, Arabian gum, gelatin, starch and the like, and, where necessary, dezintegriruetsja tools, such as carboxymethylcellulose sodium, carboxymethylcellulose calcium, croscarmellose sodium (Ac-Di-Sol, FMC production International), polyvinylpyrrolidone, nizkozameshhennoj hydroxypropylcellulose and the like, and granulating the mixture by mixing granulator, granulator extrusion of the solution, granulator, fluidized bed, etc.

The resulting particle core screened as necessary to obtain particles having the desired particle size. Although particle size is not particularly granicoat, it is usually about 50 mm to about 5 mm, preferably about 100 mm to about 3 mm, more preferably about 100 μm - about 2 mm.

In the above-mentioned part of the slow release of the intermediate layer is preferably formed between the particle core containing a compound unstable to acid and base, and a film that dissolves at pH 6.5 or above. Eliminating direct contact of the core particles with a film of the intermediate layer, the stability of the connection is unstable to acid, which is an active ingredient, can be improved.

Examples of the material for the above-mentioned intermediate layer include a mixture of polymer substrates, such as nizkozameshhennoj hydroxypropylcellulose, hydroxypropylcellulose, hypromellose (e.g., TC-5, and the like), polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxyethylmethylcellulose and the like, sugars such as sucrose [purified sucrose (peloritani (powder sugar) or pulverizadores) and the like], starch sugar, such as corn starch and the like, lactose, honey and sugar alcohol is D-mannitol, aritra etc) and similar in the relevant respect, etc. Where necessary in addition, the intermediate layer may contain excipient (for example, masking the Gent (titanium oxide, etc.), the antistatic agent (titanium oxide, talc, etc.)), etc. as appropriate.

The amount of coating of the intermediate layer is typically approximately 0.02 parts by weight to about 1.5 parts by weight, preferably about 0.05 to about 1 part by weight, relative to 1 part by weight of the particles of the nucleus. The intermediate layer can be applied using a standard method. For example, the components of the intermediate layer is preferably dissolved with purified water, etc. and is sprayed in liquid form. In this case, it is more preferable to apply a liquid spraying a binder such as hydroxypropylcellulose and the like, in the coating process.

The intermediate layer may comprise a single layer or multiple layers.

(4) Supplement

In the solid medicinal product according to the present invention, examples of additives that may be contained in part of the immediate release and/or part of a slow-release, if necessary, include excipients (for example, glucose, fructose, lactose, sucrose, D-mannitol, aritra, ▫ maltitol, trehalose, sorbitol, corn starch, potato starch, wheat starch, rice starch, microcrystalline cellulose, silicon dioxide, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, and the like); binders (e.g. the, polyvinylpyrrolidone, polyvinyl alcohol, partially reptitiously starch, reptitiously starch, sodium alginate, pullulan, Arabian gum powder, gelatin, etc.); dezintegriruetsja substances (for example, nitrosamino hydroxypropylcellulose, carmellose, carmellose calcium, carboximetilkrahmal sodium, croscarmellose sodium, crosspovidone, hydroxypropylmethyl etc.); modifiers of drug substances (e.g., citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, Acesulfame potassium, thaumatin, saccharin sodium, glycyrrhizinate of dicale, monosodium glutamate, 5'-inosinate, sodium, 5'-guanylate sodium etc); surfactants (e.g. Polysorbate, a copolymer of polyoxyethylene-polyoxypropylene, sodium lauryl sulfate, etc.); flavoring agents (such as lemon oil, orange oil, menthol, mint, etc.); lubricants (e.g. magnesium stearate, fatty acid esters of sucrose, sodium fumarate, stearic acid, talc, polyethylene glycol, etc.); dyes (for example, food color yellow No. 5, food color blue No. 2, trioxide, digesta, yellow iron oxide, etc.); antioxidants (e.g., sodium ascorbate, L-cysteine, sodium sulfite, etc. and the like. Although the particle size of these additives is not particularly limited, it is preferably not more than 500 m is m due to the efficiency of the particle and is an easy introduction.

(5) the Method of producing solid drug

Solid drug of the present invention can be obtained by combining the above antacid, part of the immediate-release and part of a slow-release. Solid medicinal product according to the present invention can be obtained by any method known in the pharmaceutical field. For example, the solid drug of the present invention can be obtained in the form of fine granules or granules by mixing antacid, part of the immediate-release and part of a slow-release manner known in the pharmaceutical field. In addition, the solid drug of the present invention can be obtained in the form of tablets by additional pressing hard drugs (fine granules or granules) in a manner known in the pharmaceutical field. Alternatively, the solid drug of the present invention can also be obtained in the form of capsules by filling solid drugs (fine granules or granules) in the capsule.

Although the total number of connections is unstable to acid, in solid medicinal product according to the present invention varies depending on the type, dose, etc. connect the tion, unstable to acid, it is usually 1.0 wt.% - 60 wt.%, preferably 10 wt.% - 50 wt.%, more preferably 10 wt.% - 40 wt.%, of the total number of hard drug of the present invention.

In the solid medicinal product according to the present invention, furthermore, the weight ratio of the content of the compound unstable to acid, part of the immediate-release and part of the slow release is preferably 10:1-1:10, preferably 5:1-1:5, most preferably 2:1-1:5.

(6) an Existing disease, the route of administration, dose, etc. of solid medicinal product according to the present invention

When solid, the drug of the present invention contains a pit, such as a compound represented by the formula (I), in the form of connection is unstable to acid, the compound is superior in anti-ulcer activity, the inhibitory action on secretion of gastric acid, which protects the mucous membrane action, anti-Helicobacter activity of the pylorus is preserved and the like, and detects low toxicity. Therefore, the solid drug of the present invention is suitable as a pharmaceutical agent. In this case, the solid drug of the present invention can be orally to enter the mammal (EmOC is emer, human, monkey, sheep, horse, dog, cat, rabbit, rat, mouse, etc) for the prevention or treatment of peptic ulcer (e.g. gastric ulcer, peptic ulcer of the duodenum, anastomoticheskih ulcer disease, syndrome Zollinger-Ellison and the like), gastritis, GERD (GERD (gastro-oesophageal reflux disease, erosive esophagitis, gastro-oesophageal reflux, not accompanied esophagitis (symptomatic GERD), and the like), NUD (NAD) (non-ulcer dyspepsia), gastric cancer (including gastric cancer, associated with the stimulation of the production of interleukin-1β genetic polymorphism of interleukin-1), lymphoma lymphoid tissue of the mucous membranes of the stomach and the like, removal or as an aid for the removal of Helicobacter pylorus is preserved, suppression of peptic ulcer, acute peptic ulcer and hemorrhagic gastric hemorrhage of the upper parts of the gastrointestinal tract due to invasive stress (stress caused by radical surgery requiring postoperative intensive control, or cerebral vascular disorder, head trauma, multiple organ failure or extensive burn requiring intensive treatment), prevention or treatment of peptic ulcers caused by nonsteroidal anti-inflammatory agent; prevention or treatment of increased Ki is lotnosti and ulcer due to postoperative stress, and the like. To remove or assist in removing Helicobacter pylorus is preserved joint use of hard drugs of the present invention and penicillin antibiotic (eg, amoxicillin) and eritromicina antibiotic (eg, clarithromycin and the like) is preferred.

Solid drug of the present invention is particularly preferably used as an agent for the prophylaxis or treatment of GERD (symptomatic GERD, erosive esophagitis, and the like).

Solid drug of the present invention can be directly administered orally. In addition, it is possible dispersing or dissolving the drug in water, juice, yogurt, etc. in advance and introduce a dispersion or solution in the form of liquid or semi-solid substance.

Daily dose of hard drugs of the present invention varies depending on the severity of the symptom, age, sex and body mass of the object the introduction, time and interval of administration, the type of active ingredient and the like and is not particularly limited. For example, for oral administration, the dose of the active ingredient of therapeutic drugs for erosive esophagitis (GERD) is about 10-200 mg/day, preferably about 30-120 mg/day DL is an adult (60 kg). Solid drug of the present invention can be injected once a day or in 2 or 3 portions a day.

Solid drug of the present invention obtained as mentioned above, preferably demonstrates the increase in intragastric medium pH to not less than 4 after about 0.5 hour after administration to a mammal and time saving pH 4 or above within one day not less than 14 hours.

The absorbance of the compound unstable to acid, in solid medicinal product according to the present invention from the gastrointestinal tract is controlled by two types of systems, using the property of the immediate-release connection is unstable to acid, in terms of immediate release and property sustained release (prolonged stay in the gastrointestinal tract) compound unstable to acid, part of a slow-release. When solid, the drug of the present invention is administered orally, the compound unstable to acid, is released from a part of the immediate release in the stomach immediately after injection, and quickly found a pharmacological effect. At this time, since the antacid is released in the stomach before releasing the connection is unstable to acid, disconnection, it is sensitive to key the lot, gastric acid suppressing, and pharmacological effect can occur quickly and steadily. Meanwhile, the compound unstable to acid, part of a slow-release not released in the stomach, gradually moving in the gastrointestinal tract, being protected by a film that dissolves at pH 6.5 or higher, and when it reaches the gastrointestinal tract at a pH of 6.5 or higher (for example, jejunum, the ileum and the like), the film begins to dissolve, and the active ingredient is released from part of a slow-release in a controlled way. In the solid medicinal product according to the present invention can provide both a rapid pharmacological effect after the introduction and pharmacological effect is maintained over a long period of time. Furthermore, since the solid drug of the present invention contains the basis in part of the immediate-release and part of a slow-release, drug is superior in stability during production and storage.

Accordingly, the solid drug of the present invention is suitable as various medicines for oral administration.

Examples

The present invention is explained in more adolescents who but below with reference to examples of the preparation, examples and experimental examples, which should not be construed as limiting.

Example obtain 1

Obtaining a granulated powder for part of the immediate release

Lansoprazole (hereinafter referred to as compound a; 10 g), calcium carbonate (to 166.67 g) and D-mannitol (155,8 g) were loaded into the granulator, fluidized bed, the mixture was granulated at the same time spraying an aqueous solution of hydroxypropylcellulose (13,87 g) in purified water (231,11 g), and the granules were dried to obtain a granulated powder (340 g) for part of the immediate release.

Example of getting 2

Receipt containing antacid granulated powder

Magnesium hydroxide (96,67 g), magnesium oxide (133,33 g), D-mannitol (121,87 g) and crosspovidone (for 10.68 g) were loaded into the granulator, fluidized bed, the mixture was granulated at the same time spraying an aqueous solution of hydroxypropylcellulose (13,42 g) in purified water (223,67 g), and the granules were dried to obtain a granulated powder (370 g)containing antacid.

Example of getting 3

Obtaining particles of nucleus

Particle nuclei, which are the core part of a slow-release, was prepared as follows. Hydroxypropylcellulose (HPC-SL, 50 g) was dissolved in purified water (640 g) and nitrosamino hydroxypropylcellulose (L-HPC-32W, 25 g) and magnesium carbonate (50 g) doba is ranged to the solution and was dispersible in it. Compound A (150 g) was evenly dispersible in the resulting dispersion to obtain the coating solution. Particles of lactose·crystalline cellulose (Nonpareil 105, 100 g) covered this contains the connection And covering solution (610 g), using a rotating device for coating fluidized bed (SPIR-A-FLOW, production Freund Industry Co., Ltd.). Conditions of the coating was the air temperature at the inlet: about 60°C, pressure air spraying: about 1 kgf/cm2the level of exhaust air: 100, pressure layer (BED): about 250 mm Hg, rotor speed: approximately 300 revolutions per minute, the spray: about 6 g/min and the position of the dispenser: the bottom surface. After completion of coating the obtained fine granules were dried in vacuum at 40°C for 16 hours, and sieved using a round sieve to obtain core particles having a particle size of 125 μm - 500 μm.

Table 1
Composition in the particle core 85 mg
Particle lactose·crystalline cellulose (Nonpareil 105)30 mg
Connection A30 mg
Carb is NAT magnesium 10 mg
Nizkozameshhennoj hydroxypropylcellulose5 mg
Hydroxypropylcellulose10 mg
Total85 mg

Example 4

Fine particles obtained in the example of a 3, covered by an intermediate layer covering the fluid using a rotating device for coating fluidized bed (SPIR-A-FLOW, production Freund Industry Co., Ltd.), and immediately dried to obtain fine granules with the following composition. The intermediate layer coating solution was obtained by dissolving hydroxypropylmethylcellulose 2910 (23,6 g) in purified water (425,5 g) and a dispersion of titanium oxide (14.2 g) and talc (9.5 g) in the resulting solution. The conditions of the coating was air temperature at the inlet: about 60°C, pressure air spraying: about 1 kgf/cm2the level of exhaust air: 100, pressure layer (BED): about 250 mm Hg, rotor speed: approximately 300 revolutions per minute, the spray: about 2.5 g/min and the position of the dispenser: the bottom surface. After completion of coating the obtained fine granules were dried in vacuum n and 40°C for 16 hours, and sieved, using a round sieve to obtain coated with an intermediate layer of fine granules having a particle size of 125 μm - 500 μm.

Table 2
The composition is coated with an intermediate layer of fine granules (191,26 mg)
The fine granules obtained in example obtain 3170 mg
The hypromellose 291010,63 mg
Talc4,25 mg
The titanium oxide6,38 mg
Total191,26 mg

Example of getting 5

Receiving enteric fine granules

Methacrylic acid copolymer S (95,7 g), methacrylic acid copolymer L (31,9 g) and triethylcitrate (12,72 g) was dissolved in a mixed solution of purified water (183,7 g) and anhydrous ethanol (1564), and talc (63,8 g) was dispersively in the resulting solution to obtain the coating solution. The fine granules obtained in example 4 was coated the above-mentioned covering solution using a rotating device for coating fluidized bed(SPIR-A-FLOW, production Freund Corporation). Controlling the release of the film, which is soluble pH-dependent (releases the active ingredient into the environment with pH at this level or above), was used in conditions of coating, representing the temperature of the inlet air: about 60°C, pressure air spraying: about 1 kgf/cm2the level of exhaust air: 100, pressure layer (BED): about 250 mm Hg, the speed of rotation of the rotor about 150 revolutions per minute, the spray: about 3.0 g/min and the position of the dispenser: the bottom surface. The obtained fine granules were sieved using a round sieve to obtain enteric fine granules having a particle size of 125 μm - 500 μm. The obtained fine granules were dried in vacuum at 40°C for 16 hours and fine granules (220 g) was mixed with talc (0,105 g) and Aerosil (0,105 g), receiving enteric fine granules.

Table 3
The composition of the enteric fine granules
(is 283.3 mg)
Fine granules in example 4191,26 mg
Methacrylic acid copolymer S4304 mg
Methacrylic acid copolymer L14,36 mg
Talc28,68 mg
Triethylcitrate5,72 mg
Talc0.135 mg
Aerosil0.135 mg
Totalis 283.3 mg

An example of obtaining 6

Receiving enteric fine granules

Methacrylic acid copolymer S (uniforms, 127.6 g) and triethylcitrate (12,72 g) was dissolved in a mixed solution of purified water (183,7 g) and anhydrous ethanol (1564), and talc (63,8 g) was dispersively in the resulting solution to obtain the coating solution. The fine granules obtained in example 4 was coated the above-mentioned covering solution using a rotating device for coating fluidized bed (SPIR-A-FLOW, production Freund Corporation). Controlling the release of the film, which is soluble pH-dependent (releases the active ingredient into the environment with pH at this level or above), was used in conditions of coating, representing the temperature of the inlet air: about 60°C, the air pressure p is spalania: about 1 kgf/cm 2the level of exhaust air: 100, pressure layer (BED): about 250 mm Hg, the speed of rotation of the rotor about 150 revolutions per minute, the spray: about 3.0 g/min and the position of the dispenser: the bottom surface. The obtained fine granules were sieved using a round sieve to obtain enteric fine granules having a particle size of 125 μm - 500 μm. The obtained fine granules were dried in vacuum at 40°C for 16 hours and fine granules (220 g) was mixed with talc (0,105 g) and Aerosil (0,105 g), receiving enteric fine granules.

is 283.3 mg
Table 4
The composition of the enteric fine granules (is 283.3 mg)
Fine granules of example 4191,26 mg
Methacrylic acid copolymer S57,40 mg
Talc28,68 mg
Triethylcitrate5,72 mg
Talc0.135 mg
Aerosil0.135 mg
Total

Example of getting 7

Obtaining particles of nucleus

Particle nuclei, which are the core part of a slow-release, was prepared as follows. The hypromellose (TC-5EW, 50 g) was dissolved in purified water (640 g) and nitrosamino hydroxypropylcellulose (L-HPC-32W, 25 g) and magnesium carbonate (50 g) was added to the solution and was dispersible in it. Compound A (150 g) were uniformly dispersible in the resulting dispersion to obtain the coating solution. Particles of lactose·crystalline cellulose (Nonpareil 105T, 130 g) covered this contains the connection And covering solution (793 g), using a rotating device for coating fluidized bed (SPIR-A-FLOW, production Freund Industry Co., Ltd.). The conditions of the coating was air temperature at the inlet: about 40°C, pressure air spraying: about 1 kgf/cm2the level of exhaust air: 100, pressure layer (BED): about 250 mm Hg, rotor speed: approximately 300 revolutions per minute, the spray: about 6 g/min and the position of the dispenser: the bottom surface. After completion of coating the obtained fine granules were dried in vacuum at 40°C for 16 hours, and sieved using a round sieve to obtain core particles having a particle size of 125 μm - 500 μm.

Table 5
The composition of the particle core (85 mg)
Particle lactose·crystalline cellulose (Nonpareil T)30 mg
Connection A30 mg
Magnesium carbonate10 mg
Nizkozameshhennoj hydroxypropylcellulose5 mg
The hypromellose10 mg
Total85 mg

Example obtain 8

The fine granules obtained in example receiving 7, covered by an intermediate layer coating solution using a rotating device for coating fluidized bed (SPIR-A-FLOW, production Freund Industry Co., Ltd.), and directly dried to obtain fine granules of the following composition. The intermediate layer coating solution was obtained by dissolving hydroxypropylmethylcellulose 2910 (23,6 g) in purified water (425,5 g) and a dispersion of titanium oxide (14.2 g) and talc (9.5 g) in the resulting solution. The conditions of the coating was air temperature at the inlet: primer is 60°C, pressure air spraying: about 1 kgf/cm2the level of exhaust air: 100, pressure layer (BED): about 250 mm Hg, rotor speed: approximately 300 revolutions per minute, the spray: about 2.5 g/min and the position of the dispenser: the bottom surface. After completion of coating the obtained fine granules were dried in vacuum at 40°C for 16 hours, and sieved using a round sieve to obtain coated with an intermediate layer of fine granules having a particle size of 125 μm - 500 μm.

Table 6
The composition is coated with an intermediate layer of fine granules (191,26 mg)
The fine granules obtained in example obtain 7170 mg
The hypromellose 291010,63 mg
Talc4,25 mg
The titanium oxide6,38 mg
Total191,26 mg

Example of getting 9

Receiving enteric fine granules

Methacrylic acid copolymer S (95,7 g), metac the sludge acid copolymer L (31,9 g) and triethylcitrate (12,72 g) was dissolved in a mixed solution of purified water (183,7 g) and anhydrous ethanol (1564), talc (63,8 g) was dispersively in the resulting solution to obtain the coating solution. The fine granules obtained in example receiving 8, covered covering the above solution using a rotating device for coating fluidized bed (SPIR-A-FLOW, production Freund Industry Co., Ltd.). Controlling the release of the film, which is soluble pH-dependent (releases the active ingredient into the environment with pH at this level or above), was used in conditions of coating, representing the temperature of the inlet air: about 60°C, pressure air spraying: about 1 kgf/cm2the level of exhaust air: 100, pressure layer (BED): about 250 mm Hg, the speed of rotation of the rotor about 150 revolutions per minute, the spray: about 3.0 g/min and the position of the dispenser: the bottom surface. The obtained fine granules were sieved using a round sieve to obtain enteric fine granules having a particle size of 125 μm - 500 μm. The obtained fine granules were dried in vacuum at 40°C for 16 hours and fine granules (220 g) was mixed with talc (0,105 g) and Aerosil (0,105 g), receiving enteric fine granules.

Table 7
The composition of the enteric fine granules (is 283.3 mg)
The fine granules obtained in example obtain 8191,26 mg
Methacrylic acid copolymer S43,04 mg
Methacrylic acid copolymer L14,36 mg
Talc24,68 mg
Triethylcitrate5,72 mg
Talc0.135 mg
Aerosil0.135 mg
Totalis 283.3 mg

Example 10

Receiving enteric fine granules

Methacrylic acid copolymer S (uniforms, 127.6 g) and triethylcitrate (12,72 g) was dissolved in a mixed solution of purified water (183,7 g) and anhydrous ethanol (1564), talc (63,8 g) was dispersively in the resulting solution to obtain the coating solution. The fine granules obtained in example receiving 8, covered covering the above solution using a rotating device for coating fluidized bed (SPIR-A-FLOW, production is in Freund Industry Co., Ltd.). Controlling the release of the film, which is soluble pH-dependent (releases the active ingredient into the environment with pH at this level or above), was used in conditions of coating, representing the temperature of the inlet air: about 60°C, pressure air spraying: about 1 kgf/cm2the level of exhaust air: 100, pressure layer (BED): about 250 mm Hg, the speed of rotation of the rotor about 150 revolutions per minute, the spray: about 3.0 g/min and the position of the dispenser: the bottom surface. The obtained fine granules were sieved using a round sieve to obtain enteric fine granules having a particle size of 125 μm - 500 μm. The obtained fine granules were dried in vacuum at 40°C for 16 hours and fine granules (220 g) was mixed with talc (0,105 g) and Aerosil (0,105 g), receiving enteric fine granules.

Table 8
The composition of the enteric fine granules (is 283.3 mg)
The fine granules obtained in example obtain 8191,26 mg
Methacrylic acid copolymer S57,40 mg
Talc28,68 mg
Triethylcitrate5,72 mg
Talc0.135 mg
Aerosil0.135 mg
Totalis 283.3 mg

Example 1

Receive solid drugs (pill)

Granulated powder (51,95 g) for part of the immediate release, obtained in example a 1, antacid-containing granulated powder (37,60 g)obtained in example getting 2, crystalline cellulose (brand name: Ceolus KG-801, the production of Asahi Kasei Chemicals, 10,96 g), crosspovidone (3,93 g) and magnesium stearate (1,61 g) were mixed in a mortar to obtain a mixed powder. This mixed powder (10.6 g) and enteric fine granules part of a slow-release (2,13 g)obtained in example receiving 9, gently mixed to obtain mixed powder. The obtained mixed powder (1273 mg) was loaded into a flat die with a diameter of 14 mm with a curved edge, from which the solid drug of the present invention (tablet, 1273 mg)containing compound a (60 mg), was obtained using Autograph (trade mark, production Shimazu Co. Ltd., the t when pelletizing: 1 ton/cm 2). The obtained tablet was not found any obscurities.

Example 2

Receive solid drugs (pill)

Granulated powder (51,95 g) for part of the immediate release, obtained in example a 1, antacid-containing granulated powder (37,60 g)obtained in the above example get 2, crystalline cellulose (brand name: Ceolus KG-801, the production of Asahi Kasei Chemicals, 10,96 g), crosspovidone (3,93 g) and magnesium stearate (1,61 g) were mixed in a mortar to obtain a mixed powder. This mixed powder (10.6 g) and enteric fine granules (2,13 g) for part of a slow-release, obtained in example 10 were mixed in a mortar to obtain a mixed powder. The obtained mixed powder (1273 mg) was loaded into a flat die with a diameter of 14 mm with a curved edge, from which the solid drug of the present invention (tablet, 1273 mg)containing compound a (60 mg), was obtained using Autograph (trade mark, production Shimazu Co. Ltd., the pressure at the pelletizing: 1 ton/cm2). The obtained tablet was not found any obscurities.

Industrial applicability

According to the present invention the solid drug, demonstrating the high stability of the active ingredient (the compound penalty is ichinoe to acid), exerts a pharmacological effect of the active ingredient is stable and fast after the introduction and retains pharmacological effect over a long period of time. Accordingly, the solid drug of the present invention is suitable as various medicines for oral administration. In particular, when the compound unstable to acid, is a pit, solid drug of the present invention may be suitable for the prevention or treatment of peptic ulcer (e.g. gastric ulcer, peptic ulcer of the duodenum, anastomoticheskih ulcer disease, syndrome Zollinger-Ellison and the like), gastritis, GERD (gastro-oesophageal reflux disease, erosive esophagitis, gastro-oesophageal reflux, not accompanied esophagitis (symptomatic GERD), and the like), NUD (NAD) (non-ulcer dyspepsia), gastric cancer (including gastric cancer, associated with the stimulation of the production of interleukin-1β genetic polymorphism of interleukin-1), lymphoma lymphoid tissue of the mucous membranes of the stomach and the like, removal or as an aid for the removal of Helicobacter pylorus is preserved, suppression of peptic ulcer, acute peptic ulcer and hemorrhagic gastric hemorrhage of upper gastrointestinal kiseon the th path due to invasive stress (stress, caused by radical surgery requiring postoperative intensive control, or cerebral vascular disorder, head trauma, multiple organ failure or extensive burn requiring intensive treatment), prevention or treatment of peptic ulcers caused by nonsteroidal anti-inflammatory agent; the prevention or treatment of acidity and ulcer due to postoperative stress, and the like.

This application is based on application No. 2005-378061 filed in Japan, the contents of which are incorporated into this description by reference. Links to patent and references to non-patent cited herein, hereby incorporated fully by reference if they have been defined in this document.

1. Solid drug controlled release, including (1) antacid, (2) the part of the immediate release, containing a compound unstable to acid and base, which is a granule or fine granule, and (3) the part of a slow-release, which includes a particle core containing a compound unstable to acid and base, and a film that dissolves at pH 6.5 or higher, which is formed on the surface of the core particles, in combination,
where the number of the film is 5 to 200% with respect to the particle core, firmly where the drug can be obtained by way comprising a mixture of (1) above antacid, (2) side immediate-release, and (3) part of a slow-release.

2. The drug according to claim 1, in which the film, which dissolves at pH 6.5 or above, contains one kind or a mixture of two or more kinds selected from the group consisting of a phthalate of hydroxypropylmethylcellulose, phthalate cellulose acetate, karboksimetiltselljulozy, copolymer of methyl methacrylate-methacrylic acid, copolymer of methacrylic acid-acrylate, copolymer of methacrylic acid-methyl acrylate-methyl methacrylate, succinate acetate hydroxypropylmethylcellulose, polyvinyl acetate phthalate and shellac.

3. The drug according to claim 1, in which part of a slow-release includes a particle core containing a compound unstable to acid and base, an intermediate layer formed on the surface of the core particles, and a film that dissolves at pH 6.5 or higher, which is formed through the intermediate layer.

4. The drug according to claim 1 in which the compound unstable to acid is a proton pump inhibitor (PPI, IDU).

5. The drug according to claim 4, in which IIT is a compound represented by the formula (I)

where ring a is a benzene ring, long is Ino having substituent(s), R1represents a hydrogen atom, aracelio group optionally having substituent(s), acyl group, or alloctype, R2, R3and R4are the same or different and each represents a hydrogen atom, alkyl group optionally having substituent(s), alkoxygroup, optionally having substituent(s)or amino group, optionally having substituent(s), and Y represents a nitrogen atom or CH, or its optically active form or salt.

6. The drug according to claim 4, in which IIT is a lansoprazole, omeprazole, rabeprazole, pantoprazole, ilaprazole or its optically active form or its salt.

7. The drug according to claim 1, in which the antacid represents at least one kind of component selected from a metal oxide, a metal hydroxide and a carbonate of alkaline earth metal.

8. The drug according to claim 1, in which a 1% aqueous solution or 1% water slurry of antacid has a pH not less than 8,0.

9. The drug according to claim 7, in which the oxide of the metal is at least one kind selected from the group consisting of magnesium oxide, magnesium silicate, dry gel of aluminum hydroxide and alumosilicate magnesium.

10. The drug according to claim 7, in which the metal hydroxide is in me is greater as one kind, selected from the group consisting of magnesium hydroxide, aluminum hydroxide, synthetic hydrotalcite, joint precipitate of aluminum hydroxide and magnesium hydroxide, joint precipitate of aluminum hydroxide, magnesium carbonate and calcium carbonate and joint precipitate of aluminum hydroxide and sodium bicarbonate.

11. The drug according to claim 7, in which the carbonate of the alkaline earth metal is calcium carbonate or magnesium carbonate.

12. The drug according to claim 1, in which the content of antacid is 5 mEq 50 mEq.

13. The drug according to claim 1, in which the weight ratio of the content of the compound unstable to acid, part of the immediate-release and part of the slow release is 10:1-1:10.

14. The drug according to claim 1, which demonstrates the increase in intragastric medium pH to 4 or higher after 0.5 h after oral administration to a mammal and time saving pH 4 or above not less than 14 hours per day.



 

Same patents:

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6 cl, 2 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and represents liquid composition for treatment of tobacco or nicotine addiction or for weight control after giving up smoking, characterised by the fact that it represents medicinal body lotion, which contains nicotine in any form in amount 0.5-15 mg, calculated relative to form of free base of nicotine per strandardised dose, and solvent, where composition is intended for transdermal delivery of nicotine to patient and does not contain tobacco, composition does not contain any uncrosslinked water-insoluble vinylpyrrolidone copolymer, copolymerised with hydrophobic comonomer.

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26 cl, 5 ex

FIELD: medicine, pharmaceutics.

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41 cl, 11 dwg, 162 ex

FIELD: medicine.

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18 cl, 2 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly using an aqueous extract of tobacco leaves for preparing an agent for treating tobacco dependence. Using an aqueous solution of the aqueous extract of tobacco leaves or a lyophilizate of the aqueous extract of tobacco leaves in sterile water for preparing the agent in the form of injections for treating tobacco dependence wherein said solution have the certain content of a dry substance. A kit for treating tobacco dependence comprising a syringe, a sterile water bottle and the lyophilizate of the aqueous extract of tobacco leaves.

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8 cl, 2 ex

FIELD: medicine, pharmaceutics.

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6 cl, 2 ex

FIELD: medicine, pharmaceutics.

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57 cl, 10 ex

FIELD: medicine, pharmaceutics.

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7 cl, 10 ex, 2 dwg

FIELD: medicine.

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19 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and its application for prevention and treatment of abuse with psychoactive substances and dependence on psychoactive substances, which contains compound of formula (R)-2-{3-[1-(acenaphthene-1-yl)pyperidin-4-yl]-2,3-dihydro-2-oxo-benzimidazol-1-yl} -N-methyl acetamide or its pharmaceutically acceptable salt as active ingredient.

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18 cl, 1 tbl, 8 dwg, 5 ex

FIELD: medicine.

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

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

17 cl, 15 ex

FIELD: medicine.

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

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

17 cl, 15 ex

FIELD: medicine.

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

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

17 cl, 15 ex

FIELD: medicine.

SUBSTANCE: drops recovering metabolism and tissue and organ energy supply represent tinctures prepared of one or two types of crude drug containing β-carotene and chlorophyll, particularly herb of horsetail, wormwood, melilot, nosebleed, leaves of nettle, wild strawberry, plantain, colt's foot, pine buds, young shoots of bilberry and others, extraction in 95% ethanol in total content of medicinal substance 15-25 mg in 1 ml of tincture.

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17 cl, 16 ex

FIELD: medicine.

SUBSTANCE: spray composition contains, wt/vol %: lidocaine hydrochloride 1.0-10.0; benzethonium chloride 5.0·10-4 - 5.0·10-3; sodium chloride 0.1-10.0; water for injections to 100 ml.

EFFECT: use of the declared composition is effective for treating damages by non-lethal irritants.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to a dosage form containing a disintegrating piece of the tablet and a solid caramelised piece, wherein: (i) the disintegrating piece of the tablet contains at least one pharmaceutically active ingredient, and (ii) the solid caramelised piece covers at least 20% of a surface of the disintegrating piece of the tablet, and wherein a disintegration time of the solid caramelised piece is at least ten times more than that of the disintegrating piece of the tablet. The pharmaceutically active ingredient is specified in a group of analgesics, anti-inflammatory and antipyretic agents, agents for treating gastrointestinal tract, neuromuscular blocking agents, anaesthetics, antihistaminic agents, decongestants, antitussive and expectorant drugs. The mass ratio of the disintegrating piece of the tablet and the solid caramelised piece makes 10:90 to 60:40. Preferentially, the disintegrating piece of the tablet as the pharmacologically active ingredient contains ibuprofen, while the caramelised piece contains ambroxol.

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29 cl, 9 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: oral pharmaceutical preparation in the form of a film-coated tablet contains substances in the following proportions, wt %: moxifloxacin 50.0-72.5; potatoe starch 5.0-20.0; polividone 1.0-5.0; calcium stearate 0.5-2.5; hydroxypropylmethylcellulose - the rest; the coating represents a film in the following proportions, wt %: dying agent - 0.0001-0.05; macrogol 4000 5.0-20.0; titanium dioxide 10.0-15.0; hydroxypropylmethylcellulose - the rest.

EFFECT: preparation improvement.

2 cl, 5 ex

FIELD: medicine.

SUBSTANCE: oral pharmaceutical preparation in the form of a film-coated tablet contains substances in the following proportions, wt %: moxifloxacin 50.0-72.5; potatoe starch 5.0-20.0; polividone 1.0-5.0; calcium stearate 0.5-2.5; hydroxypropylmethylcellulose - the rest; the coating represents a film in the following proportions, wt %: dying agent - 0.0001-0.05; macrogol 4000 5.0-20.0; titanium dioxide 10.0-15.0; hydroxypropylmethylcellulose - the rest.

EFFECT: preparation improvement.

2 cl, 5 ex

FIELD: medicine.

SUBSTANCE: what is described is a new pharmaceutically solid preparation of a vasopressin antagonist which contains: (a) 7-chlor-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro- 1H-benzoazepine and/or its salt; (b) hydroxypropylcellulose containing a hydroxypropoxyl group in the amount of 50% or more; and (c) at least one of the ingredients specified in a group consisting of carmellose, sodium carboxymethyl starch, crospovidone and hydroxypropylcellulose with a lower degree of substitution with an average diameter of particles 30 to 70 mcm and 90% of the cumulative diameter of 100 to 200 mcm.

EFFECT: pharmaceutical solid preparation shows excellent desintegration properties and solubility leading to adequate gastrointestinal absorbability of the active ingredients.

17 cl, 4 tbl, 21 ex

FIELD: medicine.

SUBSTANCE: what is described is a new pharmaceutically solid preparation of a vasopressin antagonist which contains: (a) 7-chlor-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro- 1H-benzoazepine and/or its salt; (b) hydroxypropylcellulose containing a hydroxypropoxyl group in the amount of 50% or more; and (c) at least one of the ingredients specified in a group consisting of carmellose, sodium carboxymethyl starch, crospovidone and hydroxypropylcellulose with a lower degree of substitution with an average diameter of particles 30 to 70 mcm and 90% of the cumulative diameter of 100 to 200 mcm.

EFFECT: pharmaceutical solid preparation shows excellent desintegration properties and solubility leading to adequate gastrointestinal absorbability of the active ingredients.

17 cl, 4 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to enantiomerically pure (2S)- or (2R)-N,N,N-trimethyl-2,3-bis[[(9Z)-1-oxo-9-octadecenyl]oxy]-1-propanamide chloride (DOTAP chloride) which possess the transfection properties and can find application in medicine and pharmaceutics for intracellular transportation of pharmaceutically active compounds. The invention also refers to a pharmaceutical composition and the use of enantiomerically pure (2S)- or (2R)-DOTAP chloride as an ingredient for preparing drugs.

EFFECT: preparing the compounds which possess the transfection properties and can find application in medicine and pharmaceutics for intracellular transportation of pharmaceutically active compounds.

7 cl, 2 tbl, 6 dwg, 6 ex

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