TWI407978B - Method for the preparation of a wet granulated drug product - Google Patents

Abstract

The invention relates to a method for the preparation of a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker, said method comprising a step of preparing by wet granulation a composition comprising said angiotensin II receptor antagonist and said calcium channel blocker. The solid dosage form obtainable by the method of the present invention demonstrates improved dissolution properties.

Description

Method for preparing wet granular medicine

The present invention relates to a method for preparing a solid dosage form comprising a vasopressin II receptor antagonist and a calcium channel blocker, the method comprising preparing the vasopressin II receptor antagonist by wet granulation and The step of the composition of the calcium channel blocker.

Currently, calcium channel blockers and vasopressin II receptor antagonists are clinically widely used agents for the treatment and prevention of hypertension. Since calcium channel blockers exhibit a natriuretic effect in addition to vasodilatation, they are effective against hypertension (renin-independent) caused by fluid retention. On the other hand, vasopressin II receptor antagonists are particularly effective against renin-dependent hypertension and have excellent organ protection effects. Therefore, regardless of the cause of hypertension, it is expected that a combination of a calcium channel blocker and a vasopressin II receptor antagonist can be used for stable and effective antihypertensive treatment.

A variety of combinations including vasopressin II receptor antagonists and calcium channel blockers have been proposed in the prior art, such as the following Patent Documents 1 to 4. However, a method of preparing a solid dosage form comprising a vasopressin II receptor antagonist and a calcium channel blocker is not disclosed in the prior art, and the method involves a wet granulation step.

[Patent Document 1] International Publication WO 92/10097 [Patent Document 2] International Publication WO 92/20342 [Patent Document 3] International Publication WO 00/02543 [Patent Document 4] International Publication WO 2004/067003

It is an object of the present invention to provide a method of preparing a solid dosage form comprising a vasopressin II receptor antagonist and a calcium channel blocker, the solid dosage form having improved solubility characteristics, and a solid dosage form prepared by the method.

In order to solve the aforementioned problems, the present inventors conducted extensive research and found that the preparation of a composition including a vasopressin II receptor antagonist and a calcium channel blocker includes a wet granulation step to improve the blood vessel including the blood vessel. The solubility characteristics of the solid receptor dosage form of the receptor II antagonist and the calcium channel blocker thus complete the present invention.

The present invention provides a method of preparing a solid dosage form comprising a vasopressin II receptor antagonist and a calcium channel blocker, the method comprising preparing the vasopressin II receptor antagonist and the calcium by wet granulation a step of forming a composition of a channel blocker, which comprises a solid dosage form of a vasopressin II receptor antagonist and a calcium channel blocker (especially for the prevention or treatment of hypertension), utilizing A vasopressin II receptor antagonist and the calcium channel blocker for producing the aforementioned solid dosage form (especially for use in a dosage form for preventing or treating hypertension), and a method for preventing or treating a disease (especially hypertension) Blood animals, especially humans, are administered the aforementioned solid dosage forms comprising a pharmaceutically effective amount of a vasopressin II receptor antagonist and a calcium channel blocker.

Specifically, the present invention provides: (1) A method of preparing a solid dosage form comprising a vasopressin II receptor antagonist and a calcium channel blocker, the method comprising preparing the vasopressin by wet granulation a step of a composition of the II receptor antagonist and the calcium channel blocker, (2) wherein the vasopressin II receptor antagonist is losartan, candesartan according to the method of (1) (candesartan), valsartan, telmisartan, pratosartan, olmesartan or irbesartan or a pharmaceutically acceptable salt or ester thereof, (3) The method according to (1) wherein the vasopressin II receptor antagonist is losartan, candesartan cilexetil, valsartan, telmisartan, patosartan, ol Olmasartan medoxomil or irbesartan, (4) wherein the vasopressin II receptor antagonist is olmesartan medoxomil, according to (1), (5) according to (1) to (4) The calcium channel blocker is nifedipine, nimodipine, niivadipine, manidipine (manidipine) ), barnidipine, nitrendipine, benidipine, nicardipine, lercanidipine, amlodipine, nisoldipine , efonidipine, cilnidipine, azelnidipine, felodipine, aranidipine or pranidipine or a pharmaceutically acceptable salt thereof, (6) The method according to (1) to (4) wherein the calcium channel blocker is manidipine, bainidipine, nicardipine, lercanidipine, amlodipine, effildipine or adipine or A pharmaceutically acceptable salt, (7) according to the method of (1) to (4) wherein the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof, (8) according to (1) to (4) The method wherein the calcium channel blocker is amlodipine besylate, (9) according to the method of (1) to (8), for preparing a solid dosage form selected from the group consisting of powder, granules, granules, capsules and lozenges. (10) The method according to (1) to (8), which is used for preparing a tablet.

Further, the solid dosage form is obtained by selecting a vasopressin II receptor antagonist from (2) to (4) and selecting a calcium channel blocker from (5) to (8), respectively, and arbitrarily combining them. The preparation method is also suitable, and examples thereof include the following: (11) The method according to (1) wherein the vasopressin II receptor antagonist is losartan, candesartan cilexetil, valsartan, Is valsartan, patosartan, olmesartan or irbesartan, and the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof, (12) according to the method of (1), wherein the blood vessel is elevated The vasopressin II receptor antagonist is losartan, candesartan, valsartan, telmisartan, patosatan, olmesartan or irbesartan, and the calcium channel blocker is benzene Amlodipine sulfonate, (13) The method according to (1) wherein the vasopressin II receptor antagonist is olmesartan medoxomil, and the calcium channel blocker is nifedipine, nimodipine, and nigra Dipyridin, manidipine, bainidipine, nitrendipine, benidipine, nicardipine, lercanidipine, amlodipine, nisoldipine, effildipine, cilnidipine Adesodipine, felodipine, aradadipine or pradipine or a pharmaceutically acceptable salt thereof, (14) wherein the vasopressin II receptor antagonist is olmesartan medoxomil, and The calcium channel blocker is manidipine, bainidipine, benidipine, nicardipine, lercanidipine, amlodipine, effildipine or adipine or a pharmaceutically acceptable salt thereof, (15) according to (1) The method wherein the vasopressin II receptor antagonist is olmesartan medoxomil, and the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof, (16) according to the method of (1) Wherein the vasopressin II receptor antagonist is olmesartan medoxomil, and the calcium channel blocker is amlodipine besylate, (17) according to the method of (1), wherein the vasopressin II receptor The antagonist is olmesartan medoxomil, the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof, and the solid dosage form is a tablet, and (18) according to the method of (1), wherein the blood vessel is boosted The receptor II receptor antagonist is olmesartan medoxomil, the calcium channel blocker is amlodipine besylate, and the solid dosage form is a tablet.

The above methods (1) to (18) for preparing a solid dosage form can be carried out such that the solid dosage form further comprises at least one hydrophilic polymer and the wet granulation step in the method can be carried out by a plurality of different techniques, both All are detailed below. The method of the present invention, wherein: the method according to (19), wherein the solid dosage form further comprises at least one hydrophilic polymer; (20) the method according to (19) wherein the hydrophilic polymer is at least A compound selected from the group consisting of a cellulose derivative and a synthetic polymer; (21) The method according to (19) wherein the hydrophilic polymer is at least one selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, and hydroxypropyl a compound of cellulose, sodium carboxymethylcellulose, polyethylene glycol, HA Sankyo, polyvinylpyrrolidone, and polyvinyl alcohol; (22) The method according to (19) wherein the hydrophilic polymer is at least one selected from the group consisting of fibers A compound according to (19), wherein the hydrophilic polymer is at least one selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, and carboxymethylcellulose (24) The method according to (19) wherein the hydrophilic polymer is methylcellulose or hydroxypropylcellulose or both; (25) the method according to (19) wherein the hydrophilic polymer is (26) The method according to (1) to (25), wherein the wet granulation step is Using a fluidized bed granulation, high-speed mixing and stirring granulation, extrusion granulation, mixed agitation granulation or drum granulation; and (27) a method according to (1) to (25), wherein the wet granulation step It is carried out by high speed mixing and stirring granulation.

Using the method of the present invention, a solid dosage form having improved solubility characteristics comprising a vasopressin II receptor antagonist and a calcium channel blocker can be obtained. These solid dosage forms are also part of the invention.

The solid dosage form obtained by the method of the present invention comprises a vasopressin II receptor antagonist and a calcium channel blocker as its active ingredient.

Since various agents as "vasopressin II receptor antagonists" have been proposed, which are active ingredients in the solid dosage form obtained by the method of the present invention, and most of them are clinically used, those skilled in the art can A suitable agent (provided to have the desired effect as a vasopressin II receptor antagonist) is selected for use in the present invention. Suitable, non-limiting examples of vasopressin II receptor antagonists for use in the present invention include losartan (especially losartan potassium), candesartan cilexetil, valsartan, telmisartan, pa Tosaltan, olmesartan or irbesartan. Among them, olmesartan medoxomil is preferably used. Olmesartan medoxomil can be easily produced according to the method disclosed in the art, and a suitable example includes the method disclosed in Japanese Patent No. 2082519 (corresponding to U.S. Patent No. 5,616,599).

Since various agents as "calcium channel blockers" have been proposed, which are one of the active ingredients obtained by the method of the present invention, and most of them are clinically practical, those skilled in the art can select suitable agents. (provided to have the desired effect as a calcium channel blocker) is used in the present invention. Suitable, non-limiting examples of calcium channel blockers for use in the present invention include nifedipine, nimodipine, nilvadipine, manidipine (preferably manidipine hydrochloride), and balnepine (preferably Baridipine hydrochloride), nitrendipine, benidipine (preferably benidipine hydrochloride), nicardipine (preferably nicardipine hydrochloride), lercanidipine (preferably lercanidipine hydrochloride), ammonia Clodipine (preferably amlodipine besylate), nisoldipine, effluentine (preferably iftodipine hydrochloride), cilnidipine, adipine, felodipine, adipine or prafipine . Among them, amlodipine besylate is preferably used. Amlodipine and its salts (including amlodipine besylate) can be readily produced according to the methods disclosed in the art, and suitable examples include those disclosed in Japanese Patent No. 1401088 (corresponding to U.S. Patent No. 4,572,909). method.

The above-mentioned vasopressin II receptor antagonists and pharmaceutically acceptable salts of calcium channel blockers are not particularly limited and such salts can be selected by those skilled in the art. Suitable pharmaceutically acceptable salts include, for example, alkali metal salts such as sodium, potassium or lithium salts; alkaline earth metal salts such as calcium or magnesium salts; metal salts such as aluminum, iron, zinc, copper, nickel Salt or cobalt salt; amine salt such as ammonium salt, third-octylamine salt, benzhydrylamine salt, morpholine salt, glucosamine salt, alkyl phenylglycine salt, ethylenediamine salt, N- Methyl-reducing glucosamine salt, sulfonium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-diphenylmethylethylenediamine salt, chloroprocaine salt , procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, hexahydropyridinium a salt, a tetramethylammonium salt or a tris(hydroxymethyl)aminomethane salt; a hydrohalide salt such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or hydrogen iodide; a nitrate; a perchlorate; a sulfate; a phosphate; a C ₁ -C ₄ alkane sulfonate, which may optionally be substituted with a halogen atom such as a methanesulfonate, a trifluoromethanesulfonate or an ethanesulfonate; a C ₆ -C _{1 0} arylsulfonate, which is visible Requires substitution with a C ₁ -C ₄ alkyl group, such as a besylate or p-toluenesulfonate; a C ₁ -C ₆ fatty acid salt such as acetate, malate, fumarate, succinate, a citrate, tartrate, oxalate or maleate; or an amine salt such as a glycinate, an amide, a arginine, an alanate, a glutamate or a day Aspartate.

The pharmaceutically acceptable esters of the above vasopressin II receptor antagonists are not particularly limited and can be selected by those skilled in the art. In the case of such esters, such esters are preferably those which can be cleaved by biological processes such as hydrolysis in vivo. The group constituting the ester (when its ester is represented by -COOR, the group is represented by R) may be, for example, a C ₁ -C ₄ alkoxy C1-C ₄ alkyl group such as a methoxyethyl group. , 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1 , 1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or tert-butoxymethyl; C ₁ -C ₄ alkoxylated C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl group such as 2-methoxyethoxymethyl; C ₆ -C _{1 0} aryloxy C ₁ -C ₄ An alkyl group such as a phenoxymethyl group; a halogenated C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl group such as 2,2,2-trichloroethoxymethyl or bis(2-chloroethoxy) Methyl; C ₁ -C ₄ alkoxycarbonyl C ₁ -C ₄ alkyl such as methoxycarbonylmethyl; cyano C ₁ -C ₄ alkyl such as cyanomethyl or 2-cyanoethyl; C ₁ -C ₄ alkylthio such as methylthio methyl methyl methyl or ethyl group; C ₆ -C _{1 0} aryl group, for example phenylthiomethyl or methyl naphthyl methyl group; C ₁ -C ₄ alkyl sulfonate acyl C ₁ -C ₄ lower alkanoyl , Which is optionally substituted with a halogen atom such as 2-methanesulfonamide acyl group or a 2-ethyl trifluoromethane sulfonic acyl; C ₆ -C _{1 0} aryl sulfonic acyl group C ₁ -C ₄ alkyl groups such as 2- Phenylsulfonylethyl or 2-toluenesulfonylethyl; C ₁ -C ₇ aliphatic decyloxy C ₁ -C ₄ alkyl such as methyl methoxymethyl, ethoxymethyl, propyl Oxymethyl, butenoxymethyl, trimethylacetoxymethyl, pentyloxymethyl, isopentyloxymethyl, hexamethyleneoxy, 1-methyloxy Ethyl, 1-ethenyloxyethyl, 1-propoxycarbonylethyl, 1-butoxyethyl, 1-trimethylacetoxyethyl, 1-pentyloxyethyl , 1-Isoamyloxyethyl, 1-hexyloxyethyl, 2-methyloxyethyl, 2-ethyloxyethyl, 2-propoxyethyl, 2-butyl Oxyloxyethyl, 2-trimethylacetoxyethyl, 2-pentyloxyethyl, 2-isopentyloxyethyl, 2-hexyloxyethyl, 1-carboindole Oxypropyl, 1-ethoxymethoxypropyl, 1-propoxypropyl, 1-butoxypropyl, 1-trimethylethoxypropyl, 1-醯oxypropyl, 1-isopentyloxypropyl, 1-hexyloxypropyl, 1-ethoxyoxybutyl, 1-propoxylated butyl, 1-butoxy butyl , 1-trimethylethoxyoxybutyl, 1-ethenyloxypentyl, 1-propenyloxypentyl, 1-butenoxypentyl, 1-trimethylethenyloxy Pentyl or 1-trimethylethenyloxyhexyl; C ₅ -C ₆ cycloalkylcarbonyloxy C ₁ -C ₄ alkyl such as cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxy Butyl or 1-cyclohexylcarbonyloxybutyl; C ₆ -C _{10 0} arylcarbonyloxy C ₁ -C ₄ alkyl such as benzylideneoxymethyl; C ₁ -C ₆ alkoxycarbonyl a C ₁ -C ₄ alkyl group such as methoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(methoxycarbonyloxy)propyl, 1-(methoxy Carboxyoxy)butyl, 1-(methoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl, ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy) ) Ethyl, 1-(B) Alkyloxy)propyl, 1-(ethoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)hexyl, propoxycarbonyl Oxymethyl, 1-(propoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)butyl, isopropoxycarbonyloxy Methyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)butyl, butoxycarbonyloxymethyl, 1-(butoxycarbonyloxy) Ethyl, 1-(butoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)butyl, isobutoxycarbonyloxymethyl, 1-(isobutoxycarbonyloxy) Ethyl, 1-(isobutoxycarbonyloxy)propyl, 1-(isobutoxycarbonyloxy)butyl, tert-butoxycarbonyloxymethyl, 1-(third- Butoxycarbonyloxy)ethyl, pentyloxycarbonyloxymethyl, 1-(pentyloxycarbonyloxy)ethyl, 1-(pentyloxycarbonyloxy)propyl, hexyloxycarbonyloxy Methyl, 1-(hexyloxycarbonyloxy)ethyl or 1-(hexyloxycarbonyloxy)propyl; C ₅ -C ₆ cycloalkoxycarbonyloxy C ₁ -C ₄ alkyl Cyclopentyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1 (cyclopentyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl, cyclohexyloxycarbonyloxymethyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)propyl or 1-(cyclohexyloxycarbonyloxy)butyl; [5-(C ₁ -C ₄ alkyl)-2-oxo-1,3- two Penten-4-yl]methyl such as (5-methyl-2-oxo-1,3-di Penten-4-yl)methyl, (5-ethyl-2-oxo-1,3-di Penten-4-yl)methyl, (5-propyl-2-sidedoxy-1,3-di Penten-4-yl)methyl, (5-isopropyl-2-sidedoxy-1,3-di Penten-4-yl)methyl or (5-butyl-2-oxo-1,3-di Penten-4-yl)methyl; [5-(phenyl, which may optionally be substituted by C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or halogen)-2-oxooxy-1 , 3-two Penten-4-yl]methyl such as (5-phenyl-2-oxo-1,3-di Penten-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-di Penten-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-di Penten-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1,3-di Penten-4-yl]methyl or [5-(4-chlorophenyl)-2-oxo-1,3-di a penten-4-yl]methyl group; or a fluorenyl group which may be optionally substituted by a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group, such as a decyl group, a dimethyl fluorenyl group or a dimethoxy group.酞基.

In a preferred embodiment of the invention, the solid dosage form prepared by the process of the invention may additionally comprise at least one "hydrophilic polymer", i.e., a polymer having affinity for water. The preferred "hydrophilic polymer" used in the present invention is water-soluble. The inclusion of a hydrophilic polymer allows the solid dosage form to have further improved solubility characteristics. Suitable, non-limiting examples of hydrophilic polymers for use in the present invention include cellulose derivatives such as hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, and sodium carboxymethylcellulose; synthetic polymerizations Such as polyvinylpyrrolidone, aminoalkyl methacrylate copolymer, carboxyvinyl polymer, polyvinyl alcohol and polyethylene glycol (also known as polyethylene glycol); HA Sankyo (a pre-mixed coating agent) Including 16-26% by weight of polyvinyl acetal diethyl acetate, 50-75% by weight of hydroxypropyl methylcellulose 2910, 12-17% by weight of stearic acid and 1.5-2.3% by weight a mixture of fumaric acid), gum arabic, agar, gelatin and sodium alginate. Among them, preferred are hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyethylene glycol, HA Sankyo, polyvinylpyrrolidone and polyvinyl alcohol. Preferred are hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, polyethylene glycol, and sodium carboxymethylcellulose, and the most preferred is methylcellulose. In the present invention, these hydrophilic polymers may be used singly or in combination of two or more. When at least one hydrophilic polymer is present in the solid dosage form prepared by the method of the present invention, the hydrophilic polymer (or polymer) is preferably present in an amount of from 1 to 90% by weight based on the total weight of the solid dosage form, and More preferably from 5 to 85% by weight. The one or more hydrophilic polymers may be uniformly distributed throughout the solid dosage form or may be included only in one portion of the solid dosage form. If one or more film coating layers are used in preparing the solid dosage form, one or more hydrophilic polymers may be included in the film coating layer.

If desired, the solid dosage form prepared by the method of the present invention may additionally comprise at least one additional additive such as a suitable pharmaceutically acceptable excipient, lubricant, binder, disintegrant, emulsifier, stabilizer, flavor or Thinner.

Suitable "excipients" include organic excipients which comprise a sugar derivative such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, alpha-starch or dextrin; Such as microcrystalline cellulose; gum arabic; dextrin; and polytriglucose, and inorganic excipients comprising a phthalate derivative such as light anhydrous citric acid, synthetic aluminum citrate, calcium citrate or aluminate Magnesium citrate; phosphates such as dibasic calcium hydrogen phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate.

Suitable "lubricants" include stearic acid; metal stearates such as calcium stearate or magnesium stearate; talc; phthalic acid gels; waxes such as beeswax or cetyl wax; boric acid; adipic acid; For example, sodium sulfate; ethylene glycol; fumaric acid; sodium benzoate; D, L-leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium decyl sulfate; Anthracene anhydride or citric acid hydrate; and the aforementioned starch derivative.

Suitable "bonding agents" include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, and compounds similar to the foregoing excipients.

Suitable "disintegrants" include cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose or internally crosslinked sodium carboxymethylcellulose; crosslinked Polyvinylpyrrolidone; chemically modified starch/cellulose such as carboxymethyl starch or sodium carboxymethyl starch.

Suitable "emulsifiers" include colloidal clays such as bentonite or propolis; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as hydroxyl groups. Chloroaniline; and nonionic surfactants such as polyethylene oxide alkyl ethers, polyethylene oxide sorbitan fatty acid esters or sucrose fatty acid esters.

Suitable "stabilizers" include p-hydroxybenzoic acid esters such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; hydroxychloroaniline; phenols such as phenol Or cresol; sodium thiomethic acid; dehydroacetic acid; and sorbic acid.

Suitable "flavoring agents" include sweetening agents such as sodium saccharin or aspartame; acidulants such as citric acid, malic acid or tartaric acid; and flavors such as menthol, lemon or orange flavor.

Suitable "diluents" include lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerin, starch, polyethylene. Pyrrolidone, magnesium aluminate, and mixtures thereof.

"Solid dosage forms" prepared by the methods of the present invention include any dosage form which is used by those skilled in the art to deliver one or more pharmaceutically active ingredients in solid form to a patient. Suitable solid dosage forms are those well known to those skilled in the art, and are not limited to the solid dosage forms of the present invention, which comprise a tablet (including a sublingual tablet and a tablet for disintegration in the mouth), a capsule (including soft capsules and microcapsules). ), fine granules, granules, powders, pills and rhomboid tablets. Among them, preferred are powders, granules, granules, capsules and lozenges, and most preferred are tablets.

Granulation refers to the process of producing fine particles of uniform shape and size from a feedstock wherein the feedstock is in the form of, for example, a powder, agglomerate, solution or melt. Granulation in accordance with the present invention includes procedures for providing finished particulate solid dosage forms (e.g., fines, powders, and granules), as well as procedures for producing granular intermediates for subsequent manufacture of tablets or capsules. In the method of the present invention, the "wet granulation step" means that some or all of the components of the final solid dosage form are in the form of a powder and are granulated by using a solvent (for example, water or a mixed solution of water and alcohol) as a binder. The step of the composition. Wet granulation techniques are known to those skilled in the art, and a detailed discussion of the wet granulation techniques applicable to the present invention is disclosed in publications such as The Theory and Practice of Industrial Pharmacy (third edition), (Leon Lachman et al. Person: LEA & FEBIGER, 1986) and Pharmaceutical Dosage Forms: Tablets, Volumel (Second Edition) (Herbert A. Lieberman et al.: MARCEL DEKKER INC., 1989).

Suitable non-limiting examples of the wet granulation process used in the process of the present invention include fluidized bed granulation, high speed mixing agitation granulation, extrusion granulation, mixed agitation granulation, and drum granulation. Among them, the particularly good ones are high-speed mixing and stirring granulation.

Fluidized bed granulation refers to a granulation process in which a fluidized bed of powdered raw materials is formed by air flow, a binder solution is sprayed to the bed upon drying, and particles are adhered and aggregated by liquid crosslinking. Examples of suitable devices for fluid bed granulation include a curtain coater (e.g., manufactured by Freund Corporation), a spiral coater (e.g., manufactured by Freund Corporation), and a new spherical granulator ( New Marumerizer) (for example, manufactured by Fuji Paudal).

The high-speed mixed agitation granulation refers to a granulation method in which a binder solution is added while mixing at a high speed, stirring, and causing the powdered raw material to flow. Examples of suitable devices for high-speed mixed agitation granulation include Super Mixer (manufactured by Kawata Factory), Super Fine Mixer (manufactured by Nara Machinery), Turbosphere mixer (manufactured by Moritz Mutual), and Gural mixer (Co11ett-Fuji Paudal) ).

Extrusion granulation refers to a granulation method in which a binder solution is added to a raw material of a powder, and after the resulting mixture is kneaded, the obtained kneaded product is pressed against the surface of a mold or a screw and then extrusion molded. The pressurized composition gives the desired fine particles. Examples of suitable devices for extrusion granulation include basket granulators, screw granulators, and rocking granulators.

The mixed agitation granulation means a granulation method in which a binder solution is added to a pulverized raw material, followed by granulation of the resulting mixture upon mixing and stirring. Examples of suitable means for mixing agitation granulation include a Shinagawa mixer (e.g., manufactured by Dalton), a Nauter mixer (e.g., manufactured by Hosokawa Micron), and a Topo-granulator (e.g., manufactured by Collett-Fuji Paudal). ).

Drum granulation refers to a process for producing spherical fine particles by spraying or coating a binder onto a rolled powdered raw material. Examples of suitable devices for drum granulation include centrifugal flow granulation coating devices (e.g., manufactured by Freund), Roto-Processor (e.g., manufactured by Eromatic-Fuji Sangyo), Marumerizer (e.g., manufactured by Fuji Paudal). And VG Coater (for example, manufactured by Kikusui Seisakusho).

The kind of the solvent which can be used in the wet granulation step of the method of the present invention is not particularly limited. Non-limiting examples of solvents suitable for use include acetone, methanol, ethanol, isopropanol, dichloromethane, water, or mixtures thereof.

The fine granules obtained in the wet granulation step of the process of the present invention can be formed into a desired particle diameter to form a solid dosage form such as a powder, granule or fine granule. Alternatively, the dosage forms can be filled into a capsule shell to form a capsule. Further, a pharmaceutically acceptable additive such as a disintegrator, a lubricant or the like may be added as needed, followed by compression molding of the mixture obtained by a tableting machine to form a solid dosage form of the present invention in the form of a tablet. Such procedures, such as mixing and granulation, are procedures conventional in the art of pharmaceutical technology and can be readily performed by those skilled in the art.

When the solid dosage form prepared by the method of the present invention is a tablet, at least one film coat can be provided. If a film coat is desired, any film coating equipment of the type known in the art can be used. As for the film coat substrate, suitable examples include a sugar coating base, a hydrophilic film coat base, an enteric coating base, and a sustained release film coat base.

Suitable examples of sugar-coated bases include sucrose, and such may be used in combination with one or more additives such as talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinyl pyrrolidone, and polytriglucose.

Suitable examples of hydrophilic film-coating bases include cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, and sodium carboxymethylcellulose; Synthetic polymers such as polyvinyl acetal acetate, diethyl methacrylate copolymer, polyvinyl pyrrolidone and polyethylene glycol; and polysaccharides such as polytriglucose.

Suitable examples of enteric coated bases include cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl methylcellulose succinate acetate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic acid Derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S; and natural substances such as shellac.

Suitable examples of the sustained-release film-coating base include cellulose derivatives such as ethyl cellulose; and acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer emulsion.

Mixtures of two or more of the above different coating bases may also be employed in a suitable ratio. In addition, the film coat may optionally contain suitable pharmaceutically acceptable additives such as plasticizers, excipients, lubricants, opacifiers, colorants or antibacterial agents.

Dosage and dose ratio of a vasopressin II receptor antagonist to a calcium channel blocker, which is an active ingredient in a solid dosage form obtained by the method of the present invention, which may depend on various factors such as the activity of each active ingredient and the disease The symptoms, age and weight vary. Although the dosage varies depending on the symptoms, age, etc., the dosage of each active ingredient in the case of administration into the mouth is typically from a lower limit of 0.001 mg/kg (preferably 0.01 mg/kg) to a higher daily rate. Limiting 10 mg/kg per day (preferably 1 mg/kg), and depending on the symptoms of the patient, the dose can be administered 1 to 6 times a day.

Further, the dose ratio of the vasopressin II receptor antagonist to the calcium channel blocker, which is the active ingredient in the solid dosage form obtained by the method of the present invention, can also be varied over a wide range. For example, the weight ratio of the dose of the vasopressin II receptor antagonist to the calcium channel blocker may typically range from 1:1000 to 1000:1, preferably from 1:100 to 100:1. And better preferably in the range of 1:10 to 10:1.

The solid dosage form obtained by the method of the present invention can effectively prevent or treat, for example, hypertension or diseases caused by hypertension [more specifically, hypertension, heart disease (angina pectoris, myocardial infarction, arrhythmia, cardiac insufficiency or heart) Hypertrophy), kidney disease (diabetic nephropathy, glomerulonephritis or nephrosclerosis), or cardiovascular disease (cerebral infarction or cerebral hemorrhage)].

[Examples]

The invention will be explained in more detail by the following examples, but the scope of the invention is not limited thereto.

Example 1

(1) Weigh olmesartan medoxomil, amlodipine besylate, lactose and low-substituted hydroxypropylcellulose according to the relative amounts shown in column 1 of Table 1 and mix them in an agate mortar. After 2 minutes, the resulting powdery mixture was kneaded with pure water (the amount of water added was 34% by weight of the powdery mixture). After the resulting mixture was dried in a vacuum dryer, it was passed through a 30 mesh screen (500 μm), and microcrystalline cellulose was added to the sieved mixture according to the relative amounts shown in the first column of Table 1 below. And the magnesium stearate was then mixed in an agate mortar for 2 minutes to obtain the mixed fine particles.

140 mg of the obtained mixed fine particles were loaded into a mold having a diameter of 7.0 mm and used for a hydraulic single-acting tablet press having a press having a diameter of 7.0 mm at a tablet weight of 140 mg and a pressing pressure of 10 kN. A tablet is formed. The dissolution characteristics of the obtained tablets were tested in accordance with the procedure shown in the following test examples and the results are shown in Table 2 below.

Reference example 1

Olmesartan medoxomil, amlodipine besylate, lactose, low-substituted hydroxypropylcellulose, microcrystalline cellulose and magnesium stearate were weighed according to the relative amounts shown in the second column of Table 1 below. After mixing for 2 minutes in an agate mortar, the resulting mixture was formed into a tablet using a hydraulic single-acting tablet press having a press having a surface of 7.0 mm on a tablet weight of 140 mg and a pressing pressure of 10 kN. The dissolution characteristics of the obtained tablets were tested in accordance with the procedure shown in the following test examples and the results are shown in Table 2 below.

Example 2

Olmesartan medoxomil, amlodipine besylate, microcrystalline cellulose, calcium hydrogen phosphate and sodium carboxymethyl starch were weighed according to the relative amounts shown in column 3 of Table 1 below, and then weighed in agate. The mixture was mixed for 2 minutes, after which the resulting powdery mixture was kneaded with pure water (the amount of water added was 56% by weight of the powdery mixture). After the resulting mixture was dried in a vacuum dryer, it was passed through a 30 mesh screen (500 μm), and magnesium stearate was added in the relative amounts shown in the third column of Table 1 below and mixed in an agate mortar. The mixed fine particles were obtained in 2 minutes.

140 mg of the obtained mixed fine particles were loaded into a mold having a diameter of 7.0 mm and used for a hydraulic single-acting tablet press having a press having a diameter of 7.0 mm at a tablet weight of 140 mg and a pressing pressure of 10 kN. A tablet is formed. The dissolution characteristics of the obtained tablets were tested in accordance with the procedure shown in the following test examples and the results are shown in Table 2 below.

Reference example 2

Olmesartan medoxomil, amlodipine besylate, microcrystalline cellulose, dibasic calcium phosphate, sodium carboxymethyl starch and magnesium stearate were weighed according to the relative amounts shown in the fourth column of Table 1 below. After mixing for 2 minutes in an agate mortar, the resulting mixture was formed into a tablet using a hydraulic single-acting tablet press having a press having a surface of 7.0 mm on a tablet weight of 140 mg and a pressing pressure of 10 kN. . The dissolution characteristics of the obtained tablets were tested in accordance with the procedure shown in the following test examples and the results are shown in Table 2 below.

Test case

The dissolution rate test of the tablet prepared in the above examples was carried out in accordance with the dissolution test (Paddle Method) described in the Japanese Pharmacopoeia of the 14th revision, which was used at 50 cycles per minute and used. 900 ml of Japanese Pharmacopoeia Solution 2 (JP-2) was used as the test solution. A sample of the test solution was taken at 30 minutes and 60 minutes after the start of the test, and the dissolution rate was measured and the dissolved amount of olmesartan medoxomil was measured by absorption spectroscopy (dissolution tester: Toyama Sangyo; spectrophotometer: Shimadzu). The two tablets were tested and the average values were indicated in each case.

As shown in Table 2 above, it was confirmed that the solid dosage form contained in the solid dosage form obtained by the method of the present invention having the wet granulation step was compared with the solid dosage form having the same formulation but not prepared by the wet granulation step. The vasopressin II receptor antagonist (olmesartan medoxomil in the above examples) has excellent solubility characteristics.

[Industry Utilization]

According to the present invention, there is provided a method of providing a solid dosage form comprising a vasopressin II receptor antagonist and a calcium channel blocker, wherein the solid dosage form has improved solubility characteristics.

Claims (16)

A method for preparing a solid dosage form comprising a vasopressin II receptor antagonist and a calcium channel blocker, wherein the vasopressin II receptor antagonist is selected from the group consisting of olmesartan and olmesartan a group of esters (olmesartan medoxomil), or a pharmaceutically acceptable salt thereof; and the calcium channel blocker is selected from the group consisting of amlodipine, azelnidipine, or a pharmaceutical thereof In the group consisting of salts or esters, the method comprises the step of preparing a composition comprising the vasopressin II receptor antagonist and the calcium channel blocker by wet granulation. The method of claim 1, wherein the vasopressin II receptor antagonist is olmesartan medoxomil. The method of claim 1, wherein the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof. The method of claim 3, wherein the calcium channel blocker is amlodipine besylate. The method of any one of claims 1 to 4 for the preparation of a solid dosage form selected from the group consisting of powders, granules, granules, capsules and lozenges. The method of any one of claims 1 to 4 is for the preparation of a tablet. The method of claim 5, wherein the solid dosage form further comprises at least one hydrophilic polymer. The method of claim 7, wherein the hydrophilic polymer is At least one compound selected from the group consisting of cellulose derivatives and synthetic polymers. The method of claim 7, wherein the hydrophilic polymer is at least one selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and polyethylene. A compound of an alcohol, HA Sankyo, polyvinylpyrrolidone and polyvinyl alcohol. The method of claim 7, wherein the hydrophilic polymer is at least one compound selected from the group consisting of cellulose derivatives. The method of claim 7, wherein the hydrophilic polymer is at least one compound selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, and sodium carboxymethylcellulose. The method of claim 7, wherein the hydrophilic polymer is methylcellulose or hydroxypropylcellulose or both. The method of claim 7, wherein the hydrophilic polymer is polyethylene glycol. The method of claim 1, wherein the wet granulation step is carried out using fluidized bed granulation, high speed mixed agitation granulation, extrusion granulation, mixed agitation granulation or drum granulation. The method of claim 14, wherein the wet granulation step is carried out using high speed mixed agitation granulation. The use of a vasopressin II receptor antagonist and a calcium channel blocker for the manufacture of a medicament for preventing or treating hypertension, wherein the medicament is claimed in claims 1 to 15 A solid dosage form prepared by a method.