WO2007001065A2 - Method for the preparation of a wet granulated drug product - Google Patents

Method for the preparation of a wet granulated drug product Download PDF

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Publication number
WO2007001065A2
WO2007001065A2 PCT/JP2006/313174 JP2006313174W WO2007001065A2 WO 2007001065 A2 WO2007001065 A2 WO 2007001065A2 JP 2006313174 W JP2006313174 W JP 2006313174W WO 2007001065 A2 WO2007001065 A2 WO 2007001065A2
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WO
WIPO (PCT)
Prior art keywords
angiotensin
calcium channel
receptor antagonist
channel blocker
dosage form
Prior art date
Application number
PCT/JP2006/313174
Other languages
French (fr)
Other versions
WO2007001065A3 (en
Inventor
Takeshi Hamaura
Mitsuru Kanno
Original Assignee
Daiichi Sankyo Company, Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daiichi Sankyo Company, Limited filed Critical Daiichi Sankyo Company, Limited
Priority to JP2007558254A priority Critical patent/JP5063370B2/en
Publication of WO2007001065A2 publication Critical patent/WO2007001065A2/en
Publication of WO2007001065A3 publication Critical patent/WO2007001065A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the present 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.
  • calcium channel blockers and angiotensin II receptor antagonists are widely used clinically as medicaments for the treatment and prophylaxis of hypertension. Since calcium channel blockers exert natriuretic action in addition to vasodilatory action, they are effective against hypertension caused by fluid retention (renin-independent). On the other hand, angiotensin H receptor antagonists are particularly effective against renin-dependent hypertension, and have excellent organ protective effects. Thus, it is expected that the combined use of a calcium channel blocker and an angiotensin II receptor antagonist should allow stable and effective antihypertensive therapy regardless of the cause of the hypertension.
  • 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 [DISCLOSURE OF THE INVENTION]
  • the object of the present invention is to provide a method for the preparation of a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker with improved dissolution properties, and a solid dosage form obtainable by said method.
  • the present inventors found that the dissolution properties of a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker are improved by including in its preparation a wet granulation step for the preparation a of a composition comprising said angiotensin II receptor antagonist and said calcium channel blocker, thereby leading to completion of the present invention.
  • the present invention provides 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, a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker obtainable by said method (particularly a dosage form for the prophylaxis or treatment of hypertension), the use of an angiotensin II receptor antagonist and a calcium channel blocker to manufacture the aforementioned solid dosage form (particularly a dosage form for the prophylaxis or treatment of hypertension), and methods for the prophylaxis or treatment of diseases (particularly hypertension) in which the aforementioned solid dosage form comprising pharmacologically effective doses of an angiotensin II receptor antagonist and a calcium channel blocker is administered to warm-blooded animals (particularly humans).
  • the present invention provides:
  • 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, (2) a method according to (1) wherein the angiotensin II receptor antagonist is losartan, candesartan, valsartan, telmisartan, pratosartan, olmesartan or irbesartan or a pharmacologically acceptable salt or ester thereof,
  • angiotensin II receptor antagonist is losartan, candesartan cilexetil, valsartan, telmisartan, pratosartan, olmesartan medoxomil or irbesartan,
  • angiotensin II receptor antagonist is olmesartan medoxomil
  • the calcium channel blocker is nifedipine, nimodipine, nilvadipine, manidipine, barnidipine, nitrendipine, benidipine, nicardipine, lercanidipine, amlodipine, nisoldipine, efonidipine, cilnidipine, azelnidipine, felodipine, aranidipine or pranidipine or a pharmacologically acceptable salt thereof,
  • the calcium channel blocker is manidipine, barnidipine, benidipine, nicardipine, lercanidipine, amlodipine, efonidipine or azelnidipine or a pharmacologically acceptable salt thereof,
  • angiotensin II receptor antagonist from (2) to (4) and a calcium channel blocker from (5) to (8) and arbitrarily combining them is also suitable, examples of which include those listed below:
  • angiotensin II receptor antagonist is losartan, candesartan cilexetil, valsartan, telmisartan, pratosartan, olmesartan medoxomil or irbesartan
  • the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof
  • the angiotensin II receptor antagonist is losartan, candesartan cilexetil, valsartan, telmisartan, pratosartan, olmesartan medoxomil or irbesartan
  • the calcium channel blocker is amlodipine besylate
  • angiotensin II receptor antagonist is olmesartan medoxomil
  • the calcium channel blocker is nifedipine, nimodipine, nilvadipine, manidipine, barnidipine, nitrendipine, benidipine, nicardipine, lercanidipine, amlodipine, nisoldipine, efonidipine, cilnidipine, azelnidipine, felodipine, aranidipine or pranidipine or a pharmacologically acceptable salt thereof,
  • angiotensin II receptor antagonist is olmesartan medoxomil
  • the calcium channel blocker is manidipine, barnidipine, benidipine, nicardipine, lercanidipine, amlodipine, efonidipine or azelnidipine or a pharmacologically acceptable salt thereof
  • angiotensin II receptor antagonist is olmesartan medoxomil
  • the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof
  • the solid dosage form is a tablet
  • the above methods (1) to (18) for the preparation of a solid dosage form can be performed so that the solid dosage form further comprises at least one hydrophilic polymer and the wet granulation step in the methods can be conducted using a number of different techniques, both of which are described in greater detail below. Examples of these methods include:
  • hydrophilic polymer is at least one compound selected from hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, macrogol, HA Sankyo, polyvinylpyrrolidone and polyvinyl alcohol;
  • hydrophilic polymer is at least one compound selected from cellulose derivatives
  • hydrophilic polymer is at least one compound selected from hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose;
  • hydrophilic polymer is either or both of methyl cellulose and hydroxypropyl cellulose
  • solid dosage form that contains an angiotensin II receptor antagonist and a calcium channel blocker, with improved dissolution properties is obtainable.
  • solid dosage forms also form a part of the present invention.
  • the solid dosage form obtainable using the method of the present invention contains an angiotensin II receptor antagonist and a calcium channel blocker as its active ingredients.
  • angiotensin II receptor antagonist which is one of the active ingredients in a solid dosage form obtainable using the method of the present invention, and many are actually used clinically
  • a person of ordinary skill in the art can select suitable medicaments that demonstrate the desired effect as an angiotensin II receptor antagonist for use in the present invention.
  • suitable, non-limiting examples of angiotensin II receptor antagonists for use in the present invention include losartan (preferably losartan potassium), candesartan cilexetil, valsartan, telmisartan, pratosartan, olmesartan medoxomil and irbesartan. Of these, olmesartan medoxomil is preferably used. Olmesartan medoxomil can easily be produced according to the methods disclosed in the art, suitable examples including the methods disclosed in Japanese Patent No. 2082519 (corresponding to US Patent No. 5,616,599).
  • Suitable, non- limiting examples of calcium channel blockers for use in the present invention include nifedipine, nimodipine, nilvadipine, manidipine (preferably manidipine hydrochloride), barnidipine (preferably barnidipine hydrochloride), nitrendipine, benidipine (preferably benidipine hydrochloride), nicardipine (preferably nicardipine hydrochloride), lercanidipine (preferably lercanidipine hydrochloride), amlodipine (preferably amlodipine besylate), nisoldipine, efonidipine (preferably efonidipine hydrochloride), cilnidipine, azelnidipine, felodipine, aranidipine and pranidipine.
  • amlodipine besylate is preferably used.
  • Amlodipine and its salts including amlodipine besylate can be easily produced according to the methods disclosed in the art, suitable examples including the methods disclosed in Japanese Patent No. 1401088 (corresponding to US Patent No. 4,572,909).
  • Suitable pharmacologically acceptable salts include, for example, an alkaline metal salt such as a sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as a calcium salt or magnesium salt; a metal salt such as an aluminium salt, iron salt, zinc salt, copper salt, nickel salt or cobalt salt; an amine salt such as an ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt,
  • an alkaline metal salt such as a sodium salt, potassium salt or lithium salt
  • an alkaline earth metal salt such as a calcium salt or magnesium salt
  • a metal salt such as an aluminium
  • esters of the angiotensin II receptor antagonists described above are not particularly restricted, and can be selected by a person of ordinary skill in the art. In the case of said esters, it is preferable that such esters can be cleaved by a biological process such as hydrolysis in vivo.
  • the group constituting the esters can be, for example, a C x -C 4 alkoxy Ci-C 4 alkyl group such as methoxyethyl, 1- ethoxyethyl, 1-methyl-l-methoxyethyl, l-(isopropoxy)ethyl, 2-methoxyethyl, 2- ethoxyethyl, 1,1-dimethyl-l-methoxyrnethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; a C 1 -C 4 alkoxylated C 1 -C 4 alkoxy C 1 -C 4 alkyl group such as 2-methoxyethoxymethyl; a C 6 -C 10 aryloxy C 1 -C 4 alkyl group such as phenoxymethyl; a halogenated C 1 -C 4 alkoxy C 1 -C
  • the solid dosage form obtainable by the method of the present invention additionally contains at least one "hydrophilic polymer", i.e. a polymer that has an affinity for water.
  • Preferred "hydrophilic polymers” for use in the present invention are ones which are water- soluble. Incorporation of a hydrophilic polymer can give a solid dosage form with dissolution properties which are further improved.
  • hydrophilic polymers for use in the present invention include cellulose derivatives such as hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinylpyrrolidone, aminoalkyl methacrylate copolymer, carboxyvinyl polymer, polyvinyl alcohol and macrogol (i.e.
  • HA Sankyo a pre-mixed coating agent comprising a mixture of 16-26% by weight of polyvinyl acetal diethyl aminoacetate, 50-75% by weight of hydroxypropylmethyl cellulose 2910, 12-17% by weight of stearic acid and 1.5-2.3% by weight of fumaric acid
  • gum Arabic agar, gelatin and sodium alginate.
  • hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, macrogol, HA Sankyo, polyvinylpyrrolidone and polyvinyl alcohol are preferred, hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, macrogol and sodium carboxymethyl cellulose are more preferred, and methyl cellulose is most preferred.
  • these hydrophilic polymers can be used alone or two or more kinds can be used in combination.
  • hydrophilic polymer is present in the solid dosage form obtainable using the method of the present invention
  • said hydrophilic polymer (or polymers) is preferably present in an amount of from 1 to 90% by weight of 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 entire solid dosage form, or they may be contained in only a part of said solid dosage form. If one or more film coating layers are used in the preparation of the solid dosage form, the one or more hydrophilic polymers may be contained in said film coating layers.
  • the solid dosage form obtainable using the method of the present invention can where desired additionally contain at least one further additive such as a suitable pharmacologically acceptable excipient, lubricant, binder, disintegrant, emulsifier, stabilizer, corrective or diluent.
  • excipients include organic excipients including sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, ⁇ -starch or dextrin; cellulose derivatives such as microcrystalline cellulose; gum Arabic; dextran; and pullulan, and inorganic excipients including silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate or magnesium metasilicate aluminate; phosphates such as dibasic calcium hydrogenphosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate.
  • sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol
  • starch derivatives such as corn starch, potato starch, ⁇ -starch or dextrin
  • cellulose derivatives such as microcrystalline cellulose
  • gum Arabic dextran
  • pullulan and inorganic excipients including
  • Suitable "lubricants” include stearic acid; stearic acid metal salts such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; D,L-leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicates such as silicic anhydride or silicate hydrate; and the aforementioned starch derivatives.
  • Suitable "binders” include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, macrogol and compounds similar to the aforementioned excipients.
  • Suitable “disintegrants” include cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose or internally crosslinked sodium carboxymethyl cellulose; cross-linked polyvinylpyrrolidone; and chemically modified starches/celluloses such as carboxymethyl starch or sodium carboxymethyl starch.
  • Suitable "emulsifiers” include colloidal clays such as bentonite or bee gum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzalkonium chloride; and nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester.
  • Suitable “stabilizers” include para-hydroxybenzoic acid esters such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenyl ethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; and sorbic acid.
  • Suitable “correctives” include sweeteners such as sodium saccharin or aspartame; sour flavourings such as citric acid, malic acid or tartaric acid; and fragrances such as menthol, lemon or orange fragrance.
  • Suitable "diluents” include lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate, and mixtures thereof.
  • suitable solid dosage forms will be well known to the person skilled in the art, and non-limiting examples of the solid dosage form of the present invention include tablets (including sublingual tablets and tablets that disintegrate in the mouth), capsules (including soft capsules and microcapsules), granules, grains, powders, pills, and lozenges. Of these, powders, grains, granules, capsules and tablets are preferred, and tablets are most preferred.
  • Granulation refers to a procedure for producing granules having nearly uniform shape and size from raw materials which are in a form such as powders, lumps, solutions or molten liquids.
  • Granulation in accordance with the present invention includes procedures which give a finished granular solid dosage form such as granules, powders and grains, and procedures in which intermediate granular products are produced for subsequent use in the manufacture of tablets or capsules.
  • the "wet granulation step" in the method of the present invention refers to a step in which some or all of the ingredients of the final solid dosage form are in powdered form and are granulated using a solvent such as water or a mixed solution of water and alcohol as a binder to give a granular composition.
  • wet granulation techniques are well known to those skilled in the art, and detailed discussions of wet granulation techniques suitable for use in the present invention are disclosed in publications such as The Theory and Practice of Industrial Pharmacy (Third Edition), (Leon Lachman, et al.: LEA & FEBIGER, 1986) and Pharmaceutical Dosage Forms: Tablets, Volume 1 (Second Edition) (Herbert A. Lieberman, et al.: MARCEL DEKKER INC., 1989).
  • Suitable non-limiting examples of wet granulation methods for use in the method of the present invention include fluidized bed granulation, high-speed mixing agitation granulation, extrusion granulation, mixing agitation granulation and tumbling granulation. Of these, high-speed mixing agitation granulation is particularly preferred.
  • Fluidized bed granulation refers to a granulating method in which a fluidized bed of powdered raw material is formed by an air flow, a binder solution is sprayed onto the bed while drying, and particles are caused to adhere and agglutinate by liquid cross- linking.
  • suitable devices for use in fluidized bed granulation include a flow coater (e.g. those manufactured by the Freund Corporation), a spiral coater (e.g. those manufactured by the Freund Corporation) and a New Marumerizer (e.g. those manufactured by Fuji Paudal).
  • High-speed mixing agitation granulation refers to a granulating method in which a binder solution is added while the powdered raw material is mixed, agitated and caused to flow at high speed.
  • suitable devices for use in high-speed mixing agitation granulation include a Super Mixer (manufactured by Kawata Factory), a Super Fine Matrix (Nara Machinery), a Turbosphere mixer (manufactured by Moritz Mutual) and a Gural mixer (Collett-Fuji Paudal).
  • Extrusion granulation refers to a granulating method in which a binder solution is added to the powdered raw material, the mixture thus obtained is kneaded before pressing of the resulting kneaded product onto the surface of a die or screw followed by extrusion moulding of the pressed composition thus obtained to give the desired granules.
  • suitable devices for use in extrusion granulation include a basket-type granulating machine, a screw-type extrusion granulating machine and an oscillating granulating machine.
  • Mixing agitation granulation refers to a granulating method in which a binder solution is added to the powdered raw material followed by granulation of the resulting mixture while mixing and agitating.
  • suitable devices for use in mixing agitation granulation include a Shinagawa mixer (e.g. those manufactured by Dalton), a Nauter mixer (e.g. those manufactured by Hosokawa Micron) and a Topo-granulator (e.g. those manufactured by Collett-Fuji Paudal).
  • Tumbling granulation refers to a method for producing spherical granules by spraying or coating a binder onto a tumbling powdered raw material.
  • suitable devices for use in tumbling granulation include a centrifugal flow granulation coating device (e.g. those manufactured by Freund), a Roto-Processor (e.g. those manufactured by Eromatic-Fuji Sangyo), a Marumerizer (e.g. those manufactured by Fuji Paudal) and a VG Coater (e.g. those manufactured by Kikusui Seisakusho).
  • solvents that can be used in the wet granulation step of the method of the present invention.
  • suitable, non-limiting examples of solvents for use include acetone, methanol, ethanol, isopropanol, methylene chloride, water or mixtures thereof.
  • Granules obtained in the wet granulation step of the method of the present invention can be sized to a desired particle diameter and formed into a solid dosage form as powders, grains or granules.
  • these dosage forms can be filled into capsule shells to form capsules.
  • pharmacologically acceptable additives such as disintegrating agents, lubricants and the like can be added as necessary followed by compression moulding of the resulting mixture with a tablet press to form a solid dosage form of the present invention in the form of tablets.
  • the procedures such as mixing and granulation are all procedures that are commonly used in the field of pharmaceutical technology, and can be readily performed by a person of ordinary skill in the art.
  • the solid dosage form obtainable using the method of the present invention is a tablet, it may be provided with at least one layer of a film coating.
  • a film coating any film coating apparatus of a type well known in the art can be used, and as film coating bases, suitable examples include sugar coating bases, hydrophilic film coating bases, enteric film coating bases and sustained release film coating bases.
  • Suitable examples of sugar coating bases include saccharose, and these can be used in combination with one or more additives such as talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum Arabic, polyvinylpyrrolidone and pullulan.
  • hydrophilic film coating bases include cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymer, polyvinylpyrrolidone and macrogol; and polysaccharides such as pullulan.
  • enteric film coating bases include cellulose derivatives such as hydroxypropyl methyl cellulose, phthalate hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose- 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.
  • sustained release film coating bases include cellulose derivatives such as ethyl cellulose; and acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer emulsion.
  • a mixture of two or more different coating bases such as those above may also be used in a suitable ratio.
  • the coating films may also contain suitable pharmacologically acceptable additives such as plasticizers, excipients, lubricants, opacifying agents, colorants or antiseptics as necessary.
  • suitable pharmacologically acceptable additives such as plasticizers, excipients, lubricants, opacifying agents, colorants or antiseptics as necessary.
  • the dose of each class of active ingredient in the case of oral administration is typically from 0.001 mg/kg (preferably 0.01 mg/kg) per day as a lower limit to 10 mg/kg (preferably 1 mg/kg) per day as an upper limit for a human adult, and the dosage can be administered from one to six times per day depending on the symptoms of the patients.
  • the dosing ratio of the angiotensin II receptor antagonist and calcium channel blocker which are the active ingredients in the solid dosage form obtainable using the method of the present invention, can also be changed over a wide range.
  • the dosing ratio by weight of angiotensin II receptor antagonist and calcium channel blocker can typically be within a range of 1:1000 to 1000:1, preferably within a range of 1:100 to 100:1, and more preferably within a range of 1:10 to 10:1.
  • the solid dosage form obtainable using the method of the present invention is effective for the prophylaxis or treatment of, for example, hypertension or diseases caused by hypertension [more specifically, hypertension, heart disease (angina pectoris, myocardial infarction, arrhythmia, cardiac insufficiency or hypercardia), kidney disease (diabetic nephropathy, glomerular nephritis or nephrosclerosis), or cerebrovascular disease (cerebral infarction or cerebral hemorrhage)] and the like.
  • hypertension or diseases caused by hypertension more specifically, hypertension, heart disease (angina pectoris, myocardial infarction, arrhythmia, cardiac insufficiency or hypercardia), kidney disease (diabetic nephropathy, glomerular nephritis or nephrosclerosis), or cerebrovascular disease (cerebral infarction or cerebral hemorrhage)] and the like.
  • hypertension or diseases caused by hypertension more specifically
  • Olmesartan medoxomil, amlodipine besylate, lactose and low substituted hydroxypropyl cellulose were each weighed out in the relative amounts given in column 1 of Table 1 below and they were then mixed for 2 minutes in an agate mortar before kneading the resulting powdered mixture with purified water (the amount of water added was 34% by weight of the powdered mixture). After drying the resulting mixture with a vacuum dryer, it was passed through a 30 mesh sieve (500 ⁇ m), macrocrystalline cellulose and magnesium stearate were added to the sieved mixture in the relative amounts shown in column 1 of Table 1 below and this was then mixed for 2 minutes in an agate mortar to give mixed granules.
  • Olmesartan medoxomil, amlodipine besylate, lactose, low substituted hydroxypropyl cellulose, microcrystalline cellulose and magnesium stearate were each weighed out in the relative amounts given in column 2 of Table 1 below, and after mixing for 2 minutes in an agate mortar, the resulting mixture was formed into tablets using a hydraulic single-action tablet press with a stamp having a 7.0 mm diameter surface at a tablet weight of 140 mg and pressing pressure of 10 kN. The dissolution properties of the resulting tablets were tested according to the procedure shown in the Test Example below and the results are shown in the following Table 2.
  • Olmesartan medoxomil, amlodipine besylate, microcrystalline cellulose, calcium hydrogenphosphate and sodium carboxymethyl starch were each weighed in the relative amounts given in column 3 of Table 1 below, and they were then mixed for 2 minutes in an agate mortar before kneading the resulting powdered mixture with purified water (the amount of water added was 56% by weight of the powdered mixture). After drying the resulting mixture with a vacuum dryer, it was passed through a 30 mesh sieve (500 ⁇ m) followed by the addition of magnesium stearate in the relative amounts shown in column 3 of Table 1 below and mixing for 2 minutes in an agate mortar to give mixed granules.
  • Olmesartan medoxomil, amlodipine besylate, microcrystalline cellulose, dibasic calcium phosphate, sodium carboxymethyl starch and magnesium stearate were each weighed out in the relative amounts given in column 4 of Table 1 below, and after mixing for 2 minutes in an agate mortar, the resulting mixture was formed into tablets using a hydraulic single-action tablet press with a stamp having a 7.0 mm diameter surface at a tablet weight of 140 mg and pressing pressure of 10 kN. The dissolution properties of the resulting tablets were tested according to the procedure shown in the Test Example below and the results are shown in the following Table 2.
  • Test for the rate of dissolution of the tablets prepared in the examples above was carried out in accordance with Method 2 of the Dissolution Test (Paddle Method) described in the 14th Revised Edition of the Japanese Pharmacopoeia at 50 revolutions per minute and using 900 mL of Japanese Pharmacopoeia Solution 2 (JP-2) for the test solution.
  • the test solution was sampled 30 minutes and 60 minutes after the start of testing followed by measurement of the dissolution rate and dissolved amount of olmesartan medoxomil by absorption spectrometry (dissolution tester: Toyama Sangyo; spectrophotometer: Shimadzu). Testing was carried out on two tablets and their average value is indicated in each case.
  • the solid dosage forms obtained using the method of the present invention having a wet granulation step demonstrated superior dissolution properties for the angiotensin II receptor antagonist contained therein (olmesartan medoxomil in the case of the examples above) compared to corresponding solid dosage forms having the same formulation which had been prepared without a wet granulation step.
  • a method is provided that gives a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker which has improved dissolution properties.

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

DESCRIPTION
Method for the preparation of a wet granulated drug product
[TECHNICAL FIELD]
The present 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.
[BACKGROUND ART]
Currently, calcium channel blockers and angiotensin II receptor antagonists are widely used clinically as medicaments for the treatment and prophylaxis of hypertension. Since calcium channel blockers exert natriuretic action in addition to vasodilatory action, they are effective against hypertension caused by fluid retention (renin-independent). On the other hand, angiotensin H receptor antagonists are particularly effective against renin-dependent hypertension, and have excellent organ protective effects. Thus, it is expected that the combined use of a calcium channel blocker and an angiotensin II receptor antagonist should allow stable and effective antihypertensive therapy regardless of the cause of the hypertension.
A number of combination drugs comprising an angiotensin II receptor antagonist and a calcium channel blocker have been proposed in the prior art, such as Patent Documents 1 to 4 below. However, there has been no disclosure in the prior art of a method for the preparation of a solid dosage form comprising an angiotensin II receptor antagonist and a calcium blocker which 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 [DISCLOSURE OF THE INVENTION]
The object of the present invention is to provide a method for the preparation of a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker with improved dissolution properties, and a solid dosage form obtainable by said method.
As a result of conducting extensive research to solve the aforementioned problems, the present inventors found that the dissolution properties of a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker are improved by including in its preparation a wet granulation step for the preparation a of a composition comprising said angiotensin II receptor antagonist and said calcium channel blocker, thereby leading to completion of the present invention.
The present invention provides 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, a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker obtainable by said method (particularly a dosage form for the prophylaxis or treatment of hypertension), the use of an angiotensin II receptor antagonist and a calcium channel blocker to manufacture the aforementioned solid dosage form (particularly a dosage form for the prophylaxis or treatment of hypertension), and methods for the prophylaxis or treatment of diseases (particularly hypertension) in which the aforementioned solid dosage form comprising pharmacologically effective doses of an angiotensin II receptor antagonist and a calcium channel blocker is administered to warm-blooded animals (particularly humans).
Specifically, the present invention provides:
(1) 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, (2) a method according to (1) wherein the angiotensin II receptor antagonist is losartan, candesartan, valsartan, telmisartan, pratosartan, olmesartan or irbesartan or a pharmacologically acceptable salt or ester thereof,
(3) a method according to (1) wherein the angiotensin II receptor antagonist is losartan, candesartan cilexetil, valsartan, telmisartan, pratosartan, olmesartan medoxomil or irbesartan,
(4) a method according to (1) wherein the angiotensin II receptor antagonist is olmesartan medoxomil,
(5) a method according to (1) to (4) wherein the calcium channel blocker is nifedipine, nimodipine, nilvadipine, manidipine, barnidipine, nitrendipine, benidipine, nicardipine, lercanidipine, amlodipine, nisoldipine, efonidipine, cilnidipine, azelnidipine, felodipine, aranidipine or pranidipine or a pharmacologically acceptable salt thereof,
(6) a method according to (1) to (4) wherein the calcium channel blocker is manidipine, barnidipine, benidipine, nicardipine, lercanidipine, amlodipine, efonidipine or azelnidipine or a pharmacologically acceptable salt thereof,
(7) a method according to (1) to (4) wherein the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof,
(8) a method according to (1) to (4) wherein the calcium channel blocker is amlodipine besylate,
(9) a method according to (1) to (8) for the preparation of a solid dosage form selected from powders, grains, granules, capsules and tablets,
(10) a method according to (1) to (8) for the preparation of a tablet.
In addition, a method for the preparation of a solid dosage form obtained by respectively selecting an angiotensin II receptor antagonist from (2) to (4) and a calcium channel blocker from (5) to (8) and arbitrarily combining them is also suitable, examples of which include those listed below:
(11) a method according to (1) wherein the angiotensin II receptor antagonist is losartan, candesartan cilexetil, valsartan, telmisartan, pratosartan, olmesartan medoxomil or irbesartan, and the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof, (12) a method according to (1) wherein the angiotensin II receptor antagonist is losartan, candesartan cilexetil, valsartan, telmisartan, pratosartan, olmesartan medoxomil or irbesartan, and the calcium channel blocker is amlodipine besylate,
(13) a method according to (1) wherein the angiotensin II receptor antagonist is olmesartan medoxomil, and the calcium channel blocker is nifedipine, nimodipine, nilvadipine, manidipine, barnidipine, nitrendipine, benidipine, nicardipine, lercanidipine, amlodipine, nisoldipine, efonidipine, cilnidipine, azelnidipine, felodipine, aranidipine or pranidipine or a pharmacologically acceptable salt thereof,
(14) a method according to (1) wherein the angiotensin II receptor antagonist is olmesartan medoxomil, and the calcium channel blocker is manidipine, barnidipine, benidipine, nicardipine, lercanidipine, amlodipine, efonidipine or azelnidipine or a pharmacologically acceptable salt thereof,
(15) a method according to (1) wherein the angiotensin II receptor antagonist is olmesartan medoxomil, and the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof,
(16) a method according to (1) wherein the angiotensin II receptor antagonist is olmesattan medoxomil, and the calcium channel blocker is amlodipine besylate,
(17) a method according to (1) wherein the angiotensin II receptor antagonist is olmesartan medoxomil, the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof, and the solid dosage form is a tablet, and
(18) a method according to (1) wherein the angiotensin 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 the preparation of a solid dosage form can be performed so that the solid dosage form further comprises at least one hydrophilic polymer and the wet granulation step in the methods can be conducted using a number of different techniques, both of which are described in greater detail below. Examples of these methods include:
(19) a method according to (1) to (18) wherein the solid dosage form further comprises at least one hydrophilic polymer; (20) a method according to (19) wherein the hydrophilic polymer is at least one compound selected from cellulose derivatives and synthetic polymers;
(21) a method according to (19) wherein the hydrophilic polymer is at least one compound selected from hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, macrogol, HA Sankyo, polyvinylpyrrolidone and polyvinyl alcohol;
(22) a method according to (19) wherein the hydrophilic polymer is at least one compound selected from cellulose derivatives;
(23) a method according to (19) wherein the hydrophilic polymer is at least one compound selected from hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose;
(24) A method according to (19) wherein the hydrophilic polymer is either or both of methyl cellulose and hydroxypropyl cellulose;
(25) A method according to (19) wherein the hydrophilic polymer is macrogol;
(26) a method according to (1) to (25), wherein the wet granulation step is performed using fluidized bed granulation, high-speed mixing agitation granulation, extrusion granulation, mixing agitation granulation or tumbling granulation; and
(27) a method according to (1) to (25), wherein the wet granulation step is performed using high-speed mixing agitation granulation.
Using the method of the present invention, a solid dosage form, that contains an angiotensin II receptor antagonist and a calcium channel blocker, with improved dissolution properties is obtainable. These solid dosage forms also form a part of the present invention. [BEST MODE FOR CARRYING OUT THE INVENTION]
The solid dosage form obtainable using the method of the present invention contains an angiotensin II receptor antagonist and a calcium channel blocker as its active ingredients.
Since various medicaments have been proposed as an "angiotensin II receptor antagonist", which is one of the active ingredients in a solid dosage form obtainable using the method of the present invention, and many are actually used clinically, a person of ordinary skill in the art can select suitable medicaments that demonstrate the desired effect as an angiotensin II receptor antagonist for use in the present invention. Suitable, non-limiting examples of angiotensin II receptor antagonists for use in the present invention include losartan (preferably losartan potassium), candesartan cilexetil, valsartan, telmisartan, pratosartan, olmesartan medoxomil and irbesartan. Of these, olmesartan medoxomil is preferably used. Olmesartan medoxomil can easily be produced according to the methods disclosed in the art, suitable examples including the methods disclosed in Japanese Patent No. 2082519 (corresponding to US Patent No. 5,616,599).
Since various medicaments have been proposed as a "calcium channel blocker", which is one of the active ingredients in a solid dosage form obtainable using the method of the present invention, and many are actually used clinically, a person of ordinary skill in the art can select suitable medicaments that demonstrate the desired effect as a calcium channel blocker for use 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), barnidipine (preferably barnidipine hydrochloride), nitrendipine, benidipine (preferably benidipine hydrochloride), nicardipine (preferably nicardipine hydrochloride), lercanidipine (preferably lercanidipine hydrochloride), amlodipine (preferably amlodipine besylate), nisoldipine, efonidipine (preferably efonidipine hydrochloride), cilnidipine, azelnidipine, felodipine, aranidipine and pranidipine. Of these amlodipine besylate is preferably used. Amlodipine and its salts including amlodipine besylate can be easily produced according to the methods disclosed in the art, suitable examples including the methods disclosed in Japanese Patent No. 1401088 (corresponding to US Patent No. 4,572,909).
The pharmacologically acceptable salts of angiotensin II receptor antagonists and a calcium channel blockers described above are not specifically restricted and these salts can be selected by a person of ordinary skill in the art. Suitable pharmacologically acceptable salts include, for example, an alkaline metal salt such as a sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as a calcium salt or magnesium salt; a metal salt such as an aluminium salt, iron salt, zinc salt, copper salt, nickel salt or cobalt salt; an amine salt such as an ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylammonium salt or tris(hydroxymethyl)aminomethane salt; a hydrohalogenic acid salt such as a hydrofluoride, hydrochloride, hydrobromide or hydroiodide; a nitrate; a perchlorate; a sulfate; a phosphate; a Ci-C4 alkanesulfonic acid salt, which may be optionally substituted with a halogen atom(s) such as a methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; a C6-CiO arylsulfonic acid salt, which may be optionally substituted with a Ci-C4 alkyl group(s), such as a benzenesulfonate or p-toluenesulfonate; a Ci-C6 aliphatic acid salt such as an acetate, malate, fumarate, succinate, citrate, tartrate, oxalate or maleate; or an amino acid salt such as a glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt or aspartic acid salt.
The pharmacologically acceptable esters of the angiotensin II receptor antagonists described above are not particularly restricted, and can be selected by a person of ordinary skill in the art. In the case of said esters, it is preferable that such esters can be cleaved by a biological process such as hydrolysis in vivo. The group constituting the esters (the group shown as R when the esters thereof are expressed as — COOR) can be, for example, a Cx-C4 alkoxy Ci-C4 alkyl group such as methoxyethyl, 1- ethoxyethyl, 1-methyl-l-methoxyethyl, l-(isopropoxy)ethyl, 2-methoxyethyl, 2- ethoxyethyl, 1,1-dimethyl-l-methoxyrnethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; a C1-C4 alkoxylated C1-C4 alkoxy C1-C4 alkyl group such as 2-methoxyethoxymethyl; a C6-C10 aryloxy C1-C4 alkyl group such as phenoxymethyl; a halogenated C1-C4 alkoxy C1-C4 alkyl group such as 2,2,2- trichloroethoxymethyl or bis(2-chloroethoxy)methyl; a C1-C4 alkoxycarbonyl C1-C4 alkyl group such as methoxycarbonylmethyl; a cyano C1-C4 alkyl group such as cyanomethyl or 2-cyanoethyl; a C1-C4 alkylthiomethyl group such as methylthiomethyl or ethylthiomethyl; a C6-C1O arylthiomethyl group such as phenylthiomethyl or naphthylthiomethyl; a C1-C4 alkylsulfonyl C1-C4 lower alkyl group, which may be optionally substituted with a halogen atom(s) such as 2-methanesulfonylethyl or 2- trifluoromethanesulfonylethyl; a C6-C1O arylsulfonyl C1-C4 alkyl group such as 2- benzenesulfonylethyl or 2-toluenesulfonylethyl; a Ci-C7 aliphatic acyloxy C1-C4 alkyl group such as formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyL pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxy ethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1- butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxy ethyl, 1-isovaleryloxyethyl, 1- hexanoyloxyethyl, 2-formyloxyethyl, 2-acetoxyethyl, 2-propionyloxyethyl, 2- butyryloxyethyl, 2-pivaloyloxyethyl, 2-valeryloxyethyl, 2-isovaleryloxyethyl, 2- hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1- butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1- hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1- pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1- pivaloyloxypentyl or 1-pivaloyloxyhexyl; a Cs-C6 cycloalkylcarbonyloxy C1-C4 alkyl group such as cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1- cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1- cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1- cyclopentylcarbonyloxybutyl or 1-cyclohexylcarbonyloxybutyl; a C6-C1O arylcarbonyloxy C1-C4 alkyl group such as benzoyloxymethyl; a C1-C6 alkoxycarbonyloxy C1-C4 alkyl group such as methoxycarbonyloxymethyl, 1- (methoxycarbonyloxy)ethyl, l-(methoxycarbonyloxy)propyl, 1- (methoxycarbonyloxy)butyl, l-(methoxycarbonyloxy)pentyl, 1- (methoxycarbonyloxy)hexyl, ethoxycarbonyloxymethyl, 1 -(ethoxycarbonyloxy)ethyl, l-(ethqxycarbonyloxy)propyl, l-(ethoxycarbonyloxy)butyl, 1- (ethoxycarbonyloxy)pentyl, l-(ethoxycarbonyloxy)hexyl, propoxycarbonyloxymethyl, l-(propoxycarbonyloxy)ethyl, l-(propoxycarbonyloxy)propyl, 1- (propoxycarbonyloxy)butyl, isopropoxycarbonyloxymethyl, 1- (isopropoxycarbonyloxy)ethyl, l-(isopropoxycarbonyloxy)butyl, butoxycarbonyloxymethyl, 1 -(butoxycarbonyloxy)ethyl, 1 -(butoxycarbonyloxy)propyl, l-(butoxycarbonyloxy)butyl, isobutoxycarbonyloxymethyl, 1- (isobutoxycarbonyloxy)ethyl, i-(isobutoxycarbonyloxy)propyl, 1- (isobutoxycarbonyloxy)butyl, t-butoxycarbonyloxymethyl, l-(t- butoxycarbonyloxy)ethyl, pentyloxycarbonyloxyrriefhyl, l-(pentyloxycarbonyloxy)ethyl, l-(pentyloxycarbonyloxy)propyl, hexyloxycarbonyloxymethyl, 1- (hexyloxycarbonyloxy)ethyl or l-(hexyloxycarbonyloxy)propyl; a C5-C6 cycloalkyloxycarbonyloxy C1-C4 alkyl group such as cyclopentyloxycarbonyloxymethyl, l-(cyclopentyloxycarbonyloxy)ethyl, 1- (cyclopentyloxycarbonyloxy)propyl, l-(cyclopentyloxycarbonyloxy)butyl, cyclohexyloxycarbonyloxymethyl, l-(cyclohexyloxycarbonyloxy)ethyl, 1- (cyclohexyloxycarbonyloxy)propyl or l-(cyclohexyloxycarbonyloxy)butyl; a [5-(Ci-C4 alkyl)-2-oxo-l,3-dioxolen-4-yl]methyl group such as (5-methyl-2-oxo-l,3-dioxolen-4- yl)methyl, (5-ethyl-2-oxo-l,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-l,3-dioxolen-4- yl)methyl, (5-isopropyl-2-oxo-l,3-dioxolen-4-yl)methyl or (5-butyl-2-oxo-l,3- dioxolen-4-yl)methy; a [5-(phenyl, which may be optionally substituted with a Ci-C4 alkyl, Ci-C4 alkoxy or halogen atom(s))-2-oxo-l,3-dioxolen-4-yl]methyl group such as (5-phenyl-2-oxo-l,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-l,3-dioxolen-4- yl]methyl, [5-(4-methoxyphenyl)-2-oxo-l,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyl)- 2-oxo-l,3-dioxolen-4-yl]methyl or [5-(4-chlorophenyl)-2-oxo-l,3-dioxolen-4- yl]methyl; or a phthalidyl group, which may be optionally substituted with a Ci-C4 alkyl or Ci-C4 alkoxy group(s), such as phthalidyl, dimethylphthalidyl or dimethoxyphthalidyl.
In one preferred embodiment of the present invention, the solid dosage form obtainable by the method of the present invention additionally contains at least one "hydrophilic polymer", i.e. a polymer that has an affinity for water. Preferred "hydrophilic polymers" for use in the present invention are ones which are water- soluble. Incorporation of a hydrophilic polymer can give a solid dosage form with dissolution properties which are further improved. Suitable, non-limiting examples of hydrophilic polymers for use in the present invention include cellulose derivatives such as hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinylpyrrolidone, aminoalkyl methacrylate copolymer, carboxyvinyl polymer, polyvinyl alcohol and macrogol (i.e. polyethylene glycol); HA Sankyo (a pre-mixed coating agent comprising a mixture of 16-26% by weight of polyvinyl acetal diethyl aminoacetate, 50-75% by weight of hydroxypropylmethyl cellulose 2910, 12-17% by weight of stearic acid and 1.5-2.3% by weight of fumaric acid), gum Arabic, agar, gelatin and sodium alginate. Of these, hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, macrogol, HA Sankyo, polyvinylpyrrolidone and polyvinyl alcohol are preferred, hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, macrogol and sodium carboxymethyl cellulose are more preferred, and methyl cellulose is most preferred. In the present invention, these hydrophilic polymers can be used alone or two or more kinds can be used in combination. Where at least one hydrophilic polymer is present in the solid dosage form obtainable using the method of the present invention, said hydrophilic polymer (or polymers) is preferably present in an amount of from 1 to 90% by weight of 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 entire solid dosage form, or they may be contained in only a part of said solid dosage form. If one or more film coating layers are used in the preparation of the solid dosage form, the one or more hydrophilic polymers may be contained in said film coating layers.
The solid dosage form obtainable using the method of the present invention can where desired additionally contain at least one further additive such as a suitable pharmacologically acceptable excipient, lubricant, binder, disintegrant, emulsifier, stabilizer, corrective or diluent. Suitable "excipients" include organic excipients including sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; cellulose derivatives such as microcrystalline cellulose; gum Arabic; dextran; and pullulan, and inorganic excipients including silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate or magnesium metasilicate aluminate; phosphates such as dibasic calcium hydrogenphosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate.
Suitable "lubricants" include stearic acid; stearic acid metal salts such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; D,L-leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicates such as silicic anhydride or silicate hydrate; and the aforementioned starch derivatives.
Suitable "binders" include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, macrogol and compounds similar to the aforementioned excipients.
Suitable "disintegrants" include cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose or internally crosslinked sodium carboxymethyl cellulose; cross-linked polyvinylpyrrolidone; and chemically modified starches/celluloses such as carboxymethyl starch or sodium carboxymethyl starch.
Suitable "emulsifiers" include colloidal clays such as bentonite or bee gum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzalkonium chloride; and nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester. Suitable "stabilizers" include para-hydroxybenzoic acid esters such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenyl ethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; and sorbic acid.
Suitable "correctives" include sweeteners such as sodium saccharin or aspartame; sour flavourings such as citric acid, malic acid or tartaric acid; and fragrances such as menthol, lemon or orange fragrance.
Suitable "diluents" include lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate, and mixtures thereof.
The "solid dosage form" obtainable using the method of the present invention comprises any dosage form used by the person skilled in the art to deliver one or more pharmacologically active ingredients to a patient in a solid form. Suitable solid dosage forms will be well known to the person skilled in the art, and non-limiting examples of the solid dosage form of the present invention include tablets (including sublingual tablets and tablets that disintegrate in the mouth), capsules (including soft capsules and microcapsules), granules, grains, powders, pills, and lozenges. Of these, powders, grains, granules, capsules and tablets are preferred, and tablets are most preferred.
Granulation refers to a procedure for producing granules having nearly uniform shape and size from raw materials which are in a form such as powders, lumps, solutions or molten liquids. Granulation in accordance with the present invention includes procedures which give a finished granular solid dosage form such as granules, powders and grains, and procedures in which intermediate granular products are produced for subsequent use in the manufacture of tablets or capsules. The "wet granulation step" in the method of the present invention refers to a step in which some or all of the ingredients of the final solid dosage form are in powdered form and are granulated using a solvent such as water or a mixed solution of water and alcohol as a binder to give a granular composition. Wet granulation techniques are well known to those skilled in the art, and detailed discussions of wet granulation techniques suitable for use in the present invention are disclosed in publications such as The Theory and Practice of Industrial Pharmacy (Third Edition), (Leon Lachman, et al.: LEA & FEBIGER, 1986) and Pharmaceutical Dosage Forms: Tablets, Volume 1 (Second Edition) (Herbert A. Lieberman, et al.: MARCEL DEKKER INC., 1989).
Suitable non-limiting examples of wet granulation methods for use in the method of the present invention include fluidized bed granulation, high-speed mixing agitation granulation, extrusion granulation, mixing agitation granulation and tumbling granulation. Of these, high-speed mixing agitation granulation is particularly preferred.
Fluidized bed granulation refers to a granulating method in which a fluidized bed of powdered raw material is formed by an air flow, a binder solution is sprayed onto the bed while drying, and particles are caused to adhere and agglutinate by liquid cross- linking. Examples of suitable devices for use in fluidized bed granulation include a flow coater (e.g. those manufactured by the Freund Corporation), a spiral coater (e.g. those manufactured by the Freund Corporation) and a New Marumerizer (e.g. those manufactured by Fuji Paudal).
High-speed mixing agitation granulation refers to a granulating method in which a binder solution is added while the powdered raw material is mixed, agitated and caused to flow at high speed. Examples of suitable devices for use in high-speed mixing agitation granulation include a Super Mixer (manufactured by Kawata Factory), a Super Fine Matrix (Nara Machinery), a Turbosphere mixer (manufactured by Moritz Mutual) and a Gural mixer (Collett-Fuji Paudal).
Extrusion granulation refers to a granulating method in which a binder solution is added to the powdered raw material, the mixture thus obtained is kneaded before pressing of the resulting kneaded product onto the surface of a die or screw followed by extrusion moulding of the pressed composition thus obtained to give the desired granules. Examples of suitable devices for use in extrusion granulation include a basket-type granulating machine, a screw-type extrusion granulating machine and an oscillating granulating machine.
Mixing agitation granulation refers to a granulating method in which a binder solution is added to the powdered raw material followed by granulation of the resulting mixture while mixing and agitating. Examples of suitable devices for use in mixing agitation granulation include a Shinagawa mixer (e.g. those manufactured by Dalton), a Nauter mixer (e.g. those manufactured by Hosokawa Micron) and a Topo-granulator (e.g. those manufactured by Collett-Fuji Paudal).
Tumbling granulation refers to a method for producing spherical granules by spraying or coating a binder onto a tumbling powdered raw material. Examples of suitable devices for use in tumbling granulation include a centrifugal flow granulation coating device (e.g. those manufactured by Freund), a Roto-Processor (e.g. those manufactured by Eromatic-Fuji Sangyo), a Marumerizer (e.g. those manufactured by Fuji Paudal) and a VG Coater (e.g. those manufactured by Kikusui Seisakusho).
There is no particular limitations on the kind of solvents that can be used in the wet granulation step of the method of the present invention. Suitable, non-limiting examples of solvents for use include acetone, methanol, ethanol, isopropanol, methylene chloride, water or mixtures thereof.
Granules obtained in the wet granulation step of the method of the present invention can be sized to a desired particle diameter and formed into a solid dosage form as powders, grains or granules. As one alternative, these dosage forms can be filled into capsule shells to form capsules. In a further alternative, pharmacologically acceptable additives such as disintegrating agents, lubricants and the like can be added as necessary followed by compression moulding of the resulting mixture with a tablet press to form a solid dosage form of the present invention in the form of tablets. The procedures such as mixing and granulation are all procedures that are commonly used in the field of pharmaceutical technology, and can be readily performed by a person of ordinary skill in the art. Where the solid dosage form obtainable using the method of the present invention is a tablet, it may be provided with at least one layer of a film coating. If a film coating is desired, any film coating apparatus of a type well known in the art can be used, and as film coating bases, suitable examples include sugar coating bases, hydrophilic film coating bases, enteric film coating bases and sustained release film coating bases.
Suitable examples of sugar coating bases include saccharose, and these can be used in combination with one or more additives such as talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum Arabic, polyvinylpyrrolidone and pullulan.
Suitable examples of hydrophilic film coating bases include cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymer, polyvinylpyrrolidone and macrogol; and polysaccharides such as pullulan.
Suitable examples of enteric film coating bases include cellulose derivatives such as hydroxypropyl methyl cellulose, phthalate hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose- 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 sustained release film coating bases include cellulose derivatives such as ethyl cellulose; and acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer emulsion.
A mixture of two or more different coating bases such as those above may also be used in a suitable ratio. In addition, the coating films may also contain suitable pharmacologically acceptable additives such as plasticizers, excipients, lubricants, opacifying agents, colorants or antiseptics as necessary. The doses and the dosing ratios of the angiotensin II receptor antagonist and calcium channel blocker, which are the active ingredients in the solid dosage form obtainable using the method of the present invention, can be changed depending on various factors such as the activity of each of the active ingredients and the symptoms, age and body weight of the patient. Although the dosage varies depending on symptoms, age and the like, the dose of each class of active ingredient in the case of oral administration is typically from 0.001 mg/kg (preferably 0.01 mg/kg) per day as a lower limit to 10 mg/kg (preferably 1 mg/kg) per day as an upper limit for a human adult, and the dosage can be administered from one to six times per day depending on the symptoms of the patients.
In addition, the dosing ratio of the angiotensin II receptor antagonist and calcium channel blocker, which are the active ingredients in the solid dosage form obtainable using the method of the present invention, can also be changed over a wide range. For example, the dosing ratio by weight of angiotensin II receptor antagonist and calcium channel blocker can typically be within a range of 1:1000 to 1000:1, preferably within a range of 1:100 to 100:1, and more preferably within a range of 1:10 to 10:1.
The solid dosage form obtainable using the method of the present invention is effective for the prophylaxis or treatment of, for example, hypertension or diseases caused by hypertension [more specifically, hypertension, heart disease (angina pectoris, myocardial infarction, arrhythmia, cardiac insufficiency or hypercardia), kidney disease (diabetic nephropathy, glomerular nephritis or nephrosclerosis), or cerebrovascular disease (cerebral infarction or cerebral hemorrhage)] and the like. [EXAMPLES]
The present invention will be described in more detail by way of the following examples, but the scope of the present invention is not limited thereto.
Example 1
(1) Olmesartan medoxomil, amlodipine besylate, lactose and low substituted hydroxypropyl cellulose were each weighed out in the relative amounts given in column 1 of Table 1 below and they were then mixed for 2 minutes in an agate mortar before kneading the resulting powdered mixture with purified water (the amount of water added was 34% by weight of the powdered mixture). After drying the resulting mixture with a vacuum dryer, it was passed through a 30 mesh sieve (500 μm), macrocrystalline cellulose and magnesium stearate were added to the sieved mixture in the relative amounts shown in column 1 of Table 1 below and this was then mixed for 2 minutes in an agate mortar to give mixed granules.
140 mg of the resulting mixed granules were loaded into a 7.0 mm diameter mould and formed into tablets using a hydraulic single-action tablet press with a stamp having a 7.0 mm diameter surface at a tablet weight of 140 mg and pressing pressure of 10 kN. The dissolution properties of the resulting tablets were tested according to the procedure shown in the Test Example below and the results are shown in the following Table 2.
Reference Example 1
Olmesartan medoxomil, amlodipine besylate, lactose, low substituted hydroxypropyl cellulose, microcrystalline cellulose and magnesium stearate were each weighed out in the relative amounts given in column 2 of Table 1 below, and after mixing for 2 minutes in an agate mortar, the resulting mixture was formed into tablets using a hydraulic single-action tablet press with a stamp having a 7.0 mm diameter surface at a tablet weight of 140 mg and pressing pressure of 10 kN. The dissolution properties of the resulting tablets were tested according to the procedure shown in the Test Example below and the results are shown in the following Table 2. Example 2
Olmesartan medoxomil, amlodipine besylate, microcrystalline cellulose, calcium hydrogenphosphate and sodium carboxymethyl starch were each weighed in the relative amounts given in column 3 of Table 1 below, and they were then mixed for 2 minutes in an agate mortar before kneading the resulting powdered mixture with purified water (the amount of water added was 56% by weight of the powdered mixture). After drying the resulting mixture with a vacuum dryer, it was passed through a 30 mesh sieve (500 μm) followed by the addition of magnesium stearate in the relative amounts shown in column 3 of Table 1 below and mixing for 2 minutes in an agate mortar to give mixed granules.
140 mg of the resulting mixed granules were loaded into a 7.0 mm diameter mold and formed into tablets using a hydraulic single-action tablet press with a stamp having a 7.0 mm diameter surface at a tablet weight of 140 mg and pressing pressure of 10 kN. The dissolution properties of the resulting tablets were tested according to the procedure shown in the Test Example below and the results are shown in the following Table 2.
Reference Example 2
Olmesartan medoxomil, amlodipine besylate, microcrystalline cellulose, dibasic calcium phosphate, sodium carboxymethyl starch and magnesium stearate were each weighed out in the relative amounts given in column 4 of Table 1 below, and after mixing for 2 minutes in an agate mortar, the resulting mixture was formed into tablets using a hydraulic single-action tablet press with a stamp having a 7.0 mm diameter surface at a tablet weight of 140 mg and pressing pressure of 10 kN. The dissolution properties of the resulting tablets were tested according to the procedure shown in the Test Example below and the results are shown in the following Table 2.
Test Example
Testing for the rate of dissolution of the tablets prepared in the examples above was carried out in accordance with Method 2 of the Dissolution Test (Paddle Method) described in the 14th Revised Edition of the Japanese Pharmacopoeia at 50 revolutions per minute and using 900 mL of Japanese Pharmacopoeia Solution 2 (JP-2) for the test solution. The test solution was sampled 30 minutes and 60 minutes after the start of testing followed by measurement of the dissolution rate and dissolved amount of olmesartan medoxomil by absorption spectrometry (dissolution tester: Toyama Sangyo; spectrophotometer: Shimadzu). Testing was carried out on two tablets and their average value is indicated in each case.
(Table 1)
Figure imgf000020_0001
(Table 2)
Figure imgf000021_0001
As shown in Table 2 above, the solid dosage forms obtained using the method of the present invention having a wet granulation step demonstrated superior dissolution properties for the angiotensin II receptor antagonist contained therein (olmesartan medoxomil in the case of the examples above) compared to corresponding solid dosage forms having the same formulation which had been prepared without a wet granulation step.
[INDUSTRIAL APPLICABILITY]
According to the present invention, a method is provided that gives a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker which has improved dissolution properties.

Claims

1. 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.
2. A method according to claim 1, wherein the angiotensin II receptor antagonist is losartan, candesartan, valsartan, telmisartan, pratosartan, olmesartan or irbesartan or a pharmacologically acceptable salt or ester thereof.
3. A method according to claim 1, wherein the angiotensin II receptor antagonist is losartan, candesartan cilexetil, valsartan, telmisartan, pratosartan, olmesartan medoxomil or irbesartan.
4. A method according to claim 1, wherein the angiotensin II receptor antagonist is olmesartan medoxomil.
5. A method according to any one of claims 1 to 4 wherein the calcium channel blocker is nifedipine, nimodipine, nilvadipine, manidipine, barnidipine, nitrendipine, benidipine, nicardipine, lercanidipine, amlodipine, nisoldipinej efonidipine, cilnidipine, azelnidipine, felodipine, aranidipine or pranidipine or a pharmacologically acceptable salt thereof.
6. A method according to any one of claims 1 to 4 wherein the calcium channel blocker is manidipine, barnidipine, benidipine, nicardipine, lercanidipine, amlodipine, efonidipine or azelnidipine or a pharmacologically acceptable salt thereof.
7. A method according to any one of claims 1 to 4 wherein the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof.
8. A method according to any one of claims 1 to 4 wherein the calcium channel blocker is amlodipine besylate.
9. A method according to any one of claims 1 to 8 for the preparation of a solid dosage form selected from powders, grains, granules, capsules and tablets.
10. A method according to any one of claims 1 to 8 for the preparation of a tablet.
11. A method according to claim 1 wherein the angiotensin II receptor antagonist is losartan, candesartan cilexetil, valsartan, telmisartan, pratosartan, olmesartan medoxomil or irbesartan, and the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof.
12. A method according to claim 1 wherein wherein the angiotensin II receptor antagonist is losartan, candesartan cilexetil, valsartan, telmisartan, pratosartan, olmesartan medoxomil or irbesartan, and the calcium channel blocker is amlodipine besylate.
13. A method according to claim 1 wherein the angiotensin II receptor antagonist is olmesartan medoxomil, and the calcium channel blocker is nifedipine, nimodipine, nilvadipine, manidipine, barnidipine, nitrendipine, benidipine, nicardipine, lercanidipine, amlodipine, nisoldipine, efonidipine, cilnidipine, azelnidipine, felodipine, aranidipine or pranidipine or a pharmacologically acceptable salt thereof.
14. A method according to claim 1 wherein the angiotensin II receptor antagonist is olmesartan medoxomil, and the calcium channel blocker is manidipine, barnidipine, benidipine, nicardipine, lercanidipine, amlodipine, efonidipine or azelnidipine or a pharmacologically acceptable salt thereof,
15. A method according to claim 1 wherein the angiotensin II receptor antagonist is olmesartan medoxomil, and the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof.
16. A method according to claim 1 wherein the angiotensin II receptor antagonist is olmesartan medoxomil, and the calcium channel blocker is amlodipine besylate.
17. A method according to claim 1 wherein the angiotensin II receptor antagonist is olmesartan medoxomil, the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof, and the solid dosage form is a tablet.
18. A method according to claim 1 wherein the angiotensin II receptor antagonist is olmesartan medoxomil, the calcium channel blocker is amlodipine besylate, and the solid dosage form is a tablet.
19. A method according to any one of claims 1 to 18 wherein the solid dosage form further comprises at least one hydrophilic polymer.
20. A method according to claim 19 wherein the hydrophilic polymer is at least one compound selected from cellulose derivatives and synthetic polymers.
21. A method according to claim 19 wherein the hydrophilic polymer is at least one compound selected from hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, macrogol, HA Sankyo, polyvinylpyrrolidone and polyvinyl alcohol.
22. A method according to claim 19 wherein the hydrophilic polymer is at least one compound selected from cellulose derivatives.
23. A method according to claim 19 wherein the hydrophilic polymer is at least one compound selected from hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose.
24. A method according to claim 19 wherein the hydrophilic polymer is either or both of methyl cellulose and hydroxypropyl cellulose.
25. A method according to claim 19 wherein the hydrophilic polymer is macrogol.
26. A method according to any one of claims 1 to 25, wherein the wet granulation step is performed using fluidized bed granulation, high-speed mixing agitation granulation, extrusion granulation, mixing agitation granulation or tumbling granulation.
27. A method according to any one of claims 1 to 25, wherein the wet granulation step is performed using high-speed mixing agitation granulation.
28. A solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker obtainable by a method according to any one of claims 1 to 27.
29. A solid dosage form according to claim 28 for the prophylaxis or treatment of hypertension.
30. The use of an angiotensin II receptor antagonist and a calcium channel blocker in the manufacture of a medicament for the prophylaxis or treatment of hypertension, wherein said medicament is a solid dosage form obtainable by a method according to any one of claims 1 to 28.
31. A method for the prophylaxis or treatment of hypertension in a patient in need thereof, said method comprising the administration to said patient of pharmacologically effective doses of an angiotensin II receptor antagonist and a calcium channel blocker in a solid dosage form obtainable by a method according to any one of claims 1 to 28.
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