TWI388345B - Solid dosage form comprising angiotensin iireceptor antagonist and calcium channel blocker for prophylaxis or treatment of hypertension - Google Patents

Description

Solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker for the prevention or treatment of hypertension

The present invention relates to a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker.

Currently, calcium channel blockers and angiotensin II receptor antagonists are widely used clinically as medicines for the treatment and prevention of hypertension. Since the calcium channel blocker functions in addition to vasodilatation to promote sodium urinary action, it is effective against hypertension (renin-independent type) caused by retention of body fluids. On the other hand, angiotensin II receptor antagonists are particularly effective against renin-dependent hypertension and have excellent organ protection. Thus, it is expected that the combined use of calcium channel blockers and angiotensin II receptor antagonists will be stable and effective for antihypertensive treatment, regardless of hypertension.

Several combination drugs comprising an angiotensin II receptor antagonist and a calcium channel blocker have been proposed in the prior art, such as the following Patent Documents 1 to 4. However, the prior art does not disclose a solid dosage form of the invention comprising an angiotensin II receptor antagonist and a calcium channel blocker, wherein each active ingredient is separately doped in this dosage form.

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

It is an object of the present invention to provide a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker with improved dissociation properties.

As a result of extensive research to solve the aforementioned problems, the present inventors have found that the dissociation properties of solid dosage forms comprising an angiotensin II receptor antagonist and a calcium channel blocker are formed by separately doping each active ingredient into particles, followed by mixing. This inclusion of the granules of each active ingredient is not completely mixed into the dosage form, thus resulting in the completion of the present invention.

The present invention provides a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker, wherein each active ingredient is in a particulate form and the particles comprising each active ingredient are not completely mixed in the dosage form (especially a dosage form for preventing or treating hypertension; an angiotensin II receptor antagonist and a calcium channel blocker for use in the manufacture of the aforementioned solid dosage form (and particularly for preventing or treating hypertension); and prevention Or a method of treating a disease (especially hypertension), wherein the aforementioned solid dosage form comprising a pharmacologically effective amount of an angiotensin II receptor antagonist and a calcium channel blocker is administered to a warm-blooded animal (especially a human) .

In particular, the present invention provides: (1) a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker, wherein the active ingredient is formulated so that it is not completely mixed into the dosage form, (2 A solid dosage form according to (1), wherein the angiotensin II receptor antagonist is losartan, candesartan, valsartan, telmisartan, pa Pratosartan, olmesartan or irbesartan, or a pharmacologically acceptable salt or ester thereof, (3) a solid dosage form of (1), wherein angiotensin II is The body antagonists are losartan, candesartan cilexetil, valsartan, telmisartan, patosartan, olmesartan medoxomil or ebboxartan, (4) as 1) a solid dosage form, wherein the angiotensin II receptor antagonist is olmesartan medoxomil, (5) a solid dosage form according to (1) to (4), wherein the calcium channel blocker is nifedipine (nifedipine) , nimodipine, nilvadipine, manidipine, barnidipine, nitrendipine (nitrendipine), benidipine, nicardipine, lercanidipine, amlodipine, nisoldipine, efenidipine, cilnidipine ( Cilnidipine), azelnidipine, felodipine, aranidipine or pranidipine or a pharmacologically acceptable salt thereof, (6) as (1) to (4) Solid dosage form wherein the calcium channel blocker is manidipine, bainidipine, benidipine, nicardipine, lercanidipine, amlodipine, effildipine or adipine or a pharmacologically acceptable thereof (7) The solid dosage form of (1) to (4), wherein the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof, (8) as in (1) to (4) a solid dosage form, wherein the calcium channel blocker is amlodipine besylate, (9) a solid dosage form according to (1) to (8), wherein the solid dosage form is a tablet, (10) a solid such as (9) a dosage form, wherein the tablet comprises particles comprising an angiotensin II receptor antagonist and particles comprising a calcium channel blocker, (11) a solid dosage form according to (10), wherein An intermediate layer is present between the particles of the angiotensin II receptor antagonist and the calcium channel blocker, (12) the solid dosage form of (9), wherein the tablet is a multilayer tablet, wherein the multilayer tablet Each of the individual layers contains only one active ingredient selected from the angiotensin II receptor antagonist and the calcium channel blocker, (13) a solid dosage form according to (9), wherein the tablet is a double layer ingot The angiotensin II receptor antagonist is contained in the first layer and the calcium channel blocker is contained in the second layer, (14) the solid dosage form of (13), wherein the middle layer exists between the first layer and the second layer (15) The solid dosage form of (9), wherein the tablet is a dry coated tablet, wherein the angiotensin II receptor antagonist is contained in the inner core thereof and the calcium channel blocker is contained in the outer layer, (16) The solid dosage form of (9), wherein the tablet is a dry coated tablet, wherein the calcium channel blocker is contained in the inner core and the angiotensin II receptor antagonist is contained in the outer layer, (17) A solid dosage form according to (15) or (16), wherein an intermediate layer is present between the inner core and the outer layer, (18) a solid dosage form according to (1) to (17), wherein the solid dosage form further comprises (A) The solid dosage form of (10) or (11), wherein the particle containing the angiotensin II receptor antagonist further comprises a hydrophilic polymer, (20) such as (10) or (11) a solid dosage form, wherein the particles comprising a calcium channel blocker further comprise a hydrophilic polymer, (21) a solid dosage form according to (11), wherein the intermediate layer further comprises a hydrophilic polymer, (22) such as (12) to ( A solid dosage form according to 14), wherein the layer containing the angiotensin II receptor antagonist further comprises a hydrophilic polymer, (23) the solid dosage form of (12) to (14), wherein the layer containing the calcium channel blocker is further A solid dosage form comprising (24) to (17), wherein the inner core further comprises a hydrophilic polymer, (25) a solid dosage form according to (15) to (17), wherein the outer layer further comprises (26) A solid dosage form of (18) to (25), wherein the hydrophilic polymer is at least one compound selected from the group consisting of cellulose derivatives and synthetic polymers, (27) such as (18) to ( a solid dosage form of 25), wherein the hydrophilic polymer is at least one selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, and hydroxyl groups a compound of propylcellulose, sodium carboxymethylcellulose, macrogol, HA Sankyo, polyvinylpyrrolidone, and polyvinyl alcohol, (28) a solid dosage form of (18) to (25), Wherein the hydrophilic polymer is at least one cellulose derivative, (29) the solid dosage form of (18) to (25), wherein the hydrophilic polymer is at least one selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose A compound of hydroxypropylcellulose and sodium carboxymethylcellulose, (30) a solid dosage form according to (18) to (25), wherein the hydrophilic polymer is one of methylcellulose and hydroxypropylcellulose. Or both, (31) The solid dosage form of (18) to (25), wherein the hydrophilic polymer is polyethylene glycol.

Further, solid dosage forms obtained by any combination of the above (1) to (31) are also preferred, and the examples are as follows.

(32) A solid dosage form according to (1), wherein the angiotensin II receptor antagonist is losartan, kendesartan, valsartan, telmisartan, patosartan, olmesartan medoxomil or The piracetam and the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof, (33) the solid dosage form of (1), wherein the angiotensin II receptor antagonist is olmesartan medoxomil and calcium. Channel blockers are nifidipine, nimodipine, nilvadipine, manidipine, bainidipine, nitrendipine, benidipine, nicardipine, lercanidipine, amlodipine, nisoldipine , rifampicin, cilnidipine, adipine, felodipine, adipine or pradipine or a pharmacologically acceptable salt thereof, (34) a solid dosage form of (1), wherein angiotensin II The receptor antagonist is olmesartan medoxomil and the calcium channel blocker is manidipine, benidipine, benidipine, nicardipine, lercanidipine, amlodipine, effilidipine or adipine or its pharmacology a scientifically acceptable salt, (35) a solid dosage form according to (1), wherein the angiotensin II receptor antagonist is olmesartan medoxomil and calcium channel blockage The agent is amlodipine or a pharmacologically acceptable salt thereof, (36) The solid dosage form of (1), wherein the angiotensin II receptor antagonist is olmesartan medoxomil and the calcium channel blocker is amlodipine. Or a pharmaceutically acceptable salt thereof, and the solid dosage form is a tablet comprising particles comprising an angiotensin II receptor antagonist and particles comprising a calcium channel blocker, (37) as in (1) a solid dosage form, 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 bilayer tablet, wherein the blood vessel The angiotensin II receptor antagonist is contained in the first layer and the calcium channel blocker is contained in the second layer, (38) the solid dosage form of (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 dry coated tablet, wherein the calcium channel blocker is contained in the inner core and the angiotensin II receptor antagonist is contained in The outer layer, (39) the solid dosage form of (1), wherein the angiotensin II receptor antagonist is olmesartan medoxomil, The channel blocker is amlodipine or a pharmacologically acceptable salt thereof, and the solid dosage form is a tablet containing a particle containing an angiotensin II receptor antagonist and a particle containing a calcium channel blocker. The calcium channel blocker-containing particles further comprise at least one member selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyethylene glycol, HA Sankyo, polyethylene a hydrophilic polymer of pyrrolidone and polyvinyl alcohol, (40) a solid dosage form of (1), wherein the angiotensin II receptor antagonist is olmesartan medoxomil and the calcium channel blocker is amlodipine or a pharmacologically acceptable salt, the solid dosage form being a bilayer tablet wherein the angiotensin II receptor antagonist is contained in the first layer and the calcium channel blocker is contained in the second layer, the calcium channel blocker The layer further comprises at least one member selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyethylene glycol, HA Sankyo, polyvinylpyrrolidone, and polyethylene. a hydrophilic polymer of an alcohol, (41) a solid dosage form of (1), The angiotensin II receptor antagonist is olmesartan medoxomil and the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof. The solid dosage form is a dry coated tablet, wherein the calcium channel blocker comprises The core of the angiotensin II receptor antagonist is contained in the outer layer thereof, and the inner core further comprises at least one member selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, and carboxymethylcellulose. a hydrophilic polymer of sodium, polyethylene glycol, HA Sankyo, polyvinylpyrrolidone and polyvinyl alcohol, (42) a solid dosage form of (1), wherein the angiotensin II receptor antagonist is olmesartan The ester, calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof, and the solid dosage form is a tablet comprising a particle comprising an angiotensin II receptor antagonist and a calcium channel blocking agent. The particles, the calcium channel blocker-containing particles further comprise a hydrophilic polymer selected from the group consisting of methyl cellulose and hydroxypropyl cellulose, (43) a solid dosage form according to (1), wherein the angiotensin II receptor is antagonized The agent is olmesartan medoxomil and the calcium channel blocker is amlodipine. a pharmacologically acceptable salt thereof, wherein the solid dosage form is a two-layer tablet, wherein the angiotensin II receptor antagonist is contained in the first layer and the calcium channel blocker is contained in the second layer, wherein the calcium channel is blocked The second layer of the agent further comprises a hydrophilic polymer selected from the group consisting of methyl cellulose and hydroxypropyl cellulose, (44) a solid dosage form according to (1), wherein the angiotensin II receptor antagonist is olmesartan The ester, calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof, and the solid dosage form is a dry coated tablet, wherein the calcium channel blocker is contained in the inner core thereof, and the angiotensin II receptor The antagonist is contained in the outer layer thereof, wherein the inner core of the calcium channel blocker further comprises a hydrophilic polymer of methyl cellulose and hydroxypropyl cellulose, and (45) the solid dosage form of (32) to (44) Wherein the calcium channel blocker is amlodipine besylate.

In accordance with the present invention, a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker having improved dissociation properties can be provided.

[Best Mode for Carrying Out the Invention]

The solid dosage form of the present invention contains an angiotensin II receptor antagonist and a calcium channel blocker as its active ingredient.

Since various medicines have been proposed as "angiotensin II receptor antagonists", which are one of the active ingredients in the solid dosage form of the present invention, and many of them are actually used clinically, those skilled in the art can A suitable pharmaceutical for selecting an angiotensin II receptor antagonist which exhibits the desired effect is used in the present invention. Suitable, but non-limiting examples of angiotensin II receptor antagonists include losartan (preferably losartan sodium), kendsartan, valsartan, telmisartan, patosatan, Olmesartan medoxomil and ebboxartan. Among these, olmesartan is preferably used. The 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 US Patent No. 5,616,599).

Since various medicines as "calcium channel blockers" have been proposed, which are one of the active ingredients in the solid dosage form of the present invention, and many of them are actually used clinically, those skilled in the art can select appropriate confirmation. A pharmaceutical having a desired effect is a calcium channel blocker used in the present invention. Suitable non-limiting examples of calcium channel blockers include nifidipine, nimodipine, nilvadipine, manidipine (preferably manidipine hydrochloride), and balnepine (preferably barnidipine) Hydrochloride), nitrendipine, benidipine (preferably benidipine hydrochloride), nicardipine (preferably nicardipine hydrochloride), lercanidipine (preferably lercanidipine salt) Acid salt), amlodipine (preferably amlodipine besylate), nisoldipine, effluentine (preferably rifampicin hydrochloride), cilnidipine, adipine, felodipine , adipine and praidipine. Among these, amlodipine (especially amlodipine besylate) is preferably used. According to the method disclosed in the art, amlodipine and its salts, including amlodipine besylate, can be easily produced, and suitable examples include the method disclosed in Japanese Patent No. 1401088 (equivalent to US Patent No. 4,572,909).

The above-mentioned angiotensin II receptor antagonist and the pharmacologically acceptable salt of the calcium channel blocker are not particularly limited, and such salts can be selected by those skilled in the art. Suitable pharmacologically acceptable salts are, for example, alkali metal salts such as sodium or lithium salts, and alkaline earth metal salts such as calcium or magnesium salts; metal salts such as aluminum, iron, zinc, copper, nickel a salt, or a cobalt salt; an amine salt such as an ammonium salt, a t-octylamine salt, a dibenzylamine salt, a morpholine salt, a glucosamine salt, an alkyl phenylglycine salt, an ethylenediamine salt, N -methyl glucosamine salt, sulfonium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, Proca Salt, diethanolamine salt, N-benzyl-phenethylaniline salt, piperazine a salt, a tetramethylammonium salt or a tris(hydroxymethyl)aminomethane salt; a hydrohalide such as hydrogen fluoride, a hydrochloride, hydrogen bromide or hydrogen iodide; a nitrate; a perchlorate; a sulfate; a C ₁ -C ₄ alkane sulfonate which may be optionally substituted by a halogen atom such as methanesulfonate, trifluoromethanesulfonate or ethanesulfonate, C ₆ -C _{1 0} arylsulfonate , optionally substituted by C ₁ -C ₄ alkyl, such as besylate or p-tosylate; C ₁ -C ₆ fatty acid salts such as acetate, malate, fumarate, amber An acid salt, a citrate salt, a tartrate salt, an oxalate salt or a maleic acid salt; or an amine acid salt such as a glycinate, an aminate salt, a arginine salt, an alanine salt, a glutamic acid Salt or aspartate.

The pharmacologically acceptable ester of the above angiotensin II receptor antagonist is not particularly limited and can be selected by those skilled in the art. In the case of the ester, an ester which can be cleaved by a biological process, for example, hydrolyzed in a living body, is preferred. The group constituting the ester (shown as the group of R, when the ester thereof is represented by -COOR) may, for example, be a C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl group such as a methoxyethyl group, a 1-ethoxy group. Ethyl ethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl 1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; C ₁ -C ₄ alkoxy a C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl group, such as 2-methoxyethoxymethyl; C ₆ -C _{10 0} aryloxy C ₁ -C ₄ alkyl, such as phenoxy Methyl group; 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 -alkylthiomethyl, such as methylthiomethyl or ethylthiomethyl; C ₆ -C _{10 0-} arylthiomethyl, such as phenylthiomethyl or naphthylthiomethyl; C ₁ -C ₄ alkylsulfonyl group C ₁ -C ₄ lower Group, 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, Such as 2-phenylsulfonylethyl or 2-toluenesulfonylethyl; C ₁ -C ₇ aliphatic decyloxy C ₁ -C ₄ alkyl, such as methyloxymethyl, ethoxylated , propyl methoxymethyl, butyl methoxymethyl, trimethyl ethoxymethyl, pentyloxymethyl, isopentyloxymethyl, hexyloxymethyl, 1- Methoxyethyl, 1-ethyloxyethyl, 1-propenyloxyethyl, 1-butenoxyethyl, 1-trimethylacetoxyethyl, 1-pentanyl Oxyethyl, 1-isoamyloxyethyl, 1-hexyloxyethyl, 2-methyloxyethyl, 2-ethyloxyethyl, 2-propoxyethyl , 2-Butyloxyethyl, 2-trimethylacetoxyethyl, 2-pentyloxyethyl, 2-isopentyloxyethyl, 2-hexyloxyethyl, 1-Methoxyoxypropyl, 1-ethyloxypropyl, 1-propoxypropyl, 1-butoxypropyl, 1-trimethylethoxypropyl 1-pentyloxypropyl, 1-isopentyloxypropyl, 1-hexyloxypropyl, 1-ethyloxybutyl, 1-propoxylated butyl, 1-butane Oxybutyl, 1-trimethylethoxyoxybutyl, 1-ethenyloxypentyl, 1-propenyloxypentyl, 1-butenoxypentyl, 1-trimethyl-B醯oxypentyl or 1-trimethylethenyloxy; C ₅ -C ₆ cycloalkylcarbonyloxy C ₁ -C ₄ alkyl, such as cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxy Methyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentyl Carbocarbonyloxybutyl or 1-cyclohexylcarbonyloxybutyl; C ₆ -C _{1 0} arylcarbonyloxy C ₁ -C ₄ alkyl, such as benzhydryloxymethyl; C ₁ -C ₆ alkane Oxycarbonyloxy C ₁ -C ₄ alkyl, such as methoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(methoxycarbonyloxy)propyl, 1 -(methoxycarbonyloxy)butyl, 1-(methoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl, ethoxy Carbonyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)butyl, 1-(ethoxy Carbocarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)hexyl, propoxycarbonyloxymethyl, 1-(propoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxyl) , propyl, 1-(propoxycarbonyloxy)butyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyl) Oxy)butyl, butoxycarbonyloxymethyl, 1-(butoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy) Butyl, isobutoxycarbonyloxymethyl, 1-(isobutoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)propyl, 1-(isobutoxycarbonyl) Oxy)butyl, t-butoxycarbonyloxymethyl, 1-(t-butoxycarbonyloxy)ethyl, pentoxycarbonyloxymethyl, 1-(pentyloxycarbonyloxy Ethyl, 1-(pentyloxycarbonyloxy)propyl, hexyloxycarbonyloxymethyl, 1-(hexyloxycarbonyloxy)ethyl or 1-(hexyloxycarbonyl) Oxy) propyl; C ₅ -C ₆ cycloalkoxy carbonyl group C ₁ -C ₄ alkyl groups, such as cyclopentyloxycarbonyl group, 1- (cyclopentyloxycarbonyl) 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-keto-1 , 3-extended dioxypentan-4-yl]methyl, such as (5-methyl-2-keto-1,3-desodioxet-4-yl)methyl, (5-ethyl-2 -keto-1,3-desodioxet-4-yl)methyl, (5-propyl-2-keto-1,3-desodioxet-4-yl)methyl, (5- Isopropyl-2-keto-1,3-desodioxet-4-yl)methyl or (5-butyl-2-keto-1,3-desodioxylan-4-yl)- [5-(phenyl, which may be optionally substituted by C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or halogen atom)-2-keto-1,3-dioxolane-4 -yl]methyl, such as (5-phenyl-2-keto-1,3-dioxane Cyclo-4-yl)methyl, [5-(4-methylphenyl)-2-keto-1,3-desodioxylan-4-yl]methyl, [5-(4-methoxy) Phenyl)-2-keto-1,3-desodioxylan-4-yl]methyl, [5-(4-fluorophenyl)-2-keto-1,3-dioxolane 4-yl] methyl or [5- (4-chlorophenyl) -2-one-1,3-dioxolan-4-yl projecting] methyl; or phthalidyl, which is optionally C ₁ by -C ₄ alkyl or C ₁ -C ₄ alkoxy substituted such as anthracenyl, dimethylindenyl or dimethoxyindenyl.

In a preferred embodiment of the invention, the solid dosage form of the invention further comprises at least one "hydrophilic polymer", i.e., a polymer having affinity for water. Preferred "hydrophilic polymers" for use in the present invention are those which are soluble in water. Incorporation of a hydrophilic polymer can provide a solid dosage form with further improved dissociation properties. Suitable non-limiting examples of the hydrophilic polymer used in the present invention include cellulose derivatives such as hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, and sodium carboxymethylcellulose; synthetic polymers such as Polyvinylpyrrolidone, aminoalkyl methacrylate copolymer, carboxyvinyl polymer, polyvinyl alcohol and polyethylene glycol (ie, polyethylene glycol); HA Sankyo (a premixed coating agent, Containing 16-26% by weight of polyvinyl acetal diethylaminoacetate, 50-75% by weight of hydroxypropylmethylcellulose 2910, 12-17% by weight of stearic acid and 1.5-2.3% by weight of anti-butyl a mixture of enedic acid), gum arabic, agar, gelatin and sodium alginate. Among these, hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyethylene glycol, HA Sankyo, polyvinylpyrrolidone, and polyvinyl alcohol are preferred. More preferably, hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, polyethylene glycol, and sodium carboxymethylcellulose; and methylcellulose is preferred. 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 of the present invention, the hydrophilic polymer (or polymer) is preferably present in an amount of from 1 to 90% by weight of the total solid dosage form, and more preferably from 5 to 85. weight%. The one or more hydrophilic polymers may be uniformly distributed throughout the solid dosage form, or it may be contained in a portion of the solid dosage form. If one or more film coating layers are used in the solid dosage form preparation, the one or more hydrophilic polymers may be contained in the film coating layer.

The solid dosage form of the present invention may be expected to additionally contain at least one other additive such as a suitable pharmacologically acceptable excipient, lubricant, binder, disintegrant, emulsifier, stabilizer, flavoring or diluent.

Suitable "excipients" include organic excipients, including sugar derivatives such as lactose, glucose, mannitol or sorbitol sugars; starch derivatives such as corn starch, potato starch, alpha-starch or dextrin; a derivative such as microcrystalline cellulose; gum arabic; glucose; and pullulan; and inorganic excipients, including citrate derivatives such as light anhydrous citric acid, synthetic aluminum citrate, calcium citrate or Magnesium metasilicate aluminate; phosphates such as calcium dihydrogen 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; colloidal vermiculite; waxes such as beeswax or cetyl wax; boric acid; adipic acid; Such as sodium sulfate; diol; fumaric acid; sodium benzoate; D, L-leucine; lauryl sulfate such as sodium lauryl sulfate or magnesium lauryl sulfate; citrate such as phthalic anhydride or citric acid water and And the aforementioned starch derivative.

Suitable "binding 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, carboxymethylcellulose calcium or croscarmellose sodium; crosslinked polyvinylpyrrolidine Ketone; and 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 Benzyl ammonium chloride; and a nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester.

Suitable "stabilizers" include parabens such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl or phenylethyl alcohol; benzalkonium chloride a phenol such as phenol or cresol; thimerosal; dehydroacetic acid; and sorbic acid.

Suitable "flavoring agents" include sweeteners such as sodium saccharin or aspartame; acidulants such as citric acid, malic acid or tartaric acid; and flavors such as mint, lemon or mandarin orange.

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

The "solid dosage form" of the present invention comprises any solid dosage form which is used by the skilled artisan to deliver one or more pharmacologically active ingredients to a patient in a solid form, but which must be a calcium channel blocker and an angiotensin II receptor. The antagonists are made in a manner that is not completely mixed, ie, each active ingredient is shaped into separate physical forms such as granules which do not contain other active ingredients and when the solid dosage form is produced only the granules are mixed, or in some manner The solid dosage form is formulated as a means of separating the active ingredients (e.g., by formulating the respective active ingredients in the various layers). Suitable solid dosage forms are well known to those skilled in the art, and non-limiting examples of solid dosage forms of the invention include lozenges (including sublingual lozenges and lozenges which are disintegrated in the mouth), capsules (including soft capsules and microcapsules). , granules, pellets and diamond ingots. In these cases, tablets are preferred.

The "granules" in the solid dosage form of the present invention are those having a uniform shape and size obtained from the raw material, in a form such as a powder, agglomerate, solution or molten liquid, via the use of appropriate techniques (such as wet granulation, dry granules). The granulated material is granulated. Suitable examples of the particles used in the preparation of the solid dosage form of the present invention include powders, grains or granules, and preferably have a particle size defined in the 14th revision of the Japanese Pharmacopoeia. A particle having a size distribution of all the particles passing through a No. 10 (1700 μm) sieve, no more than 5% of the total particles remaining on the No. 12 (1400 μm) sieve, and no more than 15% of the total particles passing No. 42 (355 μ m) sieve. Powders and granules (which are included in the definition of the 14th revised powder of the Japanese Pharmacopoeia) have a size distribution such that all of the powder passes through a No. 18 (850 μm) sieve and no more than 5% of the total particles remain in No. 30. (500 μ m) sieve.

In addition, although the shape and size of the particles of the present invention may be varied during formulation to provide the solid dosage form of the present invention, the particles in a manner which does not retain their original form and which change in shape and size are also included in the particles used in the solid dosage form of the present invention. The scope.

In the present invention, "multilayer tablet" means a tablet in which different active ingredients and any desired pharmacologically acceptable additives are stacked in separate layers in a stepwise manner and then compression molded into a single dosage form.

In the present invention, "bilayer tablet" means a tablet containing a first tablet of an active ingredient and any desired pharmacologically acceptable additive and containing another active ingredient and any desired pharmacological agent. The academically acceptable additives are stacked in the layer. The two layers may be in contact or may provide an intermediate layer for the use of inert additives for the purpose of avoiding direct contact between the active ingredients.

In the present invention, "dry-coated tablet" means a tablet in which the inner core containing an active ingredient and any desired pharmacologically acceptable additive contains another active ingredient and any desired pharmacologically acceptable The outer layer of the accepted additive is coated to coat the inner core. The inner core and the outer layer may be in contact, or an intermediate layer may be provided to use an inert additive for the purpose of avoiding direct contact between the active ingredients.

The dosage form of the present invention can be produced using any of the usual methods well known to those skilled in the art of pharmaceutical formulation and is not particularly limited. Examples of suitable methods include those disclosed in the literature such as Powder Technology and Pharmaceutical Processes [D. Chulia et al., Elsevier Science Pub. Co. (December 1, 1993)].

The particles of the present invention can be produced according to a granulation method generally used in the field of medical technology. Granulation by conventional methods, examples of which include wet granulation, dry granulation and heated granulation, more specifically, using a high speed agitating granulator, a fluidized granulating dryer, an extrusion granulator or a roller compaction The device is carried out. In addition, procedures such as drying and sieving may be performed after granulation as needed.

The multilayer tablet of the present invention can be produced by known methods such as direct compression molding of each layer containing the active ingredient, or conventional wet granulation or dry granulation (squeezing) can be carried out by separately producing each layer containing the active ingredient. The technique then compresses each layer.

The bilayer tablet of the present invention can be produced by known methods such as producing the first and second layers separately, using conventional wet granulation or dry granulation (squeezing) techniques followed by pressing the first and second layers, and then using conventional double The tablet molding device incorporates these two layers. Further, the bilayer tablet of the present invention may also provide at least one outer film coating (coating).

The dry coated tablet of the present invention can be produced by a known method, such as producing an inner core ingot as an inner core, and then coating the inner core ingot with an outer layer using a dry coating ingot press. In addition, the inner core ingot (inner core) may also be provided with a film coating prior to coating the outer layer. In addition, an inner core ingot or a plurality of inner core ingots may be contained in a single dosage form. The dry coated tablet of the present invention may also provide at least one outer film coating.

If the film coating is desired, a film coating device of any of the well-known types of the art may be used as a film coating substrate, and suitable examples include a sugar coating substrate, a hydrophilic film coating substrate, and a film coating substrate. And a sustained release film coating substrate.

Suitable sugar confections include, by way of example, sucrose, which may be combined with one or more additives such as talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan.

Suitable examples of the hydrophilic film coating substrate include cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, and sodium carboxymethylcellulose; Synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymers, polyvinylpyrrolidone and polyethylene glycol; and polysaccharides such as pullulan.

Suitable examples of the enteric film-coating base include cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate. Acrylic 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 substrate include cellulose derivatives such as ethyl cellulose; and acrylic acid derivatives such as aminoalkyl methacrylic acid copolymer RS, ethyl acrylate-methyl methacrylate copolymer emulsion.

Mixtures of two or more of the different coating bases listed above may also be employed in appropriate proportions. Further, the coating film may optionally contain a suitable pharmacologically acceptable additive such as a plasticizer, an excipient, a lubricant, an opacifier, a coloring agent or an antibacterial agent, as needed.

The dose and the ratio of the angiotensin II receptor antagonist and the calcium channel blocker, which are the active ingredients in the solid dosage form of the present invention, can be varied according to various factors, such as the activity and symptoms of each active ingredient, and the disease Age and weight. Although the dose change depends on the symptoms, age, etc., the dose of each active ingredient in the case of oral administration is generally 0.001 mg/kg (preferably 0.01 mg/kg) per day in human adults as a lower limit. 10 mg/kg (preferably 1 mg/kg) per day is used as the upper limit, and this dose can be administered one to six times a day depending on the symptoms of the patient.

Further, the administration ratio of the angiotensin II receptor antagonist and the calcium channel blocker is an active ingredient in the solid dosage form of the present invention, and can be widely varied. For example, the weight ratio of the angiotensin II receptor antagonist and the calcium channel blocker can typically range from 1:1000 to 1000:1, preferably from 1:100 to 100:1, and more Good range from 1:10 to 10:1.

The solid dosage form of the present invention is effective for preventing or treating diseases such as hypertension or hypertension [more specifically, hypertension, heart disease (angina pectoris, myocardial infarction, arrhythmia, cardiac dysfunction or cardiac hypertrophy), kidney Disease (diabetic nephropathy, glomerulonephritis or nephrosclerosis), or cerebrovascular disease (cerebral infarction or cerebral hemorrhage), etc.

[Examples]

The invention is described in more detail in the following examples, but the scope of the invention is not limited thereto.

Example 1 Single layer tablet containing two kinds of particles

(1) Individually weighed olmesartan medoxomil, lactose, low-substituted hydroxypropylcellulose and hydroxypropylcellulose, the relative amounts of which are provided in the column entitled "Particle A" in Table 1 below, followed by stirring at high speed. The granulator (VG-10, Powrex) was mixed, and purified water was added to the resulting powder unmixed mixture (water was added to the mixed powder in an amount of 43% by weight of the powder mixture), and then the resulting mixture was subjected to granulation and The fluidized granulating dryer (Powrex) was dried. The granules thus obtained were classified by a particle classifier (Comill, Powrex) and mixed with microcrystalline cellulose and magnesium stearate in a mixer (V-mixer, Tokuju) to obtain granule A.

(2) Individually weighed amlodipine besylate, lactose, low-substituted hydroxypropylcellulose and hydroxypropylcellulose, the relative amounts of which are given in the column entitled "Particle B" in Table 1 below, and then After kneading with pure water (water is added to the mixed powder in an amount of 34% by weight of the powdered mixture), it is mixed in an agate mortar for 2 minutes, and after drying the resulting mixture in a vacuum dryer, the dried mixture is passed through a 30 mesh. A sieve (500 μm) was then added to the microcrystalline cellulose and magnesium stearate to the sieved mixture and mixed in an agate mortar for 2 minutes to obtain pellet B.

(3) The particles A and B produced in the above (1) and (2) were mixed in an agate mortar for 2 minutes to obtain mixed particles. 240 mg of the resulting mixed granules were loaded on an 8.5 mm diameter mold and a 240 mg weight tablet having a 8.5 mm diameter surface was formed using a hydraulic single acting tablet press having a press and the pressing pressure was 10 kN. The dissociation properties of the resulting tablet (single layer tablet containing both particles) were tested according to the procedures shown in the following test examples and the results are shown in Table 2 below.

Example 2 Bilayer Lozenge

(1) Individually weighed amlodipine besylate, lactose, low-substituted hydroxypropylcellulose and magnesium stearate, the relative amounts of which are provided in the column entitled "Particle C" in Table 3 below, and then Mixing for 2 minutes in an agate mortar gave granule C.

(2) Next, 120 mg of the pellet A obtained in Example 1 was placed in a 7 mm diameter mold, then 100 mg of the pellet C was placed in the mold, and then the loaded pellet was molded into a tablet, using a hydraulic sheet having a presser. The tablet press was used to form a 220 mg tablet with a 7 mm diameter surface and a pressing pressure of 10 kN. The dissociation properties of the resulting tablet (double-layer tablet) were tested according to the procedures shown in the following test examples and the results are shown in Table 4 below.

Example 3 Bilayer Lozenge

(1) Individually weighed amlodipine besylate, lactose, low-substituted hydroxypropylcellulose, methylcellulose, and magnesium stearate, the relative amounts of which are given in Table 3 below, entitled "Particle D" The column was then mixed in an agate mortar for 2 minutes to obtain granule D.

(2) Next, 120 mg of the pellet A obtained in Example 1 was placed in a 7 mm diameter mold, and then 100 mg of the pellet D was loaded in the mold, and then the loaded pellet was molded into a tablet, using a hydraulic sheet having a presser. The tablet press was used to form a 220 mg tablet with a 7 mm diameter surface and a pressing pressure of 10 kN. The dissociation properties of the resulting tablet (double-layer tablet) were tested according to the procedures shown in the following test examples and the results are shown in Table 4 below.

Example 4 Amlodipine dry coated lozenge

(1) Individually weighed amlodipine besylate, lactose, low-substituted hydroxypropylcellulose and magnesium stearate, the relative amounts of which are provided in the column of the following table 5 as "particle E", and then The mixture was mixed in an agate mortar for 2 minutes to obtain pellet E. The resulting mixture was then molded into a tablet, and a 50 mg tablet having a 5.5 mm diameter surface was formed using a hydraulic single-acting tablet press having a press and the pressing pressure was 10 kN to obtain a tablet E.

(2) 60 mg of the granule A obtained in Example 1 was placed in a 7.5 mm diameter mold, then the tablet E was loaded into the mold, and 60 mg of the granule A was again loaded on the mold, and a hydraulic single acting tablet press was used to form 170 mg. The tablet was heavy and the pressing pressure was 10 kN. The dissociation properties of the resulting tablet (dry coated tablet) were tested according to the procedures shown in the following test examples and the results are shown in Table 6 below.

Example 5 Amlodipine dry coated lozenge

(1) Individually weighed amlodipine besylate, lactose, low-substituted hydroxypropylcellulose, methylcellulose, and magnesium stearate, the relative amounts of which are given in Table 5 below, entitled "Particle F" The field is then mixed in an agate mortar for 2 minutes. The resulting mixture was then molded into a tablet, and a 50 mg tablet having a 5.5 mm diameter surface was formed using a hydraulic single-acting tablet press having a press and the pressing pressure was 10 kN to obtain a tablet F.

(2) 60 mg of the pellet A obtained in Example 1 was placed in a 7.5 mm diameter mold, then the tablet F was loaded into the mold, and 60 mg of the pellet A was again loaded after the mold, and a hydraulic single acting tablet press was used. A 170 mg tablet was applied and the pressing pressure was 10 kN. The dissociation properties of the resulting tablet (dry coated tablet) were tested according to the procedures shown in the following test examples and the results are shown in Table 6 below.

(Example 6) Olmesartan dry coated lozenge

(1) Individually weighed olmesartan medoxomil, lactose, low-substituted hydroxypropylcellulose and magnesium stearate, the relative amounts of which are provided in the column entitled "Particle G" in Table 5 below, and then studied in agate. Mix in 2 minutes. The resulting mixture was molded into a tablet, and a 50 mg tablet having a 5.5 mm diameter surface was formed using a hydraulic single-acting tablet press having a press and the pressing pressure was 10 kN to obtain a tablet G.

(2) 60 mg of the pellet B obtained in Example 1 was placed in a 7.5 mm diameter mold, then the tablet G was loaded on the mold, and 60 mg of the pellet B was again loaded after the mold, and a hydraulic single acting tablet press was used. A 170 mg tablet was applied and the pressing pressure was 10 kN. The dissociation properties of the resulting tablet (dry coated tablet) were tested according to the procedures shown in the following test examples and the results are shown in Table 6 below.

Reference example 1

Each weight was weighed with olmesartan medoxomil, amlodipine besylate, lactose, low-substituted hydroxypropylcellulose, microcrystalline cellulose and magnesium stearate. The relative amounts are given in Table 1 below. The column of Example 1" was then mixed in an agate mortar for 2 minutes. The resulting mixture was molded into a tablet, and a 140 mg-weight tablet having a 7 mm diameter surface was formed using a hydraulic single-acting tablet press having a press and the pressing pressure was 10 kN.

Test example

The dissociation rate test of the tablet prepared in the above examples was carried out according to the method 2 of the dissociation test described in the 14th revision of the Japanese Pharmacopoeia (Paddle Method), and 900 mL of the Japanese Pharmacopoeia solution was used at 50 rotations per minute. 2 (JP-2) was used as a test solution. The test solution was sampled 30 and 60 minutes after the start of the test, and then the dissociation rate was measured and the dissociation amount of olmesartan medoxomil was measured by an absorption spectrometer (dissociation tester: Toyama Sangyo; spectrometer: Shimadzu), and the test was carried out on two tablets. The situation indicates the average.

As shown in the above Tables 2, 4 and 6, the solid dosage form of the present invention was confirmed to have excellent dissociation properties of the angiotensin II receptor antagonist (olmesartan medoxomil) contained therein.

[Industrial availability]

According to the present invention, a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker having improved dissociation properties is obtained.

Claims (37)

A solid dosage form for the prevention or treatment of hypertension comprising an angiotensin II receptor antagonist and a calcium channel blocker, the angiotensin II receptor antagonist being olmesartan or its pharmacology A physiologically acceptable salt or ester, the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof. Wherein the active ingredient is formulated so that it is not completely mixed in the solid dosage form. A solid dosage form according to claim 1 wherein the angiotensin II receptor antagonist is olmesartan medoxomil. The solid dosage form of claim 1, wherein the calcium channel blocker is amlodipine besylate. The solid dosage form of claim 1, wherein the solid dosage form is a tablet. The solid dosage form of claim 1, wherein the tablet contains particles comprising an angiotensin II receptor antagonist and particles comprising a calcium channel blocker. A solid dosage form according to claim 5, wherein an intermediate layer is present between the particles comprising the angiotensin II receptor antagonist and the particles comprising the calcium channel blocker. The solid dosage form of claim 4, wherein the tablet is a multi-layer tablet, wherein each individual layer of the multilayer tablet contains only one selected from the angiotensin II receptor antagonist and the calcium channel is blocked. The active ingredient of the agent. A solid dosage form according to claim 4, wherein the tablet is a bilayer tablet, wherein the angiotensin II receptor antagonist is contained in the first layer and the calcium channel blocker is contained in the second layer. A solid dosage form according to claim 8 wherein an intermediate layer is present between the first and second layers. A solid dosage form according to claim 4, wherein the tablet is a dry coated tablet wherein the angiotensin II receptor antagonist is contained in its inner core and the calcium channel blocker is contained in its outer layer. A solid dosage form according to claim 4, wherein the tablet is a dry coated tablet, wherein the calcium channel blocker is contained in the inner core and the angiotensin II receptor antagonist is contained in the outer layer. A solid dosage form according to claim 10 or 11, wherein an intermediate layer is present between the inner core and the outer layer. The solid dosage form of claim 1, wherein the solid dosage form further comprises a hydrophilic polymer. A solid dosage form according to claim 5 or 6, wherein the particles comprising an angiotensin II receptor antagonist further comprise a hydrophilic polymer. The solid dosage form of claim 5 or 6, wherein the calcium channel blocker-containing particles further comprise a hydrophilic polymer. The solid dosage form of claim 6, wherein the intermediate layer further comprises a hydrophilic polymer. The solid dosage form according to any one of claims 7 to 9, wherein the layer containing the angiotensin II receptor antagonist further comprises a hydrophilic polymer. The solid dosage form according to any one of claims 7 to 9, wherein the layer containing the calcium channel blocker further comprises a hydrophilic polymer. The solid dosage form of claim 10 or 11, wherein the inner core further comprises a hydrophilic polymer. A solid dosage form according to claim 10 or 11, wherein the outer layer further comprises a hydrophilic polymer. The solid dosage form of claim 13, wherein the hydrophilic polymer is at least one compound selected from the group consisting of cellulose derivatives and synthetic polymers. The solid dosage form of claim 13, wherein the hydrophilic polymer is at least one selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and polyethylene glycol. A compound of macrogol, HA Sankyo, polyvinylpyrrolidone and polyvinyl alcohol. A solid dosage form according to claim 13 wherein the hydrophilic polymer is at least one cellulose derivative. The solid dosage form of claim 13, wherein the hydrophilic polymer is at least one compound selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, and sodium carboxymethylcellulose. A solid dosage form according to claim 13 wherein the hydrophilic polymer is one or both of methyl cellulose and hydroxypropyl cellulose. A solid dosage form according to claim 13 wherein the hydrophilic polymer is polyethylene glycol. The solid dosage form of claim 1, wherein the angiotensin II receptor antagonist is olmesartan medoxomil and the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof, and the solid dosage form is a lozenge containing Particles containing an angiotensin II receptor antagonist and particles containing a calcium channel blocker. The solid dosage form of claim 1, wherein the angiotensin II receptor antagonist is olmesartan medoxomil and the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof, and the solid dosage form is A bilayer tablet wherein the angiotensin II receptor antagonist is contained in the first layer and the calcium channel blocker is contained in the second layer. The solid dosage form of 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 dry coating. A tableting agent in which a calcium channel blocker is contained in its inner core and an angiotensin II receptor antagonist is contained in its outer layer. The solid dosage form of 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 a tablet comprising particles comprising an angiotensin II receptor antagonist and particles comprising a calcium channel blocker, the particles of the calcium channel blocker further comprising at least one member selected from the group consisting of hydroxypropyl methylcellulose, A hydrophilic polymer of cellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyethylene glycol, HA Sankyo, polyvinylpyrrolidone, and polyvinyl alcohol. For example, in the solid dosage form of claim 1, the angiotensin II receptor antagonist is olmesartan medoxomil and the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof, and the solid dosage form is a double a tableting agent wherein the angiotensin II receptor antagonist is contained in the first layer and the calcium channel blocker is contained in the second layer The layer, the layer containing the calcium channel blocker further comprises at least one selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyethylene glycol, HA Sankyo, A hydrophilic polymer of polyvinylpyrrolidone and polyvinyl alcohol. The solid dosage form of claim 1, wherein the angiotensin II receptor antagonist is olmesartan medoxomil and the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof. a coated tablet wherein the calcium channel blocker is contained in the inner core thereof and the angiotensin II receptor antagonist is contained in the outer layer, the inner core further comprising at least one member selected from the group consisting of hydroxypropylmethylcellulose and methylcellulose Hydrophilic polymer of hydroxypropylcellulose, sodium carboxymethylcellulose, polyethylene glycol, HA Sankyo, polyvinylpyrrolidone and polyvinyl alcohol. The solid dosage form of claim 1, wherein the angiotensin II receptor antagonist is olmesartan medoxomil and the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof, and the solid dosage form is a a tablet comprising particles comprising an angiotensin II receptor antagonist and particles comprising a calcium channel blocker, the particles of the calcium channel blocker further comprising a surfactant selected from the group consisting of methylcellulose and hydroxypropylcellulose Hydrophilic polymer. The solid dosage form of claim 1, wherein the angiotensin II receptor antagonist is olmesartan medoxomil and the calcium channel blocker is amlodipine or a pharmacologically acceptable salt thereof, and the solid dosage form is two a tableting agent, wherein the angiotensin II receptor antagonist is contained in the first layer and the calcium channel blocking agent is contained in the second layer, wherein the second layer of the calcium channel blocking agent further comprises one selected from the group consisting of methyl cellulose And a hydrophilic polymer of hydroxypropylcellulose. The solid dosage form of 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 dry coated tablet wherein the calcium channel blocker is contained in its inner core and the angiotensin II receptor antagonist is contained in its outer layer, wherein the inner core of the calcium channel blocker is further selected from the group consisting of methyl cellulose And a hydrophilic polymer of hydroxypropylcellulose. The solid dosage form of any one of claims 27 to 35, wherein the calcium channel blocker is amlodipine besylate. An angiotensin II receptor antagonist and a calcium channel blocker for use in the manufacture of a medicament for the prevention or treatment of hypertension, wherein the medicament is a solid dosage form according to any one of claims 1 to 36.