JP2015013857A - Coated formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a formulation comprising 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl}-1H-benzimidazole-7-carboxylic acid or a salt thereof, polyethylene glycol, a diuretic, and a calcium antagonist.SOLUTION: A coated formulation consists of a core and a coating layer, the core comprising a first component comprising 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid or a salt thereof, and polyethylene glycol, a second component comprising a diuretic, and a third component comprising a calcium antagonist.

Description

  The present invention relates to a solid preparation such as a coated tablet containing an angiotensin II antagonist, a calcium antagonist and a diuretic, that is, a coated preparation useful as a therapeutic agent for hypertension.

(Background of the Invention)
As a solid preparation containing an angiotensin II antagonist, a calcium antagonist, and a diuretic, a solid preparation containing valsartan, amlodipine, hydrochlorothiazide, and an additive has been disclosed (Patent Document 1).
As a solid preparation containing an angiotensin II antagonist and a calcium antagonist, the following is disclosed:
1) 2-Ethoxy-1-{[2 ′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benz A solid preparation containing imidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl or a salt thereof and a calcium antagonist (Patent Document 2),
2) 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a salt thereof Solid preparation containing calcium antagonist and sugar alcohol, and 2-ethoxy-1-{[2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl] ) Biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid or a salt thereof, a calcium preparation and a sugar alcohol (Patent Document 3).
As a solid preparation containing an angiotensin II antagonist and a diuretic, 2-ethoxy-1-{[2 ′-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3- Yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl or a salt thereof, chlorthalidone and a pH adjuster Has disclosed a solid preparation (Patent Document 4).
2-Ethoxy-1-{[2 ′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4 which is an active ingredient contained in the preparation of the present invention -Yl] methyl} -1H-benzimidazole-7-carboxylic acid or a salt thereof is disclosed in US Pat.
Patent Document 6 discloses 2-ethoxy-1-{[2 ′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]. A solid formulation containing methyl} -1H-benzimidazole-7-carboxylic acid or a salt thereof, a low viscosity binder and a low melting point oily substance is disclosed.
Further, Patent Documents 7 and 8 include 2-ethoxy-1-{[2 ′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl. A pharmaceutical composition comprising a diuretic of methyl} -1H-benzimidazole-7-carboxylic acid or a salt thereof and a thiazide derivative is disclosed.
Patent Document 9 discloses a solid preparation comprising an angiotensin II receptor antagonist and a calcium antagonist.

International Publication No. 2008/002905 International Publication No. 2010/035806 International Publication No. 2010/126168 International Publication No. 2010/013835 European Patent Application No. 0520423 International Publication No. 2008/018569 US Patent Application Publication No. 2011/030575 Specification European Patent No. 2394638 International Publication No. 2007/001067

2-Ethoxy-1-{[2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole- A combination drug containing 7-carboxylic acid or a salt thereof (hereinafter sometimes abbreviated as “compound A or a salt thereof”), a calcium antagonist, and a diuretic as pharmaceutically active ingredients is obtained by taking an existing antihypertensive drug. However, patients with inadequate blood pressure control, especially for patients with inadequate blood pressure control even if each active ingredient is taken alone or in combination, can be expected to have clinical significance. large.
However, in order to provide a drug containing three types of pharmaceutically active ingredients, each active ingredient has a therapeutic effect in the body so that the three active ingredients do not interact within one drug. Thus, it is necessary to adjust the type and blending amount of the excipient. On the other hand, excipients suitable for certain pharmaceutically active ingredients may not be suitable for other pharmaceutically active ingredients, so such adjustments are not easy.
For example, in a preparation containing Compound A or a salt thereof, it is known to incorporate polyethylene glycol, which is a low melting point oily substance, for stabilization of Compound A or a salt thereof in the preparation (Patent Document 6). ). However, the present inventors have found that the amount of related substances increases when calcium antagonists and diuretics are directly mixed with more than a certain amount of polyethylene glycol.
Accordingly, it is desired to develop a preparation that stabilizes each active ingredient under storage conditions while minimizing the degradation of Compound A or a salt thereof, a calcium antagonist, and a diuretic that are pharmaceutically active ingredients in the preparation.

  As a result of intensive studies to solve the above problems, the inventors of the present invention designed Compound A or a salt thereof and polyethylene glycol when designing a coated preparation having a nucleus containing Compound A or a salt thereof, a calcium antagonist and a diuretic. Forming a nucleus comprising a “first component” comprising a “second ingredient” comprising a diuretic and a “third ingredient” comprising a calcium antagonist, and coating the nucleus with a coating layer; Preferably, the photostability of calcium antagonists and diuretics in the core of the coating preparation is adjusted by adjusting the amount of polyethylene glycol in the coating layer to a certain level or less, or by adding iron oxide to the coating layer. And improved stability against humidity. Furthermore, the present inventors have determined the content of polyethylene glycol in the core even when Compound A or a salt thereof, a diuretic and a calcium antagonist are uniformly mixed in the core of the coated preparation. Control has also been found to minimize degradation of Compound A or its salts, calcium antagonists and diuretics. As a result of further research based on these findings, the present inventors have completed the present invention.

That is, the present invention is as follows.
1) 2-Ethoxy-1-{[2 ′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benz A first component comprising imidazole-7-carboxylic acid or a salt thereof (sometimes abbreviated herein as “Compound A or a salt thereof”) and polyethylene glycol;
A coated preparation comprising a core comprising a third component, comprising a second component comprising a diuretic and a calcium antagonist; and a coating layer;
2) The coating preparation according to 1) above, wherein the coating layer contains titanium oxide;
3) The coating preparation according to 1) above, wherein the coating layer contains iron oxide;
4) The coating preparation according to 1) above, wherein the coating layer contains talc;
4a) The coating preparation according to 1) above, wherein the coating layer contains one or more selected from the group consisting of titanium oxide, iron oxide and talc.
5) The coating preparation according to 1) above, wherein the coating layer contains 0 to 20% polyethylene glycol in the coating layer.
5a) The coated preparation according to 1) above, wherein the coating layer contains substantially no polyethylene glycol in the coating layer.
6) The coated preparation according to 1) above, wherein the core is a single core composed of a first component, a second component, and a third component;
7) The coated preparation according to 1) above, wherein the core has a first part composed of a first component and a second part composed of a second component and a third component;
7a) The coated preparation according to 1) above, wherein the core has a first part composed of a first component and a second component, and a second part composed of a third component;
7b) The coated preparation according to 1), wherein the core has a first part composed of a first component and a third component, and a second part composed of a second component;
8) The coating preparation according to 1) above, wherein the coating layer contains iron oxide, titanium oxide, and talc;
9) The coated preparation according to 1) above, wherein the diuretic is hydrochlorothiazide;
10) The coated preparation according to 1) above, wherein the calcium antagonist is amlodipine or a salt thereof;
11) A first component comprising Compound A or a salt thereof and polyethylene glycol,
A method for producing a coated preparation, comprising a step of coating a core containing a third component, including a diuretic, a second component and a calcium antagonist;
12) The coated preparation according to 6) above, wherein the content of polyethylene glycol in the first component is 0.1 to 1% in the coated preparation;
13) The coated preparation according to 12) above, wherein the content of polyethylene glycol in the first component is 0.1 to 0.6% in the coated preparation;
About.

  The coated preparation of the present invention is useful as a prophylactic or therapeutic agent for hypertension, and is excellent in preparation characteristics such that each active ingredient is stable to light, humidity, temperature and the like.

(Detailed description of the invention)
In the present specification, unless otherwise specified, “%” indicates weight percent.

  The coated preparation of the present invention comprises a core containing a first component, a second component, and a third component, and a coating layer surrounding the core.

  In the coated preparation of the present invention, the first component constituting the core is 2-ethoxy-1-{[2 ′-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3 -Yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid (generic name: azilsartan) or a salt thereof (compound A or a salt thereof) and polyethylene glycol.

  Compound A or a salt thereof can be produced by a method known per se, for example, the method described in Examples of EP-A-0520423. Compound A or a salt thereof is useful for preventing or treating hypertension.

Examples of the salt of Compound A include a pharmaceutically acceptable salt. Examples of such a salt include a salt of Compound A with an inorganic base, a salt with an organic base, and the like.
Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like.
Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like.

  Compound A may also be used as an esterified prodrug.

  In the coated preparation of the present invention, the content of Compound A or a salt thereof in the first component may be, for example, 0.05 to 70%, preferably 1 to 50% in the coated preparation.

  The polyethylene glycol used for the first component is preferably polyethylene glycol having a molecular weight of 1000 to 10,000, and particularly preferably polyethylene glycol having a molecular weight of 3000 to 10,000 (eg, also referred to as polyethylene glycol 6000 or macrogol 6000). The content of polyethylene glycol in the first component may be, for example, 0.1 to 5% in the coated preparation, and preferably 0.1 to 2.5%.

Alternatively, in another preferred embodiment, the content of polyethylene glycol in the first component is 0.1-1%, preferably 0.1-0.6% in the coating formulation.
In this embodiment, compound A or a salt thereof and a diuretic and / or calcium antagonist are mixed in the core of the coated preparation (for example, a single-layer tablet or two-group granulation produced by one-group granulation) 1) or the laminated tablets described in 7a) or 7b) above, the degradation of Compound A or a salt thereof, a calcium antagonist and a diuretic can be suppressed significantly. That is, each active ingredient can be kept stable with respect to light, humidity, temperature, and the like.

  In still another preferred embodiment, in a preparation composed of a part containing Compound A or a salt thereof and a part containing a diuretic and a calcium antagonist (for example, a laminated tablet described in 7) above, the first component The polyethylene glycol content is 1-2% in the coating formulation.

The first component may further contain an additive conventionally used in the technical field of pharmaceutical preparation.
Examples of the additive include an excipient, a disintegrant, a binder, a lubricant, a colorant, a pH adjuster, a surfactant, a stabilizer, a sour agent, a fragrance, and a fluidizing agent. These additives are used in amounts conventionally used in the technical field of pharmaceutical preparations. These additives may be used by mixing two or more kinds at an appropriate ratio.

  Examples of excipients include, but are not limited to, starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch; lactose, fructose, glucose, mannitol, Examples thereof include one or more components selected from sugars or sugar alcohols such as sorbitol; anhydrous calcium phosphate, microcrystalline cellulose, precipitated calcium carbonate, calcium silicate and the like.

  Although it does not specifically limit as a disintegrating agent, For example, 1 or 2 or more chosen from carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, hydroxypropyl starch, etc. Of the ingredients.

  The binder is not particularly limited, and examples thereof include one or more components selected from hydroxypropylcellulose, hydroxypropylmethylcellulose (also referred to as hypromellose), polyvinylpyrrolidone, gum arabic powder and the like.

  The lubricant is not particularly limited, and examples thereof include one or more components selected from magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate and the like.

  Although it does not specifically limit as a coloring agent, For example, 1 or 2 or more components chosen from edible pigment | dye, such as edible yellow No. 5, edible red No. 2, edible blue No. 2, edible lake pigment | dye, iron sesquioxide, etc. are mentioned. It is done.

  Although it does not specifically limit as a pH adjuster, For example, 1 or 2 or more components chosen from a citrate, a phosphate, carbonate, tartrate, a fumarate, acetate, an amino acid salt, etc. are mentioned.

  The surfactant is not particularly limited, and examples thereof include one or more components selected from sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol, and the like.

The stabilizer is not particularly limited, and examples thereof include tocopherol, edetate tetrasodium, nicotinamide, and cyclodextrins.
Examples of the sour agent include one or more components selected from ascorbic acid, citric acid, tartaric acid, malic acid, and the like.

  Although it does not specifically limit as a fragrance | flavor, For example, the 1 or 2 or more component chosen from menthol, mint oil, lemon oil, vanillin etc. is mentioned.

The fluidizing agent is not particularly limited, and examples thereof include one or more components selected from light anhydrous silicic acid, hydrous silicon dioxide and the like. Here, the light anhydrous silicic acid only needs to contain hydrous silicon dioxide (SiO ₂ .nH ₂ O) (n represents an integer) as a main component. As a specific example thereof, for example, Silicia 320 (trade name, Fuji Silysia Chemical Co., Ltd.), Aerosil 200 (trade name, Nippon Aerosil Co., Ltd.), and the like.

  The content of the first component in the coated preparation of the present invention is 5 to 90% in the coated preparation.

In the coated preparation of the present invention, the second component constituting the core contains a diuretic.
Examples of diuretics include thiazide diuretics and chlorobenzenesulfonamide preparations. Examples of thiazide diuretics include ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, ventilhydrochlorothiazide, penflutide, polythiazide, methycrothiazide and the like. Examples of chlorobenzenesulfonamide-based preparations include chlorthalidone, mefluside, indapamide and the like. The diuretic used in the coated preparation of the present invention is preferably a thiazide diuretic, with hydrochlorothiazide being particularly preferred.
The content of the diuretic in the second component in the coated preparation of the present invention may be, for example, 0.1 to 60%, preferably 1 to 30% in the coated preparation.

  The second component may further contain an additive commonly used in the pharmaceutical technical field. Examples of the additive include excipients, disintegrants, binders, lubricants, colorants, pH adjusters, surfactants, stabilizers, acidulants, flavors exemplified in the first component. Examples thereof include a fluidizing agent. These additives are used in amounts conventionally used in the technical field of pharmaceutical preparations. These additives may be used by mixing two or more kinds at an appropriate ratio.

  The content of the second component in the coated preparation of the present invention is 5 to 90% in the coated preparation.

In the coated preparation of the present invention, the third component constituting the core contains a calcium antagonist.
Examples of calcium antagonists include azelnidipine, amlodipine, alanidipine, efonidipine, cilnidipine, nicardipine, nisoldipine, nitrendipine, nifedipine, nilvadipine, valnidipine, felodipine, benidipine, manidipine and other benzothiazepine compounds such as diltiazem. Is mentioned. Examples of the salt of the drug include pharmaceutically acceptable salts such as metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic amino acids, acidic amino acids. And a salt thereof.
The calcium antagonist used in the coated preparation of the present invention is preferably amlodipine or a salt thereof, and among them, amlodipine besylate is preferable.
The content of the calcium antagonist in the third component in the coated preparation of the present invention may be, for example, 0.05 to 60%, preferably 0.5 to 20% in the coated preparation.

  The third component may further contain an additive conventionally used in the technical field of pharmaceutical preparation. Examples of the additive include excipients, disintegrants, binders, lubricants, colorants, pH adjusters, surfactants, stabilizers, acidulants, flavors exemplified in the first component. Examples thereof include a fluidizing agent. These additives are used in amounts conventionally used in the technical field of pharmaceutical preparations. These additives may be used by mixing two or more kinds at an appropriate ratio.

  The content of the third component in the coated preparation of the present invention is 5 to 90% in the coated preparation.

  Examples of the components contained in the coating layer of the coating preparation of the present invention include a coating base, polyethylene glycol, titanium oxide, iron oxide, talc and the like.

  Examples of the coating base include a water-soluble film coating base, an enteric film coating base, a sustained-release film coating base, and the like.

  Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name) Synthetic polymers such as polyvinyl pyrrolidone; polysaccharides such as pullulan.

  Examples of the enteric film coating base include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name) , Rohm Pharma Co., Ltd.], acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Rohm Pharma Co., Ltd.], methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co., Ltd.] A natural product such as shellac.

Examples of the sustained-release film coating base include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Rohm Pharma Co., Ltd.], ethyl acrylate / methyl methacrylate copolymer Examples thereof include acrylic acid polymers such as suspension [Eudragit NE (trade name), Rohm Pharma Co., Ltd.].
Two or more kinds of the coating bases may be mixed and used at an appropriate ratio. The content of the coating base in the coating preparation of the present invention is 0.5 to 20%, preferably 1.5 to 10% in the coating preparation.

Moreover, you may use a coating additive in the case of coating.
As coating additives used in the coating preparation of the present invention, coloring agents; plasticizers such as triethyl citrate, castor oil, polysorbates; organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid; lactose, D- Mannitol, low substituted hydroxypropyl cellulose, carmellose calcium, crospovidone and the like can be mentioned.
Two or more of these coating additives may be mixed at an appropriate ratio. As a coating additive, a premix additive (for example, Opadry (registered trademark) (trade name), Colorcon) may be used.
The coating additive is used in an amount conventionally used in the pharmaceutical technical field.

Examples of the polyethylene glycol used in the coating layer of the coating preparation of the present invention include the same as those exemplified as the polyethylene glycol contained in the first component.
The content of polyethylene glycol used in the coating layer of the coating preparation of the present invention is 0 to 20% in the coating layer, preferably 0 to 10% in the coating layer.
Alternatively, in another preferred embodiment, the coating layer of the coating formulation of the present invention is substantially free of polyethylene glycol. Here, “substantially free” means that the properties (stability, dissolution property, etc.) of diuretics and calcium antagonists are significantly different even if polyethylene glycol is not present at all in the coating layer. It is meant to include an amount that does not change. Therefore, “the coating layer is substantially free of polyethylene glycol” specifically includes the following embodiments:
1) No polyethylene glycol is present in the coating layer of the coating formulation of the invention;
2) The coating layer of the coating preparation of the present invention contains polyethylene glycol, but the polyethylene glycol is an amount that does not significantly change the properties (stability, dissolution property, etc.) of the diuretic and calcium antagonist. is there.

In the coated preparation of the present invention, titanium oxide (TiO) has an excellent light shielding performance against light. The particle size of titanium oxide used in the coating preparation of the present invention is usually about 0.01 to about 1.5 μm, preferably about 0.1 to about 1.0 μm.
The content of titanium oxide used in the coating layer of the coating preparation of the present invention is, for example, 0 to 40% in the coating layer, preferably 1 to 30% in the coating layer, more preferably 3 to 20 in the coating layer. %.

In the coated preparation of the present invention, iron oxide has an excellent light shielding performance against light.
Examples of the iron oxide used in the coating layer of the present invention include black iron oxide, yellow iron sesquioxide, and iron sesquioxide, and these may be used in combination.
The content of iron oxide used in the coating layer of the coating preparation of the present invention is, for example, 0 to 25% in the coating layer, and preferably 0.1 to 15% in the coating layer.

In the coated preparation of the present invention, talc provides a lubricating action in the tablet manufacturing process. The talc used in the coating layer of the coating preparation of the present invention may be purified talc.
The content of talc used in the coating layer of the coating preparation of the present invention is, for example, 0 to 40% in the coating layer, and preferably 0 to 30% in the coating layer.

In a preferred embodiment, the coating layer comprises a coating base, iron oxide, titanium oxide and talc.
In a more preferred embodiment, the coating layer comprises 0.2-10% iron oxide, 3-20% titanium oxide, and 0-20% talc in the coating formulation.

  The content of the coating layer in the coated preparation of the present invention is 1 to 20%, preferably 3 to 10% in the coated preparation.

  In the present invention, examples of the coated preparation include tablets and pills.

  The present invention also includes a step of coating a core having a first component containing Compound A or a salt thereof and polyethylene glycol, a second component containing a diuretic, and a third component containing a calcium antagonist with a coating layer. It is related with the manufacturing method of a coating formulation containing this.

Here, the coated preparation can be produced by a method known per se (for example, a method described in the formulation general rules of the 16th revised Japanese Pharmacopoeia). For example, the core can be manufactured by uniformly mixing or granulating the first component, the second component, and the third component together with the above-described additives as necessary, and then compressing and forming the core. it can.
Here, the mixing operation is performed using, for example, a mixer such as a V-type mixer or a tumbler mixer.
The granulation operation is performed using a granulator such as a high-speed agitation granulator or a fluidized granulator / dryer.
The compression molding is usually performed by tableting with a pressure of 5 to 35 kN / cm ² using a machine such as a single tablet machine or a rotary tableting machine.

A coated preparation can be produced by coating the core (also referred to as “uncoated tablet”) obtained by compression formation with a coating base.
The ratio of the nucleus to 100 parts by weight of the coated preparation is usually 70 to 99 parts by weight, preferably 90 to 98 parts by weight.

Marks or letters for identification may be printed on the surface of the coated preparation of the present invention.
In addition, the coated preparation of the present invention may have a dividing line for division.

The coated preparation of the present invention comprises
(I) The first component, the second component, and the third component may be mixed and granulated (group granulation),
(Ii) Any two components and the remaining one component may be granulated separately (two-group granulation),
(Iii) Each component may be individually granulated (individual granulation or three-group granulation).

  In a preferred embodiment of the group granulation, the content of polyethylene glycol in the first component is 0.1 to 1%, preferably 0.1 to 0.6%, and is used for the coating layer of the coating preparation. The content of polyethylene glycol is 0 to 20% in the coating layer, preferably 0 to 10%, or substantially free.

In the case of two-group granulation, the first component, the second component, and the third component are divided into two granulation groups in any combination. Specifically, the combination of the three components in each of the two granulation groups includes the following:
(I) a first group comprising a first component; a second group comprising a second component and a third component;
(Ii) a first group comprising a first component and a second component; and a second group comprising a third component;
(Iii) A first group including a first component and a third component, and a second group including a second component.
The two granulation groups in the two-group granulation are preferably a combination of the first group including the first component and the second group including the second component and the third component, or the first component and the second component. A combination of a first group containing three components and a second group containing second components.

The two-group granulated components and the individually granulated components may be mixed to form a single nucleus or a nucleus having a laminated structure of two or more layers.
Suitable examples of the core preparation of the present invention forming a nucleus having a laminated structure include the following:
(I) the nucleus has a first part (layer) comprising a first component and a second part (layer) comprising a second component and a third component;
(Ii) the core has a first portion (layer) comprising a first component and a second component, and a second portion (layer) comprising a third component;
(Iii) The nucleus has a first part (layer) containing a first component and a third component, and a second part (layer) containing a second component.
In this embodiment, an inactive intermediate portion (layer) may be further provided between the first portion (layer) and the second portion (layer). Examples of such an intermediate portion (layer) include the coating bases and coating additives described above.

  In a preferred embodiment in which a single core is formed by two-group granulation, the content of polyethylene glycol in the first component is 0.1-1%, preferably 0.1-0.6% in the coating formulation. The content of polyethylene glycol used in the coating layer of the coating preparation is 0 to 20%, preferably 0 to 10%, or substantially free from the coating layer.

  In a preferred embodiment of forming a nucleus having a laminated structure by two-group granulation, the content of polyethylene glycol in the first component is 1 to 2% in the coating preparation, and the polyethylene used for the coating layer of the coating preparation The content of glycol is 0 to 20% in the coating layer, preferably 0 to 10%, or substantially free.

The coated preparation of the present invention can be safely and stably administered orally to mammals (for example, humans, dogs, rabbits, rats, mice, cats, pigs, horses, monkeys, etc.).
The compound A or a salt thereof, a diuretic, and a calcium antagonist of the present invention are each useful as a prophylactic / therapeutic agent for hypertension.

  The method for producing a coated preparation of the present invention can provide a coated preparation that does not lose the stability of the active ingredient even under long-term storage, and realizes the practical use of a preparation useful for the prevention and treatment of the above-mentioned diseases. is there.

  The dosage of the coated preparation of the present invention may be any effective amount of Compound A or a salt thereof, diuretic, and calcium antagonist contained in the preparation. More specifically, the dose of Compound A or a salt thereof, a diuretic, and a calcium antagonist to a patient is considered in consideration of age, weight, general health, sex, diet, administration time, excretion rate, etc. For example, when the diuretic is hydrochlorothiazide and the calcium antagonist is amlodipine besylate, the daily dose of each is an adult (body weight 60 kg). ) 1-100 mg, preferably 10-50 mg of compound A (as free form) per person, 1-100 mg, preferably 5-50 mg of hydrochlorothiazide, 1-50 mg of amlodipine besylate (as free form), preferably Is 2.5 to 10 mg.

  The frequency of administration of the coated preparation of the present invention to the mammal per day is 1 to 3 times per day, preferably 1 to 2 times per day, more preferably once per day.

In a preferred embodiment of the coating formulation of the present invention,
Coated tablets containing 20 mg of compound A (as a free form), 6.25 mg of hydrochlorothiazide, and 2.5 mg of amlodipine besylate (as a free form) per tablet;
Coated tablets containing 20 mg of compound A (as a free form), 6.25 mg of hydrochlorothiazide, and 5 mg of amlodipine besylate (as a free form) per tablet;
Coated tablets containing 20 mg of compound A (as a free form), 12.5 mg of hydrochlorothiazide, and 2.5 mg of amlodipine besylate (as a free form) per tablet;
Coated tablets containing 20 mg of compound A (as a free form), 12.5 mg of hydrochlorothiazide, and 5 mg of amlodipine besylate (as a free form) per tablet;
Coated tablets containing 40 mg of Compound A (as a free form), 6.25 mg of hydrochlorothiazide, and 2.5 mg of amlodipine besylate (as a free form) per tablet;
Coated tablets containing 40 mg of Compound A (as a free form), 6.25 mg of hydrochlorothiazide, and 5 mg of amlodipine besylate (as a free form) per tablet;
Coated tablets containing 40 mg of Compound A (as a free form), 12.5 mg of hydrochlorothiazide, and 2.5 mg of amlodipine besylate (as a free form) per tablet;
Coated tablets containing 40 mg of Compound A (as a free form), 12.5 mg of hydrochlorothiazide, and 5 mg of amlodipine besylate (as a free form) per tablet;
Is mentioned.

The present invention will be described in more detail with reference to Examples, Reference Examples and Test Examples below, but the present invention is not limited thereto.
As the various formulation additives used in the following Examples, Reference Examples and Test Examples, 16th revised Japanese Pharmacopoeia compatible products were used.

[Example A1]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 12.5
D-mannitol 47.65
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 0.7
Low-substituted hydroxypropylcellulose 13
Magnesium stearate 1.3
Hypromellose 2910 3.85
Titanium oxide 0.42
Talc 0.6
Iron sesquioxide 0.039
Yellow ferric oxide 0.039
Black iron oxide 0.052

(1) Hydroxypropyl cellulose (208.0 g) and macrogol 6000 (28.020 g) were dissolved in purified water (2392.0 g) to prepare a binding solution I. Compound A (802.4 g), amlodipine besylate (277.3 g), hydrochlorothiazide (499.5 g), D-mannitol (1904.0 g) in a fluidized bed granulator / dryer (FD-5S, Pauleck Co., Ltd.) ) And crystalline cellulose (388.8 g) were uniformly mixed, granulated while spraying the binding liquid I, and then dried to obtain a granulated powder. Part of the obtained granulated powder was pulverized with a 1.5 mmφ punching screen using a power mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
(2) Crystalline cellulose (442.0 g), low-substituted hydroxypropylcellulose (442.0 g) and magnesium stearate (44.224 g) are added to the obtained sized powder (3492.0 g), and a tumbler mixer ( TM-15 type, Showa Chemical Machinery Co., Ltd.) to obtain a mixed powder.
(3) The mixed powder obtained above is compressed with a rotary tableting machine (AQUA08242L2J1, Kikusui Seisakusho Co., Ltd.) using a 7.0 mm diameter punch (tablet pressure: 5 kN, weight per tablet: 130 mg) And obtained an uncoated tablet.
(4) Hypromellose 2910 (277.2 g) was dissolved in purified water (2412.0 g) and talc (43.228 g) was dispersed in a dispersion, and purified water (669.6 g) was mixed with titanium oxide (30.239 g). ), Iron sesquioxide (2.813 g), yellow iron sesquioxide (2.817 g) and black iron oxide (3.745 g) are added, and purified water (158.4 g) is added to the coating. A liquid was prepared. The above uncoated tablets were sprayed with the coating solution described above in a film coating machine (DRC-500, Powrec Co., Ltd.), and coated until the increased weight per tablet was 5 mg. 3230.7 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Example B2]
Composition per 187 mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 12.5
D-mannitol 81.95
Crystalline cellulose 28.72
Hydroxypropylcellulose 9.2
Macrogol 6000 0.7
Low-substituted hydroxypropylcellulose 18.2
Magnesium stearate 1.8
Hypromellose 2910 5.39
Titanium oxide 0.588
Talc 0.84
Iron trioxide 0.0546
Yellow ferric oxide 0.0546
Black iron oxide 0.0728

(1) Hydroxypropyl cellulose (234.0 g) and macrogol 6000 (31.509 g) were dissolved in purified water (2691.0 g) to prepare a binding solution I. Compound A (902.7 g), amlodipine besylate (312.0 g), D-mannitol (2132.0 g), and crystalline cellulose (437. g) in a fluidized bed granulator / dryer (FD-5S, Pauleck Co., Ltd.). 4 g) was mixed uniformly, granulated while spraying the binding liquid I, and then dried to obtain a granulated powder. Part of the obtained granulated powder was pulverized with a punching screen having a diameter of 1.5 mm using a power mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder I.
(2) Hydroxypropyl cellulose (260.0 g) was dissolved in purified water (4076.0 g) to prepare binding solution II. Hydrochlorthiazide (811.7 g), D-mannitol (2243.0 g), and crystalline cellulose (585.0 g) were uniformly mixed in a fluidized bed granulator / dryer (FD-5S, POWREC Co., Ltd.), and then a binding solution. Granulation was carried out while spraying II, followed by drying to obtain a granulated powder. Part of the obtained granulated powder was pulverized with a 1.0 mmφ punching screen using a power mill crusher (P-3, Showa Chemical Machinery Co., Ltd.) to obtain sized powder II.
(3) Crystalline cellulose (250.0 g), low-substituted hydroxypropylcellulose (455.0 g), and magnesium stearate (size control powder I (2250.0 g), particle size control II (1500.0 g)) 45.022 g) was added and mixed with a tumbler mixer (TM-15 type, Showa Chemical Machinery Co., Ltd.) to obtain a mixed powder.
(4) The mixed powder obtained above is compressed with a rotary tableting machine (AQUA08242L2J1, Kikusui Seisakusho Co., Ltd.) using a punch with a diameter of 7.5 mm (tablet pressure: 6 kN, weight per tablet: 180 mg) And obtained an uncoated tablet.
(5) Hypromellose 2910 (277.2 g) was dissolved in purified water (2412.0 g), and talc (43.228 g) was dispersed in a dispersion, purified water (669.6 g) and titanium oxide (30.239 g). ), Iron sesquioxide (2.813 g), yellow iron sesquioxide (2.817 g) and black iron oxide (3.745 g) are added, and purified water (158.4 g) is added to the coating. A liquid was prepared. The above uncoated tablets were sprayed with the above-described coating solution in a film coating machine (DRC-500, Powrec Co., Ltd.) and coated until the increased weight per tablet was 7 mg. 3168.7 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained. (Coating solution is common to Example A1)

[Example C3]
Composition per 239 mg of formulation (mg / tablet)
Compound A 20.0
Amlodipine besylate 6.93
Hydrochlorothiazide 12.5
Lactose hydrate 49.3
Corn starch 13.0
D-mannitol 56.44
Crystalline cellulose 41.33
Hydroxypropylcellulose 7.1
Macrogol 6000 4.0
Low substituted hydroxypropylcellulose 13.0
Carmellose calcium 5.0
Magnesium stearate 1.4
Hypromellose 2910 7.02
Titanium oxide 0.75
Talc 1.00
Iron trioxide 0.069
Yellow ferric oxide 0.069
Black iron oxide 0.092

(1) Hydroxypropyl cellulose (164.0 g) and macrogol 6000 (164.0 g) were dissolved in purified water (1476.0 g) to prepare a binding solution I. Compound A (822.5 g), lactose hydrate (2019.0 g), corn starch (533.0 g) and crystalline cellulose (533.0 g) in a fluidized bed granulator / dryer (FD-5S, Powrec Co., Ltd.) ) Were uniformly mixed, and then granulated while spraying the binding liquid I, and then dried to obtain a granulated powder. Part of the obtained granulated powder was pulverized with a punching screen having a diameter of 1.5 mm using a power mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder I.
(2) Crystalline cellulose (416.0 g), low-substituted hydroxypropyl cellulose (416.0 g) and magnesium stearate (22.418 g) are added to the obtained sized powder I (3306.0 g), and a tumbler mixer By mixing with (TM-15 type, Showa Chemical Machinery Co., Ltd.), mixed powder I was obtained.
(3) Hydroxypropyl cellulose (136.4 g) was dissolved in purified water (1228.0 g) to prepare a binding solution II. In a fluidized bed granulator / dryer (FD-5S, Pauleck Co., Ltd.), amlodipine besylate (305.0 g), hydrochlorothiazide (549.5 g), D-mannitol (2484.0 g) and crystalline cellulose (674.5 g) ) Was uniformly mixed, and then granulated while spraying the binding liquid II, and then dried to obtain a granulated powder. Part of the obtained granulated powder was pulverized with a 1.5 mmφ punching screen using a power mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain sized powder II.
(4) Carmellose calcium (160.0 g) and magnesium stearate (22.405 g) are added to the obtained sized powder II (3018.0 g), and a tumbler mixer (TM-15, Showa Chemical Machinery Co., Ltd.) is added. Mixed powder II was obtained by mixing at a workshop.
(5) The mixed powder obtained above is compressed with a rotary tableting machine (AQUA08242L2J1, Kikusui Seisakusho Co., Ltd.) using a punch with a diameter of 8.0 mm (tablet pressure: 7 kN, weight per tablet: 230 mg ( Mixed powder I: 130 mg, mixed powder II: 100 mg)) to obtain uncoated tablets.
(6) Hypromellose 2910 (196.6 g) was dissolved in purified water (1742.0 g), and talc (28.003 g) was dispersed in a dispersion, purified water (425.6 g) and titanium oxide (21.004 g). ), Iron sesquioxide (1.936 g), yellow iron sesquioxide (1.934 g) and black iron oxide (2.583 g) are added to the dispersion, and purified water (100.8 g) is added to the coating. A liquid was prepared. The above-mentioned uncoated tablets were sprayed with the above-described coating solution in a film coating machine (DRC-500, Powrec Co., Ltd.), and coated until the increased weight per tablet was 9 mg. 3318.6 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Example A4]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 12.5
D-mannitol 47.65
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 0.7
Low-substituted hydroxypropylcellulose 13
Magnesium stearate 1.3
Hypromellose 2910 3.967
Titanium oxide 0.42
Talc 0.60
Iron sesquioxide 0.010
Black iron oxide 0.003

  In a dispersion in which hypromellose 2910 (79.34 g) was dissolved in purified water (530.0 g) and talc (12.00 g) was dispersed, purified water (326.2 g) and titanium oxide (8.40 g), three A dispersion in which iron dioxide (0.2010 g) and black iron oxide (0.0600 g) were dispersed was added, and purified water (53.9 g) was further added to prepare a coating solution. The uncoated tablets of Reference Example A7 were sprayed with the coating solution described above in a film coating machine (DRC-200, Powrec Co., Ltd.), and coated until the increased weight per tablet was 5 mg. 186.1 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Example A5]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 12.5
D-mannitol 47.65
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 1.53
Low-substituted hydroxypropylcellulose 13
Magnesium stearate 1.3
Hypromellose 2910 3.62
Titanium oxide 0.42
Iron sesquioxide 0.039
Yellow ferric oxide 0.039
Black iron oxide 0.052

  In an aqueous solution in which hypromellose 2910 (72.40 g) and macrogol 6000 (16.60 g) are dissolved in purified water (530.0 g), titanium oxide (8.4029 g) and iron sesquioxide are dissolved in purified water (326.0 g). (0.7780 g), yellow ferric oxide (0.7792 g) and black iron oxide (1.0406 g) in a dispersion were added, and purified water (44.00 g) was further added to prepare a coating solution. The uncoated tablets of Reference Example A7 were sprayed with the coating solution described above in a film coating machine (DRC-200, Powrec Co., Ltd.), and coated until the increased weight per tablet was 5 mg. 258.3 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Example A6]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 12.5
D-mannitol 47.65
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 1.193
Low-substituted hydroxypropylcellulose 13
Magnesium stearate 1.3
Hypromellose 2910 3.846
Titanium oxide 0.505
Iron sesquioxide 0.0469
Yellow ferric oxide 0.0469
Black iron oxide 0.0625

  In an aqueous solution in which hypromellose 2910 (64.05 g) and macrogol 6000 (8.210 g) are dissolved in purified water (530.0 g), titanium oxide (8.4016 g) and ferric sesquioxide are dissolved in purified water (326.0 g). (0.7808 g), yellow ferric oxide (0.7806 g) and black iron oxide (1.0396 g) in a dispersion were added, and purified water (44.00 g) was further added to prepare a coating solution. The uncoated tablets of Reference Example A7 were sprayed with the coating solution described above in a film coating machine (DRC-200, Powrec Co., Ltd.), and coated until the increased weight per tablet was 5 mg. 259.3 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Example A7]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 12.5
D-mannitol 47.65
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 1.53
Low-substituted hydroxypropylcellulose 13
Magnesium stearate 1.3
Hypromellose 2910 3.75
Iron sesquioxide 0.126
Yellow ferric oxide 0.126
Black iron oxide 0.168

  In an aqueous solution in which hypromellose 2910 (75.00 g) and macrogol 6000 (16.60 g) are dissolved in purified water (536.0 g), ferric oxide (2.5209 g), yellow three A dispersion in which iron dioxide (2.5200 g) and black iron oxide (3.3610 g) were dispersed was added to prepare a coating solution. The uncoated tablets of Reference Example A7 were sprayed with the coating solution described above in a film coating machine (DRC-200, Powrec Co., Ltd.), and coated until the increased weight per tablet was 5 mg. 258.9 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Example A8]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 12.5
D-mannitol 47.65
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 1.53
Low-substituted hydroxypropylcellulose 13
Magnesium stearate 1.3
Hypromellose 2910 4.04
Iron sesquioxide 0.039
Yellow ferric oxide 0.039
Black iron oxide 0.052

  In an aqueous solution in which hypromellose 2910 (80.80 g) and macrogol 6000 (16.60 g) are dissolved in purified water (530.0 g), ferric sesquioxide (0.7798 g), yellow three A dispersion in which iron dioxide (0.7795 g) and black iron oxide (1.0396 g) were dispersed was added, and purified water (50.5 g) was further added to prepare a coating solution. The uncoated tablets of Reference Example A7 were sprayed with the coating solution described above in a film coating machine (DRC-200, Powrec Co., Ltd.), and coated until the increased weight per tablet was 5 mg. 206.5 g of a film-coated tablet having the above composition containing 20 mg of compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Example A9]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 12.5
D-mannitol 47.65
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 0.783
Low-substituted hydroxypropylcellulose 13
Magnesium stearate 1.3
Hypromellose 2910 4.367
Titanium oxide 0.42
Iron sesquioxide 0.039
Yellow ferric oxide 0.039
Black iron oxide 0.052

  In an aqueous solution in which hypromellose 2910 (87.33 g) and macrogol 6000 (1.70 g) are dissolved in purified water (530.2 g), titanium oxide (8.40 g) and iron sesquioxide are dissolved in purified water (326.3 g). (0.7808 g), yellow ferric oxide (0.7797 g) and black iron oxide (1.0399 g) in a dispersion were added, and purified water (53.1 g) was further added to prepare a coating solution. The uncoated tablets of Reference Example A7 were sprayed with the coating solution described above in a film coating machine (DRC-200, Powrec Co., Ltd.), and coated until the increased weight per tablet was 5 mg. 187.0 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Example A10]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 12.5
D-mannitol 47.65
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 1.53
Low-substituted hydroxypropylcellulose 13
Magnesium stearate 1.3
Hypromellose 2910 4.157
Ferric sesquioxide 0.0039
Yellow ferric oxide 0.0039
Black iron oxide 0.0052

  In an aqueous solution in which hypromellose 2910 (83.14 g) and macrogol 6000 (16.60 g) were dissolved in purified water (536.0 g), ferric sesquioxide (0.0779 g), yellow three A dispersion in which iron dioxide (0.0773 g) and black iron oxide (0.1045 g) were dispersed was added, and purified water (44.0 g) was further added to prepare a coating solution. The uncoated tablets of Reference Example A7 were sprayed with the coating solution described above in a film coating machine (DRC-200, Powrec Co., Ltd.), and coated until the increased weight per tablet was 5 mg. 187.1 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Reference Example A1]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 12.5
D-mannitol 47.65
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 1.53
Low-substituted hydroxypropylcellulose 13
Magnesium stearate 1.3
Hypromellose 2910 3.75
Titanium oxide 0.42

(1) Hydroxypropyl cellulose (208.0 g) and macrogol 6000 (28.000 g) were dissolved in purified water (2392.0 g) to prepare a binding solution I. Compound A (800.0 g), amlodipine besylate (277.0 g), hydrochlorothiazide (498.5 g), D-mannitol (1908.0 g) in a fluidized bed granulator / dryer (FD-5S, Pauleck Co., Ltd.) ) And crystalline cellulose (388.8 g) were uniformly mixed, granulated while spraying the binding liquid I, and then dried to obtain a granulated powder. Part of the obtained granulated powder was pulverized with a 1.5 mmφ punching screen using a power mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
(2) Crystalline cellulose (442.0 g), low-substituted hydroxypropyl cellulose (442.0 g) and magnesium stearate (44.202 g) are added to the obtained sized powder (3492.0 g), and a tumbler mixer ( TM-15 type, Showa Chemical Machinery Co., Ltd.) to obtain a mixed powder.
(3) The mixed powder obtained above is compressed with a rotary tableting machine (AQUA08242L2J1, Kikusui Seisakusho Co., Ltd.) using a 7.0 mm diameter punch (tablet pressure: 7 kN, weight per tablet: 130 mg) And obtained an uncoated tablet.
(4) In an aqueous solution in which hypromellose 2910 (180.0 g) and macrogol 6000 (39.842 g) are dissolved in purified water (1656.0 g), titanium oxide (20.163 g) is added to purified water (475.2 g). The dispersed dispersion was added, and purified water (76.8 g) was further added to prepare a coating solution. The above uncoated tablets were sprayed with the coating solution described above in a film coating machine (DRC-500, Powrec Co., Ltd.), and coated until the increased weight per tablet was 5 mg. 3218.5 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Reference Example B2]
Composition per 187 mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 12.5
D-mannitol 81.95
Crystalline cellulose 28.72
Hydroxypropylcellulose 9.2
Macrogol 6000 1.87
Low-substituted hydroxypropylcellulose 18.2
Magnesium stearate 1.8
Hypromellose 2910 5.25
Titanium oxide 0.58

(1) Hydroxypropyl cellulose (234.0 g) and macrogol 6000 (31.500 g) were dissolved in purified water (2691.0 g) to prepare a binding solution I. Compound A (900.0 g), amlodipine besylate (311.7 g), D-mannitol (2135.0 g) and crystalline cellulose (437. g) in a fluidized bed granulator / dryer (FD-5S, Pauleck Co., Ltd.). 4 g) was mixed uniformly, granulated while spraying the binding liquid I, and then dried to obtain a granulated powder. Part of the obtained granulated powder was pulverized with a punching screen having a diameter of 1.5 mm using a power mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder I.
(2) Hydroxypropyl cellulose (260.0 g) was dissolved in purified water (4076.0 g) to prepare binding solution II. Fluidized bed granulator / dryer (FD-5S, Pauleck Co., Ltd.)
In the mixture, hydrochlorothiazide (810.1 g), D-mannitol (2245.0 g) and crystalline cellulose (585.0 g) were mixed uniformly, and then granulated while spraying the binding liquid II, and then dried to prepare a mixture. Grain powder was obtained. Part of the obtained granulated powder was pulverized with a 1.5 mmφ punching screen using a power mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain sized powder II.
(3) Crystalline cellulose (250.0 g), low-substituted hydroxypropylcellulose (455.0 g), and magnesium stearate (size control powder I (2250.0 g), particle size control II (1500.0 g)) 45.000 g) was added and mixed with a tumbler mixer (TM-15 type, Showa Chemical Machinery Co., Ltd.) to obtain a mixed powder.
(4) The mixed powder obtained above is compressed with a rotary tableting machine (AQUA08242L2J1, Kikusui Seisakusho Co., Ltd.) using a 7.5 mm diameter punch (tablet pressure: 5 kN, weight per tablet: 180 mg) And obtained an uncoated tablet.
(5) Titanium oxide (19.723 g) was added to purified water (411.4 g) in an aqueous solution in which hypromellose 2910 (178.5 g) and macrogol 6000 (39.780 g) were dissolved in purified water (1652.0 g). The dispersed dispersion was added, and purified water (78.2 g) was further added to prepare a coating solution. The above uncoated tablets were sprayed with the above-described coating solution in a film coating machine (DRC-500, Powrec Co., Ltd.) and coated until the increased weight per tablet was 7 mg. 3168.3 g of a film-coated tablet having the above composition containing 20 mg of compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Reference Example C3]
Composition per 239 mg of formulation (mg / tablet)
Compound A 20.0
Amlodipine besylate 6.93
Hydrochlorothiazide 12.5
Lactose hydrate 49.3
Corn starch 13.0
D-mannitol 56.44
Crystalline cellulose 41.33
Hydroxypropylcellulose 7.1
Macrogol 6000 5.50
Low substituted hydroxypropylcellulose 13.0
Carmellose calcium 5.0
Magnesium stearate 1.4
Hypromellose 2910 6.75
Titanium oxide 0.75

(1) Hydroxypropyl cellulose (164.0 g) and macrogol 6000 (164.0 g) were dissolved in purified water (1476.0 g) to prepare a binding solution I. Compound A (820.0 g), lactose hydrate (2021.0 g), corn starch (533.0 g) and crystalline cellulose (533.0 g) in a fluidized bed granulator / dryer (FD-5S, Powrec Co., Ltd.) ) Were uniformly mixed, and then granulated while spraying the binding liquid I, and then dried to obtain a granulated powder. Part of the obtained granulated powder was pulverized with a punching screen having a diameter of 1.5 mm using a power mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder I.
(2) Crystalline cellulose (416.0 g), low-substituted hydroxypropyl cellulose (416.0 g) and magnesium stearate (22.402 g) are added to the resulting sized powder I (3306.0 g), and a tumbler mixer By mixing with (TM-15 type, Showa Chemical Machinery Co., Ltd.), mixed powder I was obtained.
(3) Hydroxypropyl cellulose (136.4 g) was dissolved in purified water (1228.0 g) to prepare a binding solution II. In a fluidized bed granulator / dryer (FD-5S, Pauleck Co., Ltd.), amlodipine besylate (304.7 g), hydrochlorothiazide (548.4 g), D-mannitol (2485.0 g) and crystalline cellulose (674.5 g) ) Was uniformly mixed, and then granulated while spraying the binding liquid II, and then dried to obtain a granulated powder. Part of the obtained granulated powder was pulverized with a 1.5 mmφ punching screen using a power mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain sized powder II.
(4) Carmellose calcium (160.0 g) and magnesium stearate (22.400 g) are added to the obtained sized powder II (3018.0 g), and a tumbler mixer (TM-15, Showa Chemical Machinery Co., Ltd.) is added. Mixed powder II was obtained by mixing at a workshop.
(5) The mixed powder obtained above is compressed with a rotary tableting machine (AQUA08242L2J1, Kikusui Seisakusho Co., Ltd.) using a punch with a diameter of 8.0 mm (tablet pressure: 6 kN, weight per tablet: 230 mg ( Mixed powder I: 130 mg, mixed powder II: 100 mg)) to obtain uncoated tablets.
(6) In an aqueous solution in which hypromellose 2910 (189.0 g) and macrogol 6000 (42.000 g) are dissolved in purified water (1742.0 g), titanium oxide (21.004 g) is added to purified water (445.2 g). The dispersed dispersion was added, and purified water (81.206 g) was further added to prepare a coating solution. The above-mentioned uncoated tablets were sprayed with the above-described coating solution in a film coating machine (DRC-500, Powrec Co., Ltd.), and coated until the increased weight per tablet was 9 mg. 3328.6 g of film-coated tablets of the above composition containing 20 mg of compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet were obtained.

[Reference Example A4a]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 6.25
D-mannitol 53.85
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 4.0
Crospovidone 9.75
Magnesium stearate 1.3
Opadry (registered trademark) White 5.0

(1) Hydroxypropyl cellulose (104.0 g) and Macrogol 6000 (80.00 g) were dissolved in purified water (1196.0 g) to prepare a binding solution I. Compound A (100.0 g), amlodipine besylate (34.7 g), hydrochlorothiazide (31.25 g), D-mannitol (269.25 g) in a fluidized bed granulator / dryer (LAB-1, Paulek, Inc.) ) And crystalline cellulose (48.60 g) were uniformly mixed, granulated while spraying the binding liquid I, and then dried to obtain a granulated powder.
(2) Crystalline cellulose (58.50 g), crospovidone (43.88 g) and magnesium stearate (5.8527 g) were added to the obtained granulated powder (476.8 g) and mixed.
(3) The mixed powder obtained above was tableted using a punch with a diameter of 7.0 mm (tablet pressure: 7 kN, weight per tablet: 130 mg) with a tableting machine (Correct19K, Kikusui Seisakusho Co., Ltd.) An uncoated tablet was obtained.
(4) Disperse Opadry (registered trademark) White (50.00 g; made by Nippon Colorcon Co., Ltd .; containing hypromellose 2910 75%, macrogol 6000 16.67%, and titanium oxide 8.33%) in purified water (283.3 g) A coating solution was prepared. The above-mentioned uncoated tablets were sprayed with the above-described coating solution in a film coating machine (HICOATER, Freund Sangyo Co., Ltd.) and coated until the weight increase per tablet was 5 mg. 269.3 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Reference Example A4b]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 6.25
D-mannitol 50.6
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 4.0
Low-substituted hydroxypropylcellulose 13
Magnesium stearate 1.3
Opadry (registered trademark) White 5.0

(1) Hydroxypropyl cellulose (104.0 g) and Macrogol 6000 (80.00 g) were dissolved in purified water (1196.0 g) to prepare a binding solution I. Compound A (100.0 g), amlodipine besylate (34.7 g), hydrochlorothiazide (31.25 g), D-mannitol (253.0 g) in a fluidized bed granulator / dryer (LAB-1, Paulek, Inc.) ) And crystalline cellulose (48.60 g) were uniformly mixed, granulated while spraying the binding liquid I, and then dried to obtain a granulated powder.
(2) Crystalline cellulose (58.50 g), low-substituted hydroxypropyl cellulose (58.50 g) and magnesium stearate (5.8525 g) were added to the obtained granulated powder (462.2 g) and mixed.
(3) The mixed powder obtained above was tableted using a punch with a diameter of 7.0 mm (tablet pressure: 6 kN, weight per tablet: 130 mg) with a tableting machine (Correct19K, Kikusui Seisakusho Co., Ltd.) An uncoated tablet was obtained.
(4) Opadry (registered trademark) White (50.00 g) was dispersed in purified water (283.3 g) to prepare a coating solution. The above-mentioned uncoated tablets were sprayed with the above-described coating solution in a film coating machine (HICOATER, Freund Sangyo Co., Ltd.) and coated until the weight increase per tablet was 5 mg. 268.1 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Reference Example A4c]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 6.25
D-mannitol 53.85
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 4.00
Akzizol 9.75
Magnesium stearate 1.3
Opadry (registered trademark) White 5

(1) Hydroxypropyl cellulose (104.0 g) and Macrogol 6000 (80.00 g) were dissolved in purified water (1196.0 g) to prepare a binding solution I. Compound A (100.0 g), amlodipine besylate (34.7 g), hydrochlorothiazide (31.25 g), D-mannitol (269.3 g) in a fluidized bed granulator / dryer (LAB-1, Paulek, Inc.) ) And crystalline cellulose (48.60 g) were uniformly mixed, granulated while spraying the binding liquid I, and then dried to obtain a granulated powder.
(2) Crystalline cellulose (58.50 g), axizol (43.88 g) and magnesium stearate (5.8514 g) were added to the obtained granulated powder (476.8 g) and mixed.
(3) The mixed powder obtained above was tableted using a punch with a diameter of 7.0 mm (tablet pressure: 6 kN, weight per tablet: 130 mg) with a tableting machine (Correct19K, Kikusui Seisakusho Co., Ltd.) An uncoated tablet was obtained.
(4) Opadry (registered trademark) White (50.00 g) was dispersed in purified water (283.3 g) to prepare a coating solution. The above-mentioned uncoated tablets were sprayed with the above-described coating solution in a film coating machine (HICOATER, Freund Sangyo Co., Ltd.) and coated until the weight increase per tablet was 5 mg. 270.3 g of a film-coated tablet having the above composition containing 20 mg of compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Reference Example A5a]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 6.25
D-mannitol 56.55
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 1.3
Crospovidone 9.75
Magnesium stearate 1.3
Opadry (registered trademark) White 5

(1) Hydroxypropylcellulose (104.0 g) and macrogol 6000 (26.00 g) were dissolved in purified water (1196.2 g) to prepare a binding solution I. Compound A (100.0 g), amlodipine besylate (34.7 g), hydrochlorothiazide (31.25 g), D-mannitol (282.75 g) in a fluidized bed granulator / dryer (LAB-1, Paulek, Inc.) ) And crystalline cellulose (48.60 g) were uniformly mixed, granulated while spraying the binding liquid I, and then dried to obtain a granulated powder.
(2) Crystalline cellulose (58.50 g), crospovidone (43.88 g) and magnesium stearate (5.8544 g) were added to the obtained granulated powder (476.8 g) and mixed.
(3) The mixed powder obtained above was tableted using a punch with a diameter of 7.0 mm (tablet pressure: 7 kN, weight per tablet: 130 mg) with a tableting machine (Correct19K, Kikusui Seisakusho Co., Ltd.) An uncoated tablet was obtained.
(4) Opadry (registered trademark) White (50.00 g) was dispersed in purified water (283.3 g) to prepare a coating solution. The above-mentioned uncoated tablets were sprayed with the above-described coating solution in a film coating machine (DRC-200, Powrec Co., Ltd.), and coated until the increased weight per tablet was 5 mg. 268.1 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Reference Example A5b]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 6.25
D-mannitol 53.3
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 1.3
Low-substituted hydroxypropylcellulose 13
Magnesium stearate 1.3
Opadry (registered trademark) White 5

(1) Hydroxypropylcellulose (104.0 g) and macrogol 6000 (26.00 g) were dissolved in purified water (1196.2 g) to prepare a binding solution I. Compound A (100.0 g), amlodipine besylate (34.7 g), hydrochlorothiazide (31.25 g), D-mannitol (266.5 g) in a fluidized bed granulator / dryer (LAB-1, Paulek, Inc.) ) And crystalline cellulose (48.60 g) were uniformly mixed, granulated while spraying the binding liquid I, and then dried to obtain a granulated powder.
(2) Crystalline cellulose (58.50 g), low-substituted hydroxypropyl cellulose (58.50 g) and magnesium stearate (5.8532 g) were added to the obtained granulated powder (462.2 g) and mixed.
(3) The mixed powder obtained above was tableted using a punch with a diameter of 7.0 mm (tablet pressure: 7 kN, weight per tablet: 130 mg) with a tableting machine (Correct19K, Kikusui Seisakusho Co., Ltd.) An uncoated tablet was obtained.
(4) Opadry (registered trademark) White (50.00 g) was dispersed in purified water (283.3 g) to prepare a coating solution. The above-mentioned uncoated tablets were sprayed with the above-described coating solution in a film coating machine (DRC-200, Powrec Co., Ltd.), and coated until the increased weight per tablet was 5 mg. 270.1 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Reference Example A5c]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 6.25
D-mannitol 56.55
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 1.3
Akzizol 9.75
Magnesium stearate 1.3
Opadry (registered trademark) White 5

(1) Hydroxypropylcellulose (104.0 g) and macrogol 6000 (26.00 g) were dissolved in purified water (1196.2 g) to prepare a binding solution I. Compound A (100.0 g), amlodipine besylate (34.7 g), hydrochlorothiazide (31.25 g), D-mannitol (282.75 g) in a fluidized bed granulator / dryer (LAB-1, Paulek, Inc.) ) And crystalline cellulose (48.60 g) were uniformly mixed, granulated while spraying the binding liquid I, and then dried to obtain a granulated powder.
(2) Crystalline cellulose (58.50 g), axizol (43.88 g) and magnesium stearate (5.8506 g) were added to the obtained granulated powder (476.8 g) and mixed.
(3) The mixed powder obtained above was tableted using a punch with a diameter of 7.0 mm (tablet pressure: 7 kN, weight per tablet: 130 mg) with a tableting machine (Correct19K, Kikusui Seisakusho Co., Ltd.) An uncoated tablet was obtained.
(4) Opadry (registered trademark) White (50.00 g) was dispersed in purified water (283.3 g) to prepare a coating solution. The above-mentioned uncoated tablets were sprayed with the above-described coating solution in a film coating machine (DRC-200, Powrec Co., Ltd.), and coated until the increased weight per tablet was 5 mg. 269.2 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Reference Example A6a]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 6.25
D-mannitol 57.15
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 0.7
Crospovidone 9.75
Magnesium stearate 1.3
Opadry (registered trademark) White 5

(1) Hydroxypropyl cellulose (104.0 g) and Macrogol 6000 (14.00 g) were dissolved in purified water (1196.0 g) to prepare a binding solution I. Compound A (100.0 g), amlodipine besylate (34.7 g), hydrochlorothiazide (31.25 g), D-mannitol (285.8 g) in a fluidized bed granulator / dryer (LAB-1, Paulek, Inc.) ) And crystalline cellulose (48.60 g) were uniformly mixed, granulated while spraying the binding liquid I, and then dried to obtain a granulated powder.
(2) Crystalline cellulose (58.50 g), crospovidone (43.88 g) and magnesium stearate (5.8509 g) were added to the obtained granulated powder (476.8 g) and mixed.
(3) The mixed powder obtained above was tableted using a punch with a diameter of 7.0 mm (tablet pressure: 7 kN, weight per tablet: 130 mg) with a tableting machine (Correct19K, Kikusui Seisakusho Co., Ltd.) An uncoated tablet was obtained.
(4) Opadry (registered trademark) White (50.00 g) was dispersed in purified water (283.3 g) to prepare a coating solution. The above-mentioned uncoated tablets were sprayed with the above-described coating solution in a film coating machine (DRC-200, Powrec Co., Ltd.), and coated until the increased weight per tablet was 5 mg. 269.7 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Reference Example A6b]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 6.25
D-mannitol 53.9
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 0.7
Low-substituted hydroxypropylcellulose 13
Magnesium stearate 1.3
Opadry (registered trademark) White 5

(1) Hydroxypropyl cellulose (104.0 g) and Macrogol 6000 (14.00 g) were dissolved in purified water (1196.0 g) to prepare a binding solution I. Compound A (100.0 g), amlodipine besylate (34.7 g), hydrochlorothiazide (31.25 g), D-mannitol (269.5 g) in a fluidized bed granulator / dryer (LAB-1, Paulek, Inc.) ) And crystalline cellulose (48.60 g) were uniformly mixed, granulated while spraying the binding liquid I, and then dried to obtain a granulated powder.
(2) Crystalline cellulose (58.50 g), low-substituted hydroxypropylcellulose (58.50 g) and magnesium stearate (5.8590 g) were added to the obtained granulated powder (462.2 g) and mixed.
(3) The mixed powder obtained above was tableted using a punch with a diameter of 7.0 mm (tablet pressure: 7 kN, weight per tablet: 130 mg) with a tableting machine (Correct19K, Kikusui Seisakusho Co., Ltd.) An uncoated tablet was obtained.
(4) Opadry (registered trademark) White (50.00 g) was dispersed in purified water (283.3 g) to prepare a coating solution. The above-mentioned uncoated tablets were sprayed with the above-described coating solution in a film coating machine (DRC-200, Powrec Co., Ltd.), and coated until the increased weight per tablet was 5 mg. 270.0 g of a film-coated tablet having the above composition containing 20 mg of Compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Reference Example A6c]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 6.25
D-mannitol 57.15
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 0.7
Akzizol 9.75
Magnesium stearate 1.3
Opadry (registered trademark) White 5

(1) Hydroxypropyl cellulose (104.0 g) and Macrogol 6000 (14.00 g) were dissolved in purified water (1196.0 g) to prepare a binding solution I. Compound A (100.0 g), amlodipine besylate (34.7 g), hydrochlorothiazide (31.25 g), D-mannitol (285.8 g) in a fluidized bed granulator / dryer (LAB-1, Paulek, Inc.) ) And crystalline cellulose (48.60 g) were uniformly mixed, granulated while spraying the binding liquid I, and then dried to obtain a granulated powder.
(2) Crystalline cellulose (58.50 g), axizol (43.88 g) and magnesium stearate (5.8505 g) were added to and mixed with the obtained granulated powder (476.8 g).
(3) The mixed powder obtained above was tableted using a punch with a diameter of 7.0 mm (tablet pressure: 7 kN, weight per tablet: 130 mg) with a tableting machine (Correct19K, Kikusui Seisakusho Co., Ltd.) An uncoated tablet was obtained.
(4) Opadry (registered trademark) White (50.00 g) was dispersed in purified water (283.3 g) to prepare a coating solution. The above-mentioned uncoated tablets were sprayed with the above-described coating solution in a film coating machine (DRC-200, Powrec Co., Ltd.), and coated until the increased weight per tablet was 5 mg. A film-coated tablet having the above composition containing 20 mg of compound A, 5 mg of amlodipine besylate (as a free form) and 12.5 mg of hydrochlorothiazide per tablet was obtained.

[Reference Example A7]
Composition per mg of formulation (mg / tablet)
Compound A 20
Amlodipine besylate 6.93
Hydrochlorothiazide 12.5
D-mannitol 47.65
Crystalline cellulose 22.72
Hydroxypropylcellulose 5.2
Macrogol 6000 0.7
Low-substituted hydroxypropylcellulose 13
Magnesium stearate 1.3

(1) Hydroxypropyl cellulose (2557.0 g) and macrogol 6000 (344.3 g) were dissolved in purified water (29410.0 g) to prepare a binding solution I. Compound A (3693.0 g), amlodipine besylate (1285.0 g), hydrochlorothiazide (2311.0 g), D-mannitol (8821) in a fluidized bed granulator / dryer (FD-WSG-30, Paulek, Inc.) 0.0 g) and crystalline cellulose (1798.0 g) were uniformly mixed, and granulated while spraying the binding liquid I, and then dried to obtain granulated powder I. Part of the obtained granulated powder I was pulverized with a punching screen of 1.5 mmΦ using a power mill crusher (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder I. .
(2) Compound A (3693.0 g), amlodipine besylate (1285.0 g), hydrochlorothiazide (2311.0 g), D- in a fluidized bed granulator / dryer (FD-WSG-30, Pauleck Co., Ltd.) After uniformly mixing mannitol (8821.0 g) and crystalline cellulose (1798.0 g), the mixture was granulated while spraying the binding liquid I and then dried to obtain granulated powder II. Part of the obtained granulated powder II was pulverized with a punching screen of 1.5 mmΦ using a power mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder II. .
(3) Crystalline cellulose (4160.0 g), low-substituted hydroxypropyl cellulose (4160.0 g), and magnesium stearate (siculated powder I (16430.0 g) and sized powder II (16430.0 g)) 416.0 g) was added and mixed with a tumbler mixer (TM-20-0-0 type, Suehiro Koki Co., Ltd.) to obtain a mixed powder.
(4) The mixed powder obtained above is compressed with a rotary tableting machine (AQUA08242L2J1, Kikusui Seisakusho Co., Ltd.) using a 7.0 mm diameter punch (tablet pressure: 5-6 kN, weight per tablet: 130 mg) to obtain an uncoated tablet.

[Test Example 1] Photostability test of amlodipine and hydrochlorothiazide in the presence of polyethylene glycol In a sealed condition in which the tablets obtained in Examples A1, B2, and C3 and Reference Examples A1, B2, and C3 were put in a petri dish and wrapped. Using a xenon fade meter (SX75, Suga Test Instruments Co., Ltd.), 100,000 Lux was directly irradiated for 12 hours. The light resistance was confirmed by confirming the amount of increase in related substances due to light irradiation by the test method described below.

[Conditions for high performance liquid chromatography analysis]
(1) Column: Inert Sustain C18, HP-3 μm, inner diameter 4.6 mm × 15 cm (manufactured by GL Sciences)
(2) Mobile phase:
Mobile phase A: 0.01 mol / L phosphate buffer (pH 3.0)
Mobile phase B: acetonitrile (3) elution gradient program:
From 0 minute to 1 minute: 85/15 (mobile phase A / mobile phase B) (constant)
From 1 minute to 15 minutes: From 85/15 (mobile phase A / mobile phase B) to 30/70 (mobile phase A / mobile phase B) From 15 minutes to 18 minutes: 30/70 (mobile phase A / mobile phase B) From 20 to 80 (mobile phase A / mobile phase B) From 18 minutes to 23 minutes: 20/80 (mobile phase A / mobile phase B) (constant)
From 23 minutes to 25 minutes: From 20/80 (mobile phase A / mobile phase B) to 85/15 (mobile phase A / mobile phase B) From 25 minutes to 30 minutes: 85/15 (mobile phase A / mobile phase B) (Constant)
(4) Flow rate: about 1.0 ml / min
(5) Detector: Photodiode array detector (measurement wavelength: 230 nm, spectrum measurement range 210 to 400 nm)
(6) Sample temperature: about 5 ° C
(7) Column temperature: about 40 ° C
[Compound A-related substances]
Similar substances derived from Compound A are substances whose relative elution times are 0.78 and 1.27, respectively, when the elution time of Compound A is 1.00 in the high performance liquid chromatography analysis under the above conditions. It is.
[Amlodipine besylate-derived related substances]
The related substances derived from amlodipine besylate have a relative elution time of 0.81 and 0.93, respectively, when the elution time of amlodipine besylate is 1.00 in the high performance liquid chromatography analysis under the above conditions. 1.09, 1.07, 1.16 and 1.60.
[Related substances derived from hydrochlorothiazide]
The related substances derived from hydrochlorothiazide were found to have a relative elution time of 0.82, 0.89 and 1.75, respectively, when the elution time of hydrochlorothiazide was 1.00 in the high performance liquid chromatography analysis under the above conditions. It is a substance.

Table 1 shows the results. The values in the table are compound A, amlodipine when the content of compound A, amlodipine besylate or hydrochlorothiazide (compound A: 20 mg / amlodipine besylate: 6.93 mg / hydrochlorothiazide: 12.5 mg) is taken as 100%. It shows the percentage (%) of total related substances derived from besylate or hydrochlorothiazide.
As shown in Table 1, in Examples A1, B2, and C3, the increase in related substances derived from amlodipine besylate and hydrochlorothiazide was significantly suppressed as compared to Reference Examples A1, B2, and C3. .

[Test Example 2]
Tablets obtained in Examples A1, B2, and C3 and Reference Examples A1, B2, and C3 were conditioned to 44% RH and 60% RH, and 3 months under conditions of glass bottle caps at 40 ° C. and 75% RH saved. The storage stability was evaluated by measuring the amount of related substances derived from Compound A, amlodipine besylate and hydrochlorothiazide by the analytical method shown in Test Example 1.
Table 2 shows the results. The values in the table are compound A, amlodipine when the content of compound A, amlodipine besylate or hydrochlorothiazide (compound A: 20 mg / amlodipine besylate: 6.93 mg / hydrochlorothiazide: 12.5 mg) is taken as 100%. It shows the percentage (%) of total related substances derived from besylate or hydrochlorothiazide.
As shown in Table 2, in Examples A1, B2, and C3, the increase in related substances derived from Compound A and amlodipine besylate was significantly suppressed as compared to Reference Examples A1, B2, and C3. It was.

[Test Example 3]
In a sealed condition where the tablets obtained in Examples A1, B2, and C3 and Reference Examples A1, B2, and C3 were put in a petri dish and wrapped, a light stability tester (LTL-200A5-15WCD, Nagano Science Co., Ltd.) was used. A total of 1.2 million Lux · h was applied directly over 100 days. The storage stability was evaluated by measuring the amount of related substances derived from Compound A, amlodipine besylate and hydrochlorothiazide by the analytical method shown in Test Example 1.
Table 3 shows the results. The values in the table are compound A, amlodipine when the content of compound A, amlodipine besylate or hydrochlorothiazide (compound A: 20 mg / amlodipine besylate: 6.93 mg / hydrochlorothiazide: 12.5 mg) is taken as 100%. It shows the percentage (%) of total related substances derived from besylate or hydrochlorothiazide.
As shown in Table 3, Examples A1, B2, and C3 significantly reduced the increase in analogs derived from Compound A, amlodipine besylate and hydrochlorothiazide compared to Reference Examples A1, B2, and C3. It was done.

  The coated preparation of the present invention is useful as a prophylactic or therapeutic agent for hypertension excellent in storage stability.

Claims (11)

2-Ethoxy-1-{[2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole- A first component comprising 7-carboxylic acid or a salt thereof and polyethylene glycol;
A coated preparation comprising a core containing a second component containing a diuretic and a third component containing a calcium antagonist, and a coating layer.   The coated preparation according to claim 1, wherein the coating layer contains titanium oxide.   The coated preparation according to claim 1, wherein the coating layer contains iron oxide.   The coated preparation according to claim 1, wherein the coating layer contains talc.   The coated preparation according to claim 1, wherein the coating layer comprises 0 to 20% polyethylene glycol in the coating layer.   The coated preparation according to claim 1, wherein the core is a single core composed of a first component, a second component and a third component.   The coated preparation according to claim 1, wherein the core has a first part composed of a first component and a second part composed of a second component and a third component.   The coated preparation according to claim 1, wherein the coating layer comprises iron oxide, titanium oxide, and talc.   The coated preparation according to claim 1, wherein the diuretic is hydrochlorothiazide.   The coated preparation according to claim 1, wherein the calcium antagonist is amlodipine or a salt thereof. 2-Ethoxy-1-{[2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole- A first component comprising 7-carboxylic acid or a salt thereof and polyethylene glycol;
The manufacturing method of a coating formulation including the process of coat | covering the core containing the 3rd component containing the 2nd component and calcium antagonist containing a diuretic agent with a coating layer.