WO2013100112A1 - Solid pharmaceutical composition containing compound having angiotensin ii antagonistic activity - Google Patents

Solid pharmaceutical composition containing compound having angiotensin ii antagonistic activity Download PDF

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Publication number
WO2013100112A1
WO2013100112A1 PCT/JP2012/084001 JP2012084001W WO2013100112A1 WO 2013100112 A1 WO2013100112 A1 WO 2013100112A1 JP 2012084001 W JP2012084001 W JP 2012084001W WO 2013100112 A1 WO2013100112 A1 WO 2013100112A1
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WIPO (PCT)
Prior art keywords
magnesium
calcium
hydrate
pharmaceutical composition
solid pharmaceutical
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PCT/JP2012/084001
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French (fr)
Japanese (ja)
Inventor
智治 谷野
宏史 更田
友里 槌谷
隆信 岩城
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ニプロ株式会社
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Priority to JP2013551847A priority Critical patent/JP6081376B2/en
Publication of WO2013100112A1 publication Critical patent/WO2013100112A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a solid pharmaceutical composition containing a compound having an angiotensin II antagonistic action.
  • Valsartan which is one of the compounds having an angiotensin II antagonism used as a therapeutic agent for hypertension, is sold as “Diovan (registered trademark) tablet” (Non-patent Document 1).
  • Patent Document 1 describes that the content of valsartan in the preparation is increased, and if necessary, hydrochlorothiazide is added to the preparation.
  • An object of the present invention is to provide a solid pharmaceutical composition containing a compound having an angiotensin II antagonistic action and having excellent stability.
  • the present inventors have formulated a solid pharmaceutical composition by blending an alkaline earth metal salt and / or a hydrate thereof with a solid pharmaceutical composition containing a compound having an angiotensin II antagonistic action.
  • the present inventors have found that the stability of a product, particularly moisture resistance, can be improved, and the present invention has been completed.
  • the present invention is a solid pharmaceutical composition containing a compound having an angiotensin II antagonistic activity and an alkaline earth metal salt and / or a hydrate thereof.
  • the compound having angiotensin II antagonism is a group consisting of losartan, eprosartan, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan, tasosartan, azilsartan, and salts or esters thereof At least one compound selected from the group consisting of:
  • the content of the compound having angiotensin II antagonism is 30% by mass or more based on the mass of the composition.
  • the alkaline earth metal is at least one metal selected from the group consisting of calcium, strontium, barium, radium, magnesium, and beryllium.
  • the alkaline earth metal salt and / or hydrate thereof is calcium chloride hydrate, calcium citrate, calcium gluconate hydrate, calcium glycerophosphate, calcium carbonate, precipitated calcium carbonate, calcium lactate.
  • Hydrate anhydrous calcium hydrogen phosphate, calcium monohydrogen phosphate, calcium monohydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, magnesium L-aspartate, magnesium chloride, dried magnesium sulfate, magnesium gluconate ,
  • Magnesium silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, magnesium alumina hydroxide, magnesium sulfate hydrate, magnesium metasilicate aluminate, and magnesium carbonate, and combinations thereof Is at least one compound selected.
  • the content of the alkaline earth metal salt and / or hydrate thereof is 2% by mass to 10% by mass based on the mass of the composition.
  • a solid pharmaceutical composition containing a compound having an angiotensin II antagonistic action and having excellent stability can be provided.
  • the solid pharmaceutical composition of the present invention contains a compound having an angiotensin II antagonism and an alkaline earth metal salt and / or a hydrate thereof.
  • the compound having an angiotensin II antagonistic action is not particularly limited, and examples thereof include losartan, eprosartan, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan, tasosartan, azilsartan, and salts or esters thereof, and These combinations are mentioned.
  • the content of the compound having an angiotensin II antagonistic action in the solid pharmaceutical composition of the present invention is not particularly limited, but is preferably 30% by mass or more, more preferably 30% by mass based on the mass of the composition. It is 70 mass% or less.
  • alkaline earth metal means calcium, strontium, barium, radium, magnesium, or beryllium.
  • the alkaline earth metal salt and / or hydrate thereof of the present invention is not particularly limited, and examples thereof include calcium chloride hydrate, calcium citrate, calcium gluconate hydrate, calcium glycerophosphate, calcium carbonate, and precipitated carbonic acid.
  • precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium carbonate, magnesium oxide, or a combination thereof are preferable because they can be obtained at low cost.
  • the content of the alkaline earth metal salt and / or hydrate thereof in the solid pharmaceutical composition of the present invention is not particularly limited, but is preferably 2% by mass to 10% by mass based on the mass of the composition, More preferably, the content is 3% by mass to 7% by mass.
  • the shape of the solid pharmaceutical composition of the present invention is not particularly limited, and examples thereof include tablets, capsules, pills, troches, granules, and powders. A tablet is preferred.
  • the solid pharmaceutical composition of the present invention includes other excipients, disintegrants, binders, fluidizers, lubricants, colorants, solubilizers, sweeteners, fragrances, foaming agents, surfactants, preservatives. And additives such as a pH adjusting agent and a coating agent.
  • the excipient is not particularly limited, and examples thereof include crystalline cellulose, low-substituted hydroxypropyl cellulose, starch, corn starch, saccharides (such as glucose, fructose, lactose, sucrose, reduced maltose, trehalose), and sugar alcohol (D -Mannitol, erythritol, sorbitol, xylitol, maltitol, lactitol, etc.), and combinations thereof.
  • saccharides such as glucose, fructose, lactose, sucrose, reduced maltose, trehalose
  • sugar alcohol D -Mannitol, erythritol, sorbitol, xylitol, maltitol, lactitol, etc.
  • the disintegrant is not particularly limited, and for example, crospovidone, sodium carboxy starch, sodium carboxymethyl starch, starch, partially pregelatinized starch, corn starch, lactose, calcium carbonate, precipitated calcium carbonate, calcium citrate, light anhydrous silicic acid Synthetic aluminum silicate crystalline cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethylcellulose calcium, carmellose, and hydroxypropyl starch, and combinations thereof.
  • the binder is not particularly limited, and examples thereof include gelatin, agar, alginic acid, sodium alginate, dextrin, chitansan gum, gum arabic powder, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, partially saponified polyvinyl alcohol, methylcellulose, Examples include pullulan, partially pregelatinized starch, and saccharides, and combinations thereof.
  • the fluidizing agent examples include silicates such as calcium silicate, silicic anhydride such as light anhydrous silicic acid, hydrated silicon dioxide, talc, and combinations thereof.
  • the lubricant is not particularly limited, for example, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, polyethylene glycol, stearic acid, light anhydrous silicic acid, hydrogenated rapeseed oil, hydrogenated castor oil, glycerin fatty acid ester, Examples include sodium stearyl fumarate, sodium benzoate, L-leucine, and L-valine, and combinations thereof.
  • the colorant is not particularly limited, and examples thereof include ferric oxide, yellow ferric oxide, edible red No. 2, edible red No. 3, edible yellow No. 4, and edible yellow No. 5, and combinations thereof.
  • the solubilizing agent is not particularly limited, and examples thereof include magnesium oxide, calcium oxide, sodium citrate, magnesium chloride, sodium carbonate, sodium bicarbonate, and combinations thereof.
  • the sweetener is not particularly limited, and examples thereof include aspartame, sodium saccharin, dipotassium glycyrrhizin, stevia, and thaumatin, and combinations thereof.
  • the fragrance is not particularly limited, and examples thereof include mint, lemon, orange, and combinations thereof.
  • the foaming agent is not particularly limited, and examples thereof include tartrate, citrate, bicarbonate, and combinations thereof.
  • the surfactant is not particularly limited, and examples thereof include anionic surfactants such as sodium alkyl sulfate, sucrose fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, and polyoxyethylene castor oil derivatives. Nonionic surfactants and the like can be mentioned.
  • the preservative is not particularly limited, and examples thereof include benzoic acid, paraoxybenzoic acid, and salts thereof.
  • the pH regulator is not particularly limited, and examples thereof include organic acids such as citric acid, tartaric acid, acetic acid and lactic acid, inorganic acids such as hydrochloric acid and phosphoric acid, and inorganic bases such as sodium hydrogen carbonate, sodium carbonate and sodium hydroxide. Can be mentioned.
  • the coating agent is not particularly limited, and examples thereof include hydroxypropyl methylcellulose (hypromellose), titanium oxide, polyethylene glycol (Macrogol 6000), and combinations thereof.
  • the content of the additive in the solid pharmaceutical composition of the present invention is appropriately set according to the purpose of blending the additive.
  • the method for producing the solid pharmaceutical composition of the present invention is not particularly limited, and for example, the steps included in the method for producing a solid pharmaceutical preparation usually used by those skilled in the art can be used.
  • granulation step for example, granulation by a wet granulation method or a dry granulation method can be employed.
  • a solid pharmaceutical composition containing a compound having an angiotensin II antagonism was sometimes produced by a dry granulation method, but the method for producing a solid pharmaceutical composition of the present invention is limited to the dry granulation method.
  • a wet granulation method can be selected. The wet granulation method is not particularly limited.
  • a granulating means such as a fluidized bed granulator / dryer, a stirring granulator, a cylindrical extrusion granulator, a rolling fluidized bed granulating / coating machine, or a spray dryer is used.
  • Granulation can be employed. It does not specifically limit as a dry granulation method,
  • the tableting process that can be used in the present invention is not particularly limited.
  • a tableting mortar, a tableting upper punch and a lower punch, a hydraulic hand press machine, a single-shot tableting machine, a rotary type Tableting using a tableting means such as a tableting machine may be employed.
  • Tableting pressure is not particularly limited, for example, in the range of 2kN / cm 2 ⁇ 7kN / cm 2.
  • the coating process that can be used in the present invention is not particularly limited.
  • a coating method in which a coating agent is dissolved or dispersed in a solvent such as water to prepare a coating solution, and the coating solution is sprayed onto the main agent particles a film Coating using a method such as a coating machine, a pan coating method, a fluid coating method, and a rolling coating method may be employed.
  • the solid pharmaceutical composition of the present invention is granulated by mixing, for example, an angiotensin II antagonistic compound, an alkaline earth metal salt and / or hydrate thereof, an excipient, a disintegrant and a binder. It is manufactured by adding and mixing a fluidizing agent, lubricant, if necessary, disintegrating agent to tablets, and coating the resulting uncoated tablet with a coating agent and, if necessary, a coloring agent. .
  • the solid pharmaceutical composition of the present invention can be produced, for example, as a tablet.
  • Example 1 Tablets containing valsartan were produced according to the formulation described in Table 1 below.
  • Valsartan (Patent Document 1) 800 g, magnesium carbonate 100 g, low-substituted hydroxypropylcellulose 770 g, crystalline cellulose 100 g, light anhydrous silicic acid 100 g, and magnesium stearate 30 g were mixed in a container-rotating mixer (S-3 manufactured by Tsutsui Rika Kikai Co., Ltd.) The mixture was mixed and the mixture was consolidated using a roller compactor (TF-MINI manufactured by Freund Sangyo Co., Ltd.) at a compaction force of 60 kg / cm 2 and a roller speed of 4 rpm.
  • TF-MINI manufactured by Freund Sangyo Co., Ltd.
  • the compacted mixed compact is passed through a granulator (P-02S, manufactured by Dalton Co., Ltd.) to form granules (dry granulation), low-substituted hydroxypropylcellulose 50 g, light anhydrous silicic acid 10 g, talc 20 g and 20 g of magnesium stearate was added and mixed, and the mixture was put into a tableting machine (VIRGO manufactured by Kikusui Seisakusho Co., Ltd.), and a tablet weight of 200 mg at a tableting pressure of 7 kN / cm 2 using a 8.5 mm diameter punch. Tableting was performed to obtain an uncoated tablet (core tablet part).
  • P-02S manufactured by Dalton Co., Ltd.
  • this uncoated tablet was put into a film coating machine (HCT-48N manufactured by Freund Sangyo Co., Ltd.), and a solution obtained by dissolving 128 g of hydroxypropylmethylcellulose, 16 g of polyethylene glycol and 16 g of titanium oxide in 1600 g of purified water was 8 mg per tablet. Film coating was performed by spraying the uncoated tablets so that the solid content was coated, and tablets were obtained.
  • HCT-48N manufactured by Freund Sangyo Co., Ltd.
  • Example 2 Tablets containing valsartan were produced according to the formulation described in Table 2 below. Production was carried out in the same manner as in Example 1 except that the magnesium carbonate in Example 1 was replaced with precipitated calcium carbonate.
  • Example 3 Tablets containing valsartan were produced according to the formulation described in Table 3 below.
  • 200 g of Valsartan (Patent Document 1), 25 g of magnesium carbonate, 210 g of low-substituted hydroxypropyl cellulose and 25 g of crystalline cellulose are put into a stirring granulator (VG-05 manufactured by Paulec Co., Ltd.) and mixed, and 15 g of hydroxypropyl cellulose is further added.
  • Wet granulation was performed by adding a solution dissolved in purified water.
  • this uncoated tablet is put into a film coating machine (HCT-48N manufactured by Freund Sangyo Co., Ltd.), and a solution obtained by dissolving 32 g of hydroxypropylmethylcellulose, 4 g of polyethylene glycol and 4 g of titanium oxide in 400 g of purified water is sprayed on the uncoated tablet. Film coating was performed to obtain tablets.
  • HCT-48N manufactured by Freund Sangyo Co., Ltd.
  • Example 4 Tablets containing valsartan were prepared according to the formulation described in Table 4 below. Production was carried out in the same manner as in Example 3 except that magnesium carbonate in Example 3 was replaced with magnesium oxide.
  • Valsartan (Patent Document 1) 800 g, low substituted hydroxypropylcellulose 870 g, crystalline cellulose 100 g, light anhydrous silicic acid 100 g, and magnesium stearate 30 g are charged into a rotating container mixer (S-3, manufactured by Tsutsui Rika Kikai Co., Ltd.) The mixture was consolidated using a roller compactor (TF-MINI manufactured by Freund Sangyo Co., Ltd.) at a compaction force of 60 kg / cm 2 and a roller speed of 4 rpm.
  • TF-MINI manufactured by Freund Sangyo Co., Ltd.
  • the compacted mixed compact is passed through a granulator (P-02S, manufactured by Dalton Co., Ltd.) to form granules (dry granulation), low-substituted hydroxypropylcellulose 50 g, light anhydrous silicic acid 10 g, talc 20 g and 20 g of magnesium stearate was added and mixed, and the mixture was put into a tableting machine (VIRGO manufactured by Kikusui Seisakusho Co., Ltd.), and a tablet weight of 200 mg at a tableting pressure of 7 kN / cm 2 using a 8.5 mm diameter punch. Tableting was performed to obtain an uncoated tablet (core tablet part).
  • P-02S manufactured by Dalton Co., Ltd.
  • this uncoated tablet was put into a film coating machine (HCT-48N manufactured by Freund Sangyo Co., Ltd.), and a solution obtained by dissolving 128 g of hydroxypropylmethylcellulose, 16 g of polyethylene glycol and 16 g of titanium oxide in 1600 g of purified water was 8 mg per tablet. Film coating was performed by spraying the uncoated tablets so that the solid content was coated, and tablets were obtained.
  • HCT-48N manufactured by Freund Sangyo Co., Ltd.
  • Example 1 to 4 and Comparative Examples 1 and 2 were stored for 3 days under conditions of 60 ° C., 75% humidity, and darkness, respectively, with aluminum packaging or without packaging.
  • the tablets after storage were subjected to a dissolution test for valsartan. Each test was performed three times. The results are shown in Table 7.
  • the tablets after storage in Examples 1 to 4 showed a very stable result with little decrease in dissolution of valsartan in either aluminum packaging or non-packaging.
  • an alkaline earth metal salt and / or a hydrate thereof added to a tablet containing valsartan, the stability of the tablet, particularly moisture resistance, could be increased.
  • a solid pharmaceutical composition containing a compound having an angiotensin II antagonistic action and having excellent stability can be provided.

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Abstract

A solid pharmaceutical composition according to the present invention comprises a compound having an angiotensin II antagonistic activity and an alkali earth metal salt and/or a hydrate thereof. The solid pharmaceutical composition according to the present invention has excellent stability, particularly excellent moisture resistance.

Description

アンギオテンシンＩＩ拮抗作用を有する化合物を含有する固形医薬組成物Solid pharmaceutical composition containing a compound having angiotensin II antagonistic activity
　本発明は、アンギオテンシンＩＩ拮抗作用を有する化合物を含有する固形医薬組成物に関する。 The present invention relates to a solid pharmaceutical composition containing a compound having an angiotensin II antagonistic action.
　高血圧症治療薬として用いられるアンギオテンシンＩＩ拮抗作用を有する化合物の１つであるバルサルタンは、「ディオバン（登録商標）錠」（非特許文献１）として販売されている。 Valsartan, which is one of the compounds having an angiotensin II antagonism used as a therapeutic agent for hypertension, is sold as “Diovan (registered trademark) tablet” (Non-patent Document 1).
　特許文献１には、製剤中のバルサルタンの含有量を高めること、必要に応じてヒドロクロロチアジドを製剤に配合することが記載されている。 Patent Document 1 describes that the content of valsartan in the preparation is increased, and if necessary, hydrochlorothiazide is added to the preparation.
特開２００７－２３８６３７号公報JP 2007-238637 A
　本発明は、アンギオテンシンＩＩ拮抗作用を有する化合物を含有する固形医薬組成物であって、安定性に優れた固形医薬組成物を提供することを目的とする。 An object of the present invention is to provide a solid pharmaceutical composition containing a compound having an angiotensin II antagonistic action and having excellent stability.
　本発明者らは、上記課題を解決するためにアンギオテンシンＩＩ拮抗作用を有する化合物を含有する固形医薬組成物にアルカリ土類金属塩および／またはその水和物を配合することによって、該固形医薬組成物の安定性、特に耐湿性を高めることができることを見出し、本発明を完成させた。 In order to solve the above-mentioned problems, the present inventors have formulated a solid pharmaceutical composition by blending an alkaline earth metal salt and / or a hydrate thereof with a solid pharmaceutical composition containing a compound having an angiotensin II antagonistic action. The present inventors have found that the stability of a product, particularly moisture resistance, can be improved, and the present invention has been completed.
　本発明は、アンギオテンシンＩＩ拮抗作用を有する化合物およびアルカリ土類金属塩および／またはその水和物を含有する固形医薬組成物である。 The present invention is a solid pharmaceutical composition containing a compound having an angiotensin II antagonistic activity and an alkaline earth metal salt and / or a hydrate thereof.
　１つの実施態様では、上記アンギオテンシンＩＩ拮抗作用を有する化合物は、ロサルタン、エプロサルタン、カンデサルタンシレキセチル、カンデサルタン、バルサルタン、テルミサルタン、イルベサルタン、オルメサルタン、タソサルタン、アジルサルタン、およびこれらの塩もしくはエステルからなる群から選択される少なくとも１種の化合物である。 In one embodiment, the compound having angiotensin II antagonism is a group consisting of losartan, eprosartan, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan, tasosartan, azilsartan, and salts or esters thereof At least one compound selected from the group consisting of:
　１つの実施態様では、上記アンギオテンシンＩＩ拮抗作用を有する化合物の含有量は上記組成物の質量を基準として３０質量％以上である。 In one embodiment, the content of the compound having angiotensin II antagonism is 30% by mass or more based on the mass of the composition.
　１つの実施態様では、上記アルカリ土類金属は、カルシウム、ストロンチウム、バリウム、ラジウム、マグネシウム、およびベリリウムからなる群から選択される少なくとも１種の金属である。 In one embodiment, the alkaline earth metal is at least one metal selected from the group consisting of calcium, strontium, barium, radium, magnesium, and beryllium.
　１つの実施態様では、上記アルカリ土類金属塩および／またはその水和物は、塩化カルシウム水和物、クエン酸カルシウム、グルコン酸カルシウム水和物、グリセロリン酸カルシウム、炭酸カルシウム、沈降炭酸カルシウム、乳酸カルシウム水和物、無水リン酸水素カルシウム、リン酸一水素カルシウム、リン酸一水素カルシウム水和物、リン酸二水素カルシウム水和物、Ｌ－アスパラギン酸マグネシウム、塩化マグネシウム、乾燥硫酸マグネシウム、グルコン酸マグネシウム、ケイ酸マグネシウム、ケイ酸マグネシウムアルミニウム、酸化マグネシウム、水酸化マグネシウム、水酸化アルミナマグネシウム、硫酸マグネシウム水和物、メタケイ酸アルミン酸マグネシウム、および炭酸マグネシウム、ならびにそれらの組合せからなる群から選択される少なくとも１種の化合物である。 In one embodiment, the alkaline earth metal salt and / or hydrate thereof is calcium chloride hydrate, calcium citrate, calcium gluconate hydrate, calcium glycerophosphate, calcium carbonate, precipitated calcium carbonate, calcium lactate. Hydrate, anhydrous calcium hydrogen phosphate, calcium monohydrogen phosphate, calcium monohydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, magnesium L-aspartate, magnesium chloride, dried magnesium sulfate, magnesium gluconate , Magnesium silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, magnesium alumina hydroxide, magnesium sulfate hydrate, magnesium metasilicate aluminate, and magnesium carbonate, and combinations thereof Is at least one compound selected.
　１つの実施態様では、上記アルカリ土類金属塩および／またはその水和物の含有量は、前記組成物の質量を基準として２質量％から１０質量％である。 In one embodiment, the content of the alkaline earth metal salt and / or hydrate thereof is 2% by mass to 10% by mass based on the mass of the composition.
　本発明によれば、アンギオテンシンＩＩ拮抗作用を有する化合物を含有する固形医薬組成物であって、安定性に優れた固形医薬組成物を提供することができる。 According to the present invention, a solid pharmaceutical composition containing a compound having an angiotensin II antagonistic action and having excellent stability can be provided.
　本発明の固形医薬組成物は、アンギオテンシンＩＩ拮抗作用を有する化合物およびアルカリ土類金属塩および／またはその水和物を含有する。 The solid pharmaceutical composition of the present invention contains a compound having an angiotensin II antagonism and an alkaline earth metal salt and / or a hydrate thereof.
　アンギオテンシンＩＩ拮抗作用を有する化合物としては、特に限定されないが、例えば、ロサルタン、エプロサルタン、カンデサルタンシレキセチル、カンデサルタン、バルサルタン、テルミサルタン、イルベサルタン、オルメサルタン、タソサルタン、アジルサルタン、およびこれらの塩もしくはエステル、ならびにこれらの組合せが挙げられる。 The compound having an angiotensin II antagonistic action is not particularly limited, and examples thereof include losartan, eprosartan, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan, tasosartan, azilsartan, and salts or esters thereof, and These combinations are mentioned.
　本発明の固形医薬組成物中のアンギオテンシンＩＩ拮抗作用を有する化合物の含有量は、特に限定されないが、当該組成物の質量を基準として、好ましくは３０質量％以上であり、より好ましくは３０質量％以上７０質量％以下である。 The content of the compound having an angiotensin II antagonistic action in the solid pharmaceutical composition of the present invention is not particularly limited, but is preferably 30% by mass or more, more preferably 30% by mass based on the mass of the composition. It is 70 mass% or less.
　本発明において、アルカリ土類金属とは、カルシウム、ストロンチウム、バリウム、ラジウム、マグネシウム、またはベリリウムをいう。 In the present invention, alkaline earth metal means calcium, strontium, barium, radium, magnesium, or beryllium.
　本発明のアルカリ土類金属塩および／またはその水和物としては、特に限定されず、例えば、塩化カルシウム水和物、クエン酸カルシウム、グルコン酸カルシウム水和物、グリセロリン酸カルシウム、炭酸カルシウム、沈降炭酸カルシウム、乳酸カルシウム水和物、無水リン酸水素カルシウム、リン酸一水素カルシウム、リン酸一水素カルシウム水和物、リン酸二水素カルシウム水和物、Ｌ－アスパラギン酸マグネシウム、塩化マグネシウム、乾燥硫酸マグネシウム、グルコン酸マグネシウム、ケイ酸マグネシウム、ケイ酸マグネシウムアルミニウム、酸化マグネシウム、水酸化マグネシウム、水酸化アルミナマグネシウム、硫酸マグネシウム水和物、メタケイ酸アルミン酸マグネシウム、および炭酸マグネシウム、ならびにそれらの組合せが挙げられる。好ましくは、沈降炭酸カルシウム、無水リン酸水素カルシウム、炭酸マグネシウム、または酸化マグネシウム、あるいはこれらの組合せである。これらは、安価に入手できるため好ましい。 The alkaline earth metal salt and / or hydrate thereof of the present invention is not particularly limited, and examples thereof include calcium chloride hydrate, calcium citrate, calcium gluconate hydrate, calcium glycerophosphate, calcium carbonate, and precipitated carbonic acid. Calcium, calcium lactate hydrate, anhydrous calcium hydrogen phosphate, calcium monohydrogen phosphate, calcium monohydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, magnesium L-aspartate, magnesium chloride, dry magnesium sulfate , Magnesium gluconate, magnesium silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, magnesium magnesium hydroxide, magnesium sulfate hydrate, magnesium magnesium metasilicate, and magnesium carbonate, and combinations thereof And the like. Preferably, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium carbonate, magnesium oxide, or a combination thereof. These are preferable because they can be obtained at low cost.
　本発明の固形医薬組成物中のアルカリ土類金属塩および／またはその水和物の含有量は、特に限定されないが、当該組成物の質量を基準として、好ましくは２質量％～１０質量％、より好ましくは３質量％～７質量％である。 The content of the alkaline earth metal salt and / or hydrate thereof in the solid pharmaceutical composition of the present invention is not particularly limited, but is preferably 2% by mass to 10% by mass based on the mass of the composition, More preferably, the content is 3% by mass to 7% by mass.
　本発明の固形医薬組成物の形状としては、特に限定されず、例えば、錠剤、カプセル剤、丸剤、トローチ剤、顆粒剤、および散剤が挙げられる。好ましくは錠剤である。 The shape of the solid pharmaceutical composition of the present invention is not particularly limited, and examples thereof include tablets, capsules, pills, troches, granules, and powders. A tablet is preferred.
　本発明の固形医薬組成物は、ほかに賦形剤、崩壊剤、結合剤、流動化剤、滑沢剤、着色剤、溶解補助剤、甘味料、香料、発泡剤、界面活性剤、防腐剤、ｐＨ調節剤、コーティング剤などの添加剤を含有し得る。 The solid pharmaceutical composition of the present invention includes other excipients, disintegrants, binders, fluidizers, lubricants, colorants, solubilizers, sweeteners, fragrances, foaming agents, surfactants, preservatives. And additives such as a pH adjusting agent and a coating agent.
　賦形剤としては、特に限定されず、例えば、結晶セルロース、低置換度ヒドロキシピロピルセルロース、澱粉、コーンスターチ、糖類（ブドウ糖、果糖、乳糖、白糖、還元麦芽糖、トレハロースなど）、および糖アルコール（Ｄ－マンニトール、エリスリトール、ソルビトール、キシリトール、マルチトール、ラクチトールなど）、ならびにそれらの組合せが挙げられる。 The excipient is not particularly limited, and examples thereof include crystalline cellulose, low-substituted hydroxypropyl cellulose, starch, corn starch, saccharides (such as glucose, fructose, lactose, sucrose, reduced maltose, trehalose), and sugar alcohol (D -Mannitol, erythritol, sorbitol, xylitol, maltitol, lactitol, etc.), and combinations thereof.
　崩壊剤としては、特に限定されず、例えば、クロスポビドン、カルボキシスターチナトリウム、カルボキシメチルスターチナトリウム、澱粉、部分α化澱粉、コーンスターチ、乳糖、炭酸カルシウム、沈降炭酸カルシウム、クエン酸カルシウム、軽質無水ケイ酸、合成ケイ酸アルミニウム結晶セルロース、低置換度ヒドロキシピロピルセルロース、クロスカルメロースナトリウム、カルボキシメチルセルロースカルシウム、カルメロース、およびヒドロキシプロピルスターチ、ならびにそれらの組合せが挙げられる。 The disintegrant is not particularly limited, and for example, crospovidone, sodium carboxy starch, sodium carboxymethyl starch, starch, partially pregelatinized starch, corn starch, lactose, calcium carbonate, precipitated calcium carbonate, calcium citrate, light anhydrous silicic acid Synthetic aluminum silicate crystalline cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethylcellulose calcium, carmellose, and hydroxypropyl starch, and combinations thereof.
　結合剤としては、特に限定されず、例えば、ゼラチン、寒天、アルギン酸、アルギン酸ナトリウム、デキストリン、キタンサンガム、アラビアゴム末、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、部分けん化ポリビニルアルコール、メチルセルロース、プルラン、部分α化澱粉、および糖類、ならびにそれらの組合せが挙げられる。 The binder is not particularly limited, and examples thereof include gelatin, agar, alginic acid, sodium alginate, dextrin, chitansan gum, gum arabic powder, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, partially saponified polyvinyl alcohol, methylcellulose, Examples include pullulan, partially pregelatinized starch, and saccharides, and combinations thereof.
　流動化剤としては、例えば、ケイ酸カルシウムなどのケイ酸塩、軽質無水ケイ酸などの無水ケイ酸、水和二酸化ケイ素、およびタルク、ならびにそれらの組合せが挙げられる。 Examples of the fluidizing agent include silicates such as calcium silicate, silicic anhydride such as light anhydrous silicic acid, hydrated silicon dioxide, talc, and combinations thereof.
　滑沢剤としては、特に限定されず、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、ショ糖脂肪酸エステル、ポリエチレングリコール、ステアリン酸、軽質無水ケイ酸、硬化ナタネ油、硬化ヒマシ油、グリセリン脂肪酸エステル、フマル酸ステアリルナトリウム、安息香酸ナトリウム、Ｌ-ロイシン、およびＬ-バリン、ならびにそれらの組合せが挙げられる。 The lubricant is not particularly limited, for example, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, polyethylene glycol, stearic acid, light anhydrous silicic acid, hydrogenated rapeseed oil, hydrogenated castor oil, glycerin fatty acid ester, Examples include sodium stearyl fumarate, sodium benzoate, L-leucine, and L-valine, and combinations thereof.
　着色剤としては、特に限定されず、例えば、三二酸化鉄、黄色三二酸化鉄、食用赤色２号、食用赤色３号、食用黄色４号、および食用黄色５号、ならびにそれらの組合せが挙げられる。 The colorant is not particularly limited, and examples thereof include ferric oxide, yellow ferric oxide, edible red No. 2, edible red No. 3, edible yellow No. 4, and edible yellow No. 5, and combinations thereof.
　溶解補助剤としては、特に限定されず、例えば、酸化マグネシウム、酸化カルシウム、クエン酸ナトリウム、塩化マグネシウム、炭酸ナトリウム、および炭酸水素ナトリウム、ならびにそれらの組合せが挙げられる。 The solubilizing agent is not particularly limited, and examples thereof include magnesium oxide, calcium oxide, sodium citrate, magnesium chloride, sodium carbonate, sodium bicarbonate, and combinations thereof.
　甘味料としては、特に限定されず、例えば、アスパルテーム、サッカリンナトリウム、グリチルリチン二カリウム、ステビア、およびソーマチン、ならびにそれらの組合せが挙げられる。 The sweetener is not particularly limited, and examples thereof include aspartame, sodium saccharin, dipotassium glycyrrhizin, stevia, and thaumatin, and combinations thereof.
　香料としては、特に限定されず、例えば、ミント、レモン、およびオレンジ、ならびにそれらの組合せが挙げられる。 The fragrance is not particularly limited, and examples thereof include mint, lemon, orange, and combinations thereof.
　発泡剤としては、特に限定されず、例えば、酒石酸塩、クエン酸塩、および重炭酸塩、ならびにそれらの組合せが挙げられる。 The foaming agent is not particularly limited, and examples thereof include tartrate, citrate, bicarbonate, and combinations thereof.
　界面活性剤としては、特に限定されず、例えば、アルキル硫酸ナトリウムなどのアニオン系界面活性剤、ショ糖脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステルおよびポリオキシエチレンヒマシ油誘導体などの非イオン系界面活性剤などが挙げられる。 The surfactant is not particularly limited, and examples thereof include anionic surfactants such as sodium alkyl sulfate, sucrose fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, and polyoxyethylene castor oil derivatives. Nonionic surfactants and the like can be mentioned.
　防腐剤としては、特に限定されず、例えば、安息香酸、パラオキシ安息香酸、およびこれらの塩が挙げられる。 The preservative is not particularly limited, and examples thereof include benzoic acid, paraoxybenzoic acid, and salts thereof.
　ｐＨ調節剤としては、特に限定されず、例えば、クエン酸、酒石酸、酢酸、乳酸などの有機酸、塩酸、リン酸などの無機酸、炭酸水素ナトリウム、炭酸ナトリウム、水酸化ナトリウムなどの無機塩基が挙げられる。 The pH regulator is not particularly limited, and examples thereof include organic acids such as citric acid, tartaric acid, acetic acid and lactic acid, inorganic acids such as hydrochloric acid and phosphoric acid, and inorganic bases such as sodium hydrogen carbonate, sodium carbonate and sodium hydroxide. Can be mentioned.
　コーティング剤としては、特に限定されず、ヒドロキシプロピルメチルセルロース（ヒプロメロース）、酸化チタン、およびポリエチレングリコール（マクロゴール６０００）、ならびにそれらの組合せが挙げられる。 The coating agent is not particularly limited, and examples thereof include hydroxypropyl methylcellulose (hypromellose), titanium oxide, polyethylene glycol (Macrogol 6000), and combinations thereof.
　本発明の固形医薬組成物中の添加剤の含有量は、添加剤の配合目的に応じて適宜設定される。 The content of the additive in the solid pharmaceutical composition of the present invention is appropriately set according to the purpose of blending the additive.
　本発明の固形医薬組成物の製造方法は、特に限定されず、例えば、当業者が通常用いる固形医薬製剤の製造方法に含まれる工程が使用され得、造粒工程、打錠工程、またはコーティング工程などの工程が挙げられる。 The method for producing the solid pharmaceutical composition of the present invention is not particularly limited, and for example, the steps included in the method for producing a solid pharmaceutical preparation usually used by those skilled in the art can be used. The granulation step, the tableting step, or the coating step And the like.
　本発明に用いられ得る造粒工程としては、例えば、湿式造粒法または乾式造粒法による造粒が採用され得る。従来、アンギオテンシンＩＩ拮抗作用を有する化合物を含有する固形医薬組成物は乾式造粒法により製造されることがあったが、本発明の固形医薬組成物の製造方法では、乾式造粒法に限定されず、湿式造粒法を選択することもできる。湿式造粒法としては、特に限定されず、例えば、流動層造粒乾燥機、攪拌造粒機、円筒押出造粒機、転動流動層造粒コーティング機、スプレードライヤーなどの造粒手段を用いた造粒が採用され得る。乾式造粒法としては、特に限定されず、例えば、ローラーコンパクターなどの造粒手段を用いた造粒が採用され得る。 As the granulation step that can be used in the present invention, for example, granulation by a wet granulation method or a dry granulation method can be employed. Conventionally, a solid pharmaceutical composition containing a compound having an angiotensin II antagonism was sometimes produced by a dry granulation method, but the method for producing a solid pharmaceutical composition of the present invention is limited to the dry granulation method. Alternatively, a wet granulation method can be selected. The wet granulation method is not particularly limited. For example, a granulating means such as a fluidized bed granulator / dryer, a stirring granulator, a cylindrical extrusion granulator, a rolling fluidized bed granulating / coating machine, or a spray dryer is used. Granulation can be employed. It does not specifically limit as a dry granulation method, For example, granulation using granulation means, such as a roller compactor, can be employ | adopted.
　本発明に用いられ得る打錠工程としては、特に限定されず、例えば、打錠用臼、打錠用上杵および下杵を用いて、油圧式ハンドプレス機、単発式打錠機、ロータリー式打錠機などの打錠手段を用いた打錠が採用され得る。打錠圧は、特に限定されず、例えば、２ｋＮ／ｃｍ２～７ｋＮ／ｃｍ２の範囲である。 The tableting process that can be used in the present invention is not particularly limited. For example, using a tableting mortar, a tableting upper punch and a lower punch, a hydraulic hand press machine, a single-shot tableting machine, a rotary type Tableting using a tableting means such as a tableting machine may be employed. Tableting pressure is not particularly limited, for example, in the range of 2kN / cm 2 ~ 7kN / cm 2.
　本発明に用いられ得るコーティング工程としては、特に限定されず、例えば、コーティング剤を水などの溶媒に溶解または分散させてコーティング液を調製し、コーティング液を主薬粒子にスプレーするスプレーコーティング法、フィルムコーティング機などを用いる方法、パンコーティング法、流動コーティング法、および転動コーティング法などの方法を用いたコーティングが採用され得る。 The coating process that can be used in the present invention is not particularly limited. For example, a coating method in which a coating agent is dissolved or dispersed in a solvent such as water to prepare a coating solution, and the coating solution is sprayed onto the main agent particles, a film Coating using a method such as a coating machine, a pan coating method, a fluid coating method, and a rolling coating method may be employed.
　本発明の固形医薬組成物は、例えばアンギオテンシンＩＩ拮抗作用を有する化合物、アルカリ土類金属塩および／またはその水和物、賦形剤、崩壊剤および結合剤を混合して造粒し、造粒物に流動化剤、滑沢剤、必要に応じて崩壊剤を添加・混合して打錠し、そして得られた素錠にコーティング剤、必要に応じて着色剤をコーティングすることによって製造される。 The solid pharmaceutical composition of the present invention is granulated by mixing, for example, an angiotensin II antagonistic compound, an alkaline earth metal salt and / or hydrate thereof, an excipient, a disintegrant and a binder. It is manufactured by adding and mixing a fluidizing agent, lubricant, if necessary, disintegrating agent to tablets, and coating the resulting uncoated tablet with a coating agent and, if necessary, a coloring agent. .
　上記のように本発明の固形医薬組成物は、例えば、錠剤として製造され得る。 As described above, the solid pharmaceutical composition of the present invention can be produced, for example, as a tablet.
　以下、実施例により本発明をより具体的に説明するが、本発明はこれらの実施例により限定されるものではない。 Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.
　（実施例１）
　バルサルタンを含有する錠剤を以下の表１に記載の処方により製造した。バルサルタン（特許文献１）８００ｇ、炭酸マグネシウム１００ｇ、低置換度ヒドロキシプロピルセルロース７７０ｇ、結晶セルロース１００ｇ、軽質無水ケイ酸１００ｇおよびステアリン酸マグネシウム３０ｇを容器回転形混合機（筒井理化学器械株式会社製Ｓ－３形）に投入して混合し、この混合物に対し、ローラーコンパクター（フロイント産業株式会社製ＴＦ－ＭＩＮＩ）を用いて、圧密力６０ｋｇ／ｃｍ２およびローラースピード４ｒｐｍにて圧密化を行った。圧密化された混合圧縮体を整粒機（株式会社ダルトン製Ｐ－０２Ｓ型）に通して顆粒状とし（乾式造粒）、低置換度ヒドロキシプロピルセルロース５０ｇ、軽質無水ケイ酸１０ｇ、タルク２０ｇおよびステアリン酸マグネシウム２０ｇを添加・混合し、この混合物を打錠機（株式会社菊水製作所製ＶＩＲＧＯ）に投入し、直径８．５ｍｍの杵を用いて打錠圧７ｋＮ／ｃｍ２にて１錠質量２００ｍｇとなるように打錠を行い、素錠（核錠部）を得た。次いで、この素錠をフィルムコーティング機（フロイント産業株式会社製ＨＣＴ－４８Ｎ）に投入し、ヒドロキシプロピルメチルセルロース１２８ｇ、ポリエチレングリコール１６ｇおよび酸化チタン１６ｇを精製水１６００ｇに溶解した液を、１錠あたり８ｍｇの固形分がコーティングされるように素錠に噴霧してフィルムコーティングを行い、錠剤を得た。 Example 1
Tablets containing valsartan were produced according to the formulation described in Table 1 below. Valsartan (Patent Document 1) 800 g, magnesium carbonate 100 g, low-substituted hydroxypropylcellulose 770 g, crystalline cellulose 100 g, light anhydrous silicic acid 100 g, and magnesium stearate 30 g were mixed in a container-rotating mixer (S-3 manufactured by Tsutsui Rika Kikai Co., Ltd.) The mixture was mixed and the mixture was consolidated using a roller compactor (TF-MINI manufactured by Freund Sangyo Co., Ltd.) at a compaction force of 60 kg / cm 2 and a roller speed of 4 rpm. The compacted mixed compact is passed through a granulator (P-02S, manufactured by Dalton Co., Ltd.) to form granules (dry granulation), low-substituted hydroxypropylcellulose 50 g, light anhydrous silicic acid 10 g, talc 20 g and 20 g of magnesium stearate was added and mixed, and the mixture was put into a tableting machine (VIRGO manufactured by Kikusui Seisakusho Co., Ltd.), and a tablet weight of 200 mg at a tableting pressure of 7 kN / cm 2 using a 8.5 mm diameter punch. Tableting was performed to obtain an uncoated tablet (core tablet part). Next, this uncoated tablet was put into a film coating machine (HCT-48N manufactured by Freund Sangyo Co., Ltd.), and a solution obtained by dissolving 128 g of hydroxypropylmethylcellulose, 16 g of polyethylene glycol and 16 g of titanium oxide in 1600 g of purified water was 8 mg per tablet. Film coating was performed by spraying the uncoated tablets so that the solid content was coated, and tablets were obtained.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　（実施例２）
　バルサルタンを含有する錠剤を以下の表２に記載の処方により製造した。実施例１の炭酸マグネシウムを沈降炭酸カルシウムに替えたこと以外は、実施例１と同様に製造した。 (Example 2)
Tablets containing valsartan were produced according to the formulation described in Table 2 below. Production was carried out in the same manner as in Example 1 except that the magnesium carbonate in Example 1 was replaced with precipitated calcium carbonate.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　（実施例３）
　バルサルタンを含有する錠剤を以下の表３に記載の処方により製造した。バルサルタン（特許文献１）２００ｇ、炭酸マグネシウム２５ｇ、低置換度ヒドロキシプロピルセルロース２１０ｇおよび結晶セルロース２５ｇを攪拌造粒機（株式会社パウレック製ＶＧ－０５）に投入して混合し、さらにヒドロキシプロピルセルロース１５ｇを精製水に溶解した液を添加して湿式造粒を行った。得られた造粒物に低置換度ヒドロキシプロピルセルロース１２．５ｇ、軽質無水ケイ酸２．５ｇ、タルク５ｇおよびステアリン酸マグネシウム５ｇを添加・混合し、この混合物を打錠機（株式会社菊水製作所製ＶＩＲＧＯ）に投入し、直径８．５ｍｍの杵を用いて打錠圧６ｋＮ／ｃｍ２にて打錠を行い、素錠（核錠部）を得た。次いで、この素錠をフィルムコーティング機（フロイント産業株式会社製ＨＣＴ－４８Ｎ）に投入し、ヒドロキシプロピルメチルセルロース３２ｇ、ポリエチレングリコール４ｇおよび酸化チタン４ｇを精製水４００ｇに溶解した液を素錠に噴霧してフィルムコーティングを行い、錠剤を得た。 (Example 3)
Tablets containing valsartan were produced according to the formulation described in Table 3 below. 200 g of Valsartan (Patent Document 1), 25 g of magnesium carbonate, 210 g of low-substituted hydroxypropyl cellulose and 25 g of crystalline cellulose are put into a stirring granulator (VG-05 manufactured by Paulec Co., Ltd.) and mixed, and 15 g of hydroxypropyl cellulose is further added. Wet granulation was performed by adding a solution dissolved in purified water. 12.5 g of low-substituted hydroxypropylcellulose, 2.5 g of light anhydrous silicic acid, 5 g of talc and 5 g of magnesium stearate were added to and mixed with the resulting granulated product, and this mixture was mixed with a tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.). VIRGO) and tableting was performed using a punch with a diameter of 8.5 mm at a tableting pressure of 6 kN / cm 2 to obtain an uncoated tablet (core tablet part). Next, this uncoated tablet is put into a film coating machine (HCT-48N manufactured by Freund Sangyo Co., Ltd.), and a solution obtained by dissolving 32 g of hydroxypropylmethylcellulose, 4 g of polyethylene glycol and 4 g of titanium oxide in 400 g of purified water is sprayed on the uncoated tablet. Film coating was performed to obtain tablets.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　（実施例４）
　バルサルタンを含有する錠剤を以下の表４に記載の処方により製造した。実施例３の炭酸マグネシウムを酸化マグネシウムに替えたこと以外は、実施例３と同様に製造した。 (Example 4)
Tablets containing valsartan were prepared according to the formulation described in Table 4 below. Production was carried out in the same manner as in Example 3 except that magnesium carbonate in Example 3 was replaced with magnesium oxide.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　（比較例１）
　バルサルタンを含有する錠剤を以下の表５に記載の処方により製造した。バルサルタン（特許文献１）８００ｇ、低置換度ヒドロキシプロピルセルロース８７０ｇ、結晶セルロース１００ｇ、軽質無水ケイ酸１００ｇおよびステアリン酸マグネシウム３０ｇを容器回転形混合機（筒井理化学器械株式会社製Ｓ－３形）に投入して混合し、この混合物に対し、ローラーコンパクター（フロイント産業株式会社製ＴＦ－ＭＩＮＩ）を用いて、圧密力６０ｋｇ／ｃｍ２およびローラースピード４ｒｐｍにて圧密化を行った。圧密化された混合圧縮体を整粒機（株式会社ダルトン製Ｐ－０２Ｓ型）に通して顆粒状とし（乾式造粒）、低置換度ヒドロキシプロピルセルロース５０ｇ、軽質無水ケイ酸１０ｇ、タルク２０ｇおよびステアリン酸マグネシウム２０ｇを添加・混合し、この混合物を打錠機（株式会社菊水製作所製ＶＩＲＧＯ）に投入し、直径８．５ｍｍの杵を用いて打錠圧７ｋＮ／ｃｍ２にて１錠質量２００ｍｇとなるように打錠を行い、素錠（核錠部）を得た。次いで、この素錠をフィルムコーティング機（フロイント産業株式会社製ＨＣＴ－４８Ｎ）に投入し、ヒドロキシプロピルメチルセルロース１２８ｇ、ポリエチレングリコール１６ｇおよび酸化チタン１６ｇを精製水１６００ｇに溶解した液を、１錠あたり８ｍｇの固形分がコーティングされるように素錠に噴霧してフィルムコーティングを行い、錠剤を得た。 (Comparative Example 1)
Tablets containing valsartan were prepared according to the formulation described in Table 5 below. Valsartan (Patent Document 1) 800 g, low substituted hydroxypropylcellulose 870 g, crystalline cellulose 100 g, light anhydrous silicic acid 100 g, and magnesium stearate 30 g are charged into a rotating container mixer (S-3, manufactured by Tsutsui Rika Kikai Co., Ltd.) The mixture was consolidated using a roller compactor (TF-MINI manufactured by Freund Sangyo Co., Ltd.) at a compaction force of 60 kg / cm 2 and a roller speed of 4 rpm. The compacted mixed compact is passed through a granulator (P-02S, manufactured by Dalton Co., Ltd.) to form granules (dry granulation), low-substituted hydroxypropylcellulose 50 g, light anhydrous silicic acid 10 g, talc 20 g and 20 g of magnesium stearate was added and mixed, and the mixture was put into a tableting machine (VIRGO manufactured by Kikusui Seisakusho Co., Ltd.), and a tablet weight of 200 mg at a tableting pressure of 7 kN / cm 2 using a 8.5 mm diameter punch. Tableting was performed to obtain an uncoated tablet (core tablet part). Next, this uncoated tablet was put into a film coating machine (HCT-48N manufactured by Freund Sangyo Co., Ltd.), and a solution obtained by dissolving 128 g of hydroxypropylmethylcellulose, 16 g of polyethylene glycol and 16 g of titanium oxide in 1600 g of purified water was 8 mg per tablet. Film coating was performed by spraying the uncoated tablets so that the solid content was coated, and tablets were obtained.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　（試験例：製剤の安定性評価　保存前後の溶出試験）
　実施例１～４および比較例１で得られた錠剤および「ディオバン（登録商標）錠８０ｍｇ」（ノバルティス社製）（比較例２）について、保存前後でバルサルタンの溶出試験を行った。試験液は９００ｍＬとし、パドル回転数５０ｒｐｍにて、３０分後の溶出率（％）を測定した。なお、「ディオバン（登録商標）錠８０ｍｇ」は、バルサルタンのほか、ヒドロキシプロピルセルロース、セルロース、無水ケイ酸、タルク、ステアリン酸マグネシウム、ヒプロメロース、マクロゴールおよび酸化チタンの８成分を含有する。 (Test example: Formulation stability evaluation Dissolution test before and after storage)
The tablets obtained in Examples 1 to 4 and Comparative Example 1 and “Dioban (registered trademark) 80 mg” (manufactured by Novartis) (Comparative Example 2) were subjected to a dissolution test of valsartan before and after storage. The test solution was 900 mL, and the elution rate (%) after 30 minutes was measured at a paddle rotation number of 50 rpm. "Dioban (registered trademark) tablet 80 mg" contains 8 components of hydroxypropyl cellulose, cellulose, silicic anhydride, talc, magnesium stearate, hypromellose, macrogol and titanium oxide in addition to valsartan.
　まず、実施例１～４および比較例１の錠剤は製造直後、比較例２の錠剤は入手直後を保存前として、この保存前の錠剤についてバルサルタンの溶出試験を行った。試験はそれぞれ３回実施した。結果を表６に示す。 First, the tablets of Examples 1 to 4 and Comparative Example 1 were subjected to a valsartan dissolution test immediately before production, and the tablets of Comparative Example 2 were stored immediately after being obtained. Each test was performed three times. The results are shown in Table 6.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
　表６から明らかなように、実施例１～４の保存前の錠剤は比較例１および２の保存前の錠剤と同等のバルサルタンの溶出性を示した。 As is apparent from Table 6, the tablets before storage of Examples 1 to 4 showed the dissolution properties of valsartan equivalent to the tablets before storage of Comparative Examples 1 and 2.
　次いで、実施例１～４ならびに比較例１および２の錠剤を、それぞれアルミ包装または無包装で、６０℃、湿度７５％、暗所下の条件にて３日間保存した。この保存後の錠剤についてバルサルタンの溶出試験を行った。試験はそれぞれ３回実施した。結果を表７に示す。 Subsequently, the tablets of Examples 1 to 4 and Comparative Examples 1 and 2 were stored for 3 days under conditions of 60 ° C., 75% humidity, and darkness, respectively, with aluminum packaging or without packaging. The tablets after storage were subjected to a dissolution test for valsartan. Each test was performed three times. The results are shown in Table 7.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
　表７より明らかなように、比較例１および２の保存後の錠剤は、保存前の錠剤と比較して、バルサルタンの溶出性に大幅な低下傾向が認められ、特に無包装では、バルサルタンがほとんど溶出しなかった。この結果は、バルサルタンが高湿度に弱いことを示している。 As is clear from Table 7, the tablets after storage in Comparative Examples 1 and 2 showed a significant decrease in the dissolution properties of valsartan compared to the tablets before storage. It did not elute. This result indicates that valsartan is vulnerable to high humidity.
　一方、実施例１～４の保存後の錠剤は、アルミ包装または無包装のいずれにおいても、バルサルタンの溶出性の低下が少なく、極めて安定な結果を示した。バルサルタンを含有する錠剤にアルカリ土類金属塩および／またはその水和物を配合することにより、錠剤の安定性、特に耐湿性を高めることができた。 On the other hand, the tablets after storage in Examples 1 to 4 showed a very stable result with little decrease in dissolution of valsartan in either aluminum packaging or non-packaging. By adding an alkaline earth metal salt and / or a hydrate thereof to a tablet containing valsartan, the stability of the tablet, particularly moisture resistance, could be increased.
　本発明によれば、アンギオテンシンＩＩ拮抗作用を有する化合物を含有する固形医薬組成物であって、安定性に優れた固形医薬組成物を提供することができる。 According to the present invention, a solid pharmaceutical composition containing a compound having an angiotensin II antagonistic action and having excellent stability can be provided.

Claims (6)

  1. 　アンギオテンシンＩＩ拮抗作用を有する化合物およびアルカリ土類金属塩および／またはその水和物を含有する固形医薬組成物。 A solid pharmaceutical composition comprising a compound having an angiotensin II antagonism and an alkaline earth metal salt and / or a hydrate thereof.
  2. 　前記アンギオテンシンＩＩ拮抗作用を有する化合物が、ロサルタン、エプロサルタン、カンデサルタンシレキセチル、カンデサルタン、バルサルタン、テルミサルタン、イルベサルタン、オルメサルタン、タソサルタン、アジルサルタン、およびこれらの塩もしくはエステルからなる群から選択される少なくとも１種の化合物である、請求項１に記載の固形医薬組成物。 The compound having angiotensin II antagonistic activity is at least one selected from the group consisting of losartan, eprosartan, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan, tasosartan, azilsartan, and salts or esters thereof. The solid pharmaceutical composition according to claim 1, which is a seed compound.
  3. 　前記アンギオテンシンＩＩ拮抗作用を有する化合物の含有量が前記組成物の質量を基準として３０質量％以上である、請求項１に記載の固形医薬組成物。 The solid pharmaceutical composition according to claim 1, wherein the content of the compound having angiotensin II antagonism is 30% by mass or more based on the mass of the composition.
  4. 　前記アルカリ土類金属が、カルシウム、ストロンチウム、バリウム、ラジウム、マグネシウム、およびベリリウムからなる群から選択される少なくとも１種の金属である、請求項１に記載の固形医薬組成物。 The solid pharmaceutical composition according to claim 1, wherein the alkaline earth metal is at least one metal selected from the group consisting of calcium, strontium, barium, radium, magnesium, and beryllium.
  5. 　前記アルカリ土類金属塩および／またはその水和物が、塩化カルシウム水和物、クエン酸カルシウム、グルコン酸カルシウム水和物、グリセロリン酸カルシウム、炭酸カルシウム、沈降炭酸カルシウム、乳酸カルシウム水和物、無水リン酸水素カルシウム、リン酸一水素カルシウム、リン酸一水素カルシウム水和物、リン酸二水素カルシウム水和物、Ｌ－アスパラギン酸マグネシウム、塩化マグネシウム、乾燥硫酸マグネシウム、グルコン酸マグネシウム、ケイ酸マグネシウム、ケイ酸マグネシウムアルミニウム、酸化マグネシウム、水酸化マグネシウム、水酸化アルミナマグネシウム、硫酸マグネシウム水和物、メタケイ酸アルミン酸マグネシウム、および炭酸マグネシウム、ならびにそれらの組合せからなる群から選択される少なくとも１種の化合物である、請求項１に記載の固形医薬組成物。 The alkaline earth metal salt and / or hydrate thereof is calcium chloride hydrate, calcium citrate, calcium gluconate hydrate, calcium glycerophosphate, calcium carbonate, precipitated calcium carbonate, calcium lactate hydrate, anhydrous phosphorus Calcium hydrogen hydrogen, calcium monohydrogen phosphate, calcium monohydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, magnesium L-aspartate, magnesium chloride, dried magnesium sulfate, magnesium gluconate, magnesium silicate, silica At least selected from the group consisting of magnesium aluminum oxide, magnesium oxide, magnesium hydroxide, magnesium hydroxide alumina, magnesium sulfate hydrate, magnesium aluminate metasilicate, and magnesium carbonate, and combinations thereof It is one of the compounds, solid pharmaceutical composition of claim 1.
  6. 　前記アルカリ土類金属塩および／またはその水和物の含有量が、前記組成物の質量を基準として２質量％から１０質量％である、請求項１に記載の固形医薬組成物。 The solid pharmaceutical composition according to claim 1, wherein the content of the alkaline earth metal salt and / or hydrate thereof is 2% by mass to 10% by mass based on the mass of the composition.
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