WO2010035806A1 - 固形医薬組成物 - Google Patents
固形医薬組成物 Download PDFInfo
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- WO2010035806A1 WO2010035806A1 PCT/JP2009/066690 JP2009066690W WO2010035806A1 WO 2010035806 A1 WO2010035806 A1 WO 2010035806A1 JP 2009066690 W JP2009066690 W JP 2009066690W WO 2010035806 A1 WO2010035806 A1 WO 2010035806A1
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- 0 *c1c2[n](Cc(cc3)ccc3-c3c(*)cccc3)c(O*)nc2ccc1 Chemical compound *c1c2[n](Cc(cc3)ccc3-c3c(*)cccc3)c(O*)nc2ccc1 0.000 description 1
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Definitions
- the present invention comprises a compound represented by the following formula (I), a pH adjuster and a calcium antagonist, and the stability and dissolution properties of the compound represented by formula (I) and the calcium antagonist It relates to an excellent solid preparation.
- a benzimidazole derivative having a potent angiotensin II receptor antagonistic activity formula (I)
- R 1 represents a monocyclic nitrogen-containing heterocyclic group having a hydrogen atom that can be deprotonated
- R 2 represents an esterified carboxyl group
- R 3 represents an optionally substituted lower alkyl.
- compound (I) Or a salt thereof (hereinafter sometimes referred to as compound (I)), especially 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 salt (Patent Document 1) Is promising as a therapeutic agent for hypertension and the like.
- compound (I) is unstable in a neutral pH range, which is a normal formulation condition, it is necessary to adjust the characteristics of the formulation so that compound (I) is stabilized.
- solubility of compound (I) is low in the pH range where compound (I) is stabilized.
- the compounding agent of Compound (I) and another active ingredient such as a calcium antagonist has a difference in chemical characteristics, and it has been difficult to formulate it into a preparation excellent in stability and dissolution.
- Patent Document 2 a combination of a compound having an angiotensin II antagonistic action and a compound having a calcium antagonistic action
- Patent Document 3 a solid preparation of acetaminophen, which is an unpleasant taste suppression / discoloration of acetaminophen A preparation (Patent Document 3) prepared by a two-group granulation method for prevention is known.
- Patent Document 3 a preparation that combines compound (I) and a calcium antagonist with both drug stability and solubility, ie, dissolution property.
- a preparation containing Compound (I) and a calcium antagonist is effective for the prevention and treatment of circulatory diseases such as hypertension, heart failure, diabetic nephropathy, arteriosclerosis, and is extremely clinically useful. high.
- the subject of this invention is providing the solid formulation which was excellent in stability of compound (I) and a calcium antagonist, and was excellent also in those elution.
- R 1 represents a monocyclic nitrogen-containing heterocyclic group having a hydrogen atom that can be deprotonated
- R 2 represents an esterified carboxyl group
- R 3 represents an optionally substituted lower alkyl.
- the compound represented by the formula (I) or a salt thereof 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 according to (1) above, which is (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl potassium salt
- Solid formulations (3) The solid preparation according to (1) or (2) above, wherein the calcium antagonist is amlodipine or an acid addition salt thereof; (4) The solid preparation according to (1) or (2) above, wherein the calcium antagonist is amlodipine
- R 1 represents a monocyclic nitrogen-containing heterocyclic group having a hydrogen atom that can be deprotonated
- R 2 represents an esterified carboxyl group
- R 3 represents an optionally substituted lower alkyl.
- R 1 represents a monocyclic nitrogen-containing heterocyclic group having a hydrogen atom that can be deprotonated
- R 2 represents an esterified carboxyl group
- R 3 represents an optionally substituted lower alkyl.
- a salt thereof and a pH adjuster and a solid preparation comprising a second part containing a calcium antagonist, the first layer comprising the first part and
- the solid preparation according to (1) above which is a laminated tablet comprising a second layer consisting of a second part;
- R 1 represents a monocyclic nitrogen-containing heterocyclic group having a hydrogen atom that can be deprotonated
- R 2 represents an esterified carboxyl group
- R 3 represents an optionally substituted lower alkyl.
- a salt thereof, and a solid preparation containing a calcium antagonist, a pH adjuster is added to the solid preparation, and the compound represented by formula (I) or a salt thereof and calcium in the solid preparation
- a method of stabilizing an antagonist (13) Formula (I):
- R 1 represents a monocyclic nitrogen-containing heterocyclic group having a hydrogen atom that can be deprotonated
- R 2 represents an esterified carboxyl group
- R 3 represents an optionally substituted lower alkyl.
- a salt thereof, and a solid preparation containing a calcium antagonist, a pH adjuster is added to the solid preparation containing the compound represented by formula (I) or a salt thereof from the solid preparation Elution improvement method; And so on.
- the solid preparation of the present invention is a solid preparation containing compound (I), a pH adjuster and a calcium antagonist.
- the solid preparation of the present invention is excellent in the stability of the compound (I) and in the dissolution property of the compound. Furthermore, the stability of calcium antagonists is also excellent.
- R 1 represents a monocyclic nitrogen-containing heterocyclic group having a hydrogen atom that can be deprotonated, such as a tetrazolyl group or a formula
- i represents —O— or —S—, and j represents>C ⁇ O,> C ⁇ S or> S (O) m (wherein m represents 0, 1 or 2).
- j represents>C ⁇ O,> C ⁇ S or> S (O) m (wherein m represents 0, 1 or 2).
- a 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group and the like are preferable.
- the 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group has the formula:
- R 2 represents an esterified carboxyl group, for example, a hydroxyl group, amino, halogen atom, lower (C 2-6 ) alkanoyloxy (eg, acetyloxy, pivaloyloxy, etc.), lower (C 4-7 ) cycloalkanoyloxy, (lower (C 1-6 ) alkoxy) carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, etc.), (lower (C 3-7 ) cycloalkoxy) carbonyloxy (eg, cyclohexyl) Oxycarbonyloxy and the like), lower (C 1-4 ) alkoxy and 5-methyl-2-oxo-1,3-dioxolen-4-yl optionally substituted lower (C 1-4 ) Alkyl esterified carboxyl groups (eg (5-methyl-2-oxo-1,3-dioxolen-4-yl) Methoxycarbon
- R 3 represents a lower alkyl which may be substituted, the R 3 hydroxyl group, an amino group, substituted with a halogen atom and lower (C 1-4) substituents selected from alkoxy groups Preferred is lower (C 1-5 ) alkyl (preferably lower (C 2-3 ) alkyl; particularly preferably ethyl).
- Examples of the salt of the compound represented by the formula (I) include a pharmaceutically acceptable salt.
- a salt of the compound represented by the formula (I) with an inorganic base a salt with an organic base
- examples thereof include salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
- 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 and ammonium salt.
- salts with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like.
- salts with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, Examples thereof include salts with p-toluenesulfonic acid.
- Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like, and preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. Can be mentioned.
- Examples of the compound represented by the formula (I) or a salt thereof include 2-ethoxy-1- ⁇ [2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl] ) Biphenyl-4-yl] methyl ⁇ -1H-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl salt is preferred, 2-ethoxy-1- ⁇ [2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl ⁇ -1H-benzimidazole-7-carboxylic acid (5 -Methyl-2-oxo-1,3-dioxol-4-yl) methyl potassium salt is particularly preferred.
- the salt of the compound represented by formula (I) may be either a hydrate or a non-hydrate.
- Compound (I) may be
- Compound (I) is preferably crystalline and has a melting point of 100 to 250 ° C., particularly 120 to 200 ° C., particularly 130 to 180 ° C.
- Compound (I) is contained in the solid preparation of the present invention in an amount of 0.1 to 60% by weight, preferably 1 to 40% by weight, more preferably 5 to 30% by weight.
- both the stability of the compound (I) in the preparation and the elution from the preparation are compatible, and any pH adjuster can be applied to pharmaceuticals.
- a plurality of pH adjusting agents may be used in combination.
- a pH adjuster having a pH of about 2 to about 5, preferably about 3 to about 5, more preferably about 3 to about 4, is preferably used.
- tartaric acid citric acid Acid substances such as lactic acid, fumaric acid, phosphoric acid, malic acid, succinic acid, ascorbic acid, acetic acid, acidic amino acids (eg glutamic acid, aspartic acid), inorganic salts of such acidic substances (eg alkali metal salts, alkaline earths) Metal salts, ammonium salts, etc.), salts of the acidic substances with organic bases (for example, basic amino acids such as lysine and arginine, meglumine, etc.), and solvates thereof (for example, hydrates) It is done.
- acidic amino acids eg glutamic acid, aspartic acid
- inorganic salts of such acidic substances eg alkali metal salts, alkaline earths
- Metal salts eg alkali metal salts, alkaline earths
- ammonium salts e.g., ammonium salts, etc.
- salts of the acidic substances with organic bases for example,
- the said pH adjuster balances the stability in a formulation, and the elution from a formulation also with respect to a calcium antagonist.
- the pH in the pH adjuster is measured under the following conditions. That is, the pH of a solution or suspension obtained by dissolving or suspending a pH adjuster in water at 25 ° C. at 1% w / v.
- a pH adjuster used in the present invention a combination of an acidic substance and a basic substance is used, and when the combined pH adjuster is dissolved or suspended in water at 25 ° C. at 1% w / v, a solution or The suspension may be adjusted to have a pH of about 2 to about 5, preferably about 3 to about 5, more preferably about 3 to about 4.
- strong acids such as hydrochloric acid, sulfuric acid and phosphoric acid can be used.
- Examples of basic substances used in combination include inorganic bases (for example, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, magnesium carbonate, calcium carbonate, magnesium oxide, ammonia, synthetic hydrotalcite), organic bases (for example, , Basic amino acids such as lysine and arginine, and meglumine).
- inorganic bases for example, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, magnesium carbonate, calcium carbonate, magnesium oxide, ammonia, synthetic hydrotalcite
- organic bases for example, Basic amino acids such as lysine and arginine, and meglumine.
- a solution having a buffering ability at the pH such as sodium dihydrogen phosphate, monosodium fumarate or a combination of donors of fumaric acid and sodium ions, etc. preferable.
- the pH adjuster used in the present invention is preferably monosodium fumarate or a combination of fumaric acid and a sodium ion donor, and fumaric acid and
- the pH adjuster is contained in the solid preparation in an amount of 0.01 to 20% by weight, preferably 0.05 to 10% by weight, more preferably 0.1 to 5% by weight.
- Examples of the calcium antagonist in the present invention include manidipine, nifedipine, amlodipine, efonidipine, nicardipine and the like.
- the calcium antagonist in the present invention includes salts of the compounds mentioned as the calcium antagonist.
- the calcium antagonist in the present invention is preferably amlodipine or a salt thereof, more preferably amlodipine or an acid addition salt thereof, and further preferably a salt of amlodipine.
- As the salt of amlodipine amlodipine besylate, amlodipine maleate and the like are preferable, and amlodipine besylate is more preferable.
- the calcium antagonist in the present invention is usually 0.05 to 60% by weight in a solid preparation (however, the total of the compound (I) and the pH adjuster is appropriately adjusted within a range not exceeding 100%), preferably Is contained in an amount of 0.1 to 40% by weight, more preferably 0.5 to 20% by weight.
- amlodipine in terms of free form is usually contained in an amount of 0.05 to 60% by weight, preferably 0.1 to 40% by weight, more preferably 0.5 to 20% by weight.
- the compound (I) 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 (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl potassium salt and calcium antagonist besyl A formulation that is acid amlodipine.
- Examples of the solid preparation of the present invention include solid preparations suitable for oral administration such as tablets, granules, fine granules, capsules and pills.
- Examples of the solid preparation in the present invention include the following preparations. (1) A solid preparation (one-group granulated preparation) obtained by mixing and granulating compound (I), a pH adjuster and a calcium antagonist. (2) A solid preparation comprising a first part containing compound (I) and a pH adjuster and a second part containing a calcium antagonist, wherein the first part and the second part are individually separated A solid preparation obtained by granulation into a two-group granulated preparation-single layer tablet.
- the solid preparation (group 1 granulated preparation) of the above (1) has both dissolution properties and stability from the respective preparations of the compound (I) and the calcium antagonist by blending the pH adjuster.
- the dissolution properties and stability of the compound (I) and the calcium antagonist are further improved.
- the solid preparation of the above (1) can be produced by a method known per se (for example, the method described in the 14th revised Japanese Pharmacopoeia General Rules for Preparations). For example, compound (I), a pH adjuster, a calcium antagonist and an additive are added and mixed, and a binder is added to form granules, and a lubricant is added to the granules and compressed into tablets. Granules and fine granules can also be produced in substantially the same manner as tablets.
- the above-mentioned granules and fine granules are filled into capsules containing gelatin, hydroxypropyl methylcellulose, etc., or the active ingredients are mixed with excipients into capsules containing gelatin, hydroxypropylmethylcellulose, etc. What is necessary is just to fill.
- additives When producing a solid preparation, it may contain additives commonly used in the preparation field.
- 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 pharmaceutical field.
- excipients include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch; lactose, fructose, glucose, mannitol (eg, D-mannitol) , Sorbitol (eg, D-sorbitol), erythritol (eg, D-erythritol), sugars or sugar alcohols such as sucrose: anhydrous calcium phosphate, crystalline cellulose, microcrystalline cellulose, licorice powder, sodium bicarbonate, calcium phosphate, calcium sulfate , Calcium carbonate, precipitated calcium carbonate, calcium silicate and the like.
- starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch
- lactose fructose, glucose, mannitol (eg, D-mannitol)
- Disintegrants include, for example, amino acids, starch, corn starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl Starch, sodium carboxymethyl starch and the like are used.
- binder examples include crystalline cellulose (eg, microcrystalline cellulose), hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, starch, gum arabic powder, tragacanth, carboxymethylcellulose, sodium alginate, pullulan, glycerin and the like. It is done.
- the lubricant include magnesium stearate, stearic acid, calcium stearate, talc (purified talc), sucrose fatty acid ester, sodium stearyl fumarate and the like.
- Examples of the colorant include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2, edible lake pigments, and iron sesquioxide.
- surfactant examples include sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol, and the like.
- stabilizer examples include tocopherol, edetate tetrasodium, nicotinamide, and cyclodextrins.
- Examples of the sour agent include ascorbic acid, citric acid, tartaric acid, malic acid and the like.
- examples of the fragrances include menthol, mint oil, lemon oil, and vanillin.
- examples of the fluidizing agent include light anhydrous silicic acid and hydrous silicon dioxide. Two or more of the above-described additives may be mixed and used at an appropriate ratio.
- the solid preparation (2) is a preparation in which the first part and the second part are separately granulated, and can be produced by a method known per se. It is a solid formulation of said (2), Comprising:
- the 1st part in this invention is a part (composition) containing compound (I) and a pH adjuster.
- the amount of the pH adjuster used in the present invention is preferably 0.01 to 20 parts by weight, more preferably 0.05 to 10 parts by weight, still more preferably 0.1 to 0.1 parts by weight based on 100 parts by weight of the first part. 5 parts by weight.
- the weight ratio of compound (I) to pH adjuster is preferably 0.1 to 50: 1, more preferably 1 to 30: 1, and still more preferably 5 to 25. : 1.
- the first part is not limited as long as it has a shape and size capable of forming a solid preparation together with a second part to be described later.
- the first part may further contain additives commonly used in the pharmaceutical field.
- additive the same ones as described above are used.
- Said 1st part can be manufactured by mixing and granulating compound (I) and a pH adjuster with the said additive if needed in accordance with a well-known method.
- the first moiety is preferably a compound (I) (preferably 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 potassium salt, hereinafter referred to as compound A); Contains pH adjusting agents (preferably fumaric acid and sodium hydroxide); excipients (preferably mannitol and crystalline cellulose); binders (preferably hydroxypropylcellulose).
- pH adjusting agents preferably fumaric acid and sodium hydroxide
- excipients preferably mannitol and crystalline cellulose
- binders preferably hydroxypropylcellulose
- the second part in the present invention is a part (composition) containing a calcium antagonist.
- the second part is not limited as long as it has a shape and size capable of forming a solid preparation together with the first part described above.
- the second part may further contain an additive commonly used in the pharmaceutical field, and the same additives as described above are used. Specifically, it contains a calcium antagonist (preferably amlodipine besylate); an excipient (preferably mannitol and crystalline cellulose); and a binder (preferably hydroxypropylcellulose).
- a calcium antagonist preferably amlodipine besylate
- an excipient preferably mannitol and crystalline cellulose
- a binder preferably hydroxypropylcellulose
- Said 2nd part can be manufactured by mixing and granulating a calcium antagonist with the said additive if needed in accordance with a method known per se.
- the calcium antagonist is preferably 0.1 to 60 parts by weight, more preferably 0.5 to 40 parts by weight, and still more preferably 1 to 30 parts by weight with respect to 100 parts by weight of the second part.
- the weight ratio of the second part to the first part is preferably 0.03 to 10: 1, more preferably 0.1 to 5. : 1, more preferably 0.3 to 3: 1.
- the solid preparation of the present invention also includes a single-layer tablet produced by mixing the individually granulated first part and the second part together with additives conventionally used in the pharmaceutical field and compression molding. Capsules prepared by filling the above monolayer tablets into capsules (eg, hydroxypropyl methylcellulose capsules) are also included in the solid preparation of the present invention.
- the solid preparation of the above (3a) can be produced by granulating the first part and the second part individually and compression-molding these parts.
- the solid preparation of the above (3b) can be produced by granulating the first part and the second part individually and coating one part with the other part.
- Specific examples of the solid preparation of the above (3b) include [1] a coated tablet (A) comprising an inner core consisting of a first part and an outer layer consisting of a second part; [2] an inner core consisting of a second part and An example is a coated tablet (B) including an outer layer composed of a first portion.
- Specific examples of the solid preparation (3a) include [3] a multilayer tablet including a first layer composed of a first portion and a second layer composed of a second portion.
- the inner core composed of the first part can be produced, for example, by granulating compound (I) and a pH adjuster together with additives as necessary. Further, after granulation, operations such as drying, sizing and compression molding may be performed as necessary.
- the outer layer which consists of a 2nd part can be manufactured by granulating a calcium antagonist, for example, amlodipine or its salt with an additive as needed.
- the coating is performed by, for example, compression molding or coating.
- the additive is preferably a binder.
- an inactive intermediate layer may be provided between them for the purpose of avoiding direct contact between the inner core and the outer layer.
- the intermediate layer contains, for example, the following coating base and coating additive.
- the intermediate layer preferably contains a water-soluble film coating base and a fluidizing agent.
- the coated tablet (B) can be produced in the same manner as the coated tablet (A) except that the second part is used as the inner core and the first part is used as the outer layer.
- the laminated tablet in the present invention is a solid preparation comprising a first part containing a compound represented by formula (I) or a salt thereof and a pH adjuster, and a second part containing a calcium antagonist, A tablet comprising a first layer comprising a first part and a second layer comprising a second part.
- the laminated tablet in the present invention is not particularly limited as long as it is a preparation in which at least a first layer comprising a first part and a second layer comprising a second part are integrally molded.
- the laminated tablet in the present invention may have an inactive intermediate layer between the first layer and the second layer.
- the layered tablet of the present invention has such an intermediate layer, adverse effects due to the active ingredients acting on each other (deterioration of storage stability such as degradation of active ingredients over time or reduction in activity, elution of active ingredients over time) It is possible to more effectively suppress a decrease in elution stability such as a pattern change.
- a laminated tablet can be manufactured according to the following manufacturing processes, for example.
- Compound (I) and a pH adjuster are mixed with additives as necessary, and the resulting mixture is granulated to obtain a first part. After granulation, operations such as drying and sizing may be performed as necessary. Then, it mixes with an additive as needed and it is set as the 1st layer. Next, the calcium antagonist is granulated with additives as necessary, and the second layer obtained is mixed with the additives as necessary, and the second layer is layered on the first layer and compressed. Molding (preferably tableting). At this time, in order to avoid direct contact between the layers, an inactive intermediate layer may be provided between the layers.
- the intermediate layer contains, for example, the above-described excipients, disintegrants, binders, lubricants, colorants and the like.
- a capsule produced by filling the above-mentioned coated tablet (A) or (B) or laminated tablet into a capsule (eg, hydroxypropylmethylcellulose capsule) is also included in the solid preparation of the present invention.
- a film coating preparation produced by film-coating the above solid preparations (1), (2), (3a) and (3b) with the following coating base and coating additive is also included in the solid preparation of the present invention. included.
- Suitable examples of the coating base include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base and the like.
- White sugar is used as the sugar coating base. Further, one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
- water-soluble film coating base examples include hydroxypropylcellulose [eg, grade: L, SL, SL-T, SSL (trade name); Nippon Soda Co., Ltd.], hydroxypropylmethylcellulose [eg, TC-5 ( Grade: MW, E, EW, R, RW) (trade name); Cellulose polymers such as Shin-Etsu Chemical Co., Ltd.], hydroxyethyl cellulose, methylhydroxyethyl cellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan.
- hydroxypropylcellulose eg, grade: L, SL, SL-T, SSL (trade name); Nippon Soda Co., Ltd.
- hydroxypropylmethylcellulose eg, TC-5 ( Grade: MW, E, EW, R
- enteric film coating bases include cellulose-based polymers such as hydroxypropyl methylcellulose ⁇ ⁇ ⁇ phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name) ], Acrylic acid-based polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)], and natural products such as shellac.
- cellulose-based polymers such as hydroxypropyl methylcellulose ⁇ ⁇ ⁇ phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, and cellulose acetate phthalate
- methacrylic acid copolymer L Eudragit L (trade name)
- Acrylic acid-based polymers such as methacrylic acid copolymer
- sustained-release film coating base examples include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate / methyl methacrylate copolymer suspension [ Acrylic polymers such as Eudragit NE (trade name)].
- cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate / methyl methacrylate copolymer suspension [ Acrylic polymers such as Eudragit NE (trade name)].
- the coating additive include a light-shielding agent such as titanium oxide, a fluidizing agent such as talc, and / or a colorant such as iron sesquioxide and yellow iron sesquioxide; polyethylene glycol [eg, Macrogol 6000 (commodity) Name)], plasticizers such as triethyl citrate, castor oil, polysorbates; organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid; and the like.
- a light-shielding agent such as titanium oxide
- a fluidizing agent such as talc
- / or a colorant such as iron sesquioxide and yellow iron sesquioxide
- polyethylene glycol eg, Macrogol 6000 (commodity) Name
- plasticizers such as triethyl citrate, castor oil, polysorbates
- organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid; and the like.
- the solid preparation of the present invention may be printed with a mark or letter for identification, or may be provided with a dividing line for division.
- the solid preparation of the present invention is preferably film-coated from the viewpoints of ingestion and preparation strength.
- operations such as mixing, compression molding, and coating are performed according to methods commonly used in the field of pharmaceutical technology.
- the mixing is performed using, for example, a mixer such as a V-type mixer or a tumbler mixer; and a granulator such as a high-speed stirring granulator, a fluidized bed granulator / dryer, an extrusion granulator, or a roller compactor.
- a mixer such as a V-type mixer or a tumbler mixer
- a granulator such as a high-speed stirring granulator, a fluidized bed granulator / dryer, an extrusion granulator, or a roller compactor.
- the compression molding is performed using, for example, a single tablet machine, a rotary tableting machine, or the like.
- a tableting pressure of 1 to 20 kN / cm 2 (preferably 5 to 15 kN / cm 2 ).
- a tapered die for the purpose of preventing capping.
- Coating is performed using, for example, a film coating apparatus.
- the solid preparation of the present invention can be safely used as a pharmaceutical for mammals (eg, human, dog, rabbit, rat, mouse, etc.).
- the solid preparation of the present invention can be safely administered orally or parenterally (eg, rectum).
- the dose of compound (I) to the patient is determined by considering the age, weight, general health, sex, diet, administration time, excretion rate, combination of drugs, etc. Although it is determined depending on the degree, the daily dose per adult (body weight 60 kg) is about 0.05 to 500 mg, preferably 0.1 to 100 mg.
- the dose of calcium antagonist to the patient is based on age, weight, general health condition, sex, diet, administration time, excretion rate, combination of drugs, etc.
- amlodipine (converted into a free form) is a daily dose of about 1 to 50 mg, preferably 2.5 to 10 mg per adult (body weight 60 kg).
- Compound (I) normalizes the intracellular insulin signal transduction mechanism which is the main cause of insulin resistance, reduces insulin resistance, enhances insulin action, and has glucose tolerance improving action. Therefore, compound (I) ) Improves or prevents and / or treats a disease (eg, human, monkey, cat, pig, horse, cow, mouse, rat, guinea pig, dog, rabbit, etc.) associated with insulin resistance. Used as an agent.
- a disease eg, human, monkey, cat, pig, horse, cow, mouse, rat, guinea pig, dog, rabbit, etc.
- Such diseases include, for example, insulin resistance and glucose intolerance; non-insulin-dependent diabetes, type II diabetes, type II diabetes with insulin resistance, type II diabetes with impaired glucose tolerance, etc .; high insulin , Hypertension with insulin resistance, hypertension with impaired glucose tolerance, hypertension with diabetes (eg, type II diabetes), hypertension with hyperinsulinemia, insulin resistance associated with hypertension , Glucose intolerance associated with hypertension, diabetes associated with hypertension, hyperinsulinemia associated with hypertension, diabetic complications [eg, microangiopathy, diabetic neuropathy, diabetic nephropathy, diabetic Retinopathy, diabetic cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, infection (eg, respiratory infection, urinary tract infection, digestive tract infection, skin soft tissue) Dysplasia, lower limb infection, etc.), diabetic gangrene, xerostomia, hearing loss, diabetic cerebrovascular disorder, diabetic peripheral blood circulation disorder, diabetic hypertension, etc.], various complications such as diabetic cache
- Compound (I) since Compound (I) has a strong angiotensin II antagonism, Compound (I) can be used in mammals (eg, humans, monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs, dogs, rabbits). Etc.), which is caused by the contraction and proliferation of blood vessels expressed through the angiotensin II receptor, organ damage, the presence of angiotensin II, or a factor induced by the presence of angiotensin II (or onset is accelerated) It is useful as a prophylactic or therapeutic drug for diseases.
- mammals eg, humans, monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs, dogs, rabbits.
- Etc. which is caused by the contraction and proliferation of blood vessels expressed through the angiotensin II receptor, organ damage, the presence of angiotensin II, or a factor induced by the presence of angiotensin II (or onset is accelerated
- Such diseases include, for example, hypertension, abnormal blood pressure fluctuations, heart disease (eg, cardiac hypertrophy, chronic heart failure including acute heart failure and congestiveness, cardiomyopathy, angina, myocarditis, atrial fibrillation, arrhythmia , Tachycardia, myocardial infarction, etc.), cerebrovascular disorders (eg, asymptomatic cerebrovascular disorder, transient ischemic attack, stroke, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction, subarachnoid hemorrhage, etc.) Cerebral edema, cerebral circulatory disorder, recurrence and sequelae of cerebrovascular disorder (eg, neurological symptoms, psychiatric symptoms, subjective symptoms, impaired daily activities), ischemic peripheral circulatory disorder, myocardial ischemia, venous dysfunction, after myocardial infarction Progression of heart failure, renal disease (eg, nephritis, glomerulonephritis, glomerulosclerosis, chronic
- respiratory diseases eg, cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombus / pulmonary embolism, etc.
- infectious diseases eg, cytomegalo Viral infections such as viruses, influenza viruses, herpes viruses, rickettsial infections, bacterial infections, etc.
- venomemia eg, sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxin shock syndrome, etc.
- ENT disorders eg, Menuel syndrome, tinnitus, taste disorder, dizziness, balance disorder, dysphagia
- skin disorders eg, keloid, hemangioma, psoriasis
- dialysis hypotension myasthenia gravis, chronic fatigue syndrome And systemic diseases.
- compound (I) can maintain a constant antihypertensive action day and night, not only can the dosage and frequency be reduced, but it can also be used before and after waking up, which is a particular problem in hypertensive patients. An increase in blood pressure can be more effectively suppressed.
- Compound (I) suppresses an angiotensin II action over a long period of time, thereby preventing impairment or abnormality of biological functions and physiological actions that cause various diseases associated with adult diseases and aging. Improvement or enhancement can be suppressed, and primary and secondary prevention or progression of diseases or pathologies caused by these can be suppressed.
- disorders or abnormalities of biological functions and physiological actions include disorders or abnormalities of cerebral circulation / renal circulation automatic regulation ability, circulatory disorders (eg, peripheral, brain, microcirculation, etc.), cerebral blood barrier disorders, Salt sensitivity, coagulation / fibrinolysis system abnormalities, abnormal blood / blood cell properties (eg, increased platelet aggregation, abnormal red blood cell deformability, increased white blood cell adhesion, increased blood viscosity), growth factors and cytokines (eg, PDGF, VEGF, FGF, interleukin, TNF- ⁇ , MCP-1, etc.) production and action enhancement, inflammatory cell production and invasion enhancement, free radical production enhancement, fat deposition promotion, endothelial dysfunction, endothelium, cells and organ failure, edema, morphological changes of cells such as smooth muscle (form change to such proliferating), vasoactive substances and thrombus inducers (e.g., endothelin, thromboxane, etc.
- compound (I) is an organ disorder associated with various diseases (eg, cerebrovascular disorder and accompanying organ disorders, organ disorders associated with cardiovascular diseases, organ disorders associated with diabetes, organ disorders after intervention, etc.)
- compound (I) since compound (I) has a proteinuria inhibitory action, compound (I) can be used as a nephroprotective agent. Therefore, compound (I) can be advantageously used even when a patient with insulin resistance, impaired glucose tolerance, diabetes, or hyperinsulinemia has the above-mentioned disease or pathological condition.
- Compound (I) has an action of suppressing body weight gain
- Compound (I) can be used as a body weight gain inhibitor for mammals.
- the mammal to be applied may be any mammal that wishes to avoid weight gain, may be a mammal that is genetically at risk of weight gain, and may have diabetes, hypertension and / or hyperlipidemia.
- Weight gain may be due to excessive dietary intake or a diet that lacks nutritional balance and has concomitant drugs (eg, PPAR ⁇ agonist-like effects such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone) It may be a weight gain derived from an insulin resistance improving agent or the like. The weight gain may be a weight gain before reaching obesity or may be a weight gain of an obese patient.
- concomitant drugs eg, PPAR ⁇ agonist-like effects such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone
- the weight gain may be a weight gain before reaching obesity or may be a weight gain of an obese patient.
- obesity means that BMI (body mass index: body weight (kg) ⁇ [height (m)] 2 ) is 25 or more (in accordance with the standards of the Japanese Society of Obesity) in Japanese, and BMI is 30 or more in Westerners. (According to WHO standards).
- Compound (I) can also be used as a prophylactic or therapeutic agent for hypertension associated with obesity, or as a prophylactic or therapeutic agent for obesity associated with hypertension.
- diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, and a 75 g oral glucose tolerance test (75 gOGTT) 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or higher.
- 75 gOGTT 75 g oral glucose tolerance test
- glucose level in venous plasma is less than 110 mg / dl or 75 g oral glucose tolerance test (75 gOGTT) 2 hour value (glucose concentration in venous plasma) is 140 mg / dl.
- a state that is not “a state indicating less than dl” (normal type) is referred to as a “boundary type”.
- diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more, and a 2-hour value of 75 g oral glucose tolerance test (glucose concentration in venous plasma) is 200 mg / dl. This is a state showing dl or more.
- abnormal glucose tolerance means that fasting blood glucose level (glucose concentration in venous plasma) is less than 126 mg / dl and 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) Is a state showing 140 mg / dl or more and less than 200 mg / dl. Furthermore, according to the report of ADA, the state where the fasting blood glucose level (glucose concentration in venous plasma) is 110 mg / dl or more and less than 126 mg / dl is called IFG (Impaired Fasting Glucose).
- the IFG is a state in which the 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is less than 140 mg / dl as IFG (Impaired Fasting Glycemia). Call.
- Compound (I) further improves or prevents or treats diabetes, borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) determined by the above new criteria It is also used as a therapeutic agent for hypertension in patients with hypertension with a criterion (for example, fasting blood glucose level of 126 mg / dl) or higher. Furthermore, compound (I) can also prevent progression from borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) to diabetes.
- a criterion for example, fasting blood glucose level of 126 mg / dl
- Compound (I) is also useful as a prophylactic / therapeutic agent for metabolic syndrome (metabolic syndrome).
- metabolic syndrome has a significantly higher rate of developing cardiovascular disease than patients with a single lifestyle-related disease, so preventing or treating metabolic syndrome prevents cardiovascular disease It is extremely important to do. Criteria for metabolic syndrome were published by WHO in 1999 and NCEP in 2001. According to WHO criteria, metabolic syndrome is diagnosed in patients with visceral obesity, dyslipidemia (high TG or low HDL), or hypertension based on hyperinsulinemia or impaired glucose tolerance.
- WHO World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications. Part I: Diagnosis and Classification of Diabetes Mellitus, World Health Organization, Geneva, 1999).
- compound (I) can be used as an anti-inflammatory agent and a prophylactic / therapeutic agent for inflammatory diseases.
- Inflammatory diseases include, for example, arthritis (eg, rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, gouty arthritis, synovitis), asthma, allergic diseases, atherosclerosis including atherosclerosis (aneurysm, Coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.) digestive diseases such as inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), diabetic complications (diabetic neuropathy, diabetic vascular disorder) ), Atopic dermatitis, chronic obstructive pulmonary disease, systemic lupus erythematosus, visceral inflammatory diseases (nephritis, hepatitis), autoimmune hemolytic anemia, psoriasis, neurodegenerative diseases (eg, Alzheimer'
- Pain diseases include, for example, acute pain due to inflammation, pain associated with chronic inflammation, pain associated with acute inflammation, postoperative pain (incisional pain, deep pain, visceral pain, postoperative chronic pain, etc.), muscle pain (chronic) Muscle pain associated with pain, stiff shoulders, etc.), joint pain, toothache, temporomandibular joint pain, headache (migraine, tension headache, fever headache, high blood pressure headache), visceral pain (heart pain, angina pain, abdominal pain) , Kidney pain, ureteral pain, bladder pain), gynecological pain (intermediate pain, dysmenorrhea, labor pain), neuralgia (disc herniation, nerve root pain, postherpetic neuralgia, trigeminal neuralgia), cancer Pain, reflex sympathetic atrophy, complex local pain syndrome and the like.
- Pain diseases include, for example, acute pain due to inflammation, pain associated with chronic inflammation, pain associated with acute inflammation, postoperative pain (incisional pain, deep pain, visceral pain, postoperative chronic pain
- Compound (I) is effective for directly and quickly relieving various pains such as neuropathic pain, cancer pain, and inflammatory pain, and patients and pathological conditions in which pain threshold is lowered (eg, hypertension) , Diabetes, and their complications).
- Compound (I) is particularly useful as an analgesic for pain associated with chronic inflammation or headache associated with hypertension, or (1) arteriosclerosis including atherosclerosis, (2) vascular thickening, occlusion or organ damage after intervention, ( 3) Vascular re-occlusion / restenosis after bypass surgery, endothelial dysfunction, (4) intermittent claudication, (5) obstructive peripheral circulation disorder, or (6) inflammatory disease or pain due to obstructive arteriosclerosis It is useful as a preventive / therapeutic agent.
- the solid preparation of the present invention can be obtained by combining the compound (I) with a calcium antagonist to prevent or treat the above-mentioned diseases (preferably, preventive or therapeutic agents for hypertension, heart failure, diabetic nephropathy, arteriosclerosis, More preferably, it is useful as a prophylactic or therapeutic agent for hypertension), and it is possible to reduce the dose when compound (I) or a calcium antagonist is used alone, and to suppress the occurrence of side effects. .
- diseases preferably, preventive or therapeutic agents for hypertension, heart failure, diabetic nephropathy, arteriosclerosis, More preferably, it is useful as a prophylactic or therapeutic agent for hypertension
- Compound (I) can be used in combination with one or more other types of drugs (hereinafter sometimes abbreviated as “concomitant drugs”).
- the compound (I) is one or more drugs selected from a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an antiobesity agent, a diuretic agent, an antithrombotic agent and the like ( Combination drugs).
- insulin preparations eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin Fragment or derivative (eg, INS-1), oral insulin preparation
- insulin resistance improving agent eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate)
- Metaglidasen AMG-131, Balaglitazone, MBX-2044, Riboglitazone, Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034 , GFT-505, THR-0921, WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 or WO2008 / 0 Compounds described in 99794)
- ⁇ -glucosidase inhibitors eg, ⁇ -glucosidase
- Diabetes complications include aldose reductase inhibitors (eg, torrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201), ridressat), neurotrophic factors and their increasing drugs (eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (eg, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- ( 2-methylphenoxy) propyl] oxazole), compounds described in WO2004 / 039365), PKC inhibitors (eg, ruboxistaurin mesylate), AGE inhibitors (eg, ALT946, N-phenacylthiazolium) Bromide (ALT766), EXO-226, pyridoline (Pyridorin), pyridoxamine), GABA receptor agonist (eg, gabapentin, pregabalin), serot
- Antihyperlipidemic agents include HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or their salts (eg, sodium salt, calcium salt)), squalene synthesis Enzyme inhibitors (eg, compounds described in WO97 / 10224, such as N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2, 3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid), fibrate compounds (eg, bezafibrate, Clofibrate, simfibrate, clinofibrate), anion exchange resin (eg, cholestyramine), probu
- Antihypertensive agents include, for example, angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan , Olmesartan, olmesartan, medoxomil, azilsartan, etc.), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine, amlodipine, sinyldipine, etc.), ⁇ -blockers (eg, metoprolol, atenolol, propranolol, carvedilol, pindolol, etc.) And clonidine.
- Anti-obesity agents include monoamine uptake inhibitors (eg, phentermine, sibutramine, mazindol, floxetine, tesofensin), serotonin 2C receptor agonists (eg, lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor, GABA Modulator (eg, topiramate), neuropeptide Y antagonist (eg, beneperit), cannabinoid receptor antagonist (eg, rimonabant, taranaban), ghrelin antagonist, ghrelin receptor antagonist, ghrelin acylase inhibitor, Opioid receptor antagonists (eg, GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 11 ⁇ -hydroxysteroid dehydrogenase inhibitors (eg, AZD-4017), pancreatic lipase inhibitors (eg, orlistat, Cetilistat), ⁇ 3 agonists (eg, N-59
- GLP-1 fragments or derivatives eg, exenatide, liraglutide
- amylin preparation eg, pramlintide, AC-2307
- neuropeptide Y Agonists eg, PYY3-36, derivatives of PYY3-36, Obineptide, TM-30339, TM-30335
- oxyntomodulin preparations eg, FGF21 preparations (eg, animal FGF21 preparations extracted from bovine, porcine pancreas; E. coli, And human FGF21 preparations synthesized by genetic engineering using yeast; FGF21 fragments or derivatives)), antifeedants (eg, P-57) and the like.
- diuretic examples include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, penflux.
- xanthine derivatives eg, sodium salicylate theobromine, calcium salicylate theobromine
- thiazide preparations eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, penflux.
- anti-aldosterone preparations eg, spironolactone, triamterene, etc.
- carbonic anhydrase inhibitors eg, acetazolamide, etc.
- chlorobenzenesulfonamide preparations eg, chlorthalidone, mefluside, indapamide, etc.
- Azosemide iso
- antithrombotic agent examples include heparin (eg, heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drug (eg, argatroban (eg, aragatroban), dabigatran), FXa inhibitors (eg, rivaroxaban, apixaban, edoxaban, YM150, WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823 or WO2005 / 113504), thrombolytic agents (eg, urokinase, tisokinase, alteplase, nateplase, monteplase, pamitepase (pamiteplase)), platelet aggregation inhibitors (eg, Ticlopidine hydrochloride, clopidogrel, prasugre
- the solid preparation of the present invention and a concomitant drug are used in combination, their administration timing is not limited, and they may be administered simultaneously to administration subjects, or may be administered with a time difference. Further, the solid preparation of the present invention and the concomitant drug may be administered as separate tablets to the administration subject, or may be administered as a single preparation containing the solid preparation of the present invention and the concomitant drug. .
- the dose of the concomitant drug can be appropriately selected based on the clinically used dose of each drug.
- the mixing ratio of the solid preparation of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
- the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the solid preparation of the present invention.
- the concomitant drug 1) the effect of enhancing the action of the compound (I) or the concomitant drug (synergistic effect of the drug action), 2) the effect of reducing the dose of the compound (I) or the concomitant drug (alone) Excellent effects such as a drug dose reduction effect as compared to the time of administration) and 3) a secondary action reduction effect of compound (I) or a concomitant drug are obtained.
- a solid preparation containing a compound represented by formula (I) or a salt thereof and a calcium antagonist is blended with a pH adjuster, which is represented by formula (I) in a solid preparation. Or a salt thereof and a method for stabilizing a calcium antagonist.
- a pH adjuster which is represented by formula (I) in a solid preparation.
- a salt thereof and a method for stabilizing a calcium antagonist According to the stabilization method of the present invention, compound (I) in the solid preparation is significantly stabilized.
- the compound represented by the formula (I) or a salt thereof, and a solid preparation containing a calcium antagonist are blended with a pH adjuster and represented by the formula (I) from the solid preparation.
- a method for improving the elution of a compound or a salt thereof is provided. According to the dissolution improving method of the present invention, the dissolution property of compound (I) from a solid preparation is significantly improved.
- a binding liquid I was prepared by dissolving hydroxypropylcellulose (5124 g) in purified water (80280 g). In a fluidized bed granulator / dryer (WSG-60, Pauleck Co., Ltd.), amlodipine besylate (2984 g), mannitol (55840 g) and crystalline cellulose (3870 g) were uniformly mixed, and then binding liquid I (38700 g) was sprayed. The mixture was granulated and then dried to obtain a granulated powder.
- WSG-60 fluidized bed granulator / dryer
- Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose (7200 g) crospovidone (3600 g) and magnesium stearate (720 g)
- TM-400S tumbler mixer
- a mixed powder A was obtained.
- (2) Sodium hydroxide (405.8 g) and fumaric acid (1176 g) were dissolved in purified water (38230 g) to prepare a buffer solution.
- Hydroxypropyl cellulose (3018 g) was dissolved in purified water (47280 g) to prepare a binding solution II.
- Compound A 20060 g
- mannitol 40860 g
- crystalline cellulose 4230 g
- WSG-60 fluidized bed granulator / dryer
- Granulation was carried out while spraying the binding liquid II (42300 g), and then dried to obtain a granulated powder.
- Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose (7380 g) crospovidone (5535 g) and magnesium stearate (738 g)
- TM-400S Showa Chemical Machinery Co., Ltd.
- Dispersion I was prepared by dissolving and dispersing hydroxypropylmethylcellulose (468 g) and talc (72 g) in purified water (4320 g).
- Dispersion II was prepared by dispersing titanium oxide (54 g) and iron oxide (6 g) in purified water (900 g).
- Dispersion II and purified water (180 g) were mixed with Dispersion I to prepare a coating solution.
- the coating liquid was sprayed until the weight of the uncoated tablet obtained in (3) increased by 10 mg per tablet, thereby obtaining a film tablet having the following composition. .
- the film tablet was then dried under reduced pressure at 40 ° C. for 18 hours.
- a binding liquid I was prepared by dissolving hydroxypropylcellulose (5124 g) in purified water (80280 g). In a fluidized bed granulator / dryer (WSG-60, Powrec Co., Ltd.), amlodipine besylate (5964 g), mannitol (52860 g) and crystalline cellulose (3870 g) were uniformly mixed, and then binding liquid I (38700 g) was sprayed. The mixture was granulated and then dried to obtain a granulated powder.
- WSG-60 fluidized bed granulator / dryer
- Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose (7200 g) crospovidone (3600 g) and magnesium stearate (720 g)
- TM-400S tumbler mixer
- a mixed powder A was obtained.
- (2) Sodium hydroxide (405.8 g) and fumaric acid (1176 g) were dissolved in purified water (38230 g) to prepare a buffer solution.
- Hydroxypropyl cellulose (3018 g) was dissolved in purified water (47280 g) to prepare a binding solution II.
- Compound A 20060 g
- mannitol 40860 g
- crystalline cellulose 4230 g
- WSG-60 fluidized bed granulator / dryer
- Granulation was carried out while spraying the binding liquid II (42300 g), and then dried to obtain a granulated powder.
- Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose (7380 g) crospovidone (5535 g) and magnesium stearate (738 g)
- TM-400S Showa Chemical Machinery Co., Ltd.
- Dispersion I was prepared by dissolving and dispersing hydroxypropylmethylcellulose (468 g) and talc (72 g) in purified water (4320 g).
- Dispersion II was prepared by dispersing titanium oxide (54 g) and iron oxide (6 g) in purified water (900 g).
- Dispersion II and purified water (180 g) were mixed with Dispersion I to prepare a coating solution.
- the coating liquid was sprayed until the weight of the uncoated tablet obtained in (3) increased by 10 mg per tablet, thereby obtaining a film tablet having the following composition. .
- the film tablet was then dried under reduced pressure at 40 ° C. for 18 hours.
- composition amlodipine besylate 13.87 mg Mannitol 122.93 mg Crystalline cellulose 9 mg Hydroxypropylcellulose 5.4 mg Crystalline cellulose 18 mg Crospovidone 9 mg Magnesium stearate 1.8 mg Compound A 21.34 mg Mannitol 43.465mg Crystalline cellulose 4.5 mg Sodium hydroxide 0.345mg 1 mg of fumaric acid Hydroxypropylcellulose 2.7 mg Crystalline cellulose 9 mg Crospovidone 6.75 mg Magnesium stearate 0.9 mg Hydroxypropyl methylcellulose 7.8 mg Talc 1.2 mg Titanium oxide 0.9 mg Iron oxide 0.1 mg 280 mg total
- a binding liquid I was prepared by dissolving hydroxypropylcellulose (5124 g) in purified water (80280 g). In a fluidized bed granulator / dryer (WSG-60, Pauleck Co., Ltd.), amlodipine besylate (2984 g), mannitol (55840 g) and crystalline cellulose (3870 g) were uniformly mixed, and then binding liquid I (38700 g) was sprayed. The mixture was granulated and then dried to obtain a granulated powder.
- WSG-60 fluidized bed granulator / dryer
- Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose (7200 g) crospovidone (3600 g) and magnesium stearate (720 g)
- TM-400S tumbler mixer
- a mixed powder A was obtained.
- (2) Sodium hydroxide (405.8 g) and fumaric acid (1176 g) were dissolved in purified water (38230 g) to prepare a buffer solution.
- Hydroxypropyl cellulose (3018 g) was dissolved in purified water (47280 g) to prepare a binding solution II.
- Compound A 20060 g
- mannitol 40860 g
- crystalline cellulose 4230 g
- WSG-60 fluidized bed granulator / dryer
- Granulation was carried out while spraying the binding liquid II (42300 g), and then dried to obtain a granulated powder.
- Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose (7380 g) crospovidone (5535 g) and magnesium stearate (738 g)
- TM-400S Showa Chemical Machinery Co., Ltd.
- Dispersion II and purified water 180 g were mixed with Dispersion I to prepare a coating solution.
- a coating machine DRC-650, POWREC Co., Ltd.
- the coating liquid was sprayed until the weight of the uncoated tablet obtained in (3) increased by 20 mg per tablet, whereby a film tablet having the following composition was obtained. .
- the film tablet was then dried under reduced pressure at 40 ° C. for 18 hours.
- a binding liquid I was prepared by dissolving hydroxypropylcellulose (5124 g) in purified water (80280 g). In a fluidized bed granulator / dryer (WSG-60, Powrec Co., Ltd.), amlodipine besylate (5964 g), mannitol (52860 g) and crystalline cellulose (3870 g) were uniformly mixed, and then binding liquid I (38700 g) was sprayed. The mixture was granulated and then dried to obtain a granulated powder.
- WSG-60 fluidized bed granulator / dryer
- Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose (7200 g) crospovidone (3600 g) and magnesium stearate (720 g)
- TM-400S tumbler mixer
- a mixed powder A was obtained.
- (2) Sodium hydroxide (405.8 g) and fumaric acid (1176 g) were dissolved in purified water (38230 g) to prepare a buffer solution.
- Hydroxypropyl cellulose (3018 g) was dissolved in purified water (47280 g) to prepare a binding solution II.
- Compound A 20060 g
- mannitol 40860 g
- crystalline cellulose 4230 g
- WSG-60 fluidized bed granulator / dryer
- Granulation was carried out while spraying the binding liquid II (42300 g), and then dried to obtain a granulated powder.
- Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose (7380 g) crospovidone (5535 g) and magnesium stearate (738 g)
- TM-400S Showa Chemical Machinery Co., Ltd.
- Dispersion II and purified water 180 g were mixed with Dispersion I to prepare a coating solution.
- a coating machine DRC-650, POWREC Co., Ltd.
- the coating liquid was sprayed until the weight of the uncoated tablet obtained in (3) increased by 20 mg per tablet, whereby a film tablet having the following composition was obtained. .
- the film tablet was then dried under reduced pressure at 40 ° C. for 18 hours.
- composition amlodipine besylate 13.87 mg Mannitol 122.93 mg Crystalline cellulose 9 mg Hydroxypropylcellulose 5.4 mg Crystalline cellulose 18 mg Crospovidone 9 mg Magnesium stearate 1.8 mg Compound A 85.36 mg Mannitol 173.86 mg Crystalline cellulose 18 mg Sodium hydroxide 1.38 mg Fumaric acid 4 mg Hydroxypropylcellulose 10.8 mg Crystalline cellulose 36 mg Crospovidone 27 mg Magnesium stearate 3.6 mg Hydroxypropyl methylcellulose 15.6 mg Talc 2.4 mg Titanium oxide 1.8 mg Iron oxide 0.2 mg 560 mg total
- a binding liquid I was prepared by dissolving hydroxypropylcellulose (5124 g) in purified water (80280 g). In a fluidized bed granulator / dryer (WSG-60, Pauleck Co., Ltd.), amlodipine besylate (2984 g), mannitol (55840 g) and crystalline cellulose (3870 g) were uniformly mixed, and then binding liquid I (38700 g) was sprayed. The mixture was granulated and then dried to obtain a granulated powder.
- WSG-60 fluidized bed granulator / dryer
- Part of the resulting granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain granulated powder A.
- Sodium hydroxide (405.8 g) and fumaric acid (1176 g) were dissolved in purified water (38230 g) to prepare a buffer solution.
- Hydroxypropyl cellulose (3018 g) was dissolved in purified water (47280 g) to prepare a binding solution II.
- Compound A (20060 g), mannitol (40860 g), and crystalline cellulose (4230 g) were uniformly mixed in a fluidized bed granulator / dryer (WSG-60, POWREC Co., Ltd.), and then sprayed with a buffer solution (31810 g). Granulation was carried out while spraying the binding liquid II (42300 g), and then dried to obtain a granulated powder. Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain sized powder B.
- P-7S Showa Chemical Machinery Co., Ltd.
- Dispersion II was prepared by dispersing titanium oxide (54 g) and iron oxide (6 g) in purified water (900 g). Dispersion II and purified water (180 g) were mixed with Dispersion I to prepare a coating solution. Using a coating machine (DRC-650, POWREC Co., Ltd.), the coating liquid was sprayed until the weight of the uncoated tablet obtained in (4) increased by 10 mg per tablet, thereby obtaining a film tablet having the following composition. . The film tablet was then dried under reduced pressure at 40 ° C. for 18 hours.
- a binding liquid I was prepared by dissolving hydroxypropylcellulose (5124 g) in purified water (80280 g). In a fluidized bed granulator / dryer (WSG-60, Powrec Co., Ltd.), amlodipine besylate (5964 g), mannitol (52860 g) and crystalline cellulose (3870 g) were uniformly mixed, and then binding liquid I (38700 g) was sprayed. The mixture was granulated and then dried to obtain a granulated powder.
- WSG-60 fluidized bed granulator / dryer
- Part of the resulting granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain granulated powder A.
- Sodium hydroxide (405.8 g) and fumaric acid (1176 g) were dissolved in purified water (38230 g) to prepare a buffer solution.
- Hydroxypropyl cellulose (3018 g) was dissolved in purified water (47280 g) to prepare a binding solution II.
- Compound A (20060 g), mannitol (40860 g), and crystalline cellulose (4230 g) were uniformly mixed in a fluidized bed granulator / dryer (WSG-60, POWREC Co., Ltd.), and then sprayed with a buffer solution (31810 g). Granulation was carried out while spraying the binding liquid II (42300 g), and then dried to obtain a granulated powder. Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain sized powder B.
- P-7S Showa Chemical Machinery Co., Ltd.
- Crystalline cellulose (1620 g), crospovidone (945 g) and magnesium stearate (162 g) are added to the obtained sized powder A (9072 g) and sized powder B (4401 g), and a tumbler mixer (TM-60S) is added.
- a mixed powder was obtained.
- the mixed powder was tableted with a 8.5 mm ⁇ punch using a rotary tableting machine (AQUA512SS2AI, Kikusui Seisakusho) (tablet pressure: 7 kN, weight per tablet: 270 mg) to obtain a plain tablet. .
- Dispersion II was prepared by dispersing titanium oxide (54 g) and iron oxide (6 g) in purified water (900 g). Dispersion II and purified water (180 g) were mixed with Dispersion I to prepare a coating solution. Using a coating machine (DRC-650, POWREC Co., Ltd.), the coating liquid was sprayed until the weight of the uncoated tablet obtained in (4) increased by 10 mg per tablet, thereby obtaining a film tablet having the following composition. . The film tablet was then dried under reduced pressure at 40 ° C. for 18 hours.
- composition amlodipine besylate 13.87 mg Mannitol 122.93 mg Crystalline cellulose 9 mg Hydroxypropylcellulose 5.4 mg Compound A 21.34 mg Mannitol 43.465mg Crystalline cellulose 4.5 mg Sodium hydroxide 0.345mg 1 mg of fumaric acid Hydroxypropylcellulose 2.7 mg Crystalline cellulose 27 mg Crospovidone 15.75 mg Magnesium stearate 2.7 mg Hydroxypropyl methylcellulose 7.8 mg Talc 1.2 mg Titanium oxide 0.9 mg Iron oxide 0.1 mg 280 mg total
- a binding liquid I was prepared by dissolving hydroxypropylcellulose (5124 g) in purified water (80280 g). In a fluidized bed granulator / dryer (WSG-60, Pauleck Co., Ltd.), amlodipine besylate (2984 g), mannitol (55840 g) and crystalline cellulose (3870 g) were uniformly mixed, and then binding liquid I (38700 g) was sprayed. The mixture was granulated and then dried to obtain a granulated powder.
- WSG-60 fluidized bed granulator / dryer
- Part of the resulting granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain granulated powder A.
- Sodium hydroxide (405.8 g) and fumaric acid (1176 g) were dissolved in purified water (38230 g) to prepare a buffer solution.
- Hydroxypropyl cellulose (3018 g) was dissolved in purified water (47280 g) to prepare a binding solution II.
- Compound A (20060 g), mannitol (40860 g), and crystalline cellulose (4230 g) were uniformly mixed in a fluidized bed granulator / dryer (WSG-60, POWREC Co., Ltd.), and then sprayed with a buffer solution (31810 g). Granulation was carried out while spraying the binding liquid II (42300 g), and then dried to obtain a granulated powder. Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain sized powder B.
- P-7S Showa Chemical Machinery Co., Ltd.
- Crystalline cellulose (1620 g), crospovidone (1080 g) and magnesium stearate (162 g) are added to the obtained sized powder A (4536 g) and sized powder B (8802 g), and a tumbler mixer (TM-60S) is added.
- a mixed powder was obtained.
- the mixed powder is tableted with a rotary tableting machine (AQUA512SS2AI, Kikusui Seisakusho) using a punch with a major axis of 14 mm and a minor axis of 8 mm (tablet pressure: 9 kN, weight per tablet: 540 mg), and uncoated tablet Got.
- Dispersion II was prepared by dispersing titanium oxide (54 g) and iron oxide (6 g) in purified water (900 g). Dispersion II and purified water (180 g) were mixed with Dispersion I to prepare a coating solution. Using a coating machine (DRC-650, POWREC Co., Ltd.), the coating liquid was sprayed until the weight of the uncoated tablet obtained in (4) increased by 20 mg per tablet, thereby obtaining a film tablet having the following composition. . The film tablet was then dried under reduced pressure at 40 ° C. for 18 hours.
- composition amlodipine besylate 6.94 mg Mannitol 129.86 mg Crystalline cellulose 9 mg Hydroxypropylcellulose 5.4 mg Compound A 85.36 mg Mannitol 173.86 mg Crystalline cellulose 18 mg Sodium hydroxide 1.38 mg Fumaric acid 4 mg Hydroxypropylcellulose 10.8 mg Crystalline cellulose 54 mg Crospovidone 36 mg Magnesium stearate 5.4 mg Hydroxypropyl methylcellulose 15.6 mg Talc 2.4 mg Titanium oxide 1.8 mg Iron oxide 0.2 mg 560 mg total
- a binding liquid I was prepared by dissolving hydroxypropylcellulose (5124 g) in purified water (80280 g). In a fluidized bed granulator / dryer (WSG-60, Powrec Co., Ltd.), amlodipine besylate (5964 g), mannitol (52860 g) and crystalline cellulose (3870 g) were uniformly mixed, and then binding liquid I (38700 g) was sprayed. The mixture was granulated and then dried to obtain a granulated powder.
- WSG-60 fluidized bed granulator / dryer
- Part of the resulting granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain granulated powder A.
- Sodium hydroxide (405.8 g) and fumaric acid (1176 g) were dissolved in purified water (38230 g) to prepare a buffer solution.
- Hydroxypropyl cellulose (3018 g) was dissolved in purified water (47280 g) to prepare a binding solution II.
- Compound A (20060 g), mannitol (40860 g), and crystalline cellulose (4230 g) were uniformly mixed in a fluidized bed granulator / dryer (WSG-60, POWREC Co., Ltd.), and then sprayed with a buffer solution (31810 g). Granulation was carried out while spraying the binding liquid II (42300 g), and then dried to obtain a granulated powder. Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain sized powder B.
- P-7S Showa Chemical Machinery Co., Ltd.
- Crystalline cellulose (1620 g), crospovidone (1080 g) and magnesium stearate (162 g) are added to the obtained sized powder A (4536 g) and sized powder B (8802 g), and a tumbler mixer (TM-60S) is added.
- a mixed powder was obtained.
- the mixed powder is tableted with a rotary tableting machine (AQUA512SS2AI, Kikusui Seisakusho) using a punch with a major axis of 14 mm and a minor axis of 8 mm (tablet pressure: 9 kN, weight per tablet: 540 mg), and uncoated tablet Got.
- Dispersion II was prepared by dispersing titanium oxide (54 g) and iron oxide (6 g) in purified water (900 g). Dispersion II and purified water (180 g) were mixed with Dispersion I to prepare a coating solution. Using a coating machine (DRC-650, POWREC Co., Ltd.), the coating liquid was sprayed until the weight of the uncoated tablet obtained in (4) increased by 20 mg per tablet, thereby obtaining a film tablet having the following composition. . The film tablet was then dried under reduced pressure at 40 ° C. for 18 hours.
- composition amlodipine besylate 13.87 mg Mannitol 122.93 mg Crystalline cellulose 9 mg Hydroxypropylcellulose 5.4 mg Compound A 85.36 mg Mannitol 173.86 mg Crystalline cellulose 18 mg Sodium hydroxide 1.38 mg Fumaric acid 4 mg Hydroxypropylcellulose 10.8 mg Crystalline cellulose 54 mg Crospovidone 36 mg Magnesium stearate 5.4 mg Hydroxypropyl methylcellulose 15.6 mg Talc 2.4 mg Titanium oxide 1.8 mg Iron oxide 0.2 mg 560 mg total
- a binding liquid I was prepared by dissolving hydroxypropyl cellulose (162 g) in purified water (2538 g). After amlodipine besylate (416.9 g), mannitol (3687 g) and crystalline cellulose (270 g) were uniformly mixed in a fluidized bed granulator / dryer (FD-5S, POWREC Co., Ltd.), the binding liquid I was sprayed. Then, it was granulated and then dried to obtain a granulated powder. Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill crusher (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-3 Showa Chemical Machinery Co., Ltd.
- Crystalline cellulose (396 g), crospovidone (198 g) and magnesium stearate (39.6 g) are added to the obtained sized powder (3326 g), and mixed with a tumbler mixer (TM-60S, Showa Chemical Machinery Co., Ltd.). As a result, mixed powder A was obtained.
- Sodium hydroxide (62.1 g) and fumaric acid (180 g) were dissolved in purified water (5850 g) to prepare a buffer solution.
- Hydroxypropyl cellulose (486 g) was dissolved in purified water (7614 g) to prepare a binding solution II.
- Compound A (1196 g), mannitol (2433 g), and crystalline cellulose (252 g) were uniformly mixed in a fluidized bed granulator / dryer (FD-5S, Powrec Co., Ltd.), and sprayed with a buffer solution (1895 g). Granulation was carried out while spraying the binding liquid II (2520 g), followed by drying to obtain a granulated powder. Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill crusher (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- a power mill crusher P-3, Showa Chemical Machinery Co., Ltd.
- Crystalline cellulose (792 g), crospovidone (594 g) and magnesium stearate (79.2 g) are added to the obtained sized powder (6455 g) and mixed with a tumbler mixer (TM-60S, Showa Chemical Machinery Co., Ltd.).
- a tumbler mixer T-60S, Showa Chemical Machinery Co., Ltd.
- mixed powder B was obtained.
- Dispersion I was prepared by dissolving and dispersing hydroxypropylmethylcellulose (390 g) and talc (60 g) in purified water (3500 g).
- Dispersion II was prepared by dispersing titanium oxide (45 g) and iron oxide (5 g) in purified water (750 g).
- Dispersion II and purified water (250 g) were mixed with Dispersion I to prepare a coating solution.
- a coating machine DRC-500, POWREC Co., Ltd.
- the coating liquid was sprayed until the weight of the uncoated tablet obtained in (3) increased by 20 mg per tablet, thereby obtaining a film tablet having the following composition. .
- the film tablet was dried under reduced pressure at 40 ° C. for 16 hours.
- composition amlodipine besylate 13.87 mg Mannitol 122.93 mg Crystalline cellulose 9 mg Hydroxypropylcellulose 5.4 mg Crystalline cellulose 18 mg Crospovidone 9 mg Magnesium stearate 1.8 mg Compound A 85.36 mg Mannitol 173.86 mg Crystalline cellulose 18 mg Sodium hydroxide 1.38 mg Fumaric acid 4 mg Hydroxypropylcellulose 10.8 mg Crystalline cellulose 36 mg Crospovidone 27 mg Magnesium stearate 3.6 mg Hydroxypropyl methylcellulose 15.6 mg Talc 2.4 mg Titanium oxide 1.8 mg Iron oxide 0.2 mg 560 mg total
- Reference example 1 Compound A (42.68 g), lactose (217.32 g), crystalline cellulose (32 g), and monosodium fumarate (10 g) were mixed uniformly in a fluidized bed granulator / dryer (Lab-1, POWREC Co., Ltd.) Thereafter, an aqueous solution of hydroxypropylcellulose (12 g) and monosodium fumarate (10 g) was sprayed and granulated, and then dried in the machine. The obtained granulated product was sieved with a sieve of 16 mesh (aperture 1.0 mm) to obtain a sized powder.
- Low-substituted hydroxypropylcellulose (0.8 g) was added to the obtained sized powder (16.2 g) and mixed in a glass bottle.
- the resulting mixture was tableted with a 9.5 mm ⁇ punch (tablet pressure: 7.5 KN / ⁇ , weight per tablet: 398.3 mg) using an autograph (manufactured by Shimadzu Corporation, AG-5000B).
- An uncoated tablet having the following composition was obtained. Subsequently, the uncoated tablet was dried under reduced pressure at 40 ° C. for 16 hours.
- Formulation Example 11 (1) Compound A (85.36 g), amlodipine besylate (13.87 g), mannitol (184.89 g), and crystalline cellulose (22.22 g) in a fluidized bed granulator / dryer (Lab-1, Paulek, Inc.). After uniformly mixing 5 g), an aqueous solution of hydroxypropylmethylcellulose (12.0 g), fumaric acid (4.0 g) and sodium hydroxide (1.38 g) was sprayed and granulated, and then dried in the machine. The obtained granulated product was sieved with a sieve of 16 mesh (aperture 1.0 mm) to obtain a sized powder A.
- Croscarmellose sodium (25.6 g), crystalline cellulose (32.0 g) and magnesium stearate (3.2 g) were added to the obtained sized powder A (259.2 g), and mixed in a bag.
- the obtained mixture was compressed with a rotary tableting machine (VEL50306SS2MZ, Kikusui Seisakusho) using a 9.5 mm ⁇ punch (tablet pressure: 7 KN / ⁇ , weight per tablet: 400 mg), and An uncoated tablet of composition was obtained. Subsequently, the uncoated tablet was dried under reduced pressure at 40 ° C. for 16 hours.
- Formulation Example 12 (1) After uniformly mixing amlodipine besylate (41.61 g), crystalline cellulose (35.1 g) and mannitol (349.89 g) in a fluidized bed granulator / dryer (Lab-1, POWREC Co., Ltd.) An aqueous solution of hydroxypropylmethylcellulose (16.2 g) was sprayed and granulated, and then dried in the machine. The obtained granulated product was sieved with a sieve of 16 mesh (aperture 1.0 mm) to obtain a sized powder A.
- the obtained granulated product was sieved with a sieve of 16 mesh (aperture 1.0 mm) to obtain sized powder B.
- croscarmellose sodium 32.4 g
- crystalline cellulose 43.2 g
- magnesium stearate 4.3 g
- the obtained mixed powder A 180 mg
- mixed powder B 360 mg
- Weight per tablet 540 mg
- uncoated tablets having the following composition were obtained.
- the uncoated tablet was dried under reduced pressure at 40 ° C. for 16 hours.
- Comparative Example 1 Compound A (42.68 g), lactose (217.32 g) and crystalline cellulose (32 g) were uniformly mixed in a fluidized bed granulator / dryer (Lab-1, POWREC Co., Ltd.), and then hydroxypropylcellulose (12 g). Was sprayed and granulated, and then dried in the machine. The obtained granulated product was sieved with a sieve of 16 mesh (aperture 1.0 mm) to obtain a sized powder. Low-substituted hydroxypropylcellulose (0.8 g) was added to the resulting sized powder (15.2 g) and mixed in a glass bottle.
- the obtained mixture was tableted with a 9.5 mm ⁇ punch using an autograph (manufactured by Shimadzu Corp., AG-5000B) (tablet pressure: 7.5 KN / ⁇ , weight per tablet: 374.9 mg).
- An uncoated tablet having the following composition was obtained. Subsequently, the uncoated tablet was dried under reduced pressure at 40 ° C. for 16 hours.
- Composition Compound A 50 mg Lactose 254.6mg Crystalline cellulose 37.5mg Hydroxypropylcellulose 14.1mg Low substituted hydroxypropylcellulose 18.7mg Total 374.9mg
- Formulation Example 13 (1) Compound A (136.58 g) and mannitol (306.98 g) were uniformly mixed in a fluidized bed granulator / dryer (Lab-1, POWREC Co., Ltd.), hydroxypropylcellulose (17.3 g), An aqueous solution of fumaric acid (6.4 g) and sodium hydroxide (2.21 g) was sprayed to granulate and then dried in the machine. The obtained granulated product was sieved with a sieve of 16 mesh (aperture 1.0 mm) to obtain a sized powder A.
- fine particles B were sieved with a sieve to obtain fine particles B of 150 to 350 ⁇ m.
- SPIR-A-FLOW rolling fluidized bed granulator / dryer
- the obtained fine particles were sieved with a sieve to obtain fine particles C of 150 to 425 ⁇ m.
- the obtained mixed powder A (126 g) and fine granules C (63 g) were mixed in a bag.
- the obtained mixture was compressed with a rotary tableting machine (VEL50306SS2MZ, Kikusui Seisakusho) using a 10.5 mm ⁇ punch (tablet pressure: 8.5 KN / ⁇ , weight per tablet: 540 mg), and the following composition
- the uncoated tablet was obtained.
- the uncoated tablet was dried under reduced pressure at 40 ° C. for 16 hours to obtain a tablet containing fine granules.
- Formulation (per 540 mg) Composition Compound A 85.36 mg Mannitol 191.86mg Hydroxypropylcellulose 10.8 mg Fumaric acid 4 mg Sodium hydroxide 1.38mg Amlodipine besylate 13.87mg Crystalline cellulose (grain) 85 mg Crystalline cellulose 3.13mg Low substituted hydroxypropylcellulose 18 mg Hydroxypropyl methylcellulose 28.8 mg Talc 7.2 mg Titanium oxide 7.2 mg Mannitol 16.8 mg Croscarmellose sodium 27 mg Crystalline cellulose 36 mg Magnesium stearate 3.6 mg 540 mg total
- a binding liquid I was prepared by dissolving hydroxypropyl cellulose (2802 g) in purified water (43900 g). In a fluidized bed granulator / dryer (WSG-60, Pauleck Co., Ltd.), amlodipine besylate (5464 g), mannitol (52860 g) and crystalline cellulose (3870 g) were mixed uniformly, and then the binding liquid I (38700 g) was sprayed. The mixture was granulated and then dried to obtain a granulated powder.
- WSG-60 fluidized bed granulator / dryer
- Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose (7290 g) crospovidone (3645 g) and magnesium stearate (729 g)
- TM-400S tumbler mixer
- a mixed powder A was obtained.
- (2) Sodium hydroxide (2.76 g) and fumaric acid (8 g) were dissolved in purified water (260 g) to prepare a buffer solution, and hydroxypropyl cellulose (16.2 g) was partially added (203.1 g).
- Crystalline cellulose (36 g), crospovidone (27 g) and magnesium stearate (3.6 g) were added to the obtained sized powder (293.4 g), and mixed in a plastic bag to obtain mixed powder B.
- (3) The mixed powder A (180 mg) and the mixed powder B (360 mg) were compressed with an autograph (AG-500B, Shimadzu Corporation) using a punch having a major axis of 14 mm and a minor axis of 8 mm ⁇ (tablet pressure: 8 kN, (Weight per tablet: 540 mg) to obtain an uncoated tablet.
- the uncoated tablets were then dried under reduced pressure at 40 ° C. for 15 hours.
- composition amlodipine besylate 13.87 mg Mannitol 122.93 mg Crystalline cellulose 9 mg Hydroxypropylcellulose 5.4 mg Crystalline cellulose 18 mg Crospovidone 9 mg Magnesium stearate 1.8 mg Compound A 85.36 mg Mannitol 173.86 mg Crystalline cellulose 18 mg Sodium hydroxide 1.38 mg Fumaric acid 4 mg Hydroxypropylcellulose 10.8 mg Crystalline cellulose 36 mg Crospovidone 27 mg Magnesium stearate 3.6 mg 540 mg total
- a binding liquid I was prepared by dissolving hydroxypropyl cellulose (2802 g) in purified water (43900 g). In a fluidized bed granulator / dryer (WSG-60, Pauleck Co., Ltd.), amlodipine besylate (5464 g), mannitol (52860 g) and crystalline cellulose (3870 g) were mixed uniformly, and then the binding liquid I (38700 g) was sprayed. The mixture was granulated and then dried to obtain a granulated powder.
- WSG-60 fluidized bed granulator / dryer
- Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose (7290 g) crospovidone (3645 g) and magnesium stearate (729 g)
- TM-400S tumbler mixer
- a mixed powder A was obtained.
- Hydroxypropyl cellulose (16.2 g) was dissolved in purified water (253.8 g) to prepare a binding solution II.
- composition amlodipine besylate 13.87 mg Mannitol 122.93 mg Crystalline cellulose 9 mg Hydroxypropylcellulose 5.4 mg Crystalline cellulose 18 mg Crospovidone 9 mg Magnesium stearate 1.8 mg Compound A 85.36 mg Mannitol 179.24 mg Crystalline cellulose 18 mg Hydroxypropylcellulose 10.8 mg Crystalline cellulose 36 mg Crospovidone 27 mg Magnesium stearate 3.6 mg 540 mg total
- a binding liquid I was prepared by dissolving hydroxypropyl cellulose (2802 g) in purified water (43900 g). In a fluidized bed granulator / dryer (WSG-60, Paulek Co., Ltd.), amlodipine besylate (2982 g), mannitol (55840 g) and crystalline cellulose (3870 g) were uniformly mixed, and then binding liquid I (38700 g) was sprayed. The mixture was granulated and then dried to obtain a granulated powder.
- WSG-60 fluidized bed granulator / dryer
- Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose 7290 g
- crospovidone 3645 g
- magnesium stearate 729 g
- a mixed powder A was obtained.
- TM-400S tumbler mixer
- Hydroxypropyl cellulose (3018 g) was dissolved in purified water (47280 g) to prepare a binding solution II.
- Compound A 20060 g
- mannitol 40860 g
- crystalline cellulose 4230 g
- WSG-60 fluidized bed granulator / dryer
- Granulation was carried out while spraying the binding liquid II (42300 g), and then dried to obtain a granulated powder.
- Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose (7380 g) crospovidone (5535 g) and magnesium stearate (738 g)
- TM-400S Showa Chemical Machinery Co., Ltd.
- Dispersion I was prepared by dissolving and dispersing hydroxypropyl methylcellulose (3978 g) and talc (612 g) in purified water (36720 g).
- Dispersion II was prepared by dispersing titanium oxide (459 g) and iron oxide (51 g) in purified water (9180 g). Dispersion II was added to Dispersion I and mixed by stirring to obtain a coating solution.
- the coating liquid was sprayed until the weight of the uncoated tablet obtained in (3) increased by 10 mg per tablet, thereby obtaining a film tablet having the following composition. . Subsequently, the film tablet was dried under reduced pressure at 40 ° C. for 15 hours.
- composition amlodipine besylate 6.935 mg Mannitol 129.865 mg Crystalline cellulose 9 mg Hydroxypropylcellulose 5.4 mg Crystalline cellulose 18 mg Crospovidone 9 mg Magnesium stearate 1.8 mg Compound A 42.68 mg Mannitol 86.93 mg Crystalline cellulose 9 mg Sodium hydroxide 0.69 mg Fumaric acid 2 mg Hydroxypropylcellulose 5.4 mg Crystalline cellulose 18 mg Crospovidone 13.5 mg Magnesium stearate 1.8 mg Hydroxypropyl methylcellulose 7.8 mg Talc 1.2 mg Titanium oxide 0.9 mg Iron oxide 0.1 mg 370 mg total
- a binding liquid I was prepared by dissolving hydroxypropyl cellulose (2802 g) in purified water (43900 g). In a fluidized bed granulator / dryer (WSG-60, Powrec Co., Ltd.), amlodipine besylate (5964 g), mannitol (52860 g) and crystalline cellulose (3870 g) were uniformly mixed, and then binding liquid I (38700 g) was sprayed. The mixture was granulated and then dried to obtain a granulated powder.
- WSG-60 fluidized bed granulator / dryer
- Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose 7290 g
- crospovidone 3645 g
- magnesium stearate 729 g
- a mixed powder A was obtained.
- TM-400S tumbler mixer
- Hydroxypropyl cellulose (3018 g) was dissolved in purified water (47280 g) to prepare a binding solution II.
- Compound A 20060 g
- mannitol 40860 g
- crystalline cellulose 4230 g
- WSG-60 fluidized bed granulator / dryer
- Granulation was carried out while spraying the binding liquid II (42300 g), and then dried to obtain a granulated powder.
- Part of the obtained granulated powder was pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose (7380 g) crospovidone (5535 g) and magnesium stearate (738 g)
- TM-400S Showa Chemical Machinery Co., Ltd.
- Dispersion I was prepared by dissolving and dispersing hydroxypropyl methylcellulose (3978 g) and talc (612 g) in purified water (36720 g).
- Dispersion II was prepared by dispersing titanium oxide (459 g) and iron oxide (51 g) in purified water (9180 g). Dispersion II was added to Dispersion I and mixed by stirring to obtain a coating solution.
- the coating liquid was sprayed until the weight of the uncoated tablet obtained in (3) increased by 10 mg per tablet, thereby obtaining a film tablet having the following composition. . Subsequently, the film tablet was dried under reduced pressure at 40 ° C. for 15 hours.
- composition amlodipine besylate 13.87 mg Mannitol 122.93 mg Crystalline cellulose 9 mg Hydroxypropylcellulose 5.4 mg Crystalline cellulose 18 mg Crospovidone 9 mg Magnesium stearate 1.8 mg Compound A 42.68 mg Mannitol 86.93 mg Crystalline cellulose 9 mg Sodium hydroxide 0.69 mg Fumaric acid 2 mg Hydroxypropylcellulose 5.4 mg Crystalline cellulose 18 mg Crospovidone 13.5 mg
- a binding liquid I is prepared by dissolving hydroxypropyl cellulose (2802 g) in purified water (43900 g). In a fluidized bed granulator / dryer (WSG-60, Paulek Co., Ltd.), amlodipine besylate (2982 g), mannitol (55840 g) and crystalline cellulose (3870 g) were uniformly mixed, and then binding liquid I (38700 g) was sprayed. Then, it is granulated and then dried to obtain a granulated powder.
- WSG-60 fluidized bed granulator / dryer
- Part of the obtained granulated powder is pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose (7290 g) crospovidone (3645 g) and magnesium stearate (729 g)
- TM-400S tumbler mixer
- Hydroxypropyl cellulose (3018 g) is dissolved in purified water (47280 g) to prepare binding solution II.
- Compound A (20060 g), mannitol (40860 g), and crystalline cellulose (4230 g) were uniformly mixed in a fluidized bed granulator / dryer (WSG-60, POWREC Co., Ltd.), and then sprayed with a buffer solution (31810 g).
- Granulation is carried out while spraying the binding liquid II (42300 g), and then dried to obtain a granulated powder.
- Part of the obtained granulated powder is pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- Dispersion I is prepared by dissolving and dispersing hydroxypropylmethylcellulose (3978 g) and talc (612 g) in purified water (36720 g).
- Dispersion II is prepared by dispersing titanium oxide (494.7 g) and iron oxide (15.3 g) in purified water (9180 g).
- Dispersion liquid II is added to dispersion liquid I and mixed by stirring to obtain a coating liquid.
- a coating machine DRC-1200, POWREC Co., Ltd.
- the coating liquid is sprayed until the weight of the uncoated tablet obtained in (3) increases by 10 mg per tablet, whereby a film tablet having the following composition is obtained.
- the film tablet is then dried under reduced pressure at 40 ° C. for 15 hours.
- a binding liquid I is prepared by dissolving hydroxypropyl cellulose (2802 g) in purified water (43900 g). In a fluidized bed granulator / dryer (WSG-60, Paulek Co., Ltd.), amlodipine besylate (2982 g), mannitol (55840 g) and crystalline cellulose (3870 g) were uniformly mixed, and then binding liquid I (38700 g) was sprayed. Then, it is granulated and then dried to obtain a granulated powder.
- WSG-60 fluidized bed granulator / dryer
- Part of the obtained granulated powder is pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose (7290 g) crospovidone (3645 g) and magnesium stearate (729 g)
- TM-400S tumbler mixer
- Hydroxypropyl cellulose (3018 g) is dissolved in purified water (47280 g) to prepare binding solution II.
- Compound A (20060 g), mannitol (40860 g), and crystalline cellulose (4230 g) were uniformly mixed in a fluidized bed granulator / dryer (WSG-60, POWREC Co., Ltd.), and then sprayed with a buffer solution (31810 g).
- Granulation is carried out while spraying the binding liquid II (42300 g), and then dried to obtain a granulated powder.
- Part of the obtained granulated powder is pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- Dispersion I is prepared by dissolving and dispersing hydroxypropylmethylcellulose (3978 g) and talc (612 g) in purified water (36720 g).
- Dispersion II is prepared by dispersing titanium oxide (494.7 g) and iron oxide (15.3 g) in purified water (9180 g).
- Dispersion liquid II is added to dispersion liquid I and mixed by stirring to obtain a coating liquid.
- a coating machine DRC-1200, POWREC Co., Ltd.
- the coating liquid is sprayed until the weight of the uncoated tablet obtained in (3) increases by 10 mg per tablet, whereby a film tablet having the following composition is obtained.
- the film tablet is then dried under reduced pressure at 40 ° C. for 15 hours.
- composition amlodipine besylate 6.935 mg Mannitol 129.865 mg Crystalline cellulose 9 mg Hydroxypropylcellulose 5.4 mg Crystalline cellulose 18 mg Crospovidone 9 mg Magnesium stearate 1.8 mg Compound A 42.68 mg Mannitol 86.93 mg Crystalline cellulose 9 mg Sodium hydroxide 0.69 mg Fumaric acid 2 mg Hydroxypropylcellulose 5.4 mg Crystalline cellulose 18 mg Crospovidone 13.5 mg Magnesium stearate 1.8 mg Hydroxypropyl methylcellulose 7.8 mg Talc 1.2 mg Titanium oxide 0.97 mg Iron oxide 0.03 mg 370 mg total
- a binding liquid I is prepared by dissolving hydroxypropyl cellulose (2802 g) in purified water (43900 g). In a fluidized bed granulator / dryer (WSG-60, Paulek Co., Ltd.), amlodipine besylate (2982 g), mannitol (55840 g) and crystalline cellulose (3870 g) were uniformly mixed, and then binding liquid I (38700 g) was sprayed. Then, it is granulated and then dried to obtain a granulated powder.
- WSG-60 fluidized bed granulator / dryer
- Part of the obtained granulated powder is pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- P-7S Power mill grinder
- crystalline cellulose (7290 g) crospovidone (3645 g) and magnesium stearate (729 g)
- TM-400S tumbler mixer
- Hydroxypropyl cellulose (3018 g) is dissolved in purified water (47280 g) to prepare binding solution II.
- Compound A (20060 g), mannitol (40860 g), and crystalline cellulose (4230 g) were uniformly mixed in a fluidized bed granulator / dryer (WSG-60, POWREC Co., Ltd.), and then sprayed with a buffer solution (31810 g).
- Granulation is carried out while spraying the binding liquid II (42300 g), and then dried to obtain a granulated powder.
- Part of the obtained granulated powder is pulverized with a 1.5 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
- Dispersion I is prepared by dissolving and dispersing hydroxypropylmethylcellulose (3978 g) and talc (612 g) in purified water (36720 g).
- Dispersion II is prepared by dispersing titanium oxide (494.7 g) and iron oxide (15.3 g) in purified water (9180 g).
- Dispersion liquid II is added to dispersion liquid I and mixed by stirring to obtain a coating liquid.
- a coating machine DRC-1200, POWREC Co., Ltd.
- the coating liquid is sprayed until the weight of the uncoated tablet obtained in (3) increases by 20 mg per tablet, whereby a film tablet having the following composition is obtained.
- the film tablet is then dried under reduced pressure at 40 ° C. for 15 hours.
- Experimental Example 4 The drug (free compound A form) dissolution properties of the dry plain tablets obtained in Formulation Example 14 and Comparative Example 2 were evaluated in the same manner as in Experimental Example 1. The results are shown in FIG. - ⁇ -indicates the result of the dry uncoated tablet of Preparation Example 14 (dissolution rate (%) of the free form of Compound A contained in the dry uncoated tablet of Preparation Example 14). - ⁇ -indicates the result of the dry uncoated tablet of Comparative Example 2 (dissolution rate (%) of the free form of Compound A contained in the dry uncoated tablet of Comparative Example 2). As shown in FIG. 2, it was shown that the dissolution property was improved by adding a pH adjusting agent.
- the present invention has an advantage that a solid preparation excellent in the dissolution property and stability of the compound (I) can be provided. Further, the combined use of compound (I) and a calcium antagonist has an advantage that a solid preparation excellent in the stability of compound (I) and calcium antagonist can be provided.
Abstract
Description
医薬品は有効かつ安全であることが重要であり、たとえ製造直後に有効かつ安全な状態であっても、流通過程で薬物が容易に分解・変質してしまうようなものは、医薬品としての有効性と安全性が担保されているとは言えない。従って、薬物の安定性は、医薬品にとって極めて重要である。
すなわち、医薬品には、有効性と安全性に加え、安定性と一定の薬物溶出性が保証されていることが要求される。
一方、薬物溶出性は、薬物の溶解度と相関することが知られている。すなわち一般に、薬物の溶解度が低いほど、薬物の溶出性は悪くなることが知られている。
本発明の課題は化合物(I)およびカルシウム拮抗剤の安定性に優れ、またそれらの溶出性にも優れた、固形製剤を提供することである。
(1)式(I)
(2)式(I)で表される化合物またはその塩が2-エトキシ-1-{[2'-(5-オキソ-4,5-ジヒドロ-1,2,4-オキサジアゾール-3-イル)ビフェニル-4-イル]メチル}-1H-ベンズイミダゾール-7-カルボン酸 (5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メチル カリウム塩である上記(1)記載の固形製剤;
(3)カルシウム拮抗剤がアムロジピンまたはその酸付加塩である、上記(1)又は(2)記載の固形製剤;
(4)カルシウム拮抗剤がベシル酸アムロジピンである、上記(1)又は(2)記載の固形製剤;
(5)式(I)で表される化合物またはその塩が2-エトキシ-1-{[2'-(5-オキソ-4,5-ジヒドロ-1,2,4-オキサジアゾール-3-イル)ビフェニル-4-イル]メチル}-1H-ベンズイミダゾール-7-カルボン酸 (5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メチル カリウム塩であり、カルシウム拮抗剤がベシル酸アムロジピンである上記(1)記載の固形製剤;
(6)pH調整剤がpH2ないし5のpH調整剤である上記(1)記載の固形製剤;
(7)pH調整剤が酒石酸、クエン酸、乳酸、フマル酸、コハク酸、リン酸、リンゴ酸、アスコルビン酸、酢酸、酸性アミノ酸から選ばれる酸性物質、もしくはその塩、またはそれらの溶媒和物である上記(1)記載の固形製剤;
(8)pH調整剤がフマル酸一ナトリウム、またはフマル酸とナトリウムイオンの供与体の組み合わせである上記(1)記載の固形製剤;
(9)式(I):
カルシウム拮抗剤を含有する第二の部分を含む固形製剤であって、第一の部分および第二の部分をそれぞれ個別に造粒して得られる固形製剤;
(10)式(I):
カルシウム拮抗剤を含有する第二の部分を含む固形製剤であって、第一の部分からなる第一層および、第二の部分からなる第二層を含む積層錠剤である、上記(1)記載の固形製剤;
(11)pH調整剤の配合量が、製剤に対して0.01~20重量%である上記(1)記載の固形製剤;
(12)式(I):
(13)式(I):
などに関する。
以下に、本発明の固形製剤を詳細に説明する。
本発明の固形製剤は、化合物(I)、pH調整剤およびカルシウム拮抗剤を含有する固形製剤である。本発明の固形製剤は、化合物(I)の安定性に優れ、かつ該化合物の溶出性にも優れている。さらにカルシウム拮抗剤の安定性にも優れている。
なお、4,5-ジヒドロ-5-オキソ-1,2,4-オキサジアゾール-3-イル基には、式:
式(I)で表される化合物の塩は水和物または非水和物のいずれであってもよい。
また、化合物(I)は水和物を含む溶媒和物または非溶媒和物のいずれであってもよい。
ここに、pH調整剤におけるpHは次の条件下に測定したものである。即ち、25℃で水に1%w/vにてpH調整剤を溶解または懸濁させて得た溶液または懸濁液のpHである。
さらに、本発明で用いるpH調整剤としては、リン酸二水素ナトリウム、フマル酸一ナトリウムまたはフマル酸とナトリウムイオンとの供与体の組合せなどのように、溶液が当該pHにおいて緩衝能を有するものが好ましい。
本発明で用いるpH調整剤としては、フマル酸一ナトリウムまたはフマル酸とナトリウムイオンの供与体の組合せが好ましく、フマル酸と水酸化ナトリウムとを組み合わせて用いてもよい。
本発明におけるカルシウム拮抗剤としてはアムロジピンまたはその塩が好ましく、アムロジピンまたはその酸付加塩がより好ましく、アムロジピンの塩がさらに好ましい。アムロジピンの塩としてはベシル酸アムロジピン、マレイン酸アムロジピン等が好ましく、ベシル酸アムロジピンがより好ましい。
本発明における固形製剤の態様としては、次のような製剤等が挙げられる。
(1)化合物(I)、pH調整剤、カルシウム拮抗剤を混合して造粒して得られる固形製剤(一群造粒製剤)。
(2)化合物(I)およびpH調整剤を含有する第一の部分、ならびにカルシウム拮抗剤を含有する第二の部分を含む固形製剤であって、第一の部分および第二の部分をそれぞれ個別に造粒して得られる固形製剤(二群造粒製剤‐単層錠剤)。
(3a)個別に造粒された第一の部分と第二の部分とを圧縮成形することによって得られる固形製剤(二群造粒製剤‐積層錠剤)。
(3b)個別に造粒された第一の部分と第二の部分において、一方の部分に他方の部分を被覆することによって得られる固形製剤(二群造粒製剤‐被覆錠剤)。
上記(2)、(3a)および(3b)の固形製剤(二群造粒製剤)においては、化合物(I)およびカルシウム拮抗剤のそれぞれの溶出性と安定性がより改善する。
例えば、化合物(I)、pH調整剤、カルシウム拮抗剤および添加剤などを加えて混合し、結合剤を加えて顆粒とし、顆粒に滑沢剤等を加えて打錠して錠剤とする。また顆粒剤、細粒剤においても錠剤とほぼ同様の方法で製造することができる。
カプセル剤の場合は、上記の顆粒剤、細粒剤をゼラチンやヒドロキシプロピルメチルセルロース等を含有するカプセルに充填するか、もしくは有効成分を賦形剤とともに、ゼラチンやヒドロキシプロピルメチルセルロース等を含有するカプセルに充填すればよい。
安定化剤としては、例えばトコフェロール、エデト酸四ナトリウム、ニコチン酸アミド、シクロデキストリン類などが挙げられる。
香料としては、例えばメントール、ハッカ油、レモン油、バニリンなどが挙げられる。
流動化剤としては、例えば軽質無水ケイ酸、含水二酸化ケイ素などが挙げられる。
上記した添加剤は、2種以上を適宜の割合で混合して用いてもよい。
上記(2)の固形製剤であって、本発明における第一の部分は、化合物(I)およびpH調整剤を含有する部分(組成物)である。
上記第一の部分は、化合物(I)とpH調整剤とを、必要により上記添加剤とともに、自体公知の方法に従って混合し、造粒することによって製造することができる。
上記第二の部分は、前述した第一の部分と一緒に固形製剤を形成できる形状、大きさであれば限定されない。
具体的には、カルシウム拮抗剤(好ましくはベシル酸アムロジピン);賦形剤(好ましくはマンニトールおよび結晶セルロース);結合剤(好ましくはヒドロキシプロピルセルロース)を含有する。
当該カルシウム拮抗剤は、上記第二の部分100重量部に対して、好ましくは0.1~60重量部、より好ましくは0.5~40重量部、さらに好ましくは1~30重量部である。
個別に造粒された第一の部分と第二の部分を、さらに製剤分野において慣用の添加剤とともに混合し、圧縮成形することによって製造される単層錠剤も本発明の固形製剤に含まれる。上記単層錠剤を、カプセル(例、ヒドロキシプロピルメチルセルロースカプセル)に充填することによって製造されるカプセル剤も本発明の固形製剤に含まれる。
また、個別に造粒された第一の部分と第二の部分を、そのまま、または上記添加剤とともに混合して、カプセル(例、ヒドロキシプロピルメチルセルロースカプセル)に充填することによって製造されるカプセル剤も本発明の固形製剤に含まれる。
当該被覆は、例えば、圧縮成形、コーティングなどによって行われる。また、該添加剤は、好ましくは結合剤などである。
化合物(I)とpH調整剤とを、必要に応じて添加剤と混合し、得られた混合物を造粒し第一の部分を得る。造粒の後、必要により乾燥、整粒などの操作を行ってもよい。その後、必要に応じて添加剤と混合し第一層とする。
次いで、カルシウム拮抗剤を、必要に応じて添加剤と共に造粒し、得られた第二の部分に、必要に応じて添加剤を混合した第二層を上記第一層に層状に積み重ねて圧縮成形(好ましくは打錠)する。
この際、各層の直接接触を回避するために、各層の間に不活性な中間層を設けてもよい。該中間層は、例えば、上記した賦形剤、崩壊剤、結合剤、滑沢剤、着色剤等を含有する。
前記製造工程において、混合、圧縮成形、コーティングなどの操作は、製剤技術分野において慣用の方法にしたがって行われる。
なお、単発錠剤機、ロータリー式打錠機などを用いて圧縮成形を行う際には、通常1~20kN/cm2(好ましくは5~15kN/cm2)の打錠圧を採用することが好ましく、さらに、キャッピング防止を目的として、テーパー形状の臼を用いることが好ましい。
本発明の固形製剤は、経口的あるいは非経口的(例、直腸)に安全に投与できる。
患者に対する化合物(I)の投与量は、年齢、体重、一般的健康状態、性別、食事、投与時間、排泄速度、薬物の組み合わせなどを考慮し、また患者のその時に治療を行っている病状の程度に応じて決められるが、成人(体重60kg)1人あたり、一日投与量は約0.05~500mg、好ましくは0.1~100mgである。
患者に対するカルシウム拮抗剤の投与量は、年齢、体重、一般的健康状態、性別、食事、投与時間、排泄速度、薬物の組み合わせなどを考慮し、また患者のその時に治療を行っている病状の程度に応じて決められるが、例えば、アムロジピン(フリー体に換算して)は、成人(体重60kg)1人あたり、一日投与量約1~50mg、好ましくは2.5~10mgである。
化合物(I)は、一定の降圧作用を昼夜を問わず維持することが可能であることから、投与量・回数の軽減が可能であるだけでなく、高血圧症患者で特に問題となる起床前後の血圧上昇をより効果的に抑制することができる。
また、化合物(I)は肥満に伴う高血圧症の予防または治療剤、高血圧症に伴う肥満の予防または治療剤として用いることができる。
この報告によれば、糖尿病とは、空腹時血糖値(静脈血漿におけるグルコース濃度)が126mg/dl以上、75g経口ブドウ糖負荷試験(75gOGTT)2時間値(静脈血漿におけるグルコース濃度)が200mg/dl以上、随時血糖値(静脈血漿におけるグルコース濃度)が200mg/dl以上のいずれかを示す状態である。また、上記糖尿病に該当せず、かつ、「空腹時血糖値(静脈血漿におけるグルコース濃度)が110mg/dl未満または75g経口ブドウ糖負荷試験(75gOGTT)2時間値(静脈血漿におけるグルコース濃度)が140mg/dl未満を示す状態」(正常型)でない状態を、「境界型」と呼ぶ。
これらの報告によれば、糖尿病とは、空腹時血糖値(静脈血漿におけるグルコース濃度)が126mg/dl以上であり、かつ、75g経口ブドウ糖負荷試験2時間値(静脈血漿におけるグルコース濃度)が200mg/dl以上を示す状態である。
また、上記報告によれば、耐糖能異常とは、空腹時血糖値(静脈血漿におけるグルコース濃度)が126mg/dl未満であり、かつ、75g経口ブドウ糖負荷試験2時間値(静脈血漿におけるグルコース濃度)が140mg/dl以上200mg/dl未満を示す状態である。さらに、ADAの報告によれば、空腹時血糖値(静脈血漿におけるグルコース濃度)が110mg/dl以上126mg/dl未満の状態をIFG(Impaired Fasting Glucose)と呼ぶ。一方、WHOの報告によれば、該IFG(Impaired Fasting Glucose)のうち、75g経口ブドウ糖負荷試験2時間値(静脈血漿におけるグルコース濃度)が140mg/dl未満である状態をIFG(Impaired Fasting Glycemia)と呼ぶ。
代謝症候群の判定基準が、1999年にWHOから、2001年にNCEPから発表されている。WHOの判定基準によれば、高インスリン血症または耐糖能異常を基本条件に、内臓肥満、異常脂質血症(高TGまたは低HDL)、高血圧のうち2つ以上を持つ場合に代謝症候群と診断される(World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications. Part I: Diagnosis and Classification of Diabetes Mellitus, World Health Organization, Geneva, 1999)。米国の虚血性心疾患の管理指標であるNational Cholesterol Education Program のAdult Treatment Panel IIIの判定基準によれば、内臓肥満、高中性脂肪血症、低HDLコレステロール血症、高血圧、耐糖能異常のうち3つ以上を持つ場合に代謝症候群と診断される(National Cholesterol Education Program: Executive Summary of the Third Report of National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adults Treatment Panel III). The Journal of the American Medical Association, Vol. 285, 2486-2497, 2001)。
化合物(I)は、メタボリックシンドロームを発症している高血圧症患者の治療に用いることができる。
また、化合物(I)は鎮痛作用を有することから、化合物(I)は鎮痛薬として、疼痛の予防・治療薬として用いることもできる。疼痛疾患としては、例えば、炎症による急性痛、慢性炎症に伴う痛み、急性炎症に伴う痛み、術後痛(切開創の痛み、深部痛、内臓痛、術後慢性痛など)、筋肉痛(慢性痛疾患に伴う筋肉痛、肩こりなど)、関節痛、歯痛、顎関節痛、頭痛(偏頭痛、緊張型頭痛、発熱に伴う頭痛、高血圧に伴う頭痛)、内臓痛(心臓痛、狭心痛、腹痛、腎臓の痛み、尿管の痛み、膀胱の痛み)、産婦人科領域の痛み(中間痛、月経困難、陣痛)、神経痛(椎間板ヘルニア、神経根痛、帯状疱疹後神経痛、三叉神経痛)、癌性疼痛、反射性交感神経性萎縮症、複雑局所痛症候群などが挙げられる。化合物(I)は、神経性疼痛、癌性疼痛、炎症性疼痛などの各種疼痛を直接的かつ即効的に鎮めるのに有効であり、痛覚閾値が低下している患者や病態(例、高血圧症、糖尿病など、およびこれらの合併症など)に対して、特に優れた鎮痛効果を示す。化合物(I)は特に、慢性炎症に伴う痛みまたは高血圧に伴う頭痛の鎮痛剤として、または(1)アテローム性を含む動脈硬化症、(2)インターベンション後の血管肥厚、閉塞または臓器障害、(3)バイパス手術後の血管再閉塞・再狭窄、内皮機能障害、(4)間欠性跛行、(5)閉塞性末梢循環障害または(6)閉塞性動脈硬化症に因る炎症性疾患または疼痛の予防・治療剤として有用である。
本発明の固形製剤は、化合物(I)とカルシウム拮抗剤を組み合わせることにより、上記疾患の予防または治療薬(好ましくは、高血圧症、心不全、糖尿病性腎症、動脈硬化症の予防または治療薬、より好ましくは、高血圧症の予防または治療薬)として有用であり、化合物(I)やカルシウム拮抗剤を単独で使用する場合における投与量を減らすことが可能であり、副作用の発現を抑えることができる。
また、投与対象に対して、本発明の固形製剤と併用薬剤とを別々の錠剤として投与してもよいし、本発明の固形製剤と併用薬剤とを含む単一の製剤として投与してもよい。
このように、併用薬剤を用いることにより、1)化合物(I)または併用薬剤の作用の増強効果(薬剤作用の相乗効果)、2)化合物(I)または併用薬剤の投与量の低減効果(単独投与時と比較した場合の薬剤投与量の低減効果)、3)化合物(I)または併用薬剤の二次的な作用の低減効果などの優れた効果が得られる。
また、式(I)で表される化合物またはその塩、およびカルシウム拮抗剤を含有する固形製剤に、pH調整剤を配合することを特徴とする、固形製剤からの式(I)で表される化合物またはその塩の溶出改善方法を提供する。本発明の溶出改善方法によれば、固形製剤からの化合物(I)の溶出性が有意に改善される。
なお、製剤例、参考例および比較例として記載された処方において活性成分以外の成分(添加物)は、日本薬局方、日本薬局方外医薬品規格または医薬品添加物規格における収載品などを用いた。
(1)精製水(80280g)にヒドロキシプロピルセルロース(5124g)を溶解して結合液Iを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で、ベシル酸アムロジピン(2984g)、マンニトール(55840g)および結晶セルロース(3870g)を均一に混合した後、結合液I(38700g)を噴霧しながら、造粒し、ついで乾燥して、造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得た。得られた整粒末(60480g)に結晶セルロース(7200g)、クロスポビドン(3600g)およびステアリン酸マグネシウム(720g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Aを得た。
(2)精製水(38230g)に水酸化ナトリウム(405.8g)およびフマル酸(1176g)を溶解して、緩衝液を調製した。精製水(47280g)にヒドロキシプロピルセルロース(3018g)を溶解して結合液IIを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で化合物A(20060g)、マンニトール(40860g)、結晶セルロース(4230g)を均一に混合した後、緩衝液(31810g)を噴霧し、さらに結合液II(42300g)を噴霧しながら造粒し、ついで乾燥して造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得た。得られた整粒末(60150g)に結晶セルロース(7380g)、クロスポビドン(5535g)およびステアリン酸マグネシウム(738g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Bを得た。
(3)混合末A(180mg)および混合末B(90mg)をロータリー式打錠機(アクア08242L2JI、菊水製作所)で8.5mmφの杵を用いて打錠(打錠圧:8kN、1錠あたりの重量:270mg)し、素錠を得た。
(4)精製水(4320g)にヒドロキシプロピルメチルセルロース(468g)とタルク(72g)を溶解、分散して分散液Iを調製した。精製水(900g)に酸化チタン(54g)、酸化鉄(6g)を分散して分散液IIを調製した。分散液Iに分散液IIおよび精製水(180g)を混合し、コーティング液を調製した。コーティング機(DRC-650、株式会社パウレック)を用いて、(3)で得た該素錠の重量が1錠あたり10mg増加するまでコーティング液を噴霧することにより、下記組成のフィルム錠を得た。次いで、該フィルム錠を40℃で18時間減圧乾燥した。
ベシル酸アムロジピン 6.94 mg
マンニトール 129.86 mg
結晶セルロース 9 mg
ヒドロキシプロピルセルロース 5.4 mg
結晶セルロース 18 mg
クロスポビドン 9 mg
ステアリン酸マグネシウム 1.8 mg
化合物A 21.34 mg
マンニトール 43.465mg
結晶セルロース 4.5 mg
水酸化ナトリウム 0.345mg
フマル酸 1 mg
ヒドロキシプロピルセルロース 2.7 mg
結晶セルロース 9 mg
クロスポビドン 6.75 mg
ステアリン酸マグネシウム 0.9 mg
ヒドロキシプロピルメチルセルロース 7.8 mg
タルク 1.2 mg
酸化チタン 0.9 mg
酸化鉄 0.1 mg
計 280 mg
(1)精製水(80280g)にヒドロキシプロピルセルロース(5124g)を溶解して結合液Iを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で、ベシル酸アムロジピン(5964g)、マンニトール(52860g)および結晶セルロース(3870g)を均一に混合した後、結合液I(38700g)を噴霧しながら、造粒し、ついで乾燥して、造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得た。得られた整粒末(60480g)に結晶セルロース(7200g)、クロスポビドン(3600g)およびステアリン酸マグネシウム(720g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Aを得た。
(2)精製水(38230g)に水酸化ナトリウム(405.8g)およびフマル酸(1176g)を溶解して、緩衝液を調製した。精製水(47280g)にヒドロキシプロピルセルロース(3018g)を溶解して結合液IIを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で化合物A(20060g)、マンニトール(40860g)、結晶セルロース(4230g)を均一に混合した後、緩衝液(31810g)を噴霧し、さらに結合液II(42300g)を噴霧しながら造粒し、ついで乾燥して造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得た。得られた整粒末(60150g)に結晶セルロース(7380g)、クロスポビドン(5535g)およびステアリン酸マグネシウム(738g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Bを得た。
(3)混合末A(180mg)および混合末B(90mg)をロータリー式打錠機(アクア08242L2JI、菊水製作所)で8.5mmφの杵を用いて打錠(打錠圧:8kN、1錠あたりの重量:270mg)し、素錠を得た。
(4)精製水(4320g)にヒドロキシプロピルメチルセルロース(468g)とタルク(72g)を溶解、分散して分散液Iを調製した。精製水(900g)に酸化チタン(54g)、酸化鉄(6g)を分散して分散液IIを調製した。分散液Iに分散液IIおよび精製水(180g)を混合し、コーティング液を調製した。コーティング機(DRC-650、株式会社パウレック)を用いて、(3)で得た該素錠の重量が1錠あたり10mg増加するまでコーティング液を噴霧することにより、下記組成のフィルム錠を得た。次いで、該フィルム錠を40℃で18時間減圧乾燥した。
ベシル酸アムロジピン 13.87 mg
マンニトール 122.93 mg
結晶セルロース 9 mg
ヒドロキシプロピルセルロース 5.4 mg
結晶セルロース 18 mg
クロスポビドン 9 mg
ステアリン酸マグネシウム 1.8 mg
化合物A 21.34 mg
マンニトール 43.465mg
結晶セルロース 4.5 mg
水酸化ナトリウム 0.345mg
フマル酸 1 mg
ヒドロキシプロピルセルロース 2.7 mg
結晶セルロース 9 mg
クロスポビドン 6.75 mg
ステアリン酸マグネシウム 0.9 mg
ヒドロキシプロピルメチルセルロース 7.8 mg
タルク 1.2 mg
酸化チタン 0.9 mg
酸化鉄 0.1 mg
計 280 mg
(1)精製水(80280g)にヒドロキシプロピルセルロース(5124g)を溶解して結合液Iを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で、ベシル酸アムロジピン(2984g)、マンニトール(55840g)および結晶セルロース(3870g)を均一に混合した後、結合液I(38700g)を噴霧しながら、造粒し、ついで乾燥して、造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得た。得られた整粒末(60480g)に結晶セルロース(7200g)、クロスポビドン(3600g)およびステアリン酸マグネシウム(720g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Aを得た。
(2)精製水(38230g)に水酸化ナトリウム(405.8g)およびフマル酸(1176g)を溶解して、緩衝液を調製した。精製水(47280g)にヒドロキシプロピルセルロース(3018g)を溶解して結合液IIを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で化合物A(20060g)、マンニトール(40860g)、結晶セルロース(4230g)を均一に混合した後、緩衝液(31810g)を噴霧し、さらに結合液II(42300g)を噴霧しながら造粒し、ついで乾燥して造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得た。得られた整粒末(60150g)に結晶セルロース(7380g)、クロスポビドン(5535g)およびステアリン酸マグネシウム(738g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Bを得た。
(3)混合末A(180mg)および混合末B(360mg)をロータリー式打錠機(アクア08242L2JI、菊水製作所)で長径14mm、短径8mmの杵を用いて打錠(打錠圧:9kN、1錠あたりの重量:540mg)し、素錠を得た。
(4)精製水(4320g)にヒドロキシプロピルメチルセルロース(468g)とタルク(72g)を溶解、分散して分散液Iを調製した。精製水(900g)に酸化チタン(54g)、酸化鉄(6g)を分散して分散液IIを調製した。分散液Iに分散液IIおよび精製水(180g)を混合し、コーティング液を調製した。コーティング機(DRC-650、株式会社パウレック)を用いて、(3)で得た該素錠の重量が1錠あたり20mg増加するまでコーティング液を噴霧することにより、下記組成のフィルム錠を得た。次いで、該フィルム錠を40℃で18時間減圧乾燥した。
ベシル酸アムロジピン 6.94 mg
マンニトール 129.86 mg
結晶セルロース 9 mg
ヒドロキシプロピルセルロース 5.4 mg
結晶セルロース 18 mg
クロスポビドン 9 mg
ステアリン酸マグネシウム 1.8 mg
化合物A 85.36 mg
マンニトール 173.86 mg
結晶セルロース 18 mg
水酸化ナトリウム 1.38 mg
フマル酸 4 mg
ヒドロキシプロピルセルロース 10.8 mg
結晶セルロース 36 mg
クロスポビドン 27 mg
ステアリン酸マグネシウム 3.6 mg
ヒドロキシプロピルメチルセルロース 15.6 mg
タルク 2.4 mg
酸化チタン 1.8 mg
酸化鉄 0.2 mg
計 560 mg
(1)精製水(80280g)にヒドロキシプロピルセルロース(5124g)を溶解して結合液Iを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で、ベシル酸アムロジピン(5964g)、マンニトール(52860g)および結晶セルロース(3870g)を均一に混合した後、結合液I(38700g)を噴霧しながら、造粒し、ついで乾燥して、造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得た。得られた整粒末(60480g)に結晶セルロース(7200g)、クロスポビドン(3600g)およびステアリン酸マグネシウム(720g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Aを得た。
(2)精製水(38230g)に水酸化ナトリウム(405.8g)およびフマル酸(1176g)を溶解して、緩衝液を調製した。精製水(47280g)にヒドロキシプロピルセルロース(3018g)を溶解して結合液IIを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で化合物A(20060g)、マンニトール(40860g)、結晶セルロース(4230g)を均一に混合した後、緩衝液(31810g)を噴霧し、さらに結合液II(42300g)を噴霧しながら造粒し、ついで乾燥して造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得た。得られた整粒末(60150g)に結晶セルロース(7380g)、クロスポビドン(5535g)およびステアリン酸マグネシウム(738g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Bを得た。
(3)混合末A(180mg)および混合末B(360mg)をロータリー式打錠機(アクア08242L2JI、菊水製作所)で長径14mm、短径8mmの杵を用いて打錠(打錠圧:9kN、1錠あたりの重量:540mg)し、素錠を得た。
(4)精製水(4320g)にヒドロキシプロピルメチルセルロース(468g)とタルク(72g)を溶解、分散して分散液Iを調製した。精製水(900g)に酸化チタン(54g)、酸化鉄(6g)を分散して分散液IIを調製した。分散液Iに分散液IIおよび精製水(180g)を混合し、コーティング液を調製した。コーティング機(DRC-650、株式会社パウレック)を用いて、(3)で得た該素錠の重量が1錠あたり20mg増加するまでコーティング液を噴霧することにより、下記組成のフィルム錠を得た。次いで、該フィルム錠を40℃で18時間減圧乾燥した。
ベシル酸アムロジピン 13.87 mg
マンニトール 122.93 mg
結晶セルロース 9 mg
ヒドロキシプロピルセルロース 5.4 mg
結晶セルロース 18 mg
クロスポビドン 9 mg
ステアリン酸マグネシウム 1.8 mg
化合物A 85.36 mg
マンニトール 173.86 mg
結晶セルロース 18 mg
水酸化ナトリウム 1.38 mg
フマル酸 4 mg
ヒドロキシプロピルセルロース 10.8 mg
結晶セルロース 36 mg
クロスポビドン 27 mg
ステアリン酸マグネシウム 3.6 mg
ヒドロキシプロピルメチルセルロース 15.6 mg
タルク 2.4 mg
酸化チタン 1.8 mg
酸化鉄 0.2 mg
計 560 mg
(1)精製水(80280g)にヒドロキシプロピルセルロース(5124g)を溶解して結合液Iを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で、ベシル酸アムロジピン(2984g)、マンニトール(55840g)および結晶セルロース(3870g)を均一に混合した後、結合液I(38700g)を噴霧しながら、造粒し、ついで乾燥して、造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末Aを得た。
(2)精製水(38230g)に水酸化ナトリウム(405.8g)およびフマル酸(1176g)を溶解して、緩衝液を調製した。精製水(47280g)にヒドロキシプロピルセルロース(3018g)を溶解して結合液IIを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で化合物A(20060g)、マンニトール(40860g)、結晶セルロース(4230g)を均一に混合した後、緩衝液(31810g)を噴霧し、さらに結合液II(42300g)を噴霧しながら造粒し、ついで乾燥して造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末Bを得た。
(3)得られた整粒末A(9072g)および整粒末B(4401g)に結晶セルロース(1620g)、クロスポビドン(945g)およびステアリン酸マグネシウム(162g)を加え、タンブラー混合機(TM-100、昭和化学機械工作所)で混合することにより、混合末を得た。
(4)混合末をロータリー式打錠機(AQUA512SS2AI、菊水製作所)で8.5mmΦの杵を用いて打錠(打錠圧:7kN、1錠あたりの重量:270mg)し、素錠を得た。
(5)精製水(4320g)にヒドロキシプロピルメチルセルロース(468g)とタルク(72g)を溶解、分散して分散液Iを調製した。精製水(900g)に酸化チタン(54g)、酸化鉄(6g)を分散して分散液IIを調製した。分散液Iに分散液IIおよび精製水(180g)を混合し、コーティング液を調製した。コーティング機(DRC-650、株式会社パウレック)を用いて、(4)で得た該素錠の重量が1錠あたり10mg増加するまでコーティング液を噴霧することにより、下記組成のフィルム錠を得た。次いで、該フィルム錠を40℃で18時間減圧乾燥した。
ベシル酸アムロジピン 6.94 mg
マンニトール 129.86 mg
結晶セルロース 9 mg
ヒドロキシプロピルセルロース 5.4 mg
化合物A 21.34 mg
マンニトール 43.465mg
結晶セルロース 4.5 mg
水酸化ナトリウム 0.345mg
フマル酸 1 mg
ヒドロキシプロピルセルロース 2.7 mg
結晶セルロース 27 mg
クロスポビドン 15.75 mg
ステアリン酸マグネシウム 2.7 mg
ヒドロキシプロピルメチルセルロース 7.8 mg
タルク 1.2 mg
酸化チタン 0.9 mg
酸化鉄 0.1 mg
計 280 mg
(1)精製水(80280g)にヒドロキシプロピルセルロース(5124g)を溶解して結合液Iを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で、ベシル酸アムロジピン(5964g)、マンニトール(52860g)および結晶セルロース(3870g)を均一に混合した後、結合液I(38700g)を噴霧しながら、造粒し、ついで乾燥して、造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末Aを得た。
(2)精製水(38230g)に水酸化ナトリウム(405.8g)およびフマル酸(1176g)を溶解して、緩衝液を調製した。精製水(47280g)にヒドロキシプロピルセルロース(3018g)を溶解して結合液IIを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で化合物A(20060g)、マンニトール(40860g)、結晶セルロース(4230g)を均一に混合した後、緩衝液(31810g)を噴霧し、さらに結合液II(42300g)を噴霧しながら造粒し、ついで乾燥して造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末Bを得た。
(3)得られた整粒末A(9072g)および整粒末B(4401g)に結晶セルロース(1620g)、クロスポビドン(945g)およびステアリン酸マグネシウム(162g)を加え、タンブラー混合機(TM-60S、昭和化学機械工作所)で混合することにより、混合末を得た。
(4)混合末をロータリー式打錠機(AQUA512SS2AI、菊水製作所)で8.5mmΦの杵を用いて打錠(打錠圧:7kN、1錠あたりの重量:270mg)し、素錠を得た。
(5)精製水(4320g)にヒドロキシプロピルメチルセルロース(468g)とタルク(72g)を溶解、分散して分散液Iを調製した。精製水(900g)に酸化チタン(54g)、酸化鉄(6g)を分散して分散液IIを調製した。分散液Iに分散液IIおよび精製水(180g)を混合し、コーティング液を調製した。コーティング機(DRC-650、株式会社パウレック)を用いて、(4)で得た該素錠の重量が1錠あたり10mg増加するまでコーティング液を噴霧することにより、下記組成のフィルム錠を得た。次いで、該フィルム錠を40℃で18時間減圧乾燥した。
ベシル酸アムロジピン 13.87 mg
マンニトール 122.93 mg
結晶セルロース 9 mg
ヒドロキシプロピルセルロース 5.4 mg
化合物A 21.34 mg
マンニトール 43.465mg
結晶セルロース 4.5 mg
水酸化ナトリウム 0.345mg
フマル酸 1 mg
ヒドロキシプロピルセルロース 2.7 mg
結晶セルロース 27 mg
クロスポビドン 15.75 mg
ステアリン酸マグネシウム 2.7 mg
ヒドロキシプロピルメチルセルロース 7.8 mg
タルク 1.2 mg
酸化チタン 0.9 mg
酸化鉄 0.1 mg
計 280 mg
(1)精製水(80280g)にヒドロキシプロピルセルロース(5124g)を溶解して結合液Iを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で、ベシル酸アムロジピン(2984g)、マンニトール(55840g)および結晶セルロース(3870g)を均一に混合した後、結合液I(38700g)を噴霧しながら、造粒し、ついで乾燥して、造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末Aを得た。
(2)精製水(38230g)に水酸化ナトリウム(405.8g)およびフマル酸(1176g)を溶解して、緩衝液を調製した。精製水(47280g)にヒドロキシプロピルセルロース(3018g)を溶解して結合液IIを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で化合物A(20060g)、マンニトール(40860g)、結晶セルロース(4230g)を均一に混合した後、緩衝液(31810g)を噴霧し、さらに結合液II(42300g)を噴霧しながら造粒し、ついで乾燥して造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末Bを得た。
(3)得られた整粒末A(4536g)および整粒末B(8802g)に結晶セルロース(1620g)、クロスポビドン(1080g)およびステアリン酸マグネシウム(162g)を加え、タンブラー混合機(TM-60S、昭和化学機械工作所)で混合することにより、混合末を得た。
(4)混合末をロータリー式打錠機(AQUA512SS2AI、菊水製作所)で長径14mm、短径8mmの杵を用いて打錠(打錠圧:9kN、1錠あたりの重量:540mg)し、素錠を得た。
(5)精製水(4320g)にヒドロキシプロピルメチルセルロース(468g)とタルク(72g)を溶解、分散して分散液Iを調製した。精製水(900g)に酸化チタン(54g)、酸化鉄(6g)を分散して分散液IIを調製した。分散液Iに分散液IIおよび精製水(180g)を混合し、コーティング液を調製した。コーティング機(DRC-650、株式会社パウレック)を用いて、(4)で得た該素錠の重量が1錠あたり20mg増加するまでコーティング液を噴霧することにより、下記組成のフィルム錠を得た。次いで、該フィルム錠を40℃で18時間減圧乾燥した。
ベシル酸アムロジピン 6.94 mg
マンニトール 129.86 mg
結晶セルロース 9 mg
ヒドロキシプロピルセルロース 5.4 mg
化合物A 85.36 mg
マンニトール 173.86 mg
結晶セルロース 18 mg
水酸化ナトリウム 1.38 mg
フマル酸 4 mg
ヒドロキシプロピルセルロース 10.8 mg
結晶セルロース 54 mg
クロスポビドン 36 mg
ステアリン酸マグネシウム 5.4 mg
ヒドロキシプロピルメチルセルロース 15.6 mg
タルク 2.4 mg
酸化チタン 1.8 mg
酸化鉄 0.2 mg
計 560 mg
(1)精製水(80280g)にヒドロキシプロピルセルロース(5124g)を溶解して結合液Iを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で、ベシル酸アムロジピン(5964g)、マンニトール(52860g)および結晶セルロース(3870g)を均一に混合した後、結合液I(38700g)を噴霧しながら、造粒し、ついで乾燥して、造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末Aを得た。
(2)精製水(38230g)に水酸化ナトリウム(405.8g)およびフマル酸(1176g)を溶解して、緩衝液を調製した。精製水(47280g)にヒドロキシプロピルセルロース(3018g)を溶解して結合液IIを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で化合物A(20060g)、マンニトール(40860g)、結晶セルロース(4230g)を均一に混合した後、緩衝液(31810g)を噴霧し、さらに結合液II(42300g)を噴霧しながら造粒し、ついで乾燥して造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末Bを得た。
(3)得られた整粒末A(4536g)および整粒末B(8802g)に結晶セルロース(1620g)、クロスポビドン(1080g)およびステアリン酸マグネシウム(162g)を加え、タンブラー混合機(TM-60S、昭和化学機械工作所)で混合することにより、混合末を得た。
(4)混合末をロータリー式打錠機(AQUA512SS2AI、菊水製作所)で長径14mm、短径8mmの杵を用いて打錠(打錠圧:9kN、1錠あたりの重量:540mg)し、素錠を得た。
(5)精製水(4320g)にヒドロキシプロピルメチルセルロース(468g)とタルク(72g)を溶解、分散して分散液Iを調製した。精製水(900g)に酸化チタン(54g)、酸化鉄(6g)を分散して分散液IIを調製した。分散液Iに分散液IIおよび精製水(180g)を混合し、コーティング液を調製した。コーティング機(DRC-650、株式会社パウレック)を用いて、(4)で得た該素錠の重量が1錠あたり20mg増加するまでコーティング液を噴霧することにより、下記組成のフィルム錠を得た。次いで、該フィルム錠を40℃で18時間減圧乾燥した。
ベシル酸アムロジピン 13.87 mg
マンニトール 122.93 mg
結晶セルロース 9 mg
ヒドロキシプロピルセルロース 5.4 mg
化合物A 85.36 mg
マンニトール 173.86 mg
結晶セルロース 18 mg
水酸化ナトリウム 1.38 mg
フマル酸 4 mg
ヒドロキシプロピルセルロース 10.8 mg
結晶セルロース 54 mg
クロスポビドン 36 mg
ステアリン酸マグネシウム 5.4 mg
ヒドロキシプロピルメチルセルロース 15.6 mg
タルク 2.4 mg
酸化チタン 1.8 mg
酸化鉄 0.2 mg
計 560 mg
(1)精製水(2538g)にヒドロキシプロピルセルロース(162g)を溶解して結合液Iを調製した。流動層造粒乾燥機(FD-5S、株式会社パウレック)中で、ベシル酸アムロジピン(416.9g)、マンニトール(3687g)および結晶セルロース(270g)を均一に混合した後、結合液Iを噴霧しながら、造粒し、ついで乾燥して、造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-3、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得た。得られた整粒末(3326g)に結晶セルロース(396g)、クロスポビドン(198g)およびステアリン酸マグネシウム(39.6g)を加え、タンブラー混合機(TM-60S、昭和化学機械工作所)で混合することにより、混合末Aを得た。
(2)精製水(5850g)に水酸化ナトリウム(62.1g)およびフマル酸(180g)を溶解して、緩衝液を調製した。精製水(7614g)にヒドロキシプロピルセルロース(486g)を溶解して結合液IIを調製した。流動層造粒乾燥機(FD-5S、株式会社パウレック)中で化合物A(1196g)、マンニトール(2433g)、結晶セルロース(252g)を均一に混合した後、緩衝液(1895g)を噴霧し、さらに結合液II(2520g)を噴霧しながら造粒し、ついで乾燥して造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-3、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得た。得られた整粒末(6455g)に結晶セルロース(792g)、クロスポビドン(594g)およびステアリン酸マグネシウム(79.2g)を加え、タンブラー混合機(TM-60S、昭和化学機械工作所)で混合することにより、混合末Bを得た。
(3)混合末A(180mg)および混合末B(360mg)をロータリー式打錠機(アクア08242L2JI、菊水製作所)で長径14.8mm、短径8mmの杵を用いて打錠(打錠圧:11kN、1錠あたりの重量:540mg)し、素錠を得た。
(4)精製水(3500g)にヒドロキシプロピルメチルセルロース(390g)とタルク(60g)を溶解、分散して分散液Iを調製した。精製水(750g)に酸化チタン(45g)、酸化鉄(5g)を分散して分散液IIを調製した。分散液Iに分散液IIおよび精製水(250g)を混合し、コーティング液を調製した。コーティング機(DRC-500、株式会社パウレック)を用いて、(3)で得た該素錠の重量が1錠あたり20mg増加するまでコーティング液を噴霧することにより、下記組成のフィルム錠を得た。次いで、該フィルム錠を40℃で16時間減圧乾燥した。
ベシル酸アムロジピン 13.87 mg
マンニトール 122.93 mg
結晶セルロース 9 mg
ヒドロキシプロピルセルロース 5.4 mg
結晶セルロース 18 mg
クロスポビドン 9 mg
ステアリン酸マグネシウム 1.8 mg
化合物A 85.36 mg
マンニトール 173.86 mg
結晶セルロース 18 mg
水酸化ナトリウム 1.38 mg
フマル酸 4 mg
ヒドロキシプロピルセルロース 10.8 mg
結晶セルロース 36 mg
クロスポビドン 27 mg
ステアリン酸マグネシウム 3.6 mg
ヒドロキシプロピルメチルセルロース 15.6 mg
タルク 2.4 mg
酸化チタン 1.8 mg
酸化鉄 0.2 mg
計 560 mg
流動層造粒乾燥機(Lab-1、株式会社パウレック)中で、化合物A(42.68g)、乳糖(217.32g)、結晶セルロース(32g)およびフマル酸一ナトリウム(10g)を均一に混合後、ヒドロキシプロピルセルロース(12g)およびフマル酸一ナトリウム(10g)の水溶液を噴霧して造粒し、ついで機内で乾燥した。得られた造粒物を16メッシュ(目開き1.0mm)の篩で篩過し整粒末を得た。得られた整粒末(16.2g)に低置換度ヒドロキシプロピルセルロース(0.8g)を加え、ガラス瓶中で混合した。得られた混合物をオートグラフ(島津製作所製、AG-5000B)で9.5mmφの杵を用いて打錠(打錠圧:7.5KN/杵、錠剤1錠あたりの重量:398.3mg)し、下記組成の素錠を得た。次いで、該素錠を40℃で16時間減圧乾燥した。
化合物A 50 mg
乳糖 254.6mg
結晶セルロース 37.5mg
ヒドロキシプロピルセルロース 14.1mg
フマル酸一ナトリウム 23.4mg
低置換度ヒドロキシプロピルセルロース 18.7mg
計 398.3mg
(1)流動層造粒乾燥機(Lab-1、株式会社パウレック)中で、化合物A(85.36g)、ベシル酸アムロジピン(13.87g)、マンニトール(184.89g)および結晶セルロース(22.5g)を均一に混合後、ヒドロキシプロピルメチルセルロース(12.0g)、フマル酸(4.0g)および水酸化ナトリウム(1.38g)の水溶液を噴霧して造粒し、ついで機内で乾燥した。得られた造粒物を16メッシュ(目開き1.0mm)の篩で篩過し整粒末Aを得た。得られた整粒末A(259.2g)にクロスカルメロースナトリウム(25.6g)、結晶セルロース(32.0g)およびステアリン酸マグネシウム(3.2g)を加え、袋中で混合した。
(2)得られた混合物をロータリー打錠機(VEL50306SS2MZ、菊水製作所)で9.5mmφの杵を用いて打錠(打錠圧:7KN/杵、錠剤1錠あたりの重量:400mg)し、下記組成の素錠を得た。次いで、該素錠を40℃で16時間減圧乾燥した。
化合物A 85.36mg
ベシル酸アムロジピン 13.87mg
マンニトール 184.89mg
結晶セルロース 22.5 mg
ヒドロキシプロピルメチルセルロース 12 mg
フマル酸 4 mg
水酸化ナトリウム 1.38mg
クロスカルメロースナトリウム 40 mg
結晶セルロース 32 mg
ステアリン酸マグネシウム 4 mg
計 400 mg
(1)流動層造粒乾燥機(Lab-1、株式会社パウレック)中で、ベシル酸アムロジピン(41.61g)、結晶セルロース(35.1g)およびマンニトール(349.89g)を均一に混合後、ヒドロキシプロピルメチルセルロース(16.2g)の水溶液を噴霧して造粒し、ついで機内で乾燥した。得られた造粒物を16メッシュ(目開き1.0mm)の篩で篩過し整粒末Aを得た。得られた整粒末A(177.12g)にクロスカルメロースナトリウム(15.12g)、結晶セルロース(21.6g)およびステアリン酸マグネシウム(2.16g)を加え、袋中で混合し混合末Aを得た。
(2)流動層造粒乾燥機(Lab-1、株式会社パウレック)中で、化合物A(136.58g)およびマンニトール(306.98g)を均一に混合後、ヒドロキシプロピルセルロース(17.3g)、フマル酸(6.4g)および水酸化ナトリウム(2.21g)の水溶液を噴霧して造粒し、ついで機内で乾燥した。得られた造粒物を16メッシュ(目開き1.0mm)の篩で篩過し整粒末Bを得た。得られた整粒末B(352.1g)にクロスカルメロースナトリウム(32.4g)、結晶セルロース(43.2g)およびステアリン酸マグネシウム(4.3g)を加え、袋中で混合し混合末Bを得た。
(3)得られた混合末A(180mg)および混合末B(360mg)をオートグラフ(島津製作所製、AG-5000B)で11mmφの杵を用いて打錠(打錠圧:9KN/杵、錠剤1錠あたりの重量:540mg)し、下記組成の素錠を得た。次いで、該素錠を40℃で16時間減圧乾燥した。
化合物A 85.36mg
ベシル酸アムロジピン 13.87mg
マンニトール 308.49mg
結晶セルロース 11.7 mg
ヒドロキシプロピルセルロース 10.8 mg
ヒドロキシプロピルメチルセルロース 5.4 mg
フマル酸 4 mg
水酸化ナトリウム 1.38mg
クロスカルメロースナトリウム 39.6 mg
結晶セルロース 54 mg
ステアリン酸マグネシウム 5.4 mg
計 540 mg
流動層造粒乾燥機(Lab-1、株式会社パウレック)中で、化合物A(42.68g)、乳糖(217.32g)および結晶セルロース(32g)を均一に混合後、ヒドロキシプロピルセルロース(12g)の水溶液を噴霧して造粒し、ついで機内で乾燥した。得られた造粒物を16メッシュ(目開き1.0mm)の篩で篩過し整粒末を得た。得られた整粒末(15.2g)に低置換度ヒドロキシプロピルセルロース(0.8g)を加え、ガラス瓶中で混合した。得られた混合物をオートグラフ(島津製作所製、AG-5000B)で9.5mmφの杵を用いて打錠(打錠圧:7.5KN/杵、錠剤1錠あたりの重量:374.9mg)し、下記組成の素錠を得た。次いで、該素錠を40℃で16時間減圧乾燥した。
化合物A 50 mg
乳糖 254.6mg
結晶セルロース 37.5mg
ヒドロキシプロピルセルロース 14.1mg
低置換度ヒドロキシプロピルセルロース 18.7mg
計 374.9mg
(1)流動層造粒乾燥機(Lab-1、株式会社パウレック)中で、化合物A(136.58g)およびマンニトール(306.98g)を均一に混合後、ヒドロキシプロピルセルロース(17.3g)、フマル酸(6.4g)および水酸化ナトリウム(2.21g)の水溶液を噴霧して造粒し、ついで機内で乾燥した。得られた造粒物を16メッシュ(目開き1.0mm)の篩で篩過し整粒末Aを得た。得られた整粒末A(352.1g)にクロスカルメロースナトリウム(32.4g)、結晶セルロース(43.2g)およびステアリン酸マグネシウム(4.3g)を加え、袋中で混合し、混合末Aを得た。
(2)転動流動層造粒乾燥機(SPIR-A-FLOW、フロイント産業株式会社)中に、結晶セルロース(粒)(212.5g)を投入し、ベシル酸アムロジピン(34.675g)、結晶セルロース(7.825g)、低置換度ヒドロキシプロピルセルロース(15g)およびヒドロキシプロピルメチルセルロース(30g)の分散液を噴霧してレイアリングし、ついで機内で乾燥した。得られた細粒を篩で篩過し、150~350μmの細粒Bを得た。
(3)精製水(810g)に低置換度ヒドロキシプロピルセルロース(18g)、ヒドロキシプロピルメチルセルロース(25.2g)、タルク(10.8g)、酸化チタン(10.8g)およびマンニトール(25.2g)を溶解・分散させ分散液を調整した。転動流動層造粒乾燥機(SPIR-A-FLOW、フロイント産業株式会社)中で得られた細粒B(180g)を総重量が50%増加するまでコーティングし、ついで機内で乾燥した。得られた細粒を篩で篩過し、150~425μmの細粒Cを得た。
(4)得られた混合末A(126g)と細粒C(63g)を袋中で混合した。得られた混合物をロータリー打錠機(VEL50306SS2MZ、菊水製作所)で10.5mmφの杵を用いて打錠(打錠圧:8.5KN/杵、錠剤1錠あたりの重量:540mg)し、下記組成の素錠を得た。次いで、該素錠を40℃で16時間減圧乾燥することで細粒を含有した錠剤を得た。
化合物A 85.36mg
マンニトール 191.86mg
ヒドロキシプロピルセルロース 10.8 mg
フマル酸 4 mg
水酸化ナトリウム 1.38mg
ベシル酸アムロジピン 13.87mg
結晶セルロース(粒) 85 mg
結晶セルロース 3.13mg
低置換度ヒドロキシプロピルセルロース 18 mg
ヒドロキシプロピルメチルセルロース 28.8 mg
タルク 7.2 mg
酸化チタン 7.2 mg
マンニトール 16.8 mg
クロスカルメロースナトリウム 27 mg
結晶セルロース 36 mg
ステアリン酸マグネシウム 3.6 mg
計 540 mg
(1)精製水(43900g)にヒドロキシプロピルセルロース(2802g)を溶解して結合液Iを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で、ベシル酸アムロジピン(5464g)、マンニトール(52860g)および結晶セルロース(3870g)を均一に混合した後、結合液I(38700g)を噴霧しながら、造粒し、ついで乾燥して、造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得た。得られた整粒末(61240g)に結晶セルロース(7290g)、クロスポビドン(3645g)およびステアリン酸マグネシウム(729g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Aを得た。
(2)精製水(260g)に水酸化ナトリウム(2.76g)およびフマル酸(8g)を溶解して、緩衝液を調製し、その一部(203.1g)にヒドロキシプロピルセルロース(16.2g)を溶解して結合液IIを調製した。流動層造粒乾燥機(Lab-1、株式会社パウレック)中で化合物A(128g)、マンニトール(260.8g)、結晶セルロース(27g)を均一に混合した後、結合液IIを噴霧しながら造粒し、ついで乾燥して造粒末を得た。得られた造粒末の一部を16メッシュ(目開き1.0mm)の篩で篩過し、整粒末を得た。得られた整粒末(293.4g)に結晶セルロース(36g)、クロスポビドン(27g)およびステアリン酸マグネシウム(3.6g)を加え、ポリ袋内で混合し、混合末Bを得た。
(3)混合末A(180mg)および混合末B(360mg)をオートグラフ(AG-500B、株式会社島津製作所)で長径14mm、短径8mmφの杵を用いて打錠(打錠圧:8kN、1錠あたりの重量:540mg)し、素錠を得た。次いで、該素錠を40℃で15時間減圧乾燥した。
ベシル酸アムロジピン 13.87 mg
マンニトール 122.93 mg
結晶セルロース 9 mg
ヒドロキシプロピルセルロース 5.4 mg
結晶セルロース 18 mg
クロスポビドン 9 mg
ステアリン酸マグネシウム 1.8 mg
化合物A 85.36 mg
マンニトール 173.86 mg
結晶セルロース 18 mg
水酸化ナトリウム 1.38 mg
フマル酸 4 mg
ヒドロキシプロピルセルロース 10.8 mg
結晶セルロース 36 mg
クロスポビドン 27 mg
ステアリン酸マグネシウム 3.6 mg
計 540 mg
(1)精製水(43900g)にヒドロキシプロピルセルロース(2802g)を溶解して結合液Iを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で、ベシル酸アムロジピン(5464g)、マンニトール(52860g)および結晶セルロース(3870g)を均一に混合した後、結合液I(38700g)を噴霧しながら、造粒し、ついで乾燥して、造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得た。得られた整粒末(61240g)に結晶セルロース(7290g)、クロスポビドン(3645g)およびステアリン酸マグネシウム(729g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Aを得た。
(2)精製水(253.8g)にヒドロキシプロピルセルロース(16.2g)を溶解して結合液IIを調製した。流動層造粒乾燥機(Lab-1、株式会社パウレック)中で化合物A(128g)、マンニトール(268.9g)、結晶セルロース(27g)を均一に混合した後、結合液IIを噴霧しながら造粒し、ついで乾燥して造粒末を得た。得られた造粒末の一部を16メッシュ(目開き1.0mm)の篩で篩過し、整粒末を得た。得られた整粒末(293.4g)に結晶セルロース(36g)、クロスポビドン(27g)およびステアリン酸マグネシウム(3.6g)を加え、ポリ袋内で混合し、混合末Bを得た。
(3)混合末A(180mg)および混合末B(360mg)をオートグラフ(AG-500B、株式会社島津製作所)で長径14mm、短径8mmφの杵を用いて打錠(打錠圧:8kN、1錠あたりの重量:540mg)し、素錠を得た。次いで、該素錠を40℃で15時間減圧乾燥した。
ベシル酸アムロジピン 13.87 mg
マンニトール 122.93 mg
結晶セルロース 9 mg
ヒドロキシプロピルセルロース 5.4 mg
結晶セルロース 18 mg
クロスポビドン 9 mg
ステアリン酸マグネシウム 1.8 mg
化合物A 85.36 mg
マンニトール 179.24 mg
結晶セルロース 18 mg
ヒドロキシプロピルセルロース 10.8 mg
結晶セルロース 36 mg
クロスポビドン 27 mg
ステアリン酸マグネシウム 3.6 mg
計 540 mg
(1)精製水(43900g)にヒドロキシプロピルセルロース(2802g)を溶解して結合液Iを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で、ベシル酸アムロジピン(2982g)、マンニトール(55840g)および結晶セルロース(3870g)を均一に混合した後、結合液I(38700g)を噴霧しながら、造粒し、ついで乾燥して、造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得た。得られた整粒末(61240g)に結晶セルロース(7290g)、クロスポビドン(3645g)およびステアリン酸マグネシウム(729g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Aを得た。
(2)精製水(38230g)に水酸化ナトリウム(405.8g)およびフマル酸(1176g)を溶解して、緩衝液を調製した。精製水(47280g)にヒドロキシプロピルセルロース(3018g)を溶解して結合液IIを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で化合物A(20060g)、マンニトール(40860g)、結晶セルロース(4230g)を均一に混合した後、緩衝液(31810g)を噴霧し、さらに結合液II(42300g)を噴霧しながら造粒し、ついで乾燥して造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得た。得られた整粒末(60150g)に結晶セルロース(7380g)、クロスポビドン(5535g)およびステアリン酸マグネシウム(738g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Bを得た。
(3)混合末A(180mg)および混合末B(180mg)をロータリー式打錠機(HT-CVX54LS-UW/C&3L、畑鉄工所)で9.5mmφの杵を用いて打錠(打錠圧:10kN、1錠あたりの重量:360mg)し、素錠を得た。
(4)精製水(36720g)にヒドロキシプロピルメチルセルロース(3978g)とタルク(612g)を溶解、分散して分散液Iを調製した。精製水(9180g)に酸化チタン(459g)、酸化鉄(51g)を分散して分散液IIを調製した。分散液Iに分散液IIを加え、攪拌混合し、コーティング液を得た。コーティング機(DRC-1200、株式会社パウレック)を用いて、(3)で得た該素錠の重量が1錠あたり10mg増加するまでコーティング液を噴霧することにより、下記組成のフィルム錠を得た。次いで、該フィルム錠を40℃で15時間減圧乾燥した。
ベシル酸アムロジピン 6.935 mg
マンニトール 129.865 mg
結晶セルロース 9 mg
ヒドロキシプロピルセルロース 5.4 mg
結晶セルロース 18 mg
クロスポビドン 9 mg
ステアリン酸マグネシウム 1.8 mg
化合物A 42.68 mg
マンニトール 86.93 mg
結晶セルロース 9 mg
水酸化ナトリウム 0.69 mg
フマル酸 2 mg
ヒドロキシプロピルセルロース 5.4 mg
結晶セルロース 18 mg
クロスポビドン 13.5 mg
ステアリン酸マグネシウム 1.8 mg
ヒドロキシプロピルメチルセルロース 7.8 mg
タルク 1.2 mg
酸化チタン 0.9 mg
酸化鉄 0.1 mg
計 370 mg
(1)精製水(43900g)にヒドロキシプロピルセルロース(2802g)を溶解して結合液Iを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で、ベシル酸アムロジピン(5964g)、マンニトール(52860g)および結晶セルロース(3870g)を均一に混合した後、結合液I(38700g)を噴霧しながら、造粒し、ついで乾燥して、造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得た。得られた整粒末(61240g)に結晶セルロース(7290g)、クロスポビドン(3645g)およびステアリン酸マグネシウム(729g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Aを得た。
(2)精製水(38230g)に水酸化ナトリウム(405.8g)およびフマル酸(1176g)を溶解して、緩衝液を調製した。精製水(47280g)にヒドロキシプロピルセルロース(3018g)を溶解して結合液IIを調製した。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で化合物A(20060g)、マンニトール(40860g)、結晶セルロース(4230g)を均一に混合した後、緩衝液(31810g)を噴霧し、さらに結合液II(42300g)を噴霧しながら造粒し、ついで乾燥して造粒末を得た。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得た。得られた整粒末(60150g)に結晶セルロース(7380g)、クロスポビドン(5535g)およびステアリン酸マグネシウム(738g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Bを得た。
(3)混合末A(180mg)および混合末B(180mg)をロータリー式打錠機(HT-CVX54LS-UW/C&3L、畑鉄工所)で9.5mmφの杵を用いて打錠(打錠圧:10kN、1錠あたりの重量:360mg)し、素錠を得た。
(4)精製水(36720g)にヒドロキシプロピルメチルセルロース(3978g)とタルク(612g)を溶解、分散して分散液Iを調製した。精製水(9180g)に酸化チタン(459g)、酸化鉄(51g)を分散して分散液IIを調製した。分散液Iに分散液IIを加え、攪拌混合し、コーティング液を得た。コーティング機(DRC-1200、株式会社パウレック)を用いて、(3)で得た該素錠の重量が1錠あたり10mg増加するまでコーティング液を噴霧することにより、下記組成のフィルム錠を得た。次いで、該フィルム錠を40℃で15時間減圧乾燥した。
ベシル酸アムロジピン 13.87 mg
マンニトール 122.93 mg
結晶セルロース 9 mg
ヒドロキシプロピルセルロース 5.4 mg
結晶セルロース 18 mg
クロスポビドン 9 mg
ステアリン酸マグネシウム 1.8 mg
化合物A 42.68 mg
マンニトール 86.93 mg
結晶セルロース 9 mg
水酸化ナトリウム 0.69 mg
フマル酸 2 mg
ヒドロキシプロピルセルロース 5.4 mg
結晶セルロース 18 mg
クロスポビドン 13.5 mg
ステアリン酸マグネシウム 1.8 mg
ヒドロキシプロピルメチルセルロース 7.8 mg
タルク 1.2 mg
酸化チタン 0.9 mg
酸化鉄 0.1 mg
計 370 mg
(1)精製水(43900g)にヒドロキシプロピルセルロース(2802g)を溶解して結合液Iを調製する。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で、ベシル酸アムロジピン(2982g)、マンニトール(55840g)および結晶セルロース(3870g)を均一に混合した後、結合液I(38700g)を噴霧しながら、造粒し、ついで乾燥して、造粒末を得る。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得る。得られた整粒末(61240g)に結晶セルロース(7290g)、クロスポビドン(3645g)およびステアリン酸マグネシウム(729g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Aを得る。
(2)精製水(38230g)に水酸化ナトリウム(405.8g)およびフマル酸(1176g)を溶解して、緩衝液を調製する。精製水(47280g)にヒドロキシプロピルセルロース(3018g)を溶解して結合液IIを調製する。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で化合物A(20060g)、マンニトール(40860g)、結晶セルロース(4230g)を均一に混合した後、緩衝液(31810g)を噴霧し、さらに結合液II(42300g)を噴霧しながら造粒し、ついで乾燥して造粒末を得る。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得る。得られた整粒末(60150g)に結晶セルロース(7380g)、クロスポビドン(5535g)およびステアリン酸マグネシウム(738g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Bを得る。
(3)混合末A(180mg)および混合末B(90mg)をロータリー式打錠機(HT-CVX54LS-UW/C&3L、畑鉄工所)で8.5mmφの杵を用いて打錠(打錠圧:9kN、1錠あたりの重量:270mg)し、素錠を得る。
(4)精製水(36720g)にヒドロキシプロピルメチルセルロース(3978g)とタルク(612g)を溶解、分散して分散液Iを調製する。精製水(9180g)に酸化チタン(494.7g)、酸化鉄(15.3g)を分散して分散液IIを調製する。分散液Iに分散液IIを加え、攪拌混合し、コーティング液を得る。コーティング機(DRC-1200、株式会社パウレック)を用いて、(3)で得た該素錠の重量が1錠あたり10mg増加するまでコーティング液を噴霧することにより、下記組成のフィルム錠を得る。次いで、該フィルム錠を40℃で15時間減圧乾燥する。
ベシル酸アムロジピン 6.935 mg
マンニトール 129.865 mg
結晶セルロース 9 mg
ヒドロキシプロピルセルロース 5.4 mg
結晶セルロース 18 mg
クロスポビドン 9 mg
ステアリン酸マグネシウム 1.8 mg
化合物A 21.34 mg
マンニトール 43.465 mg
結晶セルロース 4.5 mg
水酸化ナトリウム 0.345 mg
フマル酸 1 mg
ヒドロキシプロピルセルロース 2.7 mg
結晶セルロース 9 mg
クロスポビドン 6.75 mg
ステアリン酸マグネシウム 0.9 mg
ヒドロキシプロピルメチルセルロース 7.8 mg
タルク 1.2 mg
酸化チタン 0.97 mg
酸化鉄 0.03 mg
計 280 mg
(1)精製水(43900g)にヒドロキシプロピルセルロース(2802g)を溶解して結合液Iを調製する。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で、ベシル酸アムロジピン(2982g)、マンニトール(55840g)および結晶セルロース(3870g)を均一に混合した後、結合液I(38700g)を噴霧しながら、造粒し、ついで乾燥して、造粒末を得る。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得る。得られた整粒末(61240g)に結晶セルロース(7290g)、クロスポビドン(3645g)およびステアリン酸マグネシウム(729g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Aを得る。
(2)精製水(38230g)に水酸化ナトリウム(405.8g)およびフマル酸(1176g)を溶解して、緩衝液を調製する。精製水(47280g)にヒドロキシプロピルセルロース(3018g)を溶解して結合液IIを調製する。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で化合物A(20060g)、マンニトール(40860g)、結晶セルロース(4230g)を均一に混合した後、緩衝液(31810g)を噴霧し、さらに結合液II(42300g)を噴霧しながら造粒し、ついで乾燥して造粒末を得る。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得る。得られた整粒末(60150g)に結晶セルロース(7380g)、クロスポビドン(5535g)およびステアリン酸マグネシウム(738g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Bを得る。
(3)混合末A(180mg)および混合末B(180mg)をロータリー式打錠機(HT-CVX54LS-UW/C&3L、畑鉄工所)で9.5mmφの杵を用いて打錠(打錠圧:10kN、1錠あたりの重量:360mg)し、素錠を得る。
(4)精製水(36720g)にヒドロキシプロピルメチルセルロース(3978g)とタルク(612g)を溶解、分散して分散液Iを調製する。精製水(9180g)に酸化チタン(494.7g)、酸化鉄(15.3g)を分散して分散液IIを調製する。分散液Iに分散液IIを加え、攪拌混合し、コーティング液を得る。コーティング機(DRC-1200、株式会社パウレック)を用いて、(3)で得た該素錠の重量が1錠あたり10mg増加するまでコーティング液を噴霧することにより、下記組成のフィルム錠を得る。次いで、該フィルム錠を40℃で15時間減圧乾燥する。
ベシル酸アムロジピン 6.935 mg
マンニトール 129.865 mg
結晶セルロース 9 mg
ヒドロキシプロピルセルロース 5.4 mg
結晶セルロース 18 mg
クロスポビドン 9 mg
ステアリン酸マグネシウム 1.8 mg
化合物A 42.68 mg
マンニトール 86.93 mg
結晶セルロース 9 mg
水酸化ナトリウム 0.69 mg
フマル酸 2 mg
ヒドロキシプロピルセルロース 5.4 mg
結晶セルロース 18 mg
クロスポビドン 13.5 mg
ステアリン酸マグネシウム 1.8 mg
ヒドロキシプロピルメチルセルロース 7.8 mg
タルク 1.2 mg
酸化チタン 0.97 mg
酸化鉄 0.03 mg
計 370 mg
(1)精製水(43900g)にヒドロキシプロピルセルロース(2802g)を溶解して結合液Iを調製する。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で、ベシル酸アムロジピン(2982g)、マンニトール(55840g)および結晶セルロース(3870g)を均一に混合した後、結合液I(38700g)を噴霧しながら、造粒し、ついで乾燥して、造粒末を得る。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得る。得られた整粒末(61240g)に結晶セルロース(7290g)、クロスポビドン(3645g)およびステアリン酸マグネシウム(729g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Aを得る。
(2)精製水(38230g)に水酸化ナトリウム(405.8g)およびフマル酸(1176g)を溶解して、緩衝液を調製する。精製水(47280g)にヒドロキシプロピルセルロース(3018g)を溶解して結合液IIを調製する。流動層造粒乾燥機(WSG-60、株式会社パウレック)中で化合物A(20060g)、マンニトール(40860g)、結晶セルロース(4230g)を均一に混合した後、緩衝液(31810g)を噴霧し、さらに結合液II(42300g)を噴霧しながら造粒し、ついで乾燥して造粒末を得る。得られた造粒末の一部をパワーミル粉砕機(P-7S、昭和化学機械工作所)を用い、1.5mmφパンチングスクリーンで解砕して、整粒末を得る。得られた整粒末(60150g)に結晶セルロース(7380g)、クロスポビドン(5535g)およびステアリン酸マグネシウム(738g)を加え、タンブラー混合機(TM-400S、昭和化学機械工作所)で混合することにより、混合末Bを得る。
(3)混合末A(180mg)および混合末B(360mg)をロータリー式打錠機(HT-CVX54LS-UW/C&3L、畑鉄工所)で長径14mm、短径8mmの杵を用いて打錠(打錠圧:11kN、1錠あたりの重量:540mg)し、素錠を得る。
(4)精製水(36720g)にヒドロキシプロピルメチルセルロース(3978g)とタルク(612g)を溶解、分散して分散液Iを調製する。精製水(9180g)に酸化チタン(494.7g)、酸化鉄(15.3g)を分散して分散液IIを調製する。分散液Iに分散液IIを加え、攪拌混合し、コーティング液を得る。コーティング機(DRC-1200、株式会社パウレック)を用いて、(3)で得た該素錠の重量が1錠あたり20mg増加するまでコーティング液を噴霧することにより、下記組成のフィルム錠を得る。次いで、該フィルム錠を40℃で15時間減圧乾燥する。
ベシル酸アムロジピン 6.935 mg
マンニトール 129.865 mg
結晶セルロース 9 mg
ヒドロキシプロピルセルロース 5.4 mg
結晶セルロース 18 mg
クロスポビドン 9 mg
ステアリン酸マグネシウム 1.8 mg
化合物A 85.36 mg
マンニトール 173.86 mg
結晶セルロース 18 mg
水酸化ナトリウム 1.38 mg
フマル酸 4 mg
ヒドロキシプロピルセルロース 10.8 mg
結晶セルロース 36 mg
クロスポビドン 27 mg
ステアリン酸マグネシウム 3.6 mg
ヒドロキシプロピルメチルセルロース 15.6 mg
タルク 2.4 mg
酸化チタン 1.94 mg
酸化鉄 0.06 mg
計 560 mg
参考例1および比較例1で得た乾燥素錠の薬物(化合物Aのフリー体)の溶出性を溶出試験(0.5w/w%ドデシル硫酸ナトリウム含有リン酸緩衝液(pH6.8)900mL、パドル法、回転数50rpm、37℃)により評価した。溶出試験は第十四改正日本薬局方溶出試験法第2法(パドル法)に従って実施した。結果を図1に示す。-●-は参考例1の乾燥素錠の結果(参考例1の乾燥素錠に含有される化合物Aのフリー体の溶出率(%))を示す。-○-は比較例1の乾燥素錠の結果(比較例1の乾燥素錠に含有される化合物Aのフリー体の溶出率(%))を示す。
図1に示すように、pH調整剤の添加により、溶出性が改善されることが示された。
参考例1および比較例1で得た乾燥素錠を、ガラス瓶に乾燥剤とともに入れ、40℃に1ヶ月間保存した際の、分解物の増加量を以下のような方法で測定した。
化合物Aが約1μg/mLとなるように抽出液で溶解し、非水系フィルター(0.45μm)でろ過した後、次の条件で高速液体カラムクロマトグラフィー(HPLC)法により定量した。
検出器:紫外線吸光光度計、測定波長:240nm
カラム:YMC-Pack Pro C18、5μm、内径:4.6mm、長さ:150mm
カラム温度:25℃
移動相(A):0.05mol/Lリン酸緩衝液(pH3.0)/アセトニトリル混液(9:1)
移動相(B):0.05mol/Lリン酸緩衝液(pH3.0)/アセトニトリル混液(3:7)
流量:1mL/分
グラジェントプログラム(リニア)
製剤例11および製剤例12で得た乾燥素錠を、ガラス瓶に乾燥剤とともに入れ、60℃に2週間保存した際の、分解物の増加量を以下のような方法で測定した。
化合物Aが約1μm/mLとなるように抽出液で溶解し、非水系フィルター(0.45μm)でろ過した後、次の条件で高速液体カラムクロマトグラフィー(HPLC)法により測定した。
検出器:紫外線吸光光度計、測定波長:237nm
カラム:YMC-Pack Pro C18、5μm、内径:4.6mm、長さ:150mm
カラム温度:25℃
移動相(A):0.05mol/Lリン酸緩衝液(pH3.0)
移動相(B):アセトニトリル
流量:1mL/分
グラジェントプログラム(リニア)
製剤例14および比較例2で得た乾燥素錠の薬物(化合物Aのフリー体)溶出性を実験例1と同様の方法で評価した。結果を図2に示す。-●-は製剤例14の乾燥素錠の結果(製剤例14の乾燥素錠に含有される化合物Aのフリー体の溶出率(%))を示す。-○-は比較例2の乾燥素錠の結果(比較例2の乾燥素錠に含有される化合物Aのフリー体の溶出率(%))を示す。
図2に示すように、pH調整剤の添加により、溶出性が改善されることが示された。
製剤例14および比較例2で得た乾燥素錠を、ガラス瓶に乾燥剤とともに入れ、60℃に2週間保存した際の、分解物の増加量を以下のような方法で測定した。
化合物Aが約1.6mg/mLとなるように抽出液で溶解し、非水系フィルター(0.45μm)でろ過した後、次の条件で高速液体カラムクロマトグラフィー(HPLC)法により定量した。
検出器:紫外線吸光光度計、測定波長:240nm
カラム:YMC-Pack Pro C18、5μm、内径:4.6mm、長さ:250mm
カラム温度:25℃
移動相(A):0.05mol/Lリン酸緩衝液(pH3.0)/アセトニトリル混液(4:1)
移動相(B):0.05mol/Lリン酸緩衝液(pH3.0)/アセトニトリル混液(3:7)
流量:1mL/分
グラジェントプログラム(リニア)
Claims (13)
- 式(I)で表される化合物またはその塩が2-エトキシ-1-{[2'-(5-オキソ-4,5-ジヒドロ-1,2,4-オキサジアゾール-3-イル)ビフェニル-4-イル]メチル}-1H-ベンズイミダゾール-7-カルボン酸 (5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メチル カリウム塩である請求項1記載の固形製剤。
- カルシウム拮抗剤がアムロジピンまたはその酸付加塩である、請求項1又は2記載の固形製剤。
- カルシウム拮抗剤がベシル酸アムロジピンである、請求項1又は2記載の固形製剤。
- 式(I)で表される化合物またはその塩が2-エトキシ-1-{[2'-(5-オキソ-4,5-ジヒドロ-1,2,4-オキサジアゾール-3-イル)ビフェニル-4-イル]メチル}-1H-ベンズイミダゾール-7-カルボン酸 (5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メチル カリウム塩であり、カルシウム拮抗剤がベシル酸アムロジピンである請求項1記載の固形製剤。
- pH調整剤がpH2ないし5のpH調整剤である請求項1記載の固形製剤。
- pH調整剤が酒石酸、クエン酸、乳酸、フマル酸、コハク酸、リン酸、リンゴ酸、アスコルビン酸、酢酸、酸性アミノ酸から選ばれる酸性物質、もしくはその塩、またはそれらの溶媒和物である請求項1記載の固形製剤。
- pH調整剤がフマル酸一ナトリウム、またはフマル酸とナトリウムイオンの供与体の組み合わせである請求項1記載の固形製剤。
- pH調整剤の配合量が、製剤に対して0.01~20重量%である、請求項1記載の固形製剤。
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UAA201105161A UA102271C2 (en) | 2008-09-25 | 2009-09-25 | Solid pharmaceutical composition (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4- oxadiazole -3-yl)biphenyl-4-yl]methyl}-1h-benzimidazole-7-carboxylate |
AU2009297522A AU2009297522A1 (en) | 2008-09-25 | 2009-09-25 | Solid pharmaceutical composition |
EA201170483A EA201170483A1 (ru) | 2008-09-25 | 2009-09-25 | Твердая фармацевтическая композиция |
JP2010530880A JP5570426B2 (ja) | 2008-09-25 | 2009-09-25 | 固形医薬組成物 |
EP09816220.9A EP2332535A4 (en) | 2008-09-25 | 2009-09-25 | SOLID PHARMACEUTICAL COMPOSITION |
CN200980146684.3A CN102223884B (zh) | 2008-09-25 | 2009-09-25 | 固体药物组合物 |
MX2011003261A MX2011003261A (es) | 2008-09-25 | 2009-09-25 | Composicion farmaceutica solida. |
BRPI0918955A BRPI0918955A2 (pt) | 2008-09-25 | 2009-09-25 | preparação sólida, e, método para estabilizar um composto, e para melhorar a dissoulução de um composto |
US12/998,167 US9173849B2 (en) | 2008-09-25 | 2009-09-25 | Solid pharmaceutical composition |
NZ592225A NZ592225A (en) | 2008-09-25 | 2009-09-25 | Solid pharmaceutical composition |
CA2738147A CA2738147C (en) | 2008-09-25 | 2009-09-25 | Solid pharmaceutical composition |
IL211886A IL211886A0 (en) | 2008-09-25 | 2011-03-23 | Solid pharmaceutical composition |
TN2011000147A TN2011000147A1 (en) | 2009-09-25 | 2011-03-25 | Solid pharmaceutical composition |
ZA2011/02715A ZA201102715B (en) | 2008-09-25 | 2011-04-12 | Solid pharmaceutical composition |
MA33782A MA32721B1 (fr) | 2008-09-25 | 2011-04-20 | Composition pharmaceutique solide |
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EP (1) | EP2332535A4 (ja) |
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CN (2) | CN102223884B (ja) |
AR (1) | AR073380A1 (ja) |
AU (1) | AU2009297522A1 (ja) |
BR (1) | BRPI0918955A2 (ja) |
CA (1) | CA2738147C (ja) |
CL (1) | CL2011000625A1 (ja) |
CO (1) | CO6361934A2 (ja) |
CR (1) | CR20110209A (ja) |
EA (1) | EA201170483A1 (ja) |
EC (1) | ECSP11011001A (ja) |
GE (1) | GEP20146063B (ja) |
IL (1) | IL211886A0 (ja) |
MA (1) | MA32721B1 (ja) |
MX (1) | MX2011003261A (ja) |
NZ (1) | NZ592225A (ja) |
PE (1) | PE20110844A1 (ja) |
TW (1) | TW201014850A (ja) |
UA (1) | UA102271C2 (ja) |
UY (1) | UY32126A (ja) |
WO (1) | WO2010035806A1 (ja) |
ZA (1) | ZA201102715B (ja) |
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JP2019059706A (ja) * | 2017-09-28 | 2019-04-18 | エルメッド エーザイ株式会社 | アジルサルタン又はその塩及びアムロジピン又はその塩含有錠剤の品質向上方法、並びにアジルサルタン又はその塩及びアムロジピン又はその塩含有錠剤及びその製造方法 |
JP2020090470A (ja) * | 2018-12-07 | 2020-06-11 | ニプロ株式会社 | アジルサルタン及びアムロジピンを含有する医薬組成物及びその製造方法 |
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TR201004754A1 (tr) * | 2010-06-11 | 2012-01-23 | Sanovel �La� San. Ve T�C. A.�. | Yeni Farmasötik Kombinasyonlar |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010126168A3 (en) * | 2009-04-30 | 2011-03-03 | Takeda Pharmaceutical Company Limited | Solid preparation |
CN102481248A (zh) * | 2009-04-30 | 2012-05-30 | 武田药品工业株式会社 | 固体制剂 |
JP2019059706A (ja) * | 2017-09-28 | 2019-04-18 | エルメッド エーザイ株式会社 | アジルサルタン又はその塩及びアムロジピン又はその塩含有錠剤の品質向上方法、並びにアジルサルタン又はその塩及びアムロジピン又はその塩含有錠剤及びその製造方法 |
JP7101464B2 (ja) | 2017-09-28 | 2022-07-15 | エルメッド株式会社 | アジルサルタン又はその塩及びアムロジピン又はその塩含有錠剤の品質向上方法、並びにアジルサルタン又はその塩及びアムロジピン又はその塩含有錠剤及びその製造方法 |
JP2020090470A (ja) * | 2018-12-07 | 2020-06-11 | ニプロ株式会社 | アジルサルタン及びアムロジピンを含有する医薬組成物及びその製造方法 |
JP7206872B2 (ja) | 2018-12-07 | 2023-01-18 | ニプロ株式会社 | アジルサルタン及びアムロジピンを含有する医薬組成物及びその製造方法 |
Also Published As
Publication number | Publication date |
---|---|
TW201014850A (en) | 2010-04-16 |
US20110229567A1 (en) | 2011-09-22 |
CN104306975A (zh) | 2015-01-28 |
UY32126A (es) | 2010-04-30 |
ZA201102715B (en) | 2012-07-25 |
CL2011000625A1 (es) | 2011-07-08 |
CA2738147C (en) | 2016-10-11 |
US9173849B2 (en) | 2015-11-03 |
EA201170483A1 (ru) | 2011-10-31 |
CN102223884B (zh) | 2015-05-06 |
NZ592225A (en) | 2012-06-29 |
UA102271C2 (en) | 2013-06-25 |
EP2332535A4 (en) | 2013-11-27 |
JP5570426B2 (ja) | 2014-08-13 |
JPWO2010035806A1 (ja) | 2012-02-23 |
EP2332535A1 (en) | 2011-06-15 |
MA32721B1 (fr) | 2011-10-02 |
AR073380A1 (es) | 2010-11-03 |
CN102223884A (zh) | 2011-10-19 |
IL211886A0 (en) | 2011-06-30 |
GEP20146063B (en) | 2014-03-25 |
CO6361934A2 (es) | 2012-01-20 |
CR20110209A (es) | 2011-05-27 |
MX2011003261A (es) | 2011-04-21 |
ECSP11011001A (es) | 2011-05-31 |
AU2009297522A1 (en) | 2010-04-01 |
BRPI0918955A2 (pt) | 2015-12-01 |
PE20110844A1 (es) | 2011-12-05 |
KR20110063557A (ko) | 2011-06-10 |
CA2738147A1 (en) | 2010-04-01 |
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