WO2014002851A1 - Comprimé pharmaceutique solide et son procédé de préparation - Google Patents

Comprimé pharmaceutique solide et son procédé de préparation Download PDF

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Publication number
WO2014002851A1
WO2014002851A1 PCT/JP2013/066873 JP2013066873W WO2014002851A1 WO 2014002851 A1 WO2014002851 A1 WO 2014002851A1 JP 2013066873 W JP2013066873 W JP 2013066873W WO 2014002851 A1 WO2014002851 A1 WO 2014002851A1
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WO
WIPO (PCT)
Prior art keywords
solid pharmaceutical
pharmaceutical tablet
salt
atorvastatin
magnesium
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Application number
PCT/JP2013/066873
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English (en)
Japanese (ja)
Inventor
尭彬 城
秀夫 八柳
直久 片山
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ニプロ株式会社
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Application filed by ニプロ株式会社 filed Critical ニプロ株式会社
Priority to JP2014522568A priority Critical patent/JP6176246B2/ja
Publication of WO2014002851A1 publication Critical patent/WO2014002851A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a solid pharmaceutical tablet and a method for producing the same, and more particularly to a solid pharmaceutical tablet containing two active ingredients, atorvastatin and amlodipine, and a method for producing the same.
  • ingredients having the same or different medicinal effects have been blended into one solid preparation. This is because the combination of a plurality of components has many advantages such as higher effects than single agents, reduced side effects, and reduced physician prescriptions.
  • Patent Document 1 a solid preparation containing atorvastatin calcium hydrate used as an agent for hyperlipidemia and amlodipine besylate used as an antihypertensive agent is known (Patent Document 1 and Non-Patent Document 1).
  • atorvastatin calcium hydrate is decomposed unless it is stored in a basic environment, and atorvastatin analogues are produced.
  • Amlodipine besylate is known to be decomposed by light to produce an amlodipine related substance. It is desired to suppress the production of such related substances.
  • An object of the present invention is to solve the above-mentioned problems.
  • the object of the present invention is to provide two effective effects of atorvastatin, a salt thereof, or a hydrate thereof and amlodipine, or a pharmaceutically acceptable salt thereof.
  • An object of the present invention is to provide a solid pharmaceutical tablet excellent in stability and containing a component, wherein production of related substances of each component is reduced, and a method for producing the same.
  • the present inventors performed film coating containing a colorant when preparing a granulated product of atorvastatin, and by adding various other components as necessary, atorvastatin and It has been found that the degradation of amlodipine can be suppressed and the stability as the solid pharmaceutical tablet can be improved, and the present invention has been completed.
  • the present invention is a solid pharmaceutical tablet containing atorvastatin, a salt thereof, or a hydrate thereof and amlodipine or a pharmaceutically acceptable salt thereof
  • a solid pharmaceutical tablet containing the atorvastatin, a salt thereof, or a hydrate thereof and a granule containing at least two metal salts, and the amlodipine or a pharmaceutically acceptable salt thereof in the form of a mixture. is there.
  • the at least two metal salts are selected from the group consisting of calcium carbonate, magnesium carbonate, calcium hydroxide, magnesium hydroxide, magnesium silicate, magnesium aluminate, and magnesium aluminum hydroxide.
  • At least one of the at least two metal salts is a magnesium salt.
  • the metal salt is calcium carbonate and magnesium carbonate.
  • the mixture is film-coated with a coating agent containing polyvinyl alcohol and / or a vinyl alcohol copolymer.
  • the polyvinyl alcohol and / or vinyl alcohol copolymer is a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.
  • the granulated product comprises crospovidone, sodium carboxy starch, sodium carboxymethyl starch, starch, partially pregelatinized starch, corn starch, lactose, calcium citrate, light anhydrous silicic acid, synthetic aluminum silicate, crystals It contains at least one disintegrant selected from the group consisting of cellulose, low substituted hydroxypropyl cellulose, and hydroxypropyl starch.
  • the granulated product contains at least one disintegrant selected from the group consisting of croscarmellose, croscarmellose sodium, carboxymethylcellulose, carboxymethylcellulose calcium, and carmellose, and the mass of the solid pharmaceutical tablet. Is contained at most 3% by mass on the basis of.
  • the present invention is also a method for producing a solid pharmaceutical tablet comprising: Obtaining a granulate comprising atorvastatin, a salt thereof, or a hydrate thereof and at least two metal salts; and mixing the granulation with amlodipine or a pharmaceutically acceptable salt thereof and Locking to obtain a plain tablet; A method comprising
  • the production method of the present invention further includes a step of film-coating the uncoated tablet with a coating agent containing polyvinyl alcohol and / or a vinyl alcohol copolymer.
  • the solid pharmaceutical tablet of the present invention as a solid pharmaceutical tablet containing atorvastatin and amlodipine, it is possible to provide a solid pharmaceutical tablet excellent in stability with reduced production of related substances due to degradation.
  • the solid pharmaceutical tablet of the present invention can be stored for a long period of time as compared with a solid pharmaceutical tablet containing conventional atorvastatin calcium hydrate and amlodipine besylate.
  • FIG. 1 shows atorvastatin calcium hydrate and amlodipine besylate when the solid pharmaceutical tablets obtained in Examples 1 to 3 and Comparative Examples 1 and 2 and the conventional tablet of Comparative Example 1 are stored under certain conditions. It is a graph showing a time-dependent change over a storage period about the total amount of the content rate (%) of the related substance.
  • Solid pharmaceutical tablets The solid pharmaceutical tablet of the present invention will be described.
  • the solid pharmaceutical tablet of the present invention contains a mixture of atorvastatin, a salt thereof, or a hydrate thereof and amlodipine or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as a mixture of atorvastatin and amlodipine). .
  • Atorvastatin, a salt thereof, or a hydrate thereof used in the present invention is (3R, 5R) -7- [2- (4-fluorophenyl) -5- (1-methylethyl) -3-phenyl-4- (Phenylcarbamoyl) -1H-pyrrol-1-yl] -3,5-dihydroxyheptanoic acid (hereinafter referred to as atorvastatin), a salt thereof, or a hydrate thereof is useful as an agent for hyperlipidemia.
  • atorvastatin calcium hydrate.
  • Amlodipine or a pharmaceutically acceptable salt thereof used in the present invention is 3-ethyl 5-methyl (4RS) -2-[(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -6-methyl.
  • 1,4-dihydropyridine-3,5-dicarboxylate hereinafter amlodipine
  • amlodipine besylate useful as an antihypertensive agent.
  • the mixing ratio of atorvastatin, a salt, or a hydrate thereof used in the present invention to amlodipine, or a pharmaceutically acceptable salt thereof is not particularly limited, but is, for example, 1: 4 on the basis of each mass. To 4: 1, preferably 1: 1 to 3.2: 1.
  • the mixture of atorvastatin and amlodipine includes atorvastatin, a salt thereof, or a hydrate thereof and a granulated product containing at least two metal salts, and amlodipine or a pharmaceutically acceptable salt thereof. It is a mixture of That is, atorvastatin, a salt thereof, or a hydrate thereof is once separately granulated as a granulated product together with at least two kinds of metal salts, and the granulated product is combined with amlodipine or a pharmaceutically acceptable salt thereof. To constitute one kind of mixture.
  • Examples of the metal salt constituting the granulated product are selected from the group consisting of calcium carbonate, magnesium carbonate, calcium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium silicate, magnesium aluminate, and magnesium aluminum hydroxide. There are at least two types. In the present invention, it is preferable that at least one of the at least two metal salts is a magnesium salt.
  • an example of a preferable combination is a combination of calcium carbonate and magnesium carbonate.
  • the mixing ratio of calcium carbonate and magnesium carbonate can be appropriately set by those skilled in the art and is not particularly limited.
  • the mixing ratio is 5: 1 to 20: 1, preferably 1.5: 1 to 15: 1 on the basis of mass. More preferably, it is 2: 1 to 10: 1.
  • the metal salt contained in the granulated product is, for example, 5% by mass to 30% by mass based on the mass of the tablet.
  • the granulated product may contain, for example, an excipient, a disintegrant, and a binder in addition to the atorvastatin, a salt thereof, or a hydrate thereof, and at least two metal salts.
  • excipient that can be contained in the granulated product is a general pharmaceutically acceptable excipient.
  • excipients include, but are not limited to, crystalline cellulose, glucose, fructose, lactose, sucrose (including purified sucrose), reduced maltose, dextran, sugar alcohol (eg, D-mannitol, xylitol, sorbitol, erythritol) , Trehalose, maltitol, lactitol), glycerin fatty acid ester, inorganic powder (eg, magnesium aluminate metasilicate, synthetic hydrotalcite), and combinations thereof.
  • the content of the excipient can be appropriately set by those skilled in the art.
  • the disintegrant that can be contained in the granulated product is a general disintegrant that is pharmaceutically acceptable.
  • disintegrants include crospovidone, sodium carboxy starch, sodium carboxymethyl starch, starch, partially pregelatinized starch, corn starch, lactose, calcium citrate, light anhydrous silicic acid, synthetic aluminum silicate, crystalline cellulose, low degree of substitution Examples include hydroxypyrrolocellulose, croscarmellose, croscarmellose sodium, carboxymethylcellulose calcium, carmellose, hydroxypropyl starch, and combinations thereof.
  • the content of the disintegrant can be appropriately set by those skilled in the art.
  • a specific disintegrant as much as possible for the disintegrant that can be contained in the granulated product. That is, among the above-mentioned disintegrants, specific disintegrants such as croscarmellose, croscarmellose sodium, carboxymethylcellulose, carboxymethylcellulose calcium, carmellose are not used in the granulated product, or if used, they are kept in a very small amount. By preserving it, it is possible to further suppress the formation of a related substance due to the decomposition of atorvastatin, its salt, or its hydrate in the granulated product. An example of the content in the case where such a specific disintegrant is contained in a minute amount in the granulated product is at most 3% by mass based on the mass of the solid pharmaceutical tablet.
  • binder examples include general water-soluble substances that are pharmaceutically acceptable.
  • the binder include, but are not limited to, gelatin, agar, alginic acid, sodium alginate, dextrin, chitansan gum, gum arabic powder, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, partially saponified polyvinyl alcohol, methylcellulose, Examples include pullulan, partially pregelatinized starch, sugars, and combinations thereof.
  • the content of the binder can be appropriately set by those skilled in the art.
  • the granulated product containing such components is composed of particles whose particle size is controlled within a certain range by, for example, sieving in advance in order to stabilize the quality of the solid pharmaceutical tablet.
  • the granulated product is adjusted in particle size, for example, by passing through a sieve having an opening of 500 ⁇ m.
  • the solid pharmaceutical tablet of the present invention may contain other additives in addition to the granulated product and amlodipine or a pharmaceutically acceptable salt thereof.
  • additives include pharmaceutically acceptable excipients, disintegrants, and lubricants well known to those skilled in the art.
  • the content of other additives can also be appropriately set by those skilled in the art.
  • disintegrants examples include, but are not particularly limited to, general pharmaceutically acceptable disintegrants such as crospovidone, sodium carboxystarch, carboxy Sodium methyl starch, starch, partially pregelatinized starch, corn starch, lactose, calcium citrate, light anhydrous silicic acid, synthetic aluminum silicate, crystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose, croscarmellose sodium, carboxy Examples include methylcellulose calcium, carmellose, hydroxypropyl starch, and combinations thereof.
  • general pharmaceutically acceptable disintegrants such as crospovidone, sodium carboxystarch, carboxy Sodium methyl starch, starch, partially pregelatinized starch, corn starch, lactose, calcium citrate, light anhydrous silicic acid, synthetic aluminum silicate, crystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose, croscarmellose sodium, carboxy Examples include methylcellulose calcium
  • the mixture of atorvastatin and amlodipine is film-coated with a colorant and a coating agent containing polyvinyl alcohol and / or a vinyl alcohol copolymer.
  • colorants contained in this coating agent include edible yellow No. 5, yellow iron sesquioxide, iron sesquioxide (red), orange essence, brown iron oxide, caramel, light anhydrous silicic acid, edible blue No. 5, Food Yellow 4, Food Yellow 4 Aluminum Lake, Food Red 2, Food Red 3, Food Red 102, Food Blue 2, Talc, Fluorescein Sodium, Green Tea Powder, Vitamin C, Food Lake Dye, Carotenoid Color , Flavonoid dyes, quinone dyes, and combinations thereof.
  • examples of polyvinyl alcohol and / or vinyl alcohol-based copolymer contained in the coating agent include polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer and A combination of them is mentioned.
  • a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer is preferred.
  • the coating agent may contain a pharmaceutically acceptable third component (for example, a pigment such as titanium oxide and a lubricant) as necessary.
  • a pharmaceutically acceptable third component for example, a pigment such as titanium oxide and a lubricant
  • the type and content of the third component can be appropriately selected by those skilled in the art.
  • the amount of the coating agent necessary for film-coating the above mixture of atorvastatin and amlodipine is the active ingredient atorvastatin, its salt, or its hydrate, and amlodipine or its pharmaceutical Can be arbitrarily set by a person skilled in the art in such an amount that it can be controlled without inhibiting the release of a salt that is acceptable to the public.
  • the amount of coating agent that can be used is, for example, from 1% to 10% by weight, based on the total weight of the solid pharmaceutical tablet.
  • the solid pharmaceutical tablet of the present invention may have any form such as a disk shape, a lens shape, and a caplet shape.
  • granulation is performed on a granulated product containing atorvastatin, a salt thereof, or a hydrate thereof and at least two kinds of metal salts.
  • the atorvastatin, a salt thereof, or a hydrate thereof and the at least two kinds of metal salts, excipients, disintegrants, binders, and the like are mixed with a predetermined amount of water or an aqueous solution. And adjusted to a predetermined size by a granulator. Thereafter, the particles are appropriately dried, and sieved with a desired mesh, whereby a granulated product with an adjusted particle size can be obtained.
  • this granulated product and amlodipine or a pharmaceutically acceptable salt thereof are mixed together with other additives as necessary, and compressed together to be processed into an uncoated tablet form.
  • Tableting machines well known in the art can be used for tableting. In tableting, conditions such as the diameter and thickness of the resulting uncoated tablet can be appropriately selected by those skilled in the art.
  • the uncoated tablet is film-coated with a coating agent containing polyvinyl alcohol and / or a vinyl alcohol copolymer containing a colorant as required.
  • the coating method employed in the present invention is not particularly limited.
  • a coating solution known in the art is dissolved or dispersed in a solvent such as water to prepare a coating solution, and the resulting coating solution is used as an uncoated tablet. This can be done by spray coating.
  • the solid pharmaceutical tablet of the present invention can be produced.
  • Atorvastatin calcium hydrate 5.42 g, precipitated calcium carbonate 32.0 g and magnesium carbonate 2.0 g, crystalline cellulose 23.58 g, partially pregelatinized starch 10.0 g, croscarmellose sodium 3.0 g and hydroxypropylcellulose 2.0 g was put into a mechano mill (MM-40N manufactured by Okada Seiko Co., Ltd.), and further granulated with 30.0 g of purified water. 78.0 g of the resulting granulated product was dried with a fluidized bed granulator / dryer (MP01 manufactured by POWREC Co., Ltd.), and then sieved with a 500 ⁇ m sieve.
  • the coating solution was sprayed onto the uncoated tablet and the placebo tablet in a film coating machine and dried. Only the tablets containing the active drug were selected from the obtained tablets to obtain a solid pharmaceutical tablet having a total amount of 114 g (114 mg per tablet).
  • Example 2 As shown in Table 1, in the same manner as in Example 1 except that 30.0 g of precipitated calcium carbonate and 4.0 g of magnesium carbonate were used as the metal salts used in the granulated product during granulation, the total amount was 114 g ( A solid pharmaceutical tablet (114 mg per tablet) was obtained.
  • Example 3 As shown in Table 1, 34.0 g of precipitated calcium carbonate and 4.0 g of magnesium carbonate were used as metal salts used in the granulated product for granulation, and croscarmellose sodium as a disintegrant was not used (0 g (The amount of disintegrant croscarmellose added at the end is not changed), the amount of partially pregelatinized starch as another disintegrant is 5.0 g, and the amount of crystalline cellulose as an excipient is Solid pharmaceutical tablets with a total amount of 114 g (114 mg per tablet) were obtained in the same manner as in Example 1 except that the amount was changed to 27.58 g (the amount of excipient crystalline cellulose added at the end was not changed). It was.
  • Example 1 As shown in Table 1, the same procedure as in Example 1 was conducted except that 34.0 g of precipitated calcium carbonate alone was used in place of the precipitated calcium carbonate and magnesium carbonate, which are metal salts used in the granulated product during granulation. Thus, a total amount of 114 g (114 mg per tablet) of solid pharmaceutical tablets was obtained.
  • Example 1 and Comparative Example 1 in which the content of metal salt in the granulated product containing atorvastatin calcium hydrate was changed were stored after 7 days and stored for 14 days. Comparing the content rate of the related substances later, it can be seen that two types of metal salts contained in the granulated product showed a lower level of related substance content than one type.
  • the results of Table 3 regarding the related substance contents obtained for Examples 1 to 3 and Comparative Examples 1 and 2 are shown as the time of the related substance content ratio (%) with respect to the storage period (days).
  • the content of related substances increases in proportion to the storage period in each result.
  • the graphs showing the results of Examples 1 to 3 and the graphs showing the results of Comparative Examples 1 and 2 are compared, the slopes of the respective graphs of Examples 1 to 3 are compared with those of Comparative Example 1. It turns out that it is remarkably small.
  • a solid pharmaceutical tablet containing at least two kinds of metal salts in a granulated product as shown in Examples 1 to 3 is a tablet containing only one kind of metal salt in the granulated product.
  • the increase in related substances over time (days) was small, and the solid pharmaceutical tablets obtained in Examples 1 to 3 had a small increase in related substance content during long-term storage, and atorvastatin calcium It turns out that decomposition
  • the solid pharmaceutical tablet of the present invention improves both the stability of the atorvastatin and amlodipine.
  • atorvastatin calcium hydrate useful as an agent for hyperlipidemia and amlodipine besylate useful as an antihypertensive agent are contained, and a related substance is produced by decomposition. It is possible to provide a solid pharmaceutical tablet with reduced stability and excellent stability.

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Abstract

L'invention concerne un comprimé pharmaceutique solide et un procédé de préparation du comprimé pharmaceutique solide. Le comprimé pharmaceutique solide selon la présente invention est un comprimé qui comprend un matériau granulé comprenant de l'atorvastatine ou un sel ou hydrate de celle-ci et au moins deux sels métalliques et de l'amlodipine ou un sel pharmaceutiquement acceptable de celle-ci à l'état mélangé. Dans le comprimé pharmaceutique solide selon la présente invention, la production de substances analogues aux principes actifs peut être empêchée. Par conséquent, le comprimé pharmaceutique solide présente une excellente stabilité.
PCT/JP2013/066873 2012-06-25 2013-06-19 Comprimé pharmaceutique solide et son procédé de préparation WO2014002851A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108421045A (zh) * 2018-04-02 2018-08-21 北京海晶生物医药科技有限公司 一种阿托伐他汀钙组合物、制剂及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08505640A (ja) * 1993-01-19 1996-06-18 ワーナー−ランバート・コンパニー 安定な経口用のｃｉ−９８１製剤およびその製法
WO2006070248A1 (fr) * 2004-12-28 2006-07-06 Ranbaxy Laboratories Limited Procedes permettant de preparer des formes posologiques pharmaceutiques solides et stables a base d'atorvastatine et d'amlodipine
JP2008519835A (ja) * 2004-11-12 2008-06-12 マーソン，アール．プレストン 大動脈内皮細胞の一酸化窒素放出に対するアムロジピン及びアトルバスタチンの相乗効果
WO2011077843A1 (fr) * 2009-12-25 2011-06-30 沢井製薬株式会社 Préparation enrobée contenant de l'atrovastatine

Patent Citations (4)

* Cited by examiner, † Cited by third party
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