WO2014007065A1 - Comprimé pharmaceutique solide et son procédé de production - Google Patents

Comprimé pharmaceutique solide et son procédé de production Download PDF

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Publication number
WO2014007065A1
WO2014007065A1 PCT/JP2013/066874 JP2013066874W WO2014007065A1 WO 2014007065 A1 WO2014007065 A1 WO 2014007065A1 JP 2013066874 W JP2013066874 W JP 2013066874W WO 2014007065 A1 WO2014007065 A1 WO 2014007065A1
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WO
WIPO (PCT)
Prior art keywords
tablet
solid pharmaceutical
atorvastatin
amlodipine
salt
Prior art date
Application number
PCT/JP2013/066874
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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 JP2014523668A priority Critical patent/JPWO2014007065A1/ja
Publication of WO2014007065A1 publication Critical patent/WO2014007065A1/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
    • A61K31/40—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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • 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
    • 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.
  • Non-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 (Non-patent Document 1).
  • atorvastatin analogues are produced when polyethylene glycol is included in the formulation in the coexistence of atorvastatin calcium hydrate and amlodipine besylate.
  • Amlodipine besylate is known to be decomposed by light to produce an amlodipine related substance. Therefore, it is desired to improve the thermal stability and light stability of solid pharmaceutical tablets containing two active ingredients, atorvastatin and amlodipine, while suppressing 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 do not use polyethylene glycol on the uncoated tablet, but also perform film coating containing a colorant and, if necessary, contain various other components.
  • the present inventors have found that the degradation of atorvastatin and amlodipine can be suppressed and the stability as the solid pharmaceutical tablet can be improved.
  • 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, and comprising atorvastatin, a salt thereof, or a hydrate thereof and amlodipine or A tablet in which the mixture with its pharmaceutically acceptable salt 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 coating agent contains at least one colorant selected from the group consisting of titanium oxide, edible yellow No. 5, yellow ferric oxide, and ferric oxide.
  • the mixture of atorvastatin, a salt, or a hydrate thereof and amlodipine, or a pharmaceutically acceptable salt thereof is a granulated product containing the atorvastatin, a salt, or a hydrate thereof.
  • amlodipine or a pharmaceutically acceptable salt thereof is a granulated product containing the atorvastatin, a salt, or a hydrate thereof.
  • the present invention is also a method for producing a solid pharmaceutical tablet comprising: Obtaining a granulated product containing atorvastatin, a salt thereof, or a hydrate thereof; Mixing the granulated product with amlodipine or a pharmaceutically acceptable salt thereof and compressing them together to obtain an uncoated tablet; And film-coating the uncoated tablet with a coating agent containing polyvinyl alcohol and / or a vinyl alcohol copolymer; A method comprising
  • 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.
  • 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, for example, useful as an agent for hyperlipidemia is there.
  • atorvastatin a salt thereof, or a hydrate thereof, for example, useful as an agent for hyperlipidemia is there.
  • it is 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 is preferred.
  • 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 for example, 1: 1 based on each mass. To 4: 1, preferably in the range of 1: 1.2 to 3.2: 1.
  • the mixture of atorvastatin and amlodipine is a mixture of a granulate containing atorvastatin, a salt thereof, or a hydrate thereof and amlodipine or a pharmaceutically acceptable salt thereof. is there. That is, a granule containing atorvastatin, a salt thereof, or a hydrate thereof is once granulated separately, and the granulation and amlodipine or a pharmaceutically acceptable salt thereof are combined to form one kind of granule. Make up the mixture.
  • the granulated product may contain, for example, a metal salt, an excipient, a disintegrant, and a binder in addition to the atorvastatin, a salt thereof, or a hydrate thereof.
  • the metal salt include at least one metal salt selected from the group consisting of calcium carbonate, magnesium carbonate, calcium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium silicate, magnesium aluminate, and magnesium aluminum hydroxide. It is.
  • 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.
  • excipients that can be contained in the granulated product are common excipients that are pharmaceutically acceptable.
  • 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.
  • disintegrants examples include crospovidone, sodium carboxystarch, sodium carboxymethyl starch, starch, partially pregelatinized starch, corn starch, lactose, calcium citrate, light anhydrous silicic acid, synthetic aluminum silicate crystalline cellulose, low substituted hydroxy
  • disintegrants include pyropyrocellulose, 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 as 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, a salt thereof, or a hydrate thereof and amlodipine, or a pharmaceutically acceptable salt thereof contains polyvinyl alcohol and / or a vinyl alcohol copolymer.
  • the film is coated with a coating agent.
  • coating agent used in the present specification is a composition for coating tablets generally used in the art, and the state before use for coating is in a liquid state. , Solid, pasty, or any combination of these and the like.
  • polyvinyl alcohol and / or vinyl alcohol copolymer contained in the coating agent examples include polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, and their copolymers. Combinations are listed. A polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer is preferred.
  • this coating agent preferably contains a colorant.
  • colorants contained in the coating agent include edible yellow No. 5, yellow ferric oxide, ferric sesquioxide (red), orange essence, brown iron oxide, caramel, light anhydrous silicic acid, edible blue No. 5, edible Yellow No. 4, Edible Yellow No. 4 Aluminum Lake, Edible Red No. 2, Edible Red No. 3, Edible Red No. 102, Edible Red No. 2, Talc, Fluorescein Sodium, Green Tea Powder, Vitamin C, Edible Lake Dye, Carotenoid Dye, Examples include flavonoid dyes, quinone dyes, and combinations thereof.
  • the amount of the colorant used is preferably 0.5% by mass to 5.0% by mass and more preferably 0.8% by mass to 3.5% by mass with respect to the total mass of the coating agent.
  • the decomposition of atorvastatin, a salt thereof, or a hydrate thereof and amlodipine or a pharmaceutically acceptable salt included by the film coating cannot be sufficiently suppressed, It may promote the generation of unnecessary related substances. Even if the content of the colorant exceeds 5.0% by mass, there is no significant change in the suppression of the production of the related substance in the solid pharmaceutical tablet itself. May exceed capacity (ADI).
  • 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.
  • a granulated product containing atorvastatin, a salt thereof, or a hydrate thereof is first granulated.
  • the above-mentioned atorvastatin, a salt thereof, or a hydrate thereof, and a metal salt, an excipient, a disintegrant, a binder and the like are mixed with a predetermined amount of water or an aqueous solution and mixed in a granulator. Adjusted to a predetermined size. 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 tableted 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 65.04 g, precipitated calcium carbonate 408.0 g, crystalline cellulose 222.96 g, partially pregelatinized starch 180.0 g, croscarmellose sodium 36.0 g, and hydroxypropyl cellulose 24.0 g are stirred at high speed. (VG05 manufactured by POWREC Co., Ltd.), and 360.0 g of purified water was further added for granulation. 936.0 g of the obtained granulated product was dried with a fluidized bed granulator / dryer (FD-MP-01D manufactured by POWREC Co., Ltd.) and then sieved with a 500 ⁇ m sieve.
  • a fluidized bed granulator / dryer FD-MP-01D manufactured by POWREC Co., Ltd.
  • a placebo tablet tablette (tablet not containing an active drug) was mixed with 120 g of the uncoated tablet, and the mixture was put into a film coating machine (HCT-30N manufactured by Freund Sangyo Co., Ltd.).
  • HCT-30N manufactured by Freund Sangyo Co., Ltd.
  • POVACOAT registered trademark
  • talc polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer manufactured by Daido Kasei Kogyo Co., Ltd.
  • the coating liquid solid content concentration: 14.3% w / w
  • 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 123.0 g (123.0 mg per tablet).
  • Example 2 As shown in Table 1, about 480 g of a placebo tablet (tablet not containing an active drug) was mixed with 120 g of the uncoated tablet obtained in the same manner as in Example 1, and then a film coating machine (HCT manufactured by Freund Sangyo Co., Ltd.). -30N). On the other hand, a coating solution (solid content concentration 14.7% w / w) was prepared in the same manner as in Example 1 except that 1.0 g of titanium oxide was added. Thereafter, 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 solid pharmaceutical tablets having a total amount of 123.1 g (123.1 mg per tablet).
  • Example 3 As shown in Table 1, about 480 g of a placebo tablet (tablet not containing an active drug) was mixed with 120 g of the uncoated tablet obtained in the same manner as in Example 1, and then a film coating machine (HCT manufactured by Freund Sangyo Co., Ltd.). -30N). On the other hand, a coating liquid (solid content concentration: 14.4% w / w) was prepared in the same manner as in Example 1 except that 0.3 g of edible yellow No. 5 was added. Thereafter, 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 123.03 g (123.03 mg per tablet).
  • Example 4 As shown in Table 1, about 480 g of a placebo tablet (tablet not containing an active drug) was mixed with 120 g of the uncoated tablet obtained in the same manner as in Example 1, and then a film coating machine (HCT manufactured by Freund Sangyo Co., Ltd.). -30N). On the other hand, a coating liquid (solid content concentration 14.7% w / w) was prepared in the same manner as in Example 1 except that 1.0 g of yellow iron sesquioxide was added. Thereafter, 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 solid pharmaceutical tablets having a total amount of 123.1 g (123.1 mg per tablet).
  • Example 5 As shown in Table 1, about 480 g of a placebo tablet (tablet not containing an active drug) was mixed with 120 g of the uncoated tablet obtained in the same manner as in Example 1, and then a film coating machine (HCT manufactured by Freund Sangyo Co., Ltd.). -30N). On the other hand, a coating liquid (solid content concentration 14.7% w / w) was prepared in the same manner as in Example 1 except that 1.0 g of iron sesquioxide was added. Thereafter, 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 solid pharmaceutical tablets having a total amount of 123.1 g (123.1 mg per tablet).
  • Example 1 As shown in Table 1, about 540 g of a placebo tablet (tablet not containing an active drug) was mixed with 60 g of the uncoated tablet obtained in the same manner as in Example 1, and a film coating machine (HCT manufactured by Freund Sangyo Co., Ltd.). -30N). On the other hand, 22.5 g of hypromellose, 3.0 g of macrogol 6000 (polyethylene glycol manufactured by Sanyo Chemical Industries, Ltd.), 1.5 g of talc, and 3.0 g of titanium oxide were dissolved in 300.0 g of purified water to obtain a coating solution ( A solid concentration of 9.1% w / w) was prepared.
  • 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 123.0 g (123.0 mg per tablet).
  • Example 2 As shown in Table 1, about 540 g of a placebo tablet (tablet not containing an active drug) was mixed with 60 g of the uncoated tablet obtained in the same manner as in Example 1, and a film coating machine (HCT manufactured by Freund Sangyo Co., Ltd.). -30N). Meanwhile, 22.5 g of partially saponified polyvinyl alcohol, Macrogol 6000 (polyethylene glycol manufactured by Sanyo Chemical Industries, Ltd.) (3.0 g), 1.5 g of talc, and 3.0 g of titanium oxide were dissolved in 300.0 g of purified water. The coating liquid (solid content concentration 9.1% w / w) was prepared.
  • 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 123.0 g (123.0 mg per tablet).
  • Example 3 As shown in Table 1, the uncoated tablets obtained in the same manner as in Example 1 were not coated with a film, and as a form as they were, solid pharmaceutical tablets with a total amount of 120.0 g (120.0 mg per tablet) Obtained.
  • Example 1 Evaluation of thermal stability of solid pharmaceutical tablets
  • the tablets immediately after production in Example 1 and Comparative Examples 1 to 3 were each sealed in an aluminum bag, and the bag was stored for 14 days in an environment of a temperature of 60 ° C. and a humidity of 75%.
  • Mobile phase B A 1: 1 (volume ratio) mixed solution of acetonitrile / tetrahydrofuran was prepared. Liquid feeding: The liquid mixture was fed with the mixing ratio of mobile phase A and mobile phase B controlled as shown in Table 2 below.
  • polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer was used as the film coating agent and polyethylene glycol was not used, and other film coating agents (hypromellose or partial (Comparative Examples 1 and 2 using saponified polyvinyl alcohol) or polyethylene glycol, the content of related substances after storage for 7 days and after storage for 14 days was compared, and the tablet of Example 1 was a comparative example at any stage. It can be seen that the content rate of the related substances was lower than those of 1 and 2 and to the extent that it was not inferior to that of Comparative Example 3 in which the uncoated tablet was not applied.
  • Test Example 3 Thermal stability evaluation of solid pharmaceutical tablets
  • the tablets immediately after production in Examples 1 to 4 were sealed in aluminum bags, and the bags were stored for 14 days in an environment of temperature 60 ° C. and humidity 75%.
  • the tablets of Examples 2 to 4 formulated with a colorant as a film coating agent are also comparable to the tablets of Example 1 that do not contain a colorant as a film coating agent. It can be seen that the content of related substances was low. Further, it can be seen that even when a colorant is contained in the coating agent as in the tablets of Examples 2 to 4, the thermal stability of the resulting tablets is not adversely affected.
  • the solid pharmaceutical tablets of the present invention improve 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

La présente invention concerne un comprimé pharmaceutique solide et son procédé de production. Le comprimé pharmaceutique solide selon la présente invention contient de l'atorvastatine ou un sel ou un hydrate de celle-ci et de l'amlodipine ou un sel pharmaceutiquement acceptable de celle-ci, et est produit par pelliculage d'un mélange d'atorvastatine ou d'un sel ou d'un hydrate de celle-ci et d'amlodipine ou d'un sel pharmaceutiquement acceptable de celle-ci, au moyen d'un agent de revêtement contenant de l'alcool polyvinylique et/ou un copolymère d'alcool vinylique. Dans le comprimé pharmaceutique solide selon la présente invention, la production de substances analogues aux ingrédients actifs est inhibée. En conséquence, ledit comprimé pharmaceutique solide présente une remarquable stabilité.
PCT/JP2013/066874 2012-07-06 2013-06-19 Comprimé pharmaceutique solide et son procédé de production WO2014007065A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
JP2006306754A (ja) * 2005-04-27 2006-11-09 Dainippon Sumitomo Pharma Co Ltd 光安定性の向上した組成物
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