JP2016121197A - Solid pharmaceutical composition comprising calcium blocker - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a solid pharmaceutical composition comprising a calcium blocker having excellent storage stability.SOLUTION: Disclosed is a solid pharmaceutical composition comprising a calcium blocker and a compound having an amino group. The calcium blocker is azelnidipine or a pharmacologically acceptable salt thereof, and the compound having an amino group is arginine.SELECTED DRAWING: None

Description

  The present invention relates to a solid pharmaceutical composition containing a calcium blocker.

  A preparation composed of a dihydropyridine derivative (Patent Document 1) and containing a calcium blocker used as an antihypertensive agent is known (Patent Document 2). In these preparations, the storage stability of the calcium blocker is achieved, but it is not always sufficient.

Japanese Patent Publication No. 3-31715 Japanese Patent No. 4327376

  An object of this invention is to provide the solid pharmaceutical composition containing the calcium blocker excellent in storage stability.

  As a result of intensive investigations to solve the above problems, the present inventors have made it possible to preserve the storage stability of the calcium blocker in the solid pharmaceutical composition by including the compound having an amino group in the solid pharmaceutical composition containing the calcium blocker. As a result, the present invention was completed.

  The present invention provides a solid pharmaceutical composition, and the solid pharmaceutical composition contains a calcium blocker composed of a dihydropyridine derivative and a compound having an amino group.

  In one embodiment, the calcium blocker is azelnidipine or a pharmaceutically acceptable salt thereof.

  In one embodiment, the compound having an amino group is an amino sugar or a basic amino acid.

  In one embodiment, the amino sugar is meglumine.

  In one embodiment, the basic amino acid is arginine.

  ADVANTAGE OF THE INVENTION According to this invention, the solid pharmaceutical composition containing the calcium blocker excellent in storage stability can be provided.

  The solid pharmaceutical composition of the present invention contains a calcium blocker composed of a dihydropyridine derivative and a compound having an amino group.

  The calcium blocker is not particularly limited as long as it is a dihydropyridine derivative. For example, amlodipine (2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6- Methyl-1,4-dihydropyridine), alanidipine (3- (2-oxopropoxycarbonyl) -2,6-di-methyl-5-methoxycarbonyl-4- (2-nitrophenyl) -1,4-dihydropyridine), Azelnidipine (2-amino-3- (1-diphenylmethyl-3-azetidinyloxycarbonyl) -5-isopropoxycarbonyl-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine), balnidipine (3- (1-Benzyl-3-pyrrolidinyloxycarbonyl)- , 6-Dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine), Benidipine (3- (1-benzyl-3-piperidinyloxycarbonyl) -2,6-dimethyl -5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine), cilnidipine (2,6-dimethyl-5- (2-methoxyethoxycarbonyl) -4- (3-nitrophenyl) -3 -(3-phenyl-2-propenyloxycarbonyl) -1,4-dihydropyridine), efonidipine (3- [2- (N-benzyl-N-phenylamino) ethoxycarbonyl] -2,6-dimethyl-5 -(5,5-dimethyl-1,3,2-dioxa-2-phosphonyl) -4- (3-nitrophenyl) -1,4-dihydropyridine), Lugonidipine (2,6-dimethyl-5-isopropoxycarbonyl-4- (2,3-methylenedioxyphenyl) -3- [2- [N-methyl-N- (4-fluorophenylmethyl) amino] ethoxycarbonyl ] -1,4-dihydropyridine), ferronidipine (3-ethoxycarbonyl-4- (2,3-dichlorophenyl) -2,6-dimethyl-5-methoxycarbonyl-1,4-dihydropyridine), farnidipine (2,6- Dimethyl-5-methoxycarbonyl-4- (2-nitrophenyl) -3- (2-tetrahydrofurylmethoxycarbonyl) -1,4-dihydropyridine), remidipin (2-carbamoyloxymethyl-4- (2,3- Dichlorophenyl) -3-isopropoxycarbonyl-5-methoxycarbonyl-6-methyl -1,4-dihydropyridine), manidipine (2,6-dimethyl-3- [2- (4-diphenylmethyl-1-piperazinyl) ethoxycarbonyl] -5-methoxycarbonyl-4- (3-nitrophenyl) -1 , 4-dihydropyridine), nicardipine (2,6-dimethyl-3- [2- (N-benzyl-N-methylamino) ethoxycarbonyl] -5-methoxycarbonyl-4- (3-nitrophenyl) -1,4. -Dihydropyridine), nifedipine (2,6-dimethyl-3,5-dimethoxycarbonyl-4- (2-nitrophenyl) -1,4-dihydropyridine), nilvadipine (2-cyano-5-isopropoxycarbonyl-3-methoxy) Carbonyl-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine), nisoldi (2,6-dimethyl-3-isobutoxycarbonyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine), nitrendipine (3-ethoxycarbonyl-2,6-dimethyl-5- Methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine), pranidipine (2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -3- (3-phenyl-2-) Propen-1-yloxycarbonyl) -1,4-dihydropyridine).

  The calcium blocker may be a pharmacologically acceptable salt thereof. Pharmacologically acceptable salts of calcium blockers are acid addition salts. The acid addition salt is not particularly limited. For example, hydrohalide (hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.), nitrate, perchlorate, sulfuric acid Salt, phosphate, carbonate, alkyl sulfonate having 1 to 6 carbon atoms which may be substituted with a fluorine atom (methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, pentafluoroethanesulfonic acid) Salt, propane sulfonate, butane sulfonate, pentane sulfonate, hexane sulfonate, etc., aryl sulfonate having 6 to 10 carbon atoms (benzene sulfonate, p-toluene sulfonate, etc.), carvone Acid salt (acetate, propionate, butyrate, benzoate, fumarate, maleate, succinate, citrate, tartrate, oxalate, malonate , Amino acid salts (glutamic acid salt, such as aspartic acid salt), and the like. The calcium blocker may be a hydrate of a calcium blocker or a pharmacologically acceptable salt thereof.

  The amount of the calcium blocker contained in the solid pharmaceutical composition of the present invention is not particularly limited, and is usually 1 to 100 mg, preferably 5 to 20 mg in 160 mg of the solid pharmaceutical composition.

  Examples of the compound having an amino group include amino sugars and basic amino acids. The amino sugar of the present invention is not particularly limited, and examples thereof include meglumine. In the present invention, “meglumine” is a compound represented by another name N-methylglucamine, chemical formula 1-Deoxy-1-methylamino-D-glucitol. “Meglumine” of the present invention includes meglumine derivatives, salts of meglumine, and the like. Also included are those in which the hydroxyl group of meglumine is chemically modified.

Examples of the basic amino acid of the present invention include lysine, arginine, histidine, and tryptophan ornithine. Arginine is preferable. In the present invention, “arginine” is a compound represented by another name of 5-guanidino-2-aminopentanoic acid, chemical formula (H ₂ NC (═NH) NHCH ₂ CH ₂ CH ₂ CH (COOH) NH ₂ ). “Arginine” of the present invention includes arginine derivatives, arginine salts and the like.

  The amount of meglumine contained in the solid pharmaceutical composition of the present invention is not particularly limited, and is usually 1 to 26 mg, preferably 4 to 12 mg in 160 mg of the solid pharmaceutical composition. If it is less than 1 mg, the storage stability of the calcium blocker is not sufficient. When it is more than 26 mg, molding failure of the solid pharmaceutical composition occurs.

  The solid pharmaceutical composition of the present invention includes excipients, disintegrants, lubricants, binders, solubilizers, fluidizers, sweeteners, fragrances, foaming agents, surfactants, preservatives, pH adjusters, and the like. Of additives.

  The excipient is not particularly limited. For example, starch, corn starch, saccharides (glucose, fructose, lactose, sucrose, reduced maltose, trehalose, etc.), sugar alcohol (D-mannitol, erythritol, sorbitol, xylitol, maltitol, Lactitol, etc.).

  The disintegrant is not particularly limited, and for example, crospovidone, sodium carboxy starch, sodium carboxymethyl starch, starch, partially pregelatinized starch, corn starch, lactose, calcium carbonate, precipitated calcium carbonate, calcium citrate, light anhydrous silicic acid Synthetic aluminum silicate crystalline cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethylcellulose calcium, carmellose, hydroxypropyl starch.

  The lubricant is not particularly limited, for example, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, polyethylene glycol, stearic acid, light anhydrous silicic acid, hydrogenated rapeseed oil, hydrogenated castor oil, glycerin fatty acid ester, Examples include sodium stearyl fumarate, sodium benzoate, L-leucine, and L-valine.

  The binder is not particularly limited, and examples thereof include gelatin, agar, alginic acid, sodium alginate, dextrin, chitansan gum, gum arabic powder, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, partially saponified polyvinyl alcohol, methylcellulose, Examples include pullulan, partially pregelatinized starch, and sugars.

  The solubilizing agent is not particularly limited, and examples thereof include magnesium oxide, calcium oxide, sodium citrate, magnesium chloride, sodium carbonate, and sodium bicarbonate.

  Examples of the fluidizing agent include silicates such as calcium silicate, silicic anhydride such as light anhydrous silicic acid, and hydrated silicon dioxide.

  The sweetener is not particularly limited, and examples thereof include aspartame, sodium saccharin, dipotassium glycyrrhizin, stevia, and thaumatin.

  The fragrance is not particularly limited, and examples thereof include mint, lemon, and orange.

  The foaming agent is not particularly limited, and examples thereof include tartrate, citrate, and bicarbonate.

  The surfactant is not particularly limited. For example, an anionic surfactant (such as sodium alkyl sulfate), a nonionic surfactant (sucrose fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, Polyoxyethylene castor oil derivative, polysorbate, etc.).

  The preservative is not particularly limited, and examples thereof include benzoic acid, paraoxybenzoic acid, and salts thereof.

  The pH regulator is not particularly limited, and examples thereof include organic acids (citric acid, tartaric acid, acetic acid, lactic acid, etc.), inorganic acids (hydrochloric acid, phosphoric acid, etc.), inorganic bases (sodium bicarbonate, sodium carbonate, sodium hydroxide). Etc.).

  The amount of the additive contained in the solid pharmaceutical composition of the present invention is not particularly limited, and is appropriately set depending on the purpose.

  The shape of the solid pharmaceutical composition of the present invention is not particularly limited, and examples thereof include tablets, capsules, pills, troches, granules, and powders. A tablet is preferred.

  It does not specifically limit as a manufacturing method of the solid pharmaceutical composition of this invention, For example, the method including a granulation process and a tableting process is mentioned. Examples of the granulation method include a wet granulation method and a dry granulation method. The wet granulation method is not particularly limited, and examples thereof include a method using a fluidized bed granulation dryer, a stirring granulator, a cylindrical extrusion granulator, a rolling fluidized bed granulation coating machine, a spray dryer, and the like. . The tableting method is not particularly limited. For example, using a tableting die, an upper punch and a lower punch, a hydraulic hand press machine, a single-punch tableting machine, a rotary tableting machine, etc. A method is mentioned.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited by these Examples.

Example 1
Tablets containing azelnidipine were produced according to the formulation described in Table 1 below. Azelnidipine ((±) -3- (1-dipheylmethylazetidin-3-yl) 5-isopropyl 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate; Patent Literature 2), D-mannitol (manufactured by Kao Corporation), polysorbate 80 (manufactured by Nikko Chemicals Co., Ltd.), meglumine (manufactured by Merck Co., Ltd.), light anhydrous silicic acid (Adsolider (registered trademark) -101 produced by Freund Sangyo Co., Ltd.), hydroxy Propylcellulose-L (manufactured by Nippon Soda Co., Ltd.), carmellose calcium (manufactured by Nichirin Chemical Industry Co., Ltd.), L-hydroxypropylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.), Ethanol and water were mixed and granulated, and tableted to a tablet diameter of 8.0 mm to produce a tablet.

(Comparative Example 1)
Tablets were produced in the same manner as in Example 1 except that meglumine was not used and the amount of D-mannitol was increased.

(Evaluation of storage stability of azelnidipine 1)
Regarding the tablets produced in Example 1 and Comparative Example 1 and the commercially available “Calblock (registered trademark) 8 mg” (manufactured by Daiichi Sankyo Co., Ltd .: Comparative Example 2), the storage stability of azelnidipine was determined by a severe test. evaluated. That is, after each preparation was stored under severe conditions, the related substances that are degradation products of azelnidipine were quantified by UPLC (Ultra Performance Liquid Chromatography).

  As storage conditions, three conditions were tested: storage for 0.5 months at 40 ° C. and 75% RH, storage for 0.5 months at 60 ° C., and storage for 1 month at 60 ° C. In addition, when tablets are packaged in PTP (packaging only PTP, PTP aluminum packaging (with / without desiccant (silica gel)), sealed in glass bottles (with / without desiccant (silica gel)), and sealed in polyethylene bottles Three cases were tested (with / without desiccant (silica gel)).

  The tablets were ground with a mortar, and 10 mg of azelnidipine was weighed out and dissolved in 20 mL of acetonitrile to obtain a sample solution. The conditions of UPLC are as follows.

Column: ACQUITY C18 (1.7 μm; 2.1 × 50 mm) manufactured by Waters
Column temperature: 40 ° C
Mobile phase: A solution prepared by mixing 300 mL of a solution of 0.9 g of potassium dihydrogen phosphate in 300 mL of water and 700 mL of acetonitrile, and adjusting the pH to 6.0 with a 0.1 mol / L sodium hydroxide solution Detector: UV absorption Photometer (measurement wavelength: 254 nm)
Analysis time: 10 minutes Sample injection volume: 3 μL

  In the obtained UPLC chromatogram, a peak different from the peak showing azelnidipine was determined as a related substance peak within a range of about 5 times the retention time of azelnidipine, and the total area was measured. The total area of related substance peaks / the area of the peak showing azelnidipine × 100 was defined as the related substance content (%). The results are shown in Table 2 below.

  As is clear from Table 2, the content of the related substance that is a degradation product of azelnidipine is the same as that of the tablet produced using meglumine in Example 1 after storage under any storage condition. It was considerably less than the tablets produced without using it, and less than the commercially available tablet of Comparative Example 2 containing no meglumine. From this, it was found that meglumine sufficiently suppressed the degradation of azelnidipine in the tablet.

(Example 2)
Tablets containing azelnidipine were prepared according to the formulation described in Table 3 below. Azelnidipine, D-mannitol, polysorbate 80, meglumine, hydroxypropylcellulose-L, L-hydroxypropylcellulose, magnesium stearate, and ethanol were mixed and granulated, and tableted to a tablet diameter of 8.0 mm to produce tablets. .

Example 3
A tablet was produced in the same manner as in Example 2 except that arginine was used instead of meglumine.

(Comparative Example 3)
A tablet was produced in the same manner as in Example 2 except that sodium bicarbonate was used instead of meglumine.

(Comparative Example 4)
A tablet was produced in the same manner as in Example 2 except that calcium carbonate was used instead of meglumine.

(Storage stability evaluation 2 of azelnidipine)
The storage stability of azelnidipine for the tablets prepared in Examples 2 and 3 and Comparative Examples 3 and 4 and the commercially available “Calblock (registered trademark) 8 mg” (Daiichi Sankyo Co., Ltd .: Comparative Example 2) It evaluated by the severe test. The test was conducted in the same manner as described above except that the test was conducted only for the case where the tablet was not packaged (leaved in a petri dish without a cover and without a lid) under the condition of storage at 80 ° C. for 3 days. The results are shown in Table 4 below.

  As is clear from Table 4, the content of the related substance that is a degradation product of azelnidipine was determined using the tablets produced using meglumine in Example 2 and arginine in Example 3 after storage under any storage conditions. The number of tablets produced in Comparative Example 3 was lower than that of Comparative Example 3 using sodium hydrogencarbonate, the number of tablets prepared using calcium carbonate in 4 and the commercially available Comparative Example 2 tablet containing no meglumine. From this, it was found that meglumine and arginine sufficiently inhibit the degradation of azelnidipine in the tablet.

  ADVANTAGE OF THE INVENTION According to this invention, the solid pharmaceutical composition containing the calcium blocker excellent in storage stability can be provided.

Claims (2)

A solid pharmaceutical composition comprising a calcium blocker and a compound having an amino group,
The calcium blocker is azelnidipine or a pharmacologically acceptable salt thereof, and the compound having the amino group is arginine;
Solid pharmaceutical composition.   The solid pharmaceutical composition according to claim 1, wherein the solid pharmaceutical composition is a tablet.