JP6426115B2 - Solid pharmaceutical composition containing a calcium blocker - Google Patents

Description

  The present invention relates to solid pharmaceutical compositions containing calcium blockers.

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

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

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

  As a result of intensive studies to solve the above problems, the present inventors have found that the storage stability of a calcium blocker in a solid pharmaceutical composition can be achieved by incorporating a compound having an amino group into the solid pharmaceutical composition containing a calcium blocker. It has been found that the sex can be enhanced, and the present invention has been completed.

  The present invention provides a solid pharmaceutical composition, which comprises a calcium blocker consisting of a dihydropyridine derivative and a compound having an amino group.

  In one embodiment, the calcium blocker is azelnidipine or a pharmacologically 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 consisting 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), barnidipine (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), silnidipine (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), Rugonidipine (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), remidipine (2-carbamooxymethyl-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), nisol di (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-) And propen-1-yloxycarbonyl) -1,4-dihydropyridine).

  The calcium blocker may be a pharmacologically acceptable salt thereof. The pharmacologically acceptable salts of calcium blockers are acid addition salts. The acid addition salt is not particularly limited, and, for example, hydrohalide (hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.), nitrate, perchlorate, sulfuric acid Salts, phosphates, carbonates, C 1-6 alkyl sulfonates optionally substituted with fluorine atoms (methane sulfonates, trifluoromethane sulfonates, ethane sulfonates, pentafluoroethane sulfonates Salts, propane sulfonates, butane sulfonates, pentane sulfonates, hexane sulfonates, etc., aryl sulfonates having 6 to 10 carbon atoms (benzene sulfonates, p-toluene sulfonates, etc.), carboxylic acids 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 also 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 if it is in 160 mg of the solid pharmaceutical composition, it is usually 1 to 100 mg, preferably 5 to 20 mg.

  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, a chemical formula 1-Deoxy-1-methylamino-D-glucitol. The “meglumine” of the present invention includes meglumine derivatives, salts of meglumine and the like. In addition, those in which the hydroxyl group of meglumine is chemically modified are also included.

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

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

  The solid pharmaceutical composition of the present invention includes excipients, disintegrants, lubricants, binders, solubilizers, solubilizers, fluidizers, sweeteners, flavors, foaming agents, surfactants, preservatives, pH adjusters, etc. Can contain one or more additives.

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

  The disintegrant is not particularly limited. For example, crospovidone, sodium carboxy starch, sodium carboxymethyl starch, starch, partially gelatinized starch, corn starch, lactose, calcium carbonate, precipitated calcium carbonate, calcium citrate, light anhydrous silicic acid And synthetic aluminum silicate crystalline cellulose, low substituted hydroxypyropyl cellulose, croscarmellose sodium, carboxymethylcellulose calcium, carmellose, hydroxypropyl starch.

  The lubricant is not particularly limited, and examples thereof include 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. For example, gelatin, agar, alginic acid, sodium alginate, dextrin, xanthan gum, gum arabic powder, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, partially saponified polyvinyl alcohol, methyl cellulose, Pullulan, partially pregelatinized starch, saccharides can be mentioned.

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

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

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

  The flavor 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, anionic surfactants (such as sodium alkyl sulfate), nonionic surfactants (sucrose fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, Polyoxyethylene castor oil derivatives, polysorbate and the like).

  The preservative is not particularly limited, and examples thereof include benzoic acid, p-hydroxybenzoic acid and salts thereof.

  The pH adjuster is not particularly limited, and, for example, organic acids (citric acid, tartaric acid, acetic acid, lactic acid etc.), inorganic acids (hydrochloric acid, phosphoric acid etc.), inorganic bases (sodium hydrogencarbonate, sodium carbonate, sodium hydroxide) Etc.).

  The amount of the above-mentioned additive contained in the solid pharmaceutical composition of the present invention is not particularly limited, and is appropriately set according to the purpose.

  The form of the solid pharmaceutical composition of the present invention is not particularly limited, and examples thereof include tablets, capsules, pills, troches, granules, and powders. Preferably it is a tablet.

  The method for producing the solid pharmaceutical composition of the present invention is not particularly limited, and examples thereof include methods including a granulation step and a tableting step. The granulation method may, for example, be a wet granulation method or a dry granulation method. The wet granulation method is not particularly limited, and examples thereof include methods using a fluidized bed granulating dryer, a stirring granulator, a cylindrical extrusion granulator, a tumbling fluidized bed granulating coater, a spray dryer, etc. . The tableting method is not particularly limited. For example, a hydraulic hand press, a single-shot tableting machine, a rotary tableting machine, etc. are used using a tableting die, an upper punch and a lower punch for tableting. The method is mentioned.

  EXAMPLES Hereinafter, the present invention will be more specifically described by way of examples, but the present invention is not limited by these examples.

Example 1
Tablets containing azelnidipine were prepared 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), light anhydrous silicic acid (Adsolider (registered trademark)-101 manufactured by Freund Corporation), 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 Taiping Kagaku Sangyo Co., Ltd.) Ethanol and water were mixed and granulated, and compressed to a tablet diameter of 8.0 mm to produce tablets.

(Comparative example 1)
Tablets were produced in the same manner as 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) Tablet 8 mg" (manufactured by Daiichi Sankyo Co., Ltd .: Comparative Example 2), the storage stability of azelnidipine was subjected to a severe test. evaluated. That is, after each preparation was stored under severe conditions, related substances which are degradation products of azelnidipine were quantified by UPLC (Ultra Performance Liquid Chromatography).

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

  The tablet was ground in a mortar, and the equivalent amount of 10 mg of azelnidipine was weighed out, dissolved in 20 mL of acetonitrile, and used as a sample solution. The conditions for UPLC are as follows.

Column: Waters ACQUITY C18 (1.7 μm; 2.1 × 50 mm)
Column temperature: 40 ° C
Mobile phase: 300 mL of a solution of 0.9 g of potassium dihydrogenphosphate dissolved in 300 mL of water and 700 mL of acetonitrile mixed and adjusted to pH 6.0 with 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 peak of a related substance within the range of about 5 times the retention time of azelnidipine, and the total area was measured. The total area of peaks of related substances / the area of the peak showing azelnidipine × 100 was taken as the related substance content (%). The results are shown in Table 2 below.

  As apparent from Table 2, the content of the related substance which is a degradation product of azelnidipine was determined in the same manner as in Example 1 except that the tablet manufactured using meglumine in Example 1 was used in Comparative Example 1 even after storage under any storage conditions. It was considerably less than the tablet produced without use, and less than the tablet of Comparative Example 2 of the commercial comparative example containing no meglumine. From this, it was found that meglumine sufficiently suppresses 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, hydroxypropyl cellulose-L, L-hydroxypropyl cellulose, magnesium stearate, ethanol were mixed and granulated, and tabletted to a tablet diameter of 8.0 mm to produce a tablet .

(Example 3)
Tablets were produced in the same manner as in Example 2 except that arginine was used instead of meglumine.

(Comparative example 3)
Tablets were produced in the same manner as in Example 2 except that sodium hydrogencarbonate was used instead of meglumine.

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

(Evaluation of storage stability of azelnidipine 2)
Regarding the tablets produced in Examples 2 and 3 and Comparative Examples 3 and 4, and the commercially available "Calblock (registered trademark) Tablet 8 mg" (manufactured by Daiichi Sankyo Co., Ltd .: Comparative Example 2), the storage stability of azelnidipine was measured. It evaluated by the severe test. As a storage condition, the test was conducted in the same manner as described above except that the test was carried out for 3 days at 80 ° C. and the tablet was not packaged (it was left in a petri dish without packaging and without lid). The results are shown in Table 4 below.

  As apparent from Table 4, the content of the related substance which is a degradation product of azelnidipine was determined using the tablets prepared 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 less than the tablets prepared with sodium bicarbonate in Comparative Example 3 and the tablets prepared with calcium carbonate in 4 and the tablets of Commercial Comparative Example 2 containing no meglumine. From this, it was found that meglumine and arginine sufficiently suppress 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 (4)

A solid pharmaceutical composition, wherein
A calcium blocker comprising a dihydropyridine derivative and a compound having an amino group, and packaged in PTP, in a glass bottle, or in a polyethylene bottle,
Compounds having the amino group, Ri least one compound der selected from the group consisting of meglumine and arginine,
A solid pharmaceutical composition wherein the calcium blocker consisting of the dihydropyridine derivative is azelnidipine or a pharmacologically acceptable salt thereof.   The solid pharmaceutical composition according to claim 1, wherein the PTP package is further packaged in aluminum with or without silica gel.   The solid pharmaceutical composition according to claim 1, wherein the glass bottle or polyethylene bottle further contains silica gel. The solid pharmaceutical composition according to any one of claims 1 to 3 , wherein the solid pharmaceutical composition is a tablet.