JP2012036163A - STABLE SOLID PHARMACEUTICAL COMPOSITION CONTAINING COMPOUND HAVING HMG-CoA REDUCTASE INHIBITING ACTIVITY - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a stabilized solid pharmaceutical composition containing an active component having HMG-CoA reductase inhibiting activity or its pharmaceutically acceptable salt as the active component.SOLUTION: The composition is compounded with hydrous silicon dioxide as a method for stabilizing an HMG-CoA reductase inhibitor such as atorvastatin, pravastatin, fluvastatin and pitavastatin unstable especially in an acidic environment to frequently generate impurities.

Description

  The present invention is stabilized by using as an active ingredient a compound having an HMG-CoA reductase inhibitory activity (hereinafter referred to as “HMG-CoA reductase inhibitor”) effective for the treatment of hypercholesterolemia and hyperlipidemia. The present invention relates to a solid pharmaceutical composition and a method for preparing the same. The present invention also relates to a method for stabilizing the HMG-CoA reductase inhibitor in a solid pharmaceutical composition.

  Atorvastatin, pravastatin, fluvastatin, pitavastatin and pharmaceutically acceptable salts thereof have the following general formula (1):

(In the formula, R ₁ represents a hydrogen atom, an alkali metal salt, an alkaline earth metal salt, or an amine: R ₂ represents an organic residue corresponding to each of the above compounds: m represents an integer of 1 or 2.)
Is a hydroxy acid or a salt thereof having the structure shown by the above, and has an action of specifically inhibiting HMG-CoA reductase, which is a rate-limiting enzyme for cholesterol synthesis. Therefore, it is highly effective as an active ingredient of an HMG-CoA reductase inhibitor. Widely used in the treatment of lipemia and hypercholesterolemia.

  However, in general, hydroxy acids are likely to produce lactones, especially in acidic environments. The HMG-CoA reductase inhibitor represented by the above formula (1) and hydrates thereof (hereinafter collectively referred to as “HMG-CoA reductase inhibitors”) are also unstable in an acidic environment and contain a lactone by long-term storage. It is known that impurities are generated. Such impurities can reduce the activity of HMG-CoA reductase inhibitors and cause side effects.

  For this reason, various methods have heretofore been proposed in order to suppress the lactone formation of the HMG-CoA reductase inhibitor and improve the storage stability. For example, a method in which a certain basic additive is used to bring the aqueous dispersion to pH 9 or more (see Patent Document 1), and a method in which a specific metal salt additive such as an alkaline earth metal salt is blended (Patent Document 2). And a method of producing by a direct compression method using a specific basic additive (see Patent Document 3), a method of blending a basic amino acid as a stabilizer (see Patent Document 4), and the like.

  However, adjusting the pH of the preparation to a strongly alkaline side may cause damage to the digestive function in the stomach, particularly by oral administration to patients with low gastric acid. Even if it is not administered orally, there is a risk of cytotoxicity due to alkali, which is undesirable in any route of administration. Further, among the basic additives, alkali metal hydroxides have a problem that they are difficult to handle in the preparation process because of their deliquescent properties.

Japanese Patent No. 2935220 Japanese National Patent Publication No. 8-505640 JP 2000-229855 A JP 2003-55217 A

  In view of such circumstances, an object of the present invention is to provide a method for stabilizing an HMG-CoA reductase inhibitor that is unstable and easily generates impurities, particularly in an acidic environment. An object of the present invention is to provide a solid pharmaceutical composition stably containing an HMG-CoA reductase inhibitor and a method for preparing the same by such a method.

  The inventors of the present invention have made extensive studies to solve the above-mentioned problems. As a result, HMG-CoA reductase inhibitor, which is a hydroxy acid capable of producing a lactone or a pharmaceutically acceptable salt thereof, coexists with hydrous silicon dioxide. It has been found that the formation of hydroxy acid to lactone is suppressed by placing it below, and contamination of impurities into the HMG-CoA reductase inhibitor can be avoided and reduced.

The present invention has been completed based on such findings, and includes the following embodiments:
(I) Solid pharmaceutical composition (I-1) As an active ingredient having HMG-CoA reductase inhibitory activity, a hydroxy acid capable of forming a lactone, a pharmaceutically acceptable salt thereof, or a hydrate thereof (hereinafter, In addition to “HMG-CoA reductase inhibitor”), a solid pharmaceutical composition comprising water-containing silicon dioxide and suppressed generation or increase of impurities.

  (I-2) The solid pharmaceutical composition according to (I-1), wherein the hydrous silicon dioxide exhibits a pH of 8 to 12 when it is prepared in a suspension of 5% by mass.

  (I-3) A hydroxy acid capable of forming a lactone, a pharmaceutically acceptable salt thereof, or a hydrate thereof is contained in a ratio of 1 to 50% by mass in total (I-1 ) Or (I-2).

  (I-4) 1 to 10 parts by weight of hydrous silicon dioxide with respect to 1 part by weight of the total amount of hydroxy acid, pharmaceutically acceptable salt or hydrate thereof (HMG-CoA reductase inhibitor) capable of producing lactone (I-1) thru | or the solid pharmaceutical composition in any one of (I-3) characterized by the above-mentioned.

  (I-5) The HMG-CoA reductase inhibitor is at least one selected from the group consisting of atorvastatin, pravastatin, fluvastatin, pitavastatin, a pharmaceutically acceptable salt thereof, and a hydrate thereof. I-1) thru | or solid pharmaceutical composition in any one of (I-4).

  (I-6) The solid pharmaceutical composition according to any one of (I-1) to (I-4), wherein the HMG-CoA reductase inhibitor is atorvastatin calcium hydrate.

  (I-7) The solid pharmaceutical composition according to any one of (I-1) to (I-6), which is a therapeutic or ameliorating agent for hyperlipidemia or hypercholesterolemia.

(II) Preparation method of solid pharmaceutical composition (II-1) Hydroxy acid capable of producing lactone as an active ingredient having HMG-CoA reductase inhibitory activity, pharmaceutically acceptable salt thereof or hydrate thereof (HMG-CoA reductase inhibitor); hydrous silicon dioxide; and a pharmaceutically acceptable carrier or additive, a step of wet granulation, and a mixture obtained by blending a lubricant with the granule. A method for preparing a solid pharmaceutical composition comprising the step of forming a tablet into a tablet or filling a capsule, wherein the generation or increase of impurities is suppressed.

  (II-2) The preparation method according to (II-1), wherein the hydrous silicon dioxide exhibits a pH of 8 to 12 when it is prepared into a 5% by mass suspension aqueous solution.

  (II-3) A hydroxy acid capable of forming a lactone, a pharmaceutically acceptable salt thereof or a hydrate thereof is blended in a proportion of 1 to 50% by mass in total (II-1 ) Or (II-2).

  (II-4) Hydrous silicon dioxide is blended at a ratio of 1 to 10 parts by weight with respect to 1 part by weight of the total amount of HMG-CoA reductase inhibitor, (II-1) to (II-3) The preparation method described in any one.

  (II-5) The HMG-CoA reductase inhibitor is at least one selected from the group consisting of atorvastatin, pravastatin, fluvastatin, pitavastatin, their pharmaceutically acceptable salts, and their hydrates. , (II-1) to (II-4).

  (II-6) The preparation method according to any one of (II-1) to (II-4), wherein the HMG-CoA reductase inhibitor is atorvastatin calcium hydrate.

  (II-7) The preparation method according to any one of (II-1) to (II-6), wherein the solid pharmaceutical composition is a therapeutic or ameliorating agent for hyperlipidemia or hypercholesterolemia.

(III) Stabilization method of solid pharmaceutical composition (III-1) Hydroxy acid capable of forming lactone, HMG-CoA reductase inhibitory activity, pharmaceutically acceptable salt thereof or hydrate thereof (HMG) In the preparation of a solid pharmaceutical composition containing a -CoA reductase inhibitor) as an active ingredient, a method for suppressing the generation or increase of impurities in the solid pharmaceutical composition, which comprises adding hydrous silicon dioxide as an additive.

  (III-2) The method described in (III-1), wherein the hydrous silicon dioxide exhibits a pH of 8 to 12 when it is prepared in a 5% by mass suspension aqueous solution.

  (III-3) A hydroxy acid capable of forming a lactone, a pharmaceutically acceptable salt thereof, or a hydrate thereof is blended in a proportion of 1 to 50% by mass in total (III-1) ) Or (III-2).

  (III-4) Hydrous silicon dioxide is blended at a ratio of 1 to 10 parts by weight with respect to 1 part by weight of the total amount of the above HMG-CoA reductase inhibitor (III-1) to (III-3) The method described in any one of.

  (III-5) The HMG-CoA reductase inhibitor is at least one selected from the group consisting of atorvastatin, pravastatin, fluvastatin, pitavastatin, a pharmaceutically acceptable salt thereof, and a hydrate thereof. The method according to any one of (III-1) to (III-4).

  (III-6) The method according to any one of (III-1) to (III-4), wherein the HMG-CoA reductase inhibitor is atorvastatin calcium hydrate.

  (III-7) The method according to any one of (III-1) to (III-6), wherein the solid pharmaceutical composition is a therapeutic or ameliorating agent for hyperlipidemia or hypercholesterolemia.

  According to the present invention, a hydroxy acid capable of producing a lactone, a pharmaceutically acceptable salt thereof or a hydrate thereof (HMG-CoA reductase inhibitor) having HMG-CoA reductase inhibitory activity as an active ingredient. In a solid pharmaceutical composition, by incorporating hydrous silicon dioxide as an additive, a conventional method [a method of making the aqueous dispersion pH 9 or more by using a certain basic additive (see Patent Document 1), A method of blending a specific metal salt additive such as an alkaline earth metal salt (see Patent Document 2), a method of using a specific basic additive and a direct tableting method (see Patent Document 3), stable The generation or increase of impurities during storage can be suppressed without particularly using the method of blending a basic amino acid as an agent (see Patent Document 4). The problem content decreasing the occurrence and the active ingredients of the side effects ascribable (HMG-CoA reductase inhibitors) can be prevented.

(I) Solid pharmaceutical composition and preparation method thereof The solid pharmaceutical composition of the present invention comprises a hydroxy acid capable of producing a lactone having HMG-CoA reductase inhibitory activity, a pharmaceutically acceptable salt thereof, or water thereof. In addition to the hydrate (HMG-CoA reductase inhibitor), it is characterized by containing hydrous silicon dioxide.

(1) Active ingredient The hydroxy acid having HMG-CoA reductase inhibitory activity and capable of producing a lactone, or a pharmaceutically acceptable salt thereof, which is the subject of the present invention, is represented by the following general formula (1):

(In the formula, R ₁ represents a hydrogen atom, an alkali metal, an alkaline earth metal, or an amine: R ₂ represents an arbitrary organic residue: m represents an integer of 1 or 2.)
It is a compound which has a structure shown by these. Since the compound has an action of specifically inhibiting HMG-CoA reductase, which is a rate-limiting enzyme for cholesterol synthesis, it is widely used as a HMG-CoA reductase inhibitor for the treatment of hyperlipidemia and hypercholesterolemia. Yes.

As such a hydroxy acid (R ₁ is a hydrogen atom), specifically, atorvastatin ((3R, 5R) -7- [2- (4-fluorophenyl) -5--5 represented by the following formula (2): Isopropyl-3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrol-1-yl] -3,5-dihydroxyheptanoic acid):

Pravastatin ((1S, βR, δR, 8aβ) -1,2,6,7,8,8a-hexahydro-β, δ, 6β-trihydroxy-2β-methyl- represented by the following formula (3) 8α-[(S) -2-methyl-1-oxobutoxy] -1β-naphthaleneheptanoic acid):

Fluvastatin ((3R, 5S, 6E) -3,5-dihydroxy-7- [1-isopropyl-3- (4-fluorophenyl) -1H-indole-2-] represented by the following formula (4) Yl] -6-heptenoic acid):

Pitavastatin ((3R, 5S, 6E) -3,5-dihydroxy-7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl]-represented by the following formula (5) 6-heptenoic acid):

Can be mentioned. Atorvastatin is preferred.

These hydroxy acids can also have the form of a pharmaceutically acceptable salt (R ₁ in the general formula (1) is an alkali metal salt, alkaline earth metal salt or amine). Such pharmaceutically acceptable salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and N, N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine. And amines such as ethylenediamine, N-methylglucamine, and procaine. Alkali metal salts and alkaline earth metal salts are preferred.

  For example, atorvastatin is a calcium salt form (bis [(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole). -1-yl] -3,5-dihydroxyheptanoic acid] calcium) and its hydrate (bis [(3R, 5R) -7- [2- (4-fluorophenyl) -5- (Isopropyl-3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrol-1-yl] -3,5-dihydroxyheptanoic acid] calcium trihydrate) is more preferable.

  Pravastatin is in the form of sodium salt ((1S, βR, δR, 8aβ) -1,2,6,7,8,8a-hexahydro-β, δ, 6β-trihydroxy-2β-methyl-8α-[( S) -2-methyl-1-oxobutoxy] -1β-sodium naphthalene heptanoate). Further, fluvastatin is also in the form of a sodium salt ((3R, 5S, 6E) -3,5-dihydroxy-7- [1-isopropyl-3- (4-fluorophenyl) -1H-indol-2-yl] -6 Sodium heptenoate), and pitavastatin is in the form of a calcium salt (bis ((3R, 5S, 6E) -3,5-dihydroxy-7- [2-cyclopropyl-4- (4-fluorophenyl) Quinolin-3-yl] -6-heptenoic acid] monocalcium).

  These hydroxy acids and salts thereof can be used in a non-solvent form or as a solvated form including a hydrate form. As described above, atorvastatin or a salt thereof is preferably used in a hydrate form.

  These hydroxy acids, pharmaceutically acceptable salts or hydrates thereof are all known compounds and can be produced according to known methods.

  A pharmaceutical composition containing the above compound as an active ingredient is prepared so as to have a solid preparation form together with at least hydrous silicon dioxide described later.

  Here, as a preparation having a solid form, powders (powder), fine granules, granules, tablets, pills, buccal tablets, troches, doi syrup, capsules filled with powder or granules inside Orally administered preparations such as Preferably, it is a tablet. The tablets may be in the form of sugar-coated tablets, gelatin-encapsulated tablets, film-coated tablets, enteric-coated tablets, dry-coated tablets (compressed-encapsulated tablets), multilayer tablets (two or three layers), etc. Good.

  The proportion of the active ingredient contained in 100% by mass of the final form preparation is not particularly limited, but is usually 0.1 to 50% by mass, preferably 0.5 to 40% by mass, more preferably 1 to 30% by mass. %, Particularly about 3 to 25% by mass.

(2) Hydrous silicon dioxide In the present invention, hydrous silicon dioxide can be stabilized by coexisting with the above HMG-CoA reductase inhibitor, and the generation or increase of impurities including lactones can be suppressed.

  The hydrous silicon dioxide is not particularly limited as long as it exhibits alkalinity, but hydrous amorphous silicon dioxide such as silica gel and white carbon is particularly desirable. The hydrous amorphous silicon dioxide may be a natural product or a synthetic product obtained by reacting sodium silicate with sulfuric acid.

  Note that whether or not the hydrous silicon dioxide is alkaline can be determined by whether or not the 5% by mass aqueous suspension of hydrous silicon dioxide is in the range of pH 8-12. It is preferable to use hydrous silicon dioxide such that the pH of the aqueous suspension is in the range of 9-12.

  Hydrous silicon dioxide generally means silicon dioxide having a loss on drying value of more than 7% by mass and not more than 15% by mass, and in this respect, silicon dioxide (light anhydrous silicic acid) having a loss on drying value of 7.0% or less. Can be clearly distinguished (medicine regulations, JP standards). Preferably, silicon dioxide having a loss on drying value of 7.1 to 15% by mass.

  The loss on drying value is calculated according to the following formula from the mass (B) after precisely weighing the mass of the target hydrous silicon dioxide (about 1 g) (A) and putting it in a dryer at 105 ° C. for 3 hours. Can be calculated.

  The proportion of the hydrated silicon dioxide to be blended in the solid pharmaceutical composition of the present invention is not particularly limited, but is usually 1 to 50 wt%, preferably 5 to 40 wt% as the blending proportion in 100 wt% of the final form of the preparation. More preferably, 10 to 30% by weight can be mentioned. Moreover, as a ratio with respect to 1 mass part of total amounts of HMG-CoA reductase inhibitor (hydroxy acid, its salt, or its hydrate) contained in the solid pharmaceutical composition of this invention, it is 0.1 mass part or more normally, Preferably it is 0.8. 5 mass parts or more, More preferably, 1 mass part or more can be mentioned. Although the upper limit in particular is not restrict | limited, 10 mass parts can be mentioned. Preferably it is 8 mass parts, More preferably, it is 6 mass parts.

(3) Formulation and carriers or additives used therefor In preparation of the solid pharmaceutical composition of the present invention, its formulation form (powder (powder), granule, tablet, pill, buccal tablet, troche, Carriers and additives usually used in the art are used depending on the dry syrup, the capsule filled with powder or granules.

  However, in order to increase the stability of the HMG-CoA reductase inhibitor by adding hydrous silicon dioxide and not to impair the purpose of the present invention to suppress the generation or increase of impurities, the solid pharmaceutical composition of the present invention has a pH of It is preferable to adjust so that it may become 8 or more. The preferred pH is 8-12, more preferably 9-12. In addition, the said pH of the solid pharmaceutical composition of this invention can be evaluated by measuring the pH of the 5 mass% suspension aqueous solution.

(3-1) The excipient excipient is not limited, and examples thereof include sugars, starches, talc, calcium carbonate, and magnesium carbonate.

  Examples of the saccharide include monosaccharides (arabinose, xylose, glucose, fructose, galactose, mannose, sorbose, etc.), oligosaccharides (eg, sucrose (eg, sucrose, purified sucrose, powdered sugar, granulated sugar, etc.), lactose, maltose, Reduced maltose, isomaltose, etc.], sugar alcohols (xylitol, erythritol, sorbitol, mannitol, etc.). These saccharides can be used alone or in combination of two or more. Of these saccharides, monosaccharides such as glucose and fructose, oligosaccharides such as sucrose, lactose and reduced maltose, and sugar alcohols such as mannitol and sorbitol are usually used.

  Examples of starches include starch (corn starch, wheat starch, potato starch, rice starch, sweet potato starch, etc.). Of these starches, starches such as corn starch, wheat starch, and potato starch are usually used.

  The proportion of the excipient blended in the solid pharmaceutical composition of the present invention is not particularly limited, but the blending proportion in 100% by weight of the final form preparation is usually 5 to 95% by weight, preferably 10 to 85% by weight. More preferably, 30 to 70% by weight can be mentioned. Moreover, although it does not restrict | limit as a ratio with respect to 100 weight part of total amounts of HMG-CoA reductase inhibitor (hydroxy acid, its salt, or its hydrate) contained in the solid pharmaceutical composition of this invention, Usually, 50-1900 weight part, Preferably May be 100 to 1700 parts by weight, more preferably 300 to 1400 parts by weight.

(3-2) Binders As the binder , conventional binders can be used. For example, proteins (such as gelatin), polysaccharides (such as gum arabic, pullulan, dextrin, tragacanth, sodium alginate), modified starch (α Starch, partially pregelatinized starch, hydrolyzed dextrin, esterified starch, etherified starch, etc., cellulose derivatives (C _1-4 alkyl cellulose such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, etc.) include hydroxy C _1-4 alkyl cellulose, carboxy C _1-4 alkyl celluloses such as carboxymethyl cellulose), vinyl polymers (poly pin alkenyl pyrrolidone, polyvinyl alcohol, etc.) and the like It is done. Among these binders, nonionic binders (for example, hydroxy C _1-4 alkyl cellulose of hydroxypropyl cellulose and modified starch such as partially pregelatinized starch) are preferable. These binders can be used alone or in combination of two or more.

  The proportion of the binder to be blended in the solid pharmaceutical composition of the present invention is not particularly limited, but the blending proportion in 100% by weight of the final form preparation is usually 0.5 to 10% by weight, preferably 0.5 to 7% by weight, more preferably 1 to 5% by weight. Moreover, although it does not restrict | limit as a ratio with respect to 100 weight part of total amounts of HMG-CoA reductase inhibitor (hydroxy acid, its salt, or its hydrate) contained in the solid pharmaceutical composition of this invention, Usually, 5-200 weight part, Preferably 5 to 140 parts by weight, more preferably 10 to 100 parts by weight.

(3-3) Disintegrants As disintegrants, disintegrants commonly used in the field of solid preparations can be widely used. Preferred examples include cellulose, cellulose derivatives, crospovidone, hydroxypropyl starch, carboxymethyl starch, and salts thereof. Here, the salt includes alkali metal salts such as sodium and potassium, and alkali metal earth salts such as magnesium and calcium.

  Cellulose derivatives or salts thereof include methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose (including carmellose and croscarmellose) and Mention may be made of the sodium or calcium salts thereof, crystalline cellulose, crystalline cellulose carmellose and crystalline cellulose carmellose sodium. Preferred are low-substituted hydroxypropyl cellulose, carboxymethyl cellulose (including carmellose and croscarmellose) or a sodium salt or calcium salt thereof, and crystalline cellulose.

  These disintegrants can be used alone or in combination of two or more.

  Here, crospovidone is a cross-linked homopolymer of 1-ethenylpyrrolidin-2-one and is a component widely used as a pharmaceutical additive (such as a disintegrant). Also in the present invention, crospovidone defined by pharmaceutical additive standards can be widely used. Such crospovidone can be obtained commercially, such as Kollidon CL (manufactured by BASF), polyplastidone XL, polyplastidone XL-10, and polyplastidone INF-10 (manufactured by ISP). Can be mentioned.

  Examples of the low-substituted hydroxypropylcellulose include a low-substituted hydroxypropylcellulose having a hydroxypropoxyl group content (hereinafter sometimes abbreviated as HPC group content) in hydroxypropylcellulose of about 7 to 13% by weight. Can do. Among these, low substituted hydroxypropylcellulose having an HPC group content of about 7 to 9.9% by weight is preferable from the viewpoint of improving disintegration. These low-substituted hydroxypropyl celluloses can be obtained commercially. For example, LH-11, LH-21, B1 and LH-31 (HPC group content: 10- 12.9%), and LH-22 and LH-32 (and above, HPC group content: 7.0-9.9%).

  Carmellose is a polyvalent carboxymethyl ether of cellulose, also called carboxymethyl cellulose, CMC, or fibrin glycolic acid, and is a component that is widely used as a pharmaceutical additive (such as a disintegrant). Also in the present invention, carmellose defined by the Japanese Pharmacopoeia can be widely used. Both carmellose and its calcium salt are commercially available. For example, NS-300 (Gotoku Pharmaceutical Co., Ltd.) is used as carmellose, and E. C. And G-505 (Gotoku Pharmaceutical Co., Ltd.).

  Moreover, croscarmite mouth is a polyvalent carboxymethyl ether cross-linked product of cellulose and is also referred to as internally cross-linked carboxymethyl cellulose. As a sodium salt of croscarmellose, croscarmellose sodium defined by the Japanese Pharmacopoeia can be widely used in the present invention. Such croscarmellose sodium can be obtained commercially, for example, Akjisol (Dainippon Sumitomo Pharma Co., Ltd.).

  The disintegrant used is in the form of powder or granules. Although not limited, in order to ensure the uniformity of the final tablet, it is preferable to use a powdery or granular disintegrant having an average particle diameter of about 1 to 300 μm, preferably about 1 to 200 μm.

  The proportion of the disintegrant to be blended in the solid pharmaceutical composition of the present invention is not particularly limited. However, the blending proportion in 100% by weight of the final form preparation is usually 0.5 to 10% by weight, preferably 0.5 to 7% by weight, more preferably 1 to 5% by weight. Moreover, although it does not restrict | limit as a ratio with respect to 100 weight part of total amounts of HMG-CoA reductase inhibitor (hydroxy acid, its salt, or its hydrate) contained in the solid pharmaceutical composition of this invention, Usually, 5-200 weight part, Preferably 5 to 140 parts by weight, more preferably 10 to 100 parts by weight.

(3-4) Conventionally, as a lubricant or lubricant, a pharmaceutical additive used for improving the fluidity of powder and facilitating compression formation in the production of tablets can be used in the same manner. it can. Examples of such lubricants include stearic acid, magnesium stearate, talc, hydrogenated vegetable oil, sucrose fatty acid ester, polyethylene glycol, and sodium stearyl fumarate. Preferred are magnesium stearate and sodium stearyl fumarate.

  The ratio of the lubricant to be blended in the solid pharmaceutical composition of the present invention is not particularly limited, but the blend ratio in 100% by weight of the final form preparation is usually 0.1 to 5% by weight, preferably 0.1%. -3% by weight, more preferably 0.1-2% by weight. Moreover, although it does not restrict | limit as a ratio with respect to 100 weight part of total amounts of HMG-CoA reductase inhibitor (hydroxy acid, its salt, or its hydrate) contained in the solid pharmaceutical composition of this invention, Usually 1-100 weight part, Preferably 1 to 60 parts by weight, more preferably 1 to 40 parts by weight.

(3-5) Other components The pharmaceutical composition of the present invention is an additive other than those described above, as long as the effects of the present invention are not impaired. it can. Examples of such additives include a fluidizing agent (for example, light anhydrous silicic acid), an antioxidant, a corrigent (including a sweetener), an acidulant, a fragrance, a colorant, a solubilizing agent, or a pH adjuster. It can be illustrated.

  As the antioxidant, a conventional antioxidant can be used. For example, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), ascorbic acid, sodium ascorbate, erythorbic acid, sodium erythorbate, tocopherol, propyl gallate Guaiac fat, nordihydroguaiaretic acid, sodium pyrosulfite, sodium hydrogensulfite, Rongalite and the like. Preferred are butylhydroxyanisole, dibutylhydroxytoluene and ascorbic acid, and particularly preferred is butylhydroxyanisole. These antioxidants can be used alone or in combination of two or more. The antioxidant is preferably adjusted so that the ratio in the final pharmaceutical composition is usually 10 to 5000 ppm, preferably 20 to 1000 ppm, more preferably about 30 to 500 ppm.

  As a flavoring agent (including a sweetener), sugar, starch sugar, lactose, honey, sugar alcohol, a high-intensity sweetener, and the like can be used. Examples of the sugar include sucrose, coupling sugar, fructooligosaccharide, and palatinose; examples of the starch sugar include glucose, maltose, powdered rice cake, starch syrup, and isomerized sugar (fructose); examples of the lactose include lactose and isomerized lactose. (Lactulose), reduced lactose (lactitol), etc .; Examples of sugar alcohols include sorbitol, erythritol, mannitol, reduced maltose starch syrup (maltitol), reduced starch saccharified product, xylitol, reduced palatinose, etc. Examples of high-intensity sweeteners include saccharin sodium, aspartame, sucralose, stevia, glycyrrhizin tripotassium, licorice, and acesulfame.

  Examples of acidulants include citric acid, tartaric acid, and malic acid; examples of flavors include menthol, peppermint oil, lemon oil, orange oil, and grapefruit oil; examples of colorants include edible yellow No. 5, edible red No. 2, and edible An edible pigment such as Blue No. 2, an edible lake pigment, or iron oxide such as Bengala can be used.

  The solid pharmaceutical composition of the present invention can be produced by mixing the various components described above according to the final form using a conventional method in the pharmaceutical field and molding the desired solid dosage form.

  For example, for granulation, conventional granulation methods, specifically, extrusion granulation method, rolling granulation method, fluidized bed granulation method, mixing / stirring granulation method, spray drying granulation method, vibration granulation, A wet granulation method such as a method or a dry granulation method such as a compression molding granulation method can be employed. Of these granulation methods, wet granulation methods such as extrusion granulation method, rolling granulation method, fluidized bed granulation method, and mixing / stirring granulation method can be preferably used. For example, when the final form is a tablet, for example, an HMG-CoA reductase inhibitor that is an active ingredient, hydrous silicon dioxide and excipients, and, if necessary, an antioxidant, a stabilizer, a binder, etc. are wet granulated. After drying, if necessary, additives such as a lubricant and a fluidizing agent can be added and tableted. The solvent in the wet granulation is not particularly limited, but at least one solution selected from water and lower alcohols (for example, ethanol) and water and ethanol solutions can be preferably used from the viewpoint of safety.

Specifically, for example, when preparing a tablet, first, an HMG-CoA reductase inhibitor, hydrous silicon dioxide, and other additives are mixed by the above-described method, granulated, and sized. Here, the mixing can be performed using a machine such as a V-type mixer (manufactured by Tokuju Kogakusho Co., Ltd.), a twin blade type mixer, a stirring mixer (manufactured by Dalton Co., Ltd.), or the like. A lubricant is then blended into the mixture obtained by such a mixing step, mixed, compressed and molded into a tablet form. The compression molding uses a tableting machine usually used in the art such as a hydraulic hand press machine, a single tablet machine, or a rotary tableting machine, and is usually 0.3 to ³ ton / cm ² , preferably 0.3. It is performed by tableting at a pressure of ˜2 ton / cm ² .

  In the present invention, conventionally known as stabilizers for HMG-CoA reductase inhibitors, aluminum silicate, calcium hydrogen phosphate, calcium lactate, sodium hydrogen carbonate, magnesium carbonate, calcium carbonate, magnesium aluminate metasilicate, basic amino acid ( Hydroxy acid, its salt, or its salt, which can produce a lactone by preparing a solid formulation with hydrous silicon dioxide, substantially without using lysine, arginine, phenylalanine, tyrosine, histidine, tryptophan, proline, oxyproline) The stability of the hydrated HMG-CoA reductase inhibitor can be improved.

  The solid pharmaceutical composition of the present invention thus obtained is orally administered to a patient having hypercholesterolemia or hyperlipidemia that requires anticholesterol therapy. The dosage may be a predetermined amount depending on the type of active ingredient, for example, 0.5 to 120 mgA (mgA means milligrams of the active ingredient based on the free acid), preferably 5 to 80 mgA. It can be illustrated. When the active ingredient is atorvastatin calcium hydrate, it can be administered to a patient with hypercholesterolemia (adult) in the range of 10-20 mg once a day, and patients with familial hypercholesterolemia (Adult) can be administered in the range of 10 to 40 mg once a day.

(III) Method for Stabilizing Solid Pharmaceutical Compositions The present invention also relates to a hydroxy acid capable of producing a lactone having a HMG-CoA reductase inhibitory activity, a pharmaceutically acceptable salt thereof, or a hydrate thereof (HMG). A method for suppressing the generation or increase of impurities containing a lactone in a solid pharmaceutical composition is provided for a solid pharmaceutical composition containing a -CoA reductase inhibitor) as an active ingredient. In the production of a solid pharmaceutical composition (solid preparation), this method can be carried out by blending hydrous silicon dioxide as an additive in addition to the active ingredient HMG-CoA reductase inhibitor.

  The types of HMG-CoA reductase inhibitor and hydrous silicon dioxide used here, and their blending ratios, the types and blending ratios of other optional components, and the form and preparation method of the solid pharmaceutical composition were described in (I). Street.

  According to the method of the present invention, aluminum silicate, calcium hydrogen phosphate, calcium lactate, sodium hydrogen carbonate, magnesium carbonate, calcium carbonate, magnesium metasilicate aluminate, which are conventionally known as stabilizers for HMG-CoA reductase inhibitors, Hydroxy acids that can produce lactones by preparing solid formulations with hydrous silicon dioxide, with virtually no basic amino acids (lysine, arginine, phenylalanine, tyrosine, histidine, tryptophan, proline, oxyproline) , The stability of the HMG-CoA reductase inhibitor which is a salt thereof or a hydrate thereof can be improved.

  The stability of the HMG-CoA reductase inhibitor can be evaluated based on the degree of generation or increase of impurities. Here, the impurities mean components other than the HMG-CoA reductase inhibitor generated in the HMG-CoA reductase inhibitor. If the generation or increase of impurities in the HMG-CoA reductase inhibitor is suppressed, it can be determined that the stability of the HMG-CoA reductase inhibitor is improved. In the present invention, whether or not the generation or increase of impurities is suppressed is specifically prepared without blending a solid pharmaceutical composition (test composition) prepared by adding hydrous silicon dioxide and hydrous silicon dioxide. The solid pharmaceutical composition (comparative composition) can be judged by the amount of impurities generated or increased when left standing at a constant temperature of at least 60 ° C. for 7 days, and in the test composition compared to the comparative composition If the amount of impurities generated or increased is small, it can be determined that the generation or increase of impurities is suppressed.

  The detection of such impurities can be carried out by measuring using an ODS column by the HPLC method (gradient method) as described in Examples.

  Hereinafter, the contents of the present invention will be specifically described using the following experimental examples. However, the present invention is not limited to these experimental examples. In the following experimental examples, “%” means “mass%” and “part” means “part by mass” unless otherwise specified.

Experimental example 1
The main drug atorvastatin calcium was mixed with the additives shown in Table 1 so as to be uniform at a ratio of 3: 1 by weight to prepare a pharmaceutical composition. The obtained pharmaceutical composition was placed on an open petri dish and stored at 60 ° C. for 7 days (humidity was not adjusted). After storage, the content (%) of impurities contained in the pharmaceutical composition was determined by reverse phase high performance liquid chromatography using a column filled with octadecylsilylated silica gel for liquid chromatography. The detection was performed by measuring each peak area at a wavelength of 246 nm using an ultraviolet absorptiometer. Specifically, the ratio (%) of impurities to atorvastatin contained in the pharmaceutical composition was calculated from the following formula.

  Moreover, the decomposition suppression rate (%) by each additive was computed according to the following formula.

The results are also shown in Table 1.

  From this result, it was confirmed that the generation or increase of impurities can be significantly suppressed by adding hydrous silicon dioxide to the main drug atorvastatin calcium.

  Table 2 describes the formulation of a solid pharmaceutical composition (solid preparation) containing an HMG-CoA reductase inhibitor such as atorvastatin calcium as an active ingredient and hydrous silicon dioxide.

Claims (6)

  It contains hydrous silicon dioxide as an active ingredient having HMG-CoA reductase inhibitory activity in addition to a hydroxy acid capable of forming a lactone, a pharmaceutically acceptable salt thereof or a hydrate thereof. A solid pharmaceutical composition in which the generation or increase of impurities is suppressed.   The solid pharmaceutical composition according to claim 1, comprising a hydroxy acid capable of forming a lactone, a pharmaceutically acceptable salt thereof, or a hydrate thereof in a total amount of 1 to 50% by mass. object.   3. The active ingredient is at least one selected from the group consisting of atorvastatin, pravastatin, fluvastatin, pitavastatin, pharmaceutically acceptable salts thereof, and hydrates thereof. A solid pharmaceutical composition.   The solid pharmaceutical composition according to claim 1 or 2, wherein the active ingredient is atorvastatin calcium hydrate. As an active ingredient having HMG-CoA reductase inhibitory activity, a hydroxy acid capable of forming a lactone, a pharmaceutically acceptable salt thereof or a hydrate thereof; hydrous silicon dioxide; and a pharmaceutically acceptable carrier or addition 5. The method according to claim 1, comprising a step of mixing an agent and wet granulating, and a step of blending and mixing a lubricant with the granule, and molding the resulting mixture into a tablet or filling a capsule. A method for preparing a solid pharmaceutical composition, wherein the production or increase of impurities containing lactone is suppressed.   In the preparation of a solid pharmaceutical composition containing a hydroxy acid capable of producing a lactone, HMG-CoA reductase inhibitory activity, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, hydrous dioxide as an additive A method for suppressing generation or increase of impurities containing a lactone in the solid pharmaceutical composition, which comprises adding silicon.