WO2012056509A1 - Pharmaceutical composition - Google Patents

Abstract

The present invention provides a novel means of suppressing the generation of statin lactones. The pharmaceutical composition of the present invention is characterized by containing a compound having HMG-CoA reductase inhibiting activity represented by formula (1), or a salt thereof, and an alkali earth metal chloride salt. In the formula below, R represents an organic group, and X represents -CH₂-CH₂- or -CH=CH-.

Description

Pharmaceutical composition

The present invention relates to a pharmaceutical composition having good stability of a compound having HMG-CoA reductase inhibitory activity such as statins.

At present, a large number of pharmaceuticals containing statins having HMG-CoA reductase inhibitory activity as active ingredients have been developed and marketed as therapeutic agents for hyperlipidemia and hypercholesterolemia. Specific examples of such statins include pravastatin sodium, fluvastatin sodium, atorvastatin calcium hydrate, pitavastatin calcium, and rosuvastatin calcium. These compounds are all dihydroxycarboxylic acid (3,5-dihydroxyheptane). Acid or 3,5-dihydroxy-6-heptenoic acid) skeleton as a common skeleton.

It is known that the dihydroxycarboxylic acid skeleton, which is a common skeleton of the above-mentioned statins, is cyclized in the molecule to produce a lactone form that does not exhibit HMG-CoA reductase inhibitory activity. The production of lactones in pharmaceutical preparations can cause a decrease in the effectiveness of the pharmaceuticals and non-uniformity of effectiveness among the pharmaceuticals. For this reason, various attempts have been made to improve the stability of statins in pharmaceutical preparations, and many of them are basic substances such as calcium carbonate in consideration of the instability of the dihydroxycarboxylic acid skeleton in a low pH environment. To make the pH environment of statins basic. Specifically, for example, in Patent Document 1, a compound having an HMG-CoA reductase inhibitory activity represented by the following formula (a) typified by fluvastatin produces a decomposition product such as a lactone form at neutral to acidic pH. And the fact that it can be stabilized by combining an alkaline medium such as calcium carbonate.

[Wherein R ^a is an organic group, X ^a is —CH═CH—, and M ^a is a physiologically acceptable cation. ]

In addition, Patent Document 2 combines a compound represented by the following formula (b) represented by atorvastatin into a lactone form in an acidic environment, and a basic stabilizing metal salt additive such as calcium carbonate. It can be stabilized by this.

[Wherein, X ^b is —CH ₂ — and the like, R ¹ is 1-naphthyl, etc., R ² and R ³ are —CONH ₂ , a hydrogen atom, etc., and R ⁴ has 1 to 6 carbon atoms. Alkyl and the like, and M ^b is a pharmaceutically acceptable metal salt. ]

However, none of these documents describes or suggests that alkaline earth metal chlorides inhibit the production of lactones of statins.

Japanese Patent No. 2774037 Japanese Patent No. 3254219

The object of the present invention is to provide a new means for suppressing the production of lactones of statins.

The inventors of the present invention made extensive studies to solve the above problems, and surprisingly, alkaline earth metal chlorides such as calcium chloride and magnesium chloride are represented by the following general formula (1) including statins. The present invention was completed by discovering that the compound having the HMG-CoA reductase inhibitory activity represented has an action of suppressing lactone formation.

That is, the present invention provides a pharmaceutical composition containing a compound having an HMG-CoA reductase inhibitory activity represented by the following general formula (1) or a salt thereof, and an alkaline earth metal chloride.

[Wherein, R represents an organic group, and X represents —CH ₂ —CH ₂ — or —CH═CH—. ]

The present invention also provides a pharmaceutical comprising a compound having an HMG-CoA reductase inhibitory activity represented by the above general formula (1) or a salt thereof as an active ingredient, and an alkaline earth metal chloride as a stabilizer. A composition is provided.

In addition, the present invention provides a stabilizer for a compound having an HMG-CoA reductase inhibitory activity represented by the above general formula (1) or a salt thereof, which contains an alkaline earth metal chloride as an active ingredient (preferably, A lactone compound production inhibitor).
The present invention also relates to the use of an alkaline earth metal chloride as a stabilizer for a compound having an HMG-CoA reductase inhibitory activity represented by the general formula (1) or a salt thereof (preferably a lactone Use as a body formation inhibitor).
Further, the present invention is represented by the above general formula (1), wherein an alkaline earth metal chloride is allowed to coexist with the compound having an HMG-CoA reductase inhibitory activity represented by the above general formula (1) or a salt thereof. The present invention relates to a method for stabilizing a compound having a HMG-CoA reductase inhibitory activity or a salt thereof (preferably a method for inhibiting lactone formation).
The present invention also provides a method for producing a pharmaceutical composition in which the formation of a lactone form of a compound having a HMG-CoA reductase inhibitory activity represented by the general formula (1) or a salt thereof is suppressed, The present invention relates to a production method comprising a step of adding an alkaline earth metal chloride to a compound having a HMG-CoA reductase inhibitory activity represented by (1) or a salt thereof.

In the pharmaceutical composition of the present invention, since the formation of the lactone form of the compound having an HMG-CoA reductase inhibitory activity represented by the above general formula (1) or a salt thereof, which is an active ingredient, is suppressed, It is useful as a pharmaceutical with good properties.

In the present invention, the “compound having HMG-CoA reductase inhibitory activity represented by the general formula (1) (hereinafter also simply referred to as“ compound (1) ”) or a salt thereof” includes the compound (1) itself. In addition, a pharmaceutically acceptable salt of compound (1) is also included.

[Wherein, R represents an organic group, and X represents —CH ₂ —CH ₂ — or —CH═CH—. ]

Specific examples of the salt of compound (1) include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; organic amine salts such as phenethylamine salt; ammonium salt and the like. It is done. In addition, since compound (1) has an asymmetric carbon, various optical isomers exist. In the present invention, compound (1) or a salt thereof includes any optical isomer, and has a single optical isomer. It may be an isomer or a mixture of various optical isomers. Furthermore, the compound (1) or a salt thereof may be in a solvate state, and a solvate of the compound (1) or a salt thereof and water or alcohol is also represented by “general formula (1)”. A compound having a HMG-CoA reductase inhibitory activity or a salt thereof.

In the present invention, in the general formula (1), examples of the “organic group” represented by R include cyclic groups such as a carbocyclic group and a heterocyclic group. Note that the cyclic group may further have a substituent.

Examples of the “carbocyclic group” include a 3- to 15-membered monocyclic, bicyclic or tricyclic saturated carbocyclic group or unsaturated carbocyclic group. Specific examples of the carbocyclic group include, for example, phenyl, naphthyl, phenanthryl, anthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, Examples include cyclohexadienyl, cycloheptadienyl, cyclooctadienyl, indenyl, indanyl, dihydronaphthyl, tetrahydronaphthyl, hexahydronaphthyl and the like.

Examples of the “heterocyclic group” include, for example, a 3- to 15-membered monocyclic or bicyclic saturated heterocyclic ring containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. A formula group or an unsaturated heterocyclic group. Specific examples of the heterocyclic group include, for example, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, azepinyl, diazepinyl, furyl, pyranyl, oxepinyl, thienyl, thiapyranyl, thiepinyl, oxazolyl, isoxazolyl, Thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, oxazinyl, oxadiazinyl, oxazepinyl, oxadiazepinyl, thiadiazolyl, thiazinyl, thiadiazinyl, thiazepinyl, thiadiazepinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, quinolinyl, isoquinolinyl, quinolinyl, quinolinyl, quinolinyl Oxazolyl, benzothiazolyl, benzimidazo Pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, dihydropyridyl, tetrahydropyridyl, dihydropyrazinyl, tetrahydropyrazinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydroazepinyl, tetrahydroazepinyl, dihydrodiazepinyl , Tetrahydrodiazepinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, dihydrothiapyranyl, tetrahydrothiapyranyl, piperidyl, piperazinyl, morpholinyl, thiamorpholinyl, homopiperidyl, etc. .

Specific examples of the "substituent" that the cyclic group may have include a substituent selected from an alkyl group; a hydroxy group; an acyloxy group; an alkyl group and an alkylsulfonyl group. A good amino group; an aryl group optionally having a halogen atom as a substituent; and a carbamoyl group optionally having an aryl group as a substituent.
In the present invention, a linear or branched alkyl group having 1 to 6 carbon atoms; a cyclic alkyl group having 3 to 8 carbon atoms; a hydroxy group; a linear or branched chain alkyl group having 1 to 6 carbon atoms; An amino group which may have a substituent selected from a linear or branched alkyl group having 1 to 6 carbon atoms and a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms; a fluorine atom as a substituent A carbamoyl group optionally having a phenyl group as a substituent, a methyl group, an isopropyl group, a cyclopropyl group, a hydroxy group, a 2-methylbutanoyloxy group, methanesulfonyl (Methyl) amino group, phenyl group, 4-fluorophenyl group and phenylcarbamoyl group are particularly preferred.

In the present invention, the “organic group” includes a quinolinyl group which may have a substituent, a hexahydronaphthyl group which may have a substituent, an indolyl group which may have a substituent, and a substituent. A cyclic group selected from a pyrrolyl group which may be substituted and a pyrimidinyl group which may have a substituent is preferable, and any of the above five cyclic groups having a substituent is particularly preferable.

In the present invention, as the compound (1) or a salt thereof, the compound described in JP-A-1-279866 and US Pat. No. 5,856,336, in which R is an optionally substituted quinolinyl group, or a compound thereof Salts: Compounds described in JP-A-57-2240 and US Pat. No. 4,346,227, wherein R is a hexahydronaphthyl group which may have a substituent, or salts thereof; JP-A-60-500015 Compounds and salts thereof in which R is an indolyl group which may have a substituent, as described in JP-A No. 5347477 and US Pat. No. 5,354,772; JP-A-62-289577, JP-A-3-58967, and US Compounds described in Japanese Patent No. 5273395, wherein R is a pyrrolyl group which may have a substituent, or a salt thereof; JP-A No. 5-178411 and US Pat. Described in 260440 Pat, compound R is a good pyrimidinyl group which may have a substituent, or its salts. In addition, description of these literatures is quoted in this specification by reference.

The content of the compound (1) or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and should be determined by appropriate examination according to the strength of the pharmacological activity of the compound, the sex, age, symptoms, etc. of the user. However, it is preferable to take 0.1 to 160 mg, more preferably 0.5 to 120 mg, and particularly preferably 1 to 80 mg per day.
In the present invention, a pharmaceutical composition containing 0.01 to 80% by mass of the compound (1) or a salt thereof with respect to the total mass of the pharmaceutical composition is preferable, and a pharmaceutical composition containing 0.05 to 70% by mass is preferable. More preferred is a pharmaceutical composition containing 0.1 to 60% by mass.

In the present invention, as compound (1) or a salt thereof, a compound selected from pravastatin, fluvastatin, atorvastatin, pitavastatin and rosuvastatin or a salt thereof is preferable, and pitavastatin or a salt thereof is particularly preferable. As specifically described in Test Example 2 below, alkaline earth metal chloride has an inhibitory effect on pitavastatin or its salt, not only on the lactone but also on other decomposition products. Became clear. Accordingly, the alkaline earth metal chloride can be particularly suitably used as a stabilizer for pitavastatin or a salt thereof.

In the present invention, “pitavastatin or a salt thereof” includes, in addition to pitavastatin itself, pharmaceutically acceptable salts of pitavastatin (alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt) Organic amine salts such as phenethylamine salts; ammonium salts, and the like, and solvates of pitavastatin and pharmaceutically acceptable salts thereof with water, alcohol, and the like. In the present invention, one or two of these are included. The above can be used in combination.
In the present invention, pitavastatin calcium (chemical name: (+)-monocalcium bis {(3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] -3,5- dihydroxy-6-heptenoate}) is preferred.
Pitavastatin or a salt thereof is a known compound and can be produced, for example, by the method described in JP-A-1-279866, US Pat. No. 5,856,336, and the like.

The content of pitavastatin or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited and can be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, for example, per day, Pitavastatin calcium is preferably 0.1 to 16 mg, more preferably 0.5 to 8 mg, particularly preferably 1 to 4 mg.
In the present invention, a pharmaceutical composition containing 0.01 to 30% by mass of pitavastatin or a salt thereof in terms of pitavastatin calcium is preferable with respect to the total mass of the pharmaceutical composition, and a pharmaceutical composition containing 0.05 to 20% by mass Is more preferable, and a pharmaceutical composition containing 0.1 to 15% by mass is particularly preferable.

In the present invention, “pravastatin or a salt thereof” includes not only pravastatin itself but also a pharmaceutically acceptable salt of pravastatin (an alkali metal salt such as sodium salt or potassium salt; an alkaline earth metal salt such as calcium salt or magnesium salt). Organic amine salts such as phenethylamine salts; ammonium salts, etc.), and also solvates of pravastatin and pharmaceutically acceptable salts thereof with water, alcohol, etc., and in the present invention, one or two of these The above can be used in combination.
In the present invention, pravastatin sodium (chemical name: Monosodium (3R, 5R) -3,5-dihydroxy-7-{(1S, 2S, 6S, 8S, 8aR) -6-hydroxy-2-methyl-8 [- (2S) -2-methylbutanoyloxy] -1,2,6,7,8,8a-hexahydronaphthalen-1-yl} heptanoate) is preferred.
Pravastatin or a salt thereof is a known compound and can be produced, for example, by the method described in JP-A-57-2240, US Pat. No. 4,346,227, and the like.

The content of pravastatin or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited and can be determined by appropriate examination according to the sex, age, symptom, etc. of the user, for example, per day, From 1 to 160 mg in terms of pravastatin sodium, more preferably 2 to 120 mg, particularly preferably 5 to 80 mg can be taken.
In the present invention, a pharmaceutical composition containing pravastatin or a salt thereof in an amount of from 0.1 to 80% by mass in terms of pravastatin sodium, based on the total mass of the pharmaceutical composition, is preferred, and a pharmaceutical composition containing 0.2 to 70% by mass Is more preferable, and a pharmaceutical composition containing 0.5 to 60% by mass is particularly preferable.

In the present invention, “fluvastatin or a salt thereof” includes, in addition to fluvastatin itself, a pharmaceutically acceptable salt of fluvastatin (an alkali metal salt such as sodium salt or potassium salt; an alkaline earth such as calcium salt or magnesium salt). Metal salts; organic amine salts such as phenethylamine salts; ammonium salts, etc.), and further solvates of fluvastatin and pharmaceutically acceptable salts thereof with water, alcohol, etc. Species or two or more can be used in combination.
In the present invention, fluvastatin sodium (chemical name: (±)-(3RS, 5SR, 6E) -sodium-7- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2 -yl] -3,5-dihydroxy-6-heptenoate).
Fluvastatin or a salt thereof is a known compound and can be produced, for example, by the method described in JP-T-60-500015, US Pat. No. 5,347,772, and the like.

The content of fluvastatin or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited and can be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, for example, per day It is preferable that 1 to 160 mg, more preferably 5 to 120 mg, particularly preferably 10 to 80 mg of fluvastatin can be taken in free form.
In the present invention, a pharmaceutical composition containing 0.1 to 80% by mass of fluvastatin or a salt thereof in terms of free form of fluvastatin with respect to the total mass of the pharmaceutical composition is preferable, and 0.5 to 70% by mass is preferably contained. More preferably, the pharmaceutical composition containing 1 to 60% by mass is particularly preferable.

In the present invention, “atorvastatin or a salt thereof” includes, in addition to atorvastatin itself, pharmaceutically acceptable salts of atorvastatin (alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt) Organic amine salts such as phenethylamine salts; ammonium salts, and the like, and solvates of atorvastatin and pharmaceutically acceptable salts thereof with water, alcohol, etc. are included in the present invention. The above can be used in combination.
In the present invention, atorvastatin calcium hydrate (chemical name: (-)-Monocalcium bis {(3R, 5R) -7- [2- (4-fluorophenyl-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1H -pyrrol-1-yl) -3,5-dihydroxyheptanoate] trihydrate}).
Atorvastatin or a salt thereof is a known compound and can be produced, for example, by the method described in JP-A-3-58967, US Pat. No. 5,273,395, and the like.

The content of atorvastatin or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and can be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, for example, per day, It is preferable that atorvastatin in a free form is 1 to 160 mg, more preferably 2 to 120 mg, particularly preferably 5 to 80 mg.
In the present invention, a pharmaceutical composition containing 0.1 to 80% by mass of atorvastatin or a salt thereof in terms of a free form of atorvastatin based on the total mass of the pharmaceutical composition is preferable, and a pharmaceutical containing 0.2 to 70% by mass A composition is more preferable, and a pharmaceutical composition containing 0.5 to 60% by mass is particularly preferable.

In the present invention, “rosuvastatin or a salt thereof” includes, in addition to rosuvastatin itself, pharmaceutically acceptable salts of rosuvastatin (alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt) Organic amine salts such as phenethylamine salts; ammonium salts, and the like, and solvates of rosuvastatin and pharmaceutically acceptable salts thereof with water, alcohol, etc. are included in the present invention. The above can be used in combination.
In the present invention, rosuvastatin calcium (chemical name: Monocalcium bis ((3R, 5S, 6E) -7- {4- (4-fluorophenyl) -6-isopropyl-2- [methanesulfonyl (methyl) amino] pyrimidin-5- yl} -3,5-dihydroxyhept-6-enoate)).
Rosuvastatin or a salt thereof is a known compound and can be produced, for example, by the method described in JP-A No. 5-178411, US Pat. No. 5,260,440.

The content of rosuvastatin or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited and can be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, for example, per day, It is preferable that rosuvastatin can be taken in a free form of 0.5 to 80 mg, more preferably 1 to 60 mg, particularly preferably 2.5 to 40 mg.
In the present invention, a pharmaceutical composition containing 0.05 to 80% by mass of rosuvastatin or a salt thereof in terms of a free form of rosuvastatin relative to the total mass of the pharmaceutical composition is preferred, and a pharmaceutical containing 0.1 to 70% by mass A composition is more preferable, and a pharmaceutical composition containing 0.25 to 60% by mass is particularly preferable.

In the present invention, examples of the “alkaline earth metal chloride” include calcium chloride and magnesium chloride. Here, in the present specification, “alkaline earth metal chloride” is a concept including a hydrate.
In the present invention, the alkaline earth metal chloride specifically includes, for example, calcium chloride anhydrous, calcium chloride monohydrate, calcium chloride dihydrate, calcium chloride tetrahydrate, calcium chloride hexahydrate. Examples include calcium chloride such as magnesium chloride, magnesium chloride such as anhydride, magnesium chloride hexahydrate, and the like. In the present invention, one or more of these may be used in combination.
In the present invention, one or more selected from the group consisting of calcium chloride and magnesium chloride is preferable, calcium chloride is more preferable, and calcium chloride dihydrate is particularly preferable.

The content of the alkaline earth metal chloride in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the stability of the compound (1) or a salt thereof. In view of the above, a pharmaceutical composition containing 0.01 to 40% by mass of alkaline earth metal chloride with respect to the total mass of the pharmaceutical composition is preferable, and a pharmaceutical composition containing 0.02 to 30% by mass is more preferable. A pharmaceutical composition containing 0.05 to 20% by mass is particularly preferred.

In the pharmaceutical composition of the present invention, the mass ratio of the compound (1) or a salt thereof and the alkaline earth metal chloride is not particularly limited, and is determined by appropriately examining according to the stability of the compound (1) or a salt thereof. However, from the viewpoint of suppressing the formation of the lactone form, 0.005 to 60 parts by mass, further 0.01 to 40 parts by mass of alkaline earth metal chloride is used with respect to 1 part by mass of compound (1) or a salt thereof. Part, particularly 0.02 to 20 parts by mass. In particular, when the compound (1) or a salt thereof is pitavastatin or a salt thereof, 1 mass of pitavastatin or a salt thereof in terms of pitavastatin calcium from the viewpoint of inhibiting the production of a lactone body and inhibiting the production of a decomposition product other than the lactone body. The alkaline earth metal chloride is preferably contained in an amount of 0.005 to 30 parts by mass, more preferably 0.01 to 20 parts by mass, and particularly preferably 0.02 to 10 parts by mass with respect to parts.

The pharmaceutical composition of the present invention may contain additives usually used in the technical field depending on its specific form (dosage form). Examples of the additive include excipients, disintegrants, binders, lubricants, colorants, plasticizers, film forming agents, poorly water-soluble polymer substances, antioxidants, corrigents, sweeteners, pH Examples thereof include a regulator, a surfactant, a stabilizer, a fragrance, a fluidizing agent, a liquid medium, and the like, and these can be used alone or in combination of two or more. In addition, the usage-amount of each additive can be suitably determined within the range which does not interfere with the objective of this invention.

Examples of excipients include titanium oxide, aluminum silicate, silicon dioxide, anhydrous sodium sulfate, anhydrous calcium hydrogen phosphate, sodium chloride, hydrous amorphous silicon oxide, calcium silicate, light anhydrous silicic acid, and heavy anhydrous silica. Inorganic excipients such as acid, calcium sulfate, calcium monohydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, magnesium oxide; Flour, starch (wheat starch, rice starch, corn starch, partially pregelatinized starch, etc.), fructose, caramel, agar, xylitol, paraffin, crystalline cellulose, sucrose, fructose, maltose, lactose, sucrose, glucose, pullulan, polyoxy Ethylene hydrogenated castor oil, maltitol, reduced wheat Organic excipients such as sugar candy, powdered maltose candy, erythritol, xylitol, sorbitol, mannitol, lactitol, trehalose, reduced palatinose, maltose, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, calcium citrate, etc. It is done.
Examples of the disintegrant include super disintegrants such as sodium carboxymethyl starch, croscarmellose sodium, crospovidone, carmellose, carmellose calcium, starch, sucrose fatty acid ester, gelatin, sodium bicarbonate, dextrin, dehydroacetic acid and the like. Salt, povidone, polyoxyethylene hydrogenated castor oil 60 and the like.

Examples of the binder include methyl cellulose, hydroxypropyl cellulose, hypromellose, carmellose sodium, starch (wheat starch, rice starch, corn starch, partially pregelatinized starch, etc.), dextrin, pullulan, gum arabic, agar, gelatin, tragacanth, Examples include sodium alginate, povidone, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, and polyvinyl acetal diethylaminoacetate.
Examples of the lubricant include calcium stearate, magnesium stearate, sodium stearyl fumarate, sucrose fatty acid ester, and the like.

Examples of the colorant include yellow iron sesquioxide, brown iron oxide, caramel, black iron oxide, titanium oxide, iron sesquioxide, tar dye, aluminum lake dye, copper chlorophyllin sodium, and the like.
Examples of the plasticizer include glycerin, sesame oil, sorbitol, castor oil, propylene glycol, polyoxyethylene polyoxypropylene glycol, polysorbate 80 (polyoxyethylene (20) sorbitan oleate), polyethylene glycol [for example, Macrogol 400 (Polymerization degree n of oxyethylene units is 7 to 9: “n” indicates the degree of polymerization), Macrogol 600 (n is 11 to 13), Macrogol 1500 (n is 5 to 6, n is 28 ˜36), macrogol 4000 (n is 59 to 84), macrogol 6000 (n is 165 to 210)] and the like. The plasticizer is preferably one or a combination of two or more selected from these, and more preferably one or more selected from the group consisting of glycerin, propylene glycol and macrogol 400.

Examples of the film forming agent include alkyl celluloses such as methyl cellulose and ethyl cellulose; alginic acid such as sodium alginate or a salt thereof; carrageenan; carboxyalkyl cellulose such as carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, carboxymethyl cellulose potassium, carboxymethyl cellulose, and carboxymethyl ethyl cellulose. Xanthan gum; hydroxyalkyl cellulose such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose (hydroxypropylmethylcellulose); hydroxyalkylcellulose phthalate such as hydroxypropylmethylcellulose phthalate; pullulan; polyvinyl acetate ; Polyvinyl acetate phthalate, polyvinyl alcohol, polyvinyl pyrrolidone, and the like, one or more combinations selected from these is preferred.

Examples of the poorly water-soluble polymer substance include carboxyvinyl polymer and aminoalkyl methacrylate copolymer.
Examples of the antioxidant include ascorbic acid, sodium bisulfite, sodium sulfite, sodium edetate, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, tocopherol, butylhydroxyanisole and the like.

Examples of the corrigent include terpenes such as limonene, pinene, camphene, cymen, cineole, citronellol, geraniol, nerol, linalool, menthol, terpineol, rosinol, borneol, isoborneol, menthone, camphor, eugenol, synzeanol, etc .; Contains terpenes such as oil, orange oil, peppermint oil, camphor white oil, eucalyptus oil, turpentine oil, lemon oil, pepper oil, clove oil, cinnamon oil, lavender oil, fennel oil, chamomile oil, perilla oil, spearmint oil Essential oils (hereinafter, terpenes and essential oils containing terpenes are collectively referred to as “terpenes”); acidulants such as ascorbic acid, tartaric acid, citric acid, malic acid and their salts. Among them, terpenes are preferable, menthol is more preferable, and l-menthol is particularly preferable.

Examples of the sweetening agent include aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, saccharin sodium, etc. Among them, sucralose is preferable.

The pH of the pharmaceutical composition of the present invention is not particularly limited, but is 4 or more, preferably 4 to 13, more preferably 5 to 12, still more preferably 6 to 11, particularly preferably 7 to 11. In the present specification, the pH of the pharmaceutical composition refers to the pH of a solution obtained by dissolving or dispersing one dosage unit of the pharmaceutical composition in 4 mL of purified water in the 15th revised Japanese Pharmacopoeia General Test Methods section. It means a value when measured according to the described pH measurement method.

The dosage form of the pharmaceutical composition of the present invention is not particularly limited, and may be any of solid, semi-solid and liquid forms, and can be a form normally used in pharmaceuticals. Specifically, for example, tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets), film agents, troches, drop agents, hard capsules, soft capsules, granules, fine granules, powders, rounds Solid pharmaceutical compositions such as suppositories, dry syrups, suppositories, poultices, plasters; licks, chewing gums, jellies, jelly drops, whips, ointments, creams, foams, ins Semi-solid pharmaceutical compositions such as pills and nazar gels; liquid pharmaceutical compositions such as syrups, drinks, suspensions, spirits, liquids, eye drops, aerosols, sprays, sprays, etc. The dosage forms described in Japanese Pharmacopoeia, US Pharmacopoeia, European Pharmacopoeia and the like can be used.

The dosage form of the pharmaceutical composition of the present invention is preferably a solid pharmaceutical composition. As specifically described in Test Example 3 below, the oral earth disintegrating property of the alkaline earth metal chloride is sufficiently fast with respect to the solid pharmaceutical composition containing the compound (1) or a salt thereof. It became clear to give. Therefore, when the pharmaceutical composition of the present invention is a solid composition, the composition is rapidly disintegrated, so that rapid release of active ingredients and expression of drug efficacy can be expected. In particular, when the pharmaceutical composition of the present invention is an orally disintegrating solid preparation (preferably an orally disintegrating tablet or an orally disintegrating film), the pharmaceutical composition of the present invention is used in the oral cavity. Since it disintegrates quickly, it is easy to take and has the excellent effect of leading to improved compliance.
In the present invention, the disintegration time in the oral cavity of the orally disintegrating solid preparation (the time until the solid preparation is completely disintegrated by the saliva in the oral cavity of a healthy person) is not particularly limited. Although it varies depending on the dosage form, size, etc., for example, it is within 90 seconds, preferably within 60 seconds, particularly preferably within 30 seconds.

The pharmaceutical composition of the present invention can be produced by a known method described in Japanese Pharmacopoeia, US Pharmacopoeia, European Pharmacopoeia or the like according to the dosage form.
Specifically, for example, in the case of an orally disintegrating tablet (hereinafter referred to as “OD tablet”) which is a preferred dosage form of the present invention, compound (1) or a salt thereof, and alkaline earth metal chloride And, if desired, a method of direct compression molding using additives, etc .; compound (1) or a salt thereof, alkaline earth metal chloride, and additives, etc., if desired, are mixed to form a plate compression molding or slug tablet After compression molding, the mixture is pulverized and optionally mixed with additives, etc., and the mixture in a dry state is compression molded; Compound (1) or a salt thereof, alkaline earth metal chloride, and optionally additives After mixing, the mixture can be granulated by an appropriate method, and the mixture can be produced by compression molding a dry mixture.

The OD tablet of the present invention is a method in which a suspension or solution containing compound (1) or a salt thereof and alkaline earth metal chloride is filled in a mold such as a blister pocket, freeze-dried, and dried and solidified. Can be manufactured. The suspension or solution may further contain gelatin, dextran, alginic acid or a salt of alginic acid, sugar alcohol (erythritol, xylitol, sorbitol, mannitol, etc.), glycine and the like.

Furthermore, the OD tablet of the present invention is molded at low pressure by wetting a mixture containing compound (1) or a salt thereof, an alkaline earth metal chloride, a saccharide and / or a sugar alcohol with water, an aqueous alcohol solution or the like. It can be produced by a method, so-called wet tableting.
Furthermore, the OD tablet of the present invention comprises compound (1) or a salt thereof, an alkaline earth metal chloride, a cellulose compound such as crystalline cellulose, and an easily moldable additive such as an acrylic acid compound or gelatin. Can be produced by dry tableting using a super-disintegrant such as sodium carboxymethyl starch, croscarmellose sodium, crospovidone, etc.

Further, the OD tablet of the present invention is formed of lactose hydrate, mannitol, glucose hydrate, saccharides having low moldability such as sucrose and xylitol, and maltose, maltitol, sorbitol, oligosaccharides such as lactose and fructose, etc. It can be produced by a method in which a granulated product is produced using a highly saccharide and then the granulated product is tableted. In this method, compound (1) or a salt thereof and alkaline earth metal chloride may be contained in the granulated product, or may be mixed after the granulated product is produced. What was included in the said granulated material is preferable.

Furthermore, the OD tablet of the present invention comprises xylitol, trehalose, maltose, sorbitol, erythritol, glucose, maltitol, mannitol, sucrose, lactose, which is lower than the melting point or decomposition point of compound (1) or a salt thereof or other additives. Using a relatively low-melting saccharide such as a hydrate, a melt-solidified product with compound (1) or a salt thereof or other additives can be produced, and then the melt-solidified product can be produced by tableting. In this method, the compound (1) or a salt thereof may be contained in the melt-solidified product, or may be mixed after the melt-solidified product is produced, but is contained in the melt-solidified product. Those are preferred.

The content of additives such as excipients and disintegrants used in the OD tablet of the present invention is not particularly limited, but the excipient is 20 to 95% by mass relative to the total mass of the OD tablet of the present invention. It is preferably contained in an amount of 30 to 90% by mass, particularly 35 to 85% by mass. The disintegrant is particularly preferably contained in an amount of 0.5 to 25% by mass, more preferably 1 to 20% by mass, particularly 2 to 15% by mass, based on the total mass of the OD tablet of the present invention.

An orally disintegrating film agent (hereinafter simply referred to as “film agent”), which is another preferable dosage form of the present invention, can be appropriately produced by a known method.
Specifically, for example, a suspension in which compound (1) or a salt thereof, alkaline earth metal chloride, and an additive or the like are blended is applied / sprayed on a holding substrate such as a plastic film or a mount. Then, it can be produced by drying it. In addition, as a solvent in suspension, water, alcohol (ethanol etc.), those mixed liquids, etc. are mentioned.
Further, the film agent of the present invention may be a multi-layer film agent obtained by laminating a plurality of layers, and at least one of the plurality of layers may contain compound (1) or a salt thereof and alkaline earth. It only has to contain a metal chloride. Furthermore, the compound (1) or a salt thereof and an alkaline earth metal chloride may be contained in different layers, but from the viewpoint of suppressing the formation of a lactone body, the compound (1) or a salt thereof and an alkaline earth metal It is preferable to contain chloride in the same layer. In the case of producing a multilayer type film agent, for example, after forming a plurality of layers separately on a holding substrate, each layer may be laminated by crimping or suspended. Lamination may be performed by sequentially repeating application, spraying, and drying of the liquid.

The content of additives such as a film forming agent and a plasticizer used in the film agent of the present invention is not particularly limited, but the film forming agent is 25 to 95% by mass relative to the total mass of the film agent of the present invention, It is preferably contained in an amount of 30 to 80% by mass, particularly 35 to 65% by mass. The plasticizer is preferably contained in an amount of 1 to 25% by mass, more preferably 3 to 20% by mass, especially 5 to 15% by mass, based on the total mass of the film agent of the present invention.

Since the pharmaceutical composition of the present invention contains a compound having a HMG-CoA reductase inhibitory activity represented by the general formula (1) or a salt thereof, for example, a therapeutic agent for hyperlipidemia, a treatment for hypercholesterolemia It can be used as an agent or a treatment for familial hypercholesterolemia.
Examples of the route of taking the pharmaceutical composition of the present invention include oral and parenteral such as rectal and vaginal administration, and oral administration is preferred. In addition, the pharmaceutical composition of the present invention can be taken 1 to 4 times per day before meals, between meals, after meals, before going to bed.

Hereinafter, the present invention will be described more specifically with reference to examples and the like, but the present invention is not limited to the following examples.

[Example 1]
4.8 g of water and 11.2 g of absolute ethanol are mixed, 0.8 g of sucralose, 0.06 g of 1-menthol, 1.6 g of aminoalkyl methacrylate copolymer E, calcium chloride dihydrate (described in 15th revision Japanese Pharmacopoeia) Of calcium chloride hydrate) was dissolved, and 0.4 g of pitavastatin calcium was dispersed. In this solution, 4.74 g of hypromellose was dissolved to obtain a preparation solution.
The prepared solution was uniformly applied on a PET (polyethylene terephthalate) film and then dried with warm air to form a layer having a mass of 10 mg per area of 2.8 cm ² to obtain an intermediate product 1.
Two types of intermediate products 1 were prepared, bonded and pressure-bonded so that the layers were opposed to each other, and the PET film on one side was peeled off to obtain intermediate product 2. Two intermediate products 2 were prepared, and bonded and pressure-bonded so that the layers were opposed to each other, whereby an intermediate product 3 was obtained.
The intermediate product 3 was cut into an area of 2.8 cm ² , the PET film was peeled off, and the film agent of Example 1 was obtained.

[Example 2]
The film preparation of Example 2 was prepared in the same manner as in Example 1 except that magnesium chloride hexahydrate (magnesium chloride described in Japanese Pharmacopoeia Standard 2002) was used instead of calcium chloride dihydrate. Got.

[Comparative Example 1]
A film agent of Comparative Example 1 was obtained in the same manner as in Example 1 except that hypromellose was used instead of calcium chloride dihydrate.

[Comparative Example 2]
A film agent of Comparative Example 2 was obtained in the same manner as in Example 1 except that calcium carbonate was used instead of calcium chloride dihydrate.

[Comparative Example 3]
A film preparation of Comparative Example 3 was obtained in the same manner as in Example 1 except that magnesium metasilicate aluminate was used instead of calcium chloride dihydrate.

[Test Example 1] Lactone Formation Suppression Test The film preparations of Examples 1 and 2 and Comparative Examples 1 to 3 were evaluated for the rate of formation of the lactone immediately after preparation and after storage at 60 ° C for 1 week.
The production rate of the lactone compound was determined using an HPLC apparatus (HPLC system equipped with an Alliance 2695 separation module and a 2996 photodiode array detector: Waters) for the film agents of Examples 1 and 2 and Comparative Examples 1 to 3. It was measured as an area percentage with respect to the total peak area derived from pitavastatin and its degradation product. The results are shown in Table 1 together with the composition of each film agent (component amount (mg) per film agent).

From the test results shown in Table 1, it was confirmed that in Comparative Example 1 containing no alkaline earth metal chloride, a large amount of lactone was formed with the passage of time. In Comparative Example 2 containing calcium carbonate, which is a basic substance instead of alkaline earth metal chloride, and Comparative Example 3 containing magnesium metasilicate, which is also a basic substance, the amount of lactone produced Was not significantly different from Comparative Example 1.
On the other hand, the film agents according to Examples 1 and 2 and Comparative Examples 1 to 3 are calcium chloride, which is an alkaline earth metal chloride, regardless of whether the pH is adjusted to around 8.5. It is clear that the production of lactone is specifically suppressed in Comparative Example 1 through Comparative Example 1 in Example 1, which contains magnesium chloride which is also alkaline earth metal chloride. It became. Although the present invention is not limited to the inference, the alkaline earth metal chloride specifically suppressed the formation of the lactone body in the same pH environment, so that the action is increased in pH. It was inferred that this was due to a completely different mechanism from the accompanying suppression of lactone formation.

From the above test results, it was clarified that alkaline earth metal chloride has an action of suppressing the formation of a lactone form of compound (1) including pitavastatin or a salt thereof.

[Test Example 2] Production inhibition test of degradation products other than lactone compounds For the film agents of Examples 1 and 2 and Comparative Examples 1 to 3, the total degradation products other than lactone compounds were prepared immediately after preparation and after storage at 60 ° C for 1 week. The production rate was measured as an area percentage with respect to the total peak area derived from pitavastatin and its degradation product by the HPLC apparatus in the same manner as the method for measuring the production rate of the lactone compound in Test Example 1.
The results are shown in Table 2.

From the test results shown in Table 2, in Example 1 containing calcium chloride, which is an alkaline earth metal chloride, and in Example 2 containing magnesium chloride, which is also an alkaline earth metal chloride, decomposition other than the lactone form It was clarified that the production of products was also significantly suppressed.

From the above test results, it was revealed that alkaline earth metal chloride has an excellent stabilizing action particularly on pitavastatin or a salt thereof.

[Example 3]
20 g of water and 20 g of absolute ethanol were mixed, 3 g of macrogol and 7.5 g of trehalose were dissolved, and 3 g of titanium oxide and 0.3 g of iron sesquioxide were dispersed. In this solution, 18 g of hypromellose was dissolved to obtain a drug-free layer preparation solution.
Mix 20 g of water and 20 g of absolute ethanol to dissolve 3 g of macrogol, 6 g of calcium chloride dihydrate (calcium chloride hydrate described in the 15th revision Japanese Pharmacopoeia), 6 g of sucralose, and 0.9 g of l-menthol. 6 g of pitavastatin calcium and 3 g of magnesium oxide were dispersed. In this solution, 15 g of hydroxypropylcellulose was dissolved to obtain a drug-containing layer preparation solution.
A drug-free layer preparation solution was uniformly applied onto a PET (polyethylene terephthalate) film, and then dried with warm air to form a drug-free layer having a mass per area of 2.8 cm ² of 5.3 mg. After the drug-containing layer preparation solution is uniformly applied above the drug-free layer, it is dried with warm air to form a drug-containing layer having a mass of 6.65 mg per area of 2.8 cm ^2. Obtained.
Two intermediate products 1 are prepared, bonded and pressure-bonded so that the drug-containing layers face each other, and a drug-free layer, a drug-containing layer, and a drug-free layer are sequentially laminated between two PET films Product 2 was obtained.
The intermediate product 2 was cut into an area of 2.8 cm ² , the PET film was peeled off, and the film agent of Example 3 was obtained.

[Test Example 3] Disintegration test With respect to the film preparation of Example 3, 10 healthy adults measured the disintegration time in the oral cavity (the time until the film preparation was included in the mouth, left un chewed and completely disintegrated). The average value was calculated. The results are shown in Table 3 together with the composition of the film agent (component amount (mg) per film agent).

From the test results shown in Table 3, it was confirmed that the film agent of Example 3 had sufficient disintegration properties as an oral disintegrant.

[Production Example 1]
In a mixture of 597.6 parts by mass of D-mannitol and 201.6 parts by mass of crospovidone, 72 parts by mass of pitavastatin calcium, 86.4 parts by mass of hypromellose, 108 parts by mass of aminoalkyl methacrylate copolymer E, 72 parts by mass of sucralose, l-menthol 70% ethanol solution or dispersion containing 14.4 parts by weight, calcium chloride dihydrate (calcium chloride hydrate described in 15th revision Japanese Pharmacopoeia) 72 parts by weight, magnesium metasilicate aluminate 43.2 parts by weight The liquid is sprayed and granulated to obtain a granulated product.
A granulated product is sprayed with a 70% ethanol solution or dispersion liquid containing 72 parts by mass of hypromellose, 36 parts by mass of yellow ferric oxide and 266.4 parts by mass of titanium oxide to obtain coated granules.
456 parts by weight of the coated granule, 400 parts by weight of D-mannitol, 30 parts by weight of xylitol, 550 parts by weight of crystalline cellulose, 129 parts by weight of crospovidone, 25 parts by weight of anhydrous calcium hydrogen phosphate and 2 parts by weight of yogurt micron are further mixed. An orally disintegrating tablet having a diameter of 8 mm and a mass of 160 mg can be obtained by mixing 8 parts by mass of calcium phosphate and tableting with a rotary tableting machine.

[Production Examples 2 to 15]
By the same method as in Production Example 1, orally disintegrating tablets containing the ingredients and amounts (mg) shown in Tables 4 to 6 below can be obtained.

[Production Example 16]
480 parts by mass of water and 480 parts by mass of absolute ethanol are mixed, 30 parts by mass of macrogol, 120 parts by mass of aminoalkyl methacrylate copolymer E, 30 parts by mass of trehalose are dissolved, 30 parts by mass of titanium oxide, 3 parts by mass of yellow iron sesquioxide To distribute. In this solution, 240 parts by mass of hypromellose is dissolved to obtain a drug-free layer preparation solution.
600 parts by weight of water and 600 parts by weight of absolute ethanol are mixed, 30 parts by weight of macrogol, 30 parts by weight of sucralose, 15 parts by weight of l-menthol, calcium chloride dihydrate (calcium chloride described in the 15th revision Japanese Pharmacopoeia Hydrate) 60 parts by mass is dissolved, and 60 parts by mass of pitavastatin calcium and 6 parts by mass of magnesium oxide are dispersed. In this solution, 300 parts by mass of hydroxypropylcellulose is dissolved to obtain a drug-containing layer preparation solution.
A drug-free layer preparation solution is uniformly applied on a PET (polyethylene terephthalate) film, and then dried with warm air to form a drug-free layer having a mass per area of 2.8 cm ² of 7.55 mg. After the drug-containing layer preparation solution is uniformly applied above the drug-free layer, it is dried with warm air to form a drug-containing layer having a mass per area of 2.8 cm ² of 8.35 mg. obtain.
Two intermediate products 1 are prepared, bonded and pressure-bonded so that the drug-containing layers face each other, and a drug-free layer, a drug-containing layer, and a drug-free layer are sequentially laminated between two PET films Obtain product 2.
The intermediate product 2 can be cut into an area of 2.8 cm ² and the PET film can be peeled off to obtain an orally disintegrating film agent.

[Production Examples 17 to 30]
By the same method as in Production Example 16, an orally disintegrating film preparation containing the components and amounts (mg) shown in Tables 7 to 9 below in one sheet can be obtained.

[Production Examples 31 to 35]
By a conventional method, a tablet containing the components and the amount (mg) shown in Table 10 below in one tablet can be obtained.

According to the present invention, since the formation of a lactone form of a compound having a HMG-CoA reductase inhibitory activity represented by the above general formula (1) including statins or a salt thereof is suppressed, Can be provided in the pharmaceutical industry and the like.

Claims (11)

1. The following general formula (1)
   

   

   [Wherein, R represents an organic group, and X represents —CH ₂ —CH ₂ — or —CH═CH—. ]
   A pharmaceutical composition comprising a compound having a HMG-CoA reductase inhibitory activity represented by the formula: or a salt thereof, and an alkaline earth metal chloride.
2. The pharmaceutical composition according to claim 1, wherein the compound having HMG-CoA reductase inhibitory activity is at least one selected from the group consisting of pravastatin, fluvastatin, atorvastatin, pitavastatin and rosuvastatin.
3. The pharmaceutical composition according to claim 1, wherein the compound having HMG-CoA reductase inhibitory activity is pitavastatin.
4. The pharmaceutical composition according to claim 1, wherein the compound having HMG-CoA reductase inhibitory activity or a salt thereof is pitavastatin calcium.
5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the alkaline earth metal chloride is at least one selected from the group consisting of calcium chloride and magnesium chloride.
6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pH is 4 or more.
7. The pharmaceutical composition according to claim 6, wherein the pH is 7-11.
8. The content of the alkaline earth metal chloride is 0.005 to 60 parts by mass with respect to 1 part by mass of the compound having HMG-CoA reductase inhibitory activity or a salt thereof. The pharmaceutical composition according to 1.
9. The pharmaceutical composition according to any one of claims 1 to 8, which is a solid pharmaceutical composition.
10. The pharmaceutical composition according to claim 9, which is an orally disintegrating solid preparation.
11. The pharmaceutical composition according to claim 10, wherein the orally disintegrating solid preparation is an orally disintegrating tablet or an orally disintegrating film.