JP2020012009A - Medicine - Google Patents

Abstract

To provide a medicine which uses a solid preparation in which production of lactone forms of pitavastatin and salts thereof is suppressed.SOLUTION: The medicine comprises: a component (A) which is pitavastatin and salts thereof, of 4 mg per tablet in terms of pitavastatin calcium; and a component (B) which is one or more selected from the group consisting of carmellose and salts thereof, crospovidone and crystalline cellulose, and is stored in a hermetic package an orally disintegrating tablet with a water content of 2.9 mass% or less.SELECTED DRAWING: None

Description

  The present invention relates to a solid preparation in which the production of a lactone form of pitavastatin or a salt thereof is suppressed, and a pharmaceutical product using the solid preparation.

  Pitavastatin calcium (chemical name: (+)-monocalcium bis [(3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] -3, a kind of statins) Pitavastatin or a salt thereof such as 5-dihydroxy-6-eptenoate (II) has excellent HMG-CoA reductase inhibitory activity and is useful as an active ingredient for a therapeutic agent for hyperlipidemia, hypercholesterolemia and the like. It is known that there is (Patent Document 1).

  It is known that the dihydroxycarboxylic acid skeleton, which is a common skeleton of the above statins, is cyclized in the molecule by a dehydration condensation reaction to produce a lactone having low HMG-CoA reductase inhibitory activity. The formation of lactones in pharmaceutical preparations can cause reduced efficacy of the pharmaceuticals and heterogeneity of efficacy between pharmaceuticals. For this reason, various attempts have been made to improve the stability of statins including pitavastatin in pharmaceutical preparations, but many of them have been studied on the pH environment of statins, and specifically, in low pH environments. In consideration of the instability of the dihydroxycarboxylic acid skeleton, a basic substance such as calcium carbonate is blended to make the pH environment of statins basic (Patent Documents 2 and 3).

  In addition, Patent Document 4 discloses that when crystalline form A of pitavastatin calcium is dried, the crystallinity is reduced due to amorphousness at a water content of 4% or less, and the amorphous pitavastatin calcium has extremely high stability during storage. It is described that it gets worse. Further, Non-Patent Document 1 states that in the section of "Stability of active ingredient under various conditions", under low humidity conditions (60 ° C., 30% RH), an increase in related substances was observed along with a decrease in water content, Has been described.

JP-A-1-279866 Patent No. 2774037 Patent No. 3276962 JP 2007-516952 A International Publication No. WO2007 / 52592 pamphlet

"Livalo Tablets 1mg, Livalo Tablets 2mg, Livalo Tablets 4mg" Interview Form, June 2012

  However, Patent Literature 4 and Non-Patent Literature 1 do not disclose any instability due to moisture absorption (increase in moisture) in a solid preparation containing pitavastatin calcium and a specific disintegrant having high hygroscopicity. .

  Incidentally, carmellose such as carmellose calcium and croscarmellose sodium or a pharmaceutical additive such as a salt thereof, crospovidone and crystalline cellulose all have extremely high hygroscopicity. Therefore, when it is incorporated into a solid preparation, it exhibits the effect of swelling due to moisture absorption and water conduction inside the preparation by capillary action, and imparts good disintegration properties to the solid preparation, so that it is used as a disintegrant or the like.

The improvement of the disintegration property of the solid preparation has an advantage that the release of the active ingredient and the efficacy of the drug are more reliably achieved, and the quality of the solid preparation is improved. In addition, in the oral disintegration type solid preparation, which is a kind of solid preparation characterized by good disintegration, it can be taken without water, so it can be taken anywhere and at any time, which leads to an improvement in compliance with taking. There is also.
In view of such advantages, the present inventor has obtained a disintegrant such as carmellose or a salt thereof, crospovidone, crystalline cellulose and pitavastatin or a salt thereof in order to obtain a solid preparation having good disintegration containing pitavastatin or a salt thereof. Was found to produce a large amount of lactone over time.
Accordingly, the present invention provides a solid preparation containing pitavastatin or a salt thereof and one or more selected from the group consisting of carmellose and a salt thereof, crospovidone and microcrystalline cellulose, in which lactone production is suppressed, and the solid preparation It is an object of the present invention to provide a pharmaceutical using the same.

  In order to solve the above problems, the present inventor first described the cause and mechanism of lactone formation during mixing of pitavastatin or a salt thereof and one or more selected from the group consisting of carmellose and its salts, crospovidone and crystalline cellulose. After intensive studies, it was surprisingly found that there is a correlation between the water content in the mixture and the amount of the lactone form, and that as the water content increases, the amount of the lactone form, which is a dehydrated condensate, increases. Was. On the other hand, in the section of “Stability of the preparation under various conditions” described in Patent Document 5, the “Rivalo tablet” currently on sale is subjected to a severe test (humidity: 25 ° C., 60% RH or 85% RH). It is only described as "within specification" or "reduced dissolution" for stability. From these facts, the cause and mechanism of the lactone body formation due to the coexistence with the above-mentioned disintegrant may be attributed to the high hygroscopicity of the specific disintegrant which is not blended with the currently marketed `` Rivalo tablet '' Was suggested. Then, it was found that by setting the water content of the solid preparation to a certain value or less, the production of a lactone derivative derived from pitavastatin or a salt thereof could be suppressed, and the present invention was completed.

That is, the present invention provides the following components (A) and (B):
(A) pitavastatin or a salt thereof;
(B) one or more selected from the group consisting of carmellose and salts thereof, crospovidone and crystalline cellulose;
And a pharmaceutical product comprising a solid preparation having a water content of 2.9% by mass or less in an airtight package.

The present invention also provides the following components (A) and (B):
(A) pitavastatin or a salt thereof;
(B) one or more selected from the group consisting of carmellose and salts thereof, crospovidone and crystalline cellulose;
And a solid preparation having a water content of 2.9% by mass or less.

The solid preparation of the present invention suppresses generation of a lactone form derived from pitavastatin or a salt thereof and has excellent disintegration properties. Therefore, the solid preparation of the present invention is excellent not only in that the stability of the active ingredient is good, but also in that the release of the active ingredient and the pharmacological effect are assured, so that the solid preparation has excellent quality.
In addition, since the pharmaceutical preparation of the present invention is packaged in a package in which the solid preparation of the present invention can be hermetically stored to prevent water from entering the package, the water content of the solid preparation inside the package for a long period of time is prevented. Is maintained stably, and the production of a lactone form derived from pitavastatin or a salt thereof in a solid preparation is suppressed for a long period of time, which is useful.

In the present invention, “pitavastatin or a salt thereof (hereinafter, also referred to as“ component (A) ”)” includes pitavastatin itself and pharmaceutically acceptable salts of pitavastatin (eg, alkali metal salts such as sodium salt and potassium salt). Alkaline earth metal salts such as calcium salts and magnesium salts; organic amine salts such as phenethylamine salts; ammonium salts and the like); and solvates of pitavastatin or a pharmaceutically acceptable salt thereof with water, alcohol, and the like. included. In the present invention, one or more of these 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 methods described in JP-A-1-279866 and US Pat. No. 5,856,336.

In the present invention, the content of the component (A) in the solid preparation is not particularly limited, and can be determined by appropriately considering the sex, age, symptoms, etc. of the user. A solid preparation containing 0.1 to 16 mg, more preferably 0.5 to 12 mg, more preferably 1 to 8 mg, particularly preferably 1 to 4 mg of component (A) in terms of pitavastatin calcium is preferred.
In the present invention, a solid preparation containing 0.1 to 10% by mass in terms of pitavastatin calcium is preferable, and a solid preparation containing 0.2 to 5% by mass, based on the total mass of the solid preparation, is more preferable. , 0.5 to 4% by mass.

  In the present invention, “one or more selected from the group consisting of carmellose and salts thereof, crospovidone and crystalline cellulose (hereinafter, also referred to as“ component (B) ”)” includes carmellose and pharmaceutically acceptable salts of carmellose , Carmellose and cross-linked polymers of pharmaceutically acceptable salts thereof, crospovidone and microcrystalline cellulose. In the present invention, one or more of these can be used in combination.

  In the present invention, the content of the component (B) in the solid preparation is not particularly limited, and can be determined by appropriately examining the disintegration of the solid preparation. In the present invention, a solid preparation containing the component (B) in a total amount of 0.1 to 85% by mass relative to the total mass of the solid preparation is preferable, a solid preparation containing 0.5 to 70% by mass is more preferable, Solid preparations containing 60% by weight are particularly preferred. Further, a solid preparation containing 0.1 to 90 parts by mass in total is preferable, and a solid preparation containing 0.5 to 75 parts by mass with respect to 1 part by mass of component (A) in which component (B) is converted into pitavastatin calcium. Is more preferable, and a solid preparation containing 1 to 65 parts by mass is particularly preferable.

In the present invention, “carmellose and its salts” include carmellose itself and pharmaceutically acceptable salts of carmellose (eg, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and the like) ), And a crosslinked polymer of carmellose or a pharmaceutically acceptable salt thereof (croscarmellose). Specific examples include carmellose, carmellose potassium, carmellose calcium, carmellose sodium, croscarmellose sodium and the like. In the present invention, these can be used alone or in combination of two or more.
In the present invention, carmellose and salts thereof may be any of different molecular weights, different kinds of salts, etc., but carmellose calcium, carmellose sodium and croscarmellose sodium are preferred, and carmellose calcium and carmellose sodium Is particularly preferred.

  In the present invention, commercial products may be used as carmellose and salts thereof, and specifically, for example, NS-300, ECG-505 (all manufactured by Gotoku Pharmaceutical Co., Ltd.), Sunrose (manufactured by Nippon Paper Chemical Co., Ltd.), Cellogen (manufactured by San-Ei Gen FFI), Cellogen Series (manufactured by Daiichi Kogyo Seiyaku), Ac-Di-Sol (manufactured by Asahi Kasei Chemicals), Kikkolate ND-2HS (manufactured by Nichirin Chemical Industries), etc. No.

  In the present invention, the content of carmellose and its salt in the solid preparation is not particularly limited, and can be determined by appropriately examining the disintegration of the solid preparation. In the present invention, a solid preparation containing carmellose and its salt in a total amount of 0.01 to 25% by mass relative to the total mass of the solid preparation is preferable, a solid preparation containing 0.1 to 20% by mass is more preferable, and 0.1 to 20% by mass is preferable. Solid preparations containing 5 to 15% by weight are particularly preferred. Further, for 1 part by mass of the component (A) in terms of pitavastatin calcium, a solid preparation containing 0.01 to 30 parts by mass of carmellose and its salt in total is preferable, and a solid preparation containing 0.1 to 25 parts by mass. Is more preferable, and a solid preparation containing 0.5 to 20 parts by mass is particularly preferable.

The crospovidone used in the present invention is not particularly limited, and any crospovidone having a different molecular weight or the like may be used, and these may be used alone or in combination of two or more.
In the present invention, commercially available products may be used as crospovidone, and specifically, for example, crospovidone (manufactured by Gokyo Sangyo Co., Ltd.), Kollidon CL-F, Kollidon CL-M, Kollidon CL-SF (above, BASF ), Polyplasdone XL, polyplasdone XL-10, polyplasdone INF-10 (all manufactured by ISP Japan).

  In the present invention, the content of crospovidone in the solid preparation is not particularly limited, and can be determined by appropriately examining the disintegration of the solid preparation. In the present invention, a solid preparation containing 0.1 to 25% by mass of crospovidone based on the total mass of the solid preparation is preferable, a solid preparation containing 0.5 to 20% by mass is more preferable, and 1 to 15% by mass is contained. Particularly preferred are solid preparations. Further, for 1 part by mass of the component (A) in terms of pitavastatin calcium, a solid preparation containing 0.1 to 30 parts by mass of crospovidone is preferable, and a solid preparation containing 0.5 to 25 parts by mass is more preferable. A solid preparation containing 1 to 20 parts by mass is particularly preferred.

The crystalline cellulose used in the present invention is not particularly limited, and any crystalline cellulose having different molecular weight, particle size, etc. may be used, and these may be used alone or in combination of two or more.
In the present invention, commercially available crystalline cellulose may be used, and specific examples thereof include CEOLUS UF grade, CEOLUS KG grade, CEOLUS PH grade (all manufactured by Asahi Kasei Chemicals Corporation) and the like.

  In the present invention, the content of crystalline cellulose in the solid preparation is not particularly limited, and can be determined by appropriately examining the disintegration of the solid preparation. In the present invention, a solid preparation containing 0.1 to 80% by mass of crystalline cellulose based on the total mass of the solid preparation is preferable, a solid preparation containing 0.5 to 65% by mass is more preferable, and 1 to 50% by mass is contained. Particularly preferred are solid preparations. Further, for 1 part by mass of the component (A) in terms of pitavastatin calcium, a solid preparation containing 0.1 to 85 parts by mass of crystalline cellulose is preferable, and a solid preparation containing 0.5 to 70 parts by mass is more preferable. Solid preparations containing from 1 to 55 parts by weight are particularly preferred.

In the solid preparation of the present invention, the water content needs to be 2.9% by mass or less based on the total mass of the solid preparation in order to suppress the production of the lactone, but from the viewpoint of suppressing the production of the lactone, 2.1% by mass. It is more preferably at most 1.9 mass%.
In addition, as described in Test Example 3 below, when the water content of the solid preparation of the present invention is 1.5% by mass or more, the formation of the 5-keto form, which is a separate product from the lactone form, is suppressed. it can. As described in Patent Document 5, the 5-keto form is known to be a photodegradation product generated by exposing pitavastatin or a salt thereof to light, but there is no report on the relationship with water.
Therefore, the solid preparation of the present invention having a water content of 1.5 to 2.9% by mass (preferably 1.5 to 2.1% by mass, particularly preferably 1.5 to 1.9% by mass) Since the formation of the lactone form is suppressed and the formation of the 5-keto form is also suppressed, it has an excellent effect that the stability of pitavastatin in the solid preparation is particularly good.

Further, from another viewpoint, the present invention provides a solid preparation containing pitavastatin or a salt thereof and having a water content of 1.5% by mass or more, preferably the following components (A) and (B):
(A) pitavastatin or a salt thereof;
(B) one or more selected from the group consisting of carmellose and salts thereof, crospovidone and crystalline cellulose;
And a solid preparation having a water content of 1.5% by mass or more.

  The water content of the solid preparation of the present invention is measured by the Karl Fischer method. Specifically, it may be carried out by appropriately selecting a volume titration method or a coulometric titration method in accordance with the moisture measurement method (Karl Fischer method) of the 16th revised Japanese Pharmacopoeia.

  One feature of the present invention is to suppress the generation of a lactone derivative derived from component (A) by adjusting the water content of a solid preparation containing component (A) and component (B). Here, means for adjusting the water content of the solid preparation include a humidifying means and a drying means, and the water content according to the present invention may be adjusted by appropriately combining these means.

Examples of the humidifying unit include a unit using a water-containing solvent as a kneading liquid in a wet granulation operation.
Examples of the drying unit include a unit using a drying device and a unit using a desiccant. Here, as the drying device, those usually used in the field of pharmaceuticals and foods can be used, and specifically, for example, a box-type dryer, a fluidized-bed dryer, a spray dryer, a freeze dryer, A vacuum dryer, a high-frequency dryer, and the like can be given. As the desiccant, those usually used in the field of pharmaceuticals and foods can be used. Specifically, for example, silica gel, silica alumina gel (for example, allophane), natural zeolite, synthetic zeolite (for example, Molecular sieve), quicklime (calcium oxide), bentonite clay (eg, montmorillonite), calcium chloride, magnesium chloride, and magnesium oxide. One or more of these may be mixed with activated carbon. In the present invention, a method using a drying device is preferable because of easy adjustment of the water content of the solid preparation.
These humidifying means and drying means may be performed during the manufacture of the solid preparation or may be performed after the manufacture of the solid preparation.However, in order to accurately adjust the water content in the solid preparation, at least the solid preparation is used. Is preferably carried out after the production of

  In the present invention, depending on the specific form (dosage form), the solid preparation may contain, in addition to the above components, additives commonly used in the art. Such additives include, for example, excipients, disintegrants (excluding component (B)), binders, lubricants, coloring agents, plasticizers, film-forming agents, poorly water-soluble polymer substances, antioxidants , A flavoring agent, a sweetener, a pH adjuster, a surfactant, a fragrance, etc., and these can be used alone or in an appropriate combination of two or more. The amount of each additive used can be determined as appropriate.

Examples of the excipient 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 silicic acid. Inorganic excipients such as acids, 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, sucrose, fructose, maltose, lactose, sucrose, glucose, pullulan, polyoxyethylene cured castor Oil, maltitol, reduced maltose water candy, powder Original maltose starch syrup, erythritol, xylitol, sorbitol, mannitol, lactitol, trehalose, reduced palatinose, maltose, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylamino acetate, organic excipients such as calcium citrate and the like. These can be used alone or in combination of two or more.
Disintegrators include, for example, starch, sucrose fatty acid ester, gelatin, sodium bicarbonate, dextrin, dehydroacetic acid and its salts, polyoxyethylene hydrogenated castor oil 60, and the like. These can be used alone or in combination of two or more.

Examples of the binder include methylcellulose, hydroxypropylcellulose, hypromellose, starch (wheat starch, rice starch, corn starch, partially pregelatinized starch, etc.), dextrin, pullulan, gum arabic, agar, gelatin, tragacanth, sodium alginate, polyvinyl Examples thereof include alcohol, aminoalkyl methacrylate copolymer E, and polyvinyl acetal diethylaminoacetate. These can be used alone or in combination of two or more.
Examples of the lubricant include calcium stearate, magnesium stearate, sodium stearyl fumarate, and sucrose fatty acid ester. These can be used alone or in combination of two or more.

Examples of the coloring agent include yellow iron sesquioxide, brown iron oxide, caramel, black iron oxide, titanium oxide, iron sesquioxide, tar dye, aluminum lake dye, sodium copper chlorophyllin, and the like. These can be used alone or in combination of two or more.
Examples of the plasticizer include glycerin, sesame oil, sorbitol, castor oil, propylene glycol, polyoxyethylene polyoxypropylene glycol, polysorbate 80 (polyoxyethylene (20) sorbitan oleate), polyethylene glycol [eg, Macrogol 400 (The degree of polymerization n of the oxyethylene unit is 7 to 9; hereinafter, “n” indicates the degree of polymerization), Macrogol 600 (n is 11 to 13), Macrogol 1500 (n is 5 to 6 and n is 28 And Macrogol 4000 (n is 59 to 84), Macrogol 6000 (n is 165 to 210)] and the like. These can be used alone or in combination of two or more.

Examples of the film forming agent include alkyl cellulose such as methyl cellulose and ethyl cellulose; alginic acid such as sodium alginate or a salt thereof; carrageenan; xanthan gum; Hydroxyalkyl cellulose phthalate such as hydroxypropylmethylcellulose phthalate; pullulan; polyvinyl acetate; polyvinyl acetate phthalate; polyvinyl alcohol and the like. These can be used alone or in combination of two or more.

Examples of the poorly water-soluble polymer substance include a carboxyvinyl polymer and an aminoalkyl methacrylate copolymer. These can be used alone or in combination of two or more.
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. These can be used alone or in combination of two or more.

  Examples of the flavoring agent include terpenes such as limonene, pinene, camphene, cymen, cineol, citronellol, geraniol, nerol, linalool, menthol, terpineol, rosinol, borneol, isoborneol, menthol, camphor, eugenol, cinzeilanol and the like; Contains terpenes such as oil, orange oil, peppermint oil, camphor white oil, eucalyptus oil, turpentine oil, lemon oil, ginger oil, clove oil, cauliflower oil, lavender oil, fennel oil, chamomile oil, perilla oil, spearmint oil, etc. Essential oils (hereinafter, terpenes and terpene-containing essential oils are collectively referred to as "terpenes"); and acidulants such as ascorbic acid, tartaric acid, citric acid, malic acid, and salts thereof. These can be used alone or in combination of two or more. Among them, terpenes are preferred, menthol is more preferred, and l-menthol is particularly preferred.

  Examples of the sweetener include aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, saccharin sodium, and the like, and one or more of these can be used in combination. Among them, sucralose is preferred.

  In the present invention, the pH of the solid preparation is not particularly limited, but is 4 or more, preferably 4 to 13, more preferably 5 to 12, still more preferably 6 to 11, and particularly preferably 7 to 11. In the present specification, the pH of the solid preparation refers to the pH of a liquid obtained by dissolving or dispersing one dosage unit of solid preparation in 4 mL of purified water according to the pH measurement method described in the 16th revised Japanese Pharmacopoeia. Means the value to be measured.

In the present invention, the solid preparation can be made into various dosage forms according to a known method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations and the like. The dosage form is not particularly limited, and the dosage forms described in the 16th Revised Japanese Pharmacopoeia General Rules for Preparations, specifically, for example, tablets (orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.) ), Solid preparations for oral administration such as capsules, pills, granules, fine granules and powders, and tablets for oral cavity (including lozenges, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.) Suppositories, vaginal tablets, vaginal suppositories and the like, but solid preparations for parenteral administration are preferred. In addition, these solid preparations may be coated with a film, sugar coating or the like as necessary.
In the present invention, as the dosage form of the solid preparation, tablets, capsules, pills, granules, fine granules, and powders are preferable, tablets are more preferable, and orally disintegrating tablets are particularly preferable. When the dosage form of the solid preparation is an orally disintegrating tablet, it has an excellent effect that the tablet is easily disintegrated in the oral cavity, thereby facilitating ingestion and eventually improving compliance.
In the present invention, the disintegration time of the orally disintegrating tablet in the oral cavity (the time until the solid preparation is completely disintegrated in the saliva in the oral cavity of a healthy person) is not particularly limited, and the dosage form of the solid preparation is not limited. , For example, within 90 seconds, preferably within 60 seconds, particularly preferably within 30 seconds.

In the present invention, the solid preparation can be produced by a known method described in the 16th revised Japanese 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, component (A), component (B), and additives as desired Direct compression molding using such as: component (A), component (B), and additives, if desired, are mixed, and compression-molded into a plate-like compression molding or a slug tablet, and then pulverized, and then added if desired. A method in which a mixture in the dry state is mixed by mixing the components and the like, and the mixture in the dry state is granulated by a suitable method after mixing the component (A), the component (B), and the additives as required. It can be manufactured by a method such as compression molding.

  Further, the OD tablet of the present invention can be produced by a method in which a suspension or solution containing the component (A) and the component (B) is filled in a mold such as a blister pocket, freeze-dried, and dried and solidified. The suspensions and solutions may further contain gelatin, dextran, alginic acid or alginic acid salts, sugar alcohols (such as erythritol, xylitol, sorbitol, and mannitol), and glycine.

  Further, the OD tablet of the present invention is obtained by wet molding a mixture containing the component (A), the component (B), and at least one selected from saccharides and sugar alcohols with water or an aqueous alcohol solution and molding the mixture at low pressure. It can be manufactured by so-called wet tableting.

  Further, the OD tablet of the present invention can be used for molding low-formability saccharides such as lactose hydrate, mannitol, glucose hydrate, sucrose and xylitol, and maltose, maltitol, sorbitol, and oligosaccharides such as lactose and fructose. A granulated product can be produced by using a sugar having a high property, and then the granulated product can be tableted. In the method, the component (A) or the component (B) may be contained in the granulated product, or may be mixed after the granulated product is produced. Is preferred.

  Furthermore, the OD tablet of the present invention is characterized in that xylitol, trehalose, maltose, sorbitol, erythritol, glucose, maltitol, mannitol, sucrose, lactose hydrate, which are lower than the melting point and the decomposition point of the component (A) and other additives. And the like, using a relatively low-melting-point saccharide, etc., to produce a melt-solidified product of the component (A), the component (B) and, if desired, other additives, and then tablet the melt-solidified product. . In the method, the component (A) and the component (B) may be contained in the melt-solidified product, or may be mixed after the melt-solidified product is produced. A stiff one is preferred.

The present invention also provides a pharmaceutical product in which the above solid preparation is contained in an airtight package. By containing the solid preparation in an airtight package, the intrusion of moisture from outside the package is prevented, and as a result, the moisture content of the solid preparation present inside the package is stably maintained over a long period of time. The production of the lactone derivative derived from the component (A) in the preparation is suppressed for a long period of time.
The “pharmaceutical product” of the present invention may have a water content of 2.9% by mass or less in the solid preparation inside the airtight package. That is, it is sufficient that the water content of the solid preparation is 2.9% by mass or less immediately after taking out the solid preparation from the airtight package. For example, the water content of the solid preparation is 2.9% by mass before being housed in the airtight package. % Or more, if the moisture content of the solid preparation is 2.9% by mass or less inside the hermetic package by means such as enclosing a desiccant (that is, the solid preparation is taken out from the hermetic package). Immediately after (when the water content is 2.9% by mass or less), it is included in the "medicine" of the present invention.

  In the present invention, the "airtight package" means a package capable of suppressing substantial invasion of moisture from outside the package in a state of normal handling, transportation or storage, etc. This is a concept that includes the “airtight container” and the “sealed container” defined in the above. As the package, any one of a fixed form and an irregular form can be used, and specific examples include a bottle package, an SP (Strip Package) package, a PTP (Press Through Package) package, a pillow package, a stick package, and the like. . In the present invention, a combination of a plurality of these may be further used. Specifically, for example, a form in which a solid preparation is first packaged in a PTP package, and this is further packaged in a pillow package is exemplified.

The packaging material (material) of the airtight package is not particularly limited as long as it can exhibit moisture-proof properties. Materials used for the purpose of moisture-proofing moisture-sensitive contents in the field of pharmaceuticals and foods may be appropriately used. Can be used.
Examples of the material of the bottle body used for the bottle packaging include glass, plastic (polyester, polyethylene (including low density (LDPE), high density (HDPE)), polycarbonate, polystyrene, polypropylene, etc.), metal (aluminum), and the like. No. Examples of the material of the stopper and the lid include plastic (polyester, polyethylene, polycarbonate, polystyrene, polypropylene, and the like), metal (aluminum), and the like. When packaging in a bottle, for example, the solid preparation of the present invention may be stored in a suitable amount in a commercially available bottle, and then sealed with a suitable stopper or lid. The bottle may be appropriately selected in size according to the number of solid preparations to be stored, and the capacity of the bottle is, for example, about 10 to 500 mL, preferably 14 to 400 mL, and more preferably 24 to 350 mL. More preferred. As a material for the bottle packaging, polyethylene and polypropylene are preferable, low density polyethylene (LDPE) and high density polyethylene (HDPE) are more preferable, and high density polyethylene (HDPE) is particularly preferable.

  Examples of the packaging material used for SP packaging, PTP packaging, pillow packaging, stick packaging, and the like include biaxially oriented polypropylene (OPP), biaxially oriented polyester (PET), glucose-modified PET (PET-G), and biaxially oriented PET (PET-G). Stretched nylon (ONy, PA), cellophane, paper, low-density polyethylene (LDPE), linear low-density polyethylene (L-LDPE), ethylene-vinyl acetate copolymer (EVA), unstretched polypropylene (CPP, IPP) , Ionomer resin (IO), ethylene-methacrylic acid copolymer (EMAA), polyacrylonitrile (PAN), biaxially stretched polyvinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer resin (EVOH), polyvinyl chloride (PVC) ), Cyclic polyolefin (COC), undrawn nylon (CNy) Resins such as polycarbonate (PC), polystyrene (PS), and hard vinyl chloride (VSC); and metal foils such as aluminum foil (AL). A multilayer structure obtained by appropriately combining two or more of these may be used. Good. As such a multilayer structure, for example, a laminate of PVC and PVDC (PVC / PVDC; hereinafter abbreviated similarly), PVC / PVDC / PE / PVC, PVC / PVDC / PE / PVDC / PVC, CPP / COC / CPP, PVC / AL, CPP / AL, CPP / CPP / CPP, and the like. Examples of a method for forming such a multilayer structure include known lamination methods such as extrusion lamination, dry lamination, coextrusion lamination, thermal lamination, wet lamination, non-solvent lamination, and heat lamination. As a packaging material used for SP packaging, PTP packaging, pillow packaging, stick packaging, and the like, polyvinyl chloride and aluminum foil are preferable.

As the form of the PTP packaging, the solid preparation of the present invention is stored in a desired number of pockets formed in a resin sheet or the like by a known method, one by one or one dose unit, and then a metal foil such as an aluminum foil is used as a constituent material. Covering using a sheet as a lid material is mentioned. Note that a so-called double-sided aluminum PTP package using a sheet made of aluminum foil may also be used as the sheet forming the pocket. In the present invention, it is preferable that the PTP package is further packaged in a pillow package (for example, an aluminum pillow package) from the viewpoint of enhancing the moisture resistance.
Examples of the form of the SP packaging, the pillow packaging, and the stick packaging include a method in which a solid preparation is packaged by a known method using a resin sheet or a sheet using aluminum foil as a constituent material, one by one or one dose unit. In the present invention, it is preferable to use a sheet using an aluminum foil as a constituent material from the viewpoint of improving the moisture resistance.

  The occupancy rate (volume ratio) of the solid preparation inside the package in the pharmaceutical product of the present invention is usually 25 to 90%, preferably 28 to 75%, and more preferably 30 to 75% when the package is a bottle package. 50% is more preferred. Moreover, when a package is SP packaging, PTP packaging, pillow packaging, and stick packaging, it is usually 30 to 98%, preferably 40 to 95%, more preferably 45 to 93%, and particularly preferably 50 to 90%. . In this case, the occupancy means the occupancy of the solid preparation with respect to the volume inside the package, and the padding, inner plug, etc. for preventing breakage of the solid preparation stored inside the package are as follows: It is not taken into account when calculating the space occupancy.

  In the present invention, a commercially available package may be used as it is as an airtight package, or a commercially available packaging material may be processed and used. Examples of such commercially available products include, for example, Z-series (both manufactured by Hanshin Kasei Kogyo Co., Ltd.) and the like as a bottle package. Further, as packaging materials for SP packaging, PTP packaging, pillow packaging and stick packaging, Sumilite VSS, Sumilite VSL, Sumilite NS, Sumilite FCL (above, manufactured by Sumitomo Bakelite), TAS series (manufactured by Taisei Kako), PTP Vinyl foil for PTP, super foil for PTP (above, manufactured by Mitsubishi Plastics Co., Ltd.), nipper aluminum foil (manufactured by Nippon Foil Co., Ltd.), aluminum foil silver blank (manufactured by Daiwa Chemical Industry Co., Ltd.), and the like.

  In the present invention, the method for accommodating the solid preparation in the airtight package is not particularly limited, and can be achieved by disposing the solid preparation in the package by appropriate means such as charging the solid preparation into the package. . In this case, a means for introducing a desiccant (for example, a columnar (tablet-shaped) or a sheet-shaped) together with the solid preparation into the package may be used, but the water content of the solid preparation decreases with time. In order to avoid excessive drying, it is preferable that the moisture content of the solid preparation is adjusted to 2.9% by mass or less in advance, and that no desiccant is added.

  Since the solid preparation of the present invention contains pitavastatin having HMG-CoA reductase inhibitory activity or a salt thereof as a component thereof, for example, a therapeutic agent for hyperlipidemia, a therapeutic agent for hypercholesterolemia, familial hypercholesterol It can be used as a therapeutic agent for bloodemia and the like. The administration route of the pharmaceutical composition includes oral and parenteral, and oral administration is preferable. Further, the pharmaceutical composition can be taken about 1 to 4 times a day before a meal, between meals, after a meal, before going to bed, and the like.

With respect to the above embodiments, the present invention discloses the following medicines and solid preparations.
[1-1] The following components (A) and (B):
(A) pitavastatin or a salt thereof;
(B) one or more selected from the group consisting of carmellose and salts thereof, crospovidone and crystalline cellulose;
And containing a solid preparation having a water content of 2.9% by mass or less in an airtight package.
[1-2] The drug according to the above [1-1], wherein the solid preparation preferably has a water content of 2.1% by mass or less, more preferably 1.9% by mass or less.
[1-3] The water content of the solid preparation is preferably 1.5 to 2.9% by mass, more preferably 1.5 to 2.1% by mass, and still more preferably 1.5 to 1.9% by mass. A drug according to the above [1-1].
[1-4] The content of (A) pitavastatin or a salt thereof in the solid preparation is preferably 0.1 to 16 mg, more preferably 0.5 to 12 mg, further preferably 0.5 to 12 mg, in terms of pitavastatin calcium, per administration unit. The drug according to any one of the above [1-1] to [1-3], containing 1 to 8 mg, more preferably 1 to 4 mg.
[1-5] The content of (A) pitavastatin or a salt thereof in the solid preparation is preferably 0.1 to 10% by mass, more preferably 0.2 to 10% by mass, as pitavastatin calcium, based on the total mass of the solid preparation. The drug according to any one of the above [1-1] to [1-3], wherein the amount is from 5 to 5% by mass, more preferably from 0.5 to 4% by mass.
[1-6] The total content of at least one selected from the group consisting of (B) carmellose and its salt, crospovidone and crystalline cellulose in the solid preparation is preferably 0.1 to the total mass of the solid preparation. The drug according to any one of the above [1-1] to [1-5], wherein the amount is from 85 to 85% by mass, more preferably from 0.5 to 70% by mass, and still more preferably from 1 to 60% by mass.
[1-7] The total content of one or more selected from the group consisting of (B) carmellose and its salt, crospovidone and crystalline cellulose in the solid preparation is based on 1 part by mass of pitavastatin or a salt thereof in terms of pitavastatin calcium. And preferably from 0.1 to 90% by mass, more preferably from 0.5 to 75% by mass, and still more preferably from 1 to 65% by mass. Pharmaceuticals described in.
[1-8] The total content of (B) carmellose and its salt in the solid preparation is preferably 0.01 to 25% by mass, more preferably 0.1 to 20% by mass, based on the total mass of the solid preparation. The drug according to any one of the above [1-1] to [1-7], more preferably 0.5 to 15% by mass.
[1-9] The total content of (B) carmellose and its salt in the solid preparation is preferably 0.01 to 30% by mass, more preferably 0.01 to 30% by mass, based on 1 part by mass of pitavastatin calcium or pitavastatin calcium. The pharmaceutical according to any one of the above [1-1] to [1-7], which has a content of 0.1 to 25% by mass, more preferably 0.5 to 20% by mass.
[1-10] The content of crospovidone in the solid preparation is preferably from 0.1 to 25% by mass, more preferably from 0.5 to 20% by mass, and still more preferably from 1 to 25% by mass, based on the total mass of the solid preparation. The drug according to any one of the above [1-1] to [1-9], which is 15% by mass.
[1-11] The content of crospovidone in the solid preparation is preferably 0.1 to 30% by mass, more preferably 0.5 to 25% by mass with respect to 1 part by mass of pitavastatin or a salt thereof in terms of pitavastatin calcium. %, More preferably 1 to 20% by mass, the pharmaceutical product according to any one of the above [1-1] to [1-9].
[1-12] The content of crystalline cellulose in the solid preparation is preferably from 0.1 to 80% by mass, more preferably from 0.5 to 65% by mass, and still more preferably from 1 to 80% by mass, based on the total mass of the solid preparation. The drug according to any one of the above [1-1] to [1-11], which is 50% by mass.
[1-13] The content of crystalline cellulose in the solid preparation is preferably 0.1 to 85% by mass, more preferably 0.5 to 70% by mass, relative to 1 part by mass of pitavastatin calcium or pitavastatin calcium. %, More preferably 1 to 55% by mass, the pharmaceutical product according to any one of the above [1-1] to [1-11].
[1-14] The above-mentioned [1-14], wherein the pH of the solid preparation is preferably 4 or more, more preferably 4 to 13, still more preferably 5 to 12, still more preferably 6 to 11, and still more preferably 7 to 11. 1] The drug according to any one of [1-13].
[1-15] Any of the above [1-1] to [1-14], wherein the airtight package is at least one selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging and stick packaging. The pharmaceutical according to any one of the above.
[1-16] The medicament according to any one of the above [1-1] to [1-15], wherein the solid preparation is a tablet.

[2-1] The following components (A) and (B):
(A) pitavastatin or a salt thereof;
(B) one or more selected from the group consisting of carmellose and salts thereof, crospovidone and crystalline cellulose;
And a water content of 2.9% by mass or less.
[2-2] The solid preparation of the above-mentioned [2-1], wherein the water content is preferably 2.1% by mass or less, more preferably 1.9% by mass or less.
[2-3] The above wherein the water content is preferably 1.5 to 2.9% by mass, more preferably 1.5 to 2.1% by mass, and still more preferably 1.5 to 1.9% by mass. [2-1] The solid preparation according to the above.
[2-4] (A) The content of pitavastatin or a salt thereof is preferably 0.1 to 16 mg, more preferably 0.5 to 12 mg, and still more preferably 1 to 8 mg in terms of pitavastatin calcium per administration unit. The solid preparation according to any one of the above [2-1] to [2-3], further preferably containing 1 to 4 mg.
[2-5] (A) The content of pitavastatin or a salt thereof is preferably 0.1 to 10% by mass, more preferably 0.2 to 5% by mass, as pitavastatin calcium, based on the total mass of the solid preparation. The solid preparation according to any one of the above [2-1] to [2-3], more preferably 0.5 to 4% by mass.
[2-6] (B) The total content of at least one selected from the group consisting of carmellose and salts thereof, crospovidone and crystalline cellulose is preferably 0.1 to 85% by mass relative to the total mass of the solid preparation. The solid preparation according to any one of [2-1] to [2-5] above, more preferably 0.5 to 70% by mass, and still more preferably 1 to 60% by mass.
[2-7] (B) The total content of one or more selected from the group consisting of carmellose and salts thereof, crospovidone and microcrystalline cellulose is preferably 1 part by mass of pitavastatin or pitavastatin calcium in terms of calcium. The solid according to any one of the above [2-1] to [2-5], wherein the solid content is 0.1 to 90% by mass, more preferably 0.5 to 75% by mass, and still more preferably 1 to 65% by mass. Formulation.
[2-8] (B) The total content of carmellose and a salt thereof is preferably 0.01 to 25% by mass, more preferably 0.1 to 20% by mass, and still more preferably the total mass of the solid preparation. The solid preparation according to any one of the above [2-1] to [2-7], which is 0.5 to 15% by mass.
[2-9] (B) The total content of carmellose and a salt thereof is preferably 0.01 to 30% by mass, more preferably 0.1 to 30% by mass with respect to 1 part by mass of pitavastatin or a salt thereof in terms of pitavastatin calcium. The solid preparation according to any one of the above [2-1] to [2-7], wherein the solid preparation is 25% by mass, more preferably 0.5 to 20% by mass.
[2-10] The content of crospovidone is preferably 0.1 to 25% by mass, more preferably 0.5 to 20% by mass, and still more preferably 1 to 15% by mass based on the total mass of the solid preparation. The solid preparation according to any one of [2-1] to [2-9].
[2-11] The content of crospovidone is preferably 0.1 to 30% by mass, more preferably 0.5 to 25% by mass, more preferably 0.5 to 25% by mass, based on 1 part by mass of pitavastatin or a salt thereof in terms of pitavastatin calcium. Is the solid preparation according to any one of the above [2-1] to [2-9].
[2-12] The content of crystalline cellulose is preferably 0.1 to 80% by mass, more preferably 0.5 to 65% by mass, and still more preferably 1 to 50% by mass, based on the total mass of the solid preparation. The solid preparation according to any one of [2-1] to [2-11].
[2-13] The content of crystalline cellulose is preferably 0.1 to 85% by mass, more preferably 0.5 to 70% by mass, and still more preferably 1 part by mass of pitavastatin or a salt thereof in terms of pitavastatin calcium. Is 1 to 55% by mass, the solid preparation according to any one of the above [1-1] to [1-11].
[2-14] The above [1-1] to which the pH is preferably 4 or more, more preferably 4 to 13, still more preferably 5 to 12, still more preferably 6 to 11, and still more preferably 7 to 11. The solid preparation according to any one of [1-13].
[2-15] The solid preparation according to any one of the above [2-1] to [2-14], wherein the solid preparation is a tablet.

[3-1] The following components (A) and (B):
(A) pitavastatin or a salt thereof;
(B) one or more selected from the group consisting of carmellose and salts thereof, crospovidone and crystalline cellulose;
And a water content of 1.5% by mass or more.
[3-2] The above wherein the water content is preferably 1.5 to 2.9% by mass, more preferably 1.5 to 2.1% by mass, and still more preferably 1.5 to 1.9% by mass. [3-1] The solid preparation according to the above.

  Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

[Test Example 1] Confirmation of formation of lactone in coexistence with disintegrant having high hygroscopicity To confirm the formation of lactones derived from pitavastatin or a salt thereof in the presence of a disintegrant having high hygroscopicity, the following mixture was used Samples Nos. 1 to 4 were prepared and stored in polyethylene bags and aluminum bags at 70 ° C. for 3 days, and the lactone body formation rate in the mixture immediately after the mixture was prepared and after storage at 70 ° C. for 3 days was evaluated. The production rate of the lactone was measured for each mixture as an area percentage with respect to the total peak area derived from pitavastatin and its decomposition product using an HPLC apparatus (2695 manufactured by WATERS). For reference, the production rate of the lactone body when only pitavastatin calcium was separately stored at 70 ° C. for 3 days was similarly evaluated.

In addition, in order to confirm the presence or absence of a correlation between the formation of the lactone and the water content in the mixture, the water contents of the mixtures 1 to 4 after storage at 70 ° C. for 3 days were measured.
The water content was measured by a volume titration method in accordance with the water measurement method (Karl Fisher method) of the 16th revised Japanese Pharmacopoeia. Table 1 shows the results.

<Mixture 1>
Mixture 1 was prepared by mixing 1 part by weight of pitavastatin calcium and 10 parts by weight of crospovidone (manufactured by BASF, trade name: Kollidon CL-SF).
<Mixture 2>
Mixture 2 was prepared by mixing 1 part by weight of pitavastatin calcium and 10 parts by weight of carmellose calcium (trade name: ECG-505, manufactured by Gotoku Pharmaceutical Co., Ltd.).

<Mixture 3>
A mixture 3 was prepared by mixing 1 part by mass of pitavastatin calcium and 10 parts by mass of crystalline cellulose (trade name: CEOLUS UF-711, manufactured by Asahi Kasei Chemicals Corporation).
<Mixture 4>
A mixture 4 was prepared by mixing 1 part by mass of pitavastatin calcium and 10 parts by mass of carmellose sodium (manufactured by Daiichi Kogyo Seiyaku Co., Ltd., trade name: Serogen P-815C).

  From the test results shown in Table 1, it was clarified that there was a correlation between the water content in each mixture and the production rate of the lactone form, and that the amount of the lactone form increased as the water content increased. Since crospovidone, carmellose calcium, crystalline cellulose, and carmellose sodium all have high hygroscopicity, the production of the lactone is due to the high hygroscopicity of these disintegrants, and the coexisting disintegrant absorbs moisture. Therefore, it was presumed that pitavastatin was exposed to moisture, resulting in formation of a lactone body.

[Test Example 2] Lactone body formation suppression test The water content of the orally disintegrating tablet produced by the following method was adjusted to each of the water contents shown in Table 3 by vacuum drying. Below). Thereafter, each tablet (100 tablets) whose water content was adjusted was put into the pocket portion of a resin sheet (Sumitomo Bakelite Co., Ltd. product name: Sumilite VSS-1202-R) in which a pocket portion was formed in advance, and then an aluminum foil for PTP was used. (Made by Daiwa Chemical Industry Co., Ltd .: trade name: aluminum foil silver solid color) and PTP wrapped, and the obtained PTP package is further wrapped in an aluminum laminate bag (made by Production Japan Co., trade name: Ramizip AL series) in aluminum pillow wrapping did. The package thus obtained was stored under the conditions of 40 ° C. and 75% relative humidity for 2 months, and the lactone body formation rate in the tablet was evaluated immediately after tablet preparation, after storage for 1 month and after storage for 2 months. . The production rate of the lactone body was measured for each tablet as an area percentage with respect to the total peak area derived from pitavastatin and its decomposition product using an HPLC apparatus (LC-20 series manufactured by SHIMADZU).
Further, the water content in the tablets was measured by a volume titration method in accordance with the water measurement method (Karl Fischer method) of the 16th Revised Japanese Pharmacopoeia.

<Production of orally disintegrating tablets>
According to a conventional method, an orally disintegrating tablet containing the components and amounts (mg) shown in Table 2 below in one tablet was produced.
That is, in Table 2, granules were produced by a wet granulation method using components from pitavastatin calcium to titanium oxide.
The obtained granules and components below xylitol in Table 2 were mixed and tableted to produce an orally disintegrating tablet of 120 mg per tablet.

    Table 3 shows the results.

From the test results shown in Table 3, it was clarified that when the water content of the tablet was 2.9% by mass or less, the production of the lactone was significantly suppressed. In particular, when the tablet had a water content of 2.1% by mass or less, the production rate of the lactone body was kept low even after storage at 40 ° C. and 75% relative humidity for 2 months. In addition, as a result of preventing the invasion of moisture from the outside of the package by airtight packaging (PTP packaging, aluminum pillow packaging), the moisture content in each tablet after storage for 2 months at 40 ° C. and 75% relative humidity was reduced. No change was noted.
From the above test results, a solid preparation containing pitavastatin or a salt thereof, and one or more selected from the group consisting of carmellose and its salts, crospovidone and crystalline cellulose, and having a water content of 2.9% by mass or less It was clarified that the production of lactone was suppressed. In addition, it has also been clarified that the pharmaceutical preparation containing the solid preparation in an airtight package can stably maintain the water content, thereby suppressing lactone formation over a long period of time.

[Test Example 3] 5-Keto body formation suppression test In the same manner as in Test Example 2, the orally disintegrating tablets having various water contents were packaged by PTP and then aluminum pillows. , 75% relative humidity for 2 months, immediately after tablet preparation, and after 1 month storage and 2 months storage, the 5-keto body formation rate in the tablet was evaluated. The production rate of the 5-keto body was measured for each tablet as an area percentage with respect to the total peak area derived from pitavastatin and its decomposition product using an HPLC apparatus (LC-20 series manufactured by Shimadzu).
Table 4 shows the results.

From the test results shown in Table 4, it was found that when the water content of the tablet was 1.5% by mass or more, the formation of the 5-keto body was significantly suppressed. In addition, the movement of moisture inside and outside the package was prevented by airtight packaging (PTP packaging, aluminum pillow packaging). As a result, the moisture content in each tablet was not changed even after storage at 40 ° C. and 75% relative humidity for 2 months. No change was noted.
From the above test results, a solid preparation containing pitavastatin or a salt thereof, one or more selected from the group consisting of carmellose and its salts, crospovidone and crystalline cellulose, and having a water content of 1.5% by mass or more It was clarified that 5-keto body formation was suppressed in

[Production Example 1]
In the same manner as in Test Example 2, an orally disintegrating tablet containing the components and the amounts (mg) described in Formulation Example 2 in one tablet in Table 5 below was produced, and a water content of 2 was obtained using a box dryer. After drying to about 0.5% by mass, it is stored in a high-density polyethylene bottle (bottle) to obtain the pharmaceutical product of Production Example 1.

[Production Example 2]
In the same manner as in Test Example 2, an orally disintegrating tablet containing the components and the amounts (mg) described in Formulation Example 3 in one tablet in Table 5 below was produced, and a water content of 2 was obtained using a fluid bed dryer. After drying to about 4% by mass, it was put into the pocket portion of a resin sheet (Sumitomo Bakelite Co., Ltd .: trade name Sumilite VSS-1202) in which the pocket portion was formed in advance, and then aluminum foil for PTP (Daiwa Chemical Industry Co., Ltd .: product) Cover with PTP packaging with name aluminum foil silver plain). The obtained 3 sheets of the PTP package (containing 10 orally disintegrating tablets per sheet) are further subjected to aluminum pillow packaging to obtain the pharmaceutical product of Production Example 2.

[Production Example 3]
In the same manner as in Test Example 2, an orally disintegrating tablet containing the components and the amounts (mg) described in Formulation Example 4 in one tablet in Table 5 below was produced and stored for one day together with a desiccant (silica gel). After drying to a water content of about 2.3% by mass, the resin was put into a pocket portion of a resin sheet (product name: Sumilite VSS-1104, manufactured by Sumitomo Bakelite Co., Ltd.) in which a pocket portion was formed in advance, and then an aluminum foil for PTP ( Covered with Daiwa Chemical Industry Co., Ltd .: trade name: aluminum foil silver plain) and packaged with PTP. The obtained two sheets of the PTP package (each containing 12 orally disintegrating tablets per sheet) are packaged in an aluminum pillow to obtain the pharmaceutical product of Production Example 3.

[Production Example 4]
In the same manner as in Test Example 2, an orally disintegrating tablet containing the components and the amount (mg) described in Formulation Example 5 in one tablet in Table 5 below was produced, and a water content of 1 in a box-type drier. After being dried to about 0.8% by mass, it is put into a pocket portion of a resin sheet (Sumilite VSL-4501, manufactured by Sumitomo Bakelite Co., Ltd.) in which a pocket portion has been formed in advance, and then an aluminum foil for PTP (manufactured by Daiwa Chemical Industry Co., Ltd .: product) Cover with PTP packaging with name aluminum foil silver plain). The obtained 3 sheets of the PTP package (containing 10 orally disintegrating tablets per sheet) are further subjected to aluminum pillow packaging to obtain the pharmaceutical product of Production Example 4.

[Production Example 5]
In the same manner as in Test Example 2, an orally disintegrating tablet containing the components and the amounts (mg) described in Formulation Example 6 in one tablet in Table 5 below was produced, and a water content of 1. After being dried to about 6% by mass, it is stored in a glass bottle to obtain the pharmaceutical product of Production Example 5.

[Production Example 6]
In the same manner as in Test Example 2, an orally disintegrating tablet containing the components and the amounts (mg) described in Formulation Example 7 in one tablet in Table 5 below was produced, and was treated together with a desiccant (synthetic zeolite) for one day. After preservation, the water content is dried to about 2.2% by mass, and then SP-packaged with an aluminum foil for strip packaging (manufactured by Nissan Chemical Industries, Ltd.) to obtain the pharmaceutical product of Production Example 6.

[Production Example 7]
A tablet containing the components and the amounts (mg) described in Formulation Example 8 in Table 6 below in one tablet was produced by a conventional method, and dried to a water content of about 2.3% by mass in a fluidized bed drier. Into a pocket portion of a resin sheet (Sumitomo Bakelite Co., Ltd. product name: Sumilite VSS-1202) in which a pocket portion has been formed in advance, and then cover with a PTP aluminum foil (Daiwa Chemical Industry Co., Ltd. product name: aluminum foil silver solid color). And PTP package. The obtained 3 sheets of the PTP package (containing 10 tablets per sheet) are further packaged with an aluminum pillow to obtain the pharmaceutical product of Production Example 7.

[Production Example 8]
In a conventional manner, tablets containing the components and the amounts (mg) described in Formulation Example 9 in Table 6 below in one tablet are produced, and stored for one day together with a desiccant (silica gel) to obtain a water content of 1.8. After being dried to about mass%, it is put into a pocket portion of a resin sheet (Sumitomo Bakelite Co., Ltd .: trade name Sumilite VSS-1104) in which a pocket portion is formed in advance, and then an aluminum foil for PTP (Daiwa Chemical Industry Co., Ltd .: trade name Aluminum) (Foil silver plain) and cover with PTP. The pharmaceutical product of Production Example 8 is obtained by packing the obtained two sheets of the PTP package (each containing 12 tablets per sheet) with an aluminum pillow.

[Production Example 9]
A tablet containing the components and the amount (mg) described in Formulation Example 10 in Table 6 below in one tablet was produced by a conventional method, and dried to a water content of about 1.5% by mass in a box drier. Into a pocket of a resin sheet (Sumilite VSL-4501, manufactured by Sumitomo Bakelite Co., Ltd.) whose pocket portion has been formed in advance, and then cover with a PTP aluminum foil (manufactured by Daiwa Chemical Industry Co., Ltd .: aluminum foil silver plain). And PTP package. The obtained 3 sheets of the PTP package (containing 10 tablets per sheet) are further subjected to aluminum pillow packaging to obtain the pharmaceutical product of Production Example 9.

[Production Example 10]
According to a conventional method, a tablet containing the components and the amounts (mg) described in Formulation Example 11 in one tablet in Table 6 below was produced, and dried with a high-frequency drier to a water content of about 2.6% by mass. The medicinal product of Production Example 10 is obtained by storing in a glass bottle.

[Production Example 11]
According to a conventional method, tablets containing the components and the amounts (mg) described in Formulation Example 12 in one tablet in Table 6 below were produced, and stored for one day together with a desiccant (synthetic zeolite) to obtain a water content of 2.1. After drying to about mass%, the product is prepared by SP packaging with aluminum foil for strip packaging (manufactured by Nissan Chemical Industries, Ltd.) to obtain the pharmaceutical product of Production Example 11.

[Production Example 12]
By a conventional method, a tablet containing the components and the amounts (mg) described in Formulation Example 13 in Table 6 below in one tablet was produced, and dried in a box drier to a moisture content of about 1.9% by mass. In a low density polyethylene bottle (bottle), the pharmaceutical preparation of Production Example 12 is obtained.

[Production Example 13]
According to a conventional method, tablets containing the components and the amounts (mg) described in Formulation Example 14 in Table 1 below in one tablet were produced, and dried to a water content of about 2.7% by mass with a high frequency drier. The pharmaceutical product of Production Example 13 is obtained by containing it in a glass bottle.

[Production Example 14]
In a conventional manner, tablets containing the components and amounts (mg) described in Formulation Example 15 in Table 7 below in one tablet were produced and stored for one day together with a desiccant (synthetic zeolite) to give a water content of 2.5. After drying to about mass%, the product is packaged in SP with aluminum foil for strip packaging (manufactured by Nissan Chemical Industries, Ltd.) to obtain the pharmaceutical product of Production Example 14.

[Production Example 15]
By a conventional method, tablets containing the components and the amounts (mg) described in Formulation Example 16 in Table 1 below in one tablet were produced, and dried in a box drier to a water content of about 2.0% by mass. In a low-density polyethylene bottle (bottle) to obtain the pharmaceutical product of Production Example 15.

  ADVANTAGE OF THE INVENTION According to this invention, since the lactone form formation of pitavastatin or its salt is suppressed, a pharmaceutical with favorable stability of an active ingredient can be provided, and it can be utilized in the pharmaceutical industry and the like.

Pitavastatin calcium (chemical name: (+)-monocalcium bis {(3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] -3, a kind of statins) pitavastatin or a salt thereof, such as 5-dihydroxy-6- h eptenoate} ) has an excellent HMG-CoA reductase inhibitory activity, antihyperlipidemic agents, useful as an active ingredient, such as hypercholesterolemia therapeutic agent Is known (Patent Document 1).

Claims (5)

The following components (A) and (B):
(A) pitavastatin or a salt thereof 4 mg per tablet in terms of pitavastatin calcium;
(B) one or more selected from the group consisting of carmellose and salts thereof, crospovidone and crystalline cellulose;
And an orally disintegrating tablet having a water content of 2.9% by mass or less is contained in an airtight package.   The pharmaceutical according to claim 1, wherein the water content of the orally disintegrating tablet is 1.5 to 2.9% by mass.   3. The pharmaceutical product according to claim 1, wherein the hermetic package is at least one selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging, and stick packaging. The following components (A) and (B):
(A) pitavastatin or a salt thereof 4 mg per tablet in terms of pitavastatin calcium;
(B) one or more selected from the group consisting of carmellose and salts thereof, crospovidone and crystalline cellulose;
And an orally disintegrating tablet having a water content of 2.9% by mass or less.   The orally disintegrating tablet according to claim 4, having a water content of 1.5 to 2.9% by mass.