JP2021152057A - 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: A medicine has an orally disintegrating tablet that contains: a component (A) which is pitavastatin and salts thereof; and a component (B) which is one or more selected from the group consisting of carmellose and salts thereof, crospovidone and crystalline cellulose and has a water content of 2.9 mass% or less, the orally disintegrating tablet stored in a hermetic package.SELECTED DRAWING: None

Description

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

Pitavastatin calcium, a type of so-called statin (chemical name: (+)-monocalcium bis [(3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] -3, Pitavastatin such as 5-dihydroxy-6-eptenoate}) or a salt thereof has excellent HMG-CoA reductase inhibitory activity and is useful as an active ingredient for a therapeutic agent for hyperlipidemia and a therapeutic agent for hypercholesterolemia. 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 intramolecularly by a dehydration condensation reaction to produce a lactone having low HMG-CoA reductase inhibitory activity. The production of lactones in pharmaceutical formulations can also cause reduced efficacy of pharmaceuticals and heterogeneity of efficacy between pharmaceuticals. Therefore, various attempts have been made to improve the stability of statins including pitabastatin in pharmaceutical preparations, but most of them are studies on the pH environment of statins, specifically, in a low pH environment. In consideration of the instability of the dihydroxycarboxylic acid skeleton, a basic substance such as calcium carbonate is added to make the pH environment of statins basic (Patent Documents 2 and 3).

Further, according to Patent Document 4, when the crystalline form A of pitavastatin calcium is dried, it becomes amorphous at a water content of 4% or less and the crystallinity decreases, and the amorphous pitavastatin calcium is extremely stable during storage. It is stated that it will get worse. Further, in Non-Patent Document 1, in the section of "stability of the active ingredient under various conditions", it was found that the water content decreased and the related substances increased under low humidity conditions (60 ° C., 30% RH). Have been described.

Japanese Unexamined Patent Publication No. 1-279866 Japanese Patent No. 2774037 Patent No. 3276962 Japanese Patent Application Laid-Open No. 2007-516952 International Publication No. WO2007 / 52592 Pamphlet

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

However, Patent Document 4 and Non-Patent Document 1 do not describe at all the instability associated with moisture absorption (increased water content) in a solid preparation containing pitavastatin calcium and a disintegrant having a specific high hygroscopicity. ..

By the way, carmellose such as calcium carmellose and sodium croscarmellose or salts thereof, and pharmaceutical additives such as crospovidone and crystalline cellulose all have extremely high hygroscopicity. Therefore, when it is blended in a solid preparation, it exerts actions such as absorbing moisture and swelling, and guiding water to the inside of the preparation by capillary action, and is used as a disintegrant or the like because it imparts good disintegration property to the solid preparation.

The improvement of the disintegration property of the solid preparation has an advantage that the release of the active ingredient and the exertion of the medicinal effect are more ensured, which in turn leads to the improvement of the quality of the solid preparation. In addition, the orally disintegrating solid preparation, which is a type of solid preparation characterized by good disintegration, can be taken without water, so it can be taken anywhere, at any time, etc., and has the advantage of improving compliance. There is also.
In consideration of such merits, the present inventor uses a disintegrant such as carmellose or a salt thereof, crospovidone, crystalline cellulose and a disintegrant such as pitavastatin or a salt thereof in order to obtain a solid preparation containing pitavastatin or a salt thereof and having good disintegration property. Was mixed, and it was found that a large amount of lactone was produced over time.
Therefore, the present invention is a solid preparation in which lactone formation is suppressed, and the solid preparation containing pitavastatin or a salt thereof, and one or more selected from the group consisting of carmellose and its salt, crospovidone, and crystalline cellulose. The subject is to provide pharmaceutical products using.

In order to solve the above problems, the present inventor first describes the cause and mechanism of lactone formation when mixing pitabastatin or a salt thereof with one or more selected from the group consisting of carmellose and its salts, crospovidone and crystalline cellulose. As a result of diligent examination, it was surprisingly found that there is a correlation between the water content in the mixture and the amount of lactone, and that the amount of lactone, which is a dehydration condensate, increases as the water content increases. rice field. On the other hand, in the section of "stability of the pharmaceutical product under various conditions" described in Patent Document 5, the harsh test (humidity: 25 ° C., 60% RH or 85% RH) of the "Rhesus tablet" currently on the market The stability is only "within the standard range" or "decreased elution rate". From these facts, the cause / mechanism of lactone formation due to coexistence with the above-mentioned disintegrant is due to the high hygroscopicity of the above-mentioned specific disintegrant which is not contained in the "Rivalo Tablets" currently on the market. Was suggested. Then, they have found that the production of lactones derived from pitavastatin or a salt thereof can be suppressed by keeping the water content of the solid preparation below a certain value, and completed the present invention.

That is, the present invention describes the following components (A) and (B):
(A) Pitavastatin or a salt thereof;
(B) One or more selected from the group consisting of carmellose and its salts, crospovidone and crystalline cellulose;
The present invention provides a pharmaceutical product in which a solid preparation containing the above-mentioned material and having a water content of 2.9% by mass or less is contained in an airtight package.

Further, in the present invention, the following components (A) and (B):
(A) Pitavastatin or a salt thereof;
(B) One or more selected from the group consisting of carmellose and its salts, crospovidone and crystalline cellulose;
To provide a solid preparation containing 2.9% by mass or less of water content.

The solid preparation of the present invention suppresses the production of a lactone derived from pitavastatin or a salt thereof, and is excellent in disintegration property. Therefore, the solid preparation of the present invention is excellent in quality because not only the stability of the active ingredient is good, but also the release of the active ingredient and the exertion of the medicinal effect are certain.
Further, in the pharmaceutical product of the present invention, since the solid preparation of the present invention is packaged in a package that can be stored in an airtight manner and the invasion of water into the package is prevented, the water content of the solid preparation inside the package for a long period of time. Is kept stable, and the production of lactones derived from pitabastatin or a salt thereof in the solid preparation is suppressed for a long period of time, which is useful.

In the present invention, "pitabastatin or a salt thereof (hereinafter, also referred to as" component (A) ")" includes not only pitabastatin itself but also pharmaceutically acceptable salts of pitabastatin (for example, alkali metal salts such as sodium salt and potassium salt). Alkaline earth metal salts such as calcium salt and magnesium salt; organic amine salt such as phenethylamine salt; ammonium salt, etc.), and pitabastatin or a pharmaceutically acceptable salt thereof, and a solvent mixture of water, alcohol, etc. 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 preferable.
Pitavastatin or a salt thereof is a known compound, and can be produced, for example, by the method described in JP-A No. 1-279866, US Pat. No. 5,856,336 and the like.

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

In the present invention, "one or more selected from the group consisting of carmellose and its salt, crospovidone, and crystalline cellulose (hereinafter, also referred to as" component (B) ")" includes carmellose and a pharmaceutically acceptable salt of carmellose. , Crosslinked polymers of carmellose and pharmaceutically acceptable salts thereof, crospovidone and crystalline 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 appropriately examined and determined according to the disintegration property of the solid preparation. In the present invention, a solid preparation containing 0.1 to 85% by mass of the component (B) in total with respect to the total mass of the solid preparation is preferable, and a solid preparation containing 0.5 to 70% by mass is more preferable, and 1 to 1 to A solid preparation containing 60% by mass is particularly preferable. Further, with respect to 1 part by mass of the component (A) obtained by converting the component (B) into pitavastatin calcium, 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 is preferable. Is more preferable, and a solid preparation containing 1 to 65 parts by mass is particularly preferable.

In the present invention, "carmellose and its salt" includes not only carmellose itself but also pharmaceutically acceptable salts of carmellose (for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and the like. ), Further also includes cross-carmellose and a pharmaceutically acceptable salt cross-carmellose thereof. Specific examples thereof 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 any salt thereof having different molecular weights, salt types and the like may be used, but carmellose calcium, carmellose sodium and croscarmellose sodium are preferable, and carmellose calcium and carmellose sodium are preferable. Is particularly preferable.

In the present invention, a commercially available product may be used as carmellose and a salt thereof, and specifically, for example, NS-300, ECG-505 (all manufactured by Gotoku Pharmaceutical Co., Ltd.), Sunrose (manufactured by Nippon Paper Chemicals Co., Ltd.), and the like. Cellogen (manufactured by Saneigen FFI), cellogen series (manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd.), Ac-Di-Sol (manufactured by Asahi Kasei Chemicals Co., Ltd.), Kiccolate ND-2HS (manufactured by Nichirin Chemical Co., Ltd.), etc. Can be mentioned.

In the present invention, the content of carmellose and a salt thereof in the solid preparation is not particularly limited, and can be appropriately examined and determined according to the disintegration property of the solid preparation. In the present invention, a solid preparation containing 0.01 to 25% by mass of carmellose and a salt thereof in total with respect to the total mass of the solid preparation is preferable, and a solid preparation containing 0.1 to 20% by mass is more preferable. A solid preparation containing 5 to 15% by mass is particularly preferable. Further, with respect to 1 part by mass of the component (A) converted to pitabastatin calcium, a solid preparation containing 0.01 to 30 parts by mass of carmellose and a salt thereof in total is preferable, and a solid preparation containing 0.1 to 25 parts by mass is preferable. 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, or these may be used alone or in combination of two or more.
In the present invention, a commercially available product may be used as the cross povidone, and specifically, for example, cross povidone (manufactured by Gokyo Sangyo Co., Ltd.), corridon CL-F, corridon CL-M, corridon CL-SF (above, BASF). , Polyplusdon XL, Polyplusdon XL-10, Polyplusdon INF-10 (all manufactured by ASP Japan) and the like.

In the present invention, the content of crospovidone in the solid preparation is not particularly limited, and can be appropriately examined and determined according to the disintegration property of the solid preparation. In the present invention, a solid preparation containing 0.1 to 25% by mass of crospovidone with respect to the total mass of the solid preparation is preferable, and a solid preparation containing 0.5 to 20% by mass is more preferable, and 1 to 15% by mass is contained. The solid preparation to be produced is particularly preferable. Further, with respect to 1 part by mass of the component (A) converted to 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 preferable.

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

In the present invention, the content of crystalline cellulose in the solid preparation is not particularly limited, and can be appropriately examined and determined according to the disintegration property of the solid preparation. In the present invention, a solid preparation containing 0.1 to 80% by mass of crystalline cellulose with respect to the total mass of the solid preparation is preferable, and a solid preparation containing 0.5 to 65% by mass is more preferable, and 1 to 50% by mass is contained. The solid preparation to be produced is particularly preferable. Further, with respect to 1 part by mass of the component (A) converted to 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. A solid preparation containing 1 to 55 parts by mass is particularly preferable.

The solid preparation of the present invention needs to have a water content of 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 2.1% by mass from the viewpoint of suppressing the production of the lactone. It is more preferably less than or equal to 1.9% by mass or less.
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 5-keto form, which is a decomposition product different from the lactone form, is suppressed. can. The 5-keto form is known to be a photodegraded product produced by exposing pitavastatin or a salt thereof to light as described in Patent Document 5, but there has been no report on its 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 production of the lactone form is suppressed and the production of the 5-keto form is also suppressed, the stability of pitavastatin in the solid preparation is particularly good, which is an excellent effect.

From another point of view, the present invention is 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 its salts, crospovidone and crystalline cellulose;
To provide a solid preparation containing the above and 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, the potentiometric titration method or the potentiometric titration method may be appropriately selected in accordance with the moisture measurement method (Karl Fischer method) of the 16th revised Japanese Pharmacopoeia.

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

Examples of the humidifying means include means of using a water-containing solvent as the kneading liquid in the wet granulation operation.
Examples of the drying means include a means using a drying device and a means using a desiccant. Here, as the drying apparatus, those usually used in the fields 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, and the like. Examples include a vacuum dryer and a high frequency dryer. Further, as the desiccant, those usually used in the fields of pharmaceuticals and foods can be used, and specifically, for example, silica gel, silica alumina gel (for example, allophen), natural zeolite, synthetic zeolite (for example, for example). Zeolite sieve), quicklime (calcium oxide), bentonite clay (for example, montmorillonite), calcium chloride, magnesium chloride and magnesium oxide can be mentioned, and these may be mixed with activated charcoal. In the present invention, a method using a drying device is preferable because it is easy to adjust the water content of the solid preparation.
These humidifying means and drying means may be performed during the production of the solid preparation or after the production of the solid preparation, but at least the solid preparation is to be used in order to accurately adjust the water content in the solid preparation. It is preferable to carry out after the production of.

In the present invention, the solid preparation may contain an additive usually used in the art in addition to the above-mentioned components, depending on its specific form (dosage form). Examples of the additive include excipients, disintegrants (excluding component (B)), binders, lubricants, colorants, plasticizers, film-forming agents, poorly water-soluble polymer substances, and antioxidants. , Flavoring agents, sweeteners, pH adjusters, surfactants, fragrances and the like, and these can be used alone or in combination of two or more as appropriate. The amount of each additive used can be appropriately determined.

Excipients include, for example, 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; Powder, starch (wheat starch, rice starch, corn starch, partially pregelatinized starch, etc.), fructose, caramel, canten, xylitol, paraffin, sucrose, fructose, malt sugar, lactose, sucrose, glucose, purulan, polyoxyethylene hydrogenated castor Organics such as oil, martitol, reduced maltose water candy, powder reduced maltose water candy, erythritol, xylitol, sorbitol, mannitol, lactitol, trehalose, reduced palatinose, maltose, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, calcium citrate, etc. Examples include system excipients. These can be used alone or in combination of two or more.
Examples of the disintegrant include starch, sucrose fatty acid ester, gelatin, sodium hydrogencarbonate, dextrin, dehydroacetic acid and salts thereof, 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 methyl cellulose, hydroxypropyl cellulose, hypromellose, starch (wheat starch, rice starch, corn starch, partially pregelatinized starch, etc.), dextrin, purulan, gum arabic, canten, gelatin, tragant, sodium alginate, polyvinyl. Examples thereof include alcohol, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate and the like. These can be used alone or in combination of two or more.
Examples of the lubricant include calcium stearate, magnesium stearate, stearyl fumarate, sucrose fatty acid ester and the like. These can be used alone or in combination of two or more.

Examples of the colorant include yellow iron sesquioxide, brown iron oxide, caramel, black iron oxide, titanium oxide, iron sesquioxide, tar pigment, aluminum lake pigment, 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) sorbitanoleic acid ester), polyethylene glycol [for example, 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, n is 28). (Equal amount mixture with ~ 36), 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 such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hypromellose (hydroxypropyl methyl cellulose). Hydroxyalkyl cellulose phthalate such as hydroxypropyl methyl cellulose 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 carboxyvinyl polymers and aminoalkyl methacrylate copolymers. These can be used alone or in combination of two or more.
Examples of the antioxidant include ascorbic acid, sodium hydrogen sulfite, sodium sulfite, sodium edetate, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, tocopherol, and butylhydroxyanisole. These can be used alone or in combination of two or more.

Examples of the flavoring agent include terpenes such as limonene, pinen, camphen, cymen, cineole, citronellol, geraniol, nerol, linalol, menthol, terpineol, loginol, borneol, isobornole, menthon, camphor, eugenol, and syntheilanol; Contains terpenes such as oil, orange oil, peppermint oil, citrus oil, eucalyptus oil, terepine oil, lemon oil, ginger oil, butterfly oil, kehi oil, lavender oil, uikyo oil, chamomile oil, perilla oil, spearmint oil, etc. (Hereinafter, terpenes and essential oils containing terpenes are collectively referred to as "terpenes"); ascorbic acid, tartrate acid, citric acid, malic acid, acidulants such as salts thereof and the like can be mentioned. These can be used alone or in combination of two or more. Among them, terpenes are preferable, menthol is more preferable, and l-menthol is particularly preferable.

Examples of the sweetener include aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, sodium saccharin, and the like, and one or a combination of two or more of these can be used. Of these, 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 is the pH of the liquid obtained by dissolving or dispersing 1 administration unit of the 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 Regulations for Preparations and the like. The dosage form is not particularly limited, and the dosage form described in the 16th revised general rules of pharmaceutical formulations, etc., specifically, for example, tablets (orally disintegrating tablets, chewable tablets, effervescent tablets, dispersion tablets, dissolving tablets, etc.) Includes), capsules, suppositories, granules, fine granules, powders and other solid preparations for oral administration and oral tablets (including troches, sublingual tablets, buccal tablets, adhesive tablets, gum agents, etc.) , Solid preparations for parenteral administration such as suppositories, vaginal tablets, suppositories for vagina, etc., but solid preparations for oral administration are preferable. If necessary, these solid formulations may be coated with a film, sugar coating, or the like.
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, the tablet disintegrates rapidly in the oral cavity, which facilitates administration, which in turn has an excellent effect of improving administration 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 by saliva in the oral cavity of a healthy person) is not particularly limited, and the dosage form of the solid preparation is not particularly limited. Although it depends on the size and the like, for example, it is within 90 seconds, preferably within 60 seconds, and 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, etc., depending on the dosage form.
Specifically, for example, in the case of an orally disintegrating tablet (hereinafter referred to as "OD tablet") which is a suitable dosage form of the present invention, the component (A), the component (B), and optionally an additive. Method of direct compression molding using, etc .; component (A), component (B), and additives, if desired, are mixed, compression-molded into a plate-shaped compression mold or a slug tablet, crushed, and added if desired. A method of mixing agents and the like to compress-mold the dry mixture; the component (A), the component (B) and, if desired, additives and the like are mixed, and then granulated by an appropriate method to obtain a dry mixture. It can be manufactured by a compression molding method or the like.

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 suspension or solution can further contain gelatin, dextran, alginic acid, salts of alginic acid, sugar alcohols (erythritol, xylitol, sorbitol, mannitol, etc.), glycine and the like.

Further, the OD tablet of the present invention is a method in which a mixture containing a component (A), a component (B), and at least one selected from sugars and sugar alcohols is moistened with water, an aqueous alcohol solution, or the like and molded at low pressure. , So-called wet tableting.

Further, the OD tablet of the present invention forms low-formability saccharides such as lactose hydrate, mannitol, glucose hydrate, sucrose and xylitol, and oligosaccharides such as maltose, martitol and sorbitol, and lactose and fructose. It can be produced by producing a granulated product using highly acidic sugars and then tableting the granulated product. In the method, the component (A) and the component (B) may be contained in the granulated product, or may be mixed after the granulated product is produced, but in the granulated product. It is preferable that it is contained in.

Furthermore, the OD tablets of the present invention have xylitol, trehalose, maltitol, sorbitol, erythritol, glucose, maltitol, mannitol, sucrose, lactose hydrate, which are lower than the melting point and decomposition point of component (A) and other additives. It can be produced by a method of producing a molten solidified product of the component (A), the component (B) and, if desired, another additive using a relative low melting point saccharide such as, and then tableting the molten 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, but are contained in the melt-solidified product. The one that has been squeezed is preferable.

The present invention also provides a pharmaceutical product in which the above-mentioned solid preparation is contained in an airtight package. By accommodating the solid product in the airtight package, the invasion of water from the outside of the package is prevented, and as a result, the water content of the solid product existing inside the package is kept stable for a long period of time, and as a result, the solid is solid. The production of lactones derived from the component (A) in the formulation is suppressed over 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, the water content of the solid preparation may be 2.9% by mass or less immediately after the solid preparation is taken out from the airtight package. For example, the water content of the solid preparation is 2.9% by mass before being contained in the airtight package. Even if it is 0% or more, if the water content of the solid product is 2.9% by mass or less inside the airtight package by means such as enclosing a desiccant (that is, the solid product is taken out from the airtight package). Immediately after that, it is included in the "pharmaceutical product" of the present invention (if its water content is 2.9% by mass or less).

In the present invention, the "airtight package" means a package capable of substantially suppressing the invasion of moisture from the outside of the package under normal handling, transportation, storage, etc., and the 16th revised Japanese Pharmacopoeia General Rules. It is a concept including "airtight container" and "sealed container" defined in. As the packaging body, either a fixed form or an amorphous form can be used, and specific examples thereof include bottle packaging, SP (StripPackage) packaging, PTP (PressThroughPackage) packaging, pillow packaging, stick packaging and the like. .. In the present invention, a plurality of these may be further combined, and specific examples thereof include a form in which a solid preparation is first packaged in PTP packaging and then further packaged in pillow packaging.

The packaging material (material) for the airtight packaging is not particularly limited as long as it can exhibit moisture resistance, and a material used for the purpose of moisture proofing of moisture-sensitive contents in the fields of pharmaceuticals and foods is appropriately used. Can be used.
Examples of the material of the bottle body used for bottle packaging include glass, plastic (polyester, polyethylene (including low density (LDPE), high density (HDPE)), polycarbonate, polystyrene, polypropylene, etc.), metal (aluminum), and the like. Can be mentioned. Examples of the material for the stopper and the lid include plastic (polyester, polyethylene, polycarbonate, polystyrene, polypropylene, etc.), metal (aluminum), and the like. When packaging in a bottle, for example, the solid preparation of the present invention may be stored in an appropriate quantity in a commercially available bottle, and then sealed with an appropriate stopper or lid. The size of the bottle may be appropriately selected according to the quantity of the solid preparation to be stored, and the volume of the bottle is, for example, about 10 to 500 mL, preferably 14 to 400 mL, preferably 24 to 350 mL. More preferred. As the 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 packaging materials used for SP packaging, PTP packaging, pillow packaging, stick packaging, etc. include biaxially stretched polypropylene (OPP), biaxially stretched polyester (PET), glucose-modified PET (PET-G), and biaxially. 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 vinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer resin (EVOH), polyvinyl chloride (PVC) ), Cyclic polyolefin (COC), unstretched nylon (CNy), polycarbonate (PC), polystyrene (PS), hard vinyl acetate (VSC) and other resins, and metal foils such as aluminum foil (AL). , A multi-layer structure may be formed by appropriately combining two or more of these. Examples of such a multilayer structure include a laminated structure of PVC and PVCC (PVC / PVCC; hereinafter, abbreviated in the same manner), PVC / PVDC / PE / PVC, PVC / PVCC / PE / PVDC / PVC, and the like. Examples thereof include CPP / COC / CPP, PVC / AL, CPP / AL, CPP / CPP / CPP and the like. Examples of the method for forming such a multilayer structure include known laminating methods such as extrusion laminating, dry laminating, co-extruded laminating, thermal laminating, wet laminating, non-solvent laminating, and heat laminating. As the packaging material used for SP packaging, PTP packaging, pillow packaging, stick packaging and the like, polyvinyl chloride and aluminum foil are preferable.

As a form of PTP packaging, the solid preparation of the present invention is stored one by one or one administration unit at a time in pockets formed into a desired number of resin sheets or the like by a known method, and then a metal foil such as aluminum foil is used as a constituent material. The sheet may be used as a lid material to cover the lid. The sheet forming the pocket may be a so-called double-sided aluminum PTP packaging using a sheet made of aluminum foil as a constituent material. In the present invention, from the viewpoint of enhancing the moisture resistance, it is preferable to further wrap the PTP wrapping with pillow wrapping (for example, aluminum pillow wrapping).
Examples of the forms of SP packaging, pillow packaging, and stick packaging include packaging one solid preparation or one administration unit at a time using a resin sheet, a sheet containing aluminum foil as a constituent material, or the like by a known method. In the present invention, it is preferable to use a sheet made of aluminum foil as a constituent material from the viewpoint of enhancing moisture resistance.

In the pharmaceutical product of the present invention, the occupancy ratio (floor area ratio) of the solid preparation inside the package is usually 25 to 90%, preferably 28 to 75%, preferably 30 to 35% when the package is a bottle package. 50% is more preferable. When the package is SP packaging, PTP packaging, pillow packaging, or 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 rate means the occupancy rate of the solid preparation with respect to the volume inside the package, and the filling, the inner plug, etc. for preventing the solid preparation stored inside the package from being damaged are defined. It is not considered when calculating the space occupancy.

In the present invention, a commercially available package may be used as it is as the airtight package, or a commercially available package material may be processed and used. Examples of such commercially available products include the Z-series (all manufactured by Hanshin Kasei Kogyo Co., Ltd.) as the packaging body for bottle packaging. In addition, 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 Co., Ltd.), TAS series (manufactured by Taisei Kako Co., Ltd.), PTP. Examples include vinyl foil for vinyl, super foil for PTP (above, manufactured by Mitsubishi Resin Co., Ltd.), Nippaku aluminum foil (manufactured by Nippon Foil Co., Ltd.), and plain silver aluminum foil (manufactured by Taisei Kako Co., Ltd.).

In the present invention, the method of accommodating the solid preparation in the airtight package is not particularly limited, and it can be achieved by arranging the solid preparation in the package by an appropriate means such as putting the solid product into the package. .. In this case, a means for charging a desiccant (for example, a columnar (tablet type) or a sheet-shaped one) together with the solid preparation into the package may be used, but the water content of the solid preparation decreases with time. It is preferable that the water content of the solid preparation is adjusted to 2.9% by mass or less in advance and the desiccant is not added in order to avoid excessive use.

Since the solid preparation of the present invention contains pitavastatin having HMG-CoA reductase inhibitory activity or a salt thereof as a constituent component thereof, for example, a therapeutic agent for hyperlipidemia, a therapeutic agent for hypercholesterolemia, and familial hypercholesterolemia. It can be used as a therapeutic agent for blood pressure. In addition, oral and parenteral examples of the route of administration of the pharmaceutical composition include oral administration, and oral administration is preferable. Further, the pharmaceutical composition can be taken in 1 to 4 times a day before meals, between meals, after meals, before bedtime and the like.

With respect to the aforementioned embodiments, the present invention discloses the following pharmaceuticals and solid formulations.
[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 its salts, crospovidone and crystalline cellulose;
A pharmaceutical product containing, and having a water content of 2.9% by mass or less, contained in an airtight package.
[1-2] The pharmaceutical product according to the above [1-1], wherein the water content of the solid preparation is preferably 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, still more preferably 1.5 to 1.9% by mass. A pharmaceutical product 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, more preferably 0.5 to 12 mg, in terms of pitavastatin calcium, per administration unit. The pharmaceutical product according to any one of the above [1-1] to [1-3], which contains 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 in terms of pitavastatin calcium, based on the total mass of the solid preparation. The pharmaceutical product according to any one of the above [1-1] to [1-3], which is ~ 5% by mass, more preferably 0.5 to 4% by mass.
[1-6] 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 preferably 0.1 with respect to the total mass of the solid preparation. The pharmaceutical product according to any one of the above [1-1] to [1-5], which is ~ 85% by mass, more preferably 0.5 to 70% by mass, still more preferably 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 its salt in terms of pitavastatin calcium. Any one of the above [1-1] to [1-5], preferably 0.1 to 90% by mass, more preferably 0.5 to 75% by mass, still more preferably 1 to 65% by mass. Drugs listed in.
[1-8] The total content of (B) carmellose and a salt thereof 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 pharmaceutical product 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 a salt thereof 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 or a salt thereof converted to pitavastatin calcium. The pharmaceutical product according to any one of the above [1-1] to [1-7], which is 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 0.1 to 25% by mass, more preferably 0.5 to 20% by mass, still more preferably 1 to 1% by mass, based on the total mass of the solid preparation. The pharmaceutical product 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, based on 1 part by mass of pitavastatin or a salt thereof converted to pitavastatin calcium. %, More preferably 1 to 20% by mass, 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 0.1 to 80% by mass, more preferably 0.5 to 65% by mass, still more preferably 1 to 1 to the total mass of the solid preparation. The pharmaceutical product 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, based on 1 part by mass of pitavastatin or a salt thereof converted to pitavastatin calcium. %, More preferably 1 to 55% by mass, according to any one of the above [1-1] to [1-11].
[1-14] 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, still more preferably 7 to 11. 1] The pharmaceutical product 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 medicines listed in Kaichi.
[1-16] The drug 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 its salts, crospovidone and crystalline cellulose;
A solid preparation containing 2.9% by mass or less of water.
[2-2] The solid preparation according to the above [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 water content is preferably 1.5 to 2.9% by mass, more preferably 1.5 to 2.1% by mass, still more preferably 1.5 to 1.9% by mass. The solid preparation according to [2-1].
[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 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 8 mg, still more preferably 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, in terms of 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] The total content of one or more selected from the group consisting of (B) carmellose and its salt, crospovidone and crystalline cellulose is preferably 0.1 to 85% by mass with respect to the total mass of the solid preparation. The solid preparation according to any one of the above [2-1] to [2-5], more preferably 0.5 to 70% by mass, 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 its salt, crospovidone and crystalline cellulose is preferably with respect to 1 part by mass of pitavastatin converted to pitavastatin calcium or a salt thereof. The solid according to any one of the above [2-1] to [2-5], which is 0.1 to 90% by mass, more preferably 0.5 to 75% by mass, and further preferably 1 to 65% by mass. pharmaceutical formulation.
[2-8] The total content of (B) carmellose and a salt thereof is preferably 0.01 to 25% by mass, more preferably 0.1 to 20% by mass, still more preferably, based on 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 its salt is preferably 0.01 to 30% by mass, more preferably 0.1 to 1% by mass, based on 1 part by mass of pitabastatin or a salt thereof converted to pitabastatin calcium. The solid preparation according to any one of the above [2-1] to [2-7], which 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, 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 the above [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, still more preferably, based on 1 part by mass of pitavastatin or a salt thereof converted to pitavastatin calcium. The solid preparation according to any one of the above [2-1] to [2-9], wherein is 1 to 20% by mass.
[2-12] The content of crystalline cellulose is preferably 0.1 to 80% by mass, more preferably 0.5 to 65% by mass, 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 the above [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, still more preferably, based on 1 part by mass of pitavastatin or a salt thereof converted to pitavastatin calcium. The solid preparation according to any one of the above [1-1] to [1-11], wherein is 1 to 55% by mass.
[2-14] The pH is preferably 4 or more, more preferably 4 to 13, still more preferably 5 to 12, still more preferably 6 to 11, 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 its salts, crospovidone and crystalline cellulose;
A solid preparation containing the above and having a water content of 1.5% by mass or more.
[3-2] The water content is preferably 1.5 to 2.9% by mass, more preferably 1.5 to 2.1% by mass, still more preferably 1.5 to 1.9% by mass. The solid preparation according to [3-1].

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 lactone formation by coexistence with a disintegrant having high hygroscopicity In order to confirm lactone formation derived from pitabastatin or a salt thereof in coexistence with a disintegrant having high hygroscopicity, the following mixture 1 to 4 were prepared and placed in a polyethylene bag and an aluminum bag and stored at 70 ° C. for 3 days, and the production rate of lactones in the mixture immediately after the mixture was prepared and after storage at 70 ° C. for 3 days was evaluated. The lactone formation rate was measured for each mixture using an HPLC apparatus (WATERS 2695) as an area percentage of the total peak area derived from pitavastatin and its degradation products. For reference, the production rate of lactones when only pitavastatin calcium was separately stored at 70 ° C. for 3 days was also evaluated in the same manner.

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 content of the mixtures 1 to 4 after storage at 70 ° C. for 3 days was measured.
The water content was measured by the volumetric titration method in accordance with the 16th revised Japanese Pharmacopoeia water measurement method (Karl Fischer method). The results are shown in Table 1.

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

<Mixture 3>
Mixture 3 was prepared by mixing 1 part by mass of pitavastatin calcium and 10 parts by mass of crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd .: trade name: Theoras UF-711).
<Mixture 4>
1 part by mass of pitavastatin calcium and 10 parts by mass of sodium carmellose (manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd .: trade name Cellogen P-815C) were mixed to prepare a mixture 4.

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, and that the amount of the lactone increased as the water content increased. Since crospovidone, carmellose calcium, crystalline cellulose, and carmellose sodium all have high hygroscopicity, the formation of lactones is due to the high hygroscopicity of these disintegrants, and the coexisting disintegrants absorb moisture. It was speculated that lactone was produced as a result of exposure of pitabastatin to water.

[Test Example 2] Test for suppressing the production of lactones The water content of the orally disintegrating tablets produced by the following method was adjusted to each water content shown in Table 3 by vacuum drying (Note that the method for measuring the water content is (As follows). After that, each tablet (100 tablets) whose water content was adjusted was put into the pocket part of a resin sheet (manufactured by Sumitomo Bakelite Co., Ltd .: trade name Sumilite VSS-1202-R) in which the pocket part was molded in advance, and then aluminum foil for PTP. (Made by Daiwa Kagaku Kogyo Co., Ltd .: Product name: Aluminum foil, silver plain) Cover and PTP wrap, and then wrap the obtained PTP package in an aluminum laminate bag (Made in Japan: Product name: Lamizip AL series). bottom. The package thus obtained was stored for 2 months under the conditions of 40 ° C. and 75% relative humidity, and the production rate of lactones in the tablets was evaluated immediately after the tablet preparation, after 1 month storage and after 2 months storage. .. The production rate of the lactone was measured for each tablet using an HPLC apparatus (LC-20 series manufactured by SHIMADZU) as an area percentage with respect to the total peak area derived from pitavastatin and its decomposition products.
The water content in the tablets was measured by the volumetric titration method in accordance with the 16th revised Japanese Pharmacopoeia water measurement method (Karl Fischer method).

<Manufacturing of orally disintegrating tablets>
An orally disintegrating tablet containing the ingredients and the amount (mg) shown in Table 2 below in one tablet was produced according to a conventional method.
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 the components below xylitol in Table 2 were mixed and tableted to prepare an orally disintegrating tablet of 120 mg per tablet.

The results are shown in Table 3.

From the test results shown in Table 3, it was clarified that the formation of lactones was remarkably suppressed when the water content of the tablets was 2.9% by mass or less. In particular, when the water content of the tablet was 2.1% by mass or less, the production rate of the lactone was kept low even after storage for 2 months under the conditions of 40 ° C. and 75% relative humidity. As a result of the airtight packaging (PTP packaging, aluminum pillow packaging) preventing the ingress of water from outside the packaging, the water content in each tablet remains unchanged even after storage for 2 months under the conditions of 40 ° C and 75% relative humidity. No change was observed.
Based on 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 salt, 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. It was also clarified that the pharmaceutical product in which the solid preparation is contained in an airtight package has a stable water content, and as a result, lactone formation is suppressed for a long period of time.

[Test Example 3] 5-Keto-form formation suppression test The package obtained by PTP packaging of orally disintegrating tablets having various water contents and then aluminum pillow packaging by the same method as in Test Example 2 at 40 ° C. , The product was stored for 2 months under the condition of 75% relative humidity, and the production rate of 5-keto in the tablet was evaluated immediately after the tablet preparation, after the storage for 1 month and after the storage for 2 months. The 5-keto form production rate was measured for each tablet using an HPLC apparatus (LC-20 series manufactured by SHIMADZU) as an area percentage to the total peak area derived from pitavastatin and its degradation products.
The results are shown in Table 4.

From the test results shown in Table 4, when the water content of the tablet is 1.5% by mass or more, 5-
It was clarified that the formation of keto form was remarkably suppressed. As a result of the airtight packaging (PTP packaging, aluminum pillow packaging) hindering the movement of water inside and outside the packaging, the water content in each tablet remains unchanged even after storage for 2 months under the conditions of 40 ° C and 75% relative humidity. No change was observed.
Based on 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 salt, crospovidone, and crystalline cellulose, and having a water content of 1.5% by mass or more. It was clarified that the production of 5-keto form was suppressed.

[Manufacturing Example 1]
By the same method as in Test Example 2, an orally disintegrating tablet containing the ingredients and the amount (mg) shown in Formulation Example 2 in one tablet in Table 5 below was produced, and the water content was 2 in a box dryer. After drying to about 5.5% by mass, the drug is contained in a high-density polyethylene bottle to obtain the drug of Production Example 1.

[Manufacturing Example 2]
By the same method as in Test Example 2, an orally disintegrating tablet containing the ingredients and the amount (mg) shown in Formulation Example 3 in 1 tablet in Table 5 below was produced, and the water content was 2 in a fluidized layer dryer. After drying to about 4% by mass, put it in the pocket part of a resin sheet (manufactured by Sumitomo Bakelite Co., Ltd .: trade name Sumilite VSS-1202) in which the pocket part is molded in advance, and then put it in the aluminum foil for PTP (manufactured by Daiwa Chemical Industry Co., Ltd .: product). Cover with aluminum foil and plain silver) and wrap it in PTP. The obtained 3 sheets of PTP package (containing 10 orally disintegrating tablets per sheet) are further packaged in an aluminum pillow to obtain the drug of Production Example 2.

[Manufacturing Example 3]
By the same method as in Test Example 2, an orally disintegrating tablet containing the ingredients and the amount (mg) shown in Formulation Example 4 in Table 5 below is produced, and stored together with a desiccant (silica gel) for 1 day. After drying the water content to about 2.3% by mass, put it in the pocket part of a resin sheet (manufactured by Sumitomo Bakelite Co., Ltd .: trade name: Sumilite VSS-1104) in which the pocket part is molded in advance, and then put it in the pocket part of the aluminum foil for PTP (PTP aluminum foil). Made by Daiwa Kagaku Kogyo Co., Ltd .: Product name: Aluminum foil, silver plain), cover with PTP packaging. The obtained 2 sheets of PTP package (each sheet contains 12 orally disintegrating tablets) are packaged in an aluminum pillow to obtain the drug of Production Example 3.

[Manufacturing Example 4]
By the same method as in Test Example 2, an orally disintegrating tablet containing the ingredients and the amount (mg) shown in Formulation Example 5 in Table 5 below was produced, and the water content was 1 in a box-type dryer. After drying to about 0.8% by mass, put it in the pocket part of a resin sheet (manufactured by Sumitomo Bakelite Co., Ltd .: trade name Sumilite VSL-4501) in which the pocket part is molded in advance, and then put it in the aluminum foil for PTP (manufactured by Daiwa Chemical Industry Co., Ltd .: product). Cover with a plain aluminum foil and silver, and wrap it in PTP. The obtained 3 sheets of PTP package (containing 10 orally disintegrating tablets per sheet) are further packaged in an aluminum pillow to obtain the drug of Production Example 4.

[Manufacturing Example 5]
By the same method as in Test Example 2, an orally disintegrating tablet containing the ingredients and the amount (mg) shown in Formulation Example 6 in Table 5 below was produced, and the water content was 1. After drying to about 6% by mass, the drug is contained in a glass bottle to obtain the drug of Production Example 5.

[Manufacturing Example 6]
By the same method as in Test Example 2, an orally disintegrating tablet containing the ingredients and the amount (mg) shown in Formulation Example 7 in 1 tablet in Table 5 below was produced, and one day together with a desiccant (synthetic zeolite). After the water content is dried to about 2.2% by mass by storage, SP packaging is performed with aluminum foil for strip packaging (manufactured by Nissan Kako Co., Ltd.) to obtain the drug of Production Example 6.

[Manufacturing Example 7]
A tablet containing the ingredients and the amount (mg) shown in Formulation Example 8 in 1 tablet in Table 6 below is produced by a conventional method, and dried in a fluidized layer dryer to a water content of about 2.3% by mass. , Put it in the pocket part of a resin sheet (manufactured by Sumitomo Bakelite Co., Ltd .: product name Sumilite VSS-1202) in which the pocket part is molded in advance, and then cover it with aluminum foil for PTP (manufactured by Daiwa Chemical Industry Co., Ltd .: product name aluminum foil silver plain). And then blister pack. The obtained 3 sheets of the PTP package (containing 10 tablets per sheet) are further packaged in an aluminum pillow to obtain the drug of Production Example 7.

[Manufacturing Example 8]
In Table 6 below, a tablet containing the ingredients and the amount (mg) shown in Formulation Example 9 in one tablet is produced by a conventional method, and stored together with a desiccant (silica) for one day to increase the water content to 1.8. After drying to about mass%, put it in the pocket part of a resin sheet (manufactured by Sumitomo Bakelite Co., Ltd .: product name Sumilite VSS-1104) in which the pocket part is molded in advance, and then put it in the aluminum foil for PTP (manufactured by Daiwa Chemical Industry Co., Ltd .: product name aluminum). Cover with plain foil and silver) and wrap in PTP. The obtained 2 sheets of PTP package (containing 12 tablets per sheet) are packaged in an aluminum pillow to obtain the drug of Production Example 8.

[Manufacturing Example 9]
A tablet containing the ingredients and the amount (mg) shown in Formulation Example 10 in 1 tablet in Table 6 below is produced by a conventional method, and dried in a box-type dryer to a water content of about 1.5% by mass. , Put it in the pocket part of a resin sheet (manufactured by Sumitomo Bakelite Co., Ltd .: product name Sumilite VSL-4501) in which the pocket part is molded in advance, and then cover it with aluminum foil for PTP (manufactured by Daiwa Chemical Industry Co., Ltd .: product name aluminum foil silver plain). And then blister pack. The obtained 3 sheets of the PTP package (containing 10 tablets per sheet) are further packaged in an aluminum pillow to obtain the drug of Production Example 9.

[Manufacturing Example 10]
A tablet containing the component and the amount (mg) shown in Formulation Example 11 in 1 tablet in Table 6 below is produced by a conventional method, dried in a high-frequency dryer to a water content of about 2.6% by mass, and then dried. The drug of Production Example 10 is obtained by housing it in a glass bottle.

[Manufacturing Example 11]
By a conventional method, tablets containing the components and amounts (mg) shown in Formulation Example 12 in 1 tablet in Table 6 below are produced, and stored together with a desiccant (synthetic zeolite) for 1 day to obtain a water content of 2.1. After drying to about mass%, SP packaging is performed with aluminum foil for strip packaging (manufactured by Nissan Kako Co., Ltd.) to obtain the pharmaceutical product of Production Example 11.

[Manufacturing Example 12]
A tablet containing the component and the amount (mg) shown in Formulation Example 13 in 1 tablet in Table 6 below is produced by a conventional method, and dried in a box-type dryer to a water content of about 1.9% by mass. , The drug of Production Example 12 is obtained by housing in a bottle made of low-density polyethylene.

[Manufacturing Example 13]
A tablet containing the component and the amount (mg) shown in Formulation Example 14 in one tablet in Table 7 below is produced by a conventional method, dried in a high-frequency dryer to a water content of about 2.7% by mass, and then dried. The drug of Production Example 13 is obtained by housing it in a glass bottle.

[Manufacturing Example 14]
A tablet containing the ingredients and the amount (mg) shown in Formulation Example 15 in 1 tablet in Table 7 below is produced by a conventional method, and stored together with a desiccant (synthetic zeolite) for 1 day to obtain a water content of 2.5. After drying to about mass%, SP packaging is performed with aluminum foil for strip packaging (manufactured by Nissan Kako Co., Ltd.) to obtain the pharmaceutical product of Production Example 14.

[Manufacturing Example 15]
A tablet containing the component and the amount (mg) shown in Formulation Example 16 in one tablet in Table 7 below is produced by a conventional method, and dried in a box-type dryer to a water content of about 2.0% by mass. , The drug of Production Example 15 is obtained by housing in a bottle made of low-density polyethylene.

According to the present invention, since the production of lactones of pitavastatin or a salt thereof is suppressed, it is possible to provide a drug having good stability of the active ingredient, which can be used in the pharmaceutical industry and the like.

Claims (1)

The invention described in the specification.