WO2010098482A1 - Stable capsule preparation and method for producing same - Google Patents

Stable capsule preparation and method for producing same Download PDF

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Publication number
WO2010098482A1
WO2010098482A1 PCT/JP2010/053194 JP2010053194W WO2010098482A1 WO 2010098482 A1 WO2010098482 A1 WO 2010098482A1 JP 2010053194 W JP2010053194 W JP 2010053194W WO 2010098482 A1 WO2010098482 A1 WO 2010098482A1
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pitavastatin
capsule
fenofibrate
composition
capsules
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PCT/JP2010/053194
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French (fr)
Japanese (ja)
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伸一郎 小林
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興和株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention relates to a capsule preparation composition containing pitavastatin and fenofibrate as active ingredients, and a capsule preparation filled with the composition.
  • Statin drugs such as pitavastatin have an inhibitory action on HMG-CoA reductase, and are known to be useful as a therapeutic agent for hyperlipidemia and a therapeutic agent for atherosclerosis (Japanese Patent Laid-Open No. 01-297866). See the official gazette).
  • various measures have been taken for the formulation of compounds that are unstable at low pH (Japanese Patent Laid-Open Nos. 02-006406 and 05-246844, And Japanese Patent Publication No. 11-503763).
  • fibrates such as fenofibrate have an action of lowering blood cholesterol and blood triglycerides (see New Current, 7 (6), 9-19 (1996)).
  • compositions containing these statin drugs and fibrate drugs as active ingredients have been studied for use as therapeutic agents for hypercholesterolemia, therapeutic agents for diabetes, and the like (Pamphlet of International Publication No. 2006/011495 and International Publication No. 2008). / 015763 pamphlet).
  • the inventors have examined a capsule preparation containing pitavastatin, which is a statin drug, and fenofibrate, a fibrate drug, as active ingredients.
  • pitavastatin which is a statin drug
  • fenofibrate a fibrate drug
  • magnesium oxide and / or water are contained in the composition for capsule formulations containing pitavastatin and fenofibrate.
  • the present invention is a capsule preparation composition containing pitavastatin or a salt thereof and fenofibrate, wherein the composition contains magnesium oxide and / or magnesium hydroxide.
  • this invention is a capsule formulation obtained by filling the composition which mix
  • the present invention relates to a method for producing a capsule preparation containing pitavastatin or a salt thereof and fenofibrate, comprising a composition containing pitavastatin and magnesium oxide and / or magnesium hydroxide and a composition containing fenofibrate. It is the manufacturing method of the capsule formulation which each prepares and fills a capsule.
  • composition for capsule preparation of the present invention and the capsule preparation filled with the composition can suppress the formation of pitavastatin degradation product (lactone form) that occurs when pitavastatin and fenofibrate are filled into the capsule as active ingredients.
  • the capsule has the effect of improving the stability over time.
  • the graph which compared the stability after storage for one week at 60 degreeC by the kind of stabilizer in the capsule containing pitavastatin and fenofibrate.
  • the capsule of the present invention is a capsule preparation obtained by filling a composition for capsule preparation containing pitavastatin and fenofibrate as active ingredients.
  • pitavastatin has a strong HMG-CoA reductase inhibitory action and is useful as a hyperlipidemia treatment agent or an atherosclerosis treatment agent, but has a problem in stability at low pH and is stable. It is a compound for which various studies have been made.
  • pitavastatin may be not only free pitavastatin but also a salt with an inorganic base or an organic base, such as calcium salt, sodium salt, alkylamine salt, etc., and calcium salt is particularly preferable.
  • the above fenofibrate has an action of lowering blood cholesterol and blood triglycerides, and is useful as a prophylactic / therapeutic agent for hyperlipidemia.
  • Fenofibrate is preferably mixed and ground in advance with a solid surfactant in order to improve absorbability.
  • the solid surfactant include alkali metal sulfate of lauryl alcohol (eg, sodium lauryl sulfate), ethylene oxide / propylene oxide copolymer (eg, polyoxyethylene (105) polyoxypropylene (5) glycol), Sugar fatty acid esters and the like are used, and among these, sodium lauryl sulfate is particularly preferable.
  • the amount of the solid surfactant is preferably 1 to 10 parts by weight, particularly 2 to 5 parts by weight, based on 100 parts by weight of fenofibrate.
  • the solid surfactant and fenofibrate are mixed and pulverized by a pulverizing apparatus (eg, a jet mill, a hammer mill, a vibrating ball mill) usually used in the preparation of a preparation.
  • a pulverizing apparatus eg, a jet mill, a hammer mill, a vibrating ball mill
  • the mixing and pulverization can be performed, for example, according to the method described in JP-B-7-14876, and the average particle size thereof is preferably less than 15 ⁇ m, preferably less than 10 ⁇ m, particularly preferably less than 5 ⁇ m. .
  • the composition for capsule preparation of the present invention is characterized by containing magnesium oxide and / or magnesium hydroxide.
  • the inventors of the present invention have been studying capsules combining pitavastatin and fenofibrate. As a result, pitavastatin is decomposed in a capsule combining pitavastatin and fenofibrate, and a decomposition product such as a lactone form thereof is generated, thereby producing pitavastatin. It has been found that stability is impaired. The reason is not clear, but when pitavastatin and fenofibrate are combined, fenofibrate is acting on pitavastatin in some way, and the moisture contained in the capsule skin is somehow affecting it. The inventor thinks that.
  • magnesium oxide and / or magnesium hydroxide in the present invention, by adding magnesium oxide and / or magnesium hydroxide to a composition for capsule preparation containing both components, even when the composition is filled in a capsule, the formation of decomposition products is suppressed. Capsules that are stable over time can be obtained.
  • the composition for capsule preparation of the present invention usually contains the composition for capsule preparation within a range not impairing the effects of the present invention.
  • excipient examples include lactose hydrate, corn starch, D-mannitol, D-sorbitol, and crystalline cellulose.
  • binder examples include hydroxypropyl cellulose, hypromellose, povidone, polyvinyl Alcohol (partially saponified product), pregelatinized starch and the like can be used.
  • disintegrant examples include low-substituted hydroxypropylcellulose, carmellose, sodium carboxymethyl starch, carmellose calcium, corn starch, and partially pregelatinized starch. Croscarmellose sodium, crospovidone, etc. can be used.
  • Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, and talc.
  • Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, and talc. Can be used.
  • the capsule of the present invention can be produced by a method in which pitavastatin and fenofibrate, magnesium oxide and / or magnesium hydroxide and other components are all mixed to form a composition and then filled into a capsule. It can also be produced by separately preparing pitavastatin and fenofibrate as a pitavastatin-containing composition and a fenofibrate-containing composition, respectively, and filling them into capsules. Add magnesium.
  • capsules manufactured by filling capsules are preferable because they can further suppress the degradation of pitavastatin.
  • the composition include granules, and the particle size is not particularly limited as long as it is the size of the composition usually filled in a capsule.
  • the active ingredient pitavastatin is preferably 0.1 to 5% by weight, more preferably 0.2 to 3% by weight, and more preferably 0.3 to 3% by weight. It is particularly preferable to contain 1.5% by weight.
  • fenofibrate which is an active ingredient, is preferably contained in an amount of 1 to 99% by weight, more preferably 10 to 80% by weight, and particularly preferably 30 to 70% by weight.
  • Magnesium oxide and / or magnesium hydroxide is preferably contained in an amount of 0.001 to 20% by weight, more preferably 0.01 to 2% by weight.
  • the capsule of the present invention may be in a dosage form once a day or in a divided dosage state several times a day, for example, 2 to 6 times, preferably 3 times a day.
  • the dosage is selected as pitavastatin in the range of 0.1 to 10 mg, preferably 0.5 to 5 mg per day for adults, and as fenofibrate in the range of 10 to 400 mg, preferably 50 to 250 mg per day for adults.
  • the pitavastatin-containing composition contains pitavastatin and magnesium oxide and / or magnesium hydroxide.
  • the weight ratio of the amount is 1: 0.001 to 1:20, particularly 1: 0.01 to 1: 3, a more stable capsule can be obtained.
  • the filling ratio of the pitavastatin-containing composition and the fenofibrate-containing composition is 1: 0.1 to 1: 200, particularly 1: 0.5, from the viewpoint that the medicinal effect can be sufficiently exerted. It is preferably ⁇ 1: 100.
  • the capsule of the present invention employs a production method in which the active ingredient is filled in the capsule as separate compositions, it can be produced, for example, by the following method.
  • pitavastatin, magnesium oxide and / or magnesium hydroxide, and if necessary, an excipient, a binder and a disintegrant are mixed.
  • water is added to the mixture, granulated with stirring, dried and sized to obtain dry granules containing pitavastatin.
  • fenofibrate, solid surfactant, if necessary, excipient, binder, fluidizer and disintegrant are mixed, water is added to the mixture, stirring granulation, drying and sizing, and phenotype. Dry granules containing fibrate.
  • both dry granules obtained are filled into capsules.
  • the capsules used in the present invention are generally readily available on the market, and can be used without particular limitation as the capsule skin.
  • examples of such a coating include gelatin, hypromellose, polyvinyl alcohol, pullulan and the like, and gelatin is particularly preferable.
  • the gelatin content in the capsules may be appropriately determined in consideration of the mechanical strength of the capsules and the uniformity of the coating film during molding. 5 wt% is preferable, and 65 to 99 wt% is more preferable.
  • the capsule skin usually contains about 4 to 15% of water, but the capsule formulation composition of the present invention is stable even when capsules having a water content outside this range are used. There is an effect.
  • gelatin capsules contain about 13 to 15% of moisture, and the capsules having such a high moisture content can exhibit stability.
  • various additives such as macrogol, glycerin, sorbit, preservative, colorant, titanium oxide and the like can be blended in the capsule skin as necessary.
  • a coating containing macrogol in the gelatin coating may be used from the viewpoint of preventing softening and cracking of the capsule.
  • the content of the macrogol may be appropriately examined in consideration of the mechanical strength of the capsule and the uniformity of the film during molding, but is preferably 0.5 to 15% by weight with respect to the total amount of the capsule film. 1 to 10% by weight is more preferable.
  • the average molecular weight of macrogol is not particularly limited, but is preferably from 950 to 25000, more preferably from 2500 to 7000, from the viewpoint of preventing capsule softening and cracking.
  • Macrogol 1000, Macrogol 1500, Macrogol 1540, macrogol 4000, and macrogol 6000 are more preferable, and macrogol 4000 is particularly preferable. Only one macrogol may be used, or a plurality of mixtures may be used.
  • a granulated pitavastatin-containing composition 2 was obtained in the same manner as the pitavastatin-containing composition 1 except that the magnesium oxide was changed to sodium bicarbonate.
  • a granulated pitavastatin-containing composition 3 was obtained in the same manner as the pitavastatin-containing composition 1 except that the magnesium oxide was changed to calcium carbonate.
  • a granulated pitavastatin-containing composition 4 was obtained in the same manner as the pitavastatin-containing composition 1 except that the magnesium oxide was changed to L-arginine.
  • a granulated pitavastatin-containing composition 5 was obtained in the same manner as the pitavastatin-containing composition 1 except that the magnesium oxide was changed to dipotassium hydrogen phosphate.
  • a granulated pitavastatin-containing composition 6 was obtained in the same manner as the pitavastatin-containing composition 1 except that the magnesium oxide was changed to magnesium aluminate metasilicate.
  • fenofibrate-containing composition 7 200 g of fenofibrate and 7 g of sodium lauryl sulfate were mixed and ground to obtain micronized fenofibrate. 207 g of the finely divided fenofibrate obtained, 5.5 g of lactose hydrate, 30 g of pregelatinized starch, 5 g of crospovidone, and 2.5 g of light anhydrous silicic acid are mixed, and 50 g of purified water is added, kneaded, dried and sized. A granular fenofibrate-containing composition 7 was obtained.
  • Example 1 (one granule capsule)> 200 g of fenofibrate and 7 g of sodium lauryl sulfate were mixed and ground to obtain micronized fenofibrate.
  • Example 2 (capsule containing pitavastatin and fenofibrate)> 5 g of pitavastatin-containing composition 1 and 25 g of fenofibrate-containing composition 7 were uniformly mixed, and the mixture was filled into No. 1 gelatin capsules to give 300 mg per capsule to prepare 5 capsules.
  • ⁇ Test example> 1 1 g of pitavastatin-containing compositions 1 to 6 was filled in each brown No. 2 bottle, and the production rate of degradation products (lactones) after storage at 60 ° C. for 1 week was confirmed. The results are shown in Table 3. 2) Five capsules of Production Examples 1 to 6 were filled in a brown No. 2 bottle, and the rate of formation of degradation products (lactones) after one week storage at 60 ° C. was confirmed. The results are shown in Table 4. 3) Five capsules of Examples 1 and 2 and Comparative Examples 1 to 5 were filled in a brown No. 2 bottle, and the rate of formation of degradation products (lactones) after storage at 60 ° C. for 1 week was confirmed. The results are shown in Table 5.
  • the degradation product was quantified by a liquid chromatography method under the following conditions.
  • Detector UV absorptiometer (measurement wavelength: 245 nm)
  • Column temperature Constant temperature around 40 ° C.
  • Examples 3 to 7 In the same manner as in Example 2, capsules were prepared according to the formulation shown in Table 6, and the production rate of the degradation product after storage at 60 ° C. for 1 week was confirmed by the same method as in the test example. The results are shown in Table 6.
  • Examples 8 and 9> In the same manner as in Example 2, capsules were prepared according to the formulation shown in Table 7, and the production rate of the degradation product after storage at 40 ° C. for 6 months was confirmed by the same method as in the test example. The results are shown in Table 7.
  • Example 10 Capsules were prepared in the same manner as in Example 2 except that the magnesium oxide was changed to magnesium hydroxide, and the rate of degradation products after storage at 60 ° C. for 1 week was confirmed by the same method as in the test examples. The results are shown in Table 8.
  • capsules containing pitavastatin and fenofibrate in a composition containing magnesium oxide or magnesium hydroxide were stable over time because the formation of decomposition products was suppressed.

Abstract

Disclosed is a capsule preparation containing pitavastatin and fenofibrate as active ingredients. The capsule preparation containing pitavastatin and fenofibrate is produced by filling a composition prepared by mixing magnesium oxide and/or magnesium hydroxide with the active ingredients in a capsule. The capsule preparation is stable over time.

Description

安定なカプセル製剤及びその製造方法Stable capsule preparation and method for producing the same
　本発明は、有効成分としてピタバスタチンとフェノフィブラートを含有するカプセル製剤用組成物及び該組成物を充填したカプセル製剤に関する。 The present invention relates to a capsule preparation composition containing pitavastatin and fenofibrate as active ingredients, and a capsule preparation filled with the composition.
　ピタバスタチンなどのスタチン系薬剤は、ＨＭＧ－ＣｏＡリダクターゼ阻害作用を有し、高脂血症治療剤や、アテローム性動脈硬化症治療剤として有用であることが知られている（特開平０１－２９７８６６号公報参照）。またこれらのスタチン系薬剤の中で、低ｐＨにおいて不安定な化合物については、製剤化のために様々な対策が講じられている（特開平０２－００６４０６号公報、特開平０５－２４６８４４号公報、および特表平１１－５０３７６３号公報参照）。 Statin drugs such as pitavastatin have an inhibitory action on HMG-CoA reductase, and are known to be useful as a therapeutic agent for hyperlipidemia and a therapeutic agent for atherosclerosis (Japanese Patent Laid-Open No. 01-297866). See the official gazette). Among these statins, various measures have been taken for the formulation of compounds that are unstable at low pH (Japanese Patent Laid-Open Nos. 02-006406 and 05-246844, And Japanese Patent Publication No. 11-503763).
　一方、フェノフィブラートなどのフィブラート系薬剤は、血中コレステロール及び血中トリグリセリドを低下させる作用を有することが知られている（Ｎｅｗ　Ｃｕｒｒｅｎｔ，７（６），９－１９（１９９６）参照）。 On the other hand, it is known that fibrates such as fenofibrate have an action of lowering blood cholesterol and blood triglycerides (see New Current, 7 (6), 9-19 (1996)).
　これらスタチン系薬剤とフィブラート系薬剤を有効成分とした医薬組成物については、高コレステロール血症治療剤や糖尿病治療剤などに用いる検討がされている（国際公開２００６／０１１４９５号パンフレット、および国際公開２００８／０１５７６３号パンフレット参照）。 Pharmaceutical compositions containing these statin drugs and fibrate drugs as active ingredients have been studied for use as therapeutic agents for hypercholesterolemia, therapeutic agents for diabetes, and the like (Pamphlet of International Publication No. 2006/011495 and International Publication No. 2008). / 015763 pamphlet).
　発明者らは、有効成分としてスタチン系薬剤であるピタバスタチンとフィブラート系薬剤であるフェノフィブラートを含有するカプセル製剤を検討していたところ、両成分を組み合わせた組成物をカプセルに充填させた場合にピタバスタチンの一部が分解し分解物が生じることが判明し、ピタバスタチンの安定性に改善の余地が生じた。本課題についてはこれまでに何ら報告等はされていない。本発明は、上記ピタバスタチン及びフェノフィブラートを含有するカプセル剤におけるピタバスタチンの安定性を改善するものである。 The inventors have examined a capsule preparation containing pitavastatin, which is a statin drug, and fenofibrate, a fibrate drug, as active ingredients. When a capsule is filled with a composition in which both ingredients are combined, pitavastatin As a result, it was found that a part of the lysate was decomposed to produce a decomposition product, and there was room for improvement in the stability of pitavastatin. There have been no reports on this issue so far. The present invention improves the stability of pitavastatin in capsules containing the above pitavastatin and fenofibrate.
　そこで、本発明者らは、ピタバスタチン及びフェノフィブラートを含有するカプセル剤の安定性を改善すべく種々検討した結果、ピタバスタチン及びフェノフィブラートを含有するカプセル製剤用組成物中に、酸化マグネシウム及び／又は水酸化マグネシウムを配合することで、該組成物をカプセルに充填した場合においても、経時的に安定なカプセル剤が得られることを見出し、本発明を完成した。 Accordingly, as a result of various studies to improve the stability of capsules containing pitavastatin and fenofibrate, the present inventors have found that magnesium oxide and / or water are contained in the composition for capsule formulations containing pitavastatin and fenofibrate. By adding magnesium oxide, it was found that even when the composition was filled in a capsule, a stable capsule was obtained over time, and the present invention was completed.
　すなわち本発明は、ピタバスタチン、またはその塩及びフェノフィブラートを含有するカプセル製剤用組成物であって、酸化マグネシウム及び／又は水酸化マグネシウムを配合することを特徴とするカプセル製剤用組成物である。
　また、本発明は、ピタバスタチン、またはその塩とフェノフィブラートを含有する組成物に、酸化マグネシウム及び／又は水酸化マグネシウムを配合した組成物をカプセルに充填して得られるカプセル製剤である。
　更に、本発明は、ピタバスタチン、またはその塩及びフェノフィブラートを含有するカプセル製剤の製造方法であって、ピタバスタチンと酸化マグネシウム及び／又は水酸化マグネシウムを含有する組成物とフェノフィブラートを含有する組成物をそれぞれ調製し、カプセルに充填するカプセル製剤の製造方法である。 That is, the present invention is a capsule preparation composition containing pitavastatin or a salt thereof and fenofibrate, wherein the composition contains magnesium oxide and / or magnesium hydroxide.
Moreover, this invention is a capsule formulation obtained by filling the composition which mix | blended magnesium oxide and / or magnesium hydroxide with the composition containing pitavastatin or its salt, and fenofibrate.
Furthermore, the present invention relates to a method for producing a capsule preparation containing pitavastatin or a salt thereof and fenofibrate, comprising a composition containing pitavastatin and magnesium oxide and / or magnesium hydroxide and a composition containing fenofibrate. It is the manufacturing method of the capsule formulation which each prepares and fills a capsule.
　本発明のカプセル製剤用組成物及び該組成物を充填したカプセル製剤は、有効成分としてピタバスタチン及びフェノフィブラートをカプセルに充填した際に生じるピタバスタチンの分解物（ラクトン体）の生成を抑制することができ、カプセル剤の経時的安定性が改善するという効果を奏する。 The composition for capsule preparation of the present invention and the capsule preparation filled with the composition can suppress the formation of pitavastatin degradation product (lactone form) that occurs when pitavastatin and fenofibrate are filled into the capsule as active ingredients. The capsule has the effect of improving the stability over time.
ピタバスタチン及びフェノフィブラートを含有するカプセル剤において、安定化剤の種類による６０℃で一週間保存後の安定性を比較したグラフ。The graph which compared the stability after storage for one week at 60 degreeC by the kind of stabilizer in the capsule containing pitavastatin and fenofibrate.
　本発明のカプセル剤は、有効成分としてピタバスタチン及びフェノフィブラートを含有するカプセル製剤用組成物を充填して得られるカプセル製剤である。 The capsule of the present invention is a capsule preparation obtained by filling a composition for capsule preparation containing pitavastatin and fenofibrate as active ingredients.
　上記ピタバスタチンは、強いＨＭＧ－ＣｏＡ還元酵素阻害作用を有し、高脂血症治療剤や、アテローム性動脈硬化症治療剤として有用である一方、低ｐＨにおいての安定性に問題があり、安定性について様々な検討がなされている化合物である。本発明においてピタバスタチンとは、フリーのピタバスタチンのみならず、無機塩基又は有機塩基などとの塩、例えばカルシウム塩、ナトリウム塩、アルキルアミン塩などであってもよく、カルシウム塩が特に好ましい。 The above pitavastatin has a strong HMG-CoA reductase inhibitory action and is useful as a hyperlipidemia treatment agent or an atherosclerosis treatment agent, but has a problem in stability at low pH and is stable. It is a compound for which various studies have been made. In the present invention, pitavastatin may be not only free pitavastatin but also a salt with an inorganic base or an organic base, such as calcium salt, sodium salt, alkylamine salt, etc., and calcium salt is particularly preferable.
　上記フェノフィブラートは、血中コレステロール及び血中トリグリセリドを低下させる作用を有し、高脂血症の予防・治療剤として有用である。フェノフィブラートは、吸収性を向上させるため、予め固形界面活性剤と混合粉砕される事が好ましい。上記固形界面活性剤としては、ラウリルアルコールのアルカリ金属硫酸塩（例：ラウリル硫酸ナトリウム）、酸化エチレン・酸化プロピレン共重合物（例：ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコール）、ショ糖脂肪酸エステル等が使用され、これらの中でラウリル硫酸ナトリウムが特に好ましい。 The above fenofibrate has an action of lowering blood cholesterol and blood triglycerides, and is useful as a prophylactic / therapeutic agent for hyperlipidemia. Fenofibrate is preferably mixed and ground in advance with a solid surfactant in order to improve absorbability. Examples of the solid surfactant include alkali metal sulfate of lauryl alcohol (eg, sodium lauryl sulfate), ethylene oxide / propylene oxide copolymer (eg, polyoxyethylene (105) polyoxypropylene (5) glycol), Sugar fatty acid esters and the like are used, and among these, sodium lauryl sulfate is particularly preferable.
　上記固形界面活性剤の配合量は、フェノフィブラート１００重量部に対して１～１０重量部が好ましく、特に２～５重量部が好ましい。固形界面活性剤とフェノフィブラートは、製剤製造上通常用いられる微粉砕化装置（例：ジェットミル、ハンマーミル、振動ボールミル）によって混合粉砕される。混合粉砕は、例えば特公平７－１４８７６号公報に記載の方法に準じて行うことができ、その平均粒度は１５μｍより小さく、好ましくは１０μｍより小さく、特に好ましくは５μｍより小さい粉末であることが好ましい。 The amount of the solid surfactant is preferably 1 to 10 parts by weight, particularly 2 to 5 parts by weight, based on 100 parts by weight of fenofibrate. The solid surfactant and fenofibrate are mixed and pulverized by a pulverizing apparatus (eg, a jet mill, a hammer mill, a vibrating ball mill) usually used in the preparation of a preparation. The mixing and pulverization can be performed, for example, according to the method described in JP-B-7-14876, and the average particle size thereof is preferably less than 15 μm, preferably less than 10 μm, particularly preferably less than 5 μm. .
　本発明のカプセル製剤用組成物は、酸化マグネシウム及び／又は水酸化マグネシウムを配合することを特徴とする。本発明者らは、ピタバスタチン及びフェノフィブラートを組み合わせたカプセル剤を検討していたところ、ピタバスタチンとフェノフィブラートを組み合わせたカプセル剤においてピタバスタチンが分解し、そのラクトン体などの分解物が生じることによりピタバスタチンの安定性が損なわれることを見出した。その理由は定かではないが、ピタバスタチンとフェノフィブラートを組み合わせた場合に、フェノフィブラートが何らかの形でピタバスタチンに作用していること、及びカプセルの剤皮に含まれる水分が何らかの形で影響しているのではないかと発明者は考えている。本発明では両成分を含有するカプセル製剤用組成物に、酸化マグネシウム及び／又は水酸化マグネシウムを配合することで、該組成物をカプセルに充填した場合であっても、分解物の生成を抑制し、経時的に安定なカプセル剤を得ることができる。 The composition for capsule preparation of the present invention is characterized by containing magnesium oxide and / or magnesium hydroxide. The inventors of the present invention have been studying capsules combining pitavastatin and fenofibrate. As a result, pitavastatin is decomposed in a capsule combining pitavastatin and fenofibrate, and a decomposition product such as a lactone form thereof is generated, thereby producing pitavastatin. It has been found that stability is impaired. The reason is not clear, but when pitavastatin and fenofibrate are combined, fenofibrate is acting on pitavastatin in some way, and the moisture contained in the capsule skin is somehow affecting it. The inventor thinks that. In the present invention, by adding magnesium oxide and / or magnesium hydroxide to a composition for capsule preparation containing both components, even when the composition is filled in a capsule, the formation of decomposition products is suppressed. Capsules that are stable over time can be obtained.
　本発明のカプセル製剤用組成物には、有効成分であるピタバスタチン及びフェノフィブラート並びに酸化マグネシウム及び／又は水酸化マグネシウム以外に、本発明の効果を損なわない範囲で、カプセル製剤用組成物に通常含有することができるその他の成分を含有することができる。これらの成分としては、賦形剤、結合剤、崩壊剤、流動化剤、滑沢剤等が挙げられる。 In addition to pitavastatin and fenofibrate and magnesium oxide and / or magnesium hydroxide, which are active ingredients, the composition for capsule preparation of the present invention usually contains the composition for capsule preparation within a range not impairing the effects of the present invention. Other ingredients that can be included. These components include excipients, binders, disintegrants, fluidizing agents, lubricants and the like.
　上記賦形剤としては、例えば、乳糖水和物、コーンスターチ、Ｄ－マンニトール、Ｄ－ソルビトール、結晶セルロース等を用いることができ、上記結合剤としては、例えば、ヒドロキシプロピルセルロース、ヒプロメロース、ポビドン、ポリビニルアルコール（部分けん化物）、アルファー化デンプン等を用いることができ、上記崩壊剤としては、例えば、低置換度ヒドロキシプロピルセルロース、カルメロース、カルボキシメチルスターチナトリウム、カルメロースカルシウム、トウモロコシデンプン、部分アルファー化デンプン、クロスカルメロースナトリウム、クロスポピドン等を用いることができる。 Examples of the excipient include lactose hydrate, corn starch, D-mannitol, D-sorbitol, and crystalline cellulose. Examples of the binder include hydroxypropyl cellulose, hypromellose, povidone, polyvinyl Alcohol (partially saponified product), pregelatinized starch and the like can be used. Examples of the disintegrant include low-substituted hydroxypropylcellulose, carmellose, sodium carboxymethyl starch, carmellose calcium, corn starch, and partially pregelatinized starch. Croscarmellose sodium, crospovidone, etc. can be used.
　また、上記流動化剤としては、例えば、軽質無水ケイ酸、含水二酸化ケイ素、タルク等を用いることができ、上記滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸、ステアリン酸カルシウム、タルク等を用いることができる。 Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, and talc. Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, and talc. Can be used.
　本発明のカプセル剤は、ピタバスタチン及びフェノフィブラート、酸化マグネシウム及び／又は水酸化マグネシウム並びにその他の成分を全て混合し、組成物とした後に、カプセルに充填する方法により製造することができる。また、ピタバスタチン及びフェノフィブラートをそれぞれピタバスタチン含有組成物及びフェノフィブラート含有組成物として別々に調製した後にカプセルに充填することにより製造することもでき、上記ピタバスタチン含有組成物に上記酸化マグネシウム及び／又は水酸化マグネシウムを配合する。このようにピタバスタチンとフェノフィブラートを別々の組成物として調製した後に、カプセルに充填して製造するカプセル剤は、ピタバスタチンの分解をより抑制することができ、好ましい。上記組成物としては、例えば顆粒とすることが挙げられ、その粒径については、通常カプセル剤中に充填する組成物の大きさであれば特段の制限はない。 The capsule of the present invention can be produced by a method in which pitavastatin and fenofibrate, magnesium oxide and / or magnesium hydroxide and other components are all mixed to form a composition and then filled into a capsule. It can also be produced by separately preparing pitavastatin and fenofibrate as a pitavastatin-containing composition and a fenofibrate-containing composition, respectively, and filling them into capsules. Add magnesium. Thus, after preparing pitavastatin and fenofibrate as separate compositions, capsules manufactured by filling capsules are preferable because they can further suppress the degradation of pitavastatin. Examples of the composition include granules, and the particle size is not particularly limited as long as it is the size of the composition usually filled in a capsule.
　本発明のカプセル製剤用組成物中に於いて、有効成分であるピタバスタチンは０．１～５重量％含有することが好ましく、０．２～３重量％含有することがより好ましく、０．３～１．５重量％含有することが特に好ましい。一方、有効成分であるフェノフィブラートは、１～９９重量％含有することが好ましく、１０～８０重量％含有することがより好ましく、３０～７０重量％含有することが特に好ましい。酸化マグネシウム及び／又は水酸化マグネシウムは０．００１～２０重量％含有することが好ましく、０．０１～２重量％含有することがより好ましい。 In the capsule pharmaceutical composition of the present invention, the active ingredient pitavastatin is preferably 0.1 to 5% by weight, more preferably 0.2 to 3% by weight, and more preferably 0.3 to 3% by weight. It is particularly preferable to contain 1.5% by weight. On the other hand, fenofibrate, which is an active ingredient, is preferably contained in an amount of 1 to 99% by weight, more preferably 10 to 80% by weight, and particularly preferably 30 to 70% by weight. Magnesium oxide and / or magnesium hydroxide is preferably contained in an amount of 0.001 to 20% by weight, more preferably 0.01 to 2% by weight.
　本発明のカプセル剤は、１日１回の投与形態であっても、１日数回、例えば、２～６回、好ましくは１日３回の小分けされた投与状態であってもよい。また、投与量は、ピタバスタチンとして成人１日当たり０．１～１０ｍｇ、好ましくは０．５～５ｍｇの範囲で選択され、フェノフィブラートとして成人１日当たり１０～４００ｍｇ、好ましくは５０～２５０ｍｇの範囲で選択される。 The capsule of the present invention may be in a dosage form once a day or in a divided dosage state several times a day, for example, 2 to 6 times, preferably 3 times a day. The dosage is selected as pitavastatin in the range of 0.1 to 10 mg, preferably 0.5 to 5 mg per day for adults, and as fenofibrate in the range of 10 to 400 mg, preferably 50 to 250 mg per day for adults. The
　本発明のカプセル剤が、有効成分をそれぞれ別々の組成物としてカプセルに充填する製造方法を採用する場合には、ピタバスタチン含有組成物中に於いて、ピタバスタチンと酸化マグネシウム及び／又は水酸化マグネシウムの含有量の重量比は、１：０．００１～１：２０、特に１：０．０１～１：３とすると、より安定的なカプセル剤を得ることができ好ましい。また、本発明のカプセル剤中、ピタバスタチン含有組成物とフェノフィブラート含有組成物の充填割合は、薬効作用が十分に発揮できる観点から、１：０．１～１：２００、特に１：０．５～１：１００であることが好ましい。 When the capsule of the present invention employs a production method in which the active ingredient is filled in the capsules as separate compositions, the pitavastatin-containing composition contains pitavastatin and magnesium oxide and / or magnesium hydroxide. When the weight ratio of the amount is 1: 0.001 to 1:20, particularly 1: 0.01 to 1: 3, a more stable capsule can be obtained. In the capsule of the present invention, the filling ratio of the pitavastatin-containing composition and the fenofibrate-containing composition is 1: 0.1 to 1: 200, particularly 1: 0.5, from the viewpoint that the medicinal effect can be sufficiently exerted. It is preferably ˜1: 100.
　本発明のカプセル剤が、有効成分をそれぞれ別々の組成物としてカプセルに充填する製造方法を採用する場合には、例えば以下のような方法により製造することができる。まず、ピタバスタチン、酸化マグネシウム及び／又は水酸化マグネシウム、必要に応じ賦形剤、結合剤及び崩壊剤などを混合する。次にこの混合物に水を加え、攪拌造粒し、乾燥・整粒してピタバスタチン含有の乾燥顆粒とする。同様に、フェノフィブラート、固形界面活性剤、必要に応じ賦形剤、結合剤、流動化剤及び崩壊剤などを混合し、混合物に水を加え、攪拌造粒し、乾燥・整粒してフェノフィブラート含有の乾燥顆粒とする。最後に得られた両乾燥顆粒をカプセル中に充填する。 When the capsule of the present invention employs a production method in which the active ingredient is filled in the capsule as separate compositions, it can be produced, for example, by the following method. First, pitavastatin, magnesium oxide and / or magnesium hydroxide, and if necessary, an excipient, a binder and a disintegrant are mixed. Next, water is added to the mixture, granulated with stirring, dried and sized to obtain dry granules containing pitavastatin. Similarly, fenofibrate, solid surfactant, if necessary, excipient, binder, fluidizer and disintegrant are mixed, water is added to the mixture, stirring granulation, drying and sizing, and phenotype. Dry granules containing fibrate. Finally, both dry granules obtained are filled into capsules.
　本発明で用いるカプセルは、一般に市場において容易に入手可能なものであり、カプセルの剤皮としては、特に制限なく使用することができる。このような剤皮としては、例えば、ゼラチン、ヒプロメロース、ポリビニルアルコール、プルラン等が挙げられ、ゼラチンが特に好ましい。ゼラチンカプセルを用いる場合、カプセル中のゼラチンの含有量は、カプセルの機械的強度や成形時の皮膜の均一性を考慮して適宜検討すればよいが、カプセル皮膜全量に対して、５０～９９．５重量％が好ましく、６５～９９重量％がより好ましい。 The capsules used in the present invention are generally readily available on the market, and can be used without particular limitation as the capsule skin. Examples of such a coating include gelatin, hypromellose, polyvinyl alcohol, pullulan and the like, and gelatin is particularly preferable. When gelatin capsules are used, the gelatin content in the capsules may be appropriately determined in consideration of the mechanical strength of the capsules and the uniformity of the coating film during molding. 5 wt% is preferable, and 65 to 99 wt% is more preferable.
　また、カプセル剤皮中には、通常水分が４～１５％程度含まれているが、この範囲をはずれた水分量のカプセルを用いた場合でも、本発明のカプセル製剤用組成物は安定性の効果を奏する。特にゼラチンカプセル中には１３～１５％程度水分が含まれており、このような水分の含有量が高いカプセルに対しても安定性を発揮できる。更に、カプセル剤皮には、必要に応じて、マクロゴール、グリセリン、ソルビット、防腐剤、着色剤、酸化チタン等の各種の添加剤を配合することができる。 In addition, the capsule skin usually contains about 4 to 15% of water, but the capsule formulation composition of the present invention is stable even when capsules having a water content outside this range are used. There is an effect. In particular, gelatin capsules contain about 13 to 15% of moisture, and the capsules having such a high moisture content can exhibit stability. Furthermore, various additives such as macrogol, glycerin, sorbit, preservative, colorant, titanium oxide and the like can be blended in the capsule skin as necessary.
　ゼラチンカプセルを用いた場合には、カプセルの軟化や割れを防止する点から、ゼラチン剤皮中にマクロゴールを含有した剤皮を用いてもよい。ここで、マクロゴールの含有量は、カプセルの機械的強度や成形時の皮膜の均一性を考慮して適宜検討すればよいが、カプセル皮膜全量に対して、０．５～１５重量％が好ましく、１～１０重量％がより好ましい。マクロゴールの平均分子量は、特に限定されるものではないが、カプセルの軟化や割れを防止する点から、９５０～２５０００が好ましく、２５００～７０００がより好ましく、マクロゴール１０００、マクロゴール１５００、マクロゴール１５４０、マクロゴール４０００、マクロゴール６０００がさらに好ましく、マクロゴール４０００が特に好ましい。マクロゴールは１種だけ用いても、複数の混合物として用いてもよい。 When gelatin capsules are used, a coating containing macrogol in the gelatin coating may be used from the viewpoint of preventing softening and cracking of the capsule. Here, the content of the macrogol may be appropriately examined in consideration of the mechanical strength of the capsule and the uniformity of the film during molding, but is preferably 0.5 to 15% by weight with respect to the total amount of the capsule film. 1 to 10% by weight is more preferable. The average molecular weight of macrogol is not particularly limited, but is preferably from 950 to 25000, more preferably from 2500 to 7000, from the viewpoint of preventing capsule softening and cracking. Macrogol 1000, Macrogol 1500, Macrogol 1540, macrogol 4000, and macrogol 6000 are more preferable, and macrogol 4000 is particularly preferable. Only one macrogol may be used, or a plurality of mixtures may be used.
　以下、本発明のカプセル剤を実施例にて詳細に示すが、本発明はこれらの実施例に限定されるものではない。 Hereinafter, the capsules of the present invention will be described in detail in Examples, but the present invention is not limited to these Examples.
＜ピタバスタチン含有組成物１の製造＞
　ピタバスタチンカルシウム１２ｇ、乳糖水和物２３４．６ｇ、ヒプロメロース９ｇ、低置換度ヒドロキシプロピルセルロース（信越化学工業：ＬＨ－１１）３０ｇ、酸化マグネシウム１４．４ｇを混合し、精製水６０ｇを入れ練合・乾燥・整粒し、顆粒のピタバスタチン含有組成物１を得た。 <Production of pitavastatin-containing composition 1>
Pitavastatin calcium 12g, lactose hydrate 234.6g, hypromellose 9g, low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd .: LH-11) 30g, magnesium oxide 14.4g, mixed with purified water 60g, kneaded and dried -The particle size was adjusted to obtain a granulated pitavastatin-containing composition 1.
＜ピタバスタチン含有組成物２の製造＞
　酸化マグネシウムを炭酸水素ナトリウムに変更した以外は、上記ピタバスタチン含有組成物１と同様に製造し、顆粒のピタバスタチン含有組成物２を得た。 <Production of pitavastatin-containing composition 2>
A granulated pitavastatin-containing composition 2 was obtained in the same manner as the pitavastatin-containing composition 1 except that the magnesium oxide was changed to sodium bicarbonate.
＜ピタバスタチン含有組成物３の製造＞
　酸化マグネシウムを炭酸カルシウムに変更した以外は、上記ピタバスタチン含有組成物１と同様に製造し、顆粒のピタバスタチン含有組成物３を得た。 <Production of pitavastatin-containing composition 3>
A granulated pitavastatin-containing composition 3 was obtained in the same manner as the pitavastatin-containing composition 1 except that the magnesium oxide was changed to calcium carbonate.
＜ピタバスタチン含有組成物４の製造＞
　酸化マグネシウムをＬ－アルギニンに変更した以外は、上記ピタバスタチン含有組成物１と同様に製造し、顆粒のピタバスタチン含有組成物４を得た。 <Production of pitavastatin-containing composition 4>
A granulated pitavastatin-containing composition 4 was obtained in the same manner as the pitavastatin-containing composition 1 except that the magnesium oxide was changed to L-arginine.
＜ピタバスタチン含有組成物５の製造＞
　酸化マグネシウムをリン酸水素二カリウムに変更した以外は、上記ピタバスタチン含有組成物１と同様に製造し、顆粒のピタバスタチン含有組成物５を得た。 <Production of pitavastatin-containing composition 5>
A granulated pitavastatin-containing composition 5 was obtained in the same manner as the pitavastatin-containing composition 1 except that the magnesium oxide was changed to dipotassium hydrogen phosphate.
＜ピタバスタチン含有組成物６の製造＞
　酸化マグネシウムをメタケイ酸アルミン酸マグネシウムに変更した以外は、上記ピタバスタチン含有組成物１と同様に製造し、顆粒のピタバスタチン含有組成物６を得た。 <Production of pitavastatin-containing composition 6>
A granulated pitavastatin-containing composition 6 was obtained in the same manner as the pitavastatin-containing composition 1 except that the magnesium oxide was changed to magnesium aluminate metasilicate.
＜フェノフィブラート含有組成物７の製造＞
　フェノフィブラート２００ｇとラウリル硫酸ナトリウム７ｇを混合粉砕し、微粉化フェノフィブラートを得た。得られた微粉化フェノフィブラート２０７ｇ、乳糖水和物５．５ｇ、アルファー化デンプン３０ｇ、クロスポビドン５ｇ、軽質無水ケイ酸２．５ｇを混合し、精製水５０ｇを入れ練合・乾燥・整粒し、顆粒のフェノフィブラート含有組成物７を得た。 <Production of fenofibrate-containing composition 7>
200 g of fenofibrate and 7 g of sodium lauryl sulfate were mixed and ground to obtain micronized fenofibrate. 207 g of the finely divided fenofibrate obtained, 5.5 g of lactose hydrate, 30 g of pregelatinized starch, 5 g of crospovidone, and 2.5 g of light anhydrous silicic acid are mixed, and 50 g of purified water is added, kneaded, dried and sized. A granular fenofibrate-containing composition 7 was obtained.
＜実施例１（１顆粒カプセル剤）＞
　フェノフィブラート２００ｇとラウリル硫酸ナトリウム７ｇを混合粉砕し、微粉化フェノフィブラートを得た。
　ピタバスタチンカルシウム２ｇ、乳糖水和物４４．６ｇ、ヒプロメロース１．５ｇ、低置換度ヒドロキシプロピルセルロース５ｇ、酸化マグネシウム２．４ｇ、微粉化フェノフィブラート２０７ｇ、アルファー化デンプン３０ｇ、クロスポビドン５ｇ、軽質無水ケイ酸２．５ｇを混合し、精製水６０ｇを入れ練合・乾燥・整粒し顆粒を得た。得られた顆粒を１カプセル当たり３００ｍｇとなるように１号ゼラチンカプセルに充填し５カプセル調製した。 <Example 1 (one granule capsule)>
200 g of fenofibrate and 7 g of sodium lauryl sulfate were mixed and ground to obtain micronized fenofibrate.
Pitavastatin calcium 2 g, lactose hydrate 44.6 g, hypromellose 1.5 g, low-substituted hydroxypropylcellulose 5 g, magnesium oxide 2.4 g, micronized fenofibrate 207 g, pregelatinized starch 30 g, crospovidone 5 g, light anhydrous silicic acid 2.5 g was mixed, 60 g of purified water was added, kneaded, dried and sized to obtain granules. The obtained granules were filled into No. 1 gelatin capsules to give 300 capsules per capsule to prepare 5 capsules.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
＜製造例１～６（ピタバスタチン含有カプセル剤）＞
　ピタバスタチン含有組成物１～６を、１カプセル当たり５０ｍｇとなるように１号ゼラチンカプセルに充填し５カプセル調製した。 <Production Examples 1 to 6 (capsule containing pitavastatin)>
5 capsules were prepared by filling No. 1 gelatin capsules with pitavastatin-containing compositions 1 to 6 at 50 mg per capsule.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
＜実施例２（ピタバスタチン及びフェノフィブラート含有カプセル剤）＞
　５ｇのピタバスタチン含有組成物１と、２５ｇのフェノフィブラート含有組成物７とを均一に混合し、その混合物を１カプセル当たり３００ｍｇとなるように１号ゼラチンカプセルに充填し５カプセル調製した。 <Example 2 (capsule containing pitavastatin and fenofibrate)>
5 g of pitavastatin-containing composition 1 and 25 g of fenofibrate-containing composition 7 were uniformly mixed, and the mixture was filled into No. 1 gelatin capsules to give 300 mg per capsule to prepare 5 capsules.
＜比較例１～５（ピタバスタチン及びフェノフィブラート含有カプセル剤）＞
　ピタバスタチン含有組成物１をピタバスタチン含有組成物２～６にそれぞれ変更した以外については実施例２と同様にして、それぞれ５カプセルずつ調製した。 <Comparative Examples 1 to 5 (capsules containing pitavastatin and fenofibrate)>
Five capsules were prepared in the same manner as in Example 2 except that the pitavastatin-containing composition 1 was changed to pitavastatin-containing compositions 2 to 6, respectively.
＜試験例＞
　１）１ｇのピタバスタチン含有組成物１～６を各々褐色２号瓶に充填し、それぞれ６０℃で一週間保存後の分解物（ラクトン体）の生成率を確認した。結果を表３に示す。
　２）製造例１～６のカプセル５個を褐色２号瓶に充填し、それぞれ６０℃で一週間保存後の分解物（ラクトン体）の生成率を確認した。結果を表４に示す。
　３）実施例１、２及び比較例１～５のカプセル５個を褐色２号瓶に充填し、それぞれ６０℃で一週間保存後の分解物（ラクトン体）の生成率を確認した。結果を表５に示す。 <Test example>
1) 1 g of pitavastatin-containing compositions 1 to 6 was filled in each brown No. 2 bottle, and the production rate of degradation products (lactones) after storage at 60 ° C. for 1 week was confirmed. The results are shown in Table 3.
2) Five capsules of Production Examples 1 to 6 were filled in a brown No. 2 bottle, and the rate of formation of degradation products (lactones) after one week storage at 60 ° C. was confirmed. The results are shown in Table 4.
3) Five capsules of Examples 1 and 2 and Comparative Examples 1 to 5 were filled in a brown No. 2 bottle, and the rate of formation of degradation products (lactones) after storage at 60 ° C. for 1 week was confirmed. The results are shown in Table 5.
＜分解物の測定＞
　分解物の測定は、以下の条件にて液体クロマトグラフ法により定量した。
検出器：紫外吸光光度計（測定波長：２４５ｎｍ）
カラム温度：４０℃付近の一定温度
カラム：液体クロマトグラフ用オクタデシルシリル化シリカゲル（４．６ｍｍ×２５ｃｍ、φ５μｍ）
移動相：メタノール／０．０２ｍｏｌ／Ｌリン酸塩緩衝液（ｐＨ３）＝１３／７ <Measurement of degradation products>
The degradation product was quantified by a liquid chromatography method under the following conditions.
Detector: UV absorptiometer (measurement wavelength: 245 nm)
Column temperature: Constant temperature around 40 ° C. Column: Octadecylsilylated silica gel for liquid chromatography (4.6 mm × 25 cm, φ5 μm)
Mobile phase: methanol / 0.02 mol / L phosphate buffer (pH 3) = 13/7
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
＜実施例３～７＞
　実施例２と同様に、表６に示す処方でカプセル剤を各々調製し、試験例と同様な方法で６０℃で一週間保存後の分解物の生成率を確認した。その結果を表６に示す。 <Examples 3 to 7>
In the same manner as in Example 2, capsules were prepared according to the formulation shown in Table 6, and the production rate of the degradation product after storage at 60 ° C. for 1 week was confirmed by the same method as in the test example. The results are shown in Table 6.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
＜実施例８、９＞
　実施例２と同様に、表７に示す処方でカプセル剤を各々調製し、試験例と同様な方法で４０℃で６ヶ月間保存後の分解物の生成率を確認した。その結果を表７に示す。 <Examples 8 and 9>
In the same manner as in Example 2, capsules were prepared according to the formulation shown in Table 7, and the production rate of the degradation product after storage at 40 ° C. for 6 months was confirmed by the same method as in the test example. The results are shown in Table 7.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
＜実施例１０＞
　酸化マグネシウムを水酸化マグネシウムに変更した以外は実施例２と同様にしてカプセル剤を調製し、試験例と同様な方法で６０℃で一週間保存後の分解物の生成率を確認した。その結果を表８に示す。 <Example 10>
Capsules were prepared in the same manner as in Example 2 except that the magnesium oxide was changed to magnesium hydroxide, and the rate of degradation products after storage at 60 ° C. for 1 week was confirmed by the same method as in the test examples. The results are shown in Table 8.
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
　以上より、ピタバスタチン及びフェノフィブラートを含有する組成物中に、酸化マグネシウムまたは水酸化マグネシウムを配合したカプセル剤は、分解物の生成が抑制され、経時的に安定であった。 From the above, capsules containing pitavastatin and fenofibrate in a composition containing magnesium oxide or magnesium hydroxide were stable over time because the formation of decomposition products was suppressed.

Claims (3)

  1. 　ピタバスタチン、またはその塩及びフェノフィブラートを含有するカプセル製剤用組成物であって、酸化マグネシウム及び／又は水酸化マグネシウムを配合することを特徴とするカプセル製剤用組成物。 A capsule preparation composition containing pitavastatin or a salt thereof and fenofibrate, wherein the composition contains magnesium oxide and / or magnesium hydroxide.
  2. 　ピタバスタチン、またはその塩及びフェノフィブラートを含有するカプセル製剤であって、カプセル中に請求項１に記載のカプセル製剤用組成物を充填して得られることを特徴とするカプセル製剤。 A capsule preparation containing pitavastatin or a salt thereof and fenofibrate, wherein the capsule preparation is obtained by filling the capsule preparation composition according to claim 1 in the capsule.
  3. 　ピタバスタチン、またはその塩及びフェノフィブラートを含有するカプセル製剤の製造方法であって、ピタバスタチン、またはその塩と酸化マグネシウム及び／又は水酸化マグネシウムを含有する組成物とフェノフィブラートを含有する組成物をそれぞれ別々に調製し、カプセル中に充填することを特徴とするカプセル製剤の製造方法。 A method for producing a capsule preparation containing pitavastatin or a salt thereof and fenofibrate, wherein the composition containing pitavastatin or a salt thereof and magnesium oxide and / or magnesium hydroxide and the composition containing fenofibrate are separated from each other A method for producing a capsule preparation, characterized in that the preparation is filled in a capsule.
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