JP4138209B2 - Pravastatin-containing composition - Google Patents
Pravastatin-containing composition Download PDFInfo
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- JP4138209B2 JP4138209B2 JP2000196313A JP2000196313A JP4138209B2 JP 4138209 B2 JP4138209 B2 JP 4138209B2 JP 2000196313 A JP2000196313 A JP 2000196313A JP 2000196313 A JP2000196313 A JP 2000196313A JP 4138209 B2 JP4138209 B2 JP 4138209B2
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- pravastatin sodium
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- pravastatin
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Description
【０００１】
【発明の属する技術分野】
本発明は、高脂血症治療剤であるプラバスタチンナトリウムを含有する組成物に関するものであり医薬分野における発明である。
【０００２】
【従来の技術】
プラバスタチンナトリウムは、コレステロール生合成系の律速酵素であるHMG-CoA還元酵素を特異的・拮抗的に阻害することにより、血清コレステロール値を速やかにかつ強力に低下し血清脂質を改善する高脂血症、家族性高コレステロール血症治療剤であり、臨床的に世界中で広く用いられている薬剤である。プラバスタチンナトリウムは、白色〜微灰黄白色の粉末又は結晶性の粉末で、苦味を有している。このため治療に供される製剤、例えば細粒剤及び錠剤は高分子物質によりコーティングする等、患者が服用しやすいように工夫する必要があった。
【０００３】
【発明が解決しようとする課題】
プラバスタチンナトリウムは、比較的不安定な化合物であり、種々の製剤化助剤と反応するため、良好な安定性を確保するためにいろいろな工夫が行われている。例えば、特許第２９３５２２０号公報にはプラバスタチン及び水に分散したときのｐＨが９以上となる塩基性化剤からなる安定性良好な医薬組成物が開示されている。しかし、さらなる安定化技術及び苦味を防止できる技術が求められており、本発明者はこれら課題を解決するため鋭意検討した結果、全く意外なことに以下に示す構成により、課題を解決できることを見い出し本発明を完成した。
【０００４】
【課題を解決するための手段】
本発明は、プラバスタチンナトリウム、糖類及び結合剤からなるプラバスタチンナトリウム含有組成物である。また、本発明は、プラバスタチンナトリウム、糖類、結合剤及びl-メントールからなるプラバスタチンナトリウム含有組成物である。更に、本発明はプラバスタチンナトリウム及び糖類を混合し、結合剤を溶解した水及び／又は水溶解性有機溶媒を加えて練合し、フィルムを介して圧縮成形する錠剤の製造方法である。本発明により製造した錠剤は、第１３改正日本薬局方崩壊試験法による崩壊試験を行うとき、０．０５〜３分で崩壊する。
【０００５】
プラバスタチンナトリウムは、化学名sodium(+)-(3R,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-[(S)-2-methylbutyryloxy]-1,2,6,7,8,8a-hexahydro-1-naphthyl]heptanoateであり、コレステロール生合成系の律速酵素であるHMG-CoA還元酵素を特異的・拮抗的に阻害することによる高脂血症、家族性高コレステロール治療剤である。プラバスタチンナトリウムは、従来公知の方法により製造することができる。
【０００６】
本発明における糖類とは、乳糖及びマンニトールである。乳糖及びマンニトールは単独で使用しても両者を同時に使用してもよい。また、本発明における結合剤は、ポリビニルピロリドン、ポリビニルアルコール、ヒドロキシプロピルメチルセルロース及びヒドロキシプロピルセルロースから選ばれる結合剤であり、これらを単独で使用しても２種以上を組合わせて使用してもよい。本発明において、プラバスタチンナトリウムと糖類及び結合剤の配合量は特に限定されないが、通常プラバスタチンナトリウム１重量部に対し、糖類９〜４９重量部及び結合剤０．０５〜５重量部であり、好ましくは、プラバスタチンナトリウム１重量部に対し、糖類１０〜４０重量部及び結合剤０．１〜５重量部である。
【０００７】
本発明においては、更にl-メントールを混合することができる。これにより、糖類による甘味に加え爽快感を付与することができ、服用した際のプラバスタチンナトリウムの苦味を軽減することができる。l-メントールの配合量は、製剤全量に対して０．０１〜０．５重量％、好ましくは０．０２〜０．３重量％である。更に、甘味成分としてステビアを添加するとプラバスタチンの苦味をより軽減することができる。
【０００８】
本発明にかかる組成物は、必要に応じて製剤化助剤を加えて顆粒剤、細粒剤とすることができ、更にカプセルに充填してカプセル剤とすることもでき、あるいは打錠して錠剤とすることもできる。プラバスタチンは不安定な薬物であるので、添加する製剤化助剤は全量の１０％までとすることが好ましい。更に、本願組成物は、エタノール等の水溶性有機溶媒及び／又は水を加えて練合し、モールド錠とするのに適している。練合時には結合剤をあらかじめ水溶性有機溶媒及び／又は水に溶解したものを添加して練合することもできる。モールド錠は、口腔内で速やかに崩壊するため老人にも服用しやすい剤形であり、例えば特開平８―１９５８９号公報に開示される装置によると生産スケールで製造することができる。本発明におけるモールド錠の第１３改正日本薬局方崩壊試験法による崩壊時間は、０．０５〜３分である。
【０００９】
【効果】
本発明にかかる組成物は、プラバスタチンナトリウムの安定性が良好で、更に苦味を軽減した服用しやすいものである。以下に本発明にかかる組成物の優れた効果を詳細に説明する。
試験例１
プラバスタチン１ｇに製剤化助剤１０ｇを加え乳鉢で混合後、その約１ｇをバイアル瓶に入れ４０℃湿度７５％の条件下で１週間開放保存した。結果を表１に示した。
【表１】
【００１０】
試験例２
実施例１〜３で得られた錠剤を、ＰＴＰ包装、ＰＴＰ／アルミ包装又は開放条件下で、冷所、２５℃湿度７５％、４０℃湿度７５％、４５℃、６０℃及び１０００luxで１ヶ月間保存したときのプラバスタチンの残存量及び分解物量を高速液体クロマトグラフィーにより測定した。対照として市販のプラバスタチン錠を用いた。結果を表２に示した。
【表２】
【００１１】
【実施例】
実施例１
プラバスタチン１００ｇ及びＤ−マンニトール１８９０ｇを混合し、更にポリビニルアルコール１０ｇを溶解したエタノール・水混合溶媒を２４０ｍｌ添加し練合した。この練合物を特開平８―１９５８９号公報で開示される装置を用いて製錠し、乾燥して１錠約２００ｍｇの錠剤を得た。この錠剤の第１３改正日本薬局方崩壊試験法による崩壊時間は、１４．２秒（６錠の平均）であった。
実施例２
プラバスタチン１００ｇ及びＤ−マンニトール１８８０ｇを混合し、更にポリビニルピロリドン２０ｇを溶解したエタノール・水混合溶媒を２４０ｍｌ添加し練合した。この練合物を特開平８―１９５８９号公報で開示される装置を用いて製錠し、乾燥して１錠約２００ｍｇの錠剤を得た。この錠剤の第１３改正日本薬局方崩壊試験法による崩壊時間は、１４．７秒（６錠の平均）であった。
【００１２】
実施例３
プラバスタチン５０ｇ及びＤ−マンニトール１５４０ｇを混合し、更にポリビニルアルコール８ｇを溶解したエタノール・水混合溶媒を１９２ｍｌ添加し練合した。この練合物を特開平８―１９５８９号公報で開示される装置を用いて製錠し、乾燥して１錠約１６０ｍｇの錠剤を得た。この錠剤の第１３改正日本薬局方崩壊試験法による崩壊時間は、５．８秒（６錠の平均）であった。
実施例４
プラバスタチン５０ｇ、Ｄ−マンニトール１０００ｇ及び乳糖５４０ｇを混合し、更にポリビニルアルコール８ｇを溶解したエタノール・水混合溶媒を２００ｍｌ添加し練合した。この練合物を押出し造粒機により造粒後、乾燥し顆粒剤を得た。
実施例５
プラバスタチン１ｇ及びＤ−マンニトール１８.７ｇを混合し、別にポリビニルアルコール２ｇ、ステビア４ｇ及び ｌ―メントール０．３６ｇをエタノール・水混合溶媒３２ｍｌに溶解し、そのを１.９ｍｌを添加し練合した。この練合物をオートグラフにより圧縮成形し、乾燥して１錠約１００ｍｇの錠剤を得た。この錠剤を服用したところ、苦味はほとんど気にならなかった。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a composition containing pravastatin sodium, which is a therapeutic agent for hyperlipidemia, and is an invention in the pharmaceutical field.
[0002]
[Prior art]
Pravastatin sodium is a hyperlipidemia that reduces serum cholesterol levels quickly and strongly by specifically and antagonistically inhibiting HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis. It is a therapeutic agent for familial hypercholesterolemia and is a drug that is widely used clinically all over the world. Pravastatin sodium is a white to slightly grayish yellowish white powder or crystalline powder and has a bitter taste. For this reason, preparations for treatment, such as fine granules and tablets, need to be devised so that the patient can easily take them, such as coating with a polymer substance.
[0003]
[Problems to be solved by the invention]
Pravastatin sodium is a relatively unstable compound and reacts with various formulation aids, so various devices have been devised to ensure good stability. For example, Japanese Patent No. 2935220 discloses a pharmaceutical composition with good stability comprising pravastatin and a basifying agent having a pH of 9 or more when dispersed in water. However, there is a need for further stabilization technology and technology that can prevent bitterness, and as a result of diligent study to solve these problems, the present inventors have found that the problem can be solved by the configuration shown below. The present invention has been completed.
[0004]
[Means for Solving the Problems]
The present invention is a pravastatin sodium-containing composition comprising pravastatin sodium, a saccharide and a binder. The present invention also relates to a pravastatin sodium-containing composition comprising pravastatin sodium, a saccharide, a binder, and l-menthol. Furthermore, this invention is a manufacturing method of the tablet which mixes pravastatin sodium and saccharides, adds the water and / or water-soluble organic solvent which melt | dissolved binder, knead | mixes, and compresses through a film. The tablet produced according to the present invention disintegrates in 0.05 to 3 minutes when performing a disintegration test according to the 13th revised Japanese Pharmacopoeia disintegration test method.
[0005]
Pravastatin sodium has the chemical name sodium (+)-(3R, 5R) -3,5-dihydroxy-7-[(1S, 2S, 6S, 8S, 8aR) -6-hydroxy-2-methyl-8-[( S) -2-methylbutyryloxy] -1,2,6,7,8,8a-hexahydro-1-naphthyl] heptanoate, specific and antagonistic to HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis It is a therapeutic agent for hyperlipidemia and familial hypercholesterol. Pravastatin sodium can be produced by a conventionally known method.
[0006]
The saccharides in the present invention are lactose and mannitol. Lactose and mannitol may be used alone or in combination. The binder in the present invention is a binder selected from polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropylmethylcellulose and hydroxypropylcellulose, and these may be used alone or in combination of two or more. . In the present invention, the blending amount of pravastatin sodium, saccharide and binder is not particularly limited, but is usually 9 to 49 parts by weight of saccharide and 0.05 to 5 parts by weight of binder with respect to 1 part by weight of pravastatin sodium, preferably , 10 to 40 parts by weight of saccharide and 0.1 to 5 parts by weight of binder with respect to 1 part by weight of pravastatin sodium.
[0007]
In the present invention, l-menthol can be further mixed. Thereby, in addition to the sweetness by saccharide | sugar, a refreshing feeling can be provided and the bitter taste of pravastatin sodium at the time of taking can be reduced. The amount of l-menthol is 0.01 to 0.5% by weight, preferably 0.02 to 0.3% by weight, based on the total amount of the preparation. Furthermore, the addition of stevia as a sweetening ingredient can further reduce the bitter taste of pravastatin.
[0008]
The composition according to the present invention can be made into granules and fine granules by adding formulation aids as necessary, and can be further filled into capsules to form capsules, or compressed into tablets. It can also be a tablet. Since pravastatin is an unstable drug, it is preferable that the formulation aid added is up to 10% of the total amount. Furthermore, the composition of the present application is suitable for forming a molded tablet by adding a water-soluble organic solvent such as ethanol and / or water and kneading. At the time of kneading, a binder previously dissolved in a water-soluble organic solvent and / or water can be added and kneaded. Molded tablets disintegrate rapidly in the oral cavity and are easy to take for the elderly. For example, according to the device disclosed in JP-A-8-19589, it can be produced on a production scale. The disintegration time of the molded tablet according to the present invention according to the 13th revised Japanese Pharmacopoeia disintegration test method is 0.05 to 3 minutes.
[0009]
【effect】
The composition according to the present invention has good stability of pravastatin sodium and is easy to take with reduced bitterness. Hereinafter, the excellent effects of the composition according to the present invention will be described in detail.
Test example 1
After adding 10 g of formulation aid to 1 g of pravastatin and mixing in a mortar, about 1 g was put in a vial and stored openly for one week under conditions of 40 ° C. and 75% humidity. The results are shown in Table 1.
[Table 1]
[0010]
Test example 2
Tablets obtained in Examples 1 to 3 for 1 month in PTP packaging, PTP / aluminum packaging or open conditions at cold, 25 ° C. humidity 75%, 40 ° C. humidity 75%, 45 ° C., 60 ° C. and 1000 lux The amount of pravastatin remaining and the amount of degradation products when stored for a while were measured by high performance liquid chromatography. A commercially available pravastatin tablet was used as a control. The results are shown in Table 2.
[Table 2]
[0011]
【Example】
Example 1
Pravastatin 100 g and D-mannitol 1890 g were mixed, and 240 ml of ethanol / water mixed solvent in which 10 g of polyvinyl alcohol was further dissolved was added and kneaded. This kneaded product was tableted using an apparatus disclosed in JP-A-8-19589 and dried to obtain about 200 mg of a tablet. The disintegration time of this tablet according to the 13th revised Japanese Pharmacopoeia disintegration test method was 14.2 seconds (average of 6 tablets).
Example 2
Pravastatin 100 g and D-mannitol 1880 g were mixed, and further 240 ml of ethanol / water mixed solvent in which 20 g of polyvinylpyrrolidone was dissolved was added and kneaded. This kneaded product was tableted using an apparatus disclosed in JP-A-8-19589 and dried to obtain about 200 mg of a tablet. The disintegration time of this tablet according to the 13th revised Japanese Pharmacopoeia disintegration test method was 14.7 seconds (average of 6 tablets).
[0012]
Example 3
Pravastatin 50 g and D-mannitol 1540 g were mixed, and further 192 ml of ethanol / water mixed solvent in which 8 g of polyvinyl alcohol was dissolved was added and kneaded. This kneaded product was tableted using an apparatus disclosed in JP-A-8-19589 and dried to obtain about 160 mg of a tablet. The disintegration time of this tablet according to the 13th revised Japanese Pharmacopoeia disintegration test method was 5.8 seconds (average of 6 tablets).
Example 4
Pravastatin 50 g, D-mannitol 1000 g and lactose 540 g were mixed, and 200 ml of an ethanol / water mixed solvent in which 8 g of polyvinyl alcohol was dissolved was further added and kneaded. The kneaded product was granulated with an extrusion granulator and then dried to obtain granules.
Example 5
1 g of pravastatin and 18.7 g of D-mannitol were mixed, and 2 g of polyvinyl alcohol, 4 g of stevia and 0.36 g of l-menthol were dissolved in 32 ml of an ethanol / water mixed solvent, and 1.9 ml thereof was added and kneaded. This kneaded product was compression-molded by an autograph and dried to obtain about 100 mg of a tablet. When I took this tablet, the bitterness was hardly noticed.
Claims (3)
糖類としてマンニトール、及び
結合剤として、ポリビニルピロリドン、ポリビニルアルコール、ヒドロキシプロピルメチルセルロース及びヒドロキシプロピルセルロースから選ばれる１種以上、
からなるプラバスタチンナトリウム含有組成物であって、
前記プラバスタチンナトリウム１重量部に対して、前記糖類９〜４９重量部及び前記結合剤０．０５〜５重量部を含有するプラバスタチンナトリウム含有組成物。Pravastatin sodium,
Ma as the saccharide N'nitoru, and as a binding agent, polyvinyl pyrrolidone, polyvinyl alcohol, one or more selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose,
A pravastatin sodium-containing composition comprising:
A pravastatin sodium-containing composition comprising 9 to 49 parts by weight of the saccharide and 0.05 to 5 parts by weight of the binder with respect to 1 part by weight of the pravastatin sodium.
結合剤としてポリビニルピロリドン、ポリビニルアルコール、ヒドロキシプロピルメチルセルロース及びヒドロキシプロピルセルロースから選ばれる１種以上を溶解した水及び／又は水溶解性有機溶媒を加えて練合し、
充填穴に充填後フィルムを介して圧縮成形する錠剤の製造方法であって、
前記錠剤は、第１３改正日本薬局方崩壊試験法による崩壊時間が０．０５から３分であり、かつ、
前記プラバスタチンナトリウム１重量部に対して、前記糖類９〜４９重量部及び前記結合剤０．０５〜５重量部を含有する、
錠剤の製造方法。Pravastatin sodium, as the sugars are mixed between N'nitoru,
Water and / or water-soluble organic solvent in which one or more selected from polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylmethylcellulose and hydroxypropylcellulose are added as a binder and kneaded,
A method for producing a tablet which is compression-molded through a film after filling in a filling hole,
The tablet has a disintegration time of 0.05 to 3 minutes according to the 13th revised Japanese Pharmacopoeia Disintegration Test, and
Containing 9 to 49 parts by weight of the saccharide and 0.05 to 5 parts by weight of the binder with respect to 1 part by weight of the pravastatin sodium,
Tablet manufacturing method.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000196313A JP4138209B2 (en) | 2000-06-29 | 2000-06-29 | Pravastatin-containing composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000196313A JP4138209B2 (en) | 2000-06-29 | 2000-06-29 | Pravastatin-containing composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2002020282A JP2002020282A (en) | 2002-01-23 |
| JP4138209B2 true JP4138209B2 (en) | 2008-08-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000196313A Expired - Fee Related JP4138209B2 (en) | 2000-06-29 | 2000-06-29 | Pravastatin-containing composition |
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| Country | Link |
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| JP (1) | JP4138209B2 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK1720972T3 (en) | 2004-03-05 | 2014-04-14 | Dsm Ip Assets Bv | METHOD OF CELL CULTIVATION USING CONTINUOUS PERFUSION AND ALTERNATIVE TANGENTIAL FLOW |
| EP1731147A4 (en) * | 2004-03-31 | 2010-06-30 | Kowa Co | External preparation |
| PL2634242T3 (en) | 2006-07-14 | 2017-09-29 | Patheon Holdings I B.V. | Improved process for the culturing of cells |
| BG934U1 (en) * | 2006-12-14 | 2007-11-30 | "Софарма" Ад | Composition for solid medicinal form containing pravastatin |
| GB0713707D0 (en) * | 2007-07-13 | 2007-08-22 | Generics Uk Ltd | Stable compositions |
| JP5337430B2 (en) * | 2008-08-26 | 2013-11-06 | 高田製薬株式会社 | Orally disintegrating tablets |
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2000
- 2000-06-29 JP JP2000196313A patent/JP4138209B2/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| JP2002020282A (en) | 2002-01-23 |
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