JP4630065B2 - Topical preparation - Google Patents

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JP4630065B2
JP4630065B2 JP2004537570A JP2004537570A JP4630065B2 JP 4630065 B2 JP4630065 B2 JP 4630065B2 JP 2004537570 A JP2004537570 A JP 2004537570A JP 2004537570 A JP2004537570 A JP 2004537570A JP 4630065 B2 JP4630065 B2 JP 4630065B2
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external preparation
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polyethylene glycol
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JPWO2004026297A1 (en
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眞 金箱
昌美 芹澤
愛 平田
雅之 香西
敏男 稲木
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Kowa Co Ltd
Nissan Chemical Corp
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Nissan Chemical Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Description

本発明は、経皮吸収性に優れ、かつ、経時安定性に優れたスタチン類又はその塩を有効成分とする外用剤に関する。  The present invention relates to an external preparation containing a statin or a salt thereof having an excellent transdermal absorbability and stability over time as an active ingredient.

ピタバスタチン、プラバスタチン等のスタチン類は、優れたＨＭＧ−ＣｏＡ還元酵素阻害活性を有し、高脂血症治療薬として有用であることが知られ（米国特許第５，８５６，３３６号、米国特許第４，３４６，２２７号等）、既に安定性の良好な錠剤等の経口投与用製剤として用いられ、又は開発が進められている。
そして、これらスタチン類は、酸性領域では、異性化、ラクトン化、分解等を生じ極めて不安定であり、少なくともｐＨ７以上でなければ安定な製剤が得られないことが知られている（米国特許第５，０３０，４４７号、米国特許第５，１８０，５８９号、米国特許第５，３５６，８９６号、ＷＯ９７／２３２００）。
一方、これらのＨＭＧ−ＣｏＡ還元酵素阻害剤は高脂血症以外に、にきび、乾癬、ふけ（米国特許第５，７３０，９９２号、米国特許第６，１２６，９４７号）、体毛成長抑制（米国特許第５，８４０，７５２号）等の局所作用として有用であることが報告され、外用剤として開発することが求められていた。Statins such as pitavastatin and pravastatin have excellent HMG-CoA reductase inhibitory activity and are known to be useful as therapeutic agents for hyperlipidemia (US Pat. No. 5,856,336, US Pat. No. 4,346,227, etc.) has already been used as a preparation for oral administration such as tablets having good stability or has been developed.
These statins are extremely unstable due to isomerization, lactonization, decomposition, etc. in the acidic region, and it is known that stable formulations cannot be obtained unless the pH is at least 7 or more (US Patent No. 1). 5,030,447, US Pat. No. 5,180,589, US Pat. No. 5,356,896, WO 97/23200).
On the other hand, these HMG-CoA reductase inhibitors, other than hyperlipidemia, acne, psoriasis, dandruff (US Pat. No. 5,730,992, US Pat. No. 6,126,947), hair growth suppression ( U.S. Pat. No. 5,840,752) has been reported to be useful as a local action and has been required to be developed as an external preparation.

従って、本発明の目的は、経皮吸収性と経時安定性の良好なスタチン類含有外用剤を提供することにある。
そこで本発明者は、スタチン類の安定領域である塩基性領域における経皮吸収性を検討したところ、充分な吸収性が得られず、スタチン類の経皮吸収性は塩基性領域よりも不安定領域である酸性領域で良好であることが判明した。そこで本発明者は、経皮吸収性と経時安定性の両者を満足する外用剤を得るべく種々検討した結果、エタノール、イソプロパノール、プロピレングリコール、ジプロピレングリコール等をスタチン類に組み合せてもラクトン体が生成してしまうにもかかわらず、全く意外にも、スタチン類に一定量のポリエチレングリコールを配合するとｐＨ４．０以上７．０未満でラクトン体の生成が抑制できるため経時安定性が良好で、かつ、経皮吸収性も優れた外用剤が得られることを見出し、本発明を完成した。
すなわち、本発明は、次の一般式（１）

Figure 0004630065
（式中、Ｒ１は有機基を示し、Ｘは−ＣＨ２ＣＨ２−又は−ＣＨ＝ＣＨ−を示し、Ｒ２は水素原子又はアルキル基を示す）で表わされるスタチン類又はその塩を０．００１〜２０質量％、ポリエチレングリコールを２０〜８０質量％及び水を含有し、ｐＨが４．０以上７．０未満であることを特徴とする外用剤を提供するものである。
本発明のスタチン類又はその塩を有効成分とする外用剤は、ラクトン体の生成が抑制され経時安定性に優れ、経皮吸収性に優れた外用剤である。Accordingly, an object of the present invention is to provide a statin-containing external preparation with good transdermal absorbability and stability over time.
Therefore, the present inventor examined the transdermal absorbability in the basic region, which is a stable region of statins, and as a result, sufficient absorbability was not obtained, and the transdermal absorbability of statins was more unstable than in the basic region. It was found that the acidic region, which is a region, was good. Therefore, as a result of various studies to obtain an external preparation satisfying both percutaneous absorption and stability over time, the present inventor has found that a lactone compound can be obtained by combining ethanol, isopropanol, propylene glycol, dipropylene glycol and the like with statins. Despite the formation, quite surprisingly, when a certain amount of polyethylene glycol is blended with statins, the production of lactones can be suppressed at a pH of 4.0 or more and less than 7.0, so the stability over time is good, and The inventors have found that an external preparation excellent in transdermal absorbability can be obtained, and completed the present invention.
That is, the present invention provides the following general formula (1)
Figure 0004630065
Wherein R 1 represents an organic group, X represents —CH 2 CH 2 — or —CH═CH—, and R 2 represents a hydrogen atom or an alkyl group. The present invention provides an external preparation characterized by containing 0.001 to 20% by mass, 20 to 80% by mass of polyethylene glycol and water, and having a pH of 4.0 or more and less than 7.0.
The external preparation containing the statin of the present invention or a salt thereof as an active ingredient is an external preparation that suppresses the formation of a lactone form, has excellent temporal stability, and has excellent transdermal absorbability.

本発明で使用する一般式（１）で表わされる化合物のＲ１で示される有機基は、置換基を有していてもよい環構造を有する有機基が好ましい。
環構造を有する有機基としては、インドリル基、インデニル基、ピリジル基、ピロロピリジル基、ピラゾロピリジル基、チエノピリジル基、ピリミジル基、ピラゾリル基、ピロリル基、イミダゾリル基、インドリジル基、キノリル基、ナフチル基、ヘキサヒドロナフチル基、シクロヘキシル基、フェニルシリルフェニル基、フェニルチエニル基又はフェニルフリル基が挙げられ、特にヘキサヒドロナフチル基、インドリル基、ピリジル基、ピリミジル基、ピロリル基又はキノリル基が好ましい。
これらの環構造を有する有機基に置換していてもよい置換基としては、ヒドロキシ基、直鎖、分岐鎖又は環状のアルキル基、アルキルオキシアルキル基、アルキルカルボニルオキシ基、アルキル置換アミノ基、置換アルキルスルホニルアミノ基、置換フェニルスルホニルアミノ基、アルキル、フェニル等が置換していてもよいカルバモイル基、ハロフェニル基、アルキルフェニル基、アルコキシフェニル基、フェニル基、オキソ基等が挙げられる。
これらの環構造を有する有機基に置換してもよい置換基のうち、炭素数１〜６の直鎖、分岐鎖又は環状アルキル基、炭素数２〜７のアルキルオキシアルキル基、炭素数１〜４のアシルオキシ基、炭素数１〜４のアルキル置換アミノ基、炭素数１〜４のアルキル置換炭素数１〜４のアルキルスルホニルアミノ基、炭素数１〜４のアルキル置換フェニルスルホニルアミノ基、炭素数１〜４のアルキル置換カルバモイル基、フェニル置換カルバモイル基、フルオロフェニル基、ブロモフェニル基、ヨードフェニル基、メチルフェニル基、エチルフェニル基、メトキシフェニル基、エトキシフェニル基又はフェニル基が好ましく、特にイソプロピル基、シクロプロピル基又はｐ−フルオロフェニル基が好ましい。
Ｒ２のアルキル基としては、炭素数１〜６の直鎖、分岐鎖又は環状アルキル基が好ましい。
一般式（１）で表わされる化合物の塩は、生理学的に許容し得る塩であって、ナトリウム塩、カリウム塩等のアルカリ金属塩、カルシウム塩、マグネシウム塩等のアルカリ土類金属塩、フェネチルアミン塩等の有機アミン塩又はアンモニウム塩等が挙げられるが、ナトリウム塩、カルシウム塩がより好ましい。
これらの化合物は、例えば米国特許第４，７３９，０７３号及びヨーロッパ特許出願公開第１１４，０２７号；ヨーロッパ特許出願公開第３６７，８９５号；米国特許第５，００１，２５５号、第４，６１３，６１０号、第４，８５１，４２７号、第４，７５５，６０６号、第４，８０８，６０７号、第４，７５１，２３５号、第４，９３９，１５９号、第４，８２２，７９９号、第４，８０４，６７９号、第４，８７６，２８０号、第４，８２９，０８１号、第４，９２７，８５１号、第４，５８８，７１５号；及びＦ．Ｇ．Ｋａｔｈａｗａｌａ，Ｍｅｄｉｃａｌ Ｒｅｓｅａｒｃｈ Ｒｅｖｉｅｗｓ，１１，１２１−１４６（１９９１）、ヨーロッパ特許出願公開第３０４，０６３号；ヨーロッパ特許出願公開第３３０，０５７号、米国特許第５，０２６，７０８号、第４，８６８，１８５号；ヨーロッパ特許出願公開第３２４，３４７号；ヨーロッパ特許出願公開第３００，２７８号；米国特許第５，０１３，７４９号、第５，８７２，１３０号、第５，８５６，３３６号、第４，２３１，９３８号、第４，４４４，７８４号、第４，３４６，２２７号、第５，３５４，７７２号、第５，２７３，９９５号、第５，１７７，０８０号、第３，９８３，１４０号、日本国特許第２，６４８，８９７号、米国特許第５，２６０，４４０号、Ｂｉｏｏｒｇａｎｉｃ ＆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ，５，４３７，（１９７７）、日本国特許第２，５６９，７４６号、ヨーロッパ特許第３０４，０６３号、米国特許第５，８５６，３３６号等に記載されている。
一般式（１）で表わされるスタチン類及びその塩としては、ラクトン体を形成していないものが好ましく、例えば、プラバスタチン（米国特許第４，３４６，２２７号：（＋）−（３Ｒ，５Ｒ）−３，５−ジヒドロキシ−７−［（１Ｓ，２Ｓ，６Ｓ，８Ｓ，８ａＲ）−６−ヒドロキシ−２−メチル−８［（Ｓ）−２−メチルブチリルオキシ］−１，２，６，７，８，８ａ−ヘキサヒドロ−１−ナフチル］ヘプタン酸）、フルバスタチン（米国特許第５，３５４，７７２号：（３ＲＳ，５ＳＲ，６Ｅ）−７−［３−（４−フルオロフェニル）−１−（１−メチルエチル）−１Ｈ−インドール−２−イル］−３，５−ジヒドロキシ−６−ヘプテン酸）、アトルバスタチン（米国特許第５，２７３，９９５号：（３Ｒ，５Ｒ）−７−［２−（４−フルオロフェニル）−５−イソプロピル−３−フェニル−４−フェニルカルバモイル−１Ｈ−ピロル−１−イル］−３，５−ジヒドロキシヘプタン酸）、セリバスタチン（米国特許第５，１７７，０８０号：（３Ｒ，５Ｓ）−エリスロ−（Ｅ）−７−［４−（４−フルオロフェニル）−２，６−ジイソプロピル−５−メトキシメチル−ピリジン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸）、ロスバスタチン（米国特許第５，２６０，４４０号、日本国特許第２，６４８，８９７号：７−［４−（４−フルオロフェニル）−６−イソプロピル−２−（Ｎ−メチル−Ｎ−メタンスルホニルアミノピリミジン）−５−イル］−（３Ｒ，５Ｓ）−ジヒドロキシ−（Ｅ）−６−ヘプテン酸）、ピタバスタチン（米国特許第５，８５６，３３６号、日本国特許第２，５６９，７４６号：（３Ｒ，５Ｓ，６Ｅ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）−３−キノリル］−３，５−ジヒドロキシ−６−ヘプテン酸、又はそれらの塩等が好ましく、特にピタバスタチン又はその塩が好ましく、ピタバスタチンカルシウムが最も好ましい。
スタチン類又はその塩の含有量は、外用剤全量中に０．００１〜２０質量％であるが、好ましくは０．０１〜１０質量％、特に好ましくは０．１〜５質量％である。
本発明で使用するポリエチレングリコールの分子量は、１００〜６００００、さらに３００〜４０００、特に３００〜１５００であるのが好ましい。また、ポリエチレングリコールは、製造時の不純物であるホルムアルデヒドが酸化され、経時的にｐＨの低下することが知られている。従って、過酸化物価（ＰＯＶ）は、５ｍｅｑ／ｋｇ以下、特に１ｍｅｑ／ｋｇ以下が好ましく、ホルムアルデヒド濃度は５ｐｐｍ以下、特に２ｐｐｍ以下が好ましい。
ポリエチレングリコールの含有量はスタチン類の経時安定性の点から重要であり、外用剤全量中に２０〜８０質量％であるが、好ましくは２５〜７５質量％、特に３０〜７０質量％含有するのが好ましい。ポリエチレングリコールの含有量が２０質量％未満の場合、スタチン類のラクトン体生成抑制効果が低く、逆に含有量が８０質量％を超えると外用剤のｐＨの調整が困難となる。
水は外用剤全量中にバランス量含有するが、１０〜７５質量％、さらに２０〜７０質量％、特に２５〜６５質量％含有するのが好ましい。
本発明の外用剤のｐＨは、４．０以上７．０未満であるが、好ましくは４．０〜６．７、より好ましくは４．５〜６．７である。ｐＨの測定は、外用剤１質量部と水９質量部を混合し、充分に振り混ぜた後、２５℃においてｐＨメータで測定する。
ｐＨ調整剤としては、リン酸、酢酸、ホウ酸、乳酸、コハク酸、クエン酸、酒石酸、フタル酸及びそれらのアルカリ金属等塩、グリシン、水酸化ナトリウム等が挙げられる。さらに、ブリトン−ロビンソン緩衝液（Ｂｒｉｔｔｏｎ−Ｒｏｂｉｎｓｏｎ Ｂｕｆｆｅｒ）、クラーク−ルーブズ緩衝液（Ｃｌａｒｋ−Ｌｕｂｓ Ｂｕｆｆｅｒ）、コルトフ緩衝液（Ｋｏｌｔｈｏｆｆ Ｂｕｆｆｅｒ）等のｐＨ緩衝液を用いてもよい。
本発明の外用剤には、本発明の効果を妨げない限り、医薬品の添加物として許容される各種任意成分を所望に応じて添加することが可能であり、その例としては、溶媒、ポリエチレングリコール以外の水溶性高分子、安定化剤、基剤等が挙げられる。
溶媒としては、ベンジルアルコール、ステアリルアルコール、オレイルアルコール等の一価のアルコール、濃グリセリン、１，３−ブチレングリコール、２−エチル−１，３−ヘキサンジオール、ポリプロピレングリコール２０００等の多価アルコールが挙げられる。
前記水溶性高分子としては、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース等のセルロース類、白糖、β−シクロデキストリン等の多糖類、ソルビトール、マンニトール等の糖アルコール類、ポリビニルアルコール、ポリビニルピロリドン等の合成高分子等が挙げられる。
安定化剤としては、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル等のフェノール性物質、クロロブタノール、フェニルエチルアルコール等の中性物質、ビタミンＥ、ブチルヒドロキシアニソール、酢酸トコフェロール、没食子酸プロピル、２−メルカプトベンズイミダゾール等の抗酸化剤、アスコルビン酸、亜硫酸水素ナトリウム、チオ硫酸ナトリウム等の還元剤が挙げられる。
基剤としては、ポリアクリル酸（ナトリウム）、カルボキシビニルポリマー、ゼラチン、デンプン、エステルガム、脂環族飽和炭化水素樹脂、ジメチルポリシロキサン、スチレン・イソプレン・スチレンブロック共重合体等が挙げられる。
本発明の形態は、外用剤であれば限定されるものではないが、例えば液剤、ゲル剤、クリーム剤、ローション剤、スプレー剤、軟膏剤等が例示される。The organic group represented by R 1 of the compound represented by the general formula (1) used in the present invention is preferably an organic group having a ring structure which may have a substituent.
Examples of the organic group having a ring structure include indolyl group, indenyl group, pyridyl group, pyrrolopyridyl group, pyrazolopyridyl group, thienopyridyl group, pyrimidyl group, pyrazolyl group, pyrrolyl group, imidazolyl group, indolizyl group, quinolyl group, naphthyl group, A hexahydronaphthyl group, a cyclohexyl group, a phenylsilylphenyl group, a phenylthienyl group or a phenylfuryl group can be mentioned, and a hexahydronaphthyl group, an indolyl group, a pyridyl group, a pyrimidyl group, a pyrrolyl group or a quinolyl group is particularly preferable.
Substituents that may be substituted with organic groups having these ring structures include hydroxy groups, linear, branched or cyclic alkyl groups, alkyloxyalkyl groups, alkylcarbonyloxy groups, alkyl-substituted amino groups, and substituted groups. Examples thereof include a carbamoyl group, a halophenyl group, an alkylphenyl group, an alkoxyphenyl group, a phenyl group and an oxo group, which may be substituted with an alkylsulfonylamino group, a substituted phenylsulfonylamino group, alkyl, phenyl and the like.
Among the substituents that may be substituted for the organic group having these ring structures, a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, and 1 to 1 carbon atoms. 4 acyloxy groups, alkyl substituted amino groups having 1 to 4 carbon atoms, alkyl substituted alkyl groups having 1 to 4 carbon atoms, alkylsulfonylamino groups having 1 to 4 carbon atoms, alkyl substituted phenylsulfonylamino groups having 1 to 4 carbon atoms, carbon numbers 1-4 alkyl-substituted carbamoyl groups, phenyl-substituted carbamoyl groups, fluorophenyl groups, bromophenyl groups, iodophenyl groups, methylphenyl groups, ethylphenyl groups, methoxyphenyl groups, ethoxyphenyl groups or phenyl groups are preferred, especially isopropyl groups , A cyclopropyl group or a p-fluorophenyl group is preferable.
As the alkyl group for R 2 , a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms is preferable.
The salt of the compound represented by the general formula (1) is a physiologically acceptable salt, an alkali metal salt such as sodium salt or potassium salt, an alkaline earth metal salt such as calcium salt or magnesium salt, or a phenethylamine salt. Organic amine salt or ammonium salt such as sodium salt and calcium salt are more preferable.
These compounds are described, for example, in US Pat. No. 4,739,073 and European Patent Application Publication No. 114,027; European Patent Application Publication No. 367,895; US Pat. Nos. 5,001,255, 4,613. No. 4,610, No. 4,851,427, No. 4,755,606, No. 4,808,607, No. 4,751,235, No. 4,939,159, No. 4,822,799 No. 4,804,679, 4,876,280, 4,829,081, 4,927,851, 4,588,715; G. Kathawala, Medical Research Reviews, 11 , 121-146 (1991), European Patent Application Publication No. 304,063; European Patent Application Publication No. 330,057, US Patent Nos. 5,026,708, 4,868, European Patent Application Publication No. 324,347; European Patent Application Publication No. 300,278; US Pat. Nos. 5,013,749, 5,872,130, 5,856,336, No. 185; 4,231,938, 4,444,784, 4,346,227, 5,354,772, 5,273,995, 5,177,080, 3, 983,140, Japanese Patent No. 2,648,897, US Pat. No. 5,260,440, Bioorganic & M dicinal Chemistry, 5, 437, ( 1977), Japanese Patent No. 2,569,746, European Patent No. 304,063, is described in U.S. Patent No. 5,856,336 and the like.
As the statins represented by the general formula (1) and salts thereof, those which do not form a lactone form are preferable. For example, pravastatin (US Pat. No. 4,346,227: (+)-(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] heptanoic acid), fluvastatin (US Pat. No. 5,354,772: (3RS, 5SR, 6E) -7- [3- (4-fluorophenyl) -1 -(1-methylethyl) -1H-indol-2-yl] -3,5-dihydroxy-6-heptenoic acid), atorvastatin (US Pat. No. 5,273,995: (3R, 5R) -7- [ 2- (4-F Olophenyl) -5-isopropyl-3-phenyl-4-phenylcarbamoyl-1H-pyrrol-1-yl] -3,5-dihydroxyheptanoic acid), cerivastatin (US Pat. No. 5,177,080: (3R, 5S) ) -Erythro- (E) -7- [4- (4-fluorophenyl) -2,6-diisopropyl-5-methoxymethyl-pyridin-3-yl] -3,5-dihydroxy-6-heptenoic acid), Rosuvastatin (US Pat. No. 5,260,440, Japanese Patent 2,648,897: 7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonyl) Aminopyrimidine) -5-yl]-(3R, 5S) -dihydroxy- (E) -6-heptenoic acid), pitavastatin (US Pat. No. 5,856,336) Japanese Patent No. 2,569,746: (3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] -3,5-dihydroxy-6 Heptenoic acid or a salt thereof is preferable, pitavastatin or a salt thereof is particularly preferable, and pitavastatin calcium is most preferable.
The content of statins or salts thereof is 0.001 to 20% by mass in the total amount of the external preparation, but is preferably 0.01 to 10% by mass, and particularly preferably 0.1 to 5% by mass.
The molecular weight of the polyethylene glycol used in the present invention is preferably 100 to 60000, more preferably 300 to 4000, and particularly preferably 300 to 1500. In addition, it is known that polyethylene glycol oxidizes formaldehyde, which is an impurity during production, and the pH decreases with time. Accordingly, the peroxide value (POV) is preferably 5 meq / kg or less, particularly 1 meq / kg or less, and the formaldehyde concentration is preferably 5 ppm or less, particularly 2 ppm or less.
The content of polyethylene glycol is important from the viewpoint of the stability over time of statins, and is 20 to 80% by mass in the total amount of external preparations, preferably 25 to 75% by mass, particularly 30 to 70% by mass. Is preferred. When the content of polyethylene glycol is less than 20% by mass, the effect of inhibiting the formation of lactones by statins is low. Conversely, when the content exceeds 80% by mass, it is difficult to adjust the pH of the external preparation.
Water is contained in a balance amount in the total amount of the external preparation, but it is preferably 10 to 75% by mass, more preferably 20 to 70% by mass, and particularly preferably 25 to 65% by mass.
Although the pH of the external preparation of this invention is 4.0 or more and less than 7.0, Preferably it is 4.0-6.7, More preferably, it is 4.5-6.7. The pH is measured by mixing 1 part by mass of the external preparation and 9 parts by mass of water, thoroughly shaking and then measuring with a pH meter at 25 ° C.
Examples of the pH adjuster include phosphoric acid, acetic acid, boric acid, lactic acid, succinic acid, citric acid, tartaric acid, phthalic acid and their alkali metal salts, glycine, sodium hydroxide and the like. Further, a pH buffer solution such as Briton-Robinson Buffer, Clark-Lubbs Buffer, or Kolthoff Buffer may be used.
As long as the effects of the present invention are not hindered, the external preparation of the present invention can be added with various optional components that are acceptable as additives of pharmaceuticals as desired. Examples thereof include a solvent, polyethylene glycol Other water-soluble polymers, stabilizers, bases and the like.
Examples of the solvent include monovalent alcohols such as benzyl alcohol, stearyl alcohol, and oleyl alcohol, and polyhydric alcohols such as concentrated glycerin, 1,3-butylene glycol, 2-ethyl-1,3-hexanediol, and polypropylene glycol 2000. It is done.
Examples of the water-soluble polymer include celluloses such as hydroxyethyl cellulose and hydroxypropyl cellulose, polysaccharides such as sucrose and β-cyclodextrin, sugar alcohols such as sorbitol and mannitol, synthetic polymers such as polyvinyl alcohol and polyvinyl pyrrolidone, etc. Is mentioned.
Stabilizers include phenolic substances such as methyl paraoxybenzoate and propyl paraoxybenzoate, neutral substances such as chlorobutanol and phenylethyl alcohol, vitamin E, butylhydroxyanisole, tocopherol acetate, propyl gallate, and 2-mercapto. Antioxidants such as benzimidazole, and reducing agents such as ascorbic acid, sodium bisulfite, sodium thiosulfate and the like can be mentioned.
Examples of the base include polyacrylic acid (sodium), carboxyvinyl polymer, gelatin, starch, ester gum, alicyclic saturated hydrocarbon resin, dimethylpolysiloxane, styrene / isoprene / styrene block copolymer, and the like.
Although the form of this invention will not be limited if it is an external preparation, For example, a liquid agent, a gel agent, a cream agent, a lotion agent, a spray agent, an ointment etc. are illustrated.

以下に実施例を挙げて本発明を詳細に説明するが、本発明はこれらの実施例に限定されるものではない。  EXAMPLES Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

ピタバスタチンカルシウム０．１質量部をポリエチレングリコール４００（日本油脂製・マクロゴール４００、５質量％水溶液のｐＨは６）５０質量部に溶解した後、Ｂｒｉｔｔｏｎ−Ｒｏｂｉｎｓｏｎ Ｂｕｆｆｅｒ（ｐＨ４．０）を加えて１００質量部として外用剤を製造した。
また、上記外用剤中のポリエチレングリコール４００をイソプロパノール（比較例１）、エタノール（比較例２）、プロピレングリコール（比較例３）及びジプロピレングリコール（比較例４）に各々代えた外用剤を製造した。
製造した外用剤のｐＨ（製造直後）及び６０℃に３日間保存した後のラクトン体生成率を、次法により測定した。
ｐＨ測定 外用剤１質量部に精製水９質量部を加え、振とう機で３０分間振とう後、２５℃でｐＨを測定した（ｐＨメータ：堀場製作所Ｆ−２４）。
ラクトン体生成率測定 外用剤を６０℃に３日間保存した後のラクトン体生成率を次法により測定した。
内標準溶液：プロピルパラベン
測定波長：２４５ｎｍ
カラム：Ｄｅｖｅｌｏｓｉｌ ＯＤＳ−ＨＧ−５
カラム温度：４０℃
移動相：メタノール／０．０２ｍｏｌ／Ｌリン酸塩緩衝液（ｐＨ３）＝１３／７
以上のＨＰＬＣ条件でピタバスタチン及びラクトン体ピーク面積を求め、次式によりラクトン体生成率を算出した。
ラクトン体生成率（％）＝（Ｌ／（Ｐ＋Ｌ））×１００ （１）
Ｐ：６０℃に保存して３日経過時のピタバスタチンのピーク面積
Ｌ：６０℃に保存して３日経過時のラクトン体のピーク面積
測定結果を表１に示す。

Figure 0004630065
ポリエチレングリコールを含有する実施例１の外用剤は、ラクトン体生成が抑制され安定であったが、ポリエチレングリコールに代えてイソプロパノール（比較例１）、エタノール（比較例２）、プロピレングリコール（比較例３）、ジプロピレングリコール（比較例４）のアルコール類を添加した外用剤はいずれもラクトン体の生成は抑制されずに不安定であった。After 0.1 parts by weight of pitavastatin calcium is dissolved in 50 parts by weight of polyethylene glycol 400 (manufactured by NOF Corporation, Macrogol 400, pH of 5% by weight aqueous solution is 6), Britton-Robinson Buffer (pH 4.0) is added to add 100 An external preparation was produced as parts by mass.
In addition, an external preparation was produced by replacing the polyethylene glycol 400 in the external preparation with isopropanol (Comparative Example 1), ethanol (Comparative Example 2), propylene glycol (Comparative Example 3) and dipropylene glycol (Comparative Example 4). .
The pH of the manufactured external preparation (immediately after manufacture) and the lactone form production rate after storage at 60 ° C. for 3 days were measured by the following method.
9 parts by mass of purified water was added to 1 part by mass of the external preparation for pH measurement, and after shaking for 30 minutes with a shaker, the pH was measured at 25 ° C. (pH meter: Horiba F-24).
Measurement of Lactone Formation Rate The lactone formation rate after the external preparation was stored at 60 ° C. for 3 days was measured by the following method.
Internal standard solution: propylparaben Measurement wavelength: 245 nm
Column: Develosil ODS-HG-5
Column temperature: 40 ° C
Mobile phase: methanol / 0.02 mol / L phosphate buffer (pH 3) = 13/7
The pitavastatin and lactone peak areas were determined under the above HPLC conditions, and the lactone formation rate was calculated according to the following formula.
Lactone production rate (%) = (L / (P + L)) × 100 (1)
P: Peak area of pitavastatin after 3 days storage at 60 ° C. L: Peak area of lactone body after 3 days storage at 60 ° C. Table 1 shows the measurement results.
Figure 0004630065
The external preparation of Example 1 containing polyethylene glycol was stable because lactone formation was suppressed, but isopropanol (Comparative Example 1), ethanol (Comparative Example 2), propylene glycol (Comparative Example 3) instead of polyethylene glycol. ) And dipropylene glycol (Comparative Example 4) to which external preparations were added, and the formation of lactone was not suppressed and was unstable.

実施例２〜６Examples 2-6

実施例１と同様にして表２に示す組成の外用剤を製造した。
表２にｐＨ及びラクトン体生成率の測定結果を示す。

Figure 0004630065
ピタバスタチンを含有した外用剤にポリエチレングリコール４００を１０質量％（比較例５）添加した外用剤では、６０℃の条件下で３日間保存したときラクトン体生成率は増加した。しかし、ポリエチレングリコール４００を３０〜７０質量％（実施例２〜６）添加した外用剤では、ラクトン体生成率は抑制され安定であった。External preparations having the compositions shown in Table 2 were produced in the same manner as in Example 1.
Table 2 shows the measurement results of pH and lactone formation rate.
Figure 0004630065
In the external preparation in which 10% by mass of polyethylene glycol 400 (Comparative Example 5) was added to the external preparation containing pitavastatin, the lactone formation rate increased when stored at 60 ° C. for 3 days. However, in the external preparation to which polyethylene glycol 400 was added in an amount of 30 to 70% by mass (Examples 2 to 6), the lactone formation rate was suppressed and stable.

実施例７〜９Examples 7-9

表３に示す外用剤を製造した。
ｐＨ及びラクトン体生成率の測定結果を表３に示す。

Figure 0004630065
また、ピタバスタチンとポリエチレングリコール４００を５０質量％含有した外用剤のｐＨが４．０未満では、６０℃の条件下で３日間保存したときラクトン体生成率は増加した。しかし、外用剤のｐＨが４．０以上では、６０℃の条件下で３日間保存したときラクトン体生成率は抑制され安定であった。External preparations shown in Table 3 were produced.
Table 3 shows the measurement results of the pH and lactone formation rate.
Figure 0004630065
Moreover, when the pH of the external preparation containing 50% by mass of pitavastatin and polyethylene glycol 400 was less than 4.0, the lactone formation rate increased when stored at 60 ° C. for 3 days. However, when the pH of the external preparation was 4.0 or more, the lactone formation rate was suppressed and stable when stored for 3 days at 60 ° C.

実施例１０〜１２Examples 10-12

表４に示す外用剤を製造した。
ｐＨ及びラクトン体生成率の測定結果を表４に示す。

Figure 0004630065
ピタバスタチンを含有した外用剤に分子量が、３００，１５００，４０００のポリエチレングリコールを添加した外用剤では、６０℃の条件下で３日間保存したときラクトン体生成率は、抑制され安定であった。
試験例 皮膚透過性
実施例１、８及び実施例１のＢｒｉｔｔｏｎ−Ｒｏｂｉｎｓｏｎ Ｂｕｆｆｅｒ（ｐＨ４．０）をＢｒｉｆｆｏｎ−Ｒｏｂｉｎｓｏｎ Ｂｕｆｆｅｒ（ｐＨ８．０）に代えた比較例７の各外用剤の皮膚透過性について測定した。
皮膚透過量の測定 ドナー溶液は、実施例１、実施例８及び比較例７で製造した外用剤を用いた。レセプター溶液は、Ｂｒｉｔｔｏｎ−Ｒｏｂｉｎｓｏｎ Ｂｕｆｆｅｒ（ｐＨ６．０）を用いた。透過膜は、Ｗｉｓｔａｒ系ラット（雄性、８週齢）の腹部摘出ヒフ（以下「ヒフ」と略す）を用いた。
縦型拡散セル（Ｆｒａｎｚセル）の透過部にヒフ表面をドナー側にして置き、ドナー溶液１ｍＬ及びレセプター溶液３０ｍＬを満たした。レセプター溶液を一定温度（３２℃）に保ち、透過実験を行った。実験中の水分の蒸発を防ぐために、ドナーセル及びサンプル口をパラフィルムで覆った。６及び８時間経過時にサンプル口から０．５ｍＬレセプター溶液を採取し、新しいレセプター溶液０．５ｍＬを補充した。
採取したサンプル溶液中のピタバスタチンをｔｅｒｔ−ブチルメチルエーテルで抽出後、ＨＰＬＣ法（内標準物質：（Ｅ）−３（Ｒ），５（Ｓ）−Ｄｉｈｙｄｒｏｘｙ−７−（２′−ｉｓｏｐｒｏｐｙｌ−４′−（４″−ｆｌｕｏｒｏｐｈｅｙｌ）ｑｕｉｎｏｌｉｎ−３′−ｙｌ）ｈｅｐｔｏ−６−ｅｎｏｉｃ ａｃｉｄ、測定波長：２４５ｎｍ、カラム：Ｄｅｖｅｌｏｓｉｌ ＯＤＳ−ＨＧ−５、カラム温度：４０℃及び移動相：０．２ｍｏｌ／Ｌ酢酸／アセトニトリル／メタノール＝６０／３０／１０）によりピタバスタチン含有量を測定した。
測定結果を表５に示す。
Figure 0004630065
ピタバスタチンカルシウムを含有した外用剤にポリエチレングリコールを添加した外用剤のｐＨが７．０以上では、皮膚透過量が少なかったが、ｐＨが７．０未満に調製した外用剤では皮膚透過量が増加し、吸収性が良好であった。
実施例１３ ゲル状外用剤
ピタバスタチンカルシウム（０．１質量部）をポリエチレングリコール４００（７０質量部）に溶解し油相とした。別に、カルボキシビニルポリマー（ウルトレッツ１０：ＢＦ ＧＯＯＤＲＩＣＨ社製）０．５質量部をＢｒｉｆｆｏｎ−Ｒｏｂｉｎｓｏｎ Ｂｕｆｆｅｒ（ｐＨ８．０）２５質量部に膨潤させ水相とした。油相に水相を添加し、Ｂｒｉｔｔｏｎ−Ｒｏｂｉｎｓｏｎ Ｂｕｆｆｅｒ（ｐＨ８．０）で全量１００質量部としてゲル状外用剤を製造した。
実施例１４ クリーム状外用剤
ピタバスタチンカルシウム（０．１質量部）及びモノオレイン酸ポリオキシエチレンソルビタン（２０Ｅ．Ｏ．）（０．５質量部）をポリエチレングリコール４００（７０質量部）に溶解し油相とした。別に、カルボキシビニルポリマー（ウルトレッツ１０：ＢＦ ＧＯＯＤＲＩＣＨ社製）０．５質量部をＢｒｉｔｔｏｎ−Ｒｏｂｉｎｓｏｎ Ｂｕｆｆｅｒ（ｐＨ８．０）２５質量部に膨潤させ水相とした。油相に水相を添加し、Ｂｒｉｔｔｏｎ−Ｒｏｂｉｎｓｏｎ Ｂｕｆｆｅｒ（ｐＨ８．０）で全１００ｇとしてクリーム状外用剤を製造した。External preparations shown in Table 4 were produced.
Table 4 shows the measurement results of the pH and lactone formation rate.
Figure 0004630065
In an external preparation containing polyethylene glycol having a molecular weight of 300, 1500, 4000 added to an external preparation containing pitavastatin, the lactone formation rate was suppressed and stable when stored for 3 days at 60 ° C.
Test Example Skin Permeability Measurement of skin permeability of each external preparation of Comparative Example 7 in which Britton-Robinson Buffer (pH 4.0) in Examples 1 and 8 and Example 1 was replaced with Briffon-Robinson Buffer (pH 8.0) did.
Measurement of skin permeation amount The donor solution prepared in Example 1, Example 8 and Comparative Example 7 was used as the donor solution. Britton-Robinson Buffer (pH 6.0) was used as the receptor solution. As the permeable membrane, a Wistar rat (male, 8 weeks old) abdominal excised hiff (hereinafter abbreviated as “hiff”) was used.
The Hif surface was placed on the donor side in the permeation part of a vertical diffusion cell (Franz cell), and 1 mL of donor solution and 30 mL of receptor solution were filled. The permeation experiment was conducted while keeping the receptor solution at a constant temperature (32 ° C.). In order to prevent moisture evaporation during the experiment, the donor cell and the sample port were covered with parafilm. At 6 and 8 hours, 0.5 mL receptor solution was collected from the sample port and replenished with 0.5 mL of new receptor solution.
After extracting pitavastatin from the collected sample solution with tert-butyl methyl ether, HPLC method (internal standard substance: (E) -3 (R), 5 (S) -Dihydroxy-7- (2′-isopropyl-4 ′ -(4 "-fluorophenyl) quinolin-3'-yl) hepto-6-enoic acid, measurement wavelength: 245 nm, column: Develosil ODS-HG-5, column temperature: 40 ° C., mobile phase: 0.2 mol / L acetic acid / Acetonitrile / methanol = 60/30/10), and the pitavastatin content was measured.
Table 5 shows the measurement results.
Figure 0004630065
When the pH of an external preparation containing polyethylene glycol added to an external preparation containing pitavastatin calcium was 7.0 or higher, the amount of skin permeation was small. However, in the case of an external preparation prepared with a pH of less than 7.0, the amount of skin permeation increased. The absorbency was good.
Example 13 Gel external preparation Pitavastatin calcium (0.1 part by mass) was dissolved in polyethylene glycol 400 (70 parts by mass) to obtain an oil phase. Separately, 0.5 parts by mass of a carboxyvinyl polymer (Ultretz 10: manufactured by BF GOODRICH) was swollen in 25 parts by mass of Briffon-Robinson Buffer (pH 8.0) to obtain an aqueous phase. The aqueous phase was added to the oil phase, and a gel external preparation was produced with Britton-Robinson Buffer (pH 8.0) as a total amount of 100 parts by mass.
Example 14 Creamy topical preparation Pitavastatin calcium (0.1 part by mass) and monooleic acid polyoxyethylene sorbitan (20EO) (0.5 part by mass) dissolved in polyethylene glycol 400 (70 parts by mass) Phased. Separately, 0.5 part by mass of a carboxyvinyl polymer (Ultretz 10: manufactured by BF GOODRICH) was swollen in 25 parts by mass of Britton-Robinson Buffer (pH 8.0) to obtain an aqueous phase. The aqueous phase was added to the oil phase, and a creamy external preparation was prepared with Britton-Robinson Buffer (pH 8.0) as a total of 100 g.

Claims (3)

ピタバスタチン又はその塩を0.001〜20質量％、ポリエチレングリコールを30〜70質量％及び水を含有し、pHが4.3〜6.7であることを特徴とする外用剤。An external preparation characterized by containing 0.001 to 20% by mass of pitavastatin or a salt thereof, 30 to 70 % by mass of polyethylene glycol and water, and having a pH of 4.3 to 6.7. ポリエチレングリコールの分子量が100〜60000である請求項１記載の外用剤。  The external preparation according to claim 1, wherein the molecular weight of polyethylene glycol is 100 to 60000. ピタバスタチン又はその塩がピタバスタチンカルシウムである請求項１又は２に記載の外用剤。  The external preparation according to claim 1 or 2, wherein the pitavastatin or a salt thereof is pitavastatin calcium.
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