WO2004026297A1 - Preparation for external use - Google Patents

Preparation for external use Download PDF

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Publication number
WO2004026297A1
WO2004026297A1 PCT/JP2003/011767 JP0311767W WO2004026297A1 WO 2004026297 A1 WO2004026297 A1 WO 2004026297A1 JP 0311767 W JP0311767 W JP 0311767W WO 2004026297 A1 WO2004026297 A1 WO 2004026297A1
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WO
WIPO (PCT)
Prior art keywords
group
external preparation
mass
salt
polyethylene glycol
Prior art date
Application number
PCT/JP2003/011767
Other languages
French (fr)
Japanese (ja)
Inventor
Makoto Kanebako
Masami Serizawa
Ai Hirata
Masayuki Kanishi
Toshio Inagi
Original Assignee
Kowa Co., Ltd.
Nissan Chemical Industries, Ltd.
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Filing date
Publication date
Application filed by Kowa Co., Ltd., Nissan Chemical Industries, Ltd. filed Critical Kowa Co., Ltd.
Priority to AU2003264443A priority Critical patent/AU2003264443A1/en
Priority to JP2004537570A priority patent/JP4630065B2/en
Publication of WO2004026297A1 publication Critical patent/WO2004026297A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365Lactones
    • A61K31/366Lactones having six-membered rings, e.g. delta-lactones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic 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
    • A61K31/403Heterocyclic 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
    • A61K31/404Indoles, e.g. pindolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/47Quinolines; Isoquinolines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/10Anti-acne agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/06Antihyperlipidemics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an external preparation containing sutins or a salt thereof as an active ingredient, which is excellent in transdermal absorbability and excellent in stability over time. Itoda
  • Statins such as pivasbasin and pravastatin are known to have excellent 111 ⁇ 0- (8-reducing enzyme inhibitory activity and to be useful as a therapeutic agent for hyperlipidemia (US Patent No. 5, 856, 336, U.S. Pat. No. 4,346,227), which have already been used or are being developed as orally-administered preparations having good stability such as tablets. It is known that in the acidic region, isomerization, lactonization, decomposition, etc. occur, resulting in extremely unstable conditions, and that a stable preparation cannot be obtained unless the pH is at least 7 (US Pat. No. 5,033) 0,447, U.S. Patent No. 5,180,589, U.S. Patent No. 5,356,896, W097Z 23200).
  • HMG-CoA reductase inhibitors are used in addition to hyperlipidemia, acne, psoriasis, dandruff (US Pat. No. 5,730,992, US Pat. No. 6,126,947), hair growth It was reported to be useful as a local action such as suppression (US Pat. No. 5,840,752), and it was required to be developed as an external preparation.
  • an object of the present invention is to provide a topical sutin-containing preparation having good transdermal absorbability and stability over time. Therefore, the present inventor examined percutaneous absorption in the basic region, which is a stable region of statins, and found that sufficient absorption was not obtained, and the percutaneous absorption of statins was more unstable than in the basic region. It was found to be good in the acidic region, which is the region. Thus, the present inventors have conducted various studies to obtain an external preparation that satisfies both transdermal absorption and stability over time. As a result, even when ethanol, isopropanol, propylene glycol, dipropylene glycol, etc. are combined with statins, lactones are obtained.
  • the composition for external use contains 0.001 to 20% by mass of polyethylene glycol, 20 to 80% by mass of polyethylene glycol and water, and has a pH of 4.0 or more and less than 7.0. Things.
  • the external preparation containing the sutins or a salt thereof as an active ingredient of the present invention is an external preparation that suppresses the production of a lactone, has excellent stability over time, and has excellent transdermal absorbability.
  • the organic group represented by R 1 in 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 an indolyl group, an indenyl group, a pyridyl group, a pyropyridyl group, a pyrazopyridyl group, a chenobiridyl group, a pyrimidyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, an indolidyl group, a quinolyl group, Nuff A tyl group, a hexahydronaphthyl group, a cyclohexyl group, a phenylsilylphenyl group, a phenylthienyl group or a phenylfuryl group, particularly a hexahydronaphthyl group, an indolyl group, a pyridyl group, a pyrimidyl group, a pyrrolyl group or a
  • Examples of the substituent which may be substituted on the organic group having such a ring structure include a hydroxy group, a linear, branched or cyclic alkyl group, an alkyloxyalkyl group, an alkylcarbonyloxy group, and an alkyl substituent.
  • alkyl group for R 2 a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms is preferable.
  • Salts of the compound represented by the general formula (1) are physiologically acceptable salts, such as alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and phenethylamine salt. And the like, and an organic amine salt or an ammonium salt, etc., and a sodium salt and a calcium salt are more preferable.
  • sutins represented by the general formula (1) and salts thereof those which do not form a lactone are preferable.
  • pravasutin US Pat.
  • the content of the statin or a salt thereof is from 0.001 to 20% by mass, preferably from 0.01 to 10% by mass, particularly preferably from 0.1 to 5% by mass in the total amount of the external preparation.
  • the molecular weight of the polyethylene glycol used in the present invention is preferably from 100 to 60,000, more preferably from 300 to 4000, particularly preferably from 300 to 1500.
  • Polyethylene dalicol is known to oxidize formaldehyde, an impurity at the time of production, and decrease the pH over time. Therefore, the peroxide value (POPOV) is preferably 5 meq / kg or less, particularly preferably 1 meq / kg or less, and the formaldehyde concentration is preferably 5 ppm or less, particularly preferably 2 ppm or less.
  • the content of polyethylene glycol is important from the viewpoint of the stability of the statins with time, and is 20 to 80% by mass, preferably 25 to 75% by mass, particularly 30 to 70% by mass in the total amount of the external preparation. Is preferred. Polyethylene glycol content If the content is less than 20% by mass, the effect of inhibiting the formation of lactones of the quinones is low, and if the content exceeds 80% by mass, it becomes difficult to adjust the pH of the external preparation.
  • Water is contained in the balance amount in the total amount of the external preparation, but it is preferably contained in an amount of 10 to 75% by mass, more preferably 20 to 70% by mass, particularly preferably 25 to 65% by mass.
  • the pH of the external preparation of the present invention is 4.0 or more and less than 7.0, preferably 4.0 to 6.7, more preferably 4.5 to 6.7.
  • 7.0 preferably 4.0 to 6.7
  • 4.5 to 6.7 For pH measurement, mix 1 part by weight of the external preparation and 9 parts by weight of water, shake thoroughly, and measure at pH 25 ° C overnight.
  • pH adjuster examples include phosphoric acid, acetic acid, boric acid, lactic acid, succinic acid, citric acid, tartaric acid, phthalic acid and salts thereof such as alkali metals, glycine, sodium hydroxide and the like.
  • Britton-Robinson Buffer, Clark-Lubs Buffer, Koltov Buffer examples include phosphoric acid, acetic acid, boric acid, lactic acid, succinic acid, citric acid, tartaric acid, phthalic acid and salts thereof such as alkali metals, glycine, sodium hydroxide and the like.
  • various optional ingredients that are acceptable as pharmaceutical additives can be added to the external preparation of the present invention as needed.
  • examples thereof include a solvent and polyethylene.
  • examples include water-soluble polymers other than glycols, stabilizers, and bases.
  • the solvent examples include monohydric alcohols such as benzyl alcohol, stearyl alcohol, and oleyl alcohol, polyhydric alcohols such as concentrated glycerin, 1,3-butylene glycol, 21-ethyl-1,3-hexanediol, and polypropylene glycol 2000. Alcohol.
  • water-soluble polymer examples include celluloses such as hydroxyethylcellulose and hydroxypropylcellulose; sucrose;) polysaccharides such as 3-cyclodextrin; sugar alcohols such as sorbitol and mannitol; and polyvinyl alcohol. And synthetic polymers such as polyvinylpyrrolidone.
  • Stabilizers include methyl paraoxybenzoate, propyl paraoxybenzoate Phenolic substances such as chlorobutanol, phenylethyl alcohol, etc., antioxidants such as vitamin E, butylhydroxyanisole, tocopherol acetate, propyl gallate, 2-mercaptobenzimidazole, etc. And reducing agents such as ascorbic acid, sodium bisulfite and sodium thiosulfate.
  • 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.
  • the form of the present invention is not limited as long as it is an external preparation, and examples thereof include night creams, gels, creams, lotions, sprays, ointments and the like.
  • the pH of the prepared external preparation (immediately after production) and the lactone production rate after storage at 60 ° C for 3 days were measured by the following methods.
  • Lactone formation rate measurement Lactone formation after storage of external preparations at 60 ° C for 3 days The percentage was measured by the following method.
  • Lactone formation rate () (L / (P + L)) X 100 (1)
  • Table 1 shows the measurement results.
  • Example 1 The external preparation of Example 1 containing polyethylene glycol was stable because lactone formation was inhibited and isopropanol was used instead of polyethylene glycol.
  • the external preparations containing alcohols such as Comparative Example 1), ethanol (Comparative Example 2), propylene glycol (Comparative Example 3), and dipropylendalcol (Comparative Example 4) did not inhibit the formation of lactone bodies. It was unstable.
  • Table 2 shows the measurement results of pH and lactone formation rate. ⁇
  • Table 3 shows the measurement results of the pH and the lactone formation rate.
  • Table 4 shows the measurement results of the pH and the lactone formation rate.
  • the topical formulation containing pitapastatin has a molecular weight of 300, 150, 400
  • the lactone formation rate was suppressed and stable when stored under conditions of 60 for 3 days.
  • Example 8 the external preparations produced in Example 8 and Comparative Example 7 were used.
  • Britton-Robinson Buffer pH 6.0 was used for the reception solution.
  • the permeable membrane used was an abdominal extirpated Hiff (hereinafter abbreviated as “Hif”) of a Wistar rat (male, 8 weeks old).
  • the Hiff surface was placed on the permeation portion of a vertical diffusion cell (Franz cell) with the donor side facing one side, and filled with 1 mL of the donor solution and 3 OmL of the receptor solution.
  • Receptor solution was maintained at a constant temperature (3 '2 0 ⁇ , a transmission experiment was performed in order to prevent evaporation of water during the experiment, Donna.
  • a 0.5 mL receptor solution was taken from the mouth, and 0.5 mL of a new receptor solution was replenished.

Abstract

A preparation for external use, characterized by comprising 0.001 to 20 wt.% statin compound represented by the following general formula (1): (1) (wherein R1 represents an organic group; X represents -CH2CH2- or -CH=CH-; and R2 represents hydrogen or alkyl) or salt thereof, 20 to 80 wt.% polyethylene glycol, and water and by having a pH of 4.0 to 7.0, excluding 7.0. The preparation, which contains the statin compound or salt thereof as an active ingredient, is inhibited from yielding a lactone. It is excellent in long-term stability and percutaneous absorbability.

Description

 Light
外用剤 External preparation
技術分野 Technical field
本発明は、 経皮吸収性に優れ、 かつ、 経時安定性に優れたス夕チン類又はその 塩を有効成分とする外用剤に関する。 糸田  TECHNICAL FIELD The present invention relates to an external preparation containing sutins or a salt thereof as an active ingredient, which is excellent in transdermal absorbability and excellent in stability over time. Itoda
背景技術 Background art
ピ夕バス夕チン、 プラバスタチン等のスタチン類は、 優れた111^0—( 0八還 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 pH 7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 , 0 3 0, 4 4 7号、 米国特 許第 5, 1 80, 589号、 米国特許第 5, 356, 896号、 W097Z 23200) 。  Statins such as pivasbasin and pravastatin are known to have excellent 111 ^ 0- (8-reducing enzyme inhibitory activity and to be useful as a therapeutic agent for hyperlipidemia (US Patent No. 5, 856, 336, U.S. Pat. No. 4,346,227), which have already been used or are being developed as orally-administered preparations having good stability such as tablets. It is known that in the acidic region, isomerization, lactonization, decomposition, etc. occur, resulting in extremely unstable conditions, and that a stable preparation cannot be obtained unless the pH is at least 7 (US Pat. No. 5,033) 0,447, U.S. Patent No. 5,180,589, U.S. Patent No. 5,356,896, W097Z 23200).
一方、 これらの HMG— Co A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。  On the other hand, these HMG-CoA reductase inhibitors are used in addition to hyperlipidemia, acne, psoriasis, dandruff (US Pat. No. 5,730,992, US Pat. No. 6,126,947), hair growth It was reported to be useful as a local action such as suppression (US Pat. No. 5,840,752), and it was required to be developed as an external preparation.
発明の開示 Disclosure of the invention
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夕チン類含有外 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、 プロピレングリコ一ル、 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一ルを配合 すると PH 4 . 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。 Therefore, an object of the present invention is to provide a topical sutin-containing preparation having good transdermal absorbability and stability over time. Therefore, the present inventor examined percutaneous absorption in the basic region, which is a stable region of statins, and found that sufficient absorption was not obtained, and the percutaneous absorption of statins was more unstable than in the basic region. It was found to be good in the acidic region, which is the region. Thus, the present inventors have conducted various studies to obtain an external preparation that satisfies both transdermal absorption and stability over time. As a result, even when ethanol, isopropanol, propylene glycol, dipropylene glycol, etc. are combined with statins, lactones are obtained. Despite the body formation, surprisingly, when a certain amount of polyethylene glycol is blended with statins, the generation of lactones can be suppressed at PH 4.0 or more and less than 7.0, so that aging is stable. The present inventors have found that an external preparation having good properties and excellent transdermal absorbability can be obtained, and completed the present invention.
すなわち、 本発明は、 次の一般式 (1 )  That is, the present invention provides the following general formula (1)
OH OH OH OH
R1一 X— CH— CH2— CH_CH2 - COOR2 ( 1 ) R 1 X — CH— CH 2 — CH_CH 2 -COOR 2 (1)
(式中、 R 1は有機基を示し、 Xは- CH2CH2-又は- CH=CH-を示し、 R 2は水素原子 又はアルキル基を示す) で表わされるス夕チン類又はその塩を 0 . 0 0 1〜2 0 質量%、 ポリエチレングリコールを 2 0〜 8 0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。 本発明のス夕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。 発明を実施するための最良の形態 (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) or a salt thereof. The composition for external use contains 0.001 to 20% by mass of polyethylene glycol, 20 to 80% by mass of polyethylene glycol and water, and has a pH of 4.0 or more and less than 7.0. Things. The external preparation containing the sutins or a salt thereof as an active ingredient of the present invention is an external preparation that suppresses the production of a lactone, has excellent stability over time, and has excellent transdermal absorbability. BEST MODE FOR CARRYING OUT THE INVENTION
本発明で使用する一般式 (1 ) で表わされる化合物の R 1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。 The organic group represented by R 1 in 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.
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、 ピロ口ピリジル基、 ピラゾ口ピリジル基、 チェノビリジル基、 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、 へキサヒドロナフチル基、 シクロへキシル基、 フエニルシリルフエニル 基、 フエニルチェニル基又はフエニルフリル基が挙げられ、 特にへキサヒドロナ 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。 Examples of the organic group having a ring structure include an indolyl group, an indenyl group, a pyridyl group, a pyropyridyl group, a pyrazopyridyl group, a chenobiridyl group, a pyrimidyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, an indolidyl group, a quinolyl group, Nuff A tyl group, a hexahydronaphthyl group, a cyclohexyl group, a phenylsilylphenyl group, a phenylthienyl group or a phenylfuryl group, particularly a hexahydronaphthyl group, an indolyl group, a pyridyl group, a pyrimidyl group, a pyrrolyl group or a quinolyl group. Is preferred.
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、 アルキルォキシアルキル基、 アル キルカルポニルォキシ基、 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、 置換フエニルスルホニルァミノ基、 アルキル、 フエニル等が置換していて もよい力ルバモイル基、 ハロフエニル基、 アルキルフエニル基、 アルコキシフエ ニル基、 フエニル基、 ォキソ基等が挙げられる。  Examples of the substituent which may be substituted on the organic group having such a ring structure include a hydroxy group, a linear, branched or cyclic alkyl group, an alkyloxyalkyl group, an alkylcarbonyloxy group, and an alkyl substituent. Amino group, substituted alkylsulfonylamino group, substituted phenylsulfonylamino group, alkyl or phenyl which may be substituted, etc.Lubamoyl group, halophenyl group, alkylphenyl group, alkoxyphenyl group, phenyl group, oxo And the like.
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のアルキルォキシアルキル 基、 炭素数 1〜4のァシルォキシ基、 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ァミノ基、 炭素数 1〜 4のアルキル置換フェニルスルホニルァミノ基、 炭素数 1〜4のアルキル置 換カルバモイル基、 フエニル置換力ルバモイル基、 フルオロフェニル基、 ブロモ フエニル基、 ョードフエニル基、 メチルフエニル基、 ェチルフエニル基、 メトキ シフエ二ル基、 エトキシフエ二リレ基又はフエニソレ基が好ましく、 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。  Among these substituents which may be substituted by the organic group having a ring structure, a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, 1 to 4 carbon-substituted alkyl group, 1 to 4 carbon-substituted alkyl-substituted amino group, 1 to 4 carbon-substituted alkyl-substituted carbon atom, 1 to 4 alkyl-sulfonylamino group, 1 to 4 carbon-substituted alkyl-substituted phenylsulfonyl-amino group An alkyl-substituted carbamoyl group having 1 to 4 carbon atoms, phenyl-substituting rubamoyl group, fluorophenyl group, bromophenyl group, odophenyl group, methylphenyl group, ethenylphenyl group, methoxyphenyl group, ethoxyphenylyl group or phenylol group. Preferred are isopropyl, cyclopropyl and p-fluorophenyl.
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。 As the alkyl group for R 2 , a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms is preferable.
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、 フエネチルァミン塩等の有機アミン塩又はアンモニゥ 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。  Salts of the compound represented by the general formula (1) are physiologically acceptable salts, such as alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and phenethylamine salt. And the like, and an organic amine salt or an ammonium salt, etc., and a sodium salt and a calcium salt are more preferable.
これらの化合物は、 例えば米国特許第 4, 7 3 9 , 0 7 3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 , 0 0 1 , 2 5 5号、 第 4 , 6 1 3, 6 1 0号、 第 4, 851, 427号、 第 4, 755, 606号、 第 4, 808, 6Ό 7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These compounds are described, for example, in US Pat. No. 4,739,073 and European Patent Patent Application Publication No. 114,027; European Patent Application Publication No. 367,895; U.S. Patent Nos. 5,001,255, 4,613,610, 4,851, 427, 4,755,606, 4,808,6-7, 4,751,235, 4,939,159, 4,822,799, 4,804,679 No. 4, 876, 280, 4, 829, 081, No.
4, 927, 85 1号、 第 4, 588, 7 1 5号;及び F. G. Kathawala, Medical Research Reviews, ϋ, 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No. 4, 927, 851, No. 4, 588, 7 15; and FG Kathawala, Medical Research Reviews, ϋ, 121-146 (1991), European Patent Application Publication No. 304, 063; European Patent Application Publication No. No. 330,057, U.S. Patent No.
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5,026,708, 4,868,185; EP-A-324,347; EP-A-300,278; U.S. Patents 5,013,749, 5,872, No. 130, No. 5, 856, 336, No.
4, 231, 938号、 第 4, 444, 784号、 第 4, 346, 227号、 第No. 4, 231, 938, No. 4, 444, 784, No. 4, 346, 227, No.
5, 354, 772号、 第 5, 273, 995号、 第 5, 177, 080号、 第5, 354, 772, 5, 273, 995, 5, 177, 080,
3, 98 3, 140号、 日本国特許第 2, 648, 897号、 米国特許第 5, 260, 440号、 Bioorganic & Medicinal Chemistry, 互, 437, (1977)、 曰本国特許第 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。 No. 3,983,140; Japanese Patent No. 2,648,897; U.S. Patent No. 5,260,440; Bioorganic & Medicinal Chemistry, Mutual, 437, (1977); No. 746, European Patent No. 304,063, and US Pat. No. 5,856,336.
一般式 (1) で表わされるス夕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、 プラバス夕チン (米国特許第 As the sutins represented by the general formula (1) and salts thereof, those which do not form a lactone are preferable. For example, pravasutin (US Pat.
4, 346, 227号: (+ ) - (3 R, 5 R) 一 3, 5—ジヒドロキシ—7— [ ( 1 S, 2 S, 6 S, 8 S, 8 a R) — 6—ヒドロキシ— 2—メチル— 8 [ (S) 一 2ーメチルブチリルォキシ] — 1, 2, 6 , 7, 8, 8 a—へ キサヒドロ— 1一ナフチル] ヘプタン酸) 、 フルパスタチン (米国特許第No. 4, 346, 227: (+)-(3R, 5R) -1,3-dihydroxy-7-[(1S, 2S, 6S, 8S, 8aR) -6-hydroxy- 2-Methyl-8 [(S) -1-methylbutyryloxy] — 1,2,6,7,8,8a-Hexahydro-1-naphthyl] heptanoic acid), Flupastatin (US Patent No.
5, 354, 772号: (3 RS, 5 S R, 6 E) —7— [3— (4一フルォロ フエニル) 一 1 - (1—メチルェチル) _ 1H—インドール— 2—ィル] 一 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 , 27 3, 995号: (3R, 5 R) _7_ [.2 - (4ーフリレオ口フエニル) 一 5—ィ ソプロピル一 3—フエ二ルー 4一フエ二ルカルバモイルー 1 H—ピロルー 1ーィ ル] 一 3 , 5ージヒドロキシヘプタン酸) 、 セリバス夕チン (米国特許第 5, 177, .080号: (3R, 5 S) —エリスロー (E) —7— [4- (4— フルオロフェニル) -2, 6—ジイソプロピル— 5—メトキシメチルーピリジン 一 3 ィル] -3, 5—ジヒドロキシ— 6—ヘプテン酸) 、 ロスパスタチン (米 国特許第 5, 260, 440号、 日本国特許第 2, 648, 897号: 7_ [4 - (4一フルオロフェニル) 一 6一イソプロピル一 2一 (N—メチルー N—メタ ンスルホニルァミノピリミジン) 一 5—ィル] - (3 R, 5 S) ージヒドロキシ 一 (E) —6—ヘプテン酸) 、 ピタバス夕チン (米国特許第 5, 856, 336 号、 日本国特許第 2, 569, 746号: (3R, 5 S, 6 E) -7- [2—シ クロプロピル— 4一 (4一フルオロフェニル) 一 3—キノリル] 一 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、 特にピ夕パスタチン 又はその塩が好ましく、 ピタパスタチンカルシウムが最も好ましい。 No. 5, 354, 772: (3 RS, 5 SR, 6 E) —7— [3— (4-Fluorophenyl) 1 1- (1-methylethyl) _ 1H—indole-2-yl] 1 3, 5-dihydroxy-6-heptenoic acid), atorvastatin (US Patent 5, 27 No. 3, 995: (3R, 5R) _7_ [.2-(4-phenylophenyl) -1-5-isopropyl-1-3-phenyl-4 phenylcarbamoyl-1H-pyrrolo-1-yl] 1-3 , 5 dihydroxyheptanoic acid), ceribastin (US Patent No. 5,177, .080: (3R, 5S) -erythro (E) —7— [4- (4-fluorophenyl) -2,6 —Diisopropyl-5-methoxymethylpyridine 13-yl] -3,5-dihydroxy-6-heptenoic acid), rospastatin (US Patent No. 5,260,440, Japanese Patent No. 2,648,897) : 7_ [4- (4-fluorophenyl) -1-61-isopropyl-1- (N-methyl-N-methanesulfonylaminopyrimidine) -1-5-yl]-(3R, 5S) dihydroxy-1 (E) —6—heptenoic acid), pitavasintin (US Pat. No. 5,856,336, Japanese Patent No. 2,569,746): (3R, 5S, 6E) -7- [2-cyclo Ropyr-41- (4-fluorophenyl) -13-quinolyl] -13,5-dihydroxy-6-heptenoic acid or a salt thereof is preferred, and particularly, pipa pastatin or a salt thereof is preferred. Most preferred.
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。  The content of the statin or a salt thereof is from 0.001 to 20% by mass, preferably from 0.01 to 10% by mass, particularly preferably from 0.1 to 5% by mass in the total amount of the external preparation.
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 リエチレンダリコールは、 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 0POV) は、 5 meq/kg以下、 特に 1 meq/kg以下が好ましく、 ホルムアルデヒド濃度は 5 ppm以 下、 特に 2 ppm以下が好ましい。  The molecular weight of the polyethylene glycol used in the present invention is preferably from 100 to 60,000, more preferably from 300 to 4000, particularly preferably from 300 to 1500. Polyethylene dalicol is known to oxidize formaldehyde, an impurity at the time of production, and decrease the pH over time. Therefore, the peroxide value (POPOV) is preferably 5 meq / kg or less, particularly preferably 1 meq / kg or less, and the formaldehyde concentration is preferably 5 ppm or less, particularly preferably 2 ppm or less.
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、 ス夕 5=·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。 The content of polyethylene glycol is important from the viewpoint of the stability of the statins with time, and is 20 to 80% by mass, preferably 25 to 75% by mass, particularly 30 to 70% by mass in the total amount of the external preparation. Is preferred. Polyethylene glycol content If the content is less than 20% by mass, the effect of inhibiting the formation of lactones of the quinones is low, and if the content exceeds 80% by mass, it becomes difficult to adjust the pH of the external preparation.
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。  Water is contained in the balance amount in the total amount of the external preparation, but it is preferably contained in an amount of 10 to 75% by mass, more preferably 20 to 70% by mass, particularly preferably 25 to 65% by mass.
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°Cにおいて pHメ一夕で測定す る。  The pH of the external preparation of the present invention is 4.0 or more and less than 7.0, preferably 4.0 to 6.7, more preferably 4.5 to 6.7. For pH measurement, mix 1 part by weight of the external preparation and 9 parts by weight of water, shake thoroughly, and measure at pH 25 ° C overnight.
PH調整剤としては、 リン酸、 酢酸、 ホウ酸、 乳酸、 コハク酸、 クェン酸、 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、 水酸ィ匕ナトリウム等が 挙げられる。 さらに、 ブリ トン—ロビンソン緩衝液 (Bri tton- Robinson Buffer) 、 クラ一クール一ブズ緩衝液 (Clark-Lubs Buffer) 、 コルトフ緩衝液 Examples of the pH adjuster include phosphoric acid, acetic acid, boric acid, lactic acid, succinic acid, citric acid, tartaric acid, phthalic acid and salts thereof such as alkali metals, glycine, sodium hydroxide and the like. In addition, Britton-Robinson Buffer, Clark-Lubs Buffer, Koltov Buffer
(Kolthoff Buffer) 等の pH緩衝液を用いてもよい。 (Kolthoff Buffer) may be used.
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一ル以外の水溶性高分子、 安定化剤、 基剤等が挙 げられる。  As long as the effects of the present invention are not impaired, various optional ingredients that are acceptable as pharmaceutical additives can be added to the external preparation of the present invention as needed. Examples thereof include a solvent and polyethylene. Examples include water-soluble polymers other than glycols, stabilizers, and bases.
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、 ォレイルアルコ 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、 2一 ェチル _ 1, 3一へキサンジオール、 ボ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。  Examples of the solvent include monohydric alcohols such as benzyl alcohol, stearyl alcohol, and oleyl alcohol, polyhydric alcohols such as concentrated glycerin, 1,3-butylene glycol, 21-ethyl-1,3-hexanediol, and polypropylene glycol 2000. Alcohol.
前記水溶性高分子としては、 ヒドロキシェチルセルロース、 ヒドロキシプロピ ルセルロース等のセルロース類、 白糖、 )3—シクロデキストリン等の多糖類、 ソ ルビ! ^一ル、 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。  Examples of the water-soluble polymer include celluloses such as hydroxyethylcellulose and hydroxypropylcellulose; sucrose;) polysaccharides such as 3-cyclodextrin; sugar alcohols such as sorbitol and mannitol; and polyvinyl alcohol. And synthetic polymers such as polyvinylpyrrolidone.
安定化剤としては、 パラォキシ安息香酸メチル、 パラォキシ安息香酸プロピル 等のフエノール性物質、 クロロブ夕ノール、 フエニルエチルアルコール等の中性 物質、 ビタミン E、 プチルヒドロキシァニソ一ル、 酢酸トコフエロール、 没食子 酸プロピル、 2—メルカプトべンズイミダゾ一ル等の抗酸化剤、 ァスコルビン 酸、 亜硫酸水素ナトリウム、 チォ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) 、 カルボキシビ二ルポリマー、 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?夜剤、 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。 実施例 Stabilizers include methyl paraoxybenzoate, propyl paraoxybenzoate Phenolic substances such as chlorobutanol, phenylethyl alcohol, etc., antioxidants such as vitamin E, butylhydroxyanisole, tocopherol acetate, propyl gallate, 2-mercaptobenzimidazole, etc. And reducing agents such as ascorbic acid, sodium bisulfite and sodium thiosulfate. 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. The form of the present invention is not limited as long as it is an external preparation, and examples thereof include night creams, gels, creams, lotions, sprays, ointments and the like. Example
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。  Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.
実施例 1 Example 1
ピタパ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 4 0 0 (日 本油脂製 ·マクロゴール 4 0 0、 5質量%水溶液の pHは 6 ) 5 0質量部に溶解し た後、 Br i t ton- Robinson Buf fer (pH4. 0 ) を加えて 1 0 0質量部として外用 剤を製造した。  After dissolving 0.1 part by mass of pitapastatin calcium in 50 parts by mass of polyethylene glycol 400 (made by Nihon Yushi Fatty Co., Ltd., macrogol 400, pH of 5% by mass aqueous solution is 6), Briton-Robinson An external preparation was manufactured by adding Buf fer (pH 4.0) to 100 parts by mass.
また、 上記外用剤中のポリエチレングリコール 4 0 0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。  An external preparation in which polyethylene glycol 400 in the above external preparation was replaced with isopropanol (Comparative Example 1), ethanol (Comparative Example 2), propylene glycol (Comparative Example 3) and dipropylene glycol (Comparative Example 4), respectively. Was manufactured.
製造した外用剤の pH (製造直後) 及び 6 0 °C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。  The pH of the prepared external preparation (immediately after production) and the lactone production rate after storage at 60 ° C for 3 days were measured by the following methods.
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 3 0分間振とう 後、 2 5 °Cで pHを測定した (pHメータ:堀場製作所 F— 2 4 ) 。  PH measurement 9 parts by mass of purified water was added to 1 part by mass of an external preparation, and after shaking for 30 minutes with a shaker, the pH was measured at 25 ° C (pH meter: Horiba Seisakusho F-24).
ラクトン体生成率測定 外用剤を 6 0 °C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。 Lactone formation rate measurement Lactone formation after storage of external preparations at 60 ° C for 3 days The percentage was measured by the following method.
内標準溶液:プロピルパラベン  Internal standard solution: propylparaben
測定波長: 245 nm  Measurement wavelength: 245 nm
カラム: Develosil 〇DS— HG— 5  Column: Develosil 〇DS—HG—5
カラム温度: 40°C  Column temperature: 40 ° C
移動相:メタノ一ル Z 0. 02 mol/Lリン酸塩緩衝液 (pH 3 ) = 13/7 以上の H PLC条件でピ夕パ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。  Mobile phase: methanol Z 0.02 mol / L Phosphate buffer (pH 3) = 13/7 Under HPLC conditions, the peak area of pinaster pastatin and lactone is determined. Was calculated.
ラクトン体生成率 ( ) = (L/ (P + L) ) X 100 (1)  Lactone formation rate () = (L / (P + L)) X 100 (1)
P : 60°Cに保存して 3日経過時のピタバス夕チンのピーク面積  P: Peak area of pitavas after storage for 3 days after storing at 60 ° C
L: 60°Cに保存して 3日経過時のラクトン体のピ一ク面積  L: Peak area of lactone body after 3 days after storage at 60 ° C
測定結果を表 1に示す。 表 1  Table 1 shows the measurement results. table 1
ポリエチレングリコ一ルを含有する実施例 1の外用剤は、 ラクトン体生成が抑 制され安定であつたが、 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 ) 、 ジブ ロピレンダリコール (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。 The external preparation of Example 1 containing polyethylene glycol was stable because lactone formation was inhibited and isopropanol was used instead of polyethylene glycol. The external preparations containing alcohols such as Comparative Example 1), ethanol (Comparative Example 2), propylene glycol (Comparative Example 3), and dipropylendalcol (Comparative Example 4) did not inhibit the formation of lactone bodies. It was unstable.
実施例 2〜 6  Examples 2 to 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。  An external preparation having the composition shown in Table 2 was produced in the same manner as in Example 1.
表 2に pH及びラクトン体生成率の測定結果を示す。 ·  Table 2 shows the measurement results of pH and lactone formation rate. ·
表 2  Table 2
ピタバス夕チンを含有した外用剤にポリエチレングリコール 4 0 0を 1 0質 量% (比較例 5 ) 添加した外用剤では、 6 0 °C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 4 0 0を 3 0〜 7 0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。 In an external preparation containing 100% by mass of polyethylene glycol 400 (Comparative Example 5) added to an external preparation containing pitavasutin, the lactone body formation rate when stored at 60 ° C for 3 days was reduced. Increased. 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 form formation rate was suppressed and stable.
実施例 7〜 9  Examples 7 to 9
表 3に示す外用剤を製造した。  The external preparations shown in Table 3 were produced.
pH及びラクトン体生成率の測定結果を表 3に示す。 表 3 Table 3 shows the measurement results of the pH and the lactone formation rate. Table 3
また、 ピタバス夕チンとポリエチレングリコ一ル 40 0を 5 0質量%含有した 外用剤の pHが 4. 0未満では、 6 0 °C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、 6 0°C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つた。 In addition, when the pH of an external preparation containing 50% by mass of pitavasutin and polyethylene glycol 400 was less than 4.0, the rate of lactone formation increased when stored at 60 ° C for 3 days. . However, when the pH of the external preparation was 4.0 or more, the lactone form formation rate was suppressed and stable when stored at 60 ° C for 3 days.
実施例 1 0〜 1 2 Examples 10 to 12
表 4に示す外用剤を製造した。  The external preparations shown in Table 4 were produced.
pH及びラクトン体生成率の測定結果を表 4に示す。  Table 4 shows the measurement results of the pH and the lactone formation rate.
表 4  Table 4
ピタパスタチンを含有した外用剤に分子量が、 3 0 0, 1 5 0 0, 40 0 0の ポリエチレングリコ一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。 The topical formulation containing pitapastatin has a molecular weight of 300, 150, 400 In the case of an external preparation to which polyethylene glycol was added, the lactone formation rate was suppressed and stable when stored under conditions of 60 for 3 days.
試験例 皮膚透過性 Test example Skin permeability
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。  The skin permeability of each of the external preparations of Examples 1, 8 and Comparative Example 7 in which the Britton-Robinson Buffer (pH 4.0) of Example 1 was replaced with Briffon-Robinson Buffer (pH 8.0) was measured.
皮膚透過量の測定 ドナ一溶液は、 実施例 実施例 8及び比較例 7で製造し た外用剤を用いた。 レセプ夕一溶液は、 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。  Measurement of Skin Permeation As the donor solution, the external preparations produced in Example 8 and Comparative Example 7 were used. Britton-Robinson Buffer (pH 6.0) was used for the reception solution. The permeable membrane used was an abdominal extirpated Hiff (hereinafter abbreviated as “Hif”) of a Wistar rat (male, 8 weeks old).
縦型拡散セル (Franzセル) の透過部にヒフ表面をドナ一側にして置き、 ドナ 一溶液 lmL及びレセプター溶液 3 OmLを満たした。 レセプター溶液を一定温度 (3 '20Ο 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 —セル及びサンプル口をパラフィルムで覆つた。 6及び 8時間経過時にサンプル 口から 0. 5 mLレセプタ一溶液を採取し、 新しいレセプ夕一溶液 0. 5mLを補充 した。 The Hiff surface was placed on the permeation portion of a vertical diffusion cell (Franz cell) with the donor side facing one side, and filled with 1 mL of the donor solution and 3 OmL of the receptor solution. Sample cell and sample port with parafilm to KutsugaeTsuta 6 and at 8 hours after -. Receptor solution was maintained at a constant temperature (3 '2 0 Ο, a transmission experiment was performed in order to prevent evaporation of water during the experiment, Donna. A 0.5 mL receptor solution was taken from the mouth, and 0.5 mL of a new receptor solution was replenished.
採取したサンプル溶液中のピタバス夕チンを t er t—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 — f loorophey 1) quinol in— 3 ' 一 yl) hepto- 6 -enoic acid、 測定波長: 245nm、 カラム: Develosi 1 〇DS— HG_5、 カラム温度: 40°C及び移動相: 0. 2raol/L酢酸 Zァセトニトリル /メタノール =60/30/10) によりピ夕バス夕チン含有量を測定した。 測定結果を表 5に示す。 表 5 After extracting pitavathine in the collected sample solution with tert-butyl methyl ether, the HPLC method (internal standard substance: (E) _3 (R), 5 (S) -Dihydroxy-7--(2-isopropyl) ― 4 '― (4 — f loorophey 1) quinol in— 3' one yl) hepto-6-enoic acid, measurement wavelength: 245 nm, column: Develosi 1 〇DS—HG_5, column temperature: 40 ° C, and mobile phase: 0.2 raol / L Zacetonitrile acetate / methanol = 60/30/10) was used to determine the content of the pigment in the bath. Table 5 shows the measurement results. Table 5
ピタパ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、 ρΗ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。 When the pH of external preparations containing pita pastatin calcium and polyethylene glycol added to polyethylene glycol was 7.0 or more, the amount of permeation through the skin was small, but the amount of skin permeation increased when ρΗ was adjusted to less than 7.0. The absorption was good.
実施例 13 ゲル状外用剤 Example 13 Gel external preparation
ピタバス夕チンカルシウム (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、 カルボキシピ二ルポリマー (ウル トレッツ 10: BF GOODRICH社製) 0. 5質量部を Briffon- Robinson Buffer (pH 8. 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-Robi nson 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  Pitabas-tin calcium (0.1 parts 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 carboxypinyl polymer (Ultrez 10: manufactured by BF GOODRICH) was swollen into 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 the total amount was 100 parts by mass with Britton-Robison Buffer (pH 8.0) to produce a gel external preparation. Example 14 Cream external preparation
ピタバス夕チンカルシウム (0. 1質量部) 及びモノォレイン酸ポリオキシェ チレンソルビタン (20E. 0. ) (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、 力ルポキシビ二ルポリマー (ウルトレッツ 10 : BF GOODRICH社製) 0. 5質量部を Bri tton- 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 100 gとしてクリーム状外用剤を 製造した Pitabas-tin calcium (0.1 part by mass) and polyoxyethylene sorbitan monooleate (20E.0.) (0.5 part by mass) were dissolved in polyethylene glycol 400 (70 parts by mass) to obtain an oil phase. Separately, 0.5 parts by mass of Ripoxyvinyl polymer (Ultrez 10: manufactured by BF GOODRICH) was swollen into 25 parts by mass of Briton-Robinson Buffer (pH 8.0) to obtain an aqueous phase. Add the aqueous phase to the oil phase, and add a cream-based external preparation to a total of 100 g with Britton-Robinson Buffer (pH 8.0). Manufactured

Claims

請求の範囲 The scope of the claims
1 . 次の一般式 (1 ) 1. The following general formula (1)
OH 0H OH 0H
R1— X— CH- CH2- CH— CH2— C00R2 丄 ) R 1 — X— CH- CH 2 -CH— CH 2 — C00R 2丄)
(式中、 R 1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 . 0 0 1〜2 0 質量%、 ポリエチレングリコールを 2 0〜 8 0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。 (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) or a salt thereof. An external preparation comprising 0.1 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.
2 . ポリエチレングリコールの分子量が 1 0 0〜6 0 0 0 0である請求項 1記 載の外用剤。  2. The external preparation according to claim 1, wherein the molecular weight of the polyethylene glycol is from 100 to 600,000.
3 . スタチン類がブラバス夕チン、 フルバス夕チン、 7トルバスタチン、 セリ バス夕チン、 ロスバス夕チン、 ピタパスタチン及びそれらの塩からなる群から選 ばれたものである請求項 1記載の外用剤。  3. The external preparation according to claim 1, wherein the statin is selected from the group consisting of bravath, flubas, 7 torvastatin, seribas, rosuvastin, pitapastatin and salts thereof.
4. 塩がナトリゥム塩又はカルシウム塩である請求項 1記載の外用剤。  4. The external preparation according to claim 1, wherein the salt is a sodium salt or a calcium salt.
5 . スタチン類がピタバス夕チンである請求項 1記載の外用剤。  5. The external preparation according to claim 1, wherein the statin is pitavasutin.
6 . スタチン類の塩がピタバス夕チンカルシウムである請求項 1記載の外用 剤。  6. The external preparation according to claim 1, wherein the salt of the statin is pitavasutin calcium.
PCT/JP2003/011767 2002-09-20 2003-09-16 Preparation for external use WO2004026297A1 (en)

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JP2010126478A (en) * 2008-11-27 2010-06-10 Kowa Co Plaster
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JP4981194B2 (en) * 2010-10-25 2012-07-18 興和株式会社 Pharmaceutical composition
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