JPH07103028B2 - Imidazole antifungal topical solution - Google Patents

Imidazole antifungal topical solution

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Publication number
JPH07103028B2
JPH07103028B2 JP5444790A JP5444790A JPH07103028B2 JP H07103028 B2 JPH07103028 B2 JP H07103028B2 JP 5444790 A JP5444790 A JP 5444790A JP 5444790 A JP5444790 A JP 5444790A JP H07103028 B2 JPH07103028 B2 JP H07103028B2
Authority
JP
Japan
Prior art keywords
imidazole
test
preparation
poe
external
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
JP5444790A
Other languages
Japanese (ja)
Other versions
JPH03258717A (en
Inventor
豊 村田
健光 浅岡
勝美 今森
曜 岩佐
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SSP Co Ltd
Original Assignee
SSP Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SSP Co Ltd filed Critical SSP Co Ltd
Priority to JP5444790A priority Critical patent/JPH07103028B2/en
Priority to CA002035758A priority patent/CA2035758C/en
Priority to US07/650,969 priority patent/US5100908A/en
Priority to ES91101630T priority patent/ES2074178T3/en
Priority to DE69108964T priority patent/DE69108964T2/en
Priority to EP91101630A priority patent/EP0445540B1/en
Priority to KR1019910002229A priority patent/KR950003611B1/en
Publication of JPH03258717A publication Critical patent/JPH03258717A/en
Publication of JPH07103028B2 publication Critical patent/JPH07103028B2/en
Priority to HK98106293A priority patent/HK1007104A1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、新規なイミダゾール系抗真菌性外用液剤に関
し、更に詳細には、皮膚刺激性が少なく、その効果を最
大限かつ持続的に発揮することができ、しかも物理化学
的に安定な外用液剤に関する。
TECHNICAL FIELD The present invention relates to a novel imidazole antifungal external liquid preparation, and more specifically, it has little skin irritation and exerts its effect to the maximum and continuously. And a physicochemically stable external preparation.

〔従来の技術及び発明が解決しようとする課題〕[Problems to be Solved by Prior Art and Invention]

従来、真菌等に対する抗菌作用を有するイミダゾール系
抗真菌剤は、抗菌スペクトルが広く、臨床的にも耐性菌
の出現が少ない等の利点を有するため、クリーム剤、ゲ
ル剤、液剤等の剤形として市販されている。
Conventionally, imidazole-based antifungal agents having antibacterial activity against fungi have a wide antibacterial spectrum and have the advantage that clinically resistant bacteria are less likely to occur, so that they can be used as dosage forms such as creams, gels, and liquids. It is commercially available.

これらのうち、液剤は、一般に他の剤形より展延性に優
れ、特異な部位にも適用できるという特徴を有するが、
アルコールを含有するため皮膚刺激があるという問題が
あり、適切な基剤を選択する必要がある。また、抗菌作
用を高め、治療期間の短縮及び使用回数を減らすことも
要求されるが、このためには展延性を高め良好な放出性
を維持し、かつ貯留効果を高める等、治療における有効
性が最適になるような基剤設計をするなどの必要があ
る。しかしながら、これらの効果は未だ充分に得られて
いなかった。
Of these, liquids generally have better spreadability than other dosage forms and can be applied to specific sites, but
Since it contains alcohol, there is a problem of skin irritation, and it is necessary to select an appropriate base. It is also required to enhance the antibacterial action, shorten the treatment period, and reduce the number of times of use. For this purpose, it is effective in treatment such as enhancing spreadability, maintaining good release, and enhancing storage effect. It is necessary to design the base material so that However, these effects have not been sufficiently obtained.

このため、皮膚刺激性が少なく、優れた効果を充分に発
揮することができる抗真菌性外用液剤が望まれていた。
Therefore, there has been a demand for an antifungal external preparation which has little skin irritation and can sufficiently exhibit excellent effects.

〔課題を解決するための手段〕[Means for Solving the Problems]

斯かる実情において、本発明者らは鋭意研究を行なった
結果、(E)−1−〔2−メチルチオ−1−〔2−(ペ
ンチルオキシ)フェニル〕エテニル〕−1H−イミダゾー
ル塩酸塩を有効成分として、特定の基剤に配合した外用
液剤は、皮膚刺激性が少なく、治療効果を持続的に発揮
させることができ、しかも物理化学的に安定であること
を見出し、本発明を完成した。
Under such circumstances, as a result of intensive studies, the present inventors have found that (E) -1- [2-methylthio-1- [2- (pentyloxy) phenyl] ethenyl] -1H-imidazole hydrochloride is an active ingredient. As a result, the inventors have found that an external-use liquid formulation blended with a specific base has little skin irritation, can continuously exert a therapeutic effect, and is physicochemically stable, and completed the present invention.

すなわち、本発明は、次の(a)〜(d) (a)(E)−1−〔2−メチルチオ−1−〔2−(ペ
ンチルオキシ)フェニル〕エテニル〕−1H−イミダゾー
ル塩酸塩 0.1〜5 W/V% (b)液状油性物質 1〜50W/V% (c)非イオン性界面活性剤 1〜20W/V% (d)塩基性物質 0.01〜2 W/V% を含有することを特徴とするイミダゾール系抗真菌性外
用液剤を提供するものである。
That is, the present invention provides the following (a) to (d) (a) (E) -1- [2-methylthio-1- [2- (pentyloxy) phenyl] ethenyl] -1H-imidazole hydrochloride 0.1- 5 W / V% (b) Liquid oily substance 1-50 W / V% (c) Nonionic surfactant 1-20 W / V% (d) Basic substance 0.01-2 W / V% The present invention provides a characteristic imidazole antifungal external liquid preparation.

本発明において、有効成分として用いられる(a)成分
の(E)−1−〔2−メチルチオ−1−〔2−(ペンチ
ルオキシ)フェニル〕エテニル〕−1H−イミダゾール塩
酸塩(以下、「化合物A」という)は、細菌、真菌等に
対して優れた抗菌作用を有する既知物質である(特開昭
63−146864号)。
In the present invention, (E) -1- [2-methylthio-1- [2- (pentyloxy) phenyl] ethenyl] -1H-imidazole hydrochloride (hereinafter referred to as “compound A”) of component (a) used as an active ingredient. Is a known substance having an excellent antibacterial action against bacteria, fungi, etc.
63-146864).

化合物Aは、全組成中に0.1〜5W/V%(以下、単に%で
示す)、好ましくは0.5〜1.5%配合される。
The compound A is added in an amount of 0.1 to 5 W / V% (hereinafter simply referred to as%), preferably 0.5 to 1.5% in the total composition.

(b)成分の液状油性物質としては、常温で液体のもの
であれば特に限定されないが、特に飽和脂肪酸エステル
が好ましく、例えばアジピン酸ジイソプロピル、セバシ
ン酸ジエチル、ミリスチン酸イソプロピル等が挙げられ
る。これらは一種又は二種以上を組合わせて用いること
ができ、全組成中に1〜50%、好ましくは5〜40%配合
される。
The liquid oily substance as the component (b) is not particularly limited as long as it is liquid at room temperature, but saturated fatty acid ester is particularly preferable, and examples thereof include diisopropyl adipate, diethyl sebacate, and isopropyl myristate. These can be used alone or in combination of two or more, and are added in an amount of 1 to 50%, preferably 5 to 40% in the total composition.

(c)成分の非イオン性界面活性剤としては、ポリオキ
シアルキレンエステル型又はエーテル型界面活性剤が好
ましく、特にポリオキシエチレン(POE)と飽和脂肪酸
とのエステル型、又はPOEと飽和脂肪族アルコールとの
エーテル型界面活性剤が好ましい。具体的には、POEモ
ノラウレート、POEモノステアレート、POEラウリルエー
テル、POEセチルエーテル、POE硬化ヒマシ油誘導体等が
挙げられる。これらは、全組成中に1〜20%、好ましく
は2〜10%配合される。
As the nonionic surfactant as the component (c), a polyoxyalkylene ester type or ether type surfactant is preferable, and an ester type of polyoxyethylene (POE) and a saturated fatty acid, or POE and a saturated aliphatic alcohol is particularly preferable. And ether type surfactants are preferred. Specific examples thereof include POE monolaurate, POE monostearate, POE lauryl ether, POE cetyl ether, and POE hydrogenated castor oil derivative. These are contained in 1 to 20%, preferably 2 to 10% of the total composition.

(d)成分の塩基性物質としては、例えばアルキルアミ
ン類やモノ、ジもしくはトリアルカノールアミン等の有
機アミン;水酸化アルカリ、炭酸アルカリ等の無機アル
カリ等が挙げられ、このうち特にモノエタノールアミ
ン、ジエタノールアミン、トリエタノールアミン、水酸
化ナトリウム、水酸化カリウム等が好ましい。(d)成
分は、全組成中に0.01〜2%、好ましくは0.1〜0.5%配
合される。
Examples of the basic substance as the component (d) include alkylamines, organic amines such as mono-, di- or trialkanolamines; inorganic alkalis such as alkali hydroxides and carbonates; among them, monoethanolamine, Diethanolamine, triethanolamine, sodium hydroxide, potassium hydroxide and the like are preferable. The component (d) is mixed in the composition in an amount of 0.01 to 2%, preferably 0.1 to 0.5%.

また、本発明の外用液剤は、エタノールを全組成中に5
〜70%、好ましくは30〜60%配合することができ、その
他に精製水を配合するのが好ましい。
In addition, the external preparation of the present invention contains ethanol in an amount of 5% in the total composition.
˜70%, preferably 30 to 60% can be added, and purified water is also preferably added.

本発明の外用液剤は、化合物Aを配合し、通常の方法に
従って製造することができる。
The liquid preparation for external use of the present invention can be produced by compounding Compound A and using an ordinary method.

〔作用〕[Action]

本発明の抗真菌性外用液剤は、皮膚への親和性、展延性
に優れ、有効成分の放出が制御されるため、皮膚への貯
留性が高まり、持続的な治療効果を発揮することができ
る。また、塩基性物質を配合することにより、有効成分
の活性を高めるとともに、皮膚刺激性を低減している。
INDUSTRIAL APPLICABILITY The antifungal external preparation of the present invention has excellent affinity and spreadability to the skin and controls the release of the active ingredient, so that the storage property on the skin is enhanced and a continuous therapeutic effect can be exerted. . In addition, the addition of a basic substance enhances the activity of the active ingredient and reduces skin irritation.

〔発明の効果〕〔The invention's effect〕

本発明のイミダゾール系抗真菌性外用液剤は、皮膚刺激
性が少なく、使用感も良好で、優れた治療効果を持続的
に発揮することができ、しかも物理化学的に安定なもの
である。
INDUSTRIAL APPLICABILITY The imidazole antifungal external liquid preparation of the present invention has little skin irritation, has a good feeling in use, can continuously exhibit an excellent therapeutic effect, and is physicochemically stable.

〔実施例〕〔Example〕

以下、実施例、比較例及び試験例を挙げ、本発明を更に
詳しく説明する。
Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples.

実施例1 化合物A 1g セバシン酸ジエチル 15g POE(10)モノラウレート 5g トリエタノールアミン 0.465g エタノール 56g 精製水にて全量 100ml 化合物Aをエタノールに溶解した後、セバシン酸ジエチ
ル及びPOE(10)モノラウレートを混和する。これに、
適当量の精製水に溶解したトリエタノールアミンを加
え、精製水で全量100mlとして、外用液剤を得た。
Example 1 Compound A 1 g Diethyl sebacate 15 g POE (10) monolaurate 5 g Triethanolamine 0.465 g Ethanol 56 g Total amount 100 ml with purified water After dissolving compound A in ethanol, diethyl sebacate and POE (10) monolaurate Mix rates. to this,
Triethanolamine dissolved in an appropriate amount of purified water was added, and the total amount was 100 ml with purified water to obtain a liquid preparation for external use.

実施例2 化合物A 1g セバシン酸ジエチル 30g アジピン酸ジイソプロピル 10g POE(5.5)セチルエーテル 5g トリエタノールアミン 0.465g エタノール 35g 精製水にて全量 100ml 実施例1と同様にして、外用液剤を製造した。Example 2 Compound A 1 g Diethyl sebacate 30 g Diisopropyl adipate 10 g POE (5.5) Cetyl ether 5 g Triethanolamine 0.465 g Ethanol 35 g Purified water 100 ml in total As in Example 1, an external preparation was prepared.

実施例3 化合物A 1g セバシン酸ジエチル 30g POE(60)硬化ヒマシ油 5g 水酸化ナトリウム 0.115g エタノール 42g 精製水にて全量 100ml 実施例1と同様にして、外用液剤を製造した。Example 3 Compound A 1 g Diethyl sebacate 30 g POE (60) hydrogenated castor oil 5 g Sodium hydroxide 0.115 g Ethanol 42 g Total amount 100 ml with purified water In the same manner as in Example 1, an external preparation was prepared.

実施例4 化合物A 1g ミリスチン酸イソプロピル 10g POE(10)モノラウレート 10g トリエタノールアミン 0.465g エタノール 56g 精製水にて全量 100ml 実施例1と同様にして、外用液剤を製造した。Example 4 Compound A 1 g Isopropyl myristate 10 g POE (10) monolaurate 10 g Triethanolamine 0.465 g Ethanol 56 g Total amount 100 ml with purified water A liquid preparation for external use was produced in the same manner as in Example 1.

比較例 化合物A 1g セバシン酸ジエチル 30g POE(10)モノオレエート 5g エタノール 42g 精製水にて全量 100ml 実施例1と同様にして、外用液剤を製造した。Comparative Example Compound A 1 g Diethyl sebacate 30 g POE (10) monooleate 5 g Ethanol 42 g Total amount 100 ml with purified water In the same manner as in Example 1, a liquid preparation for external use was produced.

試験例1(有効性試験) 実施例1〜4及び比較例で製造した外用液剤について、
白癬菌感染治療試験を行なった。結果を第1図に示す。
Test Example 1 (Efficacy Test) For the external preparations produced in Examples 1 to 4 and Comparative Example,
A Trichophyton infection treatment test was performed. The results are shown in Fig. 1.

(試験方法) モルモットの背部4箇所を抜毛し、Trichophyton menta
grophytes TIMM 1189株の菌液を接種し、菌接種後5日
目より被験液剤で1日1回、連続14日間塗布し、以下の
基準により病変スコアの判定を行なった。病変スコアが
低いほど有効性が高いことを示す。
(Test method) Trichophyton menta was extracted from four places on the back of the guinea pig.
A bacterial solution of the grophytes TIMM 1189 strain was inoculated, and from the 5th day after the bacterial inoculation, the test solution was applied once a day for 14 consecutive days, and the lesion score was determined according to the following criteria. The lower the lesion score, the higher the efficacy.

+1:少数個の小さな紅斑や紅斑性丘疹が島状に散在して
認められる状態、又は病変が軽快し新しい体毛が発育し
てきた状態。
+1: A small number of small erythema or erythematous papules scattered on the islands, or a condition in which the lesions have improved and new hair has grown.

+2:紅斑が感染部位全体に広がり、表皮の剥離を伴う状
態。
+2: A condition in which erythema spreads over the entire infected area and peels the epidermis.

+3:部分的に強い発赤や腫脹の炎症症状が見られ、豊富
に鱗屑が生じる状態。
+3: Inflammatory symptoms such as strong redness and swelling are partially observed, and abundant scaling occurs.

+4:肥厚した痂皮の形成が見られる状態。+4: A state in which thick crust formation is observed.

第1図から明らかなように、本発明の外用液剤は、有効
性が高いことが認められた。
As is clear from FIG. 1, the external preparation of the present invention was found to be highly effective.

試験例2(安全性試験) 実施例1〜4及び比較例で製造した外用液剤について、
皮膚刺激試験を行なった。結果を第1表に示す。
Test Example 2 (Safety Test) Regarding the external liquid preparations produced in Examples 1 to 4 and Comparative Example,
A skin irritation test was performed. The results are shown in Table 1.

(試験方法) 市販のパッチテスト用絆創膏(鳥居薬品(株)製)に被
験液剤を塗布し、被験者(健常人28名)の中下背部に48
時間塗布した。除去1時間及び24時間後に、製剤塗布部
位の紅斑度合い(皮膚に対する刺激度合い)を判定し
た。
(Test method) A test solution was applied to a commercially available patch test plaster (manufactured by Torii Pharmaceutical Co., Ltd.), and 48 test subjects (28 healthy subjects) were applied to the lower and middle backs.
It was applied for a time. 1 hour and 24 hours after the removal, the degree of erythema (the degree of irritation to the skin) at the application site of the preparation was evaluated.

軽微な紅斑を±、明らかな紅斑を+とし、全体に対する
割合で示した。
Minor erythema was ±, and clear erythema was +, which is shown as a percentage of the whole.

第1表から明らかなように、本発明の外用液剤は、皮膚
刺激性の極めて少ないものであった。
As is clear from Table 1, the liquid preparation for external use of the present invention had very little skin irritation.

試験例3(安定性試験) 実施例1〜4及び比較例で製造した外用液剤について、
安定性試験を行なった。結果を第2表に示す。
Test Example 3 (Stability Test) Regarding the liquid preparations for external use produced in Examples 1 to 4 and Comparative Example,
Stability tests were performed. The results are shown in Table 2.

(試験方法) 40℃恒温室にて6箇月間保存し、外観変化及び成分含量
(残存率)について試験を行なった。
(Test method) The sample was stored in a thermostatic chamber at 40 ° C for 6 months, and tested for appearance change and component content (residual rate).

第2表から明らかなように、本発明の外用液剤は、物
性、成分ともに安定性に優れたものであった。
As is clear from Table 2, the external preparation of the present invention was excellent in stability both in physical properties and components.

【図面の簡単な説明】[Brief description of drawings]

第1図は、試験例1における有効性試験の結果を、接種
後日数と病変スコア平均の関係で示す図面である。
FIG. 1 is a drawing showing the results of the efficacy test in Test Example 1 as the relationship between the number of days after inoculation and the average lesion score.

Claims (3)

【特許請求の範囲】[Claims] 【請求項1】次の(a)〜(d) (a)(E)−1〔2−メチルチオ−1−〔2−(ペン
チルオキシ)フェニル〕エテニル〕−1H−イミダゾール
塩酸塩 0.1〜5 W/V% (b)液状油性物質 1〜50W/V% (c)非イオン性界面活性剤 1〜20W/V% (d)塩基性物質 0.01〜2 W/V% を含有することを特徴とするイミダゾール系抗真菌外用
液剤。
1. The following (a) to (d) (a) (E) -1 [2-methylthio-1- [2- (pentyloxy) phenyl] ethenyl] -1H-imidazole hydrochloride 0.1-5 W. / V% (b) Liquid oily substance 1 to 50 W / V% (c) Nonionic surfactant 1 to 20 W / V% (d) Basic substance 0.01 to 2 W / V% An imidazole antifungal external liquid preparation.
【請求項2】液状油性物質が飽和脂肪酸エステルである
請求項1記載のイミダゾール系抗真菌性外用液剤。
2. The imidazole antifungal external liquid preparation according to claim 1, wherein the liquid oily substance is a saturated fatty acid ester.
【請求項3】非イオン性界面活性剤が、ポリオキシエチ
レンと飽和脂肪酸とのエステル型又はポリオキシエチレ
ンと飽和脂肪族アルコールとのエーテル型非イオン性界
面活性剤である請求項1記載のイミダゾール系抗真菌性
外用液剤。
3. The imidazole according to claim 1, wherein the nonionic surfactant is an ester type nonionic surfactant of polyoxyethylene and a saturated fatty acid or an ether type polyoxyethylene and a saturated aliphatic alcohol. Antifungal external preparation.
JP5444790A 1990-03-06 1990-03-06 Imidazole antifungal topical solution Expired - Lifetime JPH07103028B2 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
JP5444790A JPH07103028B2 (en) 1990-03-06 1990-03-06 Imidazole antifungal topical solution
CA002035758A CA2035758C (en) 1990-03-06 1991-02-05 Antimycotic external imidazole preparations
US07/650,969 US5100908A (en) 1990-03-06 1991-02-05 Antimycotic external imidazole preparations
EP91101630A EP0445540B1 (en) 1990-03-06 1991-02-06 Antimycotic external imidazole preparations
DE69108964T DE69108964T2 (en) 1990-03-06 1991-02-06 Preparation containing antifungal imidazole for external use.
ES91101630T ES2074178T3 (en) 1990-03-06 1991-02-06 PREPARED FOR EXTERNAL ANTIMICOTICOS OF IMIDAZOL.
KR1019910002229A KR950003611B1 (en) 1990-03-06 1991-02-09 Antimycotic external lmidazole preparations
HK98106293A HK1007104A1 (en) 1990-03-06 1998-06-24 Antimycotic external imidazole preparations

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP5444790A JPH07103028B2 (en) 1990-03-06 1990-03-06 Imidazole antifungal topical solution

Publications (2)

Publication Number Publication Date
JPH03258717A JPH03258717A (en) 1991-11-19
JPH07103028B2 true JPH07103028B2 (en) 1995-11-08

Family

ID=12970958

Family Applications (1)

Application Number Title Priority Date Filing Date
JP5444790A Expired - Lifetime JPH07103028B2 (en) 1990-03-06 1990-03-06 Imidazole antifungal topical solution

Country Status (1)

Country Link
JP (1) JPH07103028B2 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06345646A (en) * 1993-06-08 1994-12-20 Fujisawa Pharmaceut Co Ltd Lotion preparation
CN101389333A (en) * 2006-02-22 2009-03-18 卫材R&D管理有限公司 Stabilized pharmaceutical composition

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JPH03258717A (en) 1991-11-19

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