JP4863538B2 - Antifungal liquid composition for external use - Google Patents
Antifungal liquid composition for external use Download PDFInfo
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- JP4863538B2 JP4863538B2 JP36455899A JP36455899A JP4863538B2 JP 4863538 B2 JP4863538 B2 JP 4863538B2 JP 36455899 A JP36455899 A JP 36455899A JP 36455899 A JP36455899 A JP 36455899A JP 4863538 B2 JP4863538 B2 JP 4863538B2
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- JP
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- Prior art keywords
- composition
- antifungal
- aerosol
- external
- butenafine hydrochloride
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Description
【0001】
【発明の属する技術分野】
本発明は、有効成分として塩酸ブテナフィンを含有する、有効成分の皮膚浸透性を改善した抗真菌性液体外用組成物に関する。
【0002】
【従来の技術】
塩酸ブテナフィンはベンジルアミン系抗真菌剤で、従来から、抗真菌性外用製剤の有効成分として使用されており、塩酸ブテナフィンを有効成分とする従来の外用製剤は、使用感、皮膚親和性、塩酸ブテナフィンの溶解性等から、通常、30〜70w/v%(以下、特に断らない限り「%」はw/v%を意味する)程度の水を含むクリームや外用液剤の剤形を有している。
【0003】
【発明が解決しようとする課題】
外用抗真菌製剤の効能を高めるためには、有効成分の皮膚浸透性を向上させることが必要であり、本発明は、塩酸ブテナフィンを有効成分とする抗真菌性外用製剤における該有効成分の皮膚浸透性を改善することを目的とする。
【0004】
【課題を解決するための手段】
本発明者らは、上記の目的を達成するため、鋭意研究した結果、水分含量をできるだけ少なくした液体製剤とすることにより、塩酸ブテナフィンの皮膚浸透量が増加し、皮膚浸透性を改善することができ、かつ、従来製造されていなかった塩酸ブテナフィンのエアゾール剤とすることもできることを見出し、本発明を完成するに至った。
すなわち、本発明は、塩酸ブテナフィンを有効成分とし、配合水分量が3%以下である抗真菌性液体外用組成物を提供するものである。該組成物は、外用液剤の剤形であっても、また、エアゾール剤原液であってもよく、本発明は、エアゾール剤原液の形態の本発明の抗真菌性液体外用組成物と、噴射剤とを配合してなる抗真菌性エアゾール剤も提供する。
【0005】
【発明の実施の形態】
本発明の液体外用組成物の有効成分である塩酸ブテナフィンは、抗真菌剤としての効能および溶解性の観点から、組成物全量に対し、通常、0.2〜5%、好ましくは0.5〜2%配合する。
【0006】
本発明においては、液体組成物中の配合水分量を3%以下、好ましくは実質的に水を配合しないこと、さらには配合成分の水分含量をできるだけ少なくすることが必要で、これにより有効成分である塩酸ブテナフィンの皮膚浸透量が増加し、皮膚浸透性が改善される。また、塩酸ブテナフィンは、例えば、アルミニウムエアゾール缶のような、エアゾール容器中で水と共存させると、たとえ容器の内面を樹脂コートしても、ピンホールの存在により腐蝕を引き起こす問題があり、エアゾール剤とすることが困難であるが、このように水分含量をできるだけ少なくすることによりエアゾール剤とすることが可能となる。
【0007】
かくして、本発明の液体組成物は、上記のごとく水の配合を抑制した塩酸ブテナフィンのアルコール性溶液であり、例えば、メタノール、エタノール、変性アルコール等の低級アルコールの溶液である。
【0008】
他の配合成分は、特に限定するものではないが、組成物の皮膚親和性や、塩酸ブテナフィンの溶解度を向上させるため、界面活性剤、例えば、HLBが10以上の親水性の界面活性剤、とりわけ、酸化エチレンの付加重合モル数が20から100のポリオキシエチレン硬化ヒマシ油を5%以下配合することが好ましい。
また、保湿剤として、プロピレングリコール、ジプロピレングリコール、1,3−ブチレングリコール、分子量200〜600のポリエチレングリコールのようなグリコール類、グリセリンのようなポリオール類を10%以下配合することも好ましい。
さらに、種々のキレート剤、抗酸化剤、防腐剤、保存剤、香料等の製剤上許容される添加剤を適宜添加してもよい。
【0009】
本発明の組成物は、皮膚刺激を少なくするために、pH3〜8に調整することが好ましく、例えば、ジエタノールアミン等の有機酸塩をpH調整剤として使用できる。
【0010】
本発明の組成物は、自体公知の方法に従って、各成分を混合、溶解することにより、外用液剤やエアゾール剤原液の剤形にすることができる。
また、得られたエアゾール剤原液の剤形の組成物と、ジメチルエーテル(DME)、液化プロパンガス(LPG)、フロン類、N2、CO2ガス、代替フロンガス等の通常のエアゾール剤に用いられる噴射剤とを混合し、通常のエアゾールまたはスプレー容器に充填することにより本発明のエアゾール剤を製造することができる。該組成物と噴射剤との混合割合は、特に限定するものではないが、通常、組成物:噴射剤の容量比(充填比率)1:1〜2:8の範囲から選択される。また、自体公知の方法により、タルクやその他の粉体を混合して粉末エアゾール剤としてもよい。
【0011】
本発明の外用液剤やエアゾール剤は、従来の塩酸ブテナフィン製剤と同様に抗真菌用の外用製剤として使用できる。
【0012】
【実施例】
つぎに試験例および実施例を挙げて、本発明をさらに詳しく説明するが、本発明はこれらに限定れるものではない。
試験例1
皮膚浸透性試験
表1に示す処方に従って、各成分を混合、溶解し、皮膚浸透性試験用検体を調製した。なお、表中、HCO−60は、酸化エチレンの付加モル数60のポリオキシエチレン硬化ヒマシ油を意味する。
【0013】
【表1】
【0014】
ハートレー(Hartley)系モルモット(4週齢)の腹部を電気バリカンにて除毛し、皮膚を摘出した。これを自作フランツ型セル(直径2cm)に装着した。レセプター相は1/15Mリン酸緩衝液(pH5.3)26ml(32℃)とし、各検体2mlを塗布(開放)し、22時間後皮膚上の検体を流水にて洗い流し、さらにエタノールにて洗った後、皮膚の検体塗布部分を直径2cmのパンチにて打ち抜いた。それを細切りし、メタノール中にて超音波抽出し、皮膚内塩酸ブテナフィン移行量を以下条件でHPLCにて測定し、皮膚浸透量とした。
結果を表2および図1に示す。表2の結果は、3回の測定値の平均であり、図1は、表2の結果をグラフ化したもので、縦軸は浸透量(μg/cm2)、横軸は水分量(%)を表す。
【0015】
【表2】
【0016】
表2および図1の結果から明らかなごとく、配合水分量を3%以下にすると、塩酸ブテナフィンの皮膚浸透量が増加し、浸透性が著しく改善される。
【0017】
実施例1
下記の処方により常法にて外用液剤を調製した。なお、ポリオキシエチレン硬化ヒマシ油の後の括弧内の数値は酸化エチレンの付加モル数である(以下、同様)。
成 分
塩酸ブテナフィン 1.0g
ポリオキシエチレン硬化ヒマシ油(40) 0.6g
ジプロピレングリコール 6.8g
ジエタノールアミン 0.33g
変性アルコール 100mlに調整
実施例2
下記の処方により常法にて外用液剤を調製した。
成 分
塩酸ブテナフィン 1.0g
ポリオキシエチレン硬化ヒマシ油(60) 0.6g
ジプロピレングリコール 6.8g
変性アルコール 100mlに調整
【0018】
実施例3
下記の処方により常法にて外用液剤を調製した。
成 分
塩酸ブテナフィン 1.0g
ポリオキシエチレン硬化ヒマシ油(60) 0.6g
ジプロピレングリコール 6.8g
精製水 1.0g
変性アルコール 100mlに調整
実施例4
下記の処方により常法にて外用液剤を調製した。
成 分
塩酸ブテナフィン 1.0g
ポリオキシエチレン硬化ヒマシ油(60) 0.6g
ジプロピレングリコール 6.8g
精製水 3.0g
変性アルコール 100mlに調整
【0019】
実施例5
実施例1の処方に従ってエアゾール剤原液を調製した。この原液15mlおよびLPGを35mlをエポキシフェノールユリア樹脂あるいはポリアミドイミド系コートされたエアゾール用耐圧容器に充填し、エアゾール用バルブおよびボタンを取り付けてエアゾール剤を作製した。
【0020】
【発明の効果】
以上を記載したごとく、本発明によれば、塩酸ブテナフィンを有効成分とする抗真菌性外用製剤における配合水分量を3%以下にすることにより、有効成分の皮膚浸透性を著しく改善することができ、また、エアゾール容器の腐蝕の問題を解消して塩酸ブテナフィンのエアゾール剤を製造することができる。
【図面の簡単な説明】
【図1】 塩酸ブテナフィンの皮膚浸透量と組成物中の水分含量の関係を示すグラフ。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a composition for external application of antifungal liquid containing butenafine hydrochloride as an active ingredient and having improved skin penetration of the active ingredient.
[0002]
[Prior art]
Butenafine hydrochloride is a benzylamine antifungal agent and has been used as an active ingredient in antifungal external preparations. Conventional external preparations containing butenafine hydrochloride as an active ingredient have a feeling of use, skin affinity, butenafine hydrochloride In general, it has a dosage form of cream or external liquid containing 30 to 70 w / v% (hereinafter, unless otherwise specified, “%” means w / v% unless otherwise specified). .
[0003]
[Problems to be solved by the invention]
In order to enhance the efficacy of an external antifungal preparation, it is necessary to improve the skin permeability of the active ingredient, and the present invention relates to the skin penetration of the active ingredient in an antifungal external preparation containing butenafine hydrochloride as an active ingredient. The purpose is to improve sex.
[0004]
[Means for Solving the Problems]
As a result of diligent research to achieve the above object, the inventors of the present invention can increase the skin penetration amount of butenafine hydrochloride and improve the skin permeability by making the liquid formulation with a water content as low as possible. The present invention has been completed by finding that it can be used as an aerosol of butenafine hydrochloride, which has not been produced in the past.
That is, the present invention provides an antifungal liquid composition for external use containing butenafine hydrochloride as an active ingredient and having a blended water content of 3% or less. The composition may be in the form of a solution for external use or an aerosol solution, and the present invention provides an antifungal liquid composition for external use of the present invention in the form of an aerosol solution and a propellant. Also provided is an antifungal aerosol composition.
[0005]
DETAILED DESCRIPTION OF THE INVENTION
From the viewpoint of efficacy and solubility as an antifungal agent, butenafine hydrochloride, which is an active ingredient of the liquid external composition of the present invention, is usually 0.2 to 5%, preferably 0.5 to 0.5% based on the total amount of the composition. Mix 2%.
[0006]
In the present invention, it is necessary that the blended water content in the liquid composition is 3% or less, preferably substantially no water is blended, and further, the moisture content of the blended component is made as small as possible. The skin penetration of certain butenafine hydrochloride increases and skin permeability is improved. In addition, butenafine hydrochloride has a problem that if it coexists with water in an aerosol container such as an aluminum aerosol can, even if the inner surface of the container is resin-coated, it causes corrosion due to the presence of pinholes. However, it is possible to obtain an aerosol agent by reducing the water content as much as possible.
[0007]
Thus, the liquid composition of the present invention is an alcoholic solution of butenafine hydrochloride in which the mixing of water is suppressed as described above, for example, a solution of lower alcohols such as methanol, ethanol, and denatured alcohol.
[0008]
Other ingredients are not particularly limited, but in order to improve the skin affinity of the composition and the solubility of butenafine hydrochloride, a surfactant such as a hydrophilic surfactant having an HLB of 10 or more, especially It is preferable to blend 5% or less of polyoxyethylene hydrogenated castor oil having an addition polymerization mole number of ethylene oxide of 20 to 100.
Moreover, it is also preferable to mix 10% or less of propylene glycol, dipropylene glycol, 1,3-butylene glycol, glycols such as polyethylene glycol having a molecular weight of 200 to 600, and polyols such as glycerin as humectants.
Further, various pharmaceutically acceptable additives such as various chelating agents, antioxidants, preservatives, preservatives, and fragrances may be appropriately added.
[0009]
The composition of the present invention is preferably adjusted to a pH of 3 to 8 in order to reduce skin irritation. For example, an organic acid salt such as diethanolamine can be used as a pH adjusting agent.
[0010]
The composition of the present invention can be made into a dosage form of a solution for external use or an aerosol solution by mixing and dissolving each component according to a method known per se.
Further, the composition of the dosage form of the resulting aerosol stock solution, dimethyl ether (DME), liquefied propane gas (LPG), CFCs, N 2, CO 2 gas, used for ordinary aerosol such as alternative chlorofluorocarbons injection The aerosol agent of the present invention can be produced by mixing with an agent and filling an ordinary aerosol or spray container. The mixing ratio of the composition and the propellant is not particularly limited, but is usually selected from the range of the composition: propellant volume ratio (filling ratio) of 1: 1 to 2: 8. In addition, talc and other powders may be mixed to form a powder aerosol by a method known per se.
[0011]
The externally applied solution and aerosol of the present invention can be used as an antifungal external preparation similar to the conventional butenafine hydrochloride preparation.
[0012]
【Example】
Next, although a test example and an Example are given and this invention is demonstrated further in detail, this invention is not limited to these.
Test example 1
Skin Permeability Test According to the formulation shown in Table 1, each component was mixed and dissolved to prepare a skin permeability test specimen. In the table, HCO-60 means polyoxyethylene hydrogenated castor oil having an addition mole number of ethylene oxide of 60.
[0013]
[Table 1]
[0014]
The abdomen of a Hartley guinea pig (4 weeks old) was removed with an electric clipper, and the skin was removed. This was attached to a self-made Franz-type cell (diameter 2 cm). The receptor phase is 26 ml (32 ° C.) of 1/15 M phosphate buffer (pH 5.3), 2 ml of each specimen is applied (opened), and after 22 hours, the specimen on the skin is washed away with running water and further washed with ethanol. Thereafter, the specimen application portion of the skin was punched with a punch having a diameter of 2 cm. This was cut into small pieces, extracted ultrasonically in methanol, and the amount of butenafine hydrochloride transferred into the skin was measured by HPLC under the following conditions to obtain the amount of skin penetration.
The results are shown in Table 2 and FIG. The results in Table 2 are the average of three measurements. FIG. 1 is a graph of the results in Table 2. The vertical axis represents the amount of penetration (μg / cm 2 ), and the horizontal axis represents the amount of moisture (% ).
[0015]
[Table 2]
[0016]
As is apparent from the results of Table 2 and FIG. 1, when the water content is 3% or less, the amount of butenafine hydrochloride permeating the skin increases and the permeability is remarkably improved.
[0017]
Example 1
A liquid preparation for external use was prepared by a conventional method according to the following formulation. In addition, the numerical value in the parenthesis after the polyoxyethylene hydrogenated castor oil is the number of added moles of ethylene oxide (hereinafter the same).
Component Butenafine Hydrochloride 1.0g
0.6 g of polyoxyethylene hydrogenated castor oil (40)
Dipropylene glycol 6.8g
Diethanolamine 0.33g
Example 2 adjusted to 100 ml of denatured alcohol
A liquid preparation for external use was prepared by a conventional method according to the following formulation.
Component Butenafine Hydrochloride 1.0g
0.6 g of polyoxyethylene hydrogenated castor oil (60)
Dipropylene glycol 6.8g
Adjust to 100 ml of denatured alcohol.
Example 3
A liquid preparation for external use was prepared by a conventional method according to the following formulation.
Component Butenafine Hydrochloride 1.0g
0.6 g of polyoxyethylene hydrogenated castor oil (60)
Dipropylene glycol 6.8g
Purified water 1.0g
Adjustment to denatured
A liquid preparation for external use was prepared by a conventional method according to the following formulation.
Component Butenafine Hydrochloride 1.0g
0.6 g of polyoxyethylene hydrogenated castor oil (60)
Dipropylene glycol 6.8g
Purified water 3.0g
Adjust to 100 ml of denatured alcohol.
Example 5
An aerosol stock solution was prepared according to the formulation of Example 1. 15 ml of this stock solution and 35 ml of LPG were filled into an epoxy pressure-resistant container coated with epoxyphenol urea resin or polyamideimide, and an aerosol valve and a button were attached to prepare an aerosol agent.
[0020]
【Effect of the invention】
As described above, according to the present invention, the skin permeability of the active ingredient can be remarkably improved by making the blended water content in the antifungal external preparation containing butenafine hydrochloride as the active ingredient 3% or less. Moreover, the aerosol problem of butenafine hydrochloride can be produced by solving the problem of corrosion of the aerosol container.
[Brief description of the drawings]
FIG. 1 is a graph showing the relationship between skin penetration of butenafine hydrochloride and the water content in the composition.
Claims (4)
Priority Applications (1)
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JP36455899A JP4863538B2 (en) | 1999-12-22 | 1999-12-22 | Antifungal liquid composition for external use |
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JP36455899A JP4863538B2 (en) | 1999-12-22 | 1999-12-22 | Antifungal liquid composition for external use |
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JP2001181182A JP2001181182A (en) | 2001-07-03 |
JP4863538B2 true JP4863538B2 (en) | 2012-01-25 |
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JP4615198B2 (en) * | 2003-07-25 | 2011-01-19 | 久光製薬株式会社 | Antifungal aerosol topical preparation |
JP2005104917A (en) * | 2003-09-30 | 2005-04-21 | Kobayashi Pharmaceut Co Ltd | Antifungal composition |
JP5097363B2 (en) * | 2006-06-05 | 2012-12-12 | 小林製薬株式会社 | Antifungal composition |
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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EXPY | Cancellation because of completion of term |