WO2005002561A1 - Composition a agent antifongique pour usage externe - Google Patents

Composition a agent antifongique pour usage externe Download PDF

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Publication number
WO2005002561A1
WO2005002561A1 PCT/JP2004/009411 JP2004009411W WO2005002561A1 WO 2005002561 A1 WO2005002561 A1 WO 2005002561A1 JP 2004009411 W JP2004009411 W JP 2004009411W WO 2005002561 A1 WO2005002561 A1 WO 2005002561A1
Authority
WO
WIPO (PCT)
Prior art keywords
terbinafine hydrochloride
external use
preparation
antifungal composition
hydrochloride
Prior art date
Application number
PCT/JP2004/009411
Other languages
English (en)
Japanese (ja)
Inventor
Hideki Kohita
Osamu Kondo
Yoshinori Nishioku
Megumi Ishii
Original Assignee
Taisho Pharmaceutical 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 Taisho Pharmaceutical Co.,Ltd. filed Critical Taisho Pharmaceutical Co.,Ltd.
Priority to JP2005511357A priority Critical patent/JP5435836B2/ja
Publication of WO2005002561A1 publication Critical patent/WO2005002561A1/fr

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Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to an antifungal composition. More specifically, the present invention relates to an antifungal composition for external use in which the amount of terbinafine hydrochloride transferred to the keratin is improved.
  • an antifungal agent that increases the concentration of drug in the stratum corneum immediately after application and maintains the level for a long time is ideal.
  • a drug non-dissociated type
  • a dissociated ionic type is superior in percutaneous absorbability and has a larger amount of exfoliated keratin than a dissociated ionic type.
  • Terbinafine hydrochloride is a component used as an external antifungal agent because of its excellent pharmacological effect.
  • Terbinafine hydrochloride like a general drug, is more advantageously dissolved and compounded as a molecular form in order to enhance the exfoliation of keratin.
  • the pH of the antifungal composition for external use should be set to a neutral monoalkaline region exceeding the dissociation constant (pKa) of terbinafine hydrochloride 7.13. desirable.
  • terbinafine hydrochloride has a very low solubility in a neutral monoalkaline preparation, so that it has been difficult to dissolve and mix it as a molecular form.
  • Patent Document 1 a technique has been disclosed in which an antifungal agent is present in a dissolved state in a powder aerosol.
  • Patent Document 1 JP-A-2000-229845
  • An object of the present invention is to provide an external antifungal agent containing terbinafine hydrochloride having excellent keratin transfer properties.
  • the present inventors have conducted various studies to provide a liquid preparation in which terbinafine hydrochloride is dissolved, which is a neutral mono-alkali liquid, and as a result, a lower alcohol and a polyol are simultaneously mixed, and the liquid property is specified. By limiting the range, it was found that terbinafine hydrochloride was dissolved in a molecular form and exhibited excellent exfoliation, and the present invention was completed.
  • An external antifungal composition comprising terbinafine hydrochloride, a polyol, and a lower alcohol, wherein the liquidity of the preparation is in a neutral monoalkaline region.
  • composition for external use wherein the polyol is one or more selected from the group consisting of polyethylene glycol, propylene glycol, 1,3-butylene glycol and glycerin.
  • the content of terbinafine hydrochloride is 0.22 W / V in the whole preparation. 2.
  • the compounding amount of terbinafine hydrochloride is preferably 0.22 W / V% of the whole preparation (in the case of an aerosol, in a stock solution), more preferably 0.5-1.5 W / V%. is there. 0.
  • the content is less than 2 W / V%, the efficacy will be insufficient, and if the content is more than 2 W / V%, it will be difficult to provide a product with a high solubility.
  • a lower alcohol is a straight-chain or branched-chain alcohol having 2 to 4 carbon atoms, which can be safely applied as an external preparation.
  • Preferred lower alcohols Examples include ethanol and isopropanol, with ethanol being particularly preferred.
  • the amount of the lower alcohol is preferably as large as possible in view of the solubility of terbinafine hydrochloride. However, if the lower alcohol is added in a large amount, irritation may occur at the time of application to the skin. Therefore, the blending amount of the lower alcohol is preferably 40-60 W / V%, more preferably 47 W / V% (60% by volume) and 56 W / V% (70% by volume).
  • Preferable examples of the polyol to be blended in the present invention include polyethylene glycol (Macguchi Gal), propylene glycol, 1,3-butylene glycol, glycerin and the like.
  • the amount of the polyol varies depending on the type and amount of the lower alcohol, and the amount of the polyol can be experimentally determined while confirming the dissolution of terbinafine hydrochloride. Also, if the polyol is added in a large amount, the stickiness at the time of application to the skin and the feeling of use will be very poor, so the usual compounding amount is 10-30 W / V of the whole preparation (in the case of aerosol, in the stock solution). %, Preferably 15-25 W / V%. Further, two or more kinds of polyols can be used in combination.
  • ethanol is used as a lower alcohol, and when the compounding amount is 47.7 ⁇ //% (60% by volume) of the whole preparation, the compounding amount of the polyol is 25-30 W / V%, When the amount of ethanol is 55.7 W / V% (70% by volume), the amount of polyol is 10-30 W / V%.
  • the pH of the drug product is in the region where terbinafine hydrochloride exists in a molecular form.
  • the dissociation constant (pKa) is a neutral monoalkaline region exceeding 7.13. Force S. If the alkalinity is too strong, it will damage the skin. Therefore, the range of ⁇ 7.5 ⁇ 9 ⁇ 0 is preferable.
  • composition of the present invention may be mixed with ordinary additives as necessary and prepared in an external manner such as a liquid, lotion, emulsion, tincture, cream, aqueous gel, aerosol, etc. Agent.
  • FIG. 1 is a diagram showing the results of a keratin transfer test of terbinafine hydrochloride, with the vertical axis showing keratin transfer. The application time was shown on the horizontal axis of the row ratio (%).
  • a lotion was prepared by a conventional method (the pH of Synthetic IJ was adjusted to about 8 with diisopropanolamine).
  • Purified water total lOOmL A lotion was prepared according to the above formulation by a conventional method (the pH of the preparation was adjusted to about 8 with sodium hydroxide).
  • the carboxyvinyl polymer was dissolved in water and propylene glycol, and allowed to stand at room temperature to swell the propyloxyvinyl polymer. Ethanol, terbinafine hydrochloride, lidocaine and EDTA-2Na were added thereto. Further, diisopropanolamine was added to adjust the pH of the preparation to about 8, thereby producing a gel.
  • a lotion was prepared using the above formulation in a conventional manner (the pH of the formulation was adjusted to about 8 with sodium hydroxide).
  • a lotion was prepared according to the above formulation by a conventional method (the pH of the preparation was adjusted to about 5 with sodium hydroxide).
  • a lotion was prepared according to the above formulation by a conventional method (the pH of the preparation was adjusted to about 8 with diisopropanolamine).
  • a lotion was prepared according to the above formulation by a conventional method (the pH of the preparation was adjusted to about 8 with sodium hydroxide).
  • Petano 1 50 g Diisopropanolamine qs
  • a lotion was prepared according to the above formulation by a conventional method (the pH of the preparation was adjusted to about 8 with diisopropanolamine).
  • a lotion was prepared according to the above formulation by a conventional method (the pH of the preparation was adjusted to about 8 with diisopropanolamine).
  • Polyethylene glycol 400 10.0 g
  • Petano 1 50 g Diisopropanolamine qs
  • a mouthwash was prepared by a conventional method (the pH of the formulation was adjusted to about 8 with diisopropanolamine).
  • terbinafine hydrochloride usually has extremely poor solubility at a pH of more than pKa 7.13, but the formulation of the present invention has a terbinafine hydrochloride even at a pH of 7.5 or more. It was possible to dissolve naphine (1% by weight).
  • Test Example 2 Test of terbinafine hydrochloride transfer to keratin rats
  • a hairless rat (Claire Nippon, male, 11-15 weeks old) was fixed in the dorsal position, and the abdomen was electrically sheathed. After removing the hair, the dirt was wiped off. 20 Ai L of each sample (Example 5 and Comparative Example 1) was weighed with a micropipette and uniformly applied to the abdomen (1.8 ⁇ 2.5 cm). Six hours after application or 24 hours after application, the sample remaining on the skin surface was sufficiently wiped off using absorbent cotton impregnated with 70% ethanol. Thereafter, a commercially available pressure-sensitive adhesive tape was stuck to the application site, and pressure-bonded to peel off the stratum corneum. This stratum corneum peeling operation was repeated 10 times. Terbinafine hydrochloride was extracted from 10 adhesive tapes used for peeling the stratum corneum with methanol, and the amount of exfoliated keratin was measured by high performance liquid chromatography.
  • FIG. 1 shows the results. The results are the average of three tests for each sample.
  • Example 5 in which the pH was adjusted to 8 exhibited higher exfoliating properties than the preparation of Comparative Example 1 in which the pH was adjusted to 5.
  • the present invention can be used as a therapeutic agent for athlete's foot, cotton beetle, common bug or tinea unguium.

Abstract

Pour favoriser la migration du chlorhydrate de terbinafine vers la couche cornée, il convient de dissoudre et d'ajouter le chlorure conformément au type moléculaire (type non dissociable). Cependant, il est difficile de dissoudre et d'ajouter le chlorhydrate de terbinafine conformément au type moléculaire car la solubilité du chlorhydrate de terbinafine dans des préparations pharmaceutiques neutres à alcalines est extrêmement faible. La composition à agent fongique pour usage externe de l'invention contient du chlorhydrate de terbinafine, un polyol, un alcool de faible poids moléculaire. De plus, cette composition est claire, présente un pH neutre à alcalin et possède une excellent pouvoir de migration vers la couche cornée.
PCT/JP2004/009411 2003-07-03 2004-07-02 Composition a agent antifongique pour usage externe WO2005002561A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2005511357A JP5435836B2 (ja) 2003-07-03 2004-07-02 外用抗真菌剤組成物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2003191271 2003-07-03
JP2003-191271 2003-07-03

Publications (1)

Publication Number Publication Date
WO2005002561A1 true WO2005002561A1 (fr) 2005-01-13

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2004/009411 WO2005002561A1 (fr) 2003-07-03 2004-07-02 Composition a agent antifongique pour usage externe

Country Status (2)

Country Link
JP (1) JP5435836B2 (fr)
WO (1) WO2005002561A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006131597A (ja) * 2004-11-09 2006-05-25 Hisamitsu Pharmaceut Co Inc エアゾール組成物
WO2010086727A1 (fr) * 2009-01-30 2010-08-05 Galderma Pharma Sa Compositions stables pour le traitement de l'onychomycose des ongles
JP2019006710A (ja) * 2017-06-26 2019-01-17 小林製薬株式会社 水性製剤

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016144121A2 (fr) * 2015-03-12 2016-09-15 동아제약 주식회사 Composition pharmaceutique pour traiter des maladies infectieuses fongiques de tissu de kératine
KR101690765B1 (ko) * 2015-04-17 2016-12-28 동아제약 주식회사 항진균성 활성물질을 포함하는 경피 제제

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0585929A (ja) * 1991-03-08 1993-04-06 L'oreal Sa 爪糸状菌症処置用皮フ病学的組成物中への親水性浸透剤 の使用及び相当する組成物
JPH05132419A (ja) * 1991-05-20 1993-05-28 Sandoz Ag 医薬組成物
WO2000038731A1 (fr) * 1998-12-28 2000-07-06 Taisho Pharmaceutical Co.,Ltd. Preparation externe
JP2001518879A (ja) * 1997-03-31 2001-10-16 ジョンソン・アンド・ジョンソン・コンシューマー・カンパニーズ・インコーポレイテッド 薬剤化合物の向上した浸透性のための溶媒システム

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0585929A (ja) * 1991-03-08 1993-04-06 L'oreal Sa 爪糸状菌症処置用皮フ病学的組成物中への親水性浸透剤 の使用及び相当する組成物
JPH05132419A (ja) * 1991-05-20 1993-05-28 Sandoz Ag 医薬組成物
JP2001518879A (ja) * 1997-03-31 2001-10-16 ジョンソン・アンド・ジョンソン・コンシューマー・カンパニーズ・インコーポレイテッド 薬剤化合物の向上した浸透性のための溶媒システム
WO2000038731A1 (fr) * 1998-12-28 2000-07-06 Taisho Pharmaceutical Co.,Ltd. Preparation externe

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PETRANYI G. ET AL.: "Antifungal activity of the allylamine derivative terbinafine in vitro", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 31, no. 9, September 1987 (1987-09-01), pages 1365 - 1368, XP002980982 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006131597A (ja) * 2004-11-09 2006-05-25 Hisamitsu Pharmaceut Co Inc エアゾール組成物
WO2010086727A1 (fr) * 2009-01-30 2010-08-05 Galderma Pharma Sa Compositions stables pour le traitement de l'onychomycose des ongles
JP2019006710A (ja) * 2017-06-26 2019-01-17 小林製薬株式会社 水性製剤
JP7198573B2 (ja) 2017-06-26 2023-01-04 小林製薬株式会社 水性製剤

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Publication number Publication date
JPWO2005002561A1 (ja) 2006-10-19
JP5435836B2 (ja) 2014-03-05

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