WO2014017411A1 - Préparation externe de traitement de la trichophytie unguéale - Google Patents

Préparation externe de traitement de la trichophytie unguéale Download PDF

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Publication number
WO2014017411A1
WO2014017411A1 PCT/JP2013/069732 JP2013069732W WO2014017411A1 WO 2014017411 A1 WO2014017411 A1 WO 2014017411A1 JP 2013069732 W JP2013069732 W JP 2013069732W WO 2014017411 A1 WO2014017411 A1 WO 2014017411A1
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WIPO (PCT)
Prior art keywords
weight
external preparation
preparation
nail
water
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PCT/JP2013/069732
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English (en)
Japanese (ja)
Inventor
雅 鳥越
浩司 武智
正浩 藤井
崇正 遠藤
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マルホ株式会社
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Priority to JP2014526902A priority Critical patent/JPWO2014017411A1/ja
Publication of WO2014017411A1 publication Critical patent/WO2014017411A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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 external preparation for treating nail ringworm, which contains an imidazole antifungal agent.
  • References disclosing external preparations for treating nail ringworm treatment include documents (Patent Documents 1 to 3) that contain a film-forming substance and form a hydrophobic or poorly water-soluble film when applied to the nail, An anhydrous preparation (Patent Documents 4 and 5) using only an organic solvent as a base is known.
  • Patent Documents 1 to 5 all disclose preparations containing no water or low water content.
  • the present invention aims to provide an external preparation for treating onychomycosis that contains an imidazole antifungal agent as an active ingredient and has a high water content (20% by weight or more). .
  • the present inventors have repeatedly studied the improvement of the solubility and nail permeability of imidazole antifungals for external preparations containing imidazole antifungals and using water as a base. It was. As a result, the present inventors have found that by adding a high concentration of lactic acid, the water solubility of the imidazole antifungal drug is improved and the nail permeability is also greatly improved. However, preparations containing a high concentration of lactic acid are highly irritating and difficult to use as products.
  • the present inventors have used tartaric acid and lauromacrogol together with lactic acid, so that the solubility of imidazole antifungal drugs and nail can be reduced even if the addition amount of lactic acid is small.
  • the inventors have found that a product having excellent permeability can be obtained and completed the present invention.
  • the present invention is an external preparation for treating onychomycosis, It contains imidazole antifungal agent, lactic acid, tartaric acid, lauromacrogol and 20% by weight or more of water.
  • wt% means wt% of each component when the total weight of the external preparation is 100 wt% unless otherwise specified.
  • the external preparation preferably contains 5 to 25% by weight of lactic acid, 0.5 to 5% by weight of tartaric acid, 3 to 25% by weight of lauromacrogol, and 20 to 35% by weight of water, 5 to 20 wt%, tartaric acid 0.5 to 4 wt%, lauromacrogol 5 to 20 wt%, and water 20 to 35 wt% (especially 20 to 30 wt%)
  • it contains 7 to 15% by weight of lactic acid, 1 to 3% by weight of tartaric acid, 7 to 15% by weight of lauromacrogol, and 20 to 30% by weight (especially 20 to 25% by weight) of water. More preferably.
  • the external preparation preferably contains an imidazole antifungal agent in an amount of 3 to 7% by weight.
  • imidazole antifungal agents include lanconazole and / or luliconazole.
  • the external preparation is further selected from the group consisting of benzyl alcohol, methyl ethyl ketone, absolute ethanol, acetone, polyethylene glycol, 1,3-butylene glycol, propylene glycol, glycol salicylate, phenoxyethanol, ethyl lactate, crotamiton, and diethylene glycol monoethyl ether. It is preferable to include one or more organic solvents.
  • the external preparation for treating onychomycosis according to the present invention can be contained in a state in which an imidazole antifungal drug that is hardly soluble in water is dissolved, although it is a preparation containing 20% by weight or more of water. Therefore, when the said external preparation is apply
  • the active ingredient (main drug) of the external preparation of the present invention is an imidazole antifungal drug.
  • imidazole antifungal agents that can be used include lanoconazole, luliconazole, ketoconazole, econazole and / or a salt thereof (for example, hydrochloride, nitrate, etc.).
  • Ranoconazole or luliconazole is particularly preferred.
  • the external preparation of the present invention is characterized by containing 20% by weight or more of water (preferably purified water).
  • water preferably purified water.
  • the water content is suitably in the range of 20 to 35% by weight. A more preferred range is 20 to 30% by weight, and a particularly preferred range is 20 to 25% by weight.
  • the external preparation of the present invention contains lactic acid as an essential component.
  • Lactic acid may be either D-lactic acid or L-lactic acid, and may be a mixture containing these at an arbitrary ratio, or a racemic body.
  • Preferred is L-lactic acid or a racemate, and particularly preferred is a racemate.
  • the external preparation of the present invention preferably contains 5 to 25% by weight of lactic acid. If the content of lactic acid is less than 5% by weight, the water solubility and / or nail permeability of the imidazole antifungal agent tends to be low. On the other hand, when the content of lactic acid exceeds 25% by weight, the irritation becomes strong, making it difficult to use as a product. A more preferable content of lactic acid is 5 to 20% by weight, a particularly preferable content is 7 to 15% by weight, and a further preferable content is 8 to 12% by weight.
  • the content of lauromacrogol When the content of lauromacrogol is less than 3% by weight, the water solubility and / or nail permeability of the imidazole antifungal agent tends to be low. On the other hand, when the content of lauromacrogol exceeds 25% by weight, the preparation tends to become cloudy or the feeling of use tends to decrease due to stickiness. Also, from the viewpoint of safety, it is desirable to add a small amount of surfactant to the external preparation.
  • a more preferable content of lauromacrogol is 5 to 20% by weight, a particularly preferable content is 7 to 15% by weight, and a further preferable content is 8 to 12% by weight.
  • Lactic acid, tartaric acid, and lauromacrogol have the effect of increasing the water solubility of imidazole antifungal agents. Therefore, in the case of an external preparation having a low concentration of imidazole antifungal drug, precipitation of the imidazole antifungal drug can be prevented even if the addition amount of lactic acid, tartaric acid or lauromacrogol is small.
  • an external preparation having a high concentration of imidazole antifungal drug for example, when setting the content of imidazole antifungal drug (e.g., lanoconazole) to 3% by weight or more, the content of lactic acid is 5%.
  • the content of tartaric acid is 0.5% by weight or more, and the content of lauromacrogol is 5% by weight or more.
  • the content of imidazole antifungal drugs for example, lanoconazole
  • the content of lactic acid is 7% by weight or more
  • the content of tartaric acid is 1% by weight or more
  • Lauromacrogol The content is more preferably 7% by weight or more. Preferred values for the upper limit are as described above. If the content of the imidazole antifungal agent is high, the amount of permeation to the nail is also considered to increase. Therefore, by preparing the external preparation as a high-concentration (3% by weight or more) preparation, a higher antifungal effect can be obtained. I can expect.
  • the external preparation of the present invention preferably has a pH in the range of 2.0 to 5.0. It is known that keratin, which is a main component of nails, swells and softens with an alkaline substance. Therefore, it is considered that the nail permeability of the imidazole antifungal drug is improved by making the pH of the external preparation alkaline, but if the pH is too high, the stability of the imidazole antifungal drug may be lowered. On the other hand, if the pH is less than 2.0, the external preparation becomes a corrosive substance, which makes it difficult to apply to a living body.
  • a more preferable pH range of the external preparation of the present invention is 2.5 to 4.5, and a particularly preferable range is 3.0 to 4.0.
  • the external preparation of the present invention is preferably a liquid dosage form (lotion, liquid, etc.) with high fluidity. Therefore, although the external preparation of this invention may contain a thickener, it is preferable that the viscosity of an external preparation is not too high. Specifically, the viscosity is preferably 1000 mPa ⁇ s or less, more preferably 700 mPa ⁇ s or less, particularly preferably 300 mPa ⁇ s or less, and further preferably 100 mPa ⁇ s or less. In this specification, the viscosity is the value when measured for 45 seconds at a measurement temperature of 25 ° C.
  • the thickener used for an external preparation is not specifically limited, As a preferable thickener, hydroxypropyl cellulose, hydrophobized hydroxypropyl methylcellulose, a methyl vinyl ether / maleic anhydride copolymer, etc. are mentioned. A particularly preferred thickener is methyl vinyl ether / maleic anhydride copolymer.
  • the content of the thickener may be appropriately adjusted so that the external preparation has the above viscosity, but generally 3% by weight or less is appropriate, and 0.5 to 2% by weight is more preferable.
  • the frequency of application of the external preparation of the present invention to the nail may be appropriately increased or decreased according to the symptoms, but is usually 1 to 3 times per day.
  • the application amount per time may be an amount covering the entire nail or the affected part. Since the external preparation of the present invention is intended to be repeatedly administered, it is preferable not to form a hydrophobic or poorly water-soluble film after application to the nail. This is because hydrophobic and poorly water-soluble coatings, unlike water-soluble coatings, are unlikely to be peeled off by bathing or the like, and may be a barrier to nail permeation of imidazole antifungals by repeated application. It is.
  • the external preparation of the present invention is a hydrophobic or poorly water-soluble film-forming agent as disclosed in the prior art (for example, polyvinyl acetate described in Patent Document 1, long chain having 10 to 41 carbon atoms) Fatty acid esters; poorly water-soluble or water-insoluble film forming agents such as ethyl cellulose, hydroxypropyl methylcellulose phthalate, and acrylic resin emulsion described in Patent Document 2; methacrylic acid / methacrylic acid methyl copolymer described in Patent Document 3
  • a hydrophobic film forming agent such as an alkyl / aminoethyl methacrylate copolymer and ethyl cellulose, and it is preferable to include a small amount so as not to form a hydrophobic or poorly water-soluble film.
  • the external preparation of the present invention contains components that are blended in normal nail external preparations such as preservatives (preservatives), dyes, fragrances, pigments, antioxidants, ultraviolet absorbers, etc., if necessary. It may be.
  • the external preparation of the present invention includes a composition obtained by arbitrarily combining these, and also includes a composition obtained by arbitrarily combining the concentration ranges described for each component.
  • numerical ranges such as concentration, viscosity, pH, etc. described in the preceding paragraph can be arbitrarily combined, and when multiple numerical ranges are described, the upper limit value or lower limit value of each numerical range can also be arbitrarily combined It is.
  • the prepared preparation was subjected to an appearance observation test, a stability test, and a nail permeability test.
  • the appearance observation test was performed by putting the prepared preparation into a test tube and storing it for 4 weeks at 25 ° C., and then confirming the clarity using a black background and confirming the presence or absence of crystal precipitation of laconazole. .
  • the stability test the prepared preparation was placed in a test tube and stored at 60 ° C for 4 weeks. The white background was used to confirm crystal precipitation and discoloration of the preparation. This was done by confirming the change.
  • the nail permeability test was performed by measuring the permeability to bovine nails using a Franz cell by the following method. ⁇ Measurement method of nail permeability> (1) Set a thinly cut bovine nail (thickness 70 ⁇ m) on a nail adapter for Franz cell, and then attach it to the Franz cell. (2) After filling the receptor side of Franz cell with 15% ethanol-containing phosphate buffer, circulate constant temperature water at 32 ° C on the outside. (3) After dropping 10 ⁇ L of the preparation into the nail, collect the receptor solution over time (until 28 hours), and determine the concentration of lanoconazole in the receptor using liquid chromatography mass spectrometry (LC / MS / MS). taking measurement.
  • LC / MS / MS liquid chromatography mass spectrometry
  • the formulation containing about 25% by weight of water showed no precipitation of lanconazole in the appearance observation test on the next day of preparation, or no crystal precipitation was observed in the appearance observation test. The color changed from yellow to brown over time, and sufficient stability was not observed.
  • the formulation containing no water no precipitation of crystals was observed in the appearance observation test, and the results of the stability test were good, but when the nail permeability test of ranconazole was conducted, the permeation amount of ranoconazole was zero, Ranoconazole was found to have very poor nail permeability.
  • the concentration of lactic acid in the preparation was set to 10% by weight, which is a concentration that has been confirmed to be safe, as a pre-use example in an external preparation, and the combined use with other agents was examined.
  • the solubility of lanoconazole can be improved by using tartaric acid and lauromacrogol together with lactic acid.
  • Table 3 Each preparation was weighed and mixed with each solubilizer listed in Table 3, lactic acid, tartaric acid, lauromacrogol and fragrance were weighed and added thereto, dissolved, and then lanoconazole was added thereto, It was prepared by dissolving and further adding (thickening agent and purified water) and dissolving (swelling) the thickener.
  • Formulations 4 to 11 were all liquid formulations with high fluidity (viscosity of 100 mPa ⁇ s or less), and the pH ranged from 3.0 to 4.0.
  • the preparation 11 and the preparation 13 showed a significantly higher ranoconazole concentration in any of the upper layer, middle layer and lower layer portion of the human nail.
  • the drug concentration in the nail in the steady state is 0.5 to 1.0 ⁇ g / g, which is the minimum inhibitory concentration of terbinafine ( MIC; 0.003 ⁇ g / mL) to 166 to 333 times.
  • the present invention it is possible to produce a preparation containing a high concentration of an imidazole antifungal dissolved in spite of a high water content, so that a therapeutically effective amount of an imidazole antifungal is obtained. Can reach the deep part of the nail. Therefore, the external preparation according to the present invention is very useful for the treatment of onychomycosis.

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une préparation externe destinée au traitement de la trichophytie unguéale, ladite préparation comprenant un agent antifongique de type imidazole comme agent principal et présentant une solubilité élevée de l'agent principal et une perméabilité élevée de l'agent principal dans les ongles. Selon l'invention, la préparation externe destinée au traitement de la trichophytie unguéale selon la présente invention comprend un agent antifongique de type imidazole, de l'acide lactique, de l'acide tartrique, du lauromacrogol et 20 % en poids ou plus d'eau. En particulier, la préparation externe comprend 5-25 % en poids d'acide lactique, 0,5-5 % en poids d'acide tartrique, 3-25 % en poids de lauromacrogol et 20-35 % en poids d'eau. La préparation externe comprend de préférence du lanoconazole et/ou du luliconazole comme agent antifongique de type imidazole susmentionné.
PCT/JP2013/069732 2012-07-23 2013-07-22 Préparation externe de traitement de la trichophytie unguéale WO2014017411A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2014526902A JPWO2014017411A1 (ja) 2012-07-23 2013-07-22 爪白癬治療用外用剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2012162194 2012-07-23
JP2012-162194 2012-07-23

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WO2014017411A1 true WO2014017411A1 (fr) 2014-01-30

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2019167728A1 (ja) * 2018-02-27 2020-12-10 久光製薬株式会社 ジクロフェナク含有乳化ゲル組成物
US11246830B2 (en) 2018-02-27 2022-02-15 Hisamitsu Pharmaceutical Co., Inc. Emulsified gel composition
RU2823711C2 (ru) * 2021-01-28 2024-07-29 Гленмарк Фармасьютикалс Лимитед Фармацевтические композиции луликоназола для местного применения

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007113830A2 (fr) * 2006-04-04 2007-10-11 Avner Shemer Trousse de traitement d'infection cutanée
WO2011155640A1 (fr) * 2010-06-11 2011-12-15 Pola Pharma Inc. Composition pharmaceutique antimycosique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007113830A2 (fr) * 2006-04-04 2007-10-11 Avner Shemer Trousse de traitement d'infection cutanée
WO2011155640A1 (fr) * 2010-06-11 2011-12-15 Pola Pharma Inc. Composition pharmaceutique antimycosique

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2019167728A1 (ja) * 2018-02-27 2020-12-10 久光製薬株式会社 ジクロフェナク含有乳化ゲル組成物
US11246830B2 (en) 2018-02-27 2022-02-15 Hisamitsu Pharmaceutical Co., Inc. Emulsified gel composition
JP7053790B2 (ja) 2018-02-27 2022-04-12 久光製薬株式会社 ジクロフェナク含有乳化ゲル組成物
US11660268B2 (en) 2018-02-27 2023-05-30 Hisamitsu Pharmaceutical Co.. Inc. Emulsified gel composition
RU2823711C2 (ru) * 2021-01-28 2024-07-29 Гленмарк Фармасьютикалс Лимитед Фармацевтические композиции луликоназола для местного применения

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