WO2019151282A1 - Solution à usage externe pour la prévention ou le traitement de l'onychomycose dermatophytique - Google Patents

Solution à usage externe pour la prévention ou le traitement de l'onychomycose dermatophytique Download PDF

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WO2019151282A1
WO2019151282A1 PCT/JP2019/003067 JP2019003067W WO2019151282A1 WO 2019151282 A1 WO2019151282 A1 WO 2019151282A1 JP 2019003067 W JP2019003067 W JP 2019003067W WO 2019151282 A1 WO2019151282 A1 WO 2019151282A1
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drug
pyrazol
ppg
dimethyl
onychomycosis
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PCT/JP2019/003067
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English (en)
Japanese (ja)
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千記 小松
なおみ 増田
那月 石田
優 柳樂
恭平 吾郷
朗 平田
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Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社
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Publication of WO2019151282A1 publication Critical patent/WO2019151282A1/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
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/08—Solutions
    • 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 preventing or treating onychomycosis.
  • Onychomycosis is a nail disease caused by dermatophytes, which is said to be more than 90% of the causative agents of onychomycosis in Japan, and is a disease with symptoms such as cloudiness, thickening, destruction and deformation of the nail plate.
  • dermatophytes which is said to be more than 90% of the causative agents of onychomycosis in Japan, and is a disease with symptoms such as cloudiness, thickening, destruction and deformation of the nail plate.
  • antifungal agents such as itraconazole, terbinafine, efinaconazole, and luliconazole
  • oral antifungal agents have been pointed out to have drug interactions, liver damage, and side effects caused by long-term administration.
  • elderly people with high incidence of onychomycosis, diabetics, etc. often take a plurality of drugs, and it is often difficult to orally administer antifungal drugs for the treatment of onychomycosis.
  • the drug concentration should be reduced in the horny and internal areas of the nail, which is the infection site, and in the nail plate. It is necessary to reach a high level.
  • onychomycosis which has anti-tinea fungus activity
  • onychomycosis which has anti-tinea fungus activity
  • can contain a high concentration of drug and is excellent in applicability and wiping removal properties
  • the present invention has anti-tinea fungus activity, is excellent in drug delivery to the nail plate, can contain a high concentration of drug, and is excellent in applicability and wiping removal properties.
  • An object is to provide an external solution for prevention or treatment.
  • the present inventors have included a delivery enhancer in an external liquid preparation containing a drug having anti-tinea fungi activity and a volatile alcohol, thereby providing a subnail plate. It has been found that it can be used as an externally applied liquid preparation that has excellent drug delivery to the skin, has high anti-tinea fungus activity, can contain a high concentration of drug, and is excellent in applicability and wiping off. Completed the invention.
  • Means for solving the problems are as follows. That is, ⁇ 1> An external liquid for prevention or treatment of onychomycosis comprising a drug having anti-tinea activity, a volatile alcohol, and a delivery accelerator.
  • the said various problems in the past can be solved, the said objective can be achieved, it has an anti- ringworm fungus activity, it is excellent in the delivery property of the drug to a nail plate, and a high concentration drug It is possible to provide a liquid for external use for the prevention or treatment of onychomycosis that is excellent in applicability and wiping off properties.
  • the topical solution for preventing or treating onychomycosis of the present invention contains at least a drug having anti-tinea fungi activity, a volatile alcohol, and a delivery accelerator, and further contains other components such as a wetting agent as necessary. .
  • the drug having anti-tinea activity (hereinafter sometimes referred to as “main drug”) is not particularly limited and may be appropriately selected from known drugs having anti-tinea activity according to the purpose. Examples thereof include compounds having antifungal activity, particularly compounds effective for the treatment of onychomycosis.
  • the drug having anti-tinea activity include, for example, a compound represented by the following general formula (I) or a salt thereof. ⁇ Compound Represented by Formula (I) >>
  • R 1 represents a hydrogen atom, C 1-6 alkyl, or trifluoromethyl
  • R 2 represents a hydrogen atom, C 1-6 alkyl, halogen, —COO (C 1-6 alkyl), or (CH 2 ) 1-3 COOR (R represents a hydrogen atom or C 1-6 alkyl).
  • R 3 represents a hydrogen atom, C 1-6 alkyl, amino, trifluoromethyl, or OR (R represents a hydrogen atom or C 1-6 alkyl); R 4 represents a hydroxyl group, R 5 represents a hydrogen atom, C 1-6 alkyl, hydroxyl group, or halogen, R 6 represents a hydrogen atom, C 1-6 alkyl, trifluoromethyl, halogen, amino, —NR a R b , nitro, hydroxy C 1-6 alkyl, —CONR a R b , —COO (C 1-6 alkyl) ), —COOH, — (CH 2 ) 1-3 COOR, or OR a (R represents a hydrogen atom or C 1-6 alkyl, R a and R b may be the same or different, and a hydrogen atom Represents C 1-6 alkyl, or C 1-6 acyl), R 7 represents a hydrogen atom, C 1-6 alkyl, —OR (R represents a hydrogen
  • C 1-6 alkyl "C 1-6 alkyl” portion of the group, an alkyl group having from 1 to 6 carbon atoms.
  • the alkyl group may be chain, branched or cyclic.
  • C 1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like
  • C 3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like Group and the like.
  • C 1-6 acyl "C 1-6 acyl” part of the group, an acyl group having from 1 to 6 carbon atoms.
  • the acyl group may be chain, branched or cyclic. Examples include formyl, acetyl, propionyl, butyryl, isobutyryl and the like.
  • halogen used in the general formula (I) includes fluorine, chlorine, bromine, iodine and the like.
  • R a represents a hydrogen atom, C 1-6 alkyl, or C 1-6 acyl
  • R a represents a hydroxyl group, C 1-6 alkyloxy, or C 1-6 acyloxy.
  • C 1-6 alkyl has the same meaning as the above “C 1-6 alkyl”.
  • Specific examples of the compound represented by the general formula (I) include the following compounds. 2- (3,5-Dimethyl-1H-pyrazol-1-yl) phenol 2- (3,5-Dimethyl-1H-pyrazol-1-yl) -4-fluorophenol 2- (1H- Pyrazol-1-yl) phenol 2- (5-hydroxy-3-methyl-1H-pyrazol-1-yl) phenol 2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) Phenol-2- (3,5-Bistrifluoromethyl-1H-pyrazol-1-yl) phenol-2- (3-Methyl-1H-pyrazol-1-yl) phenol-2- (5-Methyl-1H-pyrazole -1-yl) phenol ⁇ 2- (3,4,5-trimethyl-1H-pyrazol-1-yl) phenol ⁇ 2- (5-amino-3-tert-butyl-1H-pyrazol-1-yl) phenol 4-chloro-2- (3,
  • “Pharmaceutically acceptable salts” are known in the art. For example, S. M. Berge et al. Describe pharmaceutically acceptable salts in detail in Journal of Pharmaceutical Sciences, 66 p.1 et seq. (1977).
  • Typical acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, etc .; acetate, trifluoroacetate, lactate, citric acid Organic carboxylic acids such as acid, oxalate, succinate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, nicotinate, phthalate Salts; organic sulfonates such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-toluenesulfonate, 2-naphthalenesulfonate, camphorsulfonate, and the like; Examples include, but are not limited to, acidic amino acid salts such as aspartate and glutamate.
  • the acid addition salt is preferably an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; a salt with an organic acid such as oxalic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid or citric acid Is mentioned. More preferred are salts with hydrochloric acid, hydrobromic acid, sulfuric acid, and methanesulfonic acid.
  • the base addition salt can be produced in situ by reacting a carboxylic acid or phenolic hydroxyl group-containing moiety with an appropriate base during the final isolation and purification process of the compound represented by the general formula (I).
  • Examples of pharmaceutically acceptable base addition salts include alkali metal salts such as lithium salt, sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt, ammonium salt, methylamine salt, Dimethylamine salt, ethylamine salt, diethylamine salt, trimethylamine salt, triethylamine salt, tetramethylammonium salt, tetraethylammonium salt, pyridine salt, picoline salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, trishydroxymethylaminomethane salt, Organic base salts such as piperidine salts, piperazine salts, dicyclohexylamine salts, N, N-dibenzylethylenediamine salts; basic amino acid salts such as
  • the compound represented by the general formula (I) can also be used as a solvate.
  • solvate means a complex of various stoichiometry formed by a solute (the compound represented by the general formula (I) or a salt thereof) and a solvent.
  • the solvent is preferably a pharmaceutically acceptable solvent that does not interfere with the biological activity of the solute.
  • suitable solvents for solvates include, but are not limited to water, methanol, ethanol, ethylene glycol, propylene glycol, ethyl acetate, butyl acetate and the like.
  • the solvent for the solvate preferably includes water, ethanol, ethyl acetate.
  • drugs having anti-tinea activity include polyene antifungal agents such as natamycin, rimocidin, Philippines, nystatin, amphotericin B; miconazole, ketoconazole, clotrimazole, econazole, bifonazole, butconazole Imidazole compounds such as fluconazole, itraconazole, labconazole, posaconazole, voriconazole, efinaconazole, terconazole, etc .; Allylamine compounds such as amorolfine, naphthifine, butenafine; anidurafungin, cas Fangin, echinocandin compounds such as micafungin; ciclopirox, flucytosine, griseofulvin, gentian violet, Haropirojin, tolnaftate, and the like other anti-fungal agents such as undecylenic acid.
  • polyene antifungal agents such as natamycin, rimocidin, Philippines
  • the drug having anti-tinea fungi activity may be used alone or in combination of two or more.
  • the drugs having anti-tinea activity 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof is included in that the anti-tinea activity is more excellent. preferable.
  • the content of the drug having anti-tinea fungi activity in the external solution for preventing or treating onychomycosis is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the content is preferably 30% by mass, more preferably 5 to 20% by mass, still more preferably 8 to 20% by mass, and 12 to 20% by mass. It is particularly preferable to contain it.
  • the content is within the preferred range, it is advantageous in that the anti-tinea fungus activity of the solution for external use can be further enhanced.
  • the volatile alcohol refers to one that evaporates from the surface of a nail or the like when an external liquid is applied to the nail or the like.
  • the volatile alcohol is not particularly limited and can be appropriately selected according to the purpose of those usually used in the pharmaceutical field. Examples thereof include lower alcohols, higher alcohols, and polyhydric alcohols. . Specific examples of the lower alcohols include ethanol, propanol, isopropanol and the like. Specific examples of the higher alcohols include oleyl alcohol, dioleic acid propylene glycol, polyethylene glycol and the like. Specific examples of the polyhydric alcohols include glycerin, sorbitol, ethylene glycol, polyethylene glycol and the like. The said volatile alcohol may be used individually by 1 type, and may use 2 or more types together. Moreover, although the said volatile alcohol may be anhydrous and may contain water, at least 90 mass% or more alcohol is preferable.
  • the content of the volatile alcohol in the external preparation for preventing or treating onychomycosis is not particularly limited and can be appropriately selected according to the purpose.
  • the amount is preferably 50 to 90% by mass.
  • the content is within a preferable range, it is advantageous in that the precipitation of the drug can be suppressed even when the external liquid preparation is stored at a low temperature.
  • ⁇ Delivery accelerator> an external preparation for preventing or treating onychomycosis penetrates from the nail plate to the inside of the nail and from the gap between the nail plate and the skin to the nail plate (hereinafter sometimes referred to as “nail bed”). By reaching, a therapeutic effect is produced.
  • delivery refers to allowing a drug to reach the nail bed through the gap between the nail plate and the skin.
  • the delivery accelerator is not particularly limited and may be appropriately selected depending on the intended purpose.
  • These may be used individually by 1 type and may use 2 or more types together.
  • isopropyl myristate isopropyl palmitate, diisopropyl sebacate, diethyl adipate, and stearyl alcohol in terms of better delivery, and isopropyl myristate More preferably.
  • the content of the delivery enhancer in the external solution for preventing or treating onychomycosis is not particularly limited and may be appropriately selected depending on the intended purpose, but it is 2.0 to 10. It is preferably contained in a proportion of 0% by mass, particularly preferably in a proportion of 5.0 to 7.0% by mass. When the content is within a preferable range, it is advantageous in that the deliverability is more excellent.
  • the other components are not particularly limited as long as the effects of the present invention are not impaired, and components that are usually used in preparations such as external liquid preparations can be appropriately selected according to the purpose.
  • wetting agents low volatility An organic solvent, a preservative, and an antioxidant. These may be used individually by 1 type and may use 2 or more types together.
  • a moistening effect such as a moisturizing effect and tissue softening property can be obtained on the nail, and it is preferable that a wetting agent is included in that the feel at the time of application and / or after application can be further improved.
  • the wetting agent is not particularly limited and may be appropriately selected depending on the intended purpose.
  • examples thereof include PPG-higher alcohol ether derivatives, organic acid esters, hydrophobized hydroxypropylcellulose, and poloxamer.
  • the PPG-higher alcohol ether derivative is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include PPG-15 stearyl ether, PPG-11 stearyl ether, PPG-10 glyceryl ether, PPG-27 dimethicone. Etc.
  • the organic acid esters are not particularly limited and may be appropriately selected depending on the intended purpose.
  • alkyl lactate examples thereof include alkyl lactate, diisobutyl adipate, isopropyl adipate, oleyl oleate, and decyl oleate.
  • the alkyl lactate is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include C12-C15 alkyl lactate (“C12-15 alkyl lactate”, “alkyl lactate (C12-C15)”). And alkyl lactate (C12, C13).
  • the said wetting agent may be used individually by 1 type, and may use 2 or more types together.
  • 1 selected from the group consisting of PPG-15 stearyl ether, alkyl lactate, hydrophobized hydroxypropyl cellulose, and poloxamer in that the effect of the present invention can be further improved in combination with the delivery accelerator. It preferably contains at least one species, more preferably contains at least one selected from the group consisting of PPG-15 stearyl ether and alkyl lactate, and particularly preferably contains PPG-15 stearyl ether.
  • the content of the humectant in the external preparation for preventing or treating onychomycosis is not particularly limited and may be appropriately selected depending on the intended purpose, but it is 3.0 to 10.0 with respect to the entire external preparation. It is preferably contained in a proportion of mass%, particularly preferably in a proportion of 4.0 to 7.0 mass%. When the content is within the preferred range, it is advantageous in that the effect of the present invention can be further improved in combination with a delivery accelerator.
  • Low volatile solvent There is no restriction
  • the preservative is not particularly limited and may be appropriately selected depending on the purpose.
  • organic preservatives such as cationic activators, phenols, sorbates, salicylates, dehydroacetates, benzoates, etc.
  • Agents Inorganic antiseptics such as antibacterial zeolite obtained by ion exchange of antibacterial metal ions such as silver, copper and zinc with zeolite. These may be used individually by 1 type and may use 2 or more types together. There is no restriction
  • the antioxidant is not particularly limited and may be appropriately selected depending on the intended purpose.
  • 1,3-butylene glycol, citric acid hydrate (monohydrate), tocopherol, tocopherol acetate examples include palmitic acid, ascorbic acid, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), and propyl gallate. These may be used individually by 1 type and may use 2 or more types together.
  • BHA butylhydroxyanisole
  • BHT dibutylhydroxytoluene
  • propyl gallate propyl gallate.
  • additives that improve the feeling of use and the like can be appropriately selected within a range that does not impair the effects of the present invention.
  • silicon-based solvents such as cyclomethicone and dimethicone Terpene solvents such as D-limonene, pinene, terpineol and terpineol
  • glycol ether solvents such as diethylene glycol monoethyl ether and diethylene glycol
  • dimethyl isosorbide and the like can also be used.
  • the method for producing the external liquid for prevention or treatment of onychomycosis is not particularly limited, and a known method for producing the external liquid can be selected as appropriate.
  • the anti- ringworm bacteria may be added to a part of the volatile alcohol. Examples include a method of dissolving an active drug, the delivery accelerator, and, if necessary, the other components in order and adjusting the amount with a volatile alcohol to obtain a liquid for external use.
  • the viscosity of the external solution for preventing or treating onychomycosis is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 0.5 to 11 mPa ⁇ s, more preferably 1 to 8 mPa ⁇ s. 1.5 to 5 mPa ⁇ s is particularly preferable. Within the preferable range, it is advantageous in terms of more excellent usability such as applicability and delivery of drugs to the nail bed.
  • the viscosity in the present invention refers to a viscosity measured using a rotational viscometer under normal temperature conditions.
  • Onychomycosis is caused by the invasion of ringworm from the tip of the nail into the nail bed. Nail plate detachment is seen in the affected area of the nail. Therefore, it is necessary to supply sufficient drugs not only to the affected part but also to the boundary part with the healthy part to suppress the growth of ringworm and / or sterilize the ringworm.
  • the topical solution for preventing or treating onychomycosis of the present invention is used as a first-line drug for patients with mild to moderate onychomycosis, and for patients who cannot administer oral medicine such as patients with hepatic disorder Can be used.
  • the use mode of the external preparation for preventing or treating onychomycosis of the present invention is not particularly limited and may be appropriately selected depending on the intended purpose. For example, it is applied or dropped on the nails and / or skin of hands and feet. , Spraying, rubbing lightly, etc.
  • a frequency and a period using the external preparation for prevention or treatment of the onychomycosis of this invention there is no restriction
  • External liquid preparations for the prevention or treatment of onychomycosis are required to facilitate the delivery and / or permeation of drugs to the affected area.
  • volatile alcohol evaporates or the external liquid application part comes into contact with water, etc. Therefore, it is important to design the formulation so that the drug does not become cloudy or precipitate.
  • the liquid preparation for external use for prevention or treatment of onychomycosis of the present invention has an appropriate combination of additives, thereby preventing stickiness at the time of application, formation of a film after application, white turbidity and precipitation, and an appropriate viscosity. And has excellent drug delivery.
  • the liquid for external use for prevention or treatment of onychomycosis of the present invention can contain a drug at a high concentration, and when it adheres to a non-infected site or when a preparation previously administered at the time of administration remains.
  • the preparation can be easily removed by wiping off the preparation.
  • it since it has an appropriate surface tension and viscosity, it can be held well on the nail surface, and the drug can be exposed to the affected area by permeation from the nail plate into the nail.
  • the drug can be exposed to the affected area of the nail mother by absorption through the skin. Therefore, also in these respects, a preventive or therapeutic effect against onychomycosis can be obtained.
  • Example 1 Production of liquid for external use
  • C12-C15 alkyl lactate 5g, isopropyl myristate 6.3g, diisopropyl adipate 5g, benzyl alcohol 2.7g, PPG-15 stearyl ether 5g are mixed with absolute ethanol 60g, dissolved in 1g myristyl alcohol,
  • a formulation of Example 1 was obtained by dissolving 15 g of 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol.
  • Example 2 Production of liquid for external use
  • a preparation of Example 2 was obtained in the same manner as in Example 1 except that the blending amounts of isopropyl myristate, PPG-15 stearyl ether, diisopropyl adipate and C12-C15 alkyl lactate were changed to those shown in Table 1. .
  • Example 3 Production of liquid for external use
  • Example 4 Production of liquid for external use
  • cyclomethicone (0.2 g) are mixed with anhydrous ethanol (12 g), and the active ingredient 2- (3,5-dimethyl-1H-pyrazole-1- I) 3 g of 5-methylphenol was dissolved to obtain the preparation of Example 4.
  • Example 5 Production of liquid for external use
  • the active ingredient is mixed with 1 g of isopropyl myristate, 2.8 g of diethyl glycol monoethyl ether (Transcutol P) and 0.2 g of cyclomethicone in 12 g of absolute ethanol.
  • the preparation of Example 5 was obtained by dissolving 4 g of -5-methylphenol.
  • Example 6 Production of liquid for external use
  • C12-C15 alkyl lactate 2.1 g, isopropyl myristate 5.9 g, diisopropyl adipate 7 g, benzyl alcohol 2.7 g, PPG-15 stearyl ether 6.3 g are mixed with absolute ethanol 65 g and dissolved by adding myristyl alcohol 1 g, further effective 10 g of 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol as a component was dissolved to obtain a preparation of Example 6.
  • Table 1 shows the formulations of the external liquid preparations of Examples 1 to 6 and Comparative Examples 1 and 2.
  • Table 2 shows the product names and manufacturer names of the components used in Examples 1 to 6 and Comparative Examples 1 and 2.
  • Comparative Example 3 Production of liquid for external use
  • the preparation described in Example 1 of International Publication No. 2014/021282 was produced.
  • 10 g of the compound produced in Production Example 1 and 10 g of copolyvidone (Prasudone S-630) were dissolved in order in a part of ethanol to make a total of 100 mL with ethanol to obtain a preparation.
  • concentration of the main ingredient in the comparative example 3 is 11.4 w / w%.
  • ⁇ Precipitation> The drug precipitation when the formulation was in contact with water, sweat, etc. was tested as follows. The results are shown in Table 3.
  • -Additive precipitation test method for water (1) After 20 ⁇ L of the prepared preparation was dropped on a slide glass and allowed to stand for 1 hour, 20 ⁇ L of purified water was added, and the presence or absence of precipitation was visually observed after 30 minutes.
  • -Water addition precipitation test method (2) 20 ⁇ L of the prepared preparation was dropped onto an artificial nail (Vitro-Nails (registered trademark), IMS Inc.) and allowed to stand for 1 hour, then 20 ⁇ L of purified water was added, and the presence or absence of precipitation was visually observed after 30 minutes. did.
  • the preparation of the present invention does not become cloudy or precipitate even when exposed to water or the like, the drug on the nail and / or skin when applied to the nail and / or skin. Can be prevented from becoming clouded or precipitated.
  • the formulation of this invention is excellent also in removability, and also is excellent in delivery property and applicability
  • Bacteria positive rate (%) number of skin pieces showing bacteria positive / total number of skin pieces x 100 [Standard]
  • the preparation of the present invention has a strong anti-tinea fungus activity without forming a film even when it contains a drug at a high concentration or is applied to the skin, etc. It was confirmed that it has a delivery property, an effect of suppressing the precipitation of active ingredients upon contact with water after coating, ease of removal such as wiping, and excellent coating properties. Therefore, according to the present invention, it is possible to provide a nail and / or skin external solution that is easy to handle at a high concentration and has a high preventive or therapeutic effect.
  • Examples of the aspect of the present invention include the following.
  • An external liquid for prevention or treatment of onychomycosis comprising a drug having anti-tinea activity, a volatile alcohol, and a delivery accelerator.
  • ⁇ 3> Any one of ⁇ 1> to ⁇ 2>, wherein the delivery accelerator includes one or more selected from the group consisting of isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl adipate, and stearyl alcohol.
  • the delivery accelerator includes one or more selected from the group consisting of isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl adipate, and stearyl alcohol.
  • ⁇ 4> The external preparation for preventing or treating onychomycosis according to any one of ⁇ 1> to ⁇ 3>, further including a wetting agent.
  • the wetting agent comprises one or more selected from the group consisting of PPG-15 stearyl ether, alkyl lactate, hydrophobized hydroxypropylcellulose, and poloxamer. It is a liquid for external use.
  • ⁇ 6> As the drug having anti-tinea activity, 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof, As the delivery accelerator, one or more selected from the group consisting of isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl adipate and stearyl alcohol, Furthermore, for the prevention or treatment of onychomycosis according to the above ⁇ 1>, which may contain one or more selected from the group consisting of PPG-15 stearyl ether, alkyl lactate, hydrophobized hydroxypropylcellulose, and poloxamer as a wetting agent. It is a liquid for external use.
  • ⁇ 7> As the drug having anti-tinea activity, 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof,
  • the delivery accelerator one or more selected from the group consisting of isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl adipate and stearyl alcohol,
  • wetting agents PPG-15 stearyl ether, PPG-11 stearyl ether, PPG-10 glyceryl ether, PPG-27 dimethicone, diisobutyl adipate, isopropyl adipate, oleyl oleate, decyl oleate, C12-C15 alkyl lactate
  • the liquid for external use for prevention or treatment of onychomycosis according to the above ⁇ 1>, which may contain at least one selected from the group consisting of alkyl lactate (C12, C13).
  • the drug having anti-tinea activity includes 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof,
  • the delivery enhancer isopropyl myristate and The external preparation for preventing or treating onychomycosis according to the above ⁇ 4>, which contains PPG-15 stearyl ether as the wetting agent.
  • the drug having anti-tinea activity includes 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof,
  • the low-volatility solvent may be one or more selected from the group consisting of diisopropyl adipate, benzyl alcohol and myristyl alcohol.
  • the drug having anti-tinea activity 2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-methylphenol or a salt thereof, And one or more selected from the group consisting of diisopropyl adipate, benzyl alcohol and myristyl alcohol as a low volatility solvent, Further, as wetting agents, PPG-15 stearyl ether, PPG-11 stearyl ether, PPG-10 glyceryl ether, PPG-27 dimethicone, diisobutyl adipate, isopropyl adipate, oleyl oleate, decyl oleate, C12-C15 alkyl lactate And the external preparation for the prevention or treatment of onychomycosis according to the above ⁇ 1>, which may contain one or more selected from the group consisting of alkyl lactate (C12

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Abstract

La solution à usage externe pour la prévention ou le traitement de l'onychomycose dermatophytique selon l'invention contient: un médicament présentant une activité anti-bactérienne contre le trichophyton; un alcool volatile; et un promoteur de dissémination.
PCT/JP2019/003067 2018-01-31 2019-01-30 Solution à usage externe pour la prévention ou le traitement de l'onychomycose dermatophytique WO2019151282A1 (fr)

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Citations (1)

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WO2014021282A1 (fr) * 2012-07-30 2014-02-06 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 Solution anti-trichophytique à usage externe

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014021282A1 (fr) * 2012-07-30 2014-02-06 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 Solution anti-trichophytique à usage externe

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