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
  • A61K31/33—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
• • 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • 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

Definitions

• This disclosure relates to an external preparation for onychomycosis that is used to treat onychomycosis and prevent its worsening.
• Patent Document 1 The compound represented by the following formula (1) (hereinafter simply referred to as "compound (1)”) is described in Patent Document 1 as compound No. 6 (Production Example 6), and is known to be a useful compound as an antifungal agent for humans.
• compound (1) it is also known that a hydrate crystal of compound (1) has properties such as high stability against changes in temperature and humidity and the ability to reduce triboelectric charging, and can be advantageously used in efficiently producing formulations.
• Patent Documents 1 and 2 do not specifically describe the use of this compound for the treatment of onychomycosis, and naturally, there is no description or suggestion of a formulation for an external preparation for onychomycosis.
• Tinea unguium is a disease caused by infection of the nail with Trichophyton fungi, and is treated with oral or topical medications.
• oral medications are mainly used, but problems with oral medications include the fact that patients are forced to take them for long periods of time, interactions with other drugs, and side effects such as liver dysfunction, which have often been pointed out as problems. For this reason, there has been a strong demand for the development of effective topical medications.
• the main problem with topical medications is that it is difficult to deliver a sufficient amount of the medication to the affected area to exert a therapeutic effect, and research has focused on improving the penetration (permeability) into the nail, suppressing crystal precipitation during storage or application, and stabilizing the active ingredients.
• Patent document 3 claims that by incorporating ⁇ -hydroxycarboxylic acid or its salt, it is possible to suppress a phenomenon specific to luliconazole, in which fine crystals of luliconazole are instantly precipitated upon application, inhibiting its penetration and absorption into biological tissue.
• Dibasic acid diester is listed as one of the optional ingredients, and is described as an ingredient that promotes penetration into the nail.
• N-methyl-2-pyrrolidone is said to have the effect of suppressing the precipitation of crystals or insoluble matter on the administration surface, which appears 20 to 40 seconds after administration and is thought to be due to interaction with the surface structure of the skin or nail, or with substances present on the surface.
• Patent Document 4 also lists a dibasic acid diester as one of the optional ingredients, and describes it as an ingredient that promotes penetration into the nail.
• Patent Document 5 states that by incorporating at least one selected from the group consisting of a specified higher alcohol and a dibasic acid diester, and at least one selected from the group consisting of a polyoxyethylene alkyl ether and a polyoxyethylene alkenyl ether, desired properties such as inhibition of isomerization of the active ingredient, transparency at 20°C after production, and prevention of precipitation during low-temperature storage can be obtained.
• One of the reasons for incorporating a dibasic acid diester is said to be the inhibition of crystal precipitation at low temperatures, and it is described that when used in a specific ratio with a specified higher alcohol, it also exerts an inhibitory effect on crystal precipitation due to impact, such as crystal precipitation when applied to nails.
• Patent Document 6 a topical antifungal preparation containing efinaconazole as an active ingredient is known (see Patent Document 6).
• effective transungual penetration is achieved by incorporating efinaconazole, a monohydric alcohol, a glycol, and a specified excipient.
• Dimethyl sulfoxide and a dibasic acid diester are given as examples of the excipients, and the purpose of their inclusion is understood to be to promote penetration into the nail in light of the overall objective of the invention.
• topical preparations for onychomycosis that contain at least one active ingredient selected from the group consisting of compound (1) and its salts.
• paragraph 0029 of Patent Document 3 evaluates the degree of crystal precipitation after application onto a slide glass for Example 5 (a lotion containing luliconazole, diisopropyl adipate, lactic acid and ethanol) and Comparative Example 6 (i.e., a lotion containing luliconazole, diisopropyl adipate and ethanol) in which lactic acid in the formulation of Example 5 is replaced with ethanol, and shows that crystal precipitation could not be suppressed in the latter (see also Figures 4 and 5 of Patent Document 3).
• the present disclosure aims to provide an external preparation for onychomycosis that contains at least one active ingredient selected from the group consisting of compound (1) and its salts, inhibits crystal precipitation in the formulation and after application, and improves nail transmittance, thereby enabling the active ingredient to fully exert its effect on onychomycosis.
• the inventors conducted extensive research to solve the above problems and discovered that when a specific solvent is used, crystal precipitation in the formulation and after application is suppressed, nail transmittance is improved, and the product is sufficiently effective against onychomycosis, leading to the completion of the present invention.
• the present disclosure relates to an external preparation for onychomycosis that contains at least one active ingredient selected from the group consisting of compounds represented by the following formula (1) and salts thereof, and further contains at least one solvent selected from the group consisting of the following solvents (a) to (g):
• the active ingredient compound (1) and its salts it is possible to inhibit crystal precipitation in the formulation and after application, improve nail transmittance, and fully exert the effect on onychomycosis.
• 1 is a photograph showing the state of an external preparation after being left to stand for 24 hours in relation to the evaluation test "inhibition of crystal precipitation in preparation” in Example 1.
• 1 is a photograph showing the state of an external preparation after being left to stand for 24 hours in relation to the evaluation test "inhibition of crystal precipitation in the preparation” in Comparative Example 3.
• 1 is a photograph showing the state of an external preparation on a glass plate a predetermined period after application of the external preparation, in relation to the evaluation test “inhibition of crystal precipitation after application” in Example 22.
• 1 is a photograph showing the state of an external preparation on a glass plate a predetermined period after application of the external preparation, in relation to the evaluation test "inhibition of crystal precipitation after application” in Comparative Example 1.
• 1 is a photograph showing the state of an external preparation on a glass plate a predetermined period after application of the external preparation, in relation to the evaluation test "inhibition of crystal precipitation after application" in Comparative Example 2. These are photographs showing the condition around the nail when subungual efficacy tests were conducted for each of the placebos and controls of Examples 68 and 69. Photographs showing the results of fluorescent staining when a subungual fungicidal activity test was conducted on Example 68, its placebo, and two commercially available drugs.
• 1 is a graph showing the change in the amount of hydrolysate produced when the concentration of lactic acid is changed in the formulation of Example 49 or Example 59.
• 1 is a graph showing the difference in the amount of hydrolysate produced for Reference Examples 1 to 11 in which the type and/or amount of acid added is different.
• topical agent of the present disclosure The topical agent for onychomycosis disclosed herein (hereinafter, simply referred to as the “topical agent of the present disclosure") will be described in detail below, but the scope of the present disclosure is not limited to these descriptions, and modifications other than those listed below may be made as appropriate without departing from the spirit of the present disclosure.
• the topical preparation of the present disclosure contains at least one compound selected from the group consisting of compound (1) and a salt thereof as an active ingredient.
• compound (1) is a known compound and is represented by the chemical name 5-chloro-4-(3-chloro-4-methylphenyl)-1H-imidazole-2-carbonitrile.
• the salt of compound (1) is not particularly limited as long as it is a pharma- ceutically acceptable salt, and examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., and organic acid salts such as acetate, propionate, tartrate, fumarate, maleate, malate, citrate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, etc.
• Examples of basic salts include alkali metal salts such as sodium salt, potassium salt, etc., and alkaline earth metal salts such as calcium salt, magnesium salt, etc.
• At least one compound selected from the group consisting of compound (1) and its salts may have the following tautomers, but at least one compound selected from the group consisting of compound (1) and its salts in this disclosure may exist as any of these tautomers or may coexist as these tautomers (including coexistence in an equilibrium state).
• compound (1) or a salt thereof when left in the air or recrystallized, it may absorb moisture, have adsorbed water, or become a hydrate, but in the present disclosure, compound (1) or a salt thereof also includes such various hydrates, solvates, and polymorphic compounds.
• the hydrates and polymorphic compounds disclosed in WO 2023/106320 are preferably mentioned.
• the content ratio of at least one compound selected from the group consisting of compound (1) and a salt thereof relative to the total amount of the topical preparation of the present disclosure is not particularly limited, but is, for example, preferably 0.1 to 20 mass%, more preferably 0.5 to 10 mass%, and particularly preferably 1 to 5 mass%.
• the topical preparation of the present disclosure contains, as a solvent, at least one solvent selected from the group consisting of the following solvents (a) to (g) (hereinafter also simply referred to as the "prescribed solvent of the present disclosure").
• Solvent (a) dibasic acid diester
• Solvent (b) lower alcohol and dibasic acid diester
• Solvent (c) lower alcohols and dimethyl sulfoxide
• Solvent (d) dimethyl sulfoxide and dibasic acid diester
• Solvent (e) lower alcohol, dimethyl sulfoxide and dibasic acid diester
• Solvent (f) lower alcohols and glycols
• Solvent (g) lower alcohols, glycols and dibasic acid diesters.
• the dibasic acid diester in the specified solvent disclosed herein is a compound obtained by diesterifying a dibasic acid with an alcohol.
• the dibasic acid is not particularly limited, but it is preferable to use an aliphatic dibasic acid or an aromatic dibasic acid.
• the aliphatic dibasic acid include saturated aliphatic dibasic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, and sebacic acid, and unsaturated aliphatic dibasic acids such as maleic acid and fumaric acid.
• An aliphatic dibasic acid having 2 to 10 carbon atoms is preferred, an aliphatic dibasic acid having 2 to 6 carbon atoms is more preferred, and at least one selected from the group consisting of adipic acid, fumaric acid, and maleic acid is particularly preferred.
• the aromatic dibasic acid include phthalic acid, isophthalic acid, and terephthalic acid.
• the alcohol to be diesterified with the dibasic acid is not particularly limited, but examples thereof include alcohols having 1 to 4 carbon atoms such as methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, and tert-butyl alcohol, and at least one selected from the group consisting of ethanol, isopropyl alcohol, butanol, and isobutyl alcohol is more preferable.
• Examples of the dibasic acid diester are not particularly limited, but preferred examples include diisopropyl adipate, diisobutyl adipate, dibutyl fumarate, and diethyl maleate, with diisopropyl adipate being particularly preferred.
• the lower alcohol in the specified solvent disclosed herein is not particularly limited, but examples thereof include alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, and tert-butyl alcohol, and at least one selected from the group consisting of ethanol and isopropyl alcohol is particularly preferred.
• glycols in the specified solvent disclosed herein are not particularly limited, but examples of preferred glycols include ethylene glycol, propylene glycol, 1,3-propanediol, 1,4-butanediol, and dehydrated condensates thereof.
• Preferred examples of dehydrated condensates include diethylene glycol, triethylene glycol, polyethylene glycol, dipropylene glycol, tripropylene glycol, and polypropylene glycol.
• the molecular weight of the glycols as dehydrated condensates is preferably, for example, a number average molecular weight of 200 to 600, and more preferably 200 to 400. Propylene glycol and polyethylene glycol are particularly preferred.
• the content ratio of the specified solvent of the present disclosure to the total amount of the topical agent of the present disclosure is not particularly limited, but is preferably 60 to 99.9% by mass, more preferably 70 to 99.9% by mass, and particularly preferably 80 to 99.9% by mass, of the total amount of the topical agent of the present disclosure.
• the blending ratios of the lower alcohol, dimethyl sulfoxide, and dibasic acid diester, relative to the total of the three being 100% by mass are preferably 0.1 to 99.8% by mass of the lower alcohol, 0.1 to 99.8% by mass of the dimethyl sulfoxide, and 0.1 to 99.8% by mass of the dibasic acid diester, and more preferably 10 to 75% by mass of the lower alcohol, 5 to 75% by mass of the dimethyl sulfoxide, and 10 to 75% by mass of the dibasic acid diester.
• the blending ratios of the lower alcohol, the glycols, and the dibasic acid diester, relative to the total of the three being 100% by mass are preferably 0.1 to 99.8% by mass of the lower alcohol, 0.1 to 99.8% by mass of the glycols, and 0.1 to 99.8% by mass of the dibasic acid diester, and more preferably 55 to 90% by mass of the lower alcohol, 5 to 35% by mass of the glycols, and 5 to 35% by mass of the dibasic acid diester.
• the blending ratio of at least one compound selected from the group consisting of compound (1) and its salts to the specified solvent of the present disclosure is not particularly limited, but is preferably 0.1:99.9 to 40:60 by mass, more preferably 0.1:99.9 to 20:80, and particularly preferably 1:99 to 10:90.
• the topical preparation of the present disclosure may contain any solvent used in pharmaceutical compositions other than the above-mentioned specified solvent of the present disclosure.
• solvents include, for example, triglycerides such as olive oil, fatty acids such as stearic acid and oleic acid, polyhydric alcohols other than glycols (glycerin, etc.), and the like.
• N-methyl-2-pyrrolidone is suitable as a solvent for at least one compound selected from the group consisting of compound (1) and its salts, it does not contribute to the inhibition of crystal precipitation and may inhibit the crystal precipitation inhibition effect of the present disclosure, so it is preferable not to add it or to add it in a small amount if it is added.
• the amount of addition is preferably 10% by mass or less, more preferably 5% by mass or less, and particularly preferably 1% by mass or less, based on the total amount of the topical agent of the present disclosure.
• the topical preparation of the present disclosure may contain optional components other than the above components.
• optional components include general formulation additives used in external preparations, such as bulking agents, diluents, pH adjusters, dispersants, emulsifiers, preservatives, stabilizers, antioxidants, colorants, UV absorbers, moisturizers, and thickeners.
• Particularly preferred optional components are specifically exemplified below.
• a specific example of a suitable optional component is polyvinylpyrrolidone.
• Polyvinylpyrrolidone has the effect of suppressing crystal precipitation after application. This effect is presumably due to the fact that polyvinylpyrrolidone makes at least one compound selected from the group consisting of compound (1) and its salts amorphous.
• the molecular weight of the polyvinylpyrrolidone is not particularly limited, but for example, one having a weight average molecular weight of 10,000 to 360,000 can be used.
• the amount of polyvinylpyrrolidone to be blended is not particularly limited, but is preferably 0.1 to 10% by mass, and more preferably 0.5 to 5% by mass, based on the total amount of the topical agent of the present disclosure.
• components that are expected to have the same effect as polyvinylpyrrolidone (inhibition of crystallization by amorphization) include polymeric compounds such as ethylene-maleic anhydride copolymers and polyalkylene glycols (polyethylene glycol, polyoxyethylene polyoxypropylene glycol, etc.), and these may be used as optional components in the topical preparation of the present disclosure.
• an acid as a pH adjuster.
• an acid as a pH adjuster
• the stability of at least one compound selected from the group consisting of compound (1) and its salt is improved, which leads to improved permeability into the body.
• the pH adjuster include lactic acid, acetic acid, citric acid (including monohydrate), ascorbic acid, phosphoric acid, etc., and lactic acid and citric acid are more preferable, and lactic acid is particularly preferable.
• the amount of the acid as a pH adjuster is not particularly limited, but is preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, based on the total amount of the topical agent of the present disclosure.
• the upper limit is preferably 8% by mass or less, more preferably 4% by mass or less, and particularly preferably 0.5 to 2% by mass.
• benzyl alcohol benzoic acid or its salts (such as the sodium salt), sebacic acid, sorbic acid, etc. are preferably incorporated, with benzyl alcohol being particularly preferred.
• the amount of the preservative is not particularly limited, but is preferably 0.1 to 10% by mass, and more preferably 0.1 to 5% by mass, based on the total amount of the topical agent of the present disclosure.
• the above essential components and, if necessary, any optional components can be combined and formulated in a conventional manner to obtain the topical agent of the present disclosure.
• the formulation may take any form commonly used for external preparations, such as lotion, cream, emulsion, suspension, gel, patch, etc., with lotion being particularly suitable.
• the topical preparation of the present disclosure can be used to treat or prevent the worsening of onychomycosis, and depending on the specific formulation form, can be applied locally to the affected area, that is, the nail, of a target animal species (e.g., human) by painting, rubbing, pasting, or the like.
• a target animal species e.g., human
• the effective amount of at least one compound selected from the group consisting of compound (1) and a salt thereof and the number of times the topical preparation is administered are not particularly limited, and vary depending on the species, sex, age, body weight, condition and other factors of the animal to which the preparation is administered, and therefore it is difficult to specify in general terms; however, for example, the dosage when administered locally to an affected area in humans is, as the amount of at least one compound selected from the group consisting of compound (1) and a salt thereof, a daily dose per adult weighing 60 kg, usually 500 to 3,000 ⁇ g/day per nail, and a preferred weekly dose per nail is 3.5 to 15 mg/week.
• a method for treating onychomycosis in a subject comprising topically applying an effective amount of an external preparation for onychomycosis to the affected nail of the subject, the external preparation for onychomycosis containing at least one compound selected from the group consisting of the compound represented by formula (1) above and salts thereof as an active ingredient, and further containing at least one solvent selected from the group consisting of solvents (a) to (g) above as a solvent.
• this method is also referred to simply as the "treatment method.”
• a method for preventing the worsening of onychomycosis in a subject comprising topically applying an effective amount of an external preparation for onychomycosis to the affected nail of the subject, the external preparation for onychomycosis containing at least one compound selected from the group consisting of the compound represented by formula (1) above and salts thereof as an active ingredient, and further containing at least one solvent selected from the group consisting of solvents (a) to (g) above as a solvent.
• this method is also referred to simply as a "prevention method.”
• treating onychomycosis includes stopping, alleviating, or delaying the progression or worsening of onychomycosis by medical or non-medical procedures.
• preventing the worsening of onychomycosis includes preparing in advance for anticipated worsening of onychomycosis and preventing its occurrence or recurrence by medical or non-medical procedures.
• the "effective amount of topical agent for onychomycosis” varies depending on the animal species, sex, age, weight, condition, and other factors of the subject of administration, and is therefore difficult to define in general terms.
• the dosage when administered locally to an affected area in humans is preferably 500 to 3,000 ⁇ g/nail (person-day-nail) per day for an adult weighing 60 kg, and 3.5 to 15 mg/nail (person-week-nail) per week, as the amount of at least one compound selected from the group consisting of compound (1) and its salts.
• the topical agent for onychomycosis is applied locally to the affected area, the nail, of the target animal species (e.g., human) by painting, rubbing, pasting, etc., depending on the specific formulation form.
• target animal species e.g., human
• the topical preparation for onychomycosis contains, for example, at least one solvent selected from the group consisting of the solvents (a), (b), (d), and (e). It may also contain at least one solvent selected from the group consisting of the solvents (c), (d), and (e). It may also contain at least one solvent selected from the group consisting of the solvents (d) and (e).
• the dibasic acid diester is preferably a diester of a dibasic acid and an alcohol having 1 to 4 carbon atoms.
• the topical agent for onychomycosis further contains polyvinylpyrrolidone.
• the topical preparation for onychomycosis preferably further contains an acid as a pH adjuster, and the pH adjuster is more preferably lactic acid or citric acid, and even more preferably lactic acid.
• the content of at least one selected from the group consisting of the compound represented by the above formula (1) and its salt is 0.1 to 20% by mass, and the content of at least one selected from the group consisting of the above solvents (a) to (g) is 60 to 99.9% by mass.
• compositions for the manufacture of an external preparation for onychomycosis or a medicament for treating or preventing the worsening of onychomycosis comprising at least one compound selected from the group consisting of the compound represented by the above formula (1) and salts thereof as an active ingredient, and further comprising at least one solvent selected from the group consisting of the above solvents (a) to (g).
• this use is also referred to as "use of the composition.”
• treatment of onychomycosis and “prevention of the worsening of onychomycosis” are as described above.
• the topical agent for onychomycosis and the drug may contain, for example, at least one solvent selected from the group consisting of the solvents (a), (b), (d), and (e). They may also contain at least one solvent selected from the group consisting of the solvents (c), (d), and (e). They may also contain at least one solvent selected from the group consisting of the solvents (d) and (e).
• the dibasic acid diester is preferably a diester of a dibasic acid and an alcohol having 1 to 4 carbon atoms.
• topical preparation for onychomycosis and the drug further contain polyvinylpyrrolidone.
• the topical preparation for onychomycosis and the drug preferably further contain an acid as a pH adjuster, and the pH adjuster is more preferably lactic acid or citric acid, and even more preferably lactic acid.
• the content of at least one selected from the group consisting of the compound represented by the above formula (1) and its salt is 0.1 to 20 mass %, and the content of at least one selected from the group consisting of the above solvents (a) to (g) is 60 to 99.9 mass %.
• compositions for use in treating or preventing the worsening of onychomycosis comprising at least one compound selected from the group consisting of compounds represented by the following formula (1) and salts thereof as an active ingredient, and further comprising at least one solvent selected from the group consisting of the following solvents (a) to (g).
• this composition is also referred to simply as the "composition.”
• treatment of onychomycosis and “prevention of onychomycosis from worsening” are as described above.
• composition of the present disclosure is applied locally to the affected area, the nail, of the target animal species (e.g., human) by painting, rubbing, pasting, etc., depending on the specific formulation form.
• target animal species e.g., human
• composition of the present disclosure may, for example, contain at least one solvent selected from the group consisting of the above solvents (a), (b), (d), and (e). It may also contain at least one solvent selected from the group consisting of the above solvents (c), (d), and (e). It may also contain at least one solvent selected from the group consisting of the above solvents (d) and (e).
• the dibasic acid diester is preferably a diester of a dibasic acid and an alcohol having 1 to 4 carbon atoms.
• composition of the present disclosure preferably further contains polyvinylpyrrolidone.
• composition of the present disclosure preferably further contains an acid as a pH adjuster, and the pH adjuster is more preferably lactic acid or citric acid, and even more preferably lactic acid.
• the content of at least one selected from the group consisting of the compound represented by the above formula (1) and its salt is 0.1 to 20 mass %, and the content of at least one selected from the group consisting of the above solvents (a) to (g) is 60 to 99.9 mass %.
• An external preparation for onychomycosis comprising at least one compound selected from the group consisting of compounds represented by the following formula (1) and salts thereof as an active ingredient, and further comprising at least one solvent selected from the group consisting of the following solvents (a) to (g): Solvent (a): dibasic acid diester; Solvent (b): lower alcohol and dibasic acid diester; Solvent (c): lower alcohols and dimethyl sulfoxide; Solvent (d): dimethyl sulfoxide and dibasic acid diester; Solvent (e): lower alcohol, dimethyl sulfoxide and dibasic acid diester; Solvent (f): lower alcohols and glycols; and Solvent (g): lower alcohols, glycols and dibasic acid diesters.
• [2] The topical preparation for onychomycosis according to [1], which contains at least one solvent selected from the group consisting of the solvents (a), (b), (d) and (e).
• [3] The topical preparation for onychomycosis according to [1] or [2], which contains at least one selected from the group consisting of the solvents (c), (d) and (e) as a solvent.
• [4] The topical preparation for onychomycosis according to any one of [1] to [3], which contains at least one solvent selected from the group consisting of the solvents (d) and (e).
• composition comprising at least one compound represented by the following formula (1) and a salt thereof as an active ingredient, and further comprising at least one solvent selected from the group consisting of the following solvents (a) to (g), for the manufacture of an external preparation for onychomycosis or a medicament for treating onychomycosis or preventing the worsening of onychomycosis:
• Solvent (a) dibasic acid diester
• Solvent (b) lower alcohol and dibasic acid diester
• Solvent (c) lower alcohols and dimethyl sulfoxide
• Solvent (d) dimethyl sulfoxide and dibasic acid diester
• Solvent (e) lower alcohol, dimethyl sulfoxide and dibasic acid diester
• Solvent (f) lower alcohols and glycols
• Solvent (g) lower alcohols, glycols and dibasic acid diesters.
• a composition for use in treating or preventing the worsening of onychomycosis comprising at least one compound selected from the group consisting of compounds represented by the following formula (1) and salts thereof as an active ingredient, and further comprising at least one solvent selected from the group consisting of the following solvents (a) to (g): Solvent (a): dibasic acid diester; Solvent (b): lower alcohol and dibasic acid diester; Solvent (c): lower alcohols and dimethyl sulfoxide; Solvent (d): dimethyl sulfoxide and dibasic acid diester; Solvent (e): lower alcohol, dimethyl sulfoxide and dibasic acid diester; Solvent (f): lower alcohols and glycols; and Solvent (g): lower alcohols, glycols and dibasic acid diesters.
• a method for treating onychomycosis in a subject comprising: The method comprises topically applying an effective amount of an external preparation for nail tinea to the affected nail of the subject;
• the topical preparation for onychomycosis contains at least one compound selected from the group consisting of compounds represented by the following formula (1) and salts thereof as an active ingredient, and further contains at least one solvent selected from the group consisting of the following solvents (a) to (g): method.
• a method for preventing the exacerbation of onychomycosis in a subject comprising: The method comprises topically applying an effective amount of an external preparation for nail tinea to the affected nail of the subject;
• the topical preparation for onychomycosis contains at least one compound selected from the group consisting of compounds represented by the following formula (1) and salts thereof as an active ingredient, and further contains at least one solvent selected from the group consisting of the following solvents (a) to (g): method.
• [T1] Use of a combination of at least one compound selected from the group consisting of compounds represented by the following formula (1) and salts thereof and at least one solvent selected from the group consisting of the following solvents (a) to (g) for the manufacture of an external preparation for onychomycosis or a medicament for treating onychomycosis or preventing the worsening of onychomycosis.
• composition comprising at least one selected from the group consisting of a compound represented by the following formula (1) and a salt thereof as an active ingredient, and further comprising at least one selected from the group consisting of the following solvents (a) to (g) as a solvent, for the manufacture of an external preparation for onychomycosis or a medicament for treating onychomycosis or preventing the worsening of onychomycosis:
• Solvent (b) lower alcohol and dibasic acid diester;
• Solvent (d) dimethyl sulfoxide and dibasic acid diester;
• Solvent (e) lower alcohol, dimethyl sulfoxide and dibasic acid diester;
• Solvent (f) lower alcohols and glycols; and Solvent (g): lower alcohols, glycols and dibasic acid diesters.
• [T3] The use according to [T1] or [T2], wherein the topical preparation for onychomycosis or the medicament contains at least one solvent selected from the group consisting of the solvents (a), (b), (d) and (e).
• [T4] The use according to any one of [T1] to [T3], wherein the topical preparation for onychomycosis or the medicament contains at least one solvent selected from the group consisting of the solvents (c), (d) and (e).
• [T5] The use according to any one of [T1] to [T4], wherein the topical preparation for onychomycosis or the medicament contains at least one solvent selected from the group consisting of the solvents (d) and (e).
• [T6] The use according to any one of [T1] to [T5], wherein the dibasic acid diester is a diester of a dibasic acid and an alcohol having 1 to 4 carbon atoms.
• the dibasic acid diester is a diester of a dibasic acid and an alcohol having 1 to 4 carbon atoms.
• the topical preparation for onychomycosis or the medicament further contains polyvinylpyrrolidone.
• [T9] The use according to [T8], wherein the pH adjuster is lactic acid or citric acid.
• [T10] The use according to any one of [T1] to [T9], wherein the content of at least one selected from the group consisting of the compound represented by formula (1) and a salt thereof in the topical preparation for onychomycosis or the medicament is 0.1 to 20 mass %, and the content of at least one selected from the group consisting of the solvents (a) to (g) is 60 to 99.9 mass %.
• Example 1 According to the formulation below, the components were mixed in a glass screw tube (container size: 10 mL to 30 mL) at room temperature (approximately 25° C.), and the mixture was shaken by hand until the solids were dissolved to prepare the topical preparation of Example 1.
• Compound (1) 5 parts by mass Isopropyl alcohol 47.5 parts by mass Diisopropyl adipate 47.5 parts by mass
• Example 22 is an example rated as "A", in which the droplets spread after application, and as shown in FIG. 3, it can be confirmed that no crystals were produced even after the passage of time.
• Comparative Examples 1 and 2 are examples evaluated as "X.” As shown in Figure 4, in Comparative Example 1, it is confirmed that white crystalline matter has precipitated along the shape of the drug spot, and as shown in Figure 5, in Comparative Example 2, it is confirmed that needle-shaped crystals have precipitated.
• Tables 1 to 17 show the results of evaluation tests for inhibition of crystal precipitation, together with each formulation.
• IPA stands for isopropyl alcohol
• EtOH stands for ethanol
• DMSO dimethyl sulfoxide
• NMP stands for N-methyl-2-pyrrolidone
• PVP polyvinylpyrrolidone
• BzOH stands for benzyl alcohol
• PG stands for propylene glycol
• PEG stands for polyethylene glycol
• TOG stands for triethylene glycol.
• Polyvinylpyrrolidone K 30 (weight average molecular weight 40,000) manufactured by Tokyo Chemical Industry Co., Ltd. was used as polyvinylpyrrolidone (PVP).
• Polyethylene glycol 300 (number average molecular weight 300) manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. was used as polyethylene glycol (PEG). The same notation is used in the tables following Table 18 described below.
• Example 1 is a formulation using isopropyl alcohol and diisopropyl adipate as a solvent (the solvent is included in the concept of “solvent (b)”), but the solubility of the active ingredient in the formulation was good and no crystal precipitation was observed, and no crystal precipitation occurred after application.
• Example 2 is a formulation using only diisopropyl adipate as a solvent (the solvent is included in the concept of "solvent (a)”), but it was confirmed that the effect of the present disclosure was exhibited similarly to Example 1. Therefore, it was found that the effect of the present disclosure is exhibited even when diisopropyl adipate is used alone as a solvent.
• Comparative Example 1 is a formulation using only isopropyl alcohol as a solvent
• Comparative Example 2 is a formulation using only N-methyl-2-pyrrolidone as a solvent
• the solubility of the active ingredient in the preparation was good and no crystal precipitation was observed, but crystals precipitated after application. Therefore, it is clear that the suppression of crystal precipitation after application is not due solely to the good solubility of the solvent.
• Comparative Example 3 which is a formulation using isopropyl alcohol and N-methyl-2-pyrrolidone as solvents
• the solubility of the active ingredient in the formulation was insufficient, and crystal precipitation was confirmed, even after application.
• N-methyl-2-pyrrolidone was combined with other solvents, crystal precipitation occurred in the formulation, suggesting that it is not desirable to incorporate N-methyl-2-pyrrolidone as a solvent in the present disclosure.
• Example 3 is a formulation using ethanol and diisopropyl adipate as a solvent (the solvent is included in the concept of "solvent (b)"). It was confirmed that the effects of the present disclosure were exhibited in the same manner as in Example 1 using isopropyl alcohol.
• Comparative Example 4 is a formulation using only ethanol as a solvent, and although the solubility of the active ingredient in the formulation was good and no crystal precipitation was observed, crystals precipitated after application. This result, similar to the results shown in Table 1, suggests that the suppression of crystal precipitation after application is not due solely to the good solubility of the solvent.
• Comparative Example 5 which is a formulation using ethanol and N-methyl-2-pyrrolidone as solvents, the solubility of the active ingredient in the formulation was insufficient, and crystal precipitation was confirmed, and crystal precipitation was also observed after application. This result also showed a similar tendency to the results shown in Table 1, suggesting that it is not desirable to incorporate N-methyl-2-pyrrolidone as a solvent in the present disclosure.
• Examples 4 and 6 are formulations using isopropyl alcohol and dimethyl sulfoxide as solvents (solvents are included in the concept of "solvent (c)”)
• Example 5 is a formulation using ethanol and dimethyl sulfoxide as solvents (solvents are included in the concept of “solvent (c)”)
• Example 7 is a formulation using dimethyl sulfoxide and diisopropyl adipate as solvents (solvents are included in the concept of "solvent (d)”). It was confirmed that the effects of the present disclosure were also exhibited with these various combinations of solvents.
• Examples 8 to 11 are formulations using isopropyl alcohol, dimethyl sulfoxide, and diisopropyl adipate as solvents (the solvent is included in the concept of "solvent (e)”). It was confirmed that the effects of the present disclosure are exhibited at various blend ratios.
• Examples 12 to 15 are formulations using ethanol, dimethyl sulfoxide, and diisopropyl adipate as solvents (the solvent is included in the concept of "solvent (e)”). Even in these examples, it was confirmed that the effects of the present disclosure were exhibited at various blend ratios.
• Examples 16 to 29 are based on a formulation using diisopropyl adipate, and examine formulations in which the diisopropyl adipate is replaced with various dibasic acid diesters (the solvents are included in the concept of "solvent (b)” or “solvent (e)”). It was confirmed that the effects of the present disclosure were exhibited in various dibasic acid diesters other than diisopropyl adipate, similar to diisopropyl adipate.
• Examples 30 to 33 are formulations using isopropyl alcohol or ethanol, dimethyl sulfoxide, and diisopropyl adipate as a solvent (the solvent is included in the concept of "solvent (e)")
• Examples 34 to 37 are formulations using isopropyl alcohol or ethanol and diisopropyl adipate as a solvent (the solvent is included in the concept of "solvent (b)”).
• Each formulation contains polyvinylpyrrolidone, benzyl alcohol, lactic acid, etc. as a suitable optional ingredient, but the solubility of the active ingredient in the formulation is good and no crystal precipitation was observed, and no crystal precipitation occurred after application. From these results, it can be said that each of the above optional ingredients contributes to further improving the physical properties of the topical agent for nail fungus without inhibiting the effects of the present disclosure.
• Examples 38 to 40 are formulations using ethanol and various glycols as a solvent (the solvent is included in the concept of "solvent (f)"), and it was confirmed that the effects of the present disclosure are exhibited in combinations of lower alcohols and various glycols.
• Examples 41 to 66 confirmed that the effects of the present disclosure are exhibited in various combinations encompassed by the concepts of solvent (b), solvent (f), or solvent (g), and in particular that the effects of the present disclosure are not hindered by the incorporation of various optional components, and that the effects of the present disclosure are exhibited in various blending ratios.
• the cell suspension was spread on a rye medium and cultured at 28° C., after which 5 mL of physiological saline was added to the formed mycelium, and the surface was scraped with a scraper to recover the cell liquid.
• the cell liquid was stirred with a vortex and then filtered through a 100 ⁇ m filter to obtain a conidial liquid, which was then counted under a microscope and used for testing.
• Preparing human nails The nails were sterilized and washed with 70% ethanol, then immersed in 100% ethanol for 1 hour to remove moisture, and then air-dried for 1 hour under irradiation with a germicidal lamp in a safety cabinet.
• ⁇ Chemical treatment of human nails The human nails were placed one by one in a dish (diameter 35 mm), and 0.5 ⁇ L of the drug solution was applied to the upper layer of the nail plate so that the drug solution remained only on the upper surface and did not drip down from the sides. After the surface was dried, the nails were kept in an incubator at 25° C. to allow the drug solution to penetrate into the human nails. The above procedure was carried out once a day, and the application was repeated 1 to 7 times.
• the topical preparations for onychomycosis of Examples 3, 5, 7, 27, 38 to 40, 50, 51, 53, 59, 60, and 67 to 71 were used.
• ⁇ Culture test> Cellophane (10 mm length ⁇ 10 mm width ⁇ 50 ⁇ m thickness) was placed on the test medium, and a conidial solution (1 ⁇ 105 conidia /1 ⁇ L) was spot-inoculated on top of it. A human nail soaked in the drug solution was then placed on top of it so that the underside of the nail plate was in contact with the conidia and the cellophane. After culturing for 24 hours at 28°C, the conidia were stained with 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) solution to determine whether they were dead or alive.
• DAPI 4',6-diamidino-2-phenylindole dihydrochloride
• Example 68 Human nail fungicidal activity test
• the results of Example 68 are shown in Figure 7.
• the results of commercially available nail external solutions, "Leconac” (registered trademark) 5% external solution manufactured by Sato Pharmaceutical Co., Ltd. and “Clenafin” (registered trademark) 10% external solution manufactured by Kaken Pharmaceutical Co., Ltd., and the placebo corresponding to Example 68 are also shown in Figure 7.
• DAPI Human nail fungicidal activity test
• this principle was used to determine whether subungual conidia are viable or dead. It was observed in a dark field that the conidia under the nail were stained with DAPI in the case of the topical preparation for nail tinea in Example 68. On the other hand, no staining of the conidia was observed in the case of the placebo and the two commercially available drugs used for comparison. Therefore, it was confirmed that the topical preparation for onychomycosis of Example 68 killed the conidia under the nail, and that the conidia remained viable in the placebo and the two commercially available drugs.
• the prepared sample solution (about 6 mL) was placed in a glass screw tube (container size 10 mL) and sealed with bulk tape and vinyl tape to cover the cap and the body. It was stored for 4 weeks under conditions of 60 ° C and 80% RH. After storage, the sample solution was diluted with acetonitrile and analyzed by liquid chromatography. The area percentage was calculated from the sum of the peak areas obtained on the chromatogram and the peak area of the hydrolyzate, which is the main decomposition product of compound (1). The results are shown in Figure 8.
• the addition of an acid is advantageous for improving the storage stability of compound (1), and it is particularly preferable to add lactic acid or citric acid.
• the amount of addition is not necessarily increased, and for example, in the case of lactic acid, it was found that the mass ratio to the entire topical preparation is preferably 8% by mass or less, more preferably 4% by mass or less, and particularly preferably 0.5 to 2% by mass.
• This disclosure can be suitably used in the field of treating nail fungus and preventing its worsening.

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