WO2021132348A1 - エフィナコナゾールを含有する医薬 - Google Patents

エフィナコナゾールを含有する医薬 Download PDF

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WO2021132348A1
WO2021132348A1 PCT/JP2020/048199 JP2020048199W WO2021132348A1 WO 2021132348 A1 WO2021132348 A1 WO 2021132348A1 JP 2020048199 W JP2020048199 W JP 2020048199W WO 2021132348 A1 WO2021132348 A1 WO 2021132348A1
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acid
external preparation
preparation according
total amount
respect
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PCT/JP2020/048199
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English (en)
French (fr)
Japanese (ja)
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浩行 ▲高▼部
伸行 名取
卓嗣 石丸
圭一 唐澤
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科研製薬株式会社
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Priority to KR1020227015598A priority Critical patent/KR20220119363A/ko
Priority to JP2021567544A priority patent/JP7709386B2/ja
Publication of WO2021132348A1 publication Critical patent/WO2021132348A1/ja

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    • 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
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to a preparation containing efinaconazole.
  • Efinaconazole has antifungal activity in formula (I): It is a triazole-based compound represented by. Efinaconazole is known as an active ingredient for topical tinea unguium, and is marketed under the drug names of Krenafin (registered trademark) topical solution 10% in Japan and JUBLIA (registered trademark) topical solution (10%) in the United States. There is.
  • ketoconazole a treatment for dermatomycosis, is provided as a cream and lotion (see, for example, the Nizoral® Cream 2%, Lotion 2% interview form).
  • luriconazole which is a therapeutic agent for dermatomycosis and tinea unguium
  • a cream, a liquid, and an ointment as a therapeutic agent for dermatomycosis
  • a liquid preparation is provided as a therapeutic agent for tinea unguium.
  • the medicine to be applied externally is provided in various dosage forms.
  • the problem of penetration of the active ingredient into the lesion of the nail bed must be overcome, and the triazole-based active ingredient including efinaconazole must be stored within the storage period.
  • the triazole-based active ingredient including efinaconazole must be stored within the storage period.
  • discoloration There is a problem of discoloration, and it is extremely difficult to design a formulation with excellent temporal stability of the active ingredient by overcoming these problems.
  • Patent Document 1 shows a composition for treating a nail disease containing efinaconazole, for example, efinaconazole, a non-volatile solvent (diisopropyl adipate), and an antioxidant (hydroxytoluene butylated). Formulations containing and are disclosed.
  • Patent Document 2 the combination of butylated hydroxytoluene and a salt of ethylenediaminetetraacetic acid achieves the stability of the efinaconazole preparation over time, and it is colorless or pale yellow after being stored at a temperature of at least about 40 ° C. for at least 3 weeks. Is disclosed.
  • Patent Document 3 discloses a preparation containing efinaconazole, a non-volatile solvent (medium chain fatty acid triglyceride), and a permeation accelerator (ethyl lactate) as a preparation having high nail permeability. It is required to provide various dosage forms of efinaconazole preparations including anhydrous preparations by using a time-stabilization technique which is not available in the prior art as described above.
  • An object of the present invention is a stable efina that does not substantially use a salt of ethylenediaminetetraacetic acid and does not cause discoloration that does not conform to the pharmaceutical formulation standard (Krenafin (registered trademark) topical solution for nails 10%) during the storage period.
  • a naconazole preparation As a result, it becomes possible to provide various dosage forms of efinaconazole preparations including anhydrous preparations.
  • the present inventors have diligently studied to develop an efinaconazole preparation that achieves the above-mentioned problems.
  • the activation energy for decomposition of the active ingredient is 22.1 kcal / mol (Sumie Yoshioka, drug stability). , P.142, 1995, Nanedo), and the storage at 60 ° C / 4 weeks (heat harsh test) at that time corresponds to a period of 4 years or more when converted to 25 ° C storage.
  • Krenafin (registered trademark) topical nail solution 10% an increase in related substances was observed over time in a thermal harsh test (60 ° C / 4 weeks), but it was within the standard range, and the storage period was 25 ° C / 3 years. Stable in (see Krenafin® 10% Topical Nail Solution Interview Form). From this, it can be determined whether or not the storage period of 25 ° C./3 years is guaranteed for various efinaconazole preparations by evaluating the preparations stored at 60 ° C./4 weeks. Therefore, first of all, the present inventors prepared various efinaconazole preparations and conducted a preliminary study (storage at 60 ° C./8 days).
  • the present inventors prepared various efinaconazole preparations and stored them at 60 ° C./4 weeks (heat harsh test). As a result, when a specific non-volatile ester is used, the combination of the pH adjuster and the antioxidant can prevent the efinaconazole preparation from discoloring over time, resulting in discoloration over time that deviates from the preparation standard.
  • the present invention was completed by finding that it does not occur.
  • the present invention includes the following inventions.
  • a therapeutic agent for tinea unguium a) With efinaconazole, b) One or more non-volatiles selected from mono, di, and triesters of monoalcohols or polyhydric alcohols with 1-3 carbon atoms and aliphatic monocarboxylic acids or aliphatic dicarboxylic acids with 8-18 carbon atoms. With ester c) pH regulator and d) Antioxidants and An external preparation containing, and substantially free of ethylenediaminetetraacetic acid or a salt thereof.
  • the non-volatile ester is a glycerin fatty acid ester such as medium chain fatty acid triglyceride, medium chain fatty acid diglyceride, medium chain fatty acid monoglyceride, glycerin monostearate; isopropyl palmitate, isopropyl myristate, diisopropyl sebacate, diethyl sebacate, mono.
  • the external preparation according to any one of the above [01] to the above [03], which is selected from the group consisting of propylene glycol stearate, polyethylene glycol monolaurate, propylene glycol monocaprylate, and propylene glycol dicaprylate.
  • non-volatile ester is selected from the group consisting of medium-chain fatty acid triglyceride, isopropyl myristate, diethyl sebacate, propylene glycol monocaprylate, and propylene glycol dicaprylate.
  • the external preparation according to any one.
  • the pH adjuster is an organic acid selected from the group consisting of citric acid, malic acid, lactic acid, acetic acid, oxalic acid, tartaric acid, adipic acid, maleic acid, gluconic acid, and succinic acid, or carbonic acid. Any one of the above [01] to the above [09], which is an inorganic acid selected from the group consisting of boric acid, hydrochloric acid, sulfuric acid, and phosphoric acid, or a pharmaceutically acceptable salt thereof.
  • the antioxidant is selected from the group consisting of dibutylhydroxytoluene, tocopherol, butylhydroxyanisole, propyl gallate, ascorbyl palmitate, soy lecithin, thioglycolic acid ester, benzotriazole, and 2-mercaptobenzimidazole.
  • the external preparation according to any one of the above [01] to the above [15] which is an oil-soluble antioxidant.
  • the external preparation according to any one of the above [01] to the above [15] wherein the antioxidant is selected from the group consisting of dibutylhydroxytoluene, tocopherol, butylhydroxyanisole, and propyl gallate.
  • the external preparation of efinaconazole according to the present invention is effective for any type of tinea unguium.
  • the external preparation of efinaconazole according to the present invention is preferably a topically administered preparation to be applied to the nail.
  • the external preparation of the present invention contains efinaconazole as an active ingredient, and the content thereof is preferably 8w / w% to 12w / w%, particularly preferably 10w / w%, based on the total amount of the preparation.
  • the external preparation of the present invention includes a liquid agent, a lotion agent, an ointment agent, a cream agent, and a gel agent, and is preferably a liquid agent or a gel agent, and more preferably a liquid agent.
  • the "liquid agent” in the present specification is preferably in a state in which the formulation components are dissolved in a solvent and / or in a state in which they are dissolved and mixed without separation.
  • the external preparation of efinaconazole according to the present invention is a preparation that does not cause discoloration over time during the storage period and is stable as a pharmaceutical product.
  • stable storage means discoloration that does not conform to the pharmaceutical formulation standard (Krenafin (registered trademark) topical nail solution 10%) even due to temperature rise due to changes in the environment, temperature, etc. during the storage period. It means that it does not occur.
  • the storage stability of the external preparation of efinaconazole is evaluated by storage at 60 ° C. for 4 weeks (heat harsh test).
  • the "nonvolatile ester” is a mono, di, or triester of a monoalcohol or polyhydric alcohol having 1-3 carbon atoms and an aliphatic monocarboxylic acid or an aliphatic dicarboxylic acid having 8-18 carbon atoms. Is selected from.
  • the non-volatile ester is selected from mono, di and triesters of monoalcohols or polyhydric alcohols having 1-3 carbon atoms and aliphatic monocarboxylic acids or aliphatic dicarboxylic acids having 8-14 carbon atoms. ..
  • the non-volatile ester is composed of mono, di, and triesters of a monoalcohol or polyhydric alcohol having 1-3 carbon atoms and a saturated aliphatic monocarboxylic acid or saturated aliphatic dicarboxylic acid having 8-14 carbon atoms. Be selected.
  • the non-volatile ester is added for the purpose of promoting nail permeability of efinaconazole and / or for the purpose of dissolving and mixing the active ingredient or additive in a solvent. Since the selection of the non-volatile ester is extremely important, the proper selection of the non-volatile ester of the present invention impairs the prevention of precipitation of the active ingredient and additives at the coated portion, and the usability and aesthetics after coating. Good nail permeability of the active ingredient can be expected without any problem.
  • the "monoester” refers to an ester having one ester group in one molecule
  • the "diester” refers to an ester having two ester groups in one molecule
  • “Triester” refers to an ester having three ester groups in one molecule.
  • the "monoalcohol or polyhydric alcohol having 1-3 carbon atoms” refers to mono-, di-, and trialcohols having 1-3 carbon atoms.
  • the "monoalcohol” is an organic compound having one hydroxyl group (-OH) in the molecule, and specific examples thereof include methyl alcohol, ethyl alcohol, normal propyl alcohol, isopropyl alcohol and the like.
  • the "dialcohol” is an organic compound having two hydroxyl groups (-OH) in the molecule, and specific examples thereof include ethylene glycol, propylene glycol, and 1,3-propanediol.
  • the "trialcohol” is an organic compound having three hydroxyl groups (-OH) in the molecule, and specific examples thereof include glycerin and the like.
  • the "monoester” is a combination of a monoalcohol having 1-3 carbon atoms and an aliphatic monocarboxylic acid having 8-18 carbon atoms, or a polyhydric alcohol having 1-3 carbon atoms. It can be derived from a combination of one OH group and an aliphatic monocarboxylic acid having 8-18 carbon atoms.
  • the "diester” is a combination of two monoalcohols with 1-3 carbon atoms and an aliphatic dicarboxylic acid with 8-18 carbon atoms, or a polyhydric alcohol with 1-3 carbon atoms. It can be derived from a combination of two OH groups and two aliphatic monocarboxylic acids having 8-18 carbon atoms.
  • the "triester” can be derived from a combination of glycerin (glycerol) and three aliphatic monocarboxylic acids having 8-18 carbon atoms.
  • the "aliphatic monocarboxylic acid having 8-14 carbon atoms” is a fatty acid having 8-14 carbon atoms, and specific examples thereof include caprylic acid, nonanoic acid, capric acid, lauric acid, and myristic acid. Be done.
  • the "aliphatic monocarboxylic acid having 8-18 carbon atoms” is a fatty acid having 8-18 carbon atoms, and specific examples thereof include palmitic acid in addition to the above-mentioned aliphatic monocarboxylic acid having 8-14 carbon atoms. Examples include acid and stearic acid.
  • the "aliphatic dicarboxylic acid having 8-14 carbon atoms” is an organic compound having 8-14 carbon atoms and two carboxyl groups (-COOH) in the molecule, and as a specific example, suberic acid. , Azelaic acid, sebacic acid and other aliphatic dicarboxylic acids.
  • the "aliphatic dicarboxylic acid having 8-18 carbon atoms” is an organic compound having 8-18 carbon atoms and two carboxyl groups (-COOH) in the molecule.
  • preferred monoesters are, for example, medium chain fatty acid monoglycerides, glycerin fatty acid esters such as glycerin monostearate, isopropyl palmitate, isopropyl myristate, ethyl myristate, ethyl decanoate, polyethylene glycol monolaurate. , Propylene glycol monocaprylate.
  • More preferred monoesters of the present invention include isopropyl myristate and propylene glycol monocaprylate.
  • a more preferred monoester of the present invention is isopropyl myristate.
  • preferred diesters of the present invention include medium-chain fatty acid diglycerides, propylene glycol dicaprylate, diisopropyl sebacate, diethyl sebacate and the like.
  • More preferred diesters of the present invention include medium chain fatty acid diglycerides, diethyl sebacate, and propylene glycol dicaprylate. More preferred diesters of the present invention include diethyl sebacate and propylene glycol dicaprylate. A more preferred diester of the present invention is propylene glycol dicaprylate.
  • preferred triesters of the present invention include glyceryl trioctanoate, medium chain fatty acid triglyceride and the like.
  • the preferred triester of the present invention is a medium chain fatty acid triglyceride.
  • the medium-chain fatty acid triglyceride is a non-volatile fatty acid in which three fatty acids are ester-bonded to one molecule of glycerin, and the ester-bonded fatty acid is a saturated fatty acid having 8-14 carbon atoms. ..
  • the preferred carbon number of the fatty acid is 8-12, and for example, caprylic acid, capric acid, lauric acid and the like are selected.
  • Preferred medium-chain fatty acid triglycerides are caprylic acid triglyceride, caprylic acid triglyceride, caprylic acid and caprylic acid triglyceride mixture, caprylic acid, caprylic acid and lauric acid triglyceride mixture, tri (caprylic acid / capric acid) glyceride and the like.
  • Tri (caprylic acid / capric acid) glyceride and the like can be used.
  • a particularly preferred "medium chain fatty acid triglyceride" of the present invention is a tri (caprylic acid / capric acid) glyceride.
  • the medium-chain fatty acid diglyceride is a non-volatile diester in which two fatty acids are ester-bonded to one molecule of glycerin, and the medium-chain fatty acid monoglyceride is an ester of one fatty acid in one molecule of glycerin. It is a bound non-volatile monoester.
  • the pharmaceutical product of the present invention may contain two or more types of non-volatile esters.
  • the preparation of the present invention contains two or more kinds of non-volatile esters
  • a preparation containing two or more kinds of non-volatile esters selected from the above-mentioned preferable non-volatile esters is preferable.
  • the preparation of the present invention may contain two types of monoesters, monoesters and diesters, monoesters and triesters, two types of diesters, diesters and triesters, or two types of triesters.
  • the preferred formulation of the invention comprises a monoester and a triester. In one embodiment of the invention, the preferred formulation of the invention comprises isopropyl myristate and a medium chain fatty acid triglyceride.
  • the preferable content of the non-volatile ester in the present invention is 1 w / w% to 80 w / w% with respect to the total amount of the drug, and more preferably 5 w / w% to 70 w / w% with respect to the total amount of the drug. Yes, more preferably 10 w / w% to 50 w / w% with respect to the total amount of the drug, and even more preferably 15 w / w% to 40 w / w% with respect to the total amount of the drug. , 30 w / w% with respect to the total amount of the product.
  • preferred non-volatile esters include isopropyl myristate, medium chain fatty acid triglyceride, diethyl sebacate, propylene glycol monocaprylate, and propylene glycol dicaprylate, and two or more of these may be used. it can.
  • the “pH adjuster” is a pharmaceutically acceptable pH adjuster, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid or a salt thereof, or citric acid, tartaric acid, or the like.
  • an inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid or a salt thereof, or citric acid, tartaric acid, or the like.
  • the preferred pH regulator is an organic acid.
  • Organic acid refers to the acid of an organic compound.
  • the preferred organic acid used as the pH adjuster of the present invention is an acid of an organic compound having one or more carboxyl groups (-COOH).
  • the preferred pH regulator is a hydroxy acid, or a salt thereof.
  • the hydroxy acid refers to an organic acid having a hydroxyl group and a carboxyl group, and specifically includes an aliphatic hydroxy acid such as lactic acid, malic acid, tartaric acid, and citric acid, and an aromatic hydroxy acid such as salicylic acid.
  • the preferred pH adjuster is an aliphatic hydroxy acid or a salt thereof, and more preferably a C 2- C 6 aliphatic hydroxy acid or a salt thereof.
  • C 2- C 6 aliphatic hydroxy acids refer to non-aromatic hydroxy acids having 2-6 carbon atoms, for example, glycolic acid, lactic acid, tartronic acid, glyceric acid, 2-hydroxybutyric acid, 3-. Examples thereof include hydroxybutyric acid, ⁇ -hydroxybutyric acid, malic acid, tartaric acid, citric acid, isocitrate, mevalonic acid, pantoic acid and the like.
  • more preferred pH regulators are citric acid, malic acid, lactic acid, and tartaric acid, or pharmaceutically acceptable salts thereof, and more preferred pH regulators are citric acid and.
  • a tartaric acid, or a pharmaceutically acceptable salt thereof, and an even more preferred pH regulator is citric acid.
  • citric acid when simply referred to as "citric acid", it includes anhydrous citric acid, citric acid monohydrate and the like.
  • a particularly preferred pH regulator is citric acid anhydride.
  • the pharmaceutical product of the present invention may contain two or more kinds of pH adjusters. In this case, a preparation containing two or more pH regulators selected from the above preferred pH regulators is preferable.
  • the preferable content of the pH adjuster in the present invention is 0.001 w / w% to 1.0 w / w% with respect to the total amount of the pharmaceutical product.
  • the content of the more preferable pH adjuster is 0.005 w / w% to 0.75 w / w% with respect to the total amount of the drug, and more preferably 0.01 w / w% to 0.5 w / w% with respect to the total amount of the drug. It is even more preferably 0.05 w / w% to 0.25 w / w% with respect to the total amount of the drug, and particularly preferably 0.1 w / w% with respect to the total amount of the drug.
  • the "pH regulator” is preferably citric acid, malic acid, lactic acid, tartaric acid, or pharmaceutically acceptable salts thereof.
  • the preferred pH regulator is 0.001 w / w% to 1.0 w / w% anhydrous citric acid relative to the total dosage, and the more preferred pH regulator is relative to the total dosage.
  • antioxidant refers to a pharmaceutically acceptable antioxidant, an active ingredient contained in a pharmaceutical product, and an additive for preventing oxidation / deterioration of other components. ..
  • the antioxidant of the present invention refers to a substance that acts as a free radical scavenger to capture and inactivate active oxygen species (oxygen free radicals, superoxide anions, hydroxyl radicals, hydrogen peroxide, etc.).
  • chelating agents eg, EDTA, etc.
  • Antioxidants in the present invention include water-soluble antioxidants and oil-soluble antioxidants.
  • water-soluble antioxidants include ascorbic acid, sodium metabisulfite, alpha thioglycerin, erythorbic acid, potassium dichloroisocyanurate, L-cysteine hydrochloride hydrate, sodium thiophosphate, sodium pyrosulfite and the like. ..
  • oil-soluble antioxidants examples include alphathioglycerin, erythorbic acid, dibutylhydroxytoluene (BHT), tocopherol, propyl gallate, ascorbic acid palmitate, soy lecithin, butylated hydroxyanisole (BHA) and the like.
  • BHT dibutylhydroxytoluene
  • the preferred antioxidant is an oil-soluble antioxidant.
  • more preferred antioxidants include BHT, tocopherol, propyl gallate, or BHA, and more preferred antioxidants include BHT or BHA.
  • the pharmaceutical product of the present invention may contain two or more kinds of antioxidants. In this case, a preparation containing two or more kinds of antioxidants selected from the above-mentioned preferable antioxidants is preferable.
  • the preferable content of the antioxidant is 0.001 w / w% to 1.0 w / w% with respect to the total amount of the pharmaceutical product. More preferably, it is 0.005 w / w% to 0.75 w / w% with respect to the total amount of the drug, and even more preferably 0.01 w / w% to 0.5 w / w% with respect to the total amount of the drug. Is 0.05 w / w% to 0.25 w / w% with respect to the total amount of the drug, and particularly preferably 0.1 w / w% with respect to the total amount of the drug.
  • the "antioxidant” is preferably BHT, ascorbic acid, tocopherol, propyl gallate, or BHA.
  • the preferred antioxidant is 0.001 w / w% to 1.0 w / w% BHT or BHA with respect to the total amount of the drug. More preferred antioxidants are 0.01 w / w% to 0.5 w / w% BHT or BHA with respect to the total amount of the drug, and more preferred antioxidants are 0.1 w / w% BHT or BHA.
  • the external preparation of effinaconazole of the present invention comprises effinaconazole, a monoalcohol or polyhydric alcohol having 1-3 carbon atoms, and an aliphatic monocarboxylic acid having 8-18 carbon atoms. It can be prepared by dissolving one or more non-volatile esters of an aliphatic dicarboxylic acid selected from mono, di, and triesters, a pH adjuster, and an antioxidant in a solvent.
  • the solvent that can be used is any solvent that can dissolve efinaconazole and can mix other components such as a non-volatile ester at an arbitrary ratio without dissolution and / or separation.
  • ethanol includes various grades of ethanol as long as it achieves its intended purpose, including, for example, absolute ethanol and 95% ethanol.
  • the preferred ethanol is 95% ethanol.
  • the preferred ethanol is absolute ethanol.
  • the preferred content of ethanol is 20 w / w% to 90 w / w%, more preferably 30 w / w% to 80 w / w%, even more preferably, relative to the total amount of the drug.
  • the preferred content of ethanol is 50 w / w% to 90 w / w%, more preferably 50 w / w% to 85 w / w%, based on the total amount of the drug. It is preferably 50 w / w% to 80 w / w%, and even more preferably 50 w / w% to 75 w / w%.
  • the "water-free preparation” refers to a preparation to which an aqueous solution in which water and / or other additives are dissolved is not added in the manufacturing process of the preparation.
  • the “water-added preparation” refers to a preparation to which an aqueous solution in which water or another additive is dissolved is added in the manufacturing process of the preparation.
  • the preparation of the present invention is a preparation having a water content of 0w / w% to 20w / w% with respect to the total amount of the preparation, preferably 0w / w% to 10w /. It is w%, more preferably 0w / w% to 5w / w%, and even more preferably 0w / w% to 3w / w%.
  • the pharmaceutical product of the present invention is substantially free of water.
  • the preparation of the present invention is an anhydrous preparation or a water-free preparation. In another embodiment of the present invention, the preparation of the present invention is an anhydrous preparation or a preparation having a water content of 3 w / w% or less based on the total amount of the preparation.
  • a chelating agent such as EDTA when added to a formulation, it is added to the formulation as an aqueous solution of the chelating agent in order to dissolve the chelating agent. Therefore, it is difficult to use a chelating agent such as EDTA when producing an anhydrous preparation.
  • the preparation of the present invention does not substantially contain a chelating agent such as EDTA, it can also be produced as an anhydrous preparation.
  • the external preparation of the present invention is substantially free of EDTA. In another embodiment of the present invention, the external preparation of the present invention is substantially free of a chelating agent. In another embodiment of the present invention, the pharmaceutical product of the present invention does not contain an aqueous solution in which a chelating agent is dissolved in the manufacturing process. In another embodiment of the present invention, the pharmaceutical product of the present invention is not added with an aqueous solution in which EDTA is dissolved in the manufacturing process. In another embodiment of the present invention, the pharmaceutical product of the present invention does not contain EDTA in the manufacturing process. In another embodiment of the invention, the pharmaceutical product of the present invention is substantially free of surfactant. In another embodiment of the present invention, the pharmaceutical product of the present invention does not contain a surfactant in the manufacturing process.
  • substantially free means that the target formulation component is not contained at all, or the concentration is so low that the normally required function cannot be exhibited. Therefore, for example, “substantially free of EDTA” means that EDTA is not contained at all or the concentration is so low that the chelating effect of EDTA is not sufficiently exhibited.
  • substantially free means, for example, less than 0.00025w / w% with respect to the total amount of the pharmaceutical product, preferably 0.0001w / w% or less, and more preferably 0.00001. It is w / w% or less, more preferably 0.000001 w / w% or less, and even more preferably below the detection limit.
  • the external preparation of the present invention is a non-coating-based preparation that does not substantially contain a film-forming agent.
  • the external preparation of the present invention does not contain any film-forming agent, or even if it is contained in the preparation, the concentration is so low that a film is not substantially formed on the surface of the nail after application.
  • the "coating agent” is an additive for forming an aqueous or water-insoluble film having good stability after being applied to a nail.
  • the film-forming agent include water-soluble polymers: copolyvidone, povidone, polyvinyl alcohol, and the like, water-insoluble polymers: copolymers of acrylic acid ester and methacrylic acid ester, pyroxylin, methyl methacrylic acid, and methacrylic acid. Examples thereof include butyl, dimethylaminoethyl copolymer of methacrylate, polyvinyl acetal diethylaminoacetate, nitrocellulose, hydroxypropylchitosan and the like.
  • the external preparation of the present invention is substantially free of cyclomethicone. In another embodiment of the present invention, the external preparation of the present invention is substantially free of volatile silicone.
  • an external preparation of efinaconazole containing the above-mentioned preferable pH adjuster and preferable antioxidant is preferable.
  • the preparation of the present invention preferably contains a hydroxy acid and an oil-soluble antioxidant, and more preferably contains a C 2- C 6 aliphatic hydroxy acid and an oil-soluble antioxidant.
  • an external preparation of efinaconazole containing the above-mentioned preferable non-volatile ester, preferable pH adjuster, and preferable antioxidant is preferable.
  • the preferred combination of ethanol and non-volatile ester is a combination of 10 w / w% to 50 w / w% non-volatile ester and 80 w / w% to 40 w / w% ethanol.
  • a more preferred combination is a combination of 15 w / w% to 45 w / w% non-volatile ester and 75 w / w% to 45 w / w% ethanol.
  • nonvolatile ester preferably includes isopropyl myristate, medium-chain fatty acid triglyceride, diethyl sebacate, propylene glycol monocaprylate, and propylene glycol dicaprylate, and two or more of these may be used. it can.
  • the preferred combination of pH regulator and antioxidant is 0.001 w / w% to 1.0 w / w% pH regulator and 0.001 w / w% to 1.0 relative to the total dosage.
  • a combination of a pH regulator of 0.01 w / w% to 0.5 w / w% and an antioxidant of 0.01 w / w% to 0.5 w / w% is even more preferable.
  • the "pH regulator” is preferably BHT, ascorbic acid, tocopherol, propyl gallate, or BHA
  • the "antioxidant” is preferably citric acid, malic acid, lactic acid, and tartaric acid. Or these pharmaceutically acceptable salts thereof.
  • Example 1 each additive excluding the active ingredient was mixed and dissolved, and then efinaconazole was added and dissolved to prepare a pharmaceutical product.
  • Examples 2 and Comparative Examples 1 to 3 were also produced in the same manner. The prescription details are shown in the table below.
  • Comparative Examples 1 to 3 containing no antioxidant turned slightly yellow and clear on the 4th day after the start of the test.
  • Comparative Examples 1 and 2 discoloration that did not conform to the standard was observed within 8 days after the start of the test.
  • Comparative Example 3 was slightly yellow and clear even on the 8th day after the start of the test, and at this point, it conformed to the standard, but the degree of coloring became stronger with time.
  • Examples 1 and 2 containing the pH adjuster and the antioxidant together surprisingly, no change was observed in the color tone and the object color even on the 8th day after the start of the test. It was.

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JP2016532722A (ja) * 2013-10-03 2016-10-20 ダウ ファーマシューティカル サイエンシーズ，インコーポレイティド 安定化エフィナコナゾール組成物

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JP2016532722A (ja) * 2013-10-03 2016-10-20 ダウ ファーマシューティカル サイエンシーズ，インコーポレイティド 安定化エフィナコナゾール組成物

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