WO2021054532A2 - Composition pharmaceutique stabilisée contenant de l'efinaconazole comprenant un agent chélatant - Google Patents

Composition pharmaceutique stabilisée contenant de l'efinaconazole comprenant un agent chélatant Download PDF

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Publication number
WO2021054532A2
WO2021054532A2 PCT/KR2019/017063 KR2019017063W WO2021054532A2 WO 2021054532 A2 WO2021054532 A2 WO 2021054532A2 KR 2019017063 W KR2019017063 W KR 2019017063W WO 2021054532 A2 WO2021054532 A2 WO 2021054532A2
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WO
WIPO (PCT)
Prior art keywords
weight
acid
pharmaceutical composition
efinaconazole
present
Prior art date
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Ceased
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PCT/KR2019/017063
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English (en)
Korean (ko)
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WO2021054532A3 (fr
Inventor
김범준
구교탄
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Biobelief Co Ltd
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Biobelief Co Ltd
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Publication of WO2021054532A2 publication Critical patent/WO2021054532A2/fr
Publication of WO2021054532A3 publication Critical patent/WO2021054532A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/435—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
    • A61K47/06—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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino 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
    • 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 pharmaceutical composition for topical administration in the form of a solution containing efinaconazole. More particularly, it relates to efinaconazole-containing pharmaceutical compositions for topical administration in the form of a solution containing a specific chelating agent.
  • Epinaconazole is a triazole-based antifungal agent having the structure of the following formula (1), and its chemical name is (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine- 1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol[(2R,3R)-2-(2,4-difluorophenyl)-3-(4- methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol].
  • Epinaconazole has the activity of inhibiting lanosterol 14 ⁇ -demethylase in the ergosterol biosynthetic pathway, and a 10% topical solution formulation for the treatment of onychomycosis (trade names: JUBLIA TM , Kaken Pharmaceutical Co., Ltd.).
  • the topical solution formulation, together with efinaconazole, may contain ethanol as a volatile solvent; Cyclomethicone as a wetting agent; And diisopropyl adipate and C 12 -C 15 alkyl lactate as non-volatile solvents (US Pat. Nos. 7,214,506, 8,039,494, 8,486,978, 9,302,009, 9,566,272, 9,861,698, and 9,877,955, etc.).
  • Solution formulations containing efinaconazole have a problem of stability, that is, discoloration within a short storage period resulting in a composition color ranging from yellow to dark red or brown.
  • U.S. Patent No. US 9,662,394 and International Patent Publication No. WO 2015/051183 disclose specific combinations of chelating agents, antioxidants, and acids, namely ethylenediaminetetraacetic acid (EDTA) or a salt thereof, butyl.
  • EDTA ethylenediaminetetraacetic acid
  • BHT butylated hydroxytoluene
  • the present inventors have conducted various studies to develop a formulation for topical administration in the form of a solution containing efinaconazole.
  • the present inventors have studied a combination of various chelating agents, antioxidants, and acids in order to develop a formulation that can effectively improve problems such as discoloration and improve physicochemical stability by reducing the production of related substances. .
  • the present invention aims to provide a pharmaceutical composition for topical administration in the form of a solution containing efinaconazole, comprising a combination of a specific chelating agent (ie, diethylenetriaminepentaacetic acid), a specific antioxidant and citric acid. It is done.
  • a specific chelating agent ie, diethylenetriaminepentaacetic acid
  • efinaconazole ethanol
  • Cyclomethicone Diisopropyl adipate, C 12 -C 15 alkyl lactate, or mixtures thereof as non-volatile solvents
  • Chelating agents efinaconazole; ethanol; Cyclomethicone; Diisopropyl adipate, C 12 -C 15 alkyl lactate, or mixtures thereof as non-volatile solvents
  • Chelating agents e.g., efinaconazole
  • Antioxidants e.g., ethanol
  • citric acid diethylenetriaminepentaacetic acid
  • the antioxidant is selected from the group consisting of palmitic acid, chlorogenic acid, linoleic acid, butylated hydroxytoluene, and butylated hydroxyanisole.
  • the chelating agent may be present in an amount of 0.0001 to 1.5% by weight, preferably 0.0001 to 0.0025% by weight, more preferably about 0.00025% by weight, based on the total weight of the composition.
  • the antioxidant may be selected from the group consisting of palmitic acid, chlorogenic acid, and linoleic acid.
  • the antioxidant may be present in an amount of 0.01 to 2% by weight, preferably 0.1 to 1% by weight, more preferably about 0.1% by weight, based on the total weight of the composition.
  • the formulation is carried out by combining diethylenetriaminepentaacetic acid as a chelating agent with certain antioxidants (i.e., palmitic acid, chlorogenic acid, linoleic acid, butylated hydroxytoluene, and/or butylated hydroxyanisole) and citric acid.
  • certain antioxidants i.e., palmitic acid, chlorogenic acid, linoleic acid, butylated hydroxytoluene, and/or butylated hydroxyanisole
  • citric acid citric acid.
  • the present invention is efinaconazole; ethanol; Cyclomethicone; Diisopropyl adipate, C 12 -C 15 alkyl lactate, or mixtures thereof as non-volatile solvents; Chelating agents; Antioxidants; And citric acid as an acid, wherein the chelating agent is diethylenetriaminepentaacetic acid; It provides a pharmaceutical composition for topical administration in the form of a solution, wherein the antioxidant is selected from the group consisting of palmitic acid, chlorogenic acid, linoleic acid, butylated hydroxytoluene, and butylated hydroxyanisole.
  • the pharmaceutical composition of the present invention contains efinaconazole as an active ingredient.
  • Epinaconazole may be contained in therapeutically effective amounts, for example, 8 to 12% by weight, preferably about 10% by weight, based on the total weight of the composition, but It is not limited.
  • the pharmaceutical composition of the present invention includes diethylenetriaminepentaacetic acid as a chelating agent.
  • the chelating agent may be present in an amount of 0.0001 to 1.5% by weight, preferably 0.0001 to 0.0025% by weight, more preferably about 0.00025% by weight, based on the total weight of the composition.
  • the pharmaceutical composition of the present invention is an antioxidant as palmitic acid, chlorogenic acid, linoleic acid, butylated hydroxytoluene, and/or butylated hydroxyanisole. hydroxyanisole).
  • the antioxidant may preferably be palmitic acid, chlorogenic acid, and/or linoleic acid.
  • the antioxidant may be present in an amount of 0.01 to 2% by weight, preferably 0.1 to 1% by weight, more preferably about 0.1% by weight, based on the total weight of the composition.
  • the citric acid may be present in an amount of 0.05 to 0.25% by weight, preferably about 0.1% by weight, based on the total weight of the composition.
  • the pharmaceutical composition of the present invention comprises ethanol as a volatile solvent; Cyclomethicone as a wetting agent; Non-volatile solvents include diisopropyl adipate, C 12 -C 15 alkyl lactate, or mixtures thereof.
  • the volatile solvent, wetting agent, and non-volatile solvent may be used in an amount used in a conventional efinaconazole-containing solution formulation (eg, US Patent No. US 9,662,394, etc.).
  • ethanol may be present in an amount of 50 to 65% by weight, preferably about 53.79975% by weight, based on the total weight of the composition.
  • the cyclomethicone may be present in an amount of 10 to 15% by weight, preferably about 13% by weight based on the total weight of the composition.
  • diisopropyl adipate may be present in an amount of 8 to 15% by weight, preferably about 12% by weight, based on the total weight of the composition.
  • the C 12 -C 15 alkyl lactate may be present in an amount of 8 to 15% by weight, preferably about 10% by weight, based on the total weight of the composition.
  • the pharmaceutical composition of the present invention may further contain a small amount of water (for example, 5% by weight or less, preferably about 1% by weight).
  • efinaconazole 8-12% by weight of efinaconazole; Ethanol 50-65% by weight; 10 to 15% by weight of cyclomethicone; 8-15% by weight of diisopropyl adipate; 8-15% by weight of C 12 -C 15 alkyl lactate; 0.0001 to 1.5% by weight of diethylenetriaminepentaacetic acid; 0.01 to 2% by weight of an antioxidant selected from the group consisting of palmitic acid, chlorogenic acid, linoleic acid, butylated hydroxytoluene, and butylated hydroxyanisole; From 0.05 to 0.25% by weight of citric acid; And there is provided a pharmaceutical composition comprising 0 to 5% by weight of water.
  • the pharmaceutical composition of the present invention can be prepared by mixing according to a conventional method using the above ingredients. If necessary, a stock solution containing a chelating agent and a stock solution containing efinaconazole are prepared, respectively, and then appropriately mixed with other ingredients to form a solution, thereby preparing the pharmaceutical composition of the present invention.
  • a solution containing efinaconazole was prepared.
  • the content of each component in Table 1 represents the weight percent of the solution.
  • Diethylenetriaminepentaacetic acid (DTPA) was dissolved in purified water at a concentration of 0.025 mg/mL to prepare a stock solution.
  • efinaconazole (0.2 g) was dissolved in ethanol (0.076 g) to prepare an efinaconazole-containing stock solution.
  • antioxidant palmitic acid, chlorogenic acid, linoleic acid, butylated hydroxytoluene (BHT) in efinaconazole-containing ethanol solution
  • BHA butylated hydroxyanisole
  • citric acid and DTPA (added in the form of a stock solution) were sequentially added and mixed to prepare a solution containing efinaconazole.
  • diethylenetriaminepentaacetic acid was used in combination with specific antioxidants, i.e. palmitic acid, chlorogenic acid, linoleic acid, butylated hydroxytoluene (BHT), or butylated hydroxyanisole (BHA). It can be seen that the obtained solution exhibits a significantly lower absorbance value than the control formulation, and thus has excellent stability.
  • specific antioxidants i.e. palmitic acid, chlorogenic acid, linoleic acid, butylated hydroxytoluene (BHT), or butylated hydroxyanisole (BHA).
  • diethylenetriaminepentaacetic acid was used in combination with specific antioxidants, i.e. palmitic acid, chlorogenic acid, linoleic acid, butylated hydroxytoluene (BHT), or butylated hydroxyanisole (BHA). It can be seen that the obtained solution has excellent stability.
  • specific antioxidants i.e. palmitic acid, chlorogenic acid, linoleic acid, butylated hydroxytoluene (BHT), or butylated hydroxyanisole (BHA). It can be seen that the obtained solution has excellent stability.
  • HPLC high-speed liquid chromatography
  • Formulation example Total amount of related substances (%) Stored at 80°C for 3 weeks Stored at 65°C for 4 weeks 1-1 1.89 - 1-2 1.72 0.44 1-3 1.74 - 1-4 1.28 0.29 1-5 1.05 0.26 Control formulation 2.05 0.58

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Organic Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition pharmaceutique pour administration topique sous forme de solution contenant de l'efinaconazole, la composition pharmaceutique comprenant un agent chélatant spécifique. La composition pharmaceutique de la présente invention présente une excellente stabilité physique et chimique.
PCT/KR2019/017063 2019-09-17 2019-12-05 Composition pharmaceutique stabilisée contenant de l'efinaconazole comprenant un agent chélatant Ceased WO2021054532A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020190113967A KR20210032662A (ko) 2019-09-17 2019-09-17 킬레이트화제를 포함하는 안정화된 에피나코나졸-함유 약학 조성물
KR10-2019-0113967 2019-09-17

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WO2021054532A2 true WO2021054532A2 (fr) 2021-03-25
WO2021054532A3 WO2021054532A3 (fr) 2021-05-14

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PCT/KR2019/017063 Ceased WO2021054532A2 (fr) 2019-09-17 2019-12-05 Composition pharmaceutique stabilisée contenant de l'efinaconazole comprenant un agent chélatant

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WO (1) WO2021054532A2 (fr)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5372523B2 (ja) * 2006-12-28 2013-12-18 科研製薬株式会社 真菌症治療用ゲル組成物
KR102320051B1 (ko) * 2013-10-03 2021-10-29 다우 파마슈티컬 사이언시즈, 인코포레이티드 안정화된 에피나코나졸 조성물
CA3052643A1 (fr) * 2013-11-22 2015-05-28 Bausch Health Ireland Limited Procedes, compositions et dispositifs anti-infectieux
JP2018502128A (ja) * 2015-01-12 2018-01-25 アルノ セラピューティクス インコーポレイテッド 真菌感染を阻害するための組成物および方法
WO2017216722A2 (fr) * 2016-06-13 2017-12-21 Vyome Biosciences Pvt. Ltd. Compositions antifongiques synergiques et leurs procédés

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KR20210032662A (ko) 2021-03-25
WO2021054532A3 (fr) 2021-05-14

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