WO2021054533A2 - Composition pharmaceutique contenant de l'eficonazole stabilisée comprenant de l'acide sorbique en tant qu'acide - Google Patents

Composition pharmaceutique contenant de l'eficonazole stabilisée comprenant de l'acide sorbique en tant qu'acide Download PDF

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Publication number
WO2021054533A2
WO2021054533A2 PCT/KR2019/017069 KR2019017069W WO2021054533A2 WO 2021054533 A2 WO2021054533 A2 WO 2021054533A2 KR 2019017069 W KR2019017069 W KR 2019017069W WO 2021054533 A2 WO2021054533 A2 WO 2021054533A2
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WO
WIPO (PCT)
Prior art keywords
weight
acid
pharmaceutical composition
present
efinaconazole
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PCT/KR2019/017069
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English (en)
Korean (ko)
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WO2021054533A3 (fr
Inventor
김범준
구교탄
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주식회사 바이오빌리프
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Priority claimed from KR1020190125942A external-priority patent/KR20210032868A/ko
Application filed by 주식회사 바이오빌리프 filed Critical 주식회사 바이오빌리프
Publication of WO2021054533A2 publication Critical patent/WO2021054533A2/fr
Publication of WO2021054533A3 publication Critical patent/WO2021054533A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K9/08—Solutions
    • 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 specifically, it relates to a pharmaceutical composition for topical administration containing efinaconazole in the form of a solution containing sorbic acid as an acid.
  • 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 relates to a solution form containing efinaconazole, comprising a combination of a specific acid (i.e. sorbic acid) and a specific chelating agent (i.e. diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid or sodium salt thereof). It is an object of the present invention to provide a pharmaceutical composition for topical administration of.
  • a specific acid i.e. sorbic acid
  • a specific chelating agent i.e. diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid or sodium salt thereof.
  • efinaconazole ethanol
  • Cyclomethicone Diisopropyl adipate, C 12 -C 15 alkyl lactate, or mixtures thereof as non-volatile solvents
  • Butylated hydroxytoluene Chelating agents;
  • a pharmaceutical composition for topical administration in the form of a solution containing an acid wherein the chelating agent is diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid or a sodium salt thereof;
  • 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 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 can be usefully used as a formulation for topical administration having excellent stability.
  • the present invention is efinaconazole; ethanol; Cyclomethicone; Diisopropyl adipate, C 12 -C 15 alkyl lactate, or mixtures thereof as non-volatile solvents; Butylated hydroxytoluene; Chelating agents; And a pharmaceutical composition for topical administration in the form of a solution containing an acid, wherein the chelating agent is diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid or a sodium salt thereof; It provides a pharmaceutical composition for topical administration in the form of a solution, characterized in that the acid is sorbic acid.
  • the pharmaceutical composition of the present invention contains efinaconazole as an active ingredient.
  • Epinaconazole may be contained in therapeutically effective amounts, for example, in the range of 8 to 12% by weight, preferably in an amount of about 10% by weight based on the total weight of the composition. , But is not limited thereto.
  • the pharmaceutical composition of the present invention includes diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid (EDTA) or a sodium salt thereof 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 also comprises sorbic acid as an acid.
  • the acid ie, sorbic acid
  • the 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 contains butylated hydroxytoluene as an antioxidant.
  • 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 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; 0.01 to 2% by weight of butylated hydroxytoluene; 0.0001 to 1.5% by weight of diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid or sodium salt thereof; 0.05 to 0.25% by weight of sorbic 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 Tables 1 and 2 represents the weight% in the solution.
  • Stock solutions were prepared by dissolving diethylenetriaminepentaacetic acid (DTPA) and ethylenediaminetetraacetic acid disodium salt (EDTA disodium) in purified water at a concentration of 0.025 mg/mL, respectively.
  • DTPA diethylenetriaminepentaacetic acid
  • EDTA disodium ethylenediaminetetraacetic acid disodium salt
  • efinaconazole 0.2 g
  • antioxidants palmitic acid, linoleic acid, butylated hydroxytoluene (BHT), or Butylated hydroxyanisole (BHA)
  • BHT butylated hydroxyanisole
  • Formulation Example (% by weight) 1-1 1-2 1-3 1-4 Epinaconazole 10 10 10 10 ethanol 53.79975 53.79975 53.79975 53.79975 Cyclomethicone 13 13 13 13 Diisopropyl adipate 12 12 12 12 C 12 -C 15 alkyl lactate 10 10 10 10 EDTA disodium 0.00025 0.00025 0.00025 0.00025 Palmitic acid 0.1 Linoleic acid 0.1 BHT 0.1 BHA 0.1 Purified water One One One One Sorbic acid 0.1 0.1 0.1 0.1 0.1 Sum(%) 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
  • Formulation example EDTA disodium or DTPA / antioxidant / sorbic acid Absorbance 500 nm 600 nm 1-1 Palmitic acid 0.071 0.012 1-2 Linoleic acid 0.106 0.044 1-3 Butylated Hydroxytoluene (BHT) 0.018 0.014 1-4 Butylated Hydroxyanisole (BHA) 0.154 0.037 1-5 Palmitic acid 0.094 0.025 1-6 Linoleic acid 0.093 0.024 1-7 Butylated Hydroxytoluene (BHT) 0.018 0.007 1-8 Butylated Hydroxyanisole (BHA) 0.041 0.009 Control agent Butylated hydroxytoluene 0.022 0.017
  • Formulation example Absorbance 500 nm 600 nm 2-1 0.020 0.015 2-2 0.018 0.014 2-3 0.018 0.014 2-4 0.020 0.007 2-5 0.018 0.007 2-6 0.018 0.007 2-7 0.019 0.013 2-8 0.018 0.013 2-9 0.018 0.013 2-10 0.018 0.007 2-11 0.017 0.007 2-12 0.017 0.006 2-13 0.019 0.013 2-14 0.009 0.008 2-15 0.006 0.006 2-16 0.018 0.009 2-17 0.012 0.008 2-18 0.008 0.008 2-19 0.018 0.014 2-20 0.018 0.013 2-21 0.015 0.009 2-22 0.018 0.007 2-23 0.017 0.007 2-24 0.015 0.006 Control formulation 0.022 0.017
  • 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 1-3 1.77 0.48 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)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Communicable Diseases (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne une composition pharmaceutique pour administration topique, qui se présente sous la forme d'une solution contenant de l'eficonazole comprenant de l'acide sorbique en tant qu'acide. La composition pharmaceutique de la présente invention présente une excellente stabilité physico-chimique.
PCT/KR2019/017069 2019-09-17 2019-12-05 Composition pharmaceutique contenant de l'eficonazole stabilisée comprenant de l'acide sorbique en tant qu'acide WO2021054533A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2019-0113969 2019-09-17
KR20190113969 2019-09-17
KR10-2019-0125942 2019-10-11
KR1020190125942A KR20210032868A (ko) 2019-09-17 2019-10-11 산으로서 소르빈산을 포함하는 안정화된 에피나코나졸-함유 약학 조성물

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WO2021054533A2 true WO2021054533A2 (fr) 2021-03-25
WO2021054533A3 WO2021054533A3 (fr) 2021-05-14

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Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE602007009574D1 (de) * 2006-12-28 2010-11-11 Kaken Pharma Co Ltd Gelzusammensetzung zur behandlung von mykose
CN105683184B (zh) * 2013-10-03 2019-05-10 道尔医药科学公司 稳定的艾菲康唑组合物
US10245257B2 (en) * 2013-11-22 2019-04-02 Dow Pharmaceutical Sciences, Inc. Anti-infective methods, compositions, and devices
US20160199351A1 (en) * 2015-01-12 2016-07-14 Arno Therapeutics, Inc. Compositions and methods for inhibiting fungal infections
EP3468544A2 (fr) * 2016-06-13 2019-04-17 Vyome Therapeutics Limited Compositions antifongiques synergiques et leurs procédés

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