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WO2021054531A2 - Composition pharmaceutique contenant de l'efinaconazole stabilisé comprenant un antioxydant - Google Patents

Composition pharmaceutique contenant de l'efinaconazole stabilisé comprenant un antioxydant Download PDF

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Publication number
WO2021054531A2
WO2021054531A2 PCT/KR2019/017059 KR2019017059W WO2021054531A2 WO 2021054531 A2 WO2021054531 A2 WO 2021054531A2 KR 2019017059 W KR2019017059 W KR 2019017059W WO 2021054531 A2 WO2021054531 A2 WO 2021054531A2
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WO
WIPO (PCT)
Prior art keywords
weight
acid
pharmaceutical composition
antioxidant
efinaconazole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2019/017059
Other languages
English (en)
Korean (ko)
Other versions
WO2021054531A3 (fr
Inventor
김범준
구교탄
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biobelief Co Ltd
Original Assignee
Biobelief Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020190125926A external-priority patent/KR20210032867A/ko
Application filed by Biobelief Co Ltd filed Critical Biobelief Co Ltd
Publication of WO2021054531A2 publication Critical patent/WO2021054531A2/fr
Publication of WO2021054531A3 publication Critical patent/WO2021054531A3/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
    • 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
    • A61K47/10—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
    • A61K47/16—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
    • 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
    • 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 efinaconazole-containing pharmaceutical compositions for topical administration in the form of a solution containing a specific antioxidant.
  • 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 combinations of various chelating agents, antioxidants, and acids in order to develop a formulation that can effectively improve physicochemical stability problems such as discoloration.
  • physicochemical stability problems such as discoloration.
  • an object of the present invention is to provide a pharmaceutical composition for topical administration in the form of a solution containing efinaconazole, comprising a combination of a specific antioxidant, ethylenediaminetetraacetic acid or its sodium salt, and citric acid.
  • efinaconazole ethanol
  • Cyclomethicone Diisopropyl adipate, C 12 -C 15 alkyl lactate, or mixtures thereof as non-volatile solvents
  • Ethylenediaminetetraacetic acid or its sodium salt as a chelating agent
  • Antioxidants and a pharmaceutical composition for topical administration in the form of a solution containing citric acid as an acid, wherein the antioxidant is 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 When the formulation is carried out by combining a specific antioxidant, that is, palmitic acid, chlorogenic acid, and/or linoleic acid with ethylenediaminetetraacetic acid or its sodium salt and citric acid, an efinaconazole-containing pharmaceutical composition having excellent physicochemical stability is obtained. It has been found by the present invention. Therefore, the pharmaceutical composition of the present invention can be usefully used as a formulation for topical administration having excellent stability.
  • a specific antioxidant that is, palmitic acid, chlorogenic acid, and/or linoleic acid
  • ethylenediaminetetraacetic acid or its sodium salt and citric acid an efinaconazole-containing pharmaceutical composition having excellent physicochemical stability is obtained. It has been found by the present invention. Therefore, 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; Ethylenediaminetetraacetic acid or its sodium salt as a chelating agent; Antioxidants; And a pharmaceutical composition for topical administration in the form of a solution containing citric acid as an acid, wherein the antioxidant is selected from the group consisting of palmitic acid, chlorogenic acid, and linoleic acid.
  • the antioxidant is selected from the group consisting of palmitic acid, chlorogenic acid, and linoleic acid.
  • 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 comprises a combination of certain antioxidants and ethylenediaminetetraacetic acid or its sodium salt and citric acid.
  • the antioxidant i.e. palmitic acid, chlorogenic acid, and/or linoleic acid, is 0.01 to 2% by weight, preferably 0.1 to 1% by weight, more preferably based on the total weight of the composition. It may be present in an amount of about 0.1% by weight.
  • the chelating agent that is, ethylenediaminetetraacetic acid (EDTA) or its sodium salt and citric acid may be used in an amount sufficient to ensure stability.
  • ethylenediaminetetraacetic acid (EDTA) or its sodium salt 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.
  • 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 ethylenediaminetetraacetic acid or its sodium salt; 0.01 to 2% by weight of an antioxidant selected from the group consisting of palmitic acid, chlorogenic acid, and linoleic acid; 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 Tables 1 and 2 represents the weight% in the solution.
  • a stock solution was prepared by dissolving ethylenediaminetetraacetic acid disodium salt (EDTA disodium) in purified water at a concentration of 0.025 mg/mL.
  • EDTA disodium ethylenediaminetetraacetic acid disodium salt
  • efinaconazole 0.2 g
  • ethanol 0.076 g
  • cyclomethicone diisopropyl adipate, C 12 -C 15 alkyl lactate (Ashland), antioxidants (monothioglycerol, palmitic acid, tertiary-butylhydroquinone (TBHQ) ), chlorogenic acid, linoleic acid, N-acetyl-L-cysteine, benzotriazole, thioglycolic acid, epigallocatechin gallate, or 2-mercaptobenzimidazole), citric acid, and EDTA disodium (in stock solution form Addition) was sequentially added and mixed to prepare a solution containing efinaconazole.
  • antioxidants dioglycerol, palmitic acid, tertiary-butylhydroquinone (TBHQ)
  • chlorogenic acid linoleic acid
  • N-acetyl-L-cysteine benzotriazole
  • thioglycolic acid thiogly
  • the solutions prepared in Formulation Examples 1-1 to 1-10 were stored at 65° C. for 4 weeks, respectively, and then absorbance at 500 nm and 600 nm of the solution was measured.
  • As a control formulation JUBLIA TM (containing 10% efinaconazole-topical solution formulation, EDTA disodium, butylated hydroxytoluene (BHT), and citric acid, Kaken Pharmaceutical Co., Ltd.) was used. The results are shown in Table 3 below.
  • Formulation example EDTA disodium/antioxidant/citric acid Absorbance 500 nm 600 nm 1-1 Monothioglycerol 0.100 0.033 1-2 Palmitic acid 0.007 0.004 1-3 Tertiary-butylhydroquinone (TBHQ) 0.048 0.006 1-4 Chlorogenic acid 0.014 0.008 1-5 Linoleic acid 0.012 0.008 1-6 N-acetyl-L-cysteine 0.152 0.062 1-7 Benzotriazole 0.100 0.043 1-8 Thioglycolic acid 0.070 0.039 1-9 Epigallocatechin gallate 0.368 0.138 1-10 2-mercaptobenzimidazole 0.070 0.025 Control formulation Butylated hydroxytoluene 0.022 0.017
  • Formulation example Absorbance 500 nm 600 nm 2-1 0.010 0.005 2-2 0.007 0.003 2-3 0.007 0.003 2-4 0.015 0.008 2-5 0.015 0.009 2-6 0.013 0.009 2-7 0.011 0.008 2-8 0.010 0.006 2-9 0.007 0.004 2-10 0.007 0.005 2-11 0.015 0.010 2-12 0.013 0.008 2-13 0.013 0.008 2-14 0.012 0.008 2-15 0.010 0.006 2-16 0.007 0.004 2-17 0.006 0.004 2-18 0.014 0.009 2-19 0.013 0.008 2-20 0.012 0.008 2-21 0.011 0.007 Control formulation 0.022 0.017

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

Abstract

La présente invention concerne une composition pharmaceutique à administration topique de type solution contenant de l'efinaconazole comprenant un antioxydant spécifique. La composition pharmaceutique selon l'invention a une excellente stabilité physico-chimique.
PCT/KR2019/017059 2019-09-17 2019-12-05 Composition pharmaceutique contenant de l'efinaconazole stabilisé comprenant un antioxydant Ceased WO2021054531A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2019-0113964 2019-09-17
KR20190113964 2019-09-17
KR10-2019-0125926 2019-10-11
KR1020190125926A KR20210032867A (ko) 2019-09-17 2019-10-11 항산화제를 포함하는 안정화된 에피나코나졸-함유 약학 조성물

Publications (2)

Publication Number Publication Date
WO2021054531A2 true WO2021054531A2 (fr) 2021-03-25
WO2021054531A3 WO2021054531A3 (fr) 2021-05-14

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PCT/KR2019/017059 Ceased WO2021054531A2 (fr) 2019-09-17 2019-12-05 Composition pharmaceutique contenant de l'efinaconazole stabilisé comprenant un antioxydant

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Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2350806T3 (es) * 2006-12-28 2011-01-27 Kaken Pharmaceutical Co., Ltd. Composición de gel para el tratamiento de micosis.
KR100866979B1 (ko) * 2007-03-23 2008-11-05 재단법인서울대학교산학협력재단 이트라코나졸을 함유한 마이크로이멀젼계 하이드로겔 및이의 제조방법
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
CA2931144C (fr) * 2013-11-22 2020-02-04 Dow Pharmaceutical Sciences, Inc. Procedes, compositions et dispositifs anti-infectieux
BR112018075998A2 (pt) * 2016-06-13 2019-04-02 Vyome Therapeutics Limited. composições antifúngicas sinérgicas e métodos das mesmas

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