WO2023121232A1 - Composition pharmaceutique de fulvestrant ayant une solubilité améliorée, et son procédé de préparation - Google Patents

Composition pharmaceutique de fulvestrant ayant une solubilité améliorée, et son procédé de préparation Download PDF

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Publication number
WO2023121232A1
WO2023121232A1 PCT/KR2022/020858 KR2022020858W WO2023121232A1 WO 2023121232 A1 WO2023121232 A1 WO 2023121232A1 KR 2022020858 W KR2022020858 W KR 2022020858W WO 2023121232 A1 WO2023121232 A1 WO 2023121232A1
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WO
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Prior art keywords
weight
pharmaceutical composition
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fulvestrant
castor oil
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PCT/KR2022/020858
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English (en)
Korean (ko)
Inventor
이재영
박상엽
원웅록
조중웅
Original Assignee
주식회사 삼양홀딩스
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Publication of WO2023121232A1 publication Critical patent/WO2023121232A1/fr

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—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
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Fulvestrant is 7-alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5-(10)-tri N-3,17beta-diol (7-alpha-[9-(4,4,5,5,5-penta fluoropentylsulphinyl) nonyl]estra-1,3,5-(10)-triene-3,17beta- diol), which has the following chemical structure:
  • the type and amount of oil, the type and ratio of organic solvent, and the type and ratio of additives are very important.
  • the characteristics of sustained release are the main factors that determine it.
  • the present invention is to solve the problem of existing fulvestrant formulations having an excessively large administration volume due to poor solubility of fulvestrant. It is to provide a fulvestrant-containing composition capable of increasing and a method for preparing the same.
  • fulvestrant as an active ingredient; nonionic surfactants that are polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, or combinations thereof; lecithin; castor oil; And C2 to C5 alcohol; it provides a pharmaceutical composition for the treatment of cancer containing.
  • Another aspect of the present invention (1) dissolving fulvestrant and lecithin in C2 to C5 alcohol; and (2) adding a polyoxyethylene castor oil derivative, a polyoxyethylene sorbitan fatty acid ester or a nonionic surfactant that is a combination thereof, and castor oil to the product of step (1). It provides a method for preparing a pharmaceutical composition for use.
  • fulvestrant as an active ingredient; nonionic surfactants that are polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, or combinations thereof; lecithin; castor oil; And C2 to C5 alcohol; it relates to a pharmaceutical composition for the treatment of cancer, including.
  • the amount of fulvestrant included in the pharmaceutical composition is, for example, 5% by weight or more, 6% by weight or more, 7% by weight or more, 8% by weight or more, based on 100% by weight of the total composition. It may be 9 wt% or more, and may also be 20 wt% or less, 18 wt% or less, 15 wt% or less, 13 wt% or less, or 11 wt% or less, but is not limited thereto.
  • the C2 to C5 alcohol may be ethanol.
  • the content of the C2 to C5 alcohol included in the pharmaceutical composition is, for example, 1% by weight or more, 3% by weight or more, 5% by weight or more, 7% by weight or more based on 100% by weight of the total composition. , 10 wt% or more or 15 wt% or more, and may also be 40 wt% or less, 35 wt% or less, 30 wt% or less, 25 wt% or less, or 20 wt% or less, but is not limited thereto.
  • the content of the C2 to C5 alcohol included in the pharmaceutical composition is, for example, 3 parts by weight or more, 5 parts by weight or more, 7 parts by weight or more, based on 100 parts by weight of the total of the other components except for fulvestrant. It may be 10 parts by weight or more, or 15 parts by weight or more, and may be 45 parts by weight or less, 40 parts by weight or less, 35 parts by weight or less, 30 parts by weight or less, or 25 parts by weight or less, but is not limited thereto.
  • the content of the nonionic surfactant included in the pharmaceutical composition is, for example, 0.05 parts by weight or more, 0.1 parts by weight or more, 0.2 parts by weight based on 100 parts by weight of the total of the other ingredients except for fulvestrant. It may be more than or 0.3 parts by weight or more, and may also be 19 parts by weight or less, 18 parts by weight or less, 17 parts by weight or less, 16 parts by weight or less, or 15 parts by weight or less, but is not limited thereto.
  • the polyoxyethylene castor oil derivative is polyoxyl castor oil (eg, cremophor EL, cremophor ELP, polyoxyl-35 castor oil, polyoxyl-40 castor oil) , Or a combination thereof) may be used, and more specifically, Cremophor EL, Cremophor ELP, polyoxyl-35 castor oil, or a combination thereof may be used, and more specifically, Cremophor EL , Cremophor ELP, or a combination thereof may be used, but is not limited thereto.
  • polyoxyl castor oil eg, cremophor EL, cremophor ELP, polyoxyl-35 castor oil, polyoxyl-40 castor oil
  • Cremophor EL, Cremophor ELP, polyoxyl-35 castor oil, or a combination thereof may be used, and more specifically, Cremophor EL , Cremophor ELP, or a combination thereof may be used, but is not limited thereto.
  • polysorbate e.g., Tween 80, Tween 60, Tween 20, etc.
  • Tween 80 may be used, Not limited to this.
  • the polyoxyethylene sorbitan fatty acid ester content in the composition is, for example, 0.01% by weight or more, 0.05% by weight based on 100% by weight of the total composition. % or more, 0.1 wt% or more, 0.2 wt% or more, 0.3 wt% or more, 0.4 wt% or more, or 0.5 wt% or more, and also 15 wt% or less, 14 wt% or less, 13 wt% or less, 12 wt% or less. , 11% by weight or less, 10% by weight or less, or 6% by weight or less, but is not limited thereto.
  • the content of the polyoxyethylene sorbitan fatty acid ester in the composition is based on 100 parts by weight of the total of the other components except for fulvestrant, for example, 0.05 parts by weight or more, 0.1 parts by weight or more, 0.2 parts by weight or more, 0.3 parts by weight or more, 0.4 parts by weight or more, or 0.5 parts by weight or more, and also 19 parts by weight or less, 17 parts by weight or less, 15 parts by weight or less, 13 parts by weight or less. parts by weight or less, 11 parts by weight or less, or 10 parts by weight or less, but is not limited thereto.
  • the content of the lecithin included in the pharmaceutical composition is, for example, 0.1% by weight or more, 0.3% by weight or more, 0.5% by weight or more, 1% by weight or more, or 1.5% by weight based on 100% by weight of the total composition. It may be greater than or equal to, and may also be 30% by weight or less, 25% by weight or less, 20% by weight or less, 15% by weight or less, or 10% by weight or less, but is not limited thereto.
  • the content of the lecithin included in the pharmaceutical composition may be, for example, 0.1 parts by weight or more, 0.2 parts by weight or more, or 0.3 parts by weight or more based on 100 parts by weight of the total of the other components except for fulvestrant. , It may also be 20 parts by weight or less, 19 parts by weight or less, 18 parts by weight or less, 17 parts by weight or less, 16 parts by weight or less, or 15 parts by weight or less, but is not limited thereto.
  • the weight ratio of the lecithin to 1 part by weight of the nonionic surfactant contained in the pharmaceutical composition may be, for example, 1 or more, 1.1 or more, 1.2 or more, or 1.3 or more, and also 5 or less, 4.9 or less, It may be 4.8 or less or 4.7 or less, but is not limited thereto.
  • the content of the castor oil (ie, castor oil) included in the pharmaceutical composition is, for example, 1% by weight or more, 10% by weight or more, 20% by weight or more, 30% by weight or more, based on 100% by weight of the total composition. It may be 95 wt% or less, 90 wt% or less, 85 wt% or less, 80 wt% or less, or 75 wt% or less, but is not limited thereto.
  • the polyethylene glycol may have, for example, a weight average molecular weight of 200 to 1,000 g/mol, but is not limited thereto.
  • polyoxyethylene alkyl or aryl ethers, sorbitan esters, or combinations thereof may be used as the additional nonionic surfactant.
  • sorbitan fatty acid esters eg, Span 20, Span 80, etc.
  • sorbitan ester may be used as the sorbitan ester, but is not limited thereto.
  • the pharmaceutical composition may further include an additional vegetable oil other than the castor oil.
  • the concentration of fulvestrant in the injection may be 90-300 mg/mL.
  • the in vitro release time using a dialysis bag of the injection may be 14 days to 60 days.
  • the pharmaceutical composition is for the treatment of cancer, more specifically for the treatment of breast cancer, and even more specifically for the treatment of advanced breast cancer.
  • step (1) may further include removing some of the C2 to C5 alcohol from the mixture of fulvestrant, lecithin, and C2 to C5 alcohol.
  • Removal of the C2 to C5 alcohol may be performed using a rotary evaporator at 30 to 80° C., but is not limited thereto.
  • PEG polyethylene glycol
  • C-EL Cremaphor EL
  • T-80 Tween 80
  • BA benzyl alcohol
  • Comparative Example A1 was prepared in the same manner as the formulation of the control drug Faslodex ® strain. From the results of Table 1, it can be seen that the saturation solubility of fulvestrant at room temperature was improved in the formulations of Examples A1 to A5 (135.8 mg/mL or more) compared to those of Comparative Examples A1 to A6 (112.2 mg/mL or less).
  • Example C1 showed an increased bioavailability compared to the control drug, with AUC 28d of 135.8% and C max of 135.4% in rats and AUC 28d of 135.2% and C max of 156.6% in rabbits.

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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)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant du fulvestrant et son procédé de préparation et, plus particulièrement, une composition pharmaceutique et son procédé de préparation, la composition pharmaceutique comprenant une combinaison d'un tensioactif non ionique spécifique, de lécithine, d'huile de ricin et d'un alcool spécifique conjointement avec du fulvestrant, un médicament ayant une faible solubilité, ce qui permet d'améliorer la solubilité du médicament et d'augmenter la concentration du médicament dans une formulation, de telle sorte que l'utilisation de la composition pharmaceutique peut réduire le nombre d'administrations du médicament tout en présentant des effets thérapeutiques pharmacologiques équivalents par rapport aux formulations de fulvestrant existantes, ce qui permet de réduire l'inconvénient des formulations existantes et d'augmenter la commodité des patients et des fournisseurs.
PCT/KR2022/020858 2021-12-20 2022-12-20 Composition pharmaceutique de fulvestrant ayant une solubilité améliorée, et son procédé de préparation WO2023121232A1 (fr)

Applications Claiming Priority (2)

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KR20210182344 2021-12-20
KR10-2021-0182344 2021-12-20

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20020073499A (ko) * 2000-01-10 2002-09-26 아스트라제네카 아베 풀베스트란트 제제
KR20080066926A (ko) * 2005-09-26 2008-07-17 호스피라 오스트레일리아 피티와이 리미티드 풀베스트란트 제형
US20160213682A1 (en) * 2013-09-06 2016-07-28 Salah Uddin Ahmed Fulvestrant compositions
KR20200085809A (ko) * 2017-11-08 2020-07-15 이글 파마슈티컬즈 인코포레이티드 풀베스트란트 제제 및 그의 사용 방법
WO2021115389A1 (fr) * 2019-12-11 2021-06-17 上海博志研新药物技术有限公司 Composition pharmaceutique de fulvestrant, procédé de préparation et application de celle-ci

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20020073499A (ko) * 2000-01-10 2002-09-26 아스트라제네카 아베 풀베스트란트 제제
KR20080066926A (ko) * 2005-09-26 2008-07-17 호스피라 오스트레일리아 피티와이 리미티드 풀베스트란트 제형
US20160213682A1 (en) * 2013-09-06 2016-07-28 Salah Uddin Ahmed Fulvestrant compositions
KR20200085809A (ko) * 2017-11-08 2020-07-15 이글 파마슈티컬즈 인코포레이티드 풀베스트란트 제제 및 그의 사용 방법
WO2021115389A1 (fr) * 2019-12-11 2021-06-17 上海博志研新药物技术有限公司 Composition pharmaceutique de fulvestrant, procédé de préparation et application de celle-ci

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