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WO2025142803A1 - Composition pharmaceutique pour l'administration orale d'un inhibiteur de dnmt - Google Patents

Composition pharmaceutique pour l'administration orale d'un inhibiteur de dnmt Download PDF

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Publication number
WO2025142803A1
WO2025142803A1 PCT/JP2024/045339 JP2024045339W WO2025142803A1 WO 2025142803 A1 WO2025142803 A1 WO 2025142803A1 JP 2024045339 W JP2024045339 W JP 2024045339W WO 2025142803 A1 WO2025142803 A1 WO 2025142803A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
oral pharmaceutical
composition according
parts
protective layer
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.)
Pending
Application number
PCT/JP2024/045339
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English (en)
Japanese (ja)
Inventor
俊哉 谷口
達矢 三明
崇弘 松本
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.)
Ohara Pharmaceutical Co Ltd
Original Assignee
Ohara Pharmaceutical 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
Application filed by Ohara Pharmaceutical Co Ltd filed Critical Ohara Pharmaceutical Co Ltd
Publication of WO2025142803A1 publication Critical patent/WO2025142803A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K47/14—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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present disclosure relates to an orally administered pharmaceutical composition that contains an orally administered DNMT inhibitor that has high stability against the hydrolytic metabolic enzyme cytidine deaminase and can replace 5-azacytidine or its 2'-deoxy derivative.
  • DNAMTs is an abbreviation for DNA-methyltransferases, a group of enzymes that catalyze the methylation of the amino group at position 6 of the adenine ring in DNA chains (Adenine N6-specific DNA-methyltransferase: EC 2.1.1.72), the methylation of the amino group at position 4 of the cytosine ring (Cytosine N4-specific DNA-methyltransferase: EC 2.1.1.113), or the methylation of the amino group at position 5 of the cytosine ring (Cytosine C5-specific DNA-methyltransferase: EC 2.1.1.37).
  • 5-Azacytidine and its 2'-deoxy derivative (decitabine) are known as selective enzyme inhibitors (DNA methylation inhibitors, DNA demethylating agents) against DNA methyltransferase (DNMT).
  • Vidaza (registered trademark), a subcutaneous or intravenous formulation of 5-azacytidine indicated for the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), is usually administered to adults subcutaneously or by intravenous infusion over 10 minutes at 75 mg/ m2 (body surface area) of azacitidine once a day for seven days, followed by a three-week drug holiday, which constitutes one cycle, and this cycle is repeated.
  • MDS myelodysplastic syndromes
  • AML acute myeloid leukemia
  • Dacogen registered trademark
  • an intravenous formulation of decitabine indicated for the treatment of myelodysplastic syndromes is administered as a continuous intravenous infusion of 20 mg/ m2 of decitabine once a day over at least one hour for five consecutive days, followed by a 23-day rest period, in one cycle.
  • the above drugs are administered parenterally, either subcutaneously or intravenously, so patients who require treatment with the drugs must undergo multiple treatment cycles, which requires them to visit the hospital for long periods of time.
  • compositions for oral administration such as oral combination drugs that combine decitabine with prodrugs that are metabolized to decitabine in the body after subcutaneous administration and have a pharmacological effect, or decitabine metabolic enzyme inhibitors that suppress the breakdown of decitabine when administered orally.
  • An oral pharmaceutical composition having a core particle, a protective layer and an enteric layer, characterized in that (a) the core particle contains compound I represented by the following formula (I) and an additive, (b) the protective layer contains an additive coated on the core particle, and (c) the enteric layer contains an enteric polymer coated on the protective layer.
  • the additive of the core particle is at least one selected from the group consisting of excipients and binders.
  • the binder is at least one selected from the group consisting of polyethylene glycol, glyceryl monostearate, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, sodium carmellose, pregelatinized starch, polyvinyl alcohol, and polyvinyl alcohol-acrylic acid-methacrylic acid copolymer.
  • the enteric layer further contains an excipient and a plasticizer.
  • the excipient is selected from the group consisting of talc, titanium oxide, light anhydrous silicic acid, hydrous silicon dioxide, and magnesium aluminometasilicate.
  • the plasticizer is at least one selected from the group consisting of triethyl citrate, glyceryl monostearate, triacetin, and polyethylene glycol.
  • the amount of the protective layer is 15 parts by mass or more per 100 parts by mass of the core particles.
  • the protective layer of the present disclosure is a suitable polymer intermediate layer coated on the surface of the core particle of the present disclosure (between the core particle and the enteric substrate) in order to suppress or prevent chemical decomposition of Compound I due to contact with the enteric substrate.
  • the protective layer of the present disclosure is not particularly limited as long as it has the function of suppressing chemical decomposition of Compound I contained in the core particle of the present disclosure due to contact with the enteric substrate.
  • the additive contained in the protective layer of the present disclosure is at least one selected from the group consisting of excipients and binders.
  • the stick formulation of the present disclosure can be produced by filling the granules of the present disclosure into a stick package as is common in the art.
  • Compound I (as a hemihydrate) can be prepared, for example, by the following method.
  • a white solid of compound (I) was obtained according to the method described in Japanese Patent No. 6162349. 1.71 g (5 mmol) of the white solid of compound (I) was dissolved in 15 mL of acetone by heating, and then, while heating, 180 ⁇ L (10 mmol) of purified water and 75 mL of MTBE (methyl tert-butyl ether) were added and stirred overnight at room temperature. The resulting white solid was filtered to obtain 1.07 g (63% recovery) of crystalline powder (fine columnar crystals) of compound I (1/2 hydrate). The HPLC purity of the obtained crystalline powder was >99%.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente divulgation concerne une composition pharmaceutique pour l'administration orale comprenant des particules de noyau, une couche de protection et une couche entérique, la composition pharmaceutique étant caractérisée en ce que : (a) les particules de noyau comprennent chacune le composé I et un additif ; (b) la couche de protection comprend un additif revêtu sur les particules de noyau ; et (c) la couche entérique comprend un polymère entérique revêtu sur la couche de protection.
PCT/JP2024/045339 2023-12-25 2024-12-23 Composition pharmaceutique pour l'administration orale d'un inhibiteur de dnmt Pending WO2025142803A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2023217735 2023-12-25
JP2023-217735 2023-12-25

Publications (1)

Publication Number Publication Date
WO2025142803A1 true WO2025142803A1 (fr) 2025-07-03

Family

ID=96217803

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2024/045339 Pending WO2025142803A1 (fr) 2023-12-25 2024-12-23 Composition pharmaceutique pour l'administration orale d'un inhibiteur de dnmt

Country Status (1)

Country Link
WO (1) WO2025142803A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04346930A (ja) * 1991-05-25 1992-12-02 Sumitomo Pharmaceut Co Ltd 安定なアスピリン腸溶錠
JP2001524131A (ja) * 1997-05-09 2001-11-27 セイジ、ファーマスーティカルズ、インク 安定な経口医薬品剤形
JP2004035535A (ja) * 2002-07-03 2004-02-05 Yung Shin Pharm Ind Co Ltd 非ステロイド系抗炎症薬剤を含む経口医薬組成物及びその製造方法
JP6162349B1 (ja) * 2016-04-21 2017-07-12 大原薬品工業株式会社 ５−アザシチジン類の糖部シリルエーテル誘導体
JP2020152707A (ja) * 2019-03-22 2020-09-24 キョーリンリメディオ株式会社 安定化されたエソメプラゾールマグネシウム水和物含有腸溶性固形製剤
WO2021060341A1 (fr) * 2019-09-26 2021-04-01 大原薬品工業株式会社 Utilisation d'un inhibiteur de dnmt
WO2023163988A1 (fr) * 2022-02-22 2023-08-31 Otsuka Pharmaceutical Co., Ltd. Formulation combinée de cédazuridine

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04346930A (ja) * 1991-05-25 1992-12-02 Sumitomo Pharmaceut Co Ltd 安定なアスピリン腸溶錠
JP2001524131A (ja) * 1997-05-09 2001-11-27 セイジ、ファーマスーティカルズ、インク 安定な経口医薬品剤形
JP2004035535A (ja) * 2002-07-03 2004-02-05 Yung Shin Pharm Ind Co Ltd 非ステロイド系抗炎症薬剤を含む経口医薬組成物及びその製造方法
JP6162349B1 (ja) * 2016-04-21 2017-07-12 大原薬品工業株式会社 ５−アザシチジン類の糖部シリルエーテル誘導体
JP2020152707A (ja) * 2019-03-22 2020-09-24 キョーリンリメディオ株式会社 安定化されたエソメプラゾールマグネシウム水和物含有腸溶性固形製剤
WO2021060341A1 (fr) * 2019-09-26 2021-04-01 大原薬品工業株式会社 Utilisation d'un inhibiteur de dnmt
WO2023163988A1 (fr) * 2022-02-22 2023-08-31 Otsuka Pharmaceutical Co., Ltd. Formulation combinée de cédazuridine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
URESHINO HIROSHI, KURAHASHI YUKI, WATANABE TATSURO, YAMASHITA SATOSHI, KAMACHI KAZUHARU, YAMAMOTO YUTA, FUKUDA-KURAHASHI YUKI, YOS: "Silylation of Deoxynucleotide Analog Yields an Orally Available Drug with Antileukemia Effects", MOLECULAR CANCER THERAPEUTICS, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 20, no. 8, 1 August 2021 (2021-08-01), US , pages 1412 - 1421, XP093331413, ISSN: 1535-7163, DOI: 10.1158/1535-7163.MCT-20-1125 *

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