WO2023093640A1 - 一种达罗他胺药物组合物及其制备方法和用途 - Google Patents

一种达罗他胺药物组合物及其制备方法和用途 Download PDF

Info

Publication number
WO2023093640A1
WO2023093640A1 PCT/CN2022/132894 CN2022132894W WO2023093640A1 WO 2023093640 A1 WO2023093640 A1 WO 2023093640A1 CN 2022132894 W CN2022132894 W CN 2022132894W WO 2023093640 A1 WO2023093640 A1 WO 2023093640A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
darolutamide
compositions
preparation
composition
Prior art date
Application number
PCT/CN2022/132894
Other languages
English (en)
French (fr)
Inventor
钱晓明
施瑜
李坤
万建胜
盛小茜
Original Assignee
上海宣泰医药科技股份有限公司
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 上海宣泰医药科技股份有限公司 filed Critical 上海宣泰医药科技股份有限公司
Publication of WO2023093640A1 publication Critical patent/WO2023093640A1/zh

Links

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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/06—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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • 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
    • A61K47/38—Cellulose; Derivatives 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
    • A61K47/30—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
    • A61K47/40—Cyclodextrins; Derivatives 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
    • A61K47/44—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
    • 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
    • A61K9/14—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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to a darolutamide pharmaceutical composition, a preparation method and application thereof.
  • Darolutamide N-[(1S)-2-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]-1-methylethyl base]-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide, the chemical structure of which is shown below.
  • Darolutamide is an oral non-steroidal androgen receptor (AR) inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC).
  • AR oral non-steroidal androgen receptor
  • Bayer was approved by the US Food and Drug Administration (FDA).
  • FDA US Food and Drug Administration
  • phase III clinical trial of darolutamide showed that compared with placebo combined with androgen deprivation therapy (androgen deprivation therapy (ADT), darolutamide combined with ADT significantly prolonged the median metastasis-free survival (MFS) (18.4 months vs 40.4 months), and was able to reduce the risk of disease transfer or death by 59%, and also had a good safety profile.
  • MFS median metastasis-free survival
  • Darolutamide is a drug with low solubility and high permeability (BCS class II), which is basically insoluble (14-23 ⁇ g/mL) in aqueous media at pH 1-6.8.
  • BCS class II high permeability
  • darolutamide has a median Tmax of 3-6 hours, indicating slow absorption.
  • the terminal half-life of darolutamide is 10-15 hours.
  • the Cmax and AUC (0-t) of the 600mg dose were higher than 300mg under fasted and fed conditions.
  • CV%) of AUC (0-t) the administered dose of 300 mg (69.6%) was higher than that of 600 mg (41.4%).
  • the bioavailability of 300 mg of darolutamide administered in the fasted state is about 30%.
  • the bioavailability of a single dose of 300 mg or 600 mg of darolutamide increased by 2.5 times and 2.8 times, respectively.
  • the AUC (0-t) of darolutamide administered at 300 mg or 600 mg increased 2.5-fold in the fed state. It can be seen that darolutamide has obvious food effect.
  • WO2019032840A1 discloses a pharmaceutical composition comprising abiraterone acetate and darolutamide, the pharmaceutical composition further comprising polyvinylpyrrolidone or vinylpyrrolidone/vinyl acetate copolymer as the first pharmaceutical excipient, and comprising sodium lauryl sulfate As the second pharmaceutical excipient.
  • the inventors claim that the pharmaceutical composition has increased in vitro permeability in the fasted and fed state, thereby enabling lower drug doses and avoiding the restriction of fasting consumption. But the inventor does not prove above-mentioned technical effect by embodiment.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the active ingredient darolutamide or a pharmaceutically acceptable salt thereof, a carrier material, and a formulation modifier, wherein the formulation modifier is one or more selected from the following Species: Sodium Lauryl Sulfate, Tocopheryl Polyethylene Glycol Succinate, Poloxamer, Polyoxyethylene Hydrogenated Castor Oil, Stearyl Alcohol, Dibutyl Sebacate, Triethyl Citrate, Citric Acid Butyl citrate, glycerin, polyethylene glycol, lecithin, sodium dioctyl sulfosuccinate, sodium taurocholate, polysorbate, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene Ethylene castor oil; the carrier material is one or more selected from the following: hypromellose phthalate, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl a
  • the weight ratio of the active ingredient darolutamide or a pharmaceutically acceptable salt thereof to the carrier material is about 1:0.5-1:8.
  • the weight ratio of the active ingredient darolutamide or a pharmaceutically acceptable salt thereof to the formulation modifier is about 1:0.05-1:0.8.
  • the present invention relates to a solid formulation comprising the pharmaceutical composition of the present invention.
  • the present invention relates to a method for preparing the pharmaceutical composition of the present invention, which comprises the following steps: (1) weighing each component; (2) mixing the components of step (1) and performing hot-melt extrusion, to obtain a pharmaceutical composition.
  • the present invention relates to a method for preparing the solid preparation of the present invention, which comprises the following steps: (1) preparing a pharmaceutical composition according to the above method; (2) pulverizing the pharmaceutical composition in step (1) to obtain a pharmaceutical composition Granules; (3) mixing the pharmaceutical composition granules in step (2) with lubricants and other formulation modifiers to obtain blended granules; (4) compressing the blended granules in step (3) to obtain solid preparations.
  • the present invention relates to the use of the pharmaceutical composition and solid preparation of the present invention in the preparation of a medicament for treating or preventing prostate cancer.
  • measurement ratio refers to the proportioning of various substances according to a certain weight.
  • the active ingredient, the filler, the binder, and the lubricant are proportioned according to a specified weight ratio.
  • selected from refers to one or more elements of the group listed thereafter, independently selected, and may include a combination of two or more elements.
  • one or more or “at least one” means one, two, three, four, five, six, seven, eight, nine or more.
  • the term "optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that description includes that said event or circumstance occurs and that it does not.
  • pharmaceutically acceptable means that within the scope of normal medical judgment, there will be no undue toxicity, irritation, allergic reaction, etc. in contact with the tissue of the patient, and it has a reasonable benefit-contrast ratio and can be effectively used for the intended purpose.
  • pharmaceutically acceptable excipients refers to those carrier substances that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound.
  • “Pharmaceutically acceptable excipients” include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, Stabilizer, solvent or emulsifier.
  • Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oil, polyethylene glycol, and the like. Additional information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • pharmaceutical active ingredient refers to a chemical entity that is effective in the treatment or prevention of the disease or condition of interest.
  • the term "effective amount”, “therapeutically effective amount” or “prophylactically effective amount” refers to a sufficient amount of the drug or agent that has acceptable side effects but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • tablette refers to a solid pharmaceutical dosage form comprising the active ingredient, optionally with suitable excipients, such as diluents, binders, etc., and prepared by compression or shaping techniques.
  • suitable excipients such as diluents, binders, etc.
  • examples of tablets are, for example, compressed tablets, multiparticulate tablets, multi-compressed tablets, coated tablets, matrix tablets, osmotic pump tablets, caplets and the like.
  • bulk density means the mass of a given quantity of granular product divided by the total volume occupied by said quantity.
  • angle of repose refers to the maximum angle formed by the free slope formed by powder accumulation and the horizontal plane. The smaller the angle of repose, the smaller the friction and the better the fluidity.
  • dissolution rate refers to the speed and degree of dissolution of a drug from a solid preparation in a specified solvent.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the active ingredient darolutamide or a pharmaceutically acceptable salt thereof, a carrier material and a formulation modifier.
  • the active ingredient is darolutamide or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the active ingredient is darolutamide.
  • Carrier material means a material, usually in particulate form, which is used to carry an active ingredient, wherein the active ingredient is substantially distributed in the carrier material.
  • the carrier material is one or more selected from the following: hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose (Hydroxypropylmethylcellulose , HPMC), polyvinyl alcohol (Polyvinyl alcohol, PVA), polyvinyl pyrrolidone (Polyvinyl pyrrolidone, PVP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyvinyl caprolactam-polyvinyl acetate-polyethylene Ethylene glycol graft copolymers (such as ), Eudragit (e.g.
  • the carrier material is one or more selected from the following: hypromellose phthalate, hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl acetate Methylcellulose succinate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, Eudragit. Suitable carrier materials help to increase the solubility of the pharmaceutical composition.
  • carrier materials that can be used include, but are not limited to, commercially available products from Shin-Etsu Corporation (HPMCAS), a commercially available product of BASF and The commercially available product PVP K30 of Ashland Company.
  • the formulation modifier is one or more selected from the group consisting of sodium lauryl sulfate, polyethylene glycol succinate, poloxamer, polyoxyethylene hydrogenated castor oil , stearyl alcohol, dibutyl sebacate, triethyl citrate, butyl citrate, glycerin, polyethylene glycol, lecithin, sodium dioctyl sulfosuccinate, sodium taurocholate, Polysorbate, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene castor oil.
  • the formulation improving agent is one or more selected from the following: sodium lauryl sulfate, vitamin E polyethylene glycol succinate triethyl citrate.
  • the preparation improver that can be used includes but is not limited to the commercially available product VE TPGS1000 of PMC Isochem Company, the commercially available product of BASF Company TEC is a commercially available product from Merck KGaA.
  • the formulation modifier used in the present invention can achieve unexpected technical effects, such as further improving the solubility of the pharmaceutical composition, thereby improving the bioavailability of the drug, improving the stability of the drug, making the pharmaceutical composition It is easy to prepare, thereby saving energy consumption in production.
  • the carrier material is not polyvinylpyrrolidone and/or polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol. Ethylene glycol graft copolymer and/or hydroxypropyl cellulose.
  • the carrier material is not polyvinylpyrrolidone and/or polyvinylcaprolactam-polyvinyl acetate Ester-polyethylene glycol graft copolymer and/or hydroxypropyl cellulose.
  • the carrier material is not polyvinylpyrrolidone and/or polyvinylcaprolactam-polyvinyl acetate- Polyethylene glycol graft copolymer and/or hydroxypropyl cellulose.
  • the carrier is not polyvinylpyrrolidone and/or polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and/or hydroxypropyl cellulose.
  • the carrier material is not polyvinylpyrrolidone and/or Or polyethylene caprolactam-partial vinyl acetate-polyethylene glycol graft copolymer and/or hydroxypropyl cellulose.
  • the carrier material is not polyvinylpyrrolidone, not polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol Ethylene glycol graft copolymer, nor hydroxypropyl cellulose, or a combination of two or three of the above.
  • the preparation modifier is one or more selected from the following: sodium lauryl sulfate, vitamin E polyethylene glycol succinate, Dibutyl sebacate, triethyl citrate, butyl citrate, glycerin, polyethylene glycol;
  • the carrier material is one or more selected from the following: hypromellose phthalate Formate, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropylmethylcellulose acetate succinate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer , Eudragit, copovidone, methylcellulose, ethylcellulose, sodium carboxymethylcellulose; wherein when the formulation modifier is sodium lauryl sulfate or polyethylene glycol, the carrier The material is not polyvinylpyrrolidone and/or polyvinylcaprolactam-polyvinyl acetate-
  • the formulation modifier is one or more selected from the following: sodium lauryl sulfate, vitamin E polyethylene glycol succinate , triethyl citrate;
  • the carrier material is one or more selected from the following: hypromellose phthalate, hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl acetate Methylcellulose succinate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, Eudragit; wherein when the formulation improving agent is sodium lauryl sulfate, the The carrier material is not polyvinylpyrrolidone and/or polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers.
  • the formulation modifier in the pharmaceutical composition of the present invention, is vitamin E polyethylene glycol succinate, and the carrier material is hydroxypropylmethylcellulose acetate succinate.
  • the formulation modifier in the pharmaceutical composition of the present invention, is polyvinylpyrrolidone, and the carrier material is hydroxypropylmethylcellulose acetate succinate.
  • the formulation modifier in the pharmaceutical composition of the present invention, is vitamin E polyethylene glycol succinate, and the carrier material is hydroxypropylmethylcellulose acetate succinate and polyethylene glycol succinate. Vinylpyrrolidone.
  • the formulation modifier in the pharmaceutical composition of the present invention, is triethyl citrate, and the carrier material is Eudragit.
  • the pharmaceutical composition of the present invention may further comprise pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the present invention may further comprise one or more selected from the following: buffering agent, acidifying agent, stabilizer, preservative.
  • Buffer refers to a pharmaceutical excipient that stabilizes the pH of a pharmaceutical formulation.
  • the buffer is one or more selected from the following: citric acid buffer, malate buffer, maleate buffer, tartrate buffer.
  • Acidulant refers to an acid mainly used as an excipient in the preparation of a drug, which is used to adjust the pH of the drug, and which only provides acidity when used, and generally does not introduce special biological activity.
  • the acidulant is one or more selected from the following: tartaric acid, carbonic acid, acetic acid, oxalic acid, nitrous acid.
  • Stabilizers refer to specific chemical substances that interact with active ingredients in pharmaceutical compositions and/or general pharmaceutical excipients to increase their stability.
  • the stabilizer is one or more selected from the following: methionine, lysine, histidine.
  • Preservatives are compounds added to pharmaceutical compositions to prevent or delay the activity (growth and metabolism) of microorganisms.
  • the preservative is one or more selected from the group consisting of benzyl alcohol, benzyl benzoate, methylparaben, propylparaben, vitamin E, vitamin A palmitate ester.
  • the weight ratio of the active ingredient darolutamide or a pharmaceutically acceptable salt thereof to the carrier material is about 1:0.5-1:8. In a preferred embodiment, the weight ratio of the active ingredient darolutamide or a pharmaceutically acceptable salt thereof to the carrier material is about 1:1-1:4. In a more preferred embodiment, the weight ratio of the active ingredient darolutamide or a pharmaceutically acceptable salt thereof to the carrier material is about 1:2-1:4. For example about 1:0.5, about 1:0.8, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8 , and a range consisting of any two of these proportions (values).
  • a suitable weight ratio of active ingredient to carrier material is beneficial to obtain suitable solubility and dissolution rates. Too high a weight ratio of the active ingredient to the carrier material cannot effectively improve the solubility of the active ingredient; too low a weight ratio of the active ingredient to the carrier material will not improve the solubility of the active ingredient more effectively, and will make the solid preparation The viscosity is too high, making its preparation difficult.
  • the weight ratio of the active ingredient darolutamide or a pharmaceutically acceptable salt thereof to the formulation modifier is about 1:0.05-1:0.8. In a preferred embodiment, the weight ratio of the active ingredient darolutamide or a pharmaceutically acceptable salt thereof to the formulation modifier is about 1:0.1-1:0.5. For example about 1:0.05, about 1:0.1, about 1:0.15, about 1:0.2, about 1:0.25, about 1:0.3, about 1:0.35, about 1:0.4, about 1:0.45, about 1:0.5 , and a range consisting of any two of these ratios (values).
  • the proper weight ratio of the active ingredient to the formulation modifier is beneficial to obtaining proper solubility, solubility and stability, and the obtained medicine is easy to store and be absorbed by the human body. Excessively high weight ratios of active ingredients and formulation modifiers cannot effectively improve the solubility of the active ingredients; too low weight ratios of active ingredients and formulation modifiers will not improve the solubility of the active ingredients more effectively, but lead to inability to preparation.
  • the bulk density is the bulk density, which refers to dividing the mass of the pharmaceutical composition particles of the present invention by the volume they occupy. Appropriate bulk density is conducive to the preparation of drug combinations and their formulations, which in turn facilitates obtaining products with appropriate solubility and dissolution.
  • the pharmaceutical composition has a bulk density of about 0.40-0.50 g/mL. In a preferred embodiment, the pharmaceutical composition has a bulk density of about 0.42-0.49 g/mL. In a more preferred embodiment, the pharmaceutical composition has a bulk density of about 0.436-0.473 g/mL.
  • the angle of repose refers to the maximum angle formed by the free slope formed by the particles of the pharmaceutical composition of the present invention and the horizontal plane. Wherein, the smaller the angle of repose, the smaller the friction between the particles of the pharmaceutical composition of the present invention, that is, the better the fluidity of the particles of the pharmaceutical composition.
  • a suitable angle of repose of the particles of the pharmaceutical composition is beneficial to the preparation of the preparation product, which in turn is beneficial to obtaining a preparation product with suitable solubility and dissolution rate.
  • the pharmaceutical composition has an angle of repose of about 20-32°. In a preferred embodiment, the pharmaceutical composition has an angle of repose of about 21-30°. In a more preferred embodiment, the pharmaceutical composition has an angle of repose of about 22-28°. For example, about 20°, about 21°, about 22°, about 23°, about 24°, about 25°, about 26°, about 27°, about 28°, about 29°, about 30°, about 31°, about 32°.
  • the present invention relates to a solid formulation comprising the pharmaceutical composition of the present invention.
  • the present invention relates to a method for preparing the pharmaceutical composition of the present invention, comprising the steps of:
  • step (2) mixing the components of step (1) and performing hot-melt extrusion to obtain a pharmaceutical composition.
  • active ingredients are as defined above.
  • each component of the pharmaceutical composition is weighed according to a specific metering ratio (eg, weight ratio).
  • a specific metering ratio eg, weight ratio
  • each component of the pharmaceutical composition can be weighed according to the weight ratio in the following examples.
  • the hot-melt extrusion in step (2) is carried out by methods and instruments commonly used in the art.
  • Leistritz ZSE 12HP-PH-40D can be used for hot-melt extrusion of the components in step (1).
  • the temperature of the hot melt extrusion in step (2) is about 160 ⁇ 20°C.
  • the present invention also relates to the preparation method of solid preparation: it comprises the following steps:
  • step (1) (2) pulverizing the pharmaceutical composition in step (1) to obtain pharmaceutical composition granules
  • step (3) mixing the pharmaceutical composition granules in step (2) with lubricants and other formulation modifiers to obtain blended granules;
  • step (3) Compressing the blended granules of step (3) to obtain a solid preparation.
  • step (2) is carried out by methods commonly used in the art. For example, blade milling and roller milling can be used.
  • the mixing in step (3) can be carried out by methods commonly used in the art. For example, V-type mixing and hopper mixing can be used.
  • the pressing in step (4) can be carried out using methods commonly used in the art. For example, hydraulic pressing, mechanical pressing, pneumatic pressing, and the like can be used.
  • the equipment that can be used can be, for example, the ZP14 tablet press of Sinopharm Longli.
  • preparing the solid preparation of the present invention further comprises the following steps:
  • Step (5) Coating the solid preparation in step (4) to obtain a tablet.
  • the coating in step (5) can be performed using methods commonly used in the art. For example, an Ohara coater or the like can be used.
  • the present invention also relates to a method for preventing and treating prostate cancer, the method comprising administering a therapeutically effective amount of the pharmaceutical composition or solid preparation of the present invention to an individual in need.
  • the pharmaceutical composition or solid preparation of the present invention can be used for preventing and treating prostate cancer.
  • the present invention also relates to the application of the pharmaceutical composition or solid preparation of the present invention in the preparation of medicaments for preventing and treating prostate cancer.
  • the darolutamide pharmaceutical composition of the present invention can further improve the solubility of the active ingredient, thereby obtaining a pharmaceutical composition with excellent solubility, and effectively improving the composition the bioavailability of the substance. Therefore, the darolutamide pharmaceutical composition of the present invention can be administered at a low dose, and the food effect can be reduced.
  • the darolutamide pharmaceutical composition of the present invention also has excellent stability, is suitable for storage at room temperature, and reduces the requirements for storage and transportation.
  • the darolutamide pharmaceutical composition of the present invention has a suitable bulk density and angle of repose, which proves that it has good fluidity, so it is easy to make tablets and other forms, and is suitable for scale-up and industrial production.
  • the pharmaceutical composition of darolutamide of the present invention has significantly improved solubility, solubility and stability; and the obtained pharmaceutical composition particles have The improved bulk density and angle of repose make it easier to perform operations such as pressing to prepare solid preparations, thereby effectively reducing production energy consumption.
  • Darolutamide purchased from Shanghai Pengju Biotechnology Co., Ltd.;
  • PVP purchased from BASF Corporation
  • HPMACAS purchased from Shin-Etsu Corporation,
  • HPMCP purchased from Shin-Etsu Company, hypromellose phthalate
  • Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer purchased from BASF company,
  • VE TPGS purchased from PMC Isochem, VE TPGS1000;
  • TEC purchased from Merck KGaA Company, TEC.
  • Dissolution method USP II method (paddle method) Dissolution medium Phosphate buffered saline at pH 6.8 Medium volume 1000ml Rotating speed 75rpm temperature 37°C ⁇ 5°C
  • Dissolution sample analysis filter the solution obtained in the dissolution test with a 0.45 ⁇ m filter membrane, collect the filtrate, and measure it by high performance liquid chromatography at a wavelength of 260 nm.
  • Content testing method dissolve the sample to be tested in methanol so that the concentration of darolutamide is 100 ⁇ g/ml, and use high-performance liquid chromatography for determination, and the measurement wavelength is 286 nm.
  • Test method for related substances dissolve the sample to be tested in methanol so that the concentration of darolutamide is 150 ⁇ g/ml, and use high-performance liquid chromatography for determination, and the determination wavelength is 286 nm.
  • the specific preparation method is as follows:
  • the active ingredient and the carrier material were mixed according to the weight ratio of Table 1 to obtain a blend.
  • the blend was fed into a Leistritz ZSE 12HP-PH-40D hot-melt extruder at a constant rate, and hot-melt extrusion was performed at a temperature of 160 ⁇ 20°C.
  • the extrudates were collected and crushed using a FitzMill L1A pulverizer, and the crushed extrudates were sieved to 80 mesh.
  • Darolutamide pharmaceutical compositions 1-1 to 1-15 and blends of active ingredients and carrier materials 1-1 to 1-15 were respectively obtained according to the methods described above.
  • Embodiment 2 Preparation of darolutamide pharmaceutical composition of the present invention
  • the specific preparation method is as follows:
  • the active ingredient, carrier material and formulation modifier were mixed according to the weight ratio of Table 2 to obtain a blend.
  • the blend was fed into a Leistritz ZSE 12HP-PH-40D hot-melt extruder at a constant rate, and hot-melt extrusion was performed at a temperature of 160 ⁇ 20°C.
  • the extrudates were collected and crushed using a FitzMill L1A pulverizer, and the crushed extrudates were sieved to 80 mesh.
  • Darolutamide pharmaceutical compositions 2-1 to 2-9 and blends 2-1 to 2-9 of active ingredients, carrier materials and formulation modifiers were respectively obtained according to the above methods.
  • combination active ingredient carrier material Formulation Improver mass ratio Composition 2-1 darolutamide HPMCAS TPGS 1:2:0.2 Composition 2-2 darolutamide HPMCAS TPGS 1:4:0.5 Composition 2-3 darolutamide VA64+HPMCAS / 1:0.5:1.5 Composition 2-4 darolutamide VA64+HPMCAS TPGS 1:0.5:1.5:0.2 Compositions 2-5 darolutamide HPMCP-HP55 TPGS 1:3:0.1 Compositions 2-6 darolutamide Eudragit L100 TEC 1:2:0.15 Compositions 2-7 darolutamide Soluplus SLS 1:3:0.1 Compositions 2-8 darolutamide PVP K30 SLS 1:4:0.5 Compositions 2-9 darolutamide VA64 SLS 1:4:0.5
  • Darolutamide tablets were prepared according to the specific composition and weight ratio in Table 3.
  • Darolutamide tablets are administered as follows:
  • step (1) Prepare the darolutamide pharmaceutical composition according to the methods of Examples 1 and 2 respectively; (2) Mix the pharmaceutical composition in step (1) with a filler, a disintegrant and a lubricant to obtain total mixed granules (3) compressing the blended granules of step (2) by a ZP14 tablet press to obtain darolutamide tablets.
  • Embodiment 4 pharmaceutical composition crystal form determination
  • the determination of the crystal form of the pharmaceutical composition includes polycrystalline powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC), respectively by Bruker D8 advance instrument (scanning range: 3°-40°) and TA Instruments DSC2000 instrument ( Scanning range: 30°C-250°C) for measurement.
  • PXRD polycrystalline powder X-ray diffraction
  • DSC differential scanning calorimetry
  • combination crystal form combination crystal form Composition 1-1 partially amorphous Compositions 1-13 not finalized Composition 1-2 not finalized Compositions 1-14 not finalized Compositions 1-3 not finalized Compositions 1-15 not finalized Compositions 1-4 partially amorphous Composition 2-1 not finalized Compositions 1-5 not finalized Composition 2-2 not finalized Compositions 1-6 not finalized Composition 2-3 not finalized Compositions 1-7 not finalized Composition 2-4 not finalized Compositions 1-8 not finalized Compositions 2-5 not finalized Compositions 1-9 not finalized Compositions 2-6 not finalized Compositions 1-10 partially amorphous Compositions 2-7 not finalized Compositions 1-11 not finalized Compositions 2-8 not finalized Compositions 1-12 not finalized Compositions 2-9 not finalized
  • the pharmaceutical composition prepared from the active ingredient darolutamide and the carrier material can form amorphous granules and improve the solubility of darolutamide.
  • the granules of the above-mentioned pharmaceutical composition are easy to be made into medicines, and are convenient to be further prepared into solid preparations, and are suitable for large-scale enlargement and industrial production.
  • compositions/Blends Solubility of pharmaceutical composition ( ⁇ g/ml) Solubility of corresponding blends ( ⁇ g/ml) Composition 1-1 107.2 23.9 Composition 1-2 260.9 24.6 Compositions 1-3 328.5 26.3 Compositions 1-4 142.7 23.4 Compositions 1-5 488.9 24.1 Compositions 1-6 405.6 25.3 Compositions 1-7 421.6 24.9 Compositions 1-8 438.1 23.5 Compositions 1-9 406.2 23.1 Compositions 1-10 369.2 24.6 Compositions 1-11 307.5 24.7 Compositions 1-12 470.5 23.2 Compositions 1-13 490.8 25.9 Compositions 1-14 321.6 24.7 Compositions 1-15 394.2 26.8 Composition 2-1 499.6 26.2 Composition 2-2 462.3 28.1 Composition 2-3 431.2 24.3 Composition 2-4 479.1 25.3 Compositions 2-5 427.2 24.1 Compositions 2-6 538.2 24.8 Compositions 2-7 395.3 28.7 Compositions 2-8 416.5 33.5 Compositions 2-9
  • the pharmaceutical composition of darolutamide obtained by combining the active ingredient darolutamide with the carrier material has significantly improved solubility.
  • the solubility of the darolutamide composition is significantly higher, ranging from 107.2 to 490.8 ⁇ g/ml.
  • compositions 1-1 to 1-15 further adding preparation modifiers, such as TPGS, SLS or TEC, to the pharmaceutical composition of darolutamide, the pharmaceutical composition of darolutamide of the present invention can be further improved
  • the solubility is 389.6-538.2 ⁇ g/ml. It can be seen that adding the preparation improving agent of the present invention to the pharmaceutical composition can further improve the solubility of the darolutamide pharmaceutical composition.
  • compositions 2-8 and 2-9 use polyvinylpyrrolidone as a carrier material and sodium lauryl sulfate as a formulation modifier.
  • Compositions 2-1 to 2-2 and Compositions 2-4 to 2-6 have significantly improved solubility compared to Compositions 2-7 to 2-9. It can be seen that the selection of carrier materials and preparation modifiers can affect the solubility of the pharmaceutical composition, and proper solubility helps the pharmaceutical composition to obtain further improved solubility.
  • the bulk density of the pharmaceutical composition is measured by a SOTAX TD2 type bulk density meter. The test results are shown in Table 6 below.
  • compositions 2-1 to 2-9 have relatively higher bulk densities , is 0.429-0.473g/mL. It can be seen that adding a formulation modifier to the pharmaceutical composition can further increase the bulk density of the pharmaceutical composition, and the obtained pharmaceutical composition granules are suitable for tableting to prepare tablet products, which can reduce the energy consumption generated in the production process .
  • the angle of repose of the pharmaceutical composition is measured by a Granutools Granuheap type angle of repose analyzer. The test results are shown in Table 7 below.
  • compositions 2-1 to 2-9 have relatively lower angles of repose, which are 22-37°. It can be seen that adding a formulation modifier to the pharmaceutical composition can further reduce the angle of repose of the composition, thereby improving the fluidity of the composition, and the obtained pharmaceutical composition granules are suitable for tableting to prepare tablet products, which can reduce the Energy consumption during production.
  • compositions 2-1 to 2-2 and Compositions 2-4 to 2-6 have relatively lower angles of repose compared to Compositions 2-8 and 2-9. It can be seen that the selection of carrier materials and formulation modifiers can affect the angle of repose of the pharmaceutical composition, and suitable carrier materials and formulation modifiers help the composition obtain a relatively lower angle of repose, thereby further improving the fluidity of the composition , so that the pharmaceutical composition granules are suitable for the preparation of preparation products, reducing production energy consumption.
  • the pharmaceutical composition is affected by the external environment (such as temperature, humidity, etc.) on the product quality of the preparation during the placement process, which is prone to crystallization and growth of related substances, resulting in unqualified product quality.
  • the present invention tested the stability under the accelerated condition of 40° C./75% RH.
  • the specific test method is as follows:
  • the darolutamide pharmaceutical composition is filled into HDPE bottles, and the HDPE bottles are placed in a stability box. Remove the stable drug at the specified time point for testing, and obtain the crystal form state of the composition, the content of the composition and the content of related substances. For relevant data, see Table 8 below.
  • composition 2-1 contents of composition 2-1, composition 2-4 to composition 2-9 were all higher than 94.2%, which was significantly higher than that of composition 1-5.
  • the pharmaceutical composition 2-1 and compositions 2-4 to 2-9 obtained have significantly improved stability by adding a formulation modifier to the pharmaceutical composition, Can effectively reduce the production of related substances. It can be seen that, adding the preparation improving agent of the present invention to the darolutamide pharmaceutical composition, the obtained pharmaceutical composition can have significantly improved stability.
  • compositions 2-7 to 2-9 after 6 months of storage, the contents of composition 2-1 and compositions 2-4 to 2-6 are all higher than 96.3%. And the content of composition 2-7 to composition 2-9 is lower than 96.1%. It can be seen that the selection of carrier materials and formulation modifiers can also affect the stability of the pharmaceutical composition, and suitable carrier materials and formulation modifiers help the composition to obtain relatively higher stability.
  • the darolutamide drug of the present invention has significantly improved dissolution rate, and the dissolution rate and dissolution amount of darolutamide have been significantly increased.
  • the darolutamide tablet of the present invention can release more than 90% of darolutamide after 30 minutes in a phosphate buffer solution with pH 6.8, and can release the highest amount after 45 minutes. up to 97% of darolutamide.
  • the pharmaceutical composition of darolutamide of the present invention can obtain significantly improved drug dissolution.
  • Test preparation T Darolutamide tablets prepared according to the prescription and process of Tablet 2-3 in Example 3, with a specification of 300 mg/tablet.
  • Reference preparation R marketed darolutamide tablets (NUBEQA, 300mg/tablet)
  • Blood sample collection method 0h before administration (within 1h before administration) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12, 24, 4 mL of cubital venous blood was collected from the subject at 36 h, and the blood sample was placed in a blood collection tube anticoagulated with heparin sodium. Add to backup tube. The samples were stored in a -20°C refrigerator within 2 hours after collection for later use.
  • the concentration of darolutamide in each plasma sample was determined by LC-MS/MS method.
  • Blood sample collection method 0h before administration (within 1h before administration) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12, 24, 4 mL of cubital venous blood was collected from the subject at 36 h, and the blood sample was placed in a blood collection tube anticoagulated with heparin sodium. Add to backup tube. The samples were stored in a -20°C refrigerator within 2 hours after collection for later use.
  • the concentration of darolutamide in each plasma sample was determined by LC-MS/MS method.
  • the instructions for use of the reference preparation R show that the absorption of the reference preparation R under fasting conditions is only 40%-50% of the absorption under postprandial conditions, so it needs to be taken after meals.
  • the results of the above experiment 2 indicated that the absorption of the tested preparation T in the body was basically not affected by the food effect.
  • the darolutamide tablet prepared by the present invention improves the bioavailability of the drug in vivo, especially significantly improves the absorption of the drug under fasting conditions, and obviously reduces the food effect.

Landscapes

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

Abstract

本发明涉及一种药物组合物，其包含活性成分达罗他胺或其药学上可接受的盐、载体材料以及制剂改良剂。本发明还涉及一种固体制剂，其包含本发明的药物组合物。本发明还涉及制备本发明的药物组合物及固体制剂的方法。

Description

一种达罗他胺药物组合物及其制备方法和用途
本申请要求2021年11月26日提交的题为“一种达罗他胺药物组合物及其制备方法和用途”的202111422274.6号中国申请的优先权，该中国申请的内容整体援引加入本文。
技术领域
本发明涉及一种达罗他胺药物组合物及其制备方法和用途。
背景技术
达罗他胺(Darolutamide)化学名称为N-[(1S)-2-[3-(3-氯-4-氰基苯基)-1H-吡唑-1-基]-1-甲基乙基]-5-(1-羟基乙基)-1H-吡唑-3-甲酰胺，其化学结构如下所示。
Figure PCTCN2022132894-appb-000001
达罗他胺是一种口服非甾体雄激素受体(AR)抑制剂，其适用于治疗非转移性去势抵抗性前列腺癌(nmCRPC)患者。2019年，由拜耳公司开发的达罗他胺被美国食品和药品管理局(FDA)批准上市。另外，达罗他胺的III期临床试验表明，相比安慰药联合雄激素剥夺治疗(androgen deprivation therapy,ADT)，达罗他胺联合ADT显著延长中位无转移生存期(MFS)(18.4个月vs 40.4个月)，并能够将疾病转移或死亡风险降低59％，同时也具有良好的安全性。
达罗他胺是一种低溶解高渗透的药物(BCS II类)，在pH 1-6.8的水性介质中，基本不溶(14-23μg/mL)。单剂量药代动力学研究显示，达罗他胺的中位T max为3-6小时，显示其吸收较慢。达罗他胺的末端半衰期为10-15小时。在禁食和进食状态下，600mg给药剂量的C max以及AUC (0-t)高于300mg。而对于AUC (0-t)的变异系数(CV％)，300mg(69.6％)的给药剂量高于600mg(41.4％)。
另外，在禁食状态下给药300mg达罗他胺的生物利用度为约30％。而在进食状态下，单剂量给药300mg或600mg达罗他胺后的生物利用度则分别提高2.5倍及2.8倍。类似地，在进食状态下，给药300mg或600mg达罗他胺的AUC (0-t)提高2.5倍。由此可见，达罗他胺存在明显的食物效应。
WO2019032840A1公开了包含乙酸阿比特龙和达罗他胺的药物组合物，所述药物组合物还包含聚乙烯吡咯烷酮或乙烯基吡咯烷酮/乙酸乙烯酯共聚物作为第一药物辅料，并包含月桂基硫酸钠作为第二药用辅料。发明人声称该药物组合物在禁食和进食状态下具 有增加的体外渗透性，从而能够降低药物剂量，避免空腹食用的限制。但发明人并未通过实施例证实上述技术效果。
发明内容
在一方面，本发明涉及一种药物组合物，其包含活性成分达罗他胺或其药学上可接受的盐、载体材料以及制剂改良剂，其中制剂改良剂为选自以下的一种或多种：十二烷基硫酸钠、维生素E琥珀酸聚乙二醇酯、泊洛沙姆、聚氧乙烯氢化蓖麻油、十八醇、癸二酸二丁酯、枸橼酸三乙酯、枸橼酸丁酯、甘油、聚乙二醇、卵磷脂、磺基琥珀酸钠二辛脂、牛磺胆酸钠、聚山梨醇、聚氧乙烯烷基醚、聚氧乙烯脂肪酸酯、聚氧乙烯蓖麻油；所述载体材料为选自以下的一种或多种：羟丙甲纤维素邻苯二甲酸酯、羟丙基甲基纤维素、聚乙烯醇、聚乙烯吡咯烷酮、醋酸羟丙甲基纤维素琥珀酸酯、聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、尤特奇、共聚维酮、甲基纤维素、乙基纤维素、羧甲基纤维素钠、羟丙基纤维素、聚醋酸乙烯酯、环糊精、羧甲基乙基纤维素钠聚环氧乙烷、邻苯二甲酸乙酸纤维素、偏苯三酸乙酸纤维素。
在一个实施方案中，活性成分达罗他胺或其药学上可接受的盐与载体材料的重量比为约1:0.5-1:8。
在一个实施方案中，活性成分达罗他胺或其药学上可接受的盐与制剂改良剂的重量比为约1:0.05-1:0.8。
在另一方面，本发明涉及一种固体制剂，其包含本发明的药物组合物。
在又一方面，本发明涉及制备本发明的药物组合物的方法，其包括以下步骤：(1)称取各组分；(2)混合步骤(1)的组分并进行热熔挤出，以获得药物组合物。
在又一方面，本发明涉及制备本发明的固体制剂的方法，其包括以下步骤：(1)根据上述方法制备药物组合物；(2)粉碎步骤(1)的药物组合物以获得药物组合物颗粒；(3)将步骤(2)的药物组合物颗粒与润滑剂以及其他制剂改良剂混合以获得总混颗粒；(4)压制步骤(3)的总混颗粒，以获得固体制剂。
在还一方面，本发明涉及本发明的药物组合物及固体制剂在制备用于治疗或预防前列腺癌的药物中的用途。
具体实施方式
以下将对本发明进一步详细说明。这样的描述为说明目的，而非限制本发明。本领域技术人员可由本说明书公开的内容容易地了解本发明的其它优点与功效。本发明也可以通过其它不同的具体实施例加以施行或应用。本领域技术人员在不背离本发明的精神前提下，进行各种修饰与变更。
一般定义和术语
如果没有另行指出，在此所提及的所有出版物、专利申请、专利和其它参考文献通过援引以其全部并入本文。
除非另有定义，本文使用的所有技术和科学术语具有与本发明所属领域技术人员通常理解的相同的含义。若存在矛盾，则以本文提供的定义为准。
除非另有说明，所有的百分比、份数、比例等都是按重量计的。
当给出数量、浓度或其它值或参数作为范围、优选范围或优选的上限值和下限值或者具体的值时，应将其理解为特定公开了从任意上限范围或优选值与任意下限范围或优选值的成对数值所形成的所有范围，而无论范围是否单独地被公开。除非另有说明，当本文引用数值范围时，所述的范围是指包括其端点、以及所有该范围内的整数和分数。本发明的范围并不限制于当定义范围时所引用的特定数值。例如“1-20”涵盖1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20以及由其中任何两个值组成的任何亚范围，例如2-6、3-5、2-10、3-15、4-20、5-19等。
术语“约”、“大约”当与数值变量并用时，通常指该变量的数值和该变量的所有数值在实验误差内(例如对于平均值95％的置信区间内)或在指定数值的±10％内，或更宽范围内。
术语“计量比”是将各种物质按一定的重量进行配比。例如在本发明中，将活性成分与填充剂、粘合剂、润滑剂按照指定的重量比进行配比。
术语“选自…”是指在后面所列的组中的一个或多个元素，独立地加以选择，并且可以包括两个或更多个元素的组合。
本文所使用的术语“一种或多种”或“至少一种”指一种、两种、三种、四种、五种、六种、七种、八种、九种或更多种。
除非另有说明，术语“其组合”及“其混合物”，表示所述各元素的多组分混合物，例如两种、三种、四种以及直到最大可能的多组分混合物。
此外，本发明的部件或组分之前未标明个数的，表示对于部件或组分的出现(或存在)数是没有限制的。因此，应当解读为包括一个或至少一个，并且部件或组分的单数词形式也包括复数，除非该数值明显地表示单数。
本文所使用的术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的或开放式的，且不排除其它未列举的元素或方法步骤。本领域技术人员应当理解，上述术语如“包括”涵盖“由…组成”的含义。表述“由…组成”排除未指明的任何元素、步骤或成分。表述“基本上由…组成”指范围限制在指定的元素、步骤或成分，加上任选存在的不会实质上影响所要求保护的主题的基本和新的特征的元素、步骤或成分。应当理解，表述“包含”涵盖表述“基本上由…组成”和“由…组成”。
术语“药学上可接受的”是指在正常的医学判断范围内与患者的组织接触而不会有 不适当毒性、刺激性、过敏反应等，具有合理的利弊比且能有效用于目的用途。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体物质。“药学上可接受的辅料”包括但不限于助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、崩解剂、稳定剂、溶剂或乳化剂。所述载体的非限制性实例包括碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇等。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“药物活性成分”、“活性成分”、“治疗剂”、“活性物质”或“活性剂”是指一种化学实体，其可以有效地治疗或预防目标疾病或病症。
针对药物、药物单元或活性成分而言，术语“有效量”、“治疗有效量”或“预防有效量”是指副作用可接受的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“片剂”是指这样的固体药物剂型，其包含活性成分，并任选地包含适合的赋形剂，如稀释剂、粘合剂等，并通过压制或成型技术制备。片剂的实例例如有压制片、多微粒片、多压制片、包衣片、骨架片、渗透泵片和锭(caplet)等。
术语“堆密度”是指一定量的颗粒状产品的质量除以所述量所占的总体积。
术语“休止角”是指粉体堆积成的自由斜面与水平面所形成的最大角。休止角越小，摩擦力越小，流动性越好。
术语“溶出度”是指药物从固体制剂在规定溶剂中溶出的速度和程度。
药物组合物
在一方面，本发明涉及一种药物组合物，其包含活性成分达罗他胺或其药学上可接受的盐、载体材料以及制剂改良剂。
活性成分
在一个实施方案中，活性成分为达罗他胺或其药学上可接受的盐。在一个优选的实施方案中，活性成分为达罗他胺。
载体材料
载体材料是指通常呈微粒形式的材料，该材料用于承载活性成分，其中该活性成分基本上分布于载体材料中。
在一个实施方案中，所述载体材料为选自以下的一种或多种：羟丙甲纤维素邻苯二甲酸酯(Hydroxypropylmethyl cellulose phthalate,HPMCP)、羟丙基甲基纤维素 (Hydroxypropyl methylcellulose,HPMC)、聚乙烯醇(Polyvinyl alcohol,PVA)、聚乙烯吡咯烷酮(Polyvinyl pyrrolidone,PVP)、醋酸羟丙甲基纤维素琥珀酸酯(HPMCAS)、聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(例如
Figure PCTCN2022132894-appb-000002
)、尤特奇(例如
Figure PCTCN2022132894-appb-000003
)、共聚维酮、甲基纤维素、乙基纤维素、羧甲基纤维素钠、羟丙基纤维素、聚醋酸乙烯酯、环糊精、羧甲基乙基纤维素钠聚环氧乙烷、邻苯二甲酸乙酸纤维素、偏苯三酸乙酸纤维素。在一个优选的实施方案中，所述载体材料为选自以下的一种或多种：羟丙甲纤维素邻苯二甲酸酯、羟丙基甲基纤维素、聚乙烯吡咯烷酮、醋酸羟丙甲基纤维素琥珀酸酯、聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、尤特奇。合适的载体材料有助于提高药物组合物的溶解度。
作为示例，可以使用的载体材料包括但不限于Shin-Etsu公司的市售产品
Figure PCTCN2022132894-appb-000004
(HPMCAS)、BASF公司的市售产品
Figure PCTCN2022132894-appb-000005
和
Figure PCTCN2022132894-appb-000006
Ashland公司的市售产品PVP K30。
制剂改良剂
在一个实施方案中，所述制剂改良剂为选自以下的一种或多种：十二烷基硫酸钠、维生素E琥珀酸聚乙二醇酯、泊洛沙姆、聚氧乙烯氢化蓖麻油、十八醇、癸二酸二丁酯、枸橼酸三乙酯、枸橼酸丁酯、甘油、聚乙二醇、卵磷脂、磺基琥珀酸钠二辛脂、牛磺胆酸钠、聚山梨醇、聚氧乙烯烷基醚、聚氧乙烯脂肪酸酯、聚氧乙烯蓖麻油。在一个优选的实施方案中，所述制剂改良剂为选自以下的一种或多种：十二烷基硫酸钠、维生素E琥珀酸聚乙二醇酯枸橼酸三乙酯。
作为示例，可以使用的制剂改良剂包括但不限于PMC Isochem公司的市售产品VE TPGS1000、BASF公司的市售产品
Figure PCTCN2022132894-appb-000007
Merck KGaA公司的市售产品TEC。
在本领域中，十二烷基硫酸钠、维生素E琥珀酸聚乙二醇酯、泊洛沙姆、聚氧乙烯氢化蓖麻油、十八醇、癸二酸二丁酯、枸橼酸三乙酯、枸橼酸丁酯、甘油、聚乙二醇、卵磷脂、磺基琥珀酸钠二辛脂、牛磺胆酸钠、聚山梨醇、聚氧乙烯烷基醚、聚氧乙烯脂肪酸酯、聚氧乙烯蓖麻油等通常用作固体制剂的表面活性剂或增塑剂等，例如可以使包衣片剂的包衣膜更加柔软，从而使包衣片不易开裂，易于储藏和运输。发明人出人意料地发现，本发明所用的制剂改良剂则可以实现预料不到的技术效果，例如进一步提高药物组合物的溶解度、进而提高药物的生物利用度、提高药物的稳定性、使药物组合物易于制备、进而节省生产的能耗。
在一个实施方案中，在本发明的药物组合物中，当所述制剂改良剂为聚乙二醇，所述载体材料不是聚乙烯吡咯烷酮和/或聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物和/或羟丙基纤维素。
在一个实施方案中，在本发明的药物组合物中，当所述制剂改良剂为十二烷基硫酸钠时，所述载体材料不是聚乙烯吡咯烷酮和/或聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇 接枝共聚物和/或羟丙基纤维素。
在一个实施方案中，在本发明的药物组合物中，当所述制剂改良剂为泊洛沙姆时，所述载体材料不是聚乙烯吡咯烷酮和/或聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物和/或羟丙基纤维素。
在一个实施方案中，在本发明的药物组合物中，当所述制剂改良剂为聚乙二醇、十二烷基硫酸钠以及泊洛沙姆中的两种或三种时，所述载体材料不是聚乙烯吡咯烷酮和/或聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物和/或羟丙基纤维素。
在一个实施方案中，在本发明的药物组合物中，当所述制剂改良剂为聚乙二醇、十二烷基硫酸钠或泊洛沙姆时，所述载体材料不是聚乙烯吡咯烷酮和/或聚乙烯己内酰胺-局醋酸乙烯酯-聚乙二醇接枝共聚物和/或羟丙基纤维素。
换言之，当所用的制剂改良剂为聚乙二醇、十二烷基硫酸钠、泊洛沙姆或其组合时，载体材料不是聚乙烯吡咯烷酮，不是聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物，也不是羟丙基纤维素，或以上两者或三者的组合。
在一个优选的实施方案中，在本发明的药物组合物中，所述制剂改良剂为选自以下的一种或多种：十二烷基硫酸钠、维生素E琥珀酸聚乙二醇酯、癸二酸二丁酯、枸橼酸三乙酯、枸橼酸丁酯、甘油、聚乙二醇；所述载体材料为选自以下的一种或多种：羟丙甲纤维素邻苯二甲酸酯、羟丙基甲基纤维素、聚乙烯醇、聚乙烯吡咯烷酮、醋酸羟丙甲基纤维素琥珀酸酯、聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、尤特奇、共聚维酮、甲基纤维素、乙基纤维素、羧甲基纤维素钠；其中当所述制剂改良剂为十二烷基硫酸钠或聚乙二醇时，所述载体材料不是聚乙烯吡咯烷酮和/或聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物。
在一个更优选的实施方案中，在本发明的药物组合物中，所述制剂改良剂为选自以下的一种或多种：十二烷基硫酸钠、维生素E琥珀酸聚乙二醇酯、枸橼酸三乙酯；所述载体材料为选自以下的一种或多种：羟丙甲纤维素邻苯二甲酸酯、羟丙基甲基纤维素、聚乙烯吡咯烷酮、醋酸羟丙甲基纤维素琥珀酸酯、聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、尤特奇；其中当所述制剂改良剂为十二烷基硫酸钠时，所述载体材料不是聚乙烯吡咯烷酮和/或聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物。
在一个具体的实施方案中，在本发明的药物组合物中，所述制剂改良剂为维生素E琥珀酸聚乙二醇酯，所述载体材料为醋酸羟丙甲基纤维素琥珀酸酯。在一个具体的实施方案中，在本发明的药物组合物中，所述制剂改良剂为聚乙烯吡咯烷酮，所述载体材料为醋酸羟丙甲基纤维素琥珀酸酯。在一个具体的实施方案中，在本发明的药物组合物中，所述制剂改良剂为维生素E琥珀酸聚乙二醇酯，所述载体材料为醋酸羟丙甲基纤维素琥珀酸酯以及聚乙烯吡咯烷酮。在一个具体的实施方案中，在本发明的药物组合物中，所述制剂改良剂为枸橼酸三乙酯，所述载体材料为尤特奇。
其他组分
在一个实施方案中，本发明的药物组合物还可以包含药学上可接受的辅料。
在一个实施方案中，本发明的药物组合物还可以包含选自以下的一种或多种：缓冲剂、酸化剂、稳定剂、防腐剂。
缓冲剂
缓冲剂是指使药物制剂的pH稳定的药用赋形剂。
在一个实施方案中，所述缓冲剂为选自以下的一种或多种：柠檬酸缓冲剂、苹果酸盐缓冲剂、马来酸盐缓冲剂、酒石酸盐缓冲剂。
酸化剂
酸化剂是指在药物制备中主要用作辅料的酸，其用于调节药物的pH，并且其在使用时仅提供酸性，通常不引入特殊的生物活性。
在一个实施方案中，所述酸化剂为选自以下的一种或多种：酒石酸、碳酸、乙酸、草酸、亚硝酸。
稳定剂
稳定剂是指与药物组合物中的活性成分和/或一般药物赋形剂相互作用以提高其稳定性的特定化学物质。
在一个实施方案中，所述稳定剂为选自以下的一种或多种：甲硫氨酸、赖氨酸、组氨酸。
防腐剂
防腐剂是指添加到药物组合物中以防止或延迟微生物活性(生长和代谢)的化合物。
在一个实施方案中，所述防腐剂为选自以下的一种或多种：苄醇、苯甲酸苄酯、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、维生素E、维生素A棕榈酸酯。
在一个实施方案中，活性成分达罗他胺或其药学上可接受的盐与载体材料的重量比为约1:0.5-1:8。在一个优选的实施方案中，活性成分达罗他胺或其药学上可接受的盐与载体材料的重量比为约1:1-1:4。在一个更优选的实施方案中，活性成分达罗他胺或其药学上可接受的盐与载体材料的重量比为约1:2-1:4。例如约1:0.5、约1:0.8、约1:1、约1:2、约1:3、约1:4、约1:5、约1:6、约1:7、约1:8，以及由这些比例(值)中的任意两个构成的范围。活性成分与载体材料的合适的重量比有利于获得合适的溶解性及溶出度。过高的活性成分与载体材料的重量比不能有效地提高活性成分的溶解性；过低的活性成分与载体材料的重量比也不会更有效地提高活性成分的溶解性，并且会使固体制剂的粘度过大，导致其制备困难。
在一个实施方案中，活性成分达罗他胺或其药学上可接受的盐与制剂改良剂的重量比为约1:0.05-1:0.8。在一个优选的实施方案中，活性成分达罗他胺或其药学上可接受的盐与制剂改良剂的重量比为约1:0.1-1:0.5。例如约1:0.05、约1:0.1、约1:0.15、约1:0.2、 约1:0.25、约1:0.3、约1:0.35、约1:0.4、约1:0.45、约1:0.5，以及由这些比例(值)中的任意两个构成的范围。活性成分与制剂改良剂的合适的重量比有利于获得合适的溶解性、溶解度及稳定性，获得的药物易于储藏以及被人体吸收。过高的活性成分与制剂改良剂的重量比不能有效地提高活性成分的溶解性；过低的活性成分与制剂改良剂的重量比也不会更有效地提高活性成分的溶解性，反而导致无法制备。
堆密度
堆密度即为堆积密度，是指本发明的药物组合物颗粒的质量除以其所占的体积。合适的堆密度有利于药物组合及其制剂产品的制备，进而有利于获得具有合适溶解性及溶出度的产品。
在一个实施方案中，所述药物组合物的堆密度为约0.40-0.50g/mL。在一个优选的实施方案中，所述药物组合物的堆密度为约0.42-0.49g/mL。在一个更优选的实施方案中，所述药物组合物的堆密度为约0.436-0.473g/mL。例如约0.40g/mL、0.41g/mL、0.42g/mL、0.423g/mL、0.425g/mL、0.427g/mL、0.429g/mL、0.43g/mL、0.433g/mL、0.436g/mL、0.439g/mL、0.44g/mL、0.442g/mL、0.445g/mL、、0.448g/mL、0.45g/mL、0.451g/mL、0.46g/mL、0.466g/mL、0.469g/mL、0.47g/mL、0.473g/mL、0.48g/mL、0.49g/mL。
休止角
休止角是指本发明的药物组合物颗粒堆积成的自由斜面与水平面所形成的最大角。其中，休止角越小，证明本发明的药物组合物颗粒之间的摩擦力越小，即药物组合物颗粒的流动性越好。合适的药物组合物颗粒休止角有利于制剂产品的制备，进而有利于获得具有合适溶解性及溶出度的制剂产品。
在一个实施方案中，所述药物组合物的休止角为约20-32°。在一个优选的实施方案中，所述药物组合物的休止角为约21-30°。在一个更优选的实施方案中，所述药物组合物的休止角为约22-28°。例如为约20°、约21°、约22°、约23°、约24°、约25°、约26°、约27°、约28°、约29°、约30°、约31°、约32°。
固体制剂
在另一个方面，本发明涉及一种固体制剂，其包含本发明的药物组合物。
本发明的制备方法
药物组合物的制备
在另一方面，本发明涉及制备本发明的药物组合物的方法，其包括以下步骤：
(1)称取各组分；
(2)混合步骤(1)的组分并进行热熔挤出，以获得药物组合物。
其中，活性成分、载体材料以及制剂改良剂如上述所定义。
步骤(1)
根据特定的计量比(例如重量比)称取药物组合物的各个组分。例如可以根据以下实施例中的重量比称取药物组合物的各个组分。
步骤(2)
步骤(2)的热熔挤出通过本领域常用的方法以及常用的仪器进行。例如可以使用Leistritz ZSE 12HP-PH-40D对步骤(1)的组分进行热熔挤出。
在一个实施方案中，步骤(2)的热熔挤出的温度为约160±20℃。
固体制剂的制备
在另一方面，本发明还涉及固体制剂的制备方法：其包括以下步骤：
(1)根据上述方法制备药物组合物；
(2)粉碎步骤(1)的药物组合物以获得药物组合物颗粒；
(3)将步骤(2)的药物组合物颗粒与润滑剂以及其他制剂改良剂混合以获得总混颗粒；
(4)压制步骤(3)的总混颗粒，以获得固体制剂。
步骤(2)
步骤(2)的粉碎通过本领域常用的方法进行。例如，可以使用刀片粉碎和辊轴粉碎。
步骤(3)
步骤(3)的混合可以通过本领域常用的方法进行。例如，可以使用V型混合和料斗混合。
步骤(4)
步骤(4)的压制可以使用本领域常用的方法进行。例如可以使用液压压制、机械压制和气压压制等。可以使用的设备例如可以为国药龙立的ZP14压片机等。
在一个实施方案中，制备本发明的固体制剂还进一步包含如下步骤：
步骤(5)将步骤(4)的固体制剂包衣，以获得片剂。
步骤(5)的包衣可以使用本领域常用的方法进行。例如可以使用Ohara包衣机等。
应当理解，上述所列举的组合物制备方法只是阐述性和代表性的。因此，本发明的组合物制备方法并不限于仅包含本文以上所列举的方法。本领域技术人员可根据常规技术对制备方法进行各种改变、调整或等同替换，均未超出本发明的保护范围。
制药用途
本发明还涉及一种预防和治疗前列腺癌的方法，所述方法包括向有需要的个体给药治疗有效量的本发明的药物组合物或固体制剂。
本发明的药物组合物或固体制剂可用于预防和治疗前列腺癌。
本发明还涉及本发明的药物组合物或固体制剂在制备用于预防和治疗前列腺癌的 药物中的用途。
有益效果
与现有技术的达罗他胺药物组合物相比，本发明的达罗他胺药物组合物能够进一步提高活性成分的溶解性，进而获得具有优异溶解度的药物组合物，并有效地提高了组合物的生物利用度。因此，本发明的达罗他胺药物组合物可以进行低剂量的给药，并减小食物效应。
另外，本发明的达罗他胺药物组合物还具有优秀的稳定性，适于常温保存，降低了对储藏和运输的要求。
此外，本发明的达罗他胺药物组合物具有合适的堆密度和休止角，证实其具有良好的流动性，因此易于制成片剂等形式，适于规模化放大和工业生产。
再有，通过使用合适的载体材料以及制剂改良剂，相比现有技术，本发明的达罗他胺药物组合物具有明显提高的溶解度、溶解性以及稳定性；并且获得的药物组合物颗粒具有改善的堆密度及休止角，更易于进行压制等操作，以制备固体制剂，从而有效地降低了生产能耗。
实施例
下面结合具体实施例对本发明的方案做进一步详细的描述。
需要说明的是，以下实施例仅仅是为清楚地说明本发明的技术方案所作的举例，而并非对本发明的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动，这里无需也无法对所有的实施方式予以穷举，而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。除非另外指明，本文所用的仪器设备和试剂材料都是可以商购的。
材料
达罗他胺：购自上海芃蒎生物科技有限公司；
PVP：购自BASF公司，
Figure PCTCN2022132894-appb-000008
购自Ashland公司，PVP K30；
HPMACAS：购自Shin-Etsu公司，
Figure PCTCN2022132894-appb-000009
HPMCP：购自Shin-Etsu公司，羟丙甲纤维素酞酸酯；
聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物：购自BASF公司，
Figure PCTCN2022132894-appb-000010
尤特奇：购自Evonik Degussa公司，
Figure PCTCN2022132894-appb-000011
VE TPGS：购自PMC Isochem公司，VE TPGS1000；
SLS：购自BASF公司，
Figure PCTCN2022132894-appb-000012
TEC：购自Merck KGaA公司，TEC。
溶解度的测定
称取约200mg样品于50ml摇瓶中，然后加入50ml pH 6.8的介质。摇瓶混匀并放入摇床中，设定摇床温度为37.2℃，转速为50rpm。于4h时取样，并用0.45μm的滤膜过滤，以收集滤液。通过效液相色谱法进行测定，测定波长为286nm。
溶出度的测定
在以下实施例中，通过美国药典的USP II法(桨法)对制剂进行溶出度测定，具体参数如下。
溶出方法 USP II法(桨法)
溶出介质 pH 6.8的磷酸盐缓冲液
介质体积 1000ml
转速 75rpm
温度 37℃±5℃
溶出样品分析：将溶出度测定试验中获得的溶液用0.45μm滤膜过滤后收集滤液，采用高效液相色谱法测定，测定波长为260nm。
含量测试方法：将待测试样品溶于甲醇中，使达罗他胺的浓度为100μg/ml，采用高效液相色谱法测定，测定波长为286nm。
有关物质的测试方法：将待测试样品溶于甲醇中，使达罗他胺的浓度为150μg/ml，采用高效液相色谱法测定，测定波长为286nm。
制备实施例
实施例1达罗他胺药物组合物的制备
根据表1中的具体组成和重量比制备达罗他胺药物组合物颗粒。
具体制备方法如下：
根据表1的重量比将活性成分以及载体材料混合，以获得共混物。通过粉末进料器，以恒定的速率将共混物加入到Leistritz ZSE 12HP-PH-40D热熔挤出机中，在160±20℃的温度下进行热熔挤出。收集挤出物，并使用FitzMill L1A粉碎机粉碎获得的挤出物，粉碎后的挤出物过筛80目。
根据上述方法分别获得达罗他胺药物组合物1-1至1-15以及活性成分与载体材料的共混物1-1至1-15。
表1达罗他胺组合物的组成
组合物 活性成分 载体材料 活性成分：载体材料
组合物1-1 达罗他胺 VA64 1:2
组合物1-2 达罗他胺 VA64 1:3
组合物1-3 达罗他胺 VA64 1:4
组合物1-4 达罗他胺 HPMCAS 1:1
组合物1-5 达罗他胺 HPMCAS 1:2
组合物1-6 达罗他胺 HPMCAS 1:3
组合物1-7 达罗他胺 HPMCAS 1:4
组合物1-8 达罗他胺 HPMCP-HP55 1:2
组合物1-9 达罗他胺 HPMCP-HP55 1:3
组合物1-10 达罗他胺 Soluplus 1:2
组合物1-11 达罗他胺 Soluplus 1:3
组合物1-12 达罗他胺 Eudragit-L100 1:2
组合物1-13 达罗他胺 Eudragit-L100 1:3
组合物1-14 达罗他胺 PVP K30 1:3
组合物1-15 达罗他胺 PVP K30 1:4
实施例2本发明的达罗他胺药物组合物的制备
据表2中的具体组成和重量比制备达罗他胺药物组合物颗粒。
具体制备方法如下：
根据表2的重量比将活性成分、载体材料和制剂改良剂混合，以获得共混物。通过粉末进料器，以恒定的速率将共混物加入到Leistritz ZSE 12HP-PH-40D热熔挤出机中，在160±20℃的温度下进行热熔挤出。收集挤出物，并使用FitzMill L1A粉碎机粉碎获得的挤出物，粉碎后的挤出物过筛80目。
根据上述方法分别获得达罗他胺药物组合物2-1至2-9以及活性成分与载体材料及制剂改良剂的共混物2-1至2-9。
表2达罗他胺组合物的组成
组合物 活性成分 载体材料 制剂改良剂 质量比
组合物2-1 达罗他胺 HPMCAS TPGS 1:2:0.2
组合物2-2 达罗他胺 HPMCAS TPGS 1:4:0.5
组合物2-3 达罗他胺 VA64+HPMCAS / 1:0.5:1.5
组合物2-4 达罗他胺 VA64+HPMCAS TPGS 1:0.5:1.5:0.2
组合物2-5 达罗他胺 HPMCP-HP55 TPGS 1:3:0.1
组合物2-6 达罗他胺 Eudragit L100 TEC 1:2:0.15
组合物2-7 达罗他胺 Soluplus SLS 1:3:0.1
组合物2-8 达罗他胺 PVP K30 SLS 1:4:0.5
组合物2-9 达罗他胺 VA64 SLS 1:4:0.5
实施例3达罗他胺片剂的制备
根据表3中的具体组成和重量比制备达罗他胺片剂。
达罗他胺片剂的方法如下：
(1)分别根据实施例1和2的方法制备达罗他胺药物组合物；(2)将步骤(1)的药物组合物与填充剂、崩解剂以及润滑剂混合，以获得总混颗粒；(3)通过ZP14压片机，将步骤(2)的总混颗粒进行压制，以获得达罗他胺片剂。
表3达罗他胺片剂的组成
  功能 片剂2-1 片剂2-2 片剂2-3 片剂2-4 片剂2-5 片剂2-6
组合物1-5 - 900 - - - - -
组合物2-1 - - 960 - - - -
组合物2-4 - - - 960 - - -
组合物2-6 - - - - 945 - -
组合物2-8 - - - - - 1650 -
组合物2-9 - - - - - - 1650
微晶纤维素 填充剂 300 240 240 255 230 230
交联羧甲基纤维素钠 崩解剂 74 74 74 74 90 90
硬脂酸镁 润滑剂 26 26 26 26 30 30
测试实施例
实施例4药物组合物晶型测定
药物组合物的晶型测定包括多晶粉末X射线衍射(PXRD)以及差示扫描量热法(DSC)，分别通过Bruker D8 advance仪器(扫描范围：3°-40°)以及TA Instruments DSC2000仪器(扫描范围：30℃-250℃)进行测定。
表4达罗他胺组合物晶型
组合物 晶型 组合物 晶型
组合物1-1 部分无定型 组合物1-13 无定型
组合物1-2 无定型 组合物1-14 无定型
组合物1-3 无定型 组合物1-15 无定型
组合物1-4 部分无定型 组合物2-1 无定型
组合物1-5 无定型 组合物2-2 无定型
组合物1-6 无定型 组合物2-3 无定型
组合物1-7 无定型 组合物2-4 无定型
组合物1-8 无定型 组合物2-5 无定型
组合物1-9 无定型 组合物2-6 无定型
组合物1-10 部分无定型 组合物2-7 无定型
组合物1-11 无定型 组合物2-8 无定型
组合物1-12 无定型 组合物2-9 无定型
由上表4的晶型测定结果可知，活性成分达罗他胺与载体材料制备的药物组合物可形成无定型的颗粒，提高达罗他胺的溶解性。同时上述药物组合物颗粒均易于成药，方便进一步制备成固体制剂，适于规模化放大和工业生产。
实施例5药物组合物及共混物的溶解度测定
根据上述方法分别测定药物组合物1-1至1-14、2-1至2-9以及相应共混物的溶解度，获得溶出度如下表4所示。另外，在上述的实验条件下，测得达罗他胺化合物的溶解度为24.9μg/ml。
表5药物组合物及共混物的溶解度
药物组合物/共混物 药物组合物溶解度(μg/ml) 相应共混物溶解度(μg/ml)
组合物1-1 107.2 23.9
组合物1-2 260.9 24.6
组合物1-3 328.5 26.3
组合物1-4 142.7 23.4
组合物1-5 488.9 24.1
组合物1-6 405.6 25.3
组合物1-7 421.6 24.9
组合物1-8 438.1 23.5
组合物1-9 406.2 23.1
组合物1-10 369.2 24.6
组合物1-11 307.5 24.7
组合物1-12 470.5 23.2
组合物1-13 490.8 25.9
组合物1-14 321.6 24.7
组合物1-15 394.2 26.8
组合物2-1 499.6 26.2
组合物2-2 462.3 28.1
组合物2-3 431.2 24.3
组合物2-4 479.1 25.3
组合物2-5 427.2 24.1
组合物2-6 538.2 24.8
组合物2-7 395.3 28.7
组合物2-8 416.5 33.5
组合物2-9 389.6 29.6
由上表5的溶解度测试结果可知，将活性成分达罗他胺与载体材料组合，获得的达罗他胺药物组合物具有明显提高的溶解度。相比达罗他胺化合物(溶解度为24.9μg/ml)及其与载体材料和/或制剂改良剂的混合物，达罗他胺组合物的溶解度明显较高，为107.2-490.8μg/ml。
在组合物1-1至1-15的基础上，进一步向达罗他胺药物组合物中加入制剂改良剂，例如TPGS、SLS或TEC，本发明的达罗他胺药物组合物能够获得进一步提高的溶解度，为389.6-538.2μg/ml。由此可见，向药物组合物中加入本发明的制剂改良剂，能够进一步提高达罗他胺药物组合物的溶解度。
另外，组合物2-8以及组合物2-9以聚乙烯吡咯烷酮为载体材料，并以十二烷基硫酸钠作为制剂改良剂。相比组合物2-7至组合物2-9，组合物2-1至2-2以及组合物2-4至组合物2-6具有明显提高的溶解度。由此可见，载体材料以及制剂改良剂的选择能够影响药物组合物的溶解度，合适的溶解度有助于药物组合物获得进一步提高的溶解度。
实施例6药物组合物堆密度的测定
药物组合物的堆密度通过SOTAX TD2型堆密度仪进行测定。检测结果如下表6所示。
表6药物组合物的堆密度
组合物 堆密度(g/mL) 组合物 堆密度(g/mL)
组合物1-1 0.384 组合物1-13 0.415
组合物1-2 0.426 组合物1-14 0.431
组合物1-3 0.413 组合物1-15 0.419
组合物1-4 0.411 组合物2-1 0.451
组合物1-5 0.433 组合物2-2 0.466
组合物1-6 0.447 组合物2-3 0.429
组合物1-7 0.461 组合物2-4 0.473
组合物1-8 0.441 组合物2-5 0.469
组合物1-9 0.452 组合物2-6 0.436
组合物1-10 0.428 组合物2-7 0.431
组合物1-11 0.446 组合物2-8 0.429
组合物1-12 0.408 组合物2-9 0.432
由上表6的堆密度测定结果可知，相比组合物1-1至1-15(堆密度为0.384-0.461g/mL)，组合物2-1至2-9具有相对更高的堆密度，为0.429-0.473g/mL。由此可见，向药物组合物中加入制剂改良剂，还可以进一步提高药物组合物的堆密度，获得的药物组合物颗粒适于进行压片制备片剂产品，可以降低生产过程中产生的能耗。
实施例7药物组合物休止角的测定
药物组合物的休止角通过Granutools Granuheap型休止角分析仪进行测定。检测结果如下表7所示。
表7药物组合物的休止角
组合物 休止角(°) 组合物 休止角(°)
组合物1-1 45 组合物1-13 34
组合物1-2 35 组合物1-14 34
组合物1-3 34 组合物1-15 33
组合物1-4 37 组合物2-1 27
组合物1-5 32 组合物2-2 27
组合物1-6 31 组合物2-3 37
组合物1-7 29 组合物2-4 22
组合物1-8 29 组合物2-5 28
组合物1-9 31 组合物2-6 28
组合物1-10 33 组合物2-7 31
组合物1-11 32 组合物2-8 32
组合物1-12 38 组合物2-9 31
由上表7的休止角测定结果可知，相比组合物1-1至1-15(堆密度为29-45°)，组合物2-1至2-9具有相对更低的休止角，为22-37°。由此可见，向药物组合物中加入制剂改良剂，还可以进一步降低组合物的休止角，从而改善组合物的流动性，获得的药物组合物颗粒适于进行压片制备片剂产品，可以降低生产过程中产生的能耗。
另外，相比组合物2-8和组合物2-9，组合物2-1至组合物2-2以及组合物2-4至组合物2-6具有相对较低的休止角。由此可见，载体材料以及制剂改良剂的选择能够影响药物组合物的休止角，合适的载体材料以及制剂改良剂有助于组合物获得相对更低的休止角，从而进一步改善组合物的流动性，使药物组合物颗粒适用于制备制剂产品，降低生产能耗。
实施例8药物组合物的稳定性测试
药物组合物在放置过程中受外界环境(例如如温度，湿度等)对制剂产品质量的影响，容易产生析晶和有关物质的增长，导致产品质量不合格。为了评估达罗他胺药物组合物的稳定性，本发明测试了40℃/75％RH加速条件下的稳定性。具体测试方法如下：
将达罗他胺药物组合物装入HDPE瓶中，并将HDPE瓶放置于稳定性箱中。于规定的时间点去除稳定性药品以进行测试，获得组合物的晶型状态、组合物含量以及有关物 质的含量，相关数据参见下表8。
表8达罗他胺组合物稳定性
Figure PCTCN2022132894-appb-000013
由上表8的稳定性测定结果可知，经过6个月的储存后，组合物2-1、组合物2-4至组合物2-9的含量均高于94.2％，其明显高于组合物1-5。
因此，相比达罗他胺药物组合物1-5，向药物组合物中加入制剂改良剂，获得的药物组合物2-1、组合物2-4至2-9具有明显改善的稳定性，可以有效减少有关物质的产生。由此可见，向达罗他胺药物组合物中加入本发明的制剂改良剂，获得的药物组合物能够具有明显提高的稳定性。
另外，相比组合物2-7至组合物2-9，经过6个月的储存后，组合物2-1以及组合物2-4至组合物2-6含量均高于96.3％。而组合物2-7至组合物2-9的含量则低于96.1％。由此可见，载体材料以及制剂改良剂的选择也能够影响药物组合物的稳定性，合适的载体材料以及制剂改良剂有助于组合物获得相对更高的稳定性。
此外，申请人意外地发现，以HPMACAS为达罗他胺组合物的载体时，向药物组合物中加入制剂改良剂TPGS时，药物组合物可以获得相对更高的稳定性。例如，在40℃/75％RH的条件下，经过6个月，药物组合物的含量依然高达97.1％。
实施例9药物组合物的溶出度测试
根据上述方法测定达罗他胺在pH 6.8的磷酸缓冲液中的溶解度，测试结果参见下表9。
表9达罗他胺片剂的溶出度
Figure PCTCN2022132894-appb-000014
由上表9的溶出度实验结果可知，相比达罗他胺原料药以及市售的达罗他胺片剂本发明的达罗他胺片剂(NUBEQA)，本发明的达罗他胺药物组合物片剂具有明显改善的溶出度，达罗他胺的溶出速度以及溶出量获得了明显的高。例如，在本发明的实验条件下，本发明的达罗他胺片剂在pH 6.8的磷酸盐缓冲液中，30分钟后即可释放90％以上的达罗他胺，45分钟后可以释放最高达97％的达罗他胺。
由此可见，向达罗他胺及其药物组合物中进一步加入制剂改良剂，本发明的达罗他胺药物组合物能够获得明显改善的药物溶出度。
实施例10达罗他胺片剂的药代动力学研究
1.试验制剂
受试制剂T：根据实施例3中片剂2-3的处方和工艺制备的达罗他胺片，规格为300mg/片。
参比制剂R：已上市的达罗他胺片剂(NUBEQA，规格为300mg/片)
2.试验方法
2.1实验1
采用开放、随机、双周期、双交叉自身对照试验设计方法(清洗期为7天)，将入选的10名健康男性受试者随机分为2组，每组5人。分组方案如下表所示：
表10分组
Figure PCTCN2022132894-appb-000015
受试者于试验日前进入I期临床试验病房，晚上进统一清淡饮食，然后禁食过夜(至少10h，不禁水)。受试者次日早上8点左右进高脂餐后口服1片受试制剂T或参比制剂R，喝240mL水。服药后2h内不得饮水，且保持上身直立状态，4小时后进统一午餐。
血样采集方法：于给药前0h(给药前1h内)和给药后0.5、1、1.5、2、2.5、3、3.5、4、4.5、5、6、7、8、12、24、36h采集受试者肘静脉血4mL，血样置于肝素钠抗凝的采血管中，采集后于4℃条件下以3500rpm离心5min，将血浆分为两份，取1mL血浆加入正式管，剩余血浆加入备份管。样品在采集后2h内置于-20℃冰箱，备用。
采用LC-MS/MS方法，测定各血浆样品中的达罗他胺浓度。
2.2实验2
采用开放、随机、双周期、双交叉自身对照试验设计方法(清洗期为7天)，将入选的10名健康男性受试者随机分为2组，每组5人。分组方案如下表所示：
表11分组
Figure PCTCN2022132894-appb-000016
受试者于试验日前进入I期临床试验病房，晚上进统一清淡饮食，然后禁食过夜(至少10h，不禁水)。受试者次日早上8点左右按照要求进高脂餐后口服1片受试制剂T或空腹口服1片受试制剂T，喝240ml水。服药后2h内不得饮水，且保持上身直立状态，4小时后进统一午餐。
血样采集方法：于给药前0h(给药前1h内)和给药后0.5、1、1.5、2、2.5、3、3.5、4、4.5、5、6、7、8、12、24、36h采集受试者肘静脉血4mL，血样置于肝素钠抗凝的采血管中，采集后于4℃条件下以3500rpm离心5min，将血浆分为两份，取1mL血浆加入正式管，剩余血浆加入备份管。样品在采集后2h内置于-20℃冰箱，备用。
采用LC-MS/MS方法，测定各血浆样品中的达罗他胺浓度。
3.实验结果
上述实验1以及实验2的结果总结如下：
表12实验1的药代动力学数据
Figure PCTCN2022132894-appb-000017
表13实验2的药代动力学数据
Figure PCTCN2022132894-appb-000018
上述实验1(表12)的数据显示：
(1)服用受试制剂T的最高血药浓度C max显著升高，达到服用参比制剂R的最高血药浓度的144.93％；
(2)相比服用参比制剂R的血药浓度曲线下面积，服用受试制剂T的血药浓度曲线下面积AUC 0-t升高10％左右，达到服用参比制剂R的血药浓度曲线下面积的110.76％；
(3)相比服用参比制剂R的血药浓度达峰时间，服用受试制剂T的血药浓度达峰时间T max则未见显著变化。
上述结果表明，在餐后条件下，相比参比制剂R，受试制剂T在受试者体内的吸收有一定程度的改善。
从上述实验2(表13)的数据显示：
(1)相比空腹条件下的最高血药浓度C max，受试制剂T在餐后条件下的最高血药浓度C max未发生显著的变化；
(2)相比空腹条件下的血药浓度曲线下面积，受试制剂T在餐后条件下的血药浓度曲线下面积AUC 0-t提高约7％；
(3)相比空腹条件下的血药浓度达峰时间，受试制剂T在餐后条件下的血药浓度达峰时间T max显著延后，这主要是受食物效应的影响。
另外，参比制剂R的使用说明书显示，参比制剂R在空腹条件下的吸收仅为餐后条件下吸收的40％-50％，因此需餐后服用。而上述实验2的结果表明，受试制剂T在体内的吸收基本不受食物效应的影响。
由此可见，本发明制备的达罗他胺片剂提高了药物的体内生物利用度，尤其是显著提高了药物在空腹条件下的吸收，明显减少了食物效应。
以上所述仅为本发明的具体实施例，并非因此限制本发明的专利范围，凡是利用本发明作的等效变换，或直接或间接运用在其它相关的技术领域，均同理包括在本发明的专利保护范围之中。

Claims (10)

  1. 一种药物组合物，其包含活性成分达罗他胺或其药学上可接受的盐、载体材料和制剂改良剂，其中
    所述制剂改良剂为选自以下的一种或多种：十二烷基硫酸钠、维生素E琥珀酸聚乙二醇酯、泊洛沙姆、聚氧乙烯氢化蓖麻油、十八醇、癸二酸二丁酯、枸橼酸三乙酯、枸橼酸丁酯、甘油、聚乙二醇、卵磷脂、磺基琥珀酸钠二辛脂、牛磺胆酸钠、聚山梨醇、聚氧乙烯烷基醚、聚氧乙烯脂肪酸酯、聚氧乙烯蓖麻油；
    所述载体材料为选自以下的一种或多种：羟丙甲纤维素邻苯二甲酸酯、羟丙基甲基纤维素、聚乙烯醇、聚乙烯吡咯烷酮、醋酸羟丙甲基纤维素琥珀酸酯、聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、尤特奇、共聚维酮、甲基纤维素、乙基纤维素、羧甲基纤维素钠、羟丙基纤维素、聚醋酸乙烯酯、环糊精、羧甲基乙基纤维素钠聚环氧乙烷、邻苯二甲酸乙酸纤维素、偏苯三酸乙酸纤维素。
  2. 权利要求1所述的药物组合物，其中
    所述制剂改良剂为选自以下的一种或多种：十二烷基硫酸钠、维生素E琥珀酸聚乙二醇酯、枸橼酸三乙酯。
  3. 权利要求1或2所述的药物组合物，其中
    所述载体材料为选自以下的一种或多种：羟丙甲纤维素邻苯二甲酸酯、羟丙基甲基纤维素、聚乙烯吡咯烷酮、醋酸羟丙甲基纤维素琥珀酸酯、聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、尤特奇。
  4. 权利要求1-3中任一项所述的药物组合物，其中
    所述药物组合物还包含选自以下的一种或多种：缓冲剂、酸化剂、稳定剂、防腐剂；
    优选地，
    所述缓冲剂为选自以下的一种或多种：柠檬酸缓冲剂、苹果酸盐缓冲剂、马来酸盐缓冲剂、酒石酸盐缓冲剂；和/或
    所述酸化剂为选自以下的一种或多种：酒石酸、碳酸、乙酸、草酸、亚硝酸；和/或
    所述稳定剂为选自以下的一种或多种：甲硫氨酸、赖氨酸、组氨酸；
    所述防腐剂为选自以下的一种或多种：苄醇、苯甲酸苄酯、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、维生素E、维生素A棕榈酸酯。
  5. 权利要求1-4中任一项所述的药物组合物，其中
    活性成分达罗他胺或其药学上可接受的盐与载体材料的重量比为约1:0.5-1:8；优选为约1:1-1:4；更优选为约1:2-1:4；和/或
    活性成分达罗他胺或其药学上可接受的盐与所述制剂改良剂的重量比为约1:0.05-1:0.8；优选为约1:0.1-1:0.5。
  6. 权利要求1-5中任一项所述的药物组合物，其中
    所述药物组合物的堆密度为约0.40-0.50g/mL；优选为约0.42-0.49g/mL；更优选为约0.436-0.473g/mL；和/或
    所述药物组合物的休止角为约20°-32°；优选约21°-30°；更优选约22°-28°。
  7. 一种固体制剂，其包含权利要求1-6中任一项所述的药物组合物。
  8. 一种制备权利要求1-6中任一项所述的药物组合物的方法，其包括以下步骤：
    (1)称取各组分；
    (2)混合步骤(1)的组分并进行热熔挤出，以获得药物组合物。
  9. 一种制备权利要求7的固体制剂的方法，其包括以下步骤：
    (1)根据权利要求8的方法制备药物组合物；
    (2)粉碎步骤(1)的药物组合物以获得药物组合物颗粒；
    (3)将步骤(2)的药物组合物颗粒与润滑剂以及其他制剂改良剂混合以获得总混颗粒；
    (4)压制步骤(3)的总混颗粒，以获得固体制剂；
    任选地，还包括如下步骤：
    (5)将步骤(4)的固体制剂包衣，以获得片剂。
  10. 权利要求1-6中任一项所述的药物组合物或者权利要求7的固体制剂在制备用于预防或治疗前列腺癌的药物中的用途。
PCT/CN2022/132894 2021-11-26 2022-11-18 一种达罗他胺药物组合物及其制备方法和用途 WO2023093640A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111422274.6 2021-11-26
CN202111422274.6A CN116173018A (zh) 2021-11-26 2021-11-26 一种达罗他胺药物组合物及其制备方法和用途

Publications (1)

Publication Number Publication Date
WO2023093640A1 true WO2023093640A1 (zh) 2023-06-01

Family

ID=86450983

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/132894 WO2023093640A1 (zh) 2021-11-26 2022-11-18 一种达罗他胺药物组合物及其制备方法和用途

Country Status (2)

Country Link
CN (1) CN116173018A (zh)
WO (1) WO2023093640A1 (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107286094A (zh) * 2016-04-12 2017-10-24 常州爱诺新睿医药技术有限公司 一种bay-1841788与药用辅料的固体分散体及其制备方法
WO2019032840A1 (en) * 2017-08-09 2019-02-14 Druggability Technologies Ip Holdco Limited PHARMACEUTICAL COMPOSITION COMPRISING ABIRATERONE ACETATE AND DAROLUTAMIDE
WO2022049075A1 (en) * 2020-09-02 2022-03-10 Bend Research, Inc. Amorphous solid dispersion of darolutamide

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106265580B (zh) * 2015-05-18 2020-09-08 中国科学院上海药物研究所 Somcl-9112固体分散体、其制备方法及包含其的somcl-9112固体制剂
US20200009060A1 (en) * 2016-05-09 2020-01-09 Dispersol Technologies, Llc Improved drug formulations
CN114144168A (zh) * 2019-07-02 2022-03-04 奥赖恩公司 达鲁酰胺的药物组合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107286094A (zh) * 2016-04-12 2017-10-24 常州爱诺新睿医药技术有限公司 一种bay-1841788与药用辅料的固体分散体及其制备方法
WO2019032840A1 (en) * 2017-08-09 2019-02-14 Druggability Technologies Ip Holdco Limited PHARMACEUTICAL COMPOSITION COMPRISING ABIRATERONE ACETATE AND DAROLUTAMIDE
WO2022049075A1 (en) * 2020-09-02 2022-03-10 Bend Research, Inc. Amorphous solid dispersion of darolutamide

Also Published As

Publication number Publication date
CN116173018A (zh) 2023-05-30

Similar Documents

Publication Publication Date Title
CN1496738B (zh) 具有高生物利用率的非诺贝特药物组合物及其制备方法
JP5775464B2 (ja) 非晶質ｃｄｄｏ−ｍｅを含有する遅延放出性経口投薬組成物
TWI556840B (zh) 治療用組成物
EP4035657A1 (en) Drug composition containing abiraterone acetate, and preparation method therefor and application thereof
WO2015154718A1 (zh) 泊沙康唑药物组合物及其制备方法、应用和药物制剂
US20090203709A1 (en) Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor
US20150352080A1 (en) Bioavailable compositions of metaxalone comprising nonvolatile liquids and processes for producing the same
JP2009502807A (ja) 薬剤含有率の高い製剤および投与量形態
US20190358240A1 (en) Hiv treatment formulation of atazanavir and cobicistat
JP6181322B2 (ja) フェロポルフィリン固体分散体およびその製造方法
CN115518066A (zh) 一种用于治疗抗凝血的药物组合物及应用
US20090209587A1 (en) Repaglinide formulations
EP1863446A2 (en) Controlled release pharmaceutical compositions of liothyronine and methods of making and using the same
JP2015003901A (ja) イルベサルタンを含有する錠剤
JP4866170B2 (ja) 睡眠薬の放出制御医薬組成物及びその製造方法
CN107693516B (zh) 一种地拉罗司药物组合物及其药物制剂、制备方法和用途
WO2023093640A1 (zh) 一种达罗他胺药物组合物及其制备方法和用途
KR20160092956A (ko) 라록시펜, 및 비타민 d 또는 그 유도체를 포함하는 복합 캡슐제
CN118284415A (zh) 一种达罗他胺药物组合物及其制备方法和用途
CN110917157B (zh) 含炔基化合物的药物组合物、其制备方法及应用
WO2021129340A1 (zh) 一种坦度螺酮药物组合物及其制备方法和用途
US20210121419A1 (en) Metformin compounded composition and method thereof
CN117547534B (zh) 尼可地尔缓释制剂及其制备方法
CN113521020B (zh) 一种含有水溶性酸的瑞德西韦固体剂型
JP2019210262A (ja) 口腔内崩壊錠剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22897723

Country of ref document: EP

Kind code of ref document: A1