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WO2022121961A1 - Fulvestrant pharmaceutical composition, preparation therefor, and application thereof - Google Patents

Fulvestrant pharmaceutical composition, preparation therefor, and application thereof Download PDF

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Publication number
WO2022121961A1
WO2022121961A1 PCT/CN2021/136576 CN2021136576W WO2022121961A1 WO 2022121961 A1 WO2022121961 A1 WO 2022121961A1 CN 2021136576 W CN2021136576 W CN 2021136576W WO 2022121961 A1 WO2022121961 A1 WO 2022121961A1
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Prior art keywords
fulvestrant
nanometers
pharmaceutical composition
solid particles
limited
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PCT/CN2021/136576
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French (fr)
Chinese (zh)
Inventor
陈志祥
孙宝
王婷婷
应述欢
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.)
Shanghai Bocimed Pharmaceutical Co Ltd
Shanghai Bocimed Pharmaceutical Research Co Ltd
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Shanghai Bocimed Pharmaceutical Co Ltd
Shanghai Bocimed Pharmaceutical Research Co Ltd
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Publication of WO2022121961A1 publication Critical patent/WO2022121961A1/en
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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—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
    • A61K47/36—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
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • 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
    • A61P35/04—Antineoplastic agents specific for metastasis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the invention relates to a fulvestrant pharmaceutical composition, a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations.
  • Fulvestrant is a selective estrogen receptor degrader (SERD) indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression after antiestrogen therapy. It was approved by the US FDA in 2002 for the treatment of hormone receptor-positive metastatic breast cancer.
  • SESD selective estrogen receptor degrader
  • Fulvestrant is a lipophilic molecule with very low water solubility. Due to poor solubility and low oral bioavailability of fulvestrant, it is currently commonly administered by intramuscular injection of oil-based fulvestrant formulations.
  • the marketed formulation of fulvestrant, FASLOdexTM is administered at 500 mg and requires two intramuscular administrations of two 5 mL injections of the 50 mg/mL fulvestrant formulation. Each 5mL injection contains 10w/v% ethanol, 10w/v% benzyl alcohol and 15w/v% benzyl benzoate as co-solvents, supplemented to 100w/v with castor oil as another co-solvent and release rate modifier v%.
  • the present invention provides a fulvestrant pharmaceutical composition, which comprises fulvestrant solid particles, and the particle diameter of the fulvestrant solid particles is that Dv(10) is selected from the group consisting of less than or equal to 600 nm, for example, 400 nm or less, Dv(50) is selected from 700 nm or less and Dv(90) is selected from 1000 nm or less.
  • the particle size of the fulvestrant solid particles can be Dv(10) selected from less than or equal to 500 nanometers, selected from less than or equal to 400 nanometers, such as 0.01 nanometers to 400 nanometers, such as Dv(10 nanometers) ) is selected from 1 nanometer to 550 nanometers, and can also be selected from 10 nanometers to 500 nanometers, such as 20 nanometers, 30 nanometers, 40 nanometers, 50 nanometers, 60 nanometers, 70 nanometers, 80 nanometers, 90 nanometers, 100 nanometers, 110 nanometers, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm , 290 n
  • the particle size of the fulvestrant solid particles may be that Dv(50) is selected from 0.01 nm to 700 nm, for example, Dv(50) is selected from 1 nm to 600 nm, or can be selected from 10nm ⁇ 500nm, such as 10nm, 20nm, 30nm, 40nm, 50nm, 60nm, 70nm, 80nm, 90nm, 100nm, 110nm, 120nm, 130nm, 140nm, 150nm Nano, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm, 350 nm, 400 nanometers, 450 nanometers, 500 nanometers, examples of which may be selected from 401.
  • the particle size of the fulvestrant solid particles may be Dv(90) selected from 1 nanometer to 1000 nanometers, for example, Dv(90) selected from 10 nanometers to 900 nanometers, or 100 nanometers.
  • Nano to 800 nm such as 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm , 250nm, 260nm, 270nm, 280nm, 290nm, 300nm, 350nm, 400nm, 450nm, 500nm, 550nm, 600nm, 650nm, 700nm, 750nm, 800nm Examples may be selected from 716.500 nanometers, 866.720 nanometers, 599.350 nanometers, 657.69 nanometers or 657.05 nanometers.
  • the particle size of the fulvestrant solid particles can also be Dv(25) selected from 1 nanometer to 600 nanometers, for example, Dv(25) selected from 10 nanometers to 500 nanometers, or can be Dv(25) is selected from 100 nm to 400 nm, such as 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm nanometer, 230 nanometer, 240 nanometer, 250 nanometer, 260 nanometer, 270 nanometer, 280 nanometer, 290 nanometer, 300 nanometer, 350 nanometer, 400 nanometer, examples of which can be selected from 272.00 nanometer, 189.28 nanometer, 316.91 nanometer, 480.27 nanometer, or 398.95 nanometer nano.
  • the particle size of the fulvestrant solid particles can also be Dv(75) selected from 1 nanometer to 900 nanometers, for example, Dv(75) selected from 10 nanometers to 800 nanometers, or can be Dv(75) is selected from 100 nm to 700 nm, such as 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, Examples thereof may be selected from 540.00 nanometers
  • the fulvestrant pharmaceutical composition described in the present invention may also include a carrier.
  • the carrier can be a non-oily carrier.
  • the non-oily carrier includes, but is not limited to, water.
  • the water can be conventional commercially available water for injection, preferably sterile water for injection.
  • the pH of the fulvestrant pharmaceutical composition is 6.5-8.0, such as 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8 , 7.9 or 8.0, such as 7.4.
  • the pharmaceutical composition of fulvestrant may further comprise one or more selected from the group consisting of: suspending agent, wetting agent, osmotic pressure regulator, solvent, stabilizer, buffer , pH adjusters, surfactants, polymers, electrolytes and non-electrolytes.
  • the polymer may be a cross-linked polymer and/or a non-cross-linked polymer.
  • the suspending agent includes, but is not limited to, one or more of sodium carboxymethyl cellulose, polyethylene glycol and povidone.
  • the wetting agent includes, but is not limited to, one or more of poloxamer, povidone, sodium docusate, sodium deoxycholate and Tween.
  • the Tween can be a conventional commercially available Tween reagent, such as one or more of Tween 20 and Tween 80.
  • the osmotic pressure regulator includes, but is not limited to, one or more of sodium chloride, mannitol and sucrose.
  • the solvent includes, but is not limited to, water for injection.
  • the stabilizers include, but are not limited to, antioxidants, metal ion chelating agents, polyethylene oxide (PEO), polyethylene oxide derivatives, polysorbates, deoxycholic acid Sodium, Docusate Sodium, Poloxamer, Polyethoxylated Vegetable Oil, Polyethoxylated Castor Oil, Sorbitan Palmitate, Lecithin, Polyvinyl Alcohol, Human Serum Albumin, Polyvinylpyrrolidone One or more of , povidone, polyethylene glycol, sodium chloride, calcium chloride, dextrose, glycerol, mannitol, and cross-linked polymers.
  • PEO polyethylene oxide
  • polyethylene oxide derivatives polysorbates
  • deoxycholic acid Sodium Docusate Sodium
  • Poloxamer Polyethoxylated Vegetable Oil
  • Polyethoxylated Castor Oil Sorbitan Palmitate
  • Lecithin Polyvinyl Alcohol
  • Human Serum Albumin Polyvinylpyrrolidone
  • the antioxidants include, but are not limited to, one or more of citric acid, vitamin C and vitamin E.
  • the metal ion chelating agent includes but is not limited to ethylenediaminetetraacetic acid (EDTA).
  • the poloxamers include but are not limited to one or more of poloxamer 188, poloxamer 124 and poloxamer 407.
  • the polysorbate includes, but is not limited to, one or more of polysorbate 80 and polysorbate 20. Described povidone includes but is not limited to: one or more of povidone K12, povidone K17, PLASDONETM C-12 povidone, PLASDONETM C-17 povidone and PLASDONETM C-30 povidone. kind.
  • the polyethylene glycols include but are not limited to polyethylene glycol 3350.
  • the cross-linked polymer includes but is not limited to sodium carboxymethyl cellulose.
  • the buffering agent includes, but is not limited to: phosphoric acid, phosphate, citric acid (citric acid), sodium citrate (sodium citrate), tris (Tris), Buffers of sodium hydroxide, hydrochloric acid (HCl) or mixtures thereof.
  • the pH adjusting agent includes, but is not limited to, phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid and sodium hydroxide.
  • the phosphates include but are not limited to disodium hydrogen phosphate, sodium dihydrogen phosphate or mixtures or hydrates thereof, such as disodium hydrogen phosphate monohydrate (Na 2 HPO 4 ⁇ H 2 O), Disodium hydrogen phosphate dihydrate (Na 2 HPO 4 ⁇ 2H 2 O), disodium hydrogen phosphate anhydrous (anhydrous Na 2 HPO 4 ), sodium dihydrogen phosphate monohydrate (NaH 2 PO 4 ⁇ H 2 O), two One or more of anhydrous sodium dihydrogen phosphate (NaH 2 PO 4 ⁇ 2H 2 O) and anhydrous sodium dihydrogen phosphate (anhydrous NaH 2 PO 4 ).
  • the co-solvent includes, but is not limited to, one or more of ethanol and propylene glycol.
  • the weight fraction of fulvestrant solid particles is preferably 1.00% to 50.00%, preferably 2.00% to 30.00%, such as 2.00% to 25.00%, such as 2.00%, 3.00%, 4.00% %, 5.00%, 6.00%, 7.00%, 8.00%, 9.00%, 10.00%, 11.00%, 12.00%, 13.00%, 14.00%, 15.00%, 16.00%, 17.00%, 18.00%, 19.00%, 20.00%, 21.00%, 22.00%, 23.00%, 24.00%, 25.00%, such as 5.00% or 25.00%; the weight fraction refers to the percentage of the weight of fulvestrant solid particles in the total weight of the fulvestrant pharmaceutical composition.
  • the weight fraction of the wetting agent is preferably 0-5.00%, such as 1.00%, 2.00%, 3.00%, 4.00%, 5.00%, such as 1.00%; the described The weight fraction refers to the percentage of the weight of the surfactant in the total weight of the fulvestrant pharmaceutical composition.
  • the weight fraction of the suspending agent is preferably 0 to 5.00%, such as 0, 1.00%, 2.00%, 3.00%, 4.00%, 5.00%; the weight fraction It refers to the percentage of the weight of the suspending agent to the total weight of the fulvestrant pharmaceutical composition.
  • the weight fraction of the osmotic pressure regulator is preferably 0 to 5.00%, such as 0, 1.00%, 2.00%, 3.00%, 4.00%, 5.00%; the weight Fraction refers to the weight of the osmolarity modifier as a percentage of the total weight of the fulvestrant pharmaceutical composition.
  • the weight fraction of the buffer is preferably 0-1.00%, such as 0, 0.10%, 0.20%, 0.30%, 0.40%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.00%; the weight fraction refers to the percentage of the weight of the buffer in the total weight of the fulvestrant pharmaceutical composition.
  • the weight fraction of the stabilizer is preferably 0 to 1.00%, such as 0, 0.10%, 0.20%, 0.30%, 0.40%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.00%, such as 0.60% or 0.32%; the weight fraction refers to the percentage of the weight of the stabilizer in the total weight of the fulvestrant pharmaceutical composition.
  • the pH adjusting agent is preferably used in an amount to adjust the pH of the composition solution to 6.5-8.0, such as 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4 , 7.5, 7.6, 7.7, 7.8, 7.9 or 8.0, such as 7.4.
  • the fulvestrant pharmaceutical composition preferably includes the following components: 1.00%-50.00% fulvestrant solid particles, 0-5.00% wetting agent, 0-5.00% stabilizer, 0-5.00% osmotic pressure Conditioning agents, 0-1.00% buffer and solvent, and optionally 0-5.00% suspending agent, either present or absent.
  • the fulvestrant pharmaceutical composition preferably includes the following components: 1.00%-50.00% fulvestrant solid particles, 0-5.00% wetting agent, 0-5.00% stabilizer, 0-5.00% % osmotic pressure regulator and 0-1.00% buffer, and optionally 0-5.00% suspending agent present or absent, and the balance being solvent.
  • the described fulvestrant pharmaceutical composition can be any of the following formulas:
  • Formulation 1 5.00% fulvestrant solid particles, 0.50% povidone K12, 0.30% sodium deoxycholate, 2.78% mannitol, pH adjuster and water, wherein the pH adjuster adjusts the pH of the diluent to pH7. 4.
  • the pH regulators are sodium dihydrogen phosphate and disodium hydrogen phosphate;
  • Formulation 2 5.00% fulvestrant solid particles, 0.50% povidone K12, 0.20% poloxamer 188, 2.78% mannitol, pH adjuster and water, wherein the pH adjuster adjusts the pH of the diluent to pH7 .4, pH regulators are sodium dihydrogen phosphate and disodium hydrogen phosphate;
  • Formulation three 5.00% fulvestrant, 1.00% Tween 20, 0.30% povidone K12, 0.30% sodium deoxycholate, 2.76% mannitol, pH adjuster and water, wherein the pH adjuster adjusts the pH of the diluent Adjusted to pH 7.4, pH regulators are sodium dihydrogen phosphate and disodium hydrogen phosphate;
  • Formulation four 5.00% fulvestrant, 1.00% Tween 20, 0.30% povidone K12, 0.02% docusate sodium, 2.76% mannitol, pH adjuster and water, wherein the pH adjuster adjusts the pH of the diluent Adjusted to pH 7.4, pH regulators are sodium dihydrogen phosphate and disodium hydrogen phosphate;
  • Formula five 25.00% fulvestrant, 1.00% Tween 20, 0.20% CMC-Na, 0.42% disodium hydrogen phosphate, 0.09% sodium dihydrogen phosphate, 2.29% mannitol, 0.30% sodium deoxycholate, 0.30% PVP K12 and water.
  • Formula 6 25.00% fulvestrant, 1.60% Tween 20, 0.20% CMC-Na, 0.42% disodium hydrogen phosphate, 0.09% sodium dihydrogen phosphate, 2.27% mannitol, 0.30% sodium deoxycholate, 0.30% PVP K12 and water.
  • the present invention also provides the preparation method of described fulvestrant pharmaceutical composition, it comprises the following steps:
  • Step 1 Mix the solid particles of fulvestrant with other components in the formula to obtain a premix
  • Step 2 The premix obtained in Step 1 is co-milled with zirconium beads to obtain a fulvestrant pharmaceutical composition.
  • step 1 the mixing is preferably stirring and mixing.
  • the particle size of the zirconium beads may be 0.01 mm ⁇ 2 mm, such as 0.1 mm, 0.3 mm, 0.6 mm or 1 mm.
  • the volume ratio of the zirconium beads to the premix is preferably 1 to 5, such as 1, 1.5, 2 or 3.
  • the grinding time may be 1 minute to 24 hours, or 5 minutes to 20 hours, for example, 4 hours or 12 hours.
  • the zirconium beads refer to conventional commercially available zirconia beads.
  • the present invention also provides the application of the fulvestrant pharmaceutical composition in preparing the fulvestrant pharmaceutical preparation.
  • the fulvestrant pharmaceutical preparation includes, but is not limited to, one or more of tablets, granules, capsules, pellets, oral liquids, and injections.
  • the tablet includes, but is not limited to, one or more of sustained release tablet, osmotic pump tablet and orally disintegrating tablet.
  • the injection can be a liquid injection, a powder for injection or a tablet for injection; for example, the liquid injection can be a suspension, such as an aqueous suspension or a powder for suspension; for example, the suspension The powder can be lyophilized for injection.
  • the injection can be a long-acting injection; the long-acting injection can be a water suspension or a powder for suspension, and a specific diluent is used to disperse it into a suspension for temporary use. .
  • the concentration of the fulvestrant in the long-acting injection is not less than 50 mg/ml.
  • the present invention also provides a fulvestrant pharmaceutical preparation, which contains the above-mentioned fulvestrant pharmaceutical composition.
  • the fulvestrant pharmaceutical formulation has the dosage form selection and/or fulvestrant concentration as described above.
  • the present invention also provides the application of the above-mentioned fulvestrant pharmaceutical composition and/or fulvestrant pharmaceutical preparation in preventing and/or treating hormone receptor-positive metastatic breast cancer.
  • the present invention also provides a method for preventing and/or treating hormone receptor-positive metastatic breast cancer, comprising administering the above-mentioned fulvestrant pharmaceutical composition and/or fulvestrant pharmaceutical preparation to a patient in need, such as a human.
  • Dv(10)”, “Dv(25)”, “Dv(50)”, “Dv(75)” and “Dv(90)” refer to volume-weighted particles Diameter where cumulative 10 v/v%, 25 v/v%, 50 v/v%, 75 v/v% or 90 v/v% of particles respectively have equal or smaller diameters when measured. For example, if the Dv(50) of a population of particles is about 25 microns, then 50% of the particles by volume have a diameter of less than or equal to about 25 microns.
  • Particle diameter parameters in the context of this application such as “D(10)”, “D(25)”, “D(50)”, “D(75)” and “D(90)", unless otherwise specified, are Refers to the volume-weighted particle diameter, which has the same meaning as “Dv(10)”, “Dv(25)”, “Dv(50)”, “Dv(75)” and “Dv(90)", respectively.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the room temperature refers to an ambient temperature ranging from 10°C to 35°C.
  • the fulvestrant pharmaceutical composition of the present invention has a favorable release rate, rapidly reaches a peak concentration after administration, maintains a high blood drug concentration, and has high bioavailability;
  • the pharmaceutical composition has high content of active pharmaceutical ingredients, no organic solvent or oil, low irritation, convenient administration, reduced administration volume, greatly reduced injection pain, and good market prospect.
  • Fig. 1 is the particle size distribution diagram of fulvestrant solid particles in the suspension after grinding in Example 1;
  • Fig. 2 is the solid polarized light microscope observation diagram of fulvestrant in the suspension after grinding in Example 1, and the ruler is 20 microns;
  • Fig. 3 is the particle size distribution figure of fulvestrant solid particles in the suspension after grinding 12h in Example 2;
  • Fig. 4 is the solid polarized light microscope observation diagram of fulvestrant in the suspension after grinding 4h in Example 2, and the scale is 10 microns;
  • Example 5 is a solid polarized light microscope observation diagram of fulvestrant in the suspension after grinding for 12h in Example 2, and the scale is 10 microns;
  • Fig. 6 is the solid polarized light microscope observation diagram of fulvestrant in the suspension after grinding 4h in Example 3, and the scale is 10 microns;
  • Fig. 7 is the particle size distribution figure of fulvestrant solid particle in the suspension after prescription 4 grinding 17h in embodiment 4;
  • Fig. 8 is the particle size distribution diagram of fulvestrant solid particles in the suspension after prescription 5 is ground for 17h in Example 4;
  • Fig. 9 is the particle size distribution figure of fulvestrant solid particle in the suspension after prescription 6 is ground in embodiment 5;
  • Fig. 10 is the particle size distribution figure of fulvestrant solid particle in the suspension after prescription 7 grinding in embodiment 5;
  • Fig. 11 is the scanning electron microscope picture of fulvestrant solid particle in the suspension after prescription 6 grinding in embodiment 5;
  • Fig. 12 is the scanning electron microscope picture of fulvestrant solid particle in the suspension after prescription 7 grinding in embodiment 5;
  • Figure 14 The drug-time curve of fulvestrant suspension (G1) at a dose of 15 mg/kg in rats;
  • Figure 15 The drug-time curve of fulvestrant suspension (G2) at a dose of 15 mg/kg in rats;
  • Figure 16 The drug-time curve of fulvestrant suspension (G3) at a dose of 15 mg/kg in rats;
  • Figure 17 The drug-time curve of fulvestrant suspension (G4) at a dose of 30 mg/kg in rats.
  • the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods.
  • the experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.
  • the parameters of the planetary ball mill are set: fixed parameters: the diameter of the rotating disk is about 191mm, the diameter of the rotating cup is about 71mm, the height of the rotating cup is about 70mm, the capacity of the rotating cup is 100ml, and the rotating speed of the rotating disk is 10r/min. Rotation speed: 720r/ min.
  • the particle size morphology of the particles in the suspension after grinding was observed by polarized light microscope.
  • the particle size distribution data of the solid particles of fulvestrant in the suspension after grinding at different times are shown in Table 2 and Table 2.
  • the particle size distribution and morphology of the solid particles of fulvestrant in the suspension after grinding are shown in Figure 1 and Figure 2, respectively.
  • Table 2 The particle size distribution (volume weighting) of fulvestrant in the composition obtained by grinding at different times in the suspension of Example 1
  • Diluent composition (w/w% based on the total weight of the diluent): mannitol 2.95%, 0.122% sodium dihydrogen phosphate, 0.58% disodium hydrogen phosphate, the balance is water, pH 7.4.
  • the initial suspension was added with 0.3 mm zirconium beads of 1.5 times the volume, placed in a grinding jar for grinding, and ground for 12 hours to obtain a fulvestrant pharmaceutical composition. Grinding is carried out with a ball mill.
  • the parameters of the planetary ball mill are set: Fixed parameters: the diameter of the rotating disc is about 191mm, the diameter of the rotating cup is about 71mm, the height of the rotating cup is about 70mm, the capacity of the rotating cup is 100ml, and the rotating speed of the rotating disc is 10r/min. Rotation speed: 720r/ min.
  • the particle size was determined by a nanoparticle particle size analyzer (NICOMP Particle Sizing Systems, parameter setting: dispersion medium: water; refractive index of dispersion medium: 1.333; viscosity: 0.933cp; temperature: 23 °C, light intensity setting value: 300 kHz).
  • the particle size morphology of grinding 4h and grinding end point 12h was observed by polarized light microscope.
  • the particle size distribution data of the solid particles of fulvestrant in the suspension after grinding for 12 hours are shown in Table 4 and Figure 3.
  • the particle size morphology of the solid particles of fulvestrant in the suspension after grinding for 4h and 12h is shown in Figure 4 and Figure 5, respectively. After grinding for 4h and 12h, the solid particles of fulvestrant in the suspension were respectively smaller than 2 microns and smaller than 1 micron.
  • Diluent composition (w/w% based on the total weight of the diluent): mannitol 2.95%, 0.122% sodium dihydrogen phosphate, 0.58% disodium hydrogen phosphate, the balance is water, pH 7.4.
  • the initial suspension was added with 1.5 times the volume of 0.3 mm zirconium beads, placed in a grinding jar for grinding, and ground for 4 hours to obtain a fulvestrant pharmaceutical composition. Grinding is carried out with a ball mill.
  • the parameters of the planetary ball mill are set: Fixed parameters: the diameter of the rotating disc is about 191mm, the diameter of the rotating cup is about 71mm, the height of the rotating cup is about 70mm, the capacity of the rotating cup is 100ml, and the rotating speed of the rotating disc is 10r/min. Rotation speed: 720r/ min.
  • Diluent composition (w/w% based on the total weight of the diluent): mannitol 2.95%, 0.122 g sodium dihydrogen phosphate, 0.58 g disodium hydrogen phosphate, the balance is water, pH 7.4.
  • the initial suspension was added with 1.5 times the volume of 0.3 mm zirconium beads, placed in a grinding jar for grinding, and ground for 17 hours to obtain a fulvestrant pharmaceutical composition. Grinding is carried out with a ball mill.
  • the parameters of the planetary ball mill are set: Fixed parameters: the diameter of the rotating disc is about 191mm, the diameter of the rotating cup is about 71mm, the height of the rotating cup is about 70mm, the capacity of the rotating cup is 100ml, and the rotating speed of the rotating disc is 10r/min. Rotation speed: 720r/ min.
  • the particle size was determined by a nanoparticle particle size analyzer (NICOMP Particle Sizing Systems, parameter setting: dispersion medium: water; refractive index of dispersion medium: 1.333; viscosity: 0.933cp; temperature: 23 °C, light intensity setting value: 300 kHz).
  • NICOMP Particle Sizing Systems parameter setting: dispersion medium: water; refractive index of dispersion medium: 1.333; viscosity: 0.933cp; temperature: 23 °C, light intensity setting value: 300 kHz).
  • the raw and auxiliary materials were prepared, and 1.5 times the volume of zirconium beads was added and placed in a grinding jar for grinding. Among them, 0.3mm and 0.6mm zirconium beads were used in prescriptions 6 and 7, respectively, and the grinding time was 21 hours and 25 hours, respectively.
  • a fulvestrant pharmaceutical composition is obtained. Grinding is carried out with a ball mill.
  • the parameters of the planetary ball mill are set: Fixed parameters: the diameter of the rotating disc is about 191mm, the diameter of the rotating cup is about 71mm, the height of the rotating cup is about 70mm, the capacity of the rotating cup is 100ml, and the rotating speed of the rotating disc is 10r/min. Rotation speed: 720r/ min.
  • the particle size was determined by a nanoparticle particle size analyzer (NICOMP Particle Sizing Systems, parameter setting: dispersion medium: water; refractive index of dispersion medium: 1.333; viscosity: 0.933cp; temperature: 23 °C, light intensity setting value: 300 kHz).
  • the particle size distribution data of the solid particles of fulvestrant in the grinding suspension of the formulations 6 and 7 are shown in Table 4, FIG. 9 and FIG. 10 .
  • the morphology and size were observed by scanning electron microscope (FEI, model F50). Scanning electron microscope voltage 10kv, beam current 2.0 test. The electron micrographs of the solid particles of fulvestrant in the grinding suspension of the formulations 6 and 7 are shown in Figs. 11 and 12 . Irregular massive particles smaller than 1 ⁇ m were observed.
  • the related substances of fulvestrant were detected according to EP10.0 method.
  • the results of the relevant substances are shown in Table 8. The results showed that the single impurity and total impurity of the related substances in the self-made suspension were lower than those of the marketed comparative preparation, indicating that the quality was better.
  • ND means not detected
  • 6-Keto fulvestrant (6-keto fulvestrant), 6,7-fulvestrant (6,7-fulvestrant), Fulvestrant beta-Isomer (fulvestrant beta isomer), Fulvestrant Sulphone (fulvestrant) sulfone), Fulvestrant Bromo Analogue, Fulvestrant Extended, Fulvestrant Sterol Dimer.
  • the formulations 6 and 7 obtained in Example 5 were diluted to 50 mg/ml with a diluent.
  • the composition of the diluent is: 1.62% Tween 20, 0.2% sodium carboxymethyl cellulose, 2.29% mannitol, 0.09% anhydrous sodium dihydrogen phosphate, 0.42% anhydrous disodium hydrogen phosphate.
  • the diluted prescription 6 (G2) and prescription 7 (G3) fulvestrant suspension the marketed comparative preparation fulvestrant injection FASLODEX (G1, 50mg/ml, Germany VETTER Pharma-fertigung GmbH & Co KG, batch number: RH832 , the validity period is February 2024) according to fulvestrant 15mg/kg (administration volume 0.3mL/kg) and undiluted prescription 7 fulvestrant suspension according to fulvestrant 30mg/kg (G4, administration Volume 0.11mL/kg) intramuscular injection into the lateral thigh of male Wistar rats, SPF animals, 189 ⁇ 200g, 6 ⁇ 8 weeks old (Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., quality certificate number 110011200110944286, license for use No. SYXK (Su) 2018-0034), 3 per group.
  • Clinical observation was performed after administration, and the first day of administration (D1) was observed twice: before administration and in the afternoon after administration, and then once a day for a total of 45 days.
  • Clinical observations include skin, coat, eyes, ears, nose, mouth, chest, abdomen, genitourinary, limbs, etc., as well as changes in breathing, exercise, urination, defecation, and behavior, and muscle irritation at the administration site.

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Abstract

A fulvestrant pharmaceutical composition, a preparation method therefor, and an application thereof. The fulvestrant pharmaceutical composition comprises fulvestrant solid particles, wherein the size of the fulvestrant solid particles is such that Dv(10) is less than or equal to 600 nanometers, Dv(50) is less than or equal to 700 nanometers, and Dv(90) is less than or equal to 1,000 nanometers. The fulvestrant pharmaceutical composition has an appropriate release rate. Peak concentration is reached rapidly after administration and a high plasma concentration is maintained. The composition contains a high amount of drug content and no organic solvent or oil, causes little irritation, is easy to administer, allows for reduced dosage volumes and significantly reduced injection pain, and has good market prospects.

Description

氟维司群药物组合物、其制备方法及应用Fulvestrant pharmaceutical composition, its preparation method and application

本申请要求享有2020年12月10日向中国国家知识产权局提交的申请号为202011433060.4，名称为“氟维司群药物组合物、其制备方法及应用”的在先专利申请的优先权权益。该在先申请的全文以引用的方式结合至本文中。This application claims to enjoy the priority rights of the prior patent application with the application number 202011433060.4 and the title of "Fulvestrant pharmaceutical composition, its preparation method and application" filed with the State Intellectual Property Office of China on December 10, 2020. The entire contents of this prior application are incorporated herein by reference.

技术领域technical field

本发明涉及氟维司群药物组合物、其制备方法及应用，属于药物制剂技术领域。The invention relates to a fulvestrant pharmaceutical composition, a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations.

背景技术Background technique

氟维司群是一种选择性雌激素受体降解剂(SERD)，用于抗雌激素疗法后疾病进展的绝经后妇女的激素受体阳性转移性乳癌的治疗。2002年经美国FDA批准可用于治疗激素受体阳性转移性乳腺癌。Fulvestrant is a selective estrogen receptor degrader (SERD) indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression after antiestrogen therapy. It was approved by the US FDA in 2002 for the treatment of hormone receptor-positive metastatic breast cancer.

氟维司群化学名7-(9-(4,4,5,5,5-五氟戊基亚磺酰基)壬基)雌-1,3,5(10)-三烯-3,17-二醇，其结构如式I所示：Fulvestrant chemical name 7-(9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl)estra-1,3,5(10)-triene-3,17 -diol, the structure of which is shown in formula I:

Figure PCTCN2021136576-appb-000001
Figure PCTCN2021136576-appb-000001

氟维司群是一种亲脂分子，水溶性极低。由于氟维司群溶解性差和口服生物利用度低，所以目前普遍通过肌肉内注射油基氟维司群制剂来施用。目前，氟维司群的市售制剂FASLODEXTM以500mg给予，并且需要肌肉内施用两次50mg/mL氟维司群制剂的5mL注射液。每个5mL注射液含有10w/v％乙醇、10w/v％苯甲醇和15w/v％苯甲酸苯甲酯作为共溶剂，并用蓖麻油作为另一种共溶剂和释放速率调节剂补充至100w/v％。由于使用粘性油基载体来溶解氟维司群，所以施用该制剂缓慢(每次注射1-2分钟)并且疼痛。并且，FASLODEXTM标签上增加了关于注射疼痛、坐骨神经痛、神经性疼痛和外周神经病的警告。Fulvestrant is a lipophilic molecule with very low water solubility. Due to poor solubility and low oral bioavailability of fulvestrant, it is currently commonly administered by intramuscular injection of oil-based fulvestrant formulations. Currently, the marketed formulation of fulvestrant, FASLOdex™, is administered at 500 mg and requires two intramuscular administrations of two 5 mL injections of the 50 mg/mL fulvestrant formulation. Each 5mL injection contains 10w/v% ethanol, 10w/v% benzyl alcohol and 15w/v% benzyl benzoate as co-solvents, supplemented to 100w/v with castor oil as another co-solvent and release rate modifier v%. Administration of this formulation is slow (1-2 minutes per injection) and painful due to the use of a viscous oil-based vehicle to dissolve fulvestrant. Also, warnings about injection pain, sciatica, neuropathic pain, and peripheral neuropathy have been added to the FASLOdex™ label.

因此，寻找不含有机溶剂或油、刺激性小、具有适宜的释放速度，给药后迅速达到峰浓度且维持较高血药浓度、且施用方便、疼痛度低的氟维司群剂型，是目前急需解决的技术问题。Therefore, looking for a fulvestrant dosage form that does not contain organic solvents or oils, is less irritating, has a suitable release rate, quickly reaches a peak concentration after administration, maintains a higher blood concentration, and is easy to administer and less painful. Technical problems that need to be solved urgently.

发明内容SUMMARY OF THE INVENTION

为改善上述技术问题，本发明提供了一种氟维司群药物组合物，其包含氟维司群固体粒子，所述的氟维司群固体粒子的粒径为Dv(10)选自小于等于600纳米，例如小于等于400纳米，Dv(50)选自小于等于700纳米且Dv(90)选自小于等于1000纳米。In order to improve the above-mentioned technical problems, the present invention provides a fulvestrant pharmaceutical composition, which comprises fulvestrant solid particles, and the particle diameter of the fulvestrant solid particles is that Dv(10) is selected from the group consisting of less than or equal to 600 nm, for example, 400 nm or less, Dv(50) is selected from 700 nm or less and Dv(90) is selected from 1000 nm or less.

根据本发明的实施方案，所述的氟维司群固体粒子的粒径可以为Dv(10)选自小于等于500纳米，选自小于等于400纳米，如0.01纳米～400纳米，例如Dv(10)选自1纳米～550纳米，也可以选自10纳米～500纳米，如20纳米、30纳米、40纳米、50纳米、60纳米、70纳米、80纳米、90纳米、100纳米、110纳米、120纳米、130纳米、140纳米、150纳米、160纳米、170纳米、180纳米、190纳米、200纳米、210纳米、220纳米、230纳米、240纳米、250纳米、260纳米、270纳米、280纳米、290纳米、300纳米、350纳米、400纳米、450纳米、500纳米，其实例可以选自196.200纳米、132.420纳米、435.63纳米或341.71纳米。According to an embodiment of the present invention, the particle size of the fulvestrant solid particles can be Dv(10) selected from less than or equal to 500 nanometers, selected from less than or equal to 400 nanometers, such as 0.01 nanometers to 400 nanometers, such as Dv(10 nanometers) ) is selected from 1 nanometer to 550 nanometers, and can also be selected from 10 nanometers to 500 nanometers, such as 20 nanometers, 30 nanometers, 40 nanometers, 50 nanometers, 60 nanometers, 70 nanometers, 80 nanometers, 90 nanometers, 100 nanometers, 110 nanometers, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm , 290 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, examples of which may be selected from 196.200 nm, 132.420 nm, 435.63 nm, or 341.71 nm.

根据本发明的实施方案，所述的氟维司群固体粒子的粒径可以为Dv(50)选自0.01纳米～700纳米，例如Dv(50)选自1纳米～600纳米，也可以选自10纳米～500纳米，如10纳米、20纳米、30纳米、40纳米、50纳米、60纳米、70纳米、80纳米、90纳米、100纳米、110纳米、120纳米、130纳米、140纳米、150纳米、160纳米、170纳米、180纳米、190纳米、200纳米、210纳米、220纳米、230纳米、240纳米、250纳米、260纳米、270纳米、280纳米、290纳米、300纳米、350纳米、400纳米、450纳米、500纳米，其实例可以选自401.800纳米、281.630纳米、448.340纳米、473.84纳米或535.27纳米。According to an embodiment of the present invention, the particle size of the fulvestrant solid particles may be that Dv(50) is selected from 0.01 nm to 700 nm, for example, Dv(50) is selected from 1 nm to 600 nm, or can be selected from 10nm～500nm, such as 10nm, 20nm, 30nm, 40nm, 50nm, 60nm, 70nm, 80nm, 90nm, 100nm, 110nm, 120nm, 130nm, 140nm, 150nm Nano, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm, 350 nm, 400 nanometers, 450 nanometers, 500 nanometers, examples of which may be selected from 401.800 nanometers, 281.630 nanometers, 448.340 nanometers, 473.84 nanometers, or 535.27 nanometers.

根据本发明的实施方案，所述的氟维司群固体粒子的粒径可以为Dv(90)选自1纳米～1000纳米，例如Dv(90)选自10纳米～900纳米，也可以为100纳米～800纳米，如100纳米、110纳米、120纳米、130纳米、140纳米、150纳米、160纳米、170纳米、180纳米、190纳米、200纳米、210纳米、220纳米、230纳米、240纳米、250纳米、260纳米、270纳米、280纳米、290纳米、300纳米、350纳米、400纳米、450 纳米、500纳米、550纳米、600纳米、650纳米、700纳米、750纳米、800纳米，其实例可以选自716.500纳米、866.720纳米、599.350纳米、657.69纳米或657.05纳米。According to an embodiment of the present invention, the particle size of the fulvestrant solid particles may be Dv(90) selected from 1 nanometer to 1000 nanometers, for example, Dv(90) selected from 10 nanometers to 900 nanometers, or 100 nanometers. Nano to 800 nm, such as 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm , 250nm, 260nm, 270nm, 280nm, 290nm, 300nm, 350nm, 400nm, 450nm, 500nm, 550nm, 600nm, 650nm, 700nm, 750nm, 800nm Examples may be selected from 716.500 nanometers, 866.720 nanometers, 599.350 nanometers, 657.69 nanometers or 657.05 nanometers.

根据本发明的实施方案，所述的氟维司群固体粒子的粒径也可以为Dv(25)选自1纳米～600纳米，例如Dv(25)选自10纳米～500纳米，也可以为Dv(25)选自100纳米～400纳米，如100纳米、110纳米、120纳米、130纳米、140纳米、150纳米、160纳米、170纳米、180纳米、190纳米、200纳米、210纳米、220纳米、230纳米、240纳米、250纳米、260纳米、270纳米、280纳米、290纳米、300纳米、350纳米、400纳米，其实例可以选自272.00纳米、189.28纳米、316.91纳米、480.27纳米或398.95纳米。According to an embodiment of the present invention, the particle size of the fulvestrant solid particles can also be Dv(25) selected from 1 nanometer to 600 nanometers, for example, Dv(25) selected from 10 nanometers to 500 nanometers, or can be Dv(25) is selected from 100 nm to 400 nm, such as 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm nanometer, 230 nanometer, 240 nanometer, 250 nanometer, 260 nanometer, 270 nanometer, 280 nanometer, 290 nanometer, 300 nanometer, 350 nanometer, 400 nanometer, examples of which can be selected from 272.00 nanometer, 189.28 nanometer, 316.91 nanometer, 480.27 nanometer, or 398.95 nanometer nano.

根据本发明的实施方案，所述的氟维司群固体粒子的粒径也可以为Dv(75)选自1纳米～900纳米，例如Dv(75)选自10纳米～800纳米，也可以为Dv(75)选自100纳米～700纳米，如100纳米、110纳米、120纳米、130纳米、140纳米、150纳米、160纳米、170纳米、180纳米、190纳米、200纳米、210纳米、220纳米、230纳米、240纳米、250纳米、260纳米、270纳米、280纳米、290纳米、300纳米、350纳米、400纳米、450纳米、500纳米、550纳米、600纳米、650纳米、700纳米，其实例可以选自540.00纳米、419.10纳米、634.29纳米、596.56纳米或562.80纳米。According to an embodiment of the present invention, the particle size of the fulvestrant solid particles can also be Dv(75) selected from 1 nanometer to 900 nanometers, for example, Dv(75) selected from 10 nanometers to 800 nanometers, or can be Dv(75) is selected from 100 nm to 700 nm, such as 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, Examples thereof may be selected from 540.00 nanometers, 419.10 nanometers, 634.29 nanometers, 596.56 nanometers or 562.80 nanometers.

本发明中所述的氟维司群药物组合物还可以包括载体。所述的载体可以为非油性载体。优选地，所述的非油性载体包括但不限于水。所述的水可以为常规市售注射用水，优选为灭菌注射用水。The fulvestrant pharmaceutical composition described in the present invention may also include a carrier. The carrier can be a non-oily carrier. Preferably, the non-oily carrier includes, but is not limited to, water. The water can be conventional commercially available water for injection, preferably sterile water for injection.

根据本发明的实施方案，所述的氟维司群药物组合物的pH为6.5～8.0，例如6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9或8.0，如7.4。According to an embodiment of the present invention, the pH of the fulvestrant pharmaceutical composition is 6.5-8.0, such as 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8 , 7.9 or 8.0, such as 7.4.

根据本发明的实施方案，所述的氟维司群药物组合物还可以包括选自以下的一种或多种：助悬剂、润湿剂、渗透压调节剂、溶剂、稳定剂、缓冲剂、pH调节剂、表面活性剂、聚合物、电解质和非电解质。其中，所述的聚合物可以为交联聚合物和/或非交联聚合物。According to an embodiment of the present invention, the pharmaceutical composition of fulvestrant may further comprise one or more selected from the group consisting of: suspending agent, wetting agent, osmotic pressure regulator, solvent, stabilizer, buffer , pH adjusters, surfactants, polymers, electrolytes and non-electrolytes. Wherein, the polymer may be a cross-linked polymer and/or a non-cross-linked polymer.

根据本发明的实施方案，所述的助悬剂包括但不限于：羧甲基纤维素钠、聚乙二醇和聚维酮中的一种或多种。According to an embodiment of the present invention, the suspending agent includes, but is not limited to, one or more of sodium carboxymethyl cellulose, polyethylene glycol and povidone.

根据本发明的实施方案，所述的润湿剂包括但不限于：泊洛沙姆、聚维酮、多库酯钠、脱氧胆酸钠和吐温中的一种或多种。所述的吐温可以为常规市售吐温试剂，例如吐 温20和吐温80中的一种或多种。According to an embodiment of the present invention, the wetting agent includes, but is not limited to, one or more of poloxamer, povidone, sodium docusate, sodium deoxycholate and Tween. The Tween can be a conventional commercially available Tween reagent, such as one or more of Tween 20 and Tween 80.

根据本发明的实施方案，所述的渗透压调节剂包括但不限于：氯化钠、甘露醇和蔗糖中的一种或多种。According to an embodiment of the present invention, the osmotic pressure regulator includes, but is not limited to, one or more of sodium chloride, mannitol and sucrose.

根据本发明的实施方案，所述的溶剂包括但不限于：注射用水。According to an embodiment of the present invention, the solvent includes, but is not limited to, water for injection.

根据本发明的实施方案，所述的稳定剂包括但不限于：抗氧化剂、金属离子螯合剂、聚环氧乙烷(PEO)、聚环氧乙烷衍生物、聚山梨醇酯、脱氧胆酸钠、多库酯钠、泊洛沙姆、聚乙氧基化植物油、聚乙氧基化蓖麻油、脱水山梨糖醇棕榈酸酯、卵磷脂、聚乙烯醇、人血清白蛋白、聚乙烯吡咯烷酮、聚维酮、聚乙二醇、氯化钠、氯化钙、右旋糖、丙三醇、甘露糖醇和交联聚合物中的一种或多种。所述的抗氧化剂包括但不限于枸橼酸、维生素C和维生素E中的一种或多种。所述的金属离子螯合剂包括但不限于乙二胺四乙酸(EDTA)。所述的泊洛沙姆包括但不限于泊洛沙姆188、泊洛沙姆124和泊洛沙姆407中的一种或多种。所述的聚山梨醇酯包括但不限于：聚山梨醇酯80和聚山梨醇酯20中的一种或多种。所述的聚维酮包括但不限于：聚维酮K12、聚维酮K17、PLASDONETM C-12聚维酮、PLASDONETM C-17聚维酮和PLASDONETM C-30聚维酮中的一种或多种。所述的聚乙二醇包括但不限于聚乙二醇3350。所述的交联聚合物包括但不限于羧甲基纤维素钠。According to embodiments of the present invention, the stabilizers include, but are not limited to, antioxidants, metal ion chelating agents, polyethylene oxide (PEO), polyethylene oxide derivatives, polysorbates, deoxycholic acid Sodium, Docusate Sodium, Poloxamer, Polyethoxylated Vegetable Oil, Polyethoxylated Castor Oil, Sorbitan Palmitate, Lecithin, Polyvinyl Alcohol, Human Serum Albumin, Polyvinylpyrrolidone One or more of , povidone, polyethylene glycol, sodium chloride, calcium chloride, dextrose, glycerol, mannitol, and cross-linked polymers. The antioxidants include, but are not limited to, one or more of citric acid, vitamin C and vitamin E. The metal ion chelating agent includes but is not limited to ethylenediaminetetraacetic acid (EDTA). The poloxamers include but are not limited to one or more of poloxamer 188, poloxamer 124 and poloxamer 407. The polysorbate includes, but is not limited to, one or more of polysorbate 80 and polysorbate 20. Described povidone includes but is not limited to: one or more of povidone K12, povidone K17, PLASDONETM C-12 povidone, PLASDONETM C-17 povidone and PLASDONETM C-30 povidone. kind. The polyethylene glycols include but are not limited to polyethylene glycol 3350. The cross-linked polymer includes but is not limited to sodium carboxymethyl cellulose.

根据本发明的实施方案，所述的缓冲剂包括但不限于：磷酸、磷酸盐、枸橼酸(柠檬酸)、枸橼酸钠(柠檬酸钠)、三羟甲基氨基甲烷(Tris)、氢氧化钠、盐酸(HCl)或其混合物的缓冲剂。According to an embodiment of the present invention, the buffering agent includes, but is not limited to: phosphoric acid, phosphate, citric acid (citric acid), sodium citrate (sodium citrate), tris (Tris), Buffers of sodium hydroxide, hydrochloric acid (HCl) or mixtures thereof.

根据本发明的实施方案，所述的pH调节剂包括但不限于：磷酸、磷酸盐、枸橼酸、枸橼酸钠、盐酸和氢氧化钠。According to an embodiment of the present invention, the pH adjusting agent includes, but is not limited to, phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid and sodium hydroxide.

根据本发明的实施方案，所述的磷酸盐包括但不限于磷酸氢二钠、磷酸二氢钠或其混合物或水合物，例如一水磷酸氢二钠(Na 2HPO 4·H 2O)、二水磷酸氢二钠(Na 2HPO 4·2H 2O)、无水磷酸氢二钠(无水Na 2HPO 4)、一水磷酸二氢钠(NaH 2PO 4·H 2O)、二水磷酸二氢钠(NaH 2PO 4·2H 2O)和无水磷酸二氢钠(无水NaH 2PO 4)中的一种或多种。 According to an embodiment of the present invention, the phosphates include but are not limited to disodium hydrogen phosphate, sodium dihydrogen phosphate or mixtures or hydrates thereof, such as disodium hydrogen phosphate monohydrate (Na 2 HPO 4 ·H 2 O), Disodium hydrogen phosphate dihydrate (Na 2 HPO 4 ·2H 2 O), disodium hydrogen phosphate anhydrous (anhydrous Na 2 HPO 4 ), sodium dihydrogen phosphate monohydrate (NaH 2 PO 4 ·H 2 O), two One or more of anhydrous sodium dihydrogen phosphate (NaH 2 PO 4 ·2H 2 O) and anhydrous sodium dihydrogen phosphate (anhydrous NaH 2 PO 4 ).

根据本发明的实施方案，所述的助溶剂包括但不限于：乙醇和丙二醇中的一种或多种。According to an embodiment of the present invention, the co-solvent includes, but is not limited to, one or more of ethanol and propylene glycol.

所述的氟维司群药物组合物中，氟维司群固体粒子的重量分数优选1.00％～50.00％，优选2.00％～30.00％，例如2.00％～25.00％，例如2.00％、3.00％、4.00％、5.00％、6.00％、 7.00％、8.00％、9.00％、10.00％、11.00％、12.00％、13.00％、14.00％、15.00％、16.00％、17.00％、18.00％、19.00％、20.00％、21.00％、22.00％、23.00％、24.00％、25.00％，如5.00％或25.00％；所述的重量分数是指氟维司群固体粒子的重量占氟维司群药物组合物总重量的百分比。In the described fulvestrant pharmaceutical composition, the weight fraction of fulvestrant solid particles is preferably 1.00% to 50.00%, preferably 2.00% to 30.00%, such as 2.00% to 25.00%, such as 2.00%, 3.00%, 4.00% %, 5.00%, 6.00%, 7.00%, 8.00%, 9.00%, 10.00%, 11.00%, 12.00%, 13.00%, 14.00%, 15.00%, 16.00%, 17.00%, 18.00%, 19.00%, 20.00%, 21.00%, 22.00%, 23.00%, 24.00%, 25.00%, such as 5.00% or 25.00%; the weight fraction refers to the percentage of the weight of fulvestrant solid particles in the total weight of the fulvestrant pharmaceutical composition.

所述的氟维司群药物组合物中，所述的润湿剂的重量分数优选0～5.00％，例如1.00％、2.00％、3.00％、4.00％、5.00％，如1.00％；所述的重量分数是指表面活性剂的重量占氟维司群药物组合物总重量的百分比。In the fulvestrant pharmaceutical composition, the weight fraction of the wetting agent is preferably 0-5.00%, such as 1.00%, 2.00%, 3.00%, 4.00%, 5.00%, such as 1.00%; the described The weight fraction refers to the percentage of the weight of the surfactant in the total weight of the fulvestrant pharmaceutical composition.

所述的氟维司群药物组合物中，所述的助悬剂的重量分数优选0～5.00％，例如0、1.00％、2.00％、3.00％、4.00％、5.00％；所述的重量分数是指助悬剂的重量占氟维司群药物组合物总重量的百分比。In the fulvestrant pharmaceutical composition, the weight fraction of the suspending agent is preferably 0 to 5.00%, such as 0, 1.00%, 2.00%, 3.00%, 4.00%, 5.00%; the weight fraction It refers to the percentage of the weight of the suspending agent to the total weight of the fulvestrant pharmaceutical composition.

所述的氟维司群药物组合物中，所述的渗透压调节剂的重量分数优选0～5.00％，例如0、1.00％、2.00％、3.00％、4.00％、5.00％；所述的重量分数是指渗透压调节剂的重量占氟维司群药物组合物总重量的百分比。In the fulvestrant pharmaceutical composition, the weight fraction of the osmotic pressure regulator is preferably 0 to 5.00%, such as 0, 1.00%, 2.00%, 3.00%, 4.00%, 5.00%; the weight Fraction refers to the weight of the osmolarity modifier as a percentage of the total weight of the fulvestrant pharmaceutical composition.

所述的氟维司群药物组合物中，所述的缓冲剂的重量分数优选0～1.00％，例如0、0.10％、0.20％、0.30％、0.40％、0.50％、0.60％、0.70％、0.80％、0.90％、1.00％；所述的重量分数是指缓冲剂的重量占氟维司群药物组合物总重量的百分比。In the fulvestrant pharmaceutical composition, the weight fraction of the buffer is preferably 0-1.00%, such as 0, 0.10%, 0.20%, 0.30%, 0.40%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.00%; the weight fraction refers to the percentage of the weight of the buffer in the total weight of the fulvestrant pharmaceutical composition.

所述的氟维司群药物组合物中，所述的稳定剂的重量分数优选0～1.00％，例如0、0.10％、0.20％、0.30％、0.40％、0.50％、0.60％、0.70％、0.80％、0.90％、1.00％，例如0.60％或0.32％；所述的重量分数是指稳定剂的重量占氟维司群药物组合物总重量的百分比。In the fulvestrant pharmaceutical composition, the weight fraction of the stabilizer is preferably 0 to 1.00%, such as 0, 0.10%, 0.20%, 0.30%, 0.40%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.00%, such as 0.60% or 0.32%; the weight fraction refers to the percentage of the weight of the stabilizer in the total weight of the fulvestrant pharmaceutical composition.

所述的氟维司群药物组合物中，所述的pH调节剂使用量优选调节组合物溶液的pH为6.5～8.0，例如6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9或8.0，如7.4。In the fulvestrant pharmaceutical composition, the pH adjusting agent is preferably used in an amount to adjust the pH of the composition solution to 6.5-8.0, such as 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4 , 7.5, 7.6, 7.7, 7.8, 7.9 or 8.0, such as 7.4.

所述的氟维司群药物组合物，优选包括以下组分：1.00％～50.00％氟维司群固体粒子、0～5.00％润湿剂、0～5.00％稳定剂、0～5.00％渗透压调节剂、0～1.00％缓冲剂和溶剂，以及任选存在或不存在的0～5.00％的助悬剂。The fulvestrant pharmaceutical composition preferably includes the following components: 1.00%-50.00% fulvestrant solid particles, 0-5.00% wetting agent, 0-5.00% stabilizer, 0-5.00% osmotic pressure Conditioning agents, 0-1.00% buffer and solvent, and optionally 0-5.00% suspending agent, either present or absent.

优选地，所述的氟维司群药物组合物，优选包括以下组分：1.00％～50.00％氟维司群固体粒子、0～5.00％润湿剂、0～5.00％稳定剂、0～5.00％渗透压调节剂和0～1.00％缓冲剂，以及任选存在或不存在的0～5.00％的助悬剂，并且余量为溶剂。Preferably, the fulvestrant pharmaceutical composition preferably includes the following components: 1.00%-50.00% fulvestrant solid particles, 0-5.00% wetting agent, 0-5.00% stabilizer, 0-5.00% % osmotic pressure regulator and 0-1.00% buffer, and optionally 0-5.00% suspending agent present or absent, and the balance being solvent.

根据本发明的实施方案，所述的氟维司群药物组合物，可以为以下任一配方：According to an embodiment of the present invention, the described fulvestrant pharmaceutical composition can be any of the following formulas:

配方一：5.00％氟维司群固体粒子、0.50％聚维酮K12、0.30％脱氧胆酸钠、2.78％甘露醇、pH调节剂和水，其中pH调节剂将稀释剂的pH调节至pH7.4，pH调节剂为磷酸二氢钠和磷酸氢二钠；Formulation 1: 5.00% fulvestrant solid particles, 0.50% povidone K12, 0.30% sodium deoxycholate, 2.78% mannitol, pH adjuster and water, wherein the pH adjuster adjusts the pH of the diluent to pH7. 4. The pH regulators are sodium dihydrogen phosphate and disodium hydrogen phosphate;

配方二：5.00％氟维司群固体粒子、0.50％聚维酮K12、0.20％泊洛沙姆188、2.78％甘露醇、pH调节剂和水，其中pH调节剂将稀释剂的pH调节至pH7.4，pH调节剂为磷酸二氢钠和磷酸氢二钠；Formulation 2: 5.00% fulvestrant solid particles, 0.50% povidone K12, 0.20% poloxamer 188, 2.78% mannitol, pH adjuster and water, wherein the pH adjuster adjusts the pH of the diluent to pH7 .4, pH regulators are sodium dihydrogen phosphate and disodium hydrogen phosphate;

配方三：5.00％氟维司群、1.00％吐温20、0.30％聚维酮K12、0.30％脱氧胆酸钠、2.76％甘露醇、pH调节剂和水，其中pH调节剂将稀释剂的pH调节至pH7.4，pH调节剂为磷酸二氢钠和磷酸氢二钠；Formulation three: 5.00% fulvestrant, 1.00% Tween 20, 0.30% povidone K12, 0.30% sodium deoxycholate, 2.76% mannitol, pH adjuster and water, wherein the pH adjuster adjusts the pH of the diluent Adjusted to pH 7.4, pH regulators are sodium dihydrogen phosphate and disodium hydrogen phosphate;

配方四：5.00％氟维司群、1.00％吐温20、0.30％聚维酮K12、0.02％多库酯钠、2.76％甘露醇、pH调节剂和水，其中pH调节剂将稀释剂的pH调节至pH7.4，pH调节剂为磷酸二氢钠和磷酸氢二钠；Formulation four: 5.00% fulvestrant, 1.00% Tween 20, 0.30% povidone K12, 0.02% docusate sodium, 2.76% mannitol, pH adjuster and water, wherein the pH adjuster adjusts the pH of the diluent Adjusted to pH 7.4, pH regulators are sodium dihydrogen phosphate and disodium hydrogen phosphate;

配方五：25.00％氟维司群、1.00％吐温20、0.20％CMC-Na、0.42％磷酸氢二钠、0.09％磷酸二氢钠、2.29％甘露醇、0.30％脱氧胆酸钠、0.30％PVP K12和水。Formula five: 25.00% fulvestrant, 1.00% Tween 20, 0.20% CMC-Na, 0.42% disodium hydrogen phosphate, 0.09% sodium dihydrogen phosphate, 2.29% mannitol, 0.30% sodium deoxycholate, 0.30% PVP K12 and water.

配方六：25.00％氟维司群、1.60％吐温20、0.20％CMC-Na、0.42％磷酸氢二钠、0.09％磷酸二氢钠、2.27％甘露醇、0.30％脱氧胆酸钠、0.30％PVP K12和水。Formula 6: 25.00% fulvestrant, 1.60% Tween 20, 0.20% CMC-Na, 0.42% disodium hydrogen phosphate, 0.09% sodium dihydrogen phosphate, 2.27% mannitol, 0.30% sodium deoxycholate, 0.30% PVP K12 and water.

本发明还提供了所述的氟维司群药物组合物的制备方法，其包括以下步骤：The present invention also provides the preparation method of described fulvestrant pharmaceutical composition, it comprises the following steps:

步骤1：将氟维司群固体粒子与配方中的其他组分混合，得到预混物；Step 1: Mix the solid particles of fulvestrant with other components in the formula to obtain a premix;

步骤2：将步骤1得到的预混物与锆珠共同研磨，得到氟维司群药物组合物即可。Step 2: The premix obtained in Step 1 is co-milled with zirconium beads to obtain a fulvestrant pharmaceutical composition.

步骤1中，所述的混合优选搅拌混合。In step 1, the mixing is preferably stirring and mixing.

步骤2中，所述的锆珠的粒径可以为0.01mm～2mm，例如0.1mm、0.3mm、0.6mm或1mm。In step 2, the particle size of the zirconium beads may be 0.01 mm˜2 mm, such as 0.1 mm, 0.3 mm, 0.6 mm or 1 mm.

步骤2中，所述的锆珠与所述的预混物的体积比值优选1～5，例如1、1.5、2或3。In step 2, the volume ratio of the zirconium beads to the premix is preferably 1 to 5, such as 1, 1.5, 2 or 3.

步骤2中，所述的研磨的时间可以为1分钟～24小时，也可以为5分钟～20小时，例如4小时或12小时。In step 2, the grinding time may be 1 minute to 24 hours, or 5 minutes to 20 hours, for example, 4 hours or 12 hours.

根据本发明的实施方案，所述的锆珠是指常规市售氧化锆珠。According to an embodiment of the present invention, the zirconium beads refer to conventional commercially available zirconia beads.

本发明还提供了所述的氟维司群药物组合物在制备氟维司群药物制剂中的应用。The present invention also provides the application of the fulvestrant pharmaceutical composition in preparing the fulvestrant pharmaceutical preparation.

所述的氟维司群药物制剂包括但不限于片剂、颗粒剂、胶囊、微丸、口服液和注射剂等中的一种或多种。优选地，所述片剂包括但不限于缓释片、渗透泵片和口崩片中的一种或多种。优选地，所述注射剂可以为液体注射剂、注射用粉剂或注射用片剂；例如，所述液体注射剂可以为混悬剂，比如为水混悬剂或混悬用粉末；例如，所述混悬用粉末可以为冻干粉针。The fulvestrant pharmaceutical preparation includes, but is not limited to, one or more of tablets, granules, capsules, pellets, oral liquids, and injections. Preferably, the tablet includes, but is not limited to, one or more of sustained release tablet, osmotic pump tablet and orally disintegrating tablet. Preferably, the injection can be a liquid injection, a powder for injection or a tablet for injection; for example, the liquid injection can be a suspension, such as an aqueous suspension or a powder for suspension; for example, the suspension The powder can be lyophilized for injection.

根据本发明的实施方案，所述的注射剂可以为长效注射剂；所述的长效注射剂可以是水混悬剂，也可以是混悬用粉末，临用时采用特定的稀释剂分散成混悬剂。According to an embodiment of the present invention, the injection can be a long-acting injection; the long-acting injection can be a water suspension or a powder for suspension, and a specific diluent is used to disperse it into a suspension for temporary use. .

根据本发明的实施方案，所述的氟维司群在长效注射剂中的浓度不低于50mg/ml。According to an embodiment of the present invention, the concentration of the fulvestrant in the long-acting injection is not less than 50 mg/ml.

本发明还提供一种氟维司群药物制剂，其含有上述氟维司群药物组合物。The present invention also provides a fulvestrant pharmaceutical preparation, which contains the above-mentioned fulvestrant pharmaceutical composition.

根据本发明的实施方案，所述氟维司群药物制剂具有如上文所述的剂型选择和/或氟维司群浓度。According to an embodiment of the invention, the fulvestrant pharmaceutical formulation has the dosage form selection and/or fulvestrant concentration as described above.

本发明还提供上述氟维司群药物组合物和/或氟维司群药物制剂在预防和/或治疗激素受体阳性转移性乳腺癌中的应用。The present invention also provides the application of the above-mentioned fulvestrant pharmaceutical composition and/or fulvestrant pharmaceutical preparation in preventing and/or treating hormone receptor-positive metastatic breast cancer.

本发明还提供一种预防和/或治疗激素受体阳性转移性乳腺癌的方法，包括将上述氟维司群药物组合物和/或氟维司群药物制剂给予需要的患者，例如人。The present invention also provides a method for preventing and/or treating hormone receptor-positive metastatic breast cancer, comprising administering the above-mentioned fulvestrant pharmaceutical composition and/or fulvestrant pharmaceutical preparation to a patient in need, such as a human.

根据本发明的实施方案，所述的“Dv(10)”、“Dv(25)”、“Dv(50)”、“Dv(75)”和“Dv(90)”是指体积加权的粒子直径，其中在测量时分别有累积10v/v％、25v/v％、50v/v％、75v/v％或90v/v％的粒子具有相等或较小的直径。例如，如果粒子群的Dv(50)为约25微米，则50％体积的粒子具有小于或等于约25微米的直径。According to embodiments of the present invention, "Dv(10)", "Dv(25)", "Dv(50)", "Dv(75)" and "Dv(90)" refer to volume-weighted particles Diameter where cumulative 10 v/v%, 25 v/v%, 50 v/v%, 75 v/v% or 90 v/v% of particles respectively have equal or smaller diameters when measured. For example, if the Dv(50) of a population of particles is about 25 microns, then 50% of the particles by volume have a diameter of less than or equal to about 25 microns.

除非另有说明，本申请上下文中的粒子直径参数，例如“D(10)”、“D(25)”、“D(50)”、“D(75)”和“D(90)”均指体积加权的粒子直径，其分别具有与“Dv(10)”、“Dv(25)”、“Dv(50)”、“Dv(75)”和“Dv(90)”相同的含义。Particle diameter parameters in the context of this application, such as "D(10)", "D(25)", "D(50)", "D(75)" and "D(90)", unless otherwise specified, are Refers to the volume-weighted particle diameter, which has the same meaning as "Dv(10)", "Dv(25)", "Dv(50)", "Dv(75)" and "Dv(90)", respectively.

在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.

根据本发明的实施方案，所述的室温是指环境温度为10℃～35℃。According to an embodiment of the present invention, the room temperature refers to an ambient temperature ranging from 10°C to 35°C.

本发明的有益效果在于：本发明的氟维司群药物组合物具有有利的释放速度，给药后迅速达到峰浓度且维持较高血药浓度，生物利用度高；本发明的氟维司群药物组合物的活性药物成分含量高、不含有机溶剂或油，刺激性小，且施用方便，给药体积减小， 注射疼痛度大大降低，市场化前景良好。The beneficial effects of the present invention are as follows: the fulvestrant pharmaceutical composition of the present invention has a favorable release rate, rapidly reaches a peak concentration after administration, maintains a high blood drug concentration, and has high bioavailability; The pharmaceutical composition has high content of active pharmaceutical ingredients, no organic solvent or oil, low irritation, convenient administration, reduced administration volume, greatly reduced injection pain, and good market prospect.

附图说明Description of drawings

图1为实施例1中研磨后混悬液中氟维司群固体粒子的粒径分布图；Fig. 1 is the particle size distribution diagram of fulvestrant solid particles in the suspension after grinding in Example 1;

图2为实施例1中研磨后混悬液中氟维司群固体偏振光显微镜观察图，标尺为20微米；Fig. 2 is the solid polarized light microscope observation diagram of fulvestrant in the suspension after grinding in Example 1, and the ruler is 20 microns;

图3为实施例2中研磨12h后混悬液中氟维司群固体粒子的粒径分布图；Fig. 3 is the particle size distribution figure of fulvestrant solid particles in the suspension after grinding 12h in Example 2;

图4为实施例2中研磨4h后混悬液中氟维司群固体偏振光显微镜观察图，标尺为10微米；Fig. 4 is the solid polarized light microscope observation diagram of fulvestrant in the suspension after grinding 4h in Example 2, and the scale is 10 microns;

图5为实施例2中研磨12h后混悬液中氟维司群固体偏振光显微镜观察图，标尺为10微米；5 is a solid polarized light microscope observation diagram of fulvestrant in the suspension after grinding for 12h in Example 2, and the scale is 10 microns;

图6为实施例3中研磨4h后混悬液中氟维司群固体偏振光显微镜观察图，标尺为10微米；Fig. 6 is the solid polarized light microscope observation diagram of fulvestrant in the suspension after grinding 4h in Example 3, and the scale is 10 microns;

图7为实施例4中处方4研磨17h后混悬液中氟维司群固体粒子的粒径分布图；Fig. 7 is the particle size distribution figure of fulvestrant solid particle in the suspension after prescription 4 grinding 17h in embodiment 4;

图8为实施例4中处方5研磨17h后混悬液中氟维司群固体粒子的粒径分布图；Fig. 8 is the particle size distribution diagram of fulvestrant solid particles in the suspension after prescription 5 is ground for 17h in Example 4;

图9为实施例5中处方6研磨后混悬液中氟维司群固体粒子的粒径分布图；Fig. 9 is the particle size distribution figure of fulvestrant solid particle in the suspension after prescription 6 is ground in embodiment 5;

图10为实施例5中处方7研磨后混悬液中氟维司群固体粒子的粒径分布图；Fig. 10 is the particle size distribution figure of fulvestrant solid particle in the suspension after prescription 7 grinding in embodiment 5;

图11为实施例5中处方6研磨后混悬液中氟维司群固体粒子的扫描电镜图；Fig. 11 is the scanning electron microscope picture of fulvestrant solid particle in the suspension after prescription 6 grinding in embodiment 5;

图12为实施例5中处方7研磨后混悬液中氟维司群固体粒子的扫描电镜图；Fig. 12 is the scanning electron microscope picture of fulvestrant solid particle in the suspension after prescription 7 grinding in embodiment 5;

图13大鼠给予15mg/kg和30mg/kg剂量氟维司群混悬液的总药时曲线；Figure 13. The total drug-time curves of fulvestrant suspensions at doses of 15 mg/kg and 30 mg/kg in rats;

图14大鼠给予15mg/kg剂量氟维司群混悬液(G1)的药时曲线；Figure 14. The drug-time curve of fulvestrant suspension (G1) at a dose of 15 mg/kg in rats;

图15大鼠给予15mg/kg剂量氟维司群混悬液(G2)的药时曲线；Figure 15. The drug-time curve of fulvestrant suspension (G2) at a dose of 15 mg/kg in rats;

图16大鼠给予15mg/kg剂量氟维司群混悬液(G3)的药时曲线；Figure 16. The drug-time curve of fulvestrant suspension (G3) at a dose of 15 mg/kg in rats;

图17大鼠给予30mg/kg剂量氟维司群混悬液(G4)的药时曲线。Figure 17. The drug-time curve of fulvestrant suspension (G4) at a dose of 30 mg/kg in rats.

具体实施方式Detailed ways

下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the intended protection scope of the present invention.

除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。Unless otherwise stated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.

实施例1Example 1

表1混悬注射液处方表Table 1 Formulation of Suspension Injection

处方1prescription 1 组成(w/v％)Composition (w/v%) 氟维司群Fulvestrant 25.0025.00 吐温20Tween 20 1.621.62 甘露醇Mannitol 2.292.29 无水磷酸二氢钠Anhydrous sodium dihydrogen phosphate 0.090.09 无水磷酸氢二钠Anhydrous disodium hydrogen phosphate 0.420.42 灭菌注射用水Sterile water for injection 70.58(q.s.100)70.58 (q.s.100)

按表1处方1的用量配制称原辅料，混合均匀后加入1倍体积的0.3mm锆珠放置于研磨罐中进行研磨，研磨3小时，停止研磨，滤出得到氟维司群初始混悬液。将初混悬液加入1倍体积的0.1mm锆珠放置于研磨罐中进行研磨，于不同时间取样采用激光粒度仪测定(激光粒度仪参数设置：分散介质：水；散介质折射率：1.333；样品材质吸收率：0.01；样品材质折射率：1.521)测定粒径，研磨20.5小时，停止研磨，得到氟维司群药物组合物。研磨采用球磨仪进行，行星式球磨仪参数设置：固定参数：公转盘直径约191mm，自转杯直径约71mm，自转杯高度约70mm，自转杯容量100ml，公转盘转速10r/min自转速度：720r/min。Prepare raw and auxiliary materials according to the dosage of prescription 1 in Table 1. After mixing evenly, add 0.3mm zirconium beads of 1 volume and place them in a grinding jar for grinding. Grind for 3 hours, stop grinding, and filter out to obtain the initial suspension of fulvestrant. . The initial suspension was added with 1 volume of 0.1mm zirconium beads and placed in a grinding jar for grinding, and samples were taken at different times for measurement using a laser particle size analyzer (laser particle size analyzer parameter settings: dispersion medium: water; dispersion medium refractive index: 1.333; Sample material absorptivity: 0.01; sample material refractive index: 1.521) Measure particle size, grind for 20.5 hours, stop grinding, and obtain a fulvestrant pharmaceutical composition. Grinding is carried out with a ball mill, and the parameters of the planetary ball mill are set: fixed parameters: the diameter of the rotating disk is about 191mm, the diameter of the rotating cup is about 71mm, the height of the rotating cup is about 70mm, the capacity of the rotating cup is 100ml, and the rotating speed of the rotating disk is 10r/min. Rotation speed: 720r/ min.

采用偏振光显微镜观察研磨后混悬液中粒子的粒径形态。所述不同时间研磨后混悬液中氟维司群固体粒子的粒径分布数据如表2和所示。所述的研磨后混悬液中氟维司群固体粒子的粒径分布和形态分别见图1、图2。The particle size morphology of the particles in the suspension after grinding was observed by polarized light microscope. The particle size distribution data of the solid particles of fulvestrant in the suspension after grinding at different times are shown in Table 2 and Table 2. The particle size distribution and morphology of the solid particles of fulvestrant in the suspension after grinding are shown in Figure 1 and Figure 2, respectively.

结果显示，偏振光显微镜观察到的粒子形态大小与激光粒度仪粒径测定一致。研磨20.5h后混悬液中氟维司群固体为8μm左右球状物。采用处方2以及最小的研磨珠研磨后3小时后粒径达最小，再延长时间研磨，粒径不仅不减小反而增加。The results showed that the particle morphology and size observed by polarized light microscope were consistent with the particle size determination by laser particle size analyzer. After grinding for 20.5 hours, the solid of fulvestrant in the suspension was a sphere of about 8 μm. After 3 hours of grinding with prescription 2 and the smallest bead, the particle size reaches the smallest value, and if the grinding time is prolonged, the particle size does not decrease but increases.

表2实施例1混悬液中不同时间研磨得到组合物中氟维司群的粒径分布(体积加权)Table 2 The particle size distribution (volume weighting) of fulvestrant in the composition obtained by grinding at different times in the suspension of Example 1

研磨时间grinding time D10(μm)D10(μm) D25(μm)D25(μm) D50(μm)D50(μm) D75(μm)D75(μm) D90(μm)D90(μm) 00 1.1561.156 1.5431.543 2.0662.066 2.6102.610 3.1613.161 0.50.5 0.7090.709 0.9420.942 1.3491.349 1.9241.924 2.5102.510 1.51.5 0.8080.808 0.9460.946 1.1541.154 1.3881.388 1.6121.612 33 0.7440.744 0.8780.878 1.0501.050 1.2681.268 1.5371.537 17.517.5 0.9880.988 1.3521.352 5.3185.318 6.7316.731 8.1138.113 20.520.5 1.0321.032 3.6583.658 5.6495.649 7.3927.392 9.0159.015

实施例2Example 2

表3实施例2和3混悬注射液处方表Table 3 embodiment 2 and 3 suspension injection prescription table

Figure PCTCN2021136576-appb-000002
Figure PCTCN2021136576-appb-000002

按表3处方2的用量配制称原辅料。稀释剂组成(以稀释剂的总重量计，w/w％)：甘露醇2.95％，0.122％磷酸二氢钠、0.58％磷酸氢二钠，余量为水，pH7.4。将初混悬液加入1.5倍体积的0.3mm锆珠放置于研磨罐中进行研磨，研磨12小时，得到氟维司群药物组合物。研磨采用球磨仪进行，行星式球磨仪参数设置：固定参数：公转盘直径约191mm，自转杯直径约71mm，自转杯高度约70mm，自转杯容量100ml，公转盘转速10r/min自转速度：720r/min。According to the dosage of prescription 2 in table 3, it is called raw and auxiliary materials. Diluent composition (w/w% based on the total weight of the diluent): mannitol 2.95%, 0.122% sodium dihydrogen phosphate, 0.58% disodium hydrogen phosphate, the balance is water, pH 7.4. The initial suspension was added with 0.3 mm zirconium beads of 1.5 times the volume, placed in a grinding jar for grinding, and ground for 12 hours to obtain a fulvestrant pharmaceutical composition. Grinding is carried out with a ball mill. The parameters of the planetary ball mill are set: Fixed parameters: the diameter of the rotating disc is about 191mm, the diameter of the rotating cup is about 71mm, the height of the rotating cup is about 70mm, the capacity of the rotating cup is 100ml, and the rotating speed of the rotating disc is 10r/min. Rotation speed: 720r/ min.

采用纳米粒度仪测定(NICOMP Particle Sizing Systems,参数设置：分散介质：水；分散介质折射率：1.333；黏度：0.933cp；温度：23℃，光强设定值：300kHz)测定粒径。采用偏振光显微镜观察研磨4h和研磨终点12h的粒径形态。The particle size was determined by a nanoparticle particle size analyzer (NICOMP Particle Sizing Systems, parameter setting: dispersion medium: water; refractive index of dispersion medium: 1.333; viscosity: 0.933cp; temperature: 23 °C, light intensity setting value: 300 kHz). The particle size morphology of grinding 4h and grinding end point 12h was observed by polarized light microscope.

所述研磨12h后混悬液中氟维司群固体粒子的粒径分布数据如表4和图3所示。所述的研磨4h、12h后混悬液中氟维司群固体粒子的粒径形态分别见图4和图5。研磨 4h、12h后混悬液中氟维司群固体粒子分别为小于2微米和小于1微米的粒子。The particle size distribution data of the solid particles of fulvestrant in the suspension after grinding for 12 hours are shown in Table 4 and Figure 3. The particle size morphology of the solid particles of fulvestrant in the suspension after grinding for 4h and 12h is shown in Figure 4 and Figure 5, respectively. After grinding for 4h and 12h, the solid particles of fulvestrant in the suspension were respectively smaller than 2 microns and smaller than 1 micron.

表4混悬液中氟维司群的粒径分布(体积加权)Table 4 Particle Size Distribution (Volume Weighted) of Fulvestrant in Suspension

处方编号prescription number D10(nm)D10(nm) D25(nm)D25(nm) D50(nm)D50(nm) D75(nm)D75(nm) D90(nm)D90(nm) 22 196.20196.20 272.00272.00 401.80401.80 540.00540.00 716.50716.50 44 132.42132.42 189.28189.28 281.63281.63 419.10419.10 599.35599.35 55 // 316.91316.91 448.34448.34 634.29634.29 866.72866.72 66 435.63435.63 480.27480.27 535.27535.27 596.56596.56 657.69657.69 77 341.71341.71 398.95398.95 473.84473.84 562.80562.80 657.05657.05

实施例3Example 3

按表3处方3的用量配制称原辅料。稀释剂组成(以稀释剂的总重量计，w/w％)：甘露醇2.95％，0.122％磷酸二氢钠、0.58％磷酸氢二钠，余量为水，pH7.4。将初混悬液加入1.5倍体积的0.3mm锆珠放置于研磨罐中进行研磨，研磨4小时，得到氟维司群药物组合物。研磨采用球磨仪进行，行星式球磨仪参数设置：固定参数：公转盘直径约191mm，自转杯直径约71mm，自转杯高度约70mm，自转杯容量100ml，公转盘转速10r/min自转速度：720r/min。According to the dosage of prescription 3 in table 3, it is called raw and auxiliary materials. Diluent composition (w/w% based on the total weight of the diluent): mannitol 2.95%, 0.122% sodium dihydrogen phosphate, 0.58% disodium hydrogen phosphate, the balance is water, pH 7.4. The initial suspension was added with 1.5 times the volume of 0.3 mm zirconium beads, placed in a grinding jar for grinding, and ground for 4 hours to obtain a fulvestrant pharmaceutical composition. Grinding is carried out with a ball mill. The parameters of the planetary ball mill are set: Fixed parameters: the diameter of the rotating disc is about 191mm, the diameter of the rotating cup is about 71mm, the height of the rotating cup is about 70mm, the capacity of the rotating cup is 100ml, and the rotating speed of the rotating disc is 10r/min. Rotation speed: 720r/ min.

所述的研磨后混悬液中氟维司群固体粒子的粒径形态见图6。The particle size morphology of the solid particles of fulvestrant in the suspension after grinding is shown in Figure 6 .

结果显示，与处方2截然不同的是，研磨4h后混悬液中氟维司群固体粒子为5～15um块状聚集物。The results showed that, completely different from prescription 2, the solid particles of fulvestrant in the suspension after grinding for 4 hours were 5-15um aggregates.

实施例4Example 4

表5实施例4和混悬注射液处方表Table 5 embodiment 4 and suspension injection prescription table

Figure PCTCN2021136576-appb-000003
Figure PCTCN2021136576-appb-000003

按表5处方4和5的用量配制称原辅料。稀释剂组成(以稀释剂的总重量计，w/w％)：甘露醇2.95％，0.122g磷酸二氢钠、0.58g磷酸氢二钠，余量为水，pH7.4。将初混悬液加入1.5倍体积的0.3mm锆珠放置于研磨罐中进行研磨，研磨17小时，得到氟维司群药物组合物。研磨采用球磨仪进行，行星式球磨仪参数设置：固定参数：公转盘直径约191mm，自转杯直径约71mm，自转杯高度约70mm，自转杯容量100ml，公转盘转速10r/min自转速度：720r/min。According to the dosage of prescription 4 and 5 in Table 5, it is called raw and auxiliary materials. Diluent composition (w/w% based on the total weight of the diluent): mannitol 2.95%, 0.122 g sodium dihydrogen phosphate, 0.58 g disodium hydrogen phosphate, the balance is water, pH 7.4. The initial suspension was added with 1.5 times the volume of 0.3 mm zirconium beads, placed in a grinding jar for grinding, and ground for 17 hours to obtain a fulvestrant pharmaceutical composition. Grinding is carried out with a ball mill. The parameters of the planetary ball mill are set: Fixed parameters: the diameter of the rotating disc is about 191mm, the diameter of the rotating cup is about 71mm, the height of the rotating cup is about 70mm, the capacity of the rotating cup is 100ml, and the rotating speed of the rotating disc is 10r/min. Rotation speed: 720r/ min.

采用纳米粒度仪测定(NICOMP Particle Sizing Systems,参数设置：分散介质：水；分散介质折射率：1.333；黏度：0.933cp；温度：23℃，光强设定值：300kHz)测定粒径。The particle size was determined by a nanoparticle particle size analyzer (NICOMP Particle Sizing Systems, parameter setting: dispersion medium: water; refractive index of dispersion medium: 1.333; viscosity: 0.933cp; temperature: 23 °C, light intensity setting value: 300 kHz).

所述处方4和5研磨17h后混悬液中氟维司群固体粒子的粒径分布数据如表4，表6、图7和图8所示。The particle size distribution data of the solid particles of fulvestrant in the suspension after grinding for 17 hours of the formulations 4 and 5 are shown in Table 4, Table 6, Figure 7 and Figure 8.

表6处方4和处方5的高斯分布平均粒径Table 6 Gaussian distribution average particle size of prescription 4 and prescription 5

Figure PCTCN2021136576-appb-000004
Figure PCTCN2021136576-appb-000004

实施例5Example 5

表7实施例5处方6和处方7混悬注射液处方表Table 7 embodiment 5 prescription 6 and prescription 7 suspension injection prescription table

Figure PCTCN2021136576-appb-000005
Figure PCTCN2021136576-appb-000005

Figure PCTCN2021136576-appb-000006
Figure PCTCN2021136576-appb-000006

按表7处方用量配制称原辅料，加入1.5倍体积的锆珠放置于研磨罐中进行研磨,其中处方6和7分别采用0.3mm和0.6mm锆珠，研磨时间分别为21小时和25小时，得到氟维司群药物组合物。研磨采用球磨仪进行，行星式球磨仪参数设置：固定参数：公转盘直径约191mm，自转杯直径约71mm，自转杯高度约70mm，自转杯容量100ml，公转盘转速10r/min自转速度：720r/min。According to the prescription dosage in Table 7, the raw and auxiliary materials were prepared, and 1.5 times the volume of zirconium beads was added and placed in a grinding jar for grinding. Among them, 0.3mm and 0.6mm zirconium beads were used in prescriptions 6 and 7, respectively, and the grinding time was 21 hours and 25 hours, respectively. A fulvestrant pharmaceutical composition is obtained. Grinding is carried out with a ball mill. The parameters of the planetary ball mill are set: Fixed parameters: the diameter of the rotating disc is about 191mm, the diameter of the rotating cup is about 71mm, the height of the rotating cup is about 70mm, the capacity of the rotating cup is 100ml, and the rotating speed of the rotating disc is 10r/min. Rotation speed: 720r/ min.

采用纳米粒度仪测定(NICOMP Particle Sizing Systems,参数设置：分散介质：水；分散介质折射率：1.333；黏度：0.933cp；温度：23℃，光强设定值：300kHz)测定粒径。所述处方6和7研磨后混悬液中氟维司群固体粒子的粒径分布数据如表4、图9和图10所示。The particle size was determined by a nanoparticle particle size analyzer (NICOMP Particle Sizing Systems, parameter setting: dispersion medium: water; refractive index of dispersion medium: 1.333; viscosity: 0.933cp; temperature: 23 °C, light intensity setting value: 300 kHz). The particle size distribution data of the solid particles of fulvestrant in the grinding suspension of the formulations 6 and 7 are shown in Table 4, FIG. 9 and FIG. 10 .

采用扫描电镜(FEI，型号F50)观察形态大小。扫描电镜电压10kv，束流2.0测试。所述处方6和7研磨后混悬液中氟维司群固体粒子的电镜照片见图11和图12所示。均观察到小于1μm的不规则块状粒子。The morphology and size were observed by scanning electron microscope (FEI, model F50). Scanning electron microscope voltage 10kv, beam current 2.0 test. The electron micrographs of the solid particles of fulvestrant in the grinding suspension of the formulations 6 and 7 are shown in Figs. 11 and 12 . Irregular massive particles smaller than 1 μm were observed.

按照EP10.0方法检测氟维司群有关物质。有关物质结果见表8。结果显示，自制混悬液有关物质单杂和总杂均低于上市对比制剂，表明质量较优。The related substances of fulvestrant were detected according to EP10.0 method. The results of the relevant substances are shown in Table 8. The results showed that the single impurity and total impurity of the related substances in the self-made suspension were lower than those of the marketed comparative preparation, indicating that the quality was better.

表8实施例5(处方6和7)制剂与对比制剂的有关物质结果Table 8 The related substance results of the formulation of Example 5 (prescription 6 and 7) and the comparative formulation

Figure PCTCN2021136576-appb-000007
Figure PCTCN2021136576-appb-000007

Figure PCTCN2021136576-appb-000008
Figure PCTCN2021136576-appb-000008

注：ND表示未检出；Note: ND means not detected;

*为氟维司群的降解产物； * is the degradation product of fulvestrant;

6-Keto fulvestrant(6-酮氟维司群)、6,7-fulvestrant(6,7-氟维司群)、Fulvestrantβ-Isomer(氟维司群β异构体)、Fulvestrant Sulphone(氟维司群砜)、Fulvestrant Bromo Analogue(氟维司群溴类似物)、Fulvestrant Extended(氟维司群扩展)、Fulvestrant Sterol Dimer(氟维司群甾醇二聚体)。6-Keto fulvestrant (6-keto fulvestrant), 6,7-fulvestrant (6,7-fulvestrant), Fulvestrant beta-Isomer (fulvestrant beta isomer), Fulvestrant Sulphone (fulvestrant) sulfone), Fulvestrant Bromo Analogue, Fulvestrant Extended, Fulvestrant Sterol Dimer.

实施例6Example 6

将实施例5所得的处方6和处方7制剂，用稀释剂稀释至50mg/ml。稀释剂组成为：1.62％吐温20、0.2％羧甲基纤维素钠、2.29％甘露醇、0.09％无水磷酸二氢钠、0.42％无水磷酸氢二钠。The formulations 6 and 7 obtained in Example 5 were diluted to 50 mg/ml with a diluent. The composition of the diluent is: 1.62% Tween 20, 0.2% sodium carboxymethyl cellulose, 2.29% mannitol, 0.09% anhydrous sodium dihydrogen phosphate, 0.42% anhydrous disodium hydrogen phosphate.

将稀释后的处方6(G2)和处方7(G3)氟维司群混悬液、上市对比制剂氟维司群注射剂FASLODEX(G1，50mg/ml，德国VETTER Pharma-fertigung GmbH&Co KG，批号:RH832，有效期2024年2月)按氟维司群15mg/kg(给药体积0.3mL/kg)以及未稀释的处方7氟维司群混悬液按氟维司群30mg/kg(G4，给药体积0.11mL/kg)大腿外侧肌肉注射给予雄性Wistar大鼠，SPF级动物,189～200g，6～8周龄(北京维通利华实验动物技术有限公司,质量合格证号110011200110944286,使用许可证号SYXK(苏)2018-0034)，每组3只。The diluted prescription 6 (G2) and prescription 7 (G3) fulvestrant suspension, the marketed comparative preparation fulvestrant injection FASLODEX (G1, 50mg/ml, Germany VETTER Pharma-fertigung GmbH & Co KG, batch number: RH832 , the validity period is February 2024) according to fulvestrant 15mg/kg (administration volume 0.3mL/kg) and undiluted prescription 7 fulvestrant suspension according to fulvestrant 30mg/kg (G4, administration Volume 0.11mL/kg) intramuscular injection into the lateral thigh of male Wistar rats, SPF animals, 189 ~ 200g, 6 ~ 8 weeks old (Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., quality certificate number 110011200110944286, license for use No. SYXK (Su) 2018-0034), 3 per group.

给药后进行临床观察，给药第一天(D1)观察2次：给药前和给药后当天下午，此后每天观察1次，总45天。临床观察包括皮肤、被毛、眼、耳、鼻、口腔、胸部、腹部、泌尿生殖部、四肢等部位，以及呼吸、运动、泌尿、排便和行为改变和给药部位肌肉刺激反应等。并且，在给药前(0h，D-1)、D1给药后1、3、7、24h，D4(72h)、D7(144h)、D11(240h)、D15(336h)、D20(456h)、D25(576h)、D30(696h)、D35(816h)、D40(936h)和D45(1056h)采集血样，进行生物分析和采用WinNonlin 8.1版本的非房室模型计算各组的药代动力学参数Tmax，Cmax，AUC(0-t)，AUC(0-∞)，T1/2，MRT，CL、Vz等。Clinical observation was performed after administration, and the first day of administration (D1) was observed twice: before administration and in the afternoon after administration, and then once a day for a total of 45 days. Clinical observations include skin, coat, eyes, ears, nose, mouth, chest, abdomen, genitourinary, limbs, etc., as well as changes in breathing, exercise, urination, defecation, and behavior, and muscle irritation at the administration site. And before administration (0h, D-1), 1, 3, 7, 24h after D1 administration, D4 (72h), D7 (144h), D11 (240h), D15 (336h), D20 (456h) , D25(576h), D30(696h), D35(816h), D40(936h) and D45(1056h) blood samples were collected for biological analysis and the non-compartmental model of WinNonlin version 8.1 was used to calculate the pharmacokinetic parameters of each group Tmax, Cmax, AUC(0-t), AUC(0-∞), T1/2, MRT, CL, Vz, etc.

给药D45后，解剖动物并对给药部位进行组织病理学检查，观察炎症反应和药物残留。各剂量组所有受试动物临床观察、体重、给药部位刺激观察、给药部位大体解剖均未见异常，给药部位未见炎症和药物残留，组织病理学检查未见与给予供试品相关的异常。After administration of D45, the animals were dissected and histopathological examination of the administration site was performed to observe the inflammatory response and drug residues. No abnormality was found in the clinical observation, body weight, stimulation observation of the administration site, and gross anatomy of the administration site of all the tested animals in each dose group, no inflammation or drug residue was found at the administration site, and no correlation with the administration of the test product was found in histopathological examination. exception.

大鼠给予15mg/kg和30mg/kg剂量氟维司群混悬液下药代动力学参数见表9，以及图13、14、15、16和17。结果显示：Wistar大鼠单次肌肉注射给予15mg/kg给药制剂后，Cmax从大到小依次为：G1＞G3＞G2；药物浓度-时间曲线下面积AUCINF_obs从大到小依次为：G1＞G3＞G2；AUClast从大到小依次为：G1＞G3＞G2；药物末端消除半衰期T1/2_Z从大到小依次为：G1＞G3＞G2；清除率Cl_obs从大到小依次为：G2＞G3＞G1；平均驻留时间MRTINF_obs从大到小依次为：G3＞G2＞G1；分布容积Vz_obs从大到小依次为：G2＞G3＞G1。以上结果表明自制混悬液缓释效果优于上市对比制剂。上市对比制剂达峰时间Tmax大于自制混悬液，表明混悬液能更加迅速起效。Pharmacokinetic parameters of fulvestrant suspensions administered to rats at doses of 15 mg/kg and 30 mg/kg are shown in Table 9, and Figures 13, 14, 15, 16 and 17. The results showed that: after a single intramuscular injection of 15 mg/kg preparation in Wistar rats, the Cmax from large to small was: G1>G3>G2; the area under the drug concentration-time curve AUCINF_obs from large to small was: G1> G3>G2; AUClast in descending order: G1>G3>G2; Drug terminal elimination half-life T1/2_Z in descending order: G1>G3>G2; Clearance Cl_obs in descending order: G2> G3>G1; the average dwell time MRTINF_obs in descending order is: G3>G2>G1; the distribution volume Vz_obs is in descending order: G2>G3>G1. The above results show that the sustained-release effect of the self-made suspension is better than that of the marketed comparative preparation. The peak time Tmax of the listed comparative preparation is greater than that of the homemade suspension, indicating that the suspension can take effect more quickly.

Wistar大鼠单次肌肉注射给予批号为20201221-1的给药制剂后，15mg/kg和30mg/kg剂量下药代参数比较，氟维司群的血浆暴露量(AUClast)增加低于剂量的增加，MRT无差异，说明高浓度高剂量混悬剂给药后的药物持续稳定缓释，不会引起药物突释。After a single intramuscular injection of Wistar rats with the formulation of batch No. 20201221-1, the increase in plasma exposure (AUClast) of fulvestrant at 15 mg/kg and 30 mg/kg doses was lower than the increase in doses , MRT has no difference, indicating that the drug sustained stable and sustained release after high concentration and high dose suspension administration will not cause sudden drug release.

表9大鼠给予15mg/kg和30mg/kg剂量氟维司群制剂下药代动力学参数Table 9 Pharmacokinetic parameters of fulvestrant formulations administered to rats at doses of 15 mg/kg and 30 mg/kg

Figure PCTCN2021136576-appb-000009
Figure PCTCN2021136576-appb-000009

表9(续)Table 9 (continued)

Figure PCTCN2021136576-appb-000010
Figure PCTCN2021136576-appb-000010

Figure PCTCN2021136576-appb-000011
Figure PCTCN2021136576-appb-000011

Claims (10)

一种氟维司群药物组合物，其特征在于：其包含氟维司群固体粒子，所述的氟维司群固体粒子的粒径为Dv(10)选自小于等于600纳米，例如小于等于400纳米，Dv(50)选自小于等于700纳米且Dv(90)选自小于等于1000纳米；A fulvestrant pharmaceutical composition, characterized in that: it comprises fulvestrant solid particles, and the particle diameter of the fulvestrant solid particles is that Dv(10) is selected from less than or equal to 600 nanometers, such as less than or equal to 600 nanometers. 400 nanometers, Dv(50) is selected from less than or equal to 700 nanometers and Dv(90) is selected from less than or equal to 1000 nanometers; 优选地，所述的氟维司群固体粒子的粒径为Dv(10)选自0.01纳米～400纳米；Preferably, the particle size of the fulvestrant solid particles is that Dv(10) is selected from 0.01 nanometers to 400 nanometers; 优选地，所述的氟维司群固体粒子的粒径为Dv(10)选自1纳米～350纳米；Preferably, the particle size of the fulvestrant solid particles is that Dv(10) is selected from 1 nanometer to 350 nanometers; 优选地，所述的氟维司群固体粒子的粒径为Dv(10)选自10纳米～450纳米；Preferably, the particle size of the fulvestrant solid particles is that Dv(10) is selected from 10 nanometers to 450 nanometers; 例如，所述的氟维司群固体粒子的粒径为Dv(10)选自小于等于400纳米。For example, the particle size of the fulvestrant solid particles is Dv(10) selected from 400 nanometers or less. 如权利要求1所述的氟维司群药物组合物，其特征在于：所述的氟维司群固体粒子的粒径为Dv(50)选自0.01纳米～700纳米；The fulvestrant pharmaceutical composition according to claim 1, wherein the particle size of the fulvestrant solid particles is that Dv(50) is selected from 0.01 nanometers to 700 nanometers; 优选地，所述的氟维司群固体粒子的粒径为Dv(50)选自1纳米～600纳米；Preferably, the particle size of the fulvestrant solid particles is that Dv(50) is selected from 1 nanometer to 600 nanometers; 优选地，所述的氟维司群固体粒子的粒径为Dv(50)选自10纳米～500纳米；Preferably, the particle size of the fulvestrant solid particles is that Dv(50) is selected from 10 nanometers to 500 nanometers; 优选地，所述的氟维司群固体粒子的粒径为Dv(90)为选自1纳米～1000纳米；Preferably, the particle size of the fulvestrant solid particles is that Dv(90) is selected from 1 nanometer to 1000 nanometers; 优选地，所述的氟维司群固体粒子的粒径为Dv(90)选自10纳米～900纳米；Preferably, the particle size of the fulvestrant solid particles is that Dv(90) is selected from 10 nanometers to 900 nanometers; 优选地，所述的氟维司群固体粒子的粒径为Dv(90)选自100纳米～800纳米。Preferably, the particle size of the fulvestrant solid particles is Dv(90) selected from 100 nanometers to 800 nanometers. 如权利要求1或2所述的氟维司群药物组合物，其特征在于：Fulvestrant pharmaceutical composition as claimed in claim 1 or 2, is characterized in that: 所述的氟维司群固体粒子的粒径为Dv(25)选自1纳米～600纳米，例如Dv(25)选自10纳米～500纳米，也可以为Dv(25)选自100纳米～400纳米；The particle size of the fulvestrant solid particles is that Dv(25) is selected from 1 nanometer to 600 nanometers, for example, Dv(25) is selected from 10 nanometers to 500 nanometers, or Dv(25) is selected from 100 nanometers to 500 nanometers. 400 nm; 优选地，所述的氟维司群固体粒子的粒径Dv(75)选自1纳米～900纳米，例如Dv(75)选自10纳米～800纳米，也可以为Dv(75)选自100纳米～700纳米。Preferably, the particle size Dv(75) of the fulvestrant solid particles is selected from 1 nm to 900 nm, for example, Dv(75) is selected from 10 nm to 800 nm, or Dv(75) is selected from 100 nm nanometer to 700 nanometers. 如权利要求1-3任一项所述的氟维司群药物组合物，其特征在于：所述的氟维司群药物组合物还包括载体；The fulvestrant pharmaceutical composition according to any one of claims 1-3, wherein the fulvestrant pharmaceutical composition further comprises a carrier; 优选地，所述的载体为非油性载体；Preferably, the carrier is a non-oily carrier; 优选地，所述的非油性载体包括但不限于水；Preferably, the non-oily carrier includes but is not limited to water; 优选地，所述的氟维司群药物组合物中，氟维司群固体粒子的重量分数优选1.00％～50.00％，优选2.00％～30.00％，例如2.00％～25.00％；Preferably, in the fulvestrant pharmaceutical composition, the weight fraction of fulvestrant solid particles is preferably 1.00%-50.00%, preferably 2.00%-30.00%, such as 2.00%-25.00%; 优选地，所述的氟维司群药物组合物的pH为6.5～8.0。Preferably, the pH of the fulvestrant pharmaceutical composition is 6.5-8.0. 如权利要求1-4任一项所述的氟维司群药物组合物，其特征在于：所述的氟维司群药物组合物还包括选自以下的一种或多种辅料：助悬剂、润湿剂、渗透压调节剂、溶剂、稳定剂、缓冲剂、pH调节剂、表面活性剂、聚合物、电解质和非电解质；The fulvestrant pharmaceutical composition according to any one of claims 1-4, wherein the fulvestrant pharmaceutical composition further comprises one or more adjuvants selected from the following: suspending agent , wetting agents, osmotic pressure regulators, solvents, stabilizers, buffers, pH regulators, surfactants, polymers, electrolytes and non-electrolytes; 例如，所述的润湿剂的重量分数优选0～5.00％；和/或，所述的助悬剂的重量分数优选0～5.00％；和/或，所述的渗透压调节剂的重量分数优选0～5.00％；和/或，所述的缓冲剂的重量分数优选0～1.00％；和/或，所述的稳定剂的重量分数优选0～1.00％；和/或，所述的pH调节剂使用量优选调节组合物溶液的pH为6.5～8.0。For example, the weight fraction of the wetting agent is preferably 0-5.00%; and/or the weight fraction of the suspending agent is preferably 0-5.00%; and/or the weight fraction of the osmotic pressure regulator Preferably, 0-5.00%; and/or, the weight fraction of the buffer is preferably 0-1.00%; and/or, the weight fraction of the stabilizer is preferably 0-1.00%; and/or, the pH It is preferable to adjust the pH of the composition solution to 6.5-8.0 as for the usage-amount of a regulator. 如权利要求5所述的氟维司群药物组合物，其特征在于：Fulvestrant pharmaceutical composition as claimed in claim 5, is characterized in that: 所述的助悬剂包括但不限于羧甲基纤维素钠、聚乙二醇和聚维酮中的一种或多种；Described suspending agent includes but is not limited to one or more in sodium carboxymethyl cellulose, polyethylene glycol and povidone; 和/或，and / or, 所述的润湿剂包括但不限于泊洛沙姆、聚维酮、多库酯钠、脱氧胆酸钠和吐温中的一种或多种；Described wetting agent includes but is not limited to one or more in poloxamer, povidone, docusate sodium, sodium deoxycholate and Tween; 和/或，and / or, 所述的渗透压调节剂包括但不限于氯化钠、甘露醇和蔗糖中的一种或多种；Described osmotic pressure regulator includes but not limited to one or more in sodium chloride, mannitol and sucrose; 和/或，and / or, 所述的溶剂包括但不限于注射用水；Described solvent includes but is not limited to water for injection; 和/或，and / or, 所述的稳定剂包括但不限于抗氧化剂、金属离子螯合剂、聚环氧乙烷、聚环氧乙烷衍生物、聚山梨醇酯、脱氧胆酸钠、多库酯钠、泊洛沙姆、聚乙氧基化植物油、聚乙氧基化蓖麻油、脱水山梨糖醇棕榈酸酯、卵磷脂、聚乙烯醇、人血清白蛋白、聚乙烯吡咯烷酮、聚维酮、聚乙二醇、氯化钠、氯化钙、右旋糖、丙三醇、甘露糖醇和交联聚合物中的一种或多种；The stabilizers include but are not limited to antioxidants, metal ion chelating agents, polyethylene oxide, polyethylene oxide derivatives, polysorbate, sodium deoxycholate, sodium docusate, poloxamer , Polyethoxylated Vegetable Oil, Polyethoxylated Castor Oil, Sorbitan Palmitate, Lecithin, Polyvinyl Alcohol, Human Serum Albumin, Polyvinylpyrrolidone, Povidone, Polyethylene Glycol, Chlorine One or more of sodium chloride, calcium chloride, dextrose, glycerol, mannitol and cross-linked polymers; 和/或，and / or, 所述的缓冲剂包括但不限于磷酸、磷酸盐、枸橼酸、枸橼酸钠、盐酸、氢氧化钠、三羟甲基氨基甲烷、氢氧化钠、盐酸或其混合物的缓冲剂；Described buffer includes but is not limited to the buffer of phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid, sodium hydroxide, tris, sodium hydroxide, hydrochloric acid or a mixture thereof; 和/或，and / or, 所述的pH调节剂包括但不限于磷酸、磷酸盐、枸橼酸、枸橼酸钠、盐酸和氢氧化钠。The pH adjusting agents include, but are not limited to, phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid and sodium hydroxide. 如权利要求6所述的氟维司群药物组合物，其特征在于：Fulvestrant pharmaceutical composition as claimed in claim 6, is characterized in that: 所述的抗氧化剂包括但不限于枸橼酸、维生素C和维生素E中的一种或多种；The antioxidants include but are not limited to one or more of citric acid, vitamin C and vitamin E; 和/或，and / or, 所述的金属离子螯合剂包括但不限于乙二胺四乙酸；Described metal ion chelating agent includes but is not limited to ethylenediaminetetraacetic acid; 和/或，and / or, 所述的泊洛沙姆包括但不限于泊洛沙姆188、泊洛沙姆124和泊洛沙姆407中的一种或多种；Described poloxamer includes but is not limited to one or more in poloxamer 188, poloxamer 124 and poloxamer 407; 和/或，and / or, 所述的聚山梨醇酯包括但不限于聚山梨醇酯80和聚山梨醇酯20中的一种或多种；Described polysorbate includes but is not limited to one or more in polysorbate 80 and polysorbate 20; 和/或，and / or, 所述的聚维酮包括但不限于聚维酮K12、聚维酮K17、PLASDONETM C-12聚维酮、PLASDONETM C-17聚维酮和PLASDONETM C-30聚维酮中的一种或多种；Described povidone includes but is not limited to one or more of povidone K12, povidone K17, PLASDONETM C-12 povidone, PLASDONETM C-17 povidone and PLASDONETM C-30 povidone ; 和/或，and / or, 所述的聚乙二醇包括但不限于聚乙二醇3350；Described polyethylene glycol includes but is not limited to polyethylene glycol 3350; 和/或，and / or, 所述的交联聚合物包括但不限于羧甲基纤维素钠；Described cross-linked polymer includes but is not limited to sodium carboxymethyl cellulose; 和/或，and / or, 所述的磷酸盐包括但不限于一水磷酸二氢钠、二水磷酸二氢钠、无水磷酸二氢钠、一水磷酸二氢钠、二水磷酸二氢钠和无水磷酸二氢钠中的一种或多种。The phosphates include but are not limited to sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate and sodium dihydrogen phosphate anhydrous one or more of. 如权利要求1～7任一项所述的氟维司群药物组合物，其中所述的氟维司群药物组合物包括以下组分：1.00％～50.00％氟维司群固体粒子、0～5.00％润湿剂、0～5.00％稳定剂、0～5.00％渗透压调节剂、0～1.00％缓冲剂和溶剂，以及任选存在或不存在的0～5.00％的助悬剂。The fulvestrant pharmaceutical composition according to any one of claims 1 to 7, wherein the fulvestrant pharmaceutical composition comprises the following components: 1.00%-50.00% fulvestrant solid particles, 0- 5.00% wetting agent, 0-5.00% stabilizer, 0-5.00% osmotic pressure regulator, 0-1.00% buffer and solvent, and optionally 0-5.00% suspending agent present or absent. 如权利要求8所述的氟维司群药物组合物，其中所述的氟维司群药物组合物包 括以下组分：5.00％～25.00％氟维司群固体粒子、0～5.00％润湿剂、0～5.00％稳定剂、0～5.00％渗透压调节剂、0～1.00％缓冲剂、0～5.00％的助悬剂，并且余量为溶剂。The fulvestrant pharmaceutical composition according to claim 8, wherein the fulvestrant pharmaceutical composition comprises the following components: 5.00%-25.00% fulvestrant solid particles, 0-5.00% wetting agent , 0-5.00% stabilizer, 0-5.00% osmotic pressure regulator, 0-1.00% buffer, 0-5.00% suspending agent, and the balance is solvent. 如权利要求1～9任一项所述的氟维司群药物组合物在制备氟维司群药物制剂中的应用；The application of the fulvestrant pharmaceutical composition according to any one of claims 1 to 9 in the preparation of a fulvestrant pharmaceutical preparation; 优选地，所述的氟维司群药物制剂包括但不限于片剂、颗粒剂、胶囊、微丸、口服液和注射剂；Preferably, the described fulvestrant pharmaceutical preparations include but are not limited to tablets, granules, capsules, pellets, oral liquids and injections; 优选地，所述的注射剂选自长效注射剂。Preferably, the injection is selected from long-acting injections. 优选地，所述的长效注射剂选自水混悬剂或混悬用粉末。Preferably, the long-acting injection is selected from water suspension or powder for suspension.
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