WO2022121961A1 - Composition pharmaceutique de fulvestrant, préparation associée et application associée - Google Patents

Composition pharmaceutique de fulvestrant, préparation associée et application associée Download PDF

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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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fulvestrant
nanometers
pharmaceutical composition
solid particles
limited
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PCT/CN2021/136576
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Chinese (zh)
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陈志祥
孙宝
王婷婷
应述欢
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上海博志研新药物技术有限公司
上海博志研新药物研究有限公司
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Publication of WO2022121961A1 publication Critical patent/WO2022121961A1/fr

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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

Composition pharmaceutique de fulvestrant, son procédé de préparation et application associée. La composition pharmaceutique de fulvestrant comprend des particules solides de fulvestrant, la taille des particules solides de fulvestrant étant telle que Dv(10) est inférieur ou égal à 600 nanomètres, Dv(50) est inférieur ou égal à 700 nanomètres et Dv(90) est inférieur ou égal à 1000 nanomètres. La composition pharmaceutique de fulvestrant présente une vitesse de libération appropriée. La concentration maximale est atteinte rapidement après l'administration et une concentration plasmatique élevée est maintenue. La composition contient une quantité élevée de teneur en médicament et aucun solvant organique ni huile, provoque peu d'irritation, est facile à administrer, permet de réduire des volumes de dosage et de réduire considérablement une douleur d'injection, et présente de bonnes perspectives de marché.
PCT/CN2021/136576 2020-12-10 2021-12-08 Composition pharmaceutique de fulvestrant, préparation associée et application associée WO2022121961A1 (fr)

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WO2011022861A1 (fr) * 2009-08-31 2011-03-03 西安力邦医药科技有限责任公司 Nanosphère/microsphère de fulvestrant, procédé de préparation et utilisation associés
CN104434808A (zh) * 2014-07-03 2015-03-25 石药集团中奇制药技术（石家庄）有限公司 一种治疗性纳米粒子及其制备方法
CN107789320A (zh) * 2016-08-31 2018-03-13 鲁南制药集团股份有限公司 一种氟维司群缓释注射液及其制备工艺
CN109310621A (zh) * 2016-05-06 2019-02-05 伊格尔制药公司 氟维司群制剂和其使用方法
CN111479556A (zh) * 2017-11-08 2020-07-31 伊格尔制药公司 氟维司群制剂及其使用方法
CN113694017A (zh) * 2020-05-11 2021-11-26 鲁南制药集团股份有限公司 一种氟维司群注射制剂及其制备方法

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Publication number Priority date Publication date Assignee Title
WO2011022861A1 (fr) * 2009-08-31 2011-03-03 西安力邦医药科技有限责任公司 Nanosphère/microsphère de fulvestrant, procédé de préparation et utilisation associés
CN104434808A (zh) * 2014-07-03 2015-03-25 石药集团中奇制药技术（石家庄）有限公司 一种治疗性纳米粒子及其制备方法
CN109310621A (zh) * 2016-05-06 2019-02-05 伊格尔制药公司 氟维司群制剂和其使用方法
CN107789320A (zh) * 2016-08-31 2018-03-13 鲁南制药集团股份有限公司 一种氟维司群缓释注射液及其制备工艺
CN111479556A (zh) * 2017-11-08 2020-07-31 伊格尔制药公司 氟维司群制剂及其使用方法
CN113694017A (zh) * 2020-05-11 2021-11-26 鲁南制药集团股份有限公司 一种氟维司群注射制剂及其制备方法

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