WO2021115389A1 - 氟维司群药物组合物、其制备方法及应用 - Google Patents

氟维司群药物组合物、其制备方法及应用 Download PDF

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WO2021115389A1
WO2021115389A1 PCT/CN2020/135311 CN2020135311W WO2021115389A1 WO 2021115389 A1 WO2021115389 A1 WO 2021115389A1 CN 2020135311 W CN2020135311 W CN 2020135311W WO 2021115389 A1 WO2021115389 A1 WO 2021115389A1
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fulvestrant
solid particles
micrometers
injection
pharmaceutical composition
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PCT/CN2020/135311
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English (en)
French (fr)
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应述欢
李洪
陈志祥
王婷婷
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上海博志研新药物技术有限公司
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Priority to EP20900538.8A priority Critical patent/EP4074304A4/en
Priority to US17/757,245 priority patent/US20220370359A1/en
Priority to JP2022534277A priority patent/JP7497902B2/ja
Priority to CN202080007455.XA priority patent/CN113260353A/zh
Publication of WO2021115389A1 publication Critical patent/WO2021115389A1/zh

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    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/547—Chelates, e.g. Gd-DOTA or Zinc-amino acid chelates; Chelate-forming compounds, e.g. DOTA or ethylenediamine being covalently linked or complexed to the pharmacologically- or therapeutically-active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a fulvestrant pharmaceutical composition, a preparation method and application thereof.
  • Fulvestrant is a selective estrogen receptor degrading agent (SERD), used for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women whose disease has progressed after anti-estrogen therapy. Fulvestrant was approved by the US FDA in 2002 for the treatment of hormone receptor-positive metastatic breast cancer.
  • SESD selective estrogen receptor degrading agent
  • Fulvestrant 7-(9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl)estra-1,3,5(10)-triene-3 , 17-diol, its structure is shown in formula I:
  • Fulvestrant is a lipophilic molecule with very low water solubility. Due to the poor solubility and low oral bioavailability of fulvestrant, it is currently generally administered by intramuscular injection of oil-based fulvestrant preparations.
  • FASLODEXTM a commercially available formulation of Fulvestrant, is administered at 500 mg, and requires two 5 mL injections of 50 mg/mL Fulvestrant preparation intramuscularly. Each 5mL injection contains 10w/v% ethanol, 10w/v% benzyl alcohol and 15w/v% benzyl benzoate as a co-solvent, and use castor oil as another co-solvent and release rate regulator to supplement to 100w/ v%.
  • the technical problem to be solved by the present invention is to provide a fulvestrant pharmaceutical composition and its preparation in order to solve the defects of unsatisfactory sustained-release effect of fulvestrant preparations in the prior art, inconvenient application, high injection pain, etc. Methods and applications.
  • the fulvestrant pharmaceutical composition of the present invention has long-acting sustained release, high bioavailability, convenient application, reduced administration volume, greatly reduced injection pain, and good market prospects.
  • the present invention provides a fulvestrant pharmaceutical composition, which comprises fulvestrant solid particles, wherein the particle size of the fulvestrant solid particles is Dv (10) selected from 0.400 microns to 6.000 microns, Dv (50) is selected from 0.700 microns to 6.000 microns and Dv(90) is selected from 1.000 microns to 6.000 microns, provided that Dv(10) is not 0.400 microns, Dv(50) is not 0.700 microns, and Dv(90) is not 1.000 microns.
  • Dv (10) selected from 0.400 microns to 6.000 microns
  • Dv (50) is selected from 0.700 microns to 6.000 microns
  • Dv(90) is selected from 1.000 microns to 6.000 microns
  • the particle size of the fulvestrant solid particles may be Dv(10) 0.500 micrometers to 6.000 micrometers, preferably 0.600 micrometers to 2.000 micrometers, more preferably 0.900 micrometers to 1.800 micrometers, such as 1.856 micrometers, 1.794 microns, 1.500 microns, 1.373 microns, 1.300 microns, 1.100 microns, 1.058 microns, 1.010 microns, 1.000 microns, 0.920 microns, 0.910 microns, 0.903 microns or 0.806 microns.
  • the particle size of the fulvestrant solid particles may be Dv(50) 0.800 ⁇ m to 6.000 ⁇ m, preferably 0.900 ⁇ m to 4.000 ⁇ m, more preferably 1.000 ⁇ m to 3.000 ⁇ m, for example Dv(50) ) 4.215 microns, 2.939 microns, 2.610 microns, 2.500 microns, 1.983 microns, 1.887 microns, 1.500 microns, 1.493 microns, 1.241 microns, 1.202 microns, or 1.127 microns.
  • the particle size of the fulvestrant solid particles may be Dv(90) 1.000 micrometers to 5.000 micrometers, preferably 1.500 micrometers to 4.500 micrometers, such as 4.279 micrometers, 4.000 micrometers, 3.644 micrometers, 3.500 micrometers , 3.027 microns, 2.500 microns, 2.058 microns, 2.000 microns, 1.955 microns, 1.644 microns or 1.587 microns.
  • the particle size of the fulvestrant solid particles may also be Dv(25) 1.000 micrometers to 3.000 micrometers, such as 2.284 micrometers, 1.840 micrometers, 1.376 micrometers, 1.270 micrometers, 1.235 micrometers, 1.056 micrometers , 1.075 microns or 0.922 microns.
  • the particle size of the fulvestrant solid particles may also be Dv(75) 1.000 micrometers to 4.000 micrometers, such as 3.781 micrometers, 3.680 micrometers, 2.823 micrometers, 2.463 micrometers, 1.795 micrometers, 1.469 micrometers , 1.459 microns or 1.397 microns.
  • the fulvestrant pharmaceutical composition may further include a carrier.
  • the carrier may be an oily carrier and/or a non-oily carrier.
  • the oily carrier includes, but is not limited to: one or more of castor oil, triglycerides, cottonseed oil, sesame oil, and the like.
  • the non-oil carrier includes but is not limited to water.
  • the water can be conventional commercially available water for injection, preferably sterile water for injection.
  • the fulvestrant pharmaceutical composition may also include one or more selected from the group consisting of: suspending agent, wetting agent, osmotic pressure regulator, solvent, stabilizer, buffer , PH adjusters, surfactants, polymers, electrolytes, non-electrolytes and co-solvents.
  • 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 and Tween.
  • the Tween may be a conventional commercially available Tween reagent, such as Tween 20 and/or 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: one or more of water for injection and oil for injection.
  • the injection oil includes but is not limited to medium chain triglycerides (MCT).
  • MCT medium chain triglycerides
  • the water for injection may be conventional commercially available water for injection, preferably sterile water for injection.
  • the stabilizer includes, but is not limited to: antioxidants, metal ion chelating agents, polyethylene oxide (PEO), polyethylene oxide derivatives, polysorbate, poloxa Gram, polyethoxylated vegetable oil, polyethoxylated castor oil, sorbitan palmitate, lecithin, polyvinyl alcohol, human serum albumin, polyvinylpyrrolidone, povidone, polyethylene glycol, One or more of sodium chloride, calcium chloride, dextrose, glycerol, mannitol, and cross-linked polymers.
  • the antioxidant includes but is 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 poloxamer includes but is 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.
  • the povidone includes but is not limited to one of Povidone K12, Povidone K17, PLASDONETM C-12 Povidone, PLASDONETM C-17 Povidone, and PLASDONETM C-30 Povidone Or multiple.
  • the polyethylene glycol includes, but is not limited to, polyethylene glycol 3350.
  • the cross-linked polymer includes but is not limited to sodium carboxymethyl cellulose.
  • the buffer includes, but is not limited to: phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid, sodium hydroxide, sodium citrate, citric acid, tris (Tris) one or a mixture of two or more.
  • the pH adjusting agent includes, but is not limited to: one or more of phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid, and sodium hydroxide.
  • the phosphate includes, but is not limited to, 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 (Na 2 HPO 4 anhydrous), sodium dihydrogen phosphate monohydrate (NaH 2 PO 4 ⁇ H 2 O), sodium dihydrogen phosphate dihydrate (NaH 2 PO 4 ⁇ 2H 2 O) and no One or more of 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 1.00% to 50.00%, preferably 10.00% to 40.00%, such as 18.09%, 19.59%, 24.66 % Or 25.00%; the weight fraction refers to the percentage of the weight of the solid particles of fulvestrant in the total weight of the fulvestrant pharmaceutical composition.
  • the weight fraction of the wetting agent is 0 to 5.00%, preferably 1.00% to 3.00%, such as 1.67%, 1.62% or 1.74 %;
  • the weight fraction refers to the percentage of the weight of the wetting agent to the total weight of the fulvestrant pharmaceutical composition.
  • the weight fraction of the suspending agent is 0 to 5.00%, preferably 1.00% to 3.00%, such as 0.20% or 1.00%;
  • the stated weight fraction refers to the weight of the suspending agent as a percentage of the total weight of the fulvestrant pharmaceutical composition.
  • the weight fraction of the osmotic pressure regulator is 0-5.00%, preferably 1.00%-3.00%, such as 2.29%, 2.82% or 2.89%; the weight fraction refers to the percentage of the weight of the osmotic pressure regulator to the total weight of the fulvestrant pharmaceutical composition.
  • the weight fraction of the buffer is 0 to 1.00%, preferably 0.20% to 0.80%, such as 0.42%, 0.43% or 0.51% ;
  • the weight fraction refers to the weight of the buffer as a percentage of the total weight of the fulvestrant pharmaceutical composition.
  • the usage amount of the pH adjuster preferably adjusts the pH of the composition solution to 6.5-8.0, such as 7.4.
  • the fulvestrant pharmaceutical composition preferably includes the following components: 1.00 to 50.00% fulvestrant solid particles, 0 to 5.00% wetting agent, and 0 to 5.00% suspending agent , 0-5.00% osmotic pressure regulator, 0-1.00% buffer salt and solvent.
  • the fulvestrant pharmaceutical composition can be selected from any of the following formulations:
  • Formula 2 19.59% fulvestrant solid particles, 1.74% wetting agent and 78.67% water;
  • Formulation 3 24.66% fulvestrant solid particles, 1.62% wetting agent, 1.00% suspending agent, 2.82% osmotic pressure regulator, 0.42% buffer salt and 0-1% pH regulator; preferably, the rest is water ;
  • Formula 4 25.00% Fulvestrant solid particles, 1.62% wetting agent, 1.00% suspending agent, 2.89% osmotic pressure regulator, 0.43% buffer salt and 0-1% pH regulator; preferably, the rest is water ;
  • Formula 5 25.00% Fulvestrant solid particles, 1.62% wetting agent, 0.20% suspending agent, 2.29% osmotic pressure regulator, 0.51% buffer salt and 70.38% water.
  • the fulvestrant pharmaceutical composition can also be selected from any of the following formulations:
  • Formulation A 18.09% Fulvestrant solid particles, 1.67% Tween 80 and 80.24% sterile water for injection;
  • Formulation B 19.59% Fulvestrant solid particles, 1.74% Tween 80 and 78.67% sterile water for injection;
  • Formulation C 24.66% fulvestrant solid particles, 1.62% Tween 20, 1.00% sodium carboxymethyl cellulose, 2.82% mannitol, 0.42% anhydrous sodium dihydrogen phosphate, sodium hydroxide and sterile water for injection;
  • the pH of the fulvestrant pharmaceutical composition is 7.4;
  • Formulation D 25.00% Fulvestrant solid particles, 1.62% Tween 20, 1.00% sodium carboxymethyl cellulose, 2.89% mannitol, 0.43% anhydrous sodium dihydrogen phosphate, sodium hydroxide and sterile water for injection;
  • the pH of the fulvestrant pharmaceutical composition is 7.4;
  • Formulation E 25.00% Fulvestrant solid particles, 1.62% Tween 20, 0.20% sodium carboxymethyl cellulose, 2.29% mannitol, 0.09% anhydrous sodium dihydrogen phosphate, 0.42% anhydrous disodium hydrogen phosphate and 70.38% sterile water for injection;
  • the present invention also provides a preparation method of the fulvestrant pharmaceutical composition, which comprises the following steps:
  • Step 1 Mix fulvestrant solid particles with other components in the formula to obtain a premix
  • Step 2 Grind the premix obtained in step 1 and zirconium beads together or pulverize by airflow to obtain the fulvestrant pharmaceutical composition.
  • the mixing is preferably stirring and mixing.
  • the particle size of the zirconium beads may be 0.01 mm to 2 mm, for example, 0.3 mm, 0.6 mm, or 1 mm.
  • the volume ratio of the zirconium beads to the premix is 1 to 5, such as 1, 1.5, 2 or 3.
  • the grinding time in step 2, can be 1 minute to 10 hours, or 5 minutes to 8 hours, such as 7 minutes, 4 hours, 7 hours or 8 hours.
  • the zirconium beads refer to conventional commercially available zirconium oxide beads.
  • the invention also provides the application of the fulvestrant pharmaceutical composition in the preparation of fulvestrant pharmaceutical preparations.
  • the fulvestrant pharmaceutical preparations include, but are 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 tablets, osmotic pump tablets, and orally disintegrating tablets.
  • the injection may be a liquid injection, a powder for injection, or a tablet for injection; for example, the liquid injection may be a suspension, such as a water suspension or an oil suspension; for example, the injection The powder is a freeze-dried powder injection.
  • the injection can be a long-acting injection;
  • the long-acting injection can be a water suspension, an oil suspension, or a powder for suspension, and a specific diluent is used for temporary use. Disperse into a suspension.
  • the concentration of fulvestrant in the long-acting injection is not less than 50mg/ml, for example, not less than 100mg/ml, preferably 120mg/ml ⁇ 400mg/ml, exemplarily 200mg /ml, 250mg/ml, 263.8mg/ml, 270.1mg/ml, 300mg/ml, 341.9mg/ml.
  • the present invention also provides a fulvestrant pharmaceutical preparation, which contains the above-mentioned fulvestrant pharmaceutical composition.
  • the fulvestrant pharmaceutical preparation 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 the prevention and/or treatment of hormone receptor positive metastatic breast cancer.
  • the present invention also provides a method for preventing and/or treating hormone receptor positive metastatic breast cancer, which comprises administering the above-mentioned fulvestrant pharmaceutical composition and/or fulvestrant pharmaceutical preparation to a patient in need, such as a human.
  • the "Dv(10)”, “Dv(25)”, “Dv(50)”, “Dv(75)” and “Dv(90)” refer to the volume-weighted particle diameter, where During the measurement, there are cumulative 10v/v%, 25v/v%, 50v/v%, 75v/v% or 90v/v% particles with equal or smaller diameters. For example, if the Dv (50) of the particle group is about 25 microns, it means that 50% of the particles by volume have a diameter less than or equal to about 25 microns.
  • the "Dn(10)”, “Dn(25)”, “Dn(50)”, “Dn(75)” and “Dn(90)” refer to the number-weighted particle diameters, which are measured separately A cumulative 10%, 25%, 50%, 75%, or 90% of the particles have the same or smaller diameter. For example, if the Dn(50) of the particle group is about 25 microns, it means that 50% of the particles have a diameter less than or equal to about 25 microns.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the room temperature refers to an ambient temperature of 10°C to 35°C.
  • the fulvestrant pharmaceutical composition of the present invention has the characteristics of long-acting sustained release, high bioavailability, convenient application, reduced administration volume, greatly reduced injection pain, and good market prospects.
  • Fig. 1 is a morphological diagram of the particle size of fulvestrant solid particles before grinding in Example 1, and the scale is 100 microns;
  • Fig. 2 is a particle size morphology diagram of fulvestrant solid particles after grinding for 5 minutes in Example 1, and the scale is 10 microns;
  • Figure 3 is a particle size morphology diagram of fulvestrant solid particles after 7 minutes of grinding in Example 1, with a scale of 10 microns;
  • Fig. 4 is a morphological diagram of the particle size of fulvestrant solid particles before grinding in Example 2, and the scale is 100 microns;
  • Fig. 5 is a particle size morphology diagram of fulvestrant solid particles after grinding for 30 minutes in Example 2, and the scale is 10 microns;
  • Example 6 is a diagram of the particle size morphology of fulvestrant solid particles after grinding for 1 hour in Example 2, and the scale is 10 microns;
  • Fig. 7 is a particle size morphology diagram of fulvestrant solid particles after grinding for 2 hours in Example 2, and the scale is 10 microns;
  • Fig. 8 is a particle size morphology diagram of fulvestrant solid particles after 4 hours of grinding in Example 2, and the scale is 10 microns;
  • Figure 9 is the XRPD spectrum of the solid particles of Fulvestrant before grinding in Example 3.
  • Instrument model Bruker D8 Advance X-ray diffractometer, test condition: Target: Cu 40kv 40mA;
  • Figure 10 shows the suspension in Example 3 after being milled at 60°C, 20 days, 40°C, 20 days, 40°C, 30 days, 25°C, 30 days, 4°C, 30 days and -20°C, 30 days, fluorine XRPD spectra of Vestrant solid particles;
  • 1 represents the XRPD spectrum of the solid particles of Fulvestrant after being ground in Example 3 and placed at 60°C for 20 days;
  • Example 2 shows the XRPD spectrum of the solid particles of fulvestrant in the suspension placed at 40°C for 30 days after grinding in Example 3;
  • Example 3 shows the XRPD spectrum of the solid particles of fulvestrant in the suspension placed at 40°C for 20 days after grinding in Example 3;
  • Example 4 represents the XRPD spectrum of the solid particles of fulvestrant in the suspension placed at 25°C for 30 days after grinding in Example 3;
  • Example 5 represents the XRPD spectrum of the solid particles of Fulvestrant after being ground in Example 3 and placed at 4°C for 30 days;
  • Example 6 shows the XRPD spectrum of the solid particles of fulvestrant after the suspension in Example 3 is placed at -20°C for 30 days after grinding.
  • 11 is a polarized light microscope observation view of the solid particles of fulvestrant in the suspension placed at 60°C for 20 days after grinding in Example 3, and the scale is 10 microns;
  • Fig. 12 is a polarized light microscope observation view of the solid particles of Fulvestrant in the suspension placed at 40°C for 20 days after grinding in Example 3, and the scale is 10 microns;
  • Figure 13 is a polarized light microscope observation view of the solid particles of Fulvestrant in the suspension placed at 40°C for 30 days after grinding in Example 3, and the scale is 10 microns;
  • Example 14 is a polarized light microscope observation view of the solid particles of Fulvestrant after grinding in Example 3 and placed at 25°C for 30 days, with a scale of 10 microns;
  • Example 15 is a polarized light microscope observation view of the solid particles of Fulvestrant after grinding in Example 3 after being placed at 4°C for 30 days, and the scale is 10 microns;
  • 16 is a polarized light microscope observation diagram of fulvestrant solid particles in the suspension after grinding in Example 4, and the scale is 10 microns;
  • 17 is a polarized light microscope observation diagram of fulvestrant solid particles in the suspension after grinding in Example 5, with a scale of 10 microns;
  • Example 18 is a polarized light microscope observation diagram of fulvestrant solid particles in the suspension after grinding in Example 6, with a scale of 10 microns;
  • Example 19 is a diagram of the particle size distribution of fulvestrant solid particles in the suspension after grinding in Example 7;
  • 20 is a particle size morphology diagram of fulvestrant solid particles in the suspension after grinding in Example 7, and the scale is 10 microns;
  • Figure 21 is a particle size distribution diagram of fulvestrant solid particles in the suspension after grinding in Example 8.
  • Example 22 is a particle size morphology diagram of fulvestrant solid particles in the suspension after grinding in Example 8, and the scale is 10 microns;
  • Figure 23 is a particle size distribution diagram of fulvestrant solid particles in the suspension after grinding in Example 9;
  • 24 is a particle size morphology diagram of fulvestrant solid particles in the suspension after grinding in Example 9, and the scale is 10 microns;
  • Figure 25 is the pharmacokinetic curve of fulvestrant for prescription No.1 in Example 11 (i.e., marketed versus fulvestrant preparation);
  • Figure 26 is the pharmacokinetic curve of Fulvestrant, the formulation No. 2 of Example 11;
  • Figure 27 is the pharmacokinetic curve of Fulvestrant, the No. 3 formulation in Example 11;
  • Figure 28 is a pharmacokinetic curve of No. 4 Fulvestrant formulation in Example 11;
  • Figure 29 is the average pharmacokinetic curve of prescription No. 1 preparation (ie, marketed comparison fulvestrant preparation) and prescription No. 2, 3, and 4 preparations of fulvestrant;
  • the raw materials and reagents used in the following examples are all commercially available products, or can be prepared by known methods.
  • the particle diameters in the following examples are without special instructions, and are all volume-weighted particle diameters Dv.
  • composition Proportion (%, W/W) Feeding amount (g) Fulvestrant 18.09 1.94 Tween 80 1.67 0.18 Sterilized water for injection 80.24 8.60
  • the premix sample and 118.5g of 1mm zirconium beads are placed in a grinding tank (the volume ratio of the premix sample and the zirconium beads is 1:3) for grinding, and the composition is ground to obtain a fulvestrant suspension injection.
  • the grinding is carried out with a ball mill.
  • the parameters of the planetary ball mill are set: fixed parameters: the diameter of the revolving disc is about 191mm, the diameter of the rotation cup is about 71mm, the height of the rotation cup is about 70mm, the volume of the rotation cup is 100ml, the rotation speed of the revolving disc is 10r/min, and the rotation speed: 720r/min.
  • composition Proportion (%, W/W) Feeding amount (g) Fulvestrant 19.59 0.98 Tween 80 1.74 0.09 Sterilized water for injection 78.67 3.94
  • the premix sample and 60.00g 1mm zirconium beads Place the premix sample and 60.00g 1mm zirconium beads in a grinding jar (the volume ratio of the premix sample and the zirconium beads is 1:3) for grinding and grinding for 7 hours to obtain the fulvestrant pharmaceutical composition, which is a suspension Injection.
  • the grinding is carried out with a ball mill.
  • the parameters of the planetary ball mill are set: fixed parameters: the diameter of the revolving disc is about 191mm, the diameter of the rotation cup is about 71mm, the height of the rotation cup is about 70mm, the volume of the rotation cup is 100ml, the rotation speed of the revolving disc is 10r/min, and the rotation speed: 720r/min.
  • the particle size morphology of the solid particles is shown in Figure 6, the particle size morphology of the fulvestrant solid particles after 2 hours of grinding is shown in Figure 7, and the particle size morphology of the fulvestrant solid particles after 4 hours of grinding is shown in Figure 8. Show.
  • the premixed solution and 97.6g 0.3mm zirconium beads in a grinding jar (the volume ratio of the premixed solution sample and the zirconium beads is 1:1) for grinding and grinding for 3 hours to obtain the fulvestrant pharmaceutical composition, which is a suspension Injection.
  • the grinding is carried out with a ball mill.
  • the parameters of the planetary ball mill are set: fixed parameters: the diameter of the revolving disc is about 191mm, the diameter of the rotation cup is about 71mm, the height of the rotation cup is about 70mm, the volume of the rotation cup is 100ml, the rotation speed of the revolving disc is 10r/min, and the rotation speed: 720r/min.
  • the fulvestrant suspensions prepared in Examples 1 and 2 were refrigerated in a refrigerator at 4° C. for 14 days or 10 days to determine related substances. The results are shown in Table 7.
  • the fulvestrant suspension prepared in Example 3 was placed at minus 20°C, 4°C, 25°C, 40°C or 60°C to test related substances, fulvestrant solid particle morphology and particle size distribution, The results of the crystal form changes are shown in Table 8 and Table 9.
  • the XPRD test spectrum is shown in Figure 9 and Figure 10.
  • the solid particle size morphology of Fulvestrant is shown in Figure 11-15. Among them, related substances are tested in accordance with the EP10.0 method.
  • Placement conditions D10( ⁇ m) D25( ⁇ m) D50( ⁇ m) D75( ⁇ m) D90( ⁇ m) 60°C, 20 days 0.904 1.082 1.28 1.525 1.737 40°C, 30 days 1.738 2.373 3.215 4.116 5.048 25°C, 30 days 2.206 2.769 3.473 4.229 5.073 4°C, 30 days 1.347 1.973 2.777 3.601 4.325 4°C, 40 days 0.909 1.325 1.822 2.385 2.934
  • the test results of related substances showed that the related substances in the suspension increased slightly after grinding; after placing under different conditions, the related substances in the suspension did not increase significantly. Under all conditions, the maximum single impurity content is 0.07%, the maximum total impurity content is 0.36%, and the quality is up to standard.
  • the particle size morphology map (PLM) of Figures 11-15 showed that the morphology of fulvestrant solid particles in the samples did not change under various conditions, and there was no significant increase in particle size except for some samples where a small amount of particle aggregation was found.
  • Laser particle size analysis showed that the particle size of fulvestrant solid particles in the suspension under all conditions did not exceed 5 ⁇ m, and the particle size increased slightly at 25 and 40°C, which may be related to the aggregation of sample particles, but the individual particles remained unchanged; The particle size is slightly reduced at 60°C.
  • the XRPD results of FIG. 9 and FIG. 10 show that the crystalline form of the suspension fulvestrant solid particles under different conditions is consistent with the initial fulvestrant solid particles, and the crystalline form of the fulvestrant solid particles has not changed.
  • the premixed solution and 97.5g 0.3mm zirconium beads placed in a grinding jar (the volume ratio of the premixed solution sample and the zirconium beads is 2:3) for grinding and grinding for 27 hours to obtain the fulvestrant pharmaceutical composition, which is a suspension injection liquid.
  • the grinding is carried out with a ball mill.
  • the parameters of the planetary ball mill are set: fixed parameters: the diameter of the revolving disc is about 191mm, the diameter of the rotation cup is about 71mm, the height of the rotation cup is about 70mm, the volume of the rotation cup is 100ml, the rotation speed of the revolving disc is 10r/min, and the rotation speed: 720r/min.
  • Table 11 The particle size distribution of Fulvestrant in the suspension of Example 4.
  • the premixed solution and 111.6g 0.6mm zirconium beads placed in a grinding jar (the volume ratio of the premixed solution sample and the zirconium beads is 2:3) for grinding and grinding for 27 hours to obtain the fulvestrant pharmaceutical composition, which is a suspension injection liquid.
  • the grinding is carried out with a ball mill.
  • the parameters of the planetary ball mill are set: fixed parameters: the diameter of the revolving disc is about 191mm, the diameter of the rotation cup is about 71mm, the height of the rotation cup is about 70mm, the volume of the rotation cup is 100ml, the rotation speed of the revolving disc is 10r/min, and the rotation speed: 720r/min.
  • the premixed solution and 112.0g 1.0mm zirconium beads placed in a grinding jar (the volume ratio of the premixed solution sample and the zirconium beads is 2:3) for grinding and grinding for 27 hours to obtain the fulvestrant pharmaceutical composition, which is a suspension injection liquid.
  • the grinding is carried out with a ball mill.
  • the parameters of the planetary ball mill are set: fixed parameters: the diameter of the revolving disc is about 191mm, the diameter of the rotation cup is about 71mm, the height of the rotation cup is about 70mm, the volume of the rotation cup is 100ml, the rotation speed of the revolving disc is 10r/min, and the rotation speed: 720r/min.
  • the grinding is carried out with a ball mill.
  • the parameters of the planetary ball mill are set: fixed parameters: the diameter of the revolving disc is about 191mm, the diameter of the rotation cup is about 71mm, the height of the rotation cup is about 70mm, the volume of the rotation cup is 100ml, the rotation speed of the revolving disc is 10r/min, and the rotation speed: 720r/min.
  • the grinding is carried out with a ball mill.
  • the parameters of the planetary ball mill are set: fixed parameters: the diameter of the revolving disc is about 191mm, the diameter of the rotation cup is about 71mm, the height of the rotation cup is about 70mm, the volume of the rotation cup is 100ml, the rotation speed of the revolving disc is 10r/min, and the rotation speed: 720r/min.
  • laser particle size analyzer parameter settings: dispersion medium: water; refractive index of the dispersion medium: 1.333; sample material absorption rate: 0.01; sample material refractive index: 1.521.
  • Table 17 shows the content and particle size distribution data of fulvestrant solid particles in the suspension after grinding.
  • the particle size distribution diagram of the solid particles of Fulvestrant in the suspension after grinding is shown in Fig. 21, and the morphology of the solid particles of Fulvestrant in the suspension after grinding is shown in Fig. 22.
  • the results of related substances are shown in Table 19.
  • the raw and auxiliary materials Prepare and weigh the raw and auxiliary materials according to the dosage in the prescription in Table 20 and mix them evenly to obtain the fulvestrant drug suspension, which is recorded as batch 3. Among them, the raw material is obtained by air jet pulverization.
  • Example 7 Example 8, and Example 9 (respectively recorded as prescription Nos. 2, 3, 4) and the marketed comparative preparation Fulvestrant injection FASLODEX (5mL: 250mg, Germany VETTER Pharma-fertigung GmbH&Co KG, Batch number: RD693, valid in August 2023, recorded as prescription No. 1).
  • Recipe No. 2, 3 and No. 1 are stable under long-term conditions (25°C ⁇ 2°C, 60%RH ⁇ 5%RH) and accelerated conditions (40°C ⁇ 2°C, 75%RH ⁇ 5%RH) according to Table 21
  • the related substances of Fulvestrant were detected according to the EP10.0 method, and the results are shown in Table 19; the particle size and particle size distribution of formulation No. 2 and 3 were measured at the same time, and the results were shown in Tables 22 and 23.
  • the stability results showed that the degradation impurities 6-Keto fulvestrant (6-ketofulvestrant) and Fulvestrant Sulphone (fulvestrant sulfone), unknown single impurities, total impurities in the self-made fulvestrant suspension were compared under the same conditions.
  • the impurity level is lower than that of the comparative preparation Fulvestrant injection FASLODEX, indicating that the stability of the self-made Fulvestrant suspension is better than that of the marketed comparative preparation.
  • Example 7 The preparations obtained in Example 7, Example 8, and Example 9 (prescription Nos. 2, 3, and 4) were diluted with a diluent to 50 mg/ml.
  • the diluent composition 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.
  • Clinical observations include skin, coat, eyes, ears, nose, oral cavity, chest, abdomen, urogenital area, limbs and other parts, as well as breathing, exercise, urinary, defecation and behavior changes and muscle irritation at the site of administration. 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) collect blood samples, conduct biological analysis and use WinNonlin version 8.1 non-compartment model to calculate the pharmacokinetic parameters Tmax of each group , Cmax, AUC(0-t), AUC(0- ⁇ ), T1/2, MRT, CL, Vz, etc. The animals were dissected on D45 and histopathological examination was performed on the site of administration to observe the inflammatory reaction and drug residue.
  • AUCINF_obs It is 6350 ⁇ 949h*ng/mL, AUClast is 5000 ⁇ 932h*ng/mL, drug terminal elimination half-life T1/2_Z is 413 ⁇ 88.0h, clearance rate Cl_obs is 2410 ⁇ 433mL/h/kg, and average residence time MRTINF_obs is 641 ⁇ 136h, the volume of distribution Vz_obs is 1450000 ⁇ 421000mL/kg.
  • AUCINF_obs is 6990 ⁇ 2010h*ng/mL
  • AUClast is 3490 ⁇ 745h*ng/mL
  • the drug terminal elimination half-life T1/2_Z is 776 ⁇ 300h
  • the clearance rate Cl_obs is 2340 ⁇ 814mL/h/kg
  • the average residence The time MRTINF_obs is 1310 ⁇ 443h
  • the volume of distribution Vz_obs is 2470000 ⁇ 881000mL/kg.
  • AUCINF_obs is 71800 ⁇ 125000h*ng/mL
  • AUClast is 3970 ⁇ 701h*ng/mL
  • the drug terminal elimination half-life T1/2_Z is 12300 ⁇ 23900h
  • the clearance rate Cl_obs is 655 ⁇ 398mL/h/kg
  • the average residence The time MRTINF_obs is 18000 ⁇ 34500h, and the volume of distribution Vz_obs is 2950000 ⁇ 721000mL/kg.
  • AUCINF_obs is 35000 ⁇ 61100hng/mL
  • AUClast is 3280 ⁇ 518h*ng/mL
  • the drug terminal elimination half-life T1/2_Z is 5300 ⁇ 9230h
  • the clearance rate Cl_obs is 1550 ⁇ 1150mL/h/kg
  • the average residence time MRTINF_obs It is 7820 ⁇ 13300h
  • the volume of distribution Vz_obs is 3170000 ⁇ 571000mL/kg.

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Abstract

氟维司群药物组合物、其制备方法及应用。所述氟维司群药物组合物包括氟维司群固体粒子，其中所述的氟维司群固体粒子的粒径为Dv(10)选自0.400微米～6.000微米、Dv(50)选自0.700微米～6.000微米且Dv(90)选自1.000微米～6.000微米，条件是：Dv(10)不为0.400微米、Dv(50)不为0.700微米并且Dv(90)不为1.000微米。氟维司群药物组合物长效缓释，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。

Description

氟维司群药物组合物、其制备方法及应用
本申请要求以下在先申请的优先权：2019年12月11日向中国国家知识产权局提交的专利申请号为201911262544.4，发明名称为“氟维司群药物组合物、制备方法及应用”，以及2020年6月24日向中国国家知识产权局提交的专利申请号为202010590154.6，发明名称为“氟维司群药物组合物、制备方法及应用”的在先申请。所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于药物领域，具体涉及氟维司群药物组合物、其制备方法及应用。
背景技术
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批准氟维司群可用于治疗激素受体阳性转移性乳腺癌。
氟维司群的化学名为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：
Figure PCTCN2020135311-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。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。
因此，寻找长效缓释且施用方便、疼痛度低的氟维司群剂型，是目前急需解决的技术问题。
发明内容
本发明所要解决的技术问题是为了解决现有技术中氟维司群制剂缓释效果不理想、且施用不方便、注射疼痛度高等缺陷而提供了一种氟维司群药物组合物、其制备方法及应用。本发明的氟维司群药物组合物长效缓释、生物利用度高，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。
本发明提供了一种氟维司群药物组合物，其包括氟维司群固体粒子，其中所述的氟维司群固体粒子的粒径为Dv(10)选自0.400微米～6.000微米、Dv(50)选自0.700微米～6.000微米且Dv(90)选自1.000微米～6.000微米，条件是：Dv(10)不为0.400微米、Dv(50)不为0.700微米并且Dv(90)不为1.000微米。
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)0.500微米～6.000微米，优选0.600微米～2.000微米，进一步优选0.900微米～1.800微米、例如1.856微米、1.794微米、1.500微米、1.373微米、1.300微米、1.100微米、1.058微米、1.010微米、1.000微米、0.920微米、0.910微米、0.903微米或0.806微米。
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)0.800微米～6.000微米，优选0.900微米～4.000微米，进一步优选1.000微米～3.000微米，例如Dv(50)4.215微米、2.939微米、2.610微米、2.500微米、1.983微米、1.887微米、1.500微米、1.493微米、1.241微米、1.202微米或1.127微米。
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)1.000微米～5.000微米，优选1.500微米～4.500微米，例如4.279微米、4.000微米、3.644微米、3.500微米、3.027微米、2.500微米、2.058微米、2.000微米、1.955微米、1.644微米或1.587微米。
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)1.000微米～3.000微米，例如2.284微米、1.840微米、1.376微米、1.270微米、1.235微米、1.056微米、1.075微米或0.922微米。
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)1.000微米～4.000微米，例如3.781微米、3.680微米、2.823微米、2.463微米、1.795微米、1.469微米、1.459微米或1.397微米。
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载体。所述的载体可以 为油性载体和/或非油载体。所述的油性载体包括但不限于：蓖麻油、甘油三酸酯、棉籽油和芝麻油等中的一种或多种。
所述的非油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。
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、非电解质和助溶剂。其中，所述的聚合物可以为交联聚合物和/或非交联聚合物。
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。
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/或吐温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。
根据本发明的实施方案，所述的溶剂包括但不限于：注射用水和注射用油中的一种或多种。例如，所述的注射用油包括但不限于中链甘油三酸酯(MCT)。例如，所述的注射用水可以为常规市售注射用水，优选灭菌注射用水。
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、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。例如，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。例如，所述的金属离子螯合剂包括但不限于乙二胺四乙酸(EDTA)。例如，所述的泊洛沙姆包括但不限于泊洛沙姆188、泊洛沙姆124、泊洛沙姆407中的一种或多种。例如，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。例如，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。例如，所述的聚乙二醇包括但不限于聚乙二醇3350。
根据本发明的实施方案，所述的交联聚合物包括但不限于羧甲基纤维素钠。
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、枸橼酸钠、盐酸、氢氧化钠、柠檬酸钠、柠檬酸、三羟甲基氨基甲烷(Tris)中的一种或两种以上的 混合物。
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、盐酸和氢氧化钠中的一种或多种。
根据本发明的实施方案，所述的磷酸盐包括但不限于一水磷酸氢二钠(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。
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。
根据本发明的实施方案，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为1.00％～50.00％，优选10.00％～40.00％，例如18.09％、19.59％、24.66％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。
根据本发明的实施方案，所述的氟维司群药物组合物中，所述的润湿剂的重量分数为0～5.00％，优选为1.00％～3.00％，例如1.67％、1.62％或1.74％；所述的重量分数是指润湿剂的重量占氟维司群药物组合物总重量的百分比。
根据本发明的实施方案，所述的氟维司群药物组合物中，所述的助悬剂的重量分数为0～5.00％，优选为1.00％～3.00％，例如0.20％或1.00％；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。
根据本发明的实施方案，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为0～5.00％，优选为1.00％～3.00％，例如2.29％、2.82％或2.89％；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。
根据本发明的实施方案，所述的氟维司群药物组合物中，所述的缓冲剂的重量分数为0～1.00％，优选为0.20％～0.80％，例如0.42％、0.43％或0.51％；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。
根据本发明的实施方案，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7.4。
根据本发明的实施方案，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％助悬剂、0～5.00％渗透压调节剂、0～1.00％缓冲盐和溶剂。
根据本发明的实施方案，所述的氟维司群药物组合物，可以选自以下任一配方：
配方一：18.09％氟维司群固体粒子、1.67％润湿剂和80.24％水；
配方二：19.59％氟维司群固体粒子、1.74％润湿剂和78.67％水；
配方三：24.66％氟维司群固体粒子、1.62％润湿剂、1.00％助悬剂、2.82％渗透压调节剂、0.42％缓冲盐和0～1％pH调节剂；优选地，其余为水；
配方四：25.00％氟维司群固体粒子、1.62％润湿剂、1.00％助悬剂、2.89％渗透压调节剂、0.43％缓冲盐和0～1％pH调节剂；优选地，其余为水；
配方五：25.00％氟维司群固体粒子、1.62％润湿剂、0.20％助悬剂、2.29％渗透压调节剂、0.51％缓冲盐和70.38％水。
根据本发明的实施方案，所述的氟维司群药物组合物，也可以选自以下任一配方：
配方A：18.09％氟维司群固体粒子、1.67％吐温80和80.24％灭菌注射用水；
配方B：19.59％氟维司群固体粒子、1.74％吐温80和78.67％灭菌注射用水；
配方C：24.66％氟维司群固体粒子、1.62％吐温20、1.00％羧甲基纤维素钠、2.82％甘露醇、0.42％无水磷酸二氢钠、氢氧化钠和灭菌注射用水；优选地，所述氟维司群药物组合物的pH为7.4；
配方D：25.00％氟维司群固体粒子、1.62％吐温20、1.00％羧甲基纤维素钠、2.89％甘露醇、0.43％无水磷酸二氢钠、氢氧化钠和灭菌注射用水；优选地，所述氟维司群药物组合物的pH为7.4；
配方E：25.00％氟维司群固体粒子、1.62％吐温20、0.20％羧甲基纤维素钠、2.29％甘露醇、0.09％无水磷酸二氢钠、0.42％无水磷酸氢二钠和70.38％灭菌注射用水；
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：
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；
步骤2：将步骤1得到的预混物与锆珠共同研磨或者经气流粉碎，得到所述氟维司群药物组合物。
根据本发明的实施方案，步骤1中，所述的混合优选搅拌混合。
根据本发明的实施方案，步骤2中，所述的锆珠的粒径可以为0.01mm～2mm，例如0.3mm、0.6mm或1mm。
根据本发明的实施方案，步骤2中，所述的锆珠与所述的预混物的体积比值为1～5，例如1、1.5、2或3。
根据本发明的实施方案，步骤2中，所述的研磨的时间可以为1分钟～10小时，也可以为5分钟～8小时，例如7分钟、4小时、7小时或8小时。
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。
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。
根据本发明的实施方案，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，比如为水混悬剂或油混悬剂；例如，所述注射用粉剂为冻干粉针。
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、油混悬剂，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。
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，例如不低于100mg/ml，优选为120mg/ml～400mg/ml，示例性为200mg/ml、250mg/ml、263.8mg/ml、270.1mg/ml、300mg/ml、341.9mg/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。
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。
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。
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。
本发明中，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，则表示50％体积的粒子具有小于或等于约25微米的直径。所述的“Dn(10)”、“Dn(25)”、“Dn(50)”、“Dn(75)”和“Dn(90)”是指数量加权的粒子直径，其中在测量时分别有累积10％、25％、50％、75％或90％的粒子具有相等或较小的直径。例如，如果粒子群的Dn(50)为约25微米，则表示50％数量的粒子具有小于或等于约25微米的直径。
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。
本发明所用试剂和原料均市售可得。
根据本发明的实施方案，所述的室温是指环境温度为10℃～35℃。
本发明的有益效果：本发明的氟维司群药物组合物具有长效缓释、生物利用度高的特点，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。
附图说明
图1为实施例1研磨前氟维司群固体粒子的粒径形态图，标尺为100微米；
图2为实施例1中，研磨5分钟后氟维司群固体粒子的粒径形态图，标尺为10微米；
图3为实施例1中，研磨7分钟后氟维司群固体粒子的粒径形态图，标尺为10微米；
图4为实施例2研磨前氟维司群固体粒子的粒径形态图，标尺为100微米；
图5为实施例2中，研磨30分钟后氟维司群固体粒子的粒径形态图，标尺为10微米；
图6为实施例2中，研磨1小时后氟维司群固体粒子的粒径形态图，标尺为10微米；
图7为实施例2中，研磨2小时后氟维司群固体粒子的粒径形态图，标尺为10微米；
图8为实施例2中，研磨4小时后氟维司群固体粒子的粒径形态图，标尺为10微米；
图9为实施例3研磨前氟维司群固体粒子的XRPD谱图，仪器型号：Bruker D8 Advance X-射线衍射仪，测试条件：Target：Cu 40kv 40mA；
图10为实施例3研磨后混悬液放置60℃、20天，40℃、20天，40℃、30天，25℃、30天，4℃、30天和-20℃、30天，氟维司群固体粒子的XRPD谱图；
其中，1表示实施例3研磨后混悬液放置60℃、20天氟维司群固体粒子的XRPD谱图；
2表示实施例3研磨后混悬液放置40℃、30天氟维司群固体粒子的XRPD谱图；
3表示实施例3研磨后混悬液放置40℃、20天氟维司群固体粒子的XRPD谱图；
4表示实施例3研磨后混悬液放置25℃、30天氟维司群固体粒子的XRPD谱图；
5表示实施例3研磨后混悬液放置4℃、30天氟维司群固体粒子的XRPD谱图；
6表示实施例3研磨后混悬液放置-20℃、30天氟维司群固体粒子的XRPD谱图。
图11为实施例3研磨后混悬液放置60℃、20天氟维司群固体粒子的偏振光显微镜观察图，标尺为10微米；
图12为实施例3研磨后混悬液放置40℃、20天氟维司群固体粒子的偏振光显微镜观察图，标尺为10微米；
图13为实施例3研磨后混悬液放置40℃、30天氟维司群固体粒子的偏振光显微镜观察图，标尺为10微米；
图14为实施例3研磨后混悬液放置25℃、30天氟维司群固体粒子的偏振光显微镜观察图，标尺为10微米；
图15为实施例3研磨后混悬液放置4℃、30天氟维司群固体粒子的偏振光显微镜观察图，标尺为10微米；
图16为实施例4中研磨后混悬液中氟维司群固体粒子的偏振光显微镜观察图，标尺为10微米；
图17为实施例5中研磨后混悬液中氟维司群固体粒子的偏振光显微镜观察图，标尺为10微米；
图18为实施例6中研磨后混悬液中氟维司群固体粒子的偏振光显微镜观察图，标尺为10微米；
图19为实施例7中研磨后混悬液中氟维司群固体粒子的粒径分布图；
图20为实施例7中研磨后混悬液中氟维司群固体粒子的粒径形态图，标尺为10微米；
图21为实施例8中研磨后混悬液中氟维司群固体粒子的粒径分布图；
图22为实施例8中研磨后混悬液中氟维司群固体粒子的粒径形态图，标尺为10微米；
图23为实施例9中研磨后混悬液中氟维司群固体粒子的粒径分布图；
图24为实施例9中研磨后混悬液中氟维司群固体粒子的粒径形态图，标尺为10微米；
图25为实施例11处方No.1(即上市对比氟维司群制剂)氟维司群药代动力学曲线；
Figure PCTCN2020135311-appb-000002
表示动物1的药代动力学曲线；
Figure PCTCN2020135311-appb-000003
表示动物2的药代动力学曲线；
Figure PCTCN2020135311-appb-000004
表示动物3的药代动力学曲线；
Figure PCTCN2020135311-appb-000005
表示动物4的药代动力学曲线；
Figure PCTCN2020135311-appb-000006
表示动物5的药代动力学曲线；
Figure PCTCN2020135311-appb-000007
表示动物6的药代动力学曲线。
图26为实施例11处方No.2制剂氟维司群药代动力学曲线；
Figure PCTCN2020135311-appb-000008
表示动物1的药代动力学曲线；
Figure PCTCN2020135311-appb-000009
表示动物2的药代动力学曲线；
Figure PCTCN2020135311-appb-000010
表示动物3的药代动力学曲线；
Figure PCTCN2020135311-appb-000011
表示动物4的药代动力学曲线；
Figure PCTCN2020135311-appb-000012
表示动物5的药代动力学曲线；
Figure PCTCN2020135311-appb-000013
表示动物6的药代动力学曲线。
图27为实施例11处方No.3制剂氟维司群药代动力学曲线；
Figure PCTCN2020135311-appb-000014
表示动物1的药代动力学曲线；
Figure PCTCN2020135311-appb-000015
表示动物2的药代动力学曲线；
Figure PCTCN2020135311-appb-000016
表示动物3的药代动力学曲线；
Figure PCTCN2020135311-appb-000017
表示动物4的药代动力学曲线；
Figure PCTCN2020135311-appb-000018
表示动物5的药代动力学曲线；
Figure PCTCN2020135311-appb-000019
表示动物6的药代动力学曲线。
图28为实施例11处方No.4氟维司群制剂药代动力学曲线；
Figure PCTCN2020135311-appb-000020
表示动物1的药代动力学曲线；
Figure PCTCN2020135311-appb-000021
表示动物2的药代动力学曲线；
Figure PCTCN2020135311-appb-000022
表示动物3的药代动力学曲线；
Figure PCTCN2020135311-appb-000023
表示动物4的药代动力学曲线；
Figure PCTCN2020135311-appb-000024
表示动物5的药代动力学曲线；
Figure PCTCN2020135311-appb-000025
表示动物6的药代动力学曲线。
图29为处方No.1制剂(即上市对比氟维司群制剂)和处方No.2、3、4制剂氟维司群的平均药代动力学曲线；
Figure PCTCN2020135311-appb-000026
表示处方No.1制剂氟维司群的平均药代动力学曲线；
Figure PCTCN2020135311-appb-000027
表示处方No.2制剂氟维司群的平均药代动力学曲线；
Figure PCTCN2020135311-appb-000028
表示处方No.3制剂氟维司群的平均药代动力学曲线；
Figure PCTCN2020135311-appb-000029
表示处方No.4制剂氟维司群的平均药代动力学曲线。
具体实施方式
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。
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。
下述实施例中的粒径无特殊说明，均为体积加权的粒子径Dv。
实施例1
表1实施例1混悬注射液处方表
组成 比例(％，W/W) 投料量(g)
氟维司群 18.09 1.94
吐温80 1.67 0.18
灭菌注射用水 80.24 8.60
如表1所示处方，称取0.18g吐温80，加入1.94g氟维司群固体粒子后，加灭菌注射用水8.60g，搅拌混合均匀得预混液。
将预混液样品与118.5g 1mm锆珠放置于研磨罐中(预混液样品和锆珠的体积比为1∶3)进行研磨，研磨组合物，得到氟维司群混悬注射液。研磨采用球磨仪进行，行星式球磨仪的参数设置：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。
采用激光粒度仪测定(激光粒度仪的参数设置：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)，混悬液中氟维司群固体粒子的粒径分布如表2所示。混悬液中研磨前氟维司群固体粒子的粒径形态如图1所示，研磨5分钟后氟维司群固体粒子的粒径形态如图2所示，研磨7分钟后氟维司群固体粒子的粒径形态如图3所示。
表2实施例1混悬液中氟维司群的粒径分布
编号 D10(μm) D25(μm) D50(μm) D75(μm) D90(μm)
实施例1 1.794 2.284 2.939 3.68 4.279
实施例2
表3实施例2混悬注射液处方表
组成 比例(％，W/W) 投料量(g)
氟维司群 19.59 0.98
吐温80 1.74 0.09
灭菌注射用水 78.67 3.94
如表3所示处方，称取0.09g吐温80，加入0.98g氟维司群固体粒子后，加灭菌注射用水3.94g，搅拌混合均匀得预混液。
将预混液样品与60.00g 1mm锆珠放置于研磨罐中(预混液样品和锆珠的体积比为1∶3)进行研磨，研磨7小时，得到氟维司群药物组合物，其为混悬注射液。研磨采用球磨仪进行，行星式球磨仪的参数设置：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。
采用激光粒度仪测定(激光粒度仪的参数设置：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)，不同研磨时间混悬液中氟维司群固体粒子的粒径分布如表4所示。混悬液中研磨前氟维司群固体粒子的粒径形态如图4所示，研磨30分钟后氟维司群固体粒子的粒径形态如图5所示，研磨1小时后氟维司群固体粒子的粒径形态如图6所示，研磨2小时后氟维司群固体粒子的粒径形态如图7所示，研磨4小时后氟维司群固体粒子的粒径形态如图8所示。
表4实施例2混悬液中氟维司群的粒径分布
研磨时间 D10(μm) D25(μm) D50(μm) D75(μm) D90(μm)
1hr 1.215 1.764 2.468 3.238 4.012
4hrs 1.010 1.376 1.887 2.463 3.027
实施例3
表5实施例3混悬注射液处方表
Figure PCTCN2020135311-appb-000030
如表5所示处方，称取0.492g吐温20，加入7.51g氟维司群固体粒子后，加4％甘露醇-pH7.4无水磷酸二氢钠溶液定重至30g(此处的百分比是指甘露醇的质量占甘露醇-pH7.4无水磷酸二氢钠溶液总体积的百分比)，搅拌混合均匀得预混液。
将预混液与97.6g 0.3mm锆珠放置于研磨罐中(预混液样品和锆珠的体积比为1∶1)进行研磨，研磨3小时，得到氟维司群药物组合物，其为混悬注射液。研磨采用球磨仪进行，行星式球磨仪的参数设置：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。
采用激光粒度仪测定(激光粒度仪的参数设置：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)，不同研磨时间混悬液中氟维司群固体粒子的粒径分布如表6所示。研磨完成后加0.30g CMC-Na(羧甲基纤维素钠)充分搅拌均匀。
将样品取出过滤去除研磨珠。用西林瓶分装轧盖，采用铝箔包装避光保存于4℃。
表6实施例3混悬液中氟维司群的粒径分布
研磨时间 D10(μm) D25(μm) D50(μm) D75(μm) D90(μm)
0min 5.837 11.177 20.476 39.125 83.029
10mins 1.315 1.75 2.327 2.99 3.639
1hr 1.054 1.457 2.051 2.664 3.254
4hrs 0.903 1.27 1.983 2.823 3.644
实施例1-3制得的氟维司群混悬液的稳定性测试
将实施例1和2制得的氟维司群混悬液，冰箱4℃冷藏14天或10天测定有关物质，结果见表7。
将实施例3制得的氟维司群混悬液，放置于零下20℃，4℃，25℃，40℃或60℃条件，测试有关物质、氟维司群固体粒子形态和粒径分布、晶型变化情况，结果见表8和表9。XPRD测试谱图见图9和图10。氟维司群固体粒径形态图见图11～15。其中，有关物质的测试按照EP10.0方法检测。
表8实施例3制得的氟维司群混悬液不同温度放置有关物质结果表
Figure PCTCN2020135311-appb-000031
表9实施例3制得的氟维司群混悬液不同温度放置粒径分布结果表
放置条件 D10(μm) D25(μm) D50(μm) D75(μm) D90(μm)
60℃，20天 0.904 1.082 1.28 1.525 1.737
40℃，30天 1.738 2.373 3.215 4.116 5.048
25℃，30天 2.206 2.769 3.473 4.229 5.073
4℃，30天 1.347 1.973 2.777 3.601 4.325
4℃，40天 0.909 1.325 1.822 2.385 2.934
有关物质检测结果显示，研磨后，混悬液中有关物质略有增加；经过不同条件放置，混悬液有关物质无显著增加。所有条件下最大单杂的含量为0.07％，最大总杂的含量为0.36％，质量达标。
Figure PCTCN2020135311-appb-000032
图11-15的粒径形态图(PLM)观察发现，各条件下样品中氟维司群固体粒子的形态未发生变化，除部分样品发现有少量颗粒聚集外未发现明显粒径增大。激光粒度分析显示各条件下混悬液中氟维司群固体粒子的粒径均未超过5μm，25和40℃粒径略有增加，可能与样品颗粒聚集有关，但单个粒子仍未发生变化；60℃粒径有略减小。
图9和图10的XRPD结果显示不同条件下的混悬液氟维司群固体粒子晶型与初始氟维司群固体粒子一致，氟维司群固体粒子的晶型未发生变化。
实施例4
表10实施例4混悬注射液处方表
Figure PCTCN2020135311-appb-000033
如表10所示的处方，称取0.333g吐温20，加入5.00g氟维司群固体粒子后，加4％甘露醇-pH7.4无水磷酸二氢钠溶液定重至19.80g(此处的百分比是指甘露醇的质量占甘露醇-pH7.4无水磷酸二氢钠溶液总体积的百分比)，搅拌混合均匀得预混液。
将预混液与97.5g 0.3mm锆珠放置于研磨罐中(预混液样品和锆珠体积比为2∶3)进行研磨，研磨27小时，得到氟维司群药物组合物，其为混悬注射液。研磨采用球磨仪进行，行星式球磨仪的参数设置：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。
采用激光粒度仪测定(激光粒度仪的参数设置：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)，不同研磨时间混悬液中氟维司群固体粒子的粒径分布如表11所示。研磨后混悬液中氟维司群固体粒子的粒径形态见图16。
表11实施例4混悬液中氟维司群的粒径分布
研磨时间 D10(μm) D25(μm) D50(μm) D75(μm) D90(μm)
2min 1.799 2.362 3.29 4.341 5.353
5min 1.737 2.236 2.967 3.781 4.524
10min 1.597 2.058 2.699 3.397 4.116
30min 1.452 1.889 2.477 3.137 3.806
1hr 1.351 1.772 2.355 3.025 3.682
1.5hrs 1.211 1.629 2.153 2.73 3.3
3hrs 0.854 1.075 1.346 1.639 1.967
6hrs 0.914 1.094 1.304 1.551 1.795
9hrs 0.871 0.985 1.145 1.301 1.503
12hrs 0.894 1.026 1.171 1.328 1.534
27hrs 0.91 1.056 1.202 1.397 1.587
实施例5
表12实施例5混悬注射液处方表
Figure PCTCN2020135311-appb-000034
如表12所示的处方，称取0.324g吐温20，加入5.00g氟维司群固体粒子后，加4％甘露醇-pH7.4无水磷酸二氢钠溶液定重至19.80g(此处的百分比是指甘露醇的质量占甘露醇-pH7.4无水磷酸二氢钠溶液总体积的百分比)，搅拌混合均匀得预混液。
将预混液与111.6g 0.6mm锆珠放置于研磨罐中(预混液样品和锆珠体积比为2∶3)进行研磨，研磨27小时，得到氟维司群药物组合物，其为混悬注射液。研磨采用球磨仪进行，行星式球磨仪的参数设置：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。
采用激光粒度仪测定(激光粒度仪的参数设置：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)，不同研磨时间混悬液中氟维司群固体粒子的粒径分布如表13所示。研磨后混悬液中氟维司群固体粒子的粒径形态见图17。
表13实施例5混悬液中氟维司群的粒径分布
研磨时间 D10(μm) D25(μm) D50(μm) D75(μm) D90(μm)
3hrs 0.882 1.075 1.307 1.581 1.881
6hrs 0.841 0.98 1.207 1.509 1.841
9hrs 0.886 1.074 1.29 1.551 1.816
12hrs 0.915 1.093 1.307 1.561 1.825
27hrs 0.92 1.075 1.241 1.469 1.644
实施例6
表14实施例6混悬注射液处方表
Figure PCTCN2020135311-appb-000035
如表14所示的处方，称取0.328g吐温20，加入5.0g氟维司群固体粒子后，加4％甘露醇-pH7.4无水磷酸二氢钠溶液定重至19.80g(此处的百分比是指甘露醇的质量占甘露醇-pH7.4无水磷酸二氢钠溶液总体积的百分比)，搅拌混合均匀得预混液。
将预混液与112.0g 1.0mm锆珠放置于研磨罐中(预混液样品和锆珠体积比为2∶3)进行研磨，研磨27小时，得到氟维司群药物组合物，其为混悬注射液。研磨采用球磨仪进行，行星式球磨仪的参数设置：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。
采用激光粒度仪测定(激光粒度仪的参数设置：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)。精密称取混悬液适量，按照EP10.0方法检测氟维司群含量和有关物质。不同研磨时间混悬液中氟维司群固体粒子的粒径分布如表15所示。研磨后混悬液中氟维司群固体粒子的粒径形态见图18。
表15实施例6混悬液中氟维司群的粒径分布
研磨时间 D10(μm) D25(μm) D50(μm) D75(μm) D90(μm)
3hrs 0.838 1.041 1.388 1.87 2.376
6hrs 0.852 1.059 1.416 1.904 2.406
9hrs 0.906 1.087 1.327 1.629 1.969
12hrs 0.976 1.168 1.43 1.708 2.007
27hrs 1.058 1.235 1.493 1.795 2.058
实施例7
表16实施例7混悬注射液处方表
组成 比例(％，w/w)
氟维司群 25.00
吐温20 1.62
羧甲基纤维素钠 0.20
甘露醇 2.29
无水磷酸二氢钠 0.09
无水磷酸氢二钠 0.42
灭菌注射用水 q.s.100(70.38)
按表16处方中用量配制称原辅料，混合均匀后加入1.5倍体积的0.6mm锆珠放置于研磨罐中进行研磨，研磨3小时，得到氟维司群药物组合物，记为批次1。研磨采用球磨仪进行，行星式球磨仪的参数设置：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。
采用激光粒度仪测定(激光粒度仪的参数设置：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)。精密称取混悬液适量，按照EP10.0方法检测氟维司群含量和有关物质。研磨后混悬液中氟维司群固体粒子的含量和粒径分布数据如表17所示。研磨后混悬液中氟维司群固体粒子的粒径分布图见图19，研磨后混悬液中氟维司群固体粒子的形态见图20。有关物质结果见表19。
实施例8
表18实施例8混悬注射液处方表
组成 比例(％，w/w)
氟维司群 25.00
吐温20 1.62
羧甲基纤维素钠 0.20
甘露醇 2.29
无水磷酸二氢钠 0.09
无水磷酸氢二钠 0.42
灭菌注射用水 q.s.100(70.38)
按表18处方中用量配制称原辅料，混合均匀后加入3倍体积的1mm锆珠放置于研磨罐中进行研磨，研磨5分钟，得到氟维司群药物组合物，记为批次2。研磨采用球磨仪进行，行星式球磨仪的参数设置：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。
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)。精密称取混悬液适量，按照EP10.0方法检测氟维司群含量和有关物质。研磨后混悬液中氟维司群固体粒子的含量和粒径分布数据如表17所示。研磨后混悬液中氟维司群固体粒子的粒径分布图见图21，研磨后混悬液中氟维司群固体粒子的形态见图22。有关物质结果见表19。
实施例9
表20实施例9混悬注射液处方表
组成 比例(％，w/w)
氟维司群 25
吐温20 1.62
羧甲基纤维素钠 0.2
甘露醇 2.29
无水磷酸二氢钠 0.09
无水磷酸氢二钠 0.42
灭菌注射用水 q.s.100(70.38)
按表20处方中用量配制称原辅料，混合均匀，得到氟维司群药物混悬液，记为批次3。其中原料药为经气流粉碎所得。
采用激光粒度仪测定(激光粒度仪的参数设置：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)。精密称取混悬液适量，按照EP10.0方法检测氟维司群含量和有关物质。混悬液中氟维司群固体粒子的含量和粒径分布数据如表17所示。研磨后混悬液中氟维司群固体粒子的粒径分布见图23，研磨后混悬液中氟维司群固体粒子的形态见图24。有关物质结果见表19。
表17实施例7-9氟维司群混悬液中API浓度和粒径及粒径分布结果
Figure PCTCN2020135311-appb-000036
实施例10
将实施例7、实施例8、实施例9所得制剂(分别记为处方No.2、3、4)以及上市对比制剂氟维司群注射剂FASLODEX(5mL：250mg，德国VETTER Pharma-fertigung GmbH&Co KG，批号：RD693，有效期2023年8月，记为处方No.1)。处方No.2、3以及No.1按表21进行长期条件(25℃±2℃，60％RH±5％RH)和加速条件(40℃±2℃，75％RH±5％RH)稳定性放样，按照EP10.0方法检测氟维司群有关物质，结果见表19；同时测定制剂处方No.2和3的粒径及粒径分 布，结果见表22和23。
稳定性结果显示，相同条件下比较自制氟维司群混悬液中的降解杂质6-Keto fulvestrant(6-酮氟维司群)和Fulvestrant Sulphone(氟维司群砜)、未知单杂、总杂水平均低于对比制剂氟维司群注射剂FASLODEX，表明自制氟维司群混悬液稳定性优于上市对比制剂。
表21处方No.2和3制剂与对比制剂的稳定性放样
Figure PCTCN2020135311-appb-000037
表22实施例7(处方No.2)氟维司群混悬液粒径及粒径分布结果
Figure PCTCN2020135311-appb-000038
表23实施例8(处方No.3)氟维司群混悬液粒径及粒径分布结果
Figure PCTCN2020135311-appb-000039
Figure PCTCN2020135311-appb-000040
Figure PCTCN2020135311-appb-000041
实施例11
将实施例7、实施例8、实施例9所得制剂(处方No.2、3、4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。将稀释后的氟维司群混悬液以及上市对比制剂氟维司群注射剂FASLODEX(即处方No.1制剂，50mg/ml，德国VETTER Pharma-fertigung GmbH&Co KG，批号：RD693，有效期2023年8月)按氟维司群15mg/kg(0.3mL/kg)大腿外侧肌肉注射给予雄性Wistar大鼠，SPF级动物，217～235g，6～9周龄(浙江维通利华实验动物技术有限公司，质量合格证号110011200105465684，使用许可证号SYXK(苏)2018-0034)，每组6只。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。给药D45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。
Wistar大鼠单次肌肉注射给予15mg/kg氟维司群氟维司群制剂处方No.1、2、3和4(处方No.1表示上市对比氟维司群制剂；处方No.2表示实施例7制得的氟维司群制剂，处方No.3表示实施例8制得氟维司群制剂，处方No.4表示实施例9制得的氟维司群制剂)的药代动力学参数见表24。Wistar大鼠单次肌肉注射给予15mg/kg氟维司群制剂处方No.1、2、3、4的药代动力学曲线分别见图25、图26、图27和图28，处方No.1、2、3、4的平均药代动力学曲线见图29。
Wistar大鼠单次肌肉注射给予15mg/kg处方No.1(上市对比氟维司群制剂)后，血浆中氟维司群的Cmax为13.5±4.32ng/mL，药物浓度-时间曲线下面积AUCINF_obs为6350±949h*ng/mL，AUClast为5000±932h*ng/mL，药物末端消除半衰期T1/2_Z为413±88.0h，清除率Cl_obs为2410±433mL/h/kg，平均驻留时间MRTINF_obs为641±136h，分布容积Vz_obs为1450000±421000mL/kg。
Wistar大鼠单次肌肉注射给予15mg/kg处方No.2(实施例7制得的氟维司群制剂)后，血浆中氟维司群的Cmax为10.0±3.16ng/mL，药物浓度-时间曲线下面积AUCINF_obs为6990± 2010h*ng/mL，AUClast为3490±745h*ng/mL，药物末端消除半衰期T1/2_Z为776±300h，清除率Cl_obs为2340±814mL/h/kg，平均驻留时间MRTINF_obs为1310±443h，分布容积Vz_obs为2470000±881000mL/kg。
Wistar大鼠单次肌肉注射给予15mg/kg处方No.3(实施例8制得的氟维司群制剂)后，血浆中氟维司群的Cmax为8.10±2.89ng/mL，药物浓度-时间曲线下面积AUCINF_obs为71800±125000h*ng/mL，AUClast为3970±701h*ng/mL，药物末端消除半衰期T1/2_Z为12300±23900h，清除率Cl_obs为655±398mL/h/kg，平均驻留时间MRTINF_obs为18000±34500h，分布容积Vz_obs为2950000±721000mL/kg。
Wistar大鼠单次肌肉注射给予15mg/kg处方No.4(实施例9制得的氟维司群制剂)后，血浆中氟维司群的Cmax为9.23±2.78ng/mL，药物浓度-时间曲线下面积AUCINF_obs为35000±61100hng/mL，AUClast为3280±518h*ng/mL，药物末端消除半衰期T1/2_Z为5300±9230h，清除率Cl_obs为1550±1150mL/h/kg，平均驻留时间MRTINF_obs为7820±13300h，分布容积Vz_obs为3170000±571000mL/kg。
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：处方No.1＞处方No.2＞处方No.4＞处方No.3；AUClast从大到小依次为：处方No.1＞处方No.3＞处方No.2＞处方No.4；平均驻留时间MRTINF_obs从大到小依次为：处方No.3＞处方No.4＞处方No.2＞处方No.1；分布容积Vz_obs从大到小依次为：处方No.4＞处方No.3＞处方No.2＞处方No.1。以上参数比较可以看出处方No.2、3、4在体内的MRT较处方No.1更长，分布容积更大，说明实施例7-9制剂的体内缓释作用明显。
Figure PCTCN2020135311-appb-000042

Claims (10)

  1. 一种氟维司群药物组合物，其特征在于：所述药物组合物包括氟维司群固体粒子，其中所述的氟维司群固体粒子的粒径为Dv(10)选自0.400微米～6.000微米、Dv(50)选自0.700微米～6.000微米且Dv(90)选自1.000微米～6.000微米，条件是：Dv(10)不为0.400微米、Dv(50)不为0.700微米并且Dv(90)不为1.000微米。
  2. 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(10)0.500微米～6.000微米；
    优选地，所述的氟维司群固体粒子的粒径为Dv(10)0.600微米～2.000微米。
    优选地，所述的氟维司群固体粒子的粒径为Dv(10)0.900微米～1.800微米。
    优选地，所述的氟维司群固体粒子的粒径为Dv(50)0.800微米～6.000微米。
    优选地，所述的氟维司群固体粒子的粒径为Dv(50)0.900微米～4.000微米。
    优选地，所述的氟维司群固体粒子的粒径为Dv(50)1.000微米～3.000微米。
    优选地，所述的氟维司群固体粒子的粒径为Dv(75)1.000微米～4.000微米。
    优选地，所述的氟维司群固体粒子的粒径为Dv(90)为1.000微米～5.000微米。
    优选地，所述的氟维司群固体粒子的粒径为Dv(90)为1.500微米～4.500微米。
    优选地，所述的氟维司群固体粒子的粒径为Dv(25)为1.000微米～3.000微米。
  3. 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：所述的氟维司群药物组合物还包括载体。
    优选地，所述的载体为油性载体和/或非油载体。
    优选地，所述的油性载体包括但不限于蓖麻油，甘油三酸酯，棉籽油和芝麻油；和/或，
    所述的非油载体包括但不限于水。
  4. 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、非电解质和助溶剂。
    优选地，所述的聚合物为交联聚合物和/或非交联聚合物。
    优选地，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；
    优选地，所述的润湿剂包括但不限于泊洛沙姆和吐温中的一种或多种；
    优选地，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；
    优选地，所述的溶剂包括但不限于注射用水和注射用油中的一种或多种；
    优选地，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、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；
    优选地，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、柠檬酸钠、柠檬酸、三羟甲基氨基甲烷，或其混合物的缓冲剂；
    和/或，
    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、盐酸和氢氧化钠中的一种或多种；
    和/或，
    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。
  5. 如权利要求4所述的氟维司群药物组合物，其特征在于：
    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；
    和/或，
    所述的金属离子螯合剂包括但不限于乙二胺四乙酸；
    和/或，
    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；
    和/或，
    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；
    和/或，
    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；
    和/或，
    所述的聚乙二醇包括但不限于聚乙二醇3350；
    和/或，
    所述的交联聚合物包括但不限于羧甲基纤维素钠；
    和/或，
    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、一水磷酸氢二钠、二水磷酸氢二钠、无水磷酸氢二钠。
  6. 如权利要求1-5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，选自以下任一配方：
    配方一：18.09％氟维司群固体粒子、1.67％润湿剂和80.24％水；
    配方二：19.59％氟维司群固体粒子、1.74％润湿剂和78.67％水；
    配方三：24.56％氟维司群固体粒子、1.62％润湿剂、1.00％助悬剂、2.82％渗透压调节剂、0.42％缓冲盐和0～1％pH调节剂；
    配方四：25.00％氟维司群固体粒子、1.62％润湿剂、1.00％助悬剂、2.89％渗透压调节剂、0.43％缓冲盐和0～1％pH调节剂；
    配方五：25.00％氟维司群固体粒子、1.62％润湿剂、0.20％助悬剂、2.29％渗透压调节剂、0.51％缓冲盐和70.38％水。
  7. 如权利要求1-6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，选自以下任一配方：
    配方A：18.09％氟维司群固体粒子、1.67％吐温80和80.24％灭菌注射用水；
    配方B：19.59％氟维司群固体粒子、1.74％吐温80和78.67％灭菌注射用水；
    配方C：24.66％氟维司群固体粒子、1.62％吐温20、1.00％羧甲基纤维素钠、2.82％甘露醇、0.42％无水磷酸二氢钠、氢氧化钠和灭菌注射用水；
    配方D：25.00％氟维司群固体粒子、1.62％吐温20、1.00％羧甲基纤维素钠、2.89％甘露醇、0.43％无水磷酸二氢钠、氢氧化钠和灭菌注射用水；优选地，所述氟维司群药物组合物的pH为7.4；
    配方E：25.00％氟维司群固体粒子、1.62％吐温20、0.20％羧甲基纤维素钠、2.29％甘露醇、0.09％无水磷酸二氢钠、0.42％无水磷酸氢二钠和70.38％灭菌注射用水。
  8. 如权利要求1～7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。
    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。
    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，比如为水混悬剂或油混悬剂；例如，所述注射用粉剂为冻干粉针。
  9. 如权利要求8所述的应用，其特征在于：所述的注射剂为长效注射剂。优选地，所述的长效注射剂是水混悬剂、油混悬剂或混悬用粉末。
  10. 氟维司群药物制剂，其特征在于，所述氟维司群药物制剂含有权利要求1-7任一项所述的氟维司群药物组合物。
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US20220370359A1 (en) 2022-11-24
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