WO2020034989A1 - 一种可注射的药物组合物及其制备方法 - Google Patents

一种可注射的药物组合物及其制备方法 Download PDF

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Publication number
WO2020034989A1
WO2020034989A1 PCT/CN2019/100558 CN2019100558W WO2020034989A1 WO 2020034989 A1 WO2020034989 A1 WO 2020034989A1 CN 2019100558 W CN2019100558 W CN 2019100558W WO 2020034989 A1 WO2020034989 A1 WO 2020034989A1
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Prior art keywords
pharmaceutical composition
apixaban
surface stabilizer
nanoparticles
povidone
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PCT/CN2019/100558
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English (en)
French (fr)
Inventor
刘廷
孙琼
侍从建
陈新新
张雅婷
刘凯
Original Assignee
江苏恒瑞医药股份有限公司
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Application filed by 江苏恒瑞医药股份有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to EP19850475.5A priority Critical patent/EP3838265A4/en
Priority to KR1020217006781A priority patent/KR20210044245A/ko
Priority to US17/267,187 priority patent/US20210299059A1/en
Priority to CN201980039332.1A priority patent/CN112261935A/zh
Priority to BR112021002675-4A priority patent/BR112021002675A2/pt
Priority to CA3109007A priority patent/CA3109007A1/en
Priority to JP2021507619A priority patent/JP2021535094A/ja
Priority to AU2019322287A priority patent/AU2019322287A1/en
Publication of WO2020034989A1 publication Critical patent/WO2020034989A1/zh

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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
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    • 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
    • A61K9/146—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 macromolecular compounds
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • 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 the field of pharmaceutical preparations, in particular to an injectable pharmaceutical composition containing nanoparticles of apixaban and a preparation method thereof.
  • Apixaban is a white to light yellow powder. At physiological pH (1.2-6.8), apixaban does not ionize, and its solubility in the physiological pH range is about 0.04 mg / ml. LogP is 3.53, which has good permeability. Apixaban is used clinically for the prevention and treatment of thrombosis, specifically for the prevention of venous thromboembolic events (VTE) in adult patients undergoing elective hip or knee replacement surgery. The oral bioavailability of apixaban is not high, about 50%, and solubility is the limiting factor for its absorption. Apixaban has the advantages of high selectivity, high safety, and no need for routine detection of blood coagulation function.
  • apixaban It has less interaction with food, and does not need to adjust the dosage according to the age, gender, physical fitness and ethnicity of the patient.
  • the currently available apixaban tablets are taken orally twice daily, with a single dosage form and poor oral bioavailability.
  • the tablets are not easy to swallow, so it is safe, effective and convenient to use.
  • the new formulation of apixaban has important clinical value.
  • WO2011106478 discloses a pharmaceutical composition comprising crystalline apixaban particles having D90 equal to or less than about 89 ⁇ m and a pharmaceutically acceptable sedimentation inhibitor or carrier.
  • CN104736142A discloses an oral liquid formulation comprising apixaban, water, and at least two solubilizers.
  • CN101340933A discloses an injectable preparation comprising substituted ⁇ -cyclodextrin and apixaban.
  • CN102802608A discloses an improved form of solubility of apixaban, providing controlled release of apixaban.
  • the invention provides a pharmaceutical composition for injection, comprising apixaban nanoparticles and a surface stabilizer.
  • the invention also provides a stable pharmaceutical composition for injection, comprising apixaban nanoparticles and a surface stabilizer.
  • Nanoparticles can be prepared by co-milling, high-pressure homogenization, or anti-solvent methods. Co-milling methods are preferred.
  • the liquid medium used for co-milling may be selected from one or more of water, saline solution, safflower seed oil, ethanol, tert-butanol, hexane and ethylene glycol, preferably water, saline solution and safflower seed oil. One or more of these are most preferably water.
  • the preferred solution of the present invention is to use water as a liquid medium, and co-grind apixaban with a surface stabilizer to obtain nanoparticles.
  • the average particle size or D50 of the apixaban nanoparticles may be less than 2000 nm, preferably less than 1000 nm, more preferably less than 500 nm, more preferably less than 200 nm, even more preferably less than 170 nm, even more preferably less than 160 nm, and most preferably less than 150 nm.
  • Surface stabilizers can be non-ionic, anionic, cationic and zwitterionic compounds or surfactants.
  • the surface stabilizer may be one or more of a nonionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, and a zwitterionic surface stabilizer.
  • the surface stabilizer may be selected from povidone, polyvinyl alcohol, docusate sodium, hydroxypropyl methylcellulose, Tween 80, poloxamer, 15-hydroxystearic acid polyethylene glycol ester, lecithin, One or more of sodium deoxycholate and sodium cholate, preferably one or more of poloxamer, sodium deoxycholate, povidone, docusate sodium, and Tween 80, further preferably For sodium deoxycholate and povidone.
  • the surface stabilizer used in the pharmaceutical composition of the present invention does not contain sodium dodecylsulfonate or sodium dodecylsulfate which is not suitable for injection.
  • the non-ionic surface stabilizer of the present invention may include, but is not limited to, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol, povidone, poloxamer, Tween 80, and 15-hydroxystearic acid polymer
  • HPMC hydroxypropyl methylcellulose
  • polyvinyl alcohol polyvinyl alcohol
  • povidone povidone
  • poloxamer poloxamer
  • Tween 80 15-hydroxystearic acid polymer
  • One or more of the glycol esters is preferably one or more of povidone, poloxamer, and Tween 80.
  • the anionic surface stabilizer of the present invention may include, but is not limited to, one or more of sodium dioctyl succinate (DOSS), docusate sodium, sodium cholate, and sodium deoxycholate, preferably docusate.
  • DOSS sodium dioctyl succinate
  • docusate sodium sodium cholate
  • sodium deoxycholate sodium deoxycholate
  • Sodium and / or sodium deoxycholate more preferably sodium deoxycholate.
  • the cationic surface stabilizer of the present invention may include, but is not limited to, poly-N-methylpyridinium sulfate, pyridinium sulfate, cationic phospholipid, chitosan, polylysine, polyvinylimidazole, polystyrene, polystyrene One of methyl trimethyl ammonium bromide (PMMTMABr), hexyl methyl trimethyl ammonium bromide (HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate sulfate Or more.
  • PMMTMABr methyl trimethyl ammonium bromide
  • HDMAB hexyl methyl trimethyl ammonium bromide
  • the zwitterionic surface stabilizer of the present invention may include, but is not limited to, one or more of a protein, a phospholipid, and a zwitterionic surfactant, for example, it may be a phosphatidylcholine, an amino acid surfactant, and a beet alkaline surface One or more of an active agent, lecithin, and gelatin.
  • the surface stabilizer of the present invention may not only include the surface stabilizers as described above in the traditional sense, but also some additives equivalent to the above surface stabilizers, such as a mixture of deoxycholic acid and sodium phosphate and deoxycholic acid Sodium is equivalent.
  • the weight ratio of apixaban nanoparticles to the surface stabilizer may be selected from 1: 0.01 to 1: 100, preferably 1: 0.1 to 1:10, more preferably 1: 0.2 to 1: 5, even more preferably 1: 0.3 to 1: 4 (for example 1: 0.2, 1: 0.3, 1: 0.45, 1: 1.725, or 1: 3.1) or 1: 0.3 to 1: 3.
  • the surface stabilizer of the present invention may include a first surface stabilizer and / or a second surface stabilizer.
  • the surface stabilizer further includes a second surface stabilizer.
  • the first surface stabilizer may be selected from a nonionic surface stabilizer and / or a zwitterionic surface stabilizer, preferably povidone, polyvinyl alcohol, hydroxypropyl methylcellulose, Tween 80, poloxamer, 15-hydroxyl One or more of polyethylene glycol stearate and lecithin, more preferably one or more of povidone, poloxamer, and Tween 80.
  • the second surface stabilizer may be selected from an anionic surface stabilizer, preferably one or more of sodium deoxycholate, sodium cholate, and docusate sodium, more preferably sodium deoxycholate or docusate sodium, and most preferably deoxy Sodium Cholate.
  • the weight ratio of apixaban nanoparticles to the first surface stabilizer may be selected from 1: 0.01 to 1:10, preferably 1: 0.1 to 1:10, more preferably 1: 0.1 to 1: 5, even more preferably 1: 0.1 to 1: 3, more preferably from 1: 0.2, 1: 0.3, 1: 1.15, or 1: 2.1.
  • the weight ratio of apixaban nanoparticles to the second surface stabilizer may be selected from 1: 0.01 to 1:10, preferably 1: 0.1 to 1: 5, more preferably 1: 0.1 to 1: 2, or 1: 0.1 to 1 : 1, and still more preferably 1: 0.1, 1: 0.15, 1: 0.575, or 1: 1.
  • the average particle size or D50 of the apixaban nanoparticles may be less than 2000 nm, preferably less than 1000 nm, more preferably less than 500 nm, more preferably less than 200 nm, even more preferably less than 170 nm, even more preferably less than 160 nm, and most preferably less than 150 nm.
  • the preparation method of the pharmaceutical composition of the present invention comprises: co-milling a surface stabilizer with apixaban to prepare a pharmaceutical composition containing apixaban nanoparticles.
  • the method for preparing the pharmaceutical composition of the present invention may further include: co-milling the first surface stabilizer and / or the second surface stabilizer with apixaban to prepare a pharmaceutical composition containing apixaban nanoparticles.
  • the invention provides a technical solution for co-grinding apixaban with a part or all of a surface stabilizer to obtain a pharmaceutical composition containing apixaban nanoparticles.
  • apixaban is co-milled with all surface stabilizers, it means that the pharmaceutical composition contains only the surface stabilizer used in co-milling, and no surface stabilizer is added in other processes.
  • the weight ratio of apixaban to the surface stabilizer may be selected from 1: 0.01 to 1:10, preferably 1: 0.1 to 1:10, and more preferably 1: 0.2 to 1: 5 (for example, 1: 0.2, 1: 0.3 , 1: 0.45, 1: 1.725, or 1: 3.1), and more preferably 1: 0.3 to 1: 4 or 1: 0.3 to 1: 1.
  • the surface stabilizer may include a first surface stabilizer and / or a second surface stabilizer, and a weight ratio of apixaban to the first surface stabilizer may be selected from 1: 0.01 to 1:10, preferably 1: 0.1. ⁇ 1: 10, more preferably 1: 0.1 ⁇ 1: 5, more preferably 1: 0.1 ⁇ 1: 3, even more preferably 1: 0.2, 1: 0.3, 1: 1.15 or 1: 2.1; apixaban and the first
  • the weight ratio of the two surface stabilizers may be selected from 1: 0.01 to 1:10, preferably 1: 0.1 to 1: 5, more preferably 1: 0.1 to 1: 2, even more preferably 1: 0.1, 1: 0.15, 1: 0.575 or 1: 1.
  • apixaban is co-milled with a portion of the surface stabilizer, and a portion (ie, the remaining portion) of the surface stabilizer is incorporated into the pharmaceutical composition during the dilution process.
  • the ratio of the surface stabilizer co-milled with apixaban to the total surface stabilizer may be selected from 1: 2 to 1: 100, preferably 1: 2 to 1:50, more preferably 1: 2 to 1:20, more It is further preferably 1: 3 to 1:15 or 1: 3 to 1:10, and still more preferably 1: 5.75 or 1: 10.3.
  • the two-part surface stabilizer may be the same type of surface stabilizer or different types of surface stabilizers.
  • the preferred solution is that the two-part surface stabilizers are the same type.
  • the weight ratio of apixaban to the surface stabilizer may be selected from 1: 0.01 to 1:10, preferably 1: 0.1 to 1:10, and more preferably 1: 0.2 to 1: 5, and most preferably 1: 0.3 to 1: 1.
  • the partial surface stabilizer may include a first surface stabilizer and / or a second surface stabilizer, and a weight ratio of apixaban to the first surface stabilizer may be selected from 1: 0.01 to 1:10, preferably 1: 0.1 to 1:10, more preferably 1: 0.1 to 1: 5, and most preferably 1: 0.1 to 1: 0.3 (for example, 1: 0.2); the weight ratio of apixaban to the second surface stabilizer may be selected from 1: 0.01 to 1:10, preferably 1: 0.1 to 1: 5, more preferably 1: 0.1 to 1: 1, and most preferably 1: 0.1 to 1: 0.5.
  • the other part (ie the remaining part) of the surface stabilizer is mixed and diluted with the pharmaceutical composition containing apixaban nanoparticles, and the solvent used for the dilution may be selected from the aforementioned liquid medium.
  • the dilution factor can be selected from 1 to 100 times, preferably 5 to 50 times, and most preferably 10 to 30 times, and the order of mixing is not limited.
  • the weight ratio of apixaban to another part (ie, the remaining part) of the surface stabilizer may be selected from 1: 0.01 to 1:10, preferably 1: 0.1 to 1:10, more preferably 1: 0.1 to 1: 5, and most preferably 1: 1 ⁇ 1: 3.
  • the other part (ie, the remaining part) of the surface stabilizer may include a first surface stabilizer and / or a second surface stabilizer, and a weight ratio of apixaban to the first surface stabilizer may be selected from 1: 0.01 to 1 : 10, preferably 1: 0.1 to 1:10, more preferably 1: 0.1 to 1: 5 (for example, 1: 0.95, 1: 1.9), and most preferably 1: 1 to 1: 3; apixaban and the second surface
  • the weight ratio of the stabilizer may be selected from 1: 0.01 to 1:10, preferably 1: 0.1 to 1: 5 (for example, 1: 0.9, 1: 2), more preferably 1: 0.1 to 1: 1, and most preferably 1: 0.3 ⁇ 1: 1.
  • the pharmaceutical composition of the present invention may further include a sedimentation inhibitor.
  • the sedimentation inhibitor inhibits the sedimentation or aggregation of the nanoparticles for a certain period of time.
  • the sedimentation inhibitor may be selected from one or more of sugars, polyols and high molecular polymers, such as mannitol, sucrose, albumin, dextran 40, trehalose, glycerol, povidone, glycine, glycerol One or more of hydroxypropyl- ⁇ -cyclodextrin, preferably one or more of mannitol, sucrose, and dextran 40, more preferably mannitol or sucrose, and more preferably mannitol.
  • sugars such as mannitol, sucrose, albumin, dextran 40, trehalose, glycerol, povidone, glycine, glycerol
  • hydroxypropyl- ⁇ -cyclodextrin preferably one or more of mannitol, sucrose, and dextran 40, more preferably mannitol or sucrose, and more preferably mannitol.
  • the weight ratio of the apixaban nanoparticles to the sedimentation inhibitor may be selected from 1: 0.1 to 1: 100, preferably 1: 0.1 to 1:50, and more preferably 1: 0.5 to 1:30 (for example, 1: 1 to 1:30), and further preferably 1: 4.75, 1:19, or 1: 21.28.
  • a method for preparing a pharmaceutical composition of the present invention includes: co-grinding a surface stabilizer with apixaban to prepare a pharmaceutical composition comprising apixaban nanoparticles; and combining a sedimentation inhibitor with the aforementioned drug
  • the surface stabilizer comprises a first surface stabilizer and / or a second surface stabilizer.
  • the aforementioned preparation method may further include a step of lyophilization.
  • apixaban and all or part of the surface stabilizer are co-milled to prepare a concentrated suspension containing apixaban nanoparticles, and then diluted to obtain a suitable freeze-thaw.
  • the sedimentation inhibitor or the sedimentation inhibitor and the remaining surface stabilizer may be mixed with the pharmaceutical composition including apixaban nanoparticles during the dilution process, thereby maintaining the stability of the diluted liquid.
  • the pharmaceutical composition of the present invention may be a lyophilized pharmaceutical composition.
  • a pharmaceutical composition including a liquid medium may be obtained, and the liquid medium may be selected from water, saline solution, safflower seed oil, ethanol, tert-butyl One or more of alcohol, hexane and ethylene glycol, preferably one or more of water, saline solution and safflower seed oil, most preferably water.
  • the content of apixaban nanoparticles may be selected from 0.1 to 100 mg / mL, preferably 0.5 to 100 mg / mL, more preferably 1 to 100 mg / mL, and most preferably 2 to 10 mg / mL (for example, 2.5 mg / mL).
  • a pharmaceutical composition comprising a liquid medium after reconstitution may have the technical characteristics of the pharmaceutical composition as described above.
  • the invention also provides a pharmaceutical composition
  • a liquid medium which can be selected from the group consisting of water, saline solution, safflower seed oil, ethanol, tert-butanol, hexane and ethylene glycol, preferably water, saline solution and safflower One or more of the seed oils, most preferably water.
  • the content of apixaban nanoparticles may be selected from 0.1 to 100 mg / mL, preferably 0.5 to 100 mg / mL, more preferably 1 to 100 mg / mL, and most preferably 2 to 10 mg / mL (for example, 2.5 mg / mL or 5 mg / mL).
  • the content of apixaban in the pharmaceutical composition may be selected from 0.1 to 100 mg / mL (for example, 2.5 mg / mL, 5 mg / mL, 50 mg / mL or 100 mg / mL).
  • the content of apixaban in the pharmaceutical composition may be selected from 0.1 to 1000 mg / mL, preferably 1 to 200 mg / mL, and more preferably 50-100 mg / mL (for example, 50 mg / mL or 100 mg / mL).
  • the pharmaceutical composition containing a liquid medium can be lyophilized to obtain a lyophilized pharmaceutical composition.
  • the pharmaceutical composition of the present invention may be a pharmaceutical composition containing apixaban nanoparticles and a surface stabilizer, or a nanoparticle suspension containing apixaban obtained by co-milling of apixaban and a surface stabilizer. It may also be the aforementioned diluted pharmaceutical composition containing apixaban nanoparticle suspension, or the lyophilized pharmaceutical composition of the diluted pharmaceutical composition, or the reconstituted pharmaceutical composition of the lyophilized pharmaceutical composition .
  • the sedimentation inhibitor of the present invention is mixed with a pharmaceutical composition containing apixaban nanoparticles during the dilution process.
  • Settling inhibitors can stabilize a diluted suspension containing apixaban nanoparticles for a period of time.
  • a preferred solution of the present invention is that a part of the surface stabilizer can also be mixed during the dilution process, so that the suspension containing apixaban nanometer after dilution is more stable.
  • the surface stabilizer is the same as described above.
  • the invention provides an injectable pharmaceutical composition comprising apixaban nanoparticles, a first surface stabilizer, a second surface stabilizer, and a sedimentation inhibitor.
  • the first surface stabilizer, the second surface stabilizer, and the sedimentation inhibitor are the same as described above.
  • the weight ratio of the apixaban nanoparticles and the first surface stabilizer may be selected from 1: 0.01 to 1:10, preferably 1: 0.1 to 1:10, and more preferably 1: 0.1 to 1: 5. Still more preferably, 1: 0.1 to 1: 3 (for example, 1: 0.2, 1: 0.3, 1: 1.15, or 1: 2.1).
  • the weight ratio of the apixaban nanoparticles to the second surface stabilizer may be selected from 1: 0.01 to 1:10, preferably 1: 0.1 to 1: 5, and more preferably 1: 0.1 to 1: 2. , And still more preferably 1: 0.1 to 1: 1 (for example, 1: 0.1, 1: 0.15, 1: 0.575, or 1: 1).
  • the weight ratio of the apixaban nanoparticles to the sedimentation inhibitor may be selected from 1: 0.1 to 1: 100, preferably 1: 0.1 to 1:50, and more preferably 1: 0.5 to 1:30 (for example, 1: 4.75, 1:19, or 1: 21.28).
  • the average particle diameter or D50 of the apixaban nanoparticles may be less than 500 nm, preferably less than 200 nm, further preferably less than 170 nm, still more preferably less than 160 nm, and still more preferably less than 150 nm.
  • the preparation method of the pharmaceutical composition of the present invention comprises: co-milling a part of the first surface stabilizer and a part of the second surface stabilizer with apixaban to prepare a pharmaceutical composition including apixaban nanoparticles; and a sedimentation inhibitor 2. Another part of the first surface stabilizer and another part of the second surface stabilizer are mixed with the aforementioned pharmaceutical composition including apixaban nanoparticles.
  • the aforementioned preparation method may further include a step of lyophilization.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising apixaban nanoparticles, povidone, and sodium deoxycholate.
  • the weight ratio of apixaban nanoparticles to povidone may be selected from 1: 0.01 to 1:10, preferably 1: 0.1 to 1:10, more preferably 1: 0.1 to 1: 5, even more preferably 1 : 0.1 ⁇ 1: 3 or 1: 0.1 ⁇ 1: 2, most preferably 1: 0.2 or 1: 0.3;
  • the weight ratio of apixaban nanoparticles to sodium deoxycholate can be selected from 1: 0.01 ⁇ 1: 10 It is preferably 1: 0.1 to 1: 5, more preferably 1: 0.1 to 1: 1 or 1: 0.1 to 1: 0.3, and most preferably 1: 0.1 or 1: 0.15.
  • the invention provides a pharmaceutical composition comprising apixaban nanoparticles, povidone, sodium deoxycholate, and mannitol.
  • the weight ratio of apixaban nanoparticles to povidone may be selected from 1: 0.01 to 1:10, preferably 1: 0.1 to 1:10, more preferably 1: 0.1 to 1: 5, even more preferably 1 : 0.1 ⁇ 1: 3, most preferably 1: 1 ⁇ 1: 3;
  • the weight ratio of apixaban nanoparticles to sodium deoxycholate can be selected from 1: 0.01 ⁇ 1: 10, preferably 1: 0.1 ⁇ 1: 5, more preferably 1: 0.1 to 1: 1, and most preferably 1: 0.5 to 1: 1;
  • the weight ratio of apixaban nanoparticles to mannitol may be selected from 1: 0.1 to 1: 100, preferably 1: 0.1 ⁇ 1: 50, more preferably 1: 0.5 ⁇ 1: 30 (e.g. 1: 4.75, 1: 21
  • the invention provides a pharmaceutical composition comprising apixaban nanoparticles, povidone, sodium deoxycholate, and mannitol.
  • the weight-volume ratio of apixaban nanoparticles in the pharmaceutical composition is preferably 0.1-1%. Further preferred is 0.1-0.5% (for example, 0.25% or 0.5%); the weight-volume ratio of povidone is preferably 0.5-5%, and still more preferably 0.5-1% (for example, 0.575% or 0.525%); the weight of sodium deoxycholate
  • the volume ratio is preferably 0.1-3%, more preferably 0.1-0.5% (for example, 0.2875% or 0.25%); the weight-volume ratio of mannitol is preferably 1-10%, and still more preferably 2-7% (for example, 2.375% or 5.32) %).
  • the present invention provides a pharmaceutical composition of apixaban nanoparticles: povidone: sodium deoxycholate in a weight ratio of 10: 2: 1, preferably comprising a weight-volume ratio of 10% apixaban nanoparticles, 2% poly Retinone, a pharmaceutical composition of 1% sodium deoxycholate, or a pharmaceutical composition comprising a weight-volume ratio of 5% apixaban nanoparticles, 1% povidone, and 0.5% sodium deoxycholate.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising 0.5% apixaban nanoparticles, 0.575% povidone, 0.2875% sodium deoxycholate, and 2.375% mannitol.
  • the invention also provides a pharmaceutical composition comprising 0.25% apixaban nanoparticles, 0.525% povidone, 0.25% sodium deoxycholate, and 5.32% mannitol.
  • the content of apixaban nanoparticles in a unit dose may be 2.0 mg-5.0 mg, preferably 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5mg, 5.0mg.
  • the invention also provides a method for preparing a pharmaceutical composition, comprising co-milling povidone and sodium deoxycholate with apixaban to prepare a pharmaceutical composition containing apixaban nanoparticles. Further, mannitol is mixed with the aforementioned pharmaceutical composition containing apixaban nanoparticles, and the aforementioned pharmaceutical composition containing apixaban nanoparticles is preferably diluted with an aqueous solution containing mannitol.
  • povidone and sodium deoxycholate are mixed into the pharmaceutical composition in two parts, one part of povidone and sodium deoxycholate is co-milled with apixaban, and the other part of povidone and sodium deoxycholate is mixed in the pharmaceutical composition. It is mixed during the dilution process.
  • the dilution factor is selected from 1 to 100 times, preferably 5 to 50 times, and most preferably 10 to 30 times.
  • the solvent used for the dilution may be selected from the aforementioned liquid medium; "a part" and “another part” in this solution indicate the surface
  • the stabilizer is mixed into the pharmaceutical composition in two parts.
  • the present invention provides a suspension containing apixaban nanoparticles containing 10% apixaban nanoparticles, 2% povidone, 1% sodium deoxycholate, and water, containing 2.5% mannitol, 0.5%
  • a pharmaceutical composition obtained by diluting povidone and a diluent of 0.25% sodium deoxycholate and a method for preparing the same, the dilution factor can be selected from 1 to 100 times, preferably 5 to 50 times, and most preferably 10 to 30 times. For example, it can be 10 times, 20 times, 30 times.
  • the preparation method is to use 2.5% mannitol, a suspension containing apixaban nanoparticles containing 10% apixaban nanoparticles, 2% povidone, 1% sodium deoxycholate, and water. Diluted with 0.5% povidone and 0.25% sodium deoxycholate diluent, the dilution factor can be selected from 1-100 times, preferably 5-50 times, most preferably 10-30 times, such as 10 times, 20 times, 30 times.
  • the present invention provides a suspension containing apixaban nanoparticles containing 5% apixaban nanoparticles, 1% povidone, 0.5% sodium deoxycholate, and water, containing 5.6% mannitol, 0.5%
  • a pharmaceutical composition obtained by diluting povidone and a diluent of 0.2368% sodium deoxycholate and a method for preparing the same, the dilution factor may be selected from 1 to 100 times, preferably 5 to 50 times, and most preferably 10 to 30 times. For example, it may be 10 times, 20 times, 30 times.
  • the preparation method is to use 5.6% mannitol, a suspension containing apixaban nanoparticles containing 5% apixaban nanoparticles, 5% povidone, 0.5% sodium deoxycholate, and water. Diluted with 0.5% povidone and 0.2368% sodium deoxycholate diluent, the dilution factor can be selected from 1-100 times, preferably 5-50 times, most preferably 10-30 times, such as 10 times, 20 times, 30 times.
  • the present invention provides a suspension containing apixaban nanoparticles containing 10% apixaban nanoparticles, 2% povidone, 1% sodium deoxycholate, and water, containing 2.5% mannitol, 0.5%
  • the content of apixaban nanoparticles in the diluted pharmaceutical composition may be selected from 0.1 to 100 mg / mL, preferably 0.5 to 20 mg / mL, more preferably 1 to 10 mg / mL, and most preferably 5 to 10 mg / mL.
  • the preparation method is to use 2.5% mannitol, a suspension containing apixaban nanoparticles containing 10% apixaban nanoparticles, 2% povidone, 1% sodium deoxycholate, and water. Diluted with 0.5% povidone and 0.25% sodium deoxycholate diluent, the content of apixaban nanoparticles in the diluted pharmaceutical composition can be selected from 0.1 to 100 mg / mL, preferably 0.5 to 20 mg / mL, more preferably 1 to 10 mg / mL, most preferably 5 to 10 mg / mL.
  • the present invention provides a suspension containing apixaban nanoparticles containing 5% apixaban nanoparticles, 1% povidone, 0.5% sodium deoxycholate, and water, containing 5.6% mannitol, 0.5% A pharmaceutical composition diluted by povidone and a diluent of 0.2368% sodium deoxycholate and a preparation method thereof.
  • the content of apixaban nanoparticles in the diluted pharmaceutical composition may be selected from 0.1 to 100 mg / mL, preferably 0.5 to 20 mg / mL, more preferably 1 to 10 mg / mL, and most preferably 1 to 5 mg / mL, such as 1 mg / mL, 1.5 mg / mL, 2 mg / mL, 2.5 mg / mL, and 3 mg / mL.
  • the preparation method comprises the following steps: using a suspension containing apixaban nanoparticles containing 5% apixaban nanoparticles, 1% povidone, 0.5% sodium deoxycholate, and water, and containing 5.6% mannitol, Diluted with 0.5% povidone and 0.2368% sodium deoxycholate diluent, the content of apixaban nanoparticles in the diluted pharmaceutical composition can be selected from 0.1 to 100 mg / mL, preferably 0.5 to 20 mg / mL, more preferably 1 to 10 mg / mL, most preferably 1 to 5 mg / mL, such as 1 mg / mL, 1.5 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL.
  • the preferred solution of the present invention is to mix the surface stabilizer into the pharmaceutical composition in two parts, one part of the surface stabilizer is mixed with apixaban to prepare a pharmaceutical composition containing apixaban nanoparticles, and the other part of the surface stabilizer and sedimentation inhibition
  • the agent is mixed into the aforementioned pharmaceutical composition containing apixaban nanoparticles, thereby preparing a more stable diluted pharmaceutical composition containing apixaban nanoparticles.
  • the solvent in the pharmaceutical composition can be water, which avoids the introduction of organic solvents.
  • the invention also provides a reconstituted pharmaceutical composition of the freeze-dried pharmaceutical composition for injection.
  • the average particle diameter of apixaban nanoparticles may be less than 500 nm, preferably less than 300 nm, more preferably less than 200 nm, more preferably less than 170 nm, more preferably less than 160 nm, and most It is preferably less than 150 nm.
  • the PDI of apixaban nanoparticles may be less than 0.5, preferably less than 0.3, and most preferably less than 0.2.
  • the D50 of apixaban nanoparticles may be less than 500 nm, preferably less than 300 nm, more preferably less than 200 nm, and most preferably less than 170 nm.
  • the pharmaceutical composition containing apixaban nanoparticles of the present invention is stored at 2-8 ° C, 25 ° C / 60% RH for a period of time, such as 1 month, 2 months, 3 months, 6 months, 12 After a month, the average particle size of the apixaban nanoparticles can be less than 500 nm, preferably less than 300 nm, more preferably less than 200 nm, and most preferably less than 150 nm.
  • the pharmaceutical composition containing apixaban nanoparticles of the present invention is stored at 2-8 ° C, 25 ° C / 60% RH for a period of time, such as 1 month, 2 months, 3 months, 6 months, 12 After a month, the PDI of apixaban nanoparticles can be less than 0.5, preferably less than 0.3, and most preferably less than 0.2.
  • the pharmaceutical composition containing apixaban nanoparticles of the present invention is stored at 2-8 ° C, 25 ° C / 60% RH for a period of time, such as 1 month, 2 months, 3 months, 6 months, 12 After a month, the D50 of apixaban nanoparticles can be less than 500 nm, preferably less than 300 nm, more preferably less than 200 nm, and most preferably less than 170 nm.
  • the pharmaceutical composition containing apixaban nanoparticles of the present invention is stored at 40 ° C./75% RH for a period of time, such as 1 month, 2 months, 3 months, 6 months, and 12 months.
  • the mean particle size of the pisarban nanoparticles may be less than 500 nm, preferably less than 300 nm, more preferably less than 200 nm, and even more preferably less than 160 nm.
  • the pharmaceutical composition containing apixaban nanoparticles of the present invention is stored at 40 ° C./75% RH for a period of time, such as 1 month, 2 months, 3 months, 6 months, and 12 months.
  • the PDI of the pisarban nanoparticles is less than 0.5, preferably less than 0.3, and most preferably less than 0.2.
  • the pharmaceutical composition containing apixaban nanoparticles of the present invention is stored at 40 ° C./75% RH for a period of time, such as 1 month, 2 months, 3 months, 6 months, and 12 months.
  • the D50 of the pisarban nanoparticles may be less than 500 nm, preferably less than 300 nm, more preferably less than 200 nm, and still more preferably less than 170 nm.
  • the pharmaceutical composition containing apixaban nanoparticles of the present invention is stored at 2-8 ° C, 25 ° C / 60% RH, 40 ° C / 75% RH for a period of time, such as 1 month, 2 months, 3 After one month, six months, and twelve months, the average particle size of apixaban nanoparticles is basically unchanged; after storage at 2-8 ° C, 25 ° C / 60% RH, 40 ° C / 75% RH for a period of time, such as After 1 month, 2 months, 3 months, 6 months, and 12 months, the PDI of apixaban nanoparticles was basically unchanged; at 2-8 ° C, 25 ° C / 60% RH, 40 ° C / 75 After storage at% RH for a period of time, such as 1 month, 2 months, 3 months, 6 months, and 12 months, the D50 of apixaban nanoparticles is basically unchanged.
  • substantially unchanged is meant a change of less than 30%,
  • the content of apixaban nanoparticles in the pharmaceutical composition of the present invention before storage is 100%; the content of apixaban nanoparticles after storage for 5 days at 2-8 ° C. Relative to the pharmaceutical composition before storage, 95% to 105%, preferably 98% to 102%; after 5 days storage at 25 ° C / 60% RH, the content of apixaban nanoparticles relative to storage
  • the former pharmaceutical composition is 95% to 105%, preferably 98% to 102%; after 5 days storage at 40 ° C / 75% RH, the content of apixaban nanoparticles relative to the drug before storage
  • the composition is 95% to 105%, and preferably 98% to 102%.
  • the maximum single impurity content Prior to storage of the apixaban nanoparticle-containing pharmaceutical composition of the present invention, the maximum single impurity content may be less than 0.5%, preferably less than 0.1%, and most preferably less than 0.05%; in the case of 2-8 ° C After storage for 5 days, the maximum content of impurities can be less than 0.5%, preferably less than 0.1%, and most preferably less than 0.05%.
  • the content of maximum impurities can be Less than 0.5%, preferably less than 0.1%, most preferably less than 0.05%; after 5 days storage at 40 ° C / 75% RH, the maximum content of single impurities is less than 0.5%, preferably less than 0.1%, most It is preferably less than 0.05%.
  • the total impurity content may be less than 1%, preferably less than 0.5%; after 5 days of storage at 2-8 ° C, the total impurity content may be Is less than 1%, preferably less than 0.5%; the total content of impurities after storage for 5 days at 25 ° C / 60% RH may be less than 1%, preferably less than 0.5%; at 40 ° C / 75% RH After 5 days of storage, the content of total impurities may be less than 1%, preferably less than 0.5%.
  • the pharmaceutical composition containing apixaban nanoparticles of the present invention is stored at 2-8 ° C, 25 ° C / 60% RH, 40 ° C / 75% RH for a period of time, such as 1 month, 2 months, 3 After one month, six months, and twelve months, the content of apixaban nanoparticles is 95% to 105%, preferably 98% to 102%, relative to the pharmaceutical composition before storage; the maximum single impurity content It is less than 0.5%, preferably less than 0.1%, and most preferably less than 0.05%; the content of total impurities is less than 1%, and preferably less than 0.5%.
  • the pharmaceutical composition containing apixaban nanoparticles of the present invention is stored at 2-8 ° C, 25 ° C / 60% RH, 40 ° C / 75% RH for a period of time, such as 1 month, 2 months, 3 After one month, six months, and twelve months, the content of apixaban nanoparticles is basically unchanged; the pharmaceutical composition containing apixaban nanoparticles of the present invention is at 2-8 ° C, 25 ° C / 60% RH After storage at 40 °C / 75% RH for a period of time, such as 1 month, 2 months, 3 months, 6 months, and 12 months, the maximum content of single impurities is basically unchanged.
  • the content of total impurities was basically unchanged.
  • substantially unchanged is meant a change of less than 20%, preferably less than 10%, and most preferably less than 5%.
  • the pharmaceutical composition containing apixaban nanoparticles of the present invention is preferably suitable for injection administration, and particularly suitable for subcutaneous injection administration.
  • the apixaban nanoparticle composition of the present invention has high bioavailability after subcutaneous injection, a stable drug curve, and better safety and effectiveness.
  • the pharmaceutical composition comprising apixaban nanoparticles of the present invention is preferably suitable for once-daily and twice-daily administration.
  • the daily dose of the pharmaceutical composition containing apixaban nanoparticles of the present invention may be selected from 1-10 mg, preferably 2-5 mg, more preferably 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4.0 mg, 4.5 mg, or 5.0mg.
  • Grinding devices suitable for the present invention include dispersive grinders such as ball mills, attritors, vibration grinders, and media grinders such as sand mills and bead mills. These dispersion mills are well known in the art.
  • the apixaban of the present invention may represent any factor Xa inhibitor, such as rivaroxaban, edoxaban, betrixaban, and the like.
  • the present invention also relates to the use of the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating thromboembolic disease, for example, the use of a pharmaceutical composition containing apixaban nanoparticles in the preparation of a medicament for preventing or treating thromboembolic disease.
  • the present invention also relates to the use of the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating venous thrombosis, deep venous thrombosis or acute coronary syndrome.
  • the solvent of the diluent used for dilution in the present invention may be a liquid medium; the solvent used for reconstitution may be a liquid medium; the solvent used during co-milling may be a liquid medium; the liquid medium is the same as described above.
  • the saline solution according to the present invention includes, but is not limited to, physiological saline solution and buffered saline solution (including but not limited to ammonia-ammonium chloride buffer solution, citrate buffer solution, acetate-sodium acetate buffer solution, phosphate buffer solution) .
  • the average particle diameter in the present invention refers to an average particle diameter measured with a Malvern nano-particle size potentiometer Zetasizer Nano ZS.
  • the content percentage (%) of all substances in the present invention refers to the weight-volume ratio
  • the "weight-volume ratio" in the present invention refers to the weight (unit g) of the component contained in each 100 mL of the liquid system, that is, g / 100 mL.
  • the exception is, as in the lyophilized preparation in Example 3: Initially, 4-8 ° C, 5d, 25 ° C / 60% RH, 5d, 40 ° C / 75% RH, 5d, Api
  • the content of saban /% refers to the starting content of 100%.
  • the content of apixaban under other storage conditions is determined by HPLC; the maximum single impurity and total impurity content are calculated by HPLC. Area ratio.
  • the pharmaceutical composition further includes a liquid medium, and the liquid medium is the same as described above.
  • the "PDI” in the present invention refers to the polydispersity index of the particle size distribution width of a sample.
  • D50 refers to the particle size value when the light energy of a sample accumulates to 50%.
  • the definition of D10 and D90 is analogous to D50.
  • the content (including the percentage content) of the various substances described in the present invention and their mutual ratios are allowed to have an error of ⁇ 5%.
  • the content of apixaban nanoparticles in the composition is 5-10 mg / “mL” means that the content of apixaban nanoparticles in the composition is 4.75 to 10.5 mg / mL, which all belong to the scope of the present invention;
  • “including 10% apixaban nanoparticles” means 9.5 to 10.5% of apixaban The nanoparticles all belong to the scope of the present invention;
  • the weight ratio of said apixaban nanoparticles to said sedimentation inhibitor is selected from 1: 0.1 to 1: 100” means that said apixaban nanoparticles
  • the weight ratio to the sedimentation inhibitor is selected from 1: 0.095 to 1: 105 and all belong to the scope of the present invention.
  • “about” means a solution including an error of ⁇ 5%.
  • mixing and “mixing” mean that the order of adding components is not limited.
  • mixing A into B can express the meaning of A adding B, or the meaning of B adding A, and mixing A and B.
  • Can express the meaning of A and B mixed can also express the meaning of B and A mixed.
  • the present invention improves the dispersibility of nanoparticles in a suspension by adding a surface stabilizer to a pharmaceutical composition for injection containing apixaban nanoparticles.
  • precipitation or aggregation of nanoparticles can be inhibited by adding a sedimentation inhibitor such as mannitol to the composition.
  • a part of the surface stabilizer is further added during the suspension dilution process, which further improves the stability of the suspension dilution.
  • the invention uses lyophilization to remove liquid media such as water used in the preparation process, and prevents the generation of hydrolytic impurities, thereby improving the stability of the nanoparticles in the pharmaceutical composition during long-term storage and promoting its clinical application.
  • the impurity content in the nanoparticle injection solution in the following examples was determined by HPLC, and the detection conditions were using octadecylsilane bonded silica as a filler (Waters Xbridge Shield RP 18 , 3.5 ⁇ m, 4.6 ⁇ 150 mm), and the mobile phase was acetonitrile. / Ammonium acetate buffer solution, detection wavelength: 280nm.
  • Preparation method Mix a prescribed amount of 15-hydroxystearic acid polyethylene glycol ester, medium chain triglyceride and soybean oil, heat to 60 ⁇ 5 ° C, and add about 20% of the total amount to the oil phase.
  • the temperature is 45 ⁇ 5 °C water for injection, stirred at 300rpm for not less than 20min to prepare colostrum, added a prescribed amount of apixaban raw material to colostrum, and stirred at 45 ⁇ 5 °C, 300rpm for not less than 30min to raw material Dissolve, dilute the emulsion to 90% of the total amount with water for injection at 15-30 ° C, add the mixed aqueous solution of anhydrous disodium hydrogen phosphate and sodium chloride after stirring well, stir well, measure the pH, and adjust the pH to 7.0-8.0 Within the range, the volume was finally adjusted to the full volume with water for injection. At this time, the drug substance had precipitated.
  • Preparation method Dissolve a prescribed amount of hydroxypropyl- ⁇ -cyclodextrin and PEG400, add an appropriate amount of water to dissolve, add apixaban raw material, make up the water to the full amount, and stir to dissolve. At this time, the existing drug substance is precipitated.
  • Preparation method Dissolve the prescribed amount of surface stabilizer in water, add apixaban raw material, stir to make the dispersion uniform, add grinding beads and stir to make the dispersion uniform, and grind on the ball mill for 4h to prepare apixaban nanoparticle suspension liquid.
  • the average particle size of the apixaban nanoparticle suspension of the present invention is between 100-500 nm, and the PDI is below 0.5, and the particle size and distribution results of the drug are better.
  • Preparation method Formula (4) Apixaban nanoparticle suspension prepared in Example 1 is prepared by 2.5% mannitol, 2.5% glycerol aqueous solution, 10% sucrose aqueous solution, 2.5% mannitol + 0.5% polysaccharide Retinone + 0.25% sodium deoxycholate aqueous solution was diluted to apixaban concentration of 5mg / mL, and the particle size and distribution of the nanoparticles in the three dilutions were measured. The dilutions were stored at 2-8 ° C for 4 days, respectively.
  • apixaban nanoparticle suspension prepared in Example 1 was diluted with 5.6% mannitol + 0.5% povidone + 0.2368% sodium deoxycholate aqueous solution to a 2.5 mg / mL apixaban concentration.
  • the particle size and distribution of the nanoparticles were measured after grinding, before lyophilization, storage at 2-8 ° C for 24 hours, and after lyophilization (Note: After the nanoparticle suspension of prescription (5) was diluted, the Filter cartridges are sterilized and lyophilized).
  • the apixaban nanoparticle suspension of prescription (4) was diluted with an aqueous solution containing 2.5% mannitol + 0.5% povidone + 0.25% sodium deoxycholate, and the lyophilized preparations were separately at 2-8 ° C. Place at 25 ° C / 60% RH and 40 ° C / 75% RH. After reconstitution with water, measure the particle size distribution, content and related substances, and check the stability. See Table 5 (batch 1) for details.
  • the apixaban nanoparticle suspension of prescription (5) was diluted with an aqueous solution containing 5.6% mannitol + 0.5% povidone + 0.2368% sodium deoxycholate, and the lyophilized preparations were separately at 25 ° C / 60 It is placed under the conditions of% RH and 40 ° C / 75% RH. After reconstitution with water, the particle size distribution and related substances are examined, and the stability is examined. For details, see Table 5 (batch 2, 3, 4).
  • the apixaban nanoparticle suspension of prescription (5) was diluted with an aqueous solution containing 5.6% mannitol + 0.5% povidone + 0.2368% sodium deoxycholate, and then lyophilized, and then reconstituted with water.
  • the particle size distributions at 2-8 ° C after 1h, 2h, 4h, 6h, 24h, and 48h are shown in Table 6.
  • apixaban nanoparticle suspension of prescription (5) was diluted with an aqueous solution containing 5.6% mannitol + 0.5% povidone + 0.2368% sodium deoxycholate, lyophilized, and reconstituted with water to obtain apixaban.
  • 2.5 mg / mL injection was administered subcutaneously to 1 mL of 3 subjects, the plasma drug concentrations are shown in Table 7:
  • the experimental data show that the half-life of subcutaneous injection of apixaban nanoparticle pharmaceutical composition is 11.1 hours, which indicates that the subcutaneous administration of nanoparticle pharmaceutical composition has a sustained release effect on the human body; the PK curve is smoother, 1-16 hours after administration
  • the blood concentration is higher than 21ng / mL, which can meet the way of once a day; 2.5 mg single subcutaneous administration has a lower C max (51.2), and the safety of administration is controllable.

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Abstract

一种可注射的药物组合物及其制备方法。具体而言，所述的药物组合物包含阿哌沙班纳米颗粒、表面稳定剂，还可以包含沉降抑制剂。该药物组合物稳定性好，适于工业化大生产。

Description

一种可注射的药物组合物及其制备方法
本申请要求申请日为2018年8月14日的中国专利申请CN201810919343.6的优先权。本申请引用该中国专利申请的全文。
技术领域
本发明涉及药物制剂领域，具体涉及一种包含阿哌沙班的纳米颗粒的可注射的药物组合物及其制备方法。
背景技术
阿哌沙班为白色至淡黄色粉末，在生理pH(1.2-6.8)，阿哌沙班不离子化，其在生理pH范围的溶解度约0.04mg/ml。LogP为3.53，具有较好渗透性。阿哌沙班在临床上用于预防和治疗血栓，具体用于髋关节或膝关节择期置换术的成年患者预防静脉血栓栓塞事件(VTE)。阿哌沙班的口服生物利用度不高，约为50％，溶解度是其吸收的限制因素。阿哌沙班具有高选择性、高安全性以及无需常规检测凝血功能，与食物相互作用少，无需根据患者的年龄、性别、体质及种族调整剂量等优势。目前市售的阿哌沙班片剂，每日口服两次，剂型单一且口服生物利用度差，另外，对于儿童及昏迷病人来说，片剂不易吞服，因此开发安全有效且使用方便的阿哌沙班新剂型具有重要的临床价值。
WO2011106478公开了包含具有等于或小于约89μm的D90的结晶阿哌沙班颗粒和药学上可接受的沉降抑制剂或载体的药物组合物。CN104736142A公开了包含阿哌沙班、水和至少两种增溶剂的口服液体制剂。CN101340933A公开了包含取代的β-环糊精和阿哌沙班的可注射制剂。CN102802608A公开了阿哌沙班的溶解度改善形式，提供阿哌沙班的控制释放。
发明内容
本发明提供了一种注射用药物组合物，包含阿哌沙班纳米颗粒和表面稳定剂。
本发明还提供了一种稳定的注射用药物组合物，包含阿哌沙班纳米颗粒和表面稳定剂。
纳米颗粒可以通过共研磨、高压均质或反溶剂法制备得到，优选共研磨法。共研磨所用的液体介质可选自水、盐水溶液、红花籽油、乙醇、叔丁醇、己烷和乙二醇中的一种或多种，优选水、盐水溶液和红花籽油中的一种或多种，最优选水。本发明优选的方案是 用水做液体介质，阿哌沙班与表面稳定剂共研磨得到纳米颗粒。
阿哌沙班纳米颗粒的平均粒径或D50可小于2000nm，优选小于1000nm，更优选小于500nm，更优选小于200nm，进一步优选小于170nm，进一步优选小于160nm，最优选小于150nm。
表面稳定剂可以是非离子、阴离子、阳离子和两性离子化合物或表面活性剂。
表面稳定剂可以是非离子表面稳定剂、阴离子表面稳定剂、阳离子表面稳定剂和两性离子表面稳定剂中的一种或多种。
表面稳定剂可选自聚维酮、聚乙烯醇、多库酯钠、羟丙甲基纤维素、吐温80、泊洛沙姆、15-羟基硬脂酸聚乙二醇酯、卵磷脂、脱氧胆酸钠、胆酸钠中的一种或多种，优选为泊洛沙姆、脱氧胆酸钠、聚维酮、多库酯钠和吐温80中的一种或多种，进一步优选为脱氧胆酸钠和聚维酮。
本发明的药物组合物中所用到的表面稳定剂不包含不适于注射剂用的十二烷基磺酸钠或十二烷基硫酸钠。
本发明所述的非离子表面稳定剂可包括但不限于羟丙基甲基纤维素(HPMC)、聚乙烯醇、聚维酮、泊洛沙姆、吐温80和15-羟基硬脂酸聚乙二醇酯中的一种或多种，优选为聚维酮、泊洛沙姆和吐温80中的一种或多种。
本发明所述的阴离子表面稳定剂可包括但不限于二辛基琥珀酸钠(DOSS)、多库酯钠、胆酸钠和脱氧胆酸钠中的一种或多种，优选为多库酯钠和/或脱氧胆酸钠，进一步优选为脱氧胆酸钠。
本发明所述的阳离子表面稳定剂可包括但不限于聚-N-甲基吡啶鎓、硫酸吡啶鎓氯化物、阳离子磷脂、壳聚糖、聚赖氨酸、聚乙烯咪唑、聚苯乙烯、聚甲基丙烯酸甲酯三甲基溴化铵(PMMTMABr)、己基甲基三甲基溴化铵(HDMAB)和聚乙烯吡咯烷酮-2-二甲氨基乙基甲基丙烯酸二甲酯硫酸盐中的一种或多种。
本发明所述的两性离子表面稳定剂可包括但不限于蛋白质、磷脂和两性离子表面活性剂中的一种或多种，例如可以是磷脂酰胆碱、氨基酸性表面活性剂、甜菜碱性表面活性剂、卵磷脂和明胶中的一种或多种。
本发明所述的表面稳定剂可不只包含传统意义上的如上所述的表面稳定剂，还可包含一些与上述表面稳定剂等效的添加剂，例如脱氧胆酸和磷酸钠的混合物与脱氧胆酸钠是等效的。
阿哌沙班纳米颗粒与表面稳定剂的重量比可选自1:0.01～1:100，优选1:0.1～1:10，更优选1:0.2～1:5，更进一步优选1:0.3～1:4(例如1:0.2、1:0.3、1:0.45、1:1.725或1:3.1)或 者1:0.3～1:3。
本发明的表面稳定剂可包含第一表面稳定剂和/或第二表面稳定剂。当所述的第一表面稳定剂为泊洛沙姆时，所述的表面稳定剂还包括第二表面稳定剂。
第一表面稳定剂可选自非离子表面稳定剂和/或两性离子表面稳定剂，优选聚维酮、聚乙烯醇、羟丙甲基纤维素、吐温80、泊洛沙姆、15-羟基硬脂酸聚乙二醇酯和卵磷脂中的一种或多种，更优选自聚维酮、泊洛沙姆和吐温80中的一种或多种。
第二表面稳定剂可选自阴离子表面稳定剂，优选脱氧胆酸钠、胆酸钠和多库酯钠中的一种或多种，更优选脱氧胆酸钠或多库酯钠，最优选脱氧胆酸钠。
阿哌沙班纳米颗粒与第一表面稳定剂的重量比可选自1:0.01～1:10，优选1:0.1～1:10，更优选1:0.1～1:5，更进一步优选1:0.1～1:3，更进一步地优选自1:0.2、1:0.3、1:1.15或1:2.1。
阿哌沙班纳米颗粒与第二表面稳定剂的重量比可选自1:0.01～1:10，优选1:0.1～1:5，更优选1:0.1～1:2或者1:0.1～1:1，更进一步优选1:0.1、1:0.15、1:0.575或1:1。
阿哌沙班纳米颗粒的平均粒径或D50可小于2000nm，优选小于1000nm，更优选小于500nm，更优选小于200nm，进一步优选小于170nm，进一步优选小于160nm，最优选小于150nm。
本发明的药物组合物的制备方法，包括：将表面稳定剂与阿哌沙班共研磨制备包含阿哌沙班纳米颗粒的药物组合物。
本发明的药物组合物的制备方法，还可包括：将第一表面稳定剂和/或第二表面稳定剂与阿哌沙班共研磨制备包含阿哌沙班纳米颗粒的药物组合物。
本发明提供阿哌沙班与部分或全部的表面稳定剂共研磨得到包含阿哌沙班纳米颗粒的药物组合物的技术方案。
在某些实施方案中，如果阿哌沙班与全部的表面稳定剂共研磨，意味着药物组合物中只包含共研磨时使用的表面稳定剂，不会在其它过程中再加入表面稳定剂，则阿哌沙班与表面稳定剂的重量比可选自1:0.01～1:10，优选1:0.1～1:10，更优选1:0.2～1:5(例如1:0.2、1:0.3、1:0.45、1:1.725或1:3.1)，更进一步优选1:0.3～1:4或者1:0.3～1:1。所述的表面稳定剂可以包含第一表面稳定剂和/或第二表面稳定剂，阿哌沙班与第一表面稳定剂的重量比可选自1:0.01～1:10，优选1:0.1～1:10，更优选1:0.1～1:5，更优选1:0.1～1:3，更进一步优选1:0.2、1:0.3、1:1.15或1:2.1；阿哌沙班与第二表面稳定剂的重量比可选自1:0.01～1:10，优选1:0.1～1:5，更优选1:0.1～1:2，更进一步优选1:0.1、1:0.15、1:0.575或1:1。
在某些实施方案中，阿哌沙班与部分表面稳定剂共研磨，还有一部分(即剩余部分) 表面稳定剂是在稀释过程中混入药物组合物中的。与阿哌沙班共研磨的表面稳定剂与总的表面稳定剂的比例可选自1:2～1:100，优选1:2～1:50，更优选1:2～1:20，更进一步优选1:3～1:15或者1:3～1:10，再更进一步优选1:5.75或1:10.3。该方案既能避免因一开始加过多表面稳定剂而使研磨过程中起泡太多，影响工艺，又能通过补加表面稳定剂而达到使稀释后药物组合物稳定的目的。两部分表面稳定剂可以是种类相同的表面稳定剂，也可以是不同种类的表面稳定剂，优选的方案是两部分表面稳定剂的种类相同。阿哌沙班与部分表面稳定剂共研磨时，阿哌沙班与该部分表面稳定剂的重量比可选自1:0.01～1:10，优选1:0.1～1:10，更优选1:0.2～1:5，最优选1:0.3～1:1。所述的部分表面稳定剂可以包含第一表面稳定剂和/或第二表面稳定剂，阿哌沙班与第一表面稳定剂的重量比可选自1:0.01～1:10，优选1:0.1～1:10，更优选1:0.1～1:5，最优选1:0.1～1:0.3(例如1:0.2)；阿哌沙班与第二表面稳定剂的重量比可选自1:0.01～1:10，优选1:0.1～1:5，更优选1:0.1～1:1，最优选1:0.1～1:0.5。另一部分(即剩余部分)表面稳定剂与包含阿哌沙班纳米颗粒的药物组合物混合稀释，稀释所用溶剂可选自前述液体介质。稀释倍数可选自1-100倍，优选5-50倍，最优选10-30倍，不限定混合的先后次序。阿哌沙班与另一部分(即剩余部分)表面稳定剂的重量比可选自1:0.01～1:10，优选1:0.1～1:10，更优选1:0.1～1:5，最优选1:1～1:3。所述的另一部分(即剩余部分)表面稳定剂可以包含第一表面稳定剂和/或第二表面稳定剂，阿哌沙班与第一表面稳定剂的重量比可选自1:0.01～1:10，优选1:0.1～1:10，更优选1:0.1～1:5(例如1:0.95、1:1.9)，最优选1:1～1:3；阿哌沙班与第二表面稳定剂的重量比可选自1:0.01～1:10，优选1:0.1～1:5(例如1:0.9、1:2)，更优选1:0.1～1:1，最优选1:0.3～1:1。
本发明的药物组合物还可以包含沉降抑制剂。沉降抑制剂在一定时间内抑制纳米颗粒的沉降或聚集。
所述的沉降抑制剂可以选自糖类、多元醇和高分子聚合物中的一种或多种，如甘露醇、蔗糖、白蛋白、右旋糖酐40、海藻糖、甘油、聚维酮、甘氨酸、甘油、羟丙基-β-环糊精中的一种或几种，优选甘露醇、蔗糖和右旋糖酐40中的一种或几种，进一步优选为甘露醇或蔗糖，更优选甘露醇。所述的阿哌沙班纳米颗粒与所述的沉降抑制剂的重量比可选自1:0.1～1:100，优选1:0.1～1:50，更优选1:0.5～1:30(例如1:1～1:30)，更进一步优选1:4.75、1:19或1:21.28。
在一些实施方案中，本发明的药物组合物的制备方法，包括：将表面稳定剂与阿哌沙班共研磨制备包含阿哌沙班纳米颗粒的药物组合物；将沉降抑制剂与前述药物组合物混合，或者将沉降抑制剂、剩余部分的表面稳定剂与前述药物组合物混合，所述的表面稳定剂包含第一表面稳定剂和/或第二表面稳定剂。前述的制备方法，还可以进一步包括 冻干的步骤。出于工艺方面及经济方面的考虑，一般先将阿哌沙班和全部或部分表面稳定剂共研磨制备成浓的包含阿哌沙班纳米颗粒的混悬液，然后再经过稀释，得到适合冻干或者直接使用的稀的包含阿哌沙班纳米颗粒的混悬液。沉降抑制剂或者沉降抑制剂及剩余部分的表面稳定剂可以在稀释的过程中与包括阿哌沙班纳米颗粒的药物组合物混合，从而维持稀释后液体的稳定性。
本发明的药物组合物可以是冻干的药物组合物。在一些实施方案中，冻干的药物组合物经液体介质复溶后，可以得到包含液体介质的药物组合物，所述液体介质可选自水、盐水溶液、红花籽油、乙醇、叔丁醇、己烷和乙二醇中的一种或多种，优选水、盐水溶液和红花籽油中的一种或多种，最优选水。复溶后的药物组合物中，阿哌沙班纳米颗粒的含量可选自0.1～100mg/mL，优选0.5～100mg/mL，更优选1～100mg/mL，最优选2～10mg/mL(例如2.5mg/mL)。
在本发明的一些实施方案中，复溶后包含液体介质的药物组合物可具有如前所述药物组合物的技术特征。
本发明还提供包含液体介质的药物组合物，所述液体介质可选自水、盐水溶液、红花籽油、乙醇、叔丁醇、己烷和乙二醇，优选水、盐水溶液和红花籽油中的一种或多种，最优选水。包含液体介质的药物组合物中，阿哌沙班纳米颗粒的含量可选自0.1～100mg/mL，优选0.5～100mg/mL，更优选1～100mg/mL，最优选2～10mg/mL(例如2.5mg/mL或5mg/mL)。当所述的包含液体介质的药物组合物中包含沉降抑制剂时，所述的药物组合物中阿哌沙班的含量可选自0.1～100mg/mL(例如2.5mg/mL、5mg/mL、50mg/mL或100mg/mL)。当所述的包含液体介质的药物组合物中不包含沉降抑制剂时，所述的药物组合物中阿哌沙班的含量可选自0.1～1000mg/mL，优选1～200mg/mL，更优选50～100mg/mL(例如50mg/mL或100mg/mL)。包含液体介质的药物组合物可以冻干，得到冻干药物组合物。
本发明的药物组合物可以是包含阿哌沙班纳米颗粒与表面稳定剂的药物组合物，也可以是阿哌沙班与表面稳定剂共研磨得到的包含阿哌沙班的纳米颗粒混悬剂，也可以是前述包含阿哌沙班纳米颗粒混悬剂的稀释后药物组合物，或者稀释后药物组合物的冻干的药物组合物，或者冻干的药物组合物复溶后的药物组合物。
本发明的沉降抑制剂是在稀释过程中与包含阿哌沙班纳米颗粒的药物组合物混合的。沉降抑制剂能够使稀释过的包含阿哌沙班纳米颗粒的混悬液稳定存在一段时间。本发明优选的方案是稀释过程中还可以混入一部分表面稳定剂，从而使稀释过后的包含阿哌沙班纳米的混悬液更稳定。所述的表面稳定剂同前所述。
本发明提供了一种可注射的药物组合物，包含阿哌沙班纳米颗粒、第一表面稳定剂、第二表面稳定剂和沉降抑制剂。所述的第一表面稳定剂、第二表面稳定剂和沉降抑制剂同前所述。所述的阿哌沙班纳米颗粒和所述的第一表面稳定剂重量比可选自1:0.01～1:10，优选1:0.1～1:10，更优选1:0.1～1:5，更进一步优选1:0.1～1:3(例如1:0.2、1:0.3、1:1.15或1:2.1)。所述的阿哌沙班纳米颗粒与所述的第二表面稳定剂的重量比可选自1:0.01～1:10，优选1:0.1～1:5，更优选1:0.1～1:2，更进一步优选1:0.1～1:1(例如1:0.1、1:0.15、1:0.575或1:1)。所述的阿哌沙班纳米颗粒与所述的沉降抑制剂的重量比可选自1:0.1～1:100，优选1:0.1～1:50，更优选1:0.5～1:30(例如1:4.75、1:19或1:21.28)。所述阿哌沙班纳米颗粒的平均粒径或D50可小于500nm，优选小于200nm，进一步优选小于170nm，进一步优选小于160nm，更进一步优选小于150nm。
本发明的药物组合物的制备方法，包括：将一部分第一表面稳定剂和一部分第二表面稳定剂与阿哌沙班共研磨制备包括阿哌沙班纳米颗粒的药物组合物；将沉降抑制剂、另一部分第一表面稳定剂、另一部分第二表面稳定剂与前述包括阿哌沙班纳米颗粒的药物组合物混合。前述的制备方法，还可以进一步包括冻干的步骤。
本发明提供包含阿哌沙班纳米颗粒、聚维酮以及脱氧胆酸钠的药物组合物。进一步地，阿哌沙班纳米颗粒与聚维酮的重量比可选自1:0.01～1:10，优选1:0.1～1:10，更优选1:0.1～1:5，更进一步优选1:0.1～1:3或者1:0.1～1:2，最优选为1:0.2或1:0.3；阿哌沙班纳米颗粒与脱氧胆酸钠的重量比可选自1:0.01～1:10，优选1:0.1～1:5，更优选1:0.1～1:1或者1:0.1～1:0.3，最优选为1:0.1或1:0.15。
本发明提供一种包含阿哌沙班纳米颗粒、聚维酮、脱氧胆酸钠以及甘露醇的药物组合物。进一步地，阿哌沙班纳米颗粒与聚维酮的重量比可选自1:0.01～1:10，优选1:0.1～1:10，更优选1:0.1～1:5，更进一步优选1:0.1～1:3，最优选为1:1～1:3；阿哌沙班纳米颗粒与脱氧胆酸钠的重量比可选自1:0.01～1:10，优选1:0.1～1:5，更优选1:0.1～1:1，最优选为1:0.5～1:1；阿哌沙班纳米颗粒与甘露醇的重量比可选自1:0.1～1:100，优选1:0.1～1:50，更优选1:0.5～1:30(例如1:4.75、1:21.28)。
本发明提供一种药物组合物，包含阿哌沙班纳米颗粒、聚维酮、脱氧胆酸钠以及甘露醇，药物组合物中阿哌沙班纳米颗粒的重量体积比优选为0.1-1％，进一步优选0.1-0.5％(例如0.25％或0.5％)；聚维酮的重量体积比优选为0.5-5％，进一步优选0.5-1％(例如0.575％或0.525％)；脱氧胆酸钠的重量体积比优选为0.1-3％，进一步优选0.1-0.5％(例如0.2875％或0.25％)，；甘露醇的重量体积比优选为1-10％，进一步优选2-7％(例如2.375％或5.32％)。
本发明提供阿哌沙班纳米颗粒：聚维酮：脱氧胆酸钠的重量比是10:2:1的药物组合物，优选包含重量体积比为10％阿哌沙班纳米颗粒、2％聚维酮、1％脱氧胆酸钠的药物组合物或者包含重量体积比为5％阿哌沙班纳米颗粒、1％聚维酮、0.5％脱氧胆酸钠的药物组合物。
本发明还提供包含重量体积比为0.5％阿哌沙班纳米颗粒、0.575％聚维酮、0.2875％脱氧胆酸钠、2.375％甘露醇的药物组合物。
本发明还提供包含重量体积比为0.25％阿哌沙班纳米颗粒、0.525％聚维酮、0.25％脱氧胆酸钠、5.32％甘露醇的药物组合物。
在某些实施方案中，本发明的药物组合物中，单位剂量中阿哌沙班纳米颗粒的含量可为2.0mg-5.0mg，优选2.0mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg、5.0mg。本发明还提供一种药物组合物的制备方法，包括将聚维酮和脱氧胆酸钠与阿哌沙班共研磨制备包含阿哌沙班纳米颗粒的药物组合物。进一步地，将甘露醇与前述包含阿哌沙班纳米颗粒的药物组合物混合，优选用包含甘露醇的水溶液对前述包含阿哌沙班纳米颗粒的药物组合物进行稀释。进一步地，聚维酮和脱氧胆酸钠是分两部分混入药物组合物中的，一部分聚维酮和脱氧胆酸钠与阿哌沙班共研磨，另一部分聚维酮和脱氧胆酸钠在稀释过程中混入，稀释倍数选自1-100倍，优选5-50倍，最优选10-30倍，稀释所用溶剂可选自前述液体介质；本方案中“一部分”、“另一部分”表明表面稳定剂是分两部分混入药物组合物中。
本发明提供了由包含10％阿哌沙班纳米颗粒、2％聚维酮、1％脱氧胆酸钠以及水的包含阿哌沙班纳米颗粒的混悬液用包含2.5％甘露醇、0.5％聚维酮和0.25％脱氧胆酸钠的稀释剂稀释得到的药物组合物及其制备方法，稀释倍数可选自1-100倍，优选5-50倍，最优选10-30倍，例如可以是10倍、20倍、30倍。所述制备方法即为将包含10％阿哌沙班纳米颗粒、2％聚维酮、1％脱氧胆酸钠以及水的包含阿哌沙班纳米颗粒的混悬液用包含2.5％甘露醇、0.5％聚维酮和0.25％脱氧胆酸钠的稀释剂稀释得到，稀释倍数可选自1-100倍，优选5-50倍，最优选10-30倍，例如可以是10倍、20倍、30倍。
本发明提供了由包含5％阿哌沙班纳米颗粒、1％聚维酮、0.5％脱氧胆酸钠以及水的包含阿哌沙班纳米颗粒的混悬液用包含5.6％甘露醇、0.5％聚维酮和0.2368％脱氧胆酸钠的稀释剂稀释得到的药物组合物及其制备方法，稀释倍数可选自1-100倍，优选5-50倍，最优选10-30倍，例如可以是10倍、20倍、30倍。所述制备方法即为将包含5％阿哌沙班纳米颗粒、5％聚维酮、0.5％脱氧胆酸钠以及水的包含阿哌沙班纳米颗粒的混悬液用包含5.6％甘露醇、0.5％聚维酮和0.2368％脱氧胆酸钠的稀释剂稀释得到，稀释倍数可选 自1-100倍，优选5-50倍，最优选10-30倍，例如可以是10倍、20倍、30倍。
本发明提供了由包含10％阿哌沙班纳米颗粒、2％聚维酮、1％脱氧胆酸钠以及水的包含阿哌沙班纳米颗粒的混悬液用包含2.5％甘露醇、0.5％聚维酮和0.25％脱氧胆酸钠的稀释剂稀释得到的药物组合物及其制备方法，稀释后药物组合物中阿哌沙班纳米颗粒的含量可选自0.1～100mg/mL，优选0.5～20mg/mL，更优选1～10mg/mL，最优选5～10mg/mL。所述制备方法即为由包含10％阿哌沙班纳米颗粒、2％聚维酮、1％脱氧胆酸钠以及水的包含阿哌沙班纳米颗粒的混悬液用包含2.5％甘露醇、0.5％聚维酮和0.25％脱氧胆酸钠的稀释剂稀释得到，稀释后药物组合物中阿哌沙班纳米颗粒的含量可选自0.1～100mg/mL，优选0.5～20mg/mL，更优选1～10mg/mL，最优选5～10mg/mL。
本发明提供了由包含5％阿哌沙班纳米颗粒、1％聚维酮、0.5％脱氧胆酸钠以及水的包含阿哌沙班纳米颗粒的混悬液用包含5.6％甘露醇、0.5％聚维酮和0.2368％脱氧胆酸钠的稀释剂稀释得到的药物组合物及其制备方法，稀释后药物组合物中阿哌沙班纳米颗粒的含量可选自0.1～100mg/mL，优选0.5～20mg/mL，更优选1～10mg/mL，最优选1～5mg/mL，例如1mg/mL、1.5mg/mL、2mg/mL、2.5mg/mL、3mg/mL。所述制备方法即为由包含5％阿哌沙班纳米颗粒、1％聚维酮、0.5％脱氧胆酸钠以及水的包含阿哌沙班纳米颗粒的混悬液用包含5.6％甘露醇、0.5％聚维酮和0.2368％脱氧胆酸钠的稀释剂稀释得到，稀释后药物组合物中阿哌沙班纳米颗粒的含量可选自0.1～100mg/mL，优选0.5～20mg/mL，更优选1～10mg/mL，最优选1～5mg/mL，例如1mg/mL、1.5mg/mL、2mg/mL、2.5mg/mL、3mg/mL。
本发明优选的方案是将表面稳定剂分两部分混入药物组合物中，一部分表面稳定剂与阿哌沙班混合制备包含阿哌沙班纳米颗粒的药物组合物，另一部分表面稳定剂、沉降抑制剂混入前述的包含阿哌沙班纳米颗粒的药物组合物中，从而制备得到更加稳定的稀释后的包含阿哌沙班纳米颗粒的药物组合物。药物组合物中的溶剂可选用水，避免了有机溶剂的引入。
本发明还提供了所述冻干的注射用药物组合物的复溶的药物组合物。
本发明的包含阿哌沙班纳米颗粒的药物组合物中，阿哌沙班纳米颗粒的平均粒径可小于500nm，优选小于300nm，更优选小于200nm，更优选小于170nm，更优选小于160nm，最优选小于150nm。本发明的包含阿哌沙班纳米颗粒的药物组合物中，阿哌沙班纳米颗粒的PDI可小于0.5，优选小于0.3，最优选小于0.2。本发明的包含阿哌沙班纳米颗粒的药物组合物中，阿哌沙班纳米颗粒的D50可小于500nm，优选小于300nm，更优选小于200nm，最优选小于170nm。
本发明的包含阿哌沙班纳米颗粒的药物组合物，在2-8℃、25℃/60％RH储存一段时间后，例如1个月、2个月、3个月、6个月、12个月以后，阿哌沙班纳米颗粒的平均粒径可小于500nm，优选小于300nm，更优选小于200nm，最优选小于150nm。本发明的包含阿哌沙班纳米颗粒的药物组合物，在2-8℃、25℃/60％RH储存一段时间后，例如1个月、2个月、3个月、6个月、12个月以后，阿哌沙班纳米颗粒的PDI可小于0.5，优选小于0.3，最优选小于0.2。本发明的包含阿哌沙班纳米颗粒的药物组合物，在2-8℃、25℃/60％RH储存一段时间后，例如1个月、2个月、3个月、6个月、12个月以后，阿哌沙班纳米颗粒的D50可小于500nm，优选小于300nm，更优选小于200nm，最优选小于170nm。
本发明的包含阿哌沙班纳米颗粒的药物组合物，在40℃/75％RH储存一段时间后，例如1个月、2个月、3个月、6个月、12个月以后，阿哌沙班纳米颗粒的平均粒径可小于500nm，优选小于300nm，更优选小于200nm，更进一步优选小于160nm。本发明的包含阿哌沙班纳米颗粒的药物组合物，在40℃/75％RH储存一段时间后，例如1个月、2个月、3个月、6个月、12个月以后，阿哌沙班纳米颗粒的PDI小于0.5，优选小于0.3，最优选小于0.2。本发明的包含阿哌沙班纳米颗粒的药物组合物，在40℃/75％RH储存一段时间后，例如1个月、2个月、3个月、6个月、12个月以后，阿哌沙班纳米颗粒的D50可小于500nm，优选小于300nm，更优选小于200nm，更进一步优选小于170nm。
本发明的包含阿哌沙班纳米颗粒的药物组合物，在2-8℃、25℃/60％RH、40℃/75％RH储存一段时间后，例如1个月、2个月、3个月、6个月、12个月以后，阿哌沙班纳米颗粒的平均粒径基本不变；在2-8℃、25℃/60％RH、40℃/75％RH储存一段时间后，例如1个月、2个月、3个月、6个月、12个月以后，阿哌沙班纳米颗粒的PDI基本不变；在2-8℃、25℃/60％RH、40℃/75％RH储存一段时间后，例如1个月、2个月、3个月、6个月、12个月以后，阿哌沙班纳米颗粒的D50基本不变。“基本不变”是指变化小于30％，优选小于20％，更优选小于10％。
本发明的包含阿哌沙班纳米颗粒的药物组合物在储存前，阿哌沙班纳米颗粒的含量以100％计；在2-8℃情况下储存5d后，阿哌沙班纳米颗粒的含量相对于储存前的药物组合物来说为95％～105％，优选的是98％～102％；在25℃/60％RH情况下储存5d后，阿哌沙班纳米颗粒的含量相对于储存前的药物组合物来说为95％～105％，优选的是98％～102％；在40℃/75％RH情况下储存5d后，阿哌沙班纳米颗粒的含量相对于储存前的药物组合物来说为95％～105％，优选的是98％～102％。本发明的包含阿哌沙班纳米颗粒的药物组合物储存前，最大单杂的含量可为小于0.5％，优选的是小于0.1％，最优选的是小于0.05％； 在2-8℃情况下储存5d后，最大单杂的含量可为小于0.5％，优选的是小于0.1％，最优选的是小于0.05％；在25℃/60％RH情况下储存5d后，最大单杂的含量可为小于0.5％，优选的是小于0.1％，最优选的是小于0.05％；在40℃/75％RH情况下储存5d后，最大单杂的含量为小于0.5％，优选的是小于0.1％，最优选的是小于0.05％。本发明的包含阿哌沙班纳米颗粒的药物组合物储存前，总杂的含量可为小于1％，优选的是小于0.5％；在2-8℃情况下储存5d后，总杂的含量可为小于1％，优选的是小于0.5％；在25℃/60％RH情况下储存5d后总杂的含量可为小于1％，优选的是小于0.5％；在40℃/75％RH情况下储存5d后，总杂的含量可为小于1％，优选的是小于0.5％。
本发明的包含阿哌沙班纳米颗粒的药物组合物，在2-8℃、25℃/60％RH、40℃/75％RH储存一段时间后，例如1个月、2个月、3个月、6个月、12个月以后，阿哌沙班纳米颗粒的含量相对于储存前的药物组合物来说为95％～105％，优选的是98％～102％；最大单杂的含量为小于0.5％，优选的是小于0.1％，最优选的是小于0.05％；总杂的含量为小于1％，优选的是小于0.5％。
本发明的包含阿哌沙班纳米颗粒的药物组合物，在2-8℃、25℃/60％RH、40℃/75％RH储存一段时间后，例如1个月、2个月、3个月、6个月、12个月以后，阿哌沙班纳米颗粒的含量基本不变；本发明的包含阿哌沙班纳米颗粒的药物组合物，在2-8℃、25℃/60％RH、40℃/75％RH储存一段时间后，例如1个月、2个月、3个月、6个月、12个月以后，最大单杂的含量基本不变；本发明的包含阿哌沙班纳米颗粒的药物组合物，在2-8℃、25℃/60％RH、40℃/75％RH储存一段时间后，例如1个月、2个月、3个月、6个月、12个月以后，总杂的含量基本不变。“基本不变”是指变化小于20％，优选小于10％，最优选小于5％。
本发明的包含阿哌沙班纳米颗粒的药物组合物优选适合注射给药，尤其适合皮下注射给药。本发明的阿哌沙班纳米颗粒组合物皮下注射后生物利用度高，药时曲线平稳，具有更好的安全性和有效性。本发明的包含阿哌沙班纳米颗粒的药物组合物优选适合每日一次、每日两次给药。
本发明的包含阿哌沙班纳米颗粒的药物组合物的每日给药剂量可选自1-10mg，优选2-5mg，更优选2mg、2.5mg、3mg、3.5mg、4.0mg、4.5mg或者5.0mg。
适用于本发明的研磨装置包括诸如球磨机、磨碎机、振动研磨机等分散研磨机和诸如砂磨机和珠磨机等介质研磨机。这些分散研磨机在本领域中是众所周知的。
本发明的阿哌沙班可以代表任何的Xa因子抑制剂，例如利伐沙班、依度沙班、贝曲沙班等。
本发明还涉及本发明的药物组合物在制备预防或治疗血栓栓塞疾病的药物中用途，例如包含阿哌沙班纳米颗粒的药物组合物在制备预防或治疗血栓栓塞疾病的药物中用途。具体地本发明还涉及本发明的药物组合物在制备预防或治疗静脉血栓形成、深静脉血栓形成或急性冠状动脉综合症的药物中的用途。
发明详述
在本申请的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本发明，下面提供了部分相关术语的定义和解释。
本发明中稀释所用的稀释液的溶剂可为液体介质；复溶所用的溶剂可为液体介质；共研磨时所用的溶剂可为液体介质；所述的液体介质同前所述。
本发明所述的盐水溶液包括但不限于生理盐水溶液、缓冲盐水溶液(包括但不限于氨-氯化铵缓冲液、枸橼酸盐缓冲液、醋酸-醋酸钠缓冲液、磷酸盐缓冲液)。
本发明中所述的平均粒径指的是用马尔文纳米粒度电位仪Zetasizer Nano ZS测出来的平均粒径。
本发明所有物质的含量百分比(％)指重量体积比，本发明所述的“重量体积比”是指每100mL液体体系中含有所述成分的重量(单位g)，即g/100mL。例外的情况是，如实施例3中的冻干制剂中：起始，2-8℃、5d，25℃/60％RH、5d，40℃/75％RH、5d四种情况下，阿哌沙班含量/％指的是以起始含量为100％计，其他储存条件下阿哌沙班的含量，使用的是HPLC方法测定；最大单杂、总杂的含量是以HPLC方法，计算峰面积比得出。当本发明药物组合物中的物质用重量体积比表示时，该药物组合物中还进一步包括液体介质，所述的液体介质同前所述。
本发明所述的“PDI”是指一个样品的粒度分布宽度的多分散指数。“D50”是指一个样品的光能累积到50％时的粒径值，D10、D90的定义类比D50。
本发明所述的各种物质的含量(包括百分含量)及相互之间的比例，均允许存在±5％的误差，例如“组合物中阿哌沙班纳米颗粒的含量是5～10mg/mL”意味着组合物中阿哌沙班纳米颗粒含量为4.75～10.5mg/mL均属于本发明的范围；“包含10％阿哌沙班纳米颗粒”意味着包含9.5～10.5％阿哌沙班纳米颗粒均属于本发明的范围；“所述的阿哌沙班纳米颗粒与所述的沉降抑制剂的重量比选自1:0.1～1:100”意味着所述的阿哌沙班纳米颗粒与所述的沉降抑制剂的重量比选自1:0.095～1:105均属于本发明的范围。本发明中“约”表示包含误差在±5％的方案。
本发明的“混入”、“混合”表示的意思是不限定组分的加入顺序，例如将A混入B，可以表达A加入B的意思，也可以表达B加入A的意思，将A和B混合，可以表达A加入B混合的意思，也可以表达B加入A混合的意思。
发明的有益效果
本发明通过在包含阿哌沙班纳米颗粒的注射用药物组合物中加入表面稳定剂，提高了纳米颗粒在混悬液中的分散性。本发明通过在组合物中加入甘露醇等沉降抑制剂可以抑制纳米颗粒发生沉降或聚集。本发明优选的技术方案还在混悬液稀释过程中又加入了一部分表面稳定剂，进一步提高了混悬液的稀释液的稳定性。本发明通过冷冻干燥除去制备过程中使用的诸如水等液体介质，以及防止产生水解杂质，从而提高药物组合物中的纳米颗粒在长期贮存过程中的稳定性，推进其在临床上的应用。
具体实施方式
通过以下实施例和实验例进一步详细说明本发明。这些实施例和实验例仅用于说明性目的，而并不用于限制本发明的范围。
以下实施例中纳米颗粒注射剂粒度的检测方法参照中国药典2015年版四部通则0982第三法。
马尔文纳米粒度电位仪Zetasizer Nano ZS，分散介质：纯化水；稀释倍数：稀释至阿哌沙班浓度约为0.1mg/ml；测试温度：25℃；吸收率：0.01；折光率1.59；平衡时间：120s；测试位置：最佳位置。
以下实施例中纳米颗粒注射液中杂质含量通过HPLC检测，其检测条件为用十八烷基硅烷键合硅胶为填充剂(Waters Xbridge Shield RP 18，3.5μm，4.6×150mm)，流动相：乙腈/乙酸铵缓冲溶液，检测波长：280nm。
对比例1 阿哌沙班纳米乳制剂处方
表1 阿哌沙班纳米乳制剂处方
Figure PCTCN2019100558-appb-000001
Figure PCTCN2019100558-appb-000002
制备方法：将处方量的15-羟基硬脂酸聚乙二醇酯、中链甘油三酸酯和大豆油混合，加热至60±5℃，向油相中加入约占总量20％温度为45±5℃的注射用水，在300rpm转速下搅拌不少于20min制备初乳，将处方量的阿哌沙班原料加入初乳，在45±5℃、300rpm条件下搅拌不少于30min至原料溶解，使用15～30℃的注射用水将乳剂稀释至总量的90％，搅拌均匀后加入无水磷酸氢二钠和氯化钠的混合水溶液，搅拌均匀，测定pH，调节pH至7.0～8.0范围内，最后使用注射用水定容至全量，此时已有原料药析出。
对比例2 阿哌沙班环糊精包合物制剂处方
表2 阿哌沙班环糊精包合物制剂处方
Figure PCTCN2019100558-appb-000003
制备方法：将处方量的羟丙基-β-环糊精及PEG400，加适量水溶解，加入阿哌沙班原料，补足水分至全量，搅拌使溶解，此时已有原料药析出。
实施例1 阿哌沙班纳米颗粒混悬液处方
表3 阿哌沙班纳米颗粒混悬液处方
Figure PCTCN2019100558-appb-000004
Figure PCTCN2019100558-appb-000005
制备方法：将处方量的表面稳定剂加水溶解，加入阿哌沙班原料，搅拌使分散均匀，加入研磨珠后搅拌使分散均匀，在球磨机上研磨4h，制得阿哌沙班纳米颗粒混悬液。
比较对比例1、2与实施例1的制剂载药量，对比例1、2的制剂中阿哌沙班均不能有效增溶，实施例1的处方中阿哌沙班载药量可达到100mg/mL。
除处方(2)外，本发明的阿哌沙班纳米颗粒混悬液平均粒径在100-500nm之间，且PDI在0.5以下，药物的粒径和分布结果较好。
实施例2 处方(4)、(5)阿哌沙班纳米颗粒混悬液的稀释及冻干
表4 阿哌沙班纳米颗粒混悬液稀释及冻干
Figure PCTCN2019100558-appb-000006
Figure PCTCN2019100558-appb-000007
制备方法：将实施例1制得处方(4)阿哌沙班纳米颗粒混悬液分别以2.5％的甘露醇、2.5％的甘油水溶液、10％的蔗糖水溶液、2.5％甘露醇+0.5％聚维酮+0.25％脱氧胆酸钠水溶液稀释至阿哌沙班浓度为5mg/mL，分别测出三种稀释液中纳米颗粒的粒径及分布情况；稀释液2-8℃储存4天，分别测出三种稀释液中纳米颗粒的粒径及分布情况；或者稀释液直接冻干，分别测出三种稀释液处方冻干后纳米颗粒的粒径及分布情况。将实施例1制得处方(5)阿哌沙班纳米颗粒混悬液以5.6％甘露醇+0.5％聚维酮+0.2368％脱氧胆酸钠水溶液稀释至阿哌沙班浓度为2.5mg/mL，分别测出在研磨后、冻干前、2-8℃储存24h、冻干后纳米颗粒的粒径及分布情况(备注：处方(5)的纳米颗粒混悬液稀释后，经0.22微米的滤芯过滤除菌，再进行冻干)。
实施例3 处方(4)、(5)冻干制剂的性质考察
处方(4)的阿哌沙班纳米颗粒混悬液用包含2.5％甘露醇+0.5％聚维酮+0.25％脱氧胆酸钠的水溶液稀释后，又经冻干的制剂分别于2-8℃、25℃/60％RH及40℃/75％RH条件下放置，使用水复溶后，检测粒度分布、含量及有关物质，考察稳定性，具体见表5(批次1)。处方(5)的阿哌沙班纳米颗粒混悬液用包含5.6％甘露醇+0.5％聚维酮+0.2368％脱氧胆酸钠的水溶液稀释后，又经冻干的制剂分别于25℃/60％RH及40℃/75％RH条件下放置，使用水复溶后，检测粒度分布及有关物质，考察稳定性，具体见表5(批次2、3、4)。处方(5)的阿哌沙班纳米颗粒混悬液用包含5.6％甘露醇+0.5％聚维酮+0.2368％脱氧胆酸钠的水溶液稀释后，经历冻干，再用水复溶，考察室温及2-8℃条件下，1h、2h、4h、6h、24h、48h后的粒度分布情况，具体见表6。
表5 处方(4)、(5)冻干制剂的稳定性考察
Figure PCTCN2019100558-appb-000008
Figure PCTCN2019100558-appb-000009
Figure PCTCN2019100558-appb-000010
表6 粒度分布稳定性
Figure PCTCN2019100558-appb-000011
从表5的结果可以看出，阿哌沙班纳米颗粒冻干制剂在不同条件下均较为稳定，粒 度分布、含量及有关物质与起始相比均无明显变化；从表6的结果可以看出，阿哌沙班纳米颗粒冻干制剂复溶后粒度分布均匀，表明阿哌沙班纳米颗粒冻干制剂复溶后粒度分布稳定性良好。阿哌沙班含量及有关物质的含量测定均采用HPLC方法。
实施例4、药代动力学研究
处方(5)的阿哌沙班纳米颗粒混悬液，用包含5.6％甘露醇+0.5％聚维酮+0.2368％脱氧胆酸钠的水溶液稀释，冻干，加水复溶，得到阿哌沙班2.5mg/mL的注射液，分别给3个受试者皮下给药1mL，血浆药物浓度如表7所示：
表7 阿哌沙班血浆药物浓度(ng/mL)随时间的变化
Figure PCTCN2019100558-appb-000012
实验数据显示，阿哌沙班纳米颗粒药物组合物皮下注射的半衰期为11.1小时，表明纳米颗粒药物组合物皮下给药在人体上有缓释效果；PK曲线较平缓，给药后1-16小时，血药浓度均高于21ng/mL，可满足1天给药1次的方式；2.5mg单次皮下给药的C max较低(51.2)，给药的安全性可控。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (36)

  1. 一种注射用药物组合物，其包含阿哌沙班纳米颗粒和表面稳定剂。
  2. 根据权利要求1所述的药物组合物，其特征在于，表面稳定剂选自非离子表面稳定剂、阴离子表面稳定剂、阳离子表面稳定剂和两性离子表面稳定剂中的一种或多种，优选自聚维酮、聚乙烯醇、多库酯钠、羟丙甲基纤维素、吐温80、卵磷脂、脱氧胆酸钠、胆酸钠、泊洛沙姆和15-羟基硬脂酸聚乙二醇酯中的一种或多种。
  3. 根据权利要求2所述的药物组合物，其特征在于，阿哌沙班纳米颗粒与表面稳定剂的重量比选自1:0.01～1:100，优选1:0.1～1:10，更优选1:0.2～1:5，最优选1:0.3～1:4。
  4. 根据权利要求1所述的药物组合物，其特征在于，表面稳定剂包含第一表面稳定剂和/或第二表面稳定剂。
  5. 根据权利要求4所述的药物组合物，其特征在于，第一表面稳定剂选自非离子表面稳定剂和/或两性离子表面稳定剂，优选聚维酮、聚乙烯醇、羟丙甲基纤维素、吐温80、泊洛沙姆、15-羟基硬脂酸聚乙二醇酯和卵磷脂中的一种或多种，更优选聚维酮、泊洛沙姆和吐温80中的一种或多种。
  6. 根据权利要求5所述的药物组合物，其特征在于，第二表面稳定剂选自阴离子表面稳定剂，优选脱氧胆酸钠、胆酸钠和多库酯钠中的一种或多种，更优选脱氧胆酸钠。
  7. 根据权利要求4-6任一项所述的药物组合物，其特征在于，阿哌沙班纳米颗粒与第一表面稳定剂的重量比选自1:0.01～1:10，优选1:0.1～1:10，更优选1:0.1～1:5，最优选1:0.1～1:3。
  8. 根据权利要求7所述的药物组合物，其特征在于，阿哌沙班纳米颗粒与第二表面稳定剂的重量比选自1:0.01～1:10，优选1:0.1～1:5，更优选1:0.1～1:2。
  9. 根据权利要求1-8任一项所述的药物组合物，其特征在于，所述的阿哌沙班纳米颗粒的平均粒径或D50小于500nm，优选小于200nm，进一步优选小于170nm。
  10. 根据权利要求1-9任一项所述的药物组合物，其特征在于，阿哌沙班与部分或全部表面稳定剂共研磨得到包含阿哌沙班纳米颗粒的药物组合物；当阿哌沙班与部分表面稳定剂共研磨时，优选共研磨的表面稳定剂与总的表面稳定剂的重量比选自1:2～1:100，优选1:2～1:50，更优选1:2～1:20，最优选1:3～1:15。
  11. 根据权利要求1-10任一项所述的药物组合物，其特征在于，所述的药物组合物还包含沉降抑制剂。
  12. 根据权利要求11所述的药物组合物，其特征在于，所述沉降抑制剂选自甘露醇、蔗糖、右旋糖酐40、海藻糖、甘油、聚维酮、甘氨酸和羟丙基-β-环糊精中的一种或几种， 优选甘露醇、蔗糖和右旋糖酐40中的一种或几种，更优选甘露醇。
  13. 根据权利要求12所述的药物组合物，其特征在于，所述阿哌沙班纳米颗粒与沉降抑制剂的重量比选自1:0.1～1:100，优选1:0.1～1:50，更优选1:0.5～1:30，最优选1:1～1:30。
  14. 根据权利要求1-13任一项所述的药物组合物，其特征在于，所述药物组合物为冻干药物组合物。
  15. 根据权利要求1-13任一项所述的药物组合物，其特征在于，所述的药物组合物还包含液体介质，所述液体介质优选自水、盐水溶液和红花籽油中的一种或多种，更优选水。
  16. 根据权利要求15所述的药物组合物，其特征在于，阿哌沙班纳米颗粒的含量选自0.1～100mg/mL，优选0.5～100mg/mL，更优选1～100mg/mL，最优选2～10mg/mL。
  17. 一种冻干药物组合物，其由权利要求15或16所述的药物组合物冷冻干燥得到；或所述冻干药物组合物经液体介质复溶后得到权利要求15或16所述的组合物，其中复溶使用的液体介质优选为水。
  18. 一种可注射的药物组合物，其包含阿哌沙班纳米颗粒、第一表面稳定剂、第二表面稳定剂和沉降抑制剂；其中，第一表面稳定剂优选自非离子和/或两性离子表面稳定剂，进一步优选聚维酮、聚乙烯醇、羟丙甲基纤维素、吐温80、泊洛沙姆、15-羟基硬脂酸聚乙二醇酯和卵磷脂中的一种或多种，更优选聚维酮、泊洛沙姆和吐温80中的一种或多种；第二表面稳定剂优选自阴离子表面稳定剂，进一步优选脱氧胆酸钠、胆酸钠和多库酯钠中的一种或多种，更优选脱氧胆酸钠；沉降抑制剂优选自甘露醇、蔗糖、右旋糖酐40、海藻糖、甘油、聚维酮、甘氨酸、羟丙基-β-环糊精中的一种或几种，进一步优选甘露醇、蔗糖和右旋糖酐40中的一种或几种，更优选甘露醇；阿哌沙班纳米颗粒的平均粒径或D50优选小于500nm，优选小于200nm。
  19. 一种药物组合物，其包含阿哌沙班纳米颗粒、聚维酮、脱氧胆酸钠以及甘露醇，阿哌沙班纳米颗粒与聚维酮的重量比优选自1:0.01～1:10；阿哌沙班与脱氧胆酸钠的重量比优选自1:0.01～1:10；阿哌沙班与甘露醇的重量比优选自1:0.1～1:100。
  20. 一种药物组合物，其包含阿哌沙班纳米颗粒、聚维酮、脱氧胆酸钠以及甘露醇，药物组合物中阿哌沙班纳米颗粒的重量体积比优选为0.1-1％，聚维酮的重量体积比优选为0.5-5％，脱氧胆酸钠的重量体积比优选为0.1-3％。
  21. 根据权利要求1-20任一项所述的药物组合物，其特征在于，单位剂量中阿哌沙班纳米颗粒的含量为2.5mg。
  22. 一种药物组合物，其特征在于，所述药物组合物中阿哌沙班纳米颗粒：聚维酮： 脱氧胆酸钠的重量比是10:2:1，优选①包含重量体积比为10％阿哌沙班纳米颗粒、2％聚维酮、1％脱氧胆酸钠的药物组合物，或者②包含重量体积比为5％阿哌沙班纳米颗粒、1％聚维酮、0.5％脱氧胆酸钠的药物组合物。
  23. 根据权利要求20所述的药物组合物，其特征在于，所述组合物①包含重量体积比为0.5％阿哌沙班、0.575％聚维酮、0.2875％脱氧胆酸钠、2.375％甘露醇，或者②包含重量体积比为0.25％阿哌沙班、0.525％聚维酮、0.25％脱氧胆酸钠、5.32％甘露醇。
  24. 一种如权利要求1-22任一项所述的药物组合物的制备方法，其包括：将表面稳定剂与阿哌沙班共研磨制备包含阿哌沙班纳米颗粒的药物组合物。
  25. 一种如权利要求4-10任一项所述的药物组合物的制备方法，包括：将第一表面稳定剂和第二表面稳定剂与阿哌沙班共研磨制备包含阿哌沙班纳米颗粒的药物组合物。
  26. 一种如权利要求11-18任一项所述的药物组合物的制备方法，包括：将表面稳定剂与阿哌沙班共研磨制备包含阿哌沙班纳米颗粒的药物组合物；将沉降抑制剂与前述药物组合物混合，所述的表面稳定剂优选包含第一表面稳定剂和/或第二表面稳定剂。
  27. 一种如权利要求11-18任一项所述的药物组合物的制备方法，其包括：将一部分第一表面稳定剂和一部分第二表面稳定剂与阿哌沙班共研磨制备包括阿哌沙班纳米颗粒的药物组合物；将沉降抑制剂、另一部分第一表面稳定剂、另一部分第二表面稳定剂与前述包括阿哌沙班纳米颗粒的药物组合物混合。
  28. 根据权利要求24-27所述的制备方法，其特征在于，所述的制备方法还进一步包括冻干的步骤。
  29. 一种如权利要求19-23任一项所述的药物组合物的制备方法，其包括将聚维酮和脱氧胆酸钠与阿哌沙班共研磨制备包括阿哌沙班纳米颗粒的药物组合物。
  30. 一种如权利要求19-23任一项所述的药物组合物的制备方法，包括将聚维酮和脱氧胆酸钠与阿哌沙班共研磨制备包括阿哌沙班纳米颗粒的药物组合物，将甘露醇与前述包括阿哌沙班纳米颗粒的药物组合物混合。
  31. 根据权利要求30所述的制备方法，其特征在于，聚维酮和脱氧胆酸钠是分两部分混入组合物中的，一部分聚维酮和脱氧胆酸钠与阿哌沙班共研磨，另一部分聚维酮和脱氧胆酸钠在稀释过程中混入，稀释倍数优选自1-100倍，优选5-50倍，最优选10-30倍。
  32. 一种如权利要求23所述的药物组合物的制备方法，其①由包含10％阿哌沙班纳米颗粒、2％聚维酮、1％脱氧胆酸钠以及水的混悬液与包含2.5％甘露醇、0.5％聚维酮和0.25％脱氧胆酸钠的稀释剂混合稀释，稀释后组合物中阿哌沙班纳米颗粒的含量优选自 0.1～100mg/mL，优选0.5～20mg/mL，更优选1～10mg/mL，最优选5～10mg/mL；或者②由包含5％阿哌沙班、1％聚维酮、0.5％脱氧胆酸钠以及水的混悬液与包含5.6％甘露醇、0.5％聚维酮和0.2368％脱氧胆酸钠的稀释剂混合稀释，稀释后组合物中阿哌沙班纳米颗粒的含量选自0.1～100mg/mL，优选0.5～20mg/mL，更优选1～10mg/mL，最优选1～5mg/mL。
  33. 根据权利要求30-32任一项所述的制备方法，其特征在于，还可以进一步包括将稀释后的药物组合物冻干的步骤。
  34. 如权利要求1-23任一项所述的药物组合物在制备预防或治疗血栓栓塞疾病的药物中的用途。
  35. 如权利要求1-23任一项所述的药物组合物，其特征在于所述药物组合物适于皮下注射给药。
  36. 如权利要求1-23任一项所述的药物组合物，其特征在于所述药物组合物适合每日给药一次。
PCT/CN2019/100558 2018-08-14 2019-08-14 一种可注射的药物组合物及其制备方法 WO2020034989A1 (zh)

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