WO2019192195A1 - 含达比加群酯的药物组合物及其制备方法 - Google Patents

含达比加群酯的药物组合物及其制备方法 Download PDF

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WO2019192195A1
WO2019192195A1 PCT/CN2018/117619 CN2018117619W WO2019192195A1 WO 2019192195 A1 WO2019192195 A1 WO 2019192195A1 CN 2018117619 W CN2018117619 W CN 2018117619W WO 2019192195 A1 WO2019192195 A1 WO 2019192195A1
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pharmaceutical composition
core
kolliphor
acidic
active ingredient
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PCT/CN2018/117619
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English (en)
French (fr)
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董良昶
张世忠
焦艳
张丹勇
赵文芳
石劲敏
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上海汉都医药科技有限公司
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Priority to EP18913737.5A priority Critical patent/EP3777892A4/en
Priority to JP2020554215A priority patent/JP7125790B2/ja
Priority to CN201880091596.7A priority patent/CN111902161B/zh
Priority to US17/043,442 priority patent/US11707455B2/en
Publication of WO2019192195A1 publication Critical patent/WO2019192195A1/zh
Priority to US18/207,751 priority patent/US20230310401A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—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
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • 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
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    • 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
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    • 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
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • 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
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    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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    • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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Definitions

  • the present invention relates to a pharmaceutical composition comprising dabigatran etexilate and a process for the preparation thereof.
  • the chemical name of dabigatran etexilate mesylate is ⁇ -alanine, N-[[2-[[[4-[[hexyloxy)carbonyl]amino]iminomethyl]benzene Amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridyl-ethyl methanesulfonate, empirical formula C 34 H 41 N 7 O 5 ⁇ CH 4 O 3 S, molecular weight 723.86, CAS# 872728-81-9.
  • the structural formula of DEM is:
  • DEM is the pharmaceutically active ingredient (API) of the commercial Pradaxa capsule.
  • API pharmaceutically active ingredient
  • DEM is a prodrug of dabigatran and is a direct inhibitor of thrombin.
  • Pradaxa capsules are marketed by Boehringer Ingelheim, Inc., which is used to reduce the risk of stroke and thrombosis in patients with atrial fibrillation caused by non-heart valve problems, as well as to treat deep vein thrombosis and pulmonary embolism.
  • DEM is a white to pale yellow powder. It is easily soluble in methanol, slightly soluble in isopropanol, and slightly soluble in ethanol. A saturated solution of DEM in pure water has a solubility of 1.8 mg/mL. DEM has a pH-dependent solubility profile with a maximum solubility of >80 mg/mL at pH 1 and is insoluble at neutral pH. The poor solubility of DEM at neutral pH is the main culprit for poor oral absorption and instability.
  • the prior art discloses various methods aimed at increasing the dissolution of DEM.
  • U.S. Patent Application Nos. 20130052262 and 20150366807 disclose pharmaceutical formulations consisting of DEM and inorganic acids.
  • the inorganic acid in the pharmaceutical preparation can increase the solubility in gastric juice, but still cannot solve the precipitation problem of DEM in a neutral medium.
  • the pharmaceutical composition disclosed in U.S. Patent Application No. 20150030680 comprises two types of particles, one having DEM and the other having an organic acid.
  • the organic acid in the pharmaceutical preparation can increase the solubility in gastric juice, but still cannot solve the precipitation problem of DEM in neutral medium.
  • U.S. Patent Application No. 20150366813 discloses a lipophilic pharmaceutical composition comprising an easily hydrolyzable API such as DEM, and the API is suspended in the pharmaceutical composition to prevent the API from contacting moisture and increasing its dissolution.
  • the pharmaceutical composition disclosed in this patent application still does not solve the problem of precipitation of DEM in a neutral medium.
  • US Patent Application No. 20130149346 A1 discloses the use of polyethylene glycol, polyethylene glycol glycerides, block copolymers of ethylene oxide and propylene oxide, hydroxypropyl methylcellulose and polyvinylpyrrolidone as solid solvent DEM solid solutions combination. This patent application does not show how the dissolution profile at neutral pH is, so it is not possible to confirm whether the DEM dissolution of these solid solutions is increased.
  • WO 03/074056 discloses a formulation which achieves immediate release of DEM by the use of tartaric acid to enhance its dissolution in the gastrointestinal tract. As described above, this method is suitable for artificially increasing the pH of the gastric juice by pre-administering the proton pump inhibitor pantoprazole.
  • This pharmaceutical composition known as the commercially available product Pradaxa, is prepared by spraying a sealant composition onto the surface of the tartaric acid core and then spraying a suspension of DEM and a film former onto the sealed tartaric acid core. The sealing layer is used to prevent the interaction between DEM and tartaric acid. Due to the high ratio of API to polymer film former, DEM is predominantly in crystalline form, thus resulting in a dissolution profile that is strongly dependent on pH.
  • the technical problem to be solved by the present invention is to overcome the defect that the pharmaceutical preparation containing dabigatran etexilate in the prior art is prone to precipitation in intestinal juice, and to provide a pharmaceutical composition containing dabigatran etexilate and preparation thereof method.
  • the dissolution profile of the pharmaceutical composition is less affected by the pH of the gastrointestinal fluid and also prevents precipitation of DEM in the intestinal pH of the neutral pH, so the pharmaceutical composition can enhance dabigatran etexilate or a pharmaceutically acceptable salt thereof.
  • Oral absorption increase the bioavailability of the active ingredient of the drug, and also reduce absorption variability while providing a more stable concentration of dabigatran in the plasma, thereby reducing adverse side effects and reducing the likelihood of GIT bleeding; Increased absorption, a significant reduction in unabsorbed DEM in the gastrointestinal tract, which further alleviates GIT major bleeding.
  • the carrier refers to a component other than the pharmaceutically active ingredient
  • the carrier can be rapidly dissolved under the conditions of an aqueous medium and an acidic pH, thereby reducing or even eliminating the possibility of recrystallization of DEM, thereby further promoting the absorption of DEM.
  • the present invention provides a pharmaceutical composition comprising dabigatran etexilate, the pharmaceutical composition comprising a pharmaceutically active ingredient and an amphoteric polymer; wherein the pharmaceutically active ingredient is dabigatran etexilate and/or dabigatran An ester mesylate, the amphoteric polymer is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; and the mass ratio of the pharmaceutically active ingredient to the amphoteric polymer is 1:0.23- 1:3.
  • the pharmaceutically active ingredient is dabigatran etexilate or dabigatran etexilate mesylate.
  • the mass of the pharmaceutically active ingredient in the pharmaceutical composition is preferably from 30 to 180 mg, more preferably from 39.1 to 173 mg.
  • the number of repeating units of vinyl caprolactam in the amphoteric polymer is preferably 57 or less.
  • the number of repeating units of vinyl acetate in the amphoteric polymer is preferably 30 or less.
  • the number of repeating units of polyethylene glycol in the amphoteric polymer is preferably 13 or more.
  • the proportion of the vinyl caprolactam unit is preferably 57%, the proportion of the vinyl acetate unit is preferably 30%, and the proportion of the polyethylene glycol unit is preferably 13%, the percentage is the mole percentage.
  • the polyethylene glycol is preferably polyethylene glycol 6000.
  • the monomers of the amphoteric polymer are preferably polyethylene glycol 6000, vinyl caprolactam and vinyl acetate.
  • the molar ratio of the above three repeating units of polyethylene glycol 6000, vinyl caprolactam and vinyl acetate in the amphoteric polymer is preferably 13:57:30.
  • the molecular weight of the amphoteric polymer is preferably from 90,000 to 140,000 g/mol.
  • the amphoteric polymer preferably has a glass transition temperature of from 69 to 71 °C.
  • the amphoteric polymer is more preferably Said For the commercially available products, the manufacturer is BASF AG.
  • the number of repeating units of the medium vinyl caprolactam is 57 or less,
  • the number of repeating units of vinyl acetate is 30 or less,
  • the number of repeating units of the polyethylene glycol is 13 or more;
  • the repeating unit of the amphoteric polymer is polyethylene glycol 6000, vinyl caprolactam and vinyl acetate, and the above three units of polyethylene glycol 6000, ethylene
  • the molar ratio of caprolactam to vinyl acetate is 13:57:30,
  • the molecular weight is 90000-140000 g/mol (for example 118000 g/mol),
  • the glass transition temperature is about 70 °C.
  • the mass of the pharmaceutically active ingredient and the amphoteric polymer is preferably 1:0.24-1:3, 1:0.3-1:3, 1:0.5-1:3, 1:1.5-1. :3 or 1:1.0-1:2.3, for example 1:0.24, 1:0.25, 1:0.33, 1:0.77, 1:1, 1:1.2, 1:1.5, 1:1.6, 1:2 or 1: 2.3.
  • the pharmaceutical composition may further comprise a hydrophilic polymer, which may be a water-soluble material conventionally used in the art.
  • the mass of the pharmaceutically active ingredient and the hydrophilic polymer is preferably from 1:0.45 to 1:4, more preferably from 1:0.5 to 1:3, for example, 1:12. 1.25, 1:1.9, 1:2, 1:2.5 or 1:2.85.
  • the hydrophilic polymer is preferably a polyoxyethylene polyoxypropylene ether block copolymer, polyvinylpyrrolidone, polyvinylpyrrolidone-co-vinyl acetate, methyl cellulose, hydroxypropyl cellulose, One or more of hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and polyacrylate.
  • the polyoxyethylene polyoxypropylene ether block copolymer is a copolymer formed of polyethylene glycol and polypropylene glycol.
  • the polyoxyethylene polyoxypropylene ether block copolymer is preferably Kolliphor P188 and/or Kolliphor P407.
  • the polyvinylpyrrolidone is preferably PVP K12.
  • the polyvinylpyrrolidone-co-vinyl acetate is preferably Kollidon VA64.
  • the hydroxypropylcellulose is preferably Klucel EF.
  • the hydroxypropyl methylcellulose is preferably HPMC E5 and/or HPMC VLV.
  • the polyacrylate is preferably Eudragit L100.
  • the mass percentage of the pharmaceutically active ingredient in the pharmaceutical composition may be conventional in the art, and may be, for example, 5 wt% to 60 wt%, preferably 10 wt%. %-55 wt%, more preferably 20 wt% to 45 wt%, for example, may be 13.3 wt%, 14.4 wt%, 16.9 wt%, 17.0 wt%, 18.0 wt%, 24.0 wt%, 39.1 wt% or 43.4 wt%.
  • the mass percentage of the amphoteric polymer in the pharmaceutical composition is preferably from 3 wt% to 40 wt%, for example, 3.3 wt%, 6.0 wt. %, 9.2 wt%, 10.0 wt%, 12.8 wt%, 12.9 wt%, 18.6 wt%, 21.3 wt%, 22.5 wt%, 22.8 wt%, 24.3 wt%, 28.3 wt%, 38.8 wt% or 39.2 wt%.
  • the mass percentage of the hydrophilic polymer in the pharmaceutical composition may be conventional in the art, and may be, for example, 10% by weight to 90% by weight, preferably It is 20 wt% to 80 wt%, more preferably 40 wt% to 60 wt%, for example, 16.7 wt%, 19.2 wt%, 19.9 wt%, 22.2 wt%, 26.1 wt%, 27.4 wt%, 27.4 wt%, 29.6 wt. %, 31.0 wt%, 33.3 wt%, 35.9 wt%, 30.0 wt% or 36.0 wt%.
  • the above hydrophilic polymer enhances the dissolution of the pharmaceutically active ingredient in the pharmaceutical composition at an acidic pH, thereby minimizing the potential recrystallization of the pharmaceutically active ingredient dispersed in the pharmaceutical composition in a molecular form.
  • the pharmaceutical composition may further comprise a disintegrator conventionally used in the art, preferably croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium starch glycolate, and cross-linked polycondensation.
  • a disintegrator conventionally used in the art, preferably croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium starch glycolate, and cross-linked polycondensation.
  • One or more of the ketones are more preferably croscarmellose sodium and/or low-substituted hydroxypropylcellulose.
  • the mass percentage of the disintegrant in the pharmaceutical composition may be conventional in the art, and may be, for example, 0 wt% to 5 wt%, but not 0 wt%; preferably 3 wt% to 5 wt%.
  • the pharmaceutical composition may further comprise an antistatic agent conventionally used in the art, preferably one or more of a long-chain alkyl phenol, an ethoxylated amine, a glyceride, and a silica. More preferably, it is silica.
  • the mass percentage of the antistatic agent in the pharmaceutical composition may be conventional in the art, for example, may be 0 wt% to 5 wt%, but not 0 wt%; preferably 0.01 wt% to 3 wt%; Preferably, it is from 0.5 wt% to 2 wt%.
  • an antistatic agent facilitates the spraying and encapsulation of the pharmaceutical composition.
  • the pharmaceutical composition may further comprise a lubricant (also referred to as "glidant”) conventionally used in the art, preferably calcium stearate, glyceryl behenate, stearic acid.
  • a lubricant also referred to as "glidant”
  • a lubricant conventionally used in the art, preferably calcium stearate, glyceryl behenate, stearic acid.
  • a lubricant also referred to as "glidant”
  • a lubricant conventionally used in the art, preferably calcium stearate, glyceryl behenate, stearic acid.
  • a lubricant also referred to as "glidant”
  • magnesium, stearyl fumarate, talc, colloidal silica, magnesium silicate and calcium silicate more preferably magnesium stearate.
  • the mass percentage of the lubricant in the pharmaceutical composition may be conventional in the art, for example, may be 0 wt% to 5 wt%, but not 0 wt%; preferably 0.01 wt% to 3 wt%; more preferably The ground is from 0.5 wt% to 2 wt%.
  • the addition of a lubricant facilitates spray drying or spraying of the pharmaceutical composition, and filling solid particles or pellets comprising the pharmaceutical composition into a capsule.
  • the pharmaceutical composition may further comprise a diluent conventionally used in the art, preferably mannitol and/or lactose monohydrate.
  • the mass percentage of the diluent in the pharmaceutical composition may be conventional in the art, for example, may be 0 wt% to 40 wt%, but not 0 wt%; preferably 9 wt% to 38.3% wt%.
  • the pharmaceutical composition comprises the following components of a mass fraction: 9% to 48% of the pharmaceutically active ingredient, 9% to 44% of the amphoteric polymer, 0%- 53% of the hydrophilic polymer, 0% to 90% of the diluent, 0% to 20% of the disintegrant, 0% to 5% of the antistatic agent and 0%-2 % of the lubricant.
  • the pharmaceutical composition comprises the following components in a mass fraction: 9% to 48% of dabigatran etexilate mesylate, 9% to 44% 0%-30% Kolliphor P407, 0%-23% Kolliphor P188, 0%-58% lactose monohydrate, 0%-32% mannitol, 0%-20% croscarmellose fiber Sodium, 0%-5% silica and 0%-3% magnesium stearate.
  • the pharmaceutical composition comprises the following components in a mass fraction: 13% to 44% of the pharmaceutically active ingredient, 6% to 39% of the amphoteric polymer, 16%- 36% of the hydrophilic polymer, 9% to 39% of the diluent, 5% to 23% of the disintegrant, and 0.4% to 0.5% of the lubricant.
  • the pharmaceutically active ingredient is preferably dabigatran etexilate mesylate.
  • the amphoteric polymer is preferably The hydrophilic polymer is preferably Kolliphor P407 and/or Kolliphor P188.
  • the diluent is preferably lactose monohydrate and/or mannitol.
  • the disintegrant is preferably croscarmellose sodium and/or low substituted hydroxypropylcellulose.
  • the lubricant is preferably magnesium stearate.
  • the pharmaceutical composition comprises the following components in a mass fraction: 16%-19% of the pharmaceutically active ingredient, 21%-43% of the amphoteric polymer, 32%- 58% of the diluent, 5% to 20% of the disintegrant and 0% to 2% of the lubricant. More preferably, the pharmaceutical composition comprises the following components in a mass fraction: 16%-19% dabigatran etexilate mesate, 21%-43% 32%-58% lactose monohydrate, 5%-20% croscarmellose sodium and 0%-2% magnesium stearate.
  • the pharmaceutical composition comprises the following components of a mass fraction: 16% to 18% of the pharmaceutically active ingredient, 26% to 44% of the amphoteric polymer, 17%- 23% of the hydrophilic polymer, 0% to 32% of the diluent, 5% to 20% of the disintegrant, and 0% to 2% of the lubricant. More preferably, the pharmaceutical composition comprises the following components in mass fraction: 16%-18% dabigatran etexilate mesylate, 26%-44% 0%-32% mannitol, 17%-23% Kolliphor P188, 5%-20% croscarmellose sodium and 0%-2% magnesium stearate.
  • the pharmaceutical composition consists of the following components in mass fraction: 17% dabigatran etexilate mesylate, 39.2% 38.3% lactose monohydrate, 5.0% croscarmellose sodium and 0.5% magnesium stearate.
  • the pharmaceutical composition is composed of the following components of mass fraction: 16.9% of dabigatran etexilate mesylate, 38.8% 18.9% mannitol, 19.9% Kolliphor P188, 5.0% croscarmellose sodium and 0.5% magnesium stearate.
  • the pharmaceutical composition consists of the following components in mass fraction: 43.35% dabigatran etexilate mesylate, 10% 9% mannitol, 22.15% Kolliphor P407, 15.0% croscarmellose sodium and 0.5% magnesium stearate.
  • the pharmaceutical composition consists of the following components in mass fraction: 43.35% dabigatran etexilate mesylate, 10% 9% mannitol, 22.15% Kolliphor P407, 15.0% low substituted hydroxypropyl cellulose and 0.5% magnesium stearate.
  • the pharmaceutical composition consists of the following components in mass fraction: 39.1% dabigatran etexilate mesylate, 9.2% 9.2% mannitol, 19.2% Kolliphor P188, 23.0% croscarmellose sodium and 0.4% magnesium stearate.
  • the aforementioned pharmaceutical composition is generally present in the form of a powder, a pellet, a granule, a capsule or a tablet, and in the above dosage form, the pharmaceutically active ingredient may form a solid dispersion together with other components in the pharmaceutical composition.
  • the pharmaceutically active ingredient can also be physically mixed with other components of the pharmaceutical composition to form a homogeneous system.
  • the pharmaceutically active ingredient forms a solid dispersion together with other components in the pharmaceutical composition
  • the preparation method of the powder may be a conventional preparation method in the art.
  • the components in the pharmaceutical composition are dissolved in an organic solvent and spray dried.
  • the method for preparing the powder comprises the steps of dissolving each component in the pharmaceutical composition in an aqueous ethanol solution and spray-drying; wherein the mass fraction of ethanol in the aqueous ethanol solution is 90%. -95%.
  • the percentage of the pharmaceutically active ingredient present in molecularly dispersed form and/or amorphous form may be from 15% by weight to 100% by weight, preferably from 40% by weight to 100% by weight, based on the total mass of the pharmaceutically active ingredient. Preferably, it is from 60% by weight to 100% by weight.
  • the pellet has a core and a drug layer encasing the core, the drug layer referring to a solid dispersion layer of the core formed by the components in the pharmaceutical composition, and formed according to the core thereof
  • the difference in pH of the solution can be further divided into neutral core pellets and acidic core pellets.
  • the neutral core pellet When the pharmaceutical composition is in the form of a neutral core pellet, the neutral core pellet has a neutral core and a drug layer encasing the neutral core, the drug layer referring to the drug combination
  • the solid dispersion layer of the neutral core is formed by the components in the mixture, and the neutral core pellet comprises the following components of the mass fraction: 9%-30% of the pharmaceutically active ingredient 2% to 24% of the amphoteric polymer, 11% to 42% of the hydrophilic polymer and 33% to 77% of the neutral core.
  • the percentage of the pharmaceutically active ingredient present in the molecularly dispersed form and/or the amorphous form to the total mass of the pharmaceutically active ingredient may be from 15% by weight to 100% by weight, preferably from 40% by weight to 100% by weight, more preferably 60 wt% - 100 wt%.
  • the neutral core may be a neutral core used in the preparation of neutral core pellets conventionally used in the art, for example, may be a microcrystalline cellulose core and/or a sugar core.
  • the neutral core is a sugar core.
  • the neutral core pellet comprises the following components of mass fraction: 12%-30% of the pharmaceutically active ingredient, 6%-24% of the amphoteric polymer, 15%- 42% of the hydrophilic polymer and 33%-50% of the neutral core. More preferably, the neutral core pellet comprises the following components of mass fraction: 12% to 30% of dabigatran etexilate mesylate, 6% to 24% 15%-42% Kolliphor P407 and 33%-50% sugar core.
  • the neutral core pellet comprises the following components of a mass fraction: 9%-20% of the pharmaceutically active ingredient, 2%-5% of the amphoteric polymer, 11%- 25% of the hydrophilic polymer and 50% to 77% of the neutral core. More preferably, the neutral core pellet comprises the following components of mass fraction: 9%-20% dabigatran etexilate mesylate, 2%-5% 11%-25% Kolliphor P407 and 50%-77% sugar core.
  • the neutral core pellet comprises the following components of the mass fraction: 13.3%-24% of the pharmaceutically active ingredient, 3.33%-28.27% of the amphoteric polymer, 16.7%- 36% of the hydrophilic polymer and 40%-66.7% of the neutral core.
  • the pharmaceutically active ingredient is preferably dabigatran etexilate mesylate.
  • the amphoteric polymer is preferably The hydrophilic polymer is preferably Kolliphor P407 and/or Kolliphor P188.
  • the neutral core is a sugar core and/or a microcrystalline cellulose core.
  • the pharmaceutical composition is composed of the following components of mass fraction: 18% dabigatran etexilate mesylate, 6% 36% Kolliphor P407 and 40% sugar core.
  • the pharmaceutical composition is composed of the following components of mass fraction: 24% dabigatran etexilate mesylate, 6% 30% Kolliphor P407 and 40% sugar core.
  • the pharmaceutical composition consists of the following components of mass fraction: 13.3% dabigatran etexilate mesylate, 3.33% 16.7% of Kolliphor P407 and 66.7% of sugar cores.
  • the preparation method of the neutral core pellets can be conventional in the art, for example, the components in the pharmaceutical composition are dissolved in an organic solvent and sprayed on the neutral core.
  • the method for preparing the neutral core pellet comprises the steps of: dissolving each component in the pharmaceutical composition in an aqueous ethanol solution and spraying on the neutral core; wherein The mass fraction of ethanol in the aqueous ethanol solution is from 90% to 95%.
  • the acidic core pellet comprises an acidic core, a barrier layer, and a drug layer, the barrier layer coating a surface of the acidic core, the drug layer Covering the surface of the isolation layer; the isolation layer includes And Kolliphor P407.
  • the acidic core may be an acidic core conventionally used in the art, for example, may be a tartaric acid core.
  • the mass percentage of the acidic core in the acidic core pellets may be conventional in the art, preferably from 17% to 36%.
  • the isolation layer is coated on the surface of the acidic core, which means that the components in the separation layer are coated on the surface of the acidic core in a uniformly mixed state.
  • the mass percentage in the acidic core pellets is preferably from 9% to 13%.
  • the mass percentage of Kolliphor P407 in the isolating layer in the acidic core pellet is preferably from 4% to 6%.
  • the drug layer is coated on the surface of the separation layer, which means that each component in the drug layer is coated on the surface of the separation layer in the form of a solid dispersion.
  • the drug layer comprises the pharmaceutically active ingredient, And Kolliphor P407, and the mass percentage of the pharmaceutically active ingredient in the drug layer in the acidic core pellet is 14%-19%, in the drug layer The mass percentage in the acidic core pellet is 12%-17%, and the mass percentage of Kolliphor P407 in the acid core pellet in the drug layer is 22%-29%.
  • the mass percentage of the acidic core in the acidic core pellet is 17% to 36%;
  • the mass percentage in the acidic core pellet is 9%-13%, and the mass percentage of Kolliphor P407 in the isolating layer in the acidic core pellet is 4% to 6%;
  • Pharmaceutical active ingredient, And Kolliphor P407, and the mass percentage of the pharmaceutically active ingredient in the drug layer in the acidic core pellet is 14%-19%, in the drug layer
  • the mass percentage in the acidic core pellet is 12%-17%, and the mass percentage of Kolliphor P407 in the acid core pellet in the drug layer is 22%-29%.
  • the mass percentage of the acidic core in the acidic core pellet is 35.7%;
  • the mass percentage in the acidic core pellet is 9.6%, and the mass percentage of Kolliphor P407 in the separation layer in the acidic core pellet is 4.7%;
  • the drug layer includes the pharmaceutically active ingredient, And Kolliphor P407, and the mass percentage of the pharmaceutically active ingredient in the drug core layer in the acidic core pellet is 14.4%, in the drug layer
  • the mass percentage in the acidic core pellet was 12.9%, and the mass percentage of Kolliphor P407 in the acid core pellet in the drug layer was 22.6%.
  • the preparation method of the granules may be a granulation method conventional in the art, such as wet granulation (wherein the solvent used for the wet granulation is preferably isopropanol ), roll compaction, fluidized bed granulation or hot melt granulation.
  • the pharmaceutically active ingredient is physically mixed with other components in the pharmaceutical composition to form a uniformly mixed system.
  • the pharmaceutically active ingredient can also be combined with other components of the pharmaceutical composition to form a solid dispersion by employing granulation methods conventional in the art.
  • the preparation method of the particles is hot melt granulation, and when the pharmaceutical composition does not contain a lubricant, the preparation method of the particles preferably comprises the following steps:
  • the powder may be mixed with other components in the pharmaceutical composition to form uniform particles.
  • said The powder has a particle size of less than 120 mesh.
  • the mixing temperature is 70-75 °C.
  • the preparation method of the particles is hot melt granulation, and when the pharmaceutical composition comprises a lubricant, the preparation method of the particles preferably comprises the steps of: Smashed The powder is mixed with the other components of the pharmaceutical composition to form uniform granules, which are then mixed with the lubricant.
  • said The powder has a particle size of less than 120 mesh.
  • the mixing temperature is 70-75 °C.
  • the pharmaceutical composition comprises the following components in a mass fraction: 16% to 45% of the pharmaceutically active ingredient, and 9% to 40% of the amphoteric polymerization. 19% to 23% of the hydrophilic polymer, 9% to 20% of the diluent, 4% to 23% of the disintegrant, and 0.4% to 0.5% of the lubricant.
  • the pharmaceutically active ingredient is preferably dabigatran etexilate mesylate.
  • the amphoteric polymer is preferably The hydrophilic polymer is preferably Kolliphor P407 and/or Kolliphor P188.
  • the diluent is preferably lactose monohydrate and/or mannitol.
  • the disintegrant is preferably croscarmellose sodium and/or low substituted hydroxypropylcellulose.
  • the lubricant is preferably magnesium stearate.
  • the pharmaceutical composition may be in the form of a powder, pellets, granules, capsules or tablets.
  • the pharmaceutically active ingredient together with the other components of the pharmaceutical composition form a solid dispersion.
  • the amphoteric polymer in the pharmaceutical composition coexists in the presence of two forms, the first form being a solid dispersion with the pharmaceutically active ingredient and the second form being a solid particle. The form exists.
  • the mass fraction of the amphoteric polymer present in the first form is from 10% to 100%, and not more than 100%, of the total mass of the amphoteric polymer.
  • the solid particles may be a powder of the amphoteric polymer, and may also include the following components in mass fraction: 40%-100% of the amphoteric polymer, 0%-55% of the diluent, 0% to 55% of the hydrophilic polymer, 0% to 20% of the disintegrant, 0% to 5% of the antistatic agent, and 0% to 2% of the lubricant.
  • the solid particles include the following components of a mass fraction: 40% - 100% 0%-55% of Kolliphor P407 and/or Kolliphor P188, 0%-55% of lactose monohydrate and/or mannitol, 0%-20% of croscarmellose sodium, 0%-5% Silica and 0% to 2% magnesium stearate.
  • the solid particles comprise the following components of mass fraction: 40% to 58% of the amphoteric polymer, 0% to 55% of the diluent, and 0% to 55% of the pro An aqueous polymer, 5% to 20% of the disintegrant, 0% to 5% of the antistatic agent, and 0% to 2% of the lubricant.
  • the solid particles comprise the following components of mass fraction: 40%-50% 0%-55% lactose, 5%-20% croscarmellose sodium, 0%-5% silica and 0%-2% magnesium stearate.
  • the solid particles comprise the following components of mass fraction: 40%-50% 0%-55% Kolliphor P407, 5%-20% croscarmellose sodium, 0%-5% silica and 0%-2% magnesium stearate.
  • the solid particles comprise the following components of mass fraction: 41% to 58% 3%-33% mannitol, 13%-26% Kolliphor P407, 5%-20% croscarmellose sodium, 0%-5% silica and 0%-2% hard Magnesium citrate.
  • the solid particles comprise the following components in mass fraction: 41.9%-50% of the amphoteric polymer, 24.7%-51.9% of the diluent, 19.8%-51.9% of the pro- An aqueous polymer, 5.0% to 5.25% of the disintegrant, 0.1% to 1% of the lubricant, and 0.1% to 1% of the antistatic agent.
  • the pharmaceutically active ingredient is preferably dabigatran etexilate mesylate.
  • the amphoteric polymer is preferably The hydrophilic polymer is preferably Kolliphor P407 and/or Kolliphor P188.
  • the diluent is preferably lactose monohydrate and/or mannitol.
  • the disintegrant is preferably croscarmellose sodium and/or low substituted hydroxypropylcellulose.
  • the lubricant is preferably magnesium stearate.
  • the antistatic agent is preferably silica.
  • the mass of the solid particles is from 9% to 35% by mass based on the total mass of the pharmaceutical composition.
  • the solid particles are composed of the following components of mass fraction: 41.88% 51.87% lactose monohydrate, 5.25% croscarmellose sodium, 0.5% magnesium stearate, and 0.5% silica.
  • the solid particles are composed of the following components of mass fraction: 41.88% 51.87% Kolliphor P407, 5.25% croscarmellose sodium, 0.5% magnesium stearate, and 0.5% silica.
  • the solid particles are composed of the following components of mass fraction: 49.5% 24.7% mannitol, 19.8% Kolliphor P407, 5.0% croscarmellose sodium, 0.5% magnesium stearate and 0.5% silica.
  • the preparation method of the solid particles may be a granulation method conventional in the art, such as wet granulation (wherein the solvent used for the wet granulation is preferably isopropanol), Roll compaction, fluidized bed granulation or hot melt granulation.
  • the solid particle is prepared by hot melt granulation.
  • the method for preparing the solid particle preferably comprises the following steps:
  • the powder may be mixed with other components in the raw material of the solid particles to form uniform particles.
  • said The powder has a particle size of less than 120 mesh.
  • the mixing temperature is 70-75 °C.
  • the solid particle is prepared by hot melt granulation.
  • the method for preparing the solid particle preferably comprises the following steps: The powder is mixed with other components in the raw material of the solid particles to form uniform particles, which are then mixed with the lubricant.
  • said The powder has a particle size of less than 120 mesh.
  • the mixing temperature is 70-75 °C.
  • the capsule shell of the capsule contains one or more of the aforementioned powder, the aforementioned pellets and the aforementioned particles.
  • the capsule of the capsule contains the powder, the pellet or the granule.
  • the capsule shell can be a capsule shell conventionally used in the art.
  • the tablet contains one or more of the aforementioned powder, the aforementioned pellets and the aforementioned particles.
  • the tablet contains the powder, the pellets or the granules.
  • the solution or the suspension may be obtained by dispersing the aforementioned powder, the aforementioned pellets and one or more of the foregoing particles.
  • the solution or the suspension is obtained by dispersing the aforementioned pellets.
  • the volume of water in the solution or the suspension may be, for example, 10 to 50 mL.
  • the patient is orally administered in the form of a capsule or a tablet, and the content of the pharmaceutically active ingredient in the capsule or the tablet is capable of producing a maximum dabigaplus of 40-200 ng/mL.
  • Group plasma concentration More preferably, the capsule or the pharmaceutically active ingredient in the tablet is present in an amount to produce a maximum dabigatran plasma concentration of 70-175 ng/mL. Still more preferably, the capsule or the pharmaceutically active ingredient in the tablet is present in an amount to produce a maximum dabigatran plasma concentration of 100-150 ng/mL.
  • the maximum dabigatran plasma concentration can be determined based on a single dose fasting study in healthy volunteers or patients.
  • the invention also provides a method of preparing a pharmaceutical composition.
  • the method of preparing the powder preferably includes the step of dissolving each component in the pharmaceutical composition in ethanol In the aqueous solution, it can be spray dried.
  • the mass fraction of ethanol in the aqueous ethanol solution is 90%-95%
  • the method of preparing the granule preferably comprises the steps of: using isopropyl alcohol as a granulating solvent, the medicinal agent
  • the mixture of the components in the composition is subjected to wet granulation to obtain wet granules; the wet granules are passed through a 20 mesh sieve and dried.
  • the pharmaceutical composition when the pharmaceutical composition does not contain a neutral core and the pharmaceutical composition is present in the form of granules, the pharmaceutical composition more preferably employs hot melt granulation, the method of hot melt granulation preferably comprising The following steps:
  • the method for preparing the particles includes the following steps:
  • the powder may be mixed with other components in the pharmaceutical composition to form uniform particles.
  • said The powder has a particle size of less than 120 mesh.
  • the mixing temperature is 70-75 °C.
  • the method of preparing the granules comprises the steps of:
  • the powder is mixed with the other components of the pharmaceutical composition to form uniform granules, which are then mixed with the lubricant.
  • said The powder has a particle size of less than 120 mesh.
  • the mixing temperature is 70-75 °C.
  • the method of preparing the neutral core pellet preferably comprises the step of combining the drug
  • the coating liquid formed by dissolving the remaining components other than the neutral core in an organic solvent may be sprayed on the neutral core.
  • the neutral core refers to a neutral core after pre-drying, and the moisture content of the pre-dried neutral core is preferably less than 1.0 wt%.
  • the organic solvent is preferably an ethanol solution.
  • the mass fraction of ethanol in the aqueous ethanol solution is preferably from 90% to 95%.
  • the mass percentage of the pharmaceutical composition in the coating liquid is preferably from 20% to 24%.
  • the inlet temperature of the air is preferably 45-60 °C.
  • the temperature of the particles is preferably from 30 to 50 °C.
  • the granules are preferably dried to a moisture content of less than 1.0% by weight.
  • the method of preparing the acidic core pellet preferably comprises the steps of:
  • a coating liquid formed by dissolving each component of the drug layer in an organic solvent may be sprayed onto the acidic particles.
  • the acidic core refers to a pre-dried acidic core, and the pre-dried acidic core preferably has a moisture content of less than 1.0% by weight.
  • the organic solvent is preferably an ethanol solution.
  • the mass fraction of ethanol in the aqueous ethanol solution is preferably from 90% to 95%.
  • the mass percentage of the pharmaceutical composition in the coating liquid is preferably from 20% to 26%.
  • the inlet temperature of the air during the spraying is preferably from 45 to 60 °C.
  • the temperature of the acidic particles is preferably from 30 to 32 ° C during the spraying.
  • the acidic particles are preferably dried to a moisture content of less than 1.0% by weight.
  • the organic solvent is preferably an ethanol solution.
  • the mass fraction of ethanol in the aqueous ethanol solution is preferably from 90% to 95%.
  • the mass percentage of the pharmaceutical composition in the coating liquid is preferably from 20% to 24%.
  • the inlet temperature of the air during the spraying is preferably from 45 to 60 °C.
  • the temperature of the acidic core pellets during the spraying is preferably from 30 to 32 °C.
  • the acidic core pellets are preferably dried to a moisture content of less than 1.0% by weight.
  • the present invention also provides the use of the aforementioned pharmaceutical composition for the preparation of a medicament for treating a thrombus in a patient with atrial fibrillation caused by a stroke and/or a non-heart valve problem caused by a non-heart valve problem.
  • the invention also provides the use of a pharmaceutical composition as described above for the manufacture of a medicament for the treatment of deep vein thrombosis and/or pulmonary embolism.
  • the solid dosage form prepared by the pharmaceutical composition of the present invention should be stable during manufacture and storage.
  • An increase in drug impurities should be prevented during manufacture and during normal storage (25 ° C / 60% RH) and accelerated storage (40 ° C / 75% RH).
  • the impurities in the solid dosage form of the present invention should not exceed the following quality indexes: impurities 1 ⁇ 0.2%, impurities 2 ⁇ 0.5%, impurities 3 ⁇ 0.5%, impurities 4 ⁇ 0.1%, impurities 5 ⁇ 0.6%, impurities 6 ⁇ 0.5%, impurity 7 ⁇ 0.1%, impurity 8 ⁇ 0.25%, impurity 9 ⁇ 0.15%, impurity 10 ⁇ 2.5%, single unknown impurity ⁇ 0.2%, total impurity ⁇ 3.6%.
  • the solid dosage form of the present invention When the solid dosage form of the present invention is stored in a desiccant-containing container (e.g., a plastic bottle), it is stored at about 40 ° C and about 75% relative humidity for 6 months, and each degradation product and/or impurity of the solid dosage form.
  • the water level should meet the requirements of the above quality indicators.
  • the individual and total degradation products and/or impurities are based on the total amount of DEM in the solid dosage form.
  • the type and content of impurities can be determined by methods commonly used in the pharmaceutical field, for example, by high performance liquid chromatography (HPLC).
  • the manufacturer of Eudragit L100 is Evonik Special Chemicals (Shanghai) Co., Ltd.; the manufacturer of Klucel EF is Ashland; the manufacturer of Kollicoat IR is BASF; the manufacturer of Kollidon VA64 is BASF; the manufacturer of Kolliphor P188 is BASF; manufacturer of Kolliphor P407 is BASF; manufacturer of HPMC E5 is DOW; manufacturer of HPMC VLV is DOW; manufacturer of HPMCP HP55 is Samsung Precision Chemical Co., Ltd.; manufacturer of HPMCAS MG is Shin/Etsu; PVP The manufacturer of K12 is Ashland; the manufacturer of PVP K30 is Ashland; The manufacturer is BASF; the manufacturer of croscarmellose sodium is FMC; the manufacturer of low-substituted hydroxypropyl cellulose is Shin/Etsu.
  • the solid particles comprise the following components of mass fraction: 41% - 58% 3%-33% mannitol, 13%-26% Kolliphor P407, 5%-20% croscarmellose sodium, 0%-5% silica and 0%-2% hard Magnesium citrate.
  • the solid particles are composed of the following components of mass fraction: 41% - 58% 3%-33% mannitol, 13%-26% Kolliphor P407, 5%-20% croscarmellose sodium, 0%-5% silica and 0%-2% hard Magnesium citrate.
  • the reagents and starting materials used in the present invention are commercially available.
  • a positive progressive effect of the present invention resides in that the present invention provides a pharmaceutical composition comprising dabigatran etexilate and a process for the preparation thereof.
  • the dissolution profile of the pharmaceutical composition is less affected by the pH of the gastrointestinal fluid and also prevents precipitation of DEM in the intestinal pH of the neutral pH, so the pharmaceutical composition can enhance dabigatran etexilate or a pharmaceutically acceptable salt thereof.
  • Oral absorption increase the bioavailability of the active ingredient of the drug, and also reduce absorption variability while providing a more stable concentration of dabigatran in the plasma, thereby reducing adverse side effects and reducing the likelihood of GIT bleeding; Increased absorption, a significant reduction in unabsorbed DEM in the gastrointestinal tract, which further alleviates GIT major bleeding.
  • the carrier refers to a component other than the pharmaceutically active ingredient
  • the carrier can be rapidly dissolved under the conditions of an aqueous medium and an acidic pH, thereby reducing or even eliminating the possibility of recrystallization of DEM, thereby further promoting the absorption of DEM.
  • Figure 1 shows that the polymer of Example 1 is A plot of the solubility of the pharmaceutically active ingredient of the pharmaceutical composition of the pharmaceutical composition and the control composition over time in a phosphate buffer solution at pH 6.8 and 25 °C.
  • Figure 2 is a graph showing the solubility of a pharmaceutically active ingredient of a pharmaceutical composition of the polymer composition of Eudragit L100 and Kolliphor P407 in Example 1 in a phosphate buffer solution at pH 6.8 and 25 ° C as a function of time. The graph.
  • Fig. 3 is a graph showing the solubility of the pharmaceutically active ingredient of the pharmaceutical composition containing the remaining polymer in Example 1 and the pharmaceutical composition of the control group in phosphate buffer solution at pH 6.8 and 25 °C as a function of time.
  • Figure 4 shows the solubility of the pharmaceutically active ingredient of each SDF of Example 2 and the control group at 60 minutes in a phosphate buffer solution at pH 6.8 and 37 °C.
  • Fig. 5 is a graph showing the dissolution profile of the pharmaceutically active ingredient of each of the SDF and the control group of Example 3 in an acetate buffer solution at pH 4.5 and 37 °C over time.
  • Fig. 6 is a graph showing the dissolution profile of the pharmaceutically active ingredient of each of the SDF and the control group of Example 3 in a phosphate buffer solution at pH 6.8 and 37 °C over time.
  • Figure 7 is a graph showing the dissolution profile of the pharmaceutically active ingredient in each of the pharmaceutical compositions of Example 4 over time in a two-stage dissolution test of pH 4.5 acetate buffer ⁇ pH 6.8 phosphate buffer at 37 °C. .
  • Figure 8 is a graph showing the dissolution profile of the pharmaceutically active ingredient in each of the pharmaceutical compositions of Example 4 over time in a two-stage dissolution test of pH 4.5 acetate buffer ⁇ pH 6.8 phosphate buffer at 37 °C. .
  • Figure 9 is a graph showing the dissolution profile of the pharmaceutically active ingredient in each of the pharmaceutical compositions of Example 4 over time in a two-stage dissolution test of pH 4.5 acetate buffer ⁇ pH 6.8 phosphate buffer at 37 °C. .
  • Figure 11 is a pellet (F1) of Example 5, and a pellet of Example 5.
  • Figure 18 is a dissolution curve of the pellet of Example 11 (F6), a solution or suspension dispersed by pellet F6 (denoted as F6 solution), and Pradaxa Capsules in a two-stage dissolution test of pH 2.0 ⁇ pH 6.8.
  • Figure 19 is a dissolution curve of the pellet (F6) of Example 11, the solution or suspension dispersed by the pellet F6 (denoted as F6 solution), and the Pradaxa Capsules in a two-stage dissolution test of pH 6.0 ⁇ pH 6.8.
  • Eudragit L100 is Evonik Specialty Chemicals (Shanghai) Co., Ltd.
  • Klucel EF is Ashland
  • Kollicoat IR is BASF
  • Kollidon VA64 is BASF
  • the manufacturer is BASF; the manufacturer of Kolliphor P407 is BASF; the manufacturer of HPMC E5 is DOW; the manufacturer of HPMC VLV is DOW; the manufacturer of HPMCP HP55 is Samsung Precision Chemical Co., Ltd.; the manufacturer of HPMCAS MG is Shin/Etsu
  • the manufacturer of PVP K12 is Ashland; the manufacturer of PVP K30 is Ashland;
  • the manufacturer is BASF; the manufacturer of croscarmellose sodium is FMC; the manufacturer of low-substituted hydroxypropyl cellulose is Shin/Etsu.
  • the pH 1.2 solution used was a 0.085 N hydrochloric acid solution; the pH 2.0 solution used was a 0.01 N hydrochloric acid solution; the pH 3.0 solution used was 0.001N hydrochloric acid solution; the solution of pH 6.0 used is 0.000001N hydrochloric acid solution; the solution of pH 4.5 used is 50 mM sodium acetate buffer; the solution of pH 6.8 used is 50 mM sodium phosphate buffer;
  • the alkaline solution used is a mixed solution of sodium hydroxide and sodium phosphate.
  • Example 1 The screening experiment conducted in Example 1 was conducted to find a polymer capable of inhibiting precipitation of DEM at a neutral pH, and the following were the polymers to be used in the screening experiments.
  • the screening experiment includes the following steps:
  • the supernatant was diluted 20 times with a mixed solution of methanol and water (wherein the volume ratio of methanol to water was 1:1).
  • Example 2 is a micro-dissolution experiment for the purpose of evaluating the dissolution behavior of DEM solid dispersion film (SDF).
  • SDF DEM solid dispersion film
  • a DEM SDF containing 3 mg of DEM was prepared in a 20 mL glass vial by solvent evaporation, and then a dissolution test was carried out by adding a dissolution medium at 37 ° C.
  • the specific experimental steps are as follows:
  • step 3 Add the stock solution from step 1 and step 2 to a 20 mL vial according to the volume shown in the table below and mix well to obtain a mixed solution;
  • BN-009058-E is to mix the solution in step 1 into a 95% by volume ethanol solution to obtain a mixed solution; BN-009079-I does not do any treatment in this step.
  • step 8 Centrifuge the sample in step 8 at 12000 rpm for 5 minutes to obtain a supernatant.
  • the supernatant was diluted 20-fold with a mixed solution of methanol and water (wherein the volume ratio of methanol to water was 1:1).
  • the theoretical concentration of DEM in the obtained DEM solution is about 150 ⁇ g/mL.
  • Example 3 is a micro-dissolution experiment for the purpose of evaluating the dissolution behavior of DEM solid dispersion film (SDF) in pH 4.5 sodium acetate buffer and pH 6.8 sodium phosphate buffer.
  • SDF solid dispersion film
  • step 3 Add the stock solution from step 1 and step 2 to a 20 mL vial according to the volume shown in the table below and mix well to obtain a mixed solution;
  • DEM F is to mix the solution in step 1 into 95% ethanol solution to obtain a mixed solution
  • DEM P does not do any treatment in this step
  • the number is DEM F and DEM P is the control group.
  • step 8 Centrifuge the sample in step 8 at 12000 rpm for 5 minutes to obtain a supernatant.
  • the supernatant was diluted 20-fold with a mixed solution of methanol and water (wherein the volume ratio of methanol to water was 1:1).
  • Example 4 is for evaluating the inside of the solid dispersion film and the solid dispersion film. The effect of the amount on dissolution, especially on the precipitation of the drug in a neutral medium at pH 6.8.
  • Example 2 The procedure of Example 2 was repeated in this example to prepare the SDF, except that the dissolution test of SDF was carried out using a two-stage dissolution method in which the first stage was at a solution at pH 4.5 and the second stage was at pH 6.8. The solution.
  • the following table shows the composition of the SDF to be evaluated by the above two-stage dissolution method.
  • the SDF was placed in 18 mL of acetate buffer (pH 4.5 solution); at 10 minutes, 0.4 mL aliquots were taken, then 2 mL of alkaline solution was added to adjust the pH to the target pH of 6.8 (6.5-7.0). An aliquot (0.4 mL) was taken 10 minutes after pH adjustment; the DEM concentration in each aliquot was analyzed.
  • the pellets were prepared by spraying the solid dispersion composition onto a neutral core, and the solid dispersion composition contained 30% by weight of dabigatran etexilate mesylate (DEM), 10% by weight. And 60 wt% of Kolliphor P407.
  • DEM dabigatran etexilate mesylate
  • the specific preparation method is as follows:
  • the solid dispersion composition was dissolved in 95% by weight of ethanol to prepare a coating liquid containing 20% by weight of a solid dispersion composition.
  • the neutral core 300-500 mesh
  • 300 g of a coating liquid containing 60 g of the solid dispersion composition was sprayed to 40 g of pre-drying at a suitable inlet air pressure and an air inlet temperature of 45-60 ° C.
  • the spray speed and atomization pressure are adjusted to maintain the product temperature at 30-50 °C.
  • the coating liquid is exhausted, the product is dried in a fluidized bed until the water content is less than 1.0%, and the target mass ratio of the solid dispersion layer covering the neutral core to the neutral core is 1.5/1.0, that is, The pellet of Example 5.
  • the dissolution profile of pellets containing 173.0 mg DEM was measured using a USP basket two-step process at 100 rpm and 37 °C.
  • the pellets were placed in 500 mL of an acidic medium (pH 2.0 solution) containing different masses (0, 75, 150 and 300 mg).
  • 500 mL of alkaline solution was added to the acidic medium to adjust the pH to 6.8.
  • An aliquot of the sample was taken at 3, 5, 45, 55 and 90 minutes. These aliquots were centrifuged at 12000 rpm for 5 minutes, and the supernatant was diluted 10-fold with a 1/1 volume ratio methanol/water mixed solution for HPLC analysis.
  • Table 7 F1 of Example 5 contains different concentrations Dissolution of time in a medium
  • Example 5 The procedure of Example 5 was repeated to prepare pellets F1, which differed from Example 5 in that the added Solpulus in Example 6 was added in the form of a powder.
  • the Solpulus granules are first ground and passed through a 80 mesh sieve to give 150 mg of Solpulus powder ( ⁇ 80 mesh); subsequently, with 0.5 wt% (based on The powder of the powder (150 mg) was mixed with silica to obtain solid particles; finally, the pellets F1 were mixed with the solid particles to obtain the pellets of Example 6.
  • the pellets F1 prevented the precipitation of DEM eluted in the acidic medium at pH 6.8 as compared to the Pradaxa Pellets pellets. However, it contains The pellet of Example 6 of the powder slowed the dissolution of DEM in an acidic medium.
  • pellets F2 were prepared.
  • IPA isopropyl alcohol
  • pellets (240.3 mg) and solid particles (179.1 mg) were filled into gelatin capsules (#0) to obtain capsules F2-A and F2-B.
  • Example 7 contains different concentrations Dissolution of time in a medium
  • Example 7 The wet granulation step in Example 7 was repeated to prepare a pellet F3 containing DEM.
  • pellets containing DEM (339.3 mg) were filled into gelatin capsules (#0).
  • the pH of the first stage is set to 1.2 or 2.0 or 3.0, respectively, in consideration of the change of the pH value of the stomach (that is, the acidic medium used in the first stage is: pH 1.
  • the solution of 2, the solution of pH 2.0, the solution of pH 3.0), and the rest were the same as the test method of Example 5.
  • the solid particles in the capsule F4 and the particles in the capsule F5 are prepared by a hot melt granulation process.
  • the steps of the hot melt granulation process are as follows:
  • Example 7 The pellets F2 (240.3 mg) of Example 7 and the solid particles (151.5 mg) obtained in the formulation of Table 12 were placed in a gelatin capsule (#0), and the obtained capsule was designated as F4.
  • the formulations of the invention (F4 and F5) eluted significantly faster at acidic pH and less precipitated at neutral pH compared to Pradaxa Capsules.
  • Pradaxa Capsules, F4 and F5 in a solution of pH 2.0, and at 10 min, the mass percentages of DEM eluted were 16.4%, 83.4% and 78.5%, respectively.
  • Pradaxa Capsules, F4 and F5 the mass percentage of DEM dissolved in the solution at pH 6.8 was 5.4%, 39.7% and 47.4%, respectively, at 10 min.
  • the steps of the hot melt granulation process are as follows:
  • the powder will then follow the mass percentages in Table 16
  • the powder was mixed with a component other than magnesium stearate and low-substituted hydroxypropylcellulose in a glass beaker at 70-75 ° C with a stainless steel spatula until uniform particles were formed.
  • the above granules are mixed with magnesium stearate and a low-substituted hydroxypropylcellulose to obtain granules in F11.
  • the granules obtained in the formulation of Table 16 were filled into a gelatin capsule (#0) to obtain a capsule F11.
  • pellets were prepared by spraying a solid dispersion composition onto a neutral core, and the solid dispersion composition was composed of the following mass fractions: 40 wt% dabigatran etexilate mesylate ( DEM), 10wt% And 50 wt% Kolliphor P407.
  • the specific preparation method is as follows:
  • pellets The solid dispersion composition was dissolved in a mixed solution of 90 wt% of ethanol and 10 wt% of deionized water to prepare a coating liquid containing 24 wt% of a solid dispersion composition. Next, the neutral core (300-500 mesh) was pre-dried in a convection oven at 80 ° C until its moisture content was below 1.0%.
  • Powder preparation Solpulus granules were first ground and passed through an 80 mesh screen to obtain Solpulus powder ( ⁇ 80 mesh). The pellets (formulations) of Example 11 were obtained by mixing the drug particles (pellets) with Solpulus powder.
  • the pH of the first stage is set to 2.0 or 6.0, respectively (that is, the acidic medium used in the first stage is: a solution of pH 2.0, a solution of pH 6.0), The rest are the same as the test method of Example 5.
  • the dissolution profile of the pellet P6 was determined by the above test method.
  • pellet P6 was pre-dissolved into 25 mL of deionized water to obtain an F6 solution, and the dissolution profile of the F6 solution was measured by the same method. The results are shown in Table 19, Figure 18 and Figure 19.
  • F6 shows faster dissolution at acidic pH 2 and pH 6 and less precipitation at neutral pH 6.8 compared to Pradaxa Capsules; and F6 can prevent more than 60% in acidic media (pH 2.0). And DEM eluted in 6.0) precipitated at pH 6.8. At room temperature, F6 solution can promote DEM and Dissolution, thereby producing a better precipitation inhibition effect at a neutral pH (pH 6.8).
  • the preparation method of the acidic core pellets is as follows:
  • the release layer composition (in the composition, The mass fraction of 67%, the mass fraction of Kolliphor P407 is 33%) is dissolved in a mixed solution of 95 wt% ethanol and 5 wt% deionized water to prepare a coating liquid, and the quality of the separator composition in the coating liquid The score is 26%.
  • the tartaric acid core (300-500 ⁇ m) was pre-dried in a convection oven at 80 ° C until its moisture content was below 1.0%.
  • the coating solution comprising 20 g of the barrier composition was then applied to 50 g of pre-dried tartaric acid core using a fluid bed granulator with a Wurster insert at a suitable inlet air pressure and air inlet temperature of 35 °C. During the spraying process, adjust the spray speed and atomization pressure to keep the product temperature at 30-32 °C. After the coating solution is exhausted, the product is dried in a fluidized bed until the moisture content is less than 1.0% (if the moisture content does not reach less than 1.0% after drying in a fluidized bed, the secondary drying process in the oven It is necessary) and the target mass ratio of the barrier layer to the tartaric acid core is 0.4/1.0.
  • the coating process of the drug layer composition was the same as described in Example 11, and the drug layer composition was composed of the following components of mass fraction: 28.9 wt% DEM, 25.9 wt% And 45.3 wt% Kolliphor P407; and the target mass ratio of the drug layer to the barrier-coated tartaric acid core is 1.0/1.0.
  • the pH of the first stage is set to 2.0 or 6.0, respectively (that is, the acidic medium used in the first stage is: a solution of pH 2.0, a solution of pH 6.0), The rest are the same as the test method of Example 5.
  • DEM can be quickly dissolved from F7, and F7 can enhance the dissolution rate in an acidic environment (pH 6.0), and 40%-47% of dissolved DEM in an acidic environment (pH 2.0 and pH 6.0). It does not precipitate at neutral pH (pH 6.8).
  • the steps of the hot melt granulation process are as follows:
  • F4 and F5 were packaged in HDPE bottles and placed at a temperature of 40 ° C and a relative humidity of 75% for 6 months.
  • the dissolution behavior of the sample was detected by the two-stage dissolution method of pH2.0 ⁇ pH6.8 as described above.
  • the impurity content of the sample was detected by HPLC method, and the moisture content was detected by Karl Fischer method.
  • the steps of the hot melt granulation process are as follows:
  • the components other than magnesium stearate and additional croscarmellose sodium were mixed in a glass beaker at 70-75 ° C with a stainless steel spatula until uniform particles were formed.
  • the above granules are mixed with magnesium stearate and croscarmellose sodium to obtain granules in F9.
  • the granules obtained in the formulation of Table 24 were filled into a gelatin capsule (#0) to obtain a capsule F9.

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Abstract

一种含达比加群酯的药物组合物及其制备方法，该药物组合物包括药物活性成分达比加群酯和/或达比加群酯甲磺酸盐，以及两性聚合物聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物，且二者的质量比为1:0.23-1:3。该药物组合物不仅可以提高药物活性成分的生物利用度，而且可以降低吸收变异性，提供更稳定的达比加群在血浆中的浓度，从而减轻不良副作用。

Description

含达比加群酯的药物组合物及其制备方法
本申请要求申请日为2018年4月4日的中国专利申请CN201810300259.6的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种含达比加群酯的药物组合物及其制备方法。
背景技术
达比加群酯甲磺酸盐(DEM)的化学名称是β-丙氨酸，N-[[2-[[[4-[[(己氧基)羰基]氨基]亚氨基甲基]苯基]氨基]甲基]-1-甲基-1H-苯并咪唑-5-基]羰基]-N-2-吡啶基-乙酯甲磺酸盐，经验式为C 34H 41N 7O 5·CH 4O 3S，分子量为723.86，CAS#为872728-81-9。DEM的结构式是：
Figure PCTCN2018117619-appb-000001
DEM是商品Pradaxa胶囊的药物活性成分(API)。DEM是达比加群的一种前体药物，是凝血酶的直接抑制剂。Pradaxa胶囊由勃林格殷格翰公司销售，其用于降低非心脏瓣膜问题引起的房颤病人中风和血栓风险，也可用于治疗深静脉血栓和肺栓塞。
DEM是呈白色至淡黄色的粉末。它易溶于甲醇，略溶于异丙醇，微溶于乙醇。DEM在纯水中的饱和溶液具有1.8mg/mL的溶解度。DEM具有pH依赖性的溶解度分布，其在pH为1时的最大溶解度>80mg/mL，在中性pH下不溶。DEM在中性pH下的溶解度差，是其口服吸收差和不稳定的罪魁祸首。
现有技术公开了旨在提高DEM溶出度的各种方法。
美国专利申请20130052262和20150366807公开了由DEM和无机酸组成的药物制剂。该药物制剂中的无机酸，能增加在胃液中的溶解度，但还是不能解决DEM在中性介质中的沉淀问题。
美国专利申请20150030680公开的药物组合物包含两种类型的颗粒，一种颗粒具有DEM，而另一种颗粒具有有机酸。该药物制剂中的有机酸，能增加在胃液中的溶解度，但还是不能解决DEM在中性介质中的沉淀问题。
美国专利申请20150366813公开的亲脂性的药物组合物，该药物组合物包含如DEM的易水解的API，且该API悬浮于该药物组合物中，以防止API接触水分并增加其溶出度。但是，该专利申请公开的药物组合物仍旧不能解决DEM在中性介质中的沉淀问题。
美国专利申请20130149346A1公开了使用聚乙二醇，聚乙二醇甘油酯，环氧乙烷和环氧丙烷的嵌段共聚物，羟丙基甲基纤维素和聚乙烯吡咯烷酮作为固体溶剂的DEM固溶体组合物。该专利申请没有表明在中性pH下的溶出曲线如何，因此不能确认这些固溶体的DEM溶出度是否提高。
WO03/074056公开了一种制剂，其通过使用酒石酸实现DEM的立即释放以增强其在胃肠道中的溶出度。如前所述，这种方法适用于通过预先给药质子泵抑制剂潘托拉唑而人为增加胃液pH值的情形。这种药物组合物，被称为市售产品Pradaxa，通过如下方法制备：将密封层组合物喷到酒石酸核心表面上，然后将DEM和成膜剂的悬浮液喷雾到已密封的酒石酸核心上。密封层用于防止DEM和酒石酸之间的相互作用。由于API与聚合物成膜剂的比值高，DEM主要以晶体形式存在，因此导致其溶出曲线强烈依赖于pH。与不含酒石酸的制剂相比，尽管其口服生物利用度得到改善，但仍然很低，约为3-7％。此外，当口服未采用羟丙基甲基纤维素(HPMC)胶囊壳的丸剂时，Pradaxa的口服生物利用度增加了75％，这表明HPMC胶囊的缓慢溶解会降低溶解在胃液中的DEM的百分比，因此降低了DEM的生物利用度。
即使DEM在酒石酸的作用下易溶解在胃液中，但是溶解的DME在从胃排空到小肠后也可能会沉淀，从而降低其吸收。此外，Dabigatran:how the drug company withheld important analyses(Deborah Cohen,investigations editor,The BMJ，BMJ 2014；349)表明仅使用酒石酸来提高DEM在肠胃液中的溶出度，会导致DEM吸收的巨大变化，其在肠胃液中的最高浓度(C max)范围高达5倍。由于DEM的治疗指数低，变化范围过宽的C max更可能会造成有害的副作用，例如：大出血。为了缓解高血浆DEM浓度引起的潜在的大出血，美国专利8.962,574公开了采用110mg的较低剂量强度，以替代150mg。
发明内容
本发明所要解决的技术问题是为了克服现有技术中的含达比加群酯的药物制剂在肠液中易发生沉淀的缺陷，而提供一种含达比加群酯的药物组合物及其制备方法。该药物组合物的溶出曲线受肠胃液pH的影响较小，还可以避免DEM在中性pH的肠液中发生沉淀，故该药物组合物能够增强达比加群酯或其药学上可接受的盐的口服吸收，提高药物活性成分的生物利用度，还能够降低吸收变异性，同时提供更稳定的达比加群在血浆 中的浓度，从而减轻不良副作用，减少GIT出血的可能性；另外，由于吸收增强，胃肠道中未吸收DEM的显著减少，这样可进一步缓解GIT大出血。当药物活性成分与药物组合物的其他组分共同形成固体分散体时，所有的DEM都预先溶解在载体(载体指的是除药物活性成分之外的其他组分)中，因此无需担心药物的溶出；且载体能够快速在水性介质及酸性pH的条件下快速溶出，因此可以减小甚至消除DEM重结晶的可能性，故进一步促进DEM的吸收。
本发明通过以下技术方案解决上述技术问题：
本发明提供一种含达比加群酯的药物组合物，所述药物组合物包括药物活性成分和两性聚合物；其中，所述药物活性成分为达比加群酯和/或达比加群酯甲磺酸盐，所述两性聚合物为聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物；且所述药物活性成分和所述两性聚合物的质量比为1:0.23-1:3。
本发明中，较佳地，所述药物活性成分为达比加群酯或达比加群酯甲磺酸盐。
本发明中，所述药物组合物中所述药物活性成分的质量较佳地为30-180mg，更佳地为39.1-173mg。
本发明中，所述两性聚合物中乙烯基己内酰胺的重复单元的个数较佳地为57个以下。所述两性聚合物中乙酸乙烯酯的重复单元的个数较佳地为30个以下。所述两性聚合物中聚乙二醇的重复单元个数较佳地为13个以上。所述两性聚合物中，乙烯基己内酰胺单元所占的比例较佳地为57％，乙酸乙烯酯单元所占的比例较佳地为30％，聚乙二醇单元所占的比例较佳地为13％，百分数为摩尔百分数。所述聚乙二醇较佳地为聚乙二醇6000。所述两性聚合物的单体较佳地为聚乙二醇6000、乙烯基己内酰胺和乙酸乙烯酯。所述两性聚合物中上述三种重复单元聚乙二醇6000、乙烯基己内酰胺和乙酸乙烯酯的摩尔比较佳地为13：57：30。所述两性聚合物的分子量较佳地为90000-140000g/mol。所述两性聚合物的玻璃化转变温度较佳地为69-71℃。所述两性聚合物更佳地为
Figure PCTCN2018117619-appb-000002
所述
Figure PCTCN2018117619-appb-000003
为市售可得的产品，其生产厂家为巴斯夫股份公司。所述
Figure PCTCN2018117619-appb-000004
为聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物；所述
Figure PCTCN2018117619-appb-000005
中乙烯基己内酰胺的重复单元的个数为57个以下，所述
Figure PCTCN2018117619-appb-000006
中乙酸乙烯酯的重复单元的个数为30个以下，所述
Figure PCTCN2018117619-appb-000007
中聚乙二醇的重复单元个数为13个以上；所述两性聚合物的重复单元为聚乙二醇6000、乙烯基己内酰胺和乙酸乙烯酯，且上述三种单元聚乙二醇6000、乙烯基己内酰胺和乙酸乙烯酯的摩尔比为13：57：30，所述
Figure PCTCN2018117619-appb-000008
的分子量为90000-140000g/mol(例如118000g/mol)，所述
Figure PCTCN2018117619-appb-000009
的玻璃化转变温度约为70℃。
本发明中，所述药物活性成分和所述两性聚合物的质量比较佳地为1:0.24-1:3、 1:0.3-1:3、1:0.5-1:3、1:1.5-1:3或1:1.5-1:2.3，例如1:0.24、1:0.25、1:0.33、1:0.77、1:1、1:1.2、1:1.5、1:1.6、1:2或1:2.3。
本发明中，所述药物组合物中还可包含亲水性聚合物，所述亲水性聚合物可为本领域常规使用的水溶性材料。
其中，所述药物活性成分和所述亲水性聚合物的质量比较佳地为1:0.45-1:4，更佳地为1:0.5-1:3，例如可为1:1.2、1:1.25、1:1.9、1:2、1:2.5或1:2.85。
其中，所述亲水性聚合物较佳地为聚氧乙烯聚氧丙烯醚嵌段共聚物、聚乙烯吡咯烷酮、聚乙烯吡咯烷酮-共-乙酸乙烯酯、甲基纤维素、羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素和聚丙烯酸酯中的一种或多种。此处需要说明的是，所述聚氧乙烯聚氧丙烯醚嵌段共聚物是由聚乙二醇和聚丙二醇形成的共聚物。所述聚氧乙烯聚氧丙烯醚嵌段共聚物较佳地为Kolliphor P188和/或Kolliphor P407。所述聚乙烯吡咯烷酮较佳地为PVP K12。所述聚乙烯吡咯烷酮-共-乙酸乙烯酯较佳地为Kollidon VA64。所述羟丙基纤维素较佳地为Klucel EF。所述羟丙基甲基纤维素较佳地为HPMC E5和/或HPMC VLV。所述聚丙烯酸酯较佳地为Eudragit L100。
当所述药物组合物中包含亲水性聚合物时，所述药物活性成分在所述药物组合物中的质量百分比可为本领域常规，例如可为5wt％-60wt％，较佳地为10wt％-55wt％，更佳地为20wt％-45wt％，例如可为13.3wt％、14.4wt％、16.9wt％、17.0wt％、18.0wt％、24.0wt％、39.1wt％或43.4wt％。
当所述药物组合物中包含亲水性聚合物时，所述两性聚合物在所述药物组合物中的质量百分比较佳地为3wt％-40wt％，例如可为3.3wt％、、6.0wt％、9.2wt％、10.0wt％、12.8wt％、12.9wt％、18.6wt％、21.3wt％、22.5wt％、22.8wt％、24.3wt％、28.3wt％、38.8wt％或39.2wt％。
当所述药物组合物中包含亲水性聚合物时，所述亲水性聚合物在所述药物组合物中的质量百分比可为本领域常规，例如可为10wt％-90wt％，较佳地为20wt％-80wt％，更佳地为40wt％-60wt％，例如可为16.7wt％、19.2wt％、19.9wt％、22.2wt％、26.1wt％、27.4wt％、27.4wt％、29.6wt％、31.0wt％、33.3wt％、35.9wt％、30.0wt％或36.0wt％。
上述亲水性聚合物会增强药物组合物中药物活性成分在酸性pH下的溶出，进而使得以分子形式分散在药物组合物中的药物活性成分的潜在再结晶降至最低。
本发明中，所述药物组合物中还可包含本领域常规使用的崩解剂，较佳地为交联羧甲基纤维素钠、低取代羟丙纤维素、羟基乙酸淀粉钠和交联聚维酮中的一种或多种，更佳地为交联羧甲基纤维素钠和/或低取代羟丙纤维素。
其中，所述崩解剂在所述药物组合物中的质量百分比可为本领域常规，例如可为0wt％-5wt％，但不为0wt％；较佳地为3wt％-5wt％。
本发明中，所述药物组合物中还可包含本领域常规使用的抗静电剂，较佳地为长链烷基酚、乙氧基化胺、甘油酯和二氧化硅中的一种或多种，更佳地为二氧化硅。
其中，所述抗静电剂在所述药物组合物中的质量百分比可为本领域常规，例如可为0wt％-5wt％，但不为0wt％；较佳地为0.01wt％-3wt％；更佳地为0.5wt％-2wt％。抗静电剂的加入利于该药物组合物的喷涂以及包封。
本发明中，所述药物组合物中还可包含本领域常规使用的润滑剂(又可称为“助流剂”)，较佳地为硬脂酸钙、山嵛酸甘油酯、硬脂酸镁、硬脂富马酸钠、滑石粉、胶体二氧化硅、硅酸镁和硅酸钙中的一种或多种，更佳地为硬脂酸镁。
其中，所述润滑剂在所述药物组合物中的质量百分比可为本领域常规，例如可为0wt％-5wt％，但不为0wt％；较佳地为0.01wt％-3wt％；更佳地为0.5wt％-2wt％。润滑剂的加入利于该药物组合物的喷雾干燥或喷涂，以及将包含该药物组合物的固体颗粒或微丸填充到胶囊中。
本发明中，所述药物组合物中还可包含本领域常规使用的稀释剂，较佳地为甘露醇和/或乳糖一水合物。
其中，所述稀释剂在所述药物组合物中的质量百分比可为本领域常规，例如可为0wt％-40wt％，但不为0wt％；较佳地为9wt％-38.3wt％。
本发明中，较佳地，所述药物组合物包括下述质量分数的各组分：9％-48％的所述药物活性成分、9％-44％的所述两性聚合物、0％-53％的所述亲水性聚合物、0％-90％的所述稀释剂、0％-20％的所述崩解剂、0％-5％的所述抗静电剂和0％-2％的所述润滑剂。更佳地，所述药物组合物包括下述质量分数的各组分：9％-48％的达比加群酯甲磺酸盐、9％-44％的
Figure PCTCN2018117619-appb-000010
0％-30％的Kolliphor P407、0％-23％的Kolliphor P188、0％-58％的乳糖一水合物、0％-32％的甘露醇、0％-20％的交联羧甲基纤维素钠、0％-5％的二氧化硅和0％-3％的硬脂酸镁。
本发明中，较佳地，所述药物组合物包括下述质量分数的各组分：13％-44％的所述药物活性成分、6％-39％的所述两性聚合物、16％-36％的所述亲水性聚合物、9％-39％的所述稀释剂、5％-23％的所述崩解剂和0.4％-0.5％的所述润滑剂。所述药物活性成分较佳地为达比加群酯甲磺酸盐。所述两性聚合物较佳地为
Figure PCTCN2018117619-appb-000011
所述亲水性聚合物较佳地为Kolliphor P407和/或Kolliphor P188。所述稀释剂较佳地为乳糖一水合物和/或甘露醇。所述崩解剂较佳地为交联羧甲基纤维素钠和/或低取代羟丙纤维素。所述润滑剂较佳地为 硬脂酸镁。
本发明中，较佳地，所述药物组合物包括下述质量分数的各组分：16％-19％的所述药物活性成分、21％-43％的所述两性聚合物、32％-58％的所述稀释剂、5％-20％的所述崩解剂和0％-2％的所述润滑剂。更佳地，所述药物组合物包括下述质量分数的各组分：16％-19％的达比加群酯甲磺酸盐、21％-43％的
Figure PCTCN2018117619-appb-000012
32％-58％的乳糖一水合物、5％-20％的交联羧甲基纤维素钠和0％-2％的硬脂酸镁。
本发明中，较佳地，所述药物组合物包括下述质量分数的各组分：16％-18％的所述药物活性成分、26％-44％的所述两性聚合物、17％-23％的所述亲水性聚合物、0％-32％的所述稀释剂、5％-20％的所述崩解剂和0％-2％的所述润滑剂。更佳地，所述药物组合物包括下述质量分数的各组分：16％-18％的达比加群酯甲磺酸盐、26％-44％的
Figure PCTCN2018117619-appb-000013
0％-32％的甘露醇、17％-23％的Kolliphor P188、5％-20％的交联羧甲基纤维素钠和0％-2％的硬脂酸镁。
在本发明一较佳实施方式中，所述药物组合物由下述质量分数的各组分组成：17％的达比加群酯甲磺酸盐、39.2％的
Figure PCTCN2018117619-appb-000014
38.3％的乳糖一水合物、5.0％的交联羧甲基纤维素钠和0.5％的硬脂酸镁。
在本发明一较佳实施方式中，所述药物组合物由下述质量分数的各组分组成：16.9％的达比加群酯甲磺酸盐、38.8％的
Figure PCTCN2018117619-appb-000015
18.9％的甘露醇、19.9％的Kolliphor P188、5.0％的交联羧甲基纤维素钠和0.5％的硬脂酸镁。
在本发明一较佳实施方式中，所述药物组合物由下述质量分数的各组分组成：43.35％的达比加群酯甲磺酸盐、10％的
Figure PCTCN2018117619-appb-000016
9％的甘露醇、22.15％的Kolliphor P407、15.0％的交联羧甲基纤维素钠和0.5％的硬脂酸镁。
在本发明一较佳实施方式中，所述药物组合物由下述质量分数的各组分组成：43.35％的达比加群酯甲磺酸盐、10％的
Figure PCTCN2018117619-appb-000017
9％的甘露醇、22.15％的Kolliphor P407、15.0％的低取代羟丙纤维素和0.5％的硬脂酸镁。
在本发明一较佳实施方式中，所述药物组合物由下述质量分数的各组分组成：39.1％的达比加群酯甲磺酸盐、9.2％的
Figure PCTCN2018117619-appb-000018
9.2％的甘露醇、19.2％的Kolliphor P188、23.0％的交联羧甲基纤维素钠和0.4％的硬脂酸镁。
本发明中，前述的药物组合物一般以如下形式存在：粉末、微丸、颗粒、胶囊或片剂，在上述剂型中，药物活性成分可与药物组合物中的其他组分共同形成固体分散体，药物活性成分也可与药物组合物中的其他组分经物理混合后形成混合均匀的体系。
当所述药物组合物以粉末的形式存在时，所述药物活性成分与所述药物组合物中的 其他组分共同形成固体分散体，所述粉末的制备方法可为本领域常规的制备方法，例如：将所述药物组合物中的各组分溶解在有机溶剂中，喷雾干燥即可。较佳地，所述粉末的制备方法包括如下步骤：将所述药物组合物中的各组分溶解在乙醇水溶液中，喷雾干燥即可；其中，所述乙醇水溶液中乙醇的质量分数为90％-95％。所述粉末中，以分子分散形式和/或无定型形式存在的药物活性成分占所述药物活性成分的总质量的百分比可为15wt％-100wt％，较佳地为40wt％-100wt％，更佳地为60wt％-100wt％。
微丸具有核心和包裹所述核心的药物层，所述药物层指的是所述药物组合物中的各组分共同形成的包覆所述核心的固体分散体层，且根据其核心所形成的溶液的pH值的不同又可分为中性核心微丸和酸性核心微丸。
当所述药物组合物以中性核心微丸的形式存在时，所述中性核心微丸具有中性核心和包裹所述中性核心的药物层，所述药物层指的是所述药物组合物中的各组分共同形成的包覆所述中性核心的固体分散体层，所述中性核心微丸包括下述质量分数的各组分：9％-30％的所述药物活性成分、2％-24％的所述两性聚合物、11％-42％的所述亲水性聚合物和33％-77％的所述中性核心。
其中，以分子分散形式和/或无定型形式存在的药物活性成分占所述药物活性成分的总质量的百分比可为15wt％-100wt％，较佳地为40wt％-100wt％，更佳地为60wt％-100wt％。
其中，所述中性核心可为本领域常规使用的制备中性核心微丸时所用的中性核心，例如可为微晶纤维素芯和/或糖芯。较佳地，所述中性核心为糖芯。
其中，较佳地，所述中性核心微丸包括下述质量分数的各组分：12％-30％的所述药物活性成分、6％-24％的所述两性聚合物、15％-42％的所述亲水性聚合物和33％-50％的所述中性核心。更佳地，所述中性核心微丸包括下述质量分数的各组分：12％-30％的达比加群酯甲磺酸盐、6％-24％的
Figure PCTCN2018117619-appb-000019
15％-42％的Kolliphor P407和33％-50％的糖芯。
其中，较佳地，所述中性核心微丸包括下述质量分数的各组分：9％-20％的所述药物活性成分、2％-5％的所述两性聚合物、11％-25％的所述亲水性聚合物和50％-77％的所述中性核心。更佳地，所述中性核心微丸包括下述质量分数的各组分：9％-20％的达比加群酯甲磺酸盐、2％-5％的
Figure PCTCN2018117619-appb-000020
11％-25％的Kolliphor P407和50％-77％的糖芯。
其中，较佳地，所述中性核心微丸包括下述质量分数的各组分：13.3％-24％的所述药物活性成分、3.33％-28.27％的所述两性聚合物、16.7％-36％的所述亲水性聚合物和40％-66.7％的所述中性核心。所述药物活性成分较佳地为达比加群酯甲磺酸盐。所述两性聚合物较佳地为
Figure PCTCN2018117619-appb-000021
所述亲水性聚合物较佳地为Kolliphor P407和/或Kolliphor  P188。所述中性核心为糖芯和/或微晶纤维素芯。
在本发明一较佳实施方式中，所述药物组合物由下述质量分数的各组分组成：18％的达比加群酯甲磺酸盐、6％的
Figure PCTCN2018117619-appb-000022
36％的Kolliphor P407和40％的糖芯。
在本发明一较佳实施方式中，所述药物组合物由下述质量分数的各组分组成：24％的达比加群酯甲磺酸盐、6％的
Figure PCTCN2018117619-appb-000023
30％的Kolliphor P407和40％的糖芯。
在本发明一较佳实施方式中，所述药物组合物由下述质量分数的各组分组成：13.3％的达比加群酯甲磺酸盐、3.33％的
Figure PCTCN2018117619-appb-000024
16.7％的Kolliphor P407和66.7％的糖芯。
其中，所述中性核心微丸的制备方法可为本领域常规，例如：将所述药物组合物中的各组分溶解在有机溶剂中，喷涂于所述中性核心上即可。较佳地，所述中性核心微丸的制备方法包括如下步骤：将所述药物组合物中的各组分溶解在乙醇水溶液中，喷涂于所述中性核心上即可；其中，所述乙醇水溶液中乙醇的质量分数为90％-95％。
当所述药物组合物以酸性核心微丸的形式存在时，所述酸性核心微丸包括酸性核心、隔离层及药物层，所述隔离层包覆于所述酸性核心的表面，所述药物层包覆于所述隔离层的表面；所述隔离层包括
Figure PCTCN2018117619-appb-000025
和Kolliphor P407。
其中，所述酸性核心可为本领域常规使用的酸性核心，例如可为酒石酸核心。
其中，所述酸性核心在所述酸性核心微丸中的质量百分比可为本领域常规，较佳地为17％-36％。
其中，所述隔离层包覆于所述酸性核心表面，指的是所述隔离层中的各组分以均匀混合的状态包覆于所述酸性核心表面。所述隔离层中的
Figure PCTCN2018117619-appb-000026
在所述酸性核心微丸中的质量百分比较佳地为9％-13％。所述隔离层中的Kolliphor P407在所述酸性核心微丸中的质量百分比较佳地为4％-6％。
其中，所述药物层包覆于所述隔离层的表面，指的是所述药物层中的各组分以固体分散体的形式包覆于所述隔离层表面。较佳地，所述药物层包括所述药物活性成分、
Figure PCTCN2018117619-appb-000027
和Kolliphor P407，且所述药物层中的所述药物活性成分在所述酸性核心微丸中的质量百分比为14％-19％，所述药物层中的
Figure PCTCN2018117619-appb-000028
在所述酸性核心微丸中的质量百分比为12％-17％，所述药物层中的Kolliphor P407在所述酸性核心微丸中的质量百分比为22％-29％。
其中，较佳地，所述酸性核心在所述酸性核心微丸中的质量百分比为17％-36％；所述隔离层中的
Figure PCTCN2018117619-appb-000029
在所述酸性核心微丸中的质量百分比为9％-13％，所述隔离层中的Kolliphor P407在所述酸性核心微丸中的质量百分比为4％-6％；所述药物层包括所述药物活性成分、
Figure PCTCN2018117619-appb-000030
和Kolliphor P407，且所述药物层中的所述药物活性成分在所述 酸性核心微丸中的质量百分比为14％-19％，所述药物层中的
Figure PCTCN2018117619-appb-000031
在所述酸性核心微丸中的质量百分比为12％-17％，所述药物层中的Kolliphor P407在所述酸性核心微丸中的质量百分比为22％-29％。
在本发明一较佳实施方式中，所述酸性核心在所述酸性核心微丸中的质量百分比为35.7％；所述隔离层中的
Figure PCTCN2018117619-appb-000032
在所述酸性核心微丸中的质量百分比为9.6％，所述隔离层中的Kolliphor P407在所述酸性核心微丸中的质量百分比为4.7％；所述药物层包括所述药物活性成分、
Figure PCTCN2018117619-appb-000033
和Kolliphor P407，且所述药物层中的所述药物活性成分在所述酸性核心微丸中的质量百分比为14.4％，所述药物层中的
Figure PCTCN2018117619-appb-000034
在所述酸性核心微丸中的质量百分比为12.9％，所述药物层中的Kolliphor P407在所述酸性核心微丸中的质量百分比为22.6％。
当所述药物组合物以颗粒形式存在时，所述颗粒的制备方法可为本领域常规的制粒方法，例如湿法制粒(其中，所述湿法制粒采用的溶剂较佳地为异丙醇)、辊压制粒、流化床制粒或热熔制粒。通过上述制粒方法制得的颗粒中，药物活性成分与药物组合物中的其他组分经物理混合后形成混合均匀的体系。当然，为了使得所述药物组合物以颗粒的形式存在，也可通过采用本领域常规的制粒方法使得药物活性成分与药物组合物中的其他组分共同形成固体分散体。
其中，较佳地，所述颗粒的制备方法为热熔制粒，当所述药物组合物不包含润滑剂时，所述颗粒的制备方法较佳地包括如下步骤：将
Figure PCTCN2018117619-appb-000035
粉末与所述药物组合物中的其他组分混合以形成均匀的颗粒即可。较佳地，所述
Figure PCTCN2018117619-appb-000036
粉末的粒径小于120目。较佳地，所述混合的温度为70-75℃。
其中，较佳地，所述颗粒的制备方法为热熔制粒，当所述药物组合物包含润滑剂时，所述颗粒的制备方法较佳地包括如下步骤：将所述药物组合物中的
Figure PCTCN2018117619-appb-000037
粉碎后所得的
Figure PCTCN2018117619-appb-000038
粉末与所述药物组合物中的其他组分混合以形成均匀的颗粒后，再与所述润滑剂混合即可。较佳地，所述
Figure PCTCN2018117619-appb-000039
粉末的粒径小于120目。较佳地，所述混合的温度为70-75℃。
当采用前述的热熔制粒时，较佳地，所述药物组合物包括如下质量分数的各组分：16％-45％的所述药物活性成分、9％-40％的所述两性聚合物、19％-23％的所述亲水性聚合物、9％-20％的所述稀释剂、4％-23％的所述崩解剂和0.4％-0.5％的所述润滑剂。所述药物活性成分较佳地为达比加群酯甲磺酸盐。所述两性聚合物较佳地为
Figure PCTCN2018117619-appb-000040
所述亲水性聚合物较佳地为Kolliphor P407和/或Kolliphor P188。所述稀释剂较佳地为乳糖一水合物和/或甘露醇。所述崩解剂较佳地为交联羧甲基纤维素钠和/或低取代羟丙纤维素。所述 润滑剂较佳地为硬脂酸镁。
如前所述，所述药物组合物可以粉末、微丸、颗粒、胶囊或片剂形式存在。较佳地，所述药物活性成分与所述药物组合物中的其他组分共同形成固体分散体。更佳地，所述药物组合物中的所述两性聚合物以以下两种存在形式并存，第一种存在形式是与所述药物活性成分形成固体分散体，第二种存在形式是以固体颗粒的形式存在。
其中，较佳地，以所述第一种形式存在的两性聚合物的质量分数占所述两性聚合物的总质量的10％-100％，且不为100％。
其中，所述固体颗粒可为所述两性聚合物的粉末，也可包括如下质量分数的各组分：40％-100％的所述两性聚合物、0％-55％的所述稀释剂、0％-55％的所述亲水性聚合物、0％-20％的所述崩解剂、0％-5％的所述抗静电剂和0％-2％的所述润滑剂。具体地，所述固体颗粒包括下述质量分数的各组分：40％-100％的
Figure PCTCN2018117619-appb-000041
0％-55％的Kolliphor P407和/或Kolliphor P188、0％-55％的乳糖一水合物和/或甘露醇、0％-20％的交联羧甲基纤维素钠、0％-5％的二氧化硅和0％-2％的硬脂酸镁。
较佳地，所述固体颗粒包括下述质量分数的各组分：40％-58％的所述两性聚合物、0％-55％的所述稀释剂、0％-55％的所述亲水性聚合物、5％-20％的所述崩解剂、0％-5％的所述抗静电剂和0％-2％的所述润滑剂。
更佳地，所述固体颗粒包括下述质量分数的各组分：40％-50％的
Figure PCTCN2018117619-appb-000042
0％-55％的乳糖、5％-20％的交联羧甲基纤维素钠、0％-5％的二氧化硅和0％-2％的硬脂酸镁。
更佳地，所述固体颗粒包括下述质量分数的各组分：40％-50％的
Figure PCTCN2018117619-appb-000043
0％-55％的Kolliphor P407、5％-20％的交联羧甲基纤维素钠、0％-5％的二氧化硅和0％-2％的硬脂酸镁。
更佳地，所述固体颗粒包括下述质量分数的各组分：41％-58％的
Figure PCTCN2018117619-appb-000044
3％-33％的甘露醇、13％-26％的Kolliphor P407、5％-20％的交联羧甲基纤维素钠、0％-5％的二氧化硅和0％-2％的硬脂酸镁。
更佳地，所述固体颗粒包括下述质量分数的各组分：41.9％-50％的所述两性聚合物、24.7％-51.9％的所述稀释剂、19.8％-51.9％的所述亲水性聚合物、5.0％-5.25％的所述崩解剂、0.1％-1％的所述润滑剂和0.1％-1％的所述抗静电剂。所述药物活性成分较佳地为达比加群酯甲磺酸盐。所述两性聚合物较佳地为
Figure PCTCN2018117619-appb-000045
所述亲水性聚合物较佳地为Kolliphor P407和/或Kolliphor P188。所述稀释剂较佳地为乳糖一水合物和/或甘露醇。所述崩解剂较佳地为交联羧甲基纤维素钠和/或低取代羟丙纤维素。所述润滑剂较佳地为硬脂酸镁。所述抗静电剂较佳地为二氧化硅。
其中，较佳地，所述固体颗粒的质量占所述药物组合物的总质量的质量百分比为9％-35％。
在本发明一较佳实施方式中，所述固体颗粒由如下质量分数的各组分组成：41.88％的
Figure PCTCN2018117619-appb-000046
51.87％的乳糖一水合物、5.25％的交联羧甲基纤维素钠、0.5％的硬脂酸镁和0.5％的二氧化硅。
在本发明一较佳实施方式中，所述固体颗粒由如下质量分数的各组分组成：41.88％的
Figure PCTCN2018117619-appb-000047
51.87％的Kolliphor P407、5.25％的交联羧甲基纤维素钠、0.5％的硬脂酸镁和0.5％的二氧化硅。
在本发明一较佳实施方式中，所述固体颗粒由如下质量分数的各组分组成：49.5％的
Figure PCTCN2018117619-appb-000048
24.7％的甘露醇、19.8％的Kolliphor P407、5.0％的交联羧甲基纤维素钠、0.5％的硬脂酸镁和0.5％的二氧化硅。
其中，当所述固体颗粒包含辅料(此处的辅料指的是除
Figure PCTCN2018117619-appb-000049
之外的其他组分)时，所述固体颗粒的制备方法可为本领域常规的制粒方法，例如湿法制粒(其中，所述湿法制粒所用的溶剂较佳地为异丙醇)、辊压制粒、流化床制粒或热熔制粒。
其中，较佳地，所述固体颗粒的制备方法为热熔制粒，当所述固体颗粒不包含润滑剂时，所述固体颗粒的制备方法较佳地包括如下步骤：将
Figure PCTCN2018117619-appb-000050
粉末与所述固体颗粒的原料中的其他组分混合以形成均匀的颗粒即可。较佳地，所述
Figure PCTCN2018117619-appb-000051
粉末的粒径小于120目。较佳地，所述混合的温度为70-75℃。
其中，较佳地，所述固体颗粒的制备方法为热熔制粒，当所述固体颗粒不包含润滑剂时，所述固体颗粒的制备方法较佳地包括如下步骤：将
Figure PCTCN2018117619-appb-000052
粉末与所述固体颗粒的原料中的其他组分混合以形成均匀的颗粒，再与所述润滑剂混合即可。较佳地，所述
Figure PCTCN2018117619-appb-000053
粉末的粒径小于120目。较佳地，所述混合的温度为70-75℃。
当所述药物组合物以胶囊的形式存在，所述胶囊的胶囊壳内含有前述的粉末、前述的微丸和前述的颗粒中的一种或多种。较佳地，所述胶囊剂的胶囊壳内含有所述粉末、所述微丸或所述颗粒。其中，所述的胶囊壳可为本领域常规使用的胶囊壳。
当所述药物组合物以片剂的形式存在，所述片剂含有前述的粉末、前述的微丸和前述的颗粒中的一种或多种。较佳地，所述片剂含有所述粉末、所述微丸或所述颗粒。
本发明中，可以溶液或混悬液的形式给患者口服，且所述溶液或所述混悬液由前述的粉末、前述的微丸和前述的颗粒中的一种或多种分散后所得。较佳地，所述溶液或所述混悬液由前述的微丸分散后所得。其中，所述溶液或所述混悬液中的水的体积例如可为10-50mL。
本发明中，较佳地，以胶囊剂或片剂的形式给患者口服，且所述胶囊剂或所述片剂中的药物活性成分的含量须能够产生40-200ng/mL的最大达比加群血浆浓度。更佳地，所述胶囊剂或所述片剂中的药物活性成分的含量须能够产生70-175ng/mL的最大达比加群血浆浓度。进一步更佳地，所述胶囊剂或所述片剂中的药物活性成分的含量须能够产生100-150ng/mL的最大达比加群血浆浓度。所述最大达比加群血浆浓度可以基于健康志愿者或患者中的单剂量禁食研究来确定。
本发明还提供一种药物组合物的制备方法。
当所述药物组合物不含中性核心，且所述药物组合物以粉末形式存在时，所述粉末的制备方法较佳地包括如下步骤：所述药物组合物中的各组分溶解在乙醇水溶液中，喷雾干燥即可。
其中，较佳地，所述乙醇水溶液中乙醇的质量分数为90％-95％；
当所述药物组合物不含中性核心，且所述药物组合物以颗粒形式存在时，所述颗粒的制备方法较佳地包括如下步骤：采用异丙醇作为制粒溶剂，将所述药物组合物中的各组分的混合物进行湿法制粒，得湿颗粒；再将所述湿颗粒过20目筛后，干燥，即可。
当所述药物组合物不含中性核心，且所述药物组合物以颗粒形式存在时，所述药物组合物更佳地采用热熔制粒，所述热熔制粒的方法较佳地包括如下步骤：
当所述药物组合物不包含润滑剂时，所述颗粒的制备方法包括如下步骤：将
Figure PCTCN2018117619-appb-000054
粉末与所述药物组合物中的其他组分混合以形成均匀的颗粒即可。较佳地，所述
Figure PCTCN2018117619-appb-000055
粉末的粒径小于120目。较佳地，所述混合的温度为70-75℃。
当所述药物组合物包含润滑剂时，所述颗粒的制备方法包括如下步骤：将
Figure PCTCN2018117619-appb-000056
粉末与所述药物组合物中的其他组分混合以形成均匀的颗粒后，再与所述润滑剂混合即可。较佳地，所述
Figure PCTCN2018117619-appb-000057
粉末的粒径小于120目。较佳地，所述混合的温度为70-75℃。
当所述药物组合物包含中性核心，且所述药物组合物以中性核心微丸的形式存在时，所述中性核心微丸的制备方法较佳地包括如下步骤：将所述药物组合物中的除所述中性核心之外的其余组分溶解于有机溶剂中形成的涂布液喷涂于所述中性核心上即可。
其中，所述中性核心指的是预干燥后的中性核心，所述预干燥后的中性核心的水分含量较佳地低于1.0wt％。
其中，所述有机溶剂较佳地为乙醇溶液。所述乙醇水溶液中乙醇的质量分数较佳地为90％-95％。
其中，所述涂布液中所述药物组合物的质量百分数较佳地为20％-24％。
其中，所述喷涂过程中，空气的进口温度较佳地为45-60℃。
其中，所述喷涂过程中，所述颗粒的温度较佳地为30-50℃。
其中，所述喷涂结束后，较佳地将所述颗粒干燥至水分含量低于1.0wt％。
当所述药物组合物包含酸性核心，且所述药物组合物以酸性核心微丸的形式存在时，所述酸性核心微丸的制备方法较佳地包括如下步骤：
(1)将所述隔离层的各组分溶解于有机溶剂中形成的涂布液喷涂于所述酸性核心上，得酸性颗粒；
(2)将所述药物层的各组分溶解于有机溶剂中形成的涂布液喷涂于所述酸性颗粒上即可。
步骤(1)中，所述酸性核心指的是预干燥后的酸性核心，所述预干燥后的酸性核心的水分含量较佳地低于1.0wt％。
步骤(1)中，所述有机溶剂较佳地为乙醇溶液。所述乙醇水溶液中乙醇的质量分数较佳地为90％-95％。
步骤(1)中，所述涂布液中所述药物组合物的质量百分数较佳地为20％-26％。
步骤(1)中，所述喷涂过程中，空气的进口温度较佳地为45-60℃。
步骤(1)中，所述喷涂过程中，所述酸性颗粒的温度较佳地为30-32℃。
步骤(1)中，所述喷涂结束后，较佳地将所述酸性颗粒干燥至水分含量低于1.0wt％。
步骤(2)中，所述有机溶剂较佳地为乙醇溶液。所述乙醇水溶液中乙醇的质量分数较佳地为90％-95％。
步骤(2)中，所述涂布液中所述药物组合物的质量百分数较佳地为20％-24％。
步骤(2)中，所述喷涂过程中，空气的进口温度较佳地为45-60℃。
步骤(2)中，所述喷涂过程中，所述酸性核心微丸的温度较佳地为30-32℃。
步骤(2)中，所述喷涂结束后，较佳地将所述酸性核心微丸干燥至水分含量低于1.0wt％。
本发明还提供一种前述的药物组合物在制备治疗非心脏瓣膜问题引起的房颤患者的中风和/或非心脏瓣膜问题引起的房颤患者的血栓的药物中的应用。
本发明还提供一种前述的药物组合物在制备治疗深静脉血栓和/或肺栓塞的药物中的应用。
本发明的药物组合物制得的固体剂型，在制造和储存期间应当稳定。在制造以及在正常储存(25℃/60％RH)和加速储存(40℃/75％RH)期间，应防止药物杂质的增加。当在大约25℃和大约60％相对湿度下储存至少六个月，优选至少一年，最优选至少两年，或者，在大约40℃和大约75％相对湿度下储存至少三个月，最优选六个月，本发明的固体剂型 中的杂质应该不超出以下质量指标：杂质1≤0.2％，杂质2≤0.5％，杂质3≤0.5％，杂质4≤0.1％，杂质5≤0.6％，杂质6≤0.5％，杂质7≤0.1％，杂质8≤0.25％，杂质9≤0.15％，杂质10≤2.5％，单个未知杂质≤0.2％，总杂质≤3.6％。当将本发明的固体剂型储存在附有干燥剂的容器(例如塑料瓶)中时，在大约40℃和大约75％相对湿度条件下贮存6个月，固体剂型的各个降解产物和/或杂质水平均应当符合上述质量指标的要求。单独的和总的降解产物和/或杂质基于固体剂型中DEM的总量。杂质的种类和含量可以通过制药领域常用的方法来确定，例如通过高效液相色谱(HPLC)。
本发明中，Eudragit L100的生产厂家为赢创特种化学(上海)有限公司；Klucel EF的生产厂家为Ashland；Kollicoat IR的生产厂家为BASF；Kollidon VA64的生产厂家为BASF；Kolliphor P188的生产厂家为BASF；Kolliphor P407的生产厂家为BASF；HPMC E5的生产厂家为DOW；HPMC VLV的生产厂家为DOW；HPMCP HP55的生产厂家为韩国三星精密化学株式会社；HPMCAS MG的生产厂家为Shin/Etsu；PVP K12的生产厂家为Ashland；PVP K30的生产厂家为Ashland；
Figure PCTCN2018117619-appb-000058
的生产厂家为BASF；交联羧甲基纤维素钠的生产厂家为FMC；低取代羟丙纤维素的生产厂家为Shin/Etsu。
本发明中，所述的“包括……”还可表述为“由……组成”。
例如：所述固体颗粒包括下述质量分数的各组分：41％-58％的
Figure PCTCN2018117619-appb-000059
3％-33％的甘露醇、13％-26％的Kolliphor P407、5％-20％的交联羧甲基纤维素钠、0％-5％的二氧化硅和0％-2％的硬脂酸镁。
还可表述为：所述固体颗粒由下述质量分数的各组分组成：41％-58％的
Figure PCTCN2018117619-appb-000060
3％-33％的甘露醇、13％-26％的Kolliphor P407、5％-20％的交联羧甲基纤维素钠、0％-5％的二氧化硅和0％-2％的硬脂酸镁。
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。
本发明的积极进步效果在于：本发明提供一种含达比加群酯的药物组合物及其制备方法。该药物组合物的溶出曲线受肠胃液pH的影响较小，还可以避免DEM在中性pH的肠液中发生沉淀，故该药物组合物能够增强达比加群酯或其药学上可接受的盐的口服吸收，提高药物活性成分的生物利用度，还能够降低吸收变异性，同时提供更稳定的达比加群在血浆中的浓度，从而减轻不良副作用，减少GIT出血的可能性；另外，由于吸收增强，胃肠道中未吸收DEM的显着减少，这样可进一步缓解GIT大出血。当药物活性成分与药物组合物的其他组分共同形成固体分散体时，所有的DEM都预先溶解在载体 (载体指的是除药物活性成分之外的其他组分)中，因此无需担心药物的溶出；且载体能够快速在水性介质及酸性pH的条件下快速溶出，因此可以减小甚至消除DEM重结晶的可能性，故进一步促进DEM的吸收。
附图说明
图1显示的是实施例1中聚合物为
Figure PCTCN2018117619-appb-000061
的药物组合物及对照组的药物组合物的药物活性成分在pH6.8和25℃的磷酸盐缓冲溶液中的溶解度随时间变化的曲线图。
图2显示的是实施例1中聚合物为Eudragit L100及Kolliphor P407的药物组合物及对照组的药物组合物的药物活性成分在pH6.8和25℃的磷酸盐缓冲溶液中的溶解度随时间变化的曲线图。
图3显示的是实施例1中含有其余聚合物的药物组合物及对照组的药物组合物的药物活性成分在pH6.8和25℃的磷酸盐缓冲溶液中的溶解度随时间变化的曲线图。
图4显示的是实施例2的各SDF及对照组的药物活性成分在pH6.8和37℃的磷酸盐缓冲溶液中的60分钟时的溶解度。
图5显示的是实施例3的各SDF及对照组的药物活性成分在pH4.5和37℃的醋酸盐缓冲溶液中的随时间变化的溶出曲线图。
图6显示的是实施例3的各SDF及对照组的药物活性成分在pH6.8和37℃的磷酸盐缓冲溶液中的随时间变化的溶出曲线图。
图7显示的是实施例4的各药物组合物中的药物活性成分在37℃的pH4.5醋酸盐缓冲液→pH6.8磷酸盐缓冲液两阶段溶出实验中随时间变化的溶出曲线图。
图8显示的是实施例4的各药物组合物中的药物活性成分在37℃的pH4.5醋酸盐缓冲液→pH6.8磷酸盐缓冲液两阶段溶出实验中随时间变化的溶出曲线图。
图9显示的是实施例4的各药物组合物中的药物活性成分在37℃的pH4.5醋酸盐缓冲液→pH6.8磷酸盐缓冲液两阶段溶出实验中随时间变化的溶出曲线图。
图10为实施例5的微丸(F1)在含有不同浓度的两性聚合物溶液中的溶出曲线；其中，误差线表示n＝3的标准偏差。
图11为实施例5的微丸(F1)、实施例5的微丸
Figure PCTCN2018117619-appb-000062
的粉末(也即实施例6的微丸)及Pradaxa Pellets的溶出曲线；其中，Pradaxa Pellets微丸是Pradaxa Capsules的胶囊内容物，且Pradaxa Capsules的中文商品名：泰毕全，规格：150mg，厂家：勃林格殷格翰制药；其中，误差线表示n＝3的标准偏差。
图12为实施例7的胶囊剂(F2-A、F2-B、
Figure PCTCN2018117619-appb-000063
粉末)及实施6中的微丸的溶 出曲线；其中，误差线表示n＝3的标准偏差。
图13为实施例8的胶囊剂(F3)、实施例7的胶囊剂(F2-A)及Pradaxa Capsules在pH1.2→pH6.8两阶段溶出实验中的溶出曲线；其中，Pradaxa Capsules的中文商品名：泰毕全，规格：150mg，厂家：勃林格殷格翰制药；其中，误差线表示n＝3的标准偏差。
图14为实施例8的胶囊剂(F3)、实施例7的胶囊剂(F2-A)及Pradaxa Capsules在pH2.0→pH6.8两阶段溶出实验中的溶出曲线；其中，Pradaxa Capsules的中文商品名：泰毕全，规格：150mg，厂家：勃林格殷格翰制药；其中，误差线表示n＝3的标准偏差。
图15为实施例8的胶囊剂(F3)、实施例7的胶囊剂(F2-A)及Pradaxa Capsules在pH3.0→pH6.8两阶段溶出实验中的溶出曲线；其中，Pradaxa Capsules的中文商品名：泰毕全，规格：150mg，厂家：勃林格殷格翰制药；其中，误差线表示n＝3的标准偏差。
图16为实施例8的胶囊剂(F4、F5)及Pradaxa Capsules在pH2.0→pH6.8两阶段溶出实验中的溶出曲线；其中，Pradaxa Capsules的中文商品名：泰毕全，规格：150mg，厂家：勃林格殷格翰制药；其中，误差线表示n＝3的标准偏差。
图17为实施例10的分别含有两种崩解剂的胶囊剂(F10、F11)在pH2.0盐酸溶液中的溶出曲线；其中，误差线表示n＝3的标准偏差。
图18为实施例11的微丸(F6)、由微丸F6分散后的溶液或混悬液(记为F6溶液)及Pradaxa Capsules在pH2.0→pH6.8两阶段溶出实验中的溶出曲线；其中，Pradaxa Capsules的中文商品名：泰毕全，规格：150mg，厂家：勃林格殷格翰制药；其中，误差线表示n＝3的标准偏差。
图19为实施例11的微丸(F6)、由微丸F6分散后的溶液或混悬液(记为F6溶液)及Pradaxa Capsules在pH6.0→pH6.8两阶段溶出实验中的溶出曲线；其中，Pradaxa Capsules的中文商品名：泰毕全，规格：150mg，厂家：勃林格殷格翰制药；其中，误差线表示n＝3的标准偏差。
图20为实施例12的酸性核心微丸(F7)及Pradaxa Capsules在pH2.0→pH6.8两阶段溶出实验中的溶出曲线；其中，Pradaxa Capsules的中文商品名：泰毕全，规格：150mg，厂家：勃林格殷格翰制药；其中，误差线表示n＝3的标准偏差。
图21为实施例12的酸性核心微丸(F7)及Pradaxa Capsules在pH6.0→pH6.8两阶段溶出实验中的溶出曲线；其中，Pradaxa Capsules的中文商品名：泰毕全，规格：150mg，厂家：勃林格殷格翰制药；其中，误差线表示n＝3的标准偏差。
图22为实施例13及对比例1中的胶囊剂(F8、F9)及Pradaxa Capsules在pH2.0→pH6.8两阶段溶出实验中的溶出曲线；其中，Pradaxa Capsules的中文商品名：泰毕全，规格： 150mg，厂家：勃林格殷格翰制药；其中，误差线表示n＝3的标准偏差。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
下述实施例中，Eudragit L100的生产厂家为赢创特种化学(上海)有限公司；Klucel EF的生产厂家为Ashland；Kollicoat IR的生产厂家为BASF；Kollidon VA64的生产厂家为BASF；Kolliphor P188的生产厂家为BASF；Kolliphor P407的生产厂家为BASF；HPMC E5的生产厂家为DOW；HPMC VLV的生产厂家为DOW；HPMCP HP55的生产厂家为韩国三星精密化学株式会社；HPMCAS MG的生产厂家为Shin/Etsu；PVP K12的生产厂家为Ashland；PVP K30的生产厂家为Ashland；
Figure PCTCN2018117619-appb-000064
的生产厂家为BASF；交联羧甲基纤维素钠的生产厂家为FMC；低取代羟丙纤维素的生产厂家为Shin/Etsu。
下述实施例中，溶出度测定实验中，所采用的pH1.2的溶液为0.085N的盐酸溶液；所采用的pH2.0的溶液为0.01N盐酸溶液；所采用的pH3.0的溶液为0.001N盐酸溶液；所采用的pH6.0的溶液为0.000001N盐酸溶液；所采用的pH4.5的溶液为50mM醋酸钠缓冲液；所采用的pH6.8的溶液为50mM磷酸钠缓冲液；所采用的碱性溶液为氢氧化钠和磷酸钠盐的混合溶液。
实施例1
实施例1进行的为筛选实验，目的在于发现在中性pH下能够抑制DEM沉淀的聚合物，以下为拟用于筛选实验的聚合物。
Eudragit L100 Klucel EF Kollicoat IR Kollidon VA64 Kolliphor P188 Kolliphor P407 HPMC E5 HPMC VLV HPMCP HP55 HPMCAS MG PVP K12 PVP K30
Figure PCTCN2018117619-appb-000065
筛选实验包括如下步骤：
1.在0.1N HCl中以50mg/mL药物浓度制备DEM储备溶液。
2.将40mg上述聚合物放入5mL小瓶中，加入3.6mL pH6.8的磷酸钠缓冲液以溶解聚合物，得聚合物溶液。
3.将0.4mL来自步骤1的储备溶液加入来自步骤2的聚合物溶液中，同时将0.4mL的储备溶液加入到没有聚合物的pH6.8磷酸盐缓冲液中作为对照组。
4.在室温环境条件下以250rpm摇动小瓶。
5.在10分钟、20分钟、30分钟、45分钟、60分钟和120分钟的每个时间点取0.4mL的等份试样。
6.将这些等份试样以12000rpm离心5分钟，得上清液。
7.用甲醇和水的混合溶液(其中，甲醇和水的体积比为1:1)稀释上清液20倍。
8.使用HPLC方法分析来自步骤7的DEM溶液。
筛选结果列于表1中，并将结果绘制于图1、图2及图3中。从表1及图1、图2、图3可知，就在中性pH6.8下抑制DEM沉淀的效果而言，
Figure PCTCN2018117619-appb-000066
是所有已筛选的聚合物中最好的。
此处，还需要进一步说明的是，假设DEM完全溶解于上述含有聚合物的pH6.8磷酸盐缓冲液中，那么所得DEM溶液中DEM的理论浓度约为5mg/mL。由此可知，DEM与
Figure PCTCN2018117619-appb-000067
配合后，可以使得DEM接近与完全溶解的状态。
表1实施例1的药物活性成分随时间变化的溶解度
Figure PCTCN2018117619-appb-000068
实施例2
实施例2为微溶出实验，目的在于评估DEM固体分散膜(SDF)的溶出行为，下表是该微溶出实验中要评估的SDF的组成，且各百分比指的是质量百分比。
Figure PCTCN2018117619-appb-000069
该实施例中，采用溶剂蒸发法在20mL玻璃瓶中制备含有3mg DEM的DEM SDF，然后加入溶出介质在37℃进行溶出试验，具体实验步骤如下：
1.在体积分数为95％的乙醇溶液中以100mg/mL药物浓度制备DEM储备液。
2.在体积分数为95％的乙醇溶液中以100mg/mL的聚合物浓度制备聚合物储备液。
3.根据下表所示的体积将步骤1和步骤2中的储备液加入20mL小瓶中并充分混合，得混合溶液；
其中，BN-009058-E是将步骤1中的溶液加入体积分数为95％的乙醇溶液中充分混合，即得混合溶液；BN-009079-I在该步骤中不做任何处理。
Figure PCTCN2018117619-appb-000070
Figure PCTCN2018117619-appb-000071
4.将150μL每种混合溶液或3mgDEM粉末加入20mL小瓶中。
5.上述混合溶液及3mgDEM粉末，在环境条件下(烟道)干燥30分钟，然后在真空干燥箱(干燥条件为：50℃，10毫巴，30分钟)中干燥，以确保膜快速和完全干燥，得上表中各编号的SDF。
6.将18mL pH6.8磷酸钠缓冲液加入步骤5的小瓶中，包括仅含有DEM粉末的小瓶。
7.在37℃以200rpm摇动小瓶。
8.在60分钟取样。
9.将步骤8中的样品以12000rpm离心5分钟，得上清液。
10.用甲醇和水的混合溶液(其中，甲醇和水的体积比为1:1)将上清液稀释20倍。
11.使用HPLC方法分析来自步骤10的DEM溶液。
筛选结果列于表2中，并将结果绘制于图4中。从表2及图4可知，
Figure PCTCN2018117619-appb-000072
/PVP K12和
Figure PCTCN2018117619-appb-000073
/Kolliphor P188的组合在中性pH条件下显示出在促进溶出方面的最佳结果。
此处，还需要进一步说明的是，假设DEM完全溶解于上述含有聚合物的pH6.8磷酸 盐缓冲液中，那么所得DEM溶液中DEM的理论浓度约为150μg/mL。
表2实施例2的各SDF及对照组的药物活性成分在60分钟时的溶解度
Figure PCTCN2018117619-appb-000074
实施例3
实施例3为微溶出实验，目的在于评估DEM固体分散膜(SDF)在pH4.5醋酸钠缓冲液和pH6.8磷酸钠缓冲液中的溶出行为，具体实验步骤同实施例2。具体实验步骤如下：
1.在95％乙醇溶液中以100mg/mL药物浓度制备DEM储备液。
2.在95％乙醇溶液中以100mg/mL的聚合物浓度制备聚合物储备液。
3.根据下表所示的体积将步骤1和步骤2中的储备液加入20mL小瓶中并充分混合，得混合溶液；
其中，DEM F是将步骤1中的溶液加入体积分数为95％的乙醇溶液中充分混合，即得混合溶液；DEM P在该步骤中不做任何处理；编号为DEM F及DEM P的为对照组。
Figure PCTCN2018117619-appb-000075
Figure PCTCN2018117619-appb-000076
4.将150μL每种混合溶液或3mgDEM粉末加入20mL小瓶中。
5.上述混合溶液及3mgDEM粉末，在环境条件下(烟道)干燥30分钟，然后在真空干燥箱(干燥条件为：50℃，10毫巴，30分钟)中干燥，以确保膜快速和完全干燥，得上表中各编号的SDF，且为每个组成制备两个膜。
6.将18mL pH4.5醋酸盐缓冲液加入步骤5的一个膜中，包括仅含有DEM粉末的小瓶；
将18mL pH6.8磷酸盐缓冲液加入步骤5的另一个膜中，包括仅含有DEM粉末的小瓶。
7.在37℃以200rpm摇动小瓶。
8.在10、20、30、45、60和120分钟取样。
9.将步骤8中的样品以12000rpm离心5分钟，得上清液。
10.用甲醇和水的混合溶液(其中，甲醇和水的体积比为1:1)将上清液稀释20倍。
11.使用HPLC方法分析来自步骤10的DEM溶液。
筛选结果列于表3和表4中，并将结果绘制于图5和图6中。从表3、表4、图5和图6可知，D/K12(2:8)及D/S/P407(2:4:4)的SDF在pH4.5时显示出快速溶出，而D/S/K12(2:4:4)、D/P407(2:8)和D/S/P407(2:4:4)在pH6.8下显示出较好的溶出。
此处，还需要进一步说明的是，假设DEM完全溶解于上述含有聚合物的pH6.8磷酸盐缓冲液中，那么所得DEM溶液中DEM的理论浓度约为150μg/mL。
表3实施例3的各SDF及对照组的药物活性成分随时间变化的溶解度(单位μg/mL)
Figure PCTCN2018117619-appb-000077
Figure PCTCN2018117619-appb-000078
表4实施例3的各SDF及对照组的药物活性成分随时间变化的溶解度(单位μg/mL)
Figure PCTCN2018117619-appb-000079
实施例4
实施例4是为了评估固体分散膜内及固体分散膜外
Figure PCTCN2018117619-appb-000080
的量对溶出度的影响，特别是在pH6.8的中性介质中对药物沉淀的影响。
在该实施例中重复实施例2的步骤进行SDF的制备，不同之处在于使用两阶段溶出法进行SDF的溶出测试，其中，第一阶段在pH4.5的溶液，第二阶段在pH6.8的溶液。
下表是上述两阶段溶出法所要评估的SDF的组成。
Figure PCTCN2018117619-appb-000081
首先，将具有或不具有膜外
Figure PCTCN2018117619-appb-000082
的SDF置于18mL醋酸盐缓冲液(pH4.5的溶液) 中；在10分钟时，取0.4mL等份试样，然后加入2mL碱性溶液以调节pH至目标pH6.8(6.5-7.0)；在pH调节后10分钟，再取等份试样(0.4mL)；分析每个等份试样中的DEM浓度。
结果列于表5及图7、图8及图9中，从中可知，膜内
Figure PCTCN2018117619-appb-000083
减缓了溶出，因此，用膜外
Figure PCTCN2018117619-appb-000084
替换膜内
Figure PCTCN2018117619-appb-000085
不仅加速了在酸性pH(pH 4.5)下的溶出，而且防止了在中性pH(pH6.8)下DEM的析出。
表5实施例4的各药物组合物中的药物活性成分随时间变化的溶解度(单位μg/mL)
Figure PCTCN2018117619-appb-000086
实施例5
按表6，通过将固体分散体组合物喷涂到中性核心上来制备微丸，且固体分散体组合物中包含30wt％的达比加群酯甲磺酸盐(DEM)，10wt％的
Figure PCTCN2018117619-appb-000087
和60wt％的Kolliphor P407。
具体制备方法如下：
首先，将固体分散体组合物溶解于95wt％乙醇中，制成涂布液，该涂布液含有20wt％的固体分散体组合物。接下来，将中性核心(300-500目)在80℃的对流烘箱中预干燥，直到其水分含量低于1.0％。然后，在具有Wurster***物的流化床制粒机上，在合适的入口空气压力和45-60℃空气入口温度下，将300g包含60g固体分散体组合物的涂布液，喷涂到40g预干燥后的中性核心上，在喷涂过程中，调节喷雾速度和雾化压力，使产品温度保持30-50℃。在涂布液耗尽之后，将产品在流化床中干燥直至含水量低于1.0％，且包覆中性核心的固体分散体层与中性核心的目标质量比为1.5/1.0，即得实施例5的微丸。
表6微丸F1的组成
Figure PCTCN2018117619-appb-000088
使用USP篮式两步法，在100rpm和37℃下，测量包含173.0mg DEM(相当于150mg DEM游离碱)的微丸的溶出曲线。在第一阶段，将微丸置于500mL的酸性介质(pH2.0的溶液)中，该酸性介质中包含不同质量的(0、75、150和300mg)
Figure PCTCN2018117619-appb-000089
在第二阶段(45分钟)，将500mL碱性溶液加入到酸性介质中以将pH调节至6.8。在10、45、55和90分钟的时间点取样品的等份试样3mL。将这些等份试样以12000rpm离心5分钟，用1/1体积比的甲醇/水的混合溶液将上清液稀释10倍用于HPLC分析。
结果见表7及图10，从图10可知，在微丸外加入75mg或更多
Figure PCTCN2018117619-appb-000090
粉末，可以防止在中性pH(pH6.8)下沉淀出更多的DEM。
表7实施例5的F1在含有不同浓度
Figure PCTCN2018117619-appb-000091
的介质中随时间变化的溶出度
Figure PCTCN2018117619-appb-000092
实施例6
重复实施例5中的步骤，制得微丸F1，与实施例5不同的地方在于，实施例6中外加的Solpulus以粉末形式添加。
先将Solpulus颗粒磨碎，过80目筛，得150mg Solpulus粉末(<80目)；随后，与0.5wt％(基于
Figure PCTCN2018117619-appb-000093
粉末的质量150mg)的二氧化硅混合，得固体颗粒；最后，将微丸F1与固体颗粒混合即得实施例6的微丸
采用与实施例5相同的测试方法测定微丸F1、实施例6的微丸、Pradaxa Pellets微丸(Pradaxa Capsules的胶囊内容物)的溶出曲线，结果如表8及图11所示。
从表8及图11中可知，与Pradaxa Pellets微丸相比，微丸F1可以防止酸性介质中溶出的DEM在pH6.8下沉淀。然而，含有外加
Figure PCTCN2018117619-appb-000094
粉末的实施例6的微丸，减缓了DEM在酸性介质中的溶出。
表8实施例6中制剂随时间变化的溶出度
Figure PCTCN2018117619-appb-000095
Figure PCTCN2018117619-appb-000096
实施例7
采用实施例5中的制备方法，制备微丸F2。
使用异丙醇(IPA)作为制粒溶剂，将固体颗粒的各组分的混合物进行湿法制粒，得湿颗粒；再将湿颗粒过20目筛，并在环境温度下在层流罩中干燥，即得固体颗粒。
表9实施例7的胶囊剂F2-A及F2-B的组成
Figure PCTCN2018117619-appb-000097
按表9，向明胶胶囊(#0)中填充微丸(240.3mg)和固体颗粒(179.1mg)，得胶囊剂F2-A 和F2-B。
采用与实施例5相同的测试方法测定胶囊剂F2-A和F2-B的溶出曲线，结果如表10及图12所示。
从表10及图12中可知，与
Figure PCTCN2018117619-appb-000098
粉末(含有75.0mg的
Figure PCTCN2018117619-appb-000099
粉末)相比，含有实施例7中的固体颗粒的微丸制剂(F2-A和F2-B)在酸性介质中显示出更快的溶出。
表10实施例7的各制剂在含有不同浓度
Figure PCTCN2018117619-appb-000100
的介质中随时间变化的溶出度
Figure PCTCN2018117619-appb-000101
实施例8
重复实施例7中的湿法制粒步骤，制备得到包含DEM的颗粒F3。
Figure PCTCN2018117619-appb-000102
按上表，将包含DEM的颗粒(339.3mg)填充到明胶胶囊(#0)中。
测试方法：
与实施例5的测试方法不同的是，考虑到胃部pH值的变化，第一阶段的pH分别设定为1.2或2.0或3.0(也即第一阶段所采用的酸性介质分别为：pH1.2的溶液、pH2.0的溶液、pH3.0的溶液)，其余同实施例5的测试方法。
采用上述测试方法，测定Pradaxa Capsules(150mg)、F2-A及F3的溶出曲线，结果如表11、图13、图14及图15所示。从中可知，与Pradaxa Capsules相比，本发明的制剂(F2-A和F3)在酸性pH下明显更快的溶出，并且在中性pH下更少的沉淀。
表11F3、F2-A及Pradaxa Capsules随时间变化的溶出度
Figure PCTCN2018117619-appb-000103
实施例9
在该实施例中，通过热熔制粒工艺制备胶囊剂F4中的固体颗粒和胶囊剂F5中的颗粒。
表12胶囊剂F4中热熔制粒工艺所得固体颗粒的组成
Figure PCTCN2018117619-appb-000104
表13胶囊剂F5中热熔制粒工艺所得颗粒的组成
Figure PCTCN2018117619-appb-000105
热熔制粒工艺的步骤如下：
首先，将
Figure PCTCN2018117619-appb-000106
粉碎并过120目筛，即得
Figure PCTCN2018117619-appb-000107
粉末，然后按照表12中的质量百分比将
Figure PCTCN2018117619-appb-000108
粉末与除硬脂酸镁之外的其它组分在玻璃烧杯中在70-75℃下用不锈钢刮刀混合，直到形成均匀的颗粒。接着，将上述颗粒与硬脂酸镁混合，即得F4中的固体颗粒。
首先，将
Figure PCTCN2018117619-appb-000109
粉碎并过120目筛，即得
Figure PCTCN2018117619-appb-000110
粉末，然后按照表13中的质量百分比将
Figure PCTCN2018117619-appb-000111
粉末与除硬脂酸镁之外的其它组分在玻璃烧杯中在70-75℃下用不锈钢刮刀混合，直到形成均匀的颗粒。接着，将上述颗粒与硬脂酸镁混合，即得F5中的颗粒。
将实施例7中微丸F2(240.3mg)与表12配方所得的固体颗粒(151.5mg)装入明胶胶囊(#0)中，所得胶囊剂记为F4。将表13配方所得的颗粒(341.4mg)也填充到明胶胶囊(#0)中，得胶囊剂F5。
采用与实施例5相同的测试方法测定胶囊剂F4和F5的溶出曲线，结果如表14及图16所示。
从表14及图16可知，与Pradaxa Capsules相比，本发明的制剂(F4和F5)在酸性pH下明显更快的溶出，并且在中性pH下更少的沉淀。Pradaxa Capsules、F4和F5，在pH2.0的溶液中，且在10min时，溶出的DEM的质量百分比分别为16.4％、83.4％和78.5％。Pradaxa Capsules、F4和F5，在pH6.8的溶液中10min时，溶出的DEM的质量百分比分别为5.4％、39.7％和47.4％。
表14实施例9中F4、F5及Pradaxa Capsules随时间变化的溶出度
Figure PCTCN2018117619-appb-000112
实施例10
热熔制粒工艺的步骤如下：
首先，将
Figure PCTCN2018117619-appb-000113
粉碎并过120目筛，即得
Figure PCTCN2018117619-appb-000114
粉末，然后按照表15中的质量百分比将
Figure PCTCN2018117619-appb-000115
粉末与除硬脂酸镁及外加交联羧甲基纤维素钠之外的其它组分在玻璃烧杯中在70-75℃下用不锈钢刮刀混合，直到形成均匀的颗粒。接着，将上述颗粒与硬脂酸镁及外加交联羧甲基纤维素钠混合，即得F10中颗粒。将表15配方所得的颗粒填充到明胶胶囊(#0)中，得胶囊剂F10。
首先，将
Figure PCTCN2018117619-appb-000116
粉碎并过120目筛，即得
Figure PCTCN2018117619-appb-000117
粉末然后按照表16中的质量百分比将
Figure PCTCN2018117619-appb-000118
粉末与除硬脂酸镁及外加低取代羟丙纤维素之外的其它组分在玻璃烧杯中在70-75℃下用不锈钢刮刀混合，直到形成均匀的颗粒。接着，将上述颗粒与硬脂酸镁及外加低取代羟丙纤维素混合，即得F11中颗粒。将表16配方所得的颗粒填充到明胶 胶囊(#0)中，得胶囊剂F11。
表15热熔制粒工艺所得颗粒F10的组成
Figure PCTCN2018117619-appb-000119
表16热熔制粒工艺所得颗粒F11的组成
Figure PCTCN2018117619-appb-000120
将F10和F11放入pH2.0的溶液中测定溶出曲线，结果如表17及图17所示。从表17及图17可以看出，F10和F11这两种剂型的溶出结果无显著差别。
表17实施例10中F10、F11随时间变化的溶出度
Figure PCTCN2018117619-appb-000121
Figure PCTCN2018117619-appb-000122
实施例11
按表18，通过将固体分散体组合物喷涂到中性核心上来制备微丸，且固体分散体组合物由下述质量分数的各组分组成：40wt％达比加群酯甲磺酸盐(DEM)、10wt％
Figure PCTCN2018117619-appb-000123
和50wt％Kolliphor P407。
具体制备方法如下：
微丸的制备：将固体分散体组合物溶解于90wt％乙醇和10wt％去离子水的混合溶液中，制成涂布液，该涂布液含有24wt％的固体分散体组合物。接下来，将中性核心(300-500目)在80℃的对流烘箱中预干燥，直到其水分含量低于1.0％。
然后，在具有Wurster***物的流化床制粒机上，在合适的入口空气压力和45-50℃空气入口温度下，将104.2g包含25g固体分散体组合物的涂布液，喷涂到50g预干燥的糖芯上，在喷涂过程中，调整喷雾速度和雾化压力，使产品温度保持在30-50℃。在涂布溶液耗尽之后，将产品在流化床中干燥直至含水量低于1.0％，且包覆中性核心的固体分散体层与中性核心的目标质量比为0.5/1.0，得药物颗粒。
Figure PCTCN2018117619-appb-000124
粉末的制备：先将Solpulus颗粒磨碎，再过80目筛网，得Solpulus粉末(<80目)。将药物颗粒(微丸)与Solpulus粉末混合即得实施例11的微丸(制剂)。
表18微丸F6的组成
Figure PCTCN2018117619-appb-000125
测试方法：
与实施例5的测试方法不同的是，第一阶段的pH分别设定为2.0或6.0(也即第一阶段所采用的酸性介质分别为：pH2.0的溶液、pH6.0的溶液)，其余同实施例5的测试方法。
采用上述测试方法，测定微丸F6的溶出曲线。为了比较，将微丸F6预溶至25mL去离子水，得F6溶液，采用相同的方法测定F6溶液的溶出曲线，结果如表19、图18和图19所示。
从中可知，与Pradaxa Capsules相比，F6在酸性pH 2和pH 6下显示更快的溶出，在中性pH6.8下更少的沉淀；且F6能够防止60％以上在酸性介质(pH2.0和6.0)中溶出的DEM在pH6.8下发生沉淀。在室温下，F6溶液能够促进DEM和
Figure PCTCN2018117619-appb-000126
的溶出，由此，在中性pH(pH6.8)下产生更好的沉淀抑制效果。
表19实施例11中F6及Pradaxa Capsules随时间变化的溶出度
Figure PCTCN2018117619-appb-000127
实施例12
酸性核心微丸的制备方法如下：
按表20，将隔离层组合物(该组合物中，
Figure PCTCN2018117619-appb-000128
的质量分数为67％，Kolliphor P407的质量分数为33％)溶解在95wt％乙醇和5wt％去离子水组成的混合溶液中，制成涂布液，该涂布液中隔离层组合物的质量分数为26％。
接下来，将酒石酸核心(300-500μm)在80℃的对流烘箱中预干燥，直到其水分含量低于1.0％。
然后，使用具有Wurster***物的流化床制粒机，在合适的入口空气压力和空气入口温度35℃下，将包含20g隔离层组合物的涂布液涂布到50g预干燥的酒石酸核心上，在喷涂过程中，调整喷雾速度和雾化压力，使产品温度保持在30-32℃。在涂布溶液耗尽之后，将产品在流化床中干燥直至水分含量低于1.0％(如果在流化床中干燥之后水分含量未达到低于1.0％，则在烘箱中的二次干燥过程是必要的)，且隔离层与酒石酸核心的目标质量比为0.4/1.0。
药物层组合物的包衣过程与实施例11中所述的相同，且该药物层组合物由下述质量分数的各组分组成：28.9wt％DEM、25.9wt％
Figure PCTCN2018117619-appb-000129
和45.3wt％Kolliphor P407；且药物层与隔离层包覆的酒石酸核心的目标质量比为1.0/1.0。
表20酸性核心微丸F7的组成
Figure PCTCN2018117619-appb-000130
测试方法：
与实施例5的测试方法不同的是，第一阶段的pH分别设定为2.0或6.0(也即第一阶段所采用的酸性介质分别为：pH2.0的溶液、pH6.0的溶液)，其余同实施例5的测试方法。
采用上述测试方法，测定F7的溶出曲线，结果如表21、图20及图21所示。
从中可知，DEM能够快速从F7中溶出，并且F7能够增强酸性环境(pH6.0)下的溶出速率，以及40％-47％在酸性环境(pH2.0和pH6.0)的已溶出的DEM不会在中性pH(pH6.8)下沉淀。
表21实施例12中F7及Pradaxa Capsules随时间变化的溶出度
Figure PCTCN2018117619-appb-000131
Figure PCTCN2018117619-appb-000132
实施例13
热熔制粒工艺的步骤如下：
首先，将
Figure PCTCN2018117619-appb-000133
粉碎并过120目筛，即得
Figure PCTCN2018117619-appb-000134
粉末，然后按照表22中的质量百分比将
Figure PCTCN2018117619-appb-000135
粉末与除硬脂酸镁及外加交联羧甲基纤维素钠之外的其它组分在玻璃烧杯中在70-75℃下用不锈钢刮刀混合，直到形成均匀的颗粒。接着，将上述颗粒与硬脂酸镁及外加交联羧甲基纤维素钠混合，即得F8中颗粒。将表22配方所得的颗粒填充到明胶胶囊(#0)中，得胶囊剂F8。
表22热熔制粒工艺所得颗粒F8的组成
Figure PCTCN2018117619-appb-000136
Figure PCTCN2018117619-appb-000137
采用与实施例5相同的测试方法测定F8的溶出曲线，结果如表23及图22所示。
表23实施例13中F8和对比例1中F9及Pradaxa Capsules随时间变化的溶出度
Figure PCTCN2018117619-appb-000138
实施例14
该实施例中，对两个代表性配方(F4和F5)，即微丸配方和热熔制粒配方，进行了稳定性研究。
将F4和F5用HDPE瓶包装后置于温度40℃、相对湿度为75％的条件下放置6个月。
采用同前所述的pH2.0→pH6.8两阶段溶出方法，对样品进行溶出行为的检测；采用HPLC方法对样品的杂质含量进行检测，并采用卡尔·费休法对水分含量进行检测。
结果表明，上述样品，在温度40℃、相对湿度为75％的条件下放置6个月，其溶出行为、DEM含量未发生显著变化，杂质含量均在质量指标的限度范围内，水分含量符合质量指标的要求。
对比例1
热熔制粒工艺的步骤如下：
将除硬脂酸镁及外加交联羧甲基纤维素钠之外的其它组分在玻璃烧杯中在70-75℃下用不锈钢刮刀混合，直到形成均匀的颗粒。接着，将上述颗粒与硬脂酸镁及外加交联羧甲基纤维素钠混合，即得F9中颗粒。将表24配方所得的颗粒填充到明胶胶囊(#0)中，得胶囊剂F9。
表24热熔制粒工艺所得颗粒F9的组成
Figure PCTCN2018117619-appb-000139
采用与实施例5相同的测试方法测定F9的溶出曲线，结果如图22所示。
从图22中可以看出，不含
Figure PCTCN2018117619-appb-000140
的配方(F9)在pH6.8中沉淀情况与现有市售原研产品接近，而加入
Figure PCTCN2018117619-appb-000141
的配方(F8)可显著提高DEM在pH6.8中的浓度。

Claims (13)

  1. 一种含达比加群酯的药物组合物，其特征在于，所述药物组合物包括药物活性成分和两性聚合物；其中，所述药物活性成分为达比加群酯和/或达比加群酯甲磺酸盐，所述两性聚合物为聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物；且所述药物活性成分和所述两性聚合物的质量比为1:0.23-1:3。
  2. 如权利要求1所述的含达比加群酯的药物组合物，其特征在于，所述药物活性成分为达比加群酯或达比加群酯甲磺酸盐；
    和/或，所述药物组合物中所述药物活性成分的质量为30-180mg，较佳地为39.1-173mg；
    和/或，所述两性聚合物中乙烯基己内酰胺的重复单元的个数为57个以下；所述两性聚合物中乙酸乙烯酯的重复单元的个数较佳地为30个以下；所述两性聚合物中聚乙二醇的重复单元个数较佳地为13个以上；所述两性聚合物的单体较佳地为聚乙二醇6000、乙烯基己内酰胺和乙酸乙烯酯，所述两性聚合物中上述三种单体聚乙二醇6000、乙烯基己内酰胺和乙酸乙烯酯的摩尔比为13：57：30；所述两性聚合物的分子量较佳地为90000-140000g/mol；所述两性聚合物的玻璃化转变温度较佳地为69-71℃；所述两性聚合物更佳地为
    Figure PCTCN2018117619-appb-100001
    和/或，所述药物活性成分和所述两性聚合物的质量比为1:0.24-1:3、1:0.3-1:3、1:0.5-1:3、1:1.5-1:3或1:1.5-1:2.3，较佳地为1:0.24、1:0.25、1:0.33、1:0.77、1:1、1:1.2、1:1.5、1:1.6、1:2或1:2.3。
  3. 如权利要求1或2所述的含达比加群酯的药物组合物，其特征在于，所述药物组合物中还包含亲水性聚合物，所述亲水性聚合物为聚氧乙烯聚氧丙烯醚嵌段共聚物、聚乙烯吡咯烷酮、聚乙烯吡咯烷酮-共-乙酸乙烯酯、甲基纤维素、羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素和聚丙烯酸酯中的一种或多种；所述聚氧乙烯聚氧丙烯醚嵌段共聚物较佳地为Kolliphor P188和/或Kolliphor P407；所述聚乙烯吡咯烷酮较佳地为PVP K12；所述聚乙烯吡咯烷酮-共-乙酸乙烯酯较佳地为Kollidon VA64；所述羟丙基纤维素较佳地为Klucel EF；所述羟丙基甲基纤维素较佳地为HPMC E5和/或HPMC VLV；所述聚丙烯酸酯较佳地为Eudragit L100；
    当所述药物组合物中包含亲水性聚合物时，所述药物活性成分在所述药物组合物中的质量百分比为5wt％-60wt％，较佳地为10wt％-55wt％，更佳地为20wt％-45wt％，进一步更佳地为13.3wt％、14.4wt％、16.9wt％、17.0wt％、18.0wt％、24.0wt％、39.1wt％或43.4wt％；所述两性聚合物在所述药物组合物中的质量百分比为3wt％-40wt％，较佳地为 3.3wt％、、6.0wt％、9.2wt％、10.0wt％、12.8wt％、12.9wt％、18.6wt％、21.3wt％、22.5wt％、22.8wt％、24.3wt％、28.3wt％、38.8wt％或39.2wt％；所述亲水性聚合物在所述药物组合物中的质量百分比为10wt％-90wt％，较佳地为20wt％-80wt％，更佳地为40wt％-60wt％，进一步更佳地为16.7wt％、19.2wt％、19.9wt％、22.2wt％、26.1wt％、27.4wt％、27.4wt％、29.6wt％、31.0wt％、33.3wt％、35.9wt％、30.0wt％或36.0wt％。
  4. 如权利要求3所述的含达比加群酯的药物组合物，其特征在于，所述药物组合物中还包含崩解剂，较佳地为交联羧甲基纤维素钠、低取代羟丙纤维素、羟基乙酸淀粉钠和交联聚维酮中的一种或多种，更佳地为交联羧甲基纤维素钠和/或低取代羟丙纤维素；其中，所述崩解剂在所述药物组合物中的质量百分比较佳地为0wt％-5wt％，但不为0wt％；更佳地为3wt％-5wt％；
    和/或，所述药物组合物中还包含抗静电剂，较佳地为长链烷基酚、乙氧基化胺、甘油酯和二氧化硅中的一种或多种，更佳地为二氧化硅；其中，所述抗静电剂在所述药物组合物中的质量百分比较佳地为0wt％-5wt％，但不为0wt％；更佳地为0.01wt％-3wt％；进一步更佳地为0.5wt％-2wt％；
    和/或，所述药物组合物中还包含润滑剂，较佳地为硬脂酸钙、山嵛酸甘油酯、硬脂酸镁、硬脂富马酸钠、滑石粉、胶体二氧化硅、硅酸镁和硅酸钙中的一种或多种，更佳地为硬脂酸镁；其中，所述润滑剂在所述药物组合物中的质量百分比较佳地为0wt％-5wt％，但不为0wt％；更佳地为0.01wt％-3wt％；进一步更佳地为0.5wt％-2wt％；
    和/或，所述药物组合物中还包含稀释剂，较佳地为甘露醇和/或乳糖一水合物；其中，所述稀释剂在所述药物组合物中的质量百分比较佳地为0wt％-40wt％，但不为0wt％；更佳地为9wt％-38.3wt％。
  5. 如权利要求1所述的含达比加群酯的药物组合物，其特征在于，所述药物组合物包括下述质量分数的各组分：9％-48％的所述药物活性成分、9％-44％的所述两性聚合物、0％-53％的亲水性聚合物、0％-90％的稀释剂、0％-20％的崩解剂、0％-5％的抗静电剂和0％-2％的润滑剂；所述亲水性聚合物的定义同权利要求3，所述稀释剂、所述崩解剂、所述抗静电剂和所述润滑剂的定义同权利要求4；
    较佳地，所述药物组合物包括下述质量分数的各组分：9％-48％的达比加群酯甲磺酸盐、9％-44％的
    Figure PCTCN2018117619-appb-100002
    0％-30％的Kolliphor P407、0％-23％的Kolliphor P188、0％-58％的乳糖一水合物、0％-32％的甘露醇、0％-20％的交联羧甲基纤维素钠、0％-5％的二氧化硅和0-3％的硬脂酸镁。
  6. 如权利要求1-5中至少一项所述的含达比加群酯的药物组合物，其特征在于，
    所述药物组合物包括下述质量分数的各组分：13％-44％的所述药物活性成分、6％-39％的所述两性聚合物、16％-36％的亲水性聚合物、9％-39％的稀释剂、5％-23％的崩解剂和0.4％-0.5％的润滑剂，其中，所述亲水性聚合物的定义同权利要求3，所述稀释剂、所述崩解剂和所述润滑剂的定义同权利要求4；
    或者，所述药物组合物包括下述质量分数的各组分：16％-19％的所述药物活性成分、21％-43％的所述两性聚合物、32％-58％的稀释剂、5％-20％的崩解剂和0％-2％的润滑剂，其中，所述稀释剂、所述崩解剂和所述润滑剂的定义同权利要求4；较佳地，所述药物组合物包括下述质量分数的各组分：16％-19％的达比加群酯甲磺酸盐、21％-43％的
    Figure PCTCN2018117619-appb-100003
    32％-58％的乳糖一水合物、5％-20％的交联羧甲基纤维素钠和0％-2％的硬脂酸镁；
    或者，所述药物组合物包括下述质量分数的各组分：16％-18％的所述药物活性成分、26％-44％的所述两性聚合物、17％-23％的亲水性聚合物、0％-32％的稀释剂、5％-20％的崩解剂和0％-2％的润滑剂，其中，所述亲水性聚合物的定义同权利要求3，所述稀释剂、所述崩解剂和所述润滑剂的定义同权利要求4；较佳地，所述药物组合物包括下述质量分数的各组分：16％-18％的达比加群酯甲磺酸盐、26％-44％的
    Figure PCTCN2018117619-appb-100004
    0％-32％的甘露醇、17％-23％的Kolliphor P188、5％-20％的交联羧甲基纤维素钠和0％-2％的硬脂酸镁；
    或者，所述药物组合物由下述质量分数的各组分组成：17％的达比加群酯甲磺酸盐、39.2％的
    Figure PCTCN2018117619-appb-100005
    38.3％的乳糖一水合物、5.0％的交联羧甲基纤维素钠和0.5％的硬脂酸镁；
    或者，所述药物组合物由下述质量分数的各组分组成：16.9％的达比加群酯甲磺酸盐、38.8％的
    Figure PCTCN2018117619-appb-100006
    18.9％的甘露醇、19.9％的Kolliphor P188、5.0％的交联羧甲基纤维素钠和0.5％的硬脂酸镁；
    或者，所述药物组合物由下述质量分数的各组分组成：43.35％的达比加群酯甲磺酸盐、10％的
    Figure PCTCN2018117619-appb-100007
    9％的甘露醇、22.15％的Kolliphor P407、15.0％的交联羧甲基纤维素钠和0.5％的硬脂酸镁；
    或者，所述药物组合物由下述质量分数的各组分组成：43.35％的达比加群酯甲磺酸盐、10％的
    Figure PCTCN2018117619-appb-100008
    9％的甘露醇、22.15％的Kolliphor P407、15.0％的低取代羟丙纤维素和0.5％的硬脂酸镁；
    或者，所述药物组合物由下述质量分数的各组分组成：39.1％的达比加群酯甲磺酸盐、9.2％的
    Figure PCTCN2018117619-appb-100009
    9.2％的甘露醇、19.2％的Kolliphor P188、23.0％的交联羧甲基纤维素钠和0.4％的硬脂酸镁。
  7. 如权利要求1-6中至少一项所述的含达比加群酯的药物组合物，其特征在于，所述药物组合物以如下形式存在：粉末、微丸、颗粒、胶囊或片剂；所述微丸根据其核心的不同较佳地分为中性核心微丸和酸性核心微丸。
  8. 如权利要求7所述的含达比加群酯的药物组合物，其特征在于，
    当所述药物组合物以粉末的形式存在时，所述粉末的制备方法包括如下步骤：将所述药物组合物中的各组分溶解在乙醇水溶液中，喷雾干燥即可；
    其中，较佳地，所述乙醇水溶液中乙醇的质量分数为90％-95％；
    其中，较佳地，所述粉末中，以分子分散形式和/或无定型形式存在的药物活性成分占所述药物活性成分的总质量的百分比为15wt％-100wt％，更佳地为40wt％-100wt％，进一步更佳地为60wt％-100wt％；
    当所述药物组合物以中性核心微丸的形式存在，所述中性核心微丸具有中性核心和包裹所述中性核心的药物层，所述中性核心微丸包括下述质量分数的各组分：9％-30％的所述药物活性成分、2％-24％的所述两性聚合物、11％-42％的亲水性聚合物和33％-77％的所述中性核心，且所述亲水性聚合物的定义同权利要求3；
    其中，较佳地，所述中性核心微丸中，以分子分散形式和/或无定型形式存在的药物活性成分占所述药物活性成分的总质量的百分比为15wt％-100wt％，更佳地为40wt％-100wt％，进一步更佳地为60wt％-100wt％；
    其中，较佳地，所述中性核心为微晶纤维素芯和/或糖芯；更佳地，所述中性核心为糖芯；
    其中，较佳地，所述中性核心微丸包括下述质量分数的各组分：12％-30％的所述药物活性成分、6％-24％的所述两性聚合物、15％-42％的所述亲水性聚合物和33％-50％的所述中性核心；更佳地，所述中性核心微丸包括下述质量分数的各组分：12％-30％的达比加群酯甲磺酸盐、6％-24％的
    Figure PCTCN2018117619-appb-100010
    15％-42％的Kolliphor P407和33％-50％的糖芯；
    其中，较佳地，所述中性核心微丸包括下述质量分数的各组分：9％-20％的所述药物活性成分、2％-5％的所述两性聚合物、11％-25％的所述亲水性聚合物和50％-77％的所述中性核心；更佳地，所述中性核心微丸包括下述质量分数的各组分：9％-20％的达比加群酯甲磺酸盐、2％-5％的
    Figure PCTCN2018117619-appb-100011
    11％-25％的Kolliphor P407和50％-77％的糖芯；
    其中，较佳地，所述中性核心微丸包括下述质量分数的各组分：13.3％-24％的所述药物活性成分、3.33％-28.27％的所述两性聚合物、16.7％-36％的所述亲水性聚合物和40％-66.7％的所述中性核心；更佳地，所述中性核心微丸包括下述质量分数的各组分：13.3％-24％的达比加群酯甲磺酸盐、3.33％-28.27％的
    Figure PCTCN2018117619-appb-100012
    16.7％-36％的Kolliphor  P407和40％-66.7％的糖芯；
    其中，较佳地，所述药物组合物由下述质量分数的各组分组成：18％的达比加群酯甲磺酸盐、6％的
    Figure PCTCN2018117619-appb-100013
    36％的Kolliphor P407和40％的糖芯；
    其中，较佳地，所述药物组合物由下述质量分数的各组分组成：24％的达比加群酯甲磺酸盐、6％的
    Figure PCTCN2018117619-appb-100014
    30％的Kolliphor P407和40％的糖芯；
    其中，较佳地，所述药物组合物由下述质量分数的各组分组成：13.3％的达比加群酯甲磺酸盐、3.33％的
    Figure PCTCN2018117619-appb-100015
    16.7％的Kolliphor P407和66.7％的糖芯；
    其中，较佳地，所述中性核心微丸的制备方法包括如下步骤：将所述药物组合物中的各组分溶解在乙醇水溶液中，喷涂于所述中性核心上即可；更佳地，所述乙醇水溶液中乙醇的质量分数为90％-95％；
    当所述药物组合物以酸性核心微丸的形式存在时，所述酸性核心微丸包括酸性核心、隔离层及药物层，所述隔离层包覆于所述酸性核心的表面，所述药物层包覆于所述隔离层的表面；所述隔离层包括
    Figure PCTCN2018117619-appb-100016
    和Kolliphor P407；
    其中，较佳地，所述酸性核心为酒石酸核心；
    其中，较佳地，所述酸性核心在所述酸性核心微丸中的质量百分比为17％-36％；
    其中，较佳地，所述隔离层中的
    Figure PCTCN2018117619-appb-100017
    在所述酸性核心微丸中的质量百分比为9％-13％；所述隔离层中的Kolliphor P407在所述酸性核心微丸中的质量百分比为4％-6％；
    其中，较佳地，所述药物层包括所述药物活性成分、
    Figure PCTCN2018117619-appb-100018
    和Kolliphor P407，且所述药物层中的所述药物活性成分在所述酸性核心微丸中的质量百分比为14％-19％，所述药物层中的
    Figure PCTCN2018117619-appb-100019
    在所述酸性核心微丸中的质量百分比为12％-17％，所述药物层中的Kolliphor P407在所述酸性核心微丸中的质量百分比为22％-29％；
    其中，较佳地，所述酸性核心在所述酸性核心微丸中的质量百分比为17％-36％；所述隔离层中的
    Figure PCTCN2018117619-appb-100020
    在所述酸性核心微丸中的质量百分比为9％-13％，所述隔离层中的Kolliphor P407在所述酸性核心微丸中的质量百分比为4％-6％；所述药物层包括所述药物活性成分、
    Figure PCTCN2018117619-appb-100021
    和Kolliphor P407，且所述药物层中的所述药物活性成分在所述酸性核心微丸中的质量百分比为14％-19％，所述药物层中的
    Figure PCTCN2018117619-appb-100022
    在所述酸性核心微丸中的质量百分比为12％-17％，所述药物层中的Kolliphor P407在所述酸性核心微丸中的质量百分比为22％-29％；
    其中，较佳地，所述酸性核心在所述酸性核心微丸中的质量百分比为35.7％；所述隔离层中的
    Figure PCTCN2018117619-appb-100023
    在所述酸性核心微丸中的质量百分比为9.6％，所述隔离层中的Kolliphor P407在所述酸性核心微丸中的质量百分比为4.7％；所述药物层包括所述药物活 性成分、
    Figure PCTCN2018117619-appb-100024
    和Kolliphor P407，且所述药物层中的所述药物活性成分在所述酸性核心微丸中的质量百分比为14.4％，所述药物层中的
    Figure PCTCN2018117619-appb-100025
    在所述酸性核心微丸中的质量百分比为12.9％，所述药物层中的Kolliphor P407在所述酸性核心微丸中的质量百分比为22.6％；
    当所述药物组合物以颗粒形式存在时，所述颗粒的制备方法为湿法制粒、辊压制粒或流化床制粒；
    其中，较佳地，所述湿法制粒采用的溶剂为异丙醇。
  9. 如权利要求7所述的含达比加群酯的药物组合物，其特征在于，所述药物组合物以粉末、微丸、颗粒、胶囊或片剂形式存在；且所述药物活性成分与所述药物组合物中的其他组分共同形成固体分散体。
  10. 如权利要求7所述的含达比加群酯的药物组合物，其特征在于，所述药物组合物以粉末、微丸、颗粒、胶囊或片剂形式存在，且所述药物组合物中的所述两性聚合物以以下两种存在形式并存，第一种存在形式是与所述药物活性成分形成固体分散体，第二种存在形式是以固体颗粒的形式存在；
    其中，较佳地，以所述第一种形式存在的两性聚合物的质量分数占所述两性聚合物的总质量的10％-100％，且不为100％。
  11. 如权利要求10所述的含达比加群酯的药物组合物，其特征在于，所述固体颗粒包括下述质量分数的各组分：40％-58％的所述两性聚合物、0％-55％的亲水性聚合物、0％-55％的稀释剂、5％-20％的崩解剂、0％-5％的抗静电剂和0％-2％的润滑剂，其中，所述亲水性聚合物的定义同权利要求3，所述稀释剂、所述崩解剂、所述抗静电剂和所述润滑剂的定义同权利要求4；所述固体颗粒的质量占所述药物组合物的总质量的质量百分比较佳地为9％-35％；
    其中，较佳地，所述固体颗粒包括下述质量分数的各组分：40％-50％的
    Figure PCTCN2018117619-appb-100026
    0％-55％的乳糖、5％-20％的交联羧甲基纤维素钠、0％-5％的二氧化硅和0％-2％的硬脂酸镁；或者，所述固体颗粒包括下述质量分数的各组分：40％-50％的
    Figure PCTCN2018117619-appb-100027
    0％-55％的Kolliphor P407、5％-20％的交联羧甲基纤维素钠、0％-5％的二氧化硅和0％-2％的硬脂酸镁；或者，所述固体颗粒包括下述质量分数的各组分：41％-58％的
    Figure PCTCN2018117619-appb-100028
    3％-33％的甘露醇、13％-26％的Kolliphor P407、5％-20％的交联羧甲基纤维素钠、0％-5％的二氧化硅和0％-2％的硬脂酸镁；
    其中，较佳地，所述固体颗粒包括下述质量分数的各组分：41.9％-50％的所述两性聚合物、19.8％-51.9％的亲水性聚合物、24.7％-51.9％的稀释剂、5.0％-5.25％的崩解剂、 0.1％-1％的抗静电剂和0.1％-1％的润滑剂，其中，所述亲水性聚合物的定义同权利要求3，所述稀释剂、所述崩解剂、所述抗静电剂和所述润滑剂的定义同权利要求4；更佳地，所述固体颗粒由如下质量分数的各组分组成：41.88％的
    Figure PCTCN2018117619-appb-100029
    51.87％的乳糖一水合物、5.25％的交联羧甲基纤维素钠、0.5％的硬脂酸镁和0.5％的二氧化硅；或者，所述固体颗粒由如下质量分数的各组分组成：41.88％的
    Figure PCTCN2018117619-appb-100030
    51.87％的Kolliphor P407、5.25％的交联羧甲基纤维素钠、0.5％的硬脂酸镁和0.5％的二氧化硅；或者，所述固体颗粒由如下质量分数的各组分组成：49.5％的
    Figure PCTCN2018117619-appb-100031
    24.7％的甘露醇、19.8％的Kolliphor P407、5.0％的交联羧甲基纤维素钠、0.5％的硬脂酸镁和0.5％的二氧化硅。
  12. 如权利要求11所述的含达比加群酯的药物组合物，其特征在于，所述固体颗粒包含辅料，所述固体颗粒的制备方法为湿法制粒、辊压制粒或流化床制粒；其中，较佳地，所述湿法制粒采用的溶剂为异丙醇。
  13. 一种如权利要求1-6中至少一项所述的药物组合物的制备方法，其特征在于，
    当所述药物组合物不含中性核心，且所述药物组合物以粉末形式存在时，所述粉末的制备方法包括如下步骤：所述药物组合物中的各组分溶解在乙醇水溶液中，喷雾干燥即可；其中，较佳地，所述乙醇水溶液中乙醇的质量分数为90％-95％；
    当所述药物组合物不含中性核心，且所述药物组合物以颗粒形式存在时，所述颗粒的制备方法包括如下步骤：采用异丙醇作为制粒溶剂，将所述药物组合物中的各组分的混合物进行湿法制粒，得湿颗粒；再将所述湿颗粒过20目筛后，干燥，即可；
    当所述药物组合物包含中性核心，且所述药物组合物以中性核心微丸的形式存在时，所述中性核心微丸的制备方法包括如下步骤：将所述药物组合物中的除所述中性核心之外的其余组分溶解于有机溶剂中形成的涂布液喷涂于所述中性核心上即可；其中，所述中性核心为预干燥后的中性核心，所述预干燥后的中性核心的水分含量较佳地低于1.0wt％；所述有机溶剂较佳地为乙醇溶液；所述乙醇水溶液中乙醇的质量分数较佳地为90％-95％；所述涂布液中所述药物组合物的质量百分数较佳地为20％-24％；所述喷涂过程中，空气的进口温度较佳地为45-60℃；所述喷涂过程中，所述颗粒的温度较佳地为30-50℃；所述喷涂结束后，较佳地将所述颗粒干燥至水分含量低于1.0wt％；
    当所述药物组合物包含酸性核心，且所述药物组合物以酸性核心微丸的形式存在时，所述酸性核心微丸的制备方法包括如下步骤：(1)将所述隔离层的各组分溶解于有机溶剂中形成的涂布液喷涂于所述酸性核心上，得酸性颗粒；(2)将所述药物层的各组分溶解于有机溶剂中形成的涂布液喷涂于所述酸性颗粒上即可；步骤(1)中，所述酸性核心为预干燥后的酸性核心，所述预干燥后的酸性核心的水分含量较佳地低于1.0wt％；步骤 (1)中，所述有机溶剂较佳地为乙醇溶液；所述乙醇水溶液中乙醇的质量分数较佳地为90％-95％；步骤(1)中，所述涂布液中所述药物组合物的质量百分数较佳地为20％-26％；步骤(1)中，所述喷涂过程中，空气的进口温度较佳地为45-60℃；步骤(1)中，所述喷涂过程中，所述酸性颗粒的温度较佳地为30-32℃；步骤(1)中，所述喷涂结束后，较佳地将所述酸性颗粒干燥至水分含量低于1.0wt％；步骤(2)中，所述有机溶剂较佳地为乙醇溶液；所述乙醇水溶液中乙醇的质量分数较佳地为90％-95％；步骤(2)中，所述涂布液中所述药物组合物的质量百分数较佳地为20％-24％；步骤(2)中，所述喷涂过程中，空气的进口温度较佳地为45-60℃；步骤(2)中，所述喷涂过程中，所述酸性核心微丸的温度较佳地为30-32℃；步骤(2)中，所述喷涂结束后，较佳地将所述酸性核心微丸干燥至水分含量低于1.0wt％。
PCT/CN2018/117619 2018-04-04 2018-11-27 含达比加群酯的药物组合物及其制备方法 WO2019192195A1 (zh)

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