WO2016074640A1 - 一种含有达比加群酯的药用组合物、其制备方法、固体制剂和用途 - Google Patents

一种含有达比加群酯的药用组合物、其制备方法、固体制剂和用途 Download PDF

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WO2016074640A1
WO2016074640A1 PCT/CN2015/094499 CN2015094499W WO2016074640A1 WO 2016074640 A1 WO2016074640 A1 WO 2016074640A1 CN 2015094499 W CN2015094499 W CN 2015094499W WO 2016074640 A1 WO2016074640 A1 WO 2016074640A1
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Prior art keywords
layer
vitamin
water
pharmaceutical composition
dabigatran etexilate
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PCT/CN2015/094499
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English (en)
French (fr)
Inventor
何雄雄
董平
蔡佳慧
黄鑫
张喜全
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正大天晴药业集团股份有限公司
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Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to US15/525,860 priority Critical patent/US10881615B2/en
Priority to EP15859607.2A priority patent/EP3219311A4/en
Priority to CN201580060552.4A priority patent/CN107072956B/zh
Publication of WO2016074640A1 publication Critical patent/WO2016074640A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—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
    • 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
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
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    • A—HUMAN NECESSITIES
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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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—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

Definitions

  • the invention relates to a pharmaceutical composition containing dabigatran etexilate, a preparation method thereof, a solid preparation and a use thereof, and belongs to the technical field of medicine.
  • the chemical structure of the dabigatran etexilate active substance of the present invention is 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ -1- Methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester having the chemical structure shown in Formula I.
  • the compound can be used to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation, to treat deep vein thrombosis and pulmonary embolism in patients who have been treated with parenteral anticoagulants for 5-10 days, and to reduce treatment. The risk of recurrence of deep vein thrombosis and pulmonary embolism in patients.
  • Patent Publication No. CN101632668 A discloses the use of pharmaceutically acceptable organic acids such as tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid or aspartic acid as dissolution and dissolution of dabigatran etexilate Promoter.
  • the patent application also discloses that a separation layer composed of a water-soluble polymer is required for isolation between the drug layer and the acid-containing core material.
  • the formulation requires that the selected acid have a water solubility of at least greater than 1 gram per 250 ml of water.
  • CN102793699 A discloses a composition comprising vitamin C and dabigatran etexilate.
  • Vitamin C is safer to the human body than other organic acids, and the use of vitamin C will improve the safety of the drug.
  • the dissolution of dabigatran etexilate can not achieve the desired effect.
  • the present invention provides a pharmaceutical composition of dabigatran etexilate suitable for oral administration, characterized in that the composition comprises a vitamin C layer and a dabigatran etexilate layer, And separated by a semipermeable membrane layer between the vitamin C layer and the dabigatran etexilate layer.
  • the present invention also provides a method of preparing a dabigatran etexilate pharmaceutical composition suitable for oral administration, the method comprising:
  • the particles 3 are coated.
  • the present invention also provides a solid preparation comprising the above-described dabigatran etexilate pharmaceutical composition.
  • the invention also relates to the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of a thromboembolic disorder.
  • Figure 1 is a schematic cross-sectional view of a dabigatran etexilate particle as one of the preferred embodiments of the present invention.
  • the present invention provides a pharmaceutical composition of dabigatran etexilate suitable for oral administration, characterized in that the composition comprises a vitamin C layer and a dabigatran etexilate layer, And separated by a semipermeable membrane layer between the vitamin C layer and the dabigatran etexilate layer.
  • the semipermeable membrane layer of the present invention can be hydrated in the eluate to produce pores, so that the eluate penetrates into the acidic pellet core, and the acidic pellet core dissolves and slowly releases from the pores, thereby generating an acidic microenvironment, thereby promoting dissolution of the outer drug. And can encapsulate the acidic pellet core during the dissolution process to prevent its separation from the outer drug layer.
  • the semipermeable membrane layer of the present invention preferably contains a water-soluble compound and a water-insoluble compound.
  • the water-soluble compound and the water-insoluble compound are dissolved by an alcohol or an alcohol solution, which is preferably a solution of isopropanol, absolute ethanol or ethanol.
  • the water-soluble compound is selected from the group consisting of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose phthalate, and fruit.
  • the water-insoluble compound is selected from the group consisting of ethyl cellulose, HPMCAS, HPMCP, methacrylic acid copolymer or a mixture of two or more thereof, wherein the methacrylic acid copolymer includes but is not limited to Eudragit E, Eudragit R, Eudragit S, Eudragit L, Eudragit RS or Eudragit LD; preferably ethyl cellulose, HPMCAS, Eudragit S100, Eudragit L100 or HPMCP; further preferred is ethyl cellulose.
  • the mass ratio of the water-soluble compound to the water-insoluble compound is from 1:0.1 to 1:10; preferably from 1:0.2 to 1:5; further preferably from 1:0.5 to 1:1.
  • the semipermeable membrane layer may further comprise an anti-adherent and/or a plasticizer.
  • the anti-adherent agent may be selected from the group consisting of talc, magnesium stearate, stearic acid, hydrogenated vegetable oil, glyceryl behenate or a mixture of two or more thereof; preferably talc.
  • the plasticizer may be selected from triethyl citrate, tributyl citrate, triacetin, polyethylene glycol or a mixture of two or more of the above; preferably polyethylene glycol.
  • the vitamin C layer may contain only vitamin C, and may further include a binder and/or a filler.
  • the vitamin C may be particulate vitamin C, powdered vitamin C or a combination of both.
  • the binder may be selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, sodium carboxymethylcellulose, methylcellulose, pectin, gum arabic or a mixture of two or more thereof Preference is given to hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone or gum arabic; further preferred are hydroxypropylcellulose or gum arabic.
  • the filler may be selected from the group consisting of microcrystalline cellulose, lactose, starch, mannitol, pregelatinized starch, dextrin or a mixture of two or more of the above; preferably microcrystalline cellulose.
  • the dabigatran etexilate layer may comprise only dabigatran etexilate, and may further comprise a binder and/or a dispersing agent.
  • the binder may be selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, povidone, N-vinylpyrrolidone, Arabia a gum or a mixture of two or more of the above; preferably hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, povidone or gum arabic; further preferably hydroxypropylcellulose or carboxymethylcellulose Sodium; the binder is preferably dissolved by an alcohol, preferably isopropanol; the dispersant may be an anti-adhesive such as talc, magnesium stearate, stearic acid, hydrogenated vegetable oil, glyceryl behenate or a mixture of two or more of the above; preferably talc.
  • the semipermeable membrane layer has a weight gain of 0.5 wt% to 20 wt% with respect to the vitamin C layer; preferably, the semipermeable membrane layer has a weight gain of 2 wt% to 10 wt% with respect to the vitamin C layer; further preferably, the semipermeable membrane is The layer has a weight gain of from 5 wt% to 10 wt% relative to the vitamin C layer.
  • the weight ratio of the above dabigatran group layer to the vitamin C layer is from 1:0.15 to 1:1.8, preferably from 1:0.6 to 1:1.1.
  • a water-soluble polymer layer may be further included; the water-soluble polymer may be selected From hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, sodium carboxymethylcellulose, methylcellulose, pectin, gum arabic or a mixture of two or more thereof; preferably hydroxypropylcellulose Or sodium carboxymethylcellulose, povidone or gum arabic; further preferred is hydroxypropylcellulose or gum arabic.
  • the water soluble polymer is gum arabic.
  • the above water-soluble polymer layer may further include a dispersing agent and/or a plasticizer.
  • the dispersing agent may be an anti-adhesive agent such as talc, magnesium stearate, stearic acid, hydrogenated vegetable oil, glyceryl behenate or a mixture of two or more of the above, preferably talc.
  • the plasticizer may be selected from triethyl citrate, tributyl citrate, triacetin, polyethylene glycol or a mixture of two or more of the above; preferably polyethylene glycol.
  • the weight gain ratio of the water-soluble polymer layer to the semipermeable membrane layer is 1:0.1 to 1:10; the preferred ratio is 1:0.2 to 1:5; further preferably, the ratio is 1:1 to 1:1.1.
  • the pharmaceutical composition of the present invention includes, but is not limited to, granules, tablets, pills, pellets; the granules, tablets, pills or pellets may be a multilayer structure; in the multilayer structure, the vitamin C layer
  • the relative position of the dabigatran group layer can be arbitrarily changed, for example, the vitamin C layer is located in the inner layer, the dabigatran group layer is separated by the semipermeable membrane layer or is located between the water-soluble polymer layer and the semi-permeable membrane layer.
  • the outer layer; or the dabigatran group layer is located in the inner layer, the vitamin C layer is located at the outer layer via the semipermeable membrane layer or via the water soluble polymer layer and the semipermeable membrane layer.
  • the vitamin C layer or dabigatran etexilate layer may also be coated on the release layer (ie, the semipermeable membrane layer, or the water soluble polymer layer and the semipermeable membrane layer) in a coating form. .
  • a preferred embodiment of the invention is a multiparticulate formulation wherein each particle is of the structure of Figure 1.
  • the substantially spherical or spherical acid core of the granule comprises vitamin C; and then, a barrier layer composed of a water-soluble polymer layer and a semi-permeable membrane layer for isolating the vitamin C acid core and the dabigatran etexilate layer;
  • the barrier layer is then surrounded by the same spherical layer of dabigatran etexilate; optionally, the dabigatran etexilate layer can be further surrounded by a coating.
  • the above coating may comprise a film former and/or a plasticizer and/or a pigment which are commonly used in medicine.
  • the film forming agent may be hydroxypropyl fiber Or hydroxypropylmethylcellulose, povidone, sodium carboxymethylcellulose, methylcellulose or a mixture of two or more of the above.
  • the plasticizer may be triethyl citrate, tributyl citrate, triacetin, polyethylene glycol or a mixture of two or more of the above.
  • the pigment may be titanium dioxide, iron oxide yellow, iron oxide red or a mixture of two or more of the above.
  • the present invention also provides a method of preparing a dabigatran etexilate pharmaceutical composition suitable for oral administration, the method comprising the steps of:
  • the particles 3 are coated.
  • the method includes the following steps:
  • the vitamin C pellet is placed in a fluidized bed, a suspension comprising gum arabic, talc and water is fluidized to prepare a particle 1 having a water-soluble polymer layer;
  • the granule 1 is placed in a fluidized bed, the suspension containing hydroxypropyl cellulose, ethyl cellulose and talc is fluidized, and the particles within 1 mm are screened as particles 2 further having a semipermeable membrane layer;
  • the granule 2 is placed in a fluidized bed, and a suspension containing hydroxypropylcellulose, talc, dabigatran etexilate and isopropanol is fluidized, and the particles within 1.5 mm are screened as further having Darby.
  • the preparation method of the above granular vitamin C includes, but is not limited to, a fluidized bed, a coating tank or an extrusion spheronization apparatus; the above particles 3 may further be coated, and the coating coating method includes but is not limited to a fluidized bed and a package. A trough or a common film coating device.
  • the present invention provides a solid preparation comprising the above-described dabigatran etexilate pharmaceutical composition, which may be in the form of granules, tablets or capsules; in some specific embodiments In one embodiment, the solid formulation is in the form of a capsule.
  • the invention also relates to the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of a thromboembolic disorder.
  • dabigatran etexilate refers to dabigatran etexilate of formula I and pharmaceutically acceptable salts thereof; and the pharmaceutically acceptable salts include, but are not limited to, dabigab mesylate Group ester.
  • the fluidized drug application refers to a method of applying a suspension to a surface of a solid particle in a fluidized bed.
  • HPMCP means hydroxypropylmethylcellulose phthalate.
  • HPMCAS refers to hydroxypropylmethylcellulose acetate succinate.
  • the semipermeable membrane layer refers to a coating layer having a certain strength in an elution medium and capable of generating pores.
  • the inventors found in a large number of in-depth studies on the vitamin C layer, the barrier layer and the dabigatran etexilate layer, and found that the semi-permeable layer is used to isolate the vitamin C layer and the dabigatran etexilate layer, which can be the dissolution of dabigatran etexilate. Providing a good acidic microenvironment significantly improves the in vitro dissolution of dabigatran etexilate.
  • step 1.2) taking the prescription amount of granule vitamin C, placed in a fluidized bed, and the suspension prepared in step 1.1) is fluidized and applied; the process parameters: atomization pressure is 1500 mbar to 1700 mbar, and the inlet air temperature is 60 ° C. Between 70 ° C, the material temperature is maintained between 40 ° C ⁇ 50 ° C;
  • the particles with a particle size between 0.6mm and 0.8mm are sieved as the vitamin C core, and the water content should be ⁇ 0.7%;
  • step 1.3) Prepare the vitamin C core (the sum of the prescription amounts of powder vitamin C, granule vitamin C and gum arabic a in the vitamin C core material), place it in the fluidized bed, and step 2.1)
  • the prepared suspension fluidized the medicine; the process parameters: the atomization pressure is 1300 mbar to 1500 mbar, the inlet air temperature is between 50 ° C and 60 ° C, and the material temperature is maintained between 35 ° C and 45 ° C to obtain a water-soluble solution.
  • Particle 1 of the polymer layer the process parameters: the atomization pressure is 1300 mbar to 1500 mbar, the inlet air temperature is between 50 ° C and 60 ° C, and the material temperature is maintained between 35 ° C and 45 ° C to obtain a water-soluble solution.
  • step 3.2 taking a prescription of dabigatran mesylate, adding to the suspension prepared in step 3.1) with stirring, stirring to uniformly disperse;
  • a vitamin C pellet was prepared by using powdered vitamin C, granule vitamin C and gum arabic a , and then a suspension containing gum arabic b and talc a was fluidized and then contained.
  • the suspension of hydroxypropyl cellulose a and talc b is fluidized, and finally the suspension containing dabigatran etexilate, hydroxypropyl cellulose b and talc c is fluidized and filtered.
  • the resulting granules Referring to the preparation method of Comparative Example 1, a vitamin C pellet was prepared by using powdered vitamin C, granule vitamin C and gum arabic a , and then a suspension containing gum arabic b and talc a was fluidized and then contained.
  • the suspension of hydroxypropyl cellulose a and talc b is fluidized, and finally the suspension containing dabigatran etexilate, hydroxypropyl cellulose b and talc c is fluidized and filtered.
  • the pellet of 287.01 mg of the pellet of Comparative Example 1 was poured into a hollow capsule of No. 1 plant to obtain 110 mg (as C 34 H 41 N 7 O 5 ) a standard of dabigatran mesylate capsule.
  • step 1.2) taking the prescription amount of granule vitamin C, placed in a fluidized bed, and the suspension prepared in step 1.1) is fluidized and applied; the process parameters: atomization pressure is 1500 mbar to 1700 mbar, and the inlet air temperature is 60 ° C. Between 70 ° C, the material temperature is maintained between 40 ° C ⁇ 50 ° C;
  • the particles with a particle size between 0.6mm and 0.8mm are sieved as the vitamin C core, and the water content should be ⁇ 0.7%.
  • Steps for taking the prescription amount 1.3) Prepared vitamin C pellet (the sum of the prescription amounts of powdered vitamin C, granule vitamin C and gum arabic a in the vitamin C core material), placed in a fluidized bed, step 2.1 The prepared suspension fluidized the medicine; the process parameters: the atomization pressure is 1300 mbar to 1500 mbar, the inlet air temperature is between 50 ° C and 60 ° C, and the material temperature is maintained between 35 ° C and 45 ° C, and the obtained a particle 1 of a water soluble polymer layer;
  • step 3.2 Take the granule 1 prepared in step 2.2), place it in a fluidized bed, and fluidize the suspension prepared in step 3.1).
  • the particles within 1 mm are selected as the particles 2 having the semipermeable membrane layer;
  • step 4.1 taking a prescription of dabigatran mesylate, adding to the suspension prepared in step 4.1) with stirring, stirring to uniformly disperse;
  • step 4.3 taking the pellet 2 prepared in step 3.3), placing it in a fluidized bed, fluidizing the suspension prepared in step 4.2); process parameters: atomization pressure is 1800 mbar to 2200 mbar, inlet air temperature is 35 Between °C and 55 °C, the material temperature is maintained at 28 ° C ⁇ 40 ° C, the weight loss of the particles should be ⁇ 0.7%;
  • a vitamin C pellet was prepared by using powdered vitamin C, granule vitamin C and hydroxypropylmethylcellulose a ; and suspension containing hydroxypropylmethylcellulose b and talc a was further prepared .
  • the dispersion medium is water
  • the coating liquid containing lactose and HPMCAS is fluidized and applied (the dispersion medium is 80% ethanol solution) to obtain a semi-transparent The particles of the film layer; finally, the suspension containing dabigatran etexilate, hydroxypropyl methylcellulose c and talc b is fluidized and sieved to prepare particles having a dabigatran etexilate layer.
  • Example 1 granule vitamin C having a particle diameter of 0.6 mm to 0.8 mm was sieved as a vitamin C pellet; and a suspension containing povidone (K30) a and talc a was fluidized.
  • a drug (dispersion medium is water) to obtain particles having a water-soluble polymer layer; then, a suspension containing sucrose (d50 ⁇ 5 ⁇ m, d90 ⁇ 15 ⁇ m) and Eudragit S100 is fluidized (the dispersion medium is an anhydrous ethanol solution) ), obtaining a particle having a semipermeable membrane layer; finally, fluidizing the suspension containing dabigatran etexilate, povidone (K30) b and talc b , and screening to obtain dabigatran Particles of the ester layer.
  • the dispersion medium is water
  • Example 1 granule vitamin C having a particle diameter of 0.6 mm to 0.8 mm was sieved as a vitamin C pellet; and a suspension containing sodium carboxymethylcellulose a and talc a was fluidized.
  • a drug (dispersion medium is water) to obtain particles having a water-soluble polymer layer; then a suspension containing hydroxypropylcellulose and Eudragit L100 is fluidized (the dispersion medium is an anhydrous ethanol solution) to obtain a half The particles of the permeation layer; finally, the suspension containing dabigatran etexilate, sodium carboxymethylcellulose b and talc b is fluidized and sieved to prepare granules having a dabigatran etexilate layer.
  • the vitamin C core was prepared by using powdered vitamin C, granule vitamin C and gum arabic a ; then the suspension containing methyl cellulose a and talc a was fluidized (dispersion medium) For water), obtaining particles having a water-soluble polymer layer; then fluidizing the coating liquid containing methyl cellulose b and hydroxypropyl methyl cellulose phthalate (HPMCP) (dispersion medium) For 80% ethanol solution, obtain a granule with a semi-permeable membrane layer; finally, a suspension containing dabigatran etexilate, gum arabic b and talc b is fluidized and sieved to obtain Dabiga Particles of the group ester layer.
  • HPMCP hydroxypropyl methyl cellulose phthalate
  • Example 1 granule vitamin C having a particle diameter of 0.6 mm to 0.8 mm is sieved as a vitamin C pellet; and carboxymethylcellulose sodium a , talc a and polyethylene glycol-6000 are further contained.
  • a fluidizing the drug suspension (dispersion medium is water), a water-soluble polymer particles obtained layer; the suspension was then polyethylene glycol -6000 b and ethyl cellulose fluidizing the drug (dispersed
  • the medium is an anhydrous ethanol solution), and a granule having a semi-permeable membrane layer is obtained; finally, a suspension containing dabigatran etexilate, sodium carboxymethylcellulose b and talc b is fluidized, and the solution is prepared. A granule having a dabigatran etexilate layer is obtained.
  • the vitamin C pellet was prepared by using powdered vitamin C, granule vitamin C and gum arabic; and the suspension containing sodium carboxymethylcellulose a and talc a was fluidized (dispersed)
  • the medium is water), obtaining particles having a water-soluble polymer layer; then, the coating liquid containing sodium carboxymethyl cellulose b and ethyl cellulose is fluidized (the dispersion medium is an anhydrous ethanol solution), and obtained The particles of the semipermeable membrane layer; finally, the suspension containing dabigatran etexilate, sodium carboxymethylcellulose c and talc b is fluidized and sieved to prepare particles having dabigatran etexilate layer .
  • the pellet of 291.71 mg of the pellet of Example 2 was poured into a No. 1 plant hollow capsule to obtain 110 mg (as C 34 H 41 N 7 O 5 ) a standard of dabigatran mesylate capsule.
  • Example 2 198.88 mg of the pellets of Example 2 was placed and filled into a No. 1 plant hollow capsule to obtain 75 mg (as C 34 H 41 N 7 O 5 ) a standard of dabigatran mesylate capsule.
  • Comparative Example 3 Comparative Example 4, Comparative Example 5, Example 8, Example 9 and a commercially available reference preparation were respectively taken, and the dissolution test method was used (Chinese Pharmacopoeia 2010 Edition 2 Appendix X C First Method) Add 900 ml of medium, rotate at a speed of 100 rpm, and operate according to the law. Samples were taken at 10, 20, 30, 45, and 60 minutes to determine the dissolution.

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Abstract

一种含有达比加群酯的药用组合物、及其制备方法和用途，以及包含所述药用组合物的固体制剂。所述药用组合物包含维生素C层和达比加群酯层，且在两层之间通过半透膜层隔离，所述半透膜层包含水溶性化合物、水不溶性化合物以及任选的抗粘剂和/或增塑剂。

Description

一种含有达比加群酯的药用组合物、其制备方法、固体制剂和用途 技术领域
本发明涉及一种含有达比加群酯的药用组合物、其制备方法、固体制剂和用途，属于医药技术领域。
背景技术
本发明所述的达比加群酯活性物质的化学结构为3-[(2-{[4-(己氧羰基氨基-亚氨基-甲基)-苯基氨基]-甲基}-1-甲基-1H-苯并咪唑-5-羰基)-吡啶-2-基-氨基]-丙酸乙酯，其化学结构如式I所示。该化合物可用于降低非瓣膜病心房颤动患者的中风和全身性栓塞风险、治疗已用胃肠外抗凝剂治疗5-10天的患者的深静脉血栓栓塞和肺栓塞、降低已接受过治疗的患者的深静脉血栓栓塞和肺栓塞的复发风险。
Figure PCTCN2015094499-appb-000001
由于达比加群酯在pH＞4.0的介质中几乎不溶，故酸性环境有利于主要活性成分达比加群酯从药物制剂中溶出和体内吸收。专利公开号CN101632668 A公开了可采用医药上可接受的有机酸，如酒石酸、富马酸、琥珀酸、柠檬酸、苹果酸、谷氨酸或天冬氨酸作为达比加群酯溶解和溶出促进剂。该专利申请还公开了药物层与含酸的芯材料之间需要采用水溶性聚合物构成的隔离层进行隔离。该制剂要求所选酸的水溶性应至少大于1克/250ml水。
CN102793699 A公开了一种包括维生素C和达比加群酯的组合物，相对于其它的有机酸，维生素C对人体的安全性更高，采用维生素C将提高药物的安全性。但由于维生素C在体内的代谢过程非常复杂，因此无论是将维生素C和达比加群酯简单混合，还是通过物理方式隔离，达比加群酯的溶出均不能达到预期的效果。
申请人意外地发现，通过采用半透膜层隔离的方式，解决了上述技术难题，并达到了预期的效果。
发明内容
作为本发明的第一方面，本发明提供了一种适于口服给药的达比加群酯药用组合物，其特征在于：所述组合物包含维生素C层和达比加群酯层，且在维生素C层与达比加群酯层之间通过半透膜层隔离。
作为本发明的第二方面，本发明还提供了一种制备适于口服给药的达比加群酯药用组合物的方法，所述方法包括：
(1)取颗粒维生素C置于流化床内，将包含粉末维生素C、水以及任选的粘合剂和/或填充剂 的混悬液进行流化上药，筛出粒径在0.6mm～0.8mm之间的颗粒作为维生素C丸芯；
(2)将所述维生素C丸芯置于流化床内，将包含水溶性聚合物、水以及任选的分散剂和/或增塑剂的混悬液流化上药，制得具有水溶性聚合物层的颗粒1；
(3)将所述颗粒1置于流化床内，将包含水溶性化合物、水不溶性化合物、醇或醇溶液以及任选的抗粘剂和/或增塑剂的混悬液流化上药，筛选1mm以内的颗粒，作为具有半透膜层的颗粒2；
(4)将所述颗粒2置于流化床内，将包含达比加群酯或其可药用盐、醇以及任选的粘合剂和/或分散剂的混悬液流化上药，筛选1.5mm以内的颗粒作为具有达比加群酯层的颗粒3；以及
(5)任选地，对所述颗粒3包覆涂层。
作为本发明的第三方面，本发明还提供了包含上述达比加群酯药用组合物的固体制剂。
作为本发明的第四方面，本发明还涉及本发明的药用组合物在制备用于治疗血栓栓塞性疾病的药物中的用途。
附图说明
图1作为本发明优选实施方式之一的达比加群酯颗粒的断面示意图。
具体实施方式
作为本发明的第一方面，本发明提供了一种适于口服给药的达比加群酯药用组合物，其特征在于：所述组合物包含维生素C层和达比加群酯层，且在维生素C层与达比加群酯层之间通过半透膜层隔离。
本发明所述的半透膜层能够在溶出液中水化，产生孔道，使溶出液渗入酸性丸芯，酸性丸芯溶解并从孔道缓慢释放，产生酸性微环境，从而促进外层药物的溶出；且能够在溶出过程中包裹酸性丸芯，防止其与外层药物层的分离。
本发明的半透膜层优选包含水溶性化合物和水不溶性化合物。其中，水溶性化合物和水不溶性化合物通过醇或醇溶液进行溶解，所述醇或醇溶液优选异丙醇、无水乙醇或乙醇溶液。
所述水溶性化合物选自甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、聚维酮、羧甲基纤维素钠、邻苯二甲酸羟丙基甲基纤维素、果胶、环糊精、半乳甘露聚糖、平均分子量为4000以上的聚乙二醇、明胶、水溶性的单糖或多糖或上述两种以上的混合物；优选乳糖、蔗糖、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、PEG-6000、聚维酮或羧甲基纤维素钠；更进一步优选羟丙基纤维素或聚维酮。
所述水不溶性化合物选自乙基纤维素、HPMCAS、HPMCP、甲基丙烯酸共聚物或上述两种以上的混合物，其中，甲基丙烯酸共聚物包括但不限于Eudragit E、Eudragit R、Eudragit S、Eudragit L、Eudragit RS或Eudragit LD；优选乙基纤维素、HPMCAS、Eudragit S100、Eudragit L100或HPMCP；进一步优选乙基纤维素。
所述半透膜层中，水溶性化合物与水不溶性化合物的质量比为1∶0.1～1∶10；优选1∶0.2～1∶5；进一步优选1∶0.5～1∶1。
所述半透膜层还可以进一步包含抗粘剂和/或增塑剂。所述抗粘剂可以选自滑石粉、硬脂酸镁、硬脂酸、氢化植物油、山嵛酸甘油酯或上述两种以上的混合物；优选滑石粉。所述增塑剂可以选自柠檬酸三乙酯、柠檬酸三丁酯、甘油三乙酸酯、聚乙二醇或上述两种以上的混合物；优选聚乙二醇。
所述维生素C层可以仅包含维生素C，也可以进一步包括粘合剂和/或填充剂。所述维生素C可以是颗粒维生素C、粉末维生素C或者两者的组合。所述粘合剂可以选自羟丙基纤维素、羟丙基甲基纤维素、聚维酮、羧甲基纤维素钠、甲基纤维素、果胶、阿拉伯胶或上述两种以上的混合物；优选羟丙基纤维素、羟丙基甲基纤维素、聚维酮或阿拉伯胶；进一步优选羟丙基纤维素或阿拉伯胶。所述填充剂可以选自微晶纤维素、乳糖、淀粉、甘露醇、预胶化淀粉、糊精或上述两种以上的混合物；优选微晶纤维素。
所述达比加群酯层可以仅包含达比加群酯，还可以进一步包括粘合剂和/或分散剂。所述粘合剂可以选自羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、羟乙基纤维素、羧甲基纤维素钠、聚维酮、N-乙烯吡咯烷酮、阿拉伯胶或上述两种以上的混合物；优选羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、聚维酮或阿拉伯胶；进一步优选羟丙基纤维素或羧甲基纤维素钠；所述粘合剂优选通过醇、优选异丙醇进行溶解；上述分散剂可以是抗粘剂，例如滑石粉、硬脂酸镁、硬脂酸、氢化植物油、山嵛酸甘油酯或上述两种以上的混合物；优选滑石粉。
上述半透膜层相对于维生素C层增重为0.5wt％～20wt％；优选地，上述半透膜层相对于维生素C层增重为2wt％～10wt％；进一步优选地，上述半透膜层相对于维生素C层增重为5wt％～10wt％。
上述达比加群酯层和维生素C层的重量比1∶0.15～1∶1.8，优选1∶0.6～1∶1.1。
在某些特定的实施例中，在维生素C与达比加群酯层之间，除了包括上述半透膜层之外，还可以进一步包括水溶性聚合物层；所述水溶性聚合物可以选自羟丙基纤维素、羟丙基甲基纤维素、聚维酮、羧甲基纤维素钠、甲基纤维素、果胶、阿拉伯胶或上述两种以上的混合物；优选羟丙基纤维素、羧甲基纤维素钠、聚维酮或阿拉伯胶；进一步优选羟丙基纤维素或阿拉伯胶。在某些特定的实施例中，所述水溶性聚合物为阿拉伯胶。
上述水溶性聚合物层还可以进一步包括分散剂和/或增塑剂。所述分散剂可以是抗粘剂，例如滑石粉、硬脂酸镁、硬脂酸、氢化植物油、山嵛酸甘油酯或上述两种以上的混合物，优选滑石粉。所述增塑剂可以选自柠檬酸三乙酯，柠檬酸三丁酯，甘油三乙酸酯、聚乙二醇或上述两种以上的混合物；优选聚乙二醇。
上述水溶性聚合物层增重与半透膜层增重比值为1∶0.1～1∶10；优选比值为1∶0.2～1∶5；进一步优选比值为1∶1～1∶1.1。
本发明的药用组合物包括但不限于颗粒剂、片剂、丸剂、微丸；所述颗粒剂、片剂、丸剂或微丸可以是多层结构；所述多层结构中，维生素C层和达比加群酯层的相对位置可以任意调换，例如维生素C层位于较内层、达比加群酯层隔着半透膜层或者隔着水溶性聚合物层和半透膜层位于较外层；或者达比加群酯层位于较内层、维生素C层隔着半透膜层或者隔着水溶性聚合物层和半透膜层位于较外层。在此情况下，所述维生素C层或达比加群酯层还可以包衣形式包覆于所述隔离层(即，半透膜层、或者水溶性聚合物层和半透膜层)外。
本发明一个优选实施方式为多粒状制剂，其中各个颗粒是如图1的结构。该颗粒的大致球状或球状的酸芯中包含维生素C；接着，有一层由水溶性聚合物层和半透膜层构成的隔离层，用于隔离维生素C酸芯与达比加群酯层；接着，该隔离层再被达比加群酯的相同球形层包围；任选地，该达比加群酯层可进一步被涂层包围。
上述涂层可以包含药物上常用的成膜剂和/或增塑剂和/或色素。所述的成膜剂可以是羟丙基纤维 素、羟丙基甲基纤维素、聚维酮、羧甲基纤维素钠、甲基纤维素或上述两种以上的混合物。所述增塑剂可以是柠檬酸三乙酯，柠檬酸三丁酯，甘油三乙酸酯、聚乙二醇或上述两种以上的混合物。所述色素可以是二氧化钛、氧化铁黄、氧化铁红或上述两种以上的混合物。
作为本发明的第二方面，本发明还提供了一种制备适于口服给药的达比加群酯药用组合物的方法，所述方法包括如下步骤：
(1)取颗粒维生素C置于流化床内，将包含粉末维生素C、水以及任选的粘合剂和/或填充剂的混悬液进行流化上药，筛出粒径在0.6mm～0.8mm之间的颗粒作为维生素C丸芯；
(2)将所述维生素C丸芯置于流化床内，将包含水溶性聚合物、水以及任选的分散剂和/或增塑剂的混悬液流化上药，制得具有水溶性聚合物层的颗粒1；
(3)将所述颗粒1置于流化床内，将包含水溶性化合物、水不溶性化合物、醇或醇溶液以及任选的抗粘剂和/或增塑剂的混悬液流化上药，筛选1mm以内的颗粒，作为具有半透膜层的颗粒2；
(4)将所述颗粒2置于流化床内，将包含达比加群酯或其可药用盐、醇以及任选的粘合剂和/或分散剂的混悬液流化上药，筛选1.5mm以内的颗粒作为具有达比加群酯层的颗粒3；以及
(5)任选地，对所述颗粒3包覆涂层。
作为一种优选的实施方式，所述方法包括如下步骤：
取颗粒维生素C，置于流化床内，将包含阿拉伯胶、粉末维生素C和水的混悬液进行流化上药，筛出粒径在0.6mm～0.8mm之间的颗粒作为维生素C丸芯；
将维生素C丸芯置于流化床内，将包含阿拉伯胶、滑石粉和水的混悬液流化上药，制得具有水溶性聚合物层的颗粒1；
取羟丙基纤维素和乙基纤维素，加异丙醇搅拌溶解，再加入滑石粉，搅拌使充分混悬，得到混悬液；
将颗粒1置于流化床内，将包含羟丙基纤维素、乙基纤维素和滑石粉的混悬液流化上药，筛选1mm以内的颗粒作为进一步具有半透膜层的颗粒2；
将颗粒2置于流化床内，将包含羟丙基纤维素、滑石粉、达比加群酯和异丙醇的混悬液流化上药，筛选1.5mm以内的颗粒作为进一步具有达比加群酯层的颗粒3。
上述颗粒维生素C的制备方法包括但不限于流化床、包衣槽或挤出滚圆设备；上述颗粒3可进一步包覆涂层，所述涂层包覆方法包括但不限于流化床、包衣槽或常用的涂膜装置。
作为本发明的第三方面，本发明还提供了包含上述达比加群酯药用组合物的固体制剂，所述的固体制剂形式可以是颗粒剂、片剂或胶囊；在某些特定的实施例中，所述的固体制剂呈胶囊形式。
作为本发明的第四方面，本发明还涉及本发明的药用组合物在制备用于治疗血栓栓塞性疾病的药物中的用途。
本发明中，除特别说明外，达比加群酯是指式I所示的达比加群酯及其可药用盐；所述的可药用盐包括但不限于甲磺酸达比加群酯。
本发明中，流化上药是指用流化床将混悬液涂敷于固体颗粒表面的方法。
本发明中，HPMCP是指羟丙甲基纤维素邻苯二甲酸酯。
本发明中，HPMCAS是指醋酸羟丙基甲基纤维素琥珀酸酯。
本发明中，除特别说明外，所述半透膜层指在溶出介质中具有一定的强度且能够产生孔道的包衣层。
发明人在对维生素C层、隔离层和达比加群酯层的大量深入研究中，发现采用半透膜层隔离维生素C层和达比加群酯层，能够为达比加群酯的溶出提供良好的酸性微环境，显著改善达比加群酯的体外溶出。
实施例
以下以具体的实施例说明本发明的技术方案，但本发明的保护范围不限于所述实施例的范围。所采用的试剂均为市售产品。实施例中，除非特殊说明，“％”是指重量百分含量。
比较实施例1
处方：
Figure PCTCN2015094499-appb-000002
制备方法：
1.1)取处方量阿拉伯胶a，加水57ml搅拌溶解，再加入处方量粉末维生素C，搅拌使充分混悬，得到混悬液；
1.2)取处方量颗粒维生素C，置于流化床内，将步骤1.1)制备得到的混悬液进行流化上药；工艺参数：雾化压力为1500mbar～1700mbar，进风温度在60℃～70℃之间，物料温度保持在40℃～50℃之间；
1.3)上药结束后筛出粒径在0.6mm～0.8mm之间的颗粒作为维生素C丸芯，水分应≤0.7％；
2.1)取处方量阿拉伯胶b，加水搅拌溶解，再加入处方量滑石粉a，搅拌使充分混悬，得到混悬液；
2.2)取处方量步骤1.3)制备得的维生素C丸芯(维生素C芯材料中粉末维生素C、颗粒维生素C和阿拉伯胶a的处方量之和)，置于流化床内，将步骤2.1)制备得的混悬液流化上药；工艺参数：雾化压力为1300mbar～1500mbar，进风温度在50℃～60℃之间，物料温度保持在35℃～45℃之间，制得具有水溶性聚合物层的颗料1；
3.1)取处方量羟丙基纤维素，加异丙醇搅拌溶解，再加入处方量滑石粉b，搅拌使充分混悬，将得到的混悬液降温，使温度低于5℃；
3.2)取处方量甲磺酸达比加群酯，搅拌下加入步骤3.1)制备得的混悬液中，搅拌使均匀分散；
3.3)取上述步骤2.2)制备得的颗粒1，置于流化床内，将步骤3.2)制备得的混悬液流化上药；工艺参数：雾化压力为1800mbar～2200mbar；进风温度在35℃～55℃之间，物料温度保持在28℃～40℃；颗粒干燥失重应≤0.7％；
3.4)上药结束后筛选1.5mm以内的颗粒。
比较实施例2
处方：
Figure PCTCN2015094499-appb-000003
制备方法：
参照比较实施例1的制备方法，先用粉末维生素C、颗粒维生素C和阿拉伯胶a制备维生素C丸芯，再将包含阿拉伯胶b和滑石粉a的混悬液流化上药，然后将包含羟丙基纤维素a和滑石粉b的混悬液流化上药，最后再将包含达比加群酯、羟丙基纤维素b和滑石粉c的混悬液流化上药，并筛选制得的颗粒。
比较实施例3 达比加群酯胶囊的制备
取比较实施例1中微丸287.01mg，灌装入1号植物空心胶囊内，得110mg(以C34H41N7O5计)规格甲磺酸达比加群酯胶囊。
比较实施例4 达比加群酯胶囊的制备
取比较实施例1中微丸195.68mg，灌装入2号植物空心胶囊内，得75mg(以C34H41N7O5计)规格甲磺酸达比加群酯胶囊。
比较实施例5 达比加群酯胶囊的制备
取比较实施例2中微丸291.71mg，灌装入2号植物空心胶囊内，得110mg(以C34H41N7O5计)规格甲磺酸达比加群酯胶囊。
实施例1
处方：
Figure PCTCN2015094499-appb-000004
制备方法：
1.1)取阿拉伯胶a，加水57ml搅拌溶解，再加入处方量粉末维生素C，搅拌使充分混悬，得到混悬液；
1.2)取处方量颗粒维生素C，置于流化床内，将步骤1.1)制备得的混悬液进行流化上药；工艺参数：雾化压力为1500mbar～1700mbar，进风温度在60℃～70℃之间，物料温度保持在40℃～50℃之间；
1.3)上药结束后筛出粒径在0.6mm～0.8mm之间的颗粒作为维生素C丸芯，水分应≤0.7％。
2.1)取处方量阿拉伯胶b，加水搅拌溶解，再加入处方量滑石粉a，搅拌使充分混悬，得到混悬液；
2.2)取处方量的步骤1.3)制备得的维生素C丸芯(维生素C芯材料中粉末维生素C、颗粒维生素C和阿拉伯胶a的处方量之和)，置于流化床内，将步骤2.1)制备得的混悬液流化上药；工艺参数：雾化压力为1300mbar～1500mbar，进风温度在50℃～60℃之间，物料温度保持在35℃～45℃之间，制得具有水溶性聚合物层的颗粒1；
3.1)取处方量羟丙基纤维素a和乙基纤维素，加异丙醇搅拌溶解，再加入处方量滑石粉b，搅拌使充分混悬，得到混悬液；
3.2)取步骤2.2)制得的颗粒1，置于流化床内，将步骤3.1)制备得的混悬液流化上药。工艺参数：雾化压力为1800mbar～2000mbar，进风温度在50℃～60℃之间，物料温度保持在35℃～50℃之间；
3.3)上药结束后筛选1mm以内的颗粒作为具有半透膜层的颗粒2；
4.1)取处方量羟丙基纤维素b，加异丙醇搅拌溶解，再加入处方量滑石粉c，搅拌使充分混悬，将混悬液降温，使温度低于5℃；
4.2)取处方量甲磺酸达比加群酯，搅拌下加入步骤4.1)制备得的混悬液中，搅拌使均匀分散；
4.3)取步骤3.3)制备得的颗粒2，置于流化床内，将步骤4.2)制备得的混悬液流化上药；工艺参数：雾化压力为1800mbar～2200mbar，进风温度在35℃～55℃之间，物料温度保持在28℃～40℃，颗粒干燥失重应≤0.7％；
4.4)上药结束后筛选1.5mm以内的颗粒。
参照实施例1的制备方法制备实施例2～7的处方颗粒。
实施例2
处方：
Figure PCTCN2015094499-appb-000005
制备方法：
参照实施例1的制备方法，先用粉末维生素C、颗粒维生素C和羟丙基甲基纤维素a制备维生素C丸芯；再将包含羟丙基甲基纤维素b和滑石粉a的混悬液流化上药(分散介质为水)，获得具有水溶性聚合物层的颗粒；然后将包含乳糖和HPMCAS的包衣液流化上药(分散介质为80％乙醇溶 液)，获得具有半透膜层的颗粒；最后再将包含达比加群酯、羟丙基甲基纤维素c和滑石粉b的混悬液流化上药，筛选，制得具有达比加群酯层的颗粒。
实施例3
处方：
Figure PCTCN2015094499-appb-000006
制备方法：
参照实施例1的制备方法，筛分出粒径在0.6mm～0.8mm的颗粒维生素C作为维生素C丸芯；再将包含聚维酮(K30)a和滑石粉a的混悬液流化上药(分散介质为水)，获得具有水溶性聚合物层的颗粒；然后将包含蔗糖(d50≤5μm，d90≤15μm)和Eugragit S100的混悬液流化上药(分散介质为无水乙醇溶液)，获得具有半透膜层的颗粒；最后再将包含达比加群酯、聚维酮(K30)b和滑石粉b的混悬液流化上药，筛选，制得具有达比加群酯层的颗粒。
实施例4
处方：
Figure PCTCN2015094499-appb-000007
制备方法：
参照实施例1的制备方法，筛分出粒径在0.6mm～0.8mm的颗粒维生素C作为维生素C丸芯；再将包含羧甲基纤维素钠a和滑石粉a的混悬液流化上药(分散介质为水)，获得具有水溶性聚合物层的颗粒；然后将包含羟丙基纤维素和Eugragit L100的混悬液流化上药(分散介质为无水乙醇溶液)，获得具有半透膜层的颗粒；最后再将包含达比加群酯、羧甲基纤维素钠b和滑石粉b的混悬液流化上药，筛选，制得具有达比加群酯层的颗粒。
实施例5
处方：
Figure PCTCN2015094499-appb-000008
Figure PCTCN2015094499-appb-000009
制备方法：
参照实施例1的制备方法，先用粉末维生素C、颗粒维生素C和阿拉伯胶a制备维生素C丸芯；再将包含甲基纤维素a和滑石粉a的混悬液流化上药(分散介质为水)，获得具有水溶性聚合物层的颗粒；然后将包含甲基纤维素b和羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)的包衣液流化上药(分散介质为80％乙醇溶液)，获得具有半透膜层的颗粒；最后再将包含达比加群酯、阿拉伯胶b和滑石粉b的混悬液流化上药，筛选，制得具有达比加群酯层的颗粒。
实施例6
处方：
Figure PCTCN2015094499-appb-000010
制备方法：
参照实施例1的制备方法，筛分出粒径在0.6mm～0.8mm的颗粒维生素C作为维生素C丸芯；再将包含羧甲基纤维素钠a、滑石粉a和聚乙二醇-6000a的混悬液流化上药(分散介质为水)，获得具有水溶性聚合物层的颗粒；然后将聚乙二醇-6000b和乙基纤维素的混悬液流化上药(分散介质为无水乙醇溶液)，获得具有半透膜层的颗粒；最后再将包含达比加群酯、羧甲基纤维素钠b和滑石粉b的混悬液流化上药，筛选，制得具有达比加群酯层的颗粒。
实施例7
处方：
Figure PCTCN2015094499-appb-000011
制备方法：
参照实施例1的制备方法，先用粉末维生素C、颗粒维生素C和阿拉伯胶制备维生素C丸芯；再将包含羧甲基纤维素钠a和滑石粉a的混悬液流化上药(分散介质为水)，获得具有水溶性聚合物层的颗粒；然后将包含羧甲基纤维素钠b和乙基纤维素的包衣液流化上药(分散介质为无水乙醇溶液)，获得具有半透膜层的颗粒；最后再将包含达比加群酯、羧甲基纤维素钠c和滑石粉b的混悬液流化上药，筛选，制得具有达比加群酯层的颗粒。
实施例8 达比加群酯胶囊的制备
取实施例2中微丸291.71mg，灌装入1号植物空心胶囊内，得110mg(以C34H41N7O5计)规格甲磺酸达比加群酯胶囊。
实施例9 达比加群酯胶囊的制备
取实施例2中微丸198.88mg，灌装入1号植物空心胶囊内，得75mg(以C34H41N7O5计)规格甲磺酸达比加群酯胶囊。
实施例10 达比加群酯胶囊体外溶出特性比较
分别取比较实施例3、比较实施例4、比较实施例5、实施例8、实施例9和市售参比制剂，照溶出度测定法(中国药典2010年版二部附录X C第一法)，加溶出介质900ml，转速为每分钟100转，依法操作，分别于10、20、30、45、60分钟时取样测定溶出度。
结果如表1、2所示：
表1 溶出特性比较(规格：110mg(以C34H41N7O5计))
Figure PCTCN2015094499-appb-000012
表2 溶出特性比较(规格：75mg(以C34H41N7O5计))
Figure PCTCN2015094499-appb-000013

Claims (14)

  1. 一种适于口服给药的达比加群酯药用组合物，其特征在于：所述组合物包含维生素C层和达比加群酯层，且在维生素C层与达比加群酯层之间通过半透膜层隔离。
  2. 如权利要求1所述的药用组合物，其特征在于，所述半透膜层包含水溶性化合物、水不溶性化合物以及任选的抗粘剂和/或增塑剂。
  3. 如权利要求2所述的药用组合物，其特征在于，所述水溶性化合物选自甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、聚维酮、羧甲基纤维素钠、邻苯二甲酸羟丙基甲基纤维素、果胶、环糊精、半乳甘露聚糖、平均分子量为4000以上的聚乙二醇、明胶、水溶性的单糖或多糖或上述两种以上的混合物；优选乳糖、蔗糖、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、PEG-6000、聚维酮或羧甲基纤维素钠；更进一步优选羟丙基纤维素或聚维酮。
  4. 如权利要求2或3所述的药用组合物，其特征在于，所述水不溶性化合物选自乙基纤维素、HPMCAS、HPMCP、甲基丙烯酸共聚物或上述两种以上的混合物，其中，所述甲基丙烯酸共聚物包括但不限于Eudragit E、Eudragit R、Eudragit S、Eudragit L、Eudragit RS或Eudragit LD；优选乙基纤维素、HPMCAS、Eudragit S100、Eudragit L100或HPMCP；进一步优选乙基纤维素。
  5. 如权利要求2～4任一项所述的药用组合物，其特征在于，所述半透膜层中，所述水溶性化合物与所述水不溶性化合物的质量比为1∶0.1～1∶10；优选1∶0.2～1∶5；进一步优选1∶0.5～1∶1。
  6. 如权利要求5所述的药用组合物，其特征在于，所述半透膜层相对于所述维生素C层增重为0.5wt％～20wt％；优选地，所述半透膜层相对于所述维生素C层增重为2wt％～10wt％；进一步优选地，所述半透膜层相对于所述维生素C层增重为5wt％～10wt％。
  7. 如权利要求1～6所述的药用组合物，其特征在于，所述达比加群酯层和所述维生素C层的重量比1∶0.15～1∶1.8，优选1∶0.6～1∶1.1。
  8. 权利要求1～7所述的药用组合物，其特征在于，在所述维生素C与达比加群酯层之间，除了包括半透膜层之外，进一步包括水溶性聚合物层。
  9. 如权利要求8所述的药用组合物，其特征在于，所述水溶性聚合物层增重与所述半透膜层增重比值为1∶0.1～1∶10；优选比值为1∶0.2～1∶5；进一步优选比值为1∶1～1∶1.1。
  10. 如权利要求1～10所述的药用组合物，其特征在于，所述药用组合物为多粒状制剂，其中，各个颗粒的大致球状或球状的酸芯中包含所述维生素C；接着，有一层由所述水溶性聚合物层和所述半透膜层构成的隔离层，用于隔离所述维生素C酸芯与所述达比加群酯层；接着，所述隔离层再被达比加群酯的相同球形层包围；任选地，所述达比加群酯层进一步被涂层包围。
  11. 如权利要求1所述的药用组合物的制备方法，其特征在于，所述方法包括如下步骤：
    (1)取颗粒维生素C置于流化床内，将包含粉末维生素C、水以及任选的粘合剂和/或填充剂的混悬液进行流化上药，筛出粒径在0.6mm～0.8mm之间的颗粒作为维生素C丸芯；
    (2)将所述维生素C丸芯置于流化床内，将包含水溶性聚合物、水以及任选的分散剂和/或增塑剂的混悬液流化上药，制得具有水溶性聚合物层的颗粒1；
    (3)将所述颗粒1置于流化床内，将包含水溶性化合物、水不溶性化合物、醇或醇溶液以及任选的抗粘剂和/或增塑剂的混悬液流化上药，筛选1mm以内的颗粒，作为具有半透膜层的颗粒2；
    (4)将所述颗粒2置于流化床内，将包含达比加群酯或其可药用盐、醇以及任选的粘合剂和/ 或分散剂的混悬液流化上药，筛选1.5mm以内的颗粒作为具有达比加群酯层的颗粒3；以及
    (5)任选地，对所述颗粒3包覆涂层。
  12. 如权利要求11所述的方法，其中，所述方法包括如下步骤：
    取颗粒维生素C，置于流化床内，将包含阿拉伯胶、粉末维生素C和水的混悬液进行流化上药，筛出粒径在0.6mm～0.8mm之间的颗粒作为维生素C丸芯；
    将维生素C丸芯置于流化床内，将包含阿拉伯胶、滑石粉和水的混悬液流化上药，制得具有水溶性聚合物层的颗粒1；
    取羟丙基纤维素和乙基纤维素，加异丙醇搅拌溶解，再加入滑石粉，搅拌使充分混悬，得到混悬液；
    将所述颗粒1置于流化床内，将包含羟丙基纤维素、乙基纤维素和滑石粉的混悬液流化上药，筛选1mm以内的颗粒作为进一步具有半透膜层的颗粒2；
    将所述颗粒2置于流化床内，将包含羟丙基纤维素、滑石粉、达比加群酯和异丙醇的混悬液流化上药；筛选1.5mm以内的颗粒作为进一步具有达比加群酯层的颗粒3。
  13. 一种包含权利要求1～10所述的药用组合物的固体制剂，其特征在于，所述固体制剂形式是片剂、颗粒剂或胶囊；优选地，所述固体制剂呈胶囊形式。
  14. 权利要求1～10所述的药用组合物在制备用于治疗血栓栓塞性疾病的药物中的用途。
PCT/CN2015/094499 2014-11-14 2015-11-13 一种含有达比加群酯的药用组合物、其制备方法、固体制剂和用途 WO2016074640A1 (zh)

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