WO2024088266A1 - 药物组合物及其制备方法 - Google Patents

药物组合物及其制备方法 Download PDF

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Publication number
WO2024088266A1
WO2024088266A1 PCT/CN2023/126271 CN2023126271W WO2024088266A1 WO 2024088266 A1 WO2024088266 A1 WO 2024088266A1 CN 2023126271 W CN2023126271 W CN 2023126271W WO 2024088266 A1 WO2024088266 A1 WO 2024088266A1
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Prior art keywords
sustained
colon
layer
release
pharmaceutical composition
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PCT/CN2023/126271
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English (en)
French (fr)
Inventor
邹平
齐宜广
朱春水
汪妮
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江苏慧聚药业股份有限公司
江苏慧聚药业股份有限公司广州分公司
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Priority to CN202380019341.0A priority Critical patent/CN118660698A/zh
Publication of WO2024088266A1 publication Critical patent/WO2024088266A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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

Definitions

  • the present invention belongs to the field of medicine, and in particular relates to a medicine composition and a preparation method thereof.
  • Tofacitinib chemical name is 3-((3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-1-yl]-3-oxopropionitrile, molecular formula is C 16 H 20 N 6 O, molecular weight is 312.4. It can form stable salt crystals with acid, such as tofacitinib citrate with citric acid (1:1). The molecular weight of citrate is 504.5, and the chemical structure is as follows:
  • Tofacitinib is a Janus kinase (JAK) inhibitor that binds to JAK kinase, inhibits JAK signaling pathways intracellularly, and prevents STAT phosphorylation.
  • Tofacitinib is a pan-JAK kinase inhibitor, and JAK kinase is expressed in most cells.
  • Tofacitinib is used to treat rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and polyarticular juvenile idiopathic arthritis.
  • There is a black box warning in the label of Xeljanz/Xeljanz XR to indicate that these drugs increase the risk of cancer, thrombosis, serious cardiac events, and death.
  • Such adverse reactions may be related to the mechanism of action of tofacitinib.
  • the tofacitinib currently on the market is all administered orally, is not targeted, and has an inhibitory effect on JAK kinases throughout the body, leading to serious adverse reactions.
  • the site of ulcerative colitis is the "colon and rectum", which is a local lesion.
  • Conventional tablets are generally used to allow the drug to be absorbed throughout the body, and tofacitinib cannot be released at multiple points in the lesion site at high concentrations, thus reducing the effectiveness and safety of the drug. Few literature reports that tofacitinib is designed as a multi-unit colon-localized release drug delivery system.
  • Vakar et al. in "Development of Colon Targeting Tablet of a JAK Inhibitor to Combat Chronic Ulcerative Colitis: A Novel Approach for Local Drug Delivery” used wet granulation of active ingredients and skeleton materials, and then used methacrylic acid and methyl methacrylate (1:2) copolymer (Eutrice S100) for colon targeting coating.
  • the process steps are: mixing-soft material preparation-granulation-drying-dry granulation-mixing-tabletting-coating-packaging.
  • the preparation uses a single material skeleton for sustained release, which may cause sudden release, reducing the effectiveness and safety of the drug.
  • the preparation does not provide in vivo data, and its in vivo efficacy is still unknown.
  • the preparation has the disadvantages of complex prescription, many types of excipients, cumbersome preparation process, more production equipment, greater difficulty in industrial production and higher cost.
  • Patent CN108066319A reported that composite materials were used to prepare skeleton sustained-release micropellets, which solved the problem of sudden release that may occur when a single skeleton material is dissolved. Then, a copolymer of methacrylic acid and methyl methacrylate (1:1) (Eutrac L100) was used to prepare sustained-release micropellets. Enteric coating is carried out, and its process steps are: mixing-preparing soft materials-extrusion-spheronization-drying-sieving-coating-filling-packaging.
  • the preparation is sustained-released for 24 hours under medium conditions above pH 6.0, but the preparation does not take into account the actual situation of the patient's colon (pH 6.5-8.3), so the drug begins to dissolve in the small intestine stage, which ultimately leads to a low concentration in the colon tissue, reducing the effectiveness and safety of the drug.
  • the preparation also has the disadvantages of complex prescriptions, a variety of excipients, cumbersome preparation processes, a large number of production equipment, greater difficulty in industrial production and higher costs.
  • the present application provides a pharmaceutical composition and a preparation method thereof.
  • the pharmaceutical composition is a multi-unit colon-localized release drug delivery system, which can release drugs in a targeted manner in the colon.
  • the pharmaceutical composition has a simple prescription, few auxiliary materials, and a simple preparation process, and is suitable for industrial production.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pill-containing core and a colon localization layer, wherein the pill-containing core comprises a bottom core and an active ingredient layer, the colon localization layer covers the pill-containing core, and the active ingredient layer comprises an active ingredient selected from Janus kinase inhibitors.
  • a sustained-release layer is disposed between the colon localization layer and the pill-containing core.
  • the active ingredient layer covers the surface of the bottom core.
  • the material of the bottom core is selected from one or more of sucrose, microcrystalline cellulose, mannitol or tartaric acid.
  • the bottom core does not contain active ingredients and/or sustained-release materials and/or colon-localizing materials.
  • the active ingredient layer in the pill core, further includes a binder.
  • the binder is selected from one or more of povidone (e.g., K25, K30, K90, etc.), hydroxypropyl methylcellulose (2910 series E3, E5, E6, E15, etc.), hydroxypropyl cellulose (e.g., with a molecular weight of 40,000-140,000), methyl cellulose or sodium carboxymethyl cellulose.
  • povidone e.g., K25, K30, K90, etc.
  • hydroxypropyl methylcellulose 2910 series E3, E5, E6, E15, etc.
  • hydroxypropyl cellulose e.g., with a molecular weight of 40,000-140,000
  • methyl cellulose or sodium carboxymethyl cellulose e.g., sodium carboxymethyl cellulose.
  • the mass ratio of the active ingredient to the adhesive is 1:(0.5-3.0), for example 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0 or the range of any two of these values.
  • the mass ratio of the active ingredient to the base core is 1:(0.5-4.0), for example 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2 .0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4.0, or a range of any two of these values.
  • the mass ratio of the adhesive to the bottom core is 1:(0.5-3.0), for example 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0 or the range of any two of these values.
  • the colon positioning layer includes a colon positioning material, a plasticizer and an anti-adhesive agent.
  • the sustained-release layer includes a sustained-release material and/or a plasticizer, and optionally may also include an anti-adhesive agent.
  • the colon positioning material is selected from one or more of shellac, polyvinyl alcohol acetate phthalate, cellulose and its derivatives, and acrylic resins.
  • the colon positioning material is selected from one or more of a methacrylic acid and methyl methacrylate (1:1) copolymer, a methacrylic acid and methyl methacrylate (1:2) copolymer, and a methacrylic acid and methyl acrylate and methyl methacrylate (1:1:1) copolymer.
  • the sustained-release material is selected from one or more of ethyl cellulose, chitosan, polyvinyl alcohol, and acrylic resins.
  • the sustained-release material is selected from one or more of ethyl cellulose and quaternary amino methacrylate copolymers.
  • the viscosity of the ethyl cellulose is 7 to 20 cps.
  • the model of ethyl cellulose can be selected from one or more of N7, N10, N12 and N15.
  • the quaternary amino methacrylate copolymer is selected from one or more of quaternary amino methacrylate copolymer RL type and RS type.
  • the mass ratio of quaternary amino methacrylate copolymer RL type and RS type is preferably (10 to 0.1):1.
  • the quaternary amino methacrylate copolymer is a mixture of quaternary amino methacrylate copolymers RL type and RS type, and the mass ratio of RL type to RS type is (10-0.5): 1, and more preferably the mass ratio of quaternary amino methacrylate copolymer RL type to quaternary amino methacrylate copolymer RS type is (4-0.67): 1.
  • the mass ratio of quaternary amino methacrylate copolymer RL type to RS type is 10: 1, 8: 1, 5: 1, 4: 1, 3: 1, 2: 1, 1: 1, 0.5: 1 or a range consisting of any two values therein.
  • the plasticizers in the sustained-release layer and the colon localization layer can be the same or different.
  • the plasticizer is selected from one or more of triethyl citrate, castor oil, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, dibutyl sebacate, etc.
  • the anti-sticking agent is selected from one or more of talc, glyceryl monostearate, magnesium stearate, micro powder silica gel, and kaolin.
  • the mass ratio of the colon positioning material to the plasticizer is 1:(0.1-0.5). In some embodiments, the mass ratio of the colon positioning material to the plasticizer is 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45 or a range consisting of any two of these values.
  • the mass ratio of the colon positioning material to the anti-adhesive agent is 1:(0.1-0.5). In some embodiments, the mass ratio of the colon positioning material to the anti-adhesive agent is 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45 or a range consisting of any two of these values.
  • the mass ratio of the sustained-release material to the plasticizer is 1:(0.1-0.3). In some embodiments, in the sustained-release layer, the mass ratio of the sustained-release material to the plasticizer is 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3 or a range consisting of any two of these values.
  • the mass ratio of the sustained-release material to the anti-adhesive agent is 1:(0-0.7).
  • the mass ratio of the sustained-release material to the anti-adhesive agent is 1:0, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.70 or a range consisting of any two of the values.
  • the active ingredient includes one or more of Tofacitinib, Filgotinib, Upadacitinib, ritlecitinib, ivarmacitinib sulfate, peficitinib, brepocitinib, Upadacitinib, deucravacitinib, itacitinib and pharmaceutically acceptable salts or crystal forms thereof.
  • the active ingredient includes one or more of tofacitinib, a pharmaceutically acceptable salt of tofacitinib and a crystalline form thereof.
  • the D 90 of the active ingredient is less than 52 ⁇ m (e.g., 50 ⁇ m, 45 ⁇ m, 40 ⁇ m, 35 ⁇ m, 30 ⁇ m, 25 ⁇ m, 22 ⁇ m, 20 ⁇ m, 15 ⁇ m, 10 ⁇ m, 5 ⁇ m, 1 ⁇ m), more preferably D 90 ⁇ 22 ⁇ m (e.g., 20 ⁇ m, 15 ⁇ m, 10 ⁇ m, 5 ⁇ m, 1 ⁇ m).
  • the in vitro dissolution detection method of the composition adopts HPLC
  • the first stage the dissolution method is in 0.1M hydrochloric acid medium, paddle method, the dissolution medium volume is 900mL, the stirring speed is 100rpm, and the time is 2h
  • the second stage in pH6.0 medium, paddle method, the dissolution medium volume is 900mL, the stirring speed is 100rpm, and the time is 3h.
  • the cumulative active ingredient released under the conditions of the first and second stages is less than 5%
  • the third stage in pH7.2 medium, paddle method, the dissolution medium volume is 900mL, the stirring speed is 50rpm, and the active ingredient released under the conditions of time 8h is not less than 90%.
  • the mass fraction of the base core is 0.5-4.0 parts (e.g., 0.5, 1, 1.5, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.8, 2.9, 3.0, 3.5, 3.8 or 4.0)
  • the mass fraction of the adhesive is 0.5-3.0 parts (e.g., 0.5, 1, 1.5, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.8, 2.9, 3.0)
  • the mass fraction of the sustained-release layer is 0-0.80;
  • the mass fraction of the sustained-release material is 0-0.4 parts (e.g., 0, 0.1, 0.12, 0.15, 0.18, 0.20, 0.22, 0.24, 0.26, 0.28, 0.29, 0.32 or 0.35); and/or the mass fraction of the anti-adhesive in the sustained-release layer is 0-0.28 parts (e.g., 0, 0.1, 0.12, 0.15, 0.18, 0.20, 0.22, 0.24, 0.26, 0.28, 0.29, 0.32 or
  • the mass fraction of the sustained-release layer is 0-0.80 parts (e.g., 0, 0.02, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.55, 0.60, 0.65, 0.70 or 0.75); and/or the mass fraction of the colon localization layer is 0.28-4.22 parts (e.g., 0.28, 0.35, 0.40, 4, 0.50, 0.60, 0.70, 0.75, 0.8, 0.9, 1.0, 1.1, 1.2, 13, 1.4, 1.5, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0 or 4.22); and/or the mass fraction of the anti-adhesive agent of the colon positioning layer is 0.04-0.80 part (e.g., 0.04, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35,
  • a sustained-release layer is arranged between the colon positioning layer and the pill-containing core.
  • the mass fraction of the sustained-release layer is 0-0.8 parts (e.g., 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7 or 0.8 parts, etc.).
  • the mass fraction of the sustained-release layer is 0.24-0.48 parts (e.g., 0.25, 0.30, 0.35, 0.40 or 0.45).
  • the mass fraction of the colon positioning layer is 0.56-2.10 parts.
  • the mass fraction of the colon positioning layer material is 0.28-4.22 parts (for example, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 13, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3.0).
  • the mass fraction of the anti-adhesive agent in the colon positioning layer is 0.04-0.80 (for example, 0.04, 0.08, 0.10, 0.12, 0.15, 0.18, 0.20, 0.25, 0.30, 0.35, 0.38, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75 or 0.80) parts, preferably 0.12-0.60 parts.
  • the present application provides a method for preparing the pharmaceutical composition of the first aspect, comprising: coating the drug-containing pill core with a colon localization layer, or coating the drug-containing pill core with a sustained-release layer and a colon localization layer in sequence.
  • the preparation method comprises the following steps: a) preparing an active ingredient layer suspension, and spraying the active ingredient layer suspension into a bottom core using a fluidized bed process to prepare a pill-containing core.
  • the preparation method comprises the following steps: b) preparing a sustained-release layer suspension solution, and spraying the sustained-release layer suspension solution into the drug-containing pellet core using a fluidized bed process to prepare sustained-release pellets.
  • the preparation method comprises the following steps: c) preparing a colon localization layer coating solution, and spraying the colon localization layer coating solution onto the drug-containing pill cores or sustained-release pellets using a fluidized bed process to prepare colon localization sustained-release pellets.
  • the preparation method comprises the following steps: d) filling capsules with the colon-targeted sustained-release micropellets.
  • the pharmaceutical composition provided by the present invention adopts blank pill core coating, membrane-controlled sustained-release coating, colon-localized coating, and then capsule filling to prepare multi-unit colon-localized sustained-release micropellets, which can be sustained-released for 1-8 hours, and the concentration in the tissue is higher than that in the blood, thereby improving the therapeutic effect and reducing adverse reactions (compared with positive drugs).
  • Drug application on blank pill core This solution is a multi-unit drug delivery system, which can release drugs at multiple points in colon tissue compared with tablets.
  • Membrane controlled sustained release technology solves the problem of sudden release of skeleton sustained release, and membrane controlled sustained release uses less excipients than skeleton sustained release, reduces drug volume, and improves patient compliance; controlling the amount of sustained release layer material can control the sustained release time.
  • Colon positioning technology Combined with the pH value in the patient's colon, colon positioning materials are selected to prevent the drug from being released in the small intestine, and controlling the amount of colon positioning layer material can also control the sustained release time.
  • N/A herein means blank, or “N/A” means that the component is not contained or removed in the subsequent process;
  • quaternary amino methacrylate copolymer type B is also known as “Eutrac RS”
  • methacrylic acid and methyl methacrylate (1:2) copolymer is also known as “Eutrac S100”
  • quaternary amino methacrylate copolymer type A is also known as “Eutrac RL”;
  • methacrylic acid and methyl acrylate and methyl methacrylate (1:1:1) copolymer is also known as “Eutrac FS30D”;
  • methacrylic acid and methyl methacrylate (1:1) copolymer is also known as "Eutrac L100".
  • Example 13 of CN108066319A the target pellet core was prepared and the dissolution curve was tested.
  • the prescription is shown in Table 1.
  • Main production equipment wet mixer, extruder, spheronizer, oven, dry granulator, fluidized bed, capsule filling machine
  • the above soft material is placed in an extruder, the speed of the extruder is adjusted, and then the extruded strip material is placed in a spheronizer, the rotating speed of the turntable and the frequency of the fan are adjusted to obtain suitable pellets.
  • the prepared pellets are placed in an oven and dried until the moisture content is less than 3%.
  • the dried pellets are passed through a 16-mesh sieve and a 40-mesh sieve (particle size 0.38 mm-1 mm), and the pellets in the middle of 16-mesh to 40-mesh are taken for enteric coating.
  • Main equipment wet mixer, oven, dry granulator, mixer, tablet press, coating machine
  • Tablet compression Tablets were made using a tablet press, 6 mm round punch, tablet weight 100 mg, hardness 4 KP.
  • Enteric coating Prepare the coating solution according to the composition of the coating solution and use a coating machine for coating. Maintain the tablet bed temperature at 30°C, the pan rotation at 10 rpm, the atomization pressure at 2 bar, and the spray rate at 10 g/min.
  • Main production equipment fluidized bed, capsule filling machine
  • the binder is dissolved in the solvent, and then the active ingredient is dispersed in the binder solution.
  • the fluidized bed bottom spray coating is used, the material temperature is controlled at 38-45°C, the atomization pressure is 150KPa, and the spraying speed is less than 7g/min.
  • the active ingredient suspension is applied to the bottom core to prepare the pill core.
  • sustained-release layer coating suspension solution Prepare the sustained-release layer coating suspension solution according to the prescription amount, use fluidized bed bottom spray coating, control the material temperature at 25-35°C, atomization pressure at 150KPa, spray speed ⁇ 3g/min, spray the coating liquid into the pill core to prepare sustained-release micropellets.
  • the colon-targeting layer coating solution was prepared according to the prescription amount, and the fluidized bed bottom spray coating was used.
  • the material temperature was controlled at 20-30°C, the atomization pressure was 150KPa, and the spraying speed was ⁇ 3g/min.
  • the coating solution was sprayed into the sustained-release micropellets to prepare the colon-targeting sustained-release micropellets.
  • the weight of tofacitinib is converted to 10 mg and filled into No. 4 capsules.
  • Main production equipment fluidized bed, capsule filling machine
  • the binder is dissolved in the solvent, and then the active ingredient is dispersed in the binder solution.
  • the fluidized bed bottom spray coating is used, the material temperature is controlled at 38-45°C, the atomization pressure is 150KPa, and the spraying speed is less than 7g/min.
  • the active ingredient suspension is applied to the bottom core to prepare the pill core.
  • the colon positioning layer coating solution was prepared according to the prescription amount, and the fluidized bed bottom spray coating was used.
  • the material temperature was controlled at 20-30°C, the atomization pressure was 150KPa, and the spray speed was ⁇ 3g/min.
  • the coating solution was sprayed into the upper medicine pellets to prepare the colon positioning pellets.
  • the weight of tofacitinib is converted to 10 mg and filled into No. 4 capsules.
  • in vitro dissolution method refer to USP method
  • the first stage simulates the drug in the stomach stage
  • the second stage simulates the drug in the small intestine stage
  • the third stage simulates the drug in the colon stage:
  • the following text uses a unified dissolution method for testing.
  • the acid-resistant stage refers to the first and second stages of the dissolution method.
  • the sustained-release time in this article does not include the first and second stages of the dissolution method, but only refers to the third stage of dissolution. See Table 8 for the test results.
  • HPLC HPLC was used to detect the tofacitinib content, and the chromatographic conditions were as follows.
  • Comparative Example 1 is dissolved in a pH 6.0 medium; Comparative Example 2 is a tablet, which has a sustained release for about 6 hours and a burst release in 2-4 hours; Preparation 1, Preparation 2, Preparation 3, Preparation 4, and Comparative Example 3 have a sustained release of about 1 hour, 4 hours, 8 hours, 18 hours, and 24 hours, respectively.
  • Main production equipment fluidized bed, capsule filling machine
  • the binder is dissolved in the solvent, and then the active ingredient is dispersed in the binder solution.
  • the fluidized bed bottom spray coating is used, the material temperature is controlled at 38-45°C, the atomization pressure is 150KPa, and the spraying speed is less than 7g/min.
  • the active ingredient suspension is applied to the bottom core to prepare the pill core.
  • sustained-release layer coating suspension solution Prepare the sustained-release layer coating suspension solution according to the prescription amount, use fluidized bed bottom spray coating, control the material temperature at 25-35°C, atomization pressure at 150KPa, spray speed ⁇ 3g/min, spray the coating liquid into the pill core to prepare sustained-release micropellets.
  • the colon-targeting layer coating solution was prepared according to the prescription amount, and the fluidized bed bottom spray coating was used.
  • the material temperature was controlled at 20-30°C, the atomization pressure was 150KPa, and the spraying speed was ⁇ 3g/min.
  • the coating solution was sprayed into the sustained-release micropellets to prepare the colon-targeting sustained-release micropellets.
  • the weight of tofacitinib is converted to 10 mg and filled into No. 4 capsules.
  • Example 5 Active ingredients with different particle sizes
  • Particle size detection method laser particle size analyzer (Matersizer 3000 from Malvern Panalytical) was used, using dry method, injection speed of 40.0%, hopper gap of 2.5 mm, and dispersion pressure of 3.0 bar. The dissolution results are shown in Table 12 below:
  • the enteric-coated sustained-release micropellets had good roundness and basically did not dissolve at pH 1.0 and pH 6.0.
  • the enteric-coated sustained-release micropellets had poor roundness and dissolved at pH 6.0. Therefore, the particle size of the active ingredient was controlled to D90 ⁇ 52 ⁇ m, and more preferably D90 ⁇ 22 ⁇ m.
  • Example 7 Different types and models of sustained-release polymers
  • Example 8 Proportions of different sustained-release polymer types
  • the sustained-release micro-pellet capsules prepared with the sustained-release layer dosage (0.24 to 0.80 parts) can be almost completely dissolved, and the sustained-release time is 4-8 hours.
  • different types of colon positioning materials are selected, or different types are used in a mixed ratio to achieve the purpose of positioning the sample in the colon.
  • Example 12 Types of anti-adhesive agents
  • colon-specific sustained-release micro-pellets prepared with different amounts of anti-adhesive agents had almost no dissolution in hydrochloric acid and pH 6.0 medium, and could be almost completely dissolved in pH 7.2 medium.
  • the amount of anti-adhesive agent used in the colon-specific layer (0.24 to 0.60 parts) had a sustained-release time of 7-8 hours.
  • Example 14 Colon positioning layer dosage
  • colon-localized sustained-release microcapsules were prepared with different amounts of colon-localized layers (0.56 to 1.67 parts), and there was basically no dissolution in hydrochloric acid and pH 6.0 media; they could be basically completely dissolved in pH 7.2 media, and the sustained-release time was 6-8 hours.
  • the colon-targeted polymer under the condition of only enteric layer, the colon-targeted polymer was used in an amount of 0.2-3.0 parts to prepare colon-targeted micro-pellet capsules, and there was basically no dissolution in hydrochloric acid and pH 6.0 medium; it could be almost completely dissolved in pH 7.2 medium, and the sustained release time was
  • the amount of colon-targeted polymer is less than 0.2 parts (prescription 23)
  • the colon-targeted micro-pellet capsules are basically more dissolved in the pH 6.0 medium
  • the amount of colon-targeted polymer is higher than 3.0 parts
  • the colon-targeted micro-pellet capsules are basically not dissolved in hydrochloric acid and pH 6.0 medium, but the sustained-release time in the pH 7.2 medium is more than 8 hours. Therefore, under the condition of only an enteric layer, the amount of colon-targeted polymer used is 0.2 to 3.0 parts to prepare colon-targeted micro-pellet capsules, which can achieve the current sustained
  • the mass ratio of the active ingredient of the upper drug layer to the binder is 1:1, 1:1.5, 1:2 to prepare colon-targeted micro-pellet capsules
  • the cumulative dissolution in hydrochloric acid and pH 6.0 medium is less than 5.0%, and it can be basically completely dissolved in pH 7.2 medium, and the sustained release time is 4 hours. Therefore, under the condition of only an enteric layer, the mass ratio of the active ingredient of the upper drug layer to the binder is 1:1.0 to 1:2.0 to prepare colon-targeted micro-pellet capsules, which can achieve the current sustained release time.
  • 144 SD rats were selected and divided into 8 groups, 18 rats in each group, namely the positive drug group (tofacitinib citrate suspension), comparative example group 1, comparative example group 3, preparation group 1, preparation group 2, preparation group 3, prescription group 27, and preparation group 4, and the positive drug (tofacitinib citrate suspension) (control group), comparative example group 1, comparative example group 3, preparation group 1, preparation group 2, preparation group 3, prescription group 27, and preparation group 4 were gavaged respectively, and the gavage dose of each group was the same (12.5 mg/kg/day, calculated as tofacitinib).
  • preparation 1 group three SD rats were killed at 1, 2, 3, 6, 12, and 24 h, and blood and colon tissue were obtained.
  • the positive drug uses 0.5% sodium carboxymethyl cellulose as solvent and is added with tofacitinib citrate to prepare a concentration of 2.5 mg/mL Tofacitinib citrate suspension.
  • the positive drug uses 0.5% sodium carboxymethyl cellulose as solvent and is added with tofacitinib citrate to prepare a concentration of 2.5 mg/mL Tofacitinib citrate suspension.
  • 60 SD rats were selected and divided into 10 groups, 6 rats in each group, namely blank group, model group, positive drug group (tofacitinib citrate suspension), comparative group 1, comparative group 3, preparation group 1, preparation group 2, preparation group 3, prescription 27 group, and preparation group 4. Except for the blank group, the other groups were modeled with 3% dextran sulfate sodium salt (DSS) and treated by gavage. The gavage dose of each group was the same (28 mg/kg/day, calculated as tofacitinib), and the blank group was gavaged with 0.5% sodium carboxymethyl cellulose. The body weight of each rat was recorded, the feces was recorded, and the disease activity index score (DAI) was performed. After 7 days of administration, spleen and colon tissues were taken, and colon tissue pathological sections were observed. The results are shown in Tables 37 and 38.
  • DAI disease activity index score
  • the positive drug uses 0.5% sodium carboxymethyl cellulose as a solvent, and tofacitinib citrate is added to prepare a tofacitinib citrate suspension with a concentration of 2.5 mg/mL;
  • Preparation 1, Preparation 2, and Preparation 3 can significantly reduce DAI scores, reduce colon weight/length ratio, reduce spleen weight/body weight length ratio, and improve colon tissue inflammation in the treatment of DSS-induced ulcerative colitis.
  • the tofacitinib colon-targeted sustained-release capsules prepared by the present invention use less excipients and have a small capsule volume, which can improve patient compliance; the process is simple, with fewer steps and less equipment used, and the main equipment is only a fluidized bed, as shown in Table 39; the active ingredients of the colon-targeted sustained-release capsules are released more evenly, can be sustained for 1-8 hours, and are mainly distributed in the colon, with reduced plasma exposure, improved bioavailability, reduced DAI scores of rats with ulcerative colitis, reduced colon weight/length ratio, reduced spleen weight/body weight length ratio, and improved colon tissue inflammation, as shown in Tables 35 and 36, and Table 38 for details.

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Abstract

涉及一种药物组合物及其制备方法和应用。该药物组合物包括含药丸芯和结肠定位层，其中所述含药丸芯包括底芯和活性成分层，所述结肠定位层包覆所述含药丸芯，所述活性成分层包含选自Janus激酶抑制剂的活性成分；所述结肠定位层与所述含药丸芯之间任选地设置缓释层。该药物组合物是多单元结肠定位释放给药系统，能够在结肠部位定向释放药物。此外，该药物组合物处方简单，辅料少，制备工艺简单，适合工业化生产。

Description

药物组合物及其制备方法 技术领域
本发明属于药物领域，具体涉及一种药物组合物及其制备方法。
背景技术
托法替布(Tofacitinib)，化学名称为3-((3R，4R)-4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-哌啶-1-基]-3-氧代丙腈，分子式为C16H20N6O，分子量为312.4。其可与酸形成稳定的盐结晶，如：与枸橼酸(1：1)形成枸橼酸托法替布。枸橼酸盐分子量504.5，化学结构如下：
托法替布是一种Janus激酶(JAK)抑制剂，该药物与JAK激酶结合，在胞内抑制JAK信号通路，阻止STAT的磷酸化。托法替布是泛-JAK激酶抑制剂，JAK激酶在大多数细胞中都有表达。托法替布用于治疗类风湿关节炎、银屑病关节炎、溃疡性结肠炎、多关节型幼年特发性关节炎。Xeljanz/Xeljanz XR的Lable中存在黑框警告，以提示这些药物会提高癌症、血栓、严重心脏事件和死亡的风险。此类不良反应可能与托法替布的作用机理有关，现已上市的托法替布均为口服给药，不具有靶向性，对体内各处的JAK激酶具有抑制作用，从而导致严重的不良反应。
溃疡性结肠炎发病部位是“结肠与直肠”，属于局部病灶。绝大多数公开文献报道托法替布的组合物用于治疗溃疡性结肠炎时，未考虑溃疡性结肠炎的发病特点，一般采用常规片剂给药手段，使药物在全身吸收，未能使托法替布在病灶部位多点位高浓度释放，故降低了药物的有效性及安全性。鲜有文献报道将托法替布设计为多单元结肠定位释放给药系统。
Vakar等人在《Development of Colon Targeting Tablet of a JAK Inhibitor to Combat Chronic Ulcerative Colitis:A Novel Approach for Local Drug Delivery》采用活性成分与骨架材料湿法制粒，再使用甲基丙烯酸和甲基丙烯酸甲酯(1:2)共聚物(尤特奇S100)进行结肠定位包衣，其工艺步骤为：混合-制软材-制粒-干燥-干整粒-混合-压片-包衣-包装。该制剂采用单一材料骨架缓释可能出现突释，降低了药物的有效性及安全性，且该制剂未提供体内数据，其在体内疗效尚未可知。同时该制剂具有处方复杂、辅料种类多、制备工艺繁琐、生产设备较多、工业化生产难度较大且成本较高等缺点。
专利CN108066319A报道，采用复合材料制备骨架缓释微丸，解决了单一骨架材料溶出可能发生突释问题，再使用甲基丙烯酸和甲基丙烯酸甲酯(1:1)共聚物(尤特奇L100)进 行肠溶包衣，其工艺步骤为：混合-制软材-挤出-滚圆-干燥-过筛-包衣-灌装-包装。该制剂在pH 6.0以上介质条件下缓释24小时，但该制剂未考虑患者结肠部位的实际情况(pH 6.5～8.3)，使药物在小肠阶段就开始溶出，最终导致结肠组织中浓度少，降低了药物的有效性及安全性。且该制剂也具有处方复杂、辅料种类多、制备工艺繁琐、生产设备较多、工业化生产难度较大且成本较高等缺点。
发明内容
针对现有技术存在的问题，本申请提供一种药物组合物及其制备方法。该药物组合物是多单元结肠定位释放给药系统，能够在结肠部位定向释放药物。此外该药物组合物处方简单，辅料少，制备工艺简单，适合工业化生产。
在第一方面，本申请提供了一种药物组合物，该组合物包括含药丸芯和结肠定位层，其中所述含药丸芯包括底芯和活性成分层，所述结肠定位层包覆所述含药丸芯，所述活性成分层包含选自Janus激酶抑制剂的活性成分。
任选地，所述结肠定位层与所述含药丸芯之间设置缓释层。
根据本申请的实施方式，在所述含药丸芯中，所述活性成分层包覆所述底芯表面。
根据本申请的实施方式，所述底芯的材料选自蔗糖、微晶纤维素、甘露醇或酒石酸中的一种或多种。
根据本申请的实施方式，所述底芯中不含活性成分和/或缓释材料和/或结肠定位材料。
根据本申请的实施方式，所述含药丸芯中，所述活性成分层还包括粘合剂。
根据本申请的优选实施方式，所述粘合剂选自聚维酮(例如K25、K30、K90等)、羟丙甲纤维素(2910系列E3、E5、E6、E15等)、羟丙纤维素(例如分子量为40000-140000)、甲基纤维素或羧甲基纤维素钠中的一种或多种。
根据本申请的优选实施方式，所述活性成分与所述粘合剂的质量比为1：(0.5-3.0)，例如1:0.5、1:0.6、1:0.7、1:0.8、1:0.9、1:1.0、1:1.1、1:1.2、1:1.3、1:1.4、1:1.5、1:1.6、1:1.7、1:1.8、1:1.9、1:2.0、1:2.1、1:2.2、1:2.3、1:2.4、1:2.5、1:2.6、1:2.7、1:2.8、1:2.9、1:3.0或这些值中的任意二者的范围。
根据本申请的优选实施方式，所述活性成分与所述底芯的质量比为1：(0.5-4.0)，例如1:0.5、1:0.6、1:0.7、1:0.8、1:0.9、1:1.0、1:1.1、1:1.2、1:1.3、1:1.4、1:1.5、1:1.6、1:1.7、1:1.8、1:1.9、1:2.0、1:2.1、1:2.2、1:2.3、1:2.4、1:2.5、1:2.6、1:2.7、1:2.8、1:2.9、1:3.0、1:3.1、1:3.2、1:3.3、1:3.4、1:3.5、1:3.6、1:3.7、1:3.8、1:3.9、1:4.0或这些值中的任意二者的范围。
根据本申请的优选实施方式，所述粘合剂与所述底芯的质量比为1：(0.5-3.0)，例如1:0.5、1:0.6、1:0.7、1:0.8、1:0.9、1:1.0、1:1.1、1:1.2、1:1.3、1:1.4、1:1.5、1:1.6、1:1.7、1:1.8、1:1.9、1:2.0、1:2.1、1:2.2、1:2.3、1:2.4、1:2.5、1:2.6、1:2.7、1:2.8、1:2.9、1:3.0或这些值中的任意二者的范围。
根据本申请的优选实施方式，所述结肠定位层包括结肠定位材料、增塑剂和抗粘剂。根据本申请的优选实施方式，所述缓释层包括缓释材料和/或增塑剂，任选地还可以包括抗粘剂。根据本申请的优选实施方式，所述结肠定位材料选自虫胶、聚乙烯醇乙酸苯二甲酸酯、纤维素及其衍生物、丙烯酸树脂类中的一种或者多种。根据本申请的优选实施方式，所述结肠定位材料选自甲基丙烯酸和甲基丙烯酸甲酯(1:1)共聚物、甲基丙烯酸和甲基丙烯酸甲酯(1:2)共聚物、甲基丙烯酸和丙烯酸甲酯和甲基丙烯酸甲酯(1:1:1)共聚物中的一种或者多种。
根据本申请的优选实施方式，所述缓释材料选自乙基纤维素、壳聚糖、聚乙烯醇、丙烯酸树脂类中的一种或多种。根据本申请的优选实施方式，所述缓释材料选自乙基纤维素、季胺基甲基丙烯酸酯共聚物中的一种或多种。优选地，所述乙基纤维素的粘度为7～20cps。乙基纤维素的型号可以选自N7、N10、N12和N15中的一种或多种。优选地，所述季胺基甲基丙烯酸酯共聚物选自季胺基甲基丙烯酸酯共聚物RL型和RS型中的一种或多种。当季胺基甲基丙烯酸酯共聚物为季胺基甲基丙烯酸酯共聚物RL型和RS型的混合物时，优选季胺基甲基丙烯酸酯共聚物RL型和RS型的质量比为(10～0.1)：1。在一些实施方式中，季胺基甲基丙烯酸酯共聚物为季胺基甲基丙烯酸酯共聚物RL型和RS型的混合物，并且RL型和RS型的质量比为(10～0.5)：1，更优选季胺基甲基丙烯酸酯共聚物RL型、季胺基甲基丙烯酸酯共聚物RS型的质量比为(4～0.67)：1。在一些实施例中，季胺基甲基丙烯酸酯共聚物RL型和RS型的质量比为10:1、8:1、5:1、4:1、3:1、2:1、1:1、0.5:1或其中任意两个数值组成的范围。
本申请中，缓释层和结肠定位层中的增塑剂可以相同或者不同。根据本申请的优选实施方式，所述增塑剂选自柠檬酸三乙酯、蓖麻油、乙酰柠檬酸三乙酯、柠檬酸三丁酯、乙酰柠檬酸三丁酯、癸二酸二丁酯等中的一种或多种。
根据本申请的优选实施方式，所述抗粘剂选自滑石粉、单硬脂酸甘油酯、硬脂酸镁、微粉硅胶、高岭土中的一种或多种。
根据本申请的优选实施方式，所述结肠定位层中，所述结肠定位材料与所述增塑剂的质量比为1：(0.1-0.5)。在一些实施例中，所述结肠定位材料与所述增塑剂的质量比为1：0.1、1：0.15、1：0.2、1：0.25、1：0.3、1：0.35、1：0.4、1：0.45或其中任意两个数值组成的范围。
根据本申请的优选实施方式，所述结肠定位层中，所述结肠定位材料与所述抗粘剂的质量比为1：(0.1-0.5)。在一些实施例中，所述结肠定位材料与所述抗粘剂的质量比为1：0.1、1：0.15、1：0.2、1：0.25、1：0.3、1：0.35、1：0.4、1：0.45或其中任意两个数值组成的范围。
根据本申请的优选实施方式，所述缓释层中，所述缓释材料与所述增塑剂的质量比为1：(0.1-0.3)。在一些实施例中，所述缓释层中，所述缓释材料与所述增塑剂的质量比为1：0.1、1：0.15、1：0.2、1：0.25、1：0.3或其中任意两个数值组成的范围。
根据本申请的优选实施方式，所述缓释层中，所述缓释材料与所述抗粘剂的质量比为1：(0-0.7)。在一些实施例中，所述缓释层中，所述缓释材料与所述抗粘剂的质量比为1：0、1：0.1、1：0.15、1：0.2、1：0.25、1：0.3、1：0.35、1：0.4、1：0.45、1：0.5、1：0.55、1：0.6、1：0.65、1:0.70或其中任意两个数值组成的范围。
根据本申请的优选实施方式，所述活性成分包括托法替布、Filgotinib、Upadacitinib、ritlecitinib、ivarmacitinib sulfate、peficitinib、brepocitinib、Upadacitinib、deucravacitinib、itacitinib及其药用盐或晶型中的一种或多种。
根据本申请的优选实施方式，所述活性成分包括托法替布、托法替布的药用盐及其晶型中的一种或多种。
根据本申请的优选实施方式，所述活性成分的D90＜52μm，(例如50μm、45μm、40μm、35μm、30μm、25μm、22μm、20μm、15μm、10μm、5μm、1μm)，更优选D90≤22μm(例如20μm、15μm、10μm、5μm、1μm)。
根据本申请的优选实施方式，所述组合物体外溶出检测方法采用HPLC，第一阶段：溶出方法为在0.1M盐酸介质中，桨法，溶出介质体积为900mL，搅拌转速为100rpm，时间2h；第二阶段：pH6.0介质中，桨法，溶出介质体积为900mL，搅拌转速为100rpm，时间3h，第一、二阶段条件下累积释放的活性成分低于5％；第三阶段：在pH7.2介质中，桨法，溶出介质体积为900mL，搅拌转速为50rpm，时间8h条件下释放的活性成分不低于90％。
根据本申请的优选实施方式，以活性成分的质量为1份计，底芯的质量份数为0.5-4.0份(例如0.5、1、1.5、2.0、2.1、2.2、2.3、2.4、2.5、2.8、2.9、3.0、3.5、3.8或4.0)，粘合剂的质量份数为0.5-3.0份(例如0.5、1、1.5、2.0、2.1、2.2、2.3、2.4、2.5、2.8、2.9、3.0)；缓释层的质量份数为0-0.80；缓释材料质量份数0-0.4份(例如0、0.1、0.12、0.15、0.18、0.20、0.22、0.24、0.26、0.28、0.29、0.32或0.35)；和/或缓释层中的抗粘剂的质量份数0-0.28份(例如0、0.1、0.12、0.15、0.18、0.20、0.22、0.24、0.26或0.28)；和/或缓释层中的增塑剂的质量份数0-0.12份；和/或结肠定位材料质量份数0.2-3.00份(例如0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、1.1、1.2、13、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9或3.0)；和/或结肠定位层中的抗粘剂的质量份数0.02-1.50份(例如0.02、0.05、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.00、1.05、1.10、1.15、1.20、1.25、1.30、1.35、1.40、1.45或1.50)；和/或结肠定位层中的增塑剂的质量份数0.01-0.90份(例如0.01、0.02、0.05、0.08、0.10、0.12、0.15、0.18、0.20、0.22、0.25、0.30、0.32、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85或0.90)。
根据本申请的优选实施方式，以活性成分的质量为1份计，缓释层的质量份数为0-0.80份(例如0、0.02、0.05、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.55、0.60、0.65、0.70或0.75)；和/或结肠定位层的质量份数为0.28-4.22份(例如0.28、0.35、0.40、 0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.8、0.9、1.0、1.1、1.2、13、1.4、1.5、1.6、1.8、2.0、2.2、2.4、2.6、2.8、3.0、3.2、3.4、3.6、3.8、4.0或4.22)；和/或结肠定位层的抗粘剂的质量份数为0.04-0.80份(例如0.04、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.55、0.60、0.65、0.70、0.75或0.80)。
根据本申请的优选实施方式，所述结肠定位层与所述含药丸芯之间设置缓释层。根据本申请的优选实施方式，以活性组分的质量份数为1份计，缓释层的质量份数为0-0.8份(例如0份、0.1份、0.2份、0.3份、0.4份、0.5份、0.6份、0.7份或0.8份等)。优选地，以活性组分的质量份数为1份计，缓释层的质量份数为0.24-0.48份(例如0.25、0.30、0.35、0.40或0.45)。根据本申请的优选实施方式，以活性组分的质量份数为1份计，结肠定位层的质量份数为0.56-2.10份。
根据本申请的优选实施方式，所述结肠定位层与所述含药丸芯之间没有缓释层，优选地，以活性组分的质量份数为1份计，结肠定位层材料的质量份数为0.28-4.22份(例如0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、1.1、1.2、13、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9或3.0)。
根据本申请的优选实施方式，所述结肠定位层与所述含药丸芯之间没有缓释层，优选地，以活性组分的质量份数为1份计，结肠定位层的抗粘剂的质量份数为0.04-0.80(例如0.04、0.08、0.10、0.12、0.15、0.18、0.20、0.25、0.30、0.35、0.38、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75或0.80)份，优选0.12-0.60份。
在第二方面，本申请提供了第一方面所述的药物组合物的制备方法，包括：将含药丸芯进行结肠定位层包覆，或者将所述含药丸芯依次进行缓释层包覆和结肠定位层包覆。
根据本申请的优选实施方式，该制备方法包括以下步骤：a)配制活性成分层混悬液，使用流化床工艺将活性成分层混悬液喷至底芯中，制备含药丸芯。
根据本申请的优选实施方式，该制备方法包括以下步骤：b)配制缓释层混悬溶液，使用流化床工艺将缓释层混悬溶液喷至含药丸芯中，制备缓释微丸。
根据本申请的优选实施方式，该制备方法包括以下步骤：c)配制结肠定位层包衣溶液，使用流化床工艺将结肠定位层包衣溶液喷至含药丸芯或缓释微丸中，以制备结肠定位缓释微丸。
根据本申请的优选实施方式，该制备方法包括以下步骤：d)将所述结肠定位缓释微丸灌装胶囊。
本发明提供的药物组合物采用空白丸芯上药、膜控缓释包衣、结肠定位包衣、再进行胶囊灌装制备多单元结肠定位缓释微丸，其能缓释1-8小时，在组织中的浓度比血液中的浓度高，提高疗效，降低不良反应(对比阳性药)。
1、空白丸芯上药：本方案为多单元给药系统，与片剂相比更能在结肠组织中多点释 放，提高药物疗效。2、膜控缓释技术：解决骨架缓释容易突释问题，且膜控缓释比骨架缓释辅料用量少，减少药物体积，提高患者顺应性；控制缓释层材料用量可控制缓释时间。3、结肠定位技术：结合患者结肠内pH值，选用结肠定位材料，使药物在小肠内不释放，并控制结肠定位层材料用量也可控制缓释时间。
具体实施方式
为更好地说明本发明，便于理解本发明的技术方案，下面对本发明进一步详细说明。本文“N/A”为表示空白，或“N/A”代表不含该组分或者在后续工序中除去；“季胺基甲基丙烯酸酯共聚物B型”又名“尤特奇RS”，甲基丙烯酸和甲基丙烯酸甲酯(1:2)共聚物又名“尤特奇S100”，季胺基甲基丙烯酸酯共聚物A型又名“尤特奇RL”；“甲基丙烯酸和丙烯酸甲酯和甲基丙烯酸甲酯(1:1:1)共聚物”又名“尤特奇FS30D”；“甲基丙烯酸和甲基丙烯酸甲酯(1:1)共聚物”又名“尤特奇L100”。
本申请的上下文中，若无特别说明，“％”均代表质量百分比。
对比例1：
参考CN108066319A专利的实施例13，制备目标丸芯，检测溶出曲线。处方参见表1。
表1
工艺：
主要生产设备：湿法混合机、挤出机、滚圆机、烘箱、干整粒机、流化床、胶囊灌装机
(1)原辅料称量
依次称取各原辅料，纯化水单独称量。
(2)软材的制备
1)按等量递增原则将称好的原辅料混合均匀。
2)搅拌下缓缓加入粘合剂，搅拌至无团块状物料，制得过湿软材。
(3)挤出滚圆制备小丸
将上述软材置于挤出机中，调整挤出机的转速，然后将挤出的条状物料置于滚圆机中，调整转盘转速和风机频率，制得适宜小丸。
(4)干燥
将制备好的小丸置于烘箱中干燥至水分小于3％。将干燥后的小丸过16目筛和40目筛(粒径0.38mm-1mm)，取16目至40目中间部分小丸进行肠溶包衣。
(5)肠溶包衣液的配制
称取处方量的纯化水，置于烧杯中，开启搅拌，慢慢加入边加边搅拌，加完后搅拌30min，备用。
(6)肠溶包衣
取16目至40目部分小丸进行肠溶包衣，肠溶包衣液过80目筛，固含量20％，流化床包衣，得枸橼酸托法替布肠溶缓释微丸。
(7)灌装胶囊
选择合适的胶囊，灌装枸橼酸托法替布肠溶缓释微丸即可。
对比例2：片剂(非多单元给药系统)
参考文献：Vakar,Rupa Mazumder1,Swarupanjali Padhi(Development of Colon Targeting Tablet of a JAK Inhibitor to Combat Chronic Ulcerative Colitis:A Novel Approach for Local Drug Delivery)制备肠溶缓释片，检测溶出曲线。
处方参见下表2：
表2

工艺：
主要设备：湿法混合机、烘箱、干整粒机、混合机、压片机、包衣机
(1)混合：将枸橼酸托法替布、微晶纤维素和乳糖混合；
(2)以羟丙纤维素-L为粘合剂溶液进行制软材、制粒、湿整粒；
(3)干燥：烘箱60℃，干燥2h，水分不超过1％；
(4)干整粒，过40目筛网；
(5)总混：先与羧甲基纤维素钠混合10min，再加入硬脂酸镁混合10min；
(6)压片：使用压片机压片，6mm圆形凹冲，片重100mg，硬度4KP。
(7)肠溶包衣：按包衣液组成配制包衣液，使用包衣机包衣。保持片床温度为30℃，锅转10rpm，雾化压力2bar，喷雾速度10g/min。
对比例3
处方参见下表3：
表3

注1：按托法替布计；注2、3：生产过程中除去，最终不在产品中，下文同义，不作
赘述。
工艺：
主要生产设备：流化床、胶囊灌装机
1)含药丸芯的制备：
将粘合剂溶解于溶媒中，再将活性成分分散于粘合剂溶液中。使用流化床底喷包衣，控制物料温度为38-45℃，雾化压力150KPa，喷液速度＜7g/min，将活性成分混悬液上药至底芯中，制备含药丸芯。
2)膜控缓释丸芯的制备
按照处方量配制缓释层包衣混悬溶液，使用流化床底喷包衣，控制物料温度为25-35℃，雾化压力150KPa，喷液速度＜3g/min，将包衣液喷至含药丸芯中，制备缓释微丸。
3)结肠定位缓释丸芯的制备
按照处方量配制结肠定位层包衣溶液，使用流化床底喷包衣，控制物料温度为20-30℃，雾化压力150KPa，喷液速度＜3g/min，将包衣液喷至缓释微丸中，制备结肠定位缓释微丸。
4)胶囊灌装
按枸橼酸托法替布的含量，折算托法替布为10mg的重量灌装4号胶囊。
实施例1
制剂1处方参见表4。
表4
制剂1工艺：
主要生产设备：流化床、胶囊灌装机
1)含药丸芯的制备：
将粘合剂溶解于溶媒中，再将活性成分分散于粘合剂溶液中。使用流化床底喷包衣，控制物料温度为38-45℃，雾化压力150KPa，喷液速度＜7g/min，将活性成分混悬液上药至底芯中，制备含药丸芯。
2)结肠定位丸芯的制备
按照处方量配制结肠定位层包衣溶液，使用流化床底喷包衣，控制物料温度为20-30℃，雾化压力150KPa，喷液速度＜3g/min，将包衣液喷至上药微丸中，制备结肠定位微丸。
3)胶囊灌装
按枸橼酸托法替布的含量，折算托法替布为10mg的重量灌装4号胶囊。
实施例2
制剂2处方参见下表5。
表5
制剂2工艺：参考对比例3。
实施例3
制剂3处方参见下表6：
表6

制剂3工艺：参考对比例3。
制剂4处方参见下表7。
表7
制剂4工艺：参考对比例3。
2、检测：
1)体外溶出方法：参考USP方法，第一阶段模拟药物在胃阶段，第二阶段模拟药物在小肠阶段，第三阶段模拟药物在结肠阶段：

注：下文均用统一溶出方法检测。耐酸阶段指溶出方法的第一阶段、第二阶段。本文
的缓释时间不包括溶出方法第一阶段、第二阶段，仅指溶出的第三阶段。检测结果参见下表8。
2)检测方法：采用HPLC检测托法替布含量，色谱条件如下。
表8
小结：对比例1在pH6.0介质有溶出；对比例2为片剂，缓释6小时左右，且在2-4小时有突释；制剂1、制剂2、制剂3、制剂4、对比例3分别缓释1小时、4小时、8小时、18小时、24小时左右。
实施例4：活性成分托法替布及其盐型
处方参见表9：
表9

工艺：
主要生产设备：流化床、胶囊灌装机
1)含药丸芯的制备：
将粘合剂溶解于溶媒中，再将活性成分分散于粘合剂溶液中。使用流化床底喷包衣，控制物料温度为38-45℃，雾化压力150KPa，喷液速度＜7g/min，将活性成分混悬液上药至底芯中，制备含药丸芯。
2)膜控缓释丸芯的制备
按照处方量配制缓释层包衣混悬溶液，使用流化床底喷包衣，控制物料温度为25-35℃，雾化压力150KPa，喷液速度＜3g/min，将包衣液喷至含药丸芯中，制备缓释微丸。
3)结肠定位缓释丸芯的制备
按照处方量配制结肠定位层包衣溶液，使用流化床底喷包衣，控制物料温度为20-30℃，雾化压力150KPa，喷液速度＜3g/min，将包衣液喷至缓释微丸中，制备结肠定位缓释微丸。
4)胶囊灌装
按托法替布的含量，折算托法替布为10mg的重量灌装4号胶囊。
溶出结果参见下表10：
表10
结果表明：采用托法替布或其盐型化合物制备结肠定位缓释微丸胶囊，不影响胶囊的溶出情况，缓释时间均为8小时左右。
实施例5：不同粒径的活性成分
处方参见下表11：
表11
工艺：参照实施例4。
粒径检测方法：采用激光粒度分析仪(马尔文帕纳科公司的Matersizer3000)，使用干法，进样速度40.0％，料斗间隙2.5mm，分散压力为3.0bar。溶出结果参见下表12：
表12
结果表明：采用粒径D90为10±2μm或20±2μm的活性成分上药包衣，肠溶缓释微丸圆整度好，在pH1.0及pH6.0基本不溶出，但采用粒径D90为50±2μm的活性成分上药包衣，肠溶缓释微丸圆整度差，在pH6.0有溶出，故活性成分粒径控制为D90＜52μm，更优选D90≤22μm。
实施例6：不同空白丸芯的种类
处方参见下表13：
表13
工艺：参照实施例4。
溶出结果参见下表14：
表14
结果表明：采用甘露醇丸芯或蔗糖丸芯为底芯制备结肠定位缓释微丸胶囊，不影响胶囊的溶出情况，缓释时间为8小时。
实施例7：不同缓释聚合物种类及型号
处方参见下表15：
表15

工艺：参照实施例4。
溶出结果参见下表16：
表16
结果表明：采用乙基纤维素为缓释材料，粘度越高的型号，缓释时间越长，故乙基纤维素N50(50cps)不合适为缓释材料，选用N7(7cps)为本方案的优选缓释材料。
实施例8：不同缓释聚合物型号比例
处方参见下表17：
表17

工艺：参照实施例4。
溶出结果参见下表18：
表18
结果表明：采用缓释材料的不同型号配比(1:4～4:1)制备结肠定位缓释微丸胶囊，当尤特奇RS(孔径小)用量较多时候，缓释时间越长，故在本方案中优选采用尤特奇RL：尤特奇RS＝4:1～2:3，缓释时间为4～8小时。
实施例9：不同缓释层用量
处方参见下表19：
表19

工艺：参照实施例4。
溶出结果参见下表20：
表20
结果表明：缓释材料用量越多，缓释时间越长。采用缓释层用量(0.24份～0.80份)制备结肠定位缓释微丸胶囊，胶囊均能基本全部溶出，缓释时间为4-8小时。
实施例10：不同结肠定位材料种类
处方参见下表21：
表21

工艺：参照实施例4。
溶出结果参见下表22：
表22
结果表明：采用不同种类结肠定位材料制备结肠定位缓释微丸胶囊，样品均能基本全部溶出，缓释时间为8小时左右。
实施例11：不同结肠定位材料型号
根据溃疡性结肠炎患者结肠组织的pH变化情况，选用结肠定位材料的不同型号，或者通过不同型号之间的配比使用，达到样品在结肠定位的目的。
处方参见下表23：
表23

工艺：参照实施例4。
溶出结果参见下表24：
表24
结果表明：采用不同型号的结肠定位材料制备结肠定位缓释微丸胶囊，当尤特奇S100：尤特奇L100＝0:1时，样品在pH6.0有一定的溶出，为了防止样品在小肠吸收，故尤特奇S100：尤特奇L100的质量比在1:0～1:1。
实施例12：抗粘剂的种类
处方参见下表25：
表25

工艺：参照实施例4。
溶出结果参见下表26：
表26
结果表明：采用不同种类的抗粘剂制备结肠定位缓释微丸胶囊，在盐酸及pH6.0介质基本无溶出。在pH7.2介质中均能基本全部溶出，缓释时间为8小时左右。
实施例13：不同抗粘剂的用量
处方参见下表27：
表27
工艺：参照实施例4。
溶出结果参见下表28：
表28
结果表明：采用不同用量的抗粘剂制备结肠定位缓释微丸胶囊，在盐酸及pH6.0介质基本无溶出。在pH7.2介质中均能基本全部溶出，结肠定位层抗粘剂用量(0.24份～0.60份)，缓释时间为7-8小时。
实施例14：结肠定位层用量
处方参见下表29：
表29
工艺：参照实施例4。
溶出结果参见表30：
表30

结果表明：在有缓释层的基础上，采用不同用量结肠定位层(0.56份～1.67份)制备结肠定位缓释微丸胶囊，在盐酸及pH6.0介质基本无溶出；在pH7.2介质中均能基本全部溶出，缓释时间为6-8小时。
实施例15：结肠定位聚合物用量
处方参见下表31：
表31
工艺：参照实施例1。
溶出结果参见表32：
表32
结果表明：在仅有肠溶层的条件下，结肠定位聚合物用量为0.2～3.0份制备结肠定位微丸胶囊，在盐酸及pH6.0介质基本无溶出；在pH7.2介质中均能基本全部溶出，缓释时 间为1-8小时。当结肠定位聚合物用量低于0.2份(处方23)时，结肠定位微丸胶囊在pH6.0介质基本有较多溶出；当结肠定位聚合物用量高于3.0份(处方26)时，结肠定位微丸胶囊在在盐酸及pH6.0介质基本无溶出，但在pH7.2介质中缓释时间为超过8小时。故在仅有肠溶层的条件下，结肠定位聚合物用量为0.2～3.0份制备结肠定位微丸胶囊，能够达到目前缓释时间。
实施例16：上药层粘合剂用量
处方参见下表33：
表33
工艺：参照实施例1。
溶出结果参见表34：
表34
结果表明：在仅有肠溶层的条件下，上药层活性成分与所述粘合剂的质量比为1：1，1：1.5，1：2制备结肠定位微丸胶囊，在盐酸及pH6.0介质溶出累计溶出＜5.0％，在pH7.2介质中均能基本全部溶出，缓释时间为4小时。故在仅有肠溶层的条件下，上药层活性成分与所述粘合剂的质量比为1：1.0至1：2.0范围制备结肠定位微丸胶囊，能够达到目前缓释时间。
实施例17SD大鼠体内药代动力学(PK)试验
选用SD大鼠144只，分为8组，每组18只，分别为阳性药组(枸橼酸托法替布混悬液)、对比例1组、对比例3组、制剂1组、制剂2组、制剂3组、处方27组、制剂4组，分别灌胃阳性药(枸橼酸托法替布混悬液)(对照组)、对比例1组、对比例3组、制剂1组、制剂2组、制剂3组、处方27组、制剂4组，每组灌胃剂量相同(12.5mg/kg/天，以托法替布计)。
阳性药组在0.5、1、2、6、12、24h分别处死3只SD大鼠，并取血、取结肠组织。
对比例1组在2、4、8、12、16、4h分别处死3只SD大鼠，并取血、取结肠组织。
对比例3组在4、8、12、16、20、24h分别处死3只SD大鼠，并取血、取结肠组织。
制剂1组在1、2、3、6、12、24h分别处死3只SD大鼠，并取血、取结肠组织。
制剂2组在2、4、6、8、16、24h分别处死3只SD大鼠，并取血、取结肠组织。
制剂3组在3、6、9、12、18、24h分别处死3只SD大鼠，并取血、取结肠组织。
处方27组在3、6、9、12、18、24h分别处死3只SD大鼠，并取血、取结肠组织。
制剂4组在4、8、12、16、18、24h分别处死3只SD大鼠，并取血、取结肠组织。血液离心后取血浆，进行检测；组织中加入甲醇，匀浆后，采用LC-MS/MS进行检测。
PK试验结果参见表35：
表35

备注：阳性药采用0.5％羧甲基纤维素钠为溶剂，加入枸橼酸托法替布，配制成浓度为2.5mg/mL
的枸橼酸托法替布混悬液。
小结：制剂1、制剂2、制剂3组的药物在结肠组织中的浓度远高于阳性药组、对比例1、对比例3、处方27组、制剂4组，且当缓释时间为1-8小时，结肠组织中药物浓度较高。
实施例18比格犬体内药代动力学(PK)试验
选用比格犬9只，分为3组，每组3只，分别为阳性药组(枸橼酸托法替布混悬液)、 对比例2组、制剂2组，分别灌胃阳性药(枸橼酸托法替布混悬液)(对照组)、对比例2组(片剂)、制剂2组(胶囊)，每组灌胃剂量相同(3.6mg/kg/天，以托法替布计)。阳性药组在0.5h/1h/2h/6h/12h/24h取血，且在犬1号(3h)、犬2号(12h)、犬3号(24h)分别处死，取结肠组织。
对比例2组在3h/6h/9h/12h/18h/24h取血，且在犬4号(6h)、犬5号(12h)、犬6号(24h)分别处死，取结肠组织。
制剂2组在3h/6h/9h/12h/18h/24h取血，且在犬7号(3h)、犬8号(9h)、犬9号(24h)分别处死，取结肠组织。
血液离心后取血浆，进行检测；组织中加入甲醇，匀浆后，采用LC-MS/MS进行检测。
PK试验结果参见表36：
表36

备注：阳性药采用0.5％羧甲基纤维素钠为溶剂，加入枸橼酸托法替布，配制成浓度为2.5mg/mL
的枸橼酸托法替布混悬液。
小结：制剂2的药物在结肠组织中的浓度远高于阳性药组、对比例2，故多单元结肠靶向肠溶胶囊比肠溶缓释片在结肠组织中更有优势。
实施例19药效学(PD)试验
选用SD大鼠60只，分为10组，每组6只，分别为空白组、模型组、阳性药组(枸橼酸托法替布混悬液)、对比例1组、对比例3组、制剂1组、制剂2组、制剂3组、处方27组、制剂4组，除空白组外，其他组别均采用3％葡聚糖硫酸钠盐(Dextran Sulfate Sodium Salt，DSS)进行造模，并灌胃给药治疗。每组灌胃剂量相同(28mg/kg/天，以托法替布计)，空白组灌胃0.5％羧甲基纤维素钠，记录每只大鼠体重、记录粪便情况并进行疾病活动系数评分(DAI)。给药7天后，取脾脏、结肠组织、并观察结肠组织病理切片。结果参见表37和38。
表37
表38
备注：
(1)阳性药采用0.5％羧甲基纤维素钠为溶剂，加入枸橼酸托法替布，配制成浓度为2.5mg/mL的枸橼酸托法替布混悬液；
(2)DAI评分标准；
(3)结肠重量/长度比例升高说明具有一定的病变；
(4)脾脏重量/体重比例升高说明体内具有炎症，脾脏肿大。
小结：制剂1组、制剂2组、制剂3组治疗DSS诱导的溃疡性结肠炎，能够大幅度降低DAI评分、降低结肠重量/长度比例、降低脾脏重量/体重长度比、改善结肠组织炎症。
对比汇总详见下表39：
表39

总结：由以上实验结果可知，本发明制备得到的托法替布结肠定位缓释胶囊辅料用量少，胶囊体积小，能提高患者顺应性；工艺简单、工序少、使用设备少，主要设备仅为流化床，见表39；结肠定位缓释胶囊活性成分释放较均匀，能缓释1-8h，且主要分布在结肠部位，血浆暴露量减少，提高生物利用度，降低溃疡性结肠炎大鼠DAI评分、降低结肠重量/长度比例、降低脾脏重量/体重长度比、改善结肠组织炎症，详见表35和36，表38。
本领域的技术人员容易理解，以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (19)

  1. 一种药物组合物，包括含药丸芯和结肠定位层，所述结肠定位层与所述含药丸芯之间任选地设置缓释层，
    其中所述含药丸芯包括底芯和活性成分层，所述结肠定位层包覆所述含药丸芯，所述活性成分层包含选自Janus激酶抑制剂的活性成分。
  2. 根据权利要求1所述的药物组合物，其特征在于，在所述含药丸芯中，所述活性成分层包覆所述底芯表面。
  3. 根据权利要求1或2所述的药物组合物，其特征在于，所述底芯的材料选自蔗糖、微晶纤维素、甘露醇或酒石酸中的一种或多种；和/或所述底芯中不含活性成分和/或缓释材料和/或结肠定位材料。
  4. 根据权利要求1-3中任一项所述的药物组合物，其特征在于，所述含药丸芯中，
    所述活性成分层还包括粘合剂；
    优选地，所述粘合剂选自聚维酮、羟丙甲纤维素、羟丙纤维素、甲基纤维素或羧甲基纤维素钠中的一种或多种；
    优选地，所述活性成分与所述粘合剂的质量比为1：(0.5-3.0)；
    优选地，所述活性成分与所述底芯的质量比为1：(0.5-4.0)；
    优选地，所述粘合剂与所述底芯的质量比为1：(0.5-3.0)。
  5. 根据权利要求1-4中任一项所述的药物组合物，其特征在于，
    所述结肠定位层包括结肠定位材料、增塑剂和抗粘剂；和/或
    所述缓释层包括缓释材料和增塑剂，任选地抗粘剂。
  6. 根据权利要求5所述的药物组合物，其特征在于，
    所述结肠定位材料选自虫胶、聚乙烯醇乙酸苯二甲酸酯、纤维素及其衍生物、丙烯酸树脂类中的一种或者多种。
  7. 根据权利要求5或6所述的药物组合物，其特征在于，
    所述结肠定位材料选自甲基丙烯酸和甲基丙烯酸甲酯(1:1)共聚物、甲基丙烯酸和甲基丙烯酸甲酯(1:2)共聚物、甲基丙烯酸和丙烯酸甲酯和甲基丙烯酸甲酯(1:1:1)共聚物中的一种或者多种。
  8. 根据权利要求5-7中任一项所述的药物组合物，其特征在于，所述缓释材料选自乙基纤维素、壳聚糖、聚乙烯醇、丙烯酸树脂类中的一种或多种；
    优选地，所述缓释材料选自乙基纤维素、季胺基甲基丙烯酸酯共聚物中的一种或多种，
    优选地，所述乙基纤维素的粘度为7～20cps，和/或乙基纤维素的型号选自N7、N10、N12和N15中的一种或多种。
  9. 根据权利要求8所述的药物组合物，其特征在于，
    所述季胺基甲基丙烯酸酯共聚物选自季胺基甲基丙烯酸酯共聚物RL型和RS型中的一种或多种，
    当季胺基甲基丙烯酸酯共聚物为季胺基甲基丙烯酸酯共聚物RL型和RS型的混合物时，优选季胺基甲基丙烯酸酯共聚物RL型和RS型的质量比为(10～0.5)：1，更优选季胺基甲基丙烯酸酯共聚物RL型、季胺基甲基丙烯酸酯共聚物RS型的质量比为(4～0.67)：1。
  10. 根据权利要求5-9中任一项所述的药物组合物，其特征在于，所述增塑剂选自柠檬酸三乙酯、蓖麻油、乙酰柠檬酸三乙酯、柠檬酸三丁酯、乙酰柠檬酸三丁酯、癸二酸二丁酯等中的一种或多种。
  11. 根据权利要求5-10中任一项所述的药物组合物，其特征在于，所述抗粘剂选自滑石粉、单硬脂酸甘油酯、硬脂酸镁、微粉硅胶、高岭土中的一种或多种。
  12. 根据权利要求5-11中任一项所述的药物组合物，其特征在于，所述结肠定位层中，所述结肠定位材料与所述增塑剂的质量比为1：(0.1-0.5)；和/或所述结肠定位材料与所述抗粘剂的质量比为1：(0.1-0.5)；和/或
    所述缓释层中，所述缓释材料与所述增塑剂的质量比为1：(0.1-0.3)；和/或所述缓释材料与所述抗粘剂的质量比为1：(0-0.7)。
  13. 根据权利要求1-12中任一项所述的药物组合物，其特征在于，所述活性成分包括托法替布、Filgotinib、Upadacitinib、ritlecitinib、ivarmacitinib sulfate、peficitinib、brepocitinib、Upadacitinib、deucravacitinib、itacitinib及其药用盐或晶型中的一种或多种。
  14. 根据权利要求1-13中任一项所述的药物组合物，其特征在于，所述活性成分包括托法替布、托法替布的药用盐及其晶型中的一种或多种。
  15. 根据权利要求1-14中任一项所述的药物组合物，其特征在于，
    所述组合物体外溶出检测方法采用HPLC，第一阶段：溶出方法为在0.1M盐酸介质中，桨法，溶出介质体积为900mL，搅拌转速为100rpm，时间2h；第二阶段：pH6.0介质中，桨法，溶出介质体积为900mL，搅拌转速为100rpm，时间3h，第一、二阶段条件下累积释放的活性成分低于5％；第三阶段：在pH7.2介质中，桨法，溶出介质体积为900mL，搅拌转速为50rpm，时间8h条件下释放的活性成分不低于90％；和/或所述活性成分的D90＜52μm，更优选D90≤22μm。
  16. 根据权利要求1-15中任一项所述的药物组合物，其特征在于，
    以活性成分的质量为1份计，底芯的质量份数为0.5-4.0份，粘合剂的质量份数为0.5-3.0份；
    缓释层的质量份数为0-0.80份；
    缓释材料的质量份数0-0.4份；缓释层中的抗粘剂的质量份数0-0.28份；缓释层中的增塑剂的质量份数0-0.12份；
    结肠定位材料的质量份数0.2-3.0份；
    结肠定位层中的抗粘剂的质量份数0.02-1.50份；
    结肠定位层中的增塑剂的质量份数0.01-0.90份。
  17. 根据权利要求1-15中任一项所述的药物组合物，其特征在于，以活性成分的质量为1份计，
    缓释层的质量份数为0-0.80份；
    当缓释层的质量份数大于0且≤0.80份，例如0.24-0.48份时，结肠定位层的质量份数为0.56-2.10份；当缓释层的质量份数为0份时，结肠定位层的质量份数为0.28-4.22份；
    结肠定位层的抗粘剂的质量份数为0.04-0.80份，优选0.12-0.60份。
  18. 根据权利要求1-17中任一项所述的药物组合物的制备方法，包括如下步骤：
    将含药丸芯进行结肠定位层包覆，或者
    将所述含药丸芯依次进行缓释层包覆和结肠定位层包覆。
  19. 根据权利要求18所述的制备方法，其特征在于，包括如下步骤：
    a)配制活性成分层混悬液，使用流化床工艺将活性成分层混悬液喷至底芯中，制备含药丸芯；
    b)任选地，配制缓释层混悬溶液，使用流化床工艺将缓释层混悬溶液喷至含药丸芯中，制备缓释微丸；
    c)配制结肠定位层包衣溶液，使用流化床工艺将结肠定位层包衣溶液喷至含药丸芯或缓释微丸中，以制备结肠定位缓释微丸。
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