WO2021129735A1 - 一种固体制剂及其制备方法和用途 - Google Patents

一种固体制剂及其制备方法和用途 Download PDF

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WO2021129735A1
WO2021129735A1 PCT/CN2020/138988 CN2020138988W WO2021129735A1 WO 2021129735 A1 WO2021129735 A1 WO 2021129735A1 CN 2020138988 W CN2020138988 W CN 2020138988W WO 2021129735 A1 WO2021129735 A1 WO 2021129735A1
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sustained
release
active ingredient
release part
solid preparation
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PCT/CN2020/138988
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English (en)
French (fr)
Inventor
钱晓明
方云
万建胜
李钊
李坤
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上海宣泰医药科技股份有限公司
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Priority to EP20906098.7A priority Critical patent/EP4082534A4/en
Priority to US17/757,857 priority patent/US20230055404A1/en
Publication of WO2021129735A1 publication Critical patent/WO2021129735A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • 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
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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    • 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
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the invention relates to the field of pharmaceutical preparations, and in particular to a solid preparation and a preparation method and application thereof.
  • the development of suitable dosage forms for active pharmaceutical ingredients has always been the focus of the pharmaceutical field.
  • the dissolution of the drug component can reflect the speed and extent of the drug release in the body, and to a certain extent reflect the drug's therapeutic effect on the disease.
  • CN103845302A discloses a film-coated tablet of tofacitinib with excellent performance.
  • the film-coated tablet contains film-coated basic reagent, tofacitib, and medicinal additives.
  • CN104622827A discloses a tofacitinib tablet and a preparation method thereof.
  • the tablet is prepared by using direct-pressed lactose and microcrystalline cellulose with good fluidity and compression molding properties as diluents and dry binders, and is prepared by a simple powder direct compression method.
  • CN105878202A discloses a tofacitinib citrate tablet, which is composed of tofacitinib citrate and pharmaceutically acceptable excipients, the excipients including fillers, disintegrants, glidants and coating agents , Prepared by powder direct compression method.
  • CN105101952A discloses an oral sustained-release preparation of tofacitinib and a pharmaceutically acceptable salt thereof, which is a once-a-day pharmaceutical dosage form, which comprises tofacitinb or a pharmaceutically acceptable salt thereof and a pharmaceutical The acceptable carrier, wherein the dosage form is a sustained-release dosage form, and dry granulation and tableting technology is used in Example 1, Example 2, etc. to prepare the core of the sustained-release tablet.
  • the present invention relates to a solid preparation that includes an immediate-release part and a sustained-release part, and includes an active ingredient, wherein the active ingredient in the sustained-release part and the active ingredient in the immediate-release part
  • the weight ratio is about 1:1 or higher.
  • the weight ratio of the active ingredient in the sustained-release part to the active ingredient in the immediate-release part is about 1:1-20:1, preferably about 1: 1-9:1, more preferably about 1:1-4:1, particularly preferably about 1:1-7:3, for example, about 7:3-4:1.
  • the active ingredient is tofacitinib or a pharmaceutically acceptable salt thereof, especially tofacitinib citrate.
  • the immediate-release part and the sustained-release part further each independently comprise one or more pharmaceutical excipients selected from the group consisting of sustained-release matrix materials, film-forming materials, adhesives, fillers, disintegrating Antioxidant, lubricant.
  • the solid preparation is in the form of a tablet, granule, pellet or capsule; the tablet is preferably a double-layer tablet, a coated tablet or an osmotic pump tablet.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the solid preparation of the present invention.
  • the pharmaceutical composition may include one or more pharmaceutically acceptable excipients.
  • the present invention also relates to the use of the solid preparation or pharmaceutical composition in the preparation for the prevention or treatment of diseases.
  • diseases include, but are not limited to, lupus, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, type I diabetes and diabetic complications, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, moderate To severely active ulcerative colitis, Crohn’s disease, ankylosing spondylitis, juvenile idiopathic arthritis, immune system disorders alopecia, vitiligo, systemic lupus erythematosus, Alzheimer’s disease and leukemia, etc.
  • Figure 1 shows the blood concentration-time curve of tofacitinib after a single administration test, in which ⁇ represents a commercially available tofacitinib sustained-release tablet, and ⁇ represents the tofacitinib coated tablet of the present invention.
  • Figure 2 shows the blood concentration-time curve of tofacitinib after a single administration test, in which ⁇ represents the tofacitinib coated tablets 1-2 of the present invention, ⁇ represents the tofacitinib coated tablets of the present invention 1-3, ⁇ represents the tofacitinib coated tablets 1-6 of the present invention.
  • metering ratio refers to the proportioning of various substances according to a certain weight.
  • the active ingredient, the sustained-release material, and the plasticizer are proportioned according to the specified weight ratio.
  • pharmaceutically acceptable refers to contact with the patient's tissues within the scope of normal medical judgment without undue toxicity, irritation, allergic reactions, etc., has a reasonable ratio of advantages and disadvantages, and can be effectively used for the purpose.
  • the terms “pharmaceutical active ingredient”, “active ingredient”, “therapeutic agent”, “active substance” or “active agent” refer to a chemical entity that can effectively treat or prevent a target disease or condition.
  • the active ingredient used in the formulation is tofacitinib (tofacitinib, also known as “tofacitinib”) or a pharmaceutically acceptable salt thereof, especially tofacitinib citrate.
  • tofacitinib also known as “tofacitinib”
  • Different forms of active ingredients can be used in different parts of the formulations of the invention. In one embodiment of the invention, the same active ingredient is used.
  • a given compound and other corresponding forms of the compound (such as salts, polymorphs, solvates, co-crystals, amorphous and anhydrous forms, etc.) belong to the same active ingredient, but can be considered as different forms Or type.
  • tofacitib when the immediate-release part contains tofacitib and the sustained-release part contains tofacitib citrate, the tofacitib citrate needs to be converted into tofacitib. Or convert tofacitib into tofacitib citrate.
  • the immediate-release part or the sustained-release part contains tofacitinib and tofacitinib citrate, it is necessary to convert tofacitinib citrate into tofacitib or tofacitinib.
  • Tofacitib citrate when different types of salt forms of the active ingredient are simultaneously present in the solid preparation, the respective salt forms need to be converted into the corresponding free forms.
  • active ingredients such as tofacitib as used herein also encompass other forms of the active ingredient, such as polymorphs, solvates (including, for example, hydrates and mixed solvates, and salts). Hydrates), eutectic, amorphous and anhydrous forms and mixtures thereof.
  • the aforementioned form is pharmaceutically acceptable.
  • dissolution rate refers to the rate of dissolution of the drug from the solid preparation in a prescribed solvent.
  • dissolution rate refers to the rate and extent of the dissolution of a drug from a solid preparation in a prescribed solvent.
  • time to peak plasma drug concentration (T max ) refers to the average time to reach the peak plasma drug concentration (C max) after drug administration.
  • peak plasma drug concentration (C max ) refers to the average peak drug concentration reached in plasma after drug administration.
  • time to peak plasma drug concentration (T max ) refers to the time required for the drug concentration in plasma to reach the highest concentration (peak concentration) after administration.
  • AUC 0-t refers to the average integrated area under the plasma drug concentration versus time curve from 0 to t after drug administration.
  • Ta value refers to the time during which the blood drug concentration can be maintained above 17 ng/mL (IC 50 ).
  • the term “strength” refers to the drug size, that is, the weight of the active ingredient contained in each preparation unit, wherein no matter what form the active ingredient is in, its weight is the weight of the free form after conversion.
  • tofacitinib for example, in a tofacitinib preparation with a specification of 11 mg, when the active ingredient is tofacitinib, the weight of tofacitinib is 11 mg.
  • the active ingredient is tofacitinib citrate
  • the converted free tofacitinib weight is 11 mg.
  • the converted free tofacitinib weight is 11 mg.
  • the present invention relates to a solid preparation including an immediate-release part and a sustained-release part.
  • the formulation of the present invention also contains an active ingredient.
  • the active ingredients may, independently of each other, exist in the same or different forms (such as tofacitib or its pharmaceutically acceptable salt, etc.) in the immediate release part of the preparation of the present invention and/ Or in the sustained release part.
  • the active ingredient may be present as a pharmaceutically acceptable salt in the immediate release part and the sustained release part, respectively.
  • the active ingredient may be present as a pharmaceutically acceptable salt in the immediate-release part, and as a free base in the sustained-release part.
  • citrate as the active ingredient may be present in the immediate release portion and the sustained release portion, respectively.
  • citrate as the active ingredient may be present in the immediate-release part, and hydrochloride as the active ingredient may be present in the sustained-release part.
  • tofacitinib or a pharmaceutically acceptable salt thereof particularly tofacitinib citrate may be used. Therefore, in one embodiment of the formulation of the present invention, tofacitinib or a pharmaceutically acceptable salt thereof (especially tofacitinib citrate) may serve as the active ingredient (API).
  • Tofacitib (chemical name (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-yl3oxo-1 -Piperidine propionitrile) is a JAK kinase inhibitor that reduces cytokine signaling, cytokine-induced gene expression and cell activation by inhibiting the JAK pathway, thereby reducing a variety of chronic inflammatory responses (see below for structure).
  • the pharmaceutically acceptable salt of the active ingredient used may include, but is not limited to, a salt formed with an inorganic acid, a salt formed with an organic acid, and the like.
  • salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Non-limiting examples of salts formed with organic acids include, but are not limited to, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid (citric acid), succinic acid, Salts formed by methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • the salt used is citrate.
  • the active ingredient may be tofacitib citrate.
  • the active ingredient may be located in the immediate-release part and the sustained-release part. Or the active ingredient may only be present in the immediate release part and the sustained release part. In the latter case, the total amount of active ingredients in the formulation can be calculated based on the sum of the active ingredients in the immediate-release part and the sustained-release part (ie, the sum of the active ingredients in the sustained-release part and the immediate-release part may be 100%).
  • the calculation of the active ingredient in the immediate-release part and the sustained-release part may be based on the weight of the active ingredient. Or, as described above, the active ingredient should be converted into a consistent form when calculating the active ingredient, so such a ratio may also correspond to the molar ratio of the active ingredient.
  • the forms of the active ingredients used in the immediate-release part and the sustained-release part are the same, for example, both are tofacitib citrate.
  • the weight ratio of the active ingredient in the sustained-release part to the active ingredient in the immediate-release part is not less than about 1:1. In other words, the amount of active ingredient contained in the sustained-release portion is greater than or equal to the amount of active ingredient contained in the immediate-release portion.
  • the weight ratio of the active ingredient in the sustained-release portion to the active ingredient in the immediate-release portion is not greater than about 20:1.
  • the weight ratio of the active ingredient in the sustained-release part to the active ingredient in the immediate-release part may be about 1:1-19:1, preferably about 7:3-9:1, about 1:1 -4:1, about 7:3-4:1.
  • the weight ratio may be about 1:1, about 1.5:1, about 2:1, about 7:3, about 3:1, about 4:1, about 5:1, about 6:1, about 7: 1.
  • the weight ratio of the active ingredient in the sustained-release part to the active ingredient in the immediate-release part may be about 1:1-19:1 , Such as about 19:1, about 47:3, about 93:7, about 23:2, about 91:9, about 9:1, about 89:11, about 22:3, about 87:13, about 43: 7. About 17:3, about 21:4, about 83:17, about 41:9, about 81:19, about 4:1, about 79:21, about 39:11, about 77:23, about 19: 6.
  • the active ingredient in the immediate-release part (such as tofacitib or its pharmaceutically acceptable The ratio of salt) can be about 5-50%, for example, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, About 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26 %, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, About 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about
  • the active ingredient in the sustained-release part (such as tofacitib or its pharmaceutically acceptable
  • the proportion of salt) is about 50-95%, for example, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%.
  • the weight ratio of the active ingredient in the sustained-release part to the active ingredient in the immediate-release part is about 7:3-9:1, for example, about 9:1, about 89:11, about 22:3, about 87:13, about 43:7, about 17:3, about 21:4, about 83:17, about 41:9, about 81:19, about 4:1, about 79:21, about 39:11, about 77:23, about 19:6, about 3:1, about 37:13, about 73:27, about 18:7, about 71:29 or about 7:3, and a range composed of any two of these ratios (values).
  • the active ingredient in the immediate-release part (such as tofacitib or its pharmaceutically acceptable salt)
  • the ratio is about 10-30%, such as about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%, and these ratios (values) The range formed by any two of them.
  • the ratio of the active ingredient in the sustained-release part (such as tofacitib or its pharmaceutically acceptable salt) About 70-90%, for example, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80% %, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or about 90%, and these ratios (values) The range of any two of them.
  • the weight ratio of the active ingredient in the sustained-release part to the active ingredient in the immediate-release part is about 39:11-41:9, for example, about 41:9, about 81:19, about 4:1, about 79:21, about 39:11, and a range composed of any two of these ratios (values).
  • the active ingredient in the immediate-release part (such as tofacitib or its pharmaceutically acceptable salt)
  • the ratio is about 18-22%, for example, about 18%, about 19%, about 20%, about 21%, or about 22%.
  • the ratio of the active ingredient in the sustained-release part (such as tofacitib or its pharmaceutically acceptable salt) It is about 78-82%, such as about 78%, about 79%, about 80%, about 81%, or about 82%.
  • the weight ratio of the active ingredient in the sustained-release part to the active ingredient in the immediate-release part is about 39:11-41:9, Such as about 4:1.
  • the ratio of the active ingredient (such as tofacitib or its pharmaceutically acceptable salt) in the sustained-release part It is about 78-82%, such as about 80%.
  • the preparation of the present invention may be in the form of granules, pellets, tablets or capsules, or a combination of the above preparation forms.
  • the sustained-release part and the immediate-release part may each independently be in the form of granules, pellets, layers, tablets (such as osmotic pump tablets), or coatings (coatings).
  • the immediate-release part may also be in the form of granules or microparticles contained in a sustained-release part such as a sustained-release coating.
  • the formulation of the present invention may contain one or more sustained-release parts and one or more immediate-release parts. These sustained-release parts and immediate-release parts, as well as the active ingredients and other ingredients therein, can be selected independently of each other.
  • sustained-release part and the immediate-release part used herein should be understood in a broad sense and not only refer to a specific component in the formulation.
  • a formulation such as a coated tablet or an osmotic pump tablet may include a sustained-release tablet core and a coating thereon.
  • the coating is a sustained-release coating, it can also be regarded as a sustained-release part.
  • the sustained-release part of the formulation is a sustained-release granule.
  • the immediate release portion of the formulation is an immediate release granule.
  • immediate-release granules and sustained-release granules can be packed in capsules. In another preferred embodiment, immediate-release granules and sustained-release granules can be packed in bags.
  • the immediate-release granules and the sustained-release granules may be mixed and compressed into tablets.
  • the sustained-release part of the formulation is a coated sustained-release granule or a matrix sustained-release granule.
  • the immediate-release part of the formulation is located in the coating film or outside the coating film or outside the matrix sustained-release particles.
  • the sustained-release part of the formulation is a sustained-release pellet.
  • the immediate release portion of the formulation is an immediate release pellet.
  • immediate release pellets and the sustained release pellets can be packed in capsules.
  • the immediate release pellets and the sustained release pellets can be packed in a bag.
  • the immediate release pellets and the sustained release pellets may be mixed and compressed into tablets.
  • the formulation of the present invention may comprise sustained-release pellets, wherein the sustained-release pellets are coated sustained-release pellets or matrix sustained-release pellets, and the immediate-release part is located in the coating film or in the film. External or matrix sustained-release pellets.
  • the formulation of the present invention may be a double-layer tablet, one of which is a sustained-release layer (corresponding to the sustained-release part), and the other layer is an immediate-release layer (corresponding to the immediate-release part).
  • the sustained-release layer is a matrix sustained-release tablet.
  • the sustained-release layer is a film-controlled sustained-release tablet.
  • the sustained release layer is an osmotic pump tablet.
  • the formulation of the present invention may be a coated tablet, wherein the sustained-release part is a coated tablet core or matrix tablet core, and the immediate-release part is located in the coating film or outside the coating film or matrix tablet core.
  • the coated tablet is an osmotic pump tablet.
  • the preparation of the present invention may be a capsule, the content of which is sustained-release granules or pellets, and the immediate-release part is wrapped outside the capsule or located in the capsule shell.
  • the formulation is a coated tablet, wherein the sustained-release part is a coated tablet core, and the immediate-release part is a coated film, wherein the coated tablet core and the coating film each independently comprise the present invention Active ingredients.
  • the coated tablet is an osmotic pump tablet.
  • the active ingredient may be tofacitib or a pharmaceutically acceptable salt thereof, especially tofacitib citrate.
  • the sustained-release part comprises a sustained-release matrix material
  • the sustained-release matrix material may be one or more selected from the group consisting of: hydroxypropyl methylcellulose, hydroxypropyl cellulose , Hydroxyethyl cellulose, polyoxyethylene, glyceryl behenate, polymethyl methacrylate, acrylic resin, povidone, xanthan gum, sodium alginate, calcium alginate, carbomer, chitin, Polyethylene, polysiloxane.
  • Hydroxypropyl methylcellulose which can be selected from, for example, Metolose SR 90SH, a commercial product of Shin-Etsu;
  • Hydroxypropyl cellulose which can be selected from, for example, Klucel TM GF, Klucel TM JF, Klucel TM MF, Klucel TM HF, which are commercially available products of Ashland Company;
  • Hydroxyethyl cellulose which can be selected from, for example, the commercial products Natrosol G, Natrosol M, Natrosol HX, and Natrosol HHX of Ashland;
  • Glyceryl behenate which can be selected from, for example, the commercially available products of the French Jiafasai company ATO888.
  • the sustained release portion includes a sustained release matrix material.
  • the sustained-release matrix material accounts for about 40%-80% of the weight of the sustained-release part, more preferably about 40%-50% or about 50%-70%, such as about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80%.
  • the sustained-release portion and/or the immediate-release portion comprise a film-forming material.
  • the film-forming material may be one or more selected from the group consisting of cellulose acetate, ethyl cellulose, hypromellose, and acrylic resins.
  • Ethyl cellulose which can be selected from, for example, Aqualon TM ethyl cellulose produced by Ashland Company, and ETHOCEL TM produced by Dupont Company;
  • Hypromellose which can be selected from, for example, Metolose 60SH, a commercial product of Shin-Etsu;
  • Cellulose acetate which can be selected from, for example, Eastman's commercial products CA-320S, CA-394-60LF, CA-398-3, CA-398-6, CA-398-10 and CA-398-30;
  • Ethyl cellulose which can be selected from ETHOCEL TM Standard 10 Premium of Dupont Company.
  • the sustained-release part contains a film-forming material (film material).
  • the active ingredient may or may not be located in the film-forming material.
  • the active ingredient may be an immediate-release active ingredient, or it may be a sustained-release active ingredient.
  • the film-forming material may account for about 30%-70% of the weight of the sustained-release part, more preferably about 40%-67%, such as about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 67%.
  • a coated tablet or an osmotic pump tablet may include a sustained-release tablet core and/or a sustained-release coating.
  • the tablet core or coating contains materials such as film-forming materials or framework materials, its content should be calculated based on the corresponding tablet core or coating.
  • the immediate release portion contains a film-forming material (film material).
  • film material accounts for about 40%-80% of the weight of the immediate-release part, more preferably about 50%-70%, for example, about 40%, about 45%, about 50%, about 55%, about 60% , About 65%, about 70%, about 75%, or about 80%.
  • the preparation of the present invention may optionally contain one or more of the following pharmaceutically acceptable excipients in the sustained-release part, the immediate-release part, or other parts other than the two: Agents, fillers, disintegrants and lubricants, etc.
  • Agents, fillers, disintegrants and lubricants, etc. The amount of these pharmaceutically acceptable excipients can be selected by those skilled in the art according to needs.
  • the binder may be one or more selected from the group consisting of polyethylene glycol, starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pregelatinized starch, polyvinylpyrrolidone, gum arabic powder and gelatin , Preferably starch, pregelatinized starch, modified starch, microcrystalline cellulose, silicified microcrystalline cellulose, low-substituted hydroxypropyl cellulose glucose, sucrose, lactose, sorbitol, mannitol, erythritol, calcium carbonate and Calcium hydrogen phosphate is particularly preferably lactose, mannitol, microcrystalline cellulose and silicified microcrystalline cellulose.
  • the disintegrant can be one or more selected from the following: microcrystalline cellulose, carboxymethyl cellulose, crospovidone, croscarmellose sodium, carboxymethyl cellulose calcium, carboxymethyl Sodium starch base, low-substituted hydroxypropyl cellulose, hydroxymethyl starch, alginic acid, sodium alginate, guar gum, corn starch and magnesium aluminum silicate, preferably crospovidone and croscarmellose sodium.
  • the lubricant can be one or more selected from the group consisting of magnesium stearate, stearic acid, stearate, sodium stearyl fumarate, sodium lauryl sulfate, polyethylene glycol, sodium benzoate, Sucrose fatty acid esters, micronized silica gel, talc, glyceryl monostearate, glyceryl behenate, glyceryl palmitoyl stearate, stearic acid and hydrogenated vegetable oils, preferably magnesium stearate.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the solid preparation of the present invention.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable excipients.
  • the preparation of the present invention can exhibit a combination of a dual-release mode of immediate-release and sustained-release, which enables the pharmaceutical ingredients to take effect quickly while providing an effective and stable blood concentration for a longer period of time. .
  • the release amount of the active ingredient is about 5%-50%, such as about 5%, about 10%, about 15%, about 20% , About 25%, about 30%, about 45%, or about 50%. In a preferred embodiment, within 15 minutes, based on the total weight of the active ingredient in the solid preparation, the release amount of the active ingredient is about 10%-30%, such as about 10%, about 15%, about 20%, about 25%. % Or about 30%, especially about 20%.
  • the dissolution rate of the active ingredient in the immediate-release part within 15 minutes is about 0.03-0.37 mg/min, for example, about 0.07 mg/min, about 0.13 mg/min, or about 0.15 mg /min, about 0.17 mg/min, about 0.21 mg/min, about 0.24 mg/min, about 0.28 mg/min, or about 0.33 mg/min.
  • the dissolution rate of the active ingredient in the immediate-release part within 15 minutes is about 0.07-0.22 mg/min, for example, about 0.07 mg/min, about 0.13 mg/min, or about 0.15 mg/min. min, about 0.17 mg/min or about 0.21 mg/min, particularly preferably about 0.15 mg/min.
  • the ratio of the average dissolution rate of the active ingredient in the immediate-release part within 15 minutes to the average dissolution rate of the active ingredient in the sustained-release part within the full release time range is about 0.5:1- 100:1, for example, about 1.3:1, about 10.4:1, about 30:1, about 64.5:1, or about 96.5:1.
  • the ratio is about 1.4:1-11:1, such as about 1.6:1, about 3.3:1, about 6.7:1, about 8.5:1, or 10:1.
  • the ratio is about 3:1-6:1, such as about 3.3:1, about 3.9:1, about 4.5:1, about 5.2:1, or about 5.8:1.
  • the dissolution rate and release amount can be calculated from the dissolution-time curve of the active ingredient.
  • the dissolution rate can be measured by a conventional method in the art, for example, according to the USP II method (paddle method) of the United States Pharmacopoeia.
  • the total release of the active ingredient in the formulation of the present invention is about 20%-65%, such as about 20%, about 25%, about 30%, about 35%, about 40% , About 45%, about 50%, about 55%, about 60%, or about 65%.
  • the release amount is about 30%-50%, such as about 30%, about 35%, about 40%, about 45%, or about 50%.
  • the total release of the active ingredient in the formulation of the present invention is about 55%-95%, such as about 55%, about 60%, about 65%, about 70%, about 75% , About 80%, about 85%, about 90%, or about 95%.
  • the release amount is about 60%-80%, such as about 60%, about 65%, about 70%, about 75%, or about 80%.
  • the total release amount of the active ingredients in the solid preparation is not less than about 80%, for example, about 80%, about 85%, about 90%, about 95% or about 99% or higher. In a preferred embodiment, the release amount is not less than about 85%, such as about 85%, about 90%, about 95%, about 96%, or about 97% or more.
  • the total release amount of the active ingredient in the formulation of the present invention is about 5%-50%; within 1 hour, the total release amount is about 20%-65%; within 3 hours Within 5 hours, the total release amount is about 55%-90%; and within 5 hours, the total release amount is not less than about 80%.
  • the calculation of the above-mentioned release amount is based on the total amount of the active ingredient in the preparation before release.
  • the time required for the plasma concentration to reach 17ng/ml after a single administration is about 10-60 minutes, for example about 15 minutes, about 20 minutes, about 25 minutes, or about 30 minutes. , About 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, or about 60 minutes.
  • the preparation of the present invention, after a single administration is about 25-45 minutes, such as about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, or about 50 minutes.
  • the preparation of the present invention after a single administration, is about 20-30 minutes, such as about 20 minutes, about 22 minutes, about 24 minutes, About 26 minutes, about 28 minutes, or about 30 minutes.
  • the solid preparation of the present invention can maintain a blood concentration of 17ng/ml or more through a single administration for a duration of about 8-12 hours (e.g., about 8, about 8.5, about 9, About 9.5, about 10, about 10.5, about 11, about 11.5, or about 12 hours), preferably about 9-11 hours.
  • the blood concentration of 17 ng/ml in this article corresponds to the half inhibitory concentration (ie IC 50 value) of JAK1/3 in vitro.
  • single administration refers to a solid preparation of one dosage unit (for example, one tablet or one pill) administered at a time, which contains 11 mg or 22 mg of active ingredient (for example, tofacitib citrate).
  • the frequency of administration may be, for example, once a day.
  • the subject of administration may be a mammal, such as a human.
  • the active ingredient may be tofacitinib or a pharmaceutically acceptable salt thereof, especially tofacitinib citrate.
  • the present invention also relates to a method for preparing the solid preparation of the present invention, which comprises
  • step 1) and step 2) are performed independently of each other in any order;
  • step 1) and step 2) are used independently.
  • the active ingredients in step 1) and step 2) are each independently tofacitinib or a pharmaceutically acceptable salt thereof, especially tofacitinib citrate.
  • the sum of the total amount of active ingredients in step 1) and step 2) is 100%.
  • the active ingredient in the formulation is only present in the immediate release part and/or the sustained release part.
  • sustained-release part for the immediate-release part, sustained-release part, active ingredient, and auxiliary materials in the preparation of the present invention, refer to the corresponding description above.
  • a pressing method which includes:
  • Preparation of immediate-release layer granules mix the active ingredient, filler, disintegrant and half of the lubricant uniformly according to the metering ratio; use the dry granulator to prepare the above mixture into granules with the remaining half of the amount The lubricant is mixed to form the total mixed particles of the immediate release layer.
  • sustained-release layer particles mix the active ingredient, filler, sustained-release matrix material and half of the lubricant uniformly according to the metering ratio; use the dry granulating machine to prepare the above mixture into particles and the remaining half The amount of lubricant is mixed to form the total mixed particles of the sustained-release layer.
  • Coating According to needs, protective coatings commonly used in this field can be added. The coating may not contain active ingredients.
  • the method of preparing the coated tablet is to compress the sustained-release tablet and apply an immediate-release coating containing the active ingredient.
  • Such a method for preparing a coated tablet includes the following steps:
  • Preparation of sustained-release granules Mix the active ingredient, filler, sustained-release matrix material and half of the lubricant according to the metering ratio; use the dry granulator to prepare the above mixture into granules and the remaining half of the amount The lubricant is mixed into the total mixed particles.
  • Coating mix the active ingredients, fillers and membrane materials evenly and add them to the isopropanol solution containing 10% of purified water by weight. Stir thoroughly to prepare a suspension with a solid content of about 7%. The suspension is coated and sprayed onto the sustained-release tablet, and then dried to prepare a coated tablet.
  • the method for preparing the composition containing the active ingredient is to prepare immediate-release pellets by extrusion spheronization, coat part of the pellets into sustained-release pellets, and fill the two into capsules in proportion.
  • Such a method for preparing capsules includes the following steps:
  • Preparation of immediate-release pellets mix the active ingredients, fillers, binders, and lubricants evenly according to the metering ratio, then add an appropriate amount of purified water to prepare a soft material, and use an extrusion spheronizer to extrude the soft material into a round shape.
  • the wet drug-containing immediate-release pellets are then dried using a fluidized bed to prepare the immediate-release pellets.
  • sustained-release pellets Add the sustained-release coating film and filler into the isopropanol solution containing 10% of purified water by weight, fully stir and dissolve, and prepare a solution with a solid content of about 7%, according to the metering ratio Take part of the immediate-release pellets into a fluidized bed, coat the above-mentioned solution on the surface of the immediate-release pellets, and prepare sustained-release pellets after drying.
  • Carry out capsule filling use a capsule filling machine to fill the immediate-release pellets and sustained-release pellets into capsules according to their respective weights to prepare capsules.
  • composition preparation methods listed above are only illustrative and representative. Therefore, the preparation method of the composition of the present invention is not limited to only the methods listed above. Those skilled in the art can make various changes, adjustments or equivalent substitutions to the preparation method according to conventional techniques, all without exceeding the protection scope of the present invention.
  • the present invention also relates to a method for preventing and treating diseases, which comprises administering an effective amount of the solid preparation or pharmaceutical composition of the present invention to a subject in need.
  • the solid preparation or pharmaceutical composition of the present invention can be used to prevent and treat diseases.
  • the present invention also relates to the use of the solid preparation or pharmaceutical composition in the preparation of medicines for preventing and treating diseases.
  • the disease includes lupus, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, type I diabetes and diabetic complications, cancer, asthma, atopic dermatitis, autoimmune thyroid disease , Moderate to severe active ulcerative colitis, Crohn's disease, ankylosing spondylitis, juvenile idiopathic arthritis, immune system dysfunction alopecia, vitiligo, systemic lupus erythematosus, Alzheimer's disease and Leukemia, etc.
  • the solid preparation of the present invention includes an immediate-release part and a sustained-release part.
  • the immediate-release effect On the basis of the immediate-release effect, it also has a sustained-release effect, so that the effect can be quickly onset and the effect can be maintained for a long time.
  • the core of the tablet is a sustained-release part
  • the outer coating also contains a certain amount of active ingredient, which serves as the immediate-release part of a dual-release preparation, accelerating the early stage
  • the release speed of the active ingredient eliminates the delayed release phenomenon in the prior art, and at the same time the sustained release part can achieve a stable blood concentration for a long time.
  • the rapid release part of the preparation of the present invention has a relatively fast release rate, and within 15 minutes, the dissolution rate of the active ingredient (such as tofacitinib or its pharmaceutically acceptable salt) can reach about 0.03 mg/min- 0.37mg/min.
  • the dissolution rate of the active ingredient can be changed by adjusting the content of the active ingredient (such as tofacitib or its pharmaceutically acceptable salt) in the immediate-release part and the sustained-release part to adapt to different medication environments. Need to meet the needs of patients in different situations.
  • the dissolution rate ratio of the active ingredient (such as tofacitinib or its pharmaceutically acceptable salt) in the immediate-release part and the sustained-release part within 15 minutes is about 0.5:1- 100:1, by adjusting the content of the active ingredients in the immediate-release part and the sustained-release part, the dissolution rate ratio can be changed to achieve the immediate or sustained release of the active ingredients to meet the needs of different medication environments and to meet the needs of patients in different situations Demand.
  • the active ingredient such as tofacitinib or its pharmaceutically acceptable salt
  • the preparation of the present invention can provide a longer duration of a single administration blood concentration above 17 ng/ml, for example, about 9-11 hours. Compared with commercially available preparations, the duration is longer, so that the concentration of the drug in the body fluctuates smoothly, so it can be administered once a day to provide rapid and long-lasting continuous disease management.
  • Tofacitib citrate was purchased from Hiyofreda; Glyceryl behenate was purchased from France Jiafaxai Company, Compritol ATO888; Hydroxyethyl cellulose was purchased from Ashland Company , Natrosol HX; Hydroxypropyl methylcellulose was purchased from Shin-Etsu Company, Metolose SR 90SH; Cellulose acetate was purchased from Eastman Company, CA-398-10.
  • the dissolution of the preparation was determined by the USP II method (paddle method) of the United States Pharmacopoeia.
  • the specific measurement conditions are: use pH 6.8 phosphate buffer as the dissolution medium, the volume of the dissolution medium is 900 ml, and the dissolution measurement The rotation speed is 50 rpm, and the measurement temperature is 37°C.
  • the parameters of the dissolution measurement method used are as follows.
  • Dissolution method USP II method (paddle method) Dissolution medium pH 6.8 phosphate buffer Medium volume 900ml Rotating speed 50rpm temperature 37°C
  • Dissolution sample analysis The solution obtained in the dissolution test was filtered with a 0.45 ⁇ m filter membrane and the filtrate was collected and measured by high performance liquid chromatography. The measurement wavelength was 210nm. The detection instrument was Agilent 1200.
  • Immediate-release layer granules according to the metering ratio, mix the tofacitib, filler, disintegrant and half of the lubricant with a hopper mixer (Nantong Better HBD-200); the above mixture is granulated by dry granulation After being prepared into granules by a machine (Alexander WP120, Germany), the remaining half of the lubricant is mixed with a hopper mixer (Nantong Beit HBD-200) to form the total mixed granules of the immediate release layer.
  • a hopper mixer Nantong Better HBD-200
  • Sustained-release layer granules according to the metering ratio, mix the tofacitib, filler, sustained-release matrix material and half of the lubricant with a hopper mixer (Nantong Better HBD-200); the above mixture is made by dry granulation
  • the granulator (Alexander WP120, Germany) is prepared into granules and mixed with the remaining half of the lubricant using a hopper mixer (Nantong Beit HBD-200) to form the total mixed granules of the sustained release layer.
  • the total mixed particles of the immediate-release layer and the total mixed particles of the sustained-release layer are compressed into a double-layer tablet using a double-layer tableting machine (Feite P3030) to obtain the final double-layer tablet.
  • a double-layer tableting machine Feite P3030
  • the bilayer tablets 1-1 to 1-10 of the present invention are prepared.
  • the double-layer tablets prepared with different prescriptions have a wide range of drug release.
  • the 15-minute release amount is the content of the active ingredient tofacitib in the immediate-release layer.
  • the results show that the rapid-release layer of different prescriptions can release the drug completely within 15 minutes.
  • the solid preparation can also continuously release the active ingredient tofacitib at a steady rate, providing an effective and stable blood concentration for a longer time.
  • the release of formulations 1-1 to 1-8 was completed within 7 hours, and the release effect was more excellent.
  • Sustained-release granules according to the metering ratio, mix the tofacitib, filler, sustained-release matrix material and half of the lubricant with a hopper mixer (Nantong Beit HBD-200); use a dry granulator ( WP120 (Alexander, Germany) is prepared into granules and mixed with the remaining half of the lubricant using a hopper mixer (Nantong Beit HBD-200) to form a total mixed granule.
  • a hopper mixer Non Beit HBD-200
  • Tableting Use a tableting machine (Feite P2020) to compress the above-mentioned total mixed granules into sustained-release tablets.
  • Coating mix the tofacitin cloth and the membrane material evenly, add it to the isopropanol solution containing 10% of purified water by weight, stir thoroughly to prepare a suspension with a solid content of about 7%, and combine the above suspension
  • Use a coating pan O'Hara Lab coat M to coat and spray onto the sustained-release tablets, and prepare coated tablets after drying.
  • the material temperature is 25-35°C, and the inlet air volume is maintained at 50-100cm 3 /hour.
  • the coated tablets of tofacitib are dried in a coating machine at 30°C for 2 hours until the drying loss is less than 2.0% to obtain the finished coated tablets.
  • the coated tablets 1-1 to 1-10 of the present invention are prepared.
  • the coated tablets prepared with different prescriptions have a wide range of drug release.
  • the 15-minute release amount is the content of the active ingredient tofacitib in the immediate-release layer.
  • the results show that the active ingredient tofacitib can be released completely within 15 minutes in coatings of different prescriptions.
  • the solid preparation can also continuously release the active ingredient tofacitib at a steady rate, providing an effective and stable blood concentration for a longer time.
  • the release of formulations 1-1 to 1-8 was completed within 7 hours, and the release effect was more excellent.
  • Tablet core particles According to the metering ratio, use the tofacitib, filler, sustained-release matrix material and half of the lubricant to mix uniformly using a hopper mixer (Nantong Beit HBD-200); use a dry granulator for the above mixture ( WP120 (Alexander, Germany) is prepared into granules and mixed with the remaining half of the lubricant using a hopper mixer (Nantong Beit HBD-200) to form a total mixed granule.
  • Tableting Use a tableting machine (Fiite P2020) to compress the above-mentioned total mixed particles into tablet cores.
  • Coating mix the tofacitin cloth and the membrane material evenly, add it to the isopropanol solution containing 10% of purified water by weight, stir thoroughly to prepare a suspension with a solid content of about 7%, and combine the above suspension
  • Use a coating pan O'Hara Lab coat M to coat and spray onto the tablet cores, and prepare semipermeable film-coated tablets after drying.
  • the material temperature is 25-35°C, and the inlet air volume is maintained at 50-100cm 3 /hour.
  • the semipermeable membrane-coated tablets of tofacitib were dried in a coating machine at 30°C for 2 hours until the drying loss was less than 2.0%.
  • the osmotic pump tablets 1-1 to 1-10 of the present invention are prepared.
  • the osmotic pump tablets prepared with different prescriptions have a wide range of drug release.
  • the 15 minutes (0.25 hours) release amount is the content of the active ingredient tofacitib in the semipermeable membrane coating.
  • the results show that the active ingredient tofacitib can be released completely within 15 minutes in coatings of different prescriptions.
  • the solid preparation can also continuously release the active ingredient tofacitib at a steady rate, providing an effective and stable blood concentration for a longer time.
  • the release of formulations 1-1 to 1-8 was completed within 7 hours, and the release effect was more excellent.
  • the above three different dosage forms of tofacitib preparations all have a special release pattern of rapid release in the first 15 minutes and sustained release for more than 5 hours.
  • the release mode can not only maintain the rapid onset of effect after the previous medication, but also maintain the clinical effect for a longer period of time, and the blood drug concentration is more stable.
  • Test formulation T Tofatibu coated tablets prepared according to the recipe and process of coated tablets 1-3 in Example 2, with a specification of 11 mg, once a day.
  • Reference formulation R a commercially available tofacitinib sustained-release tablet (Xeljanz XR), with a specification of 11 mg, once a day.
  • Blood sample collection method 0h before administration (within 1h before administration) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12, 24, after administration. 36h (17 blood collection points) 4mL of cubital venous blood was collected from subjects. The blood sample was placed in a heparin sodium anticoagulated blood collection tube. After collection, it was centrifuged at 3500rpm at 4°C for 5min. The plasma was divided into two parts, and 1mL of plasma was taken. Add the formal tube, and add the remaining plasma to the backup tube. The samples were placed in a refrigerator at -20°C for 2 hours after collection for later use.
  • the LC-MS/MS method was used to determine the concentration of tofacitib in each plasma sample. Calculated by the pharmacokinetic statistical software DAS 2.0, and performed biostatistical analysis. See Table 9 and Figure 1 for the test results.
  • the time for the reference sustained-release tablet to reach a blood concentration of 17ng/ml is about 90 minutes.
  • the time for the corresponding blood concentration of the coated tablet of the present invention to reach 17 mg/ml is about 30 minutes.
  • Ta refers to blood concentration can be maintained at 17ng / mL (IC 50) over time.
  • the maximum blood concentration C max of the tofacitinib-coated tablet of the present invention is significantly lower than that of the marketed sustained-release tablet, and the fluctuation is more stable than that of the marketed sustained-release tablet.
  • the area under the blood drug concentration curve is Significant increase.
  • Its Ta value is about 33% longer than that of tofacitinib commercially available sustained-release tablets.
  • the coated tablets 1-2, 1-3, and 1-6 prepared in Example 2 above were used.
  • Test formulation T1 Tofatibu coated tablets prepared according to the recipe and process of coated tablets 1-2 in Example 2, with a specification of 11 mg, once a day.
  • Test preparation T2 Tofacitinib coated tablets prepared according to the recipe and process of coated tablets 1-3 in Example 2, with a specification of 11 mg, once a day.
  • Test formulation T3 Tofacitinib coated tablets prepared according to the recipe and process of coated tablets 1-6 in Example 2, with a specification of 11 mg, once a day.
  • Blood sample collection method 0h before administration (within 1h before administration) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12, 24, after administration. 36h (17 blood collection points) 4mL of cubital venous blood was collected from subjects. The blood sample was placed in a heparin sodium anticoagulated blood collection tube. After collection, it was centrifuged at 3500rpm at 4°C for 5min. The plasma was divided into two parts, and 1mL of plasma was taken. Add the formal tube, and add the remaining plasma to the backup tube. The samples were placed in a refrigerator at -20°C for 2 hours after collection for later use.
  • the LC-MS/MS method was used to determine the concentration of tofacitib in each plasma sample. Calculated by the pharmacokinetic statistical software DAS 2.0, and performed biostatistical analysis. See Table 11 and Figure 2 for the test results.
  • Ta refers to the blood concentration can be maintained at 17ng / mL (IC 50) over time.
  • the time for the test preparations T1, T2, and T3 to reach 17 ng/ml is about 50 minutes, 25 minutes, and 12 minutes, respectively.
  • the blood concentration of the preparation of the present invention fluctuates smoothly, and the area under the curve of the blood concentration is higher.
  • the Ta values of the test formulations T1, T2 and T3 were 8.6, 9.7 and 5.8 hours, respectively. It can be seen that the preparation of the present invention can achieve a high Ta value, thereby achieving a better therapeutic effect. In particular, the test preparations T1 and T2 can achieve significantly higher Ta values and higher blood drug concentration area under the curve, showing special advantages.

Abstract

一种固体制剂及其制备方法和用途。该固体制剂包括速释部分和缓释部分，并且包含活性成分，其中缓释部分中的活性成分与速释部分中的活性成分的重量比为1：1或更高，特别的，该固体制剂为托法替布制剂。

Description

一种固体制剂及其制备方法和用途
本申请要求2019年12月25日提交的题为“一种固体制剂及其制备方法和用途”的201911355327.X号中国申请的优先权，该中国申请的内容整体援引加入本文。
技术领域
本发明涉及药物制剂领域，并且具体涉及一种固体制剂及其制备方法和用途。
背景技术
在药物制剂领域，针对药物活性成分(API)开发合适的剂型一直是药物领域的关注所在。其中，对于药物的剂型而言，药物成分的溶出可以反映药物在体内释放的速度和程度，在一定程度上反映药物对疾病的治疗效果。
以药物托法替布为例，CN103845302A公开了一种优良性能的托法替布的涂膜片剂。该涂膜片剂包含涂膜基础试剂，托法替布，及药用添加剂。
又例如，CN104622827A公开了一种托法替布片剂及其制备方法。所述片剂选用了流动性、压缩成形性好的直压乳糖和微晶纤维素作为稀释剂和干粘合剂，并采用工艺简单的粉末直接压片法制备。
CN105878202A公开了一种枸橼酸托法替布片，它由枸橼酸托法替布与药学上可接受的辅料组成，所述辅料包括填充剂、崩解剂、助流剂和包衣剂，通过粉末直接压片法制备。
CN105101952A公开了一种托法替布及其药学上可接受的盐的口服持续释放制剂，这是一种每日一次的药物剂型，其包含托法替布或其药学上可接受的盐以及药学上可接受的载体，其中所述剂型为持续释放剂型，并且实施例1、实施例2等中采用了干法制粒压片技术来制备缓释片剂的片芯。
发明内容
在一方面，本发明涉及一种固体制剂，所述固体制剂包括速释部分和缓释部分，并且包括活性成分，其中所述缓释部分中的活性成分与所述速释部分中的活性成分的重量比为约1:1或更高。
在一实施方案中，在本发明的固体制剂中，所述缓释部分中的活性成分与所述速释部分中的活性成分的重量比为约1:1-20:1，优选约1:1-9:1、更优选约1:1-4:1，特别优选约1:1-7:3，例如约7:3-4:1。
在优选的实施方案中，活性成分为托法替布或其药学上可接受的盐，特别是枸橼酸托法替布。
在一优选的实施方案中，速释部分和缓释部分还各自独立地包含一种或多种选自以下的药用辅料：缓释骨架材料、成膜材料、粘合剂、填充剂、崩解剂、润滑剂。
在一具体的实施方案中，所述固体制剂为片剂、颗粒剂、微丸或胶囊剂的形式；所 述片剂优选为双层片剂、包衣片或渗透泵片。
在另一方面，本发明涉及一种药物组合物，其包含本发明的固体制剂。所述药物组合物可以包含一种或多种药学可接受的辅料。
在又一方面，本发明还涉及所述固体制剂或药物组合物在制备用于预防或治疗疾病中的用途。所述疾病包括但不限于狼疮、多发性硬化症、类风湿关节炎、银屑病关节炎、I型糖尿病及糖尿病并发症、癌症、哮喘、特应性皮炎、自身免疫性甲状腺疾病、中度至重度活动性溃疡性结肠炎、克罗恩氏病、强直性脊柱炎、幼年特发性关节炎、免疫系统失调秃顶症、白癜风、系统性红斑狼疮、阿尔兹海默氏病及白血病等。
附图说明
图1表示单次给药试验后的托法替布血药浓度-时间曲线，其中●代表市售托法替布缓释片，■代表本发明的托法替布包衣片。
图2表示单次给药试验后的托法替布血药浓度-时间曲线，其中●代表本发明的托法替布包衣片1-2，■代表本发明的托法替布包衣片1-3，▲代表本发明的托法替布包衣片1-6。
具体实施方式
以下将对本发明进一步详细说明。这样的描述为说明目的，而非限制本发明。
一般术语和定义
除非另有说明，本文使用的所述技术和科学术语具有与本发明所属领域技术人员通常所理解的相同的含义。若存在矛盾，则以本申请提供的定义为准。当以范围、优选范围、或者优选的数值上限以及优选的数值下限的形式表述某个量、浓度或其他值或参数的时候，应当理解相当于具体揭示了通过将任意一对范围上限或优选数值与任意范围下限或优选数值结合起来的任何范围，而不考虑该范围是否具体揭示。除非另有说明，本文所列出的数值范围旨在包括范围的端点和该范围内的所有整数和分数(小数)。
术语“约”、“大约”当与数值变量并用时，通常指该变量的数值和该变量的所有数值在实验误差内(例如对于平均值95％的置信区间内)或在指定数值的±10％内，或更宽范围内。
术语“计量比”是将各种物质按一定的重量进行配比。例如在本发明中，将活性成分与缓释材料、增塑剂按照指定的重量比进行配比。
术语“任选”或“任选存在”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
表述“包含”或与其同义的类似表述“包括”、“含有”和“具有”等是开放性的，不排除额外的未列举的元素、步骤或成分。表述“由…组成”排除未指明的任何元素、步骤或成分。表述“基本上由…组成”指范围限制在指定的元素、步骤或成分，加上任选存在的不会实质上影响所要求保护的主题的基本和新的特征的元素、步骤或成分。应当理解，表述“包含”涵盖表述“基本上由…组成”和“由…组成”。
表述“至少一种(个)”或“一种(个)或多种(个)”表示1、2、3、4、5、6、7、8、9种(个)或更多种(个)。
术语“药学上可接受的”是指在正常的医学判断范围内与患者的组织接触而不会有不适当毒性、刺激性、过敏反应等，具有合理的利弊比且能有效用于目的用途。
术语“药物活性成分”、“活性成分”、“治疗剂”、“活性物质”或“活性剂”是指一种化学实体，其可以有效地治疗或预防目标疾病或病症。在一实施方案中，制剂中所用的活性成分为托法替布(Tofacitinib，又可称为“托法替尼”)或其药学可接受的盐，特别是枸橼酸托法替布。本发明制剂的不同部分可以使用不同形式的活性成分。在本发明的一实施方案中，使用同一活性成分。在本文中，给定化合物与该化合物相应的其他形式(例如盐、多晶型物、溶剂化物、共晶、无定型和无水形式等)，属于同一活性成分，但是可以认为是不同的形式或类型。
本领域技术人员应当知晓，当不同形式或类型的活性成分存在于制剂中时，若计算其比例，需折算成其各自的游离形式。以托法替布为例，当速释部分中包含托法替布，而缓释部分中包含枸橼酸托法替布时，需将枸橼酸托法替布折算成托法替布，或者将托法替布折算成枸橼酸托法替布。又例如，当速释部分或缓释部分中包含托法替布及枸橼酸托法替布，需将枸橼酸托法替布折算成托法替布，或者将托法替布折算成枸橼酸托法替布。还例如，当固体制剂中同时存在活性成分的不同类型的盐形式时，需将各自的盐形式折算成对应的游离形式。除了药学上可接受的盐之外，本文所用的诸如托法替布的活性成分也涵盖该活性成分的其他形式，例如多晶型物、溶剂化物(包括例如水合物和混合的溶剂化物以及盐的水合物)、共晶、无定型和无水形式及其混合物。在优选的实施方案中，上述形式为药学上可接受的。
术语“溶出速度”是指药物从固体制剂在规定溶剂中溶出的速度。
术语“溶出度”是指药物从固体制剂在规定溶剂中溶出的速度和程度。
术语“血浆药物浓度达峰时间(T max)”是指施用药物后达到血浆药物浓度峰值(C max)的平均时间。术语“血浆药物浓度峰值(C max)”是指施用药物后血浆中达到的药物平均峰浓度。术语“血浆药物浓度达峰时间(T max)”指给药后血浆中药物浓度达到最高浓度(峰浓度)所需的时间。术语“AUC 0-t”是指施用药物后时间由0至t的血浆药物浓度对时间曲线下的平均积分面积。
在本文中，术语“Ta值”是指血药浓度能够维持在17ng/mL(IC 50)以上的时间。
在本文中，术语“规格”是指药品规格，即每一个制剂单位中含有药物活性成分的重量，其中不论活性成分以何种形式存在，其重量为折算后的游离形式的重量。以托法替布为例，例如在规格为11mg的托法替布制剂中，当活性成分为托法替布时，托法替布的重量为11mg。又例如在规格为11mg的托法替布制剂中，当活性成分为枸橼酸托法替布时，折算后的游离托法替布的重量为11mg。又例如，在规格为11mg的托法替布制剂中，当活性成分为盐酸托法替布时，折算后的游离托法替布的重量为11mg。
本发明的固体制剂
在一方面，本发明涉及一种固体制剂，其包括速释部分和缓释部分。
本发明的制剂还包含活性成分。在本发明的固体制剂中，活性成分可以，各自独立地，以相同或不同的形式(例如托法替布或其药学可接受的盐等)，分别存在于本发明制剂的速释部分和/或缓释部分中。例如，活性成分可作为药学上可接受的盐分别存在于速释部分和缓释部分中。又例如，活性成分可作为药学上可接受的盐存在于速释部分中，而作为游离碱存在于缓释部分中。还例如，作为活性成分的枸橼酸盐可分别存在于速释部分和缓释部分中。又例如，作为活性成分的枸橼酸盐可存在于速释部分中，作为活性成分的盐酸盐可存在于缓释部分中。
作为本发明制剂中所用的活性成分的一种示例，可以使用托法替布或其药学上可接受的盐，特别是枸橼酸托法替布。因此，在本发明制剂的一实施方案中，托法替布或其药学上可接受的盐(特别是枸橼酸托法替布)可以充当活性成分(API)。
托法替布(化学名为(3R,4R)-4-甲基-3-(甲基-7H-吡咯并[2,3-d]嘧啶-4-基氨基)-基3氧代-1-哌啶丙腈)是一种JAK激酶抑制剂，通过抑制剂JAK通路降低细胞因子信号传导、细胞因子诱导的基因表达及细胞的激活，从而降低多种慢性炎症反应(结构参见下文)。
作为所用活性成分的药学上可接受的盐，可以包括但不限于与无机酸形成的盐、与有机酸形成的盐等。与无机酸形成的盐的非限制性实例包括但不限于与盐酸、氢溴酸、硝酸、硫酸、磷酸等形成的盐。与有机酸形成的盐的非限制性实例包括但不限于与甲酸、乙酸、三氟乙酸、富马酸、草酸、苹果酸、马来酸、酒石酸、枸橼酸(柠檬酸)、琥珀酸、甲磺酸、苯磺酸、对甲基苯磺酸等形成的盐。在特别优选的实施方案中，所用的盐为枸橼酸盐。在该盐的一实施方案中，活性成分可以为枸橼酸托法替布。其结构示例如下：
Figure PCTCN2020138988-appb-000001
在本发明的制剂中，活性成分可以位于速释部分和缓释部分中。或者活性成分也可以仅存在于速释部分和缓释部分中。在后一情况下，计算制剂中的活性成分的总量可以基于速释部分和缓释部分中活性成分的总和(即，缓释部分和速释部分中活性成分的总和可以为100％)。
在本发明的制剂中，速释部分和缓释部分中活性成分的计算可基于活性成分的重量。或者，如上文所述，计算活性成分时应折算成一致的形式，因此这样的比例也可以对应于该活性成分的摩尔比。
在一实施方案中，速释部分和缓释部分中所用的活性成分的形式相同，例如，均为枸橼酸托法替布。
在本发明制剂的一实施方案中，缓释部分中的活性成分与速释部分中的活性成分的 重量比不小于约1:1。换言之，缓释部分中所含的活性成分的量大于或等于速释部分中所含的活性的量。
在一实施方案中，缓释部分中的活性成分与速释部分中的活性成分的重量比不大于约20:1。
在优选的实施方案中，缓释部分中的活性成分与速释部分中的活性成分的重量比可以为约1:1-19:1，优选约7:3-9:1、约1:1-4:1、约7:3-4:1。例如，该重量比可以为约1:1、约1.5:1、约2:1、约7:3、约3:1、约4:1、约5:1、约6:1、约7:1、约8:1、约9:1、约10:1、约11:1、约12:1、约13:1、约14:1、约15:1、约16:1、约17:1、约18:1、约19:1、约20:1，特别是约1.5:1、约4:1、约7:3、约9:1，以及由这些比例(值)中的任意两个构成的范围。
在又一实施方案中，缓释部分中的活性成分与速释部分中的活性成分(如托法替布或其药学上可接受的盐)的重量比可以为约1:1-19:1，例如约19:1、约47:3、约93:7、约23:2、约91:9、约9:1、约89:11、约22:3、约87:13、约43:7、约17:3、约21:4、约83:17、约41:9、约81:19、约4:1、约79:21、约39:11、约77:23、约19:6、约3:1、约37:13、约73:27、约18:7、约71:29、约7:3、约69:31、约17:8、约67:33、约33:17、约13:7、约16:9、约63:37、约31:19、约61:39、约3:2、约59:41、约29:21、约57:43、约14:11、约11:9、约27:23、约53:47、约13:12、约51:49或约1:1，以及由这些比例(值)中的任意两个构成的范围。
在本发明制剂的一具体实施方案中，基于缓释部分中的活性成分与速释部分中的活性成分的总重量，速释部分中的活性成分(如托法替布或其药学上可接受的盐)的比例可以为约5-50％，例如约5％、约6％、约7％、约8％、约9％、约10％、约11％、约12％、约13％、约14％、约15％、约16％、约17％、约18％、约19％、约20％、约21％、约22％、约23％、约24％、约25％、约26％、约27％、约28％、约29％、约30％、约31％、约32％、约33％、约34％、约35％、约36％、约37％、约38％、约39％、约40％、约41％、约42％、约43％、约44％、约45％、约46％、约47％、约48％、约49％或约50％，以及由这些比例(值)中的任意两个构成的范围。
在本发明制剂的另一实施方案中，基于缓释部分中的活性成分与速释部分中的活性成分的总重量，缓释部分中活性成分(如托法替布或其药学上可接受的盐)的比例为约50-95％，例如约50％、约51％、约52％、约53％、约54％、约55％、约56％、约57％、约58％、约59％、约60％、约61％、约62％、约63％、约64％、约65％、约66％、约67％、约68％、约69％、约70％、约71％、约72％、约73％、约74％、约75％、约76％、约77％、约78％、约79％、约80％、约81％、约82％、约83％、约84％、约85％、约86％、约87％、约88％、约89％、约90％、约91％、约92％、约93％、约94％或约95％，以及由这些比例(值)中的任意两个构成的范围。
在一实施方案中，缓释部分中的活性成分与速释部分中的活性成分(如托法替布或其药学上可接受的盐)重量比为约7:3-9:1，例如约9:1、约89:11、约22:3、约87:13、约43:7、约17:3、约21:4、约83:17、约41:9、约81:19、约4:1、约79:21、约39:11、约 77:23、约19:6、约3:1、约37:13、约73:27、约18:7、约71:29或约7:3，以及由这些比例(值)中的任意两个构成的范围。
在一具体实施方案中，基于缓释部分中的活性成分与速释部分中的活性成分的总重量，速释部分中的活性成分(如托法替布或其药学上可接受的盐)的比例为约10-30％，例如约10％、约11％、约12％、约13％、约14％、约15％、约16％、约17％、约18％、约19％、约20％、约21％、约22％、约23％、约24％、约25％、约26％、约27％、约28％、约29％或约30％，以及由这些比例(值)中的任意两个构成的范围。
在另一实施方案中，基于缓释部分中的活性成分与速释部分中的活性成分的总重量，缓释部分中活性成分(如托法替布或其药学上可接受的盐)的比例为约70-90％，例如约70％、约71％、约72％、约73％、约74％、约75％、约76％、约77％、约78％、约79％、约80％、约81％、约82％、约83％、约84％、约85％、约86％、约87％、约88％、约89％或约90％，以及由这些比例(值)中的任意两个构成的范围。
在一实施方案中，缓释部分中的活性成分与速释部分中的活性成分(如托法替布或其药学上可接受的盐)重量比为约39:11-41:9，例如约41:9、约81:19、约4:1、约79:21、约39:11，以及由这些比例(值)中的任意两个构成的范围。
在一具体实施方案中，基于缓释部分中的活性成分与速释部分中的活性成分的总重量，速释部分中的活性成分(如托法替布或其药学上可接受的盐)的比例为约18-22％，例如约18％、约19％、约20％、约21％或约22％。
在另一实施方案中，基于缓释部分中的活性成分与速释部分中的活性成分的总重量，缓释部分中活性成分(如托法替布或其药学上可接受的盐)的比例为约78-82％，例如约78％、约79％、约80％、约81％或约82％。
在一具体实施方案中，缓释部分中的活性成分与速释部分中的活性成分(如托法替布或其药学上可接受的盐)的重量比为约39:11-41:9，如约4:1。在一具体实施方案中，基于缓释部分中的活性成分与速释部分中的活性成分的总重量，缓释部分中活性成分(如托法替布或其药学上可接受的盐)的比例为约78-82％，如约80％。
制剂的形式和组成
本发明的制剂可以为颗粒剂、微丸、片剂或者胶囊等制剂形式，或上述制剂形式的组合。
在本发明制剂的实施方案中，缓释部分和速释部分可以各自独立地为颗粒、微丸、层、片(如渗透泵片)、包衣(涂层)的形式。作为示例，速释部分还可以为包含于诸如缓释包衣的缓释部分中的颗粒或微粒的形式。
本发明的制剂可以包含一个或多个缓释部分以及一个或多个速释部分。这些缓释部分和速释部分以及其中的活性成分和其他成分可以各自独立地加以选择。
本领域技术人员应当理解，本文中所用的缓释部分和速释部分应当广义地理解，而并非仅指制剂中的一个具体构件。例如，诸如包衣片或渗透泵片的制剂可以包含缓释片芯及其上的包衣。当该包衣属于缓释包衣时，同样也可以视为缓释部分。
在一个实施方案中，制剂中的缓释部分为缓释颗粒。在另一实施方案中，制剂中的速释部分为速释颗粒。
在一优选实施方案中，速释颗粒和缓释颗粒可以装填于胶囊内。在另一优选实施方案中，速释颗粒和缓释颗粒可以装填于袋子内。
在一实施方案中，速释颗粒和缓释颗粒可以被混合压成片剂。
在一个实施方案中，制剂中的缓释部分为包衣缓释颗粒或骨架缓释颗粒。在另一实施方案中，制剂中的速释部分位于包衣膜内或包衣膜外或者骨架缓释颗粒外。
在一实施方案中，制剂中的缓释部分为缓释微丸。在另一实施方案中，制剂中的速释部分为速释微丸。
在一优选实施方案中，速释微丸和缓释微丸可以装填于胶囊内。
在一优选实施方案中，速释微丸和缓释微丸可以装填于袋子内。在一实施方案中，速释微丸和缓释微丸可以被混合压成片剂。
在一具体实施方案中，本发明的制剂可以包含缓释微丸，其中所述缓释微丸为包衣缓释微丸或骨架缓释微丸，而速释部分位于包衣膜内或膜外或者骨架缓释微丸外。
在一个实施方案中，本发明的制剂可以为双层片，其中一层为缓释层(对应缓释部分)，另外一层为速释层(对应速释部分)。在一个优选实施方案中，缓释层为骨架缓释片。在另一个优选实施方案中，缓释层为膜控缓释片。在一个特别优选实施方案中，缓释层为渗透泵片。
在一个实施方案中，本发明的制剂可以为包衣片，其中缓释部分为包衣片芯或骨架片芯，而速释部分位于包衣膜内或包衣膜外或骨架片芯外。在一个优选实施方案中，包衣片为渗透泵片。
在一个实施方案中，本发明的制剂可以为胶囊，其内容物为缓释颗粒或微丸，而速释部分包裹在胶囊外或位于胶囊壳内。
在本发明制剂的一优选实施方案中，制剂为包衣片，其中缓释部分为包衣片芯，速释部分为包衣膜，其中包衣片芯和包衣膜各自独立地包含本发明的活性成分。优选地，包衣片为渗透泵片。
在本发明制剂的一优选实施方案中，活性成分可以为托法替布或其药学上可接受的盐，特别是枸橼酸托法替布。
在本发明制剂的一实施方案中，缓释部分包含缓释骨架材料，所述缓释骨架材料可以为选自以下的一种或多种：羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素、聚氧乙烯、山嵛酸甘油酯、聚甲基丙烯酸甲酯、丙烯酸树脂、聚维酮、黄原胶、海藻酸钠、海藻酸钙、卡波姆、甲壳素、聚乙烯、聚硅氧烷。
以下示例出一些可用的缓释骨架材料，但不限于此：
羟丙基甲基纤维素，其可选自例如Shin-Etsu公司的市售产品Metolose SR 90SH；
羟丙基纤维素，其可选自例如Ashland公司的市售产品Klucel TM GF、Klucel TM JF、Klucel TM MF、Klucel TM HF；
羟乙基纤维素，其可选自例如Ashland公司的市售产品Natrosol G、Natrosol M、 Natrosol HX、Natrosol HHX；
山嵛酸甘油酯，其可选自例如法国嘉法赛公司的市售产品
Figure PCTCN2020138988-appb-000002
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在一个实施方案中，缓释部分包含缓释骨架材料。优选地，缓释骨架材料占缓释部分重量的约40％-80％，更优选约40％-50％或约50％-70％，例如约40％、约45％、约50％、约55％、约60％、约65％、约70％、约75％或约80％。
在一个实施方案中，缓释部分和/或速释部分包含成膜材料。所述成膜材料可以为选自以下的一种或多种：醋酸纤维素、乙基纤维素、羟丙甲纤维素、丙烯酸树脂类。
以下示例出一些可用的成膜材料，但不限于此：
乙基纤维素，其可选自例如市售产品Ashland公司的Aqualon TM ethyl cellulose、Dupont公司的ETHOCEL TM；
羟丙甲纤维素，其可选自例如Shin-Etsu公司的市售产品Metolose 60SH；
醋酸纤维素，其可选自例如Eastman公司的市售产品CA-320S、CA-394-60LF、CA-398-3、CA-398-6、CA-398-10和CA-398-30；
乙基纤维素，其可选自Dupont公司的ETHOCEL TM Standard 10Premium。
在一个实施方案中，缓释部分包含成膜材料(膜材)。活性成分可以位于该成膜材料中，也可以不位于该成膜材料中。活性成分可以是速释的活性成分，或者可以是缓释的活性成分。
当缓释部分包含成膜材料时，成膜材料可以占缓释部分重量的约30％-70％，更优选约40％-67％，例如约30％、约35％、约40％、约45％、约50％、约55％、约60％、约67％。
应当理解，当制剂包含形态上分离的缓释部分或速释部分时，材料的含量应当基于该材料所位于的部分进行计算。例如，包衣片或渗透泵片可以包含缓释片芯和/或缓释包衣。当片芯或包衣包含诸如成膜材料或骨架材料的材料时，其含量应当基于对应的片芯或包衣计算。
在一实施方案中，速释部分包含成膜材料(膜材)。优选地，成膜材料占速释部分重量的约40％-80％，更优选约50％-70％，例如，例如约40％、约45％、约50％、约55％、约60％、约65％、约70％、约75％或约80％。
在一实施方案中，本发明的制剂，在缓释部分、速释部分或者这两者之外的其他部分，还可以任选的包含以下一种或多种药学上可接受的辅料：粘合剂、填充剂、崩解剂和润滑剂等。这些药学上可接受的辅料的量可以由本领域技术人员根据需要加以选择。
以下示例出一些药学上可接受的辅料，但不限于此：
粘合剂可以为选自以下的一种或多种：聚乙二醇、淀粉、羟丙基纤维素、羟丙基甲基纤维素、预胶化淀粉、聚乙烯吡咯烷酮、阿拉伯胶粉末和明胶，优选淀粉、预胶化淀粉、改良淀粉、微晶纤维素、硅化微晶纤维素、低取代羟丙基纤维素葡萄糖、蔗糖、乳糖、山梨糖醇、甘露醇、赤藓醇、碳酸钙和磷酸氢钙，特别是优选乳糖、甘露醇、微晶纤维素及硅化微晶纤维素。
崩解剂可以为选自以下的一种或多种：微晶纤维素、羧甲基纤维素、交联聚维酮、 交联羧甲基纤维素钠、羧甲基纤维素钙、羧甲基淀粉钠、低取代羟丙基纤维素、羟甲基淀粉、海藻酸、海藻酸钠、瓜尔胶、玉米淀粉和硅酸镁铝，优选交联聚维酮和交联羧甲基纤维素钠。
润滑剂可以为选自以下的一种或多种：硬脂酸镁、硬脂酸、硬脂酸盐、硬脂富马酸钠、十二烷基硫酸钠、聚乙二醇、苯甲酸钠、蔗糖脂肪酸酯、微粉硅胶、滑石粉、单硬脂酸甘油酯、山嵛酸甘油酯、棕榈酰硬脂酸甘油酯、硬脂酸和氢化植物油，优选硬脂酸镁。
应当理解，上述所列举的药学上可接受的辅料只是阐述性和代表性的。因此，本发明的药物制剂并不限于仅包含本文以上所列举的药学上可接受的辅料。本领域技术人员可根据常规技术对上述辅料进行各种改变、调整或等同替换，均未超出本发明的保护范围。
在另一方面，本发明还涉及一种药物组合物，其包含本发明的固体制剂。所述药物组合物还可以包含一种或多种药学上可接受的赋形剂。
本发明制剂的释放
通过包含速释部分和缓释部分，本发明的制剂可以表现出速释和缓释的双重释放模式的组合，在能够使药物成分在迅速起效的同时提供较长时间的有效平稳血药浓度。
在一个实施方案中，在15分钟内，基于固体制剂中活性成分的总重量，活性成分的释放量为约5％-50％，例如约5％、约10％、约15％、约20％、约25％、约30％、约45％或约50％。在一个优选实施方案中，在15分钟内，基于固体制剂中活性成分的总重量，活性成分的释放量为约10％-30％，例如约10％、约15％、约20％、约25％或约30％，特别是约20％。
在本发明制剂的一个实施方案中，速释部分中的活性成分，在15分钟内的溶出速度为约0.03-0.37mg/min，例如约0.07mg/min、约0.13mg/min、约0.15mg/min、约0.17mg/min、约0.21mg/min、约0.24mg/min、约0.28mg/min或约0.33mg/min。在本发明制剂的优选实施方式中，速释部分中的活性成分在15分钟内的溶出速度为约0.07-0.22mg/min，例如约0.07mg/min、约0.13mg/min、约0.15mg/min、约0.17mg/min或约0.21mg/min，特别优选约0.15mg/min。
在本发明制剂的另一个实施方案中，15分钟内的速释部分中活性成分的平均溶出速度与全部释放时间范围内的缓释部分中活性成分的平均溶出速度的比率为约0.5:1-100:1，例如约1.3:1、约10.4:1、约30:1、约64.5:1或约96.5:1。在一个优选实施方案中，该比率为约1.4:1-11:1，例如约1.6:1、约3.3:1、约6.7:1、约8.5:1或10:1。在一个特别优选实施方案中，比率为约3:1-6:1，例如约3.3:1、约3.9:1、约4.5:1、约5.2:1或约5.8:1。
溶出速度和释放量可以通过活性成分的溶出度-时间曲线计算获得。溶出度可以通过本领域的常规方法，例如根据美国药典的USP II法(桨法)进行测定。
在一个实施方案中，在1小时内，本发明的制剂中活性成分的总释放量为约 20％-65％，例如约20％、约25％、约30％、约35％、约40％、约45％、约50％、约55％、约60％或约65％。在一个优选实施方案中，释放量为约30％-50％，例如约30％、约35％、约40％、约45％或约50％。
在一个实施方案中，在3小时内，本发明的制剂中活性成分的总释放量为约55％-95％，例如约55％、约60％、约65％、约70％、约75％、约80％、约85％、约90％或约95％。在一个优选实施方案中，释放量为约60％-80％，例如约60％、约65％、约70％、约75％或约80％。
在一个实施方案中，在5小时内，所述固体制剂中活性成分的总释放量不少于约80％，例如约80％、约85％、约90％、约95％或约99％或更高。在一个优选实施方案中，该释放量不少于约85％，例如约85％、约90％、约95％、约96％或约97％或更高。
在一实施方案中，在15分钟内，本发明的制剂中活性成分的总释放量为约5％-50％；在1小时内，该总释放量为约20％-65％；在3小时内，该总释放量为约55％-90％；并且在5小时内，总释放量不少于约80％。
上述释放量的计算是基于制剂中活性成分释放前的总量。
在一个实施方案中，本发明的制剂，单次给药后血药浓度达到17ng/ml所需的时间为约10-60分钟，例如约15分钟、约20分钟、约25分钟、约30分钟、约35分钟、约40分钟、约45分钟、约50分钟、约55分钟或约60分钟。在一个优选实施方案中，本发明的制剂，单次给药后，血药浓度达到17ng/ml所需的时间为约25-45分钟，例如约25分钟、约30分钟、约35分钟、约40分钟、约45分钟或约50分钟。在一个特别优选实施方案中，本发明的制剂，单次给药后，血药浓度达到17ng/ml所需的时间为约20-30分钟，例如约20分钟、约22分钟、约24分钟、约26分钟、约28分钟或约30分钟。
在一个实施方案中，本发明的固体制剂，通过单次给药所实现的血药浓度可以维持在17ng/ml以上，持续时间为约8-12小时(例如约8、约8.5、约9、约9.5、约10、约10.5、约11、约11.5或约12小时)，优选约9-11小时。
本文中的17ng/ml的血药浓度对应为体外JAK1/3的半数抑制浓度(即IC 50值)。
本文所述的“单次给药”是指一次给药一个剂量单位(例如一片或一粒)的固体制剂，其包含11mg或22mg活性成分(如枸橼酸托法替布)。给药频率可以例如为每天一次。给药对象可以是哺乳动物，例如人。
在本文的制剂一优选实施方案中，活性成分可以为托法替布或其药学上可接受的盐，特别是枸橼酸托法替布。
本发明的制备方法
本发明还涉及一种用于制备本发明的固体制剂的方法，其包括
1)将活性成分与一种或多种药学可接受的辅料组合以制备速释部分，
2)将活性成分与一种或多种药学上可接受的辅料组合以制备缓释部分，
3)将所述速释部分与所述缓释部分组合以制备所述固体制剂；
其中，步骤1)和步骤2)互相独立地以任何次序进行；
步骤1)和步骤2)中的活性成分和辅料各自独立地使用。
在一实施方案中，步骤1)和步骤2)中的活性成分各自独立地为托法替布或其药学上可接受的盐，特别是枸橼酸托法替布。
在另一实施方案中，步骤1)和步骤2)中活性成分的总量之和为100％。换言之，制剂中的活性成分仅存在于速释部分和/或缓释部分中。
本发明的制剂中的速释部分、缓释部分、活性成分、辅料可参见上文的相应描述。
在示例性的实施方案中，可以使用压制法，其包括：
1.制备速释层颗粒：按照计量比将活性成分、填充剂、崩解剂和一半量的润滑剂混合均匀；将上述混合物使用干法制粒制粒机制备成颗粒后与剩下的一半量的润滑剂混合成为速释层的总混颗粒。
2.制备缓释层颗粒：按照计量比将活性成分、填充剂、缓释骨架材料和一半量的润滑剂混合均匀；将上述混合物使用干法制粒制粒机制备成颗粒后与剩下的一半量的润滑剂混合成为缓释层的总混颗粒。
3.进行压片：将速释层总混颗粒和缓释层总混颗粒采用双层压片机压制成双层片，制得最终的双层片。
4.进行包衣：根据需要，可增加本领域常用的防护性包衣。该包衣可以不包含活性成分。
在一实施方案中，制备包衣片的方法为压制缓释片后，施加含活性成分的速释包衣。这样的制备包衣片的方法包括如下步骤：
1.制备缓释颗粒：按照计量比将活性成分、填充剂、缓释骨架材料和一半量的润滑剂混合均匀；将上述混合物使用干法制粒制粒机制备成颗粒后与剩下的一半量的润滑剂混合成为总混颗粒。
2.进行压片：采用压片机将上述总混颗粒压制成缓释片剂。
3.进行包衣：将活性成分、填充剂和膜材混合均匀后加入含有10％纯化水重量比的异丙醇溶液中，充分搅拌均匀，配制成固含量约7％的混悬液，将上述混悬液包衣喷镀到缓释片剂上，干燥后制备成包衣片。
在一实施方案中，制备含活性成分组合物的方法为通过挤出滚圆制备速释微丸，将部分微丸包衣成缓释微丸，将两者按比例灌装入胶囊。这样的制备胶囊剂的方法包括如下步骤：
1.制备速释微丸：按照计量比将活性成分、填充剂、粘合剂和润滑剂混合均匀后加入适量的纯化水制备成软材，使用挤出滚圆机将上述软材挤出滚圆成湿的含药速释微丸，然后使用流化床将上述微丸干燥制备成速释微丸。
2.制备缓释微丸：将缓释包衣膜材、填充剂加入含有10％纯化水重量比的异丙醇溶液中，充分搅拌溶解，配制成固含量约7％的溶液，按照计量比取部分速释微丸放入流化床，将上述溶液包覆到速释微丸表面，干燥后制备成缓释微丸。
3.进行胶囊灌装：采用胶囊灌装机，按照速释微丸和缓释微丸各自的重量灌装进入 胶囊中，制备成胶囊剂。
应当理解，上述所列举的组合物制备方法只是阐述性和代表性的。因此，本发明的组合物制备方法并不限于仅包含本文以上所列举的方法。本领域技术人员可根据常规技术对制备方法进行各种改变、调整或等同替换，均未超出本发明的保护范围。
制药方法和制药用途
本发明还涉及一种预防和治疗疾病的方法，所述方法包括向有需要的对象给予有效量的本发明的固体制剂或药物组合物。
本发明的固体制剂或药物组合物可用于预防和治疗疾病。
本发明还涉及所述固体制剂或药物组合物在制备用于预防和治疗疾病的药物中的用途。
在一实施方案中，所述疾病包括狼疮、多发性硬化症、类风湿关节炎、银屑病关节炎、I型糖尿病及糖尿病并发症、癌症、哮喘、特应性皮炎、自身免疫性甲状腺疾病、中度至重度活动性溃疡性结肠炎、克罗恩氏病、强直性脊柱炎、幼年特发性关节炎、免疫系统失调秃顶症、白癜风、系统性红斑狼疮、阿尔兹海默氏病及白血病等。
有益效果
与现有技术相比，本发明的固体制剂包括速释部分和缓释部分，在速释达到药效的基础上，同时还具备缓释的效果，从而快速起效且持久地保持药效。
特别地，在本发明的包衣片和渗透泵片中，片芯为缓释部分，并且外层包衣中同样含有一定量的活性成分，作为双重释放型制剂的速释部分，加快了前期活性成分的释放速度，消除了现有技术中的滞后释放现象，同时缓释部分能够实现较长时间的平稳血药浓度。
进一步地，本发明的制剂的速释部分的释放速度较快，在15分钟内，活性成分(如托法替布或其药学上可接受的盐)的溶出速度可达到约0.03mg/min-0.37mg/min，可以通过调节活性成分(如托法替布或其药学上可接受的盐)在速释部分和缓释部分中的含量，改变活性成分的溶出速度，以适应不同用药环境的需要，满足不同情况的患者的需求。
另一方面，在本发明的制剂中，速释部分与缓释部分中活性成分(如托法替布或其药学上可接受的盐)在15分钟内的溶出速度比为约0.5:1-100:1，可以通过调节活性成分在速释部分和缓释部分中的含量，改变溶出速度比，实现活性成分的速释或持续性释放，以适应不同用药环境的需要，满足不同情况的患者的需求。
此外，本发明的制剂可以提供更长的单次给药血药浓度在17ng/ml以上的持续时间，例如为约9-11小时。相比市售的制剂，持续时间更长，从而药物在体内的浓度波动平稳，因此可以实现每日一次给药提供快速且持久的持续疾病管理。
实施例
以下将通过具体实施例来进一步描述本发明的技术方案。应注意，所述实施例仅为 示例性，而非对本发明保护范围的限制。本发明还可有其他实施方案，或能够以多种方式实践或进行。除非另有说明，本文中所有百分比、份数、比值等均是按重量计。除非另有说明，本文所用的仪器设备、试剂、原料等都是可商购的。以下列出所用的一些材料的来源：枸橼酸托法替布购自海佑福瑞达；山嵛酸甘油酯购自法国嘉法赛公司，Compritol ATO888；羟乙基纤维素购自Ashland公司，Natrosol HX；羟丙基甲基纤维素购自Shin-Etsu公司，Metolose SR 90SH；醋酸纤维素购自Eastman公司，CA-398-10。
在以下实施例中，通过美国药典的USP II法(桨法)对制剂进行溶出度测定，具体测定条件为：使用pH 6.8的磷酸盐缓冲液作为溶出介质，溶出介质体积为900ml，溶出度测定转速为50rpm，测定温度为37℃。
所用溶出度测定方法参数如下。
溶出方法 USP II法(桨法)
溶出介质 pH 6.8的磷酸盐缓冲液
介质体积 900ml
转速 50rpm
温度 37℃
溶出样品分析：将溶出度测定试验中获得的溶液用0.45μm滤膜过滤后收集滤液，采用高效液相色谱法测定，测定波长为210nm，检测仪器为安捷伦1200。
实施例1 双层片制备
1.制备：
按照表1中的具体组成和用量(重量份，下同)进行制备。
速释层颗粒：按照计量比将托法替布、填充剂、崩解剂和一半量的润滑剂使用料斗混合机(南通贝特HBD-200)混合均匀；将上述混合物使用干法制粒制粒机(德国亚历山大WP120)制备成颗粒后与剩下的一半量的润滑剂使用料斗混合机(南通贝特HBD-200)混合成为速释层的总混颗粒。
缓释层颗粒：按照计量比将托法替布、填充剂、缓释骨架材料和一半量的润滑剂使用料斗混合机(南通贝特HBD-200)混合均匀；将上述混合物使用干法制粒制粒机(德国亚历山大WP120)制备成颗粒后与剩下的一半量的润滑剂使用料斗混合机(南通贝特HBD-200)混合成为缓释层的总混颗粒。
压片：将速释层总混颗粒和缓释层总混颗粒采用双层压片机(菲特P3030)压制成双层片，制得最终的双层片。
按照上述方法，制备得到本发明的双层片剂1-1至1-10。
表1 双层片的具体组成(重量份)
Figure PCTCN2020138988-appb-000003
2.制剂的溶出度测定
根据上文所述方法，测定各双层片在pH 6.8的磷酸盐缓冲液中的溶出度，结果参看下表2。
表2 双层片的溶出度
Figure PCTCN2020138988-appb-000004
由表2数据可知，采用不同处方制备的双层片有较宽的药物释放范围。15分钟的释放量为速释层中活性成分托法替布的含量。结果表明不同处方的速释层在15分钟内均可以将药物释放完全。在随后的过程中固体制剂还可以以平稳的速度持续地释放活性成分托法替布，提供较长时间的有效平稳血药浓度。特别地，制剂1-1至1-8的释放在7小时内完成，释放效果更为优异。
实施例2包衣片的制备
1.制备：
按照表3中的具体组成和用量(重量份，下同)，
缓释颗粒：按照计量比将托法替布、填充剂、缓释骨架材料和一半量的润滑剂使用料斗混合机(南通贝特HBD-200)混合均匀；将上述混合物使用干法制粒机(德国亚历山大WP120)制备成颗粒后与剩下的一半量的润滑剂使用料斗混合机(南通贝特HBD-200)混合成为总混颗粒。
压片：采用压片机(菲特P2020)将上述总混颗粒压制成缓释片剂。
包衣：将托法替布和膜材混合均匀后加入含有10％纯化水重量比的异丙醇溶液中，充分搅拌均匀，配制成固含量约7％的混悬液，将上述混悬液使用包衣锅(O’Hara Lab coat M)包衣喷镀到缓释片剂上，干燥后制备成包衣片。其喷雾工艺过程中，物料温度为25-35℃，进风风量维持在50-100cm 3/小时。喷雾完成后，托法替布的包衣片在30℃包衣机内干燥2小时，至干燥失重小于2.0％，制得成品包衣片。
按照上述方法，制备得到本发明的包衣片剂1-1至1-10。
表3 包衣片的具体组成(重量份)
Figure PCTCN2020138988-appb-000005
*在制备过程中挥发。
2.制剂的溶出度测定
根据上文所述方法，测定各包衣片在pH 6.8的磷酸盐缓冲液中的溶出度，结果参看下表4。
表4 包衣片的溶出度
Figure PCTCN2020138988-appb-000006
由表4数据可知，采用不同处方制备的包衣片有较宽的药物释放范围。15分钟的释放量为速释层中活性成分托法替布的含量。结果表明不同处方的包衣中活性成分托法替布在15分钟内均可以释放完全。在随后的过程中固体制剂还可以以平稳的速度持续地释放活性成分托法替布，提供较长时间的有效平稳血药浓度。特别地，制剂1-1至1-8的释放在7小时内完成，释放效果更为优异。
实施例3渗透泵片的制备
1.制备：
按照表5中的具体组成和用量(重量份，下同)
片芯颗粒：按照计量比将托法替布、填充剂、缓释骨架材料和一半量的润滑剂使用料斗混合机(南通贝特HBD-200)混合均匀；将上述混合物使用干法制粒机(德国亚历山大WP120)制备成颗粒后与剩下的一半量的润滑剂使用料斗混合机(南通贝特HBD-200)混合成为总混颗粒。
压片：采用压片机(菲特P2020)将上述总混颗粒压制成片芯。
包衣：将托法替布和膜材混合均匀后加入含有10％纯化水重量比的异丙醇溶液中，充分搅拌均匀，配制成固含量约7％的混悬液，将上述混悬液使用包衣锅(O’Hara Lab coat M)包衣喷镀到片芯上，干燥后制备成半透膜包衣片。其喷雾工艺过程中，物料温度为25-35℃，进风风量维持在50-100cm 3/小时。喷雾完成后，托法替布的半透膜包衣片在30℃包衣机内干燥2小时，至干燥失重小于2.0％。
打孔：将上述半透膜包衣片采用机械打孔机(BEKING Surom)用1.0mm的钻头打孔，制得最终渗透泵片。
按照上述方法，制备得到本发明的渗透泵片1-1至1-10。
表5 渗透泵片的具体组成(重量份)
Figure PCTCN2020138988-appb-000007
*在制备过程中挥发。
2.制剂的溶出度测定
根据上文所述方法，测定各渗透泵片在pH 6.8的磷酸盐缓冲液中的溶出度，结果参看下表6。
表6 渗透泵片的溶出度
Figure PCTCN2020138988-appb-000008
由表6数据可知，采用不同处方制备的渗透泵片有较宽的药物释放范围。15分钟(0.25小时)的释放量为半透膜包衣中活性成分托法替布的含量。结果表明不同处方的包衣中活性成分托法替布在15分钟内均可以释放完全。在随后的过程中固体制剂还可以以平稳的速度持续地释放活性成分托法替布，提供较长时间的有效平稳血药浓度。特别地，制剂1-1至1-8的释放在7小时内完成，释放效果更为优异。
实施例4 溶出度比较
根据上文所述方法，测定不同剂型间的托法替布制剂的溶出度比较(速释部分托法替布为20％，缓释部分托法替布为80％)，各制剂在pH 6.8的磷酸盐缓冲液中的溶出度，结果参看下表7。
表7 制剂的溶出度
Figure PCTCN2020138988-appb-000009
由上表数据可知，以上3种不同剂型的托法替布制剂均具有前15分钟速释，而后缓释释放达5小时以上的特殊释放模式。该释放模式既能保持前期服药后的快速起效，又能将该临床效果维持较长的时间，血药浓度更加平稳。
实施例5 药代动力学研究
使用上述实施例2中制得的包衣片1-3
1.试验制剂
受试制剂T：根据实施例2中包衣片1-3的处方和工艺制备的托法替布包衣片，规格为11mg，一天一次。
参比制剂R：市售的托法替布缓释片(Xeljanz XR)，规格为11mg，一天一次。
2.试验方法
1)单次给药试验
采用开放、随机、双周期、双交叉自身对照试验设计方法(清洗期为7天)，将入选的10名健康男性受试者随机分为2组，每组5人。分组方案如下表所示：
表8 分组
Figure PCTCN2020138988-appb-000010
受试者于试验日前进入I期临床试验病房，晚上进统一清淡饮食，然后禁食过夜(至少10h，不禁水)。受试者次日早上8点左右空腹口服11mg托法替布包衣片，10分钟后喝240ml水。或者，受试者分别于次日早上8点左右和晚上8点左右空腹口服11mg托法替布缓释片，同时分别给予240ml水送服。服药后2h内不得饮水，且保持上身直立状态，4小时后进统一午餐。
血样采集方法：于给药前0h(给药前1h内)和给药后0.5、1、1.5、2、2.5、3、3.5、4、4.5、5、6、7、8、12、24、36h(17个采血点)采集受试者肘静脉血4mL，血样置于肝素钠抗凝的采血管中，采集后于4℃条件下以3500rpm离心5min，将血浆分为两份，取1mL血浆加入正式管，剩余血浆加入备份管。样品在采集后2h内置于-20℃冰箱，备用。
采用LC-MS/MS方法，测定各血浆样品中的托法替布浓度。经药代动力学统计软件DAS 2.0计算，进行生物统计分析。试验结果参见表9和图1。
从血药浓度曲线可以看出，参比的缓释片对应血药浓度达到17ng/ml的时间为约90分钟。相比之下，本发明包衣片的对应血药浓度达到17mg/ml的时间为约30分钟。
表9 托法替布单次给药主要药代动力学参数
Figure PCTCN2020138988-appb-000011
其中，Ta指血药浓度能够维持在17ng/mL(IC 50)以上的时间。
由表9可见，本发明的托法替布包衣片的最大血药浓度C max较上市缓释片剂有明显降低，波动较上市缓释片剂更平稳，血药浓度的曲线下面积有明显的增加。其Ta值较托法替布市售缓释片延长约33％左右。
实施例6 托法替布制剂的药代动力学研究
使用上述实施例2中制得的包衣片1-2、1-3和1-6。
1.试验制剂
受试制剂T1：根据实施例2中包衣片1-2的处方和工艺制备的托法替布包衣片，规格为11mg，一天一次。
受试制剂T2：根据实施例2中包衣片1-3的处方和工艺制备的托法替布包衣片，规格为11mg，一天一次。
受试制剂T3：根据实施例2中包衣片1-6的处方和工艺制备的托法替布包衣片，规格为11mg，一天一次。
2.试验方法
1)单次给药试验
采用开放、随机、双周期、三交叉自身对照试验设计方法(清洗期为7天)，将入选的9名健康男性受试者随机分为3组，每组3人。分组方案如下表所示：
表10 分组
Figure PCTCN2020138988-appb-000012
受试者于试验日前进入I期临床试验病房，晚上进统一清淡饮食，然后禁食过夜(至少10h，不禁水)。受试者次日早上8点左右空腹口服11mg托法替布包衣片，10分钟后喝240ml水。服药后2h内不得饮水，且保持上身直立状态，4小时后进统一午餐。
血样采集方法：于给药前0h(给药前1h内)和给药后0.5、1、1.5、2、2.5、3、3.5、4、4.5、5、6、7、8、12、24、36h(17个采血点)采集受试者肘静脉血4mL，血样置于肝素钠抗凝的采血管中，采集后于4℃条件下以3500rpm离心5min，将血浆分为两份，取1mL血浆加入正式管，剩余血浆加入备份管。样品在采集后2h内置于-20℃冰箱，备用。
采用LC-MS/MS方法，测定各血浆样品中的托法替布浓度。经药代动力学统计软件DAS 2.0计算，进行生物统计分析。试验结果参见表11和图2。
表11 托法替布单次给药主要药代动力学参数
Figure PCTCN2020138988-appb-000013
Ta指血药浓度能够维持在17ng/mL(IC 50)以上的时间。
从血药浓度曲线可以看出，受试制剂T1、T2、T3对应血药浓度达到17ng/ml的时间分别为约50分钟、25分钟、12分钟。
由表11可见，本发明的制剂的血药浓度波动平稳，血药浓度的曲线下面积更高。受试制剂T1、T2和T3的Ta值分别为8.6、9.7和5.8小时。可见，本发明的制剂能够实现高Ta值，从而实现更好的治疗效果。特别地，受试制剂T1、T2能够实现明显更高的Ta值以及和更高的血药浓度的曲线下面积，表现出特别的优势。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应该视为本发明的保护范围。

Claims (14)

  1. 一种固体制剂，所述固体制剂包括速释部分和缓释部分，并且包含活性成分，其中所述缓释部分中的活性成分与所述速释部分中的活性成分的重量比为约1:1或更高。
  2. 根据权利要求1所述的固体制剂，其中
    所述缓释部分中的活性成分与所述速释部分中的活性成分的重量比为约1:1-20:1，优选约1:1-9:1、更优选约1:1-4:1，例如约1:1-7:3、约4:1-9:1或约7:3-4:1。
  3. 根据权利要求1或2所述的固体制剂，其中
    所述活性成分为托法替布或其药学上可接受的盐，特别是枸橼酸托法替布。
  4. 根据权利要求1-3中任一项所述的固体制剂，其中
    所述缓释部分包含缓释骨架材料；
    优选地，缓释骨架材料占缓释部分重量的约40％-80％，更优选约40％-50％或约50％-70％。
  5. 根据权利要求1-4中任一项所述的固体制剂，其中
    所述缓释部分和/或所述速释部分包含成膜材料；
    优选地
    成膜材料占缓释部分重量的约30％-70％，更优选约40％-60％；和/或
    成膜材料占速释部分重量的约40％-80％，更优选约50％-70％。
  6. 根据权利要求1-5中任一项所述的固体制剂，其中
    所述固体制剂中活性成分在15分钟内的总溶出度为约5-50％，优选为约10-30％，特别优选为约20％；
    所述固体制剂中活性成分在1小时内的总溶出度为约20-60％，优选为约30-50％；
    所述固体制剂中活性成分在3小时内的总溶出度为约55-95％，优选为约60-80％；和/或
    所述固体制剂中活性成分在5小时内的总溶出度为至少约80％，优选为至少约85％。
  7. 根据权利要求1-6中任一项所述的固体制剂，其中
    所述固体制剂的单次给药所实现的血药浓度达到17ng/ml所需的时间为约10-60分钟，优选为约25-45分钟，特别优选为约20-30分钟；和/或
    所述固体制剂的单次给药所实现的血药浓度在17ng/ml以上的持续时间为约8-12小时，优选约9-11小时。
  8. 根据权利要求1-7中任一项所述的固体制剂，其为片剂、颗粒剂、微丸或胶囊剂的形式；所述片剂优选为包衣片或渗透泵片，所述包衣片剂或渗透泵片任选地包含缓释包衣。
  9. 根据权利要求1-8中任一项所述的固体制剂，其中所述速释部分和所述缓释部分还各自独立地包含一种或多种选自以下的药用辅料：缓释骨架材料、成膜材料、粘合剂、填充剂、崩解剂、润滑剂；
    所述缓释骨架材料优选为选自以下的一种或多种：羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素、聚氧乙烯、山嵛酸甘油酯、聚甲基丙烯酸甲酯、丙烯酸树脂、聚维酮、黄原胶、海藻酸钠、海藻酸钙、卡波姆、甲壳素、聚乙烯、聚硅氧烷，优选羟乙基纤维素或山嵛酸甘油酯；
    所述成膜材料优选为选自以下的一种或多种：醋酸纤维素、乙基纤维素、羟丙甲纤维素、丙烯酸树脂，优选乙基纤维素或醋酸纤维素；
    所述粘合剂优选为选自以下的一种或多种：聚乙二醇、淀粉、羟丙基纤维素、羟丙基甲基纤维素、预胶化淀粉、聚乙烯吡咯烷酮、阿拉伯胶粉末、明胶，优选羟丙基纤维素；
    所述填充剂优选为选自以下的一种或多种：淀粉、预胶化淀粉、改良淀粉、微晶纤维素、硅化微晶纤维素、低取代羟丙基纤维素葡萄糖、蔗糖、乳糖、山梨糖醇、甘露醇、赤藓醇、碳酸钙和磷酸氢钙，优选甘露醇、微晶纤维素、硅化微晶纤维素，优选微晶纤维素、乳糖或甘露醇；
    所述崩解剂优选为选自以下的一种或多种：微晶纤维素、羧甲基纤维素、交联聚维酮、交联羧甲基纤维素钠、羧甲基纤维素钙、羧甲基淀粉钠、低取代羟丙基纤维素、羟甲基淀粉、海藻酸、海藻酸钠、瓜尔胶、玉米淀粉和硅酸镁铝，优选交联聚维酮；
    所述润滑剂优选为选自以下的一种或多种：硬脂酸镁、硬脂酸、硬脂酸盐、硬脂富马酸钠、十二烷基硫酸钠、聚乙二醇、苯甲酸钠、蔗糖脂肪酸酯、微粉硅胶、滑石粉、单硬脂酸甘油酯、山嵛酸甘油酯、棕榈酰硬脂酸甘油酯、硬脂酸、氢化植物油，优选硬脂酸镁或山嵛酸甘油酯。
  10. 根据权利要求1-9中任一项所述的固体制剂，其中
    所述固体制剂为双层片剂，并且包含活性成分、填充剂、崩解剂、润滑剂和缓释骨架材料；或者
    所述固体制剂为包衣片剂，并且包含活性成分、填充剂、缓释骨架材料、润滑剂、成膜材料；或者
    所述固体制剂为渗透泵片，并且包含活性成分、填充剂、缓释骨架材料、润滑剂、成膜材料；或者
    所述固体制剂为胶囊剂，并且包含活性成分、填充剂、粘合剂、润滑剂、成膜材料。
  11. 根据权利要求1-10中任一项所述的固体制剂，其中
    所述缓释部分包含成膜材料，速释部分的活性成分位于所述成膜材料中。
  12. 一种药物组合物，其包含权利要求1-11中任一项所述的固体制剂。
  13. 权利要求1-11中任一项所述的固体制剂或者权利要求12所述的药物组合物在制备用于治疗或预防疾病中的用途，所述疾病包括狼疮、多发性硬化症、类风湿关节炎、银屑病关节炎、I型糖尿病及糖尿病并发症、癌症、哮喘、特应性皮炎、自身免疫性甲状腺疾病、中度至重度活动性溃疡性结肠炎、克罗恩氏病、强直性脊柱炎、幼年特发性关节炎、免疫系统失调秃顶症、白癜风、系统性红斑狼疮、阿尔兹海默氏病及白血病。
  14. 一种制备权利要求1-11中任一项的固体制剂的方法，其包括
    1)将活性成分与一种或多种药学上可接受的辅料组合以制备速释部分，
    2)将活性成分与一种或多种药学上可接受的辅料组合以制备缓释部分，
    3)将所述速释部分与所述缓释部分组合以制备所述固体制剂；
    其中，
    步骤1)和步骤2)互相独立地以任何次序进行；
    步骤1)和步骤2)中的活性成分和辅料各自独立地使用。
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