WO2022022369A1 - 一种托法替布或其盐的缓释制剂及其制备方法 - Google Patents

一种托法替布或其盐的缓释制剂及其制备方法 Download PDF

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WO2022022369A1
WO2022022369A1 PCT/CN2021/107748 CN2021107748W WO2022022369A1 WO 2022022369 A1 WO2022022369 A1 WO 2022022369A1 CN 2021107748 W CN2021107748 W CN 2021107748W WO 2022022369 A1 WO2022022369 A1 WO 2022022369A1
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release
sustained
tablet
tofacitinib
preparation
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PCT/CN2021/107748
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English (en)
French (fr)
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甘勇
朱春柳
朱全垒
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中国科学院上海药物研究所
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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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • 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
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the invention relates to the field of pharmaceutical preparations, in particular to the field of sustained-release pharmaceutical preparations, in particular to a sustained-release preparation of tofacitinib or a salt thereof and a preparation method thereof.
  • RA Rheumatoid Arthritis
  • immortal cancer Rheumatoid Arthritis
  • the clinical pathological features of RA are mainly manifested in three aspects: (1) local inflammatory cell infiltration in the joint causes chronic inflammation; (2) the infiltration and growth of synovial cells in the joint leads to synovial thickening; (3) bone erosion and cartilage tissue damage lead to joint deformity. and loss of function.
  • RA pathogenesis of RA is still unclear, and it is speculated that it is an antigen-driven "prime-chain" reaction.
  • Epidemiological surveys show that the global incidence of RA is 0.5% to 1%, and the incidence in China is 0.42%. The total affected population is about 5 million, and the ratio of male to female is about 1:4.
  • the morbidity rates of RA patients in my country were 18.6%, 43.5%, 48.1% and 61.3% respectively in the course of 1-5 years, 5-10 years, 10-15 years and ⁇ 15 years.
  • RA rheumatoid arthritis
  • RA treatment drugs in clinic include five categories: non-steroidal anti-inflammatory drugs (NASIDs), disease-modifying antirheumatic drugs (DMARDs), glucocorticoids (GCs), biological agents and targeted small molecule drugs.
  • 70% of RA patients are moderate to severe patients, and national guidelines recommend antirheumatic drug therapy, mainly methotrexate, as the first-line treatment.
  • Some patients with insufficient response to DMARDs or poor compliance with treatment can choose to use biological agents or targeted combination therapy.
  • the treatment effective rate is less than 60%; however, there are still patients receiving adalimumab, etanercept, infliximab and other biological agents. 28-41% of patients have poor curative effect, and patients with insufficient response to DMARDs or poor compliance with treatment can choose to use biological agents or targeted small molecule drugs.
  • rheumatoid arthritis is a long-term or even life-long process. Patients need to adjust their lifestyle after diagnosis.
  • the patient's treatment compliance is closely related to the rapid remission and compliance of the disease, and the route of administration also affects the patient's compliance. one of the important factors. Studies have shown that 39% of patients have poor compliance with injection therapy, and 79% of rheumatoid arthritis patients prefer oral therapy.
  • JAK inhibitors as oral small-molecule targeted drugs with novel mechanisms, have similar efficacy and safety as biologics, but are cheaper, and oral administration can significantly improve patient compliance.
  • Tofacitinib also known as tofacitinib, forms stable citrate crystals with citric acid, which makes it suitable for oral administration.
  • the chemical name for tofacitinib citrate is 3-((3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine -1-yl]-3-oxopropionitrile: citrate (1:1), the molecular formula is C 16 H 20 N 6 O C 6 H 8 O 7 , the molecular weight of the free base is 312.4, and the molecular weight of the citrate is 504.5, which has the following chemical structure:
  • Tofacitinib is a Janus kinase (JAK) inhibitor, the drug binds to JAK protein, inhibits the JAK signaling pathway in the cell, prevents the phosphorylation of STAT, and then directly or indirectly inhibits IL-2, IL-7, The production and pro-inflammatory effects of multiple cytokines such as IL-6, IL-9, IL-15, IL-21, TNF- ⁇ , IL-17, etc., relieve the inflammatory response related to RA, so as to achieve the purpose of treating RA.
  • JAK Janus kinase
  • JAK2 is minimally associated with inflammation, and JAK2 inhibition can lead to blood-related adverse reactions, including anemia and thrombocytopenia.
  • inflammation-related diseases such as RA
  • JAK2 inhibition can lead to blood-related adverse reactions, including anemia and thrombocytopenia.
  • the selectivity of JAK inhibitors should focus on JAK1/JAK3 as much as possible to reduce the inhibition of JAK2.
  • excessive inhibition of JAK1/JAK3 often weakens the body's ability to recognize and clear pathogens and cancer cells, resulting in inflammation-related adverse reactions and increased tumor risk.
  • the inhibitory effect of tofacitinib on JAK kinase has strong selectivity.
  • Tofacitinib effectively inhibits the proliferation of human T cells and mixed lymphocytes induced by JAK pathway-related IL-2 (IC 50 of 11 nmol/L and 87 nmol/L, respectively).
  • tofacitinib was pumped for 28 days (dose of 0 mg/kg, 1.5 mg/kg, 5 mg/kg, and 15 mg/kg, respectively) .
  • dose of 0 mg/kg, 1.5 mg/kg, 5 mg/kg, and 15 mg/kg, respectively was administered for 28 days (dose of 0 mg/kg, 1.5 mg/kg, 5 mg/kg, and 15 mg/kg, respectively) .
  • tofacitinib was effective in inhibiting paw swelling ( 50% effective dose ED50 was 1.5 mg/kg/d based on clinical evaluation).
  • tofacitinib (0 mg/kg, 1.5 mg/kg, 5 mg/kg, and 15 mg/kg per day) was pumped 10 days after adjuvant injection by a mini-osmotic pump for 2 weeks ).
  • Plasma neutrophils and the cytokines IL-17 and IL-6 increased significantly with disease progression.
  • the 15 mg/kg dose of tofacitinib showed good efficacy in reducing paw swelling.
  • tofacitinib still has satisfactory clinical effects on RA patients who are ineffective in biologics therapy.
  • the combination of tofacitinib and methotrexate has the same therapeutic effect as adalimumab, and has a price advantage over biopharmaceuticals , the medication is convenient, and the patient's compliance is good.
  • JAK inhibitors Based on the function and mechanism of JAK-STAT signaling pathway, JAK inhibitors over-inhibit the target at higher doses, showing a "pan-JAK” inhibitory effect, which will damage the body's immune system and produce off-target effects; Herpes zoster, malignant tumors and other adverse reactions.
  • the efficacy and safety of JAK inhibitors are closely related to their selectivity, and their selectivity is concentration-dependent. When the drug concentration is low, the drug selectivity is high; when the drug concentration is too high, the selectivity is weakened. In order to ensure the effectiveness of the drug and reduce potential adverse reactions, the dosage of JAK inhibitors needs to be controlled within a certain range.
  • the preparation of tofacitinib into a sustained-release preparation can better regulate the release behavior of the drug, reduce adverse reactions caused by excessive blood drug concentration, and improve drug safety.
  • the plasma concentration reaches a peak within 0.5 to 1 hour, and the elimination half-life is about 3 hours.
  • C max reduce the frequency of dosing and improve the compliance of patients with medication.
  • patents related to tofacitinib sustained-release preparations include: tofacitinib enteric-coated sustained-release pellets CN108066319A, tofacitinib gastric-coated sustained-release preparations WO2016IB54833, tofacitinib sustained-release tablets CN103458901B and CN201480015788 .
  • Chinese Patent Application Publication Specification CN108066319A discloses tofacitinib citrate enteric-coated sustained-release pellets and a preparation method thereof.
  • the invention discloses tofacitinib citrate enteric-coated sustained-release pellets and a preparation method thereof.
  • Enteric coating on the pellet core the enteric-coated sustained-release pellets have pH-sensitive drug release characteristics. Since the outermost layer adopts a pH-sensitive enteric coating layer, the drug release behavior of the enteric-coated sustained-release pellets is greatly affected by the pH value of the gastrointestinal tract, food effects, etc., and there are large differences between individuals.
  • WO2016IB54833 discloses a tofacitinib sustained-release oral composition comprising: tofacitinib; a controlled-release polymer and excipients, and the sustained-release oral composition further includes an external modified drug release coating stomach-soluble type Film overcoat (EPO), specifically covering dosage forms including single-layer osmotic pump, double-layer osmotic pump, gel matrix tablet, reservoir tablet. Due to the pH-dependent solubility of tofacitinib, the formulation is prone to problems such as incomplete drug release and low absorption in the lower part of the digestive tract.
  • EPO stomach-soluble type Film overcoat Due to the pH-dependent solubility of tofacitinib, the formulation is prone to problems such as incomplete drug release and low absorption in the lower part of the digestive tract.
  • the German Tongyi Pharmaceutical Company disclosed in the patent publication number CN103458901B a solid oral dosage form containing tofacitinib for improved release, which comprises: tofacitinib and non-erodible materials selected from ethyl cellulose, fiber Plain ester, acrylic copolymer, methacrylic resin, polyvinyl acetate; specific formulations include gel matrix tablets, multi-particulate drug delivery systems, and double-layer osmotic pump controlled-release tablets.
  • This patent discloses the preparation method of the modified release dosage form of tofacitinib, but the patent does not disclose the in vitro release behavior of the improved preparation, nor the in vivo pharmacokinetic or pharmacodynamic data of the preparation. There is also no mention of inventive features and solutions to the problem of lower alimentary tract absorption.
  • Chinese patent CN201480015788 discloses a once-daily pharmaceutical dosage form comprising: a core containing 11 mg or 22 mg of tofacitinib or an equivalent amount of tofacitinib in its pharmaceutically acceptable salt form and accounting for the 60-85% by weight of the pharmaceutical dosage form osmogen; and a semi-permeable membrane coating in an amount of 3-30% by weight of the core before the core, the coating being primarily a water-insoluble polymer.
  • the tofacitinib sustained-release preparation had a certain problem of incomplete absorption, and the specification was adjusted to 11 mg in order to be bioequivalent to the 10 mg immediate-release preparation.
  • the described tofacitinib sustained-release preparation uses sorbitol as the osmotic source to prepare osmotic pump tablets.
  • the melting point of sorbitol is relatively low, and the preparation process requires special humidity control, which brings certain challenges to the industrial production process of the product.
  • the technical purpose of the present invention is to provide a sustained-release preparation of tofacitinib or its salt.
  • the active ingredient tofacitinib and a special release accelerator are used to prepare the osmotic tablet core composition.
  • the compatibility of raw and auxiliary materials is good.
  • the preparation of tofacitinib sustained-release preparation has improved drug release behavior and higher cumulative release within an 8-hour drug release period, thereby improving the absorption and bioavailability of tofacitinib.
  • the present invention provides a sustained-release preparation of tofacitinib or a salt thereof, the structural composition of which sequentially includes from inside to outside:
  • an osmotic core composition containing a release enhancer containing a release enhancer
  • the core tablet composition comprises 6.4wt% to 16wt% of active pharmaceutical ingredients, 20wt% to 77wt% of a release enhancer, 0 to 56wt% of an osmotic pressure enhancer, and a binder of 16wt% to 16wt%. 50wt%, and 0.5wt% to 7wt% of other pharmaceutical excipients; wherein, the release accelerator is a cyclic oligosaccharide cyclodextrin derivative.
  • the active pharmaceutical ingredient is tofacitinib, including tofacitinib free base and salts of tofacitinib, such as hydrochloride, benzenesulfonate, citrate, sulfate etc., tofacitinib citrate is preferred.
  • the dosage form of the sustained-release preparation is a tablet, and in tofacitinib, the dosage specification is 8 mg/tablet to 24 mg/tablet, preferably 8 mg/tablet to 11 mg/tablet or 16 mg/tablet to 24 mg/tablet.
  • the release enhancer is selected from ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sulfobutyl- ⁇ -cyclodextrin and hydroxyethyl- ⁇ -cyclodextrin One or a combination of two or more; more preferably, one or a combination of hydroxypropyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin.
  • the dosage of the release accelerator is 20wt% to 77wt% of the total weight of the tablet core composition, preferably 40wt% to 70wt%.
  • the cyclic oligosaccharide cyclodextrin derivative the molecule is in the shape of a truncated cone, the inner part of the truncated truncated cone is hydrophobic, and the outer part is connected with a hydrophilic substituent; It can accommodate highly dispersed drugs through inclusion, limit the nucleation rate, inhibit crystal growth, improve apparent solubility, promote drug absorption, and improve bioavailability.
  • the cyclic oligosaccharide cyclodextrin derivative has good solubility in an aqueous medium.
  • the inventors unexpectedly found that by adding a certain proportion of cyclic oligosaccharide cyclodextrin derivatives as release promoters, the sustained-release preparation of tofacitinib of the present invention can have a higher cumulative release degree within the release period of 8 hours .
  • the solubility of tofacitinib has a certain pH dependence, and as the pH value increases, the solubility decreases; the solubility in pH 1.0 medium is greater than 28 mg/mL, and it is very slightly soluble in pH 7.4 medium (solubility is about 0.20 mg/mL), The solubility differs by about 140 times in the range of physiological media with different pH values.
  • the drug release is incomplete, which affects the absorption of the drug in the lower part of the intestine.
  • Tofacitinib and special release accelerator cyclic oligosaccharide cyclodextrin derivatives are used to prepare osmotic tablet core compositions, which can accommodate highly dispersed drugs through the inclusion of cyclic oligosaccharide cyclodextrin derivatives. Promote drug release and further improve the absorption and bioavailability of tofacitinib in the lower intestinal segment.
  • the bioavailability of tofacitinib sustained-release tablet formulation 14 (the amount of cyclic oligosaccharide cyclodextrin derivative is 20% of the total weight of the tablet core composition) is equivalent to that of the commercially available formulation;
  • Formula 15 (the dosage of cyclic oligosaccharide cyclodextrin derivatives is 40% of the total weight of the tablet core composition)
  • recipe 16 (the dosage of the cyclic oligosaccharide cyclodextrin derivatives is 60% of the total weight of the tablet core composition)
  • the relative bioavailability was 109% and 121.8% respectively; it can be seen that when the amount of cyclic oligosaccharide cyclodextrin derivatives in the
  • the osmotic pressure enhancer can be one or more of sodium chloride, lactose, mannitol, sorbitol, glucose, sucrose, fructose, and mixtures thereof.
  • the amount of the osmotic pressure enhancer is 0% to 56% by weight of the total weight of the tablet core composition.
  • the binder is selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, hypromellose, polyoxyethylene, alginic acid and/or its derivatives, povidone, copovidone One or more of; the binder can provide the desired viscosity for the release of the product.
  • the amount of the binder is 16wt% to 50wt% of the total weight of the tablet core composition.
  • the other pharmaceutical excipients are selected from one or more of surfactants, colorants, and lubricants.
  • the dosage of the other pharmaceutical excipients is 0.5wt% to 7wt% of the total weight of the tablet core composition.
  • the surfactant can further enhance and improve the solubility of active ingredients.
  • the surfactant can be selected from sodium lauryl sulfate, lauric acid, sodium docusate, benzethonium chloride, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivatives, polyoxyethylene stearate 40 , one or more of polyoxyethylene stearate and poloxamer.
  • the lubricant can be selected from stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, glycerol mono/bibehenate, polyethylene glycol-8-glycerol behenate One or more of esters, glyceryl distearate, and micropowder silica gel.
  • the colorant may be selected from one or more of iron oxide yellow, iron oxide violet, iron oxide red, and iron oxide black.
  • the sustained-release preparation of tofacitinib or a salt thereof of the present invention can be coated with a sealing and insulating coat as required, and the sealing and insulating coat is located between the tablet core and the controlled-release coat in terms of structural composition.
  • the initial release rate of the active ingredient was adjusted by adjusting the dosage of the sealing isolation coat. With the increase of the weight gain of the sealing isolation coat, the initial release rate of the active ingredient in 1 h decreased, and the sealing isolation coat had no significant effect on the average drug release rate.
  • the sealant barrier coat layer can be formed by dissolving the sealant barrier coat composition in a suitable solvent, spraying onto the tablet core and drying.
  • the sealing barrier coat composition generally includes the following materials well known to those skilled in the art, for example, selected from the group consisting of hypromellose, povidone, copovidone, hydroxyethyl cellulose, hydroxypropyl cellulose, polyethylene glycol one or more of alcohols, and mixtures thereof.
  • the typical solvent includes one or more of ethanol, water, isopropanol or a mixture thereof. Based on the total weight of the core tablet composition, the weight gain of the sealing isolation gown is not more than 20 wt % of the total weight of the core tablet composition, preferably 4 wt % to 15 wt %.
  • the controlled-release coating is the key to the composition of the osmotic pump controlled-release system.
  • the controlled-release coating can allow external liquids (such as water or biological fluids) to penetrate through, while substances such as drugs in the tablet core cannot pass through.
  • the controlled release coating material is a semi-permeable material with certain rigidity and flexibility. Commonly used controlled release coating materials are selected from one or more of cellulose acetate, ethyl cellulose and polyacrylic resin;
  • the transmembrane controlled-release coating material is dissolved in a suitable coating solvent, sprayed onto the tablet core, and dried to form the controlled-release coating.
  • the coating solvent is a mixture of one or more of alcohol, ketone and water.
  • the weight gain of the controlled release coating accounts for 5wt% to 15wt% of the total weight of the tablet core composition, preferably 5.5wt% ⁇ 8.5 wt%.
  • the controlled release coating may comprise a release rate modifier or a plasticizer; the release rate modifier is selected from the group consisting of povidone, copovidone, hydroxypropyl cellulose, polyethylene glycol, glycerin one or more of.
  • the release rate modifier in the controlled release coating accounts for 30wt% to 50wt% of the total weight of the controlled release coating, preferably 35wt% to 45wt%.
  • the plasticizer is selected from one or more of dimethyl phthalate, diethyl phthalate, dibutyl phthalate, triethyl citrate and castor oil, and the plasticizer is The plasticizer accounts for 0.1wt% to 10wt% of the total weight of the controlled release coating, preferably 1wt% to 5wt%.
  • the controlled-release coating comprises drug-release holes
  • the perforation method of the drug-release holes can be performed by a machine or a laser drilling method well-known to those skilled in the art.
  • the geometric shape is not limited, and it can have any geometric shape, such as circle, ellipse, square, triangle, etc.
  • the diameter of the drug release hole is 0.2mm-1.0mm, preferably 0.4mm-0.8mm.
  • the aesthetic garment can provide an improved appearance to the formulation.
  • the aesthetic garment is made from an aesthetic garment layer composition.
  • the aesthetic coat layer composition comprises a coating powder for forming an aesthetic coat, and one or more optional materials selected from colorants, plasticizers, opacifiers, anti-sticking agents, etc., and their amounts All are routine choices of those skilled in the art.
  • the coating powders used to form the aesthetic garments are conventional choices of those skilled in the art, including hydroxypropyl methylcellulose, hydroxypropyl cellulose and acrylate or methacrylate copolymers, Opadry, but not limited to this.
  • Such opacifiers may include titanium dioxide, talc, silicon dioxide, and mixtures thereof; such anti-sticking agents may include talc, magnesium stearate, glyceryl monostearate, and mixtures thereof.
  • the sustained-release preparation of tofacitinib or its salt according to the present invention has controllable drug release behavior, and within a predetermined period of time, in a release medium that meets sink conditions, its release behavior and release amount are controllable.
  • the release behavior is measured in 900 ml of a buffer solution with a pH value of 6.8 under the condition of 37 ° C, the release amount within 1 hour is less than 13wt% of the total amount of pharmaceutical active ingredients, The average release rate per hour in 1-4 hours is equivalent to 20wt%-30wt% of the total amount of active pharmaceutical ingredients, and the release amount in 8 hours is greater than 95wt% of the total amount of active pharmaceutical ingredients.
  • the present invention provides a core tablet composition of tofacitinib or a salt thereof, based on the total weight of the core tablet composition, the core tablet composition comprises 6.4 wt % to 16 wt % of active pharmaceutical ingredients, and the release promotes 20wt% to 77wt% of the osmotic pressure enhancer, 16wt% to 50wt% of the binder, and 0.5wt% to 7wt% of other pharmaceutical excipients; wherein, the release enhancer is a cyclic oligosaccharide ring Dextrin derivatives.
  • active pharmaceutical ingredients release enhancers, binders and other pharmaceutical excipients are as described above.
  • the present invention provides a preparation method of the sustained-release preparation of the above-mentioned tofacitinib or a salt thereof, the method comprising the steps of:
  • the method also optionally includes: between steps 1) and 2), applying a sealed barrier coat, and after step 3), performing step 4) applying an aesthetic garment.
  • the drug-containing composition permeable tablet core is prepared by the following method, mixing active pharmaceutical ingredients and release accelerator, and then fully mixing with adhesive and other pharmaceutical excipients, through different formulation processes, to obtain a uniform tablet-core combination thing.
  • the formulation process may include direct powder mixing, or wet granulation, or hot melt extrusion, and the like.
  • the tablet core composition of tofacitinib or its salt provided by the present invention has controllable physical stability.
  • the drug release behavior of the sustained-release preparation of tofacitinib or its salt after being placed under accelerated conditions (40°C, 75% RH) for 6 months is consistent with 0 month, and the stability is good.
  • the tofacitinib or its salt sustained-release preparation composition provided by the present invention can precisely control the JAK enzyme inhibition level of the drug in vivo by regulating the release behavior of the active ingredient, so as to maintain the effective concentration level required for the inhibition of JAK enzyme activity in the body .
  • the "pan-JAK" inhibitory effect caused by excessive inhibition of the target can be avoided.
  • the present invention also provides the use of the sustained-release preparation of tofacitinib or its salt in the preparation of a medicament for the treatment of immunosuppression-related diseases, including rheumatoid arthritis, active Psoriatic arthritis, ulcerative colitis, psoriasis, Crohn's disease, atopic dermatitis, ankylosing spondylitis.
  • immunosuppression-related diseases including rheumatoid arthritis, active Psoriatic arthritis, ulcerative colitis, psoriasis, Crohn's disease, atopic dermatitis, ankylosing spondylitis.
  • the present invention also provides a method for the sustained-release preparation of tofacitinib or its salt for the treatment of immunosuppression-related diseases, comprising administering to a subject in need a pharmaceutically effective dose of the tofacitinib Sustained-release preparations of Tibu or its salts.
  • the tofacitinib sustained-release preparation Compared with the existing tofacitinib sustained-release preparation, the tofacitinib sustained-release preparation provided by the present invention has the following advantages:
  • the osmotic tablet core composition prepared by tofacitinib and release accelerator has both penetration and release promotion effects.
  • the inclusion effect accommodates highly dispersed drugs, has improved drug release behavior, and can promote the release of active ingredient tofacitinib; cyclic oligosaccharide cyclodextrin derivatives have good compatibility with tofacitinib stability and good stability.
  • the tofacitinib sustained-release preparation prepared by using the osmotic tablet core composition containing the release accelerator can promote the absorption of the active ingredient tofacitinib in the gastrointestinal tract, and has improved bioavailability.
  • sustained-release formulation of tofacitinib or a salt thereof of the present invention
  • the sustained-release formulation is a single-layer osmotic layer containing an osmotic tablet core 1, a sealing barrier coat 2, a controlled release coat 3 and an aesthetic coat 4 Pump controlled release formulation.
  • FIG. 8 is the results of the apparent solubility measurement of formulations 14 to 16 in Preparation Example 1 and the tablet cores of commercially available sustained-release preparations.
  • Figure 11 is the plasma concentration-time curve of the commercially available sustained-release preparation and the sustained-release preparation of tofacitinib or its salt of the present invention (formulation 4, specification: 9.9 mg/tablet) after oral administration in beagle dogs.
  • Figure 12 is the plasma concentration-time curve of the commercially available sustained-release preparation and the sustained-release preparation of tofacitinib or its salt of the present invention (formulations 14, 15 and 16, specification: 11 mg/tablet) after oral administration in beagle dogs.
  • Figure 13 shows the blood levels of beagle dogs after oral administration of immediate-release tofacitinib tablets (5 mg/tablet ⁇ 2) and the sustained-release formulation of tofacitinib or its salt of the present invention (prescription 4, specification: 9.9 mg/tablet). Drug concentration-time curves.
  • composition of each ingredient in the sustained-release formulation of formulations 1-16 is shown in Tables 1-3 below.
  • the sustained-release preparation of tofacitinib or a salt thereof of the present invention comprises the following preparation steps according to the sequence of preparation procedures: (1) preparation of the drug-containing composition and osmotic tablet core; (2) optional sealing and barrier coating coating (3) controlled release coating; (4) perforated coated tablet; and optionally, (5) aesthetic outer coating.
  • Pretreatment According to the ratio of prescription 1 in Table 1, the raw materials and auxiliary materials are respectively passed through a 60-mesh screen for pretreatment.
  • Weighing and mixing Weigh tofacitinib citrate and cyclic oligosaccharide cyclodextrin derivatives according to the above recipes, place them in a barrel, and use a three-dimensional mixer (T 2 F, Willy A.Bachofen AG Maschinenfabrik ) to mix, rotating speed 25rpm, mixing 10min; then add the other components of the tablet core (except magnesium stearate) of prescription 1, rotating speed 25rpm, mixing 30min.
  • T 2 F Willy A.Bachofen AG Maschinenfabrik
  • Granulation Add the above mixed tablet core mixture into a high shear granulator (HLSH2-6A, AVIC), shear for 5 minutes to fully mix; When the particle size is about 30 mesh, the granulation is stopped; after drying, the dry particles pass through a 20-mesh sieve and granulate;
  • HLSH2-6A high shear granulator
  • Total mixing take by weighing the magnesium stearate of the recipe, add it into the barrel, rotate at 25rpm, mix for 3min, and set aside;
  • Tablet compression the above-mentioned uniformly mixed prescription 1 tablet core composition is added to an oval die for compression according to the prescription amount, and is compressed into a suitable hardness (hardness ⁇ 6kg by a single-layer tablet machine (TDP-1, Shanghai Huamao), YZ-20KZ hardness tester, Tianda Tianfa) tablet cores, the qualified tablet cores are marked as prescription 1.
  • a suitable hardness hardness ⁇ 6kg by a single-layer tablet machine (TDP-1, Shanghai Huamao), YZ-20KZ hardness tester, Tianda Tianfa
  • Coating liquid preparation according to the composition of prescription 1, take the formulation quantity of isolation coat composition-hypromellose E5, under mechanical stirring condition, add the 95% ethanol solution of the formulation quantity, disperse and mix evenly, and then add the formulation quantity of the aqueous solution , to dissolve, as a sealant barrier coating solution.
  • Sealed barrier coat coating Take the compressed tablet cores, set up a high-efficiency coating pot (Labcoat BT, O'HARA), coat with a sealed barrier coating liquid, adjust the coating liquid flow rate (4-8mL/min), mist Chemical pressure (0.5bar ⁇ 0.8bar), air inlet temperature (45°C ⁇ 55°C), coating pan speed (10 ⁇ 20rpm); control the temperature of tablet bed material (30°C ⁇ 40°C) until the predetermined coating increase Heavy; the coated product is dried at 45°C for 2 hours to remove excess organic solvent and moisture.
  • a high-efficiency coating pot (Labcoat BT, O'HARA)
  • mist Chemical pressure 0.5bar ⁇ 0.8bar
  • air inlet temperature 45°C ⁇ 55°C
  • coating pan speed (10 ⁇ 20rpm)
  • control the temperature of tablet bed material (30°C ⁇ 40°C) until the predetermined coating increase Heavy
  • the coated product is dried at 45°C for 2 hours to remove excess organic solvent and moisture.
  • Preparation of coating solution according to the composition of prescription 1, weigh the semipermeable membrane controlled release coating material-cellulose acetate in the prescription amount, add it to the acetone solution under mechanical stirring conditions, and dissolve it; weigh the coating film pore-forming agent in the prescription amount -Hydroxypropyl cellulose EF is added to the ethanol and the aqueous solution of the recipe quantity, fully stirred to dissolve; after the above solutions are completely dissolved, the above two solutions are mixed uniformly and used as a semipermeable membrane coating solution.
  • Controlled-release coating Take the tablet core coated with the sealing isolation coat, place it in a high-efficiency coating pot (Labcoat BT, O'HARA), coat with a semi-permeable membrane coating liquid, and adjust the flow rate of the coating liquid (8-12 mL/ min), atomization pressure (0.5bar ⁇ 0.8bar), air inlet temperature (15°C ⁇ 30°C), coating pan speed (10 ⁇ 20rpm); control the temperature of tablet bed material (15°C ⁇ 25°C) until Predetermined coating weight gain; the coated product is dried at 45°C for 2 hours to remove excess organic solvent and moisture.
  • a high-efficiency coating pot Labcoat BT, O'HARA
  • atomization pressure 0.5bar ⁇ 0.8bar
  • air inlet temperature 15°C ⁇ 30°C
  • coating pan speed 10 ⁇ 20rpm
  • control the temperature of tablet bed material (15°C ⁇ 25°C) until Predetermined coating weight gain; the coated product is dried at 45°C for 2 hours to remove excess organic solvent and moisture.
  • a laser punching machine (RC-YW-30, Nanjing Ruichi) was used to punch a drug release hole with a diameter of about 0.6 mm at the top of the tablet, and the depth of the punching hole was suitable for penetrating the controlled release coating film.
  • Coating solution preparation Disperse Opadry coating powder in water to dissolve, and prepare an aesthetic outer coating coating solution with a solid content of 5%.
  • Aesthetic coat coating the controlled-release tablet after punching is placed in a high-efficiency coating pot (Labcoat BT, O'HARA), and the above-mentioned prepared Opadry coating liquid is used for coating, to a predetermined coating weight gain; Under the condition of 60 °C, dry for 2 hours, remove excess organic solvent and water, and get it.
  • the preparation method of the sustained-release preparations of prescriptions 2-6 is the same as the preparation method of the sustained-release preparations of the above-mentioned prescription 1, the difference is that the formulas of prescriptions 2-6 shown in Table 1 are respectively used.
  • the preparation method of the sustained-release preparation of the prescription 7-16 is the same as the preparation method of the sustained-release preparation of the above-mentioned prescription 1, the difference is that the formula of the prescription 7-16 shown in Table 2 and Table 3 are respectively adopted and not coated Steps to Aesthetic Apparel.
  • Formulas 1-16 were prepared by the above method.
  • the second method of dissolution and release determination method (general rule 0931) was adopted, the osmotic pump tablet was placed in the sinker, 900 mL of pH6.8 phosphate buffer was used as the release medium, and the rotation speed was 50 rpm. , 4, 6, 8, 10h, take 5mL of the solution, and replenish the release medium with the same temperature and the same volume in time. Take the sample solution, centrifuge (8000rpm, 10min), and take the supernatant as the test solution. Another appropriate amount of tofacitinib citrate reference substance was taken, accurately weighed, dissolved in a release medium and quantitatively diluted to make about 12 ⁇ g of tofacitinib per 1ml, as a reference solution.
  • HPLC conditions use octadecylsilane bonded silica gel as filler; use acetonitrile-0.2% perchloric acid aqueous solution (17.5:82.5) as mobile phase; detection wavelength: 290 nm; column temperature: 40 °C; flow rate: 1.0ml/min.
  • the second method of dissolution and release determination method (general rule 0931) was used, the osmotic pump tablet was placed in the sinker, and 900 mL of release media with different pH values (including 1 pH 1.2 hydrochloric acid solution; 2 pH 4.5 phosphate buffer; 3pH6.8 phosphate buffer; 4pH7.4 phosphate buffer), the speed is 50rpm, operate according to the law, take 5mL of the solution after 1, 2.5, 4, 6, 8, 10h, and replenish the same temperature and volume in time release medium. Take the sample solution, centrifuge (8000rpm, 10min), and take the supernatant as the test solution.
  • pH values including 1 pH 1.2 hydrochloric acid solution; 2 pH 4.5 phosphate buffer; 3pH6.8 phosphate buffer; 4pH7.4 phosphate buffer
  • tofacitinib citrate reference substance was taken, accurately weighed, dissolved and diluted with a release medium to make a solution containing about 12 ⁇ g of tofacitinib per 1ml, as the reference solution.
  • high performance liquid chromatography generally rule 0512
  • the self-made sustained-release preparation of prescription 11 can release the drug according to the predetermined release rate, the release behavior is less affected by the medium, and the release behavior is basically the same;
  • the formulation 11 with the addition of the release enhancer cyclic oligosaccharide cyclodextrin derivative had a higher release rate than the commercial sustained-release formulation (8-hour release rate 98.87% vs 88.12%).
  • formulation 11 with the addition of the release enhancer cyclic oligosaccharide cyclodextrin derivative had a higher release than the commercial sustained-release formulation (99.4% vs 88.10% release at 8 hours). It can be seen that in a more discriminative dissolution medium, the self-made sustained-release preparation with the addition of a release enhancer has a higher cumulative release rate than the commercial preparation.
  • the simulated intestinal fluid was used to investigate the influence of the food effect of prescription 11.
  • the second method of dissolution and release determination method (general rule 0931) was used, the osmotic pump tablet was placed in the sinker, and 900 mL of different simulated intestinal fluids were used as the release medium (including 1 pH6.8 fasting state simulated intestinal fluid; 2 pH5.0 fed state Simulated intestinal juice, the composition of the two is shown in Table 7), the rotation speed is 50rpm, and the operation is performed according to the law. After 1, 2.5, 4, 6, 8, and 10 h, 5 mL of the solution is taken, and the release medium of the same temperature and the same volume is replenished in time. Take the sample solution, centrifuge (8000rpm, 10min), and take the supernatant as the test solution.
  • tofacitinib citrate reference substance was taken, accurately weighed, dissolved in a release medium and diluted to make a solution containing about 12 ⁇ g of tofacitinib per 1ml, as the reference solution.
  • high performance liquid chromatography generally rule 0512
  • Table 7 Composition of simulated intestinal fluid in fasting state and simulated intestinal fluid in fed state
  • the specification of the present invention is larger than that of the immediate-release preparation.
  • ethanol-phosphate systems with different concentrations were selected to investigate the dose dumping situation of the prescription 11 of the present invention.
  • the second method of dissolution and release determination method (general rule 0931) was used, the preparation was placed in a sinker, and 900 mL of different simulated intestinal fluids were used as the release medium (including 10% ethanol-pH6.8 buffer; 25% ethanol-pH6 .8 buffer; 320% ethanol-pH6.8 buffer; 440% ethanol-pH6.8 buffer), the speed is 50rpm, operate according to law, after 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0h Take 5 mL of the solution each time, and replenish the release medium with the same temperature and the same volume in time. Take the sample solution, centrifuge (8000rpm, 10min), and take the supernatant as the test solution.
  • tofacitinib citrate reference substance was taken, accurately weighed, dissolved in a release medium and quantitatively diluted to make a solution containing about 12 ⁇ g of tofacitinib per 1ml, as the reference solution.
  • high performance liquid chromatography generally rule 0512
  • the tablet core composition prepared by using the release accelerator of the present invention can achieve good release consistency in different concentrations of ethanol-phosphate system, and the risk of dose dumping is controllable.
  • tofacitinib The solubility of tofacitinib is pH-dependent, and the solubility decreases as the pH increases, and it is very slightly soluble in neutral and weakly alkaline media.
  • more discriminative release conditions were used to investigate the apparent solubility of osmotic pump chip cores prepared by cyclic oligosaccharide cyclodextrin derivatives with different ratios in pH6.8 and pH7.4 buffers, respectively, and their relative solubility.
  • In vitro challenge release behavior of the prepared osmotic pump controlled release tablets In vitro challenge release behavior of the prepared osmotic pump controlled release tablets.
  • Table 8 and Figure 8 show the apparent solubility results of prescription 14-16 tablet cores and commercially available sustained-release preparation tablet cores.
  • the tablet core composition prepared by using the release enhancer of the present invention has improved performance in pH 7.4 and pH 6.8 buffers. Observe solubility.
  • the second method of dissolution and release determination method (general rule 0931) was used, the osmotic pump tablet was placed in the sinker, 100 mL of pH 6.8 phosphate buffer was used as the dissolution medium, and the rotation speed was 50 rpm. At 1.5, 2, 2.5, 3, 4, 6, and 8h, take 3 mL of the solution, and supplement the dissolution medium with the same temperature and volume. Take the sample solution, centrifuge (8000rpm, 10min); accurately measure 1ml of the supernatant, add 8ml of dissolution medium to dilute, shake well, and use it as the test solution.
  • tofacitinib citrate reference substance Another appropriate amount of tofacitinib citrate reference substance was taken, accurately weighed, dissolved in dissolution medium and diluted to make a solution containing about 12 ⁇ g of tofacitinib per 1ml, as the reference solution.
  • high performance liquid chromatography generally rule 0512
  • the two groups of beagle dogs were given commercially available tofacitinib sustained-release tablets (trade name: Xeljanz XR, specification: 11 mg/tablet, dose: 1 tablet) and homemade preparation (self-made formulation: prescription 4, specification: 9.9 mg/tablet) , Dose: 1 tablet).
  • 2 mL of blood was collected from the forelimb vein of each beagle dog. Put it in a heparinized test tube, centrifuge (4° C., 4000 rpm, 10 min), separate the plasma (supernatant), and freeze it at -80° C. until use.
  • the beagle should be prevented from chewing the tablet, and 50mL of pure water should be taken. After administration, observe and record the adverse reactions of each beagle dog after administration.
  • the concentration of tofacitinib in plasma was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • the sample pretreatment and liquid quality conditions were as follows:
  • Plasma sample pretreatment Beagle plasma samples were thawed in a water bath at 37°C and centrifuged (8000rpm, 5min). Take 25 ⁇ l of the supernatant, put it in a 96-well plate, add 25 ⁇ l of radiolabeled tofacitinib ([13C, 15N]) internal standard solution, precipitate the protein with acetonitrile, vortex, centrifuge for 10 min, and take the supernatant for LC - MS/MS analysis, the peak area was quantitatively detected according to the internal standard method.
  • radiolabeled tofacitinib [13C, 15N]
  • Mass spectrometry detection conditions ABSciex Triple Quad TM 6500+ mass spectrometer, APCI ion source, positive ion detection, MRM working mode was used for primary/secondary mass spectrometry analysis; data acquisition: SCIEX Analyst1.6.3. After testing, the pharmacokinetic parameters are shown in Table 10 below, and the results of the blood drug concentration-time curve in beagle dogs are shown in Figure 11.
  • the four groups of beagle dogs were respectively given commercially available tofacitinib sustained-release tablet formulations (trade name: Xeljanz XR, specification: 11 mg/tablet, dose: 1 tablet) and self-made formulations (prescription 14 and prescription 15 in Preparation Example 1). , prescription 16, specification: 11mg/tablet, dosage: 1 tablet).
  • 2 mL of blood was collected from the forelimb vein of each beagle dog. Put it in a heparinized test tube, centrifuge (4° C., 4000 rpm, 10 min), separate out the plasma (supernatant), and freeze it at -80° C. until use.
  • the concentration of tofacitinib in plasma was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). After testing, the pharmacokinetic parameters are shown in Table 11 below, and the results of the blood drug concentration-time curve in Beagle are shown in Figure 12.
  • Table 11 shows that after oral administration of tofacitinib sustained-release tablets for Beagle dogs with preparation 1 (prescription 14, 11 mg/tablet), the peak plasma concentration was 72.4 ng/ml, and the average peak time was 5.2 hours; The peak concentration of (Xeljanz XR, 11mg/tablet) was 68.3ng/ml, and the average peak time was 4.7h; the relative bioavailability of homemade preparation 1 (prescription 14, 11mg/tablet) and the commercial preparation (Xeljanz XR, 11mg/tablet) Degree is 97.5%.
  • Homemade preparation 2 (prescription 15, 11mg/tablet) reached a peak plasma concentration of 78.2ng/ml, with an average peak time of 5.1h; homemade preparation 2 (prescription 15, 11mg/tablet) and commercial preparation (Xeljanz XR, 11mg/tablet) ) compared to the relative bioavailability of 109.0%.
  • the self-made preparation 3 (prescription 16, 11mg/tablet) reached the peak concentration of 86.4ng/ml, and the average peak time was 5.4h; /tablet) compared to the relative bioavailability of 121.8%.
  • the osmotic pump controlled release formulation prepared by using the release enhancer tablet core composition of the present invention has improved performance in pH7.4 and pH6.8 buffers. Observation solubility and drug release behavior, with higher cumulative release.
  • Tofacitinib sustained-release tablet formulation 14 (the dosage of cyclic oligosaccharide cyclodextrin derivatives is 20 wt% of the total weight of the tablet core composition) bioavailability is equivalent to that of the commercially available formulation; formulation 15 (cyclic oligosaccharide ring The relative bioavailability of the dosage of dextrin derivative is 40wt% of the total weight of the tablet core composition) and formulation 16 (the dosage of the cyclic oligosaccharide cyclodextrin derivative is 60wt% of the total weight of the tablet core composition) are 109% and 121.8 respectively %.
  • the tofacitinib sustained-release tablet of the present invention has a higher cumulative release rate, and the active ingredient is tofacitinib. Facitinib has increased absorption in the lower gastrointestinal tract with improved bioavailability.
  • the concentration of tofacitinib in plasma was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). After testing, the pharmacokinetic parameters are shown in Table 12 below, and the blood drug concentration-time curve in Beagle is shown in Figure 13.
  • the sustained-release preparation of the present invention can achieve bioavailability equivalent to the commercially available 5 mg ⁇ 2 when the dose is reduced to 9.9 mg.
  • the osmotic tablet core composition prepared by the tofacitinib and the release accelerator of the present invention has improved drug release behavior; in addition, the cyclic oligosaccharide cyclodextrin derivative has good compatibility with the raw and auxiliary materials of tofacitinib , the drug release stability is good.
  • the sustained-release preparation of tofacitinib prepared by using the osmotic core composition comprising a release enhancer can improve the absorption of the active ingredient in the gastrointestinal tract, increase and improve the in vivo exposure of tofacitinib, and has improved bioavailability.

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Abstract

本发明涉及一种托法替布或其盐的缓释制剂，其结构组成上由内至外依次包括: 含有释放促进剂的渗透片芯组合物、控释衣，和非必须的美学外衣，其中，基于片芯组合物的总重量，所述片芯组合物包含药物活性成分 6.4wt ％～ 16wt ％，释放促进剂 20wt ％～ 77wt ％，渗透压促进剂 0 ～ 56wt ％，粘合剂16wt ％～ 50wt ％，以及其他药学辅料 0.5wt ％～ 7wt ％，所述释放促进剂为环状低聚糖环糊精衍生物。采用包含释放促进剂的渗透片芯组合物制备的托法替布缓释制剂，可提升托法替布体内暴露量，具有改进的生物利用度。

Description

一种托法替布或其盐的缓释制剂及其制备方法 技术领域
本发明涉及药物制剂领域，特别涉及药物缓释制剂领域，具体涉及一种托法替布或其盐的缓释制剂及其制备方法。
背景技术
类风湿性关节炎(Rheumatoid Arthritis，RA)是一种常见的慢性、炎性、系统性自身免疫性疾病，也被称作“不死的癌症”。RA在临床上的病理特征，主要表现为三个方面：①关节局部炎症细胞浸润引发慢性炎症；②关节滑膜细胞浸润生长导致滑膜增厚；③骨侵蚀和软骨组织受损，导致关节畸形和功能丧失。
RA的发病机制目前尚不明确，推测其是受抗原所驱动的“激发-连锁”反应。流行病学调查显示，RA的全球发病率为0.5％～1％，中国地区发病率为0.42％，总患病人群约500万，男女患病比率约为1:4。我国RA患者在病程1～5年、5～10年、10～15年及≥15年的致残率分别为18.6％、43.5％、48.1％、61.3％。
如果在病变的早期没有及时、合理地进行治疗，随着疾病进展会侵犯全身各部关节，造成肌肉萎缩关节变形，患者生活无法自理，关节受损多的患者需卧床，无法工作学习，生活极度痛苦。RA不仅造成患者身体机能、生活质量和社会参与度下降，也给患者家庭和社会带来巨大的经济负担。尽管类风湿关节炎(RA)无法根治，但可采取各种积极有效的治疗，在一定时间内将炎症或病情活动度降至较低水平或达到临床缓解。
临床上常用的RA治疗药物包括非甾体抗炎药(NASIDs)、改善病情的抗风湿药物(DMARDs)、糖皮质激素(GCs)、生物制剂和靶向小分子药物等五大类。RA患者中70％为中重度患者，各国指南推荐以甲氨蝶呤为主的抗风湿药治疗为一线治疗方案。部分对DMARDs应答不足或不耐受治疗依从性差的患者，可选择与生物制剂或者靶向联用治疗。然而，由于甲氨蝶呤对于RA的治疗停药率高，导致治疗有效率低于60％；而接受阿达木单抗、依那西普、英利昔单抗等生物制剂治疗的患者中仍有28～41％的患者疗效不佳，对DMARDs应答不足或不耐受治疗依从性差的患者，可选择用生物制剂或者靶向小分子药物治疗。
有研究证实，在早期RA患者中，达标治疗可以比常规治疗更好地、更早地控制疾病，显著改善患者预后，有助于患者尽早回归工作和各类社会活动，总体提升患者生活质量。
类风湿关节炎的治疗是一个长期甚至终身的漫长过程，患者在确诊后需要进行生活方式调整，患者的治疗依从性与疾病的快速缓解和达标有密切关系，给药途径也是影响患者依从性的重要因素之一。有研究显示，39％的患者对注射治疗的依从性较差，79％的类风湿关节炎患者更愿意选择口服治疗。
JAK抑制剂作为新型机制的口服小分子靶向药物，其有效性和安全性与生物制剂相似，但价格更便宜，口服给药可显著提高患者治疗依从性。
托法替布(Tofacitinib)，又称托法替布，与柠檬酸形成稳定的柠檬酸盐结晶，该特性使其适用于口服给药。柠檬酸托法替布化学名称为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:枸橼酸盐(1:1)，分子式为C 16H 20N 6O C 6H 8O 7，游离碱分子量为312.4，枸橼酸盐分子量为504.5，具有下述化学结构：
Figure PCTCN2021107748-appb-000001
托法替布是一种Janus激酶(JAK)抑制剂，该药物与JAK蛋白结合，在胞内抑制JAK信号通路，阻止STAT的磷酸化，进而直接或间接抑制包括IL-2、IL-7、IL-6、IL-9、IL-15、IL-21、TNF-α、IL-17等多个细胞因子的产生及促炎作用，缓解与RA相关的炎症反应，以达到治疗RA的目的。
JAK家族有4个成员JAK1、JAK2、JAK3和TYK2，JAK缺陷或抑制会对身体产生一定程度的影响。JAK2与炎症相关性最小，JAK2抑制会导致血液相关不良反应，包括贫血、血小板降低等。在RA等炎症相关疾病治疗中，JAK抑制剂选择性应尽量集中于JAK1/JAK3，减少对JAK2的抑制。同时，对JAK1/JAK3过渡抑制往往使得人体对病原体和癌细胞的识别清除能力减弱，导致炎症相关的不良反应及肿瘤风险增加。
体外试验结果显示，托法替布可有效抑制JAK3(IC 50＝1.6nmol/L)，对JAK1、JAK2和TyK2也有一定抑制作用(IC 50分别为3.2nmol/L、4.1nmol/L、34.0nmol/L)。托法替布对JAK激酶的抑制作用具有较强的选择性。托法替布有效抑制JAK途径相关IL-2引起的人T细胞和混合淋巴细胞增殖(IC 50分别为11nmol/L和87nmol/L)。
在小鼠关节炎模型中，造模3天后通过背部皮下植入微型渗透泵，持续28天泵入托法替布(剂量分别为0mg/kg、1.5mg/kg、5mg/kg和15mg/kg)。结果表明，托法替布可有效抑制爪肿胀(基于临床评价半数有效剂量ED 50为1.5mg/kg/d)。在大鼠佐剂性关节炎模型中，佐剂注射10天后通过微型渗透泵泵入托法替布(每天剂量分别为0mg/kg、1.5mg/kg、5mg/kg和15mg/kg，持续2周)。血浆中性粒细胞和细胞因子IL-17和IL-6随疾病进展显著增加。托法替布15mg/kg剂量显示对降低爪肿胀有良好疗效。
研究显示，托法替布对生物制剂治疗无效的RA患者仍有满意的临床效果，托法替布与甲氨蝶呤合用，治疗效果与阿达木单抗一致，且相对于生物制药具有价格优势，服药方便，患者依从性良好。
基于JAK-STAT信号通路功能和作用机制，JAK抑制剂在较高剂量下，过度抑制靶点，表现出“泛JAK”抑制作用，会损害机体免疫系统，产生脱靶效应；引起系统性感染、 带状疱疹、恶性肿瘤等不良反应。JAK抑制剂的疗效和安全性与其选择性密切相关，其选择性为浓度依赖型，低浓度情况下时，药物选择性高；当药物浓度过高时，选择性减弱。为保证药物的有效性并降低潜在的不良反应，JAK抑制剂给药量需控制在一定范围内。
将托法替布制备成缓释制剂，可更好调控药物的释放行为，减少因血药浓度过高所致的不良反应，提高用药安全性。综合考虑托法替布的理化性质，其口服给药后，在0.5～1小时内血药浓度达峰，清除半衰期约3小时，将托法替布制备成缓释制可延长T max，降低C max，降低给药频率，提高患者用药顺应性。
经专利检索，我们可通过中国专利CN02810817.5、WO01/42246、WO002/096909及WO03/048162详细了解托法替布化合物的制备过程。我们可以通过EP20150810857、WO2017017542A1、CN106606493A、CN104622827A、CN103845302A了解托法替布速释制剂的制备过程。
经专利检索，与托法替布缓释制剂相关的专利包括：托法替布肠溶缓释微丸CN108066319A，托法替布胃溶缓释制剂WO2016IB54833，托法替布缓释片CN103458901B和CN201480015788。
中国专利申请公开说明书CN108066319A公开了一种枸橼酸托法替布肠溶缓释微丸及其制备方法。该发明公开了一种枸橼酸托法替布肠溶缓释微丸及其制备方法，所述的枸橼酸托法替布肠溶缓释微丸含有骨架型含药丸芯和包覆在丸芯上的肠溶性包衣，所述的肠溶缓释微丸具有pH敏感的释药特征。由于最外层采用pH敏感的肠溶包衣层，其肠溶缓释微丸的释药行为受到胃肠道pH值、食物效应等影响较大，个体间差异较大。
WO2016IB54833公开了一种托法替尼缓释口服组合物包括：托法替尼；一种控释聚合物和赋形剂，所述缓释口服组合物还包括外修饰释药涂层胃溶型薄膜外衣(EPO)，具体涵盖剂型包括单层渗透泵，双层渗透泵，凝胶骨架片，储库型片剂。由于托法替布的溶解度存在pH依赖性，所述制剂易出现释药不完全，消化道下段吸收量少等问题。
德国通益制药公司在公开号为CN103458901B专利中公开了用于改进释放的含托法替布的固体口服剂型，其包含：托法替布以及非易蚀材料，选自乙基纤维素，纤维素酯，丙烯酸共聚物，甲基丙烯酸树脂，聚醋酸乙烯酯；具体的制剂形式包含凝胶骨架片，多颗粒给药系统、双层渗透泵控释片。该专利公开了托法替布改进释放剂型的制备方法，但该专利中未公开所述改进制剂的体外释放行为，也未公开所述制剂的体内药动或药效数据，同样地该发明中亦未提及解决消化道下段吸收问题的发明特征和解决方案。
中国专利CN201480015788公开了每日一次的药物剂型，其包含：核，所述核含有11mg或22mg托法替布或等效量的其药学上可接受的盐形式的托法替布和占所述药物剂型重量60～85％的渗透原；以及半透膜包衣，其量为在所述核之前所述核重量的3～30％，所述包衣主要含水不溶性聚合物。所述托法替布缓释制剂存在一定吸收不完全的问题，为了与10mg速释制剂生物等效规格调整至11mg。此外，所述的托法替布缓释制剂采用山梨糖醇作为渗透原制备渗透泵片剂，山梨醇的熔点较低，制备过程需特殊控制湿度，给产品的工业化生产过程带来一定挑战。
综上，鉴于托法替布溶解度随pH值的增加而降低，将托法替布制备缓释制剂存在如下共性问题：通常的缓控释制剂由于药物释放时间的延长，药物在肠道(空肠、回肠、结肠)持续释药过程中，由于消化道下段部位水分逐渐减少，此外托法替布随着pH值升高溶解度显著降低，易导致药物释放不完全，这些因素的共同作用限制托法替布在消化道下段的吸收。因此，有必要通过制剂处方改良，选择适宜的辅料制备托法替布新型缓释制剂，提高口服吸收和生物利用度。
发明内容
本发明的技术目的是提供一种托法替布或其盐的缓释制剂。针对上述新型托法替布缓释制剂的研发和改进需求，以活性成分托法替布和特殊释放促进剂共同制备渗透片芯组合物，原辅料相容性良好，采用该片芯组合物进一步制备托法替布缓释制剂，具有改进的药物释放行为，8小时释药周期内具有更高的累积释放度，进而可改善托法替布的吸收和生物利用度。
一方面，本发明提供一种托法替布或其盐的缓释制剂，其结构组成上由内至外依次包括：
含有释放促进剂的渗透片芯组合物；
控释衣；和
非必须的美学外衣，
基于片芯组合物的总重量，所述片芯组合物包含药物活性成分6.4wt％～16wt％，释放促进剂20wt％～77wt％，渗透压促进剂0～56wt％，粘合剂16wt％～50wt％，以及其他药学辅料0.5wt％～7wt％；其中，所述释放促进剂为环状低聚糖环糊精衍生物。
在具体实施方式中，所述药物活性成分为托法替布，包括托法替布游离碱、托法替布的盐化物，如盐酸盐、苯磺酸盐、枸橼酸盐、硫酸盐等，优选枸橼酸托法替布。所述缓释制剂的剂型为片剂，以托法替布计，剂量规格为8mg/片～24mg/片，优选为8mg/片～11mg/片或16mg/片～24mg/片。
在具体实施方式中，所述的释放促进剂选自β-环糊精、羟丙基-β-环糊精、磺丁基-β-环糊精和羟乙基-β-环糊精中的一种或两种以上的组合；更优选地，选自羟丙基-β-环糊精和磺丁基-β-环糊精中的一种或其组合。所述释放促进剂的用量为片芯组合物总重量的20wt％～77wt％，优选40wt％～70wt％。
所述环状低聚糖环糊精衍生物，分子呈圆台形状，圆台内部疏水，外部连接亲水性取代基，圆台内部和侧链的烷基醚部分能较好地容纳疏水性药物分子，可通过包合作用容纳高度分散的药物，限制成核速率抑制晶体生长，改善表观溶解度，促进药物的吸收以及提高生物利用度的作用。
所述环状低聚糖环糊精衍生物，在水性介质中具有良好的溶解性。本发明人意外地发现通过添加一定比例释放促进剂环状低聚糖环糊精衍生物，可使本发明的托法替布缓释制剂在8小时的释放周期内具有更高的累积释放度。
托法替布的溶解度具有一定的pH依赖性，随着pH值增加，溶解度降低；在pH 1.0介质中溶解度大于28mg/mL，在pH 7.4介质中极微溶解(溶解度约0.20mg/mL)，在不同pH值生理介质范围内溶解度相差约140倍。鉴于托法替布在pH值相对较高和水分相对较少的小肠下段溶解度欠佳，导致药物释放不完全，从而影响药物在肠道下段的吸收。将托法替布和特殊释放促进剂环状低聚糖环糊精衍生物共同制备渗透片芯组合物，可通过环状低聚糖环糊精衍生物的包合作用容纳高度分散的药物，促进药物释放，进一步地可改善托法替布在肠道下段的吸收和生物利用度。
本发明人意外地发现，随着所述环状低聚糖环糊精衍生物用量的增加，自制的托法替布缓释片的相对生物利用度有增加的趋势。如下文实验实施例8证实，托法替布缓释片处方14(环状低聚糖环糊精衍生物用量为片芯组合物总重量20％)的生物利用度与市售制剂等效；处方15(环状低聚糖环糊精衍生物用量为片芯组合物总重量40％)和处方16(环状低聚糖环糊精衍生物用量为片芯组合物总重量60％)的相对生物利用度分别为109％和121.8％；可见，当片芯中环状低聚糖环糊精衍生物用量高于片芯组合物总重量40％时，相同剂量条件下，可改善托法替布吸收和生物利用度。
在具体实施方式中，所述的渗透压促进剂可采用氯化钠、乳糖、甘露醇、山梨醇、葡萄糖、蔗糖、果糖的一种或多种，以及它们的混合物。所述渗透压促进剂的用量为片芯组合物总重量的0％～56wt％。
在具体实施方式中，所述粘合剂选自羟丙纤维素、羟乙基纤维素、羟丙甲纤维素、聚氧乙烯、海藻酸和/或其衍生物、聚维酮、共聚维酮中的一种或者多种；粘合剂可以为本品的释放提供所需粘度。本发明中，粘合剂的用量为片芯组合物总重量的16wt％～50wt％。
在具体实施方式中，所述其他药学辅料选自表面活性剂、着色剂、润滑剂中的一种或者多种。所述其他药学辅料的用量为片芯组合物总重量的0.5wt％～7wt％。
其中，所述表面活性剂可进一步增强和提高活性成分溶解度。所述表面活性剂可选自十二烷基硫酸钠、月桂酸、多库酯钠、苄索氯铵、聚氧乙烯烷基醚、聚氧乙烯蓖麻油衍生物、硬脂酸聚烃氧40、聚氧乙烯硬脂酸酯和泊洛沙姆中的一种或多种。
其中，所述润滑剂可选自硬脂酸、硬脂酸镁、硬脂酸钙、硬脂富马酸钠、单/双山俞酸甘油酯、聚乙二醇-8-山俞酸甘油酯、双硬脂酸甘油酯、微粉硅胶中一种或多种。
其中，所述着色剂可选自氧化铁黄、氧化铁紫、氧化铁红、氧化铁黑中的一种或多种。
本发明的托法替布或其盐的缓释制剂根据需要可包被密封隔离衣，所述密封隔离衣在结构组成上，位于片芯和控释衣之间。通过密封隔离衣用量的调控调整活性成分初期释放度，随着密封隔离衣增重的提高，活性成分释药1h初期释放度有减少的趋势，密封隔离衣对药物平均释放速率未见显著影响。
可通过将密封隔离衣组合物溶于适宜溶剂中，再喷涂到片芯上经干燥形成所述密封隔离衣层。所述密封隔离衣组合物通常包括下列本领域技术人员熟知的材料，例如，选自羟丙甲纤维素、聚维酮、共聚维酮、羟乙基纤维素、羟丙纤维素、聚乙二醇中的一种或多种，以及它们的混合物。所述的典型溶剂包括乙醇、水、异丙醇中的一种或多种或其混合物。基于片芯组合物的总重量，所述密封隔离衣的增重不超过片芯组合物总重量的20wt％，优选为4wt％～15wt％。
所述控释衣是渗透泵控释系统组成的关键，控释衣可使外部的液体(如水或者生物体液)渗透通过，片芯中药物等物质则无法通过。控释衣材料属于半透性材料，具有一定的刚性和柔韧性，常用的控释衣材料选自醋酸纤维素、乙基纤维素、聚丙烯酸树脂中的一种或多种；可通过将半透膜控释衣材料溶于适宜包衣溶剂中，再喷涂到片芯上经干燥形成所述的控释衣。所述的包衣溶剂为醇、酮、水中的一种或多种的混合物。所述片芯包被控释衣后，基于包衣前的片芯组合物总重量，所述控释衣的增重占片芯组合物总重量的5wt％～15wt％，优选为5.5wt％～8.5wt％。
在具体实施方式中，所述控释衣可包含释放速率调节剂或增塑剂；所述释放速率调节剂选自聚维酮、共聚维酮、羟丙基纤维素、聚乙二醇、甘油中的一种或多种。所述控释衣中的释放速率调节剂占控释衣总重量的30wt％～50wt％，优选为35wt％～45wt％。所述增塑剂选自邻苯二甲酸二甲酯、邻苯二甲酸二乙酯、邻苯二甲酸二丁酯、柠檬酸三乙酯、蓖麻油中的一种或多种，所述增塑剂占控释衣总重量的0.1wt％～10wt％，优选为1wt％～5wt％。
在具体实施方式中，所述控释衣包含释药孔，所述释药孔的打孔方法可采用机械或本领域的技术人员所熟知的激光打孔方法进行，对所述释药孔的几何形状没有限制，其可以具有任何几何性状，如圆形、椭圆形、正方形、三角形等，释药孔的孔径为0.2mm～1.0mm，优选为0.4mm～0.8mm。
在具体实施方式中，所述美学外衣可以为制剂提供改良的外观。所述美学外衣由美学外衣层组合物制成。所述美学外衣层组合物包含用于形成美学外衣的包衣粉、及非必需的选自着色剂、增塑剂、遮光剂、抗粘剂等材料中的一种或几种，它们的用量均为本领域技术人员的常规选择。所述用于形成美学外衣的包衣粉为本领域技术人员的常规选择，包括羟丙甲基纤维素、羟丙基纤维素和丙烯酸酯或甲基丙烯酸酯共聚物，欧巴代，但不限于此。所述遮光剂可包括二氧化钛、滑石粉、二氧化硅，以及它们的混合物；所是抗粘剂可包括滑石粉、硬脂酸镁、单硬脂酸甘油酯，以及它们的混合物。
根据本发明的托法替布或其盐的缓释制剂具有可控的释药行为，在预定的时间段内，在符合漏槽条件的释放介质中，其释放行为和释放量可控。当采用中国药典溶出度与释放度测定法第二法装置，37℃条件下pH值为6.8的缓冲溶液900ml中进行释放行为测定时， 1小时内释放量小于药物活性成分总量的13wt％，1～4小时每小时平均释放速率相当于药物活性成分总量的20wt％～30wt％，8小时释放量大于药物活性成分总量的95wt％。
另一方面，本发明提供一种托法替布或其盐的片芯组合物，基于片芯组合物的总重量，所述片芯组合物包含药物活性成分6.4wt％～16wt％，释放促进剂20wt％～77wt％，渗透压促进剂0～56wt％，粘合剂16wt％～50wt％，以及其他药学辅料0.5wt％～7wt％；其中，所述释放促进剂为环状低聚糖环糊精衍生物。
所述药物活性成分、释放促进剂、粘合剂以及其他药学辅料分别如上文所述。
另一方面，本发明提供一种上述托法替布或其盐的缓释制剂的制备方法，所述方法包括如下步骤：
1)制备含药组合物渗透片芯；
2)包被控释衣；
3)对包被控释衣的包衣片打孔；以及
所述方法还任选地包括：在步骤1)和2)之间，包被密封隔离衣，以及在步骤3)之后，进行步骤4)包被美学外衣。
其中，所述含药组合物渗透片芯通过以下方法制备，将药物活性成分和释放促进剂混合，再与粘合剂及其他药学辅料充分混合，通过不同的制剂工艺，得到均匀的片芯组合物。所述制剂工艺可以包括直接粉末混合，或湿法制粒，或热熔挤出等。
本发明提供的托法替布或其盐的片芯组合物具有可控的物理稳定性。在本发明的一个实施例中，托法替布或其盐的缓释制剂加速条件下(40℃、75％RH)放置6个月后药物释放行为与0月一致，稳定性良好。
本发明提供的托法替布或其盐缓释制剂组合物，可通过调控活性成分释药行为，精确调控药物体内JAK酶抑制水平，使其维持在体内JAK酶活性抑制所需的有效浓度水平。可通过精准调控JAK酶活性，避免过度抑制靶点所致的“泛JAK”抑制效应。
再一方面，本发明还提供了所述托法替布或其盐的缓释制剂在制备用于治疗免疫抑制相关疾病的药物中的用途，所述免疫抑制相关疾病包括类风湿关节炎、活动性银屑病关节炎、溃疡性结肠炎、银屑病、克罗恩病、特异性皮炎、强直性脊柱炎。
再一方面，本发明还提供了所述托法替布或其盐的缓释制剂用于治疗免疫抑制相关疾病的方法，包括向有需要的受试者施用药学上有效剂量的所述托法替布或其盐的缓释制剂。
本发明的效果
与现有的托法替布缓释制剂相比，本发明提供的托法替布缓释制剂具有如下优点：
(1)具有改善的药物释放行为，稳定性良好：托法替布和释放促进剂制备的渗透片芯组合物，兼具渗透促进和释放促进作用，通过环状低聚糖环糊精衍生物的包合作用容纳高度分散的药物，具有改善的药物释放行为，可促进活性成分托法替布释药；环状低聚糖环糊精衍生物与托法替布具有良好的原辅料相容性，稳定性良好。
(2)提高生物利用度：采用包含释放促进剂的渗透片芯组合物制备的托法替布缓释制剂，可促进活性成分托法替布在胃肠道吸收，具有提高的生物利用度。
本发明另外的目的、优势及新颖特征将在随后的描述部分中被阐明，且通过以下内容考察部分地将对本领域熟练地技术人员变得显而易见，或通过本发明的实践领会到。
附图说明
图1是本发明的托法替布或其盐的缓释制剂的结构示意图，所述缓释制剂为含有渗透片芯1、密封隔离衣2、控释衣3和美学外衣4的单层渗透泵控释制剂。
图2是制备实施例1中的处方1～处方6的释放曲线(n＝6)。
图3是制备实施例1中的处方7～处方11的释放曲线(n＝6)。
图4是制备实施例1中的处方12～处方16的释放曲线(n＝6)。
图5是制备实施例1中的处方11和市售缓释制剂在不同pH值介质中的释放曲线(n＝6)。
图6是制备实施例1中的处方11在模拟肠液介质中的释放曲线(n＝6)。
图7是制备实施例1中的处方11的剂量倾泻的释放曲线(n＝6)。
图8是制备实施例1中的处方14～16及市售缓释制剂片芯表观溶解度测定结果。
图9是制备实施例1中的处方14～16及市售缓释制剂体外溶出挑战结果(n＝6)。
图10是制备实施例1中的处方4和处方11加速条件下放置前后释放曲线(n＝6)。
图11是比格犬口服市售缓释制剂与本发明的托法替布或其盐的缓释制剂(处方4，规格：9.9mg/片)后的血药浓度-时间曲线。
图12是比格犬口服市售缓释制剂与本发明的托法替布或其盐的缓释制剂(处方14，15和16，规格：11mg/片)后的血药浓度-时间曲线。
图13是比格犬口服速释托法替布片(5mg/片×2)与本发明的托法替布或其盐的缓释制剂(处方4，规格：9.9mg/片)后的血药浓度-时间曲线。
具体实施方式
为了能够更清楚明白地表述本发明的技术内容，以下实施例一般性地记载了本发明所述托法替布或其盐的缓释制剂的制备方法及体内外药物释放行为，所有的百分比均为重量百分比，除非另有说明。
以下实施例是对本发明的具体说明，而不应该认为是对本发明范围的限制，未详细描述的各种过程和方法是本领域人员公知的常规方法。
制备实施例1
1、处方
处方1-16的缓释制剂中各成分的组成如下表1-3中所示。
表1 处方1-6的缓释制剂中各成分的组成
Figure PCTCN2021107748-appb-000002
表2 处方7-11的缓释制剂中各成分的组成
Figure PCTCN2021107748-appb-000003
表3 处方12-16的缓释制剂中各成分的组成
Figure PCTCN2021107748-appb-000004
2、制备方法
本发明的托法替布或其盐的缓释制剂，按照制备工序的先后，包含如下制备步骤：(1)含药组合物和渗透片芯的制备；(2)非必须的密封隔离衣包被；(3)控释衣包被；(4)包衣片打孔；以及可选地，(5)美学外衣包被。
(1)片芯制备
预处理：按照表1中处方1的配比，将原料、辅料分别过60目筛网进行预处理。
称量混合：分别按照上述处方量称取枸橼酸托法替布和环状低聚糖环糊精衍生物，置于料筒中，采用三维混合器(T 2F，Willy A.Bachofen AG Maschinenfabrik)进行混合，转速25rpm，混合10min；再加入处方1的片芯其他组分(硬脂酸镁除外)，转速25rpm，混合30min。
制粒：将上述混合好的片芯混合物，加入高剪切制粒机(HLSH2-6A，中航工业)，剪切5min使充分混匀；再喷入75％的乙醇-水溶液，高剪切制粒，待颗粒粒度约为30目时，停止制粒；干燥，干颗粒过20目筛，整粒；
总混：称取处方量的硬脂酸镁，加入料筒中，转速25rpm，混合3min，备用；
压片：将上述混合均匀的处方1片芯组合物按照处方量，加入至卵形冲模中压制，采用单层压片机(TDP-1，上海华懋)压制成硬度适宜(硬度≥6kg，YZ-20KZ硬度仪，天大天发)的片芯，检验合格的片芯标记为处方1。
(2)密封隔离衣包被
包衣液配制：按照处方1组成，称取处方量隔离衣组合物-羟丙甲纤维素E5，在机械搅拌条件下，加入处方量95％乙醇溶液中，分散混合均匀，再加入处方量水溶液，使溶解，作为密封隔离包衣液。
密封隔离衣包被：取压制好的片芯，置高效包衣锅(Labcoat BT，O’HARA)，用密封隔离包衣液包衣，调整包衣液流量约(4～8mL/min)、雾化压力(0.5bar～0.8bar)、进风温度(45℃～55℃)，包衣锅转速(10～20rpm)；控制好片床物料温度(30℃～40℃)，至预定包衣增重；包衣后的产品在45℃条件下，干燥2小时，除去多余的有机溶剂和水分。
(3)控释衣包被
包衣液配制：按照处方1组成称取处方量半透膜控释衣材料-醋酸纤维素，在机械搅拌条件下，加入到丙酮溶液中，使溶解；称取处方量的衣膜致孔剂-羟丙基纤维素EF，加入到处方量的乙醇和水溶液中，充分搅拌，使溶解；待上述溶液全部溶解后，将上述两种溶液混合均匀，作为半透膜包衣液。
控释衣包被：取包被密封隔离衣的片芯，置高效包衣锅中(Labcoat BT，O’HARA)，用半透膜包衣液包衣，调整包衣液流量(8～12mL/min)、雾化压力(0.5bar～0.8bar)、进 风温度(15℃～30℃)，包衣锅转速(10～20rpm)；控制好片床物料温度(15℃～25℃)，至预定包衣增重；包衣后的产品在45℃条件下，干燥2小时，除去多余有机溶剂和水分。
(4)激光打孔
采用激光打孔机(RC-YW-30，南京瑞驰)，在片剂的顶端打成一个直径约0.6mm的释药孔，打孔的深度以穿透控释衣膜为宜。
(5)美学外衣
包衣液配制：将欧巴代包衣粉分散于水中，使溶解，配制成固含量为5％的美学外衣包衣溶液。
美学外衣包被：打孔后的控释片，置高效包衣锅中(Labcoat BT，O’HARA)，采用上述配制好的欧巴代包衣液进行包衣，至预定包衣增重；60℃条件下，干燥2小时，除去多余的有机溶剂和水分，即得。
处方2-6的缓释制剂的制备方法同上述处方1的缓释制剂的制备方法，不同之处在于，分别采用表1中所示的处方2-6的配方。
处方7-16的缓释制剂的制备方法同上述处方1的缓释制剂的制备方法，不同之处在于，分别采用表2、表3中所示的处方7-16的配方以及未进行包被美学外衣的步骤。
经上述方法制备得到处方1-16。
实验实施例1：处方1～16释放度测定
采用溶出度与释放度测定法(通则0931)第二法装置，将渗透泵片置沉降篮中，以pH6.8磷酸盐缓冲液900mL为释放介质，转速为50rpm，依法操作，经1、2.5、4、6、8、10h时各取溶液5mL，并及时补充相同温度、相同体积的释放介质。取样品溶液，离心(8000rpm，10min)，取上清液作为供试品溶液。另取枸橼酸托法替布对照品适量，精密称定，用释放介质溶解并定量稀释制成每1ml约含托法替布为12μg，作为对照品溶液。按照高效液相色谱法(通则0512)，精密量取上述对照品溶液和供试品溶液各10μl注入液相色谱仪，记录峰面积，按外标法以峰面积计算每片在不同时间的累积释放量。
高效液相色谱条件：用十八烷基硅烷键合硅胶为填充剂；以乙腈-0.2％高氯酸水溶液(17.5：82.5)为流动相；检测波长：290nm；柱温：40℃；流速：1.0ml/min。
结果：处方1～处方6释放曲线见表4及图2，处方7～处方11释放曲线见表5和图3，处方12～处方16的释放曲线见表6及图4。
表4 处方1～处方6释放度测定结果
Figure PCTCN2021107748-appb-000005
表5 处方7～处方11释放度测定结果
Figure PCTCN2021107748-appb-000006
表6 处方12～处方16释放度测定结果
Figure PCTCN2021107748-appb-000007
实验实施例2：处方11和市售缓释制剂在不同pH值介质中的释放行为比较
由于不同pH值条件下药物的溶解度、控制药物释放行为的关键辅料的水化、溶胀、溶蚀速度可能有所不同。因此，对制备实施例1中的处方11和市售缓释制剂在不同pH值的释放介质中的药物释放行为进行考察。
采用溶出度与释放度测定法(通则0931)第二法装置，将渗透泵片置沉降篮中，以不同pH值的释放介质900mL(包括①pH1.2盐酸溶液；②pH4.5磷酸盐缓冲液；③pH6.8磷酸盐缓冲液；④pH7.4磷酸盐缓冲液)，转速为50rpm，依法操作，经1、2.5、4、6、8、10h时各取溶液5mL，并及时补充相同温度、相同体积的释放介质。取样品溶液，离心(8000rpm，10min)，取上清液作为供试品溶液。另取枸橼酸托法替布对照品适量，精密称定，用释放介质溶解稀释制成每1ml约含托法替布12μg的溶液，作为对照品溶液。按照高效液相色谱法(通则0512)，精密量取上述对照品溶液和供试品溶液各10μl注入液相色谱仪，记录峰面积，按外标法以峰面积计算每片在不同时间的累积释放量。
高效液相色谱条件：同实验实施例1中的液相条件。
结果：处方11和市售缓释制剂在不同pH值的释放介质中的释放曲线见图5。
从图5中可以看出，在pH1.2和pH4.5释放介质中，处方11的自制缓释制剂可按照预定的释放速率释放药物，释放行为受介质的影响较小，释放行为基本一致；在pH6.8介质中，添加释放促进剂环状低聚糖环糊精衍生物的处方11相对于市售缓释制剂释放具有更高的释放度(8小时释放度98.87％vs 88.12％)。同样地，在pH7.4介质中，添加释放促进剂环状低聚糖环糊精衍生物的处方11相对于市售缓释制剂释放度更高(8小时释放度99.4％vs 88.10％)。可见，在更具区分力的溶出介质中，添加释放促进剂的自制缓释制剂相对于市售制剂具有更高的累积释放度。
实验实施例3 处方11在模拟肠液(空腹和进食状态)中的释放度比对
为更好地评价本发明中药物释放特征受食物效应的影响情况，采用模拟肠液考察处方11的食物效应影响情况。
采用溶出度与释放度测定法(通则0931)第二法装置，将渗透泵片置于沉降篮中，以不同模拟肠液900mL为释放介质(包括①pH6.8空腹状态模拟肠液；②pH5.0进食状态模拟肠液，两者组成参见表7)，转速为50rpm，依法操作，经1、2.5、4、6、8、10h时各取溶液5mL，并及时补充相同温度、相同体积的释放介质。取样品溶液，离心(8000rpm，10min)，取上清液作为供试品溶液。另取枸橼酸托法替布对照品适量，精密称定，用释放介质溶解并稀释制成每1ml约含托法替布12μg的溶液，作为对照品溶液。按照高效液相色谱法(通则0512)，精密量取上述对照品溶液和供试品溶液各10μl注入液相色谱仪，记录峰面积，按外标法以峰面积计算每片在不同时间的累积释放量。
高效液相色谱条件：同实验实施例1中的液相条件。
表7 空腹状态模拟肠液和进食状态模拟肠液组成
Figure PCTCN2021107748-appb-000008
结果：处方11在模拟肠液中的释放曲线见图6。
由图6中可见，在空腹和进食模拟肠液条件下，药物体外释放行为未见明显差异。
实验实施例4 处方11剂量倾泻实验
本发明的规格较速释制剂大，为更好地检测本品发生剂量倾泻的可控性，选择不同浓度的乙醇-磷酸盐体系分别对本发明处方11的剂量倾泻情况进行考察。
采用溶出度与释放度测定法(通则0931)第二法装置，将制剂置于沉降篮中，以不同模拟肠液900mL为释放介质(包括①0％乙醇-pH6.8缓冲液；②5％乙醇-pH6.8缓冲液；③20％乙醇-pH6.8缓冲液；④40％乙醇-pH6.8缓冲液)，转速为50rpm，依法操作，经0.25,0.5,0.75,1.0,1.25,1.5,1.75,2.0h时各取溶液5mL，并及时补充相同温度、相同体积的释放介质。取样品溶液，离心(8000rpm，10min)，取上清液作为供试品溶液。另取枸橼酸托法替布对照品适量，精密称定，用释放介质溶解并定量稀释制成每1ml约含托法替布12μg的溶液，作为对照品溶液。按照高效液相色谱法(通则0512)，精密量取上述对照品溶液和供试品溶液各10μl注入液相色谱仪，记录峰面积，按外标法以峰面积计算每片在不同时间的累积释放量。
高效液相色谱条件：同实验实施例1中的液相条件。
结果：处方11在不同乙醇含量的释放介质中的释放曲线见图7。
从图7中可见，采用本发明的释放促进剂制备的片芯组合物，在不同浓度的乙醇-磷酸盐体系中可实现良好的释放一致性，发生剂量倾泻的风险可控。
实验实施例5：片芯表观溶解度与体外释放挑战
托法替布的溶解度具有pH依赖性，随着pH值增加溶解度降低，在中性和弱碱性介质中呈极微溶解状态。本实验中采用更具有区分力的释放条件，分别在pH6.8和pH7.4缓冲液中，考察不同比例环状低聚糖环糊精衍生物制备渗透泵片芯的表观溶解度，及其所制备的渗透泵控释片的体外挑战释放行为。
①表观溶解度
分别取上述托法替布原料药、处方14～16片芯及市售缓释片10片，去除衣膜研磨粉碎后，分别加入10ml体积pH7.4、pH6.8缓冲液中，在37℃，100rpm条件下，平衡24小时，离心，取上清液，照实验实施例1中的液相条件测定。
结果：处方14～16片芯及市售缓释制剂片芯表观溶解度结果见表8和图8。
表8 处方14～16片芯组合物及市售缓释制剂片芯组合物表观溶解度
Figure PCTCN2021107748-appb-000009
从表8及图8结果可见，采用本发明的释放促进剂——环状低聚糖环糊精衍生物制备的片芯组合物，在pH7.4和pH6.8缓冲液中具有改进的表观溶解度。
②体外释放挑战
采用溶出度与释放度测定法(通则0931)第二法装置，将渗透泵片置于沉降篮中，以pH6.8磷酸盐缓冲液100mL为溶出介质，转速为50rpm，依法操作，经1、1.5、2、2.5、3、4、6、8h时各取溶液3mL，并补充相同温度、相同体积的溶出介质。取样品溶液，离心(8000rpm，10min)；精密量取上清液1ml，加8ml溶出介质稀释，摇匀，作为供试品溶液。另取枸橼酸托法替布对照品适量，精密称定，用溶出介质溶解并稀释制成每1ml约含托法替布12μg的溶液，作为对照品溶液。按照高效液相色谱法(通则0512)，精密量取上述对照品溶液和供试品溶液各10μl注入液相色谱仪，记录峰面积，按外标法以峰面积计算每片在不同时间的累积释放量。
高效液相色谱条件：同实验实施例1液相条件。
结果：处方14～处方16和市售缓释制剂，分别在100ml pH6.8介质的体外释放挑战实验的释放结果见表9，释放曲线见图9。
表9 处方14～处方16及市售缓释制剂释放度测定结果
Figure PCTCN2021107748-appb-000010
由释放曲线可见，当采用挑战性更具区分力的pH6.8溶出介质100ml条件下，自制制剂处方14～16相对于市售制剂，具有改进的药物释放行为，更高的累积释放度；其中，处方16在8小时释放度相对于市售制剂提高约10％(96.25％vs 86.66％)。
实验实施例6：处方4、处方11稳定性研究
将上述处方4、处方11的缓释制剂在40±2℃，75％±5％RH加速条件下放置6个月，分别采用实验实施例1所述的释放度条件和液相检测方法测定药物的释放行为(n＝6)，并绘制释放曲线(图10)。
由图10的结果可见，本发明的处方4和处方11缓释制剂药物释放平稳，释放度稳定性良好。
实验实施例7：比格犬体内药动学研究1
健康比格犬12只，体重范围8～10kg，随机分成2组，每组6只。实验前，所有比格犬均提前禁食12h，可自由取水。
两组比格犬分别给予市售托法替布缓释片(商品名：Xeljanz XR，规格：11mg/片，剂量：1片)及自制制剂(自制制剂：处方4，规格：9.9mg/片，剂量：1片)。每只比格犬在服药前(0h)、服药后0.5、1、2、3、4、6、8、10、12、24、36、48小时，分别在犬一侧前肢静脉取血2mL，置肝素化试管中，离心(4℃，4000rpm，10min)，分离血浆(上清)，置于-80℃冻存，待用。
给药过程中，应防止比格犬将药片嚼碎，50mL纯水送服。给药后，注意观察并记录每只比格犬在服药后的不良反应。
采用液相色谱-串联质谱法(LC-MS/MS)测定血浆中托法替布的浓度，样品预处理及液质条件如下：
血浆样品预处理：比格犬血浆样品置37℃水浴条件下解冻，离心(8000rpm，5min)。取上清液25μl，置96孔板中，加入25μl放射性标记的托法替布([13C，15N])内标溶液，用乙腈沉蛋白，涡旋震荡，离心10min，取上清液进行LC-MS/MS分析，峰面积按照内标法定量检测。
色谱分离条件：Venusil MP C18色谱柱(4.6×100mm，5μm 110A)；柱温30℃；以10mM醋酸铵水溶液含0.1％甲酸为流动相A，乙腈为流动相B，采用流动相A：流动相B＝50:50等度洗脱方式；流速0.6ml/min，进样量8μl。
质谱检测条件：采用AB Sciex Triple Quad TM 6500+质谱，APCI离子源，正离子检测，选择MRM工作方式进行一/二级质谱分析；数据采集：SCIEX Analyst1.6.3。经检测，药动学参数见下表10，比格犬体内血药浓度-时间曲线结果见图11。
表10 市售托法替布缓释片与本发明的缓释制剂在比格犬中的药动学参数(n＝6)
Figure PCTCN2021107748-appb-000011
由表10数据可见，比格犬口服托法替布缓释片自制制剂(处方4，9.9mg/片)血药达峰浓度80.0ng/ml，平均达峰时间5.0h；市售制剂(Xeljanz XR，11mg/片)达峰浓度65.9ng/ml，平均达峰时间4.6h；自制制剂(处方4，9.9mg/片)与市售制剂(Xeljanz XR，11mg/片)相比，相对生物利用度为108.5％。
由上表10及图11中可见，制备实施例1处方4环状低聚糖环糊精衍生物的添加，药物8小时累积释放度98.87％，活性成分托法替布在胃肠道下段吸收增加。因此，自制缓释制剂可在剂量减至9.9mg达到与市售11mg制剂等效的生物利用度。
实验实施例8：比格犬体内药动学研究2
健康比格犬12只，体重范围8～10kg，随机分成4组，每组3只。实验前，所有的比格犬提前禁食12h，可自由取水。
四组比格犬分别给予市售托法替布缓释片制剂(商品名：Xeljanz XR，规格：11mg/片，剂量：1片)及自制制剂(制备实施例1中的处方14、处方15、处方16，规格：11mg/片，剂量：1片)。每只比格犬在服药前(0h)、服药后0.5、1、2、3、4、6、8、10、12、24、36、48小时，分别在犬一侧前肢静脉取血2mL，置肝素化试管中，离心(4℃，4000rpm，10min)，分离出血浆(上清)，置于-80℃冻存，待用。
采用液相色谱-串联质谱法(LC-MS/MS)测定血浆中托法替布的浓度。经检测，药动学参数见下表11，比格体内血药浓度-时间曲线结果见图12。
表11 市售托法替布缓释片与自制缓释制剂比格犬口服药动学结果(n＝3)
Figure PCTCN2021107748-appb-000012
表11数据显示，比格犬口服托法替布缓释片自制制剂1(处方14，11mg/片)后，血药达峰浓度72.4ng/ml，平均达峰时间5.2h；口服市售制剂(Xeljanz XR，11mg/片)的达峰浓度68.3ng/ml，平均达峰时间4.7h；自制制剂1(处方14，11mg/片)与市售制剂(Xeljanz XR，11mg/片)相对生物利用度为97.5％。
自制制剂2(处方15，11mg/片)血药达峰浓度78.2ng/ml，平均达峰时间5.1h；自制制剂2(处方15，11mg/片)与市售制剂(Xeljanz XR，11mg/片)相比相对生物利用度为109.0％。
自制制剂3(处方16，11mg/片)血药达峰浓度为86.4ng/ml，平均达峰时间为5.4h；自制制剂3(处方16，11mg/片)与市售制剂(Xeljanz XR，11mg/片)相比相对生物利用度为121.8％。
由上述实验实施例5片芯表观溶解度与体外释放挑战可知，采用本发明的释放促进剂片芯组合物制备的渗透泵控释制剂，在pH7.4和pH6.8缓冲液中具有改进表观溶解度和药物释放行为，具有更高的累积释放度。
制备实施例1处方14、处方15、处方16，随着环状低聚糖环糊精衍生物在片芯组合物总重量的增加，自制托法替布缓释片相对生物利用度有增加的趋势。托法替布缓释片处方14(环状低聚糖环糊精衍生物用量为片芯组合物总重量20wt％)生物利用度与市售制剂等效；处方15(环状低聚糖环糊精衍生物用量为片芯组合物总重量40wt％)和处方16(环状低聚糖环糊精衍生物用量为片芯组合物总重量60wt％)相对生物利用度分别为109％和121.8％。可见，随着释放促进剂环状低聚糖环糊精衍生物用量的增加，表观溶解度提高，在具有区分力的溶出介质中具有更高的累积释放度。更为重要的是，当环状低聚糖环糊精衍生物用量高于40％时，相同剂量条件下，本发明的托法替布缓释片具有更高的累积释放度，活性成分托法替布在胃肠道下段吸收增加，具有改进的生物利用度。
实验实施例9：比格犬体内药动学研究3
健康比格犬12只，体重范围8～10kg，随机分成2组，每组6只。实验前，所有的比格犬提前禁食12h，可自由取水。
两组比格犬分别给予市售托法替布速释片制剂(商品名：Xeljanz，规格：5mg/片，剂量：2片，间隔12h给药1片)及自制制剂(制备实施例1中的处方4规格：9.9mg/片， 剂量：1片)。每只比格犬在服药前(0h)、服药后0.5、1、2、3、4、6、8、10、12、(12.5、13.0、14.0、15.0、16.0、18.0、22.0、24、36、48小时，分别在犬一侧前肢静脉取血2mL，置肝素化试管中，离心(4℃，4000rpm，10min)，分离出血浆(上清)，置于-80℃冻存，待用。
采用液相色谱-串联质谱法(LC-MS/MS)测定血浆中托法替布的浓度。经检测，药动学参数见下表12，比格体内血药浓度-时间曲线见图13。
表12 市售托法替布速释片与自制缓释制剂比格犬口服药动学结果(n＝6)
Figure PCTCN2021107748-appb-000013
结果表明，比格犬口服托法替布缓释片自制制剂(9.9mg/片)后，血药达峰浓度79.6ng/ml，平均达峰时间6.0h；口服托法替布速释制剂(Xeljanz，5mg/片×2)犬达峰浓度73.6ng/ml，平均达峰时间0.5h；自制制剂(9.9mg/片)与市售制剂(Xeljanz，5mg/片×2)相比相对生物利用度为108.8％。本发明的缓释制剂可在剂量减至9.9mg达到与市售5mg×2等效的生物利用度。
本发明托法替布和释放促进剂制备的渗透片芯组合物，具有改良的药物释放行为；此外，环状低聚糖环糊精衍生物与托法替布具有良好的原辅料相容性，药物释放稳定性良好。采用包含释放促进剂的渗透片芯组合物制备的托法替布缓释制剂，可改善活性成分在胃肠道吸收，提升和改善托法替布体内暴露量，具有改进的生物利用度。
本发明的目的已完整并有效的予以实现。本发明的功能及结构原理已在实施例中予以展示和说明。

Claims (12)

  1. 一种托法替布或其盐的缓释制剂，其结构组成上由内至外依次包括：
    含有释放促进剂的渗透片芯组合物；
    控释衣；和
    非必须的美学外衣，
    其中，基于片芯组合物的总重量，所述片芯组合物包含药物活性成分6.4wt％～16wt％，释放促进剂20wt％～77wt％，渗透压促进剂0～56wt％，粘合剂16wt％～50wt％，以及其他药学辅料0.5wt％～7wt％；并且
    其中，所述释放促进剂为环状低聚糖环糊精衍生物。
  2. 根据权利要求1所述的缓释制剂，其中，所述药物活性成分包括托法替布游离碱、托法替布的盐化物，如盐酸盐、苯磺酸盐、枸橼酸盐、硫酸盐，优选枸橼酸托法替布，并且
    所述缓释制剂的剂型为片剂，以托法替布计，所述缓释制剂的剂量规格为8.0mg/片～24mg/片，优选为8.0mg/片～11mg/片或16mg/片～24mg/片。
  3. 根据权利要求1所述的缓释制剂，其中，所述释放促进剂选自β-环糊精、羟丙基-β-环糊精、磺丁基-β-环糊精和羟乙基-β-环糊精中的一种或两种以上的组合，更优选地，选自羟丙基-β-环糊精和磺丁基-β-环糊精中的一种或其组合，并且所述释放促进剂的用量为片芯组合物总重量的20wt％～77wt％，优选40wt％～70wt％。
  4. 根据权利要求1所述的缓释制剂，其中，所述渗透压促进剂可采用氯化钠、乳糖、甘露醇、山梨醇、葡萄糖、蔗糖、果糖的一种或多种。
  5. 根据权利要求1所述的缓释制剂，其中，所述粘合剂选自羟丙纤维素、羟乙基纤维素、羟丙甲纤维素、聚氧乙烯、海藻酸和/或其衍生物、聚维酮、共聚维酮的一种或多种。
  6. 根据权利要求1所述的缓释制剂，其中，所述其他药学辅料选自表面活性剂、助流剂、着色剂、润滑剂中的一种或者多种。
  7. 根据权利要求1所述的缓释制剂，其中，在所述片芯组合物和所述控释衣之间还包括密封隔离衣，所述密封隔离衣包含选自羟丙甲纤维素、聚维酮、共聚维酮、羟乙基纤维素、羟丙纤维素、聚乙二醇中的一种或多种，并且
    基于片芯组合物的总重量，所述密封隔离衣的增重不超过片芯组合物总重量的20wt％，优选为4wt％～15wt％。
  8. 根据权利要求1所述的缓释制剂，其中，所述控释衣包含醋酸纤维素、乙基纤维素、聚丙烯酸树脂中的一种或多种；并且
    基于片芯组合物总重量，所述控释衣的增重占片芯组合物总重量的5wt％～15wt％，优选为5.5wt％～8.5wt％。
  9. 根据权利要求1所述的缓释制剂，其中，所述控释衣包含释放速率调节剂或增塑剂，
    其中，所述释放速率调节剂选自聚维酮、共聚维酮、羟丙基纤维素、聚乙二醇、甘油中的一种或多种，并且所述控释衣中的释放速率调节剂占所述控释衣总重量的30wt％～50wt％，优选为35wt％～45wt％；
    其中，所述增塑剂选自邻苯二甲酸二甲酯、邻苯二甲酸二乙酯、邻苯二甲酸二丁酯、柠檬酸三乙酯、蓖麻油中的一种或多种，并且所述增塑剂占所述控释衣总重量的0.1wt％～10wt％，优选为1wt％～5wt％。
  10. 根据权利要求1所述的缓释制剂，其中，所述控释衣包含释药孔，并且，所述释药孔的孔径为0.2mm～1.0mm，优选为0.4mm～0.8mm。
  11. 根据权利要求1所述的缓释制剂，其中，当采用中国药典溶出度与释放度测定法第二法装置，37℃条件下pH值为6.8的缓冲溶液900ml中进行释放行为测定时，所述缓释制剂1小时内释放量小于药物活性成分总量的13wt％，1～4小时每小时平均释放速率相当于药物活性成分总量的20wt％～30wt％，8小时释放量大于药物活性成分总量的95wt％。
  12. 一种如权利要求1至11任一项所述的托法替布或其盐的缓释制剂的制备方法，所述方法包括如下步骤：
    1)制备含药组合物渗透片芯；
    2)包被控释衣；
    3)对包被控释衣的包衣片打孔；以及
    所述方法还任选地包括：在步骤1)和2)之间，包被密封隔离衣，以及在步骤3)之后，进行步骤4)：包被美学外衣。
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