CN115381788B - Tofacitinib citrate preparation and preparation method thereof - Google Patents

Tofacitinib citrate preparation and preparation method thereof Download PDF

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CN115381788B
CN115381788B CN202211137244.5A CN202211137244A CN115381788B CN 115381788 B CN115381788 B CN 115381788B CN 202211137244 A CN202211137244 A CN 202211137244A CN 115381788 B CN115381788 B CN 115381788B
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tofacitinib citrate
preparation
sieving
adhesive
mixing
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CN115381788A (en
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陆红彬
樊超
杨颖栋
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Suzhou Homesun Pharmaceutical Co ltd
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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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

Abstract

The invention provides a tofacitinib citrate preparation and a preparation method thereof, belonging to the field of preparations of rheumatoid arthritis medicines. The tofacitinib citrate preparation comprises tofacitinib citrate and pharmaceutically or pharmacologically acceptable auxiliary materials. The auxiliary materials comprise a diluent, an adhesive, a disintegrating agent, an antioxidant, a polyol, a lubricant and coating powder.

Description

Tofacitinib citrate preparation and preparation method thereof
Technical Field
The invention relates to the field of preparations of rheumatoid arthritis medicines, in particular to a tofacitinib citrate preparation and a preparation method thereof.
Background
Tofacitinib citrate, chemical name: (3R, 4R) -4-methyl-3- (methyl-7H-pyrrolo [2, 3-d)]Pyrimidin-4-ylamino) -beta-oxo-1-piperidinepropionitrile citrate of formula: c (C) 16 H 20 N 6O ·C 6 H 8 O 7 Molecular weight: 504.5 is white to off-white crystalline in shape, is secreted, is readily soluble in DMSO, is slightly soluble in water and methanol, and is insoluble in acetonitrile. The structural formula is as follows:
Figure BDA0003852629370000011
the use of tofacitinib citrate (trade name: XELJANZ) in month 11 in 2012 and of the FDA approval of the same indications as XelJANZ for the treatment of patients suffering from moderate to severe adult RA who have an inadequate or intolerant response to methotrexate in the United states in 2016 has been successfully developed as a novel JA inhibitor, namely tofacitinib citrate (5 mg/tablet) and tofacitinib citrate controlled release tablet (11 mg/tablet), orally for the treatment of rheumatoid arthritis. Wherein the inactive ingredients in the tofacitinib citrate tablet comprise sorbitol, hydroxyethyl cellulose, magnesium stearate, cellulose acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and titanium dioxideGlycerol triacetate, and iron oxide red.
Rheumatoid arthritis (Rheumatoid arthritis, RA) is a chronic autoimmune disease with high clinical morbidity and disability rate, and its main pathological feature is chronic progressive synovitis, which can occur at any age. RA clinically causes a variety of symptoms, which are mainly manifested by multi-joint, symmetrical, invasive joint inflammation of the hand and foot facet joints, often accompanied by involvement of extra-articular organs with positive serum rheumatoid factors, leading to joint deformity and loss of function.
In the prior art, the process is complex, and the following steps are needed: mixing part of auxiliary materials, granulating by wet method, finishing, mixing the wet granules with most of auxiliary materials, adding lubricant, mixing, tabletting and coating. After wet granulation, a large amount of auxiliary materials are added to improve the fluidity so as to be capable of tabletting; meanwhile, because the physical property difference between the particles and the powder of the externally added auxiliary materials is large, the problems of difficult uniformity during mixing and large compression deformation difference during tabletting exist. Moreover, the controlled release preparation requires a large dosage to achieve a long-acting effect, and the release of the drug has a plurality of unpredictability; and the oral medicine needs to be absorbed by intestines and stomach before reaching the focus of treatment, and the onset process is easy to change uncontrollably. Therefore, the action process is uncontrollable whether the preparation is a conventional oral preparation or a sustained and controlled release preparation. Therefore, a novel preparation process for synthesizing tofacitinib citrate is urgently needed.
Chinese patent CN 108066319B discloses a tofacitinib citrate enteric sustained-release pellet and a preparation method thereof. The enteric-coated slow-release pellet of the tofacitinib citrate comprises a skeleton-type pellet-containing core and an enteric coating coated on the pellet core, but has the problems of complex auxiliary materials, complex process flow and the like, so that the slow-release effect of the obtained slow-release tablet is uneven.
Disclosure of Invention
In order to solve the technical problems, the invention provides a tofacitinib citrate preparation and a preparation method thereof. The preparation provided by the invention has the advantages of good dissolution rate, high bioavailability, good slow release effect of drug release, safety, reliability and convenience in use.
The first object of the invention is to provide a tofacitinib citrate preparation, which comprises tofacitinib citrate and pharmaceutically or pharmacologically acceptable auxiliary materials.
In one embodiment of the invention, the mass concentration of the tofacitinib citrate is 30-65%.
In one embodiment of the invention, the pharmaceutically or pharmacologically acceptable excipients comprise diluents, binders, disintegrants, antioxidants, polyols, lubricants and coating powders.
In one embodiment of the invention, the components of each auxiliary material are as follows, in percentage by mass: 20-40% of diluent, 1-2% of binder, 6-10% of disintegrating agent, 0.02-0.09% of antioxidant, 1-5% of polyalcohol, 1-5% of lubricant and 5-20% of coating powder.
In one embodiment of the invention, the components of each auxiliary material are as follows, in percentage by mass: 8-10% of diluent, 1-1.5% of binder, 5-8% of disintegrating agent, 0.05-0.08% of antioxidant, 2-5% of polyalcohol, 1-4% of lubricant and 10-20% of coating powder.
In one embodiment of the invention, the diluent is one or more of microcrystalline cellulose, lactose, starch, and pregelatinized starch.
In one embodiment of the invention, the binder is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
In one embodiment of the invention, the lubricant is magnesium stearate.
In one embodiment of the invention, the coating powder is opadry.
In one embodiment of the present invention, the disintegrant is selected from one or more of croscarmellose sodium, low substituted hydroxypropylcellulose, crospovidone, and sodium carboxymethyl starch.
In one embodiment of the invention, the disintegrant is preferably croscarmellose sodium and/or low substituted hydroxypropyl cellulose.
In one embodiment of the invention, the antioxidant is selected from one or more of sodium metabisulfite, cysteine, leucine, methionine, sodium ascorbate, vitamin E, di-tert-butyl methyl phenol, tert-butyl methoxy phenol or a pharmaceutically acceptable salt thereof.
In one embodiment of the present invention, the antioxidant is preferably one or more of sodium metabisulfite, cysteine, leucine, methionine, sodium ascorbate, and vitamin E.
In one embodiment of the invention, the polyol is selected from propylene glycol or polyethylene glycol; wherein the polymerization degree of the polyethylene glycol is 200-500.
In one embodiment of the present invention, the polyethylene glycol is preferably polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 500.
In one embodiment of the invention, the formulation is in the form of a solid oral pharmaceutical formulation.
In one embodiment of the invention, the solid oral pharmaceutical formulation is a tablet.
The second object of the present invention is to provide a method for preparing the tofacitinib citrate preparation, which comprises the following steps:
(1) Sieving the solid raw materials and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing;
(2) Weighing polyalcohol and tofacitinib citrate according to the parts, mixing, adding the mixture obtained in the step (1), and continuously uniformly mixing and sieving to obtain a mixture;
(3) Wetting the mixture obtained in the step (2) in a wet granulator, adding a prescribed amount of aqueous solution of an adhesive, and uniformly mixing to obtain a soft material;
(4) Sieving, granulating, drying, sieving and finishing the soft material in the step (3), adding the disintegrating agent with the prescription amount and the lubricant with the prescription amount, uniformly mixing, and tabletting to obtain a plain tablet;
(5) And (3) coating the plain tablet in the step (4) by using a coating powder suspension to obtain the tofacitinib citrate preparation.
In one embodiment of the present invention, in step (1), the screen size of the sieving treatment is 15-50 mesh.
In one embodiment of the present invention, in step (1), the screen size of the sieving treatment is 20-30 mesh.
In one embodiment of the present invention, in the step (2), the tofacitinib citrate has a particle size of 5-15 μm.
In one embodiment of the present invention, in the step (2), the tofacitinib citrate has a particle size of 10-15 μm.
In one embodiment of the present invention, in step (2), the sieving screen has a size of 15-60 mesh.
In one embodiment of the present invention, in step (3), the weight percentage of the binder in the aqueous binder solution is 5-8%.
In one embodiment of the present invention, in step (4), the drying temperature is 40 ℃ to 45 ℃.
Compared with the prior art, the technical scheme of the invention has the following advantages:
the alcohol in the polyol can be used for synergistically enhancing the slow release capacity of the tablet with the disintegrating agent, and enhancing the regulation and control of slow release, so that the medicine is slowly released in vivo, the release speed is stable, the biocompatibility is improved, and the action effect of the medicine is improved. And the preparation process is simple, the product is stable, and the industrial mass production is facilitated.
Detailed Description
The present invention will be further described with reference to specific examples, which are not intended to be limiting, so that those skilled in the art will better understand the present invention and practice it.
In the present invention, unless otherwise indicated, the ratio ranges and alternatives of the components in the tofacitinib citrate formulation may be combined with one another to form a new formulation.
In the present invention, the preparation process of the tofacitinib citrate formulation is performed sequentially unless otherwise indicated.
In the present invention, unless otherwise indicated, the preparation of tofacitinib citrate formulations is carried out at ambient temperature and pressure.
The first object of the invention is to provide a tofacitinib citrate preparation, which comprises tofacitinib citrate and pharmaceutically or pharmacologically acceptable auxiliary materials.
In one embodiment of the invention, the mass concentration of the tofacitinib citrate is 30-65%.
In one embodiment of the invention, the pharmaceutically or pharmacologically acceptable excipients comprise diluents, binders, disintegrants, antioxidants, polyols, lubricants and coating powders.
In one embodiment of the invention, the components of each auxiliary material are as follows, in percentage by mass: 20-40% of diluent, 1-2% of binder, 6-10% of disintegrating agent, 0.02-0.09% of antioxidant, 1-5% of polyalcohol, 1-5% of lubricant and 5-20% of coating powder.
In one embodiment of the invention, the polyol is selected from propylene glycol or polyethylene glycol; wherein the polymerization degree of the polyethylene glycol is 200-500.
In one embodiment of the invention, the formulation is in the form of a solid oral pharmaceutical formulation.
In one embodiment of the invention, the solid oral pharmaceutical formulation is a tablet.
The second object of the present invention is to provide a method for preparing the tofacitinib citrate preparation, which is characterized by comprising the following steps:
(1) Sieving the solid raw materials and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing;
(2) Weighing polyalcohol and tofacitinib citrate according to the parts, mixing, adding the mixture obtained in the step (1), and continuously uniformly mixing and sieving to obtain a mixture;
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of aqueous solution of an adhesive, and uniformly mixing to obtain a soft material;
(4) Sieving, granulating, drying, sieving and finishing the soft material in the step (3), adding the disintegrating agent with the prescription amount and the lubricant with the prescription amount, uniformly mixing, and tabletting to obtain a plain tablet;
(5) And (3) coating the plain tablet in the step (4) by using a coating powder suspension to obtain the tofacitinib citrate preparation.
Example 1
The embodiment provides a tofacitinib citrate preparation and a preparation method thereof
The components are as follows: 65g of tofacitinib citrate, 20g of diluent (starch), 1.98g of adhesive (hydroxypropyl cellulose), 6g of disintegrating agent (croscarmellose sodium), 0.02g of antioxidant (cysteine), 1g of polyalcohol (polyethylene glycol 200), 1g of lubricant (magnesium stearate) and 5g of coating powder (opard).
The preparation method comprises the following steps: (1) Sieving the solid raw materials and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen size was 30 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts, mixing, adding the mixture obtained in the step (1), and continuously uniformly mixing and sieving to obtain a mixture; the screen size was 20 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of aqueous solution of an adhesive, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the adhesive aqueous solution is 5%.
(4) Sieving and granulating the soft material in the step (3), drying at 40 ℃, sieving and granulating, controlling the moisture of the granules to be within 5.0% based on the dry matter, adding the disintegrating agent with the prescription amount and the lubricant with the prescription amount, uniformly mixing, and tabletting to obtain a plain tablet; the size of the screened screen was 15 mesh.
(5) And (3) coating the plain tablet in the step (4) by using a coating powder suspension to obtain the tofacitinib citrate preparation.
Example 2
The embodiment provides a tofacitinib citrate preparation and a preparation method thereof
The components are as follows: 55g of tofacitinib citrate, 25g of diluent (microcrystalline cellulose), 1.98g of binder (polyvinylpyrrolidone), 6g of disintegrating agent (sodium carboxymethyl starch), 0.02g of antioxidant (cysteine), 1g of polyalcohol (propylene glycol), 1g of lubricant (magnesium stearate) and 10g of coating powder (opard).
The preparation method comprises the following steps: (1) Sieving the solid raw materials and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen size was 20 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts, mixing, adding the mixture obtained in the step (1), and continuously uniformly mixing and sieving to obtain a mixture; the screen size was 30 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of aqueous solution of an adhesive, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the adhesive aqueous solution is 8%.
(4) Sieving and granulating the soft material in the step (3), drying at 45 ℃, sieving and granulating, controlling the moisture of the granules to be within 2.0% based on the dry matter, adding the disintegrating agent with the prescription amount and the lubricant with the prescription amount, uniformly mixing, and tabletting to obtain a plain tablet; the size of the screened screen was 30 mesh.
(5) And (3) coating the plain tablet in the step (4) by using a coating powder suspension to obtain the tofacitinib citrate preparation.
Example 3
The embodiment provides a tofacitinib citrate preparation and a preparation method thereof
The components are as follows: 65g of tofacitinib citrate, 20g of diluent (pregelatinized starch), 1.98g of binder (hydroxypropyl methylcellulose), 6g of disintegrating agent (sodium carboxymethyl starch), 0.02g of antioxidant (vitamin E), 1g of polyalcohol (propylene glycol), 1g of lubricant (magnesium stearate) and 5g of coating powder (opard).
The preparation method comprises the following steps: (1) Sieving the solid raw materials and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen size was 30 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts, mixing, adding the mixture obtained in the step (1), and continuously uniformly mixing and sieving to obtain a mixture; the screen size was 20 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of aqueous solution of an adhesive, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the adhesive aqueous solution is 5%.
(4) Sieving and granulating the soft material in the step (3), drying at 40 ℃, sieving and granulating, controlling the moisture of the granules to be within 5.0% based on the dry matter, adding the disintegrating agent with the prescription amount and the lubricant with the prescription amount, uniformly mixing, and tabletting to obtain a plain tablet; the size of the screened screen was 15 mesh.
(5) And (3) coating the plain tablet in the step (4) by using a coating powder suspension to obtain the tofacitinib citrate preparation.
Example 4
The embodiment provides a tofacitinib citrate preparation and a preparation method thereof
The components are as follows: 35g of tofacitinib citrate, 40g of diluent (pregelatinized starch), 1.98g of binder (hydroxypropyl cellulose), 10g of disintegrating agent (croscarmellose sodium), 0.09g of antioxidant (sodium metabisulfite), 1g of polyalcohol (polyethylene glycol 400), 1.99g of lubricant (magnesium stearate) and 12g of coating powder (opageneration).
The preparation method comprises the following steps: (1) Sieving the solid raw materials and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen size was 30 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts, mixing, adding the mixture obtained in the step (1), and continuously uniformly mixing and sieving to obtain a mixture; the screen size was 20 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of aqueous solution of an adhesive, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the adhesive aqueous solution is 5%.
(4) Sieving and granulating the soft material in the step (3), drying at 40 ℃, sieving and granulating, controlling the moisture of the granules to be within 5.0% based on the dry matter, adding the disintegrating agent with the prescription amount and the lubricant with the prescription amount, uniformly mixing, and tabletting to obtain a plain tablet; the size of the screened screen was 15 mesh.
(5) And (3) coating the plain tablet in the step (4) by using a coating powder suspension to obtain the tofacitinib citrate preparation.
Example 5
The embodiment provides a tofacitinib citrate preparation and a preparation method thereof
The components are as follows: tofacitinib citrate 50g, diluent 30g (starch), binder (polyvinylpyrrolidone) 1.98g, disintegrating agent (croscarmellose sodium) 10g, antioxidant (cysteine) 0.02g, polyalcohol (polyethylene glycol 200) 2g, lubricant (magnesium stearate) 1g and coating powder (opard) 5g.
The preparation method comprises the following steps: (1) Sieving the solid raw materials and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen size was 15 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts, mixing, adding the mixture obtained in the step (1), and continuously uniformly mixing and sieving to obtain a mixture; the screen size was 20 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of aqueous solution of an adhesive, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the adhesive aqueous solution is 5%.
(4) Sieving and granulating the soft material in the step (3), drying at 40 ℃, sieving and granulating, controlling the moisture of the granules to be within 5.0% based on the dry matter, adding the disintegrating agent with the prescription amount and the lubricant with the prescription amount, uniformly mixing, and tabletting to obtain a plain tablet; the size of the screened screen was 30 mesh.
(5) And (3) coating the plain tablet in the step (4) by using a coating powder suspension to obtain the tofacitinib citrate preparation.
Example 6
The embodiment provides a tofacitinib citrate preparation and a preparation method thereof
The components are as follows: tofacitinib citrate 40g, diluent (lactose) 30g, binder (hydroxypropyl methylcellulose) 1.95g, disintegrating agent (sodium carboxymethyl starch) 10g, antioxidant (leucine) 0.05g, polyalcohol (polyethylene glycol 300) 3g, lubricant (magnesium stearate) 5g and coating powder (opard) 10g.
The preparation method comprises the following steps: (1) Sieving the solid raw materials and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen size was 40 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts, mixing, adding the mixture obtained in the step (1), and continuously uniformly mixing and sieving to obtain a mixture; the screen size was 30 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of aqueous solution of an adhesive, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the adhesive aqueous solution is 5%.
(4) Sieving and granulating the soft material in the step (3), drying at 40 ℃, sieving and granulating, controlling the moisture of the granules to be within 5.0% based on the dry matter, adding the disintegrating agent with the prescription amount and the lubricant with the prescription amount, uniformly mixing, and tabletting to obtain a plain tablet; the size of the screened screen was 15 mesh.
(5) And (3) coating the plain tablet in the step (4) by using a coating powder suspension to obtain the tofacitinib citrate preparation.
Example 7
The embodiment provides a tofacitinib citrate preparation and a preparation method thereof
The components are as follows: 65g of tofacitinib citrate, 20g of diluent (starch), 1.98g of adhesive (hydroxypropyl cellulose), 6g of disintegrating agent (croscarmellose sodium), 0.02g of antioxidant (di-tert-butyl methyl phenol), 1g of polyalcohol (polyethylene glycol 200), 1g of lubricant (magnesium stearate) and 5g of coating powder (opard).
The preparation method comprises the following steps: (1) Sieving the solid raw materials and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen size was 20 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts, mixing, adding the mixture obtained in the step (1), and continuously uniformly mixing and sieving to obtain a mixture; the screen size was 30 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of aqueous solution of an adhesive, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the adhesive aqueous solution is 5%.
(4) Sieving and granulating the soft material in the step (3), drying at 40 ℃, sieving and granulating, controlling the moisture of the granules to be within 5.0% based on the dry matter, adding the disintegrating agent with the prescription amount and the lubricant with the prescription amount, uniformly mixing, and tabletting to obtain a plain tablet; the size of the screened screen was 15 mesh.
(5) And (3) coating the plain tablet in the step (4) by using a coating powder suspension to obtain the tofacitinib citrate preparation.
Comparative example 1 (comparison with example 1, no polyol added)
The embodiment provides a tofacitinib citrate preparation and a preparation method thereof
The components are as follows: 65g of tofacitinib citrate, 20g of diluent (starch), 1.98g of adhesive (hydroxypropyl cellulose), 6g of disintegrating agent (croscarmellose sodium), 0.02g of antioxidant (cysteine), 1g of lubricant (magnesium stearate) and 5g of coating powder (opard).
The preparation method comprises the following steps: (1) Sieving the solid raw materials and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen size was 30 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts, mixing, adding the mixture obtained in the step (1), and continuously uniformly mixing and sieving to obtain a mixture; the screen size was 20 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of aqueous solution of an adhesive, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the adhesive aqueous solution is 5%.
(4) Sieving and granulating the soft material in the step (3), drying at 40 ℃, sieving and granulating, controlling the moisture of the granules to be within 5.0% based on the dry matter, adding the disintegrating agent with the prescription amount and the lubricant with the prescription amount, uniformly mixing, and tabletting to obtain a plain tablet; the size of the screened screen was 15 mesh.
(5) And (3) coating the plain tablet in the step (4) by using a coating powder suspension to obtain the tofacitinib citrate preparation.
Comparative example 2 (comparison with example 1, no disintegrant was added)
The embodiment provides a tofacitinib citrate preparation and a preparation method thereof
The components are as follows: 65g of tofacitinib citrate, 20g of diluent (starch), 1.98g of adhesive (hydroxypropyl cellulose), 0.02g of antioxidant (cysteine), 1g of polyalcohol (polyethylene glycol 200), 1g of lubricant (magnesium stearate) and 5g of coating powder (opard).
The preparation method comprises the following steps: (1) Sieving the solid raw materials and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen size was 30 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts, mixing, adding the mixture obtained in the step (1), and continuously uniformly mixing and sieving to obtain a mixture; the screen size was 20 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of aqueous solution of an adhesive, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the adhesive aqueous solution is 5%.
(4) Sieving and granulating the soft material in the step (3), drying at 40 ℃, sieving and granulating, controlling the moisture of the granules to be within 5.0% based on the dry matter, adding the disintegrating agent with the prescription amount and the lubricant with the prescription amount, uniformly mixing, and tabletting to obtain a plain tablet; the size of the screened screen was 15 mesh.
(5) And (3) coating the plain tablet in the step (4) by using a coating powder suspension to obtain the tofacitinib citrate preparation.
Test case
The release degree was measured for examples 1 to 3 and comparative examples 2 to 3. The specific operation is as follows: samples were taken and subjected to a release assay (second method of four formulations general rule 0931, 2015 edition of Chinese pharmacopoeia) +device of sedimentation basket, and the dissolution medium was 900mL of phosphate buffer solution with pH of 6.8. The experimental results are shown in Table 1.
TABLE 1
Figure BDA0003852629370000131
As can be seen from Table 1, the embodiment of the invention has good release, and can reduce the influence of pH value of intestinal tract on the medicine to a certain extent; and the release degree conditions of the embodiment 1 and the comparative examples 1-2 show that the release degree duration of the tofacitinib citrate tablet is longer, the release degree has larger influence under the condition of lacking the disintegrating agent or the polyalcohol, and the release degree is obviously increased, thereby indicating that the disintegrating agent and the polyalcohol added by the invention can synergistically enhance the slow release speed of the tofacitinib citrate tablet.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations and modifications of the present invention will be apparent to those of ordinary skill in the art in light of the foregoing description. It is not necessary here nor is it exhaustive of all embodiments. And obvious variations or modifications thereof are contemplated as falling within the scope of the present invention.

Claims (3)

1. A method for preparing a tofacitinib citrate preparation, which is characterized by comprising the following steps:
(1) Sieving the solid raw materials and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing;
(2) Weighing polyalcohol and tofacitinib citrate according to the prescription amount, mixing, adding the mixture obtained in the step (1), and continuously uniformly mixing and sieving to obtain a mixture;
(3) Wetting the mixture obtained in the step (2) in a wet granulator, adding a prescribed amount of aqueous solution of an adhesive, and uniformly mixing to obtain a soft material;
(4) Sieving, granulating, drying, sieving and finishing the soft material in the step (3), adding the disintegrating agent with the prescription amount and the lubricant with the prescription amount, uniformly mixing, and tabletting to obtain a plain tablet;
(5) Coating the plain tablet in the step (4) by using coating powder suspension to obtain the tofacitinib citrate preparation;
the components are as follows, in mass percent: 20-40% of diluent, 1-2% of adhesive, 6-10% of disintegrating agent, 0.02-0.09% of antioxidant, 1-5% of polyalcohol, 1-5% of lubricant and 5-20% of coating powder; tofacitinib citrate 30-65%;
the polyhydric alcohol is selected from propylene glycol or polyethylene glycol; wherein the polymerization degree of the polyethylene glycol is 200-500;
the disintegrating agent is one or more selected from croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone and sodium carboxymethyl starch.
2. The method of preparing a tofacitinib citrate formulation according to claim 1, wherein the diluent is one or more of microcrystalline cellulose, lactose, starch and pregelatinized starch; the adhesive is one or two of hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone; the lubricant is magnesium stearate; the coating powder is opard.
3. The method for preparing a tofacitinib citrate formulation according to claim 1, wherein the antioxidant is selected from one or more of sodium metabisulfite, cysteine, leucine, methionine, sodium ascorbate, vitamin E, di-tert-butyl methyl phenol, tert-butyl methoxy phenol or a pharmaceutically acceptable salt thereof.
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