CN115381788A - Tofacitinib citrate preparation and preparation method thereof - Google Patents

Tofacitinib citrate preparation and preparation method thereof Download PDF

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CN115381788A
CN115381788A CN202211137244.5A CN202211137244A CN115381788A CN 115381788 A CN115381788 A CN 115381788A CN 202211137244 A CN202211137244 A CN 202211137244A CN 115381788 A CN115381788 A CN 115381788A
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tofacitinib citrate
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mixing
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CN115381788B (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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Abstract

The invention provides a tofacitinib citrate preparation and a preparation method thereof, belonging to the field of preparations of rheumatoid arthritis medicaments. 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, 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 medicaments, 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) - β -oxo-1-piperidinepropanitrile citrate of formula: 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 readily soluble in DMSO, slightly soluble in water and methanol, and insoluble in acetonitrile. The structural formula is as follows:
Figure BDA0003852629370000011
pyroxene successfully developed a novel JAK inhibitor, namely tofacitinib citrate tablet (5 mg/tablet) and tofacitinib citrate controlled release tablet (11 mg/tablet), wherein tofacitinib citrate tablet (trade name: XELJANZ) was used for 11 months in 2012, tofacitinib citrate controlled release tablet (XELJANZ XR) and 2016 were used for oral treatment of rheumatoid arthritis in patients with moderate to severe adult RA who were approved by FDA in usa to treat inadequate or intolerant to methotrexate, and the indications thereof are XELJANZ. Wherein the inactive ingredients in tofacitinib citrate tablet are sorbitol, hydroxyethyl cellulose, magnesium stearate, cellulose acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose, titanium dioxide, triacetin, and iron oxide red.
Rheumatoid Arthritis (RA) is a chronic autoimmune disease with high clinical incidence and disability rate, and its main pathological feature is chronic progressive synovitis, which can occur at any age. RA clinically causes various symptoms, which are mainly manifested by polyarticular, symmetrical and invasive arthritis of small joints of hands and feet, and often accompanied by the involvement of serum rheumatoid factor positive in extraarticular organs, thereby causing joint deformity and function loss.
In the prior art, the process is complex and needs the following steps: mixing part of adjuvants, wet granulating, grading, mixing the wet granules with most adjuvants, adding lubricant, mixing, tabletting, and coating. After wet granulation, a large amount of auxiliary materials are added to improve the fluidity so as to carry out tabletting; meanwhile, the physical property difference between the particles and the added auxiliary material powder is large, so that the problems of difficult uniformity during mixing and large compression deformation difference during tabletting exist. Moreover, controlled release formulations require large doses to achieve long-lasting effects, and there is much unpredictability in drug release; moreover, oral drugs need to be absorbed through intestines and stomach before reaching the focus of treatment, and the onset process is easy to generate uncontrollable change. Therefore, the onset process is uncontrollable whether the preparation is a conventional oral preparation or a sustained-release preparation. Therefore, a novel preparation process for synthesizing the tofacitinib citrate is urgently needed.
Chinese patent CN 108066319B discloses a tofacitinib citrate enteric-coated sustained-release pellet and a preparation method thereof. The tofacitinib citrate enteric-coated sustained-release pellet specifically comprises a skeleton-type drug-containing pellet core and an enteric-coated coating coated on the pellet core, but has the problems of complicated auxiliary material types, complicated process flow and the like, so that the problem of nonuniformity in sustained-release effect of the obtained sustained-release tablet is caused.
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 sustained release effect of drug release, safety, reliability and convenience in use.
The first purpose 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 auxiliary materials comprise the following components in percentage by mass: 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.
In one embodiment of the invention, the auxiliary materials comprise the following components in percentage by mass: 8-10% of diluent, 1-1.5% of adhesive, 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 invention, the disintegrant is selected from one or more of croscarmellose sodium, low substituted hydroxypropyl cellulose, 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 present 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 methoxyphenol 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 dosage form of the formulation is a solid oral pharmaceutical formulation.
In one embodiment of the invention, the solid oral pharmaceutical formulation is a tablet.
The second purpose of the invention is to provide a preparation method of the tofacitinib citrate preparation, which comprises the following steps:
(1) Sieving the solid raw 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 by weight, mixing, adding the mixture obtained in the step (1), continuously mixing uniformly and sieving to obtain a mixture;
(3) Wetting the mixture obtained in the step (2) in a wet granulator, adding a prescribed amount of adhesive aqueous solution, and uniformly mixing to obtain a soft material;
(4) Sieving and granulating, drying, sieving and grading the soft material obtained in the step (3), adding a disintegrant in a prescription amount and a lubricant in a prescription amount, uniformly mixing, and tabletting to obtain a plain tablet;
(5) And (5) coating the plain tablets obtained in the step (4) by using a coating powder suspension to obtain the tofacitinib citrate preparation.
In one embodiment of the present invention, in the step (1), the size of the screen for the sieving treatment is 15 to 50 mesh.
In one embodiment of the present invention, in the step (1), the size of the screen for the sieving treatment is 20 to 30 mesh.
In one embodiment of the invention, in the step (2), the particle size of the tofacitinib citrate is 5-15 μm.
In one embodiment of the invention, in the step (2), the particle size of the tofacitinib citrate is 10-15 μm.
In one embodiment of the present invention, in step (2), the size of the sieving screen is 15-60 mesh.
In one embodiment of the present invention, in the step (3), the weight percentage of the binder in the aqueous binder solution is 5 to 8%.
In one embodiment of the present invention, in the 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 cooperated with the disintegrant to enhance the sustained release capability of the tablet, enhance the regulation and control performance of sustained release, ensure that the medicament is slowly released in vivo, has stable release speed, improves the biocompatibility and improves the action effect of the medicament. And the preparation process is simple, the product is stable, and the industrial mass production is facilitated.
Detailed Description
The present invention is further described below in conjunction with specific examples to enable those skilled in the art to better understand the present invention and to practice it, but the examples are not intended to limit the present invention.
In the invention, unless otherwise stated, the ratio range and the alternative scheme of each component in the tofacitinib citrate preparation can be combined with each other to form a new preparation scheme.
In the present invention, unless otherwise stated, the preparation process of tofacitinib citrate preparation is performed sequentially.
In the present invention, unless otherwise specified, the preparation of tofacitinib citrate formulations is carried out under ambient conditions.
The first purpose 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 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 auxiliary materials comprise the following components in percentage by mass: 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.
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 dosage form of the formulation is a solid oral pharmaceutical formulation.
In one embodiment of the invention, the solid oral pharmaceutical formulation is a tablet.
The second purpose of the invention is to provide a preparation method of the tofacitinib citrate preparation, which is characterized by comprising the following steps:
(1) Sieving the solid raw and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing;
(2) Weighing polyhydric alcohol and tofacitinib citrate according to the divided parts, mixing, adding the mixture obtained in the step (1), continuously mixing uniformly and sieving to obtain a mixture;
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of adhesive aqueous solution, and uniformly mixing to obtain a soft material;
(4) Sieving and granulating, drying, sieving and grading the soft material obtained in the step (3), adding a disintegrant in a prescription amount and a lubricant in a prescription amount, uniformly mixing, and tabletting to obtain a plain tablet;
(5) And (5) coating the plain tablets obtained 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 component types and contents are as follows: 65g of tofacitinib citrate, 20g of diluent (starch), 1.98g of adhesive (hydroxypropyl cellulose), 6g of disintegrant (croscarmellose sodium), 0.02g of antioxidant (cysteine), 1g of polyol (polyethylene glycol 200), 1g of lubricant (magnesium stearate) and 5g of coating powder (opadry).
The preparation method comprises the following steps: (1) Sieving the solid raw and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen mesh size is 30 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts by weight, mixing, adding the mixture obtained in the step (1), continuously mixing uniformly and sieving to obtain a mixture; the screen mesh size is 20 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of adhesive aqueous solution, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the aqueous adhesive solution was 5%.
(4) Sieving and granulating the soft material obtained in the step (3), drying at 40 ℃, sieving and granulating, controlling the moisture of the granules within 5.0 percent of the dry matter, adding a disintegrating agent and a lubricating agent in the prescription amount, uniformly mixing, and tabletting to obtain plain tablets; the screened mesh size was 15 mesh.
(5) And (5) coating the plain tablets obtained 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 component types and contents are as follows: 55g of tofacitinib citrate, 25g of diluent (microcrystalline cellulose), 1.98g of adhesive (polyvinylpyrrolidone), 6g of disintegrant (sodium carboxymethyl starch), 0.02g of antioxidant (cysteine), 1g of polyalcohol (propylene glycol), 1g of lubricant (magnesium stearate) and 10g of coating powder (Opadry).
The preparation method comprises the following steps: (1) Sieving the solid raw and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen mesh size is 20 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts by weight, mixing, adding the mixture obtained in the step (1), continuously mixing uniformly and sieving to obtain a mixture; the screen mesh size is 30 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of adhesive aqueous solution, and uniformly mixing to obtain a soft material; the weight percentage of the binder in the aqueous binder solution was 8%.
(4) Sieving and granulating the soft material obtained in the step (3), drying at 45 ℃, sieving and granulating, controlling the moisture of the granules within 2.0 percent of the dry matter, adding a disintegrating agent and a lubricating agent in the prescription amount, uniformly mixing, and tabletting to obtain plain tablets; the size of the sieved screen is 30 meshes.
(5) And (5) coating the plain tablets obtained 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 component types and contents are as follows: 65g of tofacitinib citrate, 20g of diluent (pregelatinized starch), 1.98g of adhesive (hydroxypropyl methylcellulose), 6g of disintegrant (sodium carboxymethyl starch), 0.02g of antioxidant (vitamin E), 1g of polyol (propylene glycol), 1g of lubricant (magnesium stearate) and 5g of coating powder (Opadry).
The preparation method comprises the following steps: (1) Sieving the solid raw and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen mesh size is 30 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts by weight, mixing, adding the mixture obtained in the step (1), continuously mixing uniformly and sieving to obtain a mixture; the screen mesh size is 20 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of adhesive aqueous solution, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the aqueous adhesive solution was 5%.
(4) Sieving and granulating the soft material obtained in the step (3), drying at 40 ℃, sieving and granulating, controlling the moisture of the granules within 5.0 percent of the dry matter, adding a disintegrating agent and a lubricating agent in the prescription amount, uniformly mixing, and tabletting to obtain plain tablets; the size of the sieved screen is 15 meshes.
(5) And (5) coating the plain tablets obtained 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 component types and contents are as follows: 35g of tofacitinib citrate, 40g of diluent (pregelatinized starch), 1.98g of adhesive (hydroxypropyl cellulose), 10g of disintegrant (croscarmellose sodium), 0.09g of antioxidant (sodium metabisulfite), 1g of polyol (polyethylene glycol 400), 1.99g of lubricant (magnesium stearate) and 12g of coating powder (Opadry).
The preparation method comprises the following steps: (1) Sieving the solid raw and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen mesh size is 30 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts by weight, mixing, adding the mixture obtained in the step (1), continuously mixing uniformly and sieving to obtain a mixture; the screen mesh size is 20 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of adhesive aqueous solution, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the aqueous adhesive solution was 5%.
(4) Sieving and granulating the soft material obtained in the step (3), drying at 40 ℃, sieving and granulating, controlling the moisture of the granules within 5.0% by dry matter, adding a disintegrating agent in a prescription amount and a lubricating agent in a prescription amount, uniformly mixing, and tabletting to obtain a plain tablet; the screened mesh size was 15 mesh.
(5) And (5) coating the plain tablets obtained 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 component types and contents are as follows: 50g of tofacitinib citrate, 30g of diluent (starch), 1.98g of adhesive (polyvinylpyrrolidone), 10g of disintegrant (croscarmellose sodium), 0.02g of antioxidant (cysteine), 2g of polyalcohol (polyethylene glycol 200), 1g of lubricant (magnesium stearate) and 5g of coating powder (Opadry).
The preparation method comprises the following steps: (1) Sieving the solid raw and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen mesh size is 15 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts by weight, mixing, adding the mixture obtained in the step (1), continuously mixing uniformly and sieving to obtain a mixture; the screen mesh size is 20 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of adhesive aqueous solution, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the aqueous adhesive solution is 5%.
(4) Sieving and granulating the soft material obtained in the step (3), drying at 40 ℃, sieving and granulating, controlling the moisture of the granules within 5.0% by dry matter, adding a disintegrating agent in a prescription amount and a lubricating agent in a prescription amount, uniformly mixing, and tabletting to obtain a plain tablet; the size of the sieved screen is 30 meshes.
(5) And (5) coating the plain tablets obtained 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 component types and contents are as follows: 40g of tofacitinib citrate, 30g of a diluent (lactose), 1.95g of an adhesive (hydroxypropyl methyl cellulose), 10g of a disintegrating agent (sodium carboxymethyl starch), 0.05g of an antioxidant (leucine), 3g of a polyalcohol (polyethylene glycol 300), 5g of a lubricant (magnesium stearate) and 10g of coating powder (Opadry).
The preparation method comprises the following steps: (1) Sieving the solid raw and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen mesh size is 40 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts by weight, mixing, adding the mixture obtained in the step (1), continuously mixing uniformly and sieving to obtain a mixture; the screen mesh size is 30 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of adhesive aqueous solution, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the aqueous adhesive solution was 5%.
(4) Sieving and granulating the soft material obtained in the step (3), drying at 40 ℃, sieving and granulating, controlling the moisture of the granules within 5.0% by dry matter, adding a disintegrating agent in a prescription amount and a lubricating agent in a prescription amount, uniformly mixing, and tabletting to obtain a plain tablet; the screened mesh size was 15 mesh.
(5) And (5) coating the plain tablets obtained 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 component types and contents are as follows: 65g of tofacitinib citrate, 20g of diluent (starch), 1.98g of adhesive (hydroxypropyl cellulose), 6g of disintegrant (croscarmellose sodium), 0.02g of antioxidant (di-tert-butyl methyl phenol), 1g of polyol (polyethylene glycol 200), 1g of lubricant (magnesium stearate) and 5g of coating powder (Opadry).
The preparation method comprises the following steps: (1) Sieving the solid raw and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen mesh size is 20 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts by weight, mixing, adding the mixture obtained in the step (1), continuously mixing uniformly and sieving to obtain a mixture; the screen mesh size is 30 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of adhesive aqueous solution, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the aqueous adhesive solution was 5%.
(4) Sieving and granulating the soft material obtained in the step (3), drying at 40 ℃, sieving and granulating, controlling the moisture of the granules within 5.0% by dry matter, adding a disintegrating agent in a prescription amount and a lubricating agent in a prescription amount, uniformly mixing, and tabletting to obtain a plain tablet; the screened mesh size was 15 mesh.
(5) And (5) coating the plain tablets obtained in the step (4) by using a coating powder suspension to obtain the tofacitinib citrate preparation.
Comparative example 1 (comparison with example 1, without polyol)
The embodiment provides a tofacitinib citrate preparation and a preparation method thereof
The component types and contents are as follows: 65g of tofacitinib citrate, 20g of diluent (starch), 1.98g of adhesive (hydroxypropyl cellulose), 6g of disintegrant (croscarmellose sodium), 0.02g of antioxidant (cysteine), 1g of lubricant (magnesium stearate) and 5g of coating powder (Opadry).
The preparation method comprises the following steps: (1) Sieving the solid raw and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen mesh size is 30 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts by weight, mixing, adding the mixture obtained in the step (1), continuously mixing uniformly and sieving to obtain a mixture; the screen mesh size is 20 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of adhesive aqueous solution, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the aqueous adhesive solution was 5%.
(4) Sieving and granulating the soft material obtained in the step (3), drying at 40 ℃, sieving and granulating, controlling the moisture of the granules within 5.0% by dry matter, adding a disintegrating agent in a prescription amount and a lubricating agent in a prescription amount, uniformly mixing, and tabletting to obtain a plain tablet; the screened mesh size was 15 mesh.
(5) And (5) coating the plain tablets obtained in the step (4) by using a coating powder suspension to obtain the tofacitinib citrate preparation.
Comparative example 2 (comparison with example 1, without disintegrant)
The embodiment provides a tofacitinib citrate preparation and a preparation method thereof
The component types and contents are as follows: 65g of tofacitinib citrate, 20g of diluent (starch), 1.98g of adhesive (hydroxypropyl cellulose), 0.02g of antioxidant (cysteine), 1g of polyol (polyethylene glycol 200), 1g of lubricant (magnesium stearate) and 5g of coating powder (Opadry).
The preparation method comprises the following steps: (1) Sieving the solid raw and auxiliary materials, respectively weighing the diluent and the antioxidant according to the prescription amount, and then mixing; the screen mesh size is 30 mesh.
(2) Weighing polyalcohol and tofacitinib citrate according to the parts by weight, mixing, adding the mixture obtained in the step (1), continuously mixing uniformly and sieving to obtain a mixture; the screen mesh size is 20 mesh.
(3) Wetting the mixture obtained in the step (1) in a wet granulator, adding a prescribed amount of adhesive aqueous solution, and uniformly mixing to obtain a soft material; the weight percentage of the adhesive in the aqueous adhesive solution was 5%.
(4) Sieving and granulating the soft material obtained in the step (3), drying at 40 ℃, sieving and granulating, controlling the moisture of the granules within 5.0% by dry matter, adding a disintegrating agent in a prescription amount and a lubricating agent in a prescription amount, uniformly mixing, and tabletting to obtain a plain tablet; the screened mesh size was 15 mesh.
(5) And (5) coating the tablet obtained in the step (4) by using a coating powder suspension to obtain the tofacitinib citrate preparation.
Test example
Examples 1 to 3 and comparative examples 2 to 3 were subjected to the measurement of the release degree. The method comprises the following specific operations: a sample was taken and dissolved in 900mL of a phosphate buffer solution (pH6.8) in accordance with a device for measuring a release rate (second method of 0931 in the general rule of the fourth preparation of the pharmacopoeia 2015 edition) + a settling basket. The results are shown in Table 1.
TABLE 1
Figure BDA0003852629370000131
As can be seen from Table 1, the embodiment of the invention has better release rate, and can reduce the influence of the pH value of the intestinal tract on the medicine to a certain extent; and as can be seen from the release degree conditions of the example 1 and the comparative examples 1-2, the release degree of the tofacitinib citrate tablet disclosed by the invention is longer in duration, the release degree has a larger influence under the condition of lacking a disintegrant or polyol, and the release degree is obviously increased, so that the added disintegrant and the polyol can synergistically enhance the slow release speed of the tofacitinib citrate tablet.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications of the invention may be made without departing from the spirit or scope of the invention.

Claims (10)

1. The tofacitinib citrate preparation is characterized by comprising tofacitinib citrate and pharmaceutically or pharmacologically acceptable auxiliary materials.
2. The tofacitinib citrate preparation according to claim 1, wherein the tofacitinib citrate is present in a mass concentration of 30-65%.
3. The tofacitinib citrate formulation according to claim 1, wherein the pharmaceutically or pharmacologically acceptable excipients comprise diluents, binders, disintegrants, antioxidants, polyols, lubricants and coating powders.
4. The tofacitinib citrate preparation according to claim 3, wherein the auxiliary materials comprise the following components in percentage by mass: 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.
5. The tofacitinib citrate formulation according to claim 3, 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 Opadry; the disintegrant is selected from one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone and sodium carboxymethyl starch.
6. Tofacitinib citrate formulation according to claim 3, wherein said antioxidant is selected from one or more of sodium metabisulfite, cysteine, leucine, methionine, sodium ascorbate, vitamin E, di-tert-butyl methylphenol, tert-butyl methoxyphenol or a pharmaceutically acceptable salt thereof.
7. Tofacitinib citrate formulation according to claim 1, wherein said polyol is selected from propylene glycol or polyethylene glycol; wherein the polymerization degree of the polyethylene glycol is 200-500.
8. The tofacitinib citrate formulation according to claim 1, wherein the formulation is in the form of a solid oral pharmaceutical formulation.
9. The tofacitinib citrate formulation according to claim 8, wherein said solid oral pharmaceutical formulation is a tablet.
10. A process for the preparation of tofacitinib citrate formulation according to any of claims 1 to 9, comprising the steps of:
(1) Sieving the solid raw 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 by weight, mixing, adding the mixture obtained in the step (1), continuously mixing uniformly and sieving to obtain a mixture;
(3) Wetting the mixture obtained in the step (2) in a wet granulator, adding a prescribed amount of adhesive aqueous solution, and uniformly mixing to obtain a soft material;
(4) Sieving and granulating, drying, sieving and grading the soft material obtained in the step (3), adding a disintegrant in a prescription amount and a lubricant in a prescription amount, uniformly mixing, and tabletting to obtain a plain tablet;
(5) And (5) coating the plain tablets obtained in the step (4) by using a coating powder suspension to obtain the tofacitinib citrate preparation.
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CN106389371A (en) * 2016-11-16 2017-02-15 杭州朱养心药业有限公司 Tofacitinib citrate pharmaceutical composition
US20170304307A1 (en) * 2015-07-27 2017-10-26 Unichem Laboratories Limited Tofacitinib orally disintegrating tablets
CN112007004A (en) * 2020-09-17 2020-12-01 山东鲁抗医药股份有限公司 Tofacitinib citrate tablet and preparation method thereof
CN113712932A (en) * 2020-05-25 2021-11-30 南京帝昌医药科技有限公司 Tofacitinib citrate osmotic pump tablet and preparation method thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012076516A1 (en) * 2010-12-06 2012-06-14 Krka, Tovarna Zdravil, D.D., Novo Mesto Pharmaceutical composition comprising dutasteride
US20170304307A1 (en) * 2015-07-27 2017-10-26 Unichem Laboratories Limited Tofacitinib orally disintegrating tablets
CN106389371A (en) * 2016-11-16 2017-02-15 杭州朱养心药业有限公司 Tofacitinib citrate pharmaceutical composition
CN113712932A (en) * 2020-05-25 2021-11-30 南京帝昌医药科技有限公司 Tofacitinib citrate osmotic pump tablet and preparation method thereof
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