Tofacitinib citrate sustained release tablet and preparation method thereof

Abstract

The invention provides a tofacitinib citrate sustained-release tablet, which is composed of a sustained-release tablet core and a coating layer, the sustained-release tablet core is prepared by uniformly mixing a solid dispersion and pharmaceutically acceptable auxiliary materials and then tabletting, the tofacitinib citrate sustained release tablet is characterized in that the solid dispersion is prepared from tofacitinib citrate, acrylic resin E and isomaltitol by utilizing a solvent evaporation method, and the coating layer comprises polyvinylpyrrolidone and tert-butyl p-hydroxyanisole. The prepared tofacitinib citrate tablet core particles are high in density, good in flowability and good in compressibility; the prepared tofacitinib citrate sustained release tablet is stable in quality, simple and feasible in process and suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a tofacitinib citrate sustained-release tablet and its preparation method. Background Technology

[0002] Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized primarily by chronic, progressive joint involvement. Without timely and standardized treatment, the condition can gradually worsen, eventually leading to deformities, joint stiffness, and loss of function. It is one of the most common and leading causes of disability in clinical practice. In my country, nearly 5 million people suffer from this disease, resulting in a high rate of disability and imposing a heavy burden on both society and patients.

[0003] Tofacitinib citrate tablets are the first JAK pathway inhibitor with a specific mechanism of action, and are a novel oral protein tyrosine kinase inhibitor. This product was first approved for marketing in the United States on November 6, 2012, and has since been approved for marketing in more than 50 countries and regions worldwide, including the United States, Japan, Russia, Australia, and Canada.

[0004] Chemical name: (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-β-oxo-1-piperidinepropionitrile citrate The chemical structural formula is as follows:

[0005] Tofacitinib is indicated for adult patients with moderate to severe active rheumatoid arthritis (RA) who have not responded adequately to or are intolerant of methotrexate, and may be used in combination with methotrexate or other non-biological disease-modifying antirheumatic drugs (DMARDs).

[0006] Tofacitinib immediate-release tablets are rapidly absorbed with a short time to peak concentration (Tmax) (approximately 0.5-1 hour). This means that after administration, the drug concentration in the blood quickly reaches a peak (Cmax) and then gradually declines over time (half-life approximately 3 hours). It needs to be taken twice daily (BID). This rapid peak-to-trough fluctuation can lead to: At peak concentration: excessively high concentrations, potentially increasing the risk of peak-related side effects (such as some acute discomfort). At trough concentration: insufficiently low concentrations, which may not effectively suppress inflammation and affect efficacy. Autoimmune diseases such as rheumatoid arthritis require long-term or even lifelong medication. Reducing the dosing frequency from twice daily to once daily greatly simplifies the medication regimen. Patients are more likely to remember to take the medication and are less likely to miss or mistake doses, which is crucial for ensuring long-term efficacy.

[0007] Existing technologies for tofacitinib citrate sustained-release tablets have been extensively studied. For example, CN105101952B primarily uses 60-85% sorbitol as the core permeabilizer. Because sorbitol is highly hygroscopic, strict control of ambient humidity is necessary during production to prevent moisture absorption during mixing and compression. Furthermore, sorbitol is a polyol with a certain ability to chelate metal ions. During production, it may combine with trace metal ions (such as iron, magnesium, and calcium) generated by equipment wear. These factors can easily lead to yellowing of the tablet core and an increase in related substances.

[0008] CN119157848B discloses a tofacitinib citrate sustained-release tablet formulation and its preparation method, belonging to the field of pharmaceutical formulation technology. The sustained-release tablet comprises a double-layer core and a coating layer; the double-layer core comprises a drug-containing layer and a propulsion layer; wherein the drug-containing layer comprises: tofacitinib citrate, a binder, polyoxyethylene, a flow aid, and a lubricant; the propulsion layer comprises: mannitol, a binder, red iron oxide, polyoxyethylene, a flow aid, and a lubricant; the coating layer comprises: cellulose acetate, a pore-forming agent, a plasticizer, water, and acetone. This invention's sustained-release tablet formulation employs a double-layer osmotic pump formulation design, uses non-hygroscopic materials such as mannitol, adopts a standard circular tablet design, does not use methanol in preparing the sustained-release coating layer, and uses a coating machine for coating and curing. Osmotic pump formulations (especially double-layer osmotic pumps) are among the most technically challenging and complex oral solid dosage forms. Its production process involves several critical steps (such as double-layer tableting, precise laser drilling, controlled coating, and curing), placing extremely high demands on equipment, process control, and operators. Any minute deviation can lead to substandard release behavior. Furthermore, both the drug-containing layer and the propellant layer in the formulation use polyethylene oxide (PEO) as a key excipient. PEO is highly sensitive to oxidation, especially under heat, humidity, and trace metal ion catalysis, and is prone to auto-oxidative degradation, leading to molecular chain breakage. Summary of the Invention

[0009] In order to overcome the shortcomings of the prior art, the purpose of this invention is to provide a new tofacitinib citrate sustained-release tablet and its preparation method by exploring the formulation.

[0010] Specifically, the present invention is achieved through the following technical solution: The present invention provides a tofacitinib citrate sustained-release tablet, which is composed of a sustained-release tablet core and a coating layer. The sustained-release tablet core is obtained by compressing a solid dispersion with pharmaceutically acceptable excipients. The solid dispersion is prepared by solvent evaporation of tofacitinib citrate with acrylic resin E and isomaltitol. The coating layer contains polyvinylpyrrolidone and tert-butyl-p-hydroxyanisole.

[0011] The solvent used in the preparation of the solid dispersion by the solvent evaporation method for the tofacitinib citrate sustained-release tablets is anhydrous ethanol.

[0012] The tofacitinib citrate sustained-release tablets mentioned herein, wherein the weight ratio of tofacitinib citrate, acrylic resin E and isomaltitol is 1:2-8:1-4.

[0013] The tofacitinib citrate sustained-release tablets contain tofacitinib citrate, acrylic resin E, and isomalt in a weight ratio of 1:3-7:2-4.

[0014] The tofacitinib citrate sustained-release tablets contain tofacitinib citrate, acrylic resin E, and isomalt in a weight ratio of 1:5:3.

[0015] The tofacitinib citrate sustained-release tablets have a coating layer in which the weight ratio of polyvinylpyrrolidone to tert-butyl-p-hydroxyanisole is 10:1-3.

[0016] The preparation method of the tofacitinib citrate sustained-release tablets includes the following steps: (1) Dissolve tofacitinib citrate, acrylic resin E and isomaltitol in anhydrous ethanol, dry under reduced pressure, and pass the dried material through a 100-mesh sieve to obtain a solid dispersion for later use. (2) Pass pharmaceutically acceptable excipients through a 100-mesh sieve and set aside; (3) Weigh the sieved solid dispersion and pharmaceutically acceptable excipients, mix them evenly, compress them into tablets, and obtain sustained-release tablet cores; (4) Dissolve polyvinylpyrrolidone and tert-butyl-p-hydroxyanisole in ethanol, and use this solution as a coating solution to coat the sustained-release tablet core to obtain tofacitinib citrate sustained-release tablets.

[0017] The preparation method of the tofacitinib citrate sustained-release tablets, wherein the pharmaceutically acceptable excipients are sodium carboxymethyl starch, microcrystalline cellulose and magnesium stearate.

[0018] The preparation method of the tofacitinib citrate sustained-release tablets, wherein the weight ratio of sodium carboxymethyl starch, microcrystalline cellulose and magnesium stearate is 1:10:1.

[0019] This invention provides a tofacitinib citrate sustained-release tablet, which has the following beneficial effects: This invention, developed through long-term research, creatively employs a combination of tofacitinib citrate, acrylic resin E, and isomaltitol to prepare a solid dispersion using a solvent evaporation method. This dispersion is then used to prepare sustained-release tablet cores. Furthermore, the coating layer contains polyvinylpyrrolidone and tert-butyl-p-hydroxyanisole, effectively addressing product stability and release rate issues. The reason for this is that the pyrrolopyrimidine ring and cyano groups in the tofacitinib citrate molecular structure are highly sensitive to oxidative degradation. Sorbitol-metal ion complexes catalyze oxygen in the environment, generating reactive oxygen species (such as peroxides and hydroxyl radicals), thus significantly accelerating the oxidative degradation of tofacitinib and affecting the drug's shelf life and safety. Sorbitol is hygroscopic; absorbing moisture may cause tablets to soften and clump, affecting the drug's hardness and disintegration properties, and accelerating the hydrolysis or oxidative degradation of tofacitinib citrate. As a sugar alcohol, sorbitol has relatively poor compressibility in its crystalline form, which may result in low tablet hardness and easy top or waist cracking, affecting production efficiency and yield. During packaging and transportation, tablets are more prone to wear and breakage.

[0020] Isomaltulose is a reduced disaccharide formed by the linkage of one molecule of glucose and one molecule of fructose via an α-1,6 glycosidic bond. Isomaltulitol can be obtained by hydrogenating and reducing isomaltulose. Isomaltulitol is a white crystalline mixture of two isomers: α-D-glucopyranosyl-1,6-sorbitol (GPS) and α-D-glucopyranosyl-1,1-D-mannitol (GPM). It has low hygroscopicity, good thermal stability (does not decompose upon heating), stability to acids and alkalis, and is not easily utilized by various microorganisms. Its glycosidic bonds are not easily hydrolyzed by acids and enzymes, and it does not produce a browning reaction or a burnt odor. Isomaltulose has extremely low hygroscopicity, maintaining its powder state even under high temperature and humidity conditions, thus avoiding the hydrolysis or oxidative degradation of tofacitinib citrate. As an inert backbone, isomaltulose can control the rate of water molecule penetration and drug diffusion, contributing to a more stable release profile.

[0021] The inventors also discovered that when preparing tofacitinib citrate solid dispersions, mixing tofacitinib citrate and sorbitol, and then using a solvent evaporation method to prepare the solid dispersion and the resulting sustained-release tablet cores, the tablets tend to yellow after prolonged storage. Analysis revealed that sorbitol, being a polyol, has a certain ability to chelate metal ions. During the production process, it may combine with trace metal ions (such as iron, magnesium, and calcium) generated by equipment wear, which can also lead to yellowing of the tablet cores. Sorbitol's linear structure has a "crab claw" conformation, where the hydroxyl groups on the C1-C2-C3 or C4-C5-C6 chains can coordinate with metal ions, resulting in low steric hindrance. In contrast, isomaltitol's glycosidic bonds and larger molecular size increase steric hindrance, making it difficult to form a perfect, low-strain coordination environment. Sorbitol can easily adopt an energy-favorable cyclic conformation, placing its hydroxyl groups in positions highly suitable for coordination with metal ions. The rigid disaccharide structure of isomaltitol makes it more difficult to achieve this ideal coordination conformation, requiring the overcoming of a higher energy barrier. Therefore, isomaltitol has difficulty chelating metal ions, thus preventing the tablet core from yellowing.

[0022] Compared with the prior art, the present invention produces tofacitinib citrate sustained-release tablets with high density, good flowability, and good compressibility of the tablet core particles; the prepared tofacitinib citrate sustained-release tablets have stable quality and the process is simple and easy to implement, making them suitable for large-scale production. Attached Figure Description

[0023] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings of the embodiments will be briefly described below.

[0024] The accompanying drawings described below are only related to some embodiments of the invention and are not intended to limit the invention.

[0025] In the attached diagram: Figure 1 The cumulative release curves of tofacitinib citrate in the sustained-release tablets prepared in Examples 1-3 and Comparative Examples 1-2 are shown. Detailed Implementation

[0026] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the described embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0027] Example 1: Preparation of Tofacitinib Citrate Extended-Release Tablets Tofacitinib citrate 11g Acrylic resin E 55g Isomaltitol 33g 500ml of anhydrous ethanol 5g of sodium carboxymethyl starch 50g of microcrystalline cellulose 5g magnesium stearate 20g of polyvinylpyrrolidone 4g tert-butyl-p-hydroxyanisole Preparation process: (1) Dissolve tofacitinib citrate, acrylic resin E and isomaltitol in anhydrous ethanol, dry under reduced pressure, and pass the dried material through a 100-mesh sieve to obtain a solid dispersion for later use. (2) Pass sodium carboxymethyl starch, microcrystalline cellulose and magnesium stearate through a 100-mesh sieve and set aside; (3) Weigh the sieved solid dispersion, sodium carboxymethyl starch, microcrystalline cellulose and magnesium stearate, mix them evenly, compress them into tablets, and obtain sustained-release tablet cores; (4) Dissolve polyvinylpyrrolidone and tert-butyl-p-hydroxyanisole in ethanol, and use this solution as a coating solution to coat the sustained-release tablet core. The coating temperature is 30°C to obtain 1000 sustained-release tablets of tofacitinib citrate, each containing 11 mg of tofacitinib citrate.

[0028] Example 2: Preparation of Tofacitinib Citrate Extended-Release Tablets Tofacitinib citrate 11g Acrylic resin E 22g Isomaltitol 44g 500ml of anhydrous ethanol 5g of sodium carboxymethyl starch 50g of microcrystalline cellulose 5g magnesium stearate 20g of polyvinylpyrrolidone 2g tert-butyl-p-hydroxyanisole Preparation process: (1) Dissolve tofacitinib citrate, acrylic resin E and isomaltitol in anhydrous ethanol, dry under reduced pressure, and pass the dried material through a 100-mesh sieve to obtain a solid dispersion for later use. (2) Pass sodium carboxymethyl starch, microcrystalline cellulose and magnesium stearate through a 100-mesh sieve and set aside; (3) Weigh the sieved solid dispersion, sodium carboxymethyl starch, microcrystalline cellulose and magnesium stearate, mix them evenly, compress them into tablets, and obtain sustained-release tablet cores; (4) Dissolve polyvinylpyrrolidone and tert-butyl-p-hydroxyanisole in ethanol, and use this solution as a coating solution to coat the sustained-release tablet core. The coating temperature is 30°C to obtain 1000 sustained-release tablets of tofacitinib citrate, each containing 11 mg of tofacitinib citrate.

[0029] Example 3: Preparation of Tofacitinib Citrate Extended-Release Tablets Tofacitinib citrate 11g Acrylic resin E 88g Isomaltitol 11g 500ml of anhydrous ethanol 5g of sodium carboxymethyl starch 50g of microcrystalline cellulose 5g magnesium stearate 20g of polyvinylpyrrolidone 6g tert-butyl-p-hydroxyanisole Preparation process: (1) Dissolve tofacitinib citrate, acrylic resin E and isomaltitol in anhydrous ethanol, dry under reduced pressure, and pass the dried material through a 100-mesh sieve to obtain a solid dispersion for later use. (2) Pass sodium carboxymethyl starch, microcrystalline cellulose and magnesium stearate through a 100-mesh sieve and set aside; (3) Weigh the sieved solid dispersion, sodium carboxymethyl starch, microcrystalline cellulose and magnesium stearate, mix them evenly, compress them into tablets, and obtain sustained-release tablet cores; (4) Dissolve polyvinylpyrrolidone and tert-butyl-p-hydroxyanisole in ethanol, and use this solution as a coating solution to coat the sustained-release tablet core. The coating temperature is 30°C to obtain 1000 sustained-release tablets of tofacitinib citrate, each containing 11 mg of tofacitinib citrate.

[0030] Comparative Example 1: Preparation of Tofacitinib Citrate Extended-Release Tablets Tofacitinib citrate 11g Acrylic resin E 55g 33g of sorbitol 500ml of anhydrous ethanol 5g of sodium carboxymethyl starch 50g of microcrystalline cellulose 5g magnesium stearate 20g of polyvinylpyrrolidone 4g tert-butyl-p-hydroxyanisole Preparation process: (1) Dissolve tofacitinib citrate, acrylic resin E and sorbitol in anhydrous ethanol, dry under reduced pressure, and pass the dried material through a 100-mesh sieve to obtain a solid dispersion for later use; (2) Pass sodium carboxymethyl starch, microcrystalline cellulose and magnesium stearate through a 100-mesh sieve and set aside; (3) Weigh the sieved solid dispersion, sodium carboxymethyl starch, microcrystalline cellulose and magnesium stearate, mix them evenly, compress them into tablets, and obtain sustained-release tablet cores; (4) Dissolve polyvinylpyrrolidone and tert-butyl-p-hydroxyanisole in ethanol, and use this solution as a coating solution to coat the sustained-release tablet core. The coating temperature is 30°C to obtain 1000 sustained-release tablets of tofacitinib citrate, each containing 11 mg of tofacitinib citrate.

[0031] Comparative Example 2: Preparation of Tofacitinib Citrate Extended-Release Tablets Tofacitinib citrate 11g Acrylic resin E 55g Isomaltitol 33g 500ml of anhydrous ethanol 5g of sodium carboxymethyl starch 50g of microcrystalline cellulose 5g magnesium stearate 20g of hydroxypropyl cellulose 4g tert-butyl-p-hydroxyanisole Preparation process: (1) Dissolve tofacitinib citrate, acrylic resin E and isomaltitol in anhydrous ethanol, dry under reduced pressure, and pass the dried material through a 100-mesh sieve to obtain a solid dispersion for later use. (2) Pass sodium carboxymethyl starch, microcrystalline cellulose and magnesium stearate through a 100-mesh sieve and set aside; (3) Weigh the sieved solid dispersion, sodium carboxymethyl starch, microcrystalline cellulose and magnesium stearate, mix them evenly, compress them into tablets, and obtain sustained-release tablet cores; (4) Hydroxypropyl cellulose and tert-butyl-p-hydroxyanisole were dissolved in ethanol. This solution was used as a coating solution to coat the sustained-release tablet core. The coating temperature was 30°C to obtain 1000 sustained-release tablets of tofacitinib citrate, each containing 11 mg of tofacitinib citrate.

[0032] Example 4: Determination of release rate and core particle density of tofacitinib citrate sustained-release tablets 1. Determination method of tofacitinib citrate Tofacitinib citrate sustained-release tablets prepared in Examples 1-3 and Comparative Examples 1-2 were used in the release assay apparatus (Chinese Pharmacopoeia 2025, Part IV, General Rules for Preparations 0931, Method II). The dissolution medium was 900 mL of pH 6.8 phosphate buffer, and the rotation speed was 50 rpm. Samples were taken at different time points and filtered online. The cumulative release rate of the tablets was calculated at 286 nm. The in vitro drug release curves are shown in Table 1 and [Table data missing]. Figure 1 As shown.

[0033] 2. Determination of the particle density of tofacitinib citrate sustained-release tablet cores Before tableting, the tofacitinib citrate sustained-release tablet cores prepared in Examples 1-3 and Comparative Examples 1-2 were added to 25ml volumetric flasks, filled to the mark, weighed (minus the weight of the volumetric flask), and the bulk density was calculated as shown in Table 1.

[0034] Table 1. Cumulative release rate (%) and core particle density of tofacitinib citrate extended-release tablets Time (h) Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 0 0 0 0 0 0 2 6.5 4.5 6 5.4 4.5 4 22.3 19.4 21.5 23.1 18.7 6 41.7 39.2 42.8 37.4 32.5 8 54.2 51.7 54.4 56.8 43.8 12 81.9 80.2 81.8 83.8 68.3 16 99.7 100.3 98.7 97.4 87.7 Core particle density 0.58 0.54 0.57 0.38 0.52 According to the experimental results in Table 1, the tofacitinib citrate sustained-release tablets prepared in Examples 1-3 of this invention exhibit essentially zero-order release of tofacitinib citrate, with stable release (see Table 1). Figure 1 In Comparative Example 1, the use of sorbitol instead of isomaltitol had almost no effect on the release of tofacitinib citrate (see Example 1). Figure 1 Comparative Example 2 used hydroxypropyl cellulose instead of polyvinylpyrrolidone, resulting in slower dissolution of tofacitinib citrate (see Example 2). Figure 1 This may be related to the fact that the coating effect of hydroxypropyl cellulose is not as good as that of polyvinylpyrrolidone. In addition, in Embodiments 1-3 of the present invention and Comparative Example 2, acrylic resin E and isomaltitol were used as excipients for granulation, and the prepared tofacitinib citrate particles had a high density; in Comparative Example 1, acrylic resin E and sorbitol were used as excipients for granulation, and the particle density was low, making tableting difficult.

[0035] Example 5: Stability test of tofacitinib citrate sustained-release tablets The results of tofacitinib citrate sustained-release tablets prepared in Examples 1-3 and Comparative Examples 1-2 after 6 months of accelerated treatment at 40°C and 75%RH were observed.

[0036] 1. Preparation of reference solution: Take an appropriate amount of tofacitinib citrate reference standard, accurately weigh it, dissolve it in the mobile phase and quantitatively dilute it to a solution containing approximately 0.1 mg tofacitinib per 1 mL.

[0037] 2. Preparation of test solution: Take an appropriate amount of the fine powder of this product (approximately equivalent to 10 mg of tofacitinib), accurately weigh it, place it in a 100 mL brown volumetric flask, add an appropriate amount of mobile phase, sonicate for 5 min to dissolve tofacitinib citrate, cool, dilute to the mark with mobile phase, shake well, filter, and collect the filtrate.

[0038] 3. Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the column packing material, and acetonitrile-phosphate buffer (20:80) was used as the mobile phase; the detection wavelength was 286 nm; the flow rate was 1.0 mL / min; the column temperature was 30 ℃; the acquisition time was 20 min; the injection volume was 20 μL, the column temperature was 30 ℃, and the flow rate was 0.75 mL / min. The determination results are shown in Table 2.

[0039] Table 2. Results of Tofacitinib Citrate Determination in Each Example sample Results on day 0 (%) Results (%) after 6 months of accelerated treatment at 40℃ and 75%RH Core color Example 1 99.64 98.54 White Example 2 98.98 99.72 White Example 3 99.32 98.49 White Comparative Example 1 101.46 96.29 pale yellow Comparative Example 2 99.75 99.56 White As can be seen from the experimental results in Table 2, the tofacitinib citrate sustained-release tablets prepared in Examples 1-3 and Comparative Example 2 of this invention showed that the content remained basically unchanged and the stability was good after accelerated testing. The formulation of Comparative Example 1, which used sorbitol as an excipient, had poor drug stability, reduced content, and slightly yellow tablet core color, which may be related to the fact that sorbitol is easy to absorb moisture and form chelated metal ions.

[0040] The embodiments of the present invention are given for illustrative and descriptive purposes only, and are not intended to be exhaustive or to limit the invention to the forms disclosed. Many modifications and variations will be apparent to those skilled in the art. The embodiments were chosen and described in order to better illustrate the principles and practical application of the invention, and to enable those skilled in the art to understand the invention and to design various embodiments with various modifications suitable for a particular purpose.

Claims

1. A tofacitinib citrate sustained-release tablet, comprising a sustained-release tablet core and a coating layer, characterized in that: The sustained-release tablet core is obtained by compressing a solid dispersion with pharmaceutically acceptable excipients. The solid dispersion is prepared by solvent evaporation of tofacitinib citrate with acrylic resin E and isomaltitol. The coating layer contains polyvinylpyrrolidone and tert-butyl-p-hydroxyanisole.

2. The tofacitinib citrate sustained-release tablet according to claim 1, characterized in that: The solvent used in the preparation of the solid dispersion by the solvent evaporation method is anhydrous ethanol.

3. The tofacitinib citrate sustained-release tablet according to claim 1, characterized in that: The weight ratio of tofacitinib citrate, acrylic resin E, and isomaltitol is 1:2-8:1-4.

4. The tofacitinib citrate sustained-release tablet according to claim 3, characterized in that: The weight ratio of tofacitinib citrate, acrylic resin E, and isomaltitol is 1:3-7:2-4.

5. The tofacitinib citrate sustained-release tablet according to claim 4, characterized in that: The weight ratio of tofacitinib citrate, acrylic resin E, and isomaltitol is 1:5:

3.

6. The tofacitinib citrate sustained-release tablet according to claim 5, characterized in that: The weight ratio of polyvinylpyrrolidone to tert-butyl-p-hydroxyanisole in the coating layer is 10:1-3.

7. The tofacitinib citrate sustained-release tablet according to claim 1, characterized in that, The preparation method of tofacitinib citrate sustained-release tablets includes the following steps: (1) Dissolve tofacitinib citrate, acrylic resin E and isomaltitol in anhydrous ethanol, dry under reduced pressure, and pass the dried material through a 100-mesh sieve to obtain a solid dispersion for later use. (2) Pass pharmaceutically acceptable excipients through a 100-mesh sieve and set aside; (3) Weigh the sieved solid dispersion and pharmaceutically acceptable excipients, mix them evenly, compress them into tablets, and obtain sustained-release tablet cores; (4) Dissolve polyvinylpyrrolidone and tert-butyl-p-hydroxyanisole in ethanol, and use this solution as a coating solution to coat the sustained-release tablet core to obtain tofacitinib citrate sustained-release tablets.

8. The method for preparing tofacitinib citrate sustained-release tablets according to claim 7, characterized in that: The pharmaceutically acceptable excipients are sodium carboxymethyl starch, microcrystalline cellulose, and magnesium stearate.

9. The method for preparing tofacitinib citrate sustained-release tablets according to claim 8, characterized in that: The weight ratio of sodium carboxymethyl starch, microcrystalline cellulose, and magnesium stearate is 1:10:1.

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