Tofacitinib citrate tablet and preparation process thereof

Abstract

The invention discloses a tofacitinib citrate tablet and a preparation process thereof, and belongs to the technical field of pharmaceutical preparations. According to the tofacitinib citrate tablet, tofacitinib citrate is taken as an effective component and matched with a filling agent, a stable dissolution promoter, a disintegrating agent, an adhesive and a lubricating agent, and a coating material can be selectively added; wherein the stable dissolution promoter is a combination of polyethylene glycol 4000, glycine and ethyl maltol. The preparation process comprises the following steps: pretreatment of the active ingredients, preparation of the stable dissolution promoter, wet granulation, tabletting and optional coating. The tofacitinib citrate tablet effectively solves the technical problems of insufficient stability and poor dissolution performance of the existing tofacitinib citrate tablet by optimizing the component matching, especially the synergistic effect of the specific ternary stable dissolution promoting agent combination, so that the preparation can be quickly and fully dissolved out in different pH environments, can resist the influence of severe storage environments, and can be used for preparing the tofacitinib citrate tablet. The drug degradation is reduced, and the medication safety and the clinical curative effect are guaranteed.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a tofacitinib citrate tablet and its preparation process. Background Technology

[0002] Rheumatoid arthritis, a highly disabling chronic autoimmune disease, is characterized by inflammatory infiltration of the synovial membrane and erosion and destruction of cartilage and bone tissue, severely impacting patients' quality of life and imposing a heavy medical burden. Its core pathogenesis lies in the abnormal activation of the JAK-STAT signaling pathway, leading to the massive release of inflammatory cytokines such as tumor necrosis factor and interleukins, thereby triggering persistent immune dysregulation and tissue damage. Therefore, targeting and regulating JAK kinase activity has become a key target for the treatment of this disease.

[0003] Tofacitinib citrate, the first oral selective Janus kinase (JAK) inhibitor, precisely inhibits the activity of kinase subtypes such as JAK1 and JAK3, blocking cytokine receptor-mediated signal transduction and suppressing the expression of inflammatory factors at their source, thus achieving a dual anti-inflammatory and immunomodulatory effect. Compared to the symptomatic treatment of traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and the injection administration of biologics, this drug has advantages such as convenient oral administration, rapid onset of action, and definite efficacy. The recommended dose is 5 mg twice daily. It can be used as monotherapy or in combination with disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, and has become an important cornerstone drug for the treatment of rheumatoid arthritis. In addition, its therapeutic potential in autoimmune diseases such as psoriatic arthritis, ulcerative colitis, and ankylosing spondylitis has been clinically validated, and some indications have been approved in Europe and the United States, with market demand continuing to expand.

[0004] With the widespread clinical application, optimizing the formulation performance of tofacitinib citrate tablets has become a research focus. Among these, formulation stability and dissolution are core indicators determining the clinical efficacy and safety of the drug. The tofacitinib citrate molecule contains multiple polar groups, and its active pharmaceutical ingredient (API) crystal form is easily transformed by the manufacturing process, leading to a decrease in content and excessive impurities during long-term storage, increasing the risk of adverse drug reactions. Furthermore, the drug's water solubility is somewhat limited; poor disintegration and dissolution behavior can cause fluctuations in bioavailability after oral administration, affecting the stability of blood drug concentrations and thus reducing the predictability of clinical efficacy.

[0005] While the currently disclosed formulation technologies for tofacitinib citrate tablets have made preliminary explorations in excipient combinations, significant shortcomings still exist. For example, Chinese patent CN105878202A uses Celactose 80 (microcrystalline cellulose lactose premix) as a filler, which improves particle flowability, but this premix is ​​prone to moisture absorption in high humidity environments and lacks stabilization measures. Chinese patent CN110946834A optimizes the filling system through a combination of spray-dried lactose F100 and microcrystalline cellulose PH102, and uses talc-free coating materials to improve coating stability.

[0006] In summary, existing tofacitinib citrate tablet formulations generally suffer from insufficient stability and poor dissolution performance, which restricts the safety and efficacy of the drug in clinical applications. Therefore, developing a tofacitinib citrate tablet formulation and its preparation process that can simultaneously improve both stability and dissolution has become a critical issue that urgently needs to be addressed in the current pharmaceutical formulation field. Summary of the Invention

[0007] This invention aims to overcome the shortcomings of existing tofacitinib citrate tablet formulations, such as insufficient stability and limited water solubility, and provides a tofacitinib citrate tablet and its preparation process that can simultaneously improve formulation stability and dissolution, thus solving the above-mentioned technical problems.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows: The composition of the tofacitinib citrate tablets of this invention, calculated in parts by weight, consists of the following components: Active ingredient: 5 parts tofacitinib citrate; filler: 80-300 parts, selected from at least one of microcrystalline cellulose, lactose, mannitol, pregelatinized starch, dicalcium phosphate, and dextrin; stabilizing solubilizer: 3.1-7.3 parts, a combination of polyethylene glycol 4000, glycine, and ethyl maltol, preferably polyethylene glycol 4000. 2-4 parts by weight, glycine 1-3 parts by weight, ethyl maltol 0.1-0.3 parts by weight; disintegrant: 8-12 parts, selected from at least one of crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and sodium alginate; binder: 4-8 parts, selected from at least one of 5%-10% povidone aqueous solution, 2%-3% hydroxypropyl methyl cellulose aqueous dispersion, 3%-8% hydroxypropyl cellulose aqueous solution, and 5%-10% starch paste solution; lubricant: 1-3 parts by weight, selected from at least one of magnesium stearate, micronized silica gel, talc, and sodium stearate fumarate; optional coating material: preferably a combination of 2-4 parts hydroxypropyl methyl cellulose, 0.5-1.5 parts titanium dioxide, and 0.3-0.8 parts triacetyl ester.

[0009] The preparation process of the tofacitinib citrate tablets of the present invention includes the following steps: (1) Pretreatment of tofacitinib citrate: Pulverize tofacitinib citrate to a particle size distribution D90≤50μm and set aside; at the same time, sieve the filler and disintegrant to remove impurities and lumps, and prepare the adhesive into an aqueous solution according to the corresponding concentration for use; if it contains coating material, add hydroxypropyl methylcellulose and titanium dioxide to purified water and stir at high speed until uniform, then add triacetyl ester and continue stirring to prepare a coating solution with a solid content of 8%, and sieve for use.

[0010] (2) Preparation of stable accelerator: Polyethylene glycol 4000 was dried in a vacuum drying oven at 45°C for 2 hours. After cooling, it was ground and mixed with glycine and ethyl maltol to prepare a premixed accelerator for later use.

[0011] (3) Wet granulation: The pretreated filler, disintegrant and premixed solvent are dry mixed until uniform, and the pulverized tofacitinib citrate is added and dry mixed again. The adhesive aqueous solution is sprayed in to obtain a soft material that "can be formed into a ball when squeezed and can be easily dispersed when touched". The soft material is transferred to a fluidized bed dryer and dried to a particle moisture content of 2.0%-3.0% under the conditions of inlet air temperature of 50-55℃, outlet air temperature ≤35℃ and wind speed of 1.2-1.5m / s. After cooling, it is granulated through an 18-mesh sieve and then mixed evenly with the lubricant in a three-dimensional motion mixer.

[0012] (4) Tableting: Use a rotary tablet press to compress tablets, adjust the pressure to 8-12kN, so that the tablet hardness is controlled at 50-80N and the brittleness is ≤0.5%.

[0013] (5) Coating: Transfer the uncoated tablets into a high-efficiency coating machine, set the coating pan speed to 20-25 rpm, the inlet air temperature to 60-65℃, the outlet air temperature to 38-42℃, and the atomization pressure to 0.3-0.4 MPa, spray the coating liquid evenly onto the surface of the uncoated tablets, and stop spraying when the tablet weight increases by 2%-3%. Continue to dry with forced air and then cool to room temperature to complete the coating.

[0014] Compared with the prior art, the present invention has the following beneficial effects: (1) Significantly improved dissolution performance: This invention innovatively adopts a ternary stable solubilizing combination of polyethylene glycol 4000, glycine and ethyl maltol. The three components produce a synergistic solubilizing effect, enabling the formulation to achieve rapid and sufficient dissolution in different pH environments simulating the gastrointestinal tract, such as pH 1.0 hydrochloric acid solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer.

[0015] (2) Optimization of formulation stability: The ternary stabilizing prosolvent combination of the present invention can effectively resist the effects of high temperature and high humidity environment on tofacitinib citrate. After accelerated stability test, the content of the formulation of the present invention is still maintained above 98.8%; after long-term stability test, the content is maintained above 99.4%, which effectively reduces the degradation risk during drug storage and ensures drug safety. Detailed Implementation

[0016] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0017] Example 1: Tofacitinib Citrate Tablets and Their Preparation Process formula: Preparation process: (1) Pretreatment of main and auxiliary materials: Tofacitin citrate is placed in an air jet mill and the grinding pressure is set to 0.6-0.8MPa. After grinding, it is sieved to ensure that the particle size distribution D90≤50μm and is ready for use. Filler and disintegrant are sieved through an 80-mesh sieve to remove impurities and lumps and are ready for use. Take the binder, add purified water, stir until completely dissolved, and prepare an aqueous solution for use. Add hydroxypropyl methylcellulose and titanium dioxide to purified water in sequence, stir at high speed for 30 minutes until uniform, then add triacetylglycerol and continue stirring for 15 minutes to prepare a coating solution with a solid content of 8%, sieve through a 100-mesh sieve and is ready for use.

[0018] (2) Preparation of stable accelerator: Polyethylene glycol 4000 was dried in a vacuum drying oven at 45°C for 2 hours. After cooling, it was ground together with glycine and ethyl maltol for 3-8 minutes and mixed evenly to prepare a premixed accelerator for later use. (3) Wet granulation process Mixing and granulation: Add the pretreated filler, disintegrant, and premixed solvent to a high-efficiency wet granulator. Set the stirring speed to 150 rpm and the cutter speed to 1000 rpm. Dry mix for 5 minutes until uniform. Add the pulverized tofacitinib citrate and continue to dry mix for 3 minutes. Slowly spray the prepared adhesive aqueous solution into the mixture. Control the spraying speed at 5-8 mL / min. During the spraying process, maintain the stirring speed at 200 rpm and the cutter speed at 1200 rpm until a soft material that can be formed by "forming a clump when squeezed and crumbling when lightly touched" is formed.

[0019] Wet particle drying: Transfer the obtained wet particles into a fluidized bed dryer, set the inlet air temperature to 50-55℃, the outlet air temperature to ≤35℃, and the air velocity to 1.2-1.5m / s, and carry out fluidized bed drying. Take samples every 10 minutes to measure the particle moisture content. When the particle moisture content drops to 2.0%-3.0%, stop drying and cool to room temperature.

[0020] Granulation and mixing: The dried granules are granulated using an 18-mesh sieve to remove coarse particles and fine powder. The granulated granules are then added to a three-dimensional motion mixer with lubricant. The mixing speed is set to 25 rpm and the mixture is stirred for 5-8 minutes until it is uniform.

[0021] (4) Tableting process: A rotary tablet press is used for tableting. The pressure of the tablet press is adjusted to 8-12kN to control the tablet hardness at 50-80N and the brittleness ≤0.5%.

[0022] (5) Coating process: Transfer the compressed uncoated tablets into a high-efficiency coating machine. Set the coating pan speed to 20-25 rpm, inlet air temperature to 60-65℃, outlet air temperature to 38-42℃, and atomization pressure to 0.3-0.4 MPa. Spray the prepared coating solution evenly onto the surface of the uncoated tablets using a peristaltic pump. Control the spraying speed at 3-5 mL / min to ensure that the coating solution evenly covers the tablet surface. When the tablet weight gain reaches 2%-3%, stop spraying, continue drying with forced air for 5 minutes, and cool to room temperature to complete the coating process.

[0023] Example 2: Tofacitinib Citrate Tablets and Their Preparation Process formula: Preparation process: (1) Pretreatment of main and auxiliary materials: Tofacitin citrate is placed in an air jet mill and the grinding pressure is set to 0.6-0.8MPa. After grinding, it is sieved to ensure that the particle size distribution D90≤50μm and is ready for use. Filler and disintegrant are sieved through an 80-mesh sieve to remove impurities and lumps and are ready for use. Take the binder, add purified water, stir until completely dissolved, and prepare an aqueous solution for use. Add hydroxypropyl methylcellulose and titanium dioxide to purified water in sequence, stir at high speed for 30 minutes until uniform, then add triacetylglycerol and continue stirring for 15 minutes to prepare a coating solution with a solid content of 8%, sieve through a 100-mesh sieve and is ready for use.

[0024] (2) Preparation of stable accelerator: Polyethylene glycol 4000 was dried in a vacuum drying oven at 45°C for 2 hours. After cooling, it was ground together with glycine and ethyl maltol for 3-8 minutes and mixed evenly to prepare a premixed accelerator for later use. (3) Wet granulation process Mixing and granulation: Add the pretreated filler, disintegrant, and premixed solvent to a high-efficiency wet granulator. Set the stirring speed to 150 rpm and the cutter speed to 1000 rpm. Dry mix for 5 minutes until uniform. Add the pulverized tofacitinib citrate and continue to dry mix for 3 minutes. Slowly spray the prepared adhesive aqueous solution into the mixture. Control the spraying speed at 5-8 mL / min. During the spraying process, maintain the stirring speed at 200 rpm and the cutter speed at 1200 rpm until a soft material that can be formed by "forming a clump when squeezed and crumbling when lightly touched" is formed.

[0025] Wet particle drying: Transfer the obtained wet particles into a fluidized bed dryer, set the inlet air temperature to 50-55℃, the outlet air temperature to ≤35℃, and the air velocity to 1.2-1.5m / s, and carry out fluidized bed drying. Take samples every 10 minutes to measure the particle moisture content. When the particle moisture content drops to 2.0%-3.0%, stop drying and cool to room temperature.

[0026] Granulation and mixing: The dried granules are granulated using an 18-mesh sieve to remove coarse particles and fine powder. The granulated granules are then added to a three-dimensional motion mixer with lubricant. The mixing speed is set to 25 rpm and the mixture is stirred for 5-8 minutes until it is uniform.

[0027] (4) Tableting process: A rotary tablet press is used for tableting. The pressure of the tablet press is adjusted to 8-12kN to control the tablet hardness at 50-80N and the brittleness ≤0.5%.

[0028] (5) Coating process: Transfer the compressed uncoated tablets into a high-efficiency coating machine. Set the coating pan speed to 20-25 rpm, inlet air temperature to 60-65℃, outlet air temperature to 38-42℃, and atomization pressure to 0.3-0.4 MPa. Spray the prepared coating solution evenly onto the surface of the uncoated tablets using a peristaltic pump. Control the spraying speed at 3-5 mL / min to ensure that the coating solution evenly covers the tablet surface. When the tablet weight gain reaches 2%-3%, stop spraying, continue drying with forced air for 5 minutes, and cool to room temperature to complete the coating process.

[0029] Example 3: Tofacitinib Citrate Tablets and Their Preparation Process formula: Preparation process: (1) Pretreatment of main and auxiliary materials: Tofacitin citrate is placed in an air jet mill and the grinding pressure is set to 0.6-0.8MPa. After grinding, it is sieved to ensure that the particle size distribution D90≤50μm and is ready for use. Filler and disintegrant are sieved through an 80-mesh sieve to remove impurities and lumps and are ready for use. Take the binder, add purified water, stir until completely dissolved, and prepare an aqueous solution for use. Add hydroxypropyl methylcellulose and titanium dioxide to purified water in sequence, stir at high speed for 30 minutes until uniform, then add triacetylglycerol and continue stirring for 15 minutes to prepare a coating solution with a solid content of 8%, sieve through a 100-mesh sieve and is ready for use.

[0030] (2) Preparation of stable accelerator: Polyethylene glycol 4000 was dried in a vacuum drying oven at 45°C for 2 hours. After cooling, it was ground together with glycine and ethyl maltol for 3-8 minutes and mixed evenly to prepare a premixed accelerator for later use. (3) Wet granulation process Mixing and granulation: Add the pretreated filler, disintegrant, and premixed solvent to a high-efficiency wet granulator. Set the stirring speed to 150 rpm and the cutter speed to 1000 rpm. Dry mix for 5 minutes until uniform. Add the pulverized tofacitinib citrate and continue to dry mix for 3 minutes. Slowly spray the prepared adhesive aqueous solution into the mixture. Control the spraying speed at 5-8 mL / min. During the spraying process, maintain the stirring speed at 200 rpm and the cutter speed at 1200 rpm until a soft material that can be formed by "forming a clump when squeezed and crumbling when lightly touched" is formed.

[0031] Wet particle drying: Transfer the obtained wet particles into a fluidized bed dryer, set the inlet air temperature to 50-55℃, the outlet air temperature to ≤35℃, and the air velocity to 1.2-1.5m / s, and carry out fluidized bed drying. Take samples every 10 minutes to measure the particle moisture content. When the particle moisture content drops to 2.0%-3.0%, stop drying and cool to room temperature.

[0032] Granulation and mixing: The dried granules are granulated using an 18-mesh sieve to remove coarse particles and fine powder. The granulated granules are then added to a three-dimensional motion mixer with lubricant. The mixing speed is set to 25 rpm and the mixture is stirred for 5-8 minutes until it is uniform.

[0033] (4) Tableting process: A rotary tablet press is used for tableting. The pressure of the tablet press is adjusted to 8-12kN to control the tablet hardness at 50-80N and the brittleness ≤0.5%.

[0034] (5) Coating process: Transfer the compressed uncoated tablets into a high-efficiency coating machine. Set the coating pan speed to 20-25 rpm, inlet air temperature to 60-65℃, outlet air temperature to 38-42℃, and atomization pressure to 0.3-0.4 MPa. Spray the prepared coating solution evenly onto the surface of the uncoated tablets using a peristaltic pump. Control the spraying speed at 3-5 mL / min to ensure that the coating solution evenly covers the tablet surface. When the tablet weight gain reaches 2%-3%, stop spraying, continue drying with forced air for 5 minutes, and cool to room temperature to complete the coating process.

[0035] Example 4: Tofacitinib Citrate Tablets and Their Preparation Process formula: Preparation process: (1) Pretreatment of main and auxiliary materials: Tofacitin citrate is placed in an air jet mill and the grinding pressure is set to 0.6-0.8MPa. After grinding, it is sieved to ensure that the particle size distribution D90≤50μm and is ready for use. Filler and disintegrant are sieved through an 80-mesh sieve to remove impurities and lumps and are ready for use. Take the binder, add purified water, stir until completely dissolved, and prepare an aqueous solution for use. Add hydroxypropyl methylcellulose and titanium dioxide to purified water in sequence, stir at high speed for 30 minutes until uniform, then add triacetylglycerol and continue stirring for 15 minutes to prepare a coating solution with a solid content of 8%, sieve through a 100-mesh sieve and is ready for use.

[0036] (2) Preparation of stable accelerator: Polyethylene glycol 4000 was dried in a vacuum drying oven at 45°C for 2 hours. After cooling, it was ground together with glycine and ethyl maltol for 3-8 minutes and mixed evenly to prepare a premixed accelerator for later use. (3) Wet granulation process Mixing and granulation: Add the pretreated filler, disintegrant, and premixed solvent to a high-efficiency wet granulator. Set the stirring speed to 150 rpm and the cutter speed to 1000 rpm. Dry mix for 5 minutes until uniform. Add the pulverized tofacitinib citrate and continue to dry mix for 3 minutes. Slowly spray the prepared adhesive aqueous solution into the mixture. Control the spraying speed at 5-8 mL / min. During the spraying process, maintain the stirring speed at 200 rpm and the cutter speed at 1200 rpm until a soft material that can be formed by "forming a clump when squeezed and crumbling when lightly touched" is formed.

[0037] Wet particle drying: Transfer the obtained wet particles into a fluidized bed dryer, set the inlet air temperature to 50-55℃, the outlet air temperature to ≤35℃, and the air velocity to 1.2-1.5m / s, and carry out fluidized bed drying. Take samples every 10 minutes to measure the particle moisture content. When the particle moisture content drops to 2.0%-3.0%, stop drying and cool to room temperature.

[0038] Granulation and mixing: The dried granules are granulated using an 18-mesh sieve to remove coarse particles and fine powder. The granulated granules are then added to a three-dimensional motion mixer with lubricant. The mixing speed is set to 25 rpm and the mixture is stirred for 5-8 minutes until it is uniform.

[0039] (4) Tableting process: A rotary tablet press is used for tableting. The pressure of the tablet press is adjusted to 8-12kN to control the tablet hardness at 50-80N and the brittleness ≤0.5%.

[0040] (5) Coating process: Transfer the compressed uncoated tablets into a high-efficiency coating machine. Set the coating pan speed to 20-25 rpm, inlet air temperature to 60-65℃, outlet air temperature to 38-42℃, and atomization pressure to 0.3-0.4 MPa. Spray the prepared coating solution evenly onto the surface of the uncoated tablets using a peristaltic pump. Control the spraying speed at 3-5 mL / min to ensure that the coating solution evenly covers the tablet surface. When the tablet weight gain reaches 2%-3%, stop spraying, continue drying with forced air for 5 minutes, and cool to room temperature to complete the coating process.

[0041] Experimental Design for Screening Stable Solvents of Tofacitinib Citrate Tablets Based on the formulation and process of Example 1, multiple candidate stable solubilizers were designed to meet the requirements of dissolution performance and storage stability of tofacitinib citrate tablets. By detecting the core indicators of dissolution and stability, the optimal stable solubilizer combination with both excellent solubilizing effect and stability guarantee was screened out, clarifying the role and value of each component and combination, and providing a basis for formulation optimization.

[0042] Experimental design principles Variable focus principle: The only variable in the experiment is the "composition of the stable pro-solvent", including the presence or absence of components, single components, binary combinations, and similar excipient substitutions; the dosage of active ingredients, the types and dosages of other excipients such as fillers, disintegrants, and binders, as well as all process parameters such as granulation, tableting, and coating are strictly in accordance with Example 1 to ensure that the experimental results can accurately reflect the performance differences of the stable pro-solvent.

[0043] Weight balance principle: Based on the total amount of 5.2g of the ternary combination of "polyethylene glycol 4000 + glycine + ethyl maltol" in Example 1, the weight of the stable co-solvent component that is reduced or missing in groups G5-G14 is made up by the filler (microcrystalline cellulose) in Example 1; when similar excipients are replaced, the total weight of the stable co-solvent remains unchanged, and there is no need to adjust the amount of filler, so as to ensure that the total weight of tablets, tableting pressure and other key process parameters of each group are consistent and to avoid interference from non-variable factors.

[0044] Parallel reproducibility principle: Three batches of parallel samples are prepared for each candidate scheme, and three parallel samples are set for each test of each batch of samples. By repeating multiple times, random errors are reduced, and the reliability and reproducibility of the screening results are ensured.

[0045] Table 1. Stable Solvent Combination Design Dissolution test According to the Dissolution Determination Method (Paddle Method) of Part IV of the 2020 Edition of the Chinese Pharmacopoeia, the conditions were as follows: dissolution media were 900 mL of pH 1.0 hydrochloric acid solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer, respectively; temperature was 37℃±0.5℃; paddle speed was 50 rpm; detection time points were 2 min, 5 min, 15 min, and 30 min; detection method was high performance liquid chromatography (HPLC) to determine the concentration of tofacitinib citrate in the dissolution solution and calculate the cumulative dissolution rate (%).

[0046] Table 2 Dissolution of Tofacitinib Citrate Tablets Table 2 shows the conclusions and analysis, indicating that different stable solubilizer combinations significantly affect the dissolution performance of tofacitinib citrate tablets. The formulation containing polyethylene glycol 4000, glycine, and ethyl maltol exhibited rapid and complete dissolution in dissolution media with different pH values ​​simulating the gastrointestinal tract, with a stable dissolution process and no obvious media dependence. The solubilizing effect of single components or binary combinations was inferior to that of ternary combinations. The dissolution efficiency of the blank control group (without stable solubilizer) was significantly lower, indicating a synergistic effect of the three components in solubilization. Formulations using similar component replacements showed a decrease in dissolution performance compared to the original ternary combination, confirming the optimal compatibility of the original combination. The dissolution performance of tofacitinib citrate tablets in Examples 1-4 of this invention is superior to commercially available formulations, demonstrating the technical advantages of this formulation in improving drug dissolution and enhancing bioavailability.

[0047] Stability test (1) Accelerated stability test Conditions: 40℃±2℃, relative humidity (RH) 75%±5%, sealed packaging and stored for 6 months. Sampling time points: 0 months (initial), 1 month, 3 months, and 6 months. The content of tofacitinib citrate was determined by high performance liquid chromatography.

[0048] (2) Long-term stability test Conditions: 25℃±2℃, relative humidity (RH) 60%±5%, sealed packaging and stored for 12 months. Sampling time points: 0 months (initial), 3 months, 6 months, and 12 months. The content of tofacitinib citrate was determined by high performance liquid chromatography.

[0049] Table 3. Accelerated Test Content of Tofacitinib Citrate Table 3 shows that the content stability of tofacitinib citrate tablets under accelerated storage conditions is closely related to the stabilizing prosolvent combination. The tofacitinib citrate tablets of Examples 1-4 of this invention, containing a ternary stabilizing prosolvent, exhibited minimal content decline during 6 months of accelerated storage, maintaining a consistently high level and demonstrating excellent stability. The blank control group, lacking stabilizing prosolvent protection, showed the most significant content decline, indicating a clear risk of degradation. The content decline in the single-component or binary combination groups was greater than that in the ternary combination group, indicating that the synergistic effect of the three components can more effectively inhibit drug degradation. The content stability of similar component replacement groups and commercially available formulations was inferior to the original ternary combination formulation of this invention, further confirming the unique value of this stabilizing prosolvent combination in resisting high temperature and humidity environments and ensuring the stability of formulation quality.

[0050] Table 4. Tofacitinib citrate content in long-term trials Table 4 shows that under long-term storage conditions, the content change trend of the formulation is consistent with that of the accelerated stability test, and the overall degradation rate is more gradual, which is consistent with the quality change law of drugs under long-term storage. After 12 months of long-term storage, the contents of each of the embodiments 1-4 of this invention remained at a high level with a small decrease, meeting the quality requirements for long-term storage of the formulation. The content of the blank control group continued to decrease significantly, indicating extremely poor long-term stability; the content decrease of the single-component, binary combination, and similar component replacement groups was significantly greater than that of the ternary combination formulation of this invention, indicating insufficient stability. Although commercially available formulations can maintain a certain degree of long-term stability, they are still inferior to the performance of the embodiments of this invention, indicating that this invention significantly improves the long-term storage reliability of tofacitinib citrate tablets and reduces the risk of medication by optimizing the stable prosolvent combination.

Claims

1. A tofacitinib citrate tablet, characterized in that, The tofacitinib citrate tablets are composed of the following components by weight: 5 parts tofacitinib citrate, 80-300 parts filler, 3.1-7.3 parts stabilizing solvent, 8-12 parts disintegrant, 4-8 parts binder, and 1-3 parts lubricant; the stabilizing solvent is a combination of polyethylene glycol 4000, glycine, and ethyl maltol.

2. The tofacitinib citrate tablet according to claim 1, characterized in that, The stabilizing solvent is 2-4 parts by weight of polyethylene glycol 4000, 1-3 parts by weight of glycine, and 0.1-0.3 parts by weight of ethyl maltol.

3. The tofacitinib citrate tablet according to claim 1, characterized in that, The filler is selected from at least one of microcrystalline cellulose, lactose, mannitol, pregelatinized starch, dicalcium phosphate, and dextrin.

4. The tofacitinib citrate tablet according to claim 1, characterized in that, The disintegrant is selected from at least one of crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and sodium alginate.

5. The tofacitinib citrate tablet according to claim 1, characterized in that, The adhesive is selected from at least one of the following: 5%-10% povidone aqueous solution, 2%-3% hydroxypropyl methylcellulose aqueous dispersion, 3%-8% hydroxypropyl cellulose aqueous solution, and 5%-10% starch paste solution.

6. The tofacitinib citrate tablet according to claim 1, characterized in that, The lubricant is selected from at least one of magnesium stearate, micronized silica gel, talc, and sodium stearate fumarate.

7. The tofacitinib citrate tablet according to claim 1, characterized in that, The tofacitinib citrate tablets also contain a coating material.

8. The tofacitinib citrate tablet according to claim 7, characterized in that, The coating material is hydroxypropyl methylcellulose, titanium dioxide, and triacetin.

9. The tofacitinib citrate tablet according to claim 8, characterized in that, The coating material consists of 2-4 parts hydroxypropyl methylcellulose, 0.5-1.5 parts titanium dioxide, and 0.3-0.8 parts triacetylglycerol.

10. A process for preparing tofacitinib citrate tablets according to any one of claims 1-9, characterized in that, The preparation process includes the following steps: (1) Pretreatment of tofacitinib citrate: Tofacitinib citrate was pulverized to D90≤50μm and set aside; (2) Preparation of stable accelerator: Polyethylene glycol 4000 was dried in a vacuum drying oven at 45°C for 2 hours. After cooling, it was ground and mixed with glycine and ethyl maltol to prepare a premixed accelerator for later use. (3) Wet granulation: Dry mix the filler, disintegrant, and premixed solvent until uniform, add the pulverized tofacitinib citrate, dry mix, spray in the adhesive aqueous solution, make soft material, dry, granulate, sieve, add lubricant, and mix together. (4) Tableting; (5) Coating.

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