Tofacitinib citrate osmotic pump sustained release tablet and preparation method thereof

Abstract

The invention discloses a citric acid tofacitinib osmotic pump sustained-release tablet, which comprises a citric acid tofacitinib tablet core and a sustained-release coating layer coated on the surface of the citric acid tofacitinib tablet core, the citric acid tofacitinib tablet core contains a waxy framework material, and the sustained-release coating layer contains a sustained-release membrane material and a pore-foaming agent; the slow-release membrane material is composed of eudragit RL and eudragit RS; the pore-foaming agent is a water-soluble pore-foaming agent. The invention also discloses a preparation method of the tofacitinib citrate osmotic pump sustained release tablet, which comprises the following steps: uniformly mixing the components of the tablet core, and tabletting to obtain the tablet core; coating the tablet core, preserving heat and curing to obtain the tofacitinib citrate osmotic pump sustained release tablet. According to the invention, the corrosion controlled release of the waxy framework material and the controlled release coating layer are hierarchically coupled, so that the drug release stability is obviously improved, the tolerance to the change of the gastrointestinal tract physiological environment is stronger, and the dissolution of the drug is not reduced after long-term storage.

Description

Technical Field

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

[0002] Tofacitinib citrate is a Janus kinase (JAK) inhibitor developed by Pfizer. JAK is an intracellular enzyme that transduces signals generated by cytokine or growth factor-receptor interactions on the cell membrane, thereby affecting hematopoiesis and cellular immune function. Within this signal transduction pathway, JAK phosphorylates and activates signal transduction factors and activators of transcription (STATs), thereby regulating intracellular activities, including gene expression. Tofacitinib citrate exerts its therapeutic effect by regulating the JAK signal transduction pathway, preventing STAT phosphorylation and activation. It is currently mainly used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis.

[0003] Tofacitinib citrate was initially marketed in an immediate-release formulation, requiring adult patients to take it twice daily, which resulted in poor patient compliance. Pfizer subsequently developed a once-daily sustained-release formulation. The original tofacitinib citrate sustained-release tablet XR consists of a tablet core, a semi-permeable membrane sustained-release coating, and a gastrointestinal film coating. The sample is a pink, oval film-coated tablet, which appears white or off-white after removing the coating. A laser is used to punch release holes in the drug-containing coating film on the side of the oval tablet. The punching machine requires extremely high precision in controlling the punching position, resulting in low production efficiency, high production costs, and dissolution behavior that is greatly affected by pH fluctuations. The production process involves the use of excipients such as methanol and acetone, which pose risks to health and even blindness. The process is complex, the production equipment is expensive, requires high precision, is inconvenient to operate, and has a long production cycle.

[0004] Meanwhile, some related research has made improvements, but all of them have different drawbacks. For example, patent CN105101952B mainly uses 60-85% sorbitol as the tablet core permeation agent, and the semi-permeable membrane coating is mainly composed of cellulose acetate and hydroxypropyl cellulose in a weight ratio of 6:4. Because sorbitol is highly hygroscopic, the ambient humidity must be strictly controlled during the production process to ensure that it does not absorb moisture during the mixing and tableting process. In addition, because the semi-permeable membrane coating uses a large proportion of hydroxypropyl cellulose as a pore-forming agent, it needs to be dissolved in the polar solvent methanol before coating, which introduces a potentially blinding toxic reagent and brings safety hazards. Moreover, the dissolution data range under this patent is relatively wide, and it fails to better and more accurately control the release behavior. The dissolution rate of the formulation slows down after long-term storage.

[0005] Patent CN 112587492 A discloses a tofacitinib citrate sustained-release tablet with dual membrane-controlled and matrix-based sustained release. Its preparation process is relatively simple: (1) Tofacitinib citrate raw material, waxy matrix material, filler, lubricant, etc., are sieved separately with a mesh size of 20-30 mesh; after sieving, they are mixed using a mixer to obtain a powder for tableting; (2) The powder from (1) is taken out and compressed into tablets using a tablet press; (3) At this time, the tofacitinib citrate tablets obtained in (2) are taken out, and the sustained-release coating material is coated onto the drug tablet core using a coating device to obtain the final sustained-release coated tablet. The waxy matrix material can be one or more of hydrogenated vegetable oil, glyceryl stearate, and glyceryl behenate; the sustained-release coating material can be one or more of ethyl cellulose, cellulose acetate, and cellulose aqueous dispersion. However, research has found that its dissolution behavior is greatly affected by pH fluctuations and cannot maintain stable dissolution behavior in different pH environments.

[0006] Therefore, there is an urgent need to develop a sustained-release formulation of tofacitinib citrate that can avoid the use of toxic solvents such as methanol, has high process safety, fundamentally overcomes the long-term storage stability problem caused by strong hygroscopicity, and can precisely control drug release behavior to maintain stable dissolution in different pH environments. Summary of the Invention

[0007] Based on the technical problems existing in the background technology, this invention proposes a tofacitinib citrate osmotic pump sustained-release tablet and its preparation method. This invention hierarchically couples the controlled release of the waxy matrix material with the swelling microporous membrane control of the sustained-release membrane material, Utec RL and RS. The Utec combined sustained-release coating membrane with controlled release effect is responsible for "slow start", while the waxy matrix material is responsible for "stable release". The two work together to achieve slow and long-term drug release without burst release or incomplete release in the later stage. The dissolution behavior is not significantly different within the physiological pH range, and the in vivo and in vitro correlation is good. pH has no significant effect on drug release behavior. The tablet core of this invention does not contain highly hygroscopic excipients, so the drug does not easily absorb water during long-term storage, and the dissolution and release are stable. Moreover, this invention avoids the use of highly toxic solvents such as methanol and acetone during coating. The process is simple, the production cycle is short, the operation is simple, and it is suitable for industrialization.

[0008] This invention proposes a tofacitinib citrate osmotic pump sustained-release tablet, comprising: a tofacitinib citrate tablet core and a sustained-release coating layer covering the surface of the tofacitinib citrate tablet core, wherein the tofacitinib citrate tablet core contains a waxy skeleton material, and the sustained-release coating layer contains a sustained-release membrane material and a pore-forming agent. The waxy skeleton material is at least one of hydrogenated vegetable oil, glyceryl stearate, and glyceryl behenate; the sustained-release membrane material is composed of Utec RL and Utec RS; and the pore-forming agent is a water-soluble pore-forming agent.

[0009] Preferably, the weight ratio of ULTECH RL to ULTECH RS is 1:0.7-1.5.

[0010] Preferably, the pore-forming agent is at least one of triethyl citrate, polyethylene glycol, and glycerin.

[0011] Preferably, the coating layer accounts for 8-12 wt% of the core weight.

[0012] Preferably, the amount of pore-forming agent is 5-10 wt% of the weight of the slow-release membrane material.

[0013] Preferably, the content of waxy skeleton material in the tofacitinib citrate tablet core is 25-35 wt%; the content of tofacitinib is 5-6 wt%.

[0014] Preferably, the tofacitinib citrate core also contains one or more fillers and lubricants.

[0015] The fillers mentioned above can be lactose, etc.; the lubricants can be magnesium stearate, talc, etc.

[0016] In the above-mentioned tofacitinib citrate tablet core, the content of filler is 60-80 wt%; in the above-mentioned tofacitinib citrate tablet core, the content of lubricant is 1-3 wt%; and the total content of all components in the above-mentioned tofacitinib citrate tablet core is 100 wt%.

[0017] The above-mentioned tofacitinib citrate osmotic pump sustained-release tablets contain 11 mg of tofacitinib per tablet.

[0018] Dissolution was determined using the paddle method at 50 rpm in pH 6.8 phosphate buffer. The cumulative dissolution of tofacitinib citrate osmotic pump sustained-release tablets was ≤13% at 1 h, 36-62% at 2.5 h, and ≥85% at 6 h. The cumulative dissolution at 6 h was denoted as R1. Dissolution was determined using the paddle method at 50 rpm in hydrochloric acid at pH 1.2. The cumulative dissolution of tofacitinib citrate osmotic pump sustained-release tablets over 6 hours differed from R1 by ≤5%.

[0019] The dissolution rate was tested using the paddle method according to Method II of General Chapter 0931, Part IV, 2025 edition of the Pharmacopoeia of the People's Republic of China.

[0020] The present invention also proposes a method for preparing the above-mentioned tofacitinib citrate osmotic pump sustained-release tablets, comprising the following steps: mixing the components of the tablet core, compressing the tablet core to obtain the tablet core; coating the tablet core, and heat-curing to obtain the tofacitinib citrate osmotic pump sustained-release tablets.

[0021] Preferably, the coating conditions are: inlet air temperature of 50-60℃, outlet air temperature of 25-35℃, and atomization pressure of 0.05-0.1MPa.

[0022] Preferably, the product is cured at 30-50℃ for 20-28 hours.

[0023] The slow-release membrane material and pore-forming agent are formulated into a coating solution to coat the tablet core.

[0024] The solvent for the above coating solution is an aqueous ethanol solution with a volume fraction of 70-80%; more preferably, it is an aqueous ethanol solution with a volume fraction of 75%.

[0025] The solid content of the coating solution is 10-14 wt%; more preferably 12 wt%.

[0026] This invention combines the controlled release of a waxy matrix material through dissolution with the controlled release of a swollen microporous membrane using the sustained-release membrane materials Utec RL and RS, thereby overcoming the inherent limitations of single matrix or single membrane control technologies and achieving precise regulation of drug release with "double insurance".

[0027] The hierarchical coupling between the erosion-controlled release of the waxy framework material and the sustained-release swelling coating of the Utec RL and RS membranes is essentially an osmotic pump system with an initial barrier. Through precise time relay in three stages, it achieves the coupling of "slow start" and "stable release": In the initial release phase, after the osmotic pump sustained-release tablet enters the body, the pore-forming agent in the sustained-release coating layer can be dissolved, and the sustained-release membrane material swells to form a porous sustained-release layer. With a waxy skeleton as the main component, utilizing its hydrophobic and slow-dissolving properties, it forms a double barrier with the controllable low water permeability of the Eutectic RL / RS coating film, ensuring that the waxy sustained-release skeleton remains intact in the early stage after entering the gastric juice, effectively inhibiting drug dissolution and avoiding burst release from the source. In addition, the pore-forming agent can reduce the surface tension of the coating liquid, making it easier to coat the tablet core surface and avoiding problems such as blemishes on the sustained-release coating layer. During the mid-release phase, as water seeps in, the rate of skeleton dissolution and the water permeability rate of the coating membrane are synergistically matched. The micropores formed by skeleton dissolution become the delivery channels for the drug solution, achieving a seamless transition from skeleton dissolution controlled release to osmotic pressure controlled release. In the later stages of release, the skeleton is basically dissolved. At this point, the Eutec RL / RS hybrid coating membrane, with its pH independence and precisely regulated permeability, becomes the dominant force in controlled release, pumping out the drug at a constant rate to ensure a slow and long-lasting release. This invention achieves hierarchical coupling between the controlled release of a waxy matrix material through dissolution and the controlled release of a sustained-release membrane material, Utec RL and RS, through swelling microporous membrane control. This results in no significant difference in the dissolution behavior of tofacitinib citrate osmotic pump sustained-release tablets within the physiological pH range, demonstrating good in vitro and in vivo correlation, and showing no significant effect of pH on drug release behavior. Furthermore, this invention avoids the use of highly toxic solvents such as methanol and acetone during coating, reducing the amount of solvent material required. It is also non-hygroscopic, overcoming the long-term storage stability issues caused by hygroscopicity. The process is simple, the production cycle is short, and the operation is straightforward, making it suitable for industrialization. Attached Figure Description

[0028] Figure 1 The pharmacokinetic curves are for commercially available tofacitinib osmotic pump sustained-release tablets and the formulation obtained in Example 1. Detailed Implementation

[0029] The technical solution of the present invention will be described in detail below through specific embodiments. However, it should be clearly stated that these embodiments are only for illustrative purposes and are not intended to limit the scope of the present invention.

[0030] Examples 1-13 Tofacitinib citrate osmotic pump sustained-release tablets were prepared according to the formulations in Table 1.

[0031] Table 1 Formulations of Examples 1-13

[0032] Note: 17.8mg tofacitinib citrate contains 11mg of the active ingredient tofacitinib.

[0033] The preparation method of the tofacitinib citrate osmotic pump sustained-release tablets in Examples 1-13 above is the same, including the following steps: Pass the tofacitinib citrate through a 50-mesh sieve and the anhydrous lactose through an 80-mesh sieve, and set aside. Tofacitinib citrate, waxy matrix material, and anhydrous lactose were put into a mixer and mixed for 18 minutes. Magnesium stearate was added and mixed for 4 minutes. The mixed powder was compressed into tablets, with the hardness controlled at 6-10 kg and the tablet weight difference ±3.0%, to obtain tofacitinib citrate tablet cores. The slow-release membrane material and pore-forming agent were added to the coating solvent and magnetically stirred for 25 minutes until completely dissolved to obtain a coating solution with a solid content of 12 wt%. Take the above coating solution and coat the tofacitinib citrate tablet core with a Xiaolun coating machine. The coating conditions are: inlet air temperature of 50-60℃, outlet air temperature of 25-35℃, and atomization pressure of 0.1MPa. Then, it is cured in an oven at 30-50℃ for 20-28 hours to obtain tofacitinib citrate osmotic pump sustained-release tablets.

[0034] The products from Examples 1-13 and the original formulation (Shangjie / 11mg / batch number DP7374) were subjected to cumulative dissolution testing according to Method II of General Chapter 0931, Part IV of the 2025 Chinese Pharmacopoeia. The specific steps are as follows: Dissolution media were prepared using 900 ml of pH 1.2 hydrochloric acid (7 ml of hydrochloric acid diluted to 1000 ml) and 900 ml of pH 6.8 phosphate buffer (40.8 g of potassium dihydrogen phosphate dissolved in water and diluted to 6000 ml, pH adjusted to 6.8 ± 0.05 with 3 mol / L potassium hydroxide). The dissolution was performed at 50 rpm. The test sample was added to a settling basket, and 10 ml of the solution was collected at 1 h, 2.5 h, and 6 h. The solution was filtered, and the initial filtrate (3 ml) was discarded. The subsequent filtrate was used as the test solution, and dissolution media of the same temperature and volume were replenished promptly. The content of tofacitinib citrate in the test solution was detected by high performance liquid chromatography using the external standard method. The cumulative dissolution rate was calculated. Six tablets were tested in parallel for each group, and the average value was taken. The results are shown in Table 2-3.

[0035] Table 2. Cumulative dissolution of the original formulation in hydrochloric acid at pH 1.2, Examples 1-13.

[0036] Table 3. Cumulative dissolution of the original formulation in pH 6.8 phosphate buffer solution (Examples 1-13)

[0037] As shown in Tables 2-3, the products of Examples 1-13 achieved a cumulative dissolution rate of over 90% in pH 1.2 hydrochloric acid and pH 6.8 phosphate buffer over 6 hours, while the original formulation had a cumulative dissolution rate of 89% in pH 6.8 phosphate buffer over 6 hours. Furthermore, the dissolution RSD of Examples 1-13 was significantly better than that of the original formulation. Examples 1-13 showed significantly more complete dissolution and higher drug utilization than the original formulation. The dissolution results of Examples 2-3 show that when the content of waxy skeleton material in the tablet core is 25-35 wt%, the dissolution effect is good. The dissolution results of Examples 1 and 4-5 show that when the waxy skeleton material is hydrogenated vegetable oil, glyceryl stearate, or glyceryl behenate, the dissolution effect is good. The dissolution results of Examples 6-7 show that when the amount of pore-forming agent is 5-10 wt% of the weight of the slow-release membrane material, the dissolution effect is good.

[0038] The dissolution results of Examples 8-9 show that when the weight ratio of Eutrich RL to Eutrich RS is 1:0.7-1.5, although the dissolution rate increases slightly with the increase of the weight ratio of Eutrich RL, the change is not significant and still meets the requirements, indicating a good dissolution effect. The dissolution results of Examples 10-11 show that when the amount of sustained-release coating layer accounts for 8-12 wt% of the tablet core weight, the dissolution rate tends to decrease slightly with the increase of the amount of sustained-release coating layer, but the change is not significant and still meets the requirements, and the dissolution effect is good. The dissolution results of Examples 12-13 show that the dissolution effect is good when the solid content of the coating solution is 10-14 wt%. Furthermore, the cumulative dissolution difference of the products in Examples 1-13 over 6 hours in hydrochloric acid at pH 1.2 and phosphate buffer at pH 6.8 is ≤5%, indicating that different physiological pH has little effect on the tofacitinib citrate osmotic pump sustained-release tablets described in this invention, and the dissolution difference is better than that of the original formulation.

[0039] Comparative Examples 1-14 Tofacitinib citrate osmotic pump sustained-release tablets were prepared according to the formulations in Table 4.

[0040] Table 4 Formulations of Comparative Examples 1-14

[0041] Comparative Example 1 above prepared tofacitinib citrate cores according to the method of Example 1.

[0042] The preparation methods of Comparative Examples 2-14 are the same as those of Example 1.

[0043] The cumulative dissolution rates of Comparative Examples 1-14 were measured and compared with those of Example 1. The results are shown in Tables 5-6.

[0044] Table 5. Cumulative dissolution rates of Examples 1 and Comparative Examples 1-14 in hydrochloric acid at pH 1.2.

[0045] Table 6. Cumulative dissolution rates of Examples 1 and Comparative Examples 1-14 in pH 6.8 phosphate buffer.

[0046] Compared with Example 1, Comparative Examples 1-9 show the following differences: Comparative Example 1, using only a waxy sustained-release matrix, exhibits rapid dissolution and a risk of burst release; Comparative Example 2, using a hydrophilic gel matrix HPMC, dissolves significantly faster in hydrochloric acid at pH 1.2 than in phosphate buffer at pH 6.8, but also poses a risk of burst release in hydrochloric acid at pH 1.2; Comparative Example 3, using the insoluble matrix material ethyl cellulose, suffers from slow and difficult dissolution, exhibiting slow dissolution in both hydrochloric acid at pH 1.2 and phosphate buffer at pH 6.8; Comparative Example 4, without a waxy matrix material, exhibits rapid dissolution; and Comparative Example 5, using a water-soluble matrix material, dissolves slowly in hydrochloric acid at pH 1.2. The dissolution rate was significantly faster in hydrochloric acid than in pH 6.8 phosphate buffer, with large differences in dissolution under different pH conditions. Comparative Examples 6 and 7 used cellulose acetate and cellulose triacetate as sustained-release membrane materials, respectively. Their dissolution rate in pH 1.2 hydrochloric acid was significantly faster than that in pH 6.8 phosphate buffer. Specifically, the cumulative dissolution rates at the key point of 2.5 h in Comparative Example 6 were 62% and 48%, respectively, while those in Comparative Example 7 were 55% and 42%, respectively, showing a large difference in dissolution. Comparative Examples 8 and 9 used cellulose acetate and ethyl cellulose as sustained-release membrane materials without the addition of pore-forming agents. These materials had difficulty dissolving, resulting in a large amount of dissolution residue, and their dissolution behavior fluctuated greatly under different pH conditions.

[0047] This indicates that it is necessary to select appropriate waxy matrix materials and sustained-release membrane materials, and the two need to work together and be combined with suitable pore-forming agents to achieve the hierarchical coupling effect between the tablet core and the sustained-release coating layer. This allows for precise control of the rate and timing of water entering the tablet core, enabling slow and long-lasting drug release and maintaining the dissolution stability of the formulation under different physiological pH environments, thus avoiding problems such as burst release and incomplete release in the later stages.

[0048] Compared with Example 1, Comparative Examples 10-11 showed that dissolution was faster when the amount of behenic acid glyceride was small and slower when the amount was large, indicating that the amount of waxy skeleton material affects the dissolution behavior. Compared with Example 1, Comparative Examples 12-13 showed that the dissolution of Eucerin RL alone was very rapid, with a certain risk of burst release. This is because Eucerin RL has strong hydrophilicity and high water permeability, allowing water to quickly enter the coating and core for rapid dissolution. On the other hand, the dissolution of Eucerin RS alone was slow, with obvious residue problems, as water had difficulty entering the coating and core. This is related to the strong hydrophobicity and low water permeability of Eucerin RS. An appropriate ratio of RL / RS is needed to precisely control the porosity and permeability of the coating film, thereby controlling the rate at which gastrointestinal fluid permeates into the core. Compared with Example 1, Comparative Example 14 did not add a pore-forming agent, the dissolution was significantly slower, and there were obvious residues. The coating process was difficult to form a film, and there were obvious marks on the surface of the coating film.

[0049] Residual solvent evaluation The residual solvent was detected by taking the products of Example 1, Comparative Examples 6-9, and the original reagent (Shangjie / 11mg / batch number DP7374) according to the second method of General Chapter 0861 of Part IV of the Chinese Pharmacopoeia 2025.

[0050] The test solution and the reference solution were headspace-injected separately for detection, and the results are shown in Table 7.

[0051] Table 7. Detection results of residual solvents in Example 1, Comparative Examples 6-9, and the original formulation.

[0052] As can be seen from Table 7: In Example 1, no methanol or acetone was used for coating, and no methanol or acetone was detected. In Comparative Examples 6-9, acetone was used for coating, and acetone was detected. In contrast, the original reagent was coated with methanol and acetone, and both methanol and acetone were detected. Methanol and acetone are both unfriendly to the environment and human health.

[0053] Bottle opening stability study Take the products from Examples 1-3 and Comparative Examples 1-14, and the original formulation (Shangjie / 11mg / batch number DP7374), and investigate the effect of opening the bottle on the moisture content and solubility of each group of products. The specific steps are as follows: After each group of samples was packaged, the medicine was simulated to be opened and taken out every morning for 10 minutes each time for 30 days. The moisture content and cumulative dissolution in pH 6.8 phosphate buffer were measured at 0, 15 and 30 days. The results are shown in Table 8-9.

[0054] Table 8. Results of the open-bottle moisture stability of the products and original formulations in Examples 1-3 and Comparative Examples 1-14.

[0055] Table 9. Results of open-bottle dissolution stability of the products and original formulations in Examples 1-3 and Comparative Examples 1-14.

[0056] As shown in Tables 8-9, within 30 days of simulated opening and dispensing, the moisture content of Examples 1-3 increased more slowly than that of the original formulation, with no significant change in moisture content. The dissolution rate of Examples 1-3 did not change significantly within 30 days. Comparative Examples 10-14 showed no significant change in moisture content or dissolution rate within 30 days. Comparative Examples 1-7 showed a significant increase in moisture content within 30 days, while Comparative Examples 1-4 showed no significant change in dissolution rate, and Comparative Examples 5-7 showed an accelerated dissolution rate. Comparative Examples 8-9 showed no significant increase in moisture content or dissolution rate, but dissolution was difficult, resulting in serious dissolution residue problems. The original formulation showed a trend of increasing moisture content and accelerated dissolution, indicating that the original formulation was more hygroscopic. This invention has good anti-hygroscopic properties.

[0057] Long-term stability study The products from Example 1, Comparative Examples 5-6, and the original formulation (Shangjie / 11mg / batch number DP7374) were placed under the following long-term stability test conditions (25±2℃, RH 60%±5%): the moisture content and cumulative dissolution in pH 6.8 phosphate buffer were measured for each group of samples after 0 days, 12 months, and 24 months of storage. The results are shown in Tables 10-11. Table 10 Results of long-term moisture stability studies of the products and original formulations in Examples 1 and Comparative Examples 5-6.

[0058] Table 11 Results of long-term dissolution stability studies of the products and original formulations in Examples 1 and Comparative Examples 5-6

[0059] As can be seen from the data in Tables 10-11, the moisture content of Example 1 did not change significantly under long-term conditions, while the moisture content of Comparative Examples 5-6 and the original formulation increased to a certain extent. The dissolution rate of Example 1 did not change significantly under long-term conditions, while the dissolution rate of Comparative Examples 5-6 and the original formulation showed a certain trend of decreasing dissolution rate.

[0060] In vivo pharmacokinetic studies The specific steps for the pharmacokinetic study of beagle dogs are as follows: Sixteen healthy beagle dogs, weighing 10-12kg, were randomly divided into two groups of eight each. Before the experiment, all animals were fasted for 12 hours. Before each animal was administered the drug, 3 ml of blood was collected from the vein of the animal's forelimb at 0 h, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, and 48 h. The blood was placed in a heparinized test tube, centrifuged (3000 rpm, 10 min), and the plasma supernatant was separated and stored. Two groups of beagle dogs were administered the product of Example 1 and a commercially available tofacitinib extended-release tablet formulation (trade name: Xeljanz XR, specification: 11 mg / tablet, dosage: 1 tablet), respectively. The dosage of tofacitinib was the same for both groups of beagle dogs. During administration, the animals were prevented from chewing the tablets and were given 100 ml of purified water to swallow them. After administration, 3 ml of blood was collected from the forelimb vein at regular intervals, placed in a heparinized test tube, centrifuged (3000 rpm, 10 min), and the plasma supernatant was separated and stored. The concentration of tofacitinib in the plasma was determined by liquid chromatography-tandem mass spectrometry (LC-MS). The results are as follows: Figure 1 As shown in Table 12.

[0061] Figure 1The pharmacokinetic curves are for commercially available tofacitinib extended-release tablets and the formulation obtained in Example 1.

[0062] Table 12 Pharmacokinetic data results of commercially available tofacitinib extended-release tablets and the product of Example 1 (n=8)

[0063] As shown in Table 12, after oral administration of commercially available tofacitinib extended-release tablets (Xeljanz XR, 11 mg) to beagle dogs, the peak concentration was 90.59 ng / ml, the time to peak concentration was 4.5 h, and the AUC was [missing value]. 0-t The concentration was 433.50 ng·h / ml; after oral administration of the product in Example 1, the peak concentration was 95.15 ng / ml, the time to peak concentration was 4.3 h, and the AUC was 433.50 ng·h / ml. 0-t The concentration was 444.80 ng·h / ml, with a relative bioavailability of approximately 103%; this invention has good bioavailability.

[0064] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A tofacitinib citrate osmotic pump sustained-release tablet, characterized in that, include: The tofacitinib citrate tablet core and the sustained-release coating layer coated on the surface of the tofacitinib citrate tablet core, wherein the tofacitinib citrate tablet core contains a waxy skeleton material and the sustained-release coating layer contains a sustained-release membrane material and a pore-forming agent. The waxy skeleton material is at least one of hydrogenated vegetable oil, glyceryl stearate, and glyceryl behenate; the sustained-release membrane material is composed of Euterich RL and Euterich RS; and the pore-forming agent is a water-soluble pore-forming agent.

2. The tofacitinib citrate osmotic pump sustained-release tablet according to claim 1, characterized in that, The weight ratio of Ultrich RL to Ultrich RS is 1:0.7-1.

5.

3. The tofacitinib citrate osmotic pump sustained-release tablet according to claim 1 or 2, characterized in that, The pore-forming agent is at least one of triethyl citrate, polyethylene glycol, and glycerin.

4. The tofacitinib citrate osmotic pump sustained-release tablet according to claim 1 or 2, characterized in that, The sustained-release coating layer accounts for 8-12 wt% of the tablet core weight.

5. The tofacitinib citrate osmotic pump sustained-release tablet according to claim 1 or 2, characterized in that, The amount of pore-forming agent used is 5-10 wt% of the weight of the slow-release membrane material.

6. The tofacitinib citrate osmotic pump sustained-release tablet according to claim 1 or 2, characterized in that, In the tofacitinib citrate tablet core, the content of waxy matrix material is 25-35 wt%; the content of tofacitinib is 5-6 wt%.

7. The tofacitinib citrate osmotic pump sustained-release tablet according to claim 1 or 2, characterized in that, The core of the tofacitinib citrate tablet also contains one or more fillers and lubricants.

8. A method for preparing tofacitinib citrate osmotic pump sustained-release tablets as described in any one of claims 1-7, characterized in that, Includes the following steps: Mix all components of the tablet core, compress into tablets to obtain the tablet core; coat the tablet core, heat-cur it to obtain tofacitinib citrate osmotic pump sustained-release tablets.

9. The method for preparing tofacitinib citrate osmotic pump sustained-release tablets according to claim 8, characterized in that, The coating conditions are: inlet air temperature of 50-60℃, outlet air temperature of 25-35℃, and atomization pressure of 0.05-0.1MPa.

10. The method for preparing tofacitinib citrate osmotic pump sustained-release tablets according to claim 8, characterized in that, Incubate at 30-50℃ for 20-28 hours to cure.

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