Tofacitinib citrate sustained release tablet composition and preparation method thereof

Abstract

The invention discloses a tofacitinib citrate sustained-release tablet composition which is prepared from tofacitinib citrate, raloxifene hydrochloride and pharmaceutically acceptable auxiliary materials, and a preparation method comprises the following steps: preparing a tofacitinib citrate sustained-release tablet; tofacitinib citrate, raloxifene hydrochloride and auxiliary materials are taken, the auxiliary materials are hydroxypropyl methyl cellulose, zein, starch and polyvinylpyrrolidone and sieved through a 30-mesh sieve for standby application, tofacitinib citrate, raloxifene hydrochloride, starch and polyvinylpyrrolidone are subjected to wet granulation and size stabilization to obtain medicine particles, the medicine particles are evenly mixed with hydroxypropyl methyl cellulose, zein and magnesium stearate and tableted, and the tablet is prepared. The tofacitinib citrate and the raloxifene hydrochloride have a synergistic effect in the aspect of improving rheumatoid arthritis accompanied by bone mass loss and bone mineral density of postmenopausal women.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a tofacitinib citrate sustained-release tablet composition and a preparation method thereof. Background Art

[0002] Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease with synovitis as the basic pathological change, and erosive, symmetrical polyarthritis as the main clinical manifestation. RA is one of the main diseases causing secondary osteoporosis (OP), and is the main cause of disability due to bone and joint damage, leading to local and systemic osteoporosis. The risk of osteoporosis in RA patients is 2 times higher than that in healthy people. OP increases the risk of femoral fractures in RA patients by 1.3 times and the risk of spinal fractures by 2.4 times, which seriously reduces the quality of life of RA patients. The mechanism of osteoporosis secondary to RA is multifactorial. In addition to being related to primary osteoporosis risk factors, such as menopause and age, it may also be related to inflammation, disease activity, drug effects and physical exercise. (Zou Lin, Zhang Nana, Cui Yixia. Research progress on the pathogenesis of rheumatoid arthritis combined with osteoporosis [J]. Heilongjiang Medicine, 2024, 48(05): 634-637.) As the condition of RA patients worsens, the course of the disease prolongs, and the disease activity increases, the bone destruction becomes more serious, the BMD value of the patients tends to decrease, and the OP prevalence increases. (Zhang Nana, Cui Yixia, Zou Lin. Research progress on the correlation between bone density and vitamin D in patients with rheumatoid arthritis [J]. Clinical Metabolism, 2024, 39(01): 92-96.)

[0003] Existing drugs for treating RA include methotrexate chronic anti-rheumatic drugs (DMARDs), steroids (GC), non-steroidal anti-inflammatory drugs (NSAIDs), TNF inhibitors, and novel drug carriers such as polymer colloids. Tofacitinib citrate tablets are the first JAK pathway inhibitors with a mechanism of action and are a novel oral protein tyrosine kinase inhibitor. The product was first approved for marketing in the United States on November 6, 2012, and has been approved for marketing in more than 50 countries and regions around the world, including the United States, Japan, Russia, Australia, and Canada. Tofacitinib citrate is an immunosuppressant that affects the cell hematopoietic process and cellular immune function by conducting signals generated by the interaction of cytokines or growth factors-receptors on the cell membrane. Tofacitinib citrate is a JAK inhibitor, which is an intracellular enzyme that can effectively inhibit the activity of JAK1 and JAK3 and block the signal transduction of multiple inflammatory cytokines. Clinically confirmed, the drug has a good therapeutic effect on rheumatoid arthritis, ulcerative colitis, psoriasis and other inflammatory-related diseases. Tofacitinib citrate tablets have anti-inflammatory, immunosuppressive and joint protection effects and functions.

[0004] Osteoporosis in postmenopausal women is generally treated with drugs such as raloxifene. Raloxifene is a selective estrogen receptor modulator that activates certain estrogen pathways and blocks other pathways after binding to estrogen receptors. Raloxifene reduces bone reabsorption and can reduce biochemical indicators of bone turnover to the premenopausal range. Raloxifene can also affect lipid metabolism, reduce overall and LDL cholesterol levels, but does not increase triglyceride levels and has no effect on overall HDL levels. There are currently no reports on the combined use of tofacitinib citrate and raloxifene. Summary of the invention

[0005] Based on the deficiencies in the prior art, the present invention aims to provide a tofacitinib citrate sustained-release tablet composition and a preparation method thereof.

[0006] The present invention adopts the sustained-release mechanism of the skeleton material to ensure the stability of the product.

[0007] Rheumatoid arthritis (RA) often occurs in postmenopausal women, and postmenopausal women are also prone to osteoporosis. The inventors found in clinical practice that in the treatment of patients with rheumatoid arthritis (RA) and osteoporosis in postmenopausal women, when tofacitinib citrate was used to treat rheumatoid arthritis (RA) and raloxifene hydrochloride was used to treat osteoporosis in postmenopausal women, it was found that the serum calcium level of the patients was significantly higher than that of patients using raloxifene hydrochloride alone. For this reason, the inventors conducted clinical experiments using tofacitinib citrate and raloxifene hydrochloride as test substances, further confirming that tofacitinib citrate has the biological activity of increasing raloxifene hydrochloride in vivo to promote the increase of serum calcium level, and finally obtained the following technical solution:

[0008] A tofacitinib citrate sustained-release tablet composition is prepared from tofacitinib citrate, raloxifene hydrochloride and pharmaceutically acceptable excipients.

[0009] The tofacitinib citrate sustained-release tablet composition has a weight ratio of tofacitinib citrate to raloxifene hydrochloride of 1:4-8.

[0010] The tofacitinib citrate sustained-release tablet composition has a weight ratio of tofacitinib citrate to raloxifene hydrochloride of 1:6.

[0011] The tofacitinib citrate sustained-release tablet composition comprises 10 mg of tofacitinib citrate and 60 mg of raloxifene hydrochloride in a single-dose package of the tofacitinib citrate sustained-release tablet composition.

[0012] The tofacitinib citrate sustained-release tablet composition comprises a skeleton material, a diluent and a binder as auxiliary materials.

[0013] The tofacitinib citrate sustained-release tablet composition comprises a skeleton material in the auxiliary material which is a mixture of hydroxypropyl methylcellulose and corn protein, and the weight ratio of hydroxypropyl methylcellulose to corn protein is 2:1.

[0014] In the tofacitinib citrate sustained-release tablet composition, the diluent in the auxiliary material is one or more of starch, powdered sugar, dextrin, and microcrystalline cellulose.

[0015] In the tofacitinib citrate sustained-release tablet composition, the binder in the auxiliary material is one of polyvinyl pyrrolidone and gelatin.

[0016] The preparation method of the tofacitinib citrate sustained-release tablet composition comprises the following steps: taking tofacitinib citrate, raloxifene hydrochloride and excipients, wherein the excipients are hydroxypropyl methylcellulose, corn protein, starch and polyvinyl pyrrolidone, passing through a 30-mesh sieve for standby use, wet-granulating the tofacitinib citrate, raloxifene hydrochloride, starch and polyvinyl pyrrolidone, granulating to obtain drug granules, uniformly mixing with hydroxypropyl methylcellulose, corn protein and magnesium stearate, and tableting.

[0017] The invention discloses an application of the tofacitinib citrate sustained-release tablet composition in the preparation of a drug for treating rheumatoid arthritis accompanied by osteoporosis in postmenopausal women.

[0018] Currently, raloxifene hydrochloride tablets are ordinary tablets with a daily dosage of 60 mg, and tofacitinib citrate is a sustained-release tablet with a daily dosage of 10 mg. Therefore, in the research process of the composition of tofacitinib citrate sustained-release tablets, the weight ratio of tofacitinib citrate to raloxifene hydrochloride is selected as 1:6 to achieve the purpose of taking one tablet per day.

[0019] The release curves of the samples prepared in Examples 1-3 of the present invention are stable, and there is no burst release phenomenon in the pH 6.8 phosphate buffer dissolution medium, and the release degree in 9 hours is greater than 80%, while the samples prepared in Comparative Examples 3-5 have a burst release phenomenon, and the release is faster, and the release degree in 4 hours reaches more than 80%. This shows that the auxiliary materials used in Examples 1-3 of the present invention are reasonable and can achieve a sustained release effect, while Comparative Examples 3-5 do not use a skeleton material and cannot achieve a sustained release effect.

[0020] The statistical results of bone markers showed that after treatment, PTH in Example 1 group and Comparative Example 2 group was higher than that before treatment, and the difference was statistically significant (P < 0.05); while CTX and BGP were significantly lower than those before treatment (P > 0.05), and the bone turnover rate decreased. The use of tofacitinib citrate alone in Comparative Example 1 group had no effect on bone markers, indicating that Example 1 group and Comparative Example 2 group of the present invention have the effect of improving bone loss in postmenopausal women, and compared with Comparative Example 2 group, there were significant differences in the increase of PTH and the decrease of CTX and BGP in Example 1 group, indicating that tofacitinib citrate and raloxifene hydrochloride in Example 1 group have a synergistic effect in improving rheumatoid arthritis accompanied by bone loss in postmenopausal women.

[0021] The statistical results of bone density showed that after treatment, the L2-L4 bone density of Example 1 group and Comparative Example 2 group was higher than that before treatment, and the difference was statistically significant (P<0.05). The use of tofacitinib citrate alone in the Comparative Example 1 group had no effect on bone density, indicating that it can increase the bone density of postmenopausal women. Moreover, compared with the Comparative Example 2 group, the degree of increase in L2-L4 bone density was significantly different in the Example 1 group, indicating that tofacitinib citrate and raloxifene hydrochloride in the Example 1 group have a synergistic effect in increasing the bone density of postmenopausal women with rheumatoid arthritis. DETAILED DESCRIPTION

[0022] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content of the present invention, those skilled in the art can make various changes or modifications to the present invention, but these equivalent forms fall within the scope limited by the appended claims of the application equally.

[0023] Example 1: Take 100 g of tofacitinib citrate, 600 g of raloxifene hydrochloride, 100 g of hydroxypropyl methylcellulose, 50 g of corn protein, 40 g of starch, and 20 g of polyvinyl pyrrolidone, pass through a 30-mesh sieve for later use, wet granulate tofacitinib citrate, raloxifene hydrochloride, starch, and polyvinyl pyrrolidone, granulate to obtain drug granules, mix them evenly with hydroxypropyl methylcellulose, corn protein, and magnesium stearate, and compress them into tablets. Each tablet contains 10 mg of tofacitinib citrate and 60 mg of raloxifene hydrochloride.

[0024] Example 2: Take 100 g of tofacitinib citrate, 400 g of raloxifene hydrochloride, 100 g of hydroxypropyl methylcellulose, 50 g of corn protein, 40 g of starch, and 20 g of polyvinyl pyrrolidone, pass through a 30-mesh sieve for later use, wet granulate tofacitinib citrate, raloxifene hydrochloride, starch, and polyvinyl pyrrolidone, granulate to obtain drug granules, mix them evenly with hydroxypropyl methylcellulose, corn protein, and magnesium stearate, and press them into tablets. Each tablet contains 10 mg of tofacitinib citrate and 40 mg of raloxifene hydrochloride.

[0025] Example 3: Take 100 g of tofacitinib citrate, 800 g of raloxifene hydrochloride, 100 g of hydroxypropyl methylcellulose, 50 g of corn protein, 40 g of starch, and 20 g of polyvinyl pyrrolidone, pass through a 30-mesh sieve for later use, wet granulate tofacitinib citrate, raloxifene hydrochloride, starch, and polyvinyl pyrrolidone, granulate to obtain drug granules, mix them evenly with hydroxypropyl methylcellulose, corn protein, and magnesium stearate, and press them into tablets. Each tablet contains 10 mg of tofacitinib citrate and 80 mg of raloxifene hydrochloride.

[0026] Comparative Example 1: Take 100 g of tofacitinib citrate, 100 g of hydroxypropyl methylcellulose, 50 g of corn protein, 40 g of starch, and 20 g of polyvinyl pyrrolidone, pass through a 30-mesh sieve for later use, wet granulate tofacitinib citrate, starch, and polyvinyl pyrrolidone, granulate to obtain drug granules, mix evenly with hydroxypropyl methylcellulose, corn protein, and magnesium stearate, and press into tablets, each tablet containing 10 mg of tofacitinib citrate.

[0027] Comparative Example 2: Take 600 g of raloxifene hydrochloride, 100 g of hydroxypropyl methylcellulose, 50 g of corn protein, 40 g of starch, and 20 g of polyvinyl pyrrolidone, pass through a 30-mesh sieve for later use, granulate raloxifene hydrochloride, starch, and polyvinyl pyrrolidone, granulate to obtain drug granules, mix them evenly with hydroxypropyl methylcellulose, corn protein, and magnesium stearate, and press them into tablets, each tablet containing 60 mg of raloxifene hydrochloride.

[0028] Comparative Example 3: Take 100 g of tofacitinib citrate, 600 g of raloxifene hydrochloride, 40 g of starch, and 20 g of polyvinyl pyrrolidone, pass through a 30-mesh sieve for later use, wet granulate tofacitinib citrate, raloxifene hydrochloride, starch, and polyvinyl pyrrolidone, granulate to obtain drug granules, mix evenly with magnesium stearate, and tablet each tablet containing 10 mg of tofacitinib citrate and 60 mg of raloxifene hydrochloride.

[0029] Comparative Example 4: Take 100 g of tofacitinib citrate, 400 g of raloxifene hydrochloride, 40 g of starch, and 20 g of polyvinyl pyrrolidone, pass through a 30-mesh sieve for later use, wet granulate tofacitinib citrate, raloxifene hydrochloride, starch, and polyvinyl pyrrolidone, granulate to obtain drug granules, mix evenly with magnesium stearate, and tablet each tablet containing 10 mg of tofacitinib citrate and 40 mg of raloxifene hydrochloride.

[0030] Comparative Example 5: Take 100 g of tofacitinib citrate, 800 g of raloxifene hydrochloride, 40 g of starch, and 20 g of polyvinyl pyrrolidone, pass through a 30-mesh sieve for later use, wet granulate tofacitinib citrate, raloxifene hydrochloride, starch, and polyvinyl pyrrolidone, granulate to obtain drug granules, mix evenly with magnesium stearate, and tablet each tablet containing 10 mg of tofacitinib citrate and 80 mg of raloxifene hydrochloride.

[0031] Example 4: Cumulative drug release test: The tofacitinib citrate sustained-release tablet compositions prepared in Examples 1-3 and the tofacitinib citrate tablet compositions obtained in Comparative Examples 3-5 were tested for cumulative release at different times. The specific method is: take a sample, refer to the release determination method (Chinese Pharmacopoeia 2020 Edition Four Preparations General Rules 0931 Second Method) + sinker device, the dissolution medium is pH 6.8 phosphate buffer 900mL, the speed is 50 rpm; take samples at different times and filter online. Detect at 286nm. Calculate the cumulative release of the tablets, the results are shown in Table 1 (n = 10 tablets, representing 10 sample tablets tested, the results are averaged).

[0032] Table 1 Dissolution data

[0033] 0.5h 1h 1.5h 2h 3h 5h 7h 9h 12h Example 1 10.5 20.5 25.8 32.6 43.9 54.9 78.5 83.7 98.5 Example 2 9.2 22.8 24.7 32.1 45.8 52.8 77.6 82.1 99.4 Example 3 10.9 20.4 25.3 34.7 42.3 52.8 79.1 84.9 98.9 Comparative Example 3 32.7 54.4 68.8 73.2 98.4 99.5 98.7 99.5 99.9 Comparative Example 4 36.1 57.3 69.2 74.9 97.4 99.5 98.3 99.4 99.2 Comparative Example 5 37.1 56.8 65.8 73.2 89.3 99.1 97.9 99.9 98.3

[0034] From the above experimental data, it can be seen that the release curves of the samples prepared in Examples 1-3 of the present invention are stable, and there is no burst release phenomenon in the pH 6.8 phosphate buffer dissolution medium, and the release degree in 9 hours is greater than 80%, while the samples prepared in Comparative Examples 3-5 have a burst release phenomenon, and the release is faster, and the release degree in 4 hours reaches more than 80%. It shows that the auxiliary materials used in Examples 1-3 of the present invention are reasonable and can achieve the effect of sustained release, while Comparative Examples 3-5 do not use skeleton materials and cannot achieve the sustained release effect.

[0035] Example 5: Clinical study

[0036] 1. Research subjects: From June 1, 2022 to September 1, 2023, 60 women with rheumatoid arthritis and postmenopausal osteoporosis were selected for the study. They were aged 62.87±7.78 years, more than two years after menopause, with a T value of lumbar spine or femoral neck bone density measurement less than or equal to -2.5, with or without vertebral fractures. All subjects signed an informed consent form, filled out an osteoporosis questionnaire, including age, gender, height, weight, BMI, etc., and entered it into the database. This study was approved by the Ethics Committee.

[0037] Diagnostic criteria for osteoporosis: Referring to the diagnostic method recommended by WHO in 1994, the measured bone density is compared with the peak bone density of the same gender, and the bone density decreases by one standard deviation. If one or more parts have a T value ≤ -2.5SD, it is osteoporosis; -2.5SD<T value ≤ -1SD is bone loss; T value>-1SD is normal bone mass.

[0038] Diagnostic criteria for rheumatoid arthritis: meet the diagnostic criteria for RA in the 2018 Chinese Guidelines for the Diagnosis and Treatment of Rheumatoid Arthritis. ① Age 30-70; ② Joint function is grade II to III; ③ The disease is in the active stage; ④ The course of the disease is at least 6 weeks; ⑤ No recent anti-rheumatic drug treatment.

[0039] Research method: Before treatment, all patients were tested for bone density, blood biochemistry and bone markers, and the results were uniformly entered into the database. They were divided into three groups, namely, Example 1, Comparative Example 1 and Comparative Example 2. The samples produced by Example 1, Comparative Example 1 and Comparative Example 2 were taken respectively, and 1 tablet was taken every day until the end of the study. Each research subject supplemented 600 mg of elemental calcium (Pfizer Pharmaceuticals) and 0.5 μg of vitamin D (Shanghai Roche) daily. The study period was 6 months. After the end of the study, bone markers [including serum osteocalcin (BGP), bone metabolism indicators C-reactive protein (CTX), parathyroid hormone (PTH)] and bone density were tested again. During the treatment period, they all ate and exercised normally, and did not take other drugs that affect bone metabolism.

[0040] The bone density of lumbar vertebrae L2-L4 was measured using the American Norland dual-energy X-ray absorptiometry, and the bone markers were detected using enzyme-linked immunosorbent assay.

[0041] Research results: The comparison of bone marker changes before and after treatment is shown in Table 2, and the comparison of bone density before and after treatment is shown in Table 3.

[0042] Table 2 Comparison of bone markers before and after treatment

[0043]

[0044] Compared with before treatment, *P<0.05, **P<0.01; compared with the control group 2: #P<0.05, ##P<0.01.

[0045] The statistical results of bone markers showed that after treatment, PTH in Example 1 group and Comparative Example 2 group was higher than that before treatment, and the difference was statistically significant (P < 0.05); while CTX and BGP were significantly lower than those before treatment (P > 0.05), and the bone turnover rate decreased. The use of tofacitinib citrate alone in Comparative Example 1 group had no effect on bone markers, indicating that Example 1 group and Comparative Example 2 group of the present invention have the effect of improving bone loss in postmenopausal women, and compared with Comparative Example 2 group, there were significant differences in the increase of PTH and the decrease of CTX and BGP in Example 1 group, indicating that tofacitinib citrate and raloxifene hydrochloride in Example 1 group have a synergistic effect in improving rheumatoid arthritis accompanied by bone loss in postmenopausal women.

[0046] Table 3 Comparison of bone density before and after treatment (g / cm 2 )

[0047]

[0048] Compared with before treatment, *P<0.05, **P<0.01; compared with the control group 2: #P<0.05, ##P<0.01.

[0049] The statistical results of bone density showed that after treatment, the L2-L4 bone density of Example 1 group and Comparative Example 2 group was higher than that before treatment, and the difference was statistically significant (P<0.05). The use of tofacitinib citrate alone in the Comparative Example 1 group had no effect on bone density, indicating that it can increase the bone density of postmenopausal women. Moreover, compared with the Comparative Example 2 group, the degree of increase in L2-L4 bone density was significantly different in the Example 1 group, indicating that tofacitinib citrate and raloxifene hydrochloride in the Example 1 group have a synergistic effect in increasing the bone density of postmenopausal women with rheumatoid arthritis.

[0050] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A tofacitinib citrate sustained-release tablet composition, characterized in that: The sustained-release tablet composition is prepared from tofacitinib citrate, raloxifene hydrochloride and pharmaceutically acceptable auxiliary materials.

2. A tofacitinib citrate sustained-release tablet composition according to claim 1, characterized in that: The weight ratio of tofacitinib citrate to raloxifene hydrochloride is 1:4-8.

3. A tofacitinib citrate sustained-release tablet composition according to claim 2, characterized in that: The weight ratio of tofacitinib citrate to raloxifene hydrochloride is 1:

6.

4. A tofacitinib citrate sustained-release tablet composition according to claim 3, characterized in that: The single-dose package of the tofacitinib citrate sustained-release tablet composition contains 10 mg of tofacitinib citrate and 60 mg of raloxifene hydrochloride.

5. A tofacitinib citrate sustained-release tablet composition according to claim 1, characterized in that: In the tofacitinib citrate sustained-release tablet composition, the auxiliary materials are skeleton material, diluent and adhesive.

6. A tofacitinib citrate sustained-release tablet composition according to claim 5, characterized in that: The skeleton material in the auxiliary materials is a mixture of hydroxypropyl methylcellulose and corn protein, and the weight ratio of hydroxypropyl methylcellulose to corn protein is 2:

1.

7. A tofacitinib citrate sustained-release tablet composition according to claim 4, characterized in that: The diluent in the auxiliary material is one or more of starch, powdered sugar, dextrin and microcrystalline cellulose.

8. A tofacitinib citrate sustained-release tablet composition according to claim 4, characterized in that: The adhesive in the auxiliary material is one of polyvinyl pyrrolidone and gelatin.

9. The tofacitinib citrate sustained-release tablet composition according to claim 1, characterized in that: The preparation method comprises the following steps: taking tofacitinib citrate, raloxifene hydrochloride and excipients, wherein the excipients are hydroxypropyl methylcellulose, corn protein, starch and polyvinyl pyrrolidone, passing through a 30-mesh sieve for standby use, wet-granulating the tofacitinib citrate, raloxifene hydrochloride, starch and polyvinyl pyrrolidone, granulating to obtain drug granules, uniformly mixing with hydroxypropyl methylcellulose, corn protein and magnesium stearate, and tableting.

10. Use of the tofacitinib citrate sustained-release tablet composition as claimed in claim 1 in the preparation of a drug for treating rheumatoid arthritis accompanied by osteoporosis in postmenopausal women.

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