A kind of methotrexate tablet and preparation method thereof

Abstract

The invention discloses a kind of methotrexate tablet and its preparation method, belong to the field of medicine. The method for preparing methotrexate tablet in the present invention, including: (1) lecithin, microcrystalline cellulose, β-cyclodextrin, magnesium stearate are mixed uniformly to obtain auxiliary materials; (2) methotrexate, calcium pantothenate, fumed silica are mixed and ground to obtain active substances; (3) active substances and auxiliary materials are mixed to form a mixture; (4) the mixture is mixed uniformly with sorbitol, calcium bicarbonate, starch milk, granulated to obtain drug particles; (5) drug particles are tableted to obtain methotrexate tablets. The present invention achieves the effects of good storage stability, high bioavailability and small side effects.

Description

Technical Field

[0001] The invention relates to a methotrexate tablet and a preparation method thereof, and belongs to the field of medicine. Background Art

[0002] Methotrexate (MTX) is a drug with important clinical value. It was first discovered in the 1940s and used to treat acute leukemia. With the deepening of research, the indications of methotrexate have gradually expanded to the treatment of breast cancer, choriocarcinoma, head and neck cancer, bone tumors, lung cancer, reproductive system tumors, liver cancer and other cancers. In addition, methotrexate is also widely used in the treatment of autoimmune diseases such as rheumatoid arthritis and severe intractable psoriasis due to its immunosuppressive and anti-inflammatory effects.

[0003] Although methotrexate has significant clinical efficacy, there are still some problems in its preparation and use. First, methotrexate is almost insoluble in water, ethanol, chloroform or ether, and is only easily soluble in dilute alkaline solutions and soluble in dilute hydrochloric acid, which limits its application in oral preparations. Secondly, the stability of methotrexate is also a challenge in its formulation development. During storage and use, methotrexate is easily affected by factors such as light and temperature, which leads to drug degradation and affects efficacy and safety.

[0004] In response to these problems, researchers have been exploring methods to improve methotrexate preparations. Traditional methotrexate preparations mainly include tablets and injections. Although injections can be easily swallowed, the injection process may cause pain and affect patient compliance; moreover, the preparation and use of injections are relatively complicated, which increases medical costs. Although tablets are easy to take orally, they have problems such as poor storage stability and low bioavailability. For example: CN109475557B discloses a methotrexate orally disintegrating tablet and a preparation method thereof, which mainly solves the problem of photostability, but does not solve the problems of low bioavailability and long-term storage; CN1320887C discloses a methotrexate orally disintegrating tablet and a preparation method thereof, which is composed of methotrexate, dry binder microcrystalline cellulose, lubricant magnesium stearate, disintegrant sodium carboxymethyl starch and flavoring agent mannitol, and is obtained by tableting; however, it does not solve the problems of low storage stability and bioavailability.

[0005] In addition, methotrexate has many side effects, such as nausea, vomiting, stomatitis, pharyngitis, leukopenia and thrombocytopenia, etc. Therefore, how to reduce the side effects of methotrexate is also a problem that needs to be considered. Summary of the invention

[0006] [Technical issues]

[0007] Methotrexate tablets have problems such as poor storage stability, low bioavailability, and significant side effects.

[0008] [Technical solution]

[0009] In order to solve the above problems, the present invention achieves the effects of good storage stability, high bioavailability and small side effects by adjusting the components and operation of methotrexate tablets.

[0010] The first object of the present invention is to provide a method for preparing methotrexate tablets, comprising the steps of:

[0011] (1) mixing lecithin, microcrystalline cellulose, β-cyclodextrin, and magnesium stearate to obtain an auxiliary material;

[0012] (2) mixing and grinding methotrexate, calcium pantothenate, and fumed silica to obtain an active substance;

[0013] (3) mixing the active substance and the excipients to form a mixture;

[0014] (4) uniformly mixing the mixture with sorbitol, calcium bicarbonate, and starch milk, and granulating to obtain drug granules;

[0015] (5) compressing the drug particles into tablets to obtain methotrexate tablets;

[0016] Among them, the mass ratio of lecithin, microcrystalline cellulose, β-cyclodextrin, magnesium stearate, methotrexate, mesoporous silica, sorbitol, calcium bicarbonate, and starch in starch milk is 1-3:30-40:8-10:1-5:2-3:3-5:5-8:15-20:15-20.

[0017] In one embodiment of the present invention, the uniform mixing in step (1) is performed at 2000-3000 rpm for 3-8 min.

[0018] In one embodiment of the present invention, the grinding speed in step (2) is 10-30 rpm.

[0019] In one embodiment of the present invention, the mixing in step (3) is performed at 2000-3000 rpm for 3-8 min.

[0020] In one embodiment of the present invention, the starch milk in step (3) is obtained by dissolving starch in water, with a mass concentration of 70-80%; the starch is one of corn starch, wheat starch and potato starch.

[0021] In one embodiment of the present invention, the mixing in step (4) is performed at 2000-3000 rpm for 3-8 min.

[0022] In one embodiment of the present invention, the particle size of the granulation in step (3) is 20-30 mesh.

[0023] In one embodiment of the present invention, the granulation temperature in step (3) is 50-80°C.

[0024] In one embodiment of the present invention, step (4) is carried out by a rotary tablet press, the turntable speed is 18 rpm, the filling pressure is 23 N, the filling depth is 15 mm; the mold is circular with a diameter of 5 mm.

[0025] In one embodiment of the present invention, the unit tablet weight of the methotrexate tablet in step (4) is 100 mg.

[0026] The second object of the present invention is the methotrexate tablets prepared by the method described in the present invention.

[0027] The third object of the present invention is to provide a method for improving the storage stability, bioavailability and reducing side effects of methotrexate tablets, comprising the following steps:

[0028] (1) mixing lecithin, microcrystalline cellulose, β-cyclodextrin, and magnesium stearate to obtain an auxiliary material;

[0029] (2) mixing and grinding methotrexate, calcium pantothenate, and fumed silica to obtain an active substance;

[0030] (3) mixing the active substance and the excipients to form a mixture;

[0031] (4) uniformly mixing the mixture with sorbitol, calcium bicarbonate, and starch milk, and granulating to obtain drug granules;

[0032] (5) compressing the drug particles into tablets to obtain methotrexate tablets;

[0033] Among them, the mass ratio of lecithin, microcrystalline cellulose, β-cyclodextrin, magnesium stearate, methotrexate, mesoporous silica, sorbitol, calcium bicarbonate, and starch in starch milk is 1-3:30-40:8-10:1-5:2-3:3-5:5-8:15-20:15-20.

[0034] [Beneficial Effects]

[0035] (1) The present invention achieves good storage stability, high bioavailability and low side effects by adjusting the components and operation of methotrexate tablets; specifically, the methotrexate tablets of the present invention maintain stable tablet properties and less than 2% of total impurities for 30 days under daily light or high temperature and high humidity conditions; the solubility in simulated gastric fluid reaches 96% and the absolute bioavailability can reach 94%; the side effects of liver damage and reduced number of neutrophils after administration are small.

[0036] (2) The present invention uses microcrystalline cellulose, calcium bicarbonate, and starch to work synergistically to promote disintegration, thereby improving bioavailability.

[0037] (3) The present invention uses fumed silica to load methotrexate and calcium pantothenate, thereby reducing side effects.

[0038] (4) The present invention further improves the storage stability of methotrexate tablets by adjusting the process. DETAILED DESCRIPTION

[0039] The preferred embodiments of the present invention are described below. It should be understood that the embodiments are for better explaining the present invention and are not used to limit the present invention.

[0040] Test method:

[0041] 1. Liquid chromatography detection method:

[0042] Dissolve the sample to be tested, add 500 μL of acetonitrile, add 10uL of 10% formic acid, vortex for 2 minutes, centrifuge at 1.1×104:min' for 5 minutes, take 500 μL of the supernatant in a 1.5mL centrifuge tube, blow dry with nitrogen in a 40°C water bath, and re-dissolve with 200 μL of water. Vortex, centrifuge at 1.1×104:min' 4 Centrifuge at rpm for 5 min and take the supernatant for analysis.

[0043] A Waters UPLC BEH C18 column (50 mm×2.1 mm, 1.7 μm) was used, with a column temperature of 30°C, a flow rate of 0.2 mL / min, a mobile phase of methanol and 0.05 mol / L phosphate buffer (pH=6.2) in a ratio of 17:83, and a detection wavelength of 302 nm.

[0044] 2. Light stability:

[0045] Place the drug to be tested at D 65 Place the samples in a single layer on a sample rack in a light artificial climate box so that the illumination in four directions is not less than 5000 lx, control the temperature to (25±2)°C, and the humidity to (50±5)%, and place them for 0, 10, and 30 days respectively; use liquid chromatography to detect the impurity content (single impurity and total impurity) in the drug to be tested.

[0046] 3. Moisture stability:

[0047] The drugs to be tested are placed in a single layer at 40° C. and 75% humidity for 0, 10, and 30 days respectively; and the impurity content in the drugs to be tested is detected by liquid chromatography.

[0048] 4. Dissolution:

[0049] The dissolution of the drug to be tested (1 tablet, effective concentration of methotrexate is 2.5 mg) was detected by the paddle method, 900 mL of 0.1 mol / L hydrochloric acid solution (simulated gastric fluid) was used as the dissolution medium, the speed was 50 rpm and stirred for 30 min, and the dissolution of the drug to be tested was detected by liquid chromatography;

[0050] Dissolution (%) = liquid phase detection concentration / effective concentration of the drug to be tested.

[0051] 5. Disintegration time test:

[0052] The drug to be tested was placed in 900 mL of 0.1 mol / L hydrochloric acid solution (simulated gastric fluid) and the time required for its complete disintegration was measured.

[0053] 6. Absolute bioavailability:

[0054] The absolute bioavailability of the drug to be tested is tested using an animal model. The specific method is as follows:

[0055] 110 SD rats were divided into 11 groups. After 1 week of adaptive feeding, they were fasted for 12 hours. The drug to be tested was delivered to the root of the tongue of the SD rats with tweezers. The mouth was quickly closed and the head was slightly raised to allow the rats to swallow naturally. The effective dose of methotrexate was 10 mg (4 tablets). The methotrexate content in the blood was detected within 10 hours, and the AUC was calculated. oral The blank control group consisted of tablets in which methotrexate was replaced with starch, and the rest of the drug composition was consistent with the drug to be tested;

[0056] Use cross-control blood to inject an equal amount of methotrexate, detect the methotrexate content in the blood 10 hours later, and calculate the AUC iv value;

[0057] Absolute bioavailability (F abs ) = AUC oral / AUC iv .

[0058] 7. Side effect detection:

[0059] 110 SD rats were divided into 11 groups. After one week of adaptive feeding, the SD rats were fasted for 12 hours and orally administered twice within one week (on the second and fifth days respectively). The effective dose of methotrexate was 10 mg each time. After two weeks, the rats were killed and blood was collected to detect serum ALT and neutrophil count.

[0060] The number of samples with ALT significantly higher than 98.7U / L and neutrophil count significantly lower than 1×10 9 / L of samples, identify the above samples as samples with obvious side effects, and calculate the proportion of samples with obvious side effects in the total samples.

[0061] 8. Statistical analysis:

[0062] SPSS17.0 software was used for processing, and the data were expressed as (mean ± standard deviation). One-way analysis of variance (ANOVA) was used to calculate the F value for sample differences, and the SNK test was used to calculate the t value for pairwise comparison of samples. P < 0.05 was considered to be statistically significant.

[0063] The raw materials used in the embodiment:

[0064] Fumed silica: 8000 mesh, purchased from Guangzhou Zedanlu New Materials Co., Ltd.;

[0065] Microcrystalline cellulose: CAS: 9004-34-6;

[0066] Dicalcium phosphate: anhydrous calcium phosphate, 98%, CAS: 7757-93-9;

[0067] Starch: corn starch, purchased from Wuhan Jinfeng Fuyuan Chemical Co., Ltd.;

[0068] β-cyclodextrin: pharmaceutical grade, 99%;

[0069] Calcium pantothenate: D-calcium pantothenate, 99%, purchased from Guangzhou Jingfu Bioengineering Co., Ltd.;

[0070] Lecithin: soybean lecithin, 99%, purchased from Guangzhou Jingfu Bioengineering Co., Ltd.;

[0071] Granulation: Use a granulator with a particle size of 25 mesh and a temperature of 60°C;

[0072] Tableting: The tablets were pressed using a rotary tablet press with a turntable speed of 18 rpm, a filling pressure of 23 N, and a filling depth of 15 mm. The mold was round with a diameter of 5 mm.

[0073] Example 1

[0074] A method for preparing methotrexate tablets comprises the following steps:

[0075] (1) mixing lecithin, microcrystalline cellulose, β-cyclodextrin, and magnesium stearate at 2500 rpm for 5 min to obtain an excipient;

[0076] (2) mixing methotrexate, calcium pantothenate, and fumed silica and grinding them (20 rpm) to obtain an active substance;

[0077] (3) mixing the active substance and excipients at 2500 rpm for 5 min to form a mixture;

[0078] (4) mixing the mixture with sorbitol, calcium bicarbonate, and starch milk (starch dissolved in water, mass concentration of 80%) at 2500 rpm for 5 min, and granulating (60° C.) to obtain drug granules (25 mesh);

[0079] (5) compressing the drug granules into tablets to obtain methotrexate tablets (100 mg);

[0080] Among them, the mass ratio of lecithin, microcrystalline cellulose, β-cyclodextrin, magnesium stearate, methotrexate, mesoporous silica, sorbitol, calcium bicarbonate, and starch in starch milk is 2:35:9:3:2.5:4:7:18:18.

[0081] Example 2

[0082] The mass ratio of lecithin, microcrystalline cellulose, β-cyclodextrin, magnesium stearate, methotrexate, mesoporous silica, sorbitol, calcium bicarbonate, and starch in starch milk in Example 1 was adjusted to 3:35:8:5:3:5:8:20:20; the rest was kept consistent with Example 1 to obtain methotrexate tablets (100 mg).

[0083] Example 3

[0084] The mass ratio of lecithin, microcrystalline cellulose, β-cyclodextrin, magnesium stearate, methotrexate, mesoporous silica, sorbitol, calcium bicarbonate, and starch in starch milk in Example 1 was adjusted to 1:40:10:5:2.5:5:7:15:20; the rest was kept consistent with Example 1 to obtain methotrexate tablets (100 mg).

[0085] Comparative Example 1

[0086] A method for preparing methotrexate tablets comprises the following steps:

[0087] Lecithin, microcrystalline cellulose, β-cyclodextrin, magnesium stearate, methotrexate, mesoporous silica, sorbitol, calcium bicarbonate, and starch in starch milk are uniformly mixed in a mass ratio of 1:40:10:5:2.5:5:7:15:20, granulated, and tableted to obtain methotrexate tablets (100 mg).

[0088] Comparative Example 2

[0089] A method for preparing methotrexate tablets comprises the following steps:

[0090] (1) mixing lecithin, microcrystalline cellulose, β-cyclodextrin, and magnesium stearate at 2500 rpm for 5 min to obtain an excipient;

[0091] (2) mixing methotrexate, calcium pantothenate, and fumed silica at 2500 rpm for 5 min to obtain an active substance;

[0092] (3) mixing the active substance and excipients at 2500 rpm for 5 min to form a mixture;

[0093] (4) mixing the mixture with sorbitol, calcium bicarbonate, and starch milk (starch dissolved in water, mass concentration of 80%) at 2500 rpm for 5 min, and granulating (60° C.) to obtain drug granules (25 mesh);

[0094] (5) compressing the drug granules into tablets to obtain methotrexate tablets (100 mg);

[0095] Among them, the mass ratio of lecithin, microcrystalline cellulose, β-cyclodextrin, magnesium stearate, methotrexate, mesoporous silica, sorbitol, calcium bicarbonate, and starch in starch milk is 2:35:9:3:2.5:4:7:18:18.

[0096] Comparative Example 3

[0097] A method for preparing methotrexate tablets comprises the following steps:

[0098] (1) mixing lecithin, microcrystalline cellulose, β-cyclodextrin, magnesium stearate, methotrexate, calcium pantothenate, and fumed silicon dioxide at 2500 rpm for 10 min to form a mixture;

[0099] (2) mixing the mixture with sorbitol, calcium bicarbonate, and starch milk (starch dissolved in water, mass concentration of 80%) at 2500 rpm for 5 min, and granulating (60° C.) to obtain drug granules (25 mesh);

[0100] (3) compressing the drug particles into tablets to obtain methotrexate tablets (100 mg);

[0101] Among them, the mass ratio of lecithin, microcrystalline cellulose, β-cyclodextrin, magnesium stearate, methotrexate, mesoporous silica, sorbitol, calcium bicarbonate, and starch in starch milk is 2:35:9:3:2.5:4:7:18:18.

[0102] Comparative Example 4

[0103] The starch in the starch emulsion of Example 1 was adjusted to sodium carboxymethyl starch, and the other ingredients were kept consistent with Example 1 to obtain methotrexate tablets.

[0104] Comparative Example 5

[0105] The lecithin in Example 1 was adjusted to vitamin E, and the other ingredients were kept consistent with Example 1 to obtain methotrexate tablets.

[0106] Comparative Example 6

[0107] The β-cyclodextrin in Example 1 was adjusted to sucrose fatty acid ester, and the other ingredients were kept consistent with Example 1 to obtain methotrexate tablets.

[0108] Comparative Example 7

[0109] The calcium pantothenate in Example 1 was adjusted to nicotinamide, and the other ingredients were kept the same as in Example 1 to obtain methotrexate tablets.

[0110] Comparative Example 8

[0111] The calcium bicarbonate in Example 1 was omitted, and the amount of microcrystalline cellulose was adjusted to the sum of the masses of calcium bicarbonate and microcrystalline cellulose. Other conditions were kept consistent with Example 1 to obtain methotrexate tablets.

[0112] Comparative Example 9

[0113] The fumed silica in Example 1 was omitted, and the amount of calcium pantothenate was adjusted to the sum of the masses of calcium pantothenate and fumed silica. Other conditions were kept consistent with Example 1 to obtain methotrexate tablets.

[0114] The obtained methotrexate tablets (Example 1, Comparative Examples 1 to 9; the methotrexate tablets prepared in Examples 1 to 3 have the same properties, and Example 1 is used as an example for testing) were subjected to performance testing, and the test results are as follows:

[0115] 1. Stability test

[0116] The storage stability of the methotrexate tablets prepared in Example 1 and Comparative Examples 1 to 9 under normal light and high humidity was tested.

[0117] The test results are shown in Table 1. The results show that the methotrexate tablets prepared in Example 1 have excellent storage stability under daily light and high humidity, which is significantly better than Comparative Examples 1 to 9.

[0118] Table 1 Stability test

[0119]

[0120]

[0121] 2. Disintegration time and dissolution test

[0122] The disintegration time and solubility of the methotrexate tablets prepared in Example 1 and Comparative Examples 1 to 9 in simulated gastric juice were tested.

[0123] The results are shown in Table 2. The results show that the disintegration time of the embodiment is the fastest, and it can be completely disintegrated in 45 seconds; the solubility is the highest, reaching 96%, which is significantly better than comparative examples 1-9.

[0124] Table 2 Disintegration time and dissolution test

[0125] Disintegration time(s) Dissolution (%) Example 1 45 96％ Comparative Example 1 61 90％ Comparative Example 2 59 88％ Comparative Example 3 82 75％ Comparative Example 4 101 84％ Comparative Example 5 95 69％ Comparative Example 6 115 61％ Comparative Example 7 99 76％ Comparative Example 8 75 80％ Comparative Example 9 87 79％

[0126] 3. Bioavailability and side effects

[0127] Animal experiments were performed to detect the absolute bioavailability and the percentage of side effect samples of the methotrexate tablets prepared in Example 1 and Comparative Examples 1 to 9. 110 SD rats were divided into 11 groups, namely, a control group, an Example 1 administration group, and a Comparative Example 1 to 9 administration group.

[0128] The results are shown in Table 3. The results show that the methotrexate tablets prepared in Example 1 have a high bioavailability of 94%, and have relatively mild side effects, which are significantly lower than those in Comparative Examples 1-9.

[0129] Table 3 Bioavailability and side effects

[0130] Absolute bioavailability (%) Proportion of samples with significant ALT abnormality (%) Samples with significant decrease in neutrophils (%) Example 1 94％ 10％ 10％ Comparative Example 1 87％ 30％ 20％ Comparative Example 2 90％ 20％ 20％ Comparative Example 3 83％ 50％ 30％ Comparative Example 4 75％ 40％ 50％ Comparative Example 5 81％ 50％ 30％ Comparative Example 6 86％ 30％ 30％ Comparative Example 7 66％ 30％ 40％ Comparative Example 8 79％ 30％ 20％ Comparative Example 9 72％ 40％ 50％

[0131] In summary, the methotrexate tablets prepared in the examples of the present application have the advantages of strong storage stability, high solubility and bioavailability, and relatively mild side effects.

[0132] Although the present invention has been disclosed as above in the form of a preferred embodiment, it is not intended to limit the present invention. Anyone familiar with this technology can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be based on the definition of the claims.

Claims

1. A method for preparing methotrexate tablets, characterized in that: The steps include: (1) Evenly mixing lecithin, microcrystalline cellulose, β-cyclodextrin, and magnesium stearate to obtain an excipient; (2) mixing and grinding methotrexate, calcium pantothenate, and fumed silica to obtain an active substance; (3) Mixing the active substance and excipients to form a mixture; (4) uniformly mixing the mixture with sorbitol, calcium bicarbonate, and starch milk, and granulating to obtain drug granules; (5) tableting the drug particles to obtain methotrexate tablets; The mass ratio of lecithin, microcrystalline cellulose, beta-cyclodextrin, magnesium stearate, methotrexate, mesoporous silica, sorbitol, calcium bicarbonate, and starch in starch milk is 1-3: 30-40: 8-10: 1-5: 2-3: 3-5: 5-8: 15-20: 15-20; The starch milk in step (4) is obtained by dissolving starch in water, with a mass concentration of 70-80%; the starch is one of corn starch, wheat starch and potato starch.

2. The method according to claim 1, characterized in that The particle size of the granulation in step (4) is 20-30 mesh.

3. The method according to claim 1, characterized in that Step (5) is carried out by a rotary tablet press, with a turntable speed of 18 rpm, a filling pressure of 23 N, and a filling depth of 15 mm; the mold is circular with a diameter of 5 mm.

4. The method according to claim 1, characterized in that The unit tablet weight of the methotrexate tablet in step (5) is 100 mg.

5. The method according to claim 1, characterized in that The uniform mixing in step (1) is performed at 2000-3000 rpm for 3-8 minutes.

6. The method according to claim 1, characterized in that The mixing in step (3) is performed at 2000-3000 rpm for 3-8 min.

7. The method according to claim 1, characterized in that The mixing in step (4) is performed at 2000-3000 rpm for 3-8 min.

8. The methotrexate tablets prepared by the method according to any one of claims 1 to 7.

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