A kind of fluorouracil tablet and preparation method

Abstract

The present invention provides a fluorouracil tablet and a preparation method. Fluorouracil tablets of the present invention include a core and a coating layer, wherein the core includes the following raw materials: fluorouracil, starch, starch slurry, magnesium stearate, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone; the coating layer is made of the following excipients: pullulan, hydroxypropyl methylcellulose acetate succinate, mannitol, sodium stearate fumarate; the coating layer is made of the following excipients in weight proportion: 25-35 parts of pullulan, 18-22 parts of hydroxypropyl methylcellulose acetate succinate, 8-12 parts of mannitol, and 4-6 parts of sodium stearate fumarate. The fluorouracil tablets prepared by the present invention can better stably enter the intestine, meet the requirements of enteric-coated tablets, and have low impurity content and good stability, which is conducive to reducing the occurrence of adverse reactions, better improving the drug safety of fluorouracil, and at the same time conducive to the performance of drug efficacy.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a fluorouracil tablet and a preparation method thereof. Background Art

[0002] Fluorouracil is an anti-tumor drug, mainly used for colon cancer, rectal cancer, liver cancer, choriocarcinoma, malignant hydatidiform mole, head and neck squamous cell carcinoma and skin cancer. The mechanism of action of fluorouracil is to inhibit the proliferation of cancer cells. However, it also affects normal rapidly dividing cells, including gastric mucosal cells, which may cause adverse reactions such as gastritis, ulcers, and gastric bleeding in some patients. Therefore, it is urgent to study and improve the preparation process of fluorouracil to reduce the occurrence of adverse reactions. Summary of the invention

[0003] In view of this, the present invention provides a fluorouracil tablet and a preparation method to solve the above problems.

[0004] The technical solution of the present invention is achieved in this way:

[0005] A fluorouracil tablet comprises a tablet core and a coating layer, wherein the tablet core comprises the following raw materials and auxiliary materials: fluorouracil, starch, starch slurry, magnesium stearate, low-substituted hydroxypropyl cellulose, and cross-linked polyvinylpyrrolidone; and the coating layer is made of the following auxiliary materials: pullulan, hydroxypropyl methylcellulose acetate succinate, mannitol, and sodium stearate fumarate.

[0006] In a further embodiment, the tablet core is made of raw materials and auxiliary materials in the following weight proportions: 15 parts of fluorouracil, 8-10 parts of starch, 5-7 parts of starch slurry, 0.02-0.04 parts of magnesium stearate, 2-4 parts of low-substituted hydroxypropyl cellulose, and 1.5-2.5 parts of cross-linked polyvinylpyrimidine.

[0007] In a further embodiment, the coating layer is prepared from the following auxiliary materials in the following weight proportions: 25-35 parts of pullulan, 18-22 parts of hydroxypropyl methylcellulose acetate succinate, 8-12 parts of mannitol, and 4-6 parts of sodium stearate fumarate.

[0008] A further solution is that the mass ratio of the tablet core to the coating layer is 100:5-15, preferably 100:9-10.

[0009] A further solution is that the tablet core is made of the following raw and auxiliary materials in the following weight proportions: 15 parts of fluorouracil, 9 parts of starch, 6 parts of starch slurry, 0.03 parts of magnesium stearate, 3 parts of low-substituted hydroxypropyl cellulose, and 2 parts of cross-linked polyvinylpyrrolidone; the coating layer is made of the following auxiliary materials in the following weight proportions: 30 parts of pullulan, 20 parts of hydroxypropyl methylcellulose acetate succinate, 10 parts of mannitol, and 5 parts of sodium stearyl fumarate.

[0010] A further solution is that the mass concentration of the starch slurry is 8%-12%wt.

[0011] The preparation method of the fluorouracil tablet of the present invention comprises the following steps:

[0012] S1. Grind and sieve the raw and auxiliary materials, and mix fluorouracil with starch, low-substituted hydroxypropyl cellulose, and cross-linked polyvinylpyrimidine to obtain ingredients;

[0013] S2, adding starch slurry to the ingredients in step S1 to perform wet granulation;

[0014] S3, drying the material granulated in step S2;

[0015] S4, granulating the material dried in step S3; placing the granulated material in a total mixer, adding magnesium stearate for total mixing, and tableting to obtain tablet cores;

[0016] S5, mix pullulan and hydroxypropyl methylcellulose acetate succinate, add water according to the material-liquid ratio (kg / L) = 1:4-5, stir, add mannitol and sodium stearate fumarate, mix well, and obtain a coating solution;

[0017] S6. Use the coating liquid prepared in step S5 to coat the tablet cores prepared in step S4 using a coating machine, spray the liquid and dry for 15 to 20 minutes to obtain the target fluorouracil tablets.

[0018] A further solution is that in S3, the drying process is: drying at 75-80°C for 20-40 min, and drying at 50-55°C for 1-2 h.

[0019] In a further embodiment, in S5, the liquid ratio of the pullulan and hydroxypropyl methylcellulose acetate succinate to water is 1:4-5 (kg / L).

[0020] A further solution is that in S6, the outlet air temperature of the coating process is 35-40°C, the inlet air temperature is 60-65°C, the coating pan speed is 20-30rpm, and the atomization pressure is 0.15-0.25Mpa.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] The fluorouracil tablet prepared by the present invention consists of a tablet core and a coating layer structure. The tablet core is made of fluorouracil, starch, starch slurry, magnesium stearate, low-substituted hydroxypropyl cellulose and cross-linked polyvinylpyrrolidone as raw and auxiliary materials; the coating layer is made of pullulan, hydroxypropyl methylcellulose acetate succinate, mannitol and sodium stearate fumarate as auxiliary materials. The fluorouracil tablet of the present invention is beneficial to avoid the problem of gastric discomfort caused by the release of fluorouracil in the stomach, greatly reduces the occurrence of adverse reactions, better improves the drug safety of fluorouracil, and is beneficial to the efficacy of the drug.

[0023] The fluorouracil tablets prepared by the present invention have good dissolution release in pH 6.8 phosphate buffer, and the dissolution rate in 0.1M hydrochloric acid for 120 minutes is no more than 5%, so that the fluorouracil tablets prepared by the present invention can enter the intestine more stably and meet the requirements of enteric-coated tablets. In addition, the fluorouracil tablets prepared by the present invention have low impurity content, which is conducive to reducing the occurrence of adverse reactions.

[0024] In addition, the fluorouracil tablets prepared by the present invention have good stability, still maintain good enteric effect after the accelerated test, and the impurity content does not increase significantly. DETAILED DESCRIPTION

[0025] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0026] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0027] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0028] Example 1

[0029] Table 1 Prescription table of fluorouracil tablets

[0030]

[0031] The preparation method of the fluorouracil tablets comprises the following steps:

[0032] S1. Grind the raw materials and auxiliary materials, pass them through an 80-mesh sieve, and mix fluorouracil with starch, low-substituted hydroxypropyl cellulose, and cross-linked polyvinylpyrimidine to obtain ingredients;

[0033] S2, adding 10%wt starch slurry to the ingredients in S1 and performing wet granulation;

[0034] S3, drying the granulated material in S2, drying process: drying at 75-80°C for 30 min, and drying at 50-55°C for 90 min;

[0035] S4, granulating the dried material in S3; placing the granulated material in a total mixer, adding magnesium stearate for total mixing, and tableting to obtain tablet cores;

[0036] S5, mix pullulan and hydroxypropyl methylcellulose acetate succinate, add water for injection according to the solid-liquid ratio (kg / L) = 1:4, stir, add mannitol and sodium stearate fumarate, mix well, and obtain a coating solution;

[0037] S6. Use the coating liquid prepared in S5 to coat the S4 tablet cores using a coating machine. The outlet air temperature of the coating process is 35-40°C, the inlet air temperature is 60-65°C, the coating pan speed is 25rpm, and the atomization pressure is 0.20Mpa. Dry the spray liquid for 15 minutes and package to obtain the target fluorouracil tablets.

[0038] Test Example 1-Dissolution curve test

[0039] 1.1 The tablets prepared in Example 1 were subjected to a dissolution curve test.

[0040] 1.1 Determination method: In a dissolution cup filled with 900mL of 0.1M hydrochloric acid dissolution medium, 6 dissolution cups are placed in parallel, and a piece of test sample is placed in each rotating basket, and the dissolution test is started at a speed of 100rpm; 120min after the start of the test, samples are taken at each time point of 5min, 15min, 30min, 45min, 60min, 90min, and 120min, and 5ml of the sample is taken. Then the rotating basket is lifted, the 0.1M hydrochloric acid dissolution medium is poured out, and the dissolution cup is washed with purified water. Then 900mL of pH6.8 phosphate buffer is added, and the timing is restarted. Samples are taken at each time point of 5min, 15min, 30min, 45min, 60min, 90min, and 120min.

[0041] Requirements: The dissolution rate in 0.1M hydrochloric acid dissolution medium shall not exceed 10% in 120 minutes; the dissolution rate in pH 6.8 phosphate buffer shall not be less than 80% in 45 minutes.

[0042] 1.2 Test results

[0043] Table 2 Dissolution

[0044]

[0045]

[0046] It can be seen from the results in the above table that the fluorouracil tablets prepared by the present invention have good dissolution release in pH 6.8 phosphate buffer, and the 120 min dissolution rate in 0.1 M hydrochloric acid dissolution medium is significantly lower than 5%, so that the fluorouracil tablets prepared by the present invention can enter the intestine more stably and meet the requirements of enteric-coated tablets.

[0047] Example 2

[0048] Table 3 Prescription table of fluorouracil tablets

[0049]

[0050] The preparation method of the fluorouracil tablets comprises the following steps:

[0051] S1. Grind the raw materials and auxiliary materials, pass them through an 80-mesh sieve, and mix fluorouracil with starch, low-substituted hydroxypropyl cellulose, and cross-linked polyvinylpyrimidine to obtain ingredients;

[0052] S2, adding 10%wt starch slurry to the ingredients in S1 and performing wet granulation;

[0053] S3, drying the granulated material in S2, drying process: drying at 75-80°C for 30 min, and drying at 50-55°C for 90 min;

[0054] S4, granulating the dried material in S3; placing the granulated material in a total mixer, adding magnesium stearate for total mixing, and tableting to obtain tablet cores;

[0055] S5, mix pullulan and hydroxypropyl methylcellulose acetate succinate, add water for injection according to the solid-liquid ratio (kg / L) = 1:4, stir, add mannitol and sodium stearate fumarate, mix well, and obtain a coating solution;

[0056] S6. Use the coating liquid prepared in S5 to coat the S4 tablet cores using a coating machine. The outlet air temperature of the coating process is 35-40°C, the inlet air temperature is 60-65°C, the coating pan speed is 25rpm, and the atomization pressure is 0.20Mpa. Dry the spray liquid for 15 minutes and package to obtain the target fluorouracil tablets.

[0057] In this example, the dissolution test was carried out according to the method of Test Example 1. The dissolution curve result was close to that of Example 1, and the dissolution rate in pH 6.8 phosphate buffer after 45 min was lower than that of Example 1.

[0058] Example 3

[0059] Table 4 Prescription table of fluorouracil tablets

[0060]

[0061] The preparation method of the fluorouracil tablets comprises the following steps:

[0062] S1. Grind the raw materials and auxiliary materials, pass them through an 80-mesh sieve, and mix fluorouracil with starch, low-substituted hydroxypropyl cellulose, and cross-linked polyvinylpyrimidine to obtain ingredients;

[0063] S2, adding 10%wt starch slurry to the ingredients in S1 and performing wet granulation;

[0064] S3, drying the granulated material in S2, drying process: drying at 75-80°C for 30 min, and drying at 50-55°C for 90 min;

[0065] S4, granulating the dried material in S3; placing the granulated material in a total mixer, adding magnesium stearate for total mixing, and tableting to obtain tablet cores;

[0066] S5, mix pullulan and hydroxypropyl methylcellulose acetate succinate, add water for injection according to the solid-liquid ratio (kg / L) = 1:4, stir, add mannitol and sodium stearate fumarate, mix well, and obtain a coating solution;

[0067] S6. Use the coating liquid prepared in S5 to coat the S4 tablet cores using a coating machine. The outlet air temperature of the coating process is 35-40°C, the inlet air temperature is 60-65°C, the coating pan speed is 25rpm, and the atomization pressure is 0.20Mpa. Dry the spray liquid for 15 minutes and package to obtain the target fluorouracil tablets.

[0068] In this example, the dissolution test was carried out according to the method of Test Example 1. The dissolution curve result was close to that of Example 1, and the dissolution rate in pH 6.8 phosphate buffer after 45 min was lower than that of Example 1.

[0069] Example 4

[0070] The prescription table is consistent with that in Example 3. The preparation method of fluorouracil tablets comprises the following steps:

[0071] S1. Grind the raw materials and auxiliary materials, pass them through an 80-mesh sieve, and mix fluorouracil with starch, low-substituted hydroxypropyl cellulose, and cross-linked polyvinylpyrimidine to obtain ingredients;

[0072] S2, adding 10%wt starch slurry to the ingredients in S1 and performing wet granulation;

[0073] S3, drying the granulated material in S2, drying process: drying at 75-80°C for 40 min, and drying at 50-55°C for 80 min;

[0074] S4, granulating the dried material in S3; placing the granulated material in a total mixer, adding magnesium stearate for total mixing, and tableting to obtain tablet cores;

[0075] S5, mix pullulan and hydroxypropyl methylcellulose acetate succinate, add water for injection according to the solid-liquid ratio (kg / L) = 1:5, stir, add mannitol and sodium stearate fumarate, mix well, and obtain a coating solution;

[0076] S6. Use the coating liquid prepared in S5 to coat the S4 tablet cores using a coating machine. The outlet air temperature of the coating process is 35-40°C, the inlet air temperature is 60-65°C, the coating pan speed is 30rpm, and the atomization pressure is 0.25Mpa. Dry the spray liquid for 20 minutes and package to obtain the target fluorouracil tablets.

[0077] In this example, the dissolution test was carried out according to the method of Test Example 1. The dissolution curve result was close to that of Example 3. The dissolution rate in pH 6.8 phosphate buffer for 45 min was lower than that of Example 3.

[0078] Comparative Example 1

[0079] Sodium carboxymethyl starch and cross-linked sodium carboxymethyl cellulose are added to the tablet core formulation of this comparative example.

[0080] Table 5 Prescription table of fluorouracil tablets

[0081]

[0082] The preparation method of the fluorouracil tablets comprises the following steps:

[0083] S1. Grind the raw materials and auxiliary materials, pass them through an 80-mesh sieve, and mix fluorouracil with starch, sodium carboxymethyl starch, and cross-linked sodium carboxymethyl cellulose to obtain ingredients;

[0084] S2, adding 10%wt starch slurry to the ingredients in S1 and performing wet granulation;

[0085] S3, drying the granulated material in S2, drying process: drying at 75-80°C for 30 min, and drying at 50-55°C for 90 min;

[0086] S4, granulating the dried material in S3; placing the granulated material in a total mixer, adding magnesium stearate for total mixing, and tableting to obtain tablet cores;

[0087] S5, mix pullulan and hydroxypropyl methylcellulose acetate succinate, add water for injection according to the solid-liquid ratio (kg / L) = 1:4, stir, add mannitol and sodium stearate fumarate, mix well, and obtain a coating solution;

[0088] S6. Use the coating liquid prepared in S5 to coat the S4 tablet cores using a coating machine. The outlet air temperature of the coating process is 35-40°C, the inlet air temperature is 60-65°C, the coating pan speed is 25rpm, and the atomization pressure is 0.20Mpa. Dry the spray liquid for 15 minutes and package to obtain the target fluorouracil tablets.

[0089] This comparative example was subjected to a dissolution test according to the method of Test Example 1. The dissolution curve result was significantly worse than that of Example 1. The dissolution rate in pH 6.8 phosphate buffer was less than 80% in 45 minutes, which could not meet the requirements.

[0090] Comparative Example 2

[0091] Sodium alginate and hydroxypropyl methylcellulose were added to the coating layer formulation of this comparative example.

[0092] Table 6 Prescription table of fluorouracil tablets

[0093]

[0094] The preparation method of the fluorouracil tablets comprises the following steps:

[0095] S1. Grind the raw materials and auxiliary materials, pass them through an 80-mesh sieve, and mix fluorouracil with starch, low-substituted hydroxypropyl cellulose, and cross-linked polyvinylpyrimidine to obtain ingredients;

[0096] S2, adding 10%wt starch slurry to the ingredients in S1 and performing wet granulation;

[0097] S3, drying the granulated material in S2, drying process: drying at 75-80°C for 30 min, and drying at 50-55°C for 90 min;

[0098] S4, granulating the dried material in S3; placing the granulated material in a total mixer, adding magnesium stearate for total mixing, and tableting to obtain tablet cores;

[0099] S5, mixing sodium alginate and hydroxypropyl methylcellulose, adding water for injection according to the solid-liquid ratio (kg / L) = 1:4, stirring, adding mannitol and sodium stearyl fumarate, mixing well, and obtaining a coating solution;

[0100] S6. Use the coating liquid prepared in S5 to coat the S4 tablet cores using a coating machine. The outlet air temperature of the coating process is 35-40°C, the inlet air temperature is 60-65°C, the coating pan speed is 25rpm, and the atomization pressure is 0.20Mpa. Dry the spray liquid for 15 minutes and package to obtain the target fluorouracil tablets.

[0101] This comparative example was subjected to a dissolution test according to the method of Test Example 1. The dissolution curve result was significantly worse than that of Example 1. The dissolution rate in 0.1 M hydrochloric acid dissolution medium was also more than 10% in 120 min, which failed to meet the enteric requirements.

[0102] Test Example 2-Determination of Related Substances

[0103] Operate in accordance with high performance liquid chromatography (General Rules, Part 4, Chinese Pharmacopoeia 2020 Edition).

[0104] 1.1 Inspection operation method:

[0105] Preparation of test solution: Take 0.01 g of the product and place it in a 100 ml volumetric flask. Add mobile phase to dissolve it, then dilute it to the scale with mobile phase to make a solution containing 0.1 mg per 1 ml and shake well.

[0106] Preparation of control solution: Accurately measure 1.0 ml of the test solution, place it in a 100 ml volumetric flask, dilute it to the mark with mobile phase, shake well, then accurately measure 5 ml, place it in a 20 ml volumetric flask, dilute it to the mark with mobile phase to make a solution containing 0.25 μg per 1 ml, and shake well.

[0107] Blank solution: mobile phase.

[0108] Mobile phase: water-methanol v / v=95:5

[0109] Injection procedure: Inject according to the injection sequence in Table 7:

[0110] Serial number name Number of needle insertions 1 blank solution 1 2 Test solution 1 3 Control solution 1

[0111] System suitability test:

[0112] The number of theoretical plates calculated based on the fluorouracil peak is not less than 2500;

[0113] Record the chromatogram to 5 times the retention time of the main component peak;

[0114] The resolution of the fluorouracil peak and the adjacent impurity peaks was greater than 1.5.

[0115] calculate:

[0116] Single largest impurity = (single largest impurity peak area / control solution area * 400) * 100

[0117] 1.2 Qualification standard: If there are impurity peaks in the chromatogram of the test solution, the single impurity shall not exceed 0.5% and the total impurities shall not exceed 0.75%.

[0118] 1.2 Test results

[0119] Table 8 Determination results of related substances

[0120] Related substances Maximum single impurity Total Miscellaneous Example 1 0.10％ 0.21％ Example 2 0.13％ 0.24％ Example 3 0.12％ 0.25％ Example 4 0.14％ 0.28％ Comparative Example 1 0.21％ 0.36％ Comparative Example 2 0.20％ 0.32％

[0121] It can be seen from the results in the above table that, compared with Comparative Examples 1-2, the fluorouracil tablets prepared in Examples 1-4 have a lower maximum single impurity content and a lower total impurity content.

[0122] Test Example 4-Stability Study

[0123] The tablets prepared in Example 1 were subjected to a stability test.

[0124] 1.1 Accelerated test conditions: Place the test sample at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 6 months, and take samples for testing at the 0th, 3rd and 6th month.

[0125] 1.2 Test results

[0126] Table 9 Dissolution

[0127]

[0128]

[0129] Table 10 Related substances

[0130]

[0131] It can be seen from the results in the above table that the fluorouracil tablets prepared by the present invention have good stability, still maintain good enteric effect after the accelerated test, and have no significant difference in impurity content.

[0132] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A fluorouracil tablet, characterized in that: Including tablet core and coating layer, The tablet core is prepared from the following raw materials and auxiliary materials in the following weight proportions: 15 parts of fluorouracil, 8-10 parts of starch, 5-7 parts of starch slurry, 0.02-0.04 parts of magnesium stearate, 2-4 parts of low-substituted hydroxypropyl cellulose, and 1.5-2.5 parts of cross-linked polyvinylpyrrolidone; The coating layer is prepared from the following auxiliary materials in weight proportion: 1.2-1.8 parts of pullulan, 0.8-1.2 parts of hydroxypropyl methylcellulose acetate succinate, 0.4-0.6 parts of mannitol, and 0.2-0.3 parts of sodium stearyl fumarate; The mass ratio of the tablet core to the coating layer is 100:5-15.

2. The fluorouracil tablet according to claim 1, characterized in that: The tablet core is prepared from the following raw and auxiliary materials in weight proportion: 15 parts of fluorouracil, 9 parts of starch, 6 parts of starch slurry, 0.03 parts of magnesium stearate, 3 parts of low-substituted hydroxypropyl cellulose, and 2 parts of cross-linked polyvinylpyrrolidone; the coating layer is prepared from the following auxiliary materials in weight proportion: 1.5 parts of pullulan, 1 part of hydroxypropyl methylcellulose acetate succinate, 0.5 parts of mannitol, and 0.25 parts of sodium stearate fumarate.

3. The fluorouracil tablet according to claim 1, characterized in that: The mass concentration of the starch slurry is 8%-12%wt.

4. The method for preparing the fluorouracil tablet according to any one of claims 1 to 3, characterized in that: The following steps are involved: S1. Grind and sieve the raw and auxiliary materials, and mix fluorouracil with starch, low-substituted hydroxypropyl cellulose and cross-linked polyvinylpyrimidine to obtain ingredients; S2, adding starch slurry to the ingredients in step S1 to perform wet granulation; S3, drying the material granulated in step S2; S4, granulating the material dried in step S3; placing the granulated material in a total mixer, adding magnesium stearate for total mixing, and tableting to obtain tablet cores; S5, mix pullulan and hydroxypropyl methylcellulose acetate succinate, add water according to the solid-liquid ratio kg / L=1:4-5, stir, add mannitol and sodium stearate fumarate, mix well, and obtain a coating solution; S6. Use the coating liquid prepared in step S5 to coat the tablet cores prepared in step S4 using a coating machine, spray the liquid and dry for 15 to 20 minutes to obtain the target fluorouracil tablets.

5. The method for preparing the fluorouracil tablet according to claim 4, characterized in that: In S3, the drying process is: drying at 75-80°C for 20-40 minutes, and drying at 50-55°C for 1-2 hours.

6. The method for preparing a fluorouracil tablet according to claim 4, characterized in that: In S6, the outlet air temperature of the coating process is 35-40°C, the inlet air temperature is 60-65°C, the coating pan speed is 20-30rpm, and the atomization pressure is 0.15-0.25Mpa.

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