Famotidine tablet and preparation process thereof

Abstract

The invention provides a famotidine tablet and a preparation process thereof. The famotidine tablet is sequentially composed of a tablet core and a coating layer from inside to outside, wherein the tablet core is prepared from the following raw and auxiliary materials in parts by weight: 20 parts of famotidine, 80-120 parts of a diluent, 5-8 parts of a disintegrating agent, 0.4-0.7 part of an adhesive and 0.8-1.2 parts of a lubricant; the coating layer is prepared from the following auxiliary materials: alfalfa polysaccharide, L-fucose alcohol and sodium stearate fumarate, and the mass ratio of the alfalfa polysaccharide to the L-fucose alcohol to the sodium stearate fumarate is (2-3): (1-1.5): (0.4-0.6). The famotidine tablet prepared by adopting the prescription and the process is good in content and content uniformity, good in dissolution curve in a 0.1 mol / L hydrochloric acid solution, a phosphate buffer solution with the pH value of 4.5, a phosphate buffer solution with the pH value of 6.8 and purified water and low in total impurity content, and the stability under the acceleration condition and the long-term condition is improved.

Description

Technical Field

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

[0002] Famotidine, chemical name: 3-[[2-[(diaminomethylene)-4-thiazolyl]methyl]thio]-N-sulfamoylpropionamidine, is a third-generation guanidinylthiazole H2 receptor blocker with definite efficacy, few adverse reactions, and high affinity for H2 receptors. Its mechanism of action is similar to that of cimetidine. Famotidine can effectively inhibit the secretion of basal gastric acid, nocturnal gastric acid and gastric acid caused by food stimulation, and can also inhibit the secretion of gastric acid caused by stimulation such as histamine and pentagastrin. Its strength in inhibiting H2 receptors is 20 times stronger than that of cimetidine. In addition, famotidine can also inhibit the secretion of pepsin. It is clinically used for gastric and duodenal ulcers, stress ulcers, acute gastric mucosal bleeding, gastrinoma, and reflux esophagitis.

[0003] Famotidine tablets were first marketed in Japan in 1985 after successful research by Yamanouchi Pharmaceutical (now Astellas Pharma). The specification is 20mg. Approved for marketing in the United States under the trade name .

[0004] Famotidine tablets were first marketed in Japan in 1985 after successful research by Yamanouchi Co., Ltd. (now Astellas Pharma) of Japan. The trade name is Gaoshuda. It is used for the treatment of gastric ulcer, duodenal ulcer, anastomotic ulcer, upper gastrointestinal bleeding (due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis), reflux esophagitis, and Zollinger-Ellison syndrome. The usual adult dose of famotidine is 20 mg orally administered once, twice a day (after breakfast, after dinner, or before bedtime). In addition, 40 mg can be taken orally every day (before bedtime). However, in the case of upper gastrointestinal bleeding, treatment is usually started with an injection, and then changed to oral administration after oral administration is possible; and to improve the gastric mucosal lesions (erosion, bleeding, redness, edema) of the following diseases, acute gastritis, and the acute exacerbation of chronic gastritis. The adult dose of famotidine is usually 10 mg orally twice a day (after breakfast, after dinner, or before bedtime). Or 20 mg can be taken orally once a day (before bedtime).

[0005] The prescription excipients of the reference preparation are composed of anhydrous calcium hydrogen phosphate, crystalline cellulose, lactose hydrate, hydroxypropyl cellulose, corn starch, light anhydrous silicic acid, calcium stearate, low-substituted hydroxypropyl cellulose, sucrose, calcium lactate hydrate, polyethylene glycol, titanium oxide, talc, and carnauba wax.

[0006] In summary, it is of great significance to develop new famotidine tablets prescriptions and processes to further improve the quality of preparations. Summary of the invention

[0007] In view of this, the present invention provides a famotidine tablet and a preparation process thereof, which has the advantages of good solubility, low total impurity content, good stability, etc.

[0008] The technical scheme of the present invention is achieved as follows: a famotidine tablet, which is composed of a tablet core and a coating layer from the inside to the outside, wherein the tablet core is made of the following raw materials and auxiliary materials in parts by weight: 20 parts of famotidine, 80-120 parts of a diluent, 5-8 parts of a disintegrant, 0.4-0.7 parts of a binder, and 0.8-1.2 parts of a lubricant; the coating layer material is made of the following auxiliary materials: alfalfa polysaccharide, L-fucitol, and sodium stearate fumarate, and the mass ratio of alfalfa polysaccharide, L-fucitol, and sodium stearate fumarate is 2-3:1-1.5:0.4-0.6; and the weight of the coating layer material is 1% to 5% of the weight of the tablet core.

[0009] A further technical solution is that the tablet core is made of the following raw materials and auxiliary materials in parts by weight: 20 parts of famotidine, 90-100 parts of diluent, 6-7 parts of disintegrant, 0.5-0.6 parts of binder, and 0.9-1.1 parts of lubricant.

[0010] A further technical solution is that the diluent is composed of corn starch and lactose in a mass ratio of 8-12:80-90, the disintegrant is sodium carboxymethyl starch, the binder is hypromellose, and the lubricant is magnesium stearate.

[0011] The present invention also provides a method for preparing famotidine tablets, comprising the following steps:

[0012] (1) Granulation: Granulation is performed using a wet granulation process, wherein the raw materials and auxiliary materials of the tablet core are premixed, then granulated with 55-65% v / v ethanol solution, and then further mixed to form a soft material;

[0013] (2) Drying: Dry the soft material at a temperature of 55-65°C and a drying time of 25-85 minutes;

[0014] (3) Granulation: Granulation is performed after drying. The soft material enters the granulator and is granulated through a 18-30 mesh screen;

[0015] (4) Total mixing: After granulation, total mixing is performed at a mixing speed of 8-12 rpm and a mixing time of 5-15 min;

[0016] (5) Tableting: After the total mixing, tableting is performed with a tableting hardness of 20-60N to obtain a tablet core;

[0017] (6) Coating: Add the coating layer material into purified water to prepare a 6-15%wt coating solution; coat the core tablet to form a coating layer.

[0018] A further technical solution is that, in step (2), the specific process parameters of the wet granulation process are:

[0019] S1, premixing: stirring paddle speed: 100-150rpm, chopping speed: 1000-1500rpm, time: 2-30min;

[0020] S2, adding binder to granulate: stirring speed: 100-150rpm, chopping speed: 1000-1500rpm, time: 1-10min;

[0021] S3. Continue mixing: stirring speed: 150-200 rpm, chopping speed: 1500-2500 rpm, time: 0.5-2 min.

[0022] A further technical solution is that in step (2), the drying temperature is 60°C±5°C and the drying time is 30-50min.

[0023] A further technical solution is that in step (3), the aperture of the sieve is 24 meshes.

[0024] A further technical solution is that in step (4), the mixing speed is 12 rpm and the mixing time is 15 min; and in step (5), the tableting hardness is 40N.

[0025] A further technical solution is that in step (6), the coating process: the main engine speed of the coating machine is 2-5 rpm, the hot air temperature is set to 60-65°C, the tablet bed temperature is 39-43°C, the air outlet temperature is 30-50°C, the atomization pressure is 0.3-0.5Mpa, and the peristaltic pump speed is 15-60rpm.

[0026] A further technical solution is that the granulation equipment is a wet mixing granulator, the drying equipment is a granulation coating pan or an electric blast drying oven, the granulation equipment is a granulation machine, the total mixing equipment is a three-dimensional mixer, and the tableting equipment is a rotary tablet press.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] (1) The famotidine tablets prepared by the prescription and process of the present invention have good content and content uniformity, good dissolution curves in 0.1 mol / L hydrochloric acid solution, pH 4.5 phosphate buffer, pH 6.8 phosphate buffer and purified water, and low total impurity content, thereby improving the stability under accelerated conditions and long-term conditions.

[0029] (2) The present invention uses alfalfa polysaccharide, L-fucitol, and sodium stearyl fumarate to prepare the coating layer. The coating process of the present invention not only has a good dissolution curve and a low total impurity content, but also effectively improves the stability of famotidine tablets, is beneficial to improving drug safety, and improves product appearance. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 Dissolution test (0.1 mol / L hydrochloric acid solution) of the famotidine tablets prepared in Example 1 of the present invention and the reference preparation;

[0031] Figure 2 Dissolution test (pH 4.5 phosphate buffer) of the famotidine tablets prepared in Example 1 of the present invention and the reference preparation;

[0032] Figure 3 Dissolution test of the famotidine tablets prepared in Example 1 of the present invention and the reference preparation (pH 6.8 phosphate buffer);

[0033] Figure 4 Dissolution test (purified water) of the famotidine tablets prepared in Example 1 of the present invention and the reference preparation. DETAILED DESCRIPTION

[0034] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0035] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0036] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0037] The basic information of famotidine API is shown in Table 1.

[0038] Table 1 Basic information of famotidine API

[0039]

[0040] Table 2 Effects of prescription components

[0041]

[0042] Example 1

[0043] Table 3 Prescription 1

[0044]

[0045] The preparation method of the above-mentioned famotidine tablets comprises the following steps:

[0046] (1) Granulation: Granulation is performed using a wet mixing granulator and a wet granulation process. The raw materials and auxiliary materials of the tablet core are first premixed, then granulated with 60% v / v ethanol solution, and finally further mixed to form a soft material;

[0047] Specific process parameters of the above wet granulation process:

[0048] S1, premixing: stirring speed: 150 rpm, chopping speed: 1200 rpm, time: 3 min;

[0049] S2, adding binder to granulate: stirring speed: 150 rpm, chopping speed: 1200 rpm, time: 2 min;

[0050] S3, continue mixing: stirring speed: 180 rpm, chopping speed: 2000 rpm, time: 1 min;

[0051] (2) Drying: Use a granulator to dry the soft material at a temperature of 60°C ± 5°C for 30 min;

[0052] (3) Granulation: Granulation is performed after drying. The soft material enters the granulator and is granulated through an 18-mesh screen;

[0053] (4) Total mixing: The three-dimensional mixer is used for total mixing, and the total mixing is carried out after granulation. The mixing speed is 10 rpm and the mixing time is 15 min.

[0054] (5) Tableting: Tableting is performed using a rotary tablet press. After total mixing, tableting is performed with a tablet hardness of 40N to obtain tablet cores.

[0055] (6) Coating: Add the coating layer materials alfalfa polysaccharide, L-fucitol, and sodium stearyl fumarate into purified water to prepare a 10%wt coating solution; coat the core tablets to form a coating layer, and the coating weight gain is 3%. Coating process: The main engine speed of the coating machine is 4rpm, the hot air temperature is set to 62°C, the tablet bed temperature is 41°C, the air outlet temperature is 40°C, the atomization pressure is 0.4Mpa, and the peristaltic pump speed is 45rpm.

[0056] 1. Prescription content uniformity

[0057] Table 4 Prescription content uniformity inspection

[0058] Minimum 95.48 Maximum 105.77 average value 101.01 RSD% 3.08 A+2.2S 7.79

[0059] The content and content uniformity of this product are good.

[0060] 2. Dissolution

[0061] The dissolution test method was UV method, 266nm, basket method, 100rpm, and the medium volume was set to 900ml. Different media were used to compare the drug dissolution curves of famotidine tablets, including 0.1mol / L hydrochloric acid solution, pH4.0 acetate buffer, pH4.5 phosphate buffer, pH6.8 phosphate buffer and purified water.

[0062] like Figure 1-4 As shown, the results show that the dissolution amount of each sample and the average dissolution amount of 12 samples of this product in 0.1mol / L hydrochloric acid solution, pH4.0 acetate solution, pH4.5 phosphate solution, pH6.8 phosphate solution, and water for 30 minutes are all greater than 85%; they are rapidly dissolved under different media conditions. Under the dissolution conditions of 0.1mol / L hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, and purified water, the RSD of the famotidine dissolution amount of the homemade preparation and the reference preparation at each time point is less than 5.0%, among which the RSD of this product is less than 1%, and the RSD of the reference preparation is greater than 5%, indicating that under the dissolution conditions of 0.1mol / L hydrochloric acid solution, pH4.0 acetate buffer, pH4.5 phosphate buffer, pH6.8 phosphate buffer, and purified water, the dissolution curve of this product is more stable.

[0063] 3. Stability investigation

[0064] Acceleration conditions: temperature 40℃±2℃, humidity 75%±10%RH; acceleration time: 6 months;

[0065] Long-term conditions: temperature 25℃±2℃, humidity 60%±10%RH; long-term time: 36 months;

[0066] Dissolution stability under accelerated conditions: This product has good dissolution stability under accelerated conditions. There is no obvious downward trend under the dissolution conditions of 0.1 mol / L hydrochloric acid solution, pH 4.5 phosphate buffer, pH 6.8 phosphate buffer, and purified water basket method at 100 rpm, and it is better than the reference preparation.

[0067] Long-term dissolution stability: This product has good dissolution stability under long-term conditions. It does not show a significant downward trend under the dissolution conditions of 0.1 mol / L hydrochloric acid solution, pH 4.5 phosphate buffer, pH 6.8 phosphate buffer, purified water, and basket method 100 rpm, and is superior to the reference preparation.

[0068] Example 2

[0069] The famotidine tablets prescription is consistent with that in Example 1. The preparation method of famotidine tablets comprises the following steps:

[0070] (1) Granulation: Granulation is performed using a wet mixing granulator and a wet granulation process. The raw materials and auxiliary materials of the tablet core are first premixed, then granulated with 55% v / v ethanol solution, and finally further mixed to form a soft material;

[0071] Specific process parameters of the above wet granulation process:

[0072] S1, premixing: stirring speed: 100 rpm, chopping speed: 600 rpm, time: 4 min;

[0073] S2, adding binder to granulate: stirring speed: 100 rpm, chopping speed: 600 rpm, time: 3 min;

[0074] S3, continue mixing: stirring speed: 400 rpm, chopping speed: 1200 rpm, time: 2 min;

[0075] (2) Drying: Use an electric heating blast drying oven to granulate and dry the soft material at a drying temperature of 60°C ± 5°C and a drying time of 25 min;

[0076] (3) Granulation: Granulation is performed after drying. The soft material enters the granulator and is granulated through an 18-mesh screen;

[0077] (4) Total mixing: The three-dimensional mixer is used for total mixing, and the total mixing is carried out after granulation. The mixing speed is 10 rpm and the mixing time is 15 min.

[0078] (5) Tableting: tabletting is performed using a rotary tablet press, and tableting is performed after total mixing, with a tableting hardness of 40N to obtain a tablet core;

[0079] (6) Coating: Add the coating layer material into purified water to prepare an 8%wt coating solution; coat the tablet core to form a coating layer, and the coating weight gain is 3%. Coating process: The main engine speed of the coating machine is 2rpm, the hot air temperature is set to 60°C, the tablet bed temperature is 39°C, the air outlet temperature is 30°C, the atomization pressure is 0.3Mpa, and the peristaltic pump speed is 15rpm.

[0080] Example 3

[0081] The famotidine tablets prescription is consistent with that in Example 1. The preparation method of famotidine tablets comprises the following steps:

[0082] (1) Granulation: A wet mixing granulator is used to perform granulation using a wet granulation process. The raw materials and auxiliary materials of the tablet core are first premixed, then granulated with 65% v / v ethanol solution, and finally further mixed to form a soft material;

[0083] Specific process parameters of the above wet granulation process:

[0084] S1, premixing: stirring speed: 200 rpm, chopping speed: 800 rpm, time: 2 min;

[0085] S2, granulation with binder: stirring speed: 200 rpm, chopping speed: 800 rpm, time: 1 min;

[0086] S3, continue mixing: stirring speed: 600 rpm, chopping speed: 1600 rpm, time: 1 min;

[0087] (2) Drying: Use an electric heating blast drying oven to granulate and dry the soft material at a drying temperature of 60°C ± 5°C and a drying time of 35 min;

[0088] (3) Granulation: After drying, the soft material is granulated and enters the swing granulator to be granulated through an 18-mesh screen;

[0089] (4) Total mixing: The total mixing was carried out using a three-dimensional mixer, and the total mixing was carried out after granulation. The mixing speed was 12 rpm and the mixing time was 10 min.

[0090] (5) Tableting: tabletting is performed using a rotary tablet press, and tableting is performed after total mixing, with a tableting hardness of 40N to obtain a tablet core;

[0091] (6) Coating: Add the coating material to purified water to prepare a 12%wt coating solution; coat the core tablet to form a coating layer, and the coating weight gain is 3%. Coating process: The main engine speed of the coating machine is 5 rpm, the hot air temperature is set to 65°C, the tablet bed temperature is 43°C, the air outlet temperature is 50°C, the atomization pressure is 0.5 MPa, and the peristaltic pump speed is 60 rpm.

[0092] In addition, the content and content uniformity of the product prepared in Example 2-3 of the present invention also meet the quality standard requirements. The dissolution curve of the product in Example 2-3 of the present invention under the dissolution conditions of 0.1 mol / L hydrochloric acid solution, pH 4.5 phosphate buffer, pH 6.8 phosphate buffer, purified water, and basket method 100 rpm also meets the requirements.

[0093] Comparative Example 1

[0094] The difference from Example 1 is that alfalfa polysaccharide in the coating layer material is replaced by cellulose, and L-fucose is replaced by xylitol.

[0095] Table 5-Prescription 2

[0096]

[0097] The famotidine tablets prepared in Comparative Example 1 were examined for related substances under accelerated conditions and compared with Example 1. The results are as follows:

[0098] Table 6 Related substances

[0099]

[0100] The results show that the total impurity content of the famotidine tablets prepared in Comparative Example 1 increased significantly under accelerated conditions for 6 months, while the related substances of the famotidine tablets prepared in Examples 1-3 did not increase substantially under accelerated conditions for 6 months. This indicates that the coating layer material of the embodiment of the present invention can more effectively improve the stability of the famotidine tablets, which is beneficial to improving the safety of the drug.

[0101] 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 principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A famotidine tablet, characterized in that: The famotidine tablet is composed of a tablet core and a coating layer from the inside to the outside. The tablet core is made of the following raw materials and auxiliary materials in parts by weight: 20 parts of famotidine, 80-120 parts of diluent, 5-8 parts of disintegrant, 0.4-0.7 parts of binder, and 0.8-1.2 parts of lubricant; the coating layer material is made of the following auxiliary materials: alfalfa polysaccharide, L-fucitol, and sodium stearate fumarate, and the mass ratio of alfalfa polysaccharide, L-fucitol, and sodium stearate fumarate is 2-3:1-1.5:0.4-0.

6. The weight of the coating layer material is 1% to 5% of the weight of the tablet core.

2. The famotidine tablet according to claim 1, characterized in that The tablet core comprises the following raw materials and auxiliary materials in parts by weight: 20 parts of famotidine, 90-100 parts of diluent, 6-7 parts of disintegrant, 0.5-0.6 parts of binder and 0.9-1.1 parts of lubricant.

3. The famotidine tablet according to claim 1, characterized in that The diluent is composed of corn starch and lactose in a mass ratio of 8-12:80-90, the disintegrant is sodium starch glycolate, the binder is hydroxypropyl methylcellulose, and the lubricant is magnesium stearate.

4. The method for preparing the famotidine tablets according to any one of claims 1 to 3, characterized in that: The following steps are involved: (1) Granulation: Granulation is performed using a wet granulation process, wherein the raw materials and auxiliary materials of the tablet core are premixed, then granulated with 55-65% v / v ethanol solution, and then further mixed to form a soft material; (2) Drying: Dry the soft material at a temperature of 55-65°C and a drying time of 25-85 minutes; (3) Granulation: Granulation is performed after drying. The soft material enters the granulator and is granulated through a 18-30 mesh screen; (4) Total mixing: After granulation, total mixing is performed at a mixing speed of 8-12 rpm and a mixing time of 5-15 min; (5) Tableting: After the total mixing, tableting is performed with a tableting hardness of 20-60N to obtain a tablet core; (6) Coating: Add the coating layer material into purified water to prepare a 6-15%wt coating solution; coat the tablet core to form a coating layer.

5. The method for preparing famotidine tablets according to claim 4, characterized in that: Step (1), specific process parameters of wet granulation process: S1, premixing: stirring paddle speed: 100-150rpm, chopping speed: 1000-1500rpm, time: 2-30min; S2, adding binder to granulate: stirring speed: 100-150rpm, chopping speed: 1000-1500rpm, time: 1-10min; S3. Continue mixing: stirring speed: 150-200 rpm, chopping speed: 1500-2500 rpm, time: 0.5-2 min.

6. The method for preparing famotidine tablets according to claim 4, characterized in that: Step (2), drying temperature is 60°C ± 5°C, and drying time is 30-50min.

7. The method for preparing famotidine tablets according to claim 4, characterized in that: In step (3), the sieve has an aperture of 24 meshes.

8. The method for preparing famotidine tablets according to claim 4, characterized in that: In step (4), the mixing speed is 12 rpm and the mixing time is 15 min. In step (5), the tableting hardness is 40 N.

9. The method for preparing famotidine tablets according to claim 4, characterized in that: Step (6), the coating process: the main engine speed of the coating machine is 2-5 rpm, the hot air temperature is set to 60-65°C, the tablet bed temperature is 39-43°C, the air outlet temperature is 30-50°C, the atomization pressure is 0.3-0.5Mpa, and the peristaltic pump speed is 15-60rpm.

10. The method for preparing famotidine tablets according to claim 4, characterized in that: The granulation equipment is a wet mixing granulator, the drying equipment is a granulation coating pan or an electric blast drying oven, the granulation equipment is a granulation machine, the total mixing equipment is a three-dimensional mixer, and the tableting equipment is a rotary tablet press.

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