A famotidine tablet and its preparation process

Abstract

The present invention provides a famotidine tablet and its preparation process. The famotidine tablet is composed of a core and a coating layer from the inside to the outside, and the core includes 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 adhesive, 0.8-1.2 parts of lubricant; the coating layer material is made from the following auxiliary materials: alfalfa polysaccharide, L-fucitol, sodium stearate fumarate, and the mass ratio of alfalfa polysaccharide, L-fucitol, sodium stearate fumarate is 2-3:1-1.5:0.4-0.6. The famotidine tablets prepared by the prescription of the present invention and the process have good content and content uniformity, good dissolution curves in 0.1mol / L hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer and purified water, and low total impurity content, which improves stability under accelerated conditions and long-term conditions.

Description

Technical Field

[0001] The present 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 guanidinothiazole H2 receptor blocker. It boasts robust efficacy, few adverse reactions, and high affinity for H2 receptors. Its mechanism of action is similar to that of cimetidine. Famotidine effectively inhibits basal gastric acid secretion, nocturnal gastric acid secretion, and food-induced gastric acid secretion. It also inhibits gastric acid secretion induced by stimuli such as histamine and pentagastrin. Its H2 receptor inhibitory potency is 20 times stronger than that of cimetidine. Famotidine also inhibits pepsin secretion and is clinically used for gastric and duodenal ulcers, stress ulcers, acute gastric mucosal bleeding, gastrinoma, and reflux esophagitis. Famotidine boasts a relatively low price, stable efficacy, and a large patient population. Sales of famotidine in my country are expected to continue to grow.

[0003] Famotidine tablets were first marketed in Japan in 1985 under the trade name Gaster ® , specification is 20mg. In 1986, PEPCID ® It was approved for marketing in the United States under the trade name 10mg. Subsequently, tablets in strengths of 10mg, 20mg, and 40mg were approved for marketing in EU countries such as Germany, the United Kingdom, the Netherlands, and Finland. Currently, this product is available in hundreds of countries and regions around the world.

[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 was Gaster. ®It is used to treat gastric ulcers, duodenal ulcers, anastomotic ulcers, upper gastrointestinal bleeding (due to peptic ulcers, acute stress ulcers, hemorrhagic gastritis), reflux esophagitis, and Zollinger-Ellison syndrome. The typical adult dose of famotidine is 20 mg orally twice daily (after breakfast, after dinner, or before bedtime). Alternatively, 40 mg can be taken orally once daily (at bedtime). However, in cases of upper gastrointestinal bleeding, treatment is usually initiated with an injection and then switched to oral administration once oral administration becomes feasible. It is also used to improve gastric mucosal lesions (erosions, bleeding, redness, edema), acute gastritis, and acute exacerbations of chronic gastritis in the following conditions. The typical adult dose of famotidine is 10 mg orally twice daily (after breakfast, after dinner, or before bedtime). Alternatively, 20 mg can be taken orally once daily (at bedtime).

[0005] The prescription excipients of the reference preparation are 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 tablet 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 dissolution, low total impurity content, good stability, etc.

[0008] The technical solution of the present invention is achieved as follows: a famotidine tablet, which consists of a tablet core and a coating layer from the inside out, wherein the tablet core comprises 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 from the following auxiliary materials: alfalfa polysaccharide, L-fucitol, and sodium stearate fumarate, wherein 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 starch glycolate, 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. The tablet core raw materials and excipients 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: After drying, the soft material enters the granulator and is granulated through an 18-30 mesh screen;

[0015] (4) Total mixing: After granulation, total mixing is carried out 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 tablet hardness of 20-60N to obtain a tablet core;

[0017] (6) Coating: Add the coating layer material to 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 speed: 100-150 rpm, chopping speed: 1000-1500 rpm, time: 2-30 min;

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

[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 30-50 minutes.

[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 40 N.

[0025] A further technical solution is that, in step (6), the coating process is as follows: 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 0.3-0.5 MPa, and the peristaltic pump speed is 15-60 rpm.

[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, which improves 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 the product appearance. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

[0033] Figure 4 Dissolution testing (purified water) of the famotidine tablets prepared in Example 1 of the present invention and the reference preparation;

[0034] Figure 5 This is the microscopic appearance of famotidine raw material (magnification 500 times). DETAILED DESCRIPTION

[0035] In order to better understand the technical content of the present invention, specific examples are provided below to further illustrate the present invention.

[0036] Unless otherwise specified, the experimental methods used in the examples of the present invention are all conventional methods.

[0037] Unless otherwise specified, the materials, reagents, etc. used in the examples of the present invention can be obtained from commercial sources.

[0038] The basic information of famotidine API is shown in Table 1.

[0039] Table 1 Basic information of famotidine API

[0040]

[0041] Table 2 Effects of prescription components

[0042]

[0043] Example 1

[0044] Table 3 Prescription 1

[0045]

[0046] The preparation method of the above-mentioned famotidine tablets comprises the following steps:

[0047] (1) Granulation: A wet mixing granulator is used to granulate the tablets using a wet granulation process. The tablet raw materials and auxiliary materials are first premixed, then granulated with 60% v / v ethanol solution, and finally mixed to form a soft material.

[0048] Specific process parameters of the above wet granulation process:

[0049] S1, premixing: stirring speed: 150 rpm, chopping speed: 1200 rpm, time: 3 min;

[0050] S2, adding binder for granulation: stirring speed: 150 rpm, chopping speed: 1200 rpm, time: 2 min;

[0051] S3. Continue mixing: stirring speed: 180 rpm, chopping speed: 2000 rpm, time: 1 min;

[0052] (2) Drying: Use a granulator to dry the soft material at a temperature of 60°C ± 5°C for 30 minutes.

[0053] (3) Granulation: Granulation is carried out after drying. The soft material enters the granulator and is granulated through an 18-mesh screen;

[0054] (4) Total mixing: Use a three-dimensional mixer for total mixing, and then perform total mixing after granulation. The mixing speed is 10 rpm and the mixing time is 15 min.

[0055] (5) Tablet pressing: A rotary tablet press is used for tablet pressing. After the total mixing, tablet pressing is performed with a tablet hardness of 40N to obtain a tablet core.

[0056] (6) Coating: Add the coating layer materials alfalfa polysaccharide, L-fucitol, and sodium stearyl fumarate to purified water to prepare a 10% wt coating solution; coat the core tablets to form a coating layer. The coating weight gain is 3%. Coating process: The coating machine has a main speed of 4 rpm, a hot air temperature of 62°C, a tablet bed temperature of 41°C, an air outlet temperature of 40°C, an atomizing pressure of 0.4 MPa, and a peristaltic pump speed of 45 rpm.

[0057] 1. Prescription content uniformity

[0058] Table 4 Investigation of the uniformity of the content of the prescription

[0059]

[0060] The content and content uniformity of this product are good.

[0061] 2. Dissolution

[0062] Dissolution testing was performed using UV light at 266 nm, basket method, and 100 rpm. The medium volume was set at 900 ml. The dissolution profiles of famotidine tablets were compared using different media, including 0.1 mol / L hydrochloric acid solution, pH 4.0 acetate buffer, pH 4.5 phosphate buffer, pH 6.8 phosphate buffer, and purified water.

[0063] like Figure 1-4 The results show that the dissolution amount of each sample and the average dissolution amount of 12 samples were greater than 85% after 30 minutes in 0.1 mol / L hydrochloric acid solution, pH 4.0 acetate solution, pH 4.5 phosphate solution, pH 6.8 phosphate solution, and water, indicating rapid dissolution under various media conditions. The RSDs of famotidine dissolution at each time point for both the homemade and reference preparations were less than 5.0% 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 using a basket method at 100 rpm. The RSDs for this product were less than 1%, while those for the reference preparation were greater than 5%. This indicates that the dissolution profiles of the homemade and reference preparations were uniform across batches under the dissolution conditions of 0.1 mol / L hydrochloric acid solution, pH 4.0 acetate buffer, pH 4.5 phosphate buffer, pH 6.8 phosphate buffer, and purified water using a basket method at 100 rpm, and that the dissolution profiles of this product were more stable.

[0064] 3. Stability investigation

[0065] Accelerated conditions: temperature 40℃±2℃, humidity 75%±10%RH; accelerated time: 6 months;

[0066] Long-term conditions: temperature 25℃±2℃, humidity 60%±10%RH; long-term time: 36 months;

[0067] Dissolution stability under accelerated conditions: This product has good dissolution stability under accelerated conditions. No obvious downward trend was observed 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. The product was also better than the reference preparation.

[0068] Long-term dissolution stability: This product has good long-term dissolution stability. No obvious downward trend was observed 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 at 100 rpm. The dissolution stability was better than that of the reference preparation.

[0069] Example 2

[0070] The famotidine tablets prescription is consistent with that in Example 1. The preparation method of famotidine tablets comprises the following steps:

[0071] (1) Granulation: Use a wet mixing granulator and wet granulation process to granulate the tablet core raw materials and excipients. Then add 55% v / v ethanol solution to granulate, and continue mixing to make a soft material.

[0072] Specific process parameters of the above wet granulation process:

[0073] S1, premixing: stirring speed: 100 rpm, chopping speed: 600 rpm, time: 4 min;

[0074] S2, adding binder for granulation: stirring speed: 100 rpm, chopping speed: 600 rpm, time: 3 min;

[0075] S3. Continue mixing: stirring speed: 400 rpm, chopping speed: 1200 rpm, time: 2 min;

[0076] (2) Drying: Use an electric 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 minutes;

[0077] (3) Granulation: Granulation is carried out after drying. The soft material enters the granulator and is granulated through an 18-mesh screen;

[0078] (4) Total mixing: Use a three-dimensional mixer for total mixing, and then perform total mixing after granulation. The mixing speed is 10 rpm and the mixing time is 15 min.

[0079] (5) Tableting: A rotary tablet press is used for tableting. After the total mixing, tableting is performed with a tablet hardness of 40N to obtain tablet cores.

[0080] (6) Coating: Add the coating material to purified water to prepare an 8% wt coating solution; coat the core tablets to form a coating layer. The coating weight gain is 3%. Coating process: The coating machine has a main speed of 2 rpm, a hot air temperature of 60°C, a tablet bed temperature of 39°C, an air outlet temperature of 30°C, an atomizing pressure of 0.3 MPa, and a peristaltic pump speed of 15 rpm.

[0081] Example 3

[0082] The famotidine tablets prescription is consistent with that in Example 1. The preparation method of famotidine tablets comprises the following steps:

[0083] (1) Granulation: Use a wet mixing granulator and wet granulation process to granulate the tablet core raw materials and excipients. Then add 65% v / v ethanol solution to granulate, and continue mixing to make a soft material.

[0084] Specific process parameters of the above wet granulation process:

[0085] S1, premixing: stirring speed: 200 rpm, chopping speed: 800 rpm, time: 2 min;

[0086] S2, adding binder to granulate: stirring speed: 200 rpm, chopping speed: 800 rpm, time: 1 min;

[0087] S3. Continue mixing: stirring speed: 600 rpm, chopping speed: 1600 rpm, time: 1 min;

[0088] (2) Drying: Use an electric 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 minutes;

[0089] (3) Granulation: After drying, the soft material is granulated and enters the swing granulator and granulated through an 18-mesh screen;

[0090] (4) Total mixing: Use a three-dimensional mixer for total mixing, and then perform total mixing after granulation. The mixing speed is 12 rpm and the mixing time is 10 min.

[0091] (5) Tableting: A rotary tablet press is used for tableting. After the total mixing, tableting is performed with a tablet hardness of 40N to obtain tablet cores.

[0092] (6) Coating: Add the coating material to purified water to prepare a 12% wt coating solution; coat the core tablets to form a coating layer. The coating weight gain is 3%. Coating process: The main 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.

[0093] In addition, the content and content uniformity of the products prepared in Examples 2-3 of the present invention also met the quality standard requirements. The dissolution curves of the products in Examples 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 at 100 rpm also met the requirements.

[0094] Comparative Example 1

[0095] The difference from Example 1 is that alfalfa polysaccharide in the coating layer material is replaced by cellulose, and L-fucitol is replaced by xylitol.

[0096] Table 5-Prescription 2

[0097]

[0098] 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:

[0099] Table 6 Related substances

[0100]

[0101] The results showed 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 in the famotidine tablets prepared in Examples 1-3 did not increase substantially under accelerated conditions for 6 months. This indicates that the coating layer materials of the embodiments of the present invention more effectively improve the stability of famotidine tablets, which is beneficial to improving drug safety.

[0102] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A famotidine tablet, characterized in that The famotidine tablet consists of a tablet core and a coating layer from the inside out. 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. 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.

2. The famotidine tablet according to claim 1, wherein The tablet core comprises the following raw 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, wherein 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 hypromellose, and the lubricant is magnesium stearate.

4. The method for preparing the famotidine tablets according to any one of claims 1 to 3, wherein The following steps are involved: (1) Granulation: Granulation is performed using a wet granulation process. The tablet core raw materials and excipients 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: After drying, the soft material enters the granulator and is granulated through an 18-30 mesh screen; (4) Total mixing: After granulation, total mixing is carried out 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 tablet hardness of 20-60N to obtain a tablet core; (6) Coating: Add the coating layer material to purified water to prepare a 6-15% wt coating solution; coat the core tablet to form a coating layer.

5. The method for preparing famotidine tablets according to claim 4, wherein Step (1), specific process parameters of wet granulation process: S1. Premixing: stirring speed: 100-150 rpm, chopping speed: 1000-1500 rpm, time: 2-30 min; S2. Add binder to granulate: stirring speed: 100-150 rpm, chopping speed: 1000-1500 rpm, time: 1-10 min; 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, wherein Step (2): drying temperature is 60°C ± 5°C, and drying time is 30-50 min.

7. The method for preparing famotidine tablets according to claim 4, wherein In step (3), the aperture of the sieve is 24 mesh.

8. The method for preparing famotidine tablets according to claim 4, wherein 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, wherein 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 0.3-0.5 MPa, and the peristaltic pump speed is 15-60 rpm.

10. The method for preparing famotidine tablets according to claim 4, wherein 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 granulator, the total mixing equipment is a three-dimensional mixer, and the tableting equipment is a rotary tablet press.

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