Betahistine mesylate tablet and preparation method thereof

Abstract

The invention relates to a betahistine mesylate tablet and a preparation method thereof.The betahistine mesylate tablet comprises betahistine mesylate, a filling agent, a binding agent, a disintegrating agent and a lubricant, the prepared betahistine mesylate tablet is prepared by adopting a wet granulation process, the betahistine mesylate and the binding agent are prepared into a granulation solution, and the granulation solution is added into a disintegrating agent to prepare the betahistine mesylate tablet. Betahistine mesylate does not need to be crushed and sieved, so that the requirement on the particle size of the raw material medicine is reduced, and the process is optimized; the betahistine mesylate tablet is prepared into a granulation solution, granules can be uniformly distributed in materials, the risk of content and content uniformity is reduced, the tabletting process is smooth and unusual, and the in-vitro dissolution behavior of the betahistine mesylate tablet normal-release preparation is similar to that of an original ground betahistine mesylate tablet.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a betahistine mesylate tablet and a preparation method thereof. Background Art

[0002] Betahistine mesilate, chemically known as N-methyl-2-(2-pyridine)ethylamino dimethanesulfonate, is a histamine drug. As a strong H3 receptor antagonist, it can specifically increase blood circulation in the brain and brainstem, increase cochlear blood flow, improve inner ear microcirculation disorders, and eliminate endolymphatic edema. It is mainly used clinically to treat dizziness and vertigo caused by diseases such as Meniere's disease, Meniere's syndrome, and vertigo. It is reported that it has significant efficacy and has been widely used clinically in many countries around the world, with a considerable treatment group.

[0003] The raw material of betahistine mesylate has strong hygroscopicity and is very soluble in water. Therefore, when it is prepared into tablets, it is easy to absorb moisture, and problems such as sticking, loose tablets, and uneven tablet content are likely to occur during the tableting process. Summary of the invention

[0004] In order to solve the problems in the prior art, the present invention provides a betahistine mesylate tablet and a preparation method thereof. The betahistine mesylate tablet adopts a wet granulation process. The tablets prepared by the process will not have problems such as sticking, loose tablets, and uneven tablet content, and a process suitable for large-scale factory production is provided.

[0005] The invention provides a betahistine mesylate tablet, which comprises betahistine mesylate, a filler, a binder, a disintegrant and a lubricant. The filler is selected from any one of lactose, microcrystalline cellulose, pregelatinized starch and starch; the binder is selected from any one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose and polyvinyl alcohol; the disintegrant is selected from any one of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and crospovidone; and the lubricant is selected from any one or more of calcium stearate, stearic acid, talc, silicon dioxide and micro-powder silica gel.

[0006] Furthermore, the weight ratio of the components is: betahistine mesylate: 7.14%, filler: 50% to 80%, binder: 2% to 6%, disintegrant: 8% to 12%, lubricant: 1% to 5%.

[0007] Furthermore, the filler is microcrystalline cellulose, the binder is hydroxypropyl cellulose, the disintegrant is low-substituted hydroxypropyl cellulose, the lubricant is selected from any one or more of magnesium stearate, stearic acid, and calcium stearate, and the lubricant is calcium stearate, silicon dioxide, and talc.

[0008] The present invention provides a method for preparing betahistine mesylate tablets, and the preparation method of the betahistine mesylate tablets comprises the following steps: (1) preparing a granulation liquid by mixing a binder, betahistine mesylate and purified water; (2) Add filler and disintegrant into a fluidized bed or granulator and mix; (3) putting the mixed material in step (2) into a granulator or fluidized bed for granulation; (4) drying and granulating the mixed material in step (3); (5) Mixing the material in step (4) and the lubricant uniformly; (6) The material in step (5) is compressed into tablets according to the tablet weight.

[0009] Furthermore, the amount of purified water added in step (1) accounts for 10% to 14% by weight of the granulation liquid.

[0010] Furthermore, the mixing time in step (2) is 5 to 10 minutes.

[0011] Furthermore, in the step (3), the stirring paddle speed of the granulator is 100-200 rpm, the cutting knife speed is 300-1500 rpm, the liquid addition time is 120-240 s, and the granulation time is 30-120 s.

[0012] Furthermore, in the step (3), the fan frequency of the fluidized bed is 10-50 Hz, the air inlet temperature is 50-90° C., the product temperature is 50-55° C., the peristaltic pump speed is 6-30 rpm, and the atomization pressure is 0.2-0.3 MPa.

[0013] Furthermore, the mixed material in the step (4) is dried and granulated in a fluidized bed, the fluidized bed fan frequency is 10-50HZ, the inlet air temperature is 50-90°C, the material temperature is 45°C, the material is dried to an actual material temperature of above 45°C, and a sample is taken to detect the moisture content, and heating is stopped until the material moisture content is ≤2.0%. The material is discharged when the material temperature is lower than 40°C, and a 0.99-1.57mm sieve is installed for dry granulation, and the granulation speed is 600-1500rpm.

[0014] Furthermore, the preparation method of the betahistine mesylate tablets comprises the following steps: (1) preparing a granulation liquid by mixing hydroxypropylcellulose, betahistine mesylate and water; (2) adding microcrystalline cellulose and low-substituted hydroxypropyl cellulose into a mixer or granulator for mixing; (3) putting the mixed material in step (2) into a granulator or fluidized bed for granulation; (4) drying and granulating the mixed material in step (3); (5) Add talcum powder and silicon dioxide to the material in step (4) and mix for 10 minutes, then add calcium stearate and mix for 5 minutes; (6) The material in step (5) is compressed into tablets according to the tablet weight.

[0015] Compared with the prior art, the betahistine mesylate tablets prepared by the present invention adopt a wet granulation process, betahistine mesylate and a binder are prepared into a granulation liquid, betahistine mesylate does not need to be crushed and screened, the particle size requirement of the raw material drug is reduced, and the process is optimized; the granulation liquid is configured to be evenly distributed in the material, reducing the risk of content and content uniformity, and the tableting process is smooth and without abnormalities. The sustained-release preparation of the betahistine mesylate tablets of the present invention is similar to the in vitro dissolution behavior of the betahistine mesylate tablets originally developed and localized by Eisai (China) Pharmaceutical Co., Ltd. DETAILED DESCRIPTION

[0016] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0017] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0018] The present invention is further illustrated by the following examples, but are not intended to limit the present invention.

[0019] Example 1: Mixed direct compression method

[0020] Prescription composition: Betahistine mesylate 7.14% Hydroxypropylcellulose 2.00% Microcrystalline cellulose 78.36% Low substituted hydroxypropyl cellulose 12.00% Talc 0.50% Calcium stearate 0.50% Silicon dioxide 0.50% Preparation method: Place microcrystalline cellulose, betahistine mesylate, low-substituted hydroxypropyl cellulose, and hydroxypropyl cellulose into a mixer and mix for 5 minutes; The mixed materials are crushed and sieved by a pulverizer, and the crushing screen is selected to be 0.99mm; Add talcum powder and silicon dioxide to the crushed particles and mix for 10 minutes, then add calcium stearate and mix for 5 minutes; Tablets are compressed according to the tablet weight and packaged to obtain tablets. Evaluation of the test process: There was a large difference in tablet weight during the tableting process, which did not meet the requirements.

[0021]

[0022]

[0023] Example 2 (dry granulation): Prescription composition: Betahistine mesylate 7.14% Hydroxypropylcellulose 4.00% Microcrystalline cellulose 76.36% Low substituted hydroxypropyl cellulose 10.00% Talc 1.00% Calcium stearate 1.00% Silicon dioxide 0.50% Preparation method: Place microcrystalline cellulose, betahistine mesylate, low-substituted hydroxypropyl cellulose, and hydroxypropyl cellulose into a mixer and mix for 5 minutes; The mixed materials are crushed by a crusher with a crushing screen of 0.99 mm, and then put into a mixer for mixing for 10 minutes; After mixing evenly, dry granulation is carried out. The dry granulation parameters are set as follows: roller pressure: 45-60 kg / cm2, feeding speed: 10 rpm, tableting speed: 6 rpm, crushing screen aperture: 5.0 mm, granulation screen aperture 1.0 mm, crushing speed 180-260 rpm; Add talcum powder and silicon dioxide to the dry granulated granules and mix for 10 minutes, then add calcium stearate and mix for 5 minutes; The tablets are compressed according to their weight and packaged to obtain tablets.

[0024] Evaluation of the test process: The test process was smooth before the tableting process, but the materials in the tableting process were stratified and the tablet weights varied greatly.

[0025]

[0026]

[0027] Embodiment 3 (fluidized bed one-step granulation): Prescription composition: Betahistine mesylate 7.14% Hydroxypropylcellulose 4.00% Microcrystalline cellulose 76.36% Low substituted hydroxypropyl cellulose 10.00% Talc 1.00% Calcium stearate 1.00% Silicon dioxide 0.50% Preparation method: The binder hydroxypropylcellulose is prepared together with betahistine mesylate and purified water to prepare a granulation liquid; Add microcrystalline cellulose and low-substituted hydroxypropyl cellulose into a mixer and mix for 5 minutes; The microcrystalline cellulose and low-substituted hydroxypropyl cellulose are mixed and put into a fluidized bed for granulation. The parameters are set as fan frequency: 10-50HZ, air inlet temperature: 50-90°C, product temperature setting: 50-55°C, peristaltic pump speed: 6-30rpm, and atomization pressure 0.2-0.3Mpa; After the granulation liquid is sprayed, set the fan frequency to 10-50HZ, the air inlet temperature to 50-90℃, and the material temperature to 45℃ to start drying. After about 10 minutes, take samples to test the moisture content until the moisture content of the material is ≤2.0%, then stop heating and discharge the material when the material temperature is lower than 40℃. After drying, the granules are put into the crusher for granulation, and the granulation screen is selected to be 1.27mm; Add talcum powder and silicon dioxide to the granulated particles and mix for 10 minutes, then add calcium stearate and mix for 5 minutes; The tablets are compressed according to their weight and packaged to obtain tablets.

[0028] Evaluation of the test process: The entire test process was smooth and without abnormalities, the tablet weight differences met the requirements, the content was uniform, and the dissolution curve was similar to the original in vitro dissolution behavior.

[0029]

[0030]

[0031] Example 4 (wet granulation): Prescription composition: Betahistine mesylate 7.14% Hydroxypropylcellulose 4.00% Microcrystalline cellulose 76.36% Low substituted hydroxypropyl cellulose 10.00% Talc 1.00% Calcium stearate 1.00% Silicon dioxide 0.50% Preparation method: The binder hydroxypropylcellulose is prepared together with betahistine mesylate and purified water to prepare a granulation liquid; Put microcrystalline cellulose and low-substituted hydroxypropyl cellulose into a wet mixing granulator, the stirring paddle speed is 100-200rpm, the cutting blade speed is 300-1500rpm, and premix for 5 minutes; after premixing, add granulation liquid, the stirring paddle speed is 100-200rpm, the cutting blade speed is 300-1500rpm, and the liquid addition time is 120-240s; after the liquid addition is completed, the stirring paddle speed is 100-200rpm, the cutting blade speed is 300-1500rpm, and the granulation time is 30-120s; After granulation, the material is wet granulated, and the wet granulation screen is selected to be 3.96mm*3.96mm; After wet granulation, put it into fluidized bed drying, set the fan frequency: 10 ~ 50HZ, air inlet temperature 50 ~ 90℃, material temperature: 45℃, dry the material until the actual material temperature is above 45℃, take samples to test the moisture, stop heating when the material moisture is ≤2.0%, and discharge the material when the material temperature is below 40℃; After fluidized drying, dry granulation is performed, the dry granulation screen is selected to be 1.27 mm, and the granulation speed is 600-1500 rpm; Add talcum powder and silicon dioxide to the granulated particles and mix for 10 minutes, then add calcium stearate and mix for 5 minutes; The tablets are compressed according to their weight and packaged to obtain tablets.

[0032] Evaluation of the test process: The entire test process was smooth and without abnormalities, the tablet weight difference met the requirements, the content was uniform, and the dissolution curve was similar to the original in vitro dissolution behavior.

[0033]

[0034] Example 5: Dissolution The betahistine mesylate tablets described in the present invention are based on the dissolution and release determination method of the Chinese Pharmacopoeia (General Rules 0931 Second Method of Part II of the 2020 Edition), using 900 ml of phosphate buffer (pH 5.8) as the dissolution medium, with a rotation speed of 50 revolutions per minute, and operating in accordance with the law. Sampling is performed after 30 minutes, and the dissolution rate of the betahistine mesylate tablets prepared according to the present invention is tested, and the results show that it reaches more than 85% in 15 minutes.

[0035] The multiple dissolution media include pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer. The method for determining the dissolution of the multiple dissolution media is as follows: according to the dissolution and release determination method of the Chinese Pharmacopoeia (2020 Edition, Part II, General Rules 0931, Method 2), using 900 ml of phosphate buffer (pH 6.8) as the dissolution medium, the rotation speed is 50 revolutions per minute, and the operation is carried out in accordance with the law. The dissolution of the betahistine mesylate tablets prepared according to the present invention and the reference preparation are tested at various time points and compared for similarity, and the results show that they are similar.

[0036]

[0037]

[0038]

[0039]

[0040] Example 6 (wet granulation):

[0041] Prescription composition: Betahistine mesylate 7.14% Hydroxypropylcellulose 2.00% Mannitol 60.00% Corn starch 18.36% Low substituted hydroxypropyl cellulose 12.00% Talc 0.50% Calcium stearate 0.50% Silicon dioxide 0.50% Preparation method: The binder hydroxypropylcellulose is prepared together with betahistine mesylate and purified water to prepare a granulation liquid; Mannitol, corn starch and low-substituted hydroxypropyl cellulose are put into a wet mixing granulator, the stirring paddle speed is 100-200rpm, the cutting knife speed is 300-1500rpm, and the premixing is 5 minutes; after premixing, the granulation liquid is added, the stirring paddle speed is 100-200rpm, the cutting knife speed is 300-1500rpm, and the liquid addition time is 120-240s; after the liquid addition is completed, the stirring paddle speed is 100-200rpm, the cutting knife speed is 300-1500rpm, and the granulation time is 30-120s; After granulation, the material is wet granulated, and the wet granulation screen is selected to be 3.96mm*3.96mm; After wet granulation, put it into fluidized bed drying, set the fan frequency: 10 ~ 50HZ, air inlet temperature 50 ~ 90℃, material temperature: 45℃, dry the material until the actual material temperature is above 45℃, take samples to test the moisture, stop heating when the material moisture is ≤2.0%, and discharge the material when the material temperature is below 40℃; After fluidized drying, dry granulation is performed, the dry granulation screen is selected to be 1.27 mm, and the granulation speed is 600-1500 rpm; Add talcum powder and silicon dioxide to the granulated particles and mix for 10 minutes, then add calcium stearate and mix for 5 minutes; The tablets are compressed according to their weight and packaged to obtain tablets.

[0042] Evaluation of the test process: low hardness and flake cracking occurred during the tableting process, the disintegration time was long, and the dissolution curve was not similar to the original in vitro dissolution behavior.

[0043]

[0044]

[0045] Example 7 (wet granulation):

[0046] Prescription composition: Betahistine mesylate 7.14% Hydroxypropylcellulose 2.00% Microcrystalline cellulose 82.36% Low substituted hydroxypropyl cellulose 6.00% Talc 1.00% Calcium stearate 1.00% Silicon dioxide 0.50% Preparation method: The binder hydroxypropylcellulose is prepared together with betahistine mesylate and purified water to prepare a granulation liquid; Put microcrystalline cellulose and low-substituted hydroxypropyl cellulose into a wet mixing granulator, with a stirring paddle speed of 100-200rpm and a cutting blade speed of 300-1500rpm, and premix for 5 minutes; after premixing, add granulation liquid, with a stirring paddle speed of 100-200rpm and a cutting blade speed of 300-1500rpm, and a liquid addition time of 120-240s; after liquid addition, the stirring paddle speed is 100-200rpm, the cutting blade speed is 300-1500rpm, and the granulation time is 30-120s; After granulation, the material is wet granulated, and the wet granulation screen is selected to be 3.96mm*3.96mm; After wet granulation, put it into fluidized bed drying, set the fan frequency: 10 ~ 50HZ, air inlet temperature 50 ~ 90℃, material temperature: 45℃, dry the material until the actual material temperature is above 45℃, take samples to test the moisture, stop heating when the material moisture is ≤2.0%, and discharge the material when the material temperature is below 40℃; After fluidized drying, dry granulation is performed, the dry granulation screen is selected to be 1.27 mm, and the granulation speed is 600-1500 rpm; Add talcum powder and silicon dioxide to the granulated particles and mix for 10 minutes, then add calcium stearate and mix for 5 minutes; The tablets are compressed according to their weight and packaged to obtain tablets.

[0047] Evaluation of the test process: The hardness of the tablet compression process is too high, the disintegration time is long, and the dissolution curve is not similar to the original in vitro dissolution behavior.

[0048]

[0049]

[0050] Example 8 Stability Test

[0051] Conclusion: The quality of the samples prepared in Example 3 and Example 4 was relatively stable during the accelerated stability study, and the product quality was relatively stable, indicating that the preparation prepared by the present invention has the same effectiveness and safety as the original product.

Claims

1. A betahistine mesylate tablet, characterized in that: The betahistine mesylate tablets include betahistine mesylate, a filler, a binder, a disintegrant, and a lubricant. The filler is selected from any one of lactose, microcrystalline cellulose, pregelatinized starch, and starch; the binder is selected from any one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, and polyvinyl alcohol; the disintegrant is selected from any one of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and crospovidone; and the lubricant is selected from any one or more of calcium stearate, stearic acid, talc, silicon dioxide, and micro-powdered silica gel.

2. The betahistine mesylate tablets according to claim 1, characterized in that: The weight ratio of the components is: betahistine mesylate: 7.14%, filler: 50% to 80%, binder: 2% to 6%, disintegrant: 8% to 12%, lubricant: 1% to 5%.

3. The betahistine mesylate tablets according to claim 2, characterized in that: The filler is microcrystalline cellulose, the binder is hydroxypropyl cellulose, the disintegrant is low-substituted hydroxypropyl cellulose, the lubricant is selected from any one or more of magnesium stearate, stearic acid, and calcium stearate, and the lubricant is calcium stearate, silicon dioxide, and talc.

4. A method for preparing the betahistine mesylate tablets according to any one of claims 1 to 3, characterized in that: The preparation method of the betahistine mesylate tablets comprises the following steps: (1) preparing a granulation liquid by mixing a binder, betahistine mesylate and purified water; (2) Add filler and disintegrant into a fluidized bed or granulator and mix; (3) putting the mixed material in step (2) into a granulator or fluidized bed for granulation; (4) drying and granulating the mixed material in step (3); (5) Mixing the material in step (4) and the lubricant uniformly; (6) The material in step (5) is compressed into tablets according to the tablet weight.

5. The method according to claim 4, characterized in that The amount of purified water added in step (1) accounts for 10% to 14% by weight of the granulation liquid.

6. The method according to claim 5, characterized in that The mixing time in step (2) is 5 to 10 minutes.

7. The method according to claim 6, characterized in that In the step (3), the stirring paddle speed of the granulator is 100-200 rpm, the cutting knife speed is 300-1500 rpm, the liquid addition time is 120-240 s, and the granulation time is 30-120 s.

8. The method according to claim 6, characterized in that In the step (3), the fan frequency of the fluidized bed is 10-50 Hz, the air inlet temperature is 50-90° C., the product temperature is 50-55° C., the peristaltic pump speed is 6-30 rpm, and the atomization pressure is 0.2-0.3 MPa.

9. The method according to any one of claims 7 or 8, characterized in that: The mixed material in the step (4) is dried and granulated in a fluidized bed, wherein the fluidized bed fan frequency is 10-50 Hz, the air inlet temperature is 50-90°C, and the material temperature is 45°C. The material is dried until the actual material temperature is above 45°C, and then sampling is performed to detect the moisture content. Heating is stopped until the material moisture content is ≤2.0%. The material is discharged when the material temperature is lower than 40°C. A 0.99-1.57 mm sieve is installed for dry granulation, and the granulation speed is 600-1500 rpm for granulation.

10. The method according to claim 9, characterized in that The preparation method of the betahistine mesylate tablets comprises the following steps: (1) preparing a granulation liquid by mixing hydroxypropylcellulose, betahistine mesylate and water; (2) adding microcrystalline cellulose and low-substituted hydroxypropyl cellulose into a mixer or granulator for mixing; (3) putting the mixed material in step (2) into a granulator or fluidized bed for granulation; (4) drying and granulating the mixed material in step (3); (5) Add talcum powder and silicon dioxide to the material in step (4) and mix for 10 minutes, then add calcium stearate and mix for 5 minutes; (6) The material in step (5) is compressed into tablets according to the tablet weight.

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