Betahistine hydrochloride tablet and preparation method thereof

Abstract

The invention discloses a betahistine hydrochloride tablet and a preparation method thereof, and belongs to the technical field of medicines. The betahistine hydrochloride tablet disclosed by the invention belongs to a film coated tablet. The betahistine hydrochloride tablet comprises betahistine hydrochloride, a filling agent, a disintegrating agent, a stabilizing agent, a wetting agent, a lubricating agent, a flow aid and a film coating premix. The betahistine hydrochloride tablet prepared by the invention adopts boiling granulation, the content is uniform, the preparation process flow is simple, the effect is stable, and the production efficiency of medicines is greatly improved. The betahistine hydrochloride tablet is a film-coated tablet, the problem of cracking of a sugar-coated tablet in a betahistine hydrochloride tablet does not exist, the disintegration speed is higher than that of the sugar-coated tablet, the dissolution is good, and the bioavailability is high.

Description

Technical Field

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

[0002] Betahistine hydrochloride, English name is Betabistine Hydrochloride, chemical name is N-methyl-2-pyridineethylamine dihydrochloride.

[0003]

[0004] Appears as white or off-white crystals or crystalline powder, odorless, with a density of 0.967 g / mL, a boiling point of 210°C, and a melting point of 150-154°C. This product is highly soluble in water, slightly soluble in ethanol, and virtually insoluble in acetone. It readily absorbs moisture from the air and deliquesces, so it should be stored sealed in a cool, dry environment.

[0005] Betahistine hydrochloride is an antihistamine and vasodilator, particularly effective at dilating capillaries, improving microcirculation and vasodilation of the cerebral and cardiovascular systems. It has a significant dilating effect on the cerebral, coronary, and peripheral capillaries, particularly the vertebral artery system. It significantly increases blood flow to the brain, heart, and peripheral capillaries, and has a significant therapeutic effect on improving insufficient blood supply to the coronary artery system. It is commonly used for Meniere's syndrome, vascular headaches, cerebral arteriosclerosis, acute ischemic cerebrovascular disease, and is also effective for orthostatic vertigo and tinnitus caused by hypertension.

[0006] Currently, the preparation types of betahistine hydrochloride include tablets (plain tablets, sugar-coated tablets, film-coated tablets, freeze-dried tablets, etc.), oral solution, soft capsules, injections, etc.

[0007] Patent CN201110294984.5 discloses the production technology of betahistine hydrochloride injection. The injection is suitable for emergency patients and is used in hospitals or clinics. It is inconvenient to carry and use on a daily basis. The injection production process requires a sterile environment and high-temperature disinfection, which has high production costs. In addition, impurity A is a genotoxic impurity, and its rapid rise in a hot and humid environment makes the injection form a disadvantage.

[0008] Patent CN201911332133.8 discloses a formulation technology for betahistine hydrochloride, which uses a traditional wet granulation method. The process first involves dry mixing to prepare a first masterbatch, which is then mixed with a wetting agent to form a second masterbatch. The masterbatch is then wetted using a rocking granulator, and then dried using a boiling drying granulator to obtain the desired granules, which are then compressed into tablets to obtain the desired formulation. This method requires multiple devices, has low reproducibility, low yield, and low efficiency. Although the plain betahistine hydrochloride tablets disintegrate quickly, the product is susceptible to moisture absorption, which can easily increase impurities and pose a risk of affecting product quality. Summary of the Invention

[0009] The present invention aims to provide a betahistine hydrochloride tablet and a preparation method thereof. The process adopts a boiling granulation method, which uses less equipment, has higher granule controllability, uniform content, and stable product. Film coating replaces the previous sugar coating method, solves the problem of product cracking and flowery tablets, and has the characteristic of faster disintegration speed.

[0010] During the research and development test, the inventors found that the betahistine hydrochloride raw material is easily hygroscopic and the uniformity of mixing with other materials cannot be fully guaranteed. Considering the characteristics of the raw material being easily soluble in water, it was dissolved in purified water as a wetting agent and it was found that the material was more uniform, thereby improving the uniformity of the betahistine hydrochloride tablets.

[0011] On the basis of improving product uniformity, the ratio of excipients was optimized through repeated experiments, and film coating was adopted, which made the product disintegrate faster and improved bioavailability.

[0012] The technical solution adopted in the present invention is as follows:

[0013] A betahistine hydrochloride tablet consists of a tablet core and a coating layer. The tablet core comprises betahistine hydrochloride, a filler, a disintegrant, a wetting agent, a stabilizer, a lubricant, and a glidant.

[0014] Among them, the raw material ingredients and weight ratios used in the tablet core are as follows:

[0015] Betahistine hydrochloride: 5-10 parts;

[0016] Filler: 60-90 parts;

[0017] Disintegrant: 10-40 parts;

[0018] Stabilizer: 1-3 parts;

[0019] Wetting agent: 20-60 parts;

[0020] Lubricant: 1-3 parts;

[0021] Glidant: 3-7 parts;

[0022] Preferably, the raw material ingredients and weight ratios used in the tablet core are as follows:

[0023] Betahistine hydrochloride: 9 parts;

[0024] Filler: 60-80 parts;

[0025] Disintegrant: 20-30 parts;

[0026] Stabilizer: 2-3 parts;

[0027] Wetting agent: 30-50 parts;

[0028] Lubricant: 2-3 parts;

[0029] Glidant: 5-7 parts.

[0030] Specifically, the raw material ingredients and weight ratios used in the tablet core are as follows:

[0031] Betahistine hydrochloride: 9 parts;

[0032] Filler: 70 parts;

[0033] Disintegrant: 30 parts;

[0034] Stabilizer: 2.5 parts;

[0035] Wetting agent: 40 parts;

[0036] Lubricant: 2.5 parts;

[0037] Glidant: 6 parts.

[0038] Furthermore, the filler is one or more of starch, lactose, microcrystalline cellulose, pregelatinized starch, corn starch and dextrin; the disintegrant is one or more of dry starch, pregelatinized starch, microcrystalline cellulose and sodium starch glycolate; the stabilizer is citric acid; the wetting agent is purified water; the lubricant is one or more of magnesium stearate, calcium stearate, talc and silicon dioxide; the glidant is one or a mixture of any proportion of silicon dioxide and talc; and the film coating adds 2.0% to 4.0% weight based on the weight of the tablet core.

[0039] The coating solution is prepared by the following method: a gastric-soluble film coating premix is ​​weighed according to weight gain, purified water is poured into a stirring tank, compressed air is connected and the air pressure valve is opened to start stirring, and then the gastric-soluble film coating premix is ​​slowly poured into the mixture, stirred for 40 to 60 minutes, and a film coating solution with a concentration of 10 to 15% is prepared, which is then coated on the tablet cores to obtain a coating layer.

[0040] Preferably, the filler is one or more of lactose, pregelatinized starch and dextrin; the disintegrant is one or a mixture of microcrystalline cellulose and sodium starch glycolate in any proportion; the stabilizer is citric acid; the wetting agent is purified water; the lubricant is one or a mixture of two in any proportion of magnesium stearate and silicon dioxide; and the glidant is one or a mixture of two in any proportion of silicon dioxide and talc.

[0041] In a preferred formula component, the filler is one or more of lactose, pregelatinized starch and dextrin; specifically, the filler is pregelatinized starch and dextrin.

[0042] In a preferred formulation component, the disintegrant is microcrystalline cellulose.

[0043] In one preferred formulation component, the lubricant is silica.

[0044] In a preferred formulation, the glidant is talc.

[0045] Another object of the present invention is to provide a method for preparing the above-mentioned betahistine hydrochloride tablets, the preparation process of which is as follows:

[0046] (1) Crush citric acid and set aside; prepare a solution of betahistine hydrochloride raw material with 30% to 60% of the prescribed amount of purified water and set aside;

[0047] (2) adding a filler, a disintegrant, a stabilizer, and a wetting agent to a boiling granulator in sequence, spraying the betahistine hydrochloride solution from step (1) and the remaining purified water to prepare granules, pulling out the material bin after drying, adding a lubricant and a flow aid, selecting a suitable V-shaped screen to size the granules, and then mixing them with an automatic lifting hopper mixer to obtain granules;

[0048] (3) using a tablet press to compress the granules from step (2) into tablet cores;

[0049] (4) Use a coating pan to coat the tablet cores from step (3).

[0050] Furthermore, in a preferred embodiment, in the above step (1), the citric acid is crushed by a grinder and then passed through an 80-mesh sieve; and the betahistine hydrochloride raw material is dissolved in purified water half the prescribed amount.

[0051] In a preferred embodiment, the materials in the above step (2) are added to the boiling granulation pot in the order of pregelatinized starch (half of the amount), dextrin, citric acid, microcrystalline cellulose, and the remaining half of the pregelatinized starch, and the betahistine hydrochloride solution in step (1) and the remaining purified water are sprayed for boiling granulation. The spraying speed is controlled at 60-80 rpm / min, and the temperature of the spraying process is controlled below 50°C. After drying, the material bin is pulled out, silicon dioxide and talc are added, and a V-shaped screen with a diameter of 1.5 mm is selected for granulation. After the end, the mixture is mixed for 10 to 20 minutes using an automatic lifting hopper mixer.

[0052] In a preferred embodiment, the above step (3) uses a circular flat-bevel punching sheet with a diameter of 5.5 mm.

[0053] In a preferred embodiment, the core tablets from step (3) are coated in step (4) using a BGB-150C coating pan, with a coating weight gain of preferably 2.5%. The coating pan is equipped with three spray guns, and the coating process control parameters are:

[0054] Coating process Pot speed requirements Before film formation 3 rpm-5 rpm After film formation 5 rpm-9 rpm Finished spraying 3 rpm-5 rpm

[0055] Further explanation of the coating liquid preparation: weigh the film coating premix, pour purified water into the mixing tank, connect the compressed air and open the air pressure valve, start stirring, slowly pour in the gastric soluble film coating premix, stir for 40 to 60 minutes, and prepare a film coating solution with a concentration of 10 to 15 wt%. Maintain slow stirring during the coating process to reduce foaming and precipitation.

[0056] Compared with existing prescriptions and dosage forms, the present invention has the following advantages:

[0057] (1) In the preparation process of betahistine hydrochloride tablets, the API is dissolved in purified water and sprayed into the granulation, which can make the active ingredients of the API more evenly distributed and the granules more uniform.

[0058] (2) Most of the betahistine hydrochloride tablets on the market are sugar-coated tablets or plain tablets. Sugar-coated tablets have a high sugar content and are not suitable for diabetic patients and diabetics. They often have problems with cracked and flowery tablets. Plain tablets are irritating to the gastric mucosa. This product is a film-coated tablet, which is suitable for a wider range of patients (suitable for patients with weak gastrointestinal function and diabetes). The production process does not require drying the tablets and can directly enter the packaging process, which greatly shortens the product production cycle. At the same time, the disintegration speed is faster than that of sugar-coated tablets.

[0059] (3) The process of the present invention adopts boiling granulation. Compared with other wet granulation methods, the production equipment used is simpler. Mixing, granulation and drying operations can be completed in a single device. The granulation process can be completed in a short time. The granule fluidity and uniformity are better, and the particle size is more controllable, which is of great benefit to improving product dissolution. DETAILED DESCRIPTION

[0060] The specific embodiments of the present invention are described in detail below, but it should be understood that the protection scope of the present invention is not limited by the specific embodiments.

[0061] Example 1

[0062] A betahistine hydrochloride tablet comprising the following components:

[0063] Betahistine hydrochloride 9.0g Main drug ingredients microcrystalline cellulose 30.0g disintegrants Pregelatinized starch 55.0g Fillers dextrin 15.0g Fillers Citric acid 2.5g stabilizer purified water 40g Wetting agent Silicon dioxide 2.5g lubricant talcum powder 6.0g glidants

[0064] The preparation method of the betahistine hydrochloride tablets comprises the following steps:

[0065] (1) Crush citric acid with a grinder and pass through an 80-mesh basket, and set aside. Dissolve betahistine hydrochloride raw material with half the prescribed amount of purified water, and set aside.

[0066] (2) The air inlet temperature is set to no more than 70°C, and pregelatinized starch (half of the amount), dextrin, citric acid, microcrystalline cellulose, and the remaining half of the pregelatinized starch are added to the boiling granulation pot in the order of the order. When the material temperature reaches 45±5°C, the betahistine hydrochloride solution of step (1) and the remaining purified water are sprayed in for boiling granulation. The spraying speed is 60-80rpm / min, and the temperature of the spraying process is controlled below 50°C. After drying, the pot is removed from the material bin, and silicon dioxide and talc are added. A V-shaped screen with a diameter of 1.5mm is selected for granulation. After the end, the automatic lifting hopper mixer is used to mix for 15 minutes to obtain granules.

[0067] (3) using a tablet press equipped with a 5.5 mm diameter round flat oblique punching tablet to press the granules from step (2) into tablet cores;

[0068] (4) Preparation of coating solution: Weigh the gastric-soluble film coating premix, pour purified water into the mixing tank, connect the compressed air and open the air pressure valve to start stirring, slowly pour in the gastric-soluble film coating premix (model YS-1-7040, Shanghai Colorcon Coating Technology Co., Ltd.), stir for 40-60 minutes, and prepare a film coating solution with a concentration of 12 wt%. Maintain slow stirring during the coating process to reduce foaming and precipitation.

[0069] (5) Spray the coating solution from step (4) from the mixing tank into the coating pan, and use a BGB-150C coating pan to coat the tablet cores from step (3). The outlet air temperature of the coating pan is controlled at 35-40°C. The coating pan is equipped with three spray guns. The coating process control parameters are as follows:

[0070]

[0071]

[0072] After coating, heating was stopped and the tablets were dried in the coating pan using the residual heat of the coating pan. The coating weight gain was 2.5% based on the mass of the tablet core, and betahistine hydrochloride tablets containing 4 mg of betahistine hydrochloride per tablet were obtained.

[0073] Comparative Example 1

[0074] Betahistine hydrochloride 9.0g Main drug ingredients microcrystalline cellulose 30.0g disintegrants Pregelatinized starch 55.0g Fillers dextrin 15.0g Fillers Citric acid 2.5g stabilizer purified water 40g Wetting agent Silicon dioxide 2.5g lubricant talcum powder 6.0g glidants

[0075] The preparation method and steps of the above-mentioned betahistine hydrochloride tablets are as follows: the prescription of this example remains unchanged, the coating weight is increased by 4.0%, and the other production processes are the same as those in Example 1.

[0076] Comparative Example 2

[0077] Betahistine hydrochloride 9.0g Main drug ingredients Sodium starch glycolate 10.0g disintegrants lactose 90.0g Fillers Citric acid 2.5g stabilizer purified water 40g Wetting agent Silicon dioxide 2.5g lubricant talcum powder 6.0g glidants

[0078] Preparation method and steps of the above-mentioned betahistine hydrochloride tablets: In this comparative example, the disintegrant and filler are replaced with sodium starch glycolate and lactose, and the other production processes are the same as those in Example 1.

[0079] Comparative Example 3

[0080] Betahistine hydrochloride 9.0g Main drug ingredients microcrystalline cellulose 30.0g disintegrants dextrin 65.0g Fillers Citric acid 2.5g stabilizer Dextrin (for slurry) 5.0g (prepared into 10% slurry) Adhesives Silicon dioxide 2.5g lubricant talcum powder 6.0g glidants

[0081] The preparation method and steps of the above-mentioned Betahistine Hydrochloride Tablets are as follows:

[0082] (1) Crush citric acid with a grinder through an 80-mesh sieve and set aside; prepare a 10 wt% dextrin slurry with dextrin and set aside; grind the raw materials and the added dextrin into a 40-mesh sieve and set aside.

[0083] (2) The crushed materials (dextrin and betahistine hydrochloride raw materials), citric acid, and microcrystalline cellulose were added to a boiling granulation pot in this order, and 10% of the dextrin slurry prepared in step (1) was sprayed into the pot for boiling granulation. The coating weight was increased by 2.0%. The other production processes were the same as those in Example 1.

[0084] Comparative Example 4

[0085] Betahistine hydrochloride 9.0g Main drug ingredients microcrystalline cellulose 30.0g disintegrants Pregelatinized starch 55.0g Fillers dextrin 15.0g Fillers Citric acid 2.5g stabilizer purified water 40g Wetting agent magnesium stearate 1.0g lubricant

[0086] Preparation method and steps of the above-mentioned betahistine hydrochloride tablets: In this comparative example, the external lubricant is replaced with magnesium stearate, and the other production processes are the same as those in Example 1.

[0087] Comparison of experimental results:

[0088] (1) Inspection of appearance, uniformity, disintegration time, and viscosity

[0089] The betahistine hydrochloride granules of the examples and comparative examples were compressed into tablets, and their tablet compression, disintegration, and uniformity were investigated as follows:

[0090] sample Core appearance Compressibility Content uniformity Disintegration time Example 1 Off-white tablets, smooth surface Good compressibility 2.0 4.5min Comparative Example 1 Off-white tablets, smooth surface Good compressibility 2.5 8.5min Comparative Example 2 Off-white tablets, smooth surface Low hardness and poor compressibility 2.8 6min Comparative Example 3 Off-white tablets with pitting on one side Good compressibility 10.5 7.0min Comparative Example 4 Off-white tablets, smooth surface Sticking, poor compressibility 2.2 6min

[0091] As can be seen from the above table, from the perspective of content uniformity, the method of dissolving the betahistine hydrochloride raw material in purified water for spray granulation (Example 1) is more uniform than the boiling granulation after mixing the raw materials and excipients (Comparative Example 3), and pitting appears on the tablet surface after tableting in Comparative Example 3, and the disintegration time is prolonged compared with Example 1; Comparative Example 1 has an increased coating weight gain compared with Example 1, and the disintegration time of the obtained tablet is prolonged; Comparative Example 2 changes the excipient composition, the tablet hardness is small, and the compressibility is poor; Comparative Example 4 changes the added lubricant, sticking occurs, and the tablet disintegration time is also prolonged. Overall, all indicators of Example 1 are superior to those of other comparative examples.

[0092] (2) Dissolution test

[0093] Determine according to the dissolution and release method (General Rule 0931 Method 2)

[0094] Dissolution medium: phosphate buffer (pH 6.8) 900 mL;

[0095] Dissolution conditions: rotation speed: 50 rpm; medium temperature: 37.0°C; dissolution time: 30 minutes

[0096] Five samples were tested in parallel for each example and comparative example. The results of the examples and comparative examples are shown in the following table:

[0097] product Dissolution (≥80%) Average dissolution Example 1 98％102％100％100％100％100％ 100％ Comparative Example 1 95％94％93％93％95％91％ 94％ Comparative Example 2 99％94％93％98％95％94％ 96％ Comparative Example 3 96％85％93％84％89％95％ 90％ Comparative Example 4 92％95％89％94％94％92％ 93％

[0098] Result analysis: From the dissolution results in the above table, the product dissolution is qualified under different raw material and auxiliary material ratios or different coating weight gain conditions, but in comparison, the average result of Example 1 is better than that of other comparative examples, and the single particles are more uniform.

[0099] (3) Results of long-term testing of Example 1

[0100] According to the above experimental data, the production process of Example 1 is more advantageous, the dissolution results are good and uniform, and the disintegration rate is faster. A long-term test was conducted on the betahistine hydrochloride tablets of Example 1, and five samples were tested in parallel at each time point. The results are as follows:

[0101]

[0102] As can be seen from the table above, the content and dissolution of Example 1 are relatively stable, with a slight decrease in content and dissolution, and a slight increase in related substances. Overall, the 24-month inspection results still meet the internal control requirements, indicating that the process of the embodiment applied is feasible.

[0103] The foregoing descriptions of specific exemplary embodiments of the present invention are for purposes of illustration and description. These descriptions are not intended to limit the invention to the precise forms disclosed, and it is apparent that many variations and modifications are possible in light of the foregoing teachings. The exemplary embodiments have been selected and described for the purpose of explaining the specific principles of the invention and their practical application, thereby enabling those skilled in the art to realize and utilize a variety of exemplary embodiments of the invention and various options and modifications. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. A betahistine hydrochloride tablet, consisting of a core tablet and a coating layer, characterized in that: In parts by weight, the core tablets are composed of: Betahistine hydrochloride: 5-10 parts; Filler: 60-90 parts; Disintegrant: 10-40 parts; Stabilizer: 1-3 parts; Wetting agent: 20-60 parts; Lubricant: 1-3 parts; Glidant: 3-7 parts; The filler is one or more of starch, lactose, microcrystalline cellulose, pregelatinized starch, corn starch and dextrin; the disintegrant is one or more of dry starch, pregelatinized starch, microcrystalline cellulose and sodium starch glycolate; the stabilizer is citric acid; the wetting agent is purified water; the lubricant is one or more of magnesium stearate, calcium stearate, talc and silicon dioxide; the glidant is one or a mixture of any proportion of silicon dioxide and talc; and the coating layer has a weight gain of 2.0%-4.0% based on the weight of the tablet core.

2. The betahistine hydrochloride tablet according to claim 1, wherein In parts by weight, the core comprises: Betahistine hydrochloride: 9 parts; Filler: 60-80 parts; Disintegrant: 20-30 parts; Stabilizer: 2-3 parts; Wetting agent: 30-50 parts; Lubricant: 2-3 parts; Glidant: 5-7 parts.

3. The betahistine hydrochloride tablet according to claim 1, wherein In parts by weight, the core comprises: Betahistine hydrochloride: 9 parts; Filler: 70 parts; Disintegrant: 30 parts; Stabilizer: 2.5 parts; Wetting agent: 40 parts; Lubricant: 2.5 parts; Glidant: 6 parts.

4. The betahistine hydrochloride tablet according to claim 1, wherein The filler is one or more of lactose, microcrystalline cellulose, pregelatinized starch and dextrin; the disintegrant is one or a mixture of microcrystalline cellulose and sodium starch glycolate in any proportion; the stabilizer is citric acid; the wetting agent is purified water; the lubricant is one or a mixture of magnesium stearate and silicon dioxide in any proportion; and the glidant is one or a mixture of silicon dioxide and talc in any proportion.

5. The betahistine hydrochloride tablet according to claim 1, wherein The raw materials are dissolved in purified water and then spray granulated.

6. The betahistine hydrochloride tablet according to claim 1, wherein The coating layer is prepared by the following method: a gastric-soluble film coating premix is ​​weighed according to weight gain, purified water is poured into a stirring tank, compressed air is connected and the air pressure valve is opened to start stirring, and then the gastric-soluble film coating premix is ​​poured into the stirring tank, and stirred for 40 to 60 minutes to prepare a coating solution with a concentration of 10 to 15 wt%, and the core tablets are coated to obtain a coating layer.

7. The method for preparing the betahistine hydrochloride tablet according to any one of claims 1 to 6, characterized in that: The method comprises the following steps: (1) crushing citric acid and setting aside; preparing a solution of betahistine hydrochloride raw material with 30% to 60% of the prescribed amount of purified water and setting aside; (2) sequentially adding a filler, a disintegrant, a stabilizer and a wetting agent into a boiling granulator, spraying the betahistine hydrochloride solution of step (1) and the remaining purified water to prepare granules, and after drying, adding a lubricant and a glidant, granulating and mixing to obtain granules; (3) using a tablet press to compress the granules from step (2) into tablet cores; (4) Use a coating pan to coat the tablet cores from step (3).

8. The method for preparing the betahistine hydrochloride tablet according to claim 7, wherein: In step (2), the speed of spraying the betahistine hydrochloride solution and the remaining purified water in step (1) is controlled at 60-80 rpm / min, and the temperature during the spraying process is controlled below 50°C.

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