Bepotastine besilate tablet and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and relates to a bepotastine besilate tablet and a preparation method thereof. According to the bepotastine besilate tablet and the preparation method thereof, by reasonably screening and optimizing a prescription and adjusting the ratio of the first filler to the second filler to the adhesive to be (5-20): (90-100): (2-5), the bepotastine besilate tablet which is consistent with an originally-ground product in dissolution and is suitable for a powder direct compression process is obtained, the bepotastine besilate tablet is prepared by adopting the powder direct compression process, and on the basis of ensuring better dissolution, the content of the bepotastine besilate tablet is greatly improved. By controlling the particle size D90 of the raw material medicine to be 30-100 microns and adjusting the adding sequence of mannitol serving as a filling agent, the problems of non-uniform mixing and tabletting sticking in the powder preparation tabletting process are solved; meanwhile, the powder direct compression process also effectively avoids the problem that the bulk drugs are unstable in contact with damp and heat, the generation of R-isomers is reduced, the stability of the preparation is improved, and the powder direct compression process adopted by the invention is simple in preparation procedure, low in production cost and more beneficial to industrial large-scale production.

Description

Technical Field

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

[0002] Bepotastine besylate tablets were jointly developed by Japan's Tanabe Seiyaku Co., Ltd. and Japan's Ube Industries Co., Ltd., and were launched in Japan in July 2000 with specifications of 5 mg and 10 mg. They were then approved to enter the Chinese market in 2010 with a specification of 10 mg. The dosage form is tablets with a white film coating. Each tablet contains 10 mg of bepotastine besylate. It is indicated for allergic rhinitis, urticaria, and itching caused by skin diseases (eczema, dermatitis, pruritus, and skin pruritus).

[0003] The original preparation patent JP3909998B2 discloses the composition and preparation method of bepotastine besylate tablets, which uses a heatable wet granulator for hot melt granulation. Since the equipment is special and expensive, in order to solve the equipment problem, there is also a preparation patent application CN201610683980.9 with a similar preparation process in China. The patent adopts an oven heating melt granulation method, which effectively overcomes the equipment problem, but also has disadvantages such as cumbersome process, uneven distribution of polyethylene glycol 6000, large quality differences, and difficulty in crushing and granulation. The document "Bepotastine besylate film-coated tablets" Preparation and Quality Evaluation" (Liu Lizhong, Chinese Pharmacist, 2018, 21 (10), 1854-1857) The conventional wet granulation method was used to prepare bepotastine besylate tablets, but there were problems such as sticking during tableting and poor tablet dissolution. At the same time, since bepotastine besylate has optical isomers, the S-isomer has higher activity and safety than the R-isomer, and the S-isomer is easily converted into the R-isomer under wet and hot conditions, the wet granulation process may also affect the stability of bepotastine besylate tablets, which is not conducive to product quality control.

[0004] In summary, it is necessary to develop a tablet and a preparation method thereof that is simple in process and more conducive to the stability of bepotastine besilate. Summary of the invention

[0005] In view of the shortcomings of the prior art, the present invention provides a bepotastine besilate tablet and a preparation method thereof. The powder direct compression process is adopted, and the prepared tablets not only have a smooth appearance, uniform content, and a dissolution curve consistent with the original product, but also effectively control the generation of isomers and improve the stability of the preparation. At the same time, the preparation process of the present invention is simple, low in cost, and more conducive to commercial production.

[0006] In order to achieve the above-mentioned invention object, the main technical scheme of the present invention is as follows: The invention provides a bepotastine besilate tablet, which is characterized in that, by weight, the bepotastine besilate tablet comprises 10 parts of bepotastine besilate, 95-120 parts of a filler, 2-5 parts of an adhesive, 0.5-1.5 parts of a lubricant, and 2-4 parts of a coating material; wherein the filler comprises a first filler and a second filler, and the bepotastine besilate tablet is prepared by a powder direct compression process.

[0007] Preferably, the first filler is microcrystalline cellulose, the second filler is mannitol, the binder is hypromellose, and the lubricant is magnesium stearate.

[0008] Preferably, the microcrystalline cellulose is type 112 and the mannitol is type 200SD.

[0009] Preferably, the ratio of the first filler, the second filler and the binder is (5-20): (90-100): (2-5).

[0010] Preferably, the ratio of the first filler, the second filler and the binder is 10:(90-100):3.

[0011] Preferably, the ratio of the first filler, the second filler and the adhesive is 10:96:3.

[0012] Preferably, the bepotastine besilate tablets include 10 parts of bepotastine besilate, 96 parts of mannitol, 10 parts of microcrystalline cellulose, 3 parts of hypromellose, 1 part of magnesium stearate, and 3.6 parts of coating materials, in parts by weight.

[0013] Preferably, the particle size D90 of bepotastine besilate is 30-100 μm.

[0014] The present invention also provides a method for preparing bepotastine besilate tablets. The preparation method is direct powder compression, comprising the following steps: mixing bepotastine besilate, a first filler and a binder, adding a second filler and continuing to mix, then adding a lubricant and mixing the whole, and finally performing tableting and coating treatment to obtain bepotastine besilate tablets.

[0015] Preferably, the preparation method comprises the following specific steps: adding bepotastine besilate, microcrystalline cellulose 112 and a binder into a mixer and mixing them evenly; adding a prescribed amount of mannitol 200SD into the mixture of step 1 and mixing them evenly; adding a lubricant and mixing the whole mixture to obtain a total mixed material; and using a tablet press to perform tableting and coating treatment on the above-mentioned total mixed material to obtain bepotastine besilate tablets.

[0016] Preferably, the preparation method comprises the following specific steps: crushing bepotastine besilate to a D90 of 30-100 μm; adding bepotastine besilate, microcrystalline cellulose and hypromellose into a mixer and mixing evenly; adding a prescribed amount of mannitol into the mixture of step 2 and mixing evenly; adding magnesium stearate to the mixture to obtain a total mixed material; and using a tablet press to perform tableting and coating on the total mixed material to obtain bepotastine besilate tablets.

[0017] Preferably, the hardness of the pressed tablet is 30-70N.

[0018] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention adopts a powder direct compression process to prepare bepotastine besilate tablets. On the basis of ensuring good dissolution, the particle size D90 of the raw material drug is controlled to be 30-100 μm, and the order of adding the filler mannitol is adjusted to improve the problems of uneven mixing and tablet sticking in the powder preparation tableting process. At the same time, the powder direct compression process also effectively avoids the problem of the raw material drug being unstable when exposed to moisture and heat, reduces the generation of R-isomers, and increases the stability of the preparation. (2) Compared with hot melt granulation and wet granulation processes, the powder direct compression process of the present invention has low equipment requirements, simple preparation process, smooth operation, low production cost, and is more conducive to industrial-scale production; (3) The present invention rationally screens and optimizes the prescription and adjusts the ratio of the first filler, the second filler, and the binder to (5-20): (90-100): (2-5), thereby obtaining bepotastine besylate tablets having the same dissolution as the original product and suitable for powder direct compression technology. DETAILED DESCRIPTION

[0019] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. Based on the examples of the present application, all other examples obtained by ordinary technicians in the field without creative work are within the protection scope of the present application.

[0020] Unless otherwise specified, the materials used in the following examples and comparative examples are all commercially available.

[0021]

[0022] Preparation method: firstly, bepotastine besylate is crushed to a D90 of 30-100 μm, then bepotastine besylate, microcrystalline cellulose and hypromellose are added to a mixer and mixed evenly, mannitol is added to the above mixture and mixed evenly, and then magnesium stearate is added to mix the whole mixture to obtain a total mixed material; then, a circular shallow concave punch with a diameter of 7 mm is used for tableting, and the hardness is controlled to be 30-70N; and a film coating is applied to obtain bepotastine besylate tablets.

[0023]

[0024] Preparation method: prepare a water solution of hydroxypropyl methylcellulose for use; weigh the other raw and auxiliary materials except magnesium stearate in the prescribed amount and add them into a wet mixing granulator, set the stirring speed to 400 rpm, the cutting knife to 1500 rpm, and mix for 5 minutes; add the above-mentioned hydroxypropyl methylcellulose aqueous solution and granulate for 1-3 minutes; place the wet granules in a fluidized bed, set the inlet air temperature to 60°C, dry to a moisture content of no more than 3%, pass through a 40-mesh sieve, add the prescribed amount of magnesium stearate and mix evenly; use a 7mm diameter circular shallow concave punch to press the tablets, and control the hardness to 30-70N; apply a film coating to obtain the product.

[0025]

[0026] Preparation method: firstly crush bepotastine besilate to a corresponding particle size, and the other preparation steps are the same as those in Example 1.

[0027] Comparative Example 4: Bepotastine besilate tablets prepared in different sequences

[0028] The prescription of Example 2 was adopted, the main drug was first crushed to D90 of 30-100 μm, and then bepotastine besylate and other auxiliary materials except magnesium stearate were added to a mixer and mixed evenly, and then magnesium stearate was added to the total mixture to obtain a total mixed material; then, a circular shallow concave punch with a diameter of 7 mm was used for tableting, and the hardness was controlled at 30-70N; and a film coating was applied to obtain bepotastine besylate tablets.

[0029] Example 6: Comparative study of dissolution curves

[0030] Referring to the dissolution and release determination method (Method 0931, Part IV, General Rules, 2020 Edition of the Chinese Pharmacopoeia), water was used as the dissolution medium, the dissolution volume was 900 mL, and the rotation speed was 70 revolutions per minute. The dissolution curves of the samples prepared in Examples 1-5 were compared with those of the commercially available original products.

[0031] The results show that the dissolution curves of the tablets prepared in Examples 1-5 are all fitted with those of the original product, and the f2 values ​​are all greater than 50, namely 59.5, 73.6, 58.4, 74.8, and 62.1, respectively, which are consistent with the dissolution of the original product.

[0032] Example 7: Stability data investigation

[0033] The tablets prepared by the two processes of Example 2 and Comparative Example 1 were packaged in aluminum-plastic packaging and placed under accelerated conditions (temperature 40±2°C, relative humidity 75±5%) to examine the changes in their content and isomer impurities. The test results are shown in the following table.

[0034]

[0035] The results showed that tablets prepared by direct powder compression had better stability. After 6 months of accelerated testing, the increase in isomer impurities was significantly less than that of tablets prepared by wet granulation.

[0036] Example 8: Comparative Study of Content Uniformity

[0037] The tablets prepared in Example 2 and Comparative Examples 2-4 were tested for content uniformity, and the test results are shown in the following table.

[0038]

[0039] The results show that the tablets prepared in Comparative Example 2 have good appearance and no sticking phenomenon, but the content uniformity is poor; in the tablet pressing process of Comparative Example 3, sticking phenomenon was found, which affected the appearance of the tablets and the tablet weight difference was large, and the quality was poor; the tablets prepared in Example 2 have good appearance, uniform content, and no sticking phenomenon.

[0040] In Comparative Example 4, bepotastine besylate was uniformly mixed with other excipients except the lubricant, and the prepared tablets had no sticking phenomenon, but the content uniformity decreased, A+2.2S>15, which did not meet the requirements of the pharmacopoeia; in Example 2, bepotastine besylate, microcrystalline cellulose and hypromellose were first uniformly mixed, and then mannitol was added and mixed, which effectively improved the content uniformity of the tablets.

[0041] The above is only a preferred embodiment of the present invention. It should be pointed out that technicians in this technical field can make several improvements and modifications without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A bepotastine besilate tablet, characterized in that: By weight, the bepotastine besylate tablets include 10 parts of bepotastine besylate, 95-120 parts of fillers, 2-5 parts of adhesives, 0.5-1.5 parts of lubricants, and 2-4 parts of coating materials; the fillers include a first filler and a second filler; the bepotastine besylate tablets are prepared by a powder direct compression process.

2. A bepotastine besilate tablet according to claim 1, characterized in that: The first filler is microcrystalline cellulose, the second filler is mannitol, the binder is hypromellose, and the lubricant is magnesium stearate.

3. A bepotastine besilate tablet according to claim 1, characterized in that: The microcrystalline cellulose was type 112 and the mannitol was type 200SD.

4. A bepotastine besilate tablet according to claim 1, characterized in that: The ratio of the first filler, the second filler and the adhesive is 20:100:

5.

5. A bepotastine besilate tablet according to claim 4, characterized in that: The ratio of the first filler, the second filler and the adhesive is 10:96:

3.

6. A bepotastine besilate tablet according to claim 1, characterized in that: By weight, the bepotastine besilate tablets include 10 parts of bepotastine besilate, 96 parts of mannitol, 10 parts of microcrystalline cellulose, 3 parts of hypromellose, 1 part of magnesium stearate, and 3.6 parts of coating materials.

7. A method for preparing bepotastine besilate tablets, the method being used for preparing a bepotastine besilate tablet according to any one of claims 1 to 6, characterized in that: The preparation method is direct powder compression, which includes the following steps: mixing bepotastine besylate, a first filler and a binder, adding a second filler and continuing to mix, then adding a lubricant and mixing the whole, and finally performing tableting and coating to obtain bepotastine besylate tablets; the particle size D90 of bepotastine besylate is 30-100 μm.

8. The method for preparing bepotastine besilate tablets according to claim 7, characterized in that: The preparation method comprises the following specific steps: adding bepotastine besylate, microcrystalline cellulose 112 and a binder into a mixer and mixing them evenly; adding a prescribed amount of mannitol 200SD into the mixture of step 1 and mixing them evenly; adding a lubricant and mixing the mixture to obtain a total mixed material; and using a tablet press to perform tableting and coating treatment on the total mixed material to obtain bepotastine besylate tablets.

9. A method for preparing bepotastine besilate tablets according to claim 8, characterized in that: The preparation method comprises the following specific steps: crushing bepotastine besylate to a D90 of 30-100 μm; adding bepotastine besylate, microcrystalline cellulose and hypromellose into a mixer and mixing evenly; adding a prescribed amount of mannitol into the mixture of step 2 and mixing evenly; adding magnesium stearate to mix the mixture to obtain a total mixed material; and using a tablet press to perform tableting and coating on the total mixed material to obtain bepotastine besylate tablets.

10. The method for preparing bepotastine besilate tablets according to claim 7, characterized in that: The hardness of the tablet is 30-70N.

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