Betahistine antioxidant tablet and preparation method thereof

Abstract

The present invention provides a betahistine antioxidant tablet and a preparation method thereof, the betahistine antioxidant tablet comprises: a first zone comprising anhydrous citric acid, microcrystalline cellulose and hydroxypropyl methylcellulose; the middle buffer area is a sodium alginate aqueous solution coating; a second zone including calcium carbonate, betahistine, and microcrystalline cellulose; the first zone is located at the top of the tablet, the second zone is located at the bottom, and the buffer zone physically isolates the first zone from the second zone. The first zone, the buffer zone and the second zone are designed to form a sandwich structure, oxidation resistance is realized through dual mechanisms of physical isolation and chemical neutralization, and CO2 generated by reaction of food-grade citric acid and calcium carbonate is used for physically replacing oxygen.

Description

Technical Field

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

[0002] Betahistine, a frontline drug for the treatment of Meniere's disease, carries a significant risk of oxidation within the pyridine ring and ethylamine side chain of its molecular structure. This not only results in loss of efficacy but also potentially generates neurotoxic nitrosamine impurities. Currently, the industry primarily prevents betahistine oxidation by adding chemical antioxidants. However, some antioxidants can produce oxidation products that can render betahistine ineffective and cause color degradation. Polymer coatings are also an option, but multi-layer coatings can increase tablet brittleness. Therefore, further improvement and development are needed. Summary of the Invention

[0003] In view of the various deficiencies of the existing technology and in order to solve the above problems, a betahistine antioxidant tablet and a preparation method thereof are proposed, and the following technical solutions are provided: A betahistine antioxidant tablet, characterized in that the betahistine antioxidant tablet comprises: Zone 1, including anhydrous citric acid, microcrystalline cellulose, and hypromellose; The middle buffer zone is a sodium alginate aqueous solution coating; zone 2, including calcium carbonate, betahistine, and microcrystalline cellulose; The first zone is located at the top of the tablet, the second zone is located at the bottom, and the buffer zone physically separates the first zone and the second zone.

[0004] Furthermore, the first zone comprises 10-15 parts of anhydrous citric acid, 80-85 parts of microcrystalline cellulose, and 5-8 parts of hypromellose, calculated by weight.

[0005] Furthermore, the thickness of the intermediate buffer layer is 50-100 μm.

[0006] Furthermore, the second zone comprises 15-20 parts of calcium carbonate, 12-15 parts of betahistine, and 60-70 parts of microcrystalline cellulose in parts by mass.

[0007] Furthermore, the particle size of calcium carbonate is 20-50 μm.

[0008] In addition, the present invention also provides a method for preparing a betahistine antioxidant tablet, comprising the steps of: (1) mixing betahistine, calcium carbonate and microcrystalline cellulose and then pressing the mixture into a tablet core; (2) Spraying a sodium alginate aqueous solution on the top of the core, which solidifies into a film after spraying; (3) The tablet core sprayed with sodium alginate aqueous solution is filled with a mixed powder of anhydrous citric acid, microcrystalline cellulose and hydroxypropyl methylcellulose, and then compressed again to form betahistine antioxidant tablets.

[0009] Furthermore, the tableting pressure in step (1) is 3-5 kN, and the tableting pressure in step (3) is 15-18 kN.

[0010] Furthermore, the spraying rate in step (2) is 8-12 ml / min.

[0011] Furthermore, in step (3), after the tablet is pressed again, a hydrophobic protective film is rotary sprayed on the surface.

[0012] The raw materials of the hydrophobic protective film are ethyl cellulose and ethanol solution.

[0013] Due to the adoption of the above technical solution, the beneficial technical effects of the present invention are: 1. The present invention designs a sandwich structure of the first zone, the buffer zone, and the second zone, achieving antioxidant effect through the dual mechanisms of physical isolation and chemical neutralization, using CO2 generated by the reaction of food-grade citric acid and calcium carbonate to physically replace oxygen; 2. The intermediate buffer layer of the present invention realizes spatial separation of the first zone and the second zone, thereby preventing pre-reaction during storage. DETAILED DESCRIPTION

[0014] In order to enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention is clearly and completely described below in conjunction with the embodiments of the present invention. Based on the embodiments in this application, other similar embodiments obtained by ordinary technicians in this field without making any creative work should fall within the scope of protection of this application.

[0015] A betahistine antioxidant tablet comprises: a first zone comprising anhydrous citric acid, microcrystalline cellulose, and hypromellose; a buffer zone comprising a sodium alginate aqueous solution coating; and a second zone comprising calcium carbonate, betahistine, and microcrystalline cellulose. The first zone is located at the top of the tablet, while the second zone is located at the bottom, with the buffer zone physically separating the first and second zones. The present invention employs a sandwich structure designed to achieve antioxidant effects through both physical isolation and chemical neutralization, using CO2 generated by the reaction of food-grade citric acid and calcium carbonate to physically displace oxygen. This patent utilizes a three-layer structure to precisely control the temporal and spatial order of gas displacement: citric acid is locked at the top of the tablet, while the main drug component and calcium carbonate are loaded at the bottom layer, with a buffer layer positioned between the two. When ambient moisture penetrates the tablet surface, it preferentially activates the citric acid at the top layer to form a hydrogen ion solution. The hydrogen ions then pass through the buffer layer and combine with the calcium carbonate to generate CO2, which physically displaces oxygen, achieving antioxidant effects.

[0016] Example 1 According to mass parts: Zone 1: 13 parts anhydrous citric acid, 83 parts microcrystalline cellulose and 6 parts hypromellose; Middle buffer: sodium alginate aqueous solution coating, 80 μm thick; Zone 2: 18 parts of calcium carbonate, 13 parts of betahistine, and 65 parts of microcrystalline cellulose, with a particle size of calcium carbonate of 35 μm; Process: (1) Betahistine, calcium carbonate, and microcrystalline cellulose were added to a three-dimensional mixer in proportion and mixed at 15 rpm for 45 minutes until uniform. Nitrogen was introduced during the process. After mixing, the mixture was filled into the tablet press die and a pressure of 4 kN was applied to form tablet cores. (2) Transfer the tablet core to the fluidized bed, set the inlet air temperature to 45°C, spray the top of the tablet core with sodium alginate aqueous solution, the atomization pressure is 0.8 bar, and the sodium alginate solution is evenly sprayed at a rate of 10 mL / min to a thickness of 80 μm. After spraying, dry it with hot air at 40°C for 5 minutes to solidify it into a film; (3) After the tablet core was sprayed with sodium alginate aqueous solution, a mixed powder of anhydrous citric acid, microcrystalline cellulose and hydroxypropyl methylcellulose was filled until the die hole was full, and the tablet was compressed again at a pressure of 18 kN to form betahistine antioxidant tablets.

[0017] Example 2 According to mass parts: Zone 1: 10 parts of anhydrous citric acid, 80 parts of microcrystalline cellulose and 5 parts of hypromellose; Middle buffer: sodium alginate aqueous solution coating with a thickness of 50 μm; Zone 2: 15 parts of calcium carbonate, 12 parts of betahistine, and 60 parts of microcrystalline cellulose, with a particle size of calcium carbonate of 20 μm; Process: (1) Betahistine, calcium carbonate, and microcrystalline cellulose were added to a three-dimensional mixer in proportion and mixed at 15 rpm for 45 minutes until uniform. Nitrogen was introduced during the process. After mixing, the mixture was filled into the tablet press die and a pressure of 4 kN was applied to form tablet cores. (2) Transfer the tablet core to the fluidized bed, set the inlet air temperature to 45°C, spray the top of the tablet core with sodium alginate aqueous solution, the atomization pressure is 0.8 bar, and the sodium alginate solution is evenly sprayed at a rate of 10 mL / min to a thickness of 80 μm. After spraying, dry it with hot air at 40°C for 5 minutes to solidify it into a film; (3) After the tablet core was sprayed with sodium alginate aqueous solution, a mixed powder of anhydrous citric acid, microcrystalline cellulose and hydroxypropyl methylcellulose was filled until the die hole was full, and the tablet was compressed again at a pressure of 18 kN to form betahistine antioxidant tablets.

[0018] Example 3 According to mass parts: Zone 1: 15 parts of anhydrous citric acid, 85 parts of microcrystalline cellulose and 8 parts of hypromellose; Middle buffer: sodium alginate aqueous solution coating with a thickness of 100 μm; Zone 2: 20 parts of calcium carbonate, 15 parts of betahistine and 70 parts of microcrystalline cellulose, with a particle size of calcium carbonate of 50 μm; Process: (1) Betahistine, calcium carbonate, and microcrystalline cellulose were added to a three-dimensional mixer in proportion and mixed at 15 rpm for 45 minutes until uniform. Nitrogen was introduced during the process. After mixing, the mixture was filled into the tablet press die and a pressure of 4 kN was applied to form tablet cores. (2) Transfer the tablet core to the fluidized bed, set the inlet air temperature to 45°C, spray the top of the tablet core with sodium alginate aqueous solution, the atomization pressure is 0.8 bar, and the sodium alginate solution is evenly sprayed at a rate of 10 mL / min to a thickness of 80 μm. After spraying, dry it with hot air at 40°C for 5 minutes to solidify it into a film; (3) After the tablet core was sprayed with sodium alginate aqueous solution, a mixed powder of anhydrous citric acid, microcrystalline cellulose and hydroxypropyl methylcellulose was filled until the die hole was full, and the tablet was compressed again at a pressure of 18 kN to form betahistine antioxidant tablets.

[0019] Example 4 According to mass parts: Zone 1: 13 parts anhydrous citric acid, 83 parts microcrystalline cellulose and 6 parts hypromellose; Middle buffer: sodium alginate aqueous solution coating, 80 μm thick; Zone 2: 18 parts of calcium carbonate, 13 parts of betahistine, and 65 parts of microcrystalline cellulose, with a particle size of calcium carbonate of 35 μm; Process: (1) Betahistine, calcium carbonate, and microcrystalline cellulose were added to a three-dimensional mixer in proportion and mixed at 15 rpm for 45 minutes until uniform. Nitrogen was introduced during the process. After mixing, the mixture was filled into the tablet press die and a pressure of 4 kN was applied to form tablet cores. (2) Transfer the tablet core to the fluidized bed, set the inlet air temperature to 45°C, spray the top of the tablet core with sodium alginate aqueous solution, the atomization pressure is 0.8 bar, and the sodium alginate solution is evenly sprayed at a rate of 10 mL / min to a thickness of 80 μm. After spraying, dry it with hot air at 40°C for 5 minutes to solidify it into a film; (3) After the tablet core was sprayed with sodium alginate aqueous solution, a mixed powder of anhydrous citric acid, microcrystalline cellulose and hydroxypropyl methylcellulose was filled until the die was full. After the tablet was compressed again with a pressure of 18 kN, a 5% ethyl cellulose ethanol solution was rotary sprayed on the surface to form betahistine antioxidant tablets. The thickness of the hydrophobic protective film was 13 μm.

[0020] Example 5 According to mass parts: Zone 1: 13 parts anhydrous citric acid, 83 parts microcrystalline cellulose and 6 parts hypromellose; Middle buffer: sodium alginate aqueous solution coating, 80 μm thick; Zone 2: 18 parts of calcium carbonate, 13 parts of betahistine, and 65 parts of microcrystalline cellulose, with a particle size of calcium carbonate of 35 μm; Process: (1) Betahistine, calcium carbonate, and microcrystalline cellulose were added to a three-dimensional mixer in proportion and mixed at 15 rpm for 45 minutes until uniform. Nitrogen was introduced during the process. After mixing, the mixture was filled into the tablet press die and a pressure of 3 kN was applied to form tablet cores. (2) Transfer the tablet core to the fluidized bed, set the inlet air temperature to 45°C, spray the top of the tablet core with sodium alginate aqueous solution, the atomization pressure is 0.8 bar, and the sodium alginate solution is evenly sprayed at a rate of 8 mL / min to a thickness of 80 μm. After spraying, dry it with hot air at 40°C for 5 minutes to solidify it into a film; (3) After the tablet core was sprayed with sodium alginate aqueous solution, a mixed powder of anhydrous citric acid, microcrystalline cellulose and hydroxypropyl methylcellulose was filled until the die hole was full, and the tablet was compressed again at a pressure of 15 kN to form betahistine antioxidant tablets.

[0021] Example 6 According to mass parts: Zone 1: 13 parts anhydrous citric acid, 83 parts microcrystalline cellulose and 6 parts hypromellose; Middle buffer: sodium alginate aqueous solution coating, 80 μm thick; Zone 2: 18 parts of calcium carbonate, 13 parts of betahistine, and 65 parts of microcrystalline cellulose, with a particle size of calcium carbonate of 35 μm; Process: (1) Betahistine, calcium carbonate, and microcrystalline cellulose were added to a three-dimensional mixer in proportion and mixed at 15 rpm for 45 minutes until uniform. Nitrogen was introduced during the process. After mixing, the mixture was filled into the tablet press die and a pressure of 5 kN was applied to form tablet cores. (2) Transfer the tablet core to the fluidized bed, set the inlet air temperature to 45°C, spray the top of the tablet core with sodium alginate aqueous solution, the atomization pressure is 0.8 bar, and the sodium alginate solution is evenly sprayed at a rate of 12 mL / min to a thickness of 80 μm. After spraying, dry it with hot air at 40°C for 5 minutes to solidify it into a film; (3) After the tablet core was sprayed with sodium alginate aqueous solution, a mixed powder of anhydrous citric acid, microcrystalline cellulose and hydroxypropyl methylcellulose was filled until the die hole was full, and the tablet was compressed again at a pressure of 15 kN to form betahistine antioxidant tablets.

[0022] Comparative Example 1 According to mass parts: 13 parts of anhydrous citric acid, 83 parts of microcrystalline cellulose, 6 parts of hypromellose, 18 parts of calcium carbonate, 13 parts of betahistine and 65 parts of microcrystalline cellulose were mixed evenly and directly compressed into tablets. The particle size of calcium carbonate was 35 μm. The single-layer tableting pressure was 10 kN.

[0023] Comparative Example 2 According to mass parts: Zone 1: 13 parts anhydrous citric acid, 83 parts microcrystalline cellulose and 6 parts hypromellose; Zone 2: 18 parts of calcium carbonate, 13 parts of betahistine, and 65 parts of microcrystalline cellulose, with a particle size of calcium carbonate of 35 μm; Process: (1) Betahistine, calcium carbonate, and microcrystalline cellulose were added to a three-dimensional mixer in proportion and mixed at 15 rpm for 45 minutes until uniform. Nitrogen was introduced during the process. After mixing, the mixture was filled into the tablet press die and a pressure of 4 kN was applied to form tablet cores. (2) Fill the tablet core with a mixed powder of anhydrous citric acid, microcrystalline cellulose and hypromellose until the die is full, and then press the tablet again with a pressure of 18 kN to form betahistine antioxidant tablets.

[0024] Comparative Example 3 According to mass parts: Betahistine 13 parts, methylcellulose 65 parts, antioxidant BHA 0.1 part; Process: Betahistine, methylcellulose and antioxidant BHA were added into a three-dimensional mixer according to the proportion and mixed at a speed of 15 rpm for 45 minutes until uniform. The tablets were compressed at 10 kN and then film-coated.

[0025] The drugs obtained in the above examples and comparative examples were subjected to relevant tests.

[0026] 1. Detection of active drug content and degradation products High performance liquid chromatography (Agilent 1260) was used to detect the content of the main drug and degradation products.

[0027] 2. Delamination failure analysis Micron-scale computed tomography Layering rate = layering volume / total tablet volume × 100% The test results are shown in Table 1 below.

[0028] Table 1 Test results of the drugs obtained in the above examples and comparative examples Through comparative testing of Examples 1-6 and Comparative Examples 1-3, the present invention successfully solves the problem of oxidative degradation of betahistine. By implementing a layered design and adjusting the ratio of various raw materials to achieve synergistic effects, the oxygen concentration of the tablet core is reduced during storage, and the degradation products are reduced to below 0.15% after 6 months.

[0029] Specifically, when the citric acid dosage is too low, the H⁺ supply is insufficient, the calcium carbonate reaction rate decreases, and the oxygen concentration after 6 months is greater than in the examples. However, when the citric acid content is 13 parts per million and the calcium carbonate is 35 μm, the gas displacement dynamic equilibrium is optimal, forming a self-sustaining inert environment. When the components are not partitioned, the citric acid and calcium carbonate continue to pre-react during storage, generating CO₂ bubbles that force the tablets to expand and crack, resulting in rapid drug degradation. In Comparative Example 2, without a buffer layer, the acid-base reaction after tableting leads to delamination.

[0030] In addition, it should be understood that although this specification is described in terms of implementation methods, not every implementation method contains only one independent technical solution. This narrative method of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

Claims

1. A betahistine antioxidant tablet, characterized in that: Betahistine Antioxidant Tablets contain: Zone 1, including anhydrous citric acid, microcrystalline cellulose, and hypromellose; The middle buffer zone is a sodium alginate aqueous solution coating; zone 2, including calcium carbonate, betahistine, and microcrystalline cellulose; The first zone is located at the top of the tablet, the second zone is located at the bottom, and the buffer zone physically separates the first zone and the second zone.

2. A betahistine antioxidant tablet according to claim 1, characterized in that, In the first zone, based on weight percentage, the content of anhydrous citric acid is 10-15 parts; the content of microcrystalline cellulose is 80-85 parts; and the content of hypromellose is 5-8 parts.

3. A betahistine antioxidant tablet according to claim 1, characterized in that, The thickness of the intermediate buffer layer is 50-100 μm.

4. A betahistine antioxidant tablet according to claim 1, characterized in that The second zone contains 15-20 parts of calcium carbonate, 12-15 parts of betahistine, and 60-70 parts of microcrystalline cellulose in parts by mass.

5. A betahistine antioxidant tablet according to claim 1, characterized in that: The particle size of calcium carbonate is 20-50 μm.

6. The method for preparing a betahistine antioxidant tablet according to any one of claims 1 to 5, characterized in that the steps include: (1) Betahistine, calcium carbonate, and microcrystalline cellulose are mixed and compressed into tablets to form core tablets; (2) Spraying a sodium alginate aqueous solution on the top of the core, which solidifies into a film after spraying; (3) The tablet core sprayed with sodium alginate aqueous solution is filled with a mixed powder of anhydrous citric acid, microcrystalline cellulose and hydroxypropyl methylcellulose, and then compressed again to form betahistine antioxidant tablets.

7. The method for preparing a betahistine antioxidant tablet according to claim 6, characterized in that: The tableting pressure in step (1) is 3-5 kN, and the tableting pressure in step (3) is 15-18 kN.

8. The method for preparing a betahistine antioxidant tablet according to claim 6, characterized in that: The spraying rate in step (2) is 8-12 ml / min.

9. The method for preparing a betahistine antioxidant tablet according to claim 6, characterized in that: After the tablet is pressed again in step (3), a hydrophobic protective film is sprayed on the surface by rotation.

10. The method for preparing a betahistine antioxidant tablet according to claim 9, characterized in that: The raw materials of the hydrophobic protective film are ethyl cellulose and ethanol solution.

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