Melogabalin besylate tablet and preparation method thereof

Abstract

The invention discloses a melogabalin besylate tablet and a preparation method thereof, a tablet core of the melogabalin besylate tablet comprises melogabalin besylate, a filler, a disintegrating agent, a lubricant and an antioxidant, and the antioxidant comprises sodium ascorbate. Compared with an antioxidant disclosed in the prior art, sodium ascorbate is selected as the antioxidant, so that the content of related substances in the melogabalin besylate preparation can be effectively improved, the growth of main degradation impurities and oxidation impurities is effectively controlled, the stability of the product is improved, and the product is enabled to be quickly dissolved out and good in dissolution uniformity.

Description

Technical Field

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

[0002] Mirogabalin is a new type of chronic pain treatment drug. It binds to the voltage-gated calcium channel (VGCC) subunit a28 (CACNA2D), plays an auxiliary role in the function of voltage-dependent calcium channels in the nervous system, inhibits calcium currents, and can exert analgesic effects. Daiichi Sankyo's Tarlige (merogabalin besylate) 2.5mg, 5mg, 10mg, 15mg tablets have been approved in Japan for the treatment of peripheral neuropathic pain (PNP).

[0003] Patent CN107405322B protects a solid preparation containing melogabalin besylate, and protects a composition including a filler, a disintegrant, and an antioxidant. Patent CN104334169A protects a solid composition containing melogabalin besylate, and specifically protects a filler mannitol, a disintegrant calcium carboxymethylcellulose, and a lubricant magnesium stearate or sodium stearyl fumarate.

[0004] The prior art has obtained preparations with good stability through a lot of research. However, during the storage and placement of drugs, oxidative degradation and impurities will still occur. If the drug degrades and deteriorates, not only will the efficacy be reduced, but it may even produce toxic side effects, thereby affecting the effectiveness and safety of the drug in clinical application. Therefore, ensuring the stability of drug preparations is crucial to ensuring the quality, safety and effectiveness of the preparation products. In order to obtain drugs with better stability and meet the requirements of different storage conditions, further research is needed. Summary of the invention

[0005] In view of this, the object of the present invention is to provide a melogabalin besylate tablet and a preparation method thereof, so as to control the growth of major degradation impurities and oxidation impurities and improve the stability of the product.

[0006] In order to achieve the above object, the present invention provides the following technical solutions:

[0007] The invention discloses a melogabalin besylate tablet. The tablet core of the melogabalin besylate tablet comprises melogabalin besylate, a filler, a disintegrant, a lubricant and an antioxidant, and the antioxidant comprises sodium vitamin C.

[0008] As a preferred technical solution, the vitamin C sodium accounts for 0.5% to 1.5% of the weight of the tablet core.

[0009] As a preferred technical solution, the vitamin C sodium accounts for 1.0% of the tablet core weight.

[0010] The structural formula of melogabalin besylate is as follows:

[0011]

[0012] As a preferred technical solution, the filler comprises mannitol and microcrystalline cellulose, wherein the mannitol is preferably D-mannitol 100SD, the disintegrant comprises carboxymethylcellulose calcium, and the lubricant comprises magnesium stearate.

[0013] As a preferred technical solution, the core of the melogabalin besylate tablet further comprises an adsorbent, and the adsorbent comprises magnesium aluminum metasilicate.

[0014] As a preferred technical solution, the weight percentage of each component in the core of the melogabalin besylate tablet is: melogabalin besylate 3% to 5%, mannitol 77% to 82%, microcrystalline cellulose 5% to 15%, carboxymethylcellulose calcium 1% to 5%, sodium vitamin C 0.5% to 1.5%, magnesium stearate 1% to 2%, and magnesium aluminum metasilicate 0.1% to 0.5%.

[0015] As a preferred technical solution, the weight percentage of each component in the core of the melogabalin besylate tablet is: melogabalin besylate 4.39%, mannitol 77.56%, microcrystalline cellulose 12.25%, carboxymethylcellulose calcium 3%, sodium vitamin C 1%, magnesium stearate 1.5%, and magnesium aluminum metasilicate 0.3%.

[0016] As a preferred technical solution, the melogabalin besylate tablets contain a coating agent, and the coating weight gain of the coating agent is 2% to 5%.

[0017] The present invention also discloses a method for preparing melogabalin besylate tablets, comprising the following steps:

[0018] (1) Weigh the prescribed amount of melogabalin besylate, microcrystalline cellulose, carboxymethylcellulose calcium, sodium ascorbyl sulfate, and magnesium aluminum metasilicate, mix them in a wet granulator, and then add 20% of the prescribed amount of mannitol and mix;

[0019] (2) the mixed powder of step (1) and the remaining mannitol are sieved, added to a mixer for mixing, and a prescribed amount of magnesium stearate is added for total mixing;

[0020] (3) After mixing, use a special-shaped punch to directly press the tablets to control the tablet weight and hardness;

[0021] (4) preparing a coating solution and coating the plain tablets of step (3).

[0022] The beneficial effects of the present invention are:

[0023] The present invention finds that, compared with the antioxidants disclosed in the prior art, the selection of sodium vitamin C as an antioxidant can effectively improve the content of related substances in the melogabalin besylate preparation, effectively control the growth of major degradation impurities and oxidation impurities, improve the stability of the product, and ensure that the product is quickly dissolved and has good dissolution uniformity. DETAILED DESCRIPTION

[0024] The present invention is further described below in conjunction with specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0025] Example 1 Antioxidant Screening

[0026]

[0027] The preparation method of melogabalin besylate tablets comprises the following steps:

[0028] (1) Weigh the prescribed amount of melogabalin besylate, microcrystalline cellulose, carboxymethylcellulose calcium, sodium ascorbyl sulfate, and magnesium aluminum metasilicate, mix them in a wet granulator, and then add 20% of the prescribed amount of mannitol and mix;

[0029] (2) the mixed powder of step (1) and the remaining mannitol are sieved, added to a mixer for mixing, and a prescribed amount of magnesium stearate is added for total mixing;

[0030] (3) After mixing, the tablets were directly compressed using a special-shaped punch, with a tablet weight of 200 mg and a hardness of 100-140 N;

[0031] (4) Prepare the coating solution. Slowly add the prescribed amount of Opadry into a beaker while stirring. Stir thoroughly for 45 minutes to ensure uniform dispersion. Then start coating the plain tablets. The target weight gain is 2-5%.

[0032] The types of antioxidants were adjusted to sodium metabisulfite / sodium sulfite / sodium vitamin C / butylated hydroxytoluene, thereby preparing melogabalin besylate tablets of prescriptions 1-4, respectively.

[0033] Example 2 Antioxidant Dosage Screening

[0034]

[0035]

[0036] As shown in the table above, the dosage of sodium vitamin C was adjusted and the same preparation method as in Example 1 was used to prepare melogabalin besylate tablets of prescriptions 5-6, respectively.

[0037] Stability test:

[0038] The melogabalin besylate tablets of prescription 1-6 were sealed in aluminum-plastic bags with desiccant and placed at 60°C for 10 days and 30 days. The contents of related substances in the samples were determined by HPLC, and the results are shown in Table 1.

[0039] Table 1: Test results of related substances

[0040]

[0041] The results in Table 1 show that compared with other existing antioxidants, the formulation with added sodium vitamin C has a significant stability advantage at high temperature for 30 days. The growth rates of both oxidative impurities and degraded impurities are relatively low, and the finished product has good appearance and meets the quality requirements of drugs.

[0042] Dissolution Assay:

[0043] The dissolution test was carried out in accordance with the second method (paddle method) of Part IV General Rules 0931 of the 2020 edition of the Chinese Pharmacopoeia, and the cumulative dissolution of prescription 3 in pH 1.2 medium was determined.

[0044]

[0045] The results showed that the prescription product with added sodium vitamin C dissolved quickly and had good dissolution uniformity.

[0046] The above-described embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or changes made by those skilled in the art based on the present invention are within the protection scope of the present invention. The protection scope of the present invention shall be subject to the claims.

Claims

1. A melogabalin besylate tablet, characterized in that: The core of the melogabalin besylate tablet comprises melogabalin besylate, a filler, a disintegrant, a lubricant and an antioxidant, and the antioxidant comprises sodium vitamin C.

2. The melogabalin besylate tablets according to claim 1, characterized in that: The vitamin C sodium accounts for 0.5% to 1.5% of the weight of the tablet core.

3. The melogabalin besylate tablets according to claim 2, characterized in that: The vitamin C sodium accounts for 1.0% of the tablet core weight.

4. The melogabalin besylate tablets according to claim 1, characterized in that: The structural formula of melogabalin besylate is as follows:

5. The melogabalin besylate tablets according to claim 1, characterized in that: The filler comprises mannitol and microcrystalline cellulose, the disintegrant comprises carmellose calcium, and the lubricant comprises magnesium stearate.

6. The melogabalin besylate tablets according to claim 1, characterized in that: The core of the melogabalin besylate tablet further comprises an adsorbent, and the adsorbent comprises magnesium aluminum metasilicate.

7. The melogabalin besylate tablets according to claim 1, characterized in that: The weight percentages of the components in the core of the melogabalin besylate tablets are: 3% to 5% melogabalin besylate, 77% to 82% mannitol, 5% to 15% microcrystalline cellulose, 1% to 5% carboxymethylcellulose calcium, 0.5% to 1.5% sodium ascorbyl acetate, 1% to 2% magnesium stearate, and 0.1% to 0.5% magnesium aluminum metasilicate.

8. The melogabalin besylate tablets according to claim 7, characterized in that: In the core of the melogabalin besylate tablet, the weight percentages of the components are: melogabalin besylate 4.39%, mannitol 77.56%, microcrystalline cellulose 12.25%, carboxymethylcellulose calcium 3%, sodium vitamin C 1%, magnesium stearate 1.5%, and magnesium aluminum metasilicate 0.3%.

9. The melogabalin besylate tablets according to claim 1, characterized in that: The melogabalin besylate tablets contain a coating agent, and the coating weight gain of the coating agent is 2% to 5%.

10. The method for preparing melogabalin besylate tablets according to any one of claims 1 to 9, characterized in that: The following steps are involved: (1) Weigh the prescribed amount of melogabalin besylate, microcrystalline cellulose, carboxymethylcellulose calcium, sodium ascorbyl sulfate, and magnesium aluminum metasilicate, mix them in a wet granulator, and then add 20% of the prescribed amount of mannitol and mix; (2) the mixed powder of step (1) and the remaining mannitol are sieved, added to a mixer for mixing, and a prescribed amount of magnesium stearate is added for total mixing; (3) After mixing, use a special-shaped punch to directly press the tablets to control the tablet weight and hardness; (4) preparing a coating solution and coating the plain tablets of step (3).

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