Melogabalin besylate tablet and preparation method thereof

Abstract

The invention provides a melogabalin besylate tablet and a preparation method thereof, the melogabalin besylate tablet comprises a plain tablet and a coating, the plain tablet comprises, by mass, 4.39% of melogabalin besylate, 75-85% of mannitol 150SD, 3-10% of a disintegrating agent, 0.5-3% of a lubricant, 0.1-0.5% of an adsorbent, 1-10% of a filler, 0.5-3% of an antioxidant A and 0.1-3% of an antioxidant B; and the coating comprises the following components in percentage by mass: 30-45% of talcum powder, 2-10% of lauryl sodium sulfate, 30-45% of glycerol monocaprylate / dicaprylate, 2-10% of titanium dioxide, 30-45% of polyvinyl alcohol, 0.5-2% of iron oxide yellow and 0.5-2% of iron oxide red. The melogabalin besylate tablet prepared by the invention uses specific coating composition and specific coating parameters, so that the melogabalin besylate tablet can be stably stored without a drying agent and a composite aluminum bag for medicine packaging, the stability of the tablet is greatly improved, the complexity of equipment required by production is simplified, and the production cost is greatly saved.

Description

Technical Field

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

[0002] Melegabalin Besylate Tablets is a third-generation calcium channel modulator blocker approved for the treatment of diabetic peripheral neuropathic pain (DPNP) in adults. The original developer is Daiichi Sankyo Co., Ltd., and its specifications are 2.5mg, 5mg, 10mg, and 15mg. This product was first launched in Japan in 2019 and entered China in June 2024, with approved specifications of 2.5mg and 5mg. The original product has applied for a wealth of compound and preparation patents in China. For example, patent CN107405322B protects a solid preparation containing melogabalin besylate, and protects a composition including a filler, a disintegrant and an antioxidant; patent CN104334169B protects a solid composition containing melogabalin besylate, and specifically protects the filler mannitol, the disintegrant carboxymethylcellulose calcium and the lubricant magnesium stearate or sodium stearyl fumarate; patent CN117618375A claims to protect a melogabalin tablet, the core of which contains minobaline besylate, excipients, disintegrants, lubricants and antioxidants, and the antioxidants contain malic acid, tartaric acid, fumaric acid, ascorbyl palmitate, etc. The tablets of the original product have poor stability, complicated preparation steps, high production costs, and no reports have ever studied the effect of coating of melogabalin besylate tablets on tablets. Therefore, it is necessary to prepare new melogabalin besylate tablets to improve tablet stability. Summary of the invention

[0003] Technical problem to be solved: The purpose of the present invention is to provide a melogabalin besylate tablet and a preparation method thereof, which uses a specific coating composition and specific coating parameters so that it can be stably stored without a desiccant and a composite aluminum bag for drug packaging, greatly improving the stability of the tablets, simplifying the complexity of the equipment required for production, and greatly saving production costs.

[0004] Technical solution: A melogabalin besylate tablet, comprising a plain tablet and a coating: the plain tablet comprises, by mass percentage, 4.39% melogabalin besylate, 75-85% mannitol 150SD, 3-10% disintegrant, 0.5-3% lubricant, 0.1-0.5% adsorbent, 1-10% filler, 0.5-3% antioxidant A and 0.1-3% antioxidant B; the coating comprises, by mass percentage, 30-45% talc, 2-10% sodium lauryl sulfate, 30-45% mono- and di-octanoic acid glyceryl esters, 2-10% titanium dioxide, 30-45% polyvinyl alcohol, 0.5-2% yellow iron oxide and 0.5-2% red iron oxide. Furthermore, the disintegrant is one of carboxymethylcellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone; the lubricant is one of magnesium stearate, sodium stearyl fumarate, and talc; the adsorbent is one of magnesium aluminum metasilicate, calcium silicate, aluminum silicate, and magnesium silicate; the filler is one of microcrystalline cellulose, lactose, and starch; the antioxidant A is one of maleic acid, tartaric acid, and fumaric acid; the antioxidant B is one of vitamin C, L-cysteine, sodium pyrosulfite, ascorbyl palmitate, and butylated hydroxyanisole. Furthermore, the coating composition is, by mass percentage, 30-40% talc, 4-10% sodium lauryl sulfate, 30-40% caprylic and dicaprylic glyceryl, 2-5% titanium dioxide, 30-40% polyvinyl alcohol, 1-2% yellow iron oxide and 1-2% red iron oxide. Furthermore, the preparation method of the above-mentioned melogabalin besylate tablets comprises the following steps: S1. Tablet ingredients are mixed: melogabalin besylate, mannitol 150SD, a disintegrant, an adsorbent, a filler, an antioxidant A and an antioxidant B are added to a mixer hopper to obtain a mixture; S2. Lubrication: adding a lubricant to the mixture, mixing, and obtaining a mixture; S3. Tableting: Tableting the mixture to make plain tablets; S4. Coating: The plain tablets are coated with a film coating premix in a coating pan and dried to obtain melogabalin besylate tablets. Furthermore, in step S1, the mixing speed is 10-20 rpm and the mixing time is 10-30 min. Furthermore, in step S3, the weight of the plain tablet is 100-200 mg, and the hardness is ≥50N. Furthermore, the film coating premix in step S4 is obtained by mixing the coating ingredients. Furthermore, in step S5, the weight of the plain tablet increases by 3-5% after coating. Furthermore, in step S5, the drying temperature is 60-75° C. and the drying time is 20-40 min. Furthermore, the drying temperature is 60-70° C. and the drying time is 20-30 min. Beneficial effects: The presence of moisture can cause the stability of melogabalin besylate tablets to decrease, while the melogabalin besylate tablets prepared by the present invention use a specific coating composition, which can effectively isolate the moisture in the external environment; adopt specific coating parameters to remove moisture in the tablets, so that the tablets can be stably stored without the need for desiccant and composite aluminum bags for drug packaging, which greatly improves the stability of the tablets, simplifies the complexity of equipment required for production, and greatly saves production costs. DETAILED DESCRIPTION The present invention will be further described below in conjunction with embodiments, which are explanations of the present invention and are not limited to the following embodiments: The reference preparation is licensed by Daiichi Sankyo Co., Ltd. of Japan, with batch number YBA2280. Examples 1-6 The formulations of Examples 1-6 are shown in Table 1: Table 1 Examples 1-6 were prepared according to the following preparation method: S1. Mixing the ingredients of the plain tablets: According to the formula in Table 1, melogabalin besylate, mannitol 150SD, carboxymethylcellulose calcium, magnesium aluminum metasilicate, microcrystalline cellulose, maleic acid, and vitamin C were added to the mixer hopper and mixed, and the mixer speed was set to 15 rpm and mixed for 30 min to obtain a mixture; S2. Lubrication: adding magnesium stearate to the mixture and mixing to obtain a mixture; S3 tableting: the mixture is tableted to form a plain tablet, the tablet weight is controlled to be 200 mg, and the hardness is not less than 70N; S4. Coating: Slowly add the film coating premix into purified water under stirring, stir thoroughly for 45 minutes to make it evenly dispersed and then start coating; the coating ingredients are: 30wt.% talcum powder, 4wt.% sodium lauryl sulfate, 30wt.% mono- and di-octanoic acid glyceryl esters, 2wt.% titanium dioxide and 30wt.% polyvinyl alcohol, 2wt.% yellow iron oxide, 2wt.% red iron oxide; set the coating parameters, start the coating pot and the peristaltic pump; stop spraying when the weight of the plain tablet increases by 5%; dry for 30 minutes at a tablet bed temperature of 70°C, take out the coated tablets, and obtain melogabalin besylate tablets. Dissolution testing: Dissolution refers to the speed and degree of dissolution of a drug from a solid preparation such as a tablet in a specified solvent, and is an important indicator for tablet quality control. 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 dissolution curves of Examples 1-6 and the reference preparation in a medium pH 1.2 hydrochloric acid solution were measured. The results are shown in Table 2 below. Table 2 As shown in Table 2, the melogabalin besylate tablets prepared in Examples 1-6 of the present invention and the reference preparation all dissolve rapidly, and the dissolution curves have good consistency. The plain tablet ingredient formulas of Comparative Examples 1-6 correspond to the plain tablet ingredient formulas of Examples 1-6, respectively, and only the coating composition is changed. The tablets are prepared according to the following preparation method: S1. Mixing the ingredients of the plain tablets: According to the formula in Table 1, melogabalin besylate, mannitol 150SD, carboxymethylcellulose calcium, magnesium aluminum metasilicate, microcrystalline cellulose, maleic acid, and vitamin C were added to the mixer hopper and mixed, and the mixer speed was set to 15 rpm and mixed for 30 min to obtain a mixture; S2. Lubrication: adding magnesium stearate to the mixture and mixing to obtain a mixture; S3 tableting: the mixture is tableted to form a plain tablet, the tablet weight is controlled to be 200 mg, and the hardness is not less than 70N; S4. Coating: Slowly add the film coating premix into purified water under stirring, stir thoroughly for 45 minutes to make it evenly dispersed and then start coating; the coating ingredients are: 60wt.% hydroxypropyl methylcellulose, 34wt.% talc, 2wt.% titanium dioxide, 2wt.% yellow iron oxide and 2wt.% red iron oxide; set the coating parameters, start the coating pot and peristaltic pump; stop spraying when the weight of the plain tablet increases by 5%; dry for 30 minutes at a tablet bed temperature of 70°C, take out the coated tablets, and obtain melogabalin besylate tablets. Comparative Example 7 The difference between this comparative example and Example 2 is that the coating parameters are changed, that is, the drying temperature and time are changed, as follows: S1. Mixing the ingredients of the plain tablets: According to the formula of Example 2 in Table 1, melogabalin besylate, mannitol 150SD, carboxymethylcellulose calcium, magnesium aluminum metasilicate, microcrystalline cellulose, maleic acid, and vitamin C were added to the mixer hopper and mixed, and the mixer speed was set to 15 rpm and mixed for 30 min to obtain a mixture; S2. Lubrication: adding magnesium stearate to the mixture and mixing to obtain a mixture; S3 tableting: the mixture is tableted to form a plain tablet, the tablet weight is controlled to be 200 mg, and the hardness is not less than 70N; S4. Coating: Slowly add the film coating premix into purified water under stirring, stir thoroughly for 45 minutes to make it evenly dispersed and then start coating; the coating ingredients are: 30wt.% talc, 4wt.% sodium lauryl sulfate, 30wt.% caprylic and dicaprylic glyceryl, 2wt.% titanium dioxide and 30wt.% polyvinyl alcohol, 2wt.% yellow iron oxide, 2wt.% red iron oxide; set the coating parameters, start the coating pot and peristaltic pump; stop spraying when the weight of the plain tablet increases by 5%; dry for 5 minutes when the tablet bed temperature is 45°C, take out the coated tablets, and obtain melogabalin besylate tablets. Comparative Example 8 The difference between this comparative example and Example 2 is that the mono- and di-octanoic acid caprylic acid glyceryl in the coating composition is replaced with hydroxypropyl methylcellulose, as follows: S1. Mixing: According to the formulation of Example 2 in Table 1, melogabalin besylate, mannitol 150SD, carboxymethylcellulose calcium, magnesium aluminum metasilicate, microcrystalline cellulose, maleic acid, and vitamin C were added to the mixer hopper and mixed, and the mixer speed was set to 15 rpm and mixed for 30 min to obtain a mixture; S2. Lubrication: adding magnesium stearate to the mixture and mixing to obtain a mixture; S3 tableting: the mixture is tableted to form a plain tablet, the tablet weight is controlled to be 200 mg, and the hardness is not less than 70N; S4. Coating: Slowly add the film coating premix into purified water under stirring, stir thoroughly for 45 minutes to make it evenly dispersed and then start coating; the coating ingredients are: 30wt.% talcum powder, 4wt.% sodium lauryl sulfate, 30wt.% hydroxypropyl methylcellulose, 2wt.% titanium dioxide and 30wt.% polyvinyl alcohol, 2wt.% yellow iron oxide, 2wt.% red iron oxide; set the coating parameters, start the coating pot and peristaltic pump; stop spraying when the weight of the plain tablet increases by 5%; dry for 30 minutes at a tablet bed temperature of 70°C, take out the coated tablets, and obtain melogabalin besylate tablets. Comparative Example 9 The difference between this comparative example and Example 2 is that the ratio of the coating composition is changed, as follows: S1. Mixing: According to the formulation of Example 2 in Table 1, melogabalin besylate, mannitol 150SD, carboxymethylcellulose calcium, magnesium aluminum metasilicate, microcrystalline cellulose, maleic acid, and vitamin C were added to the mixer hopper and mixed, and the mixer speed was set to 15 rpm and mixed for 30 min to obtain a mixture; S2. Lubrication: adding magnesium stearate to the mixture and mixing to obtain a mixture; S3 tableting: the mixture is tableted to form a plain tablet, the tablet weight is controlled to be 200 mg, and the hardness is not less than 70N; S4. Coating: Slowly add the film coating premix into purified water under stirring, stir thoroughly for 45 minutes to make it evenly dispersed and then start coating; the coating ingredients are: 40wt.% talc, 4wt.% sodium lauryl sulfate, 10wt.% caprylic and dicaprylic glyceryl, 2wt.% titanium dioxide and 40wt.% polyvinyl alcohol, 2wt.% yellow iron oxide, 2wt.% red iron oxide; set the coating parameters, start the coating pot and peristaltic pump; stop spraying when the weight of the plain tablet increases by 5%; dry for 30 minutes at a tablet bed temperature of 70°C, take out the coated tablets, and obtain melogabalin besylate tablets. The packaging forms are: bare wafers (denoted as packaging A); aluminum-plastic blister packaging (denoted as packaging B); aluminum-plastic blister + desiccant + composite aluminum bag packaging for drug packaging (denoted as packaging C); the reference preparation commercially available drug adopts packaging C form. Detection method for related substances: Determined according to high performance liquid chromatography (General Chapter 0512 of the Chinese Pharmacopoeia 2020 Edition). 1. Solution preparation (1) 0.01 mol / L diammonium hydrogen phosphate buffer (pH 6.5): Dissolve 1.32 g of diammonium hydrogen phosphate in 1000 mL of water and adjust the pH to 6.5 with phosphoric acid. (2) Solvent: 0.01 mol / L diammonium hydrogen phosphate buffer (pH 6.5)-acetonitrile (9:1); (3) Impurity stock solution Melogabalin impurity 35 stock solution: accurately weigh 354 mg of Melogabalin impurity, place in a 20 mL volumetric flask, add appropriate amount of diluent to dissolve and dilute to the scale line; Melogabalin impurity 36 stock solution: 364 mg of precision Melogabalin impurity, placed in a 20 mL volumetric flask, add appropriate amount of diluent to dissolve and dilute to the scale line; Melugabalin lactam stock solution: 2 mg of precision melogabalin lactam is placed in a 20 mL volumetric flask, and an appropriate amount of diluent is added to dissolve and dilute to the mark; (4) Test solution: Take 4 tablets of this product and place them in a centrifuge tube (2.5 mg or 5 mg), add 10 mL of solvent (2.5 mg) or 20 mL of solvent (5 mg), let stand for 20 min, disintegrate, shake well, filter with a filter membrane (HPF MILLEX, Hydrophilic PTFE, 0.45 μm, or a filter membrane with equivalent performance), discard 2 mL of the initial filtrate, and take the subsequent filtrate; (5) Control solution: Accurately measure 1 mL of the test solution and place it in a 100 mL volumetric flask, dilute to the mark with solvent, and shake well; (6) System suitability solution: Accurately weigh 16.77 mg of melogabalin besylate and place it in a 10 mL volumetric flask, add an appropriate amount of diluent to dissolve it, add 0.1 mL of melogabalin impurity 35 stock solution, 0.1 mL of melogabalin impurity 36 stock solution, and 0.2 mL of melogabalin lactam stock solution, and dilute to the mark with diluent. 2. Chromatographic conditions Octadecylsilane bonded silica gel was used as filler (SunShell C18, 2.1 mm × 100 mm, 2.6 μm or equivalent chromatographic column); 0.01 mol / L diammonium phosphate buffer (pH 6.5) was used as mobile phase A, methanol-acetonitrile-0.01 mol / L diammonium phosphate buffer (pH 6.5) (9:3:4) was used as mobile phase B, and gradient elution was performed according to Table 3 below; the detection wavelength was 215 nm; the flow rate was 0.5 mL per minute; the column temperature was 45°C; and the injection volume was 10 μL. Table 3 Time (min) Mobile phase A (%) Mobile phase B (%) 0 97 3 1.5 97 3 27 32 68 27.1 5 95 31 5 95 32 97 3 37 97 3 3. Content and stability test of related substances Examples 1-6, Comparative Examples 1-9 and the reference preparation were placed at 40°C and 75% RH for 0 days and 30 days, and the contents of related substances and the stability of the samples were measured. The results are shown in Table 4 below. Table 4 As can be seen from Table 4, Comparative Examples 1-6 correspond to the formulations of Examples 1-6, respectively, and only the coating composition is changed to prepare melogabalin besylate tablets. In the packaging A form, the total impurity content of the examples is much lower than the total impurity content of the comparative examples; in the packaging B form, the total impurity content of the examples is lower than the total impurity content of the comparative examples, and is equivalent to the total impurity content of the comparative examples in the packaging C form; in the packaging C form, there is no obvious difference between the total impurity content of the examples and the total impurity content of the comparative examples; in addition, the total impurity content of Examples 1-6 is also significantly lower than the total impurity content of the reference preparation. Comparative Example 7 is a melogabalin besylate tablet prepared by changing only the coating parameters relative to Example 2. It can be seen that under the three packaging forms, the total impurity content of Example 2 is also significantly lower than the total impurity content of Comparative Example 7. In Comparative Example 8, compared with Example 2, the mono- and di-octanoin glyceryl caprate in the coating composition is replaced with hydroxypropyl methylcellulose. In the packaging forms A and B, the total impurity content is significantly increased; in the packaging form C, there is no significant difference between the total impurity content of Example 2 and the total impurity content of Comparative Example 8. It can be seen that the coating powder containing mono- and di-octanoin glyceryl caprate is more conducive to reducing the total impurity content than the coating powder containing hydroxypropyl methylcellulose. Comparative Example 9 changes the proportion of coating composition relative to Example 2. In the packaging forms A and B, the total impurity content increases significantly. In the packaging form C, there is no significant difference between the total impurity content of Example 2 and the total impurity content of Comparative Example 9. The above-mentioned changes in coating composition, coating composition ratio, and coating parameters all lead to an increase in the total impurity content. The presence of moisture will also cause the stability of melogabalin besylate tablets to decrease. Therefore, specific coating parameters are used to remove moisture from the tablets; specific coating compositions are used to effectively isolate moisture from the external environment, thereby improving the stability of the tablets. In summary, by changing the coating composition and coating parameters, the total impurity content in melogabalin besylate tablets can be reduced and the stability of melogabalin besylate tablets can be improved. The above is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any technician familiar with the art can make many possible changes and modifications to the technical solution of the present invention by using the above disclosed methods and technical contents without departing from the spirit and technical solution of the present invention, or modify it into an equivalent embodiment of equivalent changes. Therefore, any simple modification, equivalent replacement, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still falls within the scope of protection of the technical solution of the present invention.

Claims

1. A melogabalin besylate tablet, characterized in that: The melogabalin besylate tablets include plain tablets and coatings: the plain tablets contain, by mass percentage, 4.39% melogabalin besylate, 75-85% mannitol 150SD, 3-10% disintegrant, 0.5-3% lubricant, 0.1-0.5% adsorbent, 1-10% filler, 0.5-3% antioxidant A and 0.1-3% antioxidant B; the coating contains, by mass percentage, 30-45% talc, 2-10% sodium lauryl sulfate, 30-45% mono- and di-octanoic acid glyceryl esters, 2-10% titanium dioxide, 30-45% polyvinyl alcohol, 0.5-2% yellow iron oxide and 0.5-2% red iron oxide.

2. A melogabalin besylate tablet according to claim 1, characterized in that: The disintegrant is one of carboxymethylcellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone; the lubricant is one of magnesium stearate, sodium stearyl fumarate, and talc; the adsorbent is one of magnesium aluminum metasilicate, calcium silicate, aluminum silicate, and magnesium silicate; the filler is one of microcrystalline cellulose, lactose, and starch; the antioxidant A is one of maleic acid, tartaric acid, and fumaric acid; the antioxidant B is one of vitamin C, L-cysteine, sodium pyrosulfite, ascorbyl palmitate, and butylated hydroxyanisole.

3. The melogabalin besylate tablet according to claim 1, characterized in that: The coating ingredients are, by mass percentage, 30-40% talc, 4-10% sodium lauryl sulfate, 30-40% caprylic and dicaprylic glyceryl, 2-5% titanium dioxide, 30-40% polyvinyl alcohol, 1-2% yellow iron oxide and 1-2% red iron oxide.

4. A method for preparing melogabalin besylate tablets according to any one of claims 1 to 3, characterized in that: The following steps are involved: S1. Tablet ingredients are mixed: melogabalin besylate, mannitol 150SD, a disintegrant, an adsorbent, a filler, an antioxidant A and an antioxidant B are added to a mixer hopper to obtain a mixture; S2. Lubrication: adding a lubricant to the mixture, mixing, and obtaining a mixture; S3. Tableting: Tableting the mixture to make plain tablets; S4. Coating: Coat the plain tablets with a film coating premix in a coating pan and dry to obtain melogabalin besylate tablets.

5. A method for preparing melogabalin besylate tablets according to claim 4, characterized in that: In step S1, the mixing speed is 10-20 rpm and the mixing time is 10-30 min.

6. A method for preparing melogabalin besylate tablets according to claim 4, characterized in that: In step S3, the weight of the plain tablet is 100-200 mg, and the hardness is ≥50N.

7. The method for preparing melogabalin besylate tablets according to claim 4, characterized in that: The film coating premix in step S4 is obtained by mixing the coating ingredients.

8. The method for preparing melogabalin besylate tablets according to claim 4, characterized in that: After coating in step S4, the weight of the plain tablet increases by 3-5%.

9. The method for preparing melogabalin besylate tablets according to claim 4, characterized in that: In step S4, the drying temperature is 60-75° C. and the drying time is 20-40 min.

10. The method for preparing melogabalin besylate tablets according to claim 9, characterized in that: The drying temperature is 60-70° C. and the drying time is 20-30 minutes.

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