A method for preparing meloxicam benzenesulfonate tablets

Abstract

The present application relates to the technical field of medicine preparation, more particularly to a preparation method of meloxicam benzene sulfonic acid tablets. The main drug and stabilizer are crushed and sieved; the antioxidant and filler are sieved and mixed; the main drug, stabilizer, mixture and disintegrating agent are added into a mixing machine for mixing, and the discharge is sieved through a granulator, the sieved material is uniformly mixed to prepare a premix powder; the premix powder and lubricant are uniformly mixed to prepare a total mix powder for testing a semi-finished product; the semi-finished product is placed in a double-discharge high-speed tablet press for tablet pressing to prepare meloxicam benzene sulfonic acid tablet cores; the meloxicam benzene sulfonic acid tablet cores are placed in a high-efficiency coating machine for coating to prepare meloxicam benzene sulfonic acid film-coated tablets; and the film-coated tablets are placed in a packaging machine for packaging to prepare meloxicam benzene sulfonic acid tablets. The intermediate powder prepared from the material composition has good flowability and compression formability, effectively reduces the rate of defective products in the production process, and improves the efficiency and stability of industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and more specifically, to a method for preparing melogabalin besylate tablets. Background Technology

[0002] Merogabalin benzylsulfonic acid molecular formula: C 12 H 19 NO2・C6H6O3S, molecular weight: 367.46, structural formula: .

[0003] Merogabalin besylate tablets (trade name: Tarlige®) are a third-generation calcium channel modulator independently developed by Daiichi Sankyo Co., Ltd. This drug has significant clinical efficacy; Phase III studies showed that pain scores improved within 2 days of administration, and the effect could last for more than 52 weeks. Currently, the original formulation uses a complex stabilizer system of tocopherol and citric acid to inhibit oxidative degradation and intramolecular amidation reactions of merogabalin besylate during long-term storage, controlling the formation of related substances.

[0004] However, even with this stabilizer combination, impurity levels remained high during product storage, posing a potential risk to the safety and efficacy of the drug in clinical use. Therefore, there is an urgent need to screen for a stabilizer system with better compatibility and stronger impurity inhibition capabilities to further improve the formulation stability of merogabarine besylate tablets and ensure the quality controllability of its long-term storage and clinical use. Summary of the Invention

[0005] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, one aspect of the present invention is to provide a method for preparing melogabalin besylate tablets, the specific steps of which are as follows: S1. Crush and sieve the active pharmaceutical ingredient and stabilizer; S2. The antioxidant and filler are sieved through a granulator to obtain a mixture; S3. Add the pulverized and sieved active pharmaceutical ingredient S1, stabilizer, mixture S2, and disintegrant to a mixer and mix. The discharged material is sieved through a granulator and then placed in a mixer to mix evenly to obtain a premixed powder. S4. Place the premixed powder and lubricant obtained in S3 into a mixer and mix them evenly to obtain the total mixed powder. Inspect the semi-finished product. S5. Place the semi-finished product inspected in S4 into a double-discharge high-speed tablet press for tableting to obtain melogabalin benzyl sulfonate tablets; S6. Prepare a 12% coating solution using a gastric-soluble film coating premix. Place the melogabalin besylate tablets from S5 into a high-efficiency coating machine for coating. Control the coating weight gain to 2%–4% to obtain melogabalin besylate film-coated tablets. S7. Place the film-coated tablets from S6 into a packaging machine for packaging to obtain the finished melogabalin benzylsulfonic acid tablets.

[0006] Preferably, the active pharmaceutical ingredient is melogabalin besylate in total mass, the filler is mannitol in total mass and microcrystalline cellulose in total mass, the antioxidant is DL-α-tocopherol in total mass, the disintegrant is croscarmellose sodium in total mass, and the stabilizer is L(+)-tartaric acid in total mass and magnesium aluminum metasilicate in total mass.

[0007] Preferably, the total mass of melogabalin benzenesulfonic acid is 1%–10%, mannitol is 15%–30%, microcrystalline cellulose is 1%–15%, DL-α-tocopherol is 0.01%–0.5%, croscarmellose sodium is 5%–15%, L(+)-tartaric acid is 0.1%–10%, and magnesium aluminum metasilicate is 0.5%–5%.

[0008] Preferably, in S1, the active pharmaceutical ingredient is pulverized through an 80-mesh sieve, and the stabilizer is pulverized through a 100-mesh sieve.

[0009] Preferably, in S2, the granulator uses a 0.7mm screen, sieves three times, and the sieve speed is 1000rpm.

[0010] Preferably, in step S3, the mixer rotates at 8 rpm and mixes for 600 seconds; the discharged material passes through a granulator through a 1.5 mm sieve at 300 rpm, and after sieving, the mixing speed is 8 rpm and the mixing time is 600 seconds.

[0011] Preferably, the lubricant in S4 is magnesium stearate, and the lubricant accounts for 0.5% to 5% of the total mass of melogabalin benzenesulfonate tablets. The mixing speed is 8 rpm and the mixing time is 180 s.

[0012] Preferably, in S5, the standard for tablet compression is 0.200g per tablet, using a Φ8mm shallow concave punch, with the main pressure of the tablet press being 5KN~15KN and the hardness controlled at 70N~100N.

[0013] Preferably, in S6, the main unit speed of the coating machine is 1 rpm to 8 rpm, the air inlet temperature is 50℃ to 90℃, the peristaltic pump speed is 10 rpm to 100 rpm, the atomization pressure is 0.1 MPa to 0.5 MPa, and the weight gain control range is 2% to 4%.

[0014] Preferably, the packaging material in S7 is aluminum-plastic composite board (polyvinyl chloride / polyvinylidene chloride / polyvinyl chloride composite rigid sheet + pharmaceutical aluminum foil, heat-sealed) for packaging, with an outer composite film and an internal desiccant.

[0015] The beneficial effects of this invention are as follows: Excellent intermediate properties: The intermediate powder prepared by the composition of the materials of this invention has good flowability and good compressibility, which effectively reduces the defect rate in the production process and improves the efficiency and stability of industrial production.

[0016] Superior formulation performance: The tablet core prepared by this invention has excellent disintegration performance and good dissolution effect of the coated tablet, which ensures rapid release and absorption of the drug in the body and is conducive to exerting its clinical advantage of rapid onset of action (such as the improvement of pain score in 2 days as shown in clinical practice).

[0017] Significantly improved stability: The use of a more compatible stabilizer system, combined with aluminum-plastic composite blister packs (PVC / PVC / PVC composite rigid sheets + pharmaceutical aluminum foil, heat-sealed), outer composite film, and internal desiccant packaging, can effectively inhibit the oxidative degradation and intramolecular amidation reaction of melogabalin besylate during long-term storage, significantly reduce the formation of related substances, and make the overall stability of the drug better than the existing original formulation, thereby better ensuring the safety and efficacy of clinical use.

[0018] Additional aspects and advantages of the invention will become apparent from the description which follows, or may be learned by practice of the invention. Attached Figure Description

[0019] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which: Figure 1 This is a dissolution curve of Example 1 of the present invention and the reference preparation in a medium of pH 1.2; Figure 2 This is a dissolution curve of Example 1 of the present invention and the reference formulation in a medium at pH 4.5; Figure 3 Dissolution curves of Example 1 and the reference formulation in pH 6.8 medium. Detailed Implementation

[0020] To better understand the above-mentioned objectives, features, and advantages of the present invention, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. It should be noted that, unless otherwise specified, the embodiments and features described in these embodiments can be combined with each other.

[0021] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be implemented in other ways different from those described herein. Therefore, the scope of protection of the invention is not limited to the specific embodiments disclosed below.

[0022] Example 1 Prescription information:

[0023] Preparation method: S1. Pulverize melogabalin benzylsulfonic acid through an 80-mesh sieve and L(+)-tartaric acid through a 100-mesh sieve.

[0024] S2. DL-α-tocopherol and microcrystalline cellulose are sieved three times through a fixed-lift granulator (equipped with a 0.7mm screen) at a speed of 1000rpm; S3. Add mannitol, melogabalin benzenesulfonic acid, croscarmellose sodium, L(+)-tartaric acid, magnesium aluminum metasilicate, DL-α-tocopherol and microcrystalline cellulose mixture into an HFD-3000 clamp-type square cone mixer and mix for 600s at 8 rpm. The material is discharged through a fixed lifting granulator (equipped with a 1.5mm screen) at 300 rpm. The sieved material is then placed in the clamp-type square cone mixer and mixed for 600s at 8 rpm to obtain a premixed powder. S4. Place the obtained premixed powder and magnesium stearate in a clamp-type square cone mixer and mix for 180s at a speed of 8rpm to obtain the total mixed powder. Inspect the semi-finished product. S5. Place the inspected semi-finished product in a GZPTS-75 double-discharge high-speed tablet press and press it into tablets using a Φ8mm shallow concave die. The hardness is controlled at 70N~100N to obtain melogabalin benzylsulfonate tablets. S6. Prepare a 12% coating solution using a gastrointestinal film-coating premix. Place the melogabalin besylate tablets from S5 into the coating solution in a BGB-150FD high-efficiency coating machine for coating. The main unit speed is 1 rpm to 8 rpm, the inlet air temperature is 50℃ to 90℃, the peristaltic pump speed is 10 rpm to 100 rpm, the atomization pressure is 0.1 MPa to 0.5 MPa, and the weight gain control range is 2% to 4%. This will produce melogabalin besylate film-coated tablets. S7. Merogabalin besylate film-coated tablets are placed in a DPS26 high-speed blister packaging machine and packaged using aluminum-plastic composite sheets (PVC / PVC / PVC composite rigid sheets + pharmaceutical aluminum foil, heat-sealed), with an outer composite film and an internal desiccant to obtain the finished merogabalin besylate tablets. (Note: The last sentence appears to be an unrelated fragment and is omitted from the translation.) Dissolution test: The dissolution rate of the sample was determined according to the method for determining the dissolution rate of Merogabalin Besylate Tablets in the 2025 edition of the Chinese Pharmacopoeia. The media were hydrochloric acid at pH 1.2, buffer solution at pH 4.5, and buffer solution at pH 6.8, respectively. The dissolution rate was compared with that of the reference preparation sample Delijing® (batch numbers: YBA2319, YBA2321, YBA2333). The dissolution results are shown in Tables 1 to 3, and the dissolution curves are shown in Tables 1 to 3. Figures 1-3 As shown.

[0025] Table 1. Comparison of dissolution results of Example 1 and the reference formulation in pH 1.2 medium.

[0026] Table 2. Comparison of dissolution results of Example 1 and the reference formulation in pH 4.5 and aqueous media.

[0027] Table 3. Comparison of dissolution results of Example 1 and the reference formulation in pH 6.8 medium.

[0028] Dissolution rate of self-made product and reference preparation Delijing ® The dissolution behavior is completely consistent, and the preparation process of Example 1 is simple, feasible, and easy to realize for large-scale industrial production.

[0029] The stability of the product of this invention was studied: Referring to the Guidelines for Stability Testing of Active Pharmaceutical Ingredients and Pharmaceutical Preparations in General Chapter (9001) of Part IV of the 2020, 5th Edition of the Chinese Pharmacopoeia, a self-made sample (L260301Z) was placed for 6 months under accelerated test (40℃±2℃, RH75%±5%), intermediate test (30℃±2℃, RH65%±5%), and long-term test (25℃±2℃, RH60%±5%) conditions. The trend of related substances changes in the sample was investigated and compared with the data of day 0. The results of related substances under each sampling condition are shown in Table 4.

[0030] The formulation was tableted using a powder direct compression process with mannitol and microcrystalline cellulose as fillers, L(+)-tartaric acid and magnesium aluminum metasilicate as stabilizers, croscarmellose sodium as a disintegrant, DL-α-tocopherol as an antioxidant, and magnesium stearate as a lubricant. A film-coating premix was used as the coating material. The formulation was packaged in aluminum-plastic composite sheets (polyvinyl chloride / polyvinylidene chloride / polyvinyl chloride composite rigid sheets + pharmaceutical aluminum foil, heat-sealed), with an outer composite film and an internal desiccant. The related substances in the self-made product and the reference formulation showed no change compared to 0 months after 6 months of storage under accelerated, intermediate, and long-term conditions.

[0031] Table 4. Results of relevant substances under various layout conditions

[0032] The test results showed that the dissolution behavior of the self-made product and the reference formulation in pH 1.2 hydrochloric acid, pH 4.5 buffer, and pH 6.8 buffer media was similar to that of the reference formulation. After two months of accelerated testing, the self-made product showed better performance than the reference formulation in terms of related substances. This indicates that the formulation, using mannitol and microcrystalline cellulose as fillers, L(+)-tartaric acid and magnesium aluminum metasilicate as stabilizers, croscarmellose sodium as a disintegrant, DL-α-tocopherol as an antioxidant, and magnesium stearate as a lubricant, is tableted using a powder direct compression process, coated with a film-coating premix, packaged in aluminum-plastic composite sheets (PVC / PVC / PVC composite rigid sheets + pharmaceutical aluminum foil, heat-sealed), with an outer composite film and an internal desiccant, has a similar quality to the reference formulation.

[0033] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the invention by those skilled in the art. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the invention should be included within the scope of protection of the invention.

Claims

1. A method for preparing melogabalin besylate tablets, characterized in that: The specific steps of the preparation method are as follows: S1. Crush and sieve the active pharmaceutical ingredient and stabilizer; S2. The antioxidant and filler are sieved through a granulator to obtain a mixture; S3. Add the pulverized and sieved active pharmaceutical ingredient S1, stabilizer, mixture S2, and disintegrant to a mixer and mix. The discharged material is sieved through a granulator and then placed in a mixer to mix evenly to obtain a premixed powder. S4. Place the premixed powder and lubricant obtained in S3 into a mixer and mix them evenly to obtain the total mixed powder. Inspect the semi-finished product. S5. Place the semi-finished product inspected in S4 into a double-discharge high-speed tablet press for tableting to obtain melogabalin benzyl sulfonate tablets; S6. Prepare a 12% coating solution using a gastric-soluble film coating premix. Place the melogabalin besylate tablets from S5 into a high-efficiency coating machine for coating. Control the coating weight gain to 2%–4% to obtain melogabalin besylate film-coated tablets. S7. Place the film-coated tablets from S6 into a packaging machine for packaging to obtain the finished melogabalin benzylsulfonic acid tablets.

2. The method for preparing melogabalin benzylsulfonate tablets according to claim 1, characterized in that: The active pharmaceutical ingredient is melogabalin besylate, accounting for 1% of the total mass; the fillers are mannitol and microcrystalline cellulose, accounting for 1% of the total mass; the antioxidant is DL-α-tocopherol, accounting for 1% of the total mass; the disintegrant is sodium croscarmellose, accounting for 1% of the total mass; and the stabilizers are L(+)-tartaric acid and magnesium aluminum metasilicate, accounting for 1% of the total mass.

3. The method for preparing melogabalin benzylsulfonate tablets according to claim 2, characterized in that: The composition of the ingredients is as follows: melogabalin benzenesulfonic acid (1%–10% by mass), mannitol (15%–30% by mass), microcrystalline cellulose (1%–15% by mass), DL-α-tocopherol (0.01%–0.5% by mass), croscarmellose sodium (5%–15% by mass), L(+)-tartaric acid (0.1%–10% by mass), and magnesium aluminum metasilicate (0.5%–5% by mass).

4. The method for preparing melogabalin benzylsulfonate tablets according to claim 1, characterized in that: In S1, the active pharmaceutical ingredient is pulverized through an 80-mesh sieve, and the stabilizer is pulverized through a 100-mesh sieve.

5. The method for preparing melogabalin benzylsulfonate tablets according to claim 1, characterized in that: The granulator in S2 uses a 0.7mm sieve, sieves three times, and the sieve speed is 1000rpm.

6. The method for preparing melogabalin benzylsulfonate tablets according to claim 1, characterized in that: In S3, the mixer operates at 8 rpm and mixes for 600 seconds; the discharged material passes through a granulator with a 1.5 mm sieve at 300 rpm, and after sieving, it is mixed at 8 rpm for 600 seconds.

7. The method for preparing melogabalin benzylsulfonate tablets according to claim 1, characterized in that: The lubricant in S4 is magnesium stearate, and the lubricant accounts for 0.5% to 5% of the total mass of melogabalin benzenesulfonic acid tablets. The mixing speed is 8 rpm and the mixing time is 180 s.

8. The method for preparing melogabalin benzylsulfonate tablets according to claim 1, characterized in that: The standard for tablet compression in S5 is 0.200g per tablet, using a shallow concave punch with a diameter of 8mm, and the main pressure of the tablet press is 5KN~15KN, with hardness controlled at 70N~100N.

9. The method for preparing melogabalin benzylsulfonate tablets according to claim 1, characterized in that: The S6 coating machine has a main unit speed of 1 rpm to 8 rpm, an air inlet temperature of 50℃ to 90℃, a peristaltic pump speed of 10 rpm to 100 rpm, an atomization pressure of 0.1 MPa to 0.5 MPa, and a weight gain control range of 2% to 4%.

10. The method for preparing melogabalin benzylsulfonate tablets according to claim 1, characterized in that: The packaging material of the S7 is aluminum-plastic composite board, with an outer composite film and a desiccant inside.

Images