Melogabalin besylate tablet and preparation method thereof

Abstract

The invention discloses melogabalin besylate tablets and a preparation method thereof, and relates to the technical field of medicines. The melogabalin besylate tablet is prepared from melogabalin besylate, a filling agent, a disintegrating agent, a stabilizing agent, a lubricating agent and an antioxidant composition, the antioxidant composition comprises tartaric acid and squalene. The preparation process is optimized, a uniform and stable solid dispersion is prepared by means of a hot melt extrusion process, and it is guaranteed that active raw materials and the antioxidant are uniformly mixed; the antioxidant composition with compatibility of tartaric acid and squalene is screened, and the stability of the antioxidant in the long-term storage process is remarkably improved.

Description

Technical Field

[0001] The present invention relates to the technical field of medicine, and in particular to a melogabalin besylate tablet and a preparation method thereof. Background Art

[0002] Melogabalin is a novel, selective, oral α2δ ligand currently used clinically to treat diabetic peripheral neuropathic pain (DPNP), postherpetic neuralgia (PHN), and central neuropathic pain (CNP) after spinal cord injury.

[0003] Melogabalin has a similar mechanism of action to drugs such as gabapentin and pregabalin. It binds to the potential-dependent calcium channel α2δ and subunits in the nervous system, inhibiting the excessive release of neurotransmitters such as glutamate and norepinephrine, thereby reducing neuronal excitability and inhibiting the transmission of calcium-related pain signals.

[0004] The analgesic effects of melogabalin are also related to the activation of the norepinephrine pathway by the descending pain inhibitory system. It is believed that it can regulate the excitability of neurons related to pain processing in the spinal cord and brain, thereby relieving pain. In addition, it can also exert peripheral analgesic effects by inhibiting peripheral nerve sensitization and reducing the release of proinflammatory molecules.

[0005] Chinese patent CN117618375A discloses a method for preparing melogabalin besylate tablets. Malic acid is used as an antioxidant; however, malic acid's weak antioxidant capacity can lead to decreased product stability during long-term storage.

[0006] Chinese patent CN107405322B discloses a solid preparation containing an antioxidant, which lists a number of antioxidants. However, the costs of these antioxidants are relatively high, and the different forms of antioxidants can lead to uneven preparation.

[0007] The main problems in the above-mentioned patents are: uneven mixing of active raw materials and antioxidants during product preparation, and decreased stability of the antioxidants used during long-term storage. Therefore, how to solve the technical problems existing in the above-mentioned patents is a technical problem that generally skilled in the art urgently needs to solve.

[0008] The information disclosed in this background technology section is only intended to enhance understanding of the overall background of the invention and should not be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art. Summary of the Invention

[0009] In response to the above technical problems, the embodiments of the present invention provide a melogabalin besylate tablet and a preparation method thereof to solve the problems raised in the above background technology.

[0010] 1. The design principle of using tartaric acid and squalene as antioxidants in melogabalin besylate tablets is: Tartaric acid, a chelating agent, and squalene, a commonly used solvent, are used with melogabalin besylate as a raw material using a hot-melt extrusion process to increase their stability and utilize the acid-base interaction between the materials: melogabalin besylate is an alkaline drug and tartaric acid is an acidic substance. The two can undergo an acid-base neutralization reaction to form ion pairs or salts.

[0011] This interaction can change the physical and chemical properties of the drug, such as increasing the solubility and dispersibility of the drug in the system. It also helps to improve the stability of the drug and prevent the drug from degradation or crystallization during storage.

[0012] Hydrogen bonding: Hydrogen bonds can form between the hydroxyl and carboxyl groups in tartaric acid, the amino groups in melogabalin besylate, and certain polar groups in squalene. This hydrogen bonding helps strengthen the binding force between the three components, resulting in a more even distribution within the system. It also influences the structure and properties of the resulting solid dispersion, improving product quality and stability.

[0013] Plasticizing and Lubricating Effects: Squalene, acting as a plasticizer and lubricant, can insert itself into the molecular network formed by melogabalin besylate and tartaric acid, increasing the flexibility and fluidity of the molecular chains and lowering the system's glass transition temperature and melt viscosity. This makes the mixture more easily deformable and fluid during extrusion, facilitating extrusion molding. It also reduces friction between the material and the equipment, lowering extrusion pressure and improving production efficiency and product quality.

[0014] Through the effects of heat, shear force and the interaction between the various components, melogabalin besylate, tartaric acid and squalene form a uniform and stable solid dispersion during the hot melt extrusion process, thereby improving the solubility, stability and bioavailability of the drug.

[0015] 2. A melogabalin besylate tablet comprising melogabalin besylate, a filler, a disintegrant, a stabilizer, a lubricant and an antioxidant composition; the antioxidant composition comprises tartaric acid and squalene.

[0016] Preferably, the mass ratio of tartaric acid to squalene is 2:1.

[0017] Preferably, the composition comprises, by weight: 1-10 parts of melogabalin besylate, 50-90 parts of filler, 7-15 parts of disintegrant, 0.1-5 parts of stabilizer, 0.1-3 parts of lubricant, and 0.1-6 parts of antioxidant composition.

[0018] Preferably, the filler is selected from one or more of microcrystalline cellulose, lactose, starch, mannitol, pregelatinized starch, dextrin, powdered sugar, and inorganic salts; The disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carboxymethyl cellulose calcium, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, dry starch, and effervescent disintegrant; The stabilizer is selected from one or more of anhydrous citric acid, sodium citrate, magnesium aluminum metasilicate, sorbic acid, and sodium ascorbyl palmitate; The lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, glyceryl monostearate, and glyceryl distearate.

[0019] A method for preparing the melogabalin besylate tablets according to claim 1, comprising the following steps: The melogabalin besylate raw material and the antioxidant composition are uniformly mixed and then placed in a hot melt extruder for hot melt extrusion; after the extruded material is cooled, it is crushed and sieved using a crusher to obtain intermediate particles; The intermediate particles, disintegrant, and stabilizer are placed in a mixer and uniformly mixed to obtain a first intermediate material; Adding a filler to the first intermediate material and continuing to mix to obtain a second intermediate material; adding a lubricant to the second intermediate material and continuing to mix to obtain a third intermediate material; The third intermediate material is placed in the hopper of a tablet press and compressed into melogabalin besylate tablets, with the hardness controlled at 60-140N; Melogabalin besylate tablets are coated to obtain Melogabalin besylate tablets.

[0020] Preferably, the working parameters of the hot melt extruder include: heating temperature is gradually increased from 40° C. to 200° C. to melt the material; and the rotation speed is 40-80 rpm.

[0021] Preferably, the operating speed of the mixer is 10-18 rpm; and the mixer operates for 10-30 minutes each time.

[0022] Preferably, the coating powder is Opadry.

[0023] The embodiments of the present invention provide a melogabalin besylate tablet and a preparation method thereof, which have the following beneficial effects: the present invention optimizes the preparation process, prepares a uniform and stable solid dispersion by means of a hot-melt extrusion process, and ensures that the active raw materials are uniformly mixed with the antioxidant; the present invention screens an antioxidant composition of tartaric acid and squalene, and significantly improves the stability of the antioxidant during long-term storage. DETAILED DESCRIPTION

[0024] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without making any creative efforts shall fall within the scope of protection of the present invention.

[0025] In response to the above technical problems, the embodiments of the present invention provide a melogabalin besylate tablet and a preparation method thereof to solve the problems raised in the above background technology.

[0026] Example 1: Specific preparation method of melogabalin besylate tablets 1. Preparation of intermediates (1) Mix the melogabalin besylate raw material with the antioxidant and place it in a hot melt extruder. Set the heating temperature of the hot melt extruder from 40°C to 200°C to melt the material. Set the speed to 40-80 rpm.

[0027] (2) After the extruded material cools down, it is crushed using a crusher and passed through a 5# sieve.

[0028] 2. Sample preparation (1) Weigh the prescribed amount of intermediate granules, disintegrant, and stabilizer and place them in a mixer. Mix at a speed of 10-18 rpm for 10-30 minutes.

[0029] (2) Add the prescribed amount of filler and continue mixing for 10-30 minutes according to the above parameters.

[0030] (3) Weigh the prescribed amount of lubricant and continue mixing with the above parameters for 10-30 minutes.

[0031] (4) Place the mixed material in the hopper of the tablet press and set appropriate parameters such as tablet speed, tablet thickness, and hardness for tableting, controlling the hardness to be between 60-140N.

[0032] 3. Coating Slowly add Opadry to the beaker and stir thoroughly for 45 minutes to ensure uniform dispersion before beginning coating. Set coating parameters and start the coating pan and peristaltic pump. Stop spraying when the coating reaches the desired coating weight gain. Allow to dry for approximately 5 minutes before removing the coated tablets. The weight gain of the uncoated tablets should be 2-5%.

[0033] Example 2: First drug grouping The raw materials of melogabalin besylate tablets were weighed in parts by mass, as shown in Tables 1-3. The raw materials in Tables 1-3 were used to prepare melogabalin besylate tablets according to the specific preparation method of Example 1, melogabalin besylate tablets.

[0034] In order to screen suitable antioxidants, Tables 1-3 provide 15 groups of different antioxidant candidate substances.

[0035]

[0036]

[0037]

[0038] Example 3. Performance Test: First Antioxidant Screening The stability and content uniformity of the melogabalin besylate tablets prepared in Example 2 were tested respectively. The numbers in the following table represent the total content of the relevant substances in %; the specific test results are detailed in Tables 4-5.

[0039]

[0040]

[0041] Result analysis: According to the screening results in Table 4-5 above, it was found that the antioxidant effect of tartaric acid was better than that of other candidate antioxidants, but there was still a difference in stability with the reference preparation (DL-α-tocopherol). Therefore, based on the above test results, tartaric acid was used as the first antioxidant to continue screening the second antioxidant to see the difference in their common antioxidant effect with the reference preparation.

[0042] Example 4: Second drug grouping The raw materials of melogabalin besylate tablets were weighed in parts by mass, as shown in Table 6. The raw materials in Table 6 were used to prepare melogabalin besylate tablets according to the specific preparation method of melogabalin besylate tablets in Example 1.

[0043] In order to screen suitable second antioxidants, Table 6 lists 7 groups of different second antioxidant candidate substances.

[0044]

[0045] Example 5. Performance Test: Second Antioxidant Screening The stability and content uniformity of the melogabalin besylate tablets prepared in Example 4 were tested respectively. The numbers in the following table represent the total content of the relevant substances in %; the specific test results are detailed in Tables 7-8.

[0046]

[0047] Analysis of results: According to the screening results in Tables 7-8 above, it was found that according to the stability results of the above samples, when tartaric acid and squalene were used together as antioxidants, and the total amount of tartaric acid and squalene was the same as the amount of DL-α-tocopherol, the antioxidant performance of tartaric acid and squalene was significantly better than that of DL-α-tocopherol. Tartaric acid and squalene have a synergistic effect as antioxidants, which significantly improves the stability of the product, and its stability is better than that of the reference preparation.

[0048] According to the above sample content uniformity results, when tartaric acid and squalene are used together as antioxidants, the content uniformity is good and meets the requirements.

[0049] Prescription process evaluation In the samples prepared above, the use of hot melt extrusion process can optimize the uniformity of product content while also ensuring good product stability.

[0050] The embodiments described above are merely descriptions of preferred implementations of the present invention and are not intended to limit the scope of the present invention. Without departing from the spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should fall within the scope of protection determined by the claims of the present invention.

Claims

1. A melogabalin besylate tablet, characterized in that: The invention comprises melogabalin besylate, a filler, a disintegrant, a stabilizer, a lubricant and an antioxidant composition; the antioxidant composition comprises tartaric acid and squalene.

2. The melogabalin besylate tablets according to claim 1, characterized in that The mass ratio of tartaric acid to squalene is 2:

1.

3. The melogabalin besylate tablets according to claim 1, characterized in that The invention comprises, by weight, 1-10 parts of melogabalin besylate, 50-90 parts of filler, 7-15 parts of disintegrant, 0.1-5 parts of stabilizer, 0.1-3 parts of lubricant and 0.1-6 parts of antioxidant composition.

4. The melogabalin besylate tablets according to claim 1, characterized in that The filler is selected from one or more of microcrystalline cellulose, lactose, starch, mannitol, pregelatinized starch, dextrin, powdered sugar, and inorganic salts; The disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carboxymethyl cellulose calcium, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, dry starch, and effervescent disintegrant; The stabilizer is selected from one or more of anhydrous citric acid, sodium citrate, magnesium aluminum metasilicate, sorbic acid, and sodium ascorbyl palmitate; The lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, glyceryl monostearate, and glyceryl distearate.

5. A method for preparing melogabalin besylate tablets according to claim 1, characterized in that: The following steps are involved: The melogabalin besylate raw material and the antioxidant composition are uniformly mixed and then placed in a hot melt extruder for hot melt extrusion; after the extruded material is cooled, it is crushed and sieved using a crusher to obtain intermediate particles; The intermediate particles, disintegrant, and stabilizer are placed in a mixer and uniformly mixed to obtain a first intermediate material; Adding a filler to the first intermediate material and continuing to mix to obtain a second intermediate material; adding a lubricant to the second intermediate material and continuing to mix to obtain a third intermediate material; The third intermediate material is placed in the hopper of a tablet press and compressed into melogabalin besylate tablets, with the hardness controlled at 60-140N; Melogabalin besylate tablets are coated to obtain Melogabalin besylate tablets.

6. The method for preparing melogabalin besylate tablets according to claim 5, wherein: The working parameters of the hot melt extruder include: heating temperature is gradually increased from 40°C to 200°C to melt the material; the rotation speed is 40-80rpm.

7. The method for preparing melogabalin besylate tablets according to claim 5, wherein: The operating speed of the mixer is 10-18 rpm; the working time of the mixer is 10-30 minutes each time.

8. The method for preparing melogabalin besylate tablets according to claim 5, wherein: The coating powder is Opadry.

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