A meloxicam benzenesulfonate tablet and a preparation method thereof

Abstract

The application discloses a meloxicam benzene sulfonic acid tablet and a preparation method thereof, and relates to the technical field of medicines.A meloxicam benzene sulfonic acid tablet comprises meloxicam benzene sulfonic acid, 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 application optimizes a preparation process, prepares a uniform and stable solid dispersion by means of a hot melt extrusion process, and ensures that active materials are uniformly mixed with antioxidants; the application screens an antioxidant composition of tartaric acid and squalene, and significantly improves the stability of antioxidants in a long-term storage process.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a melogabalin besylate tablet and its preparation method. Background Technology

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

[0003] Merogabalin has a similar mechanism of action to drugs such as gabapentin and pregabalin. It works by binding to the α2δ subunit of potential-dependent calcium channels 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 effect of melogabalin is also related to the activation of the norepinephrine pathway by the descending pain-inhibiting system. It is believed to modulate the excitability of neurons in the spinal cord and brain associated with pain processing, thereby relieving pain. Furthermore, it can exert peripheral analgesic effects by inhibiting peripheral nerve sensitization and reducing the release of pro-inflammatory molecules.

[0005] Chinese patent CN117618375A discloses a method for preparing melogabalin benzyl sulfonate tablets. Malic acid is used as an antioxidant; however, the weak antioxidant capacity of malic acid can lead to a decrease in product stability during long-term storage.

[0006] Chinese patent CN107405322B discloses a solid formulation containing antioxidants. It lists several antioxidants, but all of them are relatively expensive, and the different forms of antioxidants can lead to uneven preparation.

[0007] The main problems with 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 those skilled in the art urgently need to solve.

[0008] The information disclosed in this background section is intended only to enhance the understanding of the overall background of the invention and should not be construed as an admission or in any way implying that the information constitutes prior art known to those skilled in the art. Summary of the Invention

[0009] To address the aforementioned technical problems, this invention provides a melogabalin benzyl sulfonate tablet and its preparation method, thereby resolving the issues raised in the background section.

[0010] The design principle of tartaric acid combined with squalene as an antioxidant in melogabalin benzyl benzyl acid tablets is as follows:

[0011] Tartaric acid, used as a chelating agent, and squalene, commonly used as a solvent, are combined with melogabalin benzyl sulfonate raw material using a hot melt extrusion process to increase its stability. This utilizes the acid-base interaction between the materials: melogabalin benzyl sulfonate 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.

[0012] This interaction can alter the physicochemical properties of a drug, such as increasing its solubility and dispersibility in the system, while also helping to improve its stability and prevent degradation or crystallization during storage.

[0013] Hydrogen bonding: Hydrogen bonds may form between the hydroxyl and carboxyl groups in tartaric acid, the amino groups in melogabalin benzenesulfonic acid, and some polar groups in squalene. The formation of hydrogen bonds helps to enhance the binding force between the three components, allowing them to be more evenly distributed in the system. It also affects the structure and properties of the resulting solid dispersion, thus improving product quality and stability.

[0014] Plasticizing and lubricating effects: Squalene, acting as a plasticizer and lubricant, can intercalate into the molecular network formed by melogabalin benzenesulfonic acid and tartaric acid, increasing the flexibility and flowability of the molecular chains and lowering the glass transition temperature and melt viscosity of the system. This makes the mixture easier to deform and flow during extrusion, which is beneficial for extrusion molding. At the same time, it reduces friction between the material and the equipment, lowers extrusion pressure, and improves production efficiency and product quality.

[0015] Through thermal action, shear force, and the interaction between the components, melogabalin benzyl sulfonate, tartaric acid, and squalene form a uniform and stable solid dispersion during hot melt extrusion, thereby improving the drug's solubility, stability, and bioavailability.

[0016] II. A melogabalin besylate tablet comprising a composition of melogabalin besylate, a filler, a disintegrant, a stabilizer, a lubricant, and an antioxidant; the antioxidant composition comprising tartaric acid and squalene.

[0017] Preferably, the mass ratio of tartaric acid to squalene is 2:1.

[0018] Preferably, by weight parts, it comprises: 1-10 parts of melogabalin benzenesulfonate, 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.

[0019] Preferably, the filler is selected from one or more of microcrystalline cellulose, lactose, starch, mannitol, pregelatinized starch, dextrin, powdered sugar, and inorganic salts;

[0020] The disintegrant is selected from one or more of the following: low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, calcium carboxymethyl cellulose, carboxymethyl cellulose, croscarmellose sodium, croscarmellose, dry starch, and effervescent disintegrant;

[0021] The stabilizer is selected from one or more of the following: anhydrous citric acid, sodium citrate, magnesium aluminum metasilicate, sorbic acid, and sodium vitamin C.

[0022] The lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, glyceryl monostearate, and glyceryl distearate.

[0023] A method for preparing merogabarine benzylsulfonate tablets as described in claim 1, comprising the following steps:

[0024] Merogabalin benzenesulfonic acid raw material is uniformly mixed with an antioxidant composition and then placed in a hot melt extruder for hot melt extrusion; after the extruded material is cooled, it is crushed and sieved to obtain intermediate particles.

[0025] The intermediate particles, disintegrant, and stabilizer are placed in a mixer and mixed evenly to obtain the first intermediate material;

[0026] The filler is added to the first intermediate material and the mixture is continued to obtain the second intermediate material;

[0027] The lubricant was added to the second intermediate material and mixed further to obtain the third intermediate material;

[0028] The third intermediate material is placed in the hopper of a tablet press and compressed to obtain melogabalin benzylsulfonate tablets, with the hardness controlled between 60-140N.

[0029] Merogabalin besylate tablets were coated to obtain merogabalin besylate tablets.

[0030] Preferably, the operating parameters of the hot melt extruder include: heating temperature gradually increasing from 40°C to 200°C to melt the material; and rotation speed of 40-80 rpm.

[0031] Preferably, the mixer operates at a speed of 10-18 rpm; and each operation lasts 10-30 minutes.

[0032] The preferred coating powder is Opadry.

[0033] The merogabaline benzyl sulfonate tablets and their preparation method provided by the present invention have the following beneficial effects: The present invention optimizes the formulation process and prepares a uniform and stable solid dispersion by means of hot melt extrusion process, ensuring that the active raw materials and antioxidants are mixed evenly; The present invention screens antioxidant compositions of tartaric acid and squalene, which significantly improves the stability of antioxidants during long-term storage. Detailed Implementation

[0034] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0035] To address the aforementioned technical problems, this invention provides a melogabalin benzyl sulfonate tablet and its preparation method, thereby resolving the issues raised in the background section.

[0036] Example 1: Specific preparation method of melogabalin besylate tablets

[0037] 1. Preparation of intermediates

[0038] (1) Mix the benzenesulfonic acid melogabalin raw material with the antioxidant and place it in a hot melt extruder. Set the heating temperature of the hot melt extruder to gradually increase from 40°C to 200°C to melt the material. Set the rotation speed to 40-80 rpm.

[0039] (2) After the material is cooled after extrusion, it is crushed by a pulverizer and passed through a No. 5 sieve.

[0040] 2. Sample preparation

[0041] (1) Weigh the prescribed amount of intermediate particles, disintegrant, and stabilizer and place them in a mixer. Mix at 10-18 rpm for 10-30 min.

[0042] (2) Add the prescribed amount of filler and continue mixing with the above parameters for 10-30 minutes.

[0043] (3) Weigh the prescribed amount of lubricant and continue mixing with the above parameters for 10-30 minutes.

[0044] (4) Place the above-mentioned mixed material into the hopper of the tablet press and set appropriate tableting speed, tablet thickness, hardness and other parameters to press the tablet, and control the hardness to 60-140N.

[0045] 3. Coating

[0046] Slowly add the Opadry to the beaker and stir thoroughly for 45 minutes to ensure even dispersion before starting the coating process. Set the coating parameters and start the coating tank and peristaltic pump. Stop spraying when the predetermined coating weight gain is achieved. Dry for approximately 5 minutes and remove the coated tablets. The uncoated tablets will gain 2-5% in weight.

[0047] Example 2: First Drug Grouping

[0048] Weigh out the raw materials of melogabalin besylate tablets by mass fraction, as shown in Table 1-3; prepare melogabalin besylate tablets according to the specific preparation method of melogabalin besylate tablets in Example 1 and Table 1-3.

[0049] In order to screen suitable antioxidants, Table 1-3 provides 15 different groups of antioxidant candidates.

[0050]

[0051]

[0052]

[0053] Example 3, Performance Testing: First Antioxidant Screening

[0054] The stability and content uniformity of the melogabalin benzyl sulfonate tablets prepared in Example 2 were investigated. The numbers in the table below represent the total content of the relevant substances; the specific results are detailed in Tables 4-5.

[0055]

[0056]

[0057] Results Analysis: According to the screening results in Table 4-5 above, tartaric acid showed better antioxidant effects compared to other antioxidant candidates. However, its stability still differed from that of the reference formulation (DL-α-tocopherol). Therefore, based on the above experimental results, tartaric acid was proposed as the first antioxidant to continue screening for a second antioxidant, and the difference in its common antioxidant effect compared to the reference formulation was examined.

[0058] Example 4: Second Drug Grouping

[0059] Weigh out the raw materials for melogabalin besylate tablets by mass fraction, as shown in Table 6; prepare melogabalin besylate tablets according to the specific preparation method of melogabalin besylate tablets in Example 1 and Table 6.

[0060] In order to screen for suitable secondary antioxidants, Table 6 lists 7 different candidate substances for secondary antioxidants.

[0061]

[0062] Example 5, Performance Testing: Second Antioxidant Screening

[0063] The stability and content uniformity of the melogabalin benzyl sulfonate tablets prepared in Example 4 were investigated. The numbers in the table below represent the total content of the relevant substances; the specific results are detailed in Tables 7-8.

[0064]

[0065] Results Analysis: Based on the screening results in Tables 7-8 above, and according to the sample stability results, when tartaric acid and squalene are used together as antioxidants, and the total amount of tartaric acid and squalene is the same as the amount of DL-α-tocopherol, the antioxidant performance of the combination of tartaric acid and squalene is significantly better than that of DL-α-tocopherol. The combination of tartaric acid and squalene as antioxidants has a synergistic effect, which significantly improves the stability of the product, and its stability is better than that of the reference formulation.

[0066] Based on the above results of sample content uniformity, when tartaric acid and squalene are used together as antioxidants, the content uniformity is good and meets the requirements.

[0067] Prescription process evaluation

[0068] In the samples prepared above, the hot melt extrusion process can optimize the uniformity of product content while also ensuring good product stability.

[0069] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A melogabalin besylate tablet, characterized in that, It includes a composition of melogabalin benzyl sulfonate, fillers, disintegrants, stabilizers, lubricants, and antioxidants; the antioxidant composition includes tartaric acid and squalene; By weight, it includes: 1-10 parts melogabalin benzenesulfonate, 50-90 parts filler, 7-15 parts disintegrant, 0.1-5 parts stabilizer, 0.1-3 parts lubricant, and 0.1-6 parts antioxidant composition; The fillers are mannitol and microcrystalline cellulose; the disintegrant is calcium carboxymethyl cellulose; the stabilizers are magnesium aluminum metasilicate and anhydrous citric acid; and the lubricant is magnesium stearate. The mass ratio of tartaric acid, squalene, magnesium aluminum metasilicate, and anhydrous citric acid is 2.5:2.5:0.2:0.

6.

2. A method for preparing melogabalin benzylsulfonate tablets as described in claim 1, characterized in that, Includes the following steps: Merogabalin benzenesulfonic acid raw material is uniformly mixed with an antioxidant composition and then placed in a hot melt extruder for hot melt extrusion; after the extruded material is cooled, it is crushed and sieved to obtain intermediate particles. The intermediate particles, disintegrant, and stabilizer are placed in a mixer and mixed evenly to obtain the first intermediate material; The filler is added to the first intermediate material and the mixture is continued to obtain the second intermediate material; The lubricant was added to the second intermediate material and mixed further to obtain the third intermediate material; The third intermediate material is placed in the hopper of a tablet press and compressed to obtain melogabalin benzyl sulfonate tablets, with the hardness controlled between 60-140N. Merogabalin besylate tablets were coated to obtain melogabalin besylate tablets.

3. The method for preparing melogabalin benzylsulfonate tablets according to claim 2, characterized in that, The operating parameters of the hot melt extruder include: heating temperature gradually increasing from 40℃ to 200℃ to melt the material; and rotation speed of 40-80 rpm.

4. The method for preparing melogabalin benzylsulfonate tablets according to claim 2, characterized in that, The mixer operates at a speed of 10-18 rpm; each operation lasts 10-30 minutes.

5. The method for preparing melogabalin benzylsulfonate tablets according to claim 2, characterized in that, Coating powder is from Oppadai.

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