A meloxicam benzenesulfonate tablet and a method for preparing the same

Abstract

The present application relates to a kind of meloxicam benzene sulfonic acid tablets and its preparation method, meloxicam benzene sulfonic acid tablet core includes meloxicam benzene sulfonic acid, one or two acid stabilizers, one or two antioxidants, the optimal acid stabilizer and antioxidant combination of the present application is screened, the total content of related substance is effectively controlled, and the stability of product is improved.

Description

Technical Field

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

[0002] Merogabalin is a novel selective oral α2δ ligand that has been approved in Japan for the treatment of 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] Merogabalin besylate tablets were first launched in Japan in 2019 by Daiichi Sankyo Co., Ltd., in tablet form, and subsequently launched in South Korea and China. Each tablet contains the active ingredient: merogabalin – 2.5mg / 5mg / 10mg / 15mg, and inactive ingredients: D-mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tocopherol, citrate hydrate, magnesium aluminum metasilicate, and magnesium stearate. However, the stability of merogabalin besylate tablets is currently poor. Therefore, it is necessary to optimize the composition of the stabilizer to improve the stability and safety of merogabalin besylate tablets.

[0006] Therefore, this invention is proposed. Summary of the Invention

[0007] To address the shortcomings of the prior art, the present invention provides a melogabalin besylate tablet with higher stability and lower content of related substances.

[0008] To solve the above technical problems, the following technical solution is adopted:

[0009] On one hand, the present invention provides a merogabarine besylate tablet, wherein the tablet core contains merogabarine besylate, an acid stabilizer, and an antioxidant, wherein the acid stabilizer and the antioxidant are selected from at least one group of the following:

[0010] (1) The acid stabilizer is tartaric acid and anhydrous citric acid, and the antioxidant is ascorbyl palmitate or tocopherol;

[0011] (2) The acid stabilizer is tartaric acid and citric acid, and the antioxidant is ascorbyl palmitate or tocopherol;

[0012] (3) The acid stabilizer is tartaric acid and malic acid, and the antioxidant is ascorbyl palmitate;

[0013] (4) The acid stabilizer is tartaric acid, and the antioxidant is ascorbyl palmitate and tocopherol;

[0014] (5) The acid stabilizer is tartaric acid, and the antioxidant is ascorbyl palmitate and propyl gallate.

[0015] Preferably, the acid stabilizer accounts for 1-5% of the weight of the core, more preferably 1-4%, and even more preferably 1.5-3.5%.

[0016] Preferably, the antioxidant accounts for 0.01-0.5% of the weight of the tablet core, more preferably 0.01-0.4%, and even more preferably 0.02-0.35%.

[0017] Preferably, when the acid stabilizer is tartaric acid and anhydrous citric acid, tartaric acid and citric acid, or tartaric acid and malic acid, the mass ratio of tartaric acid to anhydrous citric acid, citric acid, or malic acid is 0.1 to 5:1, preferably 0.2 to 3:1.

[0018] Preferably, when the antioxidant is ascorbyl palmitate and tocopherol, the mass ratio of ascorbyl palmitate and tocopherol is 1 to 5:1, more preferably 1 to 3:1, and even more preferably 2:1.

[0019] Preferably, when the antioxidant is ascorbyl palmitate and propyl gallate, the mass ratio of ascorbyl palmitate to propyl gallate is 5-25:1, more preferably 6-20:1, and even more preferably 10-20:1.

[0020] Preferably, the chip core also includes fillers, disintegrants, adsorbents, and lubricants.

[0021] Preferably, the filler is selected from one or more of mannitol, lactose, corn starch, microcrystalline cellulose, anhydrous dicalcium phosphate, and sorbitol, and is more preferably selected from one or two of mannitol and microcrystalline cellulose.

[0022] Preferably, the disintegrant is selected from one or more of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose, preferably from one or two of sodium carboxymethyl starch and calcium carboxymethyl cellulose, and more preferably from calcium carboxymethyl cellulose.

[0023] Preferably, the adsorbent is selected from one or more of magnesium aluminum metasilicate, magnesium aluminum silicate, and silicon dioxide, more preferably from magnesium aluminum metasilicate and magnesium aluminum silicate, and more preferably from magnesium aluminum metasilicate.

[0024] Preferably, the lubricant is selected from one or more of magnesium stearate, sodium stearate fumarate, and talc, with magnesium stearate being the most preferred.

[0025] Preferably, melogabalin benzyl sulfonate accounts for 1-10% of the tablet core weight, more preferably 2.5-7.5%, and more preferably 3-5%; mannitol accounts for 70-85% of the tablet core weight, more preferably 75-85%, and more preferably 78-83%; microcrystalline cellulose accounts for 0.5-5% of the tablet core weight, more preferably 0.5-2%, and more preferably 0.5-1%; calcium carboxymethyl cellulose accounts for 5%-15% of the tablet core weight, more preferably 8-12%, and more preferably 9-11%; magnesium metasilicate aluminosilicate accounts for 0.1-2% of the tablet core weight, more preferably 0.1-1%, and more preferably 0.1-0.5%; and magnesium stearate accounts for 1-3% of the tablet core weight, more preferably 1-2.5%, and more preferably 1-2%.

[0026] Preferably, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid or citric acid or malic acid, and ascorbyl palmitate, wherein the percentage of each component by weight of the tablet core is as follows:

[0027]

[0028]

[0029] Alternatively, the tablet core may contain melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid or citric acid, tocopherol, magnesium aluminum metasilicate, and magnesium stearate, with each component comprising the following percentages by weight of the tablet core:

[0030]

[0031] Alternatively, the tablet core may contain melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, ascorbyl palmitate, tocopherol, magnesium aluminum metasilicate, and magnesium stearate, with each component accounting for the following percentage of the tablet core weight:

[0032]

[0033] Alternatively, the tablet core may contain melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, ascorbyl palmitate, propyl gallate, magnesium aluminum metasilicate, and magnesium stearate, with each component accounting for the following percentage of the tablet core weight:

[0034]

[0035]

[0036] Preferably, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid or citric acid or malic acid, and ascorbyl palmitate, wherein the percentage of each component by weight of the tablet core is as follows:

[0037]

[0038] Alternatively, the tablet core may contain melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid or citric acid, tocopherol, magnesium aluminum metasilicate, and magnesium stearate, with each component comprising the following percentages by weight of the tablet core:

[0039]

[0040] Alternatively, the tablet core may contain melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, ascorbyl palmitate, tocopherol, magnesium aluminum metasilicate, and magnesium stearate, with each component accounting for the following percentage of the tablet core weight:

[0041]

[0042]

[0043] Alternatively, the tablet core may contain melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, ascorbyl palmitate, propyl gallate, magnesium aluminum metasilicate, and magnesium stearate, with each component accounting for the following percentage of the tablet core weight:

[0044]

[0045] Preferably, the melogabalin besylate tablets are available in strengths of 2.5 mg, 5 mg, 10 mg, or 15 mg.

[0046] On one hand, the present invention provides a method for preparing melogabalin besylate tablets according to any one of the above claims, comprising the following steps: mixing melogabalin besylate with one or more pharmaceutically acceptable excipients, compressing, and coating to obtain the melogabalin besylate tablets.

[0047] The effects of the invention

[0048] In the course of diligent and continuous research in the search for solid pharmaceutical formulations with excellent stability from merogabalin besylate formulations, the inventors of this invention have screened out specific acid stabilizers and antioxidants used in combination, especially those containing specific acid stabilizers and antioxidants in specific amounts and / or ratios, which can improve the content of related substances in merogabalin besylate formulations and enhance the stability of the product. Detailed Implementation

[0049] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.

[0050] Through extensive and long-term research, the inventors of this invention have sought alternative stabilizers. Compared to the original formulation, this invention provides a combination of two acid stabilizers and one antioxidant, or a combination of one acid stabilizer and two or more antioxidants. Specifically, it utilizes a combination of tartaric acid, citric acid, or anhydrous citric acid with ascorbate palmitate, or a combination of tartaric acid, citric acid, or anhydrous citric acid with tocopherol. This improves the total impurity content of melogabalin benzyl sulfonate and enhances product stability. Based on this, this invention was completed.

[0051] On one hand, the present invention provides a merogabarine besylate tablet, wherein the tablet core contains merogabarine besylate, an acid stabilizer, and an antioxidant, wherein the acid stabilizer and the antioxidant are selected from at least one group of the following:

[0052] (1) The acid stabilizer is tartaric acid and anhydrous citric acid, and the antioxidant is ascorbyl palmitate or tocopherol;

[0053] (2) The acid stabilizer is tartaric acid and citric acid, and the antioxidant is ascorbyl palmitate or tocopherol;

[0054] (3) The acid stabilizer is tartaric acid and malic acid, and the antioxidant is ascorbyl palmitate;

[0055] (4) The acid stabilizer is tartaric acid, and the antioxidant is ascorbyl palmitate and tocopherol;

[0056] (5) The acid stabilizer is tartaric acid, and the antioxidant is ascorbyl palmitate and propyl gallate.

[0057] In some embodiments, the acid stabilizer accounts for 1 to 5% of the core weight.

[0058] In some embodiments, the acid stabilizer accounts for 1-4% of the core weight.

[0059] In some embodiments, the acid stabilizer accounts for 1.5 to 3.5% of the core weight.

[0060] In some embodiments, the antioxidant accounts for 0.01 to 0.5% of the core weight.

[0061] In some embodiments, the antioxidant accounts for 0.01 to 0.4% of the core weight.

[0062] In some embodiments, the antioxidant accounts for 0.02 to 0.35% of the core weight.

[0063] In some embodiments, when the acid stabilizer is tartaric acid and anhydrous citric acid, tartaric acid and citric acid, or tartaric acid and malic acid, the mass ratio of tartaric acid to anhydrous citric acid, citric acid, or malic acid is individually and independently 0.1 to 5:1, for example 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, etc.

[0064] In some embodiments, when the acid stabilizer is tartaric acid and anhydrous citric acid, tartaric acid and citric acid, or tartaric acid and malic acid, the mass ratio of tartaric acid to anhydrous citric acid, citric acid, or malic acid is 0.2 to 3:1.

[0065] In some embodiments, when the acid stabilizer is tartaric acid and anhydrous citric acid, tartaric acid and citric acid, or tartaric acid and malic acid, the mass ratio of tartaric acid to anhydrous citric acid, citric acid, or malic acid is 0.3 to 3:1.

[0066] In some embodiments, when the antioxidant is ascorbyl palmitate and tocopherol, the mass ratio of ascorbyl palmitate and tocopherol is 1 to 5:1, for example, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, etc.

[0067] In some embodiments, when the antioxidant is ascorbyl palmitate and tocopherol, the mass ratio of ascorbyl palmitate to tocopherol is 1 to 3:1.

[0068] In some embodiments, when the antioxidant is ascorbyl palmitate and tocopherol, the mass ratio of ascorbyl palmitate to tocopherol is 2:1.

[0069] In some embodiments, when the antioxidant is ascorbate palmitate and propyl gallate, the mass ratio of ascorbate palmitate to propyl gallate is 5–25:1, for example 5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1, 10:1, 10.5:1, 11:1, 11.5:1, 12:1, 12.5:1. 13:1, 13.5:1, 14:1, 14.5:1, 15:1, 15.5:1, 16:1, 16.5:1, 17:1, 17.5:1, 18:1, 18.5:1, 19:1, 19.5:1, 20:1, 20.5:1, 21.5:1, 22:1, 22.5:1, 23:1, 23.5:1, 24:1, 24.5:1, 25:1, etc.

[0070] In some embodiments, when the antioxidant is ascorbyl palmitate and propyl gallate, the mass ratio of ascorbyl palmitate to propyl gallate is 6 to 20:1.

[0071] In some embodiments, when the antioxidant is ascorbyl palmitate and propyl gallate, the mass ratio of ascorbyl palmitate to propyl gallate is 10 to 20:1.

[0072] In some implementations, the chip core also includes fillers, disintegrants, adsorbents, and lubricants.

[0073] In some embodiments, the filler is selected from one or more of mannitol, lactose, corn starch, microcrystalline cellulose, anhydrous dicalcium phosphate, and sorbitol.

[0074] In some embodiments, the filler is selected from one or both of mannitol and microcrystalline cellulose.

[0075] In some embodiments, the filler is selected from mannitol and microcrystalline cellulose.

[0076] In some embodiments, the disintegrant is selected from one or more of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.

[0077] In some embodiments, the disintegrant is selected from one or both of sodium carboxymethyl starch and calcium carboxymethyl cellulose.

[0078] In some embodiments, the disintegrant is selected from calcium carboxymethyl cellulose.

[0079] In some embodiments, the adsorbent is selected from one or more of magnesium aluminum metasilicate, magnesium aluminum silicate, and silicon dioxide.

[0080] In some embodiments, the adsorbent is preferably selected from magnesium aluminum metasilicate and magnesium aluminum silicate.

[0081] In some embodiments, the adsorbent is selected from magnesium aluminum metasilicate.

[0082] In some embodiments, the lubricant is selected from one or more of magnesium stearate, sodium stearate fumarate, and talc.

[0083] In some embodiments, the lubricant is selected from magnesium stearate.

[0084] In some embodiments, melogabalin besylate accounts for 1% to 10% of the tablet core weight, for example 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, and 10%.

[0085] In some implementations, melogabalin benzyl sulfonate accounts for 2.5% to 7.5% of the tablet core weight.

[0086] In some implementations, melogabalin benzyl sulfonate accounts for 3 to 5% of the tablet core weight.

[0087] In some embodiments, the mannitol accounts for 70-85% of the tablet core weight, for example 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, and 85%.

[0088] In some embodiments, the mannitol accounts for 75-85% of the tablet core weight.

[0089] In some embodiments, the mannitol accounts for 78-83% of the tablet core weight.

[0090] In some embodiments, the microcrystalline cellulose accounts for 0.5% to 5% of the weight of the core, for example, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, etc.

[0091] In some embodiments, the microcrystalline cellulose accounts for 0.5% to 2% of the core weight.

[0092] In some embodiments, the microcrystalline cellulose accounts for 0.5% to 1% of the core weight.

[0093] In some embodiments, the calcium carboxymethyl cellulose accounts for 5% to 15% of the tablet core weight, such as 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, etc.

[0094] In some embodiments, the calcium carboxymethyl cellulose accounts for 8-12% of the tablet core weight.

[0095] In some embodiments, the calcium carboxymethyl cellulose accounts for 9 to 11% of the tablet core weight.

[0096] In some embodiments, the magnesium aluminosilicate accounts for 0.1% to 2% of the core weight, for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or 2%.

[0097] In some embodiments, the magnesium aluminosilicate accounts for 0.1% to 1% of the core weight.

[0098] In some embodiments, the magnesium aluminosilicate accounts for 0.1% to 0.5% of the core weight.

[0099] In some embodiments, the magnesium stearate accounts for 1 to 3% of the weight of the core.

[0100] In some embodiments, the magnesium stearate accounts for 1 to 2.5% of the core weight, for example 1.2%, 1.4%, 1.6%, 1.8%, 2%, 2.2%, 2.4%, etc.

[0101] In some embodiments, the magnesium stearate accounts for 1 to 2% of the weight of the core.

[0102] In some implementations, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid or citric acid or malic acid, ascorbyl palmitate, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0103]

[0104] In some implementations, the core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid or citric acid, tocopherol, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the core is as follows:

[0105]

[0106]

[0107] In some implementations, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, ascorbyl palmitate, tocopherol, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0108]

[0109] In some implementations, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, ascorbyl palmitate, propyl gallate, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0110]

[0111] In some implementations, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid or citric acid or malic acid, ascorbyl palmitate, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0112]

[0113]

[0114] In some implementations, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid or citric acid or malic acid, ascorbyl palmitate, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0115]

[0116] In some implementations, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid, ascorbyl palmitate, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0117]

[0118] In some implementations, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid, ascorbyl palmitate, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0119]

[0120] In some implementations, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid, ascorbyl palmitate, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0121]

[0122] In some implementations, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid, ascorbyl palmitate, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0123]

[0124] In some implementations, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid, ascorbyl palmitate, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0125]

[0126] In some implementations, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid, ascorbyl palmitate, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0127]

[0128] In some implementations, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid or citric acid, tocopherol, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0129]

[0130] In some implementations, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid or citric acid, tocopherol, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0131]

[0132] In some implementations, the tablet core contains melogabalin benzenesulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, citric acid, tocopherol, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0133]

[0134] In some implementations, the tablet core contains melogabalin benzenesulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, citric acid, tocopherol, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0135]

[0136] In some implementations, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, ascorbyl palmitate, tocopherol, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0137]

[0138] In some implementations, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, ascorbyl palmitate, propyl gallate, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0139]

[0140] In some implementations, the tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, ascorbyl palmitate, propyl gallate, magnesium aluminum metasilicate, and magnesium stearate, wherein the percentage of each component by weight of the tablet core is as follows:

[0141]

[0142]

[0143] In some embodiments, the melogabalin besylate tablets are available in strengths of 2.5 mg, 5 mg, 10 mg, or 15 mg.

[0144] In some embodiments, the melogabalin besylate tablets are in a strength of 5 mg.

[0145] In some embodiments, the melogabalin besylate tablets provided by the present invention further include a coating agent selected from gastric-soluble coatings.

[0146] In some embodiments, the coating weight gain of the coating agent of the present invention is 1-7%; preferably 2-5%; more preferably 2-4%.

[0147] On one hand, the present invention provides a method for preparing melogabalin besylate tablets according to any one of the above claims, comprising the following steps: mixing melogabalin besylate with one or more pharmaceutically acceptable excipients, compressing, and coating to obtain the melogabalin besylate tablets.

[0148] The preparation method of merogabarine besylate tablets described in this application can be carried out according to methods known in the art. Specific preparation methods may include steps such as pulverization, mixing, sieving, granulation, filling, and tableting, with the required steps selected according to actual conditions, as well as the methods or equipment for implementing the specific steps. For example, the pulverization step can be carried out using a mortar and pestle, ball mill, roller mill, impact mill, hammer mill, and / or air jet mill; the mixing step can be carried out using stirring, grinding, and / or sieving; the sieving step can be carried out using a shaking sieve and / or vibrating sieve. Alternatively, see *Pharmaceutics* (6th or 7th edition, People's Medical Publishing House), edited by Cui Fude et al.

[0149] The excipients used in this application can be specific types commonly used in the art. For example, microcrystalline cellulose that can be used includes, but is not limited to, PH101, PH102, PH103, or PH105. For example, hydroxypropyl methylcellulose that can be used includes, but is not limited to, E3, E5, or E6. Those skilled in the art can select specific types as needed, or refer to prior art such as Raymond C. Rowe et al.'s "Handbook of Pharmaceutical Excipients," 6th edition, or Luo Mingsheng et al.'s "Complete Guide to Pharmaceutical Excipients," 2nd edition, for selection.

[0150] In this invention, the weight percentage of the drug tablet core is allowed to have errors, and is usually expressed within ±2% of a given value or range. For example, minobalin besylate accounts for 4.39% of the tablet core weight, and a weight percentage of 4.30% to 4.47% can be regarded as falling within the protection scope of this invention.

[0151] The present invention will be further described below through specific embodiments. Unless otherwise specified, "%" represents a mass percentage. The materials, consumables and equipment, reference preparations and control standards involved in the embodiments and comparative examples are all commercially available.

[0152] Where specific experimental steps or conditions are not specified in the embodiments, they can be performed according to the conventional experimental steps or conditions described in the literature in this field. All materials, consumables, and equipment used are commercially available conventional products, including but not limited to the materials, consumables, and equipment used in the embodiments of this application.

[0153] Example 1

[0154] 1. Preprocessing

[0155] Merogabalin benzyl sulfonate and the acid stabilizer were passed through an 80-mesh sieve.

[0156] 2. Weighing

[0157] Weigh out the following ingredients according to the prescription: mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, acid stabilizer, antioxidant, magnesium aluminum metasilicate, magnesium stearate, and melogabalin benzenesulfonate.

[0158] 3. Mixing

[0159] Add approximately half of the mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, acid stabilizer, antioxidant, magnesium aluminum metasilicate, melogabalin benzenesulfonate, and the remaining mannitol sequentially into a universal mixer (if the antioxidant contains tocopherol, the tocopherol must be mixed with the microcrystalline cellulose first before mixing with the other raw materials and excipients), and mix thoroughly; then add magnesium stearate into the universal mixer and mix thoroughly.

[0160] 4. Tableting

[0161] Tableting was performed using a 10.6×5.6mm elliptical shallow arc die, with a target tablet weight of 200mg and a target hardness >4kg.

[0162] 5. Coating

[0163] To prepare a 12% solid content coating solution (using purified water as the solvent): While stirring, slowly and evenly add the prescribed amount of coating powder to a beaker containing purified water, and stir until homogeneous.

[0164] Set the coating parameters, start the coating pan and peristaltic pump, and begin coating. When the predetermined coating weight gain is achieved, stop spraying the solution, dry for 5–10 minutes, and remove the coated tablets. The coating weight gain is 1–7%, yielding the film-coated tablets of Formula 1.

[0165] Coated tablets of Examples 2-18 (Formulas 2-18) were prepared using the preparation method in Example 1 (Formula 1) with the components and their contents shown in Tables 1-3.

[0166] Table 1

[0167]

[0168]

[0169] Table 2

[0170]

[0171] Table 3

[0172]

[0173]

[0174] Example 19

[0175] 1. Preprocessing

[0176] Merogabalin benzyl sulfonate and the acid stabilizer were passed through an 80-mesh sieve.

[0177] 2. Weighing

[0178] Weigh out the following ingredients according to the prescription: mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, acid stabilizer, antioxidant, magnesium aluminum metasilicate, magnesium stearate, and melogabalin benzenesulfonate.

[0179] 3. Mixing

[0180] Add approximately half of the mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, acid stabilizer, antioxidant, magnesium aluminum metasilicate, melogabalin benzenesulfonate, and the remaining mannitol sequentially into a universal mixer (if the antioxidant contains tocopherol, the tocopherol must be mixed with the microcrystalline cellulose first before mixing with the other raw materials and excipients), and mix thoroughly; then add magnesium stearate into the universal mixer and mix thoroughly.

[0181] 4. Tableting

[0182] Tableting was performed using a 10.6×5.6mm elliptical shallow arc die, with a target tablet weight of 200mg and a target hardness >4kg.

[0183] 5. Coating

[0184] To prepare a 12% solid content coating solution (using purified water as the solvent): While stirring, slowly and evenly add the prescribed amount of coating powder to a beaker containing purified water, and stir until homogeneous.

[0185] Set the coating parameters, start the coating tank and peristaltic pump, and begin coating. When the predetermined coating weight gain is achieved, stop spraying the solution, dry for 5–10 minutes, and remove the coated tablets. The coating weight gain is 1–7%, yielding film-coated tablets of Formula 19.

[0186] Coated tablets of Examples 20-30 (Formulas 20-30) were prepared using the preparation method in Example 19 (Formula 19) with the components and their contents shown in Tables 4-5.

[0187] Table 4

[0188]

[0189]

[0190] Table 5

[0191]

[0192] Example 31

[0193] 1. Preprocessing

[0194] Merogabalin benzyl sulfonate and the acid stabilizer were passed through an 80-mesh sieve.

[0195] 2. Weighing

[0196] Weigh out the following ingredients according to the prescription: mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, acid stabilizer, antioxidant, magnesium aluminum metasilicate, magnesium stearate, and melogabalin benzenesulfonate.

[0197] 3. Mixing

[0198] Add approximately half of the mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, acid stabilizer, antioxidant, magnesium aluminum metasilicate, melogabalin benzenesulfonate, and the remaining mannitol sequentially into a universal mixer (if the antioxidant contains tocopherol, the tocopherol must be mixed with the microcrystalline cellulose first before mixing with the other raw materials and excipients), and mix thoroughly; then add magnesium stearate into the universal mixer and mix thoroughly.

[0199] 4. Tableting

[0200] Tableting was performed using a 10.6×5.6mm elliptical shallow arc die, with a target tablet weight of 200mg and a target hardness >4kg.

[0201] 5. Coating

[0202] To prepare a 12% solid content coating solution (using purified water as the solvent): While stirring, slowly and evenly add the prescribed amount of coating powder to a beaker containing purified water, and stir until homogeneous.

[0203] Set the coating parameters, start the coating pan and peristaltic pump, and begin coating. When the predetermined coating weight gain is reached, stop spraying the solution, dry for 5-10 minutes, and remove the coated tablets. The coating weight gain is 1-7%, yielding film-coated tablets of Formula 31.

[0204] Coated tablets of Examples 32-42 (Formulas 32-42) were prepared using the preparation method in Example 31 (Formula 31) with the components and their contents shown in Tables 6-7.

[0205] Table 6

[0206]

[0207] Table 7

[0208]

[0209]

[0210] Comparative Example 1

[0211] 1. Preprocessing

[0212] Merogabalin benzyl sulfonate and the acid stabilizer were passed through an 80-mesh sieve.

[0213] 2. Weighing

[0214] Weigh out the following ingredients according to the prescription: mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, acid stabilizer, antioxidant, magnesium aluminum metasilicate, magnesium stearate, and melogabalin benzenesulfonate.

[0215] 3. Mixing

[0216] Add approximately half of the mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, acid stabilizer, antioxidant, magnesium aluminum metasilicate, melogabalin benzenesulfonate, and the remaining mannitol sequentially into a universal mixer (if the antioxidant contains tocopherol, the tocopherol must be mixed with the microcrystalline cellulose first before mixing with the other raw materials and excipients), and mix thoroughly; then add magnesium stearate into the universal mixer and mix thoroughly.

[0217] 4. Tableting

[0218] Tableting was performed using a 10.6×5.6mm elliptical shallow arc die, with a target tablet weight of 200mg and a target hardness >4kg.

[0219] 5. Coating

[0220] To prepare a 12% solid content coating solution (using purified water as the solvent): While stirring, slowly and evenly add the prescribed amount of coating powder to a beaker containing purified water, and stir until homogeneous.

[0221] Set the coating parameters, start the coating pan and peristaltic pump, and begin coating. When the predetermined coating weight gain is reached, stop spraying, dry for 5-10 minutes, and remove the coated tablets. The coating weight gain is 1-7%, yielding the film-coated tablets of Comparative Formulation 1.

[0222] Using the preparation method in Comparative Example 1 (Comparative Formulation 1), coated tablets of Comparative Example 2 (Comparative Formulation 2) were prepared in addition to the components and their contents shown in Table 8.

[0223] Table 8

[0224]

[0225]

[0226] Stability test

[0227] The film-coated tablets from Examples 1-42 and Comparative Examples 1-2 were placed in bare tablet form at 40°C and 75% RH in the open for 0 days, 10 days, or 1 month, respectively. The stability of these samples was assessed by HPLC to detect the growth of degradation products.

[0228] The results are shown in Table 9, where the data represent the total content of related substances (calculated using the area normalization method). Table 9 shows that when the acid stabilizer is tartaric acid, anhydrous citric acid, and / or citric acid, and the antioxidant is ascorbate palmitate and / or tocopherol, the total impurity growth rate is low, and the stability is significantly improved, resulting in tablets with stable quality.

[0229] Table 9

[0230]

[0231]

[0232] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A melogabalin besylate tablet, characterized in that, The tablet core contains melogabalin benzyl sulfonate, an acid stabilizer, and an antioxidant, wherein the acid stabilizer and the antioxidant are selected from at least one group of the following: (1) The acid stabilizer is tartaric acid and anhydrous citric acid, and the antioxidant is ascorbyl palmitate or tocopherol; (2) The acid stabilizer is tartaric acid and citric acid, and the antioxidant is ascorbyl palmitate or tocopherol; (3) The acid stabilizer is tartaric acid and malic acid, and the antioxidant is ascorbyl palmitate; (4) The acid stabilizer is tartaric acid, and the antioxidant is ascorbyl palmitate and tocopherol; (5) The acid stabilizer is tartaric acid, and the antioxidant is ascorbyl palmitate and propyl gallate.

2. The merogabarine besylate tablets according to claim 1, characterized in that, The acid stabilizer accounts for 1-5% of the weight of the core, preferably 1-4%, and more preferably 1.5-3.5%. Preferably, the antioxidant accounts for 0.01-0.5% of the weight of the tablet core, more preferably 0.01-0.4%, and even more preferably 0.02-0.35%.

3. The merogabarine besylate tablet according to claim 1, characterized in that, When the acid stabilizer is tartaric acid and anhydrous citric acid, tartaric acid and citric acid, or tartaric acid and malic acid, the mass ratio of tartaric acid to anhydrous citric acid, citric acid, or malic acid is 0.1 to 5:1, preferably 0.2 to 3:1, respectively and independently. Preferably, when the antioxidant is ascorbyl palmitate and tocopherol, the mass ratio of ascorbyl palmitate to tocopherol is 1 to 5:1, more preferably 1 to 3:1, and more preferably 2:1; Preferably, when the antioxidant is ascorbyl palmitate and propyl gallate, the mass ratio of ascorbyl palmitate to propyl gallate is 5 to 25:1, more preferably 6 to 20:

1.

4. The merogabarine besylate tablet according to claim 1, characterized in that, The core also includes fillers, disintegrants, adsorbents, and lubricants.

5. The merogabarine besylate tablet according to claim 4, characterized in that, The filler is selected from one or more of mannitol, lactose, corn starch, microcrystalline cellulose, anhydrous dicalcium phosphate, and sorbitol, preferably from one or two of mannitol and microcrystalline cellulose; Preferably, the disintegrant is selected from one or more of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose, preferably from one or two of sodium carboxymethyl starch and calcium carboxymethyl cellulose, and more preferably from calcium carboxymethyl cellulose. Preferably, the adsorbent is selected from one or more of magnesium aluminum metasilicate, magnesium aluminum silicate, and silicon dioxide, more preferably from magnesium aluminum metasilicate and magnesium aluminum silicate, and more preferably from magnesium aluminum metasilicate. Preferably, the lubricant is selected from one or more of magnesium stearate, sodium stearate fumarate, and talc, with magnesium stearate being the most preferred.

6. The merogabarine besylate tablet according to claim 5, characterized in that, Merogabalin benzyl sulfonate comprises 1-10% of the tablet core by weight, preferably 2.5-7.5%, more preferably 3-5%; mannitol comprises 70-85% of the tablet core by weight, preferably 75-85%, more preferably 78-83%; microcrystalline cellulose comprises 0.5-5% of the tablet core by weight, preferably 0.5-2%, more preferably 0.5-1%; calcium carboxymethyl cellulose comprises 5%-15% of the tablet core by weight, preferably 8-12%, more preferably 9-11%; magnesium aluminosilicate comprises 0.1-2% of the tablet core by weight, preferably 0.1-1%, more preferably 0.1-0.5%; and magnesium stearate comprises 1-3% of the tablet core by weight, preferably 1-2.5%, more preferably 1-2%.

7. The merogabarine besylate tablet according to claim 1, characterized in that, The tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid or citric acid or malic acid, ascorbyl palmitate, magnesium aluminum metasilicate, and magnesium stearate. The percentage of each component by weight of the tablet core is as follows: Alternatively, the tablet core may contain melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid or citric acid, tocopherol, magnesium aluminum metasilicate, and magnesium stearate, with each component comprising the following percentages by weight of the tablet core: Alternatively, the tablet core may contain melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, ascorbyl palmitate, tocopherol, magnesium aluminum metasilicate, and magnesium stearate, with each component accounting for the following percentage of the tablet core weight: Alternatively, the tablet core may contain melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, ascorbyl palmitate, propyl gallate, magnesium aluminum metasilicate, and magnesium stearate, with each component accounting for the following percentage of the tablet core weight:

8. The merogabarine besylate tablet according to claim 1, characterized in that, The tablet core contains melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid or citric acid or malic acid, ascorbyl palmitate, magnesium aluminum metasilicate, and magnesium stearate. The percentage of each component by weight of the tablet core is as follows: Alternatively, the tablet core may contain melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, anhydrous citric acid or citric acid, tocopherol, magnesium aluminum metasilicate, and magnesium stearate, with each component comprising the following percentages by weight of the tablet core: Alternatively, the tablet core may contain melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, ascorbyl palmitate, tocopherol, magnesium aluminum metasilicate, and magnesium stearate, with each component accounting for the following percentage of the tablet core weight: Alternatively, the tablet core may contain melogabalin benzyl sulfonate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, tartaric acid, ascorbyl palmitate, propyl gallate, magnesium aluminum metasilicate, and magnesium stearate, with each component accounting for the following percentage of the tablet core weight:

9. The melogabalin besylate tablets according to any one of claims 1 to 8, characterized in that, The melogabalin besylate tablets are available in strengths of 2.5 mg, 5 mg, 10 mg, or 15 mg.

10. The method for preparing melogabalin besylate tablets according to any one of claims 1 to 9, characterized in that, Includes the following steps: Merogabalin besylate is mixed with one or more pharmaceutically acceptable excipients, compressed, and coated to obtain the melogabalin besylate tablets.

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