A pharmaceutical composition comprising meloxicam and a preparation method thereof

Abstract

The application provides a pharmaceutical composition of meloxicam, comprising meloxicam, a pharmaceutically acceptable salt of meloxicam and a stabilizer, and has the advantages of good stability, fast disintegration and better suitability for mass production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations and relates to a pharmaceutical composition containing melogabalin and its preparation method. Background Technology

[0002] Merogabalin besylate is a GABA analog developed by Daiichi Sankyo Co., Ltd. of Japan. It acts on the α2-δ1 subunit of the voltage-sensitive calcium channel complex (widely distributed throughout the nervous system mediating pain transmission and processing) and is used to treat chronic neuropathic pain, typically treating pain caused by peripheral neuropathy, central nervous system pain, and other conditions. Patients often desire medications that disintegrate quickly and take effect rapidly so that their pain can be treated and improved promptly.

[0003] In June 2024, merogabarine besylate tablets were approved for marketing in China. Current technologies, through extensive research, aim to obtain formulations with good stability, such as those described in CN202410505195.9, which uses citric acid hydrate and tocopherol as stabilizers to improve the stability of the formulation at room temperature.

[0004] However, due to issues such as light exposure and high temperatures during storage and transportation, impurities can easily increase, reducing the safety and efficacy of the drug.

[0005] Therefore, there is still a need for a melogabalin formulation with better stability, lower content of related substances, and faster disintegration rate. Summary of the Invention

[0006] This invention provides a meregabalin pharmaceutical composition comprising meregabalin or a pharmaceutically acceptable salt thereof (abbreviated as API), carboxymethyl cellulose, and a stabilizer selected from one or more of tartaric acid, anhydrous citric acid, pentiformic acid, and butylated hydroxyanisole (BHA).

[0007] Furthermore, the content of melogabalin and its pharmaceutically acceptable salts is 1-10% by weight, 1-5% in some embodiments, 2-5% in some embodiments, and 4.4% in some embodiments.

[0008] In this invention, the pharmaceutically acceptable salt includes, but is not limited to, benzenesulfonates, hydrochlorides, sulfates, etc., and in some embodiments, the pharmaceutically acceptable salt is a benzenesulfonate.

[0009] Furthermore, the stabilizer comprises a first stabilizer and a second stabilizer. In some embodiments, the first stabilizer is selected from one or more of tartaric acid, anhydrous citric acid, and pentiformin. In some embodiments, the first stabilizer is selected from one or more of tartaric acid and pentiformin. In some embodiments, the first stabilizer is anhydrous citric acid. In some embodiments, the second stabilizer is BHA.

[0010] Furthermore, the content of the first stabilizer is 1-5% by weight, 1.5-3% in some embodiments, and 1.5% in some embodiments.

[0011] Furthermore, the content of the second stabilizer is 0.1-1% by weight, in some embodiments 0.1-0.2%, and in some embodiments 0.1%.

[0012] Furthermore, the weight ratio of the first stabilizer to the second stabilizer is 30:1 to 7.5:1, preferably 15:1.

[0013] Furthermore, the carboxymethyl cellulose content is 1-20% by weight, preferably 1-10%, preferably 8-10%, and more preferably 8% or 10%.

[0014] Furthermore, the pharmaceutical composition includes fillers, lubricants, etc. The filler is selected from one or more of lactose, mannitol, starch, dextrin, and polyvinylpyrrolidone, preferably mannitol; the lubricant is selected from one or more of magnesium stearate, talc, micronized silica, or silica; preferably magnesium stearate, micronized silica, or silica; more preferably magnesium stearate. Furthermore, the pharmaceutical composition may optionally include an adsorbent, the adsorbent comprising one or more of mesoporous silica, polyethylene glycol, glycerin, povidone, copovidone, and hydroxypropyl cellulose, preferably mesoporous silica.

[0015] Furthermore, the filler comprises 60-90% by weight, in some embodiments 70-90%, in some embodiments 80-90%, in some embodiments 79.5-90%, in some embodiments 79.5-85%, in some embodiments 79.5-84.5%, in some embodiments 80-85%, in some embodiments 79.5-82.5%, in some embodiments 82.5-84.5%, in some embodiments 79.5%, in some embodiments 80%, in some embodiments 81%, in some embodiments 82%, in some embodiments 82.5%, in some embodiments 83%, in some embodiments 84%, in some embodiments 84.5%, and in some embodiments 85%.

[0016] Furthermore, the lubricant comprises 0.1-5% by weight, in some embodiments 1-5%, in some embodiments 1-3%, in some embodiments 1-1.5%, in some embodiments 1%, in some embodiments 1.5%, and in some embodiments 2%.

[0017] Furthermore, the adsorption comprises 0-5% by weight in some embodiments, 0-3% in some embodiments, 1-3% in some embodiments, 0% in some embodiments, 1% in some embodiments, 1.5% in some embodiments, 2% in some embodiments, and 3% in some embodiments.

[0018] Furthermore, the pharmaceutical composition comprises, by weight:

[0019] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0020] Filler 60-90%

[0021] Carboxymethyl cellulose 1-20%

[0022] First stabilizer 1-5%

[0023] Second stabilizer 0.1-1%

[0024] Adsorbent 0-5%

[0025] Lubricant 0.1-5%;

[0026] Furthermore, the pharmaceutical composition comprises, by weight:

[0027] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0028] 70-90% filler

[0029] Carboxymethyl cellulose 1-20%

[0030] Tartaric acid, anhydrous citric acid, or pentiformin 1-5%

[0031] BHA 0.1-1%

[0032] Adsorbent 0-5%

[0033] Lubricant 0.1-5%;

[0034] Furthermore, the pharmaceutical composition comprises, by weight:

[0035] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0036] 70-90% filler

[0037] Carboxymethyl cellulose 1-20%

[0038] Tartaric acid, anhydrous citric acid, or pentiformin 1-5%

[0039] BHA 0.1-1%

[0040] Adsorbent 0-5%

[0041] Lubricant 0.1-5%

[0042] The ratio of the first stabilizer to the second stabilizer is 30:1 to 7.5:1, preferably 15:1;

[0043] Furthermore, the pharmaceutical composition comprises, by weight:

[0044] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0045] 70-90% filler

[0046] Carboxymethyl cellulose 8-10%

[0047] Tartaric acid, anhydrous citric acid, or pentiformin 1-5%

[0048] BHA 0.1-1%

[0049] Adsorbent 0-5%

[0050] Lubricant 0.1-5%

[0051] The ratio of the first stabilizer to the second stabilizer is 30:1 to 7.5:1, preferably 15:1; further, the pharmaceutical composition comprises, by weight:

[0052] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0053] 70-90% filler

[0054] Carboxymethyl cellulose 8-10%

[0055] Tartaric acid, anhydrous citric acid, or pentiformin 1.5%

[0056] BHA 0.1%

[0057] Adsorbent 0-5%

[0058] Lubricant 0.1-5%;

[0059] Furthermore, the pharmaceutical composition comprises, by weight:

[0060] Merogabalin and its pharmaceutically acceptable salts 1-5%

[0061] 70-90% filler

[0062] Carboxymethyl cellulose 8-10%

[0063] Tartaric acid, anhydrous citric acid, or pentiformin 1.5%

[0064] BHA 0.1%

[0065] Adsorbent 0-3%

[0066] Lubricant 0.1-1.5%;

[0067] Furthermore, the pharmaceutical composition comprises, by weight:

[0068] Merogabalin and its pharmaceutically acceptable salts 1-5%

[0069] 70-90% filler

[0070] Carboxymethyl cellulose 8-10%

[0071] Tartaric acid, anhydrous citric acid, or pentiformin 1.5%

[0072] BHA 0.1%

[0073] Adsorbent 0-1%

[0074] Lubricant 0.1-1.5%;

[0075] Furthermore, the pharmaceutical composition comprises, by weight:

[0076] Merogabalin and its pharmaceutically acceptable salts 1-5%

[0077] Mannitol 70-90%

[0078] Carboxymethyl cellulose 8-10%

[0079] Tartaric acid, anhydrous citric acid, or pentiformin 1.5%

[0080] BHA 0.1%

[0081] Mesoporous silica 0-3%

[0082] Magnesium stearate 0.1-1.5%,

[0083] Furthermore, the pharmaceutical composition comprises, by weight:

[0084] Merogabalin and its pharmaceutically acceptable salts 1-5%

[0085] Mannitol 70-90%

[0086] Carboxymethyl cellulose 8-10%

[0087] Tartaric acid, anhydrous citric acid, or pentiformin 1.5%

[0088] BHA 0.1%

[0089] Mesoporous silica 0-1%

[0090] Magnesium stearate 0.1-1.5%,

[0091] Furthermore, the pharmaceutical composition comprises, by weight:

[0092] Merogabalin and its pharmaceutically acceptable salts 1-5%

[0093] Filler 79.5-85%

[0094] Carboxymethyl cellulose 8-10%

[0095] Tartaric acid, anhydrous citric acid, or pentiformin 1.5%

[0096] BHA 0.1%

[0097] Adsorbent 0-3%

[0098] Lubricant 0.1-1.5%;

[0099] Furthermore, the pharmaceutical composition comprises, by weight:

[0100] Merogabalin and its pharmaceutically acceptable salts 1-5%

[0101] 80-85% filler

[0102] Carboxymethyl cellulose 8-10%

[0103] Tartaric acid, anhydrous citric acid, or pentiformin 1.5%

[0104] BHA 0.1%

[0105] Adsorbent 0-1%

[0106] Lubricant 0.1-1.5%;

[0107] Furthermore, the pharmaceutical composition comprises, by weight:

[0108] Merogabalin and its pharmaceutically acceptable salts 1-5%

[0109] Filler content: 79.5%-84.5%

[0110] Carboxymethyl cellulose 8-10%

[0111] Tartaric acid, anhydrous citric acid, or pentiformin 1.5%

[0112] BHA 0.1%

[0113] Adsorbent 0-3%

[0114] Lubricant 1.5%.

[0115] Furthermore, the pharmaceutical composition comprises, by weight:

[0116] Merogabalin and its pharmaceutically acceptable salts 1-5%

[0117] 80-85% filler

[0118] Carboxymethyl cellulose 8-10%

[0119] Tartaric acid, anhydrous citric acid, or pentiformin 1.5%

[0120] BHA 0.1%

[0121] Adsorbent 0-1%

[0122] Lubricant 1.5%.

[0123] In some embodiments, the pharmaceutical composition comprises, by weight:

[0124] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0125] Mannitol 70-90%

[0126] Carboxymethyl cellulose 8-10%

[0127] Tartaric acid 1.5-3%

[0128] BHA 0.1-0.2%

[0129] Mesoporous silica 0-3%

[0130] Magnesium stearate 0.1-2%

[0131] The ratio of tartaric acid to BHA is 30:1-7.5:1, preferably 15:1, or

[0132] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0133] Mannitol 70-90%

[0134] Carboxymethyl cellulose 8-10%

[0135] Anhydrous citric acid 1.5-3%

[0136] BHA 0.1-0.2%

[0137] Mesoporous silica 0-3%

[0138] Magnesium stearate 0.1-2%

[0139] The ratio of anhydrous citric acid to BHA is 30:1-7.5:1, preferably 15:1; or

[0140] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0141] Mannitol 70-90%

[0142] Carboxymethyl cellulose 8-10%

[0143] Pentetracycline 1.5-3%

[0144] BHA 0.1-0.2%

[0145] Mesoporous silica 0-3%

[0146] Magnesium stearate 0.1-2%

[0147] The ratio of pentetracycline to BHA is 30:1-7.5:1, preferably 15:1. In some embodiments, the pharmaceutical composition comprises, by weight:

[0148] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0149] Mannitol 70-90%

[0150] Carboxymethyl cellulose 8-10%

[0151] Tartaric acid 1.5-3%

[0152] BHA 0.1-0.2%

[0153] Mesoporous silica 0-2%

[0154] Magnesium stearate 0.1-2%

[0155] The ratio of tartaric acid to BHA is 30:1-7.5:1, preferably 15:1, or

[0156] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0157] Mannitol 70-90%

[0158] Carboxymethyl cellulose 8-10%

[0159] Anhydrous citric acid 1.5-3%

[0160] BHA 0.1-0.2%

[0161] Mesoporous silica 0-2%

[0162] Magnesium stearate 0.1-2%

[0163] The ratio of anhydrous citric acid to BHA is 30:1-7.5:1, preferably 15:1; or

[0164] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0165] Mannitol 70-90%

[0166] Carboxymethyl cellulose 8-10%

[0167] Pentetracycline 1.5-3%

[0168] BHA 0.1-0.2%

[0169] Mesoporous silica 0-2%

[0170] Magnesium stearate 0.1-2%

[0171] The ratio of pentetracycline to BHA is 30:1-7.5:1, preferably 15:1. In some embodiments, the pharmaceutical composition comprises, by weight: 1-10% merogabarine and its pharmaceutically acceptable salts.

[0172] Mannitol 70-90%

[0173] Carboxymethyl cellulose 8-10%

[0174] Tartaric acid 1.5%

[0175] BHA 0.1%

[0176] Mesoporous silica 0-3%

[0177] Magnesium stearate 0.1-2%;

[0178] or

[0179] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0180] Mannitol 70-90%

[0181] Carboxymethyl cellulose 8-10%

[0182] Anhydrous citric acid 1.5%

[0183] BHA 0.1%

[0184] Mesoporous silica 0-3%

[0185] Magnesium stearate 0.1-2%;

[0186] or

[0187] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0188] Mannitol 70-90%

[0189] Carboxymethyl cellulose 8-10%

[0190] Pentetracycline 1.5%

[0191] BHA 0.1%

[0192] Mesoporous silica 0-3%

[0193] Magnesium stearate 0.1-2%

[0194] In some embodiments, the pharmaceutical composition comprises, by weight: 1-10% merogabaline and its pharmaceutically acceptable salts.

[0195] Mannitol 70-90%

[0196] Carboxymethyl cellulose 8-10%

[0197] Tartaric acid 1.5%

[0198] BHA 0.1%

[0199] Mesoporous silica 0-2%

[0200] Magnesium stearate 0.1-2%;

[0201] or

[0202] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0203] Mannitol 70-90%

[0204] Carboxymethyl cellulose 8-10%

[0205] Anhydrous citric acid 1.5%

[0206] BHA 0.1%

[0207] Mesoporous silica 0-2%

[0208] Magnesium stearate 0.1-2%;

[0209] or

[0210] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0211] Mannitol 70-90%

[0212] Carboxymethyl cellulose 8-10%

[0213] Pentetracycline 1.5%

[0214] BHA 0.1%

[0215] Mesoporous silica 0-2%

[0216] Magnesium stearate 0.1-2%;

[0217] In some embodiments, the pharmaceutical composition comprises, by weight: 1-10% merogabaline and its pharmaceutically acceptable salts.

[0218] Mannitol 70-90%

[0219] 10% carboxymethyl cellulose

[0220] Tartaric acid 1.5%

[0221] BHA 0.1%

[0222] Mesoporous silica 0-1%

[0223] Magnesium stearate 0.1-1.5%;

[0224] or

[0225] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0226] Mannitol 70-90%

[0227] Carboxymethyl cellulose 8-10%

[0228] Anhydrous citric acid 1.5%

[0229] BHA 0.1%

[0230] Mesoporous silica 0-3%

[0231] Magnesium stearate 0.1-1.5%;

[0232] or

[0233] Merogabalin and its pharmaceutically acceptable salts, 1-10%.

[0234] Mannitol 70-90%

[0235] 10% carboxymethyl cellulose

[0236] Pentetracycline 1.5%

[0237] BHA 0.1%

[0238] Mesoporous silica 0-1%

[0239] Magnesium stearate 0.1-1.5%;

[0240] In some embodiments, the pharmaceutical composition comprises, by weight:

[0241] Merogabalin and its pharmaceutically acceptable salts 1-5%

[0242] Mannitol 79.5-84.5%

[0243] Carboxymethyl cellulose 8-10%

[0244] Anhydrous citric acid, tartaric acid, or pentiformin 1.5%

[0245] BHA 0.1%

[0246] Mesoporous silica 0-3%

[0247] Magnesium stearate 1.5%;

[0248] In some embodiments, the pharmaceutical composition comprises, by weight:

[0249] Merogabalin and its pharmaceutically acceptable salts 1-5%

[0250] Mannitol 79.5-84.5%

[0251] Carboxymethyl cellulose 8-10%

[0252] Anhydrous citric acid 1.5%

[0253] BHA 0.1%

[0254] Mesoporous silica 0-3%

[0255] Magnesium stearate 1.5%;

[0256] In some embodiments, the pharmaceutical composition comprises, by weight:

[0257] Merogabalin and its pharmaceutically acceptable salts 1-5%

[0258] Mannitol 79.5-84.5%

[0259] Carboxymethyl cellulose 8-10%

[0260] Anhydrous citric acid, tartaric acid, or pentiformin 1.5%

[0261] BHA 0.1%

[0262] Mesoporous silica 0-1%

[0263] Magnesium stearate 1.5%;

[0264] In some embodiments, the pharmaceutical composition comprises, by weight:

[0265] Merogabalin and its pharmaceutically acceptable salts 1-5%

[0266] Mannitol 79.5-84.5%

[0267] Carboxymethyl cellulose 8-10%

[0268] Anhydrous citric acid 1.5%

[0269] BHA 0.1%

[0270] Mesoporous silica 0-1%

[0271] Magnesium stearate 1.5%;

[0272] In some embodiments, the pharmaceutical composition comprises, by weight:

[0273] Merogabalin and its pharmaceutically acceptable salts 1-5%

[0274] Mannitol 82.5-84.5%

[0275] Carboxymethyl cellulose 8-10%

[0276] Anhydrous citric acid 1.5%

[0277] BHA 0.1%

[0278] Magnesium stearate 1.5%;

[0279] In some embodiments, the pharmaceutical composition comprises, by weight:

[0280] Merogabalin and its pharmaceutically acceptable salts 1-5%

[0281] Mannitol 79.5-82.5%

[0282] 10% carboxymethyl cellulose

[0283] Anhydrous citric acid 1.5%

[0284] BHA 0.1%

[0285] Mesoporous silica 0-3%

[0286] Magnesium stearate 1.5%;

[0287] In some embodiments, the pharmaceutical composition comprises, by weight: 4.4% merogabaline and its pharmaceutically acceptable salt.

[0288] Mannitol 82.5-84.5%

[0289] Carboxymethyl cellulose 8-10%

[0290] Anhydrous citric acid 1.5%

[0291] BHA 0.1%

[0292] Magnesium stearate 1.5%;

[0293] Furthermore, the pharmaceutical composition comprises, by weight:

[0294] Merogabalin and its pharmaceutically acceptable salts 4.4%

[0295] Mannitol 82.5%

[0296] Carboxymethyl cellulose 10.0%

[0297] Anhydrous citric acid 1.5%

[0298] BHA 0.1%

[0299] Magnesium stearate 1.5%

[0300] Or merogabaline and its pharmaceutically acceptable salts, 4.4%.

[0301] Mannitol 79.5%

[0302] Carboxymethyl cellulose 10.0%

[0303] Anhydrous citric acid 1.5%

[0304] BHA 0.1%

[0305] 3% mesoporous silica

[0306] Magnesium stearate 1.5%

[0307] Or merogabaline and its pharmaceutically acceptable salts, 4.4%.

[0308] Mannitol 84.5%

[0309] Carboxymethyl cellulose 8.0%

[0310] Anhydrous citric acid 1.5%

[0311] BHA 0.1%

[0312] Magnesium stearate 1.5%

[0313] Or merogabaline and its pharmaceutically acceptable salts, 4.4%.

[0314] Mannitol 81.5%

[0315] 10% carboxymethyl cellulose

[0316] Tartaric acid 1.5%

[0317] BHA 0.1%

[0318] 1% mesoporous silica

[0319] Magnesium stearate 1.5%

[0320] or

[0321] Merogabalin and its pharmaceutically acceptable salts 4.4%

[0322] Mannitol 81.5%

[0323] 10% carboxymethyl cellulose

[0324] Anhydrous citric acid 1.5%

[0325] BHA 0.1%

[0326] 1% mesoporous silica

[0327] Magnesium stearate 1.5%;

[0328] or

[0329] Merogabalin and its pharmaceutically acceptable salts 4.4%

[0330] Mannitol 81.5%

[0331] 10% carboxymethyl cellulose

[0332] Pentetracycline 1.5%

[0333] BHA 0.1%

[0334] 1% mesoporous silica

[0335] Magnesium stearate 1.5%.

[0336] Furthermore, the present invention provides a formulation comprising melogabalin, which comprises the above-mentioned pharmaceutical composition, wherein the formulation is an oral dosage form, such as capsules, sprinkles, lozenges, sachets or tablets, preferably tablets.

[0337] Furthermore, the present invention provides a method for preparing the above-mentioned formulation, the method comprising weighing melogabalin besylate and excipients, sieving them, then mixing the materials except for magnesium stearate, and then adding magnesium stearate and mixing again to obtain a mixed powder. The mixed powder is then added to a tableting machine for tableting to obtain unprocessed tablets.

[0338] Furthermore, the method includes weighing melogabalin benzyl sulfonate and excipients, sieving them, then mixing the materials except for magnesium stearate, preferably for 10-30 minutes, then adding magnesium stearate and mixing, preferably for 5-10 minutes, to obtain a mixed powder. The mixed powder is then added to a single-punch tablet press for tableting to obtain unprocessed tablets.

[0339] Furthermore, the method includes coating the uncoated tablets with a water-soluble film using a high-efficiency coating machine, increasing the weight by 3% to 5%, to obtain coated tablets.

[0340] Furthermore, the present invention provides the use of the described melogabalin formulation in the preparation of a medicament for treating chronic pain.

[0341] The beneficial effects of this invention are as follows: The inventors unexpectedly discovered that using carboxymethyl cellulose as a filler can achieve good light stability. Furthermore, after adding a stabilizer combination, there are fewer impurities at high temperatures, and the resulting formulation has a fast disintegration time, effectively enabling faster drug dispersion and promoting drug absorption. Detailed Implementation

[0342] The technical solution of the present invention will be further described in detail below with reference to specific implementation examples, but the implementation of the present invention is not limited thereto. Equivalent substitutions, combinations, improvements, or modifications made by those skilled in the art based on the description of the present invention should all be covered within the protection scope of the present invention.

[0343] Unless otherwise stated, all reagents and materials used in the following examples are commercially available. Each experiment examined three samples, and the values ​​were averaged. The results met statistical requirements.

[0344] The specific reagents and instruments are listed in Table 1 below:

[0345] Table 1

[0346] name Model / Level source Anhydrous disodium hydrogen phosphate AR Chengdu Kelong Chemical Co., Ltd. Phosphoric acid HPLC Chengdu Nuoershi Technology Co., Ltd. Acetonitrile HPLC Chengdu Norsh Technology Co., Ltd. Light stability test chamber ICH750L MEMMERT Water-jacketed constant temperature incubator GNP-9050 Shanghai Jinghong Experimental Equipment Co., Ltd. High Performance Liquid Chromatography U3000 ThermoFisher 3D Motion Mixer / Huabao Machinery (Shenzhen) Co., Ltd. Single punch tablet press / Beijing Guoyao Longli Technology Co., Ltd. Tablet hardness tester / Shanghai Huanghai Pharmaceutical Testing Instruments Co., Ltd. Merogabalin besylate raw material / Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Mannitol 100SD Fuji Chemical Industries microcrystalline cellulose PH102 GraceGmbH Carboxymethyl cellulose NS-300 Tianjin Xincheng Kangda Pharmaceutical Co., Ltd. Carboxymethyl cellulose calcium / Jiangsu Southeast Nanomaterials Co., Ltd. Anhydrous citric acid / Hunan Ercon Pharmaceutical Co., Ltd. tartaric acid / FinarLimited Pentetracycline / Chengdu Kelong Chemical Co., Ltd. Citric acid hydrate / Sichuan Boliheng Pharmaceutical Co., Ltd. BHA / Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Tocopherol / Nichirin Chemical Industries Mesoporous silica AL-1FP DuPont Magnesium aluminum metasilicate / Rogate magnesium stearate / Yantai Wanrun Co., Ltd.

[0347] Example 1

[0348] Merogabalin besylate API was used as the formulation composition in this embodiment, and stability studies were conducted. API was mixed with calcium carboxymethyl cellulose, and API was mixed with carboxymethyl cellulose in specific proportions (see Table 2 below). 3g of the mixed sample was placed in a photostability test chamber (illuminance 4500±500 lux), and compared with the raw material as a parallel control. Samples were taken after 5, 10, and 30 days to detect relevant substances. The test results are shown in Table 2 below.

[0349] Table 2

[0350]

[0351] Conclusion: Through this experiment, the inventors unexpectedly discovered that using a mixture of carboxymethyl cellulose and API can effectively reduce related substances under light conditions. After 30 days of storage, the total impurity content was only 0.89, while the total impurity content of the scheme using calcium carboxymethyl cellulose exceeded 1, reaching 1.15.

[0352] Example 2

[0353] Prepare prescriptions 1-10 according to the prescriptions in Table 3 (prescription contents should be rounded to one decimal place):

[0354] Table 3

[0355]

[0356] Preparation method: Weigh merogabarine besylate and the corresponding excipients, then disperse them through a 50-mesh sieve. Add all materials except magnesium stearate to a three-dimensional mixer and mix for 10-30 minutes. Add magnesium stearate and mix for another 5-10 minutes to obtain a powder. Add the powder to the hopper of a single-punch tablet press and compress it into tablets, controlling the tablet weight to approximately 200 mg and the hardness to 70-120 N, to obtain unprocessed tablets.

[0357] Stability study: The prepared formulations 1-10 were placed at 60℃ for 5, 10, and 30 days. Related substances were detected by HPLC. The results are shown in Table 4 below:

[0358] Table 4

[0359]

[0360] Example 3

[0361] Prepare prescriptions 11-12 according to the prescriptions in Table 5 (prescription contents should be rounded to one decimal place):

[0362] Table 5

[0363] prescription Prescription 11 Prescription 12 Merogabalin benzyl sulfonate 4.4％ 4.4％ Mannitol 79.5％ 82.5％ Carboxymethyl cellulose 10.0％ 10.0％ Anhydrous citric acid 1.5％ 1.5％ BHA 0.1％ 0.1％ Mesoporous silica 3.0％ \ magnesium stearate 1.5％ 1.5％

[0364] Preparation method: Weigh merogabarine besylate and the corresponding excipients, then disperse them through a 50-mesh sieve. Add all materials except magnesium stearate to a three-dimensional mixer and mix for 10-30 minutes. Add magnesium stearate and mix for another 5-10 minutes to obtain a powder. Add the powder to the hopper of a single-punch tablet press and compress to obtain tablets with a weight of approximately 200 mg and a hardness of 70-120 N. Coat the uncoated tablets with a water-soluble film using a high-efficiency coating machine, increasing the weight by 3%-5%, to obtain coated tablets. Package the coated tablets in PVC / aluminum blister packaging, then cover with an aluminum-plastic bag containing a desiccant.

[0365] Stability study: The prepared packaged formulations 11-12 were stored at 40℃ / 75%RH for 3 months. Related substances were detected by HPLC. The results are shown in Table 6 below:

[0366] Table 6

[0367]

[0368] Example 4

[0369] Prepare prescription 13 according to the prescription in Table 7 (prescription content is rounded to one decimal place):

[0370] Table 7

[0371] prescription Prescription 13 Merogabalin benzyl sulfonate 4.4％ Mannitol 84.5％ Carboxymethyl cellulose 8.0％ Anhydrous citric acid 1.5％ BHA 0.1％ magnesium stearate 1.5％

[0372] Preparation method: Weigh merogabarine besylate and the corresponding excipients, then disperse them through a 50-mesh sieve. Add all materials except magnesium stearate to a three-dimensional mixer and mix for 10-30 minutes. Add magnesium stearate and mix for another 5-10 minutes to obtain a powder. Add the powder to the hopper of a single-punch tablet press and compress it into tablets, controlling the tablet weight to approximately 200 mg and the hardness to 70-120 N, to obtain unprocessed tablets.

[0373] The disintegration time of the unprocessed tablets prepared from formulations 13 and 10 was investigated, and the procedures were as follows:

[0374] The basket is suspended from the support via a stainless steel shaft at the top and immersed in a 1000ml beaker. The basket is lowered so that the sieve is 25mm from the bottom of the beaker at its lowest point. The beaker contains water at 37℃±1℃. The water level is adjusted so that the sieve is 15mm below the water surface at the highest point of the basket. The top of the basket must not be submerged in the solution. Six test tablets are placed in the glass tubes of the basket and the disintegration apparatus is started for testing. Each tablet should disintegrate completely within 15 minutes. If one tablet fails to disintegrate completely, six more tablets should be tested again. All tablets should meet the requirements. The experimental results are shown in Table 8.

[0375] Table 8

[0376]

[0377] Stability study: Sample 13 of the prepared packaged formulation (plain tablets were coated with a water-soluble film using a high-efficiency coating machine, resulting in a weight gain of 3%–5%, yielding coated tablets) were packaged in PVC / aluminum blister packs, with an outer aluminum-plastic bag containing a desiccant. The samples were then stored at 40℃ / 75% RH for 3 months. Related substances were analyzed using HPLC. The results are shown in Table 9 below.

[0378] Table 9

[0379]

[0380]

Claims

1. A meregabalin pharmaceutical composition comprising meregabalin or a pharmaceutically acceptable salt thereof, carboxymethyl cellulose, and a stabilizer, characterized in that... The stabilizer is selected from one or more of tartaric acid, anhydrous citric acid, pentiformic acid, and butylated hydroxyanisole (BHA).

2. The pharmaceutical composition according to claim 1, characterized in that... The content of melogabalin and its pharmaceutically acceptable salts is 1-10% by weight, preferably 1-5%, preferably 2-5%, and preferably 4.4%.

3. The pharmaceutical composition according to claim 1, characterized in that... The stabilizer comprises a first stabilizer and a second stabilizer. The first stabilizer is selected from one or more of tartaric acid, anhydrous citric acid, and pentiformic acid, preferably anhydrous citric acid. The second stabilizer is BHA.

4. The pharmaceutical composition according to claim 3, characterized in that... The content of the first stabilizer is 1-5% by weight, preferably 1.5-3%, more preferably 1.5%, and the content of the second stabilizer is 0.1-1% by weight, preferably 0.1-0.2%, more preferably 0.1%.

5. The pharmaceutical composition according to claim 1, characterized in that... The carboxymethyl cellulose content is 1-20% by weight, preferably 1-10%, more preferably 8-10%, and even more preferably 8% or 10%.

6. The pharmaceutical composition according to claim 5, characterized in that... The pharmaceutical composition comprises a filler and a lubricant. Preferably, the filler is selected from one or more of lactose, mannitol, starch, dextrin, and polyvinylpyrrolidone, with mannitol being preferred. The filler content is preferably 60-90% by weight, more preferably 70-90%, more preferably 79.5-85%, more preferably 79.5-84.5%, and more preferably 82.5-84.5%. The lubricant is selected from one or more of magnesium stearate, talc, micronized silica, or silica, with magnesium stearate, micronized silica, or silica being preferred. Magnesium stearate is more preferred. The lubricant content is preferably 0.1-5% by weight, more preferably 1-5%, and more preferably 1-3%. Preferably, the pharmaceutical composition comprises an adsorbent, which comprises one or more of mesoporous silica, polyethylene glycol, glycerin, povidone, copovidone, and hydroxypropyl cellulose, with mesoporous silica being preferred. The adsorbent content is preferably 0-5% by weight, and more preferably 0-3%.

7. The pharmaceutical composition according to claim 1, characterized in that... The pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts, 1-10%. Filler 60-90% Carboxymethyl cellulose 1-20% First stabilizer 1-5% Second stabilizer 0.1-1% Adsorbent 0-5% Lubricant 0.1-5%; Preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts, 1-10%. 70-90% filler Carboxymethyl cellulose 1-20% Tartaric acid, anhydrous citric acid, or pentiformin 1-5% BHA 0.1-1% Adsorbent 0-5% Lubricant 0.1-5%; Preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts, 1-10%. 70-90% filler Carboxymethyl cellulose 1-20% Tartaric acid, anhydrous citric acid, or pentiformin 1-5% BHA 0.1-1% Adsorbent 0-5% Lubricant 0.1-5% The ratio of the first stabilizer to the second stabilizer is 30:1 to 7.5:1, preferably 15:1; preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts, 1-10%. 70-90% filler Carboxymethyl cellulose 8-10% Tartaric acid, anhydrous citric acid, or pentiformin 1-5% BHA 0.1-1% Adsorbent 0-5% Lubricant 0.1-5% The ratio of the first stabilizer to the second stabilizer is 30:1 to 7.5:1, preferably 15:1; preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts, 1-10%. 70-90% filler Carboxymethyl cellulose 8-10% Tartaric acid, anhydrous citric acid, or pentiformin 1.5% BHA 0.1% Adsorbent 0-5% Lubricant 0.1-5%; Preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts 1-5% 70-90% filler Carboxymethyl cellulose 8-10% Tartaric acid, anhydrous citric acid, or pentiformin 1.5% BHA 0.1% Adsorbent 0-3% Lubricant 0.1-1.5%; Preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts 1-5% Mannitol 70-90% Carboxymethyl cellulose 8-10% Tartaric acid, anhydrous citric acid, or pentiformin 1.5% BHA 0.1% Mesoporous silica 0-3% Magnesium stearate 0.1-1.5%, Preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts 1-5% Filler 79.5-85% Carboxymethyl cellulose 8-10% Tartaric acid, anhydrous citric acid, or pentiformin 1.5% BHA 0.1% Adsorbent 0-3% Lubricant 0.1-1.5%; Furthermore, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts 1-5% Filler content: 79.5%-84.5% Carboxymethyl cellulose 8-10% Tartaric acid, anhydrous citric acid, or pentiformin 1.5% BHA 0.1% Adsorbent 0-3% Lubricant 1.5%.

8. The pharmaceutical composition according to claim 7, characterized in that... The pharmaceutical composition comprises, by weight: 1-10% merogabaline and its pharmaceutically acceptable salt. Mannitol 70-90% Carboxymethyl cellulose 8-10% Tartaric acid 1.5-3% BHA 0.1-0.2% Mesoporous silica 0-3% Magnesium stearate 0.1-2% The ratio of tartaric acid to BHA is 30:1-7.5:1, preferably 15:

1. or Merogabalin and its pharmaceutically acceptable salts, 1-10%. Mannitol 70-90% Carboxymethyl cellulose 8-10% Anhydrous citric acid 1.5-3% BHA 0.1-0.2% Mesoporous silica 0-3% Magnesium stearate 0.1-2% The ratio of anhydrous citric acid to BHA is 30:1-7.5:1, preferably 15:1; or Merogabalin and its pharmaceutically acceptable salts, 1-10%. Mannitol 70-90% Carboxymethyl cellulose 8-10% Pentetracycline 1.5-3% BHA 0.1-0.2% Mesoporous silica 0-3% Magnesium stearate 0.1-2% The ratio of penteacin to BHA is 30:1-7.5:1, preferably 15:1; Preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts, 1-10%. Mannitol 70-90% Carboxymethyl cellulose 8-10% Tartaric acid 1.5% BHA 0.1% Mesoporous silica 0-3% Magnesium stearate 0.1-2%; or Merogabalin and its pharmaceutically acceptable salts 1-10% mannitol 70-90% Carboxymethyl cellulose 8-10% Anhydrous citric acid 1.5% BHA 0.1% Mesoporous silica 0-3% Magnesium stearate 0.1-2%; or Merogabalin and its pharmaceutically acceptable salts 1-10% mannitol 70-90% Carboxymethyl cellulose 8-10% Pentetracycline 1.5% BHA 0.1% Mesoporous silica 0-3% Magnesium stearate 0.1-2%; Preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts 1-10% mannitol 70-90% 10% carboxymethyl cellulose Tartaric acid 1.5% BHA 0.1% Mesoporous silica 0-1% Magnesium stearate 0.1-1.5%; or Merogabalin and its pharmaceutically acceptable salts 1-10% mannitol 70-90% Carboxymethyl cellulose 8-10% Anhydrous citric acid 1.5% BHA 0.1% Mesoporous silica 0-3% Magnesium stearate 0.1-1.5%; or Merogabalin and its pharmaceutically acceptable salts 1-10% mannitol 70-90% 10% carboxymethyl cellulose Pentetracycline 1.5% BHA 0.1% Mesoporous silica 0-1% Magnesium stearate 0.1-1.5%; Preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts 1-5% mannitol 79.5-84.5% Carboxymethyl cellulose 8-10% Anhydrous citric acid, tartaric acid, or pentiformin 1.5% BHA 0.1% Mesoporous silica 0-3% Magnesium stearate 1.5%; Preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts 1-5% mannitol 79.5-84.5% Carboxymethyl cellulose 8-10% Anhydrous citric acid 1.5% BHA 0.1% Mesoporous silica 0-3% Magnesium stearate 1.5%; Preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts 1-5% mannitol 79.5-84.5% Carboxymethyl cellulose 8-10% Anhydrous citric acid 1.5% BHA 0.1% Mesoporous silica 0-1% Magnesium stearate 1.5%; Preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts 1-5% mannitol 82.5-84.5% Carboxymethyl cellulose 8-10% Anhydrous citric acid 1.5% BHA 0.1% Magnesium stearate 1.5%; Preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts 1-5% mannitol 79.5-82.5% 10% carboxymethyl cellulose Anhydrous citric acid 1.5% BHA 0.1% Mesoporous silica 0-3% Magnesium stearate 1.5%; Preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts: 4.4% mannitol (82.5-84.5%) Carboxymethyl cellulose 8-10% Anhydrous citric acid 1.5% BHA 0.1% Magnesium stearate 1.5%; Preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts: 4.4% mannitol, 82.5% Carboxymethyl cellulose 10.0% Anhydrous citric acid 1.5% BHA 0.1% Magnesium stearate 1.5% or Merogabalin and its pharmaceutically acceptable salts 4.4% and mannitol 79.5% Carboxymethyl cellulose 10.0% Anhydrous citric acid 1.5% BHA 0.1% 3% mesoporous silica Magnesium stearate 1.5% or Merogabalin and its pharmaceutically acceptable salts: 4.4% mannitol, 84.5%. Carboxymethyl cellulose 8.0% Tartaric acid 1.5% BHA 0.1% Magnesium stearate 1.5% or Preferably, the pharmaceutical composition comprises, by weight: Merogabalin and its pharmaceutically acceptable salts: 4.4% mannitol, 81.5% 10% carboxymethyl cellulose Tartaric acid 1.5% BHA 0.1% 1% mesoporous silica Magnesium stearate 1.5% or Merogabalin and its pharmaceutically acceptable salts 4.4% Mannitol 81.5% 10% carboxymethyl cellulose Anhydrous citric acid 1.5% BHA 0.1% 1% mesoporous silica Magnesium stearate 1.5%; or Merogabalin and its pharmaceutically acceptable salts 4.4% Mannitol 81.5% 10% carboxymethyl cellulose Pentetracycline 1.5% BHA 0.1% 1% mesoporous silica Magnesium stearate 1.5%.

9. A formulation comprising merogabarine, characterized in that... The formulation comprises the pharmaceutical composition according to any one of claims 1-8, wherein the formulation is an oral dosage form, preferably selected from capsules, sprinkles, lozenges, sachets or tablets, preferably tablets.

10. A method for preparing the formulation of claim 9, characterized in that... The method includes weighing melogabalin benzyl sulfonate and excipients, sieving them, then mixing the materials except for magnesium stearate, and then adding magnesium stearate and mixing again to obtain a mixed powder. The mixed powder is added to a tablet press and compressed to obtain uncoated tablets; preferably, the uncoated tablets are coated with a water-soluble film using a high-efficiency coating machine to increase the weight by 3% to 5% to obtain coated tablets.

11. Use of the melogabalin formulation of claim 9 in the preparation of a medicament for treating chronic pain.

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