A melogabalin besylate preparation composition with excellent stability

Abstract

A melogabalin besylate formulation composition with excellent stability comprises an active pharmaceutical ingredient, a moisture-proofing agent, and an antioxidant; the moisture-proofing agent comprises acrylic acid grafted starch; the formulation may or may not contain a coating; excluding the weight of the coating, the moisture-proofing agent is used in an amount of at least 2% of the total weight of the formulation, and the antioxidant is used in an amount of at least 1% of the total weight of the formulation. The present invention utilizes the acrylic acid grafted starch as a moisture-proofing agent to obtain a melogabalin besylate formulation composition with excellent stability. Impurity generation during storage is lower than that of the original formulation, effectively improving the safety of the melogabalin besylate formulation and simplifying drug packaging.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a melogabalin besylate preparation composition. Background Art

[0002] Mirogabalin Besilate, whose chemical name is [(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid monobenzenesulfonate, is a new type of gabapentin-type chronic pain treatment drug.

[0003] Melogabalin besylate preparations were developed by Daiichi Sankyo Co., Ltd. in Japan and approved for marketing in Japan in 2019. They were then approved for marketing in China in 2024. The marketing dosage forms are ordinary tablets and orally disintegrating tablets. The marketing specifications are 2.5mg, 5mg, 10mg, and 15mg (in C 12 H 19 NO2 meter), trade name Tarlige ® (De Lijing ® ).

[0004] The chemical structure of melogabalin besylate is as follows:

[0005]

[0006] Its chemical structure contains primary amino groups and carboxylic acid groups, among which the primary amino groups are easily oxidized and degraded, and the primary amino groups and carboxylic acid groups are easy to form intramolecular or intermolecular amide rings, resulting in extremely poor stability of melogabalin besylate preparations.

[0007] Original formulation Tarlige ® (De Lijing ® ) discloses its formula excipients as: mannitol, microcrystalline cellulose, carboxymethylcellulose calcium, tocopherol, magnesium aluminum metasilicate, citric acid, and magnesium stearate. This indicates that the original formulation uses tocopherol and citric acid as antioxidants, and magnesium aluminum metasilicate as a moisture-proofing agent or adsorbent. Furthermore, to further enhance formulation stability, the original formulation is packaged in an aluminum-plastic packaging with a pharmaceutical composite film outer bag, containing a molecular sieve desiccant.

[0008] The original formulation requires the addition of molecular sieve desiccant in the packaging, and the packaging is relatively complex, indicating that its prescription excipients cannot fully guarantee its stability; and in clinical practice, after the patient opens the package for the first time, if the patient does not strictly store the remaining drugs in accordance with the original packaging, and takes a long time (for example, one of the packaging specifications of the original marketed product is 10 tablets / plate × 10 plates / box = 100 tablets, calculated at 2 tablets / day, it takes 50 days to complete the consumption), there is a risk of a significant increase in impurities or even exceeding the limit.

[0009] Although the prior art adopts a variety of stabilization measures to ensure the stability of melogabalin besylate preparations, the drug still undergoes degradation to a certain extent during storage, such as amide bond formation and oxidative degradation, resulting in a significant increase in the content of various impurities and a significant increase in the total amount of impurities. In other words, there is still a need to study melogabalin besylate preparations with better stability. Summary of the Invention

[0010] The technical problem to be solved by the present invention is to overcome the above-mentioned defects of the prior art and provide a melogabalin besylate preparation composition with excellent stability.

[0011] The technical solution adopted by the present invention to solve the technical problem is as follows: a melogabalin besylate preparation composition with excellent stability, comprising an active pharmaceutical ingredient, a moisture-proof agent and an antioxidant; the moisture-proof agent comprises acrylic acid grafted starch; the preparation may contain a coating or not;

[0012] Excluding the coating weight, the amount of the moisture-proof agent is 1% to 10% of the total weight of the preparation;

[0013] Excluding the coating weight, the amount of the antioxidant is 2% to 5% of the total weight of the preparation.

[0014] Preferably, C 12 H 19 Each dosage unit contains 1mg~20mg of active pharmaceutical ingredient in terms of NO2.

[0015] Preferably, the antioxidant comprises glutathione and / or tocopherol.

[0016] More preferably, excluding the weight of the coating, the amount of glutathione and / or tocopherol is 2% to 5% of the total weight of the preparation.

[0017] Preferably, the water absorption rate of the acrylic acid grafted starch is 100 g / g to 10000 g / g.

[0018] Preferably, excluding the coating weight, the amount of the acrylic acid grafted starch is 2% to 10% of the total weight of the preparation.

[0019] Preferably, it further comprises one or more of a filler, a disintegrant, and a lubricant.

[0020] More preferably, the filler includes one or more of microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, starch and its derivatives, dextrin, lactose monohydrate, anhydrous lactose, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, maltodextrin, maltose, D-mannitol, sorbitol, sucrose, trehalose, and xylitol.

[0021] More preferably, the disintegrant includes one or more of carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked carboxymethylcellulose sodium, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, polacrilin potassium, sodium starch glycolate, sodium carboxymethyl starch, starch, and pregelatinized starch.

[0022] More preferably, the lubricant includes one or more of magnesium stearate, glyceryl distearate, glyceryl behenate, sodium stearyl fumarate, talc, polyethylene glycol, magnesium lauryl sulfate, sodium lauryl sulfate, micropowder silica, and colloidal silicon dioxide.

[0023] More preferably, the antioxidant further comprises citric acid hydrate, sodium edetate, sodium bisulfite, butylated hydroxytoluene, sodium sulfite, ascorbic acid, 1,3-butylene glycol, sodium metabisulfite, butylated hydroxyanisole, tocopheryl acetate, soy lecithin, propyl gallate, anhydrous magnesium citrate, isoascorbic acid, sodium thioacetate, ascorbyl palmitate, α-thioglycerol, sodium nitrite, L-ascorbyl stearate, cysteine ​​hydrochloride, benzotriazole, sodium thiomalate, natural vitamin E, potassium dichloroisocyanurate, mixed tocopherol concentrate, pentaerythritol tetrakis [3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate] ester, 2-aminobenzimidazole, magnesium citrate hydrate, - One or more cyclodextrins.

[0024] The present invention has the following beneficial effects: by using the moisture-proof agent acrylic acid grafted starch, a melogabalin besylate preparation composition with excellent stability is obtained, impurity generation during storage is lower than that of the original preparation, the safety of the melogabalin besylate preparation is effectively improved, and drug packaging can be simplified.

[0025] In addition to the above-described objects, features and advantages, the present invention has other objects, features and advantages. The present invention will be further described in detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The accompanying drawings, which constitute part of this application, are intended to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are intended to explain the present invention and do not constitute an undue limitation of the present invention. In the accompanying drawings:

[0027] Figure 1 This is a bar chart comparing the increases in impurities in Example 2-inner packaging a sample, Example 2-inner packaging b sample, Comparative Example 1 sample, and Comparative Example 2 sample after being subjected to a high temperature of 60°C for 30 days. DETAILED DESCRIPTION

[0028] In order to make the purpose, scheme and beneficial technology of the present invention clearer, the present invention is further described in detail below with reference to the embodiments and drawings. It should be noted that the embodiments described in this specification are only for explaining the present invention and are not intended to limit the present invention.

[0029] For simplicity, only some numerical ranges are explicitly disclosed herein. However, any lower limit can be combined with any upper limit to form an unspecified range; and any lower limit can be combined with other lower limits to form an unspecified range, and similarly, any upper limit can be combined with any other upper limit to form an unspecified range. In addition, although not explicitly stated, each point or individual value between the endpoints of a range is included in the range. Thus, each point or individual value can serve as its own lower limit or upper limit and be combined with any other point or individual value, or with other lower limits or upper limits, to form an unspecified range.

[0030] In the description of this article, it should be noted that, unless otherwise specified, "above" and "below" are inclusive of the number itself, and the "multiple" in "one or more" means two or more, and the "multiple" in "one or more" means two or more.

[0031] Further explanation of water absorption rate: Weigh a certain amount of a certain adsorbent, place it in a certain amount of deionized water, let it stand for 3 hours, filter it with a 100-mesh nylon bag, and calculate the water absorption rate according to the formula: Water absorption rate (g / g) = (weight of added water - weight of filtered water) / weight of adsorbent.

[0032] The embodiments of the present invention provide a melogabalin besylate preparation composition with excellent stability, comprising an active pharmaceutical ingredient, a moisture-proof agent, and an antioxidant; the moisture-proof agent comprises acrylic acid grafted starch; the preparation may contain a coating or not;

[0033] Excluding the coating weight, the amount of the moisture-proof agent is 1% to 10% of the total weight of the preparation;

[0034] Excluding the coating weight, the amount of the antioxidant is 2% to 5% of the total weight of the preparation.

[0035] Acrylic acid grafted starch is a functional material made by grafting acrylic acid monomers onto starch. It combines the biocompatibility of starch with the physicochemical properties of acrylic acid. In this invention, acrylic acid grafted starch serves as a moisture-proofing agent in melogabalin besylate formulations. It locks moisture around the API (active pharmaceutical ingredient) molecules, which are susceptible to moisture-catalyzed degradation, into the acrylic acid grafted starch molecules. This prevents or significantly slows the rate of moisture-catalyzed degradation of the API molecules, thereby improving the stability of these formulations. Whether the formulation contains a coating can be determined based on practical needs.

[0036] In the embodiment of the present invention, C 12 H 19 Each dosage unit contains 1mg~20mg of active pharmaceutical ingredient in terms of NO2.

[0037] In some embodiments of the present invention, C 12 H 19 Each dosage unit contains 2.5mg~15mg of active pharmaceutical ingredient in terms of NO2.

[0038] In an embodiment of the present invention, the antioxidant includes glutathione and / or tocopherol. The chemical structure of melogabalin besylate contains a primary amino group, which is easily oxidized and degraded; the original preparation uses tocopherol and citric acid as antioxidants, but tocopherol is a liquid antioxidant. In the production process of solid preparations using a direct mixing tableting process, the production operation of adding liquid tocopherol is relatively complicated and it is difficult to ensure its mixing uniformity; in addition, the storage conditions of liquid tocopherol are extremely harsh, which is not conducive to production, storage and operation. After research, the inventors found that the use of glutathione as an antioxidant can significantly slow down the oxidative degradation of API in melogabalin besylate preparations, achieving an effect comparable to or even better than tocopherol, while reducing the difficulty of production. Glutathione is a tripeptide containing a γ-amide bond and a sulfhydryl group, composed of glutamic acid, cysteine ​​and glycine; the sulfhydryl group on cysteine ​​is the antioxidant group of glutathione, which not only can scavenge free radicals and have antioxidant effects, but also can chelate metal ions that catalyze oxidation reactions. This dual antioxidant mechanism ensures the antioxidant capacity of glutathione.

[0039] In some embodiments of the present invention, excluding the weight of the coating, the amount of glutathione and / or tocopherol is 2% to 5% of the total weight of the preparation.

[0040] In an embodiment of the present invention, the water absorption rate of the acrylic acid grafted starch is 100 g / g to 10000 g / g.

[0041] In some embodiments of the present invention, the acrylic acid grafted starch is prepared by graft copolymerization of acrylic acid monomer and starch at a molar ratio of 2 to 10:1.

[0042] There are already many acrylic acid grafted starch products on the market that can meet the requirements of this solution, such as acrylic acid grafted starch 300 and acrylic acid grafted starch 1000, where 300 and 1000 correspond to water absorption rates of 300g / g and 1000g / g.

[0043] In the embodiments of the present invention, excluding the weight of the coating, the amount of the acrylic acid grafted starch is 2% to 10% of the total weight of the preparation.

[0044] In some embodiments of the present invention, excluding the weight of the coating, the amount of the acrylic acid grafted starch is 3% to 10% of the total weight of the preparation.

[0045] In an embodiment of the present invention, one or more of a filler, a disintegrant, and a lubricant are further included.

[0046] In some embodiments of the present invention, the filler includes one or more of microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, starch and its derivatives, dextrin, lactose monohydrate, anhydrous lactose, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, maltodextrin, maltose, D-mannitol, sorbitol, sucrose, trehalose, and xylitol.

[0047] In some embodiments of the present invention, the disintegrant includes one or more of carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked carboxymethylcellulose sodium, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, polacrilin potassium, sodium starch glycolate, sodium carboxymethyl starch, starch, and pregelatinized starch.

[0048] In some embodiments of the present invention, the lubricant includes one or more of magnesium stearate, glyceryl distearate, glyceryl behenate, sodium stearyl fumarate, talc, polyethylene glycol, magnesium lauryl sulfate, sodium lauryl sulfate, micropowder silica, and colloidal silicon dioxide.

[0049] In some embodiments of the present invention, the antioxidant further comprises citric acid hydrate, sodium edetate, sodium bisulfite, butylated hydroxytoluene, sodium sulfite, ascorbic acid, 1,3-butylene glycol, sodium metabisulfite, butylated hydroxyanisole, tocopheryl acetate, soy lecithin, propyl gallate, anhydrous magnesium citrate, isoascorbic acid, sodium thioacetate, ascorbyl palmitate, a-thioglycerol, sodium nitrite, L-ascorbyl stearate, cysteine ​​hydrochloride, benzotriazole, sodium thiomalate, natural vitamin E, potassium dichloroisocyanurate, mixed tocopherol concentrate, pentaerythritol tetrakis [3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate] ester, 2-aminobenzimidazole, magnesium citrate hydrate, - One or more cyclodextrins.

[0050] Example

[0051] The following examples describe the present disclosure in more detail and are intended to be illustrative only, as various modifications and variations within the scope of the present disclosure will be apparent to those skilled in the art. Unless otherwise stated, all parts, percentages, and ratios reported in the following examples are by weight. Unless otherwise stated, all reagents used in the examples are available through conventional commercial sources or synthesized according to conventional methods and can be used directly without further processing. Unless otherwise stated, all instruments used in the examples are available through conventional commercial sources.

[0052] Examples 1 to 8

[0053] The detailed formulas of the plain tablets of the melogabalin besylate preparation compositions of Examples 1 to 8 are shown in Table 1.

[0054] The acrylic acid grafted starch used in Examples 1 to 8 is acrylic acid grafted starch 300 produced by Sanyo Chemical Industries, Ltd. of Japan, which is obtained by graft copolymerization of acrylic acid monomer and natural starch at a molar ratio of 4 to 6:1. The water absorption rate is about 300 g / g.

[0055] The preparation method of the plain tablets of the melogabalin besylate preparation composition of Examples 1 to 8 is as follows:

[0056] Melogabalin besylate, mannitol, carboxymethylcellulose calcium, acrylic acid grafted starch, and glutathione were prepared according to the proportions listed in Table 1, mixed in a mixing device, and then lubricated with magnesium stearate to obtain a melogabalin besylate composition mixed powder. The melogabalin besylate composition mixed powder was placed in the hopper of a tablet press and compressed according to the weight standards listed in Table 1 to obtain melogabalin besylate tablets.

[0057] The obtained melogabalin besylate tablets are placed in a high-efficiency coating machine for film coating to obtain melogabalin besylate tablets (coated).

[0058] The obtained melogabalin besylate tablets (coated) are inner packaged using "aluminum-plastic packaging + boxing" (abbreviated as: inner packaging a) or "aluminum-plastic packaging + outer pharmaceutical composite film bag, molecular sieve desiccant is placed in the bag, and then boxing" (abbreviated as: inner packaging b).

[0059] Table 1 Detailed formula of the melogabalin besylate preparation composition tablets of Examples 1 to 8

[0060]

[0061] The melogabalin besylate tablets of Examples 1 to 5 contain 8.78 mg of melogabalin besylate per tablet, as C 12 H 19NO2 is calculated as 5 mg / tablet.

[0062] The melogabalin besylate tablets of Example 6 contain 4.39 mg of melogabalin besylate per tablet. 12 H 19 NO2 is calculated as 2.5 mg / tablet.

[0063] The melogabalin besylate tablets of Example 7 contain 17.56 mg of melogabalin besylate per tablet. 12 H 19 NO2 is calculated as 10 mg / tablet.

[0064] The melogabalin besylate tablets of Example 8 contain 26.34 mg of melogabalin besylate per tablet. 12 H 19 NO2 is calculated as 15 mg / tablet.

[0065] The film coating weight of the melogabalin besylate tablets of Example 1 is 6 mg, and the film coating accounts for 3.0% of the weight of the plain tablets.

[0066] The film coating weight of the melogabalin besylate tablets of Example 2 is 6 mg, and the film coating accounts for 3.0% of the weight of the plain tablets.

[0067] The film coating weight of the melogabalin besylate tablets of Example 3 is 6 mg, and the film coating accounts for 3.0% of the weight of the plain tablets.

[0068] The film coating weight of the melogabalin besylate tablets of Example 4 is 6 mg, and the film coating accounts for 3.0% of the weight of the plain tablets.

[0069] The film coating weight of the melogabalin besylate tablets of Example 5 is 6 mg, and the film coating accounts for 3.0% of the weight of the plain tablets.

[0070] The film coating weight of the melogabalin besylate tablets of Example 6 is 4 mg, and the film coating accounts for 4.0% of the weight of the plain tablets.

[0071] The film coating weight of the melogabalin besylate tablets of Example 7 is 12 mg, and the film coating accounts for 4.0% of the weight of the plain tablets.

[0072] The film coating weight of the melogabalin besylate tablets of Example 8 is 15 mg, and the film coating accounts for 5.0% of the weight of the plain tablets.

[0073] Examples 9-11

[0074] The detailed formulas of the plain tablets of the melogabalin besylate preparation compositions of Examples 9 to 11 are shown in Table 2.

[0075] Table 2 Detailed formula of the melogabalin besylate tablets of Examples 9 to 11

[0076]

[0077] The acrylic acid grafted starch used in Examples 9 to 11 was acrylic acid grafted starch 1000 produced by Sanyo Chemical Industries, Ltd. of Japan, which was obtained by graft copolymerization of acrylic acid monomer and natural starch at a molar ratio of 8:1. The water absorption rate was about 1000 g / g.

[0078] The preparation method of the plain tablets of the melogabalin besylate preparation composition of Examples 9 to 11 is the same as that of Examples 1 to 8.

[0079] The melogabalin besylate tablets of Examples 9 to 11 contain 8.78 mg of melogabalin besylate per tablet. 12 H 19 NO2 is calculated as 5 mg / tablet.

[0080] The film coating weight of the melogabalin besylate tablets of Example 9 was 6 mg, and the film coating accounted for 3.0% of the weight of the plain tablets.

[0081] The film coating weight of the melogabalin besylate tablets of Example 10 is 6 mg, and the film coating accounts for 3.0% of the weight of the plain tablets.

[0082] The film coating weight of the melogabalin besylate tablets of Example 11 is 6 mg, and the film coating accounts for 3.0% of the weight of the plain tablets.

[0083] Comparative Example 1

[0084] The tablets of comparative example 1 were the original commercially available melogabalin besylate tablets, in their original packaging. Specification: 5 mg, originally manufactured by Daiichi Sankyo Co., Ltd., Japan, under the trade name of タリージェ ® (TARLIGE ® ), listed country: Japan; batch number: YBA2293.

[0085] Comparative Example 2

[0086] The original commercially available product, melogabalin besylate tablets, was used as the tablets of Comparative Example 1, and the drug information was the same as that of Comparative Example 1; the composite film bag and molecular sieve desiccant in the packaging of the original commercially available product were removed, and only the aluminum-plastic packaging plate was placed in its original box.

[0087] Comparative Example 3, Comparative Example 4, Example 12

[0088] The detailed formulas of the plain tablets of the melogabalin besylate preparation compositions of Comparative Example 3, Comparative Example 4, and Example 12 are shown in Table 3.

[0089] Compared with Example 2, Comparative Example 3 replaces the moisture-proofing agent acrylic acid grafted starch in Example 2 with magnesium aluminum metasilicate, and other raw materials are the same.

[0090] Compared with Example 2, in Comparative Example 4, the moisture-proofing agent acrylic acid grafted starch in Example 2 is replaced by magnesium aluminum metasilicate, and the antioxidant glutathione is replaced by tocopherol, while other raw materials are the same.

[0091] Compared with Example 2, Example 12 replaces the antioxidant glutathione in Example 2 with tocopherol, while other raw materials are the same.

[0092] The preparation method of the plain tablets of the melogabalin besylate preparation composition of Comparative Example 3 is the same as that of Example 2.

[0093] Comparative Example 4 and Example 12 use tocopherol as an antioxidant, so the preparation process is relatively complicated. The preparation method of the melogabalin besylate preparation composition tablet of Comparative Example 4 and Example 12 is as follows:

[0094] Carboxymethylcellulose calcium and tocopherol were prepared according to the formula ratio in Table 3, mixed in a mortar until no obvious oil was left, and then passed through a 40-mesh sieve and mixed for not less than 5 times to obtain a premixed powder; melogabalin besylate, mannitol, the premixed powder, and a moisture-proof agent (acrylic acid grafted starch or magnesium aluminum metasilicate) were prepared according to the formula ratio in Table 3 above, placed in a mixing device and mixed, and then magnesium stearate as a lubricant was added to obtain a melogabalin besylate composition mixed powder.

[0095] The obtained mixed powder of the melogabalin besylate composition was placed in the hopper of a tablet press and compressed according to the weight standard in Table 3 to obtain melogabalin besylate tablets.

[0096] The obtained melogabalin besylate tablets are placed in a high-efficiency coating machine for film coating to obtain melogabalin besylate tablets (coated).

[0097] The obtained melogabalin besylate tablets (coated) are inner packaged using "aluminum-plastic packaging + boxing" (abbreviated as: inner packaging a) or "aluminum-plastic packaging + outer pharmaceutical composite film bag, molecular sieve desiccant is placed in the bag, and then boxing" (abbreviated as: inner packaging b).

[0098] Table 3 Detailed formula of the plain tablets of the melogabalin besylate preparation composition of Comparative Example 3, Comparative Example 4, and Example 12

[0099]

[0100] Comparative Example 3, Comparative Example 4, and Example 12 contain 8.78 mg of melogabalin besylate per tablet. 12 H 19 NO2 is calculated as 5 mg / tablet.

[0101] The film coating weight of the melogabalin besylate tablets of Comparative Example 3 was 6 mg, and the film coating accounted for 3.0% of the weight of the plain tablets.

[0102] The film coating weight of the melogabalin besylate tablets of Comparative Example 4 was 6 mg, and the film coating accounted for 3.0% of the weight of the plain tablets.

[0103] The film coating weight of the melogabalin besylate tablets of Example 12 is 6 mg, and the film coating accounts for 3.0% of the weight of the plain tablets.

[0104] For ease of comparison, the usage of moisture-proof agents and antioxidants in various embodiments and comparative examples are summarized in Table 4. The percentages in Table 4 refer to the proportion of the amount of the component used in the total weight of the plain tablet.

[0105] Table 4 The usage of moisture-proof agent and antioxidant in each embodiment and each comparative example

[0106]

[0107] Stability evaluation

[0108] The stability of samples using two types of inner packaging (inner packaging a and inner packaging b) in Examples 1 to 3, samples using inner packaging a in Examples 4 to 12, samples in Comparative Example 1 (original research and commercial product in original packaging), samples in Comparative Example 2 (original research and commercial product, removing the outer medicinal composite film bag and the molecular sieve desiccant in the bag, and only the aluminum-plastic plate + boxing, i.e., inner packaging c, equivalent to inner packaging a), and samples in Comparative Examples 3 to 4 using inner packaging a were tested.

[0109] (I) The method is as follows: the samples are placed at a high temperature of 60±2℃ for observation, and samples are taken at 0 days and 30 days for observation, and the relevant substances are detected. Explanation on the use of high temperature 60℃ to evaluate the stability of each embodiment / comparative example: (1) In the evaluation of drug stability, it is a common method to use high temperature conditions (such as 60℃) for accelerated testing, the purpose of which is to predict the stability (i.e., shelf life) of the drug under long-term storage conditions (such as 25℃) in a relatively short period of time. This prediction is usually based on the Arrhenius equation, which describes the effect of temperature on the rate of chemical reactions and assumes that the reaction activation energy (Ea) of the drug degradation reaction is a constant within a certain temperature range (such as 25℃~60℃). (2) The shelf life of the original marketed product of melogabalin besylate tablets under storage conditions (sealed and stored in a dry place not exceeding 25℃) is 36 months. Based on the above reaction activation energy assumption, a 30-day observation at 60℃ is usually equivalent to a shelf life of 2 to 4 years under long-term conditions at 25℃.

[0110] (2) The inner packaging description is as follows:

[0111] Inner packaging a: aluminum-plastic packaging + boxing;

[0112] Inner packaging b: aluminum-plastic packaging + outer medicinal composite film bag, molecular sieve desiccant is placed in the bag, and then packed in a box;

[0113] Original commercial packaging: aluminum-plastic packaging + outer medicinal composite film bag, molecular sieve desiccant is placed in the bag, and then packed in a box;

[0114] Inner packaging c: Based on the original commercial product packaging, remove the outer medicinal composite film bag and the molecular sieve desiccant inside the bag, and only retain the aluminum-plastic packaging + boxing; equivalent to inner packaging a.

[0115] (3) Detection methods for relevant substances

[0116] Determined according to high performance liquid chromatography (General Chapter 0512 of the Chinese Pharmacopoeia 2020 edition).

[0117] (1) Test solution. Take 4 tablets of this product, place them in a centrifuge tube, add 20 mL of solvent [0.01 mol / L diammonium hydrogen phosphate buffer (pH 6.2)-acetonitrile (9:1)], shake to disintegrate, shake well, filter through a filter membrane (PTFE, 0.2 μm), discard 2 mL of the initial filtrate, and take the subsequent filtrate.

[0118] (2) Control solution. Accurately measure 1 mL of the test solution into a 100 mL volumetric flask, dilute to the mark with solvent, and shake well.

[0119] (3) Chromatographic conditions. Use octadecylsilane bonded silica gel as the filler (SunShell C18, 2.1 mm × 100 mm, 2.6 μm or equivalent performance column); 0.01 mol / L diammonium hydrogen phosphate buffer (pH 6.2) as mobile phase A, methanol-acetonitrile-0.01 mol / L diammonium hydrogen phosphate buffer (pH 6.2) (volume ratio 9:3:4) as mobile phase B, and perform gradient elution; detection wavelength is 215 nm; flow rate is 0.5 mL / min; column temperature is 45°C; injection volume is 3 μL. The specific conditions of gradient elution are as follows:

[0120] .

[0121] (4) Determination method: Accurately measure the test solution and the control solution, inject them into the liquid chromatograph respectively, and record the chromatogram for 27 minutes.

[0122] (5) Limits. If there are impurity peaks in the chromatogram of the test solution, after deducting the solvent peak, excipients, benzenesulfonate, and anisole peaks, the other peak areas are divided by the relative response factor and compared with the main peak area of ​​the control solution. The corrected peak area of ​​impurity A shall not be greater than 0.8 times (0.8%) of the main peak area of ​​the control solution, the corrected peak area of ​​other single impurities shall not be greater than 0.2 times (0.2%) of the main peak area of ​​the control solution, and the corrected peak area of ​​the total amount of impurities shall not be greater than 1.0 times (1.0%) of the main peak area of ​​the control solution (the relative retention time and relative response factor of each impurity peak are shown in the table below). Impurity A is an intramolecular amide bond impurity formed by the primary amino group and the carboxylic acid group on the benzenesulfonic acid melogabalin molecule, with the molecular formula C 12 H 17 NO, the name can be recorded as:

[0123] ;

[0124] The structural formula is as follows:

[0125] .

[0126] The stability test results of the products of various embodiments and comparative examples are shown in Table 5.

[0127] The impurity increase amount of each impurity (impurity A, other largest single impurities, total impurities) of the sample of Example 2-inner packaging a, the sample of Example 2-inner packaging b, the sample of Comparative Example 1 (original packaging original research and commercial product), and the sample of Comparative Example 2 (original research and commercial product, inner packaging c - equivalent to inner packaging a) after high temperature 60℃ for 30 days is plotted as a bar graph, see Figure 1 .

[0128] Through Table 5 and Figure 1 It can be seen that:

[0129] (1) The tablet samples of Examples 1 to 3 were packaged in two ways (inner package a and inner package b), and the tablet samples of Examples 4 to 12 were packaged in inner package a. After being heated at 60°C for 30 days, the impurity A, the maximum single impurity, and the total amount of impurities were all within the limits;

[0130] (2) After being subjected to high temperature testing at 60°C for 30 days, the impurity A and the total amount of impurities in the samples of Comparative Example 1 (original research and commercial product in original packaging), Comparative Example 2 (original research and commercial product, inner packaging c - equivalent to inner packaging a), and the tablet samples of Comparative Examples 3 and 4 (inner packaging a) all significantly exceeded the limit, especially in Comparative Examples 2 and 4, where the increase in impurity A exceeded 9%;

[0131] (3) There is a significant difference in the preservation effect between the sample of Comparative Example 2 (original commercial product, inner packaging c - equivalent to inner packaging a) and the sample of Comparative Example 1 (original commercial product in original packaging), indicating that the preservation of the original commercial product is heavily dependent on its packaging; the tablet samples of Examples 1 to 3 respectively used the simpler inner packaging a and the more complex inner packaging b, and the results showed that the preservation effect of the two was similar, indicating that the product of the present invention has lower packaging requirements during storage, and its stability can be guaranteed by the formulation composition itself;

[0132] (4) Comparison of the stability results of each group showed that the stability of the samples prepared using the composition of the present invention was significantly better than that of the comparative examples, including the original commercial products in their original packaging; and the samples prepared using the composition of the present invention did not require complex inner packaging;

[0133] (5) Comparison of the stability results of each group showed that the melogabalin besylate preparation composition prepared by the technology of the present invention not only has a simple preparation process and simple packaging, but also the content of each individual impurity and the total impurity content of the prepared melogabalin besylate preparation during storage are significantly lower than those of the commercially available preparation, thereby effectively improving the safety of the melogabalin besylate preparation.

[0134] Table 5 Stability test results of Examples 1 to 8 and Comparative Examples 1 to 5

[0135]

[0136] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A melogabalin besylate preparation composition with excellent stability, characterized in that: The invention comprises an active pharmaceutical ingredient, a moisture-proof agent, an antioxidant, a filler, a disintegrant and a lubricant; the moisture-proof agent comprises acrylic acid grafted starch; the preparation contains a coating or does not contain a coating; Excluding the coating weight, the amount of the moisture-proof agent is 1% to 10% of the total weight of the preparation; Excluding the weight of the coating, the amount of the antioxidant is 2% to 5% of the total weight of the preparation; The water absorption rate of the acrylic acid grafted starch is 300g / g to 10000g / g; The filler includes one or more of microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, starch and its derivatives, dextrin, lactose monohydrate, anhydrous lactose, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, maltodextrin, maltose, D-mannitol, sorbitol, sucrose, trehalose, and xylitol; The disintegrant includes one or more of carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, polacrilin potassium, sodium starch glycolate, sodium carboxymethyl starch, starch, and pregelatinized starch; The lubricant includes one or more of magnesium stearate, glyceryl distearate, glyceryl behenate, sodium stearyl fumarate, talc, polyethylene glycol, magnesium lauryl sulfate, sodium lauryl sulfate, micropowder silica gel, and colloidal silicon dioxide.

2. The melogabalin besylate preparation composition with excellent stability according to claim 1, characterized in that: C 12 H 19 Each dosage unit contains 1mg to 20mg of active pharmaceutical ingredient in terms of NO2.

3. The melogabalin besylate preparation composition with excellent stability according to claim 1, characterized in that: The antioxidants include glutathione and / or tocopherol.

4. The melogabalin besylate preparation composition with excellent stability according to claim 3, characterized in that: Excluding the coating weight, the amount of glutathione and / or tocopherol used is 2% to 5% of the total weight of the preparation.

5. The melogabalin besylate preparation composition with excellent stability according to claim 1, characterized in that: Excluding the coating weight, the amount of the acrylic acid grafted starch is 2% to 10% of the total weight of the preparation.

6. The melogabalin besylate preparation composition having excellent stability according to claim 3 or 4, characterized in that: The antioxidant further comprises one or more of citric acid hydrate, sodium edetate, sodium bisulfite, butylated hydroxytoluene, sodium sulfite, ascorbic acid, 1,3-butylene glycol, sodium metabisulfite, butylated hydroxyanisole, tocopheryl acetate, soy lecithin, propyl gallate, anhydrous magnesium citrate, isoascorbic acid, sodium thioacetate, ascorbyl palmitate, α-thioglycerol, sodium nitrite, L-ascorbyl stearate, cysteine ​​hydrochloride, benzotriazole, sodium thiomalate, natural vitamin E, potassium dichloroisocyanurate, mixed tocopherol concentrate, pentaerythritol tetrakis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate], 2-aminobenzimidazole, magnesium citrate hydrate, and β-cyclodextrin.

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