Melogabalin besylate tablet and preparation method thereof

Abstract

The invention provides melogabalin besylate tablets and a preparation method thereof. The melogabalin besylate tablets comprise melogabalin besylate, a filler, a disintegrating agent, an acid stabilizer, an antioxidant, a lubricant, a flow aid and a gastric-soluble film coating agent. The antioxidant comprises gallic acid, the acid stabilizer comprises maleic acid, and the filler comprises directly pressed starch, isomaltitol, mannitol and microcrystalline cellulose. By screening the antioxidant and the acid stabilizer, the stability of the tablet in the storage period is improved.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a melogabalin besylate tablet and a preparation method thereof. Background Art

[0002] Mirogabalin besylate is a GABA analog that acts on the α2-δ1 subunit of the voltage-sensitive calcium channel complex (widely present in the nervous system that mediates pain transmission and processing throughout the body), thereby playing a role in treating chronic neuropathic pain. Its chemical name is [(1R, 5S, 6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid monobenzenesulfonate, and its structural formula is shown below.

[0003]

[0004] In January 2019, Daiichi Sankyo Co., Ltd.'s Tarlige (Melogabalin Besylate Tablets) 2.5mg, 5mg, 10mg, and 15mg were first approved for marketing in Japan for the treatment of peripheral neuropathic pain (PNP). The original patent CN107405322B protects a solid preparation containing melogabalin besylate, involving a composition containing a filler, a disintegrant, and an antioxidant.

[0005] The original drug used two stabilizers, tocopherol and citric acid, to inhibit the oxidative degradation of the drug during long-term storage and the impurities produced by the intramolecular amide reaction. However, the impurity level of the drug is still high during storage, which affects the safety and effectiveness of the drug in clinical application. In order to obtain drugs with lower impurity levels, it is necessary to screen other types of stabilizers. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a melogabalin besylate tablet and a preparation method thereof. The tablet comprises melogabalin besylate, a filler, a disintegrant, an acid stabilizer, an antioxidant, a lubricant, a glidant and a gastric soluble film coating agent.

[0007] According to an embodiment of the present invention, the antioxidant comprises gallic acid.

[0008] According to an embodiment of the present invention, the acidic stabilizer comprises maleic acid.

[0009] According to an embodiment of the present invention, the antioxidant (such as gallic acid) accounts for 0.5% to 8% of the weight of the tablet core, preferably 1.0 to 6.0%, more preferably 2.0 to 5.0%, and further preferably 3.0 to 5.0%, for example 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%.

[0010] According to an embodiment of the present invention, the acidic stabilizer (such as maleic acid) accounts for 0% to 8% of the tablet core weight, preferably 1.0 to 6.0%, more preferably 2.0 to 5.0%, for example 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%.

[0011] According to an embodiment of the present invention, the filler is selected from one or more of direct-compressed starch, isomalt, corn starch, pregelatinized starch, mannitol and microcrystalline cellulose, preferably one or more of direct-compressed starch, isomalt, mannitol and microcrystalline cellulose, more preferably mannitol and microcrystalline cellulose.

[0012] According to an embodiment of the present invention, the mannitol is D-mannitol, preferably D-mannitol 200SD.

[0013] According to an embodiment of the present invention, the disintegrant is selected from one or more of carboxymethylcellulose calcium, sodium carboxymethyl starch, cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose, preferably carboxymethylcellulose calcium.

[0014] According to an embodiment of the present invention, the glidant is selected from one or more of magnesium aluminum metasilicate, calcium silicate, magnesium aluminum silicate or colloidal silicon dioxide, preferably magnesium aluminum metasilicate.

[0015] According to an embodiment of the present invention, the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate or talc, preferably magnesium stearate.

[0016] According to an embodiment of the present invention, the filler accounts for 60% to 95% of the weight of the tablet core, preferably 70% to 90%, more preferably 75% to 85%, for example 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%.

[0017] According to an embodiment of the present invention, when the filler is a combination of two of direct-compressed starch, isomalt, corn starch, pregelatinized starch, mannitol and microcrystalline cellulose, one of the fillers (such as direct-compressed starch, isomalt, mannitol) accounts for 50% to 85% of the weight of the tablet core, preferably 60% to 80%, more preferably 70% to 80%, for example 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%; the other filler (such as microcrystalline cellulose) accounts for 1% to 10% of the weight of the tablet core, preferably 3% to 6%, more preferably 4% to 5%, for example 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%.

[0018] According to an embodiment of the present invention, the disintegrant accounts for 1% to 8% by weight of the tablet core, preferably 3% to 7%, and more preferably 4% to 6%.

[0019] According to an embodiment of the present invention, the glidant accounts for 0.02% to 1.5% of the weight of the tablet core, preferably 0.05% to 1%, and more preferably 0.1% to 0.5%.

[0020] According to an embodiment of the present invention, the lubricant accounts for 0.5% to 3% of the weight of the tablet core, more preferably 1% to 2%.

[0021] According to an embodiment of the present invention, the present invention provides a melogabalin besylate tablet, comprising melogabalin besylate, mannitol, microcrystalline cellulose, carboxymethylcellulose calcium, gallic acid, maleic acid, magnesium aluminum metasilicate, magnesium stearate and a film coating agent, wherein the proportion of each component to the weight of the tablet core is as follows:

[0022]

[0023] According to an embodiment of the present invention, the present invention provides a melogabalin besylate tablet, comprising melogabalin besylate, direct-compressed starch, microcrystalline cellulose, carboxymethylcellulose calcium, gallic acid, maleic acid, magnesium stearate and a film coating agent, wherein the proportion of each component to the weight of the tablet core is as follows:

[0024]

[0025] According to an embodiment of the present invention, the present invention provides a melogabalin besylate tablet, comprising melogabalin besylate, isomalt, microcrystalline cellulose, carboxymethylcellulose calcium, gallic acid, maleic acid, magnesium stearate and a film coating agent, wherein the proportion of each component to the weight of the tablet core is as follows:

[0026]

[0027] According to an embodiment of the present invention, the present invention provides a melogabalin besylate tablet, comprising melogabalin besylate, pregelatinized starch, microcrystalline cellulose, carboxymethylcellulose calcium, gallic acid, maleic acid, magnesium stearate and a film coating agent, wherein the proportion of each component to the weight of the tablet core is as follows:

[0028]

[0029]

[0030] According to an embodiment of the present invention, the present invention provides a melogabalin besylate tablet, comprising melogabalin besylate, mannitol, microcrystalline cellulose, carboxymethylcellulose calcium, gallic acid, maleic acid, magnesium stearate and a film coating agent, wherein the proportion of each component to the weight of the tablet core is as follows:

[0031]

[0032] According to an embodiment of the present invention, the present invention provides a melogabalin besylate tablet, comprising melogabalin besylate, mannitol, microcrystalline cellulose, carboxymethylcellulose calcium, gallic acid, magnesium stearate and a film coating agent, wherein the proportion of each component to the weight of the tablet core is as follows:

[0033]

[0034]

[0035] According to an embodiment of the present invention, the present invention provides a melogabalin besylate tablet, comprising melogabalin besylate, mannitol, microcrystalline cellulose, carboxymethylcellulose calcium, gallic acid, magnesium stearate and a film coating agent, wherein the proportion of each component to the weight of the tablet core is as follows:

[0036]

[0037] According to an embodiment of the present invention, the present invention provides a melogabalin besylate tablet, comprising melogabalin besylate, mannitol, microcrystalline cellulose, carboxymethylcellulose calcium, gallic acid, magnesium stearate and a film coating agent, wherein the proportion of each component to the weight of the tablet core is as follows:

[0038]

[0039] According to an embodiment of the present invention, the present invention provides a melogabalin besylate tablet, comprising melogabalin besylate, any one of mannitol / directly compressed starch / isomaltitol / pregelatinized starch, microcrystalline cellulose, carboxymethylcellulose calcium, gallic acid, maleic acid, magnesium stearate and a film coating agent, wherein the proportion of each component to the weight of the tablet core is as follows:

[0040]

[0041]

[0042] According to an embodiment of the present invention, the specification of the melogabalin besylate tablet is 2.5 mg, 5 mg, 10 mg or 15 mg.

[0043] According to an embodiment of the present invention, the gastric soluble film coating material of the melogabalin besylate tablets provided by the present invention can be selected from common polymer materials, such as hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyethylene glycol-polyvinyl alcohol (PEG-PVA) and acrylic resin, preferably hydroxypropyl methylcellulose.

[0044] According to an embodiment of the present invention, an anti-adherent, a plasticizer and a colorant are further added to the melogabalin besylate tablets of the present invention as coating materials; the anti-adherent includes talcum powder and / or stearic acid, preferably talcum powder; the plasticizer includes one or more of polyethylene glycol, triethyl citrate, propylene glycol, and glycerol, preferably polyethylene glycol; the colorant includes one or more of titanium dioxide, red iron oxide, yellow iron oxide, and carmine.

[0045] The present invention also provides a method for preparing melogabalin besylate tablets, comprising the following steps:

[0046] 1) Mix melogabalin besylate, antioxidant and acid stabilizer and pass through a 60-mesh sieve;

[0047] 2) Add the prescribed amount of filler, disintegrant and glidant and mix;

[0048] 3) Weighing the prescribed amount of lubricant and adding it to step 2) for total mixing;

[0049] 4) Use appropriate punches to directly press tablets to control tablet weight and hardness;

[0050] 5) preparing a coating solution and coating the tablet cores prepared in step 4) to increase the tablet core weight by 2-3%.

[0051] Beneficial Effects

[0052] The inventors screened antioxidants and acidic stabilizers through a large number of experiments and surprisingly found that gallic acid and maleic acid can significantly reduce the level of total impurities in melogabalin besylate tablets and improve the stability of the tablets during storage. DETAILED DESCRIPTION

[0053] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0054] The "melogabalin besylate" used in the present invention is a salt formed from melogabalin and benzenesulfonic acid, and its structural formula is shown below.

[0055]

[0056] The melogabalin besylate used in the present invention accounts for 1% to 15% of the tablet core weight, preferably 5% to 10%, for example 5%, 6%, 7%, 8%, 9%, 10%.

[0057] The tablet used in the present invention may contain various "additives" generally used in tablet production unless the effects of the present invention are impaired.

[0058] Examples of "additives" include fillers, disintegrants, acid stabilizers, antioxidants, lubricants, glidants, binders, coating agents, anti-adherent agents, plasticizers, colorants, flavoring agents, sweeteners, taste-masking agents, fluidizers, foaming agents, and surfactants.

[0059] Original formulation: Melogabalin besylate tablets, specification 5mg, is a product launched by Daiichi Sankyo in Japan. Its composition includes: Melogabalin besylate, mannitol, microcrystalline cellulose, hydroxymethylcellulose calcium, DL-α-tocopherol, magnesium aluminum metasilicate, citric acid monohydrate, magnesium stearate, and film coating premix.

[0060] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0061] Embodiment 1~4:

[0062]

[0063] The preparation method of melogabalin besylate tablets comprises the following steps:

[0064] 1) Mix melogabalin besylate, antioxidant and acid stabilizer and pass through a 60-mesh sieve;

[0065] 2) Add the prescribed amount of filler, disintegrant and glidant and mix;

[0066] 3) weighing the prescribed amount of magnesium stearate and adding it to step 2) for total mixing;

[0067] 4) Use 7mm round punch to directly press the tablets to control tablet weight and hardness;

[0068] 5) preparing a coating solution and coating the tablet cores prepared in step 4) to increase the tablet core weight by 2-3%.

[0069] Embodiment 5~8:

[0070]

[0071]

[0072] The types of fillers were selected as D-mannitol 200SD / directly compressed starch / isomaltitol / pregelatinized starch to prepare Examples 5 to 8 respectively.

[0073] The preparation method of melogabalin besylate tablets comprises the following steps:

[0074] 1) Mix melogabalin besylate, antioxidant and acid stabilizer, and pass through 80 mesh sieve;

[0075] 2) Add the prescribed amount of filler, disintegrant and glidant and mix;

[0076] 3) weighing the prescribed amount of magnesium stearate and adding it to step 2) for total mixing;

[0077] 4) Use 7mm round punch to directly press the tablets to control tablet weight and hardness;

[0078] 5) preparing a coating solution and coating the tablet cores prepared in step 4) to increase the tablet core weight by 2-3%.

[0079] Comparative Examples 1 to 3:

[0080]

[0081]

[0082] The types of fillers were selected as D-mannitol 200SD / directly compressed starch / isomaltitol to prepare comparative examples 1 to 3 respectively.

[0083] The preparation method of melogabalin besylate tablets comprises the following steps:

[0084] 1) passing melogabalin benzenesulfonate through a 80-mesh sieve;

[0085] 2) Add the prescribed amount of filler, disintegrant and glidant and mix;

[0086] 3) weighing the prescribed amount of magnesium stearate and adding it to step 2) for total mixing;

[0087] 4) Use 7mm round punch to directly press the tablets to control tablet weight and hardness;

[0088] 5) preparing a coating solution and coating the tablet cores prepared in step 4) to increase the tablet core weight by 2-3%.

[0089] Stability studies

[0090] 1. High temperature and high humidity test inspection

[0091] (1) Test conditions

[0092] Tablets of Examples 1 to 4 and the original formulation (specification: 5 mg) were placed in a high humidity environment (90% RH ± 5% RH) and a high temperature (60°C ± 2°C), respectively. The levels of oxidative degradation impurities (impurity 1) and lactamized impurities (impurity 2) of the tablets were detected by high performance liquid chromatography.

[0093] (2) Related substance detection methods

[0094] Chromatographic column: octadecylsilane bonded silica gel as filler (250mm*4.6mm, 5μm); mobile phase: 0.01mol / L dipotassium hydrogen phosphate solution (pH value adjusted to 6.5 with phosphoric acid) as mobile phase A, acetonitrile as mobile phase B, gradient elution according to the table below; flow rate: 1.5ml per minute; column temperature: 30℃; detection wavelength: 210nm; injection volume: 10μl.

[0095]

[0096]

[0097] (3) Results

[0098]

[0099] 2. Accelerated test investigation

[0100] (1) Test conditions

[0101] Examples 1 to 8 and Comparative Examples 1 to 3 were placed in a high-density polyethylene bottle and sealed with a plastic cap with a desiccant, and placed together with the original preparation (specification: 5 mg) in an environment of 40°C ± 2°C, 75% RH ± 5% RH, and the levels of oxidative degradation impurities (impurity 1) and lactamized impurities (impurity 2) in the tablets were detected by high performance liquid chromatography.

[0102] (2) Related substance detection methods

[0103] Chromatographic column: octadecylsilane bonded silica gel as filler (250mm*4.6mm, 5μm); mobile phase: 0.01mol / L dipotassium hydrogen phosphate solution (pH value adjusted to 6.5 with phosphoric acid) as mobile phase A, acetonitrile as mobile phase B, gradient elution according to the table below; flow rate: 1.5ml per minute; column temperature: 30℃; detection wavelength: 210nm; injection volume: 10μl.

[0104]

[0105] (3) Results

[0106]

[0107] Conclusion: In the presence of desiccant, the level of total impurities was significantly reduced, indicating that desiccant can be added to pharmaceutical packaging materials to extend the shelf life of the drug.

[0108] The above is a description of the exemplary embodiments of the present invention. However, the protection scope of the present application is not limited to the above embodiments. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A melogabalin besylate tablet, characterized in that: The tablet comprises melogabalin besylate, a filler, a disintegrant, an acidic stabilizer, an antioxidant, a lubricant, a glidant and a gastric soluble film coating agent, wherein the antioxidant comprises gallic acid, the acidic stabilizer comprises maleic acid, the antioxidant (such as gallic acid) accounts for 0.5% to 8% of the weight of the tablet core, preferably 1.0 to 6.0%, more preferably 2.0 to 5.0%, and further preferably 3.0 to 5.0%, and the acidic stabilizer (such as maleic acid) accounts for 0% to 8% of the weight of the tablet core, preferably 1.0 to 6.0%, and more preferably 2.0 to 5.0%.

2. The melogabalin besylate tablet according to claim 1, characterized in that: The filler is selected from one or more of direct-compressed starch, isomalt, corn starch, pregelatinized starch, mannitol and microcrystalline cellulose, preferably one or more of direct-compressed starch, isomalt, mannitol and microcrystalline cellulose, more preferably mannitol and microcrystalline cellulose; for example, the mannitol is D-mannitol, preferably D-mannitol 200SD.

3. The melogabalin besylate tablet according to claim 1 or 2, characterized in that: The filler accounts for 60% to 95% of the weight of the tablet core, preferably 70% to 90%, and more preferably 75% to 85%; when the filler is a combination of two of direct-compressed starch, isomalt, corn starch, pregelatinized starch, mannitol and microcrystalline cellulose, one of the fillers (such as direct-compressed starch, isomalt, mannitol) accounts for 50% to 85% of the weight of the tablet core, preferably 60% to 80%, and more preferably 70% to 80%, and the other filler (such as microcrystalline cellulose) accounts for 1% to 10% of the weight of the tablet core, preferably 3% to 6%, and more preferably 4% to 5%.

4. The melogabalin besylate tablet according to any one of claims 1 to 3, characterized in that: The disintegrant is selected from one or more of carboxymethylcellulose calcium, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose, preferably carboxymethylcellulose calcium; for example, the disintegrant accounts for 1% to 8% of the weight of the tablet core, preferably 3% to 7%, and more preferably 4% to 6%.

5. The melogabalin besylate tablet according to any one of claims 1 to 4, characterized in that: The glidant is selected from one or more of magnesium aluminum metasilicate, calcium silicate, magnesium aluminum silicate or colloidal silicon dioxide, preferably magnesium aluminum metasilicate; for example, the glidant accounts for 0.02% to 1.5% of the weight of the tablet core, preferably 0.05% to 1%, more preferably 0.1% to 0.5%.

6. The melogabalin besylate tablet according to any one of claims 1 to 5, characterized in that: The lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate or talc, preferably magnesium stearate; for example, the lubricant accounts for 0.5% to 3% of the weight of the tablet core, more preferably 1% to 2%.

7. The melogabalin besylate tablet according to any one of claims 1 to 6, characterized in that: The proportion of each component in the tablet core weight is as follows: Or the proportion of each component to the weight of the tablet core is as follows: Or the proportion of each component to the weight of the tablet core is as follows: Or the proportion of each component to the weight of the tablet core is as follows:

8. The melogabalin besylate tablet according to any one of claims 1 to 7, characterized in that: The specifications of the melogabalin besylate tablets are 2.5 mg, 5 mg, 10 mg or 15 mg.

9. The melogabalin besylate tablet according to any one of claims 1 to 8, characterized in that: The gastric soluble film coating material can be selected from common polymer materials, such as hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyethylene glycol-polyvinyl alcohol (PEG-PVA) and acrylic resin, preferably hydroxypropyl methylcellulose; the melogabalin besylate tablets are further added with an anti-adhesive, a plasticizer and a colorant as coating materials; the anti-adhesive includes talcum powder and / or stearic acid, preferably talcum powder; the plasticizer includes one or more of polyethylene glycol, triethyl citrate, propylene glycol, and glycerol, preferably polyethylene glycol; the colorant includes one or more of titanium dioxide, red iron oxide, yellow iron oxide, and carmine.

10. The method for preparing the melogabalin besylate tablet according to any one of claims 1 to 9, characterized in that: The following steps are involved: 1) Mix melogabalin besylate, antioxidant and acid stabilizer and pass through a 60-mesh sieve; 2) Add the prescribed amount of filler, disintegrant and glidant and mix; 3) Weighing the prescribed amount of lubricant and adding it to step 2) for total mixing; 4) Use appropriate punches to directly press tablets to control tablet weight and hardness; 5) preparing a coating solution and coating the tablet cores prepared in step 4) to increase the tablet core weight by 2-3%.

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