Antioxidant-containing melogabalin besylate solid preparation

Abstract

The invention relates to a stable melogabalin besylate solid preparation containing an antioxidant, and belongs to the technical field of pharmaceutical preparations. The invention specifically provides a melogabalin besylate solid preparation, the solid preparation comprises melogabalin besylate and an antioxidant, the antioxidant is an amino acid antioxidant, and the solid preparation also comprises a metal ion chelating agent. The chemical stability of the pharmaceutical preparation provided by the invention is far better than that of a commercially available preparation under a high-temperature condition, the preparation process of the tablet is powder direct compression, the process is simple, the preparation process is stable, and the obtained pharmaceutical preparation is relatively low in related substance level and stable during storage.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a solid preparation of melogabalin besylate which is stabilized by containing an antioxidant. Background Art

[0002] Mirogabalin besylate is a GABA analog that acts on the α2-δ1 subunit of the voltage-sensitive calcium channel complex (which is widely present in the nervous system and mediates pain transmission and processing throughout the body), thereby 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. (Daiichi Sankyo) first approved its Tarlige (meloxaline besylate tablets) in 2.5mg, 5mg, 10mg, and 15mg dosage forms in Japan for the treatment of peripheral neuropathic pain (PNP). The original patent, CN107405322B, protects a solid dosage form containing melogabalin besylate, encompassing a composition comprising a filler, a disintegrant, and an antioxidant.

[0005] The original drug used two antioxidants, tocopherol and citric acid, to inhibit oxidative degradation and impurities produced by intramolecular amide reactions during long-term storage. However, the impurity level remained high during storage, affecting the safety and efficacy of the drug in clinical applications. To obtain drugs with lower impurity levels, it was necessary to screen for other types of stabilizers. Summary of the Invention

[0006] To solve the above technical problems, the inventors screened antioxidants and stabilizers through a large number of experiments and found that calcium sodium edetate and arginine can significantly reduce the level of total impurities in melogabalin besylate tablets and improve the stability of the tablets during storage.

[0007] The present invention provides a solid formulation of melogabalin besylate stabilized by containing an antioxidant and a method for preparing the same. The pharmaceutical formulation of the present invention includes an antioxidant to enhance the stability of the formulation during preparation and storage. Furthermore, a melogabalin besylate tablet stabilized by containing an antioxidant and a method for producing the stabilized tablet are provided.

[0008] The specific technical solutions of the present invention are as follows.

[0009] (1) A solid preparation of melogabalin besylate, comprising melogabalin besylate and an antioxidant, wherein the antioxidant is an amino acid antioxidant.

[0010] The solid preparation is in the form of tablets, powders, granules or capsules.

[0011] The amino acid antioxidants are arginine, lysine and leucine.

[0012] The solid preparation further comprises a metal ion chelating agent.

[0013] The metal ion chelating agent is calcium sodium edetate.

[0014] The amino acid antioxidant accounts for 0.5% to 3% of the total weight of the solid preparation, preferably 1.0 to 3.0%.

[0015] The amino acid antioxidant accounts for 1.0-2.7% of the total weight of the solid preparation.

[0016] The metal ion chelating agent accounts for 0% to 1% of the total weight of the solid preparation, preferably 0.1 to 0.5%.

[0017] The metal ion chelating agent accounts for 0.1 to 0.2% of the total weight of the solid preparation.

[0018] When the solid preparation is a tablet, it further comprises one or more of a filler, a disintegrant and a lubricant.

[0019] The filler is selected from one or more of isomalt, lactose, mannitol and microcrystalline cellulose, preferably one or more of isomalt, mannitol and microcrystalline cellulose, more preferably mannitol and microcrystalline cellulose.

[0020] The mannitol is D-mannitol, preferably D-mannitol 200SD.

[0021] The filler accounts for 60% to 95% of the total weight of the solid preparation, preferably 70% to 90%, and more preferably 75% to 85%.

[0022] When the filler is a combination of two of isomalt, lactose, pregelatinized starch, mannitol and microcrystalline cellulose, one of the fillers (such as direct-compressed starch, isomalt, mannitol) accounts for 50% to 85% of the total weight of the solid preparation, preferably 60% to 80%, more preferably 70% to 80%; the other filler (such as microcrystalline cellulose) accounts for 1% to 10% of the total weight of the solid preparation, preferably 3% to 6%, more preferably 4% to 5%.

[0023] 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.

[0024] The disintegrant accounts for 1% to 10% of the total weight of the solid preparation, preferably 3% to 7%, more preferably 4% to 6%.

[0025] The lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate or talc, preferably magnesium stearate.

[0026] The lubricant accounts for 0.5% to 3% of the total weight of the solid preparation, preferably 1% to 2%.

[0027] The tablet further contains a stabilizer, which is selected from one or more of magnesium aluminum metasilicate, calcium silicate, and magnesium aluminum silicate, preferably magnesium aluminum metasilicate.

[0028] The specifications of the melogabalin besylate solid preparation are 2.5 mg, 5 mg, 10 mg or 15 mg.

[0029] (2) A method for preparing melogabalin besylate tablets, comprising the following steps: 1) Mixing melogabalin besylate, a prescribed amount of a filler, a disintegrant, a stabilizer, and an antioxidant; 2) Weighing the prescribed amount of lubricant and adding it to the mixture prepared in the above step for total mixing; 3) Use appropriate punches for direct tableting to control tablet weight and hardness; 4) Prepare a coating solution and coat the tablet cores obtained in the above step to increase their weight by 2-3%.

[0030] Compared with the prior art, the present invention has the following advantages.

[0031] (1) The melogabalin besylate composition contained in the present invention has a chemical stability far superior to that of marketed preparations under high temperature conditions, which enhances the stability during storage and transportation, and ensures the safety and effectiveness of patients during use.

[0032] (2) The antioxidant used in the present invention is solid and is prepared by direct powder compression. The process is simple and the preparation process is stable. The resulting pharmaceutical preparation has a low level of related substances and is stable during storage. DETAILED DESCRIPTION Example 1

[0033] Vitamin E polyethylene glycol succinate (TPGS), arginine and formulation stability Raw materials Single tablet dosage (mg) Proportion(%) Melogabaline besylate 8.78 4.39 Microcrystalline cellulose 102 8 4 Mannitol 164.02 82 Carboxymethylcellulose calcium 10 5 TPGS 0.4 0.2 Arginine 5.4 2.7 Magnesium aluminum metasilicate 0.4 0.2 Magnesium stearate (MS) 3 1.5 .

[0034] Preparation Method: 1. Mixing: Mix all weighed raw materials and excipients, except magnesium stearate (MS), thoroughly. 2. Granulation: Pass the mixed materials through a 20-mesh sieve for granulation. 3. Final Blending: Add MS to the granulated materials and mix thoroughly. 4. Tablet Compression: Control the tablet weight to 200 mg (190-210 mg) and press the tablets at a hardness of 10 kg. 5. Coating: The coating solution has a solids content of 12% and a coating weight gain of 4%.

[0035] Stability storage: Accelerated testing was conducted at 40°C and 75% RH for 1 month and 2 months, and comparative testing of relevant substances was conducted with the original formulation (trade name: Delijing, marketing authorization holder: Daiichi Sankyo Co., Ltd.).

[0036] Test results: .

[0037] Conclusion: The levels of related substances in the preparation using TPGS and arginine under accelerated two-month conditions were comparable to those in the original preparation. Example 2

[0038] Calcium sodium edetate, arginine and preparation stability Raw materials Single tablet dosage (mg) Proportion(%) Melogabaline besylate 8.78 4.39 Microcrystalline cellulose 102 8 4 Mannitol 164.02 82 Carboxymethylcellulose calcium 10 5 Calcium sodium edetate 0.4 0.2 Arginine 5.4 2.7 Magnesium aluminum metasilicate 0.4 0.2 Magnesium stearate (MS) 3 1.5 .

[0039] Preparation Method: 1. Mixing: Mix the weighed raw and excipient materials, except MS, and mix thoroughly. 2. Granulation: Pass the mixed materials through a 20-mesh sieve for granulation. 3. Final Blending: Add MS to the granulated materials and mix thoroughly. 4. Tablet Compression: Control the tablet weight to 200 mg (190-210 mg) and press the tablets at a hardness of 10 kg. 5. Coating: The coating solution solids content is 12%, and the coating weight gain is 4%.

[0040] Stability storage: Accelerated testing was conducted at 40°C and 75% RH for 1 month and 2 months, and comparative testing of relevant substances was conducted with the original formulation (trade name: Delijing, marketing authorization holder: Daiichi Sankyo Co., Ltd.).

[0041] Dosage of patented antioxidants in the original formulation: Tocopherol accounts for 0.1%~0.2% of the total weight of the uncoated tablets, and citric acid accounts for 0.1%~3.0%.

[0042] Test results: .

[0043] Conclusion: Compared with the original formulation, the combination of arginine and edetate calcium significantly reduced the levels of related substances, with single impurities below 0.2% under accelerated conditions, and maintained stable quality. This also suggests that other metal ion chelators can achieve similar results, but are not as effective as edetate calcium sodium. Examples 3-4

[0044] According to the preparation process of Example 2, the prescription samples of antioxidants with different concentrations were prepared. .

[0045] Preparation Method: 1. Mixing: Mix the weighed raw and excipient materials, except MS, and mix thoroughly. 2. Granulation: Pass the mixed materials through a 20-mesh sieve for granulation. 3. Final Blending: Add MS to the granulated materials and mix thoroughly. 4. Tablet Compression: Control the tablet weight to 200 mg (190-210 mg) and press the tablets at a hardness of 10 kg. 5. Coating: The coating solution has a solids content of 12% and a coating weight gain of 4%.

[0046] Stability storage: Accelerate the test at 40℃, 75%RH for 1 month and 2 months, and conduct comparative test on relevant substances with the original preparation.

[0047] Test results: .

[0048] Conclusion: The levels of related substances were relatively stable when the dosage of arginine was within the range of 0.5-3.0% and were superior to those of the original preparation. Examples 5-6

[0049] According to the preparation process of Example 2, the prescription samples of metal ion chelating agents with different concentrations were prepared. .

[0050] Preparation Method: 1. Mixing: Mix the weighed raw and excipient materials, except MS, and mix thoroughly. 2. Granulation: Pass the mixed materials through a 20-mesh sieve for granulation. 3. Final Blending: Add MS to the granulated materials and mix thoroughly. 4. Tablet Compression: Control the tablet weight to 200 mg (190-210 mg) and press the tablets at a hardness of 10 kg. 5. Coating: The coating solution has a solids content of 12% and a coating weight gain of 4%.

[0051] Stability storage: Accelerate the test at 40℃, 75%RH for 1 month and 2 months, and conduct comparative test on relevant substances with the original preparation.

[0052] Test results: .

[0053] Conclusion: The levels of related substances in the dosage range of 0.1-0.2% of edetate calcium sodium were relatively stable and better than those of the original preparation. Examples 7-8

[0054] According to the preparation process of Example 2, different types of filler prescription samples were prepared. .

[0055] Preparation Method: 1. Mixing: Mix the weighed raw and excipient materials, except MS, and mix thoroughly. 2. Granulation: Pass the mixed materials through a 20-mesh sieve for granulation. 3. Final Blending: Add MS to the granulated materials and mix thoroughly. 4. Tablet Compression: Control the tablet weight to 200 mg (190-210 mg) and press the tablets at a hardness of 10 kg. 5. Coating: The coating solution solids content is 12%, and the coating weight gain is 4%.

[0056] Stability storage: Accelerate the test at 40℃, 75%RH for 1 month and 2 months, and conduct comparative test on relevant substances with reference preparation.

[0057] Test results: .

[0058] Conclusion: By comparing the effects of different fillers on the levels of related substances in the preparations, it was found that different types of fillers had little effect on the related substances. Examples 9-11

[0059] According to the preparation process of Example 2, different types of disintegrant prescription samples were prepared. .

[0060] Preparation Method: 1. Mixing: Mix the weighed raw and excipient materials, except MS, and mix thoroughly. 2. Granulation: Pass the mixed materials through a 20-mesh sieve for granulation. 3. Final Blending: Add MS to the granulated materials and mix thoroughly. 4. Tablet Compression: Control the tablet weight to 200 mg (190-210 mg) and press the tablets at a hardness of 10 kg. 5. Coating: The coating solution has a solids content of 12% and a coating weight gain of 4%.

[0061] Stability storage: Accelerate the test at 40℃, 75%RH for 1 month and 2 months, and conduct comparative test on relevant substances with the original preparation.

[0062] Test results: .

[0063] Conclusion: By comparing the effects of different disintegrants on the levels of related substances in the preparations, it was found that different types of disintegrants had little effect on the related substances.

[0064]

Claims

1. A solid preparation of melogabalin besylate, comprising melogabalin besylate and an antioxidant, wherein the antioxidant is an amino acid antioxidant.

2. The solid preparation according to claim 1, which is in the form of tablets, powders, granules or capsules.

3. The solid preparation according to claim 1, wherein the amino acid antioxidant is selected from arginine, lysine, and leucine. The solid preparation according to claim 1 , further comprising a metal ion chelating agent. The solid preparation according to claim 4 , wherein the metal ion chelator is calcium sodium edetate.

6. The solid preparation according to claim 1, wherein the amino acid antioxidant accounts for 0.5% to 3% of the total weight of the solid preparation, preferably 1.0 to 3.0%.

7. The solid preparation according to claim 1, wherein the amino acid antioxidant accounts for 1.0-2.7% of the total weight of the solid preparation.

8. The solid preparation according to claim 4, wherein the metal ion chelating agent accounts for 0% to 1% of the total weight of the solid preparation, preferably 0.1 to 0.5%.

9. The solid preparation according to claim 4, wherein the metal ion chelating agent accounts for 0.1 to 0.2% of the total weight of the solid preparation. 10 . The solid preparation according to claim 2 , when the solid preparation is a tablet, further comprising one or more of a filler, a disintegrant and a lubricant.

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