Pharmaceutical composition containing melogabalin besylate and preparation method thereof

Abstract

The invention discloses a pharmaceutical composition containing melogabalin besylate with good stability and a preparation method of the pharmaceutical composition. The pharmaceutical composition comprises an active component melogabalin besylate, one or more excipients, an adsorbent, a lubricant, a coating agent and an antioxidant, the antioxidant is a combination of L-ascorbyl palmitate and tartaric acid. The invention also provides a preparation method of the melogabalin besylate tablet, and the stability of the melogabalin besylate tablet prepared by the method is obviously improved.

Description

Technical Field

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

[0002] Mirogabalin benzenesulfonate, its chemical name is: [(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetate benzenesulfonate; molecular formula: C 12 H 19 NO2·C6H6O3S; molecular weight: 367.46, its chemical structure is as follows:

[0003]

[0004] Milogabalin besylate is a new drug developed by Daiichi Sankyo Co., Ltd. of Japan for the treatment of peripheral neuropathic pain. Milogabalin is a potential ligand for the α2δ subunit of the calcium-dependent channel in the nervous system. It exerts analgesic effects by binding to the α2δ subunit and inhibiting calcium currents.

[0005] The patent CN 107405322 of Yuanyan Company provides a combination of one or two or more selected from edetate sodium, citric acid hydrate, butylated hydroxytoluene, propyl gallate, magnesium citrate (anhydrous), soy lecithin, tocopherol, tocopherol acetate and beta-cyclodextrin as an antioxidant. CN 118806717 provides a pharmaceutical solid preparation and a preparation method thereof that can further improve the stability of its pharmaceutical solid preparation. The specifically provided melogabalin besylate pharmaceutical solid preparation comprises melogabalin besylate and a stabilizer, wherein the stabilizer is selected from L-tartaric acid, D-tartaric acid, tartaric acid, sodium tartrate, malic acid, sodium citrate, fumaric acid and gallic acid. However, melogabalin besylate is very easy to degrade under high temperature conditions, and a single acidic stabilizer is difficult to ensure the stability of the solid preparation under high temperature environment. Summary of the invention

[0006] The object of the present invention is to provide a pharmaceutical composition containing melogabalin besylate and a preparation method thereof. The degradation impurity A and the total amount of impurities in the pharmaceutical composition are effectively suppressed, and the stability of the prepared solid preparation is better than the stability of the preparation product prepared by the original research prescription, especially the high temperature stability, and there is no obvious growth trend under accelerated conditions.

[0007] The objective of the present invention is achieved through the following technical solutions:

[0008] <First aspect>

[0009] The present invention relates to a pharmaceutical composition, comprising melogabalin besylate represented by formula (I) and an antioxidant, wherein the antioxidant is a combination of L-ascorbyl palmitate and tartaric acid;

[0010]

[0011] As an embodiment, it further contains one or more excipients, adsorbents, disintegrants, lubricants, and coating agents.

[0012] As an embodiment, the excipient is selected from one or more of mannitol and microcrystalline cellulose.

[0013] As an embodiment, the disintegrant is selected from carmellose calcium.

[0014] As an embodiment, the adsorbent is selected from magnesium aluminum metasilicate.

[0015] As an embodiment, the lubricant is selected from magnesium stearate.

[0016] As an embodiment, in the pharmaceutical composition, the mass ratio of L-ascorbyl palmitate to tartaric acid is 1:1 to 1:5.

[0017] As an embodiment, the pharmaceutical composition comprises the following components in parts by weight:

[0018]

[0019] As an embodiment, the pharmaceutical composition is a solid preparation.

[0020] <Second Aspect>

[0021] The present invention relates to a method for preparing a solid preparation using the aforementioned pharmaceutical composition, the method comprising the following steps:

[0022] S1. Pre-mix other raw materials and excipients except lubricant and coating agent, and sieve;

[0023] S2, adding lubricant for total mixing;

[0024] S3. Tablets are compressed and coated according to theoretical tablet weight.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] 1) In the melogabalin sulfonate pharmaceutical composition of the present invention, when the antioxidant combination is L-ascorbyl palmitate and tartaric acid, the stability of the prepared solid preparation is significantly better than the combination of L-ascorbyl palmitate and fumaric acid and L-ascorbyl palmitate and succinic acid.

[0027] 2) When the ratio of L-ascorbyl palmitate and L-tartaric acid was 1:1 to 1:5, the degradation impurity A and the total amount of impurities in the prepared tablets were effectively suppressed, and the stability was not lower than that of the reference preparation.

[0028] 3) The solid preparation prepared by using the antioxidant combination of L-ascorbyl palmitate and tartaric acid had no significant change compared with 0 day under accelerated 6-month conditions, and had good stability. DETAILED DESCRIPTION

[0029] The technical scheme of the present invention is further described in detail below in conjunction with specific examples. It should be understood that these examples are used to illustrate the basic principles, main features and advantages of the present invention, and the specific implementation conditions used in the examples can be appropriately adjusted within the scope of the art, and the protection scope of the present invention is not limited by the examples. (Examples 1-3) The ratio of the antioxidant composition is studied.

[0030] Table 1 Prescription composition and dosage of Examples 1 to 3

[0031]

[0032]

[0033] The preparation process of Examples 1-3:

[0034] (1) Pass the raw and auxiliary materials through a 40-mesh sieve and set aside.

[0035] (2) Premixing: Weigh the prescribed amount of mannitol, API, microcrystalline cellulose, L-ascorbyl palmitate, L-tartaric acid, magnesium aluminum metasilicate, and carboxymethyl cellulose calcium and mix them in a mixer. After mixing, the materials are sieved through a 40-mesh sieve.

[0036] (3) Total mixing: Add magnesium stearate and mix in a mixer.

[0037] (4) Tabletting: Tableting is performed according to the theoretical tablet weight, using a 10.6 mm × 5.6 mm special-shaped die, controlling the hardness to 60-140 N, and the tablet weight variation: ±5.0%.

[0038] (5) Coating: The film coating premix is ​​mixed with purified water to prepare a coating solution with a concentration of 12% to 15% and a weight gain of 2% to 4%.

[0039] Comparative Example 1

[0040] The sample was prepared using the formula of melogabalin tablets reported in the original preparation patent CN 111971036 A, wherein the antioxidant composition is α-tocopherol and citric acid monohydrate. The specific formula is shown in Table 2:

[0041] Table 2 Comparative Example 1 Prescription Composition and Dosage

[0042]

[0043] Comparative Example 1 Preparation process:

[0044] (1) Pass the raw and auxiliary materials through a 40-mesh sieve and set aside.

[0045] (2) Weigh half the amount of mannitol, microcrystalline cellulose, and α-tocopherol in a mortar and grind until uniform to obtain a mixture 1.

[0046] (3) Premixing: weigh the other half of mannitol, API, magnesium aluminum metasilicate, carboxymethylcellulose calcium, citric acid monohydrate, and mixture 1 in sequence, mix in a mixer, and pass the mixed materials through a 40-mesh sieve.

[0047] (4) Total mixing: Add magnesium stearate and mix in a mixer.

[0048] (5) Tabletting: Tableting is performed according to the theoretical tablet weight, using a 10.6 mm × 5.6 mm special-shaped die, controlling the hardness to 60-140 N, and the tablet weight variation: ±5.0%.

[0049] (6) Coating: The film coating premix is ​​mixed with purified water to prepare a coating solution with a concentration of 12% to 15% and a weight gain of 2% to 4%.

[0050] Comparative Example 2

[0051] The solid preparation prepared by adding only L-tartaric acid is used as Comparative Example 2. The drug combination formula of Comparative Example 2 is shown in the table below.

[0052] Table 3 Comparative Example 2 Prescription Composition and Dosage

[0053]

[0054] Comparative Example 2 Preparation Process:

[0055] (1) Pass the raw and auxiliary materials through a 40-mesh sieve and set aside.

[0056] (2) Premixing: Weigh the prescribed amount of mannitol, API, microcrystalline cellulose, magnesium aluminum metasilicate, L-tartaric acid, and carboxymethyl cellulose calcium and mix them in a mixer. After mixing, pass the mixed materials through a 40-mesh sieve.

[0057] (3) Total mixing: Add magnesium stearate and mix in a mixer.

[0058] (4) Tabletting: Tableting is performed according to the theoretical tablet weight, using a 10.6 mm × 5.6 mm special-shaped die, controlling the hardness to 60-140 N, and the tablet weight variation: ±5.0%.

[0059] (5) Coating: The film coating premix is ​​mixed with purified water to prepare a coating solution with a concentration of 12% to 15% and a weight gain of 2% to 4%.

[0060] Comparative Example 3

[0061] The samples were prepared by combining α-tocopherol and L-tartaric acid, an antioxidant with good effects reported in the original preparation patent CN 107405322A, to investigate the effect of the combination on product stability. The specific formula is shown in Table 4:

[0062] Table 4 Comparative Example 3 Prescription Composition and Dosage

[0063]

[0064] Comparative Example 3 Preparation Process:

[0065] (1) Pass the raw and auxiliary materials through a 40-mesh sieve and set aside.

[0066] (2) Weigh half the amount of mannitol, microcrystalline cellulose, and α-tocopherol in a mortar and grind until uniform to obtain a mixture 1.

[0067] (3) Premixing: weigh the other half of mannitol, API, magnesium aluminum metasilicate, carboxymethylcellulose calcium, L-tartaric acid, and mixture 1 in sequence, mix in a mixer, and pass the mixed materials through a 40-mesh sieve.

[0068] (4) Total mixing: Add magnesium stearate and mix in a mixer.

[0069] (5) Tabletting: Tableting is performed according to the theoretical tablet weight, using a 10.6 mm × 5.6 mm special-shaped die, controlling the hardness to 60-140 N, and the tablet weight variation: ±5.0%.

[0070] (6) Coating: The film coating premix is ​​mixed with purified water to prepare a coating solution with a concentration of 12% to 15% and a weight gain of 2% to 4%.

[0071] Comparative Examples 4-5

[0072] Comparative Example 4 is based on Example 1, but L-tartaric acid is replaced by fumaric acid. Comparative Example 5 is based on Example 1, but L-tartaric acid is replaced by succinic acid. Other raw materials and auxiliary materials remain unchanged to prepare melogabalin besylate tablets. The specific formula is shown in Table 5:

[0073] Table 5 Comparative Examples 4 to 5 Prescription Composition and Dosage

[0074]

[0075]

[0076] The preparation process of Comparative Examples 4 to 5 is the same as that of Examples 1 to 3, except that in the step (2) of premixing, L-tartaric acid is replaced by fumaric acid or succinic acid, respectively.

[0077] Evaluation methods and results:

[0078] (1) The tablets of Examples 1 to 3 and the reference preparation (commercially available Specification 5mg, batch number: YBA2183) and comparative examples 1 to 3 were placed at high temperature (50°C) for 1 month, and the total amount of sample degradation product A and related substances was measured by HPLC. Examples 1 to 3 and comparative examples 1 to 3 used the same batch of raw materials. The structural formula of impurity A is as follows: Based on the maximum daily dose of 30 mg, the identification limit is 0.2%.

[0079] Note: Impurity A is a lactam impurity and is the most important degradation impurity in the preparation. The import registration standard controls this impurity (the limit is not more than 0.8%), so the present invention focuses on the increase in impurity A.

[0080] The changing trends of the degradation product A and the total amount of related substances of Examples 1-3, the reference preparation, and Comparative Examples 1 to 3 are shown in Table 6 below.

[0081] Table 6

[0082]

[0083]

[0084] Conclusion: 1. When the addition ratio of L-ascorbyl palmitate and L-tartaric acid is within the range of 1:1 to 1:5, the degradation impurity A and the total amount of impurities in the prepared tablets are effectively inhibited, and the stability is not lower than that of the reference preparation.

[0085] 2. The stability of the solid preparation prepared by using L-ascorbyl palmitate and L-tartaric acid is better than that of the preparation prepared by the original research formula. At the same time, the stability of the solid preparation prepared by implementing 1 is significantly better than that of the preparation prepared by adding only L-tartaric acid in comparative example 2 and the combination of α-tocopherol and L-tartaric acid in comparative example 3.

[0086] (2) The tablets prepared in Example 1 and Comparative Examples 4-5 were placed at high temperature (50° C.) for 1 month, and the total amount of degradation product A and related substances in the samples were measured by HPLC.

[0087] The variation trends of the total amount of degradation product A and related substances of the samples prepared in Example 1 and Comparative Examples 4-5 are shown in Table 7 below.

[0088] Table 7

[0089]

[0090]

[0091] Conclusion: When the antioxidant combination is L-ascorbyl palmitate and tartaric acid, the stability of the prepared solid preparation is significantly better than that of the combination of L-ascorbyl palmitate and fumaric acid and L-ascorbyl palmitate and succinic acid.

[0092] (3) Accelerated stability test

[0093] The film-coated tablets of Example 1 (packaging form: a combination of PVC / PVDC / aluminum blisters and desiccant and aluminum bags) were subjected to accelerated storage tests (40°C, RH 75%±5%) for 1 / 3 / 6 months stability tests, and the total amount of degradation product A and related substances in the samples was measured by HPLC. The test results of each sample are shown in Table 8 below.

[0094] Table 8

[0095]

[0096] Conclusion: The solid preparation prepared with the antioxidant combination of L-ascorbyl palmitate and tartaric acid showed no significant change compared with day 0 under accelerated 6-month conditions and had good stability.

[0097] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art may make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A pharmaceutical composition comprising melogabalin besylate represented by formula (I) and an antioxidant, characterized in that: The antioxidant is a combination of L-ascorbyl palmitate and tartaric acid; 2. The pharmaceutical composition according to claim 1, characterized in that It also contains one or more excipients, adsorbents, disintegrants, lubricants, and coating agents.

3. The pharmaceutical composition according to claim 2, characterized in that The excipient is selected from one or more of mannitol and microcrystalline cellulose; the disintegrant is selected from carboxymethylcellulose calcium; the adsorbent is selected from magnesium aluminum metasilicate; and the lubricant is selected from magnesium stearate.

4. The pharmaceutical composition according to claim 1, characterized in that In the pharmaceutical composition, the mass ratio of L-ascorbyl palmitate to tartaric acid is 1:1 to 1:

5.

5. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition comprises the following components in parts by weight:

6. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition is a solid preparation.

7. A method for preparing a solid preparation using the pharmaceutical composition according to claim 1, characterized in that: The method comprises the following steps: S1. Pre-mix other raw materials and excipients except lubricant and coating agent, and sieve; S2, adding lubricant for total mixing; S3. Tablets are pressed and coated according to theoretical tablet weight.

Images