Pharmaceutical compositions containing meloxicam and methods of making the same

Abstract

The application discloses a pharmaceutical composition containing meloxicam phenylsulfonate with good stability and a preparation method thereof. The pharmaceutical composition comprises an active component meloxicam phenylsulfonate, 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 application further provides a preparation method of meloxicam phenylsulfonate tablets, and the stability of the meloxicam phenylsulfonate tablets prepared by using the method is obviously improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to a pharmaceutical composition containing melogabalin benzyl sulfonate and its preparation method. Background Technology

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

[0003]

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

[0005] The original research company's patent CN 107405322 discloses the use of one or more combinations of sodium edetate, citrate hydrate, butylated hydroxytoluene, propyl gallate, anhydrous magnesium citrate, soybean lecithin, tocopherol, tocopheryl acetate, and β-cyclodextrin as antioxidants. CN 118806717 provides a pharmaceutical solid dosage form and its preparation method that can further improve the stability of the pharmaceutical solid dosage form. Specifically, it provides a melogabalin besylate pharmaceutical solid dosage form containing melogabalin besylate and a stabilizer selected from L-tartaric acid, D-tartaric acid, sodium tartaric acid, malic acid, sodium citrate, fumaric acid, and gallic acid. However, melogabalin besylate is highly degraded under high temperature conditions, and a single acidic stabilizer is insufficient to ensure the stability of the solid dosage form under high temperature conditions. Summary of the Invention

[0006] The purpose of this invention is to provide a pharmaceutical composition containing melogabalin besylate and a method for preparing the same. In this pharmaceutical composition, degradation impurity A and the total amount of impurities are effectively suppressed. The prepared solid dosage form exhibits better stability than the formulation prepared from the original drug, especially in terms of high-temperature stability, and shows no significant increase under accelerated conditions.

[0007] The objective of this invention is achieved through the following technical solution:

[0008] <First Aspect>

[0009] This invention relates to a pharmaceutical composition comprising melogabalin benzylsulfonate as shown in formula (I) and an antioxidant, said antioxidant being a combination of L-ascorbyl palmitate and tartaric acid;

[0010]

[0011] As one implementation scheme, it also contains one or more excipients, adsorbents, disintegrants, lubricants, and coating agents.

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

[0013] As one implementation, the disintegrant is selected from calcium carboxymethyl cellulose.

[0014] As one implementation, the adsorbent is selected from magnesium aluminum metasilicate.

[0015] As one implementation, the lubricant is selected from magnesium stearate.

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

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

[0018]

[0019] As one embodiment, the pharmaceutical composition is a solid dosage form.

[0020] <Second aspect>

[0021] This invention relates to a method for preparing solid dosage forms using the aforementioned pharmaceutical composition, the method comprising the following steps:

[0022] S1. Take all raw and auxiliary materials except lubricant and coating agent, premix them, and sieve them;

[0023] S2. Add lubricant and mix thoroughly;

[0024] S3. Compress and coat the tablets according to the theoretical tablet weight.

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

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

[0027] 2) When the ratio of L-ascorbate palmitate to 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 suppressed, and the stability is not lower than that of the reference formulation.

[0028] 3) The solid dosage form prepared using the antioxidant combination of L-ascorbate palmitate and tartaric acid showed no significant change compared to day 0 under accelerated 6-month conditions, indicating good stability. Detailed Implementation

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

[0030] Table 1. Prescription composition and dosage for Examples 1-3

[0031]

[0032]

[0033] Preparation process of Examples 1-3:

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

[0035] (2) Premixing: Weigh out the prescribed amounts of mannitol, API, microcrystalline cellulose, L-ascorbate palmitate, L-tartaric acid, magnesium aluminum metasilicate, and calcium carboxymethyl cellulose and mix them in a mixer. After mixing, the material is passed through a 40-mesh sieve.

[0036] (3) Total mixing: Add magnesium stearate to the mixer for total mixing.

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

[0038] (5) Coating: Prepare a coating solution with a concentration of 12% to 15% by mixing the film coating premix with purified water, resulting in a weight gain of 2% to 4%.

[0039] Comparative Example 1

[0040] Samples were prepared using the formulation of meropenem tablets reported in the original formulation patent CN 111971036 A, wherein the antioxidant composition is α-tocopherol and citric acid monohydrate. The specific formulation is shown in Table 2.

[0041] Table 2. Prescription composition and dosage of Comparative Example 1

[0042]

[0043] Preparation process of Comparative Example 1:

[0044] (1) Pass the raw materials 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 them until uniform to obtain mixture 1.

[0046] (3) Premixing: Weigh out the other half of mannitol, API, magnesium aluminum metasilicate, calcium carboxymethyl cellulose, citric acid monohydrate, and mixture 1 in sequence, mix them in a mixer, and then pass the mixed material through a 40-mesh sieve.

[0047] (4) Total mixing: Add magnesium stearate to the mixer for total mixing.

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

[0049] (6) Coating: Prepare a coating solution with a concentration of 12% to 15% by mixing the film coating premix with purified water, resulting in a weight gain of 2% to 4%.

[0050] Comparative Example 2

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

[0052] Table 3. Prescription composition and dosage of Comparative Example 2

[0053]

[0054] Comparative Example 2 Preparation Process:

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

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

[0057] (3) Total mixing: Add magnesium stearate to the mixer for total mixing.

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

[0059] (5) Coating: Prepare a coating solution with a concentration of 12% to 15% by mixing the film coating premix with purified water, resulting in a weight gain of 2% to 4%.

[0060] Comparative Example 3

[0061] The antioxidant α-tocopherol and L-tartaric acid, which reported good effects in the original formulation patent CN 107405322A, were used to prepare samples to investigate the effect of this composition on product stability. The specific formulation is shown in Table 4.

[0062] Table 4. Prescription composition and dosage of Comparative Example 3

[0063]

[0064] Preparation process of Comparative Example 3:

[0065] (1) Pass the raw materials 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 them until uniform to obtain mixture 1.

[0067] (3) Premixing: Weigh out the other half of mannitol, API, magnesium aluminum metasilicate, calcium carboxymethyl cellulose, L-tartaric acid, and mixture 1 in sequence, mix them in a mixer, and then pass the mixed material through a 40-mesh sieve.

[0068] (4) Total mixing: Add magnesium stearate to the mixer for total mixing.

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

[0070] (6) Coating: Prepare a coating solution with a concentration of 12% to 15% by mixing the film coating premix with purified water, resulting in a weight gain of 2% to 4%.

[0071] Comparative Examples 4-5

[0072] Comparative Example 4 was prepared by replacing L-tartaric acid with fumaric acid, and Comparative Example 5 was prepared by replacing L-tartaric acid with succinic acid, while keeping other raw materials and excipients unchanged. Merogabalin besylate tablets were prepared, and the specific formulations are shown in Table 5.

[0073] Table 5. Composition and dosage of prescriptions in Comparative Examples 4-5

[0074]

[0075]

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

[0077] Evaluation methods and results:

[0078] (1) The tablets of Examples 1-3 and the reference preparation (commercially available products) were used. The sample (5mg specification, batch number: YBA2183) and Comparative Examples 1-3 were placed under high temperature (50℃) conditions for 1 month, and the total amount of degradation product A and related substances was measured by HPLC. Examples 1-3 and Comparative Examples 1-3 used the same batch of active pharmaceutical ingredient. The structural formula of impurity A is as follows: Based on the maximum daily dose of 30 mg, the limit of identification is 0.2%.

[0079] Note: Impurity A is a lactam impurity, which is the most important degradation impurity in the formulation. Import registration standards control this impurity (limited to no more than 0.8%). Therefore, this invention focuses on the increase of impurity A.

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

[0081] Table 6

[0082]

[0083]

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

[0085] 2. The solid dosage form prepared using L-ascorbic acid palmitate and L-tartaric acid exhibits better stability than the formulation prepared using the original drug formulation. Furthermore, the solid dosage form prepared in Example 1 shows significantly better stability than the formulation prepared in Comparative Example 2 with only L-tartaric acid added, and the formulation prepared in Comparative Example 3 using a combination of α-tocopherol and L-tartaric acid.

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

[0087] The trends of degradation products A and total amounts of related substances in 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 dosage form is significantly better than that of L-ascorbyl palmitate and fumaric acid, as well as the combination of L-ascorbyl palmitate and succinic acid.

[0092] (3) Accelerated stability test

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

[0094] Table 8

[0095]

[0096] Conclusion: The solid dosage form prepared by combining the antioxidants L-ascorbate palmitate and tartaric acid showed no significant change compared to day 0 under accelerated 6-month conditions, indicating good stability.

[0097] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art can 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 tablet comprising merogabarine besylate as shown in formula (I) and an antioxidant, characterized in that, The antioxidant is a combination of L-ascorbyl palmitate and tartaric acid; （Ⅰ）； In the tablets, the mass ratio of L-ascorbyl palmitate to tartaric acid is 1:1 to 1:5; The tablet comprises the following components in parts by weight: Merogabalin besylate 8-9 parts, Mannitol 155-160 parts 3-5 parts microcrystalline cellulose 15-25 parts of calcium carboxymethyl cellulose Magnesium aluminum metasilicate, 0.3-0.9 parts. 2-4 parts magnesium stearate L-Ascorbyl Palmitate 1-3 parts 3-5 parts of L-tartaric acid; The method for preparing the tablet includes the following steps: S1. Take all raw and auxiliary materials except lubricant and coating agent, premix them, and sieve them; S2. Add lubricant and mix thoroughly; S3. Compress and coat the tablets according to the theoretical tablet weight.

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