A milobalin pharmaceutical composition, its preparation method and its application

Abstract

This invention relates to a milobalin pharmaceutical composition comprising milobalin besylate, a filler, a disintegrant, a lubricant, a flow aid, and a stabilizer. The stabilizer is selected from one or more of L-tartaric acid, butylated hydroxyanisole, vitamin E polyethylene glycol succinate, epigallocatechin gallate, coenzyme Q10, ergothioneine, and sorbic acid. The stabilizer content in the composition is 0.1-2.5 wt%. In this invention, the stabilizer was screened, further reducing the total stabilizer content. The resulting milobalin pharmaceutical composition has lower levels of degradation impurities (impurity E) and antioxidant impurities, exhibiting better stability and further improving the safety and efficacy of the drug.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and specifically relates to a milobalin pharmaceutical composition, its preparation method, and its application. Background Technology

[0002] Milobalin benzenesulfonic acid, chemically named [(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3,2,0]hept-3-en-6-yl]acetic acid monobenzenesulfonate, has the following structural formula: .

[0003] Milobalin benzylsulfonate is a novel selective calcium channel α2δ ligand developed by Daiichi Sankyo Co., Ltd. of Japan, and was approved for marketing in Japan on January 8, 2019. It is primarily used to treat diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia. Milobalin has advantages such as high safety and good tolerability, and is developing into a world-class drug for the treatment of neuralgia.

[0004] Patent CN107405322B discloses a formulation containing milobalin besylate, specifically specifying that the stabilizer is selected from one or two of sodium edetate, citrate hydrate, butylated hydroxytoluene, propyl gallate, anhydrous magnesium citrate, soybean lecithin, tocopherol, tocopheryl acetate, and β-cyclodextrin. Patent CN111971036A discloses tablets containing a combination of milobalin besylate, citric anhydride or citric acid hydrate, and α-tocopherol.

[0005] The original drug used two stabilizers, tocopherol and citric acid, to inhibit the impurities generated by oxidative degradation and intramolecular amidation reactions during long-term storage. However, the impurity level remained high during storage, which was detrimental to the safety and efficacy of the drug in clinical applications. Furthermore, tocopherol is a liquid antioxidant with stringent storage conditions and complex addition methods, which was not conducive to simplified industrial production.

[0006] Ensuring the stability of pharmaceutical formulations is crucial for guaranteeing the quality, safety, and efficacy of the finished products. Further research is needed to obtain drugs with better stability that meet the requirements of different storage conditions. Summary of the Invention

[0007] The purpose of this invention is to provide a milobalin besylate formulation with lower levels of oxidizing and degrading impurities and better stability. This formulation can effectively control the generation of oxidizing and degrading impurities, thereby further improving the clinical safety of milobalin.

[0008] The technical problem to be solved by the present invention is to provide a milobalin pharmaceutical composition, wherein the pharmaceutical composition comprises milobalin besylate, a filler, a disintegrant, a lubricant, a flow aid, and a stabilizer, wherein the stabilizer is selected from one or more of L-tartaric acid, butylated hydroxyanisole (BHA), vitamin E polyethylene glycol succinate (TPGS1000), epigallocatechin gallate (EGCG), coenzyme Q10, ergothioneine, and sorbic acid, and the content of the stabilizer in the composition is 0.1-2.5 wt%.

[0009] In a further preferred embodiment of the present invention, the content of milobalin benzyl sulfonate in the composition is 1-10 wt%, preferably 2-8 wt%, and more preferably 3-6 wt%.

[0010] In a further preferred embodiment of the present invention, the content of stabilizer in the composition is 0.5-2.3 wt%, preferably 0.8-2 wt%, and more preferably 1.2-1.8 wt%.

[0011] In a further preferred embodiment of the present invention, the filler is selected from one or more of mannitol, lactose, corn starch, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and sorbitol, preferably one or two of mannitol and microcrystalline cellulose. The content of the filler is 70-90 wt%, preferably 75-88 wt%, and more preferably 80-86 wt%.

[0012] In a further preferred embodiment of the present invention, the disintegrant is selected from one or more of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose, preferably one or more of carboxymethyl cellulose and calcium carboxymethyl cellulose. The content of the disintegrant is 2-20 wt%, preferably 5-15 wt%, and more preferably 8-12 wt%.

[0013] In a further preferred embodiment of the present invention, the lubricant is selected from one or more of magnesium stearate, sodium stearate fumarate, and talc, preferably magnesium stearate. The content of the lubricant is 0.1-5 wt%, preferably 0.5-3 wt%, and more preferably 1-2 wt%.

[0014] In a further preferred embodiment of the present invention, the flow aid is selected from one or more of magnesium aluminum metasilicate, magnesium aluminum silicate, and silicon dioxide, preferably magnesium aluminum metasilicate. The content of the flow aid is 0.05-3 wt%, preferably 0.1-1 wt%, and more preferably 0.2-0.5 wt%.

[0015] In a further preferred embodiment of the present invention, the stabilizer is preferably a combination of one or more of L-tartaric acid and butylated hydroxyanisole (BHA), vitamin E polyethylene glycol succinate (TPGS1000), coenzyme Q10, epigallocatechin gallate, sorbic acid, or ergothioneine, more preferably a combination of one or more of L-tartaric acid and butylated hydroxyanisole (BHA), vitamin E polyethylene glycol succinate (TPGS1000), or coenzyme Q10.

[0016] In a further preferred embodiment of the present invention, the mass ratio of L-tartaric acid to butylated hydroxyanisole (BHA), vitamin E polyethylene glycol succinate (TPGS1000), coenzyme Q10 epigallocatechin gallate, sorbic acid or ergothioneine is 15:(0.01-2), preferably 15:(0.05-1.5), preferably 15:(0.06-1.3), preferably 15:(0.08-1.2), preferably 15:(0.1-1), preferably 15:(0.5-1.5), preferably 15:(0.7-1.2), preferably 15:(0.2-1), and more preferably 15:(0.8-1).

[0017] In a further preferred embodiment of the present invention, the pharmaceutical composition comprises 1-10 wt% milobalin besylate, 69-88 wt% mannitol, 0.5-2 wt% microcrystalline cellulose, 2-20 wt% carboxymethyl cellulose, 0.1-5 wt% magnesium stearate, 0.05-3 wt% magnesium aluminum metasilicate, and 0.1-2.5 wt% stabilizer.

[0018] In a further preferred embodiment of the present invention, the pharmaceutical composition comprises 2-8 wt% milobalin besylate, 74-86.5 wt% mannitol, 0.8-1.5 wt% microcrystalline cellulose, 5-15 wt% carboxymethyl cellulose, 0.5-3 wt% magnesium stearate, 0.1-1 wt% magnesium aluminum metasilicate, and 0.5-2.3 wt% stabilizer.

[0019] In a further preferred embodiment of the present invention, the pharmaceutical composition comprises 3-6 wt% milobalin besylate, 80-85 wt% mannitol, 0.9-1.2 wt% microcrystalline cellulose, 8-12 wt% carboxymethyl cellulose, 1-2 wt% magnesium stearate, 0.2-0.5 wt% magnesium aluminum metasilicate, and 0.8-2 wt% stabilizer.

[0020] In a further preferred embodiment of the present invention, the pharmaceutical composition comprises 1-10 wt% milobalin besylate, 69-88 wt% mannitol, 0.5-2 wt% microcrystalline cellulose, 2-20 wt% carboxymethyl cellulose, 0.1-5 wt% magnesium stearate, 0.05-3 wt% magnesium aluminum metasilicate, and 0.1-2.5 wt% L-tartaric acid.

[0021] In a further preferred embodiment of the present invention, the pharmaceutical composition comprises 1-10 wt% milobalin besylate, 69-88 wt% mannitol, 0.5-2 wt% microcrystalline cellulose, 2-20 wt% carboxymethyl cellulose, 0.1-5 wt% magnesium stearate, 0.05-3 wt% magnesium aluminum metasilicate, and 0.1-2.5 wt% butylated hydroxyanisole.

[0022] In a further preferred embodiment of the present invention, the pharmaceutical composition comprises 1-10 wt% milobalin besylate, 69-88 wt% mannitol, 0.5-2 wt% microcrystalline cellulose, 2-20 wt% carboxymethyl cellulose, 0.1-5 wt% magnesium stearate, 0.05-3 wt% magnesium aluminum metasilicate, and 0.1-2.5 wt% polyethylene glycol succinate.

[0023] In a further preferred embodiment of the present invention, the pharmaceutical composition comprises 1-10 wt% milobalin besylate, 69-88 wt% mannitol, 0.5-2 wt% microcrystalline cellulose, 2-20 wt% carboxymethyl cellulose, 0.1-5 wt% magnesium stearate, 0.05-3 wt% magnesium aluminum metasilicate, and 0.1-2.5 wt% epigallocatechin gallate.

[0024] In a further preferred embodiment of the present invention, the pharmaceutical composition comprises 1-10 wt% milobalin besylate, 69-88 wt% mannitol, 0.5-2 wt% microcrystalline cellulose, 2-20 wt% carboxymethyl cellulose, 0.1-5 wt% magnesium stearate, 0.05-3 wt% magnesium aluminum metasilicate, and 0.1-2.5 wt% coenzyme Q10.

[0025] In a further preferred embodiment of the present invention, the pharmaceutical composition comprises 1-10 wt% milobalin besylate, 69-88 wt% mannitol, 0.5-2 wt% microcrystalline cellulose, 2-20 wt% carboxymethyl cellulose, 0.1-5 wt% magnesium stearate, 0.05-3 wt% magnesium aluminum metasilicate, and 0.1-2.5 wt% ergothioneine.

[0026] In a further preferred embodiment of the present invention, the pharmaceutical composition comprises 1-10 wt% milobalin besylate, 69-88 wt% mannitol, 0.5-2 wt% microcrystalline cellulose, 2-20 wt% carboxymethyl cellulose, 0.1-5 wt% magnesium stearate, 0.05-3 wt% magnesium aluminum metasilicate, and 0.1-2.5 wt% sorbic acid.

[0027] In a further preferred embodiment of the present invention, the pharmaceutical composition comprises 1-10 wt% milobalin besylate, 69-88 wt% mannitol, 0.5-2 wt% microcrystalline cellulose, 2-20 wt% carboxymethyl cellulose, 0.1-5 wt% magnesium stearate, 0.05-3 wt% magnesium aluminum metasilicate, and 0.1-2.5 wt% stabilizer, wherein the stabilizer is a combination of L-tartaric acid and butylated hydroxyanisole (BHA), and the mass ratio of L-tartaric acid to butylated hydroxyanisole (BHA) is 15:(0.08-1.5).

[0028] In a further preferred embodiment of the present invention, the pharmaceutical composition comprises 1-10 wt% milobalin besylate, 69-88 wt% mannitol, 0.5-2 wt% microcrystalline cellulose, 2-20 wt% carboxymethyl cellulose, 0.1-5 wt% magnesium stearate, 0.05-3 wt% magnesium aluminum metasilicate, and 0.1-2.5 wt% stabilizer, wherein the stabilizer is a combination of L-tartaric acid and vitamin E polyethylene glycol succinate, and the mass ratio of L-tartaric acid to vitamin E polyethylene glycol succinate is 15:(0.08-1.5).

[0029] In a further preferred embodiment of the present invention, the pharmaceutical composition comprises 1-10 wt% milobalin besylate, 69-88 wt% mannitol, 0.5-2 wt% microcrystalline cellulose, 2-20 wt% carboxymethyl cellulose, 0.1-5 wt% magnesium stearate, 0.05-3 wt% magnesium aluminum metasilicate, and 0.1-2.5 wt% stabilizer, wherein the stabilizer is a combination of L-tartaric acid and coenzyme Q10, and the mass ratio of L-tartaric acid to coenzyme Q10 is 15:(0.08-1.5).

[0030] In a further preferred embodiment of the present invention, the pharmaceutical composition comprises 1-10 wt% milobalin besylate, 69-88 wt% mannitol, 0.5-2 wt% microcrystalline cellulose, 2-20 wt% carboxymethyl cellulose, 0.1-5 wt% magnesium stearate, 0.05-3 wt% magnesium aluminum metasilicate, and 0.1-2.5 wt% stabilizer, wherein the stabilizer is a combination of L-tartaric acid and epigallocatechin gallate, and the mass ratio of L-tartaric acid to epigallocatechin gallate is 15:(0.08-1.5).

[0031] In a further preferred embodiment of the present invention, the pharmaceutical composition comprises 1-10 wt% milobalin besylate, 69-88 wt% mannitol, 0.5-2 wt% microcrystalline cellulose, 2-20 wt% carboxymethyl cellulose, 0.1-5 wt% magnesium stearate, 0.05-3 wt% magnesium aluminum metasilicate, and 0.1-2.5 wt% stabilizer, wherein the stabilizer is a combination of L-tartaric acid and ergothioneine, and the mass ratio of L-tartaric acid to ergothioneine is 15:(0.08-1.5).

[0032] In a further preferred embodiment of the present invention, the pharmaceutical composition comprises 1-10 wt% milobalin besylate, 69-88 wt% mannitol, 0.5-2 wt% microcrystalline cellulose, 2-20 wt% carboxymethyl cellulose, 0.1-5 wt% magnesium stearate, 0.05-3 wt% magnesium aluminum metasilicate, and 0.1-2.5 wt% stabilizer, wherein the stabilizer is a combination of L-tartaric acid and sorbic acid, and the mass ratio of L-tartaric acid to sorbic acid is 15:(0.08-1.5).

[0033] In a further preferred embodiment of the present invention, the pharmaceutical composition contains <0.5% impurity E.

[0034] In a further preferred embodiment of the invention, the pharmaceutical composition further includes a coating agent selected from... Gastric-soluble coatings, such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), acrylic resin IV, polyvinylpyrrolidone (PVP), and polyvinyl acetal diethylaminoacetic acid (AEA), are preferred.

[0035] In a further preferred embodiment of the present invention, the coating agent may also contain anti-sticking agents, coloring agents and / or flavoring agents, etc.

[0036] In a further preferred embodiment of the present invention, the anti-adhesion agent is selected from one or more of talc, hydrogenated vegetable oil, magnesium stearate, lecithin, and stearic acid, with talc being preferred.

[0037] In a further preferred embodiment of the present invention, the colorant is selected from one or more of titanium dioxide, iron oxide red, iron oxide yellow, lemon yellow, and carmine.

[0038] In a further preferred embodiment of the present invention, the coating weight gain of the coating agent is 1-6%, preferably 3-5%.

[0039] Another object of the present invention is to provide a method for preparing a milobalin pharmaceutical composition, comprising the following steps: mixing milobalin besylate, a filler, a disintegrant, a lubricant, a flow aid and a stabilizer according to the prescribed amounts, and then directly compressing the mixture into tablets using a round punch to obtain tablets.

[0040] In a further preferred embodiment of the present invention, a coating solution may be further prepared for coating.

[0041] Another object of the present invention is to provide the use of a milobalin pharmaceutical composition for the treatment of chronic pain.

[0042] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. In this invention, stabilizers were screened and the content of each component was adjusted to further reduce the total content of stabilizers. The milobalin drug composition of this invention has lower content of degradation impurities (impurity E) and antioxidant impurities, better stability, and further improves the safety and efficacy of the drug.

[0043] 2. The preparation process of the present invention is simple and easy to implement, which is conducive to industrial production and widespread use.

[0044] The structure of the degradation impurity E described in this invention is as follows: Detailed Implementation

[0045] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0046] Example The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products. Unless otherwise specified, proportions or percentages used herein are by weight.

[0047] Example 1: Screening of Single Stabilizers Prescriptions 1-13

[0048] The preparation method of milobalin formulation is as follows: Merogabalin besylate was passed through an 80-mesh sieve. The prescribed amounts of merogabalin besylate, mannitol, microcrystalline cellulose, carboxymethyl cellulose, magnesium aluminum metasilicate, and stabilizer were weighed and mixed, then passed through a 40-mesh sieve. Magnesium stearate was then added for final mixing. After mixing, tablets were directly compressed using a 6.5mm round punch, controlling the tablet weight to 100mg and the hardness to 30-90 N. The coating solution was prepared by slowly adding the prescribed amount of Opadry coating solution to a beaker while stirring. The mixture was stirred thoroughly for 45 minutes to ensure even dispersion before coating began. The coating powder consisted of hydroxypropyl methylcellulose, talc, and titanium dioxide. Coating parameters were set, and the coating tank and peristaltic pump were started. When the predetermined coating weight gain was achieved, the spraying was stopped. The tablets were dried for approximately 5 minutes and then removed. The uncoated tablets showed a weight gain of 3-5%.

[0049] Example 2 Combined Oxidizing Agent Prescription 14-17

[0050] The preparation method of milobalin formulation is described in Example 1.

[0051] Results of the stability study of the formulation in Experiment Example 1 The tablets and reference formulation (5 mg, manufactured by Daiichi Sankyo Co., Ltd.) prepared according to the above prescription were placed under accelerated conditions (40℃ / 75%RH) for 7, 14, and 30 days. The growth of degradation products was detected by HPLC (General Chapter 0512 of the Chinese Pharmacopoeia 2020) using related substances as the main indicator. The results are as follows:

[0052] In the table, " / " indicates that it was not measured.

[0053] The results showed that milobalin formulations with L-tartaric acid, butylated hydroxyanisole (BHA), vitamin E polyethylene glycol succinate (TPGS1000), epigallocatechin gallate (EGCG), coenzyme Q10, ergothionein, or sorbic acid as single stabilizers exhibited good stability. When the stabilizers were a combination of L-tartaric acid with butylated hydroxyanisole (BHA), vitamin E polyethylene glycol succinate (TPGS1000), or coenzyme Q10, the stability was significantly better than that of the reference formulation.

Claims

1. A milobalin pharmaceutical composition, characterized in that, The pharmaceutical composition comprises milobalin besylate, a filler, a disintegrant, a lubricant, a flow aid, and a stabilizer. The stabilizer is selected from one or more of L-tartaric acid, butylated hydroxyanisole, vitamin E polyethylene glycol succinate, epigallocatechin gallate, coenzyme Q10, ergothioneine, and sorbic acid. The content of the stabilizer in the composition is 0.1-2.5 wt%.

2. The pharmaceutical composition according to claim 1, wherein the content of milobalin besylate in the composition is 1-10 wt%, preferably 2-8 wt%, more preferably 3-6 wt%.

3. The pharmaceutical composition according to any one of claims 1-2, wherein the content of the stabilizer in the composition is 0.5-2.3 wt%, preferably 0.8-2 wt%, more preferably 1.2-1.8 wt%.

4. The pharmaceutical composition according to any one of claims 1-3, wherein the filler is selected from one or more of mannitol, lactose, corn starch, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and sorbitol, preferably from one or two of mannitol and microcrystalline cellulose; the content of the filler is 70-90 wt%, preferably 75-88 wt%, more preferably 80-86 wt%.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the disintegrant is selected from one or more of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose, preferably one or more of carboxymethyl cellulose and calcium carboxymethyl cellulose; the content of the disintegrant is 2-20 wt%, preferably 5-15 wt%, more preferably 8-12 wt%.

6. The pharmaceutical composition according to any one of claims 1-5, wherein the lubricant is selected from one or more of magnesium stearate, sodium stearate fumarate, and talc, preferably magnesium stearate; the content of the lubricant is 0.1-5 wt%, preferably 0.5-3 wt%, more preferably 1-2 wt%.

7. The pharmaceutical composition according to any one of claims 1-6, wherein the gliding agent is selected from one or more of magnesium aluminum metasilicate, magnesium aluminum silicate, and silicon dioxide, preferably magnesium aluminum metasilicate; the content of the gliding agent is 0.05-3 wt%, preferably 0.1-1 wt%, more preferably 0.2-0.5 wt%.

8. The pharmaceutical composition according to any one of claims 1-7, wherein the stabilizer is preferably a combination of one or more of L-tartaric acid and butylated hydroxyanisole, vitamin E polyethylene glycol succinate, coenzyme Q10, epigallocatechin gallate, sorbic acid or ergothioneine, more preferably a combination of one or more of L-tartaric acid and butylated hydroxyanisole, vitamin E polyethylene glycol succinate or coenzyme Q10.

9. The pharmaceutical composition according to any one of claims 1-8, wherein, The mass ratio of L-tartaric acid to butylated hydroxyanisole, vitamin E polyethylene glycol succinate, coenzyme Q10, epigallocatechin gallate, sorbic acid or ergothioneine is 15:(0.01-2), preferably 15:(0.05-1.5), preferably 15:(0.06-1.3), preferably 15:(0.08-1.2), preferably 15:(0.1-1).

10. Use of the pharmaceutical composition according to any one of claims 1-9 for the preparation of a medicament for the treatment of chronic pain.

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