CN-121987608-A - Stable benzenesulfonic acid methyl ester oral solid preparation of lobabalin

Abstract

The invention discloses an oral solid preparation of melagatran besylate, which comprises melagatran besylate, sugar alcohol filler, lubricant and disintegrating agent, wherein the lubricant is a combination of glyceryl behenate and other lubricants, and the other lubricants are one or more selected from stearic acid, sodium lauryl sulfate, magnesium aluminum metasilicate, magnesium stearate and sodium stearyl fumarate. According to the invention, through researching the growth and change of related substances in the melagatran besylate preparation, the prescription of the oral solid preparation is optimized, and the unexpected discovery that glyceryl behenate can obviously improve the stability of the melagatran besylate preparation, is suitable for various preparation processes, and is more suitable for industrial production.

Inventors

• WANG YUGUANG
• SUN YINGJI
• LIU WENXIN
• LIU GE
• ZHAO LIN
• ZHANG YAN
• LI TIEJUN

Assignees

• 山东京卫制药有限公司

Dates

Publication Date

20260508

Application Date

20241104

Claims (8)

1. 1. The orally taken solid preparation of the methoprene besylate comprises the methoprene besylate, sugar alcohol filling agent, lubricant and disintegrating agent, and is characterized in that the lubricant is a combination of glyceryl behenate and other lubricants, and the other lubricants are one or more selected from stearic acid, sodium lauryl sulfate, magnesium aluminum metasilicate, magnesium stearate and sodium stearyl fumarate.
2. 2. The oral solid preparation of the methoprene besylate according to claim 1 characterized in that the weight percentage of the glyceryl behenate in the oral solid preparation is 0.67-6.67%, and the weight percentage of other lubricants is 0.67-4%.
3. 3. The oral solid preparation of the methoprene besylate, which is characterized by comprising, by weight, 1-50 parts of the methoprene besylate, 10-500 parts of sugar alcohol fillers and 1-40 parts of disintegrants.
4. 4. The oral solid preparation of the methoprene besylate according to claim 1, characterized in that the sugar alcohol filler is one or more selected from sorbitol, mannitol, erythritol, maltitol, lactitol and xylitol.
5. 5. The oral solid preparation of methoprene besylate according to claim 1 characterized in that the disintegrant is one or more of carboxymethylcellulose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, etc.
6. 6. The oral solid preparation of mevalonate, according to claim 1, further comprising one or more of a coating agent, a pigment, an essence, and a slow-release matrix material.
7. 7. The oral solid preparation of the methoprene besylate according to claim 1 characterized in that the oral solid preparation is a tablet, a capsule or a granule.
8. 8. The oral solid preparation of the methoprene besylate according to claim 1 characterized in that the preparation is prepared by adopting a direct mixing process, a dry granulation process, a wet granulation process or a one-step granulation process.

Description

Stable benzenesulfonic acid methyl ester oral solid preparation of lobabalin Technical Field The invention belongs to the field of pharmaceutical preparations, and particularly relates to a stable oral solid preparation of melagatran besylate. Background The English name Mirogabalin Besilate of the sulbactam is sulbactam, the trade name Tarlige, is an oral gabapentin drug for treating Peripheral Neuropathic Pain (PNP), including diabetic PNP and postherpetic neuralgia. The agent binds to and modulates molecular subunits that are widely present in voltage-gated calcium channels that regulate pain transmission areas. Mirogabalin have unique target binding characteristics and long-term effects. The drug is approved in japan for the treatment of PNP. Melagatran was the first drug approved globally for Peripheral Neuropathic Pain (PNP). The structural formula is shown in the following figure. Chinese patent document CN104334169a discloses a solid pharmaceutical composition of methoprene besylate comprising methoprene besylate in combination with (i) one or two or more components selected from D-mannitol, lactose, corn starch and crystalline cellulose, and (ii) one or both of calcium carboxymethyl cellulose and sodium carboxymethyl starch. The technical proposal research results show that when mannitol has a larger particle size (average particle size: 150 μm), a large amount of related substances are generated and the compatibility is poor. Tablets were prepared which ensured excellent stability and tablet physical properties in the range of 0.5% to 5% of methoprene besylate (in terms of its free form), 5% to 15% (in particular about 10%) of calcium carboxymethyl cellulose and 1% to 3% (in particular about 2%) of magnesium stearate. At 40 ℃, 75% RH and 6 months, the tablet can achieve a total amount of related substances produced of 1.6wt% or less. The stability of the preparation is also affected by using different preparation processes under the prescription, the stability of the direct extrusion method is better, and the wet granulation and the one-step granulation can be poor due to the introduction of water. Because the size of the solid preparation of the methoprene besylate is smaller, the effective component in each unit preparation is only 5 mg-15 mg, the mixing uniformity is difficult to ensure by adopting a direct compression process, and the problem of unqualified content uniformity caused by layering easily occurs in the production process. Chinese patent document CN107405322a discloses solid preparations of melagatran besylate containing an antioxidant selected from one or more of sodium edetate, citric acid hydrate, dibutyl hydroxytoluene, propyl gallate, magnesium citrate (anhydrous), soy lecithin, tocopherol, tocopheryl acetate and beta-cyclodextrin. Chinese patent document CN111971036a discloses solid pharmaceutical formulations of methoprene besylate containing a stabilizer which is citric anhydride or citric acid hydrate and alpha-tocopherol. The use of such antioxidants or stabilizers improves the pharmaceutical stability of the formulation to some extent, but the growth rate of the relevant substances is still relatively rapid. Disclosure of Invention Aiming at the defects of the prior art, the invention provides a stable solid preparation for orally taking the melagatran besylate, solves the problems of sticking and layering in tabletting in the prior art, does not need to precisely control the granularity of mannitol, and has better stability without adding an antioxidant. The preparation prescription provided by the invention is suitable for various processes, has a wide selection range, and is suitable for industrial production. The specific technical scheme of the invention is as follows: The orally taken solid preparation of the methoprene besylate comprises the methoprene besylate, sugar alcohol filling agent, lubricant and disintegrating agent, wherein the lubricant is the combination of glyceryl behenate and other lubricants, and the other lubricants are one or more selected from stearic acid, sodium lauryl sulfate, magnesium aluminum metasilicate, magnesium stearate and sodium stearyl fumarate. The weight percentage of the glyceryl behenate in the meloidogyne besylate oral solid preparation is 0.67-6.67%, and the weight percentage of other lubricants is 0.67-4%. The orally taken solid preparation of the methoprene besylate comprises, by weight, 1-50 parts of methoprene besylate, 10-500 parts of sugar alcohol filler and 1-40 parts of disintegrating agent except a lubricant. The invention relates to an oral solid preparation of melagatran besylate, the sugar alcohol filler is one or more selected from sorbitol, mannitol, erythritol, maltitol, lactitol and xylitol. The orally taken solid preparation of the methoxsulfonic acid and the methoxsalen provided by the invention has the advantages that the disintegrating agent is one or more of carboxymethylcellulose calcium, carboxymethyl s