Search

CN-121990949-A - Meloxbaline besylate raw material with particle size distribution controlled, preparation thereof, preparation process of preparation and application

CN121990949ACN 121990949 ACN121990949 ACN 121990949ACN-121990949-A

Abstract

The invention discloses a sulbactam besylate raw material for controlling particle size distribution, a preparation thereof, a preparation process and application of the preparation, and belongs to the technical field of pharmaceutical preparations. The technical problem to be solved is to improve the stability, the mixing uniformity and the dissolution rate of the methoprene besylate preparation. The key point of the technical scheme is that the particle size distribution of the methoprene besylate is controlled, the particle size range of the methoprene besylate is 130-210 mu m, and the D50 is 44-71 mu m. The sulbactam besylate preparation has the advantages of ensuring the uniformity and quick release of the product, effectively controlling the generation of degradation impurities and stabilizing the quality of the controllable product through the synergistic effect of specific stabilizers.

Inventors

  • WANG XIAOJUN
  • ZHANG YONGE
  • GAO QINGFENG

Assignees

  • 杭州和康药业有限公司

Dates

Publication Date
20260508
Application Date
20260302

Claims (10)

  1. 1. The methoprene besylate raw material with the particle size distribution controlled is characterized in that the particle size range of the methoprene besylate raw material is 130-210 mu m, and the D50 is 44-71 mu m.
  2. 2. A sulbactam besylate preparation comprising the sulbactam besylate raw material of claim 1 and pharmaceutically acceptable excipients.
  3. 3. The methoprene besylate preparation according to claim 2 is characterized by comprising, by weight, 4-6 parts of methoprene besylate raw materials, 1-4 parts of stabilizers, 87-94 parts of fillers, 0.1-0.5 part of glidants and 1-2 parts of lubricants.
  4. 4. A formulation of methoprene besylate according to claim 3 wherein the stabilizer is citric acid anhydrous.
  5. 5. The methoprene besylate formulation according to claim 4 wherein the filler comprises at least one of mannitol, microcrystalline cellulose and corn starch and/or the glidant comprises at least one of magnesium aluminum metasilicate and colloidal silicon dioxide and/or the lubricant comprises magnesium stearate; preferably, the filler comprises 44-82 parts by weight of mannitol, 5-29 parts by weight of microcrystalline cellulose and 7-15 parts by weight of corn starch.
  6. 6. The formulation of melagatran besylate according to any of claims 2 to 5 wherein said formulation is a tablet.
  7. 7. The formulation of melagatran besylate according to any of claims 2 to 5 further comprising a coating.
  8. 8. A process for the preparation of a formulation of methoprene besylate according to any of claims 3 to 7 comprising the steps of: (1) Premixing: Uniformly mixing the sulbactam besylate with a stabilizer to obtain a mixture A, and uniformly mixing the mixture A with a filler and a glidant to obtain a mixture B; (2) Total mixing: Adding a lubricant into the mixture B, and uniformly mixing to obtain a mixture C; (3) Tabletting: Tabletting the mixture C, and optionally coating.
  9. 9. The process according to claim 8, wherein the tabletting pressure in step (3) is 7-16KN; Preferably, the average hardness of 2.5mg of mixture C after tabletting is controlled in the range of 50-100N; preferably, the average hardness of 5mg of mixture C after tabletting is controlled in the range of 70-120N; preferably, the weight gain after coating is 3-5% of the mass of mixture C.
  10. 10. Use of the methoprene besylate as claimed in claim 1 or as claimed in any one of claims 2 to 7 or as claimed in any one of claims 8 to 9 in the manufacture of a medicament for the treatment of neuropathic pain.

Description

Meloxbaline besylate raw material with particle size distribution controlled, preparation thereof, preparation process of preparation and application Technical Field The invention relates to the technical field of pharmaceutical preparations, in particular to a sulbactam besylate raw material for controlling particle size distribution, a preparation thereof, a preparation process of the preparation and application of the preparation. Background Melabalin besylate, chemical name [ (1R, 5S, 6S) -6- (aminomethyl) -3-ethylbicyclo [3.2.0] hept-3-en-6-yl ] acetic acid monobenzenesulfonate. Melabalin besylate as a calcium channel modulator plays an important role in the treatment of neuropathic pain, such as diabetic peripheral neuropathy and postherpetic neuralgia. The mevalonate sulbactam besylate reduces the inflow of calcium ions by regulating calcium ion channels, inhibits the hyperexcitation of neurons and the excessive release of neurotransmitters, thereby effectively relieving pain symptoms. A common formulation of methoprene besylate is in the form of an oral tablet. The related patent searched: Publication No. CN104334169a, publication No. 2015, 2/4, discloses a solid composition comprising a stabilized salt of an aminocarboxylic acid, which comprises the compound [ (1 r,5s,6 s) -6- (aminomethyl) -3-ethylbicyclo [3.2.0] hept-3-en-6-yl ] acetic acid monobenzenesulfonate in combination with suitable additives. The composition has an impurity increase of about 0.17-0.29% when stored at 40 deg.C and 75% RH for 3 months, and an increase of about 4.5% when left at 60 deg.C for 4 weeks. Publication No. CN120324356A, publication No. 2025, 7 and 18, which discloses a tablet of melagatran besylate, wherein the tablet core comprises the melagatran besylate, a filler, a disintegrating agent, a lubricant, a glidant and a stabilizer, wherein the disintegrating agent is sodium carboxymethyl starch, the stabilizer is tocol and tartaric acid, and the stability (especially the quality control of impurity I) of the prepared tablet of melagatran besylate is superior to that of a reference preparation. The amount of the relevant substances produced by the tablet after 60 days of standing at 40 ℃ and 75% RH is about 0.33%. Publication number CN119235806a, publication number 2025, 1/3, discloses a tablet of melagatran besylate, the tablet core comprising melagatran besylate, filler, disintegrant, lubricant, glidant and stabilizer selected from one or more of propyl gallate, ascorbyl palmitate, disodium edetate, anhydrous or citric acid monohydrate, tocopherol, malic acid, tartaric acid, fumaric acid, maleic acid, dibutyl hydroxytoluene, preferably autogenous phenol, citric acid anhydrous, citric acid monohydrate, tartaric acid, ascorbyl palmitate, propyl gallate. Taking prescription 10 as an example, the tablet has a dissolution rate of 89.6-92.1% in 10-45min in a dissolution medium with pH of 1.2, wherein the amount of related substances generated after the tablet is placed under 40 ℃ and 75% RH for 30 days is about 0.36%. The prior art represented by the foregoing documents has at least the following technical problems or drawbacks that have not been solved: (1) The stability was poor, and the relevant evidence was that CN104334169a the composition had an impurity increase of about 0.17-0.29% after 3 months of storage at 40 ℃ and 75% RH and a related substance increase of 4.5% after 4 weeks of storage at 60 ℃. CN120324356a the amount of the relevant substances produced after the tablet is left at 40 ℃ for 60 days under 75% rh is about 0.33%. CN119235806a the amount of relevant substances produced after the tablet is left to stand at 40 ℃, 75% rh for 30 days is about 0.36%. (2) The dissolution performance is poor, and the dissolution rate of the CN119235806A tablet in a dissolution medium with the pH of 1.2 is 89.6-92.1% within 10-45 min. Therefore, there is still a need in the art to develop a material of sulbactam besylate with higher stability and better dissolution performance, a preparation thereof, a preparation process and application of the preparation. Disclosure of Invention The invention aims to provide that: the utility model provides a control particle size distribution's benzene sulfonic acid Mezlocillin raw materials and its related technique to solve the technical problems such as stability improvement, dissolution improvement, mixing uniformity improvement etc. or its combination. In a first aspect, the present invention provides a controlled particle size distribution of a starting material of melagatran besylate having a particle size in the range of from 130 to 210 μm D90 to 44 to 71. Mu.m, more preferably from 134 to 210. Mu.m, and still more preferably from 44 to 71. Mu.m D50. This particular particle size range helps to improve drug stability and mixing uniformity, reduce drug changes during storage, and thereby improve drug safety and efficacy. In a second aspect, the invention provides a methoprene be