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CN-121987577-A - Storage-stable ezetimibe-containing and rosuvastatin calcium-containing pharmaceutical composition

CN121987577ACN 121987577 ACN121987577 ACN 121987577ACN-121987577-A

Abstract

The invention provides a preparation method of ezetimibe and rosuvastatin calcium composition, which ensures the long-term stability of the preparation, has a simple and convenient process and is suitable for industrial production. The preparation is carried out by adopting conventional and accessible equipment, the key quality attribute of intermediate products in the preparation process is strictly controlled, the quality of the prepared finished product is stable in the long-term placement process, and the total degradation products in the long-term 36 months are less than 2.5%.

Inventors

  • WEI GUANGTONG
  • WANG YAMING
  • XU FENG
  • ZHANG XIAOQING

Assignees

  • 南京科默生物医药有限公司

Dates

Publication Date
20260508
Application Date
20241104

Claims (10)

  1. 1. The pharmaceutical composition is characterized by comprising ezetimibe particles, rosuvastatin calcium and pharmaceutical excipients, wherein the pharmaceutical excipients comprise one or more than two of a filling agent, a binding agent, a disintegrating agent and a lubricating agent which are used in pharmacy, and the ezetimibe particles are prepared from ezetimibe, the filling agent, a surfactant and the binding agent through a solid dispersion technology.
  2. 2. The pharmaceutical composition containing ezetimibe and rosuvastatin calcium according to claim 1, wherein the filler is one or more selected from lactose, mannitol, cyclodextrin, microcrystalline cellulose, starch, pregelatinized starch and dicalcium phosphate.
  3. 3. The pharmaceutical composition containing ezetimibe and rosuvastatin calcium according to claim 2, wherein the filler is selected from mannitol, microcrystalline cellulose and lactose, and the dosage is preferably 20% -30%, 10% -20% and 35% -45% by weight respectively.
  4. 4. The pharmaceutical composition containing ezetimibe and rosuvastatin calcium according to claim 1, wherein the binder is one or more selected from the group consisting of hyprolose, hypromellose, povidone, and sodium carboxymethyl cellulose.
  5. 5. The pharmaceutical composition containing ezetimibe and rosuvastatin calcium according to claim 4, wherein the binder is selected from hydroxypropyl cellulose and povidone, and the amount of the binder is 1.5% -3.5% and 1% -2.5% of the pharmaceutical composition by weight percent respectively.
  6. 6. The pharmaceutical composition containing ezetimibe and rosuvastatin calcium according to claim 1, wherein the disintegrating agent is selected from one or more of croscarmellose sodium, low substituted hydroxypropyl cellulose, sodium carboxymethyl starch, crospovidone, starch and pregelatinized starch.
  7. 7. The pharmaceutical composition containing ezetimibe and rosuvastatin calcium according to claim 6, wherein the disintegrating agent is selected from croscarmellose sodium and low-substituted hydroxypropyl cellulose, and the dosage is 2% -5% by weight.
  8. 8. The pharmaceutical composition containing ezetimibe and rosuvastatin calcium according to claim 1, wherein the lubricant is magnesium stearate in an amount of 0.5% -3.0%, preferably 0.5% -1.5% by weight.
  9. 9. The pharmaceutical composition containing ezetimibe and rosuvastatin calcium according to claim 1, wherein the surfactant is selected from sodium dodecyl sulfate in an amount of 0.5% -1.5% by weight.
  10. 10. The pharmaceutical composition containing ezetimibe and rosuvastatin calcium according to any one of claims 1-9, wherein the total tablet weight of the composition is 180 mg/tablet, and the ingredients comprise: 。

Description

Storage-stable ezetimibe-containing and rosuvastatin calcium-containing pharmaceutical composition Technical Field The invention belongs to the field of pharmaceutical preparations, and in particular relates to a preparation method of a composition of ezetimibe and rosuvastatin calcium, which is simple in process and stable in storage. Background Ezetimibe is a selective cholesterol absorption inhibitor. The chemical name is 1- (4-fluorophenyl) - (3R) - [3- (4-fluorophenyl) - (3S) -hydroxypropyl ] - (4S) - (4-hydroxyphenyl) -2-propiolactam, the molecular formula is C 24H21F2NO3, the relative molecular weight is 409.4, and the structural formula of ezetimibe is shown in the figure: Rosuvastatin calcium is a selective HMG-CoA reductase inhibitor. The chemical name is 1- (4-fluorophenyl) - (3R) - [3- (4-fluorophenyl) - (3S) -hydroxypropyl ] - (4S) - (4-hydroxyphenyl) -2-propiolactam, the molecular formula is (C 22H27FN3O6S)2 Ca; relative molecular weight 1002.04; structural formula of rosuvastatin calcium is shown in the figure: Ezetimibe is an oral, powerful lipid-lowering drug with a mechanism of action different from other lipid-lowering drugs, and is attached to the brush-like edge of the small intestine velvet to inhibit the absorption of cholesterol, thereby reducing the transport of cholesterol in the small intestine to the liver, reducing the storage of cholesterol in the liver and thus increasing the clearance of cholesterol in the blood. Rosuvastatin calcium is a selective HMG-CoA reductase inhibitor. HMG-CoA reductase inhibitors are rate-limiting enzymes for converting 3-hydroxy-3-methylglutaryl CoA to a precursor of mevalonate-cholesterol. Rosuvastatin increases the number of hepatic LDL cell surface receptors, promotes LDL uptake and catabolism, inhibits liver synthesis of VLDL, and thereby reduces the total number of VLDL and LDL particles. Chinese patent CN110418637A, CN117883398a discloses that the combination of ezetimibe and rosuvastatin calcium shows an increase in degradation substances, and quality during stability is not satisfactory, so that the preparation of bilayer tablet improves the stability of the pharmaceutical preparation. The preparation process adopted by the Chinese patent CN105873571B is that ezetimibe is subjected to wet granulation, then mixed with rosuvastatin calcium and other auxiliary materials, and then tabletted, and the stability of the product is improved by adding an alkaline stabilizer sodium bicarbonate into the prescription. Compared with the preparation process disclosed above, the preparation method adopts special tabletting equipment or adds new auxiliary material types based on the original prescription, thereby bringing more unpredictability to the long-term quality of the product. And the double-layer tablet press has high cost, complex process and high quality control difficulty, and is not beneficial to industrial production. Therefore, new auxiliary material types are not added on the basis of the prescription of the original developing agent, the quality of the product during the storage period is improved, and the prescription process for obtaining the product which is more convenient for industrialized production is particularly critical. Disclosure of Invention In order to overcome the defects in the prior art, the invention provides a preparation method of ezetimibe and rosuvastatin calcium composition, which ensures the long-term stability of the preparation, has a simple process and is suitable for industrial production. The preparation is carried out by adopting conventional and accessible equipment, the key quality attribute of intermediate products in the preparation process is strictly controlled, the quality of the prepared finished product is stable in the long-term placement process, and the total degradation product is less than 2.5% within 36 months. The inventor has surprisingly found that the preparation of ezetimibe particles by adopting a solid dispersion technology can remarkably improve the stability of a compound preparation and reduce the impurity growth trend of the product during storage through a single factor comparison experiment. In order to achieve the above purpose, the technical scheme of the invention is as follows: The invention provides a composition of ezetimibe and rosuvastatin calcium, which is simple in process and stable in storage. The pharmaceutical composition comprises ezetimibe particles, rosuvastatin calcium and pharmaceutical excipients, wherein the pharmaceutical excipients comprise one or more than two of a filling agent, a binding agent, a disintegrating agent and a lubricating agent which are used in pharmacy, and the ezetimibe particles are prepared from ezetimibe, the filling agent, a surfactant and the binding agent by a solid dispersion technology. According to an embodiment of the invention, the filler is selected from one or a mixture of several of lactose, mannitol, cyclodextrin, microcrystalli