Self-Micellizing Technology Improves the Properties of Ezetimibe and Increases Its Effect on Hyperlipidemic Rats.

Carlos Torrado-Salmerón,Víctor Guarnizo-Herrero,Santiago Torrado-Santiago,Javier Cerezo-Garreta,Guillermo Torrado Durán

doi:10.3390/pharmaceutics11120647

Carlos Torrado-Salmerón, Víctor Guarnizo-Herrero + Show 3 more

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https://doi.org/10.3390/pharmaceutics11120647

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Abstract

The aim of this work was to develop ezetimibe self-micellizing solid dispersions using Kolliphor® RH40 (MS-K) as a surfactant incorporating ezetimibe (EZ) into the croscarmellose hydrophilic carrier. Different ezetimibe:Kolliphor® ratios were studied to select micellar systems that improve the dissolution properties of ezetimibe. The different formulations were characterized by means of solid state analysis by SEM, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and dissolution studies. These physicochemical studies showed a decrease from the crystalline structure of ezetimibe (EZ) to its amorphous state in the micellar systems (MS-K). A rapid dissolution profile was observed in these micellar systems compared to the drug raw material and physical mixture. Efficacy studies were conducted using a high-fat diet that induced hyperlipidemic rats. The micellar system selected (MS-K 1:0.75) revealed a significant improvement in serum levels of total cholesterol (TC), low-density lipoproteins (LDL), and triglycerides (TG) compared to ezetimibe raw material. The histopathological examination of liver tissue also showed that this micellar system exhibited more beneficial effects on liver steatosis compared to ezetimibe raw material (EZ-RM) and the high-fat diet group (HFD). This study suggests that EZ micellar systems using Kolliphor® RH40 could enhance the antihyperlipidemic effect of ezetimibe and reduce liver steatosis.

Highlights

Hyperlipidemia is characterized by an increase in cholesterol, triglyceride, and lipoprotein levels [1,2]
The World Health Organization considers that hyperlipidemia has become more relevant in recent years because it is significantly associated with almost half the global cases of ischemic heart disease [2]
This study clearly demonstrates that the addition of Kolliphor® to ezetimibe in solid dispersions with croscarmellose as a carrier creates micellar systems with rapid dissolution profiles

Summary

Introduction

Hyperlipidemia is characterized by an increase in cholesterol, triglyceride, and lipoprotein levels [1,2]. Hyperlipidemia induces hardening of the arteries and decreases blood flow to the aortic valve, this is an important risk factor for coronary artery disease (CAD). Several studies have shown an association between CAD and non-alcoholic fatty liver disease (NAFLD) [3,4]. NAFLD disorders commonly feature an accumulation of excessive fat in the liver, in which non-alcoholic steatohepatitis, ballooning, lobular inflammation, and other cell injuries are observed [1,5]. EZ treatments restore basal cholesterol, triglyceride, and lipid levels [4,6]. Liver histological studies show that treatment with EZ makes it possible to eliminate ballooning, inflammation, and other cellular alterations [1,7]

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