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

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.

Improvement in the Oral Bioavailability and Efficacy of New Ezetimibe Formulations—Comparative Study of a Solid Dispersion and Different Micellar Systems

“…These results agree with the partial amorphization of EZ observed in PXRD. Similar decreases in the crystallinity of EZ have been obtained in micro and nanoparticles of poorly soluble drugs [ 21 ].…”

Multiparticulate Systems of Ezetimibe Micellar System and Atorvastatin Solid Dispersion Efficacy of Low-Dose Ezetimibe/Atorvastatin on High-Fat Diet-Induced Hyperlipidemia and Hepatic Steatosis in Diabetic Rats

“…The X-ray diffraction patterns in Figure 3 A show the EZ-RM with representative peaks at 16.44°, 19.13°, 20.37°, and 23.85° 2θ. This crystalline structure corresponds to the anhydrous form of ezetimibe [ 7 ].…”

“…The EZ-RM ( Figure 2A) displayed an endothermic peak at 162.24 °C and an enthalpy value of 77.00 J/g, caused by a micronized form of EZ [7]. The hydrophilic croscarmellose used to prepare the ezetimibe formulations exhibited a sharp melting peak at 159.37 °C Figure 1C shows the surface of ATV physical mixture.…”

“…explained by the swelling and water uptake of the hydrophilic carrier [7,9]. These improvements of dissolution profile could by related to the wettability increment of the amorphous form of ATV used in the formulation of commercial tablets [26].…”

“…However, recent studies have shown that concentrations in the liver are more important than high plasma bioavailability for the treatment of hepatic steatosis in hyperlipidemic patients [ 6 ]. To improve the poor solubility of EZ, surfactants such as Kolliphor RH40 have been used in micellar systems [ 7 ], while hydrophilic cellulose polymers such as Hydroxypropyl cellulose (HPC) or sodium croscarmellose have been selected for their pronounced hydrophilic properties [ 8 , 9 ] for the elaboration of solid dispersions of ATV, although EZ and ATV are difficult to quantify due to their low concentrations in liver tissue, meaning that the hepatic biodistribution of these active ingredients cannot be analyzed. Recent studies on other hydrophobic drugs such as voriconazole and amphotericin B showed a high liver biodistribution with similar micellar systems [ 10 ].…”