Ezetimibe-Loaded Nanostructured Lipid Carrier Based Formulation Ameliorates Hyperlipidaemia in an Experimental Model of High Fat Diet.

Chandragouda R Patil,Charu Sharma,Yogeeta O Agrawal,Vinit V Agnihotri,Sameer N Goyal,Umesh B Mahajan,Mayur S Nilange,Hitendra S Mahajan,Shreesh Ojha

doi:10.3390/molecules26051485

Abstract

Ezetimibe (EZE) possesses low aqueous solubility and poor bioavailability and in addition, its extensive hepatic metabolism supports the notion of developing a novel carrier system for EZE. Ezetimibe was encapsulated into nanostructured lipid carriers (EZE-NLCs) via a high pressure homogenization technique (HPH). A three factor, two level (23) full factorial design was employed to study the effect of amount of poloxamer 188 (X1), pressure of HPH (X2) and number of HPH cycle (X3) on dependent variables. Particle size, polydispersity index (PDI), % entrapment efficiency (%EE), zeta potential, drug content and in-vitro drug release were evaluated. The optimized formulation displays pragmatic inferences associated with particle size of 134.5 nm; polydispersity index (PDI) of 0.244 ± 0.03; zeta potential of −28.1 ± 0.3 mV; % EE of 91.32 ± 1.8% and % CDR at 24-h of 97.11%. No interaction was observed after X-ray diffraction (XRD) and differential scanning calorimetry (DSC) studies. EZE-NLCs (6 mg/kg/day p.o.) were evaluated in the high fat diet fed rats induced hyperlipidemia in comparison with EZE (10 mg/kg/day p.o.). Triglyceride, HDL-c, LDL-c and cholesterol were significantly normalized and histopathological evaluation showed normal structure and architecture of the hepatocytes. The results demonstrated the superiority of EZE-NLCs in regard to bioavailability enhancement, dose reduction and dose-dependent side effects.

Highlights

Hypercholesterolemia affects an enormous population. This condition is determined with a decline high density lipoprotein (HDL) levels and increased levels of low density lipoprotein (LDL) along with triglycerides (TG) in plasma (>200 mg/dL), which eventually results in the progression to atherosclerosis [1]
NLCs for the most part are composed of lipids, which favours bioavailability enhancement along with improvement in the solubility profile [28], so the objective of the study was to explore the feasibility of encapsulating ezetimibe in NLCs to allow sustained release of the drug by improving its dissolution rate and oral bioavailability
In the present study we have successfully developed EZE-loaded NLCs via a high pressure homogenization technique

Summary

Introduction

Ezetimibe decreases raised levels of high total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and nonhigh density lipoprotein cholesterol (non HDL-C) in patients with hyperlipidemia [4]. This BCS class II therapeutic moiety is an azetidine derivative with a low water-solubility profile and a high permeability index (log P of 4.56). Bioavailability is affected by high lipophilicity, pre-systemic clearance in the gastrointestinal mucosa and P-gp efflux mechanism In this context, novel approaches that improve the dissolution and/or apparent solubility are needed for better therapy, especially for poorly water-soluble drugs like EZE [6]

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Conclusion