Ezetimibe Loaded Nanostructured Lipid Carriers Tablets: Response Surface Methodology, In-vitro Characterization, and Pharmacokinetics Study in Rats

Abstract

Purpose: The present study aims to overcome the poor oral bioavailability of ezetimibe (EZ), a selective Biopharmaceutics Classification System (BCS) Class II cholesterol absorption inhibitor drug. EZ-loaded nanostructured lipid carriers (EZ-NLCs) were dried by lyophilization and incorporated in a convenient oral solid dosage form to enhance its dissolution, and absorption and increase patient compliance. Response surface methodology (RSM) was employed to systematically optimize formulation variables, improving the efficiency of disintegration and drug release characteristics.

Methods: RSM was adopted to study the effects of (A) increasing the amount of the super-disintegrant, crosscarmelose sodium, (CCS), and (B) varying the ratio between the used drying excipients Avicel and mannitol (A: M) on the disintegration time (R1), and the percentage drug released after 24 h (R2). Thirteen EZ-NLCs tablets were prepared and subjected to pre-compression and post-compression evaluation. Furthermore, a bioequivalence study was conducted by administering EZ-NLCs and ezetrol® tablets to Sprague Dawley male rats.

Results: The optimized EZ-NLCs tablet (prepared with the ratio of Avicel: mannitol (7.5:0) using 30 mg CCS), revealed a disintegration time of 3.85 ± 0.03 min, and 98 ± 3.09% of the drug were released at the end of the 24 h. EZ-NLCs tablet displayed a maximum concentration (Cmax) of 3.57 ± 0.27 ng/mL and an area under the curve (AUC0− 24) of 22.44 ± 2.68 ng.hr/mL, while those of ezetrol® were 2.79 ± 0.15 ng/mL and 15.36 ± 0.86 ng.hr/mL, respectively.

Conclusion: The assessed relative bioavailability demonstrated the superiority of EZ-NLCs tablet over ezetrol® with 1.5 fold improvement which proves that EZ-NLCs tablet could be a good candidate to enhance the oral bioavailability of EZ.