Formulation, Optimization, and Evaluation of Ezetimibe for Chronotherapeutic Drug Delivery using Compression-Coating Technology

Abstract

Objectives: The purpose of the present study was to Formulation, optimization and evaluation of drug for chronotherapeutic drug delivery using compression coating technology for hypercholesterolemia. Material and Methods: The drug delivery system was designed to deliver the drug at a time when it could be needed for the most in the early morning (4 to 6 a.m.) for patients in case of hypercholesterolemia. The pulsatile concept was applied to the dosage form by having a lag phase followed by an immediate release. The prepared system consisted of two parts: a core tablet containing the active ingredient and fracture outer shell with delay-release polymer having diffusion characteristics. Solid dispersion was carried out by screening of betacyclodextrin, Polyvinyl pyrrolidone (PVP K30), and HPMC using three different drug complex ratios 1:1, 1:2, and 1:3 by a solvent evaporation method through spray dryer. The immediate-release core tablet (IRCT) was prepared by using a superdisintegrant with active ingredients. Screening of IRCT was carried out by pre and post compression parameters, disintegration time and an in-vitro dissolution study. The pulsatile release tablet (PRT) of optimized IRCT was made by Glyceryl Behenate and Dibasic Calcium Phosphate. Optimization of polymer concentration of PRT was carried out by pre and post-compression parameters, pulsatile lag time, and an in-vitro dissolution study. A 32 factorial design was employed to optimize the PRT. The design consisted of two dependent variables R1, and R2 independent variables X1 and X2. The two independent formulation variables selected for the study including Concentration of coating polymer and Concentration of lubricant. The dependent variables are Lag Time and Thickness. Results: XRD, DSC and FTIR spectra showed that solid dispersion was formed by the drug and PVP K30 complex. IRCT batch RR1 containing 22mg croscarmellose sodium to achieve good 30sec disintegration time and 98.34% drug release at the end of 20 minutes of Ezetimibe respectively. PRT formulation DR6 showed good pre and post-compression parameters with a satisfactory drug release of 98.34% for Ezetimibe respectively with a lag time of 6 hours. The 32 factorial design was used for the optimization of PRT parameters. A total of 9 experiments were performed for two factors at three levels each. The optimized batch showed 98.27% DR for Ezetimibe in 6.2 hrs (within 20 min after lag time) with pulsatile lag time up to 6.0 hrs and thickness of 5.10 kp. Conclusion: It was concluded that tablet within the tablet, pulsatile drug delivery of Ezetimibe (BCS class-II drugs) was successfully formulated with the advantage of enhanced solubility, and pulsatile release behavior and had an added benefit of suitable for chronopharmacotherapy of diseases that show circadian rhythms in their pathophysiology.