Formulation, Characterization, and Pharmacokinetic Evaluation of Ivabradine-Nebivolol Co-Encapsulated Lipospheres

Abstract A Central Composite Rotatable Design (CCRD) was applied to statistically optimized lipospheres (LS) formulated for enhancing the pharmacokinetics of co-administered Ivabradine and Nebivolol as well as improving the patients’ compliance. The lipospheres (LS) were prepared by simple melt emulsification technique and impact of formulation variables (Carnauba wax, Beeswax, and surfactant) on percentage yield (Y1), IVB-release (Y2) and NEB-release (Y3) was statistically investigated. The numerical optimization technique was adopted to select optimized lipospheres (OL) which were then subjected to a comparative in vivo pharmacokinetic analysis against commercially available brands. The physicochemical analysis of LS was performed by FTIR, DSC and x-ray powder diffractometry (XRD). Lipospheres were also analysed for micromeritics, zeta potential, size, and morphology. The spherical, smooth surface, free-flowing LS having zeta potential of -40 to -60mV and size-range of 10-50 µm were successfully formulated. The physicochemical analysis demonstrated a complete lack of drugs interaction with lipids carriers, and p-XRD showed a transformation of crystalline drugs to amorphous form. The outcomes for Y1 (38-88%), IVB-release (47-96%) and NEB-release (38-88%) followed polynomial quadratic model. The pharmacokinetics analysis of LS showed a significantly decreased Cmax of IVB (39.29±6.39), NEB (56.69±3.73) with an effectively raised Tmax (13.41 h for IVB and 14.53 h for NEB) as compared to IVB (49.67±5.26 ng/mL) and NEB (71.32±4.57 ng/mL) of commercial brands. Moreover, an expressively increased half-life (17hr for IVB, 19 hr for NEB), AUC0-24 (8121 for IVB, 11368 for NEB) and mean residence time for IVB and NEB indicated the accomplishment of greater bioavailability of drugs released from LS. Conclusively, such an innovative idea of combination loaded LS of IVB, and NEB would convincingly bring an effective management of chronic cardiovascular complications by maintaining the plasma drugs concentration for a prolonged time.