Tanshinone IIA – loaded pellets developed for angina chronotherapy: Deconvolution-based formulation design and optimization, pharmacokinetic and pharmacodynamic evaluation

Abstract

This paper put forward a deconvolution-based method for designing and optimizing tanshinone IIA sustained-release pellets (TA-SRPs) with improved efficacy in the treatment of variant angina. TA-SRPs were prepared by coating TA ternary solid dispersion immediate-release pellets (TA-tSD-IRPs) with the blends of polyvinyl acetate (PVAc) and polyvinyl alcohol–polyethylene glycol (PVA–PEG) using fluidized bed technology. The plasma concentration–time curve of TA-tSD-IRPs following oral administration as a weight function was investigated in New Zealand white rabbits. The predicted/expected plasma concentration–time curve of TA-SRPs as a response function was simulated according to the circadian rhythm of variant angina during 24h based on chronotherapy theory. The desired drug release profile of TA-SRPs was obtained via the point-area deconvolution procedure using the weight function and response function, and used for formulation optimization of TA-SRPs. The coating formulation of TA-SRPs was optimized as 70:30 (w/w) PVAc/PVA–PEG with 5% (w/w) coating weight due to in vitro drug release profile of these TA-SRPs was similar to the desired release profile (similarity factor f2=64.90). Pharmacokinetic studies of these optimized TA-SRPs validated that their actual plasma concentration–time curve possessed a basically consistent trend with the predicted plasma concentration–time curve and the absolute percent errors (%PE) of concentrations in 8–12h were less than 10%. Pharmacodynamic studies further demonstrated that these TA-SRPs had stable and improved efficacy with almost simultaneous drug concentration–efficacy. In conclusion, deconvolution could be employed in the development of TA-SRPs for angina chronotherapy with simultaneous drug efficacy and reduced design blindness and complexity.