The clinical manifestations of variant angina is unevenly distributed during the 24 h, thus the in vivo performance of drugs should be tailored according to the angina circadian rhythm.
Cryptotanshinone (
CTN) is one of the representative bioactive
lipid-soluble components of Danshen which has been commonly used for
cardiovascular diseases such as
angina pectoris. The aim of this study was to develop a novel
CTN sustained-released pellets (
CTN-SRPs) to precisely synchronize the
CTN plasma concentrations with predicted occurrence of
angina pectoris for angina
chronotherapy. A deconvolution-based method was applied to develop and optimize the
CTN-SRPs. The plasma concentration-time curve of
CTN immediate-released formulation after
oral administration in rats was used as the weight function. The predicted plasma concentration-time curve of
CTN-SRPs simulated according to the incidence of variant angina during 24 h was used as the response function. Then the desired drug release profile of
CTN-SRPs was calculated based on deconvolution using weight function and response function, and subsequently used for guiding the formulation optimization.
CTN-SRPs were prepared with the combinations of PVP,
poloxamer 127 and EC as matrix using fluidized bed technology. An orthogonal design was employed to obtain the optimal formulation with its release profile similar with the desired one. Pharmacokinetic studies validated that the actual plasma concentration-time curve of these optimized
CTN-SRPs was similar with the predicted one. In addition, the percent errors (%PE) of
CTN plasma concentrations in 8-12 h were less than 10%. In conclusion, this deconvolution-based method could be applied to adjust the in vivo performance of drugs for angina
chronotherapy.