Drug Release and Pharmacokinetics Behavior of a Simple Ethylcellulose Coating Pulsatile Tablet of Time-Controlled Explosive System

Core tip: The time rhythm of the human body is associated with the occurrence and development of many diseases. Kinds of diseases of particular onset biorhythm provided the room for the development of chronopharmacological drug delivery systems. Metoprolol tartrate (MT), a medicine commonly used for treatment of cardiovascular diseases in clinic, was selected as model drug to develop a time-controlled explosive pulsatile tablet. The prepared MT pulsatile tablets showed a drug release lag time of 7.10 h in vitro perfectly consistent with the absorption lag time of 7.04 h in vivo, which ensured the pulsatile tablet a promising chronopharmacological drug delivery system for MT to prevent and treat the peak attack of hypertension and angina pectoris early in the morning. Abstract: Background The time rhythm of human body is associated with the occurrence and development of many diseases. Kinds of diseases of particular onset biorhythm provided the room for the development of chronopharmacological drug delivery systems. Aim In this work, the drug release and pharmacokinetics behavior of metoprolol tartrate (MT) pulsatile tablet developed in our lab was investigated to figure out its feasibility of convenient drug taking to exert effective chronotherapy for cardiovascular diseases like hypertension and angina pectoris. Methods The in vitro release behavior of MT pulsatile tablets was investigated by using basket method. The appearance and morphology of MT pulsatile tablets during drug release was observed by naked eye and scanning electronic microscope, respectively. In vivo pharmacokinetics performance was studied in New Zealand rabbits. Results The lag time of MT pulsatile tablets was approximately 7 h in vitro, and a fast release was observed thereafter, with more than 90% releasing within 10 min. The pharmacokinetics study in rabbits demonstrated a perfect consistence in the absorption lag time of 7.04 ± 0.29 h in vivo. Compared with the marketed conventional tablet, the MT pulsatile tablet showed a bioequivalence in absorption extent with a relative bioavailability of 110.04%, but not in absorption rate. Conclusion The designed lag time of 7 hours enabled the MT pulsatile tablets to achieve effective chronotherapy for cardiovascular diseases like hypertension and angina pectoris with a high attack rhythm around 4:00-6:00 A.M by giving medicine conveniently around 22:00 P.M. the night before.* Sha Li is corresponding author of this paper. †These authors contributed equally to this work. Sha Li conceived the idea, designed and supervised the research. Mohui Yang and Xingli Wang performed the research, conducted the analysis and wrote the paper. Jiabi Ouyang, Zhen Zhang and Yani Tan contributed to data collection and analysis. All authors contributed to the writing and revisions