Design and development of a dual-drug loaded pulsatile capsule for treatment of hypertension – in vitro and ex vivo studies

Abstract

The frequency of incidence of cardiovascular events in hypertensive patients is higher in the early morning hours between 5 a.m. to noon due to a sharp increase in blood pressure (BP), thereby suggesting a circadian pattern. Currently available antihypertensive medicines for bed time or morning dosing cannot address this early morning surge in BP. The aim of the present study was to design and evaluate a pulsatile dosage form to program the release of dual antihypertensive drugs to mimic the circadian pattern of BP. The optimized formulation meant for bedtime dosing, consisted of an insoluble capsule body housing a layer of swellable polymer, a telmisartan (TELMI) tablet sealed by an erodible polymer tablet. The capsule body was closed with a water soluble cap containing fast releasing amlodipine (AMLO)–xylitol granules. The developed formulation was studied for physical characteristics, lag time determination, in vitro release, and ex vivo dissolution absorption. The capsule cap dissolved in acidic pH to release 98.67% of the AMLO within 3 h. The swellable polymer layer at the base of capsule pushed the plug along with the TELMI tablet out after a lag time of 6–7 h with 77.97% drug being released at the end of 12 h providing a time controlled need based release. In vitro–ex vivo studies revealed a better degree of correlation in the pulsatile capsule compared to the marketed one. Thus this approach can be useful for the timed release of a combination antihypertensive medication and may provide effective 24 h control of BP in hypertensive patients.