Abstract:
Background: Hydralazine hydrochloride (HZH) is a drug candidate used to treat pulmonary arterial hypertension. Extreme variability in oral dosing, bioavailability of 31%, variable half-life of 3 to 7 h and molecular weight of 196.6 Daltons, made the drug molecule suitable for transdermal system. Objective: The objective of the present investigation is to study the effect of penetration enhancers on release kinetics of hydralazine hydrochloride both in vitro and in vivo through reservoir based transdermal systems. Materials and Methods: Rate controlling membranes were formulated by using HPMC, Eudragit RLPO and Eudragit RSPO. Reservoir was formulated by using 16% poloxamer 407 gel by cold method as it is having sol-gel temperature at 37°C. Results and Discussion: The drug release followed zero order non-fickian super case-II diffusion transport mechanism. Enhancement ratio was more with IPM as penetration enhancer. Formulation F7 [ERLPO: HPMC 5:5 and IPM 15%] had maximum in vitro release of 95.68 ± 1.16% with flux value of 64.168±0.071 μg/h/cm2, no significant difference in ex vivo permeation study was observed. The fabricated reservoir system was found to be safe for skin. In vivo kinetic studies projected a controlled release pattern with extended AUC of 25.760 ± 9.124 μg/mL/h with MRT 17.7 ± 0.37 h in transdermal route compared to oral route where AUC and MRT are 4.409 ± 2.015 μg/mL/h and 2.98 ± 1.24 h respectively. Conclusion: The drug reservoir transdermal system of HZH had varied in vitro release profile with varying the concentrations of penetration enhancer. The optimized transdermal system had extended AUC and MRT values compared to oral route and can enhance the bioavailability.
Key words: Hydralazine hydrochloride, Isopropyl myristate, In vitro kinetics, In vivo kinetics, Poloxamer 407.
