A novel transdermal patch incorporating isosorbide dinitrate with bisoprolol: in vitro and in vivo characterization.

ABSTRACT

The combination therapy of nitrate and selective beta-adrenoceptor antagonist has shown benefits for treatment of hypertension and heart disease than either drug alone. The objectives of the present study were to define effects on the anti-hypertension activity and pharmacokinetics of a novel transdermal patch incorporating isosorbide dinitrate (ISDN) with bisoprolol (BP). The 32 ratio of ISDN to BP (mg/mg) in the transdermal patches exhibited better anti-hypertension effect synergistically with a similar inhibiting heart rates effect to that of BP alone in renovascular hypertensive rats, and was therefore selected as a final formulation. The in vitro transdermal penetration of both ISDN and BP from the patches displayed a zero-order process, and the penetration rate constants were 7.4 microg/(cm(2)h) for ISDN, and 5.9 microg/(cm(2)h) for BP, respectively. After transdermal administration at single dose or multiple doses, the synergistic anti-hypertension effect was confirmed in spontaneously hypertensive rats also. The effect of each patch lasts for 3 days, and increased with the total dose of two drugs (2mg/cm(2), ISDNBP=32, mg/mg), showing a dose dependant manner. After transdermal administration to rabbits, the absolute bioavailabilities were 33.6% for ISDN, and 31.3% for BP, respectively. The maximal concentrations (C(max)) of both drugs were significantly reduced while the areas under the plasma concentration-time curve (AUC), and mean residence times (MRT) were evidently increased and extended, respectively. As a patient-friendly, convenient, and multi-day dosing therapeutic system, the transdermal patches incorporating ISDN and BP could be promising for prevention and treatment of hypertension.