A novel transdermal patch incorporating isosorbide dinitrate with bisoprolol: in vitro and in vivo characterization.
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 3:2 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), ISDN:BP=3:2, 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.
Zhao
Ji-Hui
JH
State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
Fu
Ji-Hua
JH
Wang
Shu-Ming
SM
Su
Chang-Hai
CH
Shan
Ying
Y
Kong
Shu-Jia
SJ
Wang
Yuan
Y
Lu
Wan-Liang
WL
Zhang
Hua
H
Zhang
Shuang
S
Li
Lin
L
Zhang
En-Hong
EH
Wang
Li
L
Pei
Qiu-Ling
QL
Wang
Jian-Cheng
JC
Zhang
Xuan
X
Zhang
Qiang
Q
D000279:Administration, Cutaneous; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D017298:Bisoprolol / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical; D015194:Diffusion Chambers, Culture; D004195:Disease Models, Animal; D004304:Dosage Forms; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004339:Drug Compounding; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006978:Hypertension, Renovascular / Q000188:drug therapy / Q000503:physiopathology; D007548:Isosorbide Dinitrate / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D012869:Skin Absorption; D012995:Solubility; D046509:Tissue Culture Techniques; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D004304:Dosage Forms; D004338:Drug Combinations; D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; D007548:Isosorbide Dinitrate; D017298:Bisoprolol