title: 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 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.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
authors.forename: Ji-Hui
authors.initials: JH
authors.lastname: Zhao
authors.forename: Ji-Hua
authors.initials: JH
authors.lastname: Fu
authors.forename: Shu-Ming
authors.initials: SM
authors.lastname: Wang
authors.forename: Chang-Hai
authors.initials: CH
authors.lastname: Su
authors.forename: Ying
authors.initials: Y
authors.lastname: Shan
authors.forename: Shu-Jia
authors.initials: SJ
authors.lastname: Kong
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Wan-Liang
authors.initials: WL
authors.lastname: Lu
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: En-Hong
authors.initials: EH
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Qiu-Ling
authors.initials: QL
authors.lastname: Pei
authors.forename: Jian-Cheng
authors.initials: JC
authors.lastname: Wang
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: 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*
chemical_list: 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