Mechanism of Ion-Pair Strategy in Modulating Skin Permeability of Zaltoprofen: Insight from Molecular-Level Resolution Based on Molecular Modeling and Confocal Laser Scanning Microscopy.
The study was carried out to investigate the mechanism of the ion-pair strategy in modulating zaltoprofen (ZAL) skin permeability. Seven organic amines were chosen as counter ions and the formation of ion pairs was confirmed by Fourier transform infrared and proton nuclear magnetic resonance spectroscopy. In vitro permeation studies showed that the permeation of ZAL was significantly promoted with alkylamines and cycloalkanolamines, while significantly retarded with alkanolamines. The results were further visualized by confocal laser scanning microscopy studies. Investigations from the standpoint of solubility, partition, and diffusion indicated that the modulation mechanism of ion pairs was mainly attributed to an alteration of ZAL diffusion in the skin, which was accomplished by masking the carboxyl of ZAL and adding the hydrogen-bonding groups of counter ions. A negative correlation was observed between the enhancement ratio of ion pairs and the polar surface area of counter ions. Molecular modeling revealed that ion pairs acted with the nature of different affinity to ceramide, which would be responsible for the diffusion retardation. The study indicated that the maximum effect of ion pairs tended to be achieved with counter ions of lower hydrogen-bonding potential. Besides, ZAL-triethylamine ion pair might be a promising strategy for transdermal delivery of ZAL.
Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Hongxia
H
Cui
Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Peng
P
Quan
Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Hanqing
H
Zhao
School of Life Science and Bio-Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Xue
X
Wen
Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Wenting
W
Song
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, 116024, China.
Yi
Y
Xiao
School of Life Science and Bio-Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Yongshan
Y
Zhao
Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Liang
L
Fang
D000279:Administration, Cutaneous; D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001578:Benzopyrans / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002518:Ceramides / Q000737:chemistry; D004058:Diffusion; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D018613:Microscopy, Confocal; D008958:Models, Molecular; D011422:Propionates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011817:Rabbits; D012869:Skin Absorption; D012995:Solubility
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D002518:Ceramides; D011422:Propionates; C043940:pyranoprofen
FTIR; NMR; confocal laser scanning microscopy; ion pair; molecular modeling; permeability; polar surface area; transdermal; zaltoprofen