Investigation on the Percutaneous Enhancing Permeation Mechanism of Azone for Ketoprofen Based on the Intermolecular Hydrogen-bonding Interaction  

作　　者：田青平 宋舒琴 史文静 谢茵 宋艳红 唐海飞 龚明星 钟华 张玲玲 任福德 

机构地区：[1]Department of Pharmacy, Shanxi Medical University [2]The Third Hospital of Shanxi Medical University [3]Feedstuff and Veterinary Drugs Watch Office, Department of Agriculture Shanxi Province [4]College of Chemical Engineering and Environment, North University of China

出　　处：《Chinese Journal of Structural Chemistry》2014年第2期304-318,共15页结构化学（英文）

基　　金：Supported by Natural Science Foundation of Shanxi Province(No.2012011007-5);the application and innovation project in police(No.2011YYCXSXST016)

摘　　要：The permeation enhancing activity of Azone for ketoprofen through excised cavia skins was investigated using Franz diffusion cell. The possible hydrogen-bonded complexes formed between ketoprofen and the model molecule of Azone as azacyclopentane-2-one were fully optimized at the B3LYP/6-311＋＋G＊＊ level. The intermolecular hydrogen-bonding interactions were calculated using the B3LYP/6-311＋＋G＊＊, B3LYP/6-311＋＋G（2df, 2p）, MP2（full）/6-311＋＋G＊＊ and MP2（full）/6-311＋＋G（2df, 2p） methods, respectively. The results show that the steady-state permeation rate of ketoprofen through excised cavia skins enhances over 9 times in the solvent with 2% Azone as compared with the solvent without Azone. The stable O–H…O=C and N–H…O=C hydrogen-bonded complexes could exist between azacyclopentane and ketoprofen. The hydrogen-bonding interaction energy follows the order of（a） 〉（b） 〉（c） 〉（d） 〉（g）〉（e） 〉（h） 〉（f）. The formation of the complexes leads to the change of the conformation and molecular polarity of ketoprofen, and thus causes a better percutaneous permeation for the drug. The analyses of AIM（atom in molecule） and shift of electron density were used to further reveal the nature of the enhancing permeation activity of Azone for ketoprofen. The investigations of the temperature and solvent effects confirm that ketoprofen might enter into the skin by means of the Azone complex.The permeation enhancing activity of Azone for ketoprofen through excised cavia skins was investigated using Franz diffusion cell. The possible hydrogen-bonded complexes formed between ketoprofen and the model molecule of Azone as azacyclopentane-2-one were fully optimized at the B3LYP/6-311＋＋G＊＊ level. The intermolecular hydrogen-bonding interactions were calculated using the B3LYP/6-311＋＋G＊＊, B3LYP/6-311＋＋G（2df, 2p）, MP2（full）/6-311＋＋G＊＊ and MP2（full）/6-311＋＋G（2df, 2p） methods, respectively. The results show that the steady-state permeation rate of ketoprofen through excised cavia skins enhances over 9 times in the solvent with 2% Azone as compared with the solvent without Azone. The stable O–H…O=C and N–H…O=C hydrogen-bonded complexes could exist between azacyclopentane and ketoprofen. The hydrogen-bonding interaction energy follows the order of（a） 〉（b） 〉（c） 〉（d） 〉（g）〉（e） 〉（h） 〉（f）. The formation of the complexes leads to the change of the conformation and molecular polarity of ketoprofen, and thus causes a better percutaneous permeation for the drug. The analyses of AIM（atom in molecule） and shift of electron density were used to further reveal the nature of the enhancing permeation activity of Azone for ketoprofen. The investigations of the temperature and solvent effects confirm that ketoprofen might enter into the skin by means of the Azone complex.

关 键 词：intermolecular hydrogen-bonding interaction AZONE ketoprofen transdermal delivery MP2 

分 类 号：O641.1[理学—物理化学]