Esters of 6-aminohexanoic acid as skin permeation enhancers: The effect of branching in the alkanol moiety.
In order to investigate the effect of branching and cyclization in the hydrophobic part of skin permeation enhancers, 17 novel branched-chain and cyclic 6-aminohexanoic acid esters were prepared. Their permeation enhancing activity was evaluated in vitro using human skin and theophylline as a model drug, and compared to that of the corresponding linear-chain analogues. The results showed that chain branching and cyclization has a negative influence on the enhancing activity of 6-aminohexanoates. For example, the enhancement ratios (ERs) of dodecan-1-yl, dodecan-2-yl, dodecan-4-yl, and cyclododecyl ester were 39.7, 29.3, 3.1, and 2.2, respectively. No significant change in the optimum length of the chain was observed. Dodecan-2-yl 6-aminohexanoate, the most active branched derivative, still maintains a remarkable enhancing activity (ER 29.3). Presumably, the relatively small degree of branching of these molecules does not prevent them from interacting with the lipid components of the stratum corneum. However, a higher degree of branching, cyclization of the chain, and presence of an aromatic ring resulted in a loss of activity.
Hrabálek
Alexandr
A
Department of Inorganic and Organic Chemistry, Charles University in Prague, Faculty of Pharmacy, Heyrovského 1203, 50005 Hradec Králové, Czech Republic. hrabalek@faf.cuni.cz
Vávrová
Katerina
K
Dolezal
Pavel
P
Machácek
Milos
M
D000438:Alcohols / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D000614:Aminocaproates; D015119:Aminocaproic Acid / Q000737:chemistry / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D003500:Cyclization; D004952:Esters / Q000737:chemistry* / Q000494:pharmacology*; D005079:Excipients; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D012869:Skin Absorption / Q000187:drug effects*; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D000438:Alcohols; D000596:Amino Acids; D000614:Aminocaproates; D004952:Esters; D005079:Excipients; D007202:Indicators and Reagents; D015119:Aminocaproic Acid