Overcoming the skin barrier properties efficiently, temporarily, and safely for successful transdermal drug delivery remains a challenge. We synthesized three series of potential skin permeation enhancers derived from natural amino acid derivatives proline, 4-hydroxyproline, and pyrrolidone carboxylic acid, which is a component of natural moisturizing factor. Permeation studies using in vitro human skin identified dodecyl prolinates with N-acetyl, propionyl, and butyryl chains (Pro2, Pro3, and Pro4, respectively) as potent enhancers for model drugs theophylline and diclofenac. The proline derivatives were generally more active than 4-hydroxyprolines and pyrrolidone carboxylic acid derivatives. Pro2-4 had acceptable in vitro toxicities on 3T3 fibroblast and HaCaT cell lines with IC50 values in tens of µM. Infrared spectroscopy using the human stratum corneum revealed that these enhancers preferentially interacted with the skin barrier lipids and decreased the overall chain order without causing lipid extraction, while their effects on the stratum corneum protein structures were negligible. The impacts of Pro3 and Pro4 on an in vitro transepidermal water loss and skin electrical impedance were fully reversible. Thus, proline derivatives Pro3 and Pro4 have an advantageous combination of high enhancing potency, low cellular toxicity, and reversible action, which is important for their potential in vivo use as the skin barrier would quickly recover after the drug/enhancer administration is terminated.
Limanov V, Svitova I, Kruchenok T, Tsvirova I, Yaroslavskaya L. Synthesis and bactericidal activity of amino acid higher ester hydrochlorides. Pharm. Chem. J. 1984;18:708–711.
Michniak B, Player M, Godwin D, Lockhart C, Sowell J. In vitro evaluation of azone analogs as dermal penetration enhancers: V. Miscellaneous compounds. Int. J. Pharm. 1998;161:169–178.
Snyder R, Strauss H, Elliger C. Carbon-hydrogen stretching modes and the structure of n-alkyl chains. 1. Long, disordered chains. J. Phys. Chem. 1982;86:5145–5150.
MacPhail R, Strauss H, Snyder R, Elliger C. Carbon-hydrogen stretching modes and the structure of n-alkyl chains. 2. Long, all-trans chains. J. Phys. Chem. 1984;88:334–341.
Knutson K, Krill S, Lambert W, Higuchi W. Physicochemical aspects of transdermal permeation. J. Control Release. 1987;6:59–74.
Lin S-Y, Duan K-J, Lin T-C. Simultaneous determination of the protein conversion process in porcine stratum corneum after pretreatment with skin enhancers by a combined microscopic FT-IR/DSC system. Spectrochim. Acta A Mol. Biomol. Spectrosc. 1996;52:1671–1678.
