Influences of alkyl group chain length and polar head group on chemical skin permeation enhancement

• Published in: Journal of pharmaceutical sciences Vol. 90; no. 8; pp. 1143 - 1153
• Main Authors: Warner, Kevin S., Li, S.Kevin, Higuchi, William I.
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.08.2001; John Wiley & Sons, Inc; Wiley; American Pharmaceutical Association
• Subjects: Alkanes - chemistry; Alkanes - pharmacology; Animals; Biological and medical sciences; enhancer mechanism; General pharmacology; Medical sciences; Mice; Mice, Hairless; Permeability; permeation enhancers; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Skin Absorption - drug effects; stratum corneum; Structure-Activity Relationship; transdermal; stratum corneum; transdermal; permeation enhancers; enhancer mechanism; Steroid; Stratum corneum; Transdermal system; Pharmaceutical technology; Corticosterone; Chain length; Rodentia; Permeation; Permeability; In vitro; Vertebrata; Mammalia; Structure activity relation; Mouse; Alkyl; Animal; Skin; Absorption enhancer; Mechanism of action
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.1068

Previous investigations in our laboratory on the influence of the n‐alkanols and the 1‐alkyl‐2‐pyrrolidones as skin permeation enhancers for steroid molecules as permeants demonstrated that the enhancer potencies (based on aqueous concentration values) of these two homologous series were the same when compared at the same alkyl chain length; that is, the contribution of the hydroxyl group and that of the pyrrolidone group to enhancer potency were the same. The purpose of the present study was to further investigate what was believed to be a somewhat surprising finding, and two additional homologous series, the 1,2‐alkanediols and N,N‐dimethylalkanamides, were selected for study as enhancers. Corticosterone (CS) flux enhancement along the lipoidal pathway of hairless mouse skin stratum corneum was determined with 1,2‐hexane‐, 1,2‐octane‐, and 1,2‐decanediol and with N,N‐dimethylhexanamide, N,N‐ dimethylheptanamide, N,N‐dimethyloctanamide, and N,N‐dimethylnonanamide as enhancers. The enhancement factor (E) for the lipoidal pathway was calculated from the CS permeability coefficient and the CS solubility data over a 4 to 100 range of E values. Comparisons of the enhancer potencies of all four homologous series revealed that the enhancer potencies of all were very nearly the same when compared at equal alkyl group chain length. Moreover, the contribution of each of the polar head groups toward the enhancer potency was essentially constant, independent of the alkyl group chain length. It was reasoned that this outcome was either the result of the random selection of four polar head groups making the same contribution to enhancer potency or the result of these particular polar head groups not contributing to enhancer potency. To test the hypothesis that the former was more likely than the latter and that a suitable semipolar organic phase may mimic the microenvironment of the polar head group at the site of enhancer action, n‐octanol–phosphate buffered saline (PBS) and n‐hexane–PBS partition coefficients were determined for all the enhancers. The n‐octanol–PBS partition coefficients for the enhancers, but not the n‐hexane–PBS partition coefficients, were very nearly the same when compared at equal alkyl group chain lengths; this result supports the hypothesis that each of the four polar head groups likely contributes the same toward the enhancer potency and locates in the semipolar region of the hairless mouse skin stratum corneum lipid bilayers, which is well‐approximated by water‐saturated n‐octanol. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1143–1153, 2001