IN-VITRO EVALUATION OF AZONE ANALOGS AS DERMAL PENETRATION ENHANCERS - V - MISCELLANEOUS COMPOUNDS

Dermal penetration enhancers were evaluated (14) using diffusion cell techniques, hairless mouse skin and hydrocortisone as the model drug. The following were synthesized: 1-dodecanoylpiperidine (1), 1-dodecano ylpyrrolidine (2), 1-dodecanoyl-2-piperidinone (3), 1-dodecanoyl-2-pyr rolidinone (4), 2-decylcyclohexanone (5), 2-decylcyclopentanone (6), 4 -(dodecanoyl)-thiomorpholine (7), N,N-didodecylacetamide (8) and N-dod ecyltricyclo [3.3.1.1(3,7)]decane-1-carboxamide (11). N-Acetylcaprolac tam (9), 4-acetylmorpholine (10) and N-dodecylpyrrolidinone (13) were purchased. The syntheses of Azone, N-(1-oxododecyl)morpholine (12) and N-dodecyl-2-piperidinone (14) have been reported previously. Enhancer s were applied at 0.4 M in propylene glycol (PG) (or as a suspension) to mouse skin. Hydrocortisone (0.03 M in PG) was applied 1 h following enhancer treatment. Controls (no pretreatment) yielded 24 h diffusion cell receptor concentrations (Q(24)) of 9.93 +/- 3.15 mu M and model drug skin retention of 26.1 +/- 5.6 mu g g(-1). Compound 7 yielded a h igh Q(24) of 208.18 +/- 39.52 mu M. The highest skin retention was obs erved with 6 of 566.7 +/- 39.7 mu g g(-1). Azone gave values of 218.96 +/- 47.84 mu M for Q(24) and 294.9 +/- 66.7 mu g g(-1) for skin reten tion. Compounds 13 and 14 gave Q(24) values of 274.44 +/- 50.90 and 22 0.21 +/- 59.63 mu M and skin retention values of 226.5 +/- 51.8 and 25 9.0 +/- 62.2 mu g g(-1), respectively. (C) 1998 Elsevier Science B.V.