Ion pair skin transport of a zwitterionic drug, cephalexin.

The ion pair skin transport of cephalexin was investigated using various counter ions and solvents. The permeability of cephalexin was enhanced by 1-alkylsulfonates (ASs) at pH 3.0 and by tetraalkylammoniums (AAs) at pH 7.0; the enhancing ratio increased with the number of carbon atoms in their alkyl chains. The corresponding effects of these additives were observed on the partitioning of cephalexin. Most of the additives did not affect the skin transport of D-mannitol and cortisone. These results suggest that the enhanced transport of cephalexin results from the ion pair formation with additives. Although ASs increased the partitioning of cephalexin above that of AAs, the transport enhancement effect of ASs was lower than AAs having the same number of carbon atoms in their alkyl chains, indicating higher diffusivity of the ion pairs with AAs in skin. Moreover, the transport enhancement by AAs increased even more when ethanol-buffer solutions were used as solvents. The conductivity measurement of dissolving solutes in donor solvents showed that the further enhancement might be caused by the increasing ion pair formation in solvents with low dielectric constants. To obtain the maximum enhancement of skin transport of zwitterionic drugs via ion pair concept, one should select a counter ion having high lipophilicity and small volume, and a solvent with suitable pH and low dielectric constant.

Influence of pH on skin permeation of amino acids.

Skin permeation of amino acids through excised rat skin was measured at various pH values. The permeabilities varied with the donor pH and amino acid, indicating that each ionic species of amino acid may have a different permeability. The permeability coefficient of each ion was estimated from the permeability-pH profiles using the dissociation constants. The estimated values for mono-cation and uncharged zwitterion were not dependent on the lipophilicity but on the size of the amino acid, suggesting a porous mechanism of transport. The permeability coefficient was highest for di-cation, followed by mono-cation, positively charged, uncharged and negatively charged zwitterions. The electrical potential difference across the skin was too small to affect the permeation of ions. The permselective property of skin thus seems to be determined by the difference of diffusivity in aqueous pores of skin due to the hydration of ions and other factors.

Effect of l-menthol on the permeation of indomethacin, mannitol and cortisone through excised hairless mouse skin.

The effect of l-menthol on the skin permeability of mannitol, cortisone or indomethacin was examined by an in vitro penetration technique with hairless mouse skin. The donor solution was prepared with phosphate buffered saline, ethanol:buffered saline (20:80, v/v) or ethanol:buffered saline (20:80, v/v) containing 1% (w/v) l-menthol. Although ethanol showed little enhancing effect, l-menthol in an aqueous ethanol vehicle at pH 7.4 increased the permeability coefficients of mannitol and indomethacin by about 100 times that of the control (an aqueous vehicle) and increased that of cortisone by about 10 times. l-Menthol, however, scarcely enhanced the penetration of indomethacin at pH 3.0, the majority of the species being in unionized form. These results suggested that the menthol-ethanol-aqueous system enhanced skin permeability through a direct effect on the polar and/or lipid pathways, while the thermodynamic activity of the penetrant molecule in the delivery vehicle might also influence the effectiveness of the penetration enhancer.