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.
Hatanaka
T
T
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama, Japan. thino@ms.toyama-mpu.ac.jp
Kamon
T
T
Morigaki
S
S
Katayama
K
K
Koizumi
T
T
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics; D001693:Biological Transport, Active; D002021:Buffers; D002506:Cephalexin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D002511:Cephalosporins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D003348:Cortisone / Q000493:pharmacokinetics; D004058:Diffusion; D004234:Diuretics, Osmotic / Q000493:pharmacokinetics; D006863:Hydrogen-Ion Concentration; D008297:Male; D008353:Mannitol / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption / Q000502:physiology*; D012995:Solubility
D000893:Anti-Inflammatory Agents; D002021:Buffers; D002511:Cephalosporins; D004234:Diuretics, Osmotic; D008353:Mannitol; D002506:Cephalexin; D003348:Cortisone