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658c

Influence of Enhancer Characteristics and Drug Hydrophobicity

K. Yerramsetty, V. K. Rachakonda, S. V. Madihally, R. L. Robinson Jr., and K. a. M. Gasem. School of Chemical Engineering, Oklahoma State University, 423 Engineering North, Stillwater, OK 74078

Altering the characteristics of the skin by using chemicals called penetration enhancers is one of the promising ways to breach the skin's barrier to drugs. In this work, several potential enhancers, menthone, 1-dodecyl-2-pyrrolidinone, 2-methyl-3-oxazolidinone, 1-methyl-2-pyrrolidone, nonanol, decanol, oleic acid and lauric acid, containing different functional groups were tested for their enhancement effect on three different classes of drugs viz. strongly hydrophilic insulin (Log Kow=-1.76), weakly hydrophobic melatonin (Log Kow=1.20) and strongly hydrophobic lidocaine (Log Kow=2.49). Initially, the experimental procedure was validated using permeability measurements of melatonin in the presence of four known CPEs with porcine skin, Franz Cell, and HPLC and using a similar procedure the permeabilities of the remaining drugs in the presence of CPEs is measured.

Further, three different characteristics of each CPE are measured: (i) The concentration of the CPE at the site of action, (ii) the permeability of the CPE alone through the skin and (iii) the toxic effect of the CPE on (a) Human Foreskin Fibroblasts (HFFs) using MTT assay at concentrations of three different orders of magnitude, and on (b) porcine abdominal skin by histology using H/E staining at the end of a 48-hour exposure period.

Our results suggest that (a) for a molecule to be a CPE, it has to be sufficiently hydrophobic and contain at least one hydrogen donating or accepting functional group; and (b) hydrophilic drugs respond better to CPE treatment than hydrophobic drugs. Further, the toxicity studies reveal that even though the cellular level toxicity studies are less laborious, they cannot be relied upon as a final conclusive indicator of the CPE's toxicity when compared to the more laborious but more accurate histological analysis.