Effect of penetration enhancers on the permeation of the thyrotropin releasing hormone analogue pGlu-3-methyl-His-Pro amide through human epidermis.

The effect of the enhancers, cineole and ethanol, on the transdermal penetration of the tripeptide, pGlu-3-methyl-His2-Pro amide (M-TRH), across human epidermal membrane was studied by flow-through diffusion chambers. The aim of the study was to assess whether the biologically active analogue M-TRH displays similar transdermal penetration properties as those demonstrated earlier for the parental peptide, thyrotropin-releasing hormone (TRH) (Magnusson et al., 1997a Int. J. Pharm. 157, 113-121). Steady-state fluxes with a donor solution of phosphate-buffered saline (PBS) were 0.34 +/- 0.01 microgram/cm2h for M-TRH and 0.27 +/- 0.01 microgram/cm2h for TRH. Measured over 30 h the total amount penetrated was 8.6 +/- 1.0 and 7.8 +/- 1.7 micrograms/cm2, respectively. In the presence of 50% ethanol, the flux of the peptides increased approximately 3-fold. A donor solution of 3% cineole, in combination with 47% ethanol, increased the penetration of M-TRH to 1.60 +/- 0.02 micrograms/cm2h, compared to 0.92 +/- 0.03 microgram/cm2h for TRH, as reported previously. The corresponding total amount penetrated over 30 h was 41.5 +/- 4.9 and 24.9 +/- 1.7 micrograms/cm2, respectively. Our data suggests that enhancers added together with the penetrant can theoretically induce changes in the permeability of the stratum corneum sufficient to promote the transdermal absorption of therapeutically relevant amounts of these peptides. This demonstrates the possibility to deliver classes of compounds that have been viewed as not suitable for transdermal administration.