Other Routes of Protein and Peptide Delivery: Transdermal, Topical, Uterine, and Rectal - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 630

conditions used and was inversely proportional to the permeant octanol/pH 7.4 buffer
distribution coefficient. Iontophoretic transport of a tripeptide, thyrotropin-releasing
hormone (TRH), across excised dorsal nude mouse skin was directly proportional to
the applied current density [51] . Even uncharged TRH was transported, presumably
by the electroosmotic or convective flow that accompanies iontophoresis. However,
in the absence of current, the flux of TRH across skin was undetectable [52,53] .
Another study showed that penetration enhancers also enable transdermal delivery of
TRH at physiologically relevant concentrations [52] . Another tripeptide, threonine-
lysine-proline (Thr-Lys-Pro), was successfully delivered across nude rat skin by
iontophoresis under both in vitro and in vivo conditions. The delivery of Thr-Lys-Pro
was directly proportional to the applied current density over the range 0.18-0.36 mA/
cm 2 . Following 6 h of iontophoresis, 98.4% of the radioactivity showed intact peptide
in the donor, and 94.0% of the radioactivity penetrated showed parent Thr-Lys-Pro in
the receptor phase [53] . Therefore, it can be stated that metabolism in the skin is not
likely to be a significant problem for several peptides. Iontophoretic delivery of another
tripeptide, enalaprilat, has also been investigated across hairless guinea pig skin [54] .
For the tetrapeptide hisetal, iontophoresis increased its permeation rate across human
skin by a factor of 30 [55] . The iontophoretic treatment was much more effective than
the use of penetration enhancers. The transport through skin under iontophoresis was
shown to take place mainly through water-filled pores.
Oligopeptides LHRH, a decapeptide, and its analogues have been successfully
delivered by iontophoresis [56] . Meyer et al. delivered therapeutic doses of leupro-
lide, LHRH analogue in 13 normal men using a double-blind, randomized, cross-
over study conducted under an investigational new drug (IND) process granted by
the Food and Drug Administration (FDA). Data analysis by analysis of variance
(ANOVA) showed significant differences between the active and passive patches.
The magnitude of elevation of luteinizing hormone (LH) produced by the active
patches was in the therapeutic range and comparable to that achieved by subcutane-
ous administration. The only adverse effect reported was mild erythema at the site
of the active patch in 6 of the 13 subjects. The erythema resolved rapidly without
sequelae [57] . Vasopressin, a nonapeptide antidiuretic hormone; its analogues; and
arginine vasopressin have been investigated for transdermal iontophoretic delivery
across skin [58-61] . In contrast to insulin, the flux of vasopressin under iontopho-
resis was observed to be reversible. Due to its high isoelectric point (p I  10.9),
the vasopressin molecule will stay highly charged at the pH environment of the
skin. Permeation of buserelin through isolated human SC by iontophoresis has also
been reported [62] . In this study, it was found that passive permeation of buserelin
through human SC is not feasible.
Polypeptides Iontophoretic delivery of calcitonin, salmon calcitonin (sCT), and
human calcitonin has been investigated [63-65] . sCT, when applied to the abdominal
skin of rats, did not produce any hypocalcemic effect. Conversely, when delivered
under anode as a cation, the drug produced a small hypocalcemic effect. The hypo-
calcemic effect was enhanced when aprotinin or camostat mesilate was used as a
proteolytic enzyme inhibitor, but not when soybean trypsin inhibitor was used. That