Other Routes of Protein and Peptide Delivery: Transdermal, Topical, Uterine, and Rectal - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 624

with high permeability due to the breakdown of the multilamellar system of the SC
lipids and the formation of LTRs [27,28] . The area involved in drug transport during
electroporation is subdivided into two distinct domains: a number of LTRs with radii
ranging from 10 to 100 m depending on pulse voltage, and surrounding local dis-
sipation regions (LDRs), larger than LTRs with their size depending on the length of
the applied pulse [28] . Experimental and theoretical investigations of localized heat-
ing by skin electroporation predict that LTRs formation can be partly explained by
Joule heating during pulsing and that temperature rise is relatively small in the LDRs
that surround the LTRs. This is further supported by field-driven transport, recov-
ery of the skin barrier function, and the creation of aqueous pores [23,28,29] . The
mechanisms of molecular transport during electroporation likely involve passive dif-
fusion and electrically driven transport during the brief pulsing time, but unlike ion-
tophoresis, electroosmosis (EO) is thought to be unimportant and safe. The safety
of applying high voltage was assessed in vivo [21,22,30] . The augmentation in the
horny layer water content, and consequent disorganization of the SC, is also believed
to occur but seemed to be less important than during iontophoresis [24] . The bar-
rier effects of the horny layer are also reduced for an additional period after pulsing,
which further enhances molecular penetration.
A major safety concern is associated with the use of electrical methods like elec-
troporation, even though several reports indicated the injury to the skin to be gen-
tle, reversible, and safe [22,24,30] . Electrochemotherapy has been used effectively
in preclinical and clinical studies. The only skin alteration seen with electropora-
tion was slight erythema that diminishes within a few hours. [31] . Patients subjected
to electrochemotherapy seemed to tolerate well the application of 10,000V/cm for
100 ms 2 /wave pulses. It is also observed that 10 pulses of 400V-10 ms were more
efficient than 10 low voltage, long duration pulses [31,32] . However during electro-
poration, milder conditions achieved by shortening the pulses, lowering voltage, or
improving the electrode design could be used [32] that may give less pain.
Iontophoresis Iontophoretic delivery is a system that has been successfully engaged
to introduce proteins and peptide drugs into the systemic circulation [33-37] .
Iontophoresis uses a mild electric current that facilitates the transdermal delivery
of a variety of agents. The current progress in technological advancement is due to
huge patient acceptance, and the commercial success of passive transdermal patches
such as fentanyl, nicotine, estradiol, and nitroglycerin has piqued curiosity within the
industry for additional transdermal agents. Technological breakthroughs in the micro-
electronics industry have enabled minimization of the size of electronic components
that can be programmed at lower cost. Finally, rational drug design and advancement
in recombinant DNA technology yields a growing number of therapeutically impor-
tant peptides and proteins. Peptides typically contain acidic and basic functional
groups and are usually charged at physiological conditions. Consequently, passive
transdermal diffusion of these ionic large-molecular-weight agents across the hydro-
phobic outermost layers of the skin is difficult. In recent years, a large number of
published articles, issued patents, and patent applications demonstrate the potential of
this technology for peptide and protein delivery.