Other Routes of Protein and Peptide Delivery: Transdermal, Topical, Uterine, and Rectal - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 622

subcutaneous injections. The requirement for higher frequency of administration due
to short plasma half-life and poor patient compliance stress the need for an alter-
native drug-delivery mode. Transdermal protein and peptide delivery is a unique
technique because of its ease of administration, noninvasiveness, better patient com-
pliance, and avoidance of GI degradation and the first-pass effect of active molecules
in the liver. But the highly lipophilic nature of the SC impedes the passive trans-
port of charged macromolecules across the skin into systemic circulation [6] . Several
investigations explored this aspect, studying different methods, including chemical
and physical methods, to overcome this most important barrier in transdermal protein
and peptide delivery [7] . Electrical methods like iontophoresis and electroporation
have been studied extensively to enhance the transport of macromolecules across the
skin by overcoming the barrier of the SC.
Electroporation As the human skin is the largest single organ of the body, it may
at first sight be attractive to formulators as an accessible means of drug input.
Electroporation holds many advantages that include avoidance of GI and liver first-pass
effects, controlled and continuous drug delivery, easy removal of the dosage form in
case of an accidental release, and good patient compliance. However, the skin's func-
tion as a barrier to macromolecules ensures a difficult passage for most drugs both into
and through the skin. The main reasons for the good barrier properties of the organ skin
lie within the highly organized lipid matrix within the SC, the outermost layer of the
epidermis. It is therefore desirable to devise strategies both to enhance the penetration
of molecules, which can break the skin barricade passively and reversibly, and also to
widen the spectrum of drug molecules that can penetrate the skin at therapeutically ben-
eficial doses. Many strategies have been utilized to help conquer this barrier function.
Electroporation of the cell membrane has been studied extensively and used since
the 1970s for deoxyribonucleic acid transfection of the cells by reversibly permeabi-
lizing the cell membranes with the application of brief electric pulses. Electroporation
is an electrical technique that involves the application of high-voltage electric pulses
for very short duration (microsecond or millisecond) to enhance the skin permeability
reversibly, for macromolecules. Unlike iontophoresis, which employs small currents
(0.5 mA/cm 2 ) for relatively long periods of time (many minutes to hours), electro-
poration involves exposure of the skin to relatively high voltages (on the order of
30-100V imposed across the skin) for rather short times, typically one to several hun-
dred milliseconds. The voltage-induced permeability change is consistent with the
formation of pores in the membrane. Electroporation involves the creation of new, low-
resistance pathways through the SC. Depending on the applied electrical field, the
electrical force produces partial rupture of cell membrane [8,9] . Several publications
of the application of electroporation to increase transdermal delivery have been pub-
lished within the last few years [10-14] . The use of electroporation has been shown
recently to reversibly permeabilize skin for enhancing the transdermal delivery of
several molecules such as calcein [10] , oligonucleotides [11] , and calcium-regulating
hormones [12] . Skin electroporation is believed to produce new transport pathways, in
addition to expanding existing pathways, although these new pathways shows clearly
persistent structural changes [13] .