Other Routes of Protein and Peptide Delivery: Transdermal, Topical, Uterine, and Rectal - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 636

used as a drug carrier, but the amount of coupling agent to be applied must be opti-
mized. Phonophoresis, a feasible technique for skin permeation enhancement, offers
a potential for delivery of peptides and polypeptides. Any possible effect of ultra-
sound on the stability of peptide drugs is still to be evaluated.
The efficiency of ultrasound-mediated drug delivery depends on several factors,
including ultrasound frequency, intensity, continuous versus pulsed exposure, duty
cycle, duration, coupling medium, and other considerations. The ultrasound beam is
made up of two components: the field closest to the transducer, and the field fur-
ther away (the final, diverging conical part). The relative size of these two zones,
and their separation, is a function of the ultrasound wavelength (i.e., frequency) and
the transducer radius. The mechanistic aspects of the effects of low-frequency ultra-
sound, cavitations, and thermal effects have been hypothesized, but it is not clear
how ultrasound interacts with the skin barrier to increase its permeability. Very few
publications have presented data to support that higher frequency (1 MHz) ultrasound
can be used to improve peptide delivery across the skin.
Collective application of ultrasound and iontophoresis also has practical implica-
tions. The combination of ultrasound and electric current offers a double enhance-
ment greater than that offered by each of them independently under the same
circumstances. Because ultrasonic pretreatment reduces skin resistivity, a lower volt-
age is required to deliver a given current during iontophoresis compared to that in
controls. This may result in lower power needs as well as possibly lessening skin
irritation [89] .
12.1.4.1.4 Electrical Methods in Conjunction with Other Techniques
The combinations of iontophoresis with electroporation [90] , enhancers [91] , and
poloxamer gels [92] were also found to enhance the penetration ability of insulin
through skin more than iontophoresis alone.
Iontophoresis in Conjunction with Microneedles A combination of microneedle
with iontophoresis technologies can be studied for delivery. This combination may
provide the possibility of macromolecule transdermal delivery with precise electronic
control. The Macroflux w array, 2 cm 2 , had a microprojection density of 240/cm 2 and
a needle length of 430 mm. The Macroflux w and iontophoresis combined system is
made by assembling the Macroflux w array, a drug reservoir, a membrane, a conductive
gel, and the iontophoretic electrode. Macroflux w and iontophoresis combined trans-
dermal delivery system for the delivery of an antisense oligonucleotide ISIS 2302 is
already designed [93] . The system may be capable of delivering therapeutically signif-
icant amounts of drug through the SC. The rate of delivery is controlled by duration of
the patch application, donor drug concentration, current density, and active patch area.
Iontophoresis in Conjunction with Ion-Exchange Materials The ion-exchange
process is a stoichiometric and reversible process wherein an ion from the solution is
replaced with a similarly charged ion attached to an immobile solid phase (e.g., ion-
exchange device) in order to fulfill the electroneutrality requirement. Ion-exchange
devices will exhibit greater preference for a particular ion. The higher the preference
an ion exchanger exhibits for a particular ion, the greater the exchange efficiency in