Other Routes of Protein and Peptide Delivery: Transdermal, Topical, Uterine, and Rectal - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 629

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(12.5)

AgCl e → + ( Ag Cl at cathode )

Therefore, the use of silver wire as an anode and silver-silver chloride wire as a
cathode is not accompanied by pH drifts. However, the system must provide some
chloride ions to drive the electrochemistry, as is evident from the above equations.
There could be situations when silver-silver chloride electrodes may be unsuitable as
they may react with some protein drugs or with hydrogel. In these conditions, the use
of platinum electrodes may be suggested, although other methods that control pH can
be chosen. Using mannitol as an appropriate marker molecule, electroosmotic flow
during reverse iontophoresis has been examined as a function of the pH and ionic
strength of the electrolyte solutions located on the skin surface, which were contained
within the electrode compartments [45] .

Formulation The basic principles that apply to iontophoresis are relevant to peptides
and proteins due to the charge. If the drug carries a measurable fraction of the charge
being passed, then it is important to minimize the presence of competing ions in the
formulation. Generally, lower electrolyte levels also mean that EO is slightly higher
[45-47] . Furthermore, due to stability, it may demand at least some level of back-
ground electrolyte and/or buffer; thus, polymeric buffers, for example, which are not
necessarily competitive for charge carrying, have been used to improve drug delivery
[46,48] . Because iontophoretic formulations employ aqueous-based gels, there are,
in particular, potential problems of hydrolysis that are tackled by making a dry res-
ervoir disk for iontophoresis (via compression of a mixture of freeze-dried peptide
and gelatin), which is hydrated during use [49] . Proof of concept of the idea has been
achieved via the observation of a hypocalcemic response in animal [49] . The formu-
lation ingredients in the drug and counter reservoirs typically consist of a solvent, a
drug salt or a biocompatible salt, and a matrix-forming material. A formulation may
also include additives such as buffers, antimicrobial agents, antioxidants, and addi-
tional electrolyte salts or permeation enhancers. All of these interact in a complex
fashion to affect rate of delivery, biocompatibility, and product shelf life.
Examples of Iontophoretic Delivery
Amino Acids and Small Peptides Peptide delivery seems to be one of the most
promising applications of iontophoretic transdermal delivery. Iontophoresis of amino
acids, which are building blocks of peptides, may give some information useful for
predicting the delivery of small peptides. Amino acids may also have a direct benefit
of moisturizing the skin [49,50] . It has been showed that the binding of a series of
amino acids in the excised abdominal skin of hairless rat decreased with an increase in
the alkyl side chain [50] . This suggests that binding is likely to be polar or electrostatic
in nature. A series of amino acids across excised hairless mouse skin was delivered
to investigate the effects of permeant charge (neutral, 1, or -1), lipophilicity, and
vehicle pH [50] . As usual, the positively charged amino acids (i.e., positively charged
at the vehicle pH used) had maximum flux under the anode, and the negatively charged
amino acids had maximum flux under the cathode. For zwitterions (i.e., essentially
neutral), the iontophoretic flux did not reach steady state under the experimental