Other Routes of Protein and Peptide Delivery: Transdermal, Topical, Uterine, and Rectal - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 627

hand, as molecular size increases, it is clear that, at the transition, the electrorepulsive
contribution will be cancelled by electroosmotic convective flow going in the opposite
direction. The movement of an ion across skin under the influence of an electric field
increases as molecular size decreases (in normal conditions it is inversely proportional
to size/molecular weight). This has been confirmed for a sequence of amino acids,
acetyl amino acids, and tripeptides [36] , and for alkanoic acids for a homologous
series of oligonucleotides [37] . Because the mobility of ions is related to the molecu-
lar weight, or probably more importantly molecular volume and shape, it is likely that
secondary, tertiary, and quaternary structures of the peptide are important in deter-
mining the degree of iontophoretic delivery. Because a pore pathway is most likely
involved, the flux is size reliant with a cut-off at some stage. Although an upper size
limit is not known, the largest polypeptide with respect to molecular weight investi-
gated extensively is insulin, although delivery is expected for a molecular weight of
up to about 10 KDa, provided the polypeptide has other desirable attributes such as a
high isoelectric point (p I ) value.
Drug Charge and pH The pH of the buffer used, which is related to the isoelectric
point of the peptide, controls the charge on the peptide. The peptide will be posi-
tively charged at a pH below its isoelectric point and should be delivered under anode,
whereas the peptide will have a negative charge if the pH is above the isoelectric point,
in which case it should be delivered under cathode. The techniques of isoelectric
focusing and capillary zone electrophoresis have also been used as tools to predict the
ability of a peptide to be iontophoresed. Based on such studies, native luteinizing hor-
mone-releasing hormone (LHRH) was predicted to be better suited for iontophoretic
delivery than its free-acid analogue [38] . To stay charged in the skin environment, the
isoelectric point of the protein should be away from the isoelectric point of the skin,
that is, 3-4. Typically, polypeptides with high isoelectric point values, such as vaso-
pressin or calcitonin, are good candidates for transdermal iontophoretic delivery from
a delivery efficiency point of view. Another phenomenon that needs to be considered
is electroosmotic flow.
It is suggested that the skin is a permselective membrane and exists with an “appar-
ent” net negative charge at the free solution pH of 7.4 due to its isoelectric point. This
makes the skin selectively permeable to cations (positively charged ions) and selec-
tively restricts the entry of anions (negatively charged ions) [34] . As cations move into
the skin, a solvent molecules move along with it, resulting in a mass flow of water or
other solvent. This phenomenon, called EO, enhances the transport of neutral species
across the skin. Also, the anodal (anode-to-cathode direction) flux is typically higher
because it is aided by EO. At extremely low pH, the skin will be below its isoelectric
point and will attain a positive charge, causing a change in the direction of electroos-
motic flow to support cathodic flux. Also, adsorption of a positively charged drug on
the negatively charged skin may lead to a change in the net charge of the skin, which
may affect electroosmotic flow observed for polypeptide [39] , leuprolide [40] , and
nafarelin [41] . At the pH used, these cationic peptides strongly associate with the skin
and neutralize its charge, which in turn leads to a gradual reduction and eventually a
reversal of the convective (electroosmotic) flow [42,43] .