Other Routes of Protein and Peptide Delivery: Transdermal, Topical, Uterine, and Rectal - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 652

Bile Acids Bile acids are surface-active compounds that consist of a facially amphi-
philic steroid nucleus with a hydrophobic- side and a -hydrophilic side, which are
known to enhance impermeable drugs in the rectal routes. The enhancing mecha-
nisms of bile acids for rectal absorption seem to involve sequestration of Ca 2 , an
increase in solvent drag and water channel, dissociation of protein oligomers, and
solubilization of membrane lipids.
Enamine Derivatives Amino acid enamines (phenylalanine and phenylglycine) of
-diketones (ethylacetoacetate) are known to be novel absorption enhancers in the
rectal routes. The supporting effects of enamines on the rectal absorption of other
macromolecules such as lysozyme [180] , calcitonin, and heparin are also reported.
On the other hand, enamine derivatives are somewhat labile in aqueous solution. They
may have an absorption-enhancing effect with a very short duration, and may be more
useful in prodrug development and as absorption enhancers on insulin [181-184,200] .
Salicylate and its Derivatives Salicylate and salicylic acid enhance the rectal
absorption of various drugs including macromolecules [172,190-193] . Fluorescence
spectroscopy was used to demonstrate that the salicylate ion increases plasma mem-
brane permeability by effecting the plasma membrane proteins rather than directly
interacting with the membrane lipids. The action of salicylate ion on these vesicles
could possibly promote nonabsorbable drug absorption in vivo [201,202] . However,
we must pay particular attention to pharmacological activity of salicylate derivatives.
The enhancing mechanisms of sodium salicylate may relate to the membrane per-
turbation by interaction with membrane proteins, but not membrane lipids, and a
decrease in intracellular glutathione levels [177,185,193] .
Nonsteroidal Antiinflammatory Drugs NSAIDs such as indomethacin, phenylbuta-
zone, diclofenac sodium, and aspirin have been reported to act as absorption enhanc-
ers in the rectal route [188,189] . The enhancing effect of NSAIDs could be attributed
to a change in membrane permeability of poorly permeable drugs, owing to the accu-
mulation of the drugs in rectal mucosa [203] .
Caprate and Fatty Acids The enhancing mechanisms of Na-C10 are proposed due
to an increase in the intracellular calcium level, Ca 2 sequestration, increase in pore
size and solvent drag, and interaction with membrane proteins and lipids of these
enhancers. Na-C10 has been successfully included in commercially available sup-
positories [204-207] .
Mixed Micelles Mixed micelles are composed of lipids and bile acids or surfactants.
These micelles are known to enhance poorly absorbable drugs in the small intestine
as well as the large intestine. It is believed that the mixed micelles encapsulate mol-
ecules with a high degree of efficiency (90% encapsulation). These mixed micelles
are extremely small in size (1-10 nm) and are smaller than the pores of the mem-
branes in the GI tract. It is therefore believed that the extremely small size of mixed
micelles helps encapsulated molecules penetrate efficiently through the mucosal
membranes. The absorption of proteins and peptides is thought to be enhanced by
the diffusion of large molecules entrapped in the mixed micellar form through the