Oral peptide delivery
There are currently only two oral peptide formulations available on the market—desmopressin acetate (DDAVP, Sanofi-Aventis)
approved for the treatment of diabetes insipidus, and cyclosporine (Neoral, Novartis) as an immunosuppressant (15). Both are
cyclic peptides whose structural features protect them from intestinal proteolytic degradation. In the case of desmopressin,
substitution of the last L-arginine by a D-arginine, and deamination of the first amino acid results in an oral bioavailability
enhancement of 0.08–0.16% for DDAVP (16). A self-emulsifying delivery system, which forms a cyclosporine microemulsion in
the aqueous environment of the GIT results in a bioavailability of 40% for Neoral (17).
The major challenge is enhancing the oral bioavailability of peptides from less than 1% (which is common for peptides) to
at least 10–20%, and if possible, to 30–50% (18). The enhanced potency of peptides necessitates only minute amounts to bind
to receptors. Whereas for efficacy, the low oral bioavailability requires larger doses to be administered, thereby, increasing
develop-ment costs and the costs of therapies, especially if the peptide is larger than 50 amino acids and cannot be easily
synthesized using solid-phase peptide synthesis. In such cases, cost constraints on healthcare providers limit their development
for life-threatening and unmet diseases (19).
Chemical modification and formulation strategies
Strategies to enhance peptide oral bioavailability can be divided in chemical modification or formulation strategies. Chemical
modification can involve substitution of natural amino acids with D-amino acids (20), cyclization (21), engineering peptidomimetics
by replacing labile bonds with stable constructs (22), introduction of steric bulk (N-alkylation), or formation of a prodrug
(13) to increase lipophilicity or decrease hydrogen bonding to enhance permeability across epithelial cells.
Formulation strategies for enhancing absorption across the GIT or improving peptide stability include co-administration of
enzyme inhibitors (23, 24) or absorption enhancers (e.g., low molecular weight surfactants, bile salts, and cyclodextrins),
altering the gastrointestinal retention time using mucoadhesive polymers such as chitosans (12, 25), and encapsulating or
conjugating the peptide to a suitable lipidic carrier (26) or micro/nanoparticle systems (12, 13). Despite the numerous oral
peptide delivery technologies, few have progressed beyond proof of concept to human clinical trials, with most of them designed
to enable oral delivery of insulin fuelled by the broad existing market (see Table I). Although the hurdle to commercial development was predicted to be safety, it appears to be study design and ensuring efficacy
in humans (11).
Table I: Oral peptide nanomedicines in clinical development.