Prefilled Syringes or Peptide Pills? - Pharmaceutical Technology

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PharmTech Europe

Prefilled Syringes or Peptide Pills?
The impact of new delivery technologies in designing peptide therapies.


Pharmaceutical Technology
Volume 37, Issue 5, pp. 46-49

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.


Table I: Oral peptide nanomedicines in clinical development.
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).


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