Enhancement of the intestinal absorption of peptides and nonpeptides

Abstract

It is not uncommon for peptides and structurally-similar non-peptides to have poor intestinal permeability and low oral bioavailability. One possible way to solve a permeability problem is to formulate the compound with membrane permeation-enhancing excipients. Important criteria for success of this approach are: (1) achieving reproducible intestinal permeation, (2) doing so without causing toxicity, and (3) understanding the mechanisms of permeation enhancement. Some effective and potentially safe permeation enhancers are fatty acids, glycerides, surfactants, acyl carnitines, and bile salts. The literature on permeation enhancement with these agents is briefly reviewed. We evaluated permeation enhancement approaches to increase the oral bioavailability of a non-metabolized, cyclic peptide fibrinogen antagonist, DMP 728. Sodium caprate (15 mM) increased the in vitro intestinal permeation rate 3-fold. Oral absorption in dogs was also increased approximately 3-fold using a formulation containing 150 mg sodium caprate. Inter-animal variability in absorption was considerable, though. A diacidic, non-peptide angiotensin II antagonist, DuP 532, presented another case of a poorly membrane permeable lead compound. Sodium caprate did not affect DuP 532 oral bioavailability in rats. However, oral bioavailability of DuP 532 in rats and dogs was increased approximately 3-fold using glyceride vehicles. These excipients have the advantage of already being used in marketed products. As with DMP 728, there was substantial inter-animal variability of DuP 532 oral bioavailability, and optimization of the formulation would be required to improve reproducibility. These examples demonstrate the possibilities of significantly improving oral bioavailability of poorly permeable drugs using seemingly acceptable excipients.