Lipophilic peptide character - What oral barriers fear the most

Peptide therapeutics is currently one of the fastest growing markets worldwide and consequently convenient ways of administration for these drugs are highly on demand. In particular, oral dosage forms would be preferred. A relative large molecular weight and high hydrophilicity, however, result in comparatively very low oral bioavailability being in most cases below 1%. Lipid based formulations (LBF), in particular self-emulsifying drug delivery systems (SEDDS) and solid lipid nanoparticles (SLN) as well as liposomes are among the most promising tools for oral peptide delivery. Key to success in orally delivering peptides via LBF seems to be a sufficiently high lipophilic character of those therapeutic agents. Hence, different non-covalent and covalent peptide lipidization methods from drug delivery point of view are presented. On the one hand, among non-covalent lipidization methods hydrophobic ion pairing seems to be a promising way to sufficiently increase peptide lipophilicity providing high drug payloads in the lipid phase, a protective effect against presystemic metabolism via thiol-disulphide exchange reactions and proteolysis as well as an improved intestinal membrane permeability. On the other hand, covalent methods like conjugating fatty acids via amidation, esterification, reversible aqueous lipidization (REAL) and cyclization also show potential. The present review therefore describes those lipidization methods in detail and critically evaluates their contribution in successfully overcoming the oral barriers.