Lipidic prodrug approach for improved oral drug delivery and therapy

Abstract In the past, a prodrug design was used as a last option to improve bioavailability through controlling transport, distribution, metabolism, or other mechanisms. Prodrugs are currently used even in early stages of drug development, and a significant percentage of all drugs in the market are prodrugs. The focus of this article is lipidic prodrugs, a strategy whereby a lipid carrier is covalently bound to the drug moiety. The increased lipophilicity of the lipid‐drug conjugate can improve the pharmacokinetic profile and provide meaningful advantages: increased absorption across biological barriers, prolonged circulation half‐life, selective distribution profile (eg brain penetration), reduced hepatic first‐pass metabolism, and overall enhanced bioavailability of the parent drug. Moreover, lipidic prodrugs may join the endogenous lipid trafficking pathways, thereby facilitate drug targeting, either by selective absorption pathway (eg lymphatic transport) or drug release at specific target site(s). The different lipid‐drug conjugates (triglyceride‐, fatty acids, phospholipid‐, and steroid‐based prodrugs), the physiological barriers that challenge the absorption of these conjugates, followed by their current utilization and potential clinical benefits are described and analyzed, and future opportunities this approach could provide are discussed. Altogether, lipidic prodrugs represent an exciting approach for improving different aspects of oral drug delivery/therapy and may provide solutions for various unmet needs; the use of this strategy is expected to grow.