Formulating the Un-drawable: Pharmaceutical Strategies for the Oral Delivery of Biologics (Peptides, Proteins, and Antibodies) and Their Pharmacological Challenges

Abstract

The use of biologic therapeutics such as peptides, proteins, and monoclonal antibodies is a paradigm shift in the context of modern medicine, and is almost limited to the parenteral route of administration. The gastrointestinal (GI) tract is a potent array of successive biochemical, physical, and cellular obstacles, which implies that less than 1% of the oral bioavailability is attained. This review analytically breaks down these barriers and gives a detailed account of the pharmaceutical strategies, i.e. chemical, nanocarrier, and mechanical that have been engineered to surmount these barriers. We compare the divergent action of clinically approved permeation enhancers (PEs) where gastric absorption, SNAC (salcaprozate sodium) and intestinal, paracellular absorption, MCFAs are contrasted. We examine these highly sophisticated nanocarrier vehicles, describing some of their designs as, for example, the use of a 'Zwitterionic' particle, which solves the 'stick versus slip' paradox with successive penetration into the mucus and interaction with epithelial transporters. We also look at the new technology of ingestible mechanical nanoparticle delivery systems, and microneedle capsules (LUMI) and self-orienting auto-injectors (L-SOMA) that can realize got of injection-like bioavailability (up to 80%) by circumventing the GI barriers physically. Last but not least, the key pharmacological issues that are critically assessed in this review are bioavailability, variability, immunogenicity, and long-term toxicology safety of deliberately and temporarily interfering with the intestinal barrier. The latest clinical advances have shown that oral biologic delivery is now no longer a theoretical possibility, but a clinical fact that places the field at a decisive turning point in terms of therapeutic innovation.