Medicinal formulations have evolved from the use of small molecules that act by blocking various receptors. On the contrary, therapeutic proteins are a class of medicines that have gained increased popularity owing to its low toxicity, high stability and exquisite specificity. Oral delivery of protein drugs is a very interesting but a highly challenging area of medicine that requires advancements in terms of bioavailability of oral drugs. The main objective of the present review is to provide a systematic overview of the various physiological barriers of delivery of therapeutic proteins and novel approaches available in this field in order to counter these physiological barriers. Advances in terms of inhibitors of proteases, permeation enhancers, mucoadhesives, short peptide conjugates, particulate delivery system including nanoparticles. Oral therapeutic proteins face challenges with regard to oral bioavailability, stability of the protein and reproducibility. Among the various strategies, a co-administration of permeation enhancers with protease inhibitors have proven most effective, while particulate delivery system is still under clinical studies in order to be establishes as a method. Overall, a thorough and focused research with sufficient knowledge on the structure-function relationship, substrate specificity and physiological parameters can deliver a potent therapeutic protein with high efficiency.
