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In regards to patient compliance for drug delivery, oral drug delivery is generally the preferred route of administration. However, parental injection of peptide drugs has always been the primary method of peptide drug administration. This is a result of the poor oral bioavailability of peptide drugs, which are typically under 1%. The degradation of peptides in the gastrointestinal (GI) tract by peptidase enzymes and harsh pH, combined with the poor intestinal mucosal penetration properties of the non-drug-like peptide drugs have been identified as the major barriers towards improving the oral bioavailability. Nevertheless, oral delivery of peptide drug presents a significant challenge due to the enzymatic degradation by enzymes in the GI tract and the poor penetration of the peptides across gastro-intestinal epithelium membranes, particularly for adults. Therefore, a novel peptide drug analogue or pro-drug that both protect peptide drugs from degradation by the enzymes in the GI tract that also improves its penetration across the intestinal epithelium membrane would greatly advance the development of peptide drugs as effective candidates for the treatment of various diseases. So far several approaches are being investigated to improve the oral bioavailability of peptide drugs by different researchers. Indications suggest that chemical modification such as incorporation of unnatural amino acids, unnatural peptide bonds, cyclisation and pro-drug approaches as well as nanoparticulates systems such as nanoparticles and microemulsions offer great potential for improvement and likelihood of enabling peptide drug to be administered orally. This review will focus on the chemical modification methods and other approaches (such as using variable nanoparticular delivery systems), that could be used to overcome the barriers involved in low oral bioavailability of peptide drugs.
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