Till recent, injections remained the most common means for administering therapeutic proteins and peptides because of their poor oral bioavailability. However, oral route would be preferred to any other route because of its high levels of patient acceptance and long term compliance, which increases the therapeutic value of the drug. Designing and formulating a polypeptide drug delivery through the gastro intestinal tract has been a persistent challenge because of their unfavorable physicochemical properties, which includes enzymatic degradation, poor membrane permeability and large molecular size. The main challenge is to improve the oral bioavailability from less than 1% to at least 30 50%. Consequently, efforts have intensified over the past few decades, where every oral dosage form used for the conventional small molecule drugs has been used to explore oral protein and peptide delivery.

Various strategies currently under investigation include chemical modification, formulation vehicles and use of enzyme inhibitors, absorption enhancers and mucoadhesive polymers. This review summarizes different pharmaceutical approaches which overcome various physiological barriers that help to improve oral bioavailability that ultimately achieve formulation goals for oral delivery. keywords: therapeutic proteins and peptides, oral delivery, formulation vehicles, absorption enhancers, enzyme inhibitors, mucoadhesive polymeric system due to rapid progress in biotechnology, as well as gene technology, the industry is capable of producing a large number of potential therapeutic peptides and proteins in commercial quantities.

Endogenous proteins and peptides play an important role in the regulation and integration of life processes and act with high specificity and potency 1. For example, in the form of enzymes, hormones, antibodies and globulins, they catalyze, regulate and protect the body chemistry, while in the form of haemoglobin, myoglobin and various lipoproteins, they affect the transport of oxygen and other chemical substances within the body. In the form of skin, hair, cartilage and muscles, proteins hold together, protect and provide structure to the body of a multicellular organism 2. The increasing importance of proteins and peptides can be attributed to three main developments. First, improved analytical methods have promoted the discovery of numerous hormones and peptides that have found applications as biopharmaceuticals.

Second, molecular biology and genetic engineering have enabled the large scale production of polypeptides previously available only in small quantities. Lastly, there is a better understanding of the role of regulatory proteins/peptides in the pathophysiology of human diseases 2 ,3. Simultaneously, pharmaceutical companies around the world have endeavored to develop the processes for producing therapeutically active entities at commercial scales.

Intravenous, intramuscular or subcutaneous route remain the most common means for administering these protein and peptide drugs. Patient compliance with drug administration regimens by any of these parenteral routes is generally poor and severely restricts the therapeutic value of the drug, particularly for disease such as diabetes 1. Among the alternate routes that have been tried with varying degrees of success are the oral, buccal 4. Oral administration presents a series of attractive advantages towards other drug delivery. These advantages are particularly relevant for the treatment of pediatric patients and include the avoidance of pain and discomfort associated with injections and the elimination of possible infections caused by inappropriate use or reuse of needles. Moreover, oral formulations are less expensive to produce, because they do not need to be manufactured under sterile conditions 10.

In addition, a growing body of data suggests that for certain polypeptides such as insulin the oral delivery route is more physiological 11. Designing oral peptide and protein delivery systems has been a persistent challenge to pharmaceutical scientists because of their several unfavorable physicochemical properties including large molecular size, susceptibility to enzymatic degradation, short plasma half life, ion permeability, immunogenicity, and the tendency to undergo aggregation, adsorption, and denaturation 12 ,13. Consequently, the absolute oral bioavailability levels of most peptides and proteins are less than 1%.