ABSTRACT
Recent advancement in the field of pharmaceutical biotechnology and introduction of recombinant DNA technology have led to the production of a number of therapeutic peptides and proteins for the treatment of several life-threatening diseases (Table 57.1). A number of peptide-based therapeutics such as recombinant hormones, cytokines, vaccines, monoclonal antibodies, therapeutic enzymes, and the like have been recently approved for clinical use.1 However, most of these peptides are administrated by parenteral route. Inherent short halflives of peptides and chronic therapy requirements in a majority of cases make their repetitive dosing necessary.2 Frequent injections, oscillating blood drug concentrations, and low patient acceptability make even the simple parenteral administration of these drugs problematic.3,4 In spite of significant advancement in the field of pharmaceutical research, development of a proper noninvasive delivery system for peptides remains a distant reality. Although there have been reports of successful delivery of various peptide therapeutics across nonoral mucosal routes (such as nasal and buccal), the oral route continues to be the most preferred route for drug administration.5-7 The oral route, despite enormous barriers that exist in the gastrointestinal tract (GIT), has obvious advantages such as ease of administration, patient compliance, and cost effectiveness.8,9
57.1 Introduction ........................................................................................................................ 1359 57.2Barriers to Oral Delivery of Proteins/Peptides .................................................................. 1360 57.3Strategy for Improved Oral Protein Delivery ..................................................................... 1361 57.4Polymeric Nano/Microparticles as a Possible Oral Peptide-Delivery System ................... 1361
57.4.1Synthetic Biodegradable Polymeric Nano/Microparticles ..................................... 1363 57.4.2 Nonbiodegradable Synthetic Polymers ................................................................... 1367 57.4.3Natural and Protein-Based Polymers for Oral Peptide Delivery............................ 1370
57.4.3.1Protein-Based Polymers for Oral Protein Delivery ................................. 1371 57.4.4Preparation of Nano/Microparticles....................................................................... 1372
57.4.4.1Nano/Microparticles Obtained by Polymerization of Monomers ........... 1372 57.4.4.2 Particles from Preformed Polymers ......................................................... 1374
57.5Concluding Remarks .......................................................................................................... 1375 References .................................................................................................................................... 1375
Peptide-based biotechnology products are subject to the same hostile environment faced by all peptides in the GIT. The major problems associated with oral peptide delivery are the susceptibility to degradation by the hostile gastric environment; metabolism by luminal, brush border, and cytosolic peptidases; and poor permeability across the intestinal epithelium because of size, charge, and hydrophilicity.10,11 Intestinal epithelium serves as a major barrier for the absorption of orally administered drugs and peptides into the systemic circulation. High-resistance epithelial cell barriers restrict the passage of various hydrophilic compounds from the small intestine into the human body. The high resistance is due to the formation of well-organized tight junctions that connect the cell plasma membranes by a network of apical localized seams. As the name implies, tight junctions exclude the paracellular passage of ions, peptides, and proteins. The paracellular route is the dominant pathway for passive transepithelial solute ow in the small intestine, and its permeability depends on the regulation of intercellular tight junctions. The utility of the paracellular route for oral drug delivery has remained unexplored because of a limited understanding of tight junction physiology and the lack of substances capable of increasing the tight junction permeability without irreversibly compromising intestinal integrity and function. The attempts made so far to nd ways to increase paracellular transport by loosening intestinal tight junctions have been hampered by unacceptable side effects induced by the potential absorption enhancers.12 Physiological considerations, such as gastric transit time, dilution, and interaction with intestinal debris, also inuence peptide absorption across the intestinal epithelium. Furthermore, peptides absorbed through the hepatic portal vein have to negotiate with the rst-pass metabolism in the liver.9
