Recent progress in protein and peptide delivery by noninvasive routes.

Much progress has been made in the last 5 years toward delivery of protein and peptide drugs by noninvasive routes. The obstacles of instability, poor absorption, rapid metabolism, and nonlinear pharmacokinetics are great challenges for which some solutions are now emerging. Structural modifications of the protein by chemical or recombinant means have improved stability and minimized enzymatic cleavage in some cases. Protection of the protein or peptide drug via liposomes or polymers also offers a means for increasing stability and prolonging half-life. Novel permeation enhancers, which show minimal irritation to mucosal membranes, have become available and show promise for increasing absorption of proteins delivered by a number of noninvasive routes. There are examples in which several of these methods have been used concomitantly to achieve maximum effect; for instance, a bioadhesive microsphere formulation containing a novel permeation enhancer was used to maximize nasal delivery of insulin. Therefore, general methods exist whereby delivery by any noninvasive route may be improved. In some cases, choice of the best route of delivery for a particular drug makes the difference between success and failure. A comparison of the enzyme activity at the various sites of delivery is helpful and, fortuitously, the enkephalins, model peptides whose rate of cleavage and type of degradation products offer information about the type and activity of enzymes present, have been studied extensively. This work is reviewed for each delivery site as are the effects of coadministration of enzyme inhibitors. Permeation enhancers and examples for their use at each site of delivery are presented. The use of polymers for bioadhesion and for protection from metabolism at various sites is reviewed. Since systemic delivery of proteins via the pulmonary route is now receiving more attention, special emphasis is given to that work. Generally, the focus is on work published or presented since 1988, since publications prior to that date have already been thoroughly reviewed. The studies presented indicate that the problems of delivering protein and peptide drugs by noninvasive means can be minimized; although delivery by these routes still may not be bioequivalent to invasive methods, the convenience to the patient will, in some cases, outweigh the demand for complete bioequivalence.