Oral delivery enzyme inhibitors

Shah, R.B., A. Palamakula, and M.A. Khan. 2004. Cytotoxicity evaluation of enzyme inhibitors and absorption enhancers in Caco-2 cells for oral delivery of salmon calcitonin. J Pharm Sci 93 1070. 

The drawback of this highly potent class of inhibitors is their toxicity (Stryer 1988). Only few representatives are known to be non-toxic. Therefore, enzyme inhibitors that are not based on amino acids are only of theoretical interest for oral drug delivery and other applications in human. Nevertheless, they might be interesting as lead compounds to develop novel potent and nontoxic inhibitors. 

Luessen HL, Verhoef JC, Borchard G, Lehr CM, de Boer AG, Junginger HE (1995) Mucoadhesive polymers in peroral peptide drug delivery. II. Carbomer and polycarbophil are potent inhibitors of the intestinal proteolytic enzyme trypsin. Pharm Res 12 1293-1298 Marschutz MK, Bernkop-Schnurch A (2000) Oral peptide drug delivery polymer-inhibitor conjugates protecting insulin from enzymatic degradation in vitro. Biomaterials 21 1499-1507... 

In spite of these formidable challenges, the attractiveness of oral route has fueled the exploration of an incredibly diverse set of strategies to deliver proteins and peptides and the subject has been exhaustively reviewed. The various approaches include permeation enhancers, enzyme inhibitors, mucoadhesives, multifunctional matrices that simultaneously incorporate the above strategies, enteric coatings that offer protection from the acidic environment of the stomach, encapsulation (liposomes, microspheres, and nanoparticles), pH-sensitive polymers, microemulsions, carriers (delivery agents), and protein modification either to simply enhance permeability or to exploit specific transporters. While proof-of-concept has been demonstrated with most of these delivery systems in animal... 

Various formulation concepts have been introduced as potential ways to protect peptide and protein drugs from the hostile GI environment to increase their oral absorption such as use particulate drug carriers (microspheres, lipo-somes, and lectins), coadministration of enzyme inhibitors and absorption enhancers, use of chemical modification (prodrug), and site-specific delivery to the colon or rectum. Some of these approaches are discussed later. 

Successful oral delivery of protein involves overcoming the barriers of enzymatic degradation, achieving epithelial permeability, and taking steps to conserve bioactivity during formulation processing. The coadministration of enzyme inhibitors and permeation enhancers is an approach used to enhance the bioavailability of oral protein formulations. Chemical modification of peptides and use of polymeric systems as carriers have also been attempted to overcome the inherent barriers. 

Multifunctional carrier matrices offer various advantages for oral drug delivery. Their application for oral drug delivery is described in Chapter 8. Generally, such carriers can be used either to protect the drug from enzymatic degradation via steric hindrance or to directly inhibit enzymes. Multifunctional polymers that can inhibit GI proteolytic enzymes per se are polyacrylates and modifications thereof as well as polymer-inhibitor... 

As mentioned above, the oral administration of peptides often results in very low bioavailability due to poor membrane penetration characteristics (transport barrier) and extensive hydrolysis of peptides by digestive enzymes of the gastrointestinal tract (enzymatic barrier) [1]. Of these two barriers, the latter is of great importance for certain unstable small peptides, as these peptides can be transported across the intestinal membrane unless they are degraded by proteases. Thus, the use of protease inhibitors, if effective at the absorption site, might represent a promising approach to overcome delivery problems associated with peptides and protein biopharmaceuticals. 

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