BIOADHESION TECHNOLOGIES FOR THE DELIVERY OF PEPTIDE AND PROTEIN DRUGS TO THE GASTROINTESTINAL-TRACT

For the efficient delivery of peptides, proteins, and other biopharmac euticals by nonparenteral routes, in particular via the gastrointestin al, or GI, tract, novel concepts are needed to overcome significant en zymatic and diffusional barriers. In this context, bioadhesion technol ogies offer some new perspectives. The original idea of oral bioadhesi ve drug delivery systems was to prolong and/or to intensify the contac t between controlled-release dosage forms and the stomach or gut mucos a. However, the results obtained during the past decade using existing pharmaceutical polymers for such purposes were rather disappointing. The encountered difficulties were mainly related to the physiological peculiarities of GI mucus. Nevertheless, research in this area has als o shed new light on the potential of mucoadhesive polymers. First, one important class of mucoadhesive polymers, poly(acrylic acid), could b e identified as a potent inhibitor of proteolytic enzymes. Second, the re is increasing evidence that the interaction between various types o f bio(muco)adhesive polymers and epithelial cells has direct influence on the permeability of mucosal epithelia. Rather than being just adhe sives, mucoadhesive polymers may therefore be considered as a novel cl ass of multifunctional macromolecules with a number of desirable prope rties for their use as biologically active drug delivery adjuvants. To overcome the problems related to GI mucus and to allow longer lasting fixation within the GI lumen, bioadhesion probably may be better achi eved using specific bioadhesive molecules. Ideally, these bind to surf ace structures of the epithelial cells themselves rather than to mucus by receptor-ligand-like interactions. Such compounds possibly can be found in the future among plant lectins, novel synthetic polymers, and bacterial or viral adhesion/invasion factors. Apart from the plain fi xation of drug carriers within the GI lumen, direct bioadhesive contac t to the apical cell membrane possibly can be used to induce active tr ansport processes by membrane-derived vesicles (endo- and transcytosis ). The nonspecific interaction between epithelia and some mucoadhesive polymers induces a temporary loosening of the tight intercellular jun ctions, which is suitable for the rapid absorption of smaller peptide drugs along the paracellular pathway. In contrast, specific endo- and transcytosis may ultimately allow the selectively enhanced transport o f very large bioactive molecules (polypeptides, polysaccharides, or po lynucleotides) or drug carriers across tight clusters of polarized epi - or endothelial cells, whereas the formidable barrier function of suc h tissues against all other solutes remains intact.