THE RATIONALE FOR PEPTIDE DRUG-DELIVERY TO THE COLON AND THE POTENTIAL OF POLYMERIC CARRIERS AS EFFECTIVE TOOLS

The explicit use of colon-specific drug delivery systems is for the lo cal treatment of colon diseases such as ulcerative colitis. Some effic ient therapeutic systems, primarily prodrugs and polymeric carriers of salicylate derivatives, have been developed and commercialized during the past 20 years. Speculating that the colon is a superior organ for peptide drug absorption after oral ingestion, many studies indicate t hat colon-specific drug carriers may potentially be used for the deliv ery of peptide drugs to that organ. This notion stems from the assumpt ion that the overall proteolytic activity in the colon is lower than a nd different from the proteolytic activity in the small intestine. For example, it has been found that the degradation rate of albumin, azoa lbumin casein, azocasein and collagen in human ileal effluent was fast er than the degradation rate in fecal slurries. Other studies, in whic h the degradation rates of insulin and insulin B-chain in the small an d large intestine of the guinea pig were compared, showed higher degra dation rates in the small intestine. It is noteworthy, however, that a peptide drug may stay much longer (up to ten times longer) in the lar ge intestine. Thus, even if the enzymic activity is lower, the drug is exposed longer to proteolytic activity. Yet, if the drug is properly protected or formulated with absorption enhancers, the prolonged resid ence time may increase drug absorption from the large intestine. Thus, prolonged drug blood levels of the ACE inhibitors benazepril and capt opril have been demonstrated in a number of studies after colonic admi nistration to rats and dogs. A possible explanation for the 'flat' pha rmacokinetic profiles obtained may be the 'closed compartment conditio ns' existing in the colon resulting from the extremely slow propulsive movement of digesta in that organ. These almost stationary conditions may also benefit the performance of functional adjuvants, such as abs orption enhancers or peptidase inhibitors, because their dilution rate with the luminal contents of the colon is low. For the purpose of col on-specific drug delivery a variety of polymers has been developed, in cluding acrylic polymers modified with azo cross-linkers and saccharid ic polymers. Both kinds have been tested in vitro and in animal studie s for their ability to be degraded specifically by typical enzymes of the colon. In addition, swellable polymers were utilized in new pulsat ile and delayed-release colonic delivery systems after being protected with enteric coating polymers. To secure peptide drugs in the GI trac t, especially in the colon, the use of cross-linked acrylic acid deriv atives such as polycarbophil and carbopol(R) 934 has also been suggest ed. In conclusion, new biodegradable polymers and polymers with contro llable swelling properties can be used for the specific delivery of dr ugs to the colon. Furthermore, some polymers, by virtue of their intri nsic proteolytic inhibition properties, could be used to improve the a bsorption of peptide drugs from colonic delivery systems.