2000 Volume 60 Issue 4 Pages 223-242
We designed various novel drug delivery systems based on biopharmaceutical aspects. One is to develop lymphatic delivery systems, especially for anticancer drugs. Another is to develop the intestinal delivery of poorly absorbed drugs by using absorption enhancers and chemical modification. When large substances (or carriers) are taken up into lymph vessels, lymph-selective mechanisms occur passively because of the structural difference between blood and lymph capillaries. Therefore, by using this characteristic of lymph capillary, we can develop the lymphatic delivery system through the use of appropriate carriers. These carriers may involve water-soluble macromolecules, hydrophobic microspheres, and lipoidal vesicles, which are biocompatible or biologically inert and to which active compounds can effectively be attached. The successful lymphatic targeting of anticancer drugs enhances their therapeutic efficacy and reduces their systemic toxic effects. On the other hand, to enhance the intestinal absorption of poorly absorbable drugs, including antibiotics and peptide and protein drugs, various strategies such as the use of absorption enhancers, the chemical modification of drugs to produce prodrugs and analogues, and the use of dosage forms have been examined. Of these strategies, the use of absorption enhancers is a highly popular strategy to enhance the intestinal absorption of poorly absorbed drugs. We examined the absorption-enhancing effects of unsaturated fatty acids, such as oleic acid, and found that membrane SH proteins as well as lipid portion of the membrane played an important role in their absorption enhancing effects. Furthermore, absorption enhancers with high effectiveness and less toxicity should be developed in clinical applications. An alternative strategy to improve the intestinal absorption of a poorly absorbed drug is to modify the chemical structure of drugs. We synthesized various acyl-derivatives of peptide and protein drugs by chemical modification with fatty acids. We found that the intestinal absorption of these acyl-derivatives was higher than that of native drugs, indicating that a chemical modification is also a promising strategy to improve the intestinal absorption of drugs, especially peptide and protein drugs.
