|Budget Amount *help
¥3,100,000 (Direct Cost : ¥3,100,000)
Fiscal Year 1998 : ¥800,000 (Direct Cost : ¥800,000)
Fiscal Year 1997 : ¥2,300,000 (Direct Cost : ¥2,300,000)
An antiinflammatory 4-biphenylylacetic acid (BPAA), as a model drug, was selectively conjugated onto one of the primary hydroxyl groups of alpha-, beta- and gamma-cyclodextrins (alpha-, beta- and gamma-CyDs) though an ester or amide linkage, (BPAA/alpha-, beta- and gamma-CyD conjugates). and their in-vitro and in- vivo drug release, oral absorption behavior, and antiinflammatory effect in rat model were investigate to evaluate them as a colon-specific drug delivery system. The results obtained were summarized as follows :
1) The NMR and mass spectroscopic results indicate that the BPAA moiety was introduced selectively onto one of the primary hydroxyl groups of CyDs. The aqueous solubilities of the alpha- and beta-CyD conjugates were about 100 and 10 times respectively, that of BPAA, whereas that. of the beta-CyD conjugate decreased to about one-tenth. The ester conjugates released BPAA selectively in rat cecal and colonic contents, whereas they were stable in other biological fluids of rats.
2) The serum levels of BPAA increased about 3 hours after oral administration of the alpha-and -gamma-CyD ester conjugates to rats, accompanying a marked increase in the serum levels, whereas the beta-CyD and the amide conjugates resulted in little increase of the serum levels.
3) The antiinflammatory effect of the gamma-CyD ester conjugate was evaluated, in comparison with that of the beta-CyD complex, using the model of carageenan-induced acute edema in rat paw. In the case of the beta-CyD complex a rapid antiinflammatory response was observed, because of the fast dissolution of the complex. In sharp contrast, the gamma-CyD conjugate needed a fairly long lag time to exhibit, the drug delivery, because BPAA was produced after it had reached the cecum and colon.
The present conjugate approach provides a versatile means for construction of not only colon-specific delivery system but also delay-release system of certain drugs.