FORMULATION DEVELOPMENT FOR A ZIDOVUDINE CHEMICAL DELIVERY SYSTEM .2.TOWARDS ORAL AND NONPARENTERAL DOSAGE FORMS

Steps toward the development of an oral dosage form for a dihydronicot inate chemical delivery system for zidovudine (AZT-CDS) were examined. Administration of the AZT-CDS by gavage to rats indicated poor bioava ilability consistent with the acid lability of the CDS. Furthermore, a dministration of the AZT-CDS in dimethyl sulfoxide (DMSO) intraintesti nally did not result in therapeutically relevant brain or blood levels of the AZT-CDS or its metabolites. Use of a liposome formulation, how ever, did provide for significant uptake with administration to the je junum more effective than AZT-CDS administration to the ileum or colo- caecum. Invasive administration of AZT-CDS complexed with various chem ically modified cyclodextrins to the intestine also resulted in good b ioavailability. Perfusion of a section of jejunum with a solution of A ZT-CDS in 2-hydroxypropyl-beta-cyclodextrin (HP beta CD) resulted in d emonstrable AZT-CDS uptake and pre-liver/post-liver blood concentratio n ratio of approx. 0.5. These results suggest that an enterically coat ed AZT-CDS tablet may provide for pharmacologically useful oral bioava ilability. A second route of administration considered was rectal dosi ng. AZT was significantly bioavailable from prototype suppositories in the rat and although AZT-CDS could be detected after AZT-CDS treatmen t, the absolute bioavailability for AZT after such treatment was low.