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 dihydronicotinate chemical delivery system for zidovudine (AZT-CDS) were examined. Administration of the AZT-CDS by gavage to rats indicated poor bioavailability consistent with the acid lability of the CDS. Furthermore, administration of the AZT-CDS in dimethyl sulfoxide (DMSO) intraintestinally did not result in therapeutically relevant brain or blood levels of the AZT-CDS or its metabolites. Use of a liposome formulation, however, did provide for significant uptake with administration to the jejunum more effective than AZT-CDS administration to the ileum or colo-caecum. Invasive administration of AZT-CDS complexed with various chemically modified cyclodextrins to the intestine also resulted in good bioavailability. Perfusion of a section of jejunum with a solution of AZT-CDS in 2-hydroxypropyl-beta-cyclodextrin (HP beta CD) resulted in demonstrable AZT-CDS uptake and pre-liver/post-liver blood concentration ratio of approx. 0.5. These results suggest that an enterically coated AZT-CDS tablet may provide for pharmacologically useful oral bioavailability. A second route of administration considered was rectal dosing. AZT was significantly bioavailable from prototype suppositories in the rat and although AZT-CDS could be detected after AZT-CDS treatment, the absolute bioavailability for AZT after such treatment was low.