FORMULATION DEVELOPMENT FOR A ZIDOVUDINE CHEMICAL DELIVERY SYSTEM .1. PARENTERAL DOSAGE FORMS

A chemical delivery system for zidovudine (AZT-CDS) has been shown to increase brain levels of the parent antiretroviral agent while at the same time reducing blood concentrations. Such selectivity may improve the therapeutic index for AZT. Unfortunately, the AZT-CDS is lipophilic and labile to oxidative and hydrolytic degradation thereby complicating the development of a convenient formulation. The configuration of several potentially acceptable parenteral dosage forms using cyclodextrin-based systems are described herein. A prototype formulation was developed using the AZT-CDS potassium salt in an aqueous matrix of 2-hdroxypropyl-beta-cyclodextrin (HP beta CD) (15% w/v) and Na3PO4 (0.005 M). While alkaline, the formulation was associated with a low buffering capacity and was not irritating in a rat tail model of extravasation. Systemic administration of this dosage form provided for, in addition to improved brain levels of AZT and an increased brain to blood ratio, improved bioavailability compared to a dimethyl sulfoxide (DMSO) vehicle.