Me. Brewster et al., FORMULATION DEVELOPMENT FOR A ZIDOVUDINE CHEMICAL DELIVERY SYSTEM .1.PARENTERAL DOSAGE FORMS, International journal of pharmaceutics, 125(1), 1995, pp. 17-30
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 lipophili
c and labile to oxidative and hydrolytic degradation thereby complicat
ing the development of a convenient formulation. The configuration of
several potentially acceptable parenteral dosage forms using cyclodext
rin-based systems are described herein. A prototype formulation was de
veloped using the AZT-CDS potassium salt in an aqueous matrix of 2-hdr
oxypropyl-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) veh
icle.