Poly(HEMA-Zidovudine) conjugate: A macromolecular pro-drug for improvement in the biopharmaceutical properties of the drug

Abstract

A macromolecular pro-drug of a known anti-viral agent Zidovudine (AZT) was synthesized and evaluated as a sustained drug delivery system. The pro-drug was synthesized by coupling the drug to 2-hydroxyethyl methacrylate (HEMA) through a succinic spacer to get a monomeric drug conjugate which was polymerized to obtain the polymeric pro-drug. The pr0-drug was subjected for in-vitro drug release study in buffers of pH 1.2 and 7.4. The hydrolytic stability of the pro-drug to pepsin was assessed in simulated gastric fluid (SGF, pH 1.2) and to α-chymotrypsin in simulated intestinal fluid (SIF, pH 7.4). The results showed that the drug release from the polymeric backbone takes place in a sustained manner over a period of 24 h, and the amount of drug released was comparatively higher at pH 7.4. Plasmatic hydrolysis studies of succinylzidovudine showed nearly complete release of AZT. At all pH conditions in the presence and absence of α-chymotrypsin, AZT was released preferentially in comparison with the succinyl derivative. The in-vivo release studies in rabbits after oral administration of AZT conjugate demonstrated a sustained release of parent drug over a period of 24 h. The pro-drug provided a significant increase in the area under the plasma concentration time curve as compared to free drug and extended the plasma half-life from 1.06 h to 8.08 h. This study suggested that, after oral administration, the drug–polymer conjugate can release AZT for prolonged periods, thus improving the pharmacokinetics of AZT and decreasing the fluctuation in plasma drug levels that can lead to toxicity.