Effects of GLIADEL® wafer initial molecular weight on the erosion of wafer and release of BCNU

Abstract

The GLIADEL® wafer is a polyanhydride implant used in the treatment of malignant glioma, in which the anticancer agent carmustine (BCNU) is incorporated into a copolymer matrix consisting of 1,3-bis( p-carboxyphenoxy)propane (CPP) and sebacic acid (SA) in a 20 to 80 molar ratio (p(CPP:SA, 20:80)). It is crucial to determine the relationship between the wafer's initial molecular weight and the erosion rate of polymer matrix and the subsequent release rate of drug substance BCNU. This study focuses on the effect of the initial molecular weight of GLIADEL® on polymer erosion and BCNU release from the polymer matrix. Wafer erosion in vitro was characterized by weight loss, molecular weight change and the appearance of water soluble CPP and SA in the incubation medium at 37°C. Wafer erosion and BCNU release were also investigated in the brains of normal rats. It was found that both the in vitro and in vivo erosion of wafer is independent of its initial molecular weight, which in this study ranged from 20 000–110 000 Da. The average molecular weight of the wafer was reduced to less than 10 000 Da after 10 h of incubation in phosphate buffered saline (37°C, pH 7.4) or after implantation in the brains of normal rats, despite the differences in initial wafer molecular weight. Furthermore, the release of carmustine (BCNU) from GLIADEL® is a combination of the diffusion of drug substance and the erosion of polymer matrix. The release rate of BCNU is also independent of initial wafer molecular weight.