Modelling Prolonged in vitro Release of 5-Fluorouracil From Tablets Using a Flow Chamber

Abstract

Purpose: : Multiple injections of 5-Fluorouracil (5-FU) are often needed to modulate the wound healing response following surgery. Scarring may lead to surgical failure and loss of sight in glaucoma and retinal surgery. While the clinical effect of 5-FU is currently limited by its administration as an aqueous solution, we have established that the duration of action on fibroblasts is dependent on their exposure time to 5-FU. A relatively small prolongation of intraoperative drug levels may have very significant long term activity. Prolonged release of 5-FU could be more efficacious if formulated in a tablet form for implantation at the time of surgery.

Methods: : Several excipients including poly(vinyl pyrrolidone) (PVP), poly(vinyl alcohol) (PVA), hyaluronic acid (HA), and gellan gum were examined. Aqueous solutions of 5-FU and excipients were prepared and then freeze dried to ensure the components were thoroughly blended in their solid form. The solids were then compressed into 3mm diameter tablets. The release profile was determined using a dispensing pump that supplied flow rates ranging from 2-20 µl/min through a 200 µl flow chamber. The amount of 5-FU obtained at different time points at the out flow of the rig was determined by HPLC.

Results: : The 5FU loadings in the tablets ranged from 30% to 83%. Better blending uniformity was obtained between 5-FU and HA than between 5FU and PVP or PVA. HA tablets with 50% and 83% 5-FU loading displayed nearly equivalent first order release profiles with 80% release occurring at 8 hours. This is remarkable considering that 5-FU is quite soluble (15.4 mg/ml at pH 7.25). A 5-FU concentration between 4-6 mg/ml was maintained within the rig during this period. The addition of gellan gum to these 5-FU-HA formulations to physically gel the solutions prior to freeze drying also resulted in tablets that displayed a very similar release profile of 5-FU as obtained using HA alone.

Conclusions: : Compared to simple injections of 5-FU that clear within minutes from the rig, the release profiles of 5-FU from tablets indicate that there is the potential to maintain a local concentration of 5-FU for at least 8 hours using simple formulations, which may be more efficacious than current methods.

Keywords: drug toxicity/drug effects • proliferation • wound healing