Method of evaluation of sustained release microsphere formulations using the open chemostat system

Abstract

The sustained release of cephalexin (CPX) as the monohydrate and ciprofloxacin (CFX) as the hydrochloride from separate 100000 Mol. Wt poly( l-lactic acid) microspheres (250–425 gmm sieve size range) was evaluated in an open chemostat system. Drug concentrations in pH 7.4 phosphate buffer solution (PBS) reached peak levels which were sustained for different periods of time, depending on the flow rate of PBS at a constant volume of 120 ml in the chemostat. At 0.46 ml/min flow rate CPX microspheres (33% w/w loading) sustained CPX concentrations for approx. 90 min (solubility = 40 mg/ml at pH 7.4, 37° C) whereas CFX (solubility = 5 mg/ml) was sustained for at least 6 h. Increasing drug loading increased peak levels of either antibiotic but decreased the sustained period of CPX only. Decreasing microsphere size to 125–250 gmm increased CPX or CFX concentration levels and decreased the sustained period to about 45 min and 2 h, respectively. At higher doses, CFX was sustained at higher concentrations over the 6 h period. Decreasing the flow rate in the chemostat increased sustained levels of CFX while increasing the flow rate decreased sustained levels. Thus, the chemostat system is convenient for testing the sustained release of drugs as a function of formulation parameters and to obtain information about the optimum doses of sustained release medication for in vivo administration.