Sotalol controlled-release systems for arrhythmias: in vitro characterization, in vivo drug disposition, and electrophysiologic effects.

An array of controlled-release formulations of sotalol were investigated for epicardial drug delivery in short-term and chronic long-term treatment models with dogs. A nondegradable matrix formulation of sotalol made with polyurethane was studied by use of short-term treatment model with dogs, and the electrophysiologic effects were compared with those resulting from an intravenous dose of 2 mg/kg of body weight. Epicardial sotalol-polyurethane matrices were also used in 7-day canine implant studies. A sotalol-silicone rubber matrix was used in 60-day epicardial canine implant studies. A biodegradable poly(dl-lactide-co-glycolide) (PLGA) microsphere formulation of sotalol was also studied as a pericardial injection in another series involving 30-day dog experiments. The short-term treatment electrophysiologic effects observed with the epicardial (left ventricular) implantation of a sotalol-polyurethane matrix formulation were comparable to those observed with intravenous sotalol. However, the total dose delivered by the matrix over a 2-h experimental period was 25 times smaller than the intravenous dose (0.077 versus 2 mg/kg). Furthermore, coronary venous sotalol levels after sotalol-polyurethane matrix implantation were in the therapeutic range (1812.4 +/- 415.1 ng/mL), whereas simultaneous peripheral venous levels were more than 1 order of magnitude lower (149.8 +/- 14.1 ng/mL). An intravenous bolus administration of sotalol (2 mg/kg) resulted in coronary venous levels (1537.1 +/- 44.6 ng/mL) that were very close to simultaneous peripheral venous levels (1428.6 +/- 63.9 ng/mL).(ABSTRACT TRUNCATED AT 250 WORDS)