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 longterm 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(dAlactide-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). Myocardial sotalol levels resulting from the short-term polyurethane matrix implants were highest in the epicardial layer proximal to the matrix location (21.6 ± 8.4 μ g/g) and were lower in the mid- and endocardial layers (4.3 ± 0. 9 and 4.6 ± 1.0 μg/g, respectively). Intravenous sotalol resulted in a uniform distribution of the drug throughout the myocardium: epicardial layer, 2.55 ± 0.20 /μg/g; midmyocardial layer, 2.27 ± 0.08 /μg/g; and endocardial layer, 2.39 ± 0.14 /μg/g. In the long-term sustained-release studies, myocardial levels observed after 7 days with the sotalol-polyurethane matrix implants (1.5 ± 0.7 μg/g), after 30 days with the sotalol-PLGA microsphere pericardial injections (3.4 ± 0.3 μg/g), and after 60 days with the sotalol-silicone rubber matrix implants (1.3 ± 0.2 μg/g) were comparable to myocardial levels observed with the intravenous dose studied in the short-term model (2.4 + 0.08 n μg/g). However, the estimated doses in the long-term implant studies were far below the 2-mg/kg intravenous bolus used in the short-term model. In 7-day sotalol-polyurethane matrix experiments, the approximate total dose was 2.3 mg/kg; with 30-day sotalol-PLGA microspheres, it was 2 mg/kg; and in 60-day sotalolsilicone rubber matrix experiments, it was 2.4 mg/kg. It was concluded that controlled-release sotalol produces electrophysiologic effects comparable to those noted with intravenous administration at a significantly lower dose. Long-term sotalol controlled-release implants maintain myocardial sotalol levels comparable to those observed with intravenous administration.