Epicardial propranolol administration for ventricular arrhythmias in dogs: matrix formulation and characterization

Abstract

The effect of propranolol on the prevention of ventricular tachycardia/fibrillation (VT/VF) due to acute coronary ischaemia was studied in dogs. A series of propranolol-polymer controlled release matrices in slab configuration using various polyurethanes and a polyurethane-silicone rubber copolymer were formulated and characterized. In general, drug release in vitro occurred with an initial burst phase followed by an exponentially declining delivery rate; the silicone rubber containing copolymer preparation had more sustained release properties than did pure Polyurethane matrices. In the animal studies, dogs underwent 5-hourly 10 min complete occlusions of the left anterior descending coronary artery (LAD), followed by 50 min normal perfusion. During non-drug occlusions VT occurred at a frequency of 1.22 +/- 0.12 episodes/min. A propranolol-polyurethane matrix (30% w/w, 28-42 mg) was placed on the ischaemic zone of the left ventricular epicardium immediately after the fifth occlusion. After an hour of drug delivery a sixth occlusion took place. The number of arrhythmia episodes both before and after drug were quantified and compared. The time to ventricular fibrillation (when present) and the mean blood pressure were also assessed. The drug patch delivered propranolol at a dose of 140 +/- 45 [mu]g/kg by the conclusion of the 1 h study period. Therapeutic drug levels were achieved in the peripheral blood samples (8.7-43.7 ng/ml) and were enhanced in coronary venous samples (360.9-556.2 ng/ml). Reduction of blood pressure and proarrhythmic events following epicardial controlled release propranolol administration were noted but were not statistically significant. Arrhythmia episodes before and after propranolol were not found to be significantly different (VT/min 1.02 +/- 0.31 and 1.22 +/- 0.12). The occlusion time until VF occurred was also not significantly different before versus after propranolol (t = 5.38 +/- 0.86 and 5.28 +/- 0.48 min). Therefore, despite attaining clinically therapeutic plasma levels, epicardial administration of propranolol was not found to be effective for the prevention of VT/VF due to acute ischaemia.