Preparation Of Liposomal Amiodarone Hydrochloride And Its Targeting To Inflammation After Cardiac Ablation

The objective of this study was to investigate amiodarone hydrochloride(ADHC)loaded liposome as a potential new dosage form of ADHC for arrhythmia treatment.The ADHC liposome(ADHC-L)was prepared by thin-film method combined with ultrasonication and extrusion.The formulation and preparation condition were optimized by response surface methodology.The in vitro drug release and pharmacokinetics of ADHC-L was investigated.The in vivo distribution and the fluorescence imaging in hearts showed the possible inflammation targeting of ADHC-L.We established an accurate and rapid high-performance liquid chromatography(HPLC)method to detect the concentration of ADHC.Response surface methodology was employed to optimize the formulation and preparation of liposome.Three parameters(the weight ratio of Phosphatidylcholine(PC)to cholesterol;the weight ratio of PC to ADHC;ultrasonic time)were selected to investigate.The optimum formulation and optimized condition for liposome preparation was determined:the weight ratio of PC to cholesterol was 7.43,the weight ratio of PC to ADHC was 40.48,and ultrasonic time was 30 min.Under this optimized condition,the measured entrapment efficiency value of liposome is 99.5 ± 1.3%with a diameter of 99.9 ±0.4 nm,a zeta potential of 35.1 ± 10.9 mV and a PI of 0.2.All the liposomes were well-dispersed spherical particles with integrated bilayers.The particle size and zeta potential values remained stable during their residence at 4? for 28 days.The accumulated release experiment was conducted in 30%ethanol solution.The ADHC-L showed a significant initial burst effect and then relatively slow release activities.The cumulative release of ADHC-L was 43.5%at 72 h.It had a sustained release character compared to the free ADHC.The ADHC concentration of plasma in rats was detected after intravenous administration by HPLC method.The pharmacokinetic parameters were calculated using the kinetica5.0 software.Compared with free ADHC(3 mg/kg and 9 mg/kg),the dynamic characteristics of ADHC-L were significantly improved.The MRT of ADHC-L has increased about 8.6 times respectively.The AUCo?24 h of ADHC-L has increased 5.1 times higher than the low dose ADHC,and 1.6 times higher than the higher dose of ADHC.It can indicated that liposomal ADHC also can reduce the dose of ADHC while remaining therapeutic efficiency..The model of cardiac ablation in rat was built.The drug distribution after intravenous injection of ADHC for 20 min showed that ADHC-L can significantly increase the concentration of ADHC in heart about 4.0 times after cardiac ablation.Fluorescence imaging in heart after intravenous injection of ADHC for 20 min showed that the fluorescence intensity of the rat heart after cardiac ablation is stronger than the control group.It could be assumed that the heart targeting of ADHC-L was based of inflammation after cardiac ablation.