Objective Lappaconitine-self-micellizing solid dispersion sustained-release tablets (Lap-SMSD-SRT) was prepared, and investigated its pharmacokinetics and toxicokinetics in vivo. Methods Lap-SMSD powder was prepared by solvent evaporation method, and its basic physicochemical properties were also studied. The influence of hydroxypropyl methyl cellulose (HPMC) K4M dosage, carboxymethyl starch sodium (CMS-Na) dosage and lactose dosage on the drug release behavior of Lap-SMSD-SRT were investigated by single factor experiments. Composite score of cumulative release rate at 2, 6, 12 h was used as response value, Box-Behnken design-response surface method (BBD-RSM) was employed to optimize formulation of Lap-SMSD-SRT. The release behavior of lappaconitine hydrobromide tablets, lappaconitine tablets and Lap-SMSD-SRT were compared. Six beagle dogs were used to study the pharmacokinetic behavior by a three-period crossover trial, and the relative bioavailability of Lap-SMSD-SRT was calculated. Three level of low, medium, high (0.75, 1.50, 2.25 mg/kg) dose groups of Lap-SMSD-SRT were set up, and compared the plasma concentration of lappaconitine after the first and last administration with a 4-week dosing period and a 4-week recovery period. Then the toxicokinetic parameters were calculated. The living condition of Beagle dogs was observed, and the hematology and biochemical indexes were also examined. Results The dosage ratio of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus) to lappaconitine in Lap-SMSD powder was 5:1, and quickly became into micelles with particle size of (29.44 ± 2.01) nm when dispersed in water. Optimal formulation of Lap-SMSD-SRT: HPMC K4M dosage was 19.09%, CMS-Na dosage was 15.59%, and lactose dosage was 22.63%. The cumulative release rate of Lap-SMSD-SRT at 2, 6, 12 h were 26.50%, 61.67% and 93.67%, respectively. Pharmacokinetic results showed that the peak time (t_max) of Lap-SMSD-SRT was delayed to (6.20 ± 1.61) h, the half-life (t_1/2) was prolonged to (9.13 ± 2.64) h, the peak concentration (C_max) was enhanced to (123.94 ± 46.77) ng/mL, and the relative bioavailability was enhanced to 5.21-fold. No significant accumulation of lappaconitine was observed in Beagle dogs at each dose of Lap-SMSD-SRT. There might be slight effect on the blood system and liver in the medium-dose and high-dose groups of Lap-SMSD-SRT, but these symptoms disappeared during the 4-week recovery period. Conclusion The preparation process of Lap-SMSD-SRT was reproducible, and the formulation exhibited obvious sustained-release characteristics, significantly enhanced the in vivo absorption of lappaconitine, and showed good safety.

lappaconitine  /  self-micellizing solid dispersion  /  sustained-release tablets  /  Box-Behnken design-response surface method  /  bioavailability  /  pharmacokinetics  /  toxicokinetics