Preparation Of Harmine Liposomes Coated With N-trimethylated Chitosan And Its Pharmacokinetics In Rats

Objectives：（1） To prepare harmine liposomes （HM-lip）coated with TMC.（2）To prepare the lyophilized powder of TMC-HM-lip.（3）To study the Pharmacokineticsof HM, HM-lip and TMC-HM-lip in rats by injection and oral administration.Methods:(1) HM-lip was prepared with film dispersion-pH gradient method. HM-lipwas then coated with TMC to prepare TMC-HM-lip. The release of HM, HM-lip andTMC-HM-lip in vitro was studied.(2) The appearance, particle size and encapsulationefficiency were selected as indexes, and the best lyophilization process and lyoprotectantwere studied.(3) Tinidazole was selected as the internal standard material, theconcentration of HM and Tinidazole was measured by high performance liquidchromatography (HPLC), and the marked curve of HM in vivo was obtained.(4) SD ratsweighted250-300g were given HM, HM-lip and TMC-HM-lip by either injection(20mg/kg)or oral administration(60mg/kg) respectively. The amount of0.5mL blood was extractedfrom their femoral artery at the specified time and the HM concentration in plasma wasmeasured.Results：(1)The particle size of HM-lip and TMC-HM-lip were (155.0±14.5)nmand(172±15.2) respectively. And the encapsulation efficiency was (81.20±0.02)%. Therelease of HM-lip and TMC-HM-lip were slower than that of HM. While as the release ofHM-lip and TMC-HM-lip obeyed the Higuchi equation.(2) Glucose-Lactose-mannitol(2:1:0.5) was selected as lyoprotectant and the appearance, particle size and encapsulationefficiency were ideal.(3)The Pharmacokinetics of HM, HM-lip and TMC-HM-lip iv fittedadequately with the two-compartment model. The HM in plasma could also be found12hours after the injection of HM-lip and TMC-HM-lip, as the t1/2(β)of them was20.49h and14.16h respectively. The absolute bioavailability of HM-lip and TMC-HM-lip was769.58%and490.05%respectively.(4)The HM concentration in plasma fitted adequately with the two-compartment model after the oral administration of HM. While the drugconcentration of HM-lip and TMC-HM-lip showed double peaks after oral administration.The eliminate rate of HM-lip and TMC-HM-lip was lower than that of HM, therefore drugwas found in plasma12hours later. The absolute bioavailability of HM, HM-lip andTMC-HM-lip was29.16%,50.93%and73.11%respectively.Conclusions:(1) The drug release in vitro study showed the sustained release ofHM-lip and TMC-HM-lip.(2) The stability of TMC-HM-lip was improved after made intolyophilized powder.(3)The absolute bioavailability of HM-lip was much higher than thatof HM both by injection and by oral administration. While when given to the rats by oraladministration, the absolute bioavailability was even higher after coated by TMC.