Preparation And Pharmacokinetics Of Honokiol Long-circulating Liposomes

Objective:Honokiol has strong pharmacological effects including against microbial,platelet aggregation,oxidation,and antitumor.However,its poor water solubility greatly limits its bioavailability.A large number of studies have shown that liposomes have unique advantages in drug release and increased bioavailability.To optimize the preparation process of honokiol long-circulating liposomes(HLCL)and study the stability and release in vivo and in vitro.And study the physicochemical properties of HLCL,including particle size、zeta potential.the encapsulation efficiency and drug-loading content.To provide the experimental basis for the research and development of HLCL in pharmacy and pharmacodynamics.Methods:In this study,Liposome of HLCL was prepared by thin-film dispersion method.An orthogonal experiment was designed to optimize the composition of the HLCL using entrapment efficiency,particle size and zeta potential as evaluation indicator.The effects of soya phosphatidyl choline-cholesterol-DSPE-PEG2000(A),honokiol-liposome materials(B)and the ultrasonic time(C)on the encapsulation rate were evaluated.The type and amount of the protective agent were selected based on the appearance and redispersibility of the liposome lyophilized powder.The particle size and zeta potential of HLCL were measured with a particle size analyzer.The liposome surface morphology was observed by transmission electron microscope(TEM),and the entrapment efficiency was measured by dextran G50 method.The stability of honokiol long-circulating liposomes was studied,and the liposome release in vitro was studied by dialysis method.The concentration of honokiol in rat plasma was determined by the established LC-MS/MS method,and the differences in pharmacokinetic parameters were compared after honokiol and HLCL(20 mg/kg)were orally administered to SD male rats,respectively.The blood samples were collected by post-orbital venous sinus puncture at programmed time points.Draw the concentration-time curves of honokiol and the pharmacokinetic parameters were calculated.Results:The optimal composition of HLCL was 8:1:1 for soya phosphatidyl choline-cholesterol-DSPE-PEG2000,and 1:10 for honokiol-liposome materials with the ultrasonic time of 12 min.Sucrose was used as a protective agent,and the mass ratio was 3:1 for protective agent-phospholipid.Under the optimized conditions;HLCL was sphere with mean particle size of 121.5 nm and mean zeta potential of-30.8 mV,the encapsulation efficiency and drug-loading content was 84.7%and 10.4%,respectively.The stability of HLCL lyophilized agent is good under the condition of 4 ℃ for 10 days.This product requires cryogenic storage.But they are not stable under high temperature,high humidity and strong light.In vitro release results showed that the liposomes could be gently and slowly release with the 24 h cumulative release rate at pH 1.2 and pH 6.86 dissolve medium of 80%and 71%,respectively.While free honokiol(HNK)released rapidly,it was released completely at 12h.Based on the pharmacokinetic results,the Cmax,Tmax,and t1/2 were(23.29 ± 11.76)ng/mL,(0.13 ± 0.05)h and(10.59 ± 5.72)h for HLCL,and(79.34 ± 56.32)ng/mL,(0.30 ± 0.07)h and(4.44 ± 3.14)h for honokiol,respectively.There was no significant difference about the AUC0-∞ following oral administration of honokiol and honokiol long-circulating liposomes(HLCL)at isodose honokiol(20 mg/kg).Conclusion:Results in this thesis demonstrated that the honokiol long-circulating liposomes(HLCL)formulation process is reasonable,with high encapsulation efficiency.And it is good to store in a cool,dry place away from light.Compared with honokiol,HLCL was released gently and slowly in vitro,absorpted rapidly and eliminated slowly in vivo.These results would be of great importance for the development of new nano-formulation of honokiol.