Preparation Of A Sustained-releasenebulized Aerosol Of R(-)-terbutaline Hydrochloride Liposome And Evaluation Of Its Anti-asthmatic Effects

Terbutaline is a fast-acting but short-acting bronchodilator,usually used as a "reliever" inhaler in the management of asthma symptoms.However,conventional terbutaline(TBT)aerosol formulations demonstrates a fast pharmacokinetic profile and thus the dosage must be repeated many times to sustain a bronchodilator response.Liposomes with the sustained release ability,as a carrier,were used to preparethe aerosol of R-terbutaline hydrochloride(R-TBH)liposome for inhalation to achieve the purpose of sustained relief of asthma.The preparation method of R-TBH liposomes was established on the basis of optimalprescription of Rac-terbutaline(TBT)liposomes because of similar physicochemical properties of two drugs,i.e.,blankliposomes were prepared by thin film dispersion method,and then the size of liposomes were modified through the membrane extrusion method;R-TBH were loaded by using an ammonium sulfate-induced transmembrane electrochemical gradient.The unencapsulated drugs were removed by dialysis.The content of R-TBH in liposomes was determined by reversed-phase HPLC method and the method validation was carried out.Then the liposomal R-TBH were characterized: the particle size was about 145 nm ± 20 nm,R-TBH liposomeswere spherical-like shapes under transmission electron microscope,PDI was about 0.02 and zeta potential was-8 mV or so.The drug loading was about 9% and the encapsulation efficiency was up to71%.The in vitro release assay showed that the cumulative release rate of R-TBH liposomes was 73.35% over 192 hours compared with 90.84% of R-TBH solution within 8 hours,showing a great sustained release manner.According to stability studies,these R-TBH liposomes should be stored at 4°C before usage and its sustained release ability would be influenced slightly after nebulization.The anti-asthmatic study of liposomal R-TBH conducted via pulmonary delivery in guinea pigs showed that R-TBH liposome aerosols exerted anti-asthmatic effect at 4 h post administration,whereas no anti-asthmatic effects were observed for the R-TBH solution aerosols at 4 h post administration.In conclusion,water-soluble R-TBH was efficiently encapsulated into liposomes.The high encapsulation efficiency and a sustained release in vitro of R-TBH from liposomes were achieved.And,compared to the R-TBH solution group,the R-TBHliposome group had a prolonged anti-asthma effectinvivo.