Studies On Cholesteryl Carbonate Zidovudine Liposomes

Zidovudine (AZT) is one of the foundational drugs for the treatment of AIDS. Usually it has to be administered frequently for its rapid elimination in vivo. It is known that highly active antiretroviral therapy (HAART) is an effective method to inhibit the replication of HIV, thus the improvement of the living quality of AIDS infectors. However, HAART is difficult to clean HIV in human body completely since it is hard for active compounds to reach the virus reservoir.In the studies, AZT was used as parent drug to synthesize a more lipophilic prodrug, cholesteryl carbonate zidovudine (AZTC). And then AZTC was entrapped effectively into liposomes for the purpose that the elimination time of active compounds would be prolonged and its targeting ability to liver, spleen and lung would be strengthened.Under the action of triethylamine, the catalyst, AZT and cholesterol were synthesized to AZTC at the room temperature. The obtained product was purified further with recrystallrisation method. The yield ratio was 95%. UV, IR, MS, ¹H-NMR and ¹³C-NMR were performed to identify the structure of the purified product. The purity of AZTC was more than 98.5% determined with HPLC method.A HPLC method to determine AZTC in vitro was established. The melting point of AZTC was measured with the combination of DSC and TGA as 160.54℃. The equilibrium solubilities in different solvents were determined with vibration method. The lgP value of AZTC in n-octyl alcohol-water system was predicted with on-line lgP value prediction software as 4.99. Besides, the initial stability and degradation kinetics were investigated.AZTC liposomes were prepared with ethanol injection-sonication method. The optimal formulation of AZTC liposomes was obtained by orthogonal design experiments on the basis of single factor investigation. The average entrapment efficiencies of optimal AZTC liposomes measured with both minicolumn centrigation method and ultracentrigation method were higher than 90%.The morphology of AZTC liposomes was observed under the transmission electron microscope. The mean particle diameter and zeta potential of AZTC liposomes were 82.4 ran and-40.5 mV respectively. The particle diameter variation over time, leak efficiency, compatibility with different media, peroxide value, stability in mouse plasma and long-term stability of AZTC liposomes were investigated. The results showed that AZTC liposomes were more stable when stored at 4℃than stored at room temperature.HPLC method was established for the measurement of AZTC in vivo. The pharmacokinetics and tissue distribution were assayed following administration of AZTC liposomes and AZTC suspensions via tail venous. The results proved that the elimination half-time and AUC_0→t of AZTC liposomes group were 3.3 times and 3.8 times than those of AZTC suspensions group separately. AZTC was mainly distributed in liver, spleen and lung following administration of both AZTC liposomes and AZTC suspensions. The distribution in lung and spleen of AZTC liposomes group was less than AZTC suspensions group, while the distribution in liver and brain was more than the latter.