Studies On Azidothymidine Palmitate Liposomes

To estimate degradation tendency in vivo and effects of liposome entrapment, degradation kinetics of AZTP was investigated at different pHs with various temperatures and tissue homogenates of mice. It was shown that degradation mechanism of AZTP followed pseudo-first-order. AZTP degraded faster with the increase of pH and temperature. Discrepancy among different tissue homogenates existed. The order of apparent degradation rates in different tissues were as follows: liver＞kidney＞lung＞spleen＞heart＞brain. The results proved that liposomes have protection on AZTP from degradation.Lyophilization was used to increase stability of AZTP liposomes. Optima technology and formulation were chosen: quick freezing, prefreezed 6 hours, dried 15 hours at-20℃and 3 hours at 10℃; trechalose was chosen as the cryoprotectant with the concentration of 10% (w/v), inner added. According to the selected conditions, three batches of lyophilizated liposomes were prepared to carry out long term stability test with AZTP content, entrapment efficiency, mean diameter and peroxide value of lyophilizated liposomes as index parameters. The results indicated that long-term stability of lyophilizated liposomes of AZTP at 4℃is better than at room temperature.Stereo-stable-initiative-targeted liposomes of AZTP(AZTP-PEG-S) were prepared with addition of PEG-CH-S(which can bind with gpl20 of HIV under the assistance of electrostatic force) and PEG-CHS (PEG-cholesterol-succinate, a kind of ingredients for long circulation) to common liposomes of AZTP. Characteristics of AZTP-PEG-S were that it can prolong circulation time and meanwhile target drugs to HIV store.AZT solution(AZT-S), AZTP-L, distearylphosphatidyl ethanolamine polyethylene (DSPE-PEG, a kind of long circulation ingredient) modified liposomes of AZTP (AZTP-DSPE) and AZTP-PEG-S were prepared, whose pharmacokinetics/tissue distribution were estimated respectively after i.v. to mice with AZT content as index. Targetability was evaluated with relative uptake rate(r_e) as index. The results were that half lives of AZTP-L, AZTP-DSPE and AZTP-PEG-S divided by AZT-S were 1.64, 1.96 and 1.91, respectively. With AZT-S as standard, r_e of all liposome preparations in heart, liver, spleen, lung and brain were greater than 1 but smaller than 1 in kidney. It was indicated that after entrapped by liposomes the distribution of AZT in vivo was changed prone to diminish kidney toxicity of AZT and clean up HIV store in some tissues such as brain.