Study On Self-assembled Systems Of Bolaamphiphilic Prodrug Of Zidovudine

On the basis of pharmacosomes, we designed a novel kind of drug delivery system called as self-assembled systems of bolaamphiphilic prodrug (SASBP), which may solve the problems of conventional DDS, such as lower encapsualtion efficiency and leaking.In the paper, antiviral drug zidovudine (AZT) was selected as the model drug, which was used to prepare the bolaamphiphilic lipidic derivative, i.e. PDDZ, and then PDDZ self-assembled system was prepared and studied in vitro/in vivo. The main contents were described in detail as follows:1. Synthesis of bolaamphiphilic prodrug. AZT utilized as polar headgroup was combined with a long hydrocarbon chain. Purification was identified. Because of its oil state, we just compared the solubility of prodrug in solvents through qualitative analysis. log P of PDDZ in n-octanol/phosphate buffer solution (pH 7.4) system was high, for little of it distributed into aqueous phase, which suggested the lipophilicity of PDDZ was greatly increased.2. Preparation and properties of SASBP. A variety of methods were screened during the preparation of the self-assembled system, whose physical stability, degradation rates in rabbit plasma and interaction with erythrocyte were evaluated. PDDZ self-assembled system; a kind of suspension system of highly dispersed and homogeneous, was prepared using methanol injection method. They were the 200nm-vesicles by TEM, and showed Zeta potential of—55.5mV.3. Stability of self-assembled system. Physical stability was investigated through heating, centrifugation and store for a long time, indicating self-assembled system particles of uniform, and not tended to aggregate. HPLC were established to determine PDDZ and AZT. PDDZ self-assembled system was unstable in alkaline, but kept stable for a long period in weak acid, weak base and neutral buffers, which was rapidly hydrolyzed into AZT in enzymes, plasma and homogenates.4. Pharmacodynamics and pharmacokinetics of self-assembled system. PDDZself-assembled system was quickly uptaked by macrophage system after single bolus iv administration to rabbits, from which AZT was released at targeted organs. Self-assembled system was found not only in liver and spleen, but testes.After many screening and optimization, a highly dispersed, homogeneous and stable self-assembled system was prepared in this paper, which could be hydrolyzed by enzymes, degradated into AZT, uptaked by macrophage and avoided the dose-dependence side effects of Zidovudine. But PDDZ was too easily hydrolyzed to be controlled-release.