Study On Etoposide-phospholipid Complex Self-emulsifying Drug Delivery System

Etoposide (VP-16), a semisyntheticderivative product of podophyllotoxin, is naturally effective compound extracted from the roots and rhizomes of Podophyllum peltatum and P.emodi. The mechanism of anti-tumour involve inhibiting the activity of topoisomerase II enzyme and/or breaking DNA directly. Etoposide is widely used for curing patients with small cell lung cancer, testicular tumors, Kaposi's sarcoma, lymphomas, and leukemia. For its poor solution in water and oil and high variability in absorption, etoposide oral formulations, like the tablet or soft capsule, have a shortcoming of low bioavailability in some way, which plays a major role on limiting the efficacy of these drugs. The unique mechanism of phospholipid complex and self-emulsifying drug delivery system (SEDDS) make them be a convenient carrier for insoluble, poor oral absorption and low bioavailability drugs, and a new tool to improve oral bioavailability of insoluble drugs. In this study, the etoposide- phospholipid complex (EPC) was prepared first for the following SEDDS. We supposed that there were synergistic effect between phospholipid complex and SEDDS to enhance the drug bioavailability.In the first part, preparation of etoposide-phospholipid complex and its physicochemical properties were studied. Before the preparation conditions for etoposide-phospholipid complex were optimized by means of orthogonal design, single-factor study was performed. The physicochemical properties of new complex were analyzed by using the ultraviolet spectrum, infrared spectrum and differential scanning calorimetry. The changes of solubility and oil/water apparent partition coefficient of new complex in some solvents were manipulated. The results showed that optimized preparation conditions for etoposide-phospholipid complex as follows: solvent was tetrahydrofuran, the ratio of etoposide to phospholipids was 1 to 1.2(m/m), reactants were stirred for 0.5 h at 25℃. This new complex was different from reactant monomer and physical mixture of VP-16 and Soy Phospholipids with spectral analysis. The solubility and oil/water apparent partition coefficient of etoposide were enhanced rESCectively in 0.1N HCl, water and PBS.In the second part, preparation of SEDDS and their basic characteristics were studied. The formulation and preparation of EPC-ESDDS were obtained by solubility study in oils and (co-) surfactants, pseudo-ternary phase diagram construction and droplet size analysis. Furthermore, EPC-SEDDS quality system was evaluated. Results showed, EPC solubility increased significantly in oils and (co-) surfactants, the optimum formulation: EPC 100mg, ODO (mixed decanoyl actanoyl glycerides) 200mg, Cremopher EL 480mg, PEG-400 320mg. Quality system evaluation showed, EPC-SEDDS in aqueous medium quickly formed a stable spherical emulsion which the particle size is about 200nm. Benign stability was present when EPC-SEDDS was stored at cool, dark, sealed condition. In vitro release study also showed that, about 93% EPC-SEDDS was released into media at 15min while the cumulative dissolution of EPC and VP-16 were only 71%和42%,rESCectably,which it showed EPC-SEDDS dissolution was better than EPC and VP-16.In the third part,in vivo bioavailability of EPC-SEDDS compared with other preparations and probable absorption mechanism was discussed. The etoposide in vivo analysis was set up and accorded to the analysis requirements by analysis validation. Four reference preparations were selected and their bioavailability was compared with each other. Results showed, the EPC-SEDDS, E-SEDDS (etoposide-SEDDS) and EPCS (EPC suspension) of AUC 0→24 were 60.21, 44.9 and 8.44 fold compared with ES (etoposide suspension). The EPC-SEDDS AUC 0→24 was 2.34, 7.13 and 2.55 fold compared with E-SEDDS, EPCS and commercial preparation (Wick). Results indicated that the bioavailability of EPC-SEDDS was significantly different from E-SEDDS and EPC. It is concluded that bioavailability of etoposide was enhanced by phospholipid complex and could be further enhanced by SEDDS. There was synergistic effect between phospholipid complex and SEDDS. Compared with commercial preparations, the results showed EPC-SEDDS would obviously improve the bioavailability of these drugs.