Preparation And Study Of Etoposid Microemulsio And Self-Microemulsion

Objects: Etoposide was selected as the model drug for the study of oral Microemulsion(ME) and Self-Microemulsifying drug delivery system(SMEDDS) adminisration. Microemulsion is a transparent, thermodynamically stable, low-viscosity, isotropic mixture of oil, water and surfactant, frenquently in combination with a co-surfactant. Self-Microemulsion belongs to the concentrated solution of ME. ME and SMEDDS can enhance absorption of poorly soluble drugs and improve the drug solubility and bioavailability. Though a widely used anti-tumor drug that used in the treatment of small-cell lung cancer and malignant lymphoma, Etoposide has poor solubility, low oral bioavailability and large individual difference. This paper studied ME and SMEDDS with Cremophor RH40 as the sufactant. ME and SMEDDS can enhance absorption of Etoposide and improve its solubility and bioavailability.Methods: On the basis of scientific literatures and pretesting, the blank Microemulsion formulation was constructed using isopropyl miristate(IPM) as the oil, Cremophor RH40 as the surfactant, PEG400 as the co-surfactant, water as the aqueous phase. The blank Self-Microemulsion formulation was constructed using isopropyl miristate(IPM) as the oil, Cremophor RH40 as the surfactant, PEG400 as the co-surfactant. Km value and the optimal formulation were got by constructing pseudo-ternary phase diagrams. Evaluation of blank Microemulsion and Self-Microemulsio involves particle size, the rate of Self-Microemulsiuon, cloud point, viscosity and observision of transmission electron microscope(TEM).Investigating the solubility of Etoposide in PEG400, Tween80, Cremophor RH40, IPM and Self-microemulsion, studing the blank Microemulsion and Self-Microemulsion, the optimal formation was got and evaluated. The release condition of Etoposide Self-Microemulsions and Soft Capsules were studied and compared according to ChP (2005) the release data were analyzed with traditional models to study the release mechanism.The stability research: The optimal Etoposide ME and SMEDDS formations were put in natural store condition, and mearured appearance, content and release in the first, the second, the third, and the sixth month.Pharmacokinetics study in vivo: To investigate the pharmacokinetics of Etoposide Self-Microemulsions and Soft Capsules oral administrationin in rabbits, High-performance Liquid Chromatograph with U1traviolet detector was adopted in examining concentration of serum in which Phenytoin Sodium was used as the internal standard. AUC0-∞, MRT and relative bioavailability was calculated using the trapezoid method.Results: The optimal blank ME formulation was IPM/RH40/PEG400/H2O=1/4.5/4.5/4.9 and optimal blank SMEDDS formulation was IPM/RH40/PEG400=1/4.5/4.5. Particle size of ME and SMEDDS was 20nm after diluted 20 times, and increased to follow dilution time. the distribution of particle size had two areas: 10-30nm accounting 80% and 40-60nm 20%. SMEDDS can transformed to ME in 1min. The cloud point of the ME with Cremophor RH40 as surfactant was 46℃. The viscosity of ME and water were same. ME and SMEDDS was round and particle size distribution was uniform.The solubility of Etoposide was most in PEG400, and then in SMEDDS but very small in water, IPM Tween80 and Cremophor RH40. Etoposide ME and SMEDDS was made on the basis of optimal formulation of ME and SMEDDS. The average particle size of Etoposide ME and SMEDDS was 24.5nm after diluted 10 times and 53.4nm after 100 times, The particle size was increased obviously as the increasing of dilution time. Surface of Etoposide ME and SMEDDS was round and distribution was uniform. The release of Etoposide SMEDDS and Soft Capsule was fast and achieved 100% in 45min. The release of Etoposide SMEDDS in vitro was consistent with Higuchi model.The stability reaearch: Etoposide ME got cloudy after severl days and the stability was poor after dilution. Etoposide SMEDDS had no obvious chang in appearance, content and release after six monthes. Pharmacokinetics study in vivo: The higest concentration of Etoposide SMEDDS was 7.24μg/ml in 0.5h and AUC0-∞was 16.19μg?h/ml while the higest concentration of Etoposide Soft Capsule was 2.69μg/ml in 1h and AUC0-∞was 8.24μg?h/ml. bioavailability of Etoposide Self-Microemulsion was 192.3% with Etoposide Soft Capsules as reference.Conclusions: According to the research in vitro and vivo, Etoposide Self-Microemulsion enhanced absorption, improved solubility and bioavailability.