The Research Of The Cremophor-free Paclitaxel-loaded Injection

Paclitaxel (Ptx), one of the most important antineoplastic drugs, is widely effective for various cancers, but it is insoluble in water, and it is hard to be absorbed by the oral administration. The clinical formulation of the Ptx is composed of Cremophor EL (Cr EL) and dehydrated alcohol (50:50, v/v), and diluted into determinate bulk when clinical used. The stability of the dilution is 12~ 24 h. Cr EL is widely used as a vehicle for the solubilization of hydrophobic drugs, but its amount in the Ptx formulation is much higher per administration, leading to obvious side effects such as hypersensitivity reaction, nephrotoxicity and neurotoxicity. The premedication with corticosteroids and antihistamine, therefore, is commonly used to reduce incidence and intensity of the hypersensitivity reaction. There are still many problems associated with the application of the formulation. For example, DEHP, which is leached from PVC infusion bags and sets by Cr EL, results in inconvenience to medical staff and harms to patients.Herein, we used Tween80 (Tw80)-S80 (one kind of lecithin) to instead of Cr EL in the paclitaxel-contained injection. We optimized and finally got the Tw80-S80 Ptx injection composed of Ptx, S80, Tw80 and dehydrated alcohol (1:20:83:83, mg/mg/μl/μl).In our study, the Tw80-S80 vehicle was prepared and dispersed in water to form the mixed micelles when used. The Cr EL formulation was prepared as control and also dispersed in water when used. After 3 days, the drug-loaded amount of Tw80-based single component micelle and Cr EL micelle were lower than 65% and 73%, respectively, and the mean size of the both micelles increased more than 2 orders of magnitude. But the drug-loaded stability of the Tw80 micellar system was markedly increased by the addition of S80, and when the amount of S80 was up to 12mg/ml, the mixed micellar system kept a good stability with the drug-loaded amount of 98% and mean size was lower than 25nm. The transmission electron microscope (TEM) observation and the differential thermal analysis (DTA) curves showed the Tw80-S80 mixed micelle formed. Moreover, the addition of S80 also changed the CMC of the Tw80 micelles from 0.002334mmol/l down to 0.001198mmol/l and improved the microenviromental nonpolarity of the Tw80 micelles. The pharmacokinetic study of the Tw80-S80 Ptx injection showed that it was no significant difference with Cr EL Ptx injection.Herein, the characteristics of the Tw80-S80 mixed micelles showed that the Tw80-S80 mixed micelles provide an effectively alternative approach for the formulation of Ptx.