Preformulation and development of chemically stable lipid emulsions containing a novel taxane derivative, TM-2 (pages 486–496)
Jianli Shi, Xi Chen, Yuechen Gu, Xi Hu, Ling Zhang, Yan Li, Cuifang Cai and Xing Tang
Version of Record online: 18 FEB 2014 | DOI: 10.1002/ejlt.201300371
TM-2 is a novel semisynthetic taxoid compound. This paper describes an investigation of the physicochemical properties of TM-2 to determine the use of lipid emulsions as suitable drug carriers. TM-2 is a poorly water-soluble drug like other taxanes and its solubility in PBS with a pH of 3.0–8.0 is under 1.0 µg/mL. However, it has a much higher solubility in oils than the taxanes, docetaxel and paclitaxel. The partition coefficient of TM-2 had no obvious correlation with pH, for the calculated value of log P was from 4.05 ± 0.04 to 4.41 ± 0.07 (n = 3) between pH 3.0 and 8.0. The stability of TM-2 in aqueous solutions and oils was investigated and the results showed that the drug degradation took place mostly in the water phase. Lipid emulsions, consisting of oil and water phases, have been found to be safe and excellent drug carriers. By incorporating the drugs into the interior oil phase and the oil–water interfacial film of o/w emulsions, direct contact of the drug with body fluids and tissues is avoided. Thus, the drug is protected from degradation and possible side effects are minimized. All the results from the preformulation study indicated that the characteristics of TM-2 made it an excellent candidate for o/w emulsions. During the preparation of TM-2 lipid emulsions, weak acid environment, high ionic strength and low temperature had appreciable effects on the stability of TM-2 solutions. An emulsion formulation of TM-2 which was stable enough to undergo sterilization was successfully developed and optimized. The degradation of TM-2 in emulsions followed pseudo-first-order degradation kinetics. The relationship between ln k and 1/T was determined by linear regression and the linearity coefficient of the regression was 0.9988. Using the Arrhenius equation, the shelf-life of TM-2 in lipid emulsion was estimated to be 2665.5 days at 4°C, which was much longer than that of 113.0 days in aqueous solution. So, TM-2 lipid emulsion was clearly superior to the TM-2 aqueous solution in terms of stability.