Preformulation and development of chemically stable lipid emulsions containing a novel taxane derivative, TM‐2

Abstract

AbstractTM‐2 is a novel taxane derivative. The present paper describes an investigation of the physicochemical properties and degradation kinetics of TM‐2 to determine the use of lipid emulsions as suitable drug carriers, and also to develop and evaluate a highly stable and sterile optimal formulation of a TM‐2 lipid emulsion (TLE). The properties of TM‐2, such as its solubility in water and oils, partition coefficient, stability in aqueous solutions and oils, indicated that TM‐2 was an excellent candidate for o/w emulsions. A preformulation study indicated that degradation of TM‐2 took place mostly in water compared with that in oils. Moreover, the influence of pH, temperature, and ionic strength on the stability of TM‐2 in water solutions was assessed. An emulsion formulation of TM‐2 which was stable enough to undergo sterilization was successfully developed. 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. Thus, TLE was clearly superior to the TM‐2 aqueous solution in terms of stability. Short‐term stability investigations showed that the TLE was stable for a period of 3 months at 4 and 25°C.Practical applications: The application of taxanes in anti‐cancer field is limited by de novo refractoriness or acquired resistance, which are common drawbacks to most anti‐cancer cytotoxic agents. TM‐2 is a novel semi‐synthetic taxane derivative, which can overcome multidrug resistance. Some non‐ionic surfactants, such as Cremophor EL and Tween 80 (polysorbate 80), usually used in the commercial formulations of the taxanes to improve their poor water‐solubility, have exhibited serious adverse effects including hypersensitivity reactions and peripheral neuropathy in human. In this study, preformulation study showed that TM‐2 exhibited excellent solubility in oils and, thus, the problems associated with the poor solubility of TM‐2 were overcome by loading TM‐2 into the interior oil phase of o/w lipid emulsions. According to the degradation kinetics results, the shelf lives (T0.9) of TM‐2 lipid emulsions at 25 and 4°C were dramatically prolonged.