Preparation,stability and pharmacokinetics evaluation of lipid microspheres loading a promising antitumor candidate,Timataxel

Timataxel (13-(N-Boc-3-i-butylisoserinoyl-4,10-β-diacetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,13-α-dihydroxy-9-oxo-19-norcyclopropa[g]tax-11-ene), used to be called TM-2, is a novel semi-synthetic promising candidate for cancer treatment. However the preformulation study showed that TM-2 was insoluble and chemically instable in water, which would limit its application. This study aimed at the preparation of Timataxel lipid microspheres (TM-2 LMs) and investigated the difference between TM-2 LMs and TM-2 solution in pharmacokinetics. In this work, the final formulation was as follows: 0.10% (w/v) TM-2; 10.00% (w/v) oil phase (long chain triglyceride:media chain triglyceride = 2.50%:7.50%); 1.40% (w/v) phospholipid; 0.02% (w/v) NaH₂PO₄; 2.25% (w/v) glycerin and water to a total volume of 100 ml. The particle size distribution, content and entrapment efficacy were 205.0 ± 43.3 nm, 101.00%, and 99.12%, respectively. TM-2 LMs were stable during storage at 25 °C for 3 months, even under the condition of 60 °C and 4500 lx for 10 d. Phosphatidylethanolamine (PE) in phospholipid may contribute to the stability of TM-2 LMs. The pharmacokinetic parameters for TM-2 LMs were as follows: AUC_(0-∞) 3663.71 µg/l h and the clearance 2.26 l/h/kg. As for solution, these parameters were 1712.52 µg/l h and 4.77 l/h/kg, respectively. The t_1/2 of TM-2 LMs was similar to TM-2 solution. The pharmacokinetic results indicated that the AUC of TM-2 LMs was larger, the clearance was smaller than that of TM-2 solution. In a word, lipid microspheres were a promising drug delivery system for TM-2.