Preparation and characterization of Sodium Deoxycholate- d-α-tocopheryl polyethylene glycol 1000 succinate mixed micelles for solubilization of Methotrexate

BERNABEU E.; CAGEL M.; GROTZ E.; GONZALEZ L.; MORETTON M.A.; CHIAPPETTA D.A.

Rosario

Congreso; RICIFA 2016. 4ta Reunión Internacional de Ciencias Farmacéuticas; 2016

Methotrexate (MTX), a folate antimetabolite, is approved to treat many solid tumors, hematological malignances and autoimmune diseases. High doses of MTX are administered in order to achieve high systemic exposure to the drug for the treatment of childhood acute lymphoblastic leukemia (ALL). Unfortunately, the therapeutic effect of MTX is hindered by toxic dose-related side effects, as well as the development of drug resistance by target cells. These drawbacks of MTX are closely related to its poor aqueous solubility (10µg/mL) and unfavorable pharmacokinetic profile. Therefore, the development of novel formulations capable of enhancing drug aqueous solubility is an urgent matter. In the present study, we have investigated the use of sodium deoxycholate (NaDC) and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as micellar carriers for improve the aqueous solubility of MTX. Mixed micelles of NaDC and TPGS in different molar ratios (10:0; 7.5:2.5; 5:5; 2.5:7.5 and 0:10) were prepared. Solubilization of MTX using simple and mixed micellar system was evaluated and compared in different pH value at 25°C. The solubility of mixed micellar system was higher than pure MTX in all cases. The 7.5:2.5 micellar combination incremented the apparent solubility (Sa) of MTX by more than 60-times in water and 5-times at pH=5.0. In contrast, pure TPGS showed the smallest Sa values at the same conditions. In addition, the 2.5:7.5 combination incremented the Sa 9-times at pH=2.2. This binary combination, moreover, had the lower critical micellar concentration (3.10-4M) compared to the other mixtures at 25 °C. The size of pure TPGS and mixed micelles were found around 10 nm with narrow size distribution (PDI150 nm). The micelles also exhibited a spherical morphology as characterized by transmission electronic microscopy. Finally, the significant increase in drug solubility by mixed micelles could be promising to improve intravenous delivery of MTX in leukemia therapy; however, further studies are needed to establish their potential.