Category: Formulation and Quality
Purpose: Mebendazole (MBZ) has demonstrated in in vitro and in vivo activity in Glioblastoma multiforme (GBM), the most aggressive brain tumor and with poor prognosis, however its low solubility limits the absorption of the drug, therefore other strategies are needed to improve its bioavailability. The current study was aimed to formulate and characterize microemulsions with sodium hyaluronate as a mucoadhesive agent for intranasal administration of MBZ
Methods: Mebendazole was incorporated in two O/W microemulsion systems which were prepared using combinations of oleic acid (OA) with docosahexaenoic acid (DHA) or OA and Labrafil® M2125 CS (LBRIL) in proportions of 3:1 and 1:1 respectively. Tween® 80 was selected as the surfactant; Transcutol® HP as co-surfactant, ethanol as the cosolvent and distilled water as the aqueous phase. Pseudoternary phase diagrams were developed by water titration method in order to determine the microemulsion region. Sodium hyaluronate at 0.1% was used as mucoadhesive agent. The prepared systems were characterized in relation to particle size, zeta potential, polydispersity, pH, electrical conductivity, morphology, stability, rheological behavior, and nasal toxicity. The cellular proliferation of mebendazole in C6 cell line (the most aggressive glioma cell line) was also evaluated by MTT method and IC50 was determined.
Results: Results revealed that the construction of the pseudoternary phase diagram and the use of phase titration method was a suitable technique for the preparation of microemulsions. Two drug loaded microemulsion systems were successfully prepared. System A contained 9% of the oily phase (OA/DHA), 51% of the surfactants Tween® 80 / Transcutol® / Ethanol, 1:1:1 and 40% of water. System B contained 10% of oily phase (OA/LBRIL), 51% of the surfactants (Tween® 80 / Transcutol® / Ethanol, 1:2:1) and 39% of water.
System A and system B, exhibited a particle size of 209 nm and 145 nm respectively. Both systems revealed a spherical morphology and good stability. The pH of the systems was suitable for intranasal administration (5.08 and 5.36). The polydispersity test showed that the process was optimal while the conductivity supported that the O/W microemulsion was formed. The mebendazole loaded in OA/DHA system was 154.27 µg/mL and in OA/LBRIL was 260.3.36 µg/mL.,
The rheological behavior revealed a Newtonian fluid type in OA/DHA and OA/LBRIL systems. A fivefold increase in viscosity was observed when Sodium hyaluronate was added to both Systems. Nasal toxicity confirmed the safety of the microemulsions. The IC50 of mebendazole in C6 glioma cell line was 0.92 µM.
Conclusion: The oleic acid microemulsion formulations with DHA and LBRIL may be a suitable approach for intranasal delivery of mebendazole. Future work will focus on its in vivo efficacy
Adriana Ganem-Rondero– México City, Distrito Federal, Mexico
Simón López-Ramírez– México City, Distrito Federal, Mexico
Marisol Rivera-Huerta– México City, Distrito Federal, Mexico
Lourdes Mayet-Cruz– México City, Distrito Federal, Mexico
Helgi Jung-Cook– México City, Distrito Federal, Mexico