(M1230-05-30) Exploration of the Utility of Bentonite for Developing a Pediatric Formulation of Everolimus

Purpose: Everolimus (EVR) is a poorly soluble kinase inhibitor being used for treating pediatric patients with tuberous sclerosis complex. The currently available formulations of EVR for pediatric use are expensive and therefore limit a wide clinical use. This study was performed to explore the utility of bentonite (BN) for developing an inexpensive and convenient pediatric formulation of EVR in comparison to a powder formulation of EVR.

Methods: A composite formulation of EVR with BN (EVR-BN) was produced in the ratios of EVR to BN ranging from 1:1 to 1:4 by dissolving EVR in a solution of dimethyl sulfoxide and distilled water, followed by overnight lyophilization. The surface morphology of EVR-BN was compared with the powder of EVR and BN, and the physical mixture of EVR and BN using a field-emission scanning electron microscope (FE-SEM). The pharmacokinetic characteristics of EVR in EVR-BN were compared with those in EVR alone in a cross-over study by orally administering a capsule containing either EVR-BN or EVR alone to beagle dogs at the EVR dose of 1.25 mg by separating a washout period of seven days. Blood samples were collected from the jugular vein at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 18, 24 and 36 hours post dose. The concentrations of EVR in the whole blood were measured using an ultra-performance liquid chromatographic method with tandem mass spectrometric detection. A bioequivalence test was performed to compare the pharmacokinetic parameter values of EVR between the two formulations, which were determined using a noncompartmental analysis. Assessed were the dispersion characteristics of the composite in distilled water and pediatric syrup.

Results: The surface morphology of EVR-BN exhibits an elliptical distorted shape with round edges and no pores, which is distinct from the sharp shape of EVR and the spherical sponge-like configuration of BN. When determined in eight beagle dogs, the geometric mean value of maximum concentrations of EVR (C_max) in EVR-BN was lower by 71.7% (90% confidence interval, 90% CI; 44.9% – 85.5%) of that in EVR alone (5.0 versus 17.6 ng/mL, respectively). The median value of time to C_max (t_max) in EVR-BN was slightly longer compared with that in EVR alone (2.0 versus 1.75 hours; interquartile range, IQR; 1.5 – 2.0 versus 1.0 – 3.0 hours, respectively). The geometric mean value of the area under the concentration-time curve from time 0 to infinity (AUC_inf) in EVR-BN was lower by 59.1% (90% CI; 29.8% – 76.2%) of that in EVR alone (98 versus 239 ng·h/mL, respectively). The median value of terminal half-life (t_1/2) in EVR-BN was similar compared with that in EVR alone (21.0 versus 21.5 hours; IQR, 13.6 – 41.6 versus 14.7 – 29.4 hours, respectively). The median value of the mean residence time (MRT) in EVR-BN was slightly longer compared with that in EVR alone (32.3 versus 27.2 hours; IQR, 20.0 – 65.3 versus 20.7 – 35.9 hours, respectively). When mixed in distilled water, the EVR-BN composite settled quickly but dispersed readily upon shaking. The composite was homogeneously dispersed as a colloidal suspension when the composite was mixed in pediatric syrup. As the ratio of EVR-BN composite increased from 1:1 to 1:4, the composite was more homogeneously dispersed.

Conclusion: The surface morphology of EVR-BN composite was distinct from that of EVR or BN. Based on the pharmacokinetic characteristics of EVR-BN, a reduction in the extent of absorption was smaller than that in the rate of absorption of EVR. The composite appears to be suitable for a pediatric formulation of EVR. Further studies are required to improve the extent of EVR absorption from the composite.

Acknowledgements: This study was supported by the Korean Institute of Geoscience and Mineral Resources (KIGAM, Pohang, Republic of Korea). This work was also supported by the Research Institute of Pharmaceutical Sciences and the fourth phase of the Brain Korea 21 Program in 2024.