(M1330-03-17) Alternative Methotrexate Oral Formulation: Enhanced Aqueous Solubility, Bioavailability, Photostability, and Permeability

Purpose: The purpose of this study was to develop the spray-dried amorphous inclusion complexes of methotrexate (MTX) with native β-cyclodextrin (β-CD) and its derivatives namely, HP-β-CD, M-β-CD and DM-β-CD to enhance the aqueous solubility, photostability, permeability, and oral bioavailability of MTX.

Methods: In this study, MTX, which has poor bioavailability and limited pharmaco-therapeutic implications due to its low solubility and permeability, was selected as a model drug. To determine suitable β-CD, solubility studies and in vitro dissolution studies were performed. Inclusion complexes were prepared using a spray drying technique with HP-β-CD, M-β-CD and DM-β-CD. Amongst these inclusion complexes (ICs), the IC formulation exhibiting the highest solubility and dissolution rate was selected for further studies. The pharmacological characteristics were investigated using scanning electron microscopy (SEM), particle size analyzer, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), and photostability assessments.

Results: This study shows that the 1:1 stoichiometry ratio of MTX and CDs improves aqueous solubility, stability, and pharmacokinetic profiles of the drug, the better results being obtained particularly with DM-β-CD as a host, which has a higher complexation ability with the drug compared to other β-CDs. Specifically, pharmacokinetic analysis demonstrated 2.20- and 3.29-fold increments in AUC and Cmax, respectively in comparison to free MTX. Furthermore, the physicochemical characterization confirmed the transformation of crystalline MTX to its amorphous state.

Conclusion: The aqueous solubility, bioavailability, photostability, and permeability of MTX were significantly enhanced in the IC containing DM-β-CD. This MTX/DM-β-CD is a straightforward and effective technique for improving the pharmacologically relevant properties of poorly water-soluble MTX.

Table 1. Compositions of various inclusion compounds.



Figure 1. (A) Solubility and (B) dissolution profiles of MTX and the four different MTX-CD inclusion complex formulations (IC1, IC2, IC3, and IC4) in aqueous media. Each value represents the mean ± SD (n=3).