Alternative Methotrexate Oral Formulation: Enhanced Aqueous Solubility, Bioavailability, Photostability, and...

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems
• Materials Science

Background:

• Methotrexate (MTX) exhibits poor aqueous solubility, limited permeability, and instability, restricting its therapeutic applications.
• Developing stable and bioavailable oral formulations for MTX is challenging due to these limitations.

Purpose of the Study:

• To enhance the aqueous solubility, photostability, permeability, and oral bioavailability of MTX.
• To develop spray-dried amorphous inclusion complexes (ICs) of MTX with native β-cyclodextrin (β-CD) and its derivatives (HP-β-CD, M-β-CD, DM-β-CD).

Main Methods:

• Spray-drying technique to form MTX-β-CD inclusion complexes.
• Physicochemical characterization using SEM, DSC, and PXRD.
• In vivo pharmacokinetic studies in rats and in vitro ¹H NMR analysis.

Main Results:

• Spray-dried amorphous ICs of MTX with β-CDs improved solubility, stability, and pharmacokinetic profiles.
• DM-β-CD demonstrated superior complexation ability, yielding a 2.20-fold increase in AUC and 3.29-fold increase in Cmax compared to free MTX.
• Reduced efflux of absorbed MTX from inclusion complexes (4.6-fold) compared to free MTX (8.0-fold).
• Physicochemical analyses confirmed the amorphous state of MTX within the complexes and intermolecular interactions.

Conclusions:

• Spray-dried amorphous inclusion complexes of MTX with DM-β-CD represent a promising oral formulation strategy.
• This approach effectively prevents MTX degradation and enhances its pharmacological properties.
• The developed ICs offer a viable solution for improving MTX's oral bioavailability and therapeutic efficacy.