Alternative Methotrexate Oral Formulation: Enhanced Aqueous Solubility, Bioavailability, Photostability, and Permeability
- Title
- Alternative Methotrexate Oral Formulation: Enhanced Aqueous Solubility, Bioavailability, Photostability, and Permeability
- Author
- 최한곤
- Keywords
- inclusion complex; methotrexate; solubility; bioavailability; permeability; beta-cyclodextrin (beta-CD)
- Issue Date
- 2022-10
- Publisher
- MDPI
- Citation
- PHARMACEUTICS, v. 14, NO. 10, article no. 2073,
- Abstract
- The poor aqueous solubility and/or permeability and thereby limited bioavailability largely restricts the pharmaco-therapeutic implications of potent anticancer drugs such as methotrexate (MTX). Furthermore, MTX's inherently unstable nature makes it difficult to develop a viable oral formulation. In this study we developed the spray-dried amorphous inclusion complexes of MTX with native beta-cyclodextrin (beta-CD) and its derivatives, namely HP-beta-CD, M-beta-CD, and DM-beta-CD to enhance the aqueous solubility, photostability, permeability, and oral bioavailability of MTX in rats. Our findings show that the 1:1 stoichiometry ratio of MTX and CDs improves the aqueous solubility, stability, and pharmacokinetic profiles of the drug, the better results being obtained particularly with DM-beta-CD as a host, which has a higher complexation ability with the drug compared to other beta-CDs. Specifically, the pharmacokinetic analysis demonstrated 2.20- and 3.29-fold increments in AUC and Cmax, respectively, in comparison to free MTX. Even though the absorptive permeability of MTX and MTX/DM-beta-CD inclusion complexes was similar, the efflux of the absorbed MTX from ICs was significantly lower compared to the free MTX (4.6- vs. 8.0-fold). Furthermore, the physicochemical characterization employing SEM, DSC, and PXRD confirmed the transformation of crystalline MTX to its amorphous state. In solution, H-1 NMR studies revealed that MTX embedded into the DM-beta-CD cavity resulting in both H-3 and H-5 chemical shifts implied the presence of intermolecular interaction between the drug and CD moiety. It was, therefore, evident that an MTX IC could be a successful oral formulation technique, preventing MTX degradation and enhancing its pharmacologically relevant properties.
- URI
- https://www.mdpi.com/1999-4923/14/10/2073https://repository.hanyang.ac.kr/handle/20.500.11754/182304
- ISSN
- 1999-4923;1999-4923
- DOI
- 10.3390/pharmaceutics14102073
- Appears in Collections:
- COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
- Files in This Item:
- 97263_최한곤.pdfDownload
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