Alternative Methotrexate Oral Formulation: Enhanced Aqueous Solubility, Bioavailability, Photostability, and Permeabilityopen access
- Authors
- Giri, Bhupendra Raj; Yang, Hyun Seok; Song, Im-Sook; Choi, Han-Gon; Cho, Jung Hyun; Kim, Dong Wuk
- Issue Date
- Oct-2022
- Publisher
- Multidisciplinary Digital Publishing Institute (MDPI)
- Keywords
- inclusion complex; methotrexate; solubility; bioavailability; permeability; beta-cyclodextrin (beta-CD)
- Citation
- Pharmaceutics, v.14, no.10, pp 1 - 21
- Pages
- 21
- Indexed
- SCIE
SCOPUS
- Journal Title
- Pharmaceutics
- Volume
- 14
- Number
- 10
- Start Page
- 1
- End Page
- 21
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/111496
- DOI
- 10.3390/pharmaceutics14102073
- ISSN
- 1999-4923
- 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.
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