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다양한 가용화 기술을 이용한 난용성 메토트렉세이트의 용해도, 생체이용률 및 광안정성 개선에 관한 연구

Title
다양한 가용화 기술을 이용한 난용성 메토트렉세이트의 용해도, 생체이용률 및 광안정성 개선에 관한 연구
Other Titles
Enhanced solubility, bioavailability and photostability of poorly water-soluble methotrexate using various solubilization techniques
Author
김동욱
Alternative Author(s)
Kim, Dong Wuk
Advisor(s)
최한곤
Issue Date
2015-08
Publisher
한양대학교
Degree
Doctor
Abstract
The purpose of this research was to compare the physicochemical properties, solubility, dissolution, oral bioavailability and photostability of various solubility-enhancing techniques to select the best drug delivery system with the highest oral bioavailability and excellent photostability of poorly water-soluble methotrexate. The solvent-evaporated solid dispersion and surface-attached solid dispersion were prepared with methotrexate/Na-CMC/SLS at the optimized ratio of 1/3/0.1 and 3/0.5/0.5 (w/w/w), respectively. Numerous inclusion compounds were formulated with methotrexate using β-cyclodextrin (β-CD), hydroxypropyl-β-CD, methyl-β-CD or dimethyl-β-CD as carrier matrices at 1:1 molecular ratio. The liquid self-microemulsifying drug delivery system (liquid SMEDDS) was composed of oil (castor oil), surfactant (Tween 80) and co-surfactant (plurol diisostearique) with methotrexate. The solid SMEDDS was prepared with the optimized liquid SMEDDS and inert carriers (silicon dioxide or calcium silicate). All solid state products were achieved by the spray-drying technique. Their physicochemical properties were examined by the SEM, DSC, PXRD, FTIR and particle size analyzer. Moreover, their aqueous solubility, dissolution and pharmacokinetics in rats were performed in comparison with the methotrexate powder. Moreover, their photostability was investigated under the forced degradation conditions. All the formulations significantly improved the solubility, dissolution and oral bioavailability of methotrexate as compared to the drug powder due to improved wetting, reduced particle size and conversion to the amorphous state. In particular, surface-attached solid dispersion, inclusion compound using dimethyl-β-CD, and SMEDDS using calcium silicate showed most enhanced bioavailability of the drug in each solubilization technique. In photostability study, solid dispersions and inclusion compounds exhibited the excellent photostability resulting from retained high drug contents in the testing period. However, the SMEDDS formulations demonstrated poor degradation similar to methotrexate powder. Accordingly, surface-attached solid dispersion and inclusion compound using dimethyl-β-CD could be potential drug delivery systems for oral administration of poorly water-soluble methotrexate with remarkably improved bioavailability and photostability.
URI
https://repository.hanyang.ac.kr/handle/20.500.11754/128084http://hanyang.dcollection.net/common/orgView/200000427247
Appears in Collections:
GRADUATE SCHOOL[S](대학원) > PHARMACY(약학과) > Theses (Ph.D.)
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