Development and Evaluation of Cucurbitacin B Microemulsion: the Effect of Oil Phase and Aqueous Phase on Drug Percutaneo
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Research Article Development and Evaluation of Cucurbitacin B Microemulsion: the Effect of Oil Phase and Aqueous Phase on Drug Percutaneous Absorption Based on ATR-FTIR Spectroscopy and Molecular Modeling Qi Tian,1 Jianbo Guo,2 Qi Zhang,3 Liang Fang,1 Chao Liu,1,4 and Hui Xu1,4
Received 1 July 2020; accepted 18 August 2020 Abstract.
The present study aimed to develop a cucurbitacin B microemulsion (CuB-ME) and investigate the mechanism of the enhanced drug skin absorption at the molecular level. Firstly, the pseudo-ternary phase diagrams were developed to evaluate the effect of composition on microemulsion properties systematically. The formulation composition types and ratios of oil phase, surfactant, co-surfactant, and aqueous phase were optimized by an in vitro skin permeation experiment, and the optimized formula was confirmed with the pharmacodynamics study. Furthermore, the molecular mechanism of enhanced skin permeation was investigated using ATR-FTIR and molecular modeling. As a result, the optimized CuB-ME formulation was composed of Azone:Tween 80:ethanol:water = 2.5:16.9:5.6:75.0 (w/w/w/w). The oil phase improved skin permeation by disordering the stratum corneum intercellular liquid, while the aqueous phase impacted the particle size of the microemulsion and permeability coefficient of the drug. Besides, the hydration state of skin lipid also enhanced drug permeation by the interaction of water and the polar head of ceramide. The in vitro skin permeation amount was 45.47 ± 10.39 μg/cm2, and no significant skin irritation was observed. The pharmacodynamics study demonstrated that CuB-ME had a significant therapeutic effect on the animal tumor model. In conclusion, the CuB-ME was developed successfully and the effect of the oil phase and aqueous phase on drug skin permeation was clarified at the molecular level. KEY WORDS: cucurbitacin B; microemulsion; tumor; skin permeation; Azone; water.
INTRODUCTION Cancer is a high-frequency disease nowadays. The characteristics of cancer include sustaining proliferative growth, evading growth suppressors, resisting cell death, and activating invasion and metastasis, which make cancer one of the leading causes of death all over the world (1,2). Cancer can be surgically removed or treated with chemotherapy and radiotherapy in combination. These therapies have shown satisfactory results in clinical treatment (3–5). However, systemic anti-cancer treatment (SACT) has resulted in wide and acute toxicities, such as neutropenic sepsis, diarrhea, nausea, and vomiting, which can be life threatening (6). The 1
School of Pharmacy, Shenyang Pharmaceutical University, No. 26 Huatuo Road, High & New Technology Development Zone, Benxi, 117004, Liaoning, China. 2 Shanxi Institute for Food and Drug Control, Xi’an, 710065, Shanxi, China. 3 Department of General Surgery, General Hospital of Benxi Iron and Steel CO. LTD, Benxi, 117000, Liaoning, China. 4 To whom correspondence should be addressed. (e–mail: [email protected]; [email protected])
improvement of life quality and prolong
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