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Enhancement of oral bioavailability and Anti-Parkinsonian Efficacy of resveratrol through a nanocrystal formulation

Asian Journal of Pharmaceutical Sciences 2020年第4期15卷 518-528页

作者： Sha Xiong Wei Liu Yile Zhou Yousheng Mo Yao Liu Xiaojia Chen Huafeng Pan Dongsheng Yuan QiWang Tongkai Chen Institute of Clinical Pharmacology Guangzhou University of Chinese MedicineGuangzhou 510405China Institute of Chinese Medical Sciences University of MacaoMacaoChina

Resveratrol(RES),a non-flavonoid polyphenol extracted from a wide variety of plants,exhibits neuroprotective activities against Parkinson’s disease(PD).However,undesirable water solubility of RES reduces its oral bioavailability and demonstrates lowefficacy in blood and brain,thus limiting its application.In present study,a nanocrystal formulation of RES(RES-NCs)was developed to enhance its oral bioavailability and delivery into brain for PD treatment.RES-NCs were fabricated with hydroxypropyl methylcellulose(HPMC)stabilizer via antisolvent precipitation approach.The obtained RES-NCs displayed the particle size of 222.54±1.66 nm,the PDI of 0.125±0.035,the zeta potential of−9.41±0.37mV,and a rapid in vitro dissolution rate.Molecular dynamics simulation of RES and HPMC revealed an interaction energy of−68.09 kJ/mol and a binding energy of−30.98±0.388 kJ/mol,indicating that the spontaneous binding between the two molecules is through van der Waals forces.RES-NCs conferred enhanced cellular uptake as well as improved permeability relative to pure RES.In addition,RES-NCs were able to protect neurons against cytotoxicity induced by MPP+.Meanwhile,RES-NCs exerted no significant toxic effects on zebrafish embryos and larvae,and did not influence their survival and hatching rates.When orally administered to rats,RES-NCs exhibited more favorable pharmacokinetics than pure RES,with higher plasma and brain concentrations.More importantly,MPTP-induced PD mice showed notable improvements in behavior,attenuated dopamine deficiency,and elevated levels of dopamine and its metabolites after the treatment with RES-NCs.Furthermore,immunoblot analysis revealed that the neuroprotective role of RES-NCsmay be at least partially mediated by Akt/Gsk3βsignaling pathway.Taken altogether,RES-NCs can serve as a potential treatment modality for PD,offering means of improving RES oral bioavailability and brain accumulation.

关键词： Nanocrystals Resveratrol Oral absorption Brain permeability Anti-Parkinsonian Efficacy

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Enhancement of Oral Bioavailability and Anti-Parkinsonian Efficacy of Resveratrol by a Nanocrystal Formulation

Enhancement of Oral Bioavailability and Anti-Parkinsonian Ef...

引用

2018年第十二届中国药物制剂大会

作者：熊莎 Wei Liu Xiaojia Chen Qi Wang Dongsheng Yuan Tongkai Chen Institute of Clinical Pharmacology Guangzhou University of Chinese Medicine State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macau

Resveratrol（RES）, a non-flavonoid polyphenol extracted from a wide variety of plants, possesses neuroprotective activity for the treatment of Parkinson’s disease（PD）. However, the poor water solubility of RES results in low oral bioavailability, which causes low exposure of RES in the blood and brain, and limits its Anti-Parkinsonian Efficacy and clinical application. In this study, a nanocrystal formulation of RES（RESNCs） was developed to improve its solubility and oral bioavailability and thus to treat PD. The RES-NCs were fabricated using an anti-solvent precipitation approach where hydroxypropyl methylcellulose（HPMC） was optimized as the stabilizer. The obtained RES-NCs had a particle size of 222.54 ± 1.66 nm with a PDI of 0.12 ± 0.03, and the RES-NCs exhibited a fast dissolution rate in vitro. Differential scanning calorimetry（DSC） and powder X-ray diffraction（PXRD） results demonstrated that the RES was maintained in the crystalline state in the fabricated nanocrystals. Molecular dynamics simulation of RES and HPMC exhibited an interaction and binding energy of-68.09 kJ/mol and-30.98 ± 0.388 kJ/mol, respectively with van der Waals interactions in the spontaneous binding. The cellular uptake and permeability of RES-NCs were much higher than those of the raw RES in Madin-Darby Canine Kidney（MDCK） cells（p＜0.01）. In addition, the RES-NCs afforded a significant neuroprotective effect against 1-methyl-4-phenylpyridinium ion（MPP+）-induced damage in SH-SY5 Y cells. Meanwhile, the zebrafish embryos and larvae treated with RES-NCs did not show any obvious toxic effects during the entire experiment. When RES-NCs were orally administrated to rats, the drug was absorbed quickly and a maximum plasma concentration of 2.97 ± 0.46 μg/ml was reached in 2.11 ± 0.05 h. Compared to the unformulated RES, the Cmax and AUC0-24 h of RES-NCs were increased nearly 3.09-and 3.52-fold, respectively, indicating that the RES-NCs could effectively enhance RES oral absorption. The RES-NCs also resulted in markedly higher brain Cmax and AUC0

关键词： Nanocrystals Resveratrol Oral bioavailability Anti-Parkinsonian Efficacy Parkinson’s disease

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