Department of Pharmacognosy, Faculty of Pharmacy, Poznan University of Medical Sciences, Swiecickiego 4, 60-781 Poznan, Poland.
Department of Biopharmacy, Faculty of Pharmacy, Medical University of Lublin, Chodzki 4a, 20-093 Lublin, Poland.
Int J Mol Sci. 2022 Jan 11;23(2):755. doi: 10.3390/ijms23020755.
Naringenin (NAR) is a flavonoid with excellent antioxidant and neuroprotective potential that is limited by its low solubility. Thus, solid dispersions with β-cyclodextrin (β-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD), hydroxypropylmethylcellulose (HPMC), and microenvironmental pH modifiers were prepared.
The systems formation analysis was performed by X-Ray Powder Diffraction (XRPD) and Fourier-transform infrared spectroscopy (FT-IR). Water solubility and dissolution rates were studied with a pH of 1.2 and 6.8. In vitro permeability through the gastrointestinal tract (GIT) and the blood-brain barrier (BBB) was assessed with the parallel artificial membrane permeability assay (PAMPA) assay. The antioxidant activity was studied with the 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and cupric ion reducing antioxidant capacity (CUPRAC) assays, while in vitro enzymes studies involved the inhibition of acetylcholinesterase, butyrylcholinesterase, and tyrosinase. For the most promising system, in silico studies were conducted.
NAR solubility was increased 458-fold by the solid dispersion NAR:HP-β-CD:NaHCO in a mass ratio of 1:3:1. The dissolution rate was elevated from 8.216% to 88.712% in a pH of 1.2 and from 11.644% to 88.843% in a pH of 6.8 (within 3 h). NAR GIT permeability, described as the apparent permeability coefficient, was increased from 2.789 × 10 cm s to 2.909 × 10 cm s in an acidic pH and from 1.197 × 10 cm s to 2.145 × 10 cm s in a basic pH. NAR BBB permeability was established as 4.275 × 10 cm s. The antioxidant activity and enzyme inhibition were also increased. Computational studies confirmed NAR:HP-β-CD inclusion complex formation.
A significant improvement in NAR solubility was associated with an increase in its biological activity.
柚皮素（NAR）是一种具有出色抗氧化和神经保护潜力的类黄酮，但由于其溶解度低，其应用受到限制。因此，制备了包含β-环糊精（β-CD）、羟丙基-β-环糊精（HP-β-CD）、羟丙基甲基纤维素（HPMC）和微环境 pH 调节剂的固体分散体。
通过 X 射线粉末衍射（XRPD）和傅里叶变换红外光谱（FT-IR）对系统形成进行分析。在 pH 值为 1.2 和 6.8 时，研究了水溶解度和溶解速率。通过平行人工膜渗透测定法（PAMPA）测定了胃肠道（GIT）和血脑屏障（BBB）的体外渗透性。采用 2,2'-联氮-双（3-乙基苯并噻唑啉-6-磺酸）（ABTS）和铜离子还原抗氧化能力（CUPRAC）测定法研究了抗氧化活性，而体外酶研究则涉及乙酰胆碱酯酶、丁酰胆碱酯酶和酪氨酸酶的抑制作用。对于最有前途的系统，进行了计算机模拟研究。
NAR：HP-β-CD：NaHCO 的质量比为 1:3:1 的固体分散体使 NAR 的溶解度增加了 458 倍。在 pH 值为 1.2 时，溶解速率从 8.216%提高到 88.712%，在 pH 值为 6.8 时，从 11.644%提高到 88.843%（3 小时内）。NAR 在胃肠道中的通透性，以表观渗透系数表示，在酸性 pH 下从 2.789×10-6cm s-1 增加到 2.909×10-6cm s-1，在碱性 pH 下从 1.197×10-6cm s-1 增加到 2.145×10-6cm s-1。NAR 对 BBB 的通透性为 4.275×10-6cm s-1。抗氧化活性和酶抑制作用也有所提高。计算研究证实了 NAR：HP-β-CD 包合物的形成。
NAR 溶解度的显著提高与生物活性的增加有关。
