Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China.
Department of Gastroenterology, Qingdao municipal hospital, Qingdao University, Qingdao 266011, China.
Mater Sci Eng C Mater Biol Appl. 2020 Jul;112:110926. doi: 10.1016/j.msec.2020.110926. Epub 2020 Apr 12.
In the study described here, we strove to develop an orally administered novel self-nanomicellizing formulation based on Rebaudioside A (RA) for delivering naringenin (NAR) with improved bioavailability and therapeutic efficacy. Our research found that RA and naringenin (NAR) could be formulated into self-assembling nanomicelles (RA-NAR) using a simple ethanol dissolution-evaporation method. We found that the RA-NAR self-assemblies comprised ultra-small micelles (5.234 ± 0.311 nm) in a uniform dispersion state (the polydispersity index was 0.243 ± 0.039) with a near-neutral surface charge (-[2.268 ± 0.729] mV). We also found that RA-NAR had a well-storage stability at 4 °C with light protection. In addition, we observed that RA-NAR exhibited enhanced apparent solubility, in-vitro permeability, and antioxidant activity. After we administered RA-NAR to rats orally, we observed an increase in area under the curve (AUC) to 19,500.82 ng/mL/h versus 9324.47 ng/mL/h observed with free NAR and an increase of maximum concentration (Cmax) to 27,326.10 ng/mL from the free-NAR Cmax level of 2549.04 ng/mL. The tissue distribution assessments further demonstrated that RA-NAR could effectively increase the NAR concentration in all tested intestinal segments. Our mouse model results showed as well that oral administration of RA-NAR could efficiently protect against small intestine injuries induced by indomethacin, and the mechanisms by inhibiting proinflammatory cytokines and oxidative stress were involved in its therapeutic effect. Taken together, these findings indicate that a self-nanomicellizing formulation based on RA has great potential as a novel oral nano-drug delivery system for NAR.
在本研究中，我们致力于开发一种基于甜菊糖甙 A (Rebaudioside A, RA) 的新型口服自纳米胶束制剂，用于递送柚皮苷 (Naringenin, NAR)，以提高其生物利用度和治疗效果。我们的研究发现，RA 和柚皮苷 (NAR) 可以通过简单的乙醇溶解-蒸发法制成自组装纳米胶束 (RA-NAR)。我们发现，RA-NAR 自组装体由超小的胶束（5.234 ± 0.311nm）组成，处于均匀分散状态（多分散指数为 0.243 ± 0.039），表面带负电荷（-[2.268 ± 0.729] mV）。我们还发现，RA-NAR 在 4°C 避光条件下具有良好的储存稳定性。此外，我们观察到 RA-NAR 具有增强的表观溶解度、体外渗透性和抗氧化活性。当我们给大鼠口服 RA-NAR 后，我们观察到 AUC 从游离 NAR 的 9324.47ng/mL/h 增加到 19500.82ng/mL/h，Cmax 从游离 NAR 的 2549.04ng/mL 增加到 27326.10ng/mL。组织分布评估进一步表明，RA-NAR 可以有效地增加所有测试肠道段中 NAR 的浓度。我们的小鼠模型结果也表明，口服 RA-NAR 可以有效保护吲哚美辛诱导的小肠损伤，其治疗作用涉及抑制促炎细胞因子和氧化应激。综上所述，这些发现表明，基于 RA 的自纳米胶束制剂具有作为 NAR 新型口服纳米药物递送系统的巨大潜力。
