Department of Pharmacy, University of Pisa, Via Bonanno 33, 56126 Pisa, Italy.
Department of Chemistry and Industrial Chemistry, University of Pisa, UdR INSTM Pisa, Via Moruzzi 13, 56124 Pisa, Italy.
Eur J Pharm Biopharm. 2018 Sep;130:281-289. doi: 10.1016/j.ejpb.2018.07.010. Epub 2018 Jul 10.
Nanoparticles (NP) only different in mucoadhesivity are compared for impact on drug oral bioavailability. Two polymeric NP types based on quaternary ammonium-chitosan (NP QA-Ch) and S-protected thiolated derivative thereof (NP QA-Ch-S-pro), respectively, containing the macromolecular drug model, FD4, were prepared by crosslinking each polymer with reduced MW hyaluronic acid. The structure of basic polymers was determined by HNMR analysis. NP were similar in size (371 ± 38 vs. 376 ± 82 nm); polydispersity index (0.39 ± 0.08 vs. 0.41 ± 0.10); zeta potential (13.4 ± 0.9 vs. 11.9 ± 1.2 mV); reversible interactions with drug (bound drug, 67 vs. 66%); encapsulation efficiency (23 ± 5 vs. 23 ± 8%); release properties (15% released in 15 h in both cases); and apparent permeation across excised rat intestine (P, 8.8 ± 0.8 vs. 10 ± 1 cm/s). Then the differences in NP transport ratio through mucus (TR, 0.75 vs. 0.37) and adhesion to excised rat intestinal mucosa (adsorbed fraction, 23 ± 3 vs. 45 ± 2%) were ascribed to higher mucoadhesivity of NP QA-Ch-S-pro compared to NP QA-Ch. This directly influenced drug oral bioavailability in rats (T, 1 vs. 2 h; AUC, 1.7 ± 0.3 vs. 2.9 ± 0.4 μg/mL min, for NP QA-Ch and NP QA-Ch-S-pro, respectively). Mucoadhesivity increases drug bioavailability by retaining NP at its absorption site and opposing its transit down the GI tract. Data on drug accumulation in rat liver allows the assertion that NP is absorbed by transcytosis across intestinal epithelium and transported from blood into liver by Kuppfer cells.
仅在黏膜黏附性方面存在差异的纳米颗粒（NP）被用于比较它们对药物口服生物利用度的影响。两种基于季铵化壳聚糖（NP QA-Ch）和 S-保护的巯基化衍生物（NP QA-Ch-S-pro）的聚合物 NP 分别通过用低分子量透明质酸还原交联每种聚合物而制备，其中包含大分子药物模型 FD4。基本聚合物的结构通过 HNMR 分析确定。NP 在大小（371±38 与 376±82nm）、多分散指数（0.39±0.08 与 0.41±0.10）、ζ 电位（13.4±0.9 与 11.9±1.2mV）、与药物的可逆相互作用（结合药物，67 与 66%）、包封效率（23±5 与 23±8%）、释放特性（两种情况下 15h 内释放 15%）和离体大鼠肠的表观渗透（P，8.8±0.8 与 10±1cm/s）方面相似。然后，NP 通过黏液的转运率（TR，0.75 与 0.37）和与离体大鼠肠黏膜的黏附（吸附分数，23±3 与 45±2%）的差异归因于 NP QA-Ch-S-pro 比 NP QA-Ch 具有更高的黏膜黏附性。这直接影响了大鼠的药物口服生物利用度（T，1 与 2h；AUC，1.7±0.3 与 2.9±0.4μg/mL min，对于 NP QA-Ch 和 NP QA-Ch-S-pro）。黏膜黏附性通过保留 NP 在吸收部位并阻止其在胃肠道中转运来增加药物的生物利用度。在大鼠肝脏中药物积累的数据允许断言 NP 通过肠上皮细胞的转胞吞作用被吸收，并通过库普弗细胞从血液中运输到肝脏。
