Laboratory of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
Department of Chemical & Biological Engineering, Princeton University, Princeton, New Jersey 08544.
J Pharm Sci. 2020 Feb;109(2):1079-1085. doi: 10.1016/j.xphs.2019.10.043. Epub 2019 Nov 4.
The present study develops cyclosporine A (CsA)-loaded polymeric nanocarriers with mucus-diffusive and mucus-adhesive potential to control pharmacokinetic behavior after oral administration for the treatment of inflammatory bowel diseases (IBD). CsA-loaded nanocarriers consisting of polystyrene-block-polyethylene glycol (PEG-CsA) and polystyrene-block-polyacrylic acid (PAA-CsA) were prepared by a flash nanoprecipitation. Both nanocarriers showed redispersibility from lyophilized powder back to uniform nanocarrier with a mean diameter of approximately 150 nm. The nanocarriers exhibited significantly improved release behavior of CsA under pH 6.8 condition compared. A test of mucodiffusion, using artificial mucus, demonstrated the mucus-diffusive and mucus-adhesive potential of PEG-CsA and PAA-CsA, respectively, dependent on the lack of electrostatic interactions between the surface-coated polymer and mucin. Oral administrations of PEG-CsA and PAA-CsA (10 mg-CsA/kg) in rats resulted in significant improvements of absorption, as evidenced by 50- and 25-fold higher bioavailability than crude CsA, respectively. PAA-CsA exhibited more sustained and slower absorption process of CsA than PEG-CsA because of the different diffusion behavior within the mucus layer. In the rat model of IBD, significant suppression of inflammatory symptoms could be achieved by oral treatment with both CsA nanoparticles. These polymeric nanocarriers are promising dosage options to control pharmacokinetic behavior of orally dosed CsA, contributing to the development of safe and effective treatment for IBD.
本研究开发了载环孢素 A（CsA）的聚合物纳米载体，具有粘液扩散和粘液粘附潜力，以控制口服给药后用于治疗炎症性肠病（IBD）的药代动力学行为。由聚苯乙烯嵌段聚乙二醇（PEG-CsA）和聚苯乙烯嵌段聚丙烯酸（PAA-CsA）组成的 CsA 载纳米载体通过闪蒸纳米沉淀法制备。两种纳米载体均表现出从冻干粉末重新分散为平均直径约为 150nm 的均匀纳米载体的再分散能力。纳米载体在 pH6.8 条件下表现出显著改善的 CsA 释放行为。使用人工粘液进行的粘液扩散测试分别证明了 PEG-CsA 和 PAA-CsA 的粘液扩散和粘液粘附潜力，这取决于表面涂覆聚合物与粘蛋白之间缺乏静电相互作用。在大鼠中口服给予 PEG-CsA 和 PAA-CsA（10mg-CsA/kg）导致吸收显著改善，生物利用度分别比原药 CsA 高 50 倍和 25 倍。由于在粘液层内的扩散行为不同，PAA-CsA 表现出比 PEG-CsA 更持续和更慢的 CsA 吸收过程。在 IBD 大鼠模型中，通过口服给予 CsA 纳米粒子可以显著抑制炎症症状。这些聚合物纳米载体是控制口服给予 CsA 的药代动力学行为的有前途的剂型选择，有助于开发安全有效的 IBD 治疗方法。
