Pharmacokinetic control of orally dosed cyclosporine A with mucosal drug delivery system

IF 1.7 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Kohei Yamada, Kurt D. Ristroph, Yuuki Kaneko, Hoang D. Lu, Robert K. Prud’homme, Hideyuki Sato, Satomi Onoue
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引用次数: 0

Abstract

This study aimed to control the oral absorption of cyclosporine A (CsA) with the use of a mucosal drug delivery system (mDDS). Mucopenetrating nanocarriers (MP/NCs) and mucoadhesive nanocarriers (MA/NCs) were prepared by flash nanoprecipitation employing polystyrene-block-poly(ethylene glycol) and polystyrene-block-poly(N,N-dimethyl aminoethyl methacrylate), respectively. Their particle distribution in the rat gastrointestinal tract were visualized by fluorescent imaging. Plasma concentrations were monitored after oral administration of CsA-loaded MP/NCs (MP/CsA) and MA/NCs (MA/CsA) to rats. MP/NCs and MA/NCs had a particle size below 200 nm and ζ-potentials of 4 and 40 mV, respectively. The results from in vitro experiments demonstrated mucopenetration of MP/NCs and mucoadhesion of MA/NCs. Confocal laser scanning microscopic images showed diffusion of MP/NCs in the gastrointestinal mucus towards epithelial cells and localization of MA/NCs on the surface of the gastrointestinal mucus layer. In a pH 6.8 solution, rapid and sustained release of CsA were observed for MP/CsA and MA/CsA, respectively. After oral dosing (10 mg-CsA/kg) to rats, amorphous CsA powder exhibited a time to maximum plasma concentration (Tmax) of 3.4 h, maximum plasma concentration (Cmax) of 0.12 μg/mL, and bioavailability of 0.7%. Compared with amorphous CsA powder, MP/CsA shortened Tmax by 1.1 to 2.3 h and increased the bioavailability by 43-fold to 30.1%, while MA/CsA prolonged Tmax by 3.4 to 6.8 h with Cmax and bioavailability of 0.65 μg/mL and 11.7%, respectively. These pharmacokinetic behaviors would be explained by their diffusion and release properties modulated by polymeric surface modification. The mDDS approach is a promising strategy for the pharmacokinetic control of orally administered CsA.

利用粘膜给药系统控制口服环孢素 A 的药代动力学。
本研究旨在利用粘膜给药系统(mDDS)控制环孢素A(CsA)的口服吸收。研究分别采用聚苯乙烯-块状聚(乙二醇)和聚苯乙烯-块状聚(N,N-二甲基氨基乙基甲基丙烯酸酯)闪蒸纳米沉淀法制备了粘膜渗透性纳米载体(MP/NCs)和粘膜黏附性纳米载体(MA/NCs)。通过荧光成像观察了它们在大鼠胃肠道中的颗粒分布。大鼠口服 CsA 负载 MP/NCs (MP/CsA)和 MA/NCs (MA/CsA)后,对血浆浓度进行了监测。MP/NCs 和 MA/NCs 的粒径小于 200 nm,ζ电位分别为 4 mV 和 40 mV。体外实验结果表明,MP/NCs 具有粘液渗透性,MA/NCs 具有粘液粘附性。共焦激光扫描显微镜图像显示,MP/NCs 在胃肠粘液中向上皮细胞扩散,MA/NCs 定位于胃肠粘液层表面。在 pH 值为 6.8 的溶液中,观察到 MP/CsA 和 MA/CsA 分别快速和持续释放 CsA。大鼠口服(10 毫克-CsA/千克)无定形 CsA 粉末后,达到最大血浆浓度(Tmax)的时间为 3.4 小时,最大血浆浓度(Cmax)为 0.12 微克/毫升,生物利用度为 0.7%。与无定形 CsA 粉相比,MP/CsA 的 Tmax 缩短了 1.1 到 2.3 小时,生物利用度提高了 43 倍,达到 30.1%;而 MA/CsA 的 Tmax 延长了 3.4 到 6.8 小时,Cmax 和生物利用度分别为 0.65 μg/mL 和 11.7%。这些药代动力学行为可通过聚合物表面修饰调节其扩散和释放特性来解释。mDDS 方法是口服 CsA 药代动力学控制的一种有前途的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
3.60
自引率
0.00%
发文量
35
审稿时长
6-12 weeks
期刊介绍: Biopharmaceutics & Drug Dispositionpublishes original review articles, short communications, and reports in biopharmaceutics, drug disposition, pharmacokinetics and pharmacodynamics, especially those that have a direct relation to the drug discovery/development and the therapeutic use of drugs. These includes: - animal and human pharmacological studies that focus on therapeutic response. pharmacodynamics, and toxicity related to plasma and tissue concentrations of drugs and their metabolites, - in vitro and in vivo drug absorption, distribution, metabolism, transport, and excretion studies that facilitate investigations related to the use of drugs in man - studies on membrane transport and enzymes, including their regulation and the impact of pharmacogenomics on drug absorption and disposition, - simulation and modeling in drug discovery and development - theoretical treatises - includes themed issues and reviews and exclude manuscripts on - bioavailability studies reporting only on simple PK parameters such as Cmax, tmax and t1/2 without mechanistic interpretation - analytical methods
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