Abstract

A PEGylated Tween 80–functionalized chitosan–lipidic (PEG-T-Chito-Lip) nano-vesicular hybrid was developed for intranasal administration as an alternative delivery route to help improve the poor oral bioavailability of BCS class-III model/antiemetic (metoclopramide hydrochloride; MTC). The influence of varying levels of chitosan, cholesterol, PEG 600, and Tween 80 on the stability/release parameters of the formulated nanovesicles was optimized using Draper-Lin Design. Two optimized formulations (Opti-Max and Opti-Min) with both maximized and minimized MTC-release goals, were predicted, characterized, and proved their vesicular outline via light/electron microscopy, along with the mutual prompt/extended in-vitro release patterns. The dual-optimized MTC–loaded PEG-T-Chito-Lip nanovesicles were loaded in intranasal in-situ gel (ISG) and further underwent in-vivo pharmacokinetics/nose-to-brain delivery valuation on Sprague-Dawley rats. The absorption profiles in plasma (plasma-AUC_0-∞) of the intranasal dual-optimized MTC–loaded nano-vesicular ISG formulation in pretreated rats were 2.95-fold and 1.64-fold more than rats pretreated with orally administered MTC and intranasally administered raw MTC-loaded ISG formulation, respectively. Interestingly, the brain-AUC_0-∞ of the intranasal dual-optimized MTC–loaded ISG was 10 and 3 times more than brain-AUC_0-∞ of the MTC-oral tablet and the intranasal raw MTC-loaded ISG, respectively. It was also revealed that the intranasal dual-optimized ISG significantly had the lowest liver-AUC_0-∞ (862.19 ng.g⁻¹.h⁻¹) versus the MTC-oral tablet (5732.17 ng.g⁻¹.h⁻¹) and the intranasal raw MTC-loaded ISG (1799.69 ng.g⁻¹.h⁻¹). The brain/blood ratio profile for the intranasal dual-optimized ISG was significantly enhanced over all other MTC formulations (P < 0.05). Moreover, the 198.55% drug targeting efficiency, 75.26% nose-to-brain direct transport percentage, and 4.06 drug targeting index of the dual-optimized formulation were significantly higher than those of the raw MTC-loaded ISG formulation. The performance of the dual-optimized PEG-T-Chito-Lip nano-vesicular hybrids for intranasal administration evidenced MTC-improved bioavailability, circumvented hepatic metabolism, and enhanced brain targetability, with increased potentiality in heightening the convenience and compliance for patients.

摘要

开发了聚乙二醇化吐温 80-功能化壳聚糖-脂质 (PEG-T-Chito-Lip) 纳米囊泡杂化物用于鼻内给药，作为替代递送途径，以帮助改善 BCS III 类模型/止吐药（盐酸甲氧氯普胺）口服生物利用度差的问题; 技术中心）。使用 Draper-Lin Design 优化了不同水平的壳聚糖、胆固醇、PEG 600 和吐温 80 对配制的纳米囊泡的稳定性/释放参数的影响。预测、表征并通过光学/电子显微镜以及相互提示/扩展的体外实验证明了具有最大化和最小化 MTC 释放目标的两种优化制剂（Opti-Max 和 Opti-Min ）释放模式。将双重优化的 MTC 加载的 PEG-T-Chito-Lip 纳米囊泡加载到鼻内原位凝胶 (ISG) 中，并进一步对Sprague-Dawley 大鼠进行体内药代动力学/鼻-脑传递评估。鼻内双重优化 MTC 负载纳米囊泡 ISG 制剂在预处理大鼠血浆中的吸收曲线（血浆 AUC 0-∞ ）分别是口服 MTC 预处理大鼠和鼻内原始给药大鼠的 2.95 倍和1.64_倍分别加载 MTC 的 ISG 配方。有趣的是，鼻内双重优化的 MTC 负载 ISG 的脑 AUC _{0-∞是脑 AUC 0-∞}的 10 和 3 倍分别是 MTC 口服片剂和鼻内原始 MTC 加载的 ISG。还显示鼻内双重优化的 ISG 显着具有最低的肝 AUC _0-∞ (862.19 ng.g ^-1 .h ^-1 ) 与 MTC 口服片剂 (5732.17 ng.g ^-1 .h ^-1 ) 和鼻内原始 MTC 加载的 ISG (1799.69 ng.g ^-1 .h ^-1). 与所有其他 MTC 制剂相比，鼻内双重优化 ISG 的脑/血比例曲线显着增强 (P < 0.05)。此外，双重优化制剂的 198.55% 药物靶向效率、75.26% 的鼻-脑直接转运百分比和 4.06 的药物靶向指数均显着高于载有 MTC 的原始 ISG 制剂。用于鼻内给药的双重优化 PEG-T-Chito-Lip 纳米囊泡杂化物的性能证明了 MTC 提高了生物利用度、规避了肝脏代谢和增强了大脑靶向性，并增加了提高患者便利性和依从性的潜力。