患者友好型、嗅觉靶向、刺激响应水凝胶用于脑部退行性疾病，确保在大鼠中达到 >400%的脑部靶向效率。

Patient-Friendly, Olfactory-Targeted, Stimuli-Responsive Hydrogels for Cerebral Degenerative Disorders Ensured > 400% Brain Targeting Efficiency in Rats.

机构信息

Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.

Department of Pharmaceutics, Faculty of Pharmacy, Kuwait University, POB 24923, 13110, Safat, Kuwait.

出版信息

AAPS PharmSciTech. 2020 Nov 22;22(1):6. doi: 10.1208/s12249-020-01872-0.

DOI:10.1208/s12249-020-01872-0

PMID:33222021

Abstract

Non-invasive brain therapy for chronic neurological disorders is in high demand. Vinpocetine (VIN) tablets for cerebrovascular degenerative disorders ensued < 7% oral bioavailability. The olfactory pathway (providing direct brain access) can improve VIN pharmacokinetic/pharmacodynamic profile. In this context, VIN hydrogels based on temperature-, pH-, and ion-triggered gelation in physiological milieu were formulated. Poloxamer-chitosan (PLX-CS) and carbopol-HPMC-alginate (CP-HPMC-SA) systems were optimized for appropriate gelation time, temperature, and pH. PLX-CS-hydrogels exhibited strong mucoadhesion for > 8 h, while CP-HPMC-SA hydrogels were mucoadhesive in simulated nasal fluid, owing to pH and ion-activated gelation. Along with prolonged mucosal residence, hydrogels confirmed sustained VIN release (> 24 h), especially from CP-HPMC-SA hydrogels. As proof of concept, brain exposure of intranasal VIN hydrogels was investigated in rats versus VIN-IV bolus. PLX-CS provided 146% increase in AUC and 3-fold maximum brain concentration (BC) relative to IV bolus. BC was reached after 4 h versus 1 h (IV bolus). CP-HPMC-SA hydrogel showed superior brain targeting efficiency (460%) and brain direct transport percentage (78.23%). VIN plasma pharmacokinetics confirmed 45-60% reduction in AUC versus IV bolus, while PC of CP-HPMC-SA and PLX-CS represented 17 and 28% that of IV bolus, respectively. Olfactory-targeted hydrogels grant effective, sustainable VIN brain level with minimal systemic exposure, thus, assuring lower dose, dose frequency, side effects, and per se better patient compliance.

摘要

用于慢性神经疾病的非侵入性脑治疗需求很高。用于脑血管退行性疾病的长春西汀（VIN）片剂口服生物利用度<7%。嗅觉途径（提供直接的大脑通路）可以改善 VIN 的药代动力学/药效学特征。在这种情况下，基于温度、pH 和离子触发凝胶化在生理环境中的 VIN 水凝胶被配方化。泊洛沙姆-壳聚糖（PLX-CS）和卡波姆-HPMC-海藻酸钠（CP-HPMC-SA）系统被优化为适当的凝胶时间、温度和 pH。PLX-CS 水凝胶表现出>8 小时的强黏膜黏附性，而 CP-HPMC-SA 水凝胶在模拟鼻液中具有黏膜黏附性，这是由于 pH 和离子激活凝胶化。随着黏膜停留时间的延长，水凝胶证实了 VIN 的持续释放（>24 小时），特别是 CP-HPMC-SA 水凝胶。作为概念验证，研究了与 VIN-IV 推注相比，鼻内 VIN 水凝胶在大鼠中的脑暴露。PLX-CS 相对于 IV 推注增加了 146%的 AUC 和 3 倍的最大脑浓度（BC）。BC 在 4 小时后达到，而 IV 推注则在 1 小时后达到。CP-HPMC-SA 水凝胶显示出优越的脑靶向效率（460%）和脑直接转运百分比（78.23%）。VIN 血浆药代动力学证实相对于 IV 推注，AUC 降低了 45-60%，而 CP-HPMC-SA 和 PLX-CS 的 PC 分别代表 IV 推注的 17%和 28%。嗅觉靶向水凝胶可确保最低的剂量、剂量频率、副作用和患者本身更好的顺应性，从而提供有效的、可持续的 VIN 脑水平，同时最大限度地减少全身暴露。