Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Department of Pharmaceutics, Faculty of Pharmacy, Kuwait University, POB 24923, 13110, Safat, Kuwait.
AAPS PharmSciTech. 2020 Nov 22;22(1):6. doi: 10.1208/s12249-020-01872-0.
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.
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。
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