Abstract：
Verapamil hydrochloride (VRP), an antihypertensive calcium channel blocker drug has limited bioavailability and short half-life when taken orally. The present study was aimed at developing cubosomes containing VRP for enhancing its bioavailability and targeting to brain for cluster headache (CH) treatment as an off-label use. Factorial design was conducted to analyze the impact of different components on entrapment efficiency (EE%), particle size (PS), zeta potential (ZP), and percent drug release. Various in-vitro characterizations were performed followed by pharmacokinetic and brain targeting studies. The results revealed the significant impact of glyceryl monooleate (GMO) on increasing EE%, PS, and ZP of cubosomes with a negative influence on VRP release. The remarkable effect of Poloxamer 407 (P407) on decreasing EE%, PS, and ZP of cubosomes was observed besides its influence on accelerating VRP release%. The DSC thermograms indicated the successful entrapment of the amorphous state of VRP inside the cubosomes. The design suggested an optimized formulation containing GMO (50% w/w) and P407 (5.5% w/w). Such formulation showed a significant increase in drug permeation through nasal mucosa with high Er value (2.26) when compared to VRP solution. Also, the histopathological study revealed the safety of the utilized components used in the cubosomes preparation. There was a significant enhancement in the VRP bioavailability when loaded in cubosomes owing to its sustained release favored by its direct transport to brain. The I.N optimized formulation had greater BTE% and DTP% at 183.53% and 90.19%, respectively in comparison of 41.80% and 59% for the I.N VRP solution.
摘要：
盐酸维拉帕米(VRP),抗高血压钙通道阻滞剂药物口服时生物利用度有限且半衰期短.本研究旨在开发含有VRP的立方体，以增强其生物利用度并针对大脑进行丛集性头痛（CH）治疗，作为标签外使用。进行因子设计以分析不同组分对包封效率（EE%）的影响，粒度(PS),zeta电位(ZP),和药物释放百分比。进行各种体外表征，然后进行药代动力学和脑靶向研究。结果表明，单油酸甘油酯（GMO）对增加EE%的显著影响，PS,对VRP释放有负面影响的立方体的ZP。泊洛沙姆407(P407)对降低EE%的显著效果,PS,除了对加速VRP释放%的影响外，还观察到立方体的ZP。DSC热谱图表明VRP的无定形状态成功截留在立方体内。该设计提出了含有GMO(50%w/w)和P407(5.5%w/w)的优化制剂。当与VRP溶液相比时,这种制剂显示出药物通过鼻粘膜的渗透显著增加,具有高Er值(2.26)。此外，组织病理学研究揭示了立方体制备中所用成分的安全性。当装载在立方体中时，VRP的生物利用度显着提高，这归因于其直接转运到大脑的持续释放。I.N优化配方在183.53%和90.19%时具有更大的BTE%和DTP%,I.NVRP溶液分别为41.80%和59%。
