“Exploring the Potential of Ferulic Acid loaded Nanostructured Lipid Carriers: Angiotensin Inhibition via Docking, Formulation, and Pharmacokinetic and Pharmacodynamics Studies”

Ferulic acid (FA) is a phenolic compound obtained naturally and is a versatile antioxidant identified for its potential in managing hypertension. However, its application is constrained due to its classification as a BCS Class IV moiety. To address this, we concentrated on improving its solubility and permeability by developing nanostructured lipid carriers (NLCs) of FA using emulsification probe sonication technique. Lipids stearic acid and Labrasol, surfactant Tween 80, and sonication time were adopted for the formulation studies, with optimization utilizing Box-Behnken design. The FA-NLCs were evaluated for particle size, zeta potential, PDI, entrapment efficiency, and in vitro release. Pharmacokinetic and intestinal uptake studies were carried out on male Wistar rats. Pharmacodynamic studies were performed using the high fructose diet model for hypertension in Sprague Dawley rats. In-silico studies, exposed a strong interaction between FA and ACE receptor (1UZF), with docking score of -7.144 kcal/mol and binding energy of -54.624 kcal/mol. Optimized formulation (F12 FA-NLC) established a particle size of 103.4 ± 8.89 nm, zeta potential of −43.6 mV, polydispersity index of 0.531 ± 0.021, and entrapment efficiency of 88.90 ± 6.27%. In-vitro release studies displayed, that plain FA released 103.13 ± 8.80% within 4 hours, whereas, FA-NLCs released 40.34 ± 5.35% drug after 24 hours indicating sustained release. Pharmacokinetic studies of FA-NLC showed a 2.6-fold increase in C _max and a 1.9-fold increase in AUC and half-life compared to pure <b>FA, which was extremely significant (p &lt; 0.001). Pharmacodynamic assessments specified that FA-NLC significantly reduced blood pressure by 39.9 ± 7.10 mmHg over 8 hours, compared to 30.8 ± 8.12 mmHg for plain FA (p &lt; 0.001).</b> Intestinal uptake results emphasized significant lymphatic uptake via clathrin-mediated endocytosis, bypassing first-pass metabolism, thus, improving therapeutic efficacy. Therefore, the study concluded that FA-NLC effectively reduced blood pressure as compared to plain FA.

阿魏酸（Ferulic acid, FA）是一种天然来源的酚类化合物，亦是一种多功能抗氧化剂，被证实具有潜在的高血压管理价值。然而，其被归类为生物药剂学分类系统（Biopharmaceutics Classification System, BCS）IV级药物实体，这一属性限制了其临床应用。为此，本研究采用探头超声乳化法制备阿魏酸纳米结构脂质载体（nanostructured lipid carriers, NLCs），以改善阿魏酸的溶解度与透膜性能。本研究选用硬脂酸与Labrasol作为脂质载体材料、吐温80作为表面活性剂，并以超声时间为考察变量开展制剂处方研究，同时采用Box-Behnken设计进行处方优化。对所制备的FA-NLCs，分别考察其粒径、ζ电位（zeta potential）、多分散性指数（polydispersity index, PDI）、包封率及体外释放行为。以雄性Wistar大鼠为实验对象，开展药代动力学（Pharmacokinetic）与肠道摄取研究；采用高果糖饮食诱导的Sprague Dawley大鼠高血压模型，进行药效学（Pharmacodynamic）评价。计算机模拟（In-silico）研究显示，阿魏酸与血管紧张素转换酶（angiotensin-converting enzyme, ACE）受体（1UZF）存在较强相互作用，对接得分为-7.144 kcal/mol，结合能为-54.624 kcal/mol。优化后的处方（F12 FA-NLC）粒径为103.4±8.89 nm，ζ电位为-43.6 mV，多分散性指数为0.531±0.021，包封率为88.90±6.27%。体外释放实验结果表明，游离阿魏酸在4小时内即释放103.13±8.80%的药物，而FA-NLCs在24小时内仅释放40.34±5.35%的药物，体现出明显的缓释特性。**与游离阿魏酸相比，FA-NLCs的峰浓度（C_max）提升2.6倍，药时曲线下面积（AUC）与半衰期分别提升1.9倍，差异具有极显著统计学意义（p<0.001）。药效学评估结果显示，FA-NLCs在8小时内可使血压降低39.9±7.10 mmHg，而游离阿魏酸仅降低30.8±8.12 mmHg（p<0.001）。**肠道摄取实验结果表明，FA-NLCs可通过网格蛋白介导的内吞作用（clathrin-mediated endocytosis）实现显著的淋巴摄取，绕过首过代谢（first-pass metabolism），从而提升治疗效果。综上，本研究证实，相较于游离阿魏酸，FA-NLCs可有效降低高血压模型大鼠的血压。