Nanostructured Lipid Carriers for Enhanced Transscleral Delivery of Dexamethasone Acetate: Development, Ex Vivo Characterization and Multiphoton Microscopy Studies

Abstract

Corticosteroids, although highly effective for the treatment of both anterior and posterior ocular segment inflammation, still nowadays struggle for effective drug delivery due to their poor solubilization capabilities in water. This research work aims to develop nanostructured lipid carriers (NLC) intended for periocular administration of dexamethasone acetate to the posterior segment of the eye. Pre-formulation studies were initially performed to find solid and liquid lipid mixtures for dexamethasone acetate solubilization. Pseudoternary diagrams at 65 °C were constructed to select the best surfactant based on the macroscopic transparency and microscopic isotropy of the systems. The resulting NLC, obtained following an organic solvent-free methodology, was composed of triacetin, Imwitor® 491 (glycerol monostearate >90%) and tyloxapol with Z-average = 106.9 ± 1.2 nm, PDI = 0.104 ± 0.019 and zeta potential = −6.51 ± 0.575 mV. Ex vivo porcine sclera and choroid permeation studies revealed a considerable metabolism in the sclera of dexamethasone acetate into free dexamethasone, which demonstrated higher permeation capabilities across both tissues. In addition, the NLC behavior once applied onto the sclera was further studied by means of multiphoton microscopy by loading the NLC with the fluorescent probe Nile red.

Recent Progress of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers as Ocular Drug Delivery Platforms

“…In addition to the conventional topical application, NLCs have been formulated for periocular administration (transscleral delivery), as reported by González-Fernández et al The authors prepared dexamethasone acetate-loaded NLCs intended for the treatment of posterior eye segment diseases (e.g., macular edema, age-related macular degeneration). The encapsulated prodrug acetate ester provided sustained drug release as a result of the required enzymatic conversion step, and enhanced scleral/choroidal permeability [ 205 ].…”

Application of organic nanocarriers for intraocular drug delivery

“…固体脂质纳米载体是一种近年兴起的药物递送系统，由天然或合成的固态类脂如卵磷脂、三酰甘油等组成，能够将活性成分包裹或夹嵌于类脂核中形成粒径为50~1000 nm的胶体，具有体积小、表面积大、药物释放可控、理化性能稳定、防止药物提前降解等优点 ［ 19 ］ 。同时，固体脂质纳米载体具有生物可降解和生物相容性，可大幅提升生物安全性。该载体表面的疏水性能够有效延长纳米药物的眼前段滞留时间并增加角膜吸收和渗透能力，因此显著提高了药物的生物利用度 ［ 20 ］ 。Puglia等 ［ 21 ］ 制备了一种稳定的固体脂质纳米载体平台，将 N -棕榈酰乙醇酰胺输送到眼后段，改善了药物的水溶性和稳定性差等问题。动物实验结果显示，其能够有效降低链脲霉素诱导的糖尿病大鼠模型的视网膜中肿瘤坏死因子-α的水平，目前已进入临床研究。Tan等 ［ 22 ］ 将（3-氨基甲基苯基）硼酸偶联硫酸软骨素连接在包载地塞米松的固体脂质纳米载体表面，构建了纳米药物颗粒。该纳米粒表面含有硼酸基团，可与眼表黏蛋白中的唾液酸形成复合物，明显延长了纳米药物的角膜前滞留时间，减轻了眼干燥症及并发症，被认为是一种有前途的眼科疾病给药系统。Zhan等 ［ 23 ］ 将可结合角膜糖蛋白的琥珀酰刀豆蛋白A用于功能化脂质体，显著延长了脂质载体在角膜的驻留时间；同时包载河豚毒素和右美托咪定，实现了对两者的控释；单次局部角膜滴注该纳米药物达到完全镇痛105 min和部分镇痛608 min的良好效果，适用于手术、非手术性角膜疼痛处理以及其他眼表疾病的有效治疗。综上，固体脂质纳米载体递送平台具有良好的生物安全性，在眼内药物递送中表现出优越的性能。…”

Natural-Origin Betaine Surfactants as Promising Components for the Stabilization of Lipid Carriers

“…Among the ways of application of colloidal systems based on solid lipids extensively documented in the literature are cosmetic [5,8,9], food [4,6,10], and, above all, in the pharmaceutical industry (i.e., drug delivery) [7,11,12]. In recent years, lipid formulations have enabled the effective encapsulation of active substances successfully delivered intravenously [13][14][15], orally [16][17][18], transdermally [19][20][21], and also directly into the eye [22][23][24] or nose [25][26][27].…”