Injectable in-situ Forming Lipid Liquid Crystal for Long-acting Fluocinolone Release in Posterior Ocular Therapy: In-vitro and In-vivo Evaluations.

IF 4.1 3区医学 Q2 CHEMISTRY, MULTIDISCIPLINARY

Pharmaceutical Research Pub Date : 2026-08-01 Epub Date: 2026-06-24 DOI:10.1007/s11095-026-04141-0

Malihe Karimi, Mojtaba Abrishami, Mehdi Farzadnia, Hossein Kamali, Bizhan Malaekeh-Nikouei

{"title":"Injectable in-situ Forming Lipid Liquid Crystal for Long-acting Fluocinolone Release in Posterior Ocular Therapy: In-vitro and In-vivo Evaluations.","authors":"Malihe Karimi, Mojtaba Abrishami, Mehdi Farzadnia, Hossein Kamali, Bizhan Malaekeh-Nikouei","doi":"10.1007/s11095-026-04141-0","DOIUrl":null,"url":null,"abstract":"Objective: Intravitreal injection is a preferred route for targeted drug delivery to the posterior eye. However, commercial non-biodegradable polymeric implants for fluocinolone acetonide (FA) often necessitate surgical removal after long-term release, reducing patient compliance and increase surgical risks. Biodegradable polymeric implants also typically exhibit an initial burst release. This study explores the development of an innovative biodegradable in-situ forming lipid liquid crystal (ISF-LLC) formulation for sustained FA delivery over two months via a single intravitreal injection without burst release.Methods: The optimized formulation, developed using Design of Experiment software, comprised phosphatidylcholine and sorbitan monooleate (PC: SMO 30/70 w/w%) with N-methyl-2-pyrrolidone (NMP 30w/w%).Results: The ISF-LLC formulation exhibited pseudoplastic behavior, excellent syringeability, stability, and a hexagonal crystalline structure. In-vivo pharmacokinetic analysis in rabbit vitreous humor revealed a slow, controlled release rate of 0.49 ± 0.01 μg/day over 60 days (within the clinical range 0.2-0.6 μg/day), with no burst release during the first 7 days (0.22 ± 0.01 μg/day). The vitreal half-life was 22.80 ± 0.51 days, and FA was undetectable systemically. Quantitative histopathology showed no significant differences in retinal thickness (203-209 μm vs. 203 ± 2 μm, p > 0.05) or inflammatory cell count (1-3 vs. 1.3 ± 0.6 cells/field, p > 0.05) between treated and control groups. No retinal damage or systemic toxicity was observed.Conclusions: The injectable biodegradable ISF-LLC formulation is a promising controlled-release, long-acting platform for intravitreal drug delivery, eliminating initial burst release and need for surgical removal, thereby improving patient outcomes in ocular therapy.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"2775-2793"},"PeriodicalIF":4.1000,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmaceutical Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s11095-026-04141-0","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/6/24 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}

引用次数: 0

Abstract

Objective: Intravitreal injection is a preferred route for targeted drug delivery to the posterior eye. However, commercial non-biodegradable polymeric implants for fluocinolone acetonide (FA) often necessitate surgical removal after long-term release, reducing patient compliance and increase surgical risks. Biodegradable polymeric implants also typically exhibit an initial burst release. This study explores the development of an innovative biodegradable in-situ forming lipid liquid crystal (ISF-LLC) formulation for sustained FA delivery over two months via a single intravitreal injection without burst release.

Methods: The optimized formulation, developed using Design of Experiment software, comprised phosphatidylcholine and sorbitan monooleate (PC: SMO 30/70 w/w%) with N-methyl-2-pyrrolidone (NMP 30w/w%).

Results: The ISF-LLC formulation exhibited pseudoplastic behavior, excellent syringeability, stability, and a hexagonal crystalline structure. In-vivo pharmacokinetic analysis in rabbit vitreous humor revealed a slow, controlled release rate of 0.49 ± 0.01 μg/day over 60 days (within the clinical range 0.2-0.6 μg/day), with no burst release during the first 7 days (0.22 ± 0.01 μg/day). The vitreal half-life was 22.80 ± 0.51 days, and FA was undetectable systemically. Quantitative histopathology showed no significant differences in retinal thickness (203-209 μm vs. 203 ± 2 μm, p > 0.05) or inflammatory cell count (1-3 vs. 1.3 ± 0.6 cells/field, p > 0.05) between treated and control groups. No retinal damage or systemic toxicity was observed.

Conclusions: The injectable biodegradable ISF-LLC formulation is a promising controlled-release, long-acting platform for intravitreal drug delivery, eliminating initial burst release and need for surgical removal, thereby improving patient outcomes in ocular therapy.

查看原文本刊更多论文

可注射原位形成脂质液晶用于后眼治疗长效氟西诺酮释放：体外和体内评价。

目的：玻璃体内注射是后眼靶向给药的首选途径。然而，商业上用于氟西诺酮醋酸酯（FA）的不可生物降解聚合物植入物在长期释放后往往需要手术移除，这降低了患者的依从性并增加了手术风险。可生物降解聚合物植入物通常也表现出初始爆裂释放。本研究探索了一种创新的可生物降解原位形成脂质液晶（ISF-LLC）配方的开发，该配方可通过单次玻璃体内注射持续递送FA超过两个月而不会爆裂释放。方法：以磷脂酰胆碱、山梨糖单油酸酯（PC: SMO 30/70 w/w%）和n -甲基-2-吡罗烷酮（NMP 30w/w%）为优化配方，采用实验设计软件进行优化。结果：ISF-LLC配方表现出假塑性行为、优异的注射性、稳定性和六方晶体结构。在兔玻璃体体内药代动力学分析显示，60 d内缓释率为0.49±0.01 μg/d（临床范围0.2 ~ 0.6 μg/d），前7 d无突发性释放（0.22±0.01 μg/d）。玻璃体半衰期为22.80±0.51天，系统检测不到FA。定量组织病理学结果显示，治疗组和对照组视网膜厚度（203 ~ 209 μm vs. 203±2 μm, p > 0.05）和炎症细胞计数（1 ~ 3 vs. 1.3±0.6个细胞/场，p > 0.05）差异无统计学意义。未观察到视网膜损伤或全身毒性。结论：可注射的可生物降解ISF-LLC制剂是一种很有前景的控释、长效玻璃体内给药平台，消除了初始爆发释放，无需手术切除，从而改善了眼科治疗患者的预后。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Pharmaceutical Research 医学-化学综合

CiteScore

6.60

自引率

5.40%

发文量

276

审稿时长

3.4 months

期刊介绍： Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to: -(pre)formulation engineering and processing- computational biopharmaceutics- drug delivery and targeting- molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)- pharmacokinetics, pharmacodynamics and pharmacogenetics. Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.