In Vivo Comparison of Intracameral and Intravitreal Implantation of a Timolol Maleate Miniaturized Injectable Delivery System Device

IF 4.6 Q1 OPHTHALMOLOGY

Ophthalmology science Pub Date : 2025-06-26 DOI:10.1016/j.xops.2025.100868

Chu Jian Ma MD, PhD , Youning Zhang MD , Daniel A. Bernards PhD , Michele Bloomer MD , John Dickson BS , Jayakumar Rajadas PhD , Murty Vyakarnam PhD , Tejal A. Desai PhD , Robert B. Bhisitkul MD, PhD

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Abstract

Purpose

Miniaturized injectable delivery system (MIDS) devices engineered for zero-order release of timolol maleate are evaluated for intracameral (IC) or intravitreal (IVT) injection for ocular safety, effects on intraocular pressure (IOP) reduction, and target tissue drug concentrations.

Design

Preclinical study with in vitro testing of MIDS drug delivery devices together with intraocular injection of the devices in normotensive rabbit eyes.

Subjects

Twenty-four New Zealand rabbits received intraocular injections of MIDS devices.

Methods

Timolol maleate MIDS devices were injected IC or IVT into normotensive New Zealand rabbit eyes (n = 24), with weekly ophthalmic examinations and IOP measurements for 8 or 16 weeks. Eight weeks postimplantation, eyes were enucleated for quantification of tissue drug concentrations by liquid chromatography with tandem mass spectrometry and histology on whole globes.

Main Outcome Measures

Drug release pharmacokinetics; ocular safety and biocompatibility; IOP; and blood and target tissue drug concentrations.

Results

At 8 weeks, IOP in experimental eyes was lowered by 11.1 ± 2.9% (n = 5, P = 0.019) and 18.1 ± 2.6% (n = 6, P < 0.001), for IC and IVT devices, respectively. In extended studies of IVT devices, IOP was numerically lower at 16 weeks by 8.5 ± 5.1% (n = 3, P = 0.24). Intracameral versus IVT injections achieved different tissue distributions (in ng/g; except for aqueous in ng/mL): aqueous 28.5 ± 2.7 vs. 4.5 ± 1.2 (P < 0.001), vitreous 0.3 ± 0.1 vs. 37.2 ± 11.0 (P = 0.010), and ciliary body 14.4 ± 1.8 vs. 50.9 ± 10.8 (P = 0.011). Intraocular inflammation and drug- or device-related adverse effects were absent on examinations and histopathology. Blood drug concentration was below the quantitation limit (<0.4 ng/ml).

Conclusions

Intravitreal and IC devices showed similar IOP reductions; IVT injection led to a higher drug concentration in the target ciliary body tissue, and in normotensive rabbit eyes showed general reduction of IOP over 8 weeks, indicating the potential of MIDS technology to address issues of patient adherence with glaucoma eye drops.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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马来酸替马洛尔微缩注射系统装置在蝶腔内与玻璃体内植入的比较

目的：研究用于马酸噻莫洛尔零级释放的微型注射给药系统（MIDS）装置用于眼内（IC）或玻璃体内（IVT）注射的眼部安全性、眼压降低（IOP）的影响以及靶组织药物浓度。目的：在正常血压家兔眼内注射MIDS给药装置并进行体外试验的临床前研究。24只新西兰兔接受眼内注射MIDS装置。方法24只正常血压的新西兰兔眼内注射马来酸刺激洛尔（stimolol malate MIDS）装置，每周进行眼科检查和IOP测量，持续8周或16周。眼球植入8周后，取眼球去核，用液相色谱串联质谱法和全球组织学方法测定组织药物浓度。主要观察指标：药物释放药代动力学；眼安全性和生物相容性；眼压;血液和靶组织的药物浓度。结果8周时，IC组和IVT组眼压分别降低11.1±2.9% （n = 5, P = 0.019）和18.1±2.6% （n = 6, P < 0.001）。在IVT装置的扩展研究中，IOP在16周时数值降低了8.5±5.1% （n = 3, P = 0.24）。肠腔内注射与体外注射的组织分布不同（单位：ng/g，水单位：ng/mL除外）：水单位：28.5±2.7 vs. 4.5±1.2 (P < 0.001)，玻璃体单位：0.3±0.1 vs. 37.2±11.0 (P = 0.010)，睫状体单位：14.4±1.8 vs. 50.9±10.8 （P = 0.011）。检查和组织病理学均未发现眼内炎症和药物或器械相关的不良反应。血药浓度低于定量限（0.4 ng/ml）。结论人工晶状体和人工晶状体眼压降低相似；IVT注射导致目标睫状体组织中的药物浓度升高，在正常血压的兔眼中，IOP在8周内普遍降低，这表明MIDS技术有可能解决患者对青光眼滴眼液的依从性问题。财务披露专有或商业披露可在本文末尾的脚注和披露中找到。

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