Safety and pharmacodynamics of suprachoroidal injection of triamcinolone acetonide as a controlled ocular drug release model
Safety and pharmacodynamics of suprachoroidal injection of triamcinolone acetonide as a controlled ocular drug release model
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脉络膜上注射曲安奈德作为受控眼部药物释放模型的安全性和药效学
DOI：
10.1016/j.jconrel.2015.02.021
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发表时间：
2015-04-10
影响因子：
10.8
通讯作者：
Cheng, Lingyun
中科院分区：
文献类型：
--
作者：
Chen, Mei;Li, Xiaoli;Cheng, Lingyun
脉络膜上注射是一种新兴的后段给药技术，非侵入性入路难以达到。然而，注射技术各不相同，相关的眼部安全性尚不清楚。此外，尚不清楚药物配方是否是使用该技术优化药效学的主要因素。本研究旨在比较不同药物配方的脉络膜上注射，并表征曲安奈德（TA）的安全性和药效学。将吲哚菁绿（ICG）溶液和TA悬液分别在50 μ L、100 μ L和150 μ L的脉络膜上注射，并在8周内的多个时间点进行眼压（IOP）测量、眼底摄影和视网膜电图检查。经50 μ L TA （Kenalog-40）脉络膜上注射后，在7个时间点处死4-5只动物进行水、玻璃、视网膜和血浆采集。采用超高效液相色谱串联质谱法测定TA含量。为了比较疗效研究，在10 ng玻璃体内脂多糖诱导实验性葡萄膜炎前4周给予50 μ L （2 mg）脉络膜上TA与20 mg亚tenon TA。脉络膜上注射后IOP急性升高，体积增大导致IOP升高（p < 0.0001）。等量ICG溶液导致IOP升高明显小于TA脉络膜上注射后。这一发现表明ICG溶液比TA悬液在脉络膜上空间的分布更好。脉络膜上注射50 μ L后，水溶液中TA的峰值浓度低于1 ng/mL。相比之下，后玻璃体和视网膜的TA分别为1912 ng/mL和400,369 ng/mL。血浆TA最大值为11.6 ng/mL。后视网膜的药物暴露量是水视网膜的523910倍，是全身TA暴露量的29516倍。在治疗脂多糖性葡萄膜炎时，与20 mg亚腱素注射相比，脉络膜上注射2 mg TA效果更好，房水细胞明显减少，玻璃体混浊评分明显降低（p < 0.05）。组织学显示脉络膜上注射组玻璃体炎症明显减少（p < 0.0001）。在兔眼中，50 μ L脉络膜上注射TA具有良好的耐受性，并表现出良好的后视网膜穿透性，其治疗效果优于20 mg TA。(C) 2015 Elsevier B.V.版权所有
Suprachoroidal injection is an emerging technique for drug delivery to the posterior segment, which is hard to reach by non-invasive approaches. However, the injection technique varies and the associated ocular safety is not well understood. In addition, it is not clear if drug formulation is a major factor in optimizing pharmacodynamics using this technique. The current study was designed to compare the suprachoroidal injection of different drug formulations and to characterize the safety and pharmacodynamics of triamcinolone acetonide (TA) delivered by this technique. Both indocyanine green (ICG) solution and TA suspension, at 50 mu L, 100 mu L, and 150 mu L, were suprachoroidally injected and intraocular pressure (IOP) tonometry, fundus photography, and electroretinography were performed over multiple time points up to eight weeks. After 50 mu L TA (Kenalog-40) suprachoroidal injection, 4-5 animals at 7 time points were sacrificed for aqueous, vitreous, retina, and plasma collections. TA was quantitated using ultra-performance liquid chromatography tandem mass spectrometry. For comparative efficacy study, 50 mu L (2 mg) suprachoroidal TA versus 20 mg subtenon TA were performed 4 weeks before induction of experimental uveitis with 10 ng of intravitreal lipopolysaccharide. After suprachoroidal injection, IOP had an acute elevation, higher volume caused higher IOP (p < 0.0001). Equivalent volume of ICG solution led to a significantly smaller IOP elevation than after TA suprachoroidal injection. This finding suggests better distribution of ICG solution than TA suspension in the suprachoroidal space. Following a 50 mu L suprachoroidal injection, peak TA concentration in the aqueous was below 1 ng/mL. In contrast, the posterior vitreous and retina had 1912 ng/mL and 400,369 ng/mL TA, respectively. Maximum TA in plasma was 11.6 ng/mL. Drug exposure to the posterior retina was 523,910 times more than that to the aqueous and 29,516 times more than systemic TA exposure. In the treatment of lipopolysaccharide-induced uveitis, compared with 20 mg subtenon injection, suprachoroidal 2 mg TA demonstrated much better efficacy with significantly less aqueous humor cells and lower vitreous opacity scores (p < 0.05). Histology showed much less vitreous inflammation in the suprachoroidal injection group (p < 0.0001). It seems that a 50 mu L suprachoroidal injection of TA was well tolerated in rabbit eyes and demonstrated excellent penetration into the posterior retina, providing better therapeutic effect than subtenon 20 mg TA. (C) 2015 Elsevier B.V. All rights reserved.