Chou Shih-Feng, Luo Li-Jyuan, Lai Jui-Yang, Ma David Hui-Kang
Institute of Biochemical and Biomedical Engineering, Chang Gung University, Taoyuan, 33302, Taiwan, ROC; Department of Bioengineering, University of Washington, Seattle, WA 98195-5061, USA.
Department of Chemical and Materials Engineering, Chang Gung University, Taoyuan 33302, Taiwan, ROC.
Int J Pharm. 2016 Sep 10;511(1):30-43. doi: 10.1016/j.ijpharm.2016.06.129. Epub 2016 Jun 29.
To overcome the drawbacks associated with conventional antiglaucoma eye drops, this work demonstrated the feasibility of an effective alternative strategy to administer pilocarpine directly via intracameral injections of drug-containing biodegradable in situ gelling GN copolymers composed of gelatin and poly(N-isopropylacrylamide). Specifically, this study aims to understand the importance of Bloom number of gelatin, a physicochemical parameter, to the development of GN carriers for intracameral drug delivery in glaucoma therapy. Our results showed that both imino acid and triple-helix contents increased with increasing Bloom index from 75-100 to 300. The drug encapsulation efficiency in response to temperature-triggered phase transition in GN copolymers was affected by the Bloom index of gelatin. In addition, the differences in protein secondary structure significantly influenced the degradation rates of GN carriers, which were highly correlated with drug release profiles. The increase in released pilocarpine concentration led to a high intracellular calcium level in rabbit ciliary smooth muscle cell cultures, indicating a beneficial pharmacological response to a drug. Irrespective of Bloom number of gelatin, all carrier materials exhibited excellent in vitro and in vivo biocompatibility with corneal endothelium. In a glaucomatous rabbit model, intracameral injections of pilocarpine-containing GN synthesized from gelatins with various Bloom numbers had different abilities to improve ocular hypertension and induce pupillary constriction, indicating distinct antiglaucoma efficacies due to in vivo drug release. It is concluded that the effects on pharmacological treatment using GN carriers for intracameral pilocarpine administration demonstrate a strong dependence on the Bloom number of gelatin.
为克服传统抗青光眼眼药水的缺点，本研究证明了一种有效的替代策略的可行性，即通过前房内注射由明胶和聚（N-异丙基丙烯酰胺）组成的含药可生物降解原位凝胶化GN共聚物直接给药毛果芸香碱。具体而言，本研究旨在了解明胶的一个物理化学参数——勃氏硬度值对青光眼治疗中用于前房内药物递送的GN载体开发的重要性。我们的结果表明，随着勃氏硬度值从75-100增加到300，亚氨基酸和三螺旋含量均增加。GN共聚物中温度触发的相变所导致的药物包封效率受明胶的勃氏硬度值影响。此外，蛋白质二级结构的差异显著影响了GN载体的降解速率，这与药物释放曲线高度相关。毛果芸香碱释放浓度的增加导致兔睫状平滑肌细胞培养物中的细胞内钙水平升高，表明对药物有有益的药理反应。无论明胶的勃氏硬度值如何，所有载体材料对角膜内皮均表现出优异的体外和体内生物相容性。在青光眼兔模型中，前房内注射由具有不同勃氏硬度值的明胶合成的含毛果芸香碱GN，在改善眼压升高和诱导瞳孔收缩方面具有不同的能力，这表明由于体内药物释放而产生不同的抗青光眼疗效。得出结论：使用GN载体进行前房内毛果芸香碱给药对药理治疗的影响强烈依赖于明胶的勃氏硬度值。
