Sun Yu, Jensen Henrik, Petersen Nickolaj J, Larsen Susan W, Østergaard Jesper
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark.
J Pharm Biomed Anal. 2018 Feb 20;150:95-106. doi: 10.1016/j.jpba.2017.11.065. Epub 2017 Dec 2.
For poly (lactide-co-glycolide acid) (PLGA)-based in situ forming implants, the rate of implant formation plays an important role in determining the overall drug release kinetics. Currently, in vitro techniques capable of characterizing the processes of drug release and implant formation at the same time are not available. A hydrogel-based in vitro experimental setup was recently developed requiring only microliter of formulation and forming a closed system potentially suitable for interfacing with various spectroscopic techniques. The aim of the present proof-of-concept study was to investigate the feasibility of concomitant UV imaging, Vis imaging and light microscopy for detailed characterization of the behavior of in situ forming PLGA implants in the hydrogel matrix mimicking the subcutis. The model compounds, piroxicam and α-lactalbumin were added to PLGA-1-methyl-2-pyrrolidinone and PLGA-triacetin solutions. Upon bringing the PLGA-solvent-compound pre-formulation in contact with the hydrogel, Vis imaging and light microscopy were applied to visualize the depot formation and UV imaging was used to quantify drug transport in the hydrogel. As compared to piroxicam, the α-lactalbumin invoked an acceleration of phase separation and an increase of implant size. α-Lactalbumin was released faster from the PLGA-1-methyl-2-pyrrolidinone system than the PLGA-triacetin system opposite to the piroxicam release pattern. A linear relationship between the rate of implant formation and initial compound release within the first 4h was established for the PLGA-NMP systems. This implies that phase separation may be one of the controlling factors in drug release. The rate of implant formation may be an important parameter for predicting and tailoring drug release. The approach combining UV imaging, Vis imaging and light microscopy may facilitate understanding of release processes and holds potential for becoming a useful tool in formulation development of in situ forming implants.
对于基于聚（丙交酯-乙交酯酸）（PLGA）的原位成型植入物，植入物的形成速率在决定整体药物释放动力学方面起着重要作用。目前，尚无能够同时表征药物释放和植入物形成过程的体外技术。最近开发了一种基于水凝胶的体外实验装置，只需要微升的制剂，并形成一个封闭系统，可能适用于与各种光谱技术联用。本概念验证研究的目的是探讨紫外成像、可见光成像和光学显微镜联合使用，以详细表征原位成型PLGA植入物在模拟皮下组织的水凝胶基质中的行为的可行性。将模型化合物吡罗昔康和α-乳白蛋白添加到PLGA-1-甲基-2-吡咯烷酮和PLGA-三醋精溶液中。使PLGA-溶剂-化合物预制剂与水凝胶接触后，应用可见光成像和光学显微镜观察贮库形成，并用紫外成像定量水凝胶中的药物转运。与吡罗昔康相比，α-乳白蛋白可加速相分离并增大植入物尺寸。与吡罗昔康的释放模式相反，α-乳白蛋白在PLGA-1-甲基-2-吡咯烷酮系统中的释放速度比PLGA-三醋精系统快。在PLGA-NMP系统中，在前4小时内建立了植入物形成速率与初始化合物释放之间的线性关系。这意味着相分离可能是药物释放的控制因素之一。植入物的形成速率可能是预测和调整药物释放的一个重要参数。结合紫外成像、可见光成像和光学显微镜的方法可能有助于理解释放过程，并有望成为原位成型植入物制剂开发的有用工具。
