Institute of Pharmacy, Centre of Drug Absorption and Transport, Biopharmaceutics and Pharmaceutical Technology, University of Greifswald, Germany.
Institute of Pharmacy, Centre of Drug Absorption and Transport, Biopharmaceutics and Pharmaceutical Technology, University of Greifswald, Germany.
Eur J Pharm Sci. 2017 Nov 15;109:233-243. doi: 10.1016/j.ejps.2017.08.018. Epub 2017 Aug 18.
Intravitreal administration is the method of choice for drug delivery to the posterior segment of the eye with special emphasis on the vitreous body and its surrounding retinal vasculature. In order to gain a better understanding of the underlying distribution processes, an in vitro model simulating the vitreous body (Vitreous Model, VM) and a system simulating the impact of movement on the VM (Eye Movement System, EyeMoS) was previously developed. In the study reported here, these systems were modified in regard to a standardized injection procedure, the diversity of simulated eye movements, extended periods of investigation, the opportunity to simulate the state after vitrectomy and in considering the physiological temperature. Fluorescein sodium (FS) and triamcinolone acetonide (TA) were used as (model) drugs to examine the drug distribution within the VM. Vitrectomy was simulated by replacing half the volume of the polyacrylamide gel that was used as vitreous substitute with the clinically used Siluron® 5000 whereas for a simulated liquefaction half the volume of the gel was replaced by buffer. A simulated liquefaction caused a 12-fold faster distribution of FS compared to the simulated juvenile VM, which was most likely caused by convective forces and mass transfer. Also, the injection technique (injection into the gel or into the buffer compartment) influenced the resulting distribution pattern. Without any liquefaction, the previously described initial injection channel occurred with both (model) drugs and, in the case of TA, remained almost unchanged during the investigation period of 72h. Simulating vitrectomized eyes, TA did not spread uniformly, but either remained in the depot or strongly sedimented within the VM suggesting that a homogenous distribution of a TA suspension is highly unlikely in vitrectomized eyes. High variabilities were observed with ex vivo animal eyes, demonstrating the limited benefit of explanted tissues for such distribution studies. The combination of the modified VM and EyeMoS seems a valuable tool for characterizing intravitreal dosage forms in a reproducible simulation of diversified eye movements and a partially liquefied or vitrectomized vitreous body.
玻璃体内给药是将药物递送至眼部后段的首选方法，特别强调玻璃体及其周围的视网膜血管系统。为了更好地了解潜在的分布过程，先前开发了一种模拟玻璃体的体外模型（玻璃体模型，VM）和一种模拟运动对 VM 影响的系统（眼动系统，EyeMoS）。在本报告的研究中，对这些系统进行了修改，以实现标准化注射程序、模拟眼动的多样性、延长研究时间、模拟玻璃体切割术后状态以及考虑生理温度。荧光素钠（FS）和曲安奈德（TA）被用作（模型）药物，以检查药物在 VM 中的分布情况。通过用临床上使用的 Siluron®5000 替代用作玻璃体替代物的聚丙烯酰胺凝胶的一半体积来模拟玻璃体切割术，而对于模拟液化，则用缓冲液替代凝胶的一半体积。与模拟年轻 VM 相比，模拟液化导致 FS 分布速度快 12 倍，这很可能是由对流力和质量转移引起的。此外，注射技术（注入凝胶或缓冲液室）也会影响最终的分布模式。在没有任何液化的情况下，两种（模型）药物都出现了之前描述的初始注射通道，并且在 72 小时的研究期间，TA 的注射通道几乎没有变化。模拟玻璃体切割术后的眼睛中，TA 并未均匀扩散，而是要么留在储库中，要么在 VM 中强烈沉淀，这表明 TA 混悬剂在玻璃体切割术后的眼睛中均匀分布的可能性很小。离体动物眼睛观察到高变异性，表明离体组织在这种分布研究中的获益有限。改良的 VM 和 EyeMoS 的结合似乎是一种有价值的工具，可在模拟多样化眼动和部分液化或玻璃体切割后的玻璃体的重现性模拟中对玻璃体内剂型进行表征。
