Reichel Felix, Auel Tobias, Hacker Michael C, Seidlitz Anne
Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutics and Biopharmaceutics, Universitätsstraße 1, 40225 Düsseldorf, Germany.
Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutics and Biopharmaceutics, Universitätsstraße 1, 40225 Düsseldorf, Germany; Freie Universität Berlin, Institute of Pharmacy, Pharmaceutical Technology, Kelchstraße 31, 12169 Berlin, Germany.
Eur J Pharm Sci. 2025 Sep 1;212:107156. doi: 10.1016/j.ejps.2025.107156. Epub 2025 Jun 14.
Due to an aging society and the associated increase in age-related eye diseases of the posterior segment of the eye, an optimized in vitro vitreous model would be beneficial to assess drug release and distribution in preclinical dosage form development. A key component in such a test system is a compartment simulating the vitreous body. Several hydrogels have been proposed for this purpose. In this work the rheological properties of several vitreous body substitutes based on hyaluronic acid, hypromellose, polyacrylamide, gellan gum in combination with hyaluronic acid, and hyaluronic acid in combination with agar were investigated. By systematically comparing these potential in vitro vitreous body substitutes with porcine vitreous bodies within one study employing a series of rheological characterizations, a direct comparison was achieved, allowing opportunities for optimization to be identified. The main characterization focused on the viscosity and loss factor in the linear viscoelastic region and, for the most promising gels, also on the behavior in frequency sweeps. Additionally, the recovery times, pH values, and osmolalities of the gels were determined. Initially, phosphate-buffered saline, which served as the basis for the hydrogels, was successfully adjusted to match the pH and osmolality of porcine and human vitreous bodies. Gels made from gellan gum-hyaluronic acid and hyaluronic acid-agar proved most promising. These could be adjusted in concentrations of 0.034 % gellan gum & 0.264 % hyaluronic acid or 0.22 % hyaluronic acid & 0.09 % agar to match both the viscosity of the vitreous body and the loss factor in the linear viscoelastic region. Additionally, the pH values, osmolalities, and behavior in frequency sweeps of the gels were also comparable to the vitreous body, as these exhibit physicochemical gel formation mechanisms and reversibly linked frameworks probably similar to those of the vitreous body. Under the measurement conditions used here, the gels can therefore be considered as good in vitro vitreous body substitutes. Further diffusion studies, which will likely be influenced by the adjusted rheological properties, should be conducted in the future to further investigate the suitability of the optimized gels presented here.
由于社会老龄化以及与之相关的眼后段年龄相关性眼病的增加，优化的体外玻璃体模型将有助于在临床前剂型开发中评估药物释放和分布。这种测试系统的一个关键组件是模拟玻璃体的隔室。已经提出了几种水凝胶用于此目的。在这项工作中，研究了几种基于透明质酸、羟丙甲纤维素、聚丙烯酰胺、结冷胶与透明质酸的组合以及透明质酸与琼脂的组合的玻璃体替代物的流变学性质。通过在一项研究中使用一系列流变学表征将这些潜在的体外玻璃体替代物与猪玻璃体进行系统比较，实现了直接比较，从而确定了优化的机会。主要表征集中在线性粘弹性区域的粘度和损耗因子上，对于最有前景的凝胶，还集中在频率扫描中的行为上。此外，还测定了凝胶的恢复时间、pH值和渗透压。最初，成功调整了用作水凝胶基础的磷酸盐缓冲盐水，使其与猪和人玻璃体的pH值和渗透压相匹配。由结冷胶 - 透明质酸和透明质酸 - 琼脂制成的凝胶被证明最有前景。这些凝胶可以调整为0.034%结冷胶和0.264%透明质酸或0.22%透明质酸和0.09%琼脂的浓度，以匹配玻璃体的粘度和线性粘弹性区域的损耗因子。此外，凝胶的pH值、渗透压和频率扫描中的行为也与玻璃体相当，因为它们表现出可能与玻璃体类似的物理化学凝胶形成机制和可逆连接的框架。因此，在此处使用的测量条件下，这些凝胶可被视为良好的体外玻璃体替代物。未来应进行可能受调整后的流变学性质影响的进一步扩散研究，以进一步研究此处提出的优化凝胶的适用性。
