Drug Delivery, Halozyme Therapeutics, Inc., San Diego, CA, USA.
Formerly of Halozyme Therapeutics, Inc., San Diego, CA, USA.
Drug Deliv. 2023 Dec;30(1):2252999. doi: 10.1080/10717544.2023.2252999.
Subcutaneous (SC) infusion of large volumes at rapid flow rates has historically been limited by the glycosaminoglycan hyaluronan (HA), which forms a barrier to bulk fluid flow in the SC space. Recombinant human hyaluronidase PH20 (rHuPH20) depolymerizes HA, temporarily eliminating this barrier to rapid SC delivery of large volume co-administered therapeutics. Using a miniature pig model, in-line pressure and applied force to the delivery hardware were measured when subcutaneously infusing a representative macromolecule (human polyclonal immunoglobulin [Ig]), at varying concentrations and viscosities (20-200 mg/mL), co-formulated with and without rHuPH20 (2000 U/mL and 5000 U/mL). Maximal flow rate () was calculated as the flow rate producing a statistically significant difference in mean applied force between injections administered with or without rHuPH20. There was a significant reduction in mean applied force required for SC delivery of 100 mg/mL Ig solution with 5000 U/mL rHuPH20 versus Ig solution alone. Similar significant reductions in mean applied force were observed for most Ig solution concentrations, ranging from 25-200 mg/mL when administered with or without 2000 U/mL rHuPH20. was inversely proportional to Ig solution viscosity and for solutions co-formulated with 5000 U/mL rHuPH20 was approximately double that of 2000 U/mL rHuPH20 solutions. Mathematical simulation of a hypothetical 800 mg Ig dose co-formulated with rHuPH20 showed that delivery times <30 s could be achieved across a broad range of concentrations. Addition of rHuPH20 can help overcome volume and time constraints associated with SC administration across a range of concentrations in a dose-dependent manner.
皮下（SC）输注大体积的药物时，由于糖胺聚糖透明质酸（HA）的存在，药物的流速会受到限制。重组人透明质酸酶 PH20（rHuPH20）可以降解 HA，暂时消除 SC 空间中药物输送的大体积和快速流动的障碍。使用小型猪模型，在不同浓度和粘度（20-200mg/mL）下，共配制和不共配制 rHuPH20（2000U/mL 和 5000U/mL）的情况下，皮下输注代表性大分子（人多克隆免疫球蛋白[Ig]）时，测量在线压力和输送硬件的应用力。最大流速（）定义为与不添加 rHuPH20 相比，可使平均应用力产生显著差异的流速。与 Ig 溶液单独给药相比，添加 5000U/mL rHuPH20 的 100mg/mL Ig 溶液的 SC 输送所需的平均应用力显著降低。对于大多数 Ig 溶液浓度（25-200mg/mL），无论是否添加 2000U/mL rHuPH20，观察到类似的平均应用力显著降低。与 Ig 溶液粘度成反比，与添加 2000U/mL rHuPH20 的溶液相比，添加 5000U/mL rHuPH20 的溶液的 大约是其两倍。对共配制 rHuPH20 的 800mg Ig 剂量的假设模拟表明，在广泛的浓度范围内，可以实现<30s 的输送时间。添加 rHuPH20 可以帮助克服与 SC 给药相关的体积和时间限制，在剂量依赖性方式下，可以在广泛的浓度范围内使用。
