Abstract

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 (Q_max) 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. Q_max was inversely proportional to Ig solution viscosity and Q_max 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.

摘要

历史上，快速流速的大容量皮下 (SC) 输注一直受到糖胺聚糖透明质酸 (HA) 的限制，它对 SC 空间中的大量液体流动形成屏障。重组人透明质酸酶 PH20 (rHuPH20) 可解聚 HA，暂时消除大容量联合治疗药物快速 SC 递送的障碍。使用小型猪模型，在皮下注射不同浓度和粘度 (20–200 mg/mL) 的代表性大分子（人多克隆免疫球蛋白 [Ig]）时，测量了对输送硬件的在线压力和施加的力，共配制时添加或不添加 rHuPH20（2000 U/mL 和 5000 U/mL）。最大流速( Q _max )被计算为在施用或不施用rHuPH20的注射之间产生平均施加力的统计学显着差异的流速。与单独使用 Ig 溶液相比，使用 5000 U/mL rHuPH20 进行 SC 递送 100 mg/mL Ig 溶液所需的平均施加力显着降低。当使用或不使用 2000 U/mL rHuPH20 给药时，大多数 Ig 溶液浓度（范围为 25–200 mg/mL）均观察到平均施加力显着降低。Q _max与 Ig 溶液粘度成反比，并且与 5000 U/mL rHuPH20 共同配制的溶液的Q _{max大约是 2000 U/mL rHuPH20 溶液的两倍。}与 rHuPH20 共同配制的假设 800 mg Ig 剂量的数学模拟表明，在广泛的浓度范围内可以实现 <30 秒的递送时间。添加 rHuPH20 可以帮助克服与以剂量依赖性方式在一定浓度范围内皮下注射相关的体积和时间限制。