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在小型猪模型中,用重组人透明质酸酶 PH20 皮下给药,确定最大流速与粘度之间的预测关系。

Identifying a predictive relationship between maximal flow rate and viscosity for subcutaneous administration of macromolecules with recombinant human hyaluronidase PH20 in a miniature pig model.

机构信息

Drug Delivery, Halozyme Therapeutics, Inc., San Diego, CA, USA.

Formerly of Halozyme Therapeutics, Inc., San Diego, CA, USA.

出版信息

Drug Deliv. 2023 Dec;30(1):2252999. doi: 10.1080/10717544.2023.2252999.


DOI:10.1080/10717544.2023.2252999
PMID:37702020
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10501162/
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 () 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.

摘要

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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/f79c39ea0145/IDRD_A_2252999_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/e9abb0d1117c/IDRD_A_2252999_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/5118de065239/IDRD_A_2252999_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/98f6e3fe1fad/IDRD_A_2252999_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/2078b2fb68ef/IDRD_A_2252999_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/b37247951e9f/IDRD_A_2252999_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/73ac516c1f95/IDRD_A_2252999_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/dd1152214ef1/IDRD_A_2252999_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/f79c39ea0145/IDRD_A_2252999_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/e9abb0d1117c/IDRD_A_2252999_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/5118de065239/IDRD_A_2252999_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/98f6e3fe1fad/IDRD_A_2252999_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/2078b2fb68ef/IDRD_A_2252999_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/b37247951e9f/IDRD_A_2252999_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/73ac516c1f95/IDRD_A_2252999_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/dd1152214ef1/IDRD_A_2252999_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b0a/10501162/f79c39ea0145/IDRD_A_2252999_F0008_C.jpg

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引用本文的文献

[1]
A phase I clinical study to evaluate rapid, high-volume, subcutaneous auto-injector tolerability with recombinant human hyaluronidase.

Drug Deliv Transl Res. 2025-5-30

[2]
Development and Preclinical Testing of a Rapid, High-Volume, Auto-Injector for Subcutaneous Administration with Recombinant Human Hyaluronidase.

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本文引用的文献

[1]
Safety of recombinant human hyaluronidase PH20 for subcutaneous drug delivery.

Expert Opin Drug Deliv. 2021-11

[2]
Subcutaneous Injection Performance in Yucatan Miniature Pigs with and without Human Hyaluronidase and Auto-injector Tolerability in Humans.

AAPS PharmSciTech. 2021-1-6

[3]
Clinical strategies for optimizing infusion center care through a pandemic.

J Oncol Pharm Pract. 2021-1

[4]
A portfolio of biologic self-injection devices in rheumatology: how patient involvement in device design can improve treatment experience.

Drug Deliv. 2019-12

[5]
ENHANZE drug delivery technology: a novel approach to subcutaneous administration using recombinant human hyaluronidase PH20.

Drug Deliv. 2019-12

[6]
Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities.

BioDrugs. 2018-10

[7]
Home infusion with Elosulfase alpha (Vimizim) in a UK Paediatric setting.

Mol Genet Metab Rep. 2017-11-5

[8]
High-concentration protein formulations: How high is high?

Eur J Pharm Biopharm. 2017-7-6

[9]
Home infusion: Safe, clinically effective, patient preferred, and cost saving.

Healthc (Amst). 2016-4-29

[10]
Preference for subcutaneous or intravenous administration of rituximab among patients with untreated CD20+ diffuse large B-cell lymphoma or follicular lymphoma: results from a prospective, randomized, open-label, crossover study (PrefMab).

Ann Oncol. 2017-4-1

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