A recombinant human enzyme for enhanced interstitial transport of therapeutics
Abstract
Subcutaneously injected therapeutics must pass through the interstitial matrix of the skin in order to reach their intended targets. This complex, three-dimensional structure limits the type and quantity of drugs that can be administered by local injection. Here we found that depolymerization of the viscoelastic component of the interstitial matrix in animal models with a highly purified recombinant human hyaluronidase enzyme (rHuPH20) increased the dispersion of locally injected drugs, across a broad range of molecular weights without tissue distortion. rHuPH20 increased infusion rates and the pattern and extent of appearance of locally injected drugs in systemic blood. In particular, rHuPH20 changed the pharmacokinetic profiles and significantly augmented the absolute bioavailability of locally injected large protein therapeutics. Importantly, within 24 h of injection, the interstitial viscoelastic barriers were restored without histologic alterations or signs of inflammation. rHuPH20 may function as an interstitial delivery enhancing agent capable of increasing the dispersion and bioavailability of coinjected drugs that may enable subcutaneous administration of therapeutics and replace intravenous delivery.
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rHuPH20 supports dispersion of a subcutaneously injected volume by temporarily depolymerizing the polysaccharide hyaluronic acid in the intercellular ground substance of connective tissue.
“This enzyme supports dispersion of a subcutaneously injected volume by temporarily depolymerizing the polysaccharide hyaluronic acid in the intercellular ground substance of connective tissue [63].”
From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [63]
Subcutaneous infusion of larger volumes can be further facilitated using rHuPH20.
“Subcutaneous infusion of larger volumes can be further facilitated using rHuPH20.”
From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [63]
In the same rat study, Tmax was lower for both peg-interferon alfa-2b and infliximab in the presence of hyaluronidase, indicating faster absorption; Tmax of infliximab decreased from 48 to 18.7 h.
“In addition, the time to reach Cmax (Tmax) was lower for both molecules in the presence of hyaluronidase, indicating a faster absorption into the circulation system in the presence of the hyaluronidase (Tmax of infliximab decreased from 48 to 18.7 h) [63].”
From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [63]
In a rat study, absolute intradermal bioavailability for peg-interferon alfa-2b and infliximab increased from 61 to 108% and from 59 to 94%, with and without co-injecting with hyaluronidase, respectively.
“Bioavailability was calculated to increase from 61 to 108% and from 59 to 94%, with and without co-injecting with hyaluronidase, respectively.”
From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [63]
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References 37 · Cited by 282
- Authors
- Bookbinder, L. H., Hofer, A., Haller, M. F., Zepeda, M. L., Keller, G.-A., Lim, J. E., Edgington, T. S., Shepard, H. M., Patton, J. S., & Frost, G. I.
- Affiliations
- Halozyme Therapeutics (United States) (US)
- Scripps Research Institute (US)
- Nektar Therapeutics (United States) (US)
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2006-08
- Volume
- 114
- Issue
- 2
- Pages
- 230-241
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W2110427985
- Cited by
- 282
- References
- 37
- Citations by year
- 2026: 21 · 2025: 9 · 2024: 10 · 2023: 10 · 2022: 16 · 2021: 21 · 2020: 18 · 2019: 13 · 2018: 17 · 2017: 15 · 2016: 14 · 2015: 17 · 2014: 23 · 2013: 14 · 2012: 22
- FWCI
- 2.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Health Sciences › Medicine › Emergency Medicine › Intramuscular injections and effects
- Keywords
- recombinant human hyaluronidase, rHuPH20, interstitial matrix, subcutaneous drug delivery, hyaluronan depolymerization, pharmacokinetics, bioavailability, interstitial fluid flow
- MeSH terms
- Adenoviridae, Animals, Antibodies, Monoclonal, Antibody Formation, Biological Availability, Biological Transport, Active, Capillaries, Capillary Permeability, Drug Therapy, Pharmaceutical Preparations, Female, Humans, Hyaluronoglucosaminidase, Injections, Subcutaneous, Interferon Type I, Macaca mulatta, Male, Mice, Nude, Molecular Weight, Particle Size, Polyethylene Glycols, Recombinant Proteins, Genetic Therapy, Cytokines, Drug Delivery Systems, Endothelial Cells, Mice
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