The DOI matches its Crossref record; 66 of the 66 references it cites were found in a registry or an index.
Recombinant human hyaluronidase (rHuPH20): an enabling platform for subcutaneous drug and fluid administration
Abstract
The extracellular matrix is a significant barrier to the effective subcutaneous delivery of many drugs, limiting both pharmacokinetic parameters and injection volumes. The space outside adipocytes in the hypodermis is not a fluid, but rather a solid extracellular matrix of collageneous fibrils embedded within a glycosaminoglycan-rich viscoelastic gel that buffers convective forces. The extracellular matrix limits the volume of drug that can be injected at a single site, as well as the rate and amount that reach the vascular compartment. A fully human recombinant DNA-derived hyaluronidase enzyme (rHuPH20) has been developed to leverage the historical efficacy of animal testes extract-derived spreading factors to reversibly modify the hypodermis, in light of discovery of the human hyaluronidase gene family. The application of this technology to increase both injection volumes and bioavailability from subcutaneous injection may overcome some key limitations of this route of administration in multiple settings of care.
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In the citing paper
“it has been shown that coadministration of the dispersion enhancer hyaluronidase facilitates spreading of an injected volume in the subcutaneous interstitial space and, therefore, enables injection of a larger volume at an individualized rate at the patient’s preferred injection site (e.g. thigh, abdomen, or upper arm) [18].”
From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [18]
In the citing paper
“Hyaluronan provides a barrier against the spreading of injected fluids [18].”
From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [18]
In the citing paper
“Intravenous doses from 38 to 12,000 units/kg in rhesus primates and 10,500 units/kg in rodents have been generally well-tolerated.”
From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [18]
In the citing paper
“In primates, rHuPH20 has been shown to be well-tolerated at 45,000 units per subcutaneous injection and 4500 units per periocular injection.”
From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [18]
In the citing paper
“In an attempt to increase the subcutaneous bioavailability of a biotherapeutic, subcutaneous infusions can be coadministered (or produced as coformulations) with the dispersion-enhancer hyaluronidase (discussed in detail in Sect. 4), an enzyme that facilitates spreading of an injected fluid in the subcutaneous tissue [18].”
From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [18]
Citations
Cites
On the Absorption of Fluids from the Connective Tissue Spaces
Starling, E. H. (1896) · The Journal of Physiology · doi:10.1113/jphysiol.1896.sp000596 · Cited by 2,126
Cell Biology of Extracellular Matrix
Hay, E. D. (1988) · Springer eBooks · doi:10.1007/978-1-4613-0881-2 · Cited by 1,470
Effect of Collagen Turnover on the Accumulation of Advanced Glycation End Products
Verzijl, N., DeGroot, J., Thorpe, S. R., Bank, R. A., Shaw, J., Lyons, T. J., Bijlsma, J. W. J., Lafeber, F. P. J. G., Baynes, J., & TeKoppele, J. M. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m006700200 · Cited by 979
Interstitial-lymphatic mechanisms in the control of extracellular fluid volume
Aukland, K., & Reed, R. K. (1993) · Physiological Reviews · doi:10.1152/physrev.1993.73.1.1 · Cited by 938
The six hyaluronidase-like genes in the human and mouse genomes
Csoka, A. B., Frost, G. I., & Stern, R. (2001) · Matrix Biology · doi:10.1016/s0945-053x(01)00172-x · Cited by 590
Self-citationLundin, J., Kimby, E., Björkholm, M., Broliden, P.-A., Celsing, F., Hjalmar, V., Möllgård, L., Rebello, P., Hale, G., Waldmann, H., et al. (2002) · Blood · doi:10.1182/blood-2002-01-0159 · Cited by 497
Supersaxo, A., Hein, W. R., & Steffen, H. (1990) · Pharmaceutical Research · doi:10.1023/a:1015880819328 · Cited by 386
A recombinant human enzyme for enhanced interstitial transport of therapeutics
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. (2006) · Journal of Controlled Release · doi:10.1016/j.jconrel.2006.05.027 · Cited by 282
Self-citationPurification, Cloning, and Expression of Human Plasma Hyaluronidase
Frost, G. I., Csóka, T. B., Wong, T., & Stern, R. S. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.6773 · Cited by 236
Self-citationBee venom hyaluronidase is homologous to a membrane protein of mammalian sperm.
Gmachl, M., & Kreil, G. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.8.3569 · Cited by 206
Research works printed but not linked: 18
- TAYLOR, 1984, Am. Physiol. Soc., 4, 467
- REED, 1989, Am. J. Physiol., 257, 1819
- FRASER, 1989, Ciba Found. Symp., 143, 41
- MCMINN RMH (Ed.), Last's Anatomy: Regional and applied (9th Edition). London: Churchill Livingstone (1994).
- 10.1113/expphysiol.1991.sp003536 · DOI
- DURAN, 1928, Comptes Rendus Hebdomadaires de Séances et Mémoires de la Société de Biologie, 99, 6
- DUTHIE, 1939, Nature, 977
- MEYER K, Hyaluronidases, In : BOYER PD (Ed.), The Enzymes. Academic Press, New York, (1971):307-320.
- MEYER, 1952, Adv. Enzymol. Relat. Subj. Biochem., 13, 199
- MEYER K, HOFFMAN P, LINKER A: HYALURONIDASES. In: BOYER PD, LARDY H, MYRBÄCK K (Eds), The Enzymes, 2nd Edition, Volume 4, Academic Press, New York (1960):447-460.
- HYUGA, 1993, Int. J. Dev. Biol., 37, 319
- LINSENMAYER, 1981, Plenum, 5
- WOLF, 1982, J. Pharmacol. Exp. Ther., 222, 331
- JAWORSKI, 1950, Am. J. Dis. Child., 79, 59
- ALWITRY, 2002, J. Cataract Refract. Surg., 8, 11420
- 1998, J. Intravenous Nursing, 21, S36
- RASZKA, 1990, J. Perinatol., 10, 146
- SIMON, 1949, Amer. J. Roentgen., 61, 91
Cited by
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The evolution of commercial drug delivery technologies
Vargason, A. M., Anselmo, A. C., & Mitragotri, S. (2021) · Nature Biomedical Engineering · doi:10.1038/s41551-021-00698-w · Cited by 1,361
Non-invasive delivery strategies for biologics
Anselmo, A. C., Gokarn, Y. R., & Mitragotri, S. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.183 · Cited by 671
Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities
Bittner, B., Richter, W., & Schmidt, J. (2018) · BioDrugs · doi:10.1007/s40259-018-0295-0 · Cited by 447
Mechanistic Determinants of Biotherapeutics Absorption Following SC Administration
Richter, W. F., Bhansali, S. G., & Morris, M. E. (2012) · The AAPS Journal · doi:10.1208/s12248-012-9367-0 · Cited by 377
Hyaluronan-CD44 Interactions in Cancer: Paradoxes and Possibilities
Toole, B. P. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-0479 · Cited by 370
Metadata
- Authors
- Frost, G. I.
- Affiliations
- Halozyme Therapeutics (United States) (US)
- Corresponding author
- Frost, Gregory I
- Venue
- Expert Opinion on Drug Delivery
- Publisher
- Informa UK Limited
- Published
- 2007-07
- Volume
- 4
- Issue
- 4
- Pages
- 427-440
- ISSN
- 1742-5247 (ISSN-L)
- 1744-7593
- OpenAlex
- W2158548553
- Cited by
- 323
- References
- 66
- Citations by year
- 2026: 25 · 2025: 18 · 2024: 16 · 2023: 23 · 2022: 15 · 2021: 27 · 2020: 18 · 2019: 8 · 2018: 27 · 2017: 18 · 2016: 19 · 2015: 17 · 2014: 28 · 2013: 12 · 2012: 23
- FWCI
- 0.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Expert Opinion on Drug Delivery (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Health Sciences › Medicine › Emergency Medicine › Intramuscular injections and effects
- Physical Sciences › Materials Science › Biomaterials › Hydrogels: synthesis, properties, applications
- Keywords
- recombinant human hyaluronidase, rHuPH20, subcutaneous drug delivery, extracellular matrix, hyaluronic acid, subcutaneous tissue, injection volume, bioavailability, hyaluronidase, glycosaminoglycans, collagen, pharmacokinetics
- MeSH terms
- Amino Acid Sequence, Animals, Extracellular Matrix, Humans, Hyaluronoglucosaminidase, Injections, Subcutaneous, Molecular Sequence Data, Recombinant Proteins, Solubility, Protein Engineering, Cell Adhesion Molecules, Dermis
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