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
Antidotes to vesicant chemotherapy extravasations
Dorr, R. T. (1990) · Blood Reviews · doi:10.1016/0268-960x(90)90015-k · Cited by 182
Tammi, R., Säämänen, A., Maïbach, H. I., & Tammi, M. (1991) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12478553 · Cited by 151
Lathrop, W. F., Carmichael, E. P., Myles, D. G., & Primakoff, P. (1990) · The Journal of Cell Biology · doi:10.1083/jcb.111.6.2939 · Cited by 147
The human sperm protein PH‐20 has hyaluronidase activity
Gmachl, M., Sagan, S., Ketter, S., & Kreil, G. (1993) · FEBS Letters · doi:10.1016/0014-5793(93)80873-s · Cited by 145
Extravasation of Chemotherapeutic Agents: Prevention and Treatment
Goolsby, T. V., & Lombardo, F. A. (2006) · Seminars in Oncology · doi:10.1053/j.seminoncol.2005.11.007 · Cited by 142
A Microtiter-Based Assay for Hyaluronidase Activity Not Requiring Specialized Reagents
Frost, G. I., & Stern, R. (1997) · Analytical Biochemistry · doi:10.1006/abio.1997.2262 · Cited by 135
Self-citationHyaluronidase as an antidote to extravasation ofVinca alkaloids: Clinical results
Bertelli, G., Dini, D., Forno, G. G., Gozza, A., Silvestro, S., Venturini, M., Rosso, R., & Pronzato, P. (1994) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/bf01191807 · Cited by 122
Cherr, G. N., Meyers, S. A., Yudin, A. I., VandeVoort, C. A., Myles, D. G., Primakoff, P., & Overstreet, J. W. (1996) · Developmental Biology · doi:10.1006/dbio.1996.0102 · Cited by 104
Purification and Partial Characterization of Testicular Hyaluronidase
Borders, C. L., & Raftery, M. A. (1968) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)34203-6 · Cited by 103
The permeability of interstitial connective tissue and the nature of the interfibrillary substance
Day, T. D. (1952) · The Journal of Physiology · doi:10.1113/jphysiol.1952.sp004728 · Cited by 102
USE OF HYALURONIDASE WITH LOCAL ANESTHESIA IN OPHTHALMOLOGY
Atkinson, W. S. (1949) · Archives of ophthalmology · doi:10.1001/archopht.1949.00900050638012 · Cited by 100
A Mucolytic Enzyme in Testis Extracts
CHAIK, E., & Duthie, E. S. (1939) · Nature · doi:10.1038/144977b0 · Cited by 99
Catabolism of hyaluronan in rabbit skin takes place locally, in lymph nodes and liver
Laurent, U. B. G., Dahl, L., & Reed, R. K. (1991) · Experimental Physiology · doi:10.1113/expphysiol.1991.sp003536 · Cited by 92
Hyaluronidase as an Adjuvant in Bupivacaine-Lidocaine Mixture for Retrobulbar/Peribulbar Block
Kallio, H., Paloheimo, M., & Maunuksela, E. (2000) · Anesthesia & Analgesia · doi:10.1097/00000539-200010000-00031 · Cited by 88
Gardulf, A., & Nicolay, U. (2006) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/01.all.0000246619.49494.41 · Cited by 88
Harris, E. N., Weigel, J. A., & Weigel, P. H. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405322200 · Cited by 84
Intravenous Extravasation Injuries: The Effectiveness of Hyaluronidase in Their Treatment
Laurie, S. W. S., Wilson, K., Kernahan, D. A., Bauer, B. S., & Vistnes, L. M. (1984) · Annals of Plastic Surgery · doi:10.1097/00000637-198409000-00003 · Cited by 78
Analysis of the Products Formed on Hydrolysis of Hyaluronic Acid by Testicular Hyaluronidase1,2
Rapport, M. M., Meyer, K., & Linker, A. (1951) · Journal of the American Chemical Society · doi:10.1021/ja01150a003 · Cited by 78
The clinical use of hyaluronidase in hypodermoclysis
Hechter, O., Dopkeen, S. K., & Yudell, M. H. (1947) · The Journal of Pediatrics · doi:10.1016/s0022-3476(47)80057-5 · Cited by 77
In Vitro Mutagenesis of PH‐20 Hyaluronidase from Human Sperm
Arming, S., Strobl, B., Wechselberger, C., & Kreil, G. (1997) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1997.t01-1-00810.x · Cited by 74
Ultrastructural Organization of Skin: Classification on the Basis of Mechanical Role
Craig, A. S., Eikenberry, E. F., & Parry, D. A. D. (1987) · Connective Tissue Research · doi:10.3109/03008208709006977 · Cited by 73
Hechter, O. (1947) · The Journal of Experimental Medicine · doi:10.1084/jem.85.1.77 · Cited by 68
A Cost-Cost Study Comparing Etanercept with Infliximab in Rheumatoid Arthritis
Nuijten, M. J. C., Engelfriet, P. M., Duijn, K., de Bruijn, G. S. J. T., Wierz, D., & Koopmanschap, M. A. (2001) · PharmacoEconomics · doi:10.2165/00019053-200119100-00006 · Cited by 64
A SPREADING FACTOR IN CERTAIN SNAKE VENOMS AND ITS RELATION TO THEIR MODE OF ACTION
Duran‐Reynals, F. (1939) · The Journal of Experimental Medicine · doi:10.1084/jem.69.1.69 · Cited by 63
Hyuga, M., Kodama, R., & Eguchi, G. (1993) · The International Journal of Developmental Biology · doi:10.1387/ijdb.8398679 · Cited by 60
Interstitial exclusion of albumin in rat dermis and subcutis in over- and dehydration
Reed, R. K., Lepsøe, S., & Wiig, H. (1989) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1989.257.6.h1819 · Cited by 56
The soluble hyaluronidase from bull testes is a fragment of the membrane‐bound PH‐20 enzyme
Meyer, M. F., Kreil, G., & Aschauer, H. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)00936-8 · Cited by 54
Role of Hyaluronidase in Diplopia after Peribulbar Anesthesia for Cataract Surgery
Hamada, S., Devys, J., Xuan, T., Ganem, S., Sahel, J., Héran, F., & Plaud, B. (2005) · Ophthalmology · doi:10.1016/j.ophtha.2004.11.059 · Cited by 53
Nafcillin Extravasation Injury
Zenk, K. E. (1981) · American journal of diseases of children · doi:10.1001/archpedi.1981.02130360021008 · Cited by 52
Oettl, M., Hoechstetter, J., Asen, I., Bernhardt, G., & Buschauer, A. (2003) · European Journal of Pharmaceutical Sciences · doi:10.1016/s0928-0987(03)00022-8 · Cited by 48
The use of hyaluronidase in the treatment of intravenous extravasation injuries.
Wv, R., Tk, K., Fr, S., & Jw, B. (1990) · PubMed · Cited by 47
Diplopia and ptosis following injection of local anesthesia without hyaluronidase
Jehan, F., Hagan, J. C., Whittaker, T. J., & Subramanian, M. L. (2001) · Journal of Cataract & Refractive Surgery · doi:10.1016/s0886-3350(01)01099-9 · Cited by 43
Muckenschnabel, I., Bernhardt, G., Spruß, T., & Buschauer, A. (1998) · Cancer Letters · doi:10.1016/s0304-3835(98)00203-1 · Cited by 37
An Experimental Investigation of Eye Movements1
Russell, J. S. R. (1894) · The Journal of Physiology · doi:10.1113/jphysiol.1894.sp000516 · Cited by 35
Treatment of Iodinated Contrast Material Extravasation with Hyaluronidase
Cochran, S. T., Bomyea, K., & Kahn, M. (2002) · Academic Radiology · doi:10.1016/s1076-6332(03)80288-x · Cited by 34
THE PANNICULUS CARNOSUS IN THE DOMESTIC PIC
ROSH, E. H., Vistnes, L. M., & Ksander, G. A. (1977) · Plastic & Reconstructive Surgery · doi:10.1097/00006534-197701000-00017 · Cited by 34
Wetting Properties of Bile Salt Solutions and Dissolution Media
Luner, P. E. (2000) · Journal of Pharmaceutical Sciences · doi:10.1002/(sici)1520-6017(200003)89:3 · Cited by 29
The serum kinetics of bovine testicular hyaluronidase in dogs, rats and humans.
Wolf, R., Chaung, L. Y., O’Hara, D. S., Smith, T. W., & Muller, J. E. (1982) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)33200-3 · Cited by 27
HYALURONIDASE IN ADMINISTRATION OF FLUIDS
Jaworski, A. A. (1950) · Archives of Pediatrics and Adolescent Medicine · doi:10.1001/archpedi.1950.04040010069007 · Cited by 26
Reconstitution of the Dermal Barrier to Fluid Diffusion Following Administration of Hyaluronidase.
Hechter, O. (1948) · Experimental Biology and Medicine · doi:10.3181/00379727-67-16300 · Cited by 26
CHEMICAL PROPERTIES OF THE PURIFIED SPREADING FACTOR FROM TESTICLE
Claude, A., & Duran‐Reynals, F. (1937) · The Journal of Experimental Medicine · doi:10.1084/jem.65.5.661 · Cited by 26
Effect of hyaluronidase on ocular motility in sub-Tenon's anesthesia
Alwitry, A., Chaudhary, S., Gopee, K., Butler, T. K. H., & Holden, R. (2002) · Journal of Cataract & Refractive Surgery · doi:10.1016/s0886-3350(01)01305-0 · Cited by 24
Hyaluronidase in ram semen. Quantitative determination, and isolation of multiple forms
Harrison, R. A. (1988) · Biochemical Journal · doi:10.1042/bj2520865 · Cited by 23
CLINICAL OBSERVATIONS ON THE USE OF HYALURONIDASE
Burket, L. C., & György, P. (1949) · PEDIATRICS · doi:10.1542/peds.3.1.56 · Cited by 20
PH-20 and sperm hyaluronidase: a conceptual conundrum in mammalian fertilization
Gacesa, P., Civill, N. D., & Harrison, R. A. P. (1994) · Biochemical Journal · doi:10.1042/bj3030335 · Cited by 20
The Use of Hyaluronidase to Treat Mannitol Extravasation
Kumar, M. M., & Šprung, J. (2003) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000077656.77618.6c · Cited by 19
Multiple forms of ram and bull sperm hyaluronidase revealed by using monoclonal antibodies
Harrison, R. A. P., & Gaunt, S. J. (1988) · Reproduction · doi:10.1530/jrf.0.0820777 · Cited by 18
Fatouros, A., Lidén, Y., & Sjöström, B. (2000) · Journal of Pharmacy and Pharmacology · doi:10.1211/0022357001774651 · Cited by 16
Duran‐Reynals, F. (1933) · The Journal of Experimental Medicine · doi:10.1084/jem.58.4.451 · Cited by 14
Permeability factor contaminating hyaluronidase preparations
Houck, J. C., & Chang, C. (1979) · Inflammation · doi:10.1007/bf00913502 · Cited by 13
Keiser, H. D., & Hatcher, V. B. (1979) · Connective Tissue Research · doi:10.3109/03008207909152325 · Cited by 12
The Use of Hyaluronidase in Ophthalmology
Tassman, I. S. (1952) · American Journal of Ophthalmology · doi:10.1016/0002-9394(52)90944-6 · Cited by 12
Mode of action of testicular hyaluronidase
Fessler, J. H. (1960) · Biochemical Journal · doi:10.1042/bj0760132 · Cited by 10
The effect of hyaluronidase on the absorption of a subcutaneously deposited radiopaque substance.
SIMON, N., & Narina, L. (1949) · PubMed · Cited by 8
DOCTOR, V. M., Spence, H., & Carroll, E. (1983) · Thrombosis Research · doi:10.1016/0049-3848(83)90264-5 · Cited by 3
CARDIAC ASYSTOLE SECONDARY TO CAROTID SINUS COMPRESSION IN THE FACE-LIFT OPERATION
Rose, E. H., Laub, D. R., & Avakoff, J. C. (1977) · Plastic & Reconstructive Surgery · doi:10.1097/00006534-197702000-00013 · Cited by 2
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
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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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