Status: approvals withdrawn

Organizations involved:

Wyeth – Manuf.; R&D; Tech.; World mark.; Former

Cross ref.: See the entry below for ovine hyaluronidase (Vitrase) for further information about hyaluronidase. See the Hyaluronic Acid Products entry (#925) for information about hyaluronic acid, which is broken down by hyaluronidase.

Description: Wydase refers to aqueous and lyophilized (freeze-dried) formulations of hyaluronidase extracted from bovine testes. Hyaluronidase (hyaluronate 4-glycano-hydro-lase) catalyzes the depolymerization of mucopolysaccharides, particularly hyaluronic acid (hyaluronan, a major component of intercellular matrix of connective tissue; see enty #925) and chondroitin sulfates A and C. Bovine hyaluronidase has a molecular weight of ~55 kDa.

Wydase’s primary medical use involved breaking down hyaluronic acid to increase drug diffusion, particularly to promote increased diffusion of local anesthetics for eye surgery. It was also used for hypodermoclysis or intradermal administration of large volumes of fluid when intravenous injections are contraindicated, facilitating more rapid absorption of the fluid.

Wydase was packaged in vials containing 150 NF units/mL, in 1 mL or 10 mL vials. It was also available as a lyophilized powder, which should be reconstituted with normal saline to a concentration of 150 Units per mL.

Biological.: Hyaluronidase refers to a group of naturally occurring enzymes that can digest certain forms of proteoglycan carbohydrate molecules or glycosaminoglycan polysaccharides, particularly hyaluronic acid. Hyaluronidase hydrolyzes hyaluronic acid by splitting the gluco-saminidic bond between C1 of the glucosamine moiety and C4 of glucuronic acid. Hyaluronidase causes hydrolysis of the endo-N-acetyl hexosaminic bonds of hyaluronic acid and of the chondroitin sulfate acids A and C, primarily to tetrasaccharide residues. Vertebrate hyaluronidases are separated into two general classes – the neutral hyaluronidases, such as the predominantly sperm-associated protein PH20; and the acid-active hyaluronidases, which have a distinct pH optimum between pH 3.5 to 4.0. There are basically two types of hyaluronidases: those which are relatively non-specific and cleave hyaluronic acid, chondroitin and related polysaccharides; and those which specifically cleave hyaluronic acid.

One unit of hyaluronidase enzyme is that amount which liberates one micromole of N-acetylglucosamine per minute from hyaluronic acid at 37°C and pH 4.0. A unit of enzyme has also been defined as the amount that produces the same turbidity reduction in a mixture of hyaluronic acid and albumin as 1 I.U. (International Unit) of a standard hyaluronidase preparation. Hyaluronidase activity is measured in vitro by monitoring the decrease in an insoluble serum albumin-hyaluronic acid complex as the enzyme cleaves the hyaluronic acid component.

Hyaluronidases are widely distributed in nature in for example, mammalian testes, liver and spleen and in certain microorganisms. Mammalian hyaluronidases are of the first type; that is, they cleave (non-specifically) hyaluronic acid, chondroitin and other polysaccharides. Hyaluronidase is widely distributed in animal tissues, and is found in high concentrations in the bovine (cattle) and ovine (sheep) testes. It is also produced by a number of bacteria. The enzyme is widely used as a reagent to break down tissues, e.g., for preparation of isolated cells for tissue culture techniques.

Hyaluronidase was used as a “spreading agent” to facilitate the dispersion and absorption of other drugs, e.g., to facilitate diffusion of local anesthetics used during intraocular surgery and drugs intradermally (under the outer layer of skin), by breaking down hyaluronic acid in these tissues. Hyaluronidase injected into connective tissue modifies the permeability of the tissue through the hydrolysis of hyaluronic acid, thereby decreasing the viscosity of the cellular cement and promoting diffusion of injected fluids or localized transudates or exudates, thus facilitating their absorption. When no spreading factor is present, agents injected subcutaneously or into the vitreous humor of the eye spread very slowly. Spreading is dependent on local interstitial pressure, normally initiated by injected solutions. The increase in the rate of diffusion is proportionate to the amount of enzyme, and the extent is proportionate to the volume of solution.

Hyaluronidase is also used in fertility treatments. A typical mammalian egg is surrounded by an outer layer of about 3,000 cumulus cells embedded in an extracellular matrix rich in hyaluronic acid (HA). The sperm protein PH-20 has hyaluronidase activity and is present on the plasma membrane of mouse and human sperm. PH-20 enables sperm to penetrate the egg’s cumulus barrier, an essential step in the fertilization process. PH-20 exists as both a soluble isoform and a glycosylphosphotidyl-inositol (GPI) linked isoform, in which PH-20 is bound to the membrane of the sperm acrosome. Sequence analysis indicates a GPI-anchor attachment site at amino acid position number 490. Since it occurs in sperm, PH-20 has been investigated for use in birth control vaccines. Effective contraception (100%) has been obtained in male and female guinea pigs immunized with PH-20.

Nomenclature: hyaluronidase, bovine/Wyeth [BIO]; Wydase [TR]; hyaluronate 4-glycanohydrolase [SY]; hyaluronoglucosidase [SY]; mucinase [SY]; spreading factor [SY]; hyaluronate lyase [SY]; bovine hyaluronidase [SY]; EC 3.2.1.36 [EC]

Companies.: Wydase was developed, manufactured and marketed by Wyeth.

FDA class: Medical device

Approvals: Date = unavailable

Indications: Product insert unavailable; See the Amphadase and other hyaluronidase entries currently approved for the same indications: as Wydase.

Status: In Jan. 2001, Wyeth-Ayerst announced that it would not resume manufacture of Wydase. Approval of Wydase was voluntarily withdrawn at Wyeth’s request on Jan. 23, 2003. Wydase had already been in limited supply since the company voluntarily closed its Marietta, PA, manufacturing facility (cited for multiple GMP violations; and many other older products manufactured at this site were also abandoned).

Hyaluronidase preparations (as a class) used for pathology applications are regulated as class II medical devices exempt from most premarket notifications; and for use in vitro fertilization procedures as class I medical devices, requiring PMA or 510(K) approval.

The FDA’s approval letter for a related hyaluronidase product, Vitrase, states that Wydase was originally approved through FDA’s Drug Efficacy Study Implementation (DESI) program (see Federal Register, Sept. 23, 1970, vol. 35, no. 185, p. 14800-14801). Thus, Wydase was essentially an old, grandfathered-type product, probably never received a conventional NDA, with DESI review finding it safe and effective and allowing it to remain on the market.

Medical: Hyaluronidase was reported in the literature in 1986 to enhance the diffusion of ocular anesthetics, and since then, has been widely used in injections of local anesthesia for cataract surgery and other ophthalmic surgeries. In eye surgery, particularly cataract surgery, use of hyaluronidase (injection into the vitreous humor or fluid of the eye) promotes the spread of local anesthetics. This accelerates the onset of akinesia (halt of eye movement), and also reduces the increase in intraocular pressure that can be seen after peribulbar block. Local ocular anesthetics often don’t work as well without Wydase. When Wydase is used, the local anesthetic is injected, and with just a bit of massage, it will infiltrate the surrounding tissues. Without hyaluronidase, local anesthesia is slower and there may be more swelling from the volume of the anesthetic injection. This can cause some trouble in blepharoplasty, for example, where minimal distortion is desired.

For extravasation of intravenous solutions (subcutaneous or intradermal injection), especially hypertonic solutions or those containing calcium, where intravenous administration is contraindicated, Wydase 1 mL (150 NF Units) may be given subcutaneously or intradermally as five separate 0.2-mL injections around the periphery of extravasation site.

Hyaluronidase preparations (not Wydase) are also used in some in vitro fertilization procedures to facilitate removal of the cumulus cells surrounding oocytes in assisted reproduction technology (ART) procedures.

Market: Currently (in terms of 2006 sales), hyaluronidase therapeutics are not major products. The total U.S. market size for Hyaluronidase Injection is $8.6 million, according to 2006 IMS data. Sales are likely increasing, particularly those of Hylenex.

In 1999, Wydase was used as a spreading agent in approximately 750,000 ophthalmic surgery procedures. ISTA Pharmaceuticals (see entry below for ovine hyaluronidase) has similarly reported that hyaluronidase was used in over 750,000 ophthalmic surgeries annually, and that ophthalmic uses accounted for about 75% of the total sales of Wydase.

Bovine hyaluronidase (Amphadase) and ovine hyaluronidase (Vitrase) are now the only hyaluronidase products available in the U.S.

Many ophthalmologists were very upset that Wyeth discontinued Wydase, considering it essential for many surgical anesthesia procedures. With the shortage/absence of Wydase (until approval of Amphadase and other hyaluronidase products), ophthalmologists coped initially by using smaller concentrations of Wydase or switched to topical anesthesia, which doesn’t require the use of hyaluronidase. Complications occurring in the absence of Wydase have been reported by some clinicians. Some ophthalmologists have reported that patients having undergone ophthalmic surgery experienced transient or permanent postoperative diplopia following periocular anesthesia without hyaluronidase. In the absence of hyaluronidase, either the anesthetic was in longer contact with the extraocular muscle and caused toxicity, or increased intraorbital pressure led to decreased blood flow and ischemic injury to the muscle. Some ophthamologists apparently resorted to ordering custom compounded hyaluronidase preparations from commercial pharmacies, involving considerable risks in terms of variability of enzyme content/activity, sterility, etc.

R&D: Besides the approved animal-derived hyaluronidase products and Hylenex, recombinant hyaluronidase, other companies are also developing hyaluronidase products. For example, in Feb. 2004, Theratase plc, now Biozyme, and Pharmalink formed a joint venture company, Applet MBJ AB, for development of hyaluronidase for treatment of edema and as an antiinflammatory agent in the prevention of transplant rejection.