Converting Intravenous Dosing to Subcutaneous Dosing With Recombinant Human Hyaluronidase - Pharmaceutical Technology

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Converting Intravenous Dosing to Subcutaneous Dosing With Recombinant Human Hyaluronidase
The preferred route of administration for an injected therapeutic agent is subcutaneous (SC), but SC injections are generally limited to no more than 1-2 mL in volume, representing a major challenge, especially for large protein biologics.


Pharmaceutical Technology


The extracellular matrix


Figure 2. Model of enzyme-mediated delivery through the interstitial matrix. Degradation of glycosaminoglycans (gold) by hyaluronidase (blue) promotes flow of drug molecules (magenta) through the interstitium. Collagen fibrils (grey/white) are not modified and retain the architecture of the skin. (FIGURES: HALOZYME THERAPEUTICS)
The extracellular matrix (ECM) serves to control the diffusion and bulk-fluid flow of molecules while maintaining specific tissue architecture. Within the hypodermis, the ECM is composed of a structural network of fibrous proteins embedded within a hydrated viscoelastic gel (see Figure 2). The fibrous network is composed of structural building blocks such as collagen and elastin that support adipocytes and vascular structures. This solid network is embedded within a viscoelastic gel composed of glycosaminoglycans (GAGs) that creates a barrier to bulk-fluid flow because of their viscosity and water of hydration (13). GAGs are complex linear polysaccharides characterized by repeating disaccharide structures of an N-substituted hexosamine and an uronic acid, including hyaluronan (hyaluronic acid or HA), chondroitin sulfate, dermatan sulfate, heparin sulfate, heparin and keratin sulfate. All (except HA) exist covalently bound to core proteins.

Together, collagen and HA create a volume barrier for local injections of no more than 2 mL, as the tissue distortion that occurs with larger volumes is painful and often leads to reduced patient compliance for repeat-injection drugs (14). In addition, the collagen matrix can trap certain drugs allowing them to be locally degraded, and the viscosity of the ECM can cause large proteins to be retained, leading to injection- site reactions and lowered bioavailability. Despite the obvious advantages of SC administration and the ongoing trend to convert IV and IM drugs to SC regimens, the barriers imposed by the ECM significantly reduce the feasibility of developing new therapies with SC dosing.

Hyaluronidase: a strategy for overcoming ECM's limits

Transiently degrading key components of the ECM may lower the dispersion and volume barriers of the ECM and permit the conversion of many IV and IM drugs to SC administration (15). Collagen, however, has a half-life of almost 15 years and its removal would likely lead to permanent tissue structural changes and damage (16). Modifying HA is a far more attractive target for drug delivery, as HA has a half-life of 15–20 h (17).

The clinical development of a drug-delivery system mediated by a hyaluronidase can be traced back to the discovery in 1928 of a "spreading factor" in extracts of animal testes that facilitated the dispersion of co-injected materials (18–20). Based on its ability to digest HA in vitro, the spreading activity in the extracts was defined as a hyaluronidase (21). It became clear that nature had used a HA-degrading enzyme as a delivery agent to increase the dispersion of venoms, toxins, sperm, and bacteria through the ECM (22). To use this enzyme as a drug-delivery tool, fractionated extracts containing hyaluronidase from bovine testes were developed as pharmaceutical products. The first such product, Wyeth's Wydase, was approved in 1948, followed by Searle's Alidase in 1949, and Abbott Laboratories' Hyazyme in 1951. At one point, 10 hyaluronidase-containing compounds (with approved new drug applications) were legally on the market in the United States. The active protein in these crude preparations that was responsible for the hyaluronidase activity was never actually identified. As a result of the animal origin (bovine) and lack of purity (<1%), several safety issues limited the chronic use of these agents. These crude preparations can be contaminated with proteases, immunoglobulins, and other factors that increase capillary permeability and can result in IgE-mediated allergic reactions with repeat administration (23–25). Any pharmaceutical product derived from animal tissue has the potential to be plagued with a shortage of raw materials, subsequent manufacturing and supply problems, and the real risk of transmission of viruses and other contaminants (e.g., spongiform encephalopathies such as mad cow disease).

Not surprisingly, numerous attempts were made to purify the hyaluronidase to homogeneity from testicular extracts. Unfortunately, attempts to increase the specific activity from chromatographically fractionated preparations merely served to show that the enzyme was present in only trace amounts in the original marketed preparations (26, 27). Such commercial preparations, with specific activity of approximately 750 units/mg, could be further purified with decreased yield to 50,000–100,000 units/mg (28–30).


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