The National Drug Co.

Early in the 1950s, The National Drug Company of Philadelphia introduced Parenzyme®, a 5 mg/mL suspension of trypsin in sesame oil, not for its digestant properties, but for reduction of local inflammation in phlebitis, ocular inflammation, and traumatic wounds. In this case, an enzyme
was not being used in direct contact with its substrate but for action at a distance. Before further discussing this truly novel application, some background information on National Drug and its Research Director, Gustav J. Martin, ScD, is in order.

One of five major Philadelphia drug companies at that time, National Drug
had a pharmaceutical manufacturing plant in Philadelphia and a biologics
plant in the Pocono Mountains in upstate Pennsylvania. Following several mergers, National Drug no longer exists; however, its biologics facility, now part of Sanofi Pasteur, produces a large percentage of America’s supply of flu vaccine. National Drug’s research department was also located in Philadelphia but separate from its manufacturing plant. The guiding spirit
of the research department was Gustav J. Martin.

Martin (1910–1967) earned his doctorate at Johns Hopkins, and served as National Drug’s Director of Research from 1944 to 1960. Martin thought in terms of big scientific concepts. His studies on competitive and non-competitive enzyme inhibitors led him to propound a Theory of Biological
Relativity. Of the theory’s eight main propositions, the major ones stated that there are no absolutes in biological systems to distinguish them from physical systems, that in both types of systems the only absolute is time, and that all enzymes possess only relative specificity (4). Martin once met with Albert Einstein to brief Einstein on his theory. Biological Relativity, however, did not fire the imagination of scientists and the public as Einstein’s theory had done, and it quickly faded into obscurity.

Martin had a strong practical side as well, and his research group brought forth some novel pharmaceutical products. He pioneered the use of ion-exchange resins as non-absorbable gastric antacids and antidiarrheals, as well as the use of proteolytic enzymes for systemic action.

Martin and others found, in animal studies, that injection of trypsin inhibited egg-white edema (Box 2), a sign of anti-inflammatory action. Their experimental data showed that the enzyme acts to facilitate drainage from an inflamed area by increasing permeability, causing vasodilation, and reducing the viscosity of edema fluid (5).

As the first product in a new category, Parenzyme® quickly gained a significant market. Nevertheless, it shared the disadvantages of all oily injectables: pain at the injection site, and formation of sterile abscesses. An aqueous vehicle was desirable, but trypsin is unstable in aqueous solution. This was solved by employing as the vehicle a 5% solution of gelatin, partially denatured by autoclaving. This prevented autodigestion of trypsin by providing a large concentration of protein (gelatin) to attach the enzyme. The product, protected by patent (6), was marketed as Parenzyme Aqueous.

The next extension of the Parenzyme® line was a buccal tablet. Martin hypothesized that trypsin produces local changes in permeability, permitting its absorption through the buccal mucosa (7). This was followed by an ointment, for local debridement, and finally an enteric, coated tablet containing 20 mg trypsin for oral administration, Orenzyme®. The enteric coating protected the trypsin from inactivation by the gastric juice and allowed it to be released in the small intestine. Martin claimed that the intestinal tract is not totally impervious to protein molecules, pointing out that Sabin polio virus is active as a vaccine when administered orally (8).

The commercial success of Parenzyme® led to marketing of various “me-too” products, such as Tryptar® (trypsin,Armour); Chymar® and Chymoral® (chymotrypsin, Armour); and Ananase® (bromelain), which is a protease from the stems of the pineapple plant.

Excerpt from Scheindlin's 2007 Clinical Enzymology: Enzymes as Medicine

Image of letter from National Institute of Health, Profiles

Image of building from The Antique Cannabis Book, Addendum 13a - 2nd Edition Pharmaceutical Catalogs

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