Zeneca Patent Preserves Multi-Million Dollar Anesthesia Product

Zeneca Pharmaceuticals (Wilmington, Del.) has received U.S. Patent 5,714,520 (Propofol composition containing edetate), for a novel formulation of its intravenous sedative, Diprivan. In 1996, Diprivan was the sixth leading hospital product in the United States and the world's leading anesthetic, with sales of more than $250 million. The drug (2,6-diisopropylphenol) is used to induce deep amnesia in more than half the surgeries performed each year.

The novel formulation is an oil-water emulsion containing a water-insoluble organic solvent (polyoxyethylene castor oil) and 0.005% disodium edetate, an antimicrobial agent. Edetate prevents the growth of microorganisms in the event of accidental contamination due to mishandling the anesthetic. By providing this incremental improvement in Diprivan, Zeneca ties up the drug for another 17 years.

Antimicrobial Issues

In selecting an appropriate antimicrobial agent, Zeneca looked at and rejected several candidates, as well as carriers. The idea was to avoid anaphylactic reactions in patients sensitive to common antimicrobials and surfactants. After exhaustive preclinical trials and tests on more than 1000 human subjects the company was satisfied with the current formulation.

How It's Made

Zeneca's patent outlines their manufacturing process for the new formulation:

Preparation of a sterile oil-water emulsion containing 2.25% glycerol and 0.0055% disodium edetate dihydrate (by weight), and 60 mg/mL of sodium hydroxide.

The aqueous phase is passed through a filter to remove particles, then transferred to a mixing vessel

The oil phase is prepared from soy bean oil (10% by weight), propofol (1.0%), and egg phosphatide (1.2% by weight). The mixture is stirred at 75% until all components dissolve

The oil mixture is filtered and mixed with the aqueous phase in a static mixer. The contents of the mixer are kept at 65 C and circulated in a high-pressure homogenizer and cooler until the right globule size (250 nm) is achieved.

Preparation is transferred to a filling vessel, from which it is filtered and used to charge ampules.

Antimicrobial Activity

During development, the new Diprivan formulation was tested for antimicrobial activity against infectious agents typically found in a hospital: E. coli, C. albicans, S. aureus, Ps. aeruginosa. Zeneca compared the Diprivan formulation with common typical concentrations of the following antimicrobial agents: sodium metabisulfite, sodium sulfite, and hydroxybenzoates. In every test the edetate out-performed the standard antimicrobials.

For more information, contact: Ed Seage, Investor Relateions, Zeneca Pharmaceuticals, Inc., 1800 Concord Pike, Wilmington, DE 19803. Phone: 302-886-4065.

By Angelo DePalma