2006 Annual Scientific Meeting - CLICK FOR PROGRAMME

Propofol Formulations

Professor J Robert Sneyd, Peninsula College of Medicine and Dentistry, Plymouth

Intravenous anaesthetic agents generally do not dissolve easily in water.  Hypnotic development has always had two strands, one addressing the basic pharmacology and the second which wrestles with pharmaceutical difficulties.  Propofol is no exception and its early development was substantially impaired by initial formulation in Cremofor with a late change to an oil in water emulsion.

After a tranquil period in which the manufacturer’s patents restricted activity we have in recently years seen a flurry of developments.  Incentives for innovation include commercial opportunity, reduction in lipid load, improvement of pain on injection, the consequences of bacterial contamination and the boundless ingenuity and determination of the human spirit!

Early manufacturers of rival generic propofol formulations adopted the “standard” oil in water emulsion but were stymied in the US market by a requirement that the presentation include a preservative and an unusual patent situation whereby the patent molecule propofol was available for all to copy but the addition of EDTA reserved to the original manufacturer, Astra Zeneca.  Competitors produce formulations using sodium sulphite and other additives and there was a good deal of commercially inspired squabbling about their relative merits, efficacy, adverse effects.  Although the main dispute about sulphite was extinguished by the FDA, border skirmishes continue!

Attempts to get away from lipids encompassed some well known pharmaceutical approaches (Cremofor and cyclodextrin), some startling and original polymer chemistry and some bizarre applications of industrial solvents.

If we can’t dissolve propofol on its own then perhaps we can modify it to something that is soluble.  A whole string of propofol pro-drugs have been devised but the approach seems to be intellectually flawed given their need for initial activation by the liver and a possibility, in one case, of subsequent release of formaldehyde, a substance which is generally regarded as not beneficial to the human body.  Since the main thrust of anaesthetic drug development is towards compounds with quick onset and rapid termination of action, the pro-drug approach likely unattractive for general anaesthesia however it may have possibilities for critical care sedation where the timescales are longer and the objections to lipid accumulation justifiably greater.

Perhaps we shouldn’t altogether give up trying to dissolve propofol in water?  Although propofol (which is in it’s native state an oily liquid akin to diesel) is only very sparingly soluble in water, clever physical chemistry can produce stable propofol water mixtures and these may yet prove to be clinically useful.

Clinicians with an interest in “propofol watching” can keep abreast of developments by plodding through patent databases, the biomedical literature or simply turn up for this lecture!

A helpful recent review article is:

Naguib  MB, Baker, MT. Propofol: The Challenges of Formulation. Anesthesiology. 103(4):860-876, October 2005.