MEDICINES that could be very useful, but which have toxic side effects, could become safer and more widely available thanks to some unexplained chemistry.
Many potential drugs are fat-soluble chemicals that do not dissolve or mix well with water, blood and other body fluids. To turn them into medicines, they are usually dissolved in a 鈥渃arrier鈥� oil, and then an additive such as a detergent is used to disperse the oily solution in water. A more sophisticated approach is to encase the drugs in microscopic water-soluble particles. But the carrier oils and additives can have unpleasant side effects, trigger allergic reactions and be painful to inject, while the soluble-particle approach requires a complicated manufacturing process.
Ric Pashley of the Australian National University in Canberra believes he has found a better way. Two years ago, he discovered that, contrary to what we are taught at school, oil and water will mix 鈥� providing all the gas dissolved in the liquids is removed first (快猫短视频, 22 February 2003, p 17).
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While chemists continue to puzzle over what exactly is going on (see 鈥淚t works 鈥� but why?鈥�), Pashley and Mathew Francis, also of ANU, have now shown that the technique can be used to mix fat-soluble drugs with water, which could do away with additives and their adverse reactions, as well as simplifying drug production. They will publish their results in an upcoming issue of Colloids and Surfaces A.
Pashley and Francis have demonstrated their technique on two fat-soluble drugs: propofol, a widely used sedative that comes in liquid form, and a solid drug called griseofulvin, which is taken by mouth to treat jock itch and other fungal infections. The technique also worked on soybean oil, which is commonly used to dissolve fat-soluble drugs, as well as a variety of other oils. What鈥檚 more, the oil droplets are a good size 鈥� about 0.6 micrometres in diameter 鈥� for intravenous injection, says Pashley.
鈥淵ou can minimise droplet size without dispersal agents,鈥� says Laurence Mather of the University of Sydney at the Royal North Shore Hospital. The technique has the potential to 鈥渙pen the way to making many more drugs for injection without complicated formulations鈥�, he says.
That won鈥檛 be happening just yet, though. Any new way of formulating drugs has to undergo years of testing to meet stringent regulatory requirements. But the drug testing process itself could be speeded up by Pashley鈥檚 technique. Around 40 per cent of newly formulated drugs are fat-soluble, so a way of dispersing them in solution needs to be found before they can be tested. 鈥淎t the moment new drugs may just be left on the shelf in the 鈥榯oo hard鈥� basket,鈥� Pashley says. 鈥淥ur process means you could just disperse the drug in water and start [testing].鈥�
It may also be possible to produce improved versions of available medicines. For example, patients in intensive care who receive the sedative propofol in soybean oil for long periods of time may develop dangerously high levels of fat in their blood. If propofol could be dispersed in water using the Pashley technique, that side effect would be eliminated.
The technique could even be used to create new formulations of cannabis for pain control, Mather suggests. Cannabis is very oily, which has made it difficult to come up with formulations that provide an accurate dose, he says.
The ANU and the University of California, where Pashley did the initial experiments, have applied for patents on the oil-mixing technique for use with 350 different types of drug.
It works 鈥� but why?
Anyone who has ever made French dressing knows that oil and watery solutions like vinegar don鈥檛 mix 鈥� unless you shake them hard enough to overcome the forces that hold the oil droplets together, and then use additives such as mustard to stop the emulsion separating again. If you鈥檙e a chemist preparing industrial or pharmacological emulsions, you may use a detergent instead.
But this picture began to look a little shaky when, in 2003, Ric Pashley of the Australian National University in Canberra reported that removing the gas dissolved in oil and water allows them to form a stable emulsion. No additives are required, and only minimal shaking.
A finding like that will mean rewriting chemistry textbooks 鈥� or at least, it will once the mechanism behind the effect has been worked out. But two years on, and the draft for those new textbooks is no closer. In fact the mystery has deepened.
After repeating the experiments last year, a team led by Julian Eastoe at the University of Bristol, UK, discovered that the oil that Pashley used was probably contaminated with trace amounts of surfactants (Langmuir, vol 20, p 5673). But that was not the whole story.
When Eastoe鈥檚 team added pure oil to water, they found to their surprise that they could still create stable emulsions. What鈥檚 more, they said, degassing the water turned out to be unnecessary. Instead, the key seemed to be the repeated freezing and thawing used to remove the gas 鈥� perhaps because it allows droplets of oil, which freezes more slowly, to creep into cracks in the frozen water, forcing intermingling.
But Pashley says that experiment is flawed: to prove that degassing is unnecessary, the Eastoe team added the gas back as the mixture thawed. That is too late, says Pashley, because the emulsion has already formed. What鈥檚 more, Pashley has also created emulsions by degassing the oil and water separately, and then mixing them 鈥� suggesting that the freezing and thawing is not simply forcing the oil and water together.
鈥淚t鈥檚 not a dead dodo. The jury is still out, but the mystery can only be solved by rigorous, independent research,鈥� Eastoe says.
