Many conventional methods for preparing drugs employ high temperatures and harsh solvents such as chloroform, benzene and other volatile organic compounds. Solvent residues often remain in the finished product, and these can be both toxic to the patient and environmentally damaging. They may also adversely affect drug performance.
A UK-based biotech bionanotechnology spinoff from the University of Nottingham is now exploiting the groundbreaking research of chemist Steve Howdle into supercritical fluids. A supercritical fluid is a substance with the unique ability to diffuse through solids like a gas, and dissolve materials like a liquid. With these properties the potential for use as a solvent is clear. Howdle’s company – Critical Pharmaceuticals – plans to use a process developed by his research group to remove altogether the need for organic solvents in drug preparation.
Howdle’s research focuses on supercritical carbon dioxide (scCO2) at near room temperature. The Nottingham chemists are particularly interested in using scCO2 to make polymer drug coatings using biodegradable plastics. Biodegradable polymers can be plasticised with scCO2 at near room temperatures, and the low temperature of the process means that delicate bioactive components can be mixed into the polymer without any loss of activity.
When subjected to high pressures the plastics melt, and drug particles can then be wrapped in a biodegradable coating for injection under the skin. Once injected the polymer begins to degrade, and releases the drug over the course of several days to a week.
Critical Pharmaceuticals is currently testing a human growth hormone prepared in this way. In vitro tests have confirmed that the hormone survives the plasticization process, and in vivo tests are underway. Phase I clinical trials are due to begin in the early part of next year.
“Critical Pharmaceuticals is a concept that came out of academic research I carried out with supercritical fluids in the late 90s,” says Howdle. “We found a neat effect with polymers that allowed us to mix things into them, and we filed patents on that.” Howdle put together a business plan along with his Nottingham colleague Kevin Shakesheff, and in 2002 entered this in the Research Councils’ Business Plan Competition. Howdle and Shakesheff won the competition, and with the prize fund launched the company.
Since then Critical Pharmaceuticals has gone through a seedcorn round of funding, and the company now has nine employees working in an incubator unit in central Nottingham. Critical Pharmaceuticals is currently looking for funding of around €7.5m, so that it can move forward to clinical trials.
“We intend to talk with different companies in different drug indication areas,” says Howdle. “Human growth hormone is a good test market, as everyone knows that it’s quite a difficult one to work with. If we can come up with a working product based on that, others will see that we have a technology that works, and will want to work with us on their molecules.”
Drug coating is the primary focus of Critical Pharmaceuticals, but another application with potential is tissue engineering, where a porous scaffold is used as a template and guide for cell proliferation, cell differentiation and tissue growth. The polymer can also release precise amounts of protein growth factors and other drugs.
“Here we are working again with Kevin Shakesheff, and also with Richard Oreffo in Southampton,” says Howdle. “Richard is a well known clinician in the area of bone regeneration. We have nice suite of papers from this work that show how the technologies we’ve developed can be used to make materials that can effectively fix critical defects in bone injuries. This is largely academic, but I think there is some commercial potential there as well.”
Further reading: Putting the fizz into chemistry: applications of supercritical carbon dioxide in tissue engineering, drug delivery and synthesis of novel block copolymers, Tai et al., Biochem. Soc. Trans. 35, 516 (2007).
Figure: Schematic of Critical Pharmaceuticals’ particle mixing process. (1) Polylactic acid and drug-loaded polyethylene glycol are placed in a high pressure mixing chamber. (2) Supercritical carbon dioxide is added to plasticise the polymers and mix them with the drug particles. (3) The liquefied polymer/drug mixture is released quickly through an opening, leading to rapid depressurisation and the spraying of drug-loaded microspheres (source: Critical Pharmaceuticals Ltd).
Article first published in Nanomaterials News.