Supercritical drug discovery

UNott/Critical Pharmaceuticals aim to put some “green” into biologics

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NOTTINGHAM, U.K.—In recent years, there has been increasing pressure in the pharmaceutical arena to apply green chemistry practices to its manufacturing processes—practices that have been traditionally more familiar in other branches of the chemical industry. At the September meeting of the British Association for the Advancement of Science, however, Dr. Steve Howdle of the University of Nottingham and co-founder of Critical Pharmaceuticals described how green methods can offer benefits other than environmental and may actually help make drugs better.

In particular, Howdle and his colleagues are replacing harsh, toxic solvents like benzene and chloroform with supercritical CO2 to develop drug delivery coatings. Aside from its "benign-by-design" characteristics, supercritical CO2 allows researchers to coat drugs at relatively ambient temperatures—a critical factor when working with particularly labile biologic therapeutics such as proteins.

"Many very potent new drugs based on proteins are being discovered all the time," Howdle says. "Many of these new proteins are fragile and are damaged by high temperatures and harsh solvents used in conventional processes. Our process works in CO2 at close to room temperatures so the molecule is not damaged by the mixing process."

Supercritical processes also offer scientists the option of producing very clean products, adds Dr. Andrew Naylor, process development project manager at Critical Pharmaceuticals. During the manufacturing process, the supercritical fluids are maintained at high pressure, but when the pressure is reduced, they revert to a gas and diffuse out of the product.

"Thus products can be produced that contain no solvent residues," he says."Additionally, products can be produced which would be extremely difficult, if not impossible, to make by conventional methods; for example, the formulation of temperature- or solvent-sensitive therapeutics."

Biologics are only one possible target for the supercritical methods, Naylor says, suggesting that the company has also works on formulations involving small-molecule APIs, DNA molecules, and vaccines.

The company has largely focused its efforts on the development of coatings comprised of lactic acid derivatives because of their biodegradable nature—they are similar to the materials used in dissolvable stitches—and it has particular interest in formulations that will allow sustained or controlled release of the drugs (see Catch and controlled release).

"Biodegradable polymers are particularly attractive for use in drug delivery, as once introduced into the body, they require no retrieval or further manipulation and are degraded into soluble non-toxic by-products," explains Howdle, who is company CSO. "Different polymers degrade at different rates within the body and therefore polymer selection can be tailored to achieve desired release rates."

The company's lead product is a sustained-release formulation of recombinant human growth hormone, which is currently in preclinical testing. According to Naylor, the company is looking to take this product into Phase I clinical trials during 2008.

An added benefit of using supercritical methods may be significant improvements in the activity of a drug per unit volume or mass, which could lead to reduced dosing requirements for some therapeutics.

"This could have several advantages, for example, with injectable products where patient comfort would be increased as the injection volume could be lower and potential toxicity issues could be reduced," Naylor explains."Additionally, product shelf life could be extended by the lack of degradation, as the time taken to reach any degradation limits would be extended."

Aside from its own drug pipeline, the company is looking to either partner with other pharmaceutical companies and license out its technology.

"There has been a great deal of interest in our work and in the technology," Naylor says. "This has led to a range of ongoing collaborations in a number of fields.Going forward, the company has successfully scaled up its supercritical fluid process and will have a GMP/sterile manufacturing capability during 2008."

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