Benign by design: the long road to biodegradable drugs
The technology exists to create biodegradable drugs, but is the pharmaceutical industry ready for a new way of thinking? Elly Earls finds out.
For decades pharmaceuticals have been designed to be as stable as possible, so by the time they reach their eventual recipients, there's no danger they've been degraded. The problem is that these long-lasting drugs are not only carrying out their intended function, they're leaving our bodies still undigested and unchanged, thereby causing as yet unquantified harm to animals, humans and the environment. Momentum is gathering, however, for new chemistry techniques designed to make sure drugs do their job and no more.
The question is: are pharmaceutical companies and regulators ready to embrace them?
To be approved by the US Food and Drug Administration (FDA), a new drug must be proven to be stable within its prescribed packaging and storage conditions, so that when it finally reaches a patient, there's no question about whether or not it will be able to carry out the function it was designed for. An unwanted side effect of these durable drugs is that after they leave our bodies, they accumulate in water supplies, causing damage to fish, animals and humans that we have no way of accurately measuring.
"If you make a calculation based on the concentrations of drugs we normally find in surface or drinking water, you'd need to drink about 2,000 litres a day to be affected. But we have no tools to assess what the impacts are of lifelong uptake," says Dr Klaus Kümmerer, director of the Institute for Sustainable and Environmental Chemistry at Leuphana University in Lüneburg, Germany. "There are very long time scales involved so you cannot for sure link a cause to an effect."
What's fairly safe to say, however, is that there is an accumulative effect over time. "The big fish eat the little fish, who eat the even littler fish, while all the time the water keeps circulating," explains John Warner, one of the founders of 'green chemistry', a field that by definition is 'the design of chemical products and processes that reduce or eliminate the generation of hazardous substances'.
"People can debate have we crossed that line or are we not there yet, but who decides when the level is acceptable or not? It's a pretty big problem," Warner adds.
Searching for the Holy Grail
For this reason, researchers like Warner and Kümmerer have dedicated their careers to finding what Warner calls the 'Holy Grail' of drug design: triggered instability. "If you think about it, nature is filled with all kinds of triggers, where chemical reactions are happening simultaneously and interacting with each other," he explains. "We need to learn from nature and find a way to stabilise material when we want it to be stable and destabilise it when we don't."
Both scientists are some way towards achieving this elusive balance. Warner, for example, is working on applying a process called non-covalent derivatisation to drug design. In a nutshell, a non-covalent derivative (NCD) is a bimolecular compound that, in its solid state, is stable, but when it is released into the environment, the two molecules dissociate and degrade. In the context of forming biodegradable drugs, a new molecule could be added to a drug that had failed its stability test, forming an NCD that would be stable until it had done its job and would then degrade in the environment.
"If the degradation generates innocuous by-products, that's a good thing, but if it degrades into a worse material that's not such a good thing," Warner says. "So it's still a difficult task."
Meanwhile, Kümmerer has been working on two approaches to the same problem. First, he and his colleagues have been experimenting with slightly changing the molecular structure of existing pharmaceuticals to incorporate biodegradability; and second, they have been looking into the value of designing green drug derivatives by non-targeted synthesis and screening for biodegradability.
"We still have a bit of a way to go before we understand biodegradability so that could be a bottleneck," he admits, adding that while the screening approach is a little bit trial and error, it has good prospects for success.
Education, education, education
But finding technical solutions is just one part of the puzzle; for biodegradable drugs to become commonplace, not only will regulators have to be on board, mind-sets across the pharmaceutical industry will need to evolve substantially. "It takes a different perspective of thinking," Kümmerer believes, "And I'd say we are several years away from this point of view."
That said, the pharmaceutical industry has arguably embraced the wider field of green chemistry - which is made up of 12 separate principles - more fully than any other, with operators across the sector looking at areas as diverse as developing more efficient ways to synthesise drugs and experimenting with greener solvents to reduce the amount of hazardous waste generated in the process of drug development.
Kümmerer's research has also shown that between 10-20% of commercial drugs are already biodegradable - almost by chance. "The question is: how far would we be able to go if this was done by intention?" he asks, adding that more and more companies are starting to see the business opportunity in intentionally designing drugs that disintegrate harmlessly in the environment. "It's gaining momentum I would say; companies want to be prepared if more consumers ask for better drugs without these unwanted side effects."
For both Kümmerer and Warner, the key to getting biodegradable drugs into the mainstream will be education. "We need to change the curriculum of undergraduate and graduate chemistry education to make sure this stuff is in there," Warner advises. "And wouldn't it be interesting if, alongside this, the pharmaceutical industry created a programme where every two years, the people at the bench synthesising molecules has some re-training in this area? This would mean that when chemists first put pencil to paper to invent the chemistry, they were already thinking about it, rather than after £100 million has been spent and the cows are already out of the barn."
As Kümmerer concludes: "We have the knowledge, we have the tools; we have to bring the knowledge and tools to the students and into companies directly."