Media hype about medical innovations tends to focus on new therapies emerging from laboratories and clinical trials. Sadly, many breakthroughs fail to achieve optimal results in the real world, for reasons ranging from poor adherence by their patients, to drug formulations that may bias against atypical users, from children to people with stroke.
Take cancer, for example. Billions of dollars have poured into cancer research; oncology therapies accounted for a third of drug development programs between 2006 and 2015. Yet treatments are often brutal in their side-effects, and often stave off death for a short period, while leaving the patient little enjoyment of their extended time. Dr Chris McConville, senior lecturer in pharmaceutics, formulation and drug delivery at the University of Birmingham, is exploring the role of implant technology to overcome the ‘scorched earth’ approach of current approaches like chemotherapy.
“We have good cancer drugs: they have been through the research and if we test them directly on cancer cells, they work well. But the way they are delivered is highly inefficient,” he says. Because cancer drugs target fast-diving cells, they attack many healthy ones, such as those responsible for hair growth, and the cells lining the stomach, explaining why hair loss and sickness are two common side effects. Whether taken orally or through injection, as little as 1% of a drug reaches a cancer specifically. The rest goes “everywhere else. If we don’t find a way to target locally, drugs will attack all these areas just as much”. Working with oncology experts and surgeons, McConville has developed implants to localise delivery in two of the hardest-to-treat cancers; brain and pancreas.
Brain cancer comes with an often poor prognosis - the 5-year overall survival rate is only 35%. The biggest obstacle to treatment is the blood-brain barrier, the semi-permeable membrane that protects the brain from pathogens and toxins circulating in the blood but which, by the same virtue, lets only a tiny amount of blood-borne cancer therapeutic agents through. This means drugs either cannot be delivered or have to be administered in very high doses causing major side-effects. Dr McConville is working on implantable devices that can deliver cancer-fighting drugs within the brain.
Currently, surgical removal is the first line of defence for brain tumours, but it always leaves some cancer cells behind, and subsequent chemotherapy treatment can be ineffective as cancer cells gain resistance. McConville’s implant can be placed into the resection margin of the cavity of the original tumour and deliver drugs in a more targeted way to the area to kill off remaining cells. It can be placed deeper into brain tissue in order to reach those deep seated tumour cells that can’t be reached via conventional drug delivery.
The drugs are diffused steadily and the device itself, made from polymers, biodegrades when the load is delivered. “The drug is completed released within three weeks and the brain implant then degrades away,” says McConville. Because it delivers to the brain, this entry route avoids the common side-effects of current treatments, such as diarrhoea, vomiting etc. which makes them dose limited. The blood-brain barrier flips from a treatment problem to an ally, stopping the drugs leaking back into the bloodstream.
A second implant is for pancreatic cancer, another hard-to-treat condition due, partly, to the pancreas’ encasement in arteries which makes it often impossible to remove a tumour and re-sect the area. Surgery often leaves behind cells, which grow locally or break off to form metastatic cancers elsewhere. Working with surgeons, McConville has developed an implantable device to deliver a powerful four-drug cocktail. Consulting with experts during the design phase, McConville was able to factor in technical and operational nuances.
For instance, surgeons warned against implanting a drug-loaded device straight after pancreatic surgery, a gruelling procedure lasting up to seven hours that leaves patients in a weakened state. The drug itself could impair the healing of an area that requires substantial ‘re-plumbing’ during this procedure. To work around this, McConville designed in a catheter, allowing the drugs to be piped in later and locally, protecting other areas.
McConville says collaboration with surgeons is essential to designing effective medical technology. Birmingham provides fertile context for that interaction thanks to the close collaboration with its local hospitals, especially Queen Elizabeth Hospital. “Birmingham provides a unique academic context because it has scientists working shoulder-to-shoulder with clinicians. They come to our lab and we go to their surgeries. We get to see how brain tumours are removed in theatre, and how our devices would work in that setting”.
McConville has colleagues at other Russell Group universities that are “always chasing clinicians; asking if they see a fit for their research. We have clinicians coming to us, telling us their problem and asking if we can solve it. That two-way street is unique to Birmingham. It starts you off on the right foot. You can meet with a surgeon and they can tell you things you’ve never thought of”.
Age-appropriate drugs: factoring children into drug design
A second strand of work at the university focuses on the role that formulation, design and education factors can play in ensuring patients adhere to their regimens. Adherence is one problem. “We are spending inordinate amounts of money developing new drugs but if patients don’t use them properly or at all, they are unlikely to work,” says Professor John Marriott, who leads the new pharmacy developments within the College of Medical and Dental Sciences. This amounts to eye-watering waste considering that, of the roughly £12 billion drugs bill for the NHS, around half of medicines are not adhered to properly, says Marriott.
Some obstacles are cultural; certain ethnic groups might not take formulations that contain animal products like gelatine. Social pressures might also be a factor, especially for an individual that might have to take a battery of drugs. “Young people, if there are going to a friend’s sleepover, wouldn’t want to appear different and take with them a large panoply of drugs,” says Marriot. Some patients can pursue practices that are simply bizarre. Marriot recalls one elderly woman at a community pharmacy who poured all of her pills into one bag – around 8 different agents overall – and took them on a completely ad hoc basis.
Academics at the School of Pharmacy, are also tackling another drug delivery problem: ensuring medicines work equally as well in children as adults. While laws have changed over the last decade to ensure that new medicines come in paediatric formulations, there are many products already used, such as antibiotics, which are not age appropriate.
One factor is taste. Liquids are often used for child medicine because it offers flexibility in dosing size, but liquids aren’t appropriate because of issues with taste. Mini-tablets and powder formulations are alternative options, but they bring their own challenges. Tablets need to be hard enough not to break, but then dissolve easily once swallowed, a delicate balance that becomes harder as pills become smaller in size. Turning them into powdered granules, inserted via oral syringe, is one option but swallowing particles can be harder, and the coating may dissolve in the mouth, causing taste issues to return. There are also nuances between children; those with autism, for instance, are especially averse to grainy or gravelly textures in their mouth. Understanding what parents and children want their medicines to be like is key in the development of appropriate medicines.
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Dr Chris McConville
Senior Lecturer in Pharmaceutics, Formulation and Drug Delivery
Chris McConville is a Senior Lecturer in Pharmaceutics, Formulation and Drug Delivery. His previous experience within the pharmaceutical industry and academia has provided him with expertise in preformulation, dosage form design, drug delivery and analysis.
Professor John Marriott
Professor of Clinical Pharmacy
John has active research groups examining a variety of aspects of clinical pharmacy and has published widely in scientific journals and book chapters. He has major grants from the SHA and MCRN to support this work.
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