Full of potential2 May 2018
A novel material that releases the antiseptic chlorhexidine gradually over time has huge potential to reduce the prevalence of device-related infections. Elly Earls speaks to its creator, Dr Michele Barbour, to find out how.
Antimicrobial device coatings are nothing new – neither is chlorhexidine. But a new formulation of the common antiseptic that can be released slowly and steadily over hours, days, weeks, months or even years, could offer medical device manufacturers a new approach to developing coatings – one that could improve their products’ effectiveness at protecting patients from infection.
Many medical devices, such as catheters or joint prostheses, are susceptible to colonisation by bacteria. In some cases, the body’s immune system can effectively eradicate these microbes with few or no symptoms for the patient; in others, microbes multiply and spread, resulting in infection. Sometimes the bacteria will join together to form a biofilm and, at this point, it becomes much more difficult for the body – and medicines – to attack the infection.
Conventional device-related infections are prevented or treated using topical or systemic antibiotics. However, this is far from an optimal solution, as antibiotics are under threat from the evolution of resistance among pathogenic bacteria – a situation that’s led to increasingly urgent calls from healthcare experts to reduce antibiotic use.
Another way medical device manufacturers seek to protect patients from device-related infections is by lacing devices’ coatings with antimicrobials. The limitations of these coatings typically lie in their release rate, but too much can be released early, leading to irritation and delayed healing. The dose then tends to drop off rapidly to a quantity that’s too low to be effective.
Bristol-based company Pertinax Pharma has developed a solution designed to combat these issues. Its range of novel materials, which can be incorporated into wound dressings or medical devices, deliver the antiseptic chlorhexidine over a sustained, controlled period.
“The way antibiotics operate is that they tend to have a very specific pathway for attacking the microbe,” says Dr Michele Barbour, the inventor of the Pertinax technology, and CEO and co-founder of the company. “Some attack a family of microbes, some attack a very small number and they tend to interfere with, say, a particular step on the metabolic pathway. So it’s one very small part of the process that those bacteria need to keep them alive and reproducing.
“So for the microbes to evolve to evade that process is comparatively simple. They only need to change one or two small things in that metabolic pathway to not be as influenced by that antibiotic anymore,” she adds.
Antiseptics, on the other hand, take more of a sledgehammer approach. “They’re a blunt instrument,” Barbour says. “Chlorhexidine causes the membrane of the bacteria to become more permeable so, ultimately, the contents can leach out and the nucleus precipitates. It’s like popping a balloon. It’s much harder for a microbe to evolve to evade such an onslaught and that’s true of most antiseptics.”
The idea for Pertinax was born out of trying to answer a simple question: how do we get chlorhexidine to last longer? “Chlorhexidine is a very commonly used antiseptic; it’s been used in medical, veterinary and dental care since the 1960s. It’s absolutely standard, and very effective against a wide range of bugs and fungi,” Barbour says. “But it’s very soluble, so the effect is very short-lived; for example, you can put it on wounds or abrasions, or you can rinse your mouth with chlorhexidine mouthwash, but you’ve got to use it very frequently to stop it being washed away.”
In her lab at the University of Bristol, where she heads the oral nanoscience research group, Barbour set about trying to create formulations of chlorhexidine with much lower solubilities, so they wouldn’t be washed away by liquids, whether that was tear secretions, saliva or wound fluid. What she came up with was a fine white powder that releases chlorhexidine at a steady rate – as long as those liquids are being released.
“Wherever you put the material when it’s dry, it’s stable and when it gets moist, it slowly releases chlorhexidine over a long period of time,” she explains. “For example, if we put this into a wound dressing, the wound starts to exude fluid and, as long as those liquids are being released, the chlorhexidine release continues, so you get a steady dose over as long a period of time as you need it, whether it’s a couple of weeks or a few months.”
When Barbour first started her company, just under three years ago, it would take her about a week to make half a teaspoon of the material, which involved using significant quantities of water and power. While this was fine for her purposes in the university lab, where half a gram would happily last six months, she knew that the process needed to be honed if the material was to eventually be used in thousands of dental fillings, wound-care products and medical device coatings.
Her first big challenge, then, was scaling up. “We spent the first eight months or so looking at every step in the pathway we used to produce the material, saying, ‘What can we do about that to make it more efficient to use less water and power or do it faster’,” she recalls. “We also wanted to make it a higher yield, so we would get more of our material per gram, and we needed to purify it as well.”
Barbour employed her first member of staff in April 2016, and the week before Christmas, the team was making a kilogram of its material. “We went from half a gram to 1kg in eight months and had a big celebration,” she smiles. “When we started, we thought we’d be able to make it at scale and had good reasons for thinking it would work, but we hadn’t proved it. Now, we’ve evolved our process further and can make several kilograms a day if we want to.”
A wide range of applications
Pertinax now offers a range of different chlorhexidine materials that can be used for different applications; for example, a medical device that needs to stay in position and keep a patient protected from infection for several years, such as a dental crown, would need a different formulation of Pertinax to a wound dressing that would only be in place for a few days.
“For each application, we would pick a particular formulation of Pertinax with solubility that would suit those needs,” Barbour explains. “We can also control things like particle size and the distribution of the material, which also affect the release rate. We’ve got a few levers we can pull to control the duration of the effect.”
At present, all Pertinax formulations are made in-house, so the next big task will be outsourcing production to a partner that works to good manufacturing practice (GMP) standards.
“We make Pertinax products using good practice, but not to a standard that will ultimately be suitable for use as a pharmaceutical; it’s fine for development work, all the requirements we have in-house and for our partners’ needs at the moment, but there will come a time where either the quantity or the quality we need will outstrip what we can do ourselves,” Barbour stresses.
The team is already talking to a couple of contract manufacturing organisations that operate to GMP standards and have experience of working with related materials. The aim is to scale up the process that currently happens in a production vessel about the size of a human head, to one that takes place in a vessel the size of Barbour’s office.
Once this is achieved, the number of potential applications in the medical device sector will go up. One of the most exciting for Barbour is orthopaedics. “Orthopaedic materials commonly use antibiotics at the moment, which gives rise to a lot of problems with resistance,” she explains. “The antibiotic release from orthopaedic materials is also quite short-lived – you can’t provide antibiotic release that persists as long as the surgeons would like it to.”
There are also many opportunities in the dental sector, from fillings to crowns, bridges and implants. “One of the most common reasons these devices fail is because of secondary infections [that do not occur] immediately after the process, but months or years later when bacteria have managed to infiltrate the interface between the device and the tooth, and started to nibble away at the tooth material underneath that.
“If we could create materials that deliver a low but very sustained chlorhexidine release (for years at least and decades quite possibly by our calculations) that could maintain the low-level antiseptic environment, without interfering with all the other properties of that device, protecting its longevity,” Barbour adds.
The Pertinax team will also be investigating the potential of their technology for coating catheters.
“In the developed world, urinary infections are a leading cause of antibiotic-resistant infections, particularly in the older population and in hospital or care home-dwelling patients,” Barbour notes. “And although there are other antimicrobial catheters on the market, we think ours will have particular advantages that could really help with reducing the rate of those sorts of infections.”
Making a difference
Pertinax has no intention of attempting to exploit any of these opportunities alone; the goal is to partner with leading medical device manufacturers to co-develop materials that work for their products. Discussions are already under way with several companies, but Barbour is conscious that she doesn’t want to back the company into a corner.
“There are so many things we could do and so many ways that the material could be used,” she says. “On the one hand, we’re being very open and talking to lots of people, but on the other hand, we’re going to have to be very choosy about exactly who we partner with to make sure we can exploit the technology to its full potential.”
As well as finding suitable partners, which Barbour thinks will initially be in the veterinary and wound-care fields, there will also be regulatory barriers to negotiate before the product can be commercialised on a large scale. In theory, if the team puts their efforts in the right place, Barbour believes the world is Pertinax’s oyster.
“Inevitably, it will cost a lot to get regulatory approval and the technology will be used for high-value applications first, which is what will allow us to be successful,” she says. “But ultimately, I also see applications in developing countries and low resources areas where this could make a huge difference to life. It’s not going to be an expensive technology; the starting materials we use are inexpensive and readily available from different suppliers, and the processes that we’ve developed to manufacture are not inherently expensive.
“As a scientist, I’d like to see Pertinax benefit humanity where it’s needed most, and that would often be in countries where infection is rife and could be readily treated if only the right technologies were readily available.”