‘Drugs do not necessarily deliver themselves," says Sudip Das, associate professor of pharmaceutics at Butler University. It seems like an obvious statement to make, but when scientist Stanley Davis of the University of Nottingham asked a GlaxoSmithKline (GSK) research director what his views were on advanced delivery systems, he was shocked to hear him say: "Who needs advanced drug delivery? Our chemists can synthesise drugs that deliver themselves."
To give the GSK director his due, he was working on stable drugs that had a low molecular weight and a reasonably lipophilic compound that would be easily absorbed from the gastrointestinal tract. They did not require a sophisticated delivery system. For an increasing number of today’s pharmaceuticals however, that is no longer the case.
With over 30 years’ experience in cutting-edge research on controlled drug delivery and formulation development, much of which was funded by government and foundation research grants, as well as 20 years teaching in professional pharmacy programmes in the US and Canada, few are more qualified than Das to analyse the impact of these new pharmaceuticals.
"40-50% of drugs coming to market now are water insoluble," he says. "That means their bioavailability is relatively poor, so conventional formulations like tablets or capsules will be ineffective. We need to develop new formulations to ensure efficient delivery."
Using nanoformulations to increase water solubility looks set to form a substantial part of the solution, especially in the field of oncological drugs, which was the largest therapeutic area (13%) of the 39 FDA-CDER-approved new molecule entities in 2012. Curcumin is an excellent example: a natural diphenolic compound derived from turmeric Curcuma longa, it has an extremely low water solubility of 0.0004mg/ml at pH 7.3, and a subsequently weak bioavailability: a 10/12mg oral dose resulted in only 50mg/ml serum levels.
However, another study concluded that when administered as a nanoformulation, curcumin’s solubility, bioavailability and pharmacokinetic qualities are all significantly increased. The results have led the group to conclude that the nano-modified form is likely to become far more popular within the medical community over the years to come.
Nano and biodegradable formulations
Das shares the researchers’ enthusiasm. Commissioned by the National Institute of Health (NIH), he has been conducting his own investigations into oncological nanoformulations, as well as some other disease areas.
"We’ve also been looking at using them to deliver nucleic acids for the treatment of Alzheimer’s and Huntington’s disease," he says. "The trouble we’re having at the moment is that if you inject nucleic acids directly into the blood, they degrade within half a minute and won’t reach the target. We’re hoping nanoformulation systems can circumvent this problem.
"The difficulty with any new formulation development is getting approval from the FDA. They’ve become a lot more conscious about safety and efficacy in recent years, and are asking for more clinical data than ever. It’s definitely a good thing in terms of drug quality, but at the same time, it means product approval takes longer. It’s also significantly more expensive."
Along with nano technologies, new biodegradable formulations for implants will play an increasingly important role in drug delivery. Traditional implant polymers have long been criticised for degrading too quickly, allowing little control over the rate of drug release. Recently however, the Finnish firm DelSiTech has developed a silica-based gel that can be modified to dissolve as quickly, or slowly, as clinicians desire.
"It gives much greater control over the speed at which drugs are released, and that significantly enhances their therapeutic effect," says Das. "Even though DelSiTech has only done animal testing so far, this technology definitely has a lot of potential."
The tightly controlled drug release also causes lower systemic toxicological side-effects than many other alternative delivery systems, and produces a steady plasma level, which studies have shown results in less natural resistance towards the drug.
By providing a more effective delivery system, DelSiTech’s formulation also offers a welcome new lease of life to old drugs that have run out of patent.
"I strongly believe in prolonging the lifecycle of drugs," says Das. "One of the best ways to do that is through new formulations. They can render drugs more effective, make them safer for patients, and more profitable in the long term. Pharmaceutical companies are starting to understand that, but there is still some way to go."
One of the classic pharma companies to have realised the benefits of lifecycle management early on is Eli Lilly, the original manufacturer of the antidepressant fluoxetine. After the drug went out of patent, the company developed a new version with a controlled release over seven days, enabling weekly rather than daily dosage. Considering the depressive mental states of patients, this regime was far likelier to be followed, allowing the drug to function much more efficiently.
In future, the increasing popularity of insoluble and often highly unstable biologics will no doubt force pharma companies to focus even more on formulations in order to ensure efficient delivery.
"Monoclonal antibodies look set to play a central role in biotech formulations over the years to come," says Das. "At the moment, biologics often come in a powder form that has to be mixed with sterile water and injected. Such formulations have a limited duration of therapeutic action. Prolonged release of biotech drug formulations could offer a solution, one that releases the drug over a long period of time. There’s no magic formula yet, but this sort of technology will undoubtedly develop.
"Having said that, I don’t believe that any one type of formulation will come to dominate the market," he adds. "There will no doubt be a mix of solutions for at least another 20 years."
Form and function
While integral to effective drug delivery, formulations are only one side of the coin. Medical devices are arguably just as important, particularly when facing a challenge that almost no amount of pharmaceutical innovation could hope to surmount.
"The blood-brain barrier makes cerebral access extremely difficult through conventional drug injection," says Das. "Its primary role is to prevent potentially dangerous foreign materials from entering the brain, which is achieved through the wall of endothelial cells that separates circulating blood from the brain’s extracellular fluid.
"One of the solutions is to bypass the blood-brain barrier and inject directly into the target area. But getting the needle into exactly the right part of the brain is incredibly difficult; human hand-eye coordination is often simply not up to it."
Increasingly, the sector is looking to stereotactic robots to provide an answer. Accurate to within 1mm, the machines can deliver drugs to highly specific target areas with far greater reliability than any human hand, and have already been extensively used in surgery to perform biopsies, injections, ablations and implantations. Medical device manufacturer Renishaw has started using this technology for neurosurgery.
So far, Renishaw has focused on electrode implantation for deep brain stimulation, as well as radiosurgery, biopsy and transcranial magnetic stimulation. Cerebral injection however looks likely to be developed, and the company is already working with a number of medical technology and biotech companies on the development of drug delivery systems for the treatment of central nervous system diseases.
"These robotic devices will be able to deliver drugs to areas that would otherwise be extremely difficult to reach," says Das. "It’s going to be very helpful indeed."
The success of cardiovascular stents has also been attracting a great deal of attention. Widely recommended to patients by the cardiologist community, these meshed tubes were originally developed to hold coronary arteries open and prevent dangerous flow constriction. Sirolimus and paclitaxel coatings have since been applied to limit the growth of surrounding neointimal scar tissue, reducing the likelihood of restenosis.
In the same vein
More significant than the isolated success of drug-coated stents, though, is the underlying trend they represent; a fruitful collaboration between a pharmaceutical company and medical device manufacturer.
"The development of stents is one of a handful of productive partnerships I’ve seen between device manufacturers and the classic pharma industry," says Das. "It’s crucial that we see more cross-industry interaction, and that includes the doctors and clinicians administering these therapies. Everyone stands to benefit; patients will receive better, more effective medication, and pharma and medical device companies’ sales will rise."
While undoubtedly rewarding, this sort of cross-sector collaboration can be difficult to achieve in practice, as Pfizer’s ill-fated product, an inhalable form of insulin with biotech start-up Nektar Therapeutics demonstrates. One of the project’s major problems was that while the endocrinologists involved in development understood the pharmaceutical side of the device, they had little idea about the dosage form’s influence on patient’s respiratory functions; a sound knowledge that is clearly vital in developing an effective inhalation device.
"The other difficulty is sorting out the logistics of how different companies are going to collaborate. They all have their own policies and procedures, and working around these can be incredibly tricky," says Das. "Nevertheless, it is essential that pharma and device companies do try harder to communicate. Only then can we really increase the efficacy of drug delivery techniques."
Some pharma companies have already started down this path. In 2011, Eli Lilly joined forces with device manufacturer Medtronic to develop a new treatment for Parkinson’s disease. The idea is to deliver Lilly’s biologic, a modified form of glial-cell-derived neurotrophic factor, using Medtronic’s pump and specially designed catheter into a target area of the brain consistently over a long term.
Michael Hutton, Lilly’s chief scientific officer of the neurodegeneration team, has emphasised the importance of collaborating with Medtronic from the earliest phase of research, in order to "maximise the potential for this therapy’s efficient and effective development".
Delivering the goods
In years to come, Das is confident there will be better communication between pharmaceutical manufacturers and medical device producers.
"Pharma companies are starting to see the benefits and take action," he says. "The advantages of effective lifecycle management – particularly the financial ones – are also becoming common knowledge; more drug manufacturers are working on alternative delivery methods after patent expiration.
"They’re both steps in the right direction," he continues. "But the pharma industry still has a long way to go before the significance of its role in drug delivery is fully realised."
The question of how long that will take is difficult to answer. One thing however is certain: pharmaceutical companies have a responsibility to ensure the best possible outcome for patients. The sooner they abandon the "our drugs deliver themselves" sentiment, the better.
