Patch works

C&I Issue 6, 2013

Drug delivery through the skin is minimally invasive and virtually painless. However, getting drugs across the skin is technically difficult because skin has evolved to control water movement out of the body while restricting entry of foreign bodies. As a result, only about 20 drugs – typically hydrophobic, relatively small molecules such as nicotine – are currently delivered by transdermal patches, gels or sprays. However, new research is leading to the development of ‘smart’ patches that could be used to deliver a variety of drugs, including insulin, anticancer drugs, painkillers, and vaccines.

‘An ideal goal [of transdermal delivery] would be a methodology by which drugs of any size might be made to permeate the skin in an effective amount to produce a pharmacological effect,’ says Richard Guy, professor of pharmaceutical sciences at the University of Bath, UK.

‘The holy grail of transdermal drug delivery – and indeed most drug delivery technologies – is the safe and efficacious delivery of proteins,’ says Majella Lane, senior lecturer in pharmaceutics at University College London, UK.

The transdermal delivery of many drugs is, however, limited by the excellent barrier properties of the skin, which results from its intercellular lipid content. Because they are not lipophilic, proteins cannot effectively permeate the lipid pathway to reach the blood – something that currently can only be achieved via perforations made by a needle and syringe or catheter and pump.

Moreover, proteins are typically large molecules with molecular weights exceeding 1000Da. As a result, there is a lot of current interest in minimally invasive ‘poration’ technologies, such as those involving microneedles, heat, laser radiation, small electric currents (iontophoresis), high voltage pulses (electroporation ), ultrasound, and chemical penetration enhancers. ‘These methods take skin’s barrier function out of the equation by creating a network of new pathways across the skin through which drugs – both large and small – can transport at significantly enhanced rates compared to that across the intact barrier,’ explains Guy.

Currently, transdermal drug delivery using microneedles is the focus of intense interest, says Lane. Microneedles are tiny needles that pierce the outer skin layer and penetrate the dermis without causing pain, allowing larger molecules to pass through the skin. Insulin, various anticancer drugs and vaccines are some of the molecules under investigation for delivery this way.

Researchers in the US, for example, are developing vaccine-loaded polymeric patches that combine microneedle arrays with polyelectrolyte multilayer technology (Nature Materials, doi: 10.1038/nmat3550). The patch is applied for 15 minutes to allow the coatings to be released effectively from the microneedle surfaces and implant in the skin, where they degrade on contact with water, releasing the vaccine. The researchers are trialing the system with DNA vaccines.

These microneedles contain a cationic polymer that breaks apart upon exposure to water in the skin tissue and a UV-sensitive copolymer. The latter polymer is hydrophobic but has a pendant nitrobenzyl group that is cleaved from the polymer backbone upon UV treatment, rendering it hydrophilic but only in certain pH conditions. Peter DeMuth, a researcher in the department of biological engineering at Massachusetts Institute of Technology, US, explains: ‘We have used this pH sensitivity to create a “release layer” that sits between the microneedle surface and the vaccine coating. Once the microneedles enter the skin, this release layer is rapidly dissolved upon exposure to the tissue fluids, and the vaccine is released into the skin.’

Microneedle strategies have been the subject of intense research over the past five to 10 years and previous studies have demonstrated their efficacy for vaccination in small animals. Similarly, polyelectrolyte multilayers are a proven approach for construction of surface coatings for a variety of applications. ‘The real innovation here is the combination of these technologies in a way that may enable new and more effective vaccination strategies,’ says DeMuth.

In theory, this technology could be adapted for delivery of any variety of therapeutics. However, there are some limitations in terms of the dosages that can reasonably be delivered from these microneedle arrays, says DeMuth. ‘If a specific drug is needed to be given in a very large dose, it might require a different type of microneedle strategy than the one we’ve shown. Vaccines are ideal in this case, because the required doses tend to be smaller,’ he explains.

The technique has so far undergone lab-scale studies. The next step will be to tackle some of the practical challenges to deploy the technique on a large scale, as well as additional testing in more advanced animal models of disease. The coating materials will also need to secure approval from the US Food and Drug Administration (FDA) before the vaccine technology can be tested in humans.

Meanwhile, researchers from Purdue University, US, have developed a micropump for use in drug-delivery patches containing microneedles. Babak Ziaie, professor of electrical and computer engineering, explains: ‘Although transdermal drug delivery via microneedle arrays has long been identified as a viable and promising method for delivering large hydrophilic molecules across the skin, a suitable pump [to push the drugs through the needles] has been hard to develop’.

The tiny pump contains yeast and sugar, which, when tepid water is added, generates carbon dioxide as fermentation occurs, creating enough pressure to dispense medication from a drug sack (Lab on a Chip, doi:10.1039/c21c40620a). ‘We were looking into a disposable, inexpensive battery-less pump that can work for many hours for slow rate infusion and realised that yeast fermentation is a slow process that can generate gas for pump operation,’ explains Ziaie. Achieving adequate flow rate and back-pressure from a pump is hard without requiring high voltages, he says. ‘So this is an ideal power source – all you need is water, sugar, and yeast.’

The researchers have built a prototype that can be incorporated into patches, and are working with a company to commercialise the idea and identify the ideal medication to use. The pump can potentially deliver any drug that is suitable for slow release, but an alternative driver would be needed for a fast release, according to Ziaie.

In a clever twist on the microneedle technology, scientists at Kings College London, UK, have developed a vaccination patch comprising microneedles made of sugar. As well as making vaccinations easy and safe to administer, such patches could, potentially, store live vaccines without the need for refrigeration.

The microneedle arrays comprise a dried live vaccine; sucrose and lactose to preserve the activity of the vaccine; and a biodegradable polymer to give the needles their strength. Gentle pressure applied to the flat side of a patch containing this technology for five minutes is enough to push the needles into the skin, where they dissolve and release the vaccine, says Linda Klavinskis, from the King immunobiology department.

In an experiment, the researchers formulated a dried version of a candidate HIV vaccine in sucrose. They have shown that the vaccine remains stable and effective at room temperature and, in mice, dissolves in the skin and triggers an immune response (PNAS, doi: 10.1073/pnas.1214449110).

This technique could potentially be used to deliver vaccines against other infectious diseases, such as those administered in childhood, and also vaccines to manage chronic inflammatory and autoimmune conditions,such as Type 1 diabetes. ‘Our collaborators at Theraject, who produced the vaccine moulds, are using this technology to deliver anti-ageing creams to the skin and also for delivery of local anaesthetics and a drug (triptan) for migraine treatment,’ says Klavinskis.

The sugars and biodegradable polymer are already approved for clinical use by the FDA, but it will be some years before the vaccine technology will be available to the public. The next step is to test the patch on small pieces of donated human skin.

Addiction potential

Scientists at the University of Kentucky, US, have designed a smart programmable patch that they hope will help combat addiction to painkillers, as well as nicotine. The patch comprises a membrane containing billions of carbon nanotubes, which are voltage-gated so that they open and close to allow fluid to flow through them at rates proportional to the applied electric current. At programmed times, a small voltage is applied within the device to pump nicotine, for example, to the skin surface, where it diffuses through the skin (PNAS, doi: 10.1073/pnas.1004714107).

‘We rely on very efficient electro-osmotic pumping, which works by only one charge of ion (positive) being allowed in the carbon nanotube. The applied voltage drives the ion that pushes uncharged molecules/solvent across the very slippery carbon nanotube core,’ explains Bruce Hinds, professor of materials engineering at Kentucky.

The electro-osmotic efficiency is about 10,000 times more efficient in a carbon nanotube than with a conventional material, enabling a watch battery to run a patch for  up to 10 days. This means that the small portable device can be programmed to deliver a limited dose but at flexible times, in line with expected cravings.

The researchers have built a prototype involving a simple watch battery and manual switch device to show the safety and efficacy on animals and are now testing a Bluetooth-controlled device on animals. The next step is to optimise the design and test a remotely programmed patch on animals.

‘Addiction treatment is considered the Mount Everest of therapies since it is a mixture of brain chemistry and psychology. A programmable patch can join the two camps for a big jump in effectiveness,’ according to Hinds.

However, a disadvantage of the system is a time delay while the drug diffuses through the skin. This means, for example, that if a patient has a sudden craving (or pain episode) it can take more than an hour to get relief, says Hinds. Another problem is a ‘depot’ effect, where drugs absorb in the skin and release slowly, making timed control more difficult.

A long way to go

The reality, however, is that at present there is no drug of molecular weight of over 1000Da that can be delivered across the skin by anything remotely resembling a patch. The most successful commercial patch on the market today is for delivery of the synthetic small molecule opioid painkiller fentanyl, which generates sales in excess of $1bn/year.

Moreover, there is still interest in delivering potent, small molecular weight drugs across the skin, if these can be identified, says Guy. Rotigotine, for example, a dopamine agonist used in early stage Parkinson’s disease, was the first  chemical entity developed exclusively for transdermal delivery. The patch, developed Schwarz Pharma (now part of UCB), was first approved in the US in 2007 but a reformulated patch with an improved delivery mechanism was approved in 2012.

Although the technology advances and smart patches aimed at transdermal delivery of large molecules are promising, many questions remain. For example, with microneedle formulations, the long-term safety effects of breaching the skin barrier are still not well understood, says Lane.

It is also not clear whether the greater amount of drug delivered per unit of skin through poration technologies, compared with passive patches, will result in increased skin irritation or sensitisation, points out Guy.

‘The other question is whether the added value of these approaches, in terms of their minimum invasiveness is sufficient to balance their increased cost relative to, for example, a simple needle and syringe – I think the jury is still out on that,’ he says.

Emma Dorey is a freelance medical science writer based in Brighton, UK.

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