Unless you disrupt the skin, transdermal drug delivery is restricted to compounds that can diffuse across the lipid-rich skin barrier. And the classic way of disrupting the skin is with a hypodermic needle – and also one that most people prefer to avoid. Microneedles, however, make the transdermal drug delivery route accessible to a much greater range of compounds. Furthermore, as the microneedles are so short in length, they avoid stimulation of dermal nerves or puncture of dermal blood vessels, offering a painless and blood-free alternative to a conventional hypodermic needles.
Today’s microneedle systems usually consist of a number of sub-millimeter projections arrayed on a base plate. The entire array is applied to the skin, allowing drug associated with the projections to penetrate the epidermis. The approach allows the painless transdermal delivery of drugs that are too lipid-insoluble to passively penetrate the stratum corneum. The first patent on microneedles was filed in 1976 – but the technology to make microneedles wasn’t developed until the late 1990s! In fact, the technology was borrowed from advances in the micro-electronics industry – in particular, the fabrication of increasingly complex devices from silicon. Hence, the first microneedles were made of silicon or metal. Initially they were either hollow, coated with the drug, or were used to scarify the skin as a pre-treatment for a topical formulation. Latterly, concerns over the biocompatibility of these materials have led to the development of polymer microneedles. In these devices, the drug is incorporated in polymers that are often designed to dissolve in the skin. Currently, there are several small-scale clinical trials of microneedle devices under way, and the commercialization of a microneedle patch is widely anticipated.
Spikes of innovation
Back in the early 2000s, my research focused on using microneedles as a delivery platform to enhance the delivery of photosensitive pro-drugs for treatment of superficial skin cancers. However, we ended up developing a microneedle technology that had applications far beyond photodynamic therapy alone. Uniquely, our microneedles are prepared from a biocompatible hydrogel-forming polymer. When applied to the skin, the microneedles swell due to the uptake of interstitial fluid, creating aqueous pathways for drug diffusion from an attached drug reservoir through the polymer microneedles and into the skin. One benefit of our technology is the fact that the microneedles are removed intact after drug delivery; nothing is left behind in the skin, unlike many other types of microneedles. Also, importantly, our microneedles are self-disabling – after only one minute in skin they become too soft to be reinserted, which reduces the chance of accidental contamination or transmission of infection. It also means that they don’t need to be disposed of as contaminated sharps waste. From a controlled delivery perspective, our system permits manipulation of drug egress by altering the swelling properties of the polymer. We can make it swell less to deliver a medicine slowly over a long period of time, or we can make it swell more, which delivers the medicine very rapidly for immediate effect. I’m pleased to say that there appears to be a broad appreciation of the novelty and utility of our system – I received the UK’s Biotechnology and Biological Sciences Research Council (BBSRC) Innovator of the Year award in 2013, the GSK Emerging Scientist Award in 2012 and the Royal Pharmaceutical Society Science Award in 2011. Such recognition is very gratifying! But we’re not resting on our laurels. One promising application of our hydrogel-forming microneedles is that of minimally invasive patient monitoring, and we’re investigating this right now. For most drugs, the concentration in skin interstitial fluid reflects that in blood plasma, so if you can monitor the interstitial fluid (ISF), you don’t need to take blood. We think microneedle patches can sample ISF, and give us a way of blood-free patient monitoring – something that is particularly relevant to premature babies. Each neonatal patient is different and their organs are at an indeterminate stage of development, so it is vital that drug concentrations are monitored to optimize therapy and minimize side effects in this vulnerable population. Traditional blood sampling can be difficult in neonates due to their small and fragile nature and the limited volume of blood. Moreover, it can be difficult to find a vein – and a conventional needle can cause bruising and scarring. An alternative, minimally invasive method of monitoring in this patient population is, therefore, highly desirable.The future through the eye of a needle
I think the key to microneedle progression lies in answering the regulatory questions raised by the innovative nature of the technology. To that end, we will continue to interact with regulatory groups in the UK and internationally to identify and address perceived issues regarding microneedle use. I also think we need to look beyond the device itself, to the patient. No matter how good the product, if it’s not accepted by prescribers or patients, it’s worthless. We’ve conducted surveys among healthcare professionals and the general public, and received some valuable feedback on the real-world use of microneedles. This has helped us identify the population groups and disease states where a delivery system like microneedles would be most useful, as well as highlighted important practical features for incorporation in any future product. The information is really important for developing a future microneedle product profile. Another challenge relates to scale-up. Microneedle manufacture methods vary significantly depending on drug loading characteristics, the materials used, and the dimensions and geometry of the array. We need to work out how to translate small-scale manufacturing methods into industrial-scale processes – and that demands serious engagement from industry. Equally, manufacturers require guidance relating to good manufacturing practice, pharmacopoeial standards and appropriate quality control tests that are specific to microneedle devices, so there are challenges. That said, we fully intend to see our microneedle technologies commercialized so that patients can benefit from their many advantages. To achieve that, we’ve partnered with the world’s largest transdermal patch manufacturer, which will greatly aid in the translation of our work into marketed pharmaceutical products. In summary, I think the future is very promising for microneedle-based delivery systems and, potentially, monitoring systems. Once regulatory hurdles are overcome and manufacturing processes developed, optimized and validated to current good manufacturing practice standards, we’ll get products to market. The benefits for patients and, ultimately, industry, will be considerable. Furthermore, I’m optimistic that we’ll see microneedle-mediated vaccination programs in the developing world, probably within 10 years. The fact that most microneedles formulate biomolecules in the dry state means that the cold chain can be circumvented. Needlestick injuries will also be obviated. Microneedle technology could, therefore, massively improve vaccine delivery in developing countries. Its potential impact is vast.Newsletters
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