Exploring Possibilities of Microneedles with Ryan Donnelly

Prof. Ryan Donnelly is the Chair of Pharmaceutical Technology at Queen’s University, Belfast, U.K. He is a young and dynamic researcher in the field of transdermal delivery with primary focus on microneedle drug delivery and applications. Prof. Donnelly’s research is centered on design and physicochemical characterization of advanced polymeric drug delivery systems for transdermal and topical drug delivery, with a strong emphasis on improving therapeutic outcomes for patients. The bioadhesive patch he developed during his Ph.D. studies was shown to be successful in the clinic for photodynamic therapy of over 100 patients with neoplastic and dysplastic gynecological conditions, and the patent was subsequently licensed to Swedish Pharma AB.

He secured a B.Sc. degree in pharmacy from Queen’s University Belfast (1999) and a Ph.D. in pharmaceutics from the same institution (2003). He carried out a short (3 month) period of postdoctoral research focused on delivery systems for photosensitizers and was appointed as a Lecturer in pharmaceutics at the School of Pharmacy in January 2004. He was promoted to Senior Lecturer in 2009, Reader in 2011, and Chair in Pharmaceutical Technology in 2013.

Prof. Donnelly’s current research is focused on novel polymeric microneedle arrays for transdermal administration of “difficult-to-deliver” drugs and intradermal delivery of vaccines and photosensitizers. His research work has gained a lot of attention and interest in the academic and industrial community and has been funded by the Biotechnology and Biological Sciences Research Council (BBSRC), Engineering and Physical Sciences Research Council, Medical Research Council, Wellcome Trust, Royal Society, and pharmaceutical and medical devices industries.

He has authored over 500 peer-reviewed publications, including several granted patents, five textbooks, and approximately 160 full papers. He has been an invited speaker at numerous national and international conferences. Prof. Donnelly is the editor-in-chief of Recent Patents on Drug Delivery & Formulation and a member of the editorial advisory boards of Micromachines, Pharmaceutical Technology Europe, Expert Review of Medical Devices, and Journal of Pharmacy & Bioallied Sciences and is a visiting scientist at the Norwegian Institute for Cancer Research, where he is an associate member of the Radiation Biology Group.

He won the Controlled Release Society Young Investigator Award in 2016, the BBSRC Innovator of the Year Award and the American Association of Pharmaceutical Scientists Pharmaceutical Research Meritorious Manuscript Award in 2013, the GSK Emerging Scientist Award in 2012, the Royal Pharmaceutical Society’s Science Award (2011), the Queen’s Improvement to Society Award (2011), an Innovation Leader Award from the NHS Research & Development Office (2009), a research scholarship from the Research Council of Norway (2004), and the Pharmaceutical Society of Northern Ireland’s Gold Medal in 1999. In 2013, he was listed in the 40 most influential business leaders in Northern Ireland under the age of 40 by Belfast Media Group.

Prof. Donnelly can be contacted directly at r.donnelly@qub.ac.uk.

Q: What was your research focus during your Ph.D. and your postdoctoral studies?

A: My Ph.D., supervised by Dr. Paul McCarron and Prof. David Woolfson, focused on design, development, and small-scale manufacture of bioadhesive patches intended for enhanced delivery of 5-aminolevulinic acid (ALA) to neoplastic and dysplastic vulval lesions. Patients will not die from these diseases, but symptoms can be extremely distressing. Surgical excision can be mutilating, leading to loss of function and subsequent psychological problems. In photodynamic therapy based on ALA, the precursor causes accumulation of the potent photosensitizer in target tissues, which are then destroyed selectively by illumination with red light, which generates reactive oxygen species through interaction with the accumulated photosensitizer. ALA was at the time being delivered using an extemporaneously prepared cream, which had to be refrigerated due to the drug’s instability. Patients had to be immobilized and catheterized for 6 hours to allow drug absorption and photosensitizer accumulation. This leads to unnecessary distress. My task was to produce a flexible patch that would adhere strongly in a moist environment in ambulatory patients and have a water-impermeable backing layer to allow normal micturition and bowel opening. The biggest challenge was preventing the high drug loading in the water-based patch from crystallizing during drying. I achieved this by producing very thin drug-loaded films. These dried in minutes rather than days and were then laminated multiple times to produce the required patch thickness and drug loading per unit area. This was a new way for making water-based bioadhesive patches and enabled me to respond at short notice to requests from the Belfast City Hospital, where the patients were being treated in clinical trials led by consultant gynecologist Dr. Agnieszka Zawislak. We saw symptomatic improvement in all of the patients treated, with the histological grade of vulval intraepithelial neoplasia being reduced in over half of the patients in that cohort treated. We filed a patent on the method of patch production, and it has now been granted in Australia. The company the university licensed the patent to, Swedish Pharma AB, sees it as a potential improvement on commercially available creams used in photodynamic therapy of basal cell carcinoma of the skin, which is the most common cancer in Australia. Swedish Pharma is still raising funds to take the technology forward, so unfortunately patients are not yet benefitting from this delivery system.

As for my career as a postdoc, it was very short—just three months. Indeed, I had only been in the post for a matter of weeks when I was offered a lectureship. To say that led to a steep learning curve would be an understatement. Embarking on an independent academic position at the age of 25 with little postdoctoral experience was quite an undertaking. I made a lot of early mistakes, but I learned something from them all and benefitted greatly from the continued support of my former Ph.D. supervisors and also Prof. Johan Moan at the Norwegian Radium Hospital, whose lab I had the opportunity to work in during the first summer I was in post as a lecturer.

My early work as a lecturer focused on enhancing delivery of drugs used in photodynamic therapy, and this led me to microneedles. Since photodynamic therapy is quite a niche treatment, it was difficult to get funding, and so I broadened the scope of my microneedles research to look at enhanced transdermal drug delivery and minimally invasive patient monitoring and diagnosis.

Q: What happened next? Where did you go from there?

A: Upon deciding to focus on microneedles, I quickly realized that this was a field principally focused on delivery of vaccines and highly potent drugs of biological origin. Most conventional drugs, however, have daily doses in the range of tens to hundreds of milligrams per day. Small postage stamp-sized microneedle patches coated with drug would not be capable of delivering clinically effective doses. Something very different was required. I came up with hydrogelforming microneedles prepared from crosslinked FDA-approved polymers. Such microneedles contain no drug themselves, but they rapidly swell through uptake of skin interstitial fluid upon insertion. This allows continuous, controllable delivery of high drug doses from an attached drug-containing layer, the properties of which can also be modulated to optimize the kinetics of delivery. Importantly, such microneedles are removed from skin intact, leaving no measurable polymer residue behind. This phenomenon led to another idea: using such microneedles to capture skin interstitial fluid and its contents for use in patient monitoring and diagnosis.

Q: Besides microneedles, are you interested in pursuing other R&D ventures? What is your inspiration?

A My group is currently focused exclusively on microneedle research. We have several projects focused on delivery of high drug doses for a range of applications. I am confident that the technologies we have developed can greatly expand the range of drugs that can be effectively delivered through the skin. We also have a large program on microneedle systems with applications in global health and have just started a significant collaboration with a major biosensors company

As a registered pharmacist, my inspiration is taken from patient need. I strive to develop delivery systems and blood-free monitoring and diagnostic tools that will improve therapeutic outcomes, not only for patients in the Western world but also in the world’s poorest countries.

Q: Please share a few of the most important research publications coming out of your research lab and their impact on the field

A: We have recently shown that the larger microneedle patches that will be required to deliver high drug doses can be as efficiently applied to skin as conventional small patches:

Ripolin, A, Quinn, J, Larrañeta, E, Vicente-Perez, EM, Barry, J, Donnelly, RF. Successful application of large microneedle patches by human volunteers. Int. J. Pharm.  521: 92-101 (2017). 

If a patient is being treated with a microneedle patch that is delivering a drug the patient needs every day, then repeated microneedle application must cause no skin problems or other detrimental effects for the patient. Our recent mouse study suggests that repeated microneedle application will be very safe:

Vicente-Perez, EM, Larrañeta, E, McCrudden, MTC, Kissenpfennig, A, Hegarty, S, McCarthy, HO, Donnelly, RF. Repeat application of microneedles does not alter skin appearance or barrier function and causes no measurable disturbance of serum biomarkers of infection, inflammation or immunity in mice in vivo. Eur. J. Pharm. Biopharm. doi: 10.1016/j.ejpb.2017.04.029 (In press). 

Q: Please share some publications from fellow researchers that have had the most influence in shaping the related pharmaceutical field.

A: My own career has been very much shaped by the positive influence of outstanding academics like David Woolfson, Sandy Florence, Richard Guy, Adrian Williams, Johan Moan, Michael Hamblin, and Robert Lochhead, all of whom have been generous with their time, advice, and support. Duncan Craig was an inspirational figure during his time in Belfast, and I learned much from his strategic vision and how he managed his research group. From a product development viewpoint, Werner Wessling from LTS Lohmann has been an important teacher and a good friend.

Currently, I learn a lot from other researchers studying microneedles and transdermal delivery in general. In my view, the following papers are of high current importance:

Rzhevskiy, AS, Guy, RH, Anissimov, YG. Modelling drug flux through microporated skin. J. Controlled Release 241:194-199 (2016).

Arya, J, Henry, S, Kalluri, H, McAllister, DV, Pewin, WP, Prausnitz, MR. Tolerability, usability and acceptability of dissolving microneedle patch administration in human subjects. Biomaterials 128:1-7 (2017). 

Lee, KT, Coffey, JW, Robinson, KJ, Muller, DA, Grøndahl, L, Kendall, MA, Young, PR, Corrie, SR. Investigating the effect of substrate materials on wearable immunoassay performance. Langmuir 33: 773-782 (2017). 

Q: What are your current career aspirations?

A: As a pharmacist, I would like to see microneedle technologies developed by my group reaching the market and being used to help patients. I think big pharma has traditionally seen microneedles as something that would only be useful for vaccination in the developing world, and so money could not be easily made on such products. This has clearly slowed development and clinical translation. However, our work, and that of some others, will hopefully begin to change minds soon. It is only with suitable investment to scale up manufacture and address regulatory questions that microneedles will ever realize their undoubted potential.

In terms of my leadership role in the university, I am director of a new interdisciplinary research initiative that aims to enhance collaboration between researchers in pharmacy, chemistry, engineering, medical sciences, and computing. We hope to boost research productivity and impact by addressing a range of global challenges.

Q: What are some things you enjoy in your personal life?

A: I really enjoy my job. Indeed, if I hadn’t become a pharmacist and research scientist, there are only a few things that would have appealed to me: a professional soccer player or nightclub DJ! I still play soccer every week with colleagues from the School of Pharmacy and have recently re-signed with Carrickmacross Rovers, the club in County Monghan in Ireland that I played with for many years as a schoolboy and during my undergraduate and postgraduate degrees. I live outside Warrenpoint in County Down, a small and beautiful seaside town. My wife, Johanne, and I like walking in the countryside and along the seafront in Warrenpoint when we’re not teaching pharmacy; Johanne is also a pharmacist and teaches pharmacy practice at Queen’s as well as working for Boots in community pharmacy. n