by The Cosmetic Chemist Staff
January 15, 2017
In this thought provoking interview with Dr. Richard Guy—a distinguished researcher in transdermal delivery and skin pharmacology—we delve into some of his contributions to the field and examine his take on the past, present, and future of the delivery of actives. Professor Guy is currently with the University of Bath in the UK, but also holds a post with the University of California, San Francisco. His research spans skin barrier function, transdermal drug delivery, enhancement of percutaneous absorption, iontophoresis, noninvasive biosensing of blood glucose and other analytes, and the prediction and assessment of skin penetration and topical bioavailability. He has published over 350 peer-reviewed articles and over 70 book chapters. In addition, he is the editor of one book and co-editor of seven others. His contributions in the realm of skin science are far reaching and frequently quoted in contemporary literature. Without further ado, we hope you enjoy this interview with a truly charismatic and inspirational figure.
1. Could you discuss the fate of a cosmetic material or compound when applied to the skin. For example, does it simply remain on the surface, penetrate into the deeper layers, deposit in a reservoir, or transform into something new?
A colleague of mine, Adrian Davis formerly of GSK, likes to write about the metamorphosis of a formulation. When you take a cream or lotion out of its package and rub it on your skin, all sorts of things happen, at the end of which you don’t have anything like what you squeezed out of the original container before application. The transformation of the vehicle during application makes delivery of certain ingredients particularly challenging. Ingredients in the formulation may evaporate and/or penetrate into the skin, and not all ingredients will do so at the same rate. As a result, a residual film is left on the skin surface in which the active may be considerably less soluble than it was in the original formulation. Insoluble material will no longer be available for uptake into the skin. Molecules from the formulation could be taken up by the lipids in the stratum corneum or bind with keratin structures of the corneocytes. Molecules may also migrate to appendageal structures, such as the pilosebaceous unit, and use this as a permeation route. The deeper a compound penetrates into the skin, the more things that can happen to it (e.g., more typical protein binding or even metabolism).
2. Do you believe nanoparticles penetrate the skin? What implications does this have for the personal care industry?
My group spent quite a lot time investigating if nanoparticles could penetrate beyond the so-called stratum disjunctum—see our paper in Journal of Controlled Release, Volume 162, pages 201-207 (2012). Our conclusion was that the answer to this question is no and I think the reason for that is quite clear. If you look at the structure of the stratum corneum with the keratin filled corneocytes, cornified envelope, bound lipid layers, and stacked ceramide/cholesterol/fatty acid bilayers between the cells, there is simply no space, or free volume, for a particle of roughly 100 nm to diffuse. To me, it seems illogical to think that nanoparticles can penetrate intact skin—after all, serum albumin is also a nanoparticle, and it does not diffuse out of the body transdermally! That being said, if you make holes in the skin, with microneedles or some other poration technique, then small particles can get in. Further, there is evidence that some nanoparticles show affinity for the hair fibers and the follicle openings, from which release of an encapsulated active, for example, might be envisaged. With respect to nanoparticles of titanium dioxide and zinc oxide penetrating the skin, I am not convinced that it is possible if the barrier is not broken in some way; these particles tend to aggregate too, making the chance that they can breach the stratum corneum even less likely. Of course, inhalation is another issue...
3. Could you discuss the Potts-Guy equation, and provide us with a little bit of insight as to its utility to determine the penetration of molecules into the skin.
I find it quite embarrassing that this equation is now named after Russ Potts and me. That has come about without any involvement of the two of us! Furthermore, to be frank, much credit belongs to Gerry Kasting, Ron Smith, and Gene Cooper, who published a very nice paper in Skin Pharmacokinetics (1987) that was really the springboard for what we did. Once Gordon Flynn had published a comprehensive database of human skin permeability coefficients of chemicals applied from aqueous solutions (so-called kp values), all we had to do was put the two pieces of work together and simplify the mathematics a little to come up with the 'famous' algorithm. This then allowed kp to be predicted from the molecular weight and the octanol-water partition coefficient of the chemical and, when one multiplies kp by the known or calculated water solubility, one has a predicted maximum flux (Jmax) of the chemical across human stratum corneum. Jmax is a useful parameter to determine, for example, whether a drug can be delivered transdermally to achieve a target plasma concentration required to provoke a therapeutic effect. Or, it can answer the question: If I rub this gel or emulsion on my skin with a certain concentration of active ingredient, what is the potential systemic exposure and is it safe for a consumer to use the product as envisaged? The approach has been pretty well-validated and has been improved by Annette Bunge's correction of the algorithm for very lipophilic chemicals. The original paper we published (R.O. Potts and R.H. Guy, Predicting skin permeability, Pharm. Res., 9, 663-669 (1992)) has been cited about 800 times, streets ahead of any other article that I’ve co-authored! I doubt that I’ll write another paper which will overtake this one.
4. What is the most significant scientific finding from your lifetime of work?
The “Potts & Guy equation” paper is an important lifetime achievement, without question. However, I think that our iontophoresis research has also been very significant. Iontophoresis uses an electric field to enhance molecular transport across the skin and works in both directions, either to push actives into the skin, or to extract analytes to the surface. When we appreciated the latter phenomenon, we gave some thought to potential applications and quickly arrived at the idea of ‘needle-stick-free’ glucose monitoring. We performed some key experiments, filed a patent application, and acquired funding and a collaboration with Cygnus, Inc., and demonstrated proof-of-concept in man in a relatively short period of time. Subsequently, the company performed heroics to ultimately develop the GlucoWatch Biographer that was eventually approved by the FDA in 2001. Sixteen years later, this device remains the only minimally invasive glucose monitoring device that has ever been granted regulatory approval and reached the market. Although the GlucoWatch was not a commercial success, the fact that we made an observation in the laboratory, progressed the idea and proved the concept, and ultimately transferred the technology, leading to the design of a truly novel device, was an achievement of which I am very proud. It is not very often that an academic has the chance to see a part of their scientific work evolve into an actual product.
5. As many researchers know, you were one of the founding fathers of the Gordon Research Conference on Barrier Function of Mammalian Skin. What inspired you to set out on this task?
Although I was one of the founders of the GRC on Barrier Function of Mammalian Skin, much of the credit belongs to Chris Cullander, a senior researcher in my laboratory at that time. Chris was the one who first suggested that we make an application to set up a GRC on skin barrier function. Initially, I wasn’t sure that the idea would fly, but once we had the application materials, a draft program, and a lot of enthusiasm from everyone we talked to about the plan, our proposal was accepted without any problem at all. Chris and I, in collaboration with Russ Potts, did not need to cajole any of the chosen speakers to participate in the first conference and the rest, as they say, is history. Our underpinning idea for the conference was to make a bridge between the physics and biology of barrier function, and there were plenty of strong characters involved in the field at that time. There were memorable debates about barrier lipids between Peter Elias (University of California San Francisco) and Donald Downing (University of Iowa), for example, and the never-ending battle over the existence of so-called “aqueous pathways” across the stratum corneum. I am not sure if we have ever been able to get the biologists and the physicists in the same bed together, so to speak, but it is a fantastic community of scientists. Sometimes it may seem like there is too much “bloody spectroscopy”, or too much mathematics, or too many three letter acronyms for a variety of obscure proteins, but people keep coming back for more.
6. Are there any special moments in your career that you would like to share with us?
We have already talked about the GlucoWatch, which came about because of our interest in the underlying science. When glucose is extracted across the skin by iontophoresis, the transport mechanism involved is called electroosmosis. The skin has a net negative charge and, when an electric field is imposed across it, there is a net flow of solvent in the direction of counterion (i.e. positive ion) movement. Glucose, which is uncharged, of course, is conveyed along with this electroosmotic flow. My research group (including a visiting Spanish academic who has become rather more than a lab partner...) worked hard to understand the phenomenon of electroosmosis and discovered some unexpected behaviour that had not been observed before. Other highlights include the spectroscopic and biophysical studies that we performed to better characterize skin barrier function and the mechanism of action of certain penetration enhancers. This work overlaps with our application of imaging technologies (Raman scattering, AFM, lasers) to elucidate penetration pathways across the skin and the nail. Being among the first laboratories to apply these techniques—and having great collaborators to work with—has really been special and has proved to be a real advantage of being a physical chemist playing in a biological world. I’ve also been fortunate to receive a few awards for our work and it is particularly satisfying and surprising (!) when this happens. Importantly, these are times when one really appreciates the fact that he/she has been lucky to have such excellent team members who, after all, are the people who actually do the work!
7. How do you feel research has changed the most in the last forty years? Would you like to comment on the state of academia-industry interactions?
First of all, it seems that there is a lot more to keep up with than there used to be. I think there is a lot more going on in many fields, and information is much more accessible. On the positive side, this massive increase in the quantity of material that is out there, and that can inform one’s research, means that there’s no excuse for wasting time and energy on things that have already been discovered. The sophistication of techniques and tools that are available today is incredible and this makes it possible to ask (and answer) much more complex questions than before. When I started my career about 40 years ago, personal computers didn’t exist, a programmable calculator was an expensive, luxury item, and running a computer program required a large stack of punched cards! Today’s generation thinks I’m speaking a foreign language when I try to explain how it was. No e-mail, no internet, you looked up references in the actual library? You’re kidding me!
The other significant change that I perceive is the cultural transformation in terms of collaboration and interdisciplinary research. The best papers that I have published have come from collaborations with people from entirely different disciplines and backgrounds. In general, it has taken time for that to happen, particularly in academia, where the old model was very much to work independently. We should enjoy the fact that it is easier to do clever science if you have more than one brain thinking about what to do and it’s good to see younger colleagues exploiting collaborative and inter-disciplinary research from very early in their careers. Another thing that has changed is the ease of access to information these days, and I believe that this has facilitated more and better academic-industrial interactions. It used to be hard work to find out what was going on in industry—now it’s not so difficult. Most of the time, industry wants to tell people what it is doing and why it is relevant. That has helped make contacts between academics and industry better than it used to be. Industry recognizes that there are some competitive areas of research that make sense to do in collaboration with academics, because without it they sometimes are not able to produce interesting intellectual property or new ideas for product development.
8. What do you feel was your greatest accomplishment throughout your career in skin research?
I have a very short answer that I feel very strongly about. Greatest accomplishment: training and mentoring around 40 Ph.D. students and about 80 post-doctoral fellows. These individuals have come from around the globe, and my laboratory has always been a very energetic and remarkably harmonious cultural mix.
9. Where do you foresee skin research in twenty years? Is there an emerging pattern of interdisciplinary research that is going to impact the future of skin research?
In the areas where we are active, new materials, biomarkers, monitoring, and non-invasive delivery monitoring devices are probably the areas where we will see the most progress. There is a lot of potential for information exchange across the skin, whether for therapeutics or reporting on disease status or monitoring of body functions.
10. What advice would you offer aspiring young scientists just starting their career?
To make a horrible pun, anyone considering this field of research needs a thick skin. Skin research, in no matter what specific area, is difficult. Those, who have gotten involved and made proper contributions to the field, have been hardy individuals that treat the skin seriously and with respect. There are many examples of scientists who have drifted into skin research and then packed their bags quickly after reality has struck! If one considers drug delivery, or even treating skin disease topically, the skin is always acting as an indomitable opponent. After all, it is a barrier that prevents molecular transport and, if one undermines this role to enhance permeability, the skin immediately starts work to repair any damage. So, one needs to be persistent and stubborn, have a good understanding and appreciate the barrier, and read the literature (always a good idea to avoid making the same mistakes as others or trying things that have already been shown not to work).
11. Rumor has it that you are an avid cricket player. Do you still have a passion for this sport?
Yes, I am an avid cricket player and have always had a passion for this sport. In the summer I play every Saturday and either train or play again one day during the week. I play league cricket both for a village near Bath and for the Wiltshire County 60+ Seniors team. Games typically last all afternoon, with a break for tea of course, and finish with banter and beer in the bar afterwards. The only downside is the fickle English weather, but this is only a mild distraction to the real aficionados. I’m looking forward to May and the chance to try out my new bat.
About the Interviewee
Richard Guy received an M.A. in Chemistry from Oxford University, and his Ph.D. in Pharmaceutical Chemistry from the University of London. He has held academic posts at the University of California, San Francisco and the University of Geneva. In 2004, he joined the University of Bath as Professor of Pharmaceutical Sciences in the Department of Pharmacy & Pharmacology. Dr. Guy is an elected fellow of the Royal Society of Chemistry, the Controlled Release Society, the American Association of Pharmaceutical Scientists, and the American Association for the Advancement of Science. In 2013, Dr. Guy was named a Fellow of the UCL School of Pharmacy, in recognition of “his distinguished contribution to the pharmaceutical sciences”, and was awarded the Controlled Release Society’s Founders Award. Last year, he received the Maurice-Marie Janot Award from the Association Pharmacie Galénique Industrielle (APGI) for his “original and innovative papers in the domain of pharmaceutics, biopharmaceutics and pharmaceutical technology”, and he was awarded the degree of Doctor of Science from Oxford University.