First, some numbers to set the perspective. In 2008, >10^9 transdermal patches were produced (1). Estimated to be worth ~$12.7 billion in 2005, the transdermal drug delivery market was ~$32 billion in 2015 (2) with ~one patch introduced into clinical practice every 7.5 months (1, 3). Yet, this represents <3% of total pharmaceutical output (4). 1979 saw the 1st transdermal patch approved for systemic delivery, scopolamine Rx against motion sickness sustained over 3 days (5, 6). Since then, majority of skin patches simply exploited capacity for passive diffusion across the skin. This market is now more or less saturated. Thus, expansion of scope and products through skin drug delivery beyond passive diffusion requires active approaches. For e.g., recently only two new molecular entities (NME) were 1st developed for transdermal use, Norelgestromin in ORTHO EVRA® contraception patch and Rotigotine for Parkinson’s (4). This amounts to 0.1NMEs/year for Transdermal versus 0.9/year for Topical versus 20-40/year overall (4). However, as some of the older Transdermals come off patent, generics are entering the market for conditions ranging from hypertension, estrogen and testosterone replacement, contraception, pain (Fentanyl and Lidocaine patches), smoking cessation, angina, overactive bladder (7).
Skin’s Stratum corneum Presents A Formidable Physical Barrier
Penetrating efficiently to reach the blood is the biggest technical hurdle for active drug delivery across skin. Skin structure makes this a daunting challenge. In particular, the outermost, exposed skin layer, the stratum corneum represents a formidable physical barrier. Several mm thick, stratum corneum is composed of ~90% corneocytes, ‘flattened, dead, keratin-filled cells‘ (8). This works out to ~80 to 90% protein, 5 to 15% lipids, making it lipophilic, i.e., lipid-loving, while the deeper layers of the epidermis and dermis are hydrophilic, i.e., water-loving. For a drug to traverse a biological landscape to get into the blood circulation, it doesn’t get any more starkly yin-yang than this. Specifically, in order to penetrate the various epidermal and dermal layers, a drug’s lipophilic versus hydrophilic qualities need to be within a rather narrow range (9). This restricts the range of drug molecules for the transdermal route. On top of that, there are tremendous regional variations in thickness, water permeability and diffusivity (see figure below from 10), number of hair follicles (see figure below from 11) and skin penetration fluxes.
Some examples of regional skin differences in transdermal diffusion:
- Trunk and upper arm skin appear to have similar fluxes. For e.g., Clonidine (12), Estraderm (Estradiol) (13) and Nicoderm (14) patches on chest or arm yield similar plasma concentrations.
- Transdermal testosterone patch could be interchangeably applied to skin of the upper buttocks, upper arms or upper back, giving similar plasma concentrations (15).
- Contraceptive Ortho Evra® patch also gave equivalent plasma concentrations whether applied to abdomen, buttock, arm or torso (16).
- However, Exelon® 24 hour patch on upper back, chest or upper arm gave higher plasma concentration of Rivastigmine compared to thigh and abdomen (17).
- Nicorette on upper arm or back gave higher plasma concentration compared to the abdomen (18).
Thus, location, drug and/or drug formulation influence drug diffusion efficiency across skin in different parts of the body.
In sum, stratum corneum represents such a challenging physical barrier (2, 19), it essentially restricts passive drug diffusion to
- Low drug dose (<20mg/day)
- Short half-life
- Partition coefficient between 1 and 4
- Low oral bioavailability
- Low therapeutic index
- Drugs with affinity for both lipid and water
- Low melting point (<200oC)
- Non-irritating and non-sensitizing formulations
- Low molecular weight.
That last, i.e., size of drugs, is a substantial limitation imposed by passive transdermal skin transport, with most being low molecular weight (<500 Daltons), lipophilic, high potency (see figure below from 6 for molecular weights of major approved transdermal drugs).
Active Approaches To Get Drugs Past The Skin’s Stratum Corneum
Active approaches require skin patch drug formulations to incorporate chemicals capable of physically disrupting it. This creates another problem, namely, greater likelihood of skin irritation at a minimum to more serious skin damage (6).
Potential for skin damage brings us to aging which presents another technical challenge for skin patches. In the 1st instance, skin patches can cause local skin irritation and even more serious reactions, depending on the patch formulation. Aging skin involves several changes that can exacerbate this propensity. Aging skin entails increasing dryness, less elasticity, epidermal thinning, decreased local blood flow, and steady decline of skin endocrine function and immunity (20, 21). Some studies on passive drug diffusion showed no difference between young and old (>65 years; 22). In fact, in one study on Buprenorphine (analgesic) patches, same skin patches worked for those 50 to 65 years old and >75 years (23). While aging skin changes may not affect function of skin patches using passive diffusion, they may matter for active, especially chemically active, transdermal drug delivery approaches.
Thus, in addition to chemical, a variety of non-chemical, i.e., electrical and mechanical approaches to breach stratum corneum have become the focus of greater research attention in recent years (see table from 24 and figure from 25).
One of the 1st such is Iontophoresis (see figures below from 26), i.e., using electricity to push small drug molecules like tacrine (27) across the skin. As the figures make obvious, though a few like Lidosite® have even been approved, such devices are much too complex to be convenient and portable, especially for the elderly. Similar disadvantages pertain to other research approaches such as sonophoresis, magnetophoresis, electroporation (2).
Microneedles offer a physical approach to bypass the stratum corneum. Tiny needles are tightly arranged on a patch. When applied to the skin, they punch through and past the stratum corneum (see figures below from 8 and 28).
Such microneedles can be made from a variety of materials such as metal, silicon, polymers, could be drug-coated, soluble, hollow, and even be dissolving. Such microneedles have been shown to cause minimal discomfort (29, 30). For e.g., 3 cardiovascular drugs were recently simultaneously delivered to elderly patients through a single microneedle patch (31), and found to be safe and effective. However, caution is warranted with the elderly given well-known reduction in epidermal repair capacity in those 55 years and older (32).
Summarizing pros and cons, an active transdermal drug delivery approach needs to be cost-effective and formulated such that drug concentrations of sufficient potency are delivered systemically. Another issue that experts routinely bring up is ‘unmet medical needs‘ (6, 7) as in what are the unmet medical needs transdermal drug delivery covers. This may be moot given millions of annual needle-stick accidents, needle phobia, particularly in the very young, and sheer inconvenience of the status quo, i.e., syringe and needle. Newer patch technologies incorporate principles of controlled release (see figure below from 7).
Safety’s already in the bag since drug stoppage simply requires removing the patch. Thus, by several objective measures, transdermal drug delivery will have prime time in the near future (see figures below from 1, 7, 33).
1. Prausnitz, Mark R., and Robert Langer. “Transdermal drug delivery.” Nature biotechnology 26.11 (2008): 1261-1268. http://drugdelivery.chbe.gatech….
2. Ita, K. B. “Transdermal drug delivery: progress and challenges.” Journal of Drug Delivery Science and Technology 24.3 (2014): 245-250.
3. Mitragotri, Samir, et al. “Mathematical models of skin permeability: an overview.” International journal of pharmaceutics 418.1 (2011): 115-129. http://opus.bath.ac.uk/27292/1/G…
4. Walter, Jessica R., and Shuai Xu. “Therapeutic transdermal drug innovation from 2000 to 2014: current status and outlook.” Drug discovery today 20.11 (2015): 1293-1299.
5. Anselmo, Aaron C., and Samir Mitragotri. “An overview of clinical and commercial impact of drug delivery systems.” Journal of Controlled Release 190 (2014): 15-28.
6. Wiedersberg, Sandra, and Richard H. Guy. “Transdermal drug delivery: 30+ years of war and still fighting!.” Journal of Controlled Release 190 (2014): 150-156. http://opus.bath.ac.uk/39834/1/A…
7. Pastore, Michael N., et al. “Transdermal patches: history, development and pharmacology.” British journal of pharmacology 172.9 (2015): 2179-2209. http://onlinelibrary.wiley.com/d…
8. Rattanapak, Teerawan, Camilla Foged, and Sarah Hook. “Transcutaneous Immunization.” Subunit Vaccine Delivery. Springer New York, 2015. 347-369. https://www.researchgate.net/pro…
9. Yano, Tadanori, et al. “Skin permeability of various non-steroidal anti-inflammatory drugs in man.” Life sciences 39.12 (1986): 1043-1050.
10. Marwah, Harneet, et al. “Permeation enhancer strategies in transdermal drug delivery.” Drug delivery 0 (2014): 1-15.
11. Patzelt, Alexa, and Jürgen Lademann. “The Increasing Importance of the Hair Follicle Route in Dermal and Transdermal Drug Delivery.” Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement. Springer Berlin Heidelberg, 2015. 43-53.
12. MacGregor TR, Matzek KM, Keirns JJ, Vanwayjen RGA, Vandenende A, Vantol RGL (1985). Pharmacokinetics of transdermally delivered clonidine. Clin Pharmacol Ther 38: 278–284.
13. Schenkel, Lotte, et al. “Transdermal absorption of estradiol 101 from different body sites is comparable.” Journal of controlled release 4.3 (1986): 195-201.
14. Gorsline, Jane, et al. “Comparison of plasma nicotine concentrations after application of Nicoderm (nicotine transdermal system) to different skin sites.” The Journal of Clinical Pharmacology 32.6 (1992): 576-581.
15. Yu, Zhiling, et al. “Transdermal testosterone administration in hypogonadal men: comparison of pharmacokinetics at different sites of application and at the first and fifth days of application.” The Journal of Clinical Pharmacology 37.12 (1997): 1129-1138.
16. Abrams, Larry S., et al. “Pharmacokinetics of a contraceptive patch (Evra™/Ortho Evra™) containing norelgestromin and ethinyloestradiol at four application sites.” British journal of clinical pharmacology 53.2 (2002): 141-146. http://onlinelibrary.wiley.com/d…
17. Lefevre, Gilbert, et al. “Pharmacokinetics of a rivastigmine transdermal patch formulation in healthy volunteers: relative effects of body site application.” The Journal of Clinical Pharmacology 47.4 (2007): 471-478.
18. Sobue, Satoshi, et al. “Effect of application sites and multiple doses on nicotine pharmacokinetics in healthy male Japanese smokers following application of the transdermal nicotine patch.” The Journal of Clinical Pharmacology 45.12 (2005): 1391-1399.
19. Khavari, Afshin, et al. “Different physical delivery systems: An important approach for delivery of biological molecules in vivo.” Journal of Paramedical Sciences 7.1 (2016). http://journals.sbmu.ac.ir/jps/a…
20. Zouboulis, Christos C., and Evgenia Makrantonaki. “Clinical aspects and molecular diagnostics of skin aging.” Clinics in dermatology 29.1 (2011): 3-14.
21. Quinn, Helen L., Carmel M. Hughes, and Ryan F. Donnelly. “Novel methods of drug administration for the treatment and care of older patients.” International Journal of Pharmaceutics (2016).
22. Kaestli, Laure-Zoé, et al. “Use of transdermal drug formulations in the elderly.” Drugs & aging 25.4 (2008): 269-280. https://www.researchgate.net/pro…
23. Al-Tawil, Nabil, et al. “Pharmacokinetics of transdermal buprenorphine patch in the elderly.” European journal of clinical pharmacology 69.2 (2013): 143-149. Pharmacokinetics of transdermal buprenorphine patch in the elderly
24. Prausnitz, Mark R., et al. “Skin barrier and transdermal drug delivery.” Dermatology. Philadelphia, PA: Elsevier Saunders (2012): 2065-73. http://drugdelivery.chbe.gatech….
25. Engelke, Laura, et al. “Recent insights into cutaneous immunization: How to vaccinate via the skin.” Vaccine (2015).
26. Alkilani, Ahlam Zaid, Maelíosa TC McCrudden, and Ryan F. Donnelly. “Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties of the stratum corneum.” Pharmaceutics 7.4 (2015): 438-470. http://www.mdpi.com/1999-4923/7/…
27. Patel, Niketkumar, et al. “Influence of electronic and formulation variables on transdermal iontophoresis of tacrine hydrochloride.” Pharmaceutical development and technology 20.4 (2015): 442-457.
28. Kis, Elsa E., Gerhard Winter, and Julia Myschik. “Devices for intradermal vaccination.” Vaccine 30.3 (2012): 523-538. https://www.researchgate.net/pro…
29. Donnelly, Ryan F., et al. “Hydrogel-forming microneedle arrays can be effectively inserted in skin by self-application: A pilot study centred on pharmacist intervention and a patient information leaflet.” Pharmaceutical research 31.8 (2014): 1989-1999.
30. Norman, James J., et al. “Microneedle patches: usability and acceptability for self-vaccination against influenza.” Vaccine 32.16 (2014): 1856-1862. https://www.researchgate.net/pro…
31. Quinn, Helen L., et al. “Design of a Dissolving Microneedle Platform for Transdermal Delivery of a Fixed‐Dose Combination of Cardiovascular Drugs.” Journal of pharmaceutical sciences 104.10 (2015): 3490-3500. http://ac.els-cdn.com/S002235491…
32. Berger, Timothy G., and Martin Steinhoff. “Pruritus in elderly patients—eruptions of senescence.” Seminars in cutaneous medicine and surgery. Vol. 30. No. 2. NIH Public Access, 2011. http://www.seattlederm.org/docum…
33. Teunissen, M. B., and Darin Zehrung. “Cutaneous vaccination-Protective immunization is just a skin-deep step away.” Vaccine 33.37 (2015): 4659.