Transdermal Drug Delivery Gains Traction

Transdermal patches are designed to deliver drugs through the skin, principally by diffusion, for a systemic effect. As an alternative to the oral route, transdermal drug delivery offers a number of advantages such as the avoidance of first metabolism and gastrointestinal toxicity. It allows for the administration of drugs with narrow therapeutic window, can prolong the activity of drugs with short half-lives, and eliminates the need for hypodermic injections. Patient compliance is also improved because of the ease of administration.

“Patient preference is becoming increasingly important,” observes Simmon Schaefer, director of business development, 3M Drug Delivery Systems, “and transdermal patches are a great alternative for those who struggle with swallowing pills and want a more comfortable alternative to injections.” Another advantage is that, in the event of adverse reactions or other problems, patients can terminate the therapy rapidly at any point, simply by removing the patch.

Beyond patient preference, transdermal patches offer efficacy benefits, Schaefer continues. “For instance, instead of the ‘peak and trough’ effect often seen with pills and injections, transdermal patches can maintain a steady blood level of medication,” he explains. “This technology also has the potential to deliver a drug for up to seven days.”

According to Mattias Springfelter, senior formulation scientist at Recipharm Pharmaceutical Development, transdermal patches can be designed to provide prolonged and controlled release of certain drugs, which can be convenient for pain-relief drugs, nicotine, and hormone products. Schaefer cites Sancuso (granisetron transdermal system) as an example of a drug being adapted for transdermal delivery. “The transdermal patch is a good match for this drug; it is used to treat chemotherapy-induced nausea and vomiting. The alternative forms-intravenous injections and oral tablets-both pose challenges for patients, whereas transdermal delivery provides a more comfortable and patient-friendly delivery method.”

Challenges in the development of a transdermal drug delivery system
One of the key challenges in transdermal delivery is the limited number of drugs that are suitable for administration by this route. As Springfelter points out, achieving sufficient drug absorption can prove to be a challenge for many molecules, given that the skin is such an efficient barrier against the outside environment.

“The relative impermeability of skin is well known, and this is associated with its functions as a dual protective barrier against the ingress of xenobiotics (including invasion by micro-organisms) and the prevention of the loss of physiologically essential substances such as water,” explains Majella Lane, PhD, senior lecturer in pharmaceutics at University College London, School of Pharmacy. “Notwithstanding this, transdermal therapeutic systems have been designed to provide continuous controlled delivery of drugs via this barrier to the systemic circulation.”

“The classic candidate for traditional transdermal delivery is a small, lipophilic molecule that can diffuse through the stratum corneum and pass into the systemic circulation,” notes Schaefer. “The stratum corneum is made up of dense, hydrophilic structures surrounded by an intercellular lipid matrix, so hydrophilic drugs are typically not good candidates. Most transdermal drugs are relatively hydrophobic molecules that can permeate through the lipid pathway.”

The permeation of drugs across the skin is influenced by a number of physiological and physicochemical factors (1, 2). The physiological factors that affect drug absorption include skin age, gender, ethnicity, the thickness of the stratum corneum (which varies between different anatomical sites), the degree of skin hydration, the presence of hair follicles, skin condition (e.g., disease compromises the natural barrier function of the skin), temperature, and metabolism. In terms of physicochemical factors, properties such as drug solubility, partition coefficient, molecular mass, and whether the drug is in an ionized or unionized form will influence transdermal absorption.

Types of transdermal systems
Transdermal systems include reservoir devices, matrix devices, multiple polymer devices, and multilayer matrix systems. According to Lane, reservoir and matrix systems are the two most common patch systems that are currently available with the matrix patches dominating the field. “The reservoir system is a diffusion-controlled system, which contains a drug reservoir with a rate-controlling polymer membrane. With this device, the membrane that lies between the drug reservoir and the skin controls the rate of release from the drug reservoir to the skin surface,” Lane continues. “For matrix patches, so named because the active is mixed with or contained in a polymer, the drug is released at a rate governed by the components in the matrix. For a drug-in-adhesive matrix, the polymer (in which the drug is dispersed) is an adhesive. The adhesive serves two roles-it acts as the drug reservoir, and it holds the patch on the skin.”

Neha Singh, PhD, transdermal specialist at Kemwell Biopharma, highlights that adhesives are an integral component of passive transdermal patch systems. She adds that selecting the correct type of adhesive based on its compatibility with the API, biocompatibility with the skin, optimum wear time, and skin type can be a challenge.

“Crystallization of the API from the patch has posed a challenge for many transdermal systems,” Singh remarks. “Different factors can result in the formation of crystals over the shelf life.” Selecting the formulation components based on extensive physicochemical compatibility studies and well-planned stability studies can provide valuable insight to the formulation behavior, according to Singh. “One of the main concerns for transdermal systems is the high amount of drug loading required in formulations to maintain a constant flux over the stipulated time duration. Potent drug candidates are ideal candidates for transdermal delivery; however, the saturated concentration requirement necessitates addition of larger amounts. This can also lead to abuse and risks of drug transfer from a used patch once it is disposed of.”

“Skin properties allow the transport of limited drug candidates through passive transdermal delivery,” says Singh. Advances in patch technology have resulted in the surge of first-generation transdermal delivery systems, which form the majority of transdermal patches on the market today. Their clinical use, however, is limited to the delivery of small, lipophilic drugs that are efficacious at low doses (3). The scope of candidates for this route is expanded with the second generation of transdermal delivery systems, which exploits the use of chemical enhancers, iontophoresis, and non-cavitational ultrasound to increase skin permeability (3). Third-generation transdermal delivery systems target the stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation, and cavitational ultrasound to enable more effective transdermal delivery, while still protecting the deeper tissues (3).

Recent advances in transdermal drug delivery
Lane observes that the concept of supersaturation has been exploited in the development of transdermal spray technology, where supersaturated states are generated because volatile components (e.g., ethanol or isopropanol) evaporate after the spray is applied to skin, with consequent enhancement in skin flux. “Because of the dynamic nature of these systems, we still do not fully understand the extent to which the thermodynamic activity of the enhancer, as opposed to that of the active, contributes to the overall permeation-enhancement process, but products are already on the market,” she adds. “The Australian company, Acrux, pioneered the development of a transdermal testosterone formulation based on this approach and the company has also licensed similar technology for animal health applications.”

“The advent of active transdermal systems, such as iontophoresis and microneedles, enables delivery of larger molecules with hydrophilic properties, such as peptides, proteins, and vaccines,” comments Singh. “Microneedles made from a variety of materials, including biodegradable hydrogels that dissolve in the skin, have been designed. Other skin permeabilization techniques, including low-frequency sonophoresis and electroporation, have been studied further to refine their role in enhancing delivery through skin. Modulated delivery (i.e., controlled amount of dose) is possible using iontophoresis when an appropriate amount of current is applied over a stipulated time duration. Physical enhancement techniques have thus expanded the scope of transdermal delivery and have a promising future.” Nonetheless, Singh highlights that the complex nature of these devices, for example, the electronics in iontophoresis and the sterility required for microneedles, could be a challenge for these systems.

Microneedles on the horizon
Lane agrees that microneedles have emerged as one of the most promising technologies for the realization of novel dermal and transdermal therapies. “Although microneedles were first described in the 1990s, this technology has advanced exponentially in recent years,” notes Lane. “Microneedles consist of an array of micro-projections generally ranging from 25–2000 μm in height, which are attached to a base support. The application of such arrays to biological membranes creates micron-sized transport pathways.”

According to Lane, microneedles have been shown to penetrate the skin across the stratum corneum and into the viable epidermis, but do not cause pain as they avoid contact with nerve fibres and blood vessels located in the dermal layer. “The early microneedles were fabricated with silicon, but the major development in recent years has been the design of biodegradable and biocompatible microneedles. Drug can be loaded into the microneedle or coated on to the microneedle and a reservoir patch may also be adhered to the array. As well as effectively transporting conventional small actives into skin, promising results have been reported for macromolecular targeting ex vivo and vaccine delivery in humans,” she explains.

One company that is active in this area, 3M Drug Delivery Systems, is getting closer to introducing its hollow microneedle device on the market. According to Mark Tomai, PhD, head of TLR and MTS Business Development, 3M Drug Delivery Systems Division, the company’s microneedle device consists of polymeric microstructures that utilize one of 3M’s core technologies-microreplication. “This technology was pioneered in the 1960s and first used for applications including roadway signage, but it has now been adapted by 3M Drug Delivery Systems to broaden the scope of drugs that can be delivered transdermally.” 3M has conducted a number of human tolerability studies and design verification tests; and supplies for clinical trials are available for pharmaceutical and biotech companies interested in this technology.

“There are currently two types of microneedle devices under development,” adds Tomai, “solid microneedles (sMTS), which use a dried coating of a molecule or peptide up to 300 μg on the tips of a microneedle array; and hollow microneedles (hMTS), which are compatible with small molecules as well as biologics such as proteins and peptides, and can deliver liquid formulations up to 2 mL.”

Tomai further explains that the hMTS offers a patient-friendly intradermal delivery solution. “The device’s hollow microneedles reach into the highly vascularized dermal layer of the skin, making it ideal for delivery of many treatments. The hMTS handheld delivery device contains up to 2 mL API in a conventional glass vial. The API is transmitted via a sterile flow path through the polymeric hollow microneedles. This single-use delivery system is designed for self-administration and has the potential to expand the range of drugs available for in home injections.”

Researchers from the National University of Singapore (NUS) have developed a microneedle patch that is said to offer a faster, more effective, painless, and non-invasive way to deliver lidocaine (4). A photolithography-based process was used to fabricate this novel transdermal patch. The drug is encapsulated in tiny polymeric needles attached to an adhesive patch. When applied to the skin, the microneedles deliver lidocaine rapidly into the systemic circulation without causing any discomfort to the patient. The technology can also be applied to collagen and used for cosmetic and skincare purposes.

Studies showed that the microneedle patch could deliver lidocaine within five minutes of application compared with the commercial lidocaine patch, which took 45 minutes for the drug to penetrate the skin. According to the researchers, the miniature needles on the patch create micrometre-sized porous channels in the skin, thereby, enabling rapid drug delivery. Because the needle shafts are approximately 600 µm in length, they do not cause any perceptible pain. The reservoir system in the patch acts as channels for drugs to be encapsulated in the backing layers, circumventing the premature closure of miniaturized pores created by the microneedles and ensuring continued drug permeation.

Researchers at Queen’s University Belfast have invented a unique and innovative microneedle transdermal system, based on hydrogel materials (5). The microneedles, which are less than 0.5 mm high or smaller, are made of a hydrogel of biocompatible polymers that can safely deliver constant doses of the drug. The microneedles are hard and sharp when dry, but rapidly hydrate when inserted into the skin. The swollen hydrogel projections create a continuous aqueous pathway between the external environment and dermal microcirculation enabling controlled delivery of the API.

Fujifilm’s microneedle array consists of a sheet arrayed with 100–2000 µm projections made of polysaccharides (6). The drug is delivered into the body by simply attaching the sheet onto the skin. These projections dissolve in the skin within minutes as the drug is delivered. According to Fujifilm, array types with non-dissolvable projections pose risks of the projections breaking off and remaining inside the body; however, Fujifilm’s microneedle array has been proven to be safe as the projections do not retain their form. Experiments with a model vaccine administered using the microneedle array showed that it generated the same amount of, or more, antibodies than the injected vaccine (6). 

References
1. D. N’Da, Molecules 19 (12) 20780–20807 (2014).
2. I. Singh and A.P. Morris, Int J Pharm Investig. 1 (1) 4–9 (2011).
3. M.R. Prausnitz and R. Langer, Nat Biotechnol. 26 (11) 1262–1268 (2008).
4. NUS News, “NUS researchers invent novel microneedle patch for faster and effective delivery of painkiller and collagen,” Press Release, Sept. 5, 2014.
5. R.F. Donnelly et al., Adv Funct Mater. 22 (23) 4879–4890 (2012).
6. Fujifilm, “Fujifilm develops the microneedle array,” Press Release, Nov. 14, 2012. 

Article DetailsPharmaceutical Technology
Vol. 39, No. 5
Pages: 34-36
Citation: When referring to this article, please cite it as A Siew, “Transdermal Drug Delivery Gains Traction,” Pharmaceutical Technology39 (5) 2015.