Introduction[1]

Transdermal delivery represents an attractive alternative to oral delivery of drugs and is poised to provide an alternative to hypodermic injection. The first transdermal system for systemic delivery—a three-day patch that delivers scopolamine to treat motion sickness—was approved for use in the United States in 1979. A decade later, nicotine patches became the first transdermal blockbuster, raising the profile of transdermal delivery in medicine and for the public in general.

Drug Delivery Routes Across Human Skin[2]

FIGURE 1 | Schematic representation of a cross section through human skin.

Stratum corneum, located on the outer surface of the skin, is a non-living layer of keratin-filled cells surrounded by a lipid-rich extracellular matrix that provides the primary barrier to drug delivery into skin. The epidermis below is a viable tissue devoid of blood vessels. Just below the dermal-epidermal junction, the dermis contains capillary loops that can take up transdermally administered drugs for systemic distribution. a | Transdermal diffusion, possibly in the presence of a chemical enhancer, takes place by a tortuous route across the stratum corneum, winding around cells and occurring along the interfaces of extracellular lipid bilayers. b | Low-voltage electrical enhancement by iontophoresis can make transport

pathways through hair follicles and sweat ducts more accessible. c | High-voltage enhancement by electroporation has been shown to occur via transcellular pathways made accessible by disrupting lipid bilayers. The application of ultrasound seems to make pathways a and c more permeable by disorganizing lipid bilayer structure. d | Microneedles and thermal poration create micron-scale holes in skin to provide pathways for drug transport.

Advantages and Disadvantages of Transdermal Drug Delivery[3]

Delivery via the transdermal route is an interesting option because transdermal route is convenient and safe. The positive features of delivery drugs across the skin to achieve systemic effects are:

∙ Transdermal delivery avoids the stomach environment where the drug can be degraded and rendered ineffective or where it can cause unpleasant gastrointestinal symptoms for the patient.

∙ Transdermal delivery avoids the first pass effect where active drug molecules can be converted to inactive molecules or even to molecules responsible for side effects.

∙ Transdermal drug delivery provides steady plasma levels. When a patch is applied that lasts for 24 hours, or even 7 days, once steady state is reached the plasma levels remain constant because the rate of drug delivered from the patch is constant. When a drug is given four times a day, or even once a day, the drug levels rise after administration and then gradually fall until the next administration producing peaks and troughs throughout the course of therapy.

∙ Transdermal drug delivery systems, especially simple patches, are easy to use and noninvasive and patients like noninvasive therapies.

No drug delivery system is without its disadvantages. Some of the challenges of transdermal drug delivery include:

Systems Sarawuth Noppiboon ID 56070700020 BioPhEPs

∙ Only a narrow range of molecules can currently be delivered transdermally using available technologies. Only small, relatively lipophilic molecules can pass through the lipid bilayer “mortar” of the stratum corneum using traditional patch technology. As drug treatments become more and more complex, drug molecules are becoming larger and more complex as well and new technologies will be needed to deliver these drugs through the skin.

∙ Currently, only small quantities of drug can be delivered through the stratum corneum. Therefore, drugs that are given transdermally must be relatively potent so that they can be effective at low doses.

∙ Patient trust issues can also be a barrier to effective transdermal drug therapy. The general public might have been willing to accept a 3-day scopolamine patch when it was introduced in 1979 but it was quite a challenge in 1984 to convince doctors and patients alike that a clonidine patch would control blood pressure for seven days continuously. In more recent years, there have been accidental overdose deaths from fentanyl patches[4]. As new transdermal technologies are introduced, there will certainly be questions from patients and healthcare professionals about the safety and effectiveness of these new delivery systems.

Mechanism of Action

The application of the transdermal patch and the flow of the active drug constituent from the patch to the circulatory system via skin occur through various methods.

In 2008, Prausnitz and Langer published a paper in which they proposed three generations of transdermal drug delivery systems (TDDS) [1]

∙ 1st generation TDDS include traditional patches such a clonidine or estrogen

∙ 2nd generation TDDS include patches plus some type of enhancement to improve drug delivery

∙ 3rd generation TDDS use novel technologies to increase the scope of molecules that can be delivered through the skin

First-generation transdermal delivery systems

Currently, there are two types of simple patch design (Figure 2). The original patch design is a liquid reservoir system where the patch consists of a backing material that is both protective and adhesive, a liquid drug reservoir, and a release membrane.

FIGURE 2 | Drug Reservoir and Drug-in-Adhesive Designs.

A more recent design is the adhesive matrix system where the adhesive and the drug are combined in the same layer leaving only three layers to the patch; the backing layer, the drug and adhesive layer, and the protective layer that would be removed before applying the patch to the skin.

Second-generation transdermal delivery systems

2nd Generation TDDS attempt to enhance the delivery of organic molecules through the stratum corneum by disrupting its barrier function and/or by providing some sort of driving force for the movement of molecules through the epidermis. This disruption should be reversible and avoid injury to the skin. However, it can be difficult to disrupt the barrier without causing damage or irritation, especially when using chemical enhancers. In addition, these 2nd generation enhancement techniques are limited to small, lipophilic molecules and still have little effect on larger or hydrophilic molecules. 2nd generation enhancement methods include

Conventional chemical enhancers

Recognizing the need to increase skin permeability, second-generation delivery strategies have turned largely to the development of chemical enhancers. This approach is a logical extension of the traditional pharmaceutical toolbox because it primarily involves designing new formulations with chemical excipients. Many effective chemical enhancers disrupt the highly ordered bilayer structures of the intracellular lipids found in stratum corneum by inserting amphiphilic molecules into these bilayers to disorganize molecular packing or by extracting lipids using solvents and surfactants to create lipid packing defects of nanometer dimensions.

Heat as a penetration enhancer

Another form of penetration enhancement is the use of heat to increase the permeability of the skin. Unfortunately, the medical community was made aware that heat can increase the absorption of drugs through the skin in 2005 when the FDA began issuing warnings regarding the safe use of fentanyl patches after deaths had been attributed to wearing the patch while sleeping in heated water beds or using heating pads.

Iontophoresis

Iontophoresis has been studied for moto increase transdermal delivery for more than a century by typically applying a continuous low-voltage current. While there can be increased skin permeability, iontophoresis mainly provides an electrical driving force for transport across stratum corneum. Charged drugs are moved via electrophoresis, while weakly charged and uncharged compounds can be moved by electroosmotic flow of water generated by the preferential movement of mobile cations (e.g., Na+) instead of fixed anions (e.g., keratin) in the stratum corneum. Because iontophoresis does not primarily change the skin barrier itself, it is mostly applicable to small molecules that carry a charge and some macromolecules up to a few thousand Daltons.

Non-cavitational ultrasound

Ultrasound was first widely recognized as a skin permeation enhancer when physical therapists discovered that massaging anti-inflammatory agents into the skin using ultrasonic heating probes increased efficacy. Ultrasound is an oscillating pressure wave at a frequency too high for humans to hear.

Third-generation transdermal delivery systems

3rd generation TDDS aim to severely disrupt the stratum corneum to allow large molecules to pass into the circulation. While iontophoresis can be used to deliver small molecules such as fentanyl, it can also be used to deliver much larger molecules as well.

Combinations of chemical enhancers

Recent studies have suggested that suitably designed combinations of chemical enhancers can balance trade-offs between enhancement and irritation based on the hypothesis that certain enhancer combinations are especially potent when present at specific, narrow compositions. This approach enables a strategy to target effects that enhance skin permeability in the stratum corneum, but avoids irritation in deeper tissues where the formulation composition becomes diluted or otherwise altered.

Electroporation

The use of short, high-voltage pulses is well known as a method to reversibly disrupt cell membranes for gene transfection and other applications. Electroporation has also been shown to disrupt lipid bilayer structures in the skin. Although the electric field applied for milliseconds during electroporation provides an electrophoretic driving force, diffusion through long-lived electropores can persist for up to hours, such that transdermal transport can be increased by orders of magnitude for small model drugs, peptides, vaccines and DNA.

Cavitational ultrasound

In addition to heating, ultrasound is also known to generate cavitation, which is the formation, oscillation and, in some cases, collapse of bubbles in an ultrasonic

pressure field. Cavitation is only generated under specific conditions (e.g., low-frequency ultrasound) that differ from those of ultrasonic heating or imaging devices. The opportunity for transdermal drug delivery is that cavitation bubbles concentrate the energy of ultrasound and thereby enable targeted effects at the site of bubble activity. Because bubbles are more difficult to grow and oscillate within densely-packed tissue, cavitation preferentially occurs within the coupling medium (e.g., a hydrogel) between the ultrasound transducer and skin. The expected mechanism of cavitational ultrasound is that bubbles oscillate and collapse at the skin surface, which generates localized shock waves and liquid microjets directed at the stratum corneum. This disrupts stratum corneum lipid structure and thereby increases skin permeability for up to many hours without damaging deeper tissues. Cavitational ultrasound is not believed to contribute a significant driving force for transport.

Microneedles

A conceptually straightforward way to selectively permeabilize the stratum corneum is topierce it with very short needles. Over the past decade, microneedles have been developed as a means to deliver drugs into the skin in a minimally invasive manner. Solid microneedles have been shown to painlessly pierce the skin to increase skin permeability to a variety of small molecules, proteins and nanoparticles from an extended-release patch. Alternatively, drug formulations have been coated on or encapsulated within microneedles for rapid or controlled release of peptides and vaccines in the skin. Hollow microneedles have been used to deliver insulin and vaccines by infusion.

In general, microneedles (i) increase skin permeability by creating micron-scale pathways into the skin, (ii) can actively drive drugs into the skin either as coated or encapsulated cargo introduced during microneedle insertion or via convective flow through hollow

microneedles and (iii) target their effects to the stratum corneum, although microneedles typically pierce across the epidermis and into the superficial dermis too.

Thermal ablation

Thermal ablation selectively heats the skin surface to generate micron-scale perforations in the stratum corneum. Transiently heating the skin’s surface to hundreds of degrees for microseconds to milliseconds localizes heat transfer to the skin surface without allowing heat to propagate to the viable tissues below. This spares these tissues from damage or pain. Mechanistically, thermal ablation may involve rapidly vaporizing water in the stratum corneum, such that the resulting volumetric expansion ablates micron-scale craters in the skin’s surface.

Microdermabrasion

A final way to remove the stratum corneum barrier employs abrasion by microdermabrasion or simply using sandpaper. Microdermabrasion is a widely used method to alter and remove skin tissue for cosmetic purposes. This abrasive mechanism, which is related to sand blasting on the microscopic scale, has been shown to increase skin permeability to drugs, including lidocaine and 5-fluorouracil, which suggests possible applications in transdermal drug delivery. Vaccine delivery across the skin has also been facilitated by skin abrasion using sandpaper. Initial studies in animals generated strong immune responses to several vaccines when administered topically in combination with a potent adjuvant (i.e., heat-labile enterotoxin of Escherichia coli). More recently, human trials have addressed vaccination against traveler’s diarrhea and influenza.

Table 1| Products Available in the market

*denotes products that were approved and later removed from the market

**Withdrawn from the USA in 2008, reformulated product approved by US FDA in April 2012 and relaunched in July 2012

REFERENCES

1. Prausnitz, M.R. and Langer, R., 2008, "Transdermal Drug Delivery", Nature Biotechnology, Vol. 26, No. 11, pp. 1261-1268.

2. Prausnitz, M.R., Mitragotri, S., and Langer, R., 2004, "Current Status and Future Potential of Transdermal Drug Delivery", Nature Reviews Drug Discovery, Vol. 3, No., pp. 115-124.

3. Rios and Maribel, 2007, "Advances in Transdermal Technologies: Transdermal Delivery Takes up Once-Forbidden Compounds, Reviving Markets and Creating Formulation Opportunities", Pharmaceutical Technology, Vol. 31, No. 10, pp. 54-58.

4. Administration, U.S.F.a.D., 2007, Fda Consumer Updates Page, [online], Available: [24 Oct 2013].

Approval year Drug Indication Product Name 1979 Scopolamine Motion sickness Transderm-Scop 1981 Nitroglycerin Angina pectoris Transderm-Nitro 1984 Clonidine Hypertension Catapres-TTS 1986 Estradiol Menopausal symptoms Estraderm 1990 Fentanyl Chronic pain Duragesic 1991 Nicotine Smoking cessation Nicoderm, Habitrol, ProStep 1993 Testosterone Testosterone deficiency Testoderm

1995 Lidocaine/epinephrine (iontophoresis)

Local dermal analgesia Iontocaine

1998 Estradiol/norethidrone Menopausal symptoms Combipatch 1999 Lidocaine Post-herpetic neuralgia pain Lidoderm 2001 Ethinyl estradiol/norelgestromin Contraception Ortho Evra 2003 Estradiol/levonorgestrel Menopausal symptoms Climara Pro 2003 Oxybutynin Overactive bladder Oxytrol 2004 Lidocaine (ultrasound) Local dermal anesthesia SonoPrep 2005 Lidocaine/tetracaine Local dermal analgesia Synera 2006 Fentanyl HCl (iontophoresis)* Acute postoperative pain Ionsys

2006 Methylphenidate Attention deficit hyperactivity disorder

Daytrana

2006 Selegiline Major depressive disorder Emsam 2007 and 2012** Rotigotine Parkinson’s disease Neupro 2007 Rivastigmine Dementia Exelon 2008 Granisetron Chemo-induced emesis Sancuso 2009 Oxybutynin Overactive bladder Gelnique 2010 Buprenorphine Chronic pain Butrans