Sarawuth Noppiboon ID 56070700020 BioPhEPs Systems

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 deliverya 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.

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.

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 No drug delivery system is without its disadvantages. Some extracellular lipid bilayers. b | Low-voltage electrical of the challenges of transdermal drug delivery include: enhancement by iontophoresis can make transport

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.

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

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

Ultrasound was first widely recognized as a skin permeation enhancer when physical therapists discovered Recognizing the need to increase skin permeability, that massaging anti-inflammatory agents into the skin using second-generation delivery strategies have turned largely to ultrasonic heating probes increased efficacy. Ultrasound is the development of chemical enhancers. This approach is a an oscillating pressure wave at a frequency too high for logical extension of the traditional pharmaceutical toolbox humans to hear. because it primarily involves designing new formulations with chemical excipients. Many effective chemical Third-generation transdermal delivery systems enhancers disrupt the highly ordered bilayer structures of 3rd generation TDDS aim to severely disrupt the the intracellular lipids found in stratum corneum by stratum corneum to allow large molecules to pass into the inserting amphiphilic molecules into these bilayers to circulation. While iontophoresis can be used to deliver disorganize molecular packing or by extracting lipids using small molecules such as fentanyl, it can also be used to solvents and surfactants to create lipid packing defects of deliver much larger molecules as well. nanometer dimensions. Combinations of chemical enhancers Heat as a penetration enhancer Recent studies have suggested that suitably Another form of penetration enhancement is designed combinations of chemical enhancers can balance the use of heat to increase the permeability of the trade-offs between enhancement and irritation based on skin. Unfortunately, the medical community was made the hypothesis that certain enhancer combinations are aware that heat can increase the absorption of drugs especially potent when present at specific, narrow through the skin in 2005 when the FDA began issuing compositions. This approach enables a strategy to target warnings regarding the safe use of fentanyl patches effects that enhance skin permeability in the stratum after deaths had been attributed to wearing the patch corneum, but avoids irritation in deeper tissues where the while sleeping in heated water beds or using heating pads. formulation composition becomes diluted or otherwise Iontophoresis altered. 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 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

Conventional chemical enhancers

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 skins 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 skins 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 5fluorouracil, 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 travelers diarrhea and influenza.

Table 1| Products Available in the market Approval year

1979 1981 1984 1986 1990 1991 1993 1995 1998 1999 2001 2003 2003 2004 2005 2006

Drug
Scopolamine Nitroglycerin Clonidine Estradiol Fentanyl Nicotine Testosterone Lidocaine/epinephrine (iontophoresis) Estradiol/norethidrone Lidocaine Ethinyl estradiol/norelgestromin Estradiol/levonorgestrel Oxybutynin Lidocaine (ultrasound) Lidocaine/tetracaine Fentanyl HCl (iontophoresis)*

Indication
Motion sickness Angina pectoris Hypertension Menopausal symptoms Chronic pain Smoking cessation Testosterone deficiency Local dermal analgesia

Product Name
Transderm-Scop Transderm-Nitro Catapres-TTS Estraderm Duragesic Nicoderm, Habitrol, ProStep Testoderm Iontocaine Combipatch Lidoderm Ortho Evra Climara Pro Oxytrol SonoPrep Synera Ionsys Daytrana Emsam Neupro Exelon Sancuso Gelnique Butrans

Menopausal symptoms Post-herpetic neuralgia pain Contraception Menopausal symptoms Overactive bladder Local dermal anesthesia Local dermal analgesia Acute postoperative pain Attention deficit 2006 Methylphenidate hyperactivity disorder 2006 Selegiline Major depressive disorder 2007 and 2012** Rotigotine Parkinsons disease 2007 Rivastigmine Dementia 2008 Granisetron Chemo-induced emesis 2009 Oxybutynin Overactive bladder 2010 Buprenorphine Chronic pain *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. 12611268. 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. 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. Administration, U.S.F.a.D., 2007, Fda Consumer Updates Page, [online], Available: [24 Oct 2013].

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