Trans-Dermal Drug Systems

Transdermal drug delivery systems provide an attractive alternative route to deliver medication. From the first system approved in 1979 to now, there are 19 transdermal delivery systems with FDA approval. This field has significantly grown and holds potential for further growth. Currently, the general criteria of a compound for transdermal delivery are low doses, half life less than 10 hours, molecular weight 500 Da, Log Partition coefficient between 1-3, low oral bioavailability, and low therapeutic index. These criteria limit the application of transdermal drug systems to drug development.

Another limiting aspect of transdermal drug delivery is the permeability of the skin layers consisting of the stratum corneum and the viable dermis However with increasing research on improving current methods, while developing newer advanced systems such as micro needles, ultrasound, microdermabrasion and chemical enhancers more compounds are able to be applied to transdermal systems. Through the enabling of more compounds to be pursed for transdermal drug delivery, the field can have a substantial impact on patients and drug development.

Introduction Research in transdermal drug delivery systems has significantly increased over the past ten years. Currently, the worldwide market for transdermal drugs is approximately four-billion dollars and is increasing each year with advancements in methods, strategies and technologies1. However the challenge of passing the barriers of the stratum corneum and the viable dermis are a significant limitation, reducing the amount of potential drug compounds available for transdermal drug delivery systems.

With increasing focus and improvements in enhancing the permeability of these two skin layers, capabilities of these systems increase leading to more drugs being applied to transdermal systems . Overview In theory, the approach to transdermal drug delivery systems is simple. It consists of applying a drug in high concentrations in a patch and wearing it on the skin over a period of time. With the high concentrations in the patch and a constant low concentration in the blood due to constant circulation, the drug will diffuse across the skin over a significant period of time.

The approach seems simple, however in depth these systems are extremely complex and intricate. Before even developing and designing transdermal systems, skin structure and physiology needs be understood as this is what the system is being applied too. The skin is composed of three layers the stratum corneum, the viable epidermis and the dermis. The outer most layer of the skin is called stratum corneum which is a significant barrier to transdermal drug delivery.

It is composed of approximately ten to fifteen sheets of corneocytes and is about ten to fifteen micro meters thick2. To simplify the structure has been said to have “brick and mortar” like composition with the corneocytes being the bricks whereas the fatty acids, cholesterol, and triglycerides compose the mortar2. This “brick and mortar” structure limits the diffusion of drug compounds towards the blood capillaries located in the vascular dermis. The middle layer of the skin is the viable epidermis. This layer lies just below the stratum corneum and above the epidermis.

The viable epidermis is composed of many diverse cells including Langerhans cells which cascade immune responses as well as keratinocytes, and melanocytes3. Being a non-vascular component of the skin and containing no nerve endings, the viable epidermis and the stratum corneum are ideal targets for painless drug delivery. Lastly, the dermis is the lowest layer of the skin that separates the epidermis from the subcutaneous tissues. Fibroblasts, macrophages and adipocytes are some of the different cell types that compose this layer3.

Important parts of the dermis are the matrixes of collagen and elastin, these provide both strength and elasticity to this skin layer. Capillary bodies and blood vessels are contained in this layer allowing them to be targeted for the delivery of drug compounds to the circulatory system. Analyzing the structure of the skin, the transdermal systems become increasingly difficult to design and implement. The process for drug to diffuse through the two layers the stratum corneum and the viable epidermis before moving to the dermis is complex and unique for each drug compound.

To overcome these complexities, technology and innovation are needed to improve the choices of drug compounds and feasibility of transdermal delivery systems. Advantages Compared to the traditional oral delivery of drugs, transdermal drug delivery provides an attractive alternative in delivering medication. Gastrointestinal system through very acidic conditions of the stomach and the mildly basic conditions of the intestine contributes to the modification and degradation of a drug4. By delivering drugs transdermally these effects are avoided all together.

Another effect the drug avoids through this route is the absorption through the portal vein. The portal vein leads to the liver enabling “the first pass effect”; this reduces a substantial amount of drug that is able to move into the systemic circulation4. Lastly, the side effects of vomiting or diarrhea caused when a drug taken orally are eliminated through the transdermal route. Properly designed transdermal drug systems can be regulated to determine drug delivery rates that in turn can be used to control blood plasma levels of drug.

In the oral route, differences in individual’s gastrointestinal systems and CYP450 enzymes lead to different drug metabolism rates and bioavailability5. Skin composition between patients contains less variability as it is composed of the same layers and physically similar between patients. Variation in response by two measures (gastric and CYPs) are circumvented leading to the prevention of toxic levels and improvement of pharmacological effects. Transdermal patches are also able to be loaded with higher amounts of drug leading to increased patient compliance when compared to the typical multiple oral daily dosages.

As well with having increased time between dosing regimen, consistent plasma concentrations can be maintained of drugs which can be important in treatments such as hypertension and bacterial infections Lastly, the transdermal drug route is able to quickly initiate effects while providing a quick off set rate by simply removing the patch. This provides flexibility in dosing but also the termination of drug delivery in the case of adverse drug effects. The advantages to transdermal systems seem many, there are currently limitations are the number of compounds suitable for transdermal delivery.

However with the newer generations of transdermal systems being developed, these advantages can be obtained a wider variety of drugs and therapies. 1st Generation Transdermal Drug Delivery Systems: Liquid Reservoir Systems The 1st transdermal drug approved by the FDA was scopolamine in 19791. The initial system of this patch was a liquid reservoir system based on the principle that the skin is lipophilic hence a very lipophilic drug would readily diffuse through. The patch design was a reservoir of scopolamine in mineral oil paired with a controlled release membrane6.

Being such a lipophilic drug, no absorption enhancers where needed. This high lipophilicity of a drug is a concern as side effects are apparent if patients forgot to remove the patch after a certain period of time7. This system design is very simple however it is very limited to highly lipophilic drugs and cannot be applied to drugs outside of this. 2nd Generation Systems : Conventional Chemical Enhancers, Iontophoresis, and Ultrasound Conventional Chemical Enhancers Conventional Chemical enhancers focus on disturbing the stratum corneum layer in order to improve drug delivery.

Currently there are over three hundred chemicals used to enhance transdermal drug transport8. Compared to physical methods, chemical enhancers are simple and inexpensive to formulate. They are flexible in application as low or high concentrations can be applied to increase or decrease drug permeation rate across the skin8. Synergistic effects can occur when used in different combinations enhancing disruption of the skin barrier through similar mechanisms or different mechanisms, leading to enhancement of drug permeation.

The two compounds sodium laurylsarcosinate and a non-ionic surfactant sorbitan monolaurate exhibit these effects9. A combination of these two compounds demonstrated increased skin conductivity when compared to the effects induced individually by these compounds9. Sodium laurylsarcosinate acts as a strong extractor of the lipids in the stratum corneum layer whereas sorbitan monolaurate slightly increases the fluidity of the stratum corneum hence through different mechanisms they enhance skin permeability.

In permeability studies, increases in skin conductivity are assumed to be correlated with increased skin permeabilization. A variety of different compounds can be used as conventional chemical enhancers these include water, hydrocarbons, alcohols, amines, amides, and esters10. To determine and understand the individual effects of each group on skin permeability is important. It can be more beneficial to have two different effects being exhibited on the skin surface to increase permeability rather than the same effect multiple times.

For example water acts as a hydrator of the stratum corneum layer which increases the transdermal flux of multiple drugs whereas most other enhancers act on some form of disrupting lipid bilayer structure or forming lipophilic complexes with drugs10. It is important to distinguish between compounds such that the function of them is known, especially with enhancers that form lipophilic complexes with drugs as they could significantly change permeation rate leading to an increased or decreased therapeutic effect.

This is important as if a drug has a narrow therapeutic range these enhancers can lead to a toxic dose being given to a patient or non-therapeutic levels of drug being delivered. Iontophoresis The process in which small amounts of electrical current to drive drugs into the skin is called Iontophoresis12. When compared to the traditional transdermal drug systems an important advantage in this system is that drug delivery can be modified through increasing or decreasing current.

This flexibility of drug delivery rate can be used to accommodate intra-individual and inter-individual treatment variability since the current has a significant role in drug delivery rather than the stratum corneum 13. The idea behind iontophoresis is that a charged drug will be driven into the skin through the charge repulsion of the electrodes. A positively charged drug molecule (as most drugs are paired with salts) will be present from protonation in the anode of the transdermal system13. Then upon activation of an electric current the drug molecule will be driven away from the positively charged anode.

In the situation would be reversed in the case of a negatively charged drug molecule. The applications of this system are numerous. One that is currently being reviewed is its ability to deliver pain medication. In a study with iontophoretic fentanyl HCl PCTS in post-operative pain therapy demostrated that not only was therapeutically equivalent to morphine given by IV, but also was able to slowly increase blood plasma levels of fentanyl blood levels over time14. Furthermore in another study the tmax iontophoretic was 35minutes when compared to IV and passive transdermal delivery was 35 minutes and 12-48 hours respectively15.

These results which suggests that not only is this method equivalent to IV in terms of tmax, it is also more convenient for patients and prevents the spikes in blood plasma levels which could lead to adverse drug reactions. Noncavitational Ultrasound The application of sound waves to the skin to increase the fluidity of the bilayer which increases the permeability of the skin is known as noncavitational ultrasound. This process involves having a frequency of greater than 18kHz applied to the skin16. This energy is transferred to the body by a use of a contact medium such as oil, water-oil emlusions or aqueous gels.

The mechanism in which noncavitational ultrasound acts is thought to be that it icauses disording of structural lipids in the stratum corneum17. It is also thought that the caviation known as the production of mircoscopic bubbles are present at the surface of the skin allowing for quick liquid flow into the skin layers increasing skin permablity18. This therapy is being applied in the field topical anesthesia, it was shown that the application of ultrasound followed by lidocaine cream lead to patients feeling significantly less pain (80%) during insertion of an IV compared to without treamtment18.

Ultrasound though does have some potential, currently there are some significant limitations to the application of this therapy. First, that the ultrasound machines are expensive and currently cannot be incorporated into patches hence this technology is limited to hospitals making it unready available for daily use. Secondly a concern is safety of these ultrasound waves and the reversible and irreversible effects they have to the skin tissue and deep tissue though the cavitation but also the free radicals generated in the cavitation process16.

Hence for this technology to be applied to transdermal drug systems first accessibility of this technology needs to be improved and secondly the safety of long term ultrasound use need to be evaluated before human testing. 3rd Generation Systems: Microdermabrasion and Microneedles Mircodermabrasion Mircodermabrasion is a method of enhancing skin permeability of drugs through the removal of the stratum corneum or the epidermis layer of the skin. This dramatically increases skin permeability, improving the variety of compounds available for transdermal drug delivery.

Being FDA-approved to slowly remove tattoos, scars and large pores in the 1980s, this technique has been developed significantly since then19. Microdermabrasion uses a device that pushes crystals to abrade the skin leading to the formation of micro scale holes in the skin. When microdermabrasion was applied to improve the transport of 5-fluorouracil a drug used in the treatment of cancer. In skin treated with microdermabrasion, the permeation was on average 8 to 24 times higher than across untreated skin20.

These results suggest that microdermabrasion can significantly improve drug transportation across the skin barrier especially of hydrophilic molecules such as 5-fluorouracil. Microdermabrasion is a promising has been used for now three decades in the cosmetic industry and now its applications to transdermal drug delivery are beginning to surface allowing another method of delivery that is safe, painless and effectively able to be applied to a multitude of drug systems. Microneedles.

Micro needles are extremely small micron sized needles that disrupt stratum corneum structure by creating ‘‘holes’’ big enough for molecules to pass through21. This technology can be incorporated in different and unique ways to improve transdermal drug delivery across the skin layers. It is currently being for many different purposes drug delivery. One of the approaches of micro needles are to create microscopic holes in the skin then placing a transdermal patch over the skin.

Diffusion can be enhanced using this method alone or possibly further improved using another transdermal delivery method such as thermal ablation or chemical enhancers. The delivery of 20-merphosphorothioated oligodeoxynucleotides across guinea pig skin was attempted using this approach 22. A combinational approach with iontophoresis was shown to increase transdermal drug delivery significantly approximately 100 times more than the previous method of delivery22.

Upon histological analysis it was shown that the micro needles moved the drug 800um deeper into the skin than the previous treatment of transdermal patch only which could have been the reason why drug delivery was significantly improved22. This method is currently being explored for the delivery of insulin. Micro needles can also be coated with a drug then be inserted in the skin for drug release. This method is being explored for vaccine delivery to improve both convenience and efficacy. This was done through coating micro needles with an antigen then placing these micro needles into guinea pig skin23.

Two very important results of this study were that first drug release occurred quickly approximately in 5 minutes which is important for vaccine delivery. The second was that there was a similar response shown to regular injection. This study showed that it is possible to deliver vaccines through micro needles and that the method of coating is sufficient to preserve compounds for transdermal delivery24. Micro needles appear to be a promising new approach to drug delivery, there are some substantial considerations when applying this technology to a drug.

First it is very important to know the dosing requirements of the drug, the reason being that constant piercing of the skin layer could lead to irreversible damage to the skin making it susceptible to infections and scaring limiting the potential of this drug delivery system to be used over long periods of time. It is shown that it takes approximately 24 hours for the skin to heal after micro needle insertion; hence medications that are needed to be taken more than once a day may not be feasible for this method of delivery unless a transdermal patch is designed to mimic this dosing schedule.

Another important consideration is that micro needles should be degradable over a period of time. The reason being that if these needles accumulate in this skin, significant problems could arise. Solutions to this problem could be to create micro needles out of very strong polymers such that they will not break in the skin or to create micro needles that are made of degradable polymers that they can degrade in the skin environment while not in storage conditions. Challenges of Transdermal Drug Delivery Though there are advantages of delivering drugs transdermally, there are significant challenges which currently limit suitable drugs.

Currently the general criteria for suitability of a drug for this system are a log partition coefficient of between 1-3, a molecular weight of less than 500da, half-life less than ten hours, low oral bioavailability, and a low therapeutic index4. As mentioned previously the challenge of penetrating the stratum corneum and viable epidermis limits the size and polarity of compounds. Another limitation is the amount of drug that can be loaded onto the skin, though the skin covers a significant amount of area it is not feasible to have a system that covers a large portion of it.

If a drug is needed to be concentrated into a smaller patch it can lead to skin irritation and allergic reactions. A balance between increasing skin permeability and preventing irritation and permanent damage to the skin from the disruption of the layers is important especially in therapies which require long-term compliance. Methods to prevent permanent skin damage are a treatment regime of a transdermal patch alternated with either tablets, or IV daily. Another method would be to use skin on different parts of the body.

The skin depending on its location on the body varies in thickness which could lead to a change in therapeutic effect, hence this aspect of a consistent skin thickness is important in treatment. Cost presents a significant challenge to developing transdermal drug delivery. Producing these complex systems require a significant amount of money to research and develop. Technology is improving skin permeability; nevertheless it needs to be able to be developed for mass scale quickly and economically before these can be used in patients.

If these systems are available yet unaffordable it will be difficult for them to really become successful on the open market. Future Directions Though there are current limitations to suitable compounds, with improvements in technology and methods these limitations are reduced. As seen there are many different technologies that can be applied to transdermal drug delivery even be combined synergistically. The improvement in delivery methods is leading to increased numbers of systems approved by the FDA each year and many more being pursed in development.

With more compounds becoming suitable for transdermal delivery, the opportunities for this field to expand are significant. Nevertheless focus needs to be on improving skin permeability while preventing long term damage and irritation in order for these systems to be successful. In an era of personalized medicine, transdermal systems can be used to alter release rates of drugs which could be applicable to many therapies. They are also very convenient for patients and provide a painless alternative to injections. Furthermore they are thought to improve patients compliance through a reduced dosing scheme which in turn improves patients health.

Hence development on transdermal systems in a fields from vaccines to small molecules will not only benefit drug companies and paitents, but drug development as a whole by increasing options in a field where the majority of failures is due to lack of efficacy. References 1. Prausnitz R. M. , Langer R. Transdermal drug delivery. Nature Biotechnology 26:11:1261-1268(2008). 2. Williams A. C. , Barry B. W. Terpenes and the lipid-protein partitioning theory of skin penetration enhancement, Pharm. Res. 8(1991) 17–24. 3. Kendal M. A. F. , Chong Y. , Cock, A.

The mechanical properties of the skin epidermis in relation to targeted gene and drug delivery. Biomaterials 28: 4968–4977. (2007). 4. Ranade V. Drug delivery systems. 6. Transdermal drug delivery. J. Clin. Pharmacology. 31:401-418. (1991). 5. Sugibayashi K. , Morimoto Y. Section 6 – transdermal patches. Gels handbook. 201-210. (2001). 6. Chhabaria S. , et al. Current status and future innovations in transdermal drug delivery. Intl. J. Pharmaceutical Sciences and Research. 3:8:2502-2509. (2012). 7. Wilkinson A. J. Side effects of transdermal scopolamine. J. of Emergency Medicine.

5:389-392. (1987) . 8. Karande P. et al. Design principles of chemical penetration enhancers for transdermal drug delivery. PNAS 102:13:4688-4693. (2005). 9. Karande P. , Jain A. , Mitragotri S. Insights into synergistic interactions in binary mixtures of chemical permeation enhancers for transdermal drug delivery, J. Control. Release. 115:85–93. (2006). 10. Karande P. et al. Synergistic effects of chemical enhancers on skin permeability: a case study of sodium lauroylsarcosinate and sorbitan monolaurate, Eur. J. Pharm. Sci. 31:1–7. (2007). 11. Williams A. C. , Barry B.

W. Penetration enhancers. Adv. Drug Delivery. Rev. 56:603–618. (2004). 12. Singh P. , Liu P. , Dinh S. M. Facilitated transdermal delivery by iontophoresis. Percutaneous Absorption, Drugs-Mechanisms Methodology. (1999). 13. Singh P. , Maibach H. I. Iontophoresis in drug delivery: basic principles and applications. Critical Review Therapeutic Drug Carrier Systems. 1: 161–213. (1994) 14. Celly J. An iontophoretic, fentanyl HCl patient-controlled transdermal system for acute postoperative pain management. Expert opinion on pharmacotherapy 6(7):1205-1214 (2005). 15. Power I.

Fentanyl HCl iontophoretic transdermal system (ITS): clinical application of iontophoretic technology in the management of acute postoperative pain. British Journal of Anaesthesia 98 (1): 4–11 (2007). 16. Lavon l. , Kost J. Ultrasound and transdermal drug delivery. Drug Discovery Today. 9:15:670-676. (2004). 17. Mutoh M. et al. Characterization of transdermal solute transport induced by low-frequency ultrasound in the hairless rat skin. J. Controled Release. 92:137–146. (2003). 18. Becker B. M. et al. Ultrasound with topical anesthetic rapidly decreases pain of intravenous cannulation.

Acad. Emerg. Med. 12:289–295. (2005). 19. Lee W. R. , Tsai R. Y. , Fang C. L. , Liu C. J. , Hu C. H. , Fang J. Y. Microdermabrasion as a novel tool to enhance drug delivery via the skin: an animal study. Dermatol. Surg. 32:1013-1022. (2006). 20. Herndon T. O. , Gonzalez S. , Gowrishankar T. , Anderson R. R. , Weaver J. C. Transdermal microconduits by microscission for drug delivery and sample acquisition. BMC Med. 2:12. (2004). 21. Lee J. W. , Park J. H. , Prausnitz M. R. Dissolving microneedles for transdermal drug delivery.

Biomaterials 29:2113–2124 (2008). 22. Lin W. , Cormier M., Samiee A. , Griffin A. , Johnson B. , Teng C. , Hardee G. E. , Daddona P. Transdermal delivery of antisense oligonucleotides with microprojection patch (Macroflux) technology. Pharm. Res. 18: 1789 – 1793. (2001). 23. Matriano J. A. , Cormier M. , Johnson J. , Young W. A. , Buttery M. , Nyam K. , Daddona P. E. Macroflux microprojection array patch technology: a new and efficient approach for intracutaneous immunization. Pharm. Res. 19:63 – 70. (2002). 24. Andrews S. , Lee J. W. , Choi S. , Prausnitz M. R. Transdermal Insulin Delivery Using Microdermabrasion Pharm. Res. 28:2110–2118. (2011).

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