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MatE 175

TRANSDERMAL DRUG DELIVERY SYSTEMS AND THEIR USE OF POLYMERS

Kasturi Joshi

November 26, 2008

Submitted in partial fulfillment of course requirements for MatE 175 Biomaterials Fall 2008 Course Instructor: Professor Guna Selvaduray

Table of Contents 1.0. 2.0. 2.1. 2.2. 2.3. 2.4. 2.5. 3.0. 3.1. 3.2. 3.3. 4.0. 5.0. 6.0. Abstract ................................................................................................................................ 1 Introduction .......................................................................................................................... 1 Significance of Problem ................................................................................................... 1 Mechanism of Drug Delivery in Transdermal Drug Delivery System ............................. 2 Types of Transdermal Drug Delivery Systems ................................................................ 4 Transdermal Drug Delivery System Market .................................................................... 9 FDA Regulation and Transdermal Drug Delivery System ............................................. 11 Polymers in Transdermal Drug Delivery System .............................................................. 12 Polymers in Backing Film and Release Liners ............................................................... 15 Polymers in Rate-Controlling Membrane ...................................................................... 18 Polymers in Adhesives ................................................................................................... 21 Future Considerations ........................................................................................................ 24 Conclusion.......................................................................................................................... 25 References .......................................................................................................................... 26

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TRANSDERMAL DRUG DELIVERY SYSTEMS AND THEIR USE OF POLYMERS Kasturi Joshi 1.0. Abstract

A Transdermal Patch is an adhesive patch that has a coating of medicine (drug) that is placed on the skin to deliver specific dose of the medicine (drug) into the bloodstream over a period of time. The first part of the paper will give an introduction about the transdermal drug delivery system and the types of transdermal systems currently available in the market. The second part of the section will dwell on the use of polymer as a transdermal drug delivery system. This section will also address the materials and parameters that are used in determining the rate and amount of the medicine delivery into the skin. This will be followed on with a section describing types of polymeric adhesives used in the transdermal delivery systems. Finally, the paper will finish with the future directions for Transdermal Drug Delivery Systems followed by an appropriate conclusion. 2.0. Introduction

Transdermal drug delivery patches have been in the market for over a decade. (1) The most common available transdermal drug delivery patches are the over-the-counter nicotine patches that help people quit smoking. The words transdermal drug delivery patch triggers several questions, such as what material is it made of, how does it work, so on and so forth. Transdermal patches were first introduced for astronauts going in space to cure trouble of motion sickness. (2) Soon after that the transdermal patch for controlling motion sickness was also being used for treating motion sickness in common people. 2.1. Significance of Problem

Drugs curing a diseased condition in one part of body can also have an adverse effect on some other part of the body. For instance, most of the drugs available in the market have some or the other side effect associated with using them. The side effects encountered are mainly with the liver, heart, lung, kidney, etc. Some of the oral medications have an adverse effect on the gastrointestinal system; some make the patient feel drowsy, nauseated, and dizzy. The solution to 1

get over all the side effects might not be available, but there are surely ways and means to reduce them. One way is use of transdermal drug delivery patches that target only the area that needs to be treated. Transdermal Drug Delivery systems are sometimes preferred over other methods of drug administration because they present lower risk to liver or gastrointestinal track over oral or any other form of drug administration, for instance in the case of estradiol* patches, patients are at lower risk of damaging liver compared to those who take estradiol tablets orally. (4) The pharmacokinetics of a compound significantly affects its efficacy and safety. Transdermal delivery has the potential to yield more stable drug plasma levels and to bypass major organs involved in first-pass metabolism. (3) Today, there is a wide spectrum of conditions that are treated with the use of transdermal drug delivery system and to name a few are motion sickness, nicotine drug patches for smokers, Parkinsons disease, angina pectoris, contraception. 2.2. Mechanism of Drug Delivery in Transdermal Drug Delivery System

A transdermal drug delivery system is a device that is made of one or more types of polymers embedded with drug(s) to deliver the embedded drug through the skin over a controlled period of time. Figure 1 shows the schematic of a typical transdermal drug delivery system with the patch and its different layers involved. The concept of transdermal patch was introduced in 1979 and the patch was scopolamine patch (4) that delivers a drug which is used for motion sickness. The principle mechanism for drug delivery in transdermal drug delivery system is a slow process of diffusion driven by the gradient between the high concentration in the delivery system and the zero concentration prevailing in the skin. (5) The drug permeation across the skin obeys Ficks first law where steady-state flux (J) is related to the diffusion coefficient (D) of the drug in the stratum corneum over a diffusional path
*

Estradiol is prescription drug used for women with symptoms of Menopause, bone fracture related to osteoporosis

Figure 1: Schematic Diagram of transdermal delivery system (3) length or membrane thickness (h), the partial coefficient (P) between the stratum cornuem and the vehicle, and the applied drug concentration (C0) which is assumed to be constant (6):

. Equation
1 The mechanism of drug delivery in a transdermal patch is diffusion through skin and skin poses a barrier. The original function of the skin is to give out things that are not required in the body, for instance, sweat, dirt etc. It also maintains the temperature of the body. The major obstruction is posed by the top most epidermal layer of stratum corneum. (4) The stratum corneum is the outermost layer of the skin, which is considered to be dead skin. It has the undesirable properties as follows: Hygroscopic, yet impermeable to water (5) Tough membrane (5) Flexible membrane (5) Intercellular space rich in lipids (5) 3

Thickness varies for different parts of the body (5)

Even though the stratum corneum has the above mentioned undesirable properties, it allows permeation of some chemicals to reach onto the tissue and the blood vessels underneath the skin
(5)

. The chemical also require special formulation characterized by low molecular weight,

lipophilicity, and being effective even at low dosage levels. (5) The formulation is still effectively kept and achieved by keeping the patch for several hours a day or up to several days a week. But there are only a handful of drugs that can be employed keeping low molecular weight and low dosage. This obstruction of the stratum corneum is overcome by use of other penetration enhancer techniques like use of a mechanical array on the Transdermal drug delivery patch. 2.3. Types of Transdermal Drug Delivery Systems

Transdermal drug delivery systems are vertically classified into two types. The first is called the passive transdermal delivery systems. The second type of the transdermal system is called the Active transdermal delivery system. Both the types of transdermal drug delivery system are horizontally classified into single layer, multilayer, matrix, reservoir, vapor patch etc. The difference between a passive and active transdermal system is that passive transdermal drug delivery system relies completely on the principle of diffusion based on gradients. Active Transdermal drug delivery system is also based on the same principle of diffusion but it consists of different penetration enhancing technologies ranging from electrical current, Iontophoresis, Electroporation, Microporation, Laser Ablation, Mechanical Arrays, Radio Frequency Thermal/Heat, and Ultrasound, etc. (7) Out of the technologies mechanical array is popular in the market with the giants like 3M Pharmaceuticals, Altea Therapeutics, Alza/J&J employing this technology. Mechanical array method consists of use of microneedles that penetrate the outermost layer of the skin, the stratum corneum and thus assists in more controlled and precise 4

flow of the drug by overcoming the skin barrier. A figure of classification of transdermal drug delivery systems is shown in Figure 2.

Figure 2: Classification Chart for Transdermal Drug Delivery System

Figure 3 shows the reservoir type of transdermal drug delivery patch. The Drug reservoir is the layer where the drug is stored and released in a controlled manner by the rate controlling membrane. The protective peel strip stops the drug from leaching out before it is applied on the skin and is removed prior to applying the patch onto the skin. The Backing layer acts a protection 5

layer to stop the drug from leaching out on to the surface of the patch. The contact adhesive ensures that the transdermal drug delivery system clings on to the skin while the drug is being delivered.

Figure 3: Layered Reservoir Patch (5) Figure 4 shows the schematic of a drug-in-adhesive type of a transdermal patch. The only difference in the reservoir type and the drug-in-adhesive type of transdermal patch is the absence of a specific adhesive and drug layer. The two layers of the drug reservoir and the adhesive are combined to give a single layer of drug/adhesive and hence reducing the thickness of the patch. As in the reservoir type of transdermal patch, the drug-in-adhesive patch also consists of several layers. The protective liner as in reservoir patch is removed prior to applying it onto the skin. The drug/adhesive layer consists of a matrix form of the drug and the adhesive. The film backing is to stop the leaching of the drug on to the surface of the patch. There are two types of drug-inadhesive patches.

One is the Single-layer drug-in-adhesive and the other is multi-layer drug-in-adhesive. The working principle for both the type of drug-in-adhesive patch is same, the only difference is in the numbers of layers for the drug-in-adhesive. Figure 4 shows a single-layer drug-in-adhesive patch schematic. A multi-layer drug-in-adhesive will consist of another layer of drug/adhesive layer and the drug/adhesive layers will be separated by a membrane, which is present to give the patch much needed reinforcement and also acts as a controller for sustained drug delivery.(8)

Figure 4: Drug-in-adhesive Transdermal Patch (5) Both the types of transdermal delivery systems explained above are passive transdermal delivery systems. (8) There is a lot of research underway for development of Active transdermal systems and there are many proposed technologies that are considered to be of use. An active transdermal system is typically called a Microstructured Transdermal System (8). The principle of working for a mechanical array based active transdermal system applies microneedles for transcutaneous or intradermal drug delivery (8). As described before, the outermost layer of the skin, the stratum corneum, acts as a barrier against the permeation, and only a handful of drugs 7

can overcome this barrier. So, it becomes difficult to control the rate of drug delivery. That is why the active transdermal delivery systems are being considered as a favorable alternative to the passive drug delivery systems. A typical mechanical array based microneedle active transdermal drug delivery system is shown in Figure 5. (9) The Figure 5(A) shows the schematic view of the operational principle of the microneedle based mechanical array (9), while the other part of the Figure 5(B) shows the layer by layer view of the Active transdermal drug delivery system. (9)

Figure 5: (A) Schematic View of Operational Principle of Microneedles based System (B) Layer-by-Layer View of Microneedle based System.(9) The operational principle of microneedle based mechanical array shown in Figure 5(A) is When a current is passed through the PCB heater the composite heat up and expands into the liquid reservoir, consequently ejecting through the hollow microneedles.(9) The microneedles penetrate the stratum corneum and hence overcome the barrier posed by the skin. The materials used for the construction of the microneedles are described in later sections of the paper.

2.4.

Transdermal Drug Delivery System Market

Table 1(10) gives a list of companies in transdermal drug delivery systems with their current products and technologies in the market. 3M Pharmaceuticals is a leader in pioneering the technological components in transdermal drug delivery system and components made by 3M are used for manufacturing the complete spectrum of drugs delivered transdermally. (10) Figure 6 shows a graph showing the range of transdermal drug delivery system currently sold in the market. (10) On the X-axis are the drugs that are administered transdermally, while the Yaxis in the graph shows percentage of the total transdermal products that are being sold in the market.

Figure 6: Graph of Transdermal Drug Delivery Products Vs. Percentage Total Sold Transdermal Drug Delivery Products (10)

The range of the current drugs that are administered by using Transdermal drug delivery technique is still limited due to the skin posing as a barrier against the drug diffusion or permeation.

Table 1: Companies and their Transdermal Drug Delivery Technologies & Products (10) Company Name 3M Pharmaceuticals Acrux Ltd. Adhesives Research, Inc. Adherex Technologies, Inc. Altea Therapeutics Corp. Alza Corp. Antares Pharma, Inc. Biochemics, Inc. Boehringer Ingelheim Corp. Dermisonics, Inc. Elan Transdermal Technologies, Inc. Inovio Biomedical Corp. ImaRx Therapeutics, Inc. Iomed, Inc. Noven Pharmaceuticals, Inc. L.A.M. Pharmaceuticals LLC Macrochem Corp. Norwood Abbey Ltd. Sontra Medical Corp. Travanti Pharma, Inc. Vyteris, Inc.

Transdermal Products/Technology in Market MinitranTM, Pioneer in the field of Manufacturing Transdermal Compone ACROSS, MDTS, Patchless Patch ETATM, HRT Adhesives, PIB Adhesives, MTT Adhesives ExherinTM PassPort Patch D-Trans System, E-Trans System, Macroflux System ATDTM Gel Technology PENtoCORE CATAPRES-TTS U-Strip Buspirone Patch MedPulser Electroporation Therapy System SonoDermTM Technology Iontophoreris Electrodes: TransQ Flex, IOGEL, TransQ E, OptimaA ; Numby Stuff, IONTOCAINE, Phoresor Vivelle, Vivelle-DotTM, CombiPatchTM, Estalis, MethyPatch IPM Wound GelTM, Polymer MatrixTM Technology MacroDermTM, SEPA Laser Assisted Drug Delivery(LAD), Micro-needle Drug Delivery SonoPrep Wearable Electronic Disposable Drug (WEDD) LidoSiteTM Topical System

This barrier of stratum corneum is overcome by use of active transdermal drug delivery techniques that are relatively new to the market but are considered to have great potential towards increasing the range and variety of drugs that could be administered transdermally. The annual market for transdermal Drug Delivery systems is more than $3 billion. (11)

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2.5.

FDA Regulation and Transdermal Drug Delivery System

The first FDA approved Transdermal Drug Patch was in the year 1979. (12) Since then, the transdermal drug delivery systems have come a long way. Figure 7 gives a chronology of the events in the field of transdermal technology along with the approvals that were obtained at every stage of this chronology. The FDA regulation process for Transdermal drug delivery system is very stringent. Transdermal Drug Delivery system is a combinational device as defined in 21 CFR 3.2(e) by Food and Drug Administration. (13) Transdermal drug delivery system have to undergo premarket approval (PMA) and hence requires substantial evidence including biomechanical testing, animal testing, clinical trials studies before the transdermal patch can get approval for use in the market. The most recent approval in the field of transdermal drug delivery system was the approval of Nuepro patch for treatment of Parkinsons disease. (15) In the case of Passive transdermal drug delivery system, the factor that requires consideration is ensuring that the drug in the drug-reservoir or the drug-in-adhesive is present and being delivered in a stable as well as controlled form. (4) It is also important to understand the reactivity of the drug on the skin and ensure that the material used for manufacturing the transdermal patch do not have an adverse reaction on the skin, for instance itching, inflammation, etc. The patch also needs to be kept on from several hours to, in some cases, several days (e.g., contraceptive patch) and hence the properties of the patch like the type of polymers, adhesives used in the making also need special consideration. The material used for making the patch is polymers. There are various types of polymeric materials that are utilized for the construction of transdermal drug delivery system. The following section in the paper describes the polymeric

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materials along with their properties that are used in the making of transdermal drug delivery system.

3.0.

Polymers in Transdermal Drug Delivery System

As described in the section on the FDA Regulation and Transdermal Drug Delivery system, Transdermal drug delivery system is a combinational product i.e., it is a combination of a drug and a device to administer the drug into the biological system. The primary jurisdiction for combination products (e.g., device, drug, or biologic) is determined by the primary mode of action of the product. (16) In the case of a transdermal drug delivery system, the primary mode of action of the product is controlled drug release and hence it becomes extremely crucial to understand and select materials and techniques that would make it possible to control the drug release. Controlled delivery of drug from the device to the biological system can be achieved by various means. An IV fluid drip also controls the rate of flow of drug, but the apparatus is bulky and cannot be used on a daily basis for home care patients. Controlled drug release can also be achieved by embedding the drug onto a polymeric material and then releasing the drug in a predesigned controlled manner from the polymer into the blood stream. (14) This is achieved by the use of transdermal drug delivery system that is made of polymeric materials. Table 2 gives a list of polymers that are extensively used in making transdermal patches. It becomes evident from Table 2 that there are various types of polymers that are used for different types of transdermal drug delivery systems. There are some polymers that are used as adhesives, some as backing layer for the transdermal patch, some to create a gel that would help embed the drug for the controlled delivery of the drug.

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Figure 7: Chronological Events in Transdermal Drug Delivery System and FDA Approvals (11)

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Every layer in the transdermal drug delivery system requires properties specific for that layer only. The type of polymer is chosen according to the desired properties for that specific layer. The physical properties and the polymers showing those properties are listed below: Poly (urethanes) for elasticity (14) Poly (siloxanes) or silicones for insulating ability (14) Poly (methyl methacrylate) for physical strength and transparency (14) Poly (vinyl alcohol) for hydrophilicity and strength (14) Poly (ethylene) for toughness and lack of swelling (14) Poly (vinyl pyrrolidone) for suspension capabilities (14)

The other types of polymers are those that are desired for the controlled release of the drug. The polymers that are currently used in the manufacturing of the transdermal drug delivery systems are Poly(2-hydroxy ethyl methacrylate), Poly(N-vinyl pyrrolidone), Poly(methyl methacrylate) better known as PMMA, Poly(vinyl alcohol), Poly(acrylic acid), Polyacrylamide, Poly(ethylene-co-vinyl acetate), Poly(ethylene glycol), Poly(methacrylic acid). (14) The desired type of controlled drug delivery mechanism by the above mentioned polymers are shown schematically in Figure 8.

Figure 8: Controlled Drug Release Mechanism (14)

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Figure 8(A) shows the drug delivery in a matrix type of system while (B) shows the reservoir type of transdermal drug delivery system. The other property which is of utmost importance is that of biocompatibility. The polymers that are considered to have properties desirable for transdermal drug delivery system must also be biocompatible since the application of a transdermal patch onto the surface of the skin can be for several days. The other aspect of compatibility is that of chemical compatibility, the drug that is to be embedded in the polymer must be chemically compatible and must not react with the polymer. With the active transdermal systems, it also becomes important that techniques and polymeric materials used for penetrating stratum corneum do not react with the drug that is to be administered. The following section takes into account all the factors to be considered and describes as well as differentiates the use of polymers in the transdermal drug delivery system for different components of transdermal drug delivery system. 3.1. Polymers in Backing Film and Release Liners

The most important property to be considered for the backing layer of the transdermal patch is the chemical resistance. (17) Chemical resistance is the resistance the polymeric material possesses against dissolution, cracking, and swelling when in contact with other substances or fluids. The other property that needs to be considered in the polymeric material selection is that of biocompatibility of the material to the human skin. (17) The reason being the transdermal patch will be placed on the skin for considerable amount of time and if biocompatibility of the material is not accounted for, it may cause adverse effects on the skin. The backing polymeric material should be strong enough to be able to withstand the drug, i.e. the backing layer should not leach the drug, because if leaching occurs it may result in skin coming in direct contact with the drug that may be harmful. 15

Table 2: List of Polymers and Manufacturers in Transdermal Drug Delivery System (17) Polymer Manufacturer Type of System EthylCellulose T-50 Sigma Matrix BIO PSA Dow Corning Adhesive in Matrix Scotch Pak 3M Backing/Release Liner HPMC Gel Eudragit Rhm, Germany Matrix MDX -4-421 (a silicone) Dow Corning Matrix Carboxyl Vinyl polymer Gel Acrylic PSA emulsion Neoplast Co.,Thailand Drug-in-adhesive CoTran9722 3M Drug-in-adhesive Soybean lecithin (Epikuron 200) Lucas Meyer, Germany Gel Matrices Cariflex TR-1107 Shell Chemical Co.,Japan Drug-in-adhesive Acrylic adhesives National Starch and Chemical Co. Drug-in-adhesive Polyisobutylene solutions Exxon Chemical Co. Drug-in-adhesive (Vistanex LM-MH, Vistanex MML-100) Silicone PSA Dow Corning Drug-in-adhesive Silicone Oil Adhesive Research Resevoir EVA Adhesive Research Membrane Polyisobutylene Adhesive Research Adhesive ScotchPak 1006 3M Backing Film 2-Ethylhexyl acrylate Mitsubishi Petrochem Co., Japan Drug-in-adhesive Acrylic acid copolymer Wako Purechem.Ind., Japan Matrix HEMA, Styrene and N-vinyl Polyscience Carbopol 934 gel, pyrrolidone copolymer for resevoir membrane HPMC (Methocel K4M) Colorcon,UK Matrix Urecryl MC 808 UCB,Belgium Matrix PIB Aldrich, France Matrix MDX4-4210 silicone elastomer Dow Corning Matrix Acrylate copolymer (Gelva-737) Monsanto Matrix Silicone-2920 and 2675 Dow Corning Matrix 2-Ethylhexyl acrylate and Mitsubishi Petrochem Co., Japan Drug-in-adhesive acrylic acid copolymer 2-Ethylhexyl acrylate and Wako Purechem.Ind., Japan Drug-in-adhesive acrylamide copolymer Polyvinyl alcohol (backing), MembraneHPMC (matrix), Ethylene vinyl controlled acetate (rate-controlling reservoir system membrane) 16

The other properties that are considered important for the backing layer in the transdermal drug delivery system are as follows: Low Modulus (17) High Flexibility(17) Good oxygen transmission(17) High moisture-vapor transmission rate(17)

Table 3 summaries some of the statistics of backing layers currently available in the market. Table 3: Statistics for Polymers as Backing Layers in Market (17) Moisture-Vapor Oxygen Enhancer Transmission Polymer Transmision Resistance 3 2 2 (cm /m /24h) Rate(g/m /24h) Polyurethane film Ethyl Vinyl Acetate (EVA) Polyethylene (PE) Polyvinyl chloride (PVC) foam PE, Al vapor coat, PET, EVA PE, PET laminate PET, EVA laminate 3570 700 52.8 7.9 450 High-PET side Poly(ethylene terephthalate) (polyester) High-PET side High-PET side Low Medium High

4.6 100 80

0.3 12 17

The release liner is the first layer in the transdermal drug delivery system. It is removed prior to applying the patch onto the skin. Hence, it does not come in direct contact with the skin. But the material properties of the liner are important since the liner is in direct contact with the drug permeation layer. The material properties to be considered for a release liner are as follows: The material must be chemically inert (17) 17

The material should be such that it should not permeate the drug (17) Affinity towards water should be null Material should not crack, craze, or react in any way with the mechanism that are used for penetration in active transdermal drug delivery systems 3.2. Polymers in Rate-Controlling Membrane

Transdermal drug delivery patches contain the drug either in the dispersed or dissolved form in the rate-controlling membrane. (18) The desired properties for the polymers to be used as drug permeation rate-control membrane are microporous(19), macroporous(19), semipermeable(19). Supersaturation of a drug in a Transdermal delivery system is often desirable in order to deliver a target therapeutic dose into the body since permeation rates of the drug through the patch and skin is dependent on the degree of saturation of the drug within transdermal patch. (18) This is considered to be a good property but may not be always favorable like in the case of drug-inadhesive type of patch. The presence of crystals in a transdermal patch might significantly affect the permeation of the drug through the patch, if dissolution of the drug is the rate controlling step in the mass transfer process compared to the diffusion rate. (18) It was also predicted by Variankaval et. al. (2002) that the presence of crystal in the transdermal patchs rate-controlling membrane could affect the physiochemical nature of the drug and also its diffusion through the patch. Hence it can be said with confidence that presence of crystallinity in the patch is an undesirable property. Mukherjee et. al. (2005) described the preparation of a matrix type of a patchs rate controlling membrane. Two polymers, Duro-Tak 387-2516 and 87-2852, were taken in 4:5 ratios. The two polymers were then stirred in a magnetic bead bed and with a magnetic stirrer in ethyl-acetate-isopropyl alcohol- toluene n-hexane (12:6:1:1). To this mixture the drug to be 18

administered using the patch was added in 30mg per patch weight ratio. The resulting mixture was casted and dried to form a uniform medicated matrix patch. The patch had the drug Nefopam hydrochloride used as a pain killer. The chemistry and the mixture ratio rate for every drug will vary and so will the composition of the polymers added. But the above example based on the matrix type of transdermal drug delivery system gives a pretty good idea of the process of the rate-controlling layer preparation. Figure 9 shows SEM images of the transdermal patchs rate-controlling membrane before the applying it on skin and after 50 hours of applying the patch on the skin. The SEM images show the even distribution of the drug on rate-controlling membrane in Figure 9(a) and skin permeation of the drug after 50 hours on the skin in Figure 9(b).

Figure 9: SEM image of the patch showing (a) uniform distribution of nefopam drug in the matrix layer and (b) the permeation of the nefopam drug in skin after 50 h on skin (20)

It is also important to understand the changes that would occur in the choice of the polymers used in the rate-controlling membrane in active type of transdermal drug delivery systems. Electroporation is one technique that is investigated to be of use as a penetration enhancer in case of transdermal drug delivery system. Tien et al. (2003) hypothesized that voltages greater than 50 V is the main reason to cause electroporation through stratum corneum and thus can overcome 19

the skin barrier. The study done by Prausnitz et al (1995) studied the permeation of the drug heparin via the use of electroporation technique and concluded that there was heparin drug permeation obtained that was significant enough to have the effect of anticoagulation occur, which is the desired effect of heparin. The setup for the study included applying high voltage impulses to the skin. There was also an effect of fluxes observed due to the low-voltage iontophoresis but it was reported to be not significant. The controlling of the rate of drug diffusion is mostly done via controlling the thickness of the layer of the reservoir membrane. The other factor that plays substantial role in controlling the drug diffusion rate is the solubility of the drug in the reservoir membrane. The glass transition temperature of the material also plays an important role in controlling the rate of drug diffusivity. An increase in Tg reflects a decrease in the polymer-chain mobility and hence the solute diffusivity. (16) The rate controlling membranes consists of use of copolymers; the Tg of the copolymers can be lowered by a process called copolymerization which involves polymerization of two or more types of polymers. Addition of plasticizers can also lower the Tg but may result in having an adverse chemical reaction with the drugs. Table 4 gives a list of acrylic polymers and their glass transition temperatures that are used in the rate controlling membranes in transdermal drug delivery systems. There are many polymers that are used as rate-controlling membrane. A few of the polymers are listed below: EVA(17) Silicone Rubber(17) Polyurethane(17) PSA(17) Polyisobutylene (PIB) (17)

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Polyacrylates(17) Table 4: Glass Transition Temparatures (Tg) for Acrylic Polymers (17) Glass Transition Polymer Temperature Tg (C) Methyl acrylate 6 Ethyl acrylate -24 Propyl acrylate -45 Isopropyl acrylate -3 n-Butyl acrylate -50 Hexyl acrylate -57 Heptyl acrylate -60 2-Ethylhexyl acrylate -65 2-Ethylbutyl acrylate -50 Dodecyl acrylate -30 Hexadecyl acrylate 35 Cyclohexyl acrylate 16

The next section will discuss the different polymers that are currently used as adhesives in the market. 3.3. Polymers in Adhesives

The use of adhesives on the skin for wound healing has been present through ages. The first skin-contact adhesive application of any volume was perhaps the use of pressure-sensitive adhesion in bandages, which dates back to 1899, with Johnson & Johnson introduction of hospital tapes with adhesive attached.(23) It is important to understand the fundamentals of skin before deciding on the polymers that can be used as adhesives. The measured surface energy of the adhesive must be equal to or less than that of the adherent, or human skin in this case. (23) The other fundamental conditions that need to be addressed are kinetic requirement involving wetting rates and viscoelastic nature of the adhesive. (23) These are important to know because the skin has water content which may react with the polymeric adhesive making the bond between the skin and the patch weak. The water content of the skin is again dependent on various 21

other factors like the age of the person, whether the person sweats a lot, so on and so forth. Hence, understanding and knowing the fundamentals of the skin beforehand is crucial. Every Transdermal drug delivery patch needs to be applied to the skin and kept in place for several hours and in some cases even days. There are different types of transdermal drug delivery systems and each type has its own peculiarities with respect to the adhesive layers. Though it is thought that a drug-in-adhesive type of transdermal drug delivery system is the easiest type in terms of its structure, it is considered as one of the most complicated patch due to the multiple property requirements on a single layer of the patch. The issue of crystallization in drug/adhesive membrane will have an adverse effect on the permeation rate-control which will change the rate of dissolution and will affect the final use of the patch. The high internal and specific volume of the amorphous state relative to the crystalline state can lead to enhanced dissolution and bioavailability, which is a desirable characteristic in transdermal patches. (24) Hence, there is a lot of effort taken towards preserving the drug in amorphous state in the transdermal patch for a better permeation rate control. Molecules in the amorphous state are thermodynamically metastable relative to the crystalline phase. (24) This creates the opportunity for change of amorphous phase to crystalline phase, which is an issue in most of the transdermal drug delivery systems. There is also a possibility that at some point of time there will be partial phase change and there will be coexistence of amorphous as well as crystalline phase which would lead to the following: significant structural heterogeneities. (24) batch-to-batch variation in physical properties. (24)

The change in structural and physical properties will not only affect the control rate but can also change the transition temperature of the polymers. This effect has been observed in

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salicylic acid, chlropheniramine, maleate dispersed in a polymethaacrylate amino-ester copolymer, lidocaine, ketoprofen, aminopyrine in acrylic, acrylic rubber(polyisobutylene) copolymer, polyvinylpyrrolidine and also in adsorbed water.(24) There are a certain parameters that need to be fulfilled before deciding on the polymer to be used as adhesive. The parameters that need to be fulfilled are as follows: The drug-adhesive solubility relationship (25) This is crucial when there are one or more active agents to be dissolved in the adhesive and be released over a period of time. The drug-adhesive compatibility and stability profile, especially during long term storage. (25) This is to ensure the drug does not react with the adhesive any time prior to the expiration date of the patch. Demands of an adhesive system relative to patch design and geometry. (25) Having a smaller sized patch can save manufacturing costs. Quality of wear for adhesive formulation. (24) Long term wear of the patch should not alter the physical conditions of the adhesives: sliding from the skin breakage, crazing, cracking etc. As important as it is to understand the materials behind transdermal drug delivery system, it is also essential to know what the future of transdermal drug delivery system is and where it is heading. The next section describes in brief the future course of direction for transdermal drug delivery systems.

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4.0.

Future Considerations

In terms of technical advances in transdermal drug delivery systems, with the advent of penetration enhancers, the future for transdermal drug delivery system looks bright. The use of X-ray lithography (DXRL) and LIGA (German acronym: LIthographie-GalvanoformungAbformung) technology (26) that uses a micro-gear pump and an array of microneedles is one of the latest developed penetration enhancer technique. (26) This transdermal patch is still built of polymeric material (polymethylmethacrylate) PMMA. Figure 10 shows the schematic of this PMMA based system.

Figure 10: X-ray Lithorgraphy and LIGA based Trnasdermal Drug Delivery System Though the system flow rate and flow control was controlled with this type of delivery system, the system still needs to work on the type of skin penetration since there was a lot of skin rupture observed in the testing of this system. The other issue observed was that of system being mechanically unstable and hence this technique is not in the market yet. But with some

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modification and research, X-ray lithography and LIGA based transdermal drug delivery system will surely be of importance. With all the new techniques like use of ultrasound, heat, electroporation, etc. as aids to penetration enhancer, the basic issue with the skin posing as barrier to drug permeation will be an issue of the past. In terms of the material advances, there are advances undergoing currently in terms of use of composite cellulose membrane for selective controlled drug delivery. One such study was done by Suedee et.al. (2008), in which they used molecularity imprinted polymer (MIP) that is a thinlayer cellulose membrane with selectivity for S-propranolol employed as enantioselectivecontrolled release system. The study was reported successful after in vivo studies, and concluded that the use of MIP in rats was similar to transdermal gel patch. The advantages of transdermal drug delivery system include reduced frequency of administration thereby increasing patient compliance, avoidance of gastric metabolism, and hepatic first-pass metabolism and the achievement of steady state plasma concentration levels and avoidance of high peak levels, due to continuous drug delivery, which may reduce systemic side effects. (28) But there are still inherent side effects related to the use of transdermal systems and they are adverse reaction on skin. Study done by Bennett (1998) showed that there are issues with skin reaction ranging from inflammation, etching, dryness, redness, to rash and in certain cases burns on the patch applied areas. There is still a lot of improvement that needs to be done in this area to avoid skin reaction on the applied patch area and there is constant search going on for better and more biocompatible materials for effective and safe drug delivery. 5.0. Conclusion

The true potential of transdermal drug delivery system is yet to be achieved. The research done towards completing this paper revealed that the use of drugs being delivered transdermally 25

is very limited. Latest developments in the active transdermal drug delivery system to use novel techniques like X-ray lithography & LIGA, mechanical array, electroporation, ultrasound, etc indicate that efforts are underway to increase the range of drugs that can be delivered transdermally. With the wide range of polymers that are being used in the transdermal drug delivery systems, there are still issues faced in terms of skin side effects like rash, inflammation, burn; crystallization of the drug in the rate-controlling membrane altering the rate of permeation of drug in the skin, etc. All these disadvantages suggest that more research and testing of materials being employed is required before they are put out for commercial use. With the possible use of new materials like MIP (which is composite cellular membrane), the true potential of transdermal drug delivery system will soon be realized. 6.0. References 1. From Test Tube to Patient: Now Available without a prescription (2006). FDA Consumer Magazine [Online]. Available at http://www.fda.gov/fdac/special/testtubetopatient/available.html (Accessed on 10/31/2008). 2. Ackerman. S. J. (1995). Medicines from Space: FDA Consumer Special Report. FDA Consumer Magazine [Online]. Available at http://www.fda.gov/fdac/special/newdrug/spacemed.html (Accessed on 10/31/2008). 3. Nitti Victor W., Sanders Steven., Staskin David. R., Dmochowski Roger. R., Sand Peter K., MacDiarmid Scott., Maibach Howard I. (2006). Transdermal Delivery of drugs for urologic applications: Basic Principles and Applications. Urology 2006. Vol.67.Page(s): 657-664. 4. Langer Robert. (2004). Transdermal Drug Delivery: past progress, current status, and future prospects Advanced Drug Delivery Reviews (2004). Issue: 56 Page(s): 557-558. 5. Scheindlin Stanley (2004). Transdermal Drug Delivery: Past, Present, Future. Molecular Interventions (2004) [Online]. Vol. 4, Issue: 6, Page(s): 308-312. Available online at http://molinterv.aspetjournals.org/cgi/reprint/4/6/308 (Accessed on 11/17/2008). 6. Benson Heather A.E.(2005). Transdermal Drug Delivery: Penetration Enhancement Techniques. Journal of Current Drug Delivery 2005. Vol. 2. Page(s): 23-33. Available online at http://www.bentham.org/cdd/sample/cdd2-1/003AP.pdf (Accessed on 11/19/2008).

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7. Active Transdermal Delivery (2007). Greystone Associates, October 2007. Page(s):125-. Available at www.researchandmarkets.com/reports/661618/active_transdermal_delivery.pdf (Accessed on 11/19/2008). 8. Educational Resources, Transdermal Technologies (2008). Multi-layer Drug-inadhesive. 3M Pharmaceuticals 2008. Available at http://solutions.3m.com/wps/portal/3M/en_WW/DrugDeliverySystems/DDSD/technolog y-solutions/transdermal-technologies/educational-resources/ (Accessed on 11/18/2008). 9. Roxhed N., Samel B., Nordquist L., Griss P., Stemme G.(2006). Compact, seamless, integration of active dosing and actuation with microneedles for transdermal drug delivery. Institute of Electonics Engineers Xplore. Conference on MEMS 2006, Istanbul, Turkey, 22-26 January 2006. Issue. 5. Page(s): 414-417. 10. Singh Somnath. (2005). An Overview of Transdermal Drug Delivery. Industry Overview and Deals. Drug Delivery Report Autumn/Winter 2005. Page(s):35-40. Available at: http://www.drugdeliveryreport.com/articles/ddr_w2005_article06.pdf (Accessed on 11/18/2008). 11. Prausnitz Mark. R., Mitragotri Samir., Langer Robert. (2004). Current Status and Future Potential of Transdermal Drug Delivery. Nature review, Drug Discovery, February 2004. Vol. 3. Page(s): 115-124. 12. Segal Marian (1991). Patches, Pumps and Timed Release: New Ways to Deliver Drugs. FDA Consumer Magazine October 1991. Available at http://www.fda.gov/bbs/topics/consumer/CON00112.html (Accessed on 11/21/2008). 13. Definition of a Combination Product (2005). Title 21: Food and Drugs. 21 CFR Food and Drugs CHAPTER I Food and Drug Administration, Department of Health and Human Services Subchapter A- General Part 3-Product Jurisdiction. Available at http://www.fda.gov/oc/ombudsman/part3&5.htm#21:1.0.1.1.3.1.31.2 (Accessed on 11/21/2008). 14. Brannon-Peppas Lisa. (1997). Polymers in Controlled Drug Delivery. Medical Plastics and Biomaterials Magazine [Online]. Available at http://www.devicelink.com/mpb/archive/97/11/003.html (Accessed on 10/31/2008). 15. FDA News (2007). FDA Approves Neupro Patch for Treatment of Early Parkinsons Disease. FDA News, May 9, 2007. Available at http://www.fda.gov/bbs/topics/NEWS/2007/NEW01631.html (Accessed on 11/21/2008). 16. Lyman Donald. J. (2007). Biomedical Materials. Encyclopedia of Polymer Science and Technology (2007). Page(s): 1-19. 17. Kandavilli Sateesh., Nair Vinod., Panchagnula Ramesh., (2002). Polymers in Transdermal Drug Delivery Systems. Pharmaceutical Technology May 2002. Page(s):62-80.

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18. Variankaval E.N., Jacob K.L., (2002). Polymorphism of 17- estradiol in a transdermal drug delivery system. Journal of Material Science: Materials in Medicine (2002). Vol. 13. Page(s): 271-280. 19. Bellus Daniel. (1994). How do specialty polymers modify the chemical and pharmaceutical industries?. J.M.S-Pure Appl. Chem. (1994), A31 (10)., Page(s): 13551376. 20. Mukherjee Biswajit., Das Surajit., Patra Balaram., Layek Buddadev. (2005). Nefopam Containing Transdermal-Matrix Patches: Based on pressure sensitive adhesive polymers Journal of Pharmaceutical Technology, March 2006, Vol.30, Issue. 3., Page(s): 146-163. 21. Tien H.T., Ottova Angelica.(2003). The Bilayer Lipid Membrane (BLM) under Electrical fields. IEEE Transactions on Dielectrics and Electrical Insulation, October 2003. Vol.10. Issue.5. Page(s): 717-727. 22. M. R. Prausnitz, E. R. Edelman, J. A. Gimm, R. Langer, and J. C. Weaver,(1995) Transdermal Delivery of Heparin by Skin Electroporation, Biotechnology, Vol. 13, Page(s). 1205-1209. 23. Venkatraman Subbu., Gale Robert. (1998). Skin Adhesives and Skin adhesion 1. Transdermal Drug Delivery System. Journal of Biomaterials (1998). Vol. 19. Page(s): 1119-1136. 24. Variankaval N.E., Jacob K. I., Dinh S. M. (1999). Crystallization of -estradiol in an acrylic transdermal drug delivery system. Journal of biomedical materials research (1999). Volume: 44 Issue. 4. Page(s): 397-406. 25. Hopp Melinda.S.(2002). Developing Custom Adhesive Systems for Trandermal Drug Delivery Products. Pharmaceutical Technology , March 2002. Page(s): 30-36. 26. Matteucci M., Casella M., Bedoni M., Donetti E., Fanetti M., De Angelis F., Gramatica F., Di Fabrizio E. (2008). A compact and disposable transdermal drug delivery system. Journal of Microelectronics Engineering January 12, 2008. Issue. 85. Page(s): 10661073. 27. Suedee Roongnapa., Bodhibukkana Chatchada., Tangthong Naruedom., Amnuaikit Chomchan., Kaewnopparat Sanae., Srichana Teerapol.(2008). Development of reservoir-type transdermal enantioselective-controlled delivery system for racemic propranolol using a molecularly imprinted polymer composite membrane. Journal of Controlled Release 2008. Issue. 129. Page(s): 170-178. 28. Bennett N.J. (1998). A burn-like lesion caused by a testosterone transdermal system. Journal of Burns 1998. Issue. 24, Page(s): 478-480.

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