F Transdermal DDS 1073

Li, J., Li, X., Zhou, Z., Ni, X., Wang, X., Li, H., & Leong, K. W. (2006). Self-assembled supramolecular hydrogels formed by biodegradable PEO–PHB–PEO triblock copolymers and α-cyclodextrin for controlled drug delivery. Biomaterials, 27, 4132–4140.

Li, J., Ni, X., Zhou, Z., & Leong, K. W. (2003). Preparation and characterization of polypseudorotaxanes based on block-selected inclusion complexation between poly(propylene oxide)-poly(ethylene oxide)-poly(propylene oxide) triblock copolymers and α-cyclodextrin. J. Am. Chem. Soc., 125, 1788–1795.

Okano, T., Bae, Y. H., Jacobs, H., & Kim, S. W. (1990). Thermally on-off switching polymers for drug permeation and release. J. Contr. Rel., 11, 255–265.

Rohr, U. D., Markmann, S., Oberhoff, C., Janat, M. M., Schindler, A. E., McRea, J. C., & Zentner, G. (2002). Oncogel: a techno-logical breakthrough in local treatment of paclitaxel sensitive cancers. Proc. Int. Symp. Controlled Release Biaoct. Mater., 29, 330–334.

Schild, H. G. (1992). Poly(N-isopropylacrylamide): experiment, theory, and application. Prog. Polym. Sci., 17, 163–249.

Shim, W. S., Kim, J. H., Kim, K., Kim, Y. S., Park, R. W., Kim, I. S., Kwon, I. C., & Lee, D. S. (2007). pH- and temperature-sensitive, injectable, biodegradable block copolymer hydro-gels as carriers for paclitaxel. Intl. J. Pharmaceutics, 331, 11–18.

Tipton, A. J., & Holl, R. J. (1998). U.S. Patent No. 5,747,058.

F. TRANSDERMAL DDS

Gary ClearyCorium Inc. Menlo Park, CA, USA

INTRODUCTION

In this section we describe the technologies and materials that are being used in “Passive” and “Active” Transdermal Drug Delivery Systems (TDDS), as well as the biological barriers to drug delivery through the skin. Passive TDDS refers to delivery of drugs by diffusion across the stratum corneum (SC), while Active TDDS includes physical meth-ods that disrupt or bypass the SC for such delivery. From 1980 to 2010 only 20 small drugs, ranging in molecular weight from 62 Da to 359 Da, were approved by the US Food and Drug Administration (FDA) for Passive TDDS.

1. It has been proposed that the upper limit of molecular weight is below 500 Da for reasonable drug diffusion rates through the skin.

2. Thus, Passive TDDS methods are mainly applicable for delivery of small, potent, lipophilic drugs.

With the advent of molecular biology and biotechnology in the 1980s, it became apparent that the large biomolecular drugs such as proteins, peptides, and nucleic acids would not penetrate intact SC (which is a reflection of the protec-tive behavior of the SC). From the 1990s to the present time, a number of enabling technologies have been devel-oped that use various forms of energy to disrupt the SC and allow passage of larger drugs into the body. These new

approaches are called “Active” TDDS, and they can deliver drug molecules greater than 500 Da across the skin (Barry, 2001; Prausnitz et al., 2004; Prausnitz and Langer, 2008).

Skin and the Stratum Corneum (SC)

The top layer of the epidermis (Figure F.1) is the stratum corneum (SC), which is the outermost layer of skin. The SC is packed with dying or dead cells called corneocytes. They have a “brick and mortar-like” structure, and the mortar in the intercellular space is made of lamellar lipid bilayers surrounding the aqueous cores of the dying corneocytes. There are four potential routes through the SC that drug molecules can take as they migrate through the skin and into the systemic circulation. These routes include: (1) molecular diffusion through a tortuous path-way of the intercellular lipophilic space between the cor-neocytes; (2) electrophoretic transport of charged drugs, which may be drawn through the hair follicles and sweat ducts; (3) various physical methods that can form tran-sient pores in the SC, opening a path directly through the SC for larger biomolecular drugs; and (4) diffusion through holes in the SC, punctured by microneedles (Figure F.2). This section will describe these four methods in more detail below.

The intercellular bilayers in the SC provide alternating regions of interconnected lipid and aqueous layers form-ing tortuous pathways between the corneocytes. The lip-ids found in the lipid bilayer domain are free fatty acids, cholesterol, cholesterol sulfate, and ceramides. The cor-neocyte’s outer cell layer of cross-linked protein and intra-cellular keratin fibers provide a chemical resistant layer and strength as a mechanical barrier to injury. Just below the stratum corneum is the viable epidermis, which is made up of hydrophilic cells called keratinocytes and spe-cialty cells such as langerhans cells (LCs). The LCs play an important role in the immune system, and their location in the viable epidermis is important when vaccines are deliv-ered by microneedles. The outer two layers of skin, the stratum corneum and the viable epidermis, do not contain the sensory nerve endings or the blood vessels that can cause pain and bleeding (Bodde et al., 1989; Barry, 2001;

passive Transdermal Drug Delivery Systems are sys-tems that depend on molecular diffusion of drugs across the stra-tum corneum. These systems are most suitable for transdermal delivery of small, potent, mostly lipophilic drugs from skin patches.

active Transdermal Drug Delivery Systems are systems that utilize some form of mechanical or electromag-netic energy to create micropores or temporary pathways in the stratum corneum for delivery of large biomolecular drugs.

1074 SECTION II.5 Applications of Biomaterials

Prausnitz and Langer, 2008). Below the viable epidermis layers is the dermis, where the capillary blood vessel beds, dendritic cells, and neural cells are located (Bodde et al., 1989; Cleary, 1993; Naik et al., 2000; Menon, 2002). The locations of these cells and the capillary bed are important to consider when delivering vaccines to the lymphatic sys-tem, and to minimize or eliminate bleeding and pain when using Active TDDS technologies.

PASSIVE TRANSDERMAL DELIVERY SYSTEMS (PASSIVE TDDS)

There are various types of topical ointments, lotions, creams, and sprays for applying and delivering drugs pas-sively to the skin. These methods are usually limited to drug molecules with broad therapeutic windows (e.g., testosterone, estradiol). More potent drugs with narrow

therapeutic windows are not suitable for such topical applications. With these drugs it is necessary to have a patch with a fixed surface area (footprint), and a con-trolled release rate.

The challenge with Passive TDDS is to formulate a patch that achieves a therapeutic blood level fairly rapidly, and that also can adhere to the skin without irritation for from one day to a week. Many different components go into a successful TDDS patch, including pressure sensitive adhesives, penetration and diffusion enhancers, solvents to improve drug solubility and partitioning into the SC, bar-rier membranes, and rate-controlling membranes (Menon, 2002). The patches that have reached the US marketplace are in the form of laminate film structures that consists of layers that adhere to one another within the delivery sys-tem, and ultimately adhere to the skin for a day to a week. The drug molecule and other components of this delivery system should not be irritating or cause the patch to fall off from the skin prematurely or impact on drug stability. Selection of biomaterials for Passive TDDS needs to con-sider the various conditions that the patch will face dur-ing manufacturing, storage, and wear by the user for up to several days (Cleary, 1984; Hadgraft and Lane, 2006). The

Keratinocytes

Stratum Corneum

Viable epidermisDesmosome

Corneocytes

Intercellularspace

Nucleus

FIGURE F.1 A schematic of the cross section of the stratum corneum (SC, the main barrier in skin) and the viable epidermis beneath it, showing their major components. (Bodde, Verhoeven and van Driel, 1989.)

FIGURE F.2 The diagram illustrates four potential entry points through the main skin barrier, the stratum corneum: (a) tortuous lipophilic pathways between the corneocytes cells; (b) pathways through and around the hair follicles and sweat ducts; (c) transient pathways created by high electrical voltage pulses (electroporation); and (d) micro-pore pathways through the stratum corneum created by mechanical (micronee-dles) or electromagnetic (thermal ablation) methods. (Prausnitz, Mitragotri and Langer, 2004.)

The Stratum Corneum consists of the outer cell layers of skin with a composite of the corneocytes (approximately 10–15 μ thick), with intracellular pathways made of lipid bilayers. The stratum corneum layer is the main barrier to skin permeation.

F Transdermal DDS 1075

components must meet several tests for biocompatibility, irritation, sensitization, drug and adhesive stability, human wear time, the amount and duration of drug delivery, and other quality testing required by the regulatory agencies.

Components and Biomaterials used in passive TDDS patches

Types and Structures of the Skin patch. This section will focus on the more predominant structured laminate systems found in the marketed Passive TDDS patches. The typical patch is comprised of 2 or 5 laminated lay-ers with a total thickness from around 100 to 500 μ (not including the release liner), and areas ranging typically from 2 to 40 cm2. There are three basic laminate struc-ture designs used in passive transdermal systems, shown in Figure F.3 (Cleary, 1984). Type (a) is a single adhesive plus drug reservoir/skin contact layer design. It has no rate-controlling membrane (RCM), and the SC is the rate-limiting barrier for the diffusing drug. It is often called a matrix or drug-in-adhesive patch. The type (b) design has a backing layer, a viscoelastic or gel-like reservoir, and a middle layer that can serve as a rate-controlling and/or structural membrane, and an adhesive layer. The middle layer is sometimes a non-woven film that serves as a structural support or a very porous structure that can prevent or slow down the adhesive cold flow. The third design, Figure F.3c, is similar to type (b), but it can have a liquid drug reservoir rather than a viscoelastic adhe-sive reservoir. The liquid reservoir patch is sometimes referred to as a liquid “fill and seal” patch, and may also

be called a “liquid fill patch”. Both types (b) and (c) are rate-controlled membrane “reservoir patches” (Cleary, 1984, 1991; Van Buskirk et al., 1997). The reservoir in type (c) is essentially a drug that is formulated as liquid, then sealed between two layers of film, one of which is a rate-controlling membrane. Types (b) and (c) can deliver drug at a rate that is constant (zero order). Each of these three designs utilizes polymeric films that are laminated together by either pressure sensitive adhesives (PSA) or by structural adhesives that make a permanent heat-seal bond by melting the adhesive between two non-adhesive polymer films (Cleary, 1984, 1991; Ventrakaman and Gale, 1998). The drug and excipients are typically for-mulated together in the drug-adhesive layers in these patches.

Backing Layer. This layer functions as the primary structural element of the device, it provides the device with much of its flexibility and drape (how the film lays on the curvature of the skin), and skin occlusivity (the degree of breathability of the backing film). Examples of materials useful for the backing layer can be occlu-sive films such as polyethylene terephthalate (PET), high

Liquid Drug Reservoir Layer

Backing Layer

Rate-Controlling/Support MembraneDrug & Skin Contact Adhesive LayerRelease Liner

Backing LayerDrug Reservoir/Adhesive LayerRate-Controlling Membrane

Release LinerDrug & Skin Contact Adhesive Layer

Backing LayerDrug & Skin Contact Adhesive LayerRelease Liner

(a)

(b)

(c)

FIGURE F.3 Three common passive transdermal drug delivery systems’ designs and structures include (a) a three layer patch: backing layer, single adhesive reservoir/skin contact layer, and release liner; (b) a five layer patch: backing layer, adhesive reservoir, a laminate structure as rate-controlling membrane, drug and skin contact adhesive layer, and release liner; (c) a five layer patch: backing layer, a sealed liquid reservoir, a rate-controlling membrane, drug and skin contact adhesive layer, and a release liner. (Van Buskirk et al., 1997; Cleary, 1984, 1991.)

A rate-Controlling Membrane is a membrane (either contiguous or porous) that provides a specific rate of drug diffu-sion from a device such as a skin patch. It is “rate-controlling” when it controls the rate at a lower rate than that across the stratum corneum, so that the control of drug delivery is built into the patch.

1076 SECTION II.5 Applications of Biomaterials

density polyethylene (HDPE), and polypropylene (PP) or more breathable or better drape films, such as polyure-thanes (PU) and poly(ether-amide)s (PEA).reservoir Layer. In the adhesive reservoir design the reservoir layer is comprised of a polymeric pressure-sen-sitive adhesive that contains the drug, solubilizers, and enhancers. The liquid reservoir system will have a liquid or hydrogel medium (such as a hydrogel or ethanolic/water gel using carboxymethyl cellulose or hydroxy-methyl cellulose) contained in a sealed pouch-like area where one side is an impermeable backing layer, and sealed on the other side is a rate-controlling membrane. This layer may also contain adhesive in order to adhere the rate-controlling layer to the backing layer.penetration Enhancers. Penetration enhancers are key components that enable the drug to diffuse from the sys-tem and through the skin at higher flux rates. There have been literally thousands of skin permeation enhancers that have been tested and published in the literature and patents. However, there are only a small number of enhancers that have been approved by the regula-tory agencies. These enhancers must be non-irritating and non-sensitizing to the skin, and should not interact with other components of the formulation (Bodde et al., 1989; Barry, 2004; Hadgraft and Lane, 2006).

Enhancers make it feasible for a drug molecule to permeate through the SC when the drug by itself does not have ideal physicochemical properties. Barry (2004) suggests that chemical penetration enhancers act through three mechanisms: (1) disruption of the tortuous intercel-lular lipid pathway between the corneocytes (examples of this type of enhancer are alcohols, glycols, fatty acids, and fatty acid esters); (2) opening up the dense keratin protein structure making it more permeable (examples of these enhancers are ionic surfactants such as decylmethyl sulfoxide and dimethyl sulfoxide); and (3) increasing the partitioning of the drug into the SC (an example of this type of enhancer is ethanol, which increases the SC penetration of nitroglycerin and estradiol) (Barry, 2004; Songkro, 2009).Skin Contact adhesive Layer. This layer is adhered to the release liner prior to use. Once the release liner is removed, it adheres to the skin site of application. The skin contact adhesive is responsible for maintain-ing the system at the same site for anywhere from one to seven days. Pressure-sensitive adhesives are sticky (tacky) to the slight touch of a finger, and have a range of cold-flow characteristics. Usually a very light touch of a finger is sufficient to adhere them to a surface such as skin, while they still may be removed easily from the skin without leaving any residue on its surface. Pressure-sensitive adhesives are based on three families of adhe-sives – polyacrylates (acrylates), polyisobutylene (PIB) or polydimethylsiloxane (silicone). Drugs usually have low diffusivity in the PIB and acrylate polymers, while silicone has a higher order of magnitude of diffusivity depend-ing on the drug lipophilicity. These effects are related

to the large “free volume” within the adhesive molec-ular structure of silicones (Cleary, 1984; Ventrakaman and Gale, 1998; Kandavilli et al., 2002).release Liner Layer. This layer is a disposable layer which serves only to protect the device prior to applica-tion. It is removed prior to application of the device to the skin. The liner should allow easy handling, be user-friendly, and endure the manufacturing processes. The release liner is impermeable to the drug, liquid vehicles or enhancers that could migrate into it while still in the package. Typical examples are films of PET, HDPE, PP, and polycarbonate (PC) ranging in thickness from 50 to 125 microns. Release liners are often coated with a very thin layer of 0.5 nm to several microns of silicone or perfluoroether, to facilitate ease of removal of the liner before applying the patch to the skin.

ACTIVE TRANSDERMAL DELIVERY SYSTEMS (ACTIVE TDDS)

In this section we describe two technologies in depth, microneedle devices and iontophoresis devices. They are examples of mechanical- and electromagnetic-based TDDS. In general, Active TDDS utilize some type of energy to form a transient or a physical micropore through the SC. (One exception is iontophoresis, which utilizes natural, existing skin pores such as hair follicles and sweat glands.) The sources of energy used may be: (1) mechanical, such as with microneedles, microabra-sion, solid rods, micro-liquid jets (used at moderate speeds), and micro-solid jets (used at ballistic speeds); (2) electromagnetic, such as with iontophoresis, electro-poration, and sonophoresis; and (3) thermal, which uses electric current, radio frequency current or coherent laser light to ablate the SC. Table F.1 describes these eleven different types of Active TDDS technologies. Iontopho-resis is the only Active TDDS that has reached the mar-ketplace, while the others are still in different stages of development.

Microneedle Delivery Technology

The concept of microneedle patches was patented nearly 40 years ago (Gerstel and Place, US Patent, 1976). How-ever, technologies that were needed to fabricate micronee-dles economically were not available until the 1990s. There are a number of different strategies that are being explored today to deliver drugs through the skin using microneedles (Higaki et al., 2003; Cross and Roberts, 2004; Banga, 2009; Cleary, 2009). Figure F.4 illustrates the various compositions and designs of microneedles from the late-1990s to the present day. In the 1990s they were initially made of glass or metals such as stainless steel and titanium (Prausnitz, 2004; Cleary, 2009). In the early 2000s, newer methods of microfabrication, such as heat embossing or microinjection molding, have been used to make polymeric microneedles from polysulfone

F Transdermal DDS 1077

(PS), poly(methyl methacrylate) (PMMA), and PC. Figure F.4d shows some newer materials that are biodegradable or dissolvable. Microneedles have been fabricated from degradable biomaterials such as poly(lactic-co-glycolic acid) (PLGA), polyglycolic acid (PGA), and polycaprolac-tone (PCL) (Figures F.4 and F.5) (Prausnitz, 2004; Cleary, 2009; Kalluri and Banga, 2010; Sullivan et al., 2010).

Solid microneedles can be used or applied to the skin in the following ways: (1) as a pretreatment modality

where the microneedles are inserted and removed, with the subsequent application of a drug formulation that dif-fuses through the pores; (2) by first coating the micronee-dles with the drug, which dissolves off the microneedle tips as they are inserted (in this case, the patch is applied to the skin with a special applicator device, e.g., Zosano®, 3M); (3) by fabricating the needles from a biodegrad-able drug-containing polymer (in this case, the patch is inserted in the skin with a separate or integrated

TaBLE F.1 Active Transdermal Drug Delivery Systems

active Transdermal Delivery Systems

Microporation MechanismsThrough the Stratum Corneum references

Mechanically-Based Energy

Microneedles Micropores formed using mechanical force and velocity of an array of microstructures ranging from 100 to 1000 microns long and 40 to 200 microns wide.

Prausnitz, 2004; Gill et al., 2006; Banga, 2009; Cosman et al., 2010; Kalluri and Banga, 2010; Sullivan et al., 2010; Wendorf et al., 2010

Microabrasion Removes > several mm2 of stratum corneum by abrasion, using sand paper or inert sharp-edged microparticles flowing in a gas at a moderate velocity, where skin is masked forming a 200 micron diameter micropore.

Glenn et al., 2007; Gowrishankar et al., 2009

Solid formulated rod

A solid millimeter-sized rod, formulated with a drug, is inserted into the stratum corneum at a moder-ate force and velocity.

Bennett and Potter, 2006

Micro-solid jets A range of 20 to 100 micron-sized solid particles are inserted into and through the stratum corneum at supersonic speeds using compressed gas from a hand-held delivery device.

Burkoth et al., 1999; Higaki et al., 2003; Cross and Roberts, 2004; Dean and Chen, 2004

Micro-liquid jets A large number of pulsed liquid nl-sized droplets are pulsed through the stratum corneum at a velocity greater than 100 m/s.

Arora et al., 2007

Electromagnetically-Based Energy

Iontophoresis Charged drug molecules migrate through hair follicles and sweat glands along an ion-based pathway using low level milliamp/mm2 electric current density.

Panchagnula and Pillai, 2000; Higaki et al., 2003; Cross and Roberts, 2004; Kalia et al., 2004; Sathyan et al., 2005; Subramony et al., 2006; Power, 2007

Electroporation Short microsecond pulses of high voltage AC (>100 V) creates micropores through the stratum corneum.

Higaki et al., 2003; Cross and Roberts, 2004; Denet et al., 2004; Gowrishankar et al., 2009

Sonophoresis Ultrasonic energy with frequencies less than 100 kHz initiates cavitation that temporarily disrupts the lipid structure of the stratum corneum, providing increased permeability.

Higaki et al., 2003; Cross and Roberts, 2004; Mitragotri and Kost, 2004

Electric current A brief surge of electric current (<60 Hz) occurs with ohmic resistance followed by a rapid increase in heat in microelectrodes. An array of micropores is then created from ablation of the stratum corneum to form micropores.

Badkar et al., 2007; Banga, 2009

Radio frequency current

Thermal ablation occurs using a high frequency alternating current (~100 kHz) that heats an array of of 100 microelectodes/cm2 to create micropores.

Sintov et al., 2003; Banga, 2009

Laser An erbium:YAG laser emits light at 2.94 μm (H2O absorption peak) that focuses only on water and not on surrounding tissue. A laser light scanner causes water to vaporize within the stratum corneum to form an array of micropores.

Higaki et al., 2003; Cross and Roberts, 2004; Kalia et al., 2008; Lee et al., 2008; Banga, 2009

1078 SECTION II.5 Applications of Biomaterials

(a)

(d) (e) (f)

(b) (c)

FIGURE F.4 Examples of biomaterials used to make microneedles that are in-plane designs (a) silicon with hollow structure (University of Cali-fornia, Berkeley); and solid out-of-plane designs made of (b) silicon, solid (Georgia Tech); (c) silicon, hollow (University of Twente); (d) titanium, metal, (Zosano); (e) dissolvable and non-degradable polymers, polycarbonate (3M); and (f) biodegradable polymers (Corium). Non-degradable structures (metal, silicon, polycarbonate) are typically coated at the tip of the structure (e) (red tip). A dissolvable microneedle formulation that includes the drug mixed into the dissolving/biodegradable structures (f) – the drug is compounded together with a polymer in the whole structure. (Cleary, 2009; Wendorf et al., 2010.)

Immediately after

microporationOpen Site

Occlusion

with water

Occlusion with

Plastic film

24hrs after microporation

a

(A)

(B)

a

b

b

c

c

d

d

FIGURE F.5 (A) Schematic diagram of a degradable polymer microneedle array showing the process of applying the microstructures to the skin: (a) prior to biodegrading; (b) inserted into skin; (c) beginning to degrade, backing is removed; and (d) releasing the drug as they degrade. (B) A side view of the micropore in the skin where a dissolvable maltose microneedle is inserted in the skin using Casein imaging to show presence or absence of the micropore after 24 hours following insertion. Micropores are shown by the arrows pointing towards near vertical white lines: (a) immediately after insertion; (b), (c), and (d) 24 hours later under the following three different conditions: (b) site was kept open (unoccluded); (c) site occluded with water; and (d) site occluded with a plastic film. (Kalluri and Banga, 2010.)

F Transdermal DDS 1079

applicator system, e.g., TheraJect®, Corium); or (4) by fabricating the patch with hollow microneedles, which are inserted into the skin, followed by forcing a liquid drug solution through the hollow central bores with a syringe-type applicator, for delivery through the pores (e.g., NanoPass®, 3M) (Prausnitz, 2004; Banga, 2009; Kalluri and Banga, 2010) (Figure F.4).

More recently, the microneedles have been fabricated from solids such as titanium, stainless steel, silicon, and glass, and coated with drug containing soluble polymers. Upon insertion, the coated polymers and their drugs are solubilized by the skin’s interstitial fluid, releasing the active ingredients into the body. Figure F.5 provides a side view of the micropore after the microneedle is inserted into the skin. Note that the micropore comes to closure within a few hours when not occluded or kept moist, but persists when the micropores are covered with an impermeable polymer film (Kalluri and Banga, 2010; Sullivan et al., 2010; Wendorf et al., 2010).

Another recent development is that of microneedles entirely made of biodegradable polymers, loaded with the drug (Figure F.6). The microneedles may be designed to dissolve within 15 minutes, releasing soluble drug into the micropore at the same time. With the microneedle and the drug now gone, it becomes easier to dispose of the patch, which is simpler than disposing of a syringe and needle in hazardous waste disposal cans. It also elim-inates the possibility of accidental finger sticks.

Microneedles have been used and validated in ani-mal and human clinical studies by determination of therapeutic blood levels, pain sensation, and the time it takes for closure of the micropore (Gill et al., 2006; Kalluri and Banga, 2010). Human clinical studies with

a microneedle patch delivering a polypeptide (parathy-roid hormone) have shown pharmacokinetics similar to that of a subcutaneous injection using a syringe and needle. However, the Cmax may be reached earlier with microneedles compared to a syringe and needle ( Cosman et al., 2010). Other human studies have shown that microneedles ranging from 200 to 750 microns in length are painless and bloodless. The micropores created by the microneedles take from 4 to 8 hours to reach clo-sure if they are left without any covering (non-occluded). When they are covered (occluded) it takes about 16 to 22 hours for complete resealing (Kalia et al., 2008; Cosman et al., 2010).

Iontophoresis Technology

Iontophoresis utilizes small electric fields (producing cur-rent densities around 0.5 mA/cm2 or less) to increase the flux of an ionized drug across the intact skin. Iontopho-retic delivery is primarily through the appendages: hair follicles, sebaceous glands, sweat glands, and any skin imperfections. These access pores reach into the dermis, and once the water-soluble drug reaches the aqueous viable epidermis and dermis, the drug diffusion contin-ues until it is picked up by the capillary bed in the upper level of the dermis (Kalia et al., 2004; Power, 2007) (Figure F.7).

An electrophoresis device has a power source and two electrodes, one positive (the anode) and the other negative (the cathode), typically silver-based, Ag(+) and AgCl(−) respectively. The current flows from the anode to the cathode, and this draws positively-charged drug mol-ecules (D+) through the skin and towards the cathode,

(a)

(d) (e) (f)

(b) (c)

FIGURE F.6 Example of dissolvable microneedles prior to and after they were inserted into skin. These figures show the microneedles at various times: at (a) 0; (b) 1; and (c) 5 minutes after insertion into the skin. (d) View of the microneedle array prior to erosion. (e) Top view of porcine cadaver skin after the microneedles are inserted and dissolved leaving the red Sulforhodamine dye in each hole. (f) Side view of the micropore left by the dissolving microneedles that were inserted into the skin and dissolved in the viable epidermis (Brightfield micrography with H&E staining). (Sullivan et al., 2010.)

1080 SECTION II.5 Applications of Biomaterials

as the negatively-charged counterion (Cl−) moves in the opposite direction, toward the anode. There are two res-ervoirs (or compartments) next to the two electrodes, where one of the reservoirs (the anode) contains the drug of the same charge (in this case, it is +) either as an aque-ous liquid or a formulated hydrogel. The total observed flux of the drug from the iontophoretic device is made up of two types of electrokinetic phenomena: electro- migration and electro-osmosis. Passive diffusion is con-sidered negligible, particularly for higher molecular weight drug molecules (Kalia et al., 2004).

Iontophoretic devices that have reached the mar-ket place are sold either without the drug (“no drug”) or come already prefilled with the drug (“with drug”) where the physician or paramedic adds the drug solution to a reservoir before treatment. A major advance in the capabilities of iontophoretic systems has come with the availability of microprocessors. Microprocessors allow precise control of drug dosing and delivery profile, and provide increased system safety through monitoring of system functions such as current levels and battery volt-age. The ability of microprocessor-controlled iontopho-retic systems to offer minimally invasive and controlled administration of medications to patients has spurred an increased interest in the use of iontophoresis for systemic

delivery of drugs, especially those with limited oral bio-availability or those that require a quick onset or cannot be delivered with passive transdermal technology (Kalia et al., 2004; Sathyan et al., 2005; Subramony et al., 2006; Power, 2007) (Figure F.8).

Investigators have used many different types of poly-mers as “gelling agents,” which form hydrogel reservoir films in iontophoretic devices. Examples of such cross-linked gels are agar-agar, gelatin, polyvinyl alcohol (PVA), poly(vinylpyrollidone) (PVP), poly(dimethylaminopropyl acrylamide) (PDAA), cross-linked poly(hydroxyethyl methacrylate) (PHEMA), methylcellulose (MC), and hydroxypropylmethylcellulose (HPMC) (Panchagnula and Pillai, 2000; Peppas et al., 2000; Wang et al., 2005).

Strategies to increase the permeation of large and small drug molecules have combined iontophoresis with other technologies, such as electroporation, sonophore-sis or microneedles, or with other materials, such as ion exchange materials that may also serve to improve drug stability and shelf-life. Also, chemical enhancers such as fatty acids, propylene glycol (PG), polyethylene glycol (PEG), oleic acid, terpenes, and surfactants may be added to the formulations for electrophoresis reservoirs. These combination techniques may provide improved delivery of some large drug molecules or poorly water-insoluble

FIGURE F.7 This schematic diagram describes the electrode system of an iontophoretic drug delivery device that uses an Ag/AgCl electrode where the current is flowing to the anode (+). There are two electrode compartments: the anode (+) that contains the Drug, D+A−, (here the drug D+ is placed in the reservoir of the same charge, e.g., D is lidocaine or fentanyl) and the cathode (−) or “indifferent” electrode (placed at some other site on the skin). (Kalia et al., 2004; Power, 2007.) See text for more detail on the delivery mechanism.

F Transdermal DDS 1081

drug molecules ( Panchagnula and Pillai, 2000; Peppas et al., 2000; Wang et al., 2005).

GLOSSARYEVA is poly(ethylene-co-vinylacetate), a polymer used

in Passive TDDS as a non-porous rate-controlling membrane.

FDA is the abbreviation of the US Food and Drug Administration.

HDPE is high density polyethylene, a thermoplastic polymer that is used as a release liner in Passive TDDS.

HPMC is hydroxypropylmethylcellulose, and is used as a hydrogel for the drug reservoir and counterion reservoir in ionotophoresis.

PC is polycarbonate and is melt-extruded to make arrays of microneedle structures; also used as a release liner.

PCL is polycaprolactone, a degradable polymer used to make microneedle structures.

PEA is poly(ether-amide), a polymer with breathable and elastic properties. It has been considered as a backing or rate-controlling membrane in Passive TDDS.

PEG is polyethylene glycol, a biocompatible water soluble polymer that is used as a solubilizer of components in Passive TDDS.

PET is polyethylene terephthalate, a thermoplastic polymer that has been used as a backing and a release liner in Passive TDDS laminate structures.

PG is propylene glycol, which is used as a solubilizer and skin permeation enhancer for drugs.

PGA is polyglycolic acid, a bioerodible polymer used in making bioerodible microneedle structures in Active TDDS.

PHEMA is poly(hydroxylethyl methacrylate), used in hydrogel reservoirs for iontophoresis.

PIB is polyisobutyl rubber, a hydrocarbon-based pressure-sensitive adhesive that is used as an adhesive layer in Passive TDDS.

PLGA is poly(lactic-co-glycolic acid), a bioerodible polymer used in making degradable microneedle structures in Active TDDS.

PMMA is poly(methyl methacrylate), a thermoplastic polymer used to make microneedles.

PP is polypropylene, a semi-crystalline, thermoplastic polymer that has been used as a release liner. It may also be used as a microporous rate-controlling membrane.

PS is polysulfone, it has thermoplastic properties and is a polymer that is used to make microneedles using melt-compression methodologies.

PSA is the abbreviation for pressure sensitive adhesive; PSA polymers are adhesives that bond or adhere to surfaces when pressure is applied. These adhesives have tack (sticky properties when touched), and are used to adhere Active and Passive TDDS to skin and the laminated structures found in TDDS.

PU is polyurethanes, elastomeric polymers that as a film have breathability properties, flexibility, and drape when used as a backing layer.

PVA is polyvinyl alcohol, a water-soluble polymer that is used to make hydrogel reservoirs in iontophoresis drug delivery.

BIBLIOGRAPHY

Arora, A., Itzhak, H., Baxter, J., Rathnasingham, R., Srinivasan, R., Fletcher, D. A., & Mitragotri, S. (2007). Needle-free deliv-ery of macromolecules across the skin by nanoliter-volume pulsed microjets. Proc. Nat. Acad. Sci., 104, 4255–4260.

Badkar, A. V., Smith, A. M., Eppstein, J. A., & Banga, A. K. (2007). Transdermal delivery of interferon Alpha-2B using microporation and iontophoresis in hairless rats. Pharm. Res., 24, 389–395.

Banga, A. K. (2009). Microporation applications for enhancing drug delivery. Expert Opin. Drug Del., 6, 343–354.

Barry, B. W. (2001). Novel mechanisms and devices to enable successful transdermal drug delivery. Eur. J. Pharm. Sci., 14, 101–114.

(a) (b)

FIGURE F.8 Two examples of today’s electronic iontophoretic devices with “drug on board”. These devices include microprocessors, on-demand controls, etc. along with an anode hydrogel drug reservoir for use in local and systemic pain control. (a) LidoSite® (Vyteris), a device that delivers lidocaine locally for dermal pain; and (b) Ionsys® (J&J), a device that delivers fentanyl transdermally to reach the systemic circulation. (Power, 2007.)

1082 SECTION II.5 Applications of Biomaterials

Barry, B. W. (2004). Breaching the skin barrrier to drugs. Nat. Biotechnol., 22, 165–167.

Bennett, S., & Potter, C. (2006). Pushing the boundaries of needle-free injection drug delivery. Report. Autumn/Winter, 24–28.

Bodde, H. E., Verhoeven, J., & van Driel, L. M. J. (1989). The skin compliance of transdermal drug delivery systems. Crit. Rev. Therap. Drug Carrier Systems, 6, 87–115.

Bos, J. D., & Meinardi, M. H.M. (2000). The 500 dalton rule for the skin penetration of chemical compounds and drugs. Exp. Dermatol., 9, 165–169.

Burkoth, T. L., Bellhouse, B. J., et al. (1999). Transdermal and transmucosal powdered drug delivery. Crit. Rev. Therap. Drug Carrier Systems, 16, 331–384.

Cleary, G. W. (1984). Transdermal Controlled Release Systems. In R. Langer, & D. L. Wise (Eds.), Medical Applications of Con-trolled Release (Vol. 1, pp. 203–251): CRC Press.

Cleary, G. W. (1991). Transdermal drug delivery. Cosmet. Toilet-ries, 5, 97–109.

Cleary, G. W. (1993). Transdermal Delivery Systems. In V. P. Shah, & H. I. Maibach (Eds.), A Medical Rational in Topi-cal Drug Bioavailability, Bioequivalence and Penetration (pp. 17–63): Plenum.

Cleary, G. W. (2009). Emergence of active transdermal drug deliv-ery. Plenary Presentation at the 36th Annual Meeting and Exposition of the Controlled Release Society. Copenhagen: Denmark. July 18–22.

Cosman, F., Lane, N. E., Bolognese, M. E., Zanchetta, J. R., Garcia- Hernandez, P. A., Sees, K., Matriano, J. A., Gaumer, K., & Daddona, P. E. (2010). Effect of transdermal teriparatide administration on bone mineral density in postmenopausal women. J. Clin. Endocrinol. Metab., 95, 151–158.

Cross, S. E., & Roberts, M. S. (2004). Physical enhancement of transdermal drug application: Is delivery technology keeping up with pharmaceutical development? Curr. Drug Del., 1, 81–92.

Dean, H. J., & Chen, D. (2004). Epidermal powder immunization against influenza. Vaccine, 23, 681–686.

Denet, A., Vanbever, R., & Preat, V. (2004). Skin electroporation for transdermal and topical delivery. Adv. Drug Del. Rev. 56, 659–674.

Gerstel, M. S., & Place, V. A. (1976). Drug Delivery Device. US.Patent No. 3,964,482.

Gill, H. S., Denson, D. D., Burris, B. A., & Prausnitz, M. R. (2006). Effect of microneedle design on pain in human volun-teers. Clin. J. Pain, 24, 585–594.

Glenn, G. M., Flyer, D. C., Ellingsworth, L. R., S.A., Frerichs, D. M., Seid, R. C., & Yu, J. (2007). Transcutaneous immuniza-tion with heat-labile enterotoxin: Development of a needle-free vaccine patch. Expert Rev. Vaccines, 17, 1354–1359.

Gowrishankar, T. R., Herndon, T. O., & Weaver, J. C. (2009). Transdermal drug delivery by localized intervention: Field-confined skin electroporation and dermal microscissioning. I EEE Eng. Med. Biol., Jan/Feb.

Hadgraft, J., & Lane, M. E. (2006). Passive transdermal drug delivery systems. Amer J. Drug Del., 4, 153–160.

Higaki, K., Amnuaikit, C., & Kimura, T. (2003). Strategies for over-coming the stratum corneum: Chemical and physical approaches. Am. J. Drug Del., Healthcare Technol. Rev., 1, 187–214.

Kalia, Y. N., Naik, A., Garrison, J., & Guy, R. H. (2004). Ion-tophoretic drug delivery. Adv. Drug Del. Rev., 56, 619–658.

Kalia, Y. N., Bachhav, Y. G., et al. (2008). P.L.E.A.S.E. (Painless Laser Epidermal System): A new laser microporation technol-ogy. Drug Del. Technol., 8, 25–31.

Kalluri, H., & Banga, A. K. (2010). Formation and closure of microchannels in skin following microporation. Pharm. Res., 28(1), 82–94http://dx.doi.org/10.1007/s11095-010-0122-x. Published online: March 31, 2010.

Kandavilli, S., Nair, V., & Panchagnula, R. (2002). Polymers in transdermal drug delivery systems. Pharma. Technol. May, 62–80.

Lee, W., Pan, T., Wang, P. W., Zhuo, R. Z., Huang, C. M., & Fang, J. Y. (2008). Erbium: YAG laser enhances transdermal peptide delivery and skin vaccination. J. Control. Release, 128, 200–208.

Menon, G. K. (2002). New insights into skin structure: Scratching the surface. Adv. Drug Del. Rev., 54, S3–S17.

Mitragotri, S., & Kost, J. (2004). Low-frequency sonophoresis – A review. Adv. Drug Del. Rev., 56, 589–601.

Naik, A., Kalia, Y. N., & Guy, R. H. (2000). Transdermal drug delivery: Overcoming the skin’s barrier function. Pharm. Sci. Technol. Today, 3, 318–326.

Panchagnula, R., & Pillai, O. (2000). Transdermal iontophoresis revisited. Curr. Opin. Chem., 4, 468–473.

Peppas, N. A., Bures, P., Leobandung, W., & Ichikawa, H. (2000). Hydrogels in pharmaceutical formulations. Eur. J. Pharm. Biopharm., 50, 27–46.

Power, I. (2007). Fentanyl HCl iontophoretic transdermal system (ITS): Clinical application of iontophoretic technology in the management of acute postoperative pain. Brit. J. Anesth., 98, 4–11.

Prausnitz, M. R. (2004). Microneedles for transdermal drug deliv-ery. Adv. Drug Del. Rev., 56, 581–587.

Prausnitz, M. R., & Langer, R. (2008). Transdermal drug delivery. Nat. Biotech., 26, 1261–1268.

Prausnitz, M. R., Mitragotri, S., & Langer, R. (2004). Current status and future potential of transdermal drug delivery. Nat. Rev. Drug Discov., 3, 115–124.

Sathyan, G., Zomordi, K., Gidwani, S., & Gupta, S. (2005). The effect of dosing frequency on the pharmacokinetics of fen-tanyl HCl patient-controlled transdermal system (PCTS). Clin. Pharmacokinet., 44, 17–24.

Sintov, A. C., Krymberk, I., Daniel, D., Hannan, T., Sohn, Z., & Levin, G. (2003). Radio frequency-driven skin microchannel-ing as a new way for electrically assisted transdermal delivery of hydrophilic drugs. J. Control. Release, 89, 311–320.

Songkro, S. (2009). An overview of skin penetration enhancers: Penetration enhancing activity, skin irritation potential and mechanism of action. Songklanakarin J. Sci. Technol., 31, 299–321.

Subramony, J. A., Sharma, A., & Phipps, J. B. (2006). Micropro-cesor controlled transdermal drug delivery. Intern. J. Pharm., 317, 1–6.

Sullivan, S. P., Koutonanos, D. G., Del Pilar Martin, M., Lee, J. W., Zarnitsyn, V., Choi, S. O., Murthy, N., Compans, R. W., Skountzou, I., & Prausnitz, M. R. (2010). Dissolving poly-mer microneeedle patches for influenza vaccine. Nat. Med., 16(8), 915–920. http://dx.doi.org/10.1038/nm.2182. Published online: July 18, 2010.

Van Buskirk, G. A., Gonzalez, M. A., et al. (1997). Scale-up of adhesive transdermal delivery systems. Pharm. Res., 14, 848–852.

Ventrakaman, S., & Gale, R. (1998). Skin adhesives and skin adhe-sion 1. Transdermal drug delivery Systems. Biomaterials, 19, 1119–1136.

Wang, Y., Thakur, R., Fan, Q., & Michniak, B. (2005). Transder-mal iontophoresis: Combination strategies to improve trans-dermal iontophoretic drug delivery. Eur. J. Pharm. Biopharm., 60, 179–191.

Wendorf, J. R., Ghartey-Tagoe, E. B., Williams, S. C., Enioutina, E., Singh, P., & Cleary, G. W. (2010). Transdermal delivery of macromolecules using solid-state biodegradable microstruc-tures. Pharm. Res. http://dx.doi.org/1007/s11095-010-0174-y. Published online: June 10, 2010.