Am J Drug Deliv 2006; 4 (3): 153-160 1175-9038/06/0003-0153/$39.95/0

REVIEW ARTICLE

© 2006 Adis Data Information BV. All rights reserved.

Passive Transdermal Drug Delivery Systems Recent Considerations and Advances Jonathan Hadgraft and Majella E. Lane Department of Pharmaceutics, School of Pharmacy, University of London, London, England

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 1. Membrane Transport and Drug Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 2. Transdermal Drug Delivery Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 2.1 Reservoir Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 2.2 Matrix Diffusion-Controlled Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 2.3 Multiple Polymer (Silicone/Acrylic Adhesive) Patches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 3. New Developments in Transdermal Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 3.1 New Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 3.2 New Technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

Abstract

The skin has evolved as a formidable barrier against invasion by external microorganisms and against the prevention of water loss. Notwithstanding this, transdermal drug delivery systems have been designed with the aim of providing continuous controlled delivery of drugs via this barrier to the systemic circulation. There are numerous systems now available that effectively deliver drugs across the skin. These include reservoir devices, matrix diffusion-controlled devices, multiple polymer devices, and multilayer matrix systems. This review article focuses on the design characteristics and composition of the main categories of passive transdermal delivery device available. Mechanisms controlling release of the active drug from these systems as well as patch size and irritation problems will be considered. Recent developments in the field are highlighted including advances in patch design as well as the increasing number of drug molecules now amenable to delivery via this route. From the early complex patch designs, devices have now evolved towards simpler, matrix formulations. One of the newer technologies to emerge is the delivery-optimized thermodynamic (DOT) patch system, which allows greater drug loading to be achieved in a much smaller patch size. With the DOT technology, drug is loaded in an acrylicbased adhesive. The drug/acrylic blend is dispersed through silicone adhesive, creating a semi-solid suspension. This overcomes the problem with conventional drug-in-adhesive matrix patches, in which a large drug load in the adhesive reservoir can compromise the adhesive properties or necessitate a large patch size. Transdermal drug delivery remains an attractive and evolving field offering many benefits over alternative routes of drug delivery. Future developments in the field should address problems relating to irritancy and sensitization, which currently exclude a number of therapeutic entities from delivery via this route. It is likely that further innovations in matrix composition and formulation will further expand the number of candidate drugs available for transdermal delivery.

Transdermal drug delivery may be defined, in its broadest sense, as the administration of medicines to the skin which will

deliver the active ingredient into the systemic circulation at therapeutic levels. The antecedents of modern transdermal drug deliv-

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ery may be seen in the use of ointments in the historical literature. There are reports about ‘flying ointment’, which was used by witches to make them fly. The preparations contained hallucinogens from natural extracts and were formulated into lipophilic bases. The ointments were applied on a broomstick, which was held between the legs, showing a clear but early recognition of formulation effects, site variations in permeability and prescience of transdermal delivery for systemic effects.[1] Stronger ‘mercurial ointment’ was traditionally used as a treatment for syphilis with directions to rub into areas where the skin is thinnest: the groin and the bends of the elbows and knees. When this preparation was applied, 75% of patients experienced salivation (one of the known systemic effects of mercury),[2] a clear indication of transdermal delivery. There are numerous advantages associated with transdermal delivery. It offers controlled release of the drug into the patient, thus potentially enabling a steady blood-level profile, resulting in reduced systemic adverse effects, and the possibility of improved efficacy over other dosage forms.[3] Importantly, drugs administered via this route are not subject to first-pass metabolism. Improved patient compliance is a further advantage that arises from the convenience of application and dose flexibility.[4] The worldwide transdermal drug market was worth close to $US13 billion in 2005 and is expected to increase to $US21.5 billion by the year 2010.[5] Examples of drug molecules currently delivered transdermally include fentanyl, nitroglycerin, estradiol, ethinylestradiol, norethisterone acetate, testosterone, clonidine, nicotine, scopolamine, buprenorphine, norelgestromin, and oxybutynin. In this article we review the key characteristics of the different types of passive transdermal drug delivery systems (TDS). There are three types of passive TDS currently marketed: the reservoir system, the matrix diffusion-controlled system, and multiple-polymer systems. This paper focuses on the following aspects of these systems: design characteristics, control of release, limitations in terms of patch size and dose load, adhesion, irritancy, and therapeutic utility. Active forms of transdermal drug delivery, such as iontophoresis, electroporation, microneedles and microchannels, have been covered in other reviews[6-9] and are beyond the scope of this paper. 1. Membrane Transport and Drug Release The relative impermeability of skin is well known, and this is associated with its functions as a dual protective barrier against: (i) the ingress of xenobiotics, including invasion by microorganisms; and (ii) the loss of physiologically essential substances such as water. In order to understand the factors that dictate the delivery of © 2006 Adis Data Information BV. All rights reserved.

drugs from the various devices across this formidable barrier it is important to appreciate how such molecules partition and diffuse into and across membranes. Drug absorption from passive TDS into the skin follows simple diffusion rules. The rate of penetration across the stratum corneum follows Fick’s first law of diffusion which describes steady-state flux per unit area (J) in terms of the partition of the permeant between the applied formulation and the skin (K), its diffusion coefficient (D) in the intercellular channels of diffusional path length (h), the applied concentration of the permeant in the vehicle (capp), and the concentration of the permeant in the systemic circulation or, in the case of an in vitro study, receptor phase (crec) [equation 1]: KD(capp – crec) J= h (Eq. 1) In most circumstances crec << capp and equation 1 is often simplified to (equation 2): J = KpCapp (Eq. 2) where kp (= KD/h) is the permeability coefficient. The maximum flux for a compound occurs when capp is equal to the solubility limit of the drug in the applied formulation. Inspection of the equations shows that the important physicochemical properties dictating membrane transport of a drug are partition coefficient, diffusion coefficient, and solubility. It is not surprising therefore, that drugs suitable for transdermal delivery have to possess appropriate physicochemical properties. In general they are small, with a log P (octanol – water partition coefficient) of approximately 2, and they have good solubility in both oils and water. Concomitant with this is that they have relatively low melting points. Compounds such as nicotine and nitroglycerin have properties that allow them to cross the skin relatively well. But, even so, the daily dose of nicotine and nitroglycerin that can be achieved with transdermal delivery over a reasonably sized area of skin is only of the order of 10mg; therefore, the route is only suitable for very potent moieties. The primary objective in designing better drug delivery systems is to develop mechanisms of controlling the rate of drug release and, hence, the rate of uptake into the circulation. For transdermal drug delivery it is useful to consider diffusion-controlled release either from a solution of the drug (i.e. the drug is in solution in the polymer components of the device) or from a suspension of the drug. The release kinetics then need to be compared with the rate of diffusion across the skin to determine where the rate-controlling process is; that is, whether it resides in the TDS, the skin, or a combination of both. Am J Drug Deliv 2006; 4 (3)

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When diffusion within the vehicle provides the rate-controlling step, the skin may be regarded as a sink. In this case it is necessary to use solutions to Fick’s second law of diffusion to understand the release kinetics. These are complex but approximations can be made. If the TDS release is considered up to the time when 60% of the drug has been released, the following simplified equations can be derived.[10] When the drug is in solution the relationship between m, the quantity of drug released to the sink per unit area of application, and C0, the initial concentration of solute in the TDS, Dv the diffusion coefficient of the drug in the TDS, and t, time, may be described by equation 3: m = 2C0

Dv t π (Eq. 3)

Differentiating this equation provides the release rate dm/dt (equation 4): dm = C 0 dt

Dv πt (Eq. 4)

According to equation 3, a plot of m versus the square root of t should be linear. For absorption from a suspension, and assuming that the total amount of drug both soluble and suspended per unit volume (A) is much greater than the solubility of the drug in the vehicle (Cs), the expression describing the quantity of drug released over time is given in equation 5: m=

Dvt ( 2 A − Cs )Cs (Eq. 5)

Assuming A >> Cs, the rate of drug release is written (equation 6): dm = dt

ADvCs 2t (Eq. 6)

In both cases, the rate of drug release (dm/dt) is inversely proportional to the square root of time.

2.1 Reservoir Systems

The reservoir system is a diffusion-controlled system that contains a drug reservoir with a rate-controlling polymer membrane. With this device, the membrane that lies between the drug reservoir and the skin controls the rate of release from the drug reservoir to the skin surface. This patch design can provide a true zero-order release pattern to achieve a constant serum drug level, however, the serum levels will be dictated by both diffusion from the patch and across the skin, as discussed in more detail later in this section. A schematic of the typical design for a reservoir-type device is given in figure 1 and examples of reservoir devices currently on the market are given in table I. For the drug reservoir, both liquid and solid materials may be used. Liquids such as ethanol and silicone fluid have been employed. Polymers such as polyisobutylene, silicone elastomers, and polyvinyl alcohol/polyvinylpyrrolidone blends have been used in other reservoir systems. In order to modify the drug release rate, polymer properties may be varied by altering polymer crosslinking or chemical structure, use of polymer blends and addition of plasticizers. In order to maintain an acceptable patch size and optimum drug loading, the inclusion of a permeation enhancer may be necessary. Chemical permeation enhancers are divided into two classes (depending on their mechanism of action): (i) those that alter the structure of the skin lipids, decreasing their resistance to diffusion; and (ii) those that enhance the solubility of the diffusing drug within the skin.[11] It is possible that the enhancement that occurs with transdermal drug delivery is a result of more than one of the above factors. If a combination of enhancers is used, one that acts as a powerful solvent and one that disrupts the lipid structure, a multiplicative effect can be found. There is also the possibility that the solvents may actually affect some of the skin lipids. Examples of permeation enhancers for reservoir systems include ethanol (Duragesic®, Estraderm®)1, glyceryl monooleate and methyl laurate (Androderm®). It should also be remembered that patches can be occlusive and this will result in hydrated skin that has increased permeability. Materials used to form the rate-controlling membrane include microporous polypropylene and ethylene vinyl acetate copolyBacking membrane

2. Transdermal Drug Delivery Devices

Reservoir

There are three types of passive TDS currently on the market, namely, the reservoir system, matrix diffusion-controlled system, and multiple polymer system. 1

Rate-controlling membrane Adhesive

Fig. 1. Schematic of typical reservoir transdermal drug delivery device.

The use of trade names is for product identification purposes only and does not imply endorsement.

© 2006 Adis Data Information BV. All rights reserved.

Am J Drug Deliv 2006; 4 (3)

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Table I. Examples of commercially available reservoir transdermal drug delivery systems and their components Product name

Drug reservoir

Rate-controlling membrane

Adhesive

Testoderm® TTS

Testosterone, hydroxypropyl cellulose, ethanol

EVA copolymer

PIB, mineral oil

Scopolamine, PIB, mineral oil

Microporous, polypropylene

PIB, mineral oil, scopolamine

Nitroglycerin, silicone fluid, lactose triturate

EVA copolymer

Silicone

Transderm

Scop®

Transderm Nitro® NicoDerm®

CQ®/NiQuitin

CQ™

Nicotine, EVA copolymer

Polyethylene

PIB

Duragesic®

Fentanyl, hydroxyethyl cellulose, ethanol

EVA copolymer

Silicone

Estraderm®

Estradiol, hydroxyethyl cellulose, ethanol

EVA copolymer

PIB, mineral oil

Estracombi TTS®

Estradiol, ethanol, hydroxypropyl cellulose, norethisterone acetate, polyethylene terephthalate, liquid paraffin

EVA copolymer

PIB

Catapres-TTS®

Clonidine, PIB, mineral oil, colloidal silicon dioxide

Microporous polypropylene

PIB, mineral oil, colloidal silicon dioxide, clonidine

Androderm®

Testosterone, ethanol, glycerin, glyceryl monooleate, methyl laurate, acrylic acid copolymer

Microporous polyethylene

Acrylic adhesive

EVA = ethylene vinyl acetate; PIB = polyisobutylene.

mers. For the Duragesic® system the vinyl acetate content in the rate-controlling membrane is selected to achieve the desired transport of ethanol, which, in part, controls the transport of fentanyl across the skin.[12] A pressure-sensitive adhesive is required to adhere the transdermal device to the body. The drug is required to diffuse from the drug reservoir through the adhesive while maintaining adequate adhesion to the skin. Commercially available materials for transdermal use include the polyisobutylene-, polyacrylate-, and polysiloxane-based adhesives. Backing membranes generally must exhibit a low moisture vapor transmission rate and have suitable mechanical properties (e.g. flexibility and tensile strength) for both wearing on the skin and handling during manufacturing. Polyolefins, multilayered films, polyesters, and elastomers in clear pigmented or metallized forms have been used. Peelable liners are usually composed of similar materials (polyethylene, polyesters) and may be coated with a suitable release layer (silicone or fluorocarbons). The Catapres-TTS® and Transderm-Scop® have the active ingredient incorporated into the pressure-sensitive adhesive as well as the reservoir. The rationale in these devices is that the active agent in the adhesive will saturate the skin site below the system followed by continuous controlled-release of the active drug through the rate-controlling membrane. It is self-evident that, during storage, there will be equilibration of the drug between the reservoir and adhesive, since the reservoir is saturated the adhesive will also contain the active drug at a thermodynamic activity of unity. A modification of the basic reservoir device is a dual reservoir patch which combines an estrogen and progestogen. The combina© 2006 Adis Data Information BV. All rights reserved.

tion patch (Estracombi TTS®) has two reservoirs, one for each drug, estradiol and norethisterone acetate. Reservoir devices may be considered the first generation of TDS and did not always satisfy issues of patient compliance or patient acceptability. For transdermal patches to be acceptable to patients they need to be relatively thin, flexible, small, and discreet; the early patches often fell short of these requirements. Problems such as skin irritation have also been reported with these systems. In clinical trials, approximately 9% of hypogonadal males discontinued Androderm® treatment and 4% of the discontinuations were ascribed to allergic contact dermatitis.[13] The skin irritation experienced by approximately 6% of women with the use of Estraderm® was so severe that it led to the discontinuation of therapy.[14,15] The skin irritation appeared to result from the ethanol component and/or the adhesive.[16,17] Some minor irritation can be acceptable but a balance has to be made between therapeutic benefit and skin toxicity. A significant number of people using the Catapres-TTS® system experience skin reactions but fewer other adverse effects are experienced compared with after oral delivery.[18] 2.2 Matrix Diffusion-Controlled Systems

The active drug in this type of patch is contained in a polymer matrix. The drug is released at a rate governed by the components in the matrix. Matrix patches in themselves are not designed to provide true zero-order release because as the drug closest to the skin is released, the drug deeper within the patch must travel a longer distance to reach the skin. The longer diffusional path slows the rate of absorption from the patch over time. For most wellAm J Drug Deliv 2006; 4 (3)

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designed matrix patches, however, the decrease in release rate is so slight that it does not significantly affect the rate of drug absorption. In general, there is more control of drug input into the body from the skin, and concentration-depletion effects are not significant over the application time of the patch. Examples of commercially available matrix diffusion-controlled transdermal drug delivery systems are given in table II. For a drug-in-adhesive matrix the polymer in which the drug is dispersed is an adhesive; the adhesive serves two roles – it acts as the drug reservoir and holds the patch on the skin (figure 2). In these devices, the pressure-sensitive adhesive contains all of the dissolved or dispersed drug and excipients. Thus, the solubility and stability of the drug/excipients in the adhesive and their effect on adhesion are critical issues that must be addressed. Patches designed for once-weekly applications require a strong adhesive, yet at removal they must not cause pain or irritation at the site of application. The patch design must also be sturdy enough to withstand routine handling and storage and must survive normal usage, such as showering, exercise, and rubbing against clothing. The drug’s chemical stability and patch’s physical properties, particularly those of the adhesive, must be retained over time. The requirements for mechanical properties and moisture permeability of matrix devices are similar to those for the reservoir system. Efficient drug loading can be achieved in matrix patches and this usually avoids the need for inclusion of solvents such as ethanol. A lower incidence of cutaneous reactions at the site of application for estradiol matrix devices versus the reference reservoir device has been reported.[19] Matrix patches are generally Table II. Examples of commercially available matrix transdermal drug delivery systems Product name

Matrix

Alora®

Estradiol, sorbitan monooleate, acrylic-based adhesive

Climara®

Estradiol, acrylate-based adhesive

Deponit® NT

Nitroglycerin, vinyl acetate acrylate adhesive

Nicotrol®

Nicotine, polyisobutylene

Nitro-Dur®

Nitroglycerin, acrylic-based adhesive, resinous cross-linking agent

Oxytrol®

Oxybutyinin, acrylic-based adhesive, triacetin

Ortho

Evra®

Vivelle®

Norelgestromin, ethinyl estradiol, polyisobutylene/polybutene, crospovidone, nonwoven polyester, lauryl lactate Estradiol, acrylic adhesive, polyisobutylene, EVA copolymer, butylene glycol, styrene butadiene, oleic acid, lecithin, propylene glycol, bentonite, mineral oil, dipropylene glycol

EVA = ethylene vinyl acetate. © 2006 Adis Data Information BV. All rights reserved.

157

Backing membrane Adhesive matrix Release liner

Fig. 2. Drug-in-adhesive matrix monolithic transdermal drug delivery device.

smaller and thinner than their reservoir predecessors because of advances in design and, therefore, these patches often have the benefit of improved patient acceptability and compliance. Penetration enhancers are also used in matrix-type devices; for example, sorbitan monooleate is used in the Alora® patch (containing estradiol) as a penetration enhancer. Oxytrol® is a matrixtype transdermal system with an acrylic adhesive containing oxybutynin and triacetin as a penetration enhancer. Advances in drug-in-adhesive matrix patch technology have focused on the adhesive polymer for optimal drug loading or drug compatibility. Adhesive research focuses on customizing the adhesive to improve skin adhesion over the wear period, improving drug stability and solubility, reducing lag-time, and increasing the rate of delivery. Customizing the adhesive chemistry allows the transdermal formulator to optimize the performance of the transdermal patch. For example, Schwarz Pharma AG originally marketed a drug-in-adhesive nitroglycerin patch (Deponit®) with a thickness of 300μm; subsequent research and development resulted in the selection of an adhesive formed from a cross-linked acrylate vinyl acetate copolymer which could accommodate a much higher drug loading (40%) and resulted in a thinner patch of ~90μm.[20] The backing membrane (45μm) is a biaxial-oriented (as opposed to the more conventional longitudinal-oriented) polypropylene which is permeable to water vapor but not liquid water. During use the adhesive matrix takes up water from the skin and its presence ensures a high activity state of the nitroglycerin, which promotes absorption. Where two active agents are incorporated into a patch, for example in the combination steroid systems for hormone replacement therapy or contraception, other factors need to be considered. The two drugs must be compatible with each another in the matrix and must be released to the skin surface at the appropriate rate. The transport properties of the two drugs across the skin are likely to be different and it is also possible that the presence of one in the skin may alter the transport properties of the other. This will occur, for example, if the two can interact with one another at a molecular level by hydrogen bonding or π – π electron interactions. It is interesting to note that if the in vitro release characteristics of diffusion-controlled matrix patches are examined the square root of time relationship is observed. For example, the release characteristics of various nitroglycerin patches were determined by Shah et al.[21] For the matrix systems such as Nitro-Dur® II the Am J Drug Deliv 2006; 4 (3)

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amount of drug released is found to be linearly related to the square root of time (figure 3). However, for the reservoir TDS with a rate-controlling membrane (Transderm® Nitro), the amount released is a linear function of time, that is, it is zero order (figure 3). It can be seen that these two devices have different release characteristics but when they are applied in vivo they give steady and comparable plasma levels. This is because the rate of delivery into the systemic circulation is a function of both the release kinetics of the patch and the absorption of the nitroglycerin through the skin. Analysis of the in vitro and in vivo data shows that in the case of Nitro-Dur® II about 87% of the input is controlled by the skin whereas for Transderm® Nitro it is 55%.[22] There are clear safety issues associated with the relative control of drug release by the skin and the device, and these will be more apparent for drugs with small therapeutic windows. The release rate from the device will give an upper limit for the input into the body and this may be important when a patient has very permeable skin or inadvertently applies doses to a site where the skin has been damaged. 2.3 Multiple Polymer (Silicone/Acrylic Adhesive) Patches

For conventional drug-in-adhesive patches, the dual functionality of the adhesive and reservoir may pose a problem for patch

Amount released (mg)

a 120 100 80 60 40 20 0 0

2 4 Square root of time (h)

6

b Amount released (mg)

50 40 30 20 10 0 0

6

12 Time (h)

18

24

Fig. 3. In vitro dissolution data for nitroglycerin transdermal drug delivery systems from Shah et al.[21] Data are replotted as (a) a function of the square root of time for the matrix diffusion-controlled system Nitro-Dur® II and (b) a function of time for the reservoir system Transderm-Nitro®. © 2006 Adis Data Information BV. All rights reserved.

size. A small patch needs high drug concentrations, but loading the polymer adhesive with drug can compromise its adhesive properties. To overcome this problem with estradiol, Noven Pharmaceuticals, Inc. introduced a patented DOT (delivery-optimized thermodynamics) technology. In a DOT Matrix® patch, acrylic- and silicone-based adhesives are used to achieve higher drug loadings than are feasible with drug-in-adhesive matrix systems. The acrylic-based adhesive is loaded with drug. A silicone adhesive is then added which essentially repels the drug/acrylic blend much like oil in water. The drug is present as a semi-solid suspension evenly dispersed through an uncompromised silicone adhesive. As a result, Vivelle-Dot™ is about one-third to onequarter the size of competing estrogen patches delivering the same daily dose.[23] The same technology was utilized in the design of a combination patch containing estradiol and the progestogen norethindrone acetate. A methylphenidate transdermal system utilizing similar technology was approved for marketing in the US in 2006.[24] Examples of multiple copolymer transdermal drug delivery systems are listed in table III. 3. New Developments in Transdermal Drug Delivery 3.1 New Drugs

Innovations in the field have focused on formulations that increase the flux of drug across the skin and improve TDS performance and stability, and as a consequence expand the drug candidates amenable to delivery via the transdermal route. However, many candidates are ruled out because of their inherent skin toxicity and a mechanism to prevent this has yet to be identified. Irritancy can often be exacerbated by a high flux of the drug which is inevitable if a small patch area is used. It is clear that compromises have to be made which must balance patient acceptability (aesthetic) against unacceptability (irritancy). In addition, the upper limit for passive drug delivery will always be of the order of a few milligram per day and, therefore, only potent drugs can be used. Despite this, it is evident that the number of drugs that may be delivered via the transdermal route is increasing. In March, 2006 the US FDA approved a selegiline transdermal system,[24] the first transdermal treatment for major depressive disorder. Patches for the delivery of this active agent have been described.[25] A transdermal delivery system has successfully been used to deliver the dopamine receptor antagonist rotigotine for the treatment of patients with Parkinson disease.[26] It is a matrix system in which the drug is dissolved in a silicone adhesive.[27] The patch size varied from 10–60 cm2 depending on the severity of the disease. Ongoing clinical trials have shown clinical efficacy and Am J Drug Deliv 2006; 4 (3)

Passive Transdermal Drug Delivery Systems

Table III. Examples of multiple polymer transdermal drug delivery devices Product name

Matrix

Vivelle-Dot™

Estradiol, acrylic adhesive, silicone adhesive, oleyl alcohol, povidone, dipropylene glycol

Combipatch®

Estradiol, norethindrone acetate, acrylic adhesive, silicone adhesive, oleyl alcohol, oleic acid, povidone, dipropylene glycol

the device is under regulatory review. This presents a challenge as it is the first transdermal new chemical entity. However, a successful outcome should provide the impetus for other pharmaceutical companies to consider the transdermal route in the first instance. This may be particularly valuable for drugs designed to be used in the elderly, for children, or if the oral route is not desirable as, for example, in the case of antiemetics. 3.2 New Technologies

Aveva Drug Delivery Systems has recently developed a novel transdermal device based on the application of a crystal reservoir technology. This system is based on the oversaturation of an adhesive polymer with medication, thus forcing a partial crystallization of the drug. The presence of both molecular solute and solid crystal forms allow for a considerably higher concentration and consistent supply of drug in each patch. As the skin absorbs the dissolved drug, crystals re-dissolve to maintain the drug at its solubility limit (i.e. at maximum thermodynamic activity) at the site of contact. This could result in smaller thinner patches with better patient acceptability. Clinical trials with a transdermal formulation employing this technology and containing the β2-adrenergic agonist tulobuterol confirmed the superiority of the transdermal formulation of tulobuterol over oral formulations.[28] It is also possible to combine suspensions of the drug in multilayered matrix systems that can be designed to allow predetermined rates of drug delivery to the skin surface and, hence, control systemic levels of the drug. Examples of this have been shown for estradiol.[29] The development of ‘patchless patch’ technology by Acrux Ltd has resulted in an innovative dosage form – the metered dose transdermal spray (MDTS®). The technology is based on the delivery of a precise aerosolized dose of drug in solution to a defined area on the skin. The solution is formulated so that a volatile component evaporates leaving behind a concentrated solution of drug in a vehicle that is rapidly taken up into the outer layers of the skin. The drug is then released from this reservoir in the skin in a controlled way over a prolonged period.[30] © 2006 Adis Data Information BV. All rights reserved.

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4. Conclusions Throughout the past two decades, the transdermal patch has become a proven technology that offers a variety of significant clinical benefits over other dosage formulations. From the early complex patch designs, devices have now evolved towards simpler, matrix formulations. The transdermal drug delivery market is growing, and currently there are in excess of 35 products approved for sale in the US, and approximately 16 active ingredients approved for use in products globally. Future developments in the field should address problems relating to irritancy and sensitization, which currently excludes a number of therapeutic entities from delivery via this route. Finally, we expect that further innovations in matrix composition and formulation will further expand the number of candidate drugs available for transdermal delivery. With the recognition of the advantages of transdermal delivery, companies may be encouraged to design new chemical entities specifically for this route. The physicochemical properties that these should possess are known and screening techniques are becoming available to test potential skin toxicity. Undoubtedly the design of new drugs has resulted in more potent entities, which are prerequisite for TDS. Although this article has only considered passive delivery through the skin there will also be advances in the use of physical approaches such as iontophoresis and a number of interesting reviews on penetration enhancement via active delivery discuss these areas further;[6-8] however, any physical technology will be inherently more expensive than the more straightforward passive approach. Acknowledgments The authors have no conflicts of interest or sources of funding relevant to the content of this manuscript.

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© 2006 Adis Data Information BV. All rights reserved.

Correspondence and offprints: Dr Majella E. Lane, Department of Pharmaceutics, School of Pharmacy, University of London, 29-39 Brunswick Square, London, WC1N 1AX, UK. E-mail: [email protected]

Am J Drug Deliv 2006; 4 (3)