measuring adhesive performance in transdermal delivery systems

Am J Drug Deliv 2004; 2 (3): 193-206TECHNOLOGY TOOLS 1175-9038/04/0003-0193/$31.00/0

© 2004 Adis Data Information BV. All rights reserved.

Measuring Adhesive Performance in TransdermalDelivery SystemsPaola Minghetti, Francesco Cilurzo and Antonella Casiraghi

Institute of Pharmaceutical and Toxicological Chemistry, University of Milan, Milan, Italy

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1931. The Adhesive Properties of Transdermal Delivery Systems (TDSs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

1.1 Tack . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1971.2 Creep Resistance or Shear Adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1971.3 Peel Adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

2. Tests for Measuring TDS Adhesion Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982.1 Tack Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982.2 Creep Resistance or Shear Adhesion Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1992.3 Peel Adhesion Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

3. Application of Adhesion Tests to TDS Formulation Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2003.1 Additives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2003.2 Skin Penetration Enhancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2013.3 Active Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2013.4 Matrix Thickness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2013.5 Backing Layer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2013.6 Solvent Residue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

4. Significance of Adhesion Tests in Predicting TDS In Vivo Adhesive Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2025. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

The therapeutic performance of a transdermal delivery system (TDS) can be affected by the quality of contactAbstractbetween the patch and the skin. The adhesion of a TDS to the skin is obtained by using pressure-sensitiveadhesives (PSAs), which are defined as adhesives capable of bonding to surfaces with the application of lightpressure. The adhesive properties of a TDS can only be fully and correctly characterized by considering thefollowing factors: (i) the property that enables an adhesive to form a bond with the surface of another materialupon brief contact and under light pressure (tack); (ii) the resistance of the matrix to flow that could beconsidered as an expression of the cohesiveness of the matrix itself (creep resistance); and (iii) the force requiredto peel away a patch from a surface (peel adhesion). In this paper, attention is focused on the most widely usedmethods for the measurement of TDS adhesive properties in development studies and in the quality control ofTDSs. The most critical formulative variables in the development of TDSs are the type and concentration ofadditives used, the drug loaded, the PSA thickness, the composition and thickness of the backing layer, and thesolvent residue. There is a lack of evidence for a relationship between the results obtained in in vitro adhesiontests and the in vivo adhesion performance of TDSs. Therefore, an analysis of the percentage of TDSs that liftedand/or detached during pharmacokinetic and clinical studies should be performed during development studies.No official tests for adhesive strength are currently included in the TDS monographs of the most authoritativepharmacopeias. At present, the medical application of TDS relies on tests standardized by the adhesive tapeindustry or prescribed in the adhesive tape monographs of US and Japanese Pharmacopoeias, or adaptations ofthese. The development of new methods is recommended to meet the specific requirements of evaluating TDSs,and to improve the correlation between in vitro tests and in vivo performance.

194 Minghetti et al.

Transdermal delivery systems (TDSs) are self-adhesive dosage loids such as polyvidone (polyvinylpyrrolidone) and some cellu-forms that, when applied to intact skin, are designed to deliver the lose derivatives, because of their high moisture absorption anddrug through the skin to the systemic circulation. The same types water vapor permeability. These polymers can be used without anyof system are also used today to obtain local or regional effects. modification or they can contain one or more additives, whichThis increases the number of TDSs available on the market (table modify the adhesion of the PSA.I). In the development of a TDS, three main factors should be The most widely used approach to explain the adhesive proper-considered: the skin tolerability; percutaneous absorption of the ties of all PSAs is based on the belief that the PSA will adhere toactive ingredient; and adhesiveness. The TDS should not induce the substrate because of interatomic and intermolecular attractiveskin reactions, such as primary skin irritation and skin sensitiza- forces established at the interface, providing that intimate contacttion. Moreover, the strength of the adhesive bond should not be is effected. The material is able to deform sufficiently under slightsuch that the skin is damaged when the TDS is detached. Given pressure to obtain this degree of contact, hence the term ‘pressurethat the process of drug absorption is related to the drug partition sensitive’. Generally, the formation of an assembly is achieved bybetween the TDS and the skin, followed by the drug permeation means of a liquid-solid contact step; thus, the criterion for effec-process, complete skin contact over the entire delivery surface for tive adhesion is good wetting.[8] A PSA wets and spreads onto thethe entire treatment period is essential. If the patch remains at- adherend only when its surface energy is less than that of thetached throughout the selected period, the area of permeation is adherend. After the initial adhesion, the PSA/skin bond can bemaximized, allowing for the possible development of a smaller built by stronger interactions, which can depend on the skinand more aesthetically pleasing patch.[1] If the TDS lifts or partial- characteristics and its pathophysiologic conditions. In every case,ly detaches, the effective area of TDS/skin contact, and thus the the surface energy of the PSA must be equal to or less than that ofdrug absorption, is unpredictable and therapeutic failure can occur. human skin. Unless this condition is satisfied, a material cannotOnly a constant TDS/skin contact over the whole application adhere to skin. The skin surface energy is related to its hydrolipidicperiod allows a consistent delivery and absorption of the drug; if balance.the TDS fails to adhere, the cost-effectiveness ratio increases.[2]

Ginn and colleagues reported that the surface energy of clean,A cost-effectiveness analysis of two nitroglycerin (glyceryl dry human skin was about 28–29 dynes/cm and that this value

trinitrate) TDSs showed an estimated 14.5% saving in wholesale increased when the surface energy was measured on dirty orprescription costs for the patch that adhered to the skin for 94.8% unwashed skin.[9] A more recent study showed an increase ofof the application time, compared with the other patch, which had surface energy, ranging from 38 to 56 dynes/cm when the relativeonly 78.9% adherence.[4] Other studies showed that for nitroglyc- humidity and temperature of the skin increased.[10] Thus, in ordererin TDSs, patient preference and the cost-effectiveness analysis to guarantee adhesion of the PSA to the skin in all its physiologicare influenced by adhesion, tolerability characteristics, and the conditions, the surface energy of the PSA should be less than thecosmetic appearance of the TDS.[2,4-7] Hence, the therapeutic per- lowest critical surface tension value reported for the skin (28formance and the safety profile of TDSs are largely influenced by dynes/cm).[9]

the quality of contact between the TDS and the skin. The adhesion mechanisms are the result of complex phenome-na also involving the viscoelastic properties of PSAs. In fact,The adhesive polymers used in TDS formulations are pres-adhesion can be described as a combination of bonding andsure-sensitive adhesives (PSAs), defined as adhesives capable ofdebonding processes in which two primary mechanisms are in-bonding to surfaces with the application of light pressure and thatvolved: viscous flow, which operates by biased diffusion via freedo not leave any visible residue when detached. PSAs may bevolume; and elastic distortion, which stores free energy.[11]classified according to the physical form in which they are sup-

plied or according to their chemical structure. As far as the The evaluation of the thermodynamic and dynamic-mechanicalphysical form is concerned, PSAs fall into three broad product characteristics of the PSA in bulk, even if the effects of the activecategories: solvent based, water based, and hot melt. ingredient and other additives are studied, is not sufficient toSolvent-based PSAs are traditionally used in TDS production, predict the adhesive performance of the TDS.even though water-based and hot melt PSAs are less likely to According to the TDS design (figure 1), the PSA can be usedcause skin irritation and sensitization, and have reduced environ- simply to affix the TDS to the skin (multilayer matrix TDS ormental contamination risks. reservoir TDS), or as a carrier for the drug as well as to confer

The most widely used polymers are acrylics, which, because of adhesion properties (monolayer matrix TDS). In the former case,their low level of allergenicity, have largely replaced natural the PSA can be located around the edge of the TDS or berubber-based PSAs (polyisobutylenes). Other polymer types fre- laminated as a continuous adhesive layer on the TDS surface. Inquently used for TDSs include silicone-based PSAs, because of this case, as well as in the monolayer matrix TDS, the PSA shouldtheir high biocompatibility and drug diffusibility, and hydrocol- be compatible with the drug and other excipients. The presence of

© 2004 Adis Data Information BV. All rights reserved. Am J Drug Deliv 2004; 2 (3)

Measuring Transdermal Delivery System Adhesive Performance 195


Tab

le I.

Mai

n ch

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teris

tics

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mal

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s) m

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C =

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PV

P =

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(pol

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rrol

idon

e).


the drug/excipients in the PSA should also be carefully evaluated phenomenon is not particularly relevant in determining the effica-as this can modify the mechanical characteristics of the PSA and cy or the safety of the TDS as it is generally applied on the skinthe drug delivery rate. All the TDS components, including the with accuracy and low tack values can be acceptable.flexible backing layer and the release liner, which is removed

1.2 Creep Resistance or Shear Adhesionbefore use, can affect the adhesive performance.An ideal requirement of a TDS is that it should adhere strongly

Creep resistance or shear adhesion provides an indication of theto the skin, but be easily removed with no or little trauma.

cohesion of the matrix. This adhesion property is related to theMoreover, especially in monolayer TDSs, which are relatively

rheologic performance of the adhesive matrix. The matrix mustthick, the matrix should also be sufficiently cohesive so that the

exhibit an elastic cohesiveness and a resistance to flow underTDS will not move or ooze when applied in vivo, and can be

stress.[13] High creep compliance indicates a low cohesion of thepeeled away from the skin without leaving any residue. For the

matrix; in this case the TDS can ooze or leave adhesive residues onmatrix to behave in this way, it requires specialized and character-

its outside edges after application to the skin. In addition to beingistic rheologic properties; it should have sufficient compliance to

unsightly, these residues can collect dirt and stick to clothing or toconform to surface rugosity and undergo relaxation so that thestored energy from elastic forces is dissipated before overcomingthe forces of adhesion.

In this paper, the adhesive properties of PSAs are brieflydescribed. Attention is focused on the most widely used methodsfor the measurement of the adhesive properties of TDSs, theirapplication to formulation studies, and their significance for invivo TDS performance.

1. The Adhesive Properties of Transdermal DeliverySystems (TDSs)

The adhesion of a TDS to the skin is the result of complexphenomena. Therefore, in order to assess the adhesive propertiesof a TDS, the following information should be determined: (i) theproperty that enables an adhesive to form a bond with the surfaceof another material upon brief contact and under light pressure(tack); (ii) the resistance of the matrix to flow (creep resistance orshear adhesion); and (iii) the force required to peel away a patchfrom a surface (peel adhesion).

1.1 Tack

Tack is the adhesive property related to the immediacy of thebond under low contact pressure between the TDS and the surfaceof another material (adherend); it could also be defined as quickstick, initial adhesion, or stickiness.

Tack involves molecular interactions at the adhesive/adherendinterface. If the surface energy and adhesive/adherend molecularinteraction provide the potential force of the adhesion work, thematrix rheologic properties, in particular the viscoelastic proper-ties, generally determine the rate and extent of the initial bondstrength. The matrix must be easily deformed in a very short time,usually in the order of a fraction of second, to have good tack.Tack is greater when an adhesive has the ability to distribute stressthroughout its volume.[12]

Tack plays an important role only when adhesion onto a partic-ular adherend has to form very rapidly. In the case of TDSs, the

Backing layer

Membranecontrolling thedrug diffusion Adhesive layer

Reservoir containing the drug

Membranecontrolling thedrug diffusion

Backing layer

Adhesive layer

Reservoir containing the drug

Backing layer

Matrixcontaining the drug

Adhesive layer

Backing layer

Adhesive matrix containing the drug

a

b

c d

e

Fig. 1. Cross-sectional representation of transdermal delivery system de-signs: (a) reservoir system; (b) peripheral adhesive reservoir system; (c)bilayer matrix system; (d) peripheral adhesive matrix system; and (e) mon-olayer matrix system.



cohesion of the matrix and of its adhesion to the backing layer(figure 2). When the patch is peeled away, it is expected that it willstrip cleanly from the adherend, leaving no visually noticeableresidue. If this fails to occur, this type of failure is an adhesivefailure (case I). If the matrix has not completely adhered to thebacking layer, it may transfer to the adherend, leaving no matrixon the backing layer itself (case II). In case III, the matrix has goodadhesive strength but poor cohesive strength. Case IV is a combi-nation of adhesive and cohesive failure at the same time. Failuresother than case I are usually considered a sign of faulty TDSformulation.

2. Tests for Measuring TDS Adhesion Properties

The tests used in the pharmaceutical field to characterize TDSadhesive performance come from standard procedures developedby the major interested associations in the adhesive tape industryand label industry, and by standard development organizations1.

Case I Case II

Case III Case IV

Backing layerMatrixAdherend

Fig. 2. Transdermal delivery system modes of failure. Cases I and II:adhesive failures; case III: cohesive failure; and case IV: adhesive/cohe-sive failure.

2.1 Tack Testsanother part of the body. Also, a TDS worn on a juncture may

It is difficult to measure how quickly an adhesive achieves itsmove, altering the drug-release kinetics.optimum adhesion. Hence, the tack tests developed to date mea-sure the force of debonding after a short period of contact under1.3 Peel Adhesionlow pressure.

Resistance to peel, called peel adhesion or peel force, is one of Tack tests can be classified into three different groups: (i)the most frequently measured characteristics of TDSs. Peeling is rolling-ball tack tests, when the bond-making and bond-breakingmore than just a test; it is an essential attribute of TDSs. It is well process take place simultaneously;[16-18] (ii) probe tack tests, whereknown that pain increases with an increase in the peel adhesion of a probe touches the adhesive surface with a light pressure and thea TDS. In a study by Chivers, a relationship between peel force force required to break the bond after a short period of contact isfrom the skin and blood perfusion, measured by laser-Doppler measured;[19,20] and (iii) tack tests similar to peel tests, performedperfusion imaging, was found.[14] upon the application of light pressure, such as quick stick[21-23] and

loop tack tests.[24-29]Peel resistance does not necessarily relate to the intrinsic adhe-sive performance and it should not be assumed to be an expression The rolling-ball test is the oldest tack test and is based on theof the strength of an adhesive bond. The force required to remove use of a stainless steel ball rolled down an inclined track andthe TDS is considerably higher than the force that holds the TDS in coming into contact at the bottom with a horizontal, upward-facingplace. This is because during removal a part of the force is required TDS matrix (figure 3). The distance the ball travels out along theto extend the matrix and the backing layer prior to the separation adhesive is taken as a measure of tack. The greater the distance, theand bending of the backing layer.[15] Although a medical PSA less tacky the TDS. Variations of this test include the Douglas test,must stick securely to the skin, it is essential that the TDS can be where a radius quarter circle ramp is used instead of the inclinedremoved easily and painlessly after a predefined time without track, and the Dow method, in which a series of steel balls withcausing damage to the skin. Removal involves the work done in different diameters are rolled over the adhesive surface mountedthe extension of the adhesive, in the distortion of the backing on an inclined track.[15] Although the test is very simple and hasduring the stripping action, and in the separation of the adhesive/ gained universal approval as a quality control tool for tapes, it doessurface interface, the last being the weakest of the three. not appear suitable for TDSs because they are generally character-

ized by low tack values.[30]When a TDS, or an adhesive tape in general, is peeled awayfrom a rigid surface, it can debond with different modes of failure. The precursor of the probe tack tests is the qualitative thumbThere are four different types of failures that are an index of the tack test.[3,12] The thumb is lightly put into contact with a sample

1 These organizations include the Pressure Sensitive Testing Council (PSTC), the European Association for the Self-Adhesive Tape Industry(AFERA), Tag and Label Manufacturers Industries (TLMI), the Worldwide Association for Self-Adhesive Labels and Related Products (FINAT), theAmerican Society of Testing Materials (ASTM), and the European Committee for Standardization (CEN).



for a short time and then quickly withdrawn. By varying thepressure and time of contact and noting the difficulty of pulling thethumb from the TDS, it is possible to perceive how easily, quicklyand strongly the matrix can form a bond with the skin. Some majordrawbacks of the thumb tack test are its subjectivity and the factthat the data are poorly quantifiable. However, it is the mostsimple and straightforward test for the evaluation of adhesive-skinbonding. The probe tack tests, which allow a quantitative measure-ment of this property, have been developed in an attempt to refinethe thumb tack test. Such methods measure only the maximumdetachment force, which is not sufficient to describe the initialadhesion phenomenon. As an alternative, texture analyzers can beused,[31] permitting the characterization of the entire debondingprocess by using a spherical or flat punch (figure 4).[32] Relevantparameters that can be determined to characterize the tack are the Fig. 4. Probe tack apparatus (flat punch).maximum nominal stress (σ), the maximum nominal strain (εmax)and the adhesion energy (Wadh), defined as the integral under the a direction parallel to the surface to which it has been affixed. Thestress-strain curve. Analysis of the entire debonding process pro- designed methods can be divided into dynamic and static tests. Invides some information on the viscoelastic behavior and cohesive- the dynamic tests, the specimen is pulled from the adherend at aness of the matrix as well as the tack strength.[33]

constant rate and the shear adhesion is assumed to be the maxi-The quick stick test and the loop tack test employ the same mum detachment force.[34,35]

instrument as the peel adhesion test and are therefore quite fre- In the static tests, the force required to pull the TDS is measuredquently used. The loop tack test consists of making a loop by in terms of the time required to remove the standard area of theclamping the ends of the TDS strip, bringing it into light contact TDS from the adherend plate under a standard load (figure 5), or aswith a rigid surface and then removing it from the surface. The the maximum load that can be applied to the specimen that doespeel force required to remove the TDS loop is taken as an indica- not cause the specimen to slip more than a stated amount within ation of tack. given length of time.[36-41] The adherend plate should be placed at

The principles of the quick stick test are basically the same as a an angle of 2° from vertical, thus minimizing the tendency for the90° peel adhesion test, described in section 2.3. The main differ- adhesive to peel from the surface. In shear adhesion tests, theence is that the adhesive strip is applied to the plate by exerting no adhesive should fail cohesively, leaving an adhesive layer on bothexternal pressure other than the weight of the strip itself. the adherend plate and the backing layer. Only when this mode of

failure occurs can the result be considered a true measure of the2.2 Creep Resistance or Shear Adhesion Tests internal strength of the adhesive.

The methods used for measuring shear adhesion permit the2.3 Peel Adhesion Testsdetermination of the force required to pull a standard area of a TDS

from a standard flat surface (adherend plate), e.g. stainless steel, inPeel adhesion can be measured by carrying out two different

categories of tests, dynamic and static. Dynamic peel tests use aforce applied at a given rate of speed and the results are reported inforce per unit of area.[42-49] Static peel is measured by applying afixed weight and reporting the time to failure.[50,51]

The choice of method for evaluating peel adhesion depends onthe type of stress applied in the specific application. In the case of aTDS, as the patch is peeled away from the skin, the dynamic peeltest should be used (figure 6). An exhaustive comparison of themethods proposed by the adhesive tape associations is reported byMuny.[52] For this discussion, it is sufficient to know that in all thestandardized tests a TDS strip is applied to a standard test plate(adherend plate), generally made of stainless steel, using a definedpressure to make the contact. After a predetermined time, the strip

Fig. 3. Rolling-ball apparatus used to measure tack. TDS = transdermaldelivery system.



• the type and concentration of additives used for improving theadhesion properties;

• the thickness of the matrix;

• the type and concentration of the drug loaded;

• the type and concentration of the enhancers eventually intro-duced;

• the composition and thickness of the backing layer; and

• the solvent residue.

3.1 Additives

Additives can be necessary in the polymeric matrix to conferadhesion when a nonadhesive polymer is used, to modulate theadhesive properties of a PSA, to plasticize a matrix that appearstoo brittle, or to increase the cohesion of the matrix. Thus, in allFig. 5. Creep resistance apparatus. TDS = transdermal delivery system.

these cases the effects of these excipients, which can be polymersas well as low molecular weight molecules, should be evaluated.is removed from the plate at a specified angle (180° or 90°) and

The effects of plasticizers on the adhesion strength ofspeed (300 mm/min).poly(butyl) methacrylate, (2-dimethylaminoethyl)methacrylateThe 180° peel adhesion test measures a combination of tensilemethyl methacrylate) [PAMA] films plasticized with triacetinand shear stresses, while the 90° peel adhesion test measures onlyhave been investigated.[54] The addition of a secondary plasticizertensile stresses. Therefore, the results of the two tests are nothad an effect on the peel adhesion properties, depending on itscomparable. In any case, the 90° peel is generally restricted tochemical structure and molecular weight. In particular, low molec-those backings that cannot be adequately bent through the 180°ular weight polyethylene glycol (PEG) and glycerol (glycerin)angle.increased the adhesion strength, while the addition of high molec-Part of the energy of the peel goes into flexing the patchular weight PEG did not affect the peel resistance when added tothrough 180° and part is also giving the patch a slight extension.PAMA. Isopropyl myristate decreased the adhesion strength, de-The backing layer characteristics, especially, and the matrix thick-pending on the amount loaded in the matrix,[54] while oleic acidness can affect the test angle, and the energy required to flex theincreased the adhesion strength.[55] Based on these results, Lin andpatch through 180° can be greater than the energy required to stripcolleagues concluded that when PAMA was used, the addition of athe adhesive from the test surface. To reduce the influence of theplasticizer with a high molecular weight and low solubility param-backing material, especially when the elongation of the film is soeter decreased the film adhesion strength.[54,55]evident that the test is compromised, it is possible to reinforce the

In gelatin-based matrices, glycerol did not significantly affectTDS with a rigid tape applied to its back.[3,53] This permits evalua-the peel strength. Increasing the propylene glycol in the matrixtion of the effect of the matrix on the peel process and sets asignificantly increased the initial peak stress registered during thequality control test. In the development of a peel adhesion test, ittest.[56]should also be considered that the PSA matrix builds its 3-dimen-

The addition of polyvidone to polymethylmethacrylate plasti-sional network by forming intermolecular bonds over time; conse-cized with PEG 400 and glycerol improved creep resistancequently, the adhesion of many PSAs, such as acrylics and sili-40-fold and reduced peel adhesion. The significant increase incones, can change in the first 1 or 2 weeks after preparation of thematrix cohesion was a result of attractive interactions between theTDS (figure 7). Therefore, it may be worthwhile exploring the

impact of the matrix stabilization by repeating the adhesion testover various time intervals.

3. Application of Adhesion Tests to TDSFormulation Studies

The literature reports the effects of the formulative variablesthat influence the adhesive properties of the monolayer TDS, themost widely used design for transdermal systems. Among theformulative variables in the development of these systems, themost critical are: Fig. 6. Peel adhesion test at (a) 90° and (b) 180°.



amide group of polyvidone and the carboxylic acid group ofpolymethylmethacrylate.[57]

3.2 Skin Penetration Enhancers

The effect of skin penetration enhancers on adhesion propertiesof different TDS matrices has also been studied both in vitro and invivo.[58] The use of isopropyl myristate and silicone PSA allowedthe matrix to flow easily and this permitted a rapid wetting of theskin, which increased the initial peel strength and reduced thecohesion strength.

The addition of sodium laurilsulfate or dimethyl sulfoxide topoly(isobutylene) PSA decreased both glass transition and peelstrength, indicating a trade off between the enhancer activity of thetwo molecules and the adhesive properties of the PSA.[59] Thesame pattern was found with methyl laurate[60] and sorbitan fatty

200

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180

170

160

150

140

130

120

110

100

90

80

0 4 8 12 16 20 24

Days

Pee

l adh

esio

n (g

/cm

)

Fig. 7. Effect of the storage time on the peel strength on a Teflon® (Du-Pont) plate of a transdermal delivery system (TDS) prepared by using asilicone pressure-sensitive adhesive (PSA) [BIO-PSA 7-4302, Dow Corn-ing] and Scotchpak™ 1220 (3M) as the backing layer (unpublished data).

ester acid (Arlacel® 80) 2.[61] The addition of diethylenglycolmonoethyl ether (Transcutol®) to the same acrylic matrices caused

the thickness of both placebo- and miconazole-nitrate-loaded mat-an opposite effect.[61]

rices until a maximum value was reached (figure 9b).[65] Thisresulted from the 2-fold effect of the PSA thickness on the peel

3.3 Active Drugforce. The thicker PSA increased the volume of the matrix underdeformation, thereby increasing the peel force. At the same time,The drug itself can cause unpredictable alterations to adhesivethe total thickness of the TDS increased, causing a reduction in theproperties. For example, the loading of piroxicam[55] andpeel force because of the increased angle and consequently of theketoprofen[62] caused a reduction in the peel adhesion strength inmoment arm, which reduced the work required to detach the TDSmethacrylic matrices. This is because of an antiplasticizing effectfrom the adherend. When the matrix thickness reached a certainthat probably increased the glass transition of the PSA and, thus,critical value, at which the PSA deformation in the crack area wasreduced the peel strength. The effect of piroxicam on the PAMAsufficiently large, the effect of a further thickness increase was nomatrices was counterbalanced by the authors increasing thelonger noticeable.amount of plasticizer loaded in the matrix.[55] This decreased the

The matrix thickness also affects the creep resistance. Theattractive interactions between the drug and the polymer, andexponential relationship between the creep resistance and theconsequently increased the adhesion strength of the piroxicam-adhesive layer thickness has been shown for many PSAs.[65,67]loaded PAMA matrix (figure 8). In analogous matrices, coumarinThis may be explained by the fact that when the matrix weightdid not significantly affect the peel adhesion of the TDS,[63]

increases, its cohesion decreases because of a higher number ofindicating a nonsignificant interaction between the drug and theshearing layers (figure 9a).PSA. Miconazole nitrate loaded in the same matrices did not

The simultaneous effects of the adhesive type, the type andsignificantly affect peel adhesion,[64] but it did cause a significantconcentration of additives, and the matrix thickness on the adhe-decrease in shear adhesion values.[65] The effect of miconazolesive properties were investigated by using factorial design in ordernitrate on the shear adhesion value (figure 9a) was explained byto verify possible secondary interactions that can occur among thethe fact that the addition of low molecular weight molecules, suchmain tested variables.[57-61,68]as miconazole nitrate, could reduce the number of entanglements

among the copolymer chains and increase the flow.[65]

3.5 Backing Layer3.4 Matrix Thickness

During the detachment process of removing a TDS, stress isThe matrix thickness influences both the peel adhesion and the transmitted through the adhesive matrix to the backing layer.

creep resistance of the TDS, but in different ways. Peel adhesion Thus, the composition, which affects flexibility and elongation,increases with an increase in adhesive thickness[60,61,66] and levels and the thickness of the backing layer itself can affect detachment.off at a certain thickness.[66] As an example, in the case of As the backing layer thickness and/or rigidity increase, the energymethacrylic matrices, peel adhesion was increased by increasing required to deform the backing layer itself increases, but at the

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



0

6

12

18

24

30

0 1 2 3 4 5 6 0 1 2 3 4 5 6 0 1 2 3 4 5 6 0 1 2 3 4 5 6

PG

Adh

esio

n st

reng

th (

g/cm

)Placebo matricesPiroxicam-loaded matrices

PEG 200 OADEP

Plasticizer added (%, w/w)

Fig. 8. Effect of various plasticizers and piroxicam on the peel adhesion of a polyaminomethylmethacrylate-based transdermal delivery system (repro-duced from Lin et al.,[55] with permission from Elsevier). DEP = diethyl phthalate; OA = oleic acid; PEG 200 = polyethylene glycol 200; PG = propyleneglycol.

same time the strip used in the peel test forms a larger moment 4. Significance of Adhesion Tests in Predicting TDS Inarm. This results in a lower peel force and counteracts the energy Vivo Adhesive Performancedissipated in the backing layer deformation.[66] For example, in thecase of methacrylic PSAs, the use of two different backing layers, Medical PSAs are designed for use on human skin, which is asuch as a rayon acetate tissue (artificial silk) and a polyurethane highly nonlinear and extremely compliant substrate. In TDS de-film, modified the adhesive performance of the patch. The artifi- velopment, the in vivo performance of the adhesive layer should becial silk, which is thicker and less flexible than polyurethane film, evaluated. The performance in vivo is estimated by scoring sys-decreased the peel adhesion values of patches based on tems based on the patient’s observations of the permanence of themethacrylic co-polymers by about 4-fold.[3]

patch, the behavior during detachment and other subjective con-siderations.

3.6 Solvent ResidueConsidering that TDSs have been on the market from more than

two decades, it is surprising that PSA/skin contact has only beenIn some cases, water residue in TDSs prepared from water-scantily studied to date.[14,58,72,73] Indeed, in vitro adhesion valuesbased polymers, which are being used with increasing frequency,of TDSs and their corresponding in vivo performances have beencan affect the peel adhesion and the creep resistance.[69] In general,reported in few papers. The lack of such studies could be justifiedmatrices based on acrylic derivatives are affected by water residue,considering the high costs involved. Fauth et al. focused theirwhich can cause a decrease in peel strength,[70,71] while in the caseattention on the possible correlation between the peel adhesionof methacrylic matrices, the peel strength increases as the moisturevalues, determined in vitro by using a stainless steel plate, and thecontent increases in the considered range.[65] Water content hasin vivo performance of a TDS used in transdermal estrogen ther-also been shown to affect the TDS shear adhesion (figure 10).[65]

apy.[74] They concluded that no correlation existed. The lack ofThe initial increase in creep resistance was attributed to a reduc-correlation could be attributed to the differences in the interfacetion in the hardness of the matrix, with a consequent improvedbetween the TDS and the skin versus the TDS and the stainlessadherence of the TDS to the adherend. A further increase in thesteel plate. Indeed, the surface energy of clean skin (28–29 dynes/flexibility of the polymeric chains caused a linear reduction incm)[9] is lower than that of stainless steel (40 dynes/cm).[3] Increep resistance until a minimum was reached; increasing theaddition, skin is rough while stainless steel is smooth, and skin iswater content beyond this point did not further decrease shearflexible while stainless steel is stiff. Furthermore, some compo-performance. Therefore, moisture content should also be strictlynents of the skin surface can be absorbed by the TDS matrix,investigated because when a TDS is applied in vivo, it is subjectedaccording to their compatibility with the PSA, and this mayto moisture either from physiologic origins (e.g. transepidermalinfluence the adhesive performance of the PSA itself.water loss) or from environmental origins (e.g. washing).



In order to improve the in vivo significance of the in vitro tests,the differences between the adherents reported above should beconsidered. The parameters frequently modified in the peel andcreep tests are the adherend material and/or the speed of removal.The adherend materials should have a surface energy close to thatof clean skin so that the TDS matrix wets the skin surface in all itspossible physiologic conditions. This approach was also supportedby US and Japanese monographs concerning adhesive tape thatindicate a preference for plastic materials over stainless steel as amaterial for the adherend plate.[35,49] Some authors proposedplastic materials with a critical surface tension closer to that ofclean skin than stainless steel, such as polyethylene[3] andTeflon®.[75] Moreover, a collagen-coated plate was also proposed

250

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50

04.0 4.5 5.0 5.5 6.0 6.5

Water content (mg/cm2)

Cre

ep r

esis

tanc

e (m

in)

Patch I

Patch II

Patch III

Patch IV

Patch VPatch VI

Fig. 10. Effect of the water content on the creep resistance of apolymethylmethacrylate-based transdermal delivery system (reproducedfrom Minghetti et al.,[65] with permission from Maccari Editore).in order to evaluate the effect of relative humidity, which changes

the surface energy of the skin.[30]

In the evaluation of the TDS during detachment from the skin,As far as the speed of removal is concerned, as well as the 300 other peculiarities of such a substrate should be considered. When

mm/min proposed by adhesion tapes associations, 100 mm/min is a TDS is removed from the skin, considerable skin deformationalso used as it represents the patch removal rate from the skin.[63]

can be seen as a result of its extension (figure 11).[73] Thus, whenthe peel test is performed by using the skin as a substrate, the workexpended in the TDS detachment includes the deformation of theskin itself as well as separating the TDS from the surface, de-forming the adhesive layer, and stretching and bending the TDS.The force required to achieve the maximum extension, which isgenerally quite low (1.7N), depends on the peel contact angle.[14]

Nevertheless, such a deformation might be harmful to a healingwound. Therefore, skin deformation should probably be mini-mized when peeling a TDS.

Venkatraman and Gale[76] compared some data regarding thecreep compliance of several acrylic polymers measured in vitrowith the results of peel adhesion determined in vivo. They did notfind any correlation between the measured creep compliance andthe peel adhesion from skin.

More studies are necessary to correlate skin performance withadhesive properties. Nevertheless, analysis of the cohesive proper-ties of the TDS matrix in vitro is useful for comparing the in vivoperformances of different formulations. Minghetti et al.[63] showedthat the analysis of intra-assay standard deviations of the peeladhesion pattern determined in vitro is a useful indication of the invivo performance in the case of methacrylic matrices, at least forevaluation of the behavior during detachment. In fact, TDSs withhigh intra-assay standard deviations (coefficient of variance>10%), when applied in vivo, oozed leaving adhesive residue onthe edges of the patch and left visible residue when detached,especially when the duration of application was prolonged.

5. Conclusions

The adhesive properties of TDSs are a critical factor determin-ing their safety, drug delivery, therapeutic effect and patient com-pliance.

1400

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Pee

l adh

esio

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MIC-loaded patchesPlacebo patches

a

b

MIC-loaded patchesPlacebo patches

3Patches

21 4 5 6

Fig. 9. Effect of the matrix thickness and miconazole nitrate (MIC) on (a)the creep resistance and (b) the peel adhesion of a polymethylmethacry-late-based transdermal delivery system (reproduced from Minghetti etal.,[65] with permission from Maccari Editore).



TDSs, and to improve the correlation between in vitro tests and invivo performance.

Acknowledgment

The authors have provided no information on sources of funding or onconflicts of interest directly relevant to the content of this review.

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nitroglycerin adhesive patch formulation. Clin Ther 1989; 11: 225-312. Powers Cramer M, Saks SR. Translating safety, efficacy and compliance into

economic value for controlled release dosage forms. Pharmacoeconomics 1994;5 (6): 482-504

3. Minghetti P, Cilurzo F, Montanari L. Evaluation of adhesive properties of patchesbased on acrylic matrices. Drug Dev Ind Pharm 1999; 25 (1): 1-6

4. Hay JW, Hill WL. Cost-effectiveness of two transdermal nitroglycerin control-release systems. Clin Ther 1985; 8 (1): 35-40

5. Cronin CM, Mitrano EA, Wilder RS, et al. Comparative evaluation of the threecommercially available transdermal nitroglycerin delivery systems. Drug IntellClin Pharm 1987; 21: 642-4

6. Chinoy DA, Breaux PC, Ibrahim F. Comparison of adhesive properties of twotransdermal nitroglycerin controlled-release systems. Clin Ther 1985; 8: 30-4

7. Chinoy DA, Camp J, Elchahal S, et al. A multicenter comparison of adhesion,preference, tolerability, and safety characteristics of two transdermal nitroglyc-erin delivery systems: Transderm-Nitro™ and Deponit™. Clin Ther 1989; 11:678-84

8. Shultz J, Nardin M. Theories and mechanisms of adhesion. In: Pizzi A, Mittal KL,editors. Handbook of adhesive technology. New York: Marcel Dekker Inc.,1994: 19-34

9. Ginn ME, Noyes CM, Jungermann E. The contact angle of water on viable humanskin. J Colloid Interface Sci 1968; 26 (2): 146-51

10. Kenney JF, Haddok TH, Sun RL, et al. Medical-grade acrylic adhesives for skincontact. J Appl Polym Sci 1992; 45: 355-61

a

b

Fig. 11. Photograph of a nonwoven adhesive patch being peeled from: (a)a rigid plate; and (b) the forearm of a volunteer (reproduced from Steven-Fountain et al.,[73] with permission from Elsevier).

11. Rohn CL. Rheology of pressure sensitive adhesives. In: Satas D, editor. Handbookof pressure sensitive adhesive technology. 3rd ed. Warwick (RI): Satas &Associates, 1999: 153-70There are a number of factors that affect the adhesive quality of

12. Hammond FH. Tack. In: Satas D, editor. Handbook of pressure sensitive adhesivea TDS. To measure the strength of the joint formed between thetechnology. 2nd ed. New York: Van Nostrand Reinhold, 1989: 38-60

TDS and the adherend, three fundamental adhesive properties 13. Dalhquist CA. Creep. In: Satas D, editor. Handbook of pressure sensitive adhesivetechnology. 3rd ed. Warwick (RI): Satas & Associates, 1999: 121-38have to be determined: tack, creep resistance or shear adhesion and

14. Chivers RA. Easy removal of pressure sensitive adhesives for skin applications. Intpeel adhesion. It is essential that a suitable test is selected for theJ Adhesion Adhesives 2001; 21: 381-8

determination of each property and that care is exercised in con- 15. Johnston J. Testing: general and specific. In: Johnston J, editor. Pressure sensitiveadhesive tapes. Illinois: Pressure Sensitive Tape Council, 2003: 153-78ducting the test. Considerable background knowledge is required

16. Pressure Sensitive Tape Council. PSTC-6 Tack rolling ball, revised 6/00. In: Testto properly interpret the results.methods for pressure sensitive adhesive tapes. 13th ed. Stonebridge Lane (IL):

The evaluation of these physical properties by standard tests Pressure Sensitive Tape Council, 2000: 35-617. American Society of Testing Materials. ASTM D3121-94 (1999) Standard testrates TDS characteristics, but there are no true indications of how

method for tack of pressure-sensitive adhesive by rolling ball [online]. Availa-well the TDS will perform in its intended use. Hence, an analysis ble from URL: http://www.astm.org/cgi-bin/SoftCart.exe/COMMIT/SUB-

COMMIT/D1450.htm?.L+mystore+pixb8154+1058469002 [Accessed 2003of the percentage of TDSs that lifted and/or detached duringJul 17]pharmacokinetic and clinical studies should be performed during

18. European Committee for Standardization. EN 1721:1998 Adhesives for paper anddevelopment studies. board, packaging and disposable sanitary products: tack measurement for

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