Skin adhesives and skin adhesion: 1. Transdermal drug delivery systems

Biomaterials 19 (1998) 1119—1136

Review

Skin adhesives and skin adhesion1. Transdermal drug delivery systems

Subbu Venkatraman*, Robert Gale

ALZA Corporation, 950 Page Mill Road, P.O. Box 10950, Palo Alto, CA 94303-0802, USA

Received 19 November 1997; accepted 8 January 1998

Abstract

The use of pressure-sensitive adhesives (PSAs) for skin-contact applications is discussed. The requirements of such adhesives invarious applications are examined in detail. Commercially available classes of PSAs used for skin-contact applications are theacrylics, the polyisobutylenes, and the silicones. The main application examined in this review is transdermal drug delivery. The rolesplayed by the PSA in two types of transdermal designs are described. Correlations between in vivo and ex vivo measurements ofadhesion are discussed. Also, the reported human studies of various commercially available transdermals are examined critically, witha view to assessing the relative performance capabilities of each type of transdermal design. Finally, a comprehensive listing ofcurrently commercialized transdermals is given. ( 1998 Elsevier Science Ltd. All rights reserved

Keywords: Skin adhesion; Adhesives; Transdermal drug delivery; Acrylics; Silicones; Polyisobutylenes

1. Introduction

Adhesives that attach to human skin have been knownsince the days of bandages. The earliest materials used inhospital tapes were natural-rubber based, but these havebeen superseded by synthetic materials. The syntheticswere developed not specifically for skin contact but forindustrial applications such as automobile decals or fordetachable labels. The first skin-contact adhesive ap-plication of any volume was perhaps the use of pressure-sensitive adhesives in bandages, which dates back to1899, with Johnson & Johnson’s introduction of hospitaltapes with adhesive attached. More recent applicationshave been for transdermal drug delivery systems or forattachment of medical devices to skin for EKG or ECGmeasurements. This review will focus on the followingtopics:

1. Fundamentals of skin adhesion.2. Applications of pressure-sensitive skin adhesives.3. Requirements of adhesives in different applications.

*Corresponding author. Fax: (650)496-8299.

4. Commercially available materials for skin adhesives.5. Testing of skin adhesives.6. Relationship of ex vivo testing to in vivo testing.7. Commercial transdermal systems.8. Future needs.This review is intended to provide an overview of the

applications of pressure-sensitive adhesives (PSAs) in themedical field involving skin contact; thus, areas such ascosmetic/make-up masks and depilatories will not beaddressed, even though skin-contacting PSAs are used inthese applications.

2. Fundamentals of skin adhesion

For any adhesive to adhere to a substrate, one funda-mental thermodynamic requirement has to be satisfiedfirst: the measured surface energy of the adhesive must beequal to or less than that of the adherend, or human skin inthis case. Unless this condition is satisfied, a materialcannot adhere to skin. However, this is a necessary butnot sufficient condition for adhesion. The other require-ments for adhesion are kinetic in nature, involving wet-ting rates and viscoelasticity of the adhesive.

0142-9612/98/$19.00 ( 1998 Elsevier Science Ltd. All rights reserved.PII S 0 1 4 2 - 9 6 1 2 ( 9 8 ) 0 0 0 2 0 - 9

Fig. 1. Schematic cross-section of the uppermost layers of human skin,showing the stratum corneum, the epidermis and the dermis, along withsweat glands and hair follicles.

Table 1

Polymer Critical surface tension @ 20°C Surface tension (temp. of How measured/(Ref.)mNm~1(dyn cm~1) measurement) nNm~1(dyn cm~1)

Polytetrafluoroethylene (TeflonT) 18 9.4 (180°C) Wilhemy plate/[5]High density polyethylene 31 26.5 (180°C) Pendant drop/[6]Polyethylene terephthalate 43 27.0 (290°C) Rotating bubble/[7]Poly vinyl alcohol 37 N/APoly vinyl chloride 40 N/A

Source: Adhesion and Bonding, N.M. Bikales (ed.), Wiley-Interscience, 1971. Also in Ref. [5].

2.1. Measurements of surface energy of skin

Older measurements of skin surface energies [1, 2]were actually measurements of the critical contact anglefor skin. This measurement usually involves the deter-mination of equilibrium contact angles, on a given sub-strate or adherend, for a series of liquids (usually binarymixtures) of different surface tensions, and extrapolatingto zero contact angle. Using this technique, the surfaceenergy (or to put it more accurately, the critical surfacetension) of clean, dry human skin (in vivo) was measuredto be about 28—29 dyn cm~1. These workers noted sub-stantial increases in this number if applied to dirty orunwashed skin.

As is well-known, the outermost layer of skin is a thinlayer called the stratum corneum (see Fig. 1 for details).This layer is known to consist of both lipophilic andhydrophilic domains, as well as hair follicles and sweatglands. The hydrophilic region consists mostly of keratin.In the normal state, the stratum corneum has a watercontent of approximately 20%, which lies mainly in thekeratin layers between the horny cells. The horny cellsthemselves contain lipids in which keratin filaments aredispersed. The keratin is cross-linked tightly by about

20%, which accounts for its relatively rigid and imperme-able structure. The elasticity of the skin itself is related tothe water content and age; older people generally tend tohave drier and less elastic skin. Conversely, skin that hasbeen made to take up more than its usual amount ofwater (by excessive sweating under an impermeabletransdermal patch, for example) tends to be more elastic.

Schematically, the stratum corneum is often describedin terms of a brick-and-mortar structure, wherein thebricks are thought to be the (relatively impermeable)keratin regions whereas the mortar is the losser, morepermeable lipid domain. For the discussion of surfaceproperties and of adhesion, it is sufficient to think ofclean and dry skin as mostly lipophilic (low surfaceenergy) and wet or unclean skin as being more hydro-philic, having higher surface energy.

Thus, the surface energy values of clean, dry skinreflect its dominant lipophilicity. The fact that morepolar materials such as hydrogels may also adhere toskin (although seldom as strongly as lipophilic PSAs)may be due in part to the skin being somewhat ‘wet’ andperhaps also due to the presence of hair follicles andsweat glands, which contain aqueous channels.

Other, more recent measurements [3] also use thesame technique of a binary liquid mixture, but moresophisticated measuring apparatus, such as the Rame-Hart NRL contact-angle goniometer. Here, surface ener-gies are calculated, rather than the critical surfacetension. The measurements show an increase of surfaceenergy with increases in relative humidity and temper-ature of the skin. The range measured is from 38 to56 dyn cm~1; no mention of any surface preparation ofskin is given.

2.2. Measurements of surface energies of PSAs

The Rame-Hart NRL contact-angle goniometer hasbeen used to measure the critical surface tensions (CST)of PSAs [3]. In general, there are very few reportedmeasurements of CSTs of pressure-sensitive adhesives.

Another measurement reported is by one of the au-thors and his former colleagues at Cygnus, Inc. [4]. Theyused the method of advancing and receding contactangles on a stainless-steel substrate coated with the PSAof interest. Although the apparatus used was custom-

1120 S. Venkatraman, R. Gale / Biomaterials 19 (1998) 1119—1136

Table 2

Adhesive Critical surface How measured Ref.tensionmNm~1(dyn cm~1)

Poly (dimethyl 22 Advancing & [4]siloxane) PSA receding angles

Polyacrylate PSA 27—42! Rame-Hart [3]contact angle

Polyisobutylene 30—32 Advancing & [4](PIB)#polybutene receding angles(PB) PSA

! The values are for a copolymer of n-butyl acrylate and acrylic acid,with values increasing as AA content.

made, commercial instruments using the same approachare available (Cahn Instruments, Cerritos, California,USA). Tables 1 and 2 list the CSTs or surface energies ofsome commonly used polymers and PSA materials.

As is evident from the tables, the silicones, the acrylatesand the polyisobutylenes satisfy the thermoynamic cri-terion for adhesion to clean, dry skin. As the surfaceenergy of unclean, wet skin is usually higher, these dataunderscore the need to prepare the skin before applyingan adhesive system: in particular, the skin needs to becleaned and dried. This is usually accomplished with anisopropyl alcohol (IPA) wipe.

2.3. Kinetic requirements for skin adhesion

Obviously, if the above thermodynamic requirementwere the only one needed for good skin adhesion, poly-ethylene should stick to skin. As a matter of fact, itprobably would stick to skin if it possessed sufficientmobility at room temperature. However, the presence ofcrystallites in polyethylene render it a solid, preventingflow. The flow is required for intimate molecular contact,and this defines an important kinetic criterion. Under theconditions of application, the adhesive must be able toflow sufficiently to promote intimate contact between theadhesive and the adherend. This requirement has beendifficult to quantify. The earliest attempt was made byDahlquist, and it led to the criterion that now bears hisname:

Compliance of adhesive '10~6 cm2dyn~1 or,equivalently,

Modulus of adhesive (106 dyn cm~2.

This requirement allows the adhesive to stick, but doesnot define its pressure-sensitive nature. Obviously, theremoval of the skin adhesive should be reasonably facileor skin trauma could result. Hence, there is a requirementfor easy removal of adhesive as well, which is even moredifficult to quantify. In addition, removal must not leaveany residue behind on the skin. Intuitively, it would seem

that these qualities are related to the cohesive strength ofthe adhesive relative to the strength of its adhesion to thesubstrate in question.

Quantifying these requirements has been difficult. Onemajor problem is that adhesive performance historicallyhas not been measured with a single technique. Rather,several techniques have been employed to monitor ad-hesive performance. These include tack (sometimes called‘quick stick’), peel adhesion and shear strength. All threeyield measurements of different performance aspects ofa single adhesive. Tack is a measurement of how easily (interms of applied pressure) and how quickly a given ad-hesive can be applied to a chosen substrate. Peel ad-hesion, on the other hand, is a measure of how difficult itis to remove the adhesive once it has been attached firmlyto a substrate. Shear strength is thought of as a measureof the cohesive strength, which reflects the ability of theadhesive to peel cleanly away from the substrate withoutleaving a residue. The issues regarding adhesive charac-terization then reduce to the following:

1. All of the above measurements are not true materialproperties of the adhesive, as they depend on both sub-strate and on the backing material to which the adhesiveis attached. So is there a single (or set of ) materialproperty that will reflect adhesive ex vivo performance?Obviously, for the adhesive developer, it would be muchmore convenient to screen adhesives based on a materialproperty that is independent of substrate, time of testing,backing layer, etc.

2. In order to develop specifications for the adhesive,however, the performance attributes are more relevant,provided one can correlate these performance attributesto in vivo performance. This leads to the second impor-tant question in adhesive characterization: How do wecorrelate these measures of the ex vivo performance of anadhesive to its in vivo performance? In other words, canwe define an acceptable range of values of each of theabove measured quantities?

So, for the adhesive developer, the search is for a singlematerial property that reflects all three adhesive perfor-mance attributes. For the product developer, it is moreimportant to define a range of acceptability for the threeattributes, preferably measured after the adhesive is fab-ricated into the system of interest, whether it be a ban-dage, electrode pad or transdermal system.

We will defer the discussion of the correlation betweenthese two types of measurement to Sections 5 and 6, afterhaving examined testing procedures in a little more de-tail.

3. Applications of skin adhesives

By volume, the largest application of skin adhesives isin wound protection. This market consists predomi-nantly of bandages. Popular brands are Band-AidT

S. Venkatraman, R. Gale / Biomaterials 19 (1998) 1119—1136 1121

(Johnson & Johnson) and Curad (Kendall Corporation).If hospital tapes are included, this market was worthapproximately $670 million in 1995. The second-largestapplication, by volume, is probably the electrode-attach-ment market, which utilizes PSAs for attaching elec-trodes to skin for short periods, as during an EKG orECG measurement. The 3M company dominates thismarket, with its Blenderm and Ultrapore brand prod-ucts. The next largest adhesive market, for medical ap-plications, is the developing transdermal drug deliverysystem market, where adhesives are not consumed inlarge volume, but usually command a greater price perpound, because of the more stringent toxicological pro-file that they have to satisfy.

Other applications include the use of hydrophilic skinadhesives in wound healing products, such as 2/$ SkinT,sold over the counter by Spenco Medical, Waco, Texas,and the use of PSAs for attachment of IV catheters to skin.There is also some usage of PSAs in ostomy appliances.

Non-medical applications include the use of PSA tapesas depilatories for women and the use of (mostly) siliconePSAs in face masks in the entertainment industry.

4. Requirements of skin adhesives in various applications

4.1. Toxicological

In medical applications, the overarching requirementthat drives adhesive choice is clearly toxicological. NoPSA is acceptable if it induces skin reactions. The majorskin reactions are of two types:

(a) Primary Skin irritation (PSI), categorized by a Pri-mary Irritation Index (PII):

(b) Skin sensitization, measured by a Repeat PatchInsult (RPI) test.

In case (a), the test article is typically applied for theintended duration of water, and reactions are monitoredat the site upon removal. Reactions evaluated consist ofredness (erythema) and swelling (edema). In case (b), thetest item is applied several times a week on the same site(‘induction period’). After allowing for a period of ‘wash-out’ or non-exposure, the subject is ‘challenged’ with thetest article at a different site. Again, the same type ofreactions are monitored at the new and original sites ofapplication. An intermediate test is also employed, whichinvolves repeated applications of the test article at thesame site and measuring erythema (redness) and edema(swelling), but with this test there is typically no challengephase.

It is important to note that PSI is observed upon firstexposure of the subject to the chemical, whereas the skinsensitization reactions occur upon secondary or multipleexposures; it follows that PSI reactions do not involveimmune system activation, whereas sensitization does. Itis entirely possible for a chemical to produce primary

skin irritation, but no skin sensitization at all. Anexample is acetone.

The biology involved in the PSI reaction in the PSIreaction is typically similar to the biology involved ininjury at any body site: chemicals are produced that actlocally to stimulate nerve endings (pain), to vasodilate inorder to bring red and white blood cells to the site(redness), and extravasation of various cells to the site ofinjury (swelling). The agents involved are usually hista-mines, prostaglandins and the various clotting factors (incase of blood loss). The biology behind the sensitizationreaction is much more complex; it consists of severaltypes, of which the two most important are called Im-mediate Type Hypersensitivity (ITH) and Delayed-typeHypersensitivity (DTH). As the terms imply, the twotypes are distinguished by how rapidly the reactionsdevelop after exposure to the chemical, which is typicallytermed an ‘antigen’. The immediate version producesredness, swelling and itching at the site of applicationwithin about 2 h after exposure; the delayed-type re-quires about 24—72 h after exposure to manifest rednessand swelling. The delayed type is believed to be themechanism behind most skin sensitization reactions.

In an immediate-type reaction, the chemical or antigentriggers production of a type of antibody called IgEantibodies. These antibodies then attach to receptors onthe mast cells in the epidermis and initiate a reactioncalled ‘de-granulation’. This is essentially the emptying ofhistamine by granules in the mast cells into surroundingtissue. The histamine is responsible for vasodilation,leading to onrush of extra blood to the site of histaminerelease, and thus the observed redness.

Since this happens quickly upon second exposure, it isassumed that the first exposure triggered the productionof memory cells capable of IgE production. It is alsopossible for the chemical to be directly involved in themast-cell degranulation process, without mediation byantibodies, leading to the same effects.

The mechanism of the delayed-type hypersensitivity ismore complex. The skin contains dendritic cells calledLangerhans cells. These cells are very efficient at process-ing antigen, for presentation to other cells of the immunesystem. In particular, a subset of helper T-cells are ac-tivated, leading to release of cytokines. These cytokines,in turn, activate macrophages that migrate to the site ofattack and surround the antigen-entry site. The accumu-lation of macrophages and the action of cytokines at thesite results in localized swelling and redness. Since T-cellactivation is involved, this reaction requires some time todevelop. This type of hypersensitive reaction is believedto be the dominant one in skin sensitization.

Skin adhesives used in bandages, wound healing, andin transdermal systems must meet the requirements ofboth a PSI test and a sensitization test. The initial testsare carried out on animals, typically guinea pigs orrabbits. For the PSI test, both can be used, although


Fig. 2. Schematic representation of the two predominant types oftransdermal design. The system on the left uses a rate-controllingmembrane (RCM) and the one on the right is a matrix system.

the rabbit usually is more sensitive. The guinea pig ispreferred for the sensitization study, as its immune sys-tem response is closer to the human response. These testsare carried out before any human application is started.For the PSI test, an acceptable index is a value of(3.0(Draize scoring after removal of the test article. Sensitiza-tion potential is based on the number or percentage ofanimals exhibiting reactions at the 24 an 48 h evaluations[9]. For example, a weak sensitizer stimulates 0—8% ofthe animals tested, while an extreme sensitizer stimulates81—100% of the animals.

In addition to the above tests, cytotoxicity is alsodetermined by extraction of water-soluble componentsand dermal injection into rabbits or systemic injectioninto mice. Classification of test material as USP ClassesI—V depends on the test results. Generally, the higher theclass designation, the more benign the material.

4.2. Adhesion requirements

Adhesion requirements vary, depending on the ap-plication. For instance, with transdermal drug deliverysystems, the adhesive is expected to adhere for at least24h, and it is desirable to have it adhere for 7 days inmany applications. For bandages, the duration is any-where from a few hours to a week or two. People changemost bandages daily, after a shower, so the duration isnot critical. Moreover, in the case of bandages, the back-ing material (or the material that the thin layer of adhes-ive is attached to) is expected to be ‘breathable’, and thishelps longer term adhesion.

In most other applications, the duration of wear isa few hours; thus the demands made of the adhesive aremost stringent in transdermal systems. We will nowexamine the performance attributes of a transdermaladhesive.

Although transdermal systems boast of a variety ofdesigns, broadly speaking, the designs consist of mainlytwo types: the membrane-controlled and the ‘matrix’systems. (A variation related to both the above types isthe Peripheral Adhesive System, where the drug reservoirmay make contact with the skin directly or througha membrane, and is attached to the skin by a peripherallayer of adhesive. This type of design resembles theRCM-type in terms of the requirements placed on adhes-ive performance; however, this design is a little less for-giving of the adhesive, as there is less area of contact ofthe adhesive with the skin.) The performance require-ments of the adhesive are different in the two designs, butfor both, the adhesive is expected to do the following:

1. Adhere to the skin for 24 h to 7 days.2. Allow removal without excessive trauma to skin.3. Leave no residue on skin upon removal.4. Be comfortable to wear, and not lead to itching or

unacceptable irritation of any kind.

4.2.1. Membrane-controlled systemsThis type of design is the oldest. Essentially, it consists

of three major components: the drug reservoir (oftena liquid-containing ‘form-fill-seal’ type), the rate-control-ling membrane (RCM) and the adhesive. The drug per-meates through the membrane and the adhesive to reachthe skin. Typically, the drug reservoir contains a solutionof the drug and liquid excipients. One common excipientused is an ‘enhancer’, which also permeates through thelayers to the skin, where it exerts its ‘enhancing’ effects bymodulating the skin permeability in some fashion. In thematrix-type design, the adhesive performs the roles ofdrug reservoir and adhesive, and to some extent, the roleof the rate-controlling membrane as well. See Fig. 2 forschematics of the two systems.

In the membrane-controlled systems, the adhesivemust exhibit a certain permeability for the drug and theenhancer that is defined by the delivery profile of thedrug under consideration. At any time, it is likely that theadhesive has measurable amounts of drug and enhancerdissolved in it to their solubility limits, as the typicalprocess is one of partitioning followed by diffusion. If thesolubility of either component is low, then the adhesive isnot appreciably affected by the permeation process. If itis substantial ('3% by weight), then one must formulatethe adhesive accordingly. Liquid excipients (includingdrug) will ‘plasticize’ the adhesive to some degree; if theperiod of wear is long ('24 h) this could lead to unsight-ly residue and ‘oozing’ on skin. The ‘oozing’, in additionto being unsightly, also collects dirt and lint, and occa-sionally sticks to clothing. To avoid this, one mustchoose an adhesive at the higher end of the modulusrange, while still satisfying the PSA criteria (to be dis-cussed below).

Thus, two extremes can be identified:1. Solubility of drug and excipients in adhesive is low:

In this case the adhesive requirements are straight-forward. It must adhere rapidly on contact, remain


adhered through sweating and flexing of site ofapplication; be easy to remove (no mechanicaltrauma) without leaving any residue on skin. Trans-lating these to measurable ex vivo parameters ismore difficult. We shall discuss this in more detail inSection 5.

2. Solubility of drugs and excipients is appreciable('3%): in this instance, there is equilibration of thedrug and excipients in the adhesive over time, lead-ing to a change in properties of the adhesive. Thus,it is important to measure the properties of the ‘dry’and ‘wet’ adhesives — the ‘wet’ case being the adhes-ive at saturation with excipients and drug. It isadvisable to carry out a ‘wear study’ (see Section 6)to correlate wearability to the expected extremes inadhesive composition (with and without excipi-ents/drug) as well as with different starting moduliof the PSA under consideration, to establish theacceptable range of properties. Further quality con-trol could then be based on these measured accept-ance ranges of each property.

4.2.2. Matrix systemsThe demands made of the adhesive in this design are

far more exacting. The adhesive contains all of the drugand any excipients. The drug and excipient could bedissolved or dispersed, depending on the amount neededfor the appropriate delivery profile. If the additives needto be dissolved and stay dissolved, then the choice ofadhesive is determined solely by solubility character-istics. In the case of dispersed systems, the range of usefuladhesives increases, but the effect on properties is differ-ent. Dissolved additives tend to decrease moduli andrender the adhesive more susceptible to creep/cohesivefailure. Dispersed additives tend to reinforce the adhes-ive, especially if the additive is a solid. The remarks incase (b) above, apply even more forcefully here: it isessential to test the adhesive properties with the additivesin their final form to ensure acceptable adhesive quality.

The chief advantage of a matrix system is that theentire system can be made to be thin and elegant, as wellas being made very comfortable to wear. In principle, it ismuch easier to make an extended-wear system ('3 d)using a matrix design, as the bulkiness of the form-fill-seal type of RCM systems is usually detrimental to com-fortable wear. On the other hand, stability issues aremore likely to occur in the case of matrix systems, as thedrug and excipeint could undergo phase changes (dis-solved drug may crystallize, dispersed drug may agglom-erate). Both of these causes of instability could adverselyaffect adhesive properties. Hence the initial screeningstudy (involving solubility measurements and stabiliza-tion of dispersions) is more crucial for matrix systems.

Another advantage for the matrix system is that thereis more flexibility in the choice of backing layers. All thatis required of this layer is ‘occlusivity’ to moisture, i.e.,

low moisture vapor transmission rates (MVTRs). Heatsealability is not a criterion. Typically, polyesters (Poly(ethylene terephthalate), PET), polyolefins (HDPE orLDPE), multi-layered films (Saranex from Dow Chem-ical) or elastomers can be used. In fact, it is claimed thatmore elastomeric backings lead to more acceptable long-term wear [10]. A sandwich of Polyurethane (PU)/Poly-isobutylene (PIB)/Polyurethane (PU) has been claimed[11]; the commercial system, FempatchT, utilizes an elas-tomeric backing layer. Patents for other elastomericbackings also exist [12].

In summary, it should be emphasized that while select-ing PSAs for a matrix system, several properties need tobe determined: solubility of drug and excipients; effect ofdissolved/dispersed additives on adhesion; long-termstability of dissolved/dispersed components; compatibil-ity of the backing layer with these components.

5. Commercially available adhesives for skin contact

We now turn our attention to PSAs that are availablecommercially for use on skin. Our criterion for listingthese is that all of them have been tested and approvedfor human skin contact, either by the manufacturer or thedown-line user. For those adhesives that have been usedor have been considered for use in drug delivery, most ofthese adhesives are also listed in the so-called ‘drugmaster file’ (DMF) maintained by either the manufac-turer or the user.

While many PSAs consist of a resin and a tackifier, thePIB-based line of adhesive is a notable exception, as aresome of the acrylics, although one could argue that theacrylics have a ‘built-in’ tackifier along the resin back-bone.

5.1. PIB-based adhesives

This type of adhesive was one of the earliest used intransdermal systems [13]. It is an easy formulation tomanipulate and manufacture. It was used in the earliestcommercial transdermal system, Transderm ScopT, fordelivery of scopolamine.

Essentially, these adhesives are formulated in threeways:

1. a blend of two polyisobutylenes of high and me-dium molecular weights;

2. a blend of high and medium MW PIB with a low-MW Polybutene, PB.

3. a blend o PIB, PB and a tackifier.The first two types have found application in transder-

mal systems already, but not in other fields; the last-named has been used in medical applications involvingskin contact, but also in non-medical, non-skin-contactapplications as well.


Table 3

Adhesive type Peel adhesion, stainless steel Polyken tack, (0.5 cm probe), g Thicknessg cm~1

PIB binary blend! 300—700 1000—1400 3 milPIB#PB" 910 370—800 2.5 milPIB#PB#Tackifier# 750—1200 1400—1900 4 mil

All values measured at ALZA Corporation; where range is given, several lots were measured.! High-MW PIB: low-MW PIB is approximately 15 :85."Approximately 1 :5 : 2 ratio of high-MW PIB: low-MW PIB:PB.# Adhesives Research Inc. product.

Table 4

Monomer ¹'

of homopolymer Remarks

n-Butyl acrylate (BA) !54°C Soft segment2-Ethyl hexyl acrylate (EHA) !70°C Soft segmentVinyl acetate (VA) #30°C Hard segmentAcrylic acid (AA) #106°C Hard segment

The simplest of these formulations, the blend of high-and low-MW PIBs, is easily manufactured by solution ordry blending. A certain ratio of low to high-MW PIB isrequired for pressure-sensitive adhesion; conventionallythis is accepted to be about 80% or less by weight oflow-MW PIB. This sort of formulation gives a PSA withfairly mild adhesive characteristics, as is evident in thelow peel adhesion results often cited for it.

When PB is added to the PIB mix, the formulationrange expands; one can now use higher ratios of high- tolow-MW PIB. The formulation then becomes a compro-mise between highly tacky material (high amounts of PB)and materials with high creep, or low shear strength.A typical composition is approximately PIB (HMW):PIB(LMW): PB of 1 : 5 :2, and yields a PSA with theproperties noted in Table 3.

The third type of PIB-based PSA involves the additionof a tackifier to the three-component system. The onlycommercially available PIB of this type is made by Ad-hesives Research Inc., who have qualified it for skin-contact applications. The material has higher peel ad-hesion and tack numbers than the tackifier-less version.The composition is not public information at thispoint.

5.2. Acrylic adhesives

Acrylic PSAs are typically copolymers of ‘hard’ and‘soft’ monomers. The hard monomer is one that wouldgive rise to a polymer with a high glass transition temper-ature or ¹

', when polymerized by itself. The soft mono-

mer is one that yields a low-¹'polymer. (High ¹

'values

are usually above ambient temperature and low

¹'values are below). Examples of a few of these mono-

mers and the ¹'values of the respective homopolymers

are given in Table 4.Sometimes, a third monomer is added (usually a high-

¹'monomer) to improve cohesive properties, frequently

via grafting or cross-linking.Typically, the copolymer of the hard and soft mono-

mers will yield a material with an intermediate ¹', as-

suming that the copolymer is a random copolymer. Thisleads to pressure-sensitive adhesive properties compara-ble to those seen with a typical resin/tackifier combina-tion. The added advantage is the range of copolymersthat can be synthesized, with the corresponding versatil-ity of physico-chemical properties attainable. This isa particularly interesting set of PSAs for use as matrixadhesives, given the wide range of drugs that need to bedelivered.

The major suppliers of these acrylic PSAs are given inTable 5.

Clearly, the acrylic family dominates the medical PSAmarket. The variety available is substantial, and increas-ing as more adhesives are added to the ‘Approved forSkin Contact’ list. Many of the suppliers maintain a DrugMaster File with the FDA, which can be be reviewed bythe FDA in support of a client’s product. This is clearly ofgreat benefit to the developer of pharmaceutical systems.In addition, some of these suppliers also maintain a De-vice Master File for medical device-type applications(including electrodes). The hospital tape and the bandagemarkets are dominated by this type of adhesive.

All of these adhesives have been tested by the manufac-turer for PSI (irritation) and RPI (sensitization) on eitherhumans or animals. Cytotoxicity testing is also done, butnot always. In using these adhesives in RCM-type sys-tems, there is need for only a PSI at the most, in anysystem, provided the components of the drug reservoirhave already been independently tested. For matrix sys-tems, however, retesting for both PSI and RPI at a min-imum will be necessary.

Obviously, for non-pharmaceutical applications suchas for bandages or hospital tapes, cumulative irrita-tion studies may need to be conducted; this study essen-tially looks at irritation at the same site upon repeated


Table 5

Supplier Brand Name(s) Remarks

National Starch & Chemical Duro-Tak 80- and 87-series Solvent-based for TTS! use DMF listedNACOR Not for TTS, but approved for skin contact

Avery-Dennison MED 5020, 5025, 5051, 5502 Single-coated and double-coated films;no bulk adhesives

Adhesives Research, Inc. MA-31, 36, 38, 46 Solvent-based acrylicETA-1 to 4 Grafted acrylicHY-3 High MVTR adhesiveWS-42 Water-swellable;

some listed in a DMFMMM Co. N/A For internal use onlyMonsanto Chemical Gelva GMS & GME Both solvent-based and aqueous suspensionsMorton-Thiokol Morstik 607 and 709 Solvent-based acrylics approved for skin contact

! TTS"Transdermal therapeutic system.

application of the adhesive article. This market is thesingle-largest consumer of medical-grade acrylic PSAs.

A recent publication highlights the manipulation ofproperties of an acrylic system, in order to fine-tune thedelivery rates of drugs from a matrix system [14]. Bymerely changing the ratio of the co-monomers, it ispossible to manipulate the diffusion rates of variousdrugs through the adhesive. This is a reflection of theeffects of changing ¹

'alone.

5.3. Silicone-based PSAs

Silicone PSAs have long been the ‘bete noire’ of thePSAs. Their high costs and (until recently) single sourcehave combined to give them a bad reputation, yet theyhave been used in commercial transdermal systems.Examples are the FemPatchT 7-day estradiol patch madeby Cygnus, Inc. for Parke-Davis, Transderm-NitroTmanufactured by ALZA Corporation for CibaGenevaand the 3-day DuragesicT fentanyl system manufacturedby ALZA Corporation for Janssen Pharmaceutica. Thepredominant reason for the choice was the more favor-able permeation characteristics of silicone adhesives forthose particular drugs. Although the superior adhesivecharacteristics of silicones have been touted often, nostudy to date has been able to clearly delineate siliconesas being significantly better in wear performance. Fem-PatchT is a 7-day system, an arguments have been madefor the superior adhesive characteristics of silicones overthe longer wear period [15].

Silicone PSAs are similar to conventional PSAs in thatthey are made up of a long-chain polymer (poly dimethylsiloxane, PDMS) and a benzene-soluble silicate resin.The resin has a high ¹

', while the polymer has a notably

low ¹'(!140°C). The raw material is provided as a mix-

ture of these two components in Freon, or more recently,in heptane. The ratio of resin to PDMS determine the

nature of the final product: in general, the higher thisratio, the ‘harder’ the final silicone.

The older family of silicones (sold by Dow-Corning asBio-PSA) was susceptible to reaction with amine-con-taining materials, which made them incompatible witha large number of drugs. A later generation was de-veloped to be amine-resistant [16] and is usable in a widerange of transdermal systems. The amine resistance isbrought about by end-capping the silanol groups withalkyl groups. The mixture of components now containsPDMS, tackifier resin and an end-blocker. It is believedthat the extent of cross-linking in amine-resistant siliconePSAs is much less than in the older version. Thus cohe-sive strength strength or ‘shear’ is typically lower for theamine-resistant variety than for the older family, givensimilar resin to PDMS ratios.

Given that the use of Freon is to be phased out by2001, Dow-Corning has provided alternatives: one isheptane, and the other is hot-melt silicones. The hot-melt[17] is made by pre-formulating a PSA using a resin and aPDMS fluid with silanol termination, then mixing thePSA formulation with a hydrocarbon oil and sub-sequently extruding it in sheet form to make the PSA sheet(An end-blocker may be used in the initial PSA formula-tion step to increase amine resistance as required.)

The patents on the non-amine-resistant PSAs haveexpired. This has prompted other vendors to supplysilicone PSAs of this variety. Notable among these sup-pliers is NuSil Technology (NuSil Silicone Technology,Carpinteria, California). NuSil sells three PSAs based onthe hydroxyl/alkoxy-terminated siloxanes and resins;these have the designations, PSA-9839, PSA-9930 andPSA-9931. The grades are different mainly in the natureof the solvent: ethyl acetate, hexamethyl disiloxane and1,1,1-trichloroethane. Their PSAs have passed cytotoxi-city, PSI, RPI and even intramuscular implant testing(7 and 90 d duration). These PSAs are expected to mimicthe earlier versions of the Dow-Corning PSAs.


5.4. Other PSAs

It is widely perceived that there is a need for skin-contact PSAs with some hydrophilicity. This perceptionarises from two sources: (a) the wound-care field, whichrequires a hydrophilic, ‘breathable’ system attached tothe skin for accelerated healing; and (b) and transdermaldrug delivery field, where matrix systems demand hy-drophilicity in order to dissolve more polar drugs. Also,long-term wear demands some level of hydrophilicity.This perception has given rise to a variety of patents onhydrophilic PSAs, or in some cases, completely water-soluble PSAs.

US Patent 4,898,920 (1987), assigned to Dow-Corning,claims a 2-part system, broadly based on the old, non-amine-resistant-type silicone, the PDMS backbone beingnow replaced by a poly(ethylene oxide) or PEO-graftedPDMS chain. In general, as the PEO/PDMS ratioincreases, there is a maximum in peel adhesion values,decreasing at the higher PEO levels presumably becauseof incompatibility of the grafted polymer with the resin.

US Patent 5,387,466 (1994), assigned to Adhesives Re-search, Inc., claims a copolymer of hydrophobic andhydrophilic monomers as a continuous phase, and a hy-drophilic homopolymer as the discontinuous dispersedphase. Examples of such monomer combinations are:2-hydroxy ethyl acrylate (HEA)#ethyl acrylate as thecontinuous phase (largely hydrophobic); anda homopolymer of 2-HEA as the discontinuous hy-drophilic phase. Water absorption of up to 170% over2 months, is reported. This material is currently availablecommercially.

US Patent 4,699,146 (1985), assigned to ValleyLabs,Inc., describes Polyvinyl pyrrolidone (PVP) crosslinkedby electron-beam (e-beam) radiation and plasticized bya suitable plasticizer such as polyethylene glycol (PEG).The PSA is formed by evaporation of water from themixture of PVP, PEG and water after irradiation.

US Patent 5,225,473 (1992), assigned to 3M Co., is verysimilar to the ValleyLabs patent, except that this hy-drophilic PSA is formed by chemically crosslinking PVPin a mixture with a plasticizer such as glycerol.

Two other patents merit a mention here: US Patent4,684,558 (1987), assigned to Nepera, Inc., lists a cross-linked PEO and water mixture. The cross-linking is doneusing high-energy radiation (e-beam) on the solutionof PEO and water. The resulting gel, when reinforcedwith a scrim, exhibits adequate skin adhesion and goodcohesive strength. This kind of material is commerciallysold as would dressings, such as 2/$ SkinT (Spenco Medi-cal, Waco, Texas). Variations of this idea, incorporatingnon-volatiles such as PEG and glycerol, and crosslinkingadditive, have since appeared, assigned to the samecompany.

US Patent 4,593,053 (1986) claims a blend of PVP andpolyvinyl alcohol (PVA) that forms an association com-

plex, when mixed at 90°C in the presence of water anda non-volatile plasticizer, such as glycerol. This is aninteresting PSA that is produced without crosslinking. Itis not clear what kind of stability this material exhibitsover time, particularly with regard to its creep and syner-esis characteristics.

Another uncross-linked type of hydrophilic PSA is theone marketed by Rohm GmbH (now owned by HulsAmerica) under the trade name of ‘plastoid’ and pro-tected by US Patent 5,296,512 (1994). Two varieties aresold: (1) a solution of EudragitT L-100 (a copolymer ofa methacrylate ester and methacrylic acid) in water, andadditives such as glycerol (This is Plastoid L-50); and (2)a solution EudragitT E-100 (a copolymer of a methac-rylate ester and an aminoalkyl methacrylate) in roughlythe same kind of mixture (sold as Palstoid E-35, L, M andH). Varying degrees of adhesion can be obtained byevaporation of varying amounts of water. The actualformulated PSAs are no longer being sold, but the com-position and method of manufacture are given for cus-tomers to use and fine-tune, as necessary. A crosslinkerhas also been added to the mix to improve cohesivestrength. To date, the use of these materials in a commer-cial skin-contact product has not been announced.

6. Testing of skin adhesive

At the very outset, it is convenient to divide the testingof PSAs into two broad categories:

1. testing related to adhesive performance and2. testing related to material properties.As mentioned in Section 2, the first type is useful for

the formulation or system developer, while the second isuseful for quality-control (QC) purposes or for determin-ing lot-to-lot variability. Examples of Type 1 are peel andtack; examples of Type 2 are all viscoelastic measure-ments, including creep and dynamic-mechanical proper-ties. The distinguishing feature of Type 2 measurementsis that these quantify true material properties and valuesthat are independent of geometry; the same is not true ofType 1. To so-called shear strength measurement orshear, as it is sometimes called, is a hybrid measurementthat is more material-related than geometry-related, ex-cept that non-standard units (time to failure) are used tospecify the shear strength. We will not treat this measure-ment separately but consider it reflective of cohesivestrength, which is a material property that is related toshear modulus.

Correlations between the two sets of properties doexist, and a set of measurements of Type 2 may be used toadvantage by both types of practitioners, but the faith inthe correlations is not sufficiently strong at this point towarrant extensive use. We will examine both types oftesting, as well as the few correlations that exist betweenthem.


6.1. Performance-related testing

This type of testing of skin adhesives remains relativelyprimitive: the tests used currently were all developed forindustrial PSAs, by the pressure-sensitive-tape council(PSTC). Thus, ASTM D14 ‘Pressure-sensitive Tack ofAdhesive using an inverted probe machine’ is still usedfor tack testing of skin adhesives. Similarly, the ASTMD-1000 series of tests is used for peel from substrates.PSTC tests 1, 3, 4, 8, 13, and 14 also describe peel tests forPSAs of varying constructions. Shear strength (which issometimes abbreviated to just ‘shear’) is also measuredusing an ASTM/PSTC adapted test.

6.1.1. Tack testing of PSAsAlthough various methods exist for estimating tack,

the most reliable of these is the probe tack measurementdeveloped by Hammond [18]. Hammond’s design is soldcommercially as the Polyken Probe Tack tester (distrib-uted by Testing Machines, Inc., Amityville, New York).This instrument can be programmed for different probespeeds and probe contact times. Tack is widely presumedto be a ‘surface’ property, but in reality, values do dependon the material to which the adhesive is laminated [19].The values also depend on dwell (or contact) time, as wellas contact pressure and delamination rate. It is cleartherefore that tack measures surface as well as viscoelas-tic properties of adhesive and adherend (probe material).It is a simple measurement to make but a complex one tointerpret.

In terms of skin adhesion, tack is typically a short-term(contact time in seconds) measurement, and is useful onlyin terms of the initial tendency to stick to skin. Sub-sequent wear properties on skin have very little to dowith tack, unless one were re-applying the same adhesiveand the same system. It is widely accepted, however, thata minimum value of tack is desirable for all skin adhes-ives; what is not widely accepted are the magnitude ofthis minimum value and the actual parameters ofmeasurement (nature of adherend, dwell time, pressure,rate of withdrawal, etc.) Indeed, it appears as though sucha specification may be unique to the product designunder consideration, and may need to be developed foreach type of application.

The recommended procedure for using tack measure-ments is as follows:

1. Evaluate tack as a function of contact time, pressureand rate of withdrawal.

2. As far as possible, estimate, in your application,what kinds of contact times and pressures would beinvolved, and (this is more difficult) the range of with-drawal speeds likely to be encountered.

3. Using these as a guide, set the parameters of thetack test; if these settings do not yield reproducible re-sults, then establish a set of conditions (close to theoriginal set) that does yield reproducible results.

4. Using a negative control (an adhesive that youknow does not work on skin), evaluate your candidateadhesives for minimum acceptable tack. Correlate the realexperience using a simple quick application and removal.

5. Using adverse skin reactions (due to mechanicaltrauma upon removal) as a guide, establish the maximumacceptable tack, employing quick application and re-moval.

The final form of your system should be used where-ever feasible. If that is not possible, the geometry shouldbe standardized.

6.1.2. Peel adhesion testingPeel adhesion is another test that needs to be standard-

ized for your given application. Again, the variables aretypically contact pressure and time (against the substra-te), the nature of the substrate, the angle of peel and thewithdrawal speed. The peel adhesion measurement issometimes viewed as quantifying an aspect of skin ad-hesion that is different from what the tack measurementquantifies. In other words, tack is seen as indicating anease of application and the peel as indicating ease ofremoval. We believe that this separation of the twotechniques is somewhat artificial and perhaps even inva-lid. When used properly, the peel adhesion test yieldsinformation about the quality of adhesion that is inaddition to what is obtainable from tack. For instance,evidence of cohesive failure is readily picked up in a peeladhesion test, and seldom in a tack test. The peel testis also more readily adapted for measurement underdifferent temperatures and humidities, and so might yieldinformation about adhesion under different conditions.But fundamentally, the peel adhesion suffers from thesame disadvantages that the tack measurement does: it isinfluenced by the nature of the backing, the rates ofmeasurement and the viscoelasticity of the adhesive.Comments about the substrate also apply here, as in thecase of tack. A product-specific procedure can be de-veloped for peel adhesion as well.

The peel adhesion test does suffer from a high degree ofvariability, and is unsuitable, like the tack measurement,for setting specifications. Specifying minimum values isrecommended, however.

6.2. Material property tests

There are tests for monitoring lot-to-lot variability ofadhesives. The measurements show some correlation tothe performance-related tests mentioned above. Most ofthese are viscoelastic in nature. Examples are dynamic-mechanical properties as a function of frequency andcreep compliance as a function of time.

6.2.1. Dynamic-mechanical propertiesThese are the measurements that have found the best

correlation to performance of adhesives. The adhesive


Fig. 3. A representation of the ‘universal PSA plot’ pioneered by S.G.Chu [20]. The elastic dynamic modulus at low frequency (u"

0.1 rad s~1) is plotted against a ratio of high- and low-frequencymoduli; PSAs with high values of adhesion and tack fall in the lowerright-hand quadrant. This figure is representative of blends of rubberypolymers with tackifiers.

material is pressed or formed in situ into a disc, and thensubjected to dynamic torsion or compression betweenparallel plates. The resulting moduli and viscosity valuesare measured as a function of the oscillation frequency.Either constant stress or constant strain can be used inthese measurements.

All PSAs are viscoelastic liquids. The moduli can bedivided into in-phase (G@) and out-of-phase (G@@) compo-nents in the conventional manner, and plotted as func-tions of frequency, u (usually from 0.01 to 100 rad s~1).This ‘spectrum’ can then be used to monitor all incominglots; it is fairly sensitive to small changes in molecularweight, degree of cure, copolymer composition and thelike.

The dynamic-mechanical properties (mostly G@ asa function of frequency, u) have been correlated to tackand peel [20]. The correlation is largely empirical, al-though some rationale can be provided. The correlationhas been developed for natural rubber/tackifier orSBR/tackifier blends, and may be restricted to the gen-eral class of polymer/tackifier blends; the acrylate familymay not be amenable to this correlation.

The rationale for the correlation can be briefly de-scribed as follows: Peel adhesion or tack can be thoughtof as a combination of two processes: (a) the bondingprocess, which occurs at relatively long times or smallfrequencies and (b) the debonding process, which occursat relatively short times or high frequencies. So themoduli measured at low and high frequencies should berelatable to measured tack and peel. In other words,a low G@ is required at low frequencies for the bondingprocess, and a high G@ is required at the higher frequencyassociated with debonding, as both of these would lead tohigh tack and/or peel, or the higher the slope of the G@versus u plot, the better the PSA properties.

In Chu’s ‘universal’ plots, the G@u"0,1 is plotted againstthe slope of G@ versus u, i.e., G@u"100/G@u"0.01 ; the region ofgood PSA properties (high tack and peel) occurs in thebottom right-hand corner, of low G@u"0.1 and high valuesof the slope, G@u"100/G@u"0.01 . See Fig. 3 for a schematic.

This kind of plot enables one to define a ‘region’ ofgood PSA properties for mixtures of natural or syntheticrubber with tackifiers. The region is defined by

G@(u"0.1 rad s~1)&2 to 4]105 dyn cm~2,

slope&20—300.

Although this approach could be used for screeningformulations, it does require the initial determination ofthe ‘universal’ plot. This means that formulations bemade and measured for peel and/or tack, as well as fordynamic-mechanical properties. Once the correlation isbuilt, subsequent formulation screening (for a differentset of tackifiers, for instance) becomes a matter ofmeasuring just the frequency dependence of the modulus.

Caution must be exercised in extending this to acrylicformulations, where the peel/adhesion properties are var-ied by copolymer composition rather than by tackifieramount, although there is no prima facie reason for anylack of correlation.

The main utility of dynamic-mechanicalmeasurementsstill lies in monitoring lot-to-lot variability, or in valida-tion of mixing processes for adhesives, as required inpharmaceutical product development.

6.2.2. Creep complianceThis is a viscoelastic measurement that can directly

related to performance and processing. For instance, inlong-term wear on skin, excessive creep of the adhesiveleads to an aesthetically unacceptable patch or bandage,as the adhesive oozes out from under the backing. Theexposed adhesive can pick up lint and other material, orstick to clothing. In addition, excessive creep leads tostorage problems for adhesive rolls. Typically, cast ad-hesive is stored between liners in a roll; excessive creepleads to layers of adhesive sticking to each other, causingproblems in unwinding. Once formed into a bandage ora patch, creep can lead to patches sticking to one anotherand to the inside of the pouch as well. A low creepcompliance is therefore highly desirable, but too lowa value leads to loss of tack and peel. Thus, duringformulation development, creep compliance should bemonitored in addition to dynamic-mechanical proper-ties, in order to choose adhesives of low creep consistentwith the desirable range of the dynamic-mechanicalproperties discussed above.

This measurement is conveniently carried out in a con-trolled-stress rheometer, with the adhesive between par-allel plates, and heated to the temperature of interest. The


estimation of the stress to be imposed depends onwhether it is roll storage that is an issue or creep undergravity (for applied or packaged patches).

Even though the original Dahlquist criterion fora good PSA used creep compliance, it will be clear fromthe discussion in Section 6, below, that the compliancealone is not sufficient to define a good PSA; rather,a combination of viscoelastic parameters, such as thecriterion proposed by Chu, may be necessary.

7. Relationship between in vivo performance and ex vivotesting

Reported studies of the correlation between the perfor-mance-related tests above and in vivo performance inhumans are few and far apart. (By in vivo performance,we mean the actual wear chatacteristics of systems madewith these adhesives, not just a ‘peel force’ measurementfrom human skin. The performance characteristics typi-cally include measures of ‘lift’ of the adhesive from skin,some quantification of the extent adhered to skin and anytopical effects during wear and after removal. Such obser-vations are made periodically throughout the duration ofwear for which the systems are indicated). In fact, nostudies have been reported of adhesives with measuredpeel and adhesion values, and their corresponding in vivoperformance. Studies that compare the in vivo perfor-mance of several commercial transdermal systems (forthe same drug) do exist, without correlation to any mea-sured ex vivo properties. These will be discussed in Sec-tion 7.2.

On the other hand, correlations of measured adhesiveproperties (ex vivo) to measured peel forces from humanskin do exist. One such study [21] reports some compari-son of adhesives with measured compliance valuesagainst their performance on skin. This study looked atthree classes of adhesives: a PIB blend of high and low-MW polymers, a silicone PSA and an acrylate PSA. Thethree adhesives without any additives had compliancevalues in the same range (approx. 10~6 cm2dyn~1) andtheir skin performance was similar (peel from skin, resid-ual amount on skin after peel, lift and irritation uponremoval). After an excipient (isopropyl myristate, orIPM) was added, the behavior was modified. The siliconerequires very little of IPM for plasticization, while thePIB requires more and the acrylic needs large amounts:the extent of plasticization is measured by the value of thecompliance after IPM is added. Skin adhesion in all threecases increases with IPM addition. The residue on skin isgreatest for the acrylic (which also had the largestamount of IPM by weight), while the skin irritation isalso lowest for the acrylic.

No attempt is made to rationalize these observationsbeyond suggesting the formation of an IPM interlayerbetween the adhesive and the skin (presumably more for

the acrylate than the others), but how this relates to theobservations of higher residue or lowered skin irritationis not made clear. The only conclusive statement that canbe made, based on this study, is that as the complianceincreases, the adhesion to skin increases.

In a similar vein, Lucast and Taylor [22] have mea-sured the creep compliance of several acrylic polymerswith and without side-chains and crosslinker; they alsomeasured peel adhesion from skin in vivo at t"0 andt"48 h. The only conclusion that can be drawn fromtheir reported work is that in a given family of acrylics, ifthe compliance is decreased (by crosslinking, for example)the adhesion to skin drops. No attempt is made to co-rrelate the measured creep compliance values to the ob-served adhesion across all acrylics. (The time correspond-ing to the reported creep compliance values is not given inthis paper.) In other words, does a measured complianceaccurately predict a measurable peel from skin?

We have replotted Lucast and Taylor’s data, using allcompliance values and the corresponding ¹"0 peeladhesion and ¹"24/48 h peel adhesion, in Figs. 4 and 5,respectively. As can be seen, there is no correlation be-tween the measured compliance and the measured peelfrom skin, indicating that compliance alone doth nota good PSA make! There are other factors involved, suchas the G@ versus u slope mentioned by Chu and describedin Section 5.2.1, as well as perhaps a dependence on thechemical components themselves (these were copolymersof AA, acrylamide and N-vinyl pyrrolidone in variousratios, with and without crosslinker), and the location of¹

'of the copolymer (which may be reflected completely

in the G@ versus u slope).The lack of definitive studies correlating on-skin per-

formance and measured ex vivo properties is perhapsexplained by the high cost of conducting such studies.One needs to produce adhesive with different tack andadhesion values, and evaluate performance on skin usinga sufficient number of subjects. The number of subjectshas to be necessarily large, because of skin variability inhumans. Conclusions drawn from a small subject popu-lation have to be treated with caution. In both the studiesmentioned above, it is not clear whether the observationsmade were statistically significant, as the number of sub-jects is not mentioned, nor is any idea given about thespread in the data.

Another possible explanation for the paucity of goodstudies is the lack of agreement on the correct techniquefor quantitative measurements of adhesion on skin invivo. Although in-situ peel adhesion has been used[21—23], it does not appear to tell the whole story. Edgeand side-lift measurements are also necessary, as well asan estimate of overall adhesion level. The latter twomeasurements are still fairly subjective and qualitative;there is no agreed-upon standard for such evaluations.

What is needed is an evaluation of each class of adhes-ive by itself first, followed by a cross-comparison of


Fig. 4. Peel adhesion on human skin, plotted against shear compliance values for acrylic PSAs. Values are for t"0, soon after application. Data istaken from Ref. [22]. Points are for all the acrylic types reported in the reference.

adhesive classes with the same physical properties. Inother words, using silicones as an example, producePSAs with different peel and tack, and perform a wearstudy, quantifying wear characteristics. Once these cor-relations are made, use acrylates and PIBs of similar peeland tack values to estimate the effect of adhesive class onwear performance. Such studies could serve to establishacceptance ranges for adhesive peel and tack, as well asdefining the role of adhesive chemistry, if any, in in vivoperformance.

Similar remarks apply to evaluation of additive influ-ence on adhesion, particularly in the case of matrix sys-tems.

8. Commercial transdermal systems

As described above, most commercially availabletransdermal systems can be categorized as eithera matrix-type or a rate-controlled type of design. A sub-category of matrix systems is that which contains a peri-pheral adhesive.

8.1. A discussion of all transdermal systems (alphabeticallyby trade name) in commerce as of this edition date

8.1.1. Self-adhesive matrix systemAloraT: This system is designed to deliver 17b-estra-

diol at rates of 0.05, 0.075 and 0.1 mgd~1 for 3—4 d and

contains an acrylate contact adhesive. It was developedat Thera Tec Inc, Salt Lake City, UT, and is marketed byProctor & Gamble Pharmaceuticals, Cincinnati, OH.

ClimaraT: This once-weekly system was formulated by3M Pharmaceuticals, Minneapolis, MN, to deliver 17b-estradiol to women at rates of 0.05 and 0.1 mgd~1. Thesystem contains an acrylate adhesive matrix and is mar-keted by Berlex Laboratories, Wayne, NJ.

DeponitT: This once-daily transdermal system wasdeveloped and is distributed by Pharma-Schwarz, Mil-waukee, WI, to deliver nitroglycerin at rates of 0.2 and0.4 mgh~1. The system consists of a multi-layer poly-isobutylene adhesive that is tackified and plasticized.

FemPatchT: Cygnus Therapeutics, Redwood City,CA, was the innovator of this system which delivers17b-estradiol to women at a rate of 0.025 mgd~1 forseven days. The product contains a silicone-based con-tact adhesive and is distributed by Parke-Davis, MorrisPlains, NJ.

HabitrolT: This once-daily nicotine delivery systemwas developed and distributed by Ciba Self-Medication,Woodbridge, NJ. The system was formulated to deliverdrug at 7, 14 and 21 mgd~1 and uses an acrylate pres-sure-sensitive adhesive.

MinitranT: This is a once-daily nitroglycerin deliverysystem developed and marketed by 3M Pharmaceuticals,Minneapolis, MN, and Northridge, CA, respectively. Thesystem is an acrylic-based self-adhesive monolith thatdelivers drug at rates ranging from 0.1 to 0.6 mg h~1.


Fig. 5. Peel adhesion on human skin, plotted against shear compliance values for acrylic adhesives. Values are for t"24 or 48 h after application.Data is taken from Ref. [22]. Points are for all the acrylic types reported in the reference.

Nitro-DurT: A once-daily nitroglycerin delivery sys-tem, this product contains a cross-linked acrylic-basedadhesive. The product was developed and is marketed byKey Pharmaceuticals, Kenilworth, NJ, and is available insix dosage strengths ranging from 0.1 to 0.8 mgh~1.

TestodermT with Adhesive: This product is a mono-lith containing polyisobutylene adhesive stripes arrayedacross the testosterone-releasing surface. Drug is de-livered at a rate of 6 mg d~1 for one day. The system wasdeveloped and is marketed by ALZA Pharmaceuticals,Palo Alto, CA.

VivelleT: This is an acrylate adhesive monolith de-signed to deliver 17b-estradiol at four rates ranging from0.0375 to 0.1 mgd~1 for 3 to 4 d. The contact adhesive isacrylate-based. The system was formulated by NovenPharmaceuticals and is marketed by CibaGeneva, Sum-mit, NJ; in Europe, it is marketed under the name ofMenorestT by Rhone-Poulenc Rohr.

8.1.2. Peripheral adhesive systemsAndrodermT: This once-daily product was designed

by Thera Tec Inc, Salt Lake City, UT, to deliver testo-sterone at a rate of 5 mgd~1. The polyesterurethane-based peripheral adhesive attaches a drug reservoir com-partment to the skin. The product is marketed by SmithKline-Beecham Pharmaceuticals, Philadelphia, PA.

NicotrolT: This product is replaced daily and wasdesigned by Cygnus Therapeutics, Redwood City, CA.

The single dosage strength is 15 mg 16 h~1. The productcontains a polyisobutylene-based adhesive and is sold byMcNeil Consumer Products Company, Fort Washing-ton, PA.

ProstepT: This product was innovated by ElanPharma, Ltd., Athelone, Westmeath County, Ireland,and is marked by Lederle Laboratories, Pearl River, NY.The system is available in two strengths: 11 and22 mgd~1 for one day. The adhesive system is acrylatebased.

NitrodiscT: This nitroglycerin delivery system was de-signed and sold by GD Searle, Chicago, IL. The product(now not for sale) contained a disk of drug-containingsilicone rubber that was attached to the skin with anacrylate adhesive coated onto a foam backing.

8.1.3. Rate-control membrane systemsCatapres-TTST: This system was designed by ALZA

Corp., Palo Alto, CA to deliver clonidine base at control-led rates of 0.1, 0.2 and 0.3 mgd~1 for seven days to treathypertension. The product is marketed by BoehringerIngelheim, Ridgefield, CT. The skin contact adhesive ispolyisobutylene/mineral oil based. Rate control is pro-vided by means of a microporous membrane.

DuragesicT: This is a rate-controlled system designedby ALZA Corp., Palo Alto, CA, to deliver the potentanalgesic fentanyl at rates of 25, 50, 75 and 100 lg h~1.The contact adhesive is silicone-based and is marketed


by Janssen Pharmaceutica, Titusville, NJ. Rate control isafforded by an ethylene-vinyl-acetate (EVA) polymermembrane.

EstradermT: Developed at ALZA Corp., Palo Alto,CA, and marketed by CibaGeneva, Summit, NJ, thisproduct delivers 17b-estradiol to women at rates of 0.05and 0.1 mgd~1 for 3 to 4 days. Drug delivery rate controlis brought about by an EVA membrane. The contactadhesive is polyisotbutylene/mineral oil based.

NicodermTCQTM: The rate control feature of thisnicotine delivery system lies within a polyethylene mem-brane. The drug delivery rate per day for each of the threesizes of this product is 7, 14 or 21 mg with once-a-dayapplication of a system. The contact adhesive is a blendof polyisobutylenes. The product was developed byALZA Corp., Palo Alto, CA, and is marketed bySmithKline Beecham Pharmaceuticals, Philadelphia,PA.

Transderm-NitroT: This product contains an EVArate-control membrane. Four drug delivery rates areavailable; they range from 0.1 to 0.6 mgd~1 for 16 h. Theproduct was developed at ALZA Corp., Palo Alto, CAand it is marketed by CibaGeneva, Summit, NJ. The skincontact adhesive is silicone based.

Transderm-ScopT: A microporous membrane metersthe drug scopolamine from this multilayered system. Theproduct delivers drug at a rate of approximately 3 lg h~1

for three days. The contact adhesive is polyisobuty-lene/mineral oil based. Ciba Self-Medication, Wood-bridge, NJ, markets the product.

A listing of commercialized transdermal systems ap-pears in the Appendix.

8.2. Comparison of wear properties of commercialtransdermals: in vivo studies

Although correlative studies (studies that correlatewear properties to measured physical attributes) are rare,comparative studies of wear properties of commercialtransdermal systems are fairly common. The nitrogly-cerin and estradiol transdermals have been studied exten-sively. A few of these studies will be summarized.

Although it would seem intuitively obvious that a thinmatrix system would have better adhesion characteristicsthan a bulkier RCM system, this expectation is not borneout in many studies. Although many of these studies aredecidedly semi-quantitative, and rely heavily on theuser’s assessment of wear properties, both adhesion anduser preferences favor one candidate over others in a sta-tistically significant manner.

8.2.1. Nitroglycerin systemsChinoy et al. [24] found, in a 65-patient study, that

Transderm-NitroT adheres significantly better than the

matrix system, NitroDurT. They used a three-level mea-sure of adhesion. These findings are confirmed by Riley etal. [25] in a 64-patient study using patient-rated ad-hesion scores (3-level). Presumably, the site of applicationin these and other nitro-patch studies, was the upperchest.

In a 47-patient, double-crossover study in the UK,Valle-Jones et al. [26], found that the matrix systemDeponitT (Schwarz-Pharma) was comparable to Trans-derm-NitroT (Ciba-Geigy) using patient-stated prefer-ences while washing, bathing, exercising and day andnight wear. This finding is contradicted somewhat ina larger, multi-center study [27] involving 139 patients,wearing both patches (5 mg/24 h) simultaneously, alsowhile washing, swimming, showering, etc., using botha three-level quantitation of adhesion and stated patientpreference scores. In a statistically significant sense,Transderm-NitroT was preferred, in terms of adhesion,over DeponitT. For topical effects, both patches behavedsimilarly.

In a much smaller study (12-patients: 6 men, 6 women),where the subjects wore 4 patches simultaneously on theupper back, K.A. Wick et al. [28] used Transderm-NitroT, DeponitT and the new 3M patch, MinitranT,along with a ‘control,’ which was an occlusive surgicaltape, BlendermT. For reasons that are not made clear,DeponitT, MinitranT and BlendermT were applied as7.5 cm2 patches, while Transderm-NitroT is applied asa 10 cm2 patch: this clouds an otherwise good quantitat-ive comparison of adhesion at t"0 and t"24 h forthese patches. The authors used a peel force measure-ment to assess adhesion on skin; this kind of measure-ment is much more quantitative and less subjective thanpatient ratings of adhesion. They also used qualitativemeasures of patch lift and residue on skin. When theadhesion values were compared, the MinitranT andTransderm-NitroT were clearly superior to NitroDurT att"0; after 24 h of normal activity, the MinitranT ap-peared to have a greater adhesion than Transderm-NitroT, both being much greater than Nitro-DurT after24 h. However, for a more meaningful comparison, it isclear that a larger subject population is needed.

One interesting observation the 3M workers make inthis study is that all three patches show decreased ad-hesion levels at 24 h, which they attribute to hydration ofthe stratum corneum under occlusive conditions and toloss of nitroglycerin from the patch. Why these twofactors should affect the MinitranT less was not ex-plained.

8.2.2. Estradiol systemsThere are fewer good studies reported with estradiol

transdermals. In a particularly extensive study involving265 women, J.A. Erianne and L. Winter [29], compared


the wear characteristics of an RCM patch, EstradermT(10 cm2, developed by Alza for Ciba-Geneva) and a newmatrix patch, MenorestT (14.5 cm2, manufactured byNoven for Rhone-Poulenc Rohr). All subjects wore 4placebo patches simultaneously, 2 of each type on thebuttock and abdomen (left and right). Slightly betterahesion was seen for the matrix system on the abdomen,while the reservoir system showed slightly better ad-hesion on the buttock. A five-level measure of adhesionwas used in all cases. Topical effects were similar for bothpatches.

While the above study clearly failed to show the su-periority of matrix systems in adhesion, another study[30] of 99 women showed that the new 3M patch,ClimaraT (7 d system, 0.05 mg dose, Berlex Labs), hada lower incidence of fall-offs in a 7 d period, compared toEstradermT, 0.05 mg (0.3% vs. 1.9%). Moreover,it is reported that only four of the 7 d matrix patcheshad to be retaped (for low adhesion before the endof the 7 d period) whereas 49 of the twice-weeklypatches had to be retaped (1.4 vs. 8.4%). No significantdifferences were noted in topical effects for the twopatches.

In another study of a matrix estradiol patch, Bracatet al. [31] reported on skin reactions with a new 7 dsystem developed by Beta Pharmaceuticals for Wyeth-Ayerst. This patch, called ClimadermT, has a 15 cm2

area, is applied on the abdomen and delivers 50 lg d~1.Twenty-seven woman were evaluated, and wore twoClimaderm and one ‘placebo’ patch every week for5 weeks, with a suitable washout period between weeks.(The ‘placebo’ patch was a Johnson & Johnson bandage).Skin reactions observed upon removal includederythema (23.7%); these decreased to 2.2% after 7 d.Compare this incidence with the 13.7% rate seen for thereservoir patch, EstradermT, in the study by Erianne andWinter [29].

In summary, therefore, there are conflicting data in theliterature regarding the wearability of RCM and matrixsystems. It appears that as far as skin reactions areconcerned, the systems are comparable, with the RCMpatches being slightly superior over a 3 d period. In termsof the level of adhesion and user comfort, again thesystems appear comparable, with perhaps the matrixdesigns performing a little better over the entire durationof wear. In performing head-to-head comparisons, it isclear that a large population of subjects is desirable, andthat quantitative assessments of skin adhesion, such asthe one used in the 3M study [26] would enable a moreobjective comparison.

9. Future needs

Perhaps the most important shortcoming in currentlyavailable adhesives is their inability to adhere during

periods of strenuous exercise and under humidconditions. The solution to this problem may lie inthe design of the patch, the nature of the backing mater-ials and that of the adhesive. Thus, if wear periods are tobe lengthened for transdermal or for other patches,a patch design that ensures optimum area of coverage,while minimizing overall bulkiness would be helpful,as would flexible backing materials and adhesives ofthe appropriate chemical and physical properties.A study along the lines mentioned in Section 6 wouldbe required to define the appropriate properties of theadhesive.

Ease of removal of patches or bandages is currentlyalso far from optimum. As has been noted, agressiveadhesives tend to cause trauma upon removal, leading toskin irritation. As transdermal patches find increasingacceptance, and lead to therapeutic regimens that dictatecontinuous wear for several days (involving applicationand removal of several patches), this aspect of adhesioncould assume greater importance. In this regard, ad-hesion or delamination that is triggered by an externalstimulus (e.g. temperature) would be attractive candi-dates, provided that the means of administering the ex-ternal stimulus are not too cumbersome. One approachin this direction, using temperature-activated adhesives,has been reported [32].

For the case of matrix transdermal systems, there is anincreasing demand for adhesives that are ‘compatible’with excipients, i.e., liquids that are sometimes used toenhance skin transport of certain drugs. In this context,compatibility refers to the ability of the adhesive toabsorb a significant amount of the excipient withoutlosing its adhesive character. In the same vein, adhesivesthat can dissolve substantial amounts of drug withoutlosing adhesive properties will also be in demand. Anexample is given in Ref. [19] of an enhancer, isopropylmyristate, which is absorbed by an acrylic adhesive inlarge amounts without extensive plasticization; this isclearly the desired trend with other enhancers. In otherwords, in matrix systems, one needs a range of adhesivesthat will take up enhancers without substantial increasein shear compliance, or equivalently, without a substan-tial drop in ¹

'.

In this review, it has not been possible to examine indetail the development of adhesives for another impor-tant skin application, that of wound-healing products.We propose to do this in a subsequent publication.

Acknowledgements

The authors would like to thank Greg Sawin for edit-ing the manuscript, preparing some of the figures and forgeneral advise. We would also like to Angelina Wong(Alza Corporation) for some physical measurements ofadhesion.


Appendix. Family of commercial transdermal systems

Product name Innovator Marketer Active ingredient Systems area(s) (cm2) Delivery rate(s) Rated Enhancer Typeduration

AloraT TheraTech P&G Pharm.* 17b-estradiol 18,27,36 0.05, 0.075, 0.1 mgd~1 4 d Sorbitan monoleate Adhesive matrixClimaraT 3M Pharm. BerlexLabs 17b-estradiol 12.5 & 25 0.05 & 0.1 mgd~1 7 d Fatty acid esters Adhesive matrix

Lohman PharmaDeponitT Neuwied FRG Schwarz Nitroglycerin 16 & 32 0.2 & 0.4 mgh~1 12—14 h ‘A plasticizer’ Adhesive matrix

Propylene glycolFemPatchT Cygnus ParkeDavis 17b-estradiol 30 0.025 mgd~1 7 d monolaurate Adhesive matrixHabitrolT Ciba Ciba Nicotine 10, 20, 30 7, 14, 21 mgd~1 24 h None Pad in adh. matrixMinitranT 3M Pharm. 3M Pharm. Nitroglycerin 20 0.6 mg h~1 12—14 h Fatty acid esters Adhesive matrixNitrodurT Key Key Nitroglyerin 10, 20, 30, 40 0.2, 0.3, 0.4, 0.6,

0.8 mg h~1

12—14 h None Adhesive matrix

TestodermT with ALZA ALZA Testosterone, USP 60 6 mgd~1 24 h None Matrix, striped adhadhesiveMenorestT, VivelleT Noven Ciba, RPR-Novo

Nordisk71b-estradiol 11 & 29 4 Rates, 25—100 lgd~1 3—4 d Oleic acid, propylene

glycol,Adhesive matrix

NicotrolT Cygnus McNeil Nicotine 30 15 mg 16 h~1 (1 d) 16 h None Adhesive matrixAndrodermT TheraTech Smith Kline

BeechamTestosterone, USP 37 & 44 2.5 & 5 mgd~1 24 h Ethanol, glyceryl

mono oleate, methyllaureate, glycerin

FFS**, peripheraladhesive

ProstepT Elan Elan Nicotine 3.5 & 7 11 or 22 mgd~1 24 h None Matrix, peripheraladhesive

NitrodiscT Searle Searle Nitroglycerin 8, 12, 16 0.2, 0.3, 0.4 mgh~1 24 h Polyethylene glycol,Isopropyl palmitate

Matrix, peripheraladhesive

Catapres TTST ALZA Boehringer Clonidine 3, 5, 7 & 10.5 0.1, 0.2, 0.3 mgd~1 7 d None Rate-control memb.Ingelheim

DurageslcT ALZA Janssen Fentanyl 10, 20, 30, 40 25, 50, 75, 100 mgd~1 3 d Ethanol Rate-control memb.EstradermT ALZA Ciba Geneva 17b-estradiol 10 & 20 0.05 & 0.1 mgd~1 3 d Ethanol Rate-control memb.NicodermTCQ ALZA Smith Kline Nicotine 7, 15 & 22 7, 14 & 21 mgd~1 24 h None Rate-control memb.

BeechamTransderm-NitroT ALZA Ciba Geneva Nitroglycerin 5, 10, 20, & 30 0.0, 0.2, 0.4

& 0.6 mg h~1

12—14 h None Rate-control memb.

Transderm ScopT ALZA Ciba SelfMed Scopolamine 2.5 0.5 mg/3d~1 3 d None Rate-control memb.*Proctor & Gamble **FFS"Form-fill-

seal

S.Venkatram

an,R

.G

ale/B

iomaterials

19(1998)

1119—11361135

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Skin adhesives and skin adhesion: 1. Transdermal drug delivery systems

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