reviews research focus
2 February 1999
Pressure-sensitive adhesives for
transdermal drug delivery systems
Hock S. Tan and William R. Pfister
Adhesives are a critical component in transdermal drug delivery (TDD)
devices. In addition to the usual requirements of functional adhesive
properties, adhesives for TDD applications must have good biocom-
patibility with the skin, chemical compatibility with the drug, various
components of the formulation, and provide consistent, effective
delivery of the drug. This review discusses the three most commonly
used adhesives (polyisobutylenes, polyacrylates and silicones) in TDD
devices, and provides an update on recently introduced TDD products
and recent developments of new adhesives.
▼ Transdermal drug delivery (TDD) systems are
Hock S. Tan*
drug-loaded adhesive patches which, when ap-
and William R. Pfister
Lavipharm Laboratories Inc. plied to the skin, deliver the therapeutic agent, at
131 Ethel Road West a controlled rate, through the skin to the sys-
Suite 6 temic circulation and to the target organs. The
Piscataway first commercial TDD system, Transderm-Scop®,
New Jersey 08854
a controlled delivery system for scopolamine,
USA
*tel: 11 732 572 9660
was developed by Alza Corporation (Palo Alto,
fax: 11 732 572 1306 CA, USA) and in 1980 it was introduced to the
US market for the treatment of motion sickness.
Since then, seven drugs and more than 25 differ-
ent TDD products in multiple dosages and
strengths for the systemic treatment of various
diseases have been marketed in the USA1. These
include nitroglycerin for the treatment of angina
pectoris, clonidine for hypertension treatment,
fentanyl for pain management, estradiol – alone
or in combination with norethindrone acetate –
for the relief of postmenopausal symptoms and
treatment of osteoporosis, nicotine as an aid in
smoking cessation, and testosterone for the treat-
ment of hypogonadism.The TDD product market
and dosage form designs have recently been re-
viewed1. A summary of the TDD products mar-
keted in the USA is given in Table 1. Transdermal
drug delivery products that were introduced
in 1998 included FemPatch® (Cygnus, Inc.,
60 1461-5347/99/$ – see front matter ©1999 Elsevier Science. All rights reserved. PII: S1461-5347(99)00119-4
PSTT Vol. 2, No.
Redwood City, CA, USA) and CombiPatch®
(Noven Pharmaceuticals, Miami, FL, USA) for
hormone replacement therapy.
Transdermal drug delivery systems, as com-
pared to their corresponding classical oral or in-
jectable dosage form counterparts, offer many
advantages1–3.The most important advantages are
improved systemic bioavailability of the pharma-
ceutical active ingredients (PAI), because the
first-pass metabolism by the liver and digestive
system are avoided; and the controlled, constant
drug delivery profile (that is, controlled zero-
order absorption). Also of importance is the re-
duced dose frequency compared to the conven-
tional oral dosage forms (that is, once-a-day,
twice-a-week or once-a-week). Other benefits in-
clude longer duration of therapeutic action from
a single application, and reversible action. For
example, patches can be removed to reverse any
adverse effects that may be caused by overdosing.
In TDD applications, adhesives are used to
maintain intimate contact between the patch and
the skin surface. Many classes of adhesives
are available that might be considered for use
with TDD patches, although in practice pressure-
sensitive adhesives (PSAs) are preferred. Pressure-
sensitive adhesives are generally defined as ma-
terials that adhere to a substrate with light pressure
and which leave no residual adhesive upon their
removal4.They offer the advantages of convenience
of use (PSAs do not require water/solvents or heat
in order to achieve adhesion), good stability (PSAs
are generally not sensitive to environmental hu-
midity or temperature degradation), simplicity of
manufacture, and good appearance5.
In addition to the usual requirements of func-
tional pressure-sensitive adhesive properties,
such as adequate tack, skin-adhesion and cohe-
sive strength, there are other factors to be consid-
ered in the selection and use of PSAs for TDD sys-
tems.These include biocompatibility, formulation
PSTT Vol. 2, No. 2 February 1999 research focus reviews

Table. 1. Transdermal drug delivery (TDD) products marketed in the United States

Drug Product Developer/marketer TDD system designa Pressure-sensitive

adhesive typeb

Clonidine Catapres-TTS® Alza/Boehringer Ingelheim DIA-multi-laminate PIB

Estradiol Climara® 3M Pharmaceuticals/Berlex/Schering AG DIA-monolithic Acrylate
Estradiol Estraderm® Alza/Novartis Reservoir PIB
Estradiol Vivelle® Noven/Novartis DIA-monolithic Acrylate
Estradiol FemPatch® Cygnus/Parke-Davis DIA-monolithic Silicone
Estradiol/ CombiPatch® Noven/Rhone-Poulenc Rorer DIA-monolithic Acrylate
Norethindrone
Acetate
Fentanyl Duragesic® Alza/Janssen Pharmaceutical Reservoir Silicone
Nicotine Nicoderm® Alza/SmithKline Beecham DIA-multi-laminate PIB
Nicotine Harbitrol® Lohmann/Novartis Polymer matrix Acrylate
Nicotine Nicotrol® Cygnus/McNeil Consumer Products DIA-monolithic PIB
Nicotine Prostep® Elan/Lederle Polymer matrix Acrylate
Nitroglycerin Transderm-Nitro® Alza/Novartis Reservoir Silicone
Nitroglycerin Minitran™ 3M Pharmaceuticals DIA-monolithic Acrylate
Nitroglycerin Nitro-Dur® Key Pharmaceuticals/Schering Plough DIA-monolithic Acrylate
Nitroglycerin Nitrodisc® G.D. Searle/Roberts Polymer matrix Acrylate
Nitroglycerin Deponit® Lohmann/Schwarz Pharma DIA-multi-laminate PIB
Scopolamine Transdermal-Scop® Alza/Novartis DIA-multi-laminate PIB
Testosterone Androderm® TheraTech/SmithKline Beecham Reservoir Acrylate
Testosterone Testoderm® Alza DIA-monolithic EVA

aTDD system designs: drug-in-adhesive (DIA), liquid reservoir (reservoir), multi-laminate drug-in-adhesive (DIA)/control membrane composite (multi-laminate)
bPSA Types: polyisobutylene (PIB), polyacrylate copolymer (acrylate), polysiloxane-based (silicone), ethylene-vinyl acetate copolymer (EVA).

compatibility, delivery system compatibility, and acceptable
regulatory status (that is, the availability of drug master files or
equivalent supporting documentation). Biocompatibility re-
quires that the PSAs are biologically inert, non-irritating and
non-sensitizing to skin, and have no systemic toxicity. Formu-
lation compatibility requires that the PSAs do not induce drug
or excipient degradation, do not react with the drug and other
formulation components, maintain stability and functional
properties when formulated, and offer the desired solubility.
Delivery system compatibility requires that the PSAs provide
adequate diffusivity and permeability to the drug and/or per-
meation enhancers6,7. Pressure-sensitive adhesives are therefore
regarded as one of the critical components in TDD devices1.
Thus, making a change in the PSA component of a TDD system
might be considered to be a major change that would require
the demonstration of bioequivalence and necessitate a regula-
tory amendment.
This review discusses TDD products, transdermal system de-
signs and components, and focuses on the PSAs that are cur-
rently used in TDD devices. In addition, this review highlights
some recent advances, including new TDD products and inno-
vative developments in PSA technology. Earlier reviews on the
subject of PSAs, along with other components, used in com-
mercial TTD products may be found in the References 6–9.
Transdermal drug delivery system designs
Transdermal drug delivery can be achieved via active or passive
systems, depending on whether external energy is used to as-
sist the transport of the drug through the skin10.The active sys-
tems use heat, electric current (iontophoresis), sound waves
(sonophoresis), or transient high-voltage electrical pulses
(electroporation) to enhance the delivery of drugs into the sys-
temic circulation10–12. Ionophoretic drug delivery devices have
been used for more than a decade for local delivery of PAI in
the treatment and diagnosis of disease (that is, skin inflam-
mation, psoriasis, local anesthesia, muscle ache and pain).
The ionophoretic devices are now in the clinical development
stage for systemic drug delivery, and commercial applications
can be expected within three to five years10.
In passive TDD systems, the drug diffuses through the skin into
the systemic circulation by passive means.The concentration gra-
dient of the drug across the skin and the difference in solubility

61
reviews research focus
(a) Drug-in-adhesive: (b) Drug-in-adhesive:
monolithic multilaminate
Impermeable backing
Drug-adhesive matrix
Rate-controlling
membrane
Adhesive
Release liner
(c) Liquid reservoir (d) Polymer matrix
Impermeable backing
Drug–polymer matrix
Drug reservoir
Rate-controlling
membrane
Adhesive
Release liner
Figure 1. Typical designs of transdermal drug delivery (TDD) systems.
between the adhesive and skin are the driving force for delivery
to the surface of the skin. In general, chemical permeation en-
hancers (pharmaceutical excipients) are required for passive de-
livery to achieve the required delivery of the drug from a patch
of a reasonable size (that is, a surface area of <40 cm2).There are
four major designs of the conventional passive TDD patches9, and
each imposes slightly different requirements on the PSAs.
In the simplest form, the adhesive matrix or drug-in-adhesive
(DIA) design, the drug is directly loaded or dispersed into the
PSA polymer.The monolithic DIA design configuration is shown
in Fig. 1(a). The adhesive matrix provides several functions, in-
cluding skin adhesion, storage of the drug, and control over
drug/enhancer delivery rate, and it also governs their partition-
ing into the stratum corneum. The DIA matrix is supported on
the topside by an impermeable backing film and on the side that
faces the skin it is laminated with a removable release liner.
This simplest design imposes the most stringent require-
ments on the PSA used. Drug-in-adhesive matrix patches re-
quire long-term compatibility between the adhesive, the drug,
and any excipients, such as skin permeation enhancers, incor-
porated into the formulation. The drug must be released from
the matrix in a consistent and reproducible manner, and the
drug and the excipients must not adversely affect the adhesive
properties of the PSA used. In addition, the functional adhesive
properties of the matrix formulation must be consistently
maintained throughout the application period as the drug
and/or the excipients are depleted from the DIA matrix. The
matrix construction is easier to manufacture on standard
coaters, but the drug and excipients are exposed to elevated
62
PSTT Vol. 2, No. 2 February 1999
temperature during oven drying.This may cause an undesirable
chemical reaction or the loss of active substances and excipients
because of evaporation5.
A sub-category of DIA patch design is the multi-laminate
configuration, as shown in Fig. 1(b). The multi-laminate DIA
design features either an addition of a membrane between the
DIA layer and the skin-contacting adhesive layer or merely mul-
tiple DIA layers supported by a single backing film9.
The liquid reservoir design consists of a drug-loaded reser-
voir located between a backing film and a rate-controlling
membrane, and a skin-contacting PSA layer [Fig. 1(c)].The liq-
uid reservoir compartment contains the drug and permeation
enhancer, which may be in solution or dispersion. Similar to
the adhesive matrix design, the system is supported by an im-
permeable backing film, and the adhesive surface is protected
by a release liner. Because the drug and permeation enhancers
must diffuse through the adhesive layer, the adhesive polymer
used should not be physiochemically incompatible nor have
chemical interaction with the diffusing active and inactive in-
gredients, nor should it affect the delivery rate of the drug.
The polymer matrix design is similar to the liquid reservoir-
type design but has, instead of a continuous adhesive layer, a
peripheral ring of adhesive that is located around the edge of
the patch [Fig. 1(d)]. Because the adhesive does not come into
direct contact with the drug, only its adhesive properties and
skin safety characteristics are of concern. However, because of
the smaller adhesive-contact area with the skin, the adhesive
used in this design should have a higher skin-adhesion prop-
erty than those used in other TDD design configurations.
The selection of a particular patch design and size are dic-
tated by the required rate and extent of drug delivery, which in
turn depends on the formulation of the system, stability, adhe-
sive performance properties, safety, patentability and infringe-
ment issues, pharmacodynamic profile and aesthetic character-
istics1. The various patch design configurations associated with
TDD products marketed in the USA are provided in Table 1.
Pressure-sensitive adhesives (PSAs) for TDD systems
Pressure-sensitive adhesives have been used for decades in
medical devices, tapes, and dressings13, and, naturally, since the
development of TDD devices in the 1980s the use of PSAs have
been extended to these devices. Three types of PSAs are com-
monly used in TDD devices: polyisobutylenes (PIBs), polysilox-
anes (silicones) and polyacrylate copolymers (acrylics)5,6,9,10.
These synthetic hypoallergenic PSAs are largely used in TDD
systems for local and systemic drug delivery1. Natural rub-
ber/karaya gum-based adhesives are another class of PSAs used
in many over the counter (OTC) dermal therapeutic systems1.
Although these four classes of polymers are very different in
their chemical properties and molecular structure, they are all
PSTT Vol. 2, No. 2 February 1999 research focus reviews

accepted for use in TDD and dermal therapeutic systems and Silicate resin Dimethylsiloxane polymer
other medical applications in which skin contact is required.This CH3
is because, in general, these polymers have been shown to be H3C Si CH3
biologically inert, non-sensitizing and non-irritating to skin, and CH3 CH3 CH3
O
to not cause systemic toxicity. The selection of a particular PSA to H O Si O H + OH Si O Si O Si OH
O CH3
be used in a TDD system is based on many factors, including CH3 CH3
m
H3C Si CH3
patch design, the system formulation, intended wear time (such
CH3
as 24 or 72 hours or one week), wear conditions (for example, n
Condensation
humidity, bathing and sweating), and processibility.
CH3
Polyisobutylenes H3C Si CH3
Polyisobutylenes are elastomeric polymers that are commonly O CH3 CH3 CH3
used in PSAs, both as primary-base polymers and as tacki- H O Si O Si O Si O Si OH

fiers14. They are homopolymers of isobutylene and feature a
regular structure of a carbon–hydrogen backbone with only
terminal unsaturation (Fig. 2). This molecular structure leads
to chemical inertness and good resistance to weathering, age-
ing, heat and chemicals.Their stability, inertness, and broad ac-
ceptance in FDA-regulated applications means that PIBs are a
good candidate adhesive for use in TDD devices6.
Because of their highly paraffinic and nonpolar nature, PIBs
are soluble in typical aliphatic and aromatic hydrocarbon sol-
vents, but not in common alcohols, esters, ketones and other
oxygenated solvents. The structure of the close and unstrained
molecular packing leads to the low air, moisture and gas per-
meability of PIBs14,15. The higher the molecular weight of the
PIB, the lower its permeability15. Polyisobutylenes are, there-
fore, preferred for use with drugs with a low solubility param-
eter and low polarity.
The amorphous characteristics and low glass transition tem-
perature (Tg, 2628C) of PIBs impart high flexibility and per-
manent tack. Despite the favorable tack property, adhesion of
PIBs to many surfaces is weak because of their low polarity.
This problem is overcome by the addition of tackifiers (such as
rosin ester resins) and other materials that will impart some
polar properties to the formulation.
Polyisobutylenes are produced over a wide range of molecu-
lar weights15,16. The low molecular weight PIBs are very vis-
cous, soft, and tacky semi-liquids, whereas the high molecular
weight grades are tough and elastic rubbery solids15. The low
molecular weight polymers are primarily used as tackifiers to
CH3 CH3
C CH2 C CH2
CH3 CH3
n
Isobutylene Polyisobutylene
Figure 2. Polymerization of isobutylene to polyisobutylene.
O CH3 CH3 m CH3
H3C Si CH3
CH3
n
Figure 3. The chemistry of silicone pressure-sensitive adhesives (PSAs).
provide tack to the high molecular weight PIBs or other adhe-
sive polymers. The high molecular weight PIBs are used to
impart internal strength and flow resistance of PSAs.
Because the manufacturers of PIB polymers do not supply
pre-formulated, ready-to-use adhesives, the TDD patch manu-
facturers or formulators often formulate their own PIB–PSA
formulations. Two common approaches have been used to ob-
tain the desired PSA properties. First, a combination of low and
high molecular weight PIBs is used to achieve a balance of tack
and cohesive strength. Second, tackifiers, plasticizers, fillers,
waxes, oils and other additives can be incorporated into the
formulation to impart the desired adhesive properties and vis-
cosity. Examples of tackifiers include low molecular weight
polybutenes, rosin ester resins, hydrocarbon resins and polyter-
penes17–19. Many types of plasticizers are available18; examples
include mineral oil, diethyl phthalate, dioctyl phthalate or other
phthalates and adipates, as well as citrate esters such as acetyl
tributyl citrate. Examples of fillers include fumed silicas, silica
gels, clay, microcrystalline wax and microcrystalline cellulose.
Because of their favorable stability over a wide range of tem-
peratures, humidity and electromagnetic radiation (UVA, UVB
and UVC lights), PIBs do not normally contain stabilizers. If
necessary, anti-oxidants or stabilizers can be added to signifi-
cantly extend the resistance to extreme conditions15.
A representative PIB-based PSA formulation for a TDD appli-
cation is provided in Table 2. In this formulation, toluene is used
to rapidly dissolve the polymers, while hexane gives the lowest
solution viscosity, which facilitates easier processing15. Other ex-
amples of PIB-based PSA formulations can be found in the ref-
erence handbooks14,19 and patent literature20,21. Major suppliers
of PIBs include Exxon Chemical Company (Houston, TX, USA)

63
reviews research focus PSTT Vol. 2, No. 2 February 1999

devices, and their chemical and physiological inertness are well

Table 2. Polyisobutylene (PIB)-based pressure-sensitive
documented in the scientific literature6.
adhesive (PSA) formulation for transdermal drug delivery
devices Silicone PSA formulations are based on two major compo-
nents: a polysiloxane (silicone) polymer and a silicate resin7,28
Component Description Supplier Content (Fig. 3).The polymer is a high molecular weight polydimethyl-
siloxane that contains residual silanol functionality (SiOH) on
Vistanex® High molecular Exxon Chemical 12.5% the ends of the polymer chains.The resin is a three-dimensional
MM L-100 weight PIB trimethylsiloxy and hydroxyl end-blocked silicate structure.The
Oppanol® B10 Low molecular BASF 12.5%
silicone polymer and silicate resin are dissolved together in a
weight PIB
nonpolar hydrocarbon solvent (such as xylene and hexane).
Escorez® Rosin Ester Exxon Chemical 5.0%
1310 LC tackifying resin
During processing, a condensation reaction takes place be-
Hexane Solvent Various 30.0% tween the silicone polymer and the silicate resin. This conden-
Toluene Solvent Various 40.0% sation results in a network of polymer chains that are
crosslinked with the resin molecules.The final silicone PSA for-
mulation can therefore be considered to be a one-component
system, unlike the PIB-based PSA formulations, which are
Table 3. Commercial grades of polyisobutylene commonly merely a physical blend of a high molecular base polymer and
used in pressure-sensitive adhesive15,16 a low molecular weight polymer or tackifying resin. The ratio
Supplier Product name Grade Viscosity average of resin to polymer is used to produce PSAs with a wide range
molecular weight of adhesive properties. Increasing the polymer content provides
a softer and tackier adhesive, whereas higher resin levels pro-
Exxon Vistanex® LM-MS 43,000–46,000 duce an adhesive with a lower tack but higher adhesion and re-
LM-MH 51,000–56,000 sistance to cold flow6,28. The other important factor that con-
LM-H 58,000–68,000 trols the adhesive properties is the level of silanol functionality
MM L-80 750,000–1,050,000 present in the final polymer and resin formulation.
MM L-100 1,060,000–1,440,000 Polydimethylsiloxanes have a unique molecular structure in
MM L-120 1,450,000–1,870,000
which an inorganic silica-like backbone (-Si-O-Si-) supports a
BASF Oppanol® B10 40,000
regular arrangement of pendant methyl groups7. The low Tg of
B12 55,000
21278C and the unique semi-organic structure give silicone a
B15 85,000
B30 200,000 highly flexible and extremely open macromolecular architec-
B50 400,000 ture with a high void volume. This structure enables silicone
B100 1,110,000 PSAs to have a high permeability to vapour, gases and a wide
B150 2,600,000 variety of therapeutic molecules7. Silicone PSAs that are com-
patible with amine-functional drugs have been manufactured
by end-capping the reactive silanol end groups in an additional
and BASF Corporation (Mount Olive, NJ, USA). Various grades stage of the commercial manufacturing process26,29.
of commercial PIB polymers that are suitable for TDD appli- Silicone adhesives are supplied as two types of pre-formu-
cations are listed in Table 3. Fully formulated PIB adhesives for lated products. The regular type contains residual silanol, and
TDD applications are available from Adhesives Research Inc.
(Glen Rock, PA, USA) and custom formulations can be pro-
H
vided by other vendors [such as Mactac (Moosic, PA, USA) and
O H 2C C
National Starch and Chemical Company (Bridgewater, NJ,
H2C CH C OR C O
USA)]. O
R n
Silicones Acrylic ester
monomer Polyacrylate
Silicone PSAs have been used in medical and healthcare devices
since the 1950s22, and their application in TDD devices has R = H, ethyl, butyl and 2-ethylhexyl
been extensively researched and reviewed 6,7,22–27. Their bio-
compatibility has been established through a history of many Figure 4. Polymerization of acrylic ester monomer to polyacrylate.
years of safe usage, and their application in various medical

64
PSTT Vol. 2, No. 2 February 1999
Table 4. Silicone pressure-sensitive adhesives from
Dow Corning
Resin/polymer ratio Standard product Amine compatible
product
65/34 (low tack) 7–4400 7–4100
60/40 (medium tack) 7–4500 7–4200
55/45 (high tack) 7–4600 7–4300
the amine compatible type has the reactive silanols end-capped.
To improve cohesive strength, reinforcing fillers, such as finely
divided silica, can be incorporated into the silicone PSA formu-
lation30. Water-soluble additives such as ethylene glycol, glyc-
erin, and polyethylene glycols were used to control the water
sorption into the silicone polymer matrix and to enhance the
release of drugs31. Another method of controlling the release of
active agents is to manage the degree of crosslinking in the sili-
cone polymer matrix30. Crosslinking will improve cohesive
strength with a corresponding decrease in tack, adhesion and
drug release properties.
Silicone PSAs for use in pharmaceutical applications are avail-
able from Dow Corporation under the trade name of BIO-
PSA®29.Table 4 lists some of the commercially available silicone
PSAs from Dow Corning (Midland, MI, USA).
Acrylics
Polyacrylates, or more precisely poly(acrylic esters), have been
known for a long time. They have been referred to as acrylic
polymers, or simply acrylics or acrylates. Although their inher-
ent adhesive properties were discovered as early as 1928, poly-
acrylates were not extensively used in PSAs until the 1950s19,32.
In addition to their favorable biocompatibility and good skin-
adhesion property, acrylic PSAs offer advantages of good com-
patibility with a wide range of drugs and excipients, ease of
processing, and flexibility in tailoring the polymer properties.
Acrylics are saturated hydrocarbon polymers.They are there-
fore highly resistant to oxidation, and do not require the addi-
tion of stabilizers, which have the potential to cause skin irri-
tation.The acrylic polymers have a low Tg (255 to 2158C) and
are inherently tacky, and therefore in general they do not re-
quire low molecular weight tackifiers and plasticizers to pro-
vide the tack and softness. The single-component adhesives
have advantages over compounded PSAs in that they do not re-
quire a separate compounding process step, and this avoids the
potential problem of migration of low molecular weight com-
ponents to the adhesive surface.
Acrylic PSAs are produced by copolymerization of acrylic
esters, acrylic acid and other functional monomers (Fig. 4).The
free-radical initiated polymerization process can be performed
research focus reviews
either in organic solvent systems or aqueous emulsion.Various
monomers can be copolymerized to obtain different pendant
ester groups (Fig. 4) on the backbone. These side-chain pen-
dant groups are used to effect the desired adhesive properties,
solubility and permeability. Unlike the PIBs and silicones, the
organic solvent-based and emulsion acrylic PSA prepared di-
rectly from polymerization are the final, ready-to-use adhe-
sives.
Three key parameters have been used to design acrylic poly-
mers and to tailor the polymer properties:
• types of monomers;
• crosslinking of functional groups;
• molecular weight.
In general, the PSA acrylic monomer composition comprises
the following:
• 50–90% of primary monomers;
• 10–40% of modifying monomers;
• 2–20% monomers with functional groups32.
The primary monomers are used to impart the flexibility
and tack of the adhesive. Many alkyl acrylates and methacryl-
ates, particularly those with four to 17 carbon atoms and Tg
ranges of approximately 2508C to approximately 2708C, have
been claimed in the patent literature to be suitable monomers
for this purpose32. In general, the flexibility and tack of the
polymer rises with increasing side-chain length until a certain
chain length is exceeded, beyond which crystalline regions
form which then cause stiffening of the polymer32. In practice,
for economic reasons, only four acrylic esters have been com-
monly used as primary monomers for PSAs: 2-ethylhexyl,
butyl, ethyl and iso-octyl acrylate19,32. Iso-octyl acrylate is not
commercially available, but is manufactured by 3M Company
(St Paul, MN, USA) for captive consumption19. Homopolymers
of these monomers are too soft and tacky. Other modifying
monomers that can impart higher Tg and hardness are used to
obtain a balance of tack and cohesion properties.
Commonly used modifying monomers include vinyl acetate,
methyl acrylate, methyl and ethyl methacrylate, acrylic and
methacrylic acid, acrylonitrile and certain amine-functional
monomers. Copolymerization with vinyl acetate produces a
class of copolymers that are commonly known as vinyl acrylics.
Vinyl acrylics are less polar and have a higher tack, but they
have poorer ageing properties than all-acrylic adhesives32. Also,
in general vinyl acrylics have a much higher amount of residual
monomers because of the lower reactivity of vinyl acetate. Most
newly developed TDD devices use all-acrylic PSAs to minimize
residual monomers and maximize stability.
65
reviews research focus
Modifying monomers may be used to change the solubility
or permeability of the acrylic polymers. For example, water-
soluble or hydrophilic monomers such as vinyl pyrrolidone,
2-hydroxylethyl acrylate, and 2-ethoxyl acrylate have been
used to increase the hydrophilicity of the polymers32.
Crosslinking of acrylic PSAs improves the creep or shear re-
sistance and resistance to cold flow or oozing. Resistance to cold
flow is desirable to prevent the adhesive from oozing or ‘squeez-
ing out’ from under the TDD patch during storage or wear. Ooz-
ing can manifest itself as a ‘dirty’ ring around the patch during
wear or flow beyond the backing material of the patch during
storage in the pouch. In TDD applications, the addition of drug,
permeation enhancers, and other excipients into the adhesives
often compromises the tack, adhesion, and cohesive properties
of the PSAs. Crosslinking of PSAs is one of several techniques
used to minimize these effects and increase the loading level of
the active or excipient in the PSA composition33.
There are two ways to effect crosslinking. The first approach
is crosslinking during the PSA manufacturing process. A small
amount of acrylates or methacrylates with multiple unsatu-
ration can be copolymerized with the acrylic esters to obtain a
lightly crosslinked network during polymerization. Examples
of such monomers include diethyleneglycol diacrylate,
trimethylolpropane trimethacrylate, and hexamethylene glycol
dimethacrylate. This in situ crosslinking during polymerization
usually leads to a viscous polymer solution and makes process-
ing more difficult.
The second approach is more commonly practised and can
be performed by the patch manufacturer. In this approach,
crosslinking of the acrylic polymer occurs through the pendant
functional groups of the polymer when they are coated and
dried in the oven. Monomers with functional groups are intro-
duced into the polymer chain during polymerization. Func-
tional groups commonly used for crosslinking are carboxylic,
hydroxyl, epoxy, amide, and organo-silane. Examples of
monomers with such functionality are acrylic and methacrylic
acid, hydroxylethyl acrylate, hydroxylpropyl acrylate, glycidyl
acrylate and methacrylate, acrylamide, and 3-methacryloxyl-
propyl trimethoxylsilane.
Crosslinking agents are often used to activate the crosslinking
reaction34. Various organic metal crosslinking agents, such as
aluminum or titanium acetyl acetonates, metal alkoxides, and
polybutyl titanate, have been found to be effective in cross-
linking polymers that contain carboxylic and hydroxyl
groups19,32,34. Polybutyl titanate has been reported to produce a
‘yellowish’ dried adhesive on an estradiol patch, whereas the
aluminum acetyl acetonate-crosslinked adhesive was clear35.
The epoxy groups of glycidyl monomers, such as glycidyl
acrylate or methacrylate, react with carboxyl groups without
any crosslinking agent34.
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PSTT Vol. 2, No. 2 February 1999
Molecular weight and molecular weight distribution affect
the adhesive properties of acrylic PSAs. Low molecular weight
polymers generally have good tack but poor mechanical
strength, and they are unacceptable for normal PSA appli-
cations. An increase in molecular weight generally enhances the
cohesive strength of the polymers. In general, higher molecular
weight acrylic PSAs are more tolerant to skin-penetration en-
hancers and, compared to the corresponding low molecular
weight acrylic PSAs, are able to accept a higher loading level33.
Acrylic PSAs that have optimal distribution of low and high
molecular weight components show balanced properties of
tack, adhesion and cohesive strength. The molecular weight of
acrylic polymers can be controlled by the mode of polymeriz-
ation and the polymerization conditions (such as reaction tem-
perature and reaction duration). Various modes of polymeriz-
ation may be employed. For example, polymerization may be
performed in a batch process in which all components are
charged at the start of polymerization, or a semi-batch process
with partial charge at the start of the reaction, and then the de-
layed, progressive addition of monomers, solvents or initiators
during the course of polymerization.
Table 5 provides a polymerization recipe for the preparation
of an acrylic PSA. Major suppliers of pharmaceutical-grade
acrylic PSAs include National Starch and Chemical Company,
Solutia Inc. [Springfield, MA, USA (formerly Chemical Group
of Monsanto Company)], and Adhesives Research, Inc. Most of
the PSA products supplied by National Starch and Adhesive
Research are solvent-borne. Solutia markets both solvent and
emulsion (waterborne) PSAs for medical applications.
Recent developments
Recent developments in new adhesives for TDD applications
have focused on two objectives. The first has been aimed at
the development of adhesives that enhance TDD rates. These
adhesives include PSAs that have better compatibility with a
wider range of drugs at higher drug-loading levels, and those
that tolerate higher loading levels of permeation enhancers
without sacrificing adhesive properties. The second objective
Table 5. Acrylic pressure-sensitive adhesive monomer
composition for transdermal drug delivery applications
Component Function Amount
2-ethylhexyl acrylate Backbone monomer 50
Butyl acrylate Backbone monomer 45
Acrylic acid Functional monomer 5
Azobis (2-methylbutane Initiator 0.5
nitrile)
Ethyl acetate Solvent 90
PSTT Vol. 2, No. 2 February 1999
has been focused on the development of adhesives with improved
biocompatibility, skin-adhesion and wear properties.The desired
improvements include better adhesion to skin, longer wear time,
and smoother, less painful – or even painless – peel-off.
Two approaches have been taken to achieve these objectives.
The first involves the development of new polymers, which are
beyond the conventional chemistries of PIBs, silicones, and
acrylates. These new polymers include hydrogels36–41, hydro-
philic polymers42–44, and polyurethanes45,46. The second ap-
proach is to physically or chemically modify the chemistries of
the PSAs in current use (such as PIBs, silicones, and acrylates).
Physical modification refers to the formulation of the base ad-
hesives with some unique additives so that, in synergy with the
drug and excipients in the system formulation, the result is en-
hanced drug delivery and improved skin-adhesion properties.
Chemical modification involves chemically incorporating or
grafting specialty functional monomers to the conventional
PSA polymers in order to improve drug delivery rates. The sec-
ond method may be performed by the PSA vendor and offered
as a new product or performed by the end user on a commer-
cially available PSA. Polymers developed through the use of
these two approaches will be discussed in detail.
Hydrogel PSAs
Conventional PSAs based on PIBs, silicones, and acrylates are
hydrophobic in nature with a low residual water content
(,0.1%) after drying. Hydrophilic ‘hydrogel’ PSA compos-
itions have recently been developed. These compositions have
been shown to be compatible with drugs of different chemical
structures and to provide high TDD rates even without skin-
penetration enhancers36,37. A hydrogel is defined as a water-
swollen but water-insoluble crosslinked polymer, and normally
contains at least 20% of water at equilibrium.The reported ‘hy-
drogel’ PSA features high molecular weight polyvinyl pyrroli-
done (PVP) and oligomeric polyethylene glycol (PEG)38, with
an equilibrium water content of 8–11% (Ref. 36). The cross-
links are formed through hydrogen bonding and the polymer
is therefore water soluble. This hydrophilic polymer was re-
ported to have the ability to absorb moisture from the skin39.
A two-stage mechanism for the formation of a PVP–PEG hy-
drogel PSA has recently been proposed40.The first stage is the for-
mation of hydrogen bonding between the terminal hydroxyl
groups of PEG with the carbonyls in the repeated units of longer
PVP chains40.The hydrogen-bonded PEG forms flexible interpen-
etrating chains that cross-link the longer PVP chains.The second
stage involves the gradual dissolving of the crosslinked complex in
excess PEG40. The resulting hydrogels exhibit an excess free vol-
ume, which governs the viscoelasticity, adhesion and diffusivity
properties. Several commercial TDD products have been developed
in Russia and Lithuania that are based on this formulation36.
research focus reviews
Another crosslinked, vinyl pyrrolidone-based hydrogel poly-
mer was developed with the objective of obtaining a PSA that
tolerates the incorporation of substantial amounts of water
without phase separation and a loss of adhesion properties 41.
The polymer was composed of vinyl pyrrolidone, a multi-
ethylenically unsaturated compound as crosslinker, and glycerol
and water as plasticizers, and was crosslinked with UV radi-
ation41. The resulting gel, approximately 35 mil thick, was
reported to be clear, tacky, and released cleanly from skin41.
Hydrophilic PSAs
Another approach designed to impart hydrophilicity is based
on plasticizing high Tg aminoalkyl methacrylate copoly-
mers42,43. The base polymers are cationic or anionic copoly-
mers of dimethylaminoethyl methacrylate, methacrylic acid
and methacrylic acid esters in varying ratios, and are primarily
used in oral capsule and tablet formulations as film-coating
agents43. Plasticizing these polymers with acetyl tributyl citrate
and crosslinking with succinic acid results in hydrophilic ad-
hesives with pressure-sensitive properties43. The cohesion
strength is provided by the ionic crosslinking of succinic acid
with the amino functionality of the polymers43.These PSAs are
insoluble in water but swell in water and are permeable to
water vapour43. They can be easily removed from the skin by
water washing but are able to withstand short showers for sev-
eral days in TDD applications43. Aqueous solution for this PSA
system has been prepared by formulating these polymers with
water-soluble or hydrophilic plasticizers, such as polyethylene
glycol, glycerin, triethanolamine, or triethyl citrate44.
Commercial products of the aminoalkyl methacrylate
copolymers are available from Rohm America Inc. (Somerset,
NJ, USA) under the trade name of Eudragit®.
Polyurethanes
Polyurethanes are another class of recently developed hydro-
philic PSAs45,46. Polyurethanes are polymeric products of diols
or polyols and diisocyanates or polyisocyanates. Polyurethane
PSAs with a Tg of less than 2308C have been developed for use
in medical applications45. These polymers are reported to ex-
hibit a high degree of water absorption and water vapor trans-
mission capabilities, and to have a good balance of cohesion
and adhesion properties45. The balance of cohesion and adhe-
sion is obtained by controlling the crosslink density of the poly-
mer. Water absorption properties are controlled by the amount
of polyoxyethylene in the polyols45. An increase in the amount
of polyoxyethylene promotes stronger hydrophilicity, whereas
an increase in the proportion of polyoxypropylene lessens the
hydrophilic property45. Polyurethane PSAs that are com-
pounded with water-soluble polymers, such as polyvinyl
methyl ether, have been reported to enhance water uptake46.
67
reviews research focus
Graft copolymers and enhancer-tolerant PSAs
Hydrophilic acrylic PSAs have also been prepared through the
use of a more conventional method (that is, by the copolymer-
ization of acrylic esters with hydrophilic monomers). A water-
absorbent copolymer comprising a carboxylic hydroxyalkyl
ester monomer and a water-soluble macromer, such as an
ethoxylated or propoxylated hydroxyalkyl methacrylate, has
been prepared for use in medical adhesive applications47. A
macromer is a macromonomer or a polymer with a polymer-
izable group at the end of the chain. Copolymerization of
acrylic esters with macromers is one of the approaches that
may be used to prepare graft copolymers.
Acrylic-based graft polymers from macromers of different
chemical structures have been prepared in order to obtain vari-
ous desired properties (such as better adhesion, resistance to
permeation enhancers, and improved permeability). Acrylic
PSAs with a methacrylate-terminated styrene macromer have
been prepared and were reported to feature less adhesion
build-up on skin over time48. An enhancer-tolerant PSA that
comprises a fatty acid ester-enhancer and a macromer-
reinforced acrylic polymer has been reported49,51. The
macromer is a polystyrene methacrylate macromer. It was re-
ported that the backbone of the copolymer and the grafted
macromer are incompatible and thus are ‘phase separated’49.
Reinforcement is achieved through the phase separation of the
polymeric graft domains within the continuous polymer ma-
trix50. When such a polymer system is compounded with fatty
acid esters, the resulting adhesive formulation possesses an ap-
propriate balance of flow and cohesive strength50.
Polymeric graft moiety may be attached to the acrylic poly-
mer backbone by post-polymerization reaction of a polymeric
moiety with the suitable grafting sites on the polymer back-
bone51. Polymers with a wide range of solubility parameters
(such as polyisobutylene, polyethylene oxide, polyvinyl ac-
etate, polyvinyl pyrrolidone, and polysaccharide) have been
grafted to the acrylic polymer51.These graft polymers were re-
ported to have better compatibility with many skin penetration
enhancers51.
Silicone graft copolymers have been prepared for TDD appli-
cations52. The polyethylene oxide-grafted silicones have poten-
tial application as silicone PSAs with improved permeability
and solubility for hydrophilic drugs7.
An electron-beam crosslinked acrylic PSA has been reported
to be tolerant of alcohol-based permeation enhancers53. The
monomer composition primarily comprises iso-octyl acrylate
and acrylic acid53.
Polymer modifications
Many specific polymers or PSA formulations have been
claimed, in the patent literature, to enhance the delivery of spe-
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PSTT Vol. 2, No. 2 February 1999
cific drugs. A copolymer containing 2-ethylhexyl acrylate and
vinyl pyrrolidone was reported to have the advantage of main-
taining a relatively high concentration of estradiol in the TDD
matrix without estradiol crystallization54. The two monomers
have very different reactivity ratios, and the copolymer was
therefore thought to have ‘block copolymer’ characteristics,
with distinct vinyl pyrrolidone and ethylhexyl acrylate do-
mains55. A combination TDD DIA-type patch that contained
estradiol and another steroid was prepared by using this
copolymer55. It was reported that the respective fluxes of estra-
diol and the other steroid from the matrix are independent of
the respective concentrations of the other steroid and estradiol
in the matrix55.
Adhesives based on the simple blending of conventional
PSAs with other polymers or excipients have been reported to
impart additional benefits to TDD devices. A blend of silicone
PSAs with PVP has been found to prevent the crystallization of
several drugs56. A TDD system for the delivery of flurbiprofen
using a blend of acrylic PSAs and PVP has been reported57. The
inclusion of monoglyceride into an acrylic PSA in a TDD matrix
for the delivery of isosorbide dinitrate was reported to improve
skin adhesion and the release of isosorbide dinitrate58. The
composition was claimed to have excellent adhesion to the skin
and does not cause pain and damage to the stratum corneum
when peeled off 58.The addition of clay has been claimed to im-
prove the cohesiveness of PSAs in transdermal formulations
without reducing the rate of drug delivery59.
Summary
Adhesives are, besides the drug, one of the more important
components in TDD devices. In addition to the usual require-
ments of adhesive performance properties, adhesives for TDD
applications must have good biocompatibility with the skin,
chemical compatibility with the drug formulation, and provide
consistent and effective delivery of the drug.The adhesives must
function under a wide range of conditions in order to hold the
TDD devices in intimate contact with the skin for periods of up
to seven days.The three classes of PSAs most widely used in TDD
devices are PIBs, silicones, and polyacrylates.
Polyisobutylenes are paraffinic hydrocarbon polymers with
low moisture and gas permeability, and are relatively inert,
odorless and nontoxic. Polyisobutylene PSAs are generally com-
posed of mixtures of high and low molecular weight PIBs, and
are formulated in-house. Silicone PSAs are made of silicate resin
and silicone polymer. The unique molecular structure of sili-
cone imparts good skin-adhesion properties and favorable dif-
fusion characteristics for many drugs. Acrylic PSAs are single-
component systems that are inherently tacky without requiring
additional compounding. Acrylic polymers with a wide range of
adhesive properties can be prepared by copolymerizing different
PSTT Vol. 2, No. 2 February 1999 research focus reviews

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