Polymers in Transdermal

Drug Delivery Systems

Sateesh Kandavilli, Vinod Nair, and Ramesh Panchagnula*

Polymers are
the backbone of
a transdermal
drug delivery
system.
Advances in
the field of
polymer
science have
paved the
way for transdermal delivery system designs
that have considerable flexibility. An
impressive amount of technical know-how
has been gained in this area of research.
This article summarizes the formulation
aspects of transdermal drug delivery
systems and emphasizes the physicochemical and mechanical properties of
various polymers being used in
commercially available transdermal drug
delivery systems. It is intended as a guide
for the selection of polymers for developing
such systems.

Sateesh Kandavilli, Vinod Nair, and

Ramesh Panchagnula, PhD, are
employed in the Department of
Pharmaceutics, National Institute of
Pharmaceutical Education and Research
(NIPER), Sector-67, Ph-X, SAS Nagar-160
062, Punjab, India, tel:
91 172 214 682 or
214 687, fax
91 172 214 692,
panchagnula@yahoo.com.
*To whom all correspondence should be addressed.

62

Pharmaceutical Technology

MAY 2002

he development of transdermal drug delivery systems is

a multidisciplinary activity that encompasses
fundamental feasibility studies starting from the selection of a drug molecule to the demonstration of sufficient drug flux in an ex vivo and/or in vivo model
the fabrication of a drug delivery system that meets all the
stringent needs that are specific to the drug molecule (physicochemical and stability factors), the patient (comfort and cosmetic appeal), the manufacturer (scale-up and manufacturability), and most important, the economy.

Polymers
Polymers are the backbone of a transdermal drug delivery system. Systems for transdermal delivery are fabricated as multilayered polymeric laminates in which a drug reservoir or a
drugpolymer matrix is sandwiched between two polymeric
layers: an outer impervious backing layer that prevents the loss
of drug through the backing surface and an inner polymeric
layer that functions as an adhesive and/or rate-controlling membrane. Transdermal drug delivery systems are broadly classified
into the following three types (1) (see Figure 1).
Reservoir systems. In this system, the drug reservoir is embedded between an impervious backing layer and a ratecontrolling membrane. The drug releases only through the
rate-controlling membrane, which can be microporous or nonporous. In the drug reservoir compartment, the drug can be
in the form of a solution, suspension, or gel or dispersed in a
solid polymer matrix. On the outer surface of the polymeric
membrane a thin layer of drug-compatible, hypoallergenic
adhesive polymer can be applied.
Matrix systems. Drug-in-adhesive system. The drug reservoir is
formed by dispersing the drug in an adhesive polymer and then
spreading the medicated polymer adhesive by solvent casting
or by melting the adhesive (in the case of hot-melt adhesives)
onto an impervious backing layer. On top of the reservoir, layers of unmedicated adhesive polymer are applied.
Matrix-dispersion system. The drug is dispersed homogeneously
in a hydrophilic or lipophilic polymer matrix. This drugcontaining polymer disk then is fixed onto an occlusive base
plate in a compartment fabricated from a drug-impermeable
backing layer. Instead of applying the adhesive on the face of
the drug reservoir, it is spread along the circumference to form
a strip of adhesive rim.
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Reservoir system

Matrix-dispersion
system

Peripheral adhesive
design
Backing layer
Rate controller
Adhesive layer

Microreservoir
system
Drug reservoir
Release liner
Occlusive baseplate

Figure 1: Representative designs of transdermal drug delivery systems.

Microreservoir systems. This drug delivery system is a combination of reservoir and matrix-dispersion systems. The drug
reservoir is formed by first suspending the drug in an aqueous
solution of water-soluble polymer and then dispersing the solution homogeneously in a lipophilic polymer to form thousands of unleachable, microscopic spheres of drug reservoirs.
The thermodynamically unstable dispersion is stabilized quickly
by immediately cross-linking the polymer in situ.
Transdermal drug delivery technology represents one of the
most rapidly advancing areas of novel drug delivery. This
growth is catalyzed by developments in the field of polymer
science. This article focuses on the polymeric materials used
in transdermal delivery systems, with emphasis on the materials physicochemical and mechanical properties, and it seeks
to guide formulators in the selection of polymers. Polymers
are used in transdermal delivery systems in various ways, including as
matrix formers
rate-controlling membranes
pressure-sensitive adhesives (PSAs)
backing layers
release liners.
Polymers used in transdermal delivery systems should have
biocompatibility and chemical compatibility with the drug and
other components of the system such as penetration enhancers
and PSAs. They also should provide consistent, effective delivery of a drug throughout the products intended shelf life or
delivery period and have generally-recognized-as-safe status.
From an economic point of view, a delivery tool kit rather than
a single delivery tool is most effective (2).
Companies involved in the field of transdermal delivery concentrate on a few selective polymeric systems. For example, Alza
Corporation (Mountain View, CA) mainly concentrates on ethylene vinyl acetate (EVA) copolymers or microporous polypropylene, and Searle Pharmacia (Barceloneta, PR) concentrates on
silicone rubber (3). A review of the marketed transdermal products and the formulations that are reported in various research
publications reveals an enormous diversity of polymers used
in the formulation, engineering, and manufacture of drug products (see Table I). Table II is a comprehensive list of all the polymers used for various purposes in commercially available transdermal delivery systems.
64

Pharmaceutical Technology

MAY 2002

Matrix formers
Polymer selection and design must be considered when striving to meet the diverse criteria for the fabrication of effective
transdermal delivery systems. The main challenge is in the design of a polymer matrix, followed by optimization of the drugloaded matrix not only in terms of release properties, but also
with respect to its adhesioncohesion balance, physicochemical properties, and compatibility and stability with other components of the system as well as with skin (4).
A monolithic solid-state design often is preferred for passive
transdermal delivery systems because of manufacturing considerations and cosmetic appeal. Although polymeric matrices
are used for rate control, adhesion (e.g., a PSA), or encapsulation of a drug reservoir in transdermal delivery systems (reviewed in later sections of this article), discussion in this section is limited to polymers that have been used in the design of
matrices with or without rate control.
Cross-linked poly(ethylene glycol) (PEG) networks. Biocompatibility of PEGs makes them the polymers of choice for numerous biomedical applications. Proteins can be delivered by PEGs
cross-linked with tris(6-isocyanatohexyl) isocyanurate by means
of a urethaneallophanate bond to obtain polymer networks
capable of swelling in phosphate-buffered saline or ethanol and
forming gels. These systems have been shown to release the
solutes in a biphasic manner (5).
Acrylic-acid matrices. Acrylic-acid matrices with plasticizers
have been used to make drugpolymer matrix films for transdermal delivery systems. Some of the polymers that have been
reported are Eudragit RL PM, Eudragit S-100, Eudragit RS PM,
and Eudragit E-100 (Rhm America, Piscataway, NJ) (6). Eudragit NE-40D (a copolymer of ethyl acrylate and methyl
methacrylate), a nonadhesive hydrophobic polymer, also has
been used as a matrix former (7). The release rates of drugs
from these matrix systems are more closely described by the
square-root-of-time model.
Ethyl cellulose (EC) and polyvinylpyrrolidone (PVP). EC and PVP
matrix films with 30% dibutyl phthalate as a plasticizer have
been fabricated to deliver diltiazem hydrochloride and indomethacin. The addition of hydrophilic components such as
PVP to an insoluble film former such as ethyl cellulose tends to
enhance its release-rate constants. This outcome can be attributed to the leaching of the soluble component, which leads to
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Table I: Composition of transdermal delivery systems reported in the literature. (Continued on page 67)
S.No. Polymer
1
Ethyl cellulose T-50
2
BIO PSA HighTack 7-4301
BIO PSA MediumTack 7-4201

5
6
7

Scotch Pak 1022

Scotch Pak 1006
HPMC
Eudragit NE, Eudragit E100,
Eudragit L100
MDX-4-421 (a silicone)
Carboxy vinyl polymer
Acrylic PSA emulsion

CoTran9722
Soybean lecithin (Epikuron 200)

Cariflex TR-1107

10

Acrylic adhesives

11

Polyisobutylene solutions
(Vistanex LM-MH,
Vistanex MML-100)
Acrylic adhesives

3
4

12

Polyisobutylene solutions
(Vistanex LM-MH,
Vistanex MML-100)
Silicone PSA
Silicone oil
EVA
Polyisobutylene
ScotchPak 1006

Manufacturer
Sigma
Dow Corning

Pharmaceutical Technology

MAY 2002

Type of System
Matrix
Adhesive-in-matrix
system. For matrix and
backing side layer.
Backing
Release liner
Gel
Matrix

44
45

Matrix
Gel
Drug in adhesive

46
47
48

Scopolamine,
broxaterol
Dihydro etorphine

Gel matrices

13

Drug in adhesive

49

Ketoprofen

Drug in adhesive

50

Drug in adhesive

51

Reservoir
Membrane
Adhesive
Backing film

52

3M
3M
Rhm, Germany
Dow Corning
Neoplast Co.,
Thailand
3M
Lucas Meyer,
Germany
Shell Chemical Co.,
Japan
National Starch
and Chemical Co.
Exxon Chemical Co.

Hydrocortisone
Coumarin
Melilot dry extract
L-Timolol maleate
L-Dopa
Nicotine

National Starch
Tacrine
and Chemical Co.
Exxon Chemical Co.

Dow Corning
Adhesive Research

3M

the formation of pores and thus a decrease in the mean diffusion path length of drug molecules to release into the dissolution medium. The result is higher dissolution rates. Substances
such as PVP act as antinucleating agents that retard the crystallization of a drug. Thus they play a significant role in improving the solubility of a drug in the matrix by sustaining the drug
in an amorphous form so that it undergoes rapid solubilization
by penetration of the dissolution medium (8).
Hydroxypropyl methylcellulose (HPMC). HPMC, a hydrophilic
swellable polymer widely used in oral controlled drug delivery,
also has been explored as a matrix former in the design of
patches of propranolol hydrochloride. HPMC has been shown
to yield clear films because of the adequate solubility of the drug
in the polymer. Matrices of HPMC without rate-controlling
membranes exhibited a burst effect during dissolution testing
because the polymer was hydrated easily and swelled, leading
to the fast release of the drug (9).
Organogels. Some nonionic surfactants such as sorbitane
monostearate, lecithin, and Tween tend to associate into reverse
micelles (10). These surfactants in an organic solvent, upon the
66

Drug
Isosorbide dinitrate
Trimegestone

Arecoline

Reference
41
42,43

addition of water, undergo association reorientation to form a

gel. These organogels can be used as a matrix for the transdermal delivery of drugs with greater influx (11). Bhatnagar and
Vyas proposed a reverse micelle-based microemulsion of soy
lecithin in isooctane gelled with water as a vehicle for transdermal delivery of propranolol. The transdermal flux of propranolol from this organogel increased 10-fold over a vehicle
composed of petrolatum (12). Willimann et al. also described
organogels obtained when small amounts of water were added
to a solution of lecithin in organic solvents, used as matrices
for the transdermal transport of drugs. The gels obtained in
this manner are isotropic and thermoreversible (liquefy at temperatures 40 C) and can solubilize lipophilic, hydrophilic,
and amphoteric substances, including enzymes. They are biocompatible and are stable for a long time.
Organogels can cause slight disorganization of the skin, an
outcome that is attributable to the organic solvent that is used
to make the gel. Thus, organogels can enhance the permeation
of various substances (13). Pluronic lecithin organogels also
have been used as transdermal delivery systems because both
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Table I continued: Composition of transdermal delivery systems reported in the literature.

S.No. Polymer
13
2-Ethylhexyl acrylate
and
acrylic acid copolymer
14

15

16
17

18

19
20

HEMA, Styrene and N-vinyl

pyrrolidone copolymer for
membrane
HPMC (Methocel K4M)
Urecryl MC 808
PIB
MDX4-4210 silicone elastomer
Acrylate copolymer (Gelva-737)
Silicone-2920 and 2675
Polyisobutylene solutions
(Vistanex LM-MS,
Vistanex MML-100)
2-Ethylhexyl acrylate and
acrylic acid copolymer
2-Ethylhexyl acrylate and
acrylamide copolymer
Polyisobutylene solutions
(Vistanex LM-MH,
Vistanex LM-80)
Silicone PSA
Plastoid E25L
Polyvinyl alcohol (backing)
HPMC (matrix)
Ethylene vinyl acetate
(rate-controlling membrane)

H x

O y
C

CH3

Figure 2: Structure of polyethylene vinyl

acetate.

Manufacturer
Mitsubishi Petrochem Co., Japan
Wako Purechem.
Ind., Japan
Polyscience

Drug
PGE

Type of System
Drug-in-adhesive
matrix

Reference
53

Cytarabine, ara-ADA

Carbopol 934 gel,

reservoir

54

Matrix

Matrix
Matrix

55
56

Drug in adhesive

53

Matrix
Membranecontrolled
reservoir system

7
57

Colorcon, UK
Propranolol
UCB, Belgium
Aldrich, France
Dow Corning
Nitroglycerine
Monsanto
Fentanyl
Dow Corning
Exxon Chemical Co.

Mitsubishi PetroAminopyrene,
chem Co., Japan
Ketoprofen,
Wako Purechem.
Lidocaine
Ind., Japan
Exxon Chemical Co.

Dow Corning
Rhm, Germany

hydrophobic and
hydrophilic drugs
can be incorporated into them.
Oil-soluble drugs
are miscible with
the lecithin phase,
and water-soluble
drugs are miscible
with the aqueous
phase.

Rate-controlling
membranes

Reservoir-type transdermal drug delivery systems contain an

inert membrane enclosing an active agent that diffuses through
the membrane at a finite, controllable rate. The release rate
controlling membrane can be nonporous so that the drug is released by diffusing directly through the material, or the material may contain fluid-filled micropores in which case the
drug may additionally diffuse through the fluid, thus filling the
pores. In the case of nonporous membranes, the rate of passage
of drug molecules depends on the solubility of the drug in the
membrane and the membrane thickness. Hence, the choice of

Miconazole
Propranolol

membrane material must conform to the type of drug being

used. By varying the composition and thickness of the membrane, the dosage rate per area of the device can be controlled.
EVA. EVA frequently is used to prepare rate-controlling membranes in transdermal delivery systems because it allows the
membrane permeability to be altered by adjusting the vinyl acetate content of the polymer. For example, when ethylene is
copolymerized with vinyl acetate, which is not isomorphous
with ethylene, the degree of crystallinity and the crystalline
melting point decreases and amorphousness increases (see Figure 2). As the solutes permeate easily through the amorphous
regions, the permeability increases. The copolymerization also
results in an increase in polarity. Hence, an increase in the vinyl
acetate content of a copolymer leads to an increase in solubility and thus an increase in the diffusivity of polar compounds
in the polymers. However, at vinyl acetate levels 60% by weight,
the glass-transition temperature, Tg, of polymer increases from
 25 C to 35 C. An increase in Tg reflects a decrease in
the polymer-chain mobility and hence the solute diffusivity.
The effect of these structural changes on membrane permeability is shown in the permeation of camphor through a series
of poly(ethylene vinyl acetate) copolymers, which has exhibited a maximum of limiting flux at 60% vinyl acetate content
(14).
Pharmaceutical Technology

MAY 2002

67

Table II: Composition of marketed transdermal therapeutic systems.

Product
Type of System
Androderm
Reservoir
(testosterone)
TheraTech,
Inc./SmithKline
Beecham
CatapresReservoir
TTS
(clonidine)
Alza/Boehringer
Ingelheim
Climara
Drug in
(estradiol)
adhesive
3M/Berlex/
Schering AG
Deponit
Mixed
(nitroglycerin) monolithic
Pharma
reservoir
Schwarz
Epinitril
Drug in
(nitroglycerine) adhesive
Rotta Research

Drug Reservoir
Drug, alcohol,
glyceryl monooleate
methyl laurate
gelled with acrylic
acid copolymer
Clonidine, mineral
oil, polyisobutylene
and colloidal silicon
dioxide

Estraderm
(estradiol)
Alza/CibaGeigy
Habitrol
(nicotine)
Novartis
Nitrodisc
(nitroglycerin)
Searle
Nitro-Dur-I
(nitroglycerin)
Key Pharma

Drug and alcohol

gelled with
hydroxypropyl
cellulose

Reservoir

Drug in
adhesive
Monolithic
microreservoir
Drug in
adhesive

Prostep
Reservoir
(nicotine)
Lederle
Testoderm TTS Reservoir
(testosterone)
Alza
TransdermReservoir
Nitro
(nitroglycerin)
Alza/Ciba-Geigy
TransdermReservoir
Scop
(scopolamine)
Alza/Ciba-Geigy
Vivelle
Drug in
(estradiol)
adhesive
Noven/Novartis
68

Multilayered PIB
adhesive film

Pharmaceutical Technology

MAY 2002

Hydrogel from
copolymer of PVP
PVA, glycerol as
plasticizer
Nicotine in
carrageenan gel
Drug and alcohol
gelled with hydroxypropyl cellulose
Drug adsorbed on
lactose, colloidal
silica, and silicone oil
Scopolamine, light
mineral oil, and
polyisobutylene

Backing
Metallized
polyester/
ethylenemethacrylic acid
copolymer/EVA
Pigmented
polyester film

Membrane
Polyethylene
microporous
membrane

Adhesive
Peripheral acrylic
adhesive

Release Liner
Siliconecoated
polyester

Microporous
polypropylene
film

Mineral oil,
polyisobutylene,
and colloidal
silicon dioxide

Polyester

Polyethylene
film

Acrylate
adhesive
matrix

Poly foil

PIB

Siliconized or
fluoropolymercoated polyester film
Silicone foil

Polypropylene

Acrylatevinylacetate
copolymer and
poly(butyl butane)

Polyester
polyethylene
composite

EVA
copolymer
with 5% vinyl
acetate

Aluminized
plastic backing
film
Foil
polyethylene
combination
Paperfoil
combination

Light mineral oil

and PIB

Aluminized
and siliconized
polyethylene
terephthalate
foil
Siliconized
polyethylene
terephthalate

Acrylate adhesive Aluminum foil

Cross-linked
silicone rubber

Paperfoil
combination

Acrylic adhesive

Paper
polyethylene
foil pouch

Low-density
polyethylene

Polyethylene

Acrylate-based
ring adhesive

Polyester/EVA
copolymer

EVA copolymer PIB

Flesh-colored
polyfoil

Siliconecoated
polyester
EVA copolymer Silicone adhesive Fluorocarbon
polyester film

Aluminized
polyester film

Microporous
polypropylene

EVA copolymer
film and
polyurethane film

Mineral oil,
polyisobutylene

Siliconized
polyester

PIB, EVA
copolymer

Polyester

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Acrylic-, polyisobutylene-, and

silicone-based adhesives are used
n HO
n O C
N
R
N
C
O


POLYESTER/
OH
mostly in the design of transderPOLYETHER
mal patches (21,22). The selection
Polyisocyanate
of an adhesive is based on a numPolyol
ber of factors, including the patch
design and drug formulation. For
reservoir systems with a peripheral adhesive, an incidental contact between the adhesive and the
C
N
R
N
C O
POLYESTER/
O
drug or penetration enhancers
POLYETHER
must not cause instability of the
O H
H
O
n
drug, penetration enhancer, or the
Urethane
adhesive. In the case of reservoir
bond
systems that include a face adhesive, the diffusing drug must not
Figure 3: Synthesis of polyurethane.
affect the adhesive.
Furthermore, the choice of adSilicone rubber. The silicone rubber group of polymers has hesive also may be based on the adhesion properties and on
been used in many controlled-release devices. These polymers skin compatibility. For matrix designs in which the adhesive,
have an outstanding combination of biocompatibility, ease of the drug, and the penetration enhancers must be compounded,
fabrication, and high permeability to many important classes the selection will be more complex. Once the basic criterium
of drugs, particularly steroids. The high permeability of these of chemical compatibility between all the ingredients is estabmaterials is attributed to the free rotation around the silicone lished, the selection will be based on the rate at which the drug
rubber backbone, which leads to very low microscopic viscosi- and the penetration enhancer will diffuse through the adhesive.
The physicochemical characteristics of a drugadhesive comties within the polymer.
Polyurethane. Polyurethane is the general term used for a poly- bination such as solubility and partition coefficient and admer derived from condensation of polyisocyanates and poly- hesive characteristics such as the extent of cross-linking will
ols having an intramolecular urethane bond or carbamate ester determine the choice of adhesive for a drug. In the case of adbonds (NHCOO) (see Figure 3). The polyurethanes syn- hesives that are not cross-linked, enhancers or other formulathesized from polyether polyol are termed polyether urethanes, tion ingredients that have solubility parameters similar to those
and those synthesized from polyester polyol are termed of the adhesive can reduce cohesive strength and can plasticize
polyester urethanes. Although most polyurethanes presently used the adhesive. Significant loss of cohesive strength can result in
are of the polyether type because of their high resistance to hy- an increase in tack, cold flow beyond the edge of the patch, and
drolysis (15), polyester polyurethanes recently have become the a transfer of adhesive to the release liner and to the skin durfocus of attention because of their biodegradability (16). These ing removal. Another possible result of the interaction can be
polyester or polyether urethanes are rubbery and relatively per- an increase in cohesive properties by either acting as extending
meable. The hydrophilichydrophobic ratio in these polymers or reinforcing fillers or by inducing cross-linking (23).
can be balanced to get the optimum permeability properties
The general formula for a PSA includes an elastomeric poly(17). Polyurethane membranes are suitable especially for hy- mer, a tackifying resin, a necessary filler, various antioxidants,
drophilic polar compounds having low permeability through stabilizers if required, and cross-linking agents. When formuhydrophobic polymers such as silicone rubber or EVA mem- lating a PSA, a balance of four properties must be taken into acbranes (18).
count: tack, peel adhesion, skin adhesion, and cohesive strength.
PSAs bind to the skin after a brief contact known as tack. The
PSAs
term tack is used to quantify the sticky feel of the material. This
A PSA is a material that adheres with no more than applied fin- property often is perceived by the user when the patch is applied
ger pressure, is aggressively and permanently tacky, exerts a strong to the skin and quickly pulled off. It is not necessarily related to
holding force, and should be removable from a smooth surface the strength of the ultimate adhesive bond or to the duration of
without leaving a residue (19). Adhesion involves a liquid-like adhesion to the skin. Adhesion refers to the force required to reflow resulting in wetting of the skin surface upon the applica- move the adhesive from a substrate once the bond has reached
tion of pressure, and when pressure is removed, the adhesive sets equilibrium. Some PSAs may have low tack but subsequently
in that state. For an adhesive bond to have measurable strength, may develop a high degree of adhesion to the skin. In contrast,
elastic energy must be stored during the bond-breaking process. many skin adhesives have a relatively high degree of tack and
Therefore, pressure-sensitive adhesion is a characteristic of a only modest skin-adhesion value (24).
visco-elastic material. The balance of viscous flow and the amount
Polyisobutylene (PIB). Isobutylene polymerizes in a regular
of stored elastic energy determine the usefulness of a PSA ma- head-to-tail sequence by low-temperature cationic polymeriterial (20).
zation to produce a polymer having no asymmetric carbons
70

Pharmaceutical Technology

MAY 2002

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CH3
CH2

CH3
BF3

CH2

CH3

CH3

Isobutylene

Polyisobutylene

Figure 4: Polymerization of isobutylene.

H
H2C

COR
O

Acrylic ester

COOR n

Polyacrylate

Figure 5: Polymerization of acrylic ester.

(see Figure 4). In its unstrained state, the polymer is in an amorphous state (25), and the Tg of the polymer is  70 C (26).
The physical properties of the polymer change gradually with
increasing molecular weight. Low molecular weight polymers
are viscous liquids. With increasing molecular weight, the liquids become more viscous, then change to balsam-like sticky
masses and finally form elastomeric solids. PIB PSAs usually
comprise a mixture of high molecular weight and low molecular weight fractions. High molecular weight PIB has a viscosity
average molecular weight between 450,000 and 2,100,000, and
low molecular weight PIB has an average molecular weight between 1000 and 450,000. PIB has the chemical properties of
a saturated hydrocarbon. It is readily soluble in nonpolar liquids. Cyclohexane is an excellent solvent, benzene is a moderate solvent, and dioxane is a nonsolvent for PIB polymers (27).
Un-cross-linked polymers exhibit a high degree of tack or
self-adhesion. PIB polymers have a very low fractional free volume of 0.026 as compared with 0.071 for poly(dimethylsiloxane), for example. This characteristic together with sluggish
chain motility results in a low diffusion coefficient. However,
the final properties of the polymer blend are determined by
compounding and subsequent vulcanization or cross-linking.
Various fillers, processing aids, plasticizers, tackifiers, cure systems, and antidegradants are incorporated into the final blend.
Of all these compounding ingredients, fillers most significantly influence stressstrain and dynamic properties. Carbon
black, the most frequently used reinforcing filler by virtue of its
high surface area, interacts with the surface of polymer chains
and alters chain dynamics, thus enhancing tensile properties
and abrasion resistance. Other fillers that are used are talc and
calcined clay. Colloidal silicon dioxide is used as a filler in
clonidine patches (Catapres-TTS). Nonreinforcing fillers such
as calcium carbonate and titanium dioxide are added to reduce
viscosity and cost. Fillers also are used to enhance the drug re72

Pharmaceutical Technology

MAY 2002

lease from the matrix. Titanium dioxide has been used in the
EVA matrix to reduce the amount of naloxone contained in the
depleted systems (28), and PVP has been used to enhance the
release of formoterol from acrylic PSAs (29). Petroleum-based
oils, butyl polybutenes, paraffin waxes, and low molecular weight
polyethylene can be used as plasticizers. Alkyl adipates and sebacates also are used to reduce the Tg value and improve the
low-temperature properties. Various resins with a Tg value
greater than that of the elastomer act as tackifiers.
Polyacrylates. Acrylic esters are represented by the general formula CH2CHCOOR. The nature of the R group determines
the properties of each ester and the polymer it forms (see Figure 5). Polymers of this class are amorphous and are distinguished by their water-clear color in solution and stability toward aging. As is typical of polymer systems, the mechanical
properties of acrylic polymers improve as the molecular weight
increases. However, beyond a critical molecular weight, which
is 1  103 to 2  103 for amorphous polymers, the improvement is slight and levels off asymptotically (30).
The Tg value of a copolymer can be altered by the copolymerization of two or more polymers. Most acrylic polymers
have a very low Tg value (see Table III); therefore, in copolymer
they tend to soften and flexibilize the overall composition. The
approximate Tg value for copolymers can be calculated from
the weight fraction of each monomer (W1) and the Tg of each
homopolymer as shown in the following equation (31):

1
Tg

copolymer

W1
W2


Tg
Tg
1

Plasticizers also can be used to lower the Tg. However, unlike

incorporated acrylic monomers, they can be lost through
volatilization or extraction.
Acrylic polymers are highly stable compounds. Unless they
are subjected to extreme conditions, acrylic polymers are
durable and degrade slowly. Oxidative degradation of acrylic
polymers can occur in high-pressure and high-temperature
conditions by the combination of oxygen with the free radicals generated in the polymer to form hydroperoxides (32).
Acrylic polymers and copolymers have a greater resistance to
both acidic and alkaline hydrolysis than do poly(vinyl acetate)
and vinyl acetate copolymers. In extreme conditions of acidity or alkalinity, acrylic ester polymers can be made to hydrolyze
to poly(acrylic acid) or to an acidic salt and the corresponding alcohol. Acrylic polymers are insensitive to normal UV
degradation because the primary UV absorption of acrylics
occurs below the solar spectrum. A UV absorber such as
o-hydroxybenzophenone can be incorporated to further enhance the UV stability (32).
Silicones. Silicone PSAs comprise polymer or gum and a tackifying resin. Medical-grade silicone adhesives contain a lowviscosity dimethylsiloxane polymer (12  103 cP to 15  103
cP) (24), which has a terminal silanol group. The silicone resin
has a three-dimensional silicate structure that is end capped
with trimethyl siloxy groups (OSi[CH3]3) and contains residual silanol functionality (33). The adhesive is prepared by crosslinking the reactants in solution by a condensation reaction
www.phar mtech.com

Table III: Glass transition

temperatues of acrylic polymers
(39,40).

CH3
H3C

Si

CH3

Si

HO

Si

CH3

O
H3C

CH3

CH3

Si

CH3 n

Si
CH3

Silicate resin
Condensation
CH3
Si

CH3

O
H

Si

Si

CH3

CH3
O

O
H3C

Si

CH3

Si
CH3

CH3
O
n

Si

OH

CH3

CH3 n

CH3
Silicone PSA

Figure 6: Synthesis of a silicone pressure-sensitive adhesive.

between silanol groups on the linear poly(dimethylsiloxane)

polymer and silicate resin to form siloxane bonds (SiOSi)
(see Figure 6). Unlike acrylic-, rubber-, and PIB-based adhesives, medical-grade silicone adhesives do not contain organic
tackifiers, stabilizers, antioxidants, plasticizers, catalysts, or
other potentially toxic extractables. These additives are not required because silicone PSAs are stable throughout a wide range
of temperatures (73 to
250 C).
The end-use properties of silicone-based PSAs such as tack,
peel adhesion, skin adhesion, and cohesion can be modified or
customized by varying the resinpolymer ratio, the silanol functionality, and the level and type of cross-linking agent. Normally
the shear strength and the tack of a PSA first increase and then
reach a maximum as increasing amounts of tackifying resin are
added. The peel strength usually increases with the amount of
tackifying resin. The shear-holding power often depends on the
mode of cross-linking. Although the silicone group of adhesives
has an outstanding combination of biocompatibility and ease
of fabrication for hydrophilic drugs, the solubility, permeability, and releasing properties are poor.
Some of the silicone PSAs contain a significant degree of
free silanolfunctional groups. Certain amino-functional drugs
can act as catalysts to cause further cross-links between these
silanol groups. This unwanted reaction can be reduced, thus
enhancing a PSAs chemical stability, by end capping the silanol
groups with methyl groups by means of a trimethyl silylation
74

Pharmaceutical Technology

O
n

Si
CH3

Polydimethylsiloxane

CH3

H3C

CH3

MAY 2002

OH

Polymer
Methyl acrylate
Ethyl acrylate
Propyl acrylate
Isopropyl acrylate
n-Butyl acrylate
Hexyl acrylate
Heptyl acrylate
2-Ethylhexyl acrylate
2-Ethylbutyl acrylate
Dodecyl acrylate
Hexadecyl acrylate
Cyclohexyl acrylate

Tg (C)
6
24
45
3
50
57
60
65
50
30
35
16

reaction (33). Some of the trace components in acrylic-adhesive blends

reacted with a variety of drugs and
caused coloring, which deepens with
time. This problem was overcome when
2-mercaptobenzimidazole and/or propyl
gallate were incorporated into the adhesive composition (34).
Hot-melt PSAs (HMPSAs). Typical PSAs
include a volatile organic solvent for reducing the viscosity of the composition
to a coatable room-temperature viscosity. After the product is coated, the organic solvent is removed
by evaporation. When they are heated, HMPSAs melt to a viscosity suitable for coating, but when they are cooled they generally stay in a flowless state. HMPSAs are advantageous over
solvent-based systems because they
do not require removal and containment of the solvents
do not require special precautions to avoid fire
are amenable to coating procedures other than those commonly used with solvent-based systems
are more easily coated into full thickness with minimal bubbling, which often results with solvent-containing PSAs.
Hot-melt adhesives are based on thermoplastic polymers that
may be compounded or uncompounded (see Table IV). Of these
polymers, EVA copolymers are most widely used. Polybutenes,
phthalates, and tricresyl phosphate often are added as plasticizers to improve mechanical shock resistance and thermal
properties. Antioxidants such as hindered phenols are added to
prevent oxidation of ethylene-based hot-melt adhesives. Fillers
opacify or modify an adhesives flow characteristics and reduce
the cost. Paraffin and microcrystalline wax are added to alter the
surface characteristics by decreasing the surface tension and the
viscosity of the melt and to increase the strength of the adhesive
upon solidification. Moisture-curing urethanes have been attempted as cross-linking agents to prevent creep under the load
of these thermoplastic materials.
Silicone-based adhesives also are amenable to hot-melt
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Table IV: Thermoplastic hot-melt

pressure-sensitive adhesives.
Compounded
Ethylene vinyl acetate copolymers
Paraffin waxes
Low-density polypropylene
Styrene-butadiene copolymers
Ethylene-ethacrylate copolymers
Uncompounded
Polyesters
Polyamides
Polyurethanes

coating. US Patent No.

5,352,722 describes the
process of preparing a
silicone-based HMPSA
in which the dynamic
viscosity of a basic adhesive formulation consisting of a polysilicate resin
and a silicone fluid is reduced by adding alkyl
methylsiloxane waxes.
Thus the coatability of
a PSA without solvents is

chemical resistance often may lead to stiffness and high occlusivity to moisture vapor and air, causing patches to lift and
possibly irritate the skin during long-term wear. The most comfortable backing may be the one that exhibits the lowest modulus or high flexibility, good oxygen transmission, and a high
moisture-vapor transmission rate (see Table V) (36).
In a novel modification to the conventional design, a patch
was fabricated in which the backing itself acted as a reservoir
for the drug. The upper internal portion of the drug reservoir
infiltrated the porous backing and became solidified therein
after being applied so that the reservoir and the backing were
unified. This modification enabled the backing itself to act as
a storage location for the medication-containing reservoir (37).

Table V: Characteristics of some commercialized backing materials.*

Product
CoTran 9701
CoTran 9702,
CoTran 9706
CoTran 9720,
9722
Foam Tape 9772L
Foam Tape 9773
Scotchpak 1006
Scotchpak 1109
Scotchpak 9723
Scotchpak 9732,
9733

Polymer
Polyurethane
film
EVA

Oxygen
Transmission
MVTR
(cm3/m2/24 h) (g/m2/24 h)
700

PE

4.6

52.8
26.4
9.4
7.9
450

0.3

4.6

0.3

2950
3570

PVC foam
Polyolefin foam
PE, Al vapor
coat, PET, EVA
PE, Al vapor
coat, PET
PE, PET
laminate
PET, EVA
laminate

HighPET side

80
80

15.5
17

HighPET side
HighPET side

Backing layer
When designing a backing layer, the developer must give chemical resistance of the material foremost importance. Excipient
compatibility also must be seriously considered because the
prolonged contact between the backing layer and the excipients may cause the additives to leach out of the backing layer
or may lead to diffusion of excipients, drug, or penetration enhancer through the layer. However, an overemphasis on the
MAY 2002

High

12

improved. Pretzer and Sweet (35) described a silicone-based HMPA

that contained a mixture of silicate resin and a polyorganosiloxane fluid into which polyisobutylene polymer with a functionalized silicon-containing moiety was incorporated. The adhesive was claimed to possess a reduced propensity to cold flow.

Pharmaceutical Technology

Medium
Medium
Medium
High

HighPET side

100

PE  Polyethylene
PVC  Polyvinyl chloride
EVA  Ethylene vinyl acetate
MVTR  Moisture-vapor transmission rate
PP  Polypropylene
PU  Polyurethane
PET  Poly(ethylene terephthalate) (polyester)
*http://www.3M.com

76

Enhancer
Resistance
Low

Release liner
During storage the patch is covered by
a protective liner that is removed and
discharged immediately before the application of the patch to the skin. It is
therefore regarded as a part of the primary packaging material rather than a
part of the dosage form delivering the
active principle (38). However, because
the liner is in intimate contact with the
delivery system, it should comply with
specific requirements regarding the
chemical inertness and permeation to
the drug, penetration enhancer, and
water. In case cross-linking is induced
between the adhesive and the release
liner, the force required to remove the
liner will be unacceptably high (23). 3M,
for example, manufactures release liners made of fluoro polymers (Scotchpak 1022 and Scotchpak 9742, 3M Drug
Delivery Systems, St. Paul, MN).

Acknowledgments
The authors thank Mr. Sunil T. Narisetty
for his valuable suggestions in the
preparation of this article. Vinod Nair
is supported by a senior research fellowship from the Department of Science and Technology, New Delhi, India.

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Inhalation Aerosol Technology Workshop
The University of Maryland Department of
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811 July 2002 in Baltimore,Maryland.
The workshop consists of a three-day course and
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For more information,contact Richard Dalby,PhD,
University of Maryland, Department of Pharmaceutical Sciences,20 North Pine St.,Baltimore,MD
21201-1180,tel.410.706.3245,fax 410.706.0346,
rdalby@rx.umaryland.edu, www.pharmacy.
umaryland.edu/faculty/rdalby/default.htm.

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