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Polymers in Transdermal Drug Delivery Systems
Polymers in Transdermal Drug Delivery Systems
T
he development of transdermal drug delivery systems is
a multidisciplinary activity that encompasses
Polymers are ● fundamental feasibility studies starting from the se-
the formation of pores and thus a decrease in the mean diffu- addition of water, undergo association reorientation to form a
sion path length of drug molecules to release into the dissolu- gel. These organogels can be used as a matrix for the transder-
tion medium. The result is higher dissolution rates. Substances mal delivery of drugs with greater influx (11). Bhatnagar and
such as PVP act as antinucleating agents that retard the crystal- Vyas proposed a reverse micelle-based microemulsion of soy
lization of a drug. Thus they play a significant role in improv- lecithin in isooctane gelled with water as a vehicle for trans-
ing the solubility of a drug in the matrix by sustaining the drug dermal delivery of propranolol. The transdermal flux of pro-
in an amorphous form so that it undergoes rapid solubilization pranolol from this organogel increased 10-fold over a vehicle
by penetration of the dissolution medium (8). composed of petrolatum (12). Willimann et al. also described
Hydroxypropyl methylcellulose (HPMC). HPMC, a hydrophilic organogels obtained when small amounts of water were added
swellable polymer widely used in oral controlled drug delivery, to a solution of lecithin in organic solvents, used as matrices
also has been explored as a matrix former in the design of for the transdermal transport of drugs. The gels obtained in
patches of propranolol hydrochloride. HPMC has been shown this manner are isotropic and thermoreversible (liquefy at tem-
to yield clear films because of the adequate solubility of the drug peratures 40 C) and can solubilize lipophilic, hydrophilic,
in the polymer. Matrices of HPMC without rate-controlling and amphoteric substances, including enzymes. They are bio-
membranes exhibited a burst effect during dissolution testing compatible and are stable for a long time.
because the polymer was hydrated easily and swelled, leading Organogels can cause slight disorganization of the skin, an
to the fast release of the drug (9). outcome that is attributable to the organic solvent that is used
Organogels. Some nonionic surfactants such as sorbitane to make the gel. Thus, organogels can enhance the permeation
monostearate, lecithin, and Tween tend to associate into reverse of various substances (13). Pluronic lecithin organogels also
micelles (10). These surfactants in an organic solvent, upon the have been used as transdermal delivery systems because both
66 Pharmaceutical Technology MAY 2002 www.phar mtech.com
Table I continued: Composition of transdermal delivery systems reported in the literature.
S.No. Polymer Manufacturer Drug Type of System Reference
13 2-Ethylhexyl acrylate Mitsubishi Petro- PGE Drug-in-adhesive 53
and chem Co., Japan matrix
acrylic acid copolymer Wako Purechem.
Ind., Japan
14 HEMA, Styrene and N-vinyl Polyscience Cytarabine, ara-ADA Carbopol 934 gel, 54
pyrrolidone copolymer for reservoir
membrane
15 HPMC (Methocel K4M) Colorcon, UK Propranolol Matrix 9
Urecryl MC 808 UCB, Belgium
PIB Aldrich, France
16 MDX4-4210 silicone elastomer Dow Corning Nitroglycerine Matrix 55
17 Acrylate copolymer (Gelva-737) Monsanto Fentanyl Matrix 56
Silicone-2920 and 2675 Dow Corning
Polyisobutylene solutions Exxon Chemical Co.
(Vistanex LM-MS,
Vistanex MML-100)
18 2-Ethylhexyl acrylate and Mitsubishi Petro- Aminopyrene, Drug in adhesive 53
acrylic acid copolymer chem Co., Japan Ketoprofen,
2-Ethylhexyl acrylate and Wako Purechem. Lidocaine
acrylamide copolymer Ind., Japan
Polyisobutylene solutions Exxon Chemical Co.
(Vistanex LM-MH,
Vistanex LM-80)
Silicone PSA Dow Corning
19 Plastoid E25L Röhm, Germany Miconazole Matrix 7
20 Polyvinyl alcohol (backing) Propranolol Membrane- 57
HPMC (matrix) controlled
Ethylene vinyl acetate reservoir system
(rate-controlling membrane)
hydrophobic and membrane material must conform to the type of drug being
hydrophilic drugs used. By varying the composition and thickness of the mem-
H H H H can be incorpo- brane, the dosage rate per area of the device can be controlled.
rated into them. EVA. EVA frequently is used to prepare rate-controlling mem-
C C C C
Oil-soluble drugs branes in transdermal delivery systems because it allows the
H H x H O y are miscible with membrane permeability to be altered by adjusting the vinyl ace-
the lecithin phase, tate content of the polymer. For example, when ethylene is
C CH3
and water-soluble copolymerized with vinyl acetate, which is not isomorphous
O drugs are miscible with ethylene, the degree of crystallinity and the crystalline
with the aqueous melting point decreases and amorphousness increases (see Fig-
phase. ure 2). As the solutes permeate easily through the amorphous
Figure 2: Structure of polyethylene vinyl
regions, the permeability increases. The copolymerization also
acetate.
Rate-controlling results in an increase in polarity. Hence, an increase in the vinyl
membranes acetate content of a copolymer leads to an increase in solubil-
Reservoir-type transdermal drug delivery systems contain an ity and thus an increase in the diffusivity of polar compounds
inert membrane enclosing an active agent that diffuses through in the polymers. However, at vinyl acetate levels 60% by weight,
the membrane at a finite, controllable rate. The release rate– the glass-transition temperature, Tg, of polymer increases from
controlling membrane can be nonporous so that the drug is re- 25 C to 35 C. An increase in Tg reflects a decrease in
leased by diffusing directly through the material, or the mate- the polymer-chain mobility and hence the solute diffusivity.
rial may contain fluid-filled micropores — in which case the The effect of these structural changes on membrane perme-
drug may additionally diffuse through the fluid, thus filling the ability is shown in the permeation of camphor through a series
pores. In the case of nonporous membranes, the rate of passage of poly(ethylene vinyl acetate) copolymers, which has exhib-
of drug molecules depends on the solubility of the drug in the ited a maximum of limiting flux at 60% vinyl acetate content
membrane and the membrane thickness. Hence, the choice of (14).
Pharmaceutical Technology MAY 2002 67
Table II: Composition of marketed transdermal therapeutic systems.
Product Type of System Drug Reservoir Backing Membrane Adhesive Release Liner
Androderm Reservoir Drug, alcohol, Metallized Polyethylene Peripheral acrylic Silicone-
(testosterone) glyceryl monooleate polyester/ microporous adhesive coated
TheraTech, methyl laurate ethylene- membrane polyester
Inc./SmithKline gelled with acrylic methacrylic acid
Beecham acid copolymer copolymer/EVA
Catapres- Reservoir Clonidine, mineral Pigmented Microporous Mineral oil, Polyester
TTS oil, polyisobutylene polyester film polypropylene polyisobutylene,
(clonidine) and colloidal silicon film and colloidal
Alza/Boehringer dioxide silicon dioxide
Ingelheim
Climara Drug in Polyethylene Acrylate Siliconized or
(estradiol) adhesive film adhesive fluoropolymer-
3M/Berlex/ matrix coated poly-
Schering AG ester film
Deponit Mixed Multilayered PIB Poly foil PIB Silicone foil
(nitroglycerin) monolithic adhesive film
Pharma reservoir
Schwarz
Epinitril Drug in Polypropylene Acrylate- Aluminized
(nitroglycerine) adhesive vinylacetate and siliconized
Rotta Research copolymer and polyethylene
poly(butyl butane) terephthalate
foil
Estraderm Reservoir Drug and alcohol Polyester– EVA Light mineral oil Siliconized
(estradiol) gelled with polyethylene copolymer and PIB polyethylene
Alza/Ciba- hydroxypropyl composite with 5% vinyl terephthalate
Geigy cellulose acetate
Habitrol Drug in Aluminized Acrylate adhesive Aluminum foil
(nicotine) adhesive plastic backing
Novartis film
Nitrodisc Monolithic Foil– Cross-linked Paper–foil
(nitroglycerin) microreservoir polyethylene silicone rubber combination
Searle combination
Nitro-Dur-I Drug in Hydrogel from Paper–foil Acrylic adhesive Paper–
(nitroglycerin) adhesive copolymer of PVP– combination polyethylene
Key Pharma PVA, glycerol as foil pouch
plasticizer
Prostep Reservoir Nicotine in Low-density Polyethylene Acrylate-based
(nicotine) carrageenan gel polyethylene ring adhesive
Lederle
Testoderm TTS Reservoir Drug and alcohol Polyester/EVA EVA copolymer PIB Silicone-
(testosterone) gelled with hydroxy- copolymer coated
Alza propyl cellulose polyester
Transderm- Reservoir Drug adsorbed on Flesh-colored EVA copolymer Silicone adhesive Fluorocarbon
Nitro lactose, colloidal polyfoil polyester film
(nitroglycerin) silica, and silicone oil
Alza/Ciba-Geigy
Transderm- Reservoir Scopolamine, light Aluminized Microporous Mineral oil, Siliconized
Scop mineral oil, and polyester film polypropylene polyisobutylene polyester
(scopolamine) polyisobutylene
Alza/Ciba-Geigy
Vivelle Drug in EVA copolymer PIB, EVA Polyester
(estradiol) adhesive film and copolymer
Noven/Novartis polyurethane film
quired because silicone PSAs are stable throughout a wide range ● do not require special precautions to avoid fire
of temperatures (73 to 250 C). ● are amenable to coating procedures other than those com-
The end-use properties of silicone-based PSAs such as tack, monly used with solvent-based systems
peel adhesion, skin adhesion, and cohesion can be modified or ● are more easily coated into full thickness with minimal bub-
customized by varying the resin–polymer ratio, the silanol func- bling, which often results with solvent-containing PSAs.
tionality, and the level and type of cross-linking agent. Normally Hot-melt adhesives are based on thermoplastic polymers that
the shear strength and the tack of a PSA first increase and then may be compounded or uncompounded (see Table IV). Of these
reach a maximum as increasing amounts of tackifying resin are polymers, EVA copolymers are most widely used. Polybutenes,
added. The peel strength usually increases with the amount of phthalates, and tricresyl phosphate often are added as plasti-
tackifying resin. The shear-holding power often depends on the cizers to improve mechanical shock resistance and thermal
mode of cross-linking. Although the silicone group of adhesives properties. Antioxidants such as hindered phenols are added to
has an outstanding combination of biocompatibility and ease prevent oxidation of ethylene-based hot-melt adhesives. Fillers
of fabrication for hydrophilic drugs, the solubility, permeabil- opacify or modify an adhesive’s flow characteristics and reduce
ity, and releasing properties are poor. the cost. Paraffin and microcrystalline wax are added to alter the
Some of the silicone PSAs contain a significant degree of surface characteristics by decreasing the surface tension and the
free silanol–functional groups. Certain amino-functional drugs viscosity of the melt and to increase the strength of the adhesive
can act as catalysts to cause further cross-links between these upon solidification. Moisture-curing urethanes have been at-
silanol groups. This unwanted reaction can be reduced, thus tempted as cross-linking agents to prevent creep under the load
enhancing a PSA’s chemical stability, by end capping the silanol of these thermoplastic materials.
groups with methyl groups by means of a trimethyl silylation Silicone-based adhesives also are amenable to hot-melt
74 Pharmaceutical Technology MAY 2002 www.phar mtech.com
Table IV: Thermoplastic hot-melt coating. US Patent No. chemical resistance often may lead to stiffness and high oc-
pressure-sensitive adhesives. 5,352,722 describes the clusivity to moisture vapor and air, causing patches to lift and
process of preparing a possibly irritate the skin during long-term wear. The most com-
Compounded
silicone-based HMPSA fortable backing may be the one that exhibits the lowest modu-
Ethylene vinyl acetate copolymers
in which the dynamic lus or high flexibility, good oxygen transmission, and a high
Paraffin waxes
viscosity of a basic adhe- moisture-vapor transmission rate (see Table V) (36).
Low-density polypropylene
sive formulation consist- In a novel modification to the conventional design, a patch
Styrene-butadiene copolymers
ing of a polysilicate resin was fabricated in which the backing itself acted as a reservoir
Ethylene-ethacrylate copolymers
and a silicone fluid is re- for the drug. The upper internal portion of the drug reservoir
Uncompounded duced by adding alkyl infiltrated the porous backing and became solidified therein
Polyesters methylsiloxane waxes. after being applied so that the reservoir and the backing were
Polyamides Thus the coatability of unified. This modification enabled the backing itself to act as
Polyurethanes a PSA without solvents is a storage location for the medication-containing reservoir (37).
rdalby@rx.umaryland.edu, www.pharmacy.
umaryland.edu/faculty/rdalby/default.htm.
859 Willamette Street, Eugene, OR 97401-6806, USA
Tel. 541.343.1200, www.pharmtech.com
80 Pharmaceutical Technology MAY 2002 www.phar mtech.com