Review

pubs.acs.org/IECR

Rubber Polymers for Transdermal Drug Delivery Systems

Jirapornchai Suksaeree,*,†,‡ Wiwat Pichayakorn,§,⊥ Chaowalit Monton,†,‡ Apirak Sakunpak,†,‡
Tun Chusut,†,‡ and Worawan Saingam†,‡
†
Faculty of Pharmacy, Rangsit University, Pathum Thani 12000, Thailand
‡
Sino-Thai Traditional Medicine Research Center (Cooperation between Rangsit University, Harbin Institute of Technology, and
Heilongjiang University of Chinese Medicine), Rangsit University, Pathum Thani 12000, Thailand
§
Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla 90112, Thailand
⊥
Medical Products Innovations from Polymers in Clinical Use Research Unit, Prince of Songkla University, Hat-Yai, Songkhla 90112,
Thailand

ABSTRACT: Natural rubber latex is a colloidal dispersion of polymer particles in a liquid. It is harvested from rubber trees by a
tapping process. Synthetic rubber is one type of artificial elastomer mainly synthesized from petroleum byproducts. It has good
mechanical property, thermal stability, and compatibility with petroleum products. It can undergo much more elastic deformation
under stress than most materials, and can return to its original size without changing permanently. Commonly, many drugs taken
via the oral route are ineffective because of the first pass metabolism and drug degradation in the gastrointestinal tract. Thus,
transdermal drug delivery systems can improve the disadvantage of orally taken drugs. There must be significant controlled drug
release into the systemic blood circulation to target organs via the skin. In this review article, the use of rubber polymers in both
natural and synthetic rubber types as a material for transdermal drug delivery systems will be reported.

1. INTRODUCTION
There are two types of rubber polymers: natural rubber and
synthetic rubber.1 More than one-third of the total rubber
polymers in the world is produced in Thailand. Approximately
10% is used as a raw material for products such as tires, gloves,
and condoms. Since finished products can provide a higher
income than raw materials, research about development of
products derived from natural rubber should be conducted to
increase the value of rubber polymers.
Rubber polymers are an example of an elastomer type
polymer. They have properties of interest for biomedical
application and transdermal drug delivery systems, such as its
biocompatibility, high mechanical resistance, forming films
easily, and good flexibility. More importantly, when they are
stretched or deformed, they can return to their original shape.
Although the rubber polymers are coiled when in the resting
state, their elastic properties arise from the ability to stretch
their polymer chains apart; when tension is released, the chains
snap back to the original position.
Natural rubber is obtained from the Para rubber tree Hevea
brasiliensis which is found in Southeast Asia, especially in the
south and east regions of Thailand. It is a white milky colloidal
suspension known as natural rubber latex (NRL) and is formed
of mucous liquid polymers.1 Fresh latex contains approximately
35% dry rubber content (DRC), which is not convenient for
use due to its bulky size. The NRL is coagulated using either
acetic acid or formic acid. This viscous mass is then
compressed. NRL contains the volatile monomer isoprene;
this forms the cis-1,4-polyisoprene polymer which is the main
constituent of rubber (Figure 1). Commercially, concentrated
NRL with 60% DRC is prepared by a centrifugation process.
This process can be classified into two types, depending on
preservative used: (i) high ammonia rubber latex, preserved
Figure 1. The structure of cis-1,4-polyisoprene.
with only ammonia in a concentration of more than 0.60% w/
w, and (ii) low ammonia rubber latex that is preserved with
lower than 0.29% w/w ammonia, combined with zinc, and
tetramethylthiuram disulfide.2 NRL is a soft, gum-like, sticky
mass, used as raw material for industrial rubber production. It is
insoluble in water, acids, and alkalines, but soluble in benzene,
chloroform, ether, petroleum ether, and carbon disulfide. It
absorbs a large amount of water.2,3
Rubber particles are encapsulated with lipid and a protein
layer to produce Hevea latex. Hevea latex is regarded as the
living cytoplasm of laticiferous cells and, accordingly, it is a rich
blend of organic substances, including a mélange of proteins. A
small number of these proteins have given rise to the problem
of latex allergies.4−7 Since NRL is not a homogeneous fluid,
latex proteins are not evenly dispersed. Latex proteins are found
in the latex serum, and are also associated with latex organelles
that can be separated by high-speed centrifugation.8−10
However, there are 14 types of natural rubber proteins (Hev
b1−14) recognized by the World Health Organization and
Received: October 26, 2013
Revised: December 14, 2013
Accepted: December 24, 2013
Published: December 24, 2013

© 2013 American Chemical Society 507 dx.doi.org/10.1021/ie403619b | Ind. Eng. Chem. Res. 2014, 53, 507−513
Industrial & Engineering Chemistry Research
Figure 2. Applications of rubber polymers for transdermal drug delivery systems (A) transdermal patches and (B) film forming polymeric solutions.
International Union of Immunological Societies as being
causative agents of natural rubber-allergies.11 The Hevea latex
allergens Hev b1 and Hev b3 are the two major proteins
located on the surface of the rubber particles. Hev b1 is found
mainly on the large rubber particles, whereas Hev b3 is more
abundant in smaller rubber particles. Furthermore, latex C-
serum contains various proteins and more than 200
polypeptides, some of which are enzymes associated with
rubber biosynthesis. Four types of latex allergens belong to the
group of C-serum proteins present in the cytosol fraction of the
latex: Hev b5, 7, 8, and 9. The most important allergen of this
subgroup, Hev b5, is a heat-stable protein. In addition, B-serum
contains a smaller number of proteins which are the most
prominent and makes up more than 50% of the total soluble B-
serum proteins. B-serum currently includes a group of 8
characterized latex allergens which are extra-cytosolic proteins:
Hev b2, 4, 6, 10, 11, 12, 13, and 14. It is tempting to classify the
extra cytosolic proteins in the latex B-serum as lutoidic proteins
since the B-serum is prepared from the bottom fraction which
comprises mainly lutoids. Nevertheless, other organelles that
sediment during centrifugation are also present in the bottom
fraction, and the possibility that some proteins in fact originate
from a minor organelle cannot be disregarded. Proteins from
the B-serum fractions are relatively more alkaline-stable than
those in the C-serum fractions. The proteins from the C-serum
fractions are very alkaline sensitive, and almost all are
completely degraded after 15 days of alkaline treatment.12
There are eight methods for reducing extractable and
allergenic proteins from the raw material of natural rubber to
form a protein-free finished product in the rubber industry.
These include enzyme treatment, centrifugation method,
creaming, leaching, ultrasonic leaching, fumed silica, chlorina-
tion, and miscellaneous.12 However, natural rubber also
contains impurities such as protein and dirt. It has low thermal
stability, and its compatibility with petroleum products. Thus,
synthetic rubbers are produced to improve these properties by
a polymerized reaction with organic compounds. These
synthetic rubbers may have some properties similar to rubber,
and other desirable properties. Most of these rubbers are
derived from butadiene derivatives and contain carbon−carbon
double bonds. They are homopolymers of 1,3-butadiene, or
copolymers in which one of the monomers is 1,3-butadiene or
its derivative. Therefore, the polymer has the availability of
double bonds for its vulcanization. Some examples of synthetic
rubbers are polybutadiene, chloroprene, neoprene, styrene
butadiene rubber, silicones, and polyurethane.13,14
At present, there are no studies on using rubber polymers in
transdermal drug delivery systems. The skin is a very attractive
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organ for the application of pharmaceutically active substances
because of its considerable size and easy accessibility. Drug
administration via the skin can either be local therapy of
dermatological diseases, or the transdermal delivery of drugs to
underlying tissues or the systemic circulation. Transdermal
drug delivery systems are the topically administered medi-
cations contacted to the surface of the skin. They deliver a
specific dose of drug across the skin barrier into the systemic
bloodstream. The advantages of transdermal drug delivery
systems include avoiding gastro-intestinal drug absorption
difficulties, as a substitute for oral administration of medication,
avoiding the first-pass effect, avoiding the inconveniences of
parenteral therapy, and providing capacity to terminate drug
effects rapidly.15 Generally, the polymers utilized for trans-
dermal drug delivery systems can be classified as (i) natural
polymers, that is, cellulose derivatives, zein, gelatin, shellac,
waxes, gums, and chitosan; (ii) synthetic elastomers, that is,
polybutadiene, polyisobutylene (PIB), silicone rubber, nitrile,
acrylonitrile, neoprene, and butyl rubber, and (iii) synthetic
polymers, that is, polyvinyl alcohol (PVA), polyvinyl chloride
(PVC), polyethylene, polypropylene, polyacrylate, polyamide,
polyurea, polyvinyl pyrrolidone (PVP), and polymethylmetha-
crylate,3 which mostly are not manufactured in Thailand. This
application of synthetic rubbers is the main issue of interest in
the areas of polymer sciences, pharmaceutical sciences, and
medicine. Research can be used to design and produce
advanced healthcare treatment, including developing therapeu-
tic devices with pharmaceutical apparatus, management and
therapy, and compatibility with the skin. It has now emerged as
its own discipline from being an interdisciplinary specialization
among already-established fields, to being considered a field in
itself. The release behavior of the drug occurs from the device
on the basis of three mechanisms: diffusion, degradation, or
swelling. The diffusion mechanism is when a drug is released
through a rubber polymer and distribution is usually observed.
The degradation mechanism is the release of a drug within the
body through biological processes which eliminate or remove
the carrier system. In the swelling mechanism, water penetrates
into the polymer and causes swelling which controls drug
release.16 This review describes the rubber polymer transdermal
drug delivery systems, and the using of rubber polymers as
material in transdermal drug delivery systems.
2. TRANSDERMAL DRUG DELIVERY SYSTEMS
There have been significant advances in the science of
controlled transdermal drug delivery systems. The concept of
providing systemic therapy via the skin is not a recent
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innovation as numerous attempts have been made to treat both
local and systemic aliments by the application of herbal potions
and medicaments to the skin in previous centuries.17−19 Several
ancient cultures have used ointments, poultices, and plasters in
the belief that they would alleviate a variety of symptoms. For
example, the ancient Greeks used a mixture of water, olive oil,
and lead oxide as a balm. The efficacy of this formulation is
probably attributable to the astringent properties of lead oxide,
and the emollient activity of the olive oil. This could be
considered as a transdermal delivery system because its activity
was only on the skin. The use of poultices of crushed and
pulped comfrey or longwort herbs for the treatment of
inflammation and swellings, where the active principle or
principles had to cross the skin barrier, might also be
considered as a transdermal delivery system.20
Transdermal drug delivery systems are an effective alternative
route to deliver small molecules to the target organ.21,22
Transdermal drug delivery systems can deliver a drug through
the skin into the blood circulation at a therapeutic level. It will
also be necessary for the delivered drug to maintain a
concentration at the target site.23,24 However, during this
transport process, the drug can undergo severe biochemical
degradations and the end products might be ineffective and
even toxic. Therefore, the drug substances that are used in their
controlled release system should not be easily degraded during
administration, so that the drug can be released as a plateau
state in the range between the toxic level and the minimum
effective level.25,26
2.1. Patches (Figure 2A). Patches are polymeric films
directly applied to the skin. The polymers are mainly materials
acting as pressure sensitive adhesives capable of sticking to the
skin by applying a light pressure, and that can be removed
without leaving any visually noticeable residues.27 Many classes
of polymers, such as cellulose derivatives, PVA, PVP, Carbopol,
chitosan, and polyacrylates, have been used for transdermal
drug delivery systems.28,29 Various patches have recently been
developed with an aim to achieve the objective of systemic
medication through topical applications on the intact skin
surface. They are exemplified by (i) scopolamine-releasing
patches, for example, Transderm-Scop for motion sickness; (ii)
nitroglycerin-releasing patches, for example, Deponit, Nitrodisc,
Nitro-Dur, and Transderm-Nitro for angina pectoris; (iii)
isosorbide dinitrate-releasing patches, for example, Frandol
Tape for angina pectoris; (iv) clonidine-releasing patches, for
example, Catapress-TTS for hypertension; (v) estradiol-
releasing patches, for example, Estraderm for postmenopausal
symptoms, and (vi) nicotine-releasing patches, for example,
Habitrol, Nicoderm, Nicotrol, Prostep, and Nicotinell for
smoking cessation.30
The development of patches is a multidisciplinary activity
that encompasses fundamental feasibility studies, starting from
the selection of a drug molecule to the demonstration of an
adequate drug flux in an in vitro and/or in vivo model. The
fabrication of a drug delivery system must meet all the stringent
needs that are specific to the drug molecule, such as
physicochemical and stability factors, the patient’s comfort
and cosmetic appeal, the manufacturers scale-up and
manufacturability, and the economy.17−19,29,31
Generally, patches are dosage forms of a polymer film
directly applied to the skin. They can be categorized as (i)
drugs in adhesive, (ii) drugs in matrix, and (iii) drugs in
reservoir systems.32 In each design, the components present in
patches are a backing layer, an adhesive layer, and a release
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liner.33,34 The backing layer protects the patch from the outer
environment. The adhesive secures the patch to the skin. The
release liner protects the patch during the storing period and is
removed prior to use.
2.2. Gels and Film Forming Polymeric Solutions
(Figure 2B). Film forming polymeric solutions are a novel
approach to transdermal drug delivery that might present an
alternative to the conventional dosage forms used on the skin.
The polymeric solutions are a product of the polymer in liquid
dosage form that consists mainly of the active drug, film
forming polymer, plasticizer, and other ingredients. It is applied
to the skin as a liquid and can subsequently form an almost
invisible film in situ by solvent evaporation.35−37 The formed
film is sufficiently substantial to provide a sustained release of
the active drug directly to the skin.
In the past two decades, film forming preparations have been
used predominantly in the field of surgery or wound care. For
example, film forming polymeric solutions or gels have been
used as tissue glues for the sealing of operative wounds.38 The
film-formers mainly used in this area are fibrin as a natural
material and cyanoacrylates as synthetic polymers.39
A few liquid film forming products have been approved,
mainly for the dermal therapy of warts and calluses, that is,
Verrumal (Hermal oHG, Germany), Clabin Plus (Chefaro,
Germany), Loceryl (Galderma GmbH, Germany), and Penlac
(Dermik Laboratories, USA). Although these film forming
systems are used in the pharmaceutical field, they are not
designed for transdermal administration of pharmaceutically
active substances.
Few preparations that have provided a sustained delivery
over a longer period of time have been described in the
literature. Misra et al. investigated a film forming solution with a
mixture of PVP and PVA as a film-former in isopropyl alcohol
for the transdermal delivery of testosterone. They reported that
the film forming solution provided a sustained release of the
steroidal hormone with a biphasic pharmacokinetic profile.40,41
Since this research was conducted, no liquid film forming
preparation has been approved for transdermal drug delivery.
Schröeder et al. (2007) reported the development and
characteristics of the various polymers as film forming
polymeric solutions for drug delivery of ethinylestradiol.
Bryan et al. (2002) prepared a film forming cream of lidocaine
and tetracaine eutectic mixture as a presurgical anesthesia. The
cream is left to dry on the skin for at least 20 min and is then
removed by peeling. The formulation delivered a sufficient
amount of the local anesthetic through the skin to provide a
significant pain reduction for the patient during their laser
treatment.42 Another film forming semisolid preparation is a
transdermal hydrogel of PVA and PIB that is solidified into a
substantial film in situ on the skin. The formed film is able to
provide a sustained release of testosterone over 24 h and is
removed by peeling.43
3. RUBBER POLYMERS AS MATERIAL IN
TRANSDERMAL DRUG DELIVERY SYSTEMS
The biocompatibility, high mechanical resistance, and ease in
forming a film are the interesting properties of rubber polymers
used for drug delivery systems.2 However, few researchers
report using NRL as a material for drug delivery systems
(Figures 2 and 3). In 1999, Fang et al. prepared pressure
sensitive adhesives from either natural rubber or silicone,
indicating controlled nicotine delivery from patches.44 In
addition, the natural rubber increased the adhesion of patches
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Industrial & Engineering Chemistry Research
Figure 3. Preparations scheme of transdermal drug delivery systems
from rubber polymers or blended rubber polymers.
when it acts as tackifier in formulations. The adhesion property
is close to that from a commercially available patch (Habitrol),
although the loading amount of nicotine was not the same.44
Herculano et al. reported the use of natural rubber as a polymer
membrane in drug delivery systems, such as guided bone
regeneration,45,46 with nitric oxide,47,48 and metronidazole.49,50
Natural rubber was used as an occlusive membrane when
polymerized at 27 °C. For guided bone regeneration, bone
morphogenetic protein regenerative potential cells, such as
bone cells, are incorporated into the protected wound due to
strong bone-inductive activity and provides gradual release for
dental and orthopedic uses. However, bovine serum albumin is
instead used of bone morphogenetic protein because it has a
similar molecular weight and is cheaper. Thus, in in vitro
protein delivery experiments it is incorporated into the NRL
solution. The natural rubber membrane can control the release
of bovine serum albumin up to 18 days.46 These results are
confirmed when the serum is injected into large rabbit calvarial
defects for enhancement in the bone regeneration process.45
Nitric oxide is involved in angiogenesis and inflammation.
The rubber latex matrix is used to control the release behavior
of nitric oxide. The rubber latex matrix is encapsulated with the
spin trap iron(II)-diethyldithiocarbamate complex. Its mem-
brane is detected by electron paramagnetic resonance, which
presents the signal of nitric oxide in the membrane exposed to
ambient atmosphere at 25 °C, even after 350 h. Nitric oxide
release behavior is based on the encapsulation of the spin trap
iron(II)−diethyldithiocarbamate complex in a rubber latex
matrix for the sustained and controlled delivery of nitric oxide
for medicine and pharmaceutical applications with high
stability.47,48
The natural latex membrane is mixed with metronidazole and
is polymerized at −100, −10, 27, and 40 °C for 2 h. It is noted
that the mixed metronidazole-natural latex membrane poly-
merized at −100 °C has the best potential for metronidazole
release with a slow release rate up to 310 h.49 In transdermal
delivery systems, metronidazole patches, the treatment of
protozoa, and anaerobic bacterial infections, are all developed
by using natural rubber latex, which has excellent matrix
forming property to control the release behavior of
metronidazole. However, the release behavior, as well as the
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number, size, and distribution of pores in their membranes,
varied depending on polymerization temperature, and its
overall morphology. The natural rubber membrane polymer-
ized at −100 °C showed the best drug delivery systems for
metronidazole, which released 77.1% of metronidazole content
for up 310 h.49,50
Nevertheless, both the World Health Organization and
International Union of Immunological Societies report that the
14 NRL proteins in natural rubber may cause latex allergies.11
Allergy refers to any immune-mediated reaction to latex
associated with clinical symptoms, which include Type I
mediated hypersensitivity reactions to the latex protein itself,
and delayed or Type IV mediated hypersensitivity. Another
reaction associated with natural rubber is irritant contact
dermatitis.51−53 Thus, deproteinized processes may be used to
remove these protein allergens from natural rubber that have
also been reported, to form deproteinized natural rubber.54 The
deproteinized natural rubber has improved mechanical
property, adhesion property, flexibility, and compatibility
when blended with hydroxypropylmethyl cellulose (HPMC),
methyl cellulose (MC), sodium carboxymethyl cellulose
(SCMC), PVA, poloxamer 407 (P407), and sodium alginate
(SAG). These properties depended on the types and amount of
blended polymer used, as well as other excipients such as
plasticizers. It can be safely used for direct application onto the
skin, and can therefore be applied in transdermal drug delivery
systems.54 They can also be used to control the nicotine release
from various pharmaceutical dosage form, such as film forming
polymeric solutions,35 drugs in adhesive and matrix type
patches,55−57 and reservoir type patches.58
In film forming polymeric solution, colloidal nicotine delivery
systems can easily be prepared by dissolving the nicotine in the
combined solution of deproteinized natural rubber mixed with
another polymer. The film forming polymeric solutions have a
white milky appearance and are homogeneous and smooth in
texture. As their pH levels range between of 6−7, they are
suitable for usage on the skin. These formulations demonstrate
biphasic release and skin permeation, providing an initial rapid
nicotine release followed by a constant release rate for 24 h. In
addition, these film forming polymeric solutions are stable at 4
°C in well secured containers for 3 months. These film forming
polymeric solutions are therefore successfully developed for
transdermal nicotine delivery systems.35
In drug in adhesive and matrix type patches, the nicotine is
mixed into the combined solution of deproteinized natural
rubber added to another polymer. Then, these mixtures are
poured into Petri-dishes and dried in a hot air oven at 70 ± 2
°C for 4 h to construct the blended patches. These patches are
covered by a backing layer without/with an acrylic acid
adhesion layer, and these layers are protected by a release liner.
The nicotine release has a monophasic release pattern fitting
the diffusion type, which is affected by both the amounts and
types of polymer and plasticizer. Nevertheless, skin permeation
of the nicotine occurs by zero order kinetics. The nicotine
matrix patches produced from deproteinized natural rubber
mixed with another polymer provide a controlled nicotine
release and suitable permeation patterns, obtaining stability at 4
°C and an ambient temperature for 3 months.55,56 In addition,
the backing layer is affected by the release behavior of nicotine
because nicotine is a volatile compound. The various types of
backing layer have different moisture vapor transmission rates
and oxygen transmissions. The backing layer with the highest
moisture vapor transmission rate and the lowest oxygen
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Industrial & Engineering Chemistry Research
transmission are supposed to give higher nicotine release and
skin permeation, owing to an increase of skin hydration and its
occlusive effect. Therefore, the backing layer must be
appropriate and used conveniently in the preparation of
nicotine transdermal patches.57
In reservoir type patches, the deproteinized natural rubber is
constructed to form a film. Then, it is added to the suitable
backing layer and the surrounding reservoir compartment is
closed by a heat sealing technique. The concentrated nicotine
solution is filled into the reservoir compartment using a
disposable syringe and needle. The reservoir patches are heat
sealed again to close the unsealed side of the reservoir patches
to ensure no leak of the concentrated nicotine solution from
these patches. Finally, they are covered with a release liner. The
nicotine reservoir type patches can control the nicotine release
depending on the thickness of the deproteinized natural rubber
membrane. These nicotine reservoir type patches are stable at 4
°C and maintain an ambient temperature for 3 months. Thus,
the deproteinized natural rubber membrane is suitable for use
as a controlling layer membrane for nicotine reservoir-type
patches in transdermal drug delivery systems.58
Synthetic rubber polymers have been widely used in
transdermal drug delivery systems as pressure sensitive
adhesives. They include materials for transdermal drug delivery
systems such as styrene−isoprene−styrene (SIS) block
copolymer, acrylic rubber hybrid, PIB, and silicone rubber.
Capsaicin, the active ingredient in chilli peppers, is commonly
used in topical skin preparations to relieve pain. The SIS block
copolymer, in combination with tackifying resin and plasticizer,
is used in transdermal drug delivery systems to produce
capsaicin-matrix patches.59,60 This block copolymer is the main
composition of hot melt pressure sensitive adhesives. SIS block
copolymer is a thermoplastic elastomer made of styrene-
isoprene diblock and SIS triblock. The entanglement network
structure of the copolymer is formed by the soft polyisoprene
phase and the rigid polystyrene phase. This block copolymer
has been extensively investigated and characterized including
adhesiveness, morphological and rheological properties, and
thermodynamic behaviors. Capsaicin is loaded into the SIS
block copolymer matrix by homogeneous mixing. It can be
diffused through the SIS block copolymer matrix, which is the
rate-limiting step of capsaicin percutaneous absorption. The SIS
structure and formulation compositions significantly influence
the morphological and rheological properties of the patches,
leading to a controllable drug release profile.59 In addition, the
styrene−isoprene content in SIS block copolymer and SIS
block copolymer proportions affect the capsaicin penetration
through the skin, as well as the adhesion properties of the
patches. Furthermore, transdermal administration of these
patch formulations showed no skin irritation in guinea pig
skin.60 In addition, SIS block copolymer is prepared to
epoxidize SIS resins by in situ epoxidation. These resins are
melted and mixed with synthetic hydrocarbon resin, mineral oil,
and antioxidants to make pressure sensitive adhesives for
transdermal drug delivery systems. Geniposide and oleanic acid
and hydrophilic and lipophilic drugs, respectively, are mixed in
these pressure sensitive adhesives as matrix type. These resins’
effect the cumulative release rate of both hydrophilic and
lipophilic drugs, which improves with an increase of the
epoxidation degree in the resins preparation process. Therefore,
the synthetic rubber SIS block copolymer is appropriate as a
carrier for transdermal drug delivery systems.61
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Acrylic rubber hybrid, PIB, styrene−butadiene−styrene
(SBS), and silicone are selected as pressure sensitive adhesives
in in vitro permeation of donepezil, using a flow through
diffusion cell system at 37 °C. These pressure sensitive
adhesives can systemically deliver the therapeutic amount of
donepezil for an extended period of time. Donepezil has the
half-life of 70 h and a high initial flux of drug permeation. These
adhesives performed well in their physical and chemical stability
tests conducted when they were kept in a refrigerator (2−8
°C), at room temperature, and at 40 °C for a period of 3
months.62
Silicone rubber, a rubber-like material, is an elastomer
composed of silicon together with carbon, hydrogen, and
oxygen. It is widely used in industry, and there are a wide
variety of products and multiple formulations of silicone rubber
in pharmaceutical sciences and medical applications. Compared
with organic rubber, it may have some improved properties,
such as elongation, creep, cyclic flexing, tear strength,
compression set, softer and tackier adhesive, and reduced
cost. It is generally nonchemically reactive, has no thermal
conductivity or toxicity, is stable, and has a resistance to oxygen,
ozone, and ultraviolet light.16 The matrix-type patches are made
from silicone rubber containing lidocaine hydrochloride. These
matrix-type patches can be applied to control the rapid release
behavior of the drug when the drug is restricted to the surface.
When a drug is allowed to spread evenly throughout the silicon
structure, the silicone rubber can highly control the release
behavior of the drug. If hydrophilic polymers such as PVA,
PVP, and hydroxyethyl cellulose are mixed in silicone with the
lidocaine hydrochloride, a burst effect of lidocaine hydro-
chloride is observed in the initial release stages of the
experiment.63 The improvement of the hydrophilicity of
silicone rubber is modified by incorporation of ethylenoxy
groups, through either blending or end-linking reactions with
low molecular weight polyethylene glycol (PEG),64 or through
blending or addition-grafting reaction with low molecular
weight PEG.65 This blended film significantly increases the
water uptake capacity of the films, and has a limited detrimental
effect on their mechanical properties as compared to the end-
linking reaction with low molecular weight PEG64 and an
addition-grafting reaction with low molecular weight PEG.65
The theophylline is loaded into the modified silicone rubber
matrix film. Silicone rubber reacts with PEG by an end-linked
reaction, and can highly control the release behavior of
theophylline more so than the blending reaction. This is
because the end-linked reaction is a better dispersion of the
absorbed water in their matrix film.64 On the other hand, the
addition-grafting reaction leads to inferior mechanical proper-
ties and poor controlled release properties of theophylline.65
Although the matrix-type patches can control release of the
drug so that it is uniformly distributed inside a polymeric
matrix, the drug release in these patches is mainly diffusion-
controlled, leading the early stages of the process to produce an
initial burst effect. Thus, this problem can be improved by
coating these patches with polymeric layers as in multilayer
matrixes. Both single and multilayer matrixes have been studied
experimentally and theoretically as an alternative method for
distributing the solute load; the permeation properties of the
systems independently of each other have also been explored.
For example, Soulas et al. used silicone rubber in the design
strategy of multilayer matrixes, which exhibited improved
release performance in relation to their monolithic counter-
parts. The symmetrical three-layers of silicone rubber matrixes
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Industrial & Engineering Chemistry Research
consisted of an inner drug-containing layer, proxyphylline
loaded into a silicone rubber matrix embedded between two
silicone rubber matrix layers, and PEG, a hydrophilic polymeric
excipient.66
The recent improvement and development of rubber
polymer selection and design are of great importance in
meeting the various criteria of new transdermal drug delivery
systems, including patches, gel, and film forming polymeric
solutions. The two types of rubber polymers: natural rubber
and synthetic rubber together with the physicochemical
properties of the pharmacologically active drug should be
well considered, and the rubber polymer’s biocompatibility,
especially with the skin is significant. However, this review
article proposes the potential of the concept of new raw
materials arising from basic research on the preparation of these
new transdermal drug delivery systems. Thus, there will soon
be both academic and industrial efforts to explore this new area
of transdermal drug delivery systems made from rubber
polymers. In fact, basic research in this area has already been
initiated in academia.
4. CONCLUSIONS
Rubber polymers, both natural and synthetic, are suitable
polymer carrier candidates. The development of natural
polymers represents a significant advance in drug delivery
systems. The concept of incorporating drugs into natural
polymers, patches, and film forming polymeric solutions is
widely accepted and documented. These novel devices can be
used in individual film-forms, specifically modified by blending,
and combined with other substances such as those in end-
linking and addition-grafting reactions, which do not require
special conditions for their preparations. These systems have
attracted attention as an alternate strategy for transdermal drug
delivery systems of many drug substances, because they can
control the release behavior of a drug, which plays an important
role in the designing and processing of transdermal drug
delivery devices. Developments in using natural polymers for
new formulations in drug delivery systems may increase in
future studies, with different preparation methods and
modifications. Therefore, it can be concluded that rubber
polymers as important drug carriers have made a great impact
on the advancement of drug delivery science and technology.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: jirapornchai.s@rsu.ac.th. Tel.: +(66)-(2)-9972222 ext.
4911, 1502. Fax: +(66)-(2)-9972222 ext. 1403, 1508.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
The authors would like to express their gratitude to Professor
Dr. Krisana Kraisintu from Faculty of Oriental Medicine and
Dr. Laksana Charoenchai from Faculty of Pharmacy, Rangsit
University, and Associate Professor Dr. Prapaporn Boonme
from Faculty of Pharmaceutical Sciences, Prince of Songkla
University. The authors would like to express their gratitude to
KI Tull from Rangsit University for assistance with the English
in this review.
512
■
Review
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