Review

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Therapeutic
Delivery
Recent developments in silicones for
topical and transdermal drug delivery

Silicones have been used in medicines, cosmetics and medical devices for over 60 years. Hyder Aliyar*,1
Polydimethylsiloxanes are polymers that are typically used either as an active in oral & Gerald Schalau II1
drug products or as excipients in topical and transdermal drug products. Inherent
1
Dow Corning Corporation, Midland,
MI 48686, USA
characteristics like hydrophobicity, adhesion and aesthetics allow silicones to offer
*Author for correspondence:
function and performance to drug products. Recent technologies like swollen Tel.: +1 989 496 6883
crosslinked silicone elastomer blend networks, sugar siloxanes, amphiphilic resin hyder.aliyar@dowcorning.com
linear polymers and silicone hybrid pressure sensitive adhesives promise potential
performance advantages and improved drug delivery efficacy. This article presents
a review of recent silicone material developments focusing on their function as
excipients influencing drug delivery in topical and transdermal systems.

Development of controlled release drug using permeation enhancers, shifting the

delivery systems requires simultaneous con- partitioning of the drug from the vehicle to
sideration of numerous interdependent fac- skin and delivering additional solvent leading
tors, including the drug’s physiochemical to higher convectional transport of molecules
properties, route of administration, nature of or enhancement of drug solubility, have been
delivery vehicle, mechanism of drug release, utilized successfully to overcome the barrier
ability to target and biocompatibility of the to deliver the drug to or across the skin [5] .
product [1] . This presents major challenges for A topical/transdermal formulation typi-
designing and developing a controlled release cally contains 90% or more excipients;
dosage form specific to the delivery route of inactive ingredients which are included to
administration, for instance, oral or dermal perform different functions in the product.
drug delivery. The active pharmaceutical Penetration and permeation of the drug
ingredient (drug) often gets most of the through the skin is not only dependent on
attention when it comes to a drug product, the physiochemical nature of the drug but
although the excipients or nondrug compo- also on the formulation composition, that
nents of a formulation also play a crucial role may alter the properties of the skin and hence
in delivering the active in each dosage form. influence the permeation of the drug [7] . In
Drug delivery via skin is an attractive alter- topical formulations, polymeric materials
native to oral and hypodermal delivery, as it generally provide the base or matrix for the
eliminates first pass metabolism and drug final dosage form, but can also impact drug
degradation in the GI tract [2] encountered by delivery. Since different drugs interact differ-
oral administration; and is relatively painless, ently with different polymers and affect the
and easy to use, in contrast to hypodermic release properties differently [8–10] , individ-
needles [3,4] . However, it is known that the ual polymers or polymer mixtures have his-
stratum corneum represents a major perme- torically been used to modulate drug release
ability barrier [5] . The anatomy of skin is such properties. The influence of minute changes
that the lipid bilayers are perfectly stacked in the chemical structure, the amorphous or
to exclude foreign substances [6] . Strategies crystalline state, hydrophobic or hydrophilic
part of
including, disrupting the lipid bilayer by nature of the polymers, on drug release char-

10.4155/TDE.15.39 © 2015 Future Science Ltd Ther. Deliv. (2015) 6(7), 827–839 ISSN 2041-5990 827
Review Aliyar & Schalau II

Key terms therefore relatively easy to use these two ingredients in

pharmaceutical applications. However, at times, a for-
Active pharmaceutical ingredient: The ingredient in a mulation or product form requires performance char-
pharmaceutical drug product responsible for the claimed
therapeutic benefit. Often the term is interchangeably used acteristics that may not be possible using only compen-
with ‘drug’ and ‘active’. dial excipients. When noncompendial excipients are
selected, the regulatory burden for the formulation can
Excipient: Any ingredient in a pharmaceutical drug
product excluding the drug. be much greater. Still, several noncompendial silicone
excipients exist in current commercial pharmaceutical
Pressure sensitive adhesive: A polymeric material which
provides adhesion between two surfaces upon applying
products to fulfill the performance requirements such
pressure. A pressure sensitive adhesive in the transdermal as to carry or solubilize actives, to improve aesthetic
drug delivery system provides the adhesion between skin properties in topical therapeutic formulations and as
and the patch for the intended period. adhesive matrices in transdermal drug delivery patches.
Transdermal drug delivery system: This often refers to This review describes recent advances in the applica-
the transdermal drug delivery using a patch system. The tion of silicone polymers in topical and transdermal drug
patch is applied on the undamaged skin surface and the delivery via skin and focuses on work reported in the lit-
drug is delivered from the patch to the systemic circulation.
erature in approximately the last 10 years. Several types
acteristics has also been demonstrated [10–14] . Topical of organic polymers, both natural and synthetic, are used
formulations use a variety of polymeric materials as in topical/transdermal drug delivery systems and
matrices including petrolatum, acrylic polymers, cellu- are discussed in several review articles [24–27] . Often, the
lose derivatives, chitosan, carageenan and silicones [15] . review articles include commercially used silicones as well
In transdermal patch formulations, the polymeric in the discussion along with the other polymers. This par-
pressure sensitive adhesive (PSA) material is ticular manuscript specifically focuses on silicone’s utili-
a key component, creating a bond between skin and zation in the recent years in the topical/transdermal drug
product and impacting all other performance crite- delivery area. It also provides emphasis on the advantages
ria [16] . Three PSA chemistries are commonly used associated with silicones when used in these drug deliv-
in transdermal products, namely acrylic, silicone and ery technologies. Additionally, not-yet-commercialized
synthetic or natural rubber [16] . newer silicone developmental technologies which dem-
Silicones are synthetic polymers containing Si–O onstrated potential benefits in topical/transdermal drug
siloxane bonds. The most common silicone polymers delivery have also been reported in this manuscript. The
are polydimethylsiloxanes (PDMS), the chemical authors found a greater number of references available
structure of which is shown in Figure 1. The unique in the patent literature compared with peer-reviewed
characteristics of PDMS such as low intermolecular journal articles, which are summarized here rather than
forces between pendant methyl groups, compact size reviewing each and every publication. For the readers’
of methyl groups, high-siloxane backbone flexibility, convenience, the ‘topical drug delivery’ section refers to
high-siloxane bond energy and partial ionic nature of drug delivery to and across the skin by the topical liquid
the siloxane bond account for their applications differ- or semisolid formulations.
entiated from either organic or inorganic polymers. [17] .
The multitude of physical forms and the physiochemi- Silicones in topical drug delivery
cal properties that silicones can display has led to their The use of silicone materials in many topical products
adoption in a diverse array of healthcare applications. has been reported [22] . Two of the most widely used
The silicone chemistry is known and has been well topically applied silicones in pharmaceutical applica-
documented. Interested readers can refer these text tions are compendial excipients – specifically dimethi-
books for more details [18–20] . cone and cyclomethicone, because of their unique
Although a variety of silicone forms and chemistries properties like skin protectancy, emolliency and low
have been used in medicines, cosmetics and medical surface tension [28–30] . In spite of its highly hydro-
devices for over 60 years, monographs only exist for phobic nature, several types of silicone materials have
two materials as excipients [21] , cyclomethicone and been successfully incorporated in water-based products
dimethicone. Silicones can be found in the formula- as emulsions. While the cosmetic industry benefited
tions of more than 350 registered drug products as hugely, silicones have made an impressive contribu-
actives or excipients [22] . The use of silicones has been tion to pharmaceutical drug delivery applications as
continuously increasing. For instance, a search in US well. However, other, noncompendial excipients are
National Library of Medicine for dimethicone and also used in topical pharmaceutical applications. A
simethicone (both as an active) produced 845 and recent estimate is that over 50% of current skin care
282 results [23] . From a regulatory perspective, it is products contain at least one silicone material [21] .

828 Ther. Deliv. (2015) 6(7) future science group

 Recent developments in silicones for topical & transdermal drug delivery Review

The silicones used in these applications are generally

CH3 CH3 CH3 CH3
recognized as safe and are known for having a variety
Si O (or) Si O Si O Si O
of aesthetics that are preferred by consumers. Specific n
property improvements noted in silicone-containing CH3 CH3 CH3 CH3
formulations include ease of spreading, less tackiness
and a silkier, ‘elegant’ and more lubricious feel than Figure 1. Chemical structures of polydimethylsiloxane.
c­omparable formulations without silicones [21,31,32] .
The complexity of the numerous dermatologic reac- a short time. These silicone gums are highly substan-
tion patterns fall under the heading of sensitive skin. tive on the skin and have been shown to significantly
Approximately 40% of population believes it possesses improve the substantivity of an active [39] . A pharmaceu-
the characteristics of sensitive skin creating a sizable tical product’s resistance to washing off and rubbing off
demand for products designed to minimize skin sen- may lead to more prolonged exposure of the drug on the
sitivity. Sensitive skin can be defined in both subjec- skin surface, which in turn may lead to a greater amount
tive and objective terms and the latter may include skin of drug being available, and ultimately crossing the stra-
responses like allergic contact dermatitis [33] . Though tum corneum barrier. One study demonstrated that
considered generally safe, investigations on individual 25% of the silicone gum (in hexamethyldisiloxane, a
silicones have been carried out for skin sensitivity, volatile silicone carrier fluid) applied to the forearm skin
however, not focused only on skin response like aller- surface, remained after 8 h of daily activities [40] . Consis-
gic contact dermatitis. A final report by the cosmetic tent with the substantivity of the gum, detectable levels
ingredient review expert panel provides skin irritation of the drug ketoprofen were observed 6 h after applica-
and sensitization by several individual silicones [34] . tion, as compared with 40 min in a comparative formu-
The impact of patient nonadherence on treatment lation without the silicone gum [40] . Skin hydration via
failure is an area of increasing concern and poor aesthet- occlusion can also temporarily alter the barrier proper-
ics may be a contributing factor to purposeful patient ties of the stratum corneum to allow for an enhanced
nonadherence with medical treatment regimes. Because flux of both hydrophilic and hydrophobic drugs. Most
of its chronic nature and historical reliance on topical polydimethylsiloxanes are nonocclusive, but silicone
medications, psoriasis is a condition on which the derma- gums as well as organic modified silicones (e.g., alkyl-
tology community has focused to understand the causes methylsiloxanes) are somewhat occlusive [41] , and so are
of patient nonadherence to the treatment regime. It has known to reduce transepidermal water loss and there-
been reported that more than a third of psoriatic patients fore hydrate the epidermis. As described, silicones can
are not compliant with their prescribed medication [35] impact physiochemical properties of a formulation, such
despite the well-documented link between adherence to as substantivity and occlusivity, which can impact the
a treatment regime and successful clinical outcomes [36] . efficacy of a drug formulation. The aesthetic proper-
While patients expressed frustration with the (lack of) ties of silicones may also impact the final p­roperties of a
treatment efficacy, research has suggested that vehicle- f­ormulation and thereby the treatment regimen.
related factors were ranked as ‘important’ to patients
when considering their motivations for intentional non- New silicone technologies for efficient drug
adherence to their treatment regimes [37] . Among the delivery
vehicle-related factors determining intentional nonad- Advancement in the development of innovative tech-
herence rates were aesthetic reasons such as ‘the medica- nologies and materials offer new avenues of topical drug
tion felt unpleasant’ and the time-consuming nature of delivery applications by silicones. Given the wide variety
application [37] . Dosing frequency (once- vs twice-daily of silicone forms and applications, it is difficult to fore-
application) which is sometimes suggested as having an see which, if any, of the current materials may find util-
impact on patient compliance was not a determining
factor in patient adherence to a treatment regime [37] . Key terms
In addition to the aesthetic improvements that sili-
cones may provide to a topical formulation, other more Occlusivity: The ability of a formulation ingredient(s) in
the formation of a layer/coating/film on the skin surface
objectively measured properties can also be provided. which assists for the prevention of the loss of water from
Substantivity is a term describing the adherent quali- the skin surface.
ties of a topical formulation and its ability to be retained
Substantivity: The ability of a formulation ingredient(s)
on the skin over time [38] . Silicone gums are very-high- in the formation and adherence of a layer/film on the skin
molecular-weight PDMS polymers with a viscosity in surface which resists easy wash-off or rub-off of the layer
excess of 100,000 cP, and while still liquid by definition, so that the layer may help to retain the drug incorporated
in it for a longer period.
they are no longer pourable, and can hold a shape for

future science group www.future-science.com 829

Review Aliyar & Schalau II

ity in approved topically applied pharmaceutical prod- was also demonstrated against the commercial product
ucts. The investigation for well-differentiated or novel in vivo using rats (see Figure 3).
applications is always progressing by both academia and Utilization of silicone elastomer gels in a variety of
industry not only utilizing the inherent aesthetic charac- drug delivery applications has been reported via granted
teristics of silicones but also seeking enhanced therapeu- and or sought intellectual property publications. Nota-
tic efficacy of the drug product. Current uses in other ble references include formulations or compositions to
life science-related industries, a demonstrated advantage deliver actives like ingenol angelate [47] , retinoic acid
of use at the research level and intellectual property pro- derivatives [48] , amino acids [49] , antiperspirants [50] ,
tection filed, suggest a great potential for several silicone clobetasol propionate [51] and several other actives [52,53] .
technologies and materials for the topical drug delivery Crosslinked silicone matrix-type polymers were
arena. Detailed below are some technologies and materi- reported for the encapsulation and subsequent delivery
als that have been recently reported and relate to topical of actives for improved stability and performance [54]
pharmaceutical drug delivery applications. and in some instances to deliver protein [55,56] . Using
Silicone elastomer blends are slightly crosslinked, different types of silicone elastomer gels, dual drug
3D network polymers are swollen in an organic or sili- delivery, delivery of hydrophilic and hydrophobic drugs
cone solvent to create a gel. The general procedure to from gel f­ormulations has also been reported [57] .
prepare the gels includes a platinum-catalyzed hydro-
silylation reaction of Si-H functional silicone in pres- Delivery of actives by soft skin adhesive
ence of the solvent followed by shearing the gels into Soft skin adhesive technology has revolutionized the
discrete particles [42,43] . wound care industry with its unique skin-friendly
These semi-solid silicone materials have been uti- adhesion characteristics. Like the gels described above,
lized to make nonaqueous, topically applied formula- this technology also utilizes a platinum-catalyzed
tion to efficiently deliver drugs. Forbes et al. reported hydrosilylation crosslinking reaction. However, the
efficient in vivo delivery of antiretroviral HIV drug, resulting product is a tacky, cohesive matrix rather
maraviroc, to rhesus macaques from a nonaqueous than a dispersed gel. This technology has been utilized
silicone elastomer gel formulation over nonsilicone- to deliver antimicrobial actives for wound therapy [58] .
based formulation(s) pertinent to a microbicide deliv- The loosely crosslinked structure has proven its suit-
ery system (see Figure 2) [44] . The silicone formulation ability for topical drug delivery as well. The patches
also demonstrated no irritation to mucosal tissue and made from soft skin adhesive showed noteworthy 24-h
enhanced mucosal retention for efficiency. Subse- cumulative release of 45 to 58% estradiol compared
quently, the same research team using a different sili- with 1 to 12% by other silicone polymers over the same
cone elastomer gel that was partially modified with rel- period of 24 h [59] .
atively hydrophilic silanol-terminated PDMS reported
enhanced release of maraviroc and emtricitabine Emulsions
(another antiretroviral HIV drug) over 24 h and less The possibility of delivering both lipophilic and hydro-
cytotoxicity compared with standard hydroxyethylcel- philic drugs topically has been disclosed using emul-
lulose gels [45] . The nonaqueous, silicone gels may offer sions formed by a soft silicone elastomer and a hydro-
several advantages over more conventional water-based philic polymer like polyvinyl alcohol [60,61] or polyvinyl
gels for vaginal delivery systems, including better for- pyrrolidone [62] . Depending on the ratio of silicone to
mulation of poorly water-soluble active compounds, the other polymer, the emulsions provided films of
prolonged pharmacokinetic profiles and greater varying appearance from glossy to matte, and colored
s­tability of hydrolytically vulnerable compounds. from white to transparent, with varying mechanical
While the above research reports the drug release to properties. These differences may in turn alter the
vaginal mucosal tissues, where the stratum corneum drug delivery profile too. Silicone-containing emulsion
barrier does not exist, another work reported by Ali- compositions were reported to deliver several actives
yar et al. demonstrated efficient in vitro delivery of including niacinamide [63] , thiazolium compounds [64] ,
ibuprofen across human cadaver skin using silicone chlorhexidine [65] topically. A stable three-phase emul-
elastomer gel-based formulation compared with a sion comprising an aqueous gel outer phase and a water-
commercial product and similar formulations made of in-silicone oil inner phase has been described for the
nonsilicone chemistries [46] . The increased efficiency topical delivery of pharmaceuticals [66] . A variety of
silicones in different amounts may be incorporated into
Key term the water-in-oil phase of the three-phase emulsion to
prepare emulsions with different characteristics. Emul-
Topical delivery: Delivery of a drug into the (dermal) skin.
sions made of high molecular weight uncrosslinked

830 Ther. Deliv. (2015) 6(7) future science group

 Recent developments in silicones for topical & transdermal drug delivery Review

PDMS (silicone gum) [67] or PSAs using polymeric

surfactant like ethylene oxide-propylene oxide block 250,000
copolymer [68] , have also been demonstrated utility in *

Mean maraviroc concentration

topical drug delivery applications. 200,000

in vaginal tissue (ng/ml)

Film, foam & spray dosage forms
Topical dosage forms, which provide a film on top of 150,000
the skin, offer advantages like, longer dosage reten-
tion, occlusivity, rub-off resistance and barrier prop- 100,000
erties all of which influence drug delivery. Several
novel silicone-containing film formers have been
50,000
investigated for utility in topical drug delivery. Com-
positions containing a silicone acrylate hybrid poly-
mer [69] , sugar siloxanes [70,71] and amphiphilic resin- 0
linear organosiloxane block copolymers, which may Silicone gel HEC gel
improve the solubility of hydrophilic actives into the
siloxane matrix [72] , have also been investigated for Figure 2. In vivo delivery of anti-HIV drug maraviroc
topical drug delivery. by silicone and hydroxyethylcellulose-based gels.
Low molecular weight volatile silicones like hexa- Data shown are mean concentration ± SD (ng/ml) of
maraviroc measured in the vaginal tissue of rhesus
methyldisiloxane have been utilized in many topical macaques following vaginal administration of a single
spray formulation dosages to deliver the drug. These 4 ml sample of 80/20 silicone elastomer gel or 2.2%
volatile silicones provide functional properties like w/w hydroxyethylcellulose gels containing 33 mg/ml
nonirritation [73] , moisture maintenance and solubili- maraviroc (100 mg total dose).
zation of the active [74] . Literature suggests that actives Reproduced with permission from © Elsevier BV
(2011) [44] .
like vitamin-A, diclofenac and lidocaine have been
investigated in spray formulations. The volatility of the Silicones in transdermal drug delivery
silicone in these applications helps increase the drug The commercial success of transdermal drug delivery
concentration in the formulation quickly to saturation patches commenced in 1980 with the first commercial
thereby assisting efficient drug delivery [75,76] . Sili- scopolamine patch to treat motion sickness [16] . Today
cones have also been reported for topical foam dosage drug delivery via skin is still an attractive delivery tech-
forms [32,77–81] . nology as witnessed by the number of product approv-
The exploration of the use of novel silicone tech- als in 2014. The key scientific attribute for this continu-
nologies in topical drug delivery is quite impressive ing success is the ability of the technology to provide
as observed in the literature as described above, par- sustained drug blood levels with minimal variation in
ticularly in the patent arena. Though dimethicone and blood levels of the active via a nonoral, noninjectable
cyclomethicone have been utilized in numerous topical route of delivery [83] . The features and other advantages
drug products, the use of other silicone materials as of transdermal delivery include the elimination of
a primary polymer in topical pharmaceutical formu- first pass metabolism over oral delivery and, painless
lations is infrequent, whereas other nonsilicone poly- and easy to use compared with hypodermic needles.
mers like petrolatum, carbomer (acrylic polymer), cel- Continuous drug delivery for up to a week via trans-
lulose derivatives, poly(ethylene glycol), poly(ethylene dermal patches provide compelling and differentiating
glycol)-co-poly(propylene glycol) copolymers domi- medical benefits that keep transdermal delivery an area
nate in the topical drug products. Out of the 34 topi- of active research and product development.
cal drug products approved by the US FDA in 2014 The PSA is a critical component of the transdermal
under new drug application class, none contains a sili- drug delivery system (TDDS) design irrespective of
cone material [82] , however, silicones have been used in patch design, either matrix (or drug-in-adhesive) or
many monograph-supported/over-the-counter prod- reservoir. Recent trends almost exclusively favor matrix
ucts. It is important not to ignore the time and cost type patches elevating the significance of the adhesives’
associated with the approval process a new excipient, role not only as a skin interface to adhere the patch with
either silicone or nonsilicone-based, requires. But, the the skin but also to play a key role in optimizing the
strong presence in the beauty care, and recent develop-
Key term
ments demonstrating enhanced drug delivery efficacy
suggest a promising future for silicone technologies in Transdermal delivery: Delivery of a drug through or
across the skin beyond dermal layer.
the topical drug delivery arena.

future science group www.future-science.com 831

Review Aliyar & Schalau II

delivery of the drug. In general, three adhesive chemis- Silicone PSA are primarily based on PDMS materi-
try sets are used in transdermal patches: polyacrylates, als, the product of the reaction between silanol end
silicones and rubber, specifically polyisobutenes (PIB). blocked dimethyl siloxane polymers and silicate resin.
The polymers typically used are polydimethylsilox-
Silicone PSA anes with dimethylsilanol end groups, while the res-
A family of noncompendial silicone excipients that has ins are 3D trimethylsiloxy and hydroxyl end-blocked
become widely accepted in TDDS is silicone PSAs. silicate structures. The resin-to-polymer ratio and the
Silicone adhesives serve as a skin interface that holds degree of crosslinking are two of the most important
the TDDS in place and/or act as the rate control- performance-determining factors of the PSA. The
ling matrices for the active. Medical PSA must pro- resulting material from a simple blend of the resin and
vide secure adhesion for the prescribed duration and polymer will have some PSA properties, albeit with
then have the ability to be removed cleanly from skin poor cohesive characteristics. This lack of cohesion
without causing undue trauma to the wearer [84] . The can be overcome through a condensation (or body-
chain flexibility and open molecular structure with low ing) reaction whereby the respective functional groups
molecular interactions that are inherent to silicone PSA create a covalently bonded, crosslinked network. The
provide the ability to wet out and conform to the con- adhesives created by this bodying reaction retain a
tours of the skin surface as well as have suitable tack relatively high degree of silanol functionality. These
and adhesion for a variety of skin types. Adhesives adhesives are suitable for many applications, including
designed for transdermal drug delivery must also show drug delivery for some actives. By reacting the residual
permeability to therapeutic ingredients while display- silanol groups with a trimethylsilyl end capping agent,
ing minimal deleterious interactions with the drug and the silanol content can be significantly reduced to pro-
the other excipients and components of the transder- vide enhanced chemical compatibility. The resulting
mal device. Therefore, the PSA must maintain adhesive adhesives may be referred to as ‘amine-compatible’
and cohesive properties in the presence of drugs that and have found utility in transdermal patch applica-
allow the patch to maintain intimate contact with the tions because of their increased resistance to reactivity
patient with a consistent geometry over the duration with amine functional drugs [84] .
of the dosage regime [84] . Silicone PSAs offer excellent Silicone PSA was first used in the Duragesic® (Jans-
permeability to lipophilic drugs, and can be further sen Pharmaceuticals, Inc., NJ, USA) fentanyl patch in
modified by formulating with hydrophilic fillers, copo- 1990 and its use in transdermal patch products con-
lymers, plasticizers or by modification of the network tinues today [85] . Table 1 provides the silicone-contain-
with silicone-organic copolymers to also allow delivery ing TDDS products approved in the USA in recent
of hydrophilic drugs. years and demonstrates the utility of silicone PSA in a
variety of treatment modalities, both when used solo
and in combination with other adhesive types [86] .
30
S1
Ibuprofen in blood (µg/g)

25 Benchmark Comparison of patch efficacy containing

20
different PSAs
A recent survey of commercial fentanyl patches using
15 three different adhesive chemistries; silicone, polyacry-
10 late and PIB concluded that formulators could achieve
bioequivalency of the drug dosage by formulating with
5
any of the adhesive types, although with vastly differ-
0 ent patch designs. However, commercial patches that
0 1 2 3 4 5 6 7 8
Time (h)
made use of silicone or PIB adhesives exhibited more
efficient utilization of the loaded drug (i.e., leaving less
unused fentanyl in the patch). The efficient use of the
Figure 3. In vivo delivery of ibuprofen to rats’ blood.
Data shown are the comparison of average ibuprofen drug also impacted the size of the patch where more
blood concentration measured in vivo for S1 (n = 5) efficient drug utilization typically required smaller
and benchmark (n = 4). S1 is silicone elastomer-based patch size (equating to a smaller surface area of skin
gel formulation and benchmark is a commercial gel in contact with the patch). This phenomenon was
product. Both S1 and benchmark contained ibuprofen
attributed in large measure to the higher solubility of
at 5%.
Reproduced with permission from © Wiley fentanyl in polyacrylate adhesives, which limited the
Periodicals, Inc. (2014), and the American Pharmacists likelihood of the drug passively eluting from the patch.
Association [46] . This survey concluded that adhesives with lower drug

832 Ther. Deliv. (2015) 6(7) future science group

 Recent developments in silicones for topical & transdermal drug delivery Review

Table 1. US FDA-approved silicone-containing transdermal drug delivery system patch products in

the USA (2000–2014).
Product name Drug Adhesive type
Clonidine Transdermal System Clonidine Silicone, polyacrylate
Daytrana (Noven pharmaceuticals, FL, USA)
®
Methylphenidate Polyacrylate, silicone
Fentanyl Transdermal System† Fentanyl Silicone
Fentanyl Transdermal System †
Fentanyl Silicone
Fentanyl Transdermal System †
Fentanyl Silicone
Fentanyl Transdermal System† Fentanyl Silicone
Fentanyl Transdermal System †
Fentanyl Silicone
Minivelle® (Noven Pharmaceuticals) Estradiol Polyacrylate, silicone
Neupro® (UCB, Inc., GA, USA) Rotigotine Silicone
Qutenza (Accorda Therapeutics, NY, USA)
®
Capsaicin Silicone
†
By different manufacturers/owners/distributors.

solubility may provide more efficient delivery attri- Pharmaceutical formulators have utilized the diverse
butes and therefore, should be preferentially selected drug and polymer interactions inherent to the various
when designing patches [85] . adhesive technologies as well as the adhesive’s dissimilar
Achieving the therapeutically appropriate drug compatibility with drugs to create increasingly sophis-
release profile that will support a commercial drug ticated TDDS designs. These have taken the form of
product is the ultimate factor that determines the layering silicone and other adhesives or other nonad-
relevance of a TDDS. Studies have investigated the hesive polymers that may act as drug reservoirs, or rate
permeation of many drugs from multiple adhesive controlling layers within the seemingly monolithic
matrices through different models and concluded TDDS to achieve the desired performance [85,90] . Other
that drug release from silicone matrices is generally unique and advanced patch designs have been created
higher than those from other tested adhesive matrices. by blending silicone adhesives with nonsilicone adhe-
This phenomenon is likely a result of lower interac- sives and other polymers with differing drug compat-
tion between the drug and the silicone PSA polymer ibilities to achieve patches with the desired t­herapeutic
compared with other adhesive polymers. The extent of release profiles for a number of actives [91,92] .
the drug polymer interaction can be estimated by the As the use of silicone PSA in the healthcare arena
relationship between the drug concentrations in the continues to expand in response to specific applica-
PSA and their diffusion coefficients. One such study tion needs, a number of publications describe com-
investigated the interactions of four different drugs: positions and/or constructions utilizing silicone PSA
dipropylphthalate, aminopyrine, ketoprofen and that are designed to provide delivery of specific drugs
lidocaine in four adhesive matrices, two polyacrylate and improve safety through abuse deterrent TDDS
adhesives with differing functionalities, a PIB and an dosage forms [93–95] . Patent literature discloses the use
amine compatible silicone PSA. Interactions between of silicone PSAs in transdermal patch development to
the polyacrylate adhesives and some drugs were noted, deliver variety of drugs including NSAIDs [96–101] , hor-
but no drug–polymer interactions were noted with mones [94,102–104] , retinoids [105] and vitamins [105,106] .
either the PIB or silicone adhesives which are com- In most of these cases silicone PSAs have been noted for
posed of mostly nonpolar groups [87] . Another study enhancing drug delivery in addition to other p­roperties
identified the permeation of terbinafine across porcine like less skin irritation and sensitization.
hoof membrane and determined that drug permeation
from the silicone matrix was the highest measured Hybrid silicone PSA
followed by PIB, polyacrylate adhesives and styrene Two of the more commonly chosen adhesive types are
block copolymer adhesives [88] . A separate analysis of the polyacrylate and silicone. Each adhesive chemis-
N-methyl-d-aspartate, a receptor antagonist for neu- try type provides some advantages – silicone PSA may
ropathic pain and neurological disorder, concluded release active more readily, while the polyacrylate PSA
silicone PSA would be the most suitable for the trans- have a greater affinity with many drugs and other com-
dermal delivery of N-methyl-d-aspartate compared mon excipients, making formulating more straightfor-
with other PSAs investigated (see Figure 4 ) [89] . ward. However, the converse of each advantage may

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Review Aliyar & Schalau II

Key term that has gained much interest and is potentially on the
horizon. The first approach recorded in the literature
Residual drug: The amount of drug not utilized for the describes a multistep process by which a silicone PSA
therapeutic purpose.
as described above is prepared, functionalized with a
be a disadvantage, silicones may be more difficult to free-radical reactive agent, then acrylic monomer is
formulate due to the poor compatibility with a number added and then polymerized to create the hybrid copo-
of excipients and drugs, while drug release from the lymer [107] . This polymerization yields a PSA which
polyacrylate matrix is less efficient resulting in more chemically integrates the advantageous functional-
residual drug in the used patch. ities associated with both acrylic and silicone chem-
There have been several attempts to combine poly- istries into a stable PSA that resists phase separation.
acrylate PSAs and silicone PSAs to gain the advantages The second technique to create the silicone acrylate
of both technologies. Blending two types of PSAs or copolymer hybrid uses prepolymerized acrylic poly-
emulsifying in presence of surfactants generally pro- mer containing reactive silane groups and combining
vides phase separation and stability issues [107] . In that with the precursors to the silicone PSA. During
this context, the concept of a silicone acrylate hybrid the final bodying step in the creation of the silicone
copolymer composition that retains the positive attri- PSA, the acrylates are grafted to the silicone [108] . Both
butes of both PSA types has been put forward. At techniques suggest that during polymerization, the
least two synthetic approaches have been suggested silicone to acrylic ratio, the ratio and type of mono-
by different research groups by which silicone acrylate mers chosen may be sufficiently controlled and opti-
hybrid pressure sensitive adhesives for TDDS can be mized to achieve desired physical properties [107,108] .
achieved [107,108] . Although, to date, neither approach Similarly, the balance of silicone to acrylic compo-
has been commercially realized in a pharmaceutical nents can be selectively used to control solubility of
product, it is an interesting silicone-based technology an active agent in the hybrid PSA to optimize the rate

500
Cumulative amount permeated (µg/cm2)

400

300

200

100

0
0 10 20 30 40 50
Time (h)

Figure 4. Skin permeation of CNS5161 base (a N-methyl- d -aspartate) from pressure sensitive adhesives containing
10% CNS 5161. Data shown are the cumulative amounts of CNS5161 base, expressed as the mean with the bar
shown standard deviation values of four experiments. Key: •, SIS(1); ○, SIS(2); ▪, silicone; □, acrylate (OH); Δ,
acrylate (COOH).
SIS: Styrene-isoprene-styrene block copolymers.
Reproduced with permission from © The Pharmaceutical Society of Japan (2012) [89] .

834 Ther. Deliv. (2015) 6(7) future science group

 Recent developments in silicones for topical & transdermal drug delivery Review

at which the active agent is released from the system linked to topical/transdermal applications, they were
and also the amount of active agent that is ultimately indicated for potential drug delivery applications.
released [107,108] . While the commercial utility of this Tubular polysiloxane nanostructures were formed
technology is not totally understood today, derivations via a chemical vapor deposition technique at room tem-
and applications outside TDDS are already appearing perature when ethyltrichlorosilane is used or via liquid
in literature as the nontacky adaptations of this tech- phase method when methyltriethoxysilane is used as a
nology have been s­uggested as film forming topical precursor. The very low cost of synthetic method and
compositions [69] . nontoxic and inert nature of the polysiloxane materi-
While increased drug delivery efficiency may have als make these tubes very attractive for many future
an impact on the physical characteristics of a TDDS a­pplications including drug delivery [123] .
patch such as its size and shape, some regulatory and An efficient and adaptable method for the microen-
sustainability benefits may also be realized through capsulation of active ingredients by PDMS core-shell
more efficient formulations. A recent draft guidance microcapsules has been reported by Teixeira et al. [124] .
by the FDA provided recommendations to developers The microcapsule was obtained by phase separation
and manufacturers of transdermal drug delivery sys- between the core component and the PDMS shell com-
tems, transmucosal drug delivery systems and topical ponents after repartitioning of the common solvent
patches to ensure that the residual drug content at the between the PDMS/core materials phase and the water
end of the product labeled use period is minimized [109] . phase. This microencapsulation provides environmen-
More efficient delivery as evidenced by higher release tal protection of the active ingredient and can also pro-
rates of drugs from patches is not only aligned with this vide control and triggered release of the active. Drug
draft guidance, it may have implications when seek- delivery is known in which such microe­ncapsulation
ing regulatory approval for newly designed TDDS. In can certainly be used.
recent years, numerous reports have noted the presence A novel platform that allows for reliably attaching
of pharmaceutical and personal care actives in ground drug-loaded nanodepots to the surface of PDMS and
water [110,111] , the impact of active pharmaceutical releasing the drug in a sustained manner is demon-
ingredients (API) on aquatic animal development [112] , strated. The methodology is assisting to improve the
and the inability of current waste water and drinking hydrophilicity of PDMS surface, thereby improving the
water treatment facilities to remove API from treated biocompatibility, without sacrificing the mechanical
water [113,114] . In the more efficient drug delivery for- properties of PDMS. Though it is demonstrated with
mulations detailed above, less active was needed in the budesonide-loaded ethylcellulose nanoparticles, the plat-
TDDS to achieve comparable therapeutic effect, and a form could theoretically be applied to different PDMS
higher proportion was utilized, making it likely that less medical devices and with other payload drugs [125] .
drug will find its way into the environment from these
devices. Efficient utilization of the drug has additional Conclusion
importance in some API like fentanyl due to uninten- PDMS-based silicone materials have been used in the
tional use or abuse. The number of currently available medical industry over six decades. Dimethicone and
fentanyl transdermal systems and the continuation of simethicone are used as an active in many antiacid/anti-
investigations [115–122] on the utilization of silicone PSAs gas drugs whereas many other silicones materials are
for fentanyl patch development support the suitability used in pharmaceutical applications are excipients, par-
of silicone PSAs when there is a need to deliver a drug ticularly in topical and transdermal drug delivery sys-
efficiently. tems. Unique characteristics including hydrophobicity,
adhesion, low glass transition temperature, biocom-
Inspiring future patibility, aesthetics and a general resistance to many
The unique inherent characteristics of the silicone chemical degradation pathways allow silicones to offer
materials, like hydrophobicity, wetability, low glass function and performance to drug delivery products.
transition temperature have been continuously inves- Though silicones have a strong presence in the beauty
tigated to develop innovative materials and technolo- care products, their use as a primary polymer in topi-
gies for diverse applications. Irrespective of stringent cally applied drug products is still infrequent. How-
requirements for all materials used in pharmaceutical ever, recent research reports on the role silicone may
drug delivery application, design and development of play in delivering drug efficiently in topical and trans-
creative materials and technologies are always inspir- dermal drug delivery system applications and the vast
ing. Described below are a few of the very latest research numbers of patent filings suggest a promising future
reports which portray new developments using polysi- for silicone technologies in topical dosage forms with
loxane materials. Though they have not been directly diverse therapeutic benefits. Moreover, new silicone

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Review Aliyar & Schalau II

technologies like swollen crosslinked silicone elastomer Silicone-based pressure-sensitive adhesives have
blend networks, sugar siloxanes, amphiphilic resin lin- already made a valuable contribution in transdermal
ear polymers offer performance advantages and drug drug delivery system products. It is easily observed
delivery efficacy improvements in topical or transder- from the literature that silicone PSAs are selected when
mal drug delivery systems. Silicones, as PSA, already efficient delivery from the patch is required; however
have an impressive presence in transdermal drug deliv- the solubility of the drug often in the silicone matrix is
ery system products. Silicone PSAs are often the choice insufficient. Recently introduced hybrid silicone PSA
when efficient drug delivery from the patch is required. materials may provide a solution to this situation. Reg-
However, the solubility of the drug in the silicone ulatory authorities’ insistence for efficient use of drugs
matrix is often insufficient and remains a challenge for in the patch products, new hybrid silicone PSA and
wider acceptance of silicone PSA. Recently introduced silicone PSA’s efficient drug delivery in general, would
silicone hybrid PSA materials may provide a solution make the silicone PSAs as preferred adhesives in the
to this situation and also enhance compatibility with future TDDS product development.
other excipients in the formulation. Though topical and transdermal product develop-
ment mostly focuses with low molecular weight drugs
Future perspective currently, when the technology is developed and/or
The history of silicone ingredients in the personal care established for delivering high molecular weight active
products has established their suitability in topically like biologics, proteins, vaccines transdermally in the
applied products. Though the regulatory status does not future, silicone-based excipients may play an important
favor their selection by the formulators, research sug- role in delivering them either topically or t­ransdermally
gests that silicone materials may have a role to play in in the future.
delivering drugs more efficiently. This scenario coupled
with the demand from healthcare consumer for efficient Financial & competing interests disclosure
and aesthetically pleasing topically applied products The authors have no relevant affiliations or financial involve-
may bode well for the future of novel silicone excipi- ment with any organization or entity with a financial inter-
ents as platforms in topical drug products. Properties est in or financial conflict with the subject matter or mate-
like film formation and enhanced compatibility with rials discussed in the manuscript. This includes employment,
organic materials that are inherent in some new sili- consultancies, honoraria, stock ownership or options, expert
cone technologies in addition to the intrinsic aesthetic testimony, grants or patents received or pending, or royalties.
characteristics, could further support the use of more No writing assistance was utilized in the production of this
silicone materials in topical drug products in the future. manuscript.

Executive summary
Silicones in medical applications
• Polydimethylsiloxane-based silicone materials have been used in medical applications over 60 years.
• Dimethicone and simethicone are only two silicone-based materials used as actives for therapeutic purpose;
they have also been used as excipients in many drug products; all other silicone materials used in the
pharmaceutical drug delivery products are excipients.
Benefit of silicones in topical formulations
• Silicone-based materials are used exhaustively in cosmetic or beauty care topical products; however, their use
as a primary polymer in topical drug delivery products is infrequent.
• Recent investigations have demonstrated that silicone materials could assist to deliver the drug efficiently
from topical dosage forms compared with nonsilicone-based polymeric materials.
• Silicone excipients in the form of low to high molecular weight liquid, pastes and solids have been investigated
in topical formulations of different dosage forms using different types of active pharmaceutical ingredients.
• Silicone topical excipients could provide hydrophobicity, nonocclusivity or semi-occlusivity and film formation.
Silicone pressure sensitive adhesives: current presence, benefits & new hybrid technology
• Silicone-based pressure sensitive adhesive (PSA) materials have made their significance via many approved
transdermal drug delivery patch products.
• Silicone PSAs come with variety of tack properties and in different solvents.
• Select PSAs are recommended for amine-containing drugs.
• Silicone PSAs have been used preferentially when there is a need to deliver the drug efficiently.
• Silicone PSAs provide good biocompatibility to skin and stability to the transdermal drug formulations.
• Hybrid silicone PSAs offer unique properties for drug solubility, drug delivery and stability compared with
corresponding blend of two individual PSAs.

836 Ther. Deliv. (2015) 6(7) future science group

 Recent developments in silicones for topical & transdermal drug delivery Review

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