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`Current Pharmaceutical Design, 2015, 21, 2771-2783
`2771
`
`Current Pharmaceutical Design on Adhesive Based Transdermal Drug Delivery
`Systems
`
`Animesh Ghosh'", Subham Banerjee’, Santanu Kaity' and Tin W. Wong
`
`23,4*
`
`‘Departmentof Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra Ranchi-835215,
`India; ?Non-Destructive Biomedical and Pharmaceutical Research Centre; *Particle Design Research Group,
`Faculty of Pharmacy; Universiti Teknologi MARA, 42300, Puncak Alam, Selangor, Malaysia; *CoRe Frontier
`Materials and Industry Application, Universiti Teknologi MARA, 40450, Shah Alam, Selangor, Malaysia
`
`Abstract: Drug-in-adhesive transdermal drug delivery matrix exploits intimate contact of the carrier with stratum
`comeum,the principal skin barrier to drug transport, to deliver the actives across the skin and into the systemic cir-
`culation. The main application challenges of drug-in-adhesive matrix lie in the physicochemical properties of skin
`varying with age, gender, ethnicity, health and environmental condition ofpatients. This in turn posesdifficulty to
`design a universal formulation to meet the intended adhesiveness, drug release and drug permeation performances.
`This review focuses on pressure-sensilive adhesives, and their adhesiveness and drug release/permeation modula-
`tion mechanismsas a function of adhesive molecular structure and formulation attributes. [t discusses approaches to modulate adhesive
`tackiness, strength, elasticity, hydrophilicity, molecular suspension capability and swelling capacity, which contribute to the net effect of
`adhesive on skin bonding, drug release and drug permeation.
`
`Yi Animesh Ghosh
`
`Keywords: Drug-in-adhesive, pressure-sensitive adhesive, transdermal drug delivery.
`
`INTRODUCTION
`
`Human skin provides multiple functions and is primarily a
`physical barrier against the exogenous substances such as xenobiot-
`ics. The protective role of the skin is conferred by its multi-layered
`structure. The superficial layer of the skin is known as stratum cor-
`neum. It represents the finished product of the differentiation proc-
`ess at the basal layer of epidermis where keratinocytes are formed
`by cellular mitotic division. Anatomically, the stratum corneum is
`composed of comeocytes interdispersed within a lipophilic matrix
`in a “brick and mortar” architecture.
`It represents the most critical
`barrier of the skin [1, 2]. The stratum corneum is well known to
`exhibit selective permeability and allows only relatively lipophilic
`compounds to diffuse into the lower skin layers. The solute trans-
`port is largely mediated via passive diffusion in agreement with the
`Fick's Law of diffusion [3, 4] and no active transport processes
`have been identified [5]. Distinctive delivery systems can be de-
`signed to attain transdermal or dermal drug transport. The former
`involves the breaking of skin barrier whereasthe latter only exerts a
`local effect at or near to the skin surfaces.
`
`SKIN ANATOMY
`
`Skin is characterized by an enormous surface area (approxi-
`mately 2 m?) with minimalproteolytic activities. It comprises of
`three distinct layers: 1) subcutaneous tissue layer/hypodermis,
`11)
`viable dermal layer and iii) non-viable and viable epidermal layer
`(6). The transdermal drug delivery is hindered by the stratum cor-
`neum, the uppermost dead layer of epidermis [7]. The stratum cor-
`neum is made up ofthick 10 to 20 cell layers over most parts of the
`body [8]. Each cell
`is presented in the form of a flat, plate-like
`structure (length = 34-44 um, width = 25-36 um, thickness = 0.2-
`0.5 um) with a surface area of 750 to 1200 pm’ arrangedin a brick-
`
`*Address correspondence to these authors at the Non-Destructive Biomedi-
`cal and Pharmaceutical Research Centre, Universiti Teknologi MARA,
`Puncak Alam, 42300, Selangor, Malaysia. Tel.: +60 3 32584691;
`E-mails: wongtinwui@salam.uitm.edu.my; wongtinwui@yahoo.com
`Department of Pharmaceutical Sciences and Technology, Birla Institute of
`Technology, Mesra Ranchi-835215, India; Tel: +09470339587;
`E-mail: aghosh(@bitmesra.ac.in
`
`like layering fashion within a hydrophobic matrix of phospholipids.
`glycosphingolipid, cholesterol sulfate and neutral
`lipid. The thick-
`ness and density of the stratum corneum may differ from one body
`site to another. Such differences could dictate the efficiency of
`transdermal drug delivery. The epidermal permeability is chiefly
`modulated by the intercellular lipids, arranged in lamellar sheets
`[9].
`It has been observed that the removal of epidermal lipids by
`means of organic extraction reduces the skin barrier attribute [10,
`11].
`
`three modes of solute transport have been proposed
`Broadly,
`with respect to transdermal drug delivery:
`I.
`intercellular diffusion through the lipid lamellae.
`Il.
`transcellular diffusion through both the keratinocytes and
`lipid lamellae.
`diffusion through the hair follicles and sweat ducts.
`Generally, it is recognised that the polar solutes permeate the
`skin mainly through the polar pathway within the hydrated stratum
`comeum. On the other hand,
`the non-polar solutes permeate the
`skin through the lipid matrix of the stratum corneum.
`
`Ul.
`
`TECHNOLOGICAL ENHANCEMENT OF TRANSDERMAL
`DRUG DELIVERY
`
`In the past 25 years, numerous new and modified methods have
`been reported with the aim to overcome the skin barrier and im-
`prove the transdermal drug transport. These are divided into two
`prime categories:
`l.
`Passive technology
`2. Active technology
`
`Passive Technology
`The passive transdermal drug delivery technology enhances the
`skin solute transport solely based on the principle of diffusion the-
`ory [12]. It gives rise to the development of conventional dosage
`forms namely creams, pastes, ointments, gels and patch system
`where the drug is migrated from skin exterior into dermis and sys-
`temic circulation along its concentration gradient. Currently, such
`conventional dosage forms have been redesigned to enhance the
`
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`© 2015 Bentham Science Publishers
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`2772 Current Pharmaceutical Design, 2015, Vol. 21, No. 20
`
`driving force for drug diffusion (thermodynamic activity) and/or
`enhance skin permeability for the intended solute. The feasible
`approaches include the use of permeation enhancers [13], super-
`saturated drug systems [14], pro-drug approach [15, 16], liposomes
`and other nanovesicular systems [17-20]. In spite of extensive ef-
`forts are devoted, the rate and extent of drug that can be delivered
`by these methods are still
`limited by the complex structure and
`barrier properties of skin.
`
`Active Technology
`Active transdermal drug delivery technology operates in accor-
`dance with the principle of diffusion aided by various penetration
`enhancement approaches, namely iontophoresis, electroporation,
`microporation, laser ablation, radio frequency, thermal, ultrasound
`and microwave [21-24]. The aforementioned approaches generally
`involve the application of external energy that acts as a driving
`force to reduce the barrier attribute of the stratum corneum, and to
`increase the rate and extent of drug permeation through the skin.
`The current pharmaceutical advancement in active technology
`is a resultant fruit of research and development in pharmaceutical
`and
`biopharmaceutical
`sciences,
`bioengineering,
`computing,
`chemical engineering, precision engineering and material sciences.
`Extensive works have been done to manufacture small but powerful
`devices that can produce the desired clinical responses [23]. The
`usage of active technology resolves challenges faced by the arrival
`of biotechnology, where large molecular weight (> 500 Dalton),
`hydrophilic and gastrointestinal-labile therapeutics, mostly proteins
`and peptides, are concerned. An effective transdermal drug delivery
`is deemed to be brought about by combinationstrategies [24]. The
`combination of both active and passive technologies is envisaged to
`enable a synergistic rise in the skin solute transport, with reduced
`adverse effects particularly by those of active approaches that may
`be anatomically invasive.
`Table 1 summarizes the operational modeof active technology
`andits risks in application. Further details can be obtained from the
`recent review that has described extensively about electrical, mag-
`netic, photomechanical and cavitation waves on transdermal drug
`delivery [24]. Other active technologies that have been used in the
`early phase of development include modest pressure application
`[25], skin stretching under tension forces range from 0.01 to 10
`mPa [26, 27] and skin abrasion [28-30].
`
`PRESSURE-SENSITIVE ADHESIVE
`
`With reference to passive technology, the latest advancements
`primarily focus on the new formulation strategies that facilitate
`drug diffusion through the skin. The supersaturation system has
`been designed to increase the thermodynamic activity of drugs such
`as nifedipine and lavendustin derivative, and their skin permeability
`[79-81]. The permeation enhancers, namely surfactants, fatty acids,
`terpenes and solvents, have been introduced into the transdermal
`formulations [82]. The permeation enhancer is also known as sorp-
`tion promoter or accelerant. It is able to interact with the stratum
`corneum and induce a temporary, reversible increase in skin perme-
`ability for the drug diffusion to take place effectively [83].
`To enhance the contact between skin and drug or permeation
`enhancer, it is ideal if an adhesive is introduced to the transdermal
`formulation and available particularly at the skin-dosage form inter-
`face. Amongadhesives, the pressure-sensitive acrylic adhesive has
`made tremendous strides and is now presented as a sophisticated
`science. This review intends to discuss pressure-sensitive adhesives
`and their finished dosage forms for medical application with a spe-
`cial emphasis on transdermal drug delivery.
`The pressure-sensitive adhesive refers to adhesive, which in the
`dry form, is aggressively and permanently tacky at room tempera-
`ture and firmly adhered to a variety of dissimilar surfaces through
`mere contact without the need for more than finger or hand pres-
`sure. It is a non-metallic material that exerts bonding via the adhe-
`
`0002
`
`Ghoshet al.
`
`sion and cohesion forces [84]. The application of pressure-sensitive
`adhesive does not
`involve any phase changes. The pressure-
`sensitive adhesive begins as a highly viscous and sticky liquid (vis-
`cosity in the order of 10° poise), and remains in the same form
`throughout
`their application life cycle [84].
`It
`technically never
`crosslink or cure during the process of bonding. The strength ofits
`bond to a surface is dependent upon the pressure with which it is
`applied. The bond may be broken when the adhesive becomes fluid-
`ized under the peeling forces beyond a yield value, or the adhesive
`crosslinks to form a hard and brittle layer. The natural rubber has
`long been used as an adhesive. The synthetic butyl rubber and
`poly(acrylate ester) are now gaining a widespread application [85].
`The current commercial products are typically made of a complex
`mixture. The popular pressure-sensitive adhesives are acrylic acid
`and its co-polymers, synthetic rubber-like styrene-butadiene and
`ethylene co-polymers, silicone, polyurethane, polyvinyl ether, and
`ethylenevinylacetate copolymers. The acrylate-, silicone- and rub-
`ber-based pressure-sensitive adhesives are commonly used in the
`design of transdermal drug delivery system [86]. The typical fea-
`tures of pressure-sensitive adhesives are displayed in Table 2.
`
`Rubber-Based Pressure-Sensitive Adhesive
`
`Rubber-based pressure-sensitive adhesive comprises ofeither
`natural or synthetic rubber, in addition to oils, resins and antioxi-
`dants as tackifier and stabiliser respectively.
`It is reputed as the
`cheapest pressure-sensitive adhesive among others. The classical
`examples of rubber-based pressure-sensitive adhesive are styrene-
`butadiene, polyisobutylene, polyisoprene, polybutadiene, polysty-
`rene-polyisoprene-polystyrene,
`polystyrene-polybutadiene-
`polystyrene, polystylene-poly(ethylene/butylene)-polystylene and
`polystylene-poly(ethylene/propylene)-polystylene [87]. However,
`the rubber-based pressure-sensitive adhesive is met with low phys-
`icochemical stability and is prone to aging. The synthetic rubber
`pressure-sensitive adhesive such as polyisoprene has a lower cohe-
`sive strength and its cost of production is higher than that of natural
`rubber[88].
`
`Acrylic-Based Pressure-Sensitive Adhesive
`Acrylic-based pressure-sensitive adhesive is prepared from
`acrylate esters, methacrylic acid, acrylamide, methacrylamide, N-
`alkoxyalkyl or N-alkyl-acrylamides without or with the addition of
`tackifier (Fig. 1).
`It possesses a higher level of physicochemical
`stability against the heat and light, and superior resistance to oxida-
`tion when compared to rubber-based materials [89]. The acrylic-
`based pressure-sensitive adhesive is optically transparent and char-
`acterized by an excellent water proof property [90]. In addition, it is
`non-irritant to the skin [90].
`
`Silicone-Based Pressure-Sensitive Adhesive
`
`Silicone-based pressure-sensitive adhesive is prepared mainly
`from gum andresin, The resin is a resultant product of the reaction
`of silicic or polysilicie hydrosol with trimethylchlorosilane [91].
`The gum used is a high molecular weight linear polysiloxane poly-
`mer [91]. Silicone-based pressure-sensitive adhesive is considered
`to be more supreme than other adhesives due to its consistent bond-
`ing with silicone substrates, thermostability even at elevated tem-
`peratures over 500°C or over a wide temperature range, and adhe-
`siveness to skin having high to low surface energy [92]. In spite of
`such excellent features, the silicone-based pressure-sensitive adhe-
`sive is however costly, and possesses low initial tack and adhesion
`that are detrimental to quick bonding [93].
`
`MECHANISTIC ASPECTS OF PRESSURE-SENSITIVE AD-
`HESION
`
`The transdermal drug delivery system that adopts pressure-
`sensitive adhesive is available in several designs.
`It
`is primarily
`classified as membrane, matrix or monolithic patch, and drug-in-
`
`

`

`Current Pharmaceutical Design on Adhesive Based Transdermal Drug Delivery Systems
`
`Current Pharmaceutical Design, 2015, Vol. 21, Ne. 20
`
`2773
`
`Table 1. Active transdermal drug delivery technology.
`
`lontophoresis
`
`Electrical current 0.5 mA/em’ for
`minutes or hours [31-33].
`
`Low and high molecular
`weight drugs [34-40].
`
`Pain orirritation beyond mild erythemais not induced [32].
`
`[48]. Multiple doses of pressure waves may causecell injury.
` Low and high molecular
`
`Lowand high molecular
`High frequency (~100 kHz) alter-
`
`nating current. weight drugs [57].
`Laser radiation
`
`Noirreversible damage to the skin through waterelectrolysis [41], which if occurs,
`can manifest pH shift and may induce discomfort as well as reduced drug delivery
`and stability [36, 42].
`
`Alternating current generates fewer skin burnsas a result of polarity reversal [42].
`
`Continuous direct current can be employed in acute medical situations [42]. Pulsed
`current is preferred in the treatmentofchronic illness in order to avoid skin
`irritation due to frequent electrical stimulation,
`
`Electroporation
`
`Electrical voltage 50 to 1500 V for
`microseconds to milliseconds with
`
`pulsing interval of a few seconds to
`a minute [43].
`
`Low and high molecular
`weight drugs [43-45].
`
`Jn vivo experiments using hairless rats indicate no significant skinirritation using
`short and long pulses in conjunction with stratum corneum heating [43].
`
`Overall, high voltage skin electroporation is regarded as mild and reversible on the
`skin tissue [33, 43, 46]. The most commonside effect is muscle contraction. The
`level of sensation such as muscle contraction, itching, tingling, pricking and pain
`can rise with pulse rate, duration and voltage.
`
`The adverse sensation can be minimized through concentrating the electric field on
`stratum corneum without involving the nerve endings in dermis [33, 43, 46].
`
`Skin pore can be resealed using poloxamer 188 or phosphatidylcholines [47].
`which selectively partition into low density lipid bilayers and inducetight bilayer
`packing.
`
`Ultrasound (phonophoresis/sonophoresis)
`
`Low frequency 20 to 100 kHz,
`
`therapeutic frequency | to 3 MHz
`and high frequency 2 to 16 MHz
`with a pressure between | and 5 bar
`in the order of tens of minutes [32,
`48, 49].
`
`Low and high molecular
`weight drugs [32, 50, 51].
`
`No permanent damageto the skin or underlyingtissues [49, 52].
`
`The use of high ultrasound amplitudes may bring discomfort, slight and transient
`erythema, dermal necrosis or burn [53-55].
`
`The most frequent adverse effects during or after sonophoresis are skin erythema,
`pain, and tinnitus [52, 56].
`
`In comparisonto high frequency sonophoresis, the more permeating low frequency
`sonophoresis lacks the safety evidences [50].
`
`Radiofrequency
`
`Photomechanical wavesin the
`
`hundreds of atmospheres (300 to
`1000 bar) for nanoseconds (100 ns)
`to a few microseconds (10 ys) [32,
`48, 49].
`
`weight drugs [48, 58, 59].
`
`A single application of pressure wave gives no observable injury to keratinocytes
`and only minor erythema is developed with | us pressure wave
`
`0003
`
`

`

`2774 Current Pharmaceutical Design, 2015, Vol. 21, No. 20
`
`(Table 1) Contd....
`
`Ghoshet al.
`
`Side effect
`Drug candidate
`Modeof operation
`
`Magnetophoresis
`
`Lowmolecular weight drugs
`Magnetic field5 to 300 mT [49, 60,
`
`61). [60, 61).
`
`Thermalporation/Thermophoresis
`
`Shorter exposure (< Is) to higher
`temperatures (> 100°C) [62].
`
`Nitroglycerin [63], testoster-
`one,lidocaine, tetracaine [64]
`and fentanyl! [65].
`
`Microneedle
`
`
`Minimal levels of discomfort, skin irritation and erythema/edema are indicated
`Calcein and insulin [66, 67].
`Microneedleof height between 50
`
`and 110um [66]. [68].
`
`Needleless injection
`
`Testosterone, lidocaine hy-
`drochloride, insulin and calci-
`tonin [71-74].
`
`Suction ablation
`
`Application of negative pressure or
`
`Morphine [76].
`
`Formation ofblister due to the prolonged duration of treatment (77, 78].
`
`Table2.
`
`Typical features of pressure-sensitive adhesive.
`
`Property
`
`high
`high
`
`high
`
`Low
`to
`
`Typically
`
`Typically
`low
`
`Typically
`Low
`
`Medium to
`
`Medium
`
`Peel adhesion
`
`Mediumto
`
`Mediumto
`
`Low
`
`Mediumto
`
`high
`to
`high
`high
`medium medium
`
`
`
`Cohesion
`
`Medium to
`
`High
`
`Low
`
`to
`to
`high
`
`
`mediummedium medium
`
`Solvent/chemical
`
`High
`resistance
`
`
`Excellent
`
`Medium
`
`Excellent
`
`High velocity jet (> 100 m/s) of
`compressed gas (usually helium)
`that accelerates through the nozzle
`of the injector device, carrying with
`it drug particles from the cartridge it
`disrupts on its passage into the
`
`nozzle [69-71].
`
`vacuum to isolate epidermis [75].
` Mediumto
`
`
`
`Plasticizer
`
`Medium
`
`Medium
`
`Generally
`low
`resistance
`to
`medium medium
`
`
`
`Adhesive
`
`Clear
`
`Yellow
`
`Clear
`
`Clear
`
`colour
`
`to
`(more with
`straw
`time) straw
`
`
`
`Medium
`
`Low
`
`High
`
`Medium
`
`high
`
`0004
`
`

`

`Current Pharmaceutical Design on Adhesive Based Transdermal Drug Delivery Systems
`
`Current Pharmaceutical Design, 2015, Vol. 21, Ne. 20
`
`2775
`
`Par
`Oo
`Oo
`OH
`|
`|
`acrylic
`C4He
`CH
`acid
`n-butyl
`acrylate
`
`CH-C3Hs
`
`fo ib
`oO
`oO
`oO
`|
`|
`|
`CgH17
`CH3
`CoHs
`ethyl
`n-octy] Mey’
`ethyl
`acrylate @crylate
`acrylate
`
`se
`NH>
`acryl
`amide
`
`C4Ho
`
`2-ethylhexyl
`acrylate
`
`Fig. (1). Typical chains ofpressure-sensitive acrylic copolymer.
`
`adhesive patch. The latter consists of a backing layer, a polymeric
`matrix, an adhesive and a protective liner. An effective amount of
`therapeutic agent is included within the adhesive layer. The adhe-
`sive layer is positioned between a backing membrane layer and a
`temporary protective liner. The removal of the protective liner ex-
`poses the drug-in-adhesive which initiates contact with the surface
`of a subject.
`Many theoretical adhesion models have been proposed, with
`contradictory and complementary concepts between these models.
`Examples of adhesion model theories include mechanical theory,
`electrostatic theory, chemical bonding theory, adsorption or ther-
`modynamic theory, diffusion theory of adhesion, adhesive effect of
`thin liquid films and theory of weak boundary layers [94, 95].
`These theories of adhesion have been empirically investigated and
`require further experimental evaluation to complete the mechanistic
`insights in bonding-debonding processes [95-97]. The pressure-
`sensitive adhesive elicits adhesion which involves bonding and
`debonding componentsin tack and peel operations respectively [97,
`98].
`It also demonstrates cohesion which is deemed necessary
`against debonding [96-98]. The balance of adhesion and cohesion
`embodies the pressure-sensitive character of the adhesive in a trans-
`dermal drug delivery system. An optimal balance between high
`tack, peel adhesion, and high cohesion is necessary in most cases.
`The behaviour of a pressure-sensitive adhesive can be reduced to
`three fundamental and interconnected physical properties:
`tack
`(initial adhesion), adhesion (peel adhesion) and shear strength or
`resistance (cohesion) [98-101].
`
`Tack (Initial Adhesion)
`Thetack of a pressure-sensitive adhesive is primarily a measure
`of the wettability of an adhesive undercontrolled application condi-
`tions, with due regard for its optimum adhesion value [102]. Till
`now, it is still considered and rated by many as how well it sticks to
`the finger following slight pressure and short dwell time [102]. The
`application of a pressure-sensitive adhesive onto a surface may take
`a small fraction of a second to days or weeks to wet the required
`area and develop adhesion [102]. Generally, the tack value of a
`pressure-sensitive adhesive is higher upon adding soft and viscous
`components to the formulation [102].
`
`Peel Adhesion (Adhesion)
`
`Adhesion is defined as the process in which two bodies are
`attached to each other through a sumof all intermolecular and elec-
`trostatic forces acting across the interface [103]. Alternatively,
`it
`can be described as the force or energy required to separate the two
`bodies, often known as "practical adhesion" or "adherence". In the
`latter, the process of breaking the already adhesive in contact is
`examined. A high peel adhesion requires specific tack levels for
`bonding and cohesion levels to against debonding. The bonding and
`
`0005
`
`debonding extents of a pressure-sensitive adhesive are a function of
`the ratio of elastic-to-viscous components in an adhesive formula-
`tion [104-106]. Peel adhesion measures the force required to peel
`away an adhesive onceit has been attached to a surface. Most cur-
`rently used peel adhesion test methods for transdermal drug deliv-
`ery system are based on methods developed for industrial tapes
`[107]. They typically adopt the stainless steel test panel as the sub-
`strate, cut sample with an exact width, dwell time of one minute
`and peel speed of 300 mm/min [108]. The peel adhesion measure-
`ment is greatly influenced by the experimental parameters such as
`dwell time, substrate type (stainless steel, skin or polyolefin), peel
`angle, peel speed, nature of transdermal drug delivery system back-
`ing membrane and adhesive thickness [103].
`
`Shear Strength or Resistance (Cohesion)
`In accordance with ASTM definition, cohesion refers to the
`propensity of a single substance to adhere to itself, the internal at-
`traction of molecules towards each other, the ability to resist parti-
`tion from the mass, the force holding a single substance together
`and internal adhesion [109]. The most important meansto influence
`the cohesion of a pressure-sensitive adhesive are tackification and
`crosslinking. The crosslinking results in rigidity, antagonizing the
`tackification of an adhesive. The pressure-sensitive adhesive is a
`viscoelastic material which allows it to respond to both bonding and
`debonding steps. For permanent adhesive, it should not break under
`debonding (mainly shear and peel) forces. It must be equipped with
`a higher level of cohesive or shear strength than the removable
`adhesive [110, 111].
`
`RECENT DEVELOPMENT OF PRESSURE-SENSITIVE
`ADHESIVE FOR TRANSDERMAL DRUG DELIVERY
`
`The recent development in new adhesives for transdermal drug
`delivery aims at enhancing the rate of drug transport, achieving a
`high physicochemical compatibility of adhesives with drugs, per-
`meation enhancers and skin, and having adhesives able to accom-
`modate high drug loads without their adhesive property being ne-
`gated [112].
`It is hoped that the newly designed adhesives can ac-
`quire improved skin adhesion and wear duration, smooth texture,
`have less painful or even painless peel off experiences [113].
`The development of new pressure-sensitive adhesives is medi-
`ated by two approaches. New polymers are designed and developed
`into adhesive, beyond the conventional chemistry of polyisobuty-
`lene, silicone, and acrylate. These new polymers are hydrophilic
`materials capable of forming hydrogel
`[114]. One example is
`polyurethane [115]. The second approach involves physical or
`chemical modification of the existing pressure-sensitive adhesive.
`The physical modification refers to formulation of the basic adhe-
`sive with additional functional excipients or adhesives [116]. The
`chemical modification, on the other hand, exploits grafting tech-
`
`

`

`2776 Current Pharmaceutical Design, 2015, Vol. 21, No. 20
`
`nique to introduce specific functional monomers to the parent pres-
`sure-sensitive adhesive polymers [117].
`
`Hydrogel Pressure-Sensitive Adhesive
`Conventional pressure-sensitive adhesives such as polyisobuty-
`lene, silicone and acrylate are hydrophobic in nature with residual
`water content as low as 0.1 % [117]. Hydrophilic hydrogel pres-
`sure-sensitive adhesive that features high molecular weight poly-
`vinylpyrrolidone and oligomeric polyethylene glycol has an equilib-
`rium water content of 8 to 11% [118]. A hydrogel is defined as a
`water-swollen but water-insoluble crosslinked polymeric network
`with rich water content [119]. It is typically compatible with drugs
`of varying chemical make-ups and able to soften skin thereby lead-
`ing to effective transdermal drug delivery without the use of per-
`meation enhancer [117, 120].
`A two-stage formative mechanism of polyvinylpyrrolidone-
`polyethylene glycol hydrogel pressure-sensitive adhesive has been
`recently proposed [121]. Firstly, the hydrogen bonding is formed
`between the terminal hydroxyl groups of polyethylene glycol with
`the carbonyl moieties in the repeated units of longer polyvinylpyr-
`rolidone chains. The hydrogen-bonded polyethylene glycol is then
`crosslinked with the polyvinylpyrrolidone via its flexible interpene-
`trating chains. The crosslinked complex is gradually dissolved in
`the presence of excess polyethylene glycol. The resulting hydrogel
`exhibits an excess free volume, which governs the viscoelasticity,
`adhesion and diffusivity properties of the adhesive. The adhesive
`and diffusive properties of the hydrogel polymer are modulated by
`its viscoelastic property [122].
`
`Hydrophilic Pressure-Sensitive Adhesive
`Hydrophilic pressure-sensitive adhesive can be introduced via
`plasticizing methacrylate copolymers, the film coating agent of oral
`dosage forms that are characterized by a high glass transition tem-
`perature [123, 124]. The methacrylate species can be cationic or
`anionic
`copolymers
`of
` dimethylaminoethyl methacrylate,
`methacrylic acid and methacrylic acid esters presented in varying
`proportions. The acetyl tributyl citrate is used as a plasticizer with
`succinic acid crosslinking ionically with the amino functional
`groups of the polymers to impart cohesion strength. The hydro-
`philic pressure-sensitive adhesive is insoluble in water [123, 125].
`Nonetheless, it swells in water and is permeable to water vapour
`[126].
`It can be easily removed from the skin by water flushing
`thoughit is reported to be able to withstand short showers for sev-
`eral days pertaining to transdermal drug delivery application [126].
`An aqueous solution of such adhesive is prepared by blending the
`polymers with water-soluble or hydrophilic plasticizers such as
`polyethylene glycol, glycerin,
`triethanolamine or triethyl citrate
`[125]. The aqueous solution formulation is deemed to be able to
`hydrate the skin, exfoliate hair follicles and provide temporary crea-
`tion of new aqueous pathwaysor pores within the stratum corneum
`for large and hydrophilic drug diffusion [43, 49, 60].
`
`Graft Copolymeric and Enhancer-Tolerant Pressure-Sensitive
`Adhesive
`
`Hydrophilic pressure-sensitive adhesive can also be prepared
`through copolymerization of acrylic esters with hydrophilic mono-
`mers. A water-absorbing copolymer comprising a carboxylic hy-
`droxyalkylester monomer and a water-soluble macromer, such as an
`ethoxylated or propoxylated hydroxyalkyl methacrylate has been
`prepared for use as medical adhesive [127]. A macromeris a mac-
`romonomeror a polymer with a polymerizable group at the end of
`the chain [127]. Copolymerization of acrylic esters with macromers
`is one of the approaches that may be used to prepare graft copolym-
`eric pressure-sensitive adhesive [127].
`Acrylic-based graft polymer can have its adhesion and chemical
`compatibility properties adjusted through using macromers ofspe-
`cific chemical attributes [128]. The acrylic pressure-sensitive adhe-
`
`0006
`
`Ghoshet al.
`
`sive with a methacrylate-terminated styrene macromer has been
`prepared and is reported to incur less adhesion build up on skin
`over time [128]. The pressure-sensitive adhesive that comprises a
`fatty acid ester enhancer and a polystyrene methacrylate macromer
`reinforced acrylic polymer has also been prepared [129]. The fatty
`acid ester is introduced to further promote the compatibility be-
`tween polymer and macromer.
`Polymeric graft moiety may be attached to the acrylic polymer
`backbone by post-polymerization reaction of a polymeric moiety
`with the suitable grafting sites on the polymer backbone. Polymers
`with a wide range of solubility parameters such as polyisobutylene,
`polyethylene oxide, polyvinyl acetate, polyvinyl pyrrolidone and
`polysaccharide are grafted to the acrylic polymer [129-131]. These
`graft polymers are reported to have a better compatibility with the
`skin penetration enhancers. There is no noticeable physicochemical
`interaction between them, thereby rendering their interaction with
`skin unimpeded[132].
`An electron beam crosslinked acrylic pressure-sensitive adhe-
`sive has been similarly reported to be tolerant of alcohol-based
`permeation enhancers [128-129]. The monomer composition ofthis
`adhesive is primarily comprised ofiso-octyl acrylate and acrylic
`acid [129-131]. Silicone graft copolymers have been prepared for
`transdermal drug delivery application. As a pressure-sensitive adhe-
`sive, the polyethylene oxide-grafted silicones improve skin perme-
`ability towards hydrophilic drugs [133].
`Manyspecific polymers or pressure-sensitive adhesive formula-
`tions have been claimed in the patent literature for their ability to
`enhance the delivery of specific drugs. A copolymercontaining 2-
`ethylhexyl acrylate and vinyl pyrrolidone is reported to have the
`advantage of maintaining a relatively high concentration ofestra-
`diol in the transdermal drug delivery matrix without the estradiol
`undergoing crystallization [133].
`
`Physical Blend
`Adhesive based on simple blending of conventional pressure-
`sensitive adhesive with other polymers or excipients has been re-
`ported to impart benefits to the transdermal drug delivery system. A
`blend of silicone-based pressure-sensitive adhesive with poly-
`vinylpyrrolidone has been found to prevent the crystallization of
`several drugs [134]. The inclusion of monoglyceride into an
`acrylic-based pressure-sensitive adhesive is known to improve the
`adhesion of transdermal dosage form to the skin and the release of
`isosorbide dinitrate [135]. This adhesive composition is claimed not
`to cause pain and damageto the stratum corneum when it is peeled
`off [136, 137]. The addition of clay has been indicated to improve
`the cohesiveness of pressure-sensitive adhesive in transdermal for-
`mulations without reducing the rate of drug delivery [137-140].
`Table 3 highlights recent examples of pressure-sensitive adhe-
`sives and their applications in transdermal drug delivery.
`
`CURRENT CHALLENGES IN PRESSURE-SENSITIVE AD-
`HESIVE TECHNOLOGY
`
`Three main categories of challenges are faced by the pressure-
`sensitive adhesive technology with respect
`to drug-in-adhesive
`transdermal system:
`1. Drug solubility in adhesive, 2. Drug-
`adhesive/adhesive dispersion and 3. Drug-adhesive interaction.
`
`Drug Solubility in Adhesive
`It
`is found that the solubility of the same drug molecules is
`practically low in adhesives of different chemical classes. A drug,
`which is characteriz