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`Current Pitnmecemicui Design, 2015, 21', 2771-2783
`2??!
`
`Current Pharmaceutical Design on Adhesive Based Transdermal Drug Delivery
`Systems
`
`Animcsh Ghoshl', Subham Banerjcci, Santana KaityE and Tin W. Wong
`
`2.3.4‘
`
`fDepamnenr of Phannaceuricai Sciences and Technology. Birla Instinrte of Technoiog). Mesra Ranch—8352”.
`indie: 2N0n-Desa'active Biomedical and Phannacetiticai Research Centre: j.f“ariie:'l’e Design Research Group.
`Faculty of Pharmacy; Universiti Teknolagi MARA. 42300. Puacak Alum. Selartgor. Malaysia: 1rCake Frontier
`Materials and industry Application, Universiii Teknologi WM. 40450. Shah Aiam. Selaagor. Malaysia
`
`Abstract: Dmg-in-adhesive transdermal drug delivery matrix exploits intimate contact of the carrier with stratum
`corncum. 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-adhesivc matrix lie in the physicochemical propcnics of skin
`varying with age. gender. ethnicity. health and environmental condition of patients. This in him poses difficulty to
`design a universal formulation to meet the intended adhesiveness. drug release and drug permeation performances.
`This review focuses on pressure-sensitive adhesives. and their adhesivcness and drug rcleaseipcrmcation modula-
`tion mechanisms as a function of adhesive molecular structure and formulation attributes, It discusses approaches to modulate adhesive
`tackiltess, 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.
`
`It Animesh Ghosh
`
`Keywords: Drug-in-adhesive, pressure-sensitive adhesive, transdcrmal 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 ofthc skin is conferred by its multi-laycred
`structure. The superficial laycr of the skin is known as stratum cor-
`ncum. It represents the finished product of the differentiation proc-
`ess at the basal layer of epidermis where kcratinocytes are formed
`by cellular mitotic division. Anatomically, the stratum comeum is
`composed of comeocytes interdispersed within a lipophiiic matrix
`in a “brick and mortar“ architecture.
`It represents the most critical
`barrier of the skin [1, 2]. The stratum comcurn is well known to
`exhibit selective permeability and allows only relatively lipophilic
`compounds to diffiJSC into the lower skin layers. The solute trans-
`port is largely mediated via passive diffusion in agreement with the
`Fick's Law of diffiision [3, 4] and no active transport processes
`have been identified [5]. Distinctive delivery systems can be de-
`signed to attain transdcmtal or dermal drug transport. The former
`involves the breaking of skin barrier whereas the 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 ml) with minimal proteolytic activities. It comprises of
`three distinct layers:
`i} subcutaneous tissue layerihypodennis,
`ii)
`viable dermal layer and iii) non-viable and viable epidermal layer
`[6]. The transdennal drug delivery is hindered by the stratum cor-
`neum, the uppermost dead layer of epidermis ['i]. The stratum cor-
`neum is made up of thick 10 to 20 cell layers over most pans of the
`body [8]. Each cell
`is presented in the form of a flat, plate-like
`structure {length = 34-44 pm, width = 25-36 m. thickness = 0.2-
`0.5 pm) with a surface area of750 to [200 pm arranged in a brick-
`
`‘Addrcss correspondence to these authors at the Non—Destructive Biomedi—
`cal and Pharmaceutical Research Centre. Universiti Tekuologi MARA.
`Puncak Alarm. 4230'”. Selangor. Malaysia. Tel.: +60 3 32534691;
`E-mails: wongtinwui(ajsalan1.uitm.cdu.my; wongtinwuifrpyahoocom
`Department of Pharmaceutical Sciences and Technology, Birla Institute of
`Technology. Mesra Ranch—335215. India: Tel: +094TU339587;
`E-mail: aghosht’rilbitmesra.ac.in
`
`like layering fashion within a hydrophobic matrix ol‘phospholipids.
`glycosphingolipid. cholesterol sulfate and neutral
`lipid. The thick-
`ness and density ofthe stratum corneum may differ from one body
`site to another. Such ditTerences could dictate the efficiency of
`transdeonal 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.
`ll].
`
`three modes of solute transport have been proposed
`Broadly.
`with respect to transdennal drug delivery:
`1.
`interccllular diffiJsion through the lipid lamcllac.
`II.
`transccllular diffusion through both the kcratinocytcs and
`lipid larncllae.
`diffiision through the hair follicles and sweat ducts.
`Generally. it is recognised mat the polar solutes permeate the
`skin mainly through the polar pathway within me hydrated stratum
`comeum. On the other hand.
`the non-polar solutes permeate the
`skin through the lipid matrix ofthc stratum corncum.
`
`llI.
`
`TECHNOLOGICAL ENHANCEMENT 0F 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:
`1.
`Passive technology
`2. Active technology
`
`Passive Technology
`The passive transdcrmal 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
`
`1873-4286i15 $58.0'D+.00
`
`© 2015 Bentham Science Publishers
`
`Noven Pharmaceuticals, lnc.
`EX2015
`
`0001
`
`Mylan Tech., Inc. v. Noven Pharma, Inc.
`|PR2018~00174
`
`

`

`2772 Current Pharmaceutical Design, 2015, Val. 21, Na. 20
`
`driving force for drug diffusion (thermodynamic activity} andlor
`enhance skin permeability for the intended solute. The feasible
`approaches include the use of permeation enhancers [i3]. super-
`saturated drug systems [l4]. pro—drug approach [15. I6]. liposomcs
`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 comeum, and to
`increase the rate and extent ofdrug 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 combination strategies [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 mode of active technology
`and its risks in application. Further details call be obtained from the
`recent review that has described extensively about electrical, mag—
`netic, photomechanical and cavitation waves on transdennal 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 [0
`mPa [26, 2?] 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 nifcdipine and Iavendustin derivative, and their skin permeability
`[79—81]. The permeation enhancers, namely surfactants, fatty acids,
`terpenes and solvents. have been introduced into the transderrnal
`formulations [82]. The permeation enhancer is also known as sorp—
`tion promoter or accelerant. It is able to interact with the stratum
`comeum and induce a temporary. reversible increase in skin penne—
`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. Among adhesives, 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
`
`Ghosfr of ai.
`
`sion and cohesion forces [84]. The application of pressure—sensitive
`adhesive does not
`involve any phase changes. The pressure—
`scrrsitivc adhesive begins as a highly viscous and sticky liquid (vis-
`cosity in the order of [0" poise], and remains in the same form
`throughout
`their application life cycle [84].
`1t
`technically never
`croSslink or cure during the process of bonding. The strength of its
`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
`erosslinks to form a hand 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 widesplead 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 err-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 of either
`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, Dolyisobutylene, polyisoprene. polybutadiene. polysty-
`rene—polyisoprene—polystyrene,
`polystyrene—polybutadiene—
`polystyrene, polystylene—poly{ethylenefbutylene}—polystylene and
`polystylene—poly(ethylenefpropylene)—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 poly isoprene has a lower cohe—
`sive strength and its cost ofproduction is higher than that ofnatural
`rubber [88].
`
`Acrylic-Based Pressure-Sensitive Adhesive
`Acrylic-based pressure-sensitive adhesive is prepared from
`acrylate esters, methaerylic acid, acrylamide, methacryiamide, N-
`alkoxyalkyl or N-alkyl-acrylanrides without or with the addition of
`tackifrer (Fig. 1}.
`[t possesses a higher level of physicochemical
`stability against the heat and light, and superior resistance to ox ida-
`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
`fi'om gum and resin. The resin is a resultant product of the reaction
`of silicic or polysilicic hydrosol with trimethylchlorosilane [9i].
`The gum used is a high molecular weight linear polysiloxane poly-
`mer [9]]. Silicone-based pressure-sensitive adhesive is considered
`to be more supreme than other adhesives due to its consistent bond—
`ing with silicone substrates. thcnnostability even at elevated tern-
`peraturcs 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-
`HESIDN
`
`The transdermal drug delivery system that adopts pressure-
`sensitivc adhesive is available in several designs.
`It
`is primarily
`classified as membrane. matrix or monolithic patch, and drug-in-
`
`

`

`Cm'renr Phnmacearicai Design on Adhesive Based Tmusdermal Drug Delivery Systems
`
`Current Phnmaeeuficai Design, 2015, Vol. 21, No. 20
`
`2773
`
`Table 1. Active transdermal drug delivery technology.
`
`[ontoplloresis
`
`Electrical current 0.5 mAlcm2 for
`minutes or hours [31-33].
`
`Low and high molecular
`weight drugs [34-40].
`
`Pain or irritation beyond tnild erytliema is not induced [32].
`
`No irreversible damage to the skin through water electrolysis [4i ]. 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 burns as a result of polarity reversal [42].
`
`[48]. Multiple doses of pressure waves may cause cell injury.
` Low and high molecular
`
`Continuous direct current can be employed in acute medical situations [42]. Pulsed
`current is preferred in the treatment oi‘ehronic illness in order to avoid skin
`irritation due to frequent electrical stimulation.
`
`Electroporation
`
`Electrical voltage 50 to [500 V for
`microseconds to milliseconds with
`
`pulsing interval ofa few seconds to
`a minute [43].
`
`Low and high molecular
`weight drugs [43—45].
`
`In vivo experiments using hairless rats indicate no significant skin irritation using
`short and long pulses in conjunction with stratum corneum heating [43].
`
`Overall, high voltage skin electroporalion is regarded as mild and reversible on the
`skin tissue [33, 43, 46]. The most common side 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 rescaled using poloxamer [88 or pliosphatidylcholines [4?],
`which selectively partition into low density lipid bilayers and induce tight bilayer
`packing.
`
`Ultrasound (phonophoresislsooophoresis}
`
`Low frequency 20 to [00 kHz.
`
`therapeutic frequency 1 to 3 MHZ
`and high frequency 2 to 16 MHz
`with a pressure between I and 5 bar
`in the order ol‘tens of minutes [32,
`4s, 49].
`
`Low and high molecular
`weight drugs [32, 50, 5| ].
`
`No permanent damage to the skin or underlying tissues [49. 52].
`
`The use of high ultrasound amplitudes may bring discomfort. slight and transient
`erylhcma, dermal necrosis or burn [53-55].
`
`The most frequent adverse effects during or after sonophoresis are skin erylhema.
`pain,and tinnitus [52. 56].
`
`In comparison to high Frequency sonophoresis, the more permeating low frequency
`sonophorcsis lacks the safety evidences [50].
`
`Radiofrequcncy
`
`Low and high molecular
`High Frequency [~ I 00 kHz] alter—
`
`nating current. weight drugs [5?].
`Laser radiation
`
`Photomechanieal waves in the
`
`hundreds of atmospheres (300 to
`I000 bar) for nanoseconds (100 ns)
`to a few microseconds ([0 us) [32.
`48. 49].
`
`weight drugs [48, 58, 59].
`
`A single application of pressure wave gives no observable injury lo kcralinocytes
`and only minor erythema is developed with l us pressure wave
`
`0003
`
`

`

`2774 Current Pharmaceutical Design, 2015, Val. 21, Na. 20
`
`(Table I} Contd....
`
`Ghash er al.
`
`Side eflcet
`
`Mode of operation
`Drug candidate
`
`Magnetophoresis
`
`Low molecular weight drugs
`MmmMfiflHwSWmTHiw.
`
`on [60. 6 | ]_
`
`Thermal poratinnfl‘hermnphoresis
`
`Shorter exposure (< Is) to higher
`temperatures (> lm'C) [62].
`
`Nitrnglyeerin [63], testoster—
`one. lidocaine. tetracaine [64]
`and lemanyl [65].
`
`Mieroneedle
`
`
`Calcein and insulin [66. 6?].
`Minimal levels ufdiscumt‘ort, skin irritation and erythemafiedema are indicated
`Mieroneedle of heighl between 50
`
`and llflum [66]. no
`
`Needleless injection
`
`Testosterone, lidocainc hy-
`drochloride. insulin and calci-
`tonin["l1-'F4].
`
`High velocity jet ('2 IIJLI nus] of
`compressed gas [usually helium)
`that accelerates through the nozzle
`of the injector device, carrying with
`it drug particles from the cartridge il
`disrupts on its passage into the
`
`nozzle [fig-ll].
`
`Suction ablation
`
`Application ol'negalive pressure or
`vacuum to isolate epidermis [3’5].
`
`Formation of blister due to the prolonged duration of treatment 1W. T8].
`
`Table 2.
`
`Typical features of pressure-sensitive adhesive.
`
`high
`high
`
`mg
`
`Lu w
`to
`
`Typically
`
`Typically
`10w
`
`Typically
`Low
`
`Medium to
`
`Medium to
`
`Peel adhesion
`
`Medium to
`
`Medium to
`
`Low
`to
`
`Low
`to
`
`
` Morphine [T6].
`
`
`
`
`high
`high
`high
`mediummedium medium
`
`
`
`
`
`Cohesion
`
`Medium to
`
`mg
`
`Lu w
`[0
`
`Low
`to
`
`Low
`
`lo
`
`Low
`[0
`
`mg
`mediummedium medium
`high
`
`
`
`
`
`High
`High
`Solvenflehemical
`resistancc
`
`
`Medium
`
`Excellent
`
`Excellent
`
`IO
`
`Plastieizer
`
`Low
`
`Medium
`
`Generally
`low
`
`[0
`
`resistance
`to
`medium medium
`
`
`
`Adhesive
`
`Clear
`
`Yellow
`
`Clear
`
`colour
`
`to
`(more with
`straw
`
`time]
`
`Medium
`
`Low
`
`Medium to
`
`high
`
`0004
`
`

`

`Current Pkamaceuficai Design on Adhesive Based Tmusd'ermal’ Drug Delivery Systems
`
`Current Phamnceuficai Design, 2015, VOL 21, No. 20
`
`2715
`
`T”
`O
`
`I
`C4H9
`n-butyl
`acrylate
`
`f"
`O
`
`I
`CH2
`I
`TH—Csz
`
`C4H9
`
`f”
`OH
`
`acrylic
`“'51
`
`i=0
`0
`l
`(:3qu
`
`n-octyl
`acrylatc
`
`T30
`0
`l
`CH3
`- th I
`"”3 y 1
`acrylate
`
`To
`o
`l
`(3sz
`
`ethyl
`acrylatc
`
`i=0
`NH2
`acryl
`amldc
`
`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-adhcsive 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—
`modynalnic 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—
`scnsitivc adhesive elicits adhesion which involves bonding and
`debonding components in tack and peel operations respectively [97,
`98].
`It also demonstrates cohesion which is deemed necessary
`against dcbonding [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, pcel 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)
`The tack of a pressure-sensitive adhesive is primarily a measure
`ofthe wettability of an adhesive under controlled 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 sofi 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 sum of 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". 1n 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 once it has been attached to a surface. Most cur-
`rently used peel adhesion test methods for transden'nal drug deliv-
`ery system are based on methods developed for industrial tapes
`[[07]. 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 minimin [108]. The peel adhesion measure-
`ment is greatly influenced by the experimentai parameters such as
`dwell time. substrate type {stainless steel, skin or polyolcfin), 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 means to 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 (main ly shear and peel) forces. It must be equipped with
`a higher level of cohesive or shear strength than the removable
`adhesive [[10, l
`l l].
`
`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 nee
`gated [[12],
`[t 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 offexperiences [I I3].
`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 poiyisobuty—
`lene, silicone. and acrylatc. 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 fiJnctional excipients or adhesives [116]. The
`chemical modification. on the other hand. exploits grafiing tech—
`
`

`

`2776 Current Pharmaceutical Design, ZOIS, Val. 21, Na. 20
`
`nique to introduce specific functional monomers to the parent pres—
`sure—sensitive adhesive polymers [I 17'].
`
`Hydrogel Pressure-Sensitive Adhesive
`Conventional pressure-sensitive adhesives such as polyisobuty-
`lene, silicone and acrylate arc hydrophobic in nature with residual
`water content as low as 0.1 “/1! [11?]. 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 l 1% [l 18]. A hydrogel is defined as a
`water-swollen but water-insoluble crosslinked polymeric network
`with rich water content [1 19]. 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 [l 17, 120].
`A two—stage formative mechanism of polyvinylpyrrolidone—
`polyethylene glycol liydmgel pressure-sensitive adhesive has been
`recently proposed [[21]. 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
`crossl inked 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 viseoelastic property [122].
`
`Hydrophilic Pressure-Sensitive Adhesive
`Hydrophilic pressure-sensitive adhesive can be introduced via
`plasticizing methacrylatc copolymers. the film coating agent oforal
`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 methacrylatc.
`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].
`[t can be easily removed from the skin by water flushing
`though it 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 pathways or pores within the stratum comeum
`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 copolyinerization of acrylic esters with hydropltilic 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 [12?]. A macromer is a mac-
`romonomer or a polymer with a polymerizable group at the end of
`the chain [127]. Copolymer'ization of acrylic esters with macromers
`is one of the approaches that may be used to prepare graft copolym-
`eric pressure—sensitive adhesive [1 27].
`Acrylic-based graft polymer can have its adhesion and chemical
`cotnpatibility properties adjusted through using macromers of spe-
`cific chemical attributes [128]. The acrylic pressure—sensitive adhe—
`
`0006
`
`Ghosh er al.
`
`sive with a methacrylate—tenninated styrene macromer has been
`prepared and is reported to incur less adhesion build up on skin
`over time [[28]. 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 pyrrolidonc and
`polysaccharide are grafted to the acrylic polymer [i29—l3l]. 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 of iso-oetyl acrylate and acrylic
`acid [129—131]. Silicone graft copolymers have been prepared for
`transdermal drug delivery application, As a pressuresensitive adhei
`sive. the polyethylene oxide-grafted silicones improve skin penne-
`ability towards hydrophilic drugs [133].
`Many specific 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 copolymer containing 2—
`ethylhexyl acrylate and vinyl pyrrolidone is reported to have the
`advantage of maintaining a relatively high concentration of estra-
`diol in the transdermal drug delivery matrix without the cstradiol
`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 [[34]. 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 damage to the stratum corneum when it is peeled
`off [[36, [3?]. The addition of clay has been indicated to improve
`the cohesiveness of pressure-sensitive adhesive in transdermal for-
`mulations without reducing the rate ofdrug 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—
`adhesivefadhesive dispersion and 3. Drug—adhesive interaction.
`
`Drug Solubility in Adhesive
`It
`is found that the solubility of the s