Pressure-sensitive adhesives for transdermal drug delivery systems

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Pressure-sensitive adhesives for transdermal drug delivery systems Hock S. Tan and William R. Pfister Adhesives are a critical component in transdermal drug delivery (TDD) devices. In addition to the usual requirements of functional adhesive properties, adhesives for TDD applications must have good biocompatibility with the skin, chemical compatibility with the drug, various components of the formulation, and provide consistent, effective delivery of the drug. This review discusses the three most commonly used adhesives (polyisobutylenes, polyacrylates and silicones) in TDD devices, and provides an update on recently introduced TDD products and recent developments of new adhesives.

Hock S. Tan* and William R. Pfister Lavipharm Laboratories Inc. 131 Ethel Road West Suite 6 Piscataway New Jersey 08854 USA *tel: 11 732 572 9660 fax: 11 732 572 1306

60

▼ Transdermal drug delivery (TDD) systems are

drug-loaded adhesive patches which, when applied to the skin, deliver the therapeutic agent, at a controlled rate, through the skin to the systemic circulation and to the target organs. The first commercial TDD system, Transderm-Scop®, a controlled delivery system for scopolamine, was developed by Alza Corporation (Palo Alto, CA, USA) and in 1980 it was introduced to the US market for the treatment of motion sickness. Since then, seven drugs and more than 25 different TDD products in multiple dosages and strengths for the systemic treatment of various diseases have been marketed in the USA1. These include nitroglycerin for the treatment of angina pectoris, clonidine for hypertension treatment, fentanyl for pain management, estradiol – alone or in combination with norethindrone acetate – for the relief of postmenopausal symptoms and treatment of osteoporosis, nicotine as an aid in smoking cessation, and testosterone for the treatment of hypogonadism.The TDD product market and dosage form designs have recently been reviewed1. A summary of the TDD products marketed in the USA is given in Table 1. Transdermal drug delivery products that were introduced in 1998 included FemPatch® (Cygnus, Inc.,

Redwood City, CA, USA) and CombiPatch® (Noven Pharmaceuticals, Miami, FL, USA) for hormone replacement therapy. Transdermal drug delivery systems, as compared to their corresponding classical oral or injectable dosage form counterparts, offer many advantages1–3.The most important advantages are improved systemic bioavailability of the pharmaceutical active ingredients (PAI), because the first-pass metabolism by the liver and digestive system are avoided; and the controlled, constant drug delivery profile (that is, controlled zeroorder absorption). Also of importance is the reduced dose frequency compared to the conventional oral dosage forms (that is, once-a-day, twice-a-week or once-a-week). Other benefits include longer duration of therapeutic action from a single application, and reversible action. For example, patches can be removed to reverse any adverse effects that may be caused by overdosing. In TDD applications, adhesives are used to maintain intimate contact between the patch and the skin surface. Many classes of adhesives are available that might be considered for use with TDD patches, although in practice pressuresensitive adhesives (PSAs) are preferred. Pressuresensitive adhesives are generally defined as materials that adhere to a substrate with light pressure and which leave no residual adhesive upon their removal4.They offer the advantages of convenience of use (PSAs do not require water/solvents or heat in order to achieve adhesion), good stability (PSAs are generally not sensitive to environmental humidity or temperature degradation), simplicity of manufacture, and good appearance5. In addition to the usual requirements of functional pressure-sensitive adhesive properties, such as adequate tack, skin-adhesion and cohesive strength, there are other factors to be considered in the selection and use of PSAs for TDD systems.These include biocompatibility, formulation

1461-5347/99/$ – see front matter ©1999 Elsevier Science. All rights reserved. PII: S1461-5347(99)00119-4

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Table. 1. Transdermal drug delivery (TDD) products marketed in the United States Drug

Product

Developer/marketer

TDD system designa

Pressure-sensitive adhesive typeb

Clonidine Estradiol Estradiol Estradiol Estradiol Estradiol/ Norethindrone Acetate Fentanyl Nicotine Nicotine Nicotine Nicotine Nitroglycerin Nitroglycerin Nitroglycerin Nitroglycerin Nitroglycerin Scopolamine Testosterone Testosterone

Catapres-TTS® Climara® Estraderm® Vivelle® FemPatch® CombiPatch®

Alza/Boehringer Ingelheim 3M Pharmaceuticals/Berlex/Schering AG Alza/Novartis Noven/Novartis Cygnus/Parke-Davis Noven/Rhone-Poulenc Rorer

DIA-multi-laminate DIA-monolithic Reservoir DIA-monolithic DIA-monolithic DIA-monolithic

PIB Acrylate PIB Acrylate Silicone Acrylate

Duragesic® Nicoderm® Harbitrol® Nicotrol® Prostep® Transderm-Nitro® Minitran™ Nitro-Dur® Nitrodisc® Deponit® Transdermal-Scop® Androderm® Testoderm®

Alza/Janssen Pharmaceutical Alza/SmithKline Beecham Lohmann/Novartis Cygnus/McNeil Consumer Products Elan/Lederle Alza/Novartis 3M Pharmaceuticals Key Pharmaceuticals/Schering Plough G.D. Searle/Roberts Lohmann/Schwarz Pharma Alza/Novartis TheraTech/SmithKline Beecham Alza

Reservoir DIA-multi-laminate Polymer matrix DIA-monolithic Polymer matrix Reservoir DIA-monolithic DIA-monolithic Polymer matrix DIA-multi-laminate DIA-multi-laminate Reservoir DIA-monolithic

Silicone PIB Acrylate PIB Acrylate Silicone Acrylate Acrylate Acrylate PIB PIB Acrylate EVA

aTDD

system designs: drug-in-adhesive (DIA), liquid reservoir (reservoir), multi-laminate drug-in-adhesive (DIA)/control membrane composite (multi-laminate)

bPSA

Types: polyisobutylene (PIB), polyacrylate copolymer (acrylate), polysiloxane-based (silicone), ethylene-vinyl acetate copolymer (EVA).

compatibility, delivery system compatibility, and acceptable regulatory status (that is, the availability of drug master files or equivalent supporting documentation). Biocompatibility requires that the PSAs are biologically inert, non-irritating and non-sensitizing to skin, and have no systemic toxicity. Formulation compatibility requires that the PSAs do not induce drug or excipient degradation, do not react with the drug and other formulation components, maintain stability and functional properties when formulated, and offer the desired solubility. Delivery system compatibility requires that the PSAs provide adequate diffusivity and permeability to the drug and/or permeation enhancers6,7. Pressure-sensitive adhesives are therefore regarded as one of the critical components in TDD devices1. Thus, making a change in the PSA component of a TDD system might be considered to be a major change that would require the demonstration of bioequivalence and necessitate a regulatory amendment. This review discusses TDD products, transdermal system designs and components, and focuses on the PSAs that are currently used in TDD devices. In addition, this review highlights some recent advances, including new TDD products and inno-

vative developments in PSA technology. Earlier reviews on the subject of PSAs, along with other components, used in commercial TTD products may be found in the References 6–9. Transdermal drug delivery system designs Transdermal drug delivery can be achieved via active or passive systems, depending on whether external energy is used to assist the transport of the drug through the skin10.The active systems use heat, electric current (iontophoresis), sound waves (sonophoresis), or transient high-voltage electrical pulses (electroporation) to enhance the delivery of drugs into the systemic circulation10–12. Ionophoretic drug delivery devices have been used for more than a decade for local delivery of PAI in the treatment and diagnosis of disease (that is, skin inflammation, psoriasis, local anesthesia, muscle ache and pain). The ionophoretic devices are now in the clinical development stage for systemic drug delivery, and commercial applications can be expected within three to five years10. In passive TDD systems, the drug diffuses through the skin into the systemic circulation by passive means.The concentration gradient of the drug across the skin and the difference in solubility 61

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(a) Drug-in-adhesive: monolithic

PSTT Vol. 2, No. 2 February 1999

(b) Drug-in-adhesive: multilaminate Impermeable backing Drug-adhesive matrix Rate-controlling membrane Adhesive Release liner

(c) Liquid reservoir

(d) Polymer matrix Impermeable backing Drug–polymer matrix Drug reservoir Rate-controlling membrane Adhesive Release liner

Figure 1. Typical designs of transdermal drug delivery (TDD) systems.

between the adhesive and skin are the driving force for delivery to the surface of the skin. In general, chemical permeation enhancers (pharmaceutical excipients) are required for passive delivery to achieve the required delivery of the drug from a patch of a reasonable size (that is, a surface area of <40 cm2).There are four major designs of the conventional passive TDD patches9, and each imposes slightly different requirements on the PSAs. In the simplest form, the adhesive matrix or drug-in-adhesive (DIA) design, the drug is directly loaded or dispersed into the PSA polymer.The monolithic DIA design configuration is shown in Fig. 1(a). The adhesive matrix provides several functions, including skin adhesion, storage of the drug, and control over drug/enhancer delivery rate, and it also governs their partitioning into the stratum corneum. The DIA matrix is supported on the topside by an impermeable backing film and on the side that faces the skin it is laminated with a removable release liner. This simplest design imposes the most stringent requirements on the PSA used. Drug-in-adhesive matrix patches require long-term compatibility between the adhesive, the drug, and any excipients, such as skin permeation enhancers, incorporated into the formulation. The drug must be released from the matrix in a consistent and reproducible manner, and the drug and the excipients must not adversely affect the adhesive properties of the PSA used. In addition, the functional adhesive properties of the matrix formulation must be consistently maintained throughout the application period as the drug and/or the excipients are depleted from the DIA matrix. The matrix construction is easier to manufacture on standard coaters, but the drug and excipients are exposed to elevated 62

temperature during oven drying.This may cause an undesirable chemical reaction or the loss of active substances and excipients because of evaporation5. A sub-category of DIA patch design is the multi-laminate configuration, as shown in Fig. 1(b). The multi-laminate DIA design features either an addition of a membrane between the DIA layer and the skin-contacting adhesive layer or merely multiple DIA layers supported by a single backing film9. The liquid reservoir design consists of a drug-loaded reservoir located between a backing film and a rate-controlling membrane, and a skin-contacting PSA layer [Fig. 1(c)].The liquid reservoir compartment contains the drug and permeation enhancer, which may be in solution or dispersion. Similar to the adhesive matrix design, the system is supported by an impermeable backing film, and the adhesive surface is protected by a release liner. Because the drug and permeation enhancers must diffuse through the adhesive layer, the adhesive polymer used should not be physiochemically incompatible nor have chemical interaction with the diffusing active and inactive ingredients, nor should it affect the delivery rate of the drug. The polymer matrix design is similar to the liquid reservoirtype design but has, instead of a continuous adhesive layer, a peripheral ring of adhesive that is located around the edge of the patch [Fig. 1(d)]. Because the adhesive does not come into direct contact with the drug, only its adhesive properties and skin safety characteristics are of concern. However, because of the smaller adhesive-contact area with the skin, the adhesive used in this design should have a higher skin-adhesion property than those used in other TDD design configurations. The selection of a particular patch design and size are dictated by the required rate and extent of drug delivery, which in turn depends on the formulation of the system, stability, adhesive performance properties, safety, patentability and infringement issues, pharmacodynamic profile and aesthetic characteristics1. The various patch design configurations associated with TDD products marketed in the USA are provided in Table 1. Pressure-sensitive adhesives (PSAs) for TDD systems Pressure-sensitive adhesives have been used for decades in medical devices, tapes, and dressings13, and, naturally, since the development of TDD devices in the 1980s the use of PSAs have been extended to these devices. Three types of PSAs are commonly used in TDD devices: polyisobutylenes (PIBs), polysiloxanes (silicones) and polyacrylate copolymers (acrylics)5,6,9,10. These synthetic hypoallergenic PSAs are largely used in TDD systems for local and systemic drug delivery1. Natural rubber/karaya gum-based adhesives are another class of PSAs used in many over the counter (OTC) dermal therapeutic systems1. Although these four classes of polymers are very different in their chemical properties and molecular structure, they are all

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accepted for use in TDD and dermal therapeutic systems and other medical applications in which skin contact is required.This is because, in general, these polymers have been shown to be biologically inert, non-sensitizing and non-irritating to skin, and to not cause systemic toxicity. The selection of a particular PSA to be used in a TDD system is based on many factors, including patch design, the system formulation, intended wear time (such as 24 or 72 hours or one week), wear conditions (for example, humidity, bathing and sweating), and processibility.

Silicate resin

Dimethylsiloxane polymer

CH3 H3C Si CH3 H

CH3

CH3

O O Si O

H

+

OH Si O Si

O

CH3 CH3

H3C Si CH3 CH3

n

CH3 O m

Si

OH

CH3

Condensation

CH3

Polyisobutylenes Polyisobutylenes are elastomeric polymers that are commonly used in PSAs, both as primary-base polymers and as tackifiers14. They are homopolymers of isobutylene and feature a regular structure of a carbon–hydrogen backbone with only terminal unsaturation (Fig. 2). This molecular structure leads to chemical inertness and good resistance to weathering, ageing, heat and chemicals.Their stability, inertness, and broad acceptance in FDA-regulated applications means that PIBs are a good candidate adhesive for use in TDD devices6. Because of their highly paraffinic and nonpolar nature, PIBs are soluble in typical aliphatic and aromatic hydrocarbon solvents, but not in common alcohols, esters, ketones and other oxygenated solvents. The structure of the close and unstrained molecular packing leads to the low air, moisture and gas permeability of PIBs14,15. The higher the molecular weight of the PIB, the lower its permeability15. Polyisobutylenes are, therefore, preferred for use with drugs with a low solubility parameter and low polarity. The amorphous characteristics and low glass transition temperature (Tg, 2628C) of PIBs impart high flexibility and permanent tack. Despite the favorable tack property, adhesion of PIBs to many surfaces is weak because of their low polarity. This problem is overcome by the addition of tackifiers (such as rosin ester resins) and other materials that will impart some polar properties to the formulation. Polyisobutylenes are produced over a wide range of molecular weights15,16. The low molecular weight PIBs are very viscous, soft, and tacky semi-liquids, whereas the high molecular weight grades are tough and elastic rubbery solids15. The low molecular weight polymers are primarily used as tackifiers to

CH3

CH3

C CH2

C CH2

CH3

CH3

Isobutylene

n

Polyisobutylene

Figure 2. Polymerization of isobutylene to polyisobutylene.

H3C Si CH3 O H

O Si O O

CH3 Si CH3

CH3 O Si

CH3 O

CH3 m

Si OH CH3

H3C Si CH3 CH3

n

Figure 3. The chemistry of silicone pressure-sensitive adhesives (PSAs).

provide tack to the high molecular weight PIBs or other adhesive polymers. The high molecular weight PIBs are used to impart internal strength and flow resistance of PSAs. Because the manufacturers of PIB polymers do not supply pre-formulated, ready-to-use adhesives, the TDD patch manufacturers or formulators often formulate their own PIB–PSA formulations. Two common approaches have been used to obtain the desired PSA properties. First, a combination of low and high molecular weight PIBs is used to achieve a balance of tack and cohesive strength. Second, tackifiers, plasticizers, fillers, waxes, oils and other additives can be incorporated into the formulation to impart the desired adhesive properties and viscosity. Examples of tackifiers include low molecular weight polybutenes, rosin ester resins, hydrocarbon resins and polyterpenes17–19. Many types of plasticizers are available18; examples include mineral oil, diethyl phthalate, dioctyl phthalate or other phthalates and adipates, as well as citrate esters such as acetyl tributyl citrate. Examples of fillers include fumed silicas, silica gels, clay, microcrystalline wax and microcrystalline cellulose. Because of their favorable stability over a wide range of temperatures, humidity and electromagnetic radiation (UVA, UVB and UVC lights), PIBs do not normally contain stabilizers. If necessary, anti-oxidants or stabilizers can be added to significantly extend the resistance to extreme conditions15. A representative PIB-based PSA formulation for a TDD application is provided in Table 2. In this formulation, toluene is used to rapidly dissolve the polymers, while hexane gives the lowest solution viscosity, which facilitates easier processing15. Other examples of PIB-based PSA formulations can be found in the reference handbooks14,19 and patent literature20,21. Major suppliers of PIBs include Exxon Chemical Company (Houston, TX, USA) 63

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Table 2. Polyisobutylene (PIB)-based pressure-sensitive adhesive (PSA) formulation for transdermal drug delivery devices Component

Description

Supplier

Content

Vistanex® MM L-100 Oppanol® B10

High molecular weight PIB Low molecular weight PIB Rosin Ester tackifying resin Solvent Solvent

Exxon Chemical

12.5%

BASF

12.5%

Exxon Chemical

5.0%

Various Various

30.0% 40.0%

Escorez® 1310 LC Hexane Toluene

Table 3. Commercial grades of polyisobutylene commonly used in pressure-sensitive adhesive15,16 Supplier

Product name

Grade

Viscosity average molecular weight

Exxon

Vistanex®

BASF

Oppanol®

LM-MS LM-MH LM-H MM L-80 MM L-100 MM L-120 B10 B12 B15 B30 B50 B100 B150

43,000–46,000 51,000–56,000 58,000–68,000 750,000–1,050,000 1,060,000–1,440,000 1,450,000–1,870,000 40,000 55,000 85,000 200,000 400,000 1,110,000 2,600,000

and BASF Corporation (Mount Olive, NJ, USA). Various grades of commercial PIB polymers that are suitable for TDD applications are listed in Table 3. Fully formulated PIB adhesives for TDD applications are available from Adhesives Research Inc. (Glen Rock, PA, USA) and custom formulations can be provided by other vendors [such as Mactac (Moosic, PA, USA) and National Starch and Chemical Company (Bridgewater, NJ, USA)].

devices, and their chemical and physiological inertness are well documented in the scientific literature6. Silicone PSA formulations are based on two major components: a polysiloxane (silicone) polymer and a silicate resin7,28 (Fig. 3).The polymer is a high molecular weight polydimethylsiloxane that contains residual silanol functionality (SiOH) on the ends of the polymer chains.The resin is a three-dimensional trimethylsiloxy and hydroxyl end-blocked silicate structure.The silicone polymer and silicate resin are dissolved together in a nonpolar hydrocarbon solvent (such as xylene and hexane). During processing, a condensation reaction takes place between the silicone polymer and the silicate resin. This condensation results in a network of polymer chains that are crosslinked with the resin molecules.The final silicone PSA formulation can therefore be considered to be a one-component system, unlike the PIB-based PSA formulations, which are merely a physical blend of a high molecular base polymer and a low molecular weight polymer or tackifying resin. The ratio of resin to polymer is used to produce PSAs with a wide range of adhesive properties. Increasing the polymer content provides a softer and tackier adhesive, whereas higher resin levels produce an adhesive with a lower tack but higher adhesion and resistance to cold flow6,28. The other important factor that controls the adhesive properties is the level of silanol functionality present in the final polymer and resin formulation. Polydimethylsiloxanes have a unique molecular structure in which an inorganic silica-like backbone (-Si-O-Si-) supports a regular arrangement of pendant methyl groups7. The low Tg of 21278C and the unique semi-organic structure give silicone a highly flexible and extremely open macromolecular architecture with a high void volume. This structure enables silicone PSAs to have a high permeability to vapour, gases and a wide variety of therapeutic molecules7. Silicone PSAs that are compatible with amine-functional drugs have been manufactured by end-capping the reactive silanol end groups in an additional stage of the commercial manufacturing process26,29. Silicone adhesives are supplied as two types of pre-formulated products. The regular type contains residual silanol, and

H O H2C CH C OR

H2C C C O O R

Silicones Silicone PSAs have been used in medical and healthcare devices since the 1950s22, and their application in TDD devices has been extensively researched and reviewed 6,7,22–27. Their biocompatibility has been established through a history of many years of safe usage, and their application in various medical 64

Acrylic ester monomer

n

Polyacrylate

R = H, ethyl, butyl and 2-ethylhexyl Figure 4. Polymerization of acrylic ester monomer to polyacrylate.

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Table 4. Silicone pressure-sensitive adhesives from Dow Corning Resin/polymer ratio

Standard product

Amine compatible product

65/34 (low tack) 60/40 (medium tack) 55/45 (high tack)

7–4400 7–4500 7–4600

7–4100 7–4200 7–4300

the amine compatible type has the reactive silanols end-capped. To improve cohesive strength, reinforcing fillers, such as finely divided silica, can be incorporated into the silicone PSA formulation30. Water-soluble additives such as ethylene glycol, glycerin, and polyethylene glycols were used to control the water sorption into the silicone polymer matrix and to enhance the release of drugs31. Another method of controlling the release of active agents is to manage the degree of crosslinking in the silicone polymer matrix30. Crosslinking will improve cohesive strength with a corresponding decrease in tack, adhesion and drug release properties. Silicone PSAs for use in pharmaceutical applications are available from Dow Corporation under the trade name of BIOPSA®29.Table 4 lists some of the commercially available silicone PSAs from Dow Corning (Midland, MI, USA). Acrylics Polyacrylates, or more precisely poly(acrylic esters), have been known for a long time. They have been referred to as acrylic polymers, or simply acrylics or acrylates. Although their inherent adhesive properties were discovered as early as 1928, polyacrylates were not extensively used in PSAs until the 1950s19,32. In addition to their favorable biocompatibility and good skinadhesion property, acrylic PSAs offer advantages of good compatibility with a wide range of drugs and excipients, ease of processing, and flexibility in tailoring the polymer properties. Acrylics are saturated hydrocarbon polymers.They are therefore highly resistant to oxidation, and do not require the addition of stabilizers, which have the potential to cause skin irritation.The acrylic polymers have a low Tg (255 to 2158C) and are inherently tacky, and therefore in general they do not require low molecular weight tackifiers and plasticizers to provide the tack and softness. The single-component adhesives have advantages over compounded PSAs in that they do not require a separate compounding process step, and this avoids the potential problem of migration of low molecular weight components to the adhesive surface. Acrylic PSAs are produced by copolymerization of acrylic esters, acrylic acid and other functional monomers (Fig. 4).The free-radical initiated polymerization process can be performed

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either in organic solvent systems or aqueous emulsion.Various monomers can be copolymerized to obtain different pendant ester groups (Fig. 4) on the backbone. These side-chain pendant groups are used to effect the desired adhesive properties, solubility and permeability. Unlike the PIBs and silicones, the organic solvent-based and emulsion acrylic PSA prepared directly from polymerization are the final, ready-to-use adhesives. Three key parameters have been used to design acrylic polymers and to tailor the polymer properties:

• • •

types of monomers; crosslinking of functional groups; molecular weight.

In general, the PSA acrylic monomer composition comprises the following:

• • •

50–90% of primary monomers; 10–40% of modifying monomers; 2–20% monomers with functional groups32.

The primary monomers are used to impart the flexibility and tack of the adhesive. Many alkyl acrylates and methacrylates, particularly those with four to 17 carbon atoms and Tg ranges of approximately 2508C to approximately 2708C, have been claimed in the patent literature to be suitable monomers for this purpose32. In general, the flexibility and tack of the polymer rises with increasing side-chain length until a certain chain length is exceeded, beyond which crystalline regions form which then cause stiffening of the polymer32. In practice, for economic reasons, only four acrylic esters have been commonly used as primary monomers for PSAs: 2-ethylhexyl, butyl, ethyl and iso-octyl acrylate19,32. Iso-octyl acrylate is not commercially available, but is manufactured by 3M Company (St Paul, MN, USA) for captive consumption19. Homopolymers of these monomers are too soft and tacky. Other modifying monomers that can impart higher Tg and hardness are used to obtain a balance of tack and cohesion properties. Commonly used modifying monomers include vinyl acetate, methyl acrylate, methyl and ethyl methacrylate, acrylic and methacrylic acid, acrylonitrile and certain amine-functional monomers. Copolymerization with vinyl acetate produces a class of copolymers that are commonly known as vinyl acrylics. Vinyl acrylics are less polar and have a higher tack, but they have poorer ageing properties than all-acrylic adhesives32. Also, in general vinyl acrylics have a much higher amount of residual monomers because of the lower reactivity of vinyl acetate. Most newly developed TDD devices use all-acrylic PSAs to minimize residual monomers and maximize stability. 65

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Modifying monomers may be used to change the solubility or permeability of the acrylic polymers. For example, watersoluble or hydrophilic monomers such as vinyl pyrrolidone, 2-hydroxylethyl acrylate, and 2-ethoxyl acrylate have been used to increase the hydrophilicity of the polymers32. Crosslinking of acrylic PSAs improves the creep or shear resistance and resistance to cold flow or oozing. Resistance to cold flow is desirable to prevent the adhesive from oozing or ‘squeezing out’ from under the TDD patch during storage or wear. Oozing can manifest itself as a ‘dirty’ ring around the patch during wear or flow beyond the backing material of the patch during storage in the pouch. In TDD applications, the addition of drug, permeation enhancers, and other excipients into the adhesives often compromises the tack, adhesion, and cohesive properties of the PSAs. Crosslinking of PSAs is one of several techniques used to minimize these effects and increase the loading level of the active or excipient in the PSA composition33. There are two ways to effect crosslinking. The first approach is crosslinking during the PSA manufacturing process. A small amount of acrylates or methacrylates with multiple unsaturation can be copolymerized with the acrylic esters to obtain a lightly crosslinked network during polymerization. Examples of such monomers include diethyleneglycol diacrylate, trimethylolpropane trimethacrylate, and hexamethylene glycol dimethacrylate. This in situ crosslinking during polymerization usually leads to a viscous polymer solution and makes processing more difficult. The second approach is more commonly practised and can be performed by the patch manufacturer. In this approach, crosslinking of the acrylic polymer occurs through the pendant functional groups of the polymer when they are coated and dried in the oven. Monomers with functional groups are introduced into the polymer chain during polymerization. Functional groups commonly used for crosslinking are carboxylic, hydroxyl, epoxy, amide, and organo-silane. Examples of monomers with such functionality are acrylic and methacrylic acid, hydroxylethyl acrylate, hydroxylpropyl acrylate, glycidyl acrylate and methacrylate, acrylamide, and 3-methacryloxylpropyl trimethoxylsilane. Crosslinking agents are often used to activate the crosslinking reaction34. Various organic metal crosslinking agents, such as aluminum or titanium acetyl acetonates, metal alkoxides, and polybutyl titanate, have been found to be effective in crosslinking polymers that contain carboxylic and hydroxyl groups19,32,34. Polybutyl titanate has been reported to produce a ‘yellowish’ dried adhesive on an estradiol patch, whereas the aluminum acetyl acetonate-crosslinked adhesive was clear35. The epoxy groups of glycidyl monomers, such as glycidyl acrylate or methacrylate, react with carboxyl groups without any crosslinking agent34. 66

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Molecular weight and molecular weight distribution affect the adhesive properties of acrylic PSAs. Low molecular weight polymers generally have good tack but poor mechanical strength, and they are unacceptable for normal PSA applications. An increase in molecular weight generally enhances the cohesive strength of the polymers. In general, higher molecular weight acrylic PSAs are more tolerant to skin-penetration enhancers and, compared to the corresponding low molecular weight acrylic PSAs, are able to accept a higher loading level33. Acrylic PSAs that have optimal distribution of low and high molecular weight components show balanced properties of tack, adhesion and cohesive strength. The molecular weight of acrylic polymers can be controlled by the mode of polymerization and the polymerization conditions (such as reaction temperature and reaction duration). Various modes of polymerization may be employed. For example, polymerization may be performed in a batch process in which all components are charged at the start of polymerization, or a semi-batch process with partial charge at the start of the reaction, and then the delayed, progressive addition of monomers, solvents or initiators during the course of polymerization. Table 5 provides a polymerization recipe for the preparation of an acrylic PSA. Major suppliers of pharmaceutical-grade acrylic PSAs include National Starch and Chemical Company, Solutia Inc. [Springfield, MA, USA (formerly Chemical Group of Monsanto Company)], and Adhesives Research, Inc. Most of the PSA products supplied by National Starch and Adhesive Research are solvent-borne. Solutia markets both solvent and emulsion (waterborne) PSAs for medical applications. Recent developments Recent developments in new adhesives for TDD applications have focused on two objectives. The first has been aimed at the development of adhesives that enhance TDD rates. These adhesives include PSAs that have better compatibility with a wider range of drugs at higher drug-loading levels, and those that tolerate higher loading levels of permeation enhancers without sacrificing adhesive properties. The second objective Table 5. Acrylic pressure-sensitive adhesive monomer composition for transdermal drug delivery applications Component

Function

Amount

2-ethylhexyl acrylate Butyl acrylate Acrylic acid Azobis (2-methylbutane nitrile) Ethyl acetate

Backbone monomer Backbone monomer Functional monomer Initiator

50 45 5 0.5

Solvent

90

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has been focused on the development of adhesives with improved biocompatibility, skin-adhesion and wear properties.The desired improvements include better adhesion to skin, longer wear time, and smoother, less painful – or even painless – peel-off. Two approaches have been taken to achieve these objectives. The first involves the development of new polymers, which are beyond the conventional chemistries of PIBs, silicones, and acrylates. These new polymers include hydrogels36–41, hydrophilic polymers42–44, and polyurethanes45,46. The second approach is to physically or chemically modify the chemistries of the PSAs in current use (such as PIBs, silicones, and acrylates). Physical modification refers to the formulation of the base adhesives with some unique additives so that, in synergy with the drug and excipients in the system formulation, the result is enhanced drug delivery and improved skin-adhesion properties. Chemical modification involves chemically incorporating or grafting specialty functional monomers to the conventional PSA polymers in order to improve drug delivery rates.The second method may be performed by the PSA vendor and offered as a new product or performed by the end user on a commercially available PSA. Polymers developed through the use of these two approaches will be discussed in detail. Hydrogel PSAs Conventional PSAs based on PIBs, silicones, and acrylates are hydrophobic in nature with a low residual water content (,0.1%) after drying. Hydrophilic ‘hydrogel’ PSA compositions have recently been developed. These compositions have been shown to be compatible with drugs of different chemical structures and to provide high TDD rates even without skinpenetration enhancers36,37. A hydrogel is defined as a waterswollen but water-insoluble crosslinked polymer, and normally contains at least 20% of water at equilibrium.The reported ‘hydrogel’ PSA features high molecular weight polyvinyl pyrrolidone (PVP) and oligomeric polyethylene glycol (PEG)38, with an equilibrium water content of 8–11% (Ref. 36). The crosslinks are formed through hydrogen bonding and the polymer is therefore water soluble. This hydrophilic polymer was reported to have the ability to absorb moisture from the skin39. A two-stage mechanism for the formation of a PVP–PEG hydrogel PSA has recently been proposed40.The first stage is the formation of hydrogen bonding between the terminal hydroxyl groups of PEG with the carbonyls in the repeated units of longer PVP chains40.The hydrogen-bonded PEG forms flexible interpenetrating chains that cross-link the longer PVP chains.The second stage involves the gradual dissolving of the crosslinked complex in excess PEG40. The resulting hydrogels exhibit an excess free volume, which governs the viscoelasticity, adhesion and diffusivity properties. Several commercial TDD products have been developed in Russia and Lithuania that are based on this formulation36.

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Another crosslinked, vinyl pyrrolidone-based hydrogel polymer was developed with the objective of obtaining a PSA that tolerates the incorporation of substantial amounts of water without phase separation and a loss of adhesion properties 41. The polymer was composed of vinyl pyrrolidone, a multiethylenically unsaturated compound as crosslinker, and glycerol and water as plasticizers, and was crosslinked with UV radiation41. The resulting gel, approximately 35 mil thick, was reported to be clear, tacky, and released cleanly from skin41. Hydrophilic PSAs Another approach designed to impart hydrophilicity is based on plasticizing high Tg aminoalkyl methacrylate copolymers42,43. The base polymers are cationic or anionic copolymers of dimethylaminoethyl methacrylate, methacrylic acid and methacrylic acid esters in varying ratios, and are primarily used in oral capsule and tablet formulations as film-coating agents43. Plasticizing these polymers with acetyl tributyl citrate and crosslinking with succinic acid results in hydrophilic adhesives with pressure-sensitive properties43. The cohesion strength is provided by the ionic crosslinking of succinic acid with the amino functionality of the polymers43.These PSAs are insoluble in water but swell in water and are permeable to water vapour43. They can be easily removed from the skin by water washing but are able to withstand short showers for several days in TDD applications43. Aqueous solution for this PSA system has been prepared by formulating these polymers with water-soluble or hydrophilic plasticizers, such as polyethylene glycol, glycerin, triethanolamine, or triethyl citrate44. Commercial products of the aminoalkyl methacrylate copolymers are available from Rohm America Inc. (Somerset, NJ, USA) under the trade name of Eudragit®. Polyurethanes Polyurethanes are another class of recently developed hydrophilic PSAs45,46. Polyurethanes are polymeric products of diols or polyols and diisocyanates or polyisocyanates. Polyurethane PSAs with a Tg of less than 2308C have been developed for use in medical applications45. These polymers are reported to exhibit a high degree of water absorption and water vapor transmission capabilities, and to have a good balance of cohesion and adhesion properties45. The balance of cohesion and adhesion is obtained by controlling the crosslink density of the polymer. Water absorption properties are controlled by the amount of polyoxyethylene in the polyols45. An increase in the amount of polyoxyethylene promotes stronger hydrophilicity, whereas an increase in the proportion of polyoxypropylene lessens the hydrophilic property45. Polyurethane PSAs that are compounded with water-soluble polymers, such as polyvinyl methyl ether, have been reported to enhance water uptake46. 67

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Graft copolymers and enhancer-tolerant PSAs Hydrophilic acrylic PSAs have also been prepared through the use of a more conventional method (that is, by the copolymerization of acrylic esters with hydrophilic monomers). A waterabsorbent copolymer comprising a carboxylic hydroxyalkyl ester monomer and a water-soluble macromer, such as an ethoxylated or propoxylated hydroxyalkyl methacrylate, has been prepared for use in medical adhesive applications47. A macromer is a macromonomer or a polymer with a polymerizable group at the end of the chain. Copolymerization of acrylic esters with macromers is one of the approaches that may be used to prepare graft copolymers. Acrylic-based graft polymers from macromers of different chemical structures have been prepared in order to obtain various desired properties (such as better adhesion, resistance to permeation enhancers, and improved permeability). Acrylic PSAs with a methacrylate-terminated styrene macromer have been prepared and were reported to feature less adhesion build-up on skin over time48. An enhancer-tolerant PSA that comprises a fatty acid ester-enhancer and a macromerreinforced acrylic polymer has been reported49,51. The macromer is a polystyrene methacrylate macromer. It was reported that the backbone of the copolymer and the grafted macromer are incompatible and thus are ‘phase separated’49. Reinforcement is achieved through the phase separation of the polymeric graft domains within the continuous polymer matrix50. When such a polymer system is compounded with fatty acid esters, the resulting adhesive formulation possesses an appropriate balance of flow and cohesive strength50. 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 backbone51. Polymers with a wide range of solubility parameters (such as polyisobutylene, polyethylene oxide, polyvinyl acetate, polyvinyl pyrrolidone, and polysaccharide) have been grafted to the acrylic polymer51.These graft polymers were reported to have better compatibility with many skin penetration enhancers51. Silicone graft copolymers have been prepared for TDD applications52. The polyethylene oxide-grafted silicones have potential application as silicone PSAs with improved permeability and solubility for hydrophilic drugs7. An electron-beam crosslinked acrylic PSA has been reported to be tolerant of alcohol-based permeation enhancers53. The monomer composition primarily comprises iso-octyl acrylate and acrylic acid53. Polymer modifications Many specific polymers or PSA formulations have been claimed, in the patent literature, to enhance the delivery of spe68

PSTT Vol. 2, No. 2 February 1999

cific drugs. A copolymer containing 2-ethylhexyl acrylate and vinyl pyrrolidone was reported to have the advantage of maintaining a relatively high concentration of estradiol in the TDD matrix without estradiol crystallization54. The two monomers have very different reactivity ratios, and the copolymer was therefore thought to have ‘block copolymer’ characteristics, with distinct vinyl pyrrolidone and ethylhexyl acrylate domains55. A combination TDD DIA-type patch that contained estradiol and another steroid was prepared by using this copolymer55. It was reported that the respective fluxes of estradiol and the other steroid from the matrix are independent of the respective concentrations of the other steroid and estradiol in the matrix55. Adhesives based on the simple blending of conventional PSAs with other polymers or excipients have been reported to impart additional benefits to TDD devices. A blend of silicone PSAs with PVP has been found to prevent the crystallization of several drugs56. A TDD system for the delivery of flurbiprofen using a blend of acrylic PSAs and PVP has been reported57. The inclusion of monoglyceride into an acrylic PSA in a TDD matrix for the delivery of isosorbide dinitrate was reported to improve skin adhesion and the release of isosorbide dinitrate58. The composition was claimed to have excellent adhesion to the skin and does not cause pain and damage to the stratum corneum when peeled off 58.The addition of clay has been claimed to improve the cohesiveness of PSAs in transdermal formulations without reducing the rate of drug delivery59. Summary Adhesives are, besides the drug, one of the more important components in TDD devices. In addition to the usual requirements of adhesive performance properties, adhesives for TDD applications must have good biocompatibility with the skin, chemical compatibility with the drug formulation, and provide consistent and effective delivery of the drug.The adhesives must function under a wide range of conditions in order to hold the TDD devices in intimate contact with the skin for periods of up to seven days.The three classes of PSAs most widely used in TDD devices are PIBs, silicones, and polyacrylates. Polyisobutylenes are paraffinic hydrocarbon polymers with low moisture and gas permeability, and are relatively inert, odorless and nontoxic. Polyisobutylene PSAs are generally composed of mixtures of high and low molecular weight PIBs, and are formulated in-house. Silicone PSAs are made of silicate resin and silicone polymer. The unique molecular structure of silicone imparts good skin-adhesion properties and favorable diffusion characteristics for many drugs. Acrylic PSAs are singlecomponent systems that are inherently tacky without requiring additional compounding. Acrylic polymers with a wide range of adhesive properties can be prepared by copolymerizing different

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monomers. New adhesives for TDD devices include hydrogels, hydrophilic polymers, polyurethanes and graft copolymers. These new classes of adhesive offer various benefits such as enhanced drug delivery and improved adhesive performance properties.

22

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