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Sateesh Kandavilli, Vinod Nair, and Ramesh Panchagnula*
Polymers are the backbone of a transdermal drug delivery system. Advances in the field of polymer science have paved the way for transdermal delivery system designs that have considerable flexibility. An impressive amount of technical know-how has been gained in this area of research. This article summarizes the formulation aspects of transdermal drug delivery systems and emphasizes the physicochemical and mechanical properties of various polymers being used in commercially available transdermal drug delivery systems. It is intended as a guide for the selection of polymers for developing such systems.
he development of transdermal drug delivery systems is a multidisciplinary activity that encompasses ● fundamental feasibility studies starting from the selection of a drug molecule to the demonstration of sufficient drug flux in an ex vivo and/or in vivo model ● the fabrication of a drug delivery system that meets all the stringent needs that are specific to the drug molecule (physicochemical and stability factors), the patient (comfort and cosmetic appeal), the manufacturer (scale-up and manufacturability), and most important, the economy.
Polymers are the backbone of a transdermal drug delivery system. Systems for transdermal delivery are fabricated as multilayered polymeric laminates in which a drug reservoir or a drug–polymer matrix is sandwiched between two polymeric layers: an outer impervious backing layer that prevents the loss of drug through the backing surface and an inner polymeric layer that functions as an adhesive and/or rate-controlling membrane. Transdermal drug delivery systems are broadly classified into the following three types (1) (see Figure 1). Reservoir systems. In this system, the drug reservoir is embedded between an impervious backing layer and a ratecontrolling membrane. The drug releases only through the rate-controlling membrane, which can be microporous or nonporous. In the drug reservoir compartment, the drug can be in the form of a solution, suspension, or gel or dispersed in a solid polymer matrix. On the outer surface of the polymeric membrane a thin layer of drug-compatible, hypoallergenic adhesive polymer can be applied. Matrix systems. Drug-in-adhesive system. The drug reservoir is formed by dispersing the drug in an adhesive polymer and then spreading the medicated polymer adhesive by solvent casting or by melting the adhesive (in the case of hot-melt adhesives) onto an impervious backing layer. On top of the reservoir, layers of unmedicated adhesive polymer are applied. Matrix-dispersion system. The drug is dispersed homogeneously in a hydrophilic or lipophilic polymer matrix. This drugcontaining polymer disk then is fixed onto an occlusive base plate in a compartment fabricated from a drug-impermeable backing layer. Instead of applying the adhesive on the face of the drug reservoir, it is spread along the circumference to form a strip of adhesive rim.
Sateesh Kandavilli, Vinod Nair, and Ramesh Panchagnula, PhD, are employed in the Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Ph-X, SAS Nagar-160 062, Punjab, India, tel: 91 172 214 682 or 214 687, fax 91 172 214 692, firstname.lastname@example.org.
*To whom all correspondence should be addressed.
NJ) (6). Ethyl cellulose (EC) and polyvinylpyrrolidone (PVP). Biocompatibility of PEGs makes them the polymers of choice for numerous biomedical applications. Acrylic-acid matrices with plasticizers have been used to make drug–polymer matrix films for transdermal delivery systems. This growth is catalyzed by developments in the field of polymer science. and Searle Pharmacia (Barceloneta. These systems have been shown to release the solutes in a biphasic manner (5). The addition of hydrophilic components such as PVP to an insoluble film former such as ethyl cellulose tends to enhance its release-rate constants. Although polymeric matrices are used for rate control. This outcome can be attributed to the leaching of the soluble component. which leads to www. CA) mainly concentrates on ethylene vinyl acetate (EVA) copolymers or microporous polypropylene. Companies involved in the field of transdermal delivery concentrate on a few selective polymeric systems. This article focuses on the polymeric materials used in transdermal delivery systems. Piscataway. a PSA). also has been used as a matrix former (7). This drug delivery system is a combination of reservoir and matrix-dispersion systems. engineering.phar mtech. From an economic point of view. with emphasis on the materials’ physicochemical and mechanical properties. The release rates of drugs from these matrix systems are more closely described by the square-root-of-time model. A monolithic solid-state design often is preferred for passive transdermal delivery systems because of manufacturing considerations and cosmetic appeal. A review of the marketed transdermal products and the formulations that are reported in various research publications reveals an enormous diversity of polymers used in the formulation. Polymers used in transdermal delivery systems should have biocompatibility and chemical compatibility with the drug and other components of the system such as penetration enhancers and PSAs. including as ● matrix formers ● rate-controlling membranes ● pressure-sensitive adhesives (PSAs) ● backing layers ● release liners.com Pharmaceutical Technology MAY 2002 . They also should provide consistent. For example. Transdermal drug delivery technology represents one of the most rapidly advancing areas of novel drug delivery. Proteins can be delivered by PEGs cross-linked with tris(6-isocyanatohexyl) isocyanurate by means of a urethane–allophanate bond to obtain polymer networks capable of swelling in phosphate-buffered saline or ethanol and forming gels. Some of the polymers that have been reported are Eudragit RL PM. Polymers are used in transdermal delivery systems in various ways.Reservoir system Matrix-dispersion system Peripheral adhesive design Backing layer Rate controller Adhesive layer Microreservoir system Drug reservoir Release liner Occlusive baseplate Figure 1: Representative designs of transdermal drug delivery systems. Acrylic-acid matrices. and Eudragit E-100 (Röhm America. and it seeks to guide formulators in the selection of polymers.g. Table II is a comprehensive list of all the polymers used for various purposes in commercially available transdermal delivery systems. effective delivery of a drug throughout the product’s intended shelf life or delivery period and have generally-recognized-as-safe status. Cross-linked poly(ethylene glycol) (PEG) networks. Eudragit RS PM. 64 Matrix formers Polymer selection and design must be considered when striving to meet the diverse criteria for the fabrication of effective transdermal delivery systems.. EC and PVP matrix films with 30% dibutyl phthalate as a plasticizer have been fabricated to deliver diltiazem hydrochloride and indomethacin. The drug reservoir is formed by first suspending the drug in an aqueous solution of water-soluble polymer and then dispersing the solution homogeneously in a lipophilic polymer to form thousands of unleachable. discussion in this section is limited to polymers that have been used in the design of matrices with or without rate control. a delivery tool kit rather than a single delivery tool is most effective (2). microscopic spheres of drug reservoirs. but also with respect to its adhesion–cohesion balance. adhesion (e. a nonadhesive hydrophobic polymer. Eudragit S-100. The thermodynamically unstable dispersion is stabilized quickly by immediately cross-linking the polymer in situ. Alza Corporation (Mountain View. and compatibility and stability with other components of the system as well as with skin (4). The main challenge is in the design of a polymer matrix. or encapsulation of a drug reservoir in transdermal delivery systems (reviewed in later sections of this article). followed by optimization of the drugloaded matrix not only in terms of release properties. physicochemical properties. Microreservoir systems. PR) concentrates on silicone rubber (3). Eudragit NE-40D (a copolymer of ethyl acrylate and methyl methacrylate). and manufacture of drug products (see Table I).
(Continued on page 67) S. hydrophilic. Thus they play a significant role in improving the solubility of a drug in the matrix by sustaining the drug in an amorphous form so that it undergoes rapid solubilization by penetration of the dissolution medium (8).No. an outcome that is attributable to the organic solvent that is used to make the gel. The result is higher dissolution rates. and amphoteric substances. Pluronic lecithin organogels also have been used as transdermal delivery systems because both www. broxaterol Dihydro etorphine Ketoprofen Gel matrices Drug in adhesive Drug in adhesive 13 49 50 11 National Starch Tacrine and Chemical Co. leading to the fast release of the drug (9). Organogels. Exxon Chemical Co. and Tween tend to associate into reverse micelles (10).phar mtech. For matrix and backing side layer. These surfactants in an organic solvent. lecithin. These organogels can be used as a matrix for the transdermal delivery of drugs with greater influx (11). The transdermal flux of propranolol from this organogel increased 10-fold over a vehicle composed of petrolatum (12). HPMC has been shown to yield clear films because of the adequate solubility of the drug in the polymer. Japan National Starch and Chemical Co. The gels obtained in this manner are isotropic and thermoreversible (liquefy at temperatures 40 C) and can solubilize lipophilic. Organogels can cause slight disorganization of the skin. Eudragit E100. HPMC. Germany Dow Corning Neoplast Co. also has been explored as a matrix former in the design of patches of propranolol hydrochloride.. also described organogels obtained when small amounts of water were added to a solution of lecithin in organic solvents. Some nonionic surfactants such as sorbitane monostearate. Backing Release liner Gel Matrix Matrix Gel Drug in adhesive Reference 41 42. a hydrophilic swellable polymer widely used in oral controlled drug delivery.43 3M 3M Röhm. including enzymes. Vistanex MML-100) Silicone PSA Silicone oil EVA Polyisobutylene ScotchPak 1006 Manufacturer Sigma Dow Corning Drug Isosorbide dinitrate Trimegestone Type of System Matrix Adhesive-in-matrix system. upon the 66 addition of water.Table I: Composition of transdermal delivery systems reported in the literature. Hydrocortisone Coumarin Melilot dry extract L-Timolol maleate L-Dopa Nicotine 3 4 5 6 7 44 45 46 47 48 8 9 10 Scopolamine. Bhatnagar and Vyas proposed a reverse micelle-based microemulsion of soy lecithin in isooctane gelled with water as a vehicle for transdermal delivery of propranolol. Matrices of HPMC without rate-controlling membranes exhibited a burst effect during dissolution testing because the polymer was hydrated easily and swelled. Exxon Chemical Co. Substances such as PVP act as antinucleating agents that retard the crystallization of a drug. Willimann et al. Vistanex MML-100) Acrylic adhesives Polyisobutylene solutions (Vistanex LM-MH. undergo association reorientation to form a gel. Thus. They are biocompatible and are stable for a long time. Eudragit L100 MDX-4-421 (a silicone) Carboxy vinyl polymer Acrylic PSA emulsion CoTran9722 Soybean lecithin (Epikuron 200) Cariflex TR-1107 Acrylic adhesives Polyisobutylene solutions (Vistanex LM-MH. Drug in adhesive 51 12 Dow Corning Adhesive Research Arecoline 3M Reservoir Membrane Adhesive Backing film 52 the formation of pores and thus a decrease in the mean diffusion path length of drug molecules to release into the dissolution medium. Thailand 3M Lucas Meyer. Polymer 1 Ethyl cellulose T-50 2 BIO PSA HighTack 7-4301 BIO PSA MediumTack 7-4201 Scotch Pak 1022 Scotch Pak 1006 HPMC Eudragit NE. organogels can enhance the permeation of various substances (13).. Germany Shell Chemical Co.com Pharmaceutical Technology MAY 2002 . Hydroxypropyl methylcellulose (HPMC). used as matrices for the transdermal transport of drugs.
Vistanex LM-80) Silicone PSA Plastoid E25L Polyvinyl alcohol (backing) HPMC (matrix) Ethylene vinyl acetate (rate-controlling membrane) Manufacturer Mitsubishi Petrochem Co. Germany Miconazole Propranolol Matrix Membranecontrolled reservoir system 7 57 H C H H C H x H C H H C O y C O CH3 Figure 2: Structure of polyethylene vinyl acetate. the choice of membrane material must conform to the type of drug being used. However. Japan Wako Purechem. the glass-transition temperature. the dosage rate per area of the device can be controlled. Lidocaine Ind. Drug in adhesive 53 19 20 Dow Corning Röhm. Wako Purechem. The effect of these structural changes on membrane permeability is shown in the permeation of camphor through a series of poly(ethylene vinyl acetate) copolymers. EVA frequently is used to prepare rate-controlling membranes in transdermal delivery systems because it allows the membrane permeability to be altered by adjusting the vinyl acetate content of the polymer. and water-soluble drugs are miscible with the aqueous phase. Japan Exxon Chemical Co.No. France Dow Corning Nitroglycerine Monsanto Fentanyl Dow Corning Exxon Chemical Co. the permeability increases. Hence. which is not isomorphous with ethylene. the degree of crystallinity and the crystalline melting point decreases and amorphousness increases (see Figure 2). As the solutes permeate easily through the amorphous regions. Japan Polyscience Drug PGE Type of System Drug-in-adhesive matrix Reference 53 Cytarabine. Tg.. EVA. or the material may contain fluid-filled micropores — in which case the drug may additionally diffuse through the fluid. the rate of passage of drug molecules depends on the solubility of the drug in the membrane and the membrane thickness. Japan Ketoprofen. 9 Matrix Matrix 55 56 18 Mitsubishi PetroAminopyrene. Belgium Aldrich. Styrene and N-vinyl pyrrolidone copolymer for membrane HPMC (Methocel K4M) Urecryl MC 808 PIB MDX4-4210 silicone elastomer Acrylate copolymer (Gelva-737) Silicone-2920 and 2675 Polyisobutylene solutions (Vistanex LM-MS. chem Co.. ara-ADA Carbopol 934 gel. For example.. hydrophobic and hydrophilic drugs can be incorporated into them. Polymer 13 2-Ethylhexyl acrylate and acrylic acid copolymer 14 HEMA. an increase in the vinyl acetate content of a copolymer leads to an increase in solubility and thus an increase in the diffusivity of polar compounds in the polymers. controllable rate. In the case of nonporous membranes. thus filling the pores. at vinyl acetate levels 60% by weight. of polymer increases from 25 C to 35 C..Table I continued: Composition of transdermal delivery systems reported in the literature. Hence. By varying the composition and thickness of the membrane. The copolymerization also results in an increase in polarity. Oil-soluble drugs are miscible with the lecithin phase. The release rate– controlling membrane can be nonporous so that the drug is released by diffusing directly through the material. An increase in Tg reflects a decrease in the polymer-chain mobility and hence the solute diffusivity. when ethylene is copolymerized with vinyl acetate. Vistanex MML-100) 2-Ethylhexyl acrylate and acrylic acid copolymer 2-Ethylhexyl acrylate and acrylamide copolymer Polyisobutylene solutions (Vistanex LM-MH. UK Propranolol UCB. Rate-controlling membranes Reservoir-type transdermal drug delivery systems contain an inert membrane enclosing an active agent that diffuses through the membrane at a finite. S. Pharmaceutical Technology MAY 2002 67 . reservoir Matrix 54 15 16 17 Colorcon. which has exhibited a maximum of limiting flux at 60% vinyl acetate content (14). Ind.
colloidal silica. and colloidal silicon dioxide Acrylate adhesive matrix PIB Polyester Polyethylene film Multilayered PIB adhesive film Poly foil Siliconized or fluoropolymercoated polyester film Silicone foil Polypropylene Acrylatevinylacetate copolymer and poly(butyl butane) EVA copolymer with 5% vinyl acetate Light mineral oil and PIB Estraderm (estradiol) Alza/CibaGeigy Habitrol (nicotine) Novartis Nitrodisc (nitroglycerin) Searle Nitro-Dur-I (nitroglycerin) Key Pharma Reservoir Drug and alcohol gelled with hydroxypropyl cellulose Polyester– polyethylene composite Aluminized plastic backing film Foil– polyethylene combination Paper–foil combination Aluminized and siliconized polyethylene terephthalate foil Siliconized polyethylene terephthalate Drug in adhesive Monolithic microreservoir Drug in adhesive Hydrogel from copolymer of PVP– PVA.phar mtech.Table II: Composition of marketed transdermal therapeutic systems. EVA copolymer Polyester Pharmaceutical Technology MAY 2002 www. and silicone oil Scopolamine. polyisobutylene. and polyisobutylene Acrylate adhesive Aluminum foil Cross-linked silicone rubber Acrylic adhesive Paper–foil combination Paper– polyethylene foil pouch Prostep Reservoir (nicotine) Lederle Testoderm TTS Reservoir (testosterone) Alza TransdermReservoir Nitro (nitroglycerin) Alza/Ciba-Geigy TransdermReservoir Scop (scopolamine) Alza/Ciba-Geigy Vivelle Drug in (estradiol) adhesive Noven/Novartis 68 Low-density polyethylene Polyester/EVA copolymer Flesh-colored polyfoil Polyethylene Acrylate-based ring adhesive EVA copolymer PIB Siliconecoated polyester EVA copolymer Silicone adhesive Fluorocarbon polyester film Aluminized polyester film Microporous polypropylene Mineral oil. alcohol. Inc. polyisobutylene Siliconized polyester EVA copolymer film and polyurethane film PIB. mineral oil. Product Type of System Androderm Reservoir (testosterone) TheraTech./SmithKline Beecham CatapresReservoir TTS (clonidine) Alza/Boehringer Ingelheim Climara Drug in (estradiol) adhesive 3M/Berlex/ Schering AG Deponit Mixed (nitroglycerin) monolithic Pharma reservoir Schwarz Epinitril Drug in (nitroglycerine) adhesive Rotta Research Drug Reservoir Drug. polyisobutylene and colloidal silicon dioxide Backing Metallized polyester/ ethylenemethacrylic acid copolymer/EVA Pigmented polyester film Membrane Polyethylene microporous membrane Adhesive Peripheral acrylic adhesive Release Liner Siliconecoated polyester Microporous polypropylene film Mineral oil. glyceryl monooleate methyl laurate gelled with acrylic acid copolymer Clonidine. glycerol as plasticizer Nicotine in carrageenan gel Drug and alcohol gelled with hydroxypropyl cellulose Drug adsorbed on lactose. light mineral oil.com .
phar mtech. elastic energy must be stored during the bond-breaking process. or the Urethane adhesive. Polyurethane is the general term used for a poly. Polyurethane membranes are suitable especially for hy. The hydrophilic–hydrophobic ratio in these polymers or reinforcing fillers or by inducing cross-linking (23). This A PSA is a material that adheres with no more than applied fin. including the patch design and drug formulation. visco-elastic material. skin adhesion.22). peel adhesion.property often is perceived by the user when the patch is applied ger pressure. is aggressively and permanently tacky. Significant loss of cohesive strength can result in are of the polyether type because of their high resistance to hy. The PSAs term tack is used to quantify the sticky feel of the material. Furthermore. fabrication. Adhesion refers to the force required to reflow resulting in wetting of the skin surface upon the applica.hesive characteristics such as the extent of cross-linking — will ols having an intramolecular urethane bond or carbamate ester determine the choice of adhesive for a drug. particularly steroids.an increase in cohesive properties by either acting as extending meable. enhancers or other formulathesized from polyether polyol are termed polyether urethanes. In the case of adbonds ( NHCOO ) (see Figure 3). and silicone-based adhesives are used n HO n O C N R N C O POLYESTER/ OH mostly in the design of transderPOLYETHER mal patches (21. For reservoir systems with a peripheral adhesive. The selection Polyisocyanate of an adhesive is based on a numPolyol ber of factors. For an adhesive bond to have measurable strength.move the adhesive from a substrate once the bond has reached tion of pressure. cold flow beyond the edge of the patch. and cohesive strength.bination — such as solubility and partition coefficient and admer derived from condensation of polyisocyanates and poly. The physicochemical characteristics of a drug–adhesive comties within the polymer. The silicone rubber group of polymers has hesive also may be based on the adhesion properties and on been used in many controlled-release devices. and the penetration enhancers must be compounded. and cross-linking agents. zation to produce a polymer having no asymmetric carbons 70 Pharmaceutical Technology MAY 2002 www. many skin adhesives have a relatively high degree of tack and Therefore. In contrast. Polyurethane. Some PSAs may have low tack but subsequently in that state. The balance of viscous flow and the amount Polyisobutylene (PIB). can be balanced to get the optimum permeability properties The general formula for a PSA includes an elastomeric poly(17). affect the adhesive. These polymers skin compatibility. and when pressure is removed. When formuhydrophobic polymers such as silicone rubber or EVA mem. tion ingredients that have solubility parameters similar to those and those synthesized from polyester polyol are termed of the adhesive can reduce cohesive strength and can plasticize polyester urethanes.an increase in tack. Another possible result of the interaction can be polyester or polyether urethanes are rubbery and relatively per.Acrylic-. In the case of reservoir bond systems that include a face adhesive.com .head-to-tail sequence by low-temperature cationic polymeriterial (20). and should be removable from a smooth surface the strength of the ultimate adhesive bond or to the duration of without leaving a residue (19). drophilic polar compounds having low permeability through stabilizers if required. the selection will be based on the rate at which the drug rubber backbone. It is not necessarily related to holding force. For matrix designs in which the adhesive.and the penetration enhancer will diffuse through the adhesive. may develop a high degree of adhesion to the skin. Adhesion involves a liquid-like adhesion to the skin. penetration enhancer.mer. polyester polyurethanes recently have become the a transfer of adhesive to the release liner and to the skin durfocus of attention because of their biodegradability (16). a tackifying resin. pressure-sensitive adhesion is a characteristic of a only modest skin-adhesion value (24). Isobutylene polymerizes in a regular of stored elastic energy determine the usefulness of a PSA ma. and high permeability to many important classes the selection will be more complex. and drolysis (15). the diffusing drug must not Figure 3: Synthesis of polyurethane. exerts a strong to the skin and quickly pulled off. count: tack. The high permeability of these of chemical compatibility between all the ingredients is estabmaterials is attributed to the free rotation around the silicone lished. The polyurethanes syn. the choice of adSilicone rubber. have an outstanding combination of biocompatibility. ease of the drug. a necessary filler.lating a PSA. These ing removal. Although most polyurethanes presently used the adhesive. an incidental contact between the adhesive and the C N R N C O POLYESTER/ O drug or penetration enhancers POLYETHER must not cause instability of the O H H O n drug. polyisobutylene-. PSAs bind to the skin after a brief contact known as tack. Once the basic criterium of drugs. a balance of four properties must be taken into acbranes (18). the adhesive sets equilibrium. various antioxidants.hesives that are not cross-linked. which leads to very low microscopic viscosi.
Other fillers that are used are talc and calcined clay.com Pharmaceutical Technology MAY 2002 . the polymer is in an amorphous state (25).000 and 2. Silicone PSAs comprise polymer or gum and a tackifying resin. Silicones.000. H H2C C COR O Acrylic ester H C H H C COOR n Polyacrylate Figure 5: Polymerization of acrylic ester. benzene is a moderate solvent. tackifiers. Most acrylic polymers have a very low Tg value (see Table III). butyl polybutenes. However. the liquids become more viscous. As is typical of polymer systems. therefore. Low molecular weight polymers are viscous liquids. In its unstrained state. acrylic polymers are durable and degrade slowly. and low molecular weight PIB has an average molecular weight between 1000 and 450. for example.100. they can be lost through volatilization or extraction. the mechanical properties of acrylic polymers improve as the molecular weight increases. processing aids. A UV absorber such as o-hydroxybenzophenone can be incorporated to further enhance the UV stability (32). Oxidative degradation of acrylic polymers can occur in high-pressure and high-temperature conditions by the combination of oxygen with the free radicals generated in the polymer to form hydroperoxides (32). Alkyl adipates and sebacates also are used to reduce the Tg value and improve the low-temperature properties. in copolymer they tend to soften and flexibilize the overall composition. and antidegradants are incorporated into the final blend. Un-cross-linked polymers exhibit a high degree of tack or self-adhesion. the improvement is slight and levels off asymptotically (30). PIB polymers have a very low fractional free volume of 0. Acrylic esters are represented by the general formula CH2 CH COOR. Various resins with a Tg value greater than that of the elastomer act as tackifiers. fillers most significantly influence stress–strain and dynamic properties. the most frequently used reinforcing filler by virtue of its high surface area. Fillers also are used to enhance the drug re72 lease from the matrix. The silicone resin has a three-dimensional silicate structure that is end capped with trimethyl siloxy groups ( OSi[CH3]3) and contains residual silanol functionality (33). and the Tg of the polymer is 70 C (26). acrylic ester polymers can be made to hydrolyze to poly(acrylic acid) or to an acidic salt and the corresponding alcohol. However.phar mtech. High molecular weight PIB has a viscosity average molecular weight between 450. Petroleum-based oils. The nature of the R group determines the properties of each ester and the polymer it forms (see Figure 5). Of all these compounding ingredients. Medical-grade silicone adhesives contain a lowviscosity dimethylsiloxane polymer (12 103 cP to 15 103 cP) (24). Unless they are subjected to extreme conditions. In extreme conditions of acidity or alkalinity.071 for poly(dimethylsiloxane). Polyacrylates. unlike incorporated acrylic monomers. This characteristic together with sluggish chain motility results in a low diffusion coefficient. With increasing molecular weight. However.026 as compared with 0. and PVP has been used to enhance the release of formoterol from acrylic PSAs (29).CH3 CH2 C CH3 Isobutylene BF3 CH2 CH3 C CH3 Polyisobutylene n Figure 4: Polymerization of isobutylene. which has a terminal silanol group. Acrylic polymers are highly stable compounds. Cyclohexane is an excellent solvent. Various fillers. thus enhancing tensile properties and abrasion resistance. and dioxane is a nonsolvent for PIB polymers (27). Nonreinforcing fillers such as calcium carbonate and titanium dioxide are added to reduce viscosity and cost. then change to balsam-like sticky masses and finally form elastomeric solids. PIB has the chemical properties of a saturated hydrocarbon. The Tg value of a copolymer can be altered by the copolymerization of two or more polymers. beyond a critical molecular weight. The adhesive is prepared by crosslinking the reactants in solution by a condensation reaction www. (see Figure 4). The approximate Tg value for copolymers can be calculated from the weight fraction of each monomer (W1) and the Tg of each homopolymer as shown in the following equation (31): 1 Tg copolymer W1 Tg 1 W2 Tg 2 Plasticizers also can be used to lower the Tg. It is readily soluble in nonpolar liquids. the final properties of the polymer blend are determined by compounding and subsequent vulcanization or cross-linking. paraffin waxes. Carbon black. plasticizers.000. PIB PSAs usually comprise a mixture of high molecular weight and low molecular weight fractions. which is 1 103 to 2 103 for amorphous polymers. The physical properties of the polymer change gradually with increasing molecular weight. Acrylic polymers are insensitive to normal UV degradation because the primary UV absorption of acrylics occurs below the solar spectrum. Titanium dioxide has been used in the EVA matrix to reduce the amount of naloxone contained in the depleted systems (28). cure systems. interacts with the surface of polymer chains and alters chain dynamics. and low molecular weight polyethylene can be used as plasticizers. Colloidal silicon dioxide is used as a filler in clonidine patches (Catapres-TTS). Polymers of this class are amorphous and are distinguished by their water-clear color in solution and stability toward aging. Acrylic polymers and copolymers have a greater resistance to both acidic and alkaline hydrolysis than do poly(vinyl acetate) and vinyl acetate copolymers.
and cohesion can be modified or customized by varying the resin–polymer ratio. Polybutenes. permeability. which often results with solvent-containing PSAs. Unlike acrylic-. and releasing properties are poor. Hot-melt PSAs (HMPSAs). which deepens with time. Hot-melt adhesives are based on thermoplastic polymers that may be compounded or uncompounded (see Table IV). Polymer Methyl acrylate Ethyl acrylate Propyl acrylate Isopropyl acrylate n-Butyl acrylate Hexyl acrylate Heptyl acrylate 2-Ethylhexyl acrylate 2-Ethylbutyl acrylate Dodecyl acrylate Hexadecyl acrylate Cyclohexyl acrylate Tg ( C) 6 24 45 3 50 57 60 65 50 30 35 16 Polydimethylsiloxane Figure 6: Synthesis of a silicone pressure-sensitive adhesive.40). the solubility. Some of the trace components in acrylic-adhesive blends reacted with a variety of drugs and caused coloring. and the level and type of cross-linking agent. medical-grade silicone adhesives do not contain organic tackifiers. Of these polymers. Paraffin and microcrystalline wax are added to alter the surface characteristics by decreasing the surface tension and the viscosity of the melt and to increase the strength of the adhesive upon solidification. This problem was overcome when 2-mercaptobenzimidazole and/or propyl gallate were incorporated into the adhesive composition (34). or other potentially toxic extractables. between silanol groups on the linear poly(dimethylsiloxane) polymer and silicate resin to form siloxane bonds (Si O Si) (see Figure 6). by end capping the silanol groups with methyl groups by means of a trimethyl silylation 74 reaction (33). peel adhesion. the silanol functionality. Certain amino-functional drugs can act as catalysts to cause further cross-links between these silanol groups. stabilizers. Although the silicone group of adhesives has an outstanding combination of biocompatibility and ease of fabrication for hydrophilic drugs.phar mtech. antioxidants. rubber-. Some of the silicone PSAs contain a significant degree of free silanol–functional groups. These additives are not required because silicone PSAs are stable throughout a wide range of temperatures ( 73 to 250 C). This unwanted reaction can be reduced.CH3 H3C Si O H O Si O H3C Si CH3 Silicate resin Condensation CH3 H3C Si O H O Si O H3C Si CH3 Silicone PSA O CH3 CH3 Si CH3 CH3 n O CH3 Si CH3 O n CH3 Si CH3 OH CH3 n O H HO CH3 CH3 Si CH3 O CH3 Si CH3 O n CH3 Si CH3 OH Table III: Glass transition temperatues of acrylic polymers (39. The end-use properties of silicone-based PSAs such as tack. phthalates. Normally the shear strength and the tack of a PSA first increase and then reach a maximum as increasing amounts of tackifying resin are added. The peel strength usually increases with the amount of tackifying resin. After the product is coated. EVA copolymers are most widely used.com Pharmaceutical Technology MAY 2002 . Antioxidants such as hindered phenols are added to prevent oxidation of ethylene-based hot-melt adhesives. plasticizers. HMPSAs melt to a viscosity suitable for coating. Silicone-based adhesives also are amenable to hot-melt www. Fillers opacify or modify an adhesive’s flow characteristics and reduce the cost. and PIB-based adhesives. catalysts. skin adhesion. Typical PSAs include a volatile organic solvent for reducing the viscosity of the composition to a coatable room-temperature viscosity. the organic solvent is removed by evaporation. The shear-holding power often depends on the mode of cross-linking. When they are heated. Moisture-curing urethanes have been attempted as cross-linking agents to prevent creep under the load of these thermoplastic materials. and tricresyl phosphate often are added as plasticizers to improve mechanical shock resistance and thermal properties. HMPSAs are advantageous over solvent-based systems because they ● do not require removal and containment of the solvents ● do not require special precautions to avoid fire ● are amenable to coating procedures other than those commonly used with solvent-based systems ● are more easily coated into full thickness with minimal bubbling. but when they are cooled they generally stay in a flowless state. thus enhancing a PSA’s chemical stability.
MN). manufactures release liners made of fluoro polymers (Scotchpak 1022 and Scotchpak 9742. causing patches to lift and possibly irritate the skin during long-term wear. Inc. Vinod Nair is supported by a senior research fellowship from the Department of Science and Technology.-M. Eds. because the liner is in intimate contact with the delivery system. for example.. Heller. 3M. Narisetty for his valuable suggestions in the preparation of this article. EVA PE. it should comply with specific requirements regarding the chemical inertness and permeation to the drug. Hadgraft and R. It is therefore regarded as a part of the primary packaging material rather than a part of the dosage form delivering the active principle (38). NY. good oxygen transmission.” PSTT 3 (5).. 173–181 (2000). In case cross-linking is induced between the adhesive and the release liner.5 17 Enhancer Resistance Low Medium Medium Medium High — — High–PET side High High–PET side High–PET side High–PET side Release liner During storage the patch is covered by a protective liner that is removed and discharged immediately before the application of the patch to the skin. Y.722 describes the process of preparing a silicone-based HMPSA in which the dynamic viscosity of a basic adhesive formulation consisting of a polysilicate resin and a silicone fluid is reduced by adding alkyl methylsiloxane waxes. US Patent No.com Backing layer When designing a backing layer. This modification enabled the backing itself to act as a storage location for the medication-containing reservoir (37). pp. EVA laminate Oxygen Transmission MVTR (cm3/m2/24 h) (g/m2/24 h) 700 52.phar mtech. pp. NY. CoTran 9706 CoTran 9720. New York.H. PET PE.H. 3. R. 176. S. Lee.4 7. Compounded Ethylene vinyl acetate copolymers Paraffin waxes Low-density polypropylene Styrene-butadiene copolymers Ethylene-ethacrylate copolymers Uncompounded Polyesters Polyamides Polyurethanes coating. a patch was fabricated in which the backing itself acted as a reservoir for the drug. PET. The most comfortable backing may be the one that exhibits the lowest modulus or high flexibility. 3M Drug Delivery Systems. References 1. 2d ed. 293–311. and water. Wolff.W.3 0. H. Eds. Inc. Robinson and V. 2. and a high moisture-vapor transmission rate (see Table V) (36). Pretzer and Sweet (35) described a silicone-based HMPA that contained a mixture of silicate resin and a polyorganosiloxane fluid into which polyisobutylene polymer with a functionalized silicon-containing moiety was incorporated. St. an overemphasis on the 76 Pharmaceutical Technology MAY 2002 .352. New York. drug. New Delhi. “Material Selection for Transdermal Delivery Systems. J.4 9. 1–8 (1998). J..” in Controlled Drug Delivery: Fundamentals and Applications.” in Transdermal Drug Delivery: Developmental Issues and Research Initiatives.3M.6 4. Al vapor coat. Davis and L. 2950 3570 4. PET laminate PET. J.8 26. 5. the force required to remove the liner will be unacceptably high (23). 1989). Sunil T. However. The upper internal portion of the drug reservoir infiltrated the porous backing and became solidified therein after being applied so that the reservoir and the backing were unified. 1987).R. Paul. improved.* Product CoTran 9701 CoTran 9702. In a novel modification to the conventional design.L. Illum.com Acknowledgments The authors thank Mr. India. 9722 Foam Tape 9772L Foam Tape 9773 Scotchpak 1006 Scotchpak 1109 Scotchpak 9723 Scotchpak 9732. Excipient compatibility also must be seriously considered because the prolonged contact between the backing layer and the excipients may cause the additives to leach out of the backing layer or may lead to diffusion of excipients. Al vapor coat. penetration enhancer.W. www. Thus the coatability of a PSA without solvents is chemical resistance often may lead to stiffness and high occlusivity to moisture vapor and air. the developer must give chemical resistance of the material foremost importance. Table V: Characteristics of some commercialized backing materials. “Optimal Process Design for the Manufacturing of Transdermal Drug Delivery Systems.” Int.9 450 — 0. 9733 Polymer Polyurethane film EVA PE PVC foam Polyolefin foam PE. or penetration enhancer through the layer. Pharm.3 12 15. However. 523–552. The adhesive was claimed to possess a reduced propensity to cold flow. Baker and J. Guys. “Drug Delivery Systems for Challenging Molecules.Table IV: Thermoplastic hot-melt pressure-sensitive adhesives. (Marcel Dekker.6 100 80 80 PE Polyethylene PVC Polyvinyl chloride EVA Ethylene vinyl acetate MVTR Moisture-vapor transmission rate PP Polypropylene PU Polyurethane PET Poly(ethylene terephthalate) (polyester) *http://www. Chien. (Marcel Dekker. 4. “Transdermal Therapeutic Systems.S.
R.. 24 (4). H. J.” U. Interscience Publishers: New York. and J. and S. Gardon. Kydonieus. Takayasu et al. Res. 20. N. Florence and D.” Drug Dev. 4th ed. 1991).A. T. New York. 19. Minghetti et al. NY. Metevia.L.M. 4. II: Two Years’ Experience. Technol. p. 183.. Godbey. H. Bikaless. New York. 60–69 (1999). pp. “X-ray Examination of Polyisobutylene. “Transdermal Drug Delivery Devices with Amine-Resistant Silicone Adhesives. 4th ed.” J. 679–684 (1999). Elisabeth. P.L. Pharm. 1987). A. Part B. Y. 1905–1913 (1940). Mat. Polym. Becourt. Guyot and F. and Nalbuphine.G. 37. 34.H. and G. “Percutaneous Absorption Preparation. Santoro et al. and Polyether Polyurethanes. 33.” J. and G. Appl. 14 (10). 6.. 2000). “Permeation Enhancers Compatible with Transdermal Drug Delivery Systems. 1990). MN.P.” Int. 22. NY. 6. L. Pretzer and R. NY. “Lecithin Organogel as Matrix for Transdermal Transport of Drugs.939. “Butyl Rubber. 200. Sweet. 6. R. Barnhart. Becourt. 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