Polymers in Transdermal Drug Delivery Systems 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. 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, [email protected]. *To whom all correspondence should be addressed. 62 Pharmaceutical Technology MAY 2002 T 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 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. www.phar mtech.com 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. Microreservoir systems. This drug delivery system is a combination of reservoir and matrix-dispersion systems. 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, microscopic spheres of drug reservoirs. The thermodynamically unstable dispersion is stabilized quickly by immediately cross-linking the polymer in situ. Transdermal drug delivery technology represents one of the most rapidly advancing areas of novel drug delivery. This growth is catalyzed by developments in the field of polymer science. This article focuses on the polymeric materials used in transdermal delivery systems, with emphasis on the materials’ physicochemical and mechanical properties, and it seeks to guide formulators in the selection of polymers. Polymers are used in transdermal delivery systems in various ways, including as ● matrix formers ● rate-controlling membranes ● pressure-sensitive adhesives (PSAs) ● backing layers ● release liners. 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. They also should provide consistent, effective delivery of a drug throughout the product’s intended shelf life or delivery period and have generally-recognized-as-safe status. From an economic point of view, a delivery tool kit rather than a single delivery tool is most effective (2). Companies involved in the field of transdermal delivery concentrate on a few selective polymeric systems. For example, Alza Corporation (Mountain View, CA) mainly concentrates on ethylene vinyl acetate (EVA) copolymers or microporous polypropylene, and Searle Pharmacia (Barceloneta, PR) concentrates on silicone rubber (3). 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, engineering, and manufacture of drug products (see Table I). Table II is a comprehensive list of all the polymers used for various purposes in commercially available transdermal delivery systems. 64 Pharmaceutical Technology MAY 2002 Matrix formers Polymer selection and design must be considered when striving to meet the diverse criteria for the fabrication of effective transdermal delivery systems. The main challenge is in the design of a polymer matrix, followed by optimization of the drugloaded matrix not only in terms of release properties, but also with respect to its adhesion–cohesion balance, physicochemical properties, and compatibility and stability with other components of the system as well as with skin (4). A monolithic solid-state design often is preferred for passive transdermal delivery systems because of manufacturing considerations and cosmetic appeal. Although polymeric matrices are used for rate control, adhesion (e.g., a PSA), or encapsulation of a drug reservoir in transdermal delivery systems (reviewed in later sections of this article), discussion in this section is limited to polymers that have been used in the design of matrices with or without rate control. Cross-linked poly(ethylene glycol) (PEG) networks. Biocompatibility of PEGs makes them the polymers of choice for numerous biomedical applications. 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. These systems have been shown to release the solutes in a biphasic manner (5). Acrylic-acid matrices. Acrylic-acid matrices with plasticizers have been used to make drug–polymer matrix films for transdermal delivery systems. Some of the polymers that have been reported are Eudragit RL PM, Eudragit S-100, Eudragit RS PM, and Eudragit E-100 (Röhm America, Piscataway, NJ) (6). Eudragit NE-40D (a copolymer of ethyl acrylate and methyl methacrylate), a nonadhesive hydrophobic polymer, also has been used as a matrix former (7). The release rates of drugs from these matrix systems are more closely described by the square-root-of-time model. Ethyl cellulose (EC) and polyvinylpyrrolidone (PVP). EC and PVP matrix films with 30% dibutyl phthalate as a plasticizer have been fabricated to deliver diltiazem hydrochloride and indomethacin. The addition of hydrophilic components such as PVP to an insoluble film former such as ethyl cellulose tends to enhance its release-rate constants. This outcome can be attributed to the leaching of the soluble component, which leads to www.phar mtech.com Table I: Composition of transdermal delivery systems reported in the literature. (Continued on page 67) S.No. Polymer 1 Ethyl cellulose T-50 2 BIO PSA HighTack 7-4301 BIO PSA MediumTack 7-4201 5 6 7 Scotch Pak 1022 Scotch Pak 1006 HPMC Eudragit NE, Eudragit E100, Eudragit L100 MDX-4-421 (a silicone) Carboxy vinyl polymer Acrylic PSA emulsion 8 CoTran9722 Soybean lecithin (Epikuron 200) 9 Cariflex TR-1107 10 Acrylic adhesives 11 Polyisobutylene solutions (Vistanex LM-MH, Vistanex MML-100) Acrylic adhesives 3 4 12 Polyisobutylene solutions (Vistanex LM-MH, Vistanex MML-100) Silicone PSA Silicone oil EVA Polyisobutylene ScotchPak 1006 Manufacturer Sigma Dow Corning Pharmaceutical Technology MAY 2002 Type of System Matrix Adhesive-in-matrix system. For matrix and backing side layer. Backing Release liner Gel Matrix 44 45 Matrix Gel Drug in adhesive 46 47 48 Scopolamine, broxaterol Dihydro etorphine Gel matrices 13 Drug in adhesive 49 Ketoprofen Drug in adhesive 50 Drug in adhesive 51 Reservoir Membrane Adhesive Backing film 52 3M 3M Röhm, Germany Dow Corning Neoplast Co., Thailand 3M Lucas Meyer, Germany Shell Chemical Co., Japan National Starch and Chemical Co. Exxon Chemical Co. Hydrocortisone Coumarin Melilot dry extract L-Timolol maleate L-Dopa Nicotine National Starch Tacrine and Chemical Co. Exxon Chemical Co. Dow Corning Adhesive Research 3M the formation of pores and thus a decrease in the mean diffusion path length of drug molecules to release into the dissolution medium. The result is higher dissolution rates. Substances such as PVP act as antinucleating agents that retard the crystallization of a drug. 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). Hydroxypropyl methylcellulose (HPMC). HPMC, a hydrophilic swellable polymer widely used in oral controlled drug delivery, also has been explored as a matrix former in the design of patches of propranolol hydrochloride. HPMC has been shown to yield clear films because of the adequate solubility of the drug in the polymer. Matrices of HPMC without rate-controlling membranes exhibited a burst effect during dissolution testing because the polymer was hydrated easily and swelled, leading to the fast release of the drug (9). Organogels. Some nonionic surfactants such as sorbitane monostearate, lecithin, and Tween tend to associate into reverse micelles (10). These surfactants in an organic solvent, upon the 66 Drug Isosorbide dinitrate Trimegestone Arecoline Reference 41 42,43 addition of water, undergo association reorientation to form a gel. These organogels can be used as a matrix for the transdermal delivery of drugs with greater influx (11). 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. The transdermal flux of propranolol from this organogel increased 10-fold over a vehicle composed of petrolatum (12). Willimann et al. also described organogels obtained when small amounts of water were added to a solution of lecithin in organic solvents, used as matrices for the transdermal transport of drugs. The gels obtained in this manner are isotropic and thermoreversible (liquefy at temperatures 40 C) and can solubilize lipophilic, hydrophilic, and amphoteric substances, including enzymes. They are biocompatible and are stable for a long time. Organogels can cause slight disorganization of the skin, an outcome that is attributable to the organic solvent that is used to make the gel. Thus, organogels can enhance the permeation of various substances (13). Pluronic lecithin organogels also have been used as transdermal delivery systems because both www.phar mtech.com Table I continued: Composition of transdermal delivery systems reported in the literature. S.No. Polymer 13 2-Ethylhexyl acrylate and acrylic acid copolymer 14 15 16 17 18 19 20 HEMA, 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, Vistanex MML-100) 2-Ethylhexyl acrylate and acrylic acid copolymer 2-Ethylhexyl acrylate and acrylamide copolymer Polyisobutylene solutions (Vistanex LM-MH, Vistanex LM-80) Silicone PSA Plastoid E25L Polyvinyl alcohol (backing) HPMC (matrix) Ethylene vinyl acetate (rate-controlling membrane) H H H H C C C C H H x H O y C CH3 O Figure 2: Structure of polyethylene vinyl acetate. Manufacturer Mitsubishi Petrochem Co., Japan Wako Purechem. Ind., Japan Polyscience Drug PGE Type of System Drug-in-adhesive matrix Reference 53 Cytarabine, ara-ADA Carbopol 934 gel, reservoir 54 Matrix 9 Matrix Matrix 55 56 Drug in adhesive 53 Matrix Membranecontrolled reservoir system 7 57 Colorcon, UK Propranolol UCB, Belgium Aldrich, France Dow Corning Nitroglycerine Monsanto Fentanyl Dow Corning Exxon Chemical Co. Mitsubishi PetroAminopyrene, chem Co., Japan Ketoprofen, Wako Purechem. Lidocaine Ind., Japan Exxon Chemical Co. Dow Corning Röhm, Germany hydrophobic and hydrophilic drugs can be incorporated into them. Oil-soluble drugs are miscible with the lecithin phase, and water-soluble drugs are miscible with the aqueous phase. 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, controllable rate. The release rate– controlling membrane can be nonporous so that the drug is released by diffusing directly through the material, or the material may contain fluid-filled micropores — in which case the drug may additionally diffuse through the fluid, thus filling the pores. In the case of nonporous membranes, the rate of passage of drug molecules depends on the solubility of the drug in the membrane and the membrane thickness. Hence, the choice of Miconazole Propranolol membrane material must conform to the type of drug being used. By varying the composition and thickness of the membrane, the dosage rate per area of the device can be controlled. EVA. 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. For example, when ethylene is copolymerized with vinyl acetate, 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, the permeability increases. The copolymerization also results in an increase in polarity. Hence, 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. However, at vinyl acetate levels 60% by weight, the glass-transition temperature, Tg, of polymer increases from 25 C to 35 C. An increase in Tg reflects a decrease in the polymer-chain mobility and hence the solute diffusivity. 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, which has exhibited a maximum of limiting flux at 60% vinyl acetate content (14). Pharmaceutical Technology MAY 2002 67 Table II: Composition of marketed transdermal therapeutic systems. Product Type of System Androderm Reservoir (testosterone) TheraTech, Inc./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, alcohol, glyceryl monooleate methyl laurate gelled with acrylic acid copolymer Clonidine, mineral oil, polyisobutylene and colloidal silicon dioxide Estraderm (estradiol) Alza/CibaGeigy Habitrol (nicotine) Novartis Nitrodisc (nitroglycerin) Searle Nitro-Dur-I (nitroglycerin) Key Pharma Drug and alcohol gelled with hydroxypropyl cellulose Reservoir Drug in adhesive Monolithic microreservoir Drug in adhesive 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 Multilayered PIB adhesive film Pharmaceutical Technology MAY 2002 Hydrogel from copolymer of PVP– PVA, glycerol as plasticizer Nicotine in carrageenan gel Drug and alcohol gelled with hydroxypropyl cellulose Drug adsorbed on lactose, colloidal silica, and silicone oil Scopolamine, light mineral oil, and polyisobutylene 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, polyisobutylene, and colloidal silicon dioxide Polyester Polyethylene film Acrylate adhesive matrix Poly foil PIB Siliconized or fluoropolymercoated polyester film Silicone foil Polypropylene Acrylatevinylacetate copolymer and poly(butyl butane) Polyester– polyethylene composite EVA copolymer with 5% vinyl acetate Aluminized plastic backing film Foil– polyethylene combination Paper–foil combination Light mineral oil and PIB Aluminized and siliconized polyethylene terephthalate foil Siliconized polyethylene terephthalate Acrylate adhesive Aluminum foil Cross-linked silicone rubber Paper–foil combination Acrylic adhesive Paper– polyethylene foil pouch Low-density polyethylene Polyethylene Acrylate-based ring adhesive Polyester/EVA copolymer EVA copolymer PIB Flesh-colored polyfoil Siliconecoated polyester EVA copolymer Silicone adhesive Fluorocarbon polyester film Aluminized polyester film Microporous polypropylene EVA copolymer film and polyurethane film Mineral oil, polyisobutylene Siliconized polyester PIB, EVA copolymer Polyester www.phar mtech.com Acrylic-, polyisobutylene-, 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 (21,22). The selection Polyisocyanate of an adhesive is based on a numPolyol ber of factors, including the patch design and drug formulation. For reservoir systems with a peripheral 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, penetration enhancer, or the Urethane adhesive. In the case of reservoir bond systems that include a face adhesive, the diffusing drug must not Figure 3: Synthesis of polyurethane. affect the adhesive. Furthermore, the choice of adSilicone rubber. 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. These polymers skin compatibility. For matrix designs in which the adhesive, have an outstanding combination of biocompatibility, ease of the drug, and the penetration enhancers must be compounded, fabrication, and high permeability to many important classes the selection will be more complex. Once the basic criterium of drugs, particularly steroids. 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 selection will be based on the rate at which the drug rubber backbone, which leads to very low microscopic viscosi- and the penetration enhancer will diffuse through the adhesive. The physicochemical characteristics of a drug–adhesive comties within the polymer. Polyurethane. Polyurethane is the general term used for a poly- bination — such as solubility and partition coefficient and admer derived from condensation of polyisocyanates and poly- 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. In the case of adbonds (NHCOO) (see Figure 3). The polyurethanes syn- hesives that are not cross-linked, enhancers or other formulathesized from polyether polyol are termed polyether urethanes, 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. Although most polyurethanes presently used the adhesive. Significant loss of cohesive strength can result in are of the polyether type because of their high resistance to hy- an increase in tack, cold flow beyond the edge of the patch, and drolysis (15), 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). These ing removal. Another possible result of the interaction can be polyester or polyether urethanes are rubbery and relatively per- an increase in cohesive properties by either acting as extending meable. The hydrophilic–hydrophobic ratio in these polymers or reinforcing fillers or by inducing cross-linking (23). can be balanced to get the optimum permeability properties The general formula for a PSA includes an elastomeric poly(17). Polyurethane membranes are suitable especially for hy- mer, a tackifying resin, a necessary filler, various antioxidants, drophilic polar compounds having low permeability through stabilizers if required, and cross-linking agents. When formuhydrophobic polymers such as silicone rubber or EVA mem- lating a PSA, a balance of four properties must be taken into acbranes (18). count: tack, peel adhesion, skin adhesion, and cohesive strength. PSAs bind to the skin after a brief contact known as tack. The PSAs term tack is used to quantify the sticky feel of the material. This A PSA is a material that adheres with no more than applied fin- property often is perceived by the user when the patch is applied ger pressure, is aggressively and permanently tacky, exerts a strong to the skin and quickly pulled off. It is not necessarily related to holding force, 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). Adhesion involves a liquid-like adhesion to the skin. Adhesion refers to the force required to reflow resulting in wetting of the skin surface upon the applica- move the adhesive from a substrate once the bond has reached tion of pressure, and when pressure is removed, the adhesive sets equilibrium. Some PSAs may have low tack but subsequently in that state. For an adhesive bond to have measurable strength, may develop a high degree of adhesion to the skin. In contrast, elastic energy must be stored during the bond-breaking process. many skin adhesives have a relatively high degree of tack and Therefore, pressure-sensitive adhesion is a characteristic of a only modest skin-adhesion value (24). visco-elastic material. The balance of viscous flow and the amount Polyisobutylene (PIB). Isobutylene polymerizes in a regular of stored elastic energy determine the usefulness of a PSA ma- head-to-tail sequence by low-temperature cationic polymeriterial (20). zation to produce a polymer having no asymmetric carbons 70 Pharmaceutical Technology MAY 2002 www.phar mtech.com CH3 CH2 CH3 BF3 C CH2 CH3 C n CH3 Isobutylene Polyisobutylene Figure 4: Polymerization of isobutylene. H H2C C COR O Acrylic ester H H C C H COOR n Polyacrylate Figure 5: Polymerization of acrylic ester. (see Figure 4). In its unstrained state, the polymer is in an amorphous state (25), and the Tg of the polymer is 70 C (26). The physical properties of the polymer change gradually with increasing molecular weight. Low molecular weight polymers are viscous liquids. With increasing molecular weight, the liquids become more viscous, then change to balsam-like sticky masses and finally form elastomeric solids. PIB PSAs usually comprise a mixture of high molecular weight and low molecular weight fractions. High molecular weight PIB has a viscosity average molecular weight between 450,000 and 2,100,000, and low molecular weight PIB has an average molecular weight between 1000 and 450,000. PIB has the chemical properties of a saturated hydrocarbon. It is readily soluble in nonpolar liquids. Cyclohexane is an excellent solvent, benzene is a moderate solvent, and dioxane is a nonsolvent for PIB polymers (27). Un-cross-linked polymers exhibit a high degree of tack or self-adhesion. PIB polymers have a very low fractional free volume of 0.026 as compared with 0.071 for poly(dimethylsiloxane), for example. This characteristic together with sluggish chain motility results in a low diffusion coefficient. However, the final properties of the polymer blend are determined by compounding and subsequent vulcanization or cross-linking. Various fillers, processing aids, plasticizers, tackifiers, cure systems, and antidegradants are incorporated into the final blend. Of all these compounding ingredients, fillers most significantly influence stress–strain and dynamic properties. Carbon black, the most frequently used reinforcing filler by virtue of its high surface area, interacts with the surface of polymer chains and alters chain dynamics, thus enhancing tensile properties and abrasion resistance. Other fillers that are used are talc and calcined clay. Colloidal silicon dioxide is used as a filler in clonidine patches (Catapres-TTS). Nonreinforcing fillers such as calcium carbonate and titanium dioxide are added to reduce viscosity and cost. Fillers also are used to enhance the drug re72 Pharmaceutical Technology MAY 2002 lease from the matrix. Titanium dioxide has been used in the EVA matrix to reduce the amount of naloxone contained in the depleted systems (28), and PVP has been used to enhance the release of formoterol from acrylic PSAs (29). Petroleum-based oils, butyl polybutenes, paraffin waxes, and low molecular weight polyethylene can be used as plasticizers. Alkyl adipates and sebacates also are used to reduce the Tg value and improve the low-temperature properties. Various resins with a Tg value greater than that of the elastomer act as tackifiers. Polyacrylates. Acrylic esters are represented by the general formula CH2CHCOOR. The nature of the R group determines the properties of each ester and the polymer it forms (see Figure 5). Polymers of this class are amorphous and are distinguished by their water-clear color in solution and stability toward aging. As is typical of polymer systems, the mechanical properties of acrylic polymers improve as the molecular weight increases. However, beyond a critical molecular weight, which is 1 103 to 2 103 for amorphous polymers, the improvement is slight and levels off asymptotically (30). The Tg value of a copolymer can be altered by the copolymerization of two or more polymers. Most acrylic polymers have a very low Tg value (see Table III); therefore, in copolymer they tend to soften and flexibilize the overall composition. 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 W2 Tg Tg 1 2 Plasticizers also can be used to lower the Tg. However, unlike incorporated acrylic monomers, they can be lost through volatilization or extraction. Acrylic polymers are highly stable compounds. Unless they are subjected to extreme conditions, acrylic polymers are durable and degrade slowly. 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). Acrylic polymers and copolymers have a greater resistance to both acidic and alkaline hydrolysis than do poly(vinyl acetate) and vinyl acetate copolymers. In extreme conditions of acidity or alkalinity, acrylic ester polymers can be made to hydrolyze to poly(acrylic acid) or to an acidic salt and the corresponding alcohol. Acrylic polymers are insensitive to normal UV degradation because the primary UV absorption of acrylics occurs below the solar spectrum. A UV absorber such as o-hydroxybenzophenone can be incorporated to further enhance the UV stability (32). Silicones. Silicone PSAs comprise polymer or gum and a tackifying resin. Medical-grade silicone adhesives contain a lowviscosity dimethylsiloxane polymer (12 103 cP to 15 103 cP) (24), which has a terminal silanol group. 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). The adhesive is prepared by crosslinking the reactants in solution by a condensation reaction www.phar mtech.com Table III: Glass transition temperatues of acrylic polymers (39,40). CH3 H3C Si CH3 H O Si O H HO Si O CH3 O H3C CH3 CH3 O Si CH3 n Si CH3 Silicate resin Condensation CH3 Si CH3 O H O Si Si CH3 CH3 O O H3C Si O CH3 Si CH3 CH3 O n Si OH CH3 CH3 n CH3 Silicone PSA Figure 6: Synthesis of a silicone pressure-sensitive adhesive. between silanol groups on the linear poly(dimethylsiloxane) polymer and silicate resin to form siloxane bonds (SiOSi) (see Figure 6). Unlike acrylic-, rubber-, and PIB-based adhesives, medical-grade silicone adhesives do not contain organic tackifiers, stabilizers, antioxidants, plasticizers, catalysts, or other potentially toxic extractables. These additives are not required because silicone PSAs are stable throughout a wide range of temperatures (73 to 250 C). The end-use properties of silicone-based PSAs such as tack, peel adhesion, skin adhesion, and cohesion can be modified or customized by varying the resin–polymer ratio, the silanol functionality, and the level and type of cross-linking agent. 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. The shear-holding power often depends on the mode of cross-linking. Although the silicone group of adhesives has an outstanding combination of biocompatibility and ease of fabrication for hydrophilic drugs, the solubility, permeability, and releasing properties are poor. Some of the silicone PSAs contain a significant degree of free silanol–functional groups. Certain amino-functional drugs can act as catalysts to cause further cross-links between these silanol groups. This unwanted reaction can be reduced, thus enhancing a PSA’s chemical stability, by end capping the silanol groups with methyl groups by means of a trimethyl silylation 74 Pharmaceutical Technology O n Si CH3 Polydimethylsiloxane CH3 H3C CH3 MAY 2002 OH 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 reaction (33). Some of the trace components in acrylic-adhesive blends reacted with a variety of drugs and caused coloring, which deepens with time. This problem was overcome when 2-mercaptobenzimidazole and/or propyl gallate were incorporated into the adhesive composition (34). Hot-melt PSAs (HMPSAs). Typical PSAs include a volatile organic solvent for reducing the viscosity of the composition to a coatable room-temperature viscosity. After the product is coated, the organic solvent is removed by evaporation. When they are heated, HMPSAs melt to a viscosity suitable for coating, but when they are cooled they generally stay in a flowless state. 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, which often results with solvent-containing PSAs. Hot-melt adhesives are based on thermoplastic polymers that may be compounded or uncompounded (see Table IV). Of these polymers, EVA copolymers are most widely used. Polybutenes, phthalates, and tricresyl phosphate often are added as plasticizers to improve mechanical shock resistance and thermal properties. Antioxidants such as hindered phenols are added to prevent oxidation of ethylene-based hot-melt adhesives. Fillers opacify or modify an adhesive’s flow characteristics and reduce the cost. 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. Moisture-curing urethanes have been attempted as cross-linking agents to prevent creep under the load of these thermoplastic materials. Silicone-based adhesives also are amenable to hot-melt www.phar mtech.com Table IV: Thermoplastic hot-melt pressure-sensitive adhesives. Compounded Ethylene vinyl acetate copolymers Paraffin waxes Low-density polypropylene Styrene-butadiene copolymers Ethylene-ethacrylate copolymers Uncompounded Polyesters Polyamides Polyurethanes coating. US Patent No. 5,352,722 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. Thus the coatability of a PSA without solvents is chemical resistance often may lead to stiffness and high occlusivity to moisture vapor and air, causing patches to lift and possibly irritate the skin during long-term wear. The most comfortable backing may be the one that exhibits the lowest modulus or high flexibility, good oxygen transmission, and a high moisture-vapor transmission rate (see Table V) (36). In a novel modification to the conventional design, a patch was fabricated in which the backing itself acted as a reservoir for the drug. 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. This modification enabled the backing itself to act as a storage location for the medication-containing reservoir (37). Table V: Characteristics of some commercialized backing materials.* Product CoTran 9701 CoTran 9702, CoTran 9706 CoTran 9720, 9722 Foam Tape 9772L Foam Tape 9773 Scotchpak 1006 Scotchpak 1109 Scotchpak 9723 Scotchpak 9732, 9733 Polymer Polyurethane film EVA Oxygen Transmission MVTR (cm3/m2/24 h) (g/m2/24 h) 700 PE 4.6 52.8 26.4 9.4 7.9 450 — 0.3 4.6 0.3 2950 3570 PVC foam Polyolefin foam PE, Al vapor coat, PET, EVA PE, Al vapor coat, PET PE, PET laminate PET, EVA laminate High–PET side 80 80 15.5 17 High–PET side High–PET side Backing layer When designing a backing layer, the developer must give chemical resistance of the material foremost importance. 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, drug, or penetration enhancer through the layer. However, an overemphasis on the MAY 2002 High 12 improved. 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. The adhesive was claimed to possess a reduced propensity to cold flow. Pharmaceutical Technology Medium Medium Medium High — — High–PET side 100 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.3M.com 76 Enhancer Resistance Low 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. 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). However, because the liner is in intimate contact with the delivery system, it should comply with specific requirements regarding the chemical inertness and permeation to the drug, penetration enhancer, and water. 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Controlled Release 6, 99–106 (1987). 55. P.R. Keshary, Y.C. Huang, and Y.W. Chien, “Mechanism of Transdermal Controlled Nitroglycerin Administration III: Control of SkinPermeation Rate and Optimization,” Drug Dev. Ind. Pharm. 11 (6,7), 1213–1253 (1985). 56. S.D. Roy et al., “Controlled Transdermal Delivery of Fentanyl: Characterizations of Pressure-Sensitive Adhesives for Matrix Patch Design,” J. Pharm. Sci. 85 (5), 491–495 (1996). 57. R. Krishna and J.K. Pandit, “Transdermal Delivery of Propranolol,” Drug Dev. Ind. Pharm. 20, 2459–2465 (1994). PT FYI Inhalation Aerosol Technology Workshop The University of Maryland Department of Pharmaceutical Sciences will present its 12th annual Inhalation Aerosol Technology Workshop 8–11 July 2002 in Baltimore,Maryland. The workshop consists of a three-day course and an optional laboratory session and will focus on the theoretical basis and experimental techniques of the conception,design,preparation,and evaluation of modern inhalation devices. 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