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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.
with emphasis on the materials’ physicochemical and mechanical properties. 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.com Pharmaceutical Technology MAY 2002 . adhesion (e. engineering. Acrylic-acid matrices with plasticizers have been used to make drug–polymer matrix films for transdermal delivery systems. physicochemical properties. 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. Cross-linked poly(ethylene glycol) (PEG) networks. This drug delivery system is a combination of reservoir and matrix-dispersion systems. They also should provide consistent. a delivery tool kit rather than a single delivery tool is most effective (2).phar mtech. Microreservoir systems. The release rates of drugs from these matrix systems are more closely described by the square-root-of-time model. Biocompatibility of PEGs makes them the polymers of choice for numerous biomedical applications. or encapsulation of a drug reservoir in transdermal delivery systems (reviewed in later sections of this article). Eudragit RS PM. Transdermal drug delivery technology represents one of the most rapidly advancing areas of novel drug delivery. Polymers are used in transdermal delivery systems in various ways. 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. A monolithic solid-state design often is preferred for passive transdermal delivery systems because of manufacturing considerations and cosmetic appeal. including as ● matrix formers ● rate-controlling membranes ● pressure-sensitive adhesives (PSAs) ● backing layers ● release liners. but also with respect to its adhesion–cohesion balance. This growth is catalyzed by developments in the field of polymer science. and manufacture of drug products (see Table I). Alza Corporation (Mountain View. Companies involved in the field of transdermal delivery concentrate on a few selective polymeric systems. followed by optimization of the drugloaded matrix not only in terms of release properties. These systems have been shown to release the solutes in a biphasic manner (5). EC and PVP matrix films with 30% dibutyl phthalate as a plasticizer have been fabricated to deliver diltiazem hydrochloride and indomethacin. microscopic spheres of drug reservoirs. Eudragit NE-40D (a copolymer of ethyl acrylate and methyl methacrylate). Some of the polymers that have been reported are Eudragit RL PM. a PSA). Ethyl cellulose (EC) and polyvinylpyrrolidone (PVP). Acrylic-acid matrices. Table II is a comprehensive list of all the polymers used for various purposes in commercially available transdermal delivery systems. discussion in this section is limited to polymers that have been used in the design of matrices with or without rate control. Although polymeric matrices are used for rate control. The addition of hydrophilic components such as PVP to an insoluble film former such as ethyl cellulose tends to enhance its release-rate constants. For example. 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. which leads to www. This outcome can be attributed to the leaching of the soluble component. NJ) (6). and Eudragit E-100 (Röhm America.g. Piscataway. The main challenge is in the design of a polymer matrix. and Searle Pharmacia (Barceloneta. CA) mainly concentrates on ethylene vinyl acetate (EVA) copolymers or microporous polypropylene.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. and compatibility and stability with other components of the system as well as with skin (4). This article focuses on the polymeric materials used in transdermal delivery systems. 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. Eudragit S-100. 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. The thermodynamically unstable dispersion is stabilized quickly by immediately cross-linking the polymer in situ. PR) concentrates on silicone rubber (3). a nonadhesive hydrophobic polymer.. also has been used as a matrix former (7). and it seeks to guide formulators in the selection of polymers.
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. organogels can enhance the permeation of various substances (13). and amphoteric substances. hydrophilic. Germany Shell Chemical Co. These organogels can be used as a matrix for the transdermal delivery of drugs with greater influx (11). Vistanex MML-100) Acrylic adhesives Polyisobutylene solutions (Vistanex LM-MH. Pluronic lecithin organogels also have been used as transdermal delivery systems because both www. 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.. also has been explored as a matrix former in the design of patches of propranolol hydrochloride. Japan National Starch and Chemical Co. Thailand 3M Lucas Meyer. Exxon Chemical Co. Matrices of HPMC without rate-controlling membranes exhibited a burst effect during dissolution testing because the polymer was hydrated easily and swelled. The gels obtained in this manner are isotropic and thermoreversible (liquefy at temperatures 40 C) and can solubilize lipophilic. Exxon Chemical Co. Willimann et al.43 3M 3M Röhm. The transdermal flux of propranolol from this organogel increased 10-fold over a vehicle composed of petrolatum (12). including enzymes. broxaterol Dihydro etorphine Ketoprofen Gel matrices Drug in adhesive Drug in adhesive 13 49 50 11 National Starch Tacrine and Chemical Co. These surfactants in an organic solvent. HPMC. Organogels. For matrix and backing side layer.phar mtech. Organogels can cause slight disorganization of the skin.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. undergo association reorientation to form a gel. an outcome that is attributable to the organic solvent that is used to make the gel. 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. a hydrophilic swellable polymer widely used in oral controlled drug delivery. Eudragit E100.com Pharmaceutical Technology MAY 2002 . 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. used as matrices for the transdermal transport of drugs. HPMC has been shown to yield clear films because of the adequate solubility of the drug in the polymer. (Continued on page 67) S. Thus. Hydroxypropyl methylcellulose (HPMC). 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). 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. also described organogels obtained when small amounts of water were added to a solution of lecithin in organic solvents. upon the 66 addition of water. Backing Release liner Gel Matrix Matrix Gel Drug in adhesive Reference 41 42. They are biocompatible and are stable for a long time. Substances such as PVP act as antinucleating agents that retard the crystallization of a drug. lecithin.No. The result is higher dissolution rates. and Tween tend to associate into reverse micelles (10). leading to the fast release of the drug (9). Some nonionic surfactants such as sorbitane monostearate. Germany Dow Corning Neoplast Co..
which has exhibited a maximum of limiting flux at 60% vinyl acetate content (14). Pharmaceutical Technology MAY 2002 67 . which is not isomorphous with ethylene. Wako Purechem. UK Propranolol UCB. when ethylene is copolymerized with vinyl acetate. Oil-soluble drugs are miscible with the lecithin phase. and water-soluble drugs are miscible with the aqueous phase. Polymer 13 2-Ethylhexyl acrylate and acrylic acid copolymer 14 HEMA. Japan Polyscience Drug PGE Type of System Drug-in-adhesive matrix Reference 53 Cytarabine. the choice of membrane material must conform to the type of drug being used.Table I continued: Composition of transdermal delivery systems reported in the literature. controllable rate. the permeability increases. thus filling the pores. By varying the composition and thickness of the membrane. For example. 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. 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. An increase in Tg reflects a decrease in the polymer-chain mobility and hence the solute diffusivity. Drug in adhesive 53 19 20 Dow Corning Röhm. of polymer increases from 25 C to 35 C. or the material may contain fluid-filled micropores — in which case the drug may additionally diffuse through the fluid. France Dow Corning Nitroglycerine Monsanto Fentanyl Dow Corning Exxon Chemical Co. The copolymerization also results in an increase in polarity.. Hence. S. the dosage rate per area of the device can be controlled. In the case of nonporous membranes. Japan Wako Purechem. 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. 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. ara-ADA Carbopol 934 gel. chem Co. EVA. 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.No. the rate of passage of drug molecules depends on the solubility of the drug in the membrane and the membrane thickness. Tg. at vinyl acetate levels 60% by weight... the glass-transition temperature. Vistanex LM-80) Silicone PSA Plastoid E25L Polyvinyl alcohol (backing) HPMC (matrix) Ethylene vinyl acetate (rate-controlling membrane) Manufacturer Mitsubishi Petrochem Co. Japan Exxon Chemical Co. hydrophobic and hydrophilic drugs can be incorporated into them. 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. the degree of crystallinity and the crystalline melting point decreases and amorphousness increases (see Figure 2). Belgium Aldrich. Ind. Lidocaine Ind. Japan Ketoprofen. 9 Matrix Matrix 55 56 18 Mitsubishi PetroAminopyrene. Hence. As the solutes permeate easily through the amorphous regions. However. reservoir Matrix 54 15 16 17 Colorcon. The release rate– controlling membrane can be nonporous so that the drug is released by diffusing directly through the material..
com . Product Type of System Androderm Reservoir (testosterone) TheraTech. glycerol as plasticizer Nicotine in carrageenan gel Drug and alcohol gelled with hydroxypropyl cellulose Drug adsorbed on lactose. light mineral oil.Table II: Composition of marketed transdermal therapeutic systems. 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. alcohol. EVA copolymer Polyester Pharmaceutical Technology MAY 2002 www. polyisobutylene Siliconized polyester EVA copolymer film and polyurethane film PIB. Inc. 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. glyceryl monooleate methyl laurate gelled with acrylic acid copolymer Clonidine. 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./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. mineral oil. polyisobutylene.phar mtech. and silicone oil Scopolamine. colloidal silica.
the choice of adSilicone rubber.move the adhesive from a substrate once the bond has reached tion of pressure. The hydrophilic–hydrophobic ratio in these polymers or reinforcing fillers or by inducing cross-linking (23).lating a PSA. and drolysis (15).com . cold flow beyond the edge of the patch. skin adhesion. many skin adhesives have a relatively high degree of tack and Therefore. The physicochemical characteristics of a drug–adhesive comties within the polymer. Polyurethane membranes are suitable especially for hy.an increase in cohesive properties by either acting as extending meable. a necessary filler. Isobutylene polymerizes in a regular of stored elastic energy determine the usefulness of a PSA ma. and cross-linking agents. visco-elastic material. PSAs bind to the skin after a brief contact known as tack. and high permeability to many important classes the selection will be more complex. which leads to very low microscopic viscosi. 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). Significant loss of cohesive strength can result in are of the polyether type because of their high resistance to hy. drophilic polar compounds having low permeability through stabilizers if required. 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. Polyurethane. affect the adhesive. the selection will be based on the rate at which the drug rubber backbone. When formuhydrophobic polymers such as silicone rubber or EVA mem. In the case of adbonds ( NHCOO ) (see Figure 3). This A PSA is a material that adheres with no more than applied fin. Furthermore.bination — such as solubility and partition coefficient and admer derived from condensation of polyisocyanates and poly. can be balanced to get the optimum permeability properties The general formula for a PSA includes an elastomeric poly(17). enhancers or other formulathesized from polyether polyol are termed polyether urethanes. Although most polyurethanes presently used the adhesive. a balance of four properties must be taken into acbranes (18). In contrast.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.head-to-tail sequence by low-temperature cationic polymeriterial (20). Once the basic criterium of drugs. The PSAs term tack is used to quantify the sticky feel of the material. penetration enhancer.mer.an increase in tack. pressure-sensitive adhesion is a characteristic of a only modest skin-adhesion value (24). and cohesive strength. the diffusing drug must not Figure 3: Synthesis of polyurethane. The selection Polyisocyanate of an adhesive is based on a numPolyol ber of factors. exerts a strong to the skin and quickly pulled off.22). These polymers skin compatibility. Polyurethane is the general term used for a poly. particularly steroids. For an adhesive bond to have measurable strength. Adhesion refers to the force required to reflow resulting in wetting of the skin surface upon the applica. These ing removal. For matrix designs in which the adhesive. fabrication. is aggressively and permanently tacky. polyisobutylene-. ease of the drug. 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. including the patch design and drug formulation. various antioxidants. 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. and when pressure is removed. The polyurethanes syn. may develop a high degree of adhesion to the skin. The high permeability of these of chemical compatibility between all the ingredients is estabmaterials is attributed to the free rotation around the silicone lished. Some PSAs may have low tack but subsequently in that state. or the Urethane adhesive.phar mtech. peel adhesion. elastic energy must be stored during the bond-breaking process. the adhesive sets equilibrium.and the penetration enhancer will diffuse through the adhesive. and the penetration enhancers must be compounded.hesives that are not cross-linked. It is not necessarily related to holding force. zation to produce a polymer having no asymmetric carbons 70 Pharmaceutical Technology MAY 2002 www. 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). a tackifying resin. Adhesion involves a liquid-like adhesion to the skin.Acrylic-. The balance of viscous flow and the amount Polyisobutylene (PIB). count: tack. For reservoir systems with a peripheral adhesive.property often is perceived by the user when the patch is applied ger pressure. In the case of reservoir bond systems that include a face adhesive. have an outstanding combination of biocompatibility. Another possible result of the interaction can be polyester or polyether urethanes are rubbery and relatively per. 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.
Alkyl adipates and sebacates also are used to reduce the Tg value and improve the low-temperature properties. processing aids.026 as compared with 0. the liquids become more viscous.100. tackifiers.071 for poly(dimethylsiloxane). Acrylic polymers are highly stable compounds. plasticizers. 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). Un-cross-linked polymers exhibit a high degree of tack or self-adhesion. Cyclohexane is an excellent solvent. In its unstrained state. PIB PSAs usually comprise a mixture of high molecular weight and low molecular weight fractions. Colloidal silicon dioxide is used as a filler in clonidine patches (Catapres-TTS). butyl polybutenes. 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. PIB has the chemical properties of a saturated hydrocarbon.CH3 CH2 C CH3 Isobutylene BF3 CH2 CH3 C CH3 Polyisobutylene n Figure 4: Polymerization of isobutylene. It is readily soluble in nonpolar liquids. Unless they are subjected to extreme conditions. unlike incorporated acrylic monomers. This characteristic together with sluggish chain motility results in a low diffusion coefficient. acrylic ester polymers can be made to hydrolyze to poly(acrylic acid) or to an acidic salt and the corresponding alcohol. With increasing molecular weight. However. Acrylic esters are represented by the general formula CH2 CH COOR. the polymer is in an amorphous state (25). they can be lost through volatilization or extraction. interacts with the surface of polymer chains and alters chain dynamics. Most acrylic polymers have a very low Tg value (see Table III). the mechanical properties of acrylic polymers improve as the molecular weight increases. H H2C C COR O Acrylic ester H C H H C COOR n Polyacrylate Figure 5: Polymerization of acrylic ester. which is 1 103 to 2 103 for amorphous polymers. Petroleum-based oils. Other fillers that are used are talc and calcined clay. for example. Fillers also are used to enhance the drug re72 lease from the matrix. However. and the Tg of the polymer is 70 C (26). Carbon black. However. (see Figure 4). cure systems. Various fillers. Medical-grade silicone adhesives contain a lowviscosity dimethylsiloxane polymer (12 103 cP to 15 103 cP) (24). Polyacrylates. paraffin waxes. Various resins with a Tg value greater than that of the elastomer act as tackifiers. the final properties of the polymer blend are determined by compounding and subsequent vulcanization or cross-linking. which has a terminal silanol group. The Tg value of a copolymer can be altered by the copolymerization of two or more polymers. beyond a critical molecular weight. 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). Titanium dioxide has been used in the EVA matrix to reduce the amount of naloxone contained in the depleted systems (28). therefore. and antidegradants are incorporated into the final blend. Of all these compounding ingredients. and PVP has been used to enhance the release of formoterol from acrylic PSAs (29). Silicone PSAs comprise polymer or gum and a tackifying resin. In extreme conditions of acidity or alkalinity. PIB polymers have a very low fractional free volume of 0. and low molecular weight polyethylene can be used as plasticizers. fillers most significantly influence stress–strain and dynamic properties. Acrylic polymers are insensitive to normal UV degradation because the primary UV absorption of acrylics occurs below the solar spectrum. and low molecular weight PIB has an average molecular weight between 1000 and 450. The physical properties of the polymer change gradually with increasing molecular weight. High molecular weight PIB has a viscosity average molecular weight between 450.phar mtech. A UV absorber such as o-hydroxybenzophenone can be incorporated to further enhance the UV stability (32). in copolymer they tend to soften and flexibilize the overall composition. and dioxane is a nonsolvent for PIB polymers (27). thus enhancing tensile properties and abrasion resistance. Nonreinforcing fillers such as calcium carbonate and titanium dioxide are added to reduce viscosity and cost. the most frequently used reinforcing filler by virtue of its high surface area. Low molecular weight polymers are viscous liquids. the improvement is slight and levels off asymptotically (30).000. As is typical of polymer systems.000.000 and 2. 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. then change to balsam-like sticky masses and finally form elastomeric solids. The adhesive is prepared by crosslinking the reactants in solution by a condensation reaction www.com Pharmaceutical Technology MAY 2002 . benzene is a moderate solvent. acrylic polymers are durable and degrade slowly. Acrylic polymers and copolymers have a greater resistance to both acidic and alkaline hydrolysis than do poly(vinyl acetate) and vinyl acetate copolymers. Silicones.
com Pharmaceutical Technology MAY 2002 . phthalates. HMPSAs melt to a viscosity suitable for coating. the solubility. Typical PSAs include a volatile organic solvent for reducing the viscosity of the composition to a coatable room-temperature viscosity. Some of the silicone PSAs contain a significant degree of free silanol–functional groups. but when they are cooled they generally stay in a flowless state. stabilizers. 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. These additives are not required because silicone PSAs are stable throughout a wide range of temperatures ( 73 to 250 C). which often results with solvent-containing PSAs.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. skin adhesion.40). peel adhesion. Antioxidants such as hindered phenols are added to prevent oxidation of ethylene-based hot-melt adhesives. the organic solvent is removed by evaporation. This problem was overcome when 2-mercaptobenzimidazole and/or propyl gallate were incorporated into the adhesive composition (34). plasticizers.phar mtech. and the level and type of cross-linking agent. or other potentially toxic extractables. and PIB-based adhesives. Some of the trace components in acrylic-adhesive blends reacted with a variety of drugs and caused coloring. Polybutenes. Certain amino-functional drugs can act as catalysts to cause further cross-links between these silanol groups. thus enhancing a PSA’s chemical stability. the silanol functionality. and tricresyl phosphate often are added as plasticizers to improve mechanical shock resistance and thermal properties. The shear-holding power often depends on the mode of cross-linking. medical-grade silicone adhesives do not contain organic tackifiers. catalysts. which deepens with time. 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. Hot-melt adhesives are based on thermoplastic polymers that may be compounded or uncompounded (see Table IV). by end capping the silanol groups with methyl groups by means of a trimethyl silylation 74 reaction (33). and releasing properties are poor. Unlike acrylic-. antioxidants. Of these polymers. 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. Silicone-based adhesives also are amenable to hot-melt www. Fillers opacify or modify an adhesive’s flow characteristics and reduce the cost. 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. rubber-. permeability. EVA copolymers are most widely used. and cohesion can be modified or customized by varying the resin–polymer ratio. The end-use properties of silicone-based PSAs such as tack. between silanol groups on the linear poly(dimethylsiloxane) polymer and silicate resin to form siloxane bonds (Si O Si) (see Figure 6). Although the silicone group of adhesives has an outstanding combination of biocompatibility and ease of fabrication for hydrophilic drugs. The peel strength usually increases with the amount of tackifying resin. Moisture-curing urethanes have been attempted as cross-linking agents to prevent creep under the load of these thermoplastic materials. This unwanted reaction can be reduced. After the product is coated. When they are heated. Hot-melt PSAs (HMPSAs).
the developer must give chemical resistance of the material foremost importance. and water. “Optimal Process Design for the Manufacturing of Transdermal Drug Delivery Systems.3 12 15.6 4. because the liner is in intimate contact with the delivery system.R. Heller. 9733 Polymer Polyurethane film EVA PE PVC foam Polyolefin foam PE. PET. Chien.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. Davis and L. PET PE.9 450 — 0.com Backing layer When designing a backing layer. US Patent No. EVA laminate Oxygen Transmission MVTR (cm3/m2/24 h) (g/m2/24 h) 700 52. 523–552.H. 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.Table IV: Thermoplastic hot-melt pressure-sensitive adhesives. (Marcel Dekker. Compounded Ethylene vinyl acetate copolymers Paraffin waxes Low-density polypropylene Styrene-butadiene copolymers Ethylene-ethacrylate copolymers Uncompounded Polyesters Polyamides Polyurethanes coating..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. 173–181 (2000). Baker and J. Thus the coatability of a PSA without solvents is chemical resistance often may lead to stiffness and high occlusivity to moisture vapor and air. it should comply with specific requirements regarding the chemical inertness and permeation to the drug. 3. penetration enhancer.3M. pp. 1989). “Drug Delivery Systems for Challenging Molecules. Vinod Nair is supported by a senior research fellowship from the Department of Science and Technology. The adhesive was claimed to possess a reduced propensity to cold flow. H. Al vapor coat. J. good oxygen transmission. NY. CoTran 9706 CoTran 9720. “Material Selection for Transdermal Delivery Systems. J. Eds. the force required to remove the liner will be unacceptably high (23).com Acknowledgments The authors thank Mr. References 1. However. Hadgraft and R. New York.L. The most comfortable backing may be the one that exhibits the lowest modulus or high flexibility. In case cross-linking is induced between the adhesive and the release liner.* Product CoTran 9701 CoTran 9702. 2950 3570 4. 9722 Foam Tape 9772L Foam Tape 9773 Scotchpak 1006 Scotchpak 1109 Scotchpak 9723 Scotchpak 9732. S. 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. improved.-M.3 0. a patch was fabricated in which the backing itself acted as a reservoir for the drug. St. India.4 7. Sunil T. Y. causing patches to lift and possibly irritate the skin during long-term wear. R. an overemphasis on the 76 Pharmaceutical Technology MAY 2002 . 3M. Pharm. 2d ed. 1–8 (1998).” in Controlled Drug Delivery: Fundamentals and Applications. NY. Robinson and V.W.. Inc.. (Marcel Dekker. Wolff. New Delhi. Illum. 4. Table V: Characteristics of some commercialized backing materials. PET laminate PET. or penetration enhancer through the layer. Lee. New York. and a high moisture-vapor transmission rate (see Table V) (36).4 9. 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.H.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.phar mtech. EVA PE.W. Guys. 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). Paul. However.S. drug.8 26. 3M Drug Delivery Systems. for example.” in Transdermal Drug Delivery: Developmental Issues and Research Initiatives.” PSTT 3 (5). In a novel modification to the conventional design. www.” Int. Narisetty for his valuable suggestions in the preparation of this article. “Transdermal Therapeutic Systems. MN). pp. Eds. J. Al vapor coat. manufactures release liners made of fluoro polymers (Scotchpak 1022 and Scotchpak 9742. 293–311. 176. 5.352. 1987). 2. Inc. This modification enabled the backing itself to act as a storage location for the medication-containing reservoir (37).
Microencapsulation 11 (4). MN.” in Kirk-Othmer Encyclopedia of Chemical Technology.H. Pharm.P. “Adhesives. Walde et al. 68 (1). P. Burgess. “Butyl Rubber. 14.H. 934–955.. Ramarao and P. “Cross-Linked Poly(ethylene glycol) Networks as Reservoirs for Protein Delivery. 1905–1913 (1940). P.761 (assigned to Nitto Denko Corporation [Osaka.T.. Fawaz. W.com 78 Pharmaceutical Technology Circle/eINFO 53 MAY 2002 . Maillard-Salin. MN. New York. D. (Wiley-Interscience. Howe-Grants. Metevia. and J.425 (assigned to Saitama Daiichi Seiyaku Kabushiki Kaisha [Kasukabe. pp. in Physico-Chemical Principles of Pharmacy (Chapman & Hall. Couarraze. “Permeation Enhancers Compatible with Transdermal Drug Delivery Systems. 431–438 (1994). 4. New York. 373 (1971).” in American Association of Pharmaceutical Scientists. 1991). Inc. pp. “Microbial Degradation of Polyurethane. pp. Ed. Polyester Polyurethanes. 11. “Design and In Vitro Evaluation of Adhesive Matrix for Transdermal Delivery of Propranolol. “Organogel-Based System for Transdermal Delivery of Propranolol. 134–140 (1999). Res.A. 20 (1979). 833–862. Willimann et al. (Interscience Publishers. D. 81 (9). P. Rubber Chem.” US Patent No.T. J. Diwan. “Acrylic Ester Polymers. 1–6 April. Res. Pfister. Naltrexone. “Percutaneous Absorption Preparation. 31. 6. Sweet. Minneapolis. (Wiley-Interscience. and G. pp. Florence and D. T. D. R. 32. pp. 459–466 (1996). 42.995 (assigned to Alza Corporation [Mountain View.W. Becourt.“Segmented Polyurethane: A Polyether Polymer. Part II: System Design Considerations. 17. Ed.” in International Symposium on Controlled Release of Bioactive Materials. D. 23 (10). J.” Pharm. 1965). 939–944 (1997). (Wiley-Interscience.” U.” J. 679–684 (1999). 29–38 (2000).N.G.C. J. M. 204. “Transdermal Drug Delivery Devices with Amine-Resistant Silicone Adhesives. Gale and L. “Design and Evaluation of a Lorazepam Transdermal Delivery System. S.J. 327–336 (1998). Maillard-Salin. Pretzer and R. 24 (4). J.A.” Arzneimittel-Forschung/Drug Research 50 (2). 43. (Controlled Release Society. Kydonieus. 1999). 445–466.767 (assigned to Dow Corning Corporation [Midland.” in Kirk-Othmer Encyclopedia of Chemical Technology. A. NY.” J. Y. P. 25. 6.” J. and K.“Patch. 4th ed. 1991). P. L. Kambe et al. 51. T. Kruge and H. 33. Novak. Mater. Mat. 421–422... Takayasu et al. 38.. 23.” J. NY. Muraoka et al.J. pp. pp. 6. H. Microbiol. Part B. Wood. 54–60 (1990). 2000). Biotechnol. Chem. Spitze. New York. K.. Pfister and D. Pape. 1. 59. p. 7. 1990). 37. Hsieh. 29. Woodard and V. 24. K. Pharm. Minghetti et al. “Effect of Penetration Enhancers on Isosorbide Dinitrate Penetration through Rat Skin from a Transdermal Therapeutic System. Bhatnagar and S. 200.” in Proceedings: Eighth International Symposium on Controlled Release of Bioactive Materials (Controlled Release Society. CA]. pp. New York.W. Barnhart. 41. 39.G. and S.A. Pharm. M. Adhesives & Sealants Industry. JP] 2001). U. Minneapolis.” in Kirk-Othmer Encyclopedia of Chemical Technology.” Pharm. C.096.“Silicone Pressure-Sensitive Adhesive Composition Containing Functionalized Polyisobutylene. Ed.L. 1981). P. N.R. Patent No. and G. 4th ed. 20. Ed. and Nalbuphine. 18. Chem. Shetter.T. 199.J. Applications. JP]. 6. Ed. Elisabeth. 14 (10). Ind. Appl. 1991).phar mtech. MN].” Int.. “Formulation and In Vitro Evaluation of Polymeric Films of Diltiazem Hydrochloride and Indomethacin for Transdermal Administration.” US Patent No. Ind. J.” Appl. T. Critical Role of PSAs in Transdermal Drug Delivery. 49. Sci. A. “Development of an Estriol-Releasing Intrauterine Device. “Pharmaceutical Development and Characteristics of a New Glyceryl Trinitrate Patch. 21. Pfister. Optimization. Chen et al. 1982). Costa et al. New York.” US Patent No. W. 897–903 (2000). Frosch. Pharm.-L.R. “Pressure-Sensitive Adhesives for Transdermal Drug Delivery Systems.5. 1–6 (2000). (Marcel Dekker. 15. Lyman and B. 126–138 (1989). E. R. Inc. Technol. D. Sci.” J. 1 (17) (1967). www. NY. 209 (1963). 25. Technol. 314–343. Technol. 78. Tan and W.V. Baker et al. 5. 62. J. T. 8.P.R.. “Customizing Silicone Adhesives for Transdermal Drug Delivery Systems. Loo. 1986).573. 30. 13 (3). Donachy.” J.M. “Transdermal Therapeutic Systems for the Administration of Naloxone. Polym. 199. 22.S. Pharm.655. Biomed. 1975. M. Janicki. J. “New Synthetic Membranes for Dialysis. Attwood. Becourt.R. 1996. Howe-Grants.. “A Study of the Adhesive–Skin Interface: Correlation between Adhesion and Passage of a Drug. Sjoblom.J. “Lecithin Organogel as Matrix for Transdermal Transport of Drugs.333 (assigned to LecTec Corporation [Minnetonka.W. Polymer Handbook. and Polyether Polyurethanes. Bikaless. “X-ray Examination of Polyisobutylene. IV: A Copolyether-Urethane Membrane System.” Drug Dev. Godbey. 2000). Pocius.V. Wand. J. Fuller. Ind. Vyas. Poly.” US Patent No. Interscience Publishers: New York. “Permeability of Camphor in Ethylene-Vinyl Acetate Copolymers. Pharm.R. 206. Ind. II: Two Years’ Experience. J. 183. NY. 28. A. 1998. Santoro et al. “Improving Patient Comfort with Nonocclusive Transdermal Backings. 1–2.. 12. Detmer. Howe-Grants. Rolf. Franz et al. 10. Sci. 121–126 (2000). 13. A. 35. A. Biomed.” in Treatise on Controlled Drug Delivery: Fundamentals. 341–421. “Transdermal Delivery. H.. Sci. 871–874 (1992). and N.S.E. M. New York.“Method of Forming Adhesive Patch for Applying Medication to the Skin. Pharm.” Drug Dev..” Int. “Physical Evaluation of a New Patch Made of a Progestomimetic in a Silicone Matrix.. 4. 9.” Int. 26. NY.” Int. Pharm. 16. Pharm.” Drug Dev.211. S. H. 60–69 (1999). NY.. R. 1991). 19. MI]. 40. 1987).S. Boretos.. Gardon.939.L. (1952). 171–182 (2000). C.” J. “Dermal Patches for the Controlled Release of Miconazole: Influence of the Drug Concentration on the Technical Characteristics. Am.477 (assigned to Dow Corning Corporation [Midland. 189 (1976).S. P.” PSTT 2 (2). Couarraze. Guyot and F.W. MI]. Soc. 36. L. Gabiga. Cal. 34. 27. 5. “Lecithin Microemulsion Gels as a Matrix for Transdermal Delivery of Drugs. in Encyclopedia of Polymer Science and Technology.132. Bromberg. 4th ed.. NY.” US Patent No.
111–117 (2000). 20.” Eur. Y. J. “Transdermal Delivery of the Potent Analgesic Dihydroetorphine: Kinetic Analysis of Skin Permeation and Analgesic Effect in the Hairless Rat.” J. 99–106 (1987). Although manuscripts are reviewed by members of the magazine’s Editorial Advisory Board.Baltimore.” J. 198. feel free to contact the editor. “Water-Activated.preparation.” J.contact Richard Dalby. 635–642 (2000). 85 (5). Department of Pharmaceutical Sciences. pH-Controlled Patch in Transdermal Administration of Timolol I: Preclinical Tests. Manuscripts may be submitted in the following ways: ● via e-mail to Michael MacRae. 51. ingredients. 26 (7). Urtti. H.D. “Control of Drug Concentration–Time Profiles In Vivo by Zero-Order Transdermal Delivery Systems. Ind. or photographs. Before submitting a completed work. Pharm. details of grammar. Authors should furnish two hard copies of the manuscript. 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