Polymers in Transdermal Drug Delivery Systems Sateesh Kandavilli,Vinod Nair, and Ramesh Panchagnula* he development of transdermal drug delivery systems is a multidisciplinary activity that encompasses Polymers are ● fundamental feasibility studies starting from the se- the backbone of lection of a drug molecule to the demonstration of suf- Tficient drug flux in an ex vivo and/or in vivo model a transdermal ● the fabrication of a drug delivery system that meets all the drug delivery stringent needs that are specific to the drug molecule (physico- system. chemical and stability factors), the patient (comfort and cos- Advances in metic appeal), the manufacturer (scale-up and manufac- the field of turability), and most important, the economy. polymer science have Polymers Polymers are the backbone of a transdermal drug delivery sys- paved the tem. Systems for transdermal delivery are fabricated as multi- way for trans- layered polymeric laminates in which a drug reservoir or a dermal delivery system designs drug–polymer matrix is sandwiched between two polymeric that have considerable flexibility. An layers: an outer impervious backing layer that prevents the loss impressive amount of technical know-how of drug through the backing surface and an inner polymeric has been gained in this area of research. layer that functions as an adhesive and/or rate-controlling mem- brane. Transdermal drug delivery systems are broadly classified This article summarizes the formulation into the following three types (1) (see Figure 1). aspects of transdermal drug delivery Reservoir systems. In this system, the drug reservoir is em- systems and emphasizes the physico- bedded between an impervious backing layer and a rate- chemical and mechanical properties of controlling membrane. The drug releases only through the various polymers being used in rate-controlling membrane, which can be microporous or non- commercially available transdermal drug porous. In the drug reservoir compartment, the drug can be in the form of a solution, suspension, or gel or dispersed in a delivery systems. It is intended as a guide solid polymer matrix. On the outer surface of the polymeric for the selection of polymers for developing membrane a thin layer of drug-compatible, hypoallergenic such systems. 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 Sateesh Kandavilli, Vinod Nair, and or by melting the adhesive (in the case of hot-melt adhesives) Ramesh Panchagnula, PhD, are onto an impervious backing layer. On top of the reservoir, lay- employed in the Department of ers of unmedicated adhesive polymer are applied. Pharmaceutics, National Institute of Pharmaceutical Education and Research Matrix-dispersion system. The drug is dispersed homogeneously (NIPER), Sector-67, Ph-X, SAS Nagar-160 in a hydrophilic or lipophilic polymer matrix. This drug- 062, Punjab, India, tel: ϩ91 172 214 682 or containing polymer disk then is fixed onto an occlusive base 214 687, fax ϩ91 172 214 692, plate in a compartment fabricated from a drug-impermeable [email protected]. backing layer. Instead of applying the adhesive on the face of *To whom all correspondence should be addressed. the drug reservoir, it is spread along the circumference to form a strip of adhesive rim. 62 Pharmaceutical Technology MAY 2002 www.pharmtech.com Reservoir system Matrix-dispersion Peripheral adhesive Microreservoir system design system Backing layer Drug reservoir Rate controller Release liner Adhesive layer Occlusive baseplate Figure 1: Representative designs of transdermal drug delivery systems. Microreservoir systems. This drug delivery system is a combi- Matrix formers nation of reservoir and matrix-dispersion systems. The drug Polymer selection and design must be considered when striv- reservoir is formed by first suspending the drug in an aqueous ing to meet the diverse criteria for the fabrication of effective solution of water-soluble polymer and then dispersing the so- transdermal delivery systems. The main challenge is in the de- lution homogeneously in a lipophilic polymer to form thou- sign of a polymer matrix, followed by optimization of the drug- sands of unleachable, microscopic spheres of drug reservoirs. loaded matrix not only in terms of release properties, but also The thermodynamically unstable dispersion is stabilized quickly with respect to its adhesion–cohesion balance, physicochemi- by immediately cross-linking the polymer in situ. cal properties, and compatibility and stability with other com- Transdermal drug delivery technology represents one of the ponents of the system as well as with skin (4). most rapidly advancing areas of novel drug delivery. This A monolithic solid-state design often is preferred for passive growth is catalyzed by developments in the field of polymer transdermal delivery systems because of manufacturing con- science. This article focuses on the polymeric materials used siderations and cosmetic appeal. Although polymeric matrices in transdermal delivery systems, with emphasis on the mate- are used for rate control, adhesion (e.g., a PSA), or encapsula- rials’ physicochemical and mechanical properties, and it seeks tion of a drug reservoir in transdermal delivery systems (re- to guide formulators in the selection of polymers. Polymers viewed in later sections of this article), discussion in this sec- are used in transdermal delivery systems in various ways, in- tion is limited to polymers that have been used in the design of cluding as matrices with or without rate control. ● matrix formers Cross-linked poly(ethylene glycol) (PEG) networks. Biocompati- ● rate-controlling membranes bility of PEGs makes them the polymers of choice for numer- ● pressure-sensitive adhesives (PSAs) ous biomedical applications. Proteins can be delivered by PEGs ● backing layers cross-linked with tris(6-isocyanatohexyl) isocyanurate by means ● release liners. of a urethane–allophanate bond to obtain polymer networks Polymers used in transdermal delivery systems should have capable of swelling in phosphate-buffered saline or ethanol and biocompatibility and chemical compatibility with the drug and forming gels. These systems have been shown to release the other components of the system such as penetration enhancers solutes in a biphasic manner (5). and PSAs. They also should provide consistent, effective deliv- Acrylic-acid matrices. Acrylic-acid matrices with plasticizers ery of a drug throughout the product’s intended shelf life or have been used to make drug–polymer matrix films for trans- delivery period and have generally-recognized-as-safe status. dermal delivery systems. Some of the polymers that have been From an economic point of view, a delivery tool kit rather than reported are Eudragit RL PM, Eudragit S-100, Eudragit RS PM, a single delivery tool is most effective (2). and Eudragit E-100 (Röhm America, Piscataway, NJ) (6). Eu- Companies involved in the field of transdermal delivery con- dragit NE-40D (a copolymer of ethyl acrylate and methyl centrate on a few selective polymeric systems. For example, Alza methacrylate), a nonadhesive hydrophobic polymer, also has Corporation (Mountain View, CA) mainly concentrates on ethy- been used as a matrix former (7). The release rates of drugs lene vinyl acetate (EVA) copolymers or microporous polypropy- from these matrix systems are more closely described by the lene, and Searle Pharmacia (Barceloneta, PR) concentrates on square-root-of-time model. silicone rubber (3). A review of the marketed transdermal prod- Ethyl cellulose (EC) and polyvinylpyrrolidone (PVP). EC and PVP ucts and the formulations that are reported in various research matrix films with 30% dibutyl phthalate as a plasticizer have publications reveals an enormous diversity of polymers used been fabricated to deliver diltiazem hydrochloride and in- in the formulation, engineering, and manufacture of drug prod- domethacin. The addition of hydrophilic components such as ucts (see Table I). Table II is a comprehensive list of all the poly- PVP to an insoluble film former such as ethyl cellulose tends to mers used for various purposes in commercially available trans- enhance its release-rate constants. This outcome can be attri- dermal delivery systems. buted to the leaching of the soluble component, which leads to 64 Pharmaceutical Technology MAY 2002 www.pharmtech.com Table I: Composition of transdermal delivery systems reported in the literature. (Continued on page 67) S.No. Polymer Manufacturer Drug Type of System Reference 1 Ethyl cellulose T-50 Sigma Isosorbide dinitrate Matrix 41 2 BIO PSA HighTack 7-4301 Dow Corning Trimegestone Adhesive-in-matrix 42,43 BIO PSA MediumTack 7-4201 system. For matrix and backing side layer. Scotch Pak 1022 3M Backing Scotch Pak 1006 3M Release liner 3 HPMC Hydrocortisone Gel 44 4 Eudragit NE, Eudragit E100, Röhm, Germany Coumarin Matrix 45 Eudragit L100 Melilot dry extract 5 MDX-4-421 (a silicone) Dow Corning L-Timolol maleate Matrix 46 6 Carboxy vinyl polymer L-Dopa Gel 47 7 Acrylic PSA emulsion Neoplast Co., Nicotine Drug in adhesive 48 Thailand CoTran9722 3M 8Soybean lecithin (Epikuron 200) Lucas Meyer, Scopolamine, Gel matrices 13 Germany broxaterol 9 Cariflex TR-1107 Shell Chemical Co., Dihydro etorphine Drug in adhesive 49 Japan 10 Acrylic adhesives National Starch Ketoprofen Drug in adhesive 50 and Chemical Co. Polyisobutylene solutions Exxon Chemical