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. 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 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 casting Sateesh Kandavilli, Vinod Nair, and or by melting the adhesive (in the case of hot-melt ) 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: 91 172 214 682 or containing polymer disk then is fixed onto an occlusive base 214 687, fax 91 172 214 692, 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 -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 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 (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 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 Co. (Vistanex LM-MH, Vistanex MML-100) 11 Acrylic adhesives National Starch Tacrine Drug in adhesive 51 and Chemical Co. Polyisobutylene solutions Exxon Chemical Co. (Vistanex LM-MH, Vistanex MML-100) Silicone PSA Dow Corning 12 Silicone oil Adhesive Research Arecoline Reservoir 52 EVA Membrane Polyisobutylene Adhesive ScotchPak 1006 3M Backing film the formation of pores and thus a decrease in the mean diffu- addition of water, undergo association reorientation to form a sion path length of drug molecules to release into the dissolu- gel. These organogels can be used as a matrix for the transder- tion medium. The result is higher dissolution rates. Substances mal delivery of drugs with greater influx (11). Bhatnagar and such as PVP act as antinucleating agents that retard the crystal- Vyas proposed a reverse micelle-based microemulsion of soy lization of a drug. Thus they play a significant role in improv- lecithin in isooctane gelled with water as a vehicle for trans- ing the solubility of a drug in the matrix by sustaining the drug dermal delivery of propranolol. The transdermal flux of pro- in an amorphous form so that it undergoes rapid solubilization pranolol from this organogel increased 10-fold over a vehicle by penetration of the dissolution medium (8). composed of petrolatum (12). Willimann et al. also described Hydroxypropyl methylcellulose (HPMC). HPMC, a hydrophilic organogels obtained when small amounts of water were added swellable polymer widely used in oral controlled drug delivery, to a solution of lecithin in organic , used as matrices also has been explored as a matrix former in the design of for the transdermal transport of drugs. The gels obtained in patches of propranolol hydrochloride. HPMC has been shown this manner are isotropic and thermoreversible (liquefy at tem- to yield clear films because of the adequate solubility of the drug peratures 40 C) and can solubilize lipophilic, hydrophilic, in the polymer. Matrices of HPMC without rate-controlling and amphoteric substances, including enzymes. They are bio- membranes exhibited a burst effect during dissolution testing compatible and are stable for a long time. because the polymer was hydrated easily and swelled, leading Organogels can cause slight disorganization of the skin, an to the fast release of the drug (9). outcome that is attributable to the organic solvent that is used Organogels. Some nonionic such as sorbitane to make the gel. Thus, organogels can enhance the permeation monostearate, lecithin, and Tween tend to associate into reverse of various substances (13). Pluronic lecithin organogels also micelles (10). These surfactants in an organic solvent, upon the have been used as transdermal delivery systems because both

66 Pharmaceutical Technology MAY 2002 www.pharmtech.com Table I continued: Composition of transdermal delivery systems reported in the literature. S.No. Polymer Manufacturer Drug Type of System Reference 13 2-Ethylhexyl acrylate Mitsubishi Petro- PGE Drug-in-adhesive 53 and chem Co., Japan matrix acrylic acid copolymer Wako Purechem. Ind., Japan 14 HEMA, Styrene and N-vinyl Polyscience Cytarabine, ara-ADA Carbopol 934 gel, 54 pyrrolidone copolymer for reservoir membrane 15 HPMC (Methocel K4M) Colorcon, UK Propranolol Matrix 9 Urecryl MC 808 UCB, Belgium PIB Aldrich, France 16 MDX4-4210 silicone elastomer Dow Corning Nitroglycerine Matrix 55 17 Acrylate copolymer (Gelva-737) Monsanto Fentanyl Matrix 56 Silicone-2920 and 2675 Dow Corning Polyisobutylene solutions Exxon Chemical Co. (Vistanex LM-MS, Vistanex MML-100) 18 2-Ethylhexyl acrylate and Mitsubishi Petro- Aminopyrene, Drug in adhesive 53 acrylic acid copolymer chem Co., Japan Ketoprofen, 2-Ethylhexyl acrylate and Wako Purechem. Lidocaine acrylamide copolymer Ind., Japan Polyisobutylene solutions Exxon Chemical Co. (Vistanex LM-MH, Vistanex LM-80) Silicone PSA Dow Corning 19 Plastoid E25L Röhm, Germany Matrix 7 20 Polyvinyl alcohol (backing) Propranolol Membrane- 57 HPMC (matrix) controlled Ethylene vinyl acetate reservoir system (rate-controlling membrane)

hydrophobic and membrane material must conform to the type of drug being hydrophilic drugs used. By varying the composition and thickness of the mem- H H H H can be incorpo- brane, the dosage rate per area of the device can be controlled. rated into them. EVA. EVA frequently is used to prepare rate-controlling mem- C C C C Oil-soluble drugs branes in transdermal delivery systems because it allows the H H x H O y are miscible with membrane permeability to be altered by adjusting the vinyl ace- the lecithin phase, tate content of the polymer. For example, when ethylene is C CH 3 and water-soluble copolymerized with vinyl acetate, which is not isomorphous O drugs are miscible with ethylene, the degree of crystallinity and the crystalline with the aqueous melting point decreases and amorphousness increases (see Fig- phase. ure 2). As the solutes permeate easily through the amorphous Figure 2: Structure of polyethylene vinyl regions, the permeability increases. The copolymerization also acetate. Rate-controlling results in an increase in polarity. Hence, an increase in the vinyl membranes acetate content of a copolymer leads to an increase in solubil- Reservoir-type transdermal drug delivery systems contain an ity and thus an increase in the diffusivity of polar compounds inert membrane enclosing an active agent that diffuses through in the polymers. However, at vinyl acetate levels 60% by weight, the membrane at a finite, controllable rate. The release rate– the glass-transition temperature, Tg,ofpolymer increases from controlling membrane can be nonporous so that the drug is re- 25 C to 35 C. An increase in Tg reflects a decrease in leased by diffusing directly through the material, or the mate- the polymer-chain mobility and hence the solute diffusivity. rial may contain fluid-filled micropores — in which case the The effect of these structural changes on membrane perme- drug may additionally diffuse through the fluid, thus filling the ability is shown in the permeation of camphor through a series pores. In the case of nonporous membranes, the rate of passage of poly(ethylene vinyl acetate) copolymers, which has exhib- of drug molecules depends on the solubility of the drug in the ited a maximum of limiting flux at 60% vinyl acetate content membrane and the membrane thickness. Hence, the choice of (14).

Pharmaceutical Technology MAY 2002 67 Table II: Composition of marketed transdermal therapeutic systems. Product Type of System Drug Reservoir Backing Membrane Adhesive Release Liner Androderm Reservoir Drug, alcohol, Metallized Polyethylene Peripheral acrylic Silicone- (testosterone) glyceryl monooleate polyester/ microporous adhesive coated TheraTech, methyl laurate ethylene- membrane polyester Inc./SmithKline gelled with acrylic methacrylic acid Beecham acid copolymercopolymer/EVA Catapres- Reservoir Clonidine, mineral Pigmented Microporous Mineral oil, Polyester TTS oil, polyisobutylene polyester film polypropylene polyisobutylene, (clonidine) and colloidal silicon film and colloidal Alza/Boehringer dioxide silicon dioxide Ingelheim Climara Drug in Polyethylene Acrylate Siliconized or (estradiol) adhesive film adhesive fluoropolymer- 3M/Berlex/ matrix coated poly- Schering AG ester film Deponit Mixed Multilayered PIB Poly foil PIB Silicone foil (nitroglycerin) monolithic adhesive film Pharma reservoir Schwarz Epinitril Drug in Polypropylene Acrylate- Aluminized (nitroglycerine) adhesive vinylacetate and siliconized Rotta Research copolymer and polyethylene poly(butyl butane) terephthalate foil Estraderm Reservoir Drug and alcohol PolyesterÐ EVA Light mineral oil Siliconized (estradiol) gelled with polyethylene copolymer and PIB polyethylene Alza/Ciba- hydroxypropyl composite with 5% vinyl terephthalate Geigy cellulose acetate Habitrol Drug in Aluminized Acrylate adhesive Aluminum foil (nicotine) adhesive plastic backing Novartis film Nitrodisc Monolithic FoilÐ Cross-linked PaperÐfoil (nitroglycerin) microreservoir polyethylene silicone rubber combination Searle combination Nitro-Dur-I Drug in Hydrogel from PaperÐfoil Acrylic adhesive PaperÐ (nitroglycerin) adhesive copolymer of PVPÐ combination polyethylene Key Pharma PVA, glycerol as foil pouch plasticizer Prostep Reservoir Nicotine in Low-density Polyethylene Acrylate-based (nicotine) carrageenan gel polyethylene ring adhesive Lederle Testoderm TTS Reservoir Drug and alcohol Polyester/EVA EVA copolymer PIB Silicone- (testosterone) gelled with hydroxy- copolymer coated Alza propyl cellulose polyester Transderm- Reservoir Drug adsorbed on Flesh-colored EVA copolymer Silicone adhesive Fluorocarbon Nitro lactose, colloidal polyfoil polyester film (nitroglycerin) silica, and silicone oil Alza/Ciba-Geigy Transderm- Reservoir Scopolamine, light Aluminized Microporous Mineral oil, Siliconized Scop mineral oil, and polyester film polypropylene polyisobutylene polyester (scopolamine) polyisobutylene Alza/Ciba-Geigy Vivelle Drug in EVA copolymer PIB, EVA Polyester (estradiol) adhesive film and copolymer Noven/Novartis polyurethane film

68 Pharmaceutical Technology MAY 2002 www.pharmtech.com Acrylic-, polyisobutylene-, and silicone-based adhesives are used n O CNRNCO n HO POLYESTER/ OH mostly in the design of transder- POLYETHER Polyisocyanate mal patches (21,22). The selection Polyol of an adhesive is based on a num- ber of factors, including the patch design and drug formulation. For reservoir systems with a periph- eral adhesive, an incidental con- tact between the adhesive and the C N R N C O POLYESTER/ O POLYETHER drug or penetration enhancers O H H O n must not cause instability of the Urethane drug, penetration enhancer, or the bond adhesive. In the case of reservoir systems that include a face adhe- sive, the diffusing drug must not Figure 3: Synthesis of polyurethane. affect the adhesive. Furthermore, the choice of ad- Silicone 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 estab- materials 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. ties within the polymer. The physicochemical characteristics of a drug–adhesive com- Polyurethane. Polyurethane is the general term used for a poly- bination — such as solubility and partition coefficient and ad- mer 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 ad- bonds (NHCOO) (see Figure 3). The polyurethanes syn- hesives that are not cross-linked, enhancers or other formula- thesized 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 dur- focus 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 formu- hydrophobic polymers such as silicone rubber or EVA mem- lating a PSA, a balance of four properties must be taken into ac- branes (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 re- flow 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 polymeri- terial (20). zation to produce a polymer having no asymmetric carbons

70 Pharmaceutical Technology MAY 2002 www.pharmtech.com lease from the matrix. Titanium dioxide has been used in the EVA matrix to reduce the amount of naloxone contained in the CH CH 3 3 depleted systems (28), and PVP has been used to enhance the BF CH C 3 CH C release of formoterol from acrylic PSAs (29). Petroleum-based 2 2 n oils, butyl polybutenes, paraffin waxes, and low molecular weight CH CH 3 3 polyethylene can be used as plasticizers. Alkyl adipates and se-

Isobutylene Polyisobutylene bacates 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. Figure 4: Polymerization of isobutylene. Polyacrylates. Acrylic esters are represented by the general for- mula CH2 CH COOR. The nature of the R group determines the properties of each ester and the polymer it forms (see Fig- H H H ure 5). Polymers of this class are amorphous and are distin- guished by their water-clear color in solution and stability to- H C C COR 2 C C ward aging. As is typical of polymer systems, the mechanical O H COOR properties of acrylic polymers improve as the molecular weight n increases. However, beyond a critical molecular weight, which 3 3 Acrylic ester Polyacrylate is 1 10 to 2 10 for amorphous polymers, the improve- ment is slight and levels off asymptotically (30).

The Tg value of a copolymer can be altered by the copoly- Figure 5: Polymerization of acrylic ester. merization 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

(see Figure 4). In its unstrained state, the polymer is in an amor- approximate Tg value for copolymers can be calculated from phous state (25), and the Tg of the polymer is 70 C (26). the weight fraction of each monomer (W1) and the Tg of each The physical properties of the polymer change gradually with homopolymer as shown in the following equation (31): increasing molecular weight. Low molecular weight polymers W W are viscous liquids. With increasing molecular weight, the liq- 1 1 2 T T T uids become more viscous, then change to balsam-like sticky g copolymer g 1 g 2 masses and finally form elastomeric solids. PIB PSAs usually comprise a mixture of high molecular weight and low molecu- Plasticizers also can be used to lower the Tg.However,unlike lar weight fractions. High molecular weight PIB has a viscosity incorporated acrylic monomers, they can be lost through average molecular weight between 450,000 and 2,100,000, and volatilization or extraction. low molecular weight PIB has an average molecular weight be- Acrylic polymers are highly stable compounds. Unless they tween 1000 and 450,000. PIB has the chemical properties of are subjected to extreme conditions, acrylic polymers are a saturated hydrocarbon. It is readily soluble in nonpolar liq- durable and degrade slowly. Oxidative degradation of acrylic uids. Cyclohexane is an excellent solvent, benzene is a moder- polymers can occur in high-pressure and high-temperature ate solvent, and dioxane is a nonsolvent for PIB polymers (27). conditions by the combination of oxygen with the free radi- Un-cross-linked polymers exhibit a high degree of tack or cals generated in the polymer to form hydroperoxides (32). self-adhesion. PIB polymers have a very low fractional free vol- Acrylic polymers and copolymers have a greater resistance to ume of 0.026 as compared with 0.071 for poly(dimethylsilox- both acidic and alkaline hydrolysis than do poly(vinyl acetate) ane), for example. This characteristic together with sluggish and vinyl acetate copolymers. In extreme conditions of acid- chain motility results in a low diffusion coefficient. However, ity or alkalinity, acrylic ester polymers can be made to hydrolyze the final properties of the polymer blend are determined by to poly(acrylic acid) or to an acidic salt and the correspond- compounding and subsequent vulcanization or cross-linking. ing alcohol. Acrylic polymers are insensitive to normal UV Various fillers, processing aids, plasticizers, tackifiers, cure sys- degradation because the primary UV absorption of acrylics tems, and antidegradants are incorporated into the final blend. occurs below the solar spectrum. A UV absorber such as Of all these compounding ingredients, fillers most signifi- o-hydroxybenzophenone can be incorporated to further en- cantly influence stress–strain and dynamic properties. Carbon hance the UV stability (32). black, the most frequently used reinforcing filler by virtue of its Silicones. Silicone PSAs comprise polymer or gum and a tacki- high surface area, interacts with the surface of polymer chains fying resin. Medical-grade silicone adhesives contain a low- and alters chain dynamics, thus enhancing tensile properties viscosity dimethylsiloxane polymer (12 103 cP to 15 103 and abrasion resistance. Other fillers that are used are and cP) (24), which has a terminal silanol group. The silicone resin calcined clay. Colloidal silicon dioxide is used as a filler in has a three-dimensional silicate structure that is end capped clonidine patches (Catapres-TTS). Nonreinforcing fillers such with trimethyl siloxy groups ( OSi[CH3]3) and contains resid- as calcium carbonate and titanium dioxide are added to reduce ual silanol functionality (33). The adhesive is prepared by cross- viscosity and cost. Fillers also are used to enhance the drug re- linking the reactants in solution by a condensation reaction

72 Pharmaceutical Technology MAY 2002 www.pharmtech.com Table III: Glass transition

CH3 temperatues of acrylic polymers (39,40). H3C Si CH3

O CH CH CH 3 3 3 Polymer Tg ( C) H O Si O H HOSi O Si O Si OH Methyl acrylate 6 Ethyl acrylate 24 O CH3 CH3 CH3 n Propyl acrylate 45 H C 3 Si CH3 n Isopropyl acrylate 3 Polydimethylsiloxane n-Butyl acrylate 50 CH 3 Hexyl acrylate 57 Silicate resin Heptyl acrylate 60 Condensation 2-Ethylhexyl acrylate 65

CH3 2-Ethylbutyl acrylate 50 Dodecyl acrylate 30 H C Si CH 3 3 Hexadecyl acrylate 35

O CH3 CH3 CH3 Cyclohexyl acrylate 16

H O Si O Si O Si O Si OH reaction (33). Some of the trace com- O CH CH CH 3 3 n 3 ponents in acrylic-adhesive blends reacted with a variety of drugs and H C Si CH 3 3 n caused coloring, which deepens with

CH3 time. This problem was overcome when 2-mercaptobenzimidazole and/or propyl Silicone PSA gallate were incorporated into the ad- hesive composition (34). Hot-melt PSAs (HMPSAs). Typical PSAs Figure 6: Synthesis of a silicone pressure-sensitive adhesive. include a volatile organic solvent for re- ducing the viscosity of the composition to a coatable room-temperature viscos- between silanol groups on the linear poly(dimethylsiloxane) ity. After the product is coated, the organic solvent is removed polymer and silicate resin to form siloxane bonds (SiOSi) by evaporation. When they are heated, HMPSAs melt to a vis- (see Figure 6). Unlike acrylic-, rubber-, and PIB-based adhe- cosity suitable for , but when they are cooled they gen- sives, medical-grade silicone adhesives do not contain organic erally stay in a flowless state. HMPSAs are advantageous over tackifiers, stabilizers, antioxidants, plasticizers, catalysts, or solvent-based systems because they other potentially toxic extractables. These additives are not re- ● do not require removal and containment of the solvents quired because silicone PSAs are stable throughout a wide range ● do not require special precautions to avoid fire of temperatures (73 to 250 C). ● are amenable to coating procedures other than those com- The end-use properties of silicone-based PSAs such as tack, monly used with solvent-based systems peel adhesion, skin adhesion, and cohesion can be modified or ● are more easily coated into full thickness with minimal bub- customized by varying the resin–polymer ratio, the silanol func- bling, which often results with solvent-containing PSAs. tionality, and the level and type of cross-linking agent. Normally Hot-melt adhesives are based on thermoplastic polymers that the shear strength and the tack of a PSA first increase and then may be compounded or uncompounded (see Table IV). Of these reach a maximum as increasing amounts of tackifying resin are polymers, EVA copolymers are most widely used. Polybutenes, added. The peel strength usually increases with the amount of phthalates, and tricresyl phosphate often are added as plasti- tackifying resin. The shear-holding power often depends on the cizers to improve mechanical shock resistance and thermal mode of cross-linking. Although the silicone group of adhesives properties. Antioxidants such as hindered are added to has an outstanding combination of biocompatibility and ease prevent oxidation of ethylene-based hot-melt adhesives. Fillers of fabrication for hydrophilic drugs, the solubility, permeabil- opacify or modify an adhesive’s flow characteristics and reduce ity, and releasing properties are poor. the cost. Paraffin and microcrystalline wax are added to alter the Some of the silicone PSAs contain a significant degree of surface characteristics by decreasing the surface tension and the free silanol–functional groups. Certain amino-functional drugs viscosity of the melt and to increase the strength of the adhesive can act as catalysts to cause further cross-links between these upon solidification. Moisture-curing urethanes have been at- silanol groups. This unwanted reaction can be reduced, thus tempted as cross-linking agents to prevent creep under the load enhancing a PSA’s chemical stability, by end capping the silanol of these thermoplastic materials. groups with methyl groups by means of a trimethyl silylation Silicone-based adhesives also are amenable to hot-melt

74 Pharmaceutical Technology MAY 2002 www.pharmtech.com Table IV: Thermoplastic hot-melt coating. US Patent No. chemical resistance often may lead to stiffness and high oc- pressure-sensitive adhesives. 5,352,722 describes the clusivity to moisture vapor and air, causing patches to lift and process of preparing a possibly irritate the skin during long-term wear. The most com- Compounded silicone-based HMPSA fortable backing may be the one that exhibits the lowest modu- Ethylene vinyl acetate copolymers in which the dynamic lus or high flexibility, good oxygen transmission, and a high Paraffin waxes viscosity of a basic adhe- moisture-vapor transmission rate (see Table V) (36). Low-density polypropylene sive formulation consist- In a novel modification to the conventional design, a patch Styrene-butadiene copolymers ing of a polysilicate resin was fabricated in which the backing itself acted as a reservoir Ethylene-ethacrylate copolymers and a silicone fluid is re- for the drug. The upper internal portion of the drug reservoir Uncompounded duced by adding alkyl infiltrated the porous backing and became solidified therein Polyesters methylsiloxane waxes. after being applied so that the reservoir and the backing were Polyamides Thus the coatability of unified. This modification enabled the backing itself to act as Polyurethanes a PSA without solvents is a storage location for the medication-containing reservoir (37). Table V: Characteristics of some commercialized backing materials.* Release liner During storage the patch is covered by Oxygen a protective liner that is removed and Transmission MVTR Enhancer discharged immediately before the ap- Product Polymer (cm3/m2/24 h) (g/m2/24 h) Resistance plication of the patch to the skin. It is CoTran 9701 Polyurethane 700 Low therefore regarded as a part of the pri- film mary packaging material rather than a CoTran 9702, EVA 52.8 Medium part of the dosage form delivering the CoTran 9706 26.4 Medium active principle (38). However, because CoTran 9720, PE 2950 9.4 Medium the liner is in intimate contact with the 9722 3570 7.9 High delivery system, it should comply with Foam Tape 9772L PVC foam 450 — specific requirements regarding the Foam Tape 9773 Polyolefin foam — — chemical inertness and permeation to Scotchpak 1006 PE, Al vapor 4.6 0.3 HighÐPET side the drug, penetration enhancer, and coat, PET, EVA water. In case cross-linking is induced Scotchpak 1109 PE, Al vapor 4.6 0.3 High between the adhesive and the release coat, PET liner, the force required to remove the Scotchpak 9723 PE, PET 100 12 HighÐPET side liner will be unacceptably high (23). 3M, laminate for example, manufactures release lin- Scotchpak 9732, PET, EVA 80 15.5 HighÐPET side ers made of fluoro polymers (Scotch- 9733 laminate 80 17 HighÐPET side pak 1022 and Scotchpak 9742, 3M Drug PE Polyethylene Delivery Systems, St. Paul, MN). PVC Polyvinyl chloride EVA Ethylene vinyl acetate MVTR Moisture-vapor transmission rate Acknowledgments PP Polypropylene The authors thank Mr. Sunil T. Narisetty PU Polyurethane for his valuable suggestions in the PET Poly(ethylene terephthalate) (polyester) preparation of this article. Vinod Nair *http://www.3M.com is supported by a senior research fel- lowship from the Department of Sci- improved. Pretzer and Sweet (35) described a silicone-based HMPA ence and Technology, New Delhi, India. that contained a mixture of silicate resin and a polyorgano- siloxane fluid into which polyisobutylene polymer with a func- References tionalized silicon-containing moiety was incorporated. The ad- 1. Y.W. Chien, “Transdermal Therapeutic Systems,” in Controlled Drug hesive was claimed to possess a reduced propensity to cold flow. Delivery: Fundamentals and Applications, J.R. Robinson and V.H.L. Lee, Eds. (Marcel Dekker, Inc., New York, NY, 2d ed., 1987), pp. 523–552. Backing layer 2. S.S. Davis and L. Illum,“Drug Delivery Systems for Challenging Mole- When designing a backing layer, the developer must give chemi- cules,” Int. J. Pharm. 176, 1–8 (1998). cal resistance of the material foremost importance. 3. R.W. Baker and J. Heller, “Material Selection for Transdermal Deliv- compatibility also must be seriously considered because the ery Systems,”in Transdermal Drug Delivery: Developmental Issues and Research Initiatives, J. Hadgraft and R.H. Guys, Eds. (Marcel Dekker, prolonged contact between the backing layer and the excipi- Inc., New York, NY, 1989), pp. 293–311. ents may cause the additives to leach out of the backing layer 4. H.-M. Wolff,“Optimal Process Design for the Manufacturing of Trans- or may lead to diffusion of , drug, or penetration en- dermal Drug Delivery Systems,” PSTT 3 (5), 173–181 (2000). hancer through the layer. However, an overemphasis on the

76 Pharmaceutical Technology MAY 2002 www.pharmtech.com 5. L. Bromberg,“Cross-Linked Poly(ethylene glycol) Networks as Reser- 16. T.N. Kambe et al.,“Microbial Degradation of Polyurethane, Polyester voirs for Protein Delivery,” J. Appl. Poly. Sci. 59, 459–466 (1996). Polyurethanes, and Polyether Polyurethanes,” Appl. Microbiol. Biotech- 6. P. Costa et al., “Design and Evaluation of a Lorazepam Transdermal nol. 51, 134–140 (1999). Delivery System,” Drug Dev. Ind. Pharm. 23 (10), 939–944 (1997). 17. D.J. Lyman and B.H. Loo,“New Synthetic Membranes for , IV: 7. P.Minghetti et al.,“Dermal Patches for the Controlled Release of Mi- A Copolyether-Urethane Membrane System,” J. Biomed. Mater. Res. 1 conazole: Influence of the Drug Concentration on the Technical (17) (1967). Characteristics,” Drug Dev. Ind. Pharm. 25, 679–684 (1999). 18. R.W. Baker et al., “Development of an Estriol-Releasing Intrauterine 8. P.Ramarao and P.V.Diwan,“Formulation and In Vitro Evaluation of Device,” J. Pharm. Sci. 68 (1), 20 (1979). Polymeric Films of Diltiazem Hydrochloride and Indomethacin for 19. A.V. Pocius, “Adhesives,” in Kirk-Othmer Encyclopedia of Chemical Transdermal Administration,” Drug Dev. Ind. Pharm. 24 (4), 327–336 Technology, M. Howe-Grants, Ed. (Wiley-Interscience, New York, NY, (1998). 4th ed., 1991), pp. 445–466. 9. M. Guyot and F. Fawaz, “Design and In Vitro Evaluation of Adhesive 20. T.J. Franz et al.,“Transdermal Delivery,”in Treatise on Controlled Drug Matrix for Transdermal Delivery of Propranolol,” Int. J. Pharm. 204, Delivery: Fundamentals, Optimization, Applications, A. Kydonieus, Ed. 171–182 (2000). (Marcel Dekker, Inc., New York, NY, 1991), pp. 341–421. 10. A.T. Florence and D. Attwood, in Physico-Chemical Principles of Phar- 21. S. Barnhart, Critical Role of PSAs in Transdermal Drug Delivery; Ad- macy (Chapman & Hall, New York, NY, 1982), pp. 206. hesives & Sealants Industry, 1–6 April, 1998. 11. P. Walde et al., “Lecithin Microemulsion Gels as a Matrix for Trans- 22. H.S. Tan and W.R. Pfister, “Pressure-Sensitive Adhesives for Trans- dermal Delivery of Drugs,”in International Symposium on Controlled dermal Drug Delivery Systems,” PSTT 2 (2), 60–69 (1999). Release of Bioactive Materials, (Controlled Release Society, Inc., Min- 23. W.R. Pfister and D.S.T. Hsieh, “Permeation Enhancers Compatible neapolis, MN, 1990), pp. 421–422. with Transdermal Drug Delivery Systems, Part II: System Design Con- 12. S. Bhatnagar and S.P.Vyas, “Organogel-Based System for Transder- siderations,” Pharm. Technol. 14 (10), 54–60 (1990). mal Delivery of Propranolol,” J. Microencapsulation 11 (4), 431–438 24. W.R. Pfister, “Customizing Silicone Adhesives for Transdermal Drug (1994). Delivery Systems,” Pharm. Technol. 13 (3), 126–138 (1989). 13. H. Willimann et al., “Lecithin Organogel as Matrix for Transdermal 25. C.S. Fuller, C.J. Frosch, and N.R. Pape, “X-ray Examination of Poly- Transport of Drugs,” J. Pharm. Sci. 81 (9), 871–874 (1992). isobutylene,” J. Am. Chem. Soc. 62, 1905–1913 (1940). 14. R. Gale and L.A. Spitze,“Permeability of Camphor in Ethylene-Vinyl 26. L.A. Wood, Rubber Chem. Technol. 49, 189 (1976). Acetate Copolymers,”in Proceedings: Eighth International Symposium 27. E. Kruge and H.C. Wand,“Butyl Rubber,”in Kirk-Othmer Encyclope- on Controlled Release of Bioactive Materials (Controlled Release Soci- dia of Chemical Technology, M. Howe-Grants, Ed. (Wiley-Interscience, ety, Minneapolis, MN, 1981), p. 183. New York, NY. 4th ed., 1991), pp. 934–955. 15. J.W. Boretos, D.E. Detmer, and J.H. Donachy,“Segmented Polyurethane: 28. Y.-L. Chen et al., “Transdermal Therapeutic Systems for the Admin- A Polyether Polymer, II: Two Years’ Experience,” J. Biomed. Mat. Res. istration of Naloxone, Naltrexone, and Nalbuphine,” US Patent No. 5, 373 (1971). 4,573,995 (assigned to Alza Corporation [Mountain View, CA], 1986). 29. T. Takayasu et al.,“Patch,”US Patent No. 6,211,425 (assigned to Saitama Daiichi Seiyaku Kabushiki Kaisha [Kasukabe, JP] 2001). 30. R.W. Novak,“Acrylic Ester Polymers,”in Kirk-Othmer Encyclopedia of Chemical Technology, M. Howe-Grants, Ed. (Wiley-Interscience, New York,NY, 4th ed., 1991), pp. 314–343. 31. J.A. Shetter, J. Polym. Sci. Part B. 1, 209 (1963). 32. A.R. Burgess, Chem. Ind. 78, (1952). 33. J.T. Woodard and V.L. Metevia, “Transdermal Drug Delivery Devices with Amine-Resistant Silicone Adhesives,” US Patent No. 4,655,767 (assigned to Dow Corning Corporation [Midland, MI], 1987). 34. T. Muraoka et al., “Percutaneous Absorption Preparation,” US Patent No. 6,132,761 (assigned to Nitto Denko Corporation [Osaka, JP], 2000). 35. P.W. Pretzer and R.P.Sweet,“Silicone Pressure-Sensitive Adhesive Com- position Containing Functionalized Polyisobutylene,” US Patent No. 5,939,477 (assigned to Dow Corning Corporation [Midland, MI], 1999). 36. K.J. Godbey, “Improving Patient Comfort with Nonocclusive Trans- dermal Backings,” in American Association of Pharmaceutical Scien- tists, 1996, pp. 1–2. 37. D. Rolf, U. Sjoblom, and K. Elisabeth,“Method of Forming Adhesive Patch for Applying Medication to the Skin,”U.S. Patent No. 6,096,333 (assigned to LecTec Corporation [Minnetonka, MN], 2000). 38. A. Santoro et al., “Pharmaceutical Development and Characteristics of a New Glyceryl Trinitrate Patch,” Arzneimittel-Forschung/Drug Re- search 50 (2), 897–903 (2000). 39. Polymer Handbook; Interscience Publishers: New York, NY, 1975. 40. J.L. Gardon, in Encyclopedia of Polymer Science and Technology, N.M. Bikaless, Ed. (Interscience Publishers, New York, NY, 1965), pp. 833–862. 41. H. Gabiga, K. Cal, and S. Janicki,“Effect of Penetration Enhancers on Isosorbide Dinitrate Penetration through Rat Skin from a Transder- mal Therapeutic System,” Int. J. Pharm. 199, 1–6 (2000). 42. D.G. Maillard-Salin, P. Becourt, and G. Couarraze, “Physical Evalua- tion of a New Patch Made of a Progestomimetic in a Silicone Matrix,” Int. J. Pharm. 199, 29–38 (2000). 43. D.G. Maillard-Salin, P. Becourt, and G. Couarraze, “A Study of the Adhesive–Skin Interface: Correlation between Adhesion and Passage of a Drug,” Int. J. Pharm. 200, 121–126 (2000).

Circle/eINFO 53 78 Pharmaceutical Technology MAY 2002 www.pharmtech.com INFORMATION FOR AUTHORS 44. A.F. El-Kattan, C.S. Asbil, and B.B. Michniak, “The Effect of Terpene Enhancer Lipophilicity on the Percutaneous Permeation of Hydro- cortisone Formulated in HPMC Gel Systems,” Int. J. Pharm. 198, 179–189 (2000). 45. P. Minghetti et al.,“Development of Local Patches Containing Melilot Extract and Ex Vivo–In Vivo Evaluation of Skin Permeation,” Eur. J. Pharm. Sci. 10, 111–117 (2000). 46. R. Sutinen, P.Paronen, and A. Urtti,“Water-Activated, pH-Controlled Patch in Transdermal Administration of Timolol I: Preclinical Tests,” Eur. J. Pharm. Sci. 11, 19–24 (2000). harmaceutical Technology welcomes manuscripts on sub- 47. H. Iwase et al.,“Transdermal Absorption of L-Dopa from a New Sys- jects pertinent to all aspects of applied R&D, scale-up, and tem Composed of Two Separate Layers of L-Dopa and Hydrogel in Pmanufacturing technologies for the pharmaceutical indus- Rats,” Drug Dev. Ind. Pharm. 26 (7), 755–759 (2000). try. We focus on regulatory affairs, drug delivery systems, ingre- 48. T. Pongjanyakul, S. Prakongpan, and A. Priprem, “Permeation Stud- dients, processing, packaging, contract services, and validation. ies Comparing Cobra Skin with Human Skin Using Nicotine Trans- dermal Patches,” Drug Dev. Ind. Pharm. 26 (6), 635–642 (2000). Although manuscripts are reviewed by members of the maga- 49. S. Ohmori et al., “Transdermal Delivery of the Potent Analgesic Di- zine’s Editorial Advisory Board, they must first be submitted to hydroetorphine: Kinetic Analysis of Skin Permeation and Analgesic the editor. Effect in the Hairless Rat,” J. Pharm. Pharmacol. 52, 1437–1449 (2000). Before submitting a completed work, authors are urged to 50. Y.-J. Cho and H.-K. Choi,“Enhancement of Percutaneous Absorption review manuscripts for clarity of expression, details of gram- of Ketoprofen: Effect of Vehicles and Adhesive Matrix,” Int. J. Pharm. 169, 95–104 (1998). mar, and typographical accuracy. Acronyms and abbreviations 51. J.-H. Kim, Y.-J. Cho, and H.-K. Choi,“Effect of Vehicles and Pressure- should be defined. The author is responsible for all statements Sensitive Adhesives on the Permeation of Tacrine across Hairless Mouse in his or her work. All accepted manuscripts are subject to copy Skin,” Int. J. Pharm. 196, 105–113 (2000). editing. Although rejected manuscripts are returned to the au- 52. C.D. Ebert et al., “Development of a Novel Transdermal System De- thor, Pharmaceutical Technology is not responsible for the safety sign,” J. Controlled Release 6, 107–111 (1987). 53. T. Kokubo, K. Sugibayashi, and Y. Morimoto, “Diffusion of Drug in of manuscripts, artwork, or photographs. Acrylic-Type Pressure-Sensitive Adhesive Matrices on the Drug Dif- Copyright. Manuscripts are reviewed with the understanding fusion,” J. Controlled Release 17, 69–78 (1991). that they are the authors’ original work, they have not been 54. T. Okano et al.,“Control of Drug Concentration–Time Profiles In Vivo published previously, and they are not under consideration for by Zero-Order Transdermal Delivery Systems,” J. Controlled Release 6, publication elsewhere, including on the Internet. Accepted 99–106 (1987). 55. P.R. Keshary, Y.C. Huang, and Y.W. Chien, “Mechanism of Transder- manuscripts become the property of Pharmaceutical Technol- mal Controlled Nitroglycerin Administration III: Control of Skin- ogy and may not be published elsewhere without written per- Permeation Rate and Optimization,” Drug Dev. Ind. Pharm. 11 (6,7), mission from Pharmaceutical Technology.Ifany illustrations or 1213–1253 (1985). figures in a manuscript have been published elsewhere, the au- 56. S.D. Roy et al.,“Controlled Transdermal Delivery of Fentanyl: Charac- thor is responsible for obtaining permission to republish. terizations of Pressure-Sensitive Adhesives for Matrix Patch Design,” J. Pharm. Sci. 85 (5), 491–495 (1996). Manuscripts may be submitted in the following ways: 57. R. Krishna and J.K. Pandit, “Transdermal Delivery of Propranolol,” ● via e-mail to Michael MacRae, editorial director ([email protected] Drug Dev. Ind. Pharm. 20, 2459–2465 (1994). PT advanstar.com) ● via postal mail on a Zip disk or CD. Preparing the document. The text file should be formatted in text-only code or Microsoft Word. Disks should be labeled with FYI the file name and the name of the word processing, graphics, Inhalation Aerosol Technology Workshop and/or spreadsheet programs used. Authors should furnish The University of Maryland Department of two hard copies of the manuscript. A length of 10–20 pages Pharmaceutical Sciences will present its 12th (double-spaced copy) is preferred. annual Inhalation Aerosol Technology Workshop Illustrations may be in color or black and white. Color photos 8–11 July 2002 in Baltimore,Maryland. should be enclosed with the article in the form of a transparency The workshop consists of a three-day course and or slide. TIFF (Mac), TIF (PC), JPEG, and EPS/EPSF (Mac or an optional laboratory session and will focus on the PC) files also are acceptable but must have a minimum resolu- theoretical basis and experimental techniques of tion of 300 dpi. the conception,design,preparation,and evaluation If you have questions about the submission of your manu- of modern inhalation devices. script, feel free to contact the editor. Send manuscripts to For more information,contact Richard Dalby,PhD, University of Maryland,Department of Pharma- ceutical Sciences,20 North Pine St.,Baltimore,MD 21201-1180,tel.410.706.3245,fax 410.706.0346, ¨ [email protected],www.pharmacy. umaryland.edu/faculty/rdalby/default.htm. 859 Willamette Street, Eugene, OR 97401-6806, USA Tel. 541.343.1200, www.pharmtech.com

80 Pharmaceutical Technology MAY 2002 www.pharmtech.com