INTRODUCTION:

The potential of using flawless skin as , route of drug administration has been known for several years. The application of drugs to the skin to comfort ailments is a practice that has been employed by mankind which included the application of poultices, gels, ointments, creams, and pastes. These applications were primarily utilized for a local topical effect. The purpose of adhesive skin patches, for delivering drugs in systemic circulation is a relatively new phenomenon¹.

The first adhesive transdermal delivery system (TDDS) patch was endorsed by the Food and Drug Administration in 1979, when scopolamine patch was introduced for motion sickness. Later, Nitroglycerine patches were approved in 1981. Transdermal delivery became widely recognized when nicotine patches for smoking cessation were introduced in 1991².

TDDS offers many pharmacological advantages over the oral route and thus it could improve patient acceptability and compliance. The patch is adhered to skin a providing a controlled and continuous delivery of drug. It posses several advantages, such as :

a. It scales down the typical dosing schedule, to once daily to even once weekly.

b. The non invasive peculiar and easy termination of therapy makes it patient friendly and improving patient compliance³.

c. By avoiding hepatic first pass metabolism (a phenomenon of drug metabolism in liver whereby the drug concentration is greatly reduced during the process of absorption before it reaches into the systemic circulation), it improves bioavailability,

d. It provides constant blood level in the plasma for drugs with narrow therapeutics index, thus minimizing the risk of toxic effects,

e. It is suitable for unconscious patients,

f. Low dose dumping potential (a phenomenon in which various factors (such as environmental, formulation anatomical/structural, metabolical etc.) can cause the premature and exaggerated release of a drug from the dosage form. This can greatly increase the concentration of a drug in the body; causes drug accumulation and thereby produce adverse effects or even drug induced toxicity), reduced incidence of systemic toxicity and lastly⁴,

g. Avoids gastric side effects/degradation/disorders.

In the last decades, the patches as bioadhesive dosage form have been gaining an increasing interest, as an substitute to semisolid dosage forms due to the probability of prolonged drug release over a duration upto 7 days and predetermining the administered dose⁵. The three different monographs are reported in the European Pharmacopoeia on the basis of variation in therapeutic goals pursing administration of dose onto skin⁶.The ‘Transdermal patches’ monograph refers to drug delivery systems intended to be applied to the unbroken skin in order to deliver the active substance(s) to the systemic circulation after passing through the skin barrier. In the other two monographs, patches are reported to maintain the active substance(s) in close contact with the skin such that these may be absorbed slowly, in order to guarantee a regional effect, or act as protective or keratolytic agents (medicated plasters) or to administer a drug to skin such that it may act locally (cutaneous patches).

The Japanese Pharmacopoeia distinguishes between plasters intended to locally release the active ingredient and transdermal systems assuring a systemic effect .Out of many transdermal deisgns, pharmaceutical-grade pressure-sensitive adhesives (PSAs) plays a critical role in the function and accurate delivery of TDDS⁷. Most drug delivery development projects begin by considering an existing base adhesive technology.

The base adhesive chemistries for passive TDDS include polyisobutylene, acrylics and silicone formulations in several types of patch constructions :

1. Single-layer drug in adhesive:

The inclusion of drug directly within the skin contacting adhesive. In this transdermal delivery system, the adhesive not only serves to affix the system to skin but also assist as formulation substratum, incorporating the drug and all excipients in single backing membrane.

2. Multiple-layer drug in adhesive:

It is similar to single layer drug in adhesive .It constitutes more than one adhesive layer containing the drug and bonds multiple component layers together while affixing the patch to the skin

3. Drug matrix in adhesive:

It constitutes a semi-solid matrix drug layer, which is surrounded by an adhesive overlay that affixes the patch to skin

4. Drug reservoir:

A liquid drug compartment, containing a drug solution or suspension, is separated from the adhesive layer by a diffusion-controlling membrane.

Although, transdermal patches offers advantages but passive systems are restricted to low-dosage lipophilic and low molecular-weight molecules (<500 daltons). The development of incorporating chemical enhancers, by altering the permeability of the stratum corneum layer of the skin could allows delivery of higher molecular weight compounds across skin membrane. Penetration enhancers may include chemicals such as ethanol, propylene glycol, oleic acid, azone, terpenes and bile acids⁷. The purpose of enhancers only slightly broadens the range of drugs eligible for passive delivery.

Adhesive manufacturers have responded by developing ‘enhancer-tolerant’ adhesive formulations that maintain their PSA properties when exposed to chemical enhancers.

Many of the development efforts in transdermal drug delivery are focused on active systems for delivering a wider range of drug molecules, including proteins such as vaccines.

Targeted drug delivery applications for alternative treatment sites beyond skin delivery are another area of development that can further benefit from TDDS adhesives and polymer coatings.

Polymers

Polymers are the backbone of a transdermal drug delivery system. Systems for transdermal delivery are fabricated as multilayered polymeric laminates in which a drug reservoir or a drug–polymer matrix is sandwiched between two polymeric layers: an outer impervious backing layer that prevents the loss of drug through the backing surface and an inner polymeric layer that functions as an adhesive and/or rate-controlling membrane. Transdermal drug delivery systems are broadly classified into the following three types.

Reservoir systems.

In this system, the drug reservoir is embedded between an impervious backing layer and a rate controlling 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.

Microreservoir systems:

This drug delivery system is a combination of reservoir and matrix-dispersion systems. The drug reservoir is formed by first suspending the drug in an aqueous solution of water-soluble polymer and then dispersing the solution homogeneously in a lipophilic polymer to form thousands of unleachable, microscopic spheres of drug reservoirs. The thermodynamically unstable dispersion is stabilized quickly by immediately cross-linking the polymer in situ⁸.

Transdermal drug delivery technology represents one of the most rapidly advancing areas of novel drug delivery. This growth is catalyzed by developments in the field of polymer science. This article focuses on the polymeric materials used in transdermal delivery systems, with emphasis on the materials’ physicochemical and mechanical properties, and it seeks to guide formulators in the selection of polymers. Polymers are used in transdermal delivery systems in various ways, including as

● matrix formers

● rate-controlling membranes

● pressure-sensitive adhesives (PSAs)

● backing layers

● release liners.

Polymers used in transdermal delivery systems should have biocompatibility and chemical compatibility with the drug and other components of the system such as penetration enhancers and PSAs. They also should provide consistent, effective delivery of a drug throughout the product’s intended shelf life or delivery period and have generally-recognized-as-safe status. From an economic point of view, a delivery tool kit rather than a single delivery tool is most effective⁹.

Companies involved in the field of transdermal delivery concentrate on a few selective polymeric systems. For example, Alza Corporation (Mountain View, CA) mainly concentrates on ethylene vinyl acetate (EVA) copolymers or microporous polypropylene, and Searle Pharmacia (Barceloneta, PR) concentrates on silicone rubber¹⁰. A review of the marketed transdermal products and the formulations that are reported in various research publications reveals an enormous diversity of polymers used in the formulation, engineering, and manufacture of drug products (Table 1)

Matrix formers:

Polymer selection and design must be considered when striving to meet the diverse criteria for the fabrication of effective transdermal delivery systems. The main challenge is in the design of a polymer matrix, followed by optimization of the drug loaded matrix not only in terms of release properties, but also with respect to its adhesion–cohesion balance, physicochemical properties, and compatibility and stability with other components of the system as well as with skin.

A monolithic solid-state design often is preferred for passive transdermal delivery systems because of manufacturing considerations and cosmetic appeal. Although polymeric matrices are used for rate control, adhesion (e.g., a PSA), or encapsulation of a drug reservoir in transdermal delivery systems, discussion in this section is limited to polymers that have been used in the design of matrices with or without rate control¹¹.

Cross-linked poly(ethylene glycol) (PEG) networks:

Biocompatibility of PEGs makes them the polymers of choice for numerous biomedical applications. Proteins can be delivered by PEGs cross-linked with tris(6-isocyanatohexyl) isocyanurate by means of a urethane–allophanate bond to obtain polymer networks capable of swelling in phosphate-buffered saline or ethanol and forming gels. These systems have been shown to release the solutes in a biphasic manner¹².

Acrylic-acid matrices:

Acrylic-acid matrices with plasticizers have been used to make drug–polymer matrix films for transdermal delivery systems. Some of the polymers that have been reported are Eudragit RL PM, Eudragit S-100, Eudragit RS PM, and Eudragit E-100 (Röhm America, Piscataway, NJ) (6). Eudragit NE-40D (a copolymer of ethyl acrylate and methyl methacrylate), a nonadhesive hydrophobic polymer, also has been used as a matrix former. The release rates of drugs from these matrix systems are more closely described by the square-root-of-time model.

Ethyl cellulose (EC) and polyvinylpyrrolidone (PVP):

EC and PVP matrix films with 30% dibutyl phthalate as a plasticizer have been fabricatd to deliver diltiazem hydrochloride and indomethacin. The addition of hydrophilic components such as PVP to an insoluble film former such as ethyl cellulose tends to enhance its release-rate constants. This outcome can be attributed to the leaching of the soluble component, which leads to the formation of pores and thus a decrease in the mean diffusion path length of drug molecules to release into the dissolution medium. The result is higher dissolution rates. Substances such as PVP act as antinucleating agents that retard the crystallization of a drug. Thus they play a significant role in improving the solubility of a drug in the matrix by sustaining the drug in an amorphous form so that it undergoes rapid solubilization by penetration of the dissolution medium¹³.

Hydroxypropyl methylcellulose (HPMC):

HPMC, a hydrophilic swellable polymer widely used in oral controlled drug delivery, also has been explored as a matrix former in the design of patches of propranolol hydrochloride. HPMC has been shown to yield clear films because of the adequate solubility of the drug in the polymer. Matrices of HPMC without rate-controlling membranes exhibited a burst effect during dissolution testing because the polymer was hydrated easily and swelled, leading to the fast release of the drug¹⁴.

Organogels:

Some nonionic surfactants such as sorbitane monostearate, lecithin, and Tween tend to associate into reverse micelles. These surfactants in an organic solvent, upon the addition of water, undergo association reorientation to form a gel. These organogels can be used as a matrix for the transdermal delivery of drugs with greater influx. Bhatnagar and Vyas proposed a reverse micelle-based microemulsion of soy lecithin in isooctane gelled with water as a vehicle for transdermal delivery of propranolol. The transdermal flux of propranolol from this organogel increased 10-fold over a vehicle composed of petrolatum.Willimann et al. also described organogels obtained when small amounts of water were added to a solution of lecithin in organic solvents, used as matricesfor the transdermal transport of drugs. The gels obtained in this manner are isotropic and thermoreversible (liquefy at temperature 40ºC) and can solubilize lipophilic, hydrophilic, and amphoteric substances, including enzymes. They are biocompatible and are stable for a long time¹⁵.

Organogels can cause slight disorganization of the skin, an outcome that is attributable to the organic solvent that is used to make the gel. Thus, organogels can enhance the permeation of various substances. Pluronic lecithin organogels also have been used as transdermal delivery systems because both hydrophobic and hydrophilic drugs can be incorporated into them.

Oil-soluble drugs are miscible with the lecithin phase, and water-soluble drugs are miscible with the aqueous phase.

Rate-controlling membranes:

Reservoir-type transdermal drug delivery systems contain an inert membrane enclosing an active agent that diffuses through the membrane at a finite, controllable rate. The release rate– controlling membrane can be nonporous so that the drug is released by diffusing directly through the material, or the material may contain fluid-filled micropores — in which case the drug may additionally diffuse through the fluid, thus filling the pores. In the case of nonporous membranes, the rate of passage of drug molecules depends on the solubility of the drug in the membrane and the membrane thickness. Hence, the choice of membrane material must conform to the type of drug being used. By varying the composition and thickness of the membrane, the dosage rate per area of the device can be controlled¹⁶.

EVA. EVA frequently is used to prepare rate-controlling membranes in transdermal delivery systems because it allows the membrane permeability to be altered by adjusting the vinyl acetate content of the polymer. For example, when ethylene is copolymerized with vinyl acetate, which is not isomorphous with ethylene, the degree of crystallinity and the crystalline melting point decreases and amorphousness increases . As the solutes permeate easily through the amorphous regions, the permeability increases. The copolymerization also results in an increase in polarity. Hence, an increase in the vinyl acetate content of a copolymer leads to an increase in solubility and thus an increase in the diffusivity of polar compounds in the polymers. However, at vinyl acetate levels 60% by weight, the glass-transition temperature, Tg, of polymer increases from ~ 25 º C to ~ 35º C. An increase in Tg reflects a decrease in the polymer-chain mobility and hence the solute diffusivity. The effect of these structural changes on membrane permeability is shown in the permeation of camphor through a series of poly(ethylene vinyl acetate) copolymers, which has exhibited a maximum of limiting flux at ~ 60% vinyl acetate content¹⁷.

Silicone rubber:

The silicone rubber group of polymers has been used in many controlled-release devices. These polymers have an outstanding combination of biocompatibility, ease of fabrication, and high permeability to many important classes of drugs, particularly steroids. The high permeability of these materials is attributed to the free rotation around the silicone rubber backbone, which leads to very low microscopic viscosities within the polymer¹⁸.

Polyurethane:

Polyurethane is the general term used for a polymer derived from condensation of polyisocyanates and polyols having an intramolecular urethane bond or carbamate ester bonds (NHCOO). The polyurethanes synthesized from polyether polyol are termed polyether urethanes, and those synthesized from polyester polyol are termed polyester urethanes. Although most polyurethanes presently used are of the polyether type because of their high resistance to hydrolysis , polyester polyurethanes recently have become the focus of attention because of their biodegradability . These polyester or polyether urethanes are rubbery and relatively permeable. The hydrophilic–hydrophobic ratio in these polymers can be balanced to get the optimum permeability properties. Polyurethane membranes are suitable especially for hydrophilic polar compounds having low permeability through hydrophobic polymers such as silicone rubber or EVA membranes¹⁹.

PSAs:

A PSA is a material that adheres with no more than applied finger pressure, is aggressively and permanently tacky, exerts a strong holding force, and should be removable from a smooth surface without leaving a residue . Adhesion involves a liquid-like flow resulting in wetting of the skin surface upon the application of pressure, and when pressure is removed, the adhesive sets in that state. For an adhesive bond to have measurable strength, elastic energy must be stored during the bond-breaking process. Therefore, pressure-sensitive adhesion is a characteristic of a visco-elastic material. The balance of viscous flow and the amount of stored elastic energy determine the usefulness of a PSA material²⁰.

Acrylic, polyisobutylene, and silicone-based adhesives are used mostly in the design of transdermal patches . The selection of an adhesive is based on a number of factors, including the patch design and drug formulation. For reservoir systems with a peripheral adhesive, an incidental contact between the adhesive and the drug or penetration enhancers must not cause instability of the drug, penetration enhancer, or the adhesive. In the case of reservoir systems that include a face adhesive, the diffusing drug must not affect the adhesive.

Furthermore, the choice of adhesive also may be based on the adhesion properties and on skin compatibility. For matrix designs in which the adhesive, the drug, and the penetration enhancers must be compounded, the selection will be more complex. Once the basic criterium of chemical compatibility between all the ingredients is established, the selection will be based on the rate at which the drug and the penetration enhancer will diffuse through the adhesive²¹.

The physicochemical characteristics of a drug–adhesive combination such as solubility and partition coefficient and adhesive characteristics such as the extent of cross-linking — will determine the choice of adhesive for a drug. In the case of adhesives that are not cross-linked, enhancers or other formulation ingredients that have solubility parameters similar to those of the adhesive can reduce cohesive strength and can plasticize the adhesive. Significant loss of cohesive strength can result in an increase in tack, cold flow beyond the edge of the patch, and a transfer of adhesive to the release liner and to the skin during removal. Another possible result of the interaction can be an increase in cohesive properties by either acting as extending or reinforcing fillers or by inducing cross-linking²². The general formula for a PSA includes an elastomeric polymer, a tackifying resin, a necessary filler, various antioxidants, stabilizers if required, and cross-linking agents.When formulating a PSA, a balance of four properties must be taken into account: tack, peel adhesion, skin adhesion, and cohesive strength. PSAs bind to the skin after a brief contact known as tack. The term tack is used to quantify the sticky feel of the material. This property often is perceived by the user when the patch is applied to the skin and quickly pulled off. It is not necessarily related to the strength of the ultimate adhesive bond or to the duration of adhesion to the skin. Adhesion refers to the force required to remove the adhesive from a substrate once the bond has reached equilibrium. Some PSAs may have low tack but subsequently may develop a high degree of adhesion to the skin. In contrast, many skin adhesives have a relatively high degree of tack and only modest skin-adhesion value ²⁰.

Polyisobutylene (PIB):

Isobutylene polymerizes in a regular head-to-tail sequence by low-temperature cationic polymerization to produce a polymer having no asymmetric carbons. In its unstrained state, the polymer is in an amorphous state, and the Tg of the polymer is 70ºC . The physical properties of the polymer change gradually with increasing molecular weight. Low molecular weight polymers are viscous liquids.With increasing molecular weight, the liquids become more viscous, then change to balsam-like sticky masses and finally form elastomeric solids. PIB PSAs usually comprise a mixture of high molecular weight and low molecular weight fractions.High molecular weight PIB has a viscosity average molecular weight between 450,000 and 2,100,000, and low molecular weight PIB has an average molecular weight between 1000 and 450,000. PIB has the chemical properties of a saturated hydrocarbon. It is readily soluble in nonpolar liquids. Cyclohexane is an excellent solvent, benzene is a moderate solvent, and dioxane is a nonsolvent for PIB polymers²³.

Un-cross-linked polymers exhibit a high degree of tack or self-adhesion. PIB polymers have a very low fractional free volume the most frequently used reinforcing filler by virtue of its high surface area, interacts with the surface of polymer chains and alters chain dynamics, thus enhancing tensile properties and abrasion resistance. Other fillers that are used are talc and calcined clay. Colloidal silicon dioxide is used as a filler in clonidine patches (Catapres-TTS). Nonreinforcing fillers such as calcium carbonate and titanium dioxide are added to reduce viscosity and cost. Fillers also are used to enhance the drug release from the matrix. Titanium dioxide has been used in the EVA matrix to reduce the amount of naloxone contained in the depleted systems, and PVP has been used to enhance the release of formoterol from acrylic PSAs.Petroleum-based oils, butyl polybutenes, paraffin waxes, and low molecular weight polyethylene can be used as plasticizers. Alkyl adipates and sebacates also are used to reduce the Tg value and improve the low-temperature properties. Various resins with a Tg value greater than that of the elastomer act as tackifiers.

Polyacrylates:

Acrylic esters are represented by the general formula CH2=CH-COOR. The nature of the R group determines the properties of each ester and the polymer it forms. Polymers of this class are amorphous and are distinguished by their water-clear color in solution and stability toward aging. As is typical of polymer systems, the mechanical properties of acrylic polymers improve as the molecular weight increases. However, beyond a critical molecular weight, which is ~1x10³ to 2 x 10³ for amorphous polymers, the improvement is slight and levels off asymptotically. The Tg value of a copolymer can be altered by the copolymerization of two or more polymers. Most acrylic polymers have a very low Tg value therefore, in copolymer they tend to soften and flexibilize the overall composition. The approximate Tg value for copolymers can be calculated from the weight fraction of each monomer (W1) and the Tg of each homopolymer as shown in the following equation²⁴:

1 = W₁ + W₂

T_G(copolymer)(T_G1) (T_G2)

Plasticizers also can be used to lower the Tg. However, unlike volatilization or extraction.

Acrylic polymers are highly stable compounds. Unless they are subjected to extreme conditions, acrylic polymers are durable and degrade slowly. Oxidative degradation of acrylic polymers can occur in high-pressure and high-temperature conditions by the combination of oxygen with the free radicals generated in the polymer to form hydroperoxides.

Acrylic polymers and copolymers have a greater resistance to both acidic and alkaline hydrolysis than do poly(vinyl acetate) and vinyl acetate copolymers. In extreme conditions of acidity or alkalinity, acrylic ester polymers can be made to hydrolyze to poly(acrylic acid) or to an acidic salt and the corresponding alcohol. Acrylic polymers are insensitive to normal UV degradation because the primary UV absorption of acrylics occurs below the solar spectrum. A UV absorber such as o-hydroxybenzophenone can be incorporated to further enhance the UV stability^25,26.

Silicones:

Silicone PSAs comprise polymer or gum and a tackifying resin. Medical-grade silicone adhesives contain a lowviscosity dimethylsiloxane polymer (12 x 10³ cP to 15 x 10³ cP) , which has a terminal silanol group. The silicone resin has a three-dimensional silicate structure that is end capped with trimethyl siloxy groups (-OSi[CH3]3) and contains residual silanol functionality.The adhesive is prepared by crosslinking the reactants in solution by a condensation reaction between silanol groups on the linear poly(dimethylsiloxane) polymer and silicate resin to form siloxane bonds (Si-O-Si). Unlike acrylic-, rubber-, and PIB-based adhesives, medical-grade silicone adhesives do not contain organic tackifiers, stabilizers, antioxidants, plasticizers, catalysts, or other potentially toxic extractables. These additives are not required because silicone PSAs are stable throughout a wide range of temperatures (-73 to +250ºC).

The end-use properties of silicone-based PSAs such as tack, peel adhesion, skin adhesion, and cohesion can be modified or customized by varying the resin–polymer ratio, the silanol functionality, and the level and type of cross-linking agent. Normally the shear strength and the tack of a PSA first increase and then reach a maximum as increasing amounts of tackifying resin are added. The peel strength usually increases with the amount of tackifying resin. The shear-holding power often depends on the mode of cross-linking. Although the silicone group of adhesives has an outstanding combination of biocompatibility and ease of fabrication for hydrophilic drugs, the solubility, permeability, and releasing properties are poor²⁷.

Some of the silicone PSAs contain a significant degree of free silanol–functional groups. Certain amino-functional drugs can act as catalysts to cause further cross-links between these silanol groups. This unwanted reaction can be reduced, thus enhancing a PSA’s chemical stability, by end capping the silanol groups with methyl groups by means of a trimethyl silylation reaction . Some of the trace components in acrylic-adhesive blends reacted with a variety of drugs and caused coloring, which deepens with time. This problem was overcome when 2-mercaptobenzimidazole and/or propyl gallate were incorporated into the adhesive composition

Hot-melt PSAs (HMPSAs):

Typical PSAs include a volatile organic solvent for reducing the viscosity of the composition to a coatable room-temperature viscosity. After the product is coated, the organic solvent is removed by evaporation. When they are heated, HMPSAs melt to a viscosity suitable for coating, but when they are cooled they generally stay in a flowless state. HMPSAs are advantageous over solvent-based systems because they

● do not require removal and containment of the solvents

● do not require special precautions to avoid fire

● are amenable to coating procedures other than those commonly

used with solvent-based systems

● are more easily coated into full thickness with minimal bubbling, which often results with solvent-containing PSAs.

Hot-melt adhesives are based on thermoplastic polymers that may be compounded or uncompounded. Of these polymers, EVA copolymers are most widely used. Polybutenes, phthalates, and tricresyl phosphate often are added as plasticizers to improve mechanical shock resistance and thermal properties. Antioxidants such as hindered phenols are added to prevent oxidation of ethylene-based hot-melt adhesives. Fillers opacify or modify an adhesive’s flow characteristics and reduce the cost. Paraffin and microcrystalline wax are added to alter the surface characteristics by decreasing the surface tension and the viscosity of the melt and to increase the strength of the adhesive upon solidification. Moisture-curing urethanes have been attempted as cross-linking agents to prevent creep under the load of these thermoplastic materials. Silicone-based adhesives also are amenable to hot-melt coating. US Patent No. 5,352,722 describes the process of preparing a silicone-based HMPSA in which the dynamic viscosity of a basic adhesive formulation consisting of a polysilicate resin and a silicone fluid is reduced by adding alkylmethylsiloxane waxes²⁸. Thus the coatability of a PSA without solvents is improved. Pretzer and Sweet described a silicone-based HMPA that contained a mixture of silicate resin and a polyorganosiloxane fluid into which polyisobutylene polymer with a functionalized silicon-containing moiety was incorporated. The adhesive was claimed to possess a reduced propensity to cold flow²⁹.

Backing layer:

When designing a backing layer, the developer must give chemical resistance of the material foremost importance. Excipient compatibility also must be seriously considered because the prolonged contact between the backing layer and the excipients may cause the additives to leach out of the backing layer or may lead to diffusion of excipients, drug, or penetration enhancer through the layer.However, an overemphasis on the chemical resistance often may lead to stiffness and high occlusivity to moisture vapor and air, causing patches to lift and possibly irritate the skin during long-term wear. The most comfortable backing may be the one that exhibits the lowest modulus or high flexibility, good oxygen transmission, and a high moisture-vapor transmission rate.

In a novel modification to the conventional design, a patch was fabricated in which the backing itself acted as a reservoir for the drug. The upper internal portion of the drug reservoir infiltrated the porous backing and became solidified therein after being applied so that the reservoir and the backing were unified. This modification enabled the backing itself to act as a storage location for the medication-containing reservoir³⁰.

Release liner:

During storage the patch is covered by a protective liner that is removed and discharged immediately before the application of the patch to the skin. It is therefore regarded as a part of the primary packaging material rather than a part of the dosage form delivering the active principle. However, because the liner is in intimate contact with the delivery system, it should comply with specific requirements regarding the chemical inertness and permeation to the drug, penetration enhancer, and water. In case cross-linking is induced between the adhesive and the release liner, the force required to remove the liner will be unacceptably high. 3M, for example, manufactures release liners made of fluoro polymers (Scotchpak 1022 and Scotchpak 9742, 3M Drug Delivery Systems, St. Paul, MN)³¹.

Evaluation of adhesion properties:

The adhesive performance of TDDS is a critical factor determining its drug delivery, therapeutic effect and patient compliance. Several in vitro techniques have been used to monitor adhesive performance such as peel adhesion, tack and shear strength.

However, these tests were developed for industrial pressure sensitive tapes. Peel adhesion, tack and shear measurements are not true material properties of the adhesive since they depend on substrate, backing material and test parameters.

The testing of the adhesive properties of the TDDS in its final form is very crucial to ensure acceptable adhesive quality. The evaluation of the PSA in bulk, even if the effects of the active ingredient and other excipients are studied, is not sufficient to predict the adhesive performance of the TDDS. Causes of instability such as the drug and excipients undergoing phase changes (e.g. dissolved drug may crystallize, dispersed drug may agglomerate) could adversely affect adhesive properties. Adhesive customization is important in product development. Adhesive properties can be influenced by the type and concentration of additives used for improving the adhesion properties, the thickness of the adhesive, the type and concentration of the drug loaded, the type and concentration of enhancers, the composition and thickness of the backing membrane and the solvent residue³².

Peel adhesion:

Peel adhesion measures the force required to peel away an adhesive once it has been attached to a surface. Most currently used test methods for TDDS peel adhesion are based on methods developed for industrial tapes. These typically call for the use of a stainless steel test panel as the substrate, peel angles of 901 or 1801, cutting the sample into an exact width, dwell times of one minute and a peel speed of 300 mm/min. The peel adhesion measurement is greatly influenced by the experimental parameters such as dwell time, substrate (e.g. stainless steel, skin, HDPE), peel angle, peel speed, etc. The measurement also depends on the TDDS backing and adhesive thickness. There are several complications with measuring in vitro peel adhesion. To begin with, cutting the TDDS to measure peel adhesion can be difficult. TDDS that are of the reservoir type may “leak” when cut; therefore, reservoir systems may need to be ran “as-is.” Secondly, the type of test panel and stretching of the patch backing will affect peel adhesion. The typical test panel, stainless steel, has a surface energy that is quite different from that of human skin (500 and 27 mJ/m2, respectively); the strength of the bond established between the TDDS and the stainless steel test panel may be greater than the tensile strength of the TDDS backing.

Calculation of peel adhesion can be difficult. Peel adhesion is the force per unit width required to break the bond between an adhesive and the substrate (e.g. stainless steel) when the sample is peeled back at a controlled angle (e.g. 901) at a standard rate (e.g. 300 mm/min). In other words, peel values are reported in force per unit of width (e.g. N m). The value for peel adhesion is independent of length but is dependent upon the width of the sample³³.

Peel adhesion 180º test:

Adhesive patches were cut into strips 2.5 cm wide and conditioned for 24 h at 23.6 (±2ºC) and 50.6(±5%) relative humidity (R.H). The tests were performed in the same environmental conditions with an Instron Corporation Series IX Automated Material Testing System 1.26. The samples were applied to an adherent plate made of stainless steel, smoothed with a 4.5 pound roller, and pulled from the substrate at a 1801 angle at a rate of 300 mm/min. The matrix had to strip cleanly from the plate, leaving no visually noticeable residue³³ .

Thumb tack test

The thumb is lightly put into contact for a short time with a sample and then quickly withdrawn. By varying the pressure and time of contact and noting the difficulty of pulling the thumb from the adhesive, it is possible to perceive how easily, quickly, and strongly the adhesive can form a bond with the skin. Some major drawbacks of the thumb tack test are its subjectivity and the fact that the data are poorly quantifiable. However, it is the most simple and straightforward test for the evaluation of the adhesive skin bonding. All tests were simultaneously performed, blind, on five samples. The adhesive properties of the TS were expressed by the following value range: good adhesion, poor adhesion, and no adhesion³⁴.

Tack rolling ball test:

In this procedure, an 11-mm-diameter stainless steel ball weighing 5.6 mg is rolled down an inclined track (21º, 30ʹ) to come into contact at the bottom with horizontal upward-facing adhesive. Adhesive patches are cut in strips and conditioned for 24 h at 23.6 (± 2ºC) and 50. 6 (±5%) R.H. The running of the ball on the track is of 5.5 mm. The distance the ball traveled out along the tape is taken as the measure of tack. The distance the ball rolled gives an inverse compressed scale of tack; the greater the distance, the less tacky the adhesive, but not in proportion to the ratio of distance. The reciprocal of roll out distance was taken as the tack value. When the rolling of the ball on the adhesive tape was superior to 25 cm, the tack value was considered zero. The results were the average of five determinations and were expressed as the reciprocal of running of the ball on the adhesive tape³⁵.

Shear adhesion test:

This test is to be performed for the measurement of the cohesive strength of an adhesive polymer. It can be influenced by the molecular weight, the degree of crosslinking and the composition of polymer, type and the amount of tackifier added. An adhesive coated tape is applied onto a stainless steel plate; a specified weight is hung from the tape, to affect it pulling in a direction parallel to the plate. Shear adhesion strength is determined by measuring the time it takes to pull the tape off the plate. The longer the time take for removal, greater is the shear strength³⁶.

Probe tack test:

In this test, the tip of a clean probe with a defined surface roughness is brought into contact with adhesive, and when a bond is formed between probe and adhesive. The subsequent removal of the probe mechanically breaks it. The force required to pull the probe away from the adhesive at fixed at fixed rate is recorded as tack and it is expressed in N³⁴.

Prediction of patch in vivo adhesive performances

During clinical studies, the in vivo adhesive performances of a patch are usually evaluated calculating the percentage of dosage form remained attached to the skin over the entire period of application, namely the so-called patch survival rate.

More appropriately, it has been proposed a scoring system based on the observations regarding the permanence of the patch, the behavior during detachment and other subjective considerations of the users/patients. The FDA suggests an arbitrary adhesion scoring system in which the volunteer/ patient selects one of the following scores:

§ Score 0: 90% adhered (essentially no lifting off of the skin);

§ Score 1: 75 to 90% adhered (some edges only lifting off of the skin);

§ Score 2: 50 to 75% adhered (less than 50% of the system lifting off of the skin);

§ Score 3: < 50% adhered but not detached (more than 50% of the system lifting off of the skin without falling off); and

§ Score 4: patch completely off the skin³⁷.

The feasibility to elaborate an in vivo quantitative measurement of the patch adhesion to the skin was also studied adapting assays that generally are carried out to determine the peeling force, or the tackiness by quick stick test, or modified probe tack tests. In the last case, the stress--strain curves that are generated on the patch removal are registered by means of a dynamometer connected to the patch sample applied on the forearm, or the dorsal side of the hand, of volunteers. Raynaud and coworkers reported a deeper insight on the in vivo adhesive performances of a testosterone transdermal patch. The adhesion was qualitatively and quantitatively determined by a peel test performed at the standard peel rate of 300 mm/min and an inclination of 135º. The quantitative analyses evidenced a strong dependence of the peel strength on the application site according to the following rank order: thigh > lower back > arm, other than the experimental setup.The in vivo evaluations of the adhesiveness present ethical issue due to the possible safety risks related to the drug adsorption and, therefore, these tests should be performed only using the optimized formulation and preferably during clinical study, even if this approach can give bias problems³⁸.

To reduce the in vivo studies, several efforts were made to propose in vitro assays drawing relationship between the in vivo performances and the in vitro quantitative determinations. The experimental parameters, such as removal speed and/ or the adherend material, were varying in order to improve the significance of the in vitro tests. It was demonstrated that besides the 300 mm/min proposed by standardized tests of the adhesive tape associaions, the peeling-off at slower rate (i.e., 100 mm/min) better represents the patch removal rate from the skin³⁸. Furthermore, if the detachment of the patch occurred cohesively, the use of a peel rate lower than 300 mm/min generally leads to a decrease in the peel strength. The peel adhesion values determined in vitro by using a stainless steel plate could not be correlated to the in vivo performances of patch, because of the great difference in the interface condition between the patch and the adherends, namely the skin (28 - 29 dyne/cm) and the stainless steel plate (40 dyne/cm) . Some authors suggested the use of poly(tetrafluoroethylene) (PTFE) or polyethylene (PE) plates³⁹. The former material permitted to establish a good relationship between the in vitro and in vivo data by peel adhesion test on silicon-based PSA. The latter provided contrasting results depending on the PE density. The in vitro peel force required to remove a medical tape from human skin from cadaver resulted generally closer to that registered using high-density PE plate than that determined using stainless steel. Low-density PE seemed to better discriminate different methacrylic patches with respect to stainless steel . On the contrary, the stainless steel had a greater discrimination for transdermal patches than high-density PE.

The general consideration that can be withdrawn is that the use of materials with energy surface lower than stainless steel can allow obtaining data closer to those of the human skin.

Nevertheless, a true relationship was not found since other variables play a key role in the determination of patch adhesion on and detachment from the skin. For instance, it is difficult to individuate an artificial material that is able to properly simulate the continuous variations of skin humidity, which reflects on the critical surface tension, surface roughness and peculiar mechanical properties with particular emphasis on its deformability⁴⁰.

The effects of relative adherend humidity on peel adhesion performances can be studied by using collagen-coated plate. Skin deformability is probably the most critical issue to consider in the development of in vitro tests reliable to predict the in vivo performances, because it is a high compliant substrate. When a patch is peeled off, not only the detachment angle and the tensile strength of the patch, but also the tensile deformation, bending stiffness and substrate deformation have to be considered.

The stress distribution on skin deformation was measured in vivo by tension, torsion, suction and indentation tests. These data were recently used to elaborate skin models for adhesion test, which kept into account the skin deformability and rugosity. Deformable materials were studied as skin surrogates for peel adhesion or probe tack tests. The work expended in the patch detachment includes the adherend deformation, other than the surfaces separation, adhesive layer deformation, and patch stretching and bending. The force required to achieve the maximum extension, which is generally quite low (1.7 N), depends on the peel contact angle. The production of a substrate with a Young’s modulus (about 7 - 10 kPa) close to that of human skin would better discriminate patch performances including the adhesive/ cohesive shift as a function of peel rate and application time⁴¹.

The so-called dark ring on the skin is a less frequently studied issue related to the prolonged application of patches onto the skin and due to the low resistance of a PSA to the tangential stresses caused by the body movement. In this case, the patch can ooze or leave adhesive residues on its outside edges after skin application. Beside of being un-esthetical, as these adhesive residues can collect dirt and textile fibers, this phenomenon causes an alteration of the patch/skin contact area and, consequently, can determine an alteration of the drug absorption especially for long-term applications. The possible correlation among the in vitro adhesion properties and the in vivo performances of patches over a 7-day period of application can be established by the probe tack test.

Gutschke et al. drew a good relationship between the ‘dark ring on the skin’ and the deformation compliance extrapolated from the stress--strain curves⁴².

Regulatory strategy and aspects for approval of transdermal drug products

A transdermal patch is classified by the FDA as a combination product, consisting of a medical device combined with a drug or biological product that the device is designed to deliver. Prior to sale in the market, any transdermal patch product must apply for and receive approval from the FDA, demonstrating safety and efficacy for its intended use.⁴³ (Table 2).

§ Standard irritation and sensitization studies should be performed with the patch itself in animals/humans.

§ Negotiate the timing and implementation of the toxicology requirements.

§ The dermatology division at FDA will review dermal aspects of the investigated new drug (IND) and new drug application (NDA).

§ Primary review will occur at the division which handles the indication under study.

§ Dose ranging studies will usually be required in Phase 2.

§ Single Phase 3 study could be negotiated⁴⁴.

FDA regulation on transdermal drug products

The first FDA approved transdermal drug patch was in the year 1979. Since then, the TDDS have come a long way. The FDA regulation process for TDDS is very stringent. TDDS is a combinational device as defined in 21 CFR sections 3.2(e) by FDA. TDDS have to undergo pre-market approval and hence requires substantial evidence including bio-mechanical testing, animal testing, clinical trials studies before the transdermal patch can get approval for use in the market⁴⁵. The most recent approval in the field of TDDS was the approval of Nuepro patch for treatment of Parkinsonʹs disease.

In the case of Passive transdermal drug delivery system, the factor that requires consideration is ensuring that the drug in the drug-reservoir or the DIA is present and being delivered in a stable as well as controlled form. It is also important to understand the reactivity of the drug on the skin and ensure that the material used for manufacturing the transdermal patch do not have an reaction on the skin, for instance itching, inflammation etc.

Table 2. Regulatory aspects for approval of transdermal drug products

NEW drug application (NDA)	Abbreviated NDA
Safety: Toxicity studies (animals/humans) Skin irritation Skin sensitization Systemic toxicity Cutaneous toxicity Contact sensitivity Contact photodermatitis
Safety: Toxicity studies (animals/humans) Skin irritation Skin sensitization Systemic toxicity Cutaneous toxicity Contact sensitivity Contact photodermatitis	Skin irritation Cutaneous toxicity
Safety: Toxicity studies (animals/humans) Skin irritation Skin sensitization Systemic toxicity Cutaneous toxicity Contact sensitivity Contact photodermatitis
Efficacy: Clinical studies/PD Bioavailability/PK studies Bioequivalence studies Biopharmaceutical studies	Bioeqivalence studies
Manufacturing controls In-vitro release studies	Manufacturing controls In-vitro release studies: Paddle over disc method: FDA Method: Sandwitch and paddle method USP Method: Stainless steel Disk-adhesive patch QC STUIDES (batch to batch performance)
Metabolism studies	Depot effect
Clinical nature of the active drug	Body site
Literature data on drug entity	Approved inactive ingredients
Experiences with the API/DDS	Patch adhesion Stability test Assay/content uniformity

The patch also needs to be kept on from several hours to, in some cases, several days (e.g. contraceptive patch) and hence the properties of the patch like the type of polymers, adhesives used in the making also need special consideration⁴⁶. The material used for making the patch is polymers. There are various types of adhesive materials that are utilized for the construction of TDDS. In this article Table 2 describes the status of some FDA approved transdermal therapeutic system along with their generic name and approval date that are widely used in lieu of other drug delivery systems⁴⁷.

Marketed application of adhesive system in transdermal therapy

Several TDDS containing drugs such as clonidine, estradiol, fentanyl, lidocaine, nicotine, nitroglycerin, testosterone and scopoloamine are available⁴⁸. 3M Pharmaceuticals is a leader in pioneering the technological components in TDDS and those components are used for manufacturing the complete spectrum of drugs delivered transdermally. The annual market for TDDS is more than $3 billion⁴⁹.

REFERENCES:

1. Loyd V. Allen Jr, Nicholas G. Popovich, Howard C. Ansel. Pharmaceutical dosage forms and drug delivery systems, 8th Edition., Wolter Kluwer Publishers, New Delhi, 2005 pp. 298-299.

2. Kumar P, Sankar C, Mishra B. Delivery of macromolecules through skin. The Indian Pharmacist 2004,5(3): 7-17.

3. Kumar R, Philip A. Modified Transdermal Technologies: Breaking the Barriers of Drug Permeation via the Skin. Trop J Pharm Res. 2007, 6(1):633-644.

4. Rizwan M, Aqil M, Talegoankar S, Azeem A, Sultana Y, Ali A. Enhanced transdermal drug delivery techniques: an extensive review on patents. Recent Pat Drug Deliv and formul. 2009, 3(2):105-24.

5. Patches, transdermal. In European Pharmacopoeia, 7th edition 2011 Strasbourg, accessed online on March 28, 2011

6. General rules for preparations - 20. Plasters and pressure sensitive adhesive tapes. In Japanese Pharmacopeia XV Ed, 2006, accessed online on June 26, 2011

7. General rules for preparations - 28. Transdermal Systems In Japanese Pharmacopeia XV Ed, 2006, accessed online on June 26, 2011

8. Howard. C.Ansel, Loyd V.Allen, Nicholas G.Popovich. Pharmaceutical Dosage Forms and Drug Delivery Systems. 5th ed: 311-12.

9. Rizwan M, Aqil M, Talegoankar S, Azeem A, Sultana Y, Ali A. Enhanced transdermal drug delivery techniques: an extensive review on patents. Recent Pat Drug Deliv and formul. 2009, 3(2):105-24.

10. Y.W. Chien, “Transdermal Therapeutic Systems,” in Controlled Drug 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.

11. S.S. Davis and L. Illum,“Drug Delivery Systems for Challenging Molecules,” Int. J. Pharm. 176, 1–8 (1998).

12. R.W. Baker and J. Heller, “Material Selection for Transdermal Delivery Systems,” in Transdermal Drug Delivery: Developmental Issues and Research Initiatives, J. Hadgraft and R.H. Guys, Eds. (Marcel Dekker, Inc., New York, NY, 1989), pp. 293–311.

13. H.-M.Wolff,“Optimal Process Design for the Manufacturing of Transdermal Drug Delivery Systems,” PSTT 3 (5), 173–181 (2000).

14. Ho KY, Dodou K. Rheological studies on pressure-sensitive silicone adhesives and drug-in-adhesive layers as a means to characterise adhesive performance. Int J Pharm 2007;333:24-33.

15. H. Willimann et al Lecithin organogel as matrix for transdermal transport of drugs. J Pharm Sci. 1992:81(9):871-4.

16. P. Costa et al., “Design and Evaluation of a Lorazepam Transdermal Delivery System,” Drug Dev. Ind. Pharm. 23 (10), 939–944 (1997).

17. T.N. Kambe et al.,“Microbial Degradation of Polyurethane, Polyester Polyurethanes, and Polyether Polyurethanes,” Appl.Microbiol. Biotechnol. 51, 134–140 (1999).

18. P. Ramarao and P.V. Diwan, “Formulation and In Vitro Evaluation of Polymeric Films of Diltiazem Hydrochloride and Indomethacin for Transdermal Administration,” Drug Dev. Ind. Pharm. 24 (4), 327–336 (1998).

19. P.Walde et al., “Lecithin Microemulsion Gels as a Matrix for Transdermal Delivery of Drugs,” in International Symposium on Controlled Release of Bioactive Materials, (Controlled Release Society, Inc.,Minneapolis, MN, 1990), pp. 421–422.

20. M. Guyot and F. Fawaz, “Design and In Vitro Evaluation of Adhesive Matrix for Transdermal Delivery of Propranolol,” Int. J. Pharm. 204, 171–182 (2000).A.T. Florence and D.Attwood, in Physico-Chemical Principles of Pharmacy (Chapman and Hall, New York, NY, 1982), pp. 206.

21. H.S. Tan and W.R. Pfister, “Pressure-Sensitive Adhesives for Transdermal Drug Delivery Systems,” PSTT 2 (2), 60–69 (1999).

22. S. Barnhart, Critical Role of PSAs in Transdermal Drug Delivery; Adhesives and Sealants Industry, 1–6 April, 1998.

23. Hammond FH. Tack. In: Satas D, editor. Handbook of Pressure Sensitive Adhesive Technology II. Van Nostrand Reinhold; New York: 1989. p. 38-60

24. Kyriazanou AM, Dallas PP, Rekkas DM, et al. Effect of several factors on the mechanical properties of a pressure sensitive adhesive containing penetration enhancers. STP Pharm Sci 2002;12(5):283-6

25. R. Gale and L.A. Spitze,“Permeability of Camphor in Ethylene-Vinyl Acetate Copolymers,” in Proceedings: Eighth International Symposium on Controlled Release of Bioactive Materials (Controlled Release Society, Minneapolis, MN, 1981), p. 183.

26. Demarteau W, Loutz JM. Rheology of acrylic dispersions for pressure sensitive adhesives. Prog Org Coat 1996;27:33-44

27. Johnston J. Physical testing of pressure-sensitive adhesive systems. In: Pizzi A, Mittal KI, editors. Handbook of adhesive technology. Marcel Dekker Inc.; New York: 1994. p. 93-112

28. Randall P. et al., Silicone pressure sensitive adhesive containing alkylmethylsiloxane wax and related methods. US 5352722

29. Pretzer et al. Silicone pressure sensitive adhesive composition containing functionalized polyisobutylene US005939477A Aug. 17, 1999.

30. T.J. Franz et al., “Transdermal Delivery,” in Treatise on Controlled Drug Delivery: Fundamentals, Optimization, Applications, A. Kydonieus, Ed. (Marcel Dekker, Inc., New York, NY, 1991), pp. 341–421. AW.R. Pfister and D.S.T. Hsieh, “Permeation Enhancers Compatible with Transdermal Drug Delivery Systems, Part II: System Design Considerations,” Pharm. Technol. 14 (10), 54–60 (1990).

31. Steven-Fountain AJ, Atkins AG, Jeronimidis G, et al. The effect of flexible substrates on pressure-sensitive adhesive performance. Int J Adhes Adhes 2002;22:423-30

32. Kenney JF, Haddok TH, Sun RL, Parreira HC. Medical-grade acrylic adhesives for skin contact. J Appl Polym Sci 1992;45:355-61

33. Dalhquist CA. Creep. In: Satas D, editor. Handbook of Pressure Sensitive Adhesive Technology III. Satas and Associates; Warwick: 1999. p. 121-38

34. Pfister R.W, “Customizing Silicone Adhesives for Transdermal Drug Delivery Systems,” Pharm. Technol. 13 (3), 126–138 (1989).

35. Fuller C.C et al “X-ray Examination of Polyisobutylene,” J. Am. Chem. Soc. 62, 1905–1913 (1940).

36. Minghetti P, Cilurzo F, Casiraghi A. Measuring adhesive performance in transdermal delivery systems. Am J Drug Deliv 2004;2(3):193-206A

37. Zhang 52. Zhang J, Liu Z, Du H, et al. A novel hydrophilic adhesive matrix with self-enhancement fordrug percutaneous permeation through rat skin. Pharm Res 2010;26:1398-406

38. Raynaud J et al., Prostate-specific antigen (PSA) concentrations in hypogonadal men during 6 years of transdermal testosterone treatment .BJU Int. 2013 May;111(6):880-90.

39. Satas D. Peel. In: Satas D, editor. Handbook of Pressure Sensitive Adhesive Technology III. Satas and Associates; Warwick: 1999. p. 62-86

40. Minghetti P, Cilurzo F, Casiraghi A, Montanari L. The effect of thickness and water content on the adhesive properties of methacrylic patches. Acta Tech Legis Med Xi 2000;2:81-92

41. Rajeckas V. Bond strength and its prognosis. In: Satas D, editor. Handbook of Pressure Sensitive Adhesive Technology II. Van Nostrand Reinhold; New York: 1989. p. 115-57

42. E. Gutschke, S. Bracht, S. Nagel, et al., “Adhesion Testing of Transdermal Matrix Patches with a Probe Tack Test: In Vitro and in Vivo Evaluation,” European Journal of Pharmaceutics and Biopharmaceutics, Vol. 75, No. 3, 2009, pp. 399-404. doi:10.1016/j.ejpb.2010.03.016

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).

44. Marian Segal. Patches, pumps and timed release: new ways to deliver drugs.FDA Consum Mag 1991:1991.

45. Definition of a combination product (2005). “Title 21: food and drugs”. 21 CFR food and drugs CHAPTER I food and drug administration, Department of Health and Human Services Subchapter A- General Part 3-Product Jurisdiction.

46. FDA News (2007). “FDA approves neupro patch for treatment of early Parkinson0s Disease”. FDA News, May 9, 2007.

47. Robert Langer. Transdermal drug delivery: past progress, current status, and future prospects. Adv Drug Delivery Rev 2004;2004(56):557–8.

48. Singh Somnath. (2005). An overview of transdermal drug delivery. Industry overview and deals. Drug delivery report autumn/winter 2005. Page(s):35-40.

49. Prausnitz Mark. R, Mitragotri Samir. Langer Robert. Current status and future potential of transdermal drug delivery. Natu Rev, Drug Discovery 2004;3: 115–24.

Received on 18.05.2016 Modified on 28.05.2016

Research J. Pharm. and Tech. 2016; 9(7):945-956.

DOI: 10.5958/0974-360X.2016.00182.7

S. No	Polymer	Manufacturer	Drug	Type of system
1.	Ethyl cellulose T-50	Sigma	Isosorbide dinitrate	Matrix
2.	BIO PSA HighTack 7-4301 BIO PSA MediumTack 7-4201	Dow Corning	Trimegestone	Adhesive-in-matrixsystem. For matrix and backing side layer.
3.	HPMC		Hydrocortisone	Gel
4.	Eudragit NE, Eudragit E100, Eudragit L100	Rohm, Germany	Coumarin Melilot dry extract	Matrix
5.	Acrylic PSA emulsion	Neoplast Co. Thailand	Nicotine	Drug in adhesive
8.	Soybean lecithin (Epikuron 200)	Lucas Meyer, Germany	Scopolamine, broxaterol	Gel matrices
9.	Acrylic adhesives Polyisobutylene solutions (Vistanex LM-MH, Vistanex MML-100) Silicone PSA	National Starch and Chemical Co.Exxon Chemical Co. Dow Corning	Tacrine	Drug in adhesive
10.	Acrylic adhesives Polyisobutylene solutions (Vistanex LM-MH, Vistanex MML-100)	National Starch and Chemical Co. Exxon Chemical Co.	Ketoprofen	Drug in adhesive
11.	Silicone oil EVA Polyisobutylene ScotchPak 1006	Adhesive Research 3M	Arecoline	Reservoir Membrane Adhesive Backing film