It also provides a means of direct entry into the systemic circulation of drugs that are subjected to hepatic first-pass metabolism and/or suspected of producing gastro-intestinal incompatibility. Unfortunately, such a mode of drug administration entails certain health hazards and therefore necessitates continuous hospitalization during treatment and requires close medical supervision².

To duplicate the benefits of intravenous drug infusion without its disadvantages a new techniques for drug delivery has been developed. These techniques are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity and/or targeting the delivery of drug to a particular tissue³.

The novel drug delivery system thus aims at releasing one or more drugs continuously at a predetermined pattern for a fixed period of time, either systemically or to a specified target organ. Formulations on skin can be classified into two categories according to the target site of action of the containing drugs. One has systemic action after drug uptake from the cutaneous micro vascular network, and the other exhibits local effects in the skin ⁴. When the aim is to deliver the drugs through skin in predetermined and controlled fashion, it is known as transdermal drug delivery ^5,6.

“Transdermal drug delivery systems (TDDS) are adhesive, drug containing devices of defined surface area that deliver a pre-determined amount of drug to the surface of intact skin at a pre-programmed rate”. The transdermal route of drug delivery with the intention of maintaining constant plasma levels, zero order drugs input and serves as a constant I.V. infusion. Several TDDS have recently been developed aiming to achieve the objective of systemic medication through application to the intact skin. The intensity of interest in the potential bio-medical application of transdermal controlled drug administration is demonstrated in the increasing research activities in a number of health care institutions in the development of various types of transdermal therapeutic systems (TTS) for long term continuous infusion of therapeutic agents⁷. Transdermal delivery represents an attractive alternative to oral delivery of drug and is poised to provide an alternative to hypodermic injections too^8-11.

With the concept of delivering drug into the skin for both local effects in dermatology and through the integument for the systemic treatment of disease states. This latter process has been brought into sharp focus in recent years by the efforts of pharmaceutical field to develop transdermal drug delivery system¹². The first transdermal system for systemic delivery a three day patch that delivers scopolamine used by astronauts going in space to cure trouble of motion sickness was approved in the United States in 1979¹³. A decade later, nicotine patches become the first transdermal blockbuster, raising the profile of transdermal delivery in medicine and for the public in general¹⁴.

The skin acts as a formidable barrier to the penetration of drugs and other chemicals; it does have certain advantages which make it an alternative route for systemic delivery of drugs. The skin has been commonly used as a site for topical administration of drugs, when the skin serves as a port for administration of systemically active drugs to achieve its therapeutic action¹⁵. The transdermal route now ranks with oral treatment as the most 6 successful innovative research area in drug delivery, with around 40% of the drug delivery candidate products under clinical evaluation related to transdermal system. The worldwide transdermal patch market approaches £ 2 billion; based on only scopolamine, nitroglycerine, clonidine, estrogen, testosterone, nicotine and lidocaine (Figure 1.1). In a recent market report it was suggested that the growth rate for transdermal delivery systems will increase 12% annually^16,
17. More than 20 transdermal patches containing 13 drug molecules are already available in market¹⁸.

Figure 1.1: Global TDD product sales by segment

This approach of drug delivery is more pertinent in case of chronic disorders¹⁹.Transdermal delivery system of an antihypertensive drug, clonidine, has already been marketed. Other hypertensive drugs that have been explored for their transdermal delivery potential are propranolol, pinacidil, metoprolol, mepindoldol, captopril, verapamil, diltiazem, nifedipine, nicorandil and others ^20-24.

The site of percutaneous absorption: skin and it’s different layers:

The pharmacological response, both the desired therapeutic effect and the undesired adverse effect of a drug is dependent on the concentration of the drug at the site of action. The human skin is a readily accessible surface for drug delivery.

Skin of an average adult body covers a surface of approximate 2 m² and receives about one-third of blood circulating through the body. Skin contains an upper most layer, epidermis which has morphologically distinct regions; basal layer, spiny layer, stratum granulosum and upper most stratum corneum, it consists of highly cornified (dead) cells embedded in a continuous matrix of lipid membranous sheets. These extracellular membranes are unique in their compositions and are composed of ceramides, cholesterol and free fatty acids ^25-29.

The human skin surface is known to contain on an average 10-70 hair follicles and 200-250 sweat ducts on every square centimetres of the skin area and gives out the materials not required by the body, for instance sweat, dirt etc. The potential of using the intact skin as the port of drug administration to the human body has been recognised for several decades. The major obstruction is posed by the top most epidermal layer of stratum corneum (SC)^{30, 31, 32}.

Figure 1.2: Simplified diagram of skin structure and macro routes of drug penetration

Stratum corneum (SC) and Epidermis the main barrier to percutaneous absorption:

The SC is the outermost layer of the skin, which is considered to be the dead skin. It is hygroscopic, tough flexible membrane and the intercellular space is rich in lipids. The thickness varies at different parts of the body. Inspite of these undesirable properties, it allows permeation of some chemicals that have low molecular weight and are lipophilic. The drug molecule should be effective at low dosage levels to reach the tissue and the blood vessels underneath the skin^33,34.

Dermis: The site of systemic absorption:

The dermis is 0.2-0.3 cm thick and is made up of collagen and reticulum. It is also the locus of the blood vessels, sensory nerves segments of the sweat glands and pilosebaceous units. The main function is to store water, protects the body from injury and serves as a barrier to infection ^{28, 29}

Subcutaneous fatty tissue:

It acts as a heat insulator and a shock absorber. It has no effect on the percutaneous absorption of drugs because it lies below the vascular system³⁵.

Skin appendages:

It includes hair follicles with sebaceous, eccrine and apcrine sweat glands. A less important pathway of drug penetration is the follicular route where a very little drug actually crosses the skin via follicular route. Hair follicle penetrates the SC, allowing more direct access to dermal microcirculation ^28,
36.

Mechanism of percutaneous penetration:

Until the last century the skin was supposed to be impermeable with exception to gases. However, in the current century the study indicated the permeability to lipid soluble drugs. Also it was recognized that epidermis is less permeable than dermis. After a large controversy, all doubts about stratum corneum permeability were removed and using isotopic tracers, it was suggested that stratum corneum greatly hamper permeation³⁵.

At the skin surface, drug molecules come in contact with cellular debris, microorganisms, sebum and other materials, which regularly affect permeation. The penetrant has three potential pathways to the viable tissue– through hair follicles with associated sebaceous glands, via sweat ducts, thirdly across continuous stratum corneum between these appendages. Two macroroutes of drug permeation are represented in fig 1.2.

Fractional appendageal area available for transport is only about 0.1%, this route Usually contributes negligibly to steady state drug flux. This pathway may be important for ions and large polar molecules that struggle to cross-intact stratum corneum. Appendages may also provide stunts, important at short times prior to steady state diffusion. Additionally, polymers and colloidal particles can target the follicle³⁷.

The intact stratum corneum thus provides the main barrier; its ‘brick and mortar’ structure is analogous to a wall. The corneocytes of hydrated keratin comprise the ‘bricks’, embedded in a ‘mortar’, composed of multiple lipid bilayers of ceramides, fatty acids, cholesterol and cholesterol esters. These bilayers form regions of semi crystalline gel and liquid crystals domains. Most molecules penetrate through skin via this intercellular micro route and therefore many enhancing techniques aim to disrupt or bypass its elegant molecular architecture³⁸.

Viable layers may metabolize a drug, or activate a prodrug. The dermal papillary layer is so rich in capillaries that most of the percutaneous penetrants get cleared within minutes³⁷.

Factors affecting transdermal permeability:^39-43

The principal transport mechanism across mammalian skin is by passive diffusion through, primarily, the trans-epidermal route at steady state or through trans appendageal route at initial non-steady state. The factors controlling transdermal permeability can be broadly placed in the following classes.

A. Physicochemical properties of the penetrants molecule:

Partition coefficient: Drugs possessing lipid and water solubility are favourably absorbed through the skin. Transdermal permeability coefficient shows a linear dependency on partition coefficient. A lipid/water partition coefficient of 1 or greater is generally required for optimal transdermal permeability. This parameter is mainly used to predict the capability of drug to cross biological membrane.

pH conditions: Application of solutions whose pH values are very high or very low can be destructive to the skin. With moderate pH values, the flux of ionisable drugs can be affected by changes in pH that alter the ratio of charged and uncharged species and their transdermal permeability.

Penetrants concentration: Assuming membrane limited transport, increasing concentration of dissolved drug causes a proportional increase in flux. At concentrations higher than the solubility, excess solid drug functions as a reservoir and helps to maintain a constant drug concentration for a prolonged period of time.

B. Physicochemical properties of drug delivery system:

Generally, the drug delivery System vehicles do not increase the rate of penetration of a drug into the skin but serve as carriers for the drug.

a. Release characteristics:

Solubility of the drug in the vehicle determines the release rate. The mechanisms of drug release depend on the following factors.

(i) Whether the drug molecules are dissolved or suspended in the delivery systems.

(ii) The interfacial partition coefficient of the drug from the delivery systems to the skin tissue.

(iii) pH of the vehicle.

Vijaya et al.(2011) found more than 90% release within 40 minutes from a transdermal film of amitriptyline hydrochloride prepared with eudragit L 100. This may be due to the fact that the polymer has got high solubility at higher pH value. Eudragit L 100 is comprised of copolymers that forms salts with alkali at higer pH. Thus, film prepared by the copolymers disappear above pH 5.5 and open a gateway for the drug to be dissolved⁴⁴

Rita and Mohammad (2011) observed gradual rate retarding effect of ketorolac tromethamine from transdermal film prepared with kollidon SR at increasing order due to the hydrophillicity of polymer⁴⁵.

b. Composition of drug delivery systems:

The composition of the drug delivery system not only affects the rate of drug release, but also the permeability of SC by means of hydration, mixing with skin lipids or other sorption promoting effects. Permeation decreases with PEG of low molecular weight. Similarly, methyl salicylate is more lipophillic than its parent acid and when applied to the skin, form fatty vehicles, the methyl salicylate yielded a higher percutaneous absorption than salicylic acid.

Ganjana D et al found 90 % clopidogrel bi sulfate release with the formulation containing hydrophilic components such as PVP. 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. Further PVP act as antinucleating agent, that retards the crystallization of drug, playing significant role in improving the solubility of a drug in the matrix, so it undergoes rapid solubilisation by penetration in the dissolution medium⁴⁶

c. Enhancement of transdermal permeation:

Majority of drugs will not penetrate the skin at rates sufficiently high for therapeutic efficacy. In order to allow clinically useful transdermal permeation of most drugs, the permeation can be improved by the addition of a sorption or permeation promoter into the drug delivery systems. Such promoters can be of following types:

(i) Organic solvents: These agents cause an enhancement in the absorption of oil-soluble drugs, due to the partial leaching of the epidermal liquids, resulting in the improvement of the skin conditions for wetting and for transepidermal and transfollicular penetration. e.g. dimethyl acetamide, dimethyl formamide, acetone, cineole, propylene glycol, PEG, ethanol etc.

(ii) Surface active agents: The permeation promoting activity of surfactants is assumed to be due to the decrease in the surface tension, to improve the wetting of the skin, and to enhance the distribution of the drugs. Anionic surfactants are the most effective. Their action may be due to their modification of the stratum germinativum and/or to their denaturation of the epidermal proteins. Ex. Sodium lauryl sulfate and sodium dioctyl sulfo-succinate.

Jang-suep back et al studied the feasibility of using transdermal drug delivery sytem of citalopram. Results revealed that citalopram ethylene vinyl acetate matrix transdermal film containing tween-80 as plasticizer and diethyl phthalate as permeation enhancer provided sustained plasma concentration⁴⁷.

Aboofazeli reza et al developed a transdermal delivery system of nicardipine hydrochloride and studied the vehicle effect on the percutaneous absorption by using excised skin of a hairless guinea pig. The ternary mixture of propylene glycol/oleic acid/dimethy isosorbide and a binary mixture of propylene glycol/oleic acid showed excellent flux. The result also showed that no individual solvent was capable of promoting nicardipine hydrochloride penetration⁴⁸.

C. Physiological and pathological conditions of the skin:

a. Lipid Film:

The lipid film on the skin surface acts as a protective layer to prevent the removal of moisture from the skin and helps in maintaining the barrier function of the stratum corneum. Defatting of this film was found to decrease transdermal absorption.

b. Skin Hydration:

Hydration of the SC can enhance transdermal permeability,although the degree of penetration enhancement varies from drug to drug. Simply covering or occluding the skin with plastic sheeting, leading to the accumulation of sweat and condensed water vapour can achieve skin hydration. Increased hydration appears to open up the dense, closely packed cells of the skin and increase its porosity.

c. Skin Temperature:

A rise in the skin temperature results in an increase in the rate of skin permeation. This may be due to:

(i) Thermal energy required for diffusivity.

(ii) Solubility of drug in skin tissues.

(iii) Increased vasodilatation of skin vessels

d. Regional Variation:

These may be due to differences in the nature and thickness of the barrier layer of the skin which causes variation in permeability.

e. Traumatic/Pathological injuries to the skin:

f. Injuries that disrupt the continuity of the stratum corneum, increase permeability due to increased vasodilatation caused by removal of the barrier.

g. Cutaneous drug metabolism:

Catabolic enzymes present in the viable epidermis may render a drug inactive by metabolism and thus affect the topical bioavailability of the drug.

h. Reservoir effect of the horny layer:

The horny layer, especially its deeper layers, can sometimes act as a depot and modify the transdermal permeation characteristics of some drugs.

Ideal molecular properties for TDDD:⁴⁹

From the above consideration we can conclude with some observations that can termed as ideal molecular properties for dug penetration. They are as follows.

· An adequate solubility in lipid and water is necessary for better penetration of drug (1mg/ml)

· Optimum partition coefficient is required for good therapeutic action.

· Low melting point of drug is desired (<200⁰C)

· The pH of the saturated solution should be in between 5 to 9.

Advantages of TDDS:^{1, 50, 51, 52}

The skin as a site of drug delivery has a number of significant advantages over many other routes of drug administration, the ability to avoid problems of gastric irritation, pH and emptying rates effect.

Kunal NP et al⁵³ designed transdermal drug delivery form of Diclofenac sodium, an NSAID used in the chronic treatment of rheumatic arthiritis, osteoarthiritis, to avoid problems of gastric irritation, pH, and emptying rates effect. Bhosale NR⁵⁴., et al formulated a transdermal drug delivery system of ropinirole hydrochloride an anti Parkinson’s drug to overcome the fluctuations in serum levels of drug, as Parkinson’s treatment demands prolonged and sustained plasma levels of the drug. Raju R T ⁵⁵. et al formulated transdermal therapeutic system of lercanidipine hydrochloride a potent antihypertensive and antianginal drug, which has low bioavailability as the drug undergoes extensive hepatic metabolism and improved its bioavailability as TDDS avoids heptic first pass metabolism and provides sustained constant and controlled levels of drug in plasma. Further it increases patience compliance, since frequent intake of the drug is not necessary. It utilizes a natural and passive diffusion mechanism that allows substances to penetrate the skin and enter the blood stream ^{56, 57}.

Disadvantages of TDDS:^{11, 58, 59}

The first TDDS scopolamine for motion sickness was introduced in 1981. Since then many TDDS have appeared in market with great success. In spite of the therapeutic success achieved in last 28 years by using TDDS, the number of TDDS available in the market place is very few. One of the greatest disadvantages of TDDDS is the possibility that a local irritation will develop at the site of application and in order to maintain consistent release rate, transdermal patches contains a surplus of active molecule. Most transdermal patches contain 20 times the amount of drug that will be absorbed during the time of application. Another significant disadvantage of TDDDS is that the skin’s low permeability, limits the number of drugs that can be delivered in this manner. Damage to a transdermal patch, particularly a membrane or reservoir patch, can result in poor controlled over the release rate. Ex. In 2008, two manufactures of the fentanyl patch for pain control, alza pharmaceuticals and Sandoz subsequently issued a recall of their versions of the patch due to a manufacturing defect that allowed the gel containing the medication to leak out of its pouch too quickly, which could result in over dose and death. As of 2010 sandoz no longer uses gel in its formulations. Instead, it use a matrix/ adhesive suspension ⁶⁰.

The intrinsic skin permeability of most drugs is inadequate to meet the therapeutic demand and only small numbers of drugs with a suitable profile are available. Since novel technologies ( Figure 1.3) have been developed and getting investigated to enhance the permeation rate.

Historically prodrug approach was used to develop derivatives resistant to hepatic metabolism, but recently newer approaches have been attempted to develop derivatives with higher skin permeabilities. Rothbard JB et al⁶¹ used prodrug approach for delivering cyclosporine. It was covalently attached to a polyarginine heptamer cell penetrating peptides, which led to increase in topical absorption, that inhibited cutaneous inflammation. The melting point of a drug influences solubility and hence skin permeability. The melting point of a drug delivery system can be lowered by formation of a eutectic mixture which at certain ratio inhibits the crystalline processes of each other such that the melting point of mixture is less then that of the individual component. A number of eutectic systems containing a penetration enhancer as the second component have been reported. Example Ibuprofen with terpenes, menthol and methyl nicotinate propanolol with fatty acid and lignocaine with methanol. ¹⁷

Artificially designed super saturated solutions are used to enhance the permeation rate in chemical potential adjument approach ⁶². Whereas directly injecting the solid particles in to the skin using the supersonic shock wave of helium gas is the basic mechanism in high velocity particles ³⁷. Lowering of skin resistance by chemical approach utilizes penetration enhancer, which temporarily reduce the barrier properties of the skin and can enhance drug flux ^48,63.

A final way to remove the stratum corneum (SC) barrier employs abrasion by using sand paper. The microdermabrasion method is widely used to alter and remove skin tissues for cosmetic purpose. This abrasive mechanism increases skin permeability to drug, including lidocaine and 5-flurouracil⁶⁴. Vaccine delivery across the skin has also been facilitated by skin abrasion using sand paper⁶⁵.

Another way to selectively permeablize the SC is to pierce it with short needles. Solid microneedles painlessly pierce the skin to increase permeability to a variety of small molecules, proteins and nanoparticles. Hollow microneedles have been used to deliver insulin and vaccines by infusion⁶⁶. Liposomes are used as chemicals enhancers with supramolecular structure that increase skin permeability, with increased drug solubilisation in the formulation and drug partitioning into the skin^{67, 68}.

Iontophoresis mainly provides an electrical driving force for transport across SC ⁶⁹. Charged drugs are moved via electrophoresis, Iontophoresis is currently used clinically to rapidly deliver lidocaine for local anaesthesia ⁷⁰, pilocarpine to induce sweating as part of cystic fibrosis diagnostic test ⁷¹ as well as extract glucose from the skin for glucose monitoring ⁷². Electroporation may combine with Iontophoresis to enhance penetration of peptides such as vasopressin, neurotensin, calcitonin ⁷³. Electroporation can also be combine with ultrasound. Ultrasound was first widely recognised as a skin permeation enhancer when physical therapists discovered that massaging anti-inflammatory agents into the skin using ultrasonic heating probes increased efficacy ⁷⁴

Basic Components of TDDS:^1,42,50,58

TDDS are designed to support the passage of drug substance from the surface of skin, through its various layers, and into the systemic circulation. There are two basic types of transdermal dosing system, those that control the rate of drug delivery to the skin, and those that allow the skin to control the rate of drug absorption. The fundamental components of transdermal include the following:

· Polymer matrix

· The drug substance

· Penetration enhancer

· Backing membrane

· Adhesives

· Polymer matrix:

The polymer is the back bone of TDDDS. The release of drug to the skin is controlled by the drug free film known as rate controlling membrane. Polymers are also used in the matrix devices in which the drug is embedded in polymer matrix, which control the duration of release of drugs. The polymer should be stable, non reactive with drug, easily manufactured into the desired product and inexpensive. The polymer and its degradation products must be non toxic or non antagonistic to the host.

Some of the polymers used for transdermal devices are as follows:

Natural and semi synthetic polymers: Carboxymethyl cellulose, cellulose acetate phthalate, ethyl cellulose, gelatin, methylcellulose, starch, shellac, waxes natural rubber etc.

Synthetic elastomers: Polybutadiene, polysiloxane, acrylonitrile, butyl rubber, Neoprene, polyisoprene, ethylene-propylene-diene-terpolymer etc.

Synthetic polymers: PVA, PVC, polyethylene, polystyrene, polyester, polyacrylate, polypropylene etc.

Sunita Jain et al developed TDDDS of captopril employing different ratios of polymers, ethyl cellulose and HPMC (3:1 and 2:2). The result revealed that the patches containing EC: HPMC was able to penetrate through the rabbit abdominal skin. In vivo study showed that the TDDDS were free from any irritating effect and was stable for 3 months⁷⁵.

Agarwal SS et al prepared different matrix type transdermal patches with an objective to study the effect of polymers like PVP, cellulose acetate phthalate, HPMC and EC on transdermal release of atenolol and metoprolol tartarate. It was observed that properties were within limits and satisfactory⁷⁶.

Garala KC et al developed transdermal drug delivery of tramodol- Hcl using HPMC and Eudragit S 100, and they concluded that HPMC/ ES polymer blends had the potential to formulate TDDDS as they have good film forming property and mechanical strength⁷⁷.

· Drug: ^{78, 79}

Judicious choice of drug is critical in the successful development of a transdermal product. The important drug properties that affect its diffusion from device as well as across the skin include molecular weight (>1000 daltons), affinity for both lipophillic and hydrophilic phases with solubility of 1mg/ml,low melting point (<200⁰C), the pH of the saturated solution should be in between 5 to 9. Along with these properties the drug should be potent, should have short biological half life and non irritating. The structure of the drug also affects the skin penetration. Diffusion of the drug in adequate amount to produce a satisfactory therapeutic effect is of prime importance. The first drug to formulate as TDDDS is scopolamine in 1979, patches of nitroglycerine were approved in 1981 and today there exists a number of patches for drug such as clonidine, fentanyl, lidocaine, nicotine, oestradiol, oxybutynin. There are also combination patches for contraception as well as hormone replacement ^{80, 81.}. The most recent approval in the field of TDDDS was the approval of Nuepro patch for treatment of parkinson’s disease ⁸².

Table 1.1: Ideal properties of drug candidate for TDD:

Parameter	Properties
Dose	Should be low
Half life in hr	10 or less
Molecular weight	< 400
Partition coefficient	Log P (octanol-water) between 1.0 and 4
Skin permeability coefficient	>0.5×10^-3cm/hr
Skin reaction	Non irritating and non sensitizer
Oral bioavailability	Low
Therapeutic index	Low

· Penetration enhancers: ^83,
84

Penetration enhancers are molecules, which reversibly alter the barrier properties of the SC. They aid in the systemic delivery of drugs by allowing the drug to penetrate more readily to viable tissues. They can be incorporated in transdermal formulation to obtain systemic delivery of the drug or for

delivery of drugs to the deeper layers of the skin with a reduced concentration of the active constituents.

Penetration enhancer should have the following properties:

· The material should be pharmacologically inert.

· It should be non-toxic, non-irritant, and have a low index of sensitization.

· The penetration enhancing action should be immediate and should have suitable duration of effect.

· The enhancer should be chemically and physically compatible with a wide range of drugs and pharmaceutical adjuncts.

· The material should spread well on the skin.

· It should be odourless, tasteless, and colourless.

· Backing membrane:

It provides protection from external factors during application period. The backing layer must be flexible and provide good bonding to the drug reservoir-thereby preventing the drug from detaching from the dosage form. They are usually impermeable to water vapours. The most commonly used backing materials are polyethylene terephthalate, metalized polypropylene, pigmented Polyester film etc.

Table 1.2: Different class of enhancers and their mechanism of action⁴²

Class	Examples	Mechanism of action
Hydrating Substances	Water occlusive preparations	Hydrates the SC
Keratolytics	Urea⁸⁵	Increase fluidity and hydrates the SC
Organic solvents	Alcohols, Poly ethylene glycol⁸⁶ DMSO⁸⁷	Partially extracts lipids Replace bound water in the intercellular spaces Increase lipid fluidity
Fatty acids	Oleic acid⁸⁸	Increase fluidity of intercellular lipids
Terpenes	1,8-Cineole , Menthol	Opens up polar pathway
Surfactants	Polysorbates, Sod. lauryl sufate⁸⁹	Penetrates into skin, micellar solubilisation of SC
Azone	1-Dodecylhexahydro-2H-Azepine-2on2	Disrupts the skin lipids in both the head group and tail region

In 2009, the FDA announced a public health advisory warning of the risk of burns during MRI scans from transdermal drug patches with metallic backings. Patient is advised to remove any medicated patch prior to an MRI scan and replace it with a new patch after the scan⁹⁰.

Example of some backing layers currently available in the market ⁹¹

· Adhesives:

The adhesion of all transdermal devices to the skin in an essential requirement and it has so far been accomplished using a pressure sensitive polymeric adhesive. It should fulfil the following requirements:

· It shouldn’t cause irritation, sensitization or imbalance in the normal skin flora during its contact with skin.

· It should adhere to the skin aggressively, easily removable without leaving an unwashable residue.

It should be physically and chemically compatible with the drug, the excipients and enhancers and not affect the permeation of the drug

The types of adhesives commonly used in transdermal drug delivery system are:

Rubber based adhesives: Natural gum (Karaya gum), polylisoprene, polybutene, and polyisobutelene.

Polyacrylic based: Ethyl acrylate, 2-ethylhexylacrylate, iso-octyl acrylate.

Polysiloxane based: Polydimethyl siloxane, polysilicate resins, sufloxane blends.

Ren C et al develop and evaluated a novel drug in adhesive transdermal patch system for indapamide. The effects of the type of adhesive and the content of permeation enhancers on indapamide transport across excised rat skin were evaluated. The results indicated that DURO-TAK adhesive 87-2852 is a suitable and compatible polymer for the development of TDDDS of indapamide⁹².

Product development: ^{30, 93-95}

Because of the uniqueness of this dosage form, the following questions need to be answered to define the final product

· Target therapeutic concentration

· Dose to be delivered

· Maximum patch size acceptable

· Preferred site of application

· Preferred application period (daily, biweekly, weekly, etc)

Once the preferred final product description has been established, an evaluation of the drug candidate begins. Because of the limitation of the loading dose in a patch and a practical patch size, not all drugs can be candidate for TDD.

Table No.1.3: Ideal properties of a TDDS

Properties	Comments
Shelf life	Upto 2 years
Patch life	< 40 cm²
Dose frequency	Once a daily to once a week
Aesthetic appeal	Clear, tan or white colour
Packing	Easy removal of release linear and minimum number of steps required to apply
Skin reaction	Non irritating and non sensitizing
Release	Consistent of pharmacokinetics and pharmacodynamics profile over time

The product development of a transdermal formulation generally includes the following stages:

· Selection of a drug candidate

· Selection of a appropriate physical form (acid, base, salt)

· Selection of desired design (reservoir, matrix etc.)

· Preparation of protype formulations and testing of their physicochemical properties

· Evaluation of in vitro permeation

· Development of analytical methods to quantitate drug in the formulation, skin layers, release medium and blood.

· Evaluation of potential for systemic adverse events

· Evaluation of skin toxicity in animals and humans

· Microbial and preservative testing, if necessary

· Phase I, II, III human clinical trials

· Scale up activities including development of specification.

· Post approval market surveillance.

Approaches used in the development of TDDS^{1,
39, 51, 59}

Four different approaches have been utilized to obtain transdermal drug delivery systems:

· Membrane permeation – controlled systems:

In this type of system, the drug reservoir is totally encapsulated in a shallow compartment moulded from a drug-impermeable metallic plastic laminate and a rate controlling membrane, which may be micro porous or non-porous. The drug molecules are permitted to release only through the rate-controlling membrane. In the drug reservoir compartment, the drug solids are either dispersed in a solid polymer matrix or suspended in a viscous liquid medium such as silicone fluid to form a paste like suspension (fig.-1.4).

The major advantage of membrane permeation controlled TDS is the constant release of drug. Example: Scopolamine-releasing TDS (Transderm-Scop/Ciba, USA) for 72 h. prophylaxis of motion sickness.

Figure 1.4: Membrane controlled transdermal delivery system

· Matrix diffusion-controlled systems:

In this approach, the drug reservoir can be formed by homogenously dispersing drug particles in a hydrophilic / lipophilic polymer matrix in a common solvent followed by solvent evaporation in a mould at an elevated temperature. The drug reservoir containing polymer disc is then pasted on to an occlusive base plate in a compartment fabricated from a drug impermeable plastic backing.The adhesive polymer is then spread along the circumference to form a strip of adhesive rim around the medicated disc (fig.-1.5).

The advantage of this system is the absence of dose dumping since polymer cannot rupture. Example of this type is Nitroglycerin-releasing TDS (Nitro-Dur and Nitro-Dur II / Key Pharmaceuticals, USA).

Figure 1.5: Matrix controlled transdermal delivery system

· Adhesive dispersion-type systems:

This system is a simplified form of the membrane permeation-controlled system. Here the drug reservoir is formulated by directly dispersing the drug in an adhesive polymer (eg., poly-isobutylene or poly-acrylate) and then spreading the medicated adhesive, by solvent casting or hot melt, on to a flat sheet of drug impermeable metallic plastic backing to form a thin drug reservoir layer. On the top of the drug reservoir layer, thin layers of non-medicated, rate controlling adhesive polymer are applied to produce an adhesive diffusion-controlled TDDS.For example, Isosorbide dinitrate releasing TDS (Frandol tape/Yamanouchi, Japan) once-a-day medication of angina pectoris.

Figure 1.6: Adhesive Dispersion-Type transdermal delivery systems

· Microreservoir type or microsealed dissolution controlled systems:

This system is a combination of the reservoir and matrix diffusion type drug delivery systems. The drug reservoir is formed by first suspending the drug solids in an aqueous solution of a water-soluble liquid polymer and then dispersing the drug suspension homogenously in lipophilic polymer.

For example, Nitroglycerin releasing TDS (Nitro disc, Searle, USA) once-a-day therapy of angina pectoris.

Figure 1.7: Microreservoir type transdermal delivery system

General clinical considerations in the use of TDDS ⁹⁷

The patient should be advised of the following general guidelines. The patient should be advised of the importance of using the recommended site and rotating locations within the site.

1. TDDS should be applied to clean, dry skin relatively free of hair and not oily, inflamed, irritated, broken.

2. Use of skin lotion should be avoided at the application site, because lotions affect the hydration of skin and can alter partition coefficient of drug.

3. Patient should not physically alter TDDS, since this destroys integrity of the system.

4. The protecting backing should be removed with care not to touch fingertips. The TDDS should be pressed firmly against skin site with the heel of hand for about 10 seconds

5. A TDDS should be placed at a site that will not subject it to being rubbed off by clothing or movement. TDDS should be left on when showering, bathing or swimming.

6. A TDDS should be worn for full period as stated in the product’s instructions followed by removal and replacement with fresh system.

7. The patient or caregiver should clean the hands after applying a TDDS. Patient should not rub eye or touch the mouth during handling of the system.

8. If the patient exhibits sensitivity or intolerance to a TDDS or if undue skin irritation results, the patient should seek reevaluation.

9. Upon removal, a used TDDS should be folded in its half with the adhesive layer together so that it cannot
be reused. The used patch discarded in a manner safe to children and pets. It is important to use a different application site everyday to avoid skin irritation. Suggested rotation is: Day 1 – Upper right arm; Day 2 – upper right chest; Day 3 – Upper left chest; Day 4 – Upper left arm. [Then repeat from Day 1]

Novel delivery systems in transdermal therapy:

In addition to traditional dermal and transdermal delivery formulations, such as creams, ointments, gels, and patches, several other systems have been evaluated. In the pharmaceutical semisolid and liquid formulation area, these include sprays, foams, multiple emulsions, microemulsions, liposomal formulations, transfersomes, niosomes, ethosomes, cyclodextrins, glycospheres, dermal membrane structures and microsponges. Novel transdermal formulations include soft patches, microneedles and powder delivery systems.⁹⁸

Electrotransport technology:

(referred to as E-TRANS technology at ALZA Corporation, Mountain View, CA) uses an electric potential to provide non-invasive delivery of therapeutic substances across intact skin for local and systemic applications. An electrotransport drug delivery system typically consists of a power supply connected to a pair of electrodes in contact with ionically conductive reservoirs that, in turn, are in contact with the skin.⁹⁹

The Microneedle:

The concept employs an array of micron-scale needles that is inserted into the skin sufficiently far that it can deliver drug into the body, but not so far that it hits nerves and thereby avoids causing pain. An array of microneedles measuring tens to hundreds of microns in length should be long enough to deliver drug into the epidermis and dermis, which ultimately leads to uptake by capillaries for systemic delivery. Small microneedles can also be painless if designed with an understanding of skin anatomy.¹⁰⁰

The Metered-Dose transdermal spray:

It is a topical solution made up of a volatile, non volatile vehicle containing the drug dissolved as a single-phase solution. A finite metered-dose application of the formulation to intact skin results in subsequent evaporation of the volatile component of the vehicle, leaving the remaining non-volatile penetration enhancer and drug to rapidly partition into the SC during the first minute after application, resulting in a SC reservoir of drug and enhancer. Following a once daily application of the MDTS a sustained and enhanced penetration of the drug across the skin can be achieved from the SC reservoir.¹⁰¹

Transfersome:

Modern carrier-mediated TDDS started with the work of several investigators exploring liposomes or niosomes on the skin. The original liposomes were typically water-containing phospholipid vesicles comprising mainly phosphatidylcholine supplemented with cholesterol, which stabilizes lipid bilayers and prevents leakage and vesicle aggregation. A transfersome can be made from phosphatidylcholine in the form of vesicles, but typically contain at least one component that controllably destabilizes the lipid bilayers and thus makes the vesicle ver y deformable (Additives useful for the purpose are bile salts, polysorbates, glycolipids and alkyl or acyl-polyethoxylenes, etc.¹⁰²

CONCLUSION:

This review provides valuable information about the transdermal drug delivery systems of drug through the skin and also helps in optimization in permeability by using different enhancer and also includes future aspects about modification in injector. So it can be a ready reference for the researchers who are involved in the work of TDDS. The foregoing shows that TDDS have great potentials, being able to use for both hydrophobic and hydrophilic active substance into promising deliverable drugs. Transdermal drug delivery system is useful for topical and local action of the drug. In this system, the drug bypass hepatic metabolism, salivary metabolism and intestinal metabolism due to that bioavailability and efficacy of drugs are increased. However, due to certain disadvantages like low bioavailability, large drug molecules cannot be delivered, large dose cannot be given, the rate of absorption of the drug is less, skin irritation; etc, the use of TDDS has been limited. But day to day increment in the invention of new devices and new drugs that can be administered via this system, ie., TDDS is increasing rapidly in the present time. TDDS is a realistic practical application as the next generation of drug delivery system.

REFERENCES:

1. Chein YW. Novel Drug Delivery Systems.2nd ed. New York: Marcel Dekker. 1992; 1-2: 301-50.

2. Chien Yie W. Parenteral drug deliver y and delivery systems. 2nd ed. New York: Marcel Dekker Inc; 1992.

3. Chien Yie W. Concepts and system design for rate controlled drug delivery. 2nd ed. New York: Marcel Dekker Inc; 1992.

4. Desai BG, Annamalai AR, Divya B, Dinesh BM. Effect of enhancers on permeation kinetics of captopril for transdermal system. Asian J Pharm 2008; 2:35-7.

5. Tyle P. Drug Delivery Devices. Fundamentals and Applications. New York: Marcel Dekker; 1998: 385-417.

6. Aqil M, Zafar S, Ali A and Ahmad S. Transdermal drug delivery of labetalol hydrochloride: system development, in vitro; ex vivo and in vivo characterisation. Curr Drug Deliv 2005; 2(2):125-31.

7. Carpel MC, Erasmo AME, Rawena SW, Elizebath PH, Rondoll Z. Drug Intelligence Clinical Pharmacy; 1987.

8. Guy RH, Hadgraft J. transdermal drug delivery. Editors. New York: Marcel Dekker; 2003.

9. Williams A. transdermal and topical drug delivery. London; Pharmaceutical press: 2003.

10. Prausnitz MR, Mitragotri S, Langer R. current status and future potential of

transdermal drug delivery. Nat Rev drug discovery. 2004;115-124.

11. Bronaugh RL, Maibach HI, editors. Edn 4^th. New York: Marcel Dekker; 2004. Percutaneous absorption.

12. Josep R Robinson, Vincent H Lee. Transdermal therapeutic systems. 2nd ed. Vol (29); 1987. p. 523-31.

13. Ackerman SJ. Medicines from space: FDA consumer special report. FDA Consumer magazine (online). 1995.

14. Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnology 2008; 26(11): 1261-1268.

15. Chien Yie W. Transdermal drug delivery and delivery systems. 2nd ed. New York: Marcel Dekkar Inc; 1992.

16. Pathan IB, Setty CM. Chemical penetration enhancers for transdermal drug delivery Systems. Trop J Pharm Res 2009; 8(2):173-179.

17. Benson HAE., Transdermal drug delivery: Penetration enhancement techniques. Curr Drug Deliv 2005; 2: 23-33.

18. Cleary GW, Beskar E. Transdermal and transdermals like delivery system opportunities. Today and the Future Pharmatech 2003; 82-8.

19. Banweer J, Pandey S, Pathak AK. Formulation, optimization and evaluation of matrix type transdermal system of lisinopril dihydrate using permeation enhancers. J Pharm Res 2008; 1(1):16-22.

20. Aqil M, Ali A, Sultana Y, Dubey K, Najmi AK and pillai KK. In vivo characterization of monolithic matrix type transdermal drug delivery systems of pinacidil monohydrte. AAPS PharmsciTech 2006; 7(1):E1-5.

21. Aqil M, Sultana Y, Ali A. Matrix type transdermal drug delivery systems of metoprolol tartrate: In vitro characterization. Acta Pharm 2003; 53:119-25

22. Aqil M, Ali A, Sultana Y, Najmi AK. Fabrication and evaluation of polymeric films for transdermal delivery of pinacidil. Pharmazie 2004; 59(8):631-5.

23. Al-Saidan SM, Krishnaiah YSR, Chandrasekhar DV, Lalla JK, Rama B, Jayaram B, solvent system and limonene as a penetration enhancer for enhancing in vitro transdermal delivery of nicorandil, Skin Pharmacol Physiology 2004; 17:310-320.

24. Jain SK, Gupta SP. Effective and controlled transdermal delivery of metoprolol tartarate. Indian J Pharm Sci 2005; 67(3):346-50.

25. Kanikkannan N, Kandimalla K, Lamba SS, Singh M. Structure-activity Relationship of chemical penetration enhancers in transdermal drug delivery. Curr Med Chem 2000; 7:593-608.

26. Barry BW. Drug delivery routes in skin: a novel approach. Adv Drug Deliv Rev 2002; 54:S31-40.

27. Hadgraft J. Skin deep. Eur J Pharm Biopharm 2004; 58:291-299.

28. Sing S, Singh J. Transdermal drug delivery by passive diffusion and iontophoresis: a review. Med Res Rev 1993; 13:569-621.

29. Ritschel WA, Hussain AS. The principles of permeation of substances across the skin. Methods Find Exp Clin Pharmacol 1998; 10(1):39-56.

30. Jasti BR, Abraham W, Ghosh TK. Transdermal and Topical drug Delivery System In: Ghosh TK, Jasti BR, editors. Theory and Practice of Contemporary Pharmaceutics. 1^st ed. Florida: CRC Press; 2005: 423-453.

31. Baker H. The skin as barrier. In: Rook A, Wilkinson DS, Ebling FJG, Champion RH, Burton JL, eds. Text Book of Dermatology. Vol 1, 4^th ed. Oxford: Blackwell Scientific Publications, 1986:355-366.

32. Robert L. Transdermal drug delivery: past progress, current status, and future prospects. Advanced drug delivery reviews. 2004; 6(4): 557-558.

33. Stanley S. transdermal drug delivery: past, present, future. Molecular interventions. 2004; 6(4): 308-312.

34. Shastri VP, Lee PJ, Ahmad N, Langer R, Mitragotri S. Evaluation of chemical enhancers in the transdermal delivery of lidocaine. Int J Pharm 2006; 308:33-39.

35. Hardman JG, Limbird LE, editor. Goodman and Gilman’s-The pharmacological basis of therapeutics.10 ed . New York: McGraw Hill; 1996.

36. Franz TJ, Tojo K, Shah KR, Kydonicus A. transdermal delivery. In: A kydonieus, ed. Treatise on controlled drug delivery. New york: Marcel Dekker, 1992:341-421

37. Chein YM. Transdermal Drug Delivery, In: Swarbick J. editor, Novel Drug Delivery System, second edition, New York: Marcel Dekker, 2005; 50: 301-312.

38. Barry BW, Novel mechanisms and devices to enable successful transdermal drug delivery. J Pharm Sci 2004; 21:371-7.

39. Joseph RR, Vincent HL. Controlled drug delivery fundamentals and applications. 2nd ed. New York: Marcel Dekker; 1987. p. 523-531.

40. Basak SC, Vellayan K. Transdermal drug delivery systems. The Eastern Pharmacist 1999; 40(476):63-7.

41. Misra AN. Transdermal drug delivery. In: Jain NK, editor. Controlled and novel drug delivery. New Delhi: CBS Publishers and Distributors; 2004. p. 101-17.

42. Aulton ME. Pharmaceutics: The science of dosage form design. 2nd ed. London: Churchill Livingstone; 2002. p. 499-533.

43. Murthy SN, Hiremath. Transdermal Drug Delivery systems. In: Hiremath SRR, editor. Text book of industrial pharmacy. India: Orient longman private limited; 2008. p. 27-49.

44. Vijaya R., Deepa D., Priya T.S and Ruckamani K. The development and evaluation of transdermal films of amitriptyline hydrochloride. Int. J. of pharm and technology. 2011; 3: 1920-1933.

45. Rita B and Mohammad S H. Evaluation of kollidon SR based ketorolac trometamine loaded transdermal film. J. of Appl. Pharm. Sci. 2011; 1; 123-127.

46. Ganjana D., Jain D K., Patidar V K. Formulation and evaluation of transdermal drug delivery system of clopidogrel bi sulfate. AJPLS. 2011; 1(3): 269-278.

47. Jang-suep back et al. The feasibility study of transdermal drug delivery systems for antidepressants possessing hydrophillicity or hydrophobicity. Journal of pharmaceutical investigation. 2012; 42:109-114.

48. Aboofazeli R., Zia H., Needham T.E., Transdermal delivery of nicardipine: An approach to in vitro permeation enhancement. Drug Delivery 2002; 9: 239-247

49. Shin SC, Cho CW. Enhanced transdermal delivery of atenolol from the ethylene-vinyl acetate matrix. Int J Pharm 2004; 287:67-71.

50. Misra AN. Transdermal Drug Delivery, In: Jain NK., editor, Controlled and Novel Drug Delivery, first edition, CBS publication, 1997; 100-129.

51. Jain NK. Advances in controlled and novel drug delivery.1st ed. Delhi: CBS Publishers; 2001. p. 426-48.

52. Rao YM, Gannu R, Vishnu YV and Kishan V. Development of nitrendipine transdermal patches for in vitro and ex vivo characterization. Curr Drug Deliv 2007; 4:69-76.

53. Kunal N.P., Hetal K.P., Vishnu A.P., formulation and characterization of drug in adhesive transdermal patches of diclofenac acid. Int. J. of pharmacy and pharmaceutical science. 2012; 4(1): 296-299.

54. Bhosale N.R., Hardikar S.R., Bhosale A.V. formulation and evaluation of transdermal patches of ropinirole hydrochloride. Research J. of pharmaceutical biological and chemical science. 2011;2(1): 138-148.

55. Raju R.T et al. Formulationand evaluation of transdermal drug delivery system for Lercanidipine hydrochloride. Int.J. Pharma Tech Res.2010; 2(1)253-258.

56. Cross S. E., Robert M.S. targeting local tissues by transdermal applications: understanding drug physiochemical properties. Drug Develop Res. 1999;46: 309-315.

57. Finnin B.C. transdermal drug delivery what to expect in the near future. Busines briefing. Pharma Tech. 2003; 192-193.

58. Mao Z, Zhan X, Tang G, Chen S. A new copolymer membrane controlling clonidine linear release in a transdermal drug delivery system. Int J Pharm 2006; 332:1-5.

59. Vyas SP, Khar RK. Controlled drug delivery concepts and advances. 1st ed. New Delhi: Vallabh Prakashan; 2002. p. 411-47.

60. Pros and corns of topical patches: an analysis of pericision3’s products. http://www.pericision3.com.9 amy 2012

61. Rothbard JB et al. Conjugation of arginine oligomers to cyclosporine a facilitates topical delivery and inhibiting of inflammation. Nat Med.2000;6: 1253-1257.

62. Tiwary AK, Sapra B and Jain S. Innovations in transdermal drug delivery: formulations and techniques. Recent Patents on Drug Delivery and Formulation 2007; 1:23-36.

63. Pellet MA, Castellana S, Hadgraft J, Davis AF. The penetration of supersaturated solutions of Piroxicam across silicone membranes and human skin in-vitro . J Control Rel 1997;46:205-14.

64. Herndon T.O., Gonzalez S, Gowrishankar T, Anderson R.R., Weaver JC. Transdermal micoconduits by microscission for drug delivery and sample acqvisition. BMC Med. 2004; 2: 12.

65. Glenn GM, et al transcutaneous immunization with heat-labile enterotoxin: development of a aneedle free vaccine patch. Expert Rev Vaccines. 2007; 6: 809-819.

66. Prausnitz MR, Gill HS, Park JH. Modified release drug delivery. In: Rathbone MJ, Hadgraft J, Robert MS, Lane ME. Editors. New York: informa health care; 2008.

67. Kogan A, Garti N. Microemulsion as transdermal drug delivery vehicles. Adv colloidal interface sci. 2006; 123-126.

68. Touitou E, Godin B. Enhancement in drug delivery. In: Tuitou E, Barry B, Editors. Boca Raton, FL: CRC press; 2007; 255-278.

69. Banga A.K. London: Tylor and Francis; 1998. Electrically assisted transdermal and topical drug delivery.

70. Zempsky W.T., Sullivan J, Paulson D.M., Hoat S.B. Evaluation of a low dose lidocaine iontophorisis system for topical anaesthesia in adults and children: a randomised controlled trail. Clin Ther. 2004; 26: 1110-1119.

71. Beauchamp M, Lands L.C. Sweat testing: a review of current technical requirements. Pediatr pulmonol. 2005; 39: 507-511.

72. Tamada J et al. Noninvasive glucose monitoring: comprehensive clinical results. Cygnus research team. JAMA 1999; 282: 1839-1844.

73. Machet L, Boucaud A. Phonophoresis: efficacy, mechanism and skin tolerance. Int J pharm 2002; 243: 1-15.

74. Wu J, Nyborg w, editors. London: imperial college press; 2006. Emerging therapeutic ultrasound.

75. Jain s., Joshi S.C. Development of transdermal matrix system of Captopril based on cellulose derivative. Pharmacology online 2007; 1: 379-390.

76. Agrawala S.S., Munjal P., Permeation studies of atenolol and metoprolol tartrate from three different polymer matrices for transdermal delivery. Indian J Pharm sci 2007;69(4): 535-539

77. Garala K.C., Shinde A.J., Shah P.H. Formulaiton and invitro characterization of monolicithic matrix transdermal system using HPMC/Eudragit S100 polymer blends. Int. J. of pharmacy and pharmaceutical science. 2009; 1(1): 108-120.

78. Bogner RH, Wikosz MF. Transdermal drug delivery part 1: Current Status available at: www.usppharmacist.comindex. asp?show=articleandpage=8-1061htm. Accessed on 24 Dec.2006.

79. Panchagnula R. Transdermal delivery of drugs. Indian J Pharmacol. 1997;(29):140-156.

80. Singh MC, Naik AS and Sawant SD. Transdermal drug delivery systems with major emphasis on transdermal patches: A review. J. of pharmacy research 2010; 3(10): 2537-2543.

81. Sakalle P, Dwivedi S and Dwivedi A. Design, evaluation, parameters and marketed products of transdermal patch: a review. J. of pharmacy research. 2010; 3(2): 235-240

82. FDA news (2007). FDA approves Nuepro patch for the treatment of early parkinson’s disease. FDA news, May 9 2007. http://www.fda.gov/bbs/topics/news/2007/news01631.html

83. Sadashivaiah R, Dinesh BM, Patil UA, Desai BG, Raghu KS. Design and in-vitro evaluation of haloperidol lactate transdermal patches containing EC-povidone as film formers. Asian J Pharm 2008; (2):43-49.

84. Singh BS and Kumar CP. Penetration enhancers for transdermal drug delivery of systemic agents. J Pharm Res 2007; 6(2):44-50.

85. Yogesh M, Amgaokar, Rupesh V C, Updesh B L, Dinesh M B, Milind J U. Design formulation and evaluation of transdermal drug delivery system of budesonide. Digest Journal of nanomaterial and biostructures. 2011; 6(2): 475-497.

86. Vijaya R Jayaraj T, Pratheeba C, Aneezi A and Ruckmani K. Design and invitro evaluation of hydroxy propyle methyl cellulose based transdermal films of antriptyline hydrochloride. J. Of Pharmacy Research. 2011; 4(6); 1748-1750.

87. Bhosale NR, Hardikar Sharwaree R, Bhosale AV. Formulation and evaluation of transdermal patches of Ropinirole hydrochloride. RJPBCS. 2011; 2(1): 138-148.

88. Banweer J, Pandey S, Pathak AK. Formulation, optimization and evaluation of mayrix type transdermal system of Lisinopril dehydrate using permeation enhancer. Drug Invention Today. 2010; 2(2): 134-137.

89. Jong sweep Back etal. The feasibility study of transdermal drug delivery system for antidepressants possessing hydrophilicity or hydrophobicity. J. Pharmaceutical Invetigation. 2012; 42: 109-114.

90. Pros and cons of topical patches: An analysis of precision3’s product. http://www. Precision3.com.9may2012

91. Sateesh K, Nair V, Ramesh P. Polymers in transdermal drug delivery system. Pharmaceutical technology 2002; (S): 62-80.

92. Ren C, Fang L, Ling L, Wang Q, Liu S, Zhao L, He z. Design and in vivo evaluation of an indapamide transdermal patch. Int. J. pharm 2009; 370:129-135.

93. Ren C, Fang L, li T, Wang M, Zhao L, He Z. Effect of permeation enhancers and organic acids on the skin permeation of indapamide. Int J Pharm 2008;( 350): 43–7.

94. Prochazka AV. New developments in smoking cessation. Chest 2000;117(4):169-175.

95. Riviere JE, Papich MG. Potential and problems of developming transdermal patches for veterinary applications. Adv Drug Delivery Rev. 2001;(5):175-203.

96. Chandrashekhar NS, Shobha RH. Physicochemical and pharmacokinetic parameters in drug selection and loading for transdermal drug delivery. Indian J Pharm Sci 2008;(70): 94-96.

97. Sharma N, Agarwal G, Rana AC, Bhat Z, Kumar D. A Review: Transdermal Drug Delivery System: A Tool for Novel drug delivery system. IJDDR 2011; 3(3): 70-84.

98. Walters AK. In: Swarbrick J, editor. Encyclopedia of pharmaceutical technology. New York: Informa healthcare; 2007; 3^rd ed. Vol. 1:1317-20

99. Phipps JB, Padmanabhan RV, Young W, Panos R, Chester AE. E-TRANS Technology. In: Rathbone MJ, Hadgraft J, Roberts MS, editors. Modified-Release Drug Delivery Technology. New York: Marcel Dekker Inc; 2002. p. 499-502.

100. Prausnitz MR, Ackley DE, Gyory JR. Microfabricated Microneedles for Transdermal Drug Delivery. In: Rathbone MJ, Hadgraft J, Roberts MS, editors. Modified-Release Drug Delivery Technology. New York: Marcel Dekker, Inc; 2002. p. 513-15.

101. Morgan TM, Reed Bl, Finnin BC. Metered-Dose Transdermal Spray. In: Rathbone MJ, Hadgraft J, Roberts MS, editors. Modified-Release Drug Delivery Technology. New York: Marcel Dekker, Inc; 2002. p. 523-25.

Cevc G. Transfersomes: Innovative Transdermal Drug Carriers In: Rathbone MJ, Hadgraft J, Roberts MS, editors. Modified-Release Drug Delivery echnology. New York: Marcel Dekker, Inc; 2002. p. 533-46.

Received on 15.05.2013

Modified on 16.06.2013

Accepted on 24.06.2013

Research Journal of Pharmaceutical Dosage Forms and Technology. 5(4): July-August, 2013, 177-190

Polymer	Oxygentransmission (cm³/m²/24hours)	Moisture-vapor transmission rate (g/m²/24hours)	Enhancer resistance
Polyurethane film	-	700	low
Ethyl vinyl acetate (EVA)		52.8	medium
Polyethylene	3570	7.9	high
Polyvinyl chloride (PVC) foam	-	450	-
PE, A1 vapour coat PET,EVA	4.6	0.3	High-PETside poly (ethylene terepthalate) polyester
PE, PET laminate	100	12	High PET side
PET, EVA laminate	80	17	High PET side