Transdermal drug delivery products give therapeutic benefit to patients. Approximately 16 active ingredients and more than 35 Transdermal drug delivery products have been approved for use globally and for sale in the US respectively. In the year 2005 market of $ 12.7 billion is found by statistics analysis that is expected to increase to $ 21.5 billion in the year 2011 and $31.5 billion in the year 2015⁷.

Definition:

Transdermal drug delivery systems are defined as self-contained, discrete dosage forms which, when applied to the intact skin, deliver the drug, through the skin, at a controlled rate to the systemic circulation⁸.

Fig 1.1

Advantages of Transdermal Drug Delivery System (TDDS)⁹.

The advantages of transdermal delivery over other traditional delivery modalities are as follows:

1 Hepatic first pass metabolism, salivary metabolism and intestinal metabolism are bypassed thus increasing bioavailability and efficacy of drugs.

2. Self-administration is possible.

3 In case of an emergency, termination of the patch by removal of the application from the surface of the skin at any point of time during therapy can instantly stop active ingredient input.

4 Minimal inter and intra patient variation because the composition of skin structurally and biologically is the same in almost all the humans.

5 Avoidance of gastrointestinal incompatibility.

6 Avoidance of hazards and discomfort associated with parenteral therapy and improves patient compliance, as it is easy to apply.

7 Steady and optimum blood concentration time profile achieved which reduce adverse effects.

8 Release of drug for prolonged time with single application which extend the duration of activity.

9. Drugs entity with short biological half-lives and narrow therapeutic window are utilized.

10 Avoiding the fluctuation in plasma level of drug.

11 Plasma concentration of potent drugs is maintained.

12 Termination of therapy is easy at any point of time.

13 Elimination of typical multiple dosing profile an enhancement of patient compliance.

14 When oral route is unsuitable as with vomiting and diarrhoea then transdermal route is used as alternate for deliver the drug candidate.

Disadvantage of Transdermal Drug Delivery System (TDDS)⁹:

1 Only potent drugs are suitable candidates for transdermal delivery

2 Skin irritation may occur in some patient at the site of application

3 The delivery system is not suitable for drugs needs high blood levels

4 This system is uneconomic

5 Dose dumping may occur due to Binding of drug to skin

6 It can be used only for chronic conditions not for acute condition because chronic condition require drug therapy for a long period of time e.g., hypertension, angina and diabetes etc.

7 Therapeutic performance of the system Affected by Cutaneous metabolism

8 Ionic drugs is not suitable candidate for Transdermal therapy.

Skin: A Site of Percutaneous Absorption ^10-12

It is necessary to understand the anatomy, physiology, physicochemical and biochemical properties of the skinto utilize the phenomenon of percutaneous absorption successfully. The skin of an average adult human covers a surface area of nearly 2 m² and receives about one-third of the blood circulating through the body. Microscopically skin is composed of three main histological layers: epidermis, dermis and subcutaneous tissues. The epidermis is further divided into two parts- the nonviable epidermis (stratum corneum) and the viable epidermis. The viable epidermis is divided into four layers, viz., stratum lucidium, stratumgranulosum, stratum spinosum and stratum germinativum^{13, 14}.

Stratum corneum and Epidermis the main barrier to percutaneous absorption

The SC consists of multiple layers of horny dead cells, which are compacted, flattened, dehydrated and keratinized. The horny cells are stacked in highly interdigitated columns with 15-25 cells in the stack over most of the body. It has a density of 1.55 gm/cc. The stratum corneum has a water content of only 20 % as compared to 70 % present in physiologically active stratum germinativum. It exhibits regional differences over most of the body and is approximately 10-15 µm in thickness. However the thickness may be several hundred micrometers (300-400 µm) on friction surfaces such as the palms of the hand and soles of the feet.

Keratin present in the cells of the stratum corneum is a fibrous protein, which is poor in sulphur and forms a filamentous network to assure cohesion, flexibility and recovery. The unique properties of stability, insolubility and resistance observed in the stratum corneum are due to the thick cell membrane and cell matrix, which consists of amorphous proteins rich in sulphur content and lipids with many disulphide linkages. The stratum corneum is described as the only rate-limiting barrier of the skin with regard to the viable epidermis and dermis. The stratum corneumisa heterogeneous membrane consisting of alternating lipophilic and hydrophilic layers.Below the SC remains the viable epidermis which is more accommodative of permeant molecules. The viable epidermis is an aqueous solution of protein encapsulated into cellular compartments by thin cell membranes, which are fused together by tonofibrils. The viable epidermis has a density near that of water.

The germinal (proliferative) layer above dermis undergoes cell divisions producing an outward displacement of the cell towards the surface. As the germinal layer moves upwards, it changes shape into a more rounded form with spiny projections and appears as a stratum spinosum. After the germinal layer has raised 12-15 layers above its point of origin, it becomes flattened and the basophilic nuclear material is dispersed throughout the cells as granules. The layer is referred to as stratum granulosum¹⁵.The stratum lucidium layer, which lies just below the stratum corneum, is the site where nuclei disintegrate and keratinization and sulphahydryl-rich matrix formation takes place. Eventually it moves upwards to form the stratum corneum. It should be pointed out that the epidermis contains no vascular elements. The cells receive their nourishment from the capillary beds located in the papillary layers of the dermis by diffusion of plasma and serum components.

Dermis: The site of systemic absorption:

The dermis is 0.2-0.3 cm thick and is made of a fibrous protein matrix, mainly collagen, elastin and reticulum embedded in an amorphous colloidal ground substance. It is divided into two distinct zones: a superficial finely structured thin papillary layer adjacent to the epidermis and a deeper coarse reticular layer (the main structural layer of skin). The dermis is also the locus of the blood vessels, sensorynerves segments of the sweat glands and pilosebaceous units. The blood vessels supply blood to the hair follicles, glandular skin appendages and the subcutaneous fat as well as the dermis itself. It protects the body from injury, provides flexibility with strength, and serves as a barrier to infection and functions as a water-storage ^{13, 14}.

Subcutaneous fatty tissue:

Cushioning the epidermis and dermis is the subcutaneous tissue or fat layer where fat is manufactured and stored. It acts as a heat insulator and a shock absorber. It essentially has no effect on the percutaneous absorption of drugs because it lies below the vascular system ¹⁶.

Skin appendages:

The skin has several types of appendages. These include hair follicles with sebaceous, eccrine and apocrine sweat glands and the nails (Figure 1.1). An average human skin surface is known to contain on the average 40-70 hairs follicles and 200-250 sweat ducts per square centimeter area. These skin appendages occupy only 0.1% of the total human skin surface. The eccrine sweat glands (2-5 million) produce sweat (pH 4.0-6.8) and may also secrete drugs, protein, or antibodies. Their principal function is to aid heatcontrol; approximately 400 glands per square centimeter are particularly concentrated in the palms and soles.

Sebaceous glands are most numerous and largest on the face, forehead, ear, on the midline of the back and on anogenital surfaces. The palms and soles usually lack them. The glands vary in size from 200-2000µm in diameter. The larger ones are found on the nose. They secrete an oily material known as sebum from cell disintegration. Its principal components are glycerides, free fatty acids, cholesterol, cholesterol esters and squalene. It acts as lubricant and a source of stratum corneum plasticizing lipid, maintains an acidic condition on the skins outer surface (pH-5) ¹⁵.

Mechanism of percutaneous penetration:

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 (Figure 2) to the viable tissue through hair follicles with associated sebaceous glands, via sweat ducts, thirdly across continuous stratum corneum between these appendages. 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 follicle ¹⁷.

Drug Selection Criteria for Transdermal Patch^{9, 18}:

1 The dose of drug should be low i.e.<20mg/day.

2 The drug should have short half life (which causes non-compliance due to frequent dosing).

3 The drug should have Molecular weight <400 Daltons (high molecular weight fail to penetrate the stratum corneum).

4 The drug should have partition coefficient (octanol‐water) between 1.0 and 4 (logP).

5 Drug should be non-irritating and non- sensitizing to the skin.

6 The drug should have low Oral bioavailability.

7 The drug should have low therapeutic index. The drug should have affinity for both – lipophilic and hydrophilic phases. The drug should have low melting point(less than 200°C).

Care taken while applying Transdermal patch:

1 The part of the skin where the patch is to be applied should be properly cleaned.

2 Patch should not be cut because cutting the patch destroys the drug delivery system.

3 Before applying a new patch it should be made sure that the old patch is removed from the site.

4 Care should be taken while applying or removing the patch because anyone handling the patch can absorb the drug from the patch.

5 The patch should be applied accurately to the site of administration.

Conditions in which Transdermal patches are used:

Transdermal patch is used when:

(1) When the patient has intolerable side effects (including constipation) and who is unable to take oral medication (dysphagia) and is requesting an alternative method of drug delivery.

(2) Where the pain control might be improved by reliable administration. This might be useful in patients with cognitive impairment or those who for other reasons are not able to self-medicate with their analgesia.

(3) It can be used in combination with other enhancement strategies to produce synergistic effects.

Conditions in which Transdermal patches are not used:

The use of transdermal patch is not suitable when:

(1)Cure for acute pain is required.

(2) Where rapid dose titration is required.

(3) Where requirement of dose is equal to or less than 30 mg/24 hrs.

Factors influencing Transdermal Drug Delivery⁹:

The effective transdermal drug delivery can be formulated by considering three factors as Drug, Skin, and the vehicles. So the factors affecting can be divided in to classes as biological factors and physicochemical factors.

A. Biological factors:

1 Skin condition: Acids and alkalis, many solvents like chloroform methanol damage the skin cells and promote penetration. Diseased state of patient alters the skin conditions. The intact skin is better barrier but the above mentioned conditions affect penetration.

2 Skin age: The young skin is more permeable than older. Children are more sensitive for skin absorption of toxins. Thus, skin age is one of the factors affecting penetration of drug in TDDS.

3 Blood supply: Changes in peripheral circulation can affect transdermal absorption.

4 Regional skin site: Thickness of skin, nature of stratum corneum, and density of appendages vary site to site. These factors affect significantly penetration.

5 Skin metabolism: Skin metabolizes steroids, hormones, chemical carcinogens and some drugs. So skin metabolism determines efficacy of drug permeated through the skin.

6 Species differences: The skin thickness, density of appendages, and keratinization of skin vary species to species, so affects the penetration.

B. Physicochemical factors:

1 Skin hydration: In contact with water the permeability of skin increases significantly. Hydration is most important factor increasing the permeation of skin. So use of humectants is done in transdermal delivery.

2 Temperature and pH: The permeation of drug increase ten fold with temperature variation. The diffusion coefficient decreases as temperature falls. Weak acids and weak bases dissociate depending on the pH and pKa or pKb values. The proportion of unionized drug determines the drug concentration in skin. Thus, temperature and pH are important factors affecting drug penetration.

3 Diffusion coefficient: Penetration of drug depends on diffusion coefficient of drug. At a constant temperature the diffusion coefficient of drug depends on properties of drug, diffusion medium and interaction between them.

4 Drug concentration: The flux is proportional to the concentration gradient across the barrier and concentration gradient will be higher if the concentration of drug will be more across the barrier.

5 Partition coefficient: The optimal K, partition coefficient is required for good action. Drugs with high K are not ready to leave the lipid portion of skin. Also, drugs with low K will not be permeated.

6 Molecular size and shape: Drug absorption is inversely related to molecular weight; small molecules penetrate faster than large ones. Because of partition coefficient domination, the effect of molecular size is not known.

Basic Components of TDDS⁹:

1. Polymer matrix / Drug reservoir:

Polymers are the backbone of TDDS, which control the release of the drug from the device. Polymer matrix can be prepared by dispersion of drug in liquid or solid state synthetic polymer base. Polymers used in TDDS should have biocompatibility and chemical compatibility with the drug and other components of the system such as penetration enhancers and pressure sensitive adhesive.

2. Drug:

The transdermal route is an extremely attractive option for the drugs with appropriate pharmacology and physical chemistry. The foremost requirement of TDDS is that the drug possesses the right mix of physicochemical and biological properties for transdermal drug delivery. Drug is in direct contact with release liner.

3. Permeation enhancers:

Penetration enhancers are molecules, which reversibly alter the barrier properties of the stratum corneum. 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 or to achieve a given therapeutic effect with a reduced concentration of the active constituents. Mechanism of actions of different penetration enhancers has been given in Table 1.

Mechanism of action of permeation enhancers¹⁹

Table 1: Different class of enhancers and their mechanism of action

Class	Examples	Mechanism of action
Hydrating Substances	Water occlusive preparation	Hydrates the SC
Keratolytics	Urea	Increase fluidity and hydrates the SC
Organic Solvents	Alcohol PEG DMSO	Partially extracts lipids Replace bound water in the intercellular spaces Increase lipid fluidity
Fatty acids	Oleic acid	Increase fluidity of intercellular Lipids
Terpenes	1,8-Cineole , Menthol	Open Cellular Path way
Surfactants	Polysorbates SLS	Penetrates into skin, micellarsolubilisation of SC
Azone	1-Dodecylhexahydro- 2HAzepine-2on2	Disrupts the skin lipids in both the head group and tail region

4. Pressure sensitive adhesive (PSA):

The pressure-sensitive adhesive (PSA) affixes the Transdermal drug delivery system firmly to the skin. It should adhere with not more than applied finger pressure, be aggressively and permanently tacky and exert a strong holding force. Additionally, it should be removable from the smooth surface without leaving a residue.

5. Backing laminates:

The primary function of the backing laminate is to provide support. They should be able to prevent drug from leaving the dosage form through top. They must be impermeable to drugs and permeation enhancers

6. Release liner:

During storage release liner prevents the loss of the drug that has migrated into the adhesive layer and contamination. It is therefore regarded as a part of the primary packaging material rather than a part of dosage form for delivering the drug.

7.Rate controlling membrane:

Rate controlling membranes in transdermal devices govern drug release from the dosage form. Membranes made from natural polymeric material such as chitosan show great promise for use as rate controlling membranes. It should be flexible enough not to split or crack on bending or stretching. Some of rate-controlling membranes are polyethylene sheets, ethylene vinyl acetate co-polymer, and cellulose acetate. Recently composite poly-2-hydroxyethyl methacrylate (PHEMA) membranes have been evaluated as rate controlling barriers for transdermal application.

8. Other excipients-

Various solvents such as chloroform, methanol, acetone, isopropanol and dichloromethane are used to prepare drug reservoir. In addition plasticizers such as dibutylpthalate, triethylcitrate, polyethyleneglycol and propylene glycol are added to provide plasticity to the transdermal patch.

Types of Transdermal Patches:^19-23

a) Single layer drug in adhesive:

In this type the adhesive layer contains the drug. The adhesive layer not only serves to adhere the various layers together and also responsible for the releasing the drug to the skin. The adhesive layer is surrounded by a temporary liner and a backing.

b) Multi -layer drug in adhesive:

This type is also similar to the single layer but it contains a immediate drug release layer and other layer will be a controlled release along with the adhesive layer. The adhesive layer is responsible for the releasing of the drug. This patch also has a temporary liner-layer and a permanent backing.

c) Vapour patch:

In this type of patch the role of adhesive layer not only serves to adhere the various layers together but also serves market, commonly used for releasing of essential oils in decongestion. Various other types of vapor patches are also available in the market which are used to improve the quality of sleep and reduces the cigarette smoking conditions.

d) Reservoir system:

In this system the drug reservoir is embedded between an impervious backing layer and a rate controlling membrane. The drug releases only through the ratecontrolling membrane, which can be micro porous or non porous. In the drug reservoir compartment, the drug can be in the form of a solution, suspension, gel or dispersed in a solid polymer matrix. Hypoallergenic adhesive polymer can be applied as outer surface polymeric membrane which is compatible with drug.

e) Matrix system:

i. Drug-in-adhesive system:

In this type the drug reservoir is formed by dispersing the drug in an adhesive polymer and then spreading the medicated adhesive polymer by solvent casting or melting (in the case of hot-melt adhesives) on an impervious backing layer. On top of the reservoir, unmediated adhesive polymer layers are applied for protection purpose.

ii. Matrix-dispersion system:

In this type the drug is dispersed homogenously in a hydrophilic or lipophilic polymer matrix. This drug containing polymer disk is fixed on to 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 with the circumference to form a strip of adhesive rim.

f) Microreservoir system:

In this type the drug delivery system is a combination of reservoir and matrix-dispersion system. 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 unreachable, microscopic spheres of drug reservoirs. This thermodynamically unstable dispersion is stabilized quickly by immediately cross-linking the polymer in situ by using cross linking agents.

Advances in transdermal patch technology

i) Adhesives:

For transdermal patches to provide consistent and continuous drug delivery through the skin, they must adhere well. There are several adhesives in regular use in transdermal systems including silicones and polyisobutylenes. Newer adhesives, including acrylates, have recently become available. Acrylates are known as pressure-sensitive adhesives and they are preferred because they have selective adhesive properties once in contact with the skin. Pressure-sensitive adhesives can also be removed with ease and they are compatible with skin and various drug molecules. The polymeric nature of acrylates prevents the patches from undergoing physical breakdown.

i) Penetration Enhancers:

Many drug substances will not diffuse into the skin at sufficient rates to obtain therapeutic concentrations. Substances that reduce the skin’s ability to perform its barrier function are collectively known as penetration enhancers. These substances make the skin more permeable and they allow drug molecules to cross the skin at a faster rate. With regard to both safety and efficacy, water is the optimum permeation enhancer. By increasing the hydration of the stratum corneum, the barrier function of the skin can be reduced. Alcohol is commonly considered a solvent in transdermal patches; it actually serves as effective penetration enhancer. Some penetration enhancers remove lipids from the skin.^24-26

Other advances in Trans Dermal Delivery

1. Iontophoresis^27-29

Iontophoresis it is the electrical driving of charged molecules into tissue. Iontophoresis passes a few milliamperes of current to a few square centimeters of skin through the electrode placed in contact with the formulation, which facilitates drug delivery across the barrier. It has application in dentistry, opthalmology, surgery and general medicine. A grounding electrode placed elsewhere on the body completes the electrical circuit .the port of the charged molecules is driven primarily by electrical repulsion from the driving electrode. However, polar neutral molecules can also be delivered by a current – induced connective flow of water (electro-osmosis) a problem with the method is that, although the apparent current density per unit area is low, nearely all the current penetrates via a low resistance route i.e the appendages, particularly the hair follicles, thus the actually current density in the follicle may be high enough to damaged growing hair. There is also concern about other possible irreversible changed to the skin.

2. Electroporation³⁰

Electroporation is a method of application of short, high-voltage electrical pulses to the skin. After electroporation, the permeability of the skin for diffusion of drugs is increased by 4 orders of magnitude. The electrical pulses are believed to form transient aqueous pores in the stratum corneum, through which drug transport occurs. It is safe and the electrical pulses can be administered painlessly using closely spaced electrodes to constrain the electric field within the nerve-free stratum corneum

3. Ultrasound (Phonophoresis )³¹

Application of ultrasound, particularly low frequency ultrasound, has been shown to enhance transdermal transport of various drugs including macromolecules. Used primarily in physiotherapy and sports medicine, involves placing the topical preparation on the skin over the are to be treated and massaging the site with an ultrasound source .The ultra sonic energy disturbs the lipid packaging in the intracellular spaces of the stratum corneum by heating and cavitations effects, and thus enhances drug penetration in to the tissue .This method is not readily suitable for home use.

4. Photochemical Wave²⁷

A drug solution is placed on the skin, covered by a black polystrene target, and irradiated with a laser pulse .the resultant photomechanical wave produces stresses in the horny layer that enhances drug delivery .the technique is likely to remain experimental.

5. Reverse Electroporation³²

Reversible electroporation is the temporary permeabilization of the cell membrane through the formation of nano-scale pores that are transient defects in the membrane. These pores are caused by short electrical pulses. Typically on the order of a few to several hundred microseconds that are delivered by electroporationelectrodes inserted around the treated tissue. Reversible electroporation has become an important technique in molecular medicine. It is used to introduce macromolecules such as genes or anticancer drugs, to which the cell membrane is normally not permeable, into the cytosol

6. Use Of Microscopic Projection^27,28

Transdermal patches with microscopic projections called microneedles were used to facilitate transdermal drug transport. Needles ranging from approximately 10-100 μm in length are arranged in arrays. When pressed into the skin, the arrays make microscopic punctures that are large enough to deliver macromolecules, but small enough that the patient does not feel the penetration or pain. The drug is surface coated on the microneedles to aid in rapid absorption. They are used in the development of cutaneous vaccines for tetanus and influenza.

7. Stratum Corneum Removal²⁷

Laser ablation uses high – powered pulses to vaporizes pulses from laser to vaporize a section of horny layer so as to produce permeable skin regions .the apparatus is costly and requires expert handling to avoid damages like burns.

Therapeutic agent	Marketed name (Company)
Clonidine	Catapres-TTS (Boehringer Ingelheim)
Estradiol	Vivelle (Novartis)
Fentanyl	Duragesic (Janssen)
Nicotine	Prosstep (Lederie)
Testosterone	Testoderm (Alza)
Nicotine	Habitrol (Novartis Consumer)
Nitro-glycerine	Transderm-Nitro (Novartis)
Nicotine	Nicoderm CQ (Smithkline consumer)
Scopolamine	Transderm-Scop(Novartis Consumer)

Evaluations of Transdermal Drug Delivery Systems

1. Determination of Drug partition coefficient³³

The partition coefficient study can be performed using n-octanol as the oil phase and phosphate buffer pH 7.4 as the aqueous phase. The two phases can be mixed in equal quantities and then saturated with each other on a mechanical water bath shaker having 37 °C temperature for 24 h. The saturated phases can be separated by centrifugation at 2000 rpm. Standard plots of the drug can be prepared from both phosphate buffer pH 7.4 and n-octanol. Equal volumes (10 mL) of the two phases can be placed in hexaplicate in conical flasks and, to each; 100 mg of drug can be added. The flasks should be shaken at 37 °C for 6 h to achieve complete partitioning at 100 rpm. The two phases were separated by centrifugation at1000rpm for 5 min and were then analyzed for respective drug contents

2. Transdermal Drug Delivery Kinetics³⁴

Skin permeation kinetics of drug from these technology different TDDS systems can be evaluated using a two compartment diffusion cell assembly under identical conditions. This is carried out by individually mounting a skin specimen excised from either a human cadaver or a live animal on a vertical diffusion cell and its modification on a horizontal diffusion cell such as Franz diffusion cell and Valia–Chien skin permeation cell. Each unit of the TDD system is then applied with its drug releasing surface of the skin. The release profile of drug from this TDD system can also be investigated in the same diffusion cell assembly without a skin specimen.

3. In Vitro Methods²⁷

These are valuable methods for screening and for measuring fluxes, partion coefficients and diffusion coefficients .Excised skin from rats, mice and guinea pigs (normal and hairless), rabbits, hamsters and pigs hairless dogs, monkeys etc are collected and mounted in diffusion cell but mammalian skin varies widely in stratum corneum so it is best to obtain the human skin from autopsies or cosmetic surgery. Investigator clamped the skin in diffusion cell and measure the compound passing from sratum corneum side through to a fluid bath three important quantities of drug vary with time viz1 amount of drug entering the membrane .2 amount of drug passing through diffusion cell.3 amount that remains inside .the membrane. As human skin is difficult to obtain variable investigator have used artificial membranes of material like cellulose acetate ,silicone rubber or isopropyl myristateor lamellar systems designed to mimic the intracellular lipid of the stratum corneum, however the these membranes are not as complex as human skin .

Released methods without a rate limiting membranes -

It mainly records the drug release to immiscible phase, it only measures drug vehicles interactions that affect the drug release characteristics and do not determine the skin absorption. Such procedures are important for Quality control protocol.

4. In Vivo Methods

In vivo methods animals are used, however most animals differ in features which affect precutaneous absorption .

5. Histology

These experiments are carried out to locate skin penetrations roots from microscopic sections. Problem associated with this method is that while handling, cutting and operating the skin tissue the secretions developed by skin may take away materials away from their original sites. Histo chemical techniques have been used for those few compounds that produce coloured end products after chemical reaction .Few compounds flurosce, revealing their behavior by microscopy eg vitA, tetracyclines, benzpyrene .

6. Microdialysis

In this technique micro dialysis probes are inserted in the dermis and perfused with buffer. Drug molecule passes from the extracellular fluid into the buffer through pores in the membrane. Which excludes large molecules, particularly proteins? The resulting drug solution is collected and analyzed.

7. Surface loss

In theory we able to explain the flux of material into skin from the loss rate from the vehicle however because of skin impermeability, the concentration decrease in vehicle would be generally be small and analytical techniques would be sensitive and accurate. Differences in vehicles concentration arises due to evaporation or dilution with sweat or trans epidermal water and simply drug partitioning in to the skin

8. Other physical methods of evaluation of Transderrmal patches³⁵

a. Thickness. – The thickness of patches can be measured at three different places using amicrometer (Mitutoyo Co., Japan) and mean values were calculated.

b. Mass variation. – The patches can be subjected to mass variation by individually weighing 10 randomly selected patches. Such determinations can be possibly carried out for each formulation.

c. Folding endurance. – This can be determined by repeatedly folding one film at the same place till it broke. The number of times the film could be folded at the same place without breaking/cracking gave the value of folding endurance.

d. Moisture vapour transmission (MVT). – MVT is defined as the quantity of moisture transmitted through unit area of film in unit time. Glass cells can be filled with 2 g of anhydrous calcium chloride and a film of specified area can be affixed on to the cell rim. The assembly should be accurately weighed and placed in a humidity chamber (80 ± 5% RH)at 27 ± 2 °C for 24 h.

e. Drug content uniformity. – Patches of specified area (3.14 cm) were dissolved in5 mL of Dichloromethane and the volume can be made up to 10 mL with phosphate buffer Dichloromethane should be evaporated using a rotary vacuum evaporator at 45 °C. A blank can be prepared using a drug-free patch treated similarly. The solutions can be filtered through a 0.45-μm membrane, diluted suitably and absorbance’s can be read at 242 nm in a double beam UV-Vis spectrophotometer also adherence of the patch to the surface of the skin is also evaluate die to check the required contact time for release of drug from patches and its absorption into the skin.

CONCLUSION:

Indications for Alternate Route are many, like patients unwilling or unable to swallow medications , cancers of the mouth, throat and GI tract ,compromise of the GI tract ,bowel obstruction ,intolerable side effects during administration, treating localized pain ,avoiding systemic side effects, neonatal/paediatric populations etc. TDDS can be an answer to few of above if not for all of above. Transdermal drug delivery is not only defines about patch and its application but it is a system containing other formulations like ointments, creams ,gels which are made for use as transdermal drug delivery with the help of penetration enhancers but the dose concept cannot be effectively controlled with these semisolid formulations as can be done in a patch.

Also a lot of progress has been done in the field of Transdermal Patches. Due to large advantages of the Transdermal Drug Delivery System, this system interests a lot of researchers. Many new research are going on in the present day to incorporate newer drugs via this system. Various devices which help in increasing the rate of absorption and penetration of the drug are also being studied. With the invention of the new devices and new drugs which can be incorporated via this system, it used is increasing rapidly in the present time. At the same time the research in this area is not easy as there are various other limitations for TDDS to be used very common route of administration and with 100% success. Like – Skin is very complex and tough barrier for drugs to go through and reach blood. Not all drugs can go through skin easily. Occlusion of skin and penetration enhancers can not always ensure big success in development of TDDS for a drug candidate. Its very difficult to develop TDDS for a drug having high therapeutic dose, as its difficult to achieve the blood levels of the drug by passing through skin that is why so far TDDS is a success story for “potent” drugs. Large dose cannot be given as well large drug molecules cannot be delivered by TDDS .Some drugs can give rise skin irritation and therefore their the use in the Transdermal Drug Delivery System has been limited.

All formulations based on TDDS concept need to submit the In vivo, In vitro data of drug concentration reaching the systemic circulation for their approval but at the same time consideration must be given to the systemic toxicity of the drug from topical formulations. Evidence of drug not reaching the systemic circulation can be one of the quality parameter for the topical formulations.

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Received on 15.05.2013

Modified on 18.06.2013

Accepted on 26.06.2013

Research Journal of Pharmaceutical Dosage Forms and Technology. 5(4): July-August, 2013, 202-212