INTRODUCTION:

Twentieth century marked the beginning of dermal route for long term drug delivery. For decades, utilization of skin as a route for delivering drugs has been an attractive alternative to conventional methods including injections and tablets. Today about two third of drugs available in market are taken orally, but these are not as effective as required. To improve upon the features the Transdermal drug delivery system was emerged¹.Transdermal drug delivery systems (TDDS), also known as patches are the dosage forms designed to deliver a therapeutically effective amount of drug across a patient’s skin. Transdermal delivery not only provides controlled, constant administration of the drug, but also allows continuous input of drug with short biological half lives and eliminates pulsed entry into systemic circulation, which often causes undesirable side effects.²

Transdermal patches were developed in 1970s and the first was approved by FDA in 1979 for the treatment of motion sickness. It was a three day patch that delivered scopolamine. In 1981, patches for nitroglycerin were approved, and today there exist a number of patches for drugs such as clonidine, fentanyl, lidocaine, nicotine, nitroglycerin, estradiol, oxybutinin, scopolamine and testosterone. There are also combination patches for contraception, as well as hormone replacement. Depending on the drug, the patch generally lasts from one to seven days.³

Definition

A Transdermal patch is defined as a medicated adhesive patch which is placed above the skin to deliver a specific dose of medication through a skin with a predetermined rate of release to reach into bloodstream.¹

Advantages^1,
4-9

1. Maintains stable or constant and controlled blood levels for longer period of time.

2. Avoidance of first pass metabolism of drugs.

3. A simplified medication regimen leads to improved patience compliance and reduced side effects, inter and intra patient variability.

4. Drug level can be maintained in the systemic circulation, within the therapeutic window, for prolonged period of time.

5. Suitable for administration of drugs having very short half life, narrow therapeutic window and poor oral bioavailability.

6. Improved patient compliance and comfort via non invasive, painless and simple application and reduced dosing frequency.

7. Increases the therapeutic value of many drugs via avoiding many problems associated with drugs like GI irritation, lower absorption, and decomposition due to hepatic first pass effect.

8. Self administration is possible.

9. Flexibility of terminating the drug administration by simply removing the patch from the skin.

10. Reduced adverse effects associated with intermittent dosing.

11. Beneficial for unconscious patient and those with dysphagia and constipation.

12. Useful when long term treatment is required, as in chronic pain treatment, smoking cessation therapy etc.

Disadvantages^{1,
4- 5, 8-13}

1. Not suitable for drugs with large molecular weight i.e. > 1000 Daltons.

2. Local irritation at the site of administration such as itching, erythema, local edema may be caused by the drug or excipients used in formulation.

3. The barrier function of skin changes from one site to another on the same person, from person to person and with age.

4. Transdermal drug delivery system is unable to deliver ionic drugs.

5. Poor skin permeation limits the number of drugs that can be delivered in this manner.

6. It cannot deliver drug in pulsatile fashion.

7. Transdermal drug delivery system is restricted to potent drugs.

8. Not Suitable for drugs with high dose.

Skin: structure and barrier proporties^{4, 5, 14-18}

The skin is a multilayered organ composed of many histological layers and complex in both structure and function. It performs the functions of protection of major or vital internal organs of the body from external influences, temperature regulation, control of water output and sensation. It covers the surface area of about two square meters and receives about one-third of blood circulating through the body. It allows the passage of various drugs across the skin and serves as a point of administration for systemically active drugs as well as for topical action.

Fig.1. Structure of skin

Layers of skin: Three major layers of skin are:

1. Epidermis

Epidermis is composed of stratified squamous keratinizing epithelium. The keratinocyte comprise the major cellular component and responsible for barrier function. Stratum corneum cells are formed and continuously replenished by the slow upward migration of cells produced by basal cell layers of stratum germinativum. Microscopically epidermis is divided into five anatomical layers of which stratum corneum is the outermost layer. This layer is 100-150 micrometers thick and is most important layer for Transdermal drug delivery as its composition allows it to keep water within the body and foreign substances out. Other underlying layers are stratum spinosum (prickly layer), stratum granulosum (granular layer), stratum lucidum (clear layer) and stratum germinativum.

2. Dermis

The dermis is the inner and larger (90%) skin layer, comprised primarily of connective tissue and provides support to the epidermis layer of the skin. The dermis contains the system of capillaries that transport blood throughout the body, lymphatic vesicles and nerve endings. If the drug is able to penetrate the stratum corneum, then it can enter the blood stream. A process known as passive diffusion, which occurs too slowly to transfer normal drug across the layer. Dermis can be divided into two anatomical regions; papillary dermis and reticular dermis. Papillary region consist of collagen and elastin fibres which are mostly vertically arranged. Fibres in reticular region are arranged horizontally.

3. Hypodermis

Hypodermis is the adipose tissue layer which is found in between dermis and aponurosis and fasciae of the muscles. It is composed of loose connective tissue and its thickness varies according to surface of body.

Routes of penetration^19-23

The diffusant has two potential routes to the blood vasculature: through the epidermis itself or diffusion through shunt pathway, mainly hair follicles with their associated sebaceous glands and sweat ducts. Thus there are two major routes of penetration:

A. Appendageal route

Skin appendages have small fractional area available for absorption (about 0.1%) and this route does not contribute appreciably to steady state flux of drug. However route may be important for ions and large polar molecules that cross intact stratum corneum difficulty.

B. Epidermal route

For drugs which mainly cross intact horny layer, two potential micro routes of entry exist, the transcellular (intracellular) and intercellular pathways. The principal pathway taken by the permeant is decided mainly by the partition coefficients (log K). Hydrophilic drugs partition preferentially into the intracellular domains, whereas lipophilic permeates (log K_o_/w>2) traverse the stratum corneum via the intercellular route. Most permeates permeate the stratum corneum by both routes. However, the tortuous intercellular pathway is widely considered to provide the principal route and major barrier to the permeation of most drugs.

Mechanism of transdermal permeation^{1, 9, 24, 25}

Transdermal permeation of drugs involves following steps:

1. Sorption by stratum corneum.

2. Permeation of drug through viable epidermis.

3. Uptake of drug moiety by the capillary network in the dermal papillary layer.

The rate of permeation of drug moiety across the skin is governed by following equation:

=P_S(_d-C_r)

Where,

C_d = concentration of drug in donor phase (on skin surface).

C_r= concentration of drug in receptor phase (body).

P_s = Overall permeability coefficient of skin which is defined as

P_s=K_SD_SS/h_s

Where,

K = partition coefficient of penetrant.

D_SS= apparent diffusivity of penetrant.

H_s= thickness of skin.

Fig2. Penetration pathways through skin: intercellular and intracellular.

A constant rate of drug permeation is achieved, if Cd > C_r then the equation reduces as:

[dQ/dT] =P_SC_d

The rate of skin permeation dQ/dT becomes constant, if the C value remains fairly constant throughout the course of skin permeation. To maintain Cd at a constant value, it is critical to make the drug release at the rate Rr which is always greater than the rate of skin uptake R_a i.e.

R_R>> R_a .

By doing so the drug concentration on the skin surface C_d is maintained at a level which is always greater than the equilibrium solubility of the drug in stratum corneum (C^e_s),i.e.,c_d>c; and maximum rate of skin penetration (dQ/dT)mas expressed by equation .

[dQ/dT]=PsCs^e

Factors that influence transdermal delivery^{19, 21, 23}

1. Biological parameters

2. Physicochemical parameters

1. Biological parameters:

a) Skin condition

The skin is the tough barrier to penetration, but only if it is intact. Vesicants such as acid, alkalis injure the barrier cells and there by promote penetration. Percutaneous absorption increases in case of disease characterised by defective stratum corneum.

b) Blood flow

Theoretically, changes in peripheral circulation, or blood flow through the dermis could affect percutaneous absorption. Thus an increased blood flow could reduce time for which penetrant remains in the dermis and also raise the conc. Gradient across skin.

c) Regional skin sites

Variation in cutaneous permeability around the body depends upon thickness and nature of stratum corneum and the density of skin appendages. However the rate of absorption at identical skin sites in different healthy volunteers varies.

d) Skin metabolism

It has been recently reviewed the role which the skin plays in metabolism of drugs & steroidal hormones. The topical bioavailability should account for not only skin permeation but also cutaneous drug metabolism.

e) Species difference

Mammalian skin differs widely in characteristics such as horny layer thickness, swat gland & hair follicle densities, and pelt condition, the capillary blood supply and the sweating ability from species to species so affect the permeation.

2. Physicochemical parameters

a) Hydration of skin

When water saturates the skin; tissue swells, softens & wrinkles and its permeability increases markedly.

In fact, hydration of stratum corneum is one of important factors in increasing the penetration rate of most substances that permeate the skin.

b) Temperature

The penetration rate of material through the human skin can change by tenfold for large temperature by few degrees, but any consequent increased permeability is small compared to effect of hydration.

c) Diffusion coefficient

The diffusional speed of molecule depends mainly on state of matter in the medium. In gases and air, diffusion coefficient is large because the void space available to the molecules is as large as compared to their sizes.

d) Drug concentration

The drug permeation usually follows the fick’s law. The flux of solute is proportional to the concentration gradient across the entire barrier phase.

e) Partition coefficient

Partition coefficient is important in establishing the flux of drug through the stratum corneum. The balanced Partition coefficient is required for drug permeation.

f) Molecular size

Absorption is apparently inversely related to molecular weight. Small molecule penetrates faster than larger ones.

Table1: Ideal properties of Transdermal drug delivery system.^{16, 26}

Sr. No.	Properties	Range
1.	Shelf life	Should be upto 2.5 years
2.	Patch size	Should be less than 40 cm²
3.	Dose frequency	Once a daily-Once a week
4.	Appearance	Should be clear or white colour
5.	Packaging properties	Should be easily removable of release linear
6.	Skin reaction	Should be non-irritating
7.	Release properties	Should have consistent pharmacokinetic and pharmacodynamic profiles over time.

Fig.2: Ideal properties of drug for TDDS^{,
16, 26, 27}

Sr.No.	Parameter	Properties
1.	Dose	Should be low
2.	Half life in hours	Should be ≤ 10
3.	Molecular weight	Should be < 500
4.	Partition coefficient	Log P_o/wbetween -1& 3
5.	Skin permeability coefficient	Should be < 0.5X10^-3cm/hr
6.	Skin reaction	Should be non irritating
7.	Oral bioavailability	Should be low
8.	Therapeutic index	Should be low
9.	Concentration	Minute
10.	pH of saturated aqueous solution	5-9
11.	Deliverable dose	< 10mg/day

Types of Transdermal Patch^{1, 2, 3, 19, 28}

1) 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, along with the entire system to the skin but it is also responsible for the release of the drug. The adhesive layer is surrounded by a temporary liner and a backing.

Fig 3. Single layer drug in adhesive system.

2) Multi layer drug in adhesive

Multi layer drug in adhesive patch is similar to single layer system in that both adhesive layers are also responsible for release of the drug. The multilayer system is different however that it adds another layer of drug in adhesive usually separated by a membrane. This patch also has a temporary liner layer and a permanent backing.

Fig4. Multilayer drug in adhesive system.

3) Reservoir

Unlike the Single layer and Multi level Drug in-adhesive system the reservoir Transdermal system has a separate drug layer. The drug layer is a liquid compartment containing a drug solution or suspension separated by the adhesive layer. This patch is also backed by the backing layer. In this type of system the rate of release is zero order.

Fig5. Reservoir Transdermal system.

4) Matrix

The Matrix system has a drug layer of semisolid matrix containing a drug solution or suspension .The adhesive layer in this patch surrounds the drug partially overlaying it. These are of two types.

a) Drug-in-adhesive system

b) Matrix-dispersion system

Fig.6 matrix Transdermal system.

5) Vapour patch

In this type of patch the adhesive layer not only serves to adhere the various layers together but also to release vapour. The vapour patches are new on the market and they release essential oil for upto 6 hours .The vapours patches release essential oils and are used in cases of decongestion only mainly. Other vapour patches on the market are controller vapour patches that improve the quality of sleep. Vapour patches that reduce the quantity of cigarettes that one smokes in a mouth are also available on the market.

Formulation design^{19, 27, 29, 30}

A Transdermal delivery system is a multilaminate structure composed of following components:

1. Drug reservoir

2. Polymer matrix

3. Penetration enhancer

4. Adhesives

5. Backing membrane

6. Release liner

1. Drug reservoir

It consists of drug particles dissolved or dispersed in the matrix. The reservoir is sandwiched in between a drug impermeable backing membrane and a rate controlling polymeric membrane.

2. Polymer matrix

These polymers control the release rate of drug through the membrane:

Natural polymers-shellac, gelatin, wax, gum, starch.

Synthetic polymers - polyvinyl alcohol, polyethylene, polyamide, polypropylene, polyurea, polymethyl methacrylate etc.

4. Adhesive

Adhesive serves to adhere the components of the patch together along with adhering patch to the skin. The pressure sensitive adhesives are based on natural or synthetic rubbers, polyacrylates or silicone. Silicon adhesives are preferred as they are kind to skin. They are also chemically stable, biologically inert, and transparent, retain adhesive properties in presence of moisture, and have high permeability. Acrylic based adhesives are widely used due to their good adhesive qualities and low level of allergenicity. Polyvinyl ether based adhesive are employed in moisture permeable skin patches.

5. Backing layer

It protects the patch from the outer environment. It should be impermeable to drug and penetration enhancers. It holds the entire system and protects drug reservoir from atmosphere. The commonly used backing materials are polyesters, aluminised polyethylene terpthalate and siliconised polyethylene terpthalate.

6. Release liner

Release liner protects the patch during storage. It is to be removed prior to use.

Methods for preparation of transdermal patch^{3, 33-42}

1. Asymmetric TPX membrane method

A prototype patch can be fabricated, for this a heat sealable polyester film (type 1009, 3m) with a concave of 1 cm diameter will be used as a backing membrane. Drug sample is dispensed into the concave membrane, covered by a TPX {poly (4-methyl-1-pentene)} asymmetric membrane, and sealed by an adhesive.

2. Circular Teflon mould method

Solutions containing polymers in various ratios are used in an organic solvent. Calculated amount of drug is dissolved in half the quantity of same organic solvent. Enhancers in different concentrations are dissolved in the other half of organic solvent and then added. Di-N-butylphthalate is added as a plasticizer into drug polymer solution. The total contents are to be stirred for 12hrs and then poured into a circular Teflon mould. The moulds are to be placed on a levelled surface and covered with inverted funnel to control solvent vaporisation in a laminar flow hood model with an air speed of 0.5 m/s. The solvent is then allowed to evaporate for 24hrs. The dried films are to be stored for another 24hrs at 25±0.5°C in a desiccator containing silica gel, before evaluation to eliminate aging effects.

3. Mercury substrate method

In this method drug is dissolved in a polymer solution along with plasticizer. The solution is then stirred for 10-15 min to produce a homogenous dispersion and poured onto a levelled mercury surface, covered with an inverted funnel to control the rate of evaporation.

4. Using “IPM membranes” method

In this method the drug is dispersed in a mixture of water and propylene glycol containing carbomer 940 polymer and stirred for 12 hrs using magnetic stirrer. The dispersion is to be made viscous by addition of triethanolamine. Buffer of pH 7.4 can be used in order to obtain solution gel, if the drug solubility in aqueous solution is very poor. The formed gel will be incorporated in the IPM membrane.

5. Using “EVAC membrane” method

In order to prepare the target Transdermal therapeutic system, 1% carbopol reservoir gel, polyethylene (PE), ethylene vinyl acetate copolymer (EVAC) membranes can be used as a rate controlling membrane. If the drug is not soluble in water, propylene glycol is used for preparation of gel. Drug is dissolved in propylene glycol, carbopol resin is added in the above solution and neutralised using 5% w/w sodium hydroxide solution. The drug (in gel form) is placed on sheet of backing layer covering the specified area. The rate controlling membrane will be placed over the gel and the edges will be sealed by heat to obtain a leak proof device.

6. Aluminium backed adhesive film method

TDDS may produce unstable matrices if the loading dose is greater than 10mg.This is a suitable method in which chloroform is a choice of solvent, because most of the drugs as well as adhesive are soluble in chloroform. The drug is dissolved in chloroform and adhesive material will be added to the drug solution and dissolved. A custom made aluminium former is lined with aluminium foil and the ends blanked off with tightly fitting cork blocks.

7. Using “proliosomes”

The proliosomes are prepared by carrier method using film deposition technique. These are prepared by taking 5mg of mannitol powder in a 100ml RBF which is kept at 60-70°C temp. And the flask rotated 80-90rpm.The mannitol is dried by vacuum for 30 minutes. After drying the temperature of water bath is adjusted to 20-30°C. The drug and lecithin (ratio 0.1:2.0) are dissolve in a suitable organic solvent mixture, a 0.5 ml aliquot of organic solution is introduced into the RBF at 37°C. After complete drying second aliquots (0.5ml) of solution is to be added. After the last loading, the flask containing proliosomes are connected in a lyophilizer and subsequently the drug loaded mannitol powder (proliosomes) are placed in a desiccator overnight and then sieved through 100 mesh. The powder is collected and transferred into glass bottle and stored at freeze temperature until characterization.

8. By using free film method

Free film of cellulose acetate is prepared by casting on mercury surface. A polymer solution 2% w/w is to be prepared by using chloroform. Plasticizers are to be incorporated at a concentration of 40% w/w of polymer weight. 5ml of polymer solution is to be poured in a glass ring placed over a mercury surface in a glass petri dish. The rate of evaporation of the solvent is controlled by placing an inverted funnel over the petri dish. The film formation is noted by observing the mercury surface after complete evaporation of solvent. The dry film will be separated out and stored between the sheets of wax paper in a desiccator until use. Free films of different thickness can be prepared by changing the volume of the polymer solution.

Evaluation parameters ^{1, 2, 5, 43-48}

1. Patch thickness

The thickness of the drug loaded patch is measured by using digital micrometer at different points and this determines the average thickness and standard deviation of the patch.

2. Weight uniformity

The prepared patches are to be dried at 60°C for 4 hrs before testing. A specified area of patch is to be cut in different parts of the patch and weigh in digital balance. The average weight and standard deviation values are to be calculated from the individual weights.

3. Folding endurance

A strip of specific area is to be cut evenly and repeatedly fold at the same place till it breaks. The number of times the film can be folded at the same placed without breaking is the folding endurance.

4. Flatness test

The longitudinal strips are to be cut from each film at different portion like one from centre, one from its right side and another one from the left side. The length of strips from either side of centre is to be measured and the variation in length because of non-uniformity in flatness is to be measured by determining percent constriction, with 0% constriction equivalent to 100% flatness.

5. Percentage elongation break test

The percent elongation break is to be determined by noting the length just before the break point; the percent elongation can be determined using following formula:

Elongation percentage= [ L₁-L₂ /L₂] X 100

6. Percentage moisture content

The prepared films are to be weighed individually and to be kept in a desiccator containing fused calcium chloride at room temperature for 24hrs. After 24hrs the films are to be reweighed and percentage moisture content is determined from the following formula.

Percentage moisture content= [initial weight- final weight/ final weight] x 100

7. Percentage moisture uptake

The weighed films are to be kept in a desiccator at room temperature for 24 hrs containing a saturated solution of potassium chloride in order to maintain 84%RH. After 24 hrs the films are to be reweighed and determine the percent moisture uptake by the following formula:

Percentage moisture uptake= [final weight- initial weight/ initial weight] x 100

8. Water vapour transmission test (WVT)

For the determination of WVT, weigh one gram of calcium chloride and place it in previously dried empty vials having equal diameter. The polymer films are pasted over the brim with the help of adhesive like silicon adhesive grease and the adhesive was allowed to set for 5 minutes .Then , the vials are accurately weighted and placed in humidity chamber maintained at 68% RH. The vials are again weighed at the end of every 1^st day ,2^nd day ,3^rd day upto 7 consecutive days and an increase in weight was considered as a quantitative measure of moisture transmitted through the patch. In other reported method, desiccator was used to place vials, in which 200ml of saturated sodium bromide and saturated potassium chloride solution were placed. The desiccator is to be tightly closed and humidity inside the desiccator is to be measured by using hygrometer. The weighted vials are then to be placed in desiccator and procedure to be repeated.

WVT=W/ST

Where,

W is the increase in weight in 24 hrs; S is area of film exposed (cm²); T is exposure time.

9. Drug content

A specified area of patch is to be dissolved in a suitable solvent in specific volume. Then the solution is to be filtered through a filter medium and analyse the drug content with the suitable method (UV or HPLC technique). Each value represents average of three different samples.

10. Uniformity of dosage unit test

An accurately weighted portion of the patch is to be cut into small pieces and transfer to a specific volume volumetric flask, dissolve in a suitable solvent and sonicate for complete extraction of drug from the patch and make upto mark with same. The resulting solution is allowed to settle for about an hour, and the supernatant is suitably diluted to give the desired concentration with suitable solvent. The solution is filtered using 0.2µm membrane filter and analyse by suitable analytical technique (UV or HPLC) to get the drug content per piece.

11. Polariscope examination

This test is to be performed to examine the drug crystals from patch by Polariscope. A specific surface area of the piece is to be kept on the object side and observe the drugs crystal to distinguish weather the drug is present as crystalline form in the patch.

12. Shear adhesion test

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

13. Peel adhesion test

The force required to remove an adhesive coating from the test substrate is referred to as peel adhesion. Molecular weight of adhesive polymer, the type and amount of additives are the variables that determine the peel adhesion property. A single tape is applied to a stainless steel plate or a backing membrane of choice and then the tape is pulled from the substrate at 180° angle, and the force required to remove the tape is measured.

14. Thumb tack test

It is a qualitative test applied for tack property determination of adhesive. The thumb is simply pressed on the adhesive and the relative tack property is detected.

15. Rolling ball tack test

This test measures the softness of the polymer that relates to the tack. In this test, a stainless steel ball of 7/16 inches in diameter is released on an inclined track so that it rolls down and comes into contact with horizontal, upward facing adhesive. The distance the ball travels along the adhesive provides the measurement of tack, which is expressed in inch.

16. Peel tack test

In this test the tape is pulled away from the substrate at 90° at speed of 12 inches/min.

The peel force required to break the bond between adhesive and substrate is measured and recorded as tack value, which is expressed in ounces or grams per inch width.

17. Probe tack test

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

18. In vitro drug release studies

The paddle over disc method (USP apparatus V) can be employed for assessment of the release of drug from the prepared patches. Dry films of known thickness is to be cut into definite shape, weighed and fixed over a glass plate with an adhesive. The glass plate is then placed on a 500 ml of dissolution medium or 7.4 pH phosphate buffers, and the apparatus is equilibrated to 32±0.5°C. The paddle was then set at distance of 2.5 cm from the glass plate and operated at speed of 50 rpm. Samples (5ml aliquots) can be withdrawn at appropriate time intervals upto 24hrs and analysed by UV spectrophotometer or HPLC. The experiment is to be carried out in triplicate and the mean value can be calculated.

19. In vitro skin permeation studies

An in vitro skin permeation study can be carried out by using diffusion cell. Full thickness abdominal skin of male wistar rats weighing 200-250 g. Hair from the abdominal region is to be removed carefully by using electric clipper; the dermal side of skin is thoroughly cleaned with distilled water to remove any adhering tissue or blood vessels, equilibrated for an hour in dissolution medium or phosphate buffer pH 7.4 before starting the experiment and is placed on a magnetic stirrer with a small magnetic needle for uniform distribution of diffusant. The temperature of cell is maintained at 32 ± 0.5°C using a thermostatically controlled heater. The isolated rat skin peace is to be mounted between compartments of the diffusion cell, with the epidermis facing upward into the donor compartment. Sample volume of defined volume is to be removed from the receptor compartment at regular intervals and an equal volume of fresh medium is to be replaced. Samples are to be filtered through filtering medium and can be analysed spectrophotometrically or HPLC. Flux can be determined directly as the slope of the curve between the steady state values of the amount of drug permeated (mg cm^-2) vs. Time in hours and permeability coefficients are deduced by dividing the flux by the initial drug load (mg cm^-2).

20. Skin irritation study

Skin irritation and sensitization testing can be performed on healthy rabbits (avg. weight 1.2-1.5Kg.). The dorsal surface (50cm²) of the rabbit is to be cleaned and remove the hair from the clean dorsal surface by shaving and clean the surface by using rectified spirit and the representative formulation is applied over the skin. The patch is to be removed after 24 hrs. And the skin is to be observed and classified into five grades on the basis of the severity of skin injury.

21. Stability studies.

Stability studies are to be conducted according to the ICH guidelines by storing the TDDS samples at 40 ± 0.5 °C and 75 ± 5% RH for six months. The samples were withdrawn at 0, 30, 60, 90 and 180 days and analysed suitably for the drug content.

Table 4. Marketed products of TDDS.^{5,
16, 49}

Sr no	Product	Active drug	Purpose
1	Estraderm	Estradiol	Postmenstrual syndrome
2	Duragesic	Fentanyl	Pain relief
3	Transderm-scop	Scopolamine	Motion sickness
4	Alora	Estradiol	Postmenstrual syndrome
5	Climara	Estradiol	Postmenstrual syndrome
6	Captopres TTS	Clonidine	Hypertension
7	Combipatch	Estradiol	Postmenstrual syndrome
8	Deponit	Nitroglycerin	Angina pectoris
9	Lidoderm	Lidocaine	Anesthetic
10	Ortho evra	Estradiol	Postmenstrual syndrome
11	Testoderm TTS	Testosterone	Hypogonadism in males
12	Habitraol	Nicotine	Smoking cessation
13	Prostep	Nicotine	Smoking cessation
14	Nicotrol	Nicotine	Smoking cessation
15	Matrifen	Fentanyl	Pain relief
16	Nu patch 100	Diclofenac diethylamine	Anti inflammatory
17	Nicoderm CQ	Nicotine	Smoking cessation
18	Minitran	Nitroglycerin	Angina pectoris
19	Nitrodisc	Nitroglycerin	Angina pectoris
20	Nitrodur	Nitroglycerin	Angina pectoris
21	Transderm nitro	Nitroglycerin	Angina pectoris
22	Oxytrol	Oxybutynin	Overactive bladder
23	Nuvelle TS	Estradiol	Hormone replacement therapy
24	Climaderm	Estradiol	Postmenstrual syndrome

Table 5: Representative Transdermal drugs in clinical development⁵⁰

Drug	Company	Indication	Clinical phase	Delivery technology
AB-1001	Abeille	Nausea & vomiting	Phase 3	Passive
Acyclovir	Transport	Herpes labialis	Phase 2	Iontophoresis
Bupronorphine	Purdue Pharma	Pain	Phase 3	Passive
Fertility hormone	Vyteris/ Ferring	Female infertility	Phase 1	Iontophoresis
Granisetron	Prostrakan	Nausea & vomiting	Pre registration	Passive
Heat labile enterotoxin of E.coli	Lomai	Travellers disease	Phase 2	Skin abrasion
HGH	Trans Pharma/teva	Growth hormone deficiency	Phase 1	Thermal ablation
Influenza vaccine	Sanofi-pasteur	Influenza prophylaxis	Pre-registration	Microneedles
Insulin	Altea	Diabetes mellitus	Phase 1	Thermal ablation
Insulin	phosphagenics	Diabetes mellitus	Phase 2	Vesicular carrier
Ketoprofen	ZARS	Osteoarthritis	Phase 3	Heat enhancement
PTH	Zosano	Osteoporosis	Phase 2	Microneedles
Sufetanil	Durect/ endo	Chronic pain	Phase 2	Passive
Testosterone	Acrux/VIVUS	Female sexual dysfunction	Phase 2	Metered dose Transdermal spray
Testosterone	Macro chem.	Male Hypogonadism	Phase 2	Chemical enhancer
Triamcinolone acetonide	Echo therapeutics	Deratoses	Pre registration	Chemical enhancer(azone TS)

CONCLUSION:

Transdermal Drug Delivery System is one of the invasion free method for systemic delivery of drug which serves to control the drug delivery across skin for prolonged period of time. Thus improving patient compliance over traditional dosage forms. A lot of progress has been made in the field of Transdermal patch which is evident by data shown in table 4 and 5. Present review informs about Transdermal delivery across the skin, barriers for its transportation and various methods for increasing drug permeation across skin. It also gives detailed information about various methods of preparation of patch and its evaluation methods.

REFERENCES:

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2 Kumar JA et al. Transdermal Drug Delivery System: An Overview, International Journal of Pharmaceutical Sciences Review and Research, vol 3(2), 2010, 49-54.

3. Patel D et al. Transdermal drug delivery system: A Review. The Parma Innovation vol 1(4) , 2012, 78-87.

4. Sharma A et al, Transdermal Drug Delivery System: A Review, International Journal of Research in Pharmaceutical and Biomedical Sciences, vol 4(1),2013, 286-292.

5 Vyas SP,.Khar RK. Controlled Drug Delivery: Concepts and Advances, Vallabh Prakashan, 2^nd ed, 2012, 397-433.

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Received on 16.09.2015 Accepted on 20.10.2015

Research J. Topical and Cosmetic Sci. 6(2): July-Dec. 2015 page 66-76

DOI: 10.5958/2321-5844.2015.00010.2

Sr. No.	Types /Techniques of penetration enhancers	Mechanism of action	Examples
1.	Chemical enhancers	They act by three mechanisms 1. By disruption of highly ordered structure of stratum corneum. 2. By interaction with intercellular proteins. 3. By improved partition of drug or solvent into SC.	1.Sulphoxides and similar chemicals-dimethyl sulphoxides, dimethyl formamide, dimethyl acetamide 2. azones 3. pyrrolidones 4. fatty acids 5. oxazolidinediones 6. amine and amides- urea 7. Surface active agents-SLS, BZK. 8. cyclodextrins
2.	Drug vehicle based	Interaction of enhancers with stratum corneum and development of SAR for enhancers with optimal characteristics and minimal toxicity.	Ion pairs and complex coacervates chemical potential adjustment.
3.	Natural penetration enhancers	Mechanism for terpenes It may increase one or more of following effects 1.partition coefficient 2.diffusion coefficient 3.lipid extraction 4. Drug solubility. 5.Macroscopic barrier perturbation 6. Molecular orientation of terpenes molecular with lipid bilayer.	1. Terpenes- menthol, linalool, limonene, carvacrol. 2. Essential oil- basil oil, neem oil, eucalyptus, chenopodium, ylang-ylang.
4.	Physical enhancers	These are variable techniques available for increasing the penetration by physical separation and magnetic and ultrasonic.	1.Iontophoresis 2. sonophoresis 3. phonophoresis 4. magnetophoresis 5. electroporation 6.thermophoresis 7. radiofrequency 8. needleless injection 9. hydration of stratum corneum 10. Stripping of stratum corneum.
5.	Biochemical approach	They act by modifying substances by converting it into suitable form.	1. Synthesis of bio-convertible prodrugs 2. Co-administration of skin metabolite inhibitors.
6.	Miscellaneous	Having various mechanism	1.lipid synthesis inhibitors 2.phospholipids 3. Clofibric acid.