This percutaneous absorption (process by which the drug is penetrating the skin) involves (3-5):

· Dissolution of drug in its vehicle

· Diffusion of solubilized drug from the vehicle to the skin

· Penetration of the drug through the layers of the skin, principally the stratum corneum.

Figure 2: Schematic diagram of a transdermal device for the delivery of drug

The slowest step in the process usually involves passage through the stratum corneum. Therefore this is the rate limits or controls the permeation. Diffusion of polar drug is much harder by the stratum corneum which is lipophilic in nature. Through the skin the drug diffuses mainly by passing alone the sweat glands and hair follicles and then getting absorbed through the follicular and fat glands.

Transdermal drug delivery systems are topically administered medicaments in the form of patches that deliver drugs for systemic effects at a predetermined and controlled rate. These devices allow for pharmaceuticals to be delivered accross the skin barrier.

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

TDDs use diffusion of the drug through skin into the systemic circulation for distribution and therapeutic effect. Most TDDs use passive delivery.

1.2 Advantages:

The skin offers several advantages as a route for drug delivery. In most cases, although the skin itself controls drug input into the systemic circulation, drug delivery can be controlled predictably, and over a long period of time, from simple matrix-type transdermal patches (6-8).

Some of the advantages of the TDDs over other controlled release formulations are:

· Reduces first pass effect and GI incompatibility

· Sustains therapeutic drug levels. Drugs with very short half-lives

· e.g nitroglycerine when administered as transdermal patches, release medicaments at a constant rate for a time period more than obtainable with oral formulations.

· Permits self administration

· Non-invasive (no need to use needles and injection)

· Reduces side effect

· Allows removal of drug source in case of toxicity

· Very simple and easy to use

1.3 Disadvantages:

· The drug should have desirable physicochemical properties for penetration through stratum corneum. The drug has larger molecular size makes absorption difficult. It should be ideally below 800 Daltons.

· Large dose of a drug cannot be administered.

· One of the greatest disadvantages is possibility of local irritation or skin sensitizing.

· The drugs with long half life cannot be formulated in to TDDs.

· The drugs which undergo protein binding and metabolism in the skin are not suitable.

· The drugs with high lipid or aqueous solubility are not suitable for TDDs.

· Other disadvantages of such systems include variation in absorption efficiency at different site of skin, difficult of adhesion to certain skin types etc (4, 7, 8).

1.4 Skin Permeation Kinetics:

Knowledge of skin permeation kinetics is vital to the successful development of Transdermal therapeutic systems. Transdermal permeation of a drug involves the following steps (1, 5, 9):

1. Sorption by stratum corneum.

2. Penetration of drug through viable epidermis.

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

This permeation can be possible only if the drug possesses certain physiochemical properties. The rate of permeation across the skin is given by:

dQ/dt = P_s ( C_d – C_r )

Where

C_d and C_r are the concentration of the skin penetrate in the donor compartment i.e. on the surface of stratum corneum and in the receptor compartment i.e. body respectively.

Ps is the overall permeability coefficient. This permeability coefficient is given by the relationship:

Where,

D= Diffusivity of drug in membrane (skin)

K= Partition coefficient (patch/skin)

h= Thickness of membrane.

1.5 Components of transdermal devices:

The components of transdermal devices include (3, 4, 7, 8):

· Polymer matrix or matrices.

· The drug

· Rate controlling Membrane

· Pressure sensitive adhesives

· Plasticizers

· Permeation enhancers

· Backing Layers

· Release liners

Polymer Matrix:

The Polymer controls the release of the drug from the device.

Desired Characteristics:

· Polymer used in TDDS should have biocompatibility and chemical compatibility with the drug and other components.

· They should provide effective and consistent delivery of drug throughout the products shelf-life or delivery period.

· The main challenge in design of a polymer matrix is not only in terms of release properties, but also with respect to its adhesion-cohesion balance, physicochemical properties, compatibility and stability with other components as well as with skin.

Classification:

Possible useful polymers for Transdermal devices are (4, 10):

a) Natural Polymers:

e.g. Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums and their derivatives, Natural rubber, Starch etc.

b) Synthetic Elastomers:

e.g. Polybutadieine, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Styrenebutadieine rubber, Neoprene etc.

c) Synthetic Polymers:

e.g.Polyvinylalcohol, Polyvinylchloride, Polyethylene, Polypropylene, Epoxy, Polyacrylate, Polyamide, Polyurea, Polyvinylpyrrolidone etc.

d) HPMC:

Hydrophilic swellable polymer, gives clear films.

e) Organogels:

Non ionic surfactants, like lecithin, sorbitane, monostearate, tweens, when dissolved in organic solvent followed by addition of water it forms gel. They enhance permeation by disorganization of skin.

Drug:

For successfully developing a transdermal drug delivery system, the drug should be chosen with great care. The following are some of the desirable properties of a drug for transdermal delivery.

Physicochemical properties:

1. The drug should have a molecular weight less than approximately 1000 daltons.

2. The drug should have affinity for both – lipophilic and hydrophilic phases. Extreme partitioning characteristics are not conducive to successful drug delivery via the skin.

3. The drug should have low melting point. Along with these properties the drug should be potent, having short half life and be non irritating (3).

Rate controlling membrane:

· These are used in reservoir type TDDS, through which the drug diffuses at a finite, controllable rate (7).

· They may be micro-porous or non-porous. In non-porous type membrane, the rate of passage of drug molecule depends on the solubility of drug in membrane and the membrane thickness.

· Choice of a membrane material must conform to the type of drug used.

· Ethylene Vinyl Acetate (EVA): most frequently used membrane former. This allows adjustment of membrane permeability by altering vinyl acetate content.

· Increase in vinyl acetate content increases the solubility and the diffusivity of the polar compounds.

· Silicon rubber: Used mainly in controlled release devices. It is having good biocompatibility, ease of fabrication, high permeability to many important classes of drugs(steroids)

Pressure sensitive adhesives:

It is a material which adheres, with no more than applied finger pressure. Adhesive systems should fulfill the following criteria

· Should adhere to the skin aggressively, should be easily removed.

· Should not leave an unwashable residue on the skin.

· Should not irritate or sensitize the skin.

The face adhesive system should also fulfill the following criteria.

a) Physical and chemical compatibility with the drug, excipients and enhancers of the device of which it is a part.

b) Permeation of drug should not be affected.

c) The delivery of simple or blended permeation enhancers should not be affected.

Acrylic polyisobutylene and silicone based adhesives are commonly used.

Plasticizers:

Plasticizers are used to reduce stiffness of the polymer backbone and thereby increases drug diffusion rate from the device. Commonly used plasticizers are (4):

· Butyl benzyi phthalate

· Trioctyl phosphate

· Dioctyl phthalate

· Glycerol

· Polyethylene glycol

· Poly propylene glycol

Permeation enhancer:

These are compounds, which promote skin permeability by altering the skin as a barrier. Large number of compounds have been investigated for their ability to enhance stratum corneum permeability (4,5,10).

Characteristics of permeation enhancers:

· Should be pharmacologically inert

· Nontoxic, non irritant and non allergic

· Immediately act and be suitable and predictable action.

· Upon removal of the device the skin should attain its normal barrier property.

· Compatible with drug and other excipents.

Mechanism of action:

It increases the permeability by swelling the polar pathway or by fluidizing lipids.

These may conveniently be classified under the following main headings.

Classification:

a) Solvents

Water alcohols – Methanol and ethanol;

Alkyl methyl sulfoxide – Dimethylsulfoxide

Pyrrolidones – 2 Pyrrolidone, N-methyl, 2-Purrolidone.

Miscellaneous solvents – propylene glycol, glycerol, silicone fluids, isopropyl palmitate.

b) Surfactants

Anionic Surfactants:

e.g. Dioctylsulphosuccinate, Sodium laurylsulphate, Decodecylmethylsulphoxide etc.

Nonionic Surfactants:

e.g. Pluronic F127, Pluronic F68, etc.

c) Bile Salts:

e.g. Sodium ms taurocholate, Sodium deoxycholate, Sodium tauroglycocholate.

d) Miscellaneous chemicals

These include urea, a hydrating and keratolytic agent; N, N-dimethyl-m-toluamide; calcium thioglycolate; anticholinergic agents.

Figure 3: Basic Components of Transdermal Drug Delivery Systems

Backing membrane:

Backing membranes are flexible and they provide a good bond to the drug reservoir, prevent drug from leaving the dosage form through the top, and accept printing. It is impermeable substance that protects the product during use on the skin e.g. metallic plastic laminate, plastic backing with absorbent pad and occlusive base plate (aluminium foil), adhesive foam pad (flexible polyurethane) with occlusive base plate (aluminium foil disc) etc (8).

Release liner:

During storage the patch is covered by a protective liner that is removed and discharged immediately before application of the patch to the skin. It is regarded as primary packing material rather than a part of the dosage form. Since it is in intimate contact with the drug and excipients, it should be chemically inert.

1.6 Types of TDDS:

Several types of TDDS are available but they can be basically divided into four broad categories based on the mechanism by which drug release is controlled (4,5,8).

· Monolithic or matrix devices

· Adhesive dispersion system

· Membrane permeation controlled system

· Microreservoir dissolution controlled system

All such devices are fabricated as multilayer laminated structure in which the drug –polymer matrix or a drug reservoir is sandwiched between two polymeric layers. The outer layer, called as backing layer, is impermeable and meant to prevent drug loss through it. The other layer which contacts the device with the skin is adhesive layer. It is permeable and in some cases, may act as rate-limiting membrane.

The choice of any type of system for controlling drug release depends upon the major rate-limiting step in the absorption of drug from such devices. The two rate limiting steps are:

· Rate of drug diffusion from the device, R₁, and

· Rate of drug permeation through the stratum corneum, R₂.

· The overall rate of drug transport is proportional to the sum of R₁ + R_2.

a. Monolithic or matrix devices:

These devices are used when R₂is the rate- controlling step and the drug has a large therapeutic index so that overdosing does not precipitate toxic reactions. The two categories of matrix devices are- one in which the drug is dissolved in the polymer matrix and the other in which the drug is dispersed. The polymers employed for matrix systems may be hydrophilic or lipophilic and includes, PVC, PVP, polyesters, polysaccharides, ethylene vinyl acetate copolymers. The drug release from the matrix systems is rapid initially and falls as the matrix gets depleted of drug (11).

Figure 4: Monolithic or matrix devices

Rate controlling factors:

· Drug concentration in the polymer matrix

· Chemical nature of polymer matrix.

b. Adhesive dispersion system:

It is of two types, they are-

· Single-layer Drug-in-Adhesive system :

The Single-layer Drug-in-Adhesive system is characterized by the inclusion of the drug directly within the skin-contacting adhesive. In this transdermal system design, the adhesive not only serves to affix the system to the skin, but also serves as the formulation foundation, containing the drug and all the excipients under a single backing film.

Figure 5: Single layer Adhesive dispersion system

· Multi-layer Drug-in-Adhesive :

The Multi-layer Drug-in-Adhesive is similar to the Single-layer Drug-in-Adhesive in that the drug is incorporated directly into the adhesive. However, the multi-layer encompasses either the addition of a membrane between two distinct drug-in-adhesive layers or the addition of multiple drug-in-adhesive layers under a single backing film.

Figure 6: Multi-layer Adhesive dispersion system

c. Membrane permeation controlled system:

These devices are used when drugs permeation rate is rapid and absorption should therefore be controlled by controlling drug release. That means rate of drug permeation through the stratum corneum is more so the rate of drug diffusion from the device should be decreased. It is also suitable for potent drugs with low therapeutic indices where monitoring drug levels in a narrow range is essential. The drug is usually contained within the reservoir as a suspension in a liquid (such as silicone) or gel carrier. The rate controlling thin polymeric membrane is made of olefinic polymers and copolymers, cellulose esters, polyamides, or PVC. When applied in the skin, the device shows a rapid release at first followed by a constant zero-order release as long as the solution inside the reservoir is saturated.

Rate controlling factors:

· Membrane thickness and

· Membrane permeability of the device.

Figure 7: Membrane permeation controlled system

d. Microreservoir dissolution controlled system:

In this system microscopic sphers of drug reservoir are dispersed in a polymer matrix. Eg: Nitrodisc.

Figure 8: Microreservoir dissolution controlled system

1.7 Evaluation of Transdermal Drug Delivery System:

TDDS requires systematic evaluation stages. Evaluation tests are described as following (4,7-9):

Interaction studies:

Excipients are integral components of almost all pharmaceutical dosage forms. The stability of aformulation amongst other factors depends on the compatibility of the drug with the excipients. The drug and the excipients must be compatible with one another to produce a product that is stable, thus it is mandatory to detect any possible physical or chemical interaction as it can affect the bioavailability and stability of the drug. If the excipients are new and have not been used in formulations containing the active substance, the compatibility studies play an important role in formulation development. Interaction studies are commonly carried out in Thermal analysis, FT-IR, UV and chromatographic techniques by comparing their physicochemical characters.

Thickness of the patch:

The thickness of the drug loaded patch can be measured in different points by using a digital micrometer and determines the average thickness and standard deviation for the same to ensure the thickness of the prepared patch.

Weight uniformity:

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

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 contain with the suitable method (UV or HPLC technique). Each value represents average of three different samples.(12)

Uniformity of dosage unit test:

An accurately weighed portion of the patch is to be cut into small pieces and transferred to a specific volume volumetric flask, dissolved in a suitable solvent and sonicate for complete extraction of drug from the patch and made up to the mark with same. The resulting solution was allowed to settle for about an hour, and the supernatant was suitably diluted to give the desired concentration with suitable solvent. The solution was filtered using 0.2mm membrane filter and analysed by suitable analytical technique (UV or HPLC) and the drug content per piece will be calculated.(13)

Folding endurance

Folding endurance of patches can be determined by repeatedly folding a small strip of film (2 cm x 2 cm) at the same place till it broke. The number of time the film could be folded at the same place without breaking was the folding endurance value

In vitro drug release studies:

The paddle over disc method (USP apparatus V) can be employed for assessment of the release of the drug from the prepared patches. (7).

In vitro skin permeation studies:

An in vitro permeation study can be carried out by using diffusion cell. Full thickness abdominal skin of male Wistar rats weighing 200 to 250g. Hair from the abdominal region is to be removed carefully by using a electric clipper; the dermal side of the skin was thoroughly cleaned with distilled water to remove any adhering tissues or blood vessels, equilibrated for an hour in dissolution medium or phosphate buffer before starting the experiment and was placed on a magnetic stirrer with a small magnetic needle for uniform distribution of the diffusant. The temperature of the cell was maintained at 32 ± 0.5°C using a thermostatically controlled heater. The isolated rat skin piece is to be mounted between the compartments of the diffusion cell, with the epidermis facing upward into the donor compartment. Sample volume of definite 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 analyzed 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 were deduced by dividing the flux by the initial drug load (mg cm-2) (5).

Figure 9: In vitro drug diffusion study of transdermal patches

Skin Irritation study:

Skin irritation and sensitization testing can be performed on healthy rabbits (average weight 1.2 to 1.5 kg). 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 formulations can be applied over the skin. The patch is to be removed after 24 hr and the skin is to be observed and classified into 5 grades on the basis of the severity of skin injury.(14)

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 6 months. (15). The samples were withdrawn at 0, 30, 60, 90 and 180 days and analyze suitably for the drug content.

EVALUATION OF ADHESIVE:

Peel Adhesion Properties:

Peel adhesion is a force required to remove an adhesive coating from test substrate. It is important in transdermal devices because the adhesive should provide adequate contact of the device with the skin and should not damage the skin on removal. Peel adhesion properties are affected by the molecular weight of the adhesive polymer. It is tested by measuring the force required to pull a single coated tape, applied to a substrate at an 180⁰angle (5,7).

No residue on the substrate indicates “adhesive failure” which is desirable for transdermal devices. Remnant on the substrate indicates “cohesive failure” signifying of indicates a deficit of cohesive strength in the coating.(18-19)

Figure 10: Peel adhesion test

Tack Properties:

Tack is an ability of polymer to adhere to a substrate with the little contact pressure. Tack is dependent on the molecular weight and composition of polymer.

a. Thumb Tack Test:

This is a subjective test in which evaluation is done by pressing the thumb briefly into the adhesive experience is required for using this test.(16)

b. Rolling Ball Tack Test:

This test involves measurement of the distance that a stainless steel ball travels along an upward facing adhesive. The less tacky the adhesive the further the ball will travel.(17)

Figure 11: Rolling ball tack test

c. Quick-Stick Test:

The peel force required to break the bond between an adhesive and substrate can be measured by pulling the tape away from the substrate at 90°at a speed of 12 inch\min. The force is recorded as the tack value and are expressed in ounces per gram per inch width with higher values indicating increasing tack.(20)

CONCLUSION:

A Transdermal patch is medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Transdermal drug delivery system is advantageous than other types of medication delivery such as oral, intravenous, intramuscular, etc. The patch provides a controlled release of the medication into the patients, usually through the porous membrane covering a reservoir of medication. A wide variety of pharmaceutical medicaments are now available in Transdermal patch form.

REFERENCES:

1. Sanju Nanda., KamalSaroha., BhavnaYadav., Benika Sharma., Int. J. Pharma and Chem. Sci, 1,(3), 2012, 953-969.

2. Vilegave k., Dantul B., Chandankar P., Kharjul A., Kharjul. M., Int. J. Pharma. Res. Sch, 2,(1), 2013, 71-82.

3. Sonia Dhiman., Thakur Gurjeet Singh., Ashish Kumar Rehni., Int. J. Pharm and Pharma.Sci, 3,(5), 2011, 26-34.

4. Archana K Gaikwad., Comp. J. Pharma. Sci, 1,(1), 2013, 1-10.

5. Dinesh L Dhamecha., Amit A Rathi., Maria Saifee., Swaroop R Lahoti., Mohd. Hassan G Dehghan., Int. J. Pharm and Pharma.Sci, 1,(1), 2009, 24-46.

6. KinjalRathod., Chetna Shah., HiralShah., Int. J. Pharma. Res and bio.sci, 3,(2), 2014, 540-554.

7. Farha Amna Shaik., ImranShaik Mohammad., Int. J. Inno. Pharma.sci and Res, 2,(1), 2014, 515-526.

8. Sandhu Premjeet., Ajay Bilandi., KatariaSahil., MiddhaAkanksha., Int. J. Res. Pharm and Chemistry, 1,(4), 2011, 1139-1151.

9. Richa Sachan., MeenakshiBajpai., Int. J. Res and Devlop in Pharm and Life.Sci, 3,(1), 2013, 748-765.

10. Saurabh Pandey., AshutoshBadola., Ganesh Kumar Bhatt., PreetiKothiyal., Int. J. Pharma and Chem. Sci, 2,(3), 2013, 1171-1180.

11. Jain Amit.K., SethiMittul., Int. J. Pharma. Studies and Res, 2,(1), 2011, 122-132.

12. Shaila Lewis., S Pandey., N Udupa., Ind. J. Pharma.Sci,68,(2), 2006, 179-184.

13. Karen Hitesh. D., Anand Indermeet.S., Patel Chhaganbhai. N., ChavdaHitesh. V., Patel Jitendra. K., J. Glo. Pharma. Tech, 2,(2), 2010, 75-78.

14. Shalini Asthana., Anil K. Jaiswal., Pramod K. Gupta., Vivek K. Pawar., Anuradha Dude., Manish K. Chourasia., Antimicro. Agents. Chemothera, 57, (4), 2013, 1714-1722.

15. Arvind.G., Sumit Shah., Shanmukha Mule., Prashanth.P., NoveenKonda., Int. J. pharm, 3,(3), 2013, 540-547.

16. Nadia.A. Hussein Al-Assady., EmanSaad., Inaam.M.N. Alrubayae., J. Basrah. Res(Sci), 39,(3), 2013, 114-131.

17. S.Sangeetha., Dhandapani Nagasamy Venkatesh., Rajendran Adhiyaman., Kumaraswamy Santhi., Bhojraj Suresh., Trop. J. Pharma. Res, 6,(1), 2007, 653-659.

18. http:// www.drugbank.ca/

19. Jodi. M.Lestner., Susan. J.Howard., Joanne Goodwin., Lea Gregson., Jayesh.M., Thomas.J.Walsh., Gerard. M. Jensen., William. W.Hope., Antimicro. Agent and Chemotherapy, 54,(8), 2010, 3432-3441.

20. Rowe RC., Sheskey PJ., Owen SC., Hand book of Pharmaceutical excipients 5th edition 2006, 545-550, 334-335.

Received on 11.08.2017 Modified on 28.08.2017

Research J. Pharm. and Tech. 2018; 11(1): 397-404.

DOI: 10.5958/0974-360X.2018.00073.2