INTRODUCTION:

A recent approach to drug delivery is to deliver the drug into systemic circulation at predetermined rate using skin as a site of application. Transdermal drug administration generally refers to topical application of agents to healthy intact skin either for localized treatment of tissues underlying the skin or for systemic therapy .For Transdermal products the goal of dosage design is to maximize the flux through the skin into the systemic circulation and simultaneously minimize the retention and metabolism of the drug in the skin. [1]

Transdermal delivery provides a leading edge over injectables and oral routes by increasing patient compliance and avoiding first pass metabolism respectively. Transdermal delivery has many advantages over conventional modes of drug administration, it avoids hepatic first pass metabolism, potentially decreases side effects and improves patient compliance. Drug delivery with Transdermal patch systems exhibit slow, controlled drug release and absorption. [2] The plasma drug concentration does not vary significantly over time. Transdermal delivery system is a growing market that is expected to expand in the near future with the discovery of new drug treatment applications and technologies. Transdermal delivery provides a leading edge over injectables and oral routes by increasing patient compliance and avoiding first pass metabolism respectively. Transdermal drug delivery systems (TDDS), also known as “patches,” are dosage forms designed to deliver a therapeutically effective amount of drug across a patient’sskin [3]. A transdermal patch is defined as medicated adhesive patch is placed above the skin to deliver a specific dose of medication through the skin with a predetermined rate of release of to reach into the bloodstream. Today the most common transdermal system present in the market mainly based on semi permeable membranes which were called as patches as shown in fig 1.[4] In this review article the various aspects of pharmaceutical transdermal drug delivery system where compiled together and the target audience are specifically the M Pharm and B Pharm students so that their knowledge towards the subject concern can be enhanced and also at the same time can be motivated towards the publications.

Figure 1: Transdermal patch showing its different component[adopted from amit Alexander et al .Review Approaches for breaking the barriers of drug permeation through transdermal drug delivery journal of controlled released(2012),164:26-40]

ADVANTAGE

1. Avoids chemically GI environment (drug degradation in acidic and basic environments is prevented).

2. No GI distress and the factors like Gastric emptying, intestinal motility, transit time, donot affect this route as in oral route[8].

3. Avoidance of significant presystemic metabolism (degradation in GIT or by the liver) and therefore need lower doses[8].

4. Allows effective use of drugs with short biological half-life.

5. Allow administration of drugs with narrow therapeutic window because drug levels are maintained within the therapeutic window for product.[9]

6. Enhance therapeutic efficacy, reduced fluctuations (rapid blood level spikes-low and high) due to optimization of blood concentration – time profile.[9]

7. Reduction of dosing frequency and enhancement of patient compliance.

8. Provides controlled plasma levels of very potent drugs.

DISADVANTAGES

1. Difficulty of permeation of the drug through human skin –barrier function of the skin.[8]

2. Skin irritation or dermatitis due to excipients and enhancers of drug delivery system used for increasing percutaneous absorption is another major limitation. [9]

3. Adhesive may not adhere well to all types of skin.[8]

4. Uncomfortable to wear.

5. May not be economical.[9]

Types of Transdermal Patch

Single-layer Drug-in-Adhesive

The adhesive layer of this system also contains the drug. In this type of patch the adhesive layer not only serves to adhere the various layers together, along with the entire system to the skin, but is also responsible for the releasing of the drug. The adhesive layer is surrounded by a temporary liner and a backing as shown in fig 2.[11]

Figure 2: Single-layer drug-in-adhesive[adopted from Nirav S Sheth etal. formulation and evaluation of transdermal patches and to study permeation enhancement effect of eugenol, Journal of Applied Pharmaceutical Science 01 (03); 2011: 96-101]

Multi-layer Drug-in-Adhesive

The multi-layer drug-in adhesive patch is similar to the single-layer system in that both adhesive layers are also responsible for the releasing of the drug. The multi-layer system is different however that it adds another layer of drug-in-adhesive, usually separated by a membrane (but not in all cases). This patch also has a temporary liner-layer and a permanent backing as shown in fig 3.[11]

Figure3: Multi layer drug in adhesive [adopted from Nirav S Sheth et al. Formulation and evaluation of transdermal patches and to study permeation enhancement effect of eugenol, Journal of Applied Pharmaceutical Science 01 (03); 2011: 96-101]

Drug Reservoir-in-Adhesive

Unlike the Single-layer and Multi-layer Drug in adhesive systems 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 as shown in fig 4. [12]

Figure4: Drug-reservoir-in-adhesive adhesive [adopted from Nirav S Sheth et al . Formulation and evaluation of transdermal patches and to study permeation enhancement effect of eugenol, Journal of Applied Pharmaceutical Science 01 (03); 2011: 96-101]

Drug Matrix-in-Adhesive

The Matrix system design is characterized by the inclusion of a semisolid matrix containing a drug solution or suspension which is in direct contact with the release liner. The component responsible for skin adhesion is incorporated in an overlay and forms a concentric configuration around the semisolid matrix. The Matrix system has a drug layer of a semisolid matrix containing a drug solution or suspension. The adhesive layer in this patch surrounds the drug layer partially overlaying it as shown in fig 5.[12]

Figure5: Drug-matrix-in-adhesive [ adopted from Nirav S Sheth et al . formulation and evaluation of transdermal patches and to study permeation enhancement effect of eugenol, journal of applied pharmaceutical science 01 (03); 2011: 96-101]

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 oils for up to 6 hours. The vapours patches release essential oils and are used in cases of decongestion 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 month are also available on the market. [12]

ANATOMY AND PHYSIOLOGY OF SKIN

Human skin comprises of three distinct but mutually dependent tissues, namely:

1. The stratified, a vascular, cellular epidermis;

2. Underlying dermis of connective tissues and;

3. Hypodermis.

Epidermis

The multilayered envelop of the epidermis varies in thickness, depending on cell size and number of cell layers, ranging from 0.8 mm on palms and soles down to 0.06 mm on the eyelids. Stratum corneum and the remainder of the epidermis, also called viable epidermis, cover a major area of skin.[13]

Stratum cornea

This is the outermost layer of skin, also called Horneylayer. It is approximately 10 mm thick when dry but swells to several times this thickness when fully hydrated. It contains 10 to 25 layers of parallel to the skin surface, lying dead, keratinized cells, called coenocytes. It is flexible but relatively impermeable. The stratum corneum is the principal barrier for penetration. The barrier nature of the Horney layer depends critically on its constituents: 75 to 80% proteins, 5 to 15% lipids, and 5 to 10% ondansetron material on a dry weight basis. Phospholipids are largely absent, a unique feature of mammalian membrane. [13]

Epidermis

This is situated beneath the stratum corneum and varies in thickness from 0.06 mm on the eyelids to 0.8 mm on the palms. Going inwards, it consists of various layers as stratum lucidum, stratum granulose, stratum spinosum, and the stratum basal. In the basal layer, mitosis of the cells constantly renews the epidermis and this proliferation compensates the loss of dead Horney cells from the skin surface.[13]

Dermis

Dermis is a 3 to 5 mm thick layer and is composed of a matrix of connective tissue which contains blood vessels, lymph vessels, and nerves. The continuous blood supply has essential function in regulation of body temperature. It also provides nutrients and oxygen to the skin while removing toxins and waste products. Capillaries reach to within 0.2 mm of skin surface and provide sink conditions for most molecules penetrating the skin barrier. The blood supply thus keeps the dermal concentration of permeate very low, and the resulting concentration difference across the epidermis provides the essential driving force for Transdermal permeation.[14]

Hypodermis

The hypodermis or subcutaneous fat tissue supports the dermis and epidermis. It serves as a fat storage area. This layer helps to regulate temperature, provides nutritional support and mechanic protection. It carries principal blood vessels and nerves to skin and may contain sensory pressure organ as shown in fig 6. [14]

ROUTES OF PENETRATION

The diffusion has two potential entry routes to the blood vasculature; through the epidermis itself or diffusion through shunt pathway, mainly hair follicles with their associated sebaceous glands and the sweat ducts.[15]

Intra cellular penetration

Drug molecule passes through the cells of the stratum corneum. It is generally seen in case of hydrophilic drugs. As stratum corneum hydrates, water accumulates near the outer surface of the protein filaments. Polar molecules appear to pass through this immobilized water.[15]

Figure 6: Structure of human skin [adopted from Archana K. Gaikwad Transdermal drug delivery system. Formulation aspects and evaluation comprehensive journal of pharmaceutical sciences ( feb. 2013)vol. 1(1), pp. 1 – 10]

Intercellular penetration

Non-polar substances follow the route of intercellular penetration. These molecules dissolve in and diffuse through the non- aqueous lipid matrix imbibed between the protein filaments.[16]

Tran’s appendage penetration

This is also called as the shunt pathway. In this route, the drug molecule may transverse through the hair follicles, the sebaceous pathway of the pilosebaceous apparatus or the aqueous pathway of the salty sweat glands. The Trans appendegeal pathway is considered to be of minor importance because of its relatively smaller area (less than 0.1% of total surface). However this route may be of some importance for large polar compounds as shown in fig 7.2.[16]

figure 7: schematic representation of the relationship between the rate of drug release (r) from a transdermal system and the rate of release of absorption (r) by the skin [adopted from Archana K. Gaikwad Transdermal drug delivery system. Formulation aspects and evaluation comprehensive journal of pharmaceutical sciences ( feb. 2013)vol. 1(1), pp. 1 – 10]

CARE TAKEN WHILE APPLYING TRANSDERMAL PATCH

1. The part of the skin where the patch is to 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 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 accurate to the site of administration.[17]

PROPERTIES THAT INFLUENCE TRANSDERMAL DELIVERY OF THE DRUG

a. Release of the medicament from the vehicle.

b. Penetration through the skin barrier.

c. Activation of the pharmacological response.[17-19]

FACTORS THAT INFLUENCE TRANSDERMAL DRUG DELIVERY:

Biological factors include:

1. Skin condition

2. Skin age

3. Blood flow

Physiological factors include:

1. Skin hydration

2. Temperature and pH

3. Diffusion coefficient

4. Drug concentration

5. Partition coefficient

6. Molecular size and shape

BASIC COMPONENT OF TRANSDERMAL PATCH

1. POLYMER MATRIX

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

a) Natural Polymers: Cellulose derivatives, Gelatin, Shellac, Waxes, Proteins, Gums and their derivatives, Natural rubber, Starch etc.

b) Synthetic Elastomers: Polybutadieine, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Styrenebutadieine rubber, Neoprene etc.

c) Synthetic Polymers: Polyvinyl alcohol, Polyvinyl chloride, Polyethylene, Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinylpyrrolidone, Polymethylmethacrylate, Epoxy etc.[20-25]

2. DRUG

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

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

2. The drug should have low melting point. Along with these properties the drug should be potent, having short half life and be non irritating.[20-25]

3. PERMEATION ENHANCERS

These are compounds which promote skin permeability by altering the skin as a barrier to the flux of a desired penetrates. These may conveniently be classified under the following main headings:

a) Solvents

These compounds increase penetration possibly by swallowing the polar pathway and/or by fluidizing lipids.

Examples

Water alcohols – methanol and ethanol;

Alkyl methyl sulfoxides: dimethyl sulfoxide,

Alkyl homolog’s:methyl sulfoxide dimethyl acetamide

Mechanism of permeation enhancer

1. These are the chemical compounds that increase permeability of stratum corneum so as to attain higher therapeutic level of drug.

2. Permeation enhancers interact with structural components of stratum corneum that is proteins and lipids.

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

b) Surfactants

These compounds are proposed to enhance polar pathway transport, especially of hydrophilic drugs. The ability of a surfactant to alter penetration is a function of the polar head group and the hydrocarbon chain length.

1. Anionic Surfactants: e.g. Dioctyl sulphosuccinate, Sodiumlauryl sulphate

2. Nonionic Surfactants: e.g. Pluronic F127, Pluronic F68, etc.

3. Bile Salts: e.g. Sodium ms taurocholate, Sodiumdeoxycholate.

c) Miscellaneous chemicals

These include urea, a hydrating and keratolytic agent; N, N-dimethyl-m-toluamide; calcium thioglycolate; anti cholinergic agents. Some potential permeation enhancers have recently been described but the available data on their effectiveness sparse. These include eucalyptol, di-o-methyl-ß-cyclodextrin and soybean casein.[20-25]

4. OTHER EXCIPIENTS

a) Adhesives:

The fastening of all Transdermal devices to the skin has so far been done by using a pressure sensitive adhesive which can be positioned on the face of the device or in the back of the device and extending peripherally. Both adhesive systems should fulfill the following criteria:

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

2 Should not leave an unwashable residue on the skin.

3 Should not irritate or sensitize the skin.

Ex: Silicones, Polyisobutylene

b) 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. Ex: Cellulose derivatives, Polypropylene silicon.[20-25]

ROUTES OF PENETRATION

Accordingly, a molecule may use two diffusional routes to penetrate normal intact human skin: the appendageal route and the trans epidermal route. The appendageal route comprises transport via the sweat glands and the hair follicles with their associated sebaceous glands. The routes circumvent penetration through the stratum corneum and are therefore known as shunt routes. Although these routes offer high permeability, they are considered to be of minor importance because of their relatively small area, approximately 0.1 % of the total skin area. The appendageal route seems to be most important for ions and large polar molecules which hardly permeation the stratum corneum as shown in fig 8.[26-27]

Figure 8: Stratum corneum and route of penetration [adopted from Niravs Sheth et al. Formulation and evaluation of transdermal patches and to study permeation enhancement effect of eugenol, journal of applied pharmaceutical science 01 (03);( 2011): 96-101]

METHOD OF PREPARATION

Preparation of matrix patches

Polymers of ethyl cellulose and hydroxyl propyl methyl cellulose were accurately weighed and dissolved individually in 5 ml of ethanol. The drug was then dispersed in the polymeric solution and then plasticizer of glycerol was added. The solution was stirred to attain semisolid like consistency and casted on a glass substrate containing ‘o’ ring, the rate of evaporation of solvent from polymeric solution was controlled by placed an inverted funnel at room temperature for a day. The formed films were separated. [26-31]

EVALUATION METHODS

The evaluation methods for transdermal dosage form can be classified into following types: Physicochemical evaluation, In vitro evaluation and In vivo evaluation

Physicochemical evaluation

Interaction studies

The drug and the excipients must be compatible with one another to produce a product that is stable. The interaction between drug and excipients 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 play an important role in formulation development. Interaction studies are taken out by Thermal analysis, Fourier transform infrared spectroscopy (FTIR), ultra violet (UV) and chromatographic techniques by comparing their physicochemical properties like assay, melting point, wave numbers, and absorption maxima.[32-35]

Thickness of the patch

The thickness of the drug prepared patch is measured by using a digital micrometer at different point of patch and this 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 4 h 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 between 85 to 115% of the specified value and one has content not less than 75 to 125% of the specified value, then transdermal patches pass the test of content uniformity. But if 3 patches have content in the range of 75 to 125%, then additional 20 patches are tested for drug content. If these 20 patches have range from 85 to 115%, then the transdermal patches pass the test .[32-35]

Flatness test

Three longitudinal strips were cut from each film at different portion like one from the center, other one from the left side, and another one from the right side. The length of each strip was measured, and the variation in length because of non-uniformity in flatness was measured by determining percentage constriction, with 0% constriction equivalent to 100% flatness.

Constriction (%) = I1 - I2 × 100 I1

Where, I1 = initial length of each. [32-35]

Percentage elongation break test

The percentage elongation break was determined by noting the length just before the break point and determined from the formula

Elongation percentages = L1 - L2 / L2 × 100

Where L1 = final length of each strip; L2 = initial length of each strip.

Stability studies

Stability studies were conducted according to the International Conference on Harmonization (ICH) guidelines by storing the TDDS samples at 40 ± 0.5°C and 75 ± 5% RH for 6 months. The samples were withdrawn at 0, 30, 60, 90 and 180 days and analyzed suitably for the drug content.[32-35]

In vitro evaluation of TDDS

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. Dry films of known thickness were cut into definite shape, weighed, and fixed over a glass.[32-35]

Folding endurance

A specific area of strip is cut and repeatedly folded at the same place till it broke. The number of times the film could be folded without breaking gave the value of folding endurance

Percentage moisture content

The prepared patches are to be weighed individually and to be kept in a desiccator containing fused calcium chloride at room temperature. After 24 h, the films are to be reweighed and the percentage moisture content determined by below formula.

Percentage moisture content (%) = [Initial weight - Final weight / Final weight] ×100

Percentage moisture uptake

The prepared patches are to be weighed individually and to be kept in a desiccator containing saturated solution of potassium chloride in order to maintain 84% Rhesus factor (RH). After 24 h, the films are to be reweighed and the percentage moisture uptake determined by the formula.

Percentage moisture uptake (%) = (Final weight - Initial weight / initial weight) × 100 [32-35]

Water vapour permeability (WVP) evaluation

Water vapour permeability can be determined by a natural air circulation oven. The WVP can be determined by the following formula:

WVP = W/A

Where, WVP is expressed in g/m² per 24 h, W is the amount of vapour permeated through the patch expressed in g/24 h, A is the surface area of the exposure samples expressed in m².

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 the drug content analyzed with the suitable method (UV or HPLC technique).Then, the average of three different samples is to be taken.[32-35]

Content uniformity test

Ten (10) patches were selected and content determined for individual patches. If 9 out of 10 patches have content plate with an adhesive. The glass plate was then placed in a 500 ml of the dissolution medium or phosphate buffer (pH 7.4), and the apparatus was equilibrated to 32 ± 0.5°C. The paddle was then set at a distance of 2.5 cm from the glass plate and operated at a speed of 50 rpm. Samples (5 ml aliquots) can be withdrawn at appropriate time intervals up to 24 h and analyzed by UV spectrophotometer or HPLC. The experiment was performed in triplicate and the mean value have been calculated.[32-35]

In vitro skin permeation studies

An in vitro permeation study can be carried out by using diffusion cell on thick abdominal skin of male Wistar rats weighing 200 to 250 g. Hair from the abdominal region is removed carefully by using an 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 pH 7.4 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 was mounted between the compartments of the diffusion cell, with the epidermis facing upward into the donor compartment. Sample volume of definite volume was removed from the receptor compartment at regular intervals, and an equal volume of fresh medium was replaced. Samples have been filtered through filtering medium and analyzed spectrophotometrically or using HPLC. Flux have been determined directly as the slope of the curve between the steady-state values of the amount of drug permeated (mg cm2) versus time in hours, and permeability coefficients were deduced by dividing the flux by the initial drug load (mg cm²) .[32-35]

In vivo evaluation

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 (50 cm²) of the rabbit is to be cleaned and the hair removed from the clean dorsal surface by shaving and the surface cleaned by using rectified spirit with the representative formulations applied over the skin. The patch is to be removed after 24 h and the skin have been observed and classified into 5 grades on the basis of the severity of skin injury .[32-35]

APPLICATION OF TRANSDERMAL DRUG DELIVERY SYSTEM

· Nicotine transdermal patch marketed as Nicodermis to help in smoking cessation. It is the highest selling patch in United State.[35-39]

· Two opioid medicationsFentanyl (marketed as Duragesic) and Buprenorphine (marketed as BuTrans) used to provide round the clock relief for severe pain available in patch forms:

· Estradiol patches available as Estraderm for treat menopausal symptoms as well a Postmenopausal osteoporosis. It is also available in combination with levonorgestrel as Climara Profor menopausal symptoms.[35-39]

· Nitroglycerin transdermal patches for the treatment of angina pectoris, prescribed in place of sublingual pills.

· Transdermal patch of clonidine available for treatment of hypertension.

· Transdermal patch of the selegiline ( MAO inhibitor) became the first transdermal delivery agent for major depressive disorder.

CONCLUSION:

This article provide an valuable information regarding the transdermal drug delivery systems .The method of preparation of transdermal patches of Diclofenac presented in this research work is simple. All formulation also showed good physicochemical properties like thickness, weight variation, drug content, flatness, folding endurance moisture content and moisture uptake. The foregoing showsthat TDDS have great potentials, being able to use for both hydrophobic and hydrophilic active substance into promising deliverable drugs. To optimize this drug delivery system, greater understanding of the different mechanisms of biological interactions, and polymer are required. In this compilation we assure that the content of the article would be a useful tool to understand the in-depth knowledge of this subject concern.

ACKNOWLEDGEMENT:

Authors want to acknowledge the facilities provided by the Rungta College of Pharmaceutical Sciences and Research, Kohka, Kurud Road, Bhilai, Chhattisgarh, India. The authors are also grateful to the e-library of Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, India, 490001 for providing UGC-INFLIBNET facility. The authors acknowledge Chhattisgarh Council of Science and Technology (CGCOST) for providing financial assistance under mini research project (MRP) vide letter no. 1124/CCOST/MRP/2015; Dated: September 4, 2015 and 1115/CCOST/MRP/2015; Dated: September 4, 2015.

REFERENCE:

1. Mishra AN. Controlled and Novel Drug Delivery. In: N.K. Jain (Eds.), Transdermal Drug Delivery New Delhi, India: CBS Publisher and Distributor. 1997. 100-101.

2. Dittgen M. In: Muller, R.H. and Hildebrand, G.E. Eds., Pharmazeutische Technologies, Modern Arzneiformen, Wiss. Verl. Ges. Stuttgart; 1997. p. 81-104

3. Jain NK. Advances in controlled and novel drug delivery, 1st Ed., CBS Publishers and distributors, New Delhi, 2001 pp.108-110.

4. Wilson Ellen Jett, Three Generations: The Past, Present, and Future of Transdermal Drug Delivery Systems, 2011.

5. Shingade, G.M., Aamer, Q., Sabale, P.M., Grampurohit, N.D., Gadhave, M.V. Review on: recent trend on transdermal drug delivery system, Journal of Drug Delivery and Therapeutics2 (1), (2012), 66-75.

6. Matteucci, M., Casella, M., Bedoni, M., Donetti, E., Fanetti, M., Angelis, F. D.F., Gramatica, F.,Fabrizio, E. D. A compact and disposable transdermal drug delivery system, Microelectronic Engineering85, (2008), 1066-10734.

7. Paudel, K.S., Milewski, M., Swadley, C.L. Brogden, N.K., Ghosh, P., Stinchcomb, A.L. Challenges and opportunities in dermal/ transdermal delivery,TherDeliv.1(1),(2010),109–131

8. Finnin BC, Morgan TM (1999). Transdermal penetration. J Pharm Sci. Oct 1999; 88 (10):955-958.

9. Barry B. Transdermal Drug Delivery. In Ed: Aulton M E, Pharmaceutics: The Science of Dosage Form Design, Churchill Livingston.(2002), pp :499-533

10. Singh J, Tripathi KT, Sakia TR. Effect of penetration enhancers on the in vitro transport of ephedrine through rate skin and human epidermis from matrix based Transdermal formulations. Drug. Dev. Ind. Pharm. 19, (1993).: 1623-1628

11. Bromberg L. Cross linked polyethylene glycol networks as reservoirs for protein delivery, J Apply Poly Sci. 1996; 59: 459-466.

12. Godbey KJ. Improving patient comfort with nonocclusive transdermal backings, American Association of Pharmaceutical Scientists.1996; 1-2.Ho KY,

13. Tortora G, Grabowski S.The Integumentary system. In: Principles of Anatomy and Physiology. 9th edition. John Wiley and Sons Inc. (2006) pp.150-151.

14. Barry BW. “Dermatological Formulations: Percutaneous Absorption”, Drugs and pharmaceutical sciences, Volume – 18, MARCEL DEKKER, INC, (1983). Pp.1-39.

15. Matteucci, M., Casella, M., Bedoni, M., Donetti, E., Fanetti, M.,A Gelis, F. D.F., Gramatica, F., Fabrizio, E. D. A compact and disposable transdermal drug delivery system, Microelectronic Engineering85,(2008),1066-1073

16. Encyclopedia of pharmaceutical technology -third edition edited by James Swarbrick volume-4 Microsphere Technology and Applications by Diane J. Burgess and Anthony J. Hickey

17. Controlled and Novel drug delivery edited by N.K. Jain reprint 2007

18. Encyclopedia of controlled drug delivery volume 2 encyclopedia of controlled drug delivery

19. P. K. Gaur, S. Mishra, S. Purohit, K. Dave, Asian Journal of Pharmaceutical and Clinical Research transdermal drug delivery system: A review

20. Arunachalam, A., Karthikeyan, M., Kumar, V. D., Prathap, M., Sethuraman, Ashutosh Kumar, S., Manidipa, S. Transdermal Drug Delivery System: A Review, Current Pharm Research1 (1) (2011) , 70-81.

22. Chien YW, Novel drug delivery systems, drugs and the Pharmaceutical sciences,Vol.50, Marcel Dekkar, New York, NY;1992;797.

23. Wilson KJW, Waugh A. Eds, “Ross and Wilson: Anatomy and Physiology in Health and Illness”, 8th Edition, Churchill Livingstone (1996). pp. 360-366.

24. Barry BW. Mode of Action of Penetration Enhancers on the Kinetics of Percutaneous Absorption. J. Control Release. 6(1987): pp. 43-51

25. Walker BP, Smith EW. . The role of percutaneous penetration enhancers. Advanced Drug Delivery reviews. 18(1996): 295-301

26. Reddy RK, Muttalik S, Reddy S. Once daily sustained release matrix tablets of nicorandil: formulation and in vitro evaluation. AAPS. Pharm. Sci. Tech; 4(1993):4.

27. Aarti N, Louk ARMP, Russsel OP, Richard HG. . Mechanism of oleic acid induced skin permeation enhancement in vivo in humans. Jour. control. Release. 37(1995): 299-306.

28. Hinz B, Rau T, Auge D, Werner U, Ramer R, Rietbrock S, Brune K. Aceclofenac spares cyclooxygenase 1 as a result of limited but sustained biotransformation to diclofenac. Clin Pharmacol Ther. 2003; 74(3): 222 - 35.

29. Cohen EM, Grim WM, Harwood RJ, Mehta GN. Solid state ophthalmic medication. United States Patent No. 1979; 4:179,497.

30. Jayaswal SB, Sood R, Transdermal Controlled Release Drug Administration, Eastern Pharmacist, 1987, 30(357), 47-52.

31. Devi VK, Saisivam S, Maria GR, Deepti PU. Design and evaluation of matrix diffusion controlled transdermal patches of verapamil hydrochloride, Drug Dev. Ind. Pharm.2003; 29:495–503.

32. Gennaro, A.R., Remington: The science and practice of pharmacy Volume I, 21st Edition, Preformulation and Controlled –Release Drug Delivery System,700-719 and917-918

33. Chatwal, G.R. Anand, S.K.Instrumental Methods of Chemical analysis, Infrared absorption Spectroscopy (2009)2.62-2.71.

34. Chand, S., Elementary Organic Spectroscopy, Principles and chemical applications,91-134

35. Rowe, R.C., Sheskey, P.J., Owen, S.C., Handbook of Pharmaceutical Excipients, Fifth edition.

36. Rangari N.T., Kalyankar T.M., Puranik P.K., Chaudhar S.R. Permeation studies of pioglitazone from ficuscarica fruit mucilage matrix transdermal patches, International Journal of Pharmaceutical Sciences and Research (2012) 3(10), 3927-3931.

37. Kim MK, Zhao H, Lee CH, Kim DD. Formulation of a reservoir-type testosterone transdermal delivery system .Int J Pharm.219(2012) (1-2), 51-9.

38. M. Aqil and Asgar Ali. Monolithic matrix type transdermal drug delivery systems of pinacidil (2012).

Received on 16.02.2017 Modified on 29.03.2017

Research J. Pharm. and Tech. 2017; 10(5): 1531-1538.

DOI: 10.5958/0974-360X.2017.00270.0