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Comprehensive Journal of Pharmaceutical Sciences Vol. 1(1), pp. 1 - 10, Feb. 2013
Copyright 2013 Knowledgebase Publishers.

Reviewed Article

Transdermal drug delivery system: Formulation

aspects and evaluation
Archana K. Gaikwad
Aurangabad 431001, Maharashtra India. Email:[email protected]

Accepted 7 February, 2013

The conventional oral dosage forms have significant setbacks of poor bioavailability due to hepatic first
pass metabolism. To improve characters of transdermal drug delivery system (TDDS) was emerged,
which will improve the therapeutic efficacy and safety of drugs by specific sites within the body,
thereby reducing both the size and number of doses. Skin is an effective medium from which
absorption of the drug takes place and enters into systematic circulation over a period of time. The
present article reviews the selection of drug candidates and polymers suitable to be formulated as
transdermal system, advantages, disadvantages of formulation design and the methods of evaluation.

Key words: Transdermal drug delivery system (TDDS), bioavailability, hepatic first pass metabolism.

INTRODUCTION

Recently, the use of transdermal patches for continuous input of drugs with short biological half-lives,
pharmaceuticals has been limited because only a few and eliminates pulsed entry into systemic circulation
drugs have proven to be effectively delivered through the which often causes undesirable side effects.
skin, typically cardiac drugs such as nitroglycerin and
hormones such as estrogen. A skin patch uses a special
membrane to control the rate at which the liquid drug Advantages
contained in the reservoir within the patch can pass
through the skin and into the bloodstream. The basic 1. They can avoid gastrointestinal drug absorption
components of any transdermal delivery system include difficulties caused by gastrointestinal pH, enzymatic
the drug(s) dissolved or dispersed in a reservoir or inert activity, and drug interactions with food, drink, and other
polymer matrix; an outer backing film of paper, plastic, or orally administered drugs.
foil, and a pressure-sensitive adhesive that anchors the 2. They can substitute for oral administration of
patch to the skin. The adhesive is covered by a release medication when that route is unsuitable, as with vomiting
liner which needs to be peeled off before applying the and diarrhea (Finnin and Morgan, 1999).
patch to the skin. Drugs administered via skin patches 3. They avoid the first-pass effect, that is, the initial
include scopolamine, nicotine, estrogen, nitroglycerin, passage of s drug substance through the systemic and
and lidocaine. portal circulation following gastrointestinal absorption,
Transdermal delivery not only provides controlled, possibly avoiding the deactivation by digestive and liver
constant administration of the drug, but also allows enzymes (Allen et al., 2005; Barry, 2002).
2 Compr . J. Pharm. Sci.

4. They are non invasive, avoiding the inconvenience of remainder of the epidermis, also called viable epidermis,
Parenteral therapy (Allen et al., 2005; Barry, 2002). cover a major area of skin (Tortora and Grabowski,
5. They provide extended therapy with a single 2006).
application, improving compliance over other dosage
forms requiring more frequent dose administration (Allen Stratum corneum: This is the outermost layer of skin,
et al., 2005). also called horney layer. It is approximately 10 mm thick
6. The activity of drugs having s short half-life is when dry but swells to several times this thickness when
extended through the reservoir of drug in the therapeutic fully hydrated. It contains 10 to 25 layers of parallel to the
delivery system and its controlled release (Barry, 2002; skin surface, lying dead, keratinized cells, called
Cleary). corneocytes. It is flexible but relatively impermeable. The
7. Drug therapy may be terminated rapidly by removal of stratum corneum is the principal barrier for penetration.
its application from the surface of the skin (Barry, 2002). The barrier nature of the horney layer depends critically
8. They are easily and rapidly identified in emergencies on its constituents: 75 to 80% proteins, 5 to 15% lipids,
(for example, unresponsive, unconscious, or comatose and 5 to 10% ondansetron material on a dry weight basis.
patient) because of their physical presence, features, and Protein fractions predominantly contain alpha-keratin
identifying markings. (70%) with some beta-keratin (10%) and cell envelope
At the same time, transdermal drug delivery has few (5%). Lipid constituents vary with body site (neutral lipids,
disadvantages that are limiting the use of transdermal sphingolipids, polar lipids, cholesterol). Phospholipids are
delivery (Barry, 2002). largely absent, a unique feature of mammalian
membrane (Tortora and Grabowski, 2006; Wilson and
Waugh, 1996).
Disadvantages

1. Only relatively potent drugs are suitable candidates for Viable epidermis: This is situated beneath the stratum
transdermal delivery because of the natural limits of drug corneum and varies in thickness from 0.06 mm on the
entry imposed by the skins impermeability (Allen et al., eyelids to 0.8 mm on the palms. Going inwards, it
2005; Barry, 2002). consists of various layers as stratum lucidum, stratum
2. Some patients develop contact dermatitis at the site of granulosum, stratum spinosum, and the stratum basale.
application from one or more of the system components, In the basale layer, mitosis of the cells constantly renews
necessitating discontinuation (Barry, 2002). the epidermis and this proliferation compensates the loss
3. The delivery system cannot be used for drugs requiring of dead horney cells from the skin surface. As the cells
high blood levels (Allen et al., 2005). produced by the basale layer move outward, they alter
4. The use of transdermal delivery may be uneconomical morphologically and histochemically, undergoing
(Barry, 2002). keratinization to form the outermost layer of
stratumcorneum (Tortora and Grabowski, 2006; Wilson
For better understanding of transdermal drug delivery, and Waugh, 1996).
the structure of skin should be briefly discussed along
with penetration through skin and permeation pathways
(Barry, 2002; Vyas and Khar, 2002). This is shown in Dermis
Figure 1- 3
Dermis is a 3 to 5 mm thick layer and is composed of a
matrix of connective tissue which contains blood vessels,
Anatomy and physiology of skin lymph vessels, and nerves. The continuous blood supply
has essential function in regulation of body temperature.
Human skin comprises of three distinct but mutually It also provides nutrients and oxygen to the skin while
dependent tissues (Tortora and Grabowski, 2006; Wilson removing toxins and waste products. Capillaries reach to
and Waugh, 1996), namely: within 0.2 mm of skin surface and provide sink conditions
for most molecules penetrating the skin barrier. The
1. The stratified, a vascular, cellular epidermis; blood supply thus keeps the dermal concentration of
2. Underlying dermis of connective tissues and; permeate very low, and the resulting concentration
3. Hypodermis. difference across the epidermis provides the essential
driving force for transdermal permeation (Tortora and
Grabowski, 2006; Wilson and Waugh, 1996).
Epidermis

The multilayered envelop of the epidermis varies in Hypodermis

thickness, depending on cell size and number of cell
layers, ranging from 0.8 mm on palms and soles down to The hypodermis or subcutaneous fat tissue supports the
0.06 mm on the eyelids. Stratum corneum and the dermis and epidermis. It serves as a fat storage area.
Archana Gaikwad. 3

Figure 1. Structure of human skin.

Figure 2. Simplified diagram of skin structure and macro routes of drug barrier at a penetration. Source: Allen et al. (2005).

This layer helps to regulate temperature, provides layers is desired (Tortora and Grabowski, 2006; Wilson
nutritional support and mechanic protection. It carries and Waugh, 1996).
principal blood vessels and nerves to skin and may
contain sensory pressure organs. For transdermal drug
delivery, the drug has to penetrate through all these three ROUTES OF PENETRATION
layers and reach into systemic circulation while in case of
topical drug delivery, only penetration through stratum The diffusant has two potential entry routes to the blood
corneum is essential and then retention of drug in skin vasculature; through the epidermis itself or diffusion
4 Compr . J. Pharm. Sci.

Figure 3. Simplified model of the human skin for mechanistic analysis of skin permeation. Source: Cleary (1984).

through shunt pathway, mainly hair follicles with their The route through which permeation occurs is largely
associated sebaceous glands and the sweat ducts dependent on physico-chemical characteristics of
(Barry, 1987). Therefore, there are two major routes of penetrant, most importantantly being the relative ability to
penetration (Bodde et al., 1991; Heisig et al., 1996). partition into each skin phase. The transdermal
permeation can be visualized as composite of a series in
sequence as:
Transcorneal penetration
1. Adsorption of a penetrant molecule onto the surface
Intra cellular penetration layers of stratum corneum.
2. Diffusion through stratum corneum and through viable
Drug molecule passes through the cells of the stratum epidermis.
corneum. It is generally seen in case of hydrophilic drugs. 3. Finally through the papillary dermis into the
As stratum corneum hydrates, water accumulates near microcirculation.
the outer surface of the protein filaments. Polar
molecules appear to pass through this immobilized water. The viable tissue layer and the capillaries are relatively
permeable and the peripheral circulation is sufficiently
rapid. Hence diffusion through the stratum corneum is the
Intercellular penetration rate-limiting step (Scheuplein, 1965). The stratum
corneum acts like a passive diffusion medium. So for
Non-polar substances follow the route of intercellular transdermal drug diffusion, the various skin tissue layers
penetration. These molecules dissolve in and diffuse can be represented by a simple multilayer model as
through the non- aqueous lipid matrix imbibed between shown in Figure 2.
the protein filaments.

FORMULATION DESIGN
Transappendegeal penetration
A transdermal therapeutic system is essentially a
This is also called as the shunt pathway (Bodde et al., multilaminate structure that is composed of following
1991; Heisig et al., 1996). In this route, the drug molecule constituents:
may transverse through the hair follicles, the sebaceous
pathway of the pilosebaceous apparatus or the aqueous 1. Drug;
pathway of the salty sweat glands (Barry, 1987). The 2. Polymer matrix;
transappendegeal pathway is considered to be of minor 3. Penetration enhancers;
importance because of its relatively smaller area (less 4. Adhesives;
than 0.1% of total surface). However this route may be of 5. Backing membrane;
some importance for large polar compounds. 6. Release linear.
Archana Gaikwad. 5

Table 1. Polymers useful for transdermal devices.

Polymer Category Role

Gelatin Base, adhesive
Na-alginate Base, adhesive
Gum Arabic Natural polymer Base with adhesive
Gum tragacanth Adhesive
Natural rubber Base with adhesive

Carmellose Base, adhesive

Methyl and ethyl cellulose Semi synthetic polymer Base, adhesive
Hydroxyl propyl cellulose Base, adhesive

Styrene-butadiene rubber Base with adhesive

Synthetic elastomers
Silicone rubber Base with adhesive

Polyvinyl alcohol Base, adhesive

polyethylene Linear, backing
polypropylene Membrane, linear
polystyrene Synthetic polymer Co-adhesive
Polyhydroxyethyl methacrylate (PHMA) Linear, backing
Polyvinyl chloride (PVC) Base, adhesive
Ethylene vinyl acetate Membrane
Source: Sugibayashi and Morimoto (1994), Valenta and Auner (2004) and Enclyopedia of polymer
science and technology (1976).

Drug significant transdermal absorption at pH values at which

the unionized form of the drug is predominant.
Transdermal route of administration cannot be employed Biological properties
for all types of drugs. It depends upon optimal
physicochemical properties of the drug, its biological 1. The drug should be potent with a daily dose of the
properties. In addition, consideration of the order of a few mg/day;
pharmacokinetic and pharmacodynamic properties of 2. The half life t of the drug should be short;
drug is necessary. The most important requirement of 3. The drug should be non-irritating and non allergic;
drug to be delivered transdermally is demonstrated by 4. Drugs which degrade in the gastro intestinal (GI) tract
need for controlled delivery, such as short half-life, or inactivated by hepatic first-pass effect are suitable
adverse effect associated with other route or a complex candidates for transdermal delivery.
oral or I.V. dose regimen (Barry, 1983). The drug
parameter required for ideal drug candidate for
transdermal drug delivery can be divided into: Polymer

Advances in transdermal drug delivery technology have

been rapid because of the sophistication of polymer
Physicochemical properties
science that now allows incorporation of polymers in
transdermal system (TDS) in adequate quantity. The
1. The drug should have a molecular weight less than release rate from TDS can be tailored by varying polymer
approximately 1000 Daltons; composition. Selection of polymeric membrane is very
2. The drug should have affinity for both- lipophilic and important in designing a variety of membrane permeation
hydrophilic phases. Extreme partitioning characteristic controlled TDS (Siepmann et al., 1998). The criteria for
are not conducive to successful drug delivery via the skin; the polymers are (Chien, 1987; Vyas and Khar, 2002;
3. The drug should have a low melting point; Mishra, 1998).Table 1
4. Since the skin has pH of 4.2 to 5.6, solutions which
have this pH range are used to avoid damage to the skin. 1. The polymer should be chemically non reactive
However for a number of drugs, there may also be or it should be an inert drug carrier;
6 Compr . J. Pharm. Sci.

2. The polymer must not decompose on storage or during (a) Iontophoresis;

the life span; (b) Sonophoresis: Ultrasonic energy;
3. Molecular weight, physical characteristic and chemical (c) Thermal energy;
functionality of the polymer must allow the diffusion of the (d) Stripping of stratum corneum and;
drug substance at desirable rate; (e) Hydration of stratum corneum.
4. The polymer and its decomposed product should be
nontoxic. It should be biocompatible with skin;
5. The polymer must be easy to manufacture and Adhesive layer according to Hock and William (1999),
fabricate into desired product. It should allow Qvist et al. (2002), Govil et al. (1993) and Govil (1988)
incorporation of large amounts of active agent.
The adhesive must posses sufficient property so as to
Penetration enhancer firmly secure the system to the skin surface and to
maintain it in position for as long as desired, even in the
An approach commonly researched for promoting presence of water. After removal of patch, any traces of
permeation through the skin poorly penetrating drug adhesive left behind must be capable of being washed
molecules is the incorporation of chemical penetration with water and soap. Pressure sensitive adhesives are
enhancer to the TDDS (Barry, 1987). Alternatively, used to achieve contact between the transdermal patch
physical mechanism such as intophorosis and and the skin. Adhesion is understood to be the net effect
phonophoresis can be used for certain cases of drug. of three phenomenons namely;
There are mainly three approaches for the penetration
enhancement (Walker and Smith, 1996). 1. Peel: The resistance against the breakage of the
adhesive bond;
Chemical approach according to Barry (1987) 2. Track: The ability of a polymer to adhere to a substrate
with little contact Pressure and;
This includes: 3. Creep: The viscous relaxation of the adhesive bond
upon shear.
(a) Synthesis of lipophilic analogs;
(b) Delipidization of stratum corneum; The ideal characters of adhesive materials are (Qvist et
(c) Co-administration of skin permeation enhancers. al., 2002);
This chemical approach can further be classified 1. High biocompatibility (low irritancy, toxicity, allergic
according to their chemical class; reaction etc.);
2. Good adhesive to oily, wet, wrinkled and hairy skin;
(i) Sulfoxides: Dimethyl sulfoxide, decylmethal sufoxide;
3. Good environment resistance against water and
(ii) Alcohols: Ethanol;
humidity;
(iii) Polyols: Propylene glycol;
4. Easy to remove from the skin;
(iv) Alkenes: Long chain alkanes (C7-C16);
5. High permeability of moisture to avoid excessive
(v) Fatty acids: oleic acid;
occlusion and for the drug itself and;
(vi) Esters: Isopropyl myristate;
6. Non-reactive towards drug.
(vii) Amines and amides: Urea, dimethyl acetamide,
dimethyl formamide;
There are three types of adhesive used mainly (Qvist et
(viii) Pyrrilidones: N-methylpyrrilidone, azones;
al., 2002; Govil et al., 1993);
(ix) Terpenes: Eugenol;
(x) Surface active agents: Cationic surfactants;
1. Silicone type adhesive;
(xi) Cyclodextrines.
2. Polyisobutylene adhesive and;
3. Polyacrylate based adhesive.
Biochemical approach
Backing layer according to Govil (1988)
This includes:
The backing layer must be impermeable to drug and
(a) Synthesis of bio-convertible pro-drugs and; permeation enhancers. The backing membrane serves
(b) Co-administration of skin metabolism inhibitors. the purpose of holding the entire system together and at
the same time protects the drug reservoir from exposure
to the atmosphere, which could result in the breakage or
Physical approach loss of the drug by volatilization. The most commonly
used backing materials are polyester, aluminized
This includes: polyethylene terapthalate, siliconised polyethylene
Archana Gaikwad. 7

terapthalate and aluminum foil of metalized polyester Folding endurance

laminated with polyethylene.
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
Release liner endurance (Reddy et al., 2003).

The peel strip prevents the loss of the drug that has
Percentage moisture content
migrated into the adhesive layer during storage and
protects the finished device against contamination. The prepared patches are to be weighed individually and
Polyesters foils and other metalized laminates are typical to be kept in a desiccator containing fused calcium
materials which are commonly used. chloride at room temperature. After 24 h, the films are to
be reweighed and the percentage moisture content
determined by below formula (Reddy et al., 2003):
EVALUATION METHODS
Percentage moisture content (%) = [Initial weight - Final
The evaluation methods for transdermal dosage form can weight / Final weight] 100
be classified into following types: Physicochemical
evaluation, In vitro evaluation and In vivo evaluation Percentage moisture uptake

The prepared patches are to be weighed individually and

Physicochemical evaluation to be kept in a desiccator containing saturated solution of
potassium chloride in order to maintain 84% Rhesus
Interaction studies factor (RH). After 24 h, the films are to be reweighed and
the percentage moisture uptake determined by the
The drug and the excipients must be compatible with one formula (Reddy et al., 2003).
another to produce a product that is stable. The
interaction between drug and excipients affect the Percentage moisture uptake (%) = (Final weight - Initial
bioavailability and stability of the drug. If the excipients weight / initial weight) 100
are new and have not been used in formulations
containing the active substance, the compatibility studies Water vapour permeability (WVP) evaluation
play an important role in formulation development.
Interaction studies are taken out by Thermal analysis, Water vapour permeability can be determined by a
Fourier transform infrared spectroscopy (FTIR), ultra natural air circulation oven. The WVP can be determined
violet (UV) and chromatographic techniques by by the following formula (Shaila et al., 2006):
comparing their physicochemical properties like assay,
melting point, wave numbers, and absorption maxima WVP = W/A
(Allen et al., 2005; Aarti et al., 1995; Lec et al., 1991).
Where, WVP is expressed in g/m2 per 24 h, W is the
amount of vapour permeated through the patch
Thickness of the patch expressed in g/24 h, A is the surface area of the
exposure samples expressed in m 2.
The thickness of the drug prepared patch is measured by
using a digital micrometer at different point of patch and
Drug content
this determines the average thickness and standard
deviation for the same to ensure the thickness of the
A specified area of patch is to be dissolved in a suitable
prepared patch (Reddy et al., 2003).
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
Weight uniformity technique).Then, the average of three different samples
is taken (Shaila et al., 2006).
The prepared patches are to be dried at 60C for 4 h
before testing. A specified area of patch is to be cut in
different parts of the patch and weighed in digital Content uniformity test
balance. The average weight and standard deviation
values are to be calculated from the individual weights Ten (10) patches were selected and content determined
(Reddy et al., 2003). for individual patches. If 9 out of 10 patches have content
8 Compr . J. Pharm. Sci.

between 85 to 115% of the specified value and one has plate with an adhesive. The glass plate was then placed
content not less than 75 to 125% of the specified value, in a 500 ml of the dissolution medium or phosphate buffer
then transdermal patches pass the test of content (pH 7.4), and the apparatus was equilibrated to 32
uniformity. But if 3 patches have content in the range of 0.5C. The paddle was then set at a distance of 2.5 cm
75 to 125%, then additional 20 patches are tested for from the glass plate and operated at a speed of 50 rpm.
drug content. If these 20 patches have range from 85 to Samples (5 ml aliquots) can be withdrawn at appropriate
115%, then the transdermal patches pass the test (Wolff, time intervals up to 24 h and analyzed by UV
2000). spectrophotometer or HPLC. The experiment was
performed in triplicate and the mean value calculated
(Singh et al., 1993).
Flatness test
In vitro skin permeation studies
Three longitudinal strips were cut from each film at
different portion like one from the center, other one from An in vitro permeation study can be carried out by using
the left side, and another one from the right side. The diffusion cell on thick abdominal skin of male Wistar rats
length of each strip was measured, and the variation in weighing 200 to 250 g. Hair from the abdominal region is
length because of non-uniformity in flatness was removed carefully by using an electric clipper; the dermal
measured by determining percentage constriction, with side of the skin was thoroughly cleaned with distilled
0% constriction equivalent to 100% flatness (Lec et al., water to remove any adhering tissues or blood vessels,
1991). equilibrated for an hour in dissolution medium or
phosphate buffer pH 7.4 before starting the experiment,
Constriction (%) = I1 - I2 100 I1 and was placed on a magnetic stirrer with a small
magnetic needle for uniform distribution of the diffusant.
Where, I1 = initial length of each strip. I2 = final length of The temperature of the cell was maintained at 32 0.5C
each strip. 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
Percentage elongation break test the donor compartment. Sample volume of definite
volume was removed from the receptor compartment at
The percentage elongation break was determined by regular intervals, and an equal volume of fresh medium
noting the length just before the break point and was replaced. Samples were filtered through filtering
determined from the formula (Lec et al., 1991). medium and analyzed spectrophotometrically or using
HPLC. Flux was determined directly as the slope of the
Elongation percentages = L1 - L2 / L2 100 curve between the steady-state values of the amount of
drug permeated (mg cm2) versus time in hours, and
Where L1 = final length of each strip; L2 = initial length of permeability coefficients were deduced by dividing the
each strip. flux by the initial drug load (mg cm 2) (Singh et al., 1993).

Stability studies In vivo evaluation

Stability studies were conducted according to the Skin irritation study

International Conference on Harmonization (ICH)
Skin irritation and sensitization testing can be performed
guidelines by storing the TDDS samples at 40 0.5C
on healthy rabbits (average weight 1.2 to 1.5 kg). The
and 75 5% RH for 6 months. The samples were
dorsal surface (50 cm 2) of the rabbit is to be cleaned and
withdrawn at 0, 30, 60, 90 and 180 days and analyzed
the hair removed from the clean dorsal surface by
suitably for the drug content (Singh et al., 1993).
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
In vitro evaluation of TDDS observed and classified into 5 grades on the basis of the
severity of skin injury (Aarti et al., 1995).
In vitro drug release studies

The paddle over disc method (USP apparatus V) can be CONCLUSION

employed for assessment of the release of the drug from
the prepared patches. Dry films of known thickness were Due to the recent advances in technology and the
cut into definite shape, weighed, and fixed over a glass incorporation of the drug to the site of action without
Archana Gaikwad. 9

Stratum Corneum. The biphasic brick and mortar model. Pharm

rupturing the skin, membrane transdermal route is Res.1996; 13: 421426
effective. This article provides valuable information Scheuplein RJ. (1965) .Mechanism of percutaneous absorption.
regarding the formulation and evaluation aspects of 1. Routes of penetration and the influence of solubility. J Invest
transdermal drug delivery systems. TDDS is a realistic Dermatol.; 45:334346.
practical application as the next generation of drug Barry BW. (1983)Dermatological Formulations. Percutaneous
delivery system. Absorption, Vol. 18, Marcel Dekker, New York. pp.126-134
Siepmann J Ainaoui, Vergnaud JM , Bodmeiera R. (1998).
Calculation of dimension of drug polymer devices based on
REFERENCES diffusion parameter. J. Pharm. Sci. 87: 827-832.
Mishra AN, (1998).Transdermal drug delivery in: Jain NK. (Ed).
Chien YW (1987). Novel Drug Delivery Systems, 2nd Edition, Controlled and Novel drug delivery, Varghese Publication,
Drugs and Pharmaceutical Sciences, Marcel Dekker, New Delhi. pp.100-129.
Inc.washington;D.C. pp. 50:281-299 Sugibayashi K, Morimoto Y, (1994) Polymers for Transdermal
Finnin BC, Morgan TM (1999). Transdermal penetration. J Drug Delivery Systems. J Control Release.; 29: 177-185.
Pharm Sci. Oct 1999; 88 (10):955-958. Valenta C, Auner BG. (2004). The Use of Polymers For Dermal
Allen LV, Popovich NG, Ansel HC, (2005). Ansels and Transdermal Delivery. Eur J Pharm Sci. 58: 279-289.
Pharmaceutical Dosage Forms and Drug Delivery Systems, Enclyopedia of polymer science and technology, Interscience
8th Edition, Lippincott Williams &Wilkins, pp. 298-315. publishers, A division of John Wiley and sons. Inc. 1976;
Barry B. (2002). Transdermal Drug Delivery. In Ed: Aulton M E, 12:139-168.
Pharmaceutics: The Science of Dosage Form Design, Barry BW. (1987). Mode of action of penetration enhancers in
Churchill Livingston. pp :499-533 human skin. J Control. Release. 6: 85-97.
Cleary GW, (1984). Transdermal controlled release systems. Walker BP, Smith EW. (1996). The role of percutaneous
Medical Applications of Controlled Release. (1) pp: 203-251. penetration enhancers. Advanced Drug Delivery reviews. 18:
Vyas SP, Khar RK, (2002). Controlled Drug Delivery: Concepts 295-301
and Advances, Vallabh Prakashan, 1st Edition. pp. 411-447. Hock S Tan, William R Pfister. (1999). Pressure-sensitive
Tortora G, Grabowski S. (2006). The Integumentary system. In: adhesives for transdermal drug delivery systems. PSTT. 2:
Principles of Anatomy and Physiology. 9th edition. John Wiley 60-69.
and Sons Inc. pp.150-151. Qvist MH, Hoeck U, Kreilgaard B, Madson F, Frokjaer S.
Wilson KJW, Waugh A. (1996) Eds, Ross and Wilson: Anatomy (2002). Release of Chemical Penetration Enhancers From
and Physiology in Health and Illness, 8th Edition, Churchill Drug-In-Adhesive Transdermal Patches, Int J Pharm. 231:
Livingstone. pp. 360-366. 253263.
Barry BW (1983). Dermatological Formulations: Percutaneous Govil SK, Radnic EM, Sterner DG. U.S. Patent (1993). 5:
Absorption, Drugs and pharmaceutical sciences, Volume 262,165
18, MARCEL DEKKER, INC. pp.1-39. Govil SK. (1988). In: Drug Delivery Devices, P. Tyle (Ed.),
United States Patent: 6,673,363 Issued: January 6, 2004 Title: Marcel Dekker, New York. pp. 388
Transdermal and topical administration of local anesthetic Guy, Richard H, Hadgraft, Jonathan;(2002). Transdermal Drug
agents using basic enhancers Inventors: Luo; Eric C. (Plano, Delivery Second Edition Published by Informa Health Care.
TX); Gricenko; Nicole T. (San Diego, CA); Hsu; Tsung- pp. 322
Min(San Diego, CA) Arcangelo, Virginia P., Peterson, Andrew M. (2005).
Vanbever R, Langers G, Montmayeur S, Preat V. (1998) Pharmacotherapeutics for Advanced Practice, Published by
Transdermal Delivery of Fentanyl: Rapid onset of Analgesia Lippincott Williams & Wilkins. pp. 74
using Skin Electroporation. J Control Release. Jan 2; 50(1-3). Eseldin Keleb, Rakesh Kumar Sharma, Esmaeil B mosa, Abd-
Pp.225- 235. alkadar Z aljahwi.( 2010). Transdermal Drug Delivery System-
Patel KD. (2011) Transdermal Drug Delivery System of Timolol Design and Evaluation, Int. J. of Advances in Pharm. Sci.1;
Maleate as Model Drug. American journal of pharmatech 201-211
research.pp 7-17 Singh J, Tripathi KT, Sakia TR. (1993). Effect of penetration
Aulton ME, (2007). Pharmaceutics : The Science of Dosage enhancers on the in vitro transport of ephedrine through rate
Form Design, Second Edition, Part Four, Dosage Form skin and human epidermis from matrix based Transdermal
Design and Manufacture, Chapter 33, Transdermal Drug formulations. Drug. Dev. Ind. Pharm. 19: 1623-1628
Delivery pp. 499 533 Wade A, Weller PJ. (1994). Handbook of pharmaceutical
Wolff HM (2000 ).Optimal Process Design for the Manufacture Excipients. Washington, DC: American Pharmaceutical
of Transdermal Drug Delivery Systems, PSTT. 3(5) :173 Publishing Association. pp.362-366.
181 Reddy RK, Muttalik S, Reddy S. (2003). Once daily
Barry BW. (1987) Mode of Action of Penetration Enhancers on sustainedrelease matrix tablets of nicorandil: formulation and
The Kinetics Of Percutaneous Absorption. J. Control in vitro evaluation. AAPS. Pharm. Sci. Tech.;4: 4.
Release. 6: pp. 43-51. . Shaila L, Pandey S, Udupa N. (2006). Design and evaluation
Bodde HE, I Van Den Brink, Koerten HK. (1991) Visualization of matrix type membrane controlled Transdermal drug
Of In Vitro Percutaneous Penetration Of Mercuric Chloride delivery system of nicotin suitable for use in smoking
Transport Through Intercellular Space Versus Cellular Uptake cessation. Indian. Journ. Pharm. Sci. 68: 179-84.
Through Desmosomes. J Control Release.; 15: 227236. Aarti N, Louk ARMP, Russsel OP, Richard HG. (1995).
Heisig MR, Lickfaldt G Wittum, Mazurkevich G, G LEE. (1991) Mechanism of oleic acid induced skin permeation
Non Steady- State Descriptions of Drug Permeation through enhancement in vivo in humans. Jour. control. Release. 37:
299-306.
10 Compr . J. Pharm. Sci.

Singh J, Tripathi KT, Sakia TR. (1993). Effect of penetration

Lec ST, Yac SH, Kim SW, Berner B. One way membrane for enhancers on the in vitro transport of ephedrine through rate
transdermal drug delivery systems / system optimization. Int. skin and human epidermis from matrix based Transdermal
J. Pharm.; 77: 231-237 formulations. Drug. Dev. Ind. Pharm.; 19: 1623-1628.