REVIEW ARTICLE Transdermal drug delivery system: An overview

Vaibhav Rastogi, Pragya Yadav

Department of Pharmaceutics, College of Pharmacy, IFTM University, Moradabad, Uttar Pradesh, India

T ransdermal drug delivery system (TDDS) is one of the systems lying under the category of controlled drug delivery, in
which the aim is to deliver the drug through the skin in a predetermined and controlled rate. It has various advantages,
like prolonged therapeutic effect, reduced side-effects, improved bioavailability, better patient compliance and easy termination
of drug therapy. The stratum corneum is considered as the rate limiting barrier in transdermal permeation of most molecules.
There are three main routes of drug penetration, which include the appendageal, transcellular and intercellular routes. Skin age,
condition, physicochemical factors and environmental factors are some factors that are to be considered while delivering drug
through this route. Basic components of  TDDS include polymer matrix, membrane, drug, penetration enhancers, pressure-
sensitive adhesives, backing laminates, release liner, etc.Transdermal patches can be divided into various systems like reservoir
system, matrix system and micro-reservoir system, which are used to incorporate the active ingredients into the circulatory
system via the skin.After preparation of transdermal patches, consistent methodology are adopted to test the adhesion properties,
physicochemical properties, in vitro drug release studies, in vitro skin permeation studies, skin irritation studies and stability
studies. According to the duration of therapy, various drugs are commercially available in the form of transdermal patches.

Key words: Matrix system, microreservoir system, penetration enhancer, pressure-sensitive adhesives, reservoir system,
stratum corneum,Transdermal drug delivery system

INTRODUCTION respectively.[6,7] Transdermal route has vied with oral

treatment as the most successful innovative research
Innovations in the area of drug delivery are taking area in drug delivery, as oral treatment involves
place at a much faster pace as compared with the attainment and maintenance of drug concentration in
last two decades. Improved patient compliance and the body within a therapeutically effective range by
effectiveness are inextricable aspects of new drug introduction of a fixed dose at regular intervals, due
delivery systems.[1,2] A more radical approach has been to which the drug concentration in the body follows
to explore newer interfaces on the body for introducing a peak and trough profile, leading to a greater chance
therapeutics. One such approach, transdermal drug of adverse effects or therapeutic failure; large amount
delivery, makes use of human skin as a port of entry of drug is lost in the vicinity of the target organ and
for systemic delivery of drug molecules.[3] Transdermal close attention is required to monitor therapy to
drug delivery system (TDDS) is one of the systems avoid overdosing. The limitations of the oral route
lying under the category of controlled drug delivery, can be overcome and benefits of intravenous drug
in which the aim is to deliver the drug through the infusion such as to bypass hepatic “first pass” hepatic
skin in a predetermined and controlled rate. TDDS are elimination (HEPE) to maintain constant prolonged
adhesive drug-containing devices of defined surface and therapeutic effective drug levels in the body can
area that deliver a predetermined amount of drug to be closely duplicated, without its potential hazards,
the surface of intact skin at a programmed rate to reach by transdermal drug administration through intact
the systemic circulation.[4,5] skin. [8-10] Table 1 represents the advantages and
disadvantages of delivering drug across the skin for
Transdermal delivery provides a leading edge over systemic therapy.
injectables and oral routes by increasing patient
compliance and avoiding first-pass metabolism, Access this article online
Quick Response Code:
Website:
www.asiapharmaceutics.info
Address for correspondence:
Mr.Vaibhav Rastogi,
Address: House no. 39, Gujrati Street, near paan dariba,
DOI:
Moradabad, Uttar Pradesh - 244 001, India
10.4103/0973-8398.104828
E-mail: [email protected]

Asian Journal of Pharmaceutics - July-September 2012 161

 Rastogi and Yadav: Transdermal drug delivery system: An overview

Skin and drug permeation layer toward the skin surface. The epidermis contains no
The objective of TDDS is to achieve systemic medication blood vessels; therefore, nutrients and waste products must
through topical application on intact skin; therefore, it is diffuse across the dermal–epidermal junction to maintain its
important to review the structural and biochemical features vitality. The epidermis consists of five layers, which, from the
of the human skin and those characteristics that contribute inside to the outside, are the stratum germinativum (basal
to the barrier function and the rate of drug access into the layer), stratum spinosum (spinous layer), stratum granulosum
body via the skin. (granular layer), stratum lucidum and stratum corneum (SC).
Because the SC cells are dead, the epidermis without the SC
Anatomically, the skin can be divided into two layers: is usually termed the viable epidermis. The SC is considered
epidermis and dermis or corium [Figure 1], penetrated by as the rate-limiting barrier in transdermal permeation of
hair shafts and gland ducts. The skin is one of the most most molecules. The SC comprises 15–20 layers of keratin-
extensive organs of the human body, covering an area of filled corneocytes (terminally differentiated keratinocytes)
about 2 m2 in an average human adult. The major skin layers, anchored in a lipophilic matrix. The lipids of this extracellular
from inside to outside, comprise the fatty subcutaneous matrix are distinctive in many respects: (1) they provide
layer (hypodermis), the dermis of connective tissue and the the only continuous phase (and diffusion pathway) from
stratified avascular cellular epidermis. This multilayered the skin surface to the base of the SC; (2) the composition
organ receives approximately one-third of all blood (ceramides, free fatty acids and cholesterol) is unique among
circulating through the body. Epidermis results from an active biomembranes and particularly noteworthy is the absence of
epithelial basal cell population and is approximately 150-μm phospholipids; (3) despite this deficit of polar bilayer-forming
thick. It is the outermost layer of the skin, and the process lipids, the SC lipids exist as multilamellar sheets; and (4)
of differentiation results in migration of cells from the basal the predominantly saturated, long-chain hydrocarbon tails

Table 1: Advantages and disadvantages of TDDS[5,11-13]

Advantages Disadvantages
Self-administration is possible and continuous, sustained release of Only small lipophilic drugs can be delivered currently
drug through the skin
Avoids peak and trough drug levels and longer and multiday dosing Drug molecule must be potent because patch size
intervals limits the amount that can be delivered
Avoids first-pass hepatic metabolism and enzymatic degradation by Not suitable for high drug doses
the gastrointestinal tract and also avoids gastrointestinal irritation
Less frequent dosing improves patient compliance Adhesion may vary with patch type and environmental
conditions
Alternate route for patients who are unable to take oral medications Adhesion may vary with patch type and environmental
conditions
Dose delivery unaffected by vomiting or diarrhea Skin irritation and hypersensitivity reactions may occur
Drug administration stops with patch removal The barrier functions of the skin change from one site
to another on the same person, from person to person
and with age

Figure 1: Cross-section view of human skin showing different cell layers and appendages

162 Asian Journal of Pharmaceutics - July-September 2012

 Rastogi and Yadav: Transdermal drug delivery system: An overview

facilitate a highly ordered, interdigitated configuration and historically held view of the follicles providing approximately
the formation of gel phase membrane domains as opposed 0.1% of the SC appears to be valid for forearm skin.
to the more usual (and more fluid and permeable) liquid
crystalline membrane systems. In the dry state, the SC has Transcellular route
a thickness of 10–15 μm; upon hydration, the SC swells and Drugs entering the skin via the transcellular route pass
its thickness can reach 40 μm. The structure of the SC is through the corneocytes. Corneocytes containing highly
often depicted as a bricks and mortar arrangement, where hydrated keratin provide an aqueous environment from
the keratin-rich corneocytes (bricks) are embedded in the which hydrophilic drugs can pass. The transcellular pathway
intercellular lipid-rich matrix (mortar). requires not only partitioning into and diffusion through the
keratin bricks but also into and across the intercellular lipids.
Dermis is the foundation of a firm of connective tissue upon
which the epidermis is laid, and is of mesoderm origin. The Intercellular route
dermis or corium consists of a dense network of connective The intercellular route involves drug diffusion through the
tissue in which bundles of collagen fibers predominate, continuous lipid matrix. This route is a significant obstacle
mingled with elastic tissue in the superficial levels. The dermis for two reasons: (i) recalling the “bricks and mortar” model
contains fine plexuses of blood vessels, lymphatics, nerves, of SC, the interdigitating nature of the corneocytes yields a
hair follicles, sweat glands and sebaceous glands.[8,9,14,15] tortuous pathway for intercellular drug permeation, which
is in contrast to the relatively direct path of the transcellular
ROUTES OF PENETRATION route. (ii) The intercellular domain is a region of alternating
structured bilayers. Consequently, a drug must sequentially
There are critically three ways in which a drug molecule partition into and diffuse through repeated aqueous and
can cross the intact SC: via skin appendages (shunt routes), lipid domains. This route is generally accepted as the most
through the intercellular lipid domains or by a transcellular common path for small uncharged molecules penetrating
route [Figure 2]. Physiochemical properties of the molecule the skin.
govern the flux of a particular drug to permeate by a
combination of these routes.[5,9] RATIONALE FOR TRANSDERMAL DRUG
DELIVERY
The appendageal route
The transappendageal routes are also known as the shunt Given that the skin offers such an excellent barrier to
routes, and include permeation through the sweat glands and molecular transport, the rationale for this delivery strategy
across the hair follicles with their associated sebaceous glands. needs to be carefully identified. Clearly, there are several
Skin appendages provide a continuous channel directly across instances in which the most convenient of drug intake
the SC barrier. Recent studies have re-examined the long held methods (the oral route) is not feasible and when alternative
assumption that the follicles occupy approximately 0.1% of routes must be sought.
the surface area of the human skin. Otberg et al. showed
that the follicular number, opening diameter and follicular Although intravenous introduction of the medicament
volume are important considerations in drug delivery through avoids many of these shortfalls (such as gastrointestinal and
these appendages and, indeed, the forehead provides hepatic metabolism), its invasive and apprehensive nature
13.7 mm2/cm2 as the follicular infundibula, i.e. approximately (particularly for chronic administration) has encouraged the
13.7% of the surface area of the forehead is available as search for alternative strategies, and few anatomical orifices
follicles. Interestingly, the same study also showed that the have not been investigated for their potential as optional
drug delivery routes. Nevertheless, the transdermal mode
offers several distinct advantages: (1) the skin presents a
relatively large and readily accessible surface area (1–2 m2)
for absorption; and (2) the application of a patch-like device
to the skin surface is a non-invasive (and thus a patient
compliant) procedure that allows continuous intervention
(i.e., system repositioning, removal or replacement).

Further benefits of TDDSs have emerged over the past

few years as technologies have evolved. These include the
potential for sustained release (useful for drugs with short
biological half-lives requiring frequent oral or parenteral
administration) and controlled input kinetics, which are
particularly indispensable for drugs with narrow therapeutic
Figure 2: Drug penetration pathways across skin indices. Of course, the implementation of TDD technology
Asian Journal of Pharmaceutics - July-September 2012 163
 Rastogi and Yadav: Transdermal drug delivery system: An overview

must be therapeutically “justified”: drugs with high oral the concentration of unionized drug in applied phase will
bioavailability and infrequent dosing regimens that are well determine the effective membrane gradient, which is directly
accepted by patients do not warrant such measures. Similarly, related to its pH.[17]
transdermal administration is not a means to achieve rapid
bolus-type drug inputs; rather, it is usually designed to offer Environmental factors
slow, sustained drug delivery over substantial periods of Sunlight
time and, as such, tolerance-inducing drugs or those (e.g., Because of to sunlight, the walls of blood vessels become
hormones) requiring chronopharmacological management thinner, leading to bruising, with only minor trauma in the
are, at least to date, not suitable. Nevertheless, there remains sun-exposed areas. Also, pigmentation, the most noticeable
a large pool of drugs for which TDD is desirable but presently sun-induced pigment change, is a freckle or solar lentigo.[18]
unfeasible. The nature of the SC is, in essence, the key to
this problem. The excellent diffusional resistance offered by Cold season
the membrane means that the daily drug dose that can be The cold season often results in itchy and dry skin. The skin
systemically delivered through a reasonable “patch-sized” responds by increasing oil production to compensate for the
area remains in the 10 mg range. This limitation imposes weather’s drying effects. A good moisturizer will help ease
the first criterion for a successful transdermal candidate: symptoms of dry skin. Also, drinking lots of water can keep
transdermal drugs must be pharmacologically potent, your skin hydrated and looking radiant.[18]
requiring therapeutic blood concentrations in the ng/ml
range, or less. The second criterion is that SC is very selective Air pollution
with respect to the type of molecule that can be transported Dust can clog pores and increase bacteria on the face and the
across this outer covering, and not all molecules that pass surface of skin, both of which lead to acne or spots, which
the “potency” test will have the necessary physicochemical affects drug delivery through the skin. Invisible chemical
properties.[9] pollutants in the air can interfere with the skin’s natural
protection system, breaking down the skin’s natural oils
FACTORS AFFECTING TRANSDERMAL DRUG that normally trap moisture in the skin and keep it supple.[18]
DELIVERY
BASIC COMPONENTS OF TDDS
Skin condition
The intact skin itself acts as a barrier, but many agents like • Polymer matrix/drug reservoir
acids and alkali cross the barrier cells and penetrate through • Membrane
the skin. Many solvents open the complex dense structure • Drug
of the horny layer: solvents like methanol and chloroform • Permeation enhancers
remove the lipid fraction, forming artificial shunts through • Pressure-sensitive adhesives (PSA)
which drug molecules can pass easily.[16] • Backing laminates
• Release liner
Skin age • Other excipients like plasticizers and solvents
It is seen that the skin of adults and young ones is more
permeable than that of the older ones. but there is no dramatic Polymer matrix/drug reservoir
difference. Children show toxic effects because of the greater Polymers are the backbone of TDDS, which control the
surface area per unit body weight. Thus, potent steroids, boric release of the drug from the device. A polymer matrix can
acid and hexachlorophene have produced severe side-effects. be prepared by dispersion of drug in a liquid or solid state
synthetic polymer base. Polymers used in TDDS should have
Physicochemical factors biocompatibility and chemical compatibility with the drug
Hydration of skin and other components of the system, such as penetration
Generally, when water saturates the skin, it swells tissues, enhancers and PSAs. Additionally, they should provide
softens wrinkles on the skin and its permeability increases consistent and effective delivery of a drug throughout the
for the drug molecules that penetrate through the skin.[17] product’s intended shelf-life, and should be safe.[13,19-21]

Temperature and pH of the skin The following criteria should be preferred in selecting the
The penetration rate varies if the temperature varies and polymer to be used in the transdermal system:
the diffusion coefficient decreases as the temperature falls;, (i) Molecular weight, glass transition temperature and chemical
however adequate clothing on the body prevents wide functionality of the polymer should be such that the specific
fluctuations in temperature and penetration rates. According drug diffuses properly and gets released through it.
to pH, only unionized molecules pass readily across the lipid (ii) The polymer should be stable, nonreactive with the
membrane, and weak acids and bases dissociate to different drug, easily manufactured and fabricated into the desired
degrees according to their pH and pKa or pKb values. Thus, product, and should be inexpensive.
164 Asian Journal of Pharmaceutics - July-September 2012
 Rastogi and Yadav: Transdermal drug delivery system: An overview

(iii) The polymer and its degradation products must be Table 2: Polymers used in TDDS[21,22]
nontoxic or nonantagonistic to the host. Natural Synthetic Synthetic
(iv) The mechanical properties of the polymer should not polymers elastomers polymers
deteriorate excessively when large amounts of active Cellulose Polybutadiene, Polyvinylalcohol,
ingredients are incorporated into it.[21] derivatives, zein, hydrin rubber, polyvinylchloride,
gelatin, waxes, polysiloxane polyethylene,
The polymers utilized for TDDS are presented in Table 2. proteins and their silicone rubber, polypropylene,
derivatives, nitrile, acrylonitrile, polyacrylate,
natural rubber, butyl rubber rubber, polyurea,
Membrane
starch, chitosan, styrene–butadiene polyvinyl
A membrane may be sealed to the backing to form a pocket etc. rubber, neoprene, pyrrolidone,
to enclose the drug-containing matrix or used as a single etc. polymethyl
layer in the patch construction. The diffusion properties of methacrylate,
the membrane are used to control availability of the drug epoxy, ethyl
and/or excipients to the skin. For example, ethylene vinyl cellulose,
acetate, silicone rubber, polyurethrane, etc. are used as a hydroxy propyl
rate-controlling membrane.[5,21] cellulose,
polyamide, etc.
Drug
For successfully developing a TDDS, the drug should be Table 3: Ideal properties of drugs for TDDS[5,9,23]
chosen with great care. Transdermal patches offer many
Parameters Properties
advantages to drugs that undergo extensive first-pass
Dose Should be low (less than 20 mg/day)
metabolism, drugs with narrow therapeutic window or drugs
with a short half-life, which cause noncompliance due to Half-life 10 or less (h)
frequent dosing.[13,19] Some of the desirable properties of a Molecular weight <400 Da
drug and factors to be considered for transdermal delivery Partition Log P (octanol–water) between 1.0 and
coefficient 4.0
are shown in Tables 3 and 4.
Skin permeability >0.5 × 10-3 cm/h
coefficient
There are some examples of drugs that are suitable for
Liophilicity 10 < Ko/w < 1000
TDDS, like Nicardipine hydrochloride, Captopril, Atenolol,
Oral bioavailability Low
Metoprolol tartarate, Clonidine, Indapamide, Propranolol
Therapeutic index Low
hydrochloride, Carvedilol, Verapamil hydrochloride and
Melting point <200°C
Niterdipine, etc.
pH Between 5.0 and -9.0

Permeation enhancers
One long-standing approach for improving TDD uses Table 4: Factors to be considered for transdermal dose
penetration enhancers (also called sorption promoters or calculation[24]
accelerants), which increase the permeability of the SC so Physiochemical Pharmacokinetic Biological
as to attain higher therapeutic levels of the drug candidate. Solubility Half-life Skin toxicity
Penetration enhancers interact with structural components Crystallinity Volume of Site of application
of the SC thus modifying the barrier functions, leading distribution
to increased permeability. Three pathways are suggested Molecular Total body Allergic reaction
for drug penetration through the skin: polar, nonpolar weight clearance
and polar/nonpolar. The enhancers act by altering one of Polarity Therapeutic plasma Skin metabolism
concentration
these pathways. The key to altering the polar pathway is to
Melting point Bioavailability factor Skin permeability
cause protein conformational change or solvent swelling.
The key to altering the nonpolar pathway is to alter the
rigidity of the lipid structure and fluidize the crystalline Chemical enhancers
pathway (this substantially increases diffusion). The fatty Chemicals that promote the penetration of topically applied
acid enhancers increase the fluidity of the lipid portion drugs are commonly referred to as accelerants, absorption
of the SC. Some enhancers (binary vehicles) act on both promoters or penetration enhancers.[13] Chemical enhancers
polar and nonpolar pathways by altering the multilaminate act by:
pathway for penetrants.[9,13] The methods employed for • Increasing (and optimizing) the thermodynamic activity
modifying the barrier properties of the SC to enhance the of the drug when functioning as a co-solvent
drug penetration (and absorption) through the skin can • Increasing the partition coefficient of the drug to
be categorized as (1) chemical and (2) physical methods promote its release from the vehicle into the skin
of enhancement. • Conditioning the SC to promote drug diffusion
Asian Journal of Pharmaceutics - July-September 2012 165
 Rastogi and Yadav: Transdermal drug delivery system: An overview

• Promoting penetration and establishing drug reservoir Backing laminates

in the SC. Backings are chosen for appearance, flexibility and need
for occlusion; hence, while designing a backing layer, the
Some of the more desirable properties for penetration consideration of chemical resistance of the material is most
enhancers acting within the skin have been given as: important. Excipient compatibility should also be considered
• They should be nontoxic, nonirritating and nonallergenic because the prolonged contact between the backing layer
• They should ideally work rapidly, and the activity and and the excipients may cause the additives to leach out of
duration of the effect should be both predictable and the backing layer or may lead to diffusion of excipients,
reproducible drug or penetration enhancer through the layer. The most
• They should have no pharmacological activity within the comfortable backing will be the one that exhibits lowest
body, i.e. should not bind to receptor sites modulus or high flexibity, good oxygen transmission and a
• The penetration enhancers should work unidirectionally, high moisture vapor transmission rate. Examples of backing
i.e. should allow therapeutic agents into the body while materials are vinyl, polyethylene, polyester films, aluminum
preventing the loss of endogenous material from the body and polyolefin films.[27,28]
• When removed from the skin, barrier properties should
return both rapidly and fully Release liner
• The penetration enhancers should be appropriate for During storage, the patch is covered by a protective liner
formulation into diverse topical preparations and, thus, that is removed and discarded before the application of
should be compatible with both excipients and drugs the patch to the skin. Because the liner is in intimate
• They should be cosmetically acceptable with an contact with the TDDS, the liner should be chemically
appropriate skin “feel”[5,21] inert. Typically, a release liner is composed of a base layer
that may be nonocclusive (e.g, paper fabric) or occlusive
Some of the most widely studied permeation enhancers (e.g, polyethylene, polyvinyl chloride) and a release coating
are sulphoxide (DMSO), fatty acids (oleic acid), alcohol layer made up of silicon or Teflon. Other materials used
(methanol), glycol (propylene glycol) and surfactant (anionic for TDDS release liner are polyester foil and metalized
surfactant), azone (lauracapran), etc. laminates.[5,29,30]

Physical enhancers Other excipients like plasticizers and solvents

Iontophoresis and ultrasound (also known as phonophoresis Various solvents such as chloroform, methanol, acetone,
or sonophoresis) techniques are examples of physical isopropanol and dicholoromethane are used to prepare drug
means of enhancement that have been used for enhancing reservoir. In addition, plasticizers such as dibutylphthalate,
percutaneous penetration (and absorption) of various triethyl citrate, polyethylene glycol and propylene
therapeutic agents.[8,13] glycol are added to provide plasticity to the transdermal
patch.[29,30]
PSAs
PSAs are the material that adhere to a substrate, in this case TYPES OF TRANSDERMAL PATCHES
skin, by application of light force and leave no residue when
removed. They form interatomic and intermolecular attractive Most commercially available transdermal patches are
forces at the interface, provided that the intimate contact is categorized into the following three types [Figure 3]:
formed. To obtain this degree of contact, the material must
be able to deform under slight pressure, giving rise to the Reservoir system
term “pressure sensitive.” Adhesion involves a liquid-like In this transdermal system, the drug reservoir is embedded
flow, resulting in wetting of the skin surface upon the between an impervious backing layer and a rate-controlling
application of pressure, and, when the pressure is removed, microporous or non-porous membrane.[5] The drug releases
the adhesive sets in that state. A PSA wets and spreads onto only through the rate-controlling membrane. In the drug
the skin when its surface energy is less than that of the skin. reservoir compartment, the drug can be in the form of a
After the initial adhesion, the PSA/skin bond can be built solution, suspension or gel, or may be dispersed in a solid
by stronger interactions (e.g., hydrogen bonding), which polymer matrix. Hypoallergenic adhesive polymer can be
will depend on skin characteristics and other parameters. applied as a continuous layer between the membrane and
Widely used PSA polymers in TDDS are polyisobutylene-based the release liner or in a concentric configuration around the
adhesives, acrylics and silicone-based PSAs, hydrocarbon membrane.[6]
resin, etc. The PSA can be located around the edge of the
TDDS or be laminated as a continuous adhesive layer on the Matrix system
TDDS surface. The PSA should be compatible with the drug Drug-in-adhesive system
and excipients, as their presence can modify the mechanical In this type, the drug reservoir is formed by dispersing
characteristics of the PSA and the drug delivery rate.[24-26] the drug in an adhesive polymer and then spreading the
166 Asian Journal of Pharmaceutics - July-September 2012
 Rastogi and Yadav: Transdermal drug delivery system: An overview

EVALUATION OF TRANSDERMAL FILMS

Interaction studies
Excipients are integral components of almost all pharmaceutical
dosage forms. The stability of a formulation among other
factors depends on the compatibility of the drug with the
a 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
b development. Interaction studies are commonly carried out
in thermal analysis, Fourier Transform Infrared spectroscopy,
UV and chromatographic techniques by comparing their
physicochemical characters, such as assay, melting endotherms,
characteristic wave numbers, absorption maxima, etc.[6]

Thickness of the patch

The thickness of the drug-loaded patch is measured in
c
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.[6]

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
d of the patch and weighed in a digital balance. The average
Figure 3: Types of transdermal patches: (a) Reservoir, (b) Matrix, weight and standard deviation values are to be calculated
(c) Drug-in-Adhesive, (d) Microreservoir system from the individual weights.[6]

Folding endurance
medicated adhesive polymer by solvent casting or melting A strip of the specific area is to be cut evenly and repeatedly
(in the case of hot melt adhesives) on an impervious backing folded at the same place till it breaks. The number of times
layer. On the top face of the reservoir, unmedicated adhesive the film can be folded at the same place without breaking
polymer layers are applied for protection purpose. gives the value of the folding endurance.[6]

Matrix-dispersion system Percentage moisture content

The drug is dispersed homogenously in a hydrophilic or The prepared films are to be weighed individually and are
lipophilic polymer matrix. This drug-containing polymer disk to be kept in a desiccator containing fused calcium chloride
is then fixed onto an occlusive base plate in a compartment at room temperature for 24 h. After 24 h, the films are to be
fabricated from a drug-impermeable backing layer. Instead reweighed to determine the percentage moisture content
of applying the adhesive on the face of the drug reservoir, it from the below-mentioned formula:[6]
is spread along the circumference to form a strip of adhesive
rim.[5,13,20] Percentage moisture content = [Initial weight - Final (1)
weight / Final weight] × 100
Microreservoir systems
This TDDS is a combination of a reservoir and a matrix- Percentage moisture uptake
dispersion system. The drug reservoir is formed by The weighed films are to be kept in a desiccator at room
first suspending the drug in an aqueous solution of temperature for 24 h, which contains a saturated solution of
water-soluble polymer and then dispersing the solution potassium chloride in order to maintain 84% RH. After 24 h,
homogenously in a lipophilic polymer to form thousands the films are to be reweighed to determine the percentage
of unleachable, microscopic spheres of drug reservoirs. moisture uptake from the below-mentioned formula:[6]
The thermodynamically unstable dispersion is stabilized
quickly by immediately cross-linking the polymer Percentage moisture uptake = [Final weight - Initial (2)
in situ.[6,31,32] weight / initial weight] × 100
Asian Journal of Pharmaceutics - July-September 2012 167
 Rastogi and Yadav: Transdermal drug delivery system: An overview

Water vapor permeability evaluation Molecular weight of the adhesive polymer and the type and
WVP can be determined with the foam dressing method, amount of additives are the variables that determine the peel
wherein the air-forced oven is replaced by a natural air adhesion properties. A single tape is applied to a stainless
circulation oven.[6] The WVP can be determined by the steel plate or a backing membrane of choice and then the
following formula: tape is pulled from the substrate at a 180º angle, and the
force required for tape removal is measured.[6]
WVP = W / A (3)
Thumb tack test
Where, WVP is expressed in gm/m2 per 24 h, W is the amount It is a qualitative test applied for tack property determination
of vapor permeated through the patch, expressed in gm/24 h, of the adhesive. The thumb is simply pressed on the adhesive
and A is the surface area of the exposure samples, expressed and the relative tack property is detected.[6]
in m2.
Flatness test
Drug content Three longitudinal strips are to be cut from each film at
A specified area of the patch is to be dissolved in a suitable different portions, like one from the center, one from the
solvent in a specific volume. Then, the solution is to be left side and another from the right side. The length of each
filtered through a filter medium and analyze the drug content strip was measured and the variation in length because of
with the suitable method (UV or HPLC technique). Each value nonuniformity in flatness was measured by determining
represents an average of three different samples.[6] the percent constriction, with 0% constriction equivalent to
100% flatness.[6]
Uniformity of the dosage unit test
An accurately weighed portion of the patch is to be cut into Percentage elongation break test
small pieces and transferred to a specific volume using a The percentage elongation break is to be determined by
volumetric flask, dissolved in a suitable solvent and sonicate noting the length just before the break point. The percentage
for complete extraction of the drug from the patch and elongation can be determined from the below-mentioned
made up to the mark with the same. The resulting solution formula:
was allowed to settle for about 1 h and the supernatant was
suitably diluted to give the desired concentration with the Elongation percentage = (L1 - L2) / L2 × 100 (4)
suitable solvent. The solution was filtered using a 0.2-µm
membrane, filtered and analyzed by a suitable analytical Where, L1 is the final length of each strip and L2 is the initial
technique (UV or HPLC), and the drug content per piece was length of each strip.[6]
to be calculated.[6]
Rolling ball tack test
Polariscope examination This test measures the softness of a polymer that relates
This test is to be performed to examine the drug crystals to talk. In this test, a stainless steel ball of 7/16 inches in
from the patch by a polariscope. A specific surface area of diameter is released on an inclined track so that it rolls down
the piece is to be kept on the object slide and observed for and comes in contact with the horizontal, upward facing
the drug crystals to distinguish whether the drug is present adhesive. The distance the ball travels along the adhesive
as a crystalline form or an amorphous form in the patch.[6] provides the measurement of tack, which is expressed in
inches.[6]
Shear adhesion test
This test is to be performed for measurement of the Quick stick (peel-tack) test
cohesive strength of an adhesive polymer. It can be In this test, the tape is pulled away from the substrate at
influenced by the molecular weight, the degree of cross- 90º at a speed of 12 inches/min. The peel force required to
linking and the composition of the polymer and the type break the bond between the adhesive and the substrate is
and amount of tackifier added. An adhesive-coated tape measured and recorded as tack value, which is expressed in
is applied onto a stainless steel plate; a specified weight ounces or grams per inch width.[6]
is hung from the tape to affect it, pulling in a direction
parallel to the plate. Shear adhesion strength is determined Probe tack test
by measuring the time it takes to pull the tape off the In this test, the tip of a clean probe with a defined surface
plate. The longer the time taken for removal, greater is roughness is brought into contact with the adhesive. And,
the shear strength.[6] when a bond is formed between the probe and the adhesive,
the subsequent removal of the probe mechanically breaks it.
Peel adhesion test The force required to pull the probe away from the adhesive
In this test, the force required to remove an adhesive at a fixed rate is recorded as tack, and it is expressed in
coating from a test substrate is referred to as peel adhesion. grams.[6]
168 Asian Journal of Pharmaceutics - July-September 2012
 Rastogi and Yadav: Transdermal drug delivery system: An overview

In vitro drug release studies Marketed transdermal system[22]

The paddle over disc method (USP apparatus V) can be Brand name Matrix or Duration of
employed for assessment of the release of the drug from the (active drug) membrane patch application
prepared patches. Dry films of known thickness are to be cut Alora (Estradiol) Matrix 3–4 days
into a definite shape, weighed and fixed over a glass plate Andoderm (Testosterone) Membrane 24 h
with an adhesive. The glass plate was then placed in 500 mL CatapresTTS (Clonidine) Membrane 7 days
of the dissolution medium or phosphate buffer (pH 7.4), and Climara (Estradiol) Matrix 7 days
the apparatus was equilibrated to 32 ± 0.5°C. The paddle Duragesic (Fentanyl) Membrane 72 h
was then set at a distance of 2.5 cm from the glass plate Esclim (Estradiol) Matrix 3–4 days
and operated at a speed of 50 rpm. Samples (5-mL aliquots) Estraderm (Estradiol) Membrane 3–4 days
can be withdrawn at appropriate time intervals up to 24 h Minitran (Nitroglycerin) Matrix 12–16 h
and analyzed by a UV spectrophotometer or HPLC. The Nicoderm CQ (Nicotine) Membrane 24 h
experiment is to be performed in triplicate, and the mean Nicotrol (Nicotine) Matrix 16 h
value can be calculated.[6] Nitradisc (Nitroglycerin) Matrix 24 h
Nitro-Dur (Nitroglycerin) Matrix 12–16 h
In vitro skin permeation studies Nitroglycerin Generic Matrix 12–16 h
An in vitro permeation study can be carried out by using Ortho-Evra (Norelgestromin Matrix 7 days
diffusion cells. Full-thickness abdominal skin of male / Ethynil estradiol)
Wistar rats weighing 200–250 g was selected. Hair from CombiPatch (Estradiol / Matrix 3–4 days
Norethindrone acetate)
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 0, 30, 60, 90 and 180 days and analyzed suitably for the
or blood vessels, equilibrated for 1 h in dissolution medium drug content.[6]
or phosphate buffer pH 7.4 before starting the experiment
and was placed on a magnetic stirrer with a small magnetic CONCLUSION
needle for uniform distribution of the diffusant. The
temperature of the cell was maintained at 32 ± 0.5°C using TDDS is a newer approach in the area of dosage forms for
a thermostatically controlled heater. The isolated rat skin many injected and orally delivered drugs having appropriate
piece is to be mounted between the compartments of the physicochemical and pharmacological properties. The TDD
diffusion cell, with the epidermis facing upward into the donor ensures that a pharmacologically active substance arrives at a
compartment. Definite volume of sample is to be removed relevant in vivo location with minimal side-effects. Because of
from the receptor compartment at regular intervals, and an the several advantages of the TDDS, many new researches are
equal volume of fresh medium is to be replaced. Samples going on to incorporate newer drugs in the system. Various
are to be filtered through the filtering medium, and can be devices that help in increasing the rate of absorption and
penetration of the drug are also being studied. TDDSs are
analyzed spectrophotometrically or by using HPLC. Flux can
heavily based on polymers, penetration enhancers, backing
be determined directly as the slope of the curve between the
laminates, plasticizers, liners to ensure good adhesion and
steady state values of the amount of drug permeated (mg/
controlled release of drug to systemic circulation via skin
cm2) versus time in hours, and permeability coefficients were
over a period of several hours or days. Transdermal patches
deduced by dividing the flux by the initial drug load (mg/cm2).[6]
can be divided into various systems, like reservoir system,
matrix system and microreservoir system. After preparation
Skin irritation study
of transdermal patches, consistent methodologies are
Skin irritation and sensitization testing can be performed
adopted to test the various parameters. Because of the recent
on healthy rabbits (average weight 1.2–1.5 kg). The dorsal
advances in technology and the incorporation of the drug
surface (50 cm2) of the rabbit is to be cleaned and the hair
to the site of action without rupturing the skin membrane,
is to be removed from the clean dorsal surface by shaving. the transdermal route is becoming the most widely accepted
Clean the surface by using rectified spirit and, then, the route of drug administration. This drug delivery overcomes
representative formulations can be applied over the skin. the challenges associated with current popular drug delivery;
The patch is to be removed after 24 h and the skin is to be thus, it shows a promising future. According to the duration
observed and classified into five grades on the basis of the of therapy, various drugs are commercially available in the
severity of the skin injury.[6] form of transdermal patches.
Stability studies REFERENCES
Stability studies are to be conducted according to the ICH
guidelines by storing the TDDS samples at 40 ± 0.5°C and 1. Tiwary AK, Sapra B, Jain S. Innovation in transdermal drug delivery:
75 ± 5% RH for 6 months. The samples were withdrawn at Formulation and techniques. Recent Pat Drug Deliv Formul 2007;1:23-36.

Asian Journal of Pharmaceutics - July-September 2012 169

 Rastogi and Yadav: Transdermal drug delivery system: An overview

2. Chong S, Fung HL, In: Hadgraft J, Guy RH, editors. Transdermal drug 19. Kumar TS, Selvam RP, Singh AK. Transdermal drug delivery systems for
delivery. development issues and research initiatives. New York: Marcel antihypertensive drugs. Int J Pharm Biomed Res 2010;1:1-8.
Dekker; 1989. p. 135-54. 20. Chien YW. Novel drug delivery systems, Drugs and the Pharmaceutical
3. Singh A, Singh MP, Alam G, Patel R, Vishvakarma D, Datt N. Expanding Sciences, Vol. 50. New York: Marcel Dekker; 1992. p. 797.
opportunities for transdermal delivery systems: An overview. J Pharm 21. Sugibayashi K, Morimoto Y. Polymers for transdermal drug delivery
Res 2011;4:1417-20. systems. J Control Release 1994;29:177-85.
4. Ansel HC, Allen LV and Popovich NG. Pharmaceutical dosage forms 22. Hadgraft J, Guy RH. Transdermal Drug Delivery. 2nd ed. New York:
and drug delivery system. 7th ed. New York: Lipponcott Williams and Marcel Dekker; 1989.
Wilkins; 2002. 23. Keleb E, Sharma RK, Mosa EB, Aljahwi A. Transdermal drug delivery
5. Patel RP, Baria AH. Formulation and evaluation consideration of system and evaluation. Int J Adv Pharm Sci 2010;1:201-11.
transdermal drug delivery system. Int J Pharm Res 2011;3:1-9. 24. Spencer TS, Smith SE, Conjeevaram S. Adhesive interactions between
6. Kumar JA, Pullakandam N, Prabu SL, Gopal V. Transdermal drug delivery polymers and skin in transdermal delivery systems. Polym Mater: Sci
system: An overview. Int J Pharm Sci Rev Res 2010;3:49-54. Eng 1990;63:337-9.
7. Jain NK. Advances in controlled and novel drug delivery. 1st ed. 25. Minghetti P, Cilurzo F, Tosi L, Casiraghi A, Montanari L. Design of a new
New Delhi: CBS Publishers and Distributors; 2001. p. 108-10. water-soluble pressure-sensitive adhesive for patch preparation. AAPS
8. Soni M, Kumar S, Gupta GD. Transdermal drug delivery: A novel Pharm Sci Tech 2003;4:9.
approach to skin permeation. J Pharm Res 2009;2:1184-90. 26. Tyle P. Drug Delivery device. 3rd ed. New York and Basel: Marcel Dekker;
9. Naik A, Kalia YN, Guy RH. Transdermal drug delivery: Overcoming the 2003.
skin’s barrier function. Pharm Sci Technol Today 2009;3:318-26. 27. Pfister WR, Sieh DS. Permeation Enhancer compatible with transdermal
10. Chandrashekhar NS, Shobha R. Physicochemical and pharmacokinetic drug delivery systems. Part I: Selection and Formulation consideration.
parameters in drug selection and loading for transdermal drug delivery. Med Device Technol 1990;1:48-55.
Indian J Pharm Sci 2008;70:94-5. 28. Godbey KJ. Improving patient comfort with non-occlusive transdermal
11. Merkle HP. Transdermal delivery systems. Methods Find Exp Clin backings. AAPS Pharm Sci Tech 1996;1-2.
Pharmacol 1989;11:135-53. 29. Walters KA. Transdermal drug delivery system In: Swarbick K, Boylan JC,
12. Brown L and Langer R. Transdermal delivery of drugs. Annu Rev Med editors. Encyclopedia of Pharmaceutical Technology. New York: Marcel
1988;39:221-9. Dekker; 1997. p. 253-93.
13. Arunachalam A, Karthikeyan M, Kumar DV, Prathap M, Sethuram S, 30. Foco A, Hadziabdic J, Becic F. Transdermal Drug Delivery Systems. Med
Kumar AS. Transdermal drug delivery system: A review. Curr Pharma Arch 2004;58:230-4.
Res 2010;1:70-81. 31. Sakalle P, Dwivedi S, Dwivedi A. Design, evaluation, parameters and
14. Flynn GL. Percutaneous Absorption. 3rd ed. New York: Marcel Dekker; marketed products of transdermal patches: A review. J Pharm Res
1985. 2010;3:235-40.
15. Hadgraft J. Skin Deep. Eur J Pharm Biopharm 2004;58:291-9. 32. Brahmankar DM, Jaiswal SB. Biopharmaceutics and pharmacokinetics
16. Singh MC, Naik AS, Sawant SD. Transdermal drug delivery systems A treatise. Delhi: Vallabh Prakashan; 1995. p. 335-71.
with major emphasis on Transdermal Patches: A review. J Pharm Res
2010;3:2537-43.
17. Aulton ME. Aulton’s Pharmaceutics The design and manufacture of
How to cite this article: Rastogi V, Yadav P. Transdermal drug delivery
medicine. 3rd ed. Churchill Livingstone: Elsevier; 2007. p. 567-8.
system: An overview. Asian J Pharm 2012;6:161-70.
18. Jain NK. Controlled and Novel Drug Delivery. New Delhi: CBS Publishers
and Distributors; 2002. p. 107. Source of Support: Nil. Conflict of Interest: None declared.

Announcement
Android App
A free application to browse and search the journal’s content is now available for Android based mobiles
and devices. The application provides “Table of Contents” of the latest issues, which are stored on the
device for future offline browsing. Internet connection is required to access the back issues and search
facility. The application is compatible with all the versions of Android. The application can be downloaded
from https://market.android.com/details?id=comm.app.medknow. For suggestions and comments do
write back to us.

170 Asian Journal of Pharmaceutics - July-September 2012