Introductio

Introduction

Transdermal Drug Delivery System

Transdermal drug delivery means that a pharmaceutical compound is moved across the
skin—the dermis—for subsequent systemic distribution. Hence, strictly semantically this
does not only include the more commonly understood “patch”, but also traditional
subcutaneous administration by means of a hypodermic needle and a syringe. The main
advantage of this approach is that the drug is entered into the body undistorted without
being passed through the body’s various defence systems. In contrast to oral
administration (e.g. swallowing a pill), the most convenient way of drug administration,
the transdermal route does not suffer from drug degradation in the gastrointestinal tract
and reduced potency through first-pass metabolism (i.e. in the liver). In addition, oral-
specific side-effects like liver damages are avoided, which are seen for example with
common drugs like estradiol (estrogen) or paracetamol (Panchagnula, 1997).

Transdermal delivery of medications was foreshadowed in earlier eras by the use of

certain plasters and ointments. The mustard plaster, applied as a home remedy for severe
chest congestion, may be considered as an example. Powdered mustard seeds (Brassica
nigra) were mixed with warm water, and the resulting paste was spread on a strip of
flannel, which was applied to the patient’s chest with a cloth binding wrapped around the
body to hold the plaster in place. The moisture and body warmth activated an enzyme
(myrosin) in the mustard that hydrolyzed a glycoside (sinigrin), causing the release of the
pungent active ingredient allyl isothiocyanate (CH2=CHCH2NCS). It is a low molecular
weight liquid, lipophilic, and effective at low dosage. The flannel served as an
impermeable backing and the mustard paste was the reservoir. Continuous enzymatic
action released the active substance over a period of hours, until the plaster was removed
(Scheindlin, 2004).

The history of plasters has been traced back to antiquity. In addition to mustard plasters,
several other plasters were recognized in early 20th century editions of the United States

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Pharmacopeia (USP) and National Formulary (NF). At one time, Belladonna Plaster,
containing 0.25–0.30% of belladonna root alkaloids, was believed to act transdermally as
an analgesic. Perhaps the most remarkable forerunner of modern transdermal medication
was stronger mercurial ointment, used as a treatment for syphilis (Scheindlin, 2004).
The past twenty five years have seen an explosion in the creation and discovery of new
medicinal agents. Related innovations in drug delivery systems have not only enabled the
successful implementation of many of these novel pharmaceuticals, but have also
permitted the development of new medical treatments with existing drugs. The creation
of transdermal delivery systems has been one of the most important of these innovations,
offering a number of advantages over the oral route. Therefore, the studies towards the
formulations capable of controlled release lead to development of recent advances of
transdermal drug delivery system products such as transdermal patches, transdermal
membranes, hydrogels, organogels and techniques such as iontophoresis and
sonophoresis to enhance the permeability of TDDS through skin (Prausnitz et al., 2004).

Transdermal drug delivery systems (TDDS) deliver therapeutic quantities of drug through
the skin into the systemic circulation for their general effects. In such systems, the drug
should penetrate across the skin to the underneath blood supply without drug
accumulation in the dermal area. The drug initially penetrates through stratum corneum –
the main rate limiting skin barrier and then passes through the deeper epidermis and
dermis. When drug reaches the dermal area, it becomes available for systemic circulation.
(Kim, 2007)

Several TDDS have been developed and introduced into the market place since
introduction of scopolamine in 1981. The early thinking of TDDS providing optimum
therapy with no and/or minimal side effects has changed during the last 15 years. One of
the main reasons for reasonable success of TDDS is due to patient convenience and
compliance. The main objective of TDDS is to delivery of drugs into systemic circulation
at a predetermined rate with no or minimal (statistically insignificant) interior intra-

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patient variation in transdermal absorption. Therefore the rate limiting step in transdermal
absorption is provided by TDDS rather than skin (Wester and Maibach, 1992).

Types of TDDS

Transdermal drug delivery systems are broadly classified into four types:
A. Polymer Membrane permeation-controlled TDD systems:
In this system, the drug reservoir is embedded between an impervious drug-impermeable
layer and a rate controlling membrane [Figure. 1.1 (A)]. The drug releases only through
the rate-controlling membrane, which can be microporous or non-porous. In the drug
reservoir compartment, the drug can be in the form of a solution, suspension, or gel or
dispersed in a solid polymer matrix. On the outer surface of the polymeric membrane a
thin layer of drug-compatible, hypoallergenic adhesive polymer can be applied.

B. Polymer Matrix Diffusion controlled TDD systems:

These are of two types:
I. Drug-in-adhesive system: The drug reservoir is formed by dispersing the drug in an
adhesive polymer and then spreading the medicated polymer adhesive by solvent casting
or by melting the adhesive (in the case of hot-melt adhesives) onto an impervious backing
layer [Figure. 1.1 (B)]. On top of the reservoir, layers of unmedicated adhesive polymer
are applied.

II. Matrix-dispersion system: The drug is dispersed homogeneously in a hydrophilic or

lipophilic polymer matrix. This drug containing polymer disc then is fixed onto an
occlusive base plate in a compartment fabricated from a drug-impermeable backing layer
[Figure. 1.1 (C)]. Instead of applying the adhesive on the face of the drug reservoir, it is
spread along the circumference to form a strip of adhesive rim.

C. Microreservoir systems: This drug delivery system is a combination of reservoir and

matrix-dispersion systems. The drug reservoir is formed by first suspending the drug in

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an aqueous solution of water-soluble polymer and then dispersing the solution
homogeneously in a lipophilic polymer to form thousands of unleachable, microscopic
spheres of drug reservoirs [Figure. 1.1 (D)]. The thermodynamically unstable dispersion
is stabilized quickly by immediately cross-linking the polymer in situ (Kandivli et al.,
2002).

D. Drug Reservoir Gradient-Controlled TDD Systems:

Polymer matrix drug dispersion type TDD systems can be modified to have the drug
loading level varying in an incremental manner, forming a gradient of drug reservoir
along the diffusional path across the multilaminate adhesive layers [Figure 1.1 (E)]. The
rate of drug released from this type of TDD system is gradient controlled. In this system,
the thickness of diffusional path through which drug molecules diffuse increases with
time. To compensate for this time-dependent increase in diffusional path length as a
result of drug depletion due to release, the drug loading level in the multi laminate
adhesive layers is also designed to increase proportionally (Chien, 1992).

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Figure 1.1(A-E): Representative designs of transdermal drug delivery systems

However, the major challenge in transdermal drug delivery system is to increase the
variety of drugs which can be administered. This market is dispersed amongst only
eighteen FDA-approved active agents: scopolamine, nitroglycerin, clonidine, estradiol-
norethindrone, fentanyl, nicotine, testosterone, ethinyl estradiolnorelgestromin,
oxybutynin, 17- estradiol, lidocaine, lidocaine-epinephrine, estradiol-levonorgestrel,
lidocaine-tetracaine, fentanyl HCl, methylphenidate, selegiline, rotigotine, and
rivastigmine. Only a small number of drugs are available using transdermal patch

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systems because of the low permeability of human skin (especially the outermost stratum
corneum layer) which limits daily drug dosage to about 10 mg via an acceptable sized
patch (Jadhav et al., 2009).

Although only a small numbers of drugs are currently used in transdermal systems, some
other drugs being investigated recently includes: diltiazem, isosorbide dinitrate,
propranolol, nifedipine, mepindolo, verapamil, levonorgestrel/esradiol, physostigmine,
xanomeline, naltrexone, methadone, buspirone, bupropion, and papaverine. Most of
drugs transdermally administered should be small in molecular mass, highly lipophilic
and require small dosages. Only a limited number of drugs have been successfully
delivered into the skin, so various methods for ensuring skin penetration such as
iontophoresis, electroporation, sonophoresis, stratum corneum ablation, microneedles,
and chemical enhancers have been investigated (Cosmas, 1996).

Advantages of transdermal drug delivery

Transdermal delivery is an attractive method to administer drugs that avoids the pain of
injection, reduces the enzymatic degradation associated with oral delivery, and facilitates
sustained delivery for up to many days. The other advantages are as follows:

 It can provide constant blood levels in the plasma for drugs with a narrow
therapeutic window, thus minimizing the risk of toxic side effect or lack of
efficacy.
 It can avoid first-pass metabolism in the gastrointestinal tract and liver, which
allows drugs with poor oral bioavailability and short biological half-lives to be
administered at most once a day, which can result in improved patient
compliance.
 It can also avoid the problems of the gastrointestinal environment, such as
chemical degradation of the drug and gastric irritation.

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 It can provide a non-invasive alternative to parenteral, subcutaneous and
intramuscular injections. The application of a patch-like device to the skin surface
is a procedure that allows continuous intervention.
 It can provide predictable and extended duration of activity to reduce the
frequency of dosage and minimize inter- and intra-patient variation.
 The large and readily accessible surface area (1-2 m 2) of skin allows many
placement options for transdermal absorption.
 It is suitable for patients who are unconscious or vomiting and rely on self
administration.

Limitations of transdermal drug delivery Systems (Kim, 2007)

In spite of the abundant advantages of transdermal delivery systems, there are some
obstacles to its widespread applications, which include:
 TDDS cannot deliver ionic drugs.
 TDDS cannot achieve high drug levels in blood/plasma.
 TDDS for drugs of large molecular size cannot be developed.
 TDDS cannot deliver drugs in a pulsatile fashion.
 If any drug or formulation causes irritation to skin, TDDS cannot be developed.
 Transdermal transport of molecules is slow due to low permeability of the stratum
corneum, the uppermost layer of the skin.
 There is possibility of adverse skin reactions known as contact allergic dermatitis.
The limitations of TDDS due to ionic drugs, large molecular weight drugs and delivery in
a pulsatile fashion can be overcome to some extent by novel approaches such as
iontophoresis, electroporation and ultrasound.

Skins

Human Skin

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Structure and anatomy of human skin
Skin is one of the largest organs of the body. It consists of two parts: the cellular
outermost layer, epidermis, and the inner connective tissue layer, dermis. Lying between
these two layers is a microscopic structure, the basal lamina or basement membrane zone
as shown in Figure 1.5 (Millet et al., 1997).

The epidermis is composed of two parts: the living cells of the malpighian layer and the
dead cells of the stratum corneum commonly referred to as the horny layer. The prime
function of the viable cells of the epidermis is to move progressively through a process of
differentiation, eventually expiring to generate the barrier layer of stratum corneum. The
epidermis is a continually self-renewing, stratified squamous epithelium covering the
entire outer surface of the body. Over most of the body the epidermis ranges in thickness
from 0.06 to 0.1 mm (Borgia et al., 2008).

Different layers of epidermis are shown in Figure. 1.6. The stratum corneum is the end
product of epidermal differentiation and consists of 15 to 25 cell layers over most of the
body surface. The corneocyte is the largest cell in the stratum corneum, approximately
0.5 μm in thickness and 30 to 40 μm in width.

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Figure 1.5: Schematic representation of the skin.

Figure 1.6: Different layers of epidermis.

It contains no organelles but is filled with protein, 80% of which is high molecular-
weight keratin. The intercellular space is filled with lipids organized into multiple
bilayers. Approximately 14 % of the stratum corneum, by weight, is lipids. In addition,
stratum corneum has very low water content. Formation of the stratum corneum is also
accompanied by the deposition of a 15 nm thick band of protein on the inner surface of
the plasma membrane, the cornified cell envelope, a structure unique to keratinocytes and
a hallmark of the terminal differentiation (Yamashita et al., 2003).

The natural function of the skin is to protect the body against exogenous material,
dehydration, and environmental stress. The major barrier towards inward and outward

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diffusion of compounds is the outermost layer of the skin, stratum corneum. Stratum
corneum consists of lipid-depleted and keratinized cells (corneocytes) embedded in a
lamellar lipid-rich interstitium. Unique lipid arrangements which occupy the space of
stratum corneum play a critical role in establishing the barrier function and in
maintaining cohesion between corneocytes (Godin et al., 2007).

Percutaneous Absorption
Percutaneous absorption is defined as penetration of substances into various layers of
skin and permeation across the skin into systemic circulations. The percutaneous
absorption is a step-wise process and can be divided into three parts:

 Penetration is the entry of a substance into a particular layer.

 Permeation, is the penetration from one layer into another, and is different both
functionally and structurally from the first layer.
 Absorption is the uptake of a substance into systemic circulation.

The stratum corneum is a wall-like structure with protein bricks and lipid mortar. The
lipid matrix (keratin-phospholipid complex) of the stratum corneum plays a significant
role in determining the permeability of substances across the skin. This is supported by
the evidence from controlled stripping experiments, electron microscopy studies, and also
from the analysis of penetration and permeation data (Liu et al., 1993).

Routes of Skin Permeation

When a drug system is applied topically, the drug diffuses out of its vehicle onto the
surface tissues of the skin. There are three potential portals of entry: through the follicular
region, through the sweat ducts, or through the unbroken stratum corneum between these
appendages. Figures 1.7 and 1.8 illustrates the various possible macro and micro routes of
drug permeation across intact skin respectively. The transappendageal route transports
substances via the sweat glands and the hair follicles with their associated sebaceous
glands. The transepidermal route across the continuous stratum corneum comprises
transport via intracellular and intercellular spaces. Both polar and non-polar substances

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diffuse via transcellular and intercellular routes by different mechanisms. The polar
molecules mainly diffuse through the polar pathway consisting of “boundwater” within
the hydrated stratum corneum, whereas the non-polar molecules dissolve and diffuse
through the non-aqueous lipid matrix of the stratum corneum (Lieberman et al., 1970).
 Transappendageal route
 Transepidermal route

Transepidermal Route
Transepidermal transport means that molecules cross the intact horny layer. Two
potential micro-routes of entry exist, the transcellular (or intracellular) and the
intercellular pathways (Figure). Both polar and non-polar substances diffuse via transcel I
u lar and intercellular routes by different mechanisms's.
The polar molecules mainly diffuse through the polar pathway consisting of "bound
water" within the hydrated stratum corneum whereas the non-polar molecules dissolve
and diffuse through the non-aqueous lipid matrix of the stratum corneum. Thus the
principal pathway taken by a penetrant is decided mainly by the partition coefficient (log
K). Hydrophilic drugs partition preferentially into the intracellular domains, whereas
lipophilic permeants (octanollwater log K > 2) traverse the stratum corneum via the
intercellular route. Most molecules pass the stratum corneum by both routes (Ghosh et al
1997: Mishra. 2002. Daniels, 2004).

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Figure 1.7: Possible macro routes for drug penetration across human skin (1.Entry
through sweat duct, 2.Entry through stratum corneum, 3. Follicular entry)

Transfollicular route (shunt pathway)

This route comprises transport via the sweat glands and the hair follicles with their
associated sebaceous glands. 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. This route seems to be most important for ions
and large polar molecules which hardly permeate through the stratum corneum (Ghosh et
al 1997: Mishra. 2002).

Figure 1.8: Possible micro routes for drug penetration across human skin intercellular

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or transcellular.

Factors Affecting Penetration and Permeation

The factors which influence transdermal absorption are very complex in nature and act in
a mutually dependent manner. The clinical response after TDDS application is a step-
wise process:
1. Release of drug from formulation
2. Penetration into and permeation across the skin
3. Activation of pharmacological response
The factors influencing the transdermal absorption include biological characteristics of
skin, physicochemical characteristics of drug and vehicle, and the dosing conditions
(Raabe et al., 2005).

(A) Biological factors

The biological factors viz. thickness of the skin, regional site, age, blood flow rate and
skin conditioning can influence the penetration and permeation. Skin permeability can be
altered by physical (ultraviolet, infrared or ionizing radiation), chemical (solvents,
detergent, acids, and alkalis), and pathological conditions, such as mechanical damage
and skin diseases. Mixtures of polar and non-polar solvents can delipidize the skin,
triglyceride minimal lipid forming artificial shunts in the skin (Tfayli et al., 2007).

(B) Physicochemical factors

In addition to the structure of the stratum comeum through which transdermal absorption
occurs, the physicochemical properties of both the drug and the vehicle play an important
role in determining the percutaneous absorption. These factors include the molecular
properties of the drug and the vehicle. Transdermal absorption is also dependent on the
molecular weight, size, structure, partition coefficient, pH of the drug solution in the
vehicle, and the concentration of the drug on the surface of the skin in addition to the
nature and effect of the vehicle, and other chemicals present in the vehicle which may act

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as sorption promoters. Role of individual factors and their interplay on penetration and
permeation is an important area in the field of dermal/TDDS (Bouwstra et al., 2001).

It can be concluded that along with the stratum corneum structure, factors such as
thickness of the skin, regional site, age, blood flow rate and molecular properties of the
drug and the vehicle also play an important role in determining the percutaneous
absorption.

Human cadaver skin is utilized in hospitals and research laboratories for treatment of
burn wounds and to study percutaneous absorption and transdermal delivery. Human
cadaver skin is not an easily obtained commodity, and storage for use becomes a
necessity. Skin storage maintenance and confirmation of skin viability is especially
important for the absorption process where the in vivo situation is simulated. Amputated
human skin can be used immediately or can be stored at -24 0C for a long time. The
permeability property of skin is retained even after several days of death, if tissue is
frozen for a long time. Dead skin retains its impermeability well (Wester et al., 1997).

In 1993, Liu et al., evaluated variations in permeation of ionic and neutral compounds
through human skin and concluded that different mechanisms are involved in the in vitro
skin transport for ionic and neutral compounds. In 2002, Shah et al., developed and
evaluated verapamil transdermal drug delivery system and found that steady-state plasma
concentration for total verapamil equivalent (verapamil+norverapamil) was proportional
to the surface area of the delivery System and the amount of verapamil released.

In 2003, Gondaliya et al., formulated and evaluated controlled release transdermal

delivery system of bupropion and pointed out that the conversion of hydrochloride salt to
free base increases the lipophilicity of the permeant molecules. Polar nature and low skin
permeability of the hydrochloride salt make it unsuitable for transdermal application. In
2004, Kwon et al., studied in vitro evaluation of transdermal drug delivery by a micro-
needle transdermal patch and found that micro-needle patches composed of drug in a

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fast-dissolving matrix can enhance transdermal delivery by 2.5 – 12 folds by creating
micro- channels into skin.

In 2005, Rana et al., formulated and compared the permeation characteristics of chitosan
films with human cadaver epidermis and came to the result that chitosan films cross-
linked with sodium citrate can simulate in vitro permeation of polar and non polar drugs
across human epidermis. Mittal et al., in 2009, formulated and evaluated monolithic
matrix polymer films for transdermal delivery of nitrendipine and found that polymeric
combination containing Eudragit RL 100: PVP 30 in a ratio of 4:6 showed the best
results.

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