978-3-659-16382-1 Novel

Sudip DebhaIh
Ashoke Saha
1ransdermaI Drug DeIivery
5ysIem
1o deliver drugs ihIo sysIemic circulaIioh Ihrough
skih
Durihg Ihe pasI !ew years, ihIeresI ih Ihe developmehI o! hovel drug
delivery sysIems !or exisIihg drug molecules has beeh rehewed. 1he
developmehI o! a hovel delivery sysIem !or exisIihg drug molecules hoI
ohly improves Ihe drug's per!ormahce ih Ierms o! e!!icacy ahd sa!eIy buI
also improves paIiehI compliahce ahd overall IherapeuIic behe!iI Io a
sighi!icahI exIehI. 1rahsdermally delivered drugs avoid Ihe risk ahd
ihcohvehiehce o! ihIravehous Iherapy, usually provide less chahce o! ah
overdose or uhderdose, allow easy IermihaIioh, ahd permiI boIh local ahd
sysIemic IreaImehI e!!ecIs. 1rahsdermal drug delivery o!!ers cohIrolled
release o! Ihe drug ihIo Ihe paIiehI, iI ehables a sIeady blood level pro!ile,
resulIihg ih reduced sysIemic side e!!ecIs ahd, someIimes, improved e!!icacy
over oIher dosage !orms. 1he maih ob|ecIive o! Irahsdermal drug delivery
sysIem is Io deliver drugs ihIo sysIemic circulaIioh Ihrough skih aI
predeIermihed raIe wiIh mihimal ihIer ahd ihIra paIiehI variaIioh. 1he
growIh raIe !or Irahsdermal drug delivery sysIems is expecIed Io ihcrease
12% ahhually by 2007.
5udip DebnaIh
Sudip DebhaIh is currehIly pursuihg MSc ih Medical
Cell 8iology aI UhiversiIy o! 8ergeh, Norway. Prior Io
IhaI he did his 8Sc ahd MS !rom 8iochemisIry ahd
Molecular 8iology, UhiversiIy o! Dhaka. He had more
Ihah Ihree years o! pro!essiohal experiehce ih Eskaye!
8ahgladesh LimiIed. 8esides academic acIiviIies,
DebhaIh is closely ihvolved Io research
978-3-659-16382-1
5udip DebnaIh
Ashoke 5aha
1ransdermaI Drug DeIivery 5ysIem
5udip DebnaIh
Ashoke 5aha
1ransdermaI Drug DeIivery 5ysIem
1o deIiver drugs inIo sysIemic circuIaIion Ihrough
skin
LAP LAMF1 Academic PubIishing
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CONTENTS
Topic
Page
LIST OF TABLES
LIST OF FIGURES
NOMENCLATURES
INTRODUCTION 1
DEFINITION AND OBJECTIVES 3
TYPES OF TRANSDERMAL PATCHES 3
BASIC COMPONENTS OF TRANSDERMAL DRUG DELIVERY
SYSTEMS
5
HUMAN SKIN 10
BASIC PRINCIPLES OF TRANSDERMAL PERMEATION 11
MECHANISMS OF RATE-CONTROLLED TRANSDERMAL
DRUG DELIVERY
13
VARIOUS METHODS FOR PREPARATION TDDS 15
EVALUATION PARAMETERS 17
POLYMERS IN TRANSDERMAL DRUG DELIVERY SYSTEM 22
LATEST TECHNIQUES OF IMPROVING PERMEATION FOR
TDDS
29
ADVANTAGES OF TRANSDERMAL DRUG DELIVERY
SYSTEMS
34
LIMITATIONS OF TRANSDERMAL DRUG DELIVERY
SYSTEMS
35
IDEAL PRODUCT REQUIREMENTS 35
MOST POPULAR TDDS USED WORLDWIDE 36
RECENT DEVELOPMENTS IN TRANSDERMAL DRUG
DELIVERY
37
THE FUTURE OF TRANSDERMAL DRUG DELIVERY 38
CONCLUSION 39
REFERENCES 40
LIST OF TABLES
Table No. Title Page
Table 1 Techniques of polymer matrix. 6
Table 2 Structure of skin. 11
Table 3 Factors affecting transdermal permeation 12
Table 4 List of Polymers and Manufacturers in Transdermal Drug
Delivery System.
25
Table 5 Glass Transition Temparatures (Tg) for Acrylic Polymers. 27
LIST OF FIGURES
Figure No. Title Page
Figure 1 Representative designs of transdermal drug delivery
systems.
4
Figure 2 Different layers of TDDS. 9
Figure 3 Various routes of drug absorption. 10
Figure 4 Plasma drug concentration of TDDS. 14
Figure 5 Controlled Drug Release Mechanism. 23
NOMENCLATURES
TDDS- Transdermal Drug Delivery System.
HPC- Hydroxy Propyl Cellulose.
SC- Stratum Corneum.
PEG- Poly Ethylene Glycol.
EVAC- Ethylene Vinyl Acetate Copolymer.
TPX- poly(4-methyl-1 pentene)
HPLC- High Performance Liquid Chromatography.
IPM- Isopropyl Myristate.
INTRODUCTION

During the past Iew years, interest in the development oI novel drug delivery systems Ior
existing drug molecules has been renewed. The development oI a novel delivery system Ior
existing drug molecules not only improves the drug`s perIormance in terms oI eIIicacy and
saIety but also improves patient compliance and overall therapeutic beneIit to a signiIicant
extent (Garg et al., 2003).

When properly designed and developed Ior a particular drug, novel delivery system can
overcome speciIic hurdles associated with conventional methods oI delivery, e.g., drugs that
undergo partial or complete degradation beIore reaching the site oI action could be
eIIectively delivered with improved bioavailability by using the novel concepts oI timed or
pulsatile release, or gastro-resistant delivery (Jain et al., 2002).

During the past 20 years, advances in drug Iormulations and innovative routes oI
administration have made. Our understanding oI drug transport across tissues has increased.
While topical products or drug delivery systems have been used Ior centuries Ior the
treatment oI local skin disorders, the use oI the skin as a route Ior systemic drug delivery is
oI relatively recent origin (Corrigan., Transdermal Drug Delivery Systems). The
administration oI drugs by transdermal route oIIers the advantage oI being relatively
painless. The appeal oI using the skin as a portal oI drug entry lies in case oI access, its huge
surIace area, and systemic access through underlying circulatory and lymphatic networks
and the noninvasive nature oI drug delivery. Delivery oI drugs through the skin Ior systemic
eIIect, called transdermal delivery was Iirst used in 1981, when Ciba-Geigy marketed
Transderm V (present day marketed as Transderm Scop) to prevent the nausea and vomiting
associated with motion sickness (Ghosh et al., 1993).

Throughout the past 2 decades, the transdermal patch has become a proven technology that
oIIers a variety oI signiIicant clinical beneIits over other dosage Iorms (Ryan D.G. and
Peterson et al., 2003). It constitutes a new trend in controlled delivery system and has
opened new scientiIic horizon in innovations. The delivery oI drugs transdermally (through
the skin) provides several important advantages over traditional oral and intravenous
delivery routes.
A Review on Transdermal Drug Delivery system
2
Continuous intravenous inIusion is recognized as a superior mode oI drug administration
not only to bypass hepatic "Iirst-pass" metabolism, but also to maintain a constant and
prolonged drug level in the body. A closely monitored intravenous inIusion can provide the
advantages oI both direct entry oI drug into the systemic circulation and control oI
circulating drug levels. However, such mode oI drug administration entails certain risks and,
thereIore, necessitates hospitalization oI the patients and close medical supervision oI
administration.
Recently, it is becoming evident that the beneIits oI intravenous drug inIusion can be
closely duplicated, without its hazards, by using the skin as the port oI drug administration
to provide continuous transdermal drug inIusion into the systemic circulation.
Transdermally delivered drugs avoid the risk and inconvenience oI intravenous therapy,
usually provide less chance oI an overdose or underdose, allow easy termination, and permit
both local and systemic treatment eIIects. Transdermal drug delivery oIIers controlled
release oI the drug into the patient, it enables a steady blood level proIile, resulting in
reduced systemic side eIIects and, sometimes, improved eIIicacy over other dosage Iorms
(Soni et al., 1992; Chong et al., 1989). The main objective oI transdermal drug delivery
system is to deliver drugs into systemic circulation through skin at predetermined rate with
minimal inter and intra patient variation. The growth rate Ior transdermal drug delivery
systems is expected to increase 12 annually by 2007 (Transdermal Drug Delivery Systems
Report, 1992). To provide continuous drug inIusion through an intact skin, several
transdermal therapeutic systems have been developed Ior topical application onto the intact
skin surIace to control the delivery oI drug and its subsequent permeation through the skin
tissue. It is exempliIied by the development and marketing oI scopolamine-releasing
transdermal therapeutic system Ior 72-hr prophylaxis or treatment oI motion-induced
nausea, oI nitroglycerin and isosorbide dinitrate-releasing trans-dermal therapeutic systems
Ior once-a-day medication oI angina pectoris, and oI clonidine-releasing transdermal
therapeutic system Ior weekly treatment oI hypertension . The intensity oI interests in the
potential biomedical applications oI transdermal controlled drug administration is
demonstrated in the increasing research activities in a number oI health care institutions in
the development oI various types oI transdermal therapeutic systems Ior long term
continuous inIusion oI therapeutic agents, including antihypertensive, anti-anginal, anti-
histamine, anti-inIlammatory, analgesic, anti-arthritic, steroidal, and contraceptive drugs.
3
DEFINITION AND OBJECTIVES
Transdermal Drug Delivery System
Transdermal drug delivery system is design to provide the passage oI drug substances Irom
the surIace oI the skin, through its various layers and into the systemic circulation.

The basic objectives oI transdermal dosage Iorm design are to:

Optimize drug therapy by establishing relatively constant blood level.
Release the drug according to pharmacokinetically rational rate to the intact skin Ior
systemic absorption.
Optimize the selectivity oI drug action and minimizing the number oI undesirable
side eIIects as well as their severity and incidence.
Provide a predictable and extended duration oI action.
Reduce the disincentives to regimen compliance by patients.
Minimize the inconvenience oI patient remedication.
Provide a therapeutic advantage over other drug delivery systems.
Stimulate innovation and therapeutic use oI established but unpatented drugs and
natural substances.

TYPES OF TRANSDERMAL PATCHES
There are various types oI Transdermal Patches described below (shown in Figure 1):
a) Single layer drug in adhesive
In this type the adhesive layer contains the drug. The adhesive layer not only serves to
adhere the various layers together and also responsible Ior the releasing the drug to the skin.
The adhesive layer is surrounded by a temporary liner and a backing (Willams A.C. et al.,
2004).
b) Multi-layer drug in adhesive
This type is also similar to the single layer but it contains an immediate drug release layer
and other layer will be a controlled release along with the adhesive layer (Pellet M et al.,
2003). The adhesive layer is responsible Ior the releasing oI the drug. This patch also has a
temporary liner-layer and a permanent backing.
4
c) Vapour patch
In this type oI patch the role oI adhesive layer not only serves to adhere the various layers
together but also serves as release vapour. The vapour patches are new to the market,
commonly used Ior releasing oI essential oils in decongestion. Various other types oI vapor
patches are also available in the market which are used to improve the quality oI sleep and
reduces the cigarette smoking conditions.
d) Reservoir system
In this system the drug reservoir is embedded between an impervious backing layer and rate
controlling membrane (Brown M.B et al., 2000). The drug releases only through the rate
controlling membrane, which can be micro porous or non porous. In the drug reservoir
compartment, the drug can be in the Iorm oI a solution, suspension, gel or dispersed in a
solid polymer matrix. Hypoallergenic adhesive polymer can be applied as outer surIace
polymeric membrane which is compatible with drug.

Figure 1: Representative designs oI transdermal drug delivery systems.

e) Matrix system
i. Drug-in-adhesive system
In this type the drug reservoir is Iormed by dispersing the drug in an adhesive polymer and
then spreading the medicated adhesive polymer by solvent casting or melting (in the case oI
hot-melt adhesives) on an impervious backing layer. On top oI the reservoir, unmediated
adhesive polymer layers are applied Ior protection purpose.

ii. Matrix-dispersion system
In this type the drug is dispersed homogenously in a hydrophilic or lipophilic polymer
matrix. This drug containing polymer disk is Iixed on to an occlusive base plate in a
5
compartment Iabricated Irom a drug impermeable backing layer. Instead oI applying the
adhesive on the Iace oI the drug reservoir, it is spread along with the circumIerence to Iorm
a strip oI adhesive rim.

f) Microreservoir system
In this type the drug delivery system is a combination oI reservoir and matrix-dispersion
system. The drug reservoir is Iormed by Iirst suspending the drug in an aqueous solution oI
water soluble polymer and then dispersing the solution homogeneously in a lipophilic
polymer to Iorm thousands oI unreachable, microscopic spheres oI drug reservoirs. This
thermodynamically unstable dispersion is stabilized quickly by immediately cross-linking
the polymer in situ by using cross linking agents.

BASIC COMPONENTS OF TRANSDERMAL DRUG DELIVERY SYSTEMS

1. Polymer matrix
Polymer is an integral and Ioremost important component oI transdermal drug delivery
systems. DiIIerent classes oI polymeric materials have been used to achieve rate controlled
drug delivery. The mechanism oI drug release depends upon the physicochemical properties
oI the drug and polymer used in the manuIacture oI the device. The Iollowing criteria
should be satisIied Ior a polymer to be used in a transdermal system:
Molecular weight, glass transition temperature, chemical Iunctionality or polymer
must allow diIIusion and release oI the speciIic drug.
The polymer should permit the incorporation oI a large amount oI drug.
The polymer should not react, physically or chemically with the drug
The polymer should be easily manuIactured and Iabricated into the desired product
and in expensive.
The polymer must be stable and must not decompose in the presence oI drug and
other excipients used in the Iormulation, at high humidity conditions, or at body
temperature.
Polymers and its degradation products must be non toxic.
No single material may have all these attributes; e.g., cosolvents such as ethanol, propylene
glycol, PEG 400 could be added to increase drug solubility. Various techniques which are
6
employed to modiIy the polymer properties and thus drug release rates (Patani et al., 1999,
Aslani et al., 1996)

Table 1: Techniques oI polymer matrix.
Techniques Description
Cross linked
polymers
The higher the degree oI cross linking, the more dense the polymer
and slower the diIIusion oI drug molecules through the matrix.
Polymer blends Polymers have been blended on varying ratios to combine the
advantages oI the individual polymers. Advantages oI polymer
blends include easy Iabrication oI devices, manipulation oI drug
loading and other devices properties such as hydration, degradation
rate and mechanical strength.
Plasticizers Plasticizers have been known to reduce the stiIIness oI the polymer
backbone, thereby increasing the diIIusion characteristics oI the
drug. Commonly used plasticizers are polyethylene glycol,
propylene glycol, glycerol, dibutyl phthalate.

2. Drug substance
The selection oI drug Ior transdermal drug delivery depends upon various Iactors. For
developing a transdermal drug delivery system, the drug has to be chosen with great care.
Following are some oI the desirable properties oI a drug suitable Ior transdermal delivery.
The drug should have a molecular weight less than approximately 1000 Daltons. The drug
should have aIIinity Ior bothlipophilic and hydrophilic phases. Extreme partitioning
characteristics are not conducive to successIul drug delivery via the skin. The drug should
have low melting point. Along with these properties the drug should be potent, having short
halI liIe and be nonirritating.

3. Physicochemical properties
The drug should have some degree oI solubility in both oil and water (ideally greater
than 1 mg/ml).
The substance should have melting point less than 200 F (Jayaswal et al., 1987).
Concentration gradient across the membrane is directly proportional to the log
7
solubility oI drug in the lipid phase oI membrane, which in turn is directly
proportional to the reciprocal oI melting point (in degree absolute oI the drug). In
order to obtain the best candidates Ior TDD, an attempt should be made to keep the
melting point as low as possible.
Substances having a molecular weight oI less than 1000 units are suitable.
A saturated aqueous solution oI the drug should have a pH value between 5 and 9.
Drugs highly acidic or alkaline in solution are not suitable Ior TDD (Finnin et al.,
1999); because they get ionized rapidly at physiological pH and ionized materials
generally penetrate the skin poorly.
Hydrogen bonding groups should be less than 2.

4. Biological properties (Misra et al., 2002)
Drug should be very potent, i.e., it should be eIIective in Iew mgs per day (ideally
less than 25 mg/day).
The drug should have short biological halI liIe.
The drug should be non irritant and non allergic to human skin.
The drug should be stable when in contact with the skin.
The drug should not stimulate an immune reaction to the skin.
Tolerance to drug must not develop under near zero order release proIile oI
transdermal delivery.
The drug should not get irreversibly bound in the subcutaneous tissue.
The drug should not get extensively metabolized in the skin.

5. Penetration enhancers
These are the compounds, which promote skin permeability by altering the as a barrier to
the Ilux oI a desired penetrant and are considered as an integral part oI most transdermal
Iormulations. To achieve and maintain therapeutic concentration oI drug in the blood, the
resistance oI skin to diIIusion oI drugs has to be reduced in order to allow drug molecules to
cross skin and to maintain therapeutic levels in blood. They can modiIy the skin`s barrier to
penetration either by interacting with the Iormulation that applied or with the skin itselI
(Patani et al., 1999).
The penetration enhancer should be pharmacologically inert, non toxic, non allergenic, non-
irritating and ability to act speciIically, reversibly and Ior predictable duration. It should not
cause loss oI body Iluids, electrolytes or other endogeneous materials.
8
These may conveniently be classiIied under the Iollowing main headings:

a. Solvents
These compounds increase penetration possibly by swelling the polar pathway. Examples
include water alcoholsmethanol and ethanol; alkyl methyl sulIoxidesdimethyl sulIoxide,
alkyl homologs oI methyl sulIoxide, dimethyl acetamide and dimethyl Iormamide;
pyrrolidones2 pyrrolidone, N-methyil, 2-pyrrolidone; laurocapram (Azone) miscellaneous
solventspropylene glycol, glycerol, silicone Iluids, isopropyl palmitate.

b. Surfactants
These compounds are proposed to enhance polar pathway transport, especially oI
hydrophilic drugs. The ability oI a surIactant to alter penetration is a Iunction oI the polar
head group and the hydrocarbon chain length. These compounds are, however, skin
irritants, thereIore, a balance between penetration enhancement and irritation has to be
considered. Anionic surIactants can penetrate and interact strongly with the skin. Examples
oI commonly used surIactants are:
Anionic surfactants
Dioctyl sulphosuccinate, Sodium lauryl sulphate, Decodecylmethyl sulphoxide etc.
Nonionic surfactants
Pluronic F127, Pluronic F68 etc.
Bile salts
These systems apparently open up the heterogeneous multi-laminate pathway as well as the
continuous pathways. Examples include: propylene glycol-oleic acid and 1, 4-butane diol-
linoleic acid.

c. Miscellaneous chemicals
These include urea, a hydrating and keratolytic agent; N, N-dimethyl-m-tolumide; calcium
thioglycolate; anti-cholinergic agents.

6. Drug reservoir components
It must be compatible with the drug and must allow Ior drug transport at the desired rate. II
an ointment is used, the drug reservoir must possess the desired viscosity attributes to
ensure reliable manuIacturing process. It must possess the desired adhesive and cohesive
9
properties to hold the system together. Materials used are: mineral oils, polyisobutylene, and
colloidal silica, HPC.

Figure 2: DiIIerent layers oI TDDS.
7. Backing laminates
The primary Iunction oI the backing laminate is to provide support. They should be able to
prevent drug Irom leaving the dosage Iorm through top. They must be impermeable to drugs
and permeation enhancers. They should a low moisture vapor transmission rate. They must
have optimal elasticity, Ilexibility, and tensile strength. They must be chemically
compatible with the drug, enhancer, adhesive and other excipients. They must be relatively
inexpensive and must allow printing and adhesive lamination. Type backing membranes are
composed oI a pigmented layers, an aluminium vapor coated layer, a plastic Iilm
(polyethylene, polyvinyl chloride, polyester) and a heat seal layer.

8. Rate controlling membrane
Rate controlling membranes in transdermal devices govern drug release Irom the dosage
Iorm. Membranes made Irom natural polymeric material such as chitosan show great
promise Ior use as rate controlling membranes. Recently composite poly-2-hydroxyethyl
methacrylate membranes have been evaluated as rate controlling barriers Ior transdermal
application (Sun et al., 1997).
10
9. Adhesive layer
The Iasting oI all transdermal devices to the skin using a pressure sensitive adhesive that
can be positioned on the Iace or in the back oI device is necessary. It should not cause
irritation, sensitization or imbalance in the normal skin Ilora during its contact with the skin.
It should adhere to the skin aggressively. The three major classes oI polymers evaluated Ior
potential medical applications in TDDS include:
Polyisobutylene type pressure sensitive adhesives.
Acrylic type pressure sensitive adhesives.
Silicone type pressure sensitive adhesives.

10. Release liners
The release liner has to be removed beIore the application oI transdermal system, and it
prevents the loss oI the drug that has migrated into the adhesive layer during storage. It also
helps to prevent contamination. It is composed oI a base layer, which may be nonocclusive
or occlusive, and a release coating layer made oI silicon or TeIlon. Other materials include
polyesters, Ioil, Mylar and metallized laminates.

FUNCTION OF HUMAN SKIN

The skin plays an important role in the transdermal drug delivery system. The skin oI an
average adult body covers a surIace area oI approximately 2 sq. m. and receives about one
third oI the blood circulating through the body and serves as a permeability barrier against
the transdermal absorption oI various chemical and biological agent (Shridevi et al., 1991).
Figure 3 shows diIIerent pathways oI drug delivery

Figure 3: Various routes oI drug absorption.
11
Table 2: Structure oI skin.
Layers Properties
The epidermis It is 100 m thick.
It contains various layers. The stratum germinativum is the
basal layer. Above the basal layer are the stratum spinosum, the
stratum granulosum, the stratum lucidum, and Iinally, the
stratum corneum (SC).
SC is the rate limiting barrier that restricts the inward and
outward movement oI chemical substances consists oI Ilattened
keratin-Iilled cells (e.g., corneocytes). Upon reaching the SC,
these cells are corniIied and Ilatten. The corneocytes are then
sloughed oII the skin at a rate oI about one cell layer per day, a
process called desquamation.
The main source oI resistance to penetration and permeation
through the skin is the SC.
The dermis It contains blood and lymphatic vessels, nerve endings,
pilosebaceous units (hair Iollicles and sebaceous glands) and
sweat glands (eccrine and apocrine).
It provides physiological support Ior the epidermis.
It is typically 3-5 mm thick and is the major component oI
human skin.
It is composed oI a network oI connective tissue, predominantly
collagen Iibrils providing support and elastic tissue providing
Ilexibility, embedded in a mucopolysaccharide gel (Wilkes et
al., 1973).
It provides a minimal barrier to the delivery oI most polar
drugs, although the dermal barrier may be signiIicant when
delivering highly lipophilic molecules.
The
subcutaneous
Iat layer
It bridges between the overlying dermis and the underlying
body constituents.
It is relatively thick in order oI several millimeters.
The layer oI adipose tissue serves to insulate the body and to
provide mechanical protection against physical shock.
It also provide supply oI high energy molecules
Principal blood vessels and nerves are carried to the skin in this
layer

BASIC PRINCIPLES OF TRANSDERMAL PERMEATION
Transdermal permeation is based on passive diIIusion. BeIore a topically applied drug can
act either locally or systemically, it must penetrate the stratum corneumthe skin permeation
barrier (Misra et al., 2002). In the initial transient diIIusion stage drug molecules may
penetrate the skin along the hair Iollicles or sweat ducts and then absorbed through the
12
Iollicular epithelium through the intact stratum corneum becomes the primary pathway Ior
transdermal permeation. The release oI a therapeutic agent Irom a Iormulation applied to the
skin surIace and its transport to the systemic circulation is a multistep process, which
involves (Walters., Dermatological and Transdermal Formulations, Vol. 119, 1-25)
Dissolution with in and release Irom the Iormulation.
Partitioning into the skin`s outermost layer, the stratum corneum.
DiIIusion through the SC, principally via a lipidic intercellular pathway.
Partitioning Irom the SC into the aqueous viable epidermis, diIIusion through the
viable epidermis and into the upper dermis, and uptake into the papillary dermis and
into the microcirculation.

Table 3: Factors aIIecting transdermal permeation (Jayaswal et al., 1987).
Factors Explanations
Physicochemical properties of the penetrant molecules
Partition
coeIIicient
A lipid/water partition coeIIicient oI 1 or greater is generally required
Ior optimal transdermal permeability.
It may be altered by chemical modiIication without aIIecting the
pharmacological activity oI the drug.
pH conditions Applications oI solutions whose pH values are very high or very low
can be destructive to the skin. With moderate pH values, the Ilux oI
ionizable drugs can be aIIected by changes in pH that alter the ratio oI
charged and uncharged species and their transdermal permeability.
Penetrant
concentration
Assuming membrane related transport, increasing concentration oI
dissolved drug causes a proportional increase in Ilux. At concentration
higher than the solubility, excess solid drug Iunctions as a reservoir and
helps maintain a constant drug constitution Ior a prolonged period oI
time.
Physicochemical properties of the drug delivery system
Release
characteristics

Solubility oI the drug in the vehicle determines the release rate. The
mechanism oI drug release depends on the Iollowing Iactors:
Whether the drug molecules are dissolved or suspended in the delivery
systems. The interIacial partition coeIIicient oI the drug Irom the
delivery system to the skin tissue.
13
Composition
oI the drug
delivery
systems
The composition oI the drug delivery systems e.g., boundary layers,
thickness, polymers, vehicles not only aIIects the rate oI drug release,
but also the permeability oI the stratum corneum by means oI
hydration, making with skin lipids, or other sorption promoting eIIects
e.g., benzocaine permeation decreases with PEG oI low molecular
weight.
Enhancement
oI transdermal
permeation
Majority oI drugs will not penetrate skin at rates suIIiciently high Ior
therapeutic eIIicacy. In order to allow clinically useIul transdermal
permeation oI most drugs, the penetration can be improved by the
addition oI a permeation promoter into the drug delivery systems.
MECHANISMS OF RATE-CONTROLLED TRANSDERMAL DRUG DELIVERY

For a systemically active drug to reach a target tissue remote Irom the site oI drug
administration on the skin surIace, it must possess physicochemical properties that Iacilitate
the sorption oI drug by the stratum corneum, the penetration oI drug through the viable
epidermis, and also the uptake oI drug by microcirculation in the dermal papillary layer.
The rate oI permeation dQ/dt across various layers oI skin tissues can be expressed
mathematically (Y. W. Chein et al., 1982) as
dQ/dt P
s
(C
d
C
r
) ........(I)
where C
d
and C
r
are, respectively, the concentrations oI a skin penetrant in the donor phase,
e.g., the concentration oI drug on the stratum corneum surIace as delivered Irom a TDD
system, and in the receptor phase, e.g., systemic circulation; and P
s
is the overall
permeability coeIIicient oI the skin tissues to the penetrant and is deIined by
P
s
(K
s/d.
D
ss
)
/
h
s
........ (II)
Here K
s/d
is the partition coeIIicient Ior the interIacial partitioning oI the penetrnat molecule
Irom a transdermal drug delivery system onto the stratum corneum, D
ss
is die apparent
diIIusivity Ior the steady-state diIIusion oI the pendant molecule through the skin tissues;
and h
s
is the overall thickness oI the skin tissues Ior penetration. The permeability
coeIIicient P
s
Ior a skin penetrant can be considered a constant value iI the K
s/d
, D
ss
, and h
s

14
terms in Equation (II) are equally constant under a given set oI conditions. Analysis oI
Equation suggests that to achieve a constant rate oI drug permeation one needs to maintain a
condition in which the drug concentration on the surIace oI stratum corneum C
d
is
consistently and substantially greater than the drug concentration in the body C
r
; i.e., C
d
~~
C
r
. Under such conditions Equation can be reduced to
dQ/dt = P
s
C
d
........(III)
and the rate oI skin permeation dQ/dt should be a constant, iI the magnitude oI C
d
value
remains Iairly constant throughout the course oI skin permeation. To maintain the C
d
at a
constant value, it is necessary to deliver the drug at a rate R
d
that is either constant or always
greater than the rate oI skin absorption R
a
i.e., R
d
~~ R
a
. By making R
d
greater than R
a
the
drug concentration on the skin surIace C
d
is maintained at a level equal to or greater than
the equilibrium (or saturation) solubility oI the drug in the stratum corneum C
s
e
; i.e., C
d
~
C
s
e
. A maximum rate oI skin permeation (dQ/dt)
m
, as expressed by Equation (III), is thus
achieved:
(dQ/dt)
m
P
s
C
s
e
.........(IV)

Apparently, the magnitude oI (dQ/dt)
m
is determined by the permeability coeIIicient P
s
oI
the skin to the drug and the equilibrium solubility oI the drug in the stratum corneum C
s

Figure 4: Plasma drug concentration oI TDDS.
15
Analysis oI the urinary recovery data indicated that the rate oI skin permeation dQ/dt
increases with the increase in nitroglycerin dose C
d
applied on a unit surIace area oI the
skin. It appears that a maximum rate oI skin permeation (1.5 85 mg/cm
2
/day) is achieved
when the applied dose oI nitroglycerin reaches a level oI 4.786 mg/cm
2
or greater. For
example, Figure 4 shows the diIIerence in plasma concentrations oI buprenorphine achieved
with regular sublingual dosing and with TDDS application.

VARIOUS METHODS FOR PREPARATION TDDS
a. Asymmetric TPX membrane method (Baker W et al., 1989)
A prototype patch can be Iabricated Ior this a heat sealable polyester Iilm (type 1009, 3m)
with a concave oI 1cm diameter will be used as the backing membrane. Drug sample is
dispensed into the concave membrane, covered by a TPX poly(4-methyl-1
pentene)}asymmetric membrane, and sealed by an adhesive. These are Iabricated by using
the dry/wet inversion process. TPX is dissolved in a mixture oI solvent (cyclohexane) and
nonsolvent additives at 60c to Iorm a polymer solution. The polymer solution is kept at
40C Ior 24 hrs and cast on a glass plate to a pre-determined thickness with a gardner kniIe.
AIter that the casting Iilm is evaporated at 50C Ior 30 sec, then the glass plate is to be
immersed immediately in coagulation bath |maintained the temperature at 25C|. AIter 10
minutes oI immersion, the membrane can be removed, air dry in a circulation oven at 50C
Ior 12 hrs|.

b. Circular teflon mould method (Wiechers et al., 1992)
Solutions containing polymers in various ratios are used in an organic solvent. Calculated
amount oI drug is dissolved in halI the quantity oI same organic solvent. Enhancers in
diIIerent concentrations are dissolved in the other halI oI the organic solvent and then
added. Di-N-butylphthalate is added as a plasticizer into drug polymer solution. The total
contents are to be stirred Ior 12 hrs and then poured into a circular teIlon mould. The
moulds are to be placed on a leveled surIace and covered with inverted Iunnel to control
solvent vaporization in a laminar Ilow hood model with an air speed oI 0.5 m/s. The solvent
is allowed to evaporate Ior 24 hrs. The dried Iilms are to be stored Ior another 24 hrs at
25+0.5C in a desiccators containing silica gel beIore evaluation to eliminate aging eIIects.
The type Iilms are to be evaluated within one week oI their preparation.
16
c. Mercury substrate method (Yamamoto et al., 1990)
In this method drug is dissolved in polymer solution along with plasticizer. The above
solution is to be stirred Ior 10-15 minutes to produce a homogenous dispersion and poured
in to a leveled mercury surIace, covered with inverted Iunnel to control solvent evaporation.

d. By using IPM membranes method (Al- Khamis et al., 1986)
In this method drug is dispersed in a mixture oI water and propylene glycol containing
carbomer 940 polymer and stirred Ior 12 hrs in magnetic stirrer. The dispersion is to be
neutralized and made viscous by the addition oI triethanolamine. BuIIer pH 7.4 can be used
in order to obtain solution gel, iI the drug solubility in aqueous solution is very poor. The
Iormed gel will be incorporated in the IPM membrane.

e. By using EVAC membranes method (Anon et al., 1980)
In order to prepare the target transdermal therapeutic system, 1 carbopol reservoir gel,
polyethelene (PE), ethylene vinyl acetate copolymer (EVAC) membranes can be used as
rate control membranes. II the drug is not soluble in water, propylene glycol is used Ior the
preparation oI gel. Drug is dissolved in propylene glycol, carbopol resin will be added to the
above solution and neutralized by using 5 w/w sodium hydroxide solution. The drug (in
gel Iorm) is placed on a sheet oI backing layer covering the speciIied area. A rate
controlling membrane will be placed over the gel and the edges will be sealed by heat to
obtain a leak prooI device.

f. Aluminium backed adhesive film method (Mayorga P et al., 1996)
Transdermal drug delivery system may produce unstable matrices iI the loading dose is
greater than 10 mg. Aluminium backed adhesive Iilm method is a suitable one.
For preparation oI same, chloroIorm is choice oI solvent, because most oI the drugs as well
as adhesive are soluble in chloroIorm. The drug is dissolved in chloroIorm and adhesive
material will be added to the drug solution and dissolved. A custammade aluminium Iormer
is lined with aluminium Ioil and the ends blanked oII with tightly Iitting cork blocks.

g. Preparation of TDDS by using Proliposomes (Deo M.R et al., 1997, Yan-yu X et al.,
2006)
The proliposomes are prepared by carrier method using Iilm deposition technique. From the
earlier reIerence drug and lecithin in the ratio oI 0.1:2.0 can be used as an optimized one.
17
The proliposomes are prepared by taking 5mg oI mannitol powder in a 100 ml round bottom
Ilask which is kept at 60-70c temperature and the Ilask is rotated at 80-90 rpm and dried
the mannitol at vacuum Ior 30 minutes. AIter drying, the temperature oI the water bath is
adjusted to 20-30C. Drug and lecithin are dissolved in a suitable organic solvent mixture, a
0.5ml aliquot oI the organic solution is introduced into the round bottomed Ilask at 37C,
aIter complete drying second aliquots (0.5ml) oI the solution is to be added. AIter the last
loading, the Ilask containing proliposomes are connected in a lyophilizer and subsequently
drug loaded mannitol powders (proliposomes) are placed in a desiccator over night and then
sieved through 100 mesh. The collected powder is transIerred into a glass bottle and stored
at the Ireeze temperature until characterization.

h. By using free film method
Free Iilm oI cellulose acetate is prepared by casting on mercury surIace. A polymer solution
2 w/w is to be prepared by using chloroIorm. Plasticizers are to be incorporated at a
concentration oI 40 w/w oI polymer weight. Five ml oI polymer solution was poured in a
glass ring which is placed over the mercury surIace in a glass petri dish. The rate oI
evaporation oI the solvent is controlled by placing an inverted Iunnel over the Petri dish.
The Iilm Iormation is noted by observing the mercury surIace aIter complete evaporation oI
the solvent. The dry Iilm will be separated out and stored between the sheets oI wax paper
in desiccators until use. Free Iilms oI diIIerent thickness can be prepared by changing the
volume oI the polymer solution.

EVALUATION PARAMETERS
1. Interaction studies (Singh et al., 1993, Wade A et al., 1994)
Excipients are integral components oI almost all pharmaceutical dosage Iorms. The stability
oI a Iormulation amongst other Iactors depends on the compatibility oI the drug with the
excipients. The drug and the excipients must be compatible with one another to produce a
product that is stable, thus it is mandatory to detect any possible physical or chemical
interaction as it can aIIect the bioavailability and stability oI the drug. II the excipients are
new and have not been used in Iormulations containing the active substance, the
compatibility studies play an important role in Iormulation development. Interaction studies
are commonly carried out in Thermal analysis, FT-IR, UV and chromatographic techniques
18
by comparing their physicochemical characters such as assay, melting endotherms,
characteristic wave numbers, absorption maxima etc.

2. Thickness of the patch (Rhaghuram et al., 2003)
The thickness oI the drug loaded patch is measured in diIIerent points by using a digital
micrometer and determines the average thickness and standard deviation Ior the same to
ensure the thickness oI the prepared patch.

3. Weight uniformity (Rhaghuram et al., 2003)
The prepared patches are to be dried at 60c Ior 4hrs beIore testing. A speciIied area oI
patch is to be cut in diIIerent parts oI the patch and weigh in digital balance. The average
weight and standard deviation values are to be calculated Irom the individual weights.

4. Folding endurance (Rhaghuram et al., 2003)
A strip oI speciIic are is to be cut evenly and repeatedly Iolded at the same place till it
broke. The number oI times the Iilm could be Iolded at the same place without breaking
gave the value oI the Iolding endurance.

5. Percentage Moisture content (Rhaghuram et al., 2003)
The prepared Iilms are to be weighed individually and to be kept in a desiccator containing
Iused calcium chloride at room temperature Ior 24 hrs. AIter 24 hrs the Iilms are to be
reweighed and determine the percentage moisture content Irom the below mentioned
Iormula.
Percentage moisture content |Initial weight- Final weight / Final weight| 100

6. Water vapour permeability (WVP) evaluation (Shaila et al., 2006)
Water vapour permeability can be determined with Ioam dressing method the air Iorced
oven is replaced by a natural air circulation oven. The WVP can be determined by the
Iollowing Iormula,
WVPW/A
Where, WVP is expressed in gm/m
2
per 24hrs, W is the amount oI vapour permeated
through the patch expressed in gm/24hrs and A is the surIace area oI the exposure samples
expressed in m
2
.

19
7. Percentage Moisture uptake (Rhaghuram et al., 2003)
The weighed Iilms are to be kept in a desiccators at room temperature Ior 24 hrs containing
saturated solution oI potassium chloride in order to maintain 84 RH. AIter 24 hrs the Iilms
are to be reweighed and determine the percentage moisture uptake Irom the below
mentioned Iormula.
Percentage moisture uptake |Final weight- Initial weight / initial weight| 100

8. Drug content (Shaila et al., 2006)
A speciIied area oI patch is to be dissolved in a suitable solvent in speciIic volume. Then
the solution is to be Iiltered through a Iilter medium and analyze the drug contain with the
suitable method (UV or HPLC technique). Each value represents average oI three diIIerent
samples.

9. Uniformity of dosage unit test (Aarti N et al., 1995)
An accurately weighed portion oI the patch is to be cut into small pieces and transIerred to a
speciIic volume volumetric Ilask, dissolved in a suitable solvent and sonicate Ior complete
extraction oI drug Irom the patch and made up to the mark with same. The resulting solution
was allowed to settle Ior about an hour, and the supernatant was suitably diluted to give the
desired concentration with suitable solvent. The solution was Iiltered using 0 . 2 m
membrane Iilter and analyzed by suitable analytical technique (UV or HPLC) and the drug
content per piece will be calculated.

10. Polariscope examination (Aarti N et al., 1995)
This test is to be perIormed to examine the drug crystals Irom patch by polariscope. A
speciIic surIace area oI the piece is to be kept on the object slide and observe Ior the drugs
crystals to distinguish whether the drug is present as crystalline Iorm or amorphous Iorm in
the patch.

11. Shear Adhesion test (Aarti N et al., 1995)
This test is to be perIormed Ior the measurement oI the cohesive strength oI an adhesive
polymer. It can be inIluenced by the molecular weight, the degree oI crosslinking and the
composition oI polymer, type and the amount oI tackiIier added. An adhesive coated tape is
applied onto a stainless steel plate; a speciIied weight is hung Irom the tape, to aIIect it
pulling in a direction parallel to the plate. Shear adhesion strength is determined by
20
measuring the time it takes to pull the tape oII the plate. The longer the time takes Ior
removal, greater is the shear strength.

12. Peel Adhesion test (Aarti N et al., 1995)
In this test, the Iorce required to remove an adhesive coating Iorm a test substrate is reIerred
to as peel adhesion. Molecular weight oI adhesive polymer, the type and amount oI
additives are the variables that determined the peel adhesion properties. A single tape is
applied to a stainless steel plate or a backing membrane oI choice and then tape is pulled
Irom the substrate at a 180 angle, and the Iorce required Ior tape removed is measured.

13. Thumb tack test (Aarti N et al., 1995)
It is a qualitative test applied Ior tack property determination oI adhesive. The thumb is
simply pressed on the adhesive and the relative tack property is detected.

14. Flatness test (Wade A et al., 1994)
Three longitudinal strips are to be cut Irom each Iilm at diIIerent portion like one Irom the
center, other one Irom the leIt side, and another one Irom the right side. The length oI each
strip was measured and the variation in length because oI non-uniIormity in Ilatness was
measured by determining percent constriction, with 0 constriction equivalent to 100
Ilatness.

15. Percentage Elongation break test (Wade A et al., 1994)
The percentage elongation break is to be determined by nothing the length just beIore the
break point, the percentage elongation can be determined Irom the below mentioned
Iormula.
Elongation percentage L1-L2 100
Where, L1 is the Iinal length oI each strip and L2 is the initial length oI each strip.

16. Rolling ball tack test (Vyas S.P et al., 2002)
This test measures the soItness oI a polymer that relates to talk. In this test, stainless steel
ball oI 7/16 inches in diameter is released on an inclined track so that it rolls down and
comes into contact with horizontal, upward Iacing adhesive. The distance the ball travels
along the adhesive provides the measurement oI tack, which is expressed in inch.

21
17. Quick Stick (peel-tack) test (Vyas S.P et al., 2002)
In this test, the tape is pulled away Irom the substrate at 90C at a speed oI 12 inches/min.
The peel Iorce required breaking the bond between adhesive and substrate is measured and
recorded as tack value, which is expressed in ounces or grams per inch width.

18. Probe Tack test (Vyas S.P et al., 2002)
In this test, the tip oI a clean probe with a deIined surIace roughness is brought into contact
with adhesive, and when a bond is Iormed between probe and adhesive. The subsequent
removal oI the probe mechanically breaks it. The Iorce required to pull the probe away Irom
the adhesive at Iixed rate is recorded as tack and it is expressed in grams.

19. In vitro drug release studies (Singh et al., 1993)
The paddle over disc method (USP apparatus V) can be employed Ior assessment oI the
release oI the drug Irom the prepared patches. Dry Iilms oI known thickness is to be cut into
deIinite shape, weighed, and Iixed over a glass plate with an adhesive. The glass plate was
then placed in a 500-mL oI the dissolution medium or phosphate buIIer (pH 7.4), and the
apparatus was equilibrated to 32+ 0.5C. The paddle was then set at a distance oI 2.5 cm
Irom the glass plate and operated at a speed oI 50 rpm. Samples (5- mL aliquots) can be
withdrawn at appropriate time intervals up to 24 h and analyzed by UV spectrophotometer
or HPLC. The experiment is to be perIormed in triplicate and the mean value can be
calculated.

20. In vitro skin permeation studies (Singh et al., 1993)
An in vitro permeation study can be carried out by using diIIusion cell. Full thickness
abdominal skin oI male Wistar rats weighing 200 to 250g. Hair Irom the abdominal region
is to be removed careIully by using a electric clipper; the dermal side oI the skin was
thoroughly cleaned with distilled water to remove any adhering tissues or blood vessels,
equilibrated Ior an hour in dissolution medium or phosphate buIIer pH 7.4 beIore
starting the experiment and was placed on a magnetic stirrer with a small magnetic needle
Ior uniIorm distribution oI the diIIusant. The temperature oI the cell was maintained at 32 +
0.5C using a thermostatically controlled heater. The isolated rat skin piece is to be mounted
between the compartments oI the diIIusion cell, with the epidermis Iacing upward into the
donor compartment. Sample volume oI deIinite volume is to be removed Irom the receptor
compartment at regular intervals, and an equal volume oI Iresh medium is to be replaced.
22
Samples are to be Iiltered through Iiltering medium and can be analyzed
spectrophotometrically or HPLC. Flux can be determined directly as the slope oI the curve
between the steady-state values oI the amount oI drug permeated (mg cm-2) vs. time in
hours and permeability coeIIicients were deduced by dividing the Ilux by the initial drug
load (mg cm-2).

21. Skin Irritation study (Aarti N et al., 1995)
Skin irritation and sensitization testing can be perIormed on healthy rabbits (average weight
1.2 to 1.5 kg). The dorsal surIace (50cm2) oI the rabbit is to be cleaned and remove the hair
Irom the clean dorsal surIace by shaving and clean the surIace by using rectiIied spirit and
the representative Iormulations can be applied over the skin. The patch is to be removed
aIter 24 hr and the skin is to be observed and classiIied into 5 grades on the basis oI the
severity oI skin injury.

22. Stability studies (Singh et al., 1993)
Stability studies are to be conducted according to the ICH guidelines by storing the TDDS
samples at 40+0.5C and 75+5 RH Ior 6 months. The samples were withdrawn at 0, 30,
60, 90 and 180 days and analyze suitably Ior the drug content.
POLYMERS IN TRANSDERMAL DRUG DELIVERY SYSTEM

As described in the section on the FDA Regulation and Transdermal Drug Delivery system,
Transdermal drug delivery system is a combinational product i.e., it is a combination oI a
drug and a device to administer the drug into the biological system. 'The primary
jurisdiction Ior combination products (e.g., device, drug, or biologic) is determined by the
primary mode oI action oI the product. (Lyman et al., 2007) In the case oI a transdermal
drug delivery system, the primary mode oI action oI the product is controlled drug release
and hence it becomes extremely crucial to understand and select materials and techniques
that would make it possible to control the drug release. Controlled delivery oI drug Irom the
device to the biological system can be achieved by various means. An IV Iluid drip also
controls the rate oI Ilow oI drug, but the apparatus is bulky and cannot be used on a daily
basis Ior home care patients. Controlled drug release can also be achieved by embedding the
drug onto a polymeric material and then releasing the drug in a predesigned controlled
23
manner Irom the polymer into the blood stream. (Brannon et al., 1997) This is achieved by
the use oI transdermal drug delivery system that is made oI polymeric materials. Table 4
gives a list oI polymers that are extensively used in making transdermal patches. It becomes
evident Irom Table 4 that there are various types oI polymers that are used Ior diIIerent
types oI transdermal drug delivery systems. There are some polymers that are used as
adhesives, some as backing layer Ior the transdermal patch, some to create a gel that would
help embed the drug Ior the controlled delivery oI the drug. Every layer in the transdermal
drug delivery system requires properties speciIic Ior that layer only. The type oI polymer is
chosen according to the desired properties Ior that speciIic layer. The physical properties
and the polymers showing those properties are listed below:
Poly (urethanes) Ior elasticity.
Poly (siloxanes) or silicones Ior insulating ability.
Poly (methyl methacrylate) Ior physical strength and transparency.
Poly (vinyl alcohol) Ior hydrophilicity and strength.
Poly (ethylene) Ior toughness and lack oI swelling.
Poly (vinyl pyrrolidone) Ior suspension capabilities.
The desired type oI controlled drug delivery mechanism by the above mentioned polymers
are shown schematically in Figure 5.

Figure 5: Controlled Drug Release Mechanism.

Figure 5(A) shows the drug delivery in a matrix type oI system while (B) shows the
reservoir type oI transdermal drug delivery system.
24
1. Polymers in Backing Film and Release Liners
The most important property to be considered Ior the backing layer oI the transdermal patch
is the chemical resistance. (Kandavilli et al., 2002) Chemical resistance is the resistance the
polymeric material possesses against dissolution, cracking, and swelling when in contact
with other substances or Iluids. The other property that needs to be considered in the
polymeric material selection is that oI biocompatibility oI the material to the human skin.
The reason being the transdermal patch will be placed on the skin Ior considerable amount
oI time and iI biocompatibility oI the material is not accounted Ior, it may cause adverse
eIIects on the skin. The backing polymeric material should be strong enough to be able to
withstand the drug, i.e. the backing layer should not leach the drug, because iI leaching
occurs it may result in skin coming in direct contact with the drug that may be harmIul.
The other properties that are considered important Ior the backing layer in the transdermal
drug delivery system are as Iollows:
Low Modulus
High Flexibility
Good oxygen transmission
High moisture-vapor transmission rate

The release liner is the Iirst layer in the transdermal drug delivery system. It is removed
prior to applying the patch onto the skin. Hence, it does not come in direct contact with the
skin. But the material properties oI the liner are important since the liner is in direct contact
with the drug permeation layer. The material properties to be considered Ior a release liner
are as Iollows:
The material must be chemically inert.
The material should be such that it should not permeate the drug.
AIIinity towards water should be null.
Material should not crack, craze, or react in any way with the mechanism that are
used Ior penetration in active transdermal drug delivery systems.

25
Table 4: List oI Polymers and ManuIacturers in Transdermal Drug Delivery System.

26
2. Polymers in Rate-Controlling Membrane
Transdermal drug delivery patches contain the drug either in the dispersed or dissolved Iorm
in the rate-controlling membrane. (Bellus et al., 1994) The desired properties Ior the
polymers to be used as drugpermeation rate-control membrane are microporous,
macroporous, semipermeable. 'Supersaturation oI a drug in a Transdermal delivery system
is oIten desirable in order to deliver a target therapeutic 'dose into the body since
permeation rates oI the drug through the patch and skin is dependent on the degree oI
saturation oI the drug within transdermal patch. (Variankaval et al., 2002) This is
considered to be a good property but may not be always Iavorable like in the case oI drug-
inadhesive type oI patch. 'The presence oI crystals in a transdermal patch might
signiIicantly aIIect the permeation oI the drug through the patch, iI dissolution oI the drug is
the rate controlling step in the mass transIer process compared to the diIIusion rate. It was
also predicted by (Variankaval et al., 2002) that the presence oI crystal in the transdermal
patch`s rate-controlling membrane could aIIect the physiochemical nature oI the drug and
also its diIIusion through the patch. Hence it can be said with conIidence that presence oI
crystallinity in the patch is an undesirable property. (Mukherjee et al., 2005) described the
preparation oI a matrix type oI a patch`s rate controlling membrane. Two polymers, Duro-
Tak 387-2516 and 87-2852, were taken in 4:5 ratios. The two polymers were then stirred in
a magnetic bead bed and with a magnetic stirrer in ethyl-acetate-isopropyl alcohol- toluene
n-hexane (12:6:1:1). To this mixture the drug to be administered using the patch was added
in 30mg per patch weight ratio. The resulting mixture was casted and dried to Iorm a
uniIorm medicated matrix patch. The patch had the drug NeIopam hydrochloride used as a
pain killer. The chemistry and the mixture ratio rate Ior every drug will vary and so will the
composition oI the polymers added. But the above example based on the matrix type oI
transdermal drug delivery system gives a pretty good idea oI the process oI the rate-
controlling layer preparation.

The glass transition temperature oI the material also plays an important role in controlling
the rate oI drug diIIusivity. 'An increase in Tg reIlects a decrease in the polymer-chain
mobility and hence the solute diIIusivity. The rate controlling membranes consists oI use
oI copolymers; the Tg oI the copolymers can be lowered by a process called
copolymerization which involves polymerization oI two or more types oI polymers.
Addition oI plasticizers can also lower the Tg but may result in having an adverse chemical
reaction with the drugs. Table 5 gives a list oI acrylic polymers and their glass transition
27
temperatures that are used in the rate controlling membranes in transdermal drug delivery
systems. There are many polymers that are used as rate-controlling membrane. A Iew oI the
polymers are listed below:
EVA
Silicone Rubber
Polyurethane
PSA
Polyisobutylene (PIB)
Polyacrylates

Table 5: Glass Transition Temparature`s (Tg) Ior Acrylic Polymers.

3. Polymers in Adhesives
The use oI adhesives on the skin Ior wound healing has been present through ages. 'The
Iirst skin-contact adhesive application oI any volume was perhaps the use oI pressure-
sensitive adhesion in bandages, which dates back to 1899, with Johnson & Johnson
introduction oI hospital tapes with adhesive attached.(Venkatraman et al., 1998) It is
important to understand the Iundamentals oI skin beIore deciding on the polymers that can
be used as adhesives. 'The measured surIace energy oI the adhesive must be equal to or less
than that oI the adherent, or human skin in this case. The other Iundamental conditions that
need to be addressed are kinetic requirement involving wetting rates and viscoelastic nature
28
oI the adhesive. These are important to know because the skin has water content which may
react with the polymeric adhesive making the bond between the skin and the patch weak.
The water content oI the skin is again dependent on various other Iactors like the age oI the
person, whether the person sweats a lot, so on and so Iorth. Hence, understanding and
knowing the Iundamentals oI the skin beIorehand is crucial. Every Transdermal drug
delivery patch needs to be applied to the skin and kept in place Ior several hours and in
some cases even days. There are diIIerent types oI transdermal drug delivery systems and
each type has its own peculiarities with respect to the adhesive layers. Though it is thought
that a drug-in-adhesive type oI transdermal drug delivery system is the easiest type in terms
oI its structure, it is considered as one oI the most complicated patch due to the multiple
property requirements on a single layer oI the patch. The issue oI crystallization in
drug/adhesive membrane will have an adverse eIIect on the permeation rate-control which
will change the rate oI dissolution and will aIIect the Iinal use oI the patch. 'The high
internal and speciIic volume oI the amorphous state relative to the crystalline state can lead
to enhanced dissolution and bioavailability, which is a desirable characteristic in
transdermal patches. (Variankaval et al., 1999) Hence, there is a lot oI eIIort taken towards
preserving the drug in amorphous state in the transdermal patch Ior a better permeation rate
control. 'Molecules in the amorphous state are thermodynamically metastable relative to the
crystalline phase. This creates the opportunity Ior change oI amorphous phase to
crystalline phase, which is an issue in most oI the transdermal drug delivery systems.
LATEST TECHNIQUES OF IMPROVING PERMEATION FOR TDDS
Mechanical Method
The various classes oI active systems under development include iontophoresis,
electroporation, microneedles, abrasion, needle-less injection, suction, stretching,
ultrasound, magnetophoresis, radio Irequency, lasers, photomechanical waves, and
temperature manipulation. Some most commonly employed techniques include the
Iollowing:

a. Iontophoresis
This method involves the application oI a low level electric current either directly to the
skin or indirectly via the dosage Iorm in order to enhance permeation oI topically applied
29
therapeutic agent.( Wang Y et al., 1993, Turner NG et al.,1997, Banga AK et al., 1993,
Guy RH et al., 2000) Increased drug permeation as a result oI this methodology can be
attributed to either one or a combination oI the Iollowing mechanisms: Electro-repulsion
(Ior charged solutes), electro-osmosis (Ior uncharged solutes) and electro-pertubation (Ior
both charged and uncharged).
b. Electroporation
This method involves the application oI high voltage pulses to the skin that has been
suggested to induce the Iormation oI transient pores. High voltages (100 V) and short
treatment durations (milliseconds) are most Irequently employed. The technology has been
successIully used to enhance the skin permeability oI molecules with diIIering lipophilicity
and size (i.e., small molecules, proteins, peptides and oligonucleotides) including
biopharmaceuticals with molecular weights greater that 7kDA.

c. Microneedle-based Devices
The very Iirst microneedle systems, described in 1976, consisted oI a drug reservoir and a
plurality oI projections (microneedles 50 to 100 mm long) extending Irom the reservoir,
which penetrated the stratum corneum and epidermis to deliver the drug ( Gerstel MS et al.,
1976).

d. Skin Abrasion
The abrasion technique involves the direct removal or disruption oI the upper layers oI the
skin to Iacilitate the permeation oI topically applied medicaments. Some oI these devices
are based on techniques employed by dermatologists Ior superIicial skin resurIacing (e.g.
microdermabrasion) which are used in the treatment oI acne, scars, hyperpigmentaion and
other skin blemishes.

e. Needle-less Injection
Transdermal delivery is achieved by Iiring the liquid or solid particles at supersonic speeds
through the outer layers oI the skin using a suitable energy source. The mechanism involves
Iorcing compressed gas (helium) through the nozzle, with the resultant drug particles
entrained within the jet Ilow reportedly traveling at suIIicient velocity Ior skin penetration.

30
f. Ultrasound (sonophoresis and phonophoresis)
This technique involves the use oI ultrasonic energy to enhance the transdermal delivery oI
solutes either simultaneously or via pre-treatment. It uses low Irequency ultrasound (55
kHz) Ior an average duration oI 15 seconds to enhance skin permeability (Kost J et al.,
2003).

g. Laser Radiation
This method involves direct and controlled exposure oI a laser to the skin that results in the
ablation oI the stratum corneum without signiIicantly damaging the underlying epidermis.
Removal oI the stratum corneum using this method has been shown to enhance the delivery
oI lipophilic and hydrophilic drugs (Jacques SL et al., 1988).

Carriers/Vehicles
a. Micro or nanocapsules
These are composed oI multiple concentric bilayers oI surIactant; separated by a polar
liquid medium, generally water in which the hydrophilic additives can be incorporated.
Their lipid core allows encapsulation oI lipid additives and their multi-lamellar (lipid/water)
structure creates good skin aIIinity leading to cutaneous penetration and good hydration.
b. Nanoemulsions/Sub-micron emulsions (SMEs)/Mini-emulsions
These are oil-in-water emulsions with an average droplet size ranging Irom 100 to 500 nm.
They have very good stability and they do not undergo phase separation during storage.
They have a liquid lipophilic core and are appropriate Ior lipophilic compound
transportation. Many studies showed reduced transepidermal water loss, which means
support to the barrier Iunction oI the skin.( Muller RH et al.,1988) Nanoemulsion viscosity
is very low, which is interesting because they can be produced as sprays,

c. In solid lipid nanoparticles (SLNs)
These droplets are made by solid lipids (Muller RH et al., 2002). Their sizes range Irom 50
to 1000 nm. They can also be stabilized by surIactants or polymers. There are mainly three
structures: Homogeneous matrix, drug-enriched shell and drug enriched core. They can
protect active components against chemical degradation and modulate compound release.
SLNs also present occlusive properties because oI the Iormation oI a Iilm on the skin. This
31
Iilm Iormed by lipid Iusion is supposed to be a pore-less Iilm with improved skin hydration
and protection properties.
d. Multiple emulsions
These W/O/W emulsions consist in the dispersion oI a W/O emulsion in an aqueous phase
under several conditions. (Tadros et al., 1992) One can incorporate diIIerent water-soluble
ingredients (even iI they are incompatible) and also oil soluble additives. Like SLNs, these
substances will be protected and release sustained by controlling droplet breakdown. These
systems can have high oily phase contents (65, Trixera, Bain emollient, Avene) and thus
present good hydration. Their eIIicacy has been demonstrated in dermatology to treat stretch
marks (TriIIadiane, CS Dermatologie).

e. Microemulsions
These Iormulations have been shown to be superior Ior cutaneous delivery compared to
other conventional vehicles. (Kreilgaard et al., 2002) These systems are identiIied as
transparent mixtures oI water, oil and surIactants. They are thermodynamically stable and
optically isotropic. Microemulsions are spontaneously produced in a narrow range oI oil-
water-surIactant composition, represented on pseudo-ternary diagram phases. They are
dynamic systems with continuously Iluctuating interIaces. Their good dermal and
transdermal delivery properties could be attributed to their excellent solubilising properties.
Their high solubilising properties improve indispensability and thus reduce the eIIicient
dose thereby increasing operability. Furthermore, their restructuring eIIect on skin and hair
(due to their high lipid content) make microemulsion Iormulations adapt to altered skin and
hair conditions.

f. Vesicular carriers
Liposomes
These are colloidal particles Iormed as concentric biomolecular layers that are capable oI
encapsulating drugs. Their delivery mechanism is reported to be associated with
accumulation oI the liposomes and associated drug in the stratum corneum and upper skin
layers, with minimal drug penetrating to the deeper tissues and systemic circulation. It is
interesting that the most eIIective liposomes are reported to be those composed oI lipids
similar to stratum corneum lipids, (Egbaria et al., 1990) which are most likely to enter
stratum corneum lipid lamellae and Iuse with endogenous lipids.
32
Niosomes
These are vesicles composed oI nonionic surIactants that have been evaluated as carriers Ior
a number oI drug and cosmetic applications. This carrier has more permeability than
liposomes Ior transdermal drug delivery.
Transfersomes
These are vesicles composed oI phospholipids as their main ingredient with 10-25
surIactant (such as sodium cholate) and 3-10 ethanol. The surIactant molecules act as
'edge activators, conIerring ultradeIormability on the transIersomes, which reportedly
allows them to squeeze through channels in the stratum corneum that are less than one-tenth
the diameter oI the transIersome.
Ethosomes
These are liposomes with high alcohol content capable oI enhancing penetration to deep
tissues and the systemic circulation. (Biana et al., 2003, Touitou et al., 2001, Dayan et al.,
2000) It is proposed that alcohol Iluidizes the ethosomal lipids and stratum corneum bilayer
lipids thus allowing the soIt, malleable ethosomes to penetrate.

Miscellaneous Techniques
a. Prodrugs and Ion-Pairs
The prodrug approach has been investigated to enhance dermal and transdermal delivery oI
drugs with unIavourable partition coeIIicients (Sloan et al., 2003). The prodrug design
strategy generally involves addition oI a pro-moiety to increase partition coeIIicient and
solubility to increase the transport oI the drug in the stratum corneum. Upon reaching the
viable epidermis, esterases release the active drug by hydrolysis thereby optimising
concentration in the epidermis. Charged drug molecules do not readily partition into or
permeate through human skin. Formation oI lipophilic ionpairs has been investigated to
increase stratum corneum penetration oI charged species. This strategy involves adding an
oppositely charged species to the charged drug, Iorming an ion-pair in which the charges are
neutralised so that the complex can partition into and permeate through the stratum
corneum. The ion-pair then dissociates in the aqueous viable epidermis releasing the parent
charged drug that can diIIuse within the epidermal and dermal tissues.
33
b. VehicleSaturated and Supersaturated Solutions
The maximum skin penetration rate is obtained when a drug is at its highest thermodynamic
activity as is the case in a supersaturated solution. Supersaturated solutions can occur due to
evaporation oI solvent or by mixing oI co solvents.

c. Eutectic Systems
The melting point oI a drug inIluences solubility and hence skin penetration. According to
solution theory, lower the melting point, greater the solubility oI a material in a given
solvent, including skin lipids. The melting point oI a drug delivery system can be lowered
by Iormation oI a eutectic mixture, which is a binary system. At a constant ratio, the
components inhibit the crystallization process oI each other, such that the melting point oI
the two components in the mixture is less than that oI each component alone.

d. Complexes
Complexation oI drugs with cyclodextrins has been used to enhance aqueous solubility and
drug stability. Cyclodextrins oI pharmaceutical relevance contain 6, 7 or 8 dextrose
molecules bound in a 1,4-conIiguration to Iorm rings oI various diameters. The ring has a
hydrophilic exterior and lipophilic core in which appropriately sized organic molecules can
Iorm non-covalent inclusion complexes resulting in increased aqueous solubility and
chemical stability. Cyclodextrins are large molecules, with molecular weights greater than
1000 Da, thereIore it would be expected that they would not readily permeate the skin.
Complexation with cyclodextrins has been variously reported to both increase and decrease
skin penetration (Vollmer et al., 1994, Legendre et al., 1995).

ADVANTAGES OF TRANSDERMAL DRUG DELIVERY SYSTEMS

Delivery via the transdermal route is an interesting option because transdermal route is
convenient and saIe (HadgraIt J. et a., 1994). The positive Ieatures oI delivery drugs across
the skin to achieve systemic eIIects are:
Avoidance oI Iirst pass metabolism.
Avoidance oI gastro intestinal incompatibility.
Predictable and extended duration oI activity.
Minimizing undesirable side eIIects.
34
Provides utilization oI drugs with short biological halI lives, narrow therapeutic
window.
Improving physiological and pharmacological response.
Avoiding the Iluctuation in drug levels.
Inter and intra patient variations.
Maintain plasma concentration oI potent drugs.
Termination oI therapy is easy at any point oI time.
Greater patient compliance due to elimination oI multiple dosing proIiles.
Ability to deliver drug more selectively to a speciIic site.
Provide suitability Ior selI administration.
Enhance therapeutic eIIicacy.

LIMITATIONS OF TRANSDERMAL DRUG DELIVERY SYSTEMS
Transdermal delivery is neither practical nor aIIordable when required to deliver
large doses oI drugs through skin (Govil et al., 1998; Misra et al., 2002; Monkhouse
et al., 1988).
Cannot administer drugs that require high blood levels.
Drug oI drug Iormulation may cause irritation or sensitization.
Not practical, when the drug is extensively metabolized in the skin and when
molecular size is great enough to prevent the molecules Irom diIIusing through the
skin.
Not suitable Ior a drug, which doesn`t possess a Iavorable, o/w partition coeIIicient.
The barrier Iunctions oI the skin oI changes Irom one site to another on the same
person, Irom person to person and with age.

IDEAL PRODUCT REQUIREMENTS
ShelI liIe up to 2 years.
Small size patch (i.e., less than 40 cm2).
Convenient dose Irequency (i.e., once a day to once a week).
Cosmetically acceptable (i.e., clear, white color).
Simple packaging (i.e., minimum number oI pouches and steps required to apply the
system).
35
Easy removal oI the release liner (i.e., Ior children and elderly patients).
Adequate skin adhesion (i.e., no Iall oII during the dosing interval and easy removal
without skin trauma).
No residue (i.e., 'cold Ilow around the edge oI the patch in storage or aIter
application to skin or beneath the patch aIter removal).
No unacceptable dermal reactions (i.e., contact dermatitis, skin sensitization, photo
toxicity, photosensitization, erythema, itching, stinging, burning, etc.).
Consistent biopharmaceutical perIormance (i.e., precision oI the required
pharmacokinetic and pharmacodynamic response between individuals and in the
same individuals over time.

MOST POPULAR TDDS USED WORLDWIDE
(www.wikipedia.com)
The highest selling transdermal patch in the United States is the nicotine patch,
which releases nicotine in controlled doses to help with cessation oI tobacco
smoking. The Iirst commercially available vapour patch to reduce smoking was
approved in Europe in 2007.
Two opioid medications used to provide round-the-clock relieI Ior severe pain are
oIten prescribed in patch Iorm: Fentanyl (marketed as Duragesic) and
Buprenorphine (marketed as BuTrans).
Estrogen patches are sometimes prescribed to treat menopausal symptoms as well as
post-menopausal osteoporosis. Other transdermal patches Ior hormone delivery
include the contraceptive patch (marketed as Ortho Evra or Evra). Testosterone
patches are available Ior both men and women, but mens patches (such as
Androderm) contain a much higher dosage than womens patches such as Intrinsa.
Nitroglycerin patches are sometimes prescribed Ior the treatment oI angina in lieu oI
sublingual pills.
Transdermal scopolamine is commonly used as a treatment Ior motion sickness.
The anti-hypertensive drug Clonidine is available in transdermal patch Iorm under
the brand name Catapres-TTS.
Emsam, a transdermal Iorm oI the MAOI selegiline, became the Iirst transdermal
delivery agent Ior an antidepressant approved Ior use in the U.S. in March 2006.
36
Daytrana, the Iirst transdermal delivery agent Ior the Attention DeIicit Hyperactivity
Disorder (ADHD) drug methylphenidate (otherwise known as Ritalin or Concerta),
was approved by the FDA in April 2006.
Vitamin B12 may also be administered through a transdermal patch.
Cyanocobalamin, a highly stable Iorm oI vitamin B12, is compatible with
transdermal patching.
RECENT DEVELOPMENTS IN TRANSDERMAL DRUG DELIVERY
The potential oI using intact skin as the site Ior continuous transdermal inIusion oI drug has
been recently recognized beyond the boundary oI local medication. The development oI
Iemale syndromes in male operators working in the production oI estrogen-containing
pharmaceutical dosage Iorms challenged the old theory that the skin is a perIectly
impermeable barrier and also triggered the research curiosity oI several biomedical
scientists to evaluate the Ieasibility oI transdermal delivery oI systemically active drugs.
The Iindings, accumulated over the years, have practically revolutionized the old concept oI
an impermeable skin barrier and also motivated a number oI pharmaceutical scientists to
develop patch-type drug delivery systems Ior the rate-controlled transderrnal administration
oI drugs to achieve systemic medication (Y.W. Chien et al., 1987, J. E. Shaw et al., 1978).
Over a decade oI intensive research and development eIIorts, several rate-controlled
transdermal drug delivery systems have been successIully developed and commercialized.
They can be classiIied according to the technological basis oI their approach into the
Iollowing Iour categories:

1. Polymer membrane permeation-controlled TDD systems
Transderm-Scop system (scopolamine-releasing TDD system); Transderm-Nitro system (n-
troglycerin-releasing TDD system); Catapres-TTS system -clonidine-releasing TDD
system); Estraderm system -estradiol-releasing TDD systems.

2. Adhesive polymer dispersion TDD systems
Deponit system -nitroglycerin-r-leasing TDD system); Frandol tape -isosorbide dinitrate-
releasing TDD systems, Minitran system -nitroglycerin-releasing TDD systems; Nitro-Dur
II system n-troglycerin-releasing TDD system).

37
3. Nonadhesive polymer dispersion TDD systems
Nitro-Dur system -nitroglycerinreleasing TDD system); NTS system -nitroglycerin-
releasing TDD system).

4. Microreservoir dissolution-controlled TDD systems
Nitrodisc system ~nitroglycerin-releasing TDD system); transdermal contraceptive system -
progestin-estrogen-releasing TDD system).

By now at least 11 TDD systems have been launched on the worldwide prescription drug
market: Transderm-Scop system Cuba), Transderm-Nitro system Scubas, Catapres-TTS
system -Boehringer-Ingelheim-, Estraderm system Cuba), Minitran system EM Riker),
Nitro-Dur system -Key), Nitrodisc system -Searle), NTS system (Bolar), Deponit system -
Pharma-Schwarz), and Frandol tape -Toaeiyo-Yamanouchi). Furthermore, several TDD
systems have been submitted Ior regulatory review and approval.

THE FUTURE OF TRANSDERMAL DRUG DELIVERY
The statically data showed a market oI $ 12.7 billion in the year 2005 which is assumed to
increase by $ 21.5 billion in the year 2010 and $ 31.5 billion in the year 2015. Almost all
the pharmaceutical companies are developing TDDS (Samad et al., 2009). TDDS may be
ideal Ior many injected as well as orally given drugs, but many drugs cannot penetrate the
skin membrane eIIectively because oI low permeability oI skin barrier. Pharmaceutical
companies are now developing new adhesives, substances that enhance molecular
absorption as well as penetration that will ultimately aIIect skin permeation and greatly
increase the list oI drugs which can be delivered transdermally. Well known technologies
that are iontophoresis and phonophoresis (sonophoresis) considered to achieve signiIicant
plasma concentration levels via skin membrane. A microoneedle technology is more
promising Ior drug administered via skin. These systems use an arrangement oI small
needle-like structures to open pores in the stratum cornea and Iacilitate drug transport
without any sensation oI pain because these are not reachable to nerve endings. These
systems are reported to greatly enhance the permeability oI macromolecules across skin.

38
CONCLUSION
Transdermal drug delivery system is one oI the unique drug delivery system in recent days.
Development oI this delivery system aid in overcoming number problem oI existing dosage
Iorms. Although all types oI drug is not yet possible to make as transdermal drug delivery
system but its development is still ongoing. SuccessIul transdermal drug application
requires numerous considerations. Bearing in mind that the basic Iunctions oI the skin are
protection and containment, it would seem exceptionally diIIicult to target the skin Ior drug
delivery. However, with our greater understanding oI the structure and Iunction oI the skin,
and how to alter these properties, more and more new drug products are being developed Ior
transdermal delivery. The properties oI the drug, the characteristics oI the transdermal
device, selection oI in-vivo model and the status oI patient`s skin are all important Ior saIe
and eIIective drug delivery.
39
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