Page 1
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
619
A SMART REVIEW ON APPROACHES OF DRUG PERMEATION
THROUGH TRANSDERMAL FILMS
Yogita Tyagi and Vivek Tamta*
Department of Pharmacy GRD (PG) IMT, Rajpur Road Dehradun-248001, Uttarakhand,
India.
ABSTRACT
This review focuses on the recent advancements in the TDDS which
include iontophoresis, sonophoresis, electroporation, microneedles,
magnetophoresis, photomechanical waves and electron beam
irradiation. Transdermal drug delivery system (TDDS) utilizes the skin
as executable route for drug administration but the foremost barrier
against drug permeability is the stratum corneum and therefore, it
limits therapeutic bioavailability of the bioactive. These advancements
are exhaustively discussed with techniques involved with their
beneficial claims for different categories of bioactive. However, a lot
of research has been carried out in TDDS, still the system has many
pros and cons such as inconsistent drug release, prevention of burst
release formulation and problems related to toxicity. In addition to that, to exploit the TDDS
more efficiently scientists have worked on some combinational approaches for manufacturing
TDDS viz., chemical–iontophoresis, chemical– electroporation, chemical–ultrasound,
iontophoresis–ultrasound, electroporation–iontophoresis electroporation– ultrasound and
pressure waves–chemicals and reported the synergistic effect of the same for safe, effective
and practical use of TDDS. The present article covers all the above-mentioned aspects in
detail and hence the article will assuredly serve as an enlightening tool for the visionaries
working in the concerned area.
KEYWORDS: Transdermal films, Permeation, Bioavailability, Stratum corneum.
1. INTRODUCTION
Transdermal drug delivery system (TDDS) are adhesive drug containing devices of defined
surface area that delivers predetermined amount of drug to the intact skin at the
World Journal of Pharmaceutical Research SJIF Impact Factor 8.084
Volume 9, Issue 6, 619-642. Review Article ISSN 2277– 7105
Article Received on
31 March 2020,
Revised on 21 April 2020,
Accepted on 11 May 2020,
DOI: 10.20959/wjpr20206-17577
*Corresponding Author
Vivek Tamta
Department of Pharmacy
GRD (PG) IMT, Rajpur
Road Dehradun-248001,
Uttarakhand, India.
Page 2
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
620
preprogrammed rate.[4,5]
The transdermal delivery has gained importance in the recent years.
The TDDS has potential advantages of avoiding hepatic first pass metabolism, maintaining
constant blood levels for longer period of time resulting in a reduction of dosing frequency,
improved bioavailability, decreased gastrointestinal irritation and improved patient
compliance.[6]
Since the early 1980s, transdermal patch dosage form of transdermal therapeutic system
(TTS) has been available commercially. Such a system offers a variety of significant clinical
benefits over other conventional systems. Therefore the TTS is of particular clinical
significance for the prevention and long-term treatment of chronic diseases like
hypertension.[7]
Some of the antihypertensive drugs have already been formulated and
evaluated as transdermal patches but most of them still been unexplored. Transdermal
formulation of antihypertensive drug is promising aspect in near future.
Mortality from heart diseases increases dramatically with age. Hypertension is one of the
main causes of heart disease and, in recent years, the age adjusted hypertension and
hypertensive disease death rates have been increasing.[8]
Consequently, the prevention and
treatment of hypertension is of major social significance.[9]
Hypertension is defined
conventionally as a sustained increase in blood pressure 140/90 mm Hg, a criterion that
characterizes a group of patients whose risk of hypertension-related cardiovascular disease is
high enough to merit medical attention. Actually, the risk of both fatal and nonfatal
cardiovascular disease in adults is lowest with systolic blood pressures of less than 120 mm
Hg and diastolic BP less than 80 mm Hg; these risks increase progressively with higher
systolic and diastolic blood pressures.[10]
Hypertension is directly responsible for 57% of all stroke deaths and 24% of all coronary
heart disease deaths in India. Pooling of Indian epidemiological studies shows that
hypertension is present in 25% urban and 10% rural subjects.[11]
Therefore cost effective
approaches to optimally control blood pressure among Indians are very much needed. Despite
the suitability of TDDS in the treatment of chronic disease like hypertension, the high cost of
antihypertensive patches than conventional products made the target patients to think
twice.[12]
In spite of the high cost of transdermal patches for hypertension treatment, antihypertensive
patch with the established dosage forms reduced the occurrence of hospitalization and
Page 3
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
621
diagnostic costs. These advantages prepared the target consumers to accept antihypertensive
patches as a costlier alternative to the conventional therapy. Further, the possibility of
achieving controlled zero order absorption, simple mode of administration and the option of
easy withdrawal of dose in case of adverse manifestations make them desirable in
antihypertensive therapy.[13]
During the past few years, interest in the development of novel drug delivery systems for
existing drug molecules has been renewed. The development of a novel delivery system for
existing drug molecules not only improves the drug’s performance in terms of efficacy and
safety but also improves patient compliance and overall therapeutic benefit to a significant
extent.[1]
Transdermal Drug Delivery System (TDDS) are defined as self contained, discrete
dosage forms which are also known as “patches”.[2,3]
when patches are applied to the intact
skin, deliver the drug through the skin at a controlled rate to the systemic
circulation.[4]
TDDS are dosage forms designed to deliver a therapeutically effective amount
of drug across a patient’s skin.[5]
The main objective of transdermal drug delivery system is to deliver drugs into systemic
circulation into the skin through skin at predetermined rate with minimal inter and intra
patient variation.[3]
Currently transdermal delivery is one of the most promising methods for
drug application.[6]
It reduces the load that the oral route commonly places on the digestive
tract and liver. It enhances patient compliances and minimizes harmful side effects of a drug
caused from temporary over dose and is convenience in transdermal delivered drugs that
require only once weakly application.[7]
That will improves bioavailability, more uniform plasma levels, longer duration of action
resulting in a reduction in dosing frequency, reduced side effects and improved therapy due
to maintenance of plasma levels up to the end of the dosing interval compared to a decline in
plasma levels with conventional oral dosage forms.[8]
Transdermal delivery not only provides
controlled, constant administration of drugs, but also allows continuous input of drugs with
short biological half lives and eliminates pulsed entry into systemic circulation, which often
causes undesirable side effects.[3]
Several important advantages of transdermal drug delivery
are limitations of hepatic first pass metabolism, enhancement of therapeutic efficacy and
maintenance of steady plasma level of drug.[1]
The developments of TDDS is a
multidisciplinary activity that encompasses fundamental feasibility studies starting from the
selection of drug molecule to the demonstration of sufficient drug flux in an ex vivo and in
Page 4
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
622
vivo model followed by fabrication of a drug delivery system that meets all the stringent
needs that are specific to the drug molecule (physicochemical, stability factors), the patient
(comfort and cosmetic appeal), the manufacturer (scale up and manufacturability) and most
important economy.[7]
The first transdermal system, Transderm SCOP was approved by FDA in 1979 for the
prevention of nausea and vomiting associated with travel. Most transdermal patches are
designed to release the active ingredient at a zero order rate for a period of several hours to
days following application to the skin. This is especially advantageous for prophylactic
therapy in chronic conditions.[9]
The evidence of percutaneous drug absorption may be found
through measurable blood levels of the drug, detectable excretion of the drug and its
metabolites in the urine and through the clinical response of the patient to the administered
drug therapy.
1.1.Mechanisms of transdermal permeation
For a systemically active drug to reach a target tissue, it has to possess some physicochemical
properties which facilitate the sorption of the drug through the skin and enter the
microcirculation. The release of a therapeutic agent from Knowledge of skin permeation
kinetics is vital to the successful development of transdermal systems. This permeation can
be possible if the drug possesses certain physico-chemical properties. The rate of permeation
across the skin
dt
dQ is given by.
)1.......().........( rds CCPdt
dQ
Where, Cd = concentration of skin penetrant in the donar compartment (e.g., on the surface of
stratum corneum) Cr = concentration in the receptor compartment (e.g., body) respectively Ps
= the overall permeability constant of the skin tissue to the penetrant.
)2......(....................s
ssss
h
DKP
Where, Ks is the partition coefficient for the interfacial partitioning of the penetrant molecule
from a solution medium or a transdermal therapeutic system onto the stratum corneum,
Dss is the apparent diffusivity for the steady state diffusion of the penetrant molecule through
a thickness of skin tissues and hs is the overall thickness of skin tissues.
Page 5
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
623
As Ks, Dss and hs are constant under given conditions, the permeability coefficient (Ps) for a
skin penetrant can be considered to be constant.
From Eq.1 it is clear that a constant rate of drug permeation can be obtained only when
Cd>>Cr i.e., the drug concentration at the surface of the stratum corneum (Cd) is constistently
and substantially greater than the drug concentration in the body (Cr). then Eq. 1 becomes:
ds CPdt
dQ.
And the rate of skin permeation dQ/dt) become constant (Cd) become fairly constant
throughout the course of skin permeation.to maintain the (Cd) at a constant value the drug
released rate( Rr) always greater than the rate of skin uptake (Ra)
i.e. Rr>>Ra
by doing so Cd ia maintained at level which is always greater than the equilibrium solubility
of the drug in the stratum corneum and the maximum rate of skin permeation dQ/dt as
expressed by equation (4)
(dQ/dt)m = Ps.Cs
Reached apparently, the magnitude of dQ/dt)m is determined by the skin permeability
coefficient of the drug and its equilibrium solubility in the stratum corneum.
1.2.Types of Transdermal Films
There are five main types of transdermal patches.
1.2.1. Single-layer Drug-in-Adhesive
The adhesive layer of this system also contains the drug. In this type of patch the adhesive
layer not only serves to adhere the various layers together, along with the entire system to the
skin, but is also responsible for the releasing of the drug. The adhesive layer is surrounded by
a temporary liner and a backing.
1.2.2. Multi-layer Drug-in-Adhesive
The multi-layer drug-in-adhesive patch is similar to the single-layer system; the multi-layer
system is different, however, in that it adds another layer of drug-in-adhesive, usually
separated by a membrane (but not in all cases). One of the layers is for immediate release of
the drug and other layer is for control release of drug from the reservoir. This patch also has a
Page 6
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
624
temporary liner-layer and a permanent backing. The drug release from this depends on
membrane permeability and diffusion of drug molecules.
1.2.3. Reservoir
Unlike the single-layer and multi-layer drug-in-adhesive systems, the reservoir transdermal
system has a separate drug layer. The drug layer is a liquid compartment containing a drug
solution or suspension separated by the adhesive layer. The drug reservoir is totally
encapsulated in a shallow compartment molded from a drug-impermeable metallic plastic
laminate, with a rate-controlling membrane made of a polymer like vinyl acetate on one
surface. This patch is also backed by the backing layer. In this type of system the rate of
release is zero order.
1.2.4. Matrix
The matrix system has a drug layer of a semisolid matrix containing a drug solution or
suspension. The adhesive layer in this patch surrounds the drug layer, partially overlaying it.
Also known as a monolithic device.
1.2.5. Vapour Patch
In a vapour patch, the adhesive layer not only serves to adhere the various layers together but
also to release vapour. Vapour patches release essential oils for up to 6 hours and are mainly
used for decongestion. Other vapour patches on the market improve quality of sleep or aid
in smoking cessation.
1.3.Approaches used in development of TDDS
Several technologies have been successfully developed to provide a rate control over the
release and the transdermal permeation of drugs. These technologies can be classified into
four approaches as follows.
Membrane permeation – controlled systems
Adhesive dispersion – type systems.
Matrix diffusion – controlled systems.
Micro reservoir type or micro sealed dissolution controlled systems.
1.3.1. Membrane permeation – controlled systems: In this type of system, drug reservoir
is encapsulated in a shallow compartment moulded from a drug impermeable metallic plastic
laminate and a rate controlling polymeric membrane which may be micro porous or non-
Page 7
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
625
porous as shown in fig.4. The drug molecules are permitted to release only through the rate –
controlling polymeric membrane. In the drug reservoir compartment, the drug solids are
either dispersed homogenously in a solid polymer matrix (e.g. Polyisobutylene adhesive) or
suspended in anunbleachable, viscous liquid medium (e.g. Silicon fluids) to form a paste like
suspension. Examples of thissystem are Transderm-nitro, Transderm-scop, Catapresand
Estraderm etc.
Fig 1: Membrane permeation controlled system.
1.3.2. Adhesive Dispersion – Type Systems: This is a simplified form of the membrane-
permeation controlled system. The drug reservoir is formulated by directly dispersing the
drug in an adhesive polymer e.g. Poly (isobutylene) or poly (acrylate) adhesive and then
spreading the medicated adhesive, by solvent casting or hot melt, on to a flat sheet of drug
impermeable metallic plastic backing to form a thin drug reservoir layer. On the top of the
drug reservoir layer, thin layers of non-medicated, rate controlling adhesive polymer of a
specific permeability and constant thickness are applied to produce an adhesive diffusion –
controlled delivery system.
Fig 2: Adhesive dispersion type system.
Page 8
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
626
1.3.3. Matrix Diffusion- Controlled Systems: In this approach, the drug reservoir is
formed by homogenously dispersing the drug solids in a hydrophilic or lipophillic polymer
matrix. The resultant medicated polymer is then molded into a medicated disc with a defined
surface area and controlled thickness. Drug reservoir containing polymer disc is then pasted
onto an occlusive base plate in a compartment fabricated from a drug-impermeable plastic
backing membrane (fig.6). e.g. Nitro-Door: Delivers nitroglycerin for the treatment of angina
pectoris.
Fig 3: Matrix Diffusion- Controlled Systems.
1.3.4. Micro reservoir type or Micro sealed Dissolution:- The micro reservoir type drug
delivery system can be considered a combination of the reservoir and matrix diffusion type
drug delivery systems. This transfer maltherapeutic system is then produced by positioning
the medicated disc at the centre and surrounding it with an adhesive rim The Matrix system
design is characterized by the inclusion of a semisolid matrix containing a drug solution or
suspension which is in direct contact with the release line.
2. ANATOMY OF TRANSDERMAL DRUG DELIVERY SYSTEMS
2.1. Additives
2.1.1. Release Liner: Important properties for the release liner, the system component that
is removed before application to the skin, include easy removability and excipient resistance.
To maintain potency and predictable delivery characteristics, the liner must be resistant to
drugs within the preparation and to humidity.
Page 9
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
627
2.1.2. Backing Layer: Backings are chosen for appearance, flexibility and need for
occlusion. Examples of backings are polyester film, polyethylene film and polyolefin film.
Backing Layer is visible after the system is applied; the backing layer should exhibit
excipient resistance, a low moisture vapor transmission rate and nontoxic composition. Non-
excipient-resistant backings may allow leaching of additives from the backing and alteration
of the drug. A low moisture vapor transmission rate is essential to retaining skin moisture and
hydrating the area where by increases drug penetration.
2.1.3. Adhesive Layer: Adhesives are used to maintain intimate contact between the patch
and the skin surface. Many classes of adhesives are available that might be considered for use
with TDDS, although in practice pressure sensitive adhesives (PSAs) are preferred. PSAs are
generally defined as materials that adhere to a substrate with light pressure and which leave
no residual adhesive upon their removal and offer the following advantages.
2.1.4. Overlay: A TDDS may include a drug free adhesive coated film, foam or nonwoven
component designed to be placed over a transdermal patch that has been applied onto the
skin. This overlay secures the medicated patch to the skin of the patient.
2.1.5. Membrane: A membrane may be sealed to the backing to form a pocket to enclose
the drug containing matrix or used as a single layer in the patch construction. The diffusion
properties of the membrane are used to control availability of the drug and/or excipients to
the skin.
2.1.6. Chemical Permeation Enhancers: The skin’s physical structure provides a barrier
that may limit the permeation of some agents. Skin permeation enhancers broaden the range
of drugs that can be delivered transdermally by increasing the penetration of permeants
through enhanced diffusion of the SC and/or by increasing the solubility of the penetrant.
Protein denaturation may disrupt the barrier as many fluidization and randomization of
intercellular lipids or intercellular delamination and expansion. Ideally, a permeation
enhancer functions only to reduce the barrier resistance of the SC and does not damage any
viable cells. The ideal enhancer is: Pharmacologically inert. Nontoxic. Nonirritating.
Nonallergenic. The enhancer should not extract endogenous material out of the skin but
should spread well on skin and have a suitable skin feel. If the substance is a liquid and is to
be used at high volume fractions, it should be a suitable solvent for drugs. Due to their
systemic and localized toxicity, many effective chemical permeation enhancers have not been
Page 10
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
628
explored yet. Hence natural products have increasingly been used as enhancers due to their
better safety profile. Terpenes are essential oils, which are used as fragrance, flavourings, and
medicines. They have been found effective penetration enhancers for a number of hydrophilic
and lipophilic drugs. Terpenes are highly lipophilic due to their isoprene (C5H8) units. They
are generally recognized as safe (GRAS) by the FDA. They increase the drug diffusivity in
the SC for hydrophilic drugs and they enhance partitioning of drug into the SC for lipophilic
drugs, besides causing increased diffusivity.
2.2. Selection of Drug
Drug should be chosen with great care, various parameters to be considered for the selection
of drug includes.
2.2.1. Physicochemical properties of drug
Should have molecular weight less than 1000 daltons.
Should have affinity for both lipophilic and hydrophilic phase.
Should have low melting point.
2.2.2. Biological properties of drug.
Should be potent with daily dose of few mg.
Should have short half life.
Drug must not induce cutaneous irritation or allergic response.
Drug which degrade in GIT or are inactivated by hepatic first pass effect are suitable
candidates.
Tolerance to drug must be developed under near zero order release profile of transdermal
delivery.
Drugs which have to be administered for long period of time or which causes adverse
effect to non target tissues can also be formulated.
3. ADVANTAGES OF TRANSDERMAL DRUG DELIVERY
Transdermal drug delivery enables the avoidance of gastrointestinal absorption with its
associated pitfalls of enzymatic and pH associated deactivation.
Avoidance of first pass metabolism.
The lack of peaks in plasma concentration can reduce the risk of side effects, thus drugs
that require relatively consistent plasma levels are very good candidate for transdermal
drug delivery.
Page 11
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
629
As a substitute for oral route.
The patch also permit constant dosing rather than the peaks and valley in medication level
associated with orally administered medication.
Rapid notifications of medication in the event of emergency as well as the capacity to
terminate drug effects rapidly via patch removal.
Avoidance of gastro intestinal incompatibility.
Convenience especially notable in patches that require only once weekly application, such
a simple dosing regimen can aid in patient adherence to drug therapy.
Minimizing undesirable side effects.
Provide utilization of drug with short biological half lives, narrow therapeutic window.
Avoiding in drug fluctuation drug levels.
Inter and intra patient variation.
Termination of therapy is easy at any point of time.
Provide suitability for self-administration.
They are non-invasive, avoiding the inconvenience of parentral therapy.
The activity of drugs having a short half-life is extended through the reservoir of drug in
the therapeutic delivery system and its controlled release.
It is of great advantages in patients who are nauseated or unconscious.
Transdermal patches are better way to deliver substances that are broken down by the
stomach aids, not well absorbed from the gut, or extensively degraded by the liver.
Transdermal patches are cost effective.
4. DISADVANTAGES OF TRANSDERMAL DRUG DELIVERY
Transdermal drug delivery system cannot deliver ionic drugs.
It cannot achieve high drug levels in blood.
It cannot develop for drugs of large molecular size.
It cannot deliver drugs in a pulsatile fashion.
It cannot develop if drug or formulation causes irritation to skin.
Possibility of local irritation at site of application.
May cause allergic reaction.
Sufficient aqueous and lipid solubility, a log P (octanol/ water) between 1 and 3 is
required for permeate to transverse stratum corneum and underlying aqueous layer.
Only potent drugs are suitable candidates for transdermal patch because of the natural
limits of drug entry imposed by the skin’s impermeability.
Page 12
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
630
Long time adherence is difficult.
5. TRANSDERMAL ROUTE THROUGH SKIN AND DRUG DELIVERY
PROSPECTS
5.1.Description
The skin is the largest organ of the human body which covers a surface area of approximately
2 sq.m. and receives about one third of the blood circulation through the body. It serves as a
permeability barrier against the transdermal absorption of various chemical and biological
agents. It is one of the most readily available organs of the body with a thickness of few
millimeters (2.97 0.28 mm) which,
Separates the underlying blood circulation network from the outside environment
Serves as a barrier against physical, chemical and microbiological attacks.
Acts as a thermostat in maintaining body temperature.
Plays role in the regulation of blood pressure.
Protects against the penetration of UV rays.
Skin is a major factor in determining the various drug delivery aspects like permeation
and absorption of drug across the dermis. The diffusional resistance of the skin is greatly
dependent on its anatomy and ultrastructure
5.2.Anatomy of Skin
The structure of human skin can be categorized into four main layers
The epidermis
The viable epidermis
A non-viable epidermis (Stratum corneum
The overlying dermis
The innermost subcutaneous fat layer (Hypodermis)
5.2.1. The Epidermis
The epidermis is a continually self-renewing, stratified squamous epithelium covering the
entire outer surface of the body and primarily composed of two parts: the living or viable
cells of the malpighian layer (viable epidermis) and the dead cells of the stratum
corneum commonly referred to as the horny layer.[5]
Viable epidermis is further classified
into four distinct layers.[12]
Stratum lucidum
Stratum granulosu
Page 13
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
631
Stratum spinosu
Stratum basale
Fig. 4: Schematic representation of anatomy of epidermis.
5.2.2. Stratum corneum
This is the outermost layer of skin also called as horny layer. It is the rate limiting barrier that
restricts the inward and outward movement of chemical substances. The barrier nature of the
horny layer depends critically on its constituents: 75-80% proteins, 5-15% lipids, and 5-10%
ondansetron material on a dry weight basis.
Stratum corneum is approximately 10 mm thick when dry but swells to several times when
fully hydrated. It is flexible but relatively impermeable. The architecture of horny layer may
be modeled as a wall-like structure with protein bricks and lipid mortar. It consists of horny
skin cells (corneocytes) which are connected via desmosomes (protein-rich appendages of the
cell membrane). The corneocytes are embedded in a lipid matrix which plays a significant
role in determining the permeability of substance across the skin.[11]
Fig. 5: Schematic representation of microstructure of stratum corneum.
Page 14
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
632
5.2.3. Viable epidermis
This is situated beneath the stratum corneum and varies in thickness from 0.06 mm on the
eyelids to 0.8mm on the palms. Going inwards, it consists of various layers as stratum
lucidum, stratum granulosum, stratum spinosum, and the stratum basale. In the basale layer,
mitosis of the cells constantly renews the epidermis and this proliferation compensates the
loss of dead horny cells from the skin surface. As the cells produced by the basale layer move
outward, they itself alter morphologically and histochemically, undergoing keratinization to
form the outermost layer of stratum corneum.[14]
Fig. 6: Schematic representation of different layers of epidermis.
5.2.4. Dermis
Dermis is the layer of skin just beneath the epidermis which is 3 to 5 mm thick layer and is
composed of a matrix of connective tissues, which contains blood vessels, lymph vessels, and
nerves. The cutaneous blood supply has essential function in regulation of body temperature.
It also provides nutrients and oxygen to the skin, while removing toxins and waste products.
Capillaries reach to within 0.2 mm of skin surface and provide sink conditions for most
molecules penetrating the skin barrier. The blood supply thus keeps the dermal concentration
of permeate very low, and the resulting concentration difference across the epidermis
provides the essential driving force for transdermal permeation. In terms of transdermal drug
delivery, this layer is often viewed as essentially gelled water, and thus provides a minimal
Page 15
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
633
barrier to the delivery of most polar drugs, although the dermal barrier may be significant
when delivering highly lipophillic molecules.[13]
5.2.5. Hypodermis
The hypodermis or subcutaneous fat tissue supports the dermis and epidermis. It serves as a
fat storage area. This layer helps to regulate temperature, provides nutritional support and
mechanical protection. It carries principal blood vessels and nerves to skin and may contain
sensory pressure organs. For transdermal drug delivery, drug has to penetrate through all
three layers and reach in systemic circulation.
5.2.6. Percutaneous absorption
Before a topically applied drug can act either locally or systemically, it must penetrate
through stratum corneum. Percutaneous absorption is defined as penetration of substances
into various layers of skin and permeation across the skin into systemic
circulation.[11]
Percutaneous absorption of drug molecules is of particular importance in
transdermal drug delivery system because the drug has to be absorbed to an adequate extent
and rate to achieve and maintain uniform, systemic, therapeutic levels throughout the
duration of use. In general once drug molecule cross the stratum corneal barrier, passage into
deeper dermal layers and systemic uptake occurs relatively quickly and easily.
Fig. 7: Schematic representation of percutaneous permeation.
Page 16
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
634
The release of a therapeutic agent from a formulation applied to the skin surface and its
transport to the systemic circulation is a multistep process which involves.
Dissolution within and release from the formulation
Partitioning into the skin’s outermost layer, the stratum corneum (SC)
Diffusion through the SC, principally via a lipidic intercellular pathway.
Partitioning from the SC into the aqueous viable epidermis, diffusion through the viable
epidermis and into the upper dermis, uptake into the papillary dermis (capillary system)
and into the microcirculation.
6. ROUTES OF DRUG PENETRATION THROUGH SKIN
In the process of percutaneous permeation, a drug molecule may pass through the epidermis
itself or may get diffuse through shunts, particularly those offered by the relatively widely
distributed hair follicles and eccrine glands as shown in figure 6. In the initial transient
diffusion stage, drug molecules may penetrate the skin along the hair follicles or sweat ducts
and then absorbed through the follicular epithelium and the sebaceous glands. When a steady
state has been reached the diffusion through the intact Stratum corneum becomes the primary
pathway for transdermal permeation.
6.1. Transepidermal route
In transepidermal transport, molecules cross the intact horny layer. Two potential micro-
routes of entry exist, the transcellular (or intracellular) and the intercellular pathway.
Fig. 8: Schematic representation of Transepidermal route.
Page 17
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
635
Both polar and non-polar substances diffuse via transcellular and intercellular routes by
different mechanisms. 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
lipophillic permeants (octanol/water log K > 2) traverse the stratum corneum via the
intercellular route. Most molecules pass the stratum corneum by both routes.[5]
Fig. 9: Possible micro routes for drug penetration across human skin intercellular or
transcellular.
6.2.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% area of the total
skin. This route seems to be most important for ions and large polar molecules which hardly
permeate through the stratum corneum.
Page 18
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
636
6.3.Barrier functions of the skin
The top layer of skin is most important function in maintaining the effectiveness of the
barrier. Here the individual cells overlie each other and are tightly packed, preventing
bacteria from entry and maintaining the water holding properties of the skin.[14]
Stratum
corneum mainly consists of the keratinized dead cell and water content is also less as
compared to the other skin components. Lipids are secreted by the cells from the base layer
of the skin to the top. These lipid molecules join up and form a tough connective network, in
effect acting as the mortar between the bricks of a wall.
7. IDEAL PROPERTIES OF DRUG CANDIDATE FOR TRANSDERMAL DRUG
DELIVERY
Parameter Properties
Dose Should be low (<20 mg/day)
Half-life in h 10 or less
Molecular weight <400
Partition coefficient Log P (octanol-water) between-1.0 and 4
Skin permeability coefficient >0.5 × 10−3
cm/h
Skin reaction Non irritating and non-sensitizing
Oral bioavailability Low
Therapeutic index Low
7.1.Environmental factors
7.1.1. Sunlight
Due to Sunlight the walls of blood vessels become thinner leading to bruising with only
minor trauma in sun-exposed areas. Also pigmentation: The most noticeable sun-induced
pigment change is a freckle or solar lentigo.
7.1.2. Cold Season
Often result in itchy, dry skin. Skin responds by increasing oil production to compensate for
the weather’s drying effects. A good moisturizer will help ease symptoms of dry skin. Also,
drinking lots of water can keep your skin hydrated and looking radiant.
7.1.3. Air Pollution
Dust can clog pores and increase bacteria on the face and surface of skin, both of which lead
to acne or spots. This affects drug delivery through the skin. Invisible chemical pollutants in
the air can interfere with skin’s natural protection system, breaking down the natural skin’s
oils that normally trap moisture in skin and keep it supple.
Page 19
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
637
7.1.4. Effect of Heat on Transdermal patch
Heat induced high absorption of transdermal delivered drugs. Patient should be advised to
avoid exposing the patch application site to external heat source like heated water bags, hot
water bottles. Even high body temperature may also increase the transdermally delivered
drugs. In this case the patch should be removed immediately. Transdermal drug patches are
stored in their original packing and keep in a cool, dry place until they are ready to used.
8. VARIOUS METHODS FOR PREPARATION OF TRANSDERMAL DRUG
DELIVERY SYSTEM
8.1.Asymmetric TPX membrane method
A prototype patch can be fabricated by a heat sealable polyester film (type 1009, 3m) with a
concave of 1cm diameter 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.
8.2. Asymmetric TPX membrane preparation
These are fabricated by using the dry/wet inversion process. TPX is dissolved in a mixture of
solvent (cyclohexane) and nonsolvent additives at 60°c to form a polymer solution. The
polymer solution is kept at 40°C for 24 hrs and cast on a glass plate to a pre-determined
thickness with a gardener knife. After that the casting film is evaporated at 50°C for 30 sec,
then the glass plate is to be immersed immediately in coagulation bath [maintained the
temperature at 25°C]. After 10 minutes of immersion, the membrane can be removed, air dry
in a circulation oven at 50°C for 12 hrs].
8.3. Circular teflon mould method
Solutions containing polymers in various ratios are used in an organic solvent. Calculated
amount of drug is dissolved in half the quantity of same organic solvent. Enhancers in
different concentrations are dissolved in the other half of 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 for 12 h and then poured into a circular teflon mould. The moulds are placed
on a leveled surface and covered with an inverted funnel to control solvent vaporization in a
laminar flow hood model with speed of air 1/2 m /sec. The solvent is allowed to evaporate for
24 h. Before evaluation the dried films are to be stored for another 24 h at 25±0.5 °C in a
desiccators containing silica gel before to eliminate aging effects. These types of films are to
be evaluated within one week of their preparation.
Page 20
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
638
8.4. Mercury substrate method
In this method drug is dissolved in polymer solution along with plasticizer. The above
solution is to be stirred for 10-15 min to produce a homogeneous dispersion and poured in to
a leveled mercury surface. Then the solution is covered with inverted funnel to control
solvent evaporation.
8.5. By using “EVAC membranes” method
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. If the drug is not soluble in water, propylene glycol is used for the
preparation of 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
form) is placed on a sheet of backing layer covering the specified area. A rate controlling
membrane will be placed over the gel and the edges will be sealed by heat to obtain a leak
proof device.
8.6. Aluminium backed adhesive film method
Transdermal drug delivery system may produce unstable matrices if the loading dose is
greater than 10 mg. Aluminium backed adhesive film method is a suitable one for preparation
of same, chloroform is choice of solvent, because most of the drugs as well as adhesive are
soluble in chloroform. The drug is dissolved in chloroform and adhesive material will be
added to the drug solution and dissolved. A custammade aluminium former is lined with
aluminium foil and the ends blanked off with tightly fitting cork blocks.
8.7. By using free film method
Free film of cellulose acetate is prepared by casting on mercury surface. A polymer solution
2% w/w is prepared by using chloroform. Plasticizers are incorporated at a concentration of
40% w/w of polymer weight. Five ml of polymer solution was poured in a glass ring which is
placed over the mercury surface in a glass petri dish. The rate of evaporation of the solvent is
controlled by placing an inverted funnel over the petridish. The film formation is noted by
observing the mercury surface after complete evaporation of the solvent. The dry film will be
separated out and stored between the sheets of wax paper in desiccators until use. Free films
of different thickness can be prepared by changing the volume of the polymer solution.
Page 21
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
639
9. CHARACTERIZATION OF PREPARED TRANSDERMAL PATCHES
9.1. Physical appearance
All the formulated transdermal patches of Felodipine were visually inspected for colour,
flexibility, homogeneity & smoothness.
9.2. Thickness
The thickness of the formulated patch was measured at 3 different places on a single patch
using screw gauge and average thickness of three readings was calculated.
9.3. Folding endurance
The folding endurance was measured manually for the formulated patches. A strip of patch
(2×2cm2) was cut and repeatedly folded at the same place until it broke. The number of times
the patch could be folded at the same place without breaking or cracking was observed.
9.4. Weight uniformity
To check weight uniformity, three patches from each formulation batch was randomly
selected. Patches of 2×2cm2 were weighed individually on digital balance and average
weight of three patches was calculated.
9.5. Tensile strength
The tensile strength and percent elongation of the prepared films were performed using a
Universal strength testing machine (Hounsfield, slinfold, U.K.). It is consists of two load cell
grips. The upper one was movable and lower one was fixed. The test patch of size (2 x 2cm2)
was fixed between these two cell grips and force was gradually applied till the patch broke.
The tensile strength of patch was taken directly from the dial reading in kg. The tensile
strength was calculated as;
Tensile strength = Tensile load at break/ cross sectional area
9.6. Ex-Vivo Release Studies
9.6.1. Preparation of skin
A full thickness of skin was excised from dorsal site of dead albino rat (150-200gm) and skin
was washed with water. The fatty tissue layer was removed. The outer portion with hairs was
applied with depilatory and allowed to dry. The hairs were scrubbed with the help of wet
cotton and washed with normal saline solution. The skin was kept in phosphate buffer
solution (pH-7.4) in refrigerator until skin was used for release study. Prior to use, the skin
Page 22
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
640
was allowed to equilibrate with room temperature. After that the skin was mounted between
donor and receptor compartment of cell. The skin was clamped in such a way that the dermal
side will be in contact with receptor medium.
9.6.2. Methodology
Phosphate buffer pH 7.4 was used as receptor solution. The volume of Franz diffusion cell
was 30 ml and temperature was maintained at 37 ± 1°C with the help of hot plate. The
diffusion has been carried out for 24 hours and 1 ml sample was withdrawn at different time
interval for a period of 24 hour. The same volume of phosphate buffer with pH 7.4 was added
to receptor compartment to maintain sink conditions and the samples were analyzed at 239
nm.[13,14]
9.7. Skin Irritation studies
To predict the compatibility between polymeric patch and skin, Draize test for skin irritation
was performed. Skin irritation was performed on healthy rabbits (average weight: 1.5 to 2.5
kg). The dorsal surface (50 cm2) of rabbit was cleaned, and the hair was removed by shaving.
The skin was cleared with rectified spirit. Formalin solution (0.8%) was used as control. The
optimized formulation was placed over the skin and was removed after 24 hours. The resulted
skin reaction was checked for erythema.
9.8. Stability studies
As per ICH guidelines, transdermal patches were subjected to accelerated stability studies.
Optimized formulation was exposed to controlled temperature (40±2 °C) and relative
humidity (75±5 % RH) for a period of 2 months in humidity control oven (Lab Control,
Ajinkya IM 3500 Series, India). After 15, 30 and 60 days the samples were taken out and
analyzed for Physical appearance, folding endurance and ex-vivo drug release.
10. CONCLUSION
To overcome the problems associated with the oral delivery route, transdermal drug delivery
systems are utterly used as an alternative route especially focusing improvements in the
elegance, dosage flexibility and patient compliance. This scenario surely remains continued
in the future and hence leads to more advancement of modern techniques involved for
loading a bioactive in TDDS for overcoming the problems associated with the barrier
properties of the skin. The attractiveness of the transdermal route for application of this
technology is obvious because of the accessibility of the device for adjustment, control and
Page 23
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
641
removal. New TDDS products, approved by FDA having bioactive under categories that
include hypertension, angina, motion sickness, female menopause, male hypogonadism,
severe pain, local pain control, nicotine dependence, and recently, contraception and urinary
incontinence. These products are gaining worldwide popularity and thus are considered as a
mature technology. These systems bypass many problems that concern with poor oral
bioavailability, side effect associated with high peak or poor compliance due to frequent dose
interval. Much research are still in progress for the development and scale up of TDDS under
categories like, Parkinson's disease, attention deficit and hyperactivity disorder and female
sexual dysfunction.
11. REFERENCES
1. Kakr R, Rao R, Goswami A, Nanda S, Saroha K. Proniosomes: An emerging vesicular
system in drug delivery and cosmetics. Der Pharmacia Lettre, 2010; 2: 227–39.
2. Walve JR, Rane BR, Gujrathi NA. Proniosomes: A surrogate carrier for improved
transdermal drug delivery system. Int J Res Ayurveda Pharm, 2011; 2: 743–50.
3. Dua JS, Rana AC, Bhandari AK. Liposomes methods of preparation and applications. Int
J Pharm Stud Res, 2012; 3: 14–20.
4. Daemen T, de Mare A, Bungener L, de Jonge J, Huckriede A, Wilschut J. Virosomes for
antigen and DNA delivery. Adv Drug Deliv Rev, 2005; 57: 451–63. [PubMed]
5. Mujoriya RZ, Dhamandeb K, Bodla RB. Niosomal drug delivery systems-a review. Int J
Appl Pharm, 2011; 3: 7–10.
6. Akhilesh D, Prabhu P, Faishal G. Comparative study of carriers used in proniosomes. Int
J Pharm Chem Sci, 2012; 4: 307–14.
7. Rai K, Gupta Y, Jain A, Jain SK. Transfersomes: Self-optimizing carriers for
bioactives. PDA J Pharm Sci Technol, 2008; 62: 362–79. [PubMed]
8. Kish-Trier E, Hill CP. Structural biology of the proteasome. Annu Rev Biophys, 2013;
42: 1.1–121.
9. Lankalapalli S, Damuluri M. Sphingosomes: Applications in targeted drug delivery. Int J
Pharm Chem Biol Sci, 2012; 2: 507–16.
10. Sprott GD, Sad S, Fleming LP, Dicaire CJ, Patel GB, Krishnan L. Archaeosomes varying
in lipid composition differ in receptor-mediated endocytosis and differentially adjuvant
immune responses to entrapped antigen. Archaea, 2003; 1: 151–64. [PMC free
article] [PubMed]
Page 24
Tamta et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 6, 2020.
642
11. Rattanapak T, Young K, Rades T, Hook S. Comparative study of liposomes,
transfersomes, ethosomes and cubosomes for transcutaneous immunisation:
Characterisation and in vitro skin penetration. J Pharm Pharmacol, 2012; 64: 1560–9.
[PubMed]
12. Mishra A, Kapoor A, Bhargava S. Proniosoml gel as a carrier for improved transdermal
drug delivery. Asian J Pharm Life Sci, 2011; 1: 370–9.
13. Sankar V, Ruckmani K, Durga S, Jailani S. Proniosomes as drug carriers. Pak J Pharm
Sci, 2010; 23: 103–7. [PubMed]
14. Chandra A, Sharma PK. Proniosome based drug delivery system of piroxicam. Afr J
Pharm Pharmacol, 2008; 2: 184–90.
15. Kakkar R, Rao R, Kumar DN. Formulation and characterisation of valsartan
proniosomes. Maejo Int J Sci Technol, 2011; 5: 146–58.