Kurdistan Regional Government

Ministry of Higher Education & Scientific Research

University of Duhok
College of Pharmacy

Transdermal Drug Delivery Systems

A Review Article

Prepared by
Zhehat Abdulwaheed Yaseen
B.Sc. Pharmacy

Supervised by
Asst. Prof. Dr. Mohanad Alfahad
PhD. Biopharmaceutics

2024 A.D. 2723 K. 1445 A.H.

Table of Contents
1. Abstract.......................................................................................................................... 5
2. Introduction.................................................................................................................... 6
3. Literature review ............................................................................................................ 7
4. Physiology and Anatomy of the skin ................................................................................ 8
4.1. Epidermis ............................................................................................................................9
4.2. Dermis .............................................................................................................................. 10
4.3. Hypodermis ...................................................................................................................... 10
4.4. The appendages ................................................................................................................ 10
5. Physicochemical & Biological properties of drug molecules utilized in Transdermal drug
delivery systems. ................................................................................................................. 11
5.1. Biological Properties.......................................................................................................... 11
5.2. Physicochemical properties ................................................................................................... 12
5.2.1 Partition Coefficient ...................................................................................................................................12
5.2.2. Molecular weight .....................................................................................................................................12
5.2.3. Solubility/Melting Point ...........................................................................................................................12
5.2.4 Ionization ...................................................................................................................................................12
5.2.5. Drug Binding..............................................................................................................................................12
5.2.6. Particle size ...............................................................................................................................................13

6. Dosage forms used for transdermal drug delivery systems. ........................................... 13

6.1. Drug in adhesive system ............................................................................................ 14
6.1.1. Single layer drug in adhesive .......................................................................................... 14
6.1.2. Multi-layer drug in adhesion .......................................................................................... 14
6.2. Reservoir .......................................................................................................................... 15
6.3. Matrix ............................................................................................................................... 15
6.4. Vapor Patch....................................................................................................................... 15
6.5. Micro reservoir system ...................................................................................................... 16
7. Evaluation of transdermal patches: ............................................................................... 18
7.1. Physicochemical evaluation ............................................................................................... 18
7.1.1. Thickness ...........................................................................................................................................18
7.1.2. Uniformity of weight .........................................................................................................................18
7.1.3. Drug content determination ..............................................................................................................18
7.1.5. Moisture content ...............................................................................................................................19
7.1.6. Moisture Uptake ................................................................................................................................19
7.1.7. Flatness ..............................................................................................................................................19
 7.1.8. Folding Endurance .............................................................................................................................20
7.1.9. Tensile Strength .................................................................................................................................20
7.1.10. Tack properties ..................................................................................................................................20
7.1.11. Thumb tack test .................................................................................................................................20
7.1.12. Rolling ball test ..................................................................................................................................20
7.1.13. Quick stick (Peel tack) test .................................................................................................................21
7.1.14. Probe tack test ...................................................................................................................................21
7.2. In vitro release studies ...................................................................................................... 21
7.3. In vivo Studies ........................................................................................................... 22
7.3.1. Animal models ...................................................................................................................................22
7.3.2. Human model ....................................................................................................................................22

8. Kinetics of transdermal drug delivery systems ............................................................... 22

9. Synthesis and Analysis .................................................................................................. 25
10. Discussion ................................................................................................................. 29
11. Conclusion................................................................................................................. 30
12. References ................................................................................................................ 31
List of Figures
Figure 1 Anatomy of the skin .................................................................................................................... 9
Figure 2 Representation of different types of patches .......................................................................... 14
Figure 3 Reservoir type transdermal system Reference ....................................................................... 15
Figure 4 Design of matrix type transdermal patch ............................................................................... 15
Figure 5 Microreservoir system .............................................................................................................. 16
Figure 6 Schematic examples of a static (Franz type) diffusion cell .................................................... 21
Figure 7 Skin routes of transdermal Drug passage ............................................................................... 23
Figure 8 Comparison between Plasma concentration profiles of Oral & TDD route ........................ 25

List of tables
Table 1 Excellent properties of drug candidate for transdermal drug delivery ................................. 11
Table 2 Approved Drug Products with Therapeutic Equivalence Evaluations as of 22.1.2024 ......... 16
Table 3. A summary of the various findings regarding TDD Systems………………………………..25

List of abbreviations
Abbreviation Definition
TDDS Transdermal drug delivery systems
GMP Good manufacturing practice
TDD Transdermal drug delivery
SC stratum corneum
 1. Abstract

Transdermal delivery involves applying a medication to the skin with the goal of
reaching systemically active drug levels. Because of its inherent tortuosity and
lipophilic nature, the stratum corneum almost always acts as the main barrier
preventing drug molecules from entering the body; Furthermore, the
physicochemical properties of the selected drug and dosage form add up to numerous
barriers and restrictions in transdermal delivery because of specific physiological
and anatomical features of Skin tissue layers; numerous investigations have been
carried out to address these issues. For transdermal drug delivery, a wide range of
dosage forms and delivery methods are used, with transdermal drug delivery systems
receiving the most attention. Ultimately, thorough evaluation and kinetic research
are needed to evaluate the product's bioavailability, efficacy, safety, and quality in
order to guarantee that patients receive an effective overall preparation that complies
with standards and good manufacturing practices (GMP). In this article review, we
will outline the various aspects related to transdermal drug delivery including
physiology of skin layer with particular emphasis on the transdermal drug delivery
systems, the physicochemical and biological features of drug molecules used in such
systems , their evaluation and kinetic properties.
Keywords: Transdermal; Patches; Drug delivery; Kinetics.
 2. Introduction
TDD is a painless method of applying a drug formulation onto an intact, healthy skin
in order to deliver a drug systemically (Addicks et al., 1990). Avoiding build up in
the dermal layer, the medication first enters the stratum corneum before moving on
to the deeper layers of the dermis and epidermis. Once a medication reaches the
dermal layer, the dermal microcirculation can absorb it systemically(Chiang et al.,
1989).
Transdermal patch features include; occluded applications, Relatively constant in
composition when used, predetermined system area, Application site identified,
Application method is reproducible, sustained delivery, Utilize a unit drug activity.
Steady state delivery, Zero-order delivery, serum levels represent efficacy, (blood
level) pharmacokinetic end point-based bioequivalency, inevitable local tissue
toxicity levels that are solely viable to the system, Interruptible individual dose,
Complete system removed after usage, Low delivery efficiency (Flynn, 1993).
TDD provides a range of benefits over other traditional drug delivery routes. (Tuan-
Mahmood et al., 2013). It can avoid complications like needle phobia by offering a
non-invasive substitute for parenteral routes. Numerous placement options for
transdermal absorption on the skin are made possible by the skin's large surface area
and accessibility (Schoellhammer et al., 2014). Moreover, medications have more
consistent pharmacokinetic profiles with lesser peaks, which reduces the possibility
of harmful side effects, Because fewer doses are required, it can increase patient
compliance, Patients who depend on self-administration or who are unconscious or
vomiting can also benefit from it. Because TDD circumvents pre-systemic
metabolism, thus bioavailability is improved (Ita, 2014).
Additionally, the skin is abundant in dendritic cells in the dermal and epidermal
layers, which are crucial for immune responses. This is the reason it is appealing to
use the skin as a novel site for vaccination strategies (Suh et al., 2014).
 3. Literature review
The creation of a novel delivery method for already-approved medication molecules
significantly increases patient compliance and the net therapeutic benefit of the
medication in addition to enhancing its efficacy and safety (Prausnitz & Langer,
2008).
While some liquid and semi-solid drug products (such as gels, creams, lotions,
foams, ointments, and sprays) may be designed to deliver the drug locally or
transdermally in certain situations, they are not regarded as TDDS , Topical delivery
systems are made to deliver the active ingredient to local tissue, On the other hand,
transdermal drug delivery systems are designed to transfer the medication through
the skin and into the bloodstream (FDA; guidance for industry, 2019).
When applied to intact skin, Transdermal Drug Delivery Systems (TDDS)(Patches)
are self-contained, discrete dosage forms that deliver drugs to the systemic
circulation at a controlled rate (Divya et al., 2012).
A transdermal patch ( skin patch), regulates the speed at which the liquid medication
inside the reservoir of the patch can permeate the skin and enter the bloodstream
using a unique membrane (Mali et al., 2015).
The first transdermal patch, a scopolamine patch, was developed in the 1970s and
approved by the FDA in 1979 to treat motion sickness (Shaila et al., 2006).
One of three methods is usually used for transdermal delivery of solutes: the
intracellular route, also referred to as the transcellular route (Jhawat et al., 2013);
the transappendageal route, also known as the shunt route (Rastogi & Yadav, 2012)
and the intercellular route (Jawat et al., 2013).

The fact that only certain medications can be administered via transdermal delivery
presents perhaps the biggest obstacle, Effective transdermal medications with
existing delivery systems posses molecular masses of a few hundred Daltons, show
strongly lipid-favoring octanol-water partition coefficients, and require milligrams
or fewer of a dose per day (Prausnitz et al., 2004).
The advancement of transdermal delivery systems can be categorized into three
generations; As the First generation produced many of the patches used today by
carefully selecting drugs that could cross the skin at therapeutic rates with little to
no enhancement while The second-generation increased skin permeability and
provided additional advancements for small molecule delivery and The third
generation will allow for the transdermal delivery of virus-based vaccines, small
molecules, macromolecules (such as proteins and DNA) through targeted
permeability enhancement of the stratum corneum of the skin (Gill and Prausnitz,
2007).

4. Physiology and Anatomy of the skin

The skin acts like the body's envelope and is intricately linked to the fascial
endoskeleton beneath it by lymphatics, blood vessels, nerves, and retinacular
ligaments (Wong et al., 2015). The skin is the largest & most accessible organ in
the body, making up 16% of an average person's total body mass with its 1.7 m2
surface area (Liu et al., 2014). The skin's primary purpose is to act as a barrier of
defense between the body and the external environment, retaining out germs,
chemicals, allergens, ultraviolet (UV) radiation, and water loss, The dermis,
epidermis, and hypodermis are the three primary regions of skin (Gratieri et al.,
2013). The anatomy of skin is outlined in (Fig.1).
 Figure 1 Anatomy of the skin (Alkilani et al., 2015)

4.1. Epidermis

The epidermis, or outermost layer of skin, has different thicknesses, measuring

around 0.8 mm ( soles of the feet and palms of the hands) (Benson and Watkinson,
2012).
The outermost layer of the epidermis is called the stratum corneum (El Maghraby
et al., 2008).
The stratum lucidum, which is only found in a few particular areas of the human
body, including the palms, fingertips, and soles of the feet, is the outermost layer of
the epidermis, The other three layers are the stratum granulosum, the stratum
spinosum, and the stratum basale, which is the innermost layer and contains
epidermal stem cells (Oláh et al., 2012). The last four layers, known as the viable
epidermis (Tuan-Mahmood et al., 2013).
About 95% of the cells in the epidermis are keratinocytes; melanocytes, Langerhans
cells, melanocytes, and Merkel cells are among the other cells that make the
epidermal layers (El Maghraby et al., 2008).
 4.2. Dermis

The dermis, which embarks the skin its strength and elasticity, is about 2-3 mm thick
and is made up of 70% collagenous and elastin fibers, The dermis's blood vessels
supply the epidermis and dermis with nourishment, The dermis layer also contains
lymphatic vessels, nerves, and macrophages (Domínguez-Delgado et al., 2010).
4.3. Hypodermis

The deepest layer of the skin, known as the subcutaneous layer or hypodermis, is
made up of a network of fat cells, It serves as the layer of contact between the skin
and the body's underlying tissues, including the bones and muscles. Thus, the
primary roles of the hypodermis are heat insulation, protection from physical shock,
and support and conductance of the skin's neural and vascular signals. About half of
the body's fat is made up of fat cells that reside in the hypodermis; the other main
cell types in the hypodermis are macrophages and fibroblasts (McLennan et al.,
2005).
Aside from serving as a physical barrier, the skin also performs immune response,
sensation (touch, temperature, pain, and pressure perception), endocrine (synthesis
of vitamin D), neuroendocrine (tightly linked to central stress axes), and homeostatic
(removing excess water, uric acid, ammonia, urea, and urination) (Wierzbicka et
al., 2016).
4.4. The appendages

The appendages can be thought of as "shortcuts" or shunt routes for molecules to

cross the stratum corneum barrier in terms of drug delivery. While eccrine glands
are distributed throughout the majority of the body's surface, specialized apocrine
glands are located at particular body locations, such as the axillae and nipples. The
hair follicles and related sebaceous glands, which secrete sebum, which is made up
of fatty acids, waxes, and triglycerides, are the largest appendages. These hydrate
the skin's surface and support the preservation of the normal pH of the skin (Aulton
& Taylor, 2018).

5. Physicochemical & Biological properties of drug molecules

utilized in Transdermal drug delivery systems.
5.1. Biological Properties

Ideally, patches must be highly efficacious and potent (effective at a few milligrams
per day, for example), have a short biological half-life and stable when applied on
the skin, not irritate or cause allergies to humans, with transdermal delivery's nearly
zero-order release profile, tolerance to the medication shall not develop. The
recommended daily dosage is less than 50 mg, preferably less than 10 mg. The
medication shouldn't undergo significant skin metabolism or become permanently
bound in subcutaneous tissue. (Jalwal et al., 2010; Dhiman et al., 2011). (Table.1)
outlines the Excellent properties of drug candidates in transdermal drug delivery.

Table 1 Excellent properties of drug candidate for transdermal drug delivery

(Sharma et al., 2010)
5.2. Physicochemical properties

5.2.1 Partition Coefficient

When molecules are more highly lipophilic (log P > 4), the intercellular route will
be almost the only method by which they pass through the stratum corneum , There
are still lipid bilayers to cross between the keratinocytes, but the transcellular route
becomes more significant for more hydrophilic molecules (log P <1). In the case of
molecules that are highly hydrophilic and charged, the appendageal pathway might
also assume importance (Brown & Williams, 2019).
5.2.2. Molecular weight
It is commonly known that a molecule's diffusion coefficient is influenced by its
molecular weight, with larger molecules exhibiting lower diffusivities. (Crank,
1975).
5.2.3. Solubility/Melting Point
Although transdermal candidates should ideally have a moderately high
lipophilicity, they should also have some aqueous solubility & Low melting points
because topical medications are frequently applied from an aqueous formulation and
the skin's deeper layers tend to be more hydrophilic (Brown & Williams, 2019).
5.2.4 Ionization
Although charged permeants, such as ionized medications, may be able to pass
through the membrane by the shunt route, it is possible that their permeability
coefficient will be much lower than if the species were unionized and mostly passed
through the lipoidal intercellular route (Brown & Williams, 2019).
5.2.5. Drug Binding
There are many possible interactions between drug substances and the tissue because
of the diverse nature of skin components (proteins, lipids, enzymes, aqueous regions,
etc.) and the variety within permeants (ionized species, weak acids/bases, neutral
molecules, etc.), The lag time delay is a significant effect of binding between the
drug applied and skin components (Brown & Williams, 2019).
5.2.6. Particle size
If the drug is suspended, the particle size may play a major role in controlling the
flux; if the drug is poorly soluble in the vehicle and the rate at which the particles
dissolve is therefore rate-limiting, then reducing the particle size will accelerate the
rate at which the drug dissolves in the vehicle and so facilitate transdermal delivery
(Brown & Williams, 2019).

6. Dosage forms used for transdermal drug delivery systems.

While conventional dosage forms such as ointments (e.g. nitroglycerin ointments,
gels, sprays, solutions, can be used in this type of therapy, the norm is for adhesive
systems with precisely defined sizes (Flynn, 1993; FDA, guidance for industry,
2019).
For conventional dosage forms, penetration-enhancing methods either make use of
Ultrasound, electrically assisted techniques (iontophoresis and electroporation),
velocity-based devices (jet injectors, powder injection), thermal techniques
(radiofrequency heating and lasers), and mechanical techniques (tape stripping an
microneedles (MN)) are some of the active/physical methods for skin
permeabilization (Zhang et al., 2014). Enhancers of passive/chemical nature used
for percutaneous transport improvement such as esters, alcohols, Pyrolidones, water,
esters sulfoxides (like dimethyl sulfoxide) and their derivatives, hydrocarbons,
amides (including urea and its derivatives), fatty acids, surfactants (nonionic,
anionic, and cationic), essential oils (EOs), oxazolidines, polyols, epidermal
enzymes, polymers, and lipid synthesis inhibitors (Barry, 2001).
 Figure 2 Representation of different types of patches (Di Stefano et al., 2012)

6.1. Drug in adhesive system

6.1.1. Single layer drug in adhesive

The medication is contained in this system's adhesive layer. In this patch type,The
adhesive layer is responsible of both releasing the medication and holding the system
and all of the layers to the skin together. The rate at which drugs are released from
this kind of system depends on how quickly they diffuse through the skin. A backing
layer and a transient linear surround the adhesive layer (Fig.2.A.) (Sachan B,
Bajpai, 2013).
6.1.2. Multi-layer drug in adhesion

Two layers are used: one for the drug's immediate release, and the other for the
drug’s-controlled release from the reservoir. In addition, the multilayer patch has a
permanent backing and a transient linear layer(Fig.2.B.) (Dhiman et al., 2011).
 6.2. Reservoir

It features a separate drug layer, in contrast to adhesive systems' single and

multilayer drug formulations. The drug layer is an adhesive-separated liquid
compartment that holds a drug solution or suspension. the backing layer also
supports this patch (Fig.3) (Joshi and Selvaduary, 2008).

Figure 3 Reservoir type transdermal system Reference (Lee et al., 2001)

6.3. Matrix

A semisolid matrix containing a drug suspension or solution makes up the drug

layer in the Matrix system design. This patch has a layer of adhesive covering the
drug layer to some extent. Monolithic devices are another term for these kinds of
patches (Fig.4) (Dhiman et al., 2011).

Figure 4 Design of matrix type transdermal patch (Wiliams and Barry, 2004)

6.4. Vapor Patch

This type of patch's adhesive layer not only holds the various layers together but also
emits vapor. The newest items on the market are vapor patches, which have a six-
hour essential oil release time. The vapor patches are used for decongestion and
essential oils release. There are also controlled vapor patches available that enhance
the quality of sleep (Patel et al., 2012).
6.5. Micro reservoir system

A micro reservoir system combines a matrix-dispersion system with a reservoir. To

create a reservoir, the medication is combined with the water-soluble polymer
aqueous solution. The next step is to create thousands of microscopic drug reservoirs
by the homogeneous dispersion of the the mixture by high-shear mechanical forces
in a lipophilic polymer. By in-situ cross-linking the polymer, cross-linking agents
stabilize the thermodynamically unstable dispersion (Fig.5.) (Patel and Shah,
2018).

Figure 5 Microreservoir system (Chenevas-Paule et al., 2017)

Table 2 .Approved Drug Products with Therapeutic Equivalence Evaluations

as of 22.1.2024 (Center for Drug Evaluation and Research (U.S.), 2024)

No Mkt.Status Active Ingredient Dosage Form Strength

1 RX ASENAPINE SYSTEM 3.8MG/24HR
2 RX BUPRENORPHINE FILM, 5MCG/HR
EXTENDED
RELEASE
3 RX BUPRENORPHINE FILM, 20MCG/HR
EXTENDED
RELEASE
4 RX CLONIDINE SYSTEM 0.1MG/24HR
5 RX DEXTROAMPHETAMINE SYSTEM 4.5MG/9HR
6 RX ESTRADIOL FILM, 0.025MG/24HR
EXTENDED
RELEASE
7 RX ESTRADIOL GEL 0.1%
8 RX ESTRADIOL GEL, METERED 0.06%
(0.87GM/ACTIVATION
)
9 RX ESTRADIOL SPRAY 1.53MG/SPRAY
10 RX ESTRADIOL SYSTEM 0.014MG/24HR
11 RX ESTRADIOL; FILM, 0.045MG/24HR;
LEVONORGESTREL EXTENDED 0.015MG/24HR
RELEASE
12 RX ESTRADIOL; FILM, 0.05MG/24HR;
NORETHINDRONE EXTENDED 0.14MG/24HR
ACETATE RELEASE
13 RX ETHINYL ESTRADIOL; SYSTEM 0.03MG/24HR;
LEVONORGESTREL 0.12MG/24HR
14 RX ETHINYL ESTRADIOL; FILM, 0.035MG/24HR;
NORELGESTROMIN EXTENDED 0.15MG/24HR
RELEASE
15 RX FENTANYL FILM, 100MCG/HR
EXTENDED
RELEASE
16 RX GRANISETRON FILM, 3.1MG/24HR
EXTENDED
RELEASE
17 RX METHYLPHENIDATE FILM, 10MG/9HR (1.1MG/HR)
EXTENDED
RELEASE
18 RX NITROGLYCERIN FILM, 0.1MG/HR
EXTENDED
RELEASE
19 RX NITROGLYCERIN OINTMENT 2%
20 RX OXYBUTYNIN FILM, 3.9MG/24HR
EXTENDED
RELEASE
 21 RX RIVASTIGMINE FILM, 4.6MG/24HR
EXTENDED
RELEASE
22 RX ROTIGOTINE FILM, 1MG/24HR
EXTENDED
RELEASE
23 RX SCOPOLAMINE SYSTEM 1MG/72HR
24 RX SELEGILINE FILM, 6MG/24HR
EXTENDED
RELEASE
25 RX TESTOSTERONE GEL 50MG/5GM PACKET
26 RX TESTOSTERONE GEL, METERED 1.62%
(20.25MG/1.25GM
ACTUATION)
27 RX TESTOSTERONE SOLUTION, 30MG/1.5ML
METERED ACTUATION
28 OTC NICOTINE FILM, 7MG/24HR
EXTENDED
RELEASE

7. Evaluation of transdermal patches:

7.1. Physicochemical evaluation

7.1.1. Thickness
Transdermal film thickness can be measured at various locations along the film using
a micrometer, dial gauge, screw gauge, or travelling microscope (Divya et al., 2012).
7.1.2. Uniformity of weight
Ten randomly chosen patches are weighed individually, and the average weight is
then determined in order to study weight variation. There mustn’t be a big difference
between the average weight and the individual weight (Gupta and Chokshi, 2011).
7.1.3. Drug content determination
A precisely weighed portion of the film (roughly 100 mg) dissolved in 100 mL of a
typical solvent (the drug should dissolve in this solvent). The solution is then
continuously shaken in an incubator for a full day. After that, the entire mixture is
sonicated. Drug content in solution is measured by spectrophotometric methods by
suitable dilution following sonication and filtration (Patel et al., 2012).
7.1.4. Content uniformity test

Ten patches are selected, and the contents of each patch are established. If nine out
of ten transdermal patches have content that falls between 85% and 115% of the
specified value and one patch has content that falls between 75% and 125% of the
specified value, then the transdermal patches is considered to pass the content
uniformity test. However, an additional twenty patches are evaluated for drug
content if three of the patches have content within the range of 75% to 125%. The
transdermal patches are considered to pass the test if the range of those 20 patches
are between 85% and 115% (Patel et al., 2012).
7.1.5. Moisture content
After each prepared film is weighed, it is stored for 24 hours at room temperature in
a desiccator filled with calcium chloride. After a predetermined amount of time, the
films are weighed once more until they display a consistent weight. The following
formula is utilized to determine the moisture content percentage: % Moisture content
= Initial weight – Final weight X 100 (Divya et al., 2012)
7.1.6. Moisture Uptake
For a full day, weighed films are stored in a desiccator at room temperature. After
that, they are removed & placed in a desiccator with a saturated potassium chloride
solution at 84% relative humidity, or until a constant weight is reached. The
percentage of moisture uptake is calculated as follows; % moisture uptake = Final
weight – Initial weight X 100 (Sachan and Bajpai, 2013)
7.1.7. Flatness
A transdermal patch shouldn't constrict over time and have a smooth surface. The
study of flatness can be used to illustrate this. Two strips are cut from each side of
the patches and one from the center to determine the flatness of the patches. Every
strip is measured for length, and the percentage of constriction is used to calculate
the length variation. it is considered that There is no constriction when there is 100%
flatness. (Patel et al., 2012).
7.1.8. Folding Endurance
involves figuring out how well films that are frequently folded under extreme
conditions can fold. The film is folded at the same spot repeatedly until break point
to determine the folding endurance. The folding endurance value of a film is the
number of times it could be folded in the same way without breaking (Gaikwad,
2013).
7.1.9. Tensile Strength
Corked linear iron plates are placed between polymeric films to measure their tensile
strength. The films are held in place at one end by an iron screen, and at the other
end by a freely movable thread that is connected to a pulley. The pan is gradually
filled with weights by gradually attaching the hanging end of the thread to it. The
film elongation is measured with a pointer on the thread. Noted is the weight that is
just enough to shatter the film (Gupta and Chokshi, 2011).
7.1.10. Tack properties
It is the polymer's capacity to stick to a substrate with minimal contact pressure
(Lende et al., 2011).
7.1.11. Thumb tack test
A measure of tack is the amount of force needed to remove the thumb off the
adhesive (Sakalle et al., 2010).
7.1.12. Rolling ball test
The stainless-steel ball's travel distance along an upward facing adhesive are
measured. The ball travels farther if the adhesive is less tacky (Lende et al., 2011).
 7.1.13. Quick stick (Peel tack) test
By removing the tape from the substrate at a speed of 12 inches per minute while
maintaining a 90-degree angle, the peel force necessary to break the bond between
an adhesive and substrate is determined (Dhiman et al., 2011).
7.1.14. Probe tack test
Tack is defined as the force needed to remove a probe from an adhesive at a
predetermined rate (Gupta and Chokshi, 2011).
7.2. In vitro release studies

Tape stripping, diffusion cells, spectroscopic and microscopic inspection are the
most popular techniques, each of which uses a different analysis technique (Sheth
and Mistry, 2011). All of these characterization techniques rely on the idea of
quantifying the drug's presence in each surface layer as it is absorbed, or
alternatively, storing an imaging material in place of the drug to visually verify the
absorption behavior. (Sheth and Mistry, 2011)
Diffusion cell tests are considered the gold standard for evaluating TDDS, and Franz
diffusion cells are the most widely used configuration (Fig.6.) (Lee et al., 2019).

Figure 6 Schematic examples of a static (Franz type) diffusion cell (Brown & Williams,
2019)
 7.3. In vivo Studies
Human volunteers or animal models can be utilized to evaluate TDDS in vivo
(Gupta and Chokshi, 2011).
7.3.1. Animal models
Small-scale studies involving animals are preferred over human subjects because
they require less time and funding. The animals frequently used to TDDs include
guinea pigs, mice, hairless rats, dogs, and hairless rhesus monkeys, In vivo and in
vitro experiments favor hairless animals over hairy animals (Gupta and Chokshi,
2011).
7.3.2. Human model
After the patch is applied to volunteers, the last phase of a transdermal device's
development entails gathering pharmacokinetic and pharmacodynamic data. To
evaluate the side effects, effectiveness, patient compliance, risk involved,
etc., clinical trials will be carried out (Gupta and Chokshi, 2011).

8. Kinetics of transdermal drug delivery systems

Substances are usually delivered transdermally in one of three ways (Fig.7.):-
 Figure 7 Skin routes of transdermal Drug passage (Matharoo et al., 2023)

1. The shunt route is a synonym for the trans-appendageal route. This route offers a
continuous intermediary across the SC and incorporates transdermal delivery using
hair follicles and the sweat glands that are associated with them (Rastogi & Yadav,
2012).
Sweating and secretions from sweat and sebaceous glands are examples of factors
that can impact solute permeation through this pathway,Furthermore, it has been
noted that hair follicles only make up 0.1% of the skin's surface area, meaning they
have a negligible impact on TDD (Rastogi & Yadav, 2012).
2. The transcellular pathway, also referred to as the intracellular pathway. This type
of TDD involves the solute going through the corneocytes and into the SC. Dead
cells with a high degree of hydration that are keratin-containing are called
corneocytes; the degree of hydration varies based on the temperature and moisture
content of the skin,This makes a path that is favorable for hydrophilic solutes,
however, the solute must partition through the skin in multiple steps because of the
lipid matrix that surrounds the hydrated keratinocytes (Jhawat et al., 2013).
3. the path through intercellular spaces. Diffusion occurs in this manner between the
corneocytes via the lipid matrix. Compared to earlier direct pathways, this route for
the solute delivery is more convoluted. The drug goes through several phases of
partitioning and diffusion as it passes through the epidermal layers due to the water
gradient in the SC. Eventually, it reaches the dermis and the lower viable epidermis,
after which it enters the systemic circulation (Jhawat et al., 2013).
Six essential events must take place for a drug to be released from a TDDs and enter
the systemic circulation as follows: 1) The drug travels through the delivery system
to the interface between the device and the stratum corneum; 2) The drug separates
from the transdermal device and enters the stratum corneum; 3) The drug then
diffuses through the stratum corneum's layers; 4) The drug separates into the much
more aqueous viable tissue from the stratum corneum;5) The medication permeates
both the dermal and epidermal tissue; 6) It comes into contact with the cutaneous
microcirculation, enters a blood vessel, an estribute throughout the body (Guy et al.,
1987).
The initial step in assessing the drug release kinetics from a transdermal patch
involves calculating the maximum flux (J) of the drug compound through the skin,
which is commonly given in μg/cm2/h units. Fick's law of diffusion predicts that
medicinal molecules will continue to move across skin until the concentration
gradient ceases to exist (Wiedersberg, and Guy, 2014).
Skin penetration seems to be restricted to the stratum corneum. Equation describes
the membrane limited flux (J) under steady state conditions. {J= (DCKo/w)/h}.
where D is the drug's diffusion coefficient in the membrane, C is the gradient of
concentration across the membrane, K is the membrane/vehicle partition coefficient,
and h is the membrane thickness. J is the drug amount passing through the
 membrane system per unit area per unit time (Tanwar and Sachdeva, 2016).
(Fig.8.) outlines plasma concentration behavior after consecutive transdermal rug
delivery applications.

Figure 8 Comparison between Plasma concentration profiles of Oral & TDD route (Pastore
et al., 2015)

9. Synthesis and Analysis

Table 3. A summary of the various findings regarding TDD Systems
No. Study Study Name Study Materials and method Limitation Referen Findings
design subjects s ces
1 Researc Design and In Vitro Nicotine ,HPMC K4M , , Some Lewis,
h paper Evaluation of Sodium alginate , Ethyl cellulose studies are Shaila & Rate
Matrix T Design and (20 cps) , Carbopol 934 P. The not Pandey, controlling
Evaluation of rest of the ingredients and performed Shailendr membranes in
Matrix Type and reagents were of analytical such as a& transdermal
Membrane ype and grade. adhesion, Udupa, drug delivery
Membrane pealing and Nayanab system have a
Controlled T other quality hirama. significant
Controlled control (2006). impact on
Transdermal studies Design drug release
Delivery Systems of and
ransdermal Delivery Evaluatio
Systems of n of
ransdermal Delivery matrix
Systems of Nicotine type and
Suitable for use in membran
Smoking Cessation e
 Nicotine Suitable controlle
for use in Smoking d
Cessation transder
mal
delivery
systems
of
nicotine
suitable
for use in
smoking
cessation
. Indian
Journal
of
Pharmac
eutical
Sciences.
68. 179-
184.
10.4103/
0250-
474X.25
711.
2 Researc Development of a In Vitro (BIO-PSA 7-4302 and BIO-PSA only an Cheneva Particle size
h article predictive model for 7-4202) approximati s-Paule and
the stabilizer (Kollidon 12PF and Kollidon on of the C, Wolff dissolution
concentration 90F drug HM, can affect the
estimation in Germany). partition Ashton permeation
microreservoir Ethyl between the M, amount of the
transdermal drug acetate, acetonitrile, methanol inner and Schubert drug
delivery systems and ethanol outer phases M,
(MTDDS) using acetic acid and phosphoric acid. was used, Dodou
lipophilic pressure Release which did K,
sensitive adhesives liner Scotchpak 9755 and not consider Develop
as matrix/carrier backing liner Scotchpak the impact ment
of water of a
uptake. predictiv
e model
for the
stabilizer
concentr
ation
estimatio
n in
microres
ervoir
transder
mal drug
delivery
systems
(MTDDS
) using
lipophilic
pressure
sensitive
 adhesive
s as
matrix/ca
rrier,
Journal
of
Pharmac
eutical
Sciences
(2017),
doi:
10.1016/j
.xphs.20
17.01.03
1.
3 REVIE Transdermal Drug Humans N/A N/A Alkilani, Certain
W Delivery: Innovative and A. Z., hydrophilic
ARTIC Pharmaceutical Animals McCrudd and lipophilic
LE Developments en, M. barriers of
Based on Disruption T., & drugs can be
of the Barrier Donnelly solved by
Properties , R. F. advanced
of the stratum (2015). forms of
corneum Transder patches
mal Drug
Delivery:
Innovativ
e
Pharmac
eutical
Develop
ments
Based on
Disruptio
n of the
Barrier
Propertie
s of the
stratum
corneum.
Pharma
ceutics, 7
(4), 438–
470.
https://do
i.org/10.
3390/pha
rmaceuti
cs704043
8
4 REVIE Transdermal Humans N/A N/A Ita K. Some
W Delivery of Drugs (2015). transdermal
ARTIC with Transder drug delivery
LE Microneedles— mal system
Potential and Delivery related issues
ChallengesN/A of Drugs can be
 with mandated by
Micronee controllable
dles- manufacturin
Potential g scales
and
Challeng
es. Phar
maceutic
s, 7(3),
90–105.
https://do
i.org/10.
3390/pha
rmaceuti
cs703009
0
5 UPDAT An updated review Humans N/A N/A REVIE TDDS have a
ED on transdermal drug and W lot of
REVIE delivery systems animals 6666666 potential
W an in 6666666 because they
Article Vitro 666666 can be used
to make
promising
deliverable
drugs with
both
hydrophobic
and
hydrophilic
active
substances.

6 REVIE Critical attributes of In Vitro N/A N/A P. The TDDS

W transdermal drug K. Ruby, must be
ARTIC delivery Shriram loaded with a
LE system (TDDS) – a M. Patha significant
generic product k & Dee amount of
development pika Agg drug and
review arwal (20 excipients in
14) Critic order to
al produce the
attributes necessary
of stability and
transder thermodynam
mal drug ic activity.
delivery
system
(TDDS)
–a
generic
product
develop
ment
review,
Drug
 Develop
ment and
Industrial
Pharmac
y, 40:11,
1421-
1428, D
OI: 10.31
09/03639
045.2013
.879720

10. Discussion
Although there is a great potential of TDDS, as it can be used to create promising
deliverable drugs with both hydrophobic and hydrophilic active substances (Mali et
al., 2015).
Nevertheless, in order to achieve the necessary thermodynamic activity and regulate
the patch's release rate, a significant quantity of drug and excipients must be loaded
into the TDDS, making formulation development extremely important and Sensitive
matter (Ruby et al., 2014).
It is Known that transdermal drug delivery systems aim to deliver medications at a
predetermined rate through the skin into the systemic circulation with the least
amount of variation between and within patients (Tanwar and Sachdeva, 2016),
whereas it adds to the high levels of intra- and inter-individual variability found in
the drug's pharmacokinetics (Ruby et al., 2014)
Moreover, The primary materials used to construct patches are polymers, adhesives,
and laminates, all of which have a tendency to be chemically Stable. This contributes
to the delivery environment of patches' inherent stability (Flynn, 1993), However,
The patch is most vulnerable to crystallization because of the high drug
concentration, which is either near saturation or even supersaturated concentrations.
Additionally, because transdermal patches are typically thermodynamically
unstable, there is a chance that the drug will recrystallize while being stored (Ruby
et al., 2014).
Furthermore, in terms of Transdermal delivery, Routes such as The shunt route
offers a continuous intermediary across the SC and incorporates transdermal
delivery using the sweat glands and hair follicles that are associated with them
(Rastogi & Yadav, 2012).Yet Sweating and secretions from sweat and sebaceous
glands are examples of factors that can impact solute permeation through this
pathway(Rastogi & Yadav, 2012).

11. Conclusion
Transdermal drug delivery, or TDDS, has great potential in utlizing both hydrophilic
an hydrophobic drugs into promising deliverable drugs and vaccines. Additionally,
it presents strong chances to address injection pain and inconvenience, the low
bioavailability of many oral medications, and the controlled release for controlled
release of both. However, more research and development are needed to increase the
variety of medications and macromolecules that can be applied to transdermal drug
delivery. It is crucial to gain a deeper comprehension of the various mechanisms
underlying physiological, physicochemical, and biological interactions in order to
optimize this drug delivery system. In order to provide more accurate representations
of the kinetics and assessment of transdermal drug delivery systems, additional
techniques must be developed to optimize research and the representation of the
factors affecting the drug while it passes through skin layers.
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