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TDDS Review
TDDS Review
A REVIEW
Abstract:
One technology that falls under the category of controlled drug delivery is the transdermal
drug delivery system (TDDS), whose goal is to distribute the medication via the skin at a
predefined and regulated pace. Longer therapeutic impact, fewer side effects, increased
bioavailability, greater patient compliance, and simple medication therapy termination are
just a few of its many benefits. For most compounds, the stratum corneum is thought to be the
rate-limiting barrier in transdermal penetration. Drugs can enter the body through three
primary routes: the appendageal, transcellular, and intercellular pathways. When
administering medication by this method, some considerations to be taken into account are
skin age, condition, physicochemical parameters, and ambient conditions. Release liner,
pressure-sensitive adhesives, backing laminates, drugs, penetration enhancers, polymer
matrix, and so on. are some of the basic elements of TDDS. Transdermal patches are used to
deliver active chemicals via the skin into the circulatory system. They are classified into three
types of systems: matrix, reservoir, and micro-reservoir. Following the production of
transdermal patches, standardized testing procedures are used to evaluate the drug release,
stability, adhesion, physicochemical, and in vitro skin penetration qualities. Different
medications are commercially accessible as transdermal patches based on the length of
therapy.
Key words: Matrix System, Micro reservoir System, Penetration Enhancer, Pressure-
Sensitive Adhesives, Reservoir System, Stratum Corneum, Transdermal Drug Delivery
System
INTRODUCTION:
When compared to the previous two decades, advancements in the field of drug delivery are
happening far more quickly. The effectiveness and patient compliance improvements
inherent in novel drug delivery methods are irreversible. [1,2] Investigating more recent bodily
interfaces for the introduction of treatments has shown to be a more radical strategy.
Transdermal drug delivery is one such method that uses the human skin as a point of entry
for the systemic distribution of medicate on molecules .[3] One of the methods falling under the
category of controlled drug delivery is the trans dermal drug delivery system (TDDS), whose
goal is to distribute the drug via the skin at a predetermined and regulated pace. TDDS are
sticky, drug containing devices with a specific surface area that release a dose of medication
into undamaged skin at a predetermined rate to enter the bloodstream [4,5].
Because trans dermal distribution avoids first-pass metabolism and increases patient
compliance, it offers a significant advantage over injectables and oral routes [6,7]. The
transdermal route has been in competition with oral treatment to be the most successful
innovative research area in drug delivery. This is because oral treatment involves introducing
a fixed dose at regular intervals to maintain the drug concentration in the body within a
therapeutically effective range, which increases the risk of side effects or therapeutic failure.
Additionally, a significant amount of drug is lost in the vicinity of the target organ,
necessitating close monitoring of therapy to prevent overdosing.
`Transdermal drug administration through intact skin can closely mimic the benefits of
intravenous drug infusion, without the potential risks, and overcome the limitations of the
oral route. This includes the ability to avoid hepatic "first pass" hepatic elimination (HEPE)
and maintain constant, prolonged, and therapeutic effective drug levels in the body [8,9].
The benefits and drawbacks of administering medication through the skin for systemic
therapy are shown in Table
ADVANTAGES DISADVANTAGES
Self-administration is feasible, as the Currently, the skin can only transmit tiny
medication releases continuously and lipophilic medicines.
sustainably.
Avoids peak and trough drug levels and Drug molecule must be potent because patch
longer and multiday dosing intervals size limits the amount that can be delivered
Patient compliance is improved by less The type of patch and the surrounding
frequent dosage. environment might affect adhesiveness.
Patients who are unable to take oral drugs Adhesives might change depending on the
might use an alternative method. kind of patch and the surroundings.
Dose delivery unaffected by vomiting or Skin irritation and hypersensitivity reactions
diarrhoea may occur
Non-irritating drug
Non-metabolizing drugs
Since the goal of TDDS is to achieve systemic medication through topical application on
intact skin, it is crucial to review the biochemical and structural aspects of human skin, as
well as those aspects that affect the skin's ability to function as a barrier and the rate at which
drugs enter the body through it. Anatomically, the skin is composed of two layers: the dermis,
sometimes known as the corium, and the epidermis. Hair shafts and gland ducts penetrate
both layers.
The average adult human's skin covers an area of around 2m 2, making it one of the body's
largest organs. The dermis of connective tissue, the stratified avascular cellular epidermis,
and the fatty subcutaneous layer (hypodermis) are the three main layers of skin, going from
inside to outside. About one-third of the blood that flows through the body is received by this
complex organ. The epidermis, which is roughly 150 μm thick, is produced by a population
of active epithelial basal cells. It is the skin's outermost layer, and because of differentiation,
cells move from the basal layer toward the skin's surface. Since the epidermis lacks blood
vessels, waste products and nutrients must permeate via the dermal–epidermal junction for
the skin to remain healthy. The stratum germinativum (base layer), stratum spinosum
(spinous layer), stratum granulosum (granular layer), stratum lucidum, and stratum corneum
(SC) are the five layers that make up the epidermis, arranged from inside to outside.
The dermis, which is of mesoderm origin, forms the base of a hard connective tissue layer on
which the epidermis is placed. The dermis, also known as the corium, is made up of a dense
network of connective tissue, the majority of which are bundles of collagen fibers mixed with
elastic tissue at the surface layers. Fine plexuses of blood arteries, lymphatics, nerves, sweat
glands, and sebaceous glands are found in the dermis [8,9,14,15].
ROUTES OF PENETRATION
The trans appendageal routes, often referred to as the shunt routes, include penetration
through the sebaceous glands that are connected to the hair follicles and sweat glands. A
continuous route is provided directly across the SC barrier via skin appendages. The long-
held belief that the follicles make up around 0.1% of the surface area of human skin has been
re examined by recent research. Otberg et al. demonstrated that the number, opening
diameter, and volume of follicles are significant factors in drug delivery through these
appendages. In fact, the forehead offers 13.7 mm2/cm2 as the follicular infundibula, meaning
that roughly 13.7% of the forehead's surface area is available as follicles. Remarkably, the
same study also demonstrated that, for forearm skin, the long-held belief that follicles supply
about 0.1% of the SC seems to be true.
Transcellular route
Substances that reach the skin through the transcellular pathway go through the corneocytes.
Hydrophilic medications can pass through the watery environment that corneocytes with
highly hydrated keratin offer. The transcellular pathway necessitates diffusion through and
partitioning into the intercellular lipids in addition to the keratin bricks.
Intercellular route
The medication diffuses through the continuous lipid matrix via the intercellular pathway.
This path poses a serious challenge for two reasons:
(a) (left) Diagram illustrating the human skin's anatomical structure. (b) (Right) Routes of percutaneous
absorption [13]
The reasoning behind this distribution method needs to be carefully considered, since the skin
provides such a good barrier to molecule movement. It is evident that there are several
situations in which the most practical drug consumption method—the oral route—is not
practical and when other options need to be investigated. While many of these drawbacks
(like gastrointestinal and hepatic metabolism) are avoided by intravenous introduction of the
medication, its invasive and unsettling nature (especially for long-term administration) has
prompted the search for alternative approaches, and few anatomical orifices have not been
explored for their potential as optional drug delivery routes.
As technology has advanced over the past few years, further advantages of TDDSs have
become apparent. Among these are the possibilities for regulated input kinetics, which are
especially important for medications with narrow therapeutic indices, and sustained release,
which is helpful for medications with short biological half-lives needing frequent oral or
parenteral administration. The use of TDD technology must, of course, be therapeutically
"justified"; medications with high oral bioavailability and infrequent dosage schedules that
are well-tolerated by patients do not call for such precautions. Similarly, transdermal
administration is not intended to provide fast bolus-type drug inputs; rather, it is typically
intended to provide slow, sustained drug delivery over extended periods of time. As a result,
drugs that induce tolerance or those that require chronopharmacological management—such
as hormones—are not, at least not yet, appropriate for transdermal administration. However,
there is still a sizable number of medications for which TDD is preferred but not yet practical.
Fundamentally, the SC's nature holds the key to solving this issue. The daily drug dosage that
can be systemically administered through a suitable "patch-sized" area stays in the 10 mg
range because to the membrane's exceptional diffusional resistance. The first requirement for
a successful transdermal candidate is imposed by this limitation: transdermal medications
must be pharmacologically potent and require therapeutic blood concentrations of ng/ml or
less. The second criterion is that not all molecules that pass the "potency" test will have the
required physicochemical qualities because SC is quite picky about the kind of molecules that
can be carried across its outer layer [9].
Biological factors
Skin condition - The skin's barrier function is maintained by the intact layer, however a
number of substances like acids and alkali, can pass through the skin's barrier cells.
Numerous solvents cause the horny layer's complex, dense structure to open up. Solvents like
methanol and chloroform dissolve the lipid fraction and create artificial shunts that allow
medication molecules to flow through with ease.[16]
Skin age-The skin of children and adults is seen to be more porous than that of the elderly.
However, there doesn't seem an apparent shift. Children's larger surface area per unit body
weight has harmful effects. Therefore, strong steroids, hexachlorophene, and boric acid have
caused serious side effects.[16]
Blood flow – Changes in peripheral circulation can affect Transdermal absorption. [16]
Regional Skin Sites- Site-specific differences exist in skin thickness, stratum corneum type,
and appendage density. These factors affect significantly penetration. [16]
Skin metabolism- Hormones, steroids, chemical carcinogens, and some medications are all
metabolized by skin. So skin metabolism determines efficacy of drug permeated through the
skin. [16]
Physicochemical factors
Hydration of skin - Water absorption of the skin generally causes tissues to swell, wrinkles to
soften, and an increase in the permeability of the skin to allow medication molecules to pass
through.[17]
Skin's temperature and pH - Adequate clothing on the body prevents large changes in
temperature and penetration rates. The diffusion coefficient lowers as the temperature drops
and the penetration rate fluctuates with temperature. Only unionized molecules are able to
penetrate the lipid membrane with ease, and weak acids and bases exhibit varying degrees of
dissociation based on their pH and pKa or pKb values. Thus,the concentration of unionized
drug in applied phase will determine the effective membrane gradient, which is directly
related to its pH . [17]
Partition Coefficient-Good action requires the ideal partition coefficient (K). Medication
with a high K content isn't ready to exit the skin's lipid layer. Drugs with low K content won't
permeate either. Size and Shape of Molecules Molecular weight and drug absorption are
negatively correlated; tiny molecules absorb more quickly than big ones.
Environmental factors
Sunlight - Sunlight causes blood vessel walls to thin, which can result in bruises with
minimal trauma in the sun-exposed areas. Additionally, pigmentation, often known as solar
lentigo or spots, is the most obvious pigment alteration caused by the sun. [18]
Cold season - Dry and itchy skin is a common consequence of the winter months. In response
to the drying impacts of the weather, the skin produces more oil. The signs of dry skin can be
reduced with a decent moisturizer. Moreover, consuming lots of water helps maintain the
hydration and brightness of your skin. [18]
Air pollution - Dust can alter the way drugs are delivered through the skin by blocking pores
and increasing germs on the face and skin's surface, both of which can result in acne or spots.
The natural defence mechanism of the skin can be disrupted by invisible chemical pollutants
in the air, which degrade the natural oils that typically retain moisture in the skin and keep it
supple. [18]
While selecting the polymer for the trans dermal system, the criteria that follow need to be
prioritized:
1. The polymer's molecular weight, glass transition temperature, and chemical activity
should be such that the particular medication diffuses and is delivered through it in an
appropriate manner.
2. The polymer should be affordable, conveniently generated and designed into the
desired product, stable, and nonreactive with the medication.
3. The polymer and the by products of its breakdown must not be harmful or
antagonistic to the host.
4. When significant amounts of active substances are added to a polymer, the polymer's
mechanical qualities shouldn't degrade unreasonably. [21]
Membrane
A membrane can be utilized as a single layer in the patch construction or sealed to the
backing to create a pocket that encloses the drug-containing matrix. The drug's and/or
excipients' permeability to the skin is managed by the membrane's diffusion characteristics.
As an example of a rate-controlling membrane, consider silicone rubber, polyurethane, and
ethylene vinyl acetate. [15,21]
Drug
Thoroughly selecting the medicine is essential for the effective development of a TDDS.
When it comes to medications with a limited therapeutic window, high first-pass metabolism,
or short half-lives that result in noncompliance from repeated dosage, transdermal patches
provide a number of benefits.[13,19] Some of the desirable properties of a drug and factors to be
considered for transdermal delivery are shown in Tables 3 and 4.
Nicardipine hydrochloride, Captopril, Atenolol, Metoprolol tartrate, Clonidine, Indapamide,
Propranolol hydrochloride, Carvedilol, Verapamil hydrochloride, and Niterdipine are a few
examples of medications that are appropriate for TDDS.
Permeation enhancers
Penetration enhancers, also known as sorption promoters or accelerants, are an effective
technique for enhancing TDD. They work by increasing the permeability of the SC to achieve
greater therapeutic levels of the drug candidate. Penetration enhancers alter the way the
barrier functions by interacting with the structural elements of the SC, which increases
permeability. There are three possible routes for drugs to enter the skin: polar, nonpolar, and
polar/nonpolar. One of these routes is changed by the enhancers. Causing a change in the
structure of proteins or swelling of solvents is essential for modifying the polar route. The
lipid structure's stiffness must be changed in order to fluidize the crystalline pathway and
change the nonpolar pathway (which significantly boosts diffusion).
The lipid component of the SC is more fluid because to the fatty acid enhancers. Certain
enhancers, also known as binary vehicles, alter the multilaminate pathway for penetrants,
thereby acting on both polar and nonpolar pathways .[9] Chemical and physical methods of
enhancing are the two categories of techniques used to alter the SC's barrier qualities in order
to improve drug penetration (and absorption) through the skin.
Chemical enhancers
Accelerants, absorption promoters, and penetration enhancers are terms used to describe
substances that aid in the penetration of medicines administered topically . Chemical
enhancers work in three ways:
1. Raising the drug's partition coefficient to facilitate release from the vehicle into the
skin;
2. Conditioning the SC to facilitate drug diffusion
3. Maximizing the drug's thermodynamic activity when acting as a co-solvent.
4. Building a drug reservoir to promote penetration in the SC
The following are a few of the more appealing features for penetration enhancers
working inside the skin;
They should preferably function quickly, with predictable and repeatable effects in
terms of both duration and activity. They should also be nontoxic, nonirritating, and
non-allergenic
They shouldn't bind to receptor sites or have any pharmacological action in the body.
After being removed from the skin, the barrier qualities should fully and quickly
return.
The penetration enhancers should work effectively with both excipients and
medications because they are intended to be formulated into a variety of topical
formulations.
They should have a suitable skin "feel" and be visually appealing [5,21 ].
Sulfur dioxide (DMSO – Dimethyl sulfoxide), fatty acids (oleic acid), alcohol (methanol),
glycol (propylene glycol), surfactant (anionic surfactant), azone (lauracapran), etc. are
some of the permeation enhancers that have been investigated the most.
Physical enchancers
In order to improve the percutaneous penetration (and absorption) of different therapeutic
substances, physical means of enhancing such as isotophoresis and ultrasound (sometimes
called phonophoresis or sonophoresis) approaches have been employed. .[8]
PSAs
PSAs (Pressure sensitive material) are materials that, when removed with little force and no
residue left behind, stick to a substrate—in this case, the skin. As long as there is intimate
contact, they create attractive forces between molecules and between atoms at the interface.
The phrase "pressure sensitive" refers to the material's ability to deform under light pressure
in order to achieve this degree of contact. When pressure is applied to the skin, the adhesive
flows like a liquid and wets the surface; when the pressure is released, the glue solidifies in
its wet form. When a PSA's surface energy is lower than the skin's, it wets and spreads onto
the skin.
Stronger interactions (such hydrogen bonding), which depend on the properties of the skin
and other factors, can strengthen the PSA/skin contact after the first adhesion. PSA polymers
that are frequently utilized in TDDS include hydrocarbon resin, acrylic and silicone-based
PSAs, and adhesives based on polyisobutylene. The PSA may be positioned as a continuous
sticky layer on the TDDS surface or around the edge of the TDDS. Excipients and the drug
should work well together because their presence can alter the mechanical properties of the
PSA and the pace at which the drug is delivered. [24-26]
Backing laminates
Chemical resistance of the material is the most important aspect to take into account when
developing a backing layer since backings are chosen for their look, flexibility, and occlusion
requirements. Because prolonged contact between the backing layer and the excipients may
cause the additives to leak out of the layer or may cause the excipients, medication, or
penetration enhancer to diffuse through the layer, excipient compatibility should also be
taken into account. The backing with the highest moisture vapor transfer rate, the best oxygen
transmission, and the lowest modulus or high flexibity will be the most comfortable. Vinyl,
polyethylene, polyester films, aluminum, and polyolefin films are a few types of backing
materials .[27,28]
Release liners
Prior to being applied to the skin, the protective liner covering the patch during storage is
taken off and thrown away. The liner should be chemically inert because it will be in close
contact to the TDDS. Usually, a release liner consists of a base layer consisting of silicon or
Teflon, and an occlusive (like polyethylene or polyvinyl chloride) or nonocclusive (like paper
cloth) release coating layer. Metalized laminates and polyester foil are additional materials
utilized for the TDDS release liner.[5,29,30]
Most commercially available transdermal patches are categorized into the following two
types:
I. Rate programmed system
II. Physical stimuli activated TDDS
Transdermal Drug Delivery System
A. Rate programmed TDDS: All patch type TDDS develop to date can be described by
three basic design principles (the fourth being a specialized design):
Drug in reservoir
Drug in matrix
Drug in adhesive
Drug in microreservoir
In the first case , the reservoir is separated from the skin by a rate controlling membrane.
Designs in which the adhesive in combination with a membrane-matrix device to deliver an
initial bolus dose.
Several features are common to all TDDS and includes-
Release liner
Pressure-sensitive adhesive
Impermeable backing layer
1. Drug in reservoir : The total size and profile of delivery systems have decreased as
a result of reservoir-based delivery systems that make use of microtechnology.
Smaller systems can have mechanisms or features that provide the doctor or patient
more exact control over the pace of medication administration, allow the patient to
actively initiate, adjust, and stop drug release in an interactive manner, and give
means to reach hard-to-reach places. With the use of these next-generation targeted
delivery systems, a medicine may be administered selectively to a tissue type, a
relatively inaccessible place, or just to reduce systemic exposure-related adverse
effects.
2. Drug in matrix : Here, the drug is uniformly dispersed in a polymeric matrix,
through which it diffuses to the skin surface. The polymeric matrix,which may be
comprise of silicone elastomers ,polyurethanes, PVP, and such, may be considered as
drug reservoir. Following are the various steps which are involved in the drug
delivery process-
A. Dissociation of drug molecules from the crystal lattice.
B. Drug solubilization in the polymer matrix.
C. Diffusion of drug molecules through matrix to the surface of the skin.
3. Drug in adhesive matrix : While this kind is similar to the single layer, it differs in
that it has an adhesive layer and an instant drug release layer instead of a controlled
release layer. The medication is released because of the sticky coating. This patch also
has a temporary liner layer and a permanent backing.
Chemical, biological, and physical stimuli that are naturally occurring in the body are
referred to as endogenous stimuli. Examples of these include variations in pH, temperature,
enzyme activity, pressure, and shear forces. More precisely, the ability to achieve target
specificity using these specific stimuli for release is provided by endogenous chemical
stimuli, which comprise environmental pH, redox reactions, and chemical gradients. These
stimuli are typically outside of physiological range or excluding to a particular or diseased
tissue.
I. Structured based systems e.g. microneedles - Microneedle (MN) patches, which are
made of tiny needles, have become a potential technique for minimally surgically
puncturing the stratum corneum and translocating biomolecules into the dermis.
Novel medication delivery devices known as stimuli-responsive MN patches release
cargos according on internal or exterior stimuli. This review covers the mechanisms
of action for various indications of a range of stimuli-responsive MN patches for
controlled drug release.
II. Velocity based systems e.g. jet propulsion - For transdermal medication
administration, a jet-propelled particle injection device has been created and used to
accelerate microparticle.
1. Interaction studies : -
Excipients are essential parts of nearly every dose form used in medicine. The drug's
compatibility with the excipients determines the stability of a formulation among
other things. To create a stable product, the medicine and the excipients must get
along. since a result, any potential physical or chemical interactions must be identified
since they may have an impact on the stability and bioavailability of the medication.
Compatibility studies are critical to the development of novel formulations if the
excipients have not been utilized in formulations containing the active ingredient.
Thermal analysis, Fourier Transform Infrared spectroscopy, UV, and
chromatographic methods are frequently used in interaction studies. These
investigations compare the physicochemical characteristics of the techniques, such as
assay, melting endotherms, special wave numbers.[6]
2. Thickness of the patch:-
To verify the thickness of the created patch, the thickness of the drug-loaded patch is
measured at various spots using a digital micrometer, which also calculates the
average thickness and standard deviation for the same.[6]
3. Weight uniformity:-
Before testing, the created patches must be dried for four hours at 60°C. A defined
patch area has to be divided into several sections and weighed using a digital balance.
The individual weights must be used to get the average weight and standard deviation
values.[6]
4. Folding endurance :-
A strip of the designated area needs to be cut uniformly, then folded repeatedly at the
same location until it breaks. The folding endurance of a film is measured by how
many times it can be folded in the same direction without breaking.[6]
5. Percent moisture content : -
Each of the created films needs to be weighed separately and then kept for a full day
at room temperature in a desiccator that has fused calcium chloride in it. Following a
24-hour period, the films must be reweighed in order to calculate the moisture content
percentage using the formula below.[6]
Percentage moisture content = [Initial weight - Final weight / Final weight] × 100
6. Drug content : -
A particular portion of the patch has to dissolve in a certain amount of an appropriate
solvent. After that, the mixture must be filtered through an absorbent medium before
the drug content is determined using the suitable method (UV or HPLC). An average
of three separate samples is shown for each value.[6]
7. Peel adhesion test : -
Peel adhesion in this test refers to the force needed to remove an adhesive covering
from a test substrate. The factors that affect peel adhesion functions include the kind
and quantity of additives, as well as the molecular weight of the adhesive polymer.
After applying a single tape to a chosen backing membrane or stainless steel plate, the
tape is removed from the substrate at a 180-degree angle, and the force needed to do
so is recorded.[6]
8. Thumb tack test:-
It is a qualitative test used to determine the adhesive's tack properties. The only thing
that is needed to determine the relative tack quality of the glue is pressing the thumb
down on it.[6]
9. Flatness test :-
It is necessary to cut three longitudinal strips—one from the center, one from the left,
and one from the right—from each film at various points. Every strip's length was
measured, and the percent constriction—0% constriction being equal to 100% flatness
—was used to calculate the length variation resulting from nonuniformity in flatness.
[6]
CONCLUSION:
A more recent method to determine dosage forms for many injectable and oral medications
with the right physicochemical and pharmacological characteristics is called TDDS. The
TDD ensures the fewest side-effects of a pharmacologically active drug when it reaches a
significant in vivo region. Owing to the TDDS's many benefits, several additional studies are
being conducted to bring more recent medications into the system. Also under research
there are a number of tools that speed up the drug's entry and absorption. Polymers,
penetration enhancers, backing laminates, plasticizers, and liners play a major role in TDDSs,
helping to provide effective adherence and controlled release of medication into systemic
circulation via skin over several hours or days. Systems such as reservoir systems, matrix
systems, and microreservoir systems can be used to categorize transdermal patches. Once the
transdermal patches are prepared, uniform testing procedures are used to measure the
different parameters. Transdermal drug administration is becoming the most often used
method due to recent technological advancements and the ability to deliver the medication to
the site of action without rupturing the skin barrier. This medication delivery offers promise
for the future since it solves the problems with the common drug delivery system of today.
Different medications are commercially accessible as transdermal patches based on the length
of therapy.
References: