TRANSDERMAL PATCHES

Practice School Report

Submitted in fulfilment of the requirements for B. Pharm 7th Semester

SUBMITTED TO: SUBMITTED BY:

Mr. Bansi Lal Inderjeet
Designation: Asst. Professor B. Pharm. 7th Semester
Department: Pharmaceutics Batch: 2019
Academic Session:2023-24

SURENDERA PHARMACY COLLEGE

Approved by Pharmacy Council of India & Affiliated to Rajasthan University of Health Sciences, Jaipur

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 Declaration

I hereby declare that as per the university academic regulations for Practice School from Rajasthan
University of Health Sciences, Jaipur, I have completed Practice School of 150hrs and submitted
the report in partial fulfillment of the Degree in Bachelor of Pharmacy of Rajasthan University of
Health Sciences, Jaipur, Rajasthan.

Place: SRI GANGANAGAR Inderjeet

Date: Batch: 2019

Academic Session 2023 - 24

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 SURENDERA PHARMACY COLLEGE
Approved by Pharmacy Council of India & Affiliated to Rajasthan University of Health Sciences, Jaipur

Certificate

This is to certify that Inderjeet, student of B. Pharm. Sem VII (Batch 2019, Academic Session
2023–2024) has completed Practice School of 150hours as per the B. Pharmacy Course academic
regulation from the Rajasthan University of Health Sciences RUHS), Jaipur. We wish all the
success in his/her future.

(Mr. Bansi lal)

Head of Department, Pharmaceutics

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 ACKNOWLEDGEMENT

I would like to express my gratitude to my teachers Mr. Bansi Lal for providing support and guidance. I
got to learn a lot more about this project about Equipment used.

I would like to thank my all teachers, parents and friends who have helped me with their valuable
suggestions and guidance and have been very helpful in various stages of project completion.

Date:

Place: Sri Ganganagar

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 TABLE OF CONTENT

Sr. Topic Page no.

No.

1 Introduction 6

2 How are transdermal drug delivered 7

and transdermal absorption
3 Component of transdermal patches 8

4 Types of transdermal patches 11

5 Recent advancement in transdermal patches 14

Biopharmaceutical parameters in 19
6 transdermal patches
7 Preparations of TDDS 19

8 Evaluation of transdermal patches 22

9 Advantage and disadvantage 24

10 Conclusion 25

11 Reference 26

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  INTRODUCTION
Transdermal patches are now widely used as cosmetic, topical and transdermal delivery
systems. These patches represent a key outcome from the growth in skin science, technology
and expertise developed through trial and error, clinical observation and evidence-based studies
that date back to the first existing human records. This review begins with the earliest topical
therapies and traces topical delivery to the present-day transdermal patches, describing along
the way the initial trials, devices and drug delivery systems that underpin current transdermal
patches and their actives. This is followed by consideration of the evolution in the various patch
designs and their limitations as well as requirements for actives to be used for transdermal
delivery.

Oral route is the most popular route of drug delivery system but it has some
disadvantages including first pass metabolism, drug degradation etc. in gastrointestinal tract
due to enzymes, pH etc. To overcome these problems, a novel drug delivery system was
developed by Chien in 1992, Banker in 1990, Guy in 1996. It was transdermal patches or
Transdermal delivery system. In this system medicated adhesive patches are prepared which
deliver therapeutically effective amount of drug across the skin when it placed on skin. They are
available in different sizes & having more than one ingredient. Once they apply on unbroken
skin they deliver active ingredients into systemic circulation passing via skin barriers. A
transdermal patch containing high dose of drug inside which is retained on the skin for
prolonged period of time, which get enters into blood flow via diffusion

Fig: transdermal patches

The First Transdermal drug delivery (TDD) system, Transderm-Scop developed in 1980,
contained the drug Scopolamine for treatment of motion sickness. The Transdermal device
is a membrane-moderated system. The membrane in this system is a microporous
polypropylene film. The drug reservoir is a solution of the drug in a mixture of mineral oil and
polyisobutylene. This study release is maintained over a three-day periods.

 HOW ARE TRANSDERMAL DRUGS DELIVERED?

A transdermal patch acts as a carrier for a drug, holding it until it’s applied. At the point of
application, the patch’s adhesive secures it to the skin, and the drugs contained in the patch will
begin to permeate into the bloodstream. The patch will continue to administer its Active
Pharmaceutical Ingredients (APIs) until either they are fully absorbed or the patch is removed.
Therefore, the length of wear time and the amount of drug delivered is different from patch to
patch.

 TRANSDERMAL ABSORPTION
There are two main subtypes of transdermal patch drug delivery systems: passive
and active.

I. Passive systems

Passive transdermal patch drug delivery systems rely only on natural diffusion to transfer the
drug from the patch to the skin and into the body. They provide a consistent diffusion rate,
depending upon the characteristics of the skin and the design of the patch.

II. Active systems

Active transdermal patch drug delivery systems use a specific method to aid in the
transfer of the drug to the skin and into the body. These methods include chemical enhancers
and permeators, physical aids like micro-needles, and low electrical current like iontophoresis.
The amount of diffusion depends on the active method used, the drug characteristics, and the
skin.

 BASIC COMPONENTS OF TRANSDERMAL PATCHES:

The basic components of transdermal patch consists of polymer matrix / Drug reservoir, active
ingredient (drug), permeation enhancers, pressure sensitive adhesive (PSA), backing laminates,
release liner, and other excipients like plasticizers and solvents.

I. Polymer matrix

Polymers are the backbone of a transdermal drug delivery system. Systems for
transdermal delivery are fabricated as multi-layered polymeric laminates in which a drug
reservoir or a drug– polymer matrix is sandwiched between two polymeric layers: an outer
impervious backing layer that prevents the loss of drug through the backing surface and an
inner polymeric layer that functions as an adhesive and/or rate-controlling membrane. Polymer
selection and design must be considered when striving to meet the diverse criteria for the
fabrication of effective transdermal delivery systems. The main challenge is in the design of a
Polymer matrix, followed by optimization of the drug loaded matrix not only in terms of release
properties, but also with respect to its adhesion cohesion balance, physicochemical properties,
compatibility and stability with other components of the system as well as with skin.

The polymers utilized for TDDS can be classified as :

a) natural polymers includes cellulose derivatives, zein, gelatine, shellac, waxes, gums,
natural rubber and chitosan etc.
b) Synthetic elastomers includes polybutadiene, hydrin rubber, polyisobutylene, silicon
rubber, nitrile, acrylonitrile, neoprene, butylrubber etc.,
c) synthetic polymers includes polyvinyl, Alcohol, polyvinylchloride, polyethylene,
polypropylene, polyacrylate, polyamide, polyurea, Polyvinylpyrrolidone,
polymethylmethacrylate etc. The polymers like cross linked polyethylene glycol,
eudragits, ethyl cellulose, Polyvinylpyrrolidone and Hydroxypropylmethylcellulose
 are used as matrix formers for TDDS. Other polymers like EVA, silicon rubber and
polyurethane are used as rate controlling membrane.

II. Drug

The most important criteria for TDDS are that the drug should possess the right
physicochemical and pharmacokinetic properties. Transdermal patches offer much to drugs
which undergo extensive first pass metabolism, drugs with narrow therapeutic window, or drugs
with short half-life which causes non- compliance due to frequent dosing. For example, Drugs
like rivastigmine for Alzheimer’s and Parkinson dementia, rotigotine for Parkinson,
Methylphenidate for attention deficit hyperactive disorder and selegiline for depression are
recently approved as TDDS.

III. Permeation enhancers

To increase permeability of stratum corneum so as to attain higher therapeutic levels of

the drug permeation enhancers interact with structural components of stratum corneum i.e.,
Proteins or lipids. The enhancement in absorption of oil soluble drugs is apparently due to the
partial leaching of the epidermal lipids by the chemical enhancers, resulting in the improvement
of the skin conditions for wetting and for trans-epidermal and trans-follicular permeation. The
miscibility and solution properties of the enhancers used could be responsible for the enhanced
transdermal permeation of water soluble drugs. Pharmaceutical scientists have made great
efforts in transdermal permeation studies using various enhancers for several drug moieties .

The permeation of drugs across the skin may also be enhanced by physical means
including iotophorosis, electroporation, application of ultrasound (sonophoresis), and use of
microscopic projection. Iontophoresis passes a few milliamperes of current to a few square
centimetres of skin through the electrode placed in contact with the formulation, which
facilitates drug delivery across the barrier. Mainly used for pilocarpine delivery to induce
sweating as part of cystic fibrosis diagnostic test. Iontophoretic delivery of lidocaine appears to
be a potential approach for rapid onset of anaesthesia (Schultz et al., 2002). Electroporation is a
method of application of short, high-voltage electrical pulses to the skin. After electroporation,
the permeability of the skin for diffusion of drugs is increased by 4 orders of magnitude. The
electrical pulses are believed to form transient aqueous pores in the stratum corneum, through
which drug transport occurs. It is safe and the electrical pulses can be administered painlessly
using closely spaced electrodes to constrain the electric field within the nerve-free stratum
corneum (Neumann et al., 1982; Sugar and Neumann 1984). Application of ultrasound,
particularly low frequency ultrasound, has been shown to enhance transdermal transport of
various drugs including macromolecules. It is also known as sonophoresis. Ogura et al., (2008)
reported on the use of low-frequency sonophoresis for topical delivery of EMLA cream.
Transdermal patches with microscopic projections called microneedles were used to facilitate
transdermal drug transport. Needles ranging from approximately 10-100 µm in length are
arranged in arrays. When pressed into the skin, the arrays make microscopic punctures that are
large enough to deliver macromolecules, but small enough that the patient does not feel the
permeation or pain. The drug is surface coated on the microneedles to aid in rapid absorption.
They are used in development of cutaneous vaccines for tetanus and influenza. Various other
methods are also used for the application of the transdermal patches like thermal poration,
magnetophoresis, and photomechanical waves. However, these methods are in their early stage
of development and require further detailed studies.

IV. Pressure sensitive adhesive (PSA)

A PSA maintains an intimate contact between patch and the skin surface. It should
adhere with not more than applied finger pressure, be aggressively and permanently tachy, and
exert a strong holding force. These include polyacrylates, polyisobutylene and silicon based
adhesives. The selection of an adhesive is based on numerous factors, including the patch
design and drug formulation. PSA should be physicochemically and biologically compatible and
should not alter drug release. The PSA can be positioned on the face of the device (as in
reservoir system) or in the back of the device and extending peripherally (as in case of
matrixsystem).
V. Backing laminate

The primary function of the backing laminate is to provide support. Backing layer should be
chemical resistant and excipients compatible because the prolonged contact between the
backing layer and the excipients may cause the additives to leach out or may lead to diffusion of
excipients, drug or permeation enhancer through the layer. They should have a low moisture
vapour transmission rate. They must have optimal elasticity, flexibility, and tensile strength.
Examples of some backing materials are aluminium vapour coated layer, plastic film
(polyethylene, polyvinyl chloride, polyester) and heat seal layer.

VI. Release liner

During storage release liner prevents the loss of the drug that has migrated into the
adhesive layer and contamination. It is therefore regarded as a part of the primary packaging
material rather than a part of dosage form for delivering the drug. The release liner is composed
of a base layer which may be non-occlusive (paper fabric) or occlusive (polyethylene and
polyvinylchloride) and a release coating layer made up of silicon or teflon. Other materials used
for TDDS release liner include polyester foil and metalized laminate.

VII. Other excipients

Various solvents such as chloroform, methanol, acetone, isopropanol and dichloromethane

are used to prepare drug reservoir. In addition plasticizers such as dibutylpthalate,
triethylcitrate, polyethylene glycol and propylene glycol are added to provide plasticity to the
transdermal patch.

 TYPES OF TRANSDERMAL PATCHES :

There are four types of transdermal patches:

(I) Single-layer drug in-adhesive

(II) Multi-layer drug in adhesive
 (III) Vapour patch
(IV) Reservoir system
(V) Matrix system
(VI) Micro reservoir systems

i. Single–layer drug in–adhesive

Drug is in adhesive layer. It adheres various layers together and release drug to skin. The
adhesive layer of this system also contains the drug. In this type patches the adhesive layer not
only serves to adhere the various layer together, along with 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.

ii. Multi-layer drug in adhesive:

It is also similar to the single layer but it contains a immediate drug release layer and other layer
will be a controlled release along with the adhesive layer. The adhesive layer is responsible for
the releasing of the drug. This patch also has a temporary liner-layer and a permanent backing.

iii. Vapour patch:

In this type of patch the role of adhesive layer not only serves to adhere various layers together
but also serves as release vapour. The vapour patches are new to the market, commonly used
for releasing of essential oils in decongestion. Various other types of vapour patches are also
available in the market which are used to improve the quality of sleep and reduces the cigarette
smoking conditions.

iv. Reservoir system:

In this system the drug reservoir is embedded between an impervious backing layer and a rate
controlling membrane. The drug releases only through the rate controlling membrane, which
can be micro porous or non porous. In the drug reservoir compartment, the drug can be in the
form of a solution, suspension, gel or dispersed in a solid polymer matrix. Hypoallergenic
adhesive polymer can be applied as outer surface polymeric membrane which is compatible
with drug.

v. Matrix system
a) Drug-in-adhesive system

In this type the drug reservoir is formed by dispersing the drug in an adhesive polymer and
then spreading the medicated adhesive polymer by solvent casting or melting (in the case of
hot-melt adhesives) on an impervious backing layer. On top of the reservoir, Unmediated
adhesive polymer layers are applied for protection purpose.

b) Matrix-dispersion system

In this type the drug is dispersed homogenously in a hydrophilic or lipophilic polymer matrix.
This drug containing polymer disk is fixed on to an occlusive base plate in a compartment
fabricated from a drug impermeable backing layer. Instead of applying the adhesive on the
face of the drug reservoir, it is spread along with the circumference to form a strip of
adhesive rim.

vi. Micro reservoir systems

In this type the drug delivery system is a combination of reservoir and matrix-dispersion
system. The drug reservoir is formed by first suspending the drug in an aqueous solution of
water soluble polymer and then dispersing the solution homogeneously in a lipophilic polymer
to form thousands of unreachable, microscopic spheres of drug reservoirs. This
thermodynamically unstable dispersion is stabilized quickly by immediately cross-linking the
polymer in situ by using cross linking agents.
 Fig:- different type of transdermal patches

 RECENT ADVANCEMENTS IN TRANSDERMAL PATCHES

Traditional transdermal patches serve only two purposes: storage and release of drugs.
While this method has some advantages, traditional patching has many challenges and
drawbacks, for example limited dosage or low release. To date, there have been several
advances in the field of transdermal drug delivery. These include the design of novel patches,
which include the ability to sense and release drugs accurately, higher loading, and enhanced
penetration and release of drugs. Overall, the field of transdermal drug delivery is an active area
of research and development, with many exciting new developments on the horizon, as
discussed below.

I. Smart Patches

Smart patches are equipped with sensors and other technologies that can monitor
patient conditions and adjust drug delivery accordingly. In 2014, a group of researchers
developed a microneedles-based smart patch sensor platform for painless and continuous
intradermal glucose measurement for diabetics. This patch uses a conducting polymer such as
poly (3,4-ethylenedioxythiophene) (PEDOT) as an electrical mediator for glucose detection and
as an immobilizing agent for the glucose-specific c-enzyme glucose oxidase .Further research
and development resulted in a smart insulin releasing patch consisting of 121 microneedles
containing nanoparticles. The patch painlessly penetrates into the interstitial fluid between
subcutaneous skin cells. The nanoparticles in each needle contain insulin and the glucose-
sensing enzyme glucose oxidase, which converts glucose into gluconate. These molecules are
surrounded by hypoxia-responsive polymers. Increased glucose oxidase activity in response to
increased glucose creates an oxygen-depleted environment within the nanoparticles, which is
sensed by the hypoxia-responsive polymer, triggering nanoparticle degradation and insulin
release .

Wound healing is a complex and dynamic regenerative process with constantly changing
physical and chemical parameters. Its management and monitoring offer great benefits,
especially for bedridden patients. . an inexpensive, flexible, fully printed smart patch on the skin
to measure changes in wound pH and fluid volume. Such bendable sensors can also be easily
incorporated into wound dressings. The sensor consists of various electrodes printed on a
polydimethylsiloxane (PDMS) substrate for pH and humidity measurements. The generated
sensor patch has a sensitivity of 7.1 ohm/pH to the wound pH value. Hydration sensor results
showed that the water content of the semi-porous surface can be quantified by the change in
resistivity .Besides wound healing, scientists have also developed a smart patch to monitor and
treat diabetic foot ulcers (DFU). This system is fabricated from conductive hydrogel patches with
a ultra-high transparency polymer network. Importantly, highly transparent conductive hydrogel
patches can be used to visually monitor wound healing status, promote haemostasis, improve
cell-to-cell communication, prevent wound infection, promote collagen deposition, and improve
vascularity. By promoting angiogenesis, it effectively promotes the healing of DFU. In addition,
the versatile intelligent patch can also achieve indirect blood glucose monitoring by detecting
glucose levels in wounds, and timely detect movements of various sizes of human bodies.
Interestingly, this smart patch can monitor chronic wound dressings and treat wounds at the
same time . Smart patches are also used to deliver natural compounds such as Curcumin. The
material consists of paraffin wax and polypropylene glycol as a phase change material (PCM).
PCM was combined with graphene-based heating elements obtained by the laser scribing of
polyimide films. This arrangement offers a new approach to smart patches whose release can
be electronically controlled, and which allows repeated dosing. Emission is induced and
terminated by controlled heating of the PCM rather than relying on passive diffusion, and
permeation only occurs when the PCM transitions from solid to liquid. Curcumin delivery yields
were found to be good and satisfactory .

II. Dissolving/Degradable Patches

These patches are designed to dissolve on the skin and do not need to be removed
and discarded. In general, these patches are made from biodegradable materials that are
absorbed by the body after use. In a proof-of-concept paper published in 2019, researchers
successfully administered the antibiotic gentamicin via a dissolving patch in a mouse model of
bacterial infection.

Dissolving microneedles (MNs) show high efficiency in the delivery of poorly permeable
drugs and vaccines. A two-step injection and centrifugation process was used to localize insulin
to the needle and achieve efficient transdermal delivery of insulin. The relative pharmacological
availability and relative bioavailability (RBA) of insulin from MN patches were 95.6% and 85.7%,
respectively. This study demonstrates that the use of dissolving patches for insulin delivery
achieves a satisfactory relative bioavailability (RBA) compared to conventional subcutaneous
injection, demonstrating the effectiveness of dissolving patches for diabetes treatment.

III. Three-Dimensional (3D)-Printed Patches

how the three-dimensional structures were fabricated using the 2PP technique by
manufacturing templates (of different shapes and sizes) and subsequently producing dissolvable
and hydrogel-forming microneedles through another microfabrication process called micro-
moulding. This approach allows for flexibility in the design of microneedles of different types in
an efficient and cost-effective manner. Using the 2PP technique, solid and hollow microneedles
were directly printed by and were subsequently used in the in vitro perforation of a round
window membrane. These 2PP-fabricated microneedles showed relatively good quality and
sharpness . In a similar manner, the solid and hollow microneedles that were fabricated by Szeto
et al. were adopted in the informative sampling of perilymph from guinea pigs. In this work,
biocompatible hollow microneedles were directly fabricated using two-photon polymerization;
microstructures that were manufactured using this approach displayed an excellent skin
penetrating ability and showed prospects for applications in implantation, transdermal drug
delivery, and diagnosis adopted two-photon polymerization in the microfabrication of hollow
microneedles. These microneedles were subsequently used in order to generate moulds and
replicas with very similar structures.

Other forms of photo-polymerization methods exist for the 3D-printing of microneedles.

Instead of the two-photon absorption for the polymerization of materials, laser or light-
emission technologies can be adopted in order to achieve the same purpose of polymerization,
such as DLP (digital light processing), CLIP (continuous liquid interface production), and laser
stereo-lithography. How the micro-moulding of biodegradable microneedles can be enhanced
by directly printing the moulds using the laser stereo lithography technique. The anti-cellulite
herbal product that was coated in polymeric microneedles was further studied, characterized,
and pharmacologically evaluated. Using a similar approach, Krieger et al. 3D-printed micro-
needle masters that were manufactured and further reproduced into moulds using inexpensive
and rapid production techniques. These researchers were able to manufacture micro-needle
moulds that were reproducible and customizable. The direct one-step fabrication of 3D-printed
cone-shaped microneedles was carried out through fracture tests, also established that the
fracture strength of the fabricated microneedles quadrupled the force of insertion .Microfluidic-
enabled hollow microneedles that allow for a heterogeneous mixing and transport of fluids
were fabricated by Yeung et al. This study paved the way for the application of hollow
microneedles in the delivery of different drug compositions through transdermal routes using
one-step laser stereo lithography . Additionally, the transdermal delivery of model dyes via
micro channels that were created on human skin using micro-needle patches that were
fabricated using an SLA 3D printer. Studies have revealed that human skin that is treated with
microneedles has relatively better permeability.

Microneedles are micro-meter-sized needles with a height in the range of 25 to 2000 µm. All of
the 3D-printing technologies have the capability to fabricate the microneedles in the above-
mentioned range in a reproducible manner with a high resolution and quality. Based on the
material and the application type, a particular 3D-printing technology can be utilized. As
discussed earlier, microneedles are classified into solid, hollow, coated, dissolvable, and
hydrogel-forming microneedles. Table 4 illustrates the different types of 3D-printing
technologies based on the micro-needle type, the minimum layer resolution, and the
application type. The ideal characteristics of the 3D-printed micro-needle include the optimum
size, the proper mechanical stability, efficient drug delivery, and the ability to remain leak-proof.

IV. High Loading/Release Patches

Long-acting transdermal drug delivery requires high drug loading and controlled drug
release. In order to improve drug-polymer miscibility and achieve controlled drug release, a
novel hydroxyl-phenyl (HP)-modified pressure-sensitive adhesive (PSA) was developed [89]. The
results show that the dual-ionic H-bonds between R(3)N and R(2)NH-type drugs and HP-PSA are
reversible and relatively strong, unlike ionic and neutral H-bonds. This allowed patches to
significantly increase the drug loading from 1.5- to 7-fold and control the drug release rate from
1/5 to ½ without changing the overall release profile. Pharmacokinetic results showed that the
HP-PSA-based high-load patch achieved sustained drug concentrations in plasma, avoided
sudden release, increased area under the concentration-time curve (AUC), and average dwell
time by more than 6x, indicating the potential for long-acting drug delivery. In addition, its
safety and mechanical properties are met. Mechanistic studies have shown that repulsion of
ionic drugs in HP-PSA increases drug loading, and relatively strong interactions can also control
drug release. Incomplete hydrogen bond transfer determined its reversibility, making the
percentage drug release equal to that of non-functional PSA. In short, the high drug loading
efficiency and controlled drug release capability of HP-PSA and its unique interactions will
contribute to the development of long-acting transdermal drug delivery systems. Moreover, the
construction of double-ionic H-bonds provides further inspiration for various drug delivery
systems in non-polar environments. Pharmaceutical polymers are widely used to inhibit drug
recrystallization through strong intermolecular hydrogen and ionic bonding, but at the expense
of drug release rates in transdermal patches. To overcome this difficulty, a group of researchers
came up with the idea of using a new ionic liquid (drug IL) strategy to increase drug loading [90].
A carboxyl-based pressure sensitive adhesive (PSA) was chosen as a model polymer. The results
showed a five-fold increase in PSA drug load. This was caused by the synergistic effect of strong
ionic and normal hydrogen bonds formed between the carbonyl groups of the drug and PSA.
This study demonstrated an entirely new mechanism of action and provided a powerful tool for
the development of high-drug load, high-release patches. In another study, the same group of
researchers constructed a high-capacity, high-release transdermal patch with COOH
polyacrylate polymer (PA-1) to deliver non-steroidal anti-inflammatory drugs (NSAIDs), namely
ibuprofen. The drug load and skin absorption of PA-1 were improved by 2.4-fold and 2.5-fold,
respectively. The hydrogen bond formed between the drug (COOH) and PA-1 (COOH) is
weakened by repulsive interactions, whereas the enhanced conductivity of PA-1 was confirmed
by dielectric spectroscopy, electron paramagnetic resonance (EPR) spectra, four-point probe
method, and molecular modelling with the appearance of COO.

 BIOPHARMACEUTICAL PARAMETERS IN TRANSDERMAL PATCHES

i. The dose should be kept modest, around 20mg per day.
ii. The half-life should be shorter than 10 hours.
iii. The molecular weight of the compound should be 400.
iv. Log P should be used as the partition coefficient. (Octanol water) in the range of 1.0 to 4.
v. The permeability coefficient of the skin should be 0.5X 10-3cm/h.
vi. The drug should not irritate or sensitive the skin in any way.
vii. Bioavailability in the mouth should be low.
viii. The therapeutic index should be as low as possible.

 METHODS OF PREPARATIONS OF TDDS

i. Asymmetric TPX membrane method.
ii. Circular Teflon mould method.
iii. Mercury substrate method.
iv. By using “IPM membranes” method.
v. By using “EVAC membranes” method.
 vi. Preparation of TDDS by using Pro-liposomes.
vii. By using free film method.

i. Asymmetric TPX Membrane Method:

This method was discovered by Berner and John in 1994. By this method prototype
patch can be prepared by using heat sealable polyester film (type 1009, 3m) with a concave of
1cm diameter as the backing membrane. Drug dispersed on concave membrane, covered by a
TPX [poly (4-methyl-1- pentene)] asymmetric membrane, and sealed by an adhesive.

Preparation: These are prepared by using the dry or wet inversion process. In this TPX is
dissolved in a mixture of solvent (cyclohexane) and non- solvent 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. Then
casting film use evaporated at 50°C for 30 sec, then the glass plate is to be immersed
immediately in coagulation bath (temperature maintained 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.

ii. Circular Teflon Mould Method:

It was discovered by Baker and Heller in 1989. Polymeric solution in various

proportions is used as an organic solvent. Then that solution is divided in two parts. In one parts
calculated amount of drug is dissolved & in another part enhancers in different concentration
are dissolved, and then two parts mixed together. Then plasticizer (e.g., Di-N butyl phthalate) is
added into the drug polymer solution. The total contents are to be stirred for 12 hrs and then
poured into a circular Teflon mould. The moulds are to be placed on a levelled surface and
covered with inverted funnel to control solvent vaporization in a laminar flow hood model with
an air speed of 0.5 m/s. The solvent is allowed to evaporate for 24 h. After which a dried film
formed & that is to be stored for another 24 h at 25±0.5°C in a desiccators containing silica gel
before evaluation to eliminate aging effects.

iii. Mercury Substrate Method:

 In this method drug & Plasticizer get dissolved in polymeric solution. It stirred for 10-
15 min to produce homogenous dispersion then it is poured into levelled mercury surface,
covered with inverted funnel to control solvent evaporation.

iv. By Using “IPM Membranes” Method:

In the mixture of water & polymer (propylene glycol containing Carbomer 940
polymer) drug get dispersed and stirred for 12 hrs in magnetic stirrer. The dispersion is to be
neutralized and made viscous by the addition of tri ethanolamine. If the drug solubility in
aqueous solution is very poor then solution gel is obtained by using buffer pH 7.4. The formed
gel will be incorporated in the IPM membrane.

v. By Using “EVAC Membranes” Method:

For the preparation of TDS, 1% carbopol reservoir gel, polyethylene (PE), ethylene
vinyl acetate copolymer (EVAC) membrane is needed as rate control membrane. If the drug is
insoluble in water then use propylene glycol for gel preparation. Drug is dissolved in propylene
glycol, carb -poly 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.

vi. Preparation of TDDS by Using Pro-liposomes:

By carrier method using film deposition technique pro-liposomes are prepared.

Drug and lecithin ratio should be 0.1:2.0 taken as an optimized one from previous references.
For the preparation of Pro-liposome in 100ml round bottom flask take 5mg of mannitol powder,
then it is kept at 60-70°c temperature and the flask is rotated at 80-90 rpm and dried the
mannitol at vacuum for 30 minutes. After drying, the temperature of the water bath is adjusted
to 20- 30°C. Drug and lecithin are dissolved in a suitable organic solvent mixture, a 0.5ml aliquot
of the organic solution is introduced into the round bottomed flask at 37°C, after complete
drying second aliquots (0.5ml) of the solution is to be added. After the last loading, the flask
containing pro-liposomes are connected in a lyophilize and subsequently drug loaded mannitol
powders (pro-liposomes) are placed in a desiccator overnight and then sieved through 100
mesh. The collected powder is transferred into a glass bottle and stored at the freeze
temperature until characterization.

vii. By using Free Film Method:

In this process firstly cellulose Acetate free film is prepared by casting it on mercury
surface. And 2% w/w polymer solution is prepared by using chloroform. Plasticizers are to be
added at a concentration of 40% w/w of polymer weight. Then 5 ml of polymer solution is
poured in a glass ring which is placed over the mercury surface in a glass Petri dish. The rate of
evaporation of the solvent can be controlled by placing an inverted funnel over the Petri dish.
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 a
desiccator until use. By this process we can prepare free films of different thickness can be
prepared by changing the volume of the polymer solution.

 EVALUATION OF TRANSDERMAL PATCHES

Physiochemical evaluation:

 Thickness:

The thickness of the transdermal film is determined by a traveling microscope, dial gauge, screw
gauge, or micrometre at different points of the film. Uniformity of weight: Weight variation is
studied by individually weighing 10 randomly selected patches and calculating the average
weight. The individual weight should not deviate significantly from the average weight.

 Drug content determination:

It can be determined by completely dissolving a small area of polymeric film in the suitable
solvent of definite volume. The solvent is selected in which the drug is freely soluble. The
selected area is weighed before dissolving in the solvent. The whole content is shaken
continuously for 24 h in a shaker incubator followed by sonication and filtration. The drug in
solution is assessed by the appropriate analytical method.

 Content uniformity test:

The test is applied as the gold standard to determine chemically the content of active
constituent for each unit dose. The test is completed by performing an assay to find out the
content of drug material contained in the polymeric film of the patch.

 Moisture content:

The prepared films are weighed individually and kept in a desiccator containing calcium chloride
at room temperature for 24 h. The films are weighed again after a specified interval until they
show a constant weight. The percent moisture content is calculated using the following formula.

 Moisture Uptake:

Weighed films are kept in a desiccator at room temperature for 24 h. These are then
taken out and exposed to 84% relative humidity using a saturated solution of Potassium
chloride in a desiccator until a constant weight is achieved.

 Calculated Flatness:

A transdermal patch should possess a smooth surface and should not constrict with time. This
can be demonstrated with the flatness study. For flatness determination, one strip is cut from
the centre and two from each side of the patches. The length of each strip is measured and
variation in length is measured by determining percent constriction.

 In vitro drug release studies

In vitro drug release studies were carried out using the paddle over disc method.[27] Dry films
of known thickness were cut into circular shape, weighed, and fixed over a glass plate with an
adhesive. The plate was then placed in a 500 mL phosphate buffer (pH 7.4), and the apparatus
was equilibrated to 32°C ± 0.5°C. The paddle was then set at a distance of 2.5 cm from the glass
plate and operated at a speed of 50 rpm, and samples (5 mL aliquots) were withdrawn at
appropriate time intervals up to 12 h and analysed for drug content at 264 nm using double
beam UV-visible spectrophotometer. The experiment was performed in triplicate, and the mean
value was calculated.

Based on physicochemical characterization and drug release patterns, F17, F9, and F5
formulations were selected to which permeation enhancers like oleic acid and tween 80 were
incorporated, and resultant new formulations with permeation enhancers were labelled from
F26 to F31 and details were given in Table 2. For all six formulations, ex vivo diffusion studies
were performed using pig ear skin.

 In- vivo studies

In- vivo studies are the most accurate representation of a drug’s performance. Variables that
cannot be considered in in-vitro investigations can be completely considered. In-vivo research
have been looked into. In vivo testing of the following methods can be used to perform TDDS:
Models based on animals Volunteers from the human.

The most commonly utilized animal species for testing Transdermal medication delivery system
are used in mice, hairless rats, and other animals. A hairless dog, a hairless rhesus monkey, a
rabbit, and a guinea pig are all examples of hairless animals etc.

 Skin irritation study

Skin irritation potential of different transdermal patches can be evaluated either by visual
inspection of erythema and oedema using the PII test or examined microscopically by a light
microscope for any histopathological changes. Albino rats of average weight up to 230 g can be
used to test transdermal patches for skin irritation. Patches applied over an area of 8.1 cm2 of
the rat back after it is cleaned with rectified spirit and shaved 24 h prior to the experiment. The
patch is applied for 24 h, then removed and the area is cleaned with a disinfectant swab.
Inspection is carried out visually on the sites of application for any possible changes in terms of
skin erythema and oedema. Draize scale can be used to score the changes involving erythema
and oedema between 0 and 4 . This is rated based on the degree of severity of skin reactions
(101). PII is calculated according to the following Equation:

PII= {Sum of erythema grade on many days + Sum of oedema grade on a number of
Days}/Number of animals.

 ADVANTAGES & DISADVANTAGES OF TRANSDERMAL DRUG

DELIVERY

the transdermal system has some significant advantages.

i. Because the duration of effect is greater, the frequency of dose is reduced.

ii. Drugs that require regular doses are more convenient to Deliver.
iii. Aids in the improvement of bioavailability.
iv. Controls the plasma level uniformity.
v. The drug administration can be stopped by simply removing the patch from the skin.
vi. With a non-invasive, painless, and uncomplicated application, you may be confident in
patient compliance and comfort.

Some of the greatest disadvantages of transdermal drug delivery are:

i. There is a small chance of local irritation at the application site.

ii. The medicine, the adhesive, or any excipients in the patch formulation can produce
erythema, irritation, and local oedema.
iii. Barrier function of skin varies from site to site on the same or different functions

 CONCLUSION

The development of TDDS technology is widely recognized as the development of a mass

delivery methodology, which makes it the preferred drug injection modality for transdermal
delivery across skin types, while preventing first-pass metabolism and other sensitivities
associated with various alternative drug administration routes. In various devices and TDDSs,
drugs can be delivered through the skin to the systemic circulation. Drugs are generally reliably
and safely delivered through TDDS and are safe and stable from biochemical modifications until
they reach the target tissue. TDDS is non-invasive, no allergenic, and has a set duration and
dose delivery method, which allows for uniform distribution of drugs at prescribed and
controlled rates. Many new and old formulations are in the process of improving the
bioavailability of low-absorption drugs via easy routes of administration that allow large doses
to be administered over a long period of time.

REFERENSES

i. TRANSDERMAL DRUG DELIVERY PATCHES: A REVIEW, D. Prabhakar1, J. Sreekanth2, K.N.

Jayaveera https://core.ac.uk/reader/230733076
ii. A Brief Review on Transdermal Patches, Nidhi Sharma, HIMT College of Pharmacy,
Greater Noida, India, June 05, 2018
https://juniperpublishers.com/omcij/pdf/OMCIJ.MS.ID.555707.pdf
iii. How do transdermal patches work? ,posted by marina rulieva,
https://www.tapemark.com/blog/transdermal-patches
iv. TRANSDERMAL DRUG DELIVERY SYSTEM (PATCHES),APPLICATIONS IN PRESENT
SCENARIO https://www.ijrpc.com/files/1194-49.pdf
v. TYPE, PREPARATION AND EVALUATION OF TRANSDERMAL PATCH: A REVIEW by Md.
Intakhab Alam, Nawazish Alam, Vikramjit Singh, Md. Sarfaraz Alam, Md. Sajid Ali, Tarique
 Anwer, Mohammed M. Safhi, College of Pharmacy, Jazan University, KSA., S.B.S. College
of Pharmacy,
Patti,Amritsar,Punjab,https://www.academia.edu/26307901/Type_Preparation_and_Eva
luation_of_Transder mal_Patch_A_Review
vi. Recent Advancement of Medical Patch for Transdermal Drug Delivery, Won Fen Wong,1
Kuan Ping Ang, Gautam, Sethi, and Chung Yeng Looi , Medicina (Kaunas). 2023 Apr;
59(4): 778, Published online 2023 Apr 17. doi: 10.3390/medicina59040778
vii. Transdermal Drug Delivery Systems, Review Article, Mohammed Elmowafy,
Abdelraouf Elrehaily, Adel Elharby, Tarek Ali, Ahmed Elelian, Adel Elsemaihy and
Naif Elgabry, Department of Pharmaceutics, Faculty of Pharmacy, Al-Jouf
University, Kingdom of Saudi Arabia https://sdiopr.s3.ap-south-
1.amazonaws.com/doc/Ms_JPRI_85233.pdf
viii. Nidhi S. A Brief Review on Transdermal Patches. Organic & Medicinal Chemistry
IJ. 2018; 7(2): 555707 DOI: 10.19080/OMCIJ.2018.07.555707.
ix. Transdermal patches: history, development and pharmacology Michael N Pastore et al.
Br J Pharmacology 2015 May https://pubmed.ncbi.nlm.nih.gov/25560046/
x. Formulation and evaluation of transdermal drug deliveryInt J Pharm Investig. 2017 Jan-
Mar; 7(1): 10–17. Doi:https://doi.org/10.4103%2Fjphi.JPHI_35_16
xi. Blooming Pharma Industry with Transdermal Drug Delivery System Nikhil Sharma*,
Bharat Parashar, Shalini Doi: 10.4103/jphi.JPHI_35_16, Uday Mahajan Manav Bharti
University, Solan, Himachal Pradesh,
Indiahttp://iglobaljournal.com/wp-content/uploads/2012/11/7.-Nikhi-Sharma-et-al-
2012.pdf
xii. PRASANTH T A*1, REMYA S B2, PRASOBH G R3, SUBASH CHANDRAN M P4, A Review on
Transdermal Patches
https://ijppr.humanjournals.com/wp-content/uploads/2022/04/22.PRASANTH-T-A-
REMYA-S-B-PRASOBH-G-R-SUBASH-CHANDRAN-M-P.pdf
xiii. Transdermal drug delivery and patches—An overview David Bird, Nuggehalli M.
Ravindra, 07 March 2020,https://doi.org/10.1002/mds3.10069
xiv. Recent advances in transdermal drug delivery systems: a review Woo Yeup Jeong, Mina
Kwon, …Ki Su Kimhttps://doi.org/10.1186/s40824-021-00226-6
xv. REVIEW ON TRANSDERMAL PATCH, Rajni*, Kuamr Rohit, Bharti Nitan and Bhandari
https://storage.googleapis.com/journal-uploads/wjpgps/article_issue/1461928997.pdf
xvi. A REVIEW ON TRANSDERMAL DRUG DELIVERY PATCHES https://sdiopr.s3.ap-south-
1.amazonaws.com/doc/Ms_JPRI_85233.pdf