Chapter 1 Introduction

1. TRANSDERMAL DRUG DELIVERY SYSTEM (TDDS)

Transdermal drug delivery system TDD is a painless method of delivering drugs

systemically by applying a drug formulation onto intact and healthy skin. The drug initially
penetrates through the stratum corneum and then passes through the deeper epidermis and
dermis without drug accumulation in the dermal layer. When drug reaches the dermal layer, it
becomes available for systemic absorption via the dermal microcirculation.
TDD has many advantages over other conventional routes of drug delivery. It can
provide a non-invasive alternative to parenteral routes, thus circumventing issues such as
needle phobia. A large surface area of skin and ease of access allows many placement options
on the skin for transdermal absorption. Furthermore, the pharmacokinetic profiles of drugs
are more uniform with fewer peaks, thus minimizing the risk of toxic side effects.
It can improve patient compliance due to the reduction of dosing frequencies and is
also suitable for patients who are unconscious or vomiting or those who rely on self
(1)
administration. TDD avoids pre-systemic metabolism, thus improving bioavailability . The
requirement for an inexpensive and non-invasive means of vaccination, especially in the
developing world, has given rise to substantial research focused on the development of
simple, needle-free systems such as TDD for vaccination purposes.

The mode of drug delivery can be an important consideration in prescribing drugs,

and different routes may benefit the pharmacokinetic profile of the drug or the disease or
condition. Transdermal patch delivery systems have been developed for several drugs used in
the treatment of neurologic conditions and may provide practical and pharmacokinetic
advantages over oral drug administration.

Modern transdermal patch systems are developed to provide appropriate drug dosage
in an easy-to-use formulation that is acceptable to the patient and the caregiver. To achieve
these goals, the matrix-type patch is frequently employed, as these patches are small and thin
compared to the older and less discreet reservoir-type patches and adhere better to the skin.
The matrix system comprises 4 main components: a coloured backing layer; an acrylic matrix
containing the drug, antioxidants, and an acrylic polymer mixture; a silicone matrix adhesive
layer; and a release liner that is resistant to humidity and to the drugs within the preparation (2).
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An important feature of transdermal patches is application site tolerability. In general,

matrix-type patches have been shown to be well tolerated, even in elderly populations, with
the majority of skin reactions being mild to moderate in severity and transient Advice to limit
or manage skin tolerability when using transdermal patches can be found in the prescribing
information for these medication.

The use of transdermal patches is convenient to patients, as the patches are often only
applied once daily, while oral medications may need to be taken several times a day to
maintain adequate drug levels. Transdermal patches also offer an alternative mode of drug
delivery for oral medications that cannot be crushed or chewed (3). Additionally, patches can
be used to provide the drug over longer periods of time such as a week. Also, more frequent
application site reactions may affect the tolerability of weekly formulations, as the risk of
skin reactions increases with the size of the patch and the duration of contact with the skin.

What Are the Potential Advantages and Challenges of Transdermal Patches Versus
Oral Formulations?

Transdermal patch formulations are most often developed to optimize drug delivery,
efficacy and tolerability and are particularly appropriate for those drugs with a short half-life,
poor oral absorption, or low tolerability of the oral formulation. Transdermal patch
formulations provide a non-invasive technique to deliver a steady supply of drug molecules
directly into the circulation, avoiding the first-pass effect. However, the use of transdermal
systems of delivery is restricted to those drugs able to penetrate the skin and enter the blood
system, although new technological developments may extend the range of drugs appropriate
for transdermal delivery(4).

Table 1: Challenges of Transdermal Patches versus Oral Formulations

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Advantages Challenges
Ease of use Risk of skin irritation
Simplification of treatment
Could be removed by the patient
regimen
Easier access to target doses Does not fit existing routine
No first-pass effect Unfamiliar therapy
Lack of understanding of patch
Visual reminder of treatment
therapy

1.1. ADVANTAGES OF TRANSDERMAL ROUTE (5)

1. Provides smooth plasma concentrations of a drug without fluctuations, for a long period.

2. Drug administration through skin avoids the pH variations seen with g.i.t.

3. Drug reaches the systemic circulation whilst avoiding first-pass hepatic metabolism.

4. Self- administration is possible.

5. Drug intake can be stopped at any point by simply removing the transdermal patch.

6. Transdermal patches are non-invasive, avoiding the inconvenience of parenteral therapy.

7. Can be route of drug administration of choice in patients who are nauseated or

unconscious.

1.2. DISADVANTAGES OF TRANSDERMAL ROUTE

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1. The drug, the adhesive, or excipients in the patch formulation may cause rashes, local
irritation, erythema, or contact dermatitis.

2. Only drugs with a lipophilic character can effectively cross the stratum corneum and hence
the drugs must have some desirable physicochemical properties for penetration.

3. Only potent drugs are suitable candidates for transdermal patch because of the natural
limits of drug entry imposed by the skin’s impermeability.

4. Doses of only 5mg or less can be administered in a day.

5. The barrier function of the skin changes from one site to another on the same person, from
person to person and with age.

6. The patch may be uncomfortable to wear as adhesives may not adhere well to all types of
skin.

7. Transdermal drug delivery system cannot achieve high drug levels in blood/plasma.

8. Patch may fall-off unnoticed(6).

1.3. PERMEATION THROUGH SKIN:

To improvise the current potential of TDDS it is necessary to understand the very basic of
skin anatomy. Skin is multi-layered organ composed of many histological layers. The major
divisions of the skin, from top to bottom are the epidermis the dermis and the hypodermis.

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Figue-1: Structure of the skin

Epidermis: Stratified, squamous, keratinizing epithelium. Keratinocytes comprise
the major cellular component (> 90%) and are responsible for the evolution of barrier
function. Keratinocytes change their shape, size and physical properties when migrating to
the skin surface. This is the most important layer to transdermal delivery as its composition
allows it to keep water within the body and foreign substances out.
Dermis: Dermis consists of extensive microvasculature network structures like sweat
glands, hair follicles, and the smaller blood vessels. Therefore, in order to have drug delivery
via the skin, the drug must pass through the epidermis into the dermis where it can be
absorbed by capillaries into the circulatory system.
Hypodermis : Subcutaneous, or hypodermis in histology, is the third layer beneath
the dermis. Subcutaneous is an elastic layer and includes a large amount of fat cells that work
as a shock absorber for blood vessels and nerve endings. The thickness of this layer is 4 to 9
mm on average. When a molecule reaches intact skin, it contacts with the cellular debris,
normal flora of microorganisms, sebum and other materials (7-9).

1.4. ROUTES OF SKIN PENETRATION:

The main route of transport for water-soluble molecules is transcellular. The pathway
of transport for lipid soluble molecules is intercellular; it implicates the passage apparently
through the endogenous lipid within the stratum corneum. The transcellular and intercellular
route is collectively known as trans-epidermal route as shown below.

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Figure-2: Routes of skin permeation

Solute molecules may penetrate the skin through the hair follicles, sweat duct or
through the sebaceous glands. These passages are collectively known as shunt or appendageal
route. It is generally accepted that the skin appendages comprises of approximately 0.1% of
fractional area for drug permeation. Thus, the main focus is to develop permeation strategies
through the stratum corneum rather than through the appendages .
The main barriers to absorption are the dead cells of the SC, restricting the inward and
outward movement of drug substances and having high electrical resistance. The SC is a
heterogeneous tissue, composed of flattened keratinized cells. Thus, as molecules move from
the environment into the skin, the rate limiting barrier i.e. the tissue that presents the greatest
resistance to the movement of molecules, is the SC (10).
1.5. TYPES OF TRANSDERMAL PATCHES:

There are four main types of transdermal patches (11-12).

1.5.1 Single-layer Drug-in-Adhesive:

The adhesive layer of this system also contains the drug. In this type of patch the
adhesive layer not only serves to adhere the various layers together, along with the entire
system to the skin, but is also responsible for the releasing of the drug. The adhesive layer is
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surrounded by a temporary liner and a backing. It is characterized by the inclusion of the drug
directly within the skin‐contacting adhesive placed onto the epidermis.

Figure -3: Drug -in-Adhesive Single-Layer

1.5.2 Multi-layer Drug-in-Adhesive:

The multi-layer drug-in-adhesive patch is similar to the single-layer system; the multi-
layer system is different, however, in that it adds another layer of drug-in-adhesive, usually
separated by a membrane (but not in all cases).One of the layers is for immediate release of
the drug and other layer is for control release of drug from the reservoir. This patch also has a
temporary liner-layer and a permanent backing. The drug release from this depends on
membrane permeability and diffusion of drug molecules

Figure -4: Drug – in -Adhesive Multi -Layer

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1.5.3. Reservoir:
Unlike the single-layer and multi-layer drug-in-adhesive systems, the reservoir
transdermal system has a separate drug layer. The drug layer is a liquid compartment
containing a drug solution or suspension separated by the adhesive layer. The drug reservoir
is totally encapsulated in a shallow compartment molded from a drug-impermeable metallic
plastic laminate, with a rate-controlling membrane made of a polymer like vinyl acetate on
one surface.

1.5.4. Vapour Patch:

In a vapour patch, the adhesive layer not only serves to adhere the various layers
together but also to release vapour. Vapour patches release essential oils for up to 6 hours and
are mainly used for decongestion. Other vapour patches on the market improve quality of
sleep or aid in smoking cessation.

Figure-5: Vapour Patch

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1.6. COMPONENTS OF TRANSDERMAL PATCHES:

The components of transdermal devices include (13-14):
1. Polymer matrix or matrices.
2. The drug
3. Permeation enhancers
[Link] excipients

[Link] Matrix:

The Polymer controls the release of the drug from the device. The polymer should be
stable, non-reactive with the drug, easily manufactured into the desired product and
inexpensive. Possible useful polymers for transdermal devices are:

a) Natural Polymers: Example: Cellulose derivatives, Zein, Gelatin, Shellac, Waxes,

Proteins, Gums and their derivatives, Natural rubber, Starch .

b) Synthetic Elastomers : e.g. Polybutadiene, Silicone rubber, Nitrile, Acrylonitrile, Butyl

rubber, Styrene butadiene rubber, Neoprene etc.

c) Synthetic Polymers: e.g. Polyvinyl alcohol, Polyvinyl chloride, Polyethylene,

Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinylpyrrolidone,
Polymethylmethacrylate, Epoxy etc.

1.6.2. Drug:

For successfully developing a transdermal drug delivery system, the drug should be
chosen with great care. The following are some of the desirable properties of a drug for
transdermal delivery.

Physicochemical properties:

1. The drug should have a molecular weight less than approximately 1000 daltons.

2. The drug should have affinity for both – lipophilic and hydrophilic phases. Extreme
partitioning characteristics are not conducive to successful drug delivery via the skin.

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1.6.3. Permeation Enhancers:

These are compounds which promote skin permeability by altering the skin as a
barrier to the flux of a desired penetrant.

a) Solvents : These compounds increase penetration possibly by swallowing the polar

pathway and/or by fluidizing lipids. Examples include water alcohols – methanol and
ethanol; alkyl methyl sulfoxides – dimethyl sulfoxide, alkyl homologs of methyl
sulfoxide dimethyl acetamide and dimethyl formamide.

b) Surfactants: These compounds are proposed to enhance polar pathway transport,

especially of hydrophilic drugs. The ability of a surfactant to alter penetration is a
function of the polar head group and the hydrocarbon chain length.

 Anionic Surfactants: e.g. Dioctyl sulphosuccinate, Sodium lauryl sulphate, etc.

 Non-ionic Surfactants: e.g. Pluronic F127, Pluronic F68, etc

 Bile Salts: e.g. Sodium MS taurocholate, Sodium deoxycholate.

1.6.4. Other Excipients:

a) Adhesives: The fastening of all transdermal devices to the skin has so far been done by
using a pressure sensitive adhesive which can be positioned on the face of the device or in the
back of the device and extending peripherally. Both adhesive systems should fulfil the
following:
(i) Should adhere to the skin aggressively, should be easily removed.

(ii) Should not leave an un-removable residue on the skin.

(iii) Should not irritate or sensitize the skin.

b)Backing membrane: Backing membranes are flexible and they provide a good bond to the
drug reservoir, prevent drug from leaving the dosage form through the top and accept

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printing. It is impermeable substance that protects the product during use on the skin e.g.
metallic plastic laminate, plastic backing with absorbent pad and occlusive base plate
(aluminium foil), adhesive foam pad (flexible polyurethane) with occlusive base plate
(aluminium foil disc) etc.

1.7. EVALUATION PARAMETERS (15-17):

1.7.1. Thickness of the patch:

The thickness of the drug loaded patch is measured in different points by using
a digital micro-meter and the average thickness and standard deviation is determined to
ensure the thickness of the prepared patch. The thickness of transdermal film is
determined by travelling microscope , screw-gauge at different points of the film.

1.7.2. Weight uniformity:

The prepared patches are dried at 60°c for 4hrsbefore testing. A specified area of
patch is to be cut indifferent parts of the patch and weigh in digital balance. The average
weight and standard deviation values are to be calculated from the individual weights.

1.7.3. Folding endurance:

A strip of specific area is to be cut evenly and repeatedly folded at the same
place till it breaks. The number of times the film could be folded at the same place without
breaking gives the value of the folding endurance.

1.7.4. Percentage Moisture content:

The prepared films are to be weighed individually and to be kept in a desiccators
containing fused calcium chloride at room temperature for 24 hrs. After 24 hrs the films are
to be reweighed and determine the percentage moisture content from the below mentioned
formula
% Moisture content = Initial weight – Final weight /Final weight. X 100

1.7.5. Content uniformity test:

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10 patches are selected and content is determined for individual patches. If 9 out of
10 patches have content between 85% to 115% of the specified value and one has content not
less than 75% to 125% of the specified value, then transdermal patches pass the test of
content uniformity. But if 3 patches have content in the range of 75% to 125%, then
additional 20 patches are tested for drug content. If these 20 patches have range from 85%
to 115%, then the transdermal patches pass the test.

1.7.6. Moisture Uptake:

Weighed films are kept in desiccators at room temperature for 24 h. These are
then taken out and exposed to 84% relative humidity using saturated solution of Potassium
chloride in desiccators until a constant weight is achieved. % moisture uptake is calculated as
given below.
% Moisture uptake = Final weight – Initial weight/Initial weight. X 100

1.7.7. Drug content:

A specified area of patch is to be dissolved in a suitable solvent in specific volume.
Then the solution is to be filtered through a filter medium and analyze the drug contain with
the suitable method UV. Each value represents average of three different samples.

1.7.8. In vitro drug release studies: The franz diffusion cell apparatus is employed for
assessment of the release of the drug from the prepared patches. Dry films of known
thickness are to be cut into definite shape. The patch is then placed in the dissolution
medium or phosphate buffer (pH 7.4), and the apparatus is equilibrated to 32± 0.5°C.
Samples (2-mL aliquots) can be withdrawn at appropriate time intervals up to 24 h
and analyzed by UV spectrophotometer. The experiment is to be performed in triplicate
and the mean value can be calculated.

1.8. KINETIC CHARACTERISTICS OF DRUG RELEASE :

To know the mechanism of drug release from patches, the results obtained from the in vitro
dissolution process were fitted into different kinetic equations as follows (18):
a) Zero order release kinetics : Cumulative % drug release Vs time.
b) First -order drug release :Log cumulative % drug retained Vs time.

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c) Higuchi diffusion equation : Cumulative % drug release Vs square root of time.

d) Peppas korsemeyer exponential equation : Cumulative % drug release Vs log time.

1) Zero order release kinetics :

It defines a linear relationship between the fraction of drug released versus time.
Q= kt
Where, Q is the fraction of drug released at time t.
K is the zero order release rate constant.
A plot of the fraction of drug released against time while linear if the released obeys zero
order release kinetics.

2) First order release kinetics :

Wagner assuming that the exposed surface area of a formulation decreased exponentially
with time during dissolution process suggested that drug release from most slow release
formulation could be described adequately first – order kinetics.
ln(1-Q) = -K1t
where, Q is the fraction of drug released at the time t and
K1 is the first order release rate constant.
Thus, a plot of the logarithm of the fraction of drug remained against time will be linear if the
release obeys first order release kinetics.
3) Higuchi (diffusion ) model :
It defines a linear dependent of the active fraction released per unit of surface (Q) on the
square root of time.
Q= K2 t ½
Where, K2 is the release rate constant.
A plot of the fraction of drug released against square of time will be linear if the release
obeys Higuchi equation. This equation describes drug release as a diffusion process based on
the ficks law , square root time dependent.

4) Korsmeyer – peppas model :

A plot of fraction of logarithm of % drug released against logarithm of time will be linear if
the release obeys Korsmeyer - peppas equation.

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Log Q = log K3 + n log t

Where, K3 is the release rate constant
n is diffusional exponent

1.9. RECENT ADVANCEMENTS OF TRANSDERMAL PATCHES(19).:

a) Electroporation: The use of electro permeabilization is a method of enhancing

diffusion across biological barriers dates back as far as 100 years. Electroporation
involves the application of high voltage pulses to induce skin perturbation. High
voltages and short treatment durations (milliseconds) are most frequently employed.
The technology has been successfully used to enhance the skin permeability of
molecules with differing lipophilicity and size (i.e., small molecules, proteins,
peptides and oligonucleotides).
b) Iontophoresis: This method involves enhancing the permeation of a topically applied
therapeutic agent by the application of a low- level electric current, either directly to
the skin or indirectly via the dosage form. Increasing in drug permeation as result of
this methodology can be attributed to either one or a combination of electro repulsion
(for the charged solutes), electro-osmosis (for uncharged solutes) and electro
perturbation (for both charged and uncharged)mechanisms.
c) Ultrasound: It involves the use of ultrasonic energy to enhance the transdermal
delivery of solutes either simultaneously or through pretreatment, and is frequently
referred to as sonophoresis. The proposed mechanism behind the increase in skin
permeability is attributed to the formation of gaseous cavities within the intercellular
lipids on exposure to ultrasound resulting in disruption of the stratum corneum
d) Magnetophoresis: This method involves the application of a magnetic field that acts
as an external driving force to enhance the diffusion of a diamagnetic solute across
the skin. Skin exposure to a magnetic field might also induce structural alterations that
could contribute to an increase in permeability.
e) Microneedle-based devices: one of the first patents ever field for a drug delivery
device for the percutaneous administration of drugs is based on this method. .The
micro-needles of length 50 to 110mm will penetrate the stratum corneum and
epidermis to deliver the drug from the reservoir.

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f) Needle less injection: It is reported to involve a pain free method of administrating

drugs to skin. This method therefore avoids the issues of safety, pain and fear
associated with the use of hypodermic needle.

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Chapter 2 Literature Review

LITERATURE REVIEW

K. Sravanthi [Link]., (2020): The purpose of this research was to develop a matrix-
type transdermal therapeutic system containing drug Aceclofenac with different ratios of
hydrophilic (hydroxyl propyl methyl cellulose) and hydrophobic (methyl cellulose)
(20)
polymeric systems by the solvent casting technique . Formulated transdermal patches were
physically evaluated with regard to thickness, weight variation, drug content, flatness, tensile
strength, folding endurance, percentage of moisture content and water vapour transmission
rate. All prepared formulations indicated good physical stability. In-vitro drug studies of
formulations were performed by using Franz diffusion cells. The results followed the release
profile of Aceclofenac followed mixed zero-order.

Priyanka Kriplani [Link]., (2018): Transdermal drug delivery has made an important
contribution to medical practice. It is a medicated patch that delivers a specific amount of
medication through the skin into the blood stream. The present investigation was aimed to
formulate transdermal films of non-steroidal anti-inflammatory drug, Diclofenac sodium
using mercury substrate method and evaluated for physicochemical parameters like thickness,
(21)
weight variation, moisture uptake, moisture content, folding endurance . Three transdermal
patches were prepared using different concentrations of ethyl cellulose. It was concluded that
as the concentration of polymer increases the thickness of patch, weight uniformity and
folding endurance increases.

Patel N.B et al., (2018): Formulated a iontophoretic transdermal delivery system of

Diltiazem Hcl with various hydrophilic polymers HPMC, CMC, PVA with Propylene glycol
as plasticizer. On the basis of invitro drug release and ex-vivo skin permeation performance
formulation by using polyvinyl alcohol was found to be better than the other
formulation .Electrodes for iontophoresis were made of platinum wire and current density
0.5A/cm2 has been used for permeation enhancement (22). Diltiazem Hcl could be
administered transdermally by using iontophoresis through the matrix type TDDS for
effective control of angina pectoris and hypertension.

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[Link] Kumara et al., (2016): It was reported transdermal drug delivery of

metoprolol tartrate using polymers EC, PVA, eudragit L100. Films were prepared using
solvent casting method. They studied invitro diffusion studies using rat skin and they
conclude that the combination of EC, PVP, eudragit L100 can be optimized to develop an
effective transdermal drug delivery system for metoprolol tartrate(23).

Samip Shah et al .,(2015): It was reported formulations and evaluation of

transdermal patches of papaverine hydrochloride prepared by solvent casting method using
(24)
EC: PVP, PVP : ERL-100:ERS:100, using different ratios . The formulation containing
PVA: PVP shows faster release rate (hydrophilic polymers) compared to ERL-100 : ERS-
100hydrophobic polymers) or combination of hydrophilic or hydrophobic polymers(EC &
PVP).

Shakya Pragathi [Link].,(2014): Transdermal delivery of medications was

foreshadowed in earlier eras by the use of certain plasters and ointments. The mustard plaster,
applied as a home remedy for severe chest congestion, may be considered an example. (This
author remembers his mother making mustard plasters for members of the family.) Powdered
mustard seed (Brassica nigra) was mixed with warm water, and the resulting paste was spread
on a strip of flannel, which was applied to the patient’s chest with a cloth binding wrapped
around the body to hold the plaster in place (25). This substance possesses the qualifications
listed above for transdermal absorption.

V.N.L Sirisha et al., (2012): Formulated a matrix type transdermal patches of

propranolol hydrochloride with different ratios of hydrophobic (eudragit ) polymeric systems
by using 30%of dibutyl phthalate as plasticizer. All the prepared formulations shows good
physical stability which shows that drug release follows a zero order and the mechanism of
release is diffusion from the polymers (26).

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NEED OF THE STUDY :

Transdermal patch of Diclofenac sodium to achieve more patient compliance, to

reduce the dosing frequency, to enhance the release rate of drug for quick onset of action, to
avoid the oral administration of drug to omit the GIT related bioavailability problems and to
improve local availability of drug to site of action in arthritis.
Diclofenac sodium is reportedly used for topical applications .The drug undergoes
substantial hepatic first-pass metabolism and only about 50% of administered dose reaches
systemic circulation.
Because of its short biological half-life and frequent administration, it is considered as
a suitable candidate to formulate it into a sustained release matrix type transdermal patch
system. Therefore Diclofenac sodium is an ideal drug for the transdermal drug delivery.

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PLAN OF WORK
STEP-1

 Literature review

STEP-2

 Selection of drug and excipients.

 Determination of lambda max
 Preparation of standard graph.

STEP-3

 Formulation development by using various polymers.

 Determine the appropriate concentrations of different polymers
 Selection of best formulation.

STEP-4

 Evaluation of patches
 In vitro drug release studies by Franz diffusion apparatus.
 To study the release kinetics of drugs for all the formulations.
 To select the optimized batch.

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3. DRUG PROFILE

3.1. DICLOFENAC SODIUM(27)

IUPAC name : Sodium;2-[2-(2,6-dichloroanilino)] acetate.

Chemical formula : C14H10Cl2NNaO2

Molecular weight : 318.1.

Synonyms : A non-steroidal anti-inflammatory drug (NSAID).

Trade name : Voltaren.

Chemical structure of Diclofenac sodium

Solubility : Soluble in organic solvents like ethanol , DMSO & dimethylformamide

and it is poorly soluble in water.

Melting point : 279-289 0C.

Bioavailability : 63%.

Pharmacokinetics:

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Absorption : The amount of diclofenac sodium that is systemically absorbed.

Half-life : The terminal half-life of diclofenac is approximately 2 hr, however the

apparent half-life including all metabolites is 25.8 -33h.

Metabolism : It is mainly eliminated via metabolism. Of the total dose, 60-70% is

eliminated in the urine and 30% is eliminated in the feces.

Protein binding : The drug highly bonding serum protein, mostly to it is well known
that rheumatoid arthritis patients have low serum or plasma albumin
concentrations.

Mechanism of action:

As with most NSAIDs, the primary mechanism responsible for its anti-
inflammatory, antipyretic, and analgesic action is thought to be inhibition of prostaglandin
synthesis through COX-inhibition. Diclofenac inhibits COX-1 and COX-2 with relative
equipotency
The main target in inhibition of prostaglandin synthesis appears to be the transiently
expressed prostaglandin-endoperoxide synthase-2 (PGES-2) also known as cycloxygenase-
2 (COX-2).
Diclofenac has a relatively high lipid solubility, making it one of the few NSAIDs that
are able to enter the brain by crossing the blood-brain barrier. In the brain, too, it is thought to
exert its effect through inhibition of COX-2. In addition, it may have effects inside the spinal
cord
Diclofenac may be a unique member of the NSAIDs in other aspects. Some evidence
indicates it inhibits the lipoxygenase pathways, thus reducing formation of
the leukotrienes (also pro-inflammatory autacoids). It also may inhibit phospholipase A2 as
part of its mechanism of action. These additional actions may explain its high potency – it is
the most potent NSAID on a broad basis.
It works by stopping the body’s production of a substance that causes pain . Inhibition
of prostaglandin synthesis through COX inhibition.

Uses:

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 Used in Musculo-skeletal arthritis.

 Used to treat short term pain due to minor strains, sprains and bruises in adults and
children of 6 years old.
 Used for symptomatic relief of pain and inflammation.
 Used for topical applications.

3.2. POLYMERS PROFILE:

(28)
3.2.1. Hydroxy propyl methyl cellulose (HPMC)

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Chemical structure of hydroxyl propyl methyl cellulose

Chemical formula : C56H108O30

Chemical name : Cellulose, 2-hydroxypropyl methyl ether.

Molecular weight : 1261.43 g/mol.

Grades : Methocell E5, E15, E50, F50, F4M, K4M,15M, K100 M,

E-grade is used suitable as film formers, K-grades are used as
thickners , matrix forming agents.

Description : It is odourless, tasteless, white or creamy or granular powder.

Solubility : Soluble in cold water, insoluble in alcohol, ether and chloroform.

Density : 0.25 to 0.70g/cm3.

pH : 6.0 to 8.0(1% aqueous solution).

Log P : 4.23.

Uses : Suspending agent, viscosity increasing agent, film forming agent.

Stability : Very stable in dry conditions, solutions are stable at pH 3.0-11.0

[Link] CELLULOSE (29)

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Chapter 3 Materials and Methods

Structure of methyl cellulose

Chemical formula : C29H54O16.

Molecular weight : 658.7g/mol.

Description : It is odourless , tasteless, white or creamy or granular powder.

Solubility : Soluble in cold water, insoluble in alcohol, ether and chloroform.

Synonyms : Methylated cellulose.

Solubility : Soluble in cold water but insoluble in hot water & alcohol.

Uses : Thickening agent and emulsifier.

Stability : Very stable in dry conditions.

PLASTICIZER PROFILE
3.2.3. GLYCERINE(30)
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Chapter 3 Materials and Methods

Chemical structure of glycerol

Synonyms : Glycerine, Propanetriol, 1,2,3-Trihydroxypropane.

Chemical name : Propane-1,2,3-triol.

Chemical formula : C3H8O3.

Molecular weight : 92.09g/mol.

Description : It is odourless liquid.

Solubility : Soluble in water.

Density : 1.261glcm3.

Melting point : 17.80C.

Viscosity : 1.412 Pa.s

Functional category : Humectants, sweetener, thickening agent and preservative.

PENETRATION ENHANCERS PROFILE

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Chapter 3 Materials and Methods

3.2.4. Dimethyl sulfoxide (31)

Chemical Structure of dimethyl sulfoxide

Chemical formula : C2H6OS.

Chemical name : Sulfinyl bismethane .

Molecular weight : 78.13

Description : It is colorless, odourless, slightly bitter taste.

Solubility : Miscible with water with evolution of heat.

Boiling point : 189°C.

Functional category : Penetration agent, solvent.

Stability and storage : It is stable to heat, but upon prolonged reflux, it decomposes
slightly to mercaptan and bismethyl thoimethane.

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Chapter 3 Materials and Methods

[Link] (32)

Structure of chloroform

Chemical formula : CHCl3.

Molecular weight : 119.38 g/mol.

Synonyms : Methyl trichloride.

I.U.P.A.C name : Trichloro methane.

Solubility : Slightly soluble in water ,freely soluble in alcohol, ether ,

acetone and other organic solvents.

Melting point : 63.5oC.

Functional category : Solvent.

Stability : Very stable in dry conditions.

LIST OF MATERIALS USED IN EXPERIMENTS

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Chapter 3 Materials and Methods

[Link] MATERIALS MANUFACTURERS

1 Diclofenac sodium Alm LabTraders [Link]. Hyderabad

2 Ethyl cellulose S.D Fine Chemicals Ltd. Mumbai
3 Hydroxypropyl methyl cellulose S.D Fine Chemicals Ltd. Mumbai

4 Glycerine S.D Fine Chemicals Ltd. Mumbai

5 DMSO S.D Fine Chemicals Ltd. Mumbai

6 Chloroform S.D Fine Chemicals Ltd. Mumbai

7 Dialysis membrane Hi media Pvt. Ltd. Mumbai

8 Potassium dihydrogen phosphate S. D. Fine Chem Ltd, Mumbai

9 Distilled water Laboratory made

LIST OF EQUIPMENTS USED IN EXPERIMENT

[Link] EQUIPMENT NAME OF COMPANY

1 Electronic digital balance Shimadzu, AUX220,Japan

2 UV Spectro photometer Shimadzu, AUX220, Japan

3 Screw guage Remi Hyderabad, India

4 Hot air oven Remi Hyderabad, India
5 Cyclone mixer Remi Hyderabad, India
6 Magnetic stirrer Remi Hyderabad, India
7 Digital pH meter Cyber lab, Mumbai, India

3.3. METHODS

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Chapter 3 Materials and Methods

3.3.1. Pre-formulation studies

Pre-formulation testing is the first step in the rationale of dosage forms of a drug. It can
be defined as an investigation of physical and chemical properties of drug substances, alone
and in combination with excipients. The overall objective of the pre-formulation testing is to
generate information useful to the formulator in the developing stable and well bio
availability dosage forms.

Solubility : It is the most important parameter to check the amount of solute dissolved in
various solvents (33).

Table 2 : Solubility of drug in various solvents

Solvent Solubility profile

Water Poorly soluble in water.
Chloroform Sparingly soluble.
Ethanol Freely soluble.

A) Analytical method:

Preparation of phosphate buffer pH 7.4 (34) (I.P. 1996)

Place 50 ml of 0.2 M Potassium dihydrogen phosphate in a 200ml volumetric flask,

add 39.1 ml of 0.2M sodium hydroxide and then add water to make up the volume.

0.2M potassium dihydrogen phosphate

Dissolve 27.218 g potassium dihydrogen phosphate in distilled water and dilute to 100m
with distilled water.
0.2M sodium hydroxide solution
Dissolve 8g of sodium hydroxide in distilled water and dilute to 1000ml with water.

3.3. 2. Formulation of Diclofenac Sodium Transdermal Patch:

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Chapter 3 Materials and Methods

Table-3: Formula for transdermal patches

Ingredients DSF1 DS F2 DSF3 DSF4 DS F5 DSF6 DS F7 DSF8

Diclofenac 50 50 50 50 50 50 50 50
sodium (mg)
HPMC E5(mg) 250 500 750 1000 - - - -
Methyl - - - - 250 500 750 1000
cellulose (mg)
Chloroform(ml) 1 1 1 1 1 1 1 1
Glycerine(ml) 0.25 0,25 0.25 0.25 0.25 0.25 0.25 0.25
Ethanol(ml) 5 10 15 20 5 10 15 20
DMSO(ml) 1 1 1 1 1 1 1 1

3.3. 3. Preparation of Diclofenac sodium transdermal patches

Matrix type transdermal patches containing diclofenac sodium were prepared by

using solvent casting technique. The patches were prepared by using different ratios of
polymers. The polymers were weighed in required ratios by keeping total weight of
polymers constant. DMSO is used as penetration enhancer and the drug solution was
added to the polymeric solution and this solution was casted on to petri plate which is
allowed for air-drying overnight. The rate of evaporation of the solvent was controlled by
inverting the funnel on Petri plate(35).

3.3.4. EVALUVATION OF TRANSDERMAL PATCHES (36-37) :

[Link] of the patch :

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Chapter 3 Materials and Methods

The thickness of the drug loaded patch is measured in different points by using a
screw gauge and the average thickness and standard deviation is determined to ensure the
thickness of the prepared patch.
2. Weight uniformity:
The prepared patches are dried at 60°C for 4hrs before testing. A specified area of
patch is to be cut in different parts of the patch and weigh in digital balance. The average
weight and standard deviation values are to be calculated from the individual weight.
3. Folding endurance:
A strip of specific area is to be cut evenly and repeatedly folded at the same place till
it breaks. The number of times the film could be folded at the same place without breaking
gives the value of the folding endurance.
4 . Percentage Moisture content:
The prepared films are to be weighed individually and to be kept in a desiccators
containing fused calcium chloride at room temperature for 24 hrs. After 24 hrs the films are
to be reweighed and determine the percentage moisture content from the below mentioned
formula
% Moisture content = Initial weight – Final weight * 100
Final weight

5. Content uniformity test :

Three patches are selected and content is determined for individual patches. If 2 out of
3patches have content between 85% - 115% of the specified value and one has content not
less than 75% to 125% of the specified value, then transdermal patches pass the test of
content uniformity.
6 .Moisture Uptake :
Weighed films are kept in desiccators at room temperature for 24 h. These are then
taken out and exposed to 84% relative humidity using saturated solution of Potassium
chloride in desiccators until a constant weight is achieved. % moisture uptake is calculated as
given below
% Moisture uptake = Initial weight – Final weight * 100
Initial weight

7. Drug content:

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Chapter 3 Materials and Methods

A specified area of patch is to be dissolved in a suitable solvent in specific volume.

Then the solution is to be filtered through a filter medium and analyze the drug contain with
the suitable method UV Spectrophotometer. Each value represents average of three different
sample .
8. In vitro release studies
The drug release studies from transdermal patches were performed using Franz
diffusion cell. The drug containing films was kept between a donor and receptor
compartments, separated from these compartments by dialysis membrane. The receptor
compartment containing diffusion medium was stirred with magnetic bead operated by
magnetic stirrer, to prevent the formation of concentrated drug solution below the dialysis
membrane. 3ml of sample was collected from the receptor compartment at appropriate time
intervals and replaced with phosphate buffer pH 7.4. Analysis was carried out using UV-
Visible spectrophotometer at 276 nm against phosphate buffer pH 7.4.

Figure- 6: Franz diffusion cell apparatus

3.3.5. Kinetic characteristics of drug release (38)

To know the mechanism of drug release from patches, the results obtained from the in
vitro dissolution process were fitted into different kinetic equations as follows:
a. Zero order release kinetics: cumulative % drug release Vs time
b. First-order drug release : Log cumulative % drug retained Vs time
c. Higuchi classical diffusion equation : cumulative % drug release Vs square root of
time
d. Peppas korsemeyer exponential equation : cumulative % drug release Vs Log time.

1) Zero order release kinetics

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Chapter 3 Materials and Methods

It defines a linear relationship between the fraction of drug released versus time
Q = kt
Where, Q is the fraction of drug released at time t
K is the zero order release rate constant
A plot of the fraction of drug released against time while linear if the released obeys
zero order release kinetics.
2) First order release kinetics
Wagner assuming that the exposed surface area of a formulation decreased
exponentially with time during dissolution process suggested that drug release from
most slow release formulation could be described adequately first-order kinetics.
In (1-Q) =-k1t
Where, Q is the fraction of drug released at the time t and
K1 is the first order release rate constant.
Thus, a plot of the logarithm of the fraction of drug remained against time will be
linear if the release obeys first order release kinetics.
3) Higuchi (diffusion) model
It defines a linear dependent of the active fraction released per unit of surface (Q) on
the square root of time.
Q= K2t ½
Where, K2 is the release rate constant
A plot of the fraction of drug released against square of time will be linear if the
release obeys Higuchi equation. This equation describes drug release as a diffusion
process based on the ficks law, square root time dependent.
4) Korsmeyer – peppas model
A plot of the fraction of logarithm of % drug released against logarithm of time will
be linear if the release obeys korsemeyer-peppas equation.

Log Q = log k3 + n log t

Where, k3 is the release rate constant
n= diffusional exponent
.

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Chapter-4 Results and discussion

In the present work , transdermal patches were prepared by using solvent evaporation
method as it was feasible and simple . The best parameters obtained for diclofenac sodium
patches were evaluated based on drug release.

4.1 Pre-formulation studies:

[Link] :

Solvent Solubility properties of drug (1gm)

Water Poorly soluble in water.
Chloroform Sparingly soluble.
Ethanol Freely soluble.

Table 2 : solubility.

Discussion : Diclofenac Sodium was found to be poorly soluble in water , sparingly soluble
in chloroform and freely soluble in ethanol.

[Link] methods :

Preparation of calibration curve for diclofenac sodium :

Standard graph of diclofenac sodium was plotted in 7.4 P H phosphate buffer 2µg/ml ,4µg/ml ,
6µg/ml , 8µg/ml , 110 µg/ml was prepared from 1 mg/ml stock solution and the solution was
scanned between 200-400 nm , the drug showed absorption maxima ( max) at 276 nm. The
absorbance of solution is measured at 276 nm using UV- Visible Spectrometer. The standard
graph is plotted with concentration on X-axis and absorbance on Y -axis.
The absorbance of diclofenac sodium in phosphate buffer P H 7.4 was found to be linear
over range from 5 -25 µg/ml with R2 value of 0.9965 as shown in Figure 8

Table 3. Standard plot data of diclofenac sodium in phosphate buffer PH 7.4 , max = 276
nm.

Conc.(µg/ml) Absorbance at 276 nm(A.M + S.D)

5 0.200 ± 0.055
10 0.357 ± 0.056
15 0.510 ± 0.062
20 0.648 ± 0.079
25 0.802 ± 0.092

Each value is an average of three determinations + SD

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Chapter-4 Results and discussion

Figure 8 : Standard graph data of diclofenac sodium in phosphate buffer PH 7.4 , max =
276 nm.

1.2
y = 0.0315x + 0.0261
1 2
R = 0.9965
Absorbance

0.8

0.6

0.4

0.2

0
0 5 10 15 20 25 30
Concentration(µg/ml)

4.2 Preparation of transdermal patches of Diclofenac Sodium :

Matrix type transdermal patches containing diclofenac sodium were prepared by using
solvent casting technique. The patches were prepared by using different combinations of
polymers. The polymers were weighed in required ratios by keeping total weight of polymers
constant. DMSO is used as penetration enhancer and the drug solution was added to the
polymeric solution and this solution was casted on to a Petri plate which is allowed for air-
drying overnight. The rate of evaporation of the. vent was controlled by inverting the funnel
on petri plate.

Figure 9 : Prepared transdermal patch

Table 4: Evaluvation data of

Diclofenac Sodium transdermal patches :

The following studies were carried to find the effect of different ratios of polymers.

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Chapter-4 Results and discussion

Batch Thickness Folding % of % of Weight % Swelling

code (mm) endurance Moisture Moisture Uniformity Index
content uptake (mg) 5 10 30 60
Min min min min
F1 35.5±0.025 2±1.06 6.55 5.45 14.2 ± 3.2 5.7 2.3 2.9
0.15
F2 17.5±0.015 4±1.05 7.59 6.54 18.25 ± 6.5 8.1 9.5 10.4
0.03
F3 16.5±0.017 6±1.25 13.92 12.32 23.25 ± 16.3 17.9 16.8 18.3
0.21
F4 18.5±0.016 6±2.15 16.75 15.35 30.52 ± 28.7 28.5 22 29.3
0.52
F5 32.2±0.015 51±2.15 10.0 9.05 19.25 ± 3.5 3.2 4.5 3.5
0.13
F6 20.2±0.018 41±2.35 8.06 7.03 16.75 ± 8.7 9.6 9.9 10.1
0.26
F7 24±0.015 16±2.56 7.15 6.05 17.51 ± 15.6 16.4 17 18.9
0.32
F8 44.7±0.022 12±3.12 9.57 8.13 22.53 ± 27.4 25.4 26 27.5
0.48

S.D is being calculated by taking three patches.

Thickness of the transdermal patches was in the range of 16.5 – 72.5 mm. The folding
endurance average values was found to be 2 - 51 . The % drug release data and plot which
were obtained for the transdermal patches in phosphate buffer P H was shown in Table 5 &6
and Figure 10 & 11 respectively.

Table 5 : Cumulative % drug release data of transdermal patches in phosphate buffer PH 7.4.
(DSF1 – DSF4)

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Chapter-4 Results and discussion

Time (Hr) DSF1 DSF2 DSF3 DSF4

0 0 0 0 0
1 15.30 14.27 14.01 13.75
2 25.84 22.50 21.21 23.91
3 37.15 38.44 31.50 34.20
4 46.02 45.77 47.31 45.77
5 53.22 54.64 58.50 62.35
6 65.82 68.91 68.52 72.64
7 75.47 76.88 77.14 87.17
8 81.64 84.21 88.45 91.02

Table 6 : Cumulative % drug release data of transdermal patches in phosphate buffer PH 7.4.
( DSF5 – DSF8 ).

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Chapter-4 Results and discussion

Time (Hr) DSF5 DSF6 DSF7 DSF8

0 0 0 0 0
1 14.52 13.75 15.68 14.01
2 21.21 28.15 27.25 22.75
3 33.68 37.15 38.95 32.52
4 45.51 45.64 50.27 44.48
5 51.55 57.21 64.15 53.35
6 61.07 64.92 71.35 67.37
7 71.74 72.64 79.71 79.07
8 80.10 84.21 86.91 88.01

Figure 10 : Release of Diclofenac sodium from transdermal patches F1 to F4

formulations.

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Chapter-4 Results and discussion

Department of pharmaceutics
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Chapter-4 Results and discussion

Figure 11 : Release of Diclofenac sodium from transdermal patches F5 to F8

formulations.

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Chapter-4 Results and discussion

Table 7 : kinetics data of Diclofenac sodium transdermal patches :

Batch no. Zero order First order Higuchi Korsmeyer-

(R2) (R2) (R2) Peppas
(R2)
DSF1 0.9936 0.9684 0.9459 0.6825
DSF2 0.9983 0.9970 0.9426 0.6763
DSF3 0.9936 0.9272 0.9263 0.9924
DSF4 0.9939 0.9156 0.9942 0.9180
DSF5 0.9938 0.9756 0.9362 0.6994
DSF6 0.9998 0.9963 0.9398 0.5660
DSF7 0.9974 0.9797 0.9323 0.7288
DSF8 0.9979 0.9363 0.9141 0.9924

In vitro drug release data of DSF1 – DSF8 were fitted to zero order ,first order , Higuchi and
Korsmeyer – peppas equation to ascertain the pattern of drug release in Table 7. The R 2
values were found to be higher in zero order followed by Korsmeyer -peppas , first order and
then Higuchi , which indicates all formulations ,follows zero order release pattern.

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Chapter-4 Results and discussion

Figure 12 : Zero order release kinetics of diclofenac sodium transdermal patches.

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Chapter 5 Summary and Conclusion

SUMMARY
In the present study transdermal patches of Diclofenac sodium were successfully
prepared by solvent evaporation method by taking polymers at different ratios.

The scheme of the work followed was under.

Chapter 1 : Introduction.

In this chapter the various salient features, various mechanism used in preparation and
advantages of transdermal patch formulations have been explained.

Chapter 2 :Literature Review

Past work in connection with the design and evaluation of transdermal patches were
entitled which were reported in different journals.

Chapter 3 : Materials and Methods

In this chapter different polymers which were suitable for transdermal patches were selected
and mentioned. The various materials used through out the work was entitled and methods
allowed in this investigation were discussed.

Chapter 4 : Results and Discussion

In this chapter all the results were presented in the form of tables, graphs and figures. and the
results obtained are explained and discussed in detail.

Chapter 5 : Summary and Conclusion

Scheme of the work that has been followed in the research work was given and conclusions
were entitled.

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Chapter 5 Summary and Conclusion

CONCLUSION

The study of present work is to develop transdermal patches of diclofenac

sodium using polymers in different ratios like Hydroxy propyl methyl cellulose &
Methyl cellulose by solvent casting method. . The prepared patches were evaluated for
physicochemical properties like thickness, weight variation, swelling index, percentage
index and in vitro drug release.

In most of the formulations with increasing concentration range of polymers the

% drug release attained up to 90%. But according to drug release studies conducted by
Franz diffusion apparatus the high concentration gave better drug release compared to
low concentrations of polymers.

But finally I would like to conclude that for preparation of transdermal patches high
concentration of polymers are mostly suitable. The diclofenac sodium transdermal patch
using highest HPMC concentration among all the formulations (F4) 91% drug release
showed optimum sustained release characteristics when compared with highest methyl
cellulose transdermal patch (F8) 88% drug release. So, finally based on % drug release
optimized batch was F4 which showed better release compared to all other formulations.

The R2 values were found to be higher in zero order followed by Korsmeyer-Peppass, first
order and then Higuchi, which indicates all formulations, follows zero order release pattern.

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Chapter 6 References

REFERENCES

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Chapter 6 References

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Department of Pharmaceutics
Vaageswari Institute of Pharmaceutical Sciences ,Knr
Chapter 6 References

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28)[Link]
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29)[Link] methyl cellulose.

30)[Link]

31)[Link]

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Department of Pharmaceutics
Vaageswari Institute of Pharmaceutical Sciences ,Knr
Chapter 6 References

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Effect of Various Penetration Enhancers on ,Percutaneous Absorption of
Piroxicam..Iranian Journal of Pharmaceutical Research. 2003;2: 135-14

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Department of Pharmaceutics
Vaageswari Institute of Pharmaceutical Sciences ,Knr