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NIBHA INSTITUTE OF PHARMACEUTICAL SCIENCES, RAJGIR
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CHAPTER 01 INTRODUCTION
I. INTRODUCTION
1.1 THE DERMAL BARRIER [01]
The skin plays an important role in the transdermal drug delivery system. The Skin of an
average adult body covers a surface area of approximately 2 sq. M. And receives about
one third of the blood circulating through the body and serves as a permeability barrier
against the transdermal absorption of various chemical and biological agent. The main
three layers of skin play an important role in transdermal drug delivery system. [02]
Fig. 1. Structure of skin [03]
A. Epidermis[04]
It is 100µm thick. The outermost layer of the skin and is made up of five layers.
1. Horny layer (stratum corneum)
2. Clear layer (stratum lucidum)
3. Granular layer (stratum granulosum)
4. Prickle cell layer (stratum spinosum)
5. Germinating layer or basal layer(stratum germinativum)
1. Stratum basal, also known as stratum germinativum, is the deepest layer, separated
from the dermis by the basement membrane (basal lamina) and attached to the

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basement membrane by hemidesmosomes. The cells found in this layer are cuboidal
to columnar mitotically active stem cells that are constantly producing keratinocytes.
This layer also contains melanocytes.
2. Stratum spinosum, 8-10 cell layers, also known as the prickle cell layer contains
irregular, polyhedral cells with cytoplasmic processes, sometimes called “spines”, that
extend outward and contact neighboring cells by desmosomes. Dendritic cells can be
found in this layer.
3. Stratum granulosum, 3-5 cell layers, contains diamond shaped cells with
keratohyalin granules and lamellar granules. Keratohyalin granules contain keratin
precursors that eventually aggregate, crosslink, and form bundles. The lamellar
granules contain the glycolipids that get secreted to the surface of the cells and
function as a glue, keeping the cells stuck together.
4. Stratum lucidum, 2-3 cell layers, present in thicker skin found in the palms and
soles, is a thin clear layer consisting of eliding which is a transformation product of
keratohyalin.
5. Stratum corneum, 20-30 cell layers, is the uppermost layer, made up of keratin and
horny scales made up of dead keratinocytes, known as anucleate squamous cells. This
is the layer which varies most in thickness, especially in callused skin. Within this
layer, the dead keratinocytes secrete defensing which is part of our first immune
defense.
Cells of the Epidermis are Keratinocytes, Melanocytes, Langerhans’ cells, Merkel’s cell
Keratinocytes: Keratinocytes are the predominant cell type of epidermis and originate in
the basal layer, produce keratin, and are responsible for the formation of the epidermal
water barrier by making and secreting lipids. Keratinocytes also regulate calcium
absorption by the activation of cholesterol precursors by UVB light to form vitamin D.
Melanocytes: Melanocytes are derived from neural crest cells and primarily produce
melanin, which is responsible for the pigment of the skin. They are found between cells
of stratum basale and produce melanin. UVB light stimulates melanin secretion which is

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protective against UV radiation, acting as a built-in sunscreen. Melanin is produced
during the conversion of tyrosine to DOPA by the enzyme tyrosinase. Melanin then
travels from cell to cell by a process that relies on the long processes extending from the
melanocytes to the neighboring epidermal cells. Melanin granules from melanocytes are
transferred via the long processes to the cytoplasm of basal keratinocyte. Melanin
transferred to neighboring keratinocytes by “pigment donation”; involves phagocytosis of
tips of melanocyte processes by keratinocytes.
Langerhans’ Cells: Langerhans cells, dendritic cells, are the skins first line defenders
and play a significant role in antigen presentation. These cells need special stains to
visualize, primarily found in the stratum spinosum. These cells are the mesenchymal
origin, derived from CD34 positive stem cells of bone marrow and are part of the
mononuclear phagocytic system. They contain Birbeck granules, tennis racket shaped
cytoplasmic organelles. These cells express both MHC I and MHC II molecules, uptake
antigens in skin and transport to the lymph node.
Merkel Cells: Merkel cells are oval-shaped modified epidermal cells found in stratum
Basle, directly above the basement membrane. These cells serve a sensory function as
mechanoreceptors for light touch, and are most populous in fingertips, though also found
in the palms, soles, oral, and genital mucosa. They are bound to adjoining keratinocytes
by desmosomes and contain intermediate keratin filaments and their membranes interact
with free nerve endings in the skin.

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Fig. 2. Epidermis [5]
B. Dermis
It contains blood and lymphatic vessels, nerve endings, pilosebaceous units (hair follicles
and sebaceous glands) and sweat glands (eccrine and apocrine).It provides physiological
support for the epidermis. It is typically 3-5 mm thick and is the major component of
human skin. It is composed of a network of connective tissue, predominantly collagen
fibrils providing support and elastic tissue providing flexibility, embedded in a
mucopolysaccharide gel. It provides a minimal barrier to the delivery of most polar drugs,
although the dermal barrier may be significant when delivering highly lipophilic
molecules. The dermis contains two layers:
1. Papillary layer
2. Reticular layer
1. Papillary Layer
Lies directly under the epidermis. It is quite thin and has cone like projection called
papillae. It provides nutrients and oxygen to the germinating layer of the epidermis.

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2. Reticular Layer
This lies below the papillary layer and is the main portion of the dermis. Within the
reticular layer are collagen and elastin fibers. Collagen gives the skin a plump and
youthful appearance and is a white fibrous tissue made up of proteins. Elastin gives the
skin its elastic properties and is made up of yellow elastic tissue. Within the dermis are
various other structures knows as appendages.
C. Subcutaneous
It bridges between the overlying dermis and the underlying body constituents. It is
relatively thick in order of several millimeters. The layer of adipose tissue serves to
insulate the body to provide mechanical protection against physical shock. It also
provides supply of high energy molecules. Principal blood vessels and nerves are carried
to the skin in this layer.
1.1.1 Transdermal drug delivery [06]
The transdermal drug delivery systems are used to target the drugs for purposes,
described under:
Surface of skin: Surface of skin is targeted for locally acting substances like
disinfectants, cosmetics, insect repellent etc. in which drug acts only on the surface of the
skin and no penetration of chemicals in the skin.
Skin layers itself: The delivery of drug substances within the skin layers is also known as
topical delivery and skin layers are targeted when disease or infection is present in skin
itself .e.g. microbial infection, inflammation skin and neoplasias etc.
Systemic circulation: It is considered as an alternative to oral and other considered as an
alternative to oral and other conventional delivery routes for systemic delivery of drugs.
The drug has to be permeated through the various skin layers to the blood circulation for
its systemic effect.

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1.1.2 Transdermal drug delivery approach has following advantages and
disadvantages over other routes [07]
Advantages
 Patches are easy to apply, non-invasive and painless.
 Drug can be delivered over a long period of time.
 Reduces dosing frequency as a single patch continuously delivers the drug for
prolonged period of time.
 Suitable for drugs that are degraded in stomach pH, intestine or metabolized by liver
as drug in TDDS avoids first pass metabolism by directly absorbing into the systemic
circulation.
 No interaction of drug with food, enzymes, drink and other GI flora.
 Suitable for old age peoples who cannot take medicines orally.
 Suitable for drugs which are irritating by oral route and decreases drug side effects.
 In case of toxicity drug delivery can be stopped by removing the patch.
 Self-administration is possible.
 Patches are cost effective.
 Reduces inter and intra patient variability.
Disadvantages
 Difficult to administer large dose i.e. more than 10 mg/ day.
 Ionic drugs create problems.
 Drugs having size more than 500 Dalton are not suitable for TDDS.
 Drugs in high concentration may cause skin irritation.
 Difficult to achieve high plasma drug concentration.
 Long term adherence creates discomfort to patients.
 Drugs with very low or high partition coefficient fail to reach systemic circulation7-
10.
 Local irritation possible at site of action.

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1.1.3 Marketed transdermal formulation [08, 09]
Examples of some marketed transdermal patch formulations and their duration of
applications (Eseldin et al., 2010) are highlighted in.
TABLE 1. Marketed Formulation of TDDS.
Brand name (Active Drug) Matrix or
Membrane patch
Duraion of
application
Uses
Alora (Estradiol) Matrix 3 to 4 days In menopause
Androderm (Testosterone) Membrane 24hrs Hypogonadism
CatapresTTS (Clonidine) Membrane 24 hrs Hypertension
Climara (Estradiol) Matrix 24hrs Menopause
Duragesic (Fentanyl) Membrane 3 to 4 days Pain
Esclim (Estradiol) Matrix 72 hrs Menopause
Estraderm (Estradiol) Membrane 3 to 4 days Menopause
Minitran (Nitroglycerin) Matrix 12 to 16 hrs Angina pectoris
Nicoderm CQ (Nicotine) Membrane 24 hrs Smoking
1.1.4 Pathways of drug absorption through the skin[06]
The drug can be absorbed by various pathways through the skin depending on the
physicochemical properties of the drug. Both lipophilic and hydrophilic drugs are
absorbed from different routes. The upper stratum corneum of the skin opposes the
absorption of drug but presence of various absorption routes facilitates the entry of drug
and transport of drug to the systemic circulation .various drug absorption routes are as
follows.
Transfollicular route: Trans follicular route is the shortest pathway that drug has to
follow to reach the systemic circulation that provides a large area for diffusion of drugs
.Skin has various sweat glands, oil glands ; hair follicles and pores opening to the outer
surface of the skin via their ducts. These ducts offer a continuous channel across the
stratum corneum for drug transport but various factors like secretion from glands, content
and amount of secretion etc. affect the transport of drug through this route. However

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transappendageal route occupies only 0.1% of total skin surface and therefore contributes
a little.
Transcellular route: Drug delivering through this route passes form corneocytes which
has highly hydrated keratin creating hydrophilic pathway. Corneocytes are surrounded by
lipids connecting these cells. So a drug requires a number of partitioning and diffusion
steps .it is the most widely used route drug passes through the matrix (cytoplasm)of the
cells . This route is suitable for hydrophilic drugs. The drug passes through the
corneocytes of stratum corneum . the highly hydrated keratin provide aqueous pathway to
the hydrophilic drugs. A number of partitioning and diffusion steps are needed to pass the
drug through the cell matrix
Intercellular route: As name indicates in intercellular pathway the drug diffuses through
the continuous lipid matrix present between the cells. The barrier property of this route is
due tortuous structure formed by corneocytes and the drug has to pass through the
alternating lipid and aqueous domain by partitioning into the lipid bilayer and diffusing to
the inner side. It has been found that water has to travel 50 times more by this route so, it
is suitable mainly for uncharged lipophilic drugs.
Fig. 3. Skin showing route of absorption [10]

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1.1.5 Methods for enhancing transdermal drug delivery [11]
Skin penetration can be enhanced by following methods:
Fig. 4.Various methods used to enhance the skin penetration
1. Drug/prodrug
The prodrug approach has been used to enhance the dermal and transdermal delivery of
drugs with unfavourable partition coefficients the prodrug design involves addition of a
promoiety to increase partition coefficient and also solubility and transport of the parent
drug in the stratum corneum. Upon reaching the viable epidermis, esterases release the
parent drug by hydrolysis thereby optimising solubility in the aqueous epidermis. For
example: The intrinsic poor permeability of the very polar 6- mercaptopurine was
increased up to 240 times using S6- acyloxymethyl and 9-dialkylaminomethyl
promoieties. The prodrug approach has also been investigated for increasing skin
permeability of non-steroidal anti-inflammatory drugs, like naltrexone nalbuphine
buprenorphine alpha-blocker 4 and other drugs.

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2. Eutectic system
A eutectic system is a mixture of chemical compounds or elements that has a single
chemical composition that solidifies at a lower temperature than any other composition.
According to regular solution theory, the lower the melting point, the greater the
solubility of a material in a given solvent, including skin lipids. The melting point of a
drug delivery system can be lowered EMLA cream, a formulation consisting of a eutectic
mixture of lignocaine and prilocaine applied under an occlusive film, provides effective
local anesthesia for pain-free venipuncture and other procedures.
3. Liposomes and vehicles
Liposome are colloidal particles formed as concentric bimolecular layers that are capable
of encapsulating drugs. There are many examples of cosmetic products in which theactive
ingredients are encapsulated in vesicles. These include humectants such as glycerol and
urea, unscreening and tanning agents, enzymes, etc. Phosphatidylcholine from soybean or
egg yolk is the most common composition although many other potential ingredients have
been evaluated.
4. Solid lipid Nanoparticles
Solid lipid nanoparticles (SLN) have recently been investigated as carriers for enhanced
skin delivery of sunscreens, vitamins A and E, triptolide and glucocorticoids. It is thought
their enhanced skin penetration is primarily due to an increase in skin hydration caused by
the occlusive film formed on the skin surface. Cholesterol added to the composition tends
to stabilize the structure thereby generating more rigid liposomes. The mechanism of
enhanced drug uptake into the stratum corneum is unclear. It is possible that the
liposomes either penetrate the stratum corneum to some extent then interact with the skin
lipids to release their drug or that only their components enter the stratum corneum.
5. Iontophoresis
This method involves permeation of a topically applied therapeutic agent by application
of low level electric current either directly to skin or indirectly via dosage form.
Parameters that effect design of an ionophoretic skin delivery system include electrode
type, current intensity, pH of system. Increased drug permeation as a result of this

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methodology can be attributed to either one or a combination of the following
mechanisms: Electro repulsion (for charged solutes), electro-osmosis (for uncharged
solutes) and electro-perturbation (for both charged and uncharged).
Fig. 5. Basic principle of Iontophoresis
6. Electroporation
It involves the application of high voltage pulses to the skin that has been suggested to
induce the formation of transient pores. High voltages (100 V) 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)
including biopharmaceuticals with molecular weights greater that 7kDA 6
Fig. 6. Basic principle of electroporation [12]

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7. Ultrasound (sonophoresis and phonophoresis)
This technique involves the use of ultrasonic energy to enhance the transdermal delivery
of solutes either simultaneously or via pretreatment. It uses low frequency ultrasound (55
kHz) for an average duration of 15 seconds to enhance skin permeability.
8. Laser radiation and photomechanical waves
Lasers are frequently used for treatment of dermatological conditions like acne and to
confer facial rejuvenation. This method involves direct and controlled exposure of a laser
to the skin that results in the ablation of the stratum corneum without significantly
damaging the underlying epidermis.
9. Radio frequency
It involves the exposure of skin to high frequency alternating current resulting in
formation of heat induced micro channels in the membrane. The rate of drug delivery is
controlled by number and depth of micro channels formed by device. Treatment duration
takes less than a second.
10. Magnetophoresis
It involves application of 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
fiemight also induces structural alterations that could contribute to an increase
in permeability.

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Fig. 7. Technique of magnetophoresis [13]
11. Microneedle based devices
The first ever patents for drug delivery for percutaneous administration of drug was based
on this method. These microneedles length 50-110 micrometer will penetrate SC and
epidermldeliver drug.
12. Skin abrasion
The abrasion technique involves the direct removal or disruption of the upper layers of
the skin. These devices are based on techniques employed by dermatologists for
superficial skin resurfacing which are used in the treatment of acne, scars,
hyperpigmentation and other skin blemishes.
13. Needle-less Injection
Transdermal delivery is achieved by firing the liquid or solid particles at supersonic
speeds through the outer layers of the skin using a suitable energy source. The mechanism
involves forcing compressed gas (helium) through the nozzle, with the resultant drug

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particles entrained within the jet flow reportedly traveling at sufficient velocity for skin
penetration. This method avoids issues of safety, pain and fear.
Fig. 8. Basic designs of micro needle delivery devices [14]
14. Application of pressure
The application of modest pressure i.e. 25kPa provides a potentially non-invasive and
simplest method of skin permeability of molecules such as caffeine.
1.2 FEVER [15]
Fever is a symptom! It is usually a sign of an underlying infection, characterized by
increased body temperature and sometimes symptoms like chills, body aches, headaches,
fatigue, and loss of appetite. Mostly, the fever can go away within 3-4 days by taking
proper rest and consuming ample fluids and medications. A fever usually causes no harm
but can indicate a more severe condition in rare cases.

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1.2.1 Common Types of Fever Indians Suffer From
Fever is a common symptom of many medical conditions. An elevation in body
temperature above the normal range of 97 F (36.1 ℃) and 99 F (37.2 ℃) characterizes it.
There are several types of fever, each with different causes and characteristics.
Acute Fever: Acute fever is a sudden and short-term increase in body temperature,
usually defined as a temperature greater than 100.4°F (38°C). This type of fever is often a
response to an infection or other underlying medical condition. It is a common symptom
of many illnesses, such as the flu, a cold, or pneumonia. Acute fevers generally develop
quickly and can last anywhere from a few days to a few weeks. In most cases, an acute
fever is a sign that the body is fighting an infection or illness, but in some cases, it can
indicate a more serious underlying health condition. Therefore, it is essential to seek
medical attention if an acute fever persists, is accompanied by other concerning
symptoms, or is very high.
Sub-acute Fever: Sub-acute fever refers to a low-grade, persistent increase in body
temperature that lasts longer than an acute fever, typically lasting several weeks to a few
months. It is often seen in infections or illnesses that are not severe enough to cause a
high, acute fever but persistent enough to cause a low-grade elevation in body
temperature. Sub-acute fever can also be seen in some autoimmune diseases and certain
types of cancer. Therefore, it is important to seek medical attention if a low-grade fever
persists or is accompanied by other concerning symptoms.
Recurrent Fever: Recurrent fever refers to repeated episodes of fever that occur at
regular intervals or with a specific pattern. It is a type of fever that comes and goes and
can last anywhere from a few days to several weeks before resolving. Various underlying
medical conditions, including infections, autoimmune diseases, and certain cancers, can
cause recurrent fever. Some specific examples of conditions that can cause recurrent fever
include tuberculosis, Lyme disease, periodic fever, aphthous stomatitis, pharyngitis and
adenitis (PFAPA) syndrome. It is important to seek medical attention if a fever recurs to
address the underlying cause and prevent potential complications. A thorough evaluation,
including laboratory tests and imaging studies, may be necessary to determine the cause
of recurrent fever.

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Chronic Fever: Chronic fever is a persistent elevation in body temperature that lasts for
an extended period, often greater than three weeks. It can be a sign of underlying health
conditions such as tuberculosis or HIV, autoimmune diseases, or cancers and requires a
thorough medical evaluation. Prompt and accurate diagnosis is vital to address the
underlying cause and prevent potential complications.
Intermittent Fever: Intermittent fever is characterized by periods of normal body
temperature alternating with episodes of fever lasting several days or weeks. The cause
can range from rickettsia infections, malaria and autoimmune diseases to cancers, and it is
essential to seek medical attention for accurate diagnosis and treatment.
Remittent Fever: Remittent fever is characterized by fluctuations in body temperature
that alternates between periods of elevation and normal levels. The temperature changes
can occur over the course of a day or a few days, with the fever returning to normal levels
temporarily before rising again. This pattern of temperature changes is distinct from the
continuous elevation seen in other types of fevers. Remittent fever is often seen in
infections, such as bacterial or parasitic infections, as well as in some autoimmune
diseases and certain cancers. Therefore, an accurate diagnosis and prompt treatment are
important to address the underlying cause and prevent potential complications.
Hyperpyrexia: Hyperpyrexia is a medical term to describe a high fever, defined as a
body temperature greater than 106°F (41.1°C). It can signify a serious underlying medical
condition, such as a severe infection or heat stroke, and requires prompt medical
attention. In addition, Hyperpyrexia can be dangerous and lead to dehydration and organ
damage.
Low-Grade Fever: Low-grade fever refers to a slight increase in body temperature,
usually defined as a temperature of 100.4°F (38°C) to 102°F (38.9°C). It is considered a
mild elevation in body temperature and a common symptom of many illnesses, such as
the flu or a cold. Low-grade fevers are often accompanied by other symptoms, such as a
headache, muscle aches, or fatigue, and generally resolve independently within a few
days to a week. However, in some cases, a low-grade fever can indicate a more serious

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underlying health condition, so it is important to seek medical attention if the fever
persists.
Relapsing Fever: Relapsing fever is a type of fever characterized by recurring episodes
of fever, each lasting several days. It is caused by certain species of Borrelia bacteria that
are transmitted by the bite of infected ticks or lice. Symptoms may also include headache,
muscle aches, and a rash. Early diagnosis and treatment with antibiotics are important to
prevent potential complications.
Septic Fever: Septic fever, also known as sepsis, is a severe bacterial infection that can
cause a high fever and a widespread inflammatory response in the body. It can be life-
threatening if not treated promptly with antibiotics and supportive care. Symptoms may
include high fever, chills, rapid heartbeat, low blood pressure, and confusion. Early
recognition and prompt treatment are essential to improve outcomes.
Drug-Induced Fever: Drug-induced fever is a type of fever that occurs as a side effect of
certain medications. Various medications, including antibiotics, pain medications, and
cancer treatments, can cause it. Symptoms may include a sudden increase in body
temperature, headache, chills, and muscle aches. Treatment involves discontinuing the
medication that caused the fever and may also involve supportive care to manage
symptoms.
Idiopathic Fever: Idiopathic fever is a medical term used to describe a fever of unknown
origin, meaning no apparent cause or underlying medical condition can explain the
elevated body temperature. The term idiopathic is used when a thorough evaluation,
including laboratory tests and imaging studies, has been performed and no apparent cause
can be identified. The condition is usually self-limiting and resolves on its own within a
few days to a week. Still, ongoing evaluation and monitoring may be necessary to rule out
any underlying health issues.

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1.2.2 Sign and symptoms
 Chills
 Aches and Pains
 Headache
 Sweating or Feeling flushed
 Lack of appetite
 Dehydration
 Weakness or Lack of energy
A. Sign and symptom in adults
Seek medical attention if you’re experiencing a fever with any of the following
symptoms:
 Fever of 103°F (39.4°C) or higher
 Vomiting or diarrhea
 Difficulty breathing
 Pain in your chest
 Severe headache
 Skin rash
 Abdominal pain
 Painful urination
 A stiff neck or pain in your neck when you bend your head forward
 Feelings of confusion
 Light sensitivity
 Being dizzy or lightheaded

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B. Sign and symptom in children and babies
Seek medical attention for your child if they:
 Are younger than 3 months old and have a fever with a rectal temperature of 100.4 °F
(38°C) or higher
 Are over 3 months old and have a fever of 102°F (38.9 °F) or higher
 Are over 3 months old and have had a fever for longer than 2 days
Also seek medical attention for your child if they have a fever and:
 Difficulty breathing
 Headache
 Skin rash
 Lack of energy or appear listless or lethargic
 Are inconsolable or crying continuously
 Stiff neck
 Appear confused
 Lack of appetite
 Aren’t consuming adequate fluids to produce wet diapers.

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Fig. 9. sign and symptoms of fever [15]
1.2.3 Management
Limiting exposure to infectious agents is one of the best ways to prevent a fever.
Infectious agents often cause body temperature to rise. Here are some tips that can help
reduce your exposure. Wash your hands often, especially before eating, after using the
toilet, and after being around large numbers of people. Show your children how to wash
their hands properly. Instruct them to cover both the front and back of each hand with
soap and rinse thoroughly under warm water. Carry hand sanitizer or antibacterial wipes
with you. They can come in handy when you don’t have access to soap and water.
Find hand sanitizers and antibacterial wipes online. Avoid touching your nose, mouth, or
eyes. Doing so makes it easier for viruses and bacteria to enter your body and cause
infection. Cover your mouth when you cough and your nose when you sneeze. Teach

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your children to do the same. Avoid sharing cups, glasses, and eating utensils with other
people. Use of Net.
1.2.4 Treatment
In most cases, proper rest at home and plenty of fluids can treat fever. You may also
consume acetaminophen or ibuprofen to help reduce fever if you know the correct
dosage.
1.3 TRANSDERMAL PATCHES [16]
The past few years, interest inside the development of novel drug delivery system gadget
for current drug molecules has been renewed. The development of a novel delivery
system for current drug molecules not only boost the drug`s Conduct in the terms of
effective and safety but also ameliorates patient problems and overall therapeutic benefit
to a significant extent. When perfectly designed and developed for a particular drug,
novel delivery system can reduce specific hurdles connected with prevalent methods of
delivery, e.g. drugs that go through partial or complete degradation before coming to the
site of action could be completely delivered with improved bioavailability by using the
novel concepts of timed or pulsatile release, or gastro- resistant delivery.
First used in 1981, when Ciba- Geigy marketed transdermal V (present day marketed as
transdermal scop) to prevent the nausea and vomiting associated with motion sickness.
Resulting in decreased systemic side effects and, sometimes improved efficacy over other
dosage form. The main objective of transdermal drug delivery system is to deliver drug
into systemic circulation through skin at predetermined rate with minimal inter and
intrapatient variation. In addition, because transdermal patches are user friendly,
comfortable, painless, and offer multi day dosing, it is generally accepted that they offer
improved patient compliance 10. The growth rate for transdermal drug delivery systems
is expected to increase 12% annually by 2.
Topical remedies anointed, bandaged, rubbed or applied to the skin (Figure 1A) are likely
to have been used since the origin of man, with the practices becoming evident with the
appearance of written records, such as on the clay tablets used by the Sumerians . Indeed,
it has been suggested that a liquefied ochre-rich mixture, made some 100 000 years ago

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and found at the Blombos Cave in South Africa, may have been used for decoration and
skin protection. Ancient Egyptians used oil (e.g. castor, olive and sesame), fats (mainly
animals), perfumes (e.g. bitter almond, peppermint and rosemary) and other ingredients to
make their cosmetic and dermatological products (unguents, creams, pomades, rouges,
powders, and eye and nail paints). The mineral ores of copper (malachite: green) and lead
(galena: dark grey) were used to prepare kohl, a paste used to paint the eyes. Red ochre
was used as a lip or face paint, and a mixture of powdered lime and oil was used as a
cleansing cream. The ancient lead-based products were applied for both appearance and,
based upon religious beliefs, for protection against eye diseases However, these effects
may have been real as recent studies involving incubation of low lead ion concentrations
with skin cells produced NO, which is known to provide defense against infection. On the
negative side, it could be asked if these lead products also caused toxicity, noting that
high blood levels of lead have been reported in modern kohl users.
Historical development of patches. Early topical products: (A) products from ancient
times; (B) Galen's cold cream; (C) mercurial ointment; (D) mustard and belladonna
plasters; controlled dosing of topical products. (E) First quantitative systemic delivery
(Zondek's system). (F) Individualized delivery system: nitroglycerin ointment. (G)
Topical delivery device (Wurster & Kramer's system). Passive non-invasive patches. (H)
First patch system – the reservoir – introduced for scopolamine, nitroglycerin, clonidine
and estradiol. (I, J, K) Other types of patches – matrix and drug-in-adhesive (e.g. fentanyl
and nicotine patches). Next-generation patches.

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Fig. 10. Historical development of patches
(L) Cutaneous solutions (e.g. Patch less Patch, Evamist). (M) Active patches (e.g.
iontophoresis, Zecuity). (N) Minimally invasive patches (e.g. microneedles, Nano patch).
1.3.1 Basic components of transdermal patches [17]
1. Polymer matrix / Drug reservoir [18]
2. Drug
3. Permeation enhancers
4. Pressure sensitive adhesive (PSA)
5. Backing laminates
6. Release liner and other excipients like plasticizers and solvents

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Fig. 11. Basic component of transdermal patches [19]
1. Polymers
Polymers are the important parameter of TDDS, which control the release of the drug
from the device. Polymer matrix can be prepared by dispersion of drug in liquid or solid
state synthetic polymer base. Companies involved in the field of transdermal delivery
concentrate on a few selective polymeric systems. For example, Alza Corporation mainly
concentrates on ethylene vinyl acetate (EVA) copolymers or microporous polypropylene
and Searle Pharmacia concentrates on silicon rubber. The polymers utilized for TDDS
can be classified as,
a. Natural Polymers: [20]
Cellulose derivatives, zein, gelatin, shellac, waxes, gums
b. Synthetic Elastomers:
Polybutadiene, hydrin rubber, polyisobutylene, silicon acrylonitrile, neoprene, butyl
rubber etc.

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c. Synthetic Polymers:
Polyvinyl alcohol, polyvinylchloride, polyethylene, polyacrylate, polyamide, polyurea,
polyvinylpyrrolidone etc. The following criteria should be satisfied for a polymer to be
used in transdermal system. Molecular weight and chemical functionality of the polymer
should be such that specific drug diffuses properly and get released through it. The
polymer should be stable, non-reactive, easily manufactured and fabricated into the
desired product.
2. Drug
For successfully developing a TDDS, the drug should be chosen with great care. The
following are some of the desirable properties of a drug for transdermal delivery.
a. Physiochemical properties
The drug should have a molecular weight less than approximately 1000 Dalton. The drug
should have affinity for both lipophilic and hydrophilic phases. The drug should have low
melting point.
b. Biological properties
The drug should be potent with a daily dose of the order of a few mg/day. The half-life
should be short. The drug must not induce a cutaneous irritant or allergic response. Drug
which degrades in the GI tract is suitable for transdermal delivery. Drugs which have to
be administered for a long period of time can be formulated for transdermal system.
3. Permeation enhancers
To increase the permeability of stratum corneum so as to attain higher therapeutic levels
of the drug penetration enhancer interact with structural component of stratum corneum
i.e protein and lipids. The enhancement of absorption of oil soluble drugs is apparently
due to partial leaching of the epidermal lipids by chemical enhancers, resulting in the
improvement of skin condition for wetting and transepithelial and transfollicular
penetration. Permeation enhancer is classified into two- chemical and physical enhancer.

26
a. Chemical enhancer:
Chemicals that promote the penetration of topically applied drugs are commonly referred
to as accelerants, absorption promoters, or penetration enhancers.
Classification of chemical enhancer
i. Terpenes: e.g. menthol, carvone etc.
ii. Pyrollidones: e.g. N-methyl-2- pyrollidone, azone etc.
iii. Fatty acids: e.g. oleic acid, lauric acid etc.
iv. Sulfoxides: e.g. dimethyl sulfoxide.
v. Alcohols: e.g. ethanol, octyl alcohol etc.
vi. Miscellaneous enhancer: e.g. phospholipid, cyclodextrin,amino derivative etc.
b. Physical enhancers
The iontophoresis and ultra sound (also known as phonophoresis or sonophoresis)
techniques are examples of physical means of enhancement that have been used for
enhancing percutaneous penetration (and absorption) of various therapeutic agents.
4. Pressure sensitive Adhesives
The pressure sensitive adhesive maintains an intimate contact between patch and the skin
surface. E.g. polyacrylates, polyisobutylene and silicon based adhesive. Adhesive system
should not irritate or sensitize the skin, Should adhere to the skin aggressively during the
dosing interval without its position being disturbed by activates such as bathing, exercise
etc. It Should be easily removed, not leave an unwashable residue on the skin and should
have excellent contact with skin.

27
5. Backing laminate
The primary function is to provide a good bond to the drug reservoir, prevent drug from
leaving the dosage forms through the top. It is impermeable substance that protect the
product during use on the skin.eg metallic plastic laminate, occlusive base plate
(aluminum foil), adhesive foam pad (flexible polyurethane) etc.
6. Release liner
During storage release liner prevents the loss of the drug that has migrated into adhesive
layer. It is therefore regarded as a part of primary packaging material. E.g paper fabric,
polyethylene, polyvinyl chloride etc. Solvents such as chloroform, methanol, acetone are
used to prepare drug reservoir. In addition plasticizers such as castor oil, propylene
glycols etc. are added to provide plasticity to the patch.

28
1.3.2 Mechanism of transdermal permeation [21]
For a systemically-active drug to reach a target tissue, it has to possess some physico-
chemical properties which facilitate the absorption of the drug through the skin and also
the uptake of the drug by the capillary network in the dermal papillary layer analysis of
Skin Permeation.
The rate of permeation, dQ/dt, across various layers of skin tissues can be expressed as.
dQ/dt =Ps(Cd - Cr) …………….. (1)
Where, Cd and Cr are respectively, the concentrations of skin penetrate in the donor
phase (stratum corneum) and the receptor phase (systemic circulation); and Ps is the
overall permeability coefficient of the skin and is defined by
PS = KSDSS/HS ………………...(2)
Where, Ks = Partition coefficient of the penetrant
Dss = Apparent diffusivity of penetrant
Hs = Thickness of skin
A constant rate of drug permeation achieved, if Cd>Cr, then the equation (1) may be
reduced to
dQ/dt = PS.CD ……………………..(3)
And the rate of skin permeation (dQ/dt) becomes a constant, if the Cd value remains
fairly constant throughout the course of skin permeation. To maintain the Cd at a constant
value, it is critical to make the drug to be released at a rate (Rr) which is always greater
than the rate of skin uptake (Ra), i.e., Rr>>Ra By doing so, the drug concentration on the
skin surface (Cd) is maintained at a level which is always greater than the equilibrium (or
saturation) solubility of the drug in the stratum corneum (Ce s), i.e., Cd>>Ce s ; and a
maximum rate of skin permeation (dQ/dt)m, as expressed by equation (4), is thus
reached:
(dQ/dt) m = PSC e S ………………….(4)

29
Apparently, the magnitude of (dQ/dt) m is determined by the skin permeability
coefficient (PS) of the drug and its equilibrium solubility in the stratum corneum (Ce s).
1.3.3 Factors affecting percutaneous absorption [22]
Fick’s first law
Drug permeation across the SC obeys Fick’s first law (Equation 1). Thus the equation
helps in identifying the ideal parameters involved in the diffusion of drug across the skin .
dm/dt = J = DCo P/H………… Equation 1,
where dm/dt or J is the steady-state flux, D is the diffusion coefficient of the drug in the
SC, H is the diffusional path length or membrane thickness, P is the partition coefficient
between the SC and the vehicle, Co is the applied drug concentration which is assumed to
be constant.
Molecules showing intermediate partition coefficients (log P octane/water of 1-3) have
adequate solubility within the lipid domains of the SC to permit diffusion through this
domain whilst still having sufficient hydrophilic nature to allow partitioning into the
viable tissues of the epidermis. Furthermore, optimal permeability of drug across the SC,
Other factors which affect percutaneous absorption are discussed below.
Hydration and temperature
Skin occlusion with wraps or impermeable plastic films prevents the loss of surface water
from the skin and this causes increased level of hydration in the SC thereby decreasing
the protein network density and the diffusional path length. This increases skin
penetration. Occlusion of the skin surface also increases skin temperature by 2-3 °C
resulting in increased molecular motion and skin penetration.
Biotransformation of drug in the skin
If the penetrating drug is subject to biotransformation during skin permeation (in fact,
catabolic activity of the viable epidermis is substantial), local and systemic bioavailability
can be affected drastically. This point was taken advantage of when Sloan and Bodor
reportedly synthesized 7- acyloxymethyl derivative of theophylline that diffuse through

30
the skin far more efficiently than theophylline itself but are bio transformed rapidly to
theophylline. Thus transdermal delivery of theophylline can be enhanced this way.
Dermal clearance of drug
Blood flow limits the absorption of the drug from the dermis. For instance,
vasoconstrictor drug administered through other routes can significantly affect blood flow
to the dermis hence dermal clearance of the drug into the general circulation.

CHAPTER 02 OBJECTIVE AND DRUG PROFILE 31
II. OBJECTIVE AND DRUG PROFILE
2.1 OBJECTIVE
To develop an effective, safe and patient compliant controlled release transdermal gel
formulation of Paracetamol for Fever.
2.2 SELECTION OF DRUG
 Molecular size of the drug should be less than.
 500 Daltons.
 The drug should not stimulate an immune reaction in the skin.
 The drug should not be irreversibly bound in the subcutaneous tissue.
 Molecular weight less than 1000 Da; if molecular weight more than 1000Da then
there is a problem in penetration of the drug through stratum corneum (SC).
 Nonirritant and nontoxic to the skin.
 Should be low melting point.
 The standard aqueous solution of therapeutic agent should have the pH value in the
range of 5-9. The drug undergoes extensive hepatic first pass metabolism is
particularly good candidate for transdermal delivery.
2.3 DRUG PROFILE [23]
2.3.1 Description
Name : Acetaminophen
Paracetamol is a p-aminophenol derivative that exhibits low analgesic and antipyretic
activity. It does not possess anti-inflammatory activity. Paracetamol is thought to produce
analgesia through a central inhibition of prostaglandin synthesis.

32
CHAPTER 02 OBJECTIVE AND DRUG PROFILE
Synonym : Paracetamol
Trade name : Calpol
Structural formula
Chemical formula : C8H9NO2
IUPAC name : N-(4-Hydroxyphenyl) acetamide
Molecular weight :151.16 gram/mol
2.3.2 Physico-chemical Properties
Appearance : A white crystalline solid
Melting-point :151-165 °C
Odor : Odorless
Taste : Slightly bitter
2.3.3 Solubility :>22.7µgml
Soluble in water (1:70, 1:20 at 100°C), ethanol (1:7), acetone (1:13), chloroform (1:50),
glycerol (1:40), methanol (1:10), propylene glycol (1:9) and solutions of alkali
hydroxides; insoluble in diethyl ether. A saturated aqueous solution has a pH of ~6.

33
2.3.4 Mechanism of Action
The analgesic and antipyretic effects of paracetamol are believed to be related to the
inhibiting of prostaglandin synthetase (a mechanism shared by ASA and related drug) .It
is postulated that the analgesic effect is produced by elevation of the pain threshold and
the antipyretic effect is produced through action on the hypothalamic heat – regulating
Centre. [24]
The exact mechanism of action of paracetamol remains to be determined. There is
evidence for a number of central mechanisms, including effects on prostaglandin
production, and on serotonergic, opioid, nitric oxide (NO), and cannabinoid pathways,
and it is likely that a combination of interrelated pathways are in fact involved. A few of
these are outlined below.
Prostaglandin inhibition Paracetamol is termed a simple analgesic and an antipyretic.
Despite enduring assertions that it acts by inhibition of cyclooxygenase (COX)-mediated
production of prostaglandins, unlike non-steroidal anti-inflammatory drugs (NSAIDs),
paracetamol has been demonstrated not to reduce tissue inflammation. Two explanations
have been put forward for this.
The enzyme responsible for the metabolism of arachidonic acid to the prostanoids
(including prostaglandins and thromboxane’s), commonly referred to as cyclooxygenase,
is also more appropriately called prostaglandin H2 synthetase (PGHS), and possesses two
active sites: the COX[32] and the peroxidase (POX) sites. The conversion from
arachidonic acid to the prostanoids is in fact a two-stage process, requiring activity at the
COX site to first produce the unstable intermediate hydroperoxide, prostaglandin
G2 (PGG2), which is then converted to prostaglandin H2 (PGH2) via POX. The enzymatic
activity of COX relies on its being in the oxidized form and it is suggested that
paracetamol interferes indirectly with this by acting as a reducing co-substrate at the POX
site. In intact cells, when levels of arachidonic acid are low, paracetamol is a potent
inhibitor of PG synthesis, by blocking the physiological regeneration of POX. However,
in broken cells, where the concentration of hydroperoxides is high, prostaglandin
synthesis is only weakly inhibited. This peroxide-dependent COX inhibition explains the
differential activity of paracetamol in the brain where peroxide concentrations are
low, vs peripheral sites of inflammation with high peroxide levels (Fig. 13)

34
Fig. 12. Role of Paracetamol in inhibition of prostaglandin production. [24]
An alternative suggestion was that, unlike NSAIDS, which act on COX-1 and -2,
paracetamol may act on a discrete COX-1 splice variant (initially thought to be a distinct
isoenzyme, COX-3). This COX-1 variant was thought to be active in the central nervous
system, rather than at the site of injured or inflamed tissue, such that inhibition by
paracetamol here would explain its lack of anti-inflammatory and anti-platelet activity,
whilst still affording it highly effective analgesic and antipyretic properties. However, the
original work for this was performed on canine tissue, in which the COX-1 splice variant
retains a COX-like action; in humans, however, the expressed protein has no role in the
physiology of prostaglandins.
Serotoninergic pathway activation Serotonergic pathways are part of the descending
pain system, originating in the brainstem nuclei, hypothalamus, and cortex, and interact
with pain afferents in the dorsal horn. Serotonin receptors are present throughout the
central nervous system, involved in a number of functions, including consciousness,
mood, memory, and nausea and vomiting, the latter of which are mediated via the 5-HT3-
receptor subtype. It has become widely accepted that the activation of descending
serotonergic pathways plays a key role in the action of paracetamol, and it has been
demonstrated that the anti-nociceptive effects of paracetamol can be partially inhibited by

35
co-administration of 5-HT3-receptor antagonists, interestingly using anti-emetic drugs
which are indeed frequently given together with paracetamol in the perioperative period.
Endocannabinoid enhancement In the presence of fatty acid amide hydrolase (FAAH),
an enzyme found predominantly in the central nervous system, paracetamol (via an
intermediary, p-aminophenol, formed in the liver) is conjugated with arachidonic acid to
form the active metabolite, N-arachidonoylphenolamine (AM404). Analogous to the
action of serotonin or norepinephrine reuptake inhibitors, AM404 inhibits the reuptake of
the endocannabinoid, anandamide, from synaptic clefts, increasing cannabinoid receptor
activation on the post-synaptic membrane. This would explain the experiences of
relaxation, tranquility, and euphoria reported by many paracetamol users, apparently
independent of analgesia.
Fig. 13. Conversion of Paracetamol to AM404, an endocannabinoid reuptake
inhibitor.

36
AM404 appears to be a key player in a number of pain pathways. Apart from
endocannabinoid reuptake inhibition, it has also been shown to activate transient receptor
potential vanilloid type 1 (TRPV1) and inhibit cyclooxygenase, NO and tumor necrosis
factor-alpha (TNF-α), all involved in acute and chronic pain states. The central production
of AM404 would also account for the antipyretic effect of paracetamol, known to be
related to inhibition of prostaglandin production in the brain, whilst still without
peripheral actions
2.3.5 Pharmacokinetics
Paracetamol is well absorbed transdermal and orally only about 1/4th
is protein bound in
plasma and it is uniformly distributed in the body. Metabolism occurs mainly by
conjugation with glucuronic acid and sulphate: conjugates are excreted rapidly in urine.
Plasma t1/2 is 2-3 hours. Effects after an oral dose last for 3-5 hours.[25]
2.3.6 Uses
 Headaches
 Menstrual period
 Body ache
 Toothache
 Osteoarthritis
 Backaches
 Fever
 Arthritis pain
 Cold
2.3.7 Pharmacodynamics [23]
Animal and clinical studies have determined that acetaminophen has both antipyretic and
analgesic effects. This drug has been shown to lack anti-inflammatory effects. As

37
Opposed to the salicylate drug class, acetaminophen does not disrupt tubular secretion of
uric acid and does not affect acid-base balance if taken at the recommended
doses. Acetaminophen does not disrupt hemostasis and does not have inhibitory activities
against platelet aggregation. Allergic reactions are rare occurrences following
acetaminophen use.
2.3.8 Contraindications[15]
Contraindicated in known hypersensitivity to paracetamol in hepatic and renal failure.
2.3.9 Drug Interaction[15]
 Warfarin: prolonged, regular use may prolong prothrombin time.
 Metoclopramide and domperidone: enhance absorption of paracetamol.
 Cholestyramine: reduces absorption of paracetamol.
 Zidovudine: increased risk of neutropenia.
2.4 SIDE EFFECT
 Nausea
 Swelling
 Vomiting
 Pain
 Tenderness in the upper abdomen
 Sweating
 Loss of appetite
 Stomach cramps
 Diarrhea

38
Major side effects are as follows:
 Dark-colored urine
 High fever
 Lower backache
 Skin having red spots
 Rashes
 Inflammation
 Itching
 Sore throat
 Ulcers
 Breathlessness
 Yellowish eyes
 Pale skin
2.5 POLYMER PROFILE
2.5.1 Carbopol 934
Synonyms :Unopol 934, Synthalen M – 3V, Carbopol 934, 2-Propenoic Acid
Homopolymer, T/N: Acritamer 934; Acrylic Acid Resin; 2-Propenic Acid Homopolymer;
Acrylic Acid Polymer.
Molecular Formula :C5H10OC8
Chemical weight :102.13 g/ mol.

39
IUPAC : 2 propanoic acid.
Chemical Structure:
Melting point : Greater than 300 °C.
Boiling point :116 °C
Uses : Carbopol 934 polymer is a white powder, cross-linked polyacrylic acid polymer.
It exhibits short flow properties.
2.5.2 PVA (Polyvinyl Alcohol)
Synonyms: Ethanol homopolymer, Ethenol, Hydroxyethene, Hydroxyethylene, Mowiol,
Poval, PVA, PVOH, Sloviol, Vinyl alcohol
IUPAC Name : Butan -2-ol
Melting Point : 200 °C
Boiling Point : 228 ℃
Molecular Formula :(C2H4O) n

40
Chemical Structure :
Uses: PVA polymer is used in many fields. It is used as main component in many drugs.
Many of its applications are based on its adhesive property. PVA is a type of synthetic
adhesive. PVA is used as PVA glue in many fields. Meaning of PVA glue is a glue or
fixative made up of polyvinyl alcohol.
2.5.2 PEG 600 (Polyethylene glycol)
Synonyms : Poly (ethylene glycol), PEG
Molecular formula :(OCH2CH2) nOH
Chemical weight : 500 – 600 g/m
IUPAC Nomenclature : Poly (oxyethylene)
Boiling point : 250 °C
Melting point : 200 (-65 to -50°C), 300 (-15 to -10°C), 400 (-6 to 8°C), 600 (17 to 22℃)

41
Chemical structures:
Uses : It provides enhanced solvency, lubricity, and Hygroscopicity.
2.5.4 PVP (polyvinylpyrrolidone) [26]
Synonyms: Povidone, PVP, Polyvidone, Plasdone, Kollidon, Poly [1-(2-oxo-1-
pyrrolidinyl) ethylene], 1-vinyl-2-pyrrolidinone polymer, 2-pyrrolidinone-1-ethenyl-
homopolymer.
Molecular formula :(C6H9NO) n
IUPAC Nomenclature :1-ethenylpyrrolidin-2-one
Melting point : Softens at 150 °C and decomposes after 180 °C.
Boiling point :217.6 ℃
Chemical structure:
Uses : Binder, film former, emulsion stabilizer, suspending
agent.

42
CHAPTER 03 LITERATURE REVIEW
III LITERATURE REVIEW
Sintov A.C et.al, (2003) studied that to develop a new transdermal system for optional
therapeutic administration of paracetamol in infants and children. In-vivo studies were
carried out in animals using a transdermal system of high-loaded, soluble paracetamol in
a hydrogel patch, which was also tested in-vitro for 8 h. Although the beneficial
contribution of glycerol oleate to the transdermal penetration of paracetamol seemed to be
significant in-vitro, it was shown to be insufficient in-vivo. To improve the penetration of
the drug, 4% PEG-40 stearate and 10% ethanol were incorporated as absorption
enhancers into the dermal patches. A few hours after application of the improved patches
to rats, plasma drug concentrations were elevated to levels comparable with those
obtained after oral and subcutaneous administration of a high dose of Paracetamol. Since
plasma drug concentrations did not reach a constant steady state (as a peak or plateau)
during the short-term animal experiments, longer pharmacokinetic studies in conscious
animals are necessary. [27]
John L, et.al, (2014) reviewed that the transdermal drug delivery systems are polymeric
patches containing dissolved or dispersed drug that deliver therapeutic agent at a constant
rate through skin. Transdermal delivery has made an important contribution to medical
practice but has yet to fully achieve its potential as an alternative to oral delivery and
hypodermic injections. They studied that the principle of TDDS is that they could provide
sustained drug delivery (and hence constant drug concentration in plasma) over a
prolonged period of time. TDDS can be designed to input drug at appropriate rate to
maintain plasma-drug levels for therapeutic efficacy. Ultimately the success of all the
transdermal system depends on the ability of the drug to permeate skin in sufficient
quantities to achieve its desired therapeutic effect. They provided a detailed study of
transdermal that is advantage, disadvantages, mechanism, factors affecting skin
permeation and types. They also focused on the application and future approaches of
transdermal drug delivery system.[28]
Pastore M.N et.al,(2015) discussed that 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

43
and their limitations as well as requirements for actives to be used for transdermal
delivery. The properties of and issues associated with the use of currently marketed
products, such as variability, safety and regulatory aspects, are then described. The review
concludes by examining future prospects for transdermal patches and drug delivery
systems, such as the combination of active delivery systems with patches, minimally
invasive microneedle patches and cutaneous solutions, including metered-dose systems.
[29]
Jhawat V.C et.al,(2013) Studied that the Transdermal route have a number of advantages
over conventional drug delivery routes such as avoidance of first pass effect, enhanced
bioavailability, patient compliance, steady state plasma drug level, painless delivery of
drugs, ease of application and easy removal of patch in case of toxicity. Transdermal
patch is applied over the skin and it remains in position for a specific period of time as
hrs. Days or weeks and releases the drug for that period of time. The routes of drug
absorption through the skin are intercellular, intracellular and transappendageal. The drug
has to pass through various layers of the skin after release from the transdermal patch.
The major problem in transdermal drug delivery is the barrier of stratum corneum to the
permeation of the drug and can be overcome by permeation enhancing techniques. A
transdermal patch has several components such as backing membrane, drug reservoir,
adhesive layer, release control membrane and liner etc.[06]
Mounika. P. et. Al, (2019) discussed the main aim of this research is the children who
are unable to take medicine in different dosage forms like tablets, capsules & syrups etc,
TDDS is a suitable route for administration of drug. The half-life of a drug is 1-4 hours
which makes it suitable for TDDS. Transdermal patches are prepared by solvent casting
method using Carbopol as a polymer. The main object of this study is to compare the
individual effect of penetration enhancers on Paracetamol TDDS.[13]
Alam Md. Intakhab et.al, (2013) studied Now a day about 74% of drugs are taken orally
and are found not to be as effective as desired. To improve such characters transdermal
drug delivery system was emerged. Drug delivery through the skin to achieve a systemic
effect of a drug is commonly known as transdermal drug delivery and differs from
traditional topical drug delivery. Transdermal drug delivery systems (TDDS) are dosage
forms involves drug transport to viable epidermal and or dermal tissues of the skin for

44
local therapeutic effect while a very major fraction of drug is transported into the
systemic blood circulation. The adhesive of the transdermal drug delivery system is
critical to the safety, efficacy and quality of the product. [17]
Al Hanbali O.A. et.al (2019) reviewed that the Use of transdermal patches can evade
many issues associated with oral drug delivery, such as first-pass hepatic metabolism,
enzymatic digestion attack, drug hydrolysis and degradation in acidic media, drug
fluctuations, and gastrointestinal irritation. This article reviews various transdermal
patches available in the market, types, structural components, polymer role, and the
required assessment tools. Although transdermal patches have medical applications for
smoking cessation, pain relief, antipyretic, osteoporosis, contraception, motion sickness,
angina pectoris, and cardiac disorders, advances in formulation development are ongoing
to make transdermal patches capable of delivering more challenging drugs. Transdermal
patches can be tailored and developed according to the physicochemical properties of
active and inactive components, and applicability for long-term use. Therefore, a number
of chemical approaches and physical techniques for transdermal patch development are
under investigation.[30]
Choudhury.D et al, (2021) reviewed that the transdermal drug delivery system is widely
accepted due to its numerous advantages as it is a non-invasive drug administration
process with prolonged therapeutic effect, reduced side effects, improved bioavailability,
better patient compliance, and easy termination of drug therapy. Nonsteroidal anti-
inflammatory drugs such as paracetamol Therefore, transdermal delivery of these drugs
has advantages of avoiding hepatic first-pass effect, gastric irritation and delivering the
drug for an extended period of time at a sustained level. The present article mainly
focuses on the work been done on these drugs by formulated and delivered as transdermal
patches to decrease the side effects related to the oral delivery.[31]
Chandan. S et.al, (2022) discussed transdermal route of drug administration is novel as
well as reliable means of sustained drug delivery. With more and more research being
carried out in this field and increasing interest of researchers in this form of drug delivery,
number of transdermal devices reaching the marketplace are expected to increase sharply.
The aim of this review is to present latest explorations carried out in recent years utilizing
possible drug candidates. Also, new polymer candidates along with novel penetration

45
enhancers have been presented. After going through all the research work done by
researchers in recent past it is appropriate to state that transdermal route is no longer
reliant on few polymers and penetration enhancers but studies have now provided lot
many more options for transdermal device formulation as evident from the data
compilations. It can be concluded that most of the researchers have been utilizing PVG as
the preferred film forming polymer but recently use of PVP grades also has gained
interest amongst scientists. [32]
Prabhakar.D. el.at, (2013) reviewed that the drug delivery through the skin to achieve a
systemic effect without producing any fluctuations in plasma concentration of the drug.
A Topical administration of therapeutic agents offers many advantages over conventional
oral and invasive methods of drug delivery. A And also provide controlled release of the
drug for extended period of the time. This review article covers brief outline advantages,
skin pathways for transdermal drug delivery systems (TDDS), various components of
transdermal patch, and approaches for preparation of transdermal patches, evaluation of
transdermal system, general clinical considerations in the use of tdds and limitation of
tdds.[33]
Gorle P.A et.al, (2017) Researched Transdermal drug delivery system (TDDS) was
planned to release the drug in appropriate manner and to improve patient compliance.
Present study describes the alternative route for systematic delivery of drug into the body
system which enhances the rate of absorption and increases the bioavailability of the drug
into systemic circulation by reducing the gastric irritation. Formulations were developed
by solvent casting technique. to evaluate their characteristics such as Physical appearance,
thickness, weight variations, drug content uniformity, folding endurance, tensile strength
moisture content, moisture loss, flatness, surface pH, etc. Formulations showed good
uniformity of drug content; there was no any kind of effect on moisture loss test. A result
of short‐term stability study indicated the formulations were remained stable both
physically and chemically. Hence, aforesaid study accomplishes goal such as decrease
frequency of administration, less dosing, improved patient compliance and reduced
systemic toxicity.[34]
Kumari. S. et. al,(2014) researched the transdermal drug delivery system (TDDS) is the
most important part of pharmaceutical dosage form . transdermal drug delivery system

46
established itself as an integral part of Novel drug delivery system on the delivery of the
drug across dermis gives the systemic effect .in this study transdermal patches were
prepared by mercury substrate method using poly vinyl alcohol (PVA),polyethylene
glycol (PVG) , Poly vinyl pyrrolidone (PVP) was used as a plasticizer .the prepared
patches was evaluated for thickness , folding endurance , drug contain uniformity was
found to moisture absorption and percent moisture loss. [35]
Freo. U et. al, (2021) researched that the musculoskeletal pain conditions are age-related,
leading contributors to chronic pain and pain-related disability, which are expected to rise
with the rapid global population aging. Current medical treatments provide only partial
relief. Furthermore, non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are
effective in young and otherwise healthy individuals but are often contraindicated in
elderly and frail patients. As a result of its favorable safety and tolerability record,
paracetamol has long been the most common drug for treating pain. Strikingly, recent
reports questioned its therapeutic value and safety. This review aims to present guideline
recommendations. Paracetamol patches have been assessed in different conditions and
demonstrated therapeutic efficacy on both acute and chronic pain. It is active as a single
agent and is additive or synergistic with NSAIDs and opioids, improving their efficacy
and safety. However, lacks of significant efficacy and hepatic toxicity have also been
reported. Fast dissolving formulations of paracetamol patches provide superior and more
extended pain relief that is similar to intravenous paracetamol.[36]
Mallet. C. et. al, (2023) reviewed the Despite its wide use, debate exists regarding the
analgesic mechanism of action (MoA) of paracetamol. A growing body of evidence
challenged the notion that paracetamol exerts its analgesic effect through cyclooxygenase
(COX)-dependent inhibitory effect. It is now more evident that paracetamol analgesia has
multiple pathways and is mediated by the formation of the bioactive AM404 metabolite
in the central nervous system (CNS). AM404 is a potent activator of TRPV1, a major
contributor to neuronal response to pain in the brain and dorsal horn. In the
periaqueductal grey, the bioactive metabolite AM404 activated the TRPV1 channel‐
mGlu5 receptor‐PLC‐DAGL‐CB1 receptor signaling cascade. The present article
provides a comprehensive literature review of the centrally located, COX-independent,
analgesic MoA of paracetamol and relates how the current experimental evidence can be
translated into clinical practice. The evidence discussed in this review established

47
paracetamol as a central, COX-independent, antinociceptive medication that has a distinct
MoA from non-steroidal anti-inflammatory drugs (NSAIDs) and a more tolerable safety
profile. With the establishment of the central Moa of paracetamol, we believe that
paracetamol remains the preferred first-line option for mild-to-moderate acute pain for
healthy adults, children, and patients with health concerns. However, safety concerns
remain with the high dose of paracetamol due to the NAPQI-mediated liver necrosis.[37]
BEBENISTA.M.J et. al, (2014) discussed the Paracetamol / acetaminophen is drug of
choice in patients that cannot be treated with non-steroidal anti-inflammatory drugs
(NSAID), such as people with bronchial asthma, peptic ulcer disease, hemophilia,
salicylate-sensitized people, children under 12 years of age, pregnant or breastfeeding
women. It is recommended as a first-line treatment of pain associated with osteoarthritis.
The mechanism of action is complex and includes the effects of both the peripheral (COX
inhibition), and central (COX, serotonergic descending neuronal pathway, L-arginine/NO
pathway, cannabinoid system) antinociception processes and redox mechanism.
Paracetamol is well tolerated drug and produces few side effects from the gastrointestinal
tract, however, despite that, every year, has seen a steadily increasing number of
registered cases of paracetamol-induced liver intoxication all over the world.[38]

48
CHAPTER 04 MATERIAL AND METHOD
IV. MATERIALS AND METHOD [13]
4.1 MATERIALS
Paracetamol :500mg
Carbopol :1g
PVP :300mg
PEG600 :200mg
PVA :300 mg
Methanol :5ml
Water :5ml
4.2 METHOD
4.2.1 Preparation of Paracetamol patch
Patches are prepared by using solvent casting method. Petridis with area 35.25 cm2
was used.
Polymers were weighed accurately and dissolved in 10ml of methanol & water (1:1) kept
aside to form clear solution. 500mg of drug added to the all formulation. PEG600 (20% w/w
of total polymer), PVP (10% w/w of total polymer), PVA (30% w/w of total polymer) used as
penetration enhancers. The solution was poured on the Petridis which is lubricated with
glycerin & dried at room temperature for 24 hours. An inverted funnel places over the
Petridis to prevent evaporation of the solvent. Patches are stored in decicator.

49
Fig. 14. Mixing of paracetamol with other ingredients to make gel in the laboratory
Fig. 15. prepared paracetmol gel and transferred into container

50
Table2. Formulation
Fig. 16. Three transdermal patch prepared name A, B, C as shown in the above
4.3 EVALUATION OF TRANSDERMAL PATCHES
Development of controlled release transdermal dosage form is a complex process involving
extensive research. Transdermal patches have been developed to improve clinical efficacy of
the drug and to enhance patient compliance by delivering smaller amount of drug at a
predetermined rate. This makes evaluation studies even more important in order to ensure
their desired performance and reproducibility under the specified environmental conditions.
These studies are predictive of transdermal dosage forms and can be classified into different
types including physicochemical evaluation, in-vitro evaluation, and in-vivo evaluation. After
the successful evaluation of physicochemical and in-vitro studies, in-vivo evaluations may be
conducted.
Batch No. Polymer Proportion Solvent
1 Carbopol: PVA 1:1 Methanol & Water
2 Carbopol: PEG600 1:1 Methanol & Water
3 Carbopol PVP 1:1 Methanol & Water

51
4.3.1 Physico-chemical Evaluation
Thickness: The thickness of transdermal film is determined by travelling microscope, dial
gauge, screw gauge or micrometer 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 (1
cm 2) of polymeric film in 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 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 assay to
find out the content of drug material contained in polymeric film of the patch. According to
USP the procedure consists of two stages. First stage consists of assaying the randomly
selected ten units. It is followed by second stage to be performed on twenty more units when
the first stage fails. Initially ten patches are selected and content is determined for individual
patches. Test passes when all 10 unit doses have content ≥ 85 % and ≤ 115 % (RSD < 6%). 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 RSD of all the 30 units is < 7.8%, not
more than one value is outside 85–115%, and no value is outside75–125%, the batch passes
the test if not fails the test.
Moisture content: The prepared films are weighed individually and kept in a desiccators
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 following formula

52
% Moisture content = (Initial weight – final weight )×100
Final weight
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 saturated solution of
Potassium chloride in a desiccator until a constant weight is achieved. % moisture uptake is
calculated as given below.
% moisture uptake = final weight – initial weight×100
Initial weight
Flatness: A transdermal patch should possess a smooth surface and should not constrict with
time. This can be demonstrated with flatness study. For flatness determination, one strip is
cut from the centre and two from each side of patches. The length of each strip is measured
and variation in length is measured by determining percent constriction. Zero percent
constriction is equivalent to 100 percent flatness.
% constriction = ( L1 – L2) ×100
L1
L2 = Final length of each strip
L1 = Initial length of each strip
Folding Endurance: Evaluation of folding endurance involves determining the folding
capacity of the films subjected to frequent extreme conditions of folding. Folding endurance
is determined by repeatedly folding the film at the same place until it break. The number of
times the films could be folded at the same place without breaking gives the folding
endurance value.

53
Tensile Strength: To determine tensile strength, polymeric films are sandwiched separately
by corked linear iron plates. One end of the films is kept fixed with the help of an iron screen
and other end is connected to a freely movable thread over a pulley. The weights are added
gradually to the pan attached with the hanging end of the thread. A pointer on the thread is
used to measure the elongation of the film. The weight just sufficient to break the film is
noted. The tensile strength can be calculated using the following equation.
Tensile strength = F/a.b(1+L/l)
‘F’ is the force required to break; ‘a’ is width of film; ‘b’ is thickness of film; ‘L’ is length of
film; ‘l’ is elongation of film at break point. In another study, tensile strength of the film was
determined with the help of texture analyzer. The force and elongation were measured when
the films broke.
Water vapor transmission studies (WVT): WVT is determined by taking one gram of
calcium chloride in previously dried empty vials having equal diameters. The polymer films
are pasted over the brim with the help of adhesive like silicon adhesive grease and then
allowed to set for 5 minutes. The vials are accurately weighed and placed in humidity
chamber maintained at 68 % RH. The vials are then weighed repeatedly up to seven
consecutive days and an increase in weight was considered as a quantitative measure of
moisture transmitted through the patch. In other reported method, desiccators are used to
place vials, in which 200 mL of saturated sodium bromide and saturated potassium chloride
solution are placed. The desiccators are tightly closed and humidity inside the desiccator is
measured by using hygrometer. The vials are then weighed before and after placing in the
desiccator and procedure is repeated.
WVT = W/S×T
W is the increase in weight in 24 h, S is area of film exposed (cm2
) T is exposure time.
Microscopic studies: Distribution of drug and polymer in the film can be studied using
scanning electron microscope. For this study, the sections of each sample are cut and then
mounted onto stubs using double sided adhesive tape. The sections are then coated with
goldpalladium alloy using fine coat ion sputter to render them electrically conductive. Then
the sections are examined under scanning electron microscope.

54
Adhesive studies: The therapeutic performance of TDDS can be affected by the quality of
contact between the patch and the skin. The adhesion of a TDDS to the skin is obtained by
using PSAs, which are defined as adhesives capable of bonding to surfaces with the
application of light pressure. The adhesive properties of a TDDS can be characterized by
considering the following factors.
Peel Adhesion properties: It is the force required to remove adhesive coating from test
substrate. It is tested by measuring the force required to pull a single coated tape, applied to
substrate at 180° angle. The test is passed if there is no residue on the substrate. performed
the test with a tensile testing machine Acquati model AG/MC 1
Tack properties: It is the ability of the polymer to adhere to substrate with little contact
pressure. Tack is dependent on molecular weight and composition of polymer as well as on
the use of tackifying resins in polymer . It includes thumb tack test, rolling ball test, quick
stick (Peel tack) test and probe tack test. Thumb tack test is performed by touching the
surface of a pressure sensitive adhesive with the thumb and feeling the force required to
break the bond. Thus the force required to remove thumb from adhesive is a measure of tack.
Rolling ball test involves measurement of the distance that stainless steel ball travels along
with an upward facing adhesive. The less tacky the adhesive, the further the ball will travel.
Quick stick (Peel tack) test: The peel force required breaking the bond between an adhesive
and substrate is measured by pulling the tape away from the substrate at 90◦ at the speed of
12 inch/min. Probe tack test is performed using a probe which is pushed forward into contact
with the adhesive surface and then retracted at a predefined speed. The force required to
break the bond after a short period of contact is measured. The test may be performed with
the help of Texture Analyser.
Shear strength properties or creep resistance: Shear strength is the measurement of the
cohesive strength of an adhesive polymer i.e., device should not slip on application
determined by measuring the time it takes to pull an adhesive coated tape off a stainless plate.
performed the test with an apparatus which was fabricated according to PSTC-7 (pressure
sensitive tape council) specification.

55
4.3.2 In-vitro studies
In-vitro release studies: The amount of drug available for absorption to the systemic pool
is greatly dependent on drug released from the polymeric transdermal films . Drug release
mechanisms and kinetics are two characteristics of the dosage forms which play an important
role in describing the drug dissolution profile from a controlled release dosage forms and
hence their in-vivo performance. Various methods are available for the determination of drug
release from TDDS. The paddle over disc method is identical to the USP paddle dissolution
apparatus, except that the transdermal system is attached to a disc or cell resting at the bottom
of the vessel which contains medium at 32 ±5°C. The paddle over disk method in conjunction
with a watch glass-patch-screen sandwich assembly is thought to be the preferable method. It
is easier, more convenient and exhibiting experimentally almost the same release profile
when compared with other more complicated methods . The cylinder modified USP basket
method is similar to the USP basket type dissolution apparatus, except that the system is
attached to the surface of a hollow cylinder immersed in medium at 32 ±5°C. The
reciprocating disc method consists of attaching the patches to holders and oscillated in small
volumes of medium, allowing the apparatus to be useful for systems delivering low
concentration of drug. Paddle over extraction cell method may also be used. Diffusion cells
include Franz-diffusion cell and its modification Keshary-Chien Cell. In this method
transdermal system is placed in between receptor and donor compartment of the diffusion
cell. The transdermal system faces the receptor compartment in which receptor fluid (e.g.,
drug solution) is placed. The agitation speed and temperature are kept constant. The whole
assembly is kept on magnetic stirrer and solution in the receiver compartment is constantly
and continuously stirred throughout the experiment using magnetic beads. At predetermined
time intervals, the receptor fluid is removed for analysis and is replaced with an equal volume
of fresh receptor fluid. The concentration of drug is determined by suitable analytical method.
The pH of the dissolution medium ideally should be adjusted to pH 5 to 6, reflecting
physiological skin conditions. For the same reason, the test temperature is typically set at
32°C (even though the temperature may be higher when skin is covered). PhEur considers
100 rpm a typical agitation rate and also allows for testing an aliquot patch section. The latter
may be an
In-vitro permeation studies: After release from the polymeric films, drug reaches at skin
surface is then passed to the dermal microcirculation by permeation through cells of
epidermis and/or between the cells of epidermis through skin appendages. Usually

56
permeation studies are performed by placing the fabricated transdermal patch with rat skin or
synthetic membrane in between receptor and donor compartment in a vertical diffusion cell
such as Franz diffusion cell or Keshary‐Chien diffusion cell. The transdermal system is
applied to the hydrophilic side of the membrane and then mounted in the diffusion cell with
lipophilic side in contact with receptor fluid. The receiver compartment is maintained at
specific temperature (usually 32±5°C for skin) and is continuously stirred at a constant rate.
The samples are withdrawn at different time intervals and equal amount of buffer is replaced
each time. The samples are diluted appropriately and estimated by suitable analytical method.
The amount of drug permeated per square centimeter at each time interval is calculated.
Many variables including design of system, patch size, surface area of skin, thickness of skin
and temperature may affect the in-vitro properties of drug. Thus, the permeation studies
involves preparation of skin, mounting of skin on permeation cell, setting of experimental
conditions like temperature, stirring, sink conditions, withdrawing samples at different time
intervals, sample analysis and calculation of flux (i.e., drug permeated per unit area per unit
time) .
4.3.3 In-vivo Studies
In-vivo evaluations are the true depiction of the drug performance. The variables which
cannot be taken into account during in-vitro studies can be fully explored during in vivo
studies. In-vivo evaluation of TDDS may be carried out using either animal models or human
volunteers or both.
Animal models: Considerable time and resources are required to carry out human studies, so
animal studies are preferred at small scale. The most common animal species used for
evaluating transdermal drug delivery systems are mouse, hairless rat, hairless dog, hairless
rhesus monkey, rabbit, guinea pig etc. Based on the experiments conducted so far it is
concluded that hairless animals are preferred over hairy animals in both in-vitro and in-vivo
experiments. Rhesus monkey is one of the most reliable models for in vivo evaluation of
transdermal drug delivery.
Human models The final stage of the development of a transdermal device involves
collection of pharmacokinetic and pharmacodynamic data following application of the patch
to human volunteers. Clinical trials are conducted to assess the transdermal systems including

57
the efficacy, risk involved, side effects, and patient compliance. Phase-I clinical trials are
conducted to determine mainly safety in volunteers and phase-II clinical trials determine
short term safety and mainly effectiveness in patients. Phase-III trials indicate the safety and
effectiveness in large number of patient population and phase-IV trials at post marketing
surveillance are done for marketed patches to detect adverse drug reactions. Though human
studies require considerable resources but they are the best to assess the performance of the
drug.
Fig. 17. Evaluation formulation of A, B and C gel on the skin for spreadibility, irritation
and absorption
4.4 STABILITY [39]
The accelerated stability testing study of the best optimized transdermal patch was performed
for 6 months, according to the ICH guidelines under the following conditions: 40 ± 2°C
temperature and 75 ± 5% relative humidity (RH) to confirm the stability potential of the
drugs present in the best optimized formulation. The parameters determined during the
stability study are listed in Table 7. Points of analysis 1 and 2 gave the eserine and 2-PAM
content in best optimized transdermal patch formulation, respectively.

58
TABLE3. Stability Studies according to ICH Guidelines
Types Conditions
Products in primary containers permeable to water vapor 30 ± 2 °C/75 ± 5% RH
Products in primary containers impermeable to water vapor 30 ± 2 °C/RH not specified
Accelerated studies 40 ± 2 °C/75 ± 5% RH
4.5 STORAGE [40]
You should keep Paracetamol away from moisture and heat in order to preserve it. You keep
it normal room temperature but away from the reach of children.

59
CHAPTER 05 RESULT AND DISCUSSION
V. RESULT AND DISCUSSION
The formulation A, formulation B and formulation C was successfully prepared and
evaluated all three formulation in the laboratory. After evaluation the color of formulation
A was found to be white and with good consistency. On application on the skin there is
no irritation even after 24 hour .the spread ability of formulation A found to be fair and is
no grittiness in the formulation .the extrudability was found to be fair in the formulation
and range of pH 5-7. In the color of formulation B was found to be white and good
consistency .on application on the skin there is no irritation even after 24 hour .the
spreadibility of formulation B found to be good and present grittiness in the formulation.
The extrudability was found to be good in the formulation and range of pH was 5-7. In
the color of formulation C was found to be white and Very good consistency .On
application on the skin there is no irritation even after 24 hour .the spreadibility of
formulation C found to be very good and no grittiness in the formulation. The
extrudability was found to be very good in the formulation and range of pH was 5-7.
Table 4
Parameters Formulation A Formulation B Formulation C
Color White White White
Consistency Good Good Very Good
Irritation No No No
Spread ability Fair Good Very good
Extrudability Fair Good Good
Ph 5-7 5-7 5-7

60
CHAPTER 06 CONCLUSION
VI. CONCLUSION
A comparison of PVP, PEG600 and PVA as penetration enhances for Paracetamol
transdermal were prepared. All formulation also showed good physicochemical properties
like thickness, drug content, and folding endurance. The in-vitro release data showed that
drug release from the patch formulation have been affected by different penetration
enhancers and polymer. Effect of penetration enhancer like PVP, PEG600, and PVA have
been checked on in-vitro permeation of drug. These studies indicated that as the different
penetration enhancers increased drug permeation. From the results paracetamol with PVP
shows good penetration than PEG600 and PVA. The finding of this result revealed that
the problems of Paracetamol on oral administration like dissolution rate limited
absorption and gastric side effects can be overcome by applying Paracetamol topically in
the form of transdermal patch.

61
CHAPTER 07 BIBLIOGRAPHY
VII. BIBLIOGRAPHY
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