Page 1

FORMULATION AND EVELUATION OF TRANSDERMAL

TABLETS OF PARACETAMOL

A project report submitted

In partial fulfillment of the requirement

For the award of the degree of

BACHELOR OF PHARMACY

Anuj Kumar
EnrollmentNo-131562

Under the guidance of

Dr Ritu Gupta

DEPARTMENT OF PHARMACEUTICS
INVERTIS INSTITUTE OF PHARMACY
INVERTIS UNIVERSITY
BAREILLY-LUCKNOW HIGHWAY, NH-24, BAREILLY, U.P
2016---2017
 Page 2

CERTIFICATE

This is to certify that the project report entitled Formulation and Evaluation of Fast
dissolving Tablets of Paracetamol is being submitted by Anuj Kumar bearing a Enrollment
no. 131559 in partial fulfillment of the requirement for the award of the Degree of Bachelor of
Pharmacy, for the elective subject Novel Drug Delivery System at Invertis Institute of
Pharmacy, Invertis University, Bareilly. The Institute wishes him all the success in life
.

Supervisor Head of Department

Dr .Ritu Gupta Mr. Ajit Yadav
Associate professor Associate professor

ACKNOWLEDGEMENT

It is said that accomplishments must be credited to those who had put up

 Page 3

The foundations of the particular chore. In a work of this magnitude, it was natural to solicit guidance, help and
co-operation from many people and I like to acknowledge all those who generously provided their time and
expertise to maintain the quality of work.

First and foremost I express my profound gratitude and venerable regards to my guide Dr .Ritu Gupta as a
teacher she has always strived to inculcate the scientific attitude in me. I am thankful to her for his guidance,
vital encouragement, incisive criticism and dynamic assistance. She was always present for me, whenever I
needed him and I cherish the amount of freedom I have enjoyed during this tenure under him.

I would like to express my sincere regards to Mr. Ajit yadav Head of the Department, who is guardian
figure to me. He supported me in my research and instilled confidence to reach greater heights in my life and Mr.
Vipin Agrwal for his help, fruitful knowledge, suggestions and advice for the work.

This task would have been fruitless without the blessing, support, encouragement and inspiration o f
Mr.Himanshu Joshi and Mr.Shashank Chaturvedi. Here I pay tributes to my parents for lifting me up in my
life. I sincerely thank them for their love, trust, patience & support without which I would have failed to stand
where I am standing today. My deepest sense of gratitude towards my father, Mr. Lal Ram and my mother Mrs.
Rajeshwari who has always motivated and contributed towards the pursuance of my studies, without worrying
about all odds. My sincere thanks to my brother Vikas ,who has always played a role of a wise advisor and he
really deserves heartfelt thanks for her wishes, love and support.

At this moment I really shall not forget my sister Madhuri who always dreamed of me reaching to this
level. I would really thank all the rest of my family who have directly and indirectly helped me to achieve my
goals.

I am grateful to Dr .Umesh Gautam chancellor of Invertis University for his words of encouragement and
timely support.

I express my indebtedness to our vice chancellor prof. Jadish Rai for his help and cooperation throughout
my project work.

I express my sincere thanks to Dr. Y.D.S. Arya for his kindness, helpfulness and motivating thoughts.

I really feel short of words when it comes in expressing my deep sense of gratitude towards Himanshu
Gangwar Devendra, Kunwar Pal Singh Rajat Gupta , Bharat Singh ,Anurag pdy , Keshav Sharma , and
Sachin Pathak for all their cooperation, support and making me believe that I am capable of doing even better.

Words fail to express my gratitude towards our M.pharm seniors Mr. Ashish Gangwar, Mr. Akhil
Chaudhary, and Ms. Sumbul Naaz helped me to achieve my targets.

Date: Anuj Kumar

Place:

CONTENTS
 Page 4

CHAPTER NO. TITEL NO. PAGE NO.

I NITRODUCTION 5-16

II REVIEW OF LITERATURE 17-18

III PRE FORMULATION 19-24

IV FORMULATION 25-27

V EVALUATION 28-32

VI RESULT AND DISCUSSION 33-35

 Page 5

CHAPTER I
INTRODUCTION
 Page 6

INTRODUCTION

Transdermal drug delivery systems are topically administered medicaments. In the form of patches that deliver
drugs for systemic effects at a predetermined and controlled rate. A transdermal drug delivery device, which may
be of an active or a passive design, is a device which provides an alternative route for administering medication.

Transdermal patches are flexible pharmaceutical preparation of varying sizes, containing, one or more active
ingredients. They are intended to be applied to the unbroken skin in order to deliver the active ingredient to the
systemic circulation after passing through the skin barriers.
These devices allow for pharmaceuticals to be delivered across the skin barrier. Theoretically, transdermal
patches works in a very simple way. A drug is applied in a relatively high dosage to the inside of patch, which is
worn on the skin for an extended period of time.
Though a diffusion process, the drug enters the bloodstream directly though the skin.
Since there is high concentration on the patch and low concentration in the blood, the drug will keep diffusing
into the blood, the drug will keep diffusing into the blood for a long period of time, maintaining the constant
concentration of drug in the blood flow.
Nicotin patch was the very first transdermal patch in market of India. The first transdermal patch, scopolamine
was approved in 1979.
It is recognized that continuous intravenous infusion is a superior mode of drug administration as compared to the
oral route not only to bypass hepatic first pass metabolism but also to maintain a constant and prolonged drug
level in the body. A closely monitored i.v. infusion can provide the dual advantage of direct entry of the drug into
the systemic circulation and the control of circulating drug levels. However, such a mode of administration
involves certain risks which necessitate hospitalization of the patient for close medical supervision of the drug
administration. It was realized and later demonstrated (Shaw et al., 1976) that benefits of i.v. Infusion could be
closely duplicated without its hassles by using the skin as the part of entry of drugs. This is known as transdermal
administration and the drug delivery systems are known as transdermal therapeutic systems or transdermal drug
delivery systems as patches.
ADVANTAGES
i. Transdermal medication delivers a steady infusion of a drug over an extended period of time. Adverse
effects frequently associated with intermittent dosing can also be avoided.
ii. Transdermal delivery can increase the therapeutic value of many drugs by avoiding specific problems
associated with the drug e.g., gastro-intestinal irritation, low absorption, decomposition due to hepatic
first pass effect, formation of metabolites that cause side effects short half-life necessitating frequent
dosing etc.
iii. The simplified medication regimen leads to improved patient compliance and reduced inter and intra-
patient variability.
iv. At times the maintenance of the constant drug concentration within the bio phase is not desired
.Application and removal of transdermal patch produce the optimal sequence of pharmacological effect.
v. Self-administration is possible with these systems.
vi. Topical patches are a painless, noninvasive way to deliver substances directly into the body.
 Page 7

vii. Topical patches are a better way to deliver substances that are brokendown by the stomach acids, not well-
absorbed from the gut, or extensively degraded by the liver.
viii. Topical patches have fewer side effects than oral medications or supplements.
ix. Topical patches are easier to use and remember.
x. Topical patches over an alternative to people who cannot, or prefer not to take medications or supplements
orally.
xi. Topical patches are cost-effective.
xii. People prefer topical patches.
DISADVANTAGES
i. Some patients develop contact dermatitis at the site of application from one or more of the system
components, necessitating discontinuation.
ii. Only potent drugs are suitable candidates for transdermal patch because of the natural limits of drug entry
imposed by the skin's importability.
iii. Some drugs are placed behind the ear, it is uncomfortable. e.g. scopolamine transdermal patch.
iv. The drug may cause skin irritation.
v. Drug concentration in the body follow a peak and trough profile leading to greater chances of adverse
effects.
vi. Adhesive may not adhere well to all types of skin.
vii. Transdermal drug delivery system cannot deliver ionic drugs.
viii. Transdermal drugs cannot develop if drug or formulation causes irritation to skin.
ix. It cannot achieve high drug levels in blood/plasma.
x. Long time adhere is difficult.
xi. It can produce only sustain release action not like fast action drugs.
xii. Aqueous and lipophilic for absorption.
BASIC COMPONENTS OF TRANSDERMA DRUG DELIVERY SYSTEM

1. Polymer Matrix
2. Drug
3. Permeation Enhancers
4. Other excipients

1. Polymer Matrix

The polymer controls the release of the drug from the device. The following criteria should be satisfied for a
polymer to be used in a transdermal system (Kydoineus & Berner, 1987)
i. Molecular weight, glass transition temperature and chemical functionality of the polymer should be such
that the specific drug diffuses properly and gets released through it.
ii. The polymer should be stable, non-reactive with the drug, easily manufactured and fabricated into the
desired product; and inexpensive.
iii. The polymer and its degradation products must be non-toxic or non-antagonistic to the host.
iv. The mechanical properties of the polymer should not deteriorate excessively when large amounts of active
agent are incorporated into it.
 Page 8

Possible useful polymers for transdermal devices are:

(a)Natural Polymers
Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums and their derivatives, Naural rubbers,
starch,etc.

(b)Synthetic Polymers
Polyvinyl alcohol, Polyvinylchloride, Polyethylene, Polypropylene, Polyacrylate, Polyamide, Polyurea,
Polyvinylpyrrolidine.

(c) Synthetic Elastomers

Polybutadiene, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber.

2. Drug
Fort successfully developing a transdermal drug delivery system, the drug should be chosen with great care. The
following some of the desirable properties of a drug for transdermal delivery (Guy et al., 1987; Flynn &
Stewart, 1988):

(a) Physicochemical Properties:

I. The drug should have a molecular weight less that approximately 1000 Daltons.
II. The drug should have affinity for both-lipophilic and hydrophilic phases. Extreme partitioning characteristics
are not conductive to successful drug delivery via the skin.
III. The drug should have low melting point.

(b) Biological Properties:

I. The drug should be potent with a daily dose of the order of few mg/day.
II. The half-life (t ) of the drug should be short.
III. The drug must not induce a cutaneous irritant or allergic response.
IV. Tolerance to the drug must not develop under the near zero-order release profile of transdermal delivery.

3. Permeation Enhancers:

The flux J.of drug across the skin can be write

As J=Ddc/dx
J=The flux
D=Diffusion coefficient
C=Concentration of the diffusing Spects
X=Spatial coordinate
 Page 9

Solvent
These compounds increase the penetration possibly by swelling the polar pathway. E.g. Water alcohols-Methanol
& Ethanol,/ Dimethyl acetamide propylene glycol and glycerol.

Surfactants
The ability of surfactants to alter penetration is a function of the polar head group and the hydrocarbon chain
length.
(i) Anionic surfactants:- Sodium lauryl sulphate Diacetyl sulphosuccinate
(ii) Non-ionic:-Pluronic F127,Pluronic F68
(iii) Bile Salt:- Sodium taurocholate,Sodium deoxycholate.
Miscellaneous Chemicals
Enhance the penetration by using these chemicals, e.g. Urea, Calcium thioglycolate
.
4. Other Excipients

Adhesive: - The pressure sensitive adhesive can be positioned on the face of the device or in the back of the
device.
(i) It should be not irritant.
(ii) It should be easily removed.
(iii) It should not leave an unwashable residue on the skin.
(iv) It should have excellent contact with the skin.
(v) Physcal and chemical compatibility with the drug.
(vi) Permeation of the drug should not effected.

5. Linear
Protect the patch during storage. The linear is removed prior to use.

6. Backing
Protect the patch from the outer environment.

6. TYPES OF TRANSDERMAL PATCHES

There are four types of transdermal patches:

I. Singlelayer drug inadhesive

II.Multi-layer drug in adhesive

III.Drug reservoir-in-adhesive
 Page 10

IV.Drug Matrix-in-adhesive

I. Singlelayer drug inadhesive

The adhesive layer of this system also contains the drug. In this type patches the adhesive layer not only serves to
adhere the various layer together, along with entire system to the skin but is also responsible for the releasing of
the drug. The adhesive layer is surrounded by a temporary liner and a backing.

Backing
Drug in adhesive
Liner

Fig. 1: Singlelayer drug inadhesive

II.Multi-layer drug in adhesive

The multi-layer drug in adhesive is similar to the single layer system in that both adhesive layer are also
responsible for the releasing of the drug. But it is different however that it adds another layer of drug in
adhesive, usually separated by a membrane. This patch also has a temporary liner layer and a permanent
backing.

Backing
Drug in Adhesive
Membrane
Drug in adhesive
Liner
Fig.2: Multi-layer drug in adhesive

III.Drug reservoir-in-adhesive
Reservoir transdermal system has a separate drug layer. The drug layer is a liquid compartment containing a drug
soln or suspn separated by the backing layer. In this type of system the rate of release is zero order.

Backing

Drug

Membrane 10
 Page 11

Adhesive 10

Liner 10

Fig. 3: Drug reservoir-in-adhesive

IV.Drug Matrix-in-adhesive
This matrix system has a drug layer of semisolid matrix containing a drug solution or suspension. The adhesive
layer in this patch surrounds the drug layer partially overlaying it.

Backing

Drug

Adhesive
 Page 12

DRUG PROFILE OF PARACETAMOL

Description

Paracetamol (acetaminophen) is a pain reliever and a fever reducer. The exact mechanism of action of is not

known. Paracetamol is used to treat many conditions such as headache, muscle aches, arthritis, backache,

toothaches, colds, and fevers

Chemical name: Acetaminophen; 4-acetaamidophenol; paracetamol;

Structure:

Molecular formula: C8H9NO2

Molecular weight: 151.165g/mol

 Page 13

Melting range: 1690C

Volume of distribution: 65 L

Hafe life: 2.5 hr

Bioavailability: Bioablivility of paracetamol after oral administration to healthy volunteer. The absorption rate

and the bioavailability of two commercially available paracetamol tablets were investigated in a panel of seven

volunteers; one of these tablets contained a combination of 50 mg caffeine and paracetamol

Pharmacology:

Indication

For temporary relief of fever, minor aches, and pains.

Pharmacodynamics:

Acetaminophen (USAN) or Paracetamol (INN) is a widely used analgesic and antipyretic drug that is used for the
relief of fever, headaches, and other minor aches and pains. It is a major ingredient in numerous cold and flu
medications and many prescription analgesics. It is extremely safe in standard doses, but because of its wide
availability, deliberate or accidental overdoses are not uncommon. Acetaminophen, unlike other common
analgesics such as aspirin and ibuprofen, has no anti-inflammatory properties or effects on platelet function, and
it is not a member of the class of drugs known as non-steroidal anti-inflammatory drugs or NSAIDs. At
therapeutic doses acetaminophen does not irritate the lining of the stomach nor affect blood coagulation, kidney
function, or the fetal ductus arteriosus (as NSAIDs can). Like NSAIDs and unlike opioid analgesics,
acetaminophen does not cause euphoria or alter mood in any way. Acetaminophen and NSAIDs have the benefit
of being completely free of problems with addiction, dependence, tolerance and withdrawal. Acetaminophen is
used on its own or in combination with pseudoephedrine, dextromethorphan, chlorpheniramine,
diphenhydramine, doxylamine, codeine, hydrocodone, or oxycodone.

Mechanism of action

Acetaminophen is thought to act primarily in the CNS, increasing the pain threshold by inhibiting both is forms
of cyclooxygenase, COX-1, COX-2, and COX-3 enzymes involved in prostaglandin (PG) synthesis. Unlike
NSAIDs, acetaminophen does not inhibit cyclooxygenase in peripheral tissues and, thus, has no peripheral anti-
 Page 14

inflammatory affects. While aspirin acts as an irreversible inhibitor of COX and directly blocks the enzyme's
active site, studies have found that acetaminophen indirectly blocks COX, and that this blockade is ineffective in
the presence of peroxides. This might explain why acetaminophen is effective in the central nervous system and
in endothelial cells but not in platelets and immune cells which have high levels of peroxides. Studies also report
data suggesting that acetaminophen selectively blocks a variant of the COX enzyme that is different from the
known variants COX-1 and COX-2. This enzyme is now referred to as COX-3. Its exact mechanism of action is
still poorly understood, but future research may provide further insight into how it works. The antipyretic
properties of acetaminophen are likely due to direct effects on the heat-regulating centers of the hypothalamus
resulting in peripheral vasodilatation, sweating and hence heat dissipation.

Absorption: Rapid and almost complete.

Volume of distribution: Not Available

Protein binding: 25%

Metabolism:

Acetaminophen primarily undergoes glucuronidation (45-55% of the dose) in which this process
is facilitated by UGT1A1, UGT1A6, UGT1A9, UGT2B15 in the liver or UGT1A10 in the gut.
30-35% of the dose undergoes salvation. This biotransformation is facilitated by SULT1A1,
SULT1A3, SULT1A4, SULT1E1 and SULT2A1. A small percentage of acetaminophen is
oxidized by CYP2E1 to form N-acetyl-p-benzo-quinine imine (NAPQI), a toxic metabolite
which is then conjugated to glutathione and excreted really. Studies suggest that CYP3A4 and
CYP2E1 are the primary cytochrome P450 isozymes responsible for the generation of toxic
metabolites. Accumulation of NAPQI may occur if primary metabolic pathways are saturated.

Route of elimination:

Approximately 80% of acetaminophen is excreted in the urine after conjugation and about 3% is excreted
unchanged.

Half life: 1 to 4 hours

Toxicity:

Oral, mouse: LD50 = 338 mg/kg; Oral, rat: LD50 = 1944 mg/kg. Acetaminophen is metabolized primarily in the
liver, where most of it is converted to inactive compounds by conjugation with glucuronic acid and, to a lesser
extent, sulfuric acid. Conjugates are then excreted by the kidneys. Only a small portion is excreted in unchanged
in urine or oxidized via the hepatic cytochrome P450 enzyme system (CYP2E1). Metabolism via CYP2E1
produces a toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). The toxic effects of acetaminophen are
 Page 15

due to NAPQI, not acetaminophen neither itself nor any of the major metabolites. At therapeutic doses, NAPQI
reacts with the sulfhydryl group of glutathione to produce a non-toxic conjugate that is excreted by the kidneys.
High doses of acetaminophen may cause glutathione depletion, accumulation of NAPQI and hepatic necrosis.
The maximum daily dose of acetaminophen is 4 g. Liver failure has been observed at doses as low as 6 g per day.
As such, the maximum daily and single dose of acetaminophen is currently being reviewed in some countries. N-
acetyl-cysteine, a precursor of glutathione, may be administered in the event of acetaminophen toxicity.
 Page 16

REVIEW OF LITERATURE

1. Gorle .A.P, et al (2016) a way to increase effectiveness Paracetamol drug through transdermal patch.
 Page 17

2. Sangineni. K. S. D, et al (2016) double blind randomized comparative study of transdermal fentanyl patch for
post operative pain relief in major abdominal surgery as a component multimodal analgesic therapy.

3. Verma.N.K, et al (2014) formulated and evaluated transdermal patches containing Paracetamol.

4. Kumari.S, et al (2014) Novel drug delivery systems (NDDS) formulated and emulated transdermal patches
Paracetamol drug.
 Page 18

Chapter iii
Pre Formulation

PREFORMULATION

1. Membrane permeation
These system can be multi laminate process e.g. Transdermal Nitro. These products consist of three substrates
held together by two layers of drug containing adhesive. First the drug is processed into the physical / chemical
form required for incorporation into the product. Then the drug adhesive components and excipients are mixed
with a solvent to achieve uniform solution. These adhesive composition are deposited as a thin film on moving
substances rate which are subsequently dried to remove solvent. Then lamination of the dried adhesive film and
other layer to form the five layer product consisting of release linear contact adhesive control membrane, drug
reservoir and backing substrate. The lamination then printed and die cut into final dosage form. The production is
 Page 19

then packed in individual foil pouches. After inspection the products are automatically inserted into a
continuously moving web of pouch stock which is sealed around the dosage form.

Fig.5: Multilaminate transdermal dosage from manufacturing process flow diagram

2. Adhesive dispersion type system

The manufacturing process these systems can be divided into following parts.
(I) Preparation of individual matrix solution
(II) Coating the individual matrix layers
(a) Coating unit
(b) Drying unit
(I) Building the multilayer laminate
(II) Separating unit of the multilayer laminate
(III) Packaging

(I) Preparation of individual matrix solution

 Page 20

The individual layers are made by coating the solution (above). On the smooth paper or film web and
removing the solvent by drying using coating machine.
This machine consists of two units.
(a) Coating unit
(b) Drying unit

(a) Coating unit: - The solvent based formulations are coated onto the appropriate web. Depending on the
viscosity, solid contents, flow ability and surface tension of the matrix solution.

(b) Drying unit: - Closed to the environment and is directly connected to the drying unit to avoid solvent
and this active agent evaporation. The solvent is evaporated from the adhesive mars by running the coated
web through a drying channel using a transport system like cranked shaft, conveyor belt.

(I) Building the multilayer laminate: - Lamination is used to build up the multilayer matrix system. Here
two matrix layers, each adhering to one side of the web are laminated., Then a carrier material of this
two layer laminate is removed and a third layer, with the laminated side to the laminated side of the two
layer laminate is pressed. This procedure is repeated until the final laminate is complete.

(II) Separating unit of the multilayer laminate: - The bulk product is slit longitudinally and the
individual unit is punched quit from the narrow rolls so obtained. Precision of the operations is of
paramount importance here hence it affects the release rate of the active ingredient. Then the liner is
applied with the necessary release aids to the system.

(III) Packaging: - Primary packaging is done using sealed, four cornered while secondary packaging in
cardboard boxes precedes shipment.

Fig. 6: The process and equipment involved in the manufacture of an adhesive dispersion system
 Page 21

3. Matrix diffusion controlled system:-

The drug is dispersed in an insoluble matrix of rigid non swellable hydrophobic material. Materials used for rigid
matrix are insoluble plastics such as PVC and fatty and materials like stearic and bee wax. With the plastic
materials the drug is generally kneaded with the solution of Polyvinyl chloride in an organic solvent and
granulated waxy matrix is prepared by dispersing the drug in molten fat followed by congealing. The granules are
then compressed into tablets
Swellable matrix system is popular for sustaining the release of highly water soluble drug. The material for such
matrices are generally hydrophilic gums and may be of natural origin (guar gum, tragacanth) semi synthetic
(HPMC, CMC) or synthetic (poly cryamides) The drug and the gum are granulated together with a solvent such
as alcohol and compressed into tablets.
The release of drug from such initially dehydrated hydro gels involves simultaneous absorption of water and
desorption of drug via a swelling controlled diffusion mechanism. The gum swells and the drug diffuse out of it
the swallen mars devoid of drug appears transport.

1. Microsealed dissolutionControlled system or Encapsulation: - The drug particles are coated or

encapsulated by one of the several micro encapsulation techniques with slowly dissolving materials like
cellulose, PEGs, polymethacrylates, waxes.

Exclusion criteria
1. ASA 3-4
2. History of drug abuse
3. Emergency
4. Extremes of age
5. Pregnancy
The Fentanyl patch used was Fen-Touch 25 mcg/hr by
Sparsha Pharma International Private limited. They also provided the placebo patches.
 Page 22

Figure 7: Fen-Touch (Fentanyl patch).

From the recovery room, the patients were shifted to the post-operative ward, and patients were monitored by a
nurse who was blinded to the kind of patch that had been applied to the patient. From the time of arrival details
regarding the vitals and specifically pertinent to the study that is NRS score at rest, sedation score, nausea and
vomiting score and pruritus were recorded every four hours. Patients received regular Diclofenac and
Paracetamol and, Tramadol was given for rescue analgesia. The following scores were used to monitor for
sedation, pruritus, nausea and vomiting and respiratory depression.

Ramsay sedation scores

1=awake
2=drowsy
3=sleepy but easy to arouse to verbal commands
4=sleepy but rousable to moderate stimulation
5=unconscious

Nausea and vomiting scores

0=none
1=mild (1-2)
2=moderate
3=severe

Pruritus
Present +1
 Page 23

Absent 0

Chapter IV
Formulation
 Page 24

FORMULATION

Method and material:

Material
Ethyl cellulose CDH New Delhi, Poly propylene glycol CDH New Delhi, Chloroform CDH New Delhi,
Paracetamol CDH New Delhi, HPMC CDH New Delhi, PEG CDH New Delhi.

Method
Transdermal film of Ethyl cellulose and PVP was prepared by Mercury Substrate Method. Ethyl cellulose was
dissolved in Ethyl alcohol, Chloroform and Methanol (1:2:3) mixture at concentration proportion of Ethyl
cellulose was used (10% solution). PVP is used as plasticizer into both polymeric solution, after that Paracetamol
was slowly dissolved at 50 to 100 rpm by mechanical stirrer into polymeric solution which was closed by
Aluminum foil to prevent solvent evaporation. Finally plasticizer was added and mixed well and then polymeric
solution containing drug was pored within a glass Bengal, placed on a mercury film in the patricide. Thin film
was separated, and then it was completely dried.

Structure of skin:

The skin can be considered to have four distinct layers of tissues including non-viable epidermis (stratum
corneum), viable epidermis, viable dermis and hypodermis (subcutaneous connective tissue). The epidermis is the
relatively thin, tough, outer layer of the skin. The epidermis has keratinocytes. They originate from cells in the
deepest layer of the epidermis called the basal layer. New keratinocytes slowly migrate up toward the surface of
the epidermis. Stratum corneum (Non-viable epidermis) is the outermost portion of the epidermis, relatively
waterproof and, when undamaged, prevents most bacteria, viruses, and other foreign substances from entering the
body. The epidermis also protects the internal organs, muscles, nerves, and blood vessels against trauma. The
outer keratin layer of the epidermis (stratum corneum) is much thicker. Viable Epidermis layer of the skin resides
 Page 25

between the stratum corneum and the dermis and has a thickness ranging from 50-100 m. The structure of the
cells in the viable epidermis is physiochemical similar to other living tissues. Cells are held together by ton
fibrils. The water content is about 90%. The dermis, the skin's next layer, is a thick layer of fibrous and elastic
tissue (made mostly of collagen, elastic and febrile) that gives the skin its flexibility and strength. The dermis
contains nerve endings, sweat glands and oil glands, hair follicles, and blood vessels. The subcutaneous tissue
also known as hypodermis is not actually accepted as a true part of the structured connective tissue. It is
composed of loose textured, white, fibrous connective tissue containing blood and lymph vessels. Most
investigators consider the drug permeating through the skin enter the circulatory system before reaching the
hypodermis where the fatty tissue serve as a depot of the drug.

Table1. For Formula

Sr. Name of Ingredient Amount (mg/patch)

No
.
Formulation Code F1 F2 F3 F4 F5
1 Paracetamol 100 100 100 100 100

2 HPMC 120 - 240 - 120

3 EC - 120 - 240 120
4 PEG 36% - 36% - 18
5 Poly propylene glycol - 36% - 36% 18

6 DMSO(permeation enhancer ) 12% 12% 12% 12% 12%

7 Chloroform q.s q.s q.s q.s q.s
 Page 26

Chapter V
EVALUATION

EVALUATION
 Page 27

1. Drug content determination: Drug content is important for determination of percent content of drug
product. The accurate quantity of drug material is weighed and added into the 100 ml of suitable solvent. The
mixture of solvent is shacked continuously for 24 h in shaker incubator. The complete mixture of drug
containing solution is sonicated and filtered. The solution mixture is analyses by spectrophotometry by
preparing specific dilutions.

2. Moisture Content: It is important for determination of moisture contamination of drug product and
formulation. The formulation are come into content with external environment drug product to decreases there
stability and decomposition is arises. The percent content of moisture is calculated by using following formula.

3. Stability studies: Stability is important for determination of appropriate properties and characteristics of
drug product and formulation. Stability is direct function to that activity. The thin film of drug material is
placed in USP type 1 amber colored vials. Vials are the completely closed and sealed and vials are placed in
stability chamber at 40c temperature. The atmospheric humidity (RH) is 65% for the next three months. At
particular time period films are withdrawn and evaluated the drug material for determination of their physical
properties and drug content.

4. Water vapor permeability: The glass vials having 5 ml capacity and they are washed thoroughly. After the
vials are dried in to oven. The 1 gm of calcium chloride is taken from the vials and fixed the film of polymer
with the help of adhesive tape. The vials are stored in humidity chamber at 85% for 24 hrs. The vials are
removed from humidity chamber from 3, 6, 12, 18, min. of interval and the weight gain is determined.
5. Skin irritation test: It is important type of study for determination of irritation of skin. It is important for
determination of skin sensitivity and irritancy. In this type of test is mainly conducted in healthy rabbits. The
formulation of drug product is applied on the surface of the skin of rabbit. The transdermal patch is applied on
the surface of rabbit skin. After 24 hrs. The patch is removed and observed the surface of skin for
determination of injury of skin.

6. Thickness

The average thickness of the patches was determined by measuring the thickness by using micrometer screw
gauge.

7. Tensile strength
 Page 28

Initially we have taken a small film strip of paracetamol and fixed one end between adhesive tapes to give
support to the film when placed in film holder, and the other end of the film was fixed between adhesive tapes
with a small pin sandwiched between them to keep the strip straight while stretching. A hook was inserted near
the pin in adhesive tape with a small hole. A thread was tied to this hook, passed over the pulley and a small pin
attached to the other end to hold the weights. A small pointer was attached to the thread, which travels over the
graph paper affixed on the base plate for the determination of tensile strength the film was pulled by pulley
system. Weight was gradually added to the pan to increase the pulling force till the film was broken. The weight
required to break was noted as break force.

8. Folding endurance

Folding endurance of the film was determined by repeatedly folding a small strip of film at the same place till it
broke. The number of times, the film could be folded at the same place without breaking, gave the value of
folding endurance

9. Percent Moisture Absorption

The percent moisture absorption test was carried out to check the physical stability and integrity of the films at
high humid conditions. In the present study the moisture absorption capacities of the films were determined in the
following manner. The films were placed in desecrator containing saturated solution of aluminum chloride,
keeping the humidity inside the desiccators at 79.5% RH. After 3 days the films were taken and weighed the
percentage moisture absorption of two films was found.

10. Percent Moisture Loss

This test was also carried to check the integrity of films at dry condition. Three films of 5 square centimeter area
was cut out and weighed accurately and kept in a desiccators containing fused anhydrous calcium chloride. After
72 hours the films were removed and weighed. Average percentage moisture losses of three films were found out.

11. Application
 Page 29

Transdermal drug delivery system is important to prevent problem associated to first pass metabolism or
Presystemic metabolism and give local and systemic activity. Transdermal gel is important application to prevent
the irritation of skin. Ethosome in Transdermal drug delivery systemis a Novel Approach is used for increases the
rate of drug absorption and penetration of skin to give maximum bioavailability. Transdermal drug delivery
system is important for micro emulsion, Nanoemulsion, Liposomal approach for prevention of skin infection.
Transdermal drug delivery systems is an important application for the Transdermal patches and Transferosomes
novel carrier approach for prevention of injury of skin and maintain the health of skin.

Table 2- physical evaluation of transdermal patches of paracetamol

Formulation Weight Thickness Folding Moisture Drug

code Variation (mm) endurance content% content %
(mg/2cm2)
F1 0.0900.002 0.0900.002 <120 0.980.12 89.544.62
F2 0.0720.002 0.074 0.008 <120 0.740.18 82.363.68
F3 0.0520.002 0.110 0.010 <120 0.840.08 87.343.04
F4 0.0640.002 0.104 0.006 <120 0.880.10 86.243.86
F5 0.0740.002 0.084 0.010 > 80 0.820.06 88.903.34

Table3.Products available in market of Transdermal System:

Product Name Drug Manufacturer Indication

Catapres-TTS Clonidine Alza/Boehinger Hypertension

Ingelheim

Climaderm Estradiol Ethical Holdings/Wyeth- Postmenstrual

Ayerest Syndrome
 Page 30

3M Postmenstrual
Climara Estradiol Pharmaceuticals/Berlex Syndrome
Labs

Deponit Nitroglycerin Schwarz-Pharma Angina pectoris

Duragesic Fentanyl Alza/Janssen Moderate/severe

Pharmaceutical Pain

Estraderm Estradiol Alza/Novartis Postmenstrual

Syndrome

Habitraol Nicotine Novartis Smoking cessation

Nicoderm Nicotine Alza/GlaxoSmithKline Smoking cessation

Nitrodisc Nitroglycerin Roberts Pharmaceuticals Angina pectoris

Chapter VI
 Page 31

Result s and
discussion

RESULT S AND DISCUSSION

The formulated transdermal patches of Paracetamol were evaluated for thickness, tensile strength, folding
endurance and content uniformity. The Thickness of transdermal patches was measured by micrometer screw
gauge. The average thickness of the films was found to be 0.282 mm. The tensile strength of the films was found
2.399 kg/mm2. The Tensile strength of transdermal patches prepared from cellulose acetate and ethyl cellulose
alone also showed lower values which suggest that addition of polyvinyl pyrrolidiene in to cellulose acetate and
ethyl cellulose matrix increases tensile strength of patches. Folding endurance of the transdermal patches was
measured and it was found to be 190.The drug content uniformity was determined by spectrophotometric method.
The drug content for prepared transdermal patches of Paracetamol was found to be 9.46. It was considered that
 Page 32

the drug is dispersed uniformly throughout the film. In-vitro permeation, this study was carried out for 24 hours
and cumulative percent permeated was calculated based on the amount of drug originally present in the patches.

DISCUSSION
Multi modal analgesia is defined as the simultaneous use of different classes or modes of analgesia that modulate
different pathways and receptors in order to provide superior pain control. Multimodal analgesia captures the
effectiveness of individual agents in optimal dosages that maximize efficacy and attempts to minimize side
effects from one analgesic (mainly opioids). This important concept employs the theory that agents with different
mechanisms of analgesia may have synergistic effects in preventing or treating acute pain when used in
combination.

CONCLUSION

A transdermal Fentanyl Patch of 25 g/hr when applied 10-12 hrs before surgery provides effective, non-invasive
postoperative pain relief after major abdominal surgery, as a part of multimodal analgesia. The incidence of
respiratory depression, sedation, nausea and vomiting was not significantly increased from the placebo group.
Good postoperative pain relief makes mobilization easier as well as compliance to spirometry better, thereby
reducing further complications. Further studies are needed to see the safety profile of FP in patients with
coexisting diseases especially respiratory disorders. The advantages of FP are numerous, foremost being the ease
of administration by adhesion to skin, no risk of infection, easy availability, specially trained personnel are not
needed (as for epidural insertion) and costs less than a PCA pump while providing a steady release of fentanyl.
All these effects are may be offset by the disadvantage that the onset of pain relief is 10 -15 hrs away from the
 Page 33

time of placement. To conclude Fentanyl Patch 25 g/hr can be used to alleviate postoperative pain in major
abdominal surgeries as a component of Multimodal pain strategy under close observation.

REFERENCES
1. Kandavilli S, Nair V, Panchagnula R. Polymers in transdermal drug delivery systems, Pharmaceutical
Technology 2002, 62-78. Available from: www.pharmtech.com. Accessed on 15 Jan, 2008.

2. Guy RH. Current status and future prospects of transdermal drug delivery, Pharm Res 1996, 13, 1765 1769.

3. Guy RH, Hadgraft J, Bucks DA. Transdermal drug delivery and cutaneous metabolism, Xenobiotica 1987,

4. Chein YW. Transdermal Controlled Systemic Medication. New York and Basel, Marcel Dekker Inc. 1987; 159
176.

5. Rhaghuram reddy k, Muttalik S and Reddy S. Once daily sustained- release matrix tablets of nicorandil:
Formulation and invitro evaluation. AAPS Pharm.Sci.Tech. 2003; 4:4.
 Page 34

6. Shaila L, Pandey S and Udupa N. Design and evaluation of matrix type membrane controlled Transdermal
drug delivery system of nicotin suitable for use in smoking cessation. Indian Journ. Pharm. Sci. 2006; 68: 179-
184.

7. Kusum Devi V, Saisivam S, Maria G R, Depti P U; Design and evaluation of matrix diffusion controlled
Transdermal patches of Verapamil Hydrochloride, Drug development and Industrial Pharmacy, 2003, 29

8. Lewis Sharila et al, International Journal of Pharmaceutical Sciences, 2006, 68: 179-184.

9. Vadivelu N, Mitra S, Narayan D. Recent advances in postoperative pain management. Yale J Biol Med.
2010; 83(1):11-25.

10. Canet J, Mazo V. Postoperative pulmonary complications. Minerva Anestesiologica. 2010; 76(2):138-4.

11. Kehlet H, Dahl JB. The value of multimodal or balanced analgesia in the postoperative pain treatment. Anesth
Analg. 1993; 77:1048-56.

13. Kehlet H, Dahl JB. Anaesthesia, surgery and challenges in postoperative recovery. Lancet. 2003; 362:1921-8.

14. Margetts L, Sawyer R. Continuing Education in Anaesthesia, Critical Care & Pain. 2007;7(5).

15. McCaffery M, Ferrell B. Nurses knowledge of pain assessment and management: how much progress
have we made? J Pain Symptom Manage. 1997; 14(3):175-88.
16. Ong CK, Seymour RA, Lirk P, Merry AF. Combining paracetamol (acetaminophen) with nonsteroidal anti-
inflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain. Anesth
Analg. 2010; 110(4):1170-9.

17. Sathyan G, Guo C, Sivakumar K. Evaluation of the bioequivalence of two transdermal fentanyl systems
following single and repeat applications. Curr Med Res Opin. 2005; 21(12):1961-8.

18. Davis MP. Management of cancer pain: focus on new opioid analgesic formulations. Am J Cancer. 2006;
5(3):171-82.

19. Beattie WS, Buckley DN, Forrest JB. Epidural morphine reduces risk of postoperative myocardial
ischaemia in patients with cardiac risk factors. Can J Anasth. 1993:40(6):532-44.
 Page 35

20. Basali A, Mascha EJ, Kalfas I, Schubert A. Relation between perioperative hypertension and intracranial
Hemorrhage after craniotomy. Anesthesiology 2000:93(1):48-54.

21. Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors.
Anesthesiology. 2000; 93(4):1123-33.

22. Culp WC Jr, Beyer EA. Preoperative aspiratory muscle training and postoperative complications.
JAMA. 2007:297(7)697-8.

23. Agnelli G, Bolis G, Capussoti L, Tonelli F. A clinical outcome based prospective study on venous
thromboembolism after cancer surgery: The @RISTOS project. Ann Surg. 2006; 243(1):89-95.

24. Camann W, Abouleish A, Eisenach J, Hood D. Intrathecal sufentanil and epidural bupivacaine for
Labor analgesia: dose-response of individual agents and in combination. Reg Anesth Pain Med. 1998; 23(5):457-
62.