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FORMULATION AND EVELUATION OF TRANSDERMAL

TABLETS OF ASPIRIN

A project report submitted

In partial fulfillment of the requirement

For the award of the degree of

BACHELOR OF PHARMACY

Keshav Kumar Sharma

EnrollmentNo-131573

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
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CERTIFICATE

This is to certify that the project report entitled Formulation and Evaluation of Tablets of
Aspirin is being submitted by Keshav Kumar Sharma 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
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ACKNOWLEDGEMENT
It is said that accomplishments must be credited to those who had put up

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. Suresh Kumar
Sharma and my mother Mrs. Anita Sharma who has always motivated and contributed towards the
pursuance of my studies, without worrying about all odds. My sincere thanks to my brother Anurag
Sharma 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 Payal Sharma 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 Riya Mishra 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.
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Date:

Place: Keshav Kumar Sharma

CONTENTS

CHAPTER NO. TITEL NO. PAGE NO.

I NITRODUCTION
5-15

II
REVIEW OF LITERATURE
16-17

III PRE FORMULATION

18-22

IV FORMULATION 23-25

V EVALUATION 26-30

VI RESULT AND 31-33

DISCUSSION
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CHAPTER I
INTRODUCTION
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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.
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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.
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)
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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.

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.
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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

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.
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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

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.
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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

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
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DRUG PROFILE OF ASPIRIN

Description

Aspirin is used to reduce fever and relieve mild to moderate pain from conditions such as muscle aches,
toothaches, common cold, and headaches. It may also be used to reduce pain and swelling in conditions such
as arthritis. Aspirin is known as a salicylate and a nonsteroidal anti-inflammatory drug (NSAID).

Chemical name: 2acetoxybenzoic acid

Molecular formula: C9H8O4

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Molecular weight: 180.159 g/mol

Melting range: 1350C

Volume of distribution: 11.9 L

Structure:

Bioablivility

This metabolism occurs primarily by hepatic conjugation with glycin or glucuronic acid, each involving
different metabolic pathways. The predominant pathway is the conjugation with glycin, which is saturable.
With low doses of aspirin approximately 90% of salicylate is metabolized through this pathway.

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
Page No14

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-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
Page No15

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 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.
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REVIEW OF LITERATURE

1. Gorle .A.P, et al (2016) a way to increase effectiveness Paracetamol drug through transdermal patch.
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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.
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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
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linear contact adhesive control membrane, drug reservoir and backing substrate. The lamination then printed
and die cut into final dosage form. The production is 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
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(I) Building the multilayer laminate

(II) Separating unit of the multilayer laminate
(III) Packaging

(I) Preparation of individual matrix solution

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

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.
Page No22

Chapter IV
Page No23

Formulation

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
Page No24

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 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.
Page No25

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

Chapter V
EVALUATION
Page No26

EVALUATION

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
Page No27

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

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

Page No28

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
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
Page No29

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

3M Postmenstrual
Climara Estradiol Pharmaceuticals/Berlex Syndrome
Labs

Deponit Nitroglycerin Schwarz-Pharma Angina pectoris

Page No30

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 No31

Result s and
discussion

RESULT S AND DISCUSSION

The formulated transdermal patches of Aspirin 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 pyrrolidone 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 the drug is dispersed uniformly throughout the film. In-vitro permeation,
Page No32

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.

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
Page No33

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 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.

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