Formulation Development & Evaluation of Captopril based

Floating Drug Delivery System

Thesis

SUBMITTED TO

Rajiv Gandhi Proudyogiki Vishwavidyalaya Bhopal (M.P.)

in the partial fulfillment of the requirement for the Degree of

Master of Pharmacy
In
Pharmaceutics

Submitted By
Omni Khare

Supervised By

Dr. Y. S. Dangi

Sagar Institute of Pharmaceutical Sciences

Narsinghpur Road, Sironja, Sagar (M.P.) - 470228

2019
 SAGAR INSTITUTE OF
PHARMACEUTICAL SCIENCES, SAGAR
(M.P.)
(Approved by AICTE,PCI New Delhi, Affiliated to RGPV Bhopal)

Certificate
This is to certify that Ms. Omni Khare, Enrollment No.
0602PY17MP06 has submitted Thesis entitled “Formulation
Development & Evaluation of Captopril based Floating Drug
Delivery System” In partial fulfillment of the requirement for the
degree of Master of Pharmacy in Pharmaceutics to Sagar Institute
of Pharmaceutical sciences, Sagar M.P., affiliated to Rajiv Gandhi
Proudyogiki Vishwavidyalaya, Bhopal (M.P). He has prepared this
Thesis under my supervision.

SUPERVISED BY

Dr. YUVRAJ SINGH DANGI

 SAGAR INSTITUTE OF
PHARMACEUTICAL SCIENCES, SAGAR
(M.P.)
(Approved by AICTE, PCI New Delhi, Affiliated to RGPV Bhopal)

Forwarding Letter
This is to certify that Ms Omni Khare, Enrollment No.
0602PY17MP06 has submitted Thesis entitled “Formulation
Development & Evaluation of Captopril based Floating Drug
Delivery System” To Sagar Institute of Pharmaceutical Science,
Sagar for the partial fulfillment of the requirement for the Degree
of Master of Pharmacy in Pharmaceutics.
I hereby forward his thesis.

Forwarded by

Dr.
YUVRAJ SINGH DANGI

Principal
 SAGAR INSTITUTE OF
PHARMACEUTICAL SCIENCES, SAGAR
(M.P.)
(Approved by AICTE,PCI New Delhi, Affiliated to RGPV Bhopal)

DECLARATION

This is to certify that Ms. Omni Khare, Enrollment No.

0602PY17MP06 has submitted Thesis entitled “Formulation
Development & Evaluation of Captopril based Floating Drug
Delivery System” In partial fulfillment of the requirement for the
degree of Master of Pharmacy in Pharmaceutics to Sagar Institute
of Pharmaceutical sciences, Sagar M.P., affiliated to Rajiv Gandhi
Proudyogiki Vishwavidyalaya, Bhopal (M.P). He has prepared this
Thesis under my supervision.

SUPERVISED BY

Dr. YUVRAJ SINGH DANGI

 CONTENTS

S.NO. TITLE PAGE NO.

1 Introduction 1
2 Drug Profile 18
3 Literature survey 23
 4 Research Envisaged 27
&plan of work
5 Experimental work 30
6 Result and 43
Discussion
7 Conclusion 47
8 Bibliography 50

INTRODUCTION

Pain is defined as "an unpleasant sensory and emotional experience associated with actual or
potential tissue damage, or described in terms of such damage" by the International
Association for the Study of Pain.

Chronic pain is pain that doesn’t go away after three months. Chronic pain can be intermittent
(occurring on and off). It may vary with intensity during the day or it can be persistent.
Chronic pain can result from a known cause, such as surgery or inflamed joints, or a
consequence of a disease process, such as rheumatoid arthritis. Many times the cause is
unknown. (Chronic pain report 2010)

The Two Faces of pain Acute and Chronic:-

Acute pain generally comes on suddenly for example after trauma or surgery and may be
accompanied by emotional distress. The cause of acute pain can usually be diagnosed and
treated and the pain for the most parts results from disease inflammation or injury to tissue
this type of self- limiting that is it confined to a given period of time and severity. In some
rare instances it can become Chronic.

Chronic painis widely believed to represent disease itself. It can be made much worse by
environmental and physiological factors.Chronic pain persists over a longer period of time
than acute pain and is resistant to medical treatments. It can and often dose –cause severe
problems for patients. A person may have two or more co-existing chronic pain conditions.
Syndrome endometriosis fibromyalgia inflammatory bowel disease interstitial cystitis
temporal Mandibular joint dysfunction and Volvo dyne. It is not known whether these
disorders share a common cause. There are different types of chronic pain.
Two of the major, non-cancer chronic pains are:-
Musculoskeletal Pain - Pain that affects the bones, muscles, ligaments and tendons.
Musculoskeletal pain can result from various causes including sports or occur injury motor
vehicle collisions, repetitive strain injuries and disease processes, such as, arthritis.
Neuropathic Pain - A complex, multi-faceted state of chronic pain that may have no obvious
cause. It can involve damaged tissue, injury or malfunctioning nerve fibers orchanges in brain
processing. An example of neuropathic pain is phantom limb syndrome. The brain still
receives signals from nerves that originally carried impulses from the now missing limb.
Other types of neuropathic pain include numbness, burning, "pins and needles" sensations
and shooting pain.

If you are suffering from chronic pain, there are many effective treatments and self-
management techniques that you can use to increase your functionality.

Experiences of Chronic Pain

Pain is a very complex experience and many factors contribute to how an individual
perceives, responds to and manages their chronic pain. Everyone brings a unique mix of
cultural, family and social adaptations to their pain experience. Some people appear to be
better able to manage their chronic pain than others. There are social and psychological
benefits to maintaining relationships and usual activities as much as possible at home and at
work. People who take an “active" role in learning and practicing coping behaviors tend to
experience less of the following:-
Social Isolation - Some people with chronic pain may lose their friends, strain their family
relationships and wear down social supports. With this loss of community comes a loss of
interaction and engagement with people or activities that previously helped them cope with
their pain.

Psychological Shifts - A person’s mental health and overall attitude toward life can greatly
affect their pain experience. For example, research has shown that for people with low back
pain, feelings of helplessness, fear and a ‘glass-half-empty’ perspective are linked to poorer
health outcomes. Conversely, those with a strong senseof psychological wellbeing and a more
positive outlook on life tend to cope better with chronic pain.

Work/Career Shifts–

Some people with chronic pain struggle to keep their jobs. Sometimes the challenge is
convincing employers to let affected employees modify their jobs or their workloads so that
they can manage their pain while continuing to work. Research has shown that workers who
return to work earlier have better health outcomes. Being engaged in work reduces focus and
attention on pain. The reduction of focus onself –redefinition chronic pain can lead to
fundamental changes in how people see themselves and their lives. These changes affect how
they feel. Fortunately, there are several new ideas around thinking, feeling and being or
acting that can help people recognize and control what’s going on with their bodies.

If you are feeling the effects of any of the above issues, it's important that you talk with your
doctor. You may also consider joining a local support group of others who live with chronic.

MUCOADHISIVE TRANSDERMAL PATCHES

A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a
specific dose of medication through the skin and into the bloodstream. Often, this promotes
healing to an injured area of the body. An advantage of a transdermal drug delivery route over
other types of medication delivery such as oral, topical, intravenous, intramuscular etc.
( Segal, Marian et al 2007)

The patch provides a controlled release of the medication into the patient, usually through
either a porous membrane covering a reservoir of medication or through body heat melting
thin layers of medication embedded in the adhesive. The main disadvantage to transdermal
delivery systems stems from the fact that the skin is a very effective barrier; as a result, only
medications whose molecules are small enough to penetrate the skin can be delivered by this
method. A wide variety of pharmaceuticals are now available in transdermal patch form.
FORMULATION DEVELOPMENT

Before these patches go into the market, they have to be carefully studied. One way to study
these patches are through the use of Franz Diffusion Cell systems. This system is used to
study the effects of temperature on the permeated amount of a specific drug on a certain type
of membrane, which in this case would be the membrane that is used in the patches. A Franz
Diffusion Cell system is composed of a receptor and a donor cell. In many of these research
studies the following procedure is used. The donor cell is set at a specific temperature (the
temperature of the environment), while the receptor cell is set at different one (temperature of
the body).

Different runs are performed using different temperatures to study the impact of temperature
on the release of a certain medicament through a certain type of membrane. Although
different concentrations of the medicament are used in this study, they do not affect the
amount permeated through the membrane (the process is constant). From Chemical kinetics
it’s concluded that these studies are zero order, since the concentration plays no role in the
permeated amount through the membrane.

Some pharmaceuticals must be combined with substances, such as ALCOHOL ,

within the patch to increase their ability to penetrate the skin in order to be
used in a transdermal patch. Others can overwhelm the body if applied in
only one place, and are often cut into sections and applied to different parts
of the body to avoid this, such as nitroglycerin. Many molecules, however,
such as INSULIN , are too large to pass through the skin without it being
modified in some way. Several new technologies are being investigated to
allow larger molecules to be delivered transdermally.

COMPONENTS

The main components to a transdermal patch are:-

 Liner - Protects the patch during storage. The liner is removed prior to use.

 Drug - Drug solution in direct contact with release liner.

 Adhesive - Serves to adhere the components of the patch together along with adhering
the patch to the skin.

 Membrane - Controls the release of the drug from the reservoir and multi-layer
patches.
  Backing - Protects the patch from the outer environment.

Types

Sample transdermal patches. On left is a 'reservoir' type, on the right a 'Single-layer Drug-in-
Adhesive' version. Both contain exactly the same level of the same active ingredient with
identical release rates.

There are five main types of transdermal patches.

Single-layer Drug-in-Adhesive

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

Multi-layer Drug-in-Adhesive

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

Reservoir

Unlike the Single-layer and Multi-layer Drug-in-adhesive systems the reservoir trans dermal
system has a separate drug layer. The drug layer is a liquid compartment containing a drug
solution or suspension separated by the adhesive layer. This patch is also backed by the
backing layer. In this type of system the rate of release is zero order. Here drug reservoir is
totally encapsulated in a shallow compartment molded from a drug impermeable metallic
plastic laminates, the another side of this so-called rate controlling membrane madeup of
polymeric membrane like Ethyl Vinyl Acetate.

Matrix

The Matrix system has a drug layer of a semisolid matrix containing a drug solution or
suspension. The adhesive layer in this patch surrounds the drug layer partially overlaying it.
Also known as a monolithic device.
Vapor Patches

In this type of patch the adhesive layer not only serves to adhere the various layers together
but also to release vapor. The vapor patches are new on the market and they release essential
oils for up to 6 hours. The vaporpatches release essential oils and is used in cases of
decongestion mainly. Other vapor patches on the market are controller vapor patches that
improve the quality of sleep. Vapor patches that reduce the quantity of cigarettes that one
smokes in a month are also available on the market.

Transdermal Patches

These “skin patch” drugs include pain relievers, nicotine, hormones, and drugs to treat angina
and motion sickness. There are several advantages to taking drugs via patches:

 They are absorbed at a fairly steady rate.

 You don’t have to remember to swallow frequent doses.

 You can take them even if you have an upset stomach, as you might with motion
sickness.

Scopolamine, a motion sickness drug, was the first to be used in a skin patch. Victims of
motion sickness place a patch behind the ear, ideally a few hours before symptoms are likely
to start. The same patch can remain in place for up to three days. A brand name is
Transdermal Scope.

Diclofenac in a patch is used to relieve minor pain. Examples are sprained ankles and bad
bruises. Unlike other patches, diclofenac patches are put on the skin just over the area that
hurts. Continuing pain relief can make it easier to carry out normal activities.

The active ingredient in transdermal patches has the same benefits as those drugs in other
forms. Likewise, they carry the same potential side effects and risks. Before taking any drug
in a patch, ask your doctor about:

 Expected effects.

 Possible side effects.

 Possible drug interactions.

 Fig. 1 :Application of transdermal patch

 Environmental factors to avoid, for example, staying out of the sun.

 When you should call for an urgent appointment. For example, could a fever put you
at risk for problems with this drug?

 How long will the drug be active after you remove a patch?

There are special precautions when using transdermal patches:-

 Apply the patch to clean, dry, unbroken skin. If the skin is broken or irritated, too
much drug could be absorbed.

 Be sure the patch is applied firmly. It may take 20 or 30 seconds to get all of the
adhesive to stick firmly in place.

 Wash your hands after applying a patch to yourself or someone else.

 Use only one patch at a time unless the instructions say otherwise.

 If you need an MRI, the patch may need to be removed during your test. Check with
your doctor or x-ray technician.

 If you develop skin irritation from the adhesive, put the next patch in another area.
Check with your doctor about what to do next.

 When your remove a skin patch, fold it so the adhesive edges stick together. Throw it
away so that children or pets cannot get to it.

 Gently wash the area with soap and water.

People who use transdermal patches can suffer an overdose if the patch is broken or cut open;
too much medicine gets on and through the skin.

Fig. 2 :Transdermal patch

SKIN

Fig. 3 :Stracture of Skin

The design of dosage form whether a tablet an injection or a patch, to deliver the right
amount of medicine at the right time to the right target site becomes complicated if each
medication were to be delivered in an optimal and preferred manner medication may not be
absorbed if transdermal drug delivery system provide for the controlled release of drugs
directly into the bloodstream through intact skin. It is released too slowly.If it is delivered too
rapidly the patient may suffer untoward effects and its desired effects may not last as long as
needed. If patient is expected to take the medicine more than two times a day compliance will
be adversely affected. One of the associated with parenteral therapy and improves patient
compliance as it is easy to apply a patch.

The bioavility of the drug increased as variation in absorption when it is taken orally and it is
first pass metabolism by the liver is avoided. Treatment can also be terminated rapidly by
simply removing the patch when the need arises. Transdermal delivery system provide for the
controlled release of drug delivery system provide for the controlled release of drug directly
in to the bloodstream through intact skin.

Transdermal delivery can provide a number of advantages over conventional methods of drug
administration including enhanced efficacy increased safety greater convenience and
improved patient compliance. By delivering a steady flow of drugs into the bloodstream over
an extended period of time Transdermal system can avoid the peak and valley effect of oral or
inject able therapy and can enable more controlled effective treatment. By avoiding first pass
metabolism through the gastrointestinal tract and the liver the therapeutically equivalent
dosage for the transdermal delivery of certain compounds can be significantly less than the
corresponding oral dosage, potentially reducing dosage related side effects.(Trochilin et al
2001)

ADVANTAGES OF TDDS

1. Aviodance of significant presystemic metabolism (degradation in the gastrointestinal

tract or by the liver) and the need therefore for a lower daily dose.
2. Reduced inter and intra patient variability and this is particularly true for those
situations in which drug release from the Transdermal patch is slower than drug
diffusion across the stratum corneum..
3. Drug levels can be maintained in the systemic circulation within the therapeutic
window (i.e. above the minimum effective concentration, but below the level at which
side effects become apparent)for prolonged periods of time.
4. Thus the duration of drug action following a single administration of the drug can be
extended
5. Improved patient compliance and acceptability of the drug therapy.
6. drug input can be terminated simply by removal of the patch.

CHARATERISTIC OF TDDS

Some of the characteristics of an ideal transdermal drug delivery system are specified bleow:-

1- Agent Independent-The ideal Transdermal drug delivery system is capable of

delivering any drug .regardless of size or structure at specified rate of delivery.
2- Selected Delivery Profile-Drug as per specified quantity time profile is deliverd by the
ITDDS.

3- Multiple drugs- The ITDDS is also capable of delivering more than one therapeutic
agent at a time.

4- Flexibility-The ITDDS has the capability for changing or adjusting the rate or timing of
delivery,or the quantity to be delivered.

5- Sensoring monitoring and decision making-The system will sense patient needs
determine appropriate action and deliver the necessary quantities in accordance with a
calculated quantity time delivery profile. Such system is referred to as smart delivery
system.

6- Targeting-The TDDShas the capability of focusing drug transport towards target

sites(minimum drug lossesto other than target site.)

7- Capacity-The system is capable of making repeated deliveries between replacements.

8- Absence of problems-The ITDDS raises or causes no new problems or concerns.

9- Reliability-TheITDDS consists of few parts and has reliability in keeping with other
delivery system.

10- Market place value- The ITDDS offers high value by featuring maximum functionality
at minimum system complexity and cost.

ANATOMY

The skin is a multilayered organ complex in both structure and function. The most prominent
morphological feature of the normal skins its topical stratification. Morphologically the skin
is a multilayered organ composed of many histological layers.
 Fig. 4: Anatomyof Skin

a) Epidermis:-

The epidermis is comprised of the stratum corneum and stratum germinativum. The outer
most stratum corneum layer (10-15cm thick) is quite dry and consists primarily of blocks of
cytoplasmic protein matrices (keratins)embedded in extracellular lipid.

The keratin-containing cells known as corneocytes are arranged in an interlocking structure

somewhat skin to bricks and mortar structure cells red complex containing lipids forms a
major permeability barrier for external environment. The stratum corneum cells are formed
and continuously replenished by the slow upward migration of cells produced by the basal
cell layers of stratum germinativum.(Hagg R.et al 2004)

b)Dermis:-

The dermis is composed of a network of collagen and elastin fibers embedded in a monopoly
saccharide matrix which contains blood vessels lymphatic andnerve endings thereby
providing physiological support for the epidermis because the blood vessels approach the
interface of the two layers very closely the dermis cannot be considered as a significant
barrier to inward drug permeation in vivo.(Hagg R.et al 2004)

c) Cutaneous
Catabolic enzyme activity in the viable epidermis is substantial in fact the viable epidermis is
metabolically more active than the dermis. If the topically applied drug is subject to
biotransformation during skin permeation local and systemic bioavailability can be affected
markedly enzymatic activity in the skin or for that matter in systemic fluids and tissues can be
taken advantage of to facilitate percutaneous absorption. (Hagg R.et al 2004)

ROUTE OF PENETRATION:-

The hair follicle and associated glands are comprised of pilosebaceous units. Human
pilosebsaceous unit shows and extreme diversity in regard to its localization along the human
body and various physiological attributes of the tissues that constitute the pilosebaceous unit.
Targeting specific delivery to the hair follicles represents a feasible therapeutic approach as
several dermatological abnormalities are known to originate at the hair follicle.

Pilosebaceous unit possesses sebocytes like epidermal keratinocytes which express a variety
of cytokines which are implicated in inflammatory and immune response.

Sebum is a secretion composed of natural and non polar lipids. It flows in upward direction
and may interrupt the passage of follicle penetration drug. Sebum discharge into the follicle is
constant regardless of seasons or amount of lipid already present in the follicle or on the skin.

The particles size range between 5-7m is optimum for effective passage in to the hair follicle
whereas smaller and large particles are likely to be localized in the stratum corneum and skin
surface.(Sood A et al 2000)
 Recent trends is Transdermal Drug Delivery System

Fig.5: Different Route of Penetration from Skin

RATIONAL FOR THE SELECTION TDDS:-

The skin offers such an excellent barrier to molecular transport that the rationale for this
delivery strategy needs to be carefully scrutinized and identified clearly there are several
instances in which the most convenient mode of drug administration i e .the oral route is not
feasible and hence it entails for equally effective and acceptable alternative routes. Although
intravenous administration of the medicaments avoids many of these shortfalls (such as
gastrointestinal and hepatic metabolism) its invasive and apprehensive nature particularly for
chronic administration) necessitated search for alternative strategies’ few anatomical oritices
have been investigated for their potential drug delivery routes never the less the transdermal
mode offers several distinct advantages.

1. The skin presents a relatively large and readily accessible surface area (1-2m) for
absorption.
2. The application of a patch like device to the skin surface is a non invasive procedure that
allows continuous intervention of desired (i.e. System repositioning removal orre placement)
thus ensures patient compliance.(Bae Y et al 2003)

STAGES IN DRUG DELIVERY IN A TRANSDERMAL PATCH

1. Release of medicament from the vehicle

2. Penetration through the skin barriers;

3. Activation of the pharmacological response.

Effective therapy optimizes these steps as they are affected by three components, the drug,
the vehicle and the skin.

Which represents the movement of drug molecules arising from, for example, a trans-dermal
drug delivery system with a rate-controlling membrane, illustrates the complexity of
percutaneous absorption. Any drug particles must first dissolve so that molecules may diffuse
towards the membrane within the patch. The penetrant partitions into the membrane diffuse
across the polymer and partitions into the skin adhesive. The molecules diffuse towards the
vehicle/stratum corneum interface. They then partition into the stratum corneum and diffuse
through it. Some drug may bind at a depot site; the remainder permeates further, meets a
second interface, and partitions into the viable epidermis. For a lipophilic species this
partition coefficient may be unfavorable, i.e., less than 1. Within the epidermis, enzymes may
metabolize the drug or it may interact at a receptor site.

After passing into the dermis, additional depot regions and metabolic sites may intervene as
the drug moves to capillary, partitions into its wall and out into the blood for systemic
removal. A fraction of the diffusion may partition into the subcutaneous fat to form a further
depot. A portion of the drug can reach deep muscle layers, as illustrated by, for example, the
efficacy of non-steroidal anti-inflammatory drugs.

However, there are further complications. The following factors may be important: the non-
homogeneity of the tissues; the presence of lymphatic; interstitial fluid; hair follicles and
sweat glands; cell division; cell transport to and through the stratum corneum; and cell
surface loss. The disease, the healing process, the drug and vehicle components may
progressively modify the skin barrier. As vehicle ingredients diffuse into the skin, cellular
debris, sweat, sebum and surface contaminants pass into the dermis, changing its
physicochemical characteristics. Emulsions may invert or crack when rubbed in, and volatile
solvents may evaporate.
EVALUATION OF DUAL TRANSDERMAL PATCH

Physical characterization

The physicochemical parameters such as thickness, uniformity of weight, tensile strength,

content uniformity test, moisture content, moisture uptake, drug content uniformity and
folding endurance of various patchwere determined.

Thickness

The thickness of the patch was determined by measuring the thickness at random sites on the
formulated patch using micrometer screw gauge and the averagethickness was determined.
(Amnuaikit C,et al 2005)

Uniformity of weight

Weight variation is studied by individually weighing 10randomly selected patches and

calculating the average.

Folding endurance

The folding endurance was measured manuallyfor the prepared patches. Folding endurance of
the filmwas determined by repeatedly folding a small strip of film(2cm x 2cm) at the same
place till it breaks. The number of times, the film could be folded at the same place either to
break the film or to develop visible cracks, gave thevalue of folding endurance. (Devi VK et
al 2003)

Drug content

Transdermal system of specified area (2.64cm2) was cut into small pieces and taken into a 50
ml volumetric flask and 25 ml of phosphate buffer pH 7.4 was added gently heated to 45°c
for 15 minutes and kept for 24 hours with occasional shaking. Then the volume was made up
to 50 ml with phosphate buffer of pH7.4. Similarly a blank was carried out using a drug-free
patch.The solutions were filtered and the absorbance was measured at249nm. (Mutalik S.et
al 2004)

Percentage Moisture content

The prepared patch are weighed individually and kept in a desiccators containing calcium
chloride at room temperature for 24 h. The patch is weighed again after a specified interval
until they show a constant weight. The percent moisture content is calculated using following.
(Kusum Devi et al 2008)
 Initial weight – Final weight
% Moisture content = -----------------------------------------X 100
Final weight

Tensile strength

A small film strip (40 x 15 mm) was used. One end of the strip was fixed between adhesive
tapes to give support to the film when placed in the film holder. Another end of the film was
fixed between the adhesive tapes with a small pin sandwiched between them to keep the strip
straight while stretching. A small hole was made in the adhesive tape near the pin in which a
hook was inserted. A thread was tied to this hook, passed over the pulley and a small pin
attached to the other end to the hold the weights. A small pointer was attached to the thread,
which travels over the graph paper affixed on the base plate. To determine the tensile
strength, the film was pulled by means of a pulley system. Weights were gradually added to
the pan to increase the pulling force till the film was broken. The weight required to break the
film was noted as break force. This test is to be performed for the measurement of the
cohesive strength of an adhesive polymer. It can be influenced by the molecular weight, the
degree of cross linking and the composition of polymer, type and the amount of tack it fier
added.(Kulkarni R et al 2000)
PLAN OF WORK

The work was planned to be carried out in following manner.

1. Procurement of drug

2. Identification of drug by

i) IR Spectroscopy

ii) Melting Point

iii) U.V. Spectroscopy

3. Preparation of Dosage form (Transdermal Patches)

4. Evaluation of Dosage form

i) Physical Appearance

ii) Weight variation

iii) Percentage Drug Content

iv) Percentage Drug release

v) Percentage Moisture uptake

5. Simultaneous estimation of Paracetamol and Diclofenac by UV Spectroscopy.

6. InVitro Studies

7. Stability studies

8. Compilation of data and Presentation of thesis.

DRUG PROFILE

PARACETAMOL

Paracetamol (Acetaminophen chemically named N-acetyl-p-aminophenol,) is a widely used

counter analgesic (pain reliever) and antipyretic (fever reducer),Paracetamol is classified as a
mild analgesic. It is commonly used for the relief of headaches and other minor aches.
(Bradley K et al 1996)

FIG. 6.1STRUCTUREOF PARACETAMOL

MEDICAL USES
Fever
Paracetamol is approved for reducing fever in people of all ages. The World Health
Organization (WHO) recommends that paracetamol only be used to treat fever in children if
their temperature is greater than 38.5 °C (101.3 °F). The efficacy of paracetamol by itself in
children with fevers has been questioned and a meta-analysis showed that it is less effective
than ibuprofen. (Bradley K et al 1996)
Pain
Paracetamol is used for the relief of pains associated with many parts of the body. It has
analgesic properties comparable to those of aspirin, while its anti-inflammatory effects are
weaker. It is better tolerated than aspirin in patients in whom excessive gastric acid secretion
or prolongation of bleeding time may be a concern. Available without a prescription, it has in
recent\years increasingly become a common household drug.
Paracetamol has relatively little anti-inflammatory activity, unlike other common analgesics
such as the NSAIDs aspirin and ibuprofen, but ibuprofen and paracetamol have similar
effects in the treatment of headache. Paracetamol can relieve pain in mild arthritis, but has no
effect on the underlying inflammation, redness, and swelling of the joint.

Regarding comparative efficacy, studies show conflicting results when compared to NSAIDs
and controlled trial of chronic pain from osteoarthritis in adults found similar benefit from
paracetamol and ibuprofen.
The efficacy ofparacetamol when use and pains and is a major ingredient in numerous cold
and flu remedies. In combination with opioid analgesics, paracetamol can also be used in the
management of more severe pain such as post-surgical pain and providing palliative care in
advanced cancer patients. Though paracetamol is used to treat inflammatory pain, it is not
generally classified as an NSAID because it exhibits only weak anti-inflammatory activity.
(Bradley K et al 1996)

Adverse effects

Paracetamol ismetabolized by the liver and is hepatotoxic; side effects are multiplied when
combined with alcoholic drinks, and very likely in chronic alcoholics or patients with liver
damage. Prolonged daily use increases the risk of upper gastrointestinal complications such
as stomach bleeding, and may cause kidney or liver damage. Chronic users of paracetamol
may have a higher risk of developing blood cancer. However in recommended doses and for
a limited course of treatment, the side effects of paracetamol are mild to non-existent.
(Bradley K et al 1996)

Mechanism of action

The main mechanism proposed is the inhibition of cyclooxygenase (COX), and recent
findings suggest that it is highly selective for COX-2. Because of its selectivity for COX-2 it
does not significantly inhibit the production of the pro-clotting thromoxanes. While it has
analgesic and antipyretic properties comparable to those of aspirin or other NSAIDs, its
peripheral anti-inflammatory activity is usually limited by several factors, one of which is the
high level of peroxides present in inflammatory lesions. However, in some circumstances,
even peripheral anti-inflammatory activity comparable to NSAIDs can be observed. (Bradley
K et al1996)
CHARACTERISTICS:-

Pharmacokinetic data:-

Bioavailability-100%

Half-life 1-4 hr.

Excretion-Renal

Metabolism-90 to 95% hepatic

Chemical data

Formula-C8H9NO2

Mol.Mass-151.16g/mol

Physical data:-Density-1.263g/mol

Melt. Point-169°c
DICLOFENAC

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) taken or applied to reduce

inflammation and as an analgesic reducing pain in certain conditions, supplied as or
contained in medications under a variety of trade names.

The name derives from its chemical name: 2-(2,6-dichloranilino) phenyl acetic acid.
Diclofenac originated from Ciba-Geigy (now Novartis) in 1973. It was first introduced in the
UK in 1979.

In the United Kingdom, India, Brazil, and the United States, it may be supplied as either the
sodium or potassiumsalt, in China most often as the sodium salt, while in some other
countries only as the potassium salt. Diclofenac is available as a generic drug in a number of
formulations, including diclofenacdiethylamine applied topically. Over-the-counter (OTC)
use is approved in some countries for minor aches and pains and fever associated with
common infections.

FIG. 6.2: STRUCTURE OF DICLOFENAC

MEDICAL USES

Diclofenac is used to treat pain, inflammatory disorders, anddysmenorrhea Voltaire

(diclofenac) 50 mg enteric coated tablets.

Inflammatory disorders may include musculoskeletal complaints, especially arthritis,

rheumatoid arthritis, polymyositis, dermatomyositis, osteoarthritis, dental pain, TMJ pain,
spondylarthritis, ankylosing spondylitis, gout attacks, and pain management in cases of
kidney stones and gallstones. An additional indication is the treatment of acute migraines.
Diclofenac is used commonly to treat mild to moderate postoperative or post-traumatic pain,
in particular when inflammation is also present, and is effective against menstrual pain and
endometriosis.
As long-term use of diclofenac and similar NSAIDs predisposes for peptic ulcer, many
patients at risk for this complication are prescribed Arthrotec - a combination of diclofenac
and misoprostol, a synthetic prostaglandin (PGE1) analogue, to protect the gastric mucosa.

Mechanism of action

The exact mechanism of action is not entirely known, but the primary mechanism responsible
for its anti-inflammatory, antipyretic, and analgesic action is thought to be inhibition of
prostaglandin synthesis by inhibition of cyclooxygenase (COX). It also appears to exhibit
bacteriostatic activity by inhibiting bacterial DNA synthesis.

Inhibition of COX also decreases prostaglandins in the epithelium of the stomach, making it
more sensitive to corrosion by gastric acid. This is also the main side effect of diclofenac.
Diclofenac has a low to moderate preference to block the COX2-isoenzyme (approximately
10-fold) and is said to have, therefore, a somewhat lower incidence of gastrointestinal
complaints than noted with indomethacin and aspirin.

The action of one single dose is much longer (6 to 8 hr) than the very short half-life of the
drug indicates. This could be partly because it persists for over 11 hours in synovial fluids.

Diclofenac may also be a unique member of the NSAIDs. Some evidence indicates it inhibits
the lipoxygenase pathways, thus reducing formation of the leukotriene (also pro-
inflammatory autacoids). It also may inhibit phospholipase A2 as part of its mechanism of
action. These additional actions may explain its high potency - it is the most potent NSAID
on a broad baris.

CHARACTERISTICS
IUPAC name-2-(2,6-di chlorophenyl amino)phenyl) Acetic acid
Pharmacokinetic data
Protein binding-more than99%
Metabolism-Hepatic
Half- life1 to 2 hr.
Excretion-40%biliary, 60%urine
Chemical data
Formula-C14H11CL2NO2
Mol.Mass-296.148g/mol

LITERATURE SURVEY
Grey Small et al (2007), studied a review of compliance to trein Alzheimer's disease:
potential benefits of a transdermal patch,concluded Transdermal patches may be an effective
way to optimize treatment compliance for AD, as well as an increasing number of other
chronic conditions that typically afflict the older population, offering the possibility of more
sustained clinical benefits.

Isman Asnadia Mabdouebsam et al (2010), studied formulation and stability study of

chlorpheniramine maleate transdermal patch Formulation of CPM as transdermal patch could
enhance its bioavailability due to bitter absorption from the skin and, avoiding first-pass
effect and metabolism in the gut mucosa, it increases patient compliance due to decreasing
dose frequency.

VG Jamakandi et al (2007), studied Formulation characterization and evaluation of matrix

type transdermal patches of a modal Antihypertensive drug they concluded TDDS are ideally
suited for drugs that undergo hepatic first pass metabolism along with a short elimination
half- life of less than 4 hours. Among the six different HPMC formulations, transdermal patch
with 6 cps and 6% w/v DMSO as permeation enhancer showed maximum release and
offered least resistance to the movement of the drug molecule due to its high hydrophilic
nature and high water permeability value to water.

O’Connell K’Burkmanrt et al (2007), studied the transdermal contraceptive patch: They

concluded the transdermal contractive patch which contain ethinyl estradiol and
norelgestromin has an efficacy s imilar to current oral contraceptives. The major advantages
include transdermal application and maintence of adequate hormonal levels for atleast 7days
side effects are similar to OC except for breast tenderness in the first 2 months of use and
skin irritation at the application site.

Hemant Bhaskar et al (2010), studied Comparison of Transdermal diclofenac patch with

oral diclofenac as an analgesic modality following multiple premolar extractions in
orthodontic patients. They concluded Results of this study indicate that the transdermal
diclofenac patch provides as potent analgesia as the oral diclofenac tablets with the added
advantage of better patient compliance and may be used for routine.

Margaret H. Satterfield et al (1998),studied a Meta-analysis to assess the incidence of

adverse effects associated with the transdermal nicotine patch.They concluded The results of
this meta-analysis indicate that very large studies would be needed to assess the effect of the
patch, if any, on serious, rare outcomes. These results also suggest that the rate of minor
adverse effects might be lowered by modifyinLauren.
M lopiz David et al (2008),studied Skin patch and vaginal ring versus combined oral
contraceptives for contraception. They concluded Effectiveness rates were similar for the
methods compared. The patch group had better compliance than the COC group. Compared
to COC users, patch users had more side effects. Ring users generally had fewer adverse
events than COC users but more vaginal irritation and discharge. The patch could lead to
more discontinuation while the vaginal ring showed little difference. High losses to follow
up can affect the validity of the results.

V Kusum Devi et al (2003),studied Design and Evaluation of Matrix Diffusion Controlled

Transdermal Patches of Verapamil Hydrochloride.They concluded release and permeation of
the drug from the most satisfactory formulation (A12) was evaluated through different
biological barriers (shed snake skin, rabbit skin, and rat skin) to get an idea of the drug
permeation through human skin. Shed snake's skin was found to be most permeable.

Prithvi S. Bachalli et al (2009),studied diclofenac transdermal patches against oral

diclofenac for pain control following removal of mandibular impacted third molars. They
conclused the study concludes that transdermal diclofenac sodium can be used as an
alternative form of pain control following removal of impacted mandibular third molars,
however considering that the analgesic potency might be lesser in the immediate
postoperative period, it might be prudent to use oral diclofenac sodium for immediate
postoperative pain relief, following which transdermal route can be used for pain control.

MarkR.Prausnitz Robert Langer et al (2009),studiedTransdermal drug deliverysystem they

concluded transdermal drug delivery offers compelling opportunities to address the low
bioavailability of many oral drugs; the pain and inconvenience of injections; and the limited
controlled release options of both Building off the successes of first-generation transdermal
patches, second-generation chemical enhancers and iontophoresis are expanding delivery
capabilities for small molecules, whereas third-generation physical enhancers (including
ultrasound, thermal ablation and micro needles) could enable transdermal delivery of
macromolecules and vaccines. These scientific and technological advances that enable
targeted disruption of stratum corneum while protecting deeper tissues have brought the field
to a new level of capabilities that position transdermal drug delivery for increasingly
widespread impact on medicine.

Vimal Mathew et al (2009),studied Transdermal drug delivery. They concluded taking in to

account the advantage of TDDS. It can be considered a perfect alternative for drug whose
enteral and parenteral dosages forms having drawbacks in patient compliance. After
rectifying the presently existing short coming TDDScan surely introduce.

Jatav Vijay Singh, et al (2012), studied Design Formulation and in vitro Drug Release from
Transdermal Patches containing Nebivolol Hydrochloride as Model Drug They concluded
The release rate of drug through patches increased when the contraction of hydrophilic
polymer was increased when the concentration of hydrophilic polymer was drug increased.

Andrew C. Faust et al (2011),studied Management of an Oral Ingestion of Transdermal

Fentanyl Patchesoral ingestion of a fentanyl patch and is the only to describe a treatment
modality for this situation. Contact time with the oral mucosa may be the most important
factor in determining severity of oral fentanyl ingestion, as bioavailability is significantly
higher via the buckle membrane.

Prabhu Prabhakara, et al (2010), studiedPreparation and evaluation of Transdermal patches

of Palaver in hydrochloride. They concluded Based on the physicochemical parameters and in
vitrorelease studies, it was found that formulation containing hydrophilic polymers released
faster compared to com-bination of hydrophilic and hydrophobic polymers or only
hydrophobic polymers. Further, in vivo study showed that papaverine hydrochloride helps in
decreasing the effect of isoproterenol on myocardial necrosis. Results of the present study
encore-aged that the palavering hydrochloride transdermal patch can be used as controlled
drug delivery system and frequency of administration can be minimized.

Arif Duran, et al (2013), studied Respiratory arrest caused by abuse of Fentanyl patch.They
concluded Transdermal fentanyl patch has been increasingly used recently for the
management of chronic pain. This brings about increased rates of misuse or addiction in
general population. Transdermal fentanyl patch may produce respiratory arrest as all other
opioids do. Herein, we describe a woman with meperidine dependence who developed
respiratory arrest after cutaneous application of 4 transdermal fentanyl patch.

RESEARCH ENVISAGED
Pain management is a branch of medicine employing an interdisciplinary approach for easing
the suffering and improving the quality of life of those living with pain. Pain sometimes
resolves promptly once the underlying trauma or pathology has healed, and is treated by one
practitioner, with drugs such as analgesics and anxiolytics. Effective management of chronic
(long-term) pain, however, frequently requires the coordinated efforts of the management
team.

Novel Drug delivery system refers to approaches formulation, technologies, and system for.
Transporting a pharmaceutical compound in the body as needed to safely achieve its desired
therapeutic effect. It may involve scientific site targeting within the body or it might involve
facility systemic pharmacokinetic in any case, it is typically concerned with both quantity and
duration of drug presence. Drug delivery is often approached via a drug but it may also
involve medical device combination product.

Transdermal drug delivery system (TDDS) provides a means to sustain drug release as well
as reduce the intensity of action and thus reduce the side effects associated with its oral
therapy. Transdermal drugs are self-contained, discrete dosage form. It delivers a drug
through intact skin at a controlled rate into the systemic circulation. Delivery rate is
controlled by the skin or membrane in the delivery system.

The potential of transdermal drug delivery systems has been demonstrated in recent years
with the approval of several medicines for use by patients who are unable to use conventional
dosage routes, like oral administration or injection. To enhance the TDDS (Transdermal Drug
Delivery System) potential to include other drug candidates, many researchers have been
exploring enhancement approaches to increase the permeability of various drugs through the
skin. Recently, physical enhancement systems are being reported as having big potential by
many researchers. In particular, iontophoresis is a very attractive way of delivering ionized
drugs by the application of an electric field to the skin. Sonophoresis is also an attractive
method to deliver a drug through the skin using ultrasound.

There are number of dosage forms available in market containing single drug or combination
of drugs of all the dosage forms available. transdermal patches are not available in market.

The present study deals with the fabrication of transdermal patches combination dual drug
selective deliver the drug at the target side.
The developed patches will be able to be effective in chronic pain management and better
patient compliance.

EXPERIMENTAL WORK

MATERIAL AND METHOD

Table5.1- CALIBRATION CURVE DATA OF PARACETAMOl

S. NO. Concentration(µg/ml) Absorbance

1. 0 0

2. 10 0.23

3. 20 0.363

4. 30 0.456

5. 40 0.541

6. 50 0.619

7. 60 0.745

8. 70 0.841

Table5.2- CALIBRATION CURVE DATA OF DICLOFENAC

S.NO. Concentration (µg/ml) Absorbance

1 0 0.00

2 2 0.075

3 4 0.113

4 6 0.171

5 8 0.243

6 10 0.317

7 12 0.339

8 14 0.40

9 16 0.461

10 18 0.518

11 20 0.539
Fig. 8: Standard curve of Paracetamol
 Fig. 9: Standard curve of Diclofenac

Interaction studies

Interaction studies were conducted on the medicated TDDS formulations by comparing them
with the pure drug and placebo formulations on the basis of assay, UV, IR. The TDDS was
dissolved in isopropanol and the drug content was determined by spectrophotometer.

The isopropanol solutions of the pure drug, medicated and placebo formulations were
filtered through. What man filter paper and scanned spectra photometrically between 200-400
nm.

The IR absorption spectra of the pure, medicated and placebo formulations were taken in the
range of 400-4000 cm-1 using the potassium bromide disc method.
 Fig. 9: Identification of Paracetamol by IR

Fig. 10: Identification of Diclofenac sodium byIR

Fig. 11: FTIR spectroscopic analysis of pure paracetamol
 Fig. 12: FTIR spectroscopic analysis of pure diclofenac sodium

Table-5.3 Characteristic peaks of diclofenac

IR Spectrum Standard Observed Groups Stretching

peak peak deformation
value(cm ¹) value(cm ¹)
Diclofenac 1600-1475 1556.61- C=C(aromatic) Stretching
Spectrum 1498.74

1320-1210 1305.85 C-O Stretching Stretching

1556 1556.61 Dichlorophenyl Stretching
1300-1000 1284.63 C-CO-C Stretching
Stretching
 Table 5.4- Characteristic peaks of paracetamol

Near IR 2.5µm 1250-4000

Mid IR 50 µm 4000-200

Far IR 1000 µm 200-10

Table 5.5- Characteristic peaks of paracetamol

Bond to H Triple bond Double bond Single bond

OH single bond C=C C=O C-C

NH single bond C=N C=N C-N

CH Single bond C=C C-O

4000 cm ¹ 2700cm ¹ 2000cm ¹ 1600cm ¹ 4000cm¹

Fig. 13: Identification of Paracetamol by UV

 Fig. 14: Identification of diclofenac sodium by UV

Table5.6-Composition of transdermal patches

S no. Formulation HPMC EC PEG DMSO Chloroform Drug(para&diclo)

code (gm) (gm) (gm) (mg)

1. F1 10 5 12 2% q.s. 50-50

2. F2 10 5 12 2% q.s. 50-50

3. F3 10 5 12 2% q.s. 50-50

4. F4 12 6 14 2% q.s. 50-50

5. F5 12 6 14 2% q.s. 50-50

Preparation of Matrix Type Dual Transdermal patch

Dual Transdermal patches of Diclofenac paracetamol were prepared by solvent evaporation

technique by incorporating different concentration of polymer hydroxyl propyl methyl
cellulose (HPMC) and Ethyl cellulose (EC) along with suitable solvent. The polymers were
dissolved in the solvent to get polymer solution.
Diclofenac, paracetamol in the ratio of 1:1 was added to the above solution and stirred
continuously until both the drugs soluble in the polymer solution. Then added poly ethylene
glycol (PEG) as plasticizer to increase the plasticity of the transdermal patch. Dimethyl
sulfoxide (DMSO) was added as a permeation enhancer. The polymer solutions were
prepared by dissolving appropriate polymers, plasticizer in suitable vehicle using a magnetic
stirrer. Both the drugs was added slowly to the solution and dissolved by continuous stirring
for 30 min to get a clear solution. Then the solution was spread separately uniformly in this
Petri dish, so that two solution separated by the aluminum foil partition.
The mould was kept for one day. The rate of evaporation was controlled by inverting a funnel
over the mould. After 24 h, the dried patches were then detached from the Petri dish and
patches were cut to generate dual transdermal patch of 2.0 cm in diameter. The formulated
patches were stored in desiccators.

EVALUATION OF DUAL TRANSDERMAL PATCH

Physical characterization

The physicochemical parameters such as thickness, uniformity of weight, tensile strength,

content uniformity test, moisture content, moisture uptake, drug content uniformity and
folding endurance of various patches were determined.

Thickness

The thickness of the patch was determined by measuring the thickness at random sites on the
formulated patch using micrometer screw gauge and the averagethickness was determined.
(Amnuaikit C,et al 2005)

Uniformity of weight

Weight variation is studied by individually weighing 10randomly selected patches and

calculating the average.

Folding endurance

The folding endurance was measured manually for the prepared patches. Folding endurance
of the film was determined by repeatedly folding a small strip of film (2cm x 2cm) at the
same place till it breaks. The number of times, the film could be folded at the same place
either to break the film or to develop visible cracks, gave the evaluate of folding endurance.
(Devi V.K. et al 2003)
Drug content

Transdermal system of specified area (2.64cm²) was cut into small pieces and taken into a 50
ml volumetric flask and 25 ml of phosphate buffer pH 7.4 was added gently heated to 45°c
for 15 minutes and kept for 24 hours with occasional shaking. Then the volume was made up
50 ml with phosphate buffer of pH7.4. Similarly a blank was carried out using a drug-free
patch. The Solutions were filtered and the absorbance was measured at249nm. (Mutalik S.et
al2004)

Percentage Moisture content

The prepared patch are weighed individually and kept in a desiccators containing calcium
chloride at room temperature for 24 h. The patch is weighed again after a specified interval
until they show a constant weight. (kusum Devi et al 2008)

The percent moisture content is calculated using following formula.

Initial weight – Final weight

% Moisture content = -----------------------------------------X 100
Final weight

Simultaneous estimation by UV (paracetamol and diclofenac)

Fig:15- Simultaneous estimation by UV (paracetamol and diclofenac)

Table5.7-Linearity table mixture of paracetamol and diclofenac

Concentration(µg/ml) Absorbance(248nm) Absorbance(273nm)

para/diclo
0.2:5 0.414 0.164
0.4:10 0.852 0.341
0.6:15 1.263 0.505
0.8:20 1.679 0.663
1.0:25 2.104 0.830

Table5.8-Assay result of the marketed formulation

Formulation Formulation1 Formulation2

Para Diclo Para Diclo
Observed Ammount(mg) 491±0.087 3.86±0.748 489±0.658 4.05±0.458
%Recovery 99.10 99.80 99.62 99.18

INVITRO DRUG RELEASE-

In order to study the exact mechanism of drug release from microspheres drug release data
was analyzed according to zero order, frist order, higuchi square root, hixson crowell,
korsermeyer peppas model. The criterion for selecting the most appropriate model was
chosen on the basic of goodness of fit test. Data obtained from invitro release study were
fitted to various kinetic equations. The kinetic models used are,

Zero order equation: (Q=kºt)

First order equation: {ln(100-Q)=lnQ-klt}

Higuchi equation: (Q=kt½)

Korsmeyer and peppas equation: (Q=kpt)

Further, to find out the mechanism of drug release, first 60% drug release was fitted in the
above equation. Where Q is the percent of drug release at time t and kº and kt are the
coefficients of the equation and n is the release exponent. The value is used to characterize
different release mechanism as follows. If n<0.5,the polymer relaxation does not affect the
molecular transport, Hence diffusion is fickian if 0.5<n<1.0,the solid transport will be non-
fickian and will be relaxation controlled.(Koresmeyer RW et al.,1983)
 Fig:16- Comparative invitro diclofenac and Paracetamol release profile for F1-F5

Table5.9-Invitro Drug release

Formulation Drug Release kinetics for diclofenac Drug Release kinetics for Paracetamol
code
Zero Frist Peppa’s Hixon Zero Frist Peppa’s Hixon
order order crowell order order crowell
R R r N r N r r R N r N
F1 0.97 0.91 0.97 0.71 0.82 0.62 0.98 0.95 0.97 0.62 0.80 0.06
F2 0.96 0.88 0.93 0.71 0.75 0.06 0.99 0.94 0.97 0.60 0.80 0.06
F3 0.96 0.90 0.93 0.82 0.72 0.06 0.95 0.88 0.91 0.64 0.72 0.05
F4 0.97 0.91 0.94 0.77 0.79 0.07 0.88 0.78 0.83 0.51 0.62 0.04
F5 0.98 0.91 0.93 0.64 0.73 0.06 0.97 0.96 0.97 0.60 0.82 0.06

Table-5.10 Melting point of Paracetamol and Diclofenac Sodium

S.No Drugs Melting Point(ºc)

1. Paracetamol 168-172ºc
2. Diclofenac Sodium 280ºc

Table-5.11 Solubility of Paracetamol and Diclofenac Sodium

Solvent Paracetamol Diclofenac Sodium

Water Sprightly Soluble Insoluble
Methanol Freely Soluble Freely Soluble
Alcohol Soluble Soluble

RESULT

Physicochemical Evaluation of transdermal patche

The prepared transdermal patches were evaluated for their physicochemical characteristics
such as appearance, weight variation, thickness, folding endurance, drug content, and in vitro
drug release through albino rat skin. The physical appearance of the various formulations in
terms of their transparency, smoothness ,flexibility, stickiness, homogeneity and opaque
properties were recorded.

The formulation F1 was found to be thin, opaque, flexible, formulation F2 was found to be
thin, transparent, not flexible formulation F3 was found to be thin, transdermal, and flexible
formulation F4 was found to be thin, transparent, and flexible and formulation F5 was found
to be thick ,opaque, not flexible.

The formulation F3gave the most suitable transdermal film with all desirable
physicochemical properties. The thickness of the patches was varied from 0.074 ±0.008mm
to 0.104±0.006mm. Low standard deviation values in the film thickness measurements
ensured uniformity of the patches prepared by solvent evaporation.

The weights variations range between from 0.052±0.002 mg/2cm² to0.090±0.002

mg/2cm²,which indicates that different batches patch weights variation.

Folding endurance was found to be from >55 to>70.drug content was found to be from Para-
3000µg/ml Diclo-500µg/ml to Para-4000µg/ml Diclo-500µg/ml.

The cumulative percentage drug release for F3 was found to be between diclofenac and
paracetamol 84.04±3.80% at 12 h. and F5 it was found 70.14±6.68 % at 12h. The
formulation, F3 is considered as a best formulation, Since it Shows maximum in vitro drug
release as 92.22±4.04 % at 12h.
DISCUSSION

Transdermal drug delivery system is a most suitable system for a long term treatment or for a
multi dose treatment because transdermal patches are prepared for a long period of time in a
single dose providing treatment from a day to even up to seven days.

TDDS also increases the bioavailability of drug by avoiding the first pass metabolism and
increase the therapeutic efficacy of drug by reaching into the systemic circulation. polymers
HPMC and EC were selected on the basis of their adhering property and non toxicity.

The result of the finding showed excellent adhering property and controlled release .Result
from present study concluded that paracetamol and diclofenac combination with Hydroxy
propyl methyl cellulose( HPMC,) Ethyl cellulose (EC) and with incorporation of Polly
ethylene glycole PEG-4000 and DMSO produce smooth, flexible, and transparent film.

FTIR studied showed characteristic peak of paracetamol and diclofenac, conforming the
purity of drug. FTIR spectral studies indicated there was no interaction between paracetamol
diclofenac and polymer used.

Paracetamol diclofenac patches were prepared with combination of these polymers and
evaluated it for physical parameters such as thickness, drug content, weights variation from
the result; it was observed that thickness drug content, weights variation, were suitable for
maximum stability of the prepared formulations.

The drug content of TDDS patches ranged from Para-3000µg/ml Diclo-500µg/ml to Para-
4000µg/ml diclo500µg/ml. The drug release rate increased when the concentration of
hydrophilic polymer was increased.

The cumulative percentage drug release for F3 was found to be between diclofenac and
paracetamol 84.04±3.80%at 12 h. and F5 was found to be70.14±6.68%at 24 h. The
formulation F3 is considered as a best formulation, since it shows maximum in vitro drug
release as at 12 h.

The drug release kinetics studies showed that the majority of formulation was governed by
Higuchi model and mechanism of release was non fickian mediated. Higuchi developed an
equation for the release of a drug from a homogeneous polymer matrix-type from a
homogeneous-polymer delivery system that indicates the amount of drug release s is
proposnal to the square root of time.

If the release of drug from the transdermal film when plotted against square root of time,
show a straight line, it indicates that the release pattern is obeying Higuchi’s kinetics. In our
experiments, in vitro release profile of all the different formulations of transdermal patches
could be best expressed by Higuchi’s equation, for release of drug from a homogeneous-
polymer matrix-type delivery system that depends mostly on diffusion characteristics.

From the in vitro permeation profile data of all the formulations through rat skin, kinetics of
drug release were found for zero-order, first-order, Higuchi-type release kinetics and
korsmeyer peppas-type release kinetics.

The coefficient of correlation of each of these release kinetics were calculated and compared.
The data revealed that the release pattern of selected formulations was best fitted for Higuchi
kinetics, as the formulation coefficient values predominate over zero-order, first order and
korsmeyer peppas type release kinetics, which again confirmed with higuchi’s equation for
the drug release from matrix. Thus a slow and controlled release mechanism is non-Fickian
model, as proposed by higuchi.

The regression analysis of the in vitro permeation curves were carried out for in vitro
permeation studies in rat skin. Among all these formulations, the formulation F1 showed the
maximum % drug cumulative release i.e. up to 48 hours of the study.All the formulations
showed Higuchi-type release kinetics which was diffusion mediated. Regression analyses of
the in vitro permeation curves were carried out.

The slop of the straight line obtained after plotting the mean cumulative amount release per
cm. square patch vs. square root of time was taken as the experimental flux for paracetamol
and diclofenac.

Table 6.1-Evaluation of Transdermal Patches-

S.n Parameters F1 F2 F3 F4 F5
o.

1. Appearance Thin,opeq Thin,transp Thin,transde Thin, Thick,Opaq

ue and arent and rmal and transparent ue and not
flexible not flexible flexible and flexible flexible

2. Thickness 0.090 0.074 0.110±0.010 0.104±0.00 0.084±0.010

±0.002 ±0.008mm. mm 6mm mm
mm

3. Weight 0.053±0.0 0.072±0.00 0.090±0.002 0.082±0.00 0.064±0.002

variation(mg/ 02 2 mg/2cm² mg/2cm² 2 mg/2cm² mg/2cm²
2cm²) mg/2cm²

4. Drug content Para- Para- Para- Para- Para-

3200µg/ml 3500µg/ml 4000µg/ml 3500µg/ml 3000µg/ml

diclo500µ Diclo- Diclo- Diclo- Diclo-

g/ml 500µg/ml 550µg/ml 550µg/ml 500µg/ml

5. Folding >55 >70 >70 >70 >55

endurance

6. Moisture 52.67 56.87 38.32 43.75 40.76

content

(%)
CONCLUSION

Pain management is a branch of medicine employing an interdisciplinary approach for easing

the suffering and improving the quality of life of those living with pain. Pain sometimes
resolves promptly once the underlying trauma or pathology has healed, and is treated by one
practitioner, with drugs such as analgesics and anxiolytics. Effective management of chronic
(long-term) pain, however, frequently requires the coordinated efforts of the management
team.

Chronic pain is widely believed to represent disease itself. It can be made much worse by
environmental and physiological factors. Chronic pain persists over a longer period of time
than acute pain and is resistant to medical treatments. It can and often dose –cause severe
problems for patients. A person may have two or more co-existing chronic pain conditions.

A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a
specific dose of medication through the skin and into the bloodstream. Often, this promotes
healing to an injured area of the body. An advantage of a transdermal drug delivery route
over other types of medication delivery such as oral, topical, intravenous, intramuscular etc.

The patch provides a controlled release of the medication into the patient, usually through
either a porous membrane covering a reservoir of medication or through body heat melting
thin layers of medication embedded in the adhesive.

There are number of dosage forms available in market containing single drug or combination
of drugs of all the dosage forms available. transdermal patches are not available in market.

The literature survey revealed that transdermal patch Formulation of diclofenac paracetamol
as transdermal patch could enhance its bioavailability due to bitter absorption from the skin
and, avoiding first-pass effect and metabolism in the gut mucosa, it increases patient
compliance due to decreasing dose frequency.

Controlled release formulation have provided drug release on site of action in a controlled
and continuous manner. The strategies commonly used to obtain maximum therapeutic effect
by drug releasing in controlling manner. Of all the controlled release dosage forms available,
transdermal drug delivery system represents an important particulate carrier system capable
of delivery a drug on targeted site. Mucoadhesive transdermal patches has been accepted as a
process to achieve controlled drug delivery by prolonging the residence time of the dosage
form at the site of absorption thereby improving and enhancing the bioavailability of drugs.
Mucoadhisive drug delivery system most important transdermal drug delivery system its
various advantages and it has a lot of potential in formulating dosage forms for various
chronic pain management.

The use of these carriers as targeted drug delivery system is associated with many advantages
that include excellent storage stability, easy and large scale productions. Formulation in
Patches confers stability, targeting and sustained release of the incorporated molecules.

The preliminary study confirms the suitability of ethyl cellulose and Hydorxy propyl methyl
cellulose (HPMC) for formulating dual transdermal drug delivery system of Diclofenac
Paracetamol. The Permeation of Diclofenac Paracetamol from different polymeric
membranes was found more with Hydroxy propyl methyl cellulose (HPMC) than Ethyl
cellulose (EC). The in vitro permeation and in vitro release kinetics studies confirm
reproducible release pattern of Diclofenac paracetamol from the dual transdermal patch.
Hence we conclude that dual transdermal patch containing Diclofenac Paracetamol will
maintain the plasma drug concentration required to treat pain associated with chronic
disorders like rheumatoid arthritis and for post-operative pain. Our innovative design pattern
of dual transdermal patch with along the sides of two different drugs shows added advantage
as in this design any best combinations of drugs with physical incompatibility can be
formulated as a dual trans patch, whereas with older dual transdermal patches in which drugs
are in different layers i.e. one over the another may leads to incompatibility. Similarly our
design pattern can be extended by trying with 3 or more drugs in a single transdermal patch
along the sides.

The present study deals with the fabrication of transdermal patches combination dual drug
selective deliver the drug at the target side.

The developed patches will be able to be effective in chronic pain management and better
patient compliance.

From the studies done it can be concluded that my paracetamol diclofenac Transdermal drug
delivery proved to be effective in the management of chronic pain due to which it can be
utilized by patients in pain and also showed the controlled release drug from Transdermal
drug delivery system due to which it resulted in patient compliance.

FTIR studied showed characteristic peak of paracetamol and diclofenac, conforming the
purity of drug. FTIR spectral studies indicated there was no interaction between paracetamol
diclofenac and polymer used.
The release rate of drug through patches increased when the concentration of hydrophilic
polymer was increased. Whereas, the Mechanism of drug release of all formulations were non
fickian. The properties of film did not change during the period of study. Further, in vivo
studies have to be performed to correlate with in vitro release data for the development of
suitable controlled release patches for paracetamol and diclofenac.
BIBLIOGRAPHY

 AgnihotriS.A.,Mallikarjuna N.N.Aminabhavi T.M. "recent advances on chitosan-

based micro and nanoparticles in drug delivery”,Journal of controlled Release,100,5-
28,2000.
 Alvarez Lorenzo C. concheiroA., “Molecular imprinted polymers for drug Delivery”,
Journal of chromatography B, 804,231-45, 2004.
 Amnuaikit c,Ikeuchi I,Ogawara K Higaki K,kimura T. “skin permeation of
propranolol from polymeric film containing terpene enhancers for transdermal
use”,Int J pharma 289, 2005 167- 178.
 Berna B, John VA (February 1994). “Pharmacokinetic characterization of transdermal
delivery systems”, Clinical pharmacokinetics26 (2): 121–34. Doi: 10.2165/00003088-
199426020-00005. PMID 8162656.
 Brown, MR: "Analgesic patches and defibrillators: a cautionary tale", Europace,2009
Nov;11(11):1552-33
 Bergman K, Müller L, Teigen SW (1996). "The genotoxicity and carcinogenicity of
paracetamol: a regulatory review", Mutat Res349 (2): 263–88. doi:10.1016/0027-
5107(95)00185-9. PMID 8600357.
 Bradley, N (1996). "BMJ should use "paracetamol instead of "acetaminophen"
initsindex",BMJ313(7058):689.doi:10.1136/bmj.313.7058.689.PMC 2351967.PMID
8811774.
 Bae Y., Fukushima S., Harada A.andkataoka K., “design of aviicelles that are
responsive to intracellular pH Change”, Angew. Int.Ed.,42,4640-43,2003
 Byrne M.E., park K., PeppasN., “Molecular imprinting within hydrogels”, Advanced
Drug Delivery reviews, 54, 149-61, 2002.
 Bronaugh, R.L and Maibach, H.I., “Percutaneous absorption,” Edition 3 Marcel
Decker, , New York(1989)
 Bhalla HL, Bhate AS. “Feasibility studies on transdermal films of ephedrine”, Indian
Drugs 1994; 31:328-32.
 Barry, B.W. “Dermatological formulation: Percutaneous Absorption,” Marcel Decker,
New York.(1983).
 Cabray, Matthew (2006-04-12). "Transdermal Patch Approved For Treatment Of
ADHD", Retrieved 2010-09-28. Food and Drug Administration. 2005-07-15.
Archived from the original on 2007-02-20 Retrieved 2007-02-24.
 Charman W.N. Chan H.K. Finnin B.C. and Chainman S.A, “Drug Delivery A factor in
Realizing the full therapeutic Potential of Drugs”, Drug Development Research, 46,
316-27,1999.
 Chien .Y.W. “Novel drug delivery system”, 2ndedn, Chapter 7. .Marcel Decker, New
York.(1988).
 Chung Sj “Future drug delivery research in South Korea. J Controlled Release”, 62,
1999, 73-79.
 Costa P, Ferreira DC, Morgado R, Sousa Lobo JM, “Design and evaluation of a
lorazepamtransdermal delivery system,” DrugDevInd Pharm, 23, 1997, 939-944.
 Devi VK, Saisivam S, Maria GR, DeeptiPU. “Design and evaluation of matrix
diffusion controlled transdermal patches of verapamil hydrochloride”, Drug
Develop”Ind Pharm, 39, 2003, 495–503.
 Dye S, Malgope,’ “A. Preparation of carvedilol transdermal patch and the effect of
propyleneglycol on permeation”,Int J Pharmacy and Pharmaceutical Sciences, 2(1),
2010, 137-143.
 Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA (2008). "Guidelines for the
management of paracetamol poisoning in Australia and New Zealand—explanation
and elaboration”, A consensus statement from clinical toxicologists consulting to
Australasian poisons information centres". Med J Aust188 (5): 296–301.
PMID 18312195.
 Foco A, Hadziabdic J, Becic F., “ Transdermal drug delivery systems”, 58, 2004, 230-
234.
 Gannu R, Vamshi Vishnu Y, Kishan V, MadhusudanRao Y. “Development of
nitrendipine transdermal patches”, Invitro and exvivo characterization. Current Drug
Delivery, 4, 2007, 69-76.
 Gordon RA, Peterson TA. Four myths about “transdermal drug delivery. Drug
Delivery Technology,” 3, 2003, 1-7.

 Hawkins LC, Edwards JN, Dargan PI (2007). "Impact of restricting

paracetamolpacksizes on paracetamol poisoning in the United Kingdom: a review of
the literature", Drug Saf 30 (6): 465–79. doi:10.2165/00002018-2007,30060-
00002PMID17536874
 Haag R., “Supramolecular Drug Delivery System based on the polymeric Core-Shell
Architectures”,Angew. Chem.Int Ed.,43,278-82,2004.
 Hsieh, D.S.(ED) “ Drug permeation enhancement”, Marcel Decker, New York.(1994)
 Izumoto T, Aioi A, Uenoyana S, Koriyama K, Azuma M., “ Relationship between the
transference of drug from a transdermal patch and physicochemical properties”, Chem
Pharm Bull., 40, 1992, 456-458.
 Kopecek J., “Smart and genetically engineered biomaterials and drug delivery
system”, European Journal of Pharmaceutical Sciences, 201-16, 2003.
 Khashab M, Tector AJ, Kwo PY (2007). "Epidemiology of acute liver
failure",CurrGastroenterol 66–73.Doi:10.1007/s11894-008-0023-x. 17335680.
 Ke GM, Wang L, Xue HY, Lu WL, Zhang X, Zhang Q, “In-vitro and in-vivo
characterization of a newly developed clonidine transdermal patch for treatment of
attention deficit hyperactivity disorder in children”, Biol Pharm Bull 2005; 28:305-10.
 Keith AD. “Polymer matrix consideration for transdermal devices”, Drug Developing
Pharm, 9, 1983, 605-621.
 Khatun M, Ashraful Islam SM, Akter P, Abdul Quadric M, Selim Reza M., “
Controlled release of naproxen sodium fromeudragit RS 100 transdermal film,” J
Pharm Sci, 3, 2004, 1-2.
 Koresmeyer RW, Gurny R, Doelkar E, Buri P, Peppas NA., “ Mechanisms of solute
release from porous hydrophilic polymer,”Int J Pharm., 15, 1983, 23‐25.
 Kulkarni R, Doddayya H, Marihal SC, Patil CC, HubbubPV. “Comparative evaluation
of polymeric patch for transdermal application”,The Eastern Pharmacist, 93(516),
2000, 109-11.
 Larson AM, Polson J, Fontana RJ (2005). "Acetaminophen-induced acute liver
failure: results of a United States multicenter, prospective study", Hepatology42 (6):
1364–72. Doi:10.1002/hep.20948. PMID 16317692.
 Laurent B, Annette M, Jean-Pierre D Daniel-Henri M., “Effects of Diclofenac,
Acyclofenacand meloxicam on the metabolism of proteoglycans and hyaluronan in
osteoarthritic human cartilage”, Br J Pharmacology, 131, 2000, 1413-
 MollerPSindet-Pedersen, S.; Petersen, C.; Juhl, GDillenschneider, A.; Skoglund, L.
(2005). "Onset of acetaminophen analgesia: comparison of oral and intravenous route
after third molar surgery", British journal of anaesthesia94 (5): 642–648.
doi:10.1093/bja/aei109. PMID 15790675.
 Muller GoymannC.C, “physicochemical characterization of colloidal drug delivery
system such as reverse micelles vesicles liquid crystals and nanoparticles for topical
administration”, European Journal of Pharmaceutics and biopharmaceutics,58,343-
56(2004)
 Modamio P, Lastra CF, and Marino EL. “A comparative in-vitro study of
percutaneous penetration of betablochers in human skin.”,Int J Pharm 2000; 194:249-
59.
 Mutalic S udupa N, Glibenclamide “transdermal patches:Physicochemical,
Pharmacodynamic,andpharmacokineticevaluations”,Pharmasci,2004;93(6)1577-1594.

 Nicoli S, Colombo P, Santi P. “Release and permeation kinetics of caffeine from

bioadhesive transdermal films”, AAPS J 2005; 7:E218-23.
 Nachum Z, Shupak A, Gordon CR (2006). "Transdermal scopolamine for prevention of
motion sickness: clinical pharmacokinetics and therapeutic applications". Clinical
Pharmacokinetics45 (6): 543–66. PMID 16719539.
 Prausnitz M, Langer R. “Transdermal drug delivery. Nature Biotechnology”, Volume
26, Number 11, Pages 1261-1268, November 2008
 Peck, Peggy (2006-03-01). "FDA Approves First Antidepressant Transdermal
Patch",. Retrieved 2010-09-28.
 Rennie KL, Hughes J, Lang R and Jebb SA., “ Nutritional management of rheumatoid
arthritis” ,a review of the evidence. J HumNutr Diet, 16, 2003, 97–109.
 Rosler A., Vandermeulen G.W.M. Klok H.-A., “advanced drug delivery devices via
self assemply of amphiphilic block copolymers”, Advanced Drug Delivery
Reviews,53,9108,2001
 Segal, Marian. “Patches, Pumps and Timed Release: New Ways to Deliver Drugs",
Food and Drug Administration.Archived from the original on 2007-02-10. Retrieved
2007-02-24.
 Silverman, Ed-"J&J and Sandoz Recall Fentanyl Patches", Retrieved 2010-09-28..
 Santinijr, J.T. Richards A.C., Scheidt R., Cima M.J. and Langer R, “Microcips as
controlled Drug Delivery devices”, Angew. ChemInt Ed.39, 2396-407, 2000.
 Soppimath K.S. AminabhaviT.M.Kulkarni A.R. RudzinskiW.E., “Biodegradable
polymeric nanoparticles as drug delivery devices”, Journal of controlled Release, 70,
1-20,2001.
 Sood A.and Panchagnula R., “Peroral Route an Opportunity for Protein and peptide
Drug delivery”,Chemical Reviews,101, 3275-303, 2000.
 Touitou E, Godin B, Becker Y., “Oleic acid a skin penetration enhancer affects
Langerhans cells and corneocytes”, J Control Release, 80, 2000, 1-7.
 Vandermeulen G.W.M.,Klok H-A “peptide/protein Hybrid Material Enhanced Control
of structure and improved Performance through Conjugation of biological and
synthetic polymers”, Macromolecular Bioscience4,383-98,2003.
 Ziaie B., BaldiA., Lie M., GUY., Siegel R.A., "Hard and Soft Micromachining for
Biomems Review of Techniques and examples of Applications in Microfluidics and
Drug Delivery”, Advanced Drug Delivery Reviews, 56,145-72, 2004.