Formulation And Evaluation Topical

Micro-emulgel for Treatment of

joint Pain

A Thesis Submitted
In Partial Fulfilment of the Requirements
For The Degree of
MASTER OF PHARMACY
In
PHARMACEUTICS
By
ABHISHEK SINGH
(2165001001)
Under the Supervision of

Dr. Prabhakar Vishwakarma Mr. Suraj Mandal

(Supervisor) (Co-supervisor)

DEPARTMENT OF PHARMACY,
IIMT UNIVERSITY, MEERUT-250001 UTTAR PRADESH
August-2023
 DECLARATION

I hereby declare that the work presented in this report entitled “Formulation And Evaluation Topical Micro
-emulgel for Treatment of joint Pain ”.
was carried out by me. I have not submitted the matter embodied in this report for the award of any other
degree or diploma of any other university or institute.

I have given due credit to the original authors/sources for all the words, ideas, diagrams, graphics,
computer programs, experiments, results, that are not my original contribution. I have used quotation marks
to identify verbatim sentences and given credit to the original authors/sources.

I affirm that no portion of my work is plagiarized, and the experiments and results reported in thereport
are not manipulated. In the event of a complaint of plagiarism and the manipulation of the experiments
and results, I shall be fully responsible and answerable.

Name : ABHISHEK SINGH

Roll no. : 2165001001

Branch : M. Pharma (Pharmaceutics)

(Candidate’s Signature)

II
M. Pharma Thesis 2023

IIMT College of Medical Science

DEPARTMENT OF PHARMACY

Meerut -UP

Certificate from the Dean

Certified that Abhishek Singh (2165001001)has carried out the research work presented in this thesis entitled

“Formulation And Evaluation Topical Micro-emulgel for Treatment of joint Pain"

for the award of Master of Pharmacy from college of Medical Science IIMT university,

Meerut under my supervision.

The thesis embodies results of original work and studies are carried out by the students herself and the contents

of the thesis do not from the basis for the award of any other degree to the candidate or to anybody else from

this or any other university /Institution.

(Prof. (Dr.) Umesh Kumar Sharma)

Dean

Date:

III
 IIMT College of Medical Science

DEPARTMENT OF PHARMACY

Meerut -UP

Certificate from Supervisor and Co- supervisor

Certified thatAbhishek Singh (2165001001)has carried out the research work presented in this thesis entitled
“Formulation And Evaluation Topical Micro-emulgel for Treatment of joint Pain”

for the award of Master of Pharmacy from college of Medical Science IIMT university,

Meerut under my supervision.

The thesis embodies results of original work and studies are carried out by the students herself and the

contents of the thesis do not from the basis for the award of any other degree to the candidate or to anybody

else from this or any other university /Institution.

Signature of the Supervisor Signature of the Co- Supervisor

Dr. Prabhakar Vishwakarma Mr. Suraj Mandal

(Head of Department, Associate Professor ) (Assistant Professor)

Date:

IV
 Formulation And Evaluation Topical Micro-emulgel

for Treatment of joint Pain”

BY
Abhishek Singh
ABSTRACT

Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by symmetric

joint inflammation, leading to joint pain, swelling, and eventually joint damage and disability.
This review aims to provide a comprehensive overview of the pathogenesis, clinical features, and
management of RA. It covers the underlying mechanisms driving the disease, risk factors,
and genetic predisposition. Additionally, the review explores the varied clinical manifestations of
RA, from joint symptoms to systemic effects, and highlights the importance of early diagnosis
and timely intervention. The various treatment approaches, including non-pharmacological
strategies, conventional disease-modifying drugs, biologic agents, and targeted therapies,
are discussed in detail, emphasizing their roles in symptom control, disease modification, and
overall patient well-being. Moreover, recent research insights and future perspectives in the field
of RAmanagement are also explored.

Keywords: Rheumatoid Arthritis, pathogenesis, clinical features, Joint Pain, Chronic

Autoimmune Disease.

V
 Acknowledgement
I consider this as an opportunity to express my gratitude to all the dignitaries who have been involved
directly or indirectly with the successful completion of this dissertation.

At first, I consider it as a great privilege to express my heartfelt gratitude and sincere thanks to my esteemed
guide Dr. Prabhakar Vishwakarma Associate Professor, Head of Department IIMT college of medical
science, for his valuable suggestions, encouragement, motivation, guidance and co-operation during my
thesis work.

I also consider it a great privilege to express my heartfelt gratitude and sincere thanks to my esteemed co-
guide Mr. Suraj Mandal Assistant Professor IIMT college of medical science, for his valuable suggestions,
encouragement, motivation, guidance and co-operation during my thesis work.

With great pleasure I would like to express my gratitude to my beloved Father, Mr. Jay Singh,
Mother, Mrs. Devanta devi and all my friends for their everlasting love and support .

Finally I take the privilege to express my sincere thanks, to one and all for their affection and best
wishes for the successful completion of this work.

Thankful I ever remain……………

(Signature of the student)

Abhishek Singh

2165001001
 DEDICATION

DEDICATED
TO MY
PARENTS AND GUIDES
 TABLE OF CONTENTS
S.NO Particulars Page No.
► Declaration & Certificates II & IV
► Abstract V
► Acknowledgement VI
► List of Tables XII-XV
CHAPTER 1 INTRODUCTION 16
1.1 Transdermal Drug Delivery Systems 17
1.1.1 Advantages of TDDS 17-18
1.1.2 Limitations of TDDS 18
1.2 The Human Skin 18-19
1.2.1 Anatomy of the Skin 19
1.2.2 Skin layers 19
1.2.2.1 Epidermis 19
1.2.2.2 Dermis 20
1.2.2.3 Hypodermis 20
1.3 Drug Delivery Routes Across Human Skin 20-22
1.4 Factors Affecting Transdermal Permeation 22
1.4.1 Biological Factors 22-23
1.4.2 Physicochemical Factors 23
1.5 Microemulgel 24-25
1.1.1 Advantages of Using Micro-Emulgel as a Topical Drug 25
Delivery System
1.1.1 Disadvantages of Microemulsion Based Gel 25
1.2 Selection of Oil Phase 26
1.3 Selection of Surfactants 26-27
1.4 Selection of Co-surfactants 27
1.5 Selection of Gelling Agent 27
1.6 Pseudo-ternary Phase Diagram 28
1.7 Formulation Methods of Microemulgel 28
1.1.1 Low Energy Emulsification Technique 29
1.7.2 High Energy Emulsification Technique 29
1.8 Arthritis 29
1.8.1 Epidemiology of RA 30
1.8.2 Types of Arthritis 30
1.8.3 Clinical Features 30-31
1.8.4 Etiology for Arthritis 31-32
1.9 Inflammatory Mediators in RA 33-35
1.9.1 Symptoms of Rheumatoid Arthritis 35
1.9.2 Swelling and Pain 36
1.9.3 Specific Joints Affected 36
1.9.4 Nodules 36
1.9.5 Fluid Buildup 36
1.9.6 Flu-Like Symptoms 36-37
1.9.7 Symptoms in Children 37
1.9.8 Medications 37
1.9.9 NSAIDS 37
1.9.10 Mechanism of Action 38
1.10 Inflammation 38
1.10.1 Classification of Inflammation 38
1.10.2 Symptoms of Inflammation 38-39
1.11 Anti- inflammatory Effects 40
Chapter.2 Review of Literature 41-47

Drug and Excipients Profile 48

Chapter.3
3.1 Trolamine Salicylate 48-49
3.2 Polymers Profile 49
3.2.1 Propylene Glycol 49-51
3.2.2 Sodium Methyl Paraben 51-52
3.2.3 Tween-20 52-53
3.2.4 Carbopol-940 53-54

3.2.5 Oleic acid 54-55

3.2.6 Liquid Paraffin 55-56
56-57
3.2.7 Benzyl Alcohol
3.2.8 Triethanolamine 57-58
Chapter 3 Aim and Objectives 59

3.1 59
Aim
3.1 Plan of Work 59
3.1.1 Literature Review 59
Selection of Excipients for the Preparationof 59
3.1.2
Microemulgel Formulation.
3.1.3 Preformulation Studies 59
Preparation of Trolamine Salicylate Microemulgel 59
3.1.4 Formulation.
3.1.4 Evaluation of Formulation. 59
3.1.5 In vitro drug diffusion study ofMicroemulgel. 60

3.1.6 Stability Study 60

60
3.1.7 Results and Discussion.
 Chapter.4 Materials and Methods 61

4.1 Materials: 61

4.2 Preformulation Study 61-62

4.2.1 Description 62

4.2.2 Melting Point 62

4.2.3 Solubility Studies 63

4.2.4 Estimation of the Drug by UV Spectroscopy 63
4.2.5 63
Preparation of Phosphate Buffer Solution [pH 7.4]
I.P 1996
4.2.6 Standard Curve 63
4.2.7 Fourier Transforms Infrared (FTIR) Spectral Analysis 63
4.2.7.1 Drug-Excipients Compatibility Studies by FT-IR 63-64
Analysis
4.3 Preparation of Trolamine Salicylate Microemulgel 64-65
Formulation
4.4 Evaluation of Formulation 65
4.4.1 Physical Examination 65
4.4.2 Size Distribution 65
4.4.3 pH Measurement 65
4.4.4 Viscosity Measurement 65
4.4.5 Zeta Potential 65
4.4.7 Spreadability Studies 66
4.4.8 % Drug Release: 66

4.5 In vitro Drug Diffusion Study 66

4.6 Stability Study 66

Chapter.5 Results and Discussion 67

5.1 Preformulation Study 67

5.1.1 Description 67

5.1.2 Melting Point 67

5.1.3 Solubility 67

5.1.4 Standard plot of Trolamine Salicylate in phosphate buffer 68

pH 7.4
5.1.5 FTIR Study 69-73

5.2 Evaluation of Formulation 74-77

5.3 In vitro drug diffusion study of Microemulgel 77-78

5.4 Stability Study: 78

Chapter.6 Conclusion 79

Chapter.7 References 80-86

 Synthesis and Evaluation of Newer Benzothiazole Derivatives for Developing the New
S.No TITLE
Analgesic andOF TABLE
Anti-Inflammatory Agents Page
Table 3 Types of Arthritis 30

Table 4 Cellular sources of synovial cytokines in RA 32

Table 5 Mediators in RA 34

Table.4.1 List of Chemicals 61

Table.4.2 List of Equipments Used 61

Table.4.3 Solubility Profile I.P. 1996 62

Table.4.4 Composition of different Trolamine Salicylate Microemulgel 64

Formulations
Table.5.1 Physical appearance of all batches F1-F8 67

Table.5.2 Melting Point Determination 67

Table.5.3 Solubility Profile of Trolamine Salicylate 67

Table.5.4 Abs maxima of Trolamine Salicylate in phosphate buffer pH 68

Table.5.5 UV Abs of phosphate buffer pH7.4 68

Table.5.6 FT-IR Spectral assignment of Trolamine Salicylate 69

Table.5.7 FT-IR spectral assignment of Trolamine Salicylate & 71

Triethanolamine
Table.5.8 FT-IR spectral assignment of Oleic acid 71

IIMT College of Medical Sciences, IIMT University, Meerut Page |

15
 Synthesis and Evaluation of Newer Benzothiazole Derivatives for Developing the New
S.No TITLE OF
Analgesic TABLE
and Anti-Inflammatory Agents Page
Table 5.9 FT-IR spectral assignment of Trolamine Salicylate 72
+Tween-20+Propylene Glycol
Table 5.10 FT-IR spectral assignment of Carbopol-940 73

Table 5.11 Physical Examination 74

Table.5.12 Comparative Viscosity values and Spreadibility 75

Table.5.13 Zeta Potential 75

Table.5.14 Size Distribution 76

Table.5.15 In-vitro drug diffusion study of Microemulgel 77

Table.5.16 Stability Study best formulation F7 78

Table.5.2 Melting Point Determination 62

Table.5.3 Solubility Profile of Trolamine Salicylate 62

Table.5.4 Abs maxima of Trolamine Salicylate in phosphate buffer pH 63

Table.5.5 UV Abs of phosphate buffer pH7.4 63

Table.5.6 FT-IR Spectral assignment of Trolamine Salicylate 64

Table.5.7 FT-IR spectral assignment of Trolamine Salicylate & 66

Triethanolamine
Table.5.8 FT-IR spectral assignment of Oleic acid 67

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 TITLE OF FIGURE Page
Fig 1.1 Anatomy of the Skin 19

Fig 1.2 Routes of Penetration 21

Fig 1.3 The Stratum Corneum and Intercellular and Trans 22

CellularRoutesof Penetration
Fig 1.4 Microemulgel 25

Fig 1.6 Rheumatoid Arthritis 29

Fig 1.7 Difference between Normal joints and Rheumatoid Arthritis 31

joints
Fig 1.8 Pathogenesis of Rheumatoid Arthritis 32

Fig 1.9 Synovitis in RA patients 33

Fig 1.10 Normal view joint 35

Fig 1.11 Symptoms of RA 36

Fig 1.12 Medication of RA 37

Fig 1.13 Inflammation 38

Fig 1.14 Mechanism of Inlammation 39

Fig 3.1 M.S of Trolamine Salicylate 48

Fig 3.4 Molecular Structure of Na-Methyl Paraben 51

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 Synthesis and Evaluation of Newer Benzothiazole Derivatives for Developing the New
Analgesic and Anti-Inflammatory Agents
S.No TITLE OF FIGURE Page
Fig 3.5 Molecular Structure of Tween-20 52

Fig 3.6 Molecular Structure of Carbopol-940 53

Fig 3.8 Molecular Structure of Benzyl Alcohol 58

Fig 5.1 UV spectrum of Trolamine Salicylate in phosphate buffer pH7.4 68

Fig 5.2 The standard plot exhibits linearity and has a strong regression 69
coefficient
Fig 5.3 FT-IR of Trolamine Salicylate 69

Fig 5.4 FT- IR of Trolamine Salicylate & Triethanolamine 70

Fig 5.6 FT-IR of Trolamine Salicylate +Tween-20+Propylene Glycol 72

Fig 5.7 FT-IR of Carbopol-940 73

Fig 5.9 Representative graph of % drug Content 74

Fig 5.10 Comparative Viscosity values and Spreadibility 75

Fig 5.12 Zeta Potential 76

Fig 5.13 Size Distribution 77

Fig 5.14 In-vitro drug diffusion study of Microemulgel F1-F8 78

Fig 5.16 IR and NMR of compound of VT2 132

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 CHAPTER 1

INTRODUCTION

[Type text Page 16

 Chapter-1 Introduction
1.1 Transdermal Drug Delivery Systems:
Currently, Transdermal drug delivery is one of the most promising methods for drug
application. Increasing numbers of drugs are being added to thelist of therapeutic agents that
can be delivered to the systemic circulation via skin. Transdermal drug delivery systems
(TDDS) can be defined as self contained discrete dosage forms which, when applied to the
intact skin, delivers the drug(s)through the skin at a controlled rate to the systemic circulation.
The potential of using intact skin as the route of drug administration has been known for
several years. The inspiration of using skin for delivery of drug is from ancient time. Ebers
papyrus used the husk of castor oil plant bark imbibed with water placed on aching head.
Historically, the medicated plaster can be viewed as the first development of transdermal drug
delivery; this medicated plaster became very popular in Japan as over the counter
pharmaceutical dosage form.

Transdermal delivery not only provides controlled, constant administrationof the drug, but also
allows continuous input of drugs with short biological half- life and eliminates pulsed entry
into systemic circulation, which often undesirable side effect. TDDS facilitate the passage of
therapeutic quantities of drug substances through the skin and into the general circulation for
their systemic effects.

In developing a transdermal delivery system, two criteria are considered: one is achieving
adequate flux across the skin and the other is minimizing the lagtime in skin permeation. One
strategy overcoming this constraint is the incorporation of various chemical skin enhancers
into the vehicle. Another strategy is a choice of an appropriate vehicle that corresponds to the
drug being used for the dermal route of administration. Concerning dermal application the
microemulsions can interact with the stratum Corneum changing structural rearrangement of
its lipid layers and consequently increasing transdermal drug permeation and so act as
penetration enhancer .

1.1.1 Advantages of TDDS:

 Avoidance of first pass metabolism.
 Avoidance of gastro intestinal incompatibility.
 Predictable and extended duration of activity.
 Minimizing undesirable side effects.
 Provides utilization of drugs with short biological half life.

[Type text] Page 17

  Narrow therapeutic window.
 Improving physiological and pharmacological response.
 Avoidance the fluctuation in drug levels.
 Termination of therapy is easy at any point of time.
 Greater patient compliance due to elimination of multiple dosing profile.
 Ability to deliver drug more selectively to a specific site.
 Provide suitability for self administration.
 Enhance therapeutic efficacy.

1.1.2 Limitations of TDDS:

 Transdermal route administration is unsuitable for drugs that irritate or sensitize the
skin.
 Transdermal route cannot deliver in a pulsatile fashion.
 Transdermal delivery is neither practical nor affordable when required todeliver large
doses of drugs through skin.
 Transdermal delivery cannot administer drugs that require high bloodlevels.
 Drug of drug formulation may cause irritation or sensitization.
 Not practical, when the drug is extensively metabolized in the skin and when
molecular size is great enough to prevent the molecules from diffusing through the
skin.
 Not suitable for a drug, which doesn’t possess a favourable, O/W partitioncoefficient.
 The barrier functions of the skin of changes from one site to another on thesame person,
from person to person and with age .

1.2 The Human Skin:

One highly successful alternative delivery method is the transdermal. Skinof an average adult
body covers a surface of approximately 2m2 and receives about one-third of the blood
circulating through the body. The deliver a drug into the body through transdermal layer of
skin, it is necessary to understand about theskin. The skin is the outer covering of the body. In
humans, it is the largest organ of the integumentary system made up of multiple layers of
epithelial tissuesand guards the underlying muscles, bones, ligaments and internal organs. For
theaverage adult human, the skin has a surface area between 1.5 to 2 m2 (16.1-21.5 sq ft), most of
it is between 2.3mm (0.10 inch) thick. The average square inch (6.5cm 2) of skin holds 650
sweat glands, 20 blood vessels, 60,000 melanocytes and more than a thousand nerve endings.
It performs several essential functions. The adjective cutaneous literally means “of the skin”
(from Latin cutis, skin).Thedifferent layers of the human skin is shown in fig 1 .

[Type text] Page 18

 Fig.1.1: Anatomy of the Skin

1.2.1 Anatomy of the Skin:

Structurally, the skin consists of two principle parts. The outer thinner portion, which is
composed of epithelium, is called the epidermis. The epidermisis attached to the inner thicker,
connective tissue part called the dermis. Beneath the dermis is a subcutaneous layer. This
layer is also called the superficial fascia or hypodermis. It consists of areole and adipose
tissues. Fibers from the dermis extend down into the subcutaneous layer and anchor the skin
to it. The subcutaneous layer in turn attaches to underlying tissues and organs.

1.2.2 Skin layers:

Skin is composed of three primary layers.
 Epidermis.
 Dermis.
 Hypodermis (subcutaneous adipose layer).

1.2.2.1 Epidermis:
Epidermis, “epi’ coming from the Greek meaning “over” or “upon” is the outermost layer of
the skin. It forms the water proof, protective wrap over the body’s surface and is made up of
stratified squamous epithelium with an underlying basal lamina. It contains no blood vessels
and cells in the deepest layerare nourished by diffusion from blood capillaries extending to the
upper layers ofthe dermis.

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 1.2.2.2 Dermis:
Dermis is 3 to 5mm thick layer and is composed of a matrix of connective tissue, which
contains blood vessels, lymph vessels and nerves. The cutaneous blood supply has essential
function in regulation of body temperature. It also provides nutrients and oxygen to the skin
while removing toxins and waste products. Capillaries reach to within 0.2 mm of skin surface
and provide sink conditions for most molecules penetrating the skin barrier. The blood supply
thus keeps the dermal concentration of a permeant very low and the resulting concentration
difference across the epidermis provides the essential concentration gradient for transdermal
permeation. It contains hair follicles, sweat gland, sebaceous glands, apocrine glands,
lymphatic vessels and blood vessels.

1.2.2.3 Hypodermis:
The hypodermis or subcutaneous fat tissue supports the dermis and epidermis. It serves as a
fat storage area. This layer helps to regulate temperature, provides nutritional support and
mechanical protection. It carries principle blood vessels and nerves to skin and may contain
sensory pressure organs. For transdermal drug delivery, drug has to penetrate through all these
three layers and reach into systemic circulation while in case of topical drug delivery only
penetration through stratum corneum is essential and then retention of drug in skin layers is
desired. It consists of loose connective tissue and elastic. The main cell types are fibroblasts,
macrophages and adipocytes.

1.3 Drug Delivery Routes Across Human Skin:

Drug molecules in contact with the skin surface can penetrate by three potential potential
pathways: through the sweat ducts, via the hair follicles and sebaceous glands, (collectively
called the shunt or appendageal route), or directlyacross the stratum Corneum (Fig 2).
The relative importance of the shunt or appendageal route versus transport across the stratum
corneum has been debated by scientists over the years (6-8) andis further complicated by the
lack of a suitable experimental model to permit separation of the three pathways. In vivo
experiments tend to involve the use of hydrated skin or epidermal membranes so that
appendages are closed by the swelling associated with hydration. Scheuplein and colleagues
proposed that a follicular shunt route was responsible for the presteady-State permeation of
polar molecules and flux of large polar molecules or ions that have difficulty diffusing across
the intact stratum Corneum.

[Type text] Page 20

 Fig.1.2: Routes of Penetration
 Through the Sweat Ducts.
 Directly Across the Stratum Corneum.
 Via the Hair Follicles.

The stratum corneum consists of 10-15 layers of corneocytes and varies in thickness from
approximately 10-15 m in the dry state to 40 m when hydrated. Itcomprises a multi-layered
“brick and mortar” like structure of keratin-rich corneocytes (bricks) in an intercellular matrix
(mortar) composed primarily of long chain ceramides, free fatty acids, triglycerides,
cholesterol, cholesterol sulfate and sterol/wax esters. However it is important to view this
model in the context that the corneocytes are not brick shaped but are polygonal, elongated and
flat (0.2-1.5 m thick, 34-46 m in diameter). The intercellular lipid matrix is generated by
keratinocytes in the mid to upper part of the stratum granulosum discharging their lamellar
contents into theintercellular space. In the initial layers of the stratum this extruded material
rearranges to form broad intercellular lipid lamellae, which then associate into lipid bilayers,
with the hydrocarbon chains aligned and polar head groups dissolved in an aqueous layer
Fig.3.

As a result of the stratum corneum lipid composition, the lipid phase behaviour is different
from that of other biological membranes. The hydrocarbon chains are arranged into regions
of crystalline, lamellar gel and lamellar liquid crystal phases thereby creating various domains
within the lipid bilayers. The presence of intrinsic and extrinsic proteins, such as enzymes,
may also affect the lamellar structure of the stratum corneum. Water is an essential component
of the stratum corneum, which acts as a plasticizer to prevent cracking of the stratum
corneum and is also involved in the generation of natural moisturizing factor (NMF), which
helps to maintain suppleness. In order to understand how the physicochemical properties of
the diffusing drug and vehicle influence permeation across the stratum corneum and there by
[Type text] Page 21
within the aqueous regions near the outer surface of intracellular keratin filaments (intracellular or
transcellular route) while lipophilic chemicals diffuse through thelipid matrix between the
filaments (intracellular route).

Fig.1.3: The Stratum Corneum and Intercellular and Trans CellularRoutes of Penetration

1.4 Factors Affecting Transdermal Permeation:

1.4.1 Biological Factors:

A. Skin Condition:
Acids and alkalis, many solvents like chloroform, methanol damage the skin cells and
promote penetration. Diseased state of patient alters the skin conditions. The intact skin is
better barrier but the above mentioned conditions affect penetration.

B. Skin Age:
The young skin is more permeable than older. Childrens are more sensitivefor skin absorption
of toxins. Thus, skin age is one of the factor affecting penetration of drug in TDDS.
C. Blood Supply:
Changes in peripheral circulation can affect transdermal absorption.
D. Regional Skin Site:
Thickness of skin, nature of stratum corneum and density of appendages vary site to site.
These factors affect significantly penetration.

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Skin metabolism
Skin metabolizes steroids, hormones, chemical carcinogens and some drugs. So skin metabolism
determines efficacy of drug permeated through the skin.

E. Species Differences:
The skin thickness, density of appendages and keratinization of skin varyspecies to species, so
affects the penetration.

1.4.2 Physicochemical Factors:

A. Skin hydration:
In contact with water the permeability of skin increases significantly. Hydration is most
important factor increasing the permeation of skin. So use of humectant is done in transdermal
delivery.

B. Temperature and pH:

The permeation of drug increases, ten folds with temperature variation. The diffusion
coefficient decreases as temperature falls. Weak acids and weak bases dissociate depending
on the pH and pka or pkb values. The proportion of unionized drug determines the drug
concentration in skin. Thus, temperature and pH are important factors affecting drug
penetration.

C. Diffusion coefficient:
Penetration of drug depends on diffusion coefficient of drug. At a constant temperature the
diffusion coefficient of drug depends on properties of drug, diffusion medium and interaction
between them.

D. Drug concentration:
The flux is proportional to the concentration gradient across the barrier and concentration
gradient will be higher if the concentration of drug will be more across the barrier.

E. Partition coefficient:
The optimal partition coefficient (K) is required for good action. Drugs with high K are not
ready to leave the lipid portion of skin. Also, drugs with lowK will not be permeated.

F. Molecular size and shape:

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 Drug absorption is inversely related to molecular weight, small moleculespenetrate faster than
large ones. Ideal molecular properties for Transdermal Drug Delivery.

1.5 Microemulgel:

Topical drug delivery defined as the application of a formulation directly via skin to treat disorder
with the advantages of avoiding first-pass metabolism and increasing the therapeutic efficiency of
the drug.

Topical preparations produce localized effects at the site of their application into the underlying
layers of skin or mucous membranes virtue of penetration. It provides flexibility to deliver drugs
more effectively to a selective site. It provides utilization of drugs with a short biological half-life,
narrow therapeutic window to increase the duration of action. The topical drug can be
administered anywhere in the body through ophthalmic, rectal, vaginal, and on skin as topical
routes. The route of administration depends upon the type and severity of the disease. Drug
delivery system can provide direct application of a formulation to the skin to get the localized
effect of the drug. A topical drug delivery system has many advantages as they deliver drugs more
selectively to a specific site. The reason for using topical delivery is to avoid GI incompatibility
and metabolic degradation associated with oral administration. Moreover, the topical delivery
provides an increased bioavailability and consistent delivery of drug at extended release rates from
topical dosage form depending on physicochemical properties of the carrier and the drug [10].
The concept of microemulsion was introduced by Hoar and Schulman during the 1940’s.
Microemulsion contains water, oil, and amphiphilic which are an optically isotropic and
thermodynamically stable liquid micro-dispersion. Microemulsion is the vehicle which improves
the delivery, efficacy, and bioavailability of many drugs. “Microemulsion” refers to a
thermodynamically stable and clear dispersion of two immiscible liquids; contain oil and water
which is stabilized by surfactant molecules by forming interfacial film. A microemulsion is
considered as a kinetically stable liquid dispersion of a lipid phase and an aqueous phase, with a
surfactant. The dispersed particles having a size range of 5-200 nm, and have tiny oil/water
interfacial surface tension.

Microemulsions are transparent because of their globule size (less than 25%). High energy input is
not required in the formation of the microemulsion. In several cases, a co-surfactant is use
additionally to the surfactant, the lipid phase, and therefore the aqueous phase. The microemulsion
structure is mentioned below fig.1.

There are three types of microemulsions are formed depending on the composition:
1. Oil in water micro emulsions in which oil phase is dispersed phase and water is continuous
aqueous phase.

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 2. Water in oil micro emulsions in which water phase is dispersed in the continuous oil phase;
3. Bi-continuous micro emulsions in which micro domains of lipid and aqueous phase are inter
dispersed in the system.
To stabilize the microemulsion suitable combination of surfactant and cosurfactant is necessary
.
The main principle of this system is to form o/w type of micro-emulsion following dilution by
microemulgel, they exhibit characteristics of both. Microemulgel helps to deliver the hydrophobic
drugs by formulating oil in water microemulsion and this microemulsion can be incorporated into the
gel base. They provide a larger area for absorption of drug and lipid portion intensify the
bioavailability by better penetrability of drugs. Also, the gel base provides the better stability to
micro-emulsion. In comparison to micro-emulsions, microemulgel have a firm degree of elegance and
they are easily washable if required.

Fig.1.4: Microemulgel
1.1.1 Advantages of Using Micro-Emulgel as a Topical Drug Delivery System:
 Hydrophobic drugs can be easily incorporated into gels using o/w microemulsion.
 Better loading capacity.
 Production feasibility and low preparation cost.
 No intensive sonication.
 Controlled release.
 Ability to deliver drug more selectively to a specific site.
 Avoidance of gastro-intestinal incompatibility.

1.1.2 Disadvantages of Microemulsion Based Gel:

 The larger particle size drugs not easy to absorb through the skin.
 Poor permeability of some drugs through the skin.
 Can be used only for drugs which require very small plasma concentration for action.
 Possibility of allergenic reactions.
 An enzyme in the epidermis may denature the drugs.
 Skin irritation of contact dermatitis may occur due to drug or excipien

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 1.2 Selection of Oil Phase:

The oil phase could consist of carrier oil in which the lipophilic bioactive compound is dissolved
[15]. In microemulsion formulation, low molecular weight oils are preferred with respect to high
molecular weight oils (i.e. triglycerides); they are able to penetrate the interfacial film enhancing
the formation of an optimal curvature of the interfacial film. Moreover, being thermodynamically
stable system, microemulsions do not incur in instability phenomenon such as Ostwald ripening
therefore, addition of oil as ripening inhibitors is not required.

The oil that shows excess solubility of drug is selected as an oil phase for formulating
microemulsion based gel. The consistency of these lipids may range from mobile liquid to high
solids. The lipid phase sometime acts as penetration enhancer therefore there is no need to add
penetration enhancer in microemulsion delivery system.

Researcher shows that the soyabean oil in a system composed of water, essential oils (EOs) and
Tween 80. Soybean oil was able to improve the dilutability of EOs-based microemulsions and it
had a great impact on the formation of the system, expanding the regimes of microemulsions and
reducing the droplet size. It contributed to reduce the EOs volatility as well.

1.3 Selection of Surfactants:

The second criteria for the choice of surfactants were supported their ability to make
microemulsion with designated lipid having the very best solubility for drug.
Surfactants are unit active molecules that have each a hydrophilic and a lipotropic domain in their
molecular structure.

Because of their amphiphilic nature, surfactants enable the dispersion of two incompatible phases
lowering the surface tension up to get enough versatile film ready to deform round the droplets
with the best curvature.

Throughout the emulsification method, they are quickly absorbed within the interface and stop the
droplets’ aggregation [22
The non-ionic, zwitterionic, cationic, or anionic surfactants are used to stabilize such systems.
Ionic and non-ionic surfactant is effective to the extent of the microemulsion region. Example of
non-ionic embodies polyoxyethylene surfactants like Brij 35, tween20/80, or sugar esters like
sorbitan monooleate (Span 80).

Zwitterion is notable example phospholipids. Microemulgels are combination of two dosage form
such as Microemulsion and gel, the microemulsion is either oil in water or water in oil that are
gelled by adding gelling agent to it, as compared to microemulsion, emulsions are

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 thermodynamically unstable but addition of emulsifying agents make them stabilize at some extent
by reducing its surface tension. A satisfactory surface-active agent provides the balance between
hydrophilic & lipotropic teams & capable of formulating stable emulsions. Spans and tweens are
nonionic surfactants having HLB values more than eight and area units utilized in the formulation
of o/w emulsions whereas mineral oils like liquid paraffin have HLB values less than eight & so
area unit utilized within the formulation of water in oil emulsions.

1.4 Selection of Co-surfactants:

Cosurfactants are generally short and medium-chain alcohols and polyglycerol derivatives,
including ethanol, isopropanol, isopropyl myristate, and propylene glycol (PG). Nonionic
surfactants have also been used to provide low irritancy cosurfactants.

The cosurfactants with surfactant are used to decrease the interfacial tension to transient negative
value. At this negative value, fine droplets are formed due to the interface expansion and more
surfactant/cosurfactant get adsorbed on the surface until the bulk condition is depleted enough to

make the interfacial tension positive again. Cosurfactant of short-medium chain length alcohols also
ensures that the interfacial film is flexible enough to deform readily around droplets, as the
interaction between primary surfactant molecules decreases both the polar head group interaction
and hydrocarbon chain interaction.
Polyethylene glycol derivatives of stearoyl phosphatidyl ethanolamine, ethanol, fatty acid esters of
propylene glycol, and oleic esters of polyglycerol, ethyl glycol, and propylene glycol were also
evaluated as cosurfactant in microemulsion drug delivery system.

1.5 Selection of Gelling Agent:

The gel structure is providing in formulation via adding gel phase. Natural and artificial are of two
varieties. Incorporation of gel phase to a formulation makes it thixotropic.
The thickening agents are utilized in O/W microemulsions and nanoemulsions to match the
density of the oil part with the encompassing liquid part. Thus, engaged on the impact of attraction
forces, they may retard the incidence of creaming or deposit phenomena.
Moreover, texture modifiers are widely used likewise. Generally, water-based systems have to be
compelled to contain a preservative agent to avoid the proliferation of microorganisms. Within the
specific case of EO-based systems, the addition of preservatives is typically extra since EOs is
naturally occurring antimicrobials. The study shows that the exploited EOs-based microemulgel to
encapsulate nisin, an antimicrobial agent. Rosemary, thyme, oregano, and herbaceous plant Eos
were elite to boost the system’s overall antimicrobial activity, through a synergistic impact of nisin
and EOs.

Research shows that to prepare nanoemulgel of Amophotericin B carbopol 980 was used as a gel
base and will economical, stable, and safe carrier for increased and sustained topical delivery for
Amophotericin B in native skin mycosis.

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 1.6 Pseudo-ternary Phase Diagram:
The water titration method is used to construct phase diagrams to identify the type of structure that
resulted within the following emulsification and to characterize the behavior of mixtures on
dilution.
Pseudo-ternary phase diagram of oil, water and surfactant/cosurfactant mixture are constructed at
fixed weight ratio of surfactant/cosurfactant. The emulsification region is obtained by mixing
ingredients into the vial and titrates with water. Formation of monophasic and biphasic system is
confirmed by visual inspection. In case of monophasic system, clear and transparent mixtures are
visualized after stirring and in case of biphasic system turbidity appeared followed by phase
separation. Exclusively the region, where clear microemulsion was considered. Then the prepared
microemulsion were analyzed for particle size and polydispersity index (PDI). Theoretical regions
of microemulsion system of oil (O), water (W), and surfactant+cosurfactant (S) are represented in
fig.1.5 .

Fig.1.5: Hypothetical phase regions of microemulsion system of oil (O), water (W), and surfactant
+ co-surfactant (S)

1.7 Formulation Methods of Microemulgel:

Micro-emulgel may be developed with 3 steps .
Step 1: Preparation of oil in water or water in oil micro-emulsion using oil phase and water phase.
Step 2: Preparation of gel using gelling agent and water by constant stirring and optimization of
pH.
Step 3: Incorporation of micro-emulsion into the gel base to formulate micro-emulgel.

For the preparation of micro-emulsion essentially 2 strategies i.e. low energy and high energy
emulsification techniques are used.

1.7.1 Low Energy Emulsification Technique:

Low energy technique benefits over high energy strategies for the formulation of the micro-
emulsion. The low energy technique includes the phase inversion technique and the spontaneous
technique. The phase inversion technique involves the blending of oil, water, and wetting agent in
a much-predefined ratio. The oil phase is titrated with aqueous phase at constant stirring, therefore
the formation of nano-sized drop during a continuous phase. The addition of wetting agent & co-
surfactant affects the emulsification method. The amount of wetting agent used in the formulation
determined which kind of emulsion is formed; the temperature plays an important role in the
formation of emulsion. At low temperatures, they are hydrophilic and oil in water type. At higher
temperatures, they are lipophilic and water in oil type. At associate degree intermediate
temperature, microemulsion happens with the aqueous phase & oil part to make a bicontinuous
structure. The spontaneous technique is specially used for the unstable element or else, a
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 temperature-dependent spontaneous twist of non-ionic wetter is employed for activity throughout
the part inversion technique. The emulsions fashioned at part inversion temperature are going to be
reversed on cooling with continuous stirring. This method is additionally restricted to include the
unstable element, though limitation takes as approach reduced part inversion temperature by
appropriate choosing surfactant.

1.7.2 High Energy Emulsification Technique:

Apply high shear force energy to rupture the interior introduce the nanosized drop by hard hitting
homogenizers, ultrasonicator. In this technique the external energy is required to stabilize the
formulation.

1.8 Arthritis:
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes inflammation of the joints
and may cause inflammation of other tissues in the body. The immune system consists of the cells
and proteins in our bodies that fight infections. An autoimmune disease occurs when our immune
system doesn’t recognize part of our body and attacks it as if it were an invader such as a bacteria
or virus. In rheumatoid arthritis, the immune system targets synovial membrane and attacks it. The
synovial membrane is secretes synovial fluid into the joint. Synovial fluid is the joint fluid that
lubricates and nourishes the joint. Other tissues can also be targeted by the immune system in
rheumatoid arthritis, but the synovium, or synovial membrane, is generally the primary target.
When the synovial membrane is attacked, it becomes inflamed (synovitis) and can thicken and
erode. As the synovial membrane is destroyed, the synovial fluid fluid is also destroyed because it
is not being secreted. The surrounding structures can also become involved leading to the joint
deformities that can be seen in rheumatoid arthritis.

Fig.1.6: Rheumatoid Arthritis

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 1.8.1 Epidemiology of RA:
 RA affects over 21 million people worldwide.
 There are about 3 million people living with RA in Europe.
 RA affects 3 times as many women as men.
 Obesity..
 It can affect people of all ages but it is most common in the 30-50 age range.
 Previous joint injury.
 Ethnic background

1.8.2 Types of Arthritis:

Based on the causes of arthritis changes, several forms of arthritis can be named. A particular
type of arthritis occurs in a particular age group and in a particular joint.

Table 3: Types of Arthritis

Arthritis Age Group Site

Osteoarthritis Elderly Knee, lower
back,Fingers
Juvenile Childhood Knee, hip
Rhumatoi
d
Arthritis
Septic arthritis Childhood Knee, hip
Rhumatoid arthritis Young adults Hip, Knuckles, Knee
Ankylosing spondylitis Young adults Lower back, Cheast
Psoriatic arthritis Young adults Knee
Traumatic arthritis Any Any (Commonly
knee,
hip, ankle)
Gout Young adults Big toe, knee

1.8.3 Clinical Features:

The stiffness is characteristically worse in the morning and improves during the day; its duration is
a useful indicator of the activity of the disease. The stiffness may recur especially after strenuous
active.
The usual joints affected by rheumatoid arthritis are the metacarpophalangeal joints, the PIP joints,
the wrists, knees, ankles and toes.
Entrapment syndromes may occur especially carpal tunnel syndrome
20% of patients with RA will have subcutaneous nodules, usually seen over bony prominences but
also observed in bursa and tendon sheaths; these nearly always occur in seropositive patients as do
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 most other extra- articular manifestations
 Splenomegaly and lymphadeno-pathy can occur.
 Low grade fever, anorexia, weight loss, fatigue and weakness can occur.
 After months to years, deformities can occur; the most common are Ulnar deviation of the
fingers.
 Swan neck deformity, which is hyperextension of the distal interphageal joint and flexion of the
proximal interphalangeal joint.
 Boutonniere deformity, which is flexion of the distal interphalangeal joint and extension ofthe
proximal intraphalangeal joint valgus deformity of the knee.

1.8.4 Etiology for Arthritis:

There are two main groups of theories’ regarding this disease
1. That it is non-infective in character.
2. That it is infective
The former postulates that the disease can manifest itself in the absence oforganisms that, it is
essentially due to disordered body chemistry. The latter holds that whether tissue changes
resulting from non bacterialcause are present or not, it is essential that organisms be present
locally.
Non infective character falls into three groups
1. Congential predisposition.
2. Endocrine disturbance.
3. Faulty alimentation.

Fig.1.7: Difference between Normal joints and Rheumatoid Arthritis joints

Synovial macrophages and fibroblasts interact to perpetuate inflammation most of our
knowledge of the inflammatory process and cellular infiltrate in the rheumatoid joint comes
from the study of synovium in established, rather than early, disease, CD4 T-cells and

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 monocytes-macrophages migrate into, and remain in the synovial interaction of cellular
adhesion molecules with counterligands expressed on extracellular matrix molecules (e.g.,
collagen, fibronectin). Neutrophils, in contrast, are found almost exclusively in the synovial
cavity (fluid) and only rarely in the synovial tissue. Their migration through the synovial
interstitium and across the synovial lining into the joint cavity may reflect lack of expression of
specific adhesion molecules for extracellular matrix constituents.

Fig.1.8: Pathogenesis of Rheumatoid Arthritis

According to the “T cell centric” theory of RA, activation of CD 4 cells would trigger and
maintain the inflammatory process in the rheumatoid joint Interestingly, although large
numbers of CD4 cells persist in the synovium throughout the disease course, they appear to be
inactive in the chronic phase of the disease. For example, expression of surface antigens (such
as IL2 and transferrin receptors), and secretion of specific cytokines (e.g., IL2, IL4 and g- IFN),
that are associated with an activated T cell state are very low.

Table 4: Cellular sources of synovial cytokines in RA

IL-2

IL-3
IL-4
IL-6
Products of T cells
IFNg

TNFb
GM-CSF

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 In contrast, cytokines known to be produced primarily by “effector” cells (macrophages) and
connective tissue cells (fibroblasts) are expressed in abundance in RNA synovium and synovial
fluid, as measured by ELISA or mRNA studies. These cytokines include IL1, IL6, IL8 and GM
– CSF. According to the alternative theory (the “macrophage –fibroblast theory”) of RA, these
two cell types appear to be largely responsible for creating a self perpetuating state of chronic
inflammation in which T cell participation may no longer be critical. In this scenario, the
activated macrophage continuously secretes IL-1 and TNF which maintain the synovial
fibroblast in an activated state.

Fig.1.9: Synovitis in RA patients

The fibroblast, in turn, secretes large amounts of: a) cytokines – IL6, IL8 and GM-CSF; b)
prostaglandins; c) protease enzymes. GM-CSF feeds back to promote the maturation of newly
recruited monocytes to macrophages.IL-8 and IL-6 contribute to the recruitment and/or
activation of yet other cell populations, while the prostaglandins and proteases act directly to
erode and destroy nearby connective tissues such as bone and cartilage.
1.9 Inflammatory Mediators in RA:
In addition to activating synovial cells to secrete inflammatory mediators, IL-1 and TNF also
Have profound systemic effect

Cellular Systemic
 Upregulation of adhesion molecules  Fever
 Costimulant for T cells  Decreased appetite
 Induction of prostanoid synthesis  Muscle wasting
 Induction of cytokine synthesis (IL-6,
IL-8, GMCSF)

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Table 5: Mediators in RA

Some of these systemic effects are mediated via the induction of IL-6 synthesis. Mature plasma cells that secrete
rheumatoid factor are another prominent cellular component of rheumatoid synovium. The stimulus for
maturation of B cells to immunoglobulin-secreting plasma cells has classically been ascribed to CD4 T cells;
however, as already noted CD4 T cells are not activated in the chronic phase of rheumatoid arthritis. IL-6,
however, is a potent stimulus for maturation of B cells to plasma cells. Thus, synovial fibroblasts are likely
providing the “T cell independent” stimulus for continuous plasma cell activation and rheumatoid factor
production. IL-6 also suppresses albumin synthesis by the liver and stimulates acute phase protein synthesis. IL-
6, therefore, contributes significantly to ESR elevatio

Table 6: Effects of IL-6

Effects of IL-6

B cell maturation Ig, rheumatoid factor ,

hypergammaglobulemia
Hepatocyte stimulus Acute phase proteins (high ESR)
Decreased albumin synthesis

Neutrophils are recruited in very large numbers to the rheumatoid cavity where they can be
aspirated in the synovial fluid. Complement activation is not a prominent feature of RA.
Therefore, C5a is unlikely to contribute significantly to the recruitment of neutrophils to the joint.
IL-8, however, is also a potent and specific chemotactic stimulus for neutrophils. Since synovial
fibroblasts line the Joint cavity, their elaboration of this cytokine into the joint cavity is likely to
explain the selective requirment of neutrophils to the synovial cavity. Neutrophils in the synovial
fluid are in an activated state, releasing oxygen-derived free radicals that depolymerize
hyalurionic acid and inactivate endogenous inhibitors of proteases, thus promoting damage to
the joint. Prostaglandins and proteases are also secreted from synovial

fibroblasts as the pannus invades contiguous bone and cartilage. PGE2 resorbs bone and contributes to
the radiographically demonstrable erosions at the site of synovial bone attachment. The proteases
(collagenase, stromelysin and gelatinase) act enzymatically to degrade the collagen and proteoglycan
matrix of bone and cartilage. This destructive effect is further compounded by IL1 (and TNF ) which
suppresses synthesis of these matrix molecules. Thus, IL1 provides a “double insult” to connective
tissue by both promoting its degradation (by inducing synthesis of proteases) and preventing its repair
(by suppressing synthesis of collagen and proteoglycans).
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 Fig.1.10: Normal view joint
A joint affected by arthritis loses its ability to provide smooth movement between the bones
.this is because of the following changes taking place gradually over a period of time.
 Decrease in the amount of synovial fluid.
 Wear and tear of articular cartilage.
 Thickness and stiffness of synovium.
 Stiffness and of the joint capsule
These changes can occur due to several reasons like ageing, autoimmune disorders (immune
system destroys our own body), genetic disorders, traumatic incident (accident, fall, or blunt
injury), infection, and so on. The arthritic changes are generally permanent and cannot be
reversed after a period of time. Hence, early recognition and treatment is the only way to
prevent more damage.
1.9.1 Symptoms of Rheumatoid Arthritis:
The hallmark symptom of RA is morning stiffness that lasts for at least an hour. (stiffness from
osteoarthritis , for instance , usually clears up within half an hour ).even after remaining
motionless for a few moments , the body can stiffen. Movement becomes easier again after
loosening up.

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 Fig.1.11: Symptoms of RA

1.9.2 Swelling and Pain:

Swelling and pain in the joints must occurs for at least six weeks before a diagnosis of RA is
consider the inflamed joints usually swollen and often feel warm and “boggy” when touched
.The pain often occurs symmetrically but may be more severe on one side of the body ,
depending on which hand the person uses more often(Fig 13).
1.9.3 Specific Joints Affected:
Although RA almost always develops in the wrists and knuckles, the knees and joints of the ball
of the foot are often affected as well .Indeed ,many joints may be involved ,including those in
the cervical spine , shoulders ,elbows, tips , temperomandibular joint (jaw), and even joints
between very small bones in the inner ear . RA does not usually show up in the fingertips,
where osteoarthritis is common, but joints at the base of the fingers are often painful.
1.13.3.1 Nodules:
Nodules can occur throughout the course of the disease. Rarely, nodules may become sore and
infected, particularly if they are in locations where stress occurs, such as the ankles. On rare
occasions, nodules can reflect the presence of rheumatoid vasculitis, a condition that can affect
blood vessels in the lungs, kidneys, or other organs.
1.13.3.2 Fluid Buildup:
Fluid may accumulate, particularly in the ankles. In the joint sac behind the knee accumulates
fluid and forms what is known as a Baker cyst. This cyst feels like a tumor and sometimes
extends down the back of the calf causing pain. Baker cysts often develop in people who do not
have RA.
1.13.3.3 Flu-Like Symptoms:

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Symptoms such as fatigue, weight loss, and fever may accompany early RA, some people
describe them as being similar to those of a cold or flu except, of course, RA symptoms can lastfor
years.

1.13.3.4 Symptoms in Children:

In children, juvenile RA, also known as still’s disease, is usually preceded by high fever and
shaking chills along with pain and swelling in many joints. A pink skin rash may be present
.
1.13.3.5 Medications:

Fig.1.12: Medication of RA

Many drugs used to treat rheumatoid arthritis have potentially serious side effects. Doctors
typically prescribe medications with the fewest side effects first. You may need stronger drugs
or a combination of drugs as your disease progresses.
1.13.3.5.1 NSAIDS:
Enolic acid (Oxicam) Derivatives:
 Piroxicam.
 Meloxicam.
 Tenoxicam.
 Droxicam.
 Lornoxicam.
 Isoxicam.

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 1.13.3.5.2 Mechanism of Action:

By inhibiting fatty acid COX enzyme, trolamine salicylate inhibits the production of
prostaglandins and thromboxanes in inflammatory cells involved in generating pain and
inflammation.

1.10 Inflammation:
Inflammation (Latin, inflammo, "I ignite, set alight") is part of the complex biological response
of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants
(Fig.15).Inflammation is a protective attempt by the organism to remove the injurious stimuli
and to initiate the healing process. Inflammation is not a synonym for infection, even in cases
where inflammation is caused by infection. Although infection is caused by a microorganism,
inflammation is one of the responses of the organism to the pathogen. However, inflammation
is a stereotyped response, and therefore it is considered as a mechanism of innate immunity, as
compared to adaptive immunity, which is specific for each pathogen.

Fig.1.13: Inflammation
1.10.1 Classification of Inflammation:
Inflammation can be classified as either acute or chronic. Acute inflammation is the initial
response of the body to harmful stimuli and is achieved by the increased movement of plasma
and leukocytes (especially granulocytes ) from the blood into the injured tissues. A cascade of
biochemical events propagates and matures the inflammatory response, involving the local
vascular system, the immune system, and various cells within the injured tissue. Prolonged
inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells
present at the site of inflammation and is characterized by simultaneous destruction and
healing of the tissue from the inflammatory process.

1.10.2 Symptoms of Inflammation:

 Redness.

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  Swollen joint that's tender and warm to the touch..

 Joint pain.
 Joint stiffness.
 Loss of joint function

Fig.1.14: Mechanism of Inlammation

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 1.11 Anti- inflammatory Effects:
Many mediators coordinate inflammatory and allergic reaction. While some are produced in
response to specific stimuli (e.g. Histamine in allergic inflammation) there is considerable
redundancy, and each facet of response – vasodilatation, increased vascular permeability, cell
accumulation, etc-can be produced by several separate mechanisms. The NSAIDS reduce
mainly those component of the inflammatory and immune response in which prostaglandin,
mainly derived from COX -2, play a significant part .These include:
 Vasodilatation.
 Oedema (by an indirect action; the vasodilatation facilities and potentiating the action
of mediators such as histamine that increase the permeability of postcapillary venules.
 Pain again potentiating other mediators, such as bradykinin.
The NSAIDs suppress the pain, swelling and increasing blood flow associated with
inflammation but have little or no action on the actual progress of the underlying chronic
disease itself. As a class, they are generally without effect on other aspects of inflammation,
such as leucocytes migration, lysosomal enzyme release and toxic oxygen radical production
that contribute to tissue damage in chronic inflammatory conditions such as rheumatoid
arthritis, vasculitis and nephritis.

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 Chapter.2 Review of Literature
Sharma P et. al., 2022 Microemulgel formulations of TMS were prepared from optimized
Microemulgel and effects of formulation variables such as solubility in different oils, surfactants
and co-surfactants were assessed. Oleic acid was selected as oil phase, tween-80, and ethanol as
surfactant and cosurfactant, respectively. From the ternary phase diagrams of surfactant (Tween
80)/cosurfactant (Ethanol) 1:1 ratio and oil (oleic acid), TMS-loaded Microemulgel formulation
A6* was selected on the basis of clarity. Microemulsion has low interfacial tension and allows
excellent contact with skin surface, with the vehicle filling even wrinkles and microscopic gaps.
This enhances the vehicle skin drug transfer. They have been used to improve the bioavailability
of various poorly soluble drugs including non-steroidal anti-inflammatory drugs. The
formulation was in nano range and hence the penetrability of the drug can be increased. Since
this type of formulations can be easily developed and prepared; therefore, they can be of great
help for the drugs that have less permeation across the skin. Among the distinctive formulations,
A6* showed promising results, with respect to drug entrapment and percentage drug release.

Nagoba Shivappan N. et. al., 2021 The aim of the present investigation is to develop and
evaluate Terbinafine hydrochloride microemulgel. Terbinafine hydrochloride is FDA approved
antifungal drug for treatment of topical fungal infection. It is a BCS class II drug; has poor
bioavailability. Now, microemulgel has developed as one of the most interesting topical
preparation in the field of pharmaceutical sciences. Microemulgel as a delivery system is
advantageous to use such as ease of administration, increased residence time at applied site,
steady drug release with improved bioavailability, better thermodynamic stability and high
transdermal permeability over simple conventional formulations. The microemulgel of
Terbinafine hydrochloride were prepared, using carbopol 940 and HPMC as a gelling agent,
oleic acid as oil, parabens as preservative, tween 20 as emulgent and penetration enhancer. The
prepared microemulgel formulation was inspected visually for appearance, spreadability,
homogeneity, viscosity, pH, % drug content and In vitro diffusion studies. Results obtained has
proved that development of terbinafine hydrochloride containing microemulgel will be more
effective however its clinical efficacy must be understood using clinical trials.

Aundhia C et. al., 2020 Naproxen is a non-steroidal anti-inflammatory drug (NSAID) of the
propionic acid class and is commonly used for relief of a wide variety of pain, fever, swelling
and stiffness caused by conditions including migraine, osteoarthritis, kidney stones,
rheumatoid arthritis, psoriatic arthritis, gout, ankylosing spondylitis, menstrual cramps,
tendinitis, and bursitis, among others. For the development of Naproxen loaded Microemulgel,
pseudoternary phase diagrams were prepared by using Capmul MCM as oil phase, Tween 20
as surfactant, PEG 400 as co-surfactant and water as aqueous phase. Different batches of
Naproxen loaded Microemulgel were prepared by phase titration method by using different
concentration of oil, Smix and water. The optimized batch was selected on basis of parameters
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 like % transmittance, dilution, clarity and centrifugation. F9 batch was selected as optimized
batch. Optimized batch was characterized for various tests like globule size, zeta
potential,viscosity, pH, drug content and conductivity and their results were found to be
100.2nm, - 14.0mV, 469.9 cP, 6, 93.33% and 0.65 μS respectively. The gel was prepared by
dispersing different concentration of carbopol934 in distilled water by continuous stirring
and the pH was adjusted to 5.5 to 6.5 using Triethanolamine (TEA). The optimized batch
contained 3% carbopol934. Optimized Microemulgel gel was characterized for various tests
like viscosity, pH, spreadability, drug content and the results were found to be 41897 cP, 6.5,
uniform and better and 97.86% respectively. From the In-vitro diffusion study, percent
cumulative drug release after 24 hours was found to be 97.645%. from the Ex-vivo
permeation study percent cumulative drug release after 24 hours was found to be 94.51%.
Stability of Microemulgel were carried at room temperature (25 ± 2 ˚C and %RH 65 ± 2)
and refrigerated temperature (2-8 ˚C) for three months. Stability study of Microemulgel was
carried out on the basis of various parameters like %transmittance, pH, drug content and
centrifugation.

Changmai A et. al., 2019 Microemulgel are one of the potential and emerging drug carrier
systems that helps to improve drug release and enhance the bioavailability of poorly aqueous
soluble drugs. This study was designed to formulate and evaluate Microemulgel containing clove
oil and peppermint oil. Microemulgel was prepared using tween 80 as a surfactant and ethanol as
a co - surfactant. The Microemulgel formulation characterized for its particle size, viscosity,
conductivity, pH, zeta potential and stability. The mean droplet size of clove oil and peppermint
oil Microemulgel was found in the range of 11-96nm and 11-68nm. The viscosity of the prepared
Microemulgel were found to be low. In the stability study there are no phase separation occur
after centrifuged at 3000 RPM for 30 min and even after stored for 30 days.
Bodhe A et. al., 2018 In the present study a satisfactory attempt was made to formulate a novel
o/w Microemulgel of ramipril which improves the gastrointestinal absorption by raising its water
solubility and hence oral bioavailability is also enhanced.
Shrestha S et. al., 2017 The aim of the present study was to investigate the potential of a micro-
emulgel formulation for topical delivery of Terbinafine. Terbinafine showed highest solubility in
propylene glycol among the available oil phase. Tween 80 and polyethylene glycol 400 were
used as surfactant and co-surfactant respectively. Using pseudo-ternary phase diagram 1:2 ratio
of surfactant: co-surfactant was selected. Using Central Composite Design thirteen formulations
with varying ranges of Smix and oil phase were prepared. Final formulation was selected on the
basis of transmittance. From optimization plot it was concluded that 27.93% of Smix and 6.51%
of oil phase gave maximum transmittance. Then, optimized formulation was used to prepare
final microemulgel of terbinafine. Thirteen gel formulation from varying concentration of
carbopol 934 and hydroxypropylmethyl cellulose was prepared and evaluated for extrudability,
spread ability, drug content, in-vitro drug release, rheological study and invitro antifungal
activity against Teniapedis. Formulations with suitable consistencies were selected and
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 optimization was done on the basis of drug release and ex-vivo permeation study in goat skin.
Formulation with 0.45gm of carbopol 934 and 0.3gm of HPMC showed better drug release and
skin permeation than other formulations. This formulation was further compared with marketed
terbinafine ointment and was found to give enhanced drug release and permeation.

Thakur S et. al., 2016 Arthritis is the condition which is associated with inflammation of
a joint, pain, swelling, and stiffness. Drug delivery to the target site remains a challenge
due to ineffective drug delivery system. An attempt has been made to formulate and
evaluate micro-emulgel for the effective drug delivery in the treatment of Arthritis. Micro-
emulgel was loaded with Curcumin and Tinospora cordifolia to enhance bioavailability of
extracts which have been widely used in the treatment of arthritis. Micro-emulgel was prepared
by emulsion-solvent diffusion method using carbopol 940P as a gelling agent. Micro-emulsion
was formulated using Liquid paraffin oil as oil phase; Tween 80 and Span 20 as surfactant and
co-surfactant respectively. FTIR studies proved the compatibility between drug, excipient and
carbopol. The Prepared micro-emulgel was subjected to various parameters such as pH,
rheological studies, spreadability, thermodynamic stability tests, drug content, electro
conductivity, and in-vitro release studies. The pH of all formulations was found near to the
skin pH value. Viscosity and spreadability of F1 optimized formulation was found to be
146.5×103cPs and 2.24 g×cm. From the in vitro drug release study, it was revealed that sustained
release of formulation last up to 18 hours. F1 formulation showed the highest drug release of
Curcumin (92.37%) and Tinospora cordifolia(90.75%). SEM image showed the diameter of oil
globules of Micro-emulgel were in range of 1.50 to 2.13μm. Drug release kinetics showed the
zero order drug release from the optimized F1 formulation. From the stability studies, F1
formulations had an excellent physical stability.

Neslihan U.O et. al., 2015 Naproxen (Np) is an example of a non-steroidal anti-inflammatory
drug (NSAID) commonly used for the reduction of pain and inflammation. In order to develop
an alternative formulation for the topical administration of Np, Microemulgel were evaluated as
delivery vehicles. Four formulations were prepared using isopropyl myristate (IPM) as oil phase,
Span 80, Labrafil M, Labrasol, Cremophor EL as surfactants, ethanol as co-surfactant and
distilled water or 0.5 N NaOH solution as aqueous phase. The final concentration of Np in the
Microemulgel system was 100 mg/g (w/w). The physicochemical properties such as electrical
conductivity, droplet size, viscosity, pH and phase inversion temperature of Microemulgel were
measured. Stability tests of the formulations were also performed at 5±2, 25±2 and 40±2°C. The
abilities of various Microemulgel and selected commercial (C) formulation to deliver Np through
the skin were evaluated in vitro using diffusion cells fitted with rat skins. The in vitro permeation
data showed that Microemulgel increased the permeation rate of Np between 4.335–9.040 times
over the C formulation. Furthermore Np successfully permeated across the skin from the
Microemulgel with the highest flux rate (1.347±0.005 mg·cm−2 ·h−1 ) from a formulation
(M4Np) consisting of IPM (2.36 g), Labrosol (0.13 g), Span 80 (0.62 g), ethanol (5.23 g), 0.5 N
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 NaOH solution (0.66 g) and Np (1 g). According to the histological investigations, no obvious
skin irritation was observed for the studied Microemulgel. These results indicate that the
Microemulgel formulation may be appropriate vehicles for the topical delivery of Np.
Vidya Sabale and Sejal Vora 2014 The mechanism of drug release from Microemulgel -based
hydrogel was observed to follow zero order kinetics. The studied optimized Microemulgel –
based hydrogel showed a good stability over the period of 3 months. Average globule size of
optimized Microemulgel (F5) was found to be 18.98 nm, zeta potential was found to be -5.56
mv, and permeability of drug from Microemulgel within 8 h was observed 84%. The antifungal
activity of Microemulgel -based hydrogel was found to be comparable with marketed cream.
Conclusion: The results indicate that the studied Microemulgel -based hydrogel (F5) has a
potential for sustained action of drug release and it may act as promising vehicle for topical
delivery of ibuprofen.
Jadupati et al., 2013 developed the Insulin-loaded Microemulgel for transdermal delivery
using isopropyl myristate or oleic acid as the oil phase, Tween 80 as the surfactant, and
isopropyl alcohol as the co-surfactant. The insulin permeation flux of Microemulgel
containing oleic acid through excised mouse skin and goat skin was comparatively greater
than that of Microemulgel containing isopropyl myristate. The insulin-loaded Microemulgel
containing 10% oleic acid, 38% aqueous phase, and 50% surfactant phase with 2% dimethyl
sulfoxide (DMSO) as permeation enhancer showed maximum permeation flux (4.93 ± 0.12
g/cm2/hour) through goat skin. The in vitro insulin permeation from these Microemulgel was
found to follow Zero order and the Korsmeyer-Peppas model (R2 = 0.923 to 0.973) over a
period of 24 hours.
Bhavika et al., 2012 developed a Microemulgel for enhancing the permeation of acyclovir
using different penetration enhancer like DMSO, Menthol, and Eucalyptus oil. They
concluded that 1% menthol incorporated as a penetration enhancer and it showed 10%
increase in permeation rate of drug. The Microemulgel system was investigated for viscosity,
pH, refractive index, electrical conductivity, and permeation. The optimum formulation
provided 76% drug release in 12 hr.
Xiaohui et al., 2011 studied the microstructure characterization of Microemulgel consisting of
oleic acid, cremophor RH40, ethanol and water and investigate the influence of microstructure
on the solubilization potential of the Microemulgel to meloxicam. They concluded that the
solubilization capacity of Microemulgel is closely related with its microstructure. The
solubilization of W/O Microemulgel is the best, compared with other two (O/W, Bi
continuous), where as the O/W is the weakest.
Ying et al., 2011 investigated a Microemulgel system for transdermal delivery of ligustrazine
phosphate. Microemulgel containing isopropyl myristate, labrasol, plurol oleique® and water
were investigated in pseudo-ternary phase diagrams. The optimized Microemulgel with
permeation flux of 41.01 µg/cm 2/h across rat skin in vitro, showed no obvious irritation on
back skin of rabbits. The results indicated that the studied Microemulgel system might be a

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 promising vehicle for transdermal delivery of ligustrazine phosphate.
Manish et al., 2010 formulated Glipizide Microemulgel by water titration method using oleic
acid as oil phase, tween-80 as surfactant and propylene glycol as co-surfactant. Microemulgel
were characterized for pH, viscosity, droplet size, in vitro release profile, ex-vivo diffusion

study, irritancy tests, stability and in vivo evaluation. Five Microemulgel formulations were
prepared. Oleic acid is used as oil phase in 2, 4, 6, 8, 10% concentration of formulation
content and then 6% (ME-3) obtained in clear form and have higher cumulative per]]\cent
release than others. Non–ionic surfactant Tween-80 was selected because they are generally
less toxic, produce less skin irritation. In vivo studies were carried out on wistar rats. The
optimized Microemulgel formulation was found to be o/w type emulsion and having mean
particle size of 138±4.5 nm. The results indicated that the developed Microemulgel systems,
especially ME-3, may be promising vehicles for the transdermal delivery of glipizide.
Brajesh et al., 2010 developed o/w Microemulgel for transdermal delivery of poorly water
soluble acyclovir by aqueous titration method. Characterization of Microemulgel were done
for droplet Shape and size, refractive index, pH, Viscosity, drug loading capacity. Oleic acid is
a model skin permeation enhancer for transdermal drug carrier and poorly water soluble drug.
The mean droplet size of Microemulgel was found below 50 nm. The surface morphology of
Microemulgel was evaluated by TEM. They concluded that The drug loaded Microemulgel
oily phase droplets shapes were found to be spherical, the range of 41.91 to 52.79 nm. The
viscosity values of all samples were low and relatively constant at 33.28 to 41.01 mP. All
samples exhibited Newtonian flow behaviour, as expected from Microemulgel.
Kalra et al., 2010 developed aceclofenac Microemulgel formulations to increase the effect,
controlled permeation, increased drug solubilization capacity and to minimize oral side effects
of drug. Investigated the potential of Microemulgel gel formulation using nonirritating and
pharmaceutically acceptable ingredients without using additional harmful permeation
enhancers. Permeation rate of aceclofenac evaluated by Keshary Chein diffusion cell which
confirmed that drug can easily permeate through the skin due to small particle size of
Microemulgel. In vivo studies of drug molecule was done by anti- inflammatory (Acute)
model and FCA (Chronic) model which indicated that effect of drug was enhanced by
prepared Microemulsion and Microemulsion gel.
Anjali CH et al., 2010 investigated the antibacterial activity of refined Sunflower oil, Tween
20, water Microemulgel system. Pseudo‐ternary phase diagram were constructed to obtain the
concentration range of oil, surfactant and water. Three Microemulsion formulations were
prepared. The concentration of refined sunflower oil varied from 5 % to 15 %, the surfactant
concentration varied from 10 % to 30 % and water concentration varied from 55 % to 85 %.
When water concentration increased, conductivity of the Microemulgel system increased upto
50 % of water concentration and after that become stable. When oil and surfactant
concentration was increased, pH of the Microemulsion system decreased.

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 Mrunali et al., 2010 investigated the effect of vehicle on in vitro skin permeation of
ketoconazole applied in o/w Microemulgel. The optimized Microemulgel formulation showed
a highest permeation rate of 63.28 ± 4.93 µg cm 2 h. Candida Albicans were used as a model
fungus to evaluate the antifungal activity of the best formula achieved. These results indicate
that the studied Microemulgel formulation might be a promising vehicle for future topical
delivery of KTZ.
Fathy et al., 2010 determined the in vitro release of piroxicam in Microemulsion formulations
in different gel bases, such as, methyl cellulose (MC), carboxy methyl cellulose (CMC),
hydroxypropyl methyl cellulose (HPMC), Carbopol 934, Carbopol 940, and Pluronic F-127
bases. The drug content of piroxicam, pH and viscosity was measured. The results showed
that, the incorporation of piroxicam in microemulsion formulas could lead to enhancement of
piroxicam release profiles by allowing constant and regular in vitro release. Three percent MC
gel base showed the highest release of piroxicam- microemulsion after 180 min (97.70%)
followed by 3% HPMC (94.0%) when compared to bases containing piroxicam alone.
Rohit et al., 2009 Prepared Five different Fluconozole formulations with various values of oil
(5 – 25%), water (10 – 50%), and the mixture of surfactant and co-surfactant (at the ratio of 4)
(45 – 65%). In-vitro permeation of fluconazole from the microemulsions was evaluated using
Keshary Chien diffusion cells mounted with 0.45µ cellulose acetate membrane. The amount
of drug permeated across was analyzed by HPLC and the droplet size and zeta potential of the
microemulsions was characterized. The globule size ranged between 122 - 418nm. The
permeability of optimised microemulsion formulation was increased approximately five folds
than that of the marketed formulation. The results indicated that the microemulsion system
studied would be a promising tool for enhancing the percutaneous delivery of fluconazole

Mostafa et al., 2008 were formulated fluoxetine hydrochloride as a microemulsion form for
transdermal delivery using various ratio of surfactant. Characterization of selected MEs was
achieved by pH determination, centrifugation, particle size and viscosity measurements,
determination of refractive index and morphology studies using TEM. Five ME formulation
were prepared and Selected ME3 was tested for its ability to penetrate through rat skin. ME3
exhibited an optimum composition with regard to stability, pH value, viscosity, and droplet
size and permeation rate for effective in-vitro delivery across an artificial cellulose membrane;
it also exhibited good penetration ability through rat skin confirming its feasibility as a
transdermal delivery system for fluoxetine hydrochloride
Gamal et al., 2008 self microemulsifying and microemulsion systems for transdermal
delivery of Indomethacin: Effect of phase transition was studied by in their study they
investigated five formulations with fixed surfactant-oil ratio and increasing water content.
They concluded that these formulation increased the transdermal drug flux compared to
saturated drug solution in Phosphate buffered saline.

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 Ke-Shu et al., 2007 evaluated the transdermal permeability of pentoxifylline gel in vitro and
in vivo. Gel was prepared with carbomer 934 as the base, and the Wistar rat was chosen as an
animal model. The effects of percutaneous enhancers on the transdermal permeability of
pentoxifylline gel were investigated by in vitro permeation experiments. Cumulative
permeation at different times was determined by HPLC. 3% Azone and 5% propylene glycol
were used as collaborative enhancers in an optimal formulation. Topical concentrations at
different times were measured by microdialysis in vivo. The transdermal process of
pentoxifylline fits to a zero-order kinetic equation, and its release profile remains of the zero-
order despite the addition of enhancers. In addition, a good in-vitro-in-vivo correlation was
achieved.

Anna et al., 2006 formulated a microemulsions as transdermal drug delivery vehicles by

using oleic acid as permeation enhancers, L–phosphatidylcholine from egg yolk. Thus they
concluded microemulsion were found as an effective vehicle of the solubilization of certain
drugs and as protecting medium for the entrapped of drugs from degradation, hydrolysis and
oxidation.It can provide prolonged release of the drug and prevent irritation.
Gupta et al., 2005 designed and Testing of an effective oil-in-water microemulsion drug
delivery system. They studied the new pseudoternary system of clove oil/Tween 20. Quarcetin
drug was encapsulated in the vehicle and the hepatotoxicity of the vehicle with and without
the drug was studied by estimating serum alkaline phosphates, glutamate pyruvate
transaminase, urea and creatinine.
Haubing et al., 2004 studied microemulsion systems for transdermal delivery of triptolide
posessesing immunosuppressive, anti-fertility and anti cancer activities. They formulated the
microemulsion using oleic acid as oil phase, tween 80 as surfactant and propylene glycol as a
cosurfactant. After the chacterization of the formulated microemulsion they concluded that
this microemulsion is a promising vehicle for the transdermal delivery of triptolide.
Mohammed et al., 2000 investicated the aerosol-OT (AOT)/water/isopropyl myristate
microemulsion were investigated as a carrier in transdermal drug delivery of tetracaine
hydrochloride. Studied in vivo analgesic on rats and histopathological, irritation, and oxidative
stress measurements on mice. The tetracaine hydrochloride encapsulated in
AOT/water/isopropyl myristate showed an eightfold enhancement in the analgesic response of
drug compared to the aqueous solution of the drug as measured by the tail-flick method. The
local analgesic response time of tetracaine HCl was dependent on the composition of the
microemulsion. The local analgesic responses of tetracaine hydrochloride increased as the
weight percentage of AOT and water increased up to a certain concentration in the
Microemulsion.

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 Chapter.3 Drug and Excipients Profile

3.1 Trolamine Salicylate:

Source: Synthetic
Therapeutic Category: arthritis, backache, sprains.
Chemical Name: 2-Hydroxy-N, N-bis(2-hydroxyethyl)ethan-1-aminium 2-hydroxybenzoate.
Chemical Formula: C13H21NO6.
Molecular Structure:

Fig.3.1: M.S of Trolamine Salicylate

Physical and Chemical Properties:
Appearance: Beige crystals or lumps.
M.W: 287.312g/mol
Colour: Pale reddish.
Purity: 99.9%.
Solubility: In water & PG soluble
M.P: 50°C
Taste: Bitter.
Shape: Elliptical
MOA:

Trolamine salicylate is a salicylate that inhibits cyclo-oxygenase (COX) enzymes responsible for
generating pro-inflammatory factors such as to induce pain and inflammation. It is thought to
mediate its analgesic effect through inhibition of COX-2 enzyme, which is an induced enzyme
responsible for inflammatory responses and pain in muscle and joint disorders. By inhibiting
fatty acid COX enzyme, trolamine salicylate inhibits the production of prostaglandins and
thromboxanes in inflammatory cells involved in generating pain and inflammation 5. It thereby
works to temporarily reduce mild to moderate pain.

Side Effects:

 blistering/peeling/redness/irritation at the application site, ringing in the ears.

 Dizziness.

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  Nausea.
 Vomiting.
 Skin Rash.
 Redness of the Skin.

Uses:

 It is a medication used to relieve minor aches and pains of the muscles and joints.

Pharmacokinetic:

Absorption:
Following topical administration of 10% trolamine salicylate in healthy volunteers, salicylic acid
could not be detected in serum indicating low systemic absorption 3.

Volume of Distribution:

Topical administration of 1 gram of 10% trolamine salicylate in abdominal rat skin resulted in an
approximate extravascular volume of distribution (V/F) of 24.0 mL.

Route of Elimination:

Topical administration of 10% trolamine salicylate in healthy volunteers, urinary recovery of

total salicylate during the first 24 hours was 6.9 mg (p < 0.05), which is 1.4% of total dose

Density: 1.3±.1g/cm3.

Storage: Room Temp.

Indication:
Indicated for the temporary relief of aches, and pains of muscles and joints associated with
backache, lumbago, strains, bruises, sprains and arthritic or rheumatic pain, pain of tendons and
ligaments [74-77].

3.2 Polymers Profile:

3.2.1 Propylene Glycol:

Synonyms: α-propylene, glycol, 1, 2-propanediol.

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 Molecular Structure:

Fig.3.2: M.S of Propylene Glycol

Molecular Formula: C3H5o2.

Chemical Name: Propane-1, 2-diol.

Nonproprietary Names (BP): Propylene glycol.

M.W: 76.09g/mol.

Funtional Category: Antimicrobial Preservative; Disinfectant; Humectants.

Description:

 A clear and Colorless.

 Viscous & Practically odorless.
 Sweet, Slightly acrid taste.
 Resembling Glycerol.

Typical Properties:

B.P: 188°C.

Flash Point: 99°C.

Freezing Point: -59°C.

Surface Tension: 40.1 dyne/ cm at 25°C.

Density: 1.038 g/cm3 at 20°C.

Specific Heat: 2.47 J/g (0.590 cal/g) at 20°C.

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 Solubility: Miscible with acetone, chloroform, ethanol (95%), glycerin & H2O;

Safety:

Propylene glycol is used in a wide variety of pharmaceutical formulations and is generally

regarded as a relatively nontoxic material.

Stability & Storage Conditions:

At cool temperatures, propylene glycol is stable in a well-closed container, but at high

temperatures, in the open, it tends to oxidize, giving rise to products.

Applications:

 Propylene glycol has become widely used as a solvent, extractant, and preservative in a
variety of parenteral and nonparenteral formulations.
 It is a better general solvent than glycerin and dissolves a wide variety of meterials, such
as corticosteroids, phenols, Sulfa drugs, barbiturates, Vitamins (A and D), most alkaloids,
and many local anesthetics.
 As an antiseptic it is similar to ethanol, and against molds it is similar to glycerin and
only slightly less effective than ethanol.

3.2.2 Sodium Methyl Paraben:

Synonym: Sodium 4-(methoxycarbonyl) phenolate Sodium methylparaben Methyl 4-

hydroxybenzoate.

M.F: C8H8O3Na.

Molecular Structure:

Fig.3.4 Molecular Structure of Na-Methyl Paraben M.W: 152.15 g/mol.

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 Description:

 Almost Odorless.
 Small Colorless crystals or white crystalline powder.
 It is a Slight burning taste.

Solubility: Soluble in Methanol, Propylene Glycol and CCl4.

Stability: Under recommended storage conditions.

Melting Point: 125°C.

Boiling Point: 270.5 °C

Incompatibility: It is combustible and reacts vigorously with oxidizing agent.

Storage: Stored in closed container and dry place.

Log P: 1.96

Application:

 Preservative used in the food, cosmetic, and pharmaceutical industries.

3.2.3 Tween-20:
Synonyms: Armotan PML 20, Tween 20.
Chemical Structure:

Fig.3.5: Molecular Structure of Tween-20

Chemical Name: Polyoxyethylene 20 sorbitan monolaurate.
Non-Proprietary Name: Polysorbate 20.
Molecular Formulae: C58H114O26.
M.W: 1128g/mol.
Functional Category: Nonionic surfactant; suspending Agent; Wetting Agent.

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 Description:
Colour: Yellow oily liquid at 250C.
Odour & Taste: Polysorbates have a characteristic.

Applications:

 Polysorbates containing 20 units of oxyethylene are hydrophilic nonionic surfactants

that are used widely as emulsifying agents in the preparation of stable oil-in-water
pharmaceutical emulsions.
 Used as a solubilizing agents for a variety of substances including essential oils and oil-
soluble vitamins.
 Wetting agents in the formulation of oral and parenteral suspensions.

Typical Properties:
Acid Value: 2.0%.
Specific Gravity: 1.1 at 25°C
Viscosity: 400 mPas.
Surface Tension: 34.7(mN/m) at 20°C.
Incompatibilities:
Discoloration & precipitation occur with various substances, especially pheno ls, tannins,
tars, and tarlike materials.
Stability & Storage Conditions:
 Polysorbates are stable to electrolytes and weak acids and bases; gradual
saponification occurs with strong acids and bases.
 Polysorbates should be stored in a well-closed container, protected from light, in a
cool, dry [79].

3.2.4 Carbopol-940:
Synonyms: 2-Propenoic acid Homopolymer, Acrylic acid Homopolymer.
Molecular Structure:

Fig.3.6: Molecular Structure of Carbopol-940

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 Molecular Formula: C18H34O2.
Chemical name: 2-octanoyloxypropyl Octanoate.
Non Proprietary Name BP, USP: Oleic acid.
Molecular Weight: 713.1g/mol.
Functional Category:
Polymer is an efficient Carbomer thickener at high viscosity and forms sparkling, clear, water or
hydro-alcoholic gels

Description:

 It is a white powder, Crosslinked Polyacrylic acid polymer.

 It is an extremely efficient rheology modifier capable of providing high viscosity and
forms sparkling clear gels or hydro-alcoholic gels and creams.
Solubility: Soluble in water; after neutralization, they are soluble in 95% ethanol & glycerin.
Viscosity: 6.19mPas.
Specific Properties:
M.P: 116 °C.
Flash point: 130°F.
Moisture Content: 0.05 to 0.1 wt. %.
Surface tension: 24.3dynes/cm at 20°C.
Pharmaceutical Application:

 Carbopol 940 is often used as a gelling agent in gel preparations.

 Concentration of Carbopol 940 as a gelling agent needs to be concerned to obtain a good
gel preparation.
 This study aimed to determine the effect of Carbopol 940 concentration on physical
properties, drug release and the use in eye drops.
 The research method used was descriptive method with data collection technique using
PICO (Population, Intervention, Compare, Outcame) approach.
 Based on the Descriptive research results, it was obtained that carbopol 940 had
influences on the physical properties of the gel in the form of pH, viscosity, spreadability,
adhesion, organoleptic and stability.
 Carbopol 940 is commonly used in controlled-release drug formulations.
 In addition, carbopol 940 is also safe to use in eye drops preparations which do not cause
irritation in in vivo testing.

Stability & Storage:

It should be stored in a cool, dry place in a small, well-filled, well-closed container, protected
from light.

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 3.2.5 Oleic acid:
Nonproprietary Names:

Synonyms: (9Z)-Octadecenoic acid (Z)-Octadec-9-enoic acid cis-9-Octadecenoic acid cis-Δ9-

Octadecenoic acid 18:1 cis-9.
CAS Registry Number: 90-76-3.
Empirical Formula: CH 3 (CH 2) 7CH=CH−(CH 2) 7−COOH.
Molecular Weight: 282.47g/mol.
B.P: 360°C

Description:

Oleic acid is a mono-unsaturated omega-9 fatty acid found in various animal and vegetable
sources. Triglyceride esters of oleic acid comprise the majority of olive oil. Oleic acid is used as
an excipient in pharmaceuticals and as an emulsifying or solubilizing agent in aerosol products.
Melting point: 13-14°C
Acidity/alkalinity: pH= 9.1
Solubility: Soluble in ethanol (>25 mg/ml), ether, acetone, chloroform, DMF.
Density: 1.352g/cm3
Stability:

leic acid presented a low thermal stability basically due to autoxidation at high temperature, even
under inert conditions, possibly because of endogenous peroxides.

Storage Conditions: It should be stored in a well-closed jar.

Incompatibilities:

In the existence of non-ionic surfactants, such as polysorbate 80, the antimicrobial activity of
methylparaben and other parabens is considerably decreased as a consequence of micellisation.
Safety: Preservatives as in cosmetics and oral and topical pharmaceutical formations.
Handling Precautions:
Take off immediately all contaminated clothing. Rinse skin with water/ shower.

3.2.6 Liquid Paraffin:

Synonyms: Paraffinum liquidum, mineral oil, paraffinum perliquidum, paraffinum subliquidum.

Chemical or General Formula: C2H2n+2
Functional Category:
Liquid paraffin is used as hydrating agent in various formulations such as hair shampoo and
ointments to lock moisture into formulation.
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 Description:
Liquid paraffin all is a mineral oil that is a byproduct of the distillation of petroleum.
Boiling Point: 280-3500C.
Viscosity: 7.5-100.0 cSt at 400C
Refractive Index: 1.476.
Solubility: Practically insoluble, but soluble in organic solvents, ethanol (95percent), Glycerin
and water Miscible, except fie castor oil, will volatile oils and with fixed oil.
Density: 0.877

Stability and Storage Conditions:

Responsible for oxidation during storage and light exposure, and stored in a cold, dry spot.
Incompatibilities:
Keep away from oxidizing agents and from highly acidic or alkaline materials.
Method of Manufacture:
Through distillation of petroleum, M ineral oil is attained first, Distillation Cradicate the
Hydrocarbon having lighter property and then redistillates the residue abut 330-390℃.
Safety:
In a large range of pharmaceutical formulations, mineral oil is utilized as Excipients mineral oil
has been used therapeutically in constipation treatment since. When taken orally. It utilized to
stool softening and as lubricants.
Handling Precautions:
Pay attention to standard measures necessary to the conditions and quantity of material treated.
Regulatory Status:
Identified by GRAS Accepted or approved in the Unital Kingdom for usage in some applications
for foodstuffs Encompassed in the FDA Database of Inactive ingredients.

3.2.7 Benzyl Alcohol:

Synonyms: Hydroxytoluol, Phenylcarbinol and Phenyl methanol.

Molecular Structure:

Fig.3.7: Molecular Structure of Benzyl Alcohol

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 Molecular Formula: C18H34O2.
Chemical name: Phenyl methanol.
Molecular Weight: 108.14g/mol.
Functional Category:

Benzyl alcohol is used as a general solvent for inks, waxes, shellacs, lacquers, and epoxy resin
coatings.
Description:

 It is a colorless liquid with a mild pleasant aromatic odor.

 It is a useful solvent due to its polarity, low toxicity, and low vapor pressure.
Solubility: It has moderate solubility in water (4 g/100 mL) and is miscible in alcohols and
diethyl ether.

Pharmacopeial Specifications:
Specific gravity: 1.045.
Viscosity: 5.474cPas.
Specific Properties:
M.P: -15°C.
Flash point: 93°C.
Surface tension: 72.8 dynes/cm.
Pharmaceutical Application:

 Benzyl Alcohol is an aromatic alcohol used in a wide variety of cosmetic formulations as

a fragrance component, preservative, solvent, and viscosity-decreasing agent.
 Benzoic Acid is an aromatic acid used in a wide variety of cosmetics as a pH adjuster and
preservative.

Stability & Storage:

It should be stored in a cool, dry place in a small, well-filled, well-closed container, protected
from light

3.2.8 Triethanolamine:
Synonyms: Trolamine.
Molecular Structure:

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 Fig.3.8: Molecular Structure of TRiethanolamine

Molecular Formula: C6H15NO3.

Chemical name: 2-[bis (2-hydroxyethyl) amino] ethanol.
Molecular Weight: 149.188g/mol.
Functional Category:
Triethanolamine is used primarily in making surfactants, such as for emulsifier.

Description:
 It Hygroscopic crystals, or colourless, viscous liquid with a mild.

Solubility:
It has moderate solubility in with water, methanol, acetone; soluble in benzene.
Pharmacopeial Specifications:
Specific gravity: 1.045.
Viscosity: 5.474cPas.
Specific Properties:
M.P: -21.60°C.
Surface tension: 15-40dynes/cm.
Pharmaceutical Application:

It is a clear, colorless liquid with an Ammonia or fish-like odor. It is used in making

waterproofing agents, and as a catalyst, corrosion inhibitor and propellant.
Stability & Storage:

It should be stored in a cool, dry place in a small, well-filled, well-closed container, protected
from light

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 Chapter 3 Aim and Objectives
3.1 Aim:

Objectives of the research work undertaken in detail are as follows:

 To conduct Pre-formulation studies for the selection of oil and other Co-
formulating agents.
 To conduct compatibility studies of selected oil and co-formulating agents using
API by FTIR to Formulate Trolamine Salicylate Microemulgel by using different
Surfactant mixture ratio.
 Characterization of the Formulation by Using Different Analytical Techniques.
 Designing of Trolamine Salicylate Microemulgel of different concentration by using
Polymers.
 To Formulate and Characterize Trolamine Salicylate Microemulgel.
 To Evaluate the Formulated Trolamine Salicylate Microemulgel.
 Perform Stability Study as per ICH Guideline

3.1 Plan of Work

3.1.1 Literature Review.
3.1.2 Procurement of Drugs.
3.1.3 Selection of Polymers.
3.1.4 Selection of Excipients for the Preparation of Microemulgel Formulation.
3.1.5 Preformulation Studies:
 Description
 Melting Point.
 Determination of Solubility of Drug in Different Solvent.
 Estimation of the Drug by UV Spectroscopy.
 Drug, Oil and Surfactant Compatibility Study by FTIR.
 Preparation of phase diagram.

3.1.6 Preparation of Trolamine Salicylate Microemulgel Formulation.

3.1.7 Evaluation of Formulation.

 Viscosity.

 Spreadibility.

 Drug Content.

 Visual Inspection.

 Size Distribution.

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  pH.

 Zeta Potential.
3.1.8 In vitro drug diffusion study of Microemulgel.
3.1.9 Stability Study.
3.1.10 Results and Discussion.

Conclusion.
References.

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 Chapter.4 Materials and Methods

4.1 Materials:
Table.4.1: List of Chemicals

S. No. Chemicals Brand

1 Trolamine Salicylate
2 Triethanolamine
3 Benzyl Alcohol
4 Liquid Paraffin
5 Oleic Acid
6 Carbopol-940
7 Tween-20
8 Na-Methyl Paraben
9 Propylene Glycol
Enomark Biotech India Vastral, Delhi
IIMT University Meerut
IIMT University Meerut
IIMT University Meerut
IIMT University Meerut
IIMT University Meerut
Bio-Sols Pvt. Ltd., Mumbai India
IIMT University Meerut
IIMT University Meerut

Table.4.2: List of Equipments Used

S. Equipments Manufacturer Use
No
UV-Visible double beam Shimadzu UV 1700 To measure the absorbance of
1 spectrophotometer (Pharmaspec) the sample
2 Electronic Balance Sortorius Single Pan For weighing purpose
3 Magnetic Stirrer Remi equipment, Microemulsions
Mumbai. preparation
4 pH meter Elico L 1120 Measure the pH of the sol.
5 Brookfield Viscometer LVII model To measure the viscosity
6 Cooling centrifuge Remi Phase separation study
7 FTIR Perkin Elmer Compatibility study
8 Particle size Analyser Microtrac-Blue wave To measure particlesize

4.2 Preformulation Study:

Preformulation may be described as a stage of development process during which the
researches characterize the physical, chemical and mechanical properties of the drug
substance to form effective, stable and safe dosage form. Hence, pre-formulation studies are

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 essential to characterize the drug for proper designing of the drug delivery system. The pre-
formulation studies which were performing in this project include,

4.2.1 Description:
Organoleptic characters of drug was observed and recorded by using descriptive terminology

4.2.2 Melting Point:

Capillary tube, which is sealed at one end is charged with sufficient amount of dry powder to
form a column in the bottom of the tube 2.5mm to 3.5mm, and packed down as closely as
possible by moderate tapping on a solid surface. The apparatus is operated according to the
standard operating procedure. The block is heated until the temperature is about 30 o C below
the expected melting point. The capillary tube is inserted into the heating block, and the
heating is continued at a rate of temperature increased of about 1o C to 2o C per minute until
melting is completed.
The temperature at which the detector signal first leaves its initial value is defined as the
beginning of melting, and the temperature at which the detector signal reaches its final value
is defined as the end of melting, or the melting point. The two temperatures fall within the
limits of the melting range.

4.2.3 Solubility Studies:

The spontaneous interaction of two or more substance to form a homogenous molecular
dispersion is called as solubility.
10 mg of drug was a suspended separately in 10 ml of different solvents at room temperature
in tightly closed tubes and shaken. The solubility profiles of two drugs in various solvents
are shown in the table.4.3

Table.4.3: Solubility Profile I.P. 1996

Parts of solvent
Descriptive term
required for 1
part of solute.
Very soluble Less than 1
Freely soluble From 1 to 10
Soluble From 10 to 30
Sparingly Soluble From 30 to 100
Slightly Soluble From 100 to 1000
Very slightly soluble From 1000 to 10, 000
Practically insoluble of Greater than or equal to
Insoluble 10,000

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 4.2.4 Estimation of the Drug by UV Spectroscopy:
The absorption maxima were found for drug identification. Ultraviolet visible
spectrophotometer has been used to obtain specific information on the chromophoric part of
the molecules. Organic molecules in solutions when exposed to light in the
visible/ultraviolet region of the spectrum absorb light of particular wavelength on the type of
electronic transition associated with the absorption.

4.2.5 Preparation of Phosphate Buffer Solution [pH 7.4] I.P 1996:

 27.218 g of potassium dihydrogen ortho phosphate was dissolved in 1000ml of
distilled water to give a 0.2N solution.
 8g of sodium hydroxide was dissolved in 1000ml of distilled water to give 0.2N
solution.
 1250ml of 0.2N potassium dihydrogen ortho phosphate and 977.5ml of 0.2N sodium
hydroxide were mixed together and made up to 5000ml with distilled water.
 The drug solution (10, 20, 30, 40, 50, 60g/ml) in Phosphate buffer pH 7.4 was taken
in standard cuvette, and scanned in the range of 200-300nm in a UV
spectrophotometer.
 It exhibits maxima at 260nm. UV spectrum of drug taken in phosphate buffer pH 7.4
also exhibits maxima at 260nm.
 Therefore, further all measurements were taken at 260nm. The results are shown in
fig.
4.2.6 Standard Curve:
Preparation of Standard Plot for Trolamine Salicylate in Phosphate Buffer pH 7.4:
Accurately weighed amount of Trolamine Salicylate (10mg) was dissolved in small quantity
of 0.1N sodium hydroxide and then diluted to 100ml with phosphate buffer pH 7.4. Each ml
of the stock solution contains 100mg of Trolamine Salicylate. From this stock solution
different standard of working standard solutions i.e., 10, 20, 30, 40, 50, 60µg /ml were made
up with phosphate buffer Ph 7.4 and the absorbance was measured at 260nm using
phosphate buffer pH 7.4 as blank by UV spectrophotometrically method. A graph is plotted
by using concentration at X-axis and absorbance at Y-axis. The values are given in the table
& fig.

4.2.7 Fourier Transforms Infrared (FTIR) Spectral Analysis:

FTIR is used to identify the functional groups in the molecule. The drug is mixed with KBr
disk was scanned at 4mm/s at a resolution of 2cm over a wave number region of 400 to
4000cm-1. The characteristic peaks were recorded. The results are shown in fig & table.

4.2.7.1 Drug-Excipients Compatibility Studies by FT-IR Analysis:

Infrared spectrum of any compound or drug gives information about the groups present in
that particular compound. The IR absorption spectra of the puredrug and physical admixtures

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 of drug with various Excipients were taken in the range of 4000-400 cm-1 using KBr disc
method (Schimadzu IR- Prestige-21) and observed for characteristic peaks of drug. Drug-
Excipient compatibility was carried out by FT-IR analysis. Initiallythe IR spectrums of pure
drug, Trolamine Salicylate, Liquid Paraffin, Oleic Acid, Carbopol-940, Benzyl Alcohol and
Propylene Glycol were obtained. After that admixtures of drug with other Excipients were
prepared and IR Spectra was obtained. The obtained spectra of physical admixtures was
observed for major peaks and recorded. The results of this observation were concluded that
there is no interaction between the drug (Trolamine Salicylate) & other Excipients.

4.3 Preparation of Trolamine Salicylate Microemulgel Formulation:

The preparation of microemulgel was carried out containing Trolamine Salicylate (API), oleic
acid (oil), Tween-20 (surfactant), propylene glycol (co-surfactant), carbopol-940 &
Triethanolamine as a (gelling agent), Na-Methyl Paraben (preservative), Benzyl alcohol
(solvent).
The microemulgel formulations were prepared in two steps:
1) Formation of micro-emulsion.
2) Conversion of micro-emulsion to Emulgel.
Micro-emulsions were formulated by dissolving drug into oil phase subsequently addition of
water takes place with drop wise addition of surfactant mixture on a continuous magnetic
stirrer. The clear, isotropic-micro-emulsion obtained then mixed with pre-swelled gelling
polymer and preservatives using a homogenizer to form micro-Emulgel. Quantities of
ingredients taken are mentioned in Table.4.4.

Table.4.4 Composition of different Trolamine Salicylate Microemulgel Formulations

(%W/V)
Ingredients Formulation batch
mg/ml
F1 F2 F3 F4 F5 F6 F7 F8

Trolamine 10 10 10 10 10 10 10 10
Salicylate

Triethanolamine 0.2 0.2 0.4 0.4 0.2 0.2 0.4 0.4

Benzyl Alcohol 4 6 8 10 4 6 8 10
Liquid Paraffin 0.2 0.4 0.6 0.8 0.2 0.4 0.6 0.8

Oleic acid 2 2.5 2 2.5 2 2.5 2 2.5

Carbopol-940 1.5 2 1.5 2 1.5 2 1.5 2

Tween-20 1 1.5 2 2.5 3 3.5 4 4.5

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 Na-methyl 0.2 0.4 0.2 0.4 0.2 0.4 0.2 0.4
Paraben
Propylene Glycol 4 6 4 6 4 6 4 6

Purified water Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S

4.4 Evaluation of Formulation:

4.4.1 Physical Examination:

Each formulation was visually examined for clarity, colour.

4.4.2 Size Distribution:

Size distribution measurement of microemulgel were carried out by dynamic light scattering
using (Zetasizer 3000, Malvern Instruments, Malvern UK) particle size analyzer. Samples were
placed in square glass cuvettes & droplet size analysis was carried out at temperature 25℃. The
droplet size was found of micro-Emulgel range that is 92.50nm and influenced by the conc. of
the formulation. The effect of Smix (mixture of surfactant & co-surfactant) conc. on droplet size
distribution of microemulgel was investigated.

4.4.3 pH Measurement:
A one-gram aliquot of the Microemulgel in one formulation was dissolved in distilled water and
left to settle for about 2 h before measuring the pH using a digital pH meter (Panday et al., 2015).
This was repeated for all the formulations. The acceptable pH range was 5-7 and this was
necessary to avoid any skin irritation since pH of the human skin is usually within this range.

4.4.4 Viscosity Measurement:

A viscometer was used to determine the viscosity of all the formulations at room temperature.
The torque readings were obtained between 15%–95% of the base scale. The L4 spindle type set
at 10 rotations/min was used.

4.4.5 Zeta Potential:

Zeta potential is the measurement of attraction or repulsion in between particles. Its measurement
brings details about the dispersion mechanism which is used to measure electrostatic dispersion.
The zeta potential calculation is important limitation across a various range of industries
incorporates pharmaceuticals, brewing, medicine, ceramics, and water treatment. For colloidal
stability, the repulsive forces between two particles should be ascendant. Zeta potential is a
useful index of magnitude for interaction between colloidal particles. In general, the colloidal
systems stability is determined using measurements based on zeta potential.

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 4.4.7 Spreadability Studies:
Spreadability was determined by placing 1g of each microemulgel within an already pre-marked
circle of 1cm diameter on a glass slab. Another pre-weighed glass slab was positioned on top and
a weight that totaled to about 1kg was put on the upper glass slab for 5 min. The resulting spread
of the microemulgel caused an increase in diameter which was measured using an electronic
digital caliper (Shinde et al., 2019; Singh and Bedi, 2016; Bachhav and Patravale, 2010).

4.4.8 % Drug Release:

An accurately measured amount of microemulgel formulation equivalent to 20mg was

introduced in a cellophane bag and was kept in an eight stage dissolution test apparatus
containing 1000ml of phosphate buffer pH 7.4. The temperature was set to 37 ± 0.5 °C and the
RPM was set to 50. Aliquots of 5ml of the medium were withdrawn every 30 min and replaced
with fresh phosphate buffer. The absorbance of the sample was measured by using UV-Visible
Spectrophotometer at 260nm. Percentage transmittance was used as a response to optimise the
amount of Smix and oil to get desired microemulgel. Obtained formulation was then
incorporated into the gel.

4.5 In vitro Drug Diffusion Study:

The in vitro drug diffusion study was carried out using diffusion cell method. In this method,
1gm of Micro-Emulgel is placed indoor compartment which is allowed to penetrate diffusing
membrane which separate receptor compartment containing phosphate buffer. The whole
assembly is maintained at 37°C and stirred with the help of a magnetic stirrer. Samples from
receptor compartment were withdrawn at different time intervals and replaced with fresh
buffer7.4 to maintain sink condition. Sample withdrawn were analyzed at 260nm on UV.

4.6 Stability Study:

All the formulations are subjected to short term accelerated stability study as per ICH guidelines
at in an airtight container with proper sealing and conditions maintained at 40±2°C, 75±5% RH.
The formulation was withdrawn and evaluated for physico-chemical parameters after particular
period of interval.

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 Chapter.5 Results and Discussion

5.1 Preformulation Study:

5.1.1 Description:
Table.5.1: Physical appearance of all batches F1-F8

Formulation Physical appearance

Code
F1 Clear transparent dispersion
F2 Clear transparent dispersion
F3 Clear transparent dispersion
F4 Milky White
F5 Milky White
F6 Clear transparent dispersion
F7 Clear transparent dispersion
F8 Clear transparent dispersion
5.1.2 Melting Point:
Table.5.2: Melting Point Determination
Drug Melting Point Normal Range
Trolamine Salicylate 48°C 50°C

5.1.3 Solubility:
Table.5.3: Solubility Profile of Trolamine Salicylate
S. No Solvents System Solubility (mg/ml) at 37±2˚C
1 Distilled H2O 11.3
2 Ethanol 76
3 Chloroform 82
5 CCL4 90
6 Diethyl Ether 26

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 Fig.5.1: UV spectrum of Trolamine Salicylate in phosphate buffer pH 7.4

Table.5.4: Abs maxima of Trolamine Salicylate in phosphate buffer pH

7.4

Solvent Conc. ( g)/ml max (nm) Absorbance

Phosphate
bufferpH 80 260 0.8604
7.4

5.1.4 Standard plot of Trolamine Salicylate in phosphate buffer pH 7.4:

Table.3.5: UV Abs of phosphate buffer pH 7.4

S. No Conc. (µg/ml) Abs. at 260nm

1 10 0.1432
2 20 0.2242
3 30 0.3614
4 40 0.4676
5 50 0.5830
6 60 0.6898
7 70 0.7865
8 80 0.8604

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 90
80 y = 10x
70 R² = 1
60
50 Conc. (µg/ml)
40
Abs. at 260nm
30
20
10
0
1 2 3 4 5 6 7 8

Fig.5.2: The standard plot exhibits linearity and has a strong regression coefficient

5.1.5 FTIR Study:

Fig.5.3: FT-IR of Trolamine Salicylate

Table.5.6: FT-IR Spectral assignment of Trolamine Salicylate

Wave number in (cm- Functional groups

1)

3000.65 O-H
stretching
2860.43 N-H
stretching
2620.82 C-H (Aromatic) stretching
1656.10 Carbonyl –C=O stretching
1478.54 NH (Amide) stretching

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 1310.13 S=O stretching
1289.47 C-S
Stretching
1186.42 C-O Stretching
1064.76 C-N Stretching
929.62 C-H out plane bending
Fig.1.14: Mechanism of InlammationFig.1.14: Mechanism of Inlammation

Fig.5.4: FT- IR of Trolamine Salicylate & Triethanolamine

Wave number in (cm-1) Functional groups

2870.65 C-H
Stretching
2240.43 C-O Stretching

2040.40 C-O Stretching

1688.26 C-H Out of plane bending
1264.72 NH (Amide) stretching
1162.54 S=O stretching

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 1089.32 C-S
Stretching

Table.5.7: FT-IR spectral assignment of Trolamine Salicylate & Triethanolamine

Fig. 5 . 5 : FT-IR of Oleic Acid

Table.5.8: FT-IR spectral assignment of Oleic acid

Wave number in (cm- Functional groups

1)
2613.14 C-H Stretching
1715.57 C-O Stretching
1395.96 C-O Stretching
874.65 C-H Out of plane
bending

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 Fig. 5 . 6 : FT-IR of Trolamine Salicylate +Tween-20+Propylene Glycol

Table.5.9: FT-IR spectral assignment of Trolamine Salicylate

+Tween-20+Propylene Glycol
Wave number in (cm-1) Functional groups
1708.20 O=C= stretching
1410.80 C4H4O stretching
1296.64 C-H bend Alkane
1250.56 C-O-C stretching
1107.39 C-F Bending
1100 C-O Stretching
1038 C-H Out of plane bending
721 C-H Out of plane bending

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 Fig. 5 . 7 : FT-IR of Carbopol-940
Table.5.10: FT-IR spectral assignment of Carbopol-940
Wave number in Functional groups
-1
(cm )
3389.55 N-H Stretching in Primary
amine
2932.48 C-H Stretching
2645.34 O=C= stretching
2400.54 C4H4O stretching
2010.21 C-H bend Alkane
1678.76 C-O-C stretching
1310.97 C-O Stretching
1100.32
837.76 C-O Stretching
664.32 C-H Out of plane bending

In the spectra of the mixture of the drug and excipients, there are no additional peaks
visible in addition to the typical peak, indicating that there is no interaction between the
drug and excipient and that they are compatible. When the IR spectra of the drug and
polymer combination were contrasted with those of the pure drug and individual
excipients, no appreciable peak shifting was discovered, confirming the stability of the
drug throughout the production of the microemulgel formulation.

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 5.2 Evaluation of Formulation:
Table.5.11: Physical Examination
Formulation Code Physical appearance pH % Drug Content
F1 Clear transparent dispersion 7.1 88.90
F2 Clear transparent dispersion 6.8 90.42
F3 Clear transparent dispersion 6.6 92.76
F4 Milky white 5.8 89.26
F5 Milky white 7.5 94.56
F6 Milky white 6.9 96.36
F7 Clear transparent dispersion 7.2 98.76
F8 Clear transparent dispersion 5.9 97.92

7.5 7.2
8 7.1 6.8 6.9
6.6
5.8 5.9
6

4
pH

0
F1 F2 F3 F4 F5 F6 F7 F8

Fig.5.8: Representative graph of pH

% Drug Content
98.76 97.92
100
96.36
94.56
95 92.76
90.42
88.9 89.26
90
% Drug Content
85

80
F1 F2 F3 F4 F5 F6 F7 F8

Fig.5.9: Representative graph of % drug Content

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 Table.5.12: Comparative Viscosity values and Spreadibility
Formulation Viscosity
Spreadibility
Code (cps)*
F1 56.8±0.8 16.42
F2 80.4±0.4 26.88
F3 100.5±0.2 28.90
F4 106.1±0.4 31.42
F5 128.9±0.1 32.54
F6 132.1±0.3 35.67
F7 138.6±0.5 36.98
F8 148.2±0.2 32.97

160 148.2
138.6
140 128.9132.1
120 100.5106.1
100 80.4
80
56.8 Viscosity (cps)*
60
36.9832.97 Spreadibility
40 26.88 28.9 31.4232.5435.67
16.42
20
0
F1 F2 F3 F4 F5 F6 F7 F8

Fig.5.10: Comparative Viscosity values and Spreadibility

Table.5.13: Zeta Potential

Formulation Code Zeta Potential (mv)

F1 -6.88

F2 3.07

F3 2.49

F4 -12.5

F5 -1.41

F6 2.16

F7 15.22

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 Fig.5.11: Zeta Potential Distribution

Fig.5.12: Zeta Potential

Table.5.14: Size Distribution

Formulation Globule Size (nm)

Code

F1 58.54

F2 132.10

F3 200.4

F4 37.70

F5 20.98

F6 184.4

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 F7 86.90

Fig.5.13: Size Distribution

5.3 In vitro drug diffusion study of Microemulgel:

Table.5.15: In-vitro drug diffusion study of Microemulgel

Time % Drug Diffused

(hr)
F1 F2 F3 F4 F5 F6 F7 F8

0 0 0 0 0 0 0 0 0

1 10.23 9.12 10.54 8.90 9.05 6.98 10.34 11.86

2 15.98 16.78 14.87 15.86 16.90 17.98 15.45 15.66

3 19.95 20.34 21.85 22.36 21.66 22.42 20.56 21.89

4 26.54 27.88 28.94 26.90 28.64 29.34 30.62 27.54

5 31.23 32.65 30.56 34.88 33.78 32.76 35.56 36.90

6 37.12 38.21 36.14 37.18 39.74 40.56 38.98 40.66

7 45.34 48.78 46.26 47.78 49.00 50.01 46.90 48.94

8 54.62 56.90 58.34 59.03 58.92 56.87 57.94 58.90

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 9 68.05 66.82 67.70 66.78 69.52 68.44 69.07 66.97

10 76.54 74.88 76.84 77.89 74.64 77.64 76.03 77.08

12 82.70 80.45 82.36 83.90 81.72 80.36 82.74 81.26

14 88.52 87.65 89.85 86.89 89.62 85.91 87.15 88.94

16 95.86 94.48 95.34 94.78 94.86 92.95 94.24 95.04

20 96.76 96.56 96.46 96.78 95.89 94.64 98.90 96.85

120
Time (hr)
100 % Drug Diffused F1
80 % Drug Diffused F2

60 % Drug Diffused F3
% Drug Diffused F4
40
% Drug Diffused F5
20
% Drug Diffused F6
0 % Drug Diffused F7
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
% Drug Diffused F8

Fig.5.14: In-vitro drug diffusion study of Microemulgel F1-F8

5.4 Stability Study:

Table.5.16: Stability Study best formulation F7
Evaluation Initial day Stability after Stability after Stability after
Parameters 1 month 2 month 3 month
Physical Clear No Change No Change No Change
Appearance transparent
dispersion
pH 7.2 7.1 7.00 6.96
Viscosity (cps) 138.6±0.5 138.6±0.5 138.6±0.5 138.6±0.5
% drug release 98.90 98.10 97.00 96.50

All the prepared microemulgel formulations were found to be unchanged upon the storage for
3months; no change was developed in their physical appearance but various changes in pH,
viscosity and % drug release.

[Type text] Page 78

 Conclusion:
Microemulgel as a delivery system is advantageous to use such as ease of administration,
increased residence time at applied site, steady drug release with improved bioavailability,
better thermodynamic stability and high transdermal permeability over simple conventional
formulations. The microemulgel of Trolamine Salicylate were prepared, using Carbopol-940
and Liquid Paraffin as a gelling agent, oleic acid as oil, parabens as preservative, Tween-20
as emulgent and penetration enhancer. The prepared microemulgel formulation was inspected
visually for Appearance, Spreadability, Viscosity, pH, % Drug Release and In vitro diffusion
studies. Results obtained has proved that development of Trolamine Salicylate containing
microemulgel will be more effective however its clinical efficacy must be understood using
clinical trials. So Trolamine Salicylate microemulgel can be used as pain reliever that
treatment of muscle and joint pain for topical drug delivery.

[Type text] Page 79

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 © 2023 JETIR August 2023, Volume 10, Issue 8 www.jetir.org (ISSN-2349-5162)

Rheumatoid Arthritis: A Comprehensive Review of

Pathogenesis, Clinical Features and Management
1
Abhishek Singh,2Dr. Prabhakar Vishvakarma, 3Mr. Suraj Mandal
1
M. Pharma Scholar, IIMT College of Medical Science, IIMT University Ganga Nagar Meerut.
2
Associate Professor, Professor/HOD IIMT College of Medical Science, IIMT University Ganga Nagar
Meerut.
3
Assistant Professor, IIMT College of Medical Science, IIMT University Ganga Nagar Meerut.
Abstract:
Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by symmetric joint inflammation,
leading to joint pain, swelling, and eventually joint damage and disability. This review aims to provide a
comprehensive overview of the pathogenesis, clinical features, and management of RA. It covers the underlying
mechanisms driving the disease, risk factors, and genetic predisposition. Additionally, the review explores the
varied clinical manifestations of RA, from joint symptoms to systemic effects, and highlights the importance of
early diagnosis and timely intervention. The various treatment approaches, including non-pharmacological
strategies, conventional disease-modifying drugs, biologic agents, and targeted therapies, are discussed in
detail, emphasizing their roles in symptom control, disease modification, and overall patient well-being.
Moreover, recent research insights and future perspectives in the field of RA management are also explored.
Keywords: Rheumatoid Arthritis, pathogenesis, clinical features, Joint Pain, Chronic Autoimmune Disease.
Introduction:
A series of inflammatory joint illnesses known as arthritis are distinguished by joint pain, stiffness, swelling,
and decreased mobility. People of all ages are affected, and it is one of the top causes of disability worldwide.
This article offers a thorough analysis of arthritis joint pain, covering the many forms, causes, signs and
symptoms, diagnostic procedures, and treatment options. An autoimmune illness that affects the joints and
maybe other bodily parts, rheumatoid arthritis (RA) is a chronic condition. The cells and proteins in our bodies
that fight infections make up the immune system. When a portion of our body is attacked by our immune
system as if it were an outside invader like a virus or bacteria, it is known as an autoimmune disease. The
immune system attacks the synovial membrane in rheumatoid arthritis. Synovial fluid is secreted into the joint
by the synovial membrane. The joint fluid that lubricates and nourishes the joint is called synovial fluid. In
rheumatoid arthritis, the immune system may also target other tissues, but the synovium, or synovial membrane,
is typically the main target. Attacks on the synovial membrane cause inflammation (synovitis), which can
thicken and destroy the membrane. Because it is not being secreted, synovial fluid is also eliminated along with
the synovial membrane. The surrounding structures may also get affected, which might result in the joint
abnormalities associated with rheumatoid arthritis [1-2].

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 © 2023 JETIR August 2023, Volume 10, Issue 8 www.jetir.org (ISSN-2349-5162)

Formulation and Evaluation of Topical

Microemulgel for the Treatment of Joint Pain
Abhishek Singh1, Dr. Prabhakar Vishvakarma2, Suraj Mandal3
1
M. Pharma Scholar, IIMT College of Medical Science, IIMT University Ganga Nagar Meerut.
2
Associate Professor, Professor/HOD IIMT College of Medical Science, IIMT University Ganga Nagar Meerut.
3
Assistant Professor, IIMT College of Medical Science, IIMT University Ganga Nagar Meerut.

Abstract:
When used as a delivery mechanism, microemulgel has several advantages over straightforward
conventional formulations, including simplicity of administration, increased residence duration at the
application site, constant drug release with improved bioavailability, superior thermodynamic stability,
and excellent transdermal permeability. Using Carbopol-940 and Liquid Paraffin as gelling agents, oleic
acid as the oil, parabens as the preservative, and Tween-20 as the emulgent and penetration enhancer, the
microemulgel of Trolamine Salicylate was created. The made-up microemulgel formulation underwent
visual examination for Appearance, Spreadability, Viscosity, pH% Drug Release, and In vitro diffusion
tests. The development of microemulgels containing trolamine salicylate will be more successful,
according to the results obtained, but clinical trials are necessary to understand their clinical usefulness.
In order to distribute drugs topically, trolamine salicylate microemulgel can be utilized as a painkiller for
the treatment of joint and muscle pain.
Keywords: Microemulgel, Trolamine Salicylate, Joint and Muscle Pain, Transdermal Drug Delivery
System.
Transdermal Drug Delivery Systems:
Currently, Transdermal drug delivery is one of the most promising methods for drug application.
Increasing numbers of drugs are being added to the list of therapeutic agents that can be delivered to the
systemic circulation via skin. Transdermal drug delivery systems (TDDS) can be defined as self contained
discrete dosage forms which, when applied to the intact skin, delivers the drug(s) through the skin at a
controlled rate to the systemic circulation [1].
The potential of using intact skin as the route of drug administration has been known for several years. The
inspiration of using skin for delivery of drug isfrom ancient time. Ebers papyrus used the husk of castor oil
plant bark imbibed with water placed on aching head. Historically, the medicated plaster can be viewed as
the first development of transdermal drug delivery; this medicated plaster became very popular in Japan as
over the counter pharmaceutical dosage form.
Transdermal delivery not only provides controlled, constant administration of the drug, but also allows
continuous input of drugs with short biological half- life and eliminates pulsed entry into systemic
circulation, which often undesirable side effect. TDDS facilitate the passage of therapeutic quantities of
drug substances through the skin and into the general circulation for their systemic effects.
In developing a transdermal delivery system, two criteria are considered: one is achieving adequate flux
across the skin and the other is minimizing the lagtime in skin permeation. One strategy overcoming this
constraint is the incorporation of various chemical skin enhancers into the vehicle. Another strategy is a
choice of an appropriate vehicle that corresponds to the drug being used for the dermal route of
administration. Concerning dermal application the microemulsions can interact with the stratum Corneum

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[Type text] Page 88

 The Board of
Journal of Emerging Technologies and Innovative Research (ISSN : 2349-5162)
Is hereby awarding this certificate to
ABHISHEK SINGH
In recognition of the publication of the paper entitled
Formulation and Evaluation of Topical Microemulgel for the Treatment of
Joint Pain
Published In JETIR ( www.jetir.org ) ISSN UGC Approved (Journal No: 63975) & 7.95 Impact Factor
Published in Volume 10 Issue 8 , August-2023 | Date of Publication: 2023-08-05

EDITOR EDITOR IN CHIEF

JETIR2308037 Research Paper Weblink http://www.jetir.org/view?paper=JETIR2308037 Registration ID : 522558
[Type text] Page 89
 Abhishek Singh

[Type text] Page 90

 ABHISHEK SINGH

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 Abshik pLAGRISM rEPORT.docx
ORIGINALITY REPORT

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 CERTIFICATE OF PLAGIARISM CHECK Only
UG/PG Students

1. Name of Student
2. Enrolment Number
3. Department Name
4. Course
5. Year
6. Title of the Dissertation

7. Name of the Supervisor

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Report on Plagiarism Check, Items with % of similarity is attached

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 RESUME
ABHISHEK SINGH
D.O.B 01/07/1998
Email id – surajsingh708170@gmail.com
Mob no - +918299692874

OBJECTIVE: - To be a part of an organization where I can fully utilize my skills &

make a significant contribution to the employer & at the same time my
individual growth.

EDUCATION
 HIGH SCHOOL PASSED IN 2014
 INTER PASSED IN 2016
 B.PHARMA PASSED IN 2021

EXEPERIENCE

 AAYUSH HOSPITAL IN MEDICAL IN 12 MONTHS.

PERSONAL DETAILS

Father’s Name : MR. JAY SINGH

Gender : Male
Languages Known : Hindi, English.
Permanent Address : VILL – VIJAI KAF, POST- VIJAI KAF, DIST- KUSHINAGAR
U.P (274207)
Nationality : Indian
Mobile no : +918299692874

DECLARATION

I hereby declare that the information furnished above is true to the best of my knowledge.

Place: Signature:
Date : ABHISHEK SINGH

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