DP Ii Thesis

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ACKNOWLEDGEMENT
This research work is a collaborative product of many persons. It is just single project
but involves many ideas of people at the work. This dissertation has its own personal
challenges and benefits, hence now it’s the time to say thanks to all those who have helped
me to complete entire work.
Ever since the earth has taken birth and men emerged on it; an unending quest to
unravel the truth – the research – is continued. It has widened human vision, opened newer
avenues and lightened the dark – obscure facets of mysterious universe. Today, at the acme
of my dissertation, with heartiness, I gratefully remember my parents, teacher, friends,
relatives and well-wishers; as one flower makes no garland. This presentation would not have
taken shape without their whole hearted encouragement and live involvement.
To my esteem guide, Dr. Darshit Ram Department of Pharmaceutics and our principal
sir Dr. Santosh Kirtane, I wish to express my sincere gratitude and very thankful for their
unceasing encouragement, motivation and helping nature timely help so often sought and so
generously given throughout this M. Pharm course. I wish to thank you to entire teaching
and non-teaching staff of the department of Pharmaceutics of Noble Pharmacy College.
Above all, their unbiased observation in all kinds of works inspired me a great deal to arrive
at a proper conclusion. It is a pleasure and privilege for me to acknowledge gratefully the
interest and attention lavished by him.
At this moment how can I forget my friends, colleagues and relatives, especially my
brother Vatsal Panasuriya who always was with me to help me out of certain problems. I
really had good time with them all. We all had a very great and good experience together.
I am and will always be in debt to my Mumma and Papa for their love, care and
motivation. They always motivated me for further studies and even they gave more
importance to my studies. They taught me about attaining the confidence. Only because of
them I am at this stage in my life. I will never forget their continuous encouragement and
motivation throughout my course of study. All I know is that without their care and faith in
me it was impossible to reach at this stage of my life.
Panasuriya Vidhi Bhaveshbhai
Table of content
TABLE OF CONTENT
Sr. Title Page

No. No.
1 Title Page I
2 Certificate Page II
3 Compliance Certificate III
4 Paper Publication certificate IV
5 Plagiarism certificate and Report V
6 Declaration of originality VII
7 Thesis approval certificate VIII
8 Table of Content IX
9 List of Figure X
10 List of Table XI
11 ABSTRACT XII
12 CHAPTER 1: INTRODUCTION 1-27
13 CHAPTER 2: AIM OBJECTIVES AND RATIONAL 28-29
14 CHAPTER 3: LITERATURE REVIEW 30-43
15 CHAPTER 4: DRUG AND EXCIPIENTS PROFILE 44-56
16 CHAPTER 5: MATERIAL AND METHODS 57-66
17 CHAPTER 6: RESULTS 67-88
18 CHAPTER 7: SUMMERY AND CONCLUSION 89-90
19 CHAPTER 8: REFERENCES 91-100
Appendix
IX
List of Figure
LIST OF FIGURES
Sr. Title Page
No. No.
1.1 Anatomy of the gastrointestinal tract 8
1.2 A simplified schematic representation of the interdigestive motility 9

pattern, frequency of contraction forces during each phase, and average
time Period for eachperiod
1.3 Mechanism of floating systems 12
1.4 Mechanism of temperature sensitive system 20
1.5 Mechanism of pH triggered in situ gel system 21
1.6 Mechanism of temperature sensitive system 21
4.1 Teneligliptin structure 44
4.2 Mechanism of action of teneligliptin 45
4.3 Structure of HYDROXY PROPYLMETHYL CELLULOSE 48
4.4 Structure of acrylic acid polymer 50
5.1 Schematic representation of the preparation of Oral In situ gel 60
6.1 Calibration curve of Teneligliptin Hydrobromide hydrate 68
6.2 FT-IR spectrum of Teneligliptin hydrobromide hydrate 70
6.3 FT-IR spectrum of Drug formulations 70
6.4 Prepared formulations of teneligliptin oral In situ gel 71
6.5 In vitro gelation study of the In situ gel formulations 74
6.6 Viscosity of In situ gel of Teniligliptin formulations 75
6.7 Percentage water uptake of Oral In situ gel of teneligliptin formulations 79
Panasuriya Vidhi (212690820011)

X-1
List of Figure
6.8 Zero order plot for optimized teneligliptin Oral In situ Gel(F9) 84
6.9 First order plot for optimized teneligliptin Oral In situ Gel (F9) 84
6.10 Higuchi plot for optimized teneligliptin Oral In situ Gel(F9) 85
6.11 Hixson Crowell Plot for optimized teneligliptin Oral In situ Gel (F9) 85
6.12 Kors –peppas Plot for optimized teneligliptin Oral In situ Gel (F9) 86
6.13 Invitro release of optimized teneligliptin oral insitu gel (F9) at stability 88
study

X-2
List of Table
List of Tables
Sr. Title Page
No. No.
1.1 Four phases in migrating myoelectric complex (MMC) 8
1.2 Commercial Formulations of In Situ Polymeric Systems 27
4.1 Indications with used concengtration of POLOXOMER 188 54
4.2 Indication and concentration of POLOXOMER 407 56
5.1 List of materials 57
5.2 List of Equipments 57
5.3 Composition of the In situ gelling formulations 61
5.4 Diffusion exponent and solute release mechanism 66
6.1 Preparation of standard calibration curve of Teneligliptinin 0.1N 67

HCL
6.2 Physical Compatibility of Drug and Excipients 69
6.3 Physical appearance of formulated In situ gel 72
6.4 pH of In situ gel formulations 72
6.5 Gelling capacity of formulated OralIn situ gelof teneligliptin 73
6.6 Viscosity of formulated Oral In situ gelof teneligliptin 75
6.7 In vitro buoyancy of Oral In situ gelof teneligliptin 76
6.8 Density of formulated In situ gel 77
6.9 Gel strength of formulated In situ gel 78
6.10 Percentage water uptake of In situ gel formulations 79
6.11 Percentage drug content of formulated In situ gel 80

XI-1
List of Table
6.12 In vitro Drug release of Formulated teneligliptin Oral In situ Gel 80
6.13 In vitro release kinetics of optimized teneligliptin Oral In situ Gel 82

(F9)
6.14 R2Values of various Kinetic Models of Optimized formulation (F9) 83
6.15 Stability data for Optimized Formulation – F9 86
6.16 Cumulative % drug release of Optimized formulation- F9 for stability 87

test

XI-2
Abstract
Aim and Objective: The aim of this study is to formulate a gastroretentive floating in-situ
gel (sol-gel) system of Teneligliptin Hydrobromide Hydrate to control the release and
further to improve its absorption and bioavailability.
Materials and Methods: Utilising gelling ingredients such Sodium Alginate, Gellan gum,
Iota carrageenan, and HPMC K4M, the teneligliptin oral In situ gel was created. The
medicine and excipients are physically compatible with one another, according to a
physical compatibility analysis. Physical appearance, Pourability, pH, viscosity, In vitro
gelation study, In vitro buoyancy study, Density, Gel strength, Percentage water uptake,
Drug content, and In vitro drug release were all tested for the manufactured formulations
(F1 - F10).
Result: Formulations F9 and F10 were deemed suitable for providing sustained
administration of Teneligliptin based on the findings of the evaluation of In situ gel.
Formulation F9, which contains Sodium alginate (0.5% w/v), Gellan gum (0.15% w/v),
Iota carrageenan (0.2% w/v), and HPMC K4M (0.1%), was selected as the optimized
formulation because it had a lower viscosity and was easier to pour than Formulation F10
with no appreciable differences in other parameters. The optimized formulation F9's in
vitro release kinetic investigation revealed that it used non-Fickian diffusion and zero-
order kinetics.
Conclusion: Overall findings show that oral floating formulation of teneligliptin released
in a regulated manner by in situ gel. Due to the simplicity of administration and decrease
in dosage frequency, this may result in better patient compliance. As a result, the created
formulation can be utilized instead of the conventional dosage formto treat type 2 diabetes
patients' ailment.
Keywords: Teneligliptin, gastroretentive, floating, in-situ gel, type 2 diabetes
Panasuriya Vidhi (212690820011) XII

Chapter 1 Introduction
1. INTRODUCTION
In our contemporary epoch innumerable technologies have been made to develop different
routes of administration, through which the drug is administered into the body for treatment
of various diseases and disorders. Various routes of administration are classified into the
differentcategories. The oral route currently represents the most predominant and preferable
route of drug delivery. Unlike majority of parenteral dosage forms, it allows ease of
administration by the patient and it‟s the natural, and therefore a highly convenient way for
substances to be introduced into the human body. Oral drug delivery systems have
progressed from conventional immediate release to site-specific delivery over a period of
time. Every patient would always like to have an ideal drug delivery system possessing the
two main properties that are single dose or less frequent dosing for the whole duration of
treatment and the dosage form must release active drug directly at the site of action.1-5
CONVENTIONAL DRUG DELIVERY SYSTEM

Oral drug delivery is the most widely utilized route of administration among all the routes
that have been explored for systemic delivery of drugs via pharmaceutical products of
different dosage forms.
The oral dosage form has survived due to
 Relatively simple and inexpensive to make
 Convenient for the patient
 Technology is easy to adapt to changing needs of the drug substance
 Simplifies the regulatory approval process.
Pharmaceutical products designed for oral delivery are mainly conventional drug delivery
systems, which are designed for immediate release of drug for rapid/immediate absorption6.
LIMITATIONS OF THE CONVENTIONAL DRUG DELIVERY SYSTEM:

 Drugs with short half-life require frequent administration, which increases chances
of missing the dose of drug leading to poor patient compliance.
 A typical peak-valley plasma concentration-time profile is obtained which makes
attainment of steady state condition difficult.
Panasuriya Vidhi (212690820011) Page 1

 The unavoidable fluctuations in the drug concentration may lead to under medication
or overmedication as the steady state concentration values fall or rise beyond the
therapeutic range.
 The fluctuating drug levels may lead to precipitation of adverse effects especially of
a drug with small therapeutic index, whenever overdosing occurs.
In order to overcome the drawbacks of conventional drug delivery systems, several

technical advancements have led to the development of controlled drug delivery system that
could revolutionize method of medication and provide a number of therapeutic benefits.
DRUG DELIVERY SYSTEM (CDDS)
Over the years, as the expense and complications involved in marketing newdrug entities
have increased with concomitant recognition of the therapeuticadvantages of controlled drug
delivery, greater attention has been focused on thedevelopment of modified release dosage
forms.7-9
Modified release systems have been developed to improve the pharmacokineticprofiles of

active pharmaceutical ingredients (APIs) and patient compliance, as wellas reducing side
effects. Oral modified release delivery systems are most commonlyused for
1) Delayed release (e.g., by using an enteric coating);

2) Extended release(e.g., zero-order, first-order, biphasic release, etc.);
3) Programmed release (e.g.,pulsatile, triggered, etc.) and
4) Site specific or timed release (e.g., for colonicdelivery or gastric retention).
Extended, sustained or prolonged release drug deliverysystems are terms used

synonymously to describe this group of controlled drugdelivery devices, with predictability
and reproducibility in the drug release kinetics.

Delayed release dosage forms are distinguished from the ones mentioned above asthey
exhibit a pronounced lag time before the drug is released. Oral extended releasedosage
forms offer the opportunity to provide constant or nearly constant drugplasma levels over an
extended period of time following administration.
Extended release DDS include single-unit, such as tablets or capsules, and multiple-unit
dosageforms, such as mini tablets, pellets, beads or granules, either as coated (reservoir) or
matrix devices.
Controlled Release
Controlled release systems designed to maintain plasma levels in therapeutic range and thus
minimize the effects of such problems. Furthermore; controlled release systems reduce the
dosing frequency, thereby improving patient compliance and therapeutic efficacy.
Sustained Release
Drug products that provide “extended” or “sustained” drug release appeared as a major class
of dosage form. Many terms as sustained-release, sustained-action, prolonged- action,
controlled-release, extended-release, timed-release, and long acting have been used to
describe product types and features. For the most part, these terms are used to describe
orally administered dosage forms, whereas the term rate controlled delivery is applied to
certain types of drug delivery systems in which the rate of drug delivery is controlled by
features of the device rather than by physiological or environmental conditions as
gastrointestinal pH or drug transit time through the gastro intestinal tract (GIT).
Modified-release
This term has come into general use to describe dosage forms having drug release features
based on time, course, and/or location which are designed to accomplish therapeutic or
convenience objectives not offered by conventional or immediate-release forms.

Extended-release
Extended-release dosage form is one that allows a reduction in dosing frequency to that
presented by a conventional dosage form.
Delayed-release
Dosage form is designed to release the drug from the dosage form at a time after
administration. The delay may be time- based or based on the influence of environmental
conditions, as gastrointestinal pH.
CONCEPT OF ABSORPTION WINDOW
Drug exhibiting absorption from only a particular portion of GI tract or showing difference
in absorption from various regions of GI tract are said to have regional variability in
intestinal absorption. Such drugs show absorption window which signifies the regions of GI
tract from where absorption primarily occurs. Drug released from the CRDDS after the
absorption window has been crossed goes waste with no or negligible absorption occurring
(Figure 1). This phenomenon drastically decreases the available drug for absorption, after
release of drug from CRDDS. The CRDDS possessing the ability of being retained in the
stomach are called GRDDS and they can help in optimizing the oral controlled delivery of
drugs having absorption window by continuously releasing drug prior to absorption
window, for prolonged period of time thus ensuring optimal bioavailability.10-12
GASTRORETENTIVE DRUG DELIVERY SYSTEMS
GRDDS (gastro retentive drug delivery system)are dosage forms that can be retained in the
stomach are called GRDDs. GRDDSs can improve the controlled delivery of drugs that
have an absorption window by continuously releasing the drug for a prolonged period of
time before it reaches its absorption site. 3 Prolonging the gastric retention of the drugs is
sometimes desirable for achieving therapeutic benefits of drug that are absorbed from the

proximal part of the GIT (gastro intestinal tract) or those are less soluble in or are degraded
by alkaline pH or they encounter at the lower part of the GIT. GRDDS are beneficial for
such drugs by
 Improving their Bioavailability

 Therapeutics efficiency
 Possible reduction of the dose
 Apart from these advantages, these systems offer various pharmacokinetic
advantages like, maintenance of constant therapeutic levels over a prolonged period
and thus reduction in fluctuation in the therapeutic levels
Drugs that are easily absorbed from GIT and have short half-lives are eliminated quickly
from the systemic circulation. Frequently dosing of these drugs is required to achieve
suitable therapeutic activity. To avoid this limitation, the development of oral sustained
controlled release formulations is an attempt to release the drug slowly into the GIT and
maintain an effective drug concentration in the systemic circulation for a long time. After
oral administration, such a drug delivery would be retained in the stomach and release the
drug in controlled manner, so that the drug could be supplied continuously to its absorption
sites in the GIT.
GRDD Devices are primarily site specific drug delivery systems, which gets retained in the
stomach for longer period of time, thus helping in absorption of drug for the intended
duration of time.13-17
This in turn improves:-
 Bioavailability
 Reduce drug wastage
 Improves solubility of drugs that are less soluble at high pH environment (e.g.
weakly basic drug like domperidone, papaverine)
 Also helps in achieving local delivery of drug to the stomach and proximal small
intestine.
To formulate a site specific orally administered controlled release dosage form, it is
desirable to achieve a prolong gastro residence time by the drug delivery. In addition, for

local and sustained drug delivery to the stomach and proximal part of the small intestine, to
treat certain conditions, prolonged gastric retention of the therapeutic moiety may offer
numerous advantages including
 Improved bioavailability
 Improved therapeutic efficacy
 Possible reduction of dose size
 Improves the drug solubility that is less soluble in high pH environment. E.g.
weakly basic drugs like Domperidone, papaverine etc.
 Decrease drug wastage
 Also helps in achieving local delivery of drug to the stomach and proximal part of
small intestine.
Prolonged gastric retention time in the stomach could be advantageous for local action in the
upper part of the small intestine e.g. treatment of peptic ulcer. 6 In recent year, oral dosage
forms for gastric retention have drown more and more attention for their therapeutic
advantage in permitting command over the time and site of drug release. Many drugs
categorized as once a day delivery have demonstrated on transit time of dosage. Form.
Therefore, a system designed for longer gastric retention will extend the time within which
drug absorption can occur in small intestine. The controlled gastric retention of solid dosage
forms may be achieved by the mechanism of
 Mucoadhesion
 Flotation
 Sedimentation
 Expansion
 Modified shape systems OR
 By the simultaneous administration of pharmacological agents that delay gastric
emptying.

ANATOMY OF THE GASTROINTESTINAL TRACT

The gastrointestinal tract can be divided into three main regions namely 1. Stomach 2.
Small intestine- Duodenum, Jejunum and Ileum 3. Large intestine The GIT is a continuous
muscular tube, extending from the mouth to the anus, which functions to take in nutrients
and eliminate waste by such physiological processes as secretion, motility, digestion,
absorption and excretion. The organization of the GIT, from stomach to large intestine, is
shown in Fig.1. The stomach is a Jshaped enlargement of the GIT which can be divided into
four anatomical regions: cardia, fundus, body and antrum. The main function of the stomach
is to store and mix food with gastric secretions before emptying its load (chyme) through the
pyloric sphincter and into the small intestine at a controlled rate suitable for digestion and
absorption. When empty, the stomach occupies a volume of about 50 ml, but this may
increase to as much as 1 litre when full.
The walls of the GIT, from stomach to large intestine, have the same basic arrangement of
tissues, the different layers, from outside to inside, comprising serosa, longitudinal muscle,
intermuscular plane, circular muscle, submucosa, muscularis mucosae, lamina propria and
epithelium. In addition to longitudinal and circular muscle, the stomach has a third muscle
layer known as the "oblique muscle layer", which is situated in the proximal stomach,
branching over the fundus and higher regions of the gastric body. The different smooth
muscle layers are responsible for performing the motor functions of the GIT, i.e. gastric
emptying and intestinal transit.18-20
BASIC GASTROINTESTINAL TRACT PHYSIOLOGY

Anatomically the stomach is divided into 3 regions:
 Fundus,
 Body, and
 Antrum pylorus.
The proximal part made of fundus and body acts as a reservoir for undigested material,
whereas the antrum is the main site for mixing motions and acts as a pump for gastric
emptying by propelling actions. Gastric emptying occurs during fasting as well as fed states.
The pattern of motility is however distinct in the 2 states.

Figure 1.1: Anatomy of the gastrointestinal tract
During the fasting state an interdigestive series of electrical events take place, which cycle
through both stomach and intestine every 2 to 3 hours. This is called the
interdigestivemyloelectric cycle or migrating myloelectric cycle (MMC), which is further
divided into following 4 phases.
1. Phase I (basal phase)
2. Phase II (preburst phase)
3. Phase III (burst phase)
4. Phase IV
Table1.1: Four phases in migrating myoelectric complex (MMC)

Phase I It is a quiescent period lasting from 30 to 60 minutes with no
contractions.
Phase II It consists of intermittent contractions that gradually increase in
intensity as the phase progresses, and it lasts about 20 to 40 minutes.
Gastric discharge of fluid and very small particles begins later in this
phase.
Phase III This is a short period of intense distal and proximal gastric
contractions (4–5 contractions per minute) lasting about 10 to 20
minutes; these contractions, also known as „„house-keeper wave,‟‟
sweep gastric contents down the small Intestine.

Phase IV This is a short transitory period of about 0 to 5 minutes, and the

contractions dissipate between the last part of phase III and quiescence
of phase I.
Figure 1.2: A simplified schematic representation of the interdigestive motility

pattern, frequency of contraction forces during each phase, and average time
Period for eachperiod
FACTORS CONTROLLING GASTRIC RETENTION OF DOSAGE FORMS

There are many parameters related to stomach‟s anatomy and physiology that are needed to
be considered in the development of gastroretention dosage forms. 21-23
1. Particle size
Should be in the range of 1-2 mm to pass through the pyloric valves into the smallintestine.
2. Density
Density of dosage form should be in rangeof 1g/cm3 to 2.5g/cm3
3. Size
Size should be greater than 7.5 mm in diameter.
4. Shape of dosage forms
Ring and tetrahedron devices with flexuralmodulus of 22.5-48 KSI (keto pound/inch2 show
90-100 % gastric retentiontimes (GRT).

5.Single unit/multiple unit

Multiple units are preferable because of predictable release profile, coadministration of
different units, larger safety margins.
6. Food intake
GRT is longer in fed states.
7. Nature, calorie content
Indigestible polymers, fatty acid salts, increase calorie content, increase acidity increases
GRT, Fat and protein meal increases GRT.
8. Frequency of intake
GRT increases 400 times due to low frequency of MMC
9. Posture
Varies between spine and upright ambulatory states.
10. Gender
Females have shorter GRT than males.
11. Age
Age > 70 shows longer GRT.
12. Nature of drug
Drugs with impact on gastro intestinal transit time e.g. Codeine and pharmacokinetic
agentse.g.metclopramide, cisapride increases GRT.
13. Other factors
 Diseased states of the individual (chronic disease, diabetes etc.)
 Body mass index
 Physical activity
 Molecular weight and lipophilicity of the drug depending on its ionization state.
APPROACHES TO GASTRIC RETENTION

Various approaches have been pursued to increase the retention of oral dosage forms in the
stomach. The most common approaches used to increase the gastric residence time of
pharmaceutical dosage forms include24-25
 Floating systems
 Swelling and expanding systems

 Bio adhesive systems

 Unfolding and modified- shape systems
 High density systems
 Others.
FLOATING SYSTEMS
Floating drug delivery systems (FDDS) have a bulk density less than gastric fluids and
so remain buoyant in the stomach without affecting the gastric emptying rate for a
prolonged period of time. While the system is floating on the gastric contents), the
drug is released slowly at the desired rate from the system. After release of drug, the
residual system is emptied from the stomach. This results in an increased GRT and a
better control of the fluctuations in plasma drug concentration. 26-28
However, besides a minimal gastric content needed to allow the proper achievement
of the buoyancy retention principle, a minimal level of floating force (F) is also
required to keep the dosage form reliably buoyant on the surface of the meal.
Most floating systems reported in the literature are single unit systems, such as HBS
and floating tablets. The systems are unreliable and irreproducible in prolonging
residence time in the stomach when orally administered due to their all or nothing
empting process (Kawashima et al., 1991). On the other hand, multiple unit dosage
forms, such as hollow microsphere (micro balloons), granules, powder, and pellets, are
more suitable since they are claimed to reduce the inter- and intra-subject variability in
absorption and reduce the probability of dose dumping.

Figure 1.3: Mechanism of floating systems
TYPES OF FLOATING DRUG DELIVERY SYSTEMS (FDDS)

Floating properties based on the mechanism of buoyancy are divided into:
1. Non effervescent systems with inherent low density or low density due toswelling;
and
2. Effervescent systems with low density due to gas generation andentrapment.
NON- EFFERVESCENT SYSTEMS
A) Hydro dynamically Balanced Systems

These are single-unit dosage forms, containing one or more gel-forminghydrophilic
polymers. The polymer is mixed with drug and usually administered in agelatin
capsule. The capsule rapidly dissolves in the gastric fluid, and hydration andswelling
of the surface polymers produces a floating mass. Drug release is controlledby the
formation of a hydrated boundary at the surface.Continuous erosion of the surface
allows water penetration to the inner layers,maintaining surface hydration and
buoyancy.

EFFERVESCENT SYSTEMS (GAS-GENERATING SYSTEMS):

This approach provides floating drug delivery systems based on the formation of CO2 gas. It
utilizes effervescent components such as sodium bicarbonate (NaHCO3) or sodium
carbonate, and additionally citric or tartaric acid. Alternatively matrices containing
chambers of liquids that turns into gas at body temperature could be used. Upon contact
with the acidic environment, a gas is liberated, which produces an upward motion of the
dosage form and maintains its buoyancy. A decrease in specific gravity causes the dosage
form to float on gastric contents. These buoyant systems utilize matrices prepared with
swellable polymers such as methocel, polysaccharides (e.g., chitosan), and effervescent
components. (e.g., sodium bicarbonate, citric acid or tartaric acid).
The system is so prepared that upon arrival in the stomach, carbon dioxide is released,
causing the formulation to float in the stomach. Other approaches and materials that have
been reported are a mixture of sodium alginate and sodium bicarbonate, multiple unit
floating pills that generate carbon dioxide when ingested, floating mini capsules with a core
of sodium bicarbonate, lactose and polyvinylpyrrolidone coated with hydroxyl propyl
methylcellulose (HPMC), and floating systems based on ion exchange resin technology,
etc..
CERTAIN TYPES OF DRUGS CAN BENEFIT FROM USING GASTRIC

RETENTION DEVICES.
These include drugs that:29-30
 Are acting locally in the stomach e.g. Antacids and drugs for H.pylori viz.
Misoprostol
 Primarily absorbed in the stomach. e.g. Amoxicillin
 Have an absorption window in the stomach or in the upper small intestine,
 Drugs with narrow window of absorption, e.g. Cyclosporine, Methotrexate,
Levodopa
 Are unstable in the intestinal or colonic environment, e.g. Ranitidine,
Metformin Hcl
 Exhibit low solubility at high pH values.

DRUGS THOSE ARE UNSUITABLE FOR GRDFs

1. Drugs that have very limited acid solubility e.g. Phenytoin etc.
2. Drugs that suffers instability in the gastric environment e.g. Erythromycin, Rabeprazole,
Clarithromycin, Esomeprazole etc.
3. Drugs intended for selective release in the colon e.g. 5-amino salicylic acid and
corticosteroids etc.
ADVANTAGES OF GASTRORETENTIVE DRUG DELIVERY SYSTEMS31
o Enhanced bioavailability
o Enhanced first-pass biotransformation
o Sustained drug delivery/reduced frequency of dosing
o Reduced counter-activity of the body
o Targeted therapy for local ailments in the upper GIT
o Reduced fluctuations of drug concentration
o Minimization of fluctuations in drug concentration
o Minimized adverse activity at the colon
o Site specific drug delivery
o Extended time over critical (effective) concentration
DISADVANTAGES OF GASTRORETENTIVE DRUG DELIVERY SYSTEM32

1. There are certain situations where gastric retention is not desirable. Aspirin and non-
steroidal anti-inflammatory drugs are known to cause gastric lesions and slow release of
such drugs in the stomach is unwanted.
2. Thus, drugs that may irritate the stomach lining or are unstable in its acidic environment
should not be formulated in gastroretentive systems.
3. Furthermore, other drugs, such as isosorbidedinitrate, that are absorbed equally well
throughout the GI tract will not benefit from incorporation into a gastric retention system.
4. Gastric retention is influenced by many factors such as gastric motility, pH and presence
of food. These factors are never constant and hence the buoyancy cannot be predicted
exactly or accurately.

5. Gastric emptying of floating forms in supine subjects may occur at random and become
highly dependent on the diameter. Therefore, patients should not be dosed with floating
forms just before going to bed.
6. High variability in gastric emptying time due to variations in emptying process.
7. Unpredictable bioavailability.
LIMITATIONS
1. The major disadvantage of floating systems is requirement of a sufficiently high level of
fluids in the stomach for the drug delivery i.e. upto 400ml of gastric fluids should be present
for optimum buoyancy. However, this limitation can be overcome by coating the dosage
form with bioadhesive polymers, which easily adhere to the mucosal lining of the stomach
and retain. The dosage form can be administered with a glass full of water (200- 250 ml) to
provide the initial fluid for buoyancy33-34.
2. Floating system is not feasible for those drugs that have solubility problems in gastric
fluids.
3. Drugs that are not stable at gastric pH are not suitable candidates to be formulated as
GRDDS.
4. Drugs that irritate the mucosa are not suitable candidates and should be avoided to be
formulated as GRDDS.
5. The drugs, which have multiple absorption sites in the gastrointestinal tract and are
absorbed throughout gastrointestinal tract, which under significant first pass metabolism, are
not desirable candidates.
6. Some drugs present in the floating system cause irritation to gastric mucosa.
7. Single unit floating capsules or tablets are associated with an all or none concept, but this
can be overcome by formulating multiple unit systems like floating microspheres or
microballoons.
The bioavailability of riboflavin CR-GRDF is significantly enhanced in comparison to the

administration of non-GRDF CR polymeric formulations. There are several different
processes, related to absorption and transit of the drug in the gastrointestinal tract, that
actconcomitantly to influence the magnitude of drug absorption.

GELS:
Gels are an intermediate state of matter which contains both liquid and solid components. It
consists of three-dimensional solid networks. As it has three dimensional solid networks,
gels are classified into two types based on the nature of the bonds. They are: Physical gels
which arise, when weak bonds like hydrogen bonds, electrostatic bonds and Vander Waal
bonds constitute together to maintain the gel network.
Chemical gels arise when strong covalent bonds constitute to maintain the gel network. The
gel network indicates the presence of cross-linking which helps to avoid the dissolution of
the hydrophilic polymer in an aqueous medium.
Hydrogels: Hydrogels are the three-dimensional structures that has polymeric networks
which has the capacity to absorb and retain large amounts of water and biological fluids to
swell.
Classification of hydrogels: Hydrogels are of two types. They are Preformed hydrogels are
defined as simple viscous solutions which do not undergo any modification after
administration. In-situ gels are the solutions or suspensions that undergo gelation after
reaching the site due to physicochemical changes.35-37
IN-SITU GELLING SYSTEM

In-situ gelling system has become one of the most prominent among novel drug delivery
systems due to many advantages such as improved patient compliance, reduced frequency
of drug administration. „In-situ‟ is a Latin word which means „in position‟.
There are many triggering mechanisms in in-situ gel formation some of them are pH
change, temperature modification and solvent exchange. As the gel formed from in-situ
gelling system, being lighter than gastric fluids float over stomach contents due to the
presence of bio adhesive nature of polymers resulting in prolonged gastric retention time.
In-situ gels are the formulations that are in sol form before administration in the body, but
once administration undergo gelation to form gel. Various routes administration of in-situ
gelling systems is oral, nasal, ophthalmic, vaginal, injectable, intraperitoneal and rectal
route. 38-40

ADVANTAGES OF IN SITU GEL

1) Reduced dosing frequency.
2) Decreased occurrence of toxicity and intensity of adverse effect.
3) Increase patient compliance.
4) More uniform blood concentration.
5) More consistent and prolonged therapeutic effect.
6) To maintain continuous concentration of drugs in the blood.
7) Greater selectivity of pharmacological activity.
8) Reduced dose dumping.
9) Improved stomach retention with the slow release of drugs.
DISADVANTAGES OF IN SITU GEL SYSTEM

 It requires high level of fluids.
 The sol form of the drug is more susceptible for degradation.
 Chances of stability problems due to chemical degradation.
 After placing the drug eating and drinking may become restricted up to few hours.
 The quantity and homogeneity of drug loading into hydrogels may be limited,
particularly for hydrophobic drugs.
 Only drugs with small dose requirement can be given.
 Lower mechanical strength, may result into premature dissolution or flow away of
the hydrogel from a targeted local site.
CRITERIA FOR SELCTING DRUG CANDIDATE FOR IN SITU GEL FLOATING

SYSTEM
❖ The right selection of drugs for oral in-situ drug delivery systems are drugs that have
poor colonic absorption and Drugs that having better absorption properties at the upper parts
of the GIT, so the following few points are taken into consideration:
Drug acting locally in the stomach like Antacids and drugs for H. pylori, e.g. Misoprostol
❖ Drugs that are maximum absorbed from the stomach like chlordiazepoxide and
cinnarizine.

❖ Drugs those are poorly soluble at alkaline pH like verapamil HCl and diazepam.
❖ Drugs with a narrow window of absorption like levodopa and riboflavin.

❖ Drugs which are rapidly absorbed from the GIT. Like Tetracycline.
❖ Drugs that degrade in the colon. like ranitidine and metronidazole.

❖ Drugs that disturb normal colonic microbes like ampicillin.
❖ Poor soluble of drugs at alkaline pH e.g. Furosemide, Diazepam, Verapamil, etc.
VARIOUS APPROCHES TO PRODUCE IN SITU GELATION

There are various mechanisms for the in- Situ gel formulation: physical changes in
biomaterials (e.g. Diffusion of solvent and swelling), Chemical reactions (e.g. Ionic cross
linking, enzymatic crosslinking), physiologically stimuli (e.g. Temperature and pH)41-43
Physical Mechanism:
In situ formation based on physical mechanism consists of the following:
Diffusion
Diffusion is a type physical approach that is used in in-situ gel formulation. In this method
involves the diffusion of solvent from polymer solution into surrounding tissue which
results in formation of precipitation or solidification of polymer matrix. N-methyl
pyrrolidone (NMP) has been commonly used polymer in formation of in-situ gelling system.
Swelling
Swelling is a type of physical approach that is used in in-situ formulation. In this method the
polymer are surrounding the polymer imbibe and the fluids that are present in exterior
environment and swell from out to inside and drug releases slowly. myverol (glycerol
mono-oleate) is a substance which is used as polar lipid that swells in water to form
Lyotropic liquid crystalline phase structures. This substance has some bioadhesive
properties and it can degrade in vivo by enzymatic action.
Chemical Mechanism:
In situ gelling formation based on chemical reactions mechanism
Chemical reactions that results in situ gelation may involve the following processes

Enzymatic cross-linking
Enzymatic cross linking is the most suitable method used in formation of in situ gelling
system. In this method, gel is formed by cross linking with the enzymes which are present in
body fluids. In situ formation induce by natural enzymes and that are not been investigated
widely but appear to have some advantages over chemical and photochemical methods. For
example, an enzymatic process handles efficacy under physiologic conditions and no need
for possibly destructive chemicals such as monomers and initiators. Hydrogels are used in
intelligent stimuli-responsive delivery systems that can release insulin have been
investigated. Modify the amount of enzyme also maintain a suitable mechanism for
controlling the rate of gel formation, which confess the mixtures to be injected before gel
formation.
Photo-polymerization
In photo-polymerization method19 electromagnetic radiations are used during formation of
in situ gelling system. A solution of reactive macromere or monomers and invader can be
injected into a tissues site and the application of electromagnetic radiation used to form gel.
The most suitable polymers for photo polymerization are the polymers which undergo
dissociation by polymerisable functional group in the presence of photo initiator like
acrylate or similar monomers and macromers that are typically long wavelength ultraviolet
and visible wavelengths are used. Short wavelength ultraviolet are not used often because
they are limited penetration of tissue and biologically harmful. In this method, ketone, such
as 2,2 dimethoxy-2-phenyl acetophenone, is used as the initiator for ultraviolet photo-
polymerization. camphorquinone and ethyl eosin initiators are used in visible light systems.
Ionic cross linking
In this method, the ion sensitive polymer is used. Ion sensitive polymers may undergo phase
transition in presence of various ions like Na+, K+, Ca+, and Mg+. Some polysaccharides
are also in the class of ion-sensitive ones. While k-carrageenan forms rigid, small amount of
K+ are reply in brittle gels, elastic gels are forms in i-carrageenam mainly in the presence of
Ca2+. Gellan gum mainly available as Gelrite. It is an anionic polysaccharide, in the
presence of mono and divalent cations that undergoes in situ gelling system.

Temperature triggered in situ gel

Temperature is the most widely used stimulus in environmentally responsive polymer
systems in in-situ gelling formulation. The change of temperature used in easy to control,
and also easily applicable both in vitro and in vivo. In this system, gelation is caused due to
body temperature and no need of external heat. These hydrogels are liquid at room
temperature (20–25°C) and undergo gelation when in contact with body fluids (35– 37°C),
due to an increase in temperature. There are three types of temperature induced systems.
They are negatively thermo sensitive type Eg: Poly (N-isopropylacrylamide) positively
thermo sensitive type Eg: polyacrylic acid thermally reversible type Eg: poloxamer,
pluronics, Tetronics.
In this system, thermo responsive or temperature responsive polymers are used that show a
drastic and discontinuous change in their physical properties with temperature. These
polymers show a miscibility gap at high or low temperature an upper or lower critical
solution temperature exists.
Figure 1.4: Mechanism of temperature sensitive system
pH triggered in situ gelation

In this system gel is formed due to pH changes. In this method pH sensitive polymers or pH
responsive are used. In pH sensitive polymers includes pendant acidic or basic groups that
may accept or release protons in counter to changes in environmental pH. The large number
polymers of ionizable groups are known as poly electrolytes. The poly electrolytes are
present in the formulation causes increase in external pH that leads to swelling of hydrogel
that forms in situ gel. Some suitable polymers for this approach those polymers having

anionic groups. Some are cellulose acetate phthalate (CAP), carbomer and its derivatives,
polyethylene glycol (PEG), pseudo latexes and poly methacrilic acid (PMC) etc.
Figure 1.5: Mechanism of pH triggered in situ gel system
Ion activated in situ gelation

In this method, gelling of the solution instilled is triggered by change in the ionic strength. It
is assumed that the rate of gelation depend on the osmotic gradient across the surface of the
gel. The polymer which shows osmotically induced gelation is Gelrite or Gellan gum,
Hyaluronic acid and Alginates etc.
Figure 1.6: Mechanism of temperature sensitive system
POLYMERS USED AS IN SITU GELLING AGENTS44
Pectin
Pectins are a family of polysaccharides, in which the polymer contains mainly, comprises α-
-(1-4)--D galacturonic acid residues. In the presence of free calcium ions, Low

methoxypectins (degree of esterification <50%) readily forms gels in aqueous solution,

which crosslink the galacturonic acid chains in a manner described by egg-box model. In the
presence of H+ ions the gelation of pectin will occur, a source of divalent ions, generally
calcium ions is required to produce the gels that are suitable as vehicles for drug delivery.
Pectin used mainly for these formulations is that it is water soluble, so organic solvents are
not used in the formulation. Divalent cations present in the stomach, carry out the transition
of pectin to gel state when it is orally25 administered.
Guar gum
Properties
Guar gum is also called as guaran of naturally occurring gum which is obtained from the
endosperm of the seed. Guar gum is insoluble in hydrocarbons, fats, esters, alcohols and
ketones but soluble in water. These show its dispersibility in both cold and hot water that it
is soluble in both cold and hot water to form colloidal solution at low amount. Guar gum has
derivatives are used in targeted delivery systems in the formation of coating matrix systems,
nano-microparticles and hydrogels. Guar gum also has derivatives such as graft polymers
like polyacrylamide grafted guar gums that have good colon properties. It can also be used
as a polymer in matrix tablets which shows controlled release.
Carbopol
Properties
Carbopol is a polyacrylic acid (PAA) polymer, which changed to gel as the pH is raised
from 4.0 to 7.4. Carbopol remains in solution form at acidic pH but transform into a low
viscosity gel at alkaline pH. HPMC is used in combination with carbopol which enhance
viscosity of carbopol solution, while reducing the acidity of the solution. Comparing
different types of poly (acrylic acid) (Carbopol 940-934-941and 910) concluded that
Carbopol 940 showed superiorappearance and clarity.

Xyloglucan
Properties
Xyloglucan is also called as tamarind gum which is a polysaccharide obtained from the
endosperm of the seed. Xylogulcan consists of three different oligomers like
heptasaccharide, octasaccharide, nonsaccharide, which differ in number of galactose side
chain. It is mainly used in oral, rectal, ocular drug delivery due to its non- toxic,
biodegradable and biocompatible property. Like, poloxamer it exhibits gelation28 on
heating refrigerator temperature or cooling from a higher temperature.
Gellan gum
Properties
Gellan gum is an anionic hetero polysaccharide, secreted by microbe Sphingomonas elodea.

It consists of glucose, rhamnose, glucuronic acid and linked together to obtained a
tetrasaccharide unit. Gelrite29 is deacetylatedgellan gum, obtained by treating gellan gum
with alkali to remove the acetyl group in the molecule. Due to instillation, gelrite forms gel
because in presence of calcium ions. The gelation includes the formation of double helical
junction zones followed by aggregation of double helical segment to form three dimensional
networks30 by complexaton with cations and hydrogen bonding with water. In food
industry, gellan gum is used as suspending and stabilizing agent.
Alginic acid
Properties
It is a linear block copolymer polysaccharide consists of β- D-mannuronic acid and α-L-

glucuronic acid residues joined by 1,4-glycosidic linkages. In each block and the
arrangement of blocks along the molecule vary depending on the algal source. Dilute
aqueous solutions of alginates form firm gels on addition of diandtrivalent metal ions by a
cooperative process involves consecutive glucuronic residues in the α-L glucuronic acid
blocks of the alginate chain31.Alginic acid used as a vehicle for ophthalmic formulations,
since it exhibits favorable biological properties such as biodegradable and non toxic.

Xanthum gum
Properties
Xanthan gum has high molecular weight extra cellular polysaccharide which is produced by
the fermentation of the gram-negative bacterium Xanthomonascampestris. The primary
structure of this naturally produced cellulose derivative contains a cellulosic backbone (β-
D-glucose residues) and a trisaccharide side chain of β-D-mannose- β-D-glucuronic acid-α-
D-mannose attached with alternate glucose residues of the main chain33. Xanthan gum is
soluble in cold and hot water as well as alkaline and acidic conditions. It exhibits good
stability at alkaline conditions.
Chitosan
Properties
Gelling of chitosan occurs by two changes such as pH responsive change and temperature
change. Chitosan is a natural component of shrimp and crab shell which consist of
biodegradable, thermosensitive, polycationic polymer obtained by alkaline deacetylation of
chitin. Chitosan is a biocompatible pH dependent cationic polymer, which can remains
dissolved in aqueous solutions up to a pH of 6.2. Neutralization of chitosan aqueous solution
to a pH exceeding 6.2 leads to precipitation by the formation of a hydrated gel34, 35.
HPMC
Properties
Cellulose is consists of glucan chain which has repeating β-(1, 4)-D-glucopyranose unit.
Some natural polymers like HPMC, MC and EC these exhibit temperature sensitive sol-gel
phase transition. Cellulose material will increases its viscosity when temperature is
decreases while its derivatives like HPMC, MC, will also increase its viscosity when
temperature is increased. MC is a natural polymer composed of native cellulose with
alternate methyl substitution group on its chain. At low temperature (300C) solution is in
liquid form and when temperature is increases (40-500C) and gelation occurred.

Poloxamer
Poloxamer are water soluble tri-block copolymer. It consists of two polyethylene oxide
(PEO) and polypropylene oxide (PPO) core in an ABA configuration.
Properties
Poloxamer is commercially available as Pluronic and has good thermal setting property and
increased drug residence time. It mainly used as gelling agent, emulsifying agent and
solubilizing agent. Poloxamer gives colourless, transparent gel. It depends upon the ratio
and distribution of hydrophilic and hydrophobic chain several molecular weights available,
having different gelling property.
APPLICATIONS OF IN SITU POLYMERIC DRUG DELIVERY SYSTEM 45
Oral drug delivery system
The pH-sensitive hydro gels have a potential use in site-specific delivery of drugs to specific
regions of the GI tract. Hydro gels built of varying proportions of cross linked PEG and
PAA derivatives allowed in preparing silicone microspheres, which produce prednisolone in
the gastric medium or showed gastro protective property. Cross-linked dextran hydro gels
with a faster swelling under high pH conditions, whereas other polysaccharides such as
amidaded pectin‟s, inulin and guar gum were investigated in order to improve a potential
colon-specific drug delivery system. The formulations of gellan and sodium alginate both
contain a complexed calcium ion that undergoes a process of gelation by releasing of these
ions in the acidic environment of the stomach.
Ocular drug delivery system
In ocular delivery system natural polymers like alginic acid, inulin, &xyloglucan, inulin are
most commonly used. For local ophthalmic delivery system different compounds such as
autonomic drugs, anti-inflammatory agent & antimicrobial agent,are used to release intra
ocular tension in glaucoma. Conventional delivery system often result in poor availability &
therapeutic response due to high tear fluid turn over & dynamics leads rapid elimination of
the drug from the eye so, the overcome the bioavailability problem ophthalmic in-situ gel

were developed. To improve the bioavailability viscosity enhancers such as Carboxy Methyl
Cellulose, Hydroxy Propyl Methyl Cellulose, Carbomers, Poly Vinyl alcohol used to
improve the viscosity of formulation in order to prolong the precorneal residence time &
increases the bioavailability, easy to manufacture. Penetration enhancer such as
preservatives, chelating agent, surfactants are used to develop corneal drug penetration.
Nasal drug delivery system
In nasal in-situ gel system xanthan gum and gallan gum are used as in-situ gel forming
polymers Momethasonefuroate used to evaluate for its efficacy for the treatment of allergic
rhinitis. Animal study is used to conduct allergic rhinitis model & effect of in-situ gel on
antigen induced nasal symptoms in sensitizes rats was observed. In-situ gel was found to
inhibit the increase in nasal symptoms are compared to marketed preparation nosonex
(Momethasonefuroate suspension 0.05%).
Rectal and vaginal drug delivery system
The rectal route may be used to deliver many types of drugs that are formulated as liquid,
semisolid (ointments, creams and foams) and solid dosage forms (suppositories).
Acetaminophen an anti inflammatory drug formulated as rectal in situ gel by using
polycarbophil and poloxamer F188 and poloxamer 407 as synthetic polymer forming in situ
gelling liquid suppository which is considered as an synthetic polymers forming in situ
gelling liquid suppository which is considered as an effective method shows enhance
bioavailability.
Injectable drug delivery system
In this drug delivery system are also formulated as in situ gels which obtained over the last
decade due to its uses as there is no surgical procedure is required and also patient
compliance. Mostly synthetic polymers and block copolymers are used in the formulation of
Injectable in situ gel. One example of inflammatory drug is Bupivacaine which is

formulated as a injectable in situ gel using poly(D,L-lactide), poly (D,L-lactidecoglycolide)
and PLGA as polymer shows prolong action drug in gel conditions.

Dermal and transedermal drug delivery
Pluronic F127 in thermally reversible gel was evaluated as vehicle for the percutaneous
administration of Indomethacin. In-vivo studies suggest that 20% w/w aqueous gel may be it
is used as practical base for topical administration of the drug. The combination of
iontophoresis and chemical enhancers resulted in synergistic enhancement of insulin
permeation.
Table 1.2: Commercial Formulations of In Situ Polymeric Systems46
Dosage Form Drugs Brand Name Company Country

Opthalmic Timolol maleate Timoptic-XE Merck and Co
Regel:depot- Paclitaxel Oncogel Macromed‟s drug
technology delivery
Injectable depot Interleukin -2 Cytoryn Macromed‟s drug
formulation delivery
Ophthalmic solution Azithromycin Azasite Insite Vision

Chapter 2 Aim, Objective and Rational
AIM:
The aim of this study is to formulate a gastroretentive floating in-situ gel (sol-gel) system
of Teneligliptin Hydrobromide Hydrate to control the release and further to improve its
absorption and bioavailability. This can be achieved throughstudying different related
factors and evaluations of gastroretentive property for the prepared formula.
RATIONALE FOR DRUG

Teneligliptin Hydrobromide Hydrateis aantidibetic drug which is a potent, reversible and
selective inhibitor of the enzyme DPP-4 (Dipeptidyl peptidase 4) which is involved in
the inactivation of the incretin hormones. Teneligliptin Hydrobromide Hydrate solubility
is 1.7mg/ml in water which also depends upon the pH and temperature of the solvent.
The bioavailability of Teneligliptin Hydrobromide Hydrate is63% - 85%.
RATIONALE FOR FORMULATION

To increase the bioavailability of Teneligliptin Hydrobromide Hydrate it would be
beneficial to develop a floating drug delivery system that delays the first pass
metabolism prolongs gastric residence time and releases drug in GI tract, where
absorption of Teneligliptin Hydrobromide Hydrate is more confined.
OBJECTIVES
The objective of this research work is to obtain better delivery of Teneligliptin
Hydrobromide Hydrate to the stomach and the proximal parts of the small intestine by
increasing the mean residence time (MRT) in the stomach. For this, floating insitu gel
are prepared to prolong the gastric emptying that provides maximum drug at the site of
absorption.
 Characterization of Teneligliptin Hydrobromide Hydrate
 Determination of Teneligliptin Hydrobromide Hydrate Solubility
 Preparation of Oral Teneligliptin Hydrobromide Hydrate Solution to Act as In-Situ
Gel
 Evaluation of Floating In-Situ Gel Teneligliptin Hydrobromide Hydrate Solution

Chapter 2 Aim, Objective and Rational
 To study the effect of polymer concentration by formulating different batches

containing different concentrations of the polymer blend.
 To study the effect of formulation variables such as Concentrations of Ion
Crosslinking Agent, Types and Concentrations of Polymers, Concentrations of Gas
Generating Agent.
 To evaluate the formulated insitu gel for the physio-mechanical characteristics:
physical appearance, In-Vitro Gelation Study,Gelation Time Determination,
Swelling Index, viscosity, In-Vitro Buoyancy Study, Density, pH, drug content.
 To carry out the in-vitro drug release studies of the formulated insitu gel.
 To evaluate the drug release kinetics.
 To carry out stability studies of optimized formulation.

Chapter 3 Literature Review
LITERATURE REVIEW OF FORMULATION
Swamy. N. G. N., et al. (2012)47: had reported that In situ forming polymeric
formulations are drug delivery systems that are in sol form before administration in
the nasal cavity, but once administered, undergo gelation in situ, to form a gel. The
formation of gel depends on factors like temperature modulation, pH change,
presence of ions and ultra violet irradiation, from which the drug gets released in a
sustained and controlled manner. Mucoadhesive in situ gel formulations have
demonstrated increase in the residence time in the nasal cavity as well enhancement
of the permeation characteristics of the drug. The in situ gel forming polymeric
formulations offer several advantages like sustained and prolonged action in
comparison to conventional drug delivery systems. With a brief introduction to nasal
drug delivery, in this paper, the use of novel mucoadhesive in situ gels for the
intranasal delivery of drugs is reviewed along with methods available for evaluation
of in situ gels.
Swati Pund., et al. (2012)48: had reported that Venlafaxine, a dual acting
antidepressant is a new therapeutic option for chronic depression. They analyzed the
transport of Venlafaxine through sheep nasal mucosa. Transmucosal permeation
kinetics of Venlafaxine was examined using sheep nasal mucosa mounted onto static
vertical Franz diffusion cells. Nasal mucosa was treated with Venlafaxine in situ gel
(100 μl,1% w/v) for 7 h. Amount of Venlafaxine diffused through mucosa was
measured using validated RP-HPLC method. After the completion of the study
histopathological investigation of mucosa was carried out. Ex vivo studies through
sheep nasal mucosa showed sustained diffusion of Venlafaxine with 66.5%
permeation in 7 h. Histopathological examinations showed no significant adverse
effects confirming that the barrier function of nasal mucosa remains unaffected even
after treatment with Venlafaxine in situ gel. Permeation through sheep nasal mucosa
using in situ gel demonstrated a harmless nasal delivery of Venlafaxine, providing
new dimension to the treatment of chronic depression.

Yuan Yuana., et al. (2012)49: had reported that Poloxamer 407 has excellent thermo-
sensitive gelling properties. The main aim of the present investigation was to develop
thermo sensitive and mucoadhesive rectal in situ gel of Nimesulide (NM) by using
mucoadhesive polymers such as sodium alginate (Alg–Na) and HPMC. These gels
were prepared by addition of mucoadhesive polymers (0.5%) to the formulations of
thermosensitive gelling solution containing poloxamer 407 (18%) and Nimesulide
(2.0%). Polyethylene glycol (PEG) was used to modify gelation temperature and drug
release properties. The gelation temperature and drug release rate of the prepared in
situ gels were evaluated. Gelation temperature was significantly increased with
incorporation of Nimesulide (2.0%) in the poloxamer solution, while the addition of
the mucoadhesive polymers played a reverse role on gelation temperature. The
addition of PEG polymers increased the gelation temperature and the drug release
rate. Among the formulations examined, the poloxamer 407/Nimesulide/sodium
alginate/PEG 4000 (18/2.0/0.5/1.2%) exhibited the appropriate gelation temperature,
acceptable drug release rate and rectal retention at the administration site.
Bhandwalkar M.J., et al. (2012)50: had reported that in order to improve the
bioavailability of the antidepressant drug, Venlafaxine hydrochloride, in situ
mucoadhesive thermoreversible gel, was formulated using Lutrol F127 (18%) as a
thermo gelling polymer. Mucoadhesion was modulated by trying carbopol 934, PVP
K30, HPMC K4M, sodium alginate, tamarind seed gum, and carrageen an as
mucoadhesive polymers. Results revealed that as the concentration of mucoadhesive
polymer increased the mucoadhesive strength increased but gelation temperature
decreased. Formulation was optimized on the basis of clarity, pH, gelation
temperature, mucoadhesive strength, gel strength, viscosity, drug content, diffusion
through sheep nasal mucosa, histopathological evaluation of mucosa, and
pharmacodynamic study in rats.
Jyotivardhah Jaiswal., et al. (2012)51: had reported Metoprolol Succinate undergoes

hepatic first pass metabolism and hence it shows poor bioavailability. The objective
of present research work is to improve bioavailability by formulating thermo
reversible in-situ nasal gel. Formulation was developed to reduce the mucociliary
clearance by using mucoadhesive polymer in gel, thereby increasing the contact time
with nasal mucosa and hence improving the absorption of drug. The in-situ gelation

was achieved by the use of pluronic F127, which exhibits thermo reversible gelation
property and Sodium alginate was used as the mucoadhesive agent. Gels were
prepared by cold technique method and characterized by Gelation Temperature,
Permeation Studies, Histopathological Evaluation, pH, Drug Content, Rheological
studies, Gel strength and drug polymer interaction study.
Shital Uttarwar., et al. (2012)52: had reported " Gel" is the state between the liquid
and solid which consists of physically cross linked networks of long polymer
molecules with liquid molecules trapped within a three dimensional polymeric
network swollen by a solvent. The aim of present study was formulation of in situ
gelling system for nasal administration for an antiemetic drug Ondansetron
Hydrochloride by using Pluronics 127P and Pluronics 68. All the formulations
showed compliance with pharmacopoeial standards.
Pramod K. Kolsure., et al. (2012)53: had Developed the thermo reversible

Zolmitriptan nasal gel was aimed to improve absorption and patient compliance. In
the present research work, mixture of pluronic F-127 (Poloxamer 407) and pluronic F-
68 (Poloxamer 188) were used to confer temperature- sensitive gelation property. To
modulate the gel strength and biadhesive force for Zolmitriptan nasal gel, bioadhesive
polymers such as sodium alginate, sodium carboxyl methyl cellulose and polyvinyl
pyrollidine (PVP K-25) were investigated. Incorporation of 25% w/w Zolmitriptan in
the nasal showed no effect on the gelation temperature of the pluronic mixtures, while
addition of the bioadhesive polymers reinforced the gel strength and the bioadhesive
force of the prepared nasal gel formulation. The effect was most pronounced with
sodium alginate. Increasing the concentration of bioadhesive polymers retarded the
release of Zolmitriptan from the pluronic gel. PVP has less effect on the drug release.
Histopathological examination of sheep nasal mucosa with control and optimized
formulation did not show an y histological damage to the nasal tissue.
Parmar Viram., et al. (2012)54: had reported that oral Metoclopramide hydrochloride
undergoes first-pass metabolism. Nasal delivery could protect drugs from this effect.
Mucoadhesive in situ gels for Metoclopramide hydrochloride with gellan gum were
formulated and evaluated. Metoclopramide Hydrochloride Insitu nasal gels (10%
w/w) were prepared at concentration of gellan gum 0.2%, 0.4%, 0.6% and 0.8% w/v

with xanthan gum 0.1%, 0.15% and 0.2% w/v as bioadhesive polymer and
benzalkonium chloride ( 0.01%) as preservative. The formulation were evaluated by
slower release rate during the first hr, Release kinetics followed diffusion model.
Microscopic results did not show any mucosal changes after diffusion study of the
optimized formulation.
Dattatraya J. Yadav., et al. (2012)55: had reported that aimed to formulate and
evaluate Nasal drug delivery system containing Salbutamol Sulphate was prepared for
improving the bioavailability & sustaining the drug release. Salbutamol sulphate is a
selective β2 adrenoreceptor agonist and rapidly absorbed from gastro intestinal tract
but it is subjected to first pass metabolism. Thus oral bioavailability is only 50%. The
main objective of present work is to enhance the bioavailability; reducing the dose.
Thermoreversible, bioadhesive polymers such as poloxamer and Hydroxy Propyl
Methyl Cellulose (HPMC) in the form of in situ gel by cold technique. The results
revealed that as the increase of bioadhesive polymer HPMC concentration, decrease
in gelation temperature (T1) and increase in gel melting temperature (T2). pH of all
formulation were found to be within the range between 5.5 to 6. The drug content for
all formulation was found to be 96%-100%. The mucoadhesive test indicates that the
level of HPMC increases, the mucoadhesive strength also increases. The developed
formulations had optimum viscosity. The optimized formulation shows the controlled
drug release.
Kote Amol P., et al. (2011)56: had reported that nasal drug delivery system offers
lucrative way of drug delivery of both topical and systemic therapies. The high
permeability, high vasculature and low enzymatic environment of nasal cavity are
well suitable for systemic delivery of drug molecules via nose. The noninvasiveness
and self administrative nature of nasal delivery also attracts the formulation scientists
to deliver protein and peptide compounds. Despite of all the advantages of nasal drug
delivery, the bioavailability of nasally administered products, especially for protein
and peptide molecules, is affected by many barriers such as physiological barriers,
physicochemical barriers, and formulation barriers.
Shivanand Swamy et al,57 prepare and evaluate novel in situ gum based ophthalmic
drug delivery system of linezolid. Hydroxypropyl guar (HPG) and xanthum (XG)

were used as gum with the combination of hydroxyethyl cellulose (HEC), carbopol
(CP), and sodium alginate as viscosity enhancing agents. Suitable concentrations of
buffering agents were used to adjust the pH to 7.4. All the formulations were
sterilized in an autoclave at 121°C for 15mins. The formulations were evaluated for
clarity, pH measurement, gelling capacity, drug content estimation, rheological study,
in vitro diffusion study, antibacterial activity, isotonicity testing, eye irritation testing.
The developed formulations exhibited sustained release of drug from formulation over
a period of 6hr thus increasing residence time of the drug. The optimized formulations
were tested for eye irritation on albino rabbit (male) using the Draize test protocol
with crossover studies. The formulations were found to be non-irritating with no
ocular damage or abnormal clinical signs to the cornea, iris or conjunctiva observed.
Thus these in situ gelling systems containing gums may be avaluable alternative to the
conventional systems.
Binu Chaudhary et al,58 develop an oral mucosal drug delivery system to facilitate
the local and systemic delivery of acyclovir for the treatment of oral herpes infection
caused by the herpes simplex virus (HSV). An in situ gelling system was used to
increase the residence time and thus the bioavailability of acyclovir in oral mucosa.
Temperature and pH trigged in situ gel formulations were prepared by cold method
using polymers like poloxamer 407, carbopol 934, and HPMC. Glycerin and a
mixture of tween 80 and ethanol (1 : 2 ratio) were used as the drug dissolving solvent.
The pH of carbopol containing formulation was adjusted to pH 5.8while the pHof
poloxamer solutionwas adjusted to pH 7. These formulationswere evaluated for sol-
gel transition temperature, gelling capacity, pH, viscosity, spreadability, gel strength,
drug content, ex-vitro permeation, and mucoadhesion.The gelation temperatures of all
the formulations were within the range of 28–38∘C. All the formulations exhibited
fairly uniform drug content (98.15–99.75%). Drug release study of all the
formulations showed sustained release properties.The release of drug through these in
situ gel formulations followed theHiguchi model and Korsmeyer peppasmodel
mechanism.
Dipal R. Prajapati et al,59 Floating Drug Delivery System (FDDS) are invented to
retain the drug in the stomach and applicable for drugs with poor solubility and low
stability in intestinal fluids. The Main work of FDDS is making the dosage form less
dense than the gastric fluids to make it float on them. This research is directed

towards overcoming physiological adversities such as short gastric residence time

(GRT) & unpredictable gastric emptying time (GET). The main contribution of this
work lies in the study of Floating Drug delivery System with its types and
mechanisms. This study shall help to learn about gastric retention, various approaches
to produce gastro retention of drug delivery system with special discussion on floating
in-situ gel. This offers various advantages like prolonged and sustained action in
comparison to conventional drug delivery system.
Budumuru Padmasri et al60, review on in situ gelling systems becomes one of the
most popular and prominent. It had a tremendous potential advantage of delivery
systems due to many benefits like easy to use simple manufacturing; improve both
adherence and patient comfort by minimizing the frequency of drug administration by
its unique characteristics feature of sol to gel transition. It also provides in situ gelling
nanoemulsions, nanosphere, microspheres, and liposomes. The drawbacks associated
with conventional systems of both solutions and gels, such as accurate dosing, ease of
administration overcome by using in situ gelling systems. This review focused on
definitions, types, advantages, disadvantages, polymers used, and suitable
characteristics of polymers, including the preparation of in situ gels covered in the
introduction. Approaches, applications, and evaluation of in situ gels were explained
with examples.
Jincy Elizebeth Antony et al61, develop a novel floating in-situ gelling system for
sustained drug delivery of Clarithromycin for stomach ulcer. The in-situ gelling
system were prepared by dissolving different concentrations of gelling polymers like
sodium alginate, gellan gum in deionized water at 70°C. After cooling to 40 °C fixed
amount of drug, CaCO3 and released retardant polymer xanthan gum were dispersed
with continuous stirring. All formulations showed pH in the range of 6.72 to 7.25,
drug content was found to be in the range of 86.66% to 96.66%, floating lag time was
<2 min, duration of floating was >12 h for all the formulations. It was observed that
viscosity of solution increases with an increase in polymer concentration. Invitro drug
release was found to be in between 58.88% to 82.50% up to 12 h, and the maximum
drug release was shown by formulation F1 (1.0%w/v sodium alginate). Drug release
is inversely proportional to polymer concentration. The release kinetics of best
formulation F7 (1.0%w/v sodium alginate and 0.25% w/v xanthan gum) followed first
order with Higuchi diffusion mechanism. Hence, floating in-situ gelling system of

Clarithromycin is a novel approach to increase patient compliance with reduced

dosing frequency and increased residence time of drug in the stomach.
Rabiah Bashir et al62, The drugs having a narrow absorption window in the
gastrointestinal tract (GIT) when administered by oral route are often limited by poor
bioavailability due to incomplete drug release and short residence time at the site of
absorption. Novel drug delivery systems in the form of gastroretentive systems such
as floating systems, mucoadhesive, high-density, expandable have been developed as
they provide controlled delivery of drugs with prolonged gastric residence time.
Liquid orals are more prone to low bioavailability because they are eliminated quickly
from the stomach since they are subjected to faster transit from the stomach/
duodenum. The problems of immediate release and short gastrointestinal residence of
liquids are eliminated by formulating as oral in situ gels as they provide the best
means to overcome these problems The in situ gel dosage form is a liquid before
administration and after it comes in contact with gastric contents due to one or more
mechanisms gets converted to gel which floats on gastric contents. This achieves
increased residence as well as sustained release. This approach is useful for systemic
as well as local effect of drugs administered. This review gives a brief idea about
floating oral in-situ gel formation and research done by various scientists on a number
of drugs and polymers.
Beltran et al.63, reported the effect of gel charge and solution ionic strength on the
temperature‐induced collapse of NIPA gels. Experimental swelling equilibria are
compared with predictions based on a recently proposed oriented‐quasichemical
model. This model has been shown previously to describe lower critical solution
behavior in uncharged aqueous polymer solutions and gels (i.e., aqueous NIPA gel).
We apply the model here to ionized NIPA gel. Semiquantative predictions are
obtained for the effects of gel charge and solution ionic strength on temperature
dependent swelling behavior. The Journal of Chemical Physics is copyrighted by The
American Institute of Physics
Bertram et al.64, conducted the preparation and characterization of sponge‐like, in
situ gelling inserts based on bioadhesive polymers. Hydrophilic polymers
(carrageenan, Carbopol, chitosan, hydroxypropyl methylcellulose (HPMC) K15M and
E5, sodium alginate, sodium carboxy methylcellulose (NaCMC), polyvinyl
pyrrolidone (PVP) 90, xanthan gum) were dissolved with/without the model drug
oxymetazoline HCl in demineralized water and lyophilized into small inserts. The
drug release, water uptake, mechanical properties, X‐ray diffraction and bioadhesion
potential of the nasal inserts were investigated. The drug release decreased with
higher polymer content and increased drug loading of the insert. Bioadhesive nasal
inserts have a high potential as new nasal dosage form for extended drug delivery.
RuelGariepy et al.65, developed a novel injectable thermosensitive in situ gelling

hydrogel which falls under the BST‐Gel™ platform technology developed at
Biosyntech Inc. (Laval, QC, Canada), consists of a chitosan solution (C) neutralized
with β‐glycerophosphate (GP) that is liquid at room temperature but gels when heated
to body temperature. These experiments showed that one intratumoral injection of the
thermosensitive hydrogel containing paclitaxel was as efficacious as four intravenous
injections of Taxol® in inhibiting the growth of EMT‐6 cancer cells in mice, but in a
less toxic manner. Further histological analysis revealed that while the proportion of
necrotic areas was similar for the C/GP/paclitaxel and the Taxol®‐ treated tumors, a
disparity between tumor‐associated inflammatory cell populations may suggest
differing anti‐tumor mechanisms.
Chen T et al.66, compared the ability of two enzymes to catalyze the formation of
gels from solutions of gelatin and chitosan. Tyrosinase‐catalyzed gels were
strengthened by cooling below gelatin's gel‐point, which suggests that gelatin's ability
to undergo a collagen‐like coil‐to‐helix transition is unaffected by
tyrosinase‐catalyzed reactions. Further, tyrosinase‐catalyzed gelatin–chitosan gels
were transient as their strength (i.e. elastic modulus) peaked at about 5 h after which
the gels broke spontaneously over the course of 2 days. The strength of both
transglutaminasecatalyzed and tyrosinase‐catalyzed gels could be adjusted by altering
the gelatin and chitosan compositions. Potential applications of these gels for in situ
applications are discussed.
Lin et al.67, prepared a series of alginate and Pluronic‐based solutions as the in situ
gelling vehicles for ophthalmic delivery of pilocarpine. The optimum concentration of
alginate solution for the in situ gel‐forming delivery systems was 2% (w/w) and that
for Pluronic solution was 14% (w/w). The mixture of 0.1% alginate and 14% Pluronic

solutions showed a significant increase in gel strength in the physiological condition;

this gel mixture was also found to be free flowing at pH 4.0 and 25 °C. Both in vitro
release and in vivo pharmacological studies indicated that the alginate/Pluronic
solution retained pilocarpine better than the alginate or Pluronic solutions alone. The
results demonstrated that the alginate/Pluronic mixture can be used as an in situ
gelling vehicle to increase ocular bioavailability.
Jauhari et al.68, developed an in situ gel delivery system containing paclitaxel (PTX)
and mucoadhesives for sustained and targeted delivery of anticancer drugs. The
delivery system consisted of chitosan and glyceryl monooleate (GMO) in 0.33M citric
acid containing PTX. Transport of PTX from solution and gel delivery system was
performed in side by side diffusion chambers from apical to basal (A‐B) and basal to
apical (B‐A) directions. In vitro release studies revealed that within 4 hours, only
7.61% ± 0.19%, 12.0% ± 0.98%, 31.7% ± 0.40% of PTX were released from 0.18%,
0.30%, and 0.54% drug‐loaded gel formulation, respectively, in absence of Tween 80.
Paclitaxel has shown a polarized transport in all the cell monolayers with B‐A
transport 2 to 4 times higher than in the A‐B direction.
Escobar et al.69, made use of high viscosity hydro miscible vehicles such as
hydrophilic gels for controlled drug delivery, and represents an important area of
pharmaceutical research and development. Of these systems, Pluronic F‐127 (PF‐
127) provides the pharmacist with an excellent drug delivery system for a number of
routes of administration and is compatible with many different substances. Gels
containing penetration enhancers have proven to be especially popular for
administering anti‐inflammatory medications since they are relatively easy to prepare
and very efficacious.

LITERATURE REVIEW OF FOR DRUG
Gaurav S. Lodha et al70, In the current scenario type two diabetes mellitus and
hypertension have become prevalent in large number of population. But there are
many patients which are suffering from Type II Diabetes Mellitus as well as
hypertension. Such condition is called co-existent Type II Diabetes Mellitus and
Hypertension. In the present work an attempt is made to treat co-existent type II
Diabetes Mellitus and hypertension by formulating a Bilayer tablet of Teneligliptin
and Telmisartan. Both drugs are sustained released to give a day long relief to the
patients and to also reduce the dose frequency. Both the layers of the tablets were
formulated by wet granulation method. The granules were tested for angle of repose,
bulk density, tapped density, compressibility and Hausner’s ratio to check their
efficacy. Eleven different types of formulations were made using various polymers
and excipients with the drugs such as PVP K30, HPMC K4M, Starch, Crospovidone,
Lactose, Mannitol, Talc and Magnesium Stearate. From these 11 formulations F6
showed better tablet characteristics and drug release rate than other formulations.
Thus F6 is the best formulation in this study. Biological screening of the drugs
combination of Teneligliptin and Telmisartan was also done to check the presence of
antidiabetic activity of the combination which showed positive results.
Md Tarique Nadeem et al.,71 observed that patients on Metformin-Teneligliptin

exhibited better control over glycemic profile as well as lipid profile when compared
to patients who are on Metformin-Glimepiride combination. This study was
conducted in 60 patients They were divided into two groups based on their treatment
plan-Group A and Group B. The reductions in FPG and PPG were also found to be
significantly more in the Group B. furthermore analysis of clinical trials is required
for appropriate selection of best combination of anti-diabetic medication.
Lodha Gaurav S.72 worked to treat co-existent type II Diabetes Mellitus and
hypertension by formulating a Bilayer tablet of Teneligliptin and Telmisartan. Both
drugs are sustained released to give a day long relief to the patients and to also reduce
the dose frequency. Both the layers of the tablets were formulated by wet granulation
method. The granules were evaluated to check their efficacy. Eleven different types of

formulations were made using various polymers and excipients with the drugs. From
these 11 formulations F6 showed better tablet characteristics and drug release rate
than other formulations. Biological screening of the drugs combination of
Teneligliptin and Telmisartan was also done to check the presence of antidiabetic
activity of the combination which showed positive results.
Anjani Mahesh Sharma et al73., describes a simple, accurate, precise and

reproducible RP-HPLC method for simultaneous estimation of Teneligliptin
Hydrobromide Hydrate (TEN) and Metformin Hydrochloride (MET) in a combined
tablet dosage form. Separation was achieved on Shimadzu shimpack C18 using
50mM potassium dihydrogen orthophosphate (KH2PO4) buffer pH 3: Methanol
(40:60) as mobile phase, at flow rate of 0.8mL/min. The UV detection wavelength
was 254 nm. The method was successfully employed for the simultaneous estimation
of Teneligliptin Hydrobromide Hydrate and Metformin Hydrochloride in a combined
tablet dosage form and validated as per ICH guidelines.
K.R. Danao et al.,74 reviewed that Teneligliptin as an antidiabetic drug concerning

about the mechanisms of action, pharmacokinetic study, pharmacodynamic study,
toxicological study and dose and its contraindication. Teneligliptin is used in the
treatment of type II diabetes mellitus. Teneligliptin is currently used in cases showing
insufficient improvement in glycemic control. In adults, Teneligliptin is orally
administered at a dosage of 20 mg once daily, which can be increased up to 40 mg per
day. Due to the metabolites of this drug are eliminated via renal and hepatic excretion
so, adjustable dose is not required to renal impairment patient. In this review, all the
clinical data is described.
Abhijeet Jain et al.,75 evaluated the effects of Metformin and Teneligliptin on

HbA1c. 100 adult patients (age >18 years) of type 2 DM were evaluated for possible
inclusion in this study. 50 patients were started with Teneligliptin 20 mg/day along
with Metformin 1000 mg/day. 50 patients were started with placebo while continuing
with Metformin 1000 mg daily. Various parameters were measured at baseline, 12th
week and 24th weeks. All patients tolerated drugs well without any side effects. This
study showed that Teneligliptin can be an effective alternative to other drugs for add
on therapy to the patients who are inadequately controlled with Metformin alone.

Ashim Kumar Sen et al.,76 developed and validated three new UV

spectrophotometric methods namely simultaneous equation, absorbance ratio and first
derivative (zero crossing) spectroscopic methods for simultaneous estimation of
Teneligliptin Hydrobromide Hydrate and Metformin Hydrochloride in tablet
formulation. Teneligliptin Hydrobromide Hydrate and Metformin Hydrochloride was
estimated using 237 and 247.5 nm in absorbance ratio method. Developed methods
were validated according to ICH guidelines.
M.K.Kim et al.,77 studied study was to assess the efficacy and safety of Teneligliptin
in combination with Metformin in Korean patients with type 2 diabetes mellitus who
were inadequately controlled with Metformin monotherapy. The differences between
the Teneligliptin and placebo groups regarding changes in HbA1c and fasting plasma
glucose levels were −0.78 % and −1.24 mmol/l (22.42 mg/dl), respectively, at week
16. The addition of Teneligliptin once daily to Metformin was effective and generally
well tolerated in Korean patients with type 2 diabetes.
Malviya V.R et al78, The objective of the present study was to formulate the oral
dispersible film of teneligliptin hydrobromide using Pullulan as a polymer and to
evaluate it with the different parameters. The drug-excipients studies were carried out
in order to determine any type of incompatibilities by using Fourier transmission
infrared spectroscopy (FT-IR). The oral dispersible films were prepared using solvent
casting method using Pullulan as a polymer. Propylene glycol was used as a
plasticizer. The prepared films were evaluated for the parameters like physical
appearance, thickness, folding endurance, In vitro disintegration, mechanical
properties, surface pH, drug content uniformity, taste evaluation, in vitro dissolution
test and stability study. The T6 formulation was found to be optimized, stable and
appropriate in its evaluation parameters than compared to other formulations. The
folding endurance was found to be 282 ± 1.59, disintegration time was found to be 05
± 0.57, thickness was found to be 0.064±0.001, tensile strength was found to be 5.89,
the % elongation was found to be 26.08, the maximum percentage drug release was
found to be 95.90 % in 30 minutes. The drug content was found to be 99.90 with
surface pH of 6.4. In the stability studies of the formulation the product was found to
be stable for 90 days. The oral dispersible film is simple to administer and very much

effective for the patients and the prepared film of teneligliptin proves to be potential
candidate for safe and effective oral dispersible drug delivery.
Shailesh Kulkarni et al79, During chronic treatment of diabetes mellitus, a few

patients may need combination therapy with metformin hydrochloride (MH). Such
combinations are available in the form of tablets. However, the size of these tablets is
large and may lead to difficulty in swallowing, especially in case of geriatric and
dysphagic patients. To help such patients, an alternate dosage form such as an oral
jelly of teneligliptin in immediate release form containing MH in extended release
may offer better convenience. The current research focuses on development of oral
jelly to provide palatable, unit dose, easy to swallow, easy to carry pouches, having
similar in vitro profile against marketed tablets. The developed oral jelly formulation
is optimized using design of experiments. The objective of present work is to develop
and characterize dual release jelly formulation containing teneligliptin in immediate
release form and MH in the form of an extended release pellets for the treatment of
diabetes mellitus to improve patient compliance.
Snehal S Manekar et al,86 Teneligliptin Hydrobromide is a long-acting, orally

bioavailable, pyrolidone anti-diabetic activity with a solubility of 1.7mg/ml in water
which also depends upon the pH and temperature of the solvent. So, Solid dispersion
of drug with different polymers an attempt was made to improve dissolution of
teneligliptin hydrobromide. The aim of this study was to prepare, characterize and
compare solid dispersions of poorly water soluble anti diabetic drug by using PVP
and HPMC for enhancing the dissolution rate of the drug. The solid dispersions were
prepared by physical mixing method and kneading method at 1:1, 1:2 and 2:1 ratios of
drug to polymer. The drug-excipient interaction study showed that the drug and
polymers were compatible with each other. The formulations were evaluated for
percent drug content, micromeritics and in-vitro dissolution studies. In the present
study it was seen that there was an increase in in-vitro drug release for solid
dispersion as compared to the pure drug taken alone. Based on the pattern of drug
release, the kneading method showed more drug release as compared to physical mix
method. In physical mix method, the rate of dissolution of teneligliptin hydrobromide
was increased in teneligliptin and Polyvinylpyrrolidone (PVP) with the proportion of
(1:2) when compared to the other formulations. In kneading method, the rate of

dissolution of teneligliptin hydrobromide was increased in drug and

Hydroxypropylmethylcellulose (HPMC) with the proportion of (1:2) when compared
to the other formulations. Finally, solid dispersion containing HPMC, as a carrier,
gave faster dissolution rates among all the formulations and was selected as the
optimized formulation inthis study.

Chapter 4 Drug and Excipent profile
DRUG PROFILE
Teneligliptin Hydrobromide Hydrate64
Figure 4.1: Teneligliptin structure
Structure:
Molecular formula : C44H67Br5N12O3S2
Molecular weight : 1275.741 g/mol
IUPAC name : [(2S,4S)-4-[4-(5-methyl-2-phenylpyrazol-3-yl) piperazin-1-
Yl] pyrrolidin-2-yl] -(1,3-thiazolidin-3-yl) methanone; Hydrate; pentaHydrobromide
CAS Number : 1572583-29-9
Therapeutic group : Oral antihyperglycemic drugs
Physical and chemical parameters
Appearance : off - white crystalline powder
Solubility : Freely soluble in Water and dimethyl sulfoxide, and
Sparingly soluble in methanol
Log P : 1.42
pKa : 9.38

Melting point : 223-226°C
Storage : store in well closed, light resistance containers
Pharmacokinetics
Absorption : Oral Cmax 180.20 ng/mL: Tmax 1.8 hrs for 20 mg
Protein binding : 78% - 80%
Volume of distribution : 8.906 L/Kg
Bioavailability : 63% - 85%
Half-life : 26.9 hr
Metabolism : CYP450 3A4 & FMO 1 - 3
Excretion : 45.4% excreted in the urine & 46.5% excreted in the
Faces
Mechanism of Action:
The mechanism of Teneligliptin is to increase incretin levels (GLP-1 and GIP), which
inhibit glucagon release, which in turn increases insulin secretion, decreases gastric
emptying, and decreases blood glucose levels
Figure 4.2: Mechanism of action of teneligliptin

Pharmacodynamics
Teneligliptin inhibits concentration-dependent human plasma DPP-4 activity, and its IC50
value (95% CI) was 1.75 (1.62 - 1.89) nmol/L [26]. In the glucose tolerance test using
Zucker Fatty rat, an obesity model showing insulin resistance and abnormal glucose
tolerance, Teneligliptin increased plasma active form GLP-1 concentration and plasma
insulin concentration by its single-dose administration. In patients having type 2 diabetes
mellitus, the administration of 20 mg Teneligliptin once daily inhibited the plasma DPP-4
activity and increased the plasma active form GLP-1 concentration.
Safety
The dose of Teneligliptin administrates 10 and 20 mg respectively. There was not any
significant adverse effect observed in Teneligliptin and placebo doses like hypoglycemic
symptoms. Nasopharyngitis, ketonuria, glucosuria and proteinuria were reported in ≥5% of
patients in any group. Combination of Teneligliptin with Glimepiride involving 195
patients, hypoglycemic symptoms were reported by 2.1% in the Teneligliptin group and
3.1% in the placebo group during the combined dose, showing no significant difference
between the two groups. All of the events were classified as mild and did not result in study
discontinuation.
Combination of Teneligliptin with Pioglitazone involving 200 patients, the incidence of

pioglitazone monotherapy shown effect peripheral edema at 12 weeks in the present study.
In addition, there was not observed symptoms to increase in the incidence of peripheral
edema, even if the drug was administered for a long time and the concomitant
administration of Teneligliptin and Pioglitazone doesn’t an increase in the incidence of
edema.
Drug-drug interaction
Drugs like Sulfonylurea, fast-acting insulin secretagogue, α-glucosidase inhibitor,

Biguanide, Thiazolidinediones, GLP-1 analog preparation, SGLT2 inhibitor, Insulin
preparation Since hypoglycemia might occur, these drugs should be administered while
carefully observing the patient’s Condition. Particularly, when co administered with

sulfonylurea or insulin formulation, there is a possibility of higher risk of hypoglycemia. In

order to reduce the risk of hypoglycemia caused by sulfonylurea or insulin formulation,
consider decreasing the quantity of sulfonylurea or insulin formulation.
β-blocking agents Salicylic acid Monoamine oxidase inhibitor, Since the blood sugar may
further decrease, these drugs should be administered while carefully observing the Patient’s
condition in addition to blood sugar level.
Adrenalin and adrenocortical hormone Since the blood sugar may increase, these drugs
should be administered while carefully observing the Patient’s condition in addition to
blood sugar level.
OTHER EXCIPIENTS58-64
HYDROXY PROPYLMETHYL CELLULOSE
Non-proprietaryNames :BP:Hypromellose
PhEur:Hypromellose
Synonyms:
BenecelMHPC,E464,hypromellosum;Methocel;methylcellulosepropyleneglycol
ether;methylhydroxylpropylcellulose;Metolose;MHPC;Pharmacoat;T
ylopur;TyloseMO.
Chemical Name: Cellulosehydroxypropylmethylether
StructuralFormula:

Figure 4.3: Structure of HYDROXY PROPYLMETHYL CELLULOSE

WhereRisH,CH3,or CH3CH(OH)CH2
Descriptions:
Hypromellose is an odorless and tasteless, white or creamy white fibrous or granular powder.
Typical Properties:
Acidity/alkalinity :pH=5.5–8.0fora1%w/waqueoussolution.
Ash : 1.5–3.0%
Density(bulk) : 0.341g/cm3
Density(tapped): 0.557g/cm3
Density (true) : 1.326g/cm3
Melting point : 190-208ºC
Glasstransition temperature :170–180ºC.
Loss on drying: <10.0%
Residue on ignition : 1.0%
Maximum Limits of Impurities:
Arsenic<3PPMHeavymetals<0.001%MethoxyPercent)
Moisturecontent

Hypromellose absorbs moisture from the atmosphere and surrounding air.

Solubility
Soluble in cold water, forming a viscous colloidal solution; practically

insoluble in chloroform, ethanol (95%), and ether, but soluble in mixtures of
ethanol and dichloromethane, mixtures of methanol and dichloromethane, and
mixtures of water and alcohol.
Specificgravity:1.26
Functional Category
Coating agent; film-former; rate-controlling polymer for sustained release;

stabilizing agent; suspending agent; tablet binder; viscosity-increasing agent
Pharmaceutical Applications
Hypromellose is widely used in oral, ophthalmic and topical pharmaceutical
formulations. In oral products, hypromellose is primarily used as a tablet
binder, in film-coating, and as a matrix for use in extended-release
tabletformulations. Concentrationsbetween 2% and 5% w/w may be used as
a binder in either wet- or dry- granulationprocesses. High-viscosity
gradesmay be used to retard the release of drugsfrom a matrixat levels of
10–80% w/w in tablets and capsules. Depending upon the viscosity grade,
concentrations of 2–20%w/w are used for film-forming solutions to film-
coat tablets.
CARBOPOL 934P
Non-proprietary Names:
BP: Carbomers
PhEur: Carbomera

USPNF: Carbomer
Synonyms: Acrypol, Carbomer, Polyacrylic acid.
Chemical Name: Carbomer
Empirical Formula:Carbomers comprises in the range of 56% and 68% of carboxylic acid
(COOH) monomers estimated as dry powder.
Molecular formula :C3H4O2)n
Molecular Weight: The molecular weight of carbomer resins is 7 X 105 to 4 X 109.

Estimated MC values of 104 to 400 gram per mole for Carbopol 940 and 237 to
600 gram per mole for Carbopol 941.
Functional Category:
 Emulsifying agent
 Suspending agent
 Release-modifying agent
 Bio adhesive
 Rheology modifier
 Tablet binder
Structural Formula: Carbopol polymers are made up of acrylic acid monomers

units repeated in chain. The acrylic acid polymer series are linked together by
cross linkage of allylpentaerythritol or allyl sucrose.
Figure 4.4: Structure of acrylic acid polymer

Applications
Carbomers are primarily employed for suspending or viscosity-increasing agents

in semisolid or liquid pharmaceutical formulations. Carbomers are major
ingredients in dermatological semisolid formulations such as emulsion-based
creams, oleaginous ointments, and transparent to translucent gels employed in
topical, vaginal, ophthalmic and rectal formulations.
A Carbomer grade with low benzene content as residual solvents is removed from
PhEur 2005, such as carbomer 934P. Carbomer 971P or 974P are low residuals
only of ethyl acetate, which are used in oral preparations, sustained release tablet,
in suspensions and tablets formulations. Carbomers are used in tablet formulation
as binder for dry and wet granulation processes as drug release rate controlling
excipient. In wet granulation method, granulating fluid is used as either water or
alcohol or an alcohol–water blend. Carbomer must be neutralized partly with
suitable alkalizer such as sodium hydroxide, triethanolamine, ammonia to employ
it in oil-in-water emulsion or cream. Carbomers are broadly utilized in
beautification products in cosmetics. Low viscous carbomer solutions are utilized
for medicated value for dryness of eyes.
Description:
Carbomers are white-coloured free flowing fluffy powder. Carbomer powder is

acidic in nature. Carbomers has a slight characteristic odour and the powder is
highly hygroscopic.
Typical Properties
pH: Carbomer solution are highly acidic in nature. The pH of the carbomer 0.5%
w/v dispersion in water ranges from 2.7 to 3.5. The pH of the carbomer 1.0% w/v
dispersion in water ranges from 2.5 to 3.0%.
The bulk density of the carbomer powder ranges from 1.76 to 2.08 g/cm3.
The tapped density of the carbomer powder ranges from 1.4 to 1.5 g/cm3.

The powdery form of carbomer powder changes to soft, rubbery material at

temperature range from 100 to 105°C.
Specific gravity: 1.41
Moisture content: normal water content is up to 2% w/w.
Viscosity (dynamic):Carbomers dispersions are low viscous and acidic in nature,

which when neutralized with suitable neutralizer produce highly viscous thick
gels. Carbomer powders are added in water at room temperature and dispersed
under vigorous stirring to form the colloidal dispersion. Formation of lumps
should be avoided while adding the carbomer. Carbomers should be neutralized
by the addition of a base.
Solubility: Carbomers are soluble in water. Neutralized carbomer gels are soluble
in organic solvents.
Safety
Carbomers polymers are widely employed in dermatological semisolid as well as

liquid formulation. They are also used in oral tablets and oral liquids
Regulatory Acceptance: Carbomers are enlisted in the Unites state food drug
administration IIG database for dermatological, Solid orals, liquid orals,
ophthalmic, transdermal and vaginal formulation.
POLOXOMER 188
Synonym: Kolliphor® P 188
Poloxamers are ABA-type co-polymers of poly (ethylene oxide) (PEO=A) and

poly (propylene oxide) (PPO=B). The approximate relative amount of PEO and
the average molecular weight of the PPO are indicated in the name of the
poloxamer. For example, P 188 succeeding the word Kolliphor® indicates a
poloxamer with ca. 80% m/m PEO (P 188; 8x10= 80%) and approximately
average molecular weight of PPO of 1800 (P 188; 18x100= 1800)

Kolliphor® P 188 Geismar is a block copolymer that is a synthetic copolymer of

ethylene oxide and propylene oxide represented by the following chemical
structure:
Appearance
Kolliphor® P 188 Geismar is produced as a white to almost white prill/powder.
Molecular Weight
The average molecular weight for Kolliphor® P 188 Geismar is 7680 to 9510
g/mol.
HLB
The HLB value of Kolliphor® P 188 Geismar is approximately 29.
Solubility
Kolliphor® P 188 Geismar is highly soluble in water.
Particle Size
Kolliphor® P 188 Geismar exhibits spherical prill particles of a mean diameter of

approximately 500 µm in size.
Cloud point
The cloud point for Kolliphor® P 188 Geismar is >100°C for a 1% and a 10%
aqueous solution.
Density
The true density of Kolliphor® P 188 Geismar is approximately 1.06 g/cm3.
The bulk density of Kolliphor® P 188 Geismar is approximately 0.56 g/cm3.
The tapped density of Kolliphor® P 188 Geismar is approximately 0.61 g/cm3.

Moisture sorption
The uptake of moisture for Kolliphor® P 188 Geismar is dependent on the

relative humidity of the environment, at moisture levels above 80% (RH)
significant moisture uptake is possible
Solubilization
Kolliphor® P 188 Geismar can be used in a multitude of solubilization examples

– more specifically the product may be a liquid solution, suspension or solid
tablet. Given the low critical micelle concentration (CMC) stabilizing and
solubilizing occurs at concentrations 1 to 2 orders of magnitude lower than for
standard ethoxylated surfactants.
APPLICATION
In solid solutions, such as amorphous solid dispersions (ASDs) produced via hot
melt extrusion (HME) and spray drying, Kolliphor® P 188 Geismar may be used
as a plasticizing agent and/or solubilizer to further increase poorly water drug
solubility in the matrix. As a plasticizer, it lowers the Tg of many polymers and
allows for processing at lower shear rates and/or temperatures.
Poloxamers are a widely used pharmaceutical ingredient in multitude of

applications, most notably, as a dispersing agent, emulsifier, solubilizer, tablet
and capsule lubricant, wetting agent, stabilizer for oral and topical suspensions,
gelling agent in topical formulations and shear protectant.
Tablet 4.1: Indications with used concengtration of POLOXOMER 188
Indication Concentration (w/w%)

Gelling agent 15 to 50
Suspension stabilizer 0.1 to 5
Tableting 1 to 10
Wetting Agent 0.01 to 5
Emulsifier 1 to 5
Foaming agent 1 to 3
Plasticizer (matrix) 5 to 15

POLOXOMER 407
Synonym:Kolliphor® P 407
Ph. Eur., Poloxamer USP/NF
Poloxamers are ABA-type co-polymers of poly (ethylene oxide) (PEO=A) and poly
(propylene oxide) (PPO=B). The approximate relative amount of PEO and the average
molecular weight of the PPO are indicated in the name of the poloxamer.
Appearance
Kolliphor® P 407 Geismar is produced as a white to almost white prill/powder.
Molecular Weight
The average molecular weight for Kolliphor® P 407 Geismar is 10000 to 14600 g/mol.
The product contains nominally 95 to 105 ethylene oxide units and 54 to 60 propylene
oxide units, with a rough concentration of oxyethylene of 71.5 to 74.9 % based on the
current monograph specification.
Viscosity
Poloxamers, and Kolliphor® P 407 Geismar exhibits a thermo reversible gelling behavior
that occurs as a function of temperature. At low concentrations, aqueous concentrations
exhibit Newtonian flow properties and negligible viscosity alterations to that of water,
however, at higher temperatures, the solutions begin to exhibit non-Newtonian flow
behavior.
HLB
The HLB value of Kolliphor® P 407 Geismar is approximately 22.
Solubility
Kolliphor® P 407 Geismar is highly soluble in water. Note that Kolliphor® P 407
Geismar is significantly easier to dissolve in cold water.
Particle Size
Kolliphor® P 407 Geismar exhibits spherical prill particles of a mean diameter of
approximately 500 μm in size.
Cloud Point

The cloud point for Kolliphor® P 407 Geismar is >100 °C for a 1% and a 10% aqueous
solution.
Density
The true density of Kolliphor® P 407 Geismar is approximately 1.06 g/cm3
The bulk density of Kolliphor® P 407 Geismar is approximately 0.50 g/cm3.
The tapped density of Kolliphor® P 407 Geismar is approximately 0.60 g/cm3.
Moisture Sorption
The uptake of moisture for Kolliphor® P 407 Geismar is dependent on the relative
humidity of the environment, at moisture levels above 80% (RH) significant moisture
uptake is possible.
Application
Poloxamers are a widely used pharmaceutical ingredient in multitude of applications,
most notably, as a dispersing agent, emulsifier, solubilizer, tablet and capsule lubricant,
wetting agent, stabilizer for oral and topical suspensions, gelling agent in topical
formulations.
Tablet 4.2: Indication and concentration of POLOXOMER 407
Indication Concentration (w/w%)
Gelling agent 15 to 50
Suspension stabilizer 0.1 to 5
Tableting 1 to 10
Wetting Agent 0.01 to 5
Emulsifier 1 to 5
Foaming agent 1 to 3
Plasticizer (matrix) 5 to 15
Poloxamers as Gelling agents
Poloxamers can be used as gelling agents to build structure in a topical aqueous solution.
Gels using Kolliphor® P 407 Geismar can exhibit thermo reversible behavior; they form
gels which are liquids at room temperature but solidify upon contact with skin.

Chapter 5 Materials and Methods
MATERIALS:
The following materials collected for the experimental work done.
Table 5.1: List of materials
SR.N DRUG/EXCIPIENTS GRADE GIFTED/MFG.BY

O.
1 Teneligliptin AR Amneal pharmaceuticals
2 Hydroxy Propylmethyl AR Loba Chemie Pvt
Cellulose
3 Carbopol 934p AR Loba Chemie Pvt
4 Poloxomer 188 AR Loba Chemie Pvt
5 Poloxomer 407 AR Loba Chemie Pvt
Table 5.2: List of Equipments
SrNo INSTRUMENTS SUPPLIER/MANUFACTURER

1
Digital weighing balance Sartoriousbalance– BT124S
2
UV Spectrophotometer UV–1800,M/sShimadzu
3
Infrared spectrophotometer FTIR–8700,M/sShimadzu
4 DissolutiontestapparatusLabIndiaLtd.
Dissolution test apparatus
5
pH meter LabIndia,pHmeter
6
Brookfield viscometer Brookfield viscometer DV2T/ AMETEK
IDENTIFICATION OF DRUG84-85
Method UV spetrophotometric methods for Teneligliptin
Preparation of 0.1N HCl : 8.5 ml of hydrochloric acid was diluted to 1000 ml with water
to get 0.1 N HCl. Determination of ʎmax U.V spectrum of Teneligliptin was carried out
in 0.1 N HCl Accurately weighed quantity of 10 mg Teneligliptin hydrobromide hydrate
(THH) was transferred to 100.0ml volumetric flask, added 30ml of 0.1 N HCl and
ultrasonicated for 10 minutes, volume was then made up to the mark with 0.1N HCl (100

µg/ml). The standard stock solution was diluted with 0.1 N HCl to obtain final
concentration of 20 µg/ml of THH.
The solution was then scanned in spectrum mode, from 400 nm to 200 nm, in 1.0 cm cell
against 0.1 N HCl as blank. Calibration curve Accurately weighed quantity of 10 mg
Teneligliptin hydrobromide hydrate (THH) was transferred to 100.0ml volumetric flask,
30ml of 0.1 N HCl and ultrasonicated for 10 minutes, volume was then made up to the
mark with 0.1 N HCl(100 µg/ml). From standard stock solution aliquot portions 0.5, 1.0,
2.0, 3.0, 4.0 and 5.0 ml were diluted individually to 10.0 ml with 0.1 N HCl
(concentration 10, 20, 30, 40 and 50 µg/ml, respectively). Absorbances of diluted
solutions were measured at 242.0 nm against 0.1 N HCl as blank.
PREFORMULATION STUDIES47-49
Preformulation study is defined as “investigation of physical and chemical properties of

the drug substance alone and combined with the excipients”. Preformulation studies are
the first step in the rational development of dosage form of drugs. It involves the
application of biopharmaceutical principles to the physicochemical parameters of the
drug with the goal of designing an optimum delivery system that is stable, bioavailable
and can be mass produced.
CHARACTERIZATION OF TENELIGLIPTIN48-51
Determination of Melting Point of TENELIGLIPTIN
The melting point of TENELIGLIPTIN was determined by the capillary tube method
according to the USP. A sufficient quantity of TENELIGLIPTIN powder was filled into
the capillary tube to give a compact column of 4-6 mm in height. The tube was
introduced in electrical melting point apparatus and the temperature was raised. The
melting point was recorded, which is the temperature at which the last solid particle of
TENELIGLIPTIN in the tube passed into liquid phase.

DRUG-EXCIPIENT COMPATIBILITY STUDIES45
The drug and excipients selected for the formulation were evaluated for physical and
chemical compatibility studies.
Physical Compatibility Study
The physical compatibility studies were conducted to provide valuable information to the
formulator in selecting appropriate excipients for the formulation. It was done by mixing
the drugs and the excipients and kept at room temperature and at 40°C and 75 ± 2 % RH.
Any change in colour of the physical mixture was observed visually.
Chemical Compatibility Study
Fourier transform infrared (FTIR) spectroscopy was performed using a Shimadzu FTIR
8400 Spectrophotometer from 4000 to 400/cm region, the spectrum was recorded. The
procedure consists of dispersing the sample (drug alone, Mixture of drug and excipients
and the optimized formulation) in KBr (200– 400 mg) and made into disc form by
compressing it with a pressure of 5 tons in a hydraulic press. The pellet was placed in the
light path and the spectrum was recorded.
PREPARATION OF ORAL IN SITU GEL OF TENELIGLIPTIN48-55
 •Sodium Alginate, Gellan Gum, Iota Carrageenan, HPMC K4M, Sodium Citrate,
Calcium Carbonate, Sodium bicarbonate, Sodium Saccharin, Propyl paraben
sodium and Methyl paraben sodium were weighed accurately.
 •Various concentrations of gelling polymer (Sodium Alginate or Gellan Gum)
were dissolved in deionized water with a weighed amount of Sodium Citrate on a
magnetic stirrer at 70°C.
 •Iota carrageenan solution was prepared separately by dissolving in deionized
water containing Sodium Citrate and heating to 80º C while stirring.
 •In another beaker, the required quantity of release retardant polymer HPMC
K4M was soaked in deionized water until completely dissolved.
 •Then, all the three solutions were mixed together with continuous stirring.
 •After the above solution has cooled down to 40°C, Calcium Carbonate, Sodium
bicarbonate and TENELIGLIPTIN were added.
 •Sodium Saccharin and Preservatives were mixed.
• Finally, the volume was adjusted with the deionized water, and the resultant
solution was stirred well and stored in amber-coloured bottles until further use.
Sodium Alginate
Or Gellan gum
Iota-Carrageenan HPMC K4M
solution solution
Mixed together runder Magnetic
Stirrer at40°C
Polymer Solution
Addition of Drugsolution
Iota-Carrageenan
solution
AdditionofSweeteningagenta
nd
Preservatives
In-situ gelling
formulation
Fig.5.1: Schematic representation of the preparation of Oral In situ gel46

Table 5.3: Composition of the In situ gelling formulations
Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9 F10
Teneligliptin
24 24 24 24 24 24 24 24 24 24
(mg)
Sodiumalginate
1.0 - 0.5 - 1.0 - 1.0 - 0.5 0.5
(%w/v)
Gellangum
- 0.3 0.15 - - 0.3 - 0.3 0.15 0.15
(%w/v)
Iotacarragee
nan - - - 0.25 0.2 0.2 0.25 0.25 0.2 0.25
(%w/v)
HPMC K4M
0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2
(%w/v)
Sodium citrate
0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6
(%w/v)
Calcium
carbonate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
(%w/v)
Sodium
Bicarbonate 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3
(%w/v)
Sodium
Saccharin 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
(%w/v)
Methyl
parabensodium 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
(%w/v)
Propylparaben
0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02
sodium(%w/v)
Deionized
water (to 100 100 100 100 100 100 100 100 100 100
produceml)

CHARACTERIZATION OF IN SITU GEL50-56
Visual appearance
All the formulations were visually inspected for their appearance, clarity, and
consistency.
Measurement of pH
The pH for each of the formulations was measured using a calibrated pH meter. The
readings were recorded three times for each of the formulations and the averages of the
readings were considered.
In vitro gelation study
5 ml of the simulated gastric fluid (0.1N HCl, pH 1.2) was taken in a 15ml test tube,
maintained at 37°C, followed by the addition of 1 ml of the formulation using a pipette.
The pipette was positioned facing the surface of the fluid in the test tube and slowly the
formulation was released from the pipette. When the formulation came in contact with
the gelation medium, it was quickly converted into a gel-like structure. Based on the
stiffness of gel as well as the duration for which the gel remains as such the In vitro
gelling capacity was investigated.
The In vitro gelling capacity was mainly divided into three categories based on gelation
time and the time period the formed gel remains.
(+) : Gels in few seconds, disperse immediately
(++) : Gelation immediate remains for few hours
(+++) : Gelation after few minutes remains for extended periods
Determination of viscosity
Viscosities of the formulations were determined with the help of Brookfield’s digital
Viscometer (DV-II) +Pro using S21 spindle at 50 rpm and measurement was for done for
3 times with fresh samples used each time and the average reading was taken.

In vitro buoyancy study
The studies were conducted in a USP Type II dissolution apparatus using simulated
gastric fluid (pH 1.2) as the medium at 37±0.5°C. About 10 ml of the In situ gel
formulation was placed in the medium. The time taken by the In situ gel formulation to
float on the surface of the medium (floating lag time) and time period for which the
formulation remained buoyant (duration of floating) was noted.
Measurement of water uptake by the gel
To conduct this study, the In situ gel formed in 40 ml of 0.1N HCl (pH 1.2) has been
used. From each of the formulation, the gel part was separated from the buffer and the
excess buffer was blotted out with the help of Whatman filter paper. The gel was initially
weighed, followed by the addition of 10 ml distilled water to this gel. After every 30 min
interval, water was decanted and the weight of the gel was noted and the difference
between initial and final weight was calculated.
Measurement of density of gel
30 ml of the In situ formulation was poured into a beaker containing 50 ml of 0.1N HCl.
10 ml of the gel formed was taken in measuring cylinder and the weight of the gel was
measured. Using the weight as well as the volume of the gel, the density was calculated.
This method was followed for all the formulations.
Measurement of gel strength
30 g of the gel was taken in a 50 ml beaker and a 50 g weight was placed on the centre of
the surface of the gel and allowed to penetrate through the gel. The time taken by the 50 g
weight to penetrate 5 cm down through the gel was noted for all the formulations. The
same method was followed for 3 times for each fresh formulation and the average time
was noted.
Determination of the drug content
5 ml of the formulation equivalent to 3 mg of the drug was added to 80 ml 0.1N HCl (pH
1.2) in a 100 ml standard flask and stirred for 1 h in a magnetic stirrer. After 1 h, the

solution was filtered and diluted with 0.1 N HCl (pH 1.2). The drug concentration was
then determined by ultraviolet (UV) visible spectrophotometer at 242 nm against a
suitable blank solution.
In vitro drug release study of the In situ gel formulation
The dissolution studies were performed using a USP type II (paddle method) dissolution
apparatus. The dissolution medium used was 500 ml of 0.1 N HCl (pH 1.2), maintained
at 37ºC. The stirring rate was adjusted to 50 rpm. This speed was believed to simulate the
in vivo existing mild agitation and was slow enough to avoid the breaking of the gelled
formulation. At predetermined time intervals, 10 ml samples were withdrawn and
replaced by fresh dissolution medium, filtered through Whatman filter paper, diluted, and
assayed at maximum absorbance at 242 nm using UV-Visible Spectrophotometer.
RELEASE KINETICS OF THE OPTIMIZED FORMULATION56-62
To study the In vitro release kinetics of the optimized formulation of Teneligliptin oral In
situ gel, data obtained from dissolution study were plotted in various kinetics models.
Zero-order equation
The zero order release can be obtained by plotting cumulative % percentage drug
released vs. time in hours. It is ideal for the formulation to have a release profile of zero
order to achieve pharmacological prolonged action.
C=K0t
Where,
K0= Zero order constant t= Time in hours
First order equation
The graph was plotted as log % cumulative drug remaining vs. time in hours.
Log C= log C0- Kt/2.303
Where,

C0= Initial concentration of drug K= First order
t= Time in hours
Higuchi kinetics
The graph was plotted with % cumulative drug released vs. square root of time
Q = Kt½
Where,
K= constant reflecting design variable system (differential rate constant) t= Time in hours
The drug release rate is inversely proportional to the square root of time
Hixson and Crowell erosion equation
To evaluate the drug release with changes in the surface area and the diameter of
particles, the data were plotted using the Hixson and Crowell rate equation. The graph
was plotted by the cube root of % drug remaining vs. time in hours.
Q01/3 – Qt1/3 = KHCt
Where,
Qt= amount of drug released in time t. Q0= Initial Amount of drug
KHC= Rate constant for Hixson Crowell equation
Korsmeyer-Peppas equation
To evaluate the mechanism of drug release, it was further plotted in Korsmeyer - Peppas
equation as Log cumulative % of drug released Vs. Log time.
Mt/Mα = Ktn
Where
Mt/Mα = Fraction of drug released at time t

t = Release time
K= Kinetics constant (Incorporating structural and geometric characteristics of the

formulation)
N= Diffusional exponent indicative of the mechanism of drug release.
Table 5.4: Diffusion exponent and solute release mechanism
Diffusionexponent(n) Overallsolutediffusionmechanism
0.45 Fickiandiffusion
0.45 <n <0.89 Anomalous(Non- Fickian)diffusion
0.89 Case IItransport
n >0.89 SupercaseIItransport
Stability studies65-69
The optimized formulation of the In situ gel was placed in an amber colour bottle. It was
tightly sealed. The stability study was carried out as per the ICH guideline, i.e.,
Accelerated temperature 40 ± 2 °C / 75 ± 5 % RH for 1 month. Samples were withdrawn
periodically (0 and 30 days) and evaluated for visual appearance, pH, floating behaviour,
gelling capacity, drug content as well as In vitro drug release.

Chapter 6 Results
IDENTIFICATION OF DRUG
Method UV spetrophotometric methods for Teneligliptin
Preparation of 0.1N HCl: 8.5 ml of hydrochloric acid was diluted to 1000 ml with water
to get 0.1 N HCl.
Determination of ʎmax U.V spectrum of teneligliptin was carried out in 0.1 N HCl
Accurately weighed quantity of 10 mg Teneligliptin hydrobromide hydrate (THH) was
transferred to 100.0ml volumetric flask, added 30ml of 0.1 N HCl and ultrasonicated for
10 minutes, volume was then made up to the mark with 0.1N HCl (100 µg/ml). The
standard stock solution was diluted with 0.1 N HCl to obtain final concentration of 20
µg/ml of THH.
The solution was then scanned in spectrum mode, from 400 nm to 200 nm, in 1.0 cm cell
against 0.1 N HCl as blank. Calibration curve Accurately weighed quantity of 10 mg
Teneligliptin hydrobromide hydrate (THH) was transferred to 100.0ml volumetric flask,
30ml of 0.1 N HCl and ultrasonicated for 10 minutes, volume was then made up to the
mark with 0.1 N HCl(100 µg/ml). From standard stock solution aliquot portions 0.5, 1.0,
2.0, 3.0, 4.0 and 5.0 ml were diluted individually to 10.0 ml with 0.1 N HCl
(concentration 10, 20, 30, 40 and 50 µg/ml, respectively). Absorbances of diluted
solutions were measured at 242.0 nm against 0.1 N HCl as blank.
Table 6.1: Preparation of standard calibration curve of Teneligliptinin 0.1N HCL
Concentration(μg/ml) Absorbance(nm)
0 0
10 0.156
20 0.294
30 0.476
40 0.612
50 0.756

Chapter 6 Results
Caliberation curve of Teneligliptin Hydrobromide

Hydrate in 0.1N Hcl
0.9
0.8
0.7 y = 0.0745x - 0.0025
0.6 R² = 0.9998
ABSORBANCE
0.5
0.4
0.3
0.2
0.1
0
0 10 20 30 40 50 60
CONCENTRATION
Figure 6.1: Calibration curve of Teneligliptin Hydrobromide hydrate
Melting point of Teneligliptin
Melting point was measured using capillary tube method. It was found to be 224ºC. The
melting point of Teneligliptin is within the limits (223 - 126 º C).
DRUG - EXCIPIENT COMPATIBILITY STUDY
The drug-excipient study was conducted to reveal the excipient compatibility with the
drug.
PHYSICAL COMPATIBILITY STUDY:

Chapter 6 Results
Table 6.2: Physical Compatibility of Drug and Excipients
Description and Condition

S. At 40ºC ±
Drug At
No. 2ºand75%RH±
andExcipients Initial roomtemper
2%
ature
(indays)
10 20 30 10 20 30
Teneligliptin White Granular
1. NC NC NC NC NC NC
Powder
Teneligliptin + Off-White Powder
Sodium
Alginate
Teneligliptin + Dull-White Powder
Gellan Gum
Teneligliptin + Dull-White Powder
Iota carrageenan
Teneligliptin White Powder
HPMCK4M
Teneligliptin + White Powder
Calcium
Carbonate
Teneligliptin + White crystalline
7. Powder NC NC NC NC NC NC
Sodiumbicarbon
ate
Sodium Citrate
Sodium
Saccharin
Teneligliptin+
10. Methyl White Powder NC NC NC NC NC NC
ParabenSodium
Teneligliptin +
11. Propyl Paraben White Powder NC NC NC NC NC NC
Sodium
*NC - No Change
The Physical compatibility was evaluated for 10, 20 and 30 days at room temperature and
at 40˚C±2˚C/75±5% RH. There was no change of color.
Therefore, the drug and excipients are physically compatible with each other.

Chapter 6 Results
CHEMICAL COMPATIBILITY STUDY:
The interaction study of drug and excipients was performed by FTIR spectroscopic
analysis. FTIR spectra of drug, polymer and the physical mixture of drug and polymer
were recorded on a Fourier-transform infrared spectrophotometer (FTIR-8400 S,
Shimadzu, Japan) in the range 4000– 400 cm−1 and observed for the interaction between
drug and excipients.
Figure 6.2: FT-IR spectrum of Teneligliptin hydrobromide hydrate
Figure 6.3: FT-IR spectrum of Drug formulations

Chapter 6 Results
The FTIR spectra of pure drug showed (fig.6.2) functional peak at 3367.82, 3259.81,
3049.56, 2885, 1635.69, 1518.03, 725.26, cm-1 while physical mixture shows peaks
(fig.6.3) at 3344.68 2937, 1761.07, 1448.59, 763.84, cm-1with negligible shift in wave
number. It might be due to presence of amorphous nature of excipients used. The FTIR
spectra of drug and physical mixture indicate compatibility of teneligliptin formulation
FORMULATION OF TENELIGLIPTIN ORAL IN SITU GEL
The prepared formulations (F1-F10) of teneligliptin oral In situ gel are shown in Fig 6.4.
Fig 6.4: Prepared formulations of teneligliptin oral In situ gel
Evaluation Of t eneligliptin Oral In Situ Gel
Physical Appearance of teneligliptin Oral In situ Gel
The visual appeal of the formulation is an important parameter as it has an impact on the
patient compliance. All the formulations were subjected to visual appearance and results
are given in Table

Chapter 6 Results
Table 6.3: Physical appearance of formulated In situ gel
S.No. Formulation Appearance Pourability

Code
1 F1 White Pourable
2 F2 White EasilyPourable
5 F5 White Pourable
6 F6 White Pourable
7 F7 White Pourable
8 F8 White Pourable
10 F10 White Pourable
All the prepared formulations had dull-white appearance.
The formulations were free flowing and did not produce any gelation at room
temperature.
pH of teneligliptin Oral In situ Gel
Table 6.4: pH of In situ gel formulations
S.No. FormulationCode pH*

1 F1 6.90 ± 0.02
2 F2 7.22 ± 0.02
3 F3 7.30 ± 0.02
4 F4 7.10 ± 0.02
5 F5 7.18 ± 0.02
6 F6 6.90 ± 0.02
7 F7 7.25 ± 0.02

Chapter 6 Results
8 F8 7.30± 0.02
9 F9 7.37 ± 0.02
10 F10 7.02 ± 0.02
*n=3
The pH of all the formulations was found to be satisfactory in the range of 6.90 - 7.37 as
depicted in Table 6.4.
The pH of all the formulations was within the orally acceptable range (i.e. salivary pH
range: 6.2 - 7.6) Therefore, it will not cause any irritation on administration of the
formulations.
In vitro Gelation Study of teneligliptin Oral In situ Gel
The Gelation characteristics of the formulations were assessed in 0.1N HCl (pH 1.2) on
an ordinal scale ranging between + and +++ as shown in Table.
Table 6.5: Gelling capacity of formulated OralIn situ gelof teneligliptin
Sr.No. FormulationCode Gelling capacity
1 F1 +++
2 F2 +++
3 F3 +++
4 F4 +
5 F5 +++
6 F6 +++
7 F7 +++
8 F8 +++
9 F9 +++
10 F10 +++

Chapter 6 Results
(+) : Gels in few seconds, disperses rapidly
(++) : Gelation immediate, remains for few hours
(+++) : Gelation after few minutes, remains for extended period
Fig 6.5: In vitro gelation study of the In situ gel formulations
All the formulations on contact with the gelation medium had undergone sol-to- gel
transition in the presence of gel-forming polymers.
The In situ released calcium ion from calcium citrate complex gets entrapped in
polymeric chains resulting in the cross-linking of polymer chains to form a gel
matrix.Thus, stiff gels were formed with all the formulations containing polymers such as
Sodium alginate and Gellan gum as the main polymer with or without Iota Carrageenan,
except formulation F4 containing only Iota carrageenan as the gelling polymer where the
gel formed dispersed rapidly.
Viscosity of teneligliptin Oral In situ Gel
The viscosity of all the In situ gelling formulations determined at 50 rpm at 25°C using
Brookfield Viscometer. The results of viscosity measurement of all the formulations are
shown in Table.

Chapter 6 Results
Table 6.6: Viscosity of formulated Oral In situ gelof teneligliptin
S.No. FormulationCode Viscosity(centipoise)*

1 F1 182 ± 2.25
2 F2 160.67 ± 1.53
3 F3 105.33 ± 2.62
4 F4 64 ± 3.58
5 F5 225.33 ± 2.52
6 F6 205.67 ± 2.52
7 F7 248.33 ± 5.03
8 F8 230.67 ± 3.16
9 F9 168.67 ± 3.51
10 F10 187.33 ± 2.21
*n=3
Viscosity of Insitu gel of Teniligliptin formulations

300
250
Viscosity(cps)
200
150
100
50
0
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10
Insitu gel formulations
Fig 6.6: Viscosity of In situ gel of Teniligliptin formulations
All formulations of Oral In situ gel of teneligliptin exhibited good consistency, which
was dependent on concentration of gelling agents. The increase in viscosity was observed
in formulations containing high concentration of Sodium alginate and Gellan gum.
Formulations containing combination of polymers i.e. Sodium alginate and Gellan gum
along with Iota carrageenan showed less viscosity than the formulations with high
concentration of single polymer.

Chapter 6 Results
In vitro Buoyancy of teneligliptin Oral In situ Gel
The time taken by the formulation to emerge on the surface of the medium is the floating
lag time and the time period for which the formulation constantly floated on the surface
of the medium is known as floating duration. The results of buoyancy studies are given in
Table 6.7.
Table 6.7: In vitro buoyancy of Oral In situ gelof teneligliptin
Sr.No. Formulation Floating lag Floating duration

Code time(s)* (hrs)
1 F1 12 ± 2 >12
2 F2 14 ± 4 >12
3 F3 11 ± 2 >12
4 F4 8±2 >12
5 F5 19 ± 4 >12
6 F6 12 ± 2 >12
7 F7 15 ± 2 >12
8 F8 21 ± 4 >12
9 F9 12 ± 2 >12
10 F10 18± 2 >12
*n=3
When the formulation comes in contact with the acidic environment, gelation as well as
cross-linking of the calcium ions takes place providing a gel barrier on the surface of
formulation.
The carbon dioxide released is entrapped in the gel matrix giving buoyancy to the
formulation. Then, the polymeric network further restricts the diffusion of carbon dioxide
as well as drug release. The floating ability of the formulations mainly depends on
concentration of the gelling polymer, carbon dioxide and cation source as given in earlier
reports.

Chapter 6 Results
All the In situ gel formulations had a floating lag time of <2 min and all the formulations
floated for more than 12 h.
Therefore, the extended duration of floating may be responsible for the controlled release
of drug.
Density of teneligliptin Oral In situ Gel
Density is an important evaluation parameter as far as the buoyancy ability of the

gastroretentive dosage form is concerned. For the formulation to float on the gastric
contents, it should have a density less than or equal to that of the gastric contents (~1.004
gcm−3).
Table 6.8: Density of formulated In situ gel
Sr.No. FormulationCode Density(g/cm3)*

1 F1 0.649 ± 0.001
2 F2 0.631 ± 0.002
3 F3 0.451± 0.002
4 F4 0.312 ± 0.001
5 F5 0.704 ± 0.001
6 F6 0.635 ± 0.001
7 F7 0.762 ± 0.001
8 F8 0.648 ± 0.001
9 F9 0.461 ± 0.001
10 F10 0.523 ± 0.001
*n=3
The density of all the formulations are less than that of the gastric fluid (~1.004 gcm−3).
As a result, the floating of the gastro retentive In situ gel is promoted in the stomach.

Chapter 6 Results
Measurement of Gel Strength of teneligliptin Oral In situ Gel
Table 6.9: Gel strength of formulated In situ gel
Sr.No. Formulation Code Average gel Strength(s)*
1 F1 19.8 ± 0.6
2 F2 17.1 ± 1.15
3 F3 28.9 ± 0.58
4 F4 13.9± 0.58
5 F5 28.5± 1.53
6 F6 22.7 ± 1.15
7 F7 33.4 ± 1.53
8 F8 28.2± 1.00
9 F9 43.7 ± 1.53
10 F10 50.5 ± 1.53
*n=3
Gel strength gives an indication about the tensile strength of the gelled mass. It
demonstrates the ability of the gelled mass to withstand the peristaltic movement in in
vivo. Table 6.9 gives the gel strength of all the formulations.
All the formulations showed good gel strength which ranged from as low as 13.9 s for
formulation F4 which contains only Iota carrageenan as main polymer to higher values of
43.7 s and 50.5 s for formulations F9 and F10 respectively, which contains combination
of three polymers i.e. Sodium Alginate, Gellan gum and Iota carrageenan.
When the gel strength is more, the formulation may retain its consistency for a prolonged
period of time. Thus, the release of the drug may also be prolonged.

Chapter 6 Results
Percentage Water Uptake by teneligliptin In situ Gel
Table 6.10: Percentage water uptake of In situ gel formulations
%water uptake by the formulations

Time
(mins)
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10
30 4.23 2.7 3.45 4.65 5.02 4.42 7.80 5.45 6.86 8.65
60 7.45 5.98 8.8 7.56 9.99 8.04 13.92 11.87 14.57 16.84
90 12.5 9.05 12.98 10.84 16.83 15.21 18.19 18.92 25.20 25.90
120 15.56 12.87 17.78 15.37 23/6 20.09 25.14 24.19 30.17 32.06
35
Percentage water uptake of Oral In situ gel of teneligliptin
30 formulations
% water uptake
25
20
15
10
0
30 60 Time(min)90 120
Fig.6.7: Percentage water uptake of In situ gel formulations
Fig 6.7: Percentage water uptake of Oral In situ gel of teneligliptin formulations
The quantity of water associated with the drug delivery system plays an important role in
determining the release of the drug from the polymer matrix.
The drug release involves the penetration of water into the matrix and simultaneous
release of the drug through diffusion or dissolution.

Chapter 6 Results
Drug Content of teneligliptin Oral In situ Gel
Drug content is one of the important evaluation parameters for any type of dosage form. The
percentage drug content of the formulations are given in Table 6.11.
Table 6.11: Percentage drug content of formulated In situ gel
Sr. No. Formulation Code Drug content(%)

1 F1 98.50
2 F2 98.10
3 F3 98.30
4 F4 98.56
5 F5 98.64
6 F6 98.91
7 F7 98.29
8 F8 98.86
9 F9 99.97
10 F10 99.73
The percentage drug content of all the formulations was in the range of 98.10 - 99.97 %
indicating uniform distribution of drugs in all formulations.
In vitro Dissolution Study of Formulated teneligliptin Oral In situ Gel
The results of In vitro drug release study of the In situ gel formulations are given in Table
6.12 and fig.6.8.
Table 6.12: In vitro Drug release of Formulated teneligliptin Oral In situ Gel
Time PercentageDrugRelease
(min.) F1 F2 F3 F4 F5 F6 F7 F8 F9 F10
0.5 18.65 14.57 11.98 33.94 14.63 11.93 9.71 9.89 7.82 7.54
1 30.12 25.04 20.87 49.08 20.92 20.89 16.39 14.22 12.0 9.61
1.5 48.44 34.14 26.9 70.30 27.94 25.72 21.17 23.27 18.83 14.39

Chapter 6 Results
2 55.99 50.34 43.16 80.06 35.11 37.22 28.17 30.33 21.39 21.27
3 72.00 64.24 53.45 97.21 51.12 53.39 39.78 35.39 30.61 32.67
4 88.31 75.73 69.59 - 58.78 65.39 49.33 42.66 37.81 39.94
5 97.21 83.45 77.64 - 68.71 73.28 56.13 50.11 45.17 47.33
6 - 89.49 86.72 - 86.44 81.08 66.18 55.74 52.55 54.83
7 - 97.06 94.84 - 96.80 89.19 70.12 60.12 60.21 60.22
8 - - 98.97 - - 95.04 78.81 68.19 65.12 68.07
9 - - - - - 99.05 81.92 76.05 71.73 73.27
10 - - - - - - 87.61 82.04 81.86 79.08
11 - - - - - - 98.00 99.02 87.06 83.04
12 - - - - - - - - 99.97 93.85
From the In vitro drug release studies of the In situ gel formulations (F1 - F10), it was
observed that only the Formulations F9 and F10 containing the combination of all three
polymers (Sodium Alginate, Gellan gum and Iota carrageenan) provided prolonged
release of the drug upto 12 hours.
Other formulations (F1 - F8) released the drug even before the period of 12 hours.
Formulation F9 containing Sodium alginate (0.5 % w/v), Gellan gum (0.15 % w/v) and
Iota carrageenan (0.2 % w/v) showed 99.97 % of drug release at the end of 12 hours.
Formulation F10 containing Sodium alginate (0.5 % w/v), Gellan gum (0.15 % w/v) and
Iota carrageenan (0.25 % w/v) showed 93.85 % of drug release at the end of 12 hours.
SELECTION OF OPTIMIZED FORMULATION
Based on the In vitro drug release studies of the In situ gelling formulations, formulation
F9 and F10 were considered to be suitable for providing prolonged delivery of
teneligliptin as it extended the drug release up to 12 hours.

Chapter 6 Results
Comparing other evaluation parameters like pourability, viscosity, density and drug
content of both the formulation F9 and F10, the formulation F9 was found to be a better
formulation than F10.
Hence, Formulation F9 is chosen as the optimized formulation.
IN VITRO RELEASE KINETICS
Table 6.13: In vitro release kinetics of optimized teneligliptin Oral In situ Gel (F9)
Log Log
Square % cum. % cum. Cube root
Time %cum. %cm.
root Log time Drug Drug of % drug
in(Hrs.) Drug Drug
oftime release remaining remaining release remaining
0 0 ∞ 0 100 2 ∞ 4.641
0.5 0.7071 -0.3010 7.82 92.58 1.9665 0.8704 4.524
1 1 0 12.0 88.0 1.9444 1.0792 4.448
1.5 1.2247 0.1761 18.83 81.17 1.9094 1.2749 4.329
2 1.4142 0.3010 21.39 78.61 1.8955 1.3302 4.284
3 1.7320 0.4771 30.61 69.39 1.8413 1.4859 4.109
4 2.0000 0.6020 37.81 62.19 1.7937 1.5776 3.962
5 2.2360 0.6989 45.17 54.83 1.7390 1.6549 3.799
6 2.4495 0.7781 52.55 47.45 1.6762 1.7206 3.62
7 2.6458 0.8450 60.21 39.79 1.5998 1.7797 3.414
8 2.8284 0.9031 65.12 34.28 1.5350 1.8177 3.248
9 3.0000 0.9542 71.73 28.67 1.4574 1.8533 3.061

Chapter 6 Results
10 3.1623 1.0000 81.86 18.54 1.2681 1.9109 2.647
11 3.3166 1.0414 87.06 12.67 1.1028 1.9412 2.331
12 3.4641 1.0792 99.97 0.03 -1.0458 1.999 2.331
The coefficient of determination (R2) was taken as criteria for choosing the most
appropriate model. The R2values of various models are given in the table.
Table 6.14: R2Values of various Kinetic Models of Optimized formulation (F9)
Kinetic Models Coefficient of Determination(R2)

Zero order 0.9940
First Order 0.9032
Higuchi 0.9475
Hixon-Crowell 0.9815
Korsmeyer -Peppas 0.9968
The In vitro release of optimized formulation F9 data was fit into various kinetic models
to find out the mechanism of drug release from teneligliptin oral In situ gel.
A good linearity was observed with the zero order (R2=0.9940). The zero order kinetics
explains the controlled release of drug in the prepared In situ gel over the period of 12
hours.
The slope of the regression line from the Higuchi plot (R2=0.9475) and Hixson- Crowell
plot (R2=0.9815) indicates the rate of drug release follows both diffusion and dissolution
mechanisms.
The data was fitted into the Korsmeyer-Peppas equation which showed good linearity and
the slope of the Korsmeyer-Peppas plot (n= 0.8133) was found to be more than 0.45
indicating Anomalous diffusion (Non Fickian diffusion).

Chapter 6 Results
Thus, the release kinetics of the optimized formulation showed zero order drug release
with Non-Fickian diffusion mechanism.
Zero order
120
Cumulative %drug release

100
80
60
40 y = 2.9026x + 5.7219
20 R² = 0.9940
0
0 2 4 6 8 10 12
Time (hrs.)
Fig.6.8: Zero order plot for optimized teneligliptin Oral In situ Gel(F9)
2.500
Log cumulative % drug
First order
2.000
remaining
1.500
1.000
y = -0.084x + 1.813
0.500
R² = 0.903
0.000
0 2 4 6 8 10 12
Time(Hrs.)
Fig.6.9: First order plot for optimized teneligliptin Oral In situ Gel (F9)

Chapter 6 Results
Higuchi Plot
40
cumulative %drug released

35 y = 2.9958x - 10.643
30 R² = 0.9475
25
20
Higuchi
15
10 Linear (Higuchi)
5
0
0.000 1.000 2.000 3.000
SQRT of Time
Fig.6.10: Higuchi plot for optimized teneligliptin Oral In situ Gel(F9)
Hixson Crowell Plot

2.5
Log cumulative %drug
2
1.5
release
1
y = 0.0828x + 1.1193
0.5 R² = 0.9815
0
0 2 4 6 8 10 12 14
Time (Hrs.)
Fig.6.11:Hixson Crowell Plot for optimized teneligliptin Oral In situ Gel (F9)

Chapter 6 Results
Kors-peppas
4 y = 0.0563x + 0.9812
log cumulative % drug release
3.5 R² = 0.9968
3
2.5 Kors-peppas
2
1.5
Linear (Kors-
1
peppas)
0.5
0
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
log time
Fig.6.12: Kors –peppas Plot for optimized teneligliptin Oral In situ Gel (F9)
STABILITY STUDIES
The optimized formulations (F9) subjected to stability studies as per ICH guidelines and
shown in Table 6.15.
Table 6.15: Stability data for Optimized Formulation – F9
Condition:40±2ºC/75±5%RH
Parameter
Initial After1 month
Visual Appearance White White
Pourability Easily pourable Easily pourable
pH* 7.37 ± 0.2 7.35± 0.2

Chapter 6 Results
Gelling capacity +++ +++
Floating Lag time(s)* 12± 2 14± 2
Floating duration >12 >12

(hours)
Viscosity(cps)* 168.67 ± 3.51 168.39 ± 3.15
Drug content(% w/v) 99.97 99.36
,k*n=3
Table 6.16: Cumulative % drug release of Optimized formulation- F9 for stability

test
Condition:40±2ºC/75±5%RH
Time(hrs)
(%CDR)Initial (%CDR) After1 month
0.5 7.82 8.5
1 12.0 14.42
1.5 18.83 24.57
2 21.39 28.66
3 30.61 36.12
4 37.81 41.74
5 45.17 52.72
6 52.55 57.11
7 60.21 62.72
8 65.12 67.33
9 71.73 73.11
10 81.86 85.77
11 87.06 90.72
12 99.97 96.50

Chapter 6 Results
Stability study of optimized teneligliptin Oral In situ Gel

(F9)
Cumulative %drug release

120
Before stability period
100
After stability period
80
60
40
20
0
0 2 4 6 8 10 12
Time (hrs.)
Fig.6.13: Invitro release of optimized teneligliptin oral insitu gel (F9) at stability
study
No significant changes in Physical appearance, pH, viscosity, gelling capacity, floating

lag time, drug content and In vitro drug release were observed at storage condition of
40°C ± 2°C / 75 ± 5% RH at the end of 1 month.

Chapter 7 Summary and Conclusion
SUMMARY AND CONCLUSION
Utilising gelling ingredients such Sodium Alginate, Gellan gum, Iota carrageenan, and
HPMC K4M, the teneligliptin oral In situ gel was created.
The medicine and excipients are physically compatible with one another, according to a
physical compatibility analysis.
By employing FT-IR spectroscopy to undertake a chemical compatibility research, it was

confirmed that there was no interaction between the medicine and excipients because
there was no change in the principal peaks.
Teneligliptin's calibration curve was created in Simulated Gastric Fluid (SGF) with a pH
of 1.2 and adheres to Beer Lambert law.
Teneligliptin In situ gel formulations (F1, F2, F3, F4, F5, F6, F7, F8, F9, and F10) were
made utilizing variable quantities of various polymers, including Sodium Alginate,
Gellan Gum, and Iota Carrageenan, as well as HPMC K4M (0.1% w/v) as the release
retardant.
Physical appearance, Pourability, pH, viscosity, In vitro gelation study, In vitro buoyancy
study, Density, Gel strength, Percentage water uptake, Drug content, and In vitro drug
release were all tested for the manufactured formulations (F1 - F10).
All of the formulations were well-presented physically, free-flowing, and did not gel at
room temperature.
Except for F4, all of the formulations had strong gelling abilities. The gel that developed
in the formulation F4 with Iota carrageenan as the sole major polymer quickly dissipated.
All of the formulations demonstrated floating with a lag time of less than 2 minutes and
for longer than 12 hours.
When compared to other formulations, formulations F9 and F10 showed lower density
than the density of stomach fluid (1.004 gcm3) and greater gel strength.

Chapter 7 Summary and Conclusion
Because formulations F9 and F10 contain a combination of three polymers—sodium

alginate, gellan gum, and iota carrageenan, the percentage water uptake was higher in
those formulations.
All of the formulations had a percentage drug content that ranged from 98.10 - 99.97 %,
showing a uniform distribution of medicines.
Only Formulations F9 and F10 released 99.97% and 93.85% of the drug, respectively, at
the conclusion of the 12-hour period, according to an in vitro drug release study; the other
formulations released more than 90% of the drug even before the 12-hour mark.
The Formulations F9 and F10 were deemed suitable for providing sustained
administration of Teneligliptin based on the findings of the evaluation of In situ gel.
Formulation F9, which contains Sodium alginate (0.5% w/v), Gellan gum (0.15% w/v),
Iota carrageenan (0.2% w/v), and HPMC K4M (0.1%), was selected as the optimized
formulation because it had a lower viscosity and was easier to pour than Formulation F10
with no appreciable differences in other parameters.
The optimized formulation F9's in vitro release kinetic investigation revealed that it used
non-Fickian diffusion and zero-order kinetics.
According to the stability analyses, the optimized formulation F9 was stable and did not
exhibit any appreciable changes in its physical characteristics, pH, gelling capacity,
floating time, viscosity, drug content, or in vitro drug release after a month.
Overall findings show that oral floating formulation of teneligliptin released in a

regulated manner by in situ gel. Due to the simplicity of administration and decrease in
dosage frequency, this may result in better patient compliance. As a result, the created
formulation can be utilized instead of the conventional dosage formto treat type 2
diabetes patients' ailment.

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Appendix-A
List of Abbreviation
Abbreviation Meaning
M Molar
Ml Mililitre
µg Microgram
mg Miligram
gm Gram
% Percentage
< Less than
> Greater than
NMT Not more than
NLT Not less than
API Active Pharmaceutical Ingredient
Temp. Temperature
No Number
SD Standard Deviation
RSD Relative Standard Deviation
UV Ultraviolet
HCL Hydrochloric acid
IP Indian Pharamacopoeia
USP United States Pharmacopoeia
FDA Food and Drug Administration
CDER Centre for Drug Evaluation and Research
EP European Pharmacopoeia
IVIVC Vivo In Vitro Correlation
Co-ex Co-excipient
D.T. Disintegration Time
C.I. Compressibility index
SEM Scanning electron Microscope

Appendix-B
Comments & Justification
Sr. No. Comments Justification

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1.1 Anatomy of the gastrointestinal tract 8

1.2 A simplified schematic representation of the interdigestive motility 9

1.4 Mechanism of temperature sensitive system 20

1.5 Mechanism of pH triggered in situ gel system 21

1.6 Mechanism of temperature sensitive system 21

4.1 Teneligliptin structure 44

4.2 Mechanism of action of teneligliptin 45

4.3 Structure of HYDROXY PROPYLMETHYL CELLULOSE 48

4.4 Structure of acrylic acid polymer 50

5.1 Schematic representation of the preparation of Oral In situ gel 60

6.1 Calibration curve of Teneligliptin Hydrobromide hydrate 68

6.2 FT-IR spectrum of Teneligliptin hydrobromide hydrate 70

6.3 FT-IR spectrum of Drug formulations 70

6.4 Prepared formulations of teneligliptin oral In situ gel 71

6.5 In vitro gelation study of the In situ gel formulations 74

6.6 Viscosity of In situ gel of Teniligliptin formulations 75

6.7 Percentage water uptake of Oral In situ gel of teneligliptin formulations 79

Panasuriya Vidhi (212690820011)

6.10 Higuchi plot for optimized teneligliptin Oral In situ Gel(F9) 85

Panasuriya Vidhi (212690820011)

Sr. Title Page

1.1 Four phases in migrating myoelectric complex (MMC) 8

1.2 Commercial Formulations of In Situ Polymeric Systems 27

4.1 Indications with used concengtration of POLOXOMER 188 54

4.2 Indication and concentration of POLOXOMER 407 56

5.1 List of materials 57

5.2 List of Equipments 57

5.3 Composition of the In situ gelling formulations 61

5.4 Diffusion exponent and solute release mechanism 66

6.1 Preparation of standard calibration curve of Teneligliptinin 0.1N 67

6.3 Physical appearance of formulated In situ gel 72

6.4 pH of In situ gel formulations 72

6.5 Gelling capacity of formulated OralIn situ gelof teneligliptin 73

6.6 Viscosity of formulated Oral In situ gelof teneligliptin 75

6.7 In vitro buoyancy of Oral In situ gelof teneligliptin 76

6.8 Density of formulated In situ gel 77

6.9 Gel strength of formulated In situ gel 78

6.10 Percentage water uptake of In situ gel formulations 79

6.11 Percentage drug content of formulated In situ gel 80

Panasuriya Vidhi (212690820011)

6.12 In vitro Drug release of Formulated teneligliptin Oral In situ Gel 80

6.13 In vitro release kinetics of optimized teneligliptin Oral In situ Gel 82

6.15 Stability data for Optimized Formulation – F9 86

6.16 Cumulative % drug release of Optimized formulation- F9 for stability 87

Panasuriya Vidhi (212690820011)

Keywords: Teneligliptin, gastroretentive, floating, in-situ gel, type 2 diabetes

Panasuriya Vidhi (212690820011) XII

CONVENTIONAL DRUG DELIVERY SYSTEM

LIMITATIONS OF THE CONVENTIONAL DRUG DELIVERY SYSTEM:

Panasuriya Vidhi (212690820011) Page 1

In order to overcome the drawbacks of conventional drug delivery systems, several

DRUG DELIVERY SYSTEM (CDDS)

Modified release systems have been developed to improve the pharmacokineticprofiles of

1) Delayed release (e.g., by using an enteric coating);

Extended, sustained or prolonged release drug deliverysystems are terms used

Panasuriya Vidhi (212690820011) Page 2

Panasuriya Vidhi (212690820011) Page 3

CONCEPT OF ABSORPTION WINDOW

GASTRORETENTIVE DRUG DELIVERY SYSTEMS