SYNOPSIS

OF

THE PROPOSED RESEARCH PROJECT

2018-2019

FORMULATION AND EVALUATION OF MESALAMINE LOADED

MUCOADHESIVE BEADS FOR TREATMENT OF INFLAMMATORY
BOWEL DISEASE

SUJATA KUMARI

M.PHARM II YEAR

(PHARMACEUTICS)

ROLL NO: 178444008

SUPERVISOR
Dr. ROHITAS DESHMUKH

INSTITUTE OF PHARMACEUTICAL RESEARCH

GLA UNIVERSITY, MATHURA- 281406

TOPIC OF RESEARCH WORK

FORMULATION AND EVALUATION OF MESALAMINE LOADED MUCOADHESIVE

BEADS FOR TREATMENT OF INFLAMMATORY BOWEL DISEASE

INTRODUCTION
ORAL DRUG DELIVERY:
The oral route is considered to be most suitable for administration of drug to patients, due to its
several advantages such as less pain, patient compliance, greater convenient etc. This route is
convenient particularly for chronic therapies where repeated administration is required.

Oral delivery of the drugs to the colon is precious in the treatment of diseases of the colon such
as inflammatory bowel disease, colorectal cancer, irritable bowel syndrome and infectious
disease, etc. where by high local concentration can be achieved while minimizing side effects
that occur because of release of drugs in the upper gastrointestinal tract or help to avoid
unnecessary systemic absorption of the drug.[1]

Oral administration of drugs was found to be more appropriate route of administration of drugs
to the patients. The absorption of drugs given by oral route from the gastrointestinal tract
depends upon the various physical and chemical properties of the drugs. Now a days new
approaches have been made of delivering the drugs directly into the colon without contact in the
upper gastrointestinal tract. These are known as colon specific drug delivery system or Targeted
drug delivery system.

The targeting of colon is very useful because it has longer retention time so even the absorption
of poorly absorbed drug may take place here. Also in the targeted drug delivery system higher
drug concentration is achieved with lower dose of the drugs so it may minimize the side effects
of the drugs.[2]
The colon is one of the attracting benefit as a site for drug delivery where poorly absorbed drug
molecules may have improved bioavailability and also have gained the importance for systemic
delivery of proteins and peptide drugs. For colon drug targeting the simplest method is to obtain
slower release rates or longer release periods. The drugs are targeted directly to the site of action
in the colon, would be effective.[3]

INFLAMMATORY BOWEL DISEASE:

Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the
gastrointestinal tract are recognized in children and adults.[4]

CLASSIFICATION OF INFLAMMATORY BOWEL DISEASE:

These are of 2 types -
1. Crohn’s Disease
2. Ulcerative colitis

1. Crohn’s Disease(CD):
Crohn;s Disease was first described by Dr. Burrill, B. Crohn and Colleagues in 1932. [5]
Crohn’s disease is a chronic inflammatory disorder that usually involves different sites
along the length of the gastrointestinal tract. [6] and most commonly involves the terminal
ileum and colon and can present with an inflammatory, penetrating, structuring.[7]

Figure No. 1: Representive of Crohn’s Disease

 1.1 SYMPTOMS:
 Diarrhea
 Abdominal pain
 Weight loss
 Vomiting
 Fever and chills

1.2 DISEASE COMPLICATION:

Patients with CD colitis involving at least one third of the colon are at an increased risk of colon
cancer and require ongoing surveillance.[5]

2. Ulcerative colitis (UC):

Ulcerative colitis was first described in the 1800s by Samuel wilks. It is a chronic
idiopathic inflammatory bowel disease characterized by continuous mucosal
inflammation that starts in the rectum and extends proximally from the rectum.

Figure No. 2: Representive of Normal colon and Colon with Ulcerative colitis
 2.1 SYMPTOMS:
 Bloody diarrhea
 Abdominal pain
 Urgency

2.2 DISEASE COMPLICATION:

Ulcerative colitis with an enlarged risk of colorectal cancer. It is increased in patients
with left sided and extensive disease. The classically reported incidence of colorectal
cancer is 5% to 10% at 20 years and 12% to 30% after 30 to 35 years of disease.[8]

3. DIAGNOSIS OF INFLAMMATORY BOWEL DISEASE:

1. Endoscopy
2. Hematolytic tests
3. Radiography

4. TREATMENT OF INFLAMMATORY BOWEL DISEASE:

1. Anti-inflammatory drugs –
Mesalmine, Sulfasalazine
2. Corticosteroids-
Budesonide
3. Immunodulating drugs-
Azathioprine, Methotrexate

MUCOADHESION:
The mucoadhesion can be defined as the adhesion between the two substances in which one is
biological material and other is polymeric materials in order to increase the retention time of the
drugs. The binding between the two substances occur through interfacial forces.

The mucoadhesion drug delivery system is better than the traditional drug delivery system,
different compounds can be given by different routes of administration like ocular, nasal, oral
and rectal. The systemic and local delivery of drug is better in mucoadhesion system as the
contact time on the site of application is increased. The mucoadhesive polymers may also act as
a beneficial substance for tissue protection or lubrication.

The design of a mucoadhesive depend upon the two important factors-

1. It has ability to prolong the release of the drug from matrix and strong attachment to the
mucus.
2. The adhesion with the mucus membrane is done by different types of polymers like
chitosan, pectin, aligante, starch, guar gum, xanthan gum, polyvinyl alcohol, polyvinyl
pyrrolidone etc.[9]

Mechanism of mucoadhesion:
The mechanism of mucoadhesion is generally divided into two steps-
1. Contact stage
2. Consolidation stage

Figure No. 3: The two steps of mucoadhesion process

Contact stage:
It explains the contact between the mucoadhesive polymers and the mucus membrane,
with spreading and swelling of the formulation.
Consolidation stage:
It explains the activation and bonding of mucoadhesion materials. The mucoadhesion
materials are activated by the presence of moisture.[10]

ADVANTAGES OF ORAL MUCOADHESIVE DRUG DELIVERY SYSTEMS

1. Prolongs the residence time of the dosages form at the site of absorption.
2. Rapid onset of action.
3. Rapid absorption because of enormous blood supply and good blood flow rates.
4. Drug is protected from degradation in the acidic environment in the GIT.
5. Improved patient compliance and ease of drug administration.
6. Due to an increased residence time it enhances absorption and hence the therapeutic
efficacy of the drug.
7. Enhanced efficacy of the active substances.
8. Enhanced bioavailability of drug due to avoidance of first pass metabolism.
9. Prevention of drug degradation in the gastrointestinal tract due to the presence of acid.

FACTORS AFFECTING MUCOADHESION:

Polymer related factor:
1. Molecular weight:
The bioadhesion property depends on the molecular weight of selected bioadhesive
polymer. Bioadhesion is successful if molecular weight is 100,000 and more.
2. Concentration of active polymers:
For solid dosage forms such as tablets showed that the higher the polymer concentration
the stronger the mucoadhesion. There is an optimum concentration of polymer
corresponding to the best mucoadhesion.
 3. Flexibility of polymer chains
If the polymer chains decrease, the effective length of the chain that can penetrate into
mucous layer decreases, which reduces bioadhesive strength. It is critical for inter
penetration and entanglement.[9]

B. Environment related factors:

1. pH: pH influences the charge on the surface of both mucus and the polymers.
2. Applied strength: To place a solid mucoadhesive system, it is necessary to apply a defined
strength.
3. Initial contact time: The mucoadhesive strength increases as the initial contact time
increases.
4.Swelling: Swelling depends on both polymers concentration and on presence of water.

C. Physiological Variables:
1. Mucin turn over: The mucin turnover is expected to limit the residence time of the
mucoadhesive on the mucus layers.
2. Diseased state: Mucin turnover results in substantial amounts of soluble mucin molecules.

ABSORPTION OF DRUG IN COLON

Absorption of drug in the colon takes place by two routes such as Paracellular and Transcellular
route. Mostly the absorption of lipophilic drugs occurs through the transcellular route. On the
other hand absorption through paracellular route involves the transfer of hydrophilic drugs
through tight junctions between the cells. [10] The oral absorption of peptide and protein drugs is
limited because of degradation in acidic environment of stomach, enzymatic degradation in small
and large intestine, rapid transit from small intestine, low mucosal permeability and extensive
first pass metabolism by absorbing membrane and the liver.[11]

BARRIERS IN COLON ABSORPTION

A number of barriers are responsible for limiting the absorption of drug to colon. In the lumen,
when the specific and non-specific drug binding occurs due to the interaction of drug with the
dietary components which cause a barrier in drug absorption. Non-selective interactions could
occur between regions of glycoprotein drug and undigested food stuffs such as waxes and
alginates. The mucus layer at the epithelial surface is highly charged and sieve like nature acts as
a formidable thermodynamic barrier for transit of large and negatively charged drug molecules.
These barriers enhance the colonic residence time and environmental or enzymatic degradation.
Removal of mucus barrier using mucolytic agents seems attractive which may implicate in
variety of disease processes and pathological conditions due to alteration of intact mucus layer.
[12]

GENERAL CONSIDERATIONS FOR DESIGNING OF COLONIC FORMULATIONS:

Colonic formulations should be designed in such a way that they provide a ‘burst release’ or
sustained/prolonged release when they reach the colon. Designing a formulation depends upon
various factors like pathology, pattern of disease and affected parts of the lower GIT or
physiology and physiological composition of healthy colon if formulation is not intended for
localized treatment, physiochemical and biopharmaceutical properties of the drug like solubility,
stability and permeability at intended site of delivery and the desired release profile of active
ingredient.[13]

Conventional therapies for colon diseases are not very effective, as the drug does not reach the
site of action at therapeutic concentration. Therefore, this treatment requires relatively large
doses to compensate drug loss during passing GIT which causes undue side-effects. Due to this,
colon-specific drug delivery system is required.[14]

Colon specific drug delivery system is an oral-colonic delivery system which shows negligible
release of drug in stomach and allows the complete and controlled release of drug in lower GI
tract i.e. colon.[15] [16] This delivery system is beneficial in case of drugs needed to be protected
from hostile environment of upper GI tract. The colon is a site where both local and systemic
delivery of drugs can be given. Targeted drug delivery into the colon is highly desirable for local
treatment of a variety of bowel diseases such as ulcerative colitis, Crohn’s disease and colonic
cancer. However the drug can be targeted directly into the colon to reduce the systemic side
effects, dose of administration, improves the efficacy and patient compliance.[17]
Colon specific drug delivery is used in chronotherapy, prophylaxis of colon cancer and in
treatment of nicotine addiction also Precise colon targeted drug delivery requires that the
triggering mechanism in the delivery system should only respond to the physiological conditions
particular to the colon. Hence, continuous efforts should be focused on designing colon-specific
delivery systems with improved site specificity and drug release kinetic to accommodate
different therapeutic needs.[12]

PHARMACEUTICAL APPROACHES FOR COLON SPECIFIC DRUG DELIVERY

SYSTEM:

1. Covalent linkage of drug with carrier:

 Prodrug approaches
 Polymeric prodrugs
 Hydrogels

2. Pressure dependent drug delivery

3. Time dependent delivery
4. Pulsatile drug delivery system
5. Multiple unit time controlled drug delivery system

 pH - dependent systems
 Bacteria dependent colon drug delivery

6. Osmotic controlled drug delivery system

7. Polysaccharide based delivery systems
8. Multiparticulate system based drug delivery
RATIONALE:

Oral administrations of dosage forms are limited to some extent because of

gastrointestinal (GI) transit. The duration of most oral sustained release products is
approximately 8-12 hours due to the relatively short GI transit time, and the possibilities
to localize drug delivery system in selected regions of the gastrointestinal tract (GIT) for
the purpose of localized drug delivery are need to be investigated. Thus, controlled
gastric retention of solid dosage forms may be achieved by the mechanisms of
mucoadhesion. Also, alternative approach is to employ mucoadhesive polymers that
adhere to mucin/epithelial surface. Such polymer applied to any mucus membranes and
perhaps non-mucus membrane as well. Thus, mucoadhesive polymers would find
application in the eye, nose, vagina and GIT including the buccal cavity and rectum.
The objective of present work is to design and develop various mucoadhesive drug
delivery systems by using different polymeric systems which got place in the drug
delivery research in order to prolong contact time in the various mucosal route of drug
administration as the ability to maintain a delivery system at a particular location for an
extended period of time has a great appeal for both local disease treatment as well as
systemic drug bioavailability. Considerable attention is focused on the development of
bioadhesive controlled drug delivery systems, offering the advantages of better
therapeutic efficacy and is easier to comply with than the conventional regimens
requiring more frequent dosing and minimize side effects.
In present study among various mucodhesive polymers are sodium alginate and pectin
will be studied for drug loading and mucoadhesive property.
Aims & Objectives:
The aim of the work is to utilize colon targeted drug delivery systems for the treatment of
inflammatory bowel disease for better therapeutic effects, reduction in dose and side effects.
Thus, our specific objectives are:
1. To carry out preformulation studies of polymers and mesalamine in order to evaluate its
identity, compatibility with excipients and solubility.
2. To formulate and evaluate mucoadhesive beads containing mesalamine.
3. pH and Time depended targeting of the beads through capsule coated Eudragit L and S
100 polymer.
4. Comparative study of mucoadhesive beads of mesalamine with comparison of sodium
alginate and pectin.
 DRUG PROFILE

Name: Mesalamine

Figure No. 4: Structure of Mesalamine

IUPAC name: 5-amino-2-hydroxybenzoic acid

CHEMICAL PROPERTIES:
Formula: C7H7NO3
Category: Anti inflammatory
Molar mass: 153.137 g/mol
Melting point: 283°C (536°F)
Solubility: Slightly soluble in water, alcohol, more soluble in hot water, soluble in hydrochloric
acid and insoluble in ether.
Storage: Store in a cool, dry place, away from direct heat and light.

PHARMACOKINETIC:

Routes of administration: Oral

Bioavailability: 20 to 30% absorbed orally and 10 to 35% absorbed rectally

Protein binding: 80%

Excretion: 28%
MECHANISM OF ACTION:

Although the mechanism of action of mesalazine is not fully understood, it appears to be topical
rather than systemic. Mucosal production of arachidonic acid metabolites, both through the
cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e.,
leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with chronic
inflammatory bowel disease, and it is possible that mesalazine diminishes inflammation by
blocking cyclooxygenase and inhibiting prostaglandin production in the colon.[23]

ADVERSE EFFECTS:
 Headache
 Constipation
 Dizziness
 Anxiety

USAGES:
 It is used for the treatment of active UC of mild to moderate severity
 It is used for the treatment of Crohn’s Disease
 Maintenance therapy during disease remission[24]

DOSAGES:
Oral Mesalamine is taken 1.5 to 2.4 g daily.[4]

POLYMERS PROFILE:
NAME: PECTIN
Description:
It is a natural, biodegradable, biocompatiblr, non toxic heterogenous polysaccharides that is
extracted from citrus peal.
Molecular formula: C6H10O7
Molecular weight: 194.139g/mol
Melting point: 142 -1440 C
Physical description: white, light yellow, light grey or light brown powder.
Solubility: soluble in water and insoluble in ethanol
Uses : it is used in pharmaceutical industry.

NAME: SODIUM ALGINATE

Description: It is a natural and biodegradable anionic polymer that is typically obtained from
brown seaweed. Sodium alginate is the sodium salt of alginic acid.
Molecular formula: C6H7NaO7
Molecular weight: 216.121g/mol
Physical description:
White to yellowish brown filamentous, granular or powered forms
Solubility: it is soluble in water and insoluble in ethanol and ether
Duration of Action for Sodium Alginate: 30 to 60 minutes
Uses-
It is used in pharmaceutical industries.

EUDRAGIT L 100:
EUDRAGIT L 100 are anionic copolymers based on methacrylic acic
and methyl methacrylate.
Physical properties:
It is a solid substance in form of a white powder with a faint characteristic odour.
Chemical Structure:

Figure No. 5: Chemical structure of Eudragit L100

Product Form : Powder
Targeted Drug Release Area : Jejunum
Dissolution : Dissolution above pH 6.0
characteristics:
 Effective and stable enteric coatings with a fast dissolution in the upper Bowel.
 Granulation of drug substances in powder form for controlled release.
 Site specific drug delivery in intestine by combination with EUDRAGIT® Sgrades
 Variable release profiles
CAS number : 25086 – 15 – 1
Chemical/IUPAC name : Poly(methacylic acid-co-methyl methacrylate) 1:1
Weight average molar mass : approx. 125,000 g/mol
Acid Value : 315 mg KOH/ g polymer

EUDRAGIT S 100-

EUDRAGIT S 100 are anionic copolymers based on methacrylic acic and methyl methacrylate.
Physical properties: It is a solid substance in form of a white powder with a faint characteristic
odour.
Chemical structure:

Figure No. 5: Chemical Structure of Eudragit S 100

Form of Product : Powder

Targeted Drug Release Area : Colon delivery
Dissolution : pH 7.0
Characteristics:
 Granulation of drug substances in powder form for controlled release
 Effective and stable enteric coatings with a fast dissolution in the upper Bowel
 Site specific drug delivery in intestine by combination with EUDRAGIT® S grades
Variable release profiles.
CAS number : 25086 – 15 – 1
Chemical/IUPAC name : Poly(methacylic acid-co-methyl methacrylate) 1:2
Weight average molar mass : approx. 125,000 g/mol
Acid Value : 190 mg KOH/ g polymer
MARKETED PRODUCTS:
TABLE 1: List of marketed product.

BRAND NAME DOSAGES STRENGTH TYPE

5-ASA Tablet, Delayed release 400mg Oral   

Apriso Capsule, Extended release 375mg/1 Oral

Asacol Tablet, Delayed release 400mg/1 Oral

Asacol 800 Tablet, Delayed release 800mg oral  

Canasa Suppository 1000mg/1 Rectal  

Delzicol Capsule, Delayed release 400mg/1 Oral  

Lialda Tablet, Delayed release 1.2g/1 Oral  

Mesalamine Capsule 200mg /1 Oral

Mesasal Tablet, Delayed release 500mg Oral

Mezavant Tablet, Extended release 1.2g Oral   

Mezera Suppository 1g Rectal

Pentasa Capsule 500mg/1 Oral  

Pentasa Suspension 1g Rectal  

Rowasa Suspension 4g/60 Rectal  

Salofalk Suspension 4g Rectal  

LITERATURE REVIEW-

Mukesh C. Gohel (2008) Press-coated mesalamine tablets with a coat of HPMC E-15
were overcoated with Eudragit S100. The invitro drug release study was conducted
using sequential dissolution technique at pH1.2, 6.0, 7.2 and 6.4 mimicking different
regions of gastrointestinal tract Possible colonic drug delivery system based on time and
pH sensitivity was developed for delivering mesalamine to the colon. The outermost
Eudragit S100 enteric coat prohibited drug release in conditions mimicking fasting
stomach (pH 1.2) and upper intestine (pH 6.0). The Eudragit coat dissolved in the
proximal ileum within 30 min. The inner press coat of HPMC E-15 protected the dosage
form in terminal ileum.

Sachan Nikhil K et al. (2009) studied basics and therapeutic potential of oral
mucoadhesive. This property of certain polymeric systems have got place in the drug
delivery research in order to prolong contact time in the various mucosa route of drug
administration as the ability to maintain a delivery system at a particular location for an
extended period of time has a great appeal for both local disease treatment as well as
systemic drug bioavailability. The objective of this paper is to establish the procedure to
study polymer bioadhesion to understand structural requirement of bioadhesive in order
to design improved bioadhesive polymer for oral use.

Permender Rathee et al. (2010) investigated the Gastrointestinal Mucoadhesive drug

delivery system prolong the residence time of the dosage formulation the site of
absorption and facilitate an intimate contact of the dosage form with the underline
absorption surface and thus contribute to improved and / or better therapeutic
performance of the drug.

U. Klotz et al. (2011) investigate the modified drug delivery systems were intended to
liberate sufficient 5-ASA at the sites of inflammation Such a drug targeting strategy is
desired for its topical action and especially because local concentrations in the mucosa.
Consequently, the systemic exposure of 5-ASA is low and adverse effects are in the
range of placebo treatment. In all clinical studies, the side effects of 5-ASA were very
low (5–10 %), mild and comparable to placebo. Thus, its use is very safe and 5-ASA
will remain an attractive and precious agent.

Chien Nguyen et al. (2012) investigated Novel mesalamine-loaded beads in tablets for
delayed release of drug to the colon Bead formulations include a combination of
extrusion and spheronization to create a comparatively high drug load (80%), followed
by coating (25%) with a colonic-targeted drug release polymer (polymethacrylates,
Eudragit S100), overcoated (3%) with hydroxyl propyl methylcellulose (Opadry) to
progress bead binding and compactability, and using 20% coat of lactose/sodium starch
glycolate (Explotab) as binder/disintegrant/cushioning agent, thus allowing a adequately
thick coating to be consistent and without being broken during tablet compaction

L. Prabakaran et al. (2012) studied formulation, development, optimization and study

on drug release kinetics of Eudragit L100 –HPMC E15 LV mixed with film coated
colon targeted mesalazine tablets in various simulated fluids (pH range 1.2, 6, 7.2). The
variation in colonic pH condition during IBD. Addition of HPMC E15 LV may manage
this problem by hydrophilic nature and intense film forming characteristics ductility and
elasticity and ensures the channels for allowing colonic fluids to enter into the core and
subsequent drug release at the target site. Drug release studies were conducted in
different pH situation in the presence of rat ceacel contents.

Shaik shabber et al. (2012) formulation and development of mesalazine sustained

release guar gum matrix tablets for colon drug delivery. The colon is a site where both
local and systemic delivery of drugs can take place. Treatment could be prepared more
useful if it were potential for drugs to be targeted directly on the colon. Systemic side
effects could also be reduced. Mesalazine matrix tablet were prepared by wet
granulation technique. Drug dissolution was studied invitro at different pH levels.

N. Vamsi Krishna et al. (2012) investigated Formulation And Evaluation Of Colon

targeted mesalamine matrix tablet. To develop sustained release matrix formulation of
mesalamine targeted to colon by using both hydrophilic and hydrophobic polymers and
in-vitro drug release study. Matrix tablets were prepared by direct compression method
using different concentration of Hydroxypropyl methylcellulose (HPMC) and Ethyl
Cellulose (EC). It was pragmatic that mixture of both the polymers exhibited the best
release outline and able to sustain the drug release for prolong period of time.

Surrender Verma et al. (2012) investigated The colon targeted drug delivery: current
and novel perspectives. The CTDDS is a relatively novel model for the absorption of
drugs as it offers near neutral pH. Also offers long residence time, thereby increasing the
drug absorption. Colon has justified to a site for the absorption of poorly soluble drugs.

Sahauran et al. (2013) studied the polymers for colon targeted drug delivery. Targeting
of drugs to the colon via oral administration protect the drug from degradation or release
in the stomach and small intestine. Different types of polymers used in formulation of
colon targeted drug delivery system.

Ritesh Kumar Tiwari et al. (2013) alginate micro-beads in novel drug delivery system.
The design of useful and secure novel drug delivery systems has become an essential
part for the development and formulating of new medicines. So, research always keeps
on searching for new ways to move drugs over a long period of time or for a well-
controlled release profile, to minimizing the loss of drug, to decrease the side effect.
Alginate is act as nontoxic when taken orally and also shows the protective effect on the
mucous membrane of upper gastro-intestinal tract. The technique engaged to preparation
of micro-beads with sodium alginate by ionotropic gelation technique, cross- linking,
Emulsion gelation technique, spray drying, and simple and complex co-aeration phase
separation method. This review focused on preparation, characterization of alginate
micro-beads, therapeutic application and their role in controlled or novel drug delivery
systems.

Seema Badhana et al. (2013) studied Colon specific drug delivery of mesalamine using
eudragit S100- coated chitosan microspheres for the treatment of ulcerative colitis.
Microspheres were prepared by the ionic gelation emulsification method using
tripolyphosphate (TPP) as cross linking agent. The microspheres were coated with
Eudragit S-100 by the solvent evaporation technique to prevent drug release in the
stomach. The drug release of mesalamine from microspheres was establish to decreases’
the polymer concentration increases. The release outline of mesalamine from eudragit-
coated chitosan microspheres was found to be pH dependent. It was observed that
Eudragit S100 coated chitosan microspheres gave no release in the simulated gastric
fluid, negligible release in the simulated intestinal fluid and maximum release in the
colonic environment.

Dayse Fernanda de Souza et al. (2013) investigated Development of enteric coated

sustained release minitablets containing mesalamine. This study was to prepare and
evaluate a multiparticulate modifed release system. Polyox® WSR 1105 was the
polymer used in the matrix system and Eudragit® L30D55 was used as a pH-dependent
polymer. The minitablets (with 20%, 30% or 40% Polyox® concentration) were
prepared by dry granulation, which led to good quality minitablets. The developed
minitablets were coated in a fluidized bed at 8% of the coating level. Dissolution studies
were performed in media that simulated the gastrointestinal tract (pH 1.4, 6.0 and7.2)
and showed that formulationswith higher Polyox® concentrations were capable of
retaining the drug release in pH1.4. All formulations prolonged the drug release and
presented zero-order kinetic activities.

Mayur M. Patel et al. (2013) reported Development of a novel tablet-in-capsule

formulation of mesalamine for inflammatory bowel disease. The system consists of an
enteric-coated hydroxypropyl methylcellulose capsule filled with four units of
mesalamine minitablets, each of which was further coated with different ratios of
Eudragit E100 and Eudragit RS100. In vitro evaluation of tablets coated with Eudragit
E100 and Eudragit RS100 at different pH circumstances exposed that at lower pH levels
(2.0, 3.6 and 5.5 pH), the drug release is mainly governed by the dissolution of Eudragit
E100 from the Eudragit E100 and Eudragit RS100 coat. In vitro evaluation of capsules
enteric coated with Eudragit L100 and Eudragit S100 exposed that a maximum lag time
of 3 h and 4 h was obtained, respectively.
B. Saraswathi et al. (2013) reported polymers in mucoadhesive drug delivery system.
The use of mucoadhesive polymers is for the development of pharmaceutical
formulations. Various other polymers which have mucoadhesive property are sodium
alginate, guar gum etc. hence mucoadhesive polymers can be used as means of
improving drug delivery through different routes like gastrointestinal, nasal, ocular and
rectal.

Ritesh Kumar Tiwari et al. (2013) alginate micro-beads in novel drug delivery system.
The design of effective and safe new drug delivery systems has become an integral part
for the development and formulating of new medicines. Natural polymer sodium
alginate is used as the matrix because of its natural, biodegradability, low cost,
simplicity, and biocompatibility. Alginate is act as nontoxic when taken orally and also
shows the protective effect on the mucous membrane of upper gastro-intestinal tract.
The gelation of anionic polysaccharide sodium alginate, the primary polymer of natural
origin, was achieved with oppositely charged calcium ions and to form micro-beads. The
technique employed to preparationofmicro-beadswith sodium alginate by ionotropic
gelation technique, cross- linking,Emulsiongelationtechnique, spray drying, and simple
and complex co-acervation phase separation method.

Christian Lautenschläger et al. (2013) Drug delivery strategies in the therapy of

inflammatory bowel disease. The therapy of IBD is dominated by the administration of
anti-inflammatory and immunosuppressive drugs, which suppress the intestinal
inflammatory burden and improve the disease-related symptoms. Thus, the development
of novel disease-targeted drug delivery strategies is intended for a more effective
therapy and demonstrates the potential to address unmet medical needs.

Amritpal singh et al. (2014) investigated Micro carrier as colon Drug Delivery system.
There are novel developments in site-specific formulations for targeting drug to the
colon. Colon has justify to be a position for the absorption of poorly soluble drugs.
Micro carriers as colon drug delivery system has gained significance for the delivery of
the drug in the colon because of their enlarge biocompatibility, controlled release of
drug. so microcarrier is an valuable approach to be used for colon drug delivery.

Mitra Jelvehgari et al. (2014) investigated the mucoadhesive beads of alginate and
algino-pectinate of piroxicam for colon specific drug delivery via oral route. These
formulation are prepared by ionotropic gelation method was used to capture piroxicam
into alginate and algino-pectinate polymers. Mucoadhesion strength and retention time
study showed enhanced retention of piroxicam microparticles in intestine.

Singh Amritpal et al. (2014) studied the Approaches for colon targeted drug delivery
system. This review, mainly compares the main approaches for CDDS namely pH and
time dependant system, microbially triggered system etc. which achieved limited
achievement and had limitations as compared with newer CDDS namely pressure
controlled colonic delivery, CODETS and osmotic controlled drug delivery etc.

V Sri Vajra Priya et al. (2016) polymers in drug delivery technology, types of
polymers and applications. Polymers play a major role in the development of drug
delivery technology by release of two types of drugs like hydrophilic and hydrophobic.
However they have their own limitations, such as the naturals polymers are most
abundant and biodegradable but are difficult to reproduce and purify. Synthetic
polymers have high immunogenicity, which prevent their long term usage. Non-
biodegradable polymers are needed to be sugary after they release the drug at the
targeted site.

Dinesh Kumar et al. (2016) investigated Natural polymers and herbal medicine based
therapy for colonic diseases. Colonic drug delivery has gained remarkable importance
for the delivery of the drugs for the treatment of local diseases associated with the colon.
Various natural therapies, available for the treatment of colonic diseases like
ulcerative colitis, Intestinal bowel syndrome, colon cancer, diverticulitis, etc., are based
on natural polymers such as guar gum, pectin, dextran, chitosan, inulin, amylose, etc.
Interest in these biodegradable polymers is increasing day by day because these are safe,
non-toxic, and economic and are chemically compatible with the other excipients in the
formulation. Some of the herbs used in the treatment of colonic diseases are Aloevera,
Curcuma longa, Curcuma xanthorrhiza, Cynara scolymus, Ulmus rubra, Psyllium, etc.
There are certain preparations such as Boswellia serrata nanoparticles, curcumin
microspheres available in the market to treat colon cancer.

Kusum Kaushik et al. (2016) studied Natural Polymers and their Applications.
Polymers play a vital role in any dosage form as excipients. The influencing capacity of
polymers towards the drug release and should be compatible, non-toxic, and stable and
economic etc. Natural polymers are generally used as rate controlling agents, taste
masking agents, protective and stabilizing agents in the oral drug delivery system.
Applications of natural polymers in pharmacy are large in comparison to the synthetic
polymers.

Grace Rathnam et al. (2017) studied formulate compression coated tablets of

mesalazine and prednisolone for colon specific delivery and evaluate their in vivo and
invitro performance. Pectin was used as an enzyme dependant polymer and eudragit
S100 was used to enteric coated polymer. Therapeutic efficacy of the prepared tablets
was evaluated in trinitrobenzene sulfonic acid induced rabbit colitis model. The release
35.86% of mesalazine and 45.49% of prednisolone at the end of 7h. the release increased
considerably to 73.55% of mesalazine and 87.53% of prednisolone on addition of
pectinolytic enzyme to the dissolution medium at the end 10h. The orally administered
compression coated tablets could be used successfully for the delivery of the drug to the
colon.

Ashish Garg et al. (2018) investigated Applications of natural polymers in

mucoadhesive drug delivery. Mucodhesion refers to bond formed between two
biological surfaces or a bond connecting a biological and a synthetic polymer surface.
Natural polymers used as mucoadhesive polymers. It facilitates an important tool to
improve the bioavailability of the bioactive agent by improving the residence time at the
delivery site.
Lavi Kumar Garg et al. (2018) Review on natural polymers: A carrier for colon-
targeted drug delivery approach Selection of drug for colon targeting through oral route
safeguards the drug from degradation and makes it release within the abdomen and
small intestine. It conjointly makes sure immediate or else controlled the release of the
medication within the proximal colon . Varied drug delivery systems are planned to
deliver the medication to the colon and then initiate the discharge of drug.

Sonia Dhiman et al. (2018) mucoadhesion drug delivery system. The term
mucoadhesion is the subgroup of bioadhesion and in the mucoadhesion formulation
attaches with the mucus membrane. The mucoadhesion DDS is improved than the
traditional DDS. The mucoadhesion bypasses the first pass metabolism and used for
localized delivery of biomolecules such as peptides, proteins and oligonucleotide.

Manish kumar et al. (2018) reported a Formulation development and evaluation of

colon targeted beads of mesalamine. It is a multiparticulate oral formulation that might
given an enhanced efficacy with a significant reduction in dose and systemic toxicity for
the treatment of the irritable bowel disease. The formulation of beads develops by
inotropic gelation. The polymers are used such as gellan gum and locust bean gum. The
drug release in the stomach and achieve a pH dependant release or colonic pH of 7.4 a
polymethacrylate base coating passed out by dip coating method.

Tahsean khan et al. (2018) investigated a Meropenam loaded pectin microspheres for
colon delivery. These formulation are prepared by solvent evaporation method and these
microspheres are characterized by size and size distribution, SEM, entrapment efficiency
and in-vitro release study. To prepare meropenam loaded pectin microspheres coated
with eudragit S-100 for colonic drug delivery. Eudragit S-100 is an enteric coated
polymer it defend the release of meropenam from the pectin microspheres in the upper
GIT and degraded its coating at pH 7. Thus the Eudragit coated pectin microspheres
have the potential to be used as a drug carrier for an valuable colon targeted drug
delivery.
METHODOLOGY OF RESEARCH WORK

Formulation of mesalamine loaded beads:

STEP 1:
Pectin/Sodium alginate was dissolved in distilled water

added
Mesalamine

Dispersed in
ultrahomogenizer for 2 minutes at 8000 rpm
STEP 2:
Calcium chloride solution was dispersed in water
STEP3:
Sodium alginate phase added dropwise

In calcium chloride at a constant rate under continuous stirring at a 200rpm

Filteration of mucoadhesive beads

Washing the mucoadhesive beads

Drying the mucoadhesive beads

 Coating the mucoadhesive beads
PLAN OF WORK-
1. Review of literature-

2. Pre-formulation studies

a) Percentage Purity and assay of drug

b) Melting Point

c) Drug-Polymer compatibility study

3. Preparation of different set of formulation-

a) Preparation of sodium alginate beads

b) Preparation of pectin beads

4. Characterization of prepared mucoadhesive beads-

a) Size and surface morphology

b) Percentage yield

c) Micromeretics

d) Percentage entrapment

e) Percentage release

5. In-vitro release study at the different pH

6. Stability studies

7. Data compilation
IMPACT OF PROPOSED RESEARCH ON ACADEMIC/INDUSTRY/SOCIETY

Formulation and development of sustained release mucoadhesive beads of mesalamine serves the
pharmaceuticals, biopharmaceutical, industries, contact organization government lab, university,
hospital and medical centers and other organizational unit with in pharmaceutical sciences and
market place.

Design and Development sustained release mucoadhesive beads of mesalamine oral formulation
focus on way to help the pharmaceutical and biological drug formulation to bring their treatment
to market in safer, efficacious and more cost effectively.

Design and Development of such formulations delivers the full landscape of technology, tools
and business/regulatory approaches that will help the researchers scientist and executions to
improve the pace and productivity of safer and efficacious drug research and development.

Therapeutic and aesthetic benefits to the patient:

 Patient compliance
 Easy to take
 Reduced side effect
PERT CHART

S.NO. PERT Activities Optimistic Pessimistic Most Expected

Time (in Time ( in likely Time (in
weeks) weeks) time (in weeks)
weeks)
(To) (Tp) (Te)
(Tm)

1 Review of 2 3 3 4
literature

2 Preformulation
studies

2(A) Percentage purity 1 3 2 2

and assay of drug

2(B) Melting point 1 3 2 2

2(C) Drug-Polymer 3 5 4 5
compatibility
study

3. Preparation of 3 5 4 5
mucoadhesive
beads of different
set

4. Characterization of 4 6 5 5
prepared
mucoadhesive
beads

5. In vitro release 3 5 4 4
study at different
pH
 6. Stability testing 6 8 7 7

7. Thesis compilation 6 8 7 7

Total 33 52 42 44

Tc= ¿+ 4 Tm+Tp / 6 Where,

Te= effective time

T0= optimistic time

Tp= pessimistic time

Tm=most likely time

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