FORMULATION AND IN -VITRO EVALUATION OF ......2.1 Introduction The general background of mucoadhesive buccal tablets, PPI, esomeprazole, and researches conducted on formulation of

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Subedi et al. World Journal of Pharmacy and Pharmaceutical Sciences

FORMULATION AND IN -VITRO EVALUATION OF

MUCOADHESIVE BUCCAL TABLETS OF ESOMEPRAZOLE

*Eliza Subedi, Babita Mahato and Gajasher Rai

Department of Pharmacy Karnali College of Health Sciences Gaushala, Kathmandu.

ABSTRACT

The main objective of the present work was to formulate

mucoadhesive buccal tablets of an Esomeprazole drug using polymers

by direct compression method and compare their effect on

formulations to find the best polymer for the prepared formulations

with better mucoadhesive property, better in-vitro dissolution profile

and better in vitro drug permeation. Mucoadhesive Buccal Tablets of

Esomeprazole were prepared by using polymers in different

concentrations. Carbopol 934, HPMC K4M, guar gum and sod CMC

were used as polymers. The tablets were subjected to the various

parameters like hardness, thickness, weight variation, friability, surface

pH, stability in saliva, in-vitro drug release, swelling index, bioadhesive strength and in vitro

drug permeation. FTIR-IR study shows good compatibility between drug and other

ingredients including polymers. In the present study all the powder blend showed good flow

ability because all blends show angle of repose below 30°, bulk density in the range between

0.558 to 0.803 g/cm3, tapped density in the range between 0.629 to 0.979 g/cm3, and the

compressibility index was found to be between 7.016 to 30.000 which ensures the blend that

may be suitable for direct compression into tablets. In-vitro dissolution study for all tablets

was performed and formulation (F8) containing sod carboxy methyl cellulose drug release of

102.021% within 4 hr. The assay range of eight batch was found to be 90 to 105%. In vitro

drug permeation study for best formulation performed i.e. for F8 shows drug permeation of

101.045% within 4 hr.

KEYWORDS: Esomeprazole, Mucoadhesive Buccal Tablet, carbopol 934, HPMC K4M,

Guar gum, sod. CMC, Dissolution, Permeation.

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 9, Issue 10, 1565-1625 Research Article ISSN 2278 – 4357

*Corresponding Author

Eliza Subedi

Department of Pharmacy

Karnali College of Health

Sciences Gaushala,

Kathmandu.

Article Received on

04 August 2020,

Revised on 24 August 2020,

Accepted on 14 Sept. 2020

DOI: 10.20959/wjpps202010-17196


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INTRODUCTION

1.1 Introduction to Esomeprazole

Esomeprazole is a proton pump inhibitor (PPI) which is the analog of omeprazole. Its

chemical name is 5-methoxy-2-{(s)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-

1H-benzimidazole. Its chemical formula is (C17H18N3O3S) and the molecular weight of

esomeprazole is 345.417. Its recommended dose is 20mg once daily.[1]

Esomeprazole is a

proton pump inhibitor which reduces acid secretion through inhibition of the H+/K

+ ATPase

in gastric parietal cell. It is used in treatment of dyspepsia, peptic ulcer disease(PUD), gastro

esophageal reflux disease(GERD) and Zollinger Ellison Syndrome. Esomeprazole is the S –

enantiomer of omeprazole. Single 20-40 mg oral doses generally give rise to peak plasma

esomeprazole concentrations of 0.5-1.0mg/L within 1-4 hrs, but after several days of once

daily administration these levels may increase by about 50%.[2]

Acidity occurs when there is

excess secretion of acids in gastric glands of the stomach.[3]

Tablets are solid dosage form

manufactured either by dry granulation, wet granulation or direct compression containing

medicaments with or without excipients, intended to produce desired pharmacological

response. Buccal tablets are formulated and compressed with sufficient pressure to give

desired buccal effect administered in buccal pouch.[4]

Drug delivery refers to approaches,

formulations, technologies, and systems for transporting a pharmaceutical compound in the

body as needed to safely achieve its desired therapeutic effect and minimum adverse effect.

The drug should be delivered to its site of action with such rate and concentration to achieve

maximum therapeutic effect and minimum adverse effect. There are different types of dosage

forms available such as tablets, syrups, suspensions, suppositories, injections, transdermal

patches having different drug delivery mechanism. It may involve scientific site-targeting

within the body, or it might involve facilitating systemic pharmacokinetics; in any case, it is

typically concerned with both quantity and duration of drug presence. Drug delivery is often

approached via a drug's chemical formulation, but it may also involve medical devices or

drug-device combination products.[5]

1.2 Introduction of Mucoadhesive Buccal Tablets

In the recent years, mucoadhesive drug delivery system has shown remarkable interest for

increment of residence time at the site where it is applied and to accomplish intimate contact

of the dosage form with the underlying mucosa, mainly to promote absorption and elevate the

percentage by availability of drugs due to its extensive surface area and high flow rate of

blood.[6]

Nowadays, the use of mucoadhesive polymers has been accepted as an important


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strategy to prolong the residence time and to improve the localized effects of drug delivery

systems on various mucus membranes of a biological system mucoadhesive dosage forms can

be placed.[7]

The buccal delivery is defined as the drug administration through the mucosal

membranes lining the cheeks (buccal mucosa).[8]

The mucoadhesive drug delivery system in

the mucus membrane of oral cavity can be categorized into three delivery systems;

Sublingual delivery, Buccal delivery and Local delivery. There are many advantage of this

systems like they can be used for both local as well as systemic delivery of many drugs, easy

to apply as compare to other adhesive dosage forms, increased patient compliance over the

injectables, it is the most preferred delivery system for the local treatment of drugs.[9]

Esomeprazole exhibits significantly higher bioavailability leading to the greater inhibition of

gastric acid secretion compared to omeprazole.[10]

1.3 Rational of Study

In order to increase the bioavailability the mucoadhesive buccal tablet are needed.

Conventional esomeprazole tablets available in the market causes gastric irritation and isn't

suitable for unconscious and less co-operative patients, also they show poor bioavailability

thus mucoadhesive buccal tablets of esomeprazole is suitable to relief immediate gastric

irritation and other gastrointestinal problem because of its highly vascularized supply which

leads to greater absorption of drug. Furthermore Esomeprazole buccal dosage form are easy

to apply with lower incidence of gastro-intestinal irritation.[11,12,13]

1.4. Objectives

The main objectives of this project work is formulate, optimize and perform the in-vitro

evaluation of mucoadhesive buccal tablet of Esomeprazole. The specific objectives of this

project work are presented below:

1. To carry out the pre-formulation study of powder such as angle of repose, bulk density,

tapped density, hausner ratio and Carr's index.

2. To estimate the drug concentration in prepared formulation (assay of each batch).

3. To carryout post compression parameters for the developed mucoadhesive buccal tablet

such as hardness, friability, thickness and weight variation of each batches.

4. To carry out evaluation parameter such as swelling index, surface pH, bioadhesive

strength, force of adhesion and stability in saliva.

5. To carry out in-vitro release studies using USP dissolution apparatus type-II with paddle

assembly and study the drug release.


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6. To compare the various formulations using different excipients and choose the best

formulation.

7. To carry drug excipients compatibility studies by FTIR.

REVIEW OF LITERATURE

2.1 Introduction

The general background of mucoadhesive buccal tablets, PPI, esomeprazole, and researches

conducted on formulation of various mucoadhesive buccal tablets including esomeprazole are

presented in this chapter.

2.2 Review to Drug Delivery System

Drug delivery refers to approaches, formulations, technologies and systems for transporting a

pharmaceutical compound in the body as needed to safely achieve its desired therapeutic

effect and minimum adverse effect. The drug should be delivered to its site of action with

such rate and concentration to achieve maximum therapeutic effect and minimum adverse

effect. There are different types of dosage forms available such as tablets, syrups,

suspensions, suppositories, injections, transdermal patches having different drug delivery

mechanism. It may involve scientific site-targeting within the body, or it might involve

facilitating systemic pharmacokinetics; in any case, it is typically concerned with both

quantity and duration of drug presence. Drug delivery is often approached via a drug's

chemical formulation, but it may also involve medical devices or drug-device combination

products.

Development of new drug molecule is expensive and time consuming improving safety

efficacy ratio of old drugs has been attempted using different methods such as

individualization drug therapy, dose titration and therapeutic drug monitoring.[14]

2.3 Alternative to Conventional Tablets

Oral routes of drug administration have wide acceptance up to 50-60% of total dosage forms.

It is the most popular route for systemic effects due to its ease of ingestion, pain avoidance,

self-medication, versatility and most importantly, patient compliance. Oral route is most

popular route but have common drawback of difficulty in swallowing of tablets and capsules.

Drinking water plays an important role in the swallowing of oral dosage forms. Often times

people experience inconvenience in swallowing conventional dosage forms such as tablet

when water is not available. Because of the increase in the average human lifespan and the


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decline, with age, in swallow inability, oral tablet administration to patients is a significant

problem and has become the object of public attention. Therefore a lot of research has been

done on novel drug delivery systems. Mucoadhesive buccal tablet is a novel approach in drug

delivery systems that are now a day's more focused in formulation world, and laid a new path

that, helped the patients to build their compliance level with the therapy and ease the

administration especially. Quick absorption, rapid onset of action and reduction in drug loss

properties are the basic advantages of this dosage form. For the development of a suitable

dosage form a thorough study about the physicochemical principles that governs a specific

formulation of a drug should be subjected.[15]

2.4 History of Mucoadhesive Buccal Tablets

In 2007, Ramana et al. designed and evaluated the buccal mucoadhesive drug delivery system

of Metoprolol Tartarate using the mucoadhesive polymers such as carbopol 934, HPMC,

hydroxyl ethyl cellulose and sodium CMC.[16]

In 2010, study on Velmurugan et al. formulate

the buccal tablets of Piroxicam using HPMC K4M and Carbopol-934 in different ratios.[17]

In

2011, Naga Rain et al. formulate the buccal tablets of Metoprolol Tartate and evaluate in

vitro bioadhesive strength and study of drug release using different mucoadhesive

polymers.[18]

2.5 Review to Mucoadhesive Buccal Tablets

Buccal drug delivery is one of the novel drug delivery which localized the delivery of drug to

tissues of the buccal cavity for treatment of bacterial, fungal infection as well as periodontal

disease.[19]

Buccal drug delivery is safer mode of drug delivery system and can be able to

remove in case of toxicity and adverse effect. Buccal mucosa has an excellent accessibility,

which leads to direct access to systemic circulation through the internal jugular vein bypasses

the drugs from hepatic first pass metabolism.[20]

Mucoadhesive buccal tablets are dry dosage

forms and it is to be moistened prior to placing in contact with buccal mucosa.[21]

Mucoadhesive buccal tablets are developed by addition of polymers like carbopol, HPMC-

K4M, HPMC-K100M, Ethyl cellulose, sodium carboxymethyl cellulose, sodium alginate,

which gives better mucoadhesive property when gets in contact with buccal lining. The

bioavailability of some drugs may be increased due to high blood flow in buccal cavity and

also due to pre- gastric absorption of saliva containing mucoadhesive drugs. Moreover, the

amount of drug that is subjected to first pass metabolism is reduced as compared to standard

tablets.[22]


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2.5.1 Anatomy of Buccal Mucosa[41]

Buccal region is that part of the mouth bounded anteriorly and laterally by the lips and the

cheeks, posteriorly and medially by the teeth and/or gums, and above and below by the

reflections of the mucosa from the lips and cheeks to the gums. Maxillary artery supplies

blood to buccal mucosa and blood flow is faster and richer (2.4mL/min/cm2) than that in the

sublingual, gingival and palatal regions thus facilitate passive diffusion of drug molecules

across the mucosa.

Buccal mucosa composed of several layers of different cells as shown in Fig 2.2.

Fig. 2.1 Cross Section of Buccal mucosa.

The outermost layer is stratified squamous epithelium; below this lies a basement membrane,

a lamina propria followed by the sub mucosa as the innermost layer. The epithelium is similar

to stratified squamous epithelia found in rest of the body and is about 40–50 cell layers thick.

The epithelium, as a protective layer for the tissues beneath and is divided into:

a) Non- keratinized epithelium

This present in the mucosal lining of the soft palate, the ventral surface of the tongue, the

floor of the mouth, vestibule, lips and cheeks.

b) Keratinized epithelium

This is found in the hard palate and non-flexible regions of the oral cavity. The keratinized

epithelia contain neutral lipids like ceramides and acyl ceramides, which are associated with

the barrier function. These epithelia are impermeable to water.


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The non-keratinized epithelia do not contain acy lceramides and only have small amounts of

ceramides and also contain small amounts of neutral but polar lipids, mainly cholesterol

sulfate and glucosylceramides. Basement membrane, lamina propria followed by the

submucosa is present below the epithelial layer. Lamina propria is rich with blood vessels

and capillaries that open to the internal jugular vein. The primary function of buccal

epithelium is the protection of the underlying tissue.

2.5.2 Mechanism of Bioadhesion

Mucoadhesive form must proliferate over the substrate to induct a close contact and hike the

surface contact, assisting the diffusion of mucus chains.[23,24]

Attraction and repulsion forces

arise and the attraction forces must dominate for a mucoadhesion to be successful. There are

mainly 3 steps:

STEP-1. Contact Stage

Contact between mucoadhesive drug and mucus membrane with spreading and swelling of

formulation initiates its deep contact with mucus layer.[25]

STEP-2. Interpenetration Stage

The mucous membrane surface has high molecular weight polymers called glycoproteins. In

this step of the bioadhesive bond formation, the mucosal polymer chains and the bioadhesive

polymer chains intermingle and embrangle to form adhesive bonds. The bond strength

depends on the degree of inter-penetration between the two polymer groups. If both the

polymers are of similar chemical structure i.e. both are hydrophilic, then strong chemical

bond is formed.[26]

STEP-3. Consolidation Stage

In the consolidation step, activation of mucoadhesive materials occur in presence of moisture

where the mucoadhesive molecules break free and link up again by weak Van der Waals and

hydrogen bonds. Basically, two theories explain the consolidation step: the theory of

diffusion and the theory of dehydration. According to the theory of diffusion, the

mucoadhesive materials and the glycoproteins of the mucus collectively interact through

entanglement of their chains and forming of secondary bonds. According to the theory of

dehydration, as shown in Fig.2.3. materials that easily gelify in an aqueous environment,

when placed in contact with the mucus can cause its dehydration due to the osmotic pressure

difference. Water is drawn into the formulation due to concentration gradient until the

osmotic balance is reached leading to rise in contact time.[27,28,29,30,31]


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Fig 2.2 Mechanism of mucoadhesion.

2.5.3 Theory of Mucoadhesion

Electronic theory

According to the electronic theory, there is difference in the electronic structure of mucin

surfaces and bio adhesive system which results in attaining a electronic gradient. Due to

presence this electronic structure difference, the transfer of electrons occurs in these two

systems (mucin surface and bioadhesive system) when they come in contact with each. As a

result of this electron transfer there is the formation of an electronic bi-layer at the interface

of the two surfaces. This interfacial bi-layer exerts an attractive force in the interface of two

surfaces that may produce an effective mucoadhesion.[32]

Adsorption theory

This theory describes the involvement of both type of chemical bond, that is, primary and

secondary bond in the bio adhesion mechanism. Both the surface that is mucin and drug

delivery system has their own surface energy. When they come in contact, the adhesion

occurs due to the surface energy and results in the formation of two types of chemical bond.

Primary chemical bond such as covalent bond, which is strong in nature, thus produces a

permanent bonding, whereas secondary chemical bond involves Vander-Waals forces,

hydrophobic interaction and hydrogen bonding, which are weak in nature, thus produces a

semi-permanent bond.[33]

Wetting theory

This theory is based on the mechanism of spreadability of drug dosage form across the

biological layer. This theory is mainly applicable to liquids or low viscous mucoadhesive

system. According to this theory, the active components penetrate in to the surface

irregularities and gets harden it that finally results in mucoadhesion.[34]


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Diffusion interlocking theory

This theory describes the involvement of a mechanical bond between the polymeric chain of

drug delivery system and polymeric chain of mucus membrane, that is, glycol proteins. When

two surfaces are in intimate contact, the polymeric chain of drug delivery system penetrates

in to the glycoprotein network. According to this theory, the bioadhesion basically depends

on the diffusion coefficient of both polymeric chains. The other factors that may influence the

inter movement of polymeric chain are molecular weight, cross linking density, chain

flexibility, and temperature in order to achieve a good bio adhesion, the bio adhesive medium

should have a similar solubility with glycoprotein resulting in effective mucoadhesion.[35]

Fracture theory[35]

The fracture theory is mainly based on the fact that, the force required to detach the

polymeric chain from the mucin layer is the strength of their adhesive forces. This strength

may be also called as fracture strength. The fracture strength can be determined by using the

formula given below G=(E. e/L)½

G-Fracture strength,

E-Young’s modules of electricity,

e-Fracture energy,

L-Critical crack length.

2.5.4 Factors Affecting Mucoadhesion[33,34,35,36,37]

Polymer related factors Molecular weight: The mucoadhesion strength of a mucoadhesive

polymer mainly depends upon its molecular weight and polymeric linearity. Generally, for

the linear polymers (e.g., Polyethylene glycol), the bioadhesive property is directly

proportional to the molecular weight i.e., PEG-200000 having greater mucoadhesive strength

than that of PEG-20000. But in case of nonlinear polymer, the mucoadhesive strength of

polymer may or may not be dependent of its molecular weight. This is mainly because the

helical or coiled structures of such polymer may shield some of the adhesive group, which are

mainly responsible for the adhesive property.

Concentration of polymer: The concentration of a mucoadhesive polymer is a significant

factor of determining its mucoadhesive strength. There is an optimum concentration for a

mucoadhesive polymer where it produces the maximum mucoadhesion. For some highly

concentrated polymeric systems, beyond the optimum level of polymer, the mucoadhesive

strength of polymer starts to fall down significantly because the concentration of polymer


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molecules starts rising over the molecular concentration of the liquid medium so that there is

no further chain formation between liquid medium and polymer. As a result of this, the

polymer particles remain separated from liquid medium, due to this the mucoadhesive

strength of that polymer starts fallen down. On the other hand, when the concentration of the

polymer is too low as compare to the concentration of liquid medium, the number of polymer

chains per unit volume of liquid medium is less, the mucoadhesive strength of polymer at that

concentration is also very less.

Flexibility of polymer chains: Greater the flexibility of the mucoadhesive chain causes the

greater diffusion into the mucus network of buccal cavity. This results in increased

mucoadhesion. The flexibility of polymer chain decreases with increase in the concentration

of polymer. For an effective bioadhesion, the polymer chain should effectively diffuse into

the mucus layer. The flexibility of polymer chain depends on the viscosity and diffusion

coefficient of that chain.

Spatial confirmation: The mucoadhesive strength of a polymer is also dependent on the

conformation or spatial arrangement of polymers i.e., helical or linear. The polymers showing

linear conformation having the greater mucoadhesive strength as compare to the polymers

showing helical conformation. Because, the helical conformation of polymer may shield

various active groups, that are primarily responsible for mucoadhesion, thus reducing the

mucoadhesive strength of the polymer.

Swelling or hydration: The proper hydration of mucoadhesive polymer is essential for the

desired mucoadhesive strength. With increase in hydration the pore size of polymer increases

which results induced mobility and enhanced interpenetration.

Tissue movement: Tissue movement occurs on consumption of liquid and food, speaking,

peristalsis in the GIT and it affects the mucoadhesive system especially in case of gastro

retentive dosage forms.

Rate of renewal of mucosal cells: Rate of renewal of mucosal cells varies extensively from

different types of mucosa. It limits the persistence of bioadhesive systems on mucosal

surfaces.

Disease state: In some disease states, the secretion of mucus from the mucus membrane gets

decreased (e.g., in Dry Mouth Syndrome and in old age). So that there is not sufficient


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amount of mucus present at the site of attachment of mucoadhesive dosage form. This may

leads to improper moistening and swelling of polymer. Due to which there is decreased

mucoadhesive strength of mucoadhesive dosage form.

Concomitant diseases: Concomitant diseases can alter the physicochemical properties of

mucous or its quantity (for example, hypo and hyper secretion of gastric juice), increases in

body temperature, ulcer disease, colitis, tissue fibrosis, allergic rhinitis, bacterial or fungal

infection and inflammation.

Hydrogen bonding capacity: Hydrogen bonding is another important factor for

mucoadhesion of a polymer. For mucoadhesion to occur, desired polymers must have

functional groups that are able to form hydrogen bonds. Ability to form hydrogen bonds is

due to the presence of (COOH, OH etc.,). Flexibility of the polymer is important to improve

its hydrogen bonding potential. Polymers such as polyvinyl alcohol, hydroxylated

methacrylate and poly (methacrylic acid) as well as all their co-polymers are having good

hydrogen bonding capacity.

Cross linking density: The cross linking density of the polymer determines its higher

molecular weight. The cross linking density indicates the number of average molecular

weight of the cross linked polymer, which determines the average pore size. When the cross

linking density of polymer is higher, it reduces the pore size of polymer chain which results

in reduced diffusion of water into the polymer network. The reduced diffusion results in the

decreased penetration of polymer into the mucin and finally decreases the mucoadhesive

strength.

Charge: The bioadhesive property of ionic polymer is always higher than that of non-ionic

polymer. In neutral or slightly alkaline medium, the cationic polymer shows superior

mucoadhesive property. It has been proven that, cationic high molecular weight polymer such

as chitosan possess good bioadhesive property.

pH of polymer-substrate interface: The pH of polymer-mucin interface should be same as

it is possible, because, the difference in pH amongst the two systems may results in the

transfer of charge due to the higher pH gradient. This may affect the mucoadhesion.

Applied strength: While placing a buccal mucoadhesive drug delivery system, sufficient

strength should be applied in order to provide a good bioadhesive property. Even though


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there is no attractive forces between polymer and mucus, then application of high pressure for

sufficient long time make the polymer become bioadhesive with mucus.

Initial contact time: Greater the initial contact time between the mucoadhesive polymer and

the mucus layer results in the increased swelling as well as interpenetration of the

mucoadhesive polymer chain. Hence, increases the mucoadhesion strength of the polymer

chain.

Moistening: Moistening is required to allow the mucoadhesive polymer to spread over the

surface. It creates a network of polymer chains of sufficient pore size. Through these pores,

the interpenetration of polymer and mucin molecules takes place that results in increasing the

mobility of polymer chains for the proper diffusion of mucoadhesive polymer in mucin layer.

Mucin turnover: High mucin turnover is not beneficial for the mucoadhesive property

because of following reasons; high mucin turn over limits the residence time of bioadhesive

polymer as it detaches from the mucin layer, even though it has a good bioadhesive property.

High mucin turn over may produce soluble mucin molecule, thus molecule interact with the

polymer before they interact with mucin layer. Hence there will not be sufficient

mucoadhesion.

2.5.5 Advantages of mucoadhesive drug delivery system[38,39,40]

• It provides a relatively rapid onset of action as compare to the other non-oral routes, hence,

has a high patient acceptability.

• Improved patient compliance due to the easy application of dosage forms in comparison to

the injections and don’t provide any painful sensation.

• The mucosal membranes are highly vascularized so that the administration as well as

removal of a dosage form is easy.

• The sustained drug delivery can be achieved by using the mucoadhesive polymers of ‘SR’

grades.

• Due to the high extent of perfusion the rate of drug absorption is fast.

2.5.6 Advantages of Buccal Mucoadhesive Drug Delivery System[41,42]

1. It can be used for both local as well as systemic delivery of many drugs.

2. Buccal mucoadhesive dosage forms are easy to applicate as compare to other adhesive

dosage forms.


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3. Prolongs the residence time of the dosage form at the site of absorption.

4. Due to an increased residence time it enhances absorption and hence the therapeutic

efficacy of the drug.

5. Excellent accessibility.

6. Rapid absorption because of enormous blood supply and good blood flow rates.

7. Increase in drug bioavailability due to first pass metabolism avoidance.

8. Drug is protected from degradation in the acidic environment in the GIT.

9. Improved patient compliance- ease of drug administration.

10. Faster onset of action is achieved due to mucosal surface.

2.5.7 Challenges of Buccal Drug Delivery System[43]

• Low permeability of the buccal membrane, specifically when compared to the sublingual

membrane.

• Smaller surface area. The total surface area of membranes of the oral cavity available for

drug absorption is 170 cm2 of which ~50 cm represents non-keratinized tissues, including the

buccal membrane.

• The continuous secretion of saliva (0.5-2 l/day) leads to subsequent dilution of the drug.

• Swallowing of saliva can also potentially lead to the loss of dissolved or suspended drug

and ultimately the involuntary removal of the dosage form.

2.5.8 Polymers[45]

Mucoadhesive polymers are water-soluble and water insoluble polymers. Mucoadhesive

polymers that adhere to the mucin-epithelial surface can be conveniently divided into three

broad classes:

· Polymers that become sticky when placed in water and owe their mucoadhesion to

stickiness.

· Polymers that adhere through nonspecific, non-covalent interactions those are primarily

electrostatic in nature (although hydrogen and hydrophobic bonding may be significant).

· Polymers that bind to specific receptor site on tile self surface.

2.5.8.1 Ideal Property of mucoadhesive polymer

1. They should be nontoxic and should be non-absorbable from the gastrointestinal tract.

2. It should be nonirritant to the mucous membrane.

3. It should preferably form a strong non-covalent bond with the mucin-epithelial cell

surfaces.


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4. It should adhere quickly to most tissue and should possess some site-specificity.

5. It should allow daily incorporation to the drug and offer no hindrance to its release.

6. The polymer must not decompose on storage or during the shelf life of the dosage form.

7. The cost of polymer should not be high so that the prepared dosage form remains

competitive.

The polymers are discussed below.[46,47,48,49,50,51]

2.5.8.1.1 Guar gum

Non- proprietary : Benefiber

Synonyms: Guaran, Clusterbean

Chemical name: Galactomannan[7,18]

Molecular weight: 535.146 g/mol

Molecular formula: C10H14N5Na2O12P3

Structure

Functional category: Natural polymer

Application: As a natural polymer in compression of tablet and a dietary fiber.

Description: It is a natural non-ionic, water soluble polysaccharide exhausted from the

refined endosperm of cluster bean seeds. It occurs as off-whitish and yellowish-white powder

consisting of slight odour.

Solubility: Soluble in cold water and insoluble in most of the hydrocarbon solvents.

Storage condition: Guar gum property remains unchanged for 12-18 months. A model tablet

formulation prepared by direct compression, with Guar gum as polymer, are stored in cool

dry place away from heat and sunlight.

Incompatibilities: Guar gum significantly decrease the the digestion of starch i.e. act as

barrier between starch and starch hydrolyzing enzymes.


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Safety: Guar gum is mainly used as polymer in oral pharmaceutical formulations and is

generally regarded as an essentially non toxic and non-irritant material.

2.5.8.1.2 HPMC K4M

Nonproprietary Names

• BP : Hypromellose

• JP : Hydroxypropylmethylcellulose

• PhEur : Hypromellosum

• USP : Hypromellose

Synonyms: Benecel MHPC; E464; Hydroxypropyl methylcellulose; HPMC; Methocel;

methylcellulose propylene glycol ether; methyl hydroxy propyl cellulose; Metolose; Tylopur.

Chemical Name and CAS Registry Number

Cellulose hydroxy propyl methyl ether [9004-65-3]

Molecular formula: C56H108O30

Molecular weight: 1261.45

Structure

Functional Category: Coating agent, film-former, rate-controlling polymer for sustained

release, stabilizing agent, suspending agent, tablet binder, viscosity increasing agent.

Application: It is commonly used in tablet prepared by direct compression or wet

granulation processes. Concentrations between 2% and 5% w/w may be used as a binder in

either wet- or dry-granulation processes. In oral products, hypromellose is primarily used as a

tablet binder, in film coating, and as a matrix for use in extended-release tablet formulations.


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Description

Hypromellose is an odorless and tasteless, white or creamy-white fibrous or granular powder.

Typical Properties: Acidity/alkalinity : pH = 5.5–8.0 for a 1% w/w aqueous solution.

Melting point : Browns at 190–200°C; chars at 225– 230°C.

Glass transition point : 170–180°C.

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.

Stability and storage: Hypromellose powder is a stable material, although it is hygroscopic

after drying. Solutions are stable at pH 3–11. Hypromellose powder should be stored in a

well-closed container, in a cool and dry place.

Incompatibilities: Hypromellose is incompatible with some oxidizing agents. Since it is

nonionic, hypromellose will not complex with metallic salts or ionic organics to form

insoluble precipitates.

Safety: HPMC K4M is mainly used as polymer in oral pharmaceutical formulation and is

generally regarded as an essentially non toxic and non-irritant material.

2.5.8.1.3 Sodium CMC

Nonproprietary Names

• BP : Carmellose sodium

• JP : Carmellose sodium

• PhEur : Carmellosum natricum

• USP : Carboxymethylcellulose sodium

Synonyms

Akucell, Aquasorb, Blanose, cellulose gum, CMC sodium; E466, Finnfix, Nymcel

Chemical Name and CAS Registry Number: Cellulose, carboxymethyl ether, sodium salt

[9004-32-4]

Molecular Weight: 90 000–700 000.


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Structure

Functional Category: Polymer, Coating agent, stabilizing agent, suspending agent, tablet

disintegrant, tablet binder, viscosity-increasing agent.

Application: Carboxymethylcellulose sodium is additionally one of the main ingredients

used as a muco-adhesive agent, used as a tablet binder and disintegrant and to stabilize

emulsions.

Description: Carboxymethylcellulose sodium occurs as a white to almost white, odorless,

granular powder, is hygroscopic and absorbs significant amounts of water at temperatures up

to 37°C at relative humidities of about 80%.

Solubility: Practically insoluble in acetone, ethanol (95%), ether, and toluene. Easily

dispersed in water at all temperatures, forming clear, colloidal solutions. The aqueous

solubility varies with the degree of substitution.

Stability and Storage Conditions: Carboxymethylcellulose sodium is a stable, though

hygroscopic material. Under highhumidity conditions, carboxymethylcellulose sodium can

absorb a large quantity (>50%) of water. The bulk material should be stored in a well-closed

container in a cool and dry place.

Incompatibilities: It is incompatible with strongly acidic solutions and with the soluble salts

of iron and some other metals, such as aluminum, mercury, and zinc. Precipitation may occur

at pH <2, and also when it is mixed with ethanol (95%).

Safety: Sod CMC is widely used in oral pharmaceutical formulation and is generally

regarded as non-toxic and non irritant material.


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2.5.8.1.4 Carbopol 934

Non-proprietary name: Carbopol 934, Lubrizol

Synonyms: Cross linked acrylic acid, carbomer 934

Molecular weight: Approx. 500,000 to 4,000,000. g (CIR, 1979)

Structure

Description: White, light, acidic, hygroscopic powder.

Particle size: Flocculated powder having a median diameter of 2 to 7 microns.

Application: As a polymer in tablet (wet granulation and direct compression) formulation.

Solubility / swelling properties: They are insoluble due to their cross linked nature and high

molecular weight. They get swell in water and some polar solvents, producing viscous

dispersions.

Safety: Carbopol is mainly used as polymer in oral pharmaceutical formulations having

mucoadhesive property and is generally regarded as an essentially non toxic and non irritant

material.

Other excipients

2.5.8.1.5 Magnesium Stearate

Non-proprietary name: NF- Magnesium stearate; BP/EP- Magnesium stearate

Synonyms: Metallic stearic; magnesium salt

Empirical formula: C36H70MgO4

Chemical names: Octadecanoic acid; magnesium salt; magnesium stearate

Molecular weight: 591.3

Functional category: Tablet and capsule lubricant

Applications: Tablet and capsule lubricant, glidant and antiadherent in the concentration

range of 0.25 to 2.0%.


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Description: It is a fine, white, precipitated or milled, impalpable powder of low bulk

density, having a faint characteristic odor and taste. The powder is greasy to touch and

readily adheres to the skin.

Stability and storage conditions: Stable, non-self polymerizable. Store in a cool, dry place

in a well closed container.

Incompatibilities: Incompatible with strong acids, alkalies, iron salts and with strong

oxidizing materials.

Safety: Described as inert or nuisance dust. Dust clouds of magnesium stearate may be

explosive. However, oral consumption of large quantities may result in some laxative effect

or mucosal irritation.

2.5.8.1.6 Sodium Lauryl Sulfate

Non Proprietary Names BP: Sodium Lauryl SulphateJP:Sodium Lauryl SulfatePhEur:

Sodium LaurilsulfateUSP-NF: Sodium Lauryl Sulfate

Synonyms: Lauryl sulfate, Elfan 240

Chemical Name: Sulfuric acid monododecyl ester sodium salt(1:1) [151-21-3]

Empirical Formula and molecular weight: C12H22NaO4S 288.38

Structural Formula

Functional category: Anionic surfactant; detergent; emulsifying agent; skin penetrant; tablet

and capsule lubricant; wetting agent.

Description: Sodium lauryl sulfate consists of white or cream to pale yellowcolored crystals,

flakes, or powder having a smooth feel, a soapy, bitter taste, and a faint odor of fatty

substances.

Stability and Storage Conditions: Sodium lauryl sulfate is stable under normal storage

conditions. However, in solution, under extreme conditions, i.e. pH 2.5 or below, it


1584


undergoes hydrolysis to lauryl alcohol and sodium bisulfate. The bulk material should be

stored in a well-closed container away from strong oxidizing agents in a cool, dry place.

Incompatibilities: Sodium lauryl sulfate reacts with cationic surfactants, causing loss of

activity even in concentrations too low to cause precipitation. Unlike soaps, it is compatible

with dilute acids and calcium and magnesium ions. Sodium lauryl sulfate is incompatible

with salts of polyvalent metalions, suchasaluminum, lead, tinorzinc, and precipitates with

potassium salts. Solutions of sodium lauryl sulfate (pH 9.5–10.0) are mildly corrosive to mild

steel, copper, brass, bronze, and aluminum.

2.5.8.1.7 Talc

Nonproprietary Names BP: Purified Talc JP: Talc PhEur: Talc USP: Talc

Synonyms: Altalc; E553b; hydrous magnesium calcium silicate; hydrous magnesium silicate

Chemical Name and CAS Registry Number: Talc[14807-96-6]

Empirical Formula and Molecular Weight: Talc is a purified, hydrated, magnesium

silicate, approximating to the formula Mg6 (Si2O5)4(OH)4. It may contain small, variable

amounts of aluminum silicate and iron.

Structural Formula

Functional Category: Anticaking agent; glidant; tablet and capsule diluent; tablet and

capsule lubricant.

Use: It is used as glidant and lubricant in 1-10%

Description: Talc is a very fine, white to grayish-white, odorless, impalpable, unctuous,

crystalline powder. It adheres readily to the skin and is soft to the touch and free from

grittiness.


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Stability and Storage Conditions: Talc is a stable material and may be sterilized by heating

at 1608C for not less than 1 hour. It may also be sterilized by exposure to ethylene oxide or

gamma irradiation. Talc should be stored in a well-closed container in a cool, dry place.

Incompatibilities: Incompatible with quaternary ammonium compounds.

2.5.8.1.8 Saccharin

Nonproprietary Names BP: Saccharin JP: Saccharin PhEur: Saccharin USP-NF: Saccharin

Chemical Name and CAS Registry Number: 1, 2-Benzisothiazol-3(2H)-one 1,1-dioxide

[81-07-2]

Empirical Formula and Molecular Weight: C7 H 5 NO 3S183.18

Structural Formula

Functional Category: Sweetening agent.

Applications: Saccharin is an intense sweetening agent used in beverages, food products,

table-top sweeteners, and oral hygiene products such as toothpastes and mouthwashes. In oral

pharmaceutical formulations, it is used at a concentration of 0.02–0.5% w/w. It has been used

in chewable tablet formulations as a sweetening agent. Saccharin has been used to form

various pharmaceutical cocrystals. Saccharin can be used to mask some unpleasant taste

characteristics or to enhance flavor systems. Its sweetening power is approximately 300–600

times that of sucrose.

Description: Saccharin occurs as odorless white crystals or a white crystalline powder. It has

an intensely sweet taste, with a metallic or bitter aftertaste that at normal levels of use can be

detected by approximately 25% of the population. The aftertaste can be masked by blending

saccharin with other sweeteners.


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Stability and Storage Conditions: Saccharin is stable under the normal range of conditions

employed in formulations. In the bulk form it shows no detectable decomposition and only

when it is exposed to a high temperature (1258C) at a low pH (pH 2) for over 1 hour does

significant decomposition occur. The decomposition product formed is (ammonium-o-

sulfo)benzoic acid, which is not sweet. The aqueous stability of saccharin is excellent.

Saccharin should be stored in a well-closed container in a dry place.

Incompatibilities: Saccharin can react with large molecules, resulting in a precipitate being

formed. It does not undergo Maillard browning.

2.5.9 Classification of drugs used in GIT disorder[52]

A. Reduction of gastric acid secretion:

H2 antihistamines: Cimetidine, ranitidine

PPI's: Omeprazole, Esomeprazole, Rabeprazole

Anticholinergics: Piperazine, Oxyphenonium

Prostaglandin analogue: Misoprostol

B. Neutralization of gastric acid:

Systemic: Sod. bicarbonate

Non-systemic: Calcium carbonate, Magnesium hydroxide

C. Ulcer protectives: Sucralfate, Colloidal bismuth subcitrate

D. Anti-H. pylori drugs: Amoxicillin, Clarithromycin

2.6 Drug Profile: Esomeprazole[1,2,52]

Description: Esomeprazole is a white or almost white, crystalline powder. It is PPI with

marked highly effective inhibitor of gastric acid secretion used in therapy of stomach ulcers

and other GIT disorder.

Usual strength: Its usual strenth is 20 - 40 mg.

Molecular formula: C17H18N3O3S

Molecular weight : 345.417

IUPAC Name: 5-methoxy-2-{(s)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-

1H-benzimidazole.

Trade name: Nexium, Esofine, Esotrax, Rasiper


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Half life: The mean plasma elimination half- life is approximately 1- 1.5hrs.

Uses: It is indicated for the relief of gastric disorder i.e. gastritis, Zollinger's disorder and

other GIT disorder.

Dose: 20 - 40 mg once daily

Solubility: It is partially soluble in water, freely soluble in n- butanol, soluble in methanol.

Structure

Figure 2.3 Structure of esomeprazole.

2.6.1 Mechanism of Action of Esomeprazole

Through inhibition of the H+/K

+ ATPase in gastric parietal cell, esomeprazole regulates

gastric acid secretion by proton pump action.

Storage: Store protected from light and moisture, at a temperature not exceeding 300C.

Pharmacokinetics: Single 20-40 mg oral doses generally give rise to peak plasma

concentration of 0.5 - 1.0 mg/L within 1-4 hrs, but after several days of once- daily

administration these level may increase by about 50%. Esomeprazole is 97% bound to plasma

protein binding. In poor metabolizers, the AUC is lower for esomeprazole than for

omeprazole, contributing to less overall inter individual variability for esomeprazole than for

omeprazole. The dose-dependent increase in AUC of esomeprazole with repeated

administration results from a combination of decreased first-pass elimination and decreased

systemic clearance.

Adverse effect: Abdominal pain, headache, heartburn, allergic rxn, chest pain.

Contraindication: Contraindicated in patients with hip fractures and Clostridium difficile

associated diarrhoea.


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Precaution: Caution should be exercised in patients with history of kidney disease, during

pregnancy, breastfeeding, liver disease.

Drug interaction: Diazepam, Warfarin, Clopidogrel

2.7 Researches on Formulation of Mucoadhesive buccal tablets

In this section, researches conducted on the formulation of mucoadhesive buccal tablets are

presented.

Sameera and Niranjan et al.[53]

have formulated and evaluated mucoadhesive buccal tablets

of Sumatriptan succinate by direct compression method. In this study, mucoadhesive

polymers such as HPMC K4M, Carbopol 934P, ethyl cellulose and guar gum in alone and in

combination was used for release retarding agent to prolong the drug release, to increase

mucoadhesive strength and to avoid first pass metabolism. Ex vivo mucoadhesive strength,

and in vitro release studies showed that formulation SMF12 containing 12.5% of each

polymer combination showed satisfactory bioadhesive strength and exhibited optimum drug

release (99.33% after 10hrs). The result demonstrated that different mucoadhesive polymers

(HPMC K4M, Carbopol 934P, ethyl cellulose and guar gum) in various proportions can be

used for formulation of Sumatriptan succinate MBT.

Amit E. Birari et al.[54]

have formulated and evaluated chitosan based omeprazole MBT

using direct compression method. Nine formulations were prepared with Chitosan as primary

polymer and Carbopol 934, Hydroxy Propyl Methyl Cellulose (HPMC K4M) and Xanthan

gum as a secondary polymer. The best in-vitro drug release profile was achieved with the

formulation F8 which contains the Chitosan combine with Xanthan gum. The surface pH and

swelling index of formulation F8 was found to be 6.8, and 60%, respectively.

B.Gavaskaret al.[55]

have established mucoadhesive buccal tablets of Baclofen in the forms

of monolayered tablets. The tablets were prepared using Sodium methyl cellulose (NaMC),

sodium alginate and Methocel K15M as bioadhesive polymers to impart mucoadhesion.

Buccal tablets were evaluated by different parameters such as weight uniformity, content

uniformity, thickness, hardness, surface pH, Swelling index, ex vivo mucoadhesive strength,

in vitro drug release, and in vitro drug permeation. The present study concluded that

mucoadhesive buccal tablets of Baclofen can improve the bio availability of Baclofen.


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Margret Chandira*, Sachin, Debjit Bhowmik, B. Jayakar[56]

have developed

mucoadhesive tablets of Clarithromycin which were designed using four mucoadhesive

polymers namely Carbopol 974P, HPMC K15M and HPMC K4M to prolong the gastric

residence time after oral administration. They concluded F9 and F12 formulated by using

polymers; HPMC K14M, HPMC K15M and Carbopol 974P provided controlled release of

Clarithromycin over the period of 12 hrs with cumulative % of drug release of 93.16 and

96.82 respectively and stability studies showed that there was no significant change in

adhesive strength.

Nausheen Fathima*, Pradip Das and Vijaya Kuchana[57]

formulated MBT of Carvedilol

using direct compression method using natural binders such as Chitosan and Guar Gum to

reduce the first pass metabolism and frequency of administration. Cross Carmellose Sodium

was used as superdisintegrating agent and Carbopol 940P was used as polymer and evaluated

for various pre-compression and post compression parameters. Results indicated that

optimized formula consisting of Carvedilol (6.25mg), Carbopol 940P and Chitosan in the

ratio of 3:1, showed a maximum drug release after 7hrs, maximum swelling was attained in

6hrs and the highest mucoadhesive strength was 0.95N and fits zero order kinetics and can

by-pass the first pass metabolism and enhance the release of drug for extended period of time.

Monica RP Rao* and Priyanka Sadaphule[58]

formulated and evaluated MBT of Ketorolac

Tromethamine using direct compression method followed by coating using various

hydrophilic polymers like Hydroxy propyl methyl cellulose K4M (HPMC), Carbopol 934P

(CP) and xanthan gum singly and in combination to obtain unidirectional release of drug.

They concluded that buccal route is a promising alternative for administration of Ketorolac

tromethamine and formulation containing CP-HPMC combinations were found to be uniform

in thickness, weight, drug content and adequate mucoadhesive strength and swelling index

and histological studies revealed no damage to buccal mucosa.

Mohit Basotra et al.[59]

formulated and evaluated MBT of cispalstin. Eight formulations

were developed by direct compression method using various proportions of mucoadhesive

polymers, HPMC (400 cps) and carbopol 940. F4C (containing carbopol 940) was found to

be the best as it showed high swelling index 125.51± 1.63% at 12 h, optimum mucoadhesive

strength of 13.11±0.65 g and superior in vitro drug release of 91.30% in 12 h respectively.

They concluded that 20% Eudragit coated sustained release mucoadhesive tablets of cisplatin


1590


(F4C) containing 100 mg of carbopol has shown desired in vitro drug release as well as

mucoadhesive strength and could be further explored for its in vivo performance.

Gajananv. Shinde et al.[60]

have made MBT of niacin and evaluated its parameters along

with in- vitro study by using direct compression method and wet granulation method. The

tablets were prepared using Sodium Carboxy methyl cellulose (SCMC), carbopol940P and

Hydroxy Propyl Methyl Cellulose (HPMC K4M) as bioadhesive polymers to impart

mucoadhesion. Result indicated that batch B-11 containing Sodium CMC (10%), Carbopol

940P (25%) and HPMC K4M (15%) can successfully be employed as a sustain release of

niacin and they concluded that MBT of niacin can be a good approach to improve the

bioavailability of niacin.

D. Mahalaxmi et al.[61]

have formulated and evaluated MBT of glipizide, an antidiabetic

drug by direct compression method using bioadhesive polymers like Carbopol 974P,

Methocel K4M and Methocel K15M in different concentrations and evaluated by different

parameters such as thickness, hardness, weight uniformity, content uniformity, swelling

index, surface pH, ex vivo bioadhesive strength, in vitro drug release, ex vivo drug

permeation and FTIR studies. They concluded that MethocelK15M in the ratio of 1:2 could

be used to design effective and stable buccoadhesive tablets of glipizide.

S.B. Shirsand et al.[62]

have formulated and evaluated MBT of Carvedilol using direct

compression method. Tablets were prepared using mucoadhesive polymers like HPMC

15cps, 50 cps, K4M and carbopol 934p along with impermeable backing layer. Among 15

formulation, F15 containing HPMC 15 cps was best; 84.73% was dissolved in 8 hr with

bioadhesion strength 5.71N, relative bioavailability was found to be 121.27. They concluded

that MBT of carvedilol can be succesfully developed with satisfactory drug dissolution

profile and bioadhesion strength along with good bioavailability.

R Indira Prasanna, P Anitha and C Madhusudhana[63]

have formulated and evaluated

MBT of sumatriptan succinate by direct compression technique. Tablet was made using

blends of different bio-adhesive polymeric combinations such as hydroxy propyl methyl

cellulose K4M, sodium carboxy methyl cellulose, and Carbopol 934P with a backing layer of

ethyl cellulose. The result concluded that developed MBT might be the alternative routes

available to bypass the first pass metabolism and might be a milestone in the therapy of


1591


migraine and among all formulations S4 (HPMC and carbopol) shows good controlled

release results correlated with ex vivo permeation studies.

Sudeesh Edavalath et al.[64]

have formulated and evaluated rabeprazole sodium

mucoadhesive buccal tablets by using direct compression method. Twelve different

formulations of MBT of Rabiprazole sodium containing polymers such as Carbopol 934 P,

Hydroxyl propyl methyl cellulose K4M (HPMC K4M), Sodium carboxyl methyl cellulose

(Sod CMC), Hydroxyl ethyl cellulose (HEC) and Hydroxyl propyl cellulose (HPC) in various

combinations were prepared and characterized by swelling studies, % matrix erosion, surface

pH, bioadhesive strength, in vitro drug dissolution and in vitro diffusion studies. The best

mucoadhesive performance and best in vitro drug release profile were achieved by using

drug: Hydroxyl ethyl cellulose (HEC): Carbopol 934 P in a ratio of 1: 6: 1.5. and chosed

tablet containing 20 mg of Rabiprazole sodium performed 12 h sustained drug release with

desired therapeutic concentration.

Dr. N.G Raghavendra Rao and Gururaj S. Kulkarni[65]

have formulated and evaluated

mucoadhesive bilayered buccal tablet of salbutamol by direct compression method using

different bioadhesive polymers such as xanthan gum, sodium alginate and carbopol 937p.

The result revealed that the release of salbutamol buccal tablets was slower in F4 and F5

containing xanthum gum in comparison to other formulations. Among all formulations F4

and F5 containing xanthum gum were best and they concluded that MBT of salbutamol can

be formulated.

Murali Krishna.B and Praveen Kumar Uppala et al.[66]

have made an attempt and

formulated and evaluated MBT of Linagliptin by using direct compression method. Tablets

of Linagliptin were prepared using mucoadhesive polymers carbopol 934-P and HPMC K4M,

Hydroxy ethyl cellulose and evaluated different parameters like thickness, hardness, weight

uniformity, content uniformity, swelling index, surface pH, in vitro drug release, in vitro drug

permeation and FTIR studies. The results indicated that polymers API and carbopol 934 in

the ratio of 1:6 showed satisfactory mucoadhesive properties. They concluded that F6

containing carbopol shows the satisfactory result with improvement in bioavailability.

SB Shirsand, Sarasija Suresh et al[67]

have formulated and optimized mucoadhesive bilayer

buccal tablets of atenolol by direct compression method using simplex method of

optimization to investigate the combined effect of hydroxypropyl methylcellulose 15 cps


1592


(X1), Carbopol (X2) and mannitol (X3); the in vitro drug release (Y1) and mucoadhesive

strength (Y2) were taken as responses. They concluded that formulation C containing

hydroxypropyl methylcellulose 15 cps (10% w/w of matrix layer), Carbopol 934p (10% w/w

of matrix layer) and mannitol (channeling agent, 40% w/w of matrix layer) was found to be

promising and exhibited an in vitro drug release of 89.43% in 9 h along with satisfactory

bioadhesion strength (7.20 g) also short-term stability studies indicated that there are no

significant changes in drug content and in vitro dissolution characteristics (P<0.05) and IR

spectroscopic studies indicated that there are no drug-excipient interactions.

Chul Soon Yong et al.[68]

have developed an effective omeprazole buccal adhesive tablet

with excellent bioadhesive force and good drug stability in human saliva. The omeprazole

buccal adhesive tablets were prepared with various bioadhesive polymers, alkali materials,

and croscarmellose sodium. As bioadhesive polymers for the omeprazole tablet, a mixture of

sodium alginate and hydroxyl propyl methylcellulose (HPMC) was selected. They concluded

that the omeprazole MBT would be useful for delivery of an omeprazole that degrades very

rapidly in acidic aqueous medium and undergoes hepatic first-pass metabolism after oral

administration.

Anna Balaji, Vaddepalli Radhika and Vishnuvardhan goud[69]

have formulated MBT

containing Carvedilol by wet granulation method. The effect of two independent variables,

Casein (X1) and hydroxypropylmethyl cellulose (HPMC K4M) (X2) at three different levels

(-1, 0, +1) on dependent variable including hardness (Y1), cumulative percentage drug release

at 6 hrs (Y2) and 12 hrs (Y3) using 32 full factorial design. All physico-chemical parameters

were within permissible Pharmacopoeial limits. The study revealed that MBT can be

successfully formulated using Casein and HPMC K4M using 32 full factorial design in the

buccal delivery of Carvedilol and concluded that result indicated that suitable innovative

mucoadhesive buccal tablets may be prepared with desired bioavailability and mucoadhesion

and it can be better option to by-pass hepatic metabolism.

Burak Çelik et al.[70]

have formulated and evaluated MBT of riserpidone by direct

compression method using polymers like Carbopol® (CP) and sodium alginate (SA) were

selected for further optimization studies by applying response surface methodology. They

suggested that optimized buccal tablets of riserpidone would be a promising and alternative

delivery system for the treatment of schizophrenia with optimum formulation consisted of

16.4% CP and 20.3% SA, which provided 7.67±0.29 hour ex vivo RT, 45.52±4.85 N TH, and


1593


2.12±0.17 N DF and cumulative release of >90% was achieved after 8 hours of in vitro

dissolution studies, which was supported by swelling and matrix erosion analysis.

Han-Gan Choi et. al. (2000)[71]

have formulated buccal adhesive tablet of Omeprazole by

using Sodium alginate and Hydroxy propyl methyl cellulose polymer. Croscarmellose

Sodium was used to enhance the release from buccal adhesive tablet. They have reported

marked increase in release of Omeprazole from the prepared buccal tablet.

N.Parvez, et. al. (2002)[72]

have developed and evaluated mucoadhesive buccal tablet of

Lignocaine Hydrochloride using mucoadhesive polymers Carbopol-934P, Sodium carboxy

methyl cellulose. They have reported a good sustain release and buccal adhesive property

from the prepared formulation.

M V Raman, et. al. (2007)[73]

have formulated a mucoadhesive buccal drug delivery system

by using Metoprolol Tartrate a model drug. The mucoadhesive polymers used in formulation

were Carbopol-934, HPMC, Hydroxy ethyl cellulose and Sodium carboxy methyl cellulose.

They have concluded that formulation containing Hydroxy ethyl cellulose and Carbopol-934

in the ratio of 1:2 showed the best result.

R. Manivannan, et. al. (2008)[74]

have formulated mucoadhesive buccal tablet of Diltiazem

Hydrochloride. Carbopol-934, Sodium Carboxy methyl cellulose, HPMC, Sodium alginate

and Gaur gum were selected as mucoadhesive polymer. They have reported a suitable

mucoadhesive buccal tablet with desired property could be prepared.

Bhavain Patel et. al.[75]

have formulated Nifedipine buccal adhesive tablet with objective of

avoiding first-pass metabolism and prolonging duration of action HPMC K4M and Carboxy

methyl cellulose are used as polymer. They have reported a satisfactory drug release and

good bioadhesion from prepared formulation.

Margat Chandira, et. al.[76]

have formulated buccoadhesive tablet of Verapamil

Hydrochloride tablet using Cabopol-934P, HPMC K4M, Hydroxy ethyl cellulose and Sodium

carboxy methyl cellulose. They concluded that formulation with Carbopol-934P and Hydroxy

ethyl cellulose was optimized formulation with optimum bioadhesive strength swelling index

and desire in-vitro drug release.


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Ashvini Madgulkar et. al.[77]

have developed tri-layer mucoadhesive tablet with

Itraconazole. Tri-layered mucoadhesive tablet were prepared with inner core containing solid

dispersion of the drug and with Carbopol and HPMC sandwiched between two layers of

hydrophilic mucoadhesive polymer. The prepared formulations gave adequate bioadhesive

strength and sustain release profile with zero-order kinetics.

Ali Riza Kepsutlu et al.[78]

formulated and evaluated mucoadhesive buccal tablet of

piroxicam by direct compression method using hydroxy propyl methylcellulose and chitosan

as mucoadhesive agents. Tablets were evaluated for physical properties. In vitro dissolution

studies showed that the release rate of PX from the formulations affected by type and ratio of

polymers. The release mechanism of PX from buccal tablets follows diffusive mechanism

with first order and Higuchi release kinetics. In vivo studies of optimum buccal tablet

formulation carried out on human healthy volunteers showed that the relative bioavailability

of PX was 67.52 ± 21.47%. They concluded that buccal tablet formulation of PX seems to be

an alternative drug delivery for patients especially suffering from GI disturbances.

Bhanja S.B et al.[79]

have formulated and evaluated MBT of Timolol maleate to circumvent

the first pass effect and to improve its bioavailability with reduction in dosing frequency and

dose related side effects by direct compression method. Eight formulations were developed

with varying concentrations of polymers like Carbopol 934, Polyethylene oxide and Hydroxy

Propyl Methyl Cellulose. The best in-vitro drug release profile was achieved with the

formulation F5 which contains the drug, Carbopol 934p and HPMC K4M in the ratio of

1:2.5:10. They concluded formulation F5, containing 10 mg of Timolol maleate exhibited 7 h

sustained drug release i.e. 98.18% with desired therapeutic concentration and revealed that all

formulations fits well with zero order kinetics followed by Korsmeyer-Peppas, first order and

then Higuchi's model and the mechanism of drug release is non-Fickian diffusion.

A.M. Pethe and S.P. Salunkhe.[80]

have formulated and evaluated MBT of simvastatin by

using direct compression method. Six different formulations of tablets of Simvastatin

containing the polymers in various combinations were prepared and characterized for

swelling studies, % matrix erosion, surface pH, mucoadhesive properties, in-vitro release

studies. The swelling index was proportional to carbopol content & other bio -adhesive

polym er. Tablets containing Carbopol and HPMC K100 in the ratio of 4:1 had the maximum

percentage of in-vitro drug release for 7h. They concluded that formulation F 4 containing

carbopol and HPMC K100M was optimized based on good bioadhesive strength (45 ± 0.55


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g) and sustained in vitro drug release (65.96 % for 7h) and chosen tablet containing 10 mg of

simvastatin performed 7h sustained drug release with desired therapeutic concentration.

Guda Aditya et al.[81]

have formulated and evaluated MBT of Lisinopril by direct

compression method using Carbopol‐934, Hydroxy propyl methyl cellulose (HPMC),

Hydroxy ethyl cellulose (HEC) as mucoadhesive polymers. Six formulations were developed

with varying concentration of polymers. The tablets were evaluated and formulation (F4)

containing Carbopol‐934 and HPMC K4M in the ratio of (2: 4) showed good mucoadhesive

strength (36.8) and maximum drug release of 97.1% in 10 hrs. Swelling increase with

increase in concentration of HPMC K4M in tablets and follows zero‐order drug release. FTIR

studied showed no evidence on interaction between drug and polymers. They concluded that

the MBT of Lisinopril may be good choice to bypass the extensive hepatic first pass

metabolism with an improvement in the bioavailability of Lisinopril through buccal mucosa.

MATERIALS AND METHODS

3.1 Materials

The following materials of Pharma grade or the best possible Laboratory Reagent (LR) were

used as supplied by the manufacturer. The distilled water was used in all experiments.

Table 3.1: List of Chemicals Used With Supplier.

S.N. MATERIALS SOURCE

1. Esomeprazole Gifted by Deurali Janata Pharmaceutical Pvt. LTD.e

2. Carbopol 934 Gifted by CTL Pharmaceutical Pvt. LTD.

3. HPMC K4M Gifted by Deurali Janata Pharmaceutical Pvt. LTD

4. Gaur gum Gifted by CTL Pharmaceutical Pvt. LTD

5. Sodium Carboxy Methyl Cellulose Gifted by CTL Pharmaceutical Pvt. LTD.

6. Magnesium stearate HIMEDIA

7. Talc LOBA CHEMIE Pvt. LTD.

8. Sodium Saccharin HIMEDIA

9. Lactose HIMEDIA

10. Sodium Lauryl Sulphate LOBA CHEMIE Pvt. LTD.

3.2 Equipment /Instrument

The equipment used in this project are presented in Table 3.2.


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Table 3.2: List of equipment, instrument and machineries used.

S. N. Instrument Manufacturer

1 Dissolution Test Apparatus Aastha International/PDA-65

2. Digital Electronic balance Kern & Sohn GmbH/D- 72335

3. Friability test apparatus Dica India® /FTA-23/D

4. Tablet hardness tester Monsanto type

5. UV spectrophotometer (double beam) ELICO

®/SL210UV

SPECTROPHOTOMETER

6. Disintegration test apparatus EI/1209578

7. pH Meter Simtronics®

8. Bulk density apparatus Dica India

9. Digital Vernier caliper Stainless Hardened

10. Glass wares Borosilicate Grade

11. 8 station rotatory tablet punching machine Cemech machineries Ltd/R & D

labpress

12. Digital ultrasonic mixture Ambala cantt India

3.3 Pre-formulation study

Pre-formulation studies relates to pharmaceutical and analytical investigation carried out

proceeding and supporting formulation development efforts of the dosage form of the drug

substance. It gives information needed to define the nature of drug substance and provide

framework for the drug combination with pharmaceutical excipients in the dosage form.

Hence, following pre-formulation studies were performed.

3.3.1 Determination of solubility

The solubility of Esomeprazole was performed in solvents water, methanol, acetone,

benzene, chloroform, Dimethyl sulphoxide, n-butanol, ethyl acetate.

3.3.2 Determination of λmax

A solution of Esomeprazole containing conc. 10μg/ml was prepared in phosphate buffer pH

6.8 and another solution of esomeprazole containing conc 10 μg/ml was prepared in water

and UV spectrum was taken using spectrophotometer respectively. The solution was scanned

in the range of 200-400 nm for both.

3.3.3 Preparation of Standard Calibration Curve for Esmoprazole

Accurately weighed 10mg of Esomeprazole was dissolved in phosphate buffer 6.8 pH

solution and volume was made up to 1000 ml by phosphate buffer 6.8 pH which is the stock

solution containing 10μg/ml concentration. Similarly from the Stock solution different aliquot

of 0.4, 0.8, 1.2, 1.6, 2 μg/ml were prepared respectively. Then, the absorbance was measured

at 302 nm using UV Spectrophotometer. The standard curve was obtained by plotting


1597


absorbance versus concentration in μg/ml. And similar process was repeated in water solution

and calibration curve of esomeprazole was prepared in water also.

3.3.4 Preparation of Phosphate Buffer Solution at pH 6.8

The preparation of phosphate buffer pH 6.8 was done according to Indian pharmacopoeia

2010. In this, 28.80 gm of disodium hydrogen phosphate and 11.45 gm of potassium

dihydrogen phosphate was dissolved in small quantity of distilled water and volume was

made up to 1000 ml.

3.3.5 Drug-Excipients Compatibility Studies

In the preparation of tablets formulation, drug and excipients may interact as they are in close

contact with each other, which could lead to the instability of drug. Pre-formulation studies

regarding the drug-excipients interaction are therefore very critical in selecting appropriate

polymers. FT-IR spectroscopy was employed to ascertain the compatibility between

Esomeprazole and the selected excipients.

3.4 Formulation development

Esomeprazole mucoadhesive buccal tablets were manufactured in eight formulations F1 to F8

using the ingredients mentioned in the Table keeping the total weight (300 mg) of the tablet

constant in all the formulations by direct compression method. An excipients; lubricant (mag

nesium stearate and talc) were passed through sieve no 100#, polymers were passed through

sieve no. 40#, filler was passed through sieve no. 30#, sweetner like sod.saccharin was passed

through sieve no. 80#, solubilizing agent was passed through sieve no. 30# and active drug

was passed through the sieve no.60#. All the above ingredients were properly mixed together

(in an air tight plastic container). Mucoadhesive buccal tablet containing an Esomeprazole

drug were prepared by this procedure.

3.5 Formulation of Esomeprazole

Eight batch of Esomeprazole tablets were prepared using the formulation shown in Table 3.3


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Table 3.3 Formulation chart of Esomeprazole Mucoadhesive Buccal Tablets. (F1-F8)

S.NO Ingredients (mg) F1 F2 F3 F4 F5 F6 F7 F8

1. Esomeprazole 20 20 20 20 20 20 20 20

2. Carbopol 934 25 50 - - - - - -

3. HPMC K4M - - 25 50 - - - -

4. Gaur gum - - - - 25 50 - -

5. Sodium CMC - - - - - - 25 50

6. Magnesium stearate 10 10 10 10 10 10 10 10

7. Sodium Lauryl Sulfate 2 2 2 2 2 2 2 2

8. Sodium saccharin 5 5 5 5 5 5 5 5

9. Lactose 234 209 234 209 234 209 234 209

10. Talc 4 4 4 4 4 4 4 4

Total 300mg

3.6 Evaluations of Mucoadhesive Buccal Tablet 53

3.6.1 Pre- Compression Parameters

The following pre-compression evaluation were performed.

3.6.1.1 Angle of Repose

The powder mixture was taken in a funnel. The height of the funnel was adjusted at definite

height in such a way that the tip of the funnel just touches the apex of the heap of blend. The

drug blend was allowed to flow through the funnel freely on to the surface. The diameter of

the powdered cone was measured and the angle of repose was calculated using the following

equation;

Tan θ = 2h/D

Where, θ = Angle of repose

h = height of the cone

D = Diameter of the cone

The angle of repose and corresponding types of flow is shown in Table 3.4. Angle of Repose

less than 30 shows the free flowing of the material.

Table 3.4 Angle of Repose and powder flow properties.

S. No. Angle of Repose Type of Flow

1 < 20 Excellent

2 20 – 30 Good

3 30 – 34 Passable

4 > 34 Very Poor


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3.6.1.2 Bulk Density (Db)

It is the ratio of total mass of powder to bulk volume of powder. It is expressed in g/ml. This

was determined by pouring an accurately weighed quantity of blend into a graduated cylinder

and then the volume and weight was measured.

Db =M/ Vb

Where, Db= bulk density, M = Weight of powder, Vb = bulk volume of the powder

3.6.1.3 Hausner’s ratio

Hausner’s ratios is an indirect index of ease of powder flow. The Hausner’s ratios of prepared

mucoadhesive dry powder blends were determined by following formula.

Hausner’s ratio = Tapped density / poured density

According to specifications values less than 1.25 indicate good flow (=20% of Carr’s index),

where as greater than 1.25 indicates poor flow (=33% of Carr’s index). Between 1.25 and 1.5,

added glidant normally improves flow.

3.6.1.4 Tapped Density (Dt)

It is the ratio of total mass of the powder to the tapped volume of the powder. Volume was

measured by tapping the powder for 100 times in a bulk density apparatus) and tapped

volume is noted. It is expressed in g/ml and given by,

Dt= M/Vt

Where M is the mass of powder, Vᵼ is the tapped volume of the powder

3.6.1.5 Carr’s Index

The compressibility index of the granules was determined by Carr’s compressibility index.

Grading of the powders for their flow properties according to Carr’s Index is shown in below

Table 3.5.

Table 3.5 Carr’s Index Flow Property.

Compressibility Flow ability

5-12 Excellent

12-16 Good

18-21 Fair Passable

23-25 Poor

33-38 Very poor

>40 Very very poor


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3.6.2 Post - Compression

3.6.2.1 Weight variation

The tablets were then weighed individually using a digital balance to determine the weight of

each tablet. The tablets were subjected to weight variation by individually weighing 20

randomly selected tablets. Such determinations were carried out for each formulation.

3.6.2.2 Tablet thickness

The thickness of tablet was measured by placing the tablet between two arms of the digital

vernier caliber.

3.6.2.3 Tablet hardness

The tablet hardness, which is the force required to break a tablet in diametric compression

force. The hardness tester used in the study was Monsanto hardness tester, which applies

force to the tablet diametrically with the help of an inbuilt spring.

3.6.2.4 Friability Test

The friability of the tablets was measured in a Roche friabilator. Tablets of a known weight

(Wo) or a sample of 20 tablets are dedusted in a drum for a fixed time (100 revolutions) and

weighed (W1) again. Percentage friability was calculated from the loss in weight as given in

equation as below. The weight loss should not be more than 1%

Friability (%) = × 100%

3.6.3 Surface pH

The bioadhesive tablet was allowed to swell by keeping it in contact with 1 mL of phosphate

buffer 6.8 for 2 h at room temperature. The pH was measured by bringing the pH-meter

electrode, in contact with the surface of the tablet and allowing it to equilibrate for 1 min.

3.6.4 Swelling index

Buccal tablets were weighed individually (designated as W1) and placed separately in Petri

dishes containing 15 mL of phosphate buffer (pH 6.8) solution. At regular intervals (1hr, 2hr

and 3hr) the buccal tablets were removed from the Petri dishes and excess surface water was

removed carefully using the filter paper. The swollen tablets were then reweighed (W2). This


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experiment was performed in triplicate. The swelling index (water uptake) calculated

according to the following equation;

Swelling index = (W2 – W1)/W1* 100

3.6.5 Stability in Human Saliva:

Stability studies of the buccal tablet were performed for optimized formulation in normal

human saliva. The human saliva was collected from humans and filtered through a filter

paper. The buccal tablet was placed in separate petri dishes containing 5 mL of human saliva

and placed in a temperature controlled oven for 9 h at 37 °C ± 0.2 °C at regular intervals (0,

3, 6, and 9 h), the buccal tablet was examined for change in color, surface area, and integrity.

3.6.6 Measurement of bioadhesive force

Bioadhesive force of the tablets was measured on a modified physical balance. Thread was

tied and thread was hanged in one end of buccal membrane containing tablet and slowly the

weight was increased in the balance until the tablet is de-attached from membrane. By using

this weight, bio-adhesive force for all the formulations of Esomeprazole MBT were

calculated using following equation;

N = (W * g) / 1000

Where N is bio adhesive force, W is the weight required for the detachment of two vials in

grams, and g is the acceleration due to gravity.

3.6.7 Ex vivo residence time

Tablets residence time was determined using a modified dissolution apparatus. The medium

used was 800 ml pH 6.8 phosphate buffer kept at 37oC in goat buccal mucosa obtained from a

local slaughterhouse was fixed to a glass slab using an adhesive. The slab was vertically

attached to the dissolution apparatus. Each buccal tablet was wetted from one surface by 0.5

mL of pH 6.8 phosphate buffer. The wet surface was kept in contact with the mucosal

membrane for 5 min. The glass slab was allowed to move downwards and upwards so that

the tablet was kept completely immersed in the solution. The time required for complete

dissolving or detachment of each tablet from the mucous membrane surface was determined.

3.6.8 Force of adhesion

The work of adhesion was determined from the area under the force distance curve.

Force of adhesion = (Bioadhesion strength x 9.8)/ 1000


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3.6.9 Assay[2]

Preparation of standards

Accurately 20 mg standard esomeprazole was weighed and transferred to 100 ml volumetric

flask (VF). Drug was dissolved in water and volume was made up to the 100ml with water.

From this stock solution 1ml was taken and transferred to 10ml volumetric flask and volume

was maintained. Again from this 2nd

stock solution 1ml was taken and transferred to 10ml

volumetric flask and volume was made upto mark.

Preparation of sample

The amount of active ingredient was determined by taking 5 tablets randomly. Tablets were

then weighed accurately, and then powdered in motar and pestle. Tablet drug powder

equivalent to 20mg of drug was taken in 100ml volumetric flask which was first dissolved in

water and volume was maintained up to mark with water. From this stock solution 1ml was

withdrawn and volume maintained up to 10ml with water in volumetric flask. Again 1ml was

taken out from this second stock solution in 10 ml volumetric flask. Then this solution was

filtered, diluted properly and analyzed spectrophotometrically at 302 nm.

Procedure: The absorbance was measured at 302 nm to find out the content of

Esomeprazole. Content of esomeprazole in tablet in percentage was calculated by using

following formula.

3.6.10 In vitro Drug release[2]

Preparation of standard

Accurately 22 mg standard Esomeprazole was weighed and transferred to 1000 ml volumetric

flask (VF). Drug was dissolved in phosphate buffer pH 6.8 and sonicated for 15min and

volume was made up to the 1000ml and from this stock solution 2ml was taken out and

volume was made up to 50ml by phosphate buffer pH 6.8.

Preparation of Sample

In-vitro drug release of the samples was carried out using USP – type II dissolution apparatus

(paddle type). The dissolution medium, 900 ml of buffer solution, was placed into the

dissolution flask maintaining the temperature of 37±0.5ºC and of 50 RPM. Tablets were

placed in each flask of dissolution apparatus. Accurately 20mg tablet was taken in 900ml

buffer solution. The apparatus was allowed to run for 30 min. Samples measuring 10 ml were

taken out in each 30 minutes which was filtered and 2ml was taken from it and diluted to


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50ml volumetric flask. The collected samples were analyzed at 302 nm using dissolution

medium as blank. The percentage drug release was calculated. The details of the in-vitro

dissolution study are presented in Table 3.5

Table 3.6 In Vitro Dissolution Studied Detail.

3.6.11 In-vitro permeation study

The in vitro buccal drug permeation study of Esomeprazole through egg membrane using the

modified franz diffusion cell was performed at 37°C ± 0.2°C. Egg membrane was obtained

by placing egg into conc HCl for 10 to 15min then membrane was extracted from it. Then

egg membrane was placed between the donor and receptor compartments. The buccal tablet

of best formulation was placed with the core facing the membrane and the compartments

clamped together. The donor compartment was filled with 1 ml of phosphate buffer pH 6.8.

The receptor compartment was filled with 25 ml of phosphate buffer pH 6.8 and the

hydrodynamics in the receptor compartment was maintained by stirring with a magnetic bead

at 50 rpm. Then solution was filtered then 20ml of solution was pipetted and volume was

maintained up to 25ml by phosphate buffer pH 6.8. Then from this stock solution 1ml was

taken and volume was made up to 100ml by phosphate buffer pH 6.8 ml again from this

second stock 1ml was taken and then volume was maintained upto 10ml which was analyzed

for drug content at 302 nm using a UV-spectrophotometer.

3.6.12 Kinetics of drug release

To study the release kinetics of in-vitro drug release, data obtained from in-vitro release study

were plotted in various kinetic models; zero order as % drug release vs time, first order as

log% drug retained vs time, higuchi as % drug release vs time, korsmeyer peppas as log %

drug release vs log time.

Apparatus used USP type II dissolution apparatus

Dissolution medium Phosphate buffer pH 6.8

Dissolution medium volume 900 ml

Temperature 37±0.5ºC

Speed of paddle 50 rpm

Sample withdrawn 10 ml

wavelength 302nm


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RESULTS

4.1 Authentication of Drugs

4.1.1 Determination of Solubility

Solubility studies were carried out in different solvents and observations are presented in

Table 4.1.

Table 4.1 Solubility Profile of Esomeprazole.

Solvent Solubility

Water Partially soluble

n-butanol Freely soluble

Acetone Insoluble

Methanol Soluble

Chloroform Slightly soluble

Benzene Insoluble

Dimethyl sulphoxide Soluble

Ethyl acetate Insoluble

Determination of λmax of Esomeprazole in water and in phosphate buffer at pH

4.1.2 Determination of λmax

The different concentrations were prepared using water and Esomeprazole. Similarly, process

was repeated in phosphate buffer and esomeprazole. λmax was found to be 302 nm. The

result is plotted as shown in Figure 4.1. and 4.2.

Figure 4.1 ʎmax of Esomeprazole in water.


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Figure 4.2 λmax of Esmoprazole in phosphate buffer of pH 6.8.

4.1.2.1 Standard Calibration Curve for Esomeprazole with water

A Standard Calibration Curve for Esomeprazole was obtained by measuring absorbance at

302 nm and by plotting graph of absorbance vs concentration. The absorbance reading of

Esomeprazole with water having 10μg/ml concentrations were showed in Table 4.3.

Table 4.2 Absorbance Values of Esomeprazole in water.

S. N. Concentration (μg/ml) Absorbance (302 nm)*

1. 0 0

2. 0.4 0.027

3. 0.8 0.0508

4. 1.2 0.0728

5. 1.6 0.0940

6. 2 0.1168


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Figure 4.3 Standard Calibration Curve of Esomeprazole on water.

4.1.2.2 Standard Calibration Curve for Esomeprazole with phosphate buffer at pH 6.8

A Standard Calibration Curve for esomeprazole was obtained by measuring absorbance at

302nm and by plotting graph of absorbance vs concentration. The absorbance reading of

esomeprazole with phosphate buffer having 10μg/mlconcentrations were showed in Table

4.3.

Table 4.3 Absorbance Values of Esomeprazole at Phosphate buffer at pH 6.8.

S. N. Concentration (μg/ml) Absorbance (302nm)*

1. 0 0

2. 0.4 0.0135

3. 0.8 0.0300

4. 1.2 0.0466

5. 1.6 0.0590

6. 2 0.0757


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Figure 4.4 Standard Calibration Curve of Esomeprazole on Phosphate Buffer at pH 6.8.

4.2 Evaluation parameters of Mucoadhesive Buccal tablets Esomeprazole

4.2.1 Drug - polymer compatibility studies

Figure 4.5 FTIR spectra for standard Esomeprazole.


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Figure 4.6 FTIR spectra for F8 formulation.

4.3 Pre-Compression Parameter of Mucoadhesive Buccal Tablets Esomeprazole

Pre-compression parameter including bulk density, tapped density, compressibility index,

angle of repose and hausner ratio are presented in Table 4.3.

Table 4.4 Pre-Compression Parameters.

S.

N.

Formulation

code

Bulk

Density

(g/cm³)

Tapped

Density

(g/cm³)

Compressibility

index(%)

Angle of

repose(θ) Hausner ratio

1 F1 0.633 0.784 19.000 19.074 1.002

2 F2 0.571 0.828 30.000 21.060 1.004

3 F3 0.599 0.797 24.008 21.045 1.003

4 F4 0.558 0.629 11.000 24.051 1.001

5 F5 0.623 0.863 27.000 17.038 1.003

6 F6 0.803 0.865 7.016 20.030 1.007

7 F7 0.701 0.764 8.024 20.035 1.008

8 F8 0.735 0.979 24.009 20.015 1.003

4.4 Post-Compression Parameters of Mucoadhesive Buccal Tablets of Esomeprazole

4.4.1 Thickness, Hardness, Friability, Surface pH, Weight variation

Table 4.5 Table Showing Post Compression Parameters.

S. N. Formulation

code

Thickness

(mm)

Hardness

(Kg/cm²)

Weight

variation

(%)

Friability

%

1 F1 3.19 4.1 0.950 0.8

2 F2 3.24 4.7 0.951 0.6

3 F3 3.22 5 0.949 0.9

4 F4 3.33 6 0.952 0.6


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5 F5 3.38 4.8 0.951 0.9

6 F6 3.31 4.5 0.950 0.6

7 F7 3.28 5.5 0.948 0.5

8 F8 3.32 5.1 0.951 0.6

Table 4.6: Surface pH.

Code F1 F2 F3 F4 F5 F6 F7 F8

Surface pH 6.6 5.9 6.7 6.4 6.6 6.9 6.5 6.3

4.4.2 Swelling Index

Table 4.7: Table for swelling index.

Swelling index 1hr 2hr 3hr 4hr

F1 49.028% 96.009% - -

F2 48.021% 97.119% - -

F3 44.423% 88.089% - -

F4 48.001% 85.080% 95.099% -

F5 63.035% 101.009% - -

F6 40.088% 77.089% 103.009% -

F7 52.009% 96.832% 101.052% -

F8 48.021% 87.891% 90.127% 101.652%

4.4.3 Bioadhesive strength, ex-vivo time and force of adhesion

Table 4.8 Table for bioadhesive strength, ex-vivo time and force of adhesion.

Code F1 F2 F3 F4 F5 F6 F7 F8

Bioadhesive

strength 18.348g 19.923g 10.762g 14.623g 9.887g 10.326g 31.106g 26.157g

Ex- vivo

residence time 3hr 3hr 3hr 3.30hr 2hr 3hr 3.30hr 4hr

Force of the

adhesion 0.170N 0.195N 0.105N 0.143N 0.096N 0.101N 0.304N 0.256N

4.4.4 Stability in Human Saliva

Table 4.9: Stability in Human Saliva.

Stability Profile In Human Saliva

Formulation code Change in color Change in integrity Change in Surface

area (cm2)

F1 0hr NO NO NO

6hr NO NO 1.916

9hr Brown NO 1.958

F2 0hr NO NO NO

6hr NO NO 0.628

9hr Brown NO 2.523

F3

0hr NO NO NO

6hr NO NO 1.643

9hr NO YES 2.012


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F4

0hr NO NO NO

6hr NO NO 0.539

9hr NO NO 0.626

F5

0hr NO NO NO

6hr NO NO 0.326

9hr NO NO 0.582

F6

0hr NO NO NO

6hr NO NO 0.512

9hr NO NO 0.647

F7

0hr NO NO NO

6hr NO NO 1.023

9hr NO NO 1.586

F8 0hr NO NO NO

6hr NO NO 0.786

9hr NO NO 1.142

4.4.5 Assay of Formulate Batches

Table 4.10: Table for Assay.

S. No. Formulation code Assay %

1. F1 96.500

2. F2 101.150

3. F3 97.007

4. F4 103.714

5. F5 102.430

6 F6 100.203

7 F7 103.025

8 F8 104.023

Figure 4.7 Assay for Different Formulations.


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4.4.6 In-Vitro Drug Release

Table 4.11: Cumulative Drug Release.

Formulation

Code

Time

0.5hr 1hr 1.5hr 2hr 2.5hr 3hr 3.5 hr 4 hr

F1 33.007% 49.032% 63.221% 79.015% 85.031% 98.001% - -

F2 28.001% 47.043% 60.011% 77.012% 88.021% 99.019% - -

F3 35.002% 44.023% 58.002% 69.012% 81.066% 95.001% - -

F4 30.031% 45.221% 56.011% 66.001% 79.021% 89.015% 101.001% -

F5 41.002% 66.022% 88.032% 100.002% - - - -

F6 24.023% 36.052% 52.033% 67.043% 77.023% 88.001% 103.033% -

F7 26.042% 33.023% 48.325% 69.023% 81.012% 93.001% 100.989%

F8 22.030% 35.007% 48.040% 62.012% 72.030% 83.004% 91.018% 102.009%

Figure 4.8 % Drug release for different formulation.

4.4.7 Drug kinetics

Table 4.12: Curve fitting data of the release rate profile for selected formulations.

Formulation Best fit

model (r2)

Zero

order(r2)

1st

order

(r2)

Higuchi

matrix (r) 2

Korsmeyer-

peppas (r)2

F8 Korsmeyer-

peppas 0.993 0.923 0.994 0.998


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Figure 4.9 Zero order Drug release kinetics.

Figure 4.10 First order Drug release kinetics.


1613


Figure 4.11 Higuchi Drug release kinetics.

Figure 4.12 Korsmeyer-peppas Drug release kinetics.

DISCUSSION

5.1 Pre-Compression Parameters

Pre compression parameters play an important role in improving the flow properties of

pharmaceuticals especially in tablet formulation. These include angle of repose, bulk density,

tapped density, hausner ratio and Carr’s index. Before formulation of tablets the drug were

evaluated for all the above said parameters and it was found that all the observations were

within the prescribed limits of IP.


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5.1.1 Drug Compatibility Study

In the FTIR spectra of pure drug and formulation with other ingredients is observed that the

peaks of major functional group of Esomeprazole, which are present in spectrum of pure

drug, are observed. It means that there are no interactions between drug and other ingredients

in a physical mixture and drug is compatible with other ingredients. The FTIR-IR spectra

shows the peak around 1630 cm-1

and 1581 cm-1

indicate the presence of carbonyl group. The

drug and poloymers employed were found to be compatible as similar peaks were observed

with minor differences.

5.1.2 Angle of Repose

The data obtained from angle of repose for all the formulations were found to be within the

range of 17.38 to 24.51 which reveals flow property of powder between excellent to good.

5.1.3 Bulk Density

The bulk density of the powder primarily depends on particle size distribution, particle shape,

and the tendency of particle to adhere together. The value of bulk density of all formulation

prepared fall within the range of 0.558-0.803 g/cm³.

5.1.4 Tapped Density

It was found that the value of tapped density of all the formulation range from 0.629-0.979

g/cm3.

5.1.5 Carr’s Index/ Compressibility Index

The compressibility index of the powder was found to be within the range of 7.16 to 30. This

shows excellent to fair passable flowability and compressibility of powder prepared.

5.1.6 Hausner ratio

The hausner ratio of the powder was found to be within the range of 1.07-1.4. This shows

excellent to passable flowability of the powder prepared.

5.2 Post Compression Parameters

5.2.1 Weight variation

The result obtained shows that there is not much variation in weight of tablet. Weight

variation range falls between 0.948 to 0.952%.


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5.2.2 Tablet Thickness

The thickness of all formulated tablet falls within the range of 3.19 to 3.38 mm.

5.2.3 Hardness

Hardness of tablet was found to be 4.1 to 6 kg/cm2.

5.2.4 Friability

Friability indicates the ability of tablet to withstand mechanical shocks while hand. The

friability range was found to be 0.5 to 0.9%. which indicates that all formulation batches can

withstand mechanical shock while handling before administration.

5.2.5 Surface pH

Surface pH of tablets of each formulation (F1 to F8) was tested and results are provided in

table 4.4. The maximum and minimum value were found to be 5.9 to 6.9 respectively. The

acceptable pH of saliva is in range of 5 to 7 and the surface ph of all tablets is within limits.

Hence, the formulations may not produce any irritation to buccal mucosa.

5.2.6 Swelling Index

Swelling index indicates the tablet ability to swell up. The swelling index of F8 batch was

found to be 48.021%, 87.891%, 90.127% and 101.652% in 1hr, 2hr, 3hr and 4hr respectively.

5.2.7 Bioadhesive strength

The bioadhesive strength of the tablets was found to be a function of nature and concentration

of polymer. The tablets of carbopol 343 have bioadhesive strength between 18.348g to

19.923 g. The tablets with the HPMC K4M have bioadhesive strength between 10.762g to

14.623 g. The tablets with Guar gum have bioadhesive strength between the 9.887g to

10.326g. The tablets with sod CMC have bioadhesive strength in between the 26.157g to

31.106g. The bioadhesive strength exhibited by the Sod CMC can be considered satisfactory

for maintaining them in the oral cavity.

5.2.8 Force of adhesion

The Bioadesion Characteristics were affected by the type and ratio of the bioadhesion

polymers. The Bioadhesion force test was conducted for all forfulation (F1-F8) of

mucoadhesive buccal tablets determined by using Goat mucosa at various mixing ratio of

polymers(HPMC, Carbopol, Sod CMC ,Guar gum) and evaluation data represented in table

4.7 . The highest force was observed with the formulation F7 (SCMC). The tablets (F7)


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showed 0.304N of bioadhesive force. The Force of adhesion exhibited by the sod CMC can

be considered strong than in formulation containing Guar gum.

5.2.9 Assay

The result obtained shows that all formulation contains esomeprazole not less than 90% and

not more than 110%. This indicates uniformity of dose in each batch and therapeutically

equivalent.

5.2.10 In Vitro dissolution study

After getting all the physical parameters satisfactory, the dissolution for all the batches was

tested. The dissolution study was carried out as per the procedure mentioned in the

methodology chapter. Among all the formulation the batch containing sod CMC, F8 showed

the release of 102.021% of drug in 4 hr.

5.2.11 In vitro permeation study

After getting all the physical parameters, diffusion was tested for best formulation only F8.

The in vitro permeation study was carried out as per the procedure mentioned in the

methodology chapter. Best formulation batch F8 showed te release of 101.045% of drug in

4hr.

5.2.12. Drug Release Kinetics

From the data obtained from drug dissolution the best curve fitting model was Korsmeyer

Peppas with r2

0.998.

CONCLUSION

Based on our laboratory, studies the following conclusions can be drawn. The mucoadhesive

buccal tablet of esomeprazole were successfully prepared by using different polymer agent

namely carbopol, HPMC K4M, gaur gum and sod.CMC. All samples of different formulation

were subjected to pre-compression and post-compression evaluations. The result indicate that

F8 was the best formulation among the all formulation developed for mucoadhesive buccal

tablets. FTIR study shows no drug interaction with other ingredients of formulation.

The polymer studies shows that the tablets prepared with sod CMC shows good

muchoadhesive property as compared to other tablets prepared with carbopol, HPMC K4M,

Guar gum.


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The in- vitro dissolution study for tablets were carried out and tablet of formulation batch 8

containing sodium carboxy methyl cellulose exhibited significant swelling properties with

optimum release profile of 102.021% of drug during 4 hr and in vitro permeation study for

tablets prepared with sod CMC shows optimum release profile of 101.045% of best

formulation during 4hr. From the above, it can be concluded that the mucodhesive buccal

tablets of Esomeprazole prepared with sod CMC showed better muchoadhesive property and

dissolution profile as compared to other polymer.

SUMMARY

Solid dosage form is popular because of the ease of administration, accurate dose, self-

medication, pain avoidance, and most importantly the patient compliance. Tablets and

capsules are the most popular solid dosage form. However, many patient groups such as the

elderly, children and patient who are mentally retarded, uncooperative on reduced liquid

intake/diets have difficulties swallowing these tablets and hard gelatin capsules. Thus, these

conventional dosage form results in high incidence of non-compliance and ineffective

therapy with respect to swallowing specially in the case of pediatric, geriatric, or any

mentally retarded persons. The concept of formulating mucoadhesive buccal tablet containing

esomeprazole offers suitable and practically approach in serving such patients with

characteristic increases bioavailability and patient compliance.

In the present work, an effort is made to formulate and evaluate mucoadhesive buccal tablets

of esomeprazole. The polymers such as Carbopol, HPMC K4M, Guar gum and sod. CMC

were used along with sweetener i.e. Saccharin and lactose to impart better mouth feel in

developing mucoadhesive buccal tablets. Prior to the formulation development,

Preformulation studies were conducted for drugs compatibility by taking infrared spectrum to

determine any interaction between the components for mucoadhesive buccal tablets. Pre-

compression parameters were carried out to determine the flow properties of powder blend.

Angle of repose, Bulk density, and Tapped density, hausner ratio and also Carr’s Index were

determined for all the formulations, which showed good results indicating good flow

properties. Post-compression parameters were conducted for the tablets. The results of the

evaluation parameters demonstrate that it is possible to design and develop Mucoadhesive

buccal tablets of esomeprazole by using different polymers. Among the polymer used sod

CMC showed better mucoadhesive property and dissolution profile compared to other

polymers along with swelling index.


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ACKNOWLEDGEMENTS

We would like to express our deepest appreciation to our supervisor Mr. Ayush Acharya for

his continuous support, guidance, valuable suggestions, time and encouragement for research.

Without his support, the thesis would not have been possible. We would like to express our

sincere gratitude to Mr. Anurodh Ghimire, HOD, Department of Pharmacy Karnali College

of Health Sciences, for his continuous support to conduct this research work.

We are very much obliged to Mr. Y.P. Adhikari, Chairman and Principal, Karnali College

of Health Sciences for his support throughout the research period.

Similarly, we extend our sincere gratitude to Phr. AmritKhanal, Lecturer, Department of

Pharmacy, Karnali College of Health Sciences, for the suggestion and instruction during the

research work and we would like to thank our Phr. Rajan Ghimire for helping us in our

research work.

We would like to thank Deurali janata Pharmaceuticals and CTL Pharmaceutical Pvt. Ltd.,

for providing Esomeprazole (API and excipients). We express our cordial thanks to Mr.

Kalyan Subedi and Lab Assistants, Department of Pharmacy, Karnali College of Health

Sciences for their valuable support on lab works. Furthermore, we also extend our deepest

gratitude to entire faculty for helping us to develop background in the pharmacy.

We would also like to thank all seniors and friends of Karnali College of Health Sciences, for

their moral support and valuable suggestion throughout the project work preparation.

REFERENCES

1. Indian Pharmacopoeia Vol II. Ghaziabad, India: The India Pharmacopeia Commission,

2010.

2. Jagadesh Kumar Ega, Ravinder Vadde. Formulation and Evaluation of Esmoprazole

magnesium Delayed Release Tablet. International Journal of Research and Application,

2015; April-June: 2(6): 242-252.

3. KD Tripathi, editors. Essentials of Medical Pharmacology. New Delhi; Jaypee Brothers

Medical Publishers. 2006; 6th

edition: 647-655.

4. Nagashree K et al. Solid Dosage Forms. Journal of pharmaceutical Analysis, 2015; June.

5. Tiwari G, Tiwari R, Sriwastawa B, Bhati L, Pandey S, Pandey P, Bannerjee SK. Drug

delivery systems: An updated review. International journal of pharmaceutical


1619


investigation, 2012 Jan; 2(1): 2.

6. Bhatt D.A., Pethe A.M. Mucoadhesive drug delivery systems: An Overview. Journal of

Pharmacy Research, 2010; 3(8): 1743-1747.

7. Senthil KM Mucoadhesive Buccal Drug Delivery System - An Overview. International

Journal of Pharm & Tech, 2012; 4: 3951-3969.

8. Ali J, Khar R, Ahuja A, Karla R. Buccoadhesive erodible disk for treatment of orodental

infections design and characterization. Int. J. Pharm, 2002; 283: 99‐103.

9. Subal CB. 15. Peppas NA, Buri PA. Surface interfacial and molecular aspects of polymer

bioadhesion on soft tissues. J Control Release, 1985; 2: 257-275.

10. Miller NS, Johnston TP. The use of mucoadhesive polymers in buccal drug delivery.

Advanced Drug Delivery Reviews, 2005; 57: 1666-1691.

11. Lalla JK, Gurnancy RA. Polymers for mucosal Delivery-Swelling and Mucoadhesive

Evaluation. Indian Drugs, 2002.

12. Mitra AK, Alur HH (2002) Peptides and Protein- Buccal Absorption, Encyclopedia of

Pharmaceutical technology, Marcel Dekker Inc., 2081-2093.

13. Tiwari G, Tiwari R, Sriwastawa B, Bhati L, Pandey S, Pandey P, Bannerjee SK. Drug

delivery systems: An updated review. International journal of pharmaceutical

investigation, 2012 Jan; 2(1): 2.

14. Pranshu Tangri, N.V.Satheesh Madhav et al. Oral Mucoadhesive Drug Delivery Systems:

A Review. International Journal of Biopharmaceutics, 2011; 2(1): 36-46.

15. Ramana MV, Nagdaand C, Himaja M. Design and Evaluation of Mucoadhesive Buccal

Drug Delivery Systems containing Metoprolol Tartrate. Ind J of Pharmaceutical Sci.,

2007; 69: 515-518.

16. Velmurugan S, Deepika B,Nagaraju K,Vinushitha S. Formulation and in vitro Evaluation

of Buccal Tablets of Piroxicam. International Journal of Pharm Tech Research, 2010; 2:

1958-1968.

17. Naga Raju K, Velmurugan S, Deepika B, Vinushitha S. Formulation and in-vitro

Evaluation of Buccal Tablets of Metoprolol Tartrate. Int J of Pharm and Pharmaceutical

Sci., 2011; 3: 239–246.

18. Martin L, Wilson CG, Koosha F, Uchegbu IF. Sustained buccal delivery of hydrophobic

drug Denbufylline using physically cross linked palmitoyl chitosan hydrogels. Eur J

Pharm Biopharm, 2003; 55: 35-45.


1620


19. Ganesh GN, Pallaprola M, Gowthamarajan K et al. Design and development of buccal

drug delivery system for labetalol using natural polymer. Int J Pharm Res & Dev., 2011;

3: 37– 49.

20. Amir H Shojaei, Richard K Chang, Xiaodi Guo, Beth A et al. Systemic Drug Delivery via

the Buccal Mucosal Route. Pharmaceutical Technology, 2001; 70-81.

21. Velmurugan S, Srinivas P. Formulation and in- vitro Evaluation of Losartan Potassium

Mucoadhesive Buccal Tablets. Asian J Pharm Clinical Research, 2013; 125-130.

22. Duchene D et al. Pharmaceutical and medical aspects of bioadhesive systems for drug

administration. Drug Developement and Industrial Pharmacy, 1988; 14: 283-318.

23. Khurana SH et al. Mucoadhesive drug delivery: mechanism and methods of evaluation.

Int J Pharm Biosci, 2011; 2: 458-67.

24. Jimenez-Castellanos MR et al. Mucoadhesive drug delivery systems. Drug Dev Ind

Pharm, 1993; 19: 143-94.

25. Vinod KR et al. Critical review on mucoadhesive drug delivery systems. Hygeia JD Med,

2012; 4: 1-5.

26. Carvalho FC et al. Mucoadhesive drug delivery systems. Brazilian Journal of

Pharmaceutical Sciences, 2010; 46: 1-7.

27. Khan et al. Mucoadhesive Drug Delivery System: A Review. World Journal of Pharmacy

and Pharmaceutical Sciences, 2016; 5(5): 392-405.

28. Sudhakar Y, Bandyopadhyay AK. Buccal bioadhesive drug delivery- A promising option

for orally less efficient drugs. J.Control. Rel., 2006; 114: 15–40.

29. Phanindra B et al. Recent advances in mucoadhesive/bioadhesive drug delivery system: A

review. Int J Pharm Med and Bio Sci., 2013; 2(1): 68-84.

30. Woodley J. Bioadhesion new possibilities for drug administration. Clin Pharmacokinet,

2001; 40: 77-84.

31. Bhowmik D, Niladry C. Mucoadhesive Buccal Drug Delivery System; An overview.

Journal of Advance Pharm Edu and Res., 2013; 3: 319-331.

32. Varma N, Chattopadayay P (2011). Polymeric Platform for Mucoadhesive Buccal Drug

Delivery System; a Review. International Journal of Current Pharmaceutical Research.

33. Alexander A, Ajazuddin S, Tripathi DK, Verma T, Swarna G et al. Mechanism

responsible for mucoadhesion of mucoadhesive drug delivery system: a review. Int J App

Bio and Pharm Tech., 2011; 2: 434-450.

34. Madhav NVS, Ojha A, Tyagi Y, Negi M. Mucoadhesion: a novelistic platform for drug

delivery system. Int J Pharm, 2014; 2: 246-258.


1621


35. Jimenez-Castellannos MR., Zia H, Rhodes CT. Binding of acrylic polymers to

mucin/epithelial surfaces: Structure-property-relationship. Drug Dev Ind Pharm, 1993;

19: 142-143.

36. Shijith KV, Chandran CS. A review on basics behind development of muco adhesive

buccal drug delivery systems. Int J Adv Pharm Bio Chem., 2013; 2: 310-317.

37. Harris D, Robinson JR. Drug Delivery via the Mucous Membrane of the Oral Cavity. J

Pharm Sci., 1992; 81: 1-10.

38. Miller NS, Johnston TP. The use of mucoadhesive polymers in buccal drug delivery.

Advanced Drug Delivery Reviews, 2005; 57: 1666-1691.

39. Lalla JK, Gurnancy RA. (2002). Polymers for mucosal Delivery-Swelling and

Mucoadhesive Evaluation. Indian Drugs.

40. Mitra AK, Alur HH. Peptides and Protein- Buccal Absorption, Encyclopedia of

Pharmaceutical technology, Marcel Dekker Inc., 2002; 2081-2093.

41. Pranshu Tangri, N.V. Satheesh Madav et al. Oral Mucoadhesive Drug Delivery System;

A Review. International Journal of Biopharmaceutical, 2011; 2(1): 36-46: 0976-1047.

42. Mamatha Y, Prasanth VV, Arun KS, Altaf BMS, Vandana Y. Buccal Drug Delivery: A

Technical Approach. J of Drug Delivery & Therapeutics, 2012; 2: 326-329.

43. Janet AJ, Hoogstraate, Philip W. Drug delivery via the buccal mucosal. Wertz PSTT.,

1998; 1: 306-316.

44. Doijad R.C, Sompur C.K., Goje A.J, Maske A.P and Tamboli F.A. Development and

Characterization of Lovastatin Controlled Release Buccoadhesive Dosage Form.

International Journal of Pharma and Bio Sciences, 2011.

45. S.B. Patil, R. S. R. Murthy, H. S. Mahajan, R. D. Wagh, S. G. Gattani. Mucoadhesive

polymers: means of improving drug delivery. Pharma Times, 2006; (38): 25-8.

46. Yoon, S.J., Chu, D. C., Juneja, L.R.. Chemical and physical properties, Safety and

Application of Partially Hydrolized Guar Gum as Dietary Fiber. J. Clin. Biochem. Nutr.,

2008; 42: 1–7.

47. Shaikh, T., Kumar, S.S. Pharmaceutical and Pharmacological Profile of Guar Gum; An

Overview. International Journal of Pharmacy and Pharmaceutical Sciences, 2011; 3(5):

38-40.

48. Anek Pal Gupta, Devendra Kumar Verma et al. Guar gum and their Derivatives; A

Research Profile. International Journal of Advanced Research, 2014; 2: 1, 680-690.


1622


49. Tamasree Majumder, Gopa Roy Biswas et al. Hydroxy Propyl Methyl Cellulose;

Different Aspects in Drug Delivery. Journal of Pharmacy and Pharmacology, 2016; 4:

381-385.

50. Rowe RC, Sheskey PJ, Weller PJ, editors. Handbook of pharmaceutical excipients.

London: Pharmaceutical press, 2006.

51. Sahoo S, Chakraborti CK et al. Qualitative analysis of Controlled Release Ciprofloxacin/

Carbopol 934 Mucoadhesive Suspension. Journal of Advanced Pharm Tech Res., 2011.

52. KD Tripathi, editors. Essentials of Medical Pharmacology. New Delhi; Jaypee Brothers

Medical Publishers. 2006; 6th

edition: 630-631.

53. Sameera Fatima, Niranjan Panda et al. Buccal Mucoadhesive Tablets of Sumatriptan

Succinate for treatment of Sustainable Migraine: Design, Formulation and In Vitro

Evaluation. International Journal of Pharmaceutical Research and Allied Sciences, 2015;

4: 114-126.

54. Amit E. Birari, Dhiraj et al. Formulation and In vitro Evaluation of Chitosan Based

Omeprazole Mucoadhesive Buccal Tablets. International Journal of Pharma Sciences and

Research, 2014; oct 10: 5, 630-638.

55. B.Gavaskar, Venkateswarlu et al. Formulation and Evaluation of Mucoadhesive Tablet of

Baclofen. International Journal of Pharmacy and Technology, 2010; Jun-9; 2: 396-409.

56. Margret Chandra, Sachin, Debjit Bhowmik, B. Jayakar. Formulation and Evaluation of

Mucoadhesive Oral Tablet of Clarithromycin. The Pharma Research (T. Pharm. Res),

2009; Aug-21; 2: 30-42.

57. Nausheen Fathima, Pradeep Das et al. Formulation and Evaluation of Mucoadhesive

Tablets of Carvedilol using Natural Binders. International Journal of Research in

Pharmacy and Chemistry, 2015; 5(4): 699-707.

58. Monica RP Rao, Priyanka Sadaphule. Development and Evaluation of Mucoadhesive

Buccal Tablets of Ketorolac Tromethamine. Indian Journal of Pharmaceutical Education

and Research, 2014; 48(1): 69- 74.

59. Mohit Basotra et al. Formulation and Evaluation of Oral Mucoadhesive Tablets of

Cisplastin. Journal of Pharmacy Research, 2017; 11(7): 798-806.

60. Gajananv. Shinde, Sudarshini et al. Formulation and Evaluation of Mucoadhesive Tablets

of Niacin Using Different Bioadhesive Polymes. International Journal of Pharma and Bio

Sciences, 2010; 1(2): 1-12.

61. D. Mahalaxmi et al. Formulation and Evaluation of Mucoadhesive Buccal Tablets of

Glipizide. International Journal of Biopharmaceuticals, 2010; 1(2): 100-107.


1623


62. S.B. Shirsand, G.V.Wadageri, S.A. Raju and Gopikrishna Kolli. Formulation and In Vivo

Evaluation of Mucoadhesive Buccal Tablets of Carvedilol. International Journal of

Pharmaceutical Sciences and Nanotechnology, 2013; 6(3): 2164 - 2171.

63. R.Indira Prasanna, P Anitha, C Madhusudhana Chetty. Formulation and Evaluation of

Bucco-adhesive Tablets of Sumatriptan succinate. International Journal of Pharmaceutical

Investigation, 2011; 1(3): 182-191.

64. Sudeesh Edavalath et al. Formulation Development of Rabiprazole Sodium

Mucoadhesive Buccal Tablets; A Novel approach to treat zollinger-ellison syndrome.

Journal of Pharmacy Research, 2012; 5(1): 474-479.

65. Dr.N.G Raghavendra Rao, Gururaj S. Kulkarni. Formulation and Evaluation of

Mucoadhesive Buccal Bilayered Tablets of Salbutamol. International Journal of Drug

Development and Research, 2012; 4(4): 375-384.

66. Murali Krishna B et al. Formulation and Evaluation of Mucoadhesive Tablets of

Linagliptin. International Journal of Pharmacy and Pharmaceutical Research, 2015; 4(2):

141-158.

67. SB Shirsand et al. Formulation and Optimization of Mucoadhesive Buccal Tablets of

Atenolol using Simplex Design Method. International Journal of Pharmaceutical

Investigation, 2012; 2(1): 34-41.

68. Chu Soon Yang et al. Physicochemical Characterization and Evaluation of Buccal

Adhesive Tablets Containing Omeprazole. Journal of Drug Development and Industrial

Pharmacy, 2001; 27(5): 447-455.

69. Anna Balaji, Vaddepalli Radhika and Vishnuvardhan goud. Formulation and Evaluation

of Mucoadhesive Buccal Tablets of Carvediol By Using Natural Polymer. International

Journal of Pharmaceutical Sciences and Research, 2017.

70. Celik B. Risperidone Mucoadhesive Buccal Tablets: Formulation, Design, Optimization

and Evaluation. Journal of Drug Design, Development and Therapy, 2017; 11:

3355-3365.

71. Choi H,Jung J,Yong C, Rhee.C. Formulation and in-vitro evaluation of Omeprazole

buccal adhesive tablet. Journal of controlled release, 2000; 68: 405-412.

72. Parvez N, Ahuja A, Khar RK. Development and evaluation of mucoadhesive buccal

tablets of Lignocaine Hydrochloride Indian J. Pharm. Sci., 2002; 64(6): 563-67.

73. Raman MV, Nagada C, Himaja M. Design and evaluation of mucoadhesive buccal drug

delivery systems containing Metoprolol Tartrate. International Journal of Pharmaceutical

Sciences, 2007; 6; 9(4): 515-18.


1624


74. Manivannan R, Balasubramaniam A. Formulation and in-vitro evaluation of

mucoadhesive buccal tablets of Deltiazem Hydrochloride. Research J. Pharm. and Tech.,

2008; 1(4): 478-80.

75. Patel B, Patel P, Bhosale A. Evaluation of Tamarinde seed polysaccharide as

mucoadhesive and sustained release component of Nifedipine buccoadhsive tablet and

comparison with HPMC and Sodium carboxy methyl cellulose. International Journal of

Pharm Tech. Research, 2009; 1: 404-10.

76. Chandira M, Debjit M. Formulation, Design and Development of buccoadhesive tablets

of Verapamil Hydrochloride. International Journal of Pharm. Tech research, 2009; 1(4):

1663-77.

77. Madgulkar A, Kadam S, Pokharkar V. Development of Trilayered Mucoadhesive Tablet

of Itraconazole with zero-order release. Asian Journal of Pharmaceutics, 2008; 57-60.

78. Ali Riza Kepsutlu et al. Delivery of Piroxicam with Mucoadhesive Buccal Tablet: In

vitro, Ex vivo and In vivo Evaluation. Research and Reviews in Pharmacy and

Pharmaceutical Sciences, 2016.

79. Bhanja SB et al. Design and Evaluation of Timolol Maleate mucoadhesive buccal tablets.

Int J Pharm & Health Sci., 2010; 1(2): 100-108.

80. A.M.Pethe and S.P.Salunkhe. Formulation and Evaluation of Mucoadhesive Buccal

Tablet of Simvastatin. International Journal of Pharma and Bio Sciences, 2014; 5(3):

268-278.

81. Guda A, Gudas A K, Manasa B, Subal D, Rajesham V V. Design and evaluation of

controlled release mucoadhesive buccal tablet of lisinopril, International Journal of

Current Pharmaceutical Research, 2010; 2(4): 24-27.

ANNEX

ERRATA

S. No. Page No. Printed As Read As


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Documents

FORMULATION AND IN -VITRO EVALUATION OF ......2.1 Introduction The general background of mucoadhesive buccal tablets, PPI, esomeprazole, and researches conducted on formulation of