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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
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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
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(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
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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
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(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
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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
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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.
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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.
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ANNEX
ERRATA
S. No. Page No. Printed As Read As
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