1

INTRODUCTION

1.1. Buccal drug delivery system

Buccal drug delivery is a favorable route compare to

parenterals, injectable and adds a several advantages over other

routes1. The parenteral route offers excellent bioavailability, similarly

having poor patient compliance, anaphylaxis, and some other

infections. Peroral route posses some inconvenience to patients. Hence

for the immediate release of medication and for instant release at

desire location in which the drug is absorbed distributer and easily

metabolized. This limitation leads to the development of alternative

routes of administration. Buccal mucosa has absorptive function and

offers many benefits like avoidance of first pass effect, which is a non

invasive route, increase in bioavailability, a rapid action is possible

and reduce side effects2,3.

Buccal, sublingual, palatal and gingival4 regions shows effective

drug delivery in oral cavity. Buccal and sublingual route of drug

delivery are most widely in which local and systemic effects are

treated. The permeability of oral mucosa denotes the physical nature

of the tissues. The permeable part is sublingual mucosa and buccal

mucosa is thinner part and in which there is a high blood flow and

surface area; it is a feasible site when a rapid onset of action is

desired. For the treatment of acute disorders sublingual route is a

preferred one; however its surface washed with saliva which makes

formulations in the oral cavity hard in nature.

2

Buccal drug delivery system is well accepted because it is

having several advantages. Buccal areas offer a control release system

which is having immobile surface. The buccal layer is tolerate to

potential allergens and has capability of preventing damage compare

to other mucosal tissues. In treatment of the local or systemic

therapies, buccal mucosa favors a useful measure by overcoming

drawbacks and as convenient route for the administration. This type

of route is well vascularized draining to the heart unswervingly via the

internal jugular vein. In chronic systemic therapies, buccal drug

delivery acts as potential site and chemical modification due to

salivary production and its composition. There is a chance of drug loss

at site of absorption in case of the oral route and for some dosage form

salivary scavenging is constant with in oral cavity which make difficult

for retaining to an extensive duration at the site to enhance the

absorption. Bioadhesive polymers have prolonged contact time with

the tissues and can notably maintain the performance of several

drugs6. The controlled drug delivery products have high patient

compliance and a low cost with enhanced bioavailability.

Advantages

1. It is richly vascularised and additional reachable for

administration and removal of formulations.

2. Patient accessibility is high.

3. Retentive dosage forms are suitable for administration.

4. Improves bioavailability by eliminating first pass metabolism.

3

5. Surface of buccal mucosa achieves a fast cellular recovery.

6. Low enzyme activity.

7. Non-invasive method of drug administration.

8. Ability to incorporate permeation enhancer in the formulation.

Disadvantages

1. Buccal membrane has low permeability.

2. Small surface area (170 cm2).

3. Continuous secretion of saliva results in following dilution of the

drug.

4. Inconvenience route of drug administration when the patient is

swallowing or taking.

Limitations

1. There is a chance of swallowing and the effect of salivary

scavenging.

2. Protective characteristics of buccal mucosa.

3. Relatively small absorption area.

1.1.1. Anatomy of oral mucosa

Buccal cavity is a component of mouth in which lips and cheeks

are anteriorly bounded and teeth, gums bounded posteriorly and

medially. The buccal glands are positioned between the mucous

membrane and buccinator muscle. The thickness of buccal mucosa is

having uneven texture and about 500-800 µm7 and buccal epithelium

return time at 5-6 days8. The non-keratinised stratified squamous

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epithelium lines the buccal mucosa and having 500-600µ and surface

area of about 50.2 cm2

1.1.2. Structure

The oral mucosa consists of three distinctive layers. They are

epithelium, basement membrane and connective tissues.

Buccal cavity is lined with epithelium; supported by basement

membrane which intern supported by connective tissues. In

underlying tissues, protective layer is epithelium which is divided in

to9,10

(a) Surface which is non-keratinised lining of soft palate, tongue

surface, lips and vestibule.

(b) Hard palate and other non flexible regions keratinized epithelium

present in oral cavity.

Fig: 1.1. Cross-section of buccal mucosa

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The epithelial cells originating from the basal cells mature,

change their shape, and increase in size while moving towards the

surface. The basement membrane acts as mechanical support for the

epithelium and forms a distinctive layer between the connective

tissues and the epithelium. The underlying connective tissues provide

many of the mechanical properties of oral mucosa. The non

keratinized tissue is a part of buccal epithelium which is penetrated

by connective tissues that are tall and conical in form. These tissues,

which are also referred to as the lamina propria, consisting collagen

fibers, smooth muscles, blood vessels and an underneath film

of connective tissues. Lamina propria is followed by the sub mucosa

(Fig 1).

The external carotid artery supplies to the oral mucosa. The

main sources of blood supply to the lining of the cheek in the buccal

cavity are derived from the buccal artery, some terminal branches of

the facial artery, the posterior alveolar artery, and the infra orbital

artery.

1.1.2.1. Permeability

The oral mucosal epithelium is somewhat leaky and

intermediate between that of the epidermis and intestinal mucosa.

Buccal mucosal having 4-4000 times greater permeability11 than skin

and different regions having difference in permeability of oral cavity

because of its diverse structures and functions of the oral mucosa12,13.

The relative thickness and degree of keratinization of the tissues

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precedes the ranking. Both the sublingual mucosa and buccal mucosa

are non-keratinized, however they differ in thickness. The buccal

mucosa is thicker than the sublingual mucosa and the palatal

mucosa is intermediate in thickness but keratinized. The permeability

of the oral mucosa is in the decreasing order14 sublingual >buccal >

palatal.

1.1.2.2. Environment

The intercellular ground substance surrounds the oral

epithelium known as mucus which envelops the complete oral cavity.

Mucus gives protection to the cells under by bounding to the apical

cell surface15. Mucus primarily consists of about 95–99% water, 0.5–

5% of water insoluble glycoproteins and several other components in

small quantities, such as free proteins (1%), enzymes, electrolytes,

and nucleic acids16. Mucus looks like a visco-elastic hydrogel. Mucus

composition can vary based on the origin of the mucus secretion in

the body17.

At physiological pH, the mucus network carries a negative

charge due to the presence of sialic acid and sulfate residues. Mucus

plays a major role in mucoadhesion by forming a strong cohesive gel

structure which attached to the epithelial cell surface as a gelatinous

layer18. Depending on the flow rate the pH of saliva ranges from 5.5 to

7. At high flow rates, the pH is proportional to the concentration of

sodium and bicarbonate. The daily salivary volume of secretion is

between 0.5 to 2 liters and plays a major role to hydrate oral mucosal

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dosage forms19. The chief reason behind the selection of hydrophilic

polymeric matrices as vehicles for oral transmucosal drug delivery

systems is rich environment of water in the oral cavity.

1.1.2.3. Barriers to penetration across buccal mucosa

About quarter to one third of the epithelium consists of barrier

which is mainly useful for penetration. The barriers which retard the

rate and extent of drug absorption through the buccal mucosa are,

Membrane coating granules

Basement membrane

Mucus

Saliva

Membrane coating granules

Membrane coating granules20,21 are which extrudes into the

intercellular region of both keratinized and non-keratinized oral

epithelium and are responsible for preventing the transmucosal

penetration. The component of the membrane coating granules is

different in keratinized and non-keratinized epithelia22.

Basement membrane

The superficial layers of the oral epithelium represent the

primary barrier to the entry of substances from the exterior; the

basement membrane also plays a role in limiting the passage of

materials across the junction between epithelium and connective

tissue. The charge on the constituents of the basal lamina may limit

the rate of penetration of lipophilic compounds that can traverse the

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superficial epithelial barrier relatively easily23. The molecular weight of

the permeant molecule and its reactivity with the barrier as well as the

structural and functional factors of the barrier influences the barrier

function of basal lamina24.

Mucus

Mucus is having mainly of water where mucins and inorganic

salts are present25. Mucin chiefly includes glycosylated proteins

having oligosaccharide chains26. These are responsible for gel like

character of mucus. The composition of mucin are 70–80%

carbohydrate, 12–25% protein and 5% ester sulphate27,28. The sugar

coating layer responsible for withstanding of water and acting against

proteolysis, this is very essential for the barrier properties of

mucosa29.

Saliva

The mucosal surface has a salivary coating estimated to be 70

μm thick, which act as unstirred layer. Saliva consists of high

molecular weight mucin named MG1 which maintains hydration,

provides lubrication, concentrate protective molecules such as

secretory immunoglobulin’s and limit the attachment of

microorganisms by binding to the surface of oral cavity30. The

constant flow of saliva within the oral cavity makes it very difficult for

drugs to be retained for a significant amount of time in order to

facilitate absorption at this site. The intercellular spaces act as a

major source for permeation of hydrophilic compounds, and major

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transport barrier for lipophilic compounds is the cell membrane which

is lipophilic in nature. Due to a low partition coefficient it is difficult to

permeate through the cell membrane31,32.

1.1.3. Drug transport mechanisms

The main mechanisms involved for the penetration of various

substances include simple diffusion (paracellular and transcellular),

carrier mediated transport and endocytosis33. The convey of drugs

across the buccal mucosa follows the mechanism involved in passive

diffusion; although it has been reported that carrier mediated

transport plays a small role upto some extent. Depending on the

physicochemical properties of the molecule and the type of tissue

being traversed rate of penetration may vary and leads to the

suggestion that materials uses one or more of the following routes

simultaneously to cross the barrier region in the process of absorption

which depends on the physicochemical properties of the diffusant34,

but one route is predominant over the other.

i. Passive diffusion

a. Transcellular or intracellular route

b. Paracellular or intercellular route

ii. Carrier mediated transport

iii. Endocytosis

The transport of drugs across buccal epithelium may follow

different pathways but their selection depends upon the nature of the

permeant, i.e. the overall molecular geometry, lipophilicity and charge.

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Most of the compounds diffuse through the buccal mucosa by passive

diffusion or simple Fickian diffusion35.

Under sink condition, the flux of drug passing through the

membrane for paracellular route can be written as36

Where, Dp is diffusion coefficient, hp is path length, cd is

concentration in donar compartment έ is paracellular route area.

In transcellular route under sink conditions flux of drug can be

given as follows37,38,

Where, Kc is partition coefficient, Dc is the diffusion coefficient and hc

is the path length.

The permeation across buccal epithelium via carrier mediated

diffusion provided by the substances like Glucose, monocarboxylic

acids, salicylic acid and nicotinic acid39. The enzyme inhibitors are

used as mucoadhesive agents for protein and peptide delivery40.

1.1.3.1. Enhancement of buccal transport

The buccal mucosa exhibits insufficient permeability depending

on physicochemical characters of the drug and represents a major

limitation in the development of a transmucosal drug delivery

system41. Also, the limited absorptive area and the short exposure

time, due to the washing effect of saliva can decrease absorption

efficiency even more. ‘Permeation enhancers’ are used to permeate the

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drugs across epithelial barriers. However, proper penetration

enhancers are used to improve the drug permeability42.

Ideal permeation enhancers should have the following properties

Safest and non-toxic nature

Pharmacologically and chemically inert and non irritant.

Should be non-allergenic

1.1.4. Classification of permeation enhancers43

a) Chelators: sodium salicylate, methoxy salicylates, EDTA, citric

acid.

b) Surfactants: SLS, Polyoxyethylene-9-laurylether, cetyltrimethyl

ammonium bromide, Benzalkonium chloride.

c) Bile salts: sodium glycocholate, sodium tauro cholate, sodium

deoxy cholate, sodium tauro deoxycholate.

d) Fatty acids: phosphatidylcholine, oleic acid, propylene glycol,

methyl oleate.

e) Inclusion complexes: cyclodextrins.

f) Others: polysorbate 80, sulfoxides, aprotinin, azone, cyclodextrin,

dextran sulfate, menthol and various alkyl glycosides.

g) Thiolated polymers: chitosan - 4 - thiobutylamide, chitosan -

cysteine, chitosan -4- thioglycholic acid.

1.1.5. Mechanisms of action

1.1.5.1. Changing mucus rheology

The drug absorption is affected by forming viscoelastic layer by

the mucus of varying thickness44. Further, the absorption is hindered

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by saliva covering the mucus layers. So permeation enhancers are

used to increase the absorption, they act by reducing the viscosity of

the mucus and saliva which overcomes this barrier.

1.1.5.2. Fluidity of lipid bilayer membrane

Intracellular route favors the buccal mucosa to show

mechanism of action for the drug absorption and lipid at protein

components interacts with some enhancers to disturb the intracellular

lipid packaging.45.

1.1.5.3. Acting on the components at tight junctions

Some enhancers act on desmosomes, a major component at the

tight junctions there by increases drug absorption46.

1.1.5.4. By overcoming the enzymatic barrier

Some of the substances overcome the enzymatic barrier by

inhibiting the various peptidases and proteases present within buccal

mucosa. In addition, enzymatic activity is indirectly affected by the

changes in membrane fluidity.

1.1.5.5. Increasing the thermodynamic activity of drugs

Some enhancers may alter the partition coefficient by increase

the solubility of drug. Better absorption is achieved by increased

thermodynamic activity. The intracellular lipid penetration is followed

for permeability of drugs by which surfactants like cationic, anionic,

nonionic, bile salts increases and calcium ion interference is mainly

due to which chelates, phospholipid fluidity increases with the help of

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fatty acids and interaction of ions on mucosa with the help of positive

and negative charges.

1.1.6. Mucoadhesive polymers

Polymer is a generic term used to describe a very long molecule

consisting of structural units and repeating units of monomers

connected by covalent chemical bonds. Polymers act as adhesive

component bioadhesive formulations. These formulations are often

water soluble and forms strong interaction by attracting water from

the biological surface. When hydrated with water these polymers form

viscous liquids and allow long retention time on the mucosal surfaces

leading to the formation of adhesive interactions. Bioadhesive

polymers should possess certain physicochemical features including

hydrophilicity, viscoelastic properties, flexibility for interpenetration

with mucus and epithelial tissue47.

1.1.6.1. Ideal characteristics

1. Shows better spreading, wetting, swelling, solubility and

biodegradability characters.

2. Should have biocompatible pH and possess good visco-elastic

properties.

3. Should attach rapidly to buccal mucosa and hold adequate

mechanical strength.

4. Have wide bioadhesive ranges of peel, tensile and shear

strengths.

5. The polymers are not having high cost and easily available.

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6. Bioadhesive nature in both anhydrous and hydrous condition.

7. Should posse’s penetration enhancement properties by

inhibiting local enzyme.

8. It exhibit satisfactory stability.

9. The molecular weight is optimum.

10. Should not help in progress of secondary illness like dental

caries.

1.1.6.2. Classification mucoadhesive polymers9

a) Based on source

Natural: e.g. Agarose, chitosan, gelatin, Hyaluronic acid, and gums.

Synthetic: e.g. Cellulose derivatives like CMC, SCMC, HEC, HPC, MC,

Thiolated CMC and HPMC.

Based on aqueous solubility

Water soluble: e.g. CP, HEC, HPC, HPMC, SCMC, sodium alginate.

Water insoluble: e.g. Chitosan and EC.

b) Based on charge

Cationic: e.g. Chitosan, Dimethylaminoethyl (DEAE), Dextran,

Anionic: e.g. CP, Carboxy methyl cellulose, Na alginate, Sodium

carboxy methyl cellulose, xanthan gum.

Non-ionic: e.g. Hydroxy propyl cellulose, Poly ethylene oxide, Polyvinyl

alcohol, Polyvinyl pyrrolidone.

c) Based on potential bioadhesive forces

Covalent bond: e.g. Cyanoacrylate.

Hydrogen bond: e.g. Acrylates, CP, PVA

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Electro-static interaction: e.g.Chitosan

1.1.7. Formulation design

Buccoadhesive formulations with the size 1–3 cm2 and a daily

dose of 25 mg or less are convenient19. The general considerations in

buccal dosage form design includes

Pharmaceutical considerations.

Physiological considerations.

Pathological considerations.

Pharmacological considerations.

Pharmaceutical considerations

The release of core from the dosage form can be retarded by its

solubility in saliva. The absorption of weakly water soluble drugs can

be increased by solubilizing the drug in Cyclodextrin and administered

via buccal route. The physicochemical characteristics, morphological

characters of the drug all influence the desirable drug release and

absorption48.In case of dosage forms, for enhancing the effectiveness

and acceptability, some excipients are incorporated. Various

permeation enhancers increase permeability of buccal mucosa49.

Enzyme inhibitors may be included in the dosage forms to prevent

enzyme degradation and pH modifiers may be included in order to

temporarily modulate the microenvironment at the application site for

better drug absorption.

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Physiological considerations

Challenges of drug delivery to the oral cavity are Constant flow

of saliva and mobility of tissues. The residence time of drugs in the

oral cavity is typically short, in the range of <5–10 min50. The problem

is mainly overcome by use of buccal formulation. The device size is 1-

3 cm and daily dose of 25 mg in case of buccal delivery and ellipsoid

shape favors to be more acceptable and thickness is usually limited to

few mm for buccal formulation52.

Pathological considerations

Thickness of epithelium is affected mainly with many diseases

in which the barrier of mucosa results in alteration. Mucus properties

are influenced with some diseases, hence in pathologic conditions

which complicate bio adhesive device to be retention and at site of

application.

Pharmacological aspects

In case of systemic circulation buccal dosage form is designed

and in local therapy of oral mucosa. The dosage form is affected

mainly due to drug characteristics, target site of action and at the

treated site9.

Ideal properties of novel buccal drug delivery systems

Should release the drug in a controlled fashion

Unidirectional way of drug release towards the mucosa.

Should facilitate the rate and extent of drug absorption.

Should not cause any irritation or inconvenience to the patient.

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Should not interfere with the normal functions such as talking,

drinking etc.

1.1.8. Approaches of buccal drug delivery system

Non-attached drug delivery systems

This includes Fast dissolving tablet dosage forms, Chewing

gum formulations and Micro-porous hollow fibers.

Bio-adhesive drug delivery systems

a) Solid buccal adhesive dosage forms.

b) Semi solid buccal adhesive dosage forms.

c) Liquid buccal adhesive dosage forms.

Liposome

Delivery of proteins and peptides

Non-attached drug delivery systems

The local physiological environment greatly affects the non-

attached drug delivery system, e.g. the presence of saliva and the

intake of foods and liquids41.

Bio-adhesive drug delivery systems

a) Solid buccal adhesive dosage forms

Dry formulations achieve bio-adhesion via dehydration of the

local mucosal surface.

Buccal tablets

Buccal tablets are small, flat and oval in shape with a diameter

of approximately 5–8 mm. The direct compression technique is most

widely used for preparation of buccal tablets; other techniques like

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wet granulation can also be employed. These tablets stick to the

buccal mucosa in presence of saliva. They are designed to release the

drug either unidirectional, targeting buccal mucosa or multidirectional

in to the saliva53.

Microspheres, microcapsules, micro particles

The local irritation caused by microspheres54,55 or

microcapsules56 or micro particles57 at the site of adhesion is less and

provide comfortable sensation of a foreign object within the oral cavity.

Wafers

Wafer is a drug delivery system with surface layers possessing

adhesive properties58.

Lozenges

Bioadhesive lozenge offers prolonged drug release with improved

patient compliance compared to Conventional lozenges, thus avoiding

multiple daily dose59.

b) Semi-solid buccal adhesive dosage forms.

Gels

Bioadhesive polymers forming gels which form cross linked

polyacrylic acid used in which mucosal surfaces are fixed to provide

the release in control manner for extensive period of time and drug at

the absorption site. Bioadhesive polymers forming gels are of limited

use for drugs with narrow therapeutic window due to their inability to

deliver a measured dose of drug to the site60.

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Buccal patches

Patches are laminates consists of drug-containing reservoir

layer and an impermeable backing layer. Drug is released in a

controlled manner from the drug-containing reservoir layer, and a

bioadhesive surface for mucosal attachment61. Buccal adhesive

Patches can be prepared by two methods, Solvent casting technique

and Direct milling method. In solvent casting technique, the solvent is

evaporated by casting the solution of the drug and polymer onto a

backing layer sheet and the patches were punched in intermediate

sheet. In method like direct milling in which the constituents of

formulation forms desire thickness by proper mixing, by which the

desired shapes are cut and punched out in case of patches. Backing

layer acts as protective layer which is impermeable and is applied to

control the prevention of drug loss and direction of drug release

during the administration.

Buccal films

These are the most recently developed dosage form which meant

for buccal administration. Buccal films62 have more flexibility and

comfort when compared with adhesive tablets. So, buccal films are

preferred instead of adhesive tablets. In addition to these, they have

saliva which removes and wash easy and short residence time on

mucosa of oral gels. The wound surface is protected mainly by films,

when the drugs are administered orally for local delivery and treat the

disease more effectively by reducing the pain. An ideal film should be

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soft, elastic, flexible and posses adequate strength to withstand

breakage due to stress from mouth movements. It should retain in the

mouth to produce desired action with good bioadhesive strength.

Swelling of film should not be too extensive in order to prevent

discomfort. Solvent casting method is widely used for the preparation

of buccal films. In solvent mixture, drug and polymer(s) are dissolved.

The solution made in to film and dried, a liner or a backing layer are

used to finally laminate. The salivary diffusion in to drug layer is

avoided by the backing layer; there is a reduction in the drug loss and

by enhancing adhesion time in oral cavity. The main disadvantage

with solvent casting technique is time consuming, long processing and

some concerns with the environment by the usage of different type of

solvents. Hot-melt extrusion method is used to overcome the

drawbacks.

c) Liquid buccal adhesive dosage forms

Liquids used to coat buccal surface are viscous and serve as

either protective agents or as drug vehicles for delivery of drug on to

the mucosal surface. Recently, pharmaceutically acceptable polymers

were used to improve the viscosity of products to aid their

maintenance in the oral cavity. Lubrication can be provided by

treating dry mouth with artificial saliva solutions and to retain the

drug on mucosal surfaces. This solution consists of SCMC as

bioadhesive polymer.

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Liposomes

Drugs which are encapsulated in liposome formulations have

been investigated for buccal administration. Applications of liposome

formulation in buccal delivery resulted in a decrease of systemic and

an increase of local, drug concentration. Peptides can be entrapped

within the liposome63-65. The transport of hydrophilic substances to

the layer of the epithelium through liposome formulations can be

limited. Poly methyl methacrylate is a hydrophilic polymer and found

to be the most appropriate mucoadhesive ointment for local

application in the oral cavity since the liposomes were shown to be

more stable in this polymer. The performance of less effective liposome

peptide delivery systems can be improved by incorporation of protease

inhibitors.

Delivery of proteins and peptides

The buccal drug delivery systems avoids pre systemic (or)

hepatic first-pass metabolism, acidity and protease activity come

across in the gastrointestinal tract hence provide as potential

important site for controlled delivery of macromolecular therapeutic

agents, such as peptides and protein drugs66. Another attractive

advantage is its tolerance (in comparison with the nasal mucosa and

skin) to potential sensitizers.

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1.2. DRUG PROFILE

1.2.1. Famotidine

Generic name

Famotidine

Class

H2 receptor antagonist67

Structural formula

Fig: 1.2. Structure of FamotidineChemical name

Propanimidamide, N-(aminosulfonyl)-3[[[2[diaminomethylene)

amino]-4-thiazolyl] methyl] thio]-[1-amino-3-[[[2-[diaminomethylene)

amino]-4-[thiazolyl]-methyl] thio] propylidene] sulfamide68.

Molecular formula

C8H15N7O2S3

Molecular weight

337.45

Description

It occurs as yellowish white or white crystalline powder.

Melting point

1630C and1640C.

23

Solubility

Freely soluble in dimethyl formamide and in glacial acetic acid,

practically insoluble in ether and in ethyl acetate, slightly soluble in

methanol, water and in dehydrated alcohol, it gets dissolved in dilute

mineral acids.

Standards

Famotidine contains not less than 98.5% and not more than

101.0% of C8H15N7O2S3 calculated on dried basis.

Heavy metals : Not more than 0.001%.

Sulphated Ash : Not more than 0.1%, determined for 1.0 g.

Loss on drying

Dry it at a pressure between 1 and 5 mmHg at 80oC for 5 h, it

loses not more than 0.5% of its weight.

Pharmacological profile69

Famotidine is antihistamine drugs particularly serve as H2-

receptor antagonist. Inhibition of gastric secretion is the primary

clinical importance. The volume of gastric secretion and acid

concentration are suppressed by Famotidine, changes in pepsin

secretion are proportional to volume output.

Mechanism of action

H2 receptor antagonists inhibit acid production by reversibly

competes the binding of H2 receptors with histamine on the baso -

lateral membrane of parietal cells. It competitively inhibits the actions

24

of histamine at all H2 receptors but their main clinical use is as

inhibition of gastric acid secretion.

Pharmacokinetic parameters of Famotidine69

Bio availability 40 – 45%

Plasma half life 2.5 to 4 h

Plasma protein binding 15 – 20%

Peak plasma concentration (Cmax) 1 to 3 h

Renal excretion

Metabolic excretion

65 – 70%

30 – 35%.

Renal clearance 250 – 450 ml/min.

Approximate duration of therapeutic effect 12 h

Drug interactions

It does not inhibit hepatic microsomal enzyme CytP450 system

and hence it does not interact with the drugs which are substrates for

CytP450 systems like Caffeine, Phenytoin, Warfarin, Quinidine, etc.

Food Interactions

Alcohol intake should be avoided.

Intake of caffeine should be limited.

Slight increase in the product's bioavailability is seen when

reacts with meal.

Adverse effects

Famotidine when administered intravenously, low incidence of

adverse effects is seen (< 3%) it causes diarrhoea, dizziness, fatigue,

muscle pain, transient rashes, hypergastrinemia, less common side

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effects affecting the CNS include (confusion, delirium, hallucinations,

slurred speech and headaches), teratogenicity not associated and used

during pregnancy.

Therapeutic uses

1. Healing of gastric and duodenal ulcers is the major therapeutic

indication.

2. Treatment is not complicated for treating GERD.

3. Stress ulcers can be treated Prophylactically.

4. Famotidine when given along with antibiotics useful for the

treatment of infection caused with Helicobacter pylori i.e. in the

treatment of Gastritis.

Dosage and administration70

Duodenal Ulcer and Benign Gastric Ulcer

40 mg once at bedtime (or) 20 mg twice a day

Gastro Esophageal Reflux Disease (GERD)

20 mg twice a day up to 6 weeks

Orally Disintegrating Tablets

Famotidine tablets can be replaced by orally disintegrating

tablets with same dose.

26

1.3. POLYMER PROFILES

1.3.1.HYDROXY PROPYL METHYL CELLULOSE (HPMC)71

Nonproprietary Names

BP: Hypromellose, JP: Hydroxypropylmethylcellulose,

PhEur: Hypromellosum, USP: Hypromellose

Synonyms

Methocel, methyl cellulose propylene glycol ether, methyl

hydroxyl propy lcellulose.

Structural formula

Where R is H, CH3 or [CH3CH (OH) CH2]

Fig: 1.3. Structure of HPMC

Molecular weight

10000-1500000

Description

It is an odorless and tasteless, white or creamy white colored

fibrous powder.

Solubility

It is soluble in cold water and forming a viscous colloidal

solution, soluble in mixtures of ethanol and dichloromethane,

27

mixtures of methanol and dichloromethane. It is practically insoluble

in chloroform, 95% ethanol and ether.

Viscosity

HPMC 2% w/v aqueous solutions viscosities measured at 20ºC.

HPMC grades K4M, K15M, K100M having viscosity of 4000, 15000

and 100000 cps respectively.

Typical properties of HPMC

Glass transition temperature 170–180 ºC

Density (bulk) 0.341 g/cm3

Density (tapped) 0.557 g/cm3

Density (true) 1.326 g/cm3

Specific gravity 1.26

Melting point 225–230 ºC.

Functional Category

HPMC posses a wide variety of functional categories such as

rate controlling polymer for sustained release, film former, coating

agent, stabilizing agent, viscosity-increasing agent, suspending agent

and tablet binder.

1.3.2.CARBOPOL71

Nonproprietary Names

BP: Carbopols, , PhEur: Carbopola, USPNF: Carbopol.

Synonyms

Acritamer, poly acrylic acid polymer, carbopol, carboxy poly

methylene, acrylic acid, carboxyvinyl polymer.

28

Structural formula

Acrylic acid monomer unit in carbopol resins.

Fig: 1.4. Structure of Carbopol

Acrylic acid monomer is the repeating monomer unit in carbopol

polymer. The monomer unit is shown above. Allyl sucrose or allyl

pentaerythritol are the cross linked polymer chains in carbopol.

Molecular Weight

12000-140000

Description

Carbopols are colorless, fluffy, acidic, hygroscopic powders with

a slight characteristic odor.

Solubility

It is soluble in water after neutralization in ethanol (95%) and

glycerin. Carbopols merely swell to a remarkable extent but do not

dissolve.

Viscosity

Carbopols forms low viscosity colloidal dispersions which are

acidic in nature and forms viscous gels when gets neutralized.

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Typical properties of Carbopol

Glass transition temperature 100–105ºC

Density (bulk) 1.76–2.08 g/cm3

Density (tapped) 1.4 g/cm3

Specific gravity 1.41

Melting point 260ºC

Functional Category

Bioadhesive, emulsifying and release modifying agent, viscosity

promoters, tablet binder and suspending agent

1.3.3. POLY VINYL PYRROLIDONE (PVP) 71

Nonproprietary Names

USP: Povidone, BP: Povidone, JP: Povidone, PhEur: Povidonum

Synonyms

Plasdone, Kollidon, polyvidone, poly vinyl pyrrolidone and 1-

vinyl-2-pyrrolidinone polymer

Structural formula

Fig: 1.5. Structure of PVP

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Molecular Weight

2500–30, 00,000

Description

Povidone exists as a fine, white to creamy white colored,

odorless, hygroscopic in nature.

Moisture content

Povidone at low relative humidity absorbs significant amounts

of moisture and is very hygroscopic.

Solubility

It is freely soluble in water, methanol, ethanol (95%) and acids.

Viscosity

Both the concentration and the molecular weight of the polymer

employed influence the viscosity of aqueous povidone solutions.

Typical properties of PVP

Density (bulk) 1.76–2.08 g/cm3

Density (tapped) 1.4 g/cm3

Density (true) 1.180 g/cm3

Melting point Softens at 150 ºC.

Functional category

PVP serves as tablet binder, suspending agent, film forming

agent, disintegrating agent, dissolution aid.

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1.3.4. SODIUM CARBOXY METHYL CELLULOSE (SCMC) 71

Nonproprietary Names

USP: Carboxy methyl cellulose sodium,

JP: Carmellose sodium

BP: Carmellose sodium,

PhEur: Carmellosum natricum

Synonyms

Akucell, aquasorb, cellulose gum, sodium cellulose glycolate

Structural Formula

Fig: 1.6. Structure of SCMC

Molecular Weight

90,000-7, 00,000

Description

It occurs as odorless granular white powder.

Solubility

SCMC forms clear, colloidal solution with water at all

temperatures and insoluble in acetone, ethanol, ether and toluene.

Viscosity

Aqueous 1% w/v solutions with viscosities of 5–13,000 cp and

solutions were stable at pH 4–10.

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Typical properties of SCMC

Dissociation constant pKa = 4.30

Bulk density 0.52g/cm3

Tapped density 0.78 g/cm3

Melting point 252 ºC.

Functional category

Suspending agent, stabilizing agent, viscosity promoters,

coating agent, tablet binder, disintegrating agent.

1.3.5. ETHYL CELLULOSE (EC) 71

Non proprietary Names

USPNF: Ethylcellulose, BP: Ethylcellulose, PhEur : Ethylcellulosum

Synonyms

Aqualon; surelease; Aqua coat ECD; Aqualon; E 462; Ethocel;.

Structural Formula

Fig: 1.7. Structure of EC

Chemical name

Cellulose ethyl ether

Description

White to light tan colored, tasteless and free flowing powder.

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Moisture content

During immersion or humid air, EC absorbs very little amount

of water and that small amount evaporates readily.

Solubility

It is freely soluble in chloroform, ethanol (95%), ethyl acetate,

methanol and toluene. It is insoluble in water.

Viscosity

The viscosity of 5% w/v ethyl cellulose dissolved in toluene and

ethanol at the ratio of 80:20 were calculated at room temperature and

this solution is proportional to concentration of ethyl cellulose.

Typical properties of EC

Glass transition temperature 129-133ºC

Density (bulk) 0.4 g/cm3

Specific gravity 1.12-1.15 g/cm3

Functional category

Used as a tablet binder, tablet filler, viscosity promoters and

coating agent.

1.3.6. SODIUM ALGINATE71

Non proprietary Names

USPNF: Sodium alginate, BP: Sodium alginate,

PhEur : Natrii alginas,

Synonyms

Algin, alginic acid, Kelcosol, Protanal.

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Structural Formula

Fig: 1.8. Structure of Sodium alginate

Description

It occurs as white to pale yellowish-brown colored powder of

odorless and tasteless.

Solubility

Sodium alginate is soluble in water and slowly forming a viscous

colloidal solution. Insoluble in 95% ethanol, ether, chloroform and

ethanol/water mixtures, organic solvents and aqueous acidic

solutions in which the pH is less than 3.

Viscosity

Sodium alginate is commercially available in various grades of

varying viscosity. Typically, a 1% w/v aqueous solution, at 20oC, will

have a viscosity of 20–400 CP.

Functional category

Tablet binder, Stabilizer, suspending agent, tablet and capsule

disintegrating agent, viscosity promoters

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1.3.7. POLYMETHACRYLATES (EUDRAGIT) 71

Non-proprietary Names

BP: Methacrylic acid–ethyl acrylate copolymer (1:1)

BP: Ammonio methacrylate copolymer

Synonyms

Methacrylic acid and Polymeric methacrylate

Chemical Name

Poly (ethyl acrylate, methyl methacrylate, tri methyl ammonio

ethyl methacrylate chloride)

Structural Formula

CH2C

O

OC

CH2C

O

OC

CH2C

O

OC

C

O

OC

CH2

R1 R3R3 R1

R2 R2R4 R4

For Eudragit RL and RS 100

Fig: 1.9. Structure of Eudragit

R1 = H, CH3, R2 = CH3, C2H5, R3 = CH3, R4 = CH2 CH2 N(CH3)3+Cl-

Molecular Weight

100,000 and approximately 135,000

Description

Eudragit RS and Eudragit RL also referred to as ammonio

methacrylate copolymers. Both polymers are Cationic, non-

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biodegradable,which are insoluble in water and films that are

prepared from Eudragit RL shows free permeability in water and

Eudragit RS formed films shows slight permeation with water.

Solubility

It is Soluble in acetone, alcohol and dichloromethane, and

insoluble in water and petroleum ether.

Viscosity

Eudragit RS100 is less than15 mp.

Functional category

Film former, binder and diluent in tablet formulations