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CHAPTER 1

Introduction, Literature

Survey and Objectives

Chapter 1 Introduction, Literature Survey and Objectives

1 | B H A G W A N T U N I V E R S I T Y , A J M E R

INTRODUCTION, LITERATURE SURVEY AND OBJECTIVES

Oral administration of pharmaceutical compositions has some drawbacks. For

instance, it is difficult to keep the medicament at the desired location so that it can be

absorbed, distributed and metabolized easily. Accordingly, there has been much

interest in the use of the mucosal lining of body cavities. Regions in the oral cavity

where effective drug delivery can be achieved are buccal, sublingual, palatal and

gingival. Buccal and sublingual sectors are the most commonly used routes for drug

delivery and they may be used for the treatment of local or systemic diseases. The

permeability of the oral mucosa is probably related to the physical characteristics of

the tissues (Studzinska et al., 2009). The buccal mucosa offers many advantages

because of its smooth and relatively immobile surface and its suitability for the

placement of controlled-release system which is well accepted by patients. The buccal

mucosa is a useful route for the treatment of either local or systemic therapies

overcoming the drawbacks of conventional administration routes. The buccal mucosa

is relatively permeable, robust in comparison to the other mucosal tissues and is more

tolerant to potential allergens which have a reduced tendency to irreversible irritation

or damage. So, it has been largely investigate as a potential site for controlled drug

delivery in various chronic systemic therapies. However, salivary production and

composition may contribute to chemical modification of certain drugs. Moreover;

involuntary swallowing can result in drug loss from the site of absorption.

Furthermore, constant salivary scavenging within the oral cavity makes it very

difficult for dosage forms to be retained for an extended period of time in order to

facilitate absorption in this site. The relatively small absorption area and the barrier

property of the buccal mucosa contribute to the inherent limitations of this delivery

route (Puthli et al., 2009). Both the buccal and sublingual membranes offer

advantages over other routes for administration. For example, drugs administered

through the buccal and sublingual routes have a rapid onset of action and improved

bioavailability of certain drugs. These routes can bypass the first-pass effect and

exposure of the drugs to the gastrointestinal fluids. Additional advantages include

easy access to the membrane sites so that the delivery system can be applied,

localized, and removed easily. Further, there is good potential for prolonged delivery

through the mucosal membrane within the oral mucosal cavity. The palatal mucosa is

intermediate in thickness and keratinized thus lessening its permeability. All of these



epithelia are coated with a layer of mucus (Shakya et al., 2009). Bioadhesive polymer

can significantly improve the performance of many drugs, as they are having

prolonged contact time with these tissues. These patient compliance controlled drug

delivery products have improved drug bioavailability at suitable cost. Drug selection

for oral transmucosal delivery is limited by the physicochemical properties of the

drugs themselves. To be delivered transmucosally, drugs must have unique

physicochemical properties, i.e. a proper balance between solubility and lipophilicity.

Generally only a few milligrams of drug can cross the oral mucosa, even if the drug

has a favourable profile for oral mucosal delivery (Giannola et al., 2007).

Since the early 1980s there has been renewed interest in the use of bioadhesive

polymers to prolong contact time in the various mucosal routes of drug

administration. The ability to maintain a delivery system at a particular location for an

extended period of time has great appeal for both local as well as systemic drug

bioavailability. Drug absorption through a mucosal surface is efficient because

mucosal surfaces are usually rich in blood supply, providing rapid drug transport to

the systemic circulation and avoiding degradation by gastrointestinal enzymes and

first pass hepatic metabolism (Scholz et al., 2008).

1.1. Oral Transmucosal Drug Delivery

Within the oral cavity delivery of drug is classified into the categories. Due to its

excellent accessibility and reasonable patient compliance oral mucosal cavity offers

attractive route of drug administration. Within the oral mucosal cavity delivery of

drug is classified into following categories:

(a) Sublingual delivery which is a systemic delivery of drug through the mucosal

membrane lining the floor of the mouth

(b) Buccal delivery & local delivery, for the treatment of conditions of the oral

cavity. The oral cavity is foremost part of digestive system of human body. It

is also referred to as “buccal cavity”. It is accountable for various primary

functions of body. The careful examination of various features of oral cavity

can help in development of a suitable buccoadhesive drug delivery system

(Khanna et al., 1998).

1.2. Oral Cavity

1.2.1. Components or structural features of oral cavity

Oral cavity is that area of mouth delineated by the lips, cheeks, hard palate, soft palate

and floor of mouth. The oral cavity consists of two regions.



• Outer oral vestibule, which is bounded by cheeks, lips, teeth and gingival (gums).

• Oral cavity proper, which extends from teeth and gums back to the fauces (which

lead to pharynx) with the roof comprising the hard and soft palate. The tongue

projects from the floor of the cavity.

Figure 1.1: Structure of Oral Cavity

1.2.2. Anatomical Features

The outer surface of the oral cavity is a mucous membrane consisting of an

epithelium, basement membrane and lamina propria overlying a submucousa

containing blood vessels and nerves. The mucosa can be divided into three types

(Ross and Wilson, 2001):

• Masticatory mucosa, found on the gingiva and hard palate.

• Lining mucosa, found on the lips, cheeks, floor of mouth, undersurface of the tongue

and the soft palate.

• Specialized mucosa found on the upper surface of the tongue and parts of the lips.



Figure 1.2: Structure of Buccal Mucosa

All consists of a squamous stratified epithelium, many cell layers (40-50 for buccal

mucosa) overlying a connective tissue, layer, the lamina propria. Intercellular

connection in buccal tissue is characterized by desmosomes and tight junctions and

the tissue is a somewhat leaky epithelium. The intercellular material between the

superficial epithelial layers is extended by a unique organelle called “membrane

coating granule”. It has been shown in rabbit keratinized epithelium that the lamella

contents of the membrane-coating granules mix with existing material and form broad

sheets in the intercellular spaces. These sheets are oriented parallel to the cell

membrane and therefore may act as a barrier to permeability. Connective tissue

papillae, which penetrate into the epithelia, give the basement membrane an enormous

surface area compared to that of the surface of the epithelium (Amir et al., 2001).

1.2.3. Absorption pathways

Studies with microscopically visible tracers such as small proteins and dextrans

suggest that the major pathway across stratified epithelium of large molecules is via

the intercellular spaces and that there is a barrier to penetration as a result of

modifications to the intercellular substance in the superficial layers. However, rate of

penetration varies depending on the physicochemical properties of the molecule and

the type of tissue being traversed. This has led to the suggestion that materials uses

one or more of the following routes simultaneously to cross the barrier region in the

process of absorption, but one route is predominant over the other depending on the

physicochemical properties of the diffusant (Hoogstraate et al., 1996 & Hao et al.,

2003).

Submucousa

Lamina propria

Epithilium



➢ Passive diffusion

◦ Transcellular or intracellular route (crossing the cell membrane and entering the

cell)

◦ Paracellular or intercellular route (passing between the cells) ➢ Carrier mediated transport ➢ Endocytosis

The flux of drug through the membrane under sink condition for paracellular route

can be written as Eq. (1)

----------------------------------- (1)

Where, Dp is diffusion coefficient of the permeate in the intercellular spaces, hp is the

path length of the paracellular route, ε is the area fraction of the paracellular route and

Cd is the donor drug concentration.

Similarly, flux of drug through the membrane under sink condition for transcellular

route can be written as Eq. (2).

---------------------------- (2)

Where, Kc is partition coefficient between lipophilic cell membrane and the aqueous

phase, Dc is the diffusion coefficient of the drug in the transcellular spaces and hc is

the path length of the transcellular route.

In very few cases absorption also takes place by the process of endocytosis where the

drug molecules were engulfed by the cells. It is unlikely that active transport

processes operate within the oral mucosa; however, it is believed that acidic

stimulation of the salivary glands, with the accompanying vasodilatation, facilitates

absorption and uptake into the circulatory system.

1.2.4. Biochemistry of oral mucosa

All the layers of the oral mucosal membranes contain a large amount of protein in the

form of tonafilaments, consisting at least seven proteins called “keratins” with

molecular sizes of 40-70 Kda. Both keratinized and nonkeratinized tissues of varying

thickness and composition are found in oral cavity. Keratinized and non-keratinized

tissues occupy about 50% and 30% respectively of the total surface area of the mouth.

Dp ε

Jp = ------------- x Cd

hp

(1 - ε) DcKc

Jc = --------------- x Cd

hc



The difference between keratinized and non-keratinized epithelia is merely the

difference in the molecular size of existing keratins. Cells of non-keratinized epithelia

contain lower molecular weight protein while those in keratinized epithelia contain

mainly higher-molecular weight keratins. The lipid content of the cells varies between

tissues (Jain et al., 1997).

1.2.5. Physiological aspects and functions of oral cavity

The oral cavity is accountable for the following primary functions:

• As a portal for intake of food material and water.

• To bring chewing, mastication and mixing of food stuff.

• Lubrication of food material and formation of bolus.

• Identification of ingested material by taste buds of tongue.

• Initiation of carbohydrate and fat metabolism. Absorption of catabolic products

thereafter metabolism.

• To aid in speech and breathing process.

• Slight antisepsis of ingested material and within oral cavity by saliva.

1.2.6. Secretions of Oral Cavity (Yamahara et al., 1990 & Kumar et al., 2004)

The secretions in the oral cavity include saliva, crevicular fluid and mucus.

1.2.7. Saliva

Saliva is a complex fluid containing organic and inorganic materials. It is produced by

the three pairs of major glands (parotid, submandibular and sublingual) each situated

outside the oral cavity and in minor salivary glands situated in the tissues lining most

of the oral cavity. The total average volume of saliva produced daily in an adult is

around 750 ml. The flow rates of saliva depend upon the type of stimulus used, the

time of day, the length of time glands had been stimulated, the age and sex of the

individual and by their state of health. The average resting flow rate for whole saliva

is 0.3 ml/ min (range 0.1-0.5 ml/min). For stimulated saliva the average flow rate is

1.7 ml/min (range 1.1 to 3.0 ml/min). Chemically, saliva is 99.5% water and 0.5%

solutes. The solutes include ions (sodium, potassium, magnesium, phosphate,

bicarbonate and chloride), dissolved gases, urea, uric acid, serum albumin, globulin,

mucin and enzymes [lysozyme and amylase (ptyalin)].

The various physiological functions of saliva are:

• Modulation of oral flora

• Remineralization of the teeth with calcium phosphate salts

• Neutralization of acid in the oral cavity and esophagus



• Lubrication and the cleansing of the oral, pharyngeal and esophageal mucosae

• Assistance in bolus formation

• Stimulation of epithelial proliferation

• Initiation of fat and starch digestion

The pH of whole saliva varies between 6.5 and 7.5. The main buffering system is the

bicarbonate system; however, phosphate and protein buffers also play a minor role

1.2.8. Crevicular Fluid

It is a fluid secreted from the gingival glands of oral cavity.

1.2.9. Mucus

Mucus is a thick secretion composed mainly of water, electrolytes and a mixture of

several glycoproteins, which themselves are composed of large polysaccharides

bound with smaller quantities of protein. It is secreted over many biological

membranes of body for example, throughout the gastrointestinal tract walls. Mucus is

secreted by special type of epithelia called mucosa. The mucus secreted in buccal

cavity admixtures with saliva of salivary glands in oral cavity to produce whole

saliva.

Mucus has two main functions:

• Protectant for biological membranes (exposed epithelia).

• Excellent lubricant.

1.3. Drug Delivery Via Oral Cavity

The oral cavity can be used for local and systemic therapy. Examples of local therapy

would be the treatment of oral infections, dental caries, mouth ulcers and stomatitis.

The buccal route is of particular interest with regard to the systemic delivery of small

molecules that are subjected to first pass metabolism, or for the administration of

proteins and peptides (Amir et al., 2001). The two main-routes for administration with

oral cavity are:

• Sublingual route

• Buccal route.

1.3.1. Drug Delivery via Sublingual Route

Sublingual administration implies systemic administration of drugs via the

membranes that line the floor of the mouth and ventral surface of the tongue. A

rapidly dissolving tablet is generally given by the sublingual route (Amir et al., 2001).

The sublingual region suffers with one major drawback. The two major salivary

glands (submandibular and sublingual glands) open their ducts in sublingual area to



release saliva. There is constant flushing of saliva in this region because of which it is

difficult to retain drugs and delivery system and build or maintain high concentration

of drug, in the sublingual region.

1.3.2. Drug delivery via buccal route

Buccal delivery refers to drug release which can occur when a dosage form is placed

in the outer vestibule between the buccal mucosa and gingiva (Sevdsenel et al., 2001).

Terminology

Various terms to be used in theoretical elucidation of buccal absorption are:

• Oral cavity mucosa: The membranes that line the oral cavity which include the

sublingual, buccal mucosa, the gums (gingiva), the palatal mucosa and the labial

mucosa.

• Buccal membrane: The membrane inside the mouth that lines the cheek.

• Buccal drug delivery system: A delivery system designed to deliver drugs

systemically or locally via or to the buccal mucosa.

• Salivary pellicle: The components of saliva are adsorbed on to the surface of the oral

mucosa to form a salivary pellicle. This pellicle coats all surfaces in the mouth and is

a multilayered structure.

1.4. Buccal Absorption

Buccal administration involves systemic or local administration via or to the buccal

membrane (Yamahara et al., 1990 & Kumar et al., 2004).

1.4.1. Mechanism

Oral mucosal drug absorption occurs by passive diffusion of the nonionized species, a

process governed primarily by a concentration gradient, through the intercellular

spaces of the epithelium. An investigation showed, using a variety of organic drugs

from acids to bases, that the passive transfer of non-ionic species across the lipid

membrane of the buccal cavity was the primary transport mechanism. The buccal

mucosa has been said to behave predominately as a lipoidal barrier to the passage of

drugs; as is the case with many other mucosa and (within limits) the more lipophilic

(or less ionized) the drug molecule, the more readily it is absorbed. It has been

concluded that the passive diffuses in accordance with the pH partition theory of drug

absorption is the major route of drug absorption for most drugs. However, it has been

reported that certain molecules e.g., some sugars and vitamins may be transported by

a specialized transport system capable of saturation.



It has been proposed that the intercellular route, rather than the transcellular route, is

the predominant route for drug absorption. Large hydrophilic molecules in particular

are believed to be transported by the intercellular route and the presence of the

contents of membrane-coating granules in the intercellular space may inhibit

penetration in both keratinized and nonkeratinized mucosae.

1.4.2. Dynamics

The oral mucosal absorption of drugs could be adequately described by first order rate

process. Several potential barriers to oral mucosa drug absorption have been

identified. These include the mucus layer, keratinized layer, intercellular lipid of

epithelium, basement membrane and lamina propria. In addition, the absorptive

membrane thickness, blood supply blood/lymph drainage, cell renewal and enzyme

content will all contribute to reducing the rate and amount of drug entering the

systemic circulation. Some time salivary secretion alters the buccal absorption

kinetics from drug solution by changing the concentration of drug in the mouth. They

proposed a linear relationship between salivary secretion and time thus Eq. (3):

------------------------ (3)

Where ‘m’ and ‘C’ are the mass and concentration of drug in mouth at time ‘t’, Vi,

the volume of solution put into mouth cavity and ‘V’ is salivary secretion rate.

1.5. Factors Affecting Buccal Absorption

The oral cavity is a complex environment for drug delivery as there are many

interdependent and independent factors which reduce the absorbable concentration at

the site of absorption.

1.5.1. Membrane Factors

This involves degree of keratinization, surface area available for absorption, mucus

layer of salivary pellicle, intercellular lipids of epithelium; basement membrane and

lamina propria. In addition, the absorptive membrane thickness, blood supply/ lymph

drainage, cell renewal and enzyme content will all contribute to reducing the rate and

amount of drug entering the systemic circulation (Jain et al., 1997).

1.5.2. Environmental Factors

(a) Saliva: The thin film of saliva coats throughout the lining of buccal mucosa and

is called salivary pellicle or film. The thickness of salivary film is 0.07 to 0.10

dm KC ------ = ----------------

dt Vi + Vt



mm. The thickness, composition and movement of this film effects buccal

absorption. (Kumar et al., 2004)

(b) Salivary glands: The minor salivary glands are located in epithelial or deep

epithelial region of buccal mucosa. They constantly secrete mucus on surface of

buccal mucosa. Although, mucus helps to retain mucoadhesive dosage forms, it is

potential barrier to drug penetration (Edsman et al., 2005).

1.5.3. Movement of oral tissues

Buccal region of oral cavity shows less active movements. The mucoadhesive

polymers are to be incorporated to keep dosage form at buccal region for long periods

while withstanding tissue movements during talking and if possible during eating

food or swallowing.

1.6. Advantages of Buccal Absorption

The oral mucosa has a rich blood supply. Drugs are absorbed from the oral cavity

through the oral mucosa, and transported through the deep lingual or facial vein,

internal jugular vein and braciocephalic vein into the systemic circulation. Following

buccal administration, the drug gains direct entry into the systemic circulation thereby

bypassing the first pass effect. Contact with the digestive fluids of gastrointestinal

tract is avoided which might be unsuitable for stability of many drugs like insulin or

other proteins, peptides and steroids. In addition, the rate of drug absorption is not

influenced by food or gastric emptying rate (Khanna et al., 1998).

The area of buccal membrane is sufficiently large to allow a delivery system to be

placed at different occasions, which may be advantageous if the drug delivery system

or other excipients reversibly damage or irritate the mucosa. Additionally, there are

two areas of buccal membranes per mouth, which would allow buccal drug delivery

systems to be placed, alternatively on the left and right buccal membranes (Amir et

al., 2001).

The oral mucosa is routinely exposed to a multitude of different foreign compounds

and physical insult. So it has evolved a robust membrane that is less prone to

irreversible damage by drug, dosage form or additives used therein. Thus, it may be

feasible to include permeation enhancers in the formulation to increase systemic

availability of the drug without observing permanent damaging effects.

Additional advantages of the oral cavity as a site for systemic drug delivery include:

sterile techniques are not required during manufacture or administration, the oral

cavity contains teeth upon which drug delivery systems can be physically attached



using dental adhesives, the oral mucosa is low in enzyme activity and enzymatic

degradation is relatively slow, hence, from the point of drug inactivation, the oral

musocal route would be preferred to the nasal or rectal routes (Rao et al., 1998).

1.7. Limitations In Buccal Absorption

(a) The area of absorptive membrane is relatively smaller. If the effective area for

absorption was dictated by the dimensions of a delivery system, this area then

becomes even smaller (Kumar et al., 2004).

(b) Saliva is continuously secreted into the oral cavity diluting drugs at the site of

absorption resulting in low drug concentrations at the surface of the absorbing

membrane. Involuntary swallowing of saliva results in a major part of

dissolved or suspended released drug being removed from the site of

absorption. Furthermore, there is risk that the delivery system itself would be

swallowed (Rao et al., 1998).

(c) Drug characteristics may limit the use of the oral cavity as a site for drug

delivery. Taste, irritancy, allerginicity and adverse properties such as

discoloration or erosion of the teeth may limit the drug candidate list for this

route. In addition, the drug should not adversely effects the natural microbial

flora of the oral cavity (Amir et al., 2001).

(d) Conventional type of buccal drug delivery systems did not allow the patient to

concurrently eat, drink or in some cases, talk (Khanna et al., 1998).

(e) The permeability of the oral mucosa is not great compared to other mucosal

membranes.

1.8. Buccal Dosage Forms

Buccal Dosage forms are meant to be placed between gingiva and cheek.

1.8.1. Conventional Dosage Form

The conventional type of buccal dosage forms are buccal tablets, troches and

lozenges, and mouth washers. Buccal tablets are small, flat, oval tablets and are

intended to be held between the cheek and the teeth or in the cheek pouch (buccal

tablets). Progesterone tablets can be administered this way. These tablets should be

designed not to disintegrate but to slowly dissolve, typically over a 15 to 30 minutes

period to provide for effective absorption. Troches and lozenges are two other types

of tablets used in oral cavity where they are intended to exert a local effect in the

mouth or throat. These tablet forms are commonly used to treat sore throat or to

control coughing in common cold. Lozenges (pastilles or cough drops), these two



classes of tablets are designed not to disintegrate in the mouth but to dissolve or

slowly erode over a period of perhaps 30 minute or less. A mouth wash is an aqueous

solution, which is most often used for its deodorant, refreshing or antiseptic effect on

buccal mucosa (Nakhat et al., 2007 & Madgulkar et al., 2009).

1.8.2. Advanced Buccal Dosage Forms

The novel type buccal dosage forms include buccal adhesive tablets, patches, films,

tapes, semisolids (ointments and gels) and powders.

1.8.3. Mucoadhesive Tablets

Buccal mucoadhesive tablets are dry dosage forms that move to be moistened prior to

placing in contact with buccal mucosa. A double layer tablets, consisting of adhesive

matrix layer of hydroxy propyl cellulose and poly (acrylic acid) with an inner core of

cocoa butter containing insulin and a penetration enhancer (sodium glycocholate)

have been reported (Giannola et al., 2007).

1.8.4. Patches, Tapes & Films

Buccal patches consists of two ply laminates, with an aqueous solution of the

adhesive polymer being cast onto an impermeable backing sheet, which was then cut

to the required oval shape. A novel mucosal adhesive film called “Zilactin” consisting

of an alcoholic solution of hydroxy propyl cellulose and three organic acids, forms a

film which applied to the oral mucosal surface which can be retained in place for at

least 4 hours, even where challenged with fluids (Baviskar et al., 2009, Pandit et al.,

2001 & Cilurzo et al., 2008).

1.8.5. Semisolid Preparations (Ointments and Gels)

Bioadhesive gels or ointments have less patient acceptability than solid dosage

adhesive forms, and most are used only for localized drug therapy within the oral

cavity. One of the original oral mucosal-adhesive delivery systems “orabase” consists

of finely ground pectin, gelatin and sodium carboxy methyl cellulose dispersed in a

poly (ethylene) and a mineral oil gel base, which can be maintained at its site of

application for 15-150 minutes (Khairnar et al. 2010 & Perioli et al. 2008).

1.8.6. Powders

A hydroxpropyl cellulose containing powder are also used for the purpose of

mucoadhesive drug delivery system that retain the drug on mucus membrane for a

longer period of time and release the drug in a constant manner to maintain the drug

concentration.



1.8.7. Properties of an ideal buccal adhesive system

(a) Polymer must be easily available and its cost should not be high.

(b) Should adhere to the site of attachment for a few hours

(c) Should show bioadhesive properties in both dry and liquid state

(d) Should release the drug in a controlled fashion

(e) Should provide drug release in an unidirectional way toward the mucosa

(f) Should facilitate the rate and extent of drug absorption

(g) Should not cause any irritation or inconvenience to the patient

(h) Should not aid in development of secondary infections such as dental

caries.

(i) Should not interfere with the normal functions such as talking, drinking etc

1.8.8. Commercial buccal adhesive drug delivery systems

Some of the commercially available buccal adhesive formulations are (Jones et al.,

1997 & Bandyopadhyay et al., 2006):-

S.No. Commercial

Name

Bioadhesive

polymer

Company Dosage

form

1. Buccastem PVP, Xanthum gum,

Locust bean gum

Rickitt

Benckiser

Tablet

2. Suscard HPMC Forest Tablet

3. Gaviscon liquid Sodium alginate Rickitt

Benckiser

Oral liquid

4. Orabase Pectin, gelatin ConvaTech Oral paste

5. Corcodyl gel HPMC Glaxosmithkline Oromucosal

gel

6. Corlan pellets Acacia Celltech Oromucosal

pellets

7. Fentanyl Oralet Sodium alginate Lexicomp Lozenge

8. Miconaczole

Lauriad

Xanthum gum Bioalliance Tablet

9. Zilactin HPMC Zila Buccal film

10. Luborant Sodium CMC Antigen Artificial

Saliva

11. Tibozole PVP, Xanthum gum

Tibotec Tablet

Table 1.1: Commercially available buccal adhesive formulations



1.9.Design Of Buccal Mucoadhesive Patches

1.9.1. Different Components of Buccal Mucoadhesive Patches

1.9.2. Profile of Each component (Jain et al., 1997)

1.9.2.1. Drug

The important drug properties that affect its diffusion through the patch as well as the

buccal include molecular weight, chemical functionality and melting point. The

selection of a suitable drug for design of buccal mucoadhesive drug delivery system

should be based on pharmacokinetic properties. Following are the critical properties

for candidature to buccal mucoadhesive drug delivery (Puratchikody et al. 2011).

• The conventional single dose of drug should be low.

• Through oral route, the drug may exhibit first pass effect or presystemic drug

elimination. The fraction of oral bioavailability F is low (F<0.5 in comparison to IV

dose) and liver extraction ratio (ER) is high (ER>0.7).

• Drug absorption should be passive when given orally.

• The drug should not adversely affect the natural microbial flora or oral cavity.

• Drug should not have bad taste and be free from irritancy, allergenicity and

discoloration or erosion of teeth.

• The drug must be appreciably absorbed via buccal mucosa as evaluated by buccal

absorption test.

1.9.2.2. Polymers

In buccal mucoadhesive patches, three different categories of polymers differing

functionally are used. These are as follows (Madgulkar et al., 2009):

(a) Bioadhesive polymers.

(b)Polymers controlling rate of release of drug from matrix.

(c) Polymers used to prepare backing membrane.

(d) Plasticizer

1.9.2.2.1. Ideal characteristic of Polymer

1. Polymer and its degradation products should be non-toxic, non-irritant and

free from leachable impurities.

2. Should have good spreadability, wetting, swelling, solubility and

biodegradability properties.

3. pH should be biocompatible and should possess good viscoelastic properties.



4. Should adhere quickly to buccal mucosa and should possess sufficient

mechanical strength.

5. Should possess peel, tensile and shear strengths at the bioadhesive range.

6. Polymer must be easily available and its cost should not be high.

7. Should show bioadhesive properties in both dry and liquid state.

8. Should demonstrate local enzyme inhibition and penetration enhancement

properties.

9. Should demonstrate acceptable shelf life.

10. Should have optimum molecular weight.

11. Should possess adhesively active groups.

12. Should have required spatial conformation.

13. Should be sufficiently cross-linked but not to the degree of suppression of

bond forming groups.

14. Should not aid in development of secondary infections such as dental caries.

(a) Bioadhesive polymers: These are hydrophilic macromolecules that contain

numerous hydrogen bond forming groups. These polymers become

bioadhesive on hydration and are therefore called “wet adhesives”. The

characteristic properties of ideal bioadhesive are (Gupta et al., 2011):

1. It should have good mucoadhesive property and at the same time it should be

innocuous to buccal mucosa.

2. It should not chemically react with the drug and other excipients in

formulation.

3. Molecular weight, glass transition temperature and chemical functionality of

polymer must allow proper diffusion and release of drug.

4. It should be pharmacologically bland-free from irritancy, allergenicity, bad

taste and adverse properties such as discoloration or erosion of teeth. Cost of

polymer should not be excessive.



Criteria Categories Examples

Source Seminatural/

natural

Agarose, chitosan, gelatin, Hyaluronic acid, Various

gums (guar, xanthan, gellan, carragenan, pectin and

sodium alginate)

Synthetic Cellulose derivatives [CMC, thiolated CMC, sodium

CMC, HEC, HPC, HPMC, MC, Methyl hydroxyl ethyl

cellulose], Poly(acrylic acid)-based polymers

[CP, PC, PAA, polyacrylates, poly(methylvinylether-

co-methacrylic acid), poly(2- hydroxyethyl

methacrylate), poly(acrylic acidco-thylhexylacrylate),

poly(methacrylate),

poly(alkylcyanoacrylate),poly(isohexylcyanoacrylate),

poly(isobutylcyanoacrylate), copolymer of acrylic acid

and PEG]

Others: polyoxyethylene, PVA, PVP, thiolated

polymers

Aqueous

solubility

Water-soluble CP, HEC, HPC (waterb38 8C), HPMC (cold water),

PAA,sodium CMC, sodium alginate

Water-

insoluble

Chitosan (soluble in dilute aqueous acids), EC, PC

Charge Cationic Aminodextran, chitosan, (DEAE)-dextran, TMC

Anionic Chitosan-EDTA, CP, CMC, pectin, PAA, PC, sodium

alginate, sodium CMC, xanthan gum

Non-ionic Hydroxyethyl starch, HPC, poly(ethylene oxide),

PVA,PVP, scleroglucan

Potential Covalent Cyanoacrylate

Hydrogen

bond

Acrylates [hydroxylated methacrylate,

poly(methacrylic acid)], CP, PC, PVA

Electrostatic

interaction

Chitosan (Gandhi et al., 2011)

Table 1.2: Mucoadhesive Polymers Used In The Oral Cavity



(b) Polymers controlling rate of release of drug from buccal mucoadhesive

patches

The polymers which are insoluble in saliva or water can be used as efficient matrix

systems through which rate of release of drug can be controlled as desired. Examples

for this category include ethylcellulose and butyl rubber. Water-soluble polymers can

be used for controlling rate of release in which, rate of polymer dissolution will be

release rate determining step (Veillard et al., 1987).

(c) Polymers used to prepare backing membrane

The polymer whose solution can be casted into thin poreless uniform water

impermeable film can be used to prepare backing membrane of patches. It should

have good flexibility and high tensile strength and low water permeation. They should

be stable on long storage maintaining there initial physical properties. The backing

membrane can be of two types:

• A polymer solution casted into thin film. It is biodegradable in nature.

• A polyester laminated paper with polyethylene. It is not biodegradable.

The main function of backing membrane is to provide unidirectional drug flow to

buccal mucosa. It prevents the drug to be dissolved in saliva and hence swallowed

avoiding the contact between drug and saliva. The material used for the backing

membrane must be inert and impermeable to drugs and penetration enhancers. The

thickness of the backing membrane must be thin and should be around 75-100

microns. The most commonly used backing materials are polyester laminated paper

with polyethylene. Other examples include cellophane, multiphor sheet and

polyglassine paper.

(d) Plasticizer

These are the materials used to achieve softness and flexibility of thin films of

polymer or blend of polymers. Examples of common plasticizers used are glycerol,

propylene glycol, PEG 200, PEG 400, castor oil etc. Usually the percentage of

polymer falls in the range of 10-50% of total polymer weight. The plasticizers help in

release of the drug substance from the polymer base as well as act as penetration

enhancers. The choice of the plasticizer depends upon the ability of plasticizer

material to solvate the polymer and alters the polymer – polymer interactions. When

used in correct proportion to the polymer, these materials impart flexibility by

relieving the molecular rigidity (Jain et al., 1997).



1.10. Mucoadhesion/ Bioadhesion: Bioadhesion is an interfacial phenomenon in

which, two materials, at least one of which is biological, are held together by

means of interfacial forces. The attachment could be between an artificial material

and biological substrate, such as the adhesion between polymer and/or copolymer

and a biological membrane. In the case of polymer attached to the mucin layer of

mucosal tissue, the term “mucoadhesion” is employed.

1.10.1. Theories of Bioadhesion/ Mucoadhesion:

Mucoadhesion is proposed to occur in three stages. Initially, an intimate contact must

form between the mucoadhesive and mucus (i.e., they must “wet” each other) then the

mucus/ mucoadhesive macromolecules interpenetrate and finally the molecules

interact with each other by secondary non-covalent bonds. The bonding occurs chiefly

through both physical and chemical interactions. Physical or mechanical bonds result

from entanglement of the adhesive material and the extended mucus chains.

Secondary chemical bonds may be due to electrostatic interactions, hydrophonic

interactions, hydrogen bonding and dispersion forces. Covalent bonding, such as

occurs with cyanoacrylates, is also possible for mucoadhesion but is not yet common

in pharmaceutical systems. Several theories of bioadhesion have been proposed to

explain fundamental mechanism(s) of attachment. In a particular system one or more

theories can equally well explain or contribute to the formation of bioadhesive bonds

various theories propounded to explain mucoadhesion/ bioadhesion are (Lee et al.,

2000):

A. Wetting Theory

This theory best describes the adhesion of liquid or paste to a biological surface. The

work of adhesion can be expressed in terms of surface and interfacial tension (γ)

being defined as the energy per cm² released when an interface is formed. Work of

adhesion is given by:

Wa = γA + γb - γB

Where the subscript A and B refer to the biological membrane and the bioadhesive

formulation respectively, the work of cohesion is given by:

We = 2γA = 2γB

For a bioadhesive material B spreading on a biological substrate A the spreading

coefficient is given by:

SB/A = γA – (γB + γAB)



SB/A should be positive for a bioadhesive material to adhere to a biological membrane.

For a bioadhesive liquid B adhering to a biological membrane A the contact angle is

given by:

Cos ɸ - (γA - γAB / γB)

B. Diffusion Theory

According to this theory the polymer chains and the mucus co-mingle to a sufficient

depth to create a semi-permanent adhesive bond. The polymer chains penetrate the

mucus; the exact depth to which it penetrates to achieve sufficient mucoadhesion

depends on diffusion coefficient, time of contact, and other experimental variables.

The diffusion coefficient depends on molecular weight and decreases rapidly as the

cross-linking density increases. The molecular weight, chain flexibility, expanded

nature of both the mucoadhesive and substrates as well as similarity in chemicals

structure are required for good mucoadhesion. The penetration depth is estimated as-

L = (tDp)1/2

Where L is the penetration depth, t is the time of contact and Dp is the diffusion

coefficient.

C. Electronic theory

According to this theory electron transfer occurs on contact of adhesive polymer and

the mucus glycoprotein network because of difference in their electronic structure.

This results in the formation of electrical double layer at the interface. Adhesion

occurs due to attractive forces across the double layer.

D. Fracture Theory:

This theory analyses the force required to separate two surfaces after adhesion. The

maximum tensile stress produced during detachment of polymer and mucus

membrane can be calculated as-

Sm = Fm / A

Where Sm is the tensile stress, Fm & A are the maximum force of detachment and

surface area involve in the adhesive interaction respectively.

E. Adsorption Theory

According to this theory after an initial contact of two surfaces the material will

adhere because of surface forces acting between the atoms in the two surfaces. Weak

interaction of Vander Wall type plays an important role. However, if adsorption is due

to chemical bonding i.e., chemisorption, then ionic, covalent and metallic bonds play

an important role at the interface. From a drug delivery point of view the mechanism



of mucoadhesion appears best explained by a combination of diffusion and electronic

theory, although other mechanisms may simultaneously be operative at minor level. It

may also be more appropriate to restrict the term “mucoadhesion” to describing the

adhesion of hydrated dosage forms to those mucus membranes having a substantial

mucus layer. The term “bioadhesion” or “mucosal adhesion” may be more suitable to

describe adhesion to the mucosal of the oral cavity.

1.11. Structure and Design of Buccal Dosage Form

Buccal Dosage form can be of two types (Mitra et al., 2002):

1. Matrix type: The buccal patch designed in a matrix configuration contains drug,

adhesive and additives mixed together.

2. Reservoir type: The buccal patch designed in a reservoir system contains a cavity

for the drug and additives separate from the adhesive. An impermeable backing is

applied to control the direction of drug delivery; to reduce patch deformation and

disintegration while in the mouth; and to prevent drug loss. Additionally, the patch

can be constructed to undergo minimal degradation in the mouth, or can be designed

to dissolve almost immediately.

1.12. LITERATURE SURVEY ON BUCCAL DRUG DELIVERY

Bioadhesive films of fentanyl were developed using PVP K30 and PVP K 90 as

polymers, for the delivery in buccal cavity. The in-vitro performance was done on pig

oesophagus. Films were evaluated for the permeation of drug across the mucosa and

effect of pH on it. Delivery of fentanyl was determined across full thickness mucosa

and across heat separated epithelium. The influence of film pH was also investigated

and it was found that fentanyl permeation increases with increasing pH (Jacques et al.,

2007). Eight formulations of mucoadhesive buccal patches of aceclofenac were

prepared, using gelatin, poly sodium CMC and poly vinyl alcohol by varying the

Backing Membrane

Drug + Mucoadhesive Matrix

------------------------------------------------

------------------------------------------------

Mucoadhesive Matrix



concentration of polymer. The evaluation was performed for weight variation, patch

thickness, entrapment efficiency, folding endurance, in-vitro drug release and stability

study. Formulation containing 6% aceclofenac, 4.5% gelatin, 5.5% poly sodium

CMC, 2.5% poly vinyl alcohol and distilled water up to 100%, release the drug 88.4%

in 8 hours (Baviskar et al., 2009). Mucoadhesive buccal tablets of Naltrexone HCl

were developed HCl by direct compression method using poly-octylcyanocrylate as

matrix. Franz diffusion cell was used for ex-vivo permeation study across porcine

buccal mucosa 800 µm; data was compared with in-vitro data previously obtained by

reconstituted human oral epithelium 100 µm in thickness. Release pattern was

Higuchian and there was no any sign of flogosis when evaluated histopathologically

(Giannola et al., 2007). Solvent casting technique was used for the preparation of

buccoadhesive delivery system of isosorbide. Carbopol 934P, PVP as mucoadhesive

polymers and propylene glycol, diethyl phthalate as plasticizers were used. Physical

characters, bioadhesive performance, and other parameters were evaluated. In the

carbopol films containing ratio of Eudragid RL100 and PVP in proportion of 1:2 &

2:1, respectively & both the plasticizers release rate was higher. The kinetics was zero

order and mechanism was diffusion controlled (Doijad et al., 2006). For the systemic

delivery of propranolol hydrochloride buccoadhesive films were prepared using

carbopol 934P, NaCMC and polycarbophil. The ex-vivo mucoadhesive study showed

that there was a correlation between concentration of polymer and mucoadhesivity.

The in-vivo study was carried out on oral mucosa of rabbit by inducing tachycardia

with the help of isoprenaline. The results of in-vivo study showed a correlation with

in-vitro study. Release pattern was zero order kinetics and the system was successful

to avoiding the first pass metabolism of the drug (Pandit et al., 2001). Mucoadhesive

microspheres of metoprolol tartarate were prepared using HPMC, Carbopol and

polycarbophil by ionic gelation technique. Rotating cylindrical method was used for

mucoadhesive strength studies. For mucoadhesive microspheres HPMC had greater

mucoadhesive properties than carbopol and polycarbophil. With the help of falling

film technique in vitro mucoadhesive strength was determined and compared with ex

vivo studies (Belgamwar et al., 2009). Mucoadhesive bilayered buccal tablets of

Atorvastatin calcium were developed using Carbopol 934P, Sodium CMC,

Hydroxyethyl cellulose and Sodium alginate along with ethyl cellulose as an

impermeable backing layer by direct compression method. In the buccal cavity no any

irritation was observed because the surface pH of all tablets was close to neutral pH



(John et al., 2010). Principles of mucoadhesive drug delivery systems based on

adhesion to biological surfaces that are covered by mucus were studied. The

mucoadhesive drug delivery systems is one of the most important novel drug delivery

systems with its various advantages and it has a lot of potential in formulating dosage

forms for various chronic diseases (Tangri et al., 2011). A carvedilol-Methyl-β-

cyclodextrin complex was prepared by kneading method and characterized by Fourier

Transformation Infrared spectroscopy, Differential Scanning Calorimetry and powder

X-Ray Diffractometry studies. The complex was incorporated into buccal tablet and

evaluated for drug release, mucoadhesive strength and ex-vivo permeability. The

bioavailability of buccal tablet was improved after incorporation of complexed

carvedilol (Hirlekar et al., 2009). Direct compression method was used for the

preparation of mucoadhesive buccal tablet of Domperidone using Carbopol 934P,

Methocel K4M, Methocel E15LV and Chitosan. Mucoadhesive performance and in-

vitro drug release was best in the tablet containing chitosan and Methocel K4M in

ratio of 1:1. The release pattern from the tablet was Hixson Crowel release kinetics

(Ganesh et al., 2008). Plain and medicated mucoadhesive patches of cetylpyridinium

chloride (CPC) were prepared using polyvinyl alcohol (PVA), hydroxyethyl cellulose

(HEC) and chitosan. Both plain and medicated patches were evaluated but when the

CPC was added in the formulation the radial swelling was increased (Ismail et al.,

2003). With the help of low dextrose equivalent as film forming material oral fast-

dissolving films of maltodextrins were developed. This basic formulation was adapted

to the main production technologies, casting and solvent evaporation or hot-melt

extrusion, by adding sorbitan monoleate or cellulose microcrystalline (MCC),

respectively. MCC decreased the film ductility and significantly affected the film

disintegration time both in vitro and in vivo (Cilurzo et al., 2008). A simple; isocratic

and sensitive high-performance liquid chromatographic (HPLC) method was

developed and validated for the simultaneous analysis of marker compounds for the

atenolol and lidocaine pathways during permeation enhancement studies across the

buccal mucosa. After pre-treatment with glycodeoxycholate-Na an increase in the

permeation of atenolol was observed by the application of this method, while the

permeation of lidocaine did not change significantly (Jasti et al., 2008). By an

investigation the ability of galantamine to permeate through the buccal epithelium

using two permeation models was done. Firstly, in vitro permeation experiments were

carried out using reconstituted human oral non-keratinised epithelium. Then results



were validated by ex vivo experiments using porcine buccal mucosa as membrane and

Franz type diffusion cells as permeation model, the buccal mucosa does not block

diffusion of galantamine (Caro et al., 2008). A complex omeprazole with

cyclodextrins in the absence and in the presence of an alkali, L-arginine agent was

prepared to check the effect of cyclodextrins on the buccal permeation. . In vitro

transbuccal permeation of omeprazole non-complexed and complexed with b-

cyclodextrin and in presence of L-arginine was examined using freshly obtained

porcine buccal mucosa, and in the complexed form the drug permeation was more

(Veiga et al., 2009). For the measurement of mucoadhesion films of pectin and

chitosan were formed. Mucoadhesive controlled release tablets of lercanidipine

hydrochloride were developed by direct compression method using polyethylene

oxide and HPMC individually or in combinations. The tablets containing only

polyethylene oxide shows good mucoadhesion and depends on the concentration of

polymer (Charde et al., 2008). Chitosan and pectin interpolymer complexes were used

for the preparation of bioadhesive patches of carvedilol. Optimized patches

demonstrated good in vitro & in vivo results, and significantly improve the

bioavailability of drug (Kaur et al., 2011). A number of mucoadhesive polymers like

thiolated polymers were used for the preparation of buccal drug delivery system.

Discussion was also made about the anatomy of oral mucosa and mechanism of drug

permeation, this route shows advantages over the others route for the delivery of a

variety of drugs (Khairnar et al., 2010). Sustained release mucoadhesive tablets of

flurbiprofen were prepared using chitosan as primary polymer and HPMC and sodium

CMC as secondary polymer, and characterized the prepared tablet for weight

variation, thickness, hardness, swelling index and in vitro drug release. Both the

polymers showed synergistic effect on in vitro drug release (Darwish et al., 2009).

Buccal patches of propranolol hydrochloride were prepared by solvent casting method

using a natural bioadhesive polymer chitosan. For the enhancement of drug release

different concentration of PVP K-30 also used (Patel et al., 2006). Investigation was

made on the benefit of thiolated polymers by preparing buccal tablets and compared

the disintegration time unmodified polymer and conjugated polymer. A complex of L-

Cysteine by covalently attachment with polycarbophil mediated by carbodibide was

formed for the preparation of tablet. The tablets based on thiolated polycarbophil

remained attached on mucosa (Schnurch et al., 2003). Based on poly ethyleneoxide

(PEO) as bioadhesive sustained release platform and hydroxyprolpyl-β –cyclodextrin



HPβCD as modulator of drug release tablet dosage form of the poorly soluble drugs

carvedilol (CAR) was prepared. The drug permeation through PEO was higher than

the HPβCD tablets (Rotonda et al., 2006). Bi-laminated films & bilayered tablets were

prepared by solvent casting method and direct compression method using chitosan

and ethyl cellulose. Both the prepared films and tablets show a sustained release of

drug (Lopez et al., 1998). Some authors were discussed about the buccal and oral

administration of drugs which undergoes severe first pass metabolism through

hydrogel. They claimed that hydrogel was an appropriate material for the buccal

delivery system because of its mucoadhesiveness and sustained release properties

(Machida et al., 1993). Transport of fluorescein isothiocyanate labelled dextran of

different molecular weights as model compounds for peptides and proteins through

buccal mucosa was characterized. Investigation was made on the penetration of these

dextrans through buccal mucosa by measuring transbuccal fluxes and by analysing the

distribution of the fluorescent probe in the epithelium (Jungingeret al., 1999). In the

buccal films prepared by different polymers like carbopol, sodium alginate and

HPMC, the sodium alginate films exhibited greater bioadhesion and showed higher

tensile strength and elasticity than carbopol films (Sklason et al., 2009). With the help

of drug/cyclodextrin inclusion buccal bioadhesive films of atenolol were prepared.

Freeze drying method was used for the preparation of complex in solid state. For the

preparation of buccal drug delivery system complexes were incorporated into films

(Jug et al., 2009). Nanoparticles were developed based on mucoadhesive system

(diskettes), an alternative novel transmucosal (buccal) delivery of Fluoxetine

hydrochloride by emulsion solvent evaporation method. The optimized formulation

using 32 factorial designs indicated it is possible to develop a novel mucoadhesive

system for buccal route that could be effectively maintain the drug release (Sapre et

al., 2009). Investigation was made on the influence of different formulation

parameters on the rheological and functional properties of emulgels, intended for the

buccal administration of flurbiprofen. Analysis on the emulgel in term of size &

morphology and also for in vitro release studies was performed, and the emulgels

were able to remain on buccal mucosa for an average period of 1 h (Perioli et al.,

2008). Monolayered multipolymeric films comprising of Propranolol HCl were

prepared using Eudragit and Chitosan, by emulsification and casted by a new

approach using a silicone-molded tray with individual wells. The study confirmed the

potential of monolayered multipolymeric films as a promising candidate for buccal



delivery of propranolol (Govender et al., 2008). For the controlled release of

piroxicam buccoadhesive controlled release tablets were prepared, and evaluated the

tablets for their dissolution, swelling and mucoadhesive properties, the differences in

release rates of piroxicam from the tablets could be attributed to the presence of the

polymers and to cyclodextrin complexation (Jug et al., 2004). For the delivery

through buccal route the fast dissolving film of salbutamol were prepared by solvent

evaporation method using polyvinyl alcohol as polymers and glycerol as plasticizer.

The concentration of polymer and plasticizer showed effect on mechanical properties

and % drug release (Mashru et al., 2005). Two water soluble drugs diltiazem

hydrochloride and metclopramide were used for the preparation of buccal

mucoadhesive tablets. Effect of drug and dose on the mucoadhesive properties and in-

vitro drug release was determined. An observation was performed on the effect of

ageing, for 6 months at 40oC and 75% RH, there was no effect on mucoadhesive

performance (Boraie et al., 2004). Relative bioavailability of Fentanyl effervescent

buccal tablets (FEBT) with that of oral transmucosal fentanyl citrate (OTFC) was

compared, the total systemic exposure was statistically similar between FEBT and

OTFC (Darwish et al., 2006). Buccal administration of ibuprofen was done with the

help of mucoadhesive patches using PVP as film forming polymer and NaCMC as

mucoadhesive polymer. In-vitro results, revealed that the diffusion process was the

main drug release studies mechanism and the Higuchi’s model provided the best fit

(Perioli et al., 2004). The effect of formulation variables on the buccal absorption of

the drug was determined by preparing the buccal tablets of nifedipine. Natural flax

seed polymer was incorporated, and compared the bioavailability of drug per oral

administration with buccal administration, the presence of natural flax seed polymer

enhance of bioavailability due to increase in mucoadhesion (Vijayaraghavan et al.,

2004). Mucoadhesive buccal patches of miconazole nitrate were prepared using

NaCMC, chitosan, PVA, HEC and HPMC. The bioadhesion, swelling index, surface

pH and in-vitro drug release was determined. The patches exhibited sustained release

over mare than 5 hours (Ismail et al., 2003). Buccal patches of metoprolol tartrate

were developed by using Eudragit NE40D, NaCMC and carbopol. The bioadhesion as

well as the drug release was determined, on addition of hydrophilic polymers the drug

release as well as the enhanced the bioadhesiveness was observed (Yuen et al., 1999).

Bilayered buccoadhesive tablets of atenolol were formulated by direct compression

method, using different mucoadhesive polymers such as carbopol, sodium alginate



and HPMC, to prepared tablets were evaluated for the different physicochemical and

bioadhesive parameters. The preparation containing combination of carbopol and

HPMC showed better bioadhesive strength (Pannier et al., 2011). Buccal films of

losartan were prepared using HPMC, EC and Eudragit RS 100, and evaluated for

mucoadhesive forces, thickness, weight, drug contents, and surface pH. The

mucoadhesive force, swelling index, tensile strength and % elongation was higher in

formulation containing HPMC (Koland et al., 2010). The advantages of buccal films

over the dosage forms were explained. The films have improved patient compliance

due to their small size and reduce thickness, compared to lozenges and tablets. The

suitable method for the preparation of buccal films was solvent casting (McConville

et al., 2011). HPMC E-15 and NaCMC alone or in combinations were used for the

preparation of buccal patches of lidocaine hydrochloride by solvent casting technique.

The prepared patches were evaluated for weight, thickness, surface pH, in-vitro drug

release and in-vitro permeation. The optimized patch showed more than 80% drug

release in 3 hrs (Parmar et al., 2011). A discussion was made about the mucoadhesion

and buccal route of administration. Within the oral mucosal cavity, the buccal region

offers an adorable route of administration for systemic drug delivery. The degree of

mucoadhesion was calculated, the bonding was influenced by various polymer-based

properties (Patel et al., 2011). It was found that major hindrance for the absorption of

a drug taken orally was extensive first pass metabolism and this problem may be

overcome by buccal transmucosal delivery which helps to bypass first- pass

metabolism by allowing direct access to the systemic circulation through the internal

jugular vein (Puratchikody et al., 2011). Fast dissolving buccal films, which dissolve

or disintegrate instantly on the patient buccal mucosa which improved bioavailability

with reducing dosing frequency to mouth plasma peak levels, and minimize

adverse/side effects and also make it cost effective were developed (Mahajan et al.,

2011). Buccal film of Rasagiline for intraoral delivery was prepared using carbopol P

940 and sodium alginate as mucoadhesive polymers. The prepared films were

evaluated for surface pH, percentage moisture absorption, Percentage moisture loss,

folding endurance and content uniformity. Carbopol has more pronounced effect than

sodium alginate on the mucoadhesive strength (Bukka et al., 2010).



1.13. OBJECTIVE OF THE WORK

Present research aims at prepare and evaluate the mucoadhesive buccal device of

cardiovascular drugs (Metoprolol succinate and Carvedilol) using Chitosan,

NaCMC and PVA as polymer, to improve the bioavailability.

The main objectives of this work to:

� Perform preformulation studies of metoprolol succinate and carvedilol.

� Prepare the mucoadhesive buccal patches of metoprolol succinate and

carvedilol using chitosan, NaCMC and PVA.

� Evaluate the prepared buccal patches for

o Content uniformity,

o Patch thickness,

o Weight variation,

o % swelling,

o Folding endurance,

o Residence time,

o Mechanical properties,

o Bioadhesion study,

o In vitro permeation

o Release study,

o Pharmacodynamic study,

o Pharmacokinetic study,

o Effects of ageing on patches.



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