INTRODUCTION:

Buccal drug Delivery System:

Amongst the various routes of drug delivery, oral route is perhaps the most preferred to the patient and the clinician alike. However, peroral administration of drugs has disadvantages such as hepatic first pass metabolism and enzymatic degradation within the GI tract, that prohibit oral administration of certain classes of drugs especially peptides and proteins. Consequently, other absorptive mucosa is considered as potential sites for drug administration. Transmucosal routes of drug delivery offer distinct advantages over peroral administration for systemic drug delivery. These advantages include possible bypass of first pass effect, avoidance of Presystemic elimination within the GI tract, and, depending on the particular drug, a better enzymatic flora for drug absorption.

Received on 27.01.2015 Modified on 10.02.2015

Research J. Pharm. and Tech. 8(3): Mar., 2015; Page 227-234

DOI: 10.5958/0974-360X.2015.00026.8

The nasal cavity as a site for systemic drug delivery has been investigated by many research groups and the route has already reached commercial status with several drugs including LHRH and calcitonin. However, the potential irritation and the irreversible damage to the ciliary action of the nasal cavity from chronic application of nasal dosage forms, as well as the large intra- and inter-subject variability in mucus secretion in the nasal mucosa, could significantly affect drug absorption from this site. Even though the rectal, vaginal, and ocular mucosa all offer certain advantages, the poor patient acceptability associated with these sites renders them reserved for local applications rather than systemic drug administration.

The oral cavity, on the other hand, is highly acceptable by patients, the mucosa is relatively permeable with a rich blood supply, it is robust and shows short recovery times after stress or damage, and the virtual lack of Langerhans cells makes the oral mucosa tolerant to potential allergens. Furthermore, oral transmucosal drug delivery bypasses first pass effect and avoids pre-systemic elimination in the GI tract. These factors make the oral mucosal cavity a very attractive and feasible site for systemic drug delivery. Within the oral mucosal cavity, delivery of drugs is classified into three categories: (i) sublingual delivery, which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth, (ii) Buccal delivery, which is drug administration through the mucosal membranes lining the cheeks (buccal mucosa), and (iii) local delivery, which is drug delivery into the oral cavity.^[1]

What is Bioadhesion?

Bioadhesion is the state in which two materials, (at least one of which is biological in nature), are held together for an extended period of time by interfacial forces. The term bioadhesion implies attachment of drug-carrier system to specific biological location. This biological surface can be epithelial tissue or the mucous coat on the surface of tissue.

If adhesive attachment is to mucous coat then phenomenon is referred as mucoadhesion.^[1]

Mechanism of Adhesion:

The drug is adhered to buccal mucosa in following manner:

Wetting and swelling of polymer to permit intimate contact with biological tissue

(1).Inter-penetration of bioadhesive polymer (BP) chains and entanglement of polymer and mucin chains.

(2).Formation of chemical bonds between the entangled chains.^[1]

I. Overview of the Oral Mucosa^[1]

Figure 1: Structure of oral cavity

(A). Structure: The oral mucosa is composed of an outermost layer of stratified squamous epithelium (Figure 2). Below this lies a basement membrane, a lamina propria followed by the submucosa as the innermost layer. The epithelium is similar to stratified squamous epithelia found in the rest of the body in that it has a mitotically active basal cell layer, advancing through a number of differentiating intermediate layers to the superficial layers, where cells are shed from the surface of the epithelium. The epithelium of the buccal mucosa is about 40-50 cell layers thick, while that of the sublingual epithelium contains somewhat fewer. The epithelial cells increase in size and become flatter as they travel from the basal layers to the superficial layers. The turnover time for the buccal epithelium has been estimated at 5-6 days and this is probably representative of the oral mucosa as a whole. The oral mucosal thickness varies depending on the site: the buccal mucosa measures at 500-800 µm, while the mucosal thickness of the hard and soft palates, the floor of the mouth, the ventral tongue, and the Gingivae measure at about 100-200 µm. The composition of the epithelium also varies depending on the site in the oral cavity. The mucosae of areas subject to mechanical stress (the gingivae and hard palate) are keratinized similar to the epidermis. The mucosa of the soft palate, the sublingual, and the buccal regions, however, are not keratinized. The keratinized epithelia contain neutral lipids like ceramides and acylceramides which have been associated with the barrier function. These epithelia are relatively impermeable to water. In contrast, non-keratinized epithelia, such as the floor of the mouth and the buccal epithelia, do not contain acylceramides and only have small amounts of ceramide. They also contain small amounts of neutral but polar lipids, mainly cholesterol sulfate and glucosyl ceramides. These epithelia have been found to be considerably more permeable to water than keratinized epithelia.^[2]

Epithelium

Lamina Propiria

Submucosa

Figure 2: Structure of Oral Mucosa ^[2]

(B). Permeability: The oral mucosa in general is somewhat leaky epithelia intermediate between that of the epidermis and intestinal mucosa. It is estimated that the permeability of the buccal mucosa is 4-4000 times greater than that of the skin. As indicative by the wide range in this reported value, there are considerable differences in permeability between different regions of the oral cavity because of the diverse structures and functions of the different oral mucosa. In general, the permeabilities of the oral mucosa decrease in the order of sublingual greater than buccal, and buccal greater than palatal. This rank order is based on the relative thickness and degree of keratinization of these tissues, with the sublingual mucosa being relatively thin and non-keratinized, the buccal thicker and non-keratinized, and the palatal intermediate in thickness but keratinized.

It is currently believed that the permeability barrier in the oral mucosa is a result of intercellular material derived from the so-called ‘membrane coating granules’ (MCG). When cells go through differentiation, MCGs start forming and at the apical cell surfaces they fuse with the plasma membrane and their contents are discharged into the intercellular spaces at the upper one third of the epithelium. This barrier exists in the outermost 200µm of the superficial layer. Permeation studies have been performed using a number of very large molecular weight tracers, such as horseradish peroxidase and lanthanum nitrate. When applied to the outer surface of the epithelium, these tracers penetrate only through outermost layer or two of cells. When applied to the submucosal surface, they permeate up to, but not into, the outermost cell layers of the epithelium.

According to these results, it seems apparent that flattened surface cell layers present the main barrier to permeation, while the more isodiametric cell layers are relatively permeable. In both keratinized and non-keratinized epithelia, the limit of penetration coincided with the level where the MCGs could be seen adjacent to the superficial plasma membranes of the epithelial cells. Since the same result was obtained in both keratinized and non-keratinized epithelia, keratinization by itself is not expected to play a significant role in the barrier function. The components of the MCGs in keratinized and non-keratinized epithelia are different, however. The MCGs of keratinized epithelium are composed of lamellar lipid stacks, whereas the non-keratinized epithelium contains MCGs that are non-lamellar. The MCG lipids of keratinized epithelia include sphingomyelin, glucosylceramides, ceramides, and other nonpolar lipids, however for non-keratinized epithelia, the major MCG lipid components are cholesterol esters, cholesterol, and glycosphingolipids. Aside from the MCGs, the basement membrane may present some resistance to permeation as well, however the outer epithelium is still considered to be the rate limiting step to mucosal penetration. The structure of the basement membrane is not dense enough to exclude even relatively large molecules.^[2]

(C). Environment: The cells of the oral epithelia are surrounded by an intercellular ground substance, mucus, the principle components of which are complexes made up of proteins and carbohydrates. These complexes may be free of association or some maybe attached to certain regions on the cell surfaces. This matrix may actually play a role in cell-cell adhesion, as well as acting as a lubricant, allowing cells to move relative to one another. Along the same lines, the mucus is also believed to play a role in bioadhesion of mucoadhesive drug delivery systems. In stratified squamous epithelia found elsewhere in the body, mucus is synthesized by specialized mucus secreting cells like the goblet cells, however in the oral mucosa, mucus is secreted by the major and minor salivary glands as part of saliva. Up to 70% of the total mucin found in saliva is contributed by the minor salivary glands. At physiological pH the mucus network carries a negative charge (due to the Sialic acid and sulphate residues) which may play a role in mucoadhesion. At this pH mucus can form a strongly cohesive gel structure that will bind to the epithelial cell surface as a gelatinous layer. Another feature of the environment of the oral cavity is the presence of saliva produced by the salivary glands. Saliva is the protective fluid for all tissues of the oral cavity.

It protects the soft tissues from abrasion by rough materials and from chemicals. It allows for the continuous mineralisation of the tooth enamel after eruption and helps in remineralisation of the enamel in the early stages of dental caries. Saliva is an aqueous fluid with 1% organic and inorganic materials. The major determinant of the salivary composition is the flow rate which in turn depends upon three factors: the time of day, the type of stimulus, and the degree of stimulation. The salivary pH ranges from 5.5 to 7 depending on the flow rate. At high flow rates, the sodium and bicarbonate concentrations increase leading to an increase in the pH. The daily salivary volume is between 0.5 to 2 liters and it is this amount of fluid that is available to hydrate oral mucosal dosage forms. A main reason behind the selection of hydrophilic polymeric matrices as vehicles for oral transmucosal drug delivery systems is this water rich environment of the oral cavity.^[2]

II. Buccal Routes of Drug Absorption:

There are two permeation pathways for passive drug transport across the oral mucosa: paracellular and transcellular routes. Permeants can use these two routes simultaneously, but one route is usually preferred over the other depending on the physicochemical properties of the diffusant. Since the intercellular spaces and cytoplasm are hydrophilic in character, lipophilic compounds would have low solubilities in this environment. The cell membrane, however, is rather lipophilic in nature and hydrophilic solutes will have difficulty permeating through the cell membrane due to a low partition coefficient. Therefore, the intercellular spaces pose as the major barrier to permeation of lipophilic compounds and the cell membrane acts as the major transport barrier for hydrophilic compounds. Since the oral epithelium is stratified, solute permeation may involve a combination of these two routes. The route that predominates, however, is generally the one that provides the least amount of hindrance to passage.^[2]

III. Buccal Mucosa as a Site for Drug Delivery:

There are three different categories of drug delivery within the oral cavity (i.e., sublingual, buccal, and local drug delivery). Selecting one over another is mainly based on anatomical and permeability differences that exist among the various oral mucosal sites. The sublingual mucosa is relatively permeable, giving rapid absorption and acceptable bioavailabilities of many drugs, and is convenient, accessible, and generally well accepted. The sublingual route is by far the most widely studied of these routes. Sublingual dosage forms are of two different designs, those composed of rapidly disintegrating tablets, and those consisting of soft gelatin capsules filled with liquid drug. Such systems create a very high drug concentration in the sublingual region before they are systemically absorbed across the mucosa. The buccal mucosa is considerably less permeable than the sublingual area, and is generally not able to provide the rapid absorption and good bioavailabilities seen with sublingual administration. Local delivery to tissues of the oral cavity has a number of applications, including the treatment of toothaches, periodontal disease, bacterial and fungal infections, aphthous and dental stomatitis, and in facilitating tooth movement with prostaglandins.

Even though the sublingual mucosa is relatively more permeable than the buccal mucosa, it is not suitable for an oral transmucosal delivery system. The sublingual region lacks an expanse of smooth muscle or immobile mucosa and is constantly washed by a considerable amount of saliva making it difficult for device placement. Because of the high permeability and the rich blood supply, the sublingual route is capable of producing a rapid onset of action making it appropriate for drugs with short delivery period requirements with infrequent dosing regimen. Due to two important differences between the sublingual mucosa and the buccal mucosa, the latter is a more preferred route for systemic transmucosal drug delivery. First difference being in the permeability characteristics of the region, where the buccal mucosa is less permeable and is thus not able to give a rapid onset of absorption. Second being that, the buccal mucosa has an expanse of smooth muscle and relatively immobile mucosa which makes it a more desirable region for retentive systems used for oral transmucosal drug delivery. Thus the buccal mucosa is more fitted for sustained delivery applications, delivery of less permeable molecules, and perhaps peptide drugs.Similar to any other mucosal membrane, the buccal mucosa as a site for drug delivery has limitations as well. One of the major disadvantages associated with buccal drug delivery is the low flux which results in low drug bioavailibility.^[2]

Table: 1 Route of Delivery and Properties^[1]

Route of delivery	Property	Permeability
Sublingual	Relatively thin and non keratinized	High
Buccal	Thicker and non keratinized	Lower than sublingual
Palatal	Intermediate in thickness but keratinized	Lower than buccal

IV. Secretion of Salivary glands: The oral cavity is marked by presence of saliva produced by salivary glands and mucus which is secreted by major and minor salivary glands as part of saliva.

Role of Saliva:

• Protective fluid for all tissues of oral cavity.

• Continuous mineralization / demineralization of tooth enamel.

• To hydrate oral mucosal dosage forms.

Role of Mucus:

• Made up of proteins and carbohydrates

• Cell-cell adhesion

• Lubrication

• Bioadhesion of mucoadhesive drug delivery systems^[3]

V. Pathways of Drug Absorption from buccal mucosa:

Two major routes are involved: (1) Transcellular (intracellular) and

(2) Paracellular (intercellular).

The transcellular route may involve permeation across the apical cell membrane, intracellular space and basolateral membrane either by passive transport or by active transport. The transcellular permeability of drug is a complex function of various physicochemical properties including size, lipophilicity, hydrogen bond potential, charge and conformation. Transportation through aqueous pores in cell membranes of epithelium is also possible for substances with low molar volume (80cm³/mol).

The Paracellular route, available to substances with a wide range of molar volumes, is the intercellular route (paracellular route).within the intercellular space, hydrophobic molecules pass through the lipidic bilayer, while the hydrophilic molecules pass through the narrow aqueous regions adjacent to the polar head groups of the lipids.^[3]

VI. Structure and Design of Buccal Dosage Form: Buccal Dosage form can be of;

1. Matrix type: The buccal tablet designed in a matrix configuration containing drug, adhesive, and additives mixed together.

2. Reservoir type: The buccal tablet 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.^[3]

VII. Factors affecting drug delivery via buccal route:

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.^[3]

1. Membrane Factors:

These involve 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.^[3]

2. Environmental Factors:

A. Saliva: Thin film of saliva coats lining of buccal mucosa throughout and is called salivary pellicle or film. The thickness of salivary film is 0.07 to 0.10 mm. Thickness, composition and movement of this film affects the rate of buccal absorption.

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.

C. Movement of buccal 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 to withstand tissue movements during talking and if possible during eating food or swallowing.^[3]

3. Formulation related factors:

A. Molecular size: Smaller molecules (75 100 DA) generally exhibit rapid transport across the mucosa, with permeability decreasing as molecular size increases. For hydrophilic macromolecules such as peptides, absorption enhancers have been used to successfully alter the permeability of buccal epithelium, making this route more suitable for delivery of larger molecules.^[3]

B. Partition coefficient: partition coefficient is a useful tool to determine the absorption potential of a drug. In general, increasing a drug’s polarity by ionization or hydroxyl, carboxyl, or amino groups, will increase the water solubility of any particular drug and cause a decrease in lipid water partition coefficient. Conversely, decreasing the polarity of a drug (e.g. adding methyl or methylene groups) results in an increased partition coefficient and decreased water solubility.^[3]

C. pH: partition coefficient is also affected by pH at the site of drug absorption. With increasing pH, the partition co-efficient of acidic drugs decrease, while that of basic drugs increase. Partition coefficient is also an important indicator of drug storage in fat deposits. Obese individuals can store large amounts of lipid soluble drug in fat stores. These drugs are dissolved in lipid and are a reservoir of slow release from these fat deposits.^[3]

D. pKa: Ionization of a drug is directly related to both its pKa and pH at the mucosal surface. Only the nonionized form of many weak acids and weak bases exhibit appreciable lipid solubility, and thus the ability to cross lipoidal membranes. As a result, maximal absorption of these compounds has been shown to occur at the pH at which they are unionized, with absorbability diminishing as ionization increases.^[3]

VIII. Attractiveness of Buccoadhesive drug delivery system^[3-9]:

• Permits the localization of delivery system.

• Patients are well adapted to oral administration of drugs.

• Patient acceptance and compliance is good compared to other drug delivery system.

• Ability to easily recover after local treatment is prominent.

• Allows a wide range of formulations that can be used e.g. buccoadhesive patches and ointments.

Ø Mechanism of Buccoadhesion:

Buccoadhesion is the attachment of the drug along with a suitable carrier to the mucous membrane. Buccoadhesion is a complex phenomenon which involves wetting, adsorption and interpenetration of polymer chains. Buccoadhesion has the following mechanism-(1).Intimate contact between a bioadhesive and a membrane (wetting or swelling phenomenon) (2).Penetration of the bioadhesive into the tissue or into the surface of the mucous membrane (interpenetration).^[4,12]

Ø Advantages of buccoadhesive drug delivery system:

(I) Drug administration via the buccoadhesive drug delivery offers several advantages such as:

• Drug is easily administered and extinction of therapy in emergency can be facilitated. Drug release for prolonged period of time.

• Drug can be administered in unconscious and trauma patients.

• Drugs bypass first pass metabolism so increases bioavailability.

• Drugs that are unstable in acidic environment of stomach can be administered by buccal delivery.

• Drug absorption by passive diffusion.

• Flexibility in physical state, shape, size and surface.

• Maximized absorption rate due to close contact with absorbing membrane.

• Rapid onset of action.

• Formulation can be removed if therapy is required to be discontinued

• Large contact surface of the oral cavity contributes to rapid and extensive drug absorption.

• Extent of perfusion is more therefore quick and effective absorption.

• Nausea and vomiting are greatly avoided.

• In comparison to TDDS, mucosal surfaces do not have a stratum corneum. Thus, the major barrier layer to transdermal drug delivery is not a factor in transmucosal routes of administration. Hence transmucosal systems exhibit a faster initiation and decline of delivery than do transdermal patches.

• Transmucosal delivery occurs is less variable between patients, resulting in lower inter subject variability as compaired to transdermal patches. Excellent accessibility

• Presence of smooth muscle and relatively immobile mucosa, hence suitable for administration of retentive dosage forms. Low enzymatic activity.

• Suitability for drugs or excipients that mildly and reversibly damage or irritate the mucosa. Painless administration.

• Facility to include permeation enhancer/enzyme inhibitor or pH modifier in the formulation.

• Versatility in designing as multidirectional or unidirectional release systems for local or systemic actions.

• Thin film is more stable, durable and quick dissolving than other conventional dosage forms.

• Thin film enables to improve dosage accuracy relative to liquid formulations, since every strip is manufactured in such a way that it contains a precise amount of drug.

• Buccal films has the ability to dissolve rapidly without the need for water, which provides an alternate way to the patients to swallow and to patients who do not want suffering from nausea, such as those patients receiving chemotherapy. ^{[5,7,9,13,14]}

(II) Limitations of buccoadhesive drug delivery system:

There are some limitations of buccal drug delivery system such as-

• Drugs which are unstable at buccal pH cannot be administered.

• Drugs which cause allergic reactions, discoloration of teeth cannot be formulated.

• If formulation contains antimicrobial agents, which affects the natural microbes in the buccal cavity.

• Buccal membrane has low permeability, specifically when compared to the sublingualmembrane.

• Drugs which have a bitter taste or unpleasant taste or an obnoxious odour or irritate the mucosa cannot be administered by this route.

• Drug with small dose can only be administered.

• Drugs which are absorbed by passive diffusion can only be administered by this route.

• Eating and drinking may become restricted.

• For local action the rapid elimination of drugs due to the flushing action of saliva or theingestion of foods stuffs may lead to the requirement for frequent dosing.

• The non-uniform distribution of drugs within saliva on release from a solid or semisoliddelivery system could mean that some areas of the oral cavity may not receive effective levels.^[5,14,15]

Ø Methods to increase drug delivery via buccal route:

1. Absorption enhancers: Absorption enhancers have demonstrated their effectiveness in delivering high molecular weight compounds, such as peptides, that generally exhibit low buccal absorption rates. These may act by a number of mechanisms, such as increasing the fluidity of the cell membrane, extracting inters/intracellular lipids, altering cellular proteins or altering surface mucin. The most common absorption enhancers are azone, fatty acids, bile salts and surfactants such as sodium dodecyl sulfate. Solutions/gels of chitosan were also found to promote the transport of mannitol and fluorescent-labelled dextrans across a tissue culture model of the buccal epithelium while Glyceryl monooleates were reported to enhance peptide absorption by a co-transport mechanism.

2. Prodrugs: Delivering of opioid agonists and antagonists in bitter less prodrug forms and found that the drug exhibited low bioavailability as prodrug. Nalbuphine and naloxone bitter drugs when administered to dogs via the buccal mucosa, the caused excess salivation and swallowing. As a result, the drug exhibited low bioavailability. Administration of nalbuphine and naloxone in prodrug form caused no adverse effects, with bioavailability ranging from 35 to 50% showing marked improvement over the oral bioavailability of these compounds, which is generally 5% or less.

3. pH: The permeability of acyclovir at pH ranges of 3.3 to 8.8 and in the presence of the absorption enhancer, sodium glycocholate. The in-vitro permeability of acyclovir was found to be pH dependent with an increase in flux and permeability coefficient at both pH extremes (pH 3.3 and 8.8), as compared to the mid-range values (pH 4.1, 5.8 and 7.0).

4. Formulation Design: Several in-vitro studies have been conducted regarding on the type and amount of backing materials and the drug release profile and it showed that both are interrelated.

Ø Theories of Bioadhesion or Buccoadhesion:

The theories of polymer- polymer adhesion can be adapted to polymer-tissue adhesion or bioadhesion by recognizing that bioadhesion is different only because of the differing properties of the tissue as opposed to those of the polymer.

a) Electronic theory: According to this theory, electron transfer occurs upon contact of an adhesive polymer with a mucus glycoprotein network because of differences in their electronic structures. This results in the formation of an electrical double layer at the interface.^[5]

b) Absorption theory: According to this theory, after an initial contact between two Surfaces, the material adheres because of surface forces acting between the atoms in the two surfaces. There are two types of chemical bonds resulting from these forces. Primary chemical bonds are of covalent nature, which are undesirable in bioadhesion because their strength may result in permanent bonds. Secondary chemical bonds are having many different forces of attraction, including electrostatic forces, Vander Waal forces and hydrogen bonds.^[5]

c) Wetting theory: It is predominantly applicable to liquid bioadhesive systems and analyses adhesive and contact behavior in terms of the ability of a liquid or a paste to spread over a biological system.^[5]

d) Diffusion theory: According to this theory, the polymer chains and the mucusmix to a sufficient depth to create a semipermanent adhesive bond. The exact depth to which the polymer chains penetrate the mucus depends on the diffusion coefficient and the time of contact.^[5]

e) Fracture theory: this theory attempts to relate the difficulty of separating of two surfaces after addition.

G = (Eε/L) 1/2

Where, E is the Young’s constant; ε is the fracture energy; L is the critical crack length.^[5]

Ø Polymers used in buccal delivery systems ^[5,16]

Buccal adhesive polymers are the important component in the development of buccal delivery systems. These polymers enable retention of dosage form at the buccal mucosal surface and thereby provide intimate contact between the dosage form and the absorbing tissue.

Ideal characteristics of buccoadhesive polymer^[5]

The buccoadhesive polymers should possess following characteristics.

ØPolymer and its degradation products should be non-toxic, non-irritant and free from leachable impurities.

It should have good spread ability, wetting, swelling and solubility and biodegradability properties.

It should have biocompatible pH and should possess good visco-elastic properties.

It should be adhere quickly to buccal mucosa and should sufficient mechanical strength.

It should possess peel, tensile and shear strengths at the bioadhesive range.

It must be easily available and its cost should not be high.

It should show bioadhesive properties in both dry and liquid state.

It should demonstrate local enzyme inhibition and penetration enhancement properties.

It should have acceptable shelf life.

CONCLUSION:

Buccal drug delivery system is good for systemic drug delivery as it offers a rich blood supply and permeable mucosa. The area is well suited for the retentive device and appears to be acceptable to the patient. This route provides prolonged drug delivery, targeted therapy, and good bioavailability. It is a better delivery system for the protein and peptide drugs by using the mucoadhesive polymer property of inhibiting enzyme degradation.

REFERENCES:

1. Supriya Upadhyaya, Akanksha Bhatt, Ashutosh Badola. A Review: Different Buccal Formulations and Mucoadhessive Polymers as Enzyme Inhibitors. Journal of Advance Pharmaceutical Research and Bioscience.1(3); 2013: 79-85.

2. Amir H. Shojaei, University of Alberta, Faculty of Pharmacy and Pharmaceutical Sciences, Edmonton, Alberta. Buccal Mucosa as A Route for Systemic Drug Delivery: A Review. J Pharma Pharmaceutics Science (www.ualberta.ca/~csps) 1 (1); 1998: 15-30.

3. Neha Sharma, Saroj Jain, Satish Sardana. Buccoadhesive Drug Delivery System: A Review: Journal of Advanced Pharmacy Education and Research. 3(1); 2013. 1-15.

4. Phanindra B, B Krishna Moorthy and M Muthukumaran. Recent advances in Mucoadhesive/ Bioadhesive Drug Delivery System: A Review: International Journal of Pharma Medicines and Biological Science. 2(1); 2013: 67-84.

5. Bharat Jhanwar, Umesh Kumar Gilhotra, Prashant Mutha, Vivek Saraswat. A Review on Buccal Bioadhesive: An Advance Approach for Drug Delivery. International Journal of Pharmaceutical Erudition. 3(3); 2013: 22-40.

6. Kulkarni AP, Yunus RS, Dehghan MHD. Application of Neem Gum for Aqueous Film Coating of Ciprofloxacin Tablets. International Journal of Applied Research in Natural Products. 5(3); 2008-2013: 11-19.

7. Sellappan Velmurugan, P. Srinivas. Formulation and In vitro Evaluation of Losartan Potassium Mucoadhesive Buccal Tablets. Asian Journal of Pharmaceutical and Clinical Research. 6(3); 2013: 125-130.

8. Sellappan Velmurugan and Kiran Kumar. Raghavarapu. Formulation and In vitro Evaluation of Glipizide Mucoadhesive Buccal Tablets. International Journal of Pharma and Bio Sciences. 4(2); 2013: 594-607.

9. G. Vamsi Krishnamurthy, B. V. Narasimharao, K. Gayathridevi, G. Pavani, Ch. Harikrishna. Formulation and Evaluation of Carvedilol Bilayered Buccal Adhesive Tablets by Direct Compression Technique. International Journal of Pharmacy and Pharmaceutical Science Research.3(2); 2013: 61-66.

10. R. Jagadeeshwar Reddy, Maimuna Anjum and Mohammed Asif Hussain. A Comprehensive Review on Buccal Drug Delivery System. American Journal of Advanced Drug Delivery.1(3); 2013. 300-312.

11. Dhruba Sankar Goswami, Manoj Sharma, Shri Ramnath Singh. Development of new Mucoadhesive polymer from Natural source. Asian Journal of Pharmaceutical and Clinical Research. 5(3); 2012: 247-250.

12. Prasanth Vasantha Viswanadhan, Anand Padole, Abin Abraham and Sam Thomarayil Mathew. Buccal Tablets of Lisinopril by Direct Compression Method for Buccal Drug Delivery. International Research Journal of Pharmaceutics.2(2); 2012: 30-38.

13. AR. Shabaraya, K. Aiswarya and Mohd Azharuddin. Formulation and Evaluation of Mucoadhesive Bi-layer Buccal Tablets of Labetalol Hydrochloride Using Natural Polymers. International Journal of Advances in Pharmacy, Biology and Chemistry. 1(3); 2012: 305-314.

14. Ganesh G. N. K, Manjusha Pallaprola, Gowthamarajan K, Suresh Kumar R, Senthil V, Jawahar N, Venkatesh N. Design and Development of Buccal drug Delivery System for Labetalol using Natural Polymer. International Journal of Pharmaceutical Research and Development.4(4); 2011: 37-49.

15. L. Naga Vamsi Krishna, P.K. Kulkarni, Mudit Dixit, D. Lavanya, Prudhvi Kanth Raavi. Brief Introduction of Natural gums, Mucilage and Their Applications in Novel Drug Delivery System review. International Journal of Drug Formulation and Research. 2(6); 2011: 54-71.

16. Guda Aditya, Ganesh Kumar Gudas, Manasa Bingi, Subal Debnath, V. V Rajesham. Design and Evaluation of Controlled Release Mucoadhesive Buccal Tablets of Lisinopril. International Journal of Current Pharmaceutical Research. 2(4); 2010: 24-27.