INTRODUCTION:

The peroral route of drug delivery is the most preferred by patient and clinician alike. But, peroral administration of drugs has it’s own disadvantages, such as hepatic first-pass metabolism and enzymatic degradation within the gastrointestinal tract. These disadvantages limit or prevent the oral administration of certain classes of drugs, especially peptides and proteins¹. These limitations motivated the exploration of other mucosa for drug delivery in the systemic circulation. Transmucosal routes of drug delivery (e.g., the mucosal linings of the oral cavity, ocular, rectal, vaginal, and nasal) offer distinct advantages over peroral administration for systemic drug delivery. These advantages include bypassing of first-pass effect and avoidance of presystemic elimination within the gastrointestinal tract². The rectal, vaginal, and ocular mucosa offer certain advantages, but the poor patient acceptability associated with these sites render them reserved for local applications rather than systemic drug administration¹.

There are many factors which make the oral mucosal cavity a very attractive and feasible site for drug delivery³. The oral mucosa is relatively permeable with rich blood supply, it is robust and shows short recovery times after stress or damage^{4, 5}. Also drug delivery across the buccal epithelium bypasses the first-pass effect, avoids presystemic metabolism in the gastrointestinal tract. This route of drug delivery offers a safer method of drug utilization, as drug absorption can be promptly terminated in cases of toxicity by removing the dosage form from the buccal cavity⁶.

Within the oral mucosal cavity, delivery of drugs is classified into three categories¹:

(i) Sublingual delivery- In this the systemic delivery of drugs through the mucosal membranes lining the floor of the mouth takes place,

(ii) Buccal delivery- In this the drug administration through the mucosal membranes lining the cheeks (buccal mucosa) is done,

(iii) Local delivery, which is drug delivery into the oral cavity.

OVER VIEW OF THE ORAL MUCOSA

Buccal region is bound anteriorly and laterally by the lips and the cheeks, posteriorly and medially by the teeth and/or gums, and above and below by the reflections of the mucosa from the lips and cheeks to the gums. There are various mucous or serous glands present in the submucous tissue of the cheeks⁷. The buccal glands are placed between the mucous membrane and buccinator muscle⁸. The maxillary artery supplies blood to buccal mucosa. The blood flow in the buccal mucosa is faster and richer (2.4ml/min/cm²) than that in the sublingual, gingival and palatal regions, so this facilitates the passive diffusion of drug molecules across the mucosa. The thickness of the buccal mucosa is 500–800 μm and is rough textured, so it is suitable for retentive delivery systems⁹. The Buccal mucosa is composed of several layers of different cells as shown in the figure 1.

The epithelium is similar to the stratified squamous epithelia found in rest of the body and is about 40–50 cell layers thick⁸. The lining epithelium of buccal mucosa is made up of nonkeratinized stratified squamous epithelium having thickness of approximately 500–600 μ and surface area of 50.2 cm². Basement membrane, lamina propria followed by the submucosa is present below the epithelial layer¹⁰. Lamina propria is rich with blood vessels and capillaries that open to the internal jugular vein. Lipid analysis of buccal tissues shows the presence of phospholipid 76.3%, glucosphingolipid 23.0% and ceramide NS at 0.72%¹¹. The primary function of buccal epithelium is to protect the underlying tissue. In the nonkeratinized regions, lipid-based permeability barriers present in the outer epithelial layers protect the underlying tissues against fluid loss and also avoid the entry of potentially harmful environmental agents such as antigens, carcinogens, microbial toxins and enzymes from foods and beverages¹².

Fig 1: Cross section of oral mucosa

Permeability:

The oral mucosa is like a leaky epithelium intermediate between that of the epidermis and intestinal mucosa. The estimated permeability of oral mucosa is 4–4000 times greater than that of the skin. In general, the permeability of the oral mucosa decreases in the order of sublingual greater than buccal, and buccal greater than palatal¹. The permeability barrier in the oral mucosa is due to intercellular material derived from the ‘‘membrane coating granules’’ (MCG)¹³.

The components of the MCGs are different in keratinized and non-keratinized epithelia. The MCGs of keratinized epithelium are composed of lamellar lipid stacks represented by sphingomyelin, glucosylceramides, ceramides, and other nonpolar lipids. Whereas, the non-keratinized epithelium contains MCGs that are nonlamellar; the major MCG lipid components are cholesterol esters, cholesterol, and glycosphingolipids.

The Buccal mucosa is able to maintain the moist surface just as that in the gut. But when the permeability is concerned, saliva may act as the barrier for permeation, but the hydration may lead to increased permeability. The substances can cross the cells by endocytosis, by active transport, and by diffusion through the intercellular spaces. In endocytosis, a large number of different cell types are capable of taking up solid particles (phagocytosis) or fluids (pinocytosis) from the outer environment by engulfing the material in membranous vesicles¹³.

DEFINITION OF BUCCOADHESION/ MUCOADHESION:¹⁴

The term Mucoadhesion is defined as “attachment of a synthetic or natural macromolecule to mucus and/or an epithelial surface”.

Theories of Mucoadhesion:^15-19

Mainly five theories have been put forward to play a major role in bioadhesion. They are adsorption, diffusion, electronic, fracture, and wetting theories.

1. The adsorption theory describes the formation of primary and secondary chemical bonds of the covalent and non-covalent (electrostatic and Vander Waals’ forces, hydrogen, and hydrophobic bonds) upon initial contact between the mucus and the mucoadhesive polymer. Most of the initial interfacial bonding forces are attributed to non-covalent forces.

2. The concept of the diffusion theory is chain entanglement between glycoproteins of the mucus and the mucoadhesive polymer. Upon the initial contact between these two polymers, diffusion of the polymer chain into the mucus network takes place. This leads to formation of entangled network between the two polymers. Factors such as chain flexibility, adequate surface area for the contact of both the polymers, similar chemical structures, and the diffusion coefficient of the bioadhesive polymer play an important role in the inter-diffusion of the macromolecule network.

3. The electronic theory describes the electron transfer between the mucoadhesive polymer and the mucus glycoproteins. This occurs due to the difference in the electronic properties of both the polymers. This electron transfer leads to the formation of a charged double layer at the interface of the mucus and the polymer, which results in forces of attraction in this region and interdiffusion of the two surface.

4. The fracture theory is about the relation between the force required for the detachment of polymers from the mucus to the strength of their adhesive bond. It has been noted when the network strands are longer or the degree of cross-linking is reduced the work fracture is greater.

5. The wetting theory is mainly applicable for the liquid bioadhesive systems. This theory describes about the ability of a bioadhesive polymer to spread on the biological surface.

FACTORS AFFECTING THE MUCCOADHESION IN BUCCAL REGION:^20-26

Mucoadheson depends mainly upon two factors, namely the bioadhesive polymer and the medium in which the polymer will reside.

Polymer related factors:

a. Molecular weight: The bioadhesive strength of the polymer increases with the increase in the molecular weight, above 10, 0000.

b. Flexibility: The higher flexibility of the polymer leads to greater diffusion in the mucus network.

c. Hydrogen bonding capacity: Hydrogen bonding is one of the important factors for the mucoadhesion of a polymer. For mucoadhesion, the polymers should have the functional groups that are capable of forming the hydrogen bong with mucus.

d. Cross-linking density: The three important structural parameters of a polymer for muccoadhesion are the average pore size, the average molecular weight of the cross-linked polymers and the density of cross-linking. As the density of cross linking increases, the diffusion of water in the polymer network takes place very slowly; this leads to insufficient swelling thus results in reduced interpenetration of the polymer in the mucin layer.

e. Charge: Strong anionic charge is onr of the basic requirement for the strong bioadhesion. However, studies have revealed that some cationic high molecular weight polymers such as chitosan, also show good muccoadhesive properties.

f. Concentration: If the concentration of the polymer is too low, the number of penetrating polymer chains per unit volume of the mucus becomes very less, and thus the interaction between polymer and mucus is unstable. But for each polymer there is a certain amount of concentration, above which the polymer will produce a unperturbed state because of the significantly coiled structure. As a result of which, the solvent accessibility of the polymer decreases and chain penetration of the polymers is drastically reduced. Thus, the higher concentrations of the polymers do not necessarily improve the mucoadhsesive properties.

g. Hydration: For muccoadhesive polymer to expand and create a proper macromolecular mesh, hydration is required. The polymer swelling allows a mechanical entanglement by exposing the bioadhesive sites for hydrogen bonding and/or electrostatic interaction between the polymer and the mucus network.

Environmental Factors:²⁷

Along with the properties of the polymer, muccoadhesion also depends on the environmental factors where the dosage has to adhere. The pH of the microenvironment surrounding the muccoadhesive polymer alters the ionization state, thus affecting the adhesion properties of a polymer.

The pH of the saliva if about 6.5-7.5. Movement of the buccal tissues while eating as well as during sleeping has to be considered while administering the buccoadhesive dosage.

MUCCOADHESION:²⁸

There are basically two stages of muccoadhesion.

Contact Stage: An intimate contact i.e. wetting occurs between the muccoadhesive polymer and mucus membrane.

Consolidation Stage: In this stage prolonged adhesion is obtained, due to various physicochemical interactions which leads to consolidation and strengthening of the adhesive joint

Figure 2 gives the pictorial idea of the above stated stages

Fig 2: The two stages of muccoadhesion

Formulation aspects/design for Buccal Adhesive Drug Delivery System:

The drugs having the daily dose of less than 25mg and the buccal adhesive drug delivery systems having size between 1 and 3 cm² are preferred. The maximum duration of the bucccal delivery is approximately 4-6 hours²⁹.

Buccal Adhesive Polymers:

Polymers are used as adhesive components for the buccal bioadhesion. The bioadhesive polymers should have certain desired physicochemical features like hydrophilicilty, various hydrogen bond forming groups and flexibility³⁰.

Ideal characteristics of a buccal adhesive polymer:³¹

a. Polymers should have good spreadability, wetting, swelling and solubility properties.

b. Polymer should be non-toxic.

c. pH should be compatible with the surrounding medium. i.e. salivary pH.

d. Adhesion to the buccal mucosa should be quick and with sufficient adhesion strength.

e. The polymer should have bioadhesive properties in both dry and liquid state.

Table 1 contains the list of polymers that have been investigated for buccal adhesive systems¹:

Permeation enhancers:³¹

The epithelium lining of the buccal mucosa acts as the barrier for the drug absorption. Table 2 lists of permeation enhancers with few examples.

There are basically five mechanisms considered for the action of the permeation enhancers³¹:

a. Changing mucus rheology: Mucus forms a viscoelastic layer around the epithelium, thus hindering the absorption of the drugs. So few enhancers reduce the viscosity of the mucus and thus the drug overcomes the barrier and can easily penetrate the epithelium lining on buccal mucosa.

Table 1: List of polymers used for bioadhesion

Bioadhesive Polymer(s) Studied	Investigation Objectives
HPC and CP	Preferred mucoadhesive strength on CP, HPC, and HPC-CP combination.
HPC and CP	Measured Bioadhesive property using mouse peritoneal membrane.
CP, HPC, PVP, CMC	Studied inter polymer complexation and it’s effect on bioadhesive strength.
CP and HPMC	Formulation and evaluation of buccoadhesive controlled release delivery systems.
HPC, HEC,PVP and PVA	Tested mucoadhesion on patches with two- ply laminates with an impermeable backing layer and hydrocolloid polymer layer.
HPC and CP	Used HPC-CP powder mixture as peripheral base for strong adhesion and HPC-CP freeze dried mixture as core base.
Xanthum gum and Locust bean gum	Hydrogel formation by combination of natural gums.
Chitosan, HPC, CMC, Pectin, Xantham gum, and polycarbophil	Evaluate mucoadhesive properties by routinely measuring the detachment force from pig intestinal mucosa.
Hyaluronic acid benzyl esters, Polycarbophil, and HPMC	Evaluate mucoadhesive properties.
Hydroxyethylcellulose	Design and synthesis of a bilayer patch (polytef-disk) for thyroid gland diagnosis.
Polycarbophil	Design of a unidirectional buccal patch for oral mucosal delivery of peptide drugs.
Poly(acrylic acid) and poly(methacrylic acid)	Synthesized and evaluated crosslinked polymers.
Numbers of Polymers including HPC, HPMC, CP, CMC	Measurement of bioadhesive potential and to derive meaningful information on the structural requirement for bioadhesion.

Table 2: List of permeation enhancers

Sr. No.	Type of permeation enhancer	Examples
1.	Chelators	EDTA, citric acid, sodium salicylate, methoxy salicylates
2.	Surfactants	Sodium laurly sulphate, cetyl trimethyl ammonium bromide, benzalkonium chloride
3.	Bile salts	Sodium glychocolate, sodium deoxycholate, sodium taurocholate
4.	Fatty acids	Oleic acid, capric acid, lauric acid, methyloleate, phosphatidylcholine
5.	Non-surfactants	Unsaturated cyclic ureas

1. By increasing the fluidity of the lipid membrane: Permeation enhancers disturb the intracellular lipid packing by interacting with either the lipid or protein components.

2. By action on the components at the tight junction: Permeation enhancers increase the permeation by acting on the desmosomes also, which are the major components at the tight junctions.

3. By increasing the thermodynamic activity of the drug: Some enhancers alter the partition coefficient of the drug by increasing its solubility. Resulting in higher thermodynamic stability, thereby increasing the absorption of the drug.

4. By overcoming the enzymatic barrier: The mechanism of action is inhibition of the various enzymes like peptidases and proteases present within the buccal cavity, resulting in the crossing of the enzymatic barrier.

THE DRUG RELEASE FROM THE POLYMER:³¹

The release of the drug from the polymer matrix takes place by diffusion or by polymer degradation. Sometimes the release of drug takes place by both the mechanism. Enzymes play an important role in the degradation of the polymer. Whereas, hydrolysis is responsible for the polymer erosion.

MUCCOADHESIVE DOSAGE FORMS FOR BUCCAL ADMINISTRATION:

Buccal Tablets:

Buccal tablets are small, flat, and oval, with a diameter of approximately 5–8 mm. The tablet softens and adheres to the substrate and is retained in position until dissolution and/or release is complete. The buccal adhesive tablets do not hinder in the daily activities like drinking, eating and speaking³². The tablets once applied in the buccal cavity should not be moved in the mouth as it may cause the drug to release faster³³.

The buccoadhesive tablets are prepared by direct compression method. For achieving unidirectional flow of the drug form the dosage formulation, every side of the tablet except the side which is in contact with the mucus membrane is coated with the water impermeable membrane/polymer. The various impermeable polymers/ agents used are ethyl cellulose, hydrogenated castor oil etc²⁷. (Table 3)

The excipients used should not cause excessive salivation as this may lead to swallowing of the drug rather than absorption from the buccal mucosa³³. The figure 3 shows the cross-section of the buccal adhesive tablet.

Fig 3: Cross-section of the buccal adhesive tablet

Table 3: List of few investigated buccal mucoadhesive tablets²⁷

Active ingredients	Polymers used
Acitretin	Carbopol 934p and HPMC
Cetylpyridinium chloride	Sodium CMC and HPMC
Insulin	Carbopol 934p and HPC
Omeprazole	Sodium Alginate and HPMC
Proparanolol hydrochloride	HPMC, HPC and carbopol
Morphine sulphate	HPMC with carbopol
Nicotine	Carbopol 974p, Sodium alginate and HPC
Nifedipine	Sodium alginate, PVP and PEG
Diltiazem Hydrochloride	Carbopol 934p and HPMC
Zinc sulphate	Ethyl Cellulose and Eudragit

Table 4: List of few investigated buccal patches

Active ingredients	Polymers
Acyclovir	Chitosan hydrochloride
Buprenophrine	Carbopol 934p and polyisobutylene
Melatonin	Carbopol 934p and polyisobutylene
Oxytocin	Carbopol 974p
Metropolol tartarate	Eudragit with carbopol, HPMC ND Sodium CMC

Table 5: The list of few investigated buccal gels²⁷

Active ingredients	Polymers
Arecoline	Carbopol 934p
Chlorhexidiene	Collagen
Diclofenac sodium	Hydroxyethyl methacrylate
Lidocaine	PEG, carbopol 934p and PVP
Propolis	HPC
Tetracycline	HEC and PVP

Buccal Patches:

Buccal patches are same like the transdermal patches. They consist of a backing layer which is impermeable to water, and a drug containing reservoir layer²⁷. The normal size of a buccal patch is about 1-3cm². But the size can increase up to 10-15 cm^{2 34}.

The buccal patches are prepared by two methods, namely solvent casting and second one is milling³⁴. The table 4 contains the list of few investigated buccal patches²⁷

Buccal gels and ointments:

This semi-solid dosage forms have the advantage of easy dispersion throughout the oral mucosa. The gels provide extended retention time in the oral cavity, with adequate drug penetration, and high efficacy along with patient acceptability. A major application of adhesive gels is the local delivery of medicinal agents for the treatment of periodontitis. (Table 5)

CONCLUSION:

Buccal mucosa can be used as a site for the retention of the drug delivery system. The mucosa is well supplied with both vascular and lymphatic drainage. Bioavailability of the drug administered through this route increases as it avoids hepatic first pass metabolism. Muccoadhesion gives the controlled drug release. The various kinds of biodhesive polymers along with different permeation enhancers can be used for the delivery of drug through this route. There are various kinds of dosage forms like buccal tablets, buccal patches and gels available for drug administration through this route. Marketed preparations used as buccal administrations are listed in table-6.

Table 6: Marketed preparations of buccal adhesive systems³¹

Commercial name	Bioadhesive polymer	Company	Dosage form
Buccastem	PVP, Xanthum gum, Locust bean gumm	Rickitt Benckiser	Tablet
Suscard	HPMC	Forest	Tablet
Gaviscon liquid	Sodium Alginate	Rickitt Benckiser	Oral liquid
Orabase	Pectin, Gelatin	Convatech	Oral paste
Corcodyl gel	HPMC	Glaxosmithkline	Oromucosal gel
Corlan pellets	Acacia	Celltech	Oromucosal pellets
Luborant	Sodium CMC	Antigen	Artificial saliva
Saliveze	Sodium CMC	Wyvern	Artificial saliva

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Received on 19.01.2010 Modified on 05.02.2010

Research J. Pharm. and Tech.3 (3): July-Sept. 2010; Page 676-681