INTRODUCTION:

Considerable attention has been focused in recent years on the delivery of drugs through the oral mucosa which have a high first pass metabolism or degrade in the gastrointestinal tract. Transmucosal delivery has also been considered for treatment of oral disorders and as a local anesthetic. ^[1]

· Bioadhesion:

Bioadhesion can be defined as the state in which two materials, at least one of which is biological in nature, are held together for extended periods of time by interfacial forces. When the adhesive attachment is to mucus or a mucous membrane, the phenomenon is referred to as mucoadhesion. ^[2]

· Concepts of Buccal Drug Delivery System:

Mucoadhesive polymers as drug delivery vehicles: The common principle underlying this drug administration route is the adhesion of the dosage form to the mucous layer until the polymer dissolves or the mucin replaces itself.

Benefits for this route of drug administration are: prolonged drug delivery, targeted therapy and often improved bioavailability.^[3-5]Mucoadhesion has become an interesting topic for research over the last two decades, for its potential to optimize localized drug delivery, by retaining dosage forms at the site of action or systemic delivery, by retaining a formulation in intimate contact with the absorption site. ^[6]

During the 1980s, this concept began to be applied to drug delivery systems. It consists of the incorporation of adhesive molecules into some kind of pharmaceutical formulation intended to stay in close contact with the absorption tissue, releasing the drug near to the action site, thereby increasing its bioavailability and promoting local or systemic effects^.
[7]

· Mucoadhesive drug delivery systems include the following:

• Buccal delivery system

• Oral delivery system

• Vaginal delivery system

• Rectal delivery system

• Nasal delivery system

• Ocular delivery system ^[8]

· In biological systems, four types of bioadhesion can be distinguished as follows:

1. Adhesion of a normal cell on another normal cell.

2. Adhesion of a cell with a foreign substance.

3. Adhesion of a normal cell to a pathological cell.

4. .Adhesion of an adhesive to a biological substance. ^[8-11]

· Need of Mucoadhesive:

Ø Controlled release.

Ø Target &localised drug delivery.

Ø By pass first pass metabolism.

Ø Avoidance of drug degradation.

Ø Prolonged effect.

Ø High drug flux through the absorbing tissue.

^ØReduction in fluctuation of steady state plasma level. ^[12]

· Advantages of Buccoadhesive Drug Delivery:

Drug administration via the buccoadhesive drug delivery offers several advantages such as:-

a) Drug is easily administered and extinction of therapy in emergency can be facilitated.

b) Drug release for prolonged period of time.

c) In unconscious and trauma patient’s drug can be administered.

d) Drugs bypass first pass metabolism so increases bioavailability.

e) Some drugs that are unstable in acidic environment of stomach can be administered by buccal delivery.

f) Drug absorption by the passive diffusion.

g) Flexibility in physical state, shape, size and surface.

h) Maximized absorption rate due to close contact with the absorbing membrane.

i) Rapid onset of action. ^[13]

· Limitations of Buccoadhesive Drug Delivery:

There are some limitations of buccal drug delivery system such as

a) Drugs which are unstable at buccal pH cannot be administered.

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

c) Drug required with small dose can only be administered.

d) Those drugs which are absorbed by passive diffusion can only be administered by this route.

e) Eating and drinking may become restricted. ^[14].

· Oral Mucosal Sites:

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

1) Sublingual delivery: is the administration of the drug via the sublingual mucosa (the membrane of the ventral surface of the tongue and the floor of the mouth) to the systemic circulation.

2) Buccal delivery: is the administration of drug via the buccal mucosa (the lining of the cheek) to the systemic circulation.

3) Local delivery: for the treatment of conditions of the oral cavity, principally ulcers, fungal conditions and periodontal disease.

These oral mucosal sites differ greatly from one another in terms of anatomy, permeability to an applied drug and their ability to retain a delivery system for a desired length of time. ^[15,
16].

· Characteristics of an Ideal Buccoadhesive System:

An ideal buccal adhesive system should possess the following characteristics:

1. Quick adherence to the buccal mucosa and sufficient mechanical strength.

2. Drug release in a controlled fashion.

3. Facilitates the rate and extent of drug absorption.

4. Should have good patient compliance.

5. Should not hinder normal functions such as talking, eating and drinking.

6. Should accomplish unidirectional release of drug towards the mucosa.

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

8. Possess a wide margin of safety both locally and systemically.

9. Should have good resistance to the flushing action of saliva. ^[17-20]

· Ideal Drug Candidates for Buccal Drug Delivery System:

1. Molecular size – 75-600 daltons

2. Molecular weight between 200-500 daltons.

3. Drug should be lipophilic or hydrophilic in nature.

4. Stable at buccal pH.

5. Taste – bland

6. Drug should be odourless.

7. Drugs which are absorbed only by passive diffusion should be used. ^[3-5]

· STRUCTURE OF ORAL MUCOSA:

The oral mucosa is made up of an outermost layer of stratified squamous epithelium, which is covered with mucus and consists of stratum distendum, stratum filamentosum, stratum suprabasale, and a stratum basale. Below this layer lies a basal lamina, the lamina propria followed by the submucosa as the innermost layer.

The epithelium serves as a mechanical barrier protecting the underlying tissues where as the lamina propria acts as a mechanical support and carries blood vessels and nerves ^[21]. The stratified squamous epithelium has a mitotically active basal layer and produces different cell layers, where cells are shed from the Surface of the epithelium^[15].

The epithelium 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 differentiate from the basal layers to the superficial layers. The turnover time for the oral mucosal epithelium has been estimated at 5-6 days. The oral mucosal thickness varies depending on the site: the buccal mucosa measures at 500-800 ìm, while the mucosal thickness of the hard and soft palates, the floor of the mouth, the ventral tongue, and the gingival measure at about 100-200 ìm ^[15].

The mucosa of the soft palate, the sublingual, and the buccal are the non-keratinized regions of oral mucosa. These are more permeable than keratinized regions such as that of hard palate due to thecomposition of intercellular lipids comprising those particular regions ^[21].

The keratinizedepithelia contain predominantly the neutral lipids like ceramides and acylceramideswhich have been associated with the barrier function. These epithelia are relativelyimpermeable to water. The non-keratinized epithelia are composed of small amounts ofneutral but polar lipids, mainly cholesterol sulfate and glucosyl ceramides. This epithelium has been found to be considerably more permeable to water than keratinized epithelia ^[22]. Structure of oral mucosa consist of numerous racemose, mucous or serons glands are present in the sub mucous tissue of the cheeks ^[23].

Fig 1: Cross section of oral mucosa ^[24]

· Composition of Mucous Membrane:^[25-26]

Sr. No.	Composition	% Amount
1	Water	95%
2	Glycoprotein & Lipids	0.5-5.0%
3	Mineral Salts	1%
4	Free Proteins	0.5-1%

· Functions of mucous layer:

The mucous layer, which covers the epithelial surface, has various roles.

1. Protective role: The Protective role results particularly from its hydrophobicity and protecting the mucosa from the lumen diffusion of hydrochloric acid from the lumen to the epithelial surface. ^[25,
27]

2. Barrier role: The role of mucus layer as barrier in tissue absorption of drugs and other substances is well known as it influences the bioavailibity of the drugs. The mucus constitutes diffusion barrier for molecules, and especially against drug absorption diffusion through mucus layer depends on molecule charge, hydration radius, ability to form hydrogen bonds and molecular weight. ^{[9, 25, 27]}

3. Adhesion role: Mucus has strong cohesive properties and firmly binds the epithelial cells surface as a continuous gel layer.

4. Lubrication role: An important role of the mucus layer is to keep the membrane moist. Continuous secretion of mucus from the goblet cells is necessary to compensate for the removal of the mucus layer due to digestion, bacterial degradation and solubilisation of mucin molecules. ^[9,
25]

5. Mucoadhesion role: One of the most important factors for bioadhesion is tissue surface roughness. (G.S.Asane,2007), Adhesive joints may fail at relatively low applied stresses if cracks, air bubbles, voids, inclusions or other surface defects are present. Viscosity and wetting power are the most important factors for satisfactory bioadhesion. ^[25,
27]

At physiological pH, the mucus network may carry a significant negative charge because of the presence of sialic acid and sulphate residues and this high charge density due to negative charge contributes significantly to the bioadhesion. ^[25]

Ø Drug Permeability through Buccal Mucosa:

There are two possible routes of drug absorption through the squamous stratified epithelium of the oral mucosa:

1. Transcellular (intracellular, passing through the cell) and;

2. Paracellular (intercellular, passing around the cell).

Permeation across the buccal mucosa has been reported to be mainly by the paracellular route through the intercellular lipids produced by membrane-coating granules.

Fig 2: The paracellular and transcellular routes of Transport have been designated to the buccal mucosa. ^[29]..

Ø Steps of Mucoadhesion: ^[30]

1. Contact stage

2. Consolidation stage.

Fig 3: Two steps of Mucoadhesion

The first stage or the contact stage is characterized by the contact between the mucoadhesive and the mucous membrane, with spreading and swelling of the formulation, initiating its deep contact with the mucus layer. In the consolidation step, the mucoadhesive materials are activated by the presence of moisture. Moisture plasticizes the system, allowing the mucoadhesive molecules to break free and to link up by weak van der Waals and hydrogen bonds. ^[31]

· THEORIES OF MUCOADHESION:

Bioadhesion may be defined as the state in which two materials, at least one of which is biological in nature, are held together for extended periods of time by interfacial forces. In the pharmaceutical sciences, when the adhesive attachment is to mucus or a mucous membrane, the phenomenon is referred to as mucoadhesion.

Several theories have been developed in the formation of bioadhesive bonds and are based on the formation of mechanical bonds, while others focus on chemical interactions. ^[21]

1. The electronic theory:

This assumes that bioadhesive material and the glycol-protein mucin network have different electronic structures. Formation of a charged double layer at the interface of the mucus and the polymer due to the electron transfer results in attraction in the interface region and contributes to the inter diffusion of the two surfaces. ^[21]

2. The adsorption theory:

This is the most widely accepted theory of bioadhesion. Based on this theory, the bioadhesive bonds formed between an adhesive substrate and intestinal mucosa is due to Vander Waals’ interactions, hydrogen bonds, and related forces. ^[21]

3. The wetting theory:

This theory describes the ability of bioadhesive polymer to spread over biological surfaces to develop intimate contact with the corresponding substrate for bond formation. This theory is used predominantly in liquid adhesives.

The general rule states that the lower the contact angle then the greater the affinity. The contact angle should be equal or close to zero to provide adequate spreadability. ^[30]

The spreadability coefficient, SAB, can be calculated from the difference between the surface energies γ_B and γ_A and the interfacial energy γ_AB, as indicated in equation.

S_AB = γ_B - γ_A - γ_AB ^[29]Eq. 1

The greater the individual surface energy of mucus and device in relation to the interfacial energy, the greater the adhesion work, WA, i.e. the greater the energy needed to separate the two phases.

W_A= γ_A+ γ_B- γ_AB^[29]Eq.2

Fig 4: Schematic diagram showing influence of contact angle between device and mucous membrane on bioadhesion. ^[30]

4. The diffusion theory:

This theory is based on the formation of semi permanent adhesive bonds due to the interpenetration and entanglement of bioadhesive polymer chains and mucus polymer chain .The depth of penetration of polymer chains increase with the bond strength. The bioadhesive polymers and mucus should have similar chemical structures for the formation of strongest bioadhesive bond. For the diffusion to occur, it is important to have good solubility of one component in the other.

Fig 5: Secondary interactions resulting from inter diffusion of polymer chains of bioadhesive device and of mucus. ^[30]

The exact depth needed for good bioadhesive bonds is unclear, but is estimated to be in the range of 0.2–0.5 μm.^[31]The mean diffusional depth of the bioadhesive polymer segments, s, may be represented eqation bellow.

Eq.3

where D is the diffusion coefficient and t is the contact time. Duchene ^[32] adapted Equation 4 to giveEquation 5, which can be used to determine the time, t, to bioadhesion of a particular polymer:

Eq.4

In which l represents the interpenetrating depth and Db the diffusion coefficient of a bioadhesive through the substrate.

Once intimate contact is achieved, the substrate and adhesive chains move along their respective concentration gradients into the opposite phases. Depth of diffusion is dependent on the diffusion coefficient of both phases. Reinhart and Peppas ^[33] reported that the diffusion coefficient depended on the molecular weight of the polymer strand and that it decreased with increasing cross-linking density.

5. The fracture theory:

This theory states that, the force required for the detachment of polymers from the mucus depends on the strength of the adhesive bond. This is the most useful theory for studying bioadhesion strength through tensile experiments. The maximum tensile stress produced during detachment is the ratio of maximum force of detachment and the total surface area involvedin the adhesive interaction.

It analyses the force required to separate two surfaces after adhesion is established. ^[29]This force, Sm, is frequently calculated in tests of resistance to rupture by the ratio of the maximal detachment force, Fm, and the total surface area, Ao, involved in the adhesive interaction.

Sm = Fm/Ao

Fig 6: Regions where the mucoadhesive bond ruptures can occur. ^[30]

· MECHANISM OF MUCOADHESION:

The concept of mucoadhesion is one that has the potential to improve the highly variable residence times experienced by drugs and dosage forms at various sites in the gastrointestinal tract, and consequently, toreduce variability and improve efficacy. Intimate contact with the mucosa should enhance absorption. ^[35]. the mechanisms responsible in the formation of bioadhesive bonds are notfully known, however most research has described bioadhesive bond formation as a three step process:-

STEP1: Wetting and swelling of polymer

STEP2: Interpenetration between the polymer chains and the mucosal membrane.

STEP3: Formation of Chemical bonds between the entangled chains. ^[40]

Step 1: The wetting and swelling step occurs when the polymer spreads over the surface of the biological substrate or mucosal membrane in order to develop an intimate contact with the substrate ^[36-37]. This can be readily achieved for example by placing abioadhesive formulation such as a tablet or paste within the oral cavity or vagina. Bioadhesives are able to adhere to or bond with biological tissues by the help of the surface tension and forces that exist at the site of adsorption or contact. Swelling of polymers occurs because the components within the polymers have an affinity for water. ^[39]

Fig 7: Wetting and Swelling of Polymer ^[39] Fig 8: Interdiffusion and Interpenetration of Polymer and Mucus ^[39]

Step 2: The surface of mucosal membranes are composed of high molecular weight polymers known as glycoproteins. In this step interdiffusion and interpenetration take place between the chains ofmucoadhesive polymers and the mucous gel network creating a great area of contact The strength of these bond depends on the degree of penetration be ^[29,
37] tween the two polymer groups. In order to form strong adhesive bonds, one polymer group must be soluble in the other and both polymer types must be of similar chemical structure. ^{[38, 40]}

Step 3: In this step entanglement and formation of weak chemical bonds as well as secondary bonds between the polymer chains mucin molecule. ^[37-38] The types of bonding formed between the chains includes primary bonds such as covalent bonds and weaker secondary interactions such as van der Waals Interactions and hydrogen bonds. Both primary and secondary bonds are exploited in the manufacture of bioadhesive formulations in which strong adhesions between polymers are formed. ^[37]

Fig 9: Entanglement of Polymer and Mucus by Chemical bonds ^[39]

v FACTORS AFFECTING MUCOADHESION: ^[40]

The mucoadhesion of a drug carrier system to the mucous membrane depends on the below mentioned factors.

· Polymer based factors

Molecular weight of the polymer

Concentration of polymer used

Flexibility of polymer chains

Swelling factor

Stereochemistry of polymer

· Physical factors

Ph at polymer

Substrate interface

Applied strength

Contact time

· Physiological factors

Mucin turnover rate

Diseased state

· CLASSIFICATION OF MUCOADHESIVE POLYMERS: ^[41]

A short list of mucoadhesive polymers is given below

1. Synthetic polymers:

Cellulose derivatives (methylcellulose, ethylcellulose, hydroxy-ethylcellulose, Hydroxyl propyl cellulose, hydroxy propyl methylcellulose, sodium carboxy methylcellulose, Poly (acrylic acid) polymers (carbomers, polycarbophil), Poly (hydroxyethyl methylacrylate), Poly (ethylene oxide), Poly (vinyl pyrrolidone), Poly (vinyl alcohol), Natural polymers, Tragacanth, Sodium alginate, Karaya gum, Guar gum, Xanthan gum, Lectin, Soluble starch,Gelatin, Pectin, Chitosan.

2. Hydrophilic Polymers:

These are the water-soluble polymers that swell indefinitely in contact with water and eventually undergo complete dissolution, e.g. Methyl Cellulose, Hydroxyl Ethyl Cellulose, Hydroxyl PropylMethyl Cellulose, Sodium Carboxy Methyl Cellulose, Carbomers, Chitosan and Plant gums.

3. Hydrogels:

These are water swellable materials, usually a cross-link polymer with limited swelling capacity, e.g. poly (acrylic acid co acrylamide) copolymers, carrageenan, sodium alginate, guar gum andmodified guar gum, etc.

4. Thermoplastic Polymers:

These polymers include the non-erodible neutral polystyrene and semi-crystalline bio-erodible polymers, which generate the carboxylic acid groups as they degrade, e.g. polyanhydrides andpolylactic acid. Various synthetic polymers used in mucoadhesive formulations include polyvinyl alcohol, polyamides, polycarbonates, polyalkylene glycols, polyvinyl ethers, esters and halides, polymethacrylic acid, polymethylmethacrylic acid, Methyl Cellulose, Hydroxyl PropylCellulose, Hydroxyl Propyl Methyl Cellulose, and Sodium Carboxy Methyl Cellulose.Various biocompatible polymers used in mucoadhesive formulations include cellulose-based polymers, ethylene glycol polymers and its copolymers, oxyethylene polymers, polyvinyl alcohol, polyvinyl acetate and esters of hyaluronic acid. Various biodegradable polymers used in mucoadhesive formulations are poly (lactides), poly(glycolides), poly (lactide-co-glycolides), polycaprolactones, and polyalkyl cyanoacrylates.Polyorthoesters, polyphosphoesters, polyanhydrides, polyphosphazenes are the recent additions to the polymers.

· An ideal mucoadhesive polymer has the following characteristics: ^[42]

1. The polymer and its degradation products should be nontoxic and should be no absorbable from the gastrointestinal tract.

2. It should be non-irritant to the mucous membrane.

3. It should preferably form a strong non-covalent bond with the mucin-epithelial cell surfaces.

4. It should adhere quickly to most tissue and should possess some site-specificity.

5. It should allow daily incorporation to the drug and offer no hindrance to its release.

6. The polymer must not decompose on storage or during the shelf life of the dosage form.

7. The cost of polymer should not be high so that the prepared dosage form remains competitive.

· PERMEABILITY ENHANCERS: ^[3-5]

Permeability enhancers are substances added to pharmaceutical formulation in order to increase the membrane permeation rate or absorption rate of co administered drug.

E.g.: By using di- and tri-hydroxy bile salts, the permeability of buccal mucosa to fluorescein isothiocynate (FITC) increased by 100-200 folds compared to FITC alone.

Applications - Enhance bioavailability of drugs – 5% – 40%

Limitations - May cause potential membrane damage.

· Mechanisms of action of permeation: ^[43]

1. Changing mucus rheology: By reducing the viscosity of the mucus and saliva overcomes this barrier.

2. Increasing the fluidity of lipid bilayer membrane: Disturb the intracellular lipid packing by interaction with either lipid packing by interaction with either lipid or protein components.

3. Acting on the components at tight junctions: By inhibiting the various peptidases and proteases present within buccal mucosa, thereby overcoming the enzymatic barrier. In addition, changes in membrane fluidity also alter the enzymatic activity indirectly.

4. Increasing the thermodynamic activity of drugs: Some enhancers increase the solubility of drug there by alters the partition coefficient.

· BUCCAL DOSAGE FORMS:

Several buccal adhesive delivery devices were developed at the laboratory scale by many researchers either for local or systemic actions and can be broadly classified in to solid buccal adhesive dosage forms, semi-solid buccal adhesive dosage forms and liquid buccal adhesive dosage forms.

· Solid buccal adhesive formulations

Solid buccal adhesive formulations achieve bioadhesion via dehydration of the local mucosal surface. They include tablets, micro particles, wafers, lozenges etc.

1. Tablets:

Buccal adhesive tablets that are placed directly onto the mucosal surface for local or systemic drug delivery have been demonstrated to be excellent bioadhesive formulations. Two types of tablets i.e. monolithic and double-layered matrix tablets have been investigated for buccal delivery of drugs.

a. Monolithic tablets: consist of a mixture that contains drug and swelling bioadhesive/sustained release polymer. These tablets exhibit a bidirectional release. They can be coated on the outer or on all sides but one face with water impermeable hydrophobic substances to allow a unidirectional drug release for systemic delivery.

b. Double layered tablets comprise: an inner layer based on a bioadhesive polymer and an outer non-bioadhesive layer containing the drug for a bi-directional release but mainly a local action. In the case of systemic action, the drug is loaded into the inner bioadhesive layer whereas the outer layer is inert and acts as a protective layer. Alternatively, the drug is loaded into a controlled release layer and diffuses towards the absorbing mucosa through the bioadhesive layer, whereas a water impermeable layer assures the mono-directional release. ^[45-48]

Fig 10: Schematic representation of different types of matrix tablets designed for buccal drug delivery system ^[52]

2. Microparticles

Bioadhesive microparticles offer the same advantages as tablets but their physical properties enable them to make intimate contact with a lager mucosal surface area. In addition, they can also be delivered to less accessible sites including the GI tract and upper nasal cavity.

3. Wafers

A conceptually novel periodontal drug delivery system that is intended for the treatment of microbial infections associated with peridontitis was described elsewhere. . The delivery system is a composite wafer with surface layers possessing adhesive properties, while the bulk layer consists of antimicrobial agents, biodegradable polymers and matrix polymers.

4. Lozenges

Bioadhesive lozenges may be used for the delivery of drugs that act topically within the mouth including antimicrobials, corticosteroids, local anaesthetics, antibiotics and antifungals.

· Semi-solid dosage forms

1. Gels

Gel forming bioadhesive polymers include crosslinked polyacrylic acid that has been used to adhere to mucosal surfaces for extended periods of time and provide controlled release of drugs.

2. Patches/films

Flexible films may be used to deliver drugs directly to a mucosal membrane. They also offer advantages over creams and ointments in that they provide a measured dose of drug to the site. Buccal adhesive films are already in use commercially.

Patch systems are the formulations that have received the greatest attention for buccal delivery of drugs. They present a greater patient compliance compared with tablets owing to their physical flexibility that causes only minor discomfort to the patient. Patches are laminated and generally consist of an impermeable backing layer and a drug-containing layer that has mucoadhesive properties and from which the drug is released in a controlled manner.

· Liquid dosage forms

Viscous liquids may be used to coat buccal surface either as protectants or as drug vehicles for delivery to the mucosal surface.

A novel liquid aerosol formulation (Oralin, Generex Biotechnology) has been recently developed, and it is now in clinical phase II trials.This system allows precise insulin dose delivery via a metered dose inhaler in the form of fine aerosolized droplets directed into the mouth. ^[23]

· Structure and Design of Buccal dosage form:

Buccal Dosage form can be of-

1. Matrix type: The buccal patch designed in a matrix configuration contains drug, adhesive and additivesmixed together. Transmucosal drug delivery systems can be bidirectional or unidirectional. Bi-directional patches release drug in both the mucosa and the mouth.

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. Unidirectional patches release the drug only into the mucosa. ^[49]

· EVALUATION OF BUCCAL DELIVERY SYSTEM: ^[51]

In addition of weight variation, thickness, content uniformity, bioadhesive strength, dissolution tests some specific tests for patches/films, tablets, gels

· Specific tests for patches/films

1. Folding Endurance:

Folding endurance of the patches was determined by repeatedly folding one patch at the same place till it broke or folded up to 300 times manually, which was considered satisfactory to reveal good patch properties. The number of times of patch could be folded at the same place without breaking gave the value of the folding endurance. This test was done on three patches.

Swelling study: Swell on the surface of agar plate kept in an incubator maintained at 37⁰C. Increase in the weight and diameter of the patches (n = 3) was determined at preset time intervals (1–5 h). The percent swelling, %S was calculated using the following equation:

%S = (Xt – Xo/Xo) × 100

Where Xt is the weight or diameter of the swollen patch after time t, and Xo is the original patch weight or diameter at zero time.

Tensile strength of the film: Tensile strength of the film is total weight, which is necessary to break or rupture the films and this was done by a device has rectangular frame with two plates made up of Plexiglas.

The one plate is in the front and is the movable part of the device and can be pulled by loading weights on the string, which is connected to the movable part. The required diameter of films containing dose were fixed between the stationary and movable plate. The force needed to fracture the films was determined by measuring the total weight loaded in the string.

Tensile strength = Breaking load (N) /Cross sectional area of the film

2. Specific tests for tablets

Friability:

Five tablets were weighed and placed in the Roche friabilator and apparatus was rotated at 25 rpm for 4 minutes. After revolutions the tablets were dusted and weighed again. The percentage friability was measured using the formula. % F = {1-(W/Wo)} ×100 Where, % F = friability in percentage Wo = Initial weight of tablet W = weight of tablets after revolution

Hardness:

Hardness was measured using Monsanto hardness tester. For each batch two tablets were tested.

· Measurement of bioadhesive strength of buccal dosage forms

Modified physical balance test:

Bioadhesive strength of the tablet was measured on the modified physical balance. The apparatus consist of a modified double beam physical balance in which the right pan has been replaced by a glass slide with copper wire and additional weight, to make the right side weight equal with left side pan. A taflone block of 3.8 cm diameter and 2 cm height was fabricated with an upward portion of 2 cm height and 1.5 cm diameter on one side. This was kept in beaker filled with phosphate buffer pH 6.8, which was then placed below right side of the balance. Goat buccal mucosa was used as a model membrane and phosphate buffer pH 6.8 was used as moistening fluid. The goat buccal mucosa was obtained from local slaughter house and kept in a Krebs buffer during transportation. The underlying mucous membrane was separated using surgical blade and wash thoroughly with buffer media phosphate buffer pH 6.8. It was then tied over the protrusion in the Teflon block using a thread. The block was then kept in glass beaker. The beaker was filled with phosphate buffer pH 6.8 up to the upper surface of the goat buccal mucosa to maintain buccal mucosa viability during the experiments. The one side of the tablet was attached to the glass slide of the right arm of the balance and then the beaker was raised slowly until contact between goat mucosa and buccoadhesive dosage form was established. A preload of 10 mg was placed on the slide for 5 min (preload time) to established adhesion bonding between buccoadhesive tablet and goat buccal mucosa. The preload and preload time were kept constant for all formulations. After the completion of preload time, preload was removed from the glass slide and water was then added in the plastic bottle in left side arm by peristaltic pump at a constant rate of 100 drops per min. The addition of water was stopped when Buccoadesive tablet was detached from the goat buccal mucosa. The weight of water required to detach buccoadhesive tablet from buccal mucosa was noted as bioadhesive strength in grams. From the bioadhesive strength following parameter was calculated.

Force of adhesion (N) =Bioadhesive strength (g) ×9.81/1000

Bond strength (Nm-2) =Force of adhesion/Disk surface.

· Measurement of dissolution and drug release form bioadhesive dosage forms

1. Dissolution apparatus:

Standard USP or IP dissolution apparatus have been used to study in vitro release profile using both basket and rotating paddle. Place the tablet in a dry basket at the beginning of each test. Lower the Basket before rotation operates the apparatus immediately at 50 rpm. Medium used for release rate study was 900ml phosphate buffer pH 6.8 during the course of study whole assembly was maintained at 37±0.5⁰C. Withdraw a 5 ml of sample at specific time interval and replaced with 5 ml of fresh dissolution medium. The withdrawn samples were dilute with dissolution medium and then filter it with whattman filter paper and assayed.

2. Franz diffusion cell:

The release of drug from tablets was studied using modified Franz diffusion cells. The dissolution medium was phosphate buffer saline (PBS) at 37⁰C. Uniform mixing of the medium was provided by magnetic stirring at 300 rpm. To provide unidirectional release, each bioadhesive tablet was embedded into paraffin wax in a die with a 12mm central hole, which was placed on top of the tissue. Samples of 1ml were taken from the medium at certain time intervals and replaced with the same amount of PBS. The samples were filtered and assayed for drug. ^[50]

Mumtaz and Ch’ng introduced another method for studying the dissolution of buccal tablets. The buccal tablet was attached on chicken pouches. Samples were removed at different time intervals for drug content analysis. They stated “the results obtained by using this apparatus for the release of drug from bioadhesive tablets concurred with the predicted patterns”

· FUTURE CHALLENGES

Researchers are now interest to develop other innovative drug transport systems with the help of traditional polymer networks. In that controlled release buccal adhesive drug delivery is more important and which is focusing on the preparation and use of responsive polymeric system. The use of many hydrophilic macromolecular drugs as potential therapeutic agents is their inadequate and erratic oral absorption. Recent evolution of recombinant DNA research and modern synthetic and biotechnological methodologies allow the biochemist and chemist to produce vast quantities of variety of peptides and proteins possessing better pharmacological efficacy. The future challenge of pharmaceutical scientists will not only be polypeptide cloning and synthesis, but also to develop effective non-parenteral delivery of intact proteins and peptides to the systemic circulation. Buccal permeation can be improved by using various classes of transmucosal and transdermal penetration enhancers such as bile salts, surfactants, fatty acids and derivatives, chelators and cyclodextrins. Exciting challenges remain to influence the bioavailability of drugs across the buccal mucosa. Many issues are yet to be resolved before the safe and effective delivery through buccal mucosa. Successfully developing these novel formulations requires assimilation of a great deal of emerging information about the chemical nature and physical structure of these new materials. ^[23]

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Received on 21.02.2013 Modified on 28.02.2013

Research J. Pharm. and Tech. 6(5): May 2013; Page 506-515