INTRODUCTION:

Mucoadhesive tablets are unconventional formulations with a few numbers of products registered by regulatory agencies such as FDA and ANVISA, and available to the population. However, there are a high number of patents and articles using this pharmaceutical form as an alternative to the oral administration. These formulations can be applied in areas with low vascularization, aiming local administration, or with high vascularization, when systemic absorption is desired; in opposition to the oral tablets, whose pharmacological efficacy depends necessarily on the absorption and systemic distribution.

The main advantages of these formulations are: drug targeting, sustained release, increased permanence time in the buccal mucosa, increased bioavailability, and decreased potential adverse effects. Among the various routes of drug delivery, the oral route is an attractive site for the delivery of drugs. The buccal cavity was found to be the most suitable and easily accessible site for the delivery of therapeutic agents for both local and systemic delivery. Buccal Adhesive drug delivery system extend the residence time of the dosage form at the site of absorption and facilitate an intimate contact of the dosage form with the absorption surface and thus contribute to improved therapeutic performance of the drug. Bioadhesion can be defined as phenomenon of interfacial molecular attractive forces in the midst surfaces of the biological substrate and the natural and synthetic polymers, which allows the polymer to stick to the biological surface for a prolonged period of time. Among the many routes of drug delivery the oral route is perhaps the most preferred by clinicians and patients alike. The thought of mucosal adhesion was introduced into controlled drug delivery area in the early 1980’s, which is become a most important part of novel drug delivery system in the recent era. The possible sites for attachment of any bioadhesive system are include buccal cavity, eyes, nasal cavity, vagina, rectal area, sublingual route as well as gastrointestinal area. Buccal drug delivery is the one of the noval drug delivery systems. It is also a safer mode of drug delivery system. Buccal mucosa has a tremendous availability, which leads to direct access to systemic circulation through the internal jugular vein bypasses the drug from hepatic first pass metabolism. The buccal route administration delivers a direct entry of drug molecule into systemic circulation.^1-11

Salient feature:

Polymer and its degradation products should be nonpoisonous, non-irritant and free from leachable impurities.

Should have good wetting, swelling, spreadability, solubility and biodegradability properties.

1. It should show suitable shelf life.

2. It should have adhesively active groups.

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

4. Drug release in a controlled fashion.

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

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

7. The molecular weight should be optimum.

8. Should adhere quickly to buccal mucosa and should have sufficient mechanical strength.

Advantages:^12-15

1. Avoid hepatic first pass metabolism, Rapid onset of action.

2. Maintains constant blood levels for extended period of time.

3. Decrease gastrointestinal side effects.

4. Self medication is possible, Improved patient compliance.

5. Allow the administration of drug with narrow therapeutic window because drug levels are maintained within the therapeutic window for longer time.

6. Buccal drug delivery has a high patient suitability compared to other non-oral routes of drug administration.

7. Harsh environmental factors that occur in oral delivery of a drug are circumvented by buccal delivery.

Disadvantages:^16-19

Limited absorption area- the total surface area of the membranes of the oral cavity available for drug absorption is 170 cm² of which ~50 cm² represents non-keratinized tissues, including buccal membrane.

1. The continuous secretion of the saliva (0.5-2 l/day) leads to subsequent dilution of the drug.

2. The barrier function of the skin changes from one site to the other and from one person to other person with age.

3. The ionic drugs cannot be delivered by this route.

4. The poor skin permeability limits the number of drugs that can be delivered in this manner.

5. clinical need must be clearly established.

6. large dose of drug are difficult to be administered.

7. Drugs, which are not stable at buccal PH cannot be administered.

8. If formulation contains anti-microbial agents, affects the microbes in the buccal cavity.

9. Low permeability of the buccal membrane specifically when compared to the sublingual membrane.

Emerging technology:^20-38

1. Melt granulation:

Melt granulation technique is a process by which pharmaceutical powders are capably agglomerated by a meltable binder. The advantage of this technique compared to a conventional granulation is that no organic solvents or water is required. Because there is no drying step, the process uses less energy and less time consuming than wet granulation. This is a useful technique to increase the dissolution rate of poorly water-soluble drugs such as griseofulvin. This approach to prepare FDT with adequate mechanical integrity, involves the use of a hydrophilic waxy binder (Superpolystate©, PEG – 6 – stearate). Superpolystate© is a waxy material and amelting point of 33–37°C and a HLB value of 9. So it will not only act as a binder as well as increase the physical resistance of tablets but will also help the disintegration of the tablets as it melts in the mouth and solublises speedily leaving no residues.

2. Phase transition process:

It is concluded that a combination of high and low melting point sugar alcohols, as well as a phase transition in the manufacturing process, are important for making FDTs without any special apparatus. FDT were formed by compressing powder containing erythritol (melting point: 122°C) and xylitol (melting point: 93-95 °C), and then heating 15 min at about 93°C . After heat is provided to the median pore size of the tablet, the tablet hardness was increased with heating. Storage did not depend on the crystal state of the lower melting point sugar and alcohol.

3. Sublimation:

In this method a subliming material like camphor is uninvolved by sublimation from compacted tablets and high absorbency is achieved due to the formation of several pores. where camphor particles earlier existed in the compressed tablets prior to sublimation of the camphor. A high porosity was found due to the formation of many pores. where the camphor particles previously existed in the compressed mannitol tablets prior to sublimation of the camphor. These compressed tablets which have high porosity (approximately 30%) speedly dissolved within 15 seconds in saliva. Granules containing nimusulide, lactose and camphor were prepared by using wet granulation technique. By vacuum exposure Camphor was sublimed from the dried granules. Conventional methods like dry granulation, wet granulation and direct compression with extremely soluble excipients, super disintegrants and effervescent systems can also be used.’

4. Three-dimensional Printing (3DP):

Three-dimensional printing (3DP) is a rapid prototyping (RP) technology. Prototyping involves constructing particular layers that uses powder processing and liquid binding materials. By using the three dimensional printing (3DP) loose powders was fabricated in a novel fast dissolving drug delivery device (DDS). The DDD containing the drug acetaminophen were prepared automatically by 3DP system and it is based on computer-aided design model. It was found that rapidly disintegrating oral tablets with appropriate hardness can be formulated using TAG. The rapid disintegration of the TAG tablets seemed due to the rapid water penetration into the tablet resulting large pore size and large overall pore volume.

5. Mass Extrusion:

This technology involves softening of the active blend by using a solvent mixture of water soluble polyethylene glycol and methanol and expulsion of softened mass through the extruder or syringe to form a cylindrical shaped extrude which are then lastly cut into even segments by using heated blade to form tablets. This method used for coat granules of bitter drugs to mask their taste.

6. Spray Drying:

In this technique, gelatin used as a supporting agent and as a matrix. mannitol is used as a bulking agent and sodium starch glycolate or crospovidone are used as superdisintegrants. Tablets manufactured from the spray-dried powder and it is disintegrate in aqueous medium in less than 20 seconds. The formulation contained mannitol and lactose used as bulking agent. A superdisintegrant such as sodium starch glycolate and croscarmellose sodium and acidic ingredient (citric acid) and/or alkaline ingredients (e.g. sodium bicarbonate) are used. This spray-dried powder, which compressed into tablets showed fast disintegration and enhanced dissolution. Kollidon CL excipient base are used in this method Maximum drug release and minimum disintegration time were observed compared to tablets prepared by direct compression, showing the superiority of the spray dried excipient base method over direct compression method.

7. Cotton Candy Process:

In this process FLASHDOSE® is prepared by using Shearform™ technology in association with Ceform TI™ technology used in the medicament to eliminate the bitter taste . The Shearform technology is help in the formulation of a matrix known as ‘floss’, made from a combination of excipients, either alone or with drugs. Similar to cotton-candy fibers floss is fibrous material , commonly made of saccharides such as sucrose, dextrose, lactose and fructose at temperatures ranging between 180–266°F. However, other polysaccharides such as polymaltodextrins and polydextrose can be converted into fibers at 30–40 lower temperature than sucrose. This modification help in the safe incorporation of thermolabile drugs into the preparation. The tablets manufactured by this process they are highly porous in nature and this offer mouth feel pleasant due to rapid solubilization of sugars in presence of saliva. The manufacturing process can be divided into four steps as described below:

a. Floss Blend:

In the first step of cotton candy 80% sucrose is used in combination with mannitol/dextrose and 1% surfactant is mixed to form the floss mix. The surfactant acts as a crystallization enhancer and surfactants maintains the structural integrity of the floss fibers. This step is used in the conversion of amorphous sugar into crystalline form from an outer portion of amorphous sugar mass and subsequently converting the remaining portion of the mass to complete crystalline structure. This process helps to retain the dispersed drug in the matrix and Minimizing migration out of the mixture.

b. Floss Processing:

The floss formation machine uses flash heat and flash flow processes to form matrix from the carrier material. The machine used in this process is similar to that used in ‘cotton-candy’ formation which consists of a spinning head and heating elements. In the flash heat process, the heat are induces in an internal flow condition of the carrier material. This is followed by its exit through the spinning head (2000–3600rpm) that throws the floss under centrifugal force. It is draws into long and thin floss fibers, which are usually amorphous in nature.

c. Floss Chopping and Conditioning:

This step involve the conversion of fibers into smaller particles in a high shear mixer granulator. This is performed by partial crystallization through an ethanol treatment (1%) which is sprayed onto the floss and it is subsequently evaporated. Improved flow and cohesive properties to the floss. d. Blending and Compression: Finally, the chopped and conditioned floss fibers are blended with the drug along with other essential excipients and compressed into tablets. This process improve the mechanical strength of the tablets. This step is also carried out which involves the exposure of the dosage forms to elevated temperature and humidity conditions, (40°C and 85% RH for 15 min). This process cause crystallization of the floss material that results in binding and bridging to improve the structural strength of the dosage form.

8. Tablet Molding:

Molding process include two type of method i.e. solvent method and heat method. Solvent method involve moistening the powder blend with a hydroalcoholic solvent followed by compression at low pressures in molded plates to form a wetted mass . This solvent is then removed by air-drying. The tablets manufactured in this manner are less compacted than compressed tablets. It posses a porous structure that hastens dissolution. In the heat molding process preparation of a suspension that contains a drug, agar and sugar (e.g. lactose or mannitol) and pouring the suspension in the blister packaging wells, solidifying the agar at the room temperature form jelly and then it is dried at the 30^◦C under vacuum. Binding agents are incorporated in the formulation which increase the mechanical strength of the tablets. Taste masking is an additional problem to this technology. The taste masked drug particles were formulated by spray congealing process. A molten mixture of hydrogenated cottonseed oil, sodium carbonate, lecithin, polyethylene glycol and an active ingredient incorporate into a lactose based triturate form of tablet. Tablets produced by the molding technique are easier to scale up for industrial manufacture than lyophilisation technique.

9. Lyophilization or Freeze-Drying:

In the freez drying process water is sublimed from the product after it is frozen. This technique creates an amorphous porous structure that can dissolve quickly. A typical procedure include in the manufacturing of ODT using this technique is mentioned here. The active drug is dissolved in an aqueous solution of a carrier/polymer. The mixture is done by weight and it is poured in the walls of the preformed blister packs. The trays holding the blister packs are passed through liquid nitrogen freezing tunnel for freezing the drug solution. Then the frozen blister packs are placed in refrigerated cabinets for continue the freeze-drying. After freez drying the aluminum foil is applied on a blister-sealing machine. Finally the blisters are packaged . The freeze-drying technique improved absorption and increase in bioavailability. The major disadvantages of lyophillization technique are that it is expensive and time consuming method. fragility makes conventional packaging not suitable for these products and poor stability under stressed conditions.

10. Direct Compression:

This very simple and most cost effective tablet manufacturing technique. This technique can be recently for the preparation of ODT because of the availability of excipients especially superdisintegrants and sugar based excipients. a) Superdisintegrants: In many orally disintegrating tablet technologies based on direct compression, the addition of superdisintegrants affects the rate of disintegration and hence the dissolution. Sugar Based Excipients: This is another method to manufacture ODT by direct compression. The use of sugar based excipients especially bulking agents like dextrose, fructose, isomalt, lactilol, maltose, mannitol, sorbitol, starch hydrolysate, polydextrose and xylitol, which show high aqueous solubility and sweetness, and impart taste masking property and a pleasing mouthfeel. Mizumito have classified two types of sugar-based excipients on the basis of molding and dissolution rate, Nanonizationis a recently developed technique. By using Nanomelt technology reduction in the particle size of drug to nanosize by milling the drug using a wet-milling technique. The nanocrystals of the drug are stabilized against agglomeration by surface adsorption on particular stabilizers and which are then incorporated into MDTs. This technique is especially used for poor water soluble drugs. Other advantageous of this technology involve rapid disintegration and dissolution of nanoparticles.

METHOD OF PREPARATION:^39-44

1. Solvent casting:

In this method, all cover excipients containing the drug co-dispersed in an organic solvent as well as coated onto a sheet of release liner. Later solvent evaporation, a thin layer of the defensive backing material is coated onto the sheet of coated release liner to form a laminate that is die-cut to form patches of the desired size and geometry.

2. Direct milling:

Drug and excipients are mixed by kneading, usually without the presence of any liquids. Later the mixing process, material is rolled on a release linear. until the desired thickness is achieved. The backing material is then laminated as previously described. While there are only minor or even no differences in patch performance between patches fabricated by the two processes, the solvent-free process is preferred because there is no possibility of residual solvents and no associated solvent related health issues.

3. Hot melt extrusion of films:

In hot melt extrusion blend of pharmaceutical ingredients is molten and then forced through an orifice to yield a more homogeneous material in different shapes such as granules, tablets, or films. Hot melt extrusion has been used for the manufacture of controlled release matrix tablets, pellets and granules, as well as oral disintegrating films.

4. Direct compression:

The mucoadhesive bilayered buccal tablets consist of drug-releasing polymer layer and a backing layer of ethyl cellulose, which allow unidirectional release of the drug. They are prepared by the direct compression method involving two steps. In the first step, the drug polymer mixture is to be prepared by homogeneously mixing the drug with mucoadhesive polymers. The other excipients present in the formulation like the diluents, permeation enhancers, organoleptic agents.

Table No. 1: Marketed and Under Research Formulations:

Brand name	Active ingredient	Bioadhesive Polymer	Dosage form
1. Aphtach	Triamcinolone acetonide	Triamcinolone acetonide	Tablet
2.Buccastem	Prochlorperazine	Xanthan gum, Povidone, Locust bean gum	Tablet
3. Lauriad	Miconazole	Unknown	Tablet
4. Striant	Testosterone	Carbomer 934P, Hypromellose, PC	Tablet
5. Suscard	Glyceryltrinitrate	Hypromellose	Tablet

Applications:

Drugs which on oral administration result in poor bioavailability and are rapidly degraded provides advantages of high accessibility and low enzymatic activity. These systems involve the delivery of peptides, proteins and polysaccharides, hydrophilic polymers like SCMC, HPC and polycarbophil were used for the treatment of periodontal diseases.

CONCLUSION:

Review paper concluded that among the many routes of drug delivery the oral route is perhaps the most preferred by cliniciansand patients alike.The main advantages of these formulations are: drug targeting, sustained release, increased permanence time in the buccal mucosa, increased bioavailability, and decreased potential adverse effects and Maintains constant blood levels for extended period of time.

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Received on 22.12.2019 Modified on 10.03.2020

Research J. Pharm. and Tech. 2021; 14(8):4495-4500.

DOI: 10.52711/0974-360X.2021.00781