AN ASSESSMENT ON BUCCAL MUCOADHESIVE DRUG DELIVERY SYSTEM Review Article

Buccal drug delivery system (BDDS) has won a variety of exposure and traction as it possesses plenty of advantages and benefits as evaluate to different mucosal drug delivery systems. Buccal path for systemic drug delivery, the use of mucoadhesive polymers twill significantly increase the efficacy of many tablets, has been of outstanding interest over the previous couple of decades. This article affords a precise of BDDS mechanisms, consisting of a composition of the oral mucosa, delivery mechanism, numerous forms of BDDS, formulation, assessment and application of BDDS. Additionally, this text affords a precis over the patents, advertised products and destiny factors of BDDS. In this evaluation article, we've got tried to assemble the maximum significant reports (1988 to 2021) of formulation, assessment, application, patents of BDDS. This review will help pharmaceutical researchers to clarify the potential of BDDS to overcome the various existing drug delivery dispute like the efficiency of absorption, permeability and bioavailability of drugs.


INTRODUCTION
Advancement and the progress made by the pharmaceutical industry that greatly contributed to treat the diseases, thus improving the quality of life [1]. With the passage of time researchers who are involved in the drug development industries focus on the alternative routes of administration of potentially capable pharmaceutical products and as well as to overcome defects that are associated with the oral route of administration. Though oral route is the most preferred route for the administration of major drugs, but it possesses certain drawbacks such as, the first pass metabolism in the liver, the local GI and enzymatic degradation inside the GI tracts [2].
In order to overcome the above mention drawbacks, one such strategy was used that is to deliver the drug through the alternative route such as Intranasal, Sublingual, Buccal, Pulmonary or Transdermal drug delivery systems [3]. Transmucosal method of drug transmission comprise of the mucosal lining of mouth, eye, vagina, rectum and nasal cavity which provides potential benefits over oral systemic drug delivery system. These features include the ability to bypass the first-pass metabolism, avoid the pre-elimination of the drug in the GI tack and dependence on the drug characters, it shows better enzymatic flora for the drug absorption [4].
Among the different mucosal pathways, the buccal mucosa has excellent accessibility, stretching of smooth muscle and relatively immobile mucosa; thus, this route of administration is suitable for controlled release of drugs from the dosage forms. By eliminating firstpass metabolism and enzymatic degradation owing to GI microbial flora, the oral mucosal drug delivery method is extensively applicable as a unique site for drug administration for immediate and controlled release action. Local and systemic action is provided through the oral mucosal medication delivery system. In addition, it exhibit great patient compliance as compare to other non-oral mucosal methods of drug administration. The Buccal drug delivery avoids acidolysis of the drug in GI system and bypasses the first-pass hepatic metabolism, which results the high bioavailability of the drug [5].
This article summarizes the advantage and disadvantages, application, evaluation, mechanism of the drug penetration, patents and marketed available pelletized drug delivery system. And also it will highlight the important terms and descriptions in the advantages, disadvantages, application, evaluation, mechanism of the drug penetration, patents and marketed available pelletized drug delivery system. This review was conducted using Google search terms such as buccal mucoadhesive drug delivery system and articles relating to its formulation, evaluation, application and patents, which were collected from standard journals such as science direct, pubmed and scopus indexed journals.

Physiological, anatomical features of the oral cavity
The lips, hard palate (the bony front portion of the roof of the mouth), soft palate (the muscular back portion of the roof of the mouth), retromolar trigone (the area behind the wisdom teeth), front two-thirds of the tongue, gingiva (gums), buccal mucosa (the inner lining of the lips and cheeks), and floor of the mouth under the tongue are all parts of the oral cavity. In the following fig. 1 and table 1, it show the composition of the oral cavity and its respective role in drug penetration.

Basement Membrane
It forms a distinct layer between the epithelium and connective layer Role: Provides the adherence between the epithelium and connective tissue and provide mechanical support to the epithelium layer 1-2 µm Addition of positively charged polymers like Chitosan, Cationic compounds like Poly-L-arginine, L-lysine will show an Ionic interaction with the negative charge on the mucosal surface will paves the way to the enhancement of drug through the mucosa [4,5] 3.

Transport mechanism
Drug transport mechanism through the Buccal drug delivery is carried out by two mechanisms i.e. transcellular (intracellular) and paracellular (intercellular) as shown in fig. 2 (F). Paracellular route of permeation of the drug across the buccal epithelium is carried out through the passive diffusion. It is the most common route of transportation of various drug especially for the hydrophilic drugs i.e. protein or peptide which undergoes rapid dissolution in the aqueous fluid present in the intercellular spaces. For example caffeine is the drug which undergoes absorption via paracellular route and more often used as a marker for the paracellular absorption [9]. Whereas in case of trancellular pathway drug is penetrated through the cells i.e. by transferring the drug through the lipodial barrier i.e. cell membrane followed by the hydrophilic content of the series cell in order to reach the cytoplasmic content of the next cell. Example of the drug that penetrates via transcellular route of permeation is fentanyl [10]. Certain drugs may penetrate by using both the pathways which is possible only when the drug exhibit proper hydrophilic and lipophilic balance with a slight predominance of hydrophilic property. These drugs undergoes faster penetration, apart from these pathways alternative pathway like carrier mediated transport also play an major role for the penetration of the certain drugs across the membrane [11]. The major factors that influencing the penetration and bioavailability of the drug through the Buccal drug delivery includes permeability and thickness of the epithelium, blood supply, metabolic activity, saliva and mucous, species difference and route of mechanism [12]. - [17][18][19] Advantages and disadvantages of Buccal drug delivery system Table 3: Advantages and Disadvantages of the buccal drug delivery system Advantages Disadvantages Reference • In contrast to the other mucosal tissues, the buccal mucosa is relatively permeable and has a good blood supply.

Novel buccal dosage formulations
• Bypass first pass metabolism • Exhibits localized therapy • Many medications would work better because they have a longer contact time with the mucosa.
• Patient acceptance is high as compared to other non-oral drug delivery methods.
• Lower administration frequency may result from increased residence time combined with controlled API release.
• API localization at the disease site can also result in substantial cost savings and a reduction in dose-related side effects.
• The formulation stays longer at the delivery site as a result of adhesion and personal touch, improving API bioavailability while using lower API concentrations for disease care.
• Buccal drug delivery removes the harsh environmental conditions that occur in oral drug delivery.
• It is a passive drug absorption mechanism that does not need any activation.
• In comparison to rectal or transdermal pathways, the presence of saliva guarantees a comparatively large volume of water for drug dissolution.
• Provides a various different ways to administer hormones, narcotic analgesics, steroids, enzymes, cardiovascular agents, and other medications.
• It allows for localized tissue permeability alteration, protease inhibition, and immunogenic response reduction. As a result, therapeutic agents such as peptides, proteins, and ionized species can be easily administered.
• The total surface area of the oral cavity membranes usable for drug absorption is 170 cm 2 , with nonkeratinized tissues, such as the buccal membrane, accounting for 50 cm 2 .
• The medication is diluted as a result of the continuous secretion of saliva (0.5-2 l/day).
• The risk of choking if the delivery system is swallowed involuntarily is a concern.
• Swallowing saliva may result in the loss of dissolved or suspended drugs, as well as the inadvertent removal of the dosage type.

Enzyme inhibitor
Enzyme inhibitors are used in the formulation of BDDS in order to enchance the drug absorption by decrease the affect of the enzyme over the drug by altering the structural configuration of enzyme and in order to make the drug less susceptible towards the enzyme degradation.

Solvent casting
This method is widely used for the manufacturing of the controlled release matrix and liquid reservoir type buccal film, oral disintegrating films, pellets and granules [35,39].

Direct milling
This method is widely used for the manufacturing of the oral buccal films and buccal wafers [54,69].

Hot melt extrusion of films
This method is widely used for the manufacturing of the controlled release matrix tablets, oral disintegrating films, pellets and granules. The procedure of hot melts extrusion as follows [80,97]: Application of buccal drug delivery  Marketed products of bdds formulation

Future outcomes
Buccal drug delivery system offers advantages in accessibility, administration, economy, patient compliance. Novel preparations are focusing on the use of responsive polymeric system using copolymer with desirable hydrophilic/hydrophobic interaction, complexation networks, block or graft polymers from the natural edible sources. At the current global scenario, experts are finding ways to develop Buccal drug delivery with improved bioavailability of orally inefficient drugs by manipulating the formulation with enzyme inhibitors, inclusion of pH, permeation enhancers. At present solid dosage forms, liquids, patches and gels are commercially successful.

CONCLUSION
The Buccal drug delivery system predominantly serves more advantages when compared to controlled drug delivery. It was a promising area for the systemic drug delivery of orally inefficient drugs. It has significant advantages like avoidance of presystemic elimination in GIT and first pass metabolism in liver. Buccal drug delivery can be affected by thickness of mucosal layer, barrier properties of mucosa, area of absorption site and it can be enhanced by penetration enhancers, bio-adhesive agents. In this review we have concluded that with the right dosage form design, mucoadhesive polymers and ideal formulation, the permeability and the local environment of mucosa can be controlled and manipulated in order to enhance drug permeation. This review will help pharmaceutical researchers to clarify the potential of BDDS to overcome the various existing drug delivery dispute like efficiency of absorption, permeability and bioavailability of drugs.

FUNDING
There was no specific funding for this case study from any source

AUTHORS CONTRIBUTIONS
Mrs. V. Leelalakshmi was involved in review of literature and collection of data and preparation of the manuscript. Mr. Umashankar MS, Mr Alagusundaram M was involved in reviewing, and editing of the manuscript.