1Department of Pharmaceutics, Jagan’s College of Pharmacy, Nellore, Andhra Pradesh, India, 2Department of Pharmaceutics, SRM College of Pharmacy, Chennai, India
Email: [email protected]
Received: 27 Jul 2021, Revised and Accepted: 14 Sep 2021
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.
Keywords: Buccal drug delivery, mucoadhesive polymer, Formulation, Evaluation, Application, Patents
© 2021 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijap.2021v13i6.42760. Journal homepage: https://innovareacademics.in/journals/index.php/ijap
Advancement and the progress made by the pharmaceutical industry that greatly contributed to treat the diseases, thus improving the quality of life . 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 .
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 . 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 .
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 first-pass 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 .
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.
Fig. 1: (A) Anatomy of oral mucosa; (B) Transverse section of oral mucosa 
Table 1: Composition of the oral cavity and mechanism of permeation enhancers
|S. No.||Composition of the oral cavity and its role||Thickness||Drug permeation enhancement mechanism||Reference|
Epithelium Layer as shown in fig. 1 possesses two type
Non keratinized epithelium
It covers the soft palate, ventral surface of the tongue, inner lip, floor of the mount and inner cheeks
It covers the gingiva, dorsal surface of the tongue and hard palate. Role: Protective layer
|500-800 µm||The pores of the protective layer can be enhanced by the addition of surfactant (Anionic: Sodium lauryl sulfate Cationic: Cetyl pyridinium chloride Nonionic: Poloxamer, Brij, Span, Myrj, Tween) by the agitation of intercellular Lipids and its protein (keratin) domain structure||[2, 3]|
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]|
It consists of lamina propria and submucosa layer. The lamina propria consists of collagen fibers, supporting layers, blood vessels and smooth muscles.
Role: Responsible for the blood supply to the oral cavity. The Buccal artery like facial artery and infraorbital artery are the predominant source of blood supply to cheek lining in the Buccal cavity. Which will be responsible for enhancement of drug penetration due to the predominant source of blood supply
|150-500 µm||By adding a surfactant, Cyclodextrins, Chelators, anionic and cationic polymers may interfere with Ca+ions, negative charge on the mucosal surface will leads to enhancement of drug permeability.||[6, 7]|
Gel like secretion which was translucent and continuous;
Role: It is a visco-elastic hydrogel which act as a protective layer to the cell below.
(Keratinized)-250 µm with 0.89 ml/min/cm2
By adding anionic and cationic surfactant, bile salts (Sodium glycocholate, Sodium tauro deoxycholate, Sodium tauro cholate), Fatty acids (Oleic acid, Caprylic acid, Lauric acid), Cyclodextrin, Chelator (EDTA, Citric acid, Sodium salicylate, Methoxy salicylates)
will either increase the fluidity of phospholipid domains or agitate the intercellular Lipids and its protein(keratin) domain structure
Role: Protective fluid, Source of mineralization for the tooth enamel, Hydrate the oral drug delivery system
|viscosity-1.05 cP and 1.29 cP, respectively||
Drug Permeation enhancement mechanism:
will either increase the fluidity of phospholipid domains by adding bile salt, fatty acids to the BDDS
Fig. 2: (a) Buccal mucoadhesive tablet ; (b) Administration sites of buccal mucoadhesive tablets ; (C) Schematic representation of bioadhesion mechanism ; Buccal mucoadhesive films ; (D) Contact of Bdds to buccal mucosa ; (E) Buccal patch ; (F) Scheme of route of permeation from BDDS through buccal mucosa 
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 . 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 . 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 . 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 .
Novel buccal dosage formulations
Table 2: Novel buccal dosage formulations
|S. No.||Dosage form||Description||Example||Reference|
|1.||Buccal mucoadhesive tablets as shown in fig. 2(A,B)||
||Double layer tablet||[13, 14]|
Buccal patches as shown in fig. 2(E)
It is of two types
|3.||Semisolid dosage form(ointments and gel)||
||Hydroxypropyl cellulose and beclomethasone combination||[18, 19]|
|5.||Sprays||It is made up of Mucoadhesive suspension, especially used through nasal route||-||[17-19]|
Advantages and disadvantages of Buccal drug delivery system
Table 3: advantages and disadvantages of the buccal drug delivery system
Formulation of buccal drug delivery
Table 4: Types of excipients and their role in the buccal drug delivery system
Mucoadhesives are synthetic or natural polymers that bind with the mucus layer that coats the mucosal epithelial surface and the major molecules that make up mucus.
Semi synthetic/natural polymer:
Agarose, gelatin, Hyaluronic acid, pectin and cellulose derivatives.
Poly(acrylic acid)-based polymers
i.e. poly(acrylic acid-co-thylhexylacrylate), poly(methacrylate)
Water soluble polymer:
Water insoluble polymer:
Chitosan (soluble in dilute aqueous acids), EC, PC
chitosan, dimethylaminoethyl (DEAE)-dextran, trimethylated chitosan
Non ionic polymer:
poly(ethylene oxide), PVA, PVP, scleroglucan
Chitosan-EDTA, CP, CMC, pectin, PAA, PC, sodium alginate, sodium CMC, xanthan gum
Permeation enhancer (<1%) enhances the permeation ability of the drug through the epithelium membrane. The permeation enhancer mechanism depends upon the fick’s first law of diffusion.
Its mechanism is as follows:
Ionic: Dioctyl Sodium sulfosuccinate, Polyoxyethylene-20-cetyl ether
Polyoxyethylene-9-lauryl ether (PLE) (nonionic)
Fatty acids and derivatives:
Acylcarnitine, Oleic acid, Caprylic acid, Mono(di)glycerides and Lauric acid
EDTA,Citric acid and Salicylates
Polyols: Propylene glycol and Polyethylene glycol
Bile salts and derivatives:
Sodium deoxycholate), Sodium glycodihydrofusidate and Sodium deoxycholate
Sulfoxides: Dimethyl sulfoxide(DMSO)
Urea and derivative Azone(1-dodecylazacycloheptan-2-one) (laurocapram) and cholines
|3.||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.||Aprotinin, bestatin, puromycin, bile salts stabilize and polyacrylic acid.||[27-29]|
Manufacturing methods of the buccal tablets [6, 10, 26]
Evaluation parameters of buccal drug delivery system
Table 5: Evaluation parameters of BDDS
|S. No.||Evaluation parameter||Type of buccal dosage form||Method used||Instrument||Reference|
|1.||Surface pH||Patch, Tablets Films||Visual colour change||pH meter||[32-35]|
|2.||Morphology||Tablets, Patches Films||Microscopy||Scanning Electron Microscopy (SEM)||[36-39]|
|3.||Swelling index||Patches, Films Tablets, Wafers||Swelling of patch and tablet in pH 6.4 phosphate buffer||Agar gel plates||[39-43]|
|4.||Folding endurance||Patches, Films||Repeated folding in same point||Manually folded||[43-45]|
Patches, Films Tablets
|FTIR, DSC, XRD||[46-48]|
|Standard deviation||Vernier calipers, Screw guaze, Electronic digital micrometer||[49-51]|
|7.||Mucoadhesive strength||Patches, Films Tablets||Tensile strength||texture analyzer||[42, 58, 62]|
|8.||Water absorption capacity test||Patches Films||Agar plate technique||Desiccators||[52-54]|
|9.||Invitro drug release||
Tablets, Patches, Films
|Beaker method; Dissolution method; Rotating paddle method||
Kesary chein cell;
Franz diffusion cell
|Wilhelmy plate technique||Microprocessor Modified tensile strength tester||[59-62]|
|11.||Residence time||Patches Films||Disintegration||Modified disintegrator||[63, 64]|
|12.||Palatability test||Patches Films||Grading of taste||E-taste meter||[65-68]|
|13.||Flatness||Patches Films||Percent constriction||Vernier calipers||[69, 70]|
|14.||Drug content||Tablets, Patches Films||Titration||RP-HPLC method, UV spectrophotometer||[71-74]|
|15.||Hardness||Tablets Wafers||Crushing force||Monsanto hardness tester||[75-78]|
|17.||Contact angle||Films||Wetting||Optical tensiometer||[72, 84-86]|
|19.||Water vapour transmission rate||Patches Films||Dressing method||Ovens||[90, 91]|
|20.||Drug entrapment||Patches, Films, Microspheres||Assay||UV spectrophotometer||[82, 91,]|
Colloidal gold staining method
Florescence probe method
|Dissolution cells||[92, 93]|
|22.||Percentage moisture loss||Patches Films||Gravimetry method||Desicator||[94, 95]|
|23.||ex vivo residence time (RT)||Patches Films Tablets||Modified disintegration test apparatus||disintegration tester||[96-98]|
Manufacturing methods of the buccal patches/films
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].
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
Table 6: applications of bdds
Patents of bdds formulations
Table 7: Patents of BDDS formulations
|S. No.||Title||Author||Patent number||Year|
|1.||Buccal and/or sublingual therapeutic formulation||Cumming Alisthair, Kannar david, Sparrow lance||AU2016238901A1||2016|
|2.||Bioadhesive films for oral and/or systemic delivery||Mcconville Jason Thomas, Morales Javier O, Ross Alistair||US2016128947A1||2016|
|3.||Buccal delivery system||Rubina Mughal||GB2568554A||2017|
|4.||Composition and method for Buccal administration of GNRH agonists||De groot Aldemar B, Taneja Rajneesh||WO2017208076A1||2017|
|5.||Sublingual or Buccal administration of DIM for treatment of skin diseases||Scaife michael||WO2018051183A1||2018|
|6.||Transmucosal delivery devices with enhanced uptake||Finn Andrew, Vasisht Niraj||US2018133210A1||2018|
|7.||Chewable composition for rapid Buccal absorption||Purcell Marc||US2019015324A1||2019|
|8.||Transdermal drug delivery systems for levonorgestrel and ethinyl estradiol||Liao Jun, Nguyen Viet, Patel Prashant||US10231977B2||2019|
|9.||Buccal swab delivery system||Azimi Nooshin, Cauley Thomas H, Cohen Bruce A, Schnipper Edward F||US2020376241A1||2020|
|10.||Device and methods for ultrasonic delivery of an agent within an oral cavity||France Marion, Schoellhammmer carl, Sheppard Norman||WO2020018866A1||2020|
|11.||Enhancing drug activity through accentuated Buccal/sublingual administration||Banerjee Debasish, Banerjee Priyangbada||WO2021019278A1||2021|
Marketed products of bdds formulation
Table 8: Marketed products of BDDS formulation
|S. No.||Marketed product||Active ingredient||Bioadhesive agent||Dosage form||Company/Manufacturer||Therapeutic class|
|1.||Buccastem®||Prochlorperazine maleate||Xanthum gum||Buccal tablet||Reckitt Benckiser||Antipsychotics|
|2.||Corsodyl gel®||Chlorhexidine Digluconate||HPMC||Oral paste||GlaxoSmith Kline||Antimicrobial|
|3.||Actiq||Fentanyl citrate||Magnesium stearate||Lozenge||Cephalon||Opiod analgesics|
|4.||Suscard||Glyceryl trinitrate||Hypromellase||Tablet||Forest laboratories||Vasodilator|
|5.||Corlan pellets||Hydrocortisone sodium succinate||Acacia||Oral mucosal pellets||Celltech||Corticosteroids|
|7.||Coreg||Carvedilol||HPMC||Buccal patch||GlaxoSmith Kline||Hypertension|
|8.||Loramyc||Miconazole||Corn starch||Tablet||BioAliance pharma SA||Antifungal|
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.
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.
There was no specific funding for this case study from any source
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.
there is no conflict of interest for this review.
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