Int J App Pharm, Vol 13, Issue 6, 2021, 66-74Review Article

AN ASSESSMENT ON BUCCAL MUCOADHESIVE DRUG DELIVERY SYSTEM

LEELA LAKSHMI V.1, UMASHANKAR M. S.2*, ALAGUSUNDARAM M.1

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


ABSTRACT

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


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 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 [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.

Fig. 1: (A) Anatomy of oral mucosa; (B) Transverse section of oral mucosa [2]

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
1.

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

Keratinized epithelium

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]
2.

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.

Connective Tissue

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]
4.

Mucus

Gel like secretion which was translucent and continuous;

Composition

  • Water insoluble glycoprotein(Mucin): 1-5%

  • Water: 95-99%

  • Proteins, enzymes, electrolytes and nucleic acids.

Role: It is a visco-elastic hydrogel which act as a protective layer to the cell below.

  • Buccal (Nonkeratinized)-500-600 µm with 2.40 ml/min/cm2

  • Sublingual (Nonkeratinized)-100-200 µm with 0.97 ml/min/cm2

  • Gingival (keratinized)-200 µm with 1.47 ml/min/cm2

  • Palatal

(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

[8, 9]
5

Saliva

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

[10, 11]

Fig. 2: (a) Buccal mucoadhesive tablet [5]; (b) Administration sites of buccal mucoadhesive tablets [6]; (C) Schematic representation of bioadhesion mechanism [8]; Buccal mucoadhesive films [9]; (D) Contact of Bdds to buccal mucosa [8]; (E) Buccal patch [9]; (F) Scheme of route of permeation from BDDS through buccal mucosa [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].

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)
  • Dry dosage form

  • Must be moistened before use prior coming in contact with the Buccal mucosa

Double layer tablet [13, 14]
2.

Buccal patches as shown in fig. 2(E)

It is of two types

  • Reservoir type

  • Matrix type

  • Consists of two laminates with adhesive polymer(aqueous form) which is glued over the backing sheet

  • When it comes in contact with the mucosal membrane results in the formation of the mucoadhesive bond between the adhesive polymer and the mucosal polymer which is known as bioadhesion.

  • Mechanism of bioadhesion can be explained by theories of bioadhesion which include electronic, adsorption, wetting, diffusion and fracture theory.

  • Formation of mucoadhesive bond is carried out by three major steps as shown in fig. 2

  1. Wetting and swelling of polymer (contact stage).

  2. Interpenetration between the adhesive polymer and mucosal membrane (mucin).

  3. Chemical bond formation (consolidation stage).

Zilactin [15, 16]
3. Semisolid dosage form(ointments and gel)
  • Less patient compliance

  • Exhibit localized action which is limited to oral cavity

Orabase [17]
4. Powders
  • It increase the residence time of the drug in oral mucosa

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

Advantages Disadvantages Reference
  • In contrast to the other mucosal tissues, the buccal mucosa is relatively permeable and has a good blood supply.

  • 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 cm2, with non-keratinized tissues, such as the buccal membrane, accounting for 50 cm2.

  • The mucosa's barrier properties.

  • 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.

[ 16-20]

Formulation of buccal drug delivery

Table 4: Types of excipients and their role in the buccal drug delivery system

S. No. Excipient Role Example Reference
1. Mucoadhesive polymer

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.

  • It is the main excipients for adhesion by attracting water, swells and adheres to the mucous through forming a channel by linking to mucin polymer

  • They bind with mucin with help of H-bonding group, hydrophilic group

Semi synthetic/natural polymer:

Agarose, gelatin, Hyaluronic acid, pectin and cellulose derivatives.

Synthetic polymer:

Poly(acrylic acid)-based polymers

i.e. poly(acrylic acid-co-thylhexylacrylate), poly(methacrylate)

Water soluble polymer:

PAA,sodium CMC,sodiumalginate

Water insoluble polymer:

Chitosan (soluble in dilute aqueous acids), EC, PC

Cationic polymer:

chitosan, dimethylaminoethyl (DEAE)-dextran, trimethylated chitosan

Non ionic polymer:

poly(ethylene oxide), PVA, PVP, scleroglucan

Anionic polymer:

Chitosan-EDTA, CP, CMC, pectin, PAA, PC, sodium alginate, sodium CMC, xanthan gum

[21-23]
2. Permeation enhancer

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:

  • Increasing fluidity and integrity of cell membranes

  • Extracting inter and intracellular lipids

  • Altering cellular proteins

  • Varying mucus rheology

  • Enhancing thermodynamic activity of drugs

  • Decreasing surface tension

Surfactant:

Ionic: Dioctyl Sodium sulfosuccinate, Polyoxyethylene-20-cetyl ether

Nonionic: Nonylphenoxypolyoxyethylene(NP-POE)(nonionic),

Polyoxyethylene-9-lauryl ether (PLE) (nonionic)

Fatty acids and derivatives:

Acylcarnitine, Oleic acid, Caprylic acid, Mono(di)glycerides and Lauric acid

Chelating agents:

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)

Others (non-surfactants):

Urea and derivative Azone(1-dodecylazacycloheptan-2-one) (laurocapram) and cholines

[24-26]
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]
5. Drug compatibility

Patches, Films Tablets

Wafers

Thermal analysis,

Spectral analysis

FTIR, DSC, XRD [46-48]
6. Thickness

Patches, Films

Tablets, Wafers

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

Microspheres

Beaker method; Dissolution method; Rotating paddle method

Kesary chein cell;

Franz diffusion cell

[55-58]
10. Mechanical properties

Patches, Films

Buccal hydrogels

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]
16. Friability Tablets Weighing Roche friabilator [79-83]
17. Contact angle Films Wetting Optical tensiometer [72, 84-86]
18. Transparency Films Transmittance UV spectrophotometer [87-89]
19. Water vapour transmission rate Patches Films Dressing method Ovens [90, 91]
20. Drug entrapment Patches, Films, Microspheres Assay UV spectrophotometer [82, 91,]
21. Bio-adhesion Patches Films

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

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

Table 6: applications of bdds

Applications References
  • Hypertension. Eg: Atenolol patches.

  • Hormone replacement therapy.

  • Angina pectoris. Eg: Nitroglycerine patches.

  • Cancer. Eg: Opiod analgesics.

  • Smoking cessation therapy. Eg: Nicotine patches.

  • Treatment of microbial infections associated with peridontitis.

  • Local therapy includes oral infections, moth ulcers, dental caries, gingivitis, stomatitis.

[86-102]

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
6. Fastum Ketoprofen PEG Gel A,Menarini industries NSAIDS
7. Coreg Carvedilol HPMC Buccal patch GlaxoSmith Kline Hypertension
8. Loramyc Miconazole Corn starch Tablet BioAliance pharma SA Antifungal
9. Bonjela®

Cetalkonium chloride,

Choline salicylate

Hypromellose Gel Reckitt Benckiser Antiulcer
10. Dentipatch® Lidocaine Xanthum gum Patch Noven Analgesic

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.

CONFLICT OF INTERESTS

there is no conflict of interest for this review.

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