Anuradha college of Pharmacy, Sakegaon Road, Chikhali Dist Buldana (MH) India 443201.
Buccal drug delivery systems (BDDS) offer a number of therapeutic benefits for systemic drug delivery, making them a viable substitute for conventional oral dose forms. Bypassing the gastrointestinal tract and the liver's first-pass metabolism, these mechanisms allow medications to be absorbed through the buccal mucosa, increasing their bioavailability. BDDS are especially helpful for medications that are sensitive to gastrointestinal disorders, have a high first-pass metabolism, or are poorly absorbed. Compared to traditional oral formulations, the buccal mucosa's high vascularization enables quick and direct drug absorption into the systemic circulation, resulting in a quicker commencement of action. Modern formulation technologies, such as films, tablets, patches, and gels, have accelerated the development of buccal drug delivery systems by optimizing drug release and absorption. These systems improve patient compliance, especially when continuous drug administration is necessary, by providing controlled or sustained release profiles. Additionally, the buccal route makes administration simple and eliminates the necessity for swallowing, which makes it a good choice for patients who are dysphagic, elderly, or juvenile. For the wider clinical use of BDDS, however, issues such restricted drug penetration, mucosal irritation, and formulation stability must be resolved. Potential solutions for getting beyond these obstacles include the use of bioadhesive polymers, innovative excipients, and permeation enhancers. All things considered, buccal drug delivery devices offer a more efficient, practical, and patient-friendly method of oral drug administration, hence presenting substantial therapeutic prospects. Their clinical use in a variety of therapeutic domains will be improved by additional study and creativity.
The most popular route of drug delivery among patients and physicians has been the oral route. However, given our current understanding of the physiological and biochemical aspects of absorption and metabolism, many drugs cannot be delivered effectively through the conventional oral route because they undergo extensive pre-systemic clearance in the liver after administration, which frequently results in a lack of significant correlation between membrane permeability, absorption, and bioavailability (1). The need to investigate different delivery methods for these medications was fuelled by issues with parenteral administration and low oral availability. As a result, more absorptive mucosae are thought to be viable drug delivery sites. When it comes to systemic action, transmucosal drug delivery routes—that is, the mucosal linings of the nasal, rectal, vaginal, ocular, and oral cavities—offer clear advantages over oral administration (2). Poor oral availability and challenges with parenteral distribution served as the catalyst for investigating alternate delivery methods for these medications. These include the buccal, sublingual, vaginal, nasal, rectal, pulmonary, ophthalmic, and transdermal routes. The placement of a medication or drug delivery system in a specific area of the body for prolonged periods of time has recently attracted a lot of attention.
Numerous body parts, such as the mouth, gastrointestinal system, urogenital tract, airways, ear, nose, and eye, are lined with the mucosal layer. Therefore, based on its possible application site, the mucoadhesive drug delivery method can be considered to be a good option for drug delivery (3). The buccal portion of the oral cavity is a desirable location for medication delivery due to ease of administration. Buccal drug distribution is the process of administering a medication through the oral cavity's buccal mucosal membrane lining. Both mucosal (local effect) and transmucosal (systemic effect) medication administration benefit from this route. While the second scenario entails drug absorption via the mucosal barrier to reach the systemic circulation, the first scenario aims to achieve a site-specific release of the medication on the mucosa (4). There is frequently no discernible relationship between membrane permeability, absorption, and bioavailability since many medications undergo considerable pre-systemic clearance in the liver following oral delivery. The external jugular vein provides direct access to the systemic circulation by avoiding the medications' first pass processing in the liver, which could increase their bioavailability. Additionally, these dose forms are inexpensive, self-administerable, and have excellent patient compliance (5). This review aims to explore the design, formulation strategies, advantages, limitations, and recent advancements in buccal drug delivery systems. Various delivery forms, such as tablets, films, patches, and gels, will be discussed in terms of their applications. Furthermore, the challenges related to the permeability of the buccal mucosa, the stability of formulations, and patient acceptability will be examined to provide a comprehensive understanding of the current state and future directions in buccal drug delivery technology.
Advantages of Buccal Drug Delivery Systems
Pathways of drug absorption
There are two main paths involved in the drug transport mechanism across the buccal mucosa: para-cellular (intercellular) and trans-cellular (intracellular) pathways. According to studies using microscopically visible tracers like small proteins and dextrans, the main route for large molecules to pass through the stratified epithelium is through the intercellular spaces, where there is a barrier to penetration because of changes made to the intercellular substance in the superficial layers. The barrier function of the para-cellular route is known to be significantly influenced by the lipid matrix of the extracellular space, particularly when hydrophilic substances with a large molecular weight, like peptides, are present (8). Certain medications are reported to be more readily absorbed through the buccal mucosa when the pH of the carrier is lowered, and to decrease when the pH is raised. It is generally believed that peptide medications enter the body through the paracellular pathway by passive diffusion across the buccal epithelium. According to a recent investigation, medications with a monocarboxylic acid residue could enter the bloodstream through the oral mucosa's carrier (9). In a variety of In-vitro and In-vivo settings, the permeability of the oral mucosa and the effectiveness of penetration enhancers have been examined. To ascertain the permeability of the oral mucosa, several types of diffusion cells have been employed, including Franz diffusion cells, Using chambers, continuous flow perfusion chambers, and Grass-Sweetana.
Design of Formulations for Buccal Drug Delivery
The ideal dosage for buccal adhesive drug delivery devices is 25 mg or less per day, and they should be between 1 and 3 cm2 in size. The maximum amount of time that buccal delivery can last is roughly four to six hours. Traditional buccal dosage forms frequently fail to maintain desired drug concentration level either on the targeted mucosal site and/or in the systemic circulation. The key formulation challenges are salivary renovation cycle and mechanical stress due to masticatory effect during eating and drinking (10). This can shift the drug aside from the site of absorption hence decreasing the contact time and change in distribution kinetics of the drug. To sustain the therapeutic effect, it is essential to extend the intimate association between active(s) and the membrane barrier of buccal tissue. To address these issues, buccal delivery system should be designed in such a manner to remain at the absorption site for desired duration of time, enhance the drug permeation across the mucosa to systemic circulation or into sub-mucosal epithelial layers unaffected by the impact of salivary flow, pH, electrolytes, and mucosal enzymes. The components in the buccal dosage forms are mainly classified as mucoadhesive polymers, penetration enhancers and enzyme inhibitors (11-12).
Pharmaceutical considerations
Great attention must be taken in the development of a buccal adhesive medicine delivery system that is both safe and effective. When creating a formulation, aspects such as drug release, penetration through the buccal mucosa, organoleptic characteristics, and impact of additional excipients used to enhance drug release pattern and absorption, and irritation at the application site must be taken into consideration. Pharmaceutical buccal adhesive drug delivery systems should ideally include enzyme inhibitors, penetration enhancers, and mucoadhesive agents. Penetration enhancers increase the drug's ability to penetrate the mucosa (trans-mucosal delivery) or the deepest layers of the epithelium (mucosal delivery), while mucoadhesive compounds help the formulations to maintain a close and extended contact with the absorption site. Ideally, the enzyme inhibitors shield the medication from being broken down by mucosal enzymes (13-14).
Buccoadhesive polymers used in the oral cavity
Increased residence time of the drug-containing device in the oral cavity and drug localization in a specific area are the main benefits of bioadhesive systems. The electrical, adsorption, wetting, diffusion, and fracture theories have all been used to describe the bioadhesion process. Strong hydrogen bonding groups, strong anionic or cationic charges, high molecular weight, chain flexibility, and surface energy qualities that promote spreading on the mucus layer are often required structural features for bioadhesive polymers (15). Generally speaking, the sources of sticky polymers should be synthetic or natural, soluble in water, and polymers that are both charged and uncharged and insoluble in water.
Table 6.1 Different permeation enhancers used in buccal drug delivery systems (16-18)
|
Class of permeation enhancers/polymer |
Examples |
Mechanism of action |
|
Thiolated polymers |
Chitosan-4-thiobutylamide, chitosan- 4-thiobutylamide/GSH, chitosan-cysteine, Poly (acrylic acid)-homocysteine, polycarbophil cysteine, polycarbophil-cysteine/GSH, chitosan-4-thioethylamide/GSH, chitosan-thioglycholic acid |
Ionic interaction with negative charge on the mucosal surface |
|
Surfactants |
Anionic: Sodium lauryl sulfate Cationic: Cetyl pyridinium chloride Nonionic: Poloxamer, Brij, Span, Myrj, Tween |
Perturbation of intercellular Lipids and protein domain integrity |
|
Chelators |
EDTA, citric acid, sodium salicylate, methoxy salicylates. |
Interfere with Ca+ |
|
Non-surfactants |
Unsaturated cyclic ureas. |
They enhance desorption and bioavailability by increasing solubility and dispersion of poorly soluble. |
|
Fatty acids |
Oleic acid, capric acid, lauric acid, lauric acid/propylene glycol, methyloleate, lysophosphatidylcholine, phosphatidylcholine |
Increase fluidity of phospholipid domains |
|
Inclusion complexes |
α, β, γ, Cyclodextrin, methylated β –cyclodextrins |
Inclusion of membrane Compounds |
|
Bile salts |
Sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate |
Perturbation of intercellular Lipids and protein domain integrity |
|
Others
|
Aprotinin, azone, cyclodextrin, dextran sulfate, menthol, polysorbate 80, sulfoxides and various alkyl glycosides |
|
Solid buccal adhesive dosage forms
They are dry formulations which achieve biosadhesion via dehydration of the local mucosal surface.
7.1 Tablets of Buccal
The most often researched dosage type for buccal medication administration has been tablets. In recent years, a number of bio-adhesive buccal tablet formulations for systemic or local drug delivery have been created using the direct compression approach. They are made to deliver the medication either multi-directionally into the saliva or unidirectionally by targeting the buccal mucosa. As an alternative, an impermeable backing layer may be used in the dosage form to guarantee unidirectional drug delivery (19). The nonubiquitous distribution of the drug in saliva for local therapy and patient acceptance (mouth feel, taste, and discomfort) could be drawbacks of buccal tablets. It is crucial to draw attention to the potential issues that children and the elderly may encounter when using adhesive tablets, including potential discomfort brought on by the substance applied to the mucosa and the potential for dosage separation from the mucosa, swallowing, and subsequent adherence to the esophageal wall. A bioadhesive polymer (like polyacrylic acids or cellulose derivatives) is typically used alone or in combination with an active agent, excipients, and possibly a second impermeable layer to enable unidirectional drug delivery in bioadhesive formulations of this kind (20-21).
Table 7.1 lists the findings from a few experiments conducted to develop buccal tablets (22-25)
|
Drug |
Bioadhesive polymer used |
|
Buprenorphine |
HEMA and Polymeg |
|
Buspirone HCL |
Carbopol 974, HPMCK4M |
|
Chlorhexidine diacetate |
Chitosan and sodium alginate |
|
Chlorpheneramine maleate |
Hakea gum, Carbopol 934, HPMC |
|
Clotrimazole |
Carbopol 974P, HPMC K4M |
|
Carvedilol |
Carbopol 934 with HPC, HPMC |
|
Cetylpyridinium chloride |
Sodium CMC and HPMC |
|
Diltiazem HCl |
Carbopol 934, HPMCK4M |
|
Ergotamine tartrate |
Carboxyvinyl polymer and HPC |
|
Felodipine and Pioglitazone |
HPMC,Sodium CMC, and carbopol |
|
Felodipine |
HP-β-CD - felodipine complex and HPMC |
|
Hydralazine HCL |
Carbopol 934P and CMC |
|
Hydrocortisone acetate |
HPMC, Carbopol 974P, or PC |
|
Insulin |
Carbopol 934 with HPC or HPMC |
7.2 Bioadhesive Micro/Nanoparticles
Bioadhesive micro/nanoparticles offer the same advantages as tablets but their physical properties enable them to make intimate contact with a lager mucosal surface area. These are typically delivered as an aqueous suspension or are incorporated into a paste or ointment or applied in the form of aerosols. Particulates have an advantage of being relatively small and more likely to be acceptable by the patients (26). Bioadhesive polymeric microparticles of carbopol, polycarbophil, chitosan or Gantrez adhere to porcine esophageal mucosa, with particles prepared from the polyacrylic acids exhibiting greater mucoadhesive strength during tensile testing studies. However in elution studies, particles of chitosan or Gantrez were found to persist on mucosal tissue for longer periods of time (27). The use of nanoparticles for local delivery to the oral mucosa has been reported. Two types of nanoparticles, solid lipid nanoparticles incorporating either idarubicin or Bodipy®FL C12 as model fluorescent probes and polystyrene nanoparticles (Fluo-Spheres®), were investigated using monolayer-cultured human oral squamous cell carcinoma (OSCC) cell lines and normal human oral mucosal explants in a proof of concept study (28).
7.3 Bioadhesive Wafers
The delivery system is a composite wafer with surface layers possessing adhesive properties, while the bulk layer consists of antimicrobial agents, biodegradable and matrix polymers. A conceptually novel periodontal drug delivery system intended for the treatment of microbial infections associated with periodontitis has been reported (29).
7.4 Bioadhesive Lozenges
A slow release bioadhesive lozenge offers the potential for prolonged drug release with improved patient compliance. Bioadhesive lozenges may be used for the delivery of drugs that act within the mouth including antimicrobials, corticosteroids, local anaesthetics, antibiotics and antifungals. A Bioadhesive lozenge has been reported as a means to deliver antifungal agents to the oral cavity. The limitation of these bioadhesive lozenzes is the short residence time at the site of absorption which depends on the size, type of formulation and dissolution time (30).
Semi-Solid Dosage Forms
Medicated Chewing Gums
Although medicated chewing gums pose difficulties in regulation of the administered dose, they still have some advantages as drug delivery devices, particularly in the treatment of diseases of the oral cavity and in nicotine replacement therapy. Some commercial products are available in the market. Caffeine chewing gum, Stay Alert®, was developed recently for alleviation of sleepiness. It is absorbed at a significantly faster rate and its bioavailability was comparable to the capsule formulation. Nicotine chewing gums (e.g., Nicorette® and Nicotinell®) have been marketed for smoking cessation (31).
Adhesive Gels
Various adhesive gels may be used to deliver drugs via the buccal mucosa and allow sustained release. Gel forming bioadhesive polymers include cross linked polyacrylic acid that has been used to adhere to the mucosal surfaces for extended period of time and provide controlled release of drug at the site of absorption. Design of a novel, hydrogel based, bioadhesive, and intelligent response system for controlled drug release has been reported (32). This system combined several desirable facets into a single formulation; a poly hydroxyethyl methacrylate layer as barrier, poly methacrylic acid-g-ethylene glycol as a biosensor and poly ethylene oxide to promote mucoadhesion. The limitations for gel formulations are inability to deliver a measured dose of drug to the site and as a result have limited uses for drugs with narrow therapeutic window (33).
8.3 Buccal Patches/Films
Patches are laminates consisting of an impermeable backing layer, a drug-containing reservoir layer from which the drug is released in a controlled manner, and a bioadhesive surface for mucosal attachment. Flexible films/patches have been prepared either by solvent casting or hot melt extrusion technique to deliver drugs directly to a mucosal membrane. Compared to creams and ointments they offer advantages in delivering a measured dose of drug to the site (34).
Recent developments in buccal drug delivery systems
Recent developments in buccal drug delivery systems, such as lipophilic gel, buccal spray and phospholipid vesicles have been recently proposed to deliver peptides via the buccal route. In particular, some authors proposed the use of cubic and lamellar liquid crystalline phases of glyceryl mono-oleate as buccal drug carrier for peptide drugs (35). A novel liquid aerosol formulation (Oralin, Generex Biotechnology) has been recently developed. Phospholipid deformable vesicles, transfersomes, have been recently devised for the delivery of insulin in the buccal cavity (36).
Commercial buccal adhesive drug delivery systems
Commercial formulations or formulations in clinical trials, intended for buccal delivery are presented in table 10.1. Only few formulations are available on market or under clinical evaluations which indicate the difficulty to develop drug delivery systems with clear efficacy and safety profiles (37-39).
Table 10.1: Summary of the different buccal dosage forms
|
Dosage forms |
Structures |
Release |
Effect |
Active ingredients |
|
Matrix tablets |
Monolithic matrix |
Sustained/bidirectional |
Local/systemic |
Local administration: metronidazole Systemic administration: propanolol, timolol, metoclopramide, morphine sulphate, nitroglycerin, codein, insulin, calcitonin, glucagone-like peptide |
|
Coating matrix (coated on the outer side or on all but one faces) |
Unidirectional |
Systemic |
||
|
Two layer matrix |
Bidirectional |
Local (Mainly) |
||
|
Two-layer matrix coated with impermeable layer |
Unidirectional |
Systemic |
||
|
Patches |
Laminated film with coating layer |
Monodirectional |
Local/systemic |
Local administration: diclofenac, tannic acid, boric acid. Systemic administration: thyrotropin-releasing hormone, octreotide, oxytocin, buserelin, calcitonin, leuenkephalin |
|
Lipophilic gels |
Patches Cubic and lamellar liquid crystalline phases of glyceryl monooleate |
- |
Systemic |
Systemic administration: (D-Ala2, D-Leu5) enkephalin |
|
Transfersomes |
Phospholipid deformable vesicles |
- |
Systemic |
Systemic administration: insulin |
Specific challenges and critical parameters associated with buccal drug delivery systems
The development and design of buccal medication delivery systems must consider a number of specific considerations and problems. These difficulties stem from the unique buccal cavity's anatomical, physiological, and environmental features. The following are some of the main difficulties and important factors related to buccal medication delivery systems: -
· Restricted Absorption Area: In comparison to other delivery routes, such as gastrointestinal system, the buccal mucosa has a comparatively narrow absorption area. The quantity of medication that may be delivered by the buccal route is restricted by this small surface area (40).
· Permeability: In comparison to other mucosal membranes, such as the nasal or pulmonary pathways, the buccal mucosa has a lesser permeability. Therefore, for medication delivery through the buccal mucosa to be successful, it must possess sufficient permeability qualities (41).
· Saliva Flow and Swallowing: The drug's bioavailability may be decreased if saliva is produced or if drug gets washed away before being absorbed by the process of swallowing. Proper management of these variables is necessary for a successful buccal delivery (42).
· Medication Formulation: It might be difficult to formulate medications for buccal distribution. To guarantee drug compatibility with the buccal mucosa, factors like the medication's physicochemical characteristics, solubility, and stability must be carefully considered (43).
· Patient Acceptance and Compliance: Compared to other methods, patients may regard buccal medication administration to be less convenient or socially acceptable. Important factors to consider include patient compliance, acceptability, and simplicity of usage (44).
· Taste and Irritation: A lot of medications have an unpleasant or bitter taste, which can make utilizing the buccal route quite difficult. Furthermore, some medications may irritate the buccal mucosa or have negative effects on it (45).
· Mucosal Permeability Variability: The buccal mucosa's permeability varies from person to person and between locations inside the mouth cavity. These differences may impact the bioavailability and absorption of drugs (46).
· Medication Clearance: Because swallowing and salivation cause drugs to be quickly removed from the buccal cavity, it is crucial to keep medication concentrations at the site of absorption (47).
· Dosing Precision: Use of buccal delivery systems to administer medication can be difficult since changes in the oral environment and the patient's activities, such as eating, drinking, and talking, can affect how well the drug is absorbed and retained (44).
· Local and Systemic Effects: It's important to evaluate and reduce the potential for some medications to have systemic adverse effects or local discomfort when taken by the buccal route (45).
· Regulatory Considerations: Safety and efficacy evaluations, as well as certain regulations and recommendations, are applicable to buccal drug delivery systems from regulatory bodies (47).
Future Perspectives and Directions
The drug delivery of macromolecules through buccal mucosa is comparatively less investigated than other routes of administration. Solvent casting method is the most frequently used method for dissolving/dispersing actives in biocompatible polymeric films. However, there is a growing interest in 3D printing techniques using HME, fused deposition modelling and inkjet method (48). The main drawback associated with film dosage form is difficulty of achieving high payload within the limited surface area of these mucoadhesive systems. This occurs even though the stability and permeability of macromolecules is apparently increased compared to oral formulations. Encapsulating with high payload in nanoparticles and embedding them in mucoadhesive polymeric may resolve this issue to certain extent (49). Investigations are currently progressing in the field of nanoparticles enabled buccal film and various functionalization strategies to allow permeation through the buccal mucosa and systemic targeting. Finding new functional excipients such as thiolated polymers with potential for permeation enhancement, exploring new pathways for buccal permeation such as ion-pair strategy, increasing the drug loading, 3D printing methods to incorporate multiple drug combinations and compartmentalization to separate incompatible drugs are other novel areas of future research and developments in trans-buccal delivery systems (50). Successful design and development of microneedles patch to deliver 1 mg of human insulin and human growth hormone in the buccal cavity of swine in a short time (<30 s) has also been demonstrated in the latest researches. Clinical trials in human volunteers indicated that microneedle patches applied on buccal surfaces could enhance patient compliance and promote the pain free delivery of biologics and other drugs particularly to pediatric, bed ridden and elderly populations (51). The oral mucosa is an attractive site for vaccination, but a water rich environment can limit accurate dose delivery of vaccines. Ovalbumin dip coated on the tips of microneedle patch was found to deliver vaccine into the epithelium of the mice buccal mucosa in a short period of time compared to flat disk patch coated with ovalbumin substrate without microneedles (52). The advent of nanohybrid materials as drug-delivery systems can hold the beneficial properties of their precursors and present additional advantages namely versatile methods for their production, improved mechanical and thermal stability, higher capacity of co-loading multiple drugs and diagnostic agents with diverse characteristics (53). Hydrogel nanoparticles can significantly function as pharmaceutical carriers for buccal delivery by encapsulating oppositely charged low molecular- weight drugs and macromolecules such as oligo- and polynucleotides (siRNA, DNA) as well as proteins as targeting motifs.
CONCLUSION
Highly vascularized and immunologically competent buccal mucosa can be considered to be a feasible and attractive alternate delivery route for potent drugs with rapid onset of action, macromolecules and vaccines. However, the need for safe and effective permeation/absorption enhancers is essential for rapid advancement in the field of buccal drug delivery. New functionalization strategies to modify the surface of nanoparticles could transport different types of drugs efficiently through the buccal route.
REFERENCES
Komal Chaudhari*, Rahul Kalwe, Kailas Biyani, Buccal Drug Delivery Systems: A Therapeutic Opportunity by Oral Route, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 5, 4270-4282. https://doi.org/10.5281/zenodo.15513356
10.5281/zenodo.15513356
