INTRODUCTION:

In recent years, the drug delivery system has become more advanced in drug administration highlighting the influence of drug pharmacokinetic characteristics for effective treatment¹. This drug delivery system offers several routes of drug administration such as oral, parenteral, rectal, buccal, sublingual, nasal, transdermal etc.

When compared to other routes, the buccal delivery system has gained lot of interest due to its advantages like eliminating first pass metabolism, delivers the drug that directly enter into bloodstream, enhance bioavailability and reducing adverse effects².

However, the buccal administration faces numerous problems like limited permeability, poor surface area, enzyme degradation and drug absorption is typically inadequate to provide effective therapy because of tongue movement, high salivary excretion and accidental swallowing^3,4. The advancement of nanotechnology has made promising approaches for administration of drug through the buccal mucosa because nanoparticles act as versatile nanocarriers that can improve the drug bioavailability and reduce side effects^5,6. The nanoparticle has been formulated by using various materials like lipids, natural or synthetic polymers and hybrid material for buccal drug delivery which gives different properties and behaviours⁷. In this review article, we are discussing the recent developments in nanoparticle-based buccal drug delivery systems and how they can enhance drug administration via the buccal route to treat various medical conditions.

BUCCAL DRUG DELIVERY SYSTEM:

The buccal drug delivery system is a novel technique that delivers the drug via buccal mucosa membrane in mouth cavity. Instead of swallowing a pill or receiving an injection, the drugs are placed between the cheek and gum and directly enter into bloodstream through the buccal mucosa. The mucosa in buccal region provides an accessible and desired location for drug administration in both locally and systemically because of its abundant blood supply and relative permeability⁸. The Buccal area has a pH of approximately 6.2 to 7.4 with limited enzymatic activity compared to other oral cavity areas^9,10. When compared to the traditional approach this method provides several advantages such as a non-invasive and easy method to administer the drug and it bypasses the gastrointestinal system and eliminates the first–pass effect that helps to reduce the potential side effects¹¹.

Figure 1. Various types of Buccal Dosage Forms

ANATOMY OF ORAL CAVITY:

The oral cavity is the area of mouth that charactertics by lips, tongue, cheeks, uvula, hard palate, gingival and soft palate. It is commonly used as drug administration because it is the initial section of the GI tract and chemosensory organ that acts as additional respiratory route. The mucosal surface of the oral cavity has 170cm²consists of three layers: epithelium, lamina propria and submucosa¹¹.

Figure 2. Anatomy of oral cavity

This oral mucosa is protected by a keratinized epithelium which varies in cell maturation depending on the region. The buccal mucosa is thickest epithelium ranging from 500 to 600 μm in oral cavity and it has a rich blood supply and a thin epithelial layer that allows for efficient drug absorption. Saliva produced by the salivary gland in the oral cavity and high saliva turnover can decrease the drug concentration at the absorption site as well as it reduce retention time in buccal mucosa. The pH of the saliva is 6.0 to 7.5 however it can be as low as 5.5 in the case of oral infection¹¹,¹². Mucus is another substance that submerged in the epithelial cell, can increase or decrease drug absorption by forming a gel layer on the surface of oral epithelium.. This mucus layer has a 50 -450μm thickness and is composed of water, glycoprotein, enzymes, electrolytes and mucin. The tongue serves to move food during mastication, swallowing and drug absorption¹³.

STRATEGIES TO TARGET BUCCAL MUCOSA:

There are several ways for targeting buccal mucosa such as use of mucoadhesion material, penetration enhancers and enzyme inhibitors.

Mucoadhesion:

The mucoadhesion is a promising method for buccal drug administration, where dosage form interacts with either mucus or mucosal membrane¹⁴. The properties of mucoadhesive have large surface area, high blood flow in the mucosa cavities and improve contact time so it increases absorption and improve bioavailability of dosage form. The key component of mucoadhesion is polymeric structure of mucin which interpenetrates and entangles with the polymer chain due to weak bonds, Vander Waals force, hydrogen bond and electrostatics interaction¹⁵. Mucoadhesion is also affecting the charactertics like saliva production, pH level and different composition of delivery system. Therefore, several studies have been developed for drug administration depending on polymers with mucoadhesive properties to increase penetration via buccal mucosa¹⁶.

Penetration Enhancers:

Penetration enhancers are chemical agents that facilitate penetration or permeation of active compound via the buccal mucosa as well as they have the ability to change the mucosa’s barrier properties in a reversible manner¹⁹. The choice of penetration enhancer and it performance are categorized based on their structure, method of action and kind of drug. Penetration enhancer can improve drug absorption involves directly interacting with cell protein of the epithelium or altering intercellular lipid, proteins and other epithelial components. The substances that are most likely to gain from the addition of penetration enhancer include hydrophilic, low molecular – weight actives, proteins and peptides²⁰.

Table 1. Various types of mucoadhesive polymers used to deliver the drug via buccal route

Criteria	Categories	Example	Reference
Source	Natural/Semi natural	Chitosan, Gelatin, Agarose, Hyaluronic acid, several gums like Carrageenan, Guar, Sodium alginate, Pectin, Xanthan gellan.	17, 18
Source	Synthetic	Cellulose derivative (Carboxymethyl cellulose, Sodium carboxymethyl cellulose, Hydroxypropyl methyl cellulose, Hydroxyl ethyl cellulose), Polyacrylicacid, polymethacrylate, polyethylene glycol, Poly(lactic-co-glycolic acid), Polyvinyl alcohol, Polyvinyl pyrrolidone, Thiolate polymer
Aqueous solubility	Water soluble	Hydroxyethyl cellulose, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose
Aqueous solubility	Water insoluble	Chitosan, Ethyl cellulose, Polycarbonate
Charge	Cationic	Amino dextran, Trimethylated chitosan, chitosan
	Anionic	Chitosan, Ethylenediaminetetraacetic acid, pectin, carboxymethyl cellulose poly acrylic acid
	Non ionic	Hydroxypropyl cellulose, Poly ethylene oxide, Hydroxyethyl starch, Polyvinyl alcohol, Polyvinyl pyrrolidone.
Force	Covalent	Cyanoacrylate
	Hydrogen bond	Acrylates [hydroxylated methacrylate, poly (methacrylic acid)]
	Electrostatic force	Chitosan

Table 2. Penetration enhancer used in buccal delivery

Category	Example	Reference
Surfactant	Anionic: Sodium lauryl sulphate Cationic: Cetylpyridinium chloride, cetyltrimethyl ammonium bromide Non-ionic: poloxamer, Span, Brij, Tween Bile salt: sodium glycodeoxycholate, sodium taurocholate, sodium glycocholate	21,22,23
Fatty acids	Oleic acid, Lauricacid, Phosphatidylcholine, Propylene glycol, methyloleate, Caprylic acid
Chelators	Ethylenediaminetetraacetic acid, Citric acid, Methoxy salicylates, Sodium salicylates
Polymers	Trimethyl chitosan, Chitosan, L-lysine, poly- L-arginine
Cyclodextrins	α, β, γ Cyclodextrins, Methylated Cyclodextrins

Enzyme Inhibitor:

Enzyme inhibitor also used in formulation to increase the buccal absorption of protein and peptide drugs. This enzyme inhibitor can alter the pH in the oral cavity which can lead to decrease enzyme function. There are several enzyme inhibitors has been used including puromycin, bestatin, broleucine, amastatin andaprotinin^24,25. A few mucoadhesive polymer like polyacrylic acid and chitosan (citrate and EDTA) can limit the activity of certain enzyme, Especially when bound to enzyme cofactor like Ca2+ and Zn2+. Likewise, Chitosan can be chelated in divalent ions and inhibits metallopeptidase as carboxypeptidase. In recent year, thiolate polymer such as chitosan and polyacrylate derivative use to enhance the inhibitory properties of polymer enzyme^26,27.

Nanoparticle-Based Buccal Drug Delivery System:

The nanoparticle are submicron-sized particles ranging from 1 to 100nm and it used in variety of sectors such as medicine, bioengineering, physics, agriculture chemistry, and food technology²⁸. Nanoparticle used as carrier in drug delivery system that has been proved to be effective in administering drugs to particular tissue or cells and penetrate regions where the traditional methods are inaccessible²⁹. The use of nanoparticles is the effective approach to overcome the hindrance of buccal delivery because nanoparticles has various advantages like increasing the rate of drug distribution through the mucus layer, preventing the drug form deterioration (e.g., peptides), prolonged buccal residence duration via mucoadhesion that allows for therapeutics concentration at the target site and it reduce unwanted side effects^30,31. In addition, nanocarriers have the potential to reduce oral clearance and maintain controlled delivery which reduces the number of doses administered and improves patient compliance. This nanoparticle is formulated using various materials lipids, natural or synthetic polymers, hybrid materials and incorporated into various buccal dosage forms such as tablets, patches, film, gel to enhance the effective drug delivery^32,33. To formulate a successful nanoparticle-based buccal drug delivery system two important factors must be evaluated. Firstly, nanoparticles in physicochemical qualities like charge, dimension, structure and surface features for effective interface in buccal mucosa. The second important factor is to take an account how the nanoparticles interacts with the formulation base and it should kept intact during the production and storage procedure, especially if it is intended for long-term use ³⁴.

Figure 3. Various types of Nanoparticles used in buccal drug delivery system

LIPID BASED NANOPARTICLE:

Lipid based nanoparticle is mainly composed of phospholipids, a surfactant-based monolayer and a middle layer filled with hydrophobic material and because of their unique charactertics lipids serve as versatile carrier to address the drug delivery difficulties such as low solubility, poor bioavailability, poor specificity and excessive toxicity³⁵. According to types or number of lipids used in lipid-based nanoparticles can be categorized as liposome, solid lipid nanoparticle and nanostructure lipid carrier³⁶. They provides several advantages when it comes to drug delivery via the buccal route such as it enhances drug stability, controlled or sustained release kinetics, enhance mucoadhesion and improve permeability through buccal mucosa. When compared to other types of nanoparticles lipid based nanoparticles more stable physically and have a higher drug loading capacity. Therefore, this could be wise move to enhance drug absorption and total bioavailability³⁷.

LIPOSOMES:

Liposomes is the efficient nanocarriers that are intended to deliver the drugs to certain cells and tissue. They are spherical vesicles made up of lipid bilayer enveloped by aqueous core, containing both hydrophobic and hydrophilic medication³⁸. Liposome have superior characteristics like targeted site specificity and controlled release, protect the drug form degradation, more effective and lower side effects³⁹. Liposomes in buccal drug administration increase the permeability of drug via the buccal cavity by interacting with lipid bilayer of the mucosal cells and disruption their structure. This facilitates enhance drug absorption and bioavailability^40,37. Liposomes loaded vitamin B6 was distributed in mucoadhesive film used to enhance the bioavailability of drugs. The mucosal surface of the buccal epithelium becomes more porous due to the prolonged presence of buccal film which increases drug penetration⁴¹. Recently a study suggested the use elastic liposomes significantly enhances the permeation of insulin solution and sustained release over a period of 6 hours⁴². Another study showed that self -assembling liposome made of chitosan coated core- sheath nanofibers have shown long residence time and higher drug permeation rate than a traditional oral tablet⁴³.

SOLID LIPID NANOPARTICLE:

Solid lipid nanoparticle (SLNs) is submicron size nanoparticle that distributed in water – based surfactant solution, offering several advantages like greater surface area, long term stability, high drug loading efficacy, potential for targeted responses, improve bioavailability⁴⁴. When buccal mucosa delivery it is essential to ensure sufficient duration in solid lipid nanoparticle and epithelial interaction to avoid rapid swallowing (i.e. chewing, high salivary excretion, tongue movement)⁴⁴. In recent year, few studies have been published that describe the preparation based on the concept of combining SLNs into formulation for buccal delivery. Didanosine SLNs were synthesised and inserted as polymeric film with complex formulation composed of ploxamer188 and glyceryl tripalmitate. This nanoparticle film released the drug faster than conventional films, with higher adhesive and mechanical strength. The permeation rate remained unchanged and proving the advantages of nanotechnology film for buccal administration⁴⁵. Recently the Mucoadhesive nimodipine tablet loaded with solid lipid nanoparticle were achieved by using surfactant like tween 80 and lipid matrix as stearic acid and palmitic. This tablet exhibited excellent swelling properties in distilled water up to 6 hours, while maintaining the formulation integrity for bioadhesion and also it demonstrate in vitro drug release 89.08% at 8 hours⁴⁶. Similar to this, another research studied prednisolone loaded solid lipid carriers are fabricated by using stearic acid and tween 80. The mixture of solid and liquid surfactant has better tablet formulation and improved the dissolution rate of prednisolone in both immediate release and sustained release. The outcome of this study might lead to novel technique for increasing the bioavailability of low water soluble drug via buccal administration⁴⁷.

NANOSTRUCTURE LIPID CARRIER:

A nanostructure lipid carrier (NLCs) is a type of colloidal system composed of a lipid mixture containing both lipid and solid lipids. NLCs have better bioavailability and permeability, lesser chance of adverse effects and has capacity for large- scale production. NLCs used in buccal delivery to enhance the permeation and absorption of drug across the buccal mucosa^48,37. For example, paliperidone- loaded NLCs buccal film was recently studied by using HPMC and Polycarbophil polymer. It showed sustained release and higher flux, and greater bioavailability (236%) making them ideal for the treatment of schizophrenia⁴⁹. Triamcinolone acetonide with spermaceti wax and soya bean oil where combined to create NLCs as buccal delivery, with the particle size less than 200nm and encapsulation efficiency more than 80%⁵⁰. The domperidone loaded NLC was made by mixture of liquid lipid (oleic acid) and solid lipid (palmitic acid) under high pressure to increase permeability across the buccal epithelium in order to provide the medication in oral cavity⁵¹. Another researcher worked with NLC composed of Precirol and Miglyol to dispersed ibuprofen throughout buccal mucosa with ibuprofen loaded NLC encapsulated in mucoadhesive hydrogel matrices using carbopol and polycarbophil polymer. This shows that benefits of therapeutic efficacy of drug administration by buccal route extent the nanoparticles time during drug absorption and interaction with the buccal mucosa and also its easiness for topical application⁵². Abdella et al., recently studied 3D printing technology buccal film containing cannabidiol - Nanostructure lipid carrier. The emulsification – ultra sonication and pressure assisted micro- syringe printing process were used to prepare the NLC film. The physicochemical properties of buccal film containing cannabidiol – NLC film shown encourage qualities including excellent flexibility, strength and prolong drug release⁵³.

Polymeric Nanoparticle:

Polymeric nanoparticle is the particle within the size range of 1to 1000 nm, are biodegradable and biocompatible with excellent drug release characteristics particularly in buccal drug delivery system, because it has prolong duration of drug administration which improve drug absorption and quantity that enters the bloodstream⁵⁴. Chitosan, sodium alginate, gelatin, polyethylene glycol, polyvinyl alcohol, poly (lactide co-glycolide polylactides), Polycaprolactone, poly (N-vinyl pyrrolidone), polymethacrylate are the some examples of natural and synthetic source of polymer used in polymeric nanoparticle in buccal delivery⁵⁵. Recently, polymeric nanoparticles become extensively researched as prospective carrier for buccal administration of insulin. Nemrawi et al., studied insulin loaded chitosan nanoparticle which showed high entrapment effectiveness up to 70% and reduce blood glucose level in diabetic rats⁵⁶. Similarly, another researcher developed a mucoadhesive film containing curcumin- loaded nanoparticle coated with chitosan to improve drug absorption and extend the dose residence in the oral cavity⁵⁷. In order to improve drug permeability and bioavailability El-Nahas et al., studies mucoadhesive tablets containing Eudragit- loaded silymarin nanoparticle⁵⁸. Low molecular weight heparin has been administered by buccal delivery using Cationic polymethacrylate nanoparticles as carrier. The rheological synergy between polymethacrylate and heparin increased the formulation residence time contact with buccal mucos⁵⁹. A recent study demonstrates that carbopol- coated poly (lactide-co-glycolide) nanoparticle shows promising drug delivery to treat xerostomia by administering pilocarpine locally through buccal route, with high drug loading efficiencies (9.0-9.7%), as well it has acceptable manufacturing yields and storage condition⁶⁰. In another study, PLGA nanospheres were encapsulated in buccal films improved selegiline systemic bioavailability due to its low oral therapeutic effect. The composition of film mostly determines the selegiline permeability rate when compared to oral solution⁶¹. Similar to this, another author created acyclovir- loaded nanospheres using double emulsion solvent evaporation and embedded into the mucoadhesive film to improve systemic bioavailability because acyclovir has low bioavailability and low permeability. This film showed excellent physical properties adequate hydration and Mucoadhesive strength making them suitable for controlled drug release for prolonged duration time⁶².

Hybrid Nanoparticles:

A hybrid nanoparticle is a nano-scale particle made up of two or more material that belongs to different classes of organic and inorganic components⁶³. In buccal drug delivery, hybrid nanoparticles can be achieved through various synthesis methods that allow unique properties like targeted delivery, improved mucoadhesion degeneration with several layers at the site of buccal mucosa^64,37. The hybrid nanoparticles formation of chitosan – clay nanocomposite enhances the thermal stability and mechanical properties of chitosan while simultaneously delaying its swelling properties, also it acts as cross-linked multi-functional material and making it suitable for tablet coating⁶⁵. A study found that using of nicotine- chitosan magnesium aluminium silicate film can be prepared using solvent evaporation method with higher magnesium aluminium silicate has potential for buccal delivery because of mucoadhesive properties⁶⁶. Chitosan also used to develop hybrid nanoparticle using PLGA nanoparticle for Cecropia glaziovii (EFF-Cg), which as antihypertensive, antacid and anti-inflammatory effects; however, its chemical complexity limits oral bioavailability. The buccal mucosa is biocompatible with this nanoparticle because pH value were approroximately 4.4 and there is no significant alternation in chitosan polymer chain when interact with water molecules. After 48 hours of incubation, the EFF-Cg loaded PLGA nanoparticle formulation doesn’t exhibit any toxicity⁶⁷. Also, another research was tried to combine carbon nanotube with multiple walls with starch (enriched with oleic acid) nanocomposite film to create a novel delivery that might be applied to provide drug via buccal route⁶⁸. Using zinc oxide nanoparticle research was analysed the propranolol HCL-loaded composite containing acrylic acid and polyethylene glycol. The presence of immobilized Zinc oxide nanoparticles within hydrogel has enhanced thermal and swelling properties and regulated drug release behaviours and mucoadhesive strength⁶⁹. Similar to this Raafat et al., developed a silver nanocomposite with self- disinfecting properties and the propranolol HCL- loaded nanocomposite could sustainably delivery the loaded drug for approximately 600 minutes and utilized as mucoadhesive carrier for buccal drug administration with effective antibacterial charactertics⁷⁰.

CONCLUSION:

The Buccal drug delivery system has attractive drug delivery route because it is non- invasive and easy method to administer the drug. So this delivery method is used as alternative for drug administration that undergoes first-pass metabolism, enzymatic degradation happen in gastrointestinal tract. However, the buccal route faces some challenges like low permeability and low absorption in buccal mucosa due to tongue movement, accidental swallowing. So nanoparticles are used as advance drug delivery in buccal mucosa because the nanoparticles act as versatile carrier that can increase the bioavailability of loaded drug and enchane drug absorption and permeability in buccal mucosa. Numerous effective methods have been put to provide drug containing nanoparticles by buccal administration like tablet, film patch and gel. It is important to note that felid of buccal drug delivery using nanoparticles is still evolving and further research is need to address challenges such as scalability, safety and long term stability. However the potential benefits of nanoparticles based buccal drug delivery system make them exciting area of research for improving drug delivery and patient compliance.

CONFLICT OF INTEREST:

All others declare no relevant conflicts of interest. All authors contributed to the review and are responsible for the article content.

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Received on 01.05.2024 Revised on 13.09.2024

Accepted on 14.12.2024 Published on 02.08.2025

Available online from August 08, 2025

Research J. Pharmacy and Technology. 2025;18(8):3961-3968.

DOI: 10.52711/0974-360X.2025.00569

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