Dept. of Pharmacy: Shri Ram College of Pharmacy Muzaffarnagar U.P India.
The effectiveness of drugs can be enhanced by creating innovative delivery methods, including Mucoadhesive drug delivery systems (MDDS) offer a novel approach for delivering medications via oral routes like the buccal, sublingual, and gingival regions. These systems utilize either natural or synthetic polymers to maintain adhesion to the mucus layer and mucin present on the mucosal epithelial surface, thereby prolonging the retention of a dosage form at a specific location and regulating its drug release is particularly advantageous for maintaining consistent plasma drug levels and enhancing bioavailability. Administering such formulations to mucosal surfaces can be especially beneficial for drugs that are unsuitable for traditional oral delivery, such as those that degrade in acidic environments or are subject to significant first-pass metabolism. This review covers the core principles of buccal patch development, including the selection of suitable polymers, preparation methods, advantages, challenges, and the latest research trends in this field. Special focus is given to how these systems enhance patient adherence and enable targeted therapy.
The oral route remains the most favored method for drug administration due to its simplicity, non-invasive nature, and high patient acceptability. Oral drug formulations are typically developed with two main therapeutic objectives:
(i) Systemic drug delivery: where the medication is absorbed through the mucosal lining into the bloodstream.
(ii) localized treatment: targeting conditions such as gastric or colorectal cancers and bacterial infections. In the latter case, the drug acts directly at the site of application without entering the systemic circulation. 1
Theories of Mucoadhesion
Mucus adhesion is a multi-step process that begins with the interaction between a mucoadhesive formulation and the mucosal surface. It typically progresses through three key stages:
Interpenetration Phase: At this stage, the mucoadhesive polymer begins to diffuse into the mucus layer, allowing deeper interaction and closer contact with the mucosal surface.
This interaction increases the absorption of the drug, enhancing its bioavailability.2
Figure 01: The three steps of the mucus adhesion process
Theories Explaining Mucus Adhesion Mechanisms [3]
Electronic Theory: This concept suggests that an electrical double layer forms at the interface between the mucoadhesive and the mucus layer due to differences in their electron densities. This layer generates attractive electrostatic forces that promote adhesion.
Diffusion (Interpenetration) Theory: According to this theory, the mucoadhesive polymer chains penetrate deeply into the mucus layer, forming a semi-permanent bond. The depth of this interpenetration is influenced by factors like the polymer's molecular weight and its diffusion coefficient. Unlike simple surface contact, this theory views adhesion as a three-dimensional phenomenon.
Adsorption Theory: This model proposes that adhesion occurs through a variety of weak, secondary forces such as hydrogen bonding, van der Waals forces, and hydrophobic interactions. Although individually weak, the large number of these bonds collectively provide significant adhesive strength.
Wetting Theory: Applicable mainly to liquid adhesives, this theory evaluates how well an adhesive can spread across a mucosal surface based on interfacial tension. Better spreading leads to stronger adhesion.
Fracture Theory: While other theories focus on the formation of adhesion, this one examines the force needed to break the adhesive bond. It assumes that the fracture occurs at the mucoadhesive interface, with the strength of the bond being dependent on factors such as the polymer chain length and the degree of cross-linking.
Challenges associated with the mucoadhesive dosage formulation.
|
Challenges |
Description and Impact |
|
Mucosal structure |
The oral cavity contains different types of mucosae, and the epithelial layer acts as a physical barrier, impacting drug absorption. |
|
Saliva flow |
Constant saliva production and its movement can lead to dislodgement of the mucoadhesive formulation. |
|
Individual variation |
Differences in tongue activity and saliva output among individuals influence the stability and effectiveness of the formulation. |
|
Application site |
The limited surface area for administering the mucoadhesive dosage form restricts the amount of drug that can be loaded. |
|
User comfort |
The formulation must be designed for easy placement and removal while maintaining user comfort during application. |
2. Factors Influencing Mucus adhesion:
Mucoadhesive behavior is largely determined by the type of bio adhesive polymer used and the surface on which it interacts. The key elements influencing Mucus adhesion are as follows:
2.1. Polymer related factor:
The adhesive capability of polymers to mucosal surfaces improves as the polymer chain's molecular weight surpasses 100,000. In linear polymers, higher molecular weight typically enhances mucoadhesive strength. For instance, the adhesive capacity of polyethylene glycols increases with molecular weight: 2×10? < 2×10? < 4×10?. While high molecular weight polymers encourage physical entanglement, lower molecular weight polymers are more effective in penetrating the mucus layer.
In Liquid Muco adhesive:
At higher concentrations, polymer chains tend to coil tightly, reducing their interaction with the solvent and limiting the availability of chains to penetrate the mucosal surface.
In Solid Mucoadhesive:
Increasing the polymer concentration generally enhances the mucoadhesive strength, resulting in stronger adhesion.
For example, polymers like polyvinyl alcohol (PVA) and polyethylene glycol (PEG) exhibit high chain flexibility, allowing them to interlock with mucus layers and improve adhesion.
2.1 Environmental factor:8
The acidity or alkalinity where the bio adhesive contacts the biological surface significantly impacts adhesion performance. Most bio adhesives are polyanions with carboxylic acid groups. For instance, poly (acrylic acid) polymers, which have a pKa between 4 and 5, show their strongest adhesion around this pH range. When the local pH is above the polymer's pKa, such as in a pH 7 environment like blood, the polymer becomes mostly ionized, enhancing interaction with the surface. Conversely, below the pKa, like in the acidic environment of the stomach (pH ~2), the polymer remains largely unionized, reducing adhesion strength.
Applying a controlled pressure when placing a solid bio adhesive is crucial. For example, pressing a wound dressing firmly onto the skin for several seconds increases the adhesive bond. Adhesion strength rises with the amount of force applied or the length of time the pressure is maintained, up to an optimal point.
Mucoadhesive strength enhances with longer initial contact duration between the adhesive and the mucosal surface. For example, a bio adhesive patch applied to the mucosal lining of the mouth will adhere more strongly if left undisturbed for a longer period during the initial application phase.
2.3 Physiological Factors:
3.Buccal Drug Delivery System:
3.1 Advantages of Mucoadhesive Buccal Drug Delivery Systems:[11]
3.2 Buccal Dosage Form Design: [11][12]
Matrix System:
The buccal patch is crafted using a matrix design where the active drug, adhesive components, and other additives are uniformly blended into a single layer.
These bi-directional patches facilitate drug delivery both through the mucosal lining and into the oral cavity. Composition: Drug combined within a mucoadhesive matrix for effective adherence and controlled release.
Reservoir System: In a buccal patch reservoir system, a distinct compartment is created to contain the drug and excipients, keeping them separated from the adhesive layer. sThis design enables controlled, sustained drug release through the mucosa and prevents interaction that could reduce effectiveness or adhesion.
Impermeable Backing: The impermeable backing directs drug delivery toward the mucosal surface, enhancing absorption. It also protects the patch from moisture and damage, maintaining its shape and preventing drug loss for consistent dosing.
4. Evaluation of mucoadhesive drug delivery
|
Parameter |
Purpose / Significance |
|
Thickness & Weight Uniformity |
Ensures consistent film dimensions and dosage across batches |
|
Tensile Strength & Elongation |
Evaluates mechanical strength and flexibility during handling and application |
|
Surface pH |
Confirms compatibility with oral mucosa to prevent irritation |
|
Folding Endurance |
Evaluates the film’s ability to resist damage when folded repeatedly without tearing. |
|
Drug Content Uniformity |
Verifies accurate and consistent distribution of the active ingredient |
|
Swelling Index & Mucoadhesive Strength |
Assesses hydration capacity and adhesion to mucosal tissue for effective drug delivery |
|
In Vitro Drug Release & Permeation |
Estimates the rate of drug release and its absorption efficiency within the oral cavity. |
5. Classification of Mucoadhesive Dosage Forms
Mucoadhesive drug delivery systems have been developed in several dosage forms to adhere to mucosal surfaces and deliver drugs either locally or systemically. The selection of the dosage form depends on the therapeutic objective, required drug release profile, and patient compliance considerations (Sudhakar et al., 2006; Shojaei, 1998).[11]
5.1 Tablets
Buccal tablets are one of the most extensively studied dosage forms for oral transmucosal drug delivery. They are typically small, flat, and oval-shaped compressed units designed to adhere to the mucosal surface and gradually release the drug either for local treatment or systemic absorption. The strong adhesive property ensures prolonged contact with the mucosa, improving drug absorption and bioavailability (Patel et al., 2011). [12] Controlled-release buccal tablets have been reported to offer consistent therapeutic levels while reducing dosing frequency (Shojaei, 1998). [11] However, their rigid structure may cause discomfort during extended application, which can affect patient compliance (Sudhakar et al., 2006). [13]
5.2 Buccal Patches
Buccal patches are typically composed of several layers: a drug reservoir, a mucoadhesive layer that ensures attachment to the mucosa, and an impermeable backing layer that guides drug release toward the intended site tissue while preventing drug loss into the oral cavity. Manufacturing methods include solvent casting, where drug-polymer mixtures are spread and dried, and direct milling, which involves mixing, compressing, and cutting the dosage form (Patel et al., 2011). .[12] Compared with semi-solid preparations, patches provide accurate dosing, sustained drug release, and improved patient acceptability (Sudhakar et al., 2006). [13]
5.3 Buccal Films
Buccal films have gained popularity due to their thin, flexible, and comfortable nature. They enable precise dosing, prolonged mucosal contact, and adaptability to the movements within the oral cavity, making them more acceptable to patients compared to tablets or discs (Patel et al., 2011)..[12] An ideal buccal film should be soft, elastic, and tear-resistant, allowing effective drug delivery without interfering with speech or swallowing (Shojaei, 1998). [11]
5.4 Gels and Ointments
Semi-solid formulations such as gels and ointments can be applied directly to the mucosal surface and are often formulated with bio adhesive polymers such as sodium carboxymethyl cellulose, Carbopol, and xanthan gum. Upon hydration with saliva, these polymers swell to form a gel matrix that allows sustained drug release (Sudhakar et al., 2006). [13] Bio adhesive gels are particularly useful in periodontal therapy, where antibacterial agents can be targeted directly into gum pockets. However, they have limitations in dose precision and retention compared to solid dosage forms (Patel et al., 2011).[12]
6. Some important mucoadhesive polymers used in drug delivery:[14]
Polymers may be water-soluble or insoluble, forming swellable networks. Proper polymer polarity promotes efficient mucus wetting, improving fluidity and strengthening interactions between the polymer and mucus.
Polymer Classification:
By Rheology:
1.Hydrophilic Polymers: Contain carboxylic groups; strong Muco adhesion.
Examples: PVP, MC, SCMC, HPC.
2.Hydrogels: Swell in water and stick to mucosa; classified by charge: Anionic: Carbopol, polyacrylates
Positively charged: Chitosan
Uncharged: Eudragit derivatives
3. By natural Source:
Natural: Tragacanth, pectin, gelatin
Synthetic: Cellulose derivatives, Carbopol
6.1 Lectins in Mucoadhesive Drug Delivery
Lectins are naturally occurring carbohydrate-binding proteins that play a central role in biological recognition processes, particularly in cell–cell and cell–protein interactions (Sharon & Lis, 2004) [13]. They are a diverse group of proteins and glycoproteins capable of reversibly binding to specific carbohydrate moieties on glycoproteins and glycolipids present on cell membranes (Gabor et al., 2010) [14]. When applied in drug delivery, lectins can adhere to mucosal cells either by remaining on the cell surface or, in cases involving receptor-mediated binding, through endocytosis into the cell (Lehr, 2000) [15]. This property offers a dual advantage—first, enabling targeted attachment to the mucosal epithelium, and second, allowing active cellular uptake of therapeutic agents, particularly beneficial for macromolecular drugs such as peptides and proteins (Huang et al., 2011) [16]. The mucus layer serves as a temporary and reversible binding site, permitting the delivery system to bypass mucus clearance and establish intimate contact with epithelial cells. Based on molecular architecture, lectins are classified into three types (Lis & Sharon, 1998) [17]
Lectin conjugation has been shown to increase the adhesion of drug-loaded microparticles to the gastrointestinal mucosa, thereby enhancing absorption. For example, tomato lectin-coated polystyrene microparticles exhibited specific binding to intestinal enterocytes, significantly improving mucosal retention (Lehr et al., 1992) [15]. Furthermore, lectin-based targeting is under investigation for oncological applications, as certain tumor cells demonstrate stronger lectin-binding affinity compared to normal cells in the colon (Gabor et al., 2010) [14].
6.2) Chitosan:
Chitosan is a biodegradable, naturally occurring polysaccharide produced by deacetylating chitin, which is mainly sourced from the shells of crustaceans. It is widely recognized for its biocompatibility, non-toxicity, and versatility in biomedical and pharmaceutical applications, particularly in mucoadhesive drug delivery systems (Rinaudo, 2006; Dash et al., 2011) [19].
Characterization of Chitosan
Chitosan exhibits excellent biocompatibility, making it safe for human use and suitable for the formulation of advanced drug delivery systems (Illum, 1998) [21]. Its mucoadhesive nature allows strong interaction with mucosal tissues, such as those of the gastrointestinal and respiratory tracts, thereby enhancing drug absorption and improving bioavailability (Thanou et al., 2001) [22]. Additionally, chitosan can be engineered for controlled drug release, which helps sustain therapeutic levels, improve patient compliance, and minimize adverse effects (Bernkop-Schnürch & Dünnhaupt, 2012) [23]. Through chemical modifications, chitosan can be tailored for targeted drug delivery to specific cells or tissues—such as malignant tumor sites—thereby increasing therapeutic efficacy while minimizing toxicity to healthy tissues (Jayakumar et al., 2010) [24]. It also demonstrates high stability across a broad pH range and temperature spectrum, contributing to the extended shelf life of drug formulations (Kumar et al., 2004) [25].
Recent Innovations in Chitosan Applications
6.3) sodium alginate [29]is a naturally derived, water-soluble, biodegradable polysaccharide primarily made up of mannuronic and guluronic acid units. It is extensively utilized in the pharmaceutical field due to its gel-forming capability when it interacts with calcium ions, a process known as ionotropic gelation. This distinctive characteristic enables sodium alginate to be utilized in multiple pharmaceutical dosage forms, including mucoadhesive systems, microspheres, microcapsules, tablets, and even surgical sutures, to achieve controlled drug release. From a structural perspective, sodium alginate is an anionic linear polysaccharide composed of β-D-mannuronic acid (M) and α-L-guluronic acid (G) units interconnected by 1,4-glycosidic linkages. These units can form either homopolymer or heteropolymer blocks, with acetyl groups dispersed along the chain. Mucus adhesion occurs through both physical and chemical interactions, mainly via electrostatic attraction or hydrogen bonding between the carboxylate (COO?) groups on sodium alginate and the ammonium (NH??) groups of mucins. The molecular weight of sodium alginate, which ranges from 12,000 to 180,000 Daltons, influences its physiological effects such as lowering blood sugar and cholesterol levels. Alginates with molecular weights of 50 kDa or higher have demonstrated potential in reducing obesity and diabetes-like symptoms. At around pH 4, carboxylic acid groups in sodium alginate are converted to their sodium salt forms (COO?), allowing cross-linking with calcium ions—an essential mechanism for drug encapsulation in novel delivery systems. One of the valuable features of sodium alginate is its strong affinity for chelating metal ions, especially calcium, making it useful in the formulation of microcapsules for pharmaceutical, food, and biotechnological applications. Its biocompatibility, non-toxic nature, and inability to trigger immune responses make it a suitable candidate for use in drug formulations. To evaluate the mucoadhesive properties of formulations, test methods are generally categorized as either static or dynamic.
6.4) Hydrogels: are 3D networks mainly made up of organic polymers that have the capacity to absorb and hold substantial amounts of water. These structures are capable of encapsulating small drug molecules within their hydrated matrix and gradually releasing them over time. Due to their high-water content, hydrogels are highly biocompatible and are considered safe for use in human applications. Mucoadhesive hydrogels are specifically formulated to deliver drugs to mucosal tissues such as those found in the oral, gastrointestinal, nasal, ocular, vaginal, and rectal regions. These hydrogels can enhance drug concentration at the target site or reduce systemic exposure and associated side effects. They can also offer controlled and prolonged drug release, improving bioavailability by bypassing the liver’s first-pass metabolism when the drug is absorbed through the mucosa. The adhesive nature of these hydrogels arises from their interactions with mucin—a glycoprotein found in mucus secretions. Their ability to bind to mucin depends on functional groups like carboxyl, amine, or thiol, which enable the formation of intermolecular forces such as hydrogen bonding, ionic interactions, or van der Waals forces. Factors such as the hydrogel’s ionization state, swelling behavior, wettability, and rheological properties influence the formation and strength of these mucin-hydrogel interactions. One of the key challenges in using mucoadhesive hydrogels for drug delivery is maintaining their adhesion under physiological conditions, where fluids such as saliva or mucus can wash them away. To address this, researchers aim to enhance the hydrogel’s mucoadhesive strength and reduce its solubility in bodily fluids to prolong its retention on mucosal surfaces. Poly (acrylic acid) (PAA) is a common example of a mucoadhesive polymer used in hydrogel formulations. Its mucoadhesive ability stems from the presence of carboxylic acid side chains that can form hydrogen bonds with mucin. When PAA absorbs water and swells, it forms a stable entangled network with mucin, anchoring the hydrogel to the mucosal surface. However, despite its mucoadhesive capabilities, PAA-based hydrogels may still be vulnerable to displacement by bodily fluids.
7.Oral Bio adhesive Products [30]
7.2 Buccal Mucosa -
Bucca stem is a medicine designed to alleviate nausea, vomiting, and dizziness. It incorporates bio adhesive components such as Polyvinylpyrrolidone and Xanthan gum to enhance its effectiveness.
Sus card: A buccal tablet formulated for angina relief, containing the bio adhesive agent Hydroxypropyl methylcellulose (HPMC) to ensure proper adhesion and drug delivery.
Sublingual Mucosa: Notable sublingual treatments include Glyceryl Trinitrate (GTN), available as both an aerosol spray and tablet. These are administered beneath the tongue to prevent angina episodes effectively
8.Recent Advances and Emerging Strategies:
Ongoing innovations in buccal film technology are enhancing the efficiency and precision of drug delivery. These include:
ACKNOWLEDGMENTS:
The authors wish to thank the Management and HOD, Department of Pharmaceutics, JNTU CPS of Pharmacy, Hyderabad, Telangana, India, and Faculty of Pharmacy, JNTU University, for providing facilities to carry out this review work.
REFERENCES
G. Vennela*, M. Sunitha Reddy, K. Anie Vijetha, A Review on Advances in Mucoadhesive drug delivery Technology: Theories of Mucoadhesion, Polymers, Evaluation, and Clinical Applications, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 8, 2138-2150 https://doi.org/10.5281/zenodo.16916890
10.5281/zenodo.16916890
