A Review on Mucoadhesive Drug Delivery Systems: Formulation Strategies and Evaluation Parameters

Oral drug delivery remains the most widely used route of drug administration because of its low cost, convenience, ease of self-administration, and the resulting improvement in patient compliance. Conventional oral dosage forms, however, are frequently limited by short residence times at the site of absorption, the need for frequent dosing, rapid drug release, and reduced bioavailability for certain drugs ^1-3. These limitations can lead to fluctuating plasma drug concentrations and reduced therapeutic efficacy. Controlled and sustained-release drug delivery systems have therefore been developed to maintain drug concentrations within the therapeutic range for a longer period ¹.

Among the strategies used for controlled drug delivery, mucoadhesive drug delivery systems have received considerable research attention in recent years ⁴. Mucoadhesion is the process by which a dosage form adheres to a mucosal surface using natural or synthetic polymeric materials. When a dosage form adheres to the mucosal membrane, drug absorption and residence time at the application site are both extended, which can improve therapeutic efficacy ⁵. Mucoadhesive systems can also improve patient compliance by reducing the frequency of dosing ⁶.

Mucoadhesive drug delivery systems are used across a range of administration routes, including buccal, sublingual, nasal, ocular, gastrointestinal, vaginal, and rectal delivery ^2,3. Oral mucoadhesive tablets are among the most widely studied of these because they are straightforward to manufacture and can provide extended drug release ⁷. The performance of a mucoadhesive system depends heavily on the choice of polymer; HPMC and Carbopol are commonly selected for their swelling, gel-forming, and adhesive properties ^6,7.

Mucoadhesive tablets are typically prepared by direct compression, wet granulation, or dry granulation ^1,2. To confirm the quality and performance of the finished dosage form, these formulations are assessed through a range of pre-compression and post-compression parameters, including angle of repose, hardness, friability, swelling index, mucoadhesive strength, surface pH, drug content, and in-vitro dissolution ^1,2.

This review discusses the mechanisms and theories of mucoadhesion, the polymers used in formulation development, preparation techniques, formulation design considerations, evaluation parameters, applications, and recent developments in mucoadhesive drug delivery systems.

TYPES OF MUCOADHESIVE DRUG DELIVERY SYSTEMS

Mucoadhesive drug delivery systems are generally classified by administration route and application site. Each route offers a different balance of bioavailability, patient compliance, and controlled-release potential ^3,4,7.

Buccal Mucoadhesive Drug Delivery Systems

Buccal mucoadhesive systems deliver drug through the buccal mucosa of the oral cavity. By adhering to the mucosal surface for an extended period, these systems can improve both residence time and bioavailability while avoiding hepatic first-pass metabolism ⁷. Mucoadhesive polymers such as HPMC, Carbopol, and chitosan are used to formulate buccal tablets, films, patches, and gels for both local and systemic drug delivery ^7,8.

Figure 1. Common buccal mucoadhesive dosage forms: tablet, patch, film, and gel.

Figure 2. Categories of gastroretentive drug delivery systems, showing floating (buoyant), bioadhesive (mucoadhesive), swelling/expandable, and high-density approaches within the stomach.

Figure 3. Schematic representation of the two stages of mucoadhesion — contact (hydration and swelling) and consolidation (polymer–mucin chain interpenetration and secondary bonding).

ADVANTAGES AND LIMITATIONS

Advantages

• Increases the contact time of the dosage form at the site of absorption ^2,4
• Enhances drug absorption and reduces drug loss ^2-4
• Provides prolonged drug release and sustained therapeutic effect ^1,2,4
• Reduces dosing frequency ^2-4
• Enables site-specific drug delivery ^2,3
• Can improve the systemic availability of certain drugs ^2,3

Limitations

• Some mucoadhesive polymers can irritate the application site ^3,6,10
• Local pH and mucus turnover can affect drug absorption and adhesion ^5,6,10
• Some drugs show poor permeation across mucosal membranes ^2,7,10
• Formulation requires careful selection of polymers and excipients, since excessive polymer content can impair drug release even as it improves adhesion ^1,6,10

EVALUATION OF MUCOADHESIVE DRUG DELIVERY SYSTEMS

Evaluating a mucoadhesive drug delivery system is essential to confirm its quality, stability, drug-release behaviour, and mucoadhesive performance. Formulations are typically assessed through a series of pre-compression and post-compression parameters ^11,20.

Pre-Compression Evaluation

Bulk Density

Bulk density is determined by weighing a known quantity of powder blend and transferring it, without compaction, into a graduated cylinder. The bulk volume is recorded, and bulk density is calculated as the ratio of powder mass to bulk volume ²¹.

Tapped Density

Tapped density is measured by placing a graduated cylinder containing the powder blend on a tapped-density apparatus and tapping it until the powder volume no longer changes. Tapped density is then calculated by dividing powder mass by the final tapped volume ²¹.

Angle of Repose

The angle of repose is determined by allowing the powder to flow through a funnel of fixed height onto a level surface, forming a conical pile. The angle between the slope of the pile and the horizontal plane is then measured ²¹.

Carr's Index

Carr's Index is calculated from bulk and tapped density and is used to assess the compressibility and flow behaviour of a powder blend; a lower Carr's Index indicates better flow properties ²¹.

Hausner Ratio

The Hausner ratio is calculated by dividing tapped density by bulk density, and reflects interparticle friction and powder flow. A lower Hausner ratio indicates better flowability of the powder blend ²¹.

Post-Compression / Dosage-Form Evaluation

Weight Variation

Individual tablet weights are compared against the average weight of the batch as part of routine dosage-unit quality control ²².

Thickness

Tablet thickness is measured with a calibrated micrometer or digital caliper across a representative sample of tablets, since consistent thickness reflects uniform die fill and compression force during manufacture ¹¹.

Hardness

Tablet hardness is measured with a tablet hardness tester, which records the force required to break the tablet; this provides an indirect measure of mechanical strength and resistance to handling stresses ^22,23.

Friability

Friability is assessed with a Roche friabilator. Pre-weighed tablets are rotated at 25 rpm for four minutes, then dedusted and reweighed; the percentage weight loss is reported as the friability value ²².

Drug Content and Content Uniformity

Drug content is determined by assaying a defined number of tablets against a validated analytical method (commonly UV spectrophotometry or HPLC) and expressing the result as a percentage of the labelled dose; content uniformity testing extends this assessment across individual dosage units to confirm consistent drug distribution within the batch ^22,24.

Swelling Index

Swelling index reflects the percentage increase in the weight or volume of a tablet or polymer after exposure to water or a swelling medium over a defined period, and indicates the extent to which the formulation can absorb fluid and swell ^5,11.

Surface pH

Surface pH is measured to confirm that a formulation will not irritate the target mucosal tissue. Tablets are allowed to swell on moistened filter paper or agar gel for approximately two hours, after which a calibrated pH electrode is placed on the tablet surface. A surface pH close to the physiological pH of the intended mucosal site is generally preferred to minimise irritation ^10,25.

Mucoadhesive Strength

Mucoadhesive strength is the force required to detach a tablet from a mucosal surface, typically measured using fresh animal (commonly goat, pig, or rabbit) buccal or gastric mucosa mounted between two platforms on a texture analyser or a modified balance. The mucosal tissue is fixed to one platform and the tablet to the other; the force needed to separate them is recorded as the mucoadhesive strength. Higher mucoadhesive strength is generally associated with longer residence time and stronger adherence ^11,25.

In-Vitro Drug Release and Release Kinetics

In-vitro drug release is assessed using standard dissolution apparatus under conditions representative of the intended application site (for example, pH 6.8 phosphate buffer for buccal formulations). Release data are commonly fitted to kinetic models  zero-order, first-order, Higuchi, and Korsmeyer–Peppas  to characterise the release mechanism and rate-controlling step. In a mucoadhesive buccal tablet combining metformin and sitagliptin, for example, the optimised formulation best fitted a first-order model for metformin and a Korsmeyer–Peppas model for sitagliptin ²⁴.

Ex-Vivo and In-Vivo Residence Time

Residence time is assessed ex vivo by monitoring how long a formulation remains attached to excised mucosal tissue under simulated physiological flow, and in vivo by direct observation or pharmacokinetic sampling in animal or human volunteers; both approaches have been used to characterise the retention of mucoadhesive buccal tablets ^24,25.

FTIR and DSC Compatibility Studies

Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) are used to assess physical and chemical compatibility between the drug and the selected polymers and excipients. The absence of new or shifted spectral peaks (FTIR) or unexpected thermal events (DSC) in the physical mixture, relative to the individual components, supports the absence of a significant drug–excipient interaction ²⁴.

Stability Studies

Short- and long-term stability studies assess whether a mucoadhesive formulation retains its physicochemical and mucoadhesive properties, and its drug content, over a defined storage period under controlled temperature and humidity conditions ²⁴.

APPLICATIONS OF MUCOADHESIVE DRUG DELIVERY SYSTEMS IN DISEASE MANAGEMENT

Mucoadhesive drug delivery systems are used across a range of therapeutic areas because of their ability to improve bioavailability, extend residence time, and enable site-specific, controlled drug release. They are particularly useful for drugs with a short half-life, poor gastrointestinal stability, or extensive first-pass metabolism ^2,4,12.

In hypertension, mucoadhesive buccal tablets have been formulated and evaluated for both captopril and propranolol hydrochloride. Captopril mucoadhesive buccal tablets have been prepared by direct compression using the bioadhesive polymers Acritamer 940 (a carbomer, structurally analogous to Carbopol), sodium alginate (Manugel), and hypromellose (Hypromellose K100) in varying ratios, and evaluated for thickness, hardness, weight uniformity, and content uniformity ²⁶. Propranolol hydrochloride mucoadhesive buccal tablets have been developed and evaluated both in vitro and, in one study, in vivo in spontaneously hypertensive rats, where the extended-release mucoadhesive tablets produced a significantly greater extent of propranolol absorption (higher AUC) and a more pronounced, longer-lasting reduction in heart rate and blood pressure than a commercial immediate-release tablet ^23,25.

In diabetes mellitus, a mucoadhesive buccal tablet combining metformin hydrochloride and sitagliptin has been formulated using a Carbopol 940/polyvinylpyrrolidone K30 polymer blend, prepared by direct compression, and characterised in vitro and in an in-vivo volunteer study; the optimised formulation showed sustained drug release, adequate ex-vivo mucoadhesive strength and residence time, and confirmed drug–excipient compatibility by FTIR and DSC ²⁴. This class of formulation illustrates a genuine, evidence-based application of mucoadhesive delivery in diabetes management, in contrast to earlier, more general claims about compliance benefits that were not tied to a specific published formulation.

In ocular disease, chitosan and its derivatives have been used to formulate mucoadhesive nanoparticles, gels, inserts, and coatings intended to prolong retention on the ocular surface and improve drug bioavailability relative to conventional eye drops ¹⁰.

Gastroretentive mucoadhesive systems extend the residence time of drugs absorbed in the stomach or upper gastrointestinal tract, and are used for site-specific gastric drug delivery in addition to, or instead of, floating gastroretentive approaches ⁹. Mucoadhesive systems are also used for mouth infections, oral mucosal disease, and other site-specific applications where local, prolonged drug contact with the mucosa is therapeutically useful ^3,8.

RECENT ADVANCES IN MUCOADHESIVE DRUG DELIVERY SYSTEMS

Recent work in mucoadhesive drug delivery has focused on improving bioavailability, site-specific targeting, and patient compliance through new polymers and delivery technologies. Natural biopolymers such as chitosan, sodium alginate, and hyaluronic acid have attracted particular interest for their mucoadhesive character and biocompatibility ^12,13.

Nanotechnology has extended mucoadhesive drug delivery through nanoparticles, nanogels, microspheres, and lipid-based carriers, which have been investigated for controlled drug release, improved delivery of poorly absorbed drugs, enhanced drug stability, and closer interaction with the mucus layer across oral, buccal, nasal, ocular, and vaginal routes ^10,12,27.

Three-dimensional printing has also been applied to mucoadhesive dosage-form design. A 3D-printed Carbopol/Eudragit tablet platform incorporating the permeation enhancer SNAC has, for example, been used to formulate a mucoadhesive oral dosage form for enoxaparin, a macromolecule that is not normally suited to oral delivery, demonstrating that 3D printing can support both dose customisation and the formulation of drugs with challenging permeability profiles ¹⁴.

FUTURE PERSPECTIVES

Biopolymer-based mucoadhesive drug delivery systems continue to show promise for improving oral drug delivery through enhanced mucoadhesion, prolonged gastrointestinal residence time, and controlled drug release. Future work should focus on developing natural biopolymers with improved mucoadhesive strength, biocompatibility, and reduced toxicity; further tuning of cross-linking density and polymer blend ratios may improve formulation stability and drug-loading capacity ^12,16.

Precision medicine and 3D printing represent emerging approaches to mucoadhesive dosage-form design, allowing dose, geometry, and release profile to be tailored to individual patient needs ¹⁴. Artificial intelligence and machine-learning approaches, including artificial neural networks, are also being investigated for formulation prediction and optimisation, including excipient selection and drug-release modelling; while these approaches may improve the efficiency of future formulation development, their practical adoption in mucoadhesive drug delivery still requires further validation and regulatory consideration ²⁸.

CONCLUSION

Mucoadhesive drug delivery systems offer a well-established route to improving the residence time, bioavailability, and controlled release of a wide range of drugs across buccal, sublingual, gastroretentive, and ocular sites. Their performance depends on a combination of polymer selection, formulation design, and manufacturing method, and is characterised through a defined set of pre-compression and post-compression evaluation parameters. Published formulation studies of captopril, propranolol, and metformin/sitagliptin mucoadhesive buccal tablets illustrate that these systems can be translated into evaluable, evidence-based dosage forms rather than remaining a purely conceptual delivery strategy. Continued development of natural biopolymers, nanotechnology-based carriers, 3D-printed dosage forms, and computationally guided formulation design is likely to extend the range of drugs  including macromolecules that are otherwise difficult to deliver orally  that can benefit from mucoadhesive drug delivery in the future.

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