K. K. College of Pharmacy, The Tamil Nadu Dr. M.G.R Medical University, Chennai
Oral mucosal diseases such as gingivitis, periodontitis, and Vincent’s disease significantly affect oral health, causing inflammation, infection, and tissue damage. Conventional topical and systemic treatments often face limitations like poor drug bioavailability, rapid clearance, and systemic side effects. Niosomes, non-ionic surfactant-based vesicular carriers, have emerged as a promising approach for controlled and targeted drug delivery across the oral mucosa. This review explores the current advancements in niosomal preparation techniques, including thin-film hydration, reverse-phase evaporation, ether injection, sonication, micro fluidization, bubble, and heating methods. Each method offers unique advantages in terms of encapsulation efficiency, vesicle size, scalability, and stability. However, challenges such as solvent toxicity, particle heterogeneity, and limited scalability remain key barriers to clinical translation. Among these, the thin-film hydration method stands out for its simplicity, cost-effectiveness, and suitability for oral mucosal formulations. Niosomes demonstrate excellent potential to enhance drug retention, minimize systemic exposure, and improve patient compliance in localized therapy. Future developments focusing on solvent-free and scalable methods could further advance their clinical applicability, making niosomal systems a promising strategy for effective management of oral mucosal diseases.
Oral mucosal diseases[1,2,3,4]
Oral mucosal diseases (gingivitis, periodontitis, oral ulcers, ANUG/Vincent’s disease) cause local pain, infection and impaired oral function. Local topical therapy offers high local drug levels while reducing systemic side effects.
The inflammatory breakdown of the gingiva, cementum, periodontal ligament, and alveolar bone is referred to as a periodontal disease. There are two types of periodontal disease: gingivitis and periodontitis. Gingivitis is the milder, reversible form, where gums become swollen, red, and may bleed due to plaque buildup. If untreated, it can progress to periodontitis, a more serious condition involving inflammation that damages the gums, bone, and supporting structures of the teeth, potentially leading to tooth loss. Redness, bleeding, and swelling are signs of gingivitis, a reversible inflammation of the gingiva. Periodontitis affects a significant proportion of the global adult population, with the mildest (50%) and the most severe forms (9.8%). Failure to treat this disease can lead to a range of negative consequences including tooth loss, lower self-esteem, altered speech, and diminished quality of life. Because it increases the risk of cardiovascular disease, diabetes, hypertension, respiratory conditions, myocardial and cerebral infarction, and other conditions, periodontitis can be harmful to overall health. An increased risk of periodontal disease is linked to a number of factors, including age, diabetes, and smoking, as well as systemic factors including hormones and medications, hereditary factors, immune system abnormalities, and a history of periodontal surgery.
Antimicrobial medicines can be administered locally or systemically to treat periodontal infections. Local delivery of antibiotics has become a preferred option because to the possible disadvantages of systemic antibiotics, including side effects, bacterial resistance, poor distribution, inadequate selectivity, and burst release. Since there isn't a topical formulation with these qualities in clinical practice, this method has a number of benefits, such as focused drug administration, prolonged drug release, low side effects, and high medication concentration at the infection site.
Vincent disease, sometimes referred to as trench mouth, acute necrotizing ulcerative gingivitis (ANUG), or Vincent's angina, is a severe and acute infection of the gums and oral mucosa that is marked by the quick development of ulcerations and necrosis. It is mostly brought on by an overabundance of anaerobic bacteria, particularly fusiform bacilli and Borrelia vincentii, which are typically found in the oral flora but can turn harmful in specific situations. Gums that hurt and bleed, ulcerations with a gray pseudomembrane, foul breath, and occasionally tonsil and pharyngeal involvement are some of the symptoms of this condition.
For topical and mucosal delivery, niosomes- non-ionic surfactant vesicles—are a desirable class of vesicular nanocarriers due to their stability, affordability, and ability to encapsulate hydrophilic and lipophilic medications. Compared to free medication, they can offer better penetration, controlled release, and decreased toxicity.
1.1 Niosomes[5,6,7]
Niosomes or non-ionic surfactant vesicles are microscopic lamellar structures formed on admixture of non-ionic surfactant of the alkyl or dialkyl polyglycerol ether class and cholesterol with subsequent hydration in aqueous media. Niosomes are promising vehicle for drug delivery and being non-ionic, Niosomes are unilamellar or multilamellar vesicles formed from synthetic non-ionic surfactants. They are very similar to the liposomes. Niosomal drug delivery is potentially applicable to many pharmacological agents for their action against various diseases. Niosomes have shown promise in the release studies and serve as a better option for drug delivery system. The drug is incorporated into niosomes for a better targeting of the drug at appropriate tissue destination.
1.2 Structure of Niosomes[6,8,9]
Niosomes structures are formed on the mixture of cholesterol and surfactant which are being hydrated in water. In niosomes, the hydrophobic chains express one another within the bilayer, while the hydrophilic ends of the bilayer are exposed on the outside and inside of the vesicle in preparation for a non-ionic surfactant. The hydrophobic tail and water have a high interfacial tension, which causes monomer units to group together to form vesicles, which are closed bilayer structures. Amphiphilic medicines are consistent with pharmaceuticals whose lipophilicity is fixed in the space between the hydrophilic core and the lipophilic tail, whereas hydrophilic drugs are entrapped within the bilayer itself and hydrophilic drugs are held within the vesicle's surrounding space.
1.3 Advantages of Niosomes in Mucosal drug delivery system[10,11,12]
Fig 1 – Advantages of Niosomes
2. METHODOLOGY
Preparation of Niosomes using Different Methods
Niosomes are vesicular systems composed of mainly of non-ionic surfactants and cholesterol, widely used as drug delivery carriers. Various methods have been developed to prepare niosomes, each with specific principles, advantages and limitations suited to different applications
The most common and traditional approach is the hydration method. Organic solvents such as ethanol or chloroform dissolve cholesterol and surfactants. In a rotating evaporator, the solvent is evaporated at a lower pressure, leaving a thin coating on the vessel sides. Multilamellar niosomes are created when the film is moistened with an aqueous phase that contains the medication. For hydrophobic medications, this method is economical, repeatable, and appropriate; however, for long-term storage, freeze-drying would be necessary. It's simple, cost-effective, and ideal for hydrophobic drugs but requires careful storage.
This process produces a water-in-oil emulsion by dissolving cholesterol and surfactants in an organic solvent and combining it with an aqueous phase. Niosomes are created when the organic solvent evaporates. It offers great encapsulation efficiency for both hydrophilic and lipophilic pharmaceuticals but necessitates the use of organic solvents and can be time-consuming.
Ethyl-dissolved surfactants are gradually added to the aqueous phase while being stirred. The ether's low boiling point causes it to evaporate, which leads to the production of niosomes. Both hydrophilic and lipophilic medicines can be produced using this approach, which yields homogeneous vesicles but necessitates exact temperature control.
Surfactants, cholesterol, and aqueous medication solutions are combined in this solvent-free process, which is then sonicated at high temperatures. It creates tiny, multilamellar vesicles that work well with hydrophilic medications. It is less appropriate for water-insoluble medications, although it is inexpensive and environmentally friendly.
This technique creates niosomes with exact size control and excellent repeatability by combining surfactants and aqueous phases using microfluidic devices under regulated shear forces. Although it requires specialized equipment, it is perfect for scaling up.
In this green technology, surfactants and drugs in aqueous solution are bubbled with nitrogen gas, producing niosomes after sonication and purification. It avoids organic solvents and is mild, suitable for sensitive biomolecules but may cause particle heterogeneity. Eco-friendly, mild process ideal for sensitive biomolecules.
This process creates niosomes by combining drugs, cholesterol, and surfactants and heating them to regulated temperatures. It works well for heat-stable substances, is safe for the environment, and stays away from hazardous solvents. Controlled heating of surfactants and cholesterol to form niosomes, avoiding toxic solvents, suitable for heat-stable agents.
3. CHALLENGES INVOLVED IN EACH PREPARATION METHOD
Vesicle size, encapsulation effectiveness, scalability, and appropriateness for hydrophilic or hydrophobic medicines are all different for each approach. The intended use, the drug's characteristics, and the volume of production all influence the choice. Each method presents unique challenges that must be addressed through careful optimization of process parameters, formulation components and equipment settings to ensure reproducible, stable and effective Niosomal drug delivery system.
Aqueous suspension stability problems necessitate freeze-drying for extended storage. Reproducibility may be impacted by sensitivity to the polymer ratio and hydration temperature. Organic solvents are hazardous to the environment and can be poisonous. may result in multilamellar vesicles with a wide range of sizes that need to be uniformly processed further.
The use of organic solvents raises the possibility of toxicity and solvent residues. Complex solvent evaporation and vesicle stabilization result in moderate scalability. more preparation time than alternative techniques. Possible deterioration of delicate medications throughout the procedure.
It inhibits widespread use by requiring costly, specialized equipment. The stability of sensitive medications or biomolecules may be impacted by high shear stress. To ensure reproducibility, surfactant kinds and concentrations must be optimized.
It requires exact temperature control to stop components from degrading thermally. danger of contamination from leftover solvent. Consistent vesicles require careful control of the injection rate and solvent evaporation. moderate scalability while maintaining meticulous process management.
The method was restricted to medications that dissolve in water; hydrophobic medications are not well encapsulated. Stable vesicles require precise surfactant and charge agent balancing. Scaling up could be difficult because of the sonicator's capacity and repeatability. Possible minor variations in medication release characteristics based on the type of surfactants utilized.
Adjusting the gas flow is necessary to address issues with excessive foaming at the beginning. higher particle heterogeneity than previous approaches (polydispersity index ~0.5). Long-term bubbling increases the danger of phospholipid hydrolysis, which compromises vesicle stability. For scale-up, bubbling parameters and vessel geometry must be optimized.
The surfactant ratio and formulation factors determine size variability. reliance on vesicle stability chemicals such as dicetyl phosphate and cholesterol. Optimizing the process temperature is necessary to prevent drug or surfactant degradation. For reproducibility, scaling necessitates constant thermal control.
4. CHALLENGES FACED DURING SELECTION OF PREPARATION METHOD:
The varying needs and characteristics of the intended vesicles present a number of difficulties in choosing the most effective niosomes preparation technique. Important difficulties include:
1) Scalability[36,37,38]
Certain processes, such reverse-phase evaporation and thin-film hydration, are straightforward and repeatable, but because of batch variability and solvent management, they could be challenging to scale up for large-scale production. Though they need costly and specialized equipment, advanced techniques like micro fluidization offer good scalability, making them inaccessible for smaller labs or early-stage studies.
2) Encapsulation Efficiency and Drug Compatibility[39,40,41]
The efficiency with which different techniques may encapsulate hydrophilic versus hydrophobic medications varies. For instance, sonication may not be effective with water-insoluble medications but is more appropriate for hydrophilic ones. Organic solvent-based techniques (ether injection, reverse-phase evaporation) offer high encapsulation but also run the risk of drug degradation and residual toxicity, particularly for delicate compounds.
3) Particle Size and Uniformity Control[42,43]
For continuous medication administration, the vesicle size must be consistent and ideal. Although simpler procedures may result in diverse populations, methods such as micro fluidization offer exact size control. Process variables and surfactant composition have a significant impact on size variability in techniques like heating and ethanol injection, necessitating careful optimization.
4) Stability and Storage[44,45,46]
Certain niosomes preparation techniques (such as thin-film hydration) need freeze-drying for long-term preservation due to their low stability in aqueous suspension, which adds complication. It is still difficult to preserve vesicle integrity and stop drug leakage during preparation, storage, and administration using any of the available techniques.
5) Process Complexity and Equipment Requirements[47,48]
Certain methods like the bubble method and micro fluidization increase operational complexity and cost since they call for specialized equipment and exact process control. Although they are easier and less expensive, simpler techniques like sonication and thin-film hydration may sacrifice scalability and reproducibility.
6) Environmental and Safety Concerns[49]
Concerns regarding residual solvent toxicity and environmental impact are raised by the use of organic solvents in a variety of processes, which calls for careful solvent removal procedures.
Although solvent-free techniques like heating and sonication are environmentally friendly substitutes, they could also have drawbacks in terms of vesicle properties or medication compatibility.
5. RESULTS AND DISCUSSION
Niosomes can be prepared using a variety of techniques, and the method used has a significant impact on the size of the vesicles, stability, entrapment effectiveness, and, ultimately, the formulation's therapeutic efficacy. Thin film hydration (TFH), ether injection, reverse phase evaporation (REV), sonication or extrusion-based size reduction, the proniosome approach, and, more recently, microfluidics or supercritical fluid-based techniques are the most often described techniques.
Because of its ease of use and adaptability, the thin film hydration approach is still the most popular among them. A thin lipid film is created by dissolving cholesterol and surfactants in an organic solvent, which is subsequently evaporated. Aqueous drug solution hydration results in the production of multilamellar vesicles. Despite its convenience, this procedure produces vesicles that are usually heterogeneous in size and frequently larger than 200 nm. To achieve smaller, more homogeneous niosomes, post-processing techniques like sonication or extrusion are required. Its usefulness for long-term or large-scale applications is limited by its poor entrapment effectiveness and the possibility of vesicle fusion or leakage during storage.
It is evident from comparing these methods that each has particular advantages and disadvantages. Although polydispersity and long-term stability concerns limit the direct clinical application of thin film hydration and reverse phase evaporation, both techniques are useful for laboratory-scale development and preliminary screening. Although ether injection and sonication are effective methods for producing tiny vesicles, delicate medications may be at danger due to their dependence on heat and mechanical stress. Because of their excellent stability, high entrapment effectiveness, and simplicity of inclusion into gels or patches, pioniosome-based techniques are clearly the most practicable option for oral mucosal formulations. Microfluidics might offer the most scalable and repeatable platform for clinical translation in the future, but further research is needed in the context of oral mucosal delivery systems.
In summary, while several preparation methods exist, the selection must be guided by the physicochemical nature of the drug, desired vesicle characteristics, stability needs, and intended clinical application. For topical therapy of oral mucosal diseases such as Vincent’s disease, Thin-film hydration method currently represent the most rational choice, balancing stability, patient compliance, and therapeutic efficacy.
CONCLUSION:
Niosomal drug delivery systems offer an innovative and efficient approach for treating oral mucosal diseases. Despite challenges in scalability and stability, optimized niosomal formulations—particularly via thin-film hydration—present a viable path toward improved therapeutic efficacy and patient outcomes.
ACKNOWLEDGEMENT
We would like to thank Prof. Dr. A. Meena, Principal , Prof. Dr. A. Shanthy, Vice Principal, K. K. College of Pharmacy for motivating us for our review work.
REFERENCES
Vignesh R, Laura SL, Gopinath E, Suresh K, Niosomes-Based Controlled Drug Delivery for Oral Mucosal Diseases: Current Status of Preparation, Methods and Future Prospects: A Review, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 10, 2791-2800. https://doi.org/10.5281/zenodo.17448303
10.5281/zenodo.17448303
