St. Joseph’s College of Pharmacy, Cherthala, Kerala, India 688524
Niosomes are non-ionic surfactant-based vesicular carriers that have gained increasing attention as a novel drug delivery system for dermal and transdermal applications. These nanosized vesicles are capable of entrapping both water-soluble and lipid-soluble drugs, thereby improving their solubility, stability, and overall therapeutic efficiency. In comparison with conventional formulations, niosomes provide enhanced penetration through the skin barrier, prolonged release of drugs, and improved bioavailability, while at the same time minimizing systemic side effects by enabling localized action at the target site. This review provides a detailed overview of the structural organization of the skin and its barrier functions, followed by an explanation of the structural components and types of niosomes. Different preparation techniques, along with their advantages and limitations, are discussed to highlight the versatility of this carrier system. Evaluation methods for determining particle size, zeta potential, entrapment efficiency, and release characteristics are also summarized to establish their pharmaceutical importance. Therapeutically, niosomes have demonstrated promising applications in dermatological conditions such as psoriasis, microbial infections, and chronic wounds, as well as in systemic delivery of hormones, analgesics, and anticancer agents. In addition, recent advancements—including polymer coating, hybrid vesicles, and integration with technologies like iontophoresis or microneedles—are expected to overcome current limitations such as stability issues and drug leakage. Overall, niosomes represent a cost-effective, stable, and biocompatible nanocarrier platform with immense potential to enhance the effectiveness of dermal and transdermal drug delivery systems.
In the field of pharmaceutics, ’topical drug delivery’ refers the method of applying drugs directly to the skin surface in order to achieve localized therapeutic effects. The largest and organ skin, is approximately two square meters in size on average for adults and receives nearly one-third of the blood that circulate the body. Apart from maintaining blood pressure homeostasis and regulating body temperature, it acts as barrier against environmental hazards such as ultraviolet(UV) radiation.[1]Serious side effect can cause by conventional drug therapy, which based on systemic delivery through different route. Systematic administration of conventional formulation, can lead to decrease therapeutic performance and may increase the risk of adverse effects, which could contribute to greater clinical and economic burden. Multiple benefits of topical delivery of medication which include extended drug action, prevention of first-pass metabolism, increased patient compliance, and minimized systemic side effects. Nevertheless, the stratum corenum, which is the the outermost layer of the epidermis, possess limited drug permeability, which can lead to local irritation, erythema, itching, and other side effects. This layer that is made up of dead keratinized cells known as coenocytes, functions as a tough, water-resistant barrier. Thus, the altering the method of administration may significaly improve the drug effectiveness.[2]
Nano therapeutics has enabled versatile drug delivery systems that are designed to improve patient compliance, reduce systemic side effects and enhanced therapeutic effectiveness. Among these systems, niosomal vesicular carrier that lies in the Nano metric range comprised of of cholesterol and non-ionic surfactants have proven to be a promising platform for topical treatment. Because of their structural flexibility, chemical stability and biocompatibility, they are perfect for using the skin to target both local and systemic conditions, additionally they can also encapsulate wide range of drugs like hydrophilic and lipophilic.There are various similarity between noisome and liposomes but niosome have a number of advantages to liposomes despite having a comparable structure.[3-6]Although both liposomes and niosomes are rigid lipid-based vesicles, phospholipids act as the key structural component in liposomes, whereas non-ionic surfactants are used in niosomes. Even though both carriers have comparable physical characteristics and function as amphiphilic vesicles, niosomes have a number of benefits that make it as a good choice for industrial manufacturing which include increased chemical stability, lower costs, and intrinsic skin penetration that enhances properties.Expanding research into these structure which lead to new drug delivery approaches that niosomes have recently demonstrated to significantly increase transdermal delivery of drug and can also targeted delivery.[7]
Skin is the largest organ of the body which consists of three primary layers:
1.11 Epidermis: As the skin's outermost layer, the epidermis controls body temperature and acts as a waterproof, protective barrier. Because it lacks blood arteries, it gets its nourishment from the oxygen in the air. The primary cell types found in the epidermis are Merkel's cells, Langerhans cells, melanocytes, and keratinocytes.
1.12 Dermis: The layer of epithelial tissue that lies beneath the epidermis is called the dermis, and it protects the body from strain and stress. The follicles of hair, sweat glands, blood vessels, lymphatic vessels, apocrine glands, and sebaceous glands are found there.
1.13 Hypodermis: The Hypodermis tissue is a layer of fat & connective tissue containing larger blood vessels & nerves. This layer regulates the temperature of the skin & the body.
1.2 BARRIER FUNCTION OF STRATUM CORNEUM
The stratum corneum is the main barrier to transdermal medication absorption. This structure is composed of dead, flattened keratinocytes, also called corneocytes, contained in a lipid matrix. This highly structured structure is sometimes described by the "brick-and-mortar" concept, in which corneocytes are the bricks and intercellular lipids are the mortar. The lipids multilamellar structure inhibits the penetration of hydrophilic and high molecular weight molecules.
Topical drug delivery solutions must eliminate or get over this barrier. Niosomes can fluidize SC lipids, improve drug diffusion, and act as reservoirs due to their lipid compatibility and amphiphilic, which improves drug delivery through the skin both locally and systemically.[6]
1.3 STRUCTURE OF NIOSOMES:
In terms of structure, niosomes and liposomes are comparable as both are composed of a bilayer. Niosomes, on the other hand, have a bilayer composed of non-ionic surface active
agents as opposed to phospholipids, which are what liposomes are. In water, the majority of surface active chemicals form micellar structures; nevertheless, certain surfactants can form niosomes, which are bilayer vesicles. Depending on how they are made, niosomes can be either unilamellar or multilamellar.The components of the niosome are surfactant bilayer in which the hydrophobic chains face one another within the bilayer and the hydrophilic ends are exposed on the vesicle's outside and interior. Therefore, hydrophilic medications are contained within the vesicle's confined region, whereas hydrophobic medications are entrenched within the bilayer.Typically, a niosome is made up of lipids like cholesterol, charge-inducing chemicals, hydration medium, and non-ionic surfactants, all of which are rather harmless and biocompatible.
1.4 COMPONENTS OF NIOSOME:
1.41 Non-ionic surfactant
The essential components in the niosome preparation process are non-ionic surface-active compounds. With a polar head and a non-polar tail, these molecules are amphiphilic. Compared to anionic, cationic, and amphoteric surfactants, these uncharged surfactants are less hazardous and more stable. Among its many uses are the inhibition of p-glycoprotein, reduction of hemolysis and cellular surface irritation, improvement of permeability, and solubility. These non-ionic surface-active agents, wetting agents, and emulsifiers.
1.42 Cholesterol
Drug trapping effectiveness, stability, storage conditions, toxicity, rehydration of dried niosomes, and membrane permeability and stiffness can all be impacted by cholesterol . Cholesterol prevents undesirable pharmacological and immunological effects in addition to shielding the medications from early breakdown.
The niosomes are stabilized by electrostatic repulsion and their fusion is inhibited by charge-inducing substances. Among the compounds that induce charge are stearylamine (positively charged), phosphatidic acid (negatively charged), and diethylphosphate (negatively charged).
Alongside other essential components, the fabrication of niosomes requires a synthesis environment referred to as the hydration medium. This step is vital for initiating the formation of niosomal vesicles. Phosphate buffer is commonly selected as the hydration medium due to its capacity to support both the assembly of niosomes and the loading of drugs into them. The properties of the hydration medium such as its composition, pH, temperature, and the duration of hydration—play a crucial role in determining the physical and chemical characteristics of the niosomes, including particle size, distribution, entrapment efficiency, and drug release behaviour. The pH level, in particular, is a key factor in both vesicle formation and drug encapsulation. It is typically chosen based on the solubility of the drug being used. A pH of 7.4, when using phosphate buffer, has been found to produce stable vesicles with smaller particle sizes.[8]
1.5 TYPES:
Niosomes can be categorized based on several criteria: the number of bilayers (such as MLV and SUV), their size (like LUV and SUV), or the technique used in their preparation (for example, REV and DRV). The different types of niosomes are explained below.
1.51 Multi lamellar vesicles
Multi lamellar vesicles consist of multiple bilayers enclosing separate aqueous lipid compartments. These vesicles typically range in size from 0.5 to 10 µm in diameter. They are the most commonly used type of niosomes due to their ease of preparation and mechanical stability during long-term storage.
1.52 Large uni lamellar vesicle
This type of niosome has a high aqueous-to-lipid compartment ratio, allowing for the encapsulation of larger quantities of bioactive substances while using membrane lipids efficiently and cost-effectively.
1.53 Small unilamellar vesicles
Small unilamellar vesicles are typically produced from multilamellar vesicles using techniques such as sonication or French press extrusion.[3]
1.6 ADVANTAGES OF NIOSOME:
1.7 DISAVANTAGES:
1.8 COMPARISON WITH LIPOSOMES:
The bilayer structure of niosomes is comparable to that of liposomes. But niosomes are more stable because of the ingredients that are utilised to make them. Cholesterol and uncharged single-chain surfactants are used to make niosomes. On the other hand, neutral or charged double chain phospholipids are used to make liposomes. Compared to niosomes, liposomes have a higher cholesterol content. Consequently, liposomes drug entrapment effectiveness is lower than niosomes. Industrial production of niosomes is economical, and they don't need the particular storage conditions needed to make liposomes. The phospholipids, which are unstable chemical elements that degrade oxidatively, contribute to the high cost of liposome manufacturing.
Liposomes must therefore be handled carefully . The shelf life of niosomes is longer than that of liposomes . They boost metabolic stability in an emulsified form and prolong the circulation of medications that are encapsulated, while liposomes have a limited shelf life due to the rancidification of their lipid components. [4]
2. FORMULATION TECHNIQUES:
Using this approach, three neck flasks are filled with all the ingredients at a specific temperature. A thermometer mounts one of the system's necks, another is used to remove nitrogen, and the final one is attached to a water-cooled reflux. Every component is distributed at 70°C and homogenised for roughly 15 seconds. A stream of nitrogen gas is introduced to the mixture immediately. Large, monolayer generated vesicles are produced using this technique.
This technique bears similarities to the thin-layer hydration technique that follows. This involves dissolving surfactants, cholesterol, and other lipophilic ingredients in an organic solvent, which then evaporates to produce a thin film. After the thin layer is hydrated and gently shaken mechanically, the milky mixture containing the niosomes is created
Surfactants, cholesterol, and other additives are separately hydrated in a buffer solution under a nitrogen atmosphere. The glass containing cholesterol is heated to about 120?C for 15–20 min and cooled to 60?C. The other ingredients are then added to the stirring cholesterol container for 15 min. The prepared niosomes are placed at room tem perature for 30 min and stored in a refrigerator (at a temperature of 4–5 C) under an Nitrogen atmosphere to stabilize them.
This technique involves dissolving medications and surfactants in a solvent and pumping them under pressure from a reservoir to an ice-filled interaction chamber. To absorb the heat produced during the operation, the solution is run through a cooling loop. Smaller niosomes with superior homogeneity can be produced using this technique.
2.5 Multiple Membrane extrusion method
This technique works well for managing a niosomal formulation's size. By evaporating a mixture of surfactant, cholesterol, and diacetyl phosphate in chloroform, a thin film is created. An aqueous drug solution is added to the resultant film, and the suspension is then extruded via polycarbonate membranes.
2.6 Reverse phase evaporation method
After combining cholesterol and surfactants in an organic solvent, the organic phase is supplemented with an aqueous solution. Under negative pressure, the organic phase is eliminated and the two-phase system is homogenised. Large monolayer vesicles can then be produced.
2.7 Sonication Method
In a glass vial, a combination of cholesterol and surfactants is first mixed with the drug-containing buffer solution . In order to produce niosomes, the mixture is then probe-sonicated using a titanium probe for three minutes at 60 °C. Unilamellar vesicles can also be produced, in addition to multilamellar vesicles (MLVs).
2.8 THIN FILM HYDRATION METHOD
An organic solvent is used in a round-bottom flask to dissolve surfactants, cholesterol, and other lipophilic additions. Utilizing a rotating vacuum evaporator, the organic solvent is eliminated. A thin, dry coating of organic solvent-soluble compounds then develops on the flask's inner surface. In order to hydrate the thin layer, water or an aqueous solvent containing the medication is added to the flask at temperatures higher than the transfer temperature. Once hydrated, multilayer vesicles develop. High-pressure homogenizers or membranes with the proper cut-off size can be employed to create tiny niosomes.
2.9 Transmembrane PH gradient method
The pH of the outer membrane and the core can be changed to generate niosomes. The organic sol vent dissolves cholesterol and surfactants. Afterward, the solvent evaporates, forming a thin coating that is hydrated by the acidic solution before the result is frozen. To keep the pH of niosomes constant, a buffer with a neutral pH of 7.0 is supplied, along with an aqueous medication solution. Changing the pH from the outside membrane to the core can ionise weakly acidic medicines (often with a pKa <5) provides a summary of the benefits and drawbacks of the identified niosome preparation methods. In accordance with research on the use of niosomes to administer various treatments, scientists have long been considering integrating[8]
3. EVALUATION:
The surface morphology (roundness, smoothness, and aggregation formation) and size distribution of niosomes can be investigated using scanning electron microscopy (SEM).
To determine the Vesicle size, a particle size analyzer is utilised.The material is agitated with a stirrer prior to calculating the vesicle size.
To determine the colloidal properties of the produced formulations, the Zeta potential is analysed using a Zeta potential analyzer based on the electrophoretic light scattering and laser Doppler velocimetry method. 25°C is the fixed temperature.
Method 1
From niosomal dispersion, the unentrapped medication is separated by gel filtration, centrifugation, or dialysis. Using either 50% n-propanol or 0.1 percent Triton X-100, the vesicle is broken up, and the resulting solution is examined using the drug's suitable test technique.The percentage of entrapment efficiency is calculated by percentage of drug entrapped divided by the total amount of drug.
Method 2
The methods of gel filtration, centrifugation, and dialysis are used to separate the unentrapped medication. The supernatant was diluted using five millilitres of pH 7.4 phosphate buffer. One millilitre of the aforementioned solution is taken, put into a ten millilitre standard flask, and then filled with phosphate buffer (pH 7.4) to reach ten millilitres. Phosphate buffer pH 7.4 is used as a blank in the proper assay procedure to examine the resulting solution. The following formula was used to determine the drug encapsulation percentage:
EE (%) = [(Ct - Cf)/Ct] 100
Where, Cf is the concentration of the medication that is not entrapped,
Ct is the concentration of the entire drug.
Method 1
To measure the in vitro release rate, a glass tube with a diameter of 2.5 cm and an effective length of 8 cm that has to previously wrapped with cellophane membrane is utilised. A measured quantity of niosomes is put in the cylinder with 100 millilitres of phosphate buffer saline (pH 7.4). This saline phosphate buffer serves as a receptor capsule. A magnetic stirrer was used to stir the receptor media at a speed of 100 rpm while maintaining the temperature at 37±1°C. For three days, 5 ml sample aliquots are taken out of the receptor compartment every 24 hours. The receptor compartment's volume is maintained throughout each sample period by adding an equivalent volume of phosphate buffer saline, pH 7.4. According to the published assay method, the amount of drug in withdrew samples is estimated using blank.
Method 2
The dialysis bag is used to study the in-vitro release method (the dialysis bag's pore size is determined by the drug's molecular weight). The unentrapped drug is separated, and the niosomal suspension containing the drug is pipetted into the dialysis bag that has been previously socked and repeatedly cleaned with distilled water.
This is held at a temperature of 370 C while being constantly stirred on a magnetic stirrer in 100 millilitres of phosphate buffer saline pH 7.4. Every period, the same volume of a new sample is substituted for the reported amount of sample. The samples are then tested using the assay method that uses the medium as a blank. The release and a pure drug solution were contrasted.
3.6 Stability studies
PH stability:After being stored at a different pH for two hours, the niosomal dispersion (1 mg of drug-entrapped niosome and 5 ml of pH 7.4 phosphate buffer) is removed from the airtight containers. After centrifugation, the supernatant is examined using a documented assay technique.
Temperature Stability:The niosomal formulation was kept at various temperatures for one to three months, including room temperature (25° ± 0.5°C), refrigerator temperature (2°-8°C), and high temperature (45° ± 0.5°C), in order to evaluate the drug retention capacity of the vesicle. Niosome formulations were kept in glass vials sealed with aluminium foil, and samples were taken out at various points along the course of time. Drug content was determined by spectrophotometrically analysing drug leakage from the formulations. [9]
An appropriate solvent about 100 ml have to combined with 1 g of the produced gel. Following filtering of the stock solution, aliquots of varying concentrations were made using appropriate dilutions, and absorbance was assessed using UV visible spectrophotometry.
All of the formulations have to examined under a light microscope to check for the presence of any noticeable particle debris. Therefore, it is evident that the gel preparation satisfies the requisite independence from grittiness and particulate matter.
3.9 Spreaadability
The glass slide apparatus and wooden block were used to determine it. Small amount of gel placed between two glass slides for five minutes to compress the extra sample to a consistent thickness in order to determine the spreadability. Above the slides a known weight has to place .The time required to separate two slides have to calculate using the formula;
S =M·L/T
Where, S =Spreadability
M =weight tide to upper slide
L =length moved on the glass slide
T = time taken to separate the slide completely from each other.
Filling the collapsible tubes with mixtures came after the gels had solidified in the container. In terms of weight in grammes needed to extrude a 0.5 cm gel in 10 seconds, the formulation's extrudability is assessed.
All developed gels were visually inspected for homogeneity after they have placed in the container. Both their appearance and the existence of any aggregates is to exam.[10]
3.12 Number of lamellae
To determine the number of lamellae, NMR spectroscopy, electron microscopy, and small angle X-ray spectroscopy can be use.
3.13 Membrane rigidity
Membrane stiffness of certain niosomal formulations has been determined using the mobility of a fluorescence probe as a function of temperature.
This method is also employed to observe the size and form of niosomes. Particle size determination uses almost 100 niosomes. This technique records the stage micrometer's size that coincides with the eye piece micrometre, and it then computes the niosome's size. The determination of niosome size distribution, mean surface diameter, and mass distribution is now accomplished using a laser beam-based mastersizer. The size distribution, mean diameter, and zeta potential are also determined by DLS analysis utilising the Malvern Zeta Sizer. [11]
4. THERAPEUTIC APPLICATIONS OF NIOSOMES IN SKIN BASED DRUG DELIVERY:
Recently, the use of nanocarriers for drug encapsulation—especially in the development of parenteral and oral formulations—has received a lot of attention. But the many benefits of topical and transdermal delivery methods, including increased patient compliance , a greater surface area for absorption and bypassing hepatic metabolism are also driving interest in the use of these nanocarriers for these routes of administration.
Niosomial nanocarriers have been used in some of their most recent applications to improve cutaneous drug delivery, achieve a prolonged release profile, or enhance the stability profile of the produced formulation during storage . These systems' APIs address the treatment of ailments such hormone therapy, diabetes, pain management, wound healing with bioactive substances, psoriasis, mycoses, and anaesthetic.
A chronic inflammatory skin condition, psoriasis is characterised by an overabundance of keratinocytes that produce thicker skin plaques as a result of immune-mediated cytokine reactions. Cyclosporine, a frequent treatment for severe cases, can cause major side effects when taken orally. Pentoxifylline, which is also used to treat psoriasis, has been shown to lessen these side effects. Niosomes prepared with a 7:3 ratio of cholesterol to surfactant have been explored for their potential in psoriasis treatment. In vitro permeation studies demonstrated that the formulation exhibited effective drug delivery through the skin, indicating its suitability for topical application.[12-17]
5. POTENTIAL FUTURE ADVANCEMENTS OF NIOSOMAL SYSTEMS IN TRANSDERMAL DRUG DELIVERY:
Several studies in recent literature have demonstrated that niosomes are a nanoparticulate drug delivery method with multiple uses in transdermal administration. enhanced skin penetration, sustained/delayed release, high biocompatibility, and enhanced efficacy of the encapsulated active pharmaceutical ingredients (APIs)
However, stability concerns, such as encapsulated API leakage and aggregation and sedimentation phenomena, continue to impede the development of niosomal pharmaceutical products. Compared to other nanosystems, particularly ethosomes and transethosomes, there are still instances when skin penetration is restricted. Furthermore, the literature from recent years has documented a number of skin interaction mechanisms, but no one has standardised the most common one.
With all vesicular nanosystems, poor loading of hydrophilic APIs is a typical issue. Lack of uniformity and scalability are common issues with all nanopharmaceuticals. In conclusion, the lack of transdermal niosomal nanomedicines on the market leaves a knowledge gap regarding the long-term safety and therapeutic effectiveness of niosomes. Current issues with stability, drug loading, and controlled release for transdermal administration may be resolved by developments in nanoparticulate pharmaceutical engineering, such as the use of polymer-coated or dual-layer niosomes. Furthermore, by integrating niosomes with alternative drug delivery techniques, a hybrid drug delivery platform like iontophoresis or microneedles could improve transdermal penetration and get around the limits of the skin barrier. To confirm the safety and effectiveness of niosomal systems in people, further thorough in vivo investigations and clinical trials are required.[18-32]
CONCLUSION:
Niosomal carriers provide a versatile and effective approach for improving the dermal and transdermal administration of therapeutic agents. Their amphiphilic structure allows the incorporation of both hydrophilic and lipophilic drugs, while their stability, biocompatibility, and cost-effectiveness make them attractive alternatives to conventional systems such as liposomes. By enhancing drug penetration through the stratum corneum, enabling controlled release, and reducing systemic side effects, niosomes significantly improve therapeutic outcomes in localized as well as systemic treatments.
Despite these advantages, several limitations continue to restrict their large-scale application. Problems such as vesicle aggregation, leakage of encapsulated drugs, and relatively poor loading of hydrophilic molecules remain challenges for researchers. To overcome these issues, innovations including polymer-coated niosomes, dual-layered structures, and integration with penetration-enhancing technologies such as microneedles and iontophoresis are being explored. These approaches have shown promise in enhancing stability, prolonging drug release, and improving patient compliance.
Experimental studies have already demonstrated the potential of niosomal formulations in dermatological applications like psoriasis, eczema, fungal infections, and wound healing. In addition, their role in systemic delivery of hormones, analgesics, and anticancer drugs highlights their adaptability for broader therapeutic use.
Looking ahead, the successful clinical translation of niosomes will depend on extensive in vivo research and well-designed clinical trials to confirm their safety, stability, and therapeutic reliability. With continuous progress in formulation science and nanotechnology, niosomes are expected to become a significant component of next-generation drug delivery platforms, bridging the gap between laboratory research and real-world therapeutic application.
REFERENCES
Riya Marium Philip, Dr. Boby John G, Jayasankar K R, Formulation Techniques and Biomedical Significance of Niosomal Carriers in Dermal and Transdernal Drug Delivery, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 9, 299-312. https://doi.org/10.5281/zenodo.17046563
10.5281/zenodo.17046563
