Ultrasonic Formulation of Niosomes

Niosomes are nano-sized vesicles, which can be used as carrier for drugs (e.g. cancer drugs) and other bioactive substances. Ultrasonic emulsification is a simple and rapid method to formulate small niosomes with a high drug load.

Niosome Vesicles as Nano-Carrier for Active Ingredients

Structure of a niosomeA niosome is a non-ionic surfactant-based vesicle, mostly formed by non-ionic surfactant and cholesterol incorporation as excipient. Niosomes are more stable against chemical degradation or oxidation and have long storage time in comparison to liposomes. Due to the surfactants used for niosome preparation, they are biodegradable, biocompatible, and non-immunogenic. Niosomes are osmotically active, chemically stable and offer a longer storage time in comparison to liposomes. Depending on size and lamellarity, various preparation methods are available such as sonication, reverse phase evaporation, thin film hydration or trans-membrane pH gradient drug uptake process. Ultrasonic niosome preparation is the preferred technique to produce unilamellar vesicles, which are small and uniform in size.

Ultrasonic Niosome Formulation

To formulate niosomes, an oil-in-water (o/w) emulsion must be prepared from an organic solution of surfactant, cholesterol, and an aqueous solution containing the bioactive compound, i.e. the drug. Ultrasonic emulsification is the superior technique to mix immiscible liquids such as oil and water. By shearing the droplets of both phases ans breaking them to nano-size, a nano-emulsion is obtained. Subsequently, the organic solvent is evaporated, resulting in niosomes loaded with therapeutic agents, which are dispersed in the aqueous phase.When compared to mechanical stirring, the ultrasonic niosome formulation technique excels by forming niosomes with a smaller average dimension and a lower polydispersity index in a fast process. The use of smaller vesicles is generally preferable, considering that they tend to avoid the body clearance mechanisms better than larger particles, and remain for longer times in the bloodstream. (cf. Bragagni et al. 2014)

Advantages of Ultrasonic Niosome Preparation

  • unilamellar, small, uniform vesicles
  • simple and fast process
  • reproducible
  • precisely controllable
  • safe
  • easily scalable

Ultrasonic Niosome Preparation Protocols

Niosome formulation using sonication has been extensively researched so that numerous scientifically validated protocols for ultrasonic niosome production are available.
Below, you can find a short overview over a few formulation protocols preparing and loading niosomes using sonication.

Niosomes Loaded with Withania somnifera Extracts
Chinembiri et al. (2017) formulated Withania somnifera crude extract into niosomes intended for topical application. The bioactive compounds were encapsulated via solvent injection. Therefore, the organic and aqueous phases were continuously magnetically stirred, and the temperature maintained at 60°C ± 2°C until the organic solvent was driven off. The resulting formulation was cooled and sonicated on ice using the Hielscher UP200ST sonicator. The niosomes had an average sizes ranging of approx. 165.9 ± 9.4 and showed a high entrapment efficiency (EE%) of withanolide A.

Doxorubicin-Loaded Niosomes
N-palmitoyl glucosamine niosomes (Glu) loaded with doxorubicin, an anti-cancer drug, were prepared by shaking a mixture of NPG (16 mg), Span 60 (65 mg), cholesterol (58 mg), and Solulan C24 (54 mg) in doxorubicin solution (1.5 mg/ml, 2 ml, prepared in PBS) at 90°C for 1 h, followed by probe sonication for 10 min (75% of max).
Palmitoyl glycol chitosan (GCP) vesicles were prepared as previously described (11) by probe sonicating glycol chitosan (10 mg) and cholesterol (4 mg) in doxorubicin solution (1.5 mg/ml). (Dufes et al. 2004)

Hielscher UP400St with sonotrode S26d22L2D

UP400세인트 – 400W ultrasonic device for the formulation of nano-carriers such as niosomes

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Alternative Niosome Preparation Methods

Alternative niosome formulation methods such as the reverse phase evaporation technique or the trans-membrane pH gradient drug uptake process involve the application of ultrasonic energy. Both techniques are mainly used to formulate multilamellar vesicles (MLVs). Below you can find a short description of both techniques and the sonication step involved.

Sonication in Niosome Preparation via Reverse Phase Evaporation

In the Reverse Phase Evaporation (REV) method, the components of the niosomal formulation are dissolved in a mixture of ether and chloroform and added to the aqueous phase, which contains the drug. Ultrasonic emulsification is used to turn the mixture into a fine-size emulsion. Subsequently, the organic phase is evaporated. The niosome obtained during the evaporation of the organic solvent are unilamellar vesicles of large size.

Trans-membrane pH gradient drug uptake process

For the trans-membrane pH gradient (inside acidic) drug uptake process (with remote loading), surfactant and cholesterol are dissolved in chloroform. The solvent is then evaporated under vacuum to obtain a thin film on the wall of the round-bottom flask. The film is hydrated with 300 mM citric acid (pH 4.0) by vortexing the suspension. The multilamellar vesicles are frozen and thawed three times and subsequently sonicated using a probe-type ultrasonicator. To this niosomal suspension, aqueous solution containing 10 mg/ml of drug is added and vortexed. The pH of the sample is then raised to pH 7.0-7.2 with 1M disodium phosphate. Then, the mixture is heated to 60°C for 10 minutes. This technique yields in multilamellar vesicles. (cf. Kazi et al. 2010)

Ultrasonic Size Reduction of Niosomes

Niosomes are usually within the size range of 10nm to 1000nm.Depending on the preparation technique, niosomes are often of relatively large size and tend to form aggregates. However, specific niosome sizes are an important factor when it comes to the targeted type of delivery system. For instance, a very small niosome size in the nanometer range is most suitable for systemic drug delivery, where the drug must be delivered across cell membranes to reach the cellular target site, whilst larger niosomes are recommended for intramuscular and intra-cavity drug delivery or ophthalmic applications. Ultrasonic size reduction of niosomes is a common step during the preparation of highly potent niosomes. Ultrasonic shear forces deagglomerate and disperse the niosomes into mono-dispersed nano-niosomes.

ProtocolUltrasonic Size Reduction of LipoNiosomes

Naderinezhad et al. (2017) formulated biocompatible LipoNiosomes (a combination of niosome and liposome) containing Tween 60: cholesterol: DPPC (at 55 : 30 : 15 : 3) with 3% DSPE-mPEG. To reduce the size of the prepared LipoNiosomes, after hydration they sonicated the suspension for 45 min (15 seconds on and 10 seconds off, amplitude 70% at 100 watts) to minimize particle aggregation using ultrasonic homogenizer UP200St (Hielscher Ultrasonics GmbH, Germany). For pH-gradient method, the dried films of CUR, surfactants and lipids were hydrated with 1300 mL of ammonium sulfate (pH 1⁄4 4) at 63 C for 47 min. Then, nanoparticles were sonicated over an ice bath to produce small vesicles.

Ultrasonicators for Niosome Preparation

Hielscher Ultrasonic is long-time experienced in the design, manufacturing, distribution and service of high-performance ultrasonic homogenisers for the pharmaceutical, food, and cosmetic industry.
The preparation of high-quality niosomes, liposomes, solid lipid nanoparticles, polymeric nanoparticles, cyclodextrin complexes and other nano-structured drug carriers are processes, in which Hielscher ultrasonic systems excel due to their high reliability, consistent power output, and precise controllability. Hielscher ultrasonicators allow for precise control over all process parameters, such as amplitude, temperature, pressure and sonication energy. The intelligent software automatically protocols all sonication parameters (time, date, amplitude, net energy, total energy, temperature, pressure) on the built-in SD-card.
The robustness of Hielscher’s ultrasonic equipment allows for 24/7 operation at heavy duty and in demanding environments.
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Niosomes vs Liposomes

Liposomes and niosomes are microscopic vesicles, which can be loaded with bioactive compounds for drug delivery. Niosomes are similar to liposomes, but they differ in their bilayer composition. Whilst liposomes have a phospholipid bilayer, the niosome bilayer is made from nonionic surfactants, which leads to a chemical difference in structural units. This structural difference gives niosomes a higher chemical stability, superior skin penetration ability, and less impurity.

Niosomes are differentiated by size into three major groups: Small unilamellar vesicles (SUV) have an average diameter of 10–100 nm, large unilamellar vesicles (LUV) have an average size of 100–3000nm, and multilamellar vesicles (MLV) are characterised by more than one bilayer.

“Niosomes behave in vivo like liposomes, prolonging the circulation of entrapped drug and altering its organ distribution and metabolic stability. As with liposomes, the properties of niosomes depend on the composition of the bilayer as well as method of their production. It is reported that the intercalation of cholesterol in the bilayers decreases the entrapment volume during formulation, and thus entrapment efficiency.” (Kazi et al. 2010)

Niosomes can be prepared via various techniques such as thin film hydration technique, ultrasonication, reverse phase evaporation method, freeze-thaw method, microfluidization, or dehydration rehydration method. By choosing the appropriate form of preparation, surfactant, cholesterol content, surface charge additives, and suspension concentration, the composition, lamellarity, stability, and surface charge of niosomes can be formulated in order to fulfil specific drug carrier requirements.
In order to produce highly biocompatible niosomes with a very low cytotoxicity, the surfactants used in niosome preparation should be biodegradable, biocompatible and non-immunogenic.

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