Nanoemulsion: A new concept of Delivery System
Kanchan R. Pagar, A. B. Darekar
R. G. Sapkal Institute of Pharmacy, Anjaneri, Nasik
Nanoemulsion has been identified as a promising delivery system for various drugs including biopharmaceuticals. Nanoemulsion is a heterogeneous system composed of one immiscible liquid dispersed as droplets within another liquid. The droplets size of nano emulsion is between 20 to 500 nm. Diameter and surface properties of droplets of nanoemulsion plays an important role in the biological behavior of the formulation. Small droplet sizes lead to transparent emulsions so that product appearance is not altered by the addition of an oil phase. In this paper various aspects of nanoemulsion have been discussed including advantages, disadvantages and methods of preparation. Furthermore new approaches of stability of formulation, effect of types and concentration of surfactant, process variables and method are also discussed to improve the stability of nanoemulsion formulation
Nanoemulsions consist of fine oil-in-water dispersions, having droplets covering the size range of 100–600 nm. Nanoemulsions, usually spherical, are a group of dispersed particles used for pharmaceuticals biomedical aids and vehicles that shows great promise for the future of cosmetics, diagnostics, drug therapies and biotechnologies.  The terms sub-micron emulsion (SME),  mini-emulsion  and ultra fine emulsion  are used as synonyms. Nanoemulsion is a heterogeneous mixture of lipid and aqueous phase and stability are achieved by using a suitable material known as emulsifying agents. Nanoemulsion is a translucent system compare to ordinary emulsion or some time microemulsion.
It has been demonstrated that with the help of nanoemulsion as a delivery system retention time of a drug in the body can be increased, so low amount of drug is required for the therapeutic action. Past studies shows the utilization of nanoemulsion technology for the enhancement of bioavailability of lipophilic drug .
Nowadays this dosage form is frequently used for the delivery of various biopharmaceuticals as vaccines, DNA encoded drugs , and antibiotics . Nanoemulsion technology is used as a cosmetics and topical preparations. This technology has a great advantage over the other dosage forms that the formulation can be delivered by various routes including oral , ocular  and transdermal . The smaller droplet size of emulsions not only suppresses the coalescence or coagulation of emulsion droplets but also suppresses the precipitation of emulsions and also helps to deliver the active agents . Oil in water type of nanoemulsion formulation are prepared since long ago [2,3,11,12] but water in oil type of nanoemulsion is recently investigated by K. Landfester [13,14]. Both of these type of nanoemulsion have various advantages as pharmaceuticals and in cosmetics science as well as. In this paper we are trying to understand various aspects related to the manufacturing of nanoemulsion, type of emulsifying agents, and various problems during the formulation of nanoemulsion delivery system. Due to the very small size of droplets it provides the stability against sedimentation and creaming with Ostwald ripening forming the main mechanism of nanoemulsion breakdown. Structure of o/w nanoemulsion droplets are demonstrated in Fig.1.  The term nanoemulsion' also refers to a miniemulsion which is fine oil/water or water/oil dispersion stabilized by an interfacial film of surfactant molecule having droplet size range 20–600 nm. Because of small size, nanoemulsions are transparent. There arethree types of nanoemulsion which can be formed:
a) Oil in water nanoemulsion in which oil is dispersed in the continuous aqueous phase,
b) Water in oil nanoemulsion in which water droplets are dispersed in continuous oil phase, and
c) Bi- continuous nanoemulsions [16,17]
Application of nanoemulsion:
Nanoemulsion has become a very attractive formulation for the delivery of pharmaceuticals. Nanoemulsion also shows a good advantage in the field of cosmetics. The attraction of nanoemulsion formulation in pharmaceuticals and cosmetics is due to following reasons .
· Nanoemulsion never shows the creaming and sedimentation kind of problems due to its very small droplet size. These problems are very common with conventional emulsion and even microemulsion. Basically both problems are associated with the influence of gravitational force over the droplet of emulsion. But in case of nanoemulsion the droplet size is very small which minimized the working of gravitational force over the droplets and posses creaming and sedimentation of emulsion.
· Again small droplet size of nanoemulsion prevents the coalescence of droplets. In the coalescence process droplets come together and form a large droplet with increased size which is responsible for the instability of emulsion. But the small droplet size of nanoemulsion prevent the coalescence among them and prevent the deformation and than surface fluctuation.
· Dispersibility of nanoemulsion is very high as compared to microemulsion because small droplet size prevents the flocculation of droplets and this process makes the system dispersed without separation.
· Nanoemulsion formulation provides a rapid penetration of active ingredients through skin due to the large surface area of droplets. Even sometimes it is found that nanoemulsion penetrate easily through rough skin. This property of nanoemulsion minimizes the additional utilization of special penetration enhancer which is responsible for incompatibility of formulation.
· Nanoemulsion formulation required low amount of surfactant compared to microemulsion. For example about 20- 25 % surfactant is required for the preparation of microemulsion but 5-10 % surfactant is sufficient in case of nanoemulsion. Again with the help of nanoemulsion surfactant utilization can be minimized.
· Nanoemulsion has a transparent and fluidy property which improves the formulation patient compliance and safe for administration due to the absence of any thickening agent and colloidal particles.
· It is also reported that nanoemulsion may be used for the target delivery of active ingredient especially in cancer therapy.
· Nanoemulsion formulation may become the stable alternate for the liposomes and vesicle type of delivery systems.
· Nanoemulsion formulation can be administered by the various routes of body. There are various reported methods which support the administration of nanoemulsion formulation through paranteral [18-21], oral [22-24], topical [25,26], nasal  and ocular [28,29] route.
· These formulations may be used to increase the bioavailability of poor water soluble drug by developing oil in water type of nanoemulsion [30,31].
Limitation of nanoemulsion:
Although this formulation provide great advantages as a delivery system for the consumers but sometimes the reduced size of droplets are responsible for the limited use of nanoemulsion formulation. Some limitations of nanoemulsionare as follows .
· The manufacturing of nanoemulsion formulation is anexpensive process because size reduction of droplets is very difficult as it required a special kind of instruments and process methods. For example, homogenizer (instrument required for the nanoemulsion formulation) arrangement is an expensive process. Again microfludization and ultrasonication (manufacturing process) require high amount of financial support. Stability of nanoemulsion is quite unacceptable and creates a big problem during the storage of formulation for the longer time period. Ostwald ripening is the main factor associated with unacceptability of nanoemulsion formulations. This is due to the high rate of curvature of small droplet show greater solubility as compared to large drop with a low radius of curvature.
· Less availability of surfactant and cosurfactant required for the manufacturing of nanoemulsion is another factorwhich marks as a limitation to nanoemulsion manufacturing.
Preparation Methods of nanoemulsion:
Several methods have been suggested for the preparation of nanoemulsion. The basic objectives of the nanoemulsion preparation to achieve the droplet size range of 100-600 nm and another is to provide the stability condition. Formation of nanoemulsion system required a high amount of energy. This energy can be provided either by mechanical equipment or the chemical potential inherent within the component. Here some methods are discussed which are freely used for the nanoemulsion preparation.
Fig:1. An o/w type nanoemulsion with structural droplets demonstration
Techniques of Nanoemulsions Preparation:
(Pershing et al., 1993) Nanoemulsions have very small particle size range; they can be most effectively produced using high-pressure equipment. The most commonly used methods for producing nanoemulsions are High-pressure homogenization and Microfluidization used at both laboratory and industrial scale. Other methods like. Ultrasonification and In-situ emulsification are also suitable for preparation of nanoemulsion.
1. High-Pressure Homogenization:
The preparation of nanoemulsions requires high- pressure homogenization. This technique makes use of high-pressure homogenizer/piston homogenizer to produce nanoemulsions of extremely low particle size (up to 1nm). The dispersion of two liquids (oily phase and aqueous phase) is achieved by forcing their mixture through a small inlet orifice at very high pressure (500 to 5000 psi), which subjects the product to intense turbulence and hydraulic shear resulting in extremely fine particles of emulsion. The particles which are formed exhibit a liquid, lipophilic core separated from the surrounding aqueous phase by a monomolecular layer of phospholipids. This technique has great efficiency, the only disadvantage being high energy consumption and increase in temperature of emulsion during processing. To obtain the optimized formulation following process variables should be investigated: Effect of Homogenization Pressure: It is optimized the process parameter ranging from 100 to 150 bars. The higher is the size the lower is the particle size obtained e.g., RMRP 22. No. of Homogenization cycles: The higher the homogenization cycles the smaller is the particle size obtained. The cycles are carried out in 3, 4 or 10 cycles. The number of cycles is analysed by poly disparity index of drug after each cycle.
· Ease of scale-up and little batch-to-batch variation.
· Narrow size distribution of the nanoparticulate drug.
· Flexibility in handling the drug quality.
· Effectively used for thermolabile substances. 
2. Microfluidization (Hadgraft, 2001)
Micro-fluidization is a mixing technique, which makes use of a device called micro-fluidizer. This device uses a high pressure positive displacement pump (500 to 20000psi), which forces the product through the interaction chamber, which consists of small channels called „micro-channels‟. The product flows through the micro channels on to an impingement area resulting in very fine particles of submicron range. The two solutions (aqueous phase and oily phase) are combined together and processed in an inline homogenizer to yield a coarse emulsion. The coarse emulsion is into a micro-fluidizer where it is further processed to obtain a stable nanoemulsion. The coarse emulsion is passed through the interaction chamber micro-fluidizer repeatedly until desired particle size is obtained. The bulk emulsion is then filtered through a filter under nitrogen to remove large droplets resulting in a uniform nanoemulsion. 
3. Ultrasonication (Bhatt and Madgav, 2011)
The preparation of Nanoemulsion is reported in various research papers which aim to use the ultrasonic sound frequency for the reduction of the droplet size. Another approach is the use of a constant amplitude sonotrode at system pressures in excess of the ambient value. It is well known that increasing the external pressure increases the cavitations threshold within an ultrasonic field and thus fewer bubbles form. However, increasing the external pressure also increases the collapse pressure of cavitations bubbles. This means that the collapse of the bubbles when cavitation occurs becomes stronger and more violent than when the pressure is at atmospheric conditions. As cavitation is the most important mechanism of power dissipation in a low frequency ultrasonic system, these changes in navigational intensity can be related directly to changes in the power density. The system also uses a water jacket to control the temperature to optimum level. 
Phase inversion method:
In this method fine dispersion is obtained by chemical energy resulting of phase transitions taking place through emulsification path. The adequate phase transitions are produced by varying the composition at constant temperature or by varying the temperature at constant composition, phase inversion temperature (PIT) method was introduced by Shinoda et al. based on the changes of solubility of polyoxyethylene- type surfactant with temperature. This surfactant becomes lipophilic with increase in temperature due to dehydration of polymer chain. But at low temperature, the surfactant monolayer has a large positive spontaneous curvature forming oil-swollen micellar solution phase .
2. Sonication method:
Sonication method is another best way to prepare nanoemulsion. In this method the droplet size of conventional emulsion or even microemulsion are reduced with the help of sonication mechanism. This method is not suitable for large batches only small batches of nanoemulsion can be prepared by this method .
High pressure homogenizer:
This method is performed by applying a high pressure over the system having oil phase, aqueous phase and surfactant or co-surfactant. The pressure is applied with the help of a special equipment know as homogenizer. There are some problems which are associated with homogenizer such as poor productivity, component deterioration due to difficult mass production and generation of much heat. With this method only oil in water (o/w) liquid nanoemulsion of less than 20% oil phase can be prepared and cream nanoemulsion of high viscosity or hardness with a mean droplet diameter lower than 200 nm cannot be prepared .
Characterization of Nanoemulsion:
The unique qualities and performance of nanoparticles as devices of drug delivery arise directly from their physicochemical properties. Hence, it is keen to understand and determine them to characterize its behavior. A good understanding allows prediction of in vivo performance as well as allowing particle design, formulation development, and process troubleshooting to be carried out in a rational fashion (Haskell, 2012). It will includes characteristics such as thermodynamic stability testing. (Shinha and Ganesh, 2015; Tadros, 2004; Guglielmini, 2008; Tadros, 1982) Dilution stability transmittance measurement, Globule size distribution. Zeta potential and in vitro assay. Apart from that it should be evaluated for pH, conductivity, refractive index etc. (Pershing et al., 1993). The droplet size, viscosity, density, turbidity, refractive index, phase separation and pH measurements shall be performed to characterize the Nanoemulsion. The droplet size distribution of Nanoemulsion vesicles can be determined by either light scattering technique or electron microscopy. This technique has been advocated as the best method for predicting Nanoemulsion stability. 
(i) Phase behaviour study:
This study is a characterization and optimization of ingredients (surfactant, oil phase and aqueous phase). Generally the study is necessary in case of nanoemulsion formulation prepared by phase inversion temperature method and self emulsification method in order to determine the phase of nanoemulsion and dispersibility. Study is done by placing the different ingredients of nanoemulsion by varying the concentration in glass ampules and thoroughly homogenized at a certain temperature for a time until equilibrium. Anisotropic phase can be identified by polarized light.
(ii) Particle Size Analysis:
Formulated nanoemulsion should be analyzed for their hydrodynamic particle size and particle size distribution. Generally in case of nanoemulsion dynamic light scattering (DLS) method are used for the measurement of particles and further particle size distribution. 
1. Dye Solubilisation
A water soluble dye is solubilized within the aqueous phase of the W/O globule but is dispersible in the O/W globule. An oil soluble dye is solubilized within the oil phase of the O/W globule but is dispersible in the W/O globule. 
2. Dilutability Test
O/W Nanoemulsions are dilutable with water whereas W/O are not and undergo phase inversion into O/W Nanoemulsion. 
3. Conductance Measurement:
O/W Nanoemulsion where the external phase is water, are highly conducting whereas W/O are not, since water is the internal or dispersal phase. To determine the nature of the continuous phase and to detect phase inversion phenomena, the electrical conductivity measurements are highly useful. A sharp increase in conductivity in certain W/O Nanoemulsion systems was observed at low volume fractions and such behaviour was interpreted as an indication of a „ percolative behaviour‟ or exchange of ions between droplets before the formation of bicontinuous structures. Dielectric measurements are a powerful means of probing both structural and dynamic features of Nanoemulsion systems. 
Surface charge measurement: Surface zeta potential of nanoemulsion droplets should be measured with the help of mini electrode to predict the surface properties of nanoemulsion.
(v) Drug contain:
This method is used to determine the amount of drug contained in the formulation. Various methods (especially Western Blot method) are used in this order.
Viscosity should be measured to ensure the better delivery of the formulation. 
4. Dynamic Light-Scattering measurements (Tanojo et al.,1997)
The DLS measurements are taken at 90° in a dynamic light scattering spectrophotometer which uses a neon laser of wavelength 632 nm. The data processing is done in the built-in computer with the instrument.
The average diameters and polydispersity index of samples were measured by Photon Correlation Spectroscopy. The measurements were performed at 25oC using a He-Ne laser. 
6. Phase Analysis
To determine the type if Nanoemulsion that has formed the phasesystem (O/W or W/O) of the Nanoemulsions is determined by measuring the electrical conductivity using a conductometer. 
7. Interfacial Tension (Leong et al., 2009)
The formation and the properties of Nanoemulsion can be studied by measuring the interfacial tension. Ultra low values of interfacial tension are correlated with phase behaviour, particularly the existence of surfactant phase or middlephase Nanoemulsions in equilibrium with aqueous and oil phases. Spinning-drop apparatus can be used to measure the ultra low interfacial tension. Interfacial tensions are derived from the measurement of the shape of a drop of the low-density phase, rotating it in cylindrical capillary filled with highdensity phase. 
8. Viscosity measurement
Temperatures using Brookfield type rotary viscometer. The sample room of the instrument The viscosity of Nanoemulsions of several compositions can be measured at different shear rates at different must be maintained at 37±0.2°C by a thermo bath, and the samples for the measurement are to be immersed in it before testing. 
The apparent pH of the formulation was measured by pH meter.
10. Refractive Index (Aubrun et al., 2004)
The refractive index, n, of a medium is defined as the ration f the speed, c, of a wave such as light or sound in a reference medium to the phase speed, vp, of the wave in the medium. n=c/vp; It was determined using an Abbes type refractrometer (Nirmal International) at 25±0.5°C. 
11. Transmission Electron Microscopy (TEM)
Morphology and structure of the nanoemulsion were studied using transmission electron microscopy. Combination of bright field imaging at increasing magnification and of diffraction modes was used to reveal the form and size of nanoemulsion droplets. Observations was performed as, a drop of the nanoemulsion was directly deposited on the holey film grid and observed after drying. 
nanoemulsion instability and its prevention methods the instability of nanoemulsion is due to some main factors including creaming flocculation coalescence and Ostwald ripening. Among them ostwald ripening is the main mechanism of nanoemulsion instability because rest of the problem are minimized by the small size of nanoemulsion and use of nonionic type of surfactant. Creaming of nanoemulsion is prevented by the faster diffusion rate of smaller droplets. Vanderwall force is responsible for the attraction of droplets and leads to the flocculation of emulsion. But in case of nanoemulsion nonionic surfactant, it does not create any kind of attractive force, hence no flocculation occurs. The droplet size of nanoemulsion also prevent the flocculation because these small droplets show high curvature and laplace pressure opposes the deformation of large droplets. Coalescence of droplets of nanoemulsion can be prevented by a thick multilamellar surfactant film adsorbed over the interface of droplets.
The only problem of instability of nanoemulsion can arise by the ostwald ripening. In ostwald ripening small droplets with high radius of curvature converted into large droplets with low radius of curvature . Two droplets diffuse and become one large droplet. Thus, after the storage for a long time period, droplets size distribution shifted to large sizes and the transparency of nanoemulsion become turbid. It is also identified that ostwald ripening create a problem during the delivery of formulations. Several theories have been suggested for the demonstration of ostwald ripening, among them LSW theory properly justified the factors affecting the ostwald ripening. Tadros et al demonstrated the addition of a small amount of insoluble oil (squalane) can reduce the diffusion of the smaller oil droplets from the small to the large droplet. Another method to prevent the effect of Ostwald ripening is addition of polymeric surfactant on the interface which increase the elasticity of droplets and further reduce the effect of ostwald ripening [47,48].
Paqui Izquier do et al successfully demonstrates the influence of surfactant mixing ratio on the stability of nanoemulsion when phase inversion transition method are used as a nanoemulsion preparation method. The formation of O/W nanoemulsions by the PIT emulsification method in water/mixed nonionic surfactant/oil systems was studied.
The hydrophilic–lipophilic properties of the surfactant were varied by mixing polyoxyethylene 4-lauryl ether (C12E14) and polyoxyethylene 6-lauryl ether (C12E6). Emulsification was performed in samples with constant oil concentration (20 wt %) by fast cooling from the corresponding HLB temperature to 25 °C. Nanoemulsions with droplet radius 60–70 nm and 25–30 nm were obtained at total surfactant concentrations of 4 and 8 wt%, respectively. The nanoemulsion with 8% surfactant ratio was showing high stability over the nanoemulsion with 4% surfactant concentration . In another study Sher L. et al successfully demonstrated the effect of process variables over the droplet size of nanoemulsion which further leads to the stability of nanoemulsion. In the work they studied the formation and stability of n-decane in water nanoemulsion produced by the PIT method by using polyoxyethylene lauryl ether as a surfactant. The result of this work clearly indicate that the droplet size of nanoemulsion depends on the various process variables such as heating and cooling temperature of formulations and final temperature to which the mixture is cooled after phase inversion .
In another investigation the influence of both, the nature of the surfactant and surfactant concentration on the processes of droplet breakup and coalescence in the formation of decane in water nanoemulsions in a high-pressure homogenizer were investigated. Food proteins, phosphatidylglycerol and phosphatidylcholine were used as surfactant by varying concentration and droplet size were investigated for each formulation. It was found that for the proteins the increase in droplet volume was shown to be linear with respect to time, indicating an Ostwald ripening process. Although there was coalescence on storage at the lowest concentrations of phospholipids used, there was no observed ripening at any emulsifier concentration showing that phospholipids interfaces are structured in such a way as to resist ripening. It is demonstrated that the mixture of surfactant enhances the stability a compared to single surfactant by Porras M. It was also demonstrated that the stability of the electrostatically- and sterically-stabilized dispersions can be controlled by the charge of the electrical double layer and the thickness of the droplet surface layer formed by non-ionic emulsifier .
SUMMARY AND CONCLUSION:
An advanced mode of drug delivery system has been developed to overcome the major drawbacks associated with conventional drug delivery systems. This review gives a detailed idea about a nanoemulsion system. Nanoemulsions are nano-sized emulsions, which are manufactured for improving the delivery of active pharmaceutical ingredients. These are the thermodynamically stable isotropic system in which two immiscible liquids are mixed to form a single phase by means of an emulsifying agent, i.e., surfactant and co-surfactant. The droplet size of nanoemulsion falls typically in the range 20–200 nm. The main difference between emulsion and nanoemulsion lies in the size and shape of particles dispersed in the continuous phase. In this review, the attention is focused to give a basic idea about its formulation, method of preparation, characterization techniques, evaluation parameters, and various applications of nanoemulsion.
Nanoemulsions are biphasic dispersion of two immiscible liquids: either water in oil (W/O) or oil in water (O/W) droplets stabilized by an amphiphilic surfactant. These come across as ultrafine dispersions whose differential drug loading; viscoelastic as well as visual properties can cater to a wide range of functionalities including drug delivery. However there is still relatively narrow insight regarding development, manufacturing, fabrication and manipulation of nanoemulsions which primarily stems from the fact that conventional aspects of emulsion formation and stabilization only partially apply to nanoemulsions. This general deficiency sets up the premise for current review. We attempt to explore varying intricacies, excipients, manufacturing techniques and their underlying principles, production conditions, structural dynamics, prevalent destabilization mechanisms, and drug delivery applications of nanoemulsions to spike interest of those contemplating a foray in this field.
Nanoemulsions are widely used in pharmaceutical systems. Nanoemulsion formulation offers several advantages such as delivery of drugs, biological or diagnostic agents. The most important application of nanoemulsion is for masking the disagreeable taste of oily liquids. Nanoemulsion may also protect the drugs, which are susceptible to hydrolysis and oxidation. Nowadays, nanoemulsions are used for targeted drug delivery of various anticancer drugs, photo sensitizers or therapeutic agents. Nanoemulsion can also provide prolonged action of the medicaments. Overall all nanoemulsion formulation may be considered as effective, safe and with increased bioavailability. It is expected that further research and development will be carried out in the future regarding nanoemulsion. Arguments made in this review suggest increasing influence of nanoemulsions in each and every aspect of drug delivery. Nanoemulsions are:
1) Inherently resistant to normal destabilizing mechanisms persistent in emulsions;
2) They are usually transparent which gives the cosmetic appeal, and
3) Present many opportunities of increasing oral availability of strongly lipophilic drugs.
Oral delivery was the principal concept which led to development of emulsions, and it is in this aspect that nanoemulsions are especially suited. Other routes of drug delivery are equally approachable via nanoemulsions. Their minute dimensions make them special candidates for innocuous intravenous entry. Nanoemulsions are expected to progressively become center of research and development. Never the less many challenges still need to be overcome, in order to ensure that nanoemulsions enter mainstream pharmaceutical market and reach from a laboratory bench side to an actual patient bed side. Principal amongst them are the cost implications for scaling up nanoemulsion production, quest for nontoxic solvents in formulation, and also enhancing toxicity database available for various excipients employed in fabrication of nanoemulsions.
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