Keywords

3.1 Introduction

An emulsion is defined as the dispersion of two immiscible phases (Becher 2001). Based on their droplet size, stability, and appearance, emulsions can be classified into three main groups, namely, macroemulsions, nanoemulsions, and microemulsions. Conventional macroemulsions are thermodynamically unstable turbid suspension of droplet with sizes between 0.1 and 100 μm and with polydispersity index (PDI) >0.4. On the other hand, nanoemulsions have a droplet size between 5 and 200 nm and are kinetically stable and usually transparent in nature with PDI <0.1–0.2. In contrast, microemulsions are thermodynamically stable and transparent suspensions with a droplet size 1–100 nm and PDI <0.1 (Fernandez et al. 2004; Thakur et al. 2013; Gupta et al. 2016; Kadir 2017). Although nano- and microemulsions possess a similar droplet size, they differ in their basic compositions and preparation methods. One of the main differences is the amount of surfactant used; mostly nanoemulsions are prepared using a lower amount of surfactant (5–10% w/w) compared to that employed for microemulsions (>20% w/w). Due to low amount of surfactant, nanoemulsions are more attractive and demanding for industrial applications.

Nanoemulsions principally consist of three main components, i.e., water, oil, and a surfactant/emulsifying agent. The emulsifier is an important constituent since it not only allows to attain a small droplet size by decreasing the interfacial tension (surface energy) per unit area between the oil and water phase but also stabilizes the nanoemulsion by repulsive electrostatic interactions and steric hindrance. In recent years, nanoemulsions have gained enormous attention due to their wide applicability in various industries. Nanosized emulsions offer considerable advantages associated with their large surface area, which has an obvious effect on their bioavailability. In addition, they may serve as protective shields for the bioactive components encapsulated within and also improve the solubility of lipophilic compounds in aqueous media.

3.2 Types of Nanoemulsions

Nanoemulsions can be broadly classified into three major groups (Kriwet and Müller-Goymann 1995):

  1. (i)

    Oil-in-water emulsions (O/W): the oil droplets are surrounded by the surfactant and ramify into the water phase (Fig. 3.1).

  2. (ii)

    Water-in-oil emulsions (W/O): the water droplets are distributed throughout the continuous oil phase. These are commonly known as reverse micelles.

  3. (iii)

    Bi-continuous nanoemulsions: microdomains of either water or oil are interspersed within the system.

Fig. 3.1
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Representation of an oil-in-water emulsion (O/W). (Figure reprinted with permission (Prakash et al. 2018) of the Elsevier Copyright Clearance Center (2018))

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3.3 Constituents of Nanoemulsions

As mentioned above, there are three main components of nanoemulsions, i.e., water, oil, and a surfactant/emulsifier (Liu et al. 1991; Kriwet and Müller-Goymann 1995; Trotta 1999). The different types of oils used for the preparation of nanoemulsions can be classified into two groups based on their viscosity, i.e., high or low, and include castor oil, corn oil, coconut oil, evening primrose oil, mineral oil, olive oil, peanut oil, triglycerides, and hexadecane. Mixing of oil in water yields a temporary emulsion, which separates into two distinct phases by coalescence. The addition of a surfactant to an oil-water suspension increases the stability of the biphasic system. Common emulsifiers used for the formation of nanoemulsions are spans, tweens, hydrophilic colloids like acacia, bentonite, and bee gum, as well as polysorbate 80 and sorbitan oleate. An ideal surfactant must possess the following properties (Jaiswal et al. 2015): (i) nontoxic in nature and chemically stable, (ii) able to reduce the surface tension below 10 dynes/cm, (iii) easily adsorbed in the dispersed phase to prevent coalescence, (iv) aiding to build a sufficient zeta potential (surface charge), and (v) effective at low concentrations.

The solubility of a particular type of surfactant in a given nanoemulsion can be evaluated in terms of hydrophilic-lipophilic balance (HLB), which highly depends on the concentration and phase volume of both water and oil (Myers 1999). Utilizing the solubility parameter (SP) value, HLB is used to characterize most oil phases. The value of HLB can be derived mathematically by using the equation:

$$ \mathrm{HLB}=4\times \left[\frac{\mathrm{SP}+7}{8}\right] $$

This equation gives an idea about selecting an optimal emulsifying agent as well as the stability of the emulsion. In general, a low HLB value is indicative of O/W emulsions, while a high HLB value is indicative of W/O emulsions. In other words, the HLB indicates the solubility of the surfactant in the oil and water phase. A low HLB suggests that the surfactant is more lipophilic, while a high HLB value suggests that it has a hydrophilic nature. In general, HLB values higher than 7 are typically suitable for W/O emulsions, while HLB values lower than 7 are suitable for O/W emulsions (Sajjadi et al. 2003; Tadros et al. 2004).

3.4 Methodology for the Preparation of Nanoemulsions

Nanoemulsions are non-equilibrated systems; therefore, they need energy and a surfactant to form. They can be formed either by high- or low-energy methods (Anton and Vandamme 2009) (Fig. 3.2). Traditionally, high-energy methods are employed; however, low-energy methods are also attractive due to several advantages such as the mild conditions employed, which lead to reduced adverse effects on the encapsulated bioactive components.

Fig. 3.2
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Different high- and low-energy methods for the preparation of nanoemulsions

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3.4.1 High-Energy Methods

Nanoemulsions are nonequilibrium systems that cannot be formed spontaneously, but need an external energy. Such energy is usually applied by using a high-pressure homogenizer, high shear stirring, and ultrasonication (Graves et al. 2005; Mason et al. 2006; Jafari et al. 2007). A device able to produce an input energy in the range from 108 to 1010 W/kg is required as external energy source. For the large-scale production of nanoemulsions, a high-pressure homogenizer is the most frequently used device (Solans et al. 2005). However, in recent times, ultrasounds generated by a sonicator have emerged as a cost-effective substitute (Kaltsa et al. 2013).

3.4.1.1 High-Pressure Homogenizer

A high-pressure homogenizer or piston homogenizer is the most common device to produce nanosized emulsions with a droplet size up to 1.0 nm (Fig. 3.3). In a high-pressure homogenizer, a macroemulsion is forced to pass through a small orifice under a pressure in the range from 5 × 102 to 5 × 103 psi (Chime et al. 2014). During the process, forces like deep turbulence, hydraulic shear, and cavitation work collectively to form nanoemulsion. The desired size and homogeneity of a nanoemulsion are achieved by passing it many times through a high-pressure homogenizer. An ideal nanoemulsion consists of a monodispersed sample with a PDI lower than 0.08. Undoubtedly, a high-pressure homogenizer is the most effective device for nanoemulsion preparation. However, the basic disadvantage of this method is the generation of heat during the preparation (Setya et al. 2014), which may have an adverse effect on heat-labile components such as nucleic acids, proteins, and enzymes (Floury et al. 2000; Chime et al. 2014).

Fig. 3.3
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Ray diagram representing a high-pressure homogenizer/piston homogenizer for the preparation of nanoemulsions

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3.4.1.2 High Shear Stirring

A high shear stirrer is a powerful mixing device used to obtain nanoemulsions. In such device, a powerful rotor generates an external force, which creates an intense agitation that in turn converts a macroemulsion into a nanoemulsion. Such devices are easy to handle, and the cost-effectiveness is the major advantage of this technique. However, a droplet size lower than 200–300 nm is hard to achieve, representing the principal limitation of these devices (Koroleva and Yurtov 2012).

3.4.1.3 Ultrasonication Method

In the ultrasonication method , the external energy is generated by applying sound waves that create an intense agitation in the solution. The ultrasonication energy is provided by a sonicator probe/sonotrode at the contact point of the macroemulsion, which gives rise to an intense vibration leading to the formation and collapse of vapor cavities and eventually nanosized droplets (Fig. 3.4). In this method, a macroemulsion is agitated at 29 kHz or larger frequencies. In most of the ultrasonic systems, the recirculation of the emulsion is required to attain a nanoemulsion with uniform droplet size (Mason et al. 2006). The basic advantages of these methods are their easy handling and cost-effectiveness, while the major drawback is the adverse effects on many functional components such as protein denaturation, polysaccharide depolymerization, and lipid oxidation due to the sound waves (Jafari et al. 2007; McClements and Rao 2011).

Fig. 3.4
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Ultrasonication method for the preparation of nanoemulsions. (Figure reprinted with permission (Singh et al. 2017) of the Elsevier Copyright Clearance Center (2018))

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3.4.1.4 Microfluidization

Microfluidization is the most widely accepted technique for the preparation of nanoemulsions in the pharmaceutical industry. In this technique, a macroemulsion is suspended and passed through a narrow bifurcated pipe at high pressure (150–650 MPa); it then collides in the interaction chamber, thus leading to the formation of a nanoemulsion (Fig. 3.5). A homogenous nanoemulsion of the desired size can be produced by repeating the process several times by applying different pressures (Chime et al. 2014; Jaiswal et al. 2015).

Fig. 3.5
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Diagram representing micro-desulfurizer device for the preparation of nanoemulsions. (Figure reprinted with permission (Singh et al. 2017) of the Elsevier Copyright Clearance Center (2018))

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3.4.2 Low-Energy Methods

Homogenous small sized nanoemulsions can be prepared by using low-energy emulsification methods such as phase inversion component and phase inversion temperature (Fig. 3.2). These methods exploit the physiochemical properties of the system to generate the emulsion (Caldero et al. 2011). Although low-energy methods are more effective in producing nanoemulsions as compared to high-energy ones, nonetheless, they have certain limitations as only definite types of components such as proteins and polysaccharides can be used. In order to overcome such issue, many synthetic surfactants are used.

3.4.2.1 Spontaneous Nanoemulsions

Spontaneous nanoemulsions are prepared without any external pressure at a constant temperature without phase transition of the system during emulsification (Solans and Sole 2012). This method depends on the interfacial tension, viscosity of the interfacial phase transition region, type of surfactant, and surfactant concentration. Such emulsions are commonly known as self-emulsifying drug delivery systems in the pharmaceutical industry. During the spontaneous nanoemulsion formation, the oil phase containing an aqueous soluble surfactant is mixed with water; upon movement of the water-dispersible substance from the oil to the water phase, an interfacial turbulence is generated, thereby resulting in the spontaneous formation of small oil droplets (McClements and Rao 2011).

3.4.2.2 Phase Inversion Method

This method utilizes the chemical energy that is released during the emulsification process. The varied degree of phase transition can be achieved by changing the basic composition at a constant temperature or by constant composition at varied temperature.

3.4.2.3 Phase Inversion Temperature (PIT)

In this method, emulsions are formed by varying the temperature while maintaining constant amount of the basic constituents. Nonionic surfactants with altering solubility in relation to temperature are required for the preparation of such types of emulsions. Thus, emulsions are formed by changing the temperature of the system, which in turn changes the solubility of the surfactant in water and oil (Chime et al. 2014). In order to prepare nanoemulsions using the PIT method, it is mandatory that the sample temperature reaches the PIT or HLB level, where the emulsification is promoted by an extremely low interfacial tension.

3.4.2.4 Phase Inversion Composition (PIC)

According to this methodology , emulsions are prepared at a constant temperature with a varying amount of either water, oil, water plus surfactant, or oil plus surfactant. The PIC method is more suitable for industrial applications as compared to PIT.

3.4.3 Bubble Bursting Method

In the bubble bursting method , gas is bubbled from the bottom of the water plus surfactant phase. As the bubbles reach the interphase of oil and water, they burst resulting in the spray of oil droplets in the water phase. A constant repetition of this process results in the formation of homogenous nanoemulsions (Gupta et al. 2016).

3.5 Firmness of Nanoemulsions

The stability of nanoemulsions is a key factor for their long-term storage and application, which highly depends on phenomena like coalescence, flocculation, sedimentation, creaming, and Ostwald ripening. The principal limiting factor to the nanoemulsion stability is the choice of surfactant, which makes the emulsion stable against heating, cooling, as well as changes of pH and ionic strength (McClements and Rao 2011). A surfactant can provide stability in various ways. For instance, an ionic surfactant imparts an electric charge to the nanodroplets present in the emulsion creating a sufficient repulsive force, which hinders the droplet aggregation. In contrast, a nonionic surfactant provides a steric barrier, thus preserving the structure of the nanoemulsion (Silva et al. 2012). Owing to their unique size, nanoemulsions display a great stability against coalescence, flocculation, sedimentation, or creaming. A small droplet within a nanoemulsion exhibits a Brownian movement rather than being subjected to the gravitational force, thus averting sedimentation or creaming (Klang et al. 2012). In addition, small droplets resist to adhesion due to the electronic repulsion and steric hindrance avoiding flocculation. The Ostwald ripening in which small droplets aggregate to form a larger one is the only serious concern regarding the stability of nanoemulsions. In the process of Ostwald ripening due to the variation of the droplet radius, a change in the chemical potential of the material inside the droplet occurs; consequently, the free energy of the system is reduced, leading to a decrease of the interfacial area; as a result, small droplets start to aggregate to form bigger ones, destabilizing the nanoemulsion. The rate of Ostwald ripening can be reduced by providing a kinetic barrier using less polar chain lipids. In addition, the use of high molecular weight oils, which are associated with the diffusion coefficient, can also be used to prevent the Ostwald ripening (Kadir 2017).

3.6 Characterization of Nanoemulsions

The characterization of nanoemulsions involves the assessments of their morphology, droplet size, charge (zeta potential), PDI, viscosity, refractive index, and thermodynamic stability.

3.6.1 Morphology

The morphology of nanoemulsions is often determined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) (Klang et al. 2012). SEM provides 3D images of the droplets, while TEM allows to obtain higher resolution images of the dispersed phase (Fig. 3.6).

Fig. 3.6
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Electron microscopic images of a nanoemulsion: (a) Cryo SEM image (Figure reprinted with permission (Saupe et al. 2006) of the Elsevier Copyright Clearance Center (2018)) and (b) TEM image. (Figure reprinted with permission (Thomas et al. 2017) of the Elsevier Copyright Clearance Center (2018))

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3.6.2 Size

Dynamic light scattering (DLS) analysis is the most commonly employed technique for the examination of the droplet size of nanoemulsions, and this method relies on the fluctuations of the scattering intensity owing to the Brownian motion of particles (Jaiswal et al. 2015). In addition, electron microscopy can also be employed to analyze the droplet size (Alka et al. 2007; Farhan et al. 2008).

3.6.3 Zeta Potential (Surface Charge)

The zeta potential denotes the charge on the droplets present within a nanoemulsion and can be determined by using a zeta particle size analyzer (Erol and Hans-Hubert 2005). Zeta potential is directly associated with the stability of nanoemulsion, indicating a similar charge repulsion between adjacent particles within the suspension. It can fall in both negative and positive ranges, which highly depends on the nature of the surfactant, electrolyte concentration, size, morphology of the particles, and pH of the solution. When the zeta potential value is low (either with negative or positive charges), the attraction between particles increases resulting in sedimentation or flocculation. A zeta potential value between 0 and ± 30 mV indicates instability of the nanoemulsion. In order to achieve the formation of a stable nanoemulsion, the zeta potential value must be higher than ±30 mV (Silva et al. 2012).

3.6.4 Polydispersity Index (PDI)

The PDI , which represents the uniformity of the droplet size within an emulsion, can be evaluated by DLS analysis. A higher value of PDI suggests heterogeneity of the system. In contrast, a lower PDI value indicates a uniformity of the droplets within the emulsion. The numerical value of PDI is calculated by the ratio of the mean standard deviation of the droplet size to the average droplet diameter (Jaiswal et al. 2015). The PDI also gives an insight on the stability of the formed nanoemulsion. The numeric value of PDI falls in the range from 0 (perfectly uniform preparation) to 1 (highly heterogeneous preparation). PDI values below 0.3 are acceptable for free drug delivery applications (Danaei et al. 2018).

3.6.5 Viscosity

Viscosity is one of the important parameters to evaluate the nanoemulsion stability and release of the active components. It can be measured by a Brookfield-type rotary viscometer at different temperatures and shear rates.

3.6.6 Refractive Index

The chemical stability of nanoemulsions at different storage time points is determined by measuring the refractive index using an Abbe refractometer.

3.6.7 Dye Test

A dye test is used to assess the successful preparation of O/W or W/O nanoemulsions. When a water soluble dye is added to an O/W nanoemulsion, it uniformly colors such emulsion. In contrast, in W/O emulsions, the dye imparts the color only to the dispersed phase, which can be easily detected by microscopic analysis (Jaiswal et al. 2015).

3.6.8 Thermodynamic Stability

The thermodynamic stability of nanoemulsions is characterized through heating and cooling cycles, centrifugation, and repeated freeze and thaw cycles (Kazimiera et al. 2009).

3.6.8.1 Heating and Cooling Cycles

Six alternating cycles of heating (45 °C) and cooling (4 °C) are performed, and finally the nanoemulsion is examined for any change in size and viscosity. An ideal nanoemulsion resists against any changes during this process.

3.6.8.2 Centrifugation

A nanoemulsion is centrifuged at 3500 rpm for 20 min and further examined for any sedimentation and phase separation. An ideal nanoemulsion does not show any changes in its structure after centrifugation.

3.6.8.3 Freeze and Thaw Cycles

Finally, to confirm the stability of nanoemulsions, freeze and thaw cycles are carried out. The nanoemulsion is stored at a freezing temperature (−21 °C) for 24 h followed by thawing at room temperature. Several cycles of freezing and thawing are repeated, and the emulsion is examined for any changes. An ideal nanoemulsion is stable during this process and does not undergo any changes related to size, shape, viscosity, and phase separation.

3.7 Application of Nanoemulsions

Nanotechnology is emerging as a large-scale business due to its wide application in various fields. Its overall market reached 1 trillion USD in 2015, and it is constantly growing at a rapid pace (Neethirajan and Jayas 2011). The application of nanoemulsions is also gaining popularity in various areas such as the cosmetic, medical, drug delivery, and food sectors.

3.7.1 Antimicrobial Nanoemulsions

Antimicrobial nanoemulsions are constituted of O/W droplets that exhibit broad-spectrum activities against various Gram-positive and Gram-negative bacteria, fungi like Candida, dermatophytes, viruses like herpes simplex, and spores such as anthrax. Such nanoemulsions are thermodynamically driven to fuse with a lipid-containing organism. Owing to its unique size, surface charge, and formulation, nanoemulsions facilitate passive transport through cell membrane, fusion with phospholipid bilayer, and partition in aqueous phase. Additionally, an electrostatic interaction between the cationic charges of the nanoemulsion and the anionic charges of a pathogen facilitates a direct association of emulsions with pathogen (Donsì and Ferrari 2016) (Fig. 3.7). When a nanoemulsion is adequately fused with the pathogen, a part of the energy is released, which together with the entrapped active ingredient damages the pathogen lipid membrane leading to cell death (Patil and Bhutkar 2016).

Fig. 3.7
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Various routes of nanoemulsions interaction with microbial cell membrane. (Figure reprinted with permission (Donsì and Ferrari 2016) of the Elsevier Copyright Clearance Center (2018))

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Nanoemulsions prepared by using citral as functional ingredient displayed a wide spectrum of antimicrobial potency against a group of Gram-positive and Gram-negative bacteria (Lu et al. 2018).

In order to achieve spore eradication, the addition of a spore germinator or direct sporicidal substance is added to the nanoemulsions. Once the spores are germinated by the spore germinator, the active ingredient present in the nanoemulsion easily attacks the pathogen and kills it. A direct sporicidal effect of nanoemulsions BCTP and BCTP401 against the spores of Bacillus species has been successfully documented (Hamouda et al. 1999).

3.7.2 Preventive Agents Against Bioterrorism

Many reports describe nanoemulsions as prophylactic agents to prevent biological attacks against anthrax and Ebola. A broad-spectrum nanoemulsion has been tested against the spores of anthrax by the US Army in 1999. It was further scrutinized by RestOps in 2001 as a chemical decontamination agent. A similar technology was tested against Clostridium botulinum spores. The company NanoStat™ (Nanobio Corp.) marketed a nanoemulsion in the form of liquid, spray, and foam to decontaminate a large number of materials (Subhashis et al. 2011).

3.7.3 Disinfectant Cleaners

Nanoemulsions have been employed to develop nontoxic disinfectant cleaners. Nanoemulsion-based disinfectants have been found to be effective against a large spectrum of viruses, bacteria, and fungi without posing any hazard to the environment. A nanoemulsion is made of nanospheres; therefore, only a small amount of active ingredient such as parachlorometaxylenol is required for the preparation of an effective disinfectant.

The mode of action of such disinfectants is based on the electrostatic attraction between the microspheres (cations) and the anionic microbial surface, followed by the release of the encapsulated functional component (e.g., parachlorometaxylenol) that effectively kills the pathogen. The efficiency of such types of disinfectants is based on the direct delivery of the active components to the pathogen; consequently, a reduced amount of functional components is required to achieve the desired results. For example, the amount of parachlorometaxylenol used in such disinfectants was found to be two times lower than that of conventional disinfectants, suggesting the high efficacy of nanoemulsion-based formulations (Subhashis et al. 2011).

3.7.4 Nanoemulsions in Delivery of Vaccine

Nanoemulsions have proved effective to deliver inactivated viruses to a target and serve as suitable vectors. Many recent studies showed that HIV infects the mucosal immune system. Hence, developing mucosal immunity might provide protection against the HIV infection. Oil-based nanoemulsions are excellent vehicles for the interaction with the mucosal layer due to their unique composition. Many nanoemulsion-based vaccines against influenza virus and HIV are under clinical trials. The nanoemulsion transfers the antigen (inactivated pathogen) to the mucosal surface, where it is taken by the nearby antigen-presenting cells. This leads to the stimulation of the humoral immune system upon activation of specific B lymphocytes that further develop a memory and thus boost the immune system for future challenges. In many studies, the successful use of nanoemulsions for the prevention of influenza infections has been shown by a single mucosal exposure of the nanoemulsions mixed with the virus. In some recent studies, the nasal mucosa exposure of nanoemulsions comprising recombinant gp120 antigen showed a great promise as anti-HIV vaccine. Many clinical trials are currently underway aiming to the development of vaccines against anthrax and hepatitis B infections (Patil and Bhutkar 2016).

3.7.5 Nanoemulsions for Oral Delivery

Nanoemulsions provide several advantages over traditional formulations by enhancing the absorption potency and decreasing drug toxicity. In particular, oil and water emulsion is suitable for enhancing the bioavailability of the hydrophobic drug, thus having a tremendous effect on the potency. Nanoemulsions have been proved to be effective for the oral delivery of steroids, hormones, diuretics, and antibiotics. In the case of the drug primaquine, a 25% lower dose was required against Plasmodium berghei infection when it was delivered as nanoemulsion compared to the conventional type. Furthermore, a higher content (45%) of the drug was detected in the liver of tested mice treated with nanoemulsion as compared to the plain drug, suggesting an enhanced bioavailability and accumulation imposed in the form of the nanoemulsion (Mishra et al. 2014).

3.7.6 Nanoemulsions in Cell Culture

Cell culture technology is used for many in vitro assays to produce various important biological substances including antibodies, hormones, and recombinant proteins. To optimize the cell growth, many components are needed in the culture media. However, it is nearly impossible to provide any oil-soluble substance to the media due to its low solubility in water. Nanoemulsions represent a way to supplement lipophilic substances to the media, which can be further absorbed by the cells. The advantages of using nanoemulsions in cell culture technology include an enhanced uptake of oil-soluble components, which leads to an improved cellular growth, that eventually affects the production of the desired products such as antibodies or enzymes and proteins (Patil and Bhutkar 2016).

3.7.7 Nanoemulsions as Ocular Drug Delivery

Conventional eye drops suffer from poor bioavailability and thus reduced therapeutic response, owing to the lacrimal secretion and nasolacrimal drainage occurring in the eyes (Sieg and Robinson 1977). Most of the drug is drained away without absorption in the eyes; as a result, a high amount or repeated applications of the medication are required to achieve the desired effect. In order to improve the absorption efficiency of drug, different methodologies can be employed. For instance, nanoemulsions provide an advantage of stimulating the penetration of the drug into the deeper layer of the ocular structure. An available nanoemulsion for the antiglaucoma, containing dorzolamide hydrochloride, has been shown to enhance the bioavailability by slowing down the release of the drug, thus affording a prolonged effect compared to conventional eye drops (Hussein et al. 2009).

3.7.8 Nanoemulsions as Transdermal Drug Delivery System

The delivery of a drug through the skin to the circulation represents a convenient and effective method, which offers several advantages such as a steady release of the drug for a prolonged time, self-administration in contrast to the parental route, and elimination of the drug input at any time by simple removal of the transdermal patch. Furthermore, it allows to avoid the gastrointestinal route associated with oral delivery. Transdermal drugs have been developed against many diseases such as anxiety, depression, and Alzheimer’s and Parkinson’s diseases. A drug can penetrate through the skin either via the hair follicles, via sweat ducts, or directly across the stratum corneum. For an effective drug absorption, these barriers must be crossed. Nanosized emulsions are capable of crossing the pores of the skin and thus transferring their active components into the circulation (Ravi and Padma 2011). Caffeine is a common oral drug for the treatment of different types of cancer. A nanoemulsion containing caffeine showed a greater promise as a transdermal delivery system compared to the conventional ones in many in vitro studies (Shakee and Ramadan 2010). Similar to caffeine, an indomethacin-based nanoemulsion showed a great promise as a transdermal delivery system against inflammatory-related diseases (Barakat et al. 2011).

3.7.9 Nanoemulsions in Cancer Therapy and Targeted Drug Delivery

Another important application of nanoemulsions is in the controlled drug delivery and targeting. To cure cancer, magnetic nanoemulsion poses a new possibility which can deliver Foscan (photosensitizer) inside the tissue layer. A hyperthermic condition subsequently generated the huge amount of reactive oxygen species form Foscan that effectively kills the tumor cells. This approach of nanoemulsion can be utilized for cancer treatment in conjunction with photodynamic therapy (Primo et al. 2007).

3.7.10 Nanoemulsions in Parenteral Drug Delivery

Parenteral delivery is the most common route for the administration of drugs with low bioavailability and narrow therapeutic index. The administration of a parenteral drug in the form of a nanoemulsion may protect the active component from the enzymatic degradation and permit the release of the drug in a sustainable manner for a longer time. The parental drug chlorambucil, which is used against breast and ovarian cancer, was delivered more effectively within a nanoemulsion compared to its free form (Ganta et al. 2010). The effectiveness of parenteral nanoemulsions for the delivery of drugs such as dexamethasone, diazepam, propofol, flurbiprofen, etomidate, and prostaglandin E1 has been well documented in the literature (Chime et al. 2014).

3.7.11 Nanoemulsions in Cosmetics

In case of cosmetics, the main issues are the uneven distribution and absorption of the bioactive component through the skin layer. These drawbacks can be overcome by using a nanoemulsion due to its small droplet size and high surface area, which eventually improve the absorption. The role of O/W nanoemulsions in the improvement of the permeability and skin whitening properties of ellagic acid has been demonstrated (Zhang et al. 2018).

3.7.12 Nanoemulsions for Nutraceuticals

Most of the natural compounds particularly belonging to essential oil displayed a great promise as a therapeutic agent. However, their physicochemical instability is a fundamental concern for their industrial application. Nanoemulsions can effectively overcome with this issue through the encapsulation of the active components. Physicochemical instability and functional behavior of carvacrol, an essential oil of thyme, have been improved by utilizing it in the form of oil-in-water nanoemulsion (Khan et al. 2018). Similarly, the efficacy of a nanoemulsion to increase the anti-inflammatory activity of curcumin compared to the free form has been documented (Patil and Bhutkar 2016).

3.7.13 Nanoemulsions in Food

Food quality, preservation, and safety are major concerns of the food industry. Approximately, more than 400 nano-based companies have been dealing in the food sector up to 2012 (Silva et al. 2012). In the food industry, different types of chemical substances are used to inactivate some enzymes and the microbial population that decreases the shelf life of food materials. However, occasionally such chemical compounds resulted to be corrosive and ineffective, particularly for the foods with high organic loads. Furthermore, their long-term consumption can also be associated with toxicological implications (Amaral and Bhargava 2015). Presently, most of the food industries focused on the use of natural compounds, which are generally regarded as safe for human consumption. In particular, essential oils have gained great attention as food preservatives owing to their broad antifungal, antibacterial, and antiviral activities (Burt 2004). Moreover, many components of essential oils possess antioxidant (Misharina and Samusenko 2008), antidiabetic (Tahir et al. 2016), and anti-inflammatory (Hajhashemi et al. 2003) properties, thus providing additional beneficial functions to the supplemented food. Although essential oil emerges as an alternative to the chemical method, but still there are many limitations of using it in the food, including their high volatility, strong odor, and low water solubility (Liang et al. 2012). However, some of these issues can be overcome by using essential oils in the form of nanoemulsions. Although in the preparation of nanoemulsions for food, a great precaution has to be taken by utilizing the only food, grade surfactant and oil. There are many successful examples showing the utility of nanoemulsion in foods. A study demonstrated the effective role of an oregano oil-based nanoemulsion to protect lettuce against Listeria monocytogenes, Salmonella typhimurium, and Escherichia coli (Bhargava et al. 2015). The protection of broccoli and radish seed by employing a carvacrol nanoemulsion has also been demonstrated by Landry et al. (2015). In addition, the same emulsion protected mung bean and alfalfa seeds against food pathogenic microbes S. typhimurium and E. coli (Landry et al. 2014).

Another study carried out in plumps highlighted the role of a lemongrass oil-based nanoemulsion to provide protection against S. typhimurium and E. coli (Kim et al. 2013). No adverse effects were detected with regard to the flavor and glossiness of these essential oil-supplemented nanoemulsions. However, a decreased ethylene production was observed, which prolonged the ripening process.

Demand of minimally processed foods is growing nowadays owing to its high nutritive value and absence of any harsh physical and chemical treatment. Essential oil-based nanoemulsions emerged as effective natural preservative agents for minimally processed fruits and vegetables. There are many successful reports elucidating the potential of essential oil nanoemulsions in fresh and minimally processed foods. A preservative role of oregano oil (Bhargava et al. 2015) and carvacrol/eugenol (Ruengvisesh et al. 2015) nanoemulsions for fresh lettuce and spinach leaves, respectively, has been well documented. Besides, few studies demonstrated a successful application of edible film coating of nanoemulsions in minimally processed food system (Prakash et al. 2018). In one such study, sodium alginate coating supplemented with lemongrass nanoemulsion demonstrated inhibition of E. coli and extension of the self-life of apple (Prakash et al. 2018). Many essential oil-based nanoemulsions have been proved effective against the formation of biofilm. Inhibitory role of Eucalyptus globulus essential oil nanoemulsion against the biofilm formation of Candida species has been well documented (Quatrin et al. 2017). The role of Citrus medica L. var. sarcodactylis essential oil-supplemented nanoemulsion against biofilm of Staphylococcus aureus was noticed. Similar inhibitory effect of cumin oil nanoemulsion was observed against the biofilm production of E. coli and S. aureus (Amrutha et al. 2017). Interestingly, an enhanced anti-biofilm activity of essential oil was noticed in the form of nanoemulsion compared to their free form (Lou et al. 2017).

Encapsulation and delivery of a bioactive functional component are two of the major objectives of using nanoemulsions in the food sector. Nanoemulsions can be used in the food industry to supplement the ingredients that possess low solubility in water, e.g., β-carotene (Gupta et al. 2016). In many studies, it has been shown that nanoemulsions allow easy digestion of many encapsulated food supplements. In particular, the use of curcumin in the form of a nanoemulsion led to easy and high digestion compared to its free form (Gupta et al. 2016).

Many functional components such as lycopene, lutein, β-carotene, coenzyme Q10, omega-3, vitamins A, D3, and E, isoflavones, and phytosterols have been encapsulated in nanoemulsions and successfully used in beverages by Nutralean. The scientist of Nutralean claimed an improved bioavailability of the encapsulated compounds in the form of the nanoemulsion (Silva et al. 2012). Furthermore, it was also observed that nanoemulsions preserve and protect the flavor of compounds from enzymatic hydrolysis as well as temperature and pH variations.

An improved stability of functional components (e.g., DL-α-tocopheryl acetate, omega-3 fatty acids, coenzyme Q10, and vitamins A, D, D3, E, and K) and coloring agents (e.g., chlorophyll, β-carotene, curcumin, lutein, apocarotenal, and sweet pepper extract) in beverages was demonstrated by Aquanova (Silva et al. 2012).

The company Unilever produced a healthier ice cream by using a nanoemulsion with the aim of reducing the fat content from 16% to 1%. It was reported that the reduction of the fat content did not change the taste of the ice cream (Silva et al. 2012).

3.8 Summary and Conclusion

Nanoemulsions offer several advantages due to their nanosize, enhanced surface area, and the possibility to be formulated as foams, liquids, and sprays. Additionally, they provide an ideal way for the dissolution and administration of hydrophobic substances. Currently, nanoemulsions are used in various areas of medicine and food sector and have been shown to have a tremendous potential by enhancing the bioavailability and shelf life of the encapsulated components. Continuous research is ongoing to improve the stability and functional properties of nanoemulsions in order to enhance their applicability. In food system, applicability of nanoemulsions still poses challenges both in terms of production cost and safety. This issue should be addressed in the future to accept it the terms of food safety.