Nanoemulsion: An Emerging Novel Technology for Improving the Bioavailability of Drugs

The pharmaceutical sector has made considerable strides recently, emphasizing improving drug delivery methods to increase the bioavailability of various drugs. When used as a medication delivery method, nanoemulsions have multiple benefits. Their small droplet size, which is generally between 20 and 200 nanometers, creates a significant interfacial area for drug dissolution, improving the solubility and bioavailability of drugs that are weakly water-soluble. Additionally, nanoemulsions are a flexible platform for drug administration across various therapeutic areas since they can encapsulate hydrophilic and hydrophobic medicines. Nanoemulsion can be formulated in multiple dosage forms, for example, gels, creams, foams, aerosols, and sprays by using low-cost standard operative processes and also be taken orally, topically, topically, intravenously, intrapulmonary, intranasally, and intraocularly. The article explores nanoemulsion formulation and production methods, emphasizing the role of surfactants and cosurfactants in creating stable formulations. In order to customize nanoemulsions to particular medication delivery requirements, the choice of components and production techniques is crucial in assuring the stability and efficacy of the finished product. Nanoemulsions are a cutting-edge technology with a lot of potential for improving medication bioavailability in a variety of therapeutic contexts. They are a useful tool in the creation of innovative pharmaceutical formulations due to their capacity to enhance drug solubility, stability, and delivery. Nanoemulsions are positioned to play a crucial role in boosting medication delivery and enhancing patient outcomes as this field of study continues to advance.


Introduction
Nanoemulsions, also known as nanometric-sized emulsions, are fne water-in-oil (w/o) and oil-in-water (o/w) dispersions of two immiscible fuids, as opposed to the milky-white hue concomitant with coarse dispersion.Tese 20-200 nm droplets are stabilized by adding the appropriate amphiphilic emulsifers or emulsifers.Consequently, nanoemulsions are also known as mini-emulsions.Due to kinetic stability, nanoemulsions (NE) are stable on heterogeneous systems, in contrast to microemulsions (ME).
Although nanoemulsions are unique due to their extended physical constancy and are also known as "potential thermodynamic stability," they do not appear to aggregate or focculate.Te history of nanoemulsions can be traced back to the early 20th century when researchers frst began experimenting with colloidal systems.Initial work focused on macroemulsions and microemulsions, but it laid the groundwork for the development of nanoemulsions.Nanoemulsions as a distinct category of emulsions gained signifcant attention in the 1990s.Researchers started to explore their unique properties, such as their extremely small droplet sizes, typically ranging from 20 to 200 nanometers.Tis period marked a shift toward understanding the potential applications of nanoemulsions, particularly in the pharmaceutical and food industries [1][2][3][4][5].
(1) Nanoemulsion can be produced with lower concentrations of emulsifer (3-10%) than ME, which needs a high concentration (20%).(2) Nanoemulsion helps in the efective transportation of active substances through a semipermeable membrane, and due to the large surface area, penetration increases in the emulsion system.(3) Besides preventing droplet focculation, nanoemulsions' small globule size additionally avoids larger droplet focculation.Tis enables the system to survive in solitude without being divided.(4) Tiny droplets or globules in a nanoemulsion are responsible for the reduction in gravitational forces and Brownian motion.Consequently, there is no creaming or sedimentation while the product is being stored.(5) Nanoemulsions are simple to make and do not require a lot of energy to create.Nanoemulsion formulations are said to improve the reproducibility of the plasma concentration profle and bioavailability.(6) Nanoemulsions are super solvents because they include both hydrophilic and lipophilic drugs.(7) When the active ingredient is enclosed within a nanoemulsion formulation, the medicine is protected against environmental variables including pH hydrolysis and oxidation.(8) Nanoemulsions can be formed as gels, creams, foams, aerosols, and sprays, among other dosage forms.Additionally, they may be given orally, topically, intravenously, intrapulmonary, intranasally, and intramuscularly.In comparison to micelles dispersion, nanoemulsions have a higher solubilization capacity, and they are more thermokinetically stable.(9) It helps avoid hepatic frst-pass metabolism because it is an oil/lipid-based drug delivery mechanism.(10) Nanoemulsion can also efectively mask the metallic and bitter tastes of medications that might induce unpleasant side efects such as nausea and vomiting.(11) Nanoemulsions can be useful as an alternative to liposomes and vesicles (which have poor stability), and they can occasionally be built to form lamellar liquid crystalline encircling globules.
Despite these tools, there is still a somewhat unimportant perception of the creation, production, construction, and handling of nanoemulsions.Tis impression is primarily attributable to the reality that traditional notions of the formation of emulsion and stability barely get extended.Te proof for current perception is built up by this collective insufciency.Tis study focuses on the nanoemulsion concept as a novel delivery system for poorly aqueous soluble drug candidates to enhance their bioavailability through encapsulation into oil/lipid for the management of numerous diseases, such as hypertension, diabetes, and cancer disease, and reduces the dose-related side efect of the drugs.
A wide range of advantages and standout benefts are provided by creating nanoemulsions for diverse drug delivery methods, greatly enhancing the efcacy and adaptability of pharmaceutical formulations.Transdermal gel formulations are examples of nonnanoemulsion formulations compared to nanoemulsion-based formulations that show a signifcant improvement in drug bioavailability.Nanoemulsions, distinguished by their nanoscale droplets, ofer increased solubility for medications with low water solubility and a large interfacial area for drug dissolution.Higher drug-loading capacities as a result of this beneft enable the delivery of a larger variety of therapeutic agents.Nanoemulsions can increase medication penetration through the skin in the case of transdermal gels, resulting in a quicker beginning of action and better therapeutic results [26].Additionally, nanoemulsions have outstanding stability, which shields drugs from deterioration and extends the shelf life of pharmaceuticals.Tis characteristic is particularly important when discussing transdermal gels since consistent medication administration depends on the formulation's ability to hold up over time.
Te diferences between transdermal gels with and without nanoemulsions highlight the advantages of the latter.Gels made from nanoemulsions have a larger drugloading capacity, better skin penetration, and a lower risk of skin irritation.Tey make it possible to precisely regulate the kinetics of medication release, which improves patient compliance and therapeutic efciency.Additionally, nanoemulsions can be administered orally, intravenously, or topically with great fexibility.Due to their adaptability, they are useful in a variety of medication delivery applications and can meet various patient demands.

Types of Nanoemulsion
Depending on the relative composition and dispersal of the more ubiquitous continuous phase and the internally distributed phases, nanoemulsions were categorized into biphasic (O/W or W/O) or multiple nanoemulsions.A nanoemulsion droplet quantity and overall durability are determined by the phase volume ratio (Φ), which also refects the relative relevance of the internal and exterior 2 Scientifca phases that make up the nanoemulsion.Te phase that is present in a greater volume typically evolves the exterior phase.Te interaction of the many components that make up the nanoemulsion must be approximated to ascertain the kind of nanoemulsion that is generated under the specifed parameters.O/W emulsifcation is favored when the emulsifer is hydrophilic or vice versa, i.e., if the emulsifer is lipophilic.Typically, an emulsifer's polar area functions as a better coalescence barrier than its hydrocarbon region.

Theories of Nanoemulsion Formulations
To investigate the mechanism of nanoemulsion production and stability, numerous methods have been employed.Some ideas (mixed flm theories) emphasize the development of the interface flm and the creation of extremely poor interfacial stress, whereas others (solubilization theories) emphasize the monophasic environment of the many nanoemulsions.Here are a few of these theories [27,28].

Mixed Film Teories.
It explains the concept of a duplex picture (i.e., displaying diverse features on both the oil and water sides) and the twisting of the interface to create o/w or w/o microemulsions.Te emulsifer and coemulsifers as oil-inwater contact create a complicated layer.Tis led to an extremely low level of oil-in-water interfacial tension.It was planned for the mixed interfacial layer to be fuid and dual in an environment with two-dimensional dispersion pressure, πi, which defned the interfacial tension, ci, by the following equation: where c o/w symbolizes the oil-water interfacial tension [27].

Solubilization Teories.
Te idea of normal and inverse micelles is explained by the theory.Te team led by Shinoda and Friberg debated on nanoemulsions as being thermodynamically established monophasic solutions of spherical micelles that are either w/o swollen or both.Oil-water emulsifer and coemulsifer quaternary phase diagrams are created [27,28].

Termodynamic Treatments.
Te degree to which the emulsifer reduces the surface tension between oil-water interfaces can be viewed as a determinant of the free energy of the nanoemulsion formulation.Entropy has changed in such a way that where ∆Gf is the free energy of development, c represents interfacial tension at the oil-water interface, ∆A is the change in the interfacial area caused by nanoemulsifcation, T represents the temperature, and ∆S represents change in the system's entropy.[27,28]

Formulation Consideration for Nanoemulsion
To develop nanoemulsion, a variety of semisynthetic oily esters, triglycerides, partial glycerides, and nonionic ester emulsifers are commonly used.Te main factor to take into account when choosing suitable excipients for lipid formulation is their ability to solubilize the entire dose in a volume adequate for unit oral administration.Te type of oil-emulsifer mixture, the concentration, the ratio of the emulsifer, and the conditions or temperature at which excipients are chosen play important roles in emulsifcation.
Tese facts are further corroborated by the discovery that only very specifc combinations of pharmacological excipients may produce efcient emulsifying systems.Te excipients should be chosen from the USFDA's list of "GRAS" (generally recognized as safe) excipients or from other inactive ingredients that have been authorized and published by regulatory bodies.Drug release properties must not change over the course of the formulation's shelf life, and the drug must be both physically and chemically stable in the formulation.Te main excipients used in emulsifying systems are lipids/oils emulsifers and coemulsifers [29,30].A few examples of diverse excipients in use are shown in Table 1.

Components of Nanoemulsion
5.1.Oil/Lipid.In o/w emulsions, the formulation of nanoemulsions typically contains 5-20% oil/lipid globules, while it can occasionally be much bigger (about 70%).To create nanoemulsions, re-esterifed fractions from various sources including coconut oil [32], sesame oil [33], rice bran oil [34], safower oil [35], soybean oil [36][37][38][39], and cottonseed oil [40], often categorized as short chain, medium chain, or long chain triglycerides, are used either individually or in combination.Vitamin E (D-tocopherol) has been commonly used as a lipid carrier in the development of nanoemulsions [21,38,39].Nanoemulsions for topical, parenteral, and oral administration have also been made with oleic acid and ethyl oleate.Te oils are chosen on the basis of how well they can dissolve drug molecules.When nanoemulsions are used for oral delivery, the oil phase of the nanoemulsions' ability to solubilize drugs is more important.You can use the oil either alone or in combination.Although the latter is preferred and safe, medium and long-chain triglyceride oils have been employed as oil phases with varying degrees of saturation.   1 because of their acceptability to increase permeability.

Construction of Pseudoternary Phase Diagram
Te initial concentration of the constituents is determined using the water titration method at room temperature by building pseudoternary phase diagrams in the nanoemulsion system [40].Diferent ratios of the weight of the emulsifer and coemulsifer are used to produce various phase diagrams.Tese ratios are selected with increasing concentrations of coemulsifer relative to emulsifer and emulsifer relative to coemulsifer in order to thoroughly examine the phase diagrams.For each phase diagram for a specifc weight ratio of emulsifer to coemulsifer, the ratios of oil to the mixture of emulsifer and coemulsifer are altered.Drop-by-drop water is added to the oil, emulsifer, and coemulsifer mixtures as they are moderately magnetically agitated.Visual observations are done for nanoemulsions that are transparent and fow readily.An artifcial ternary phase diagram shows that the frst axis represents the aqueous phase, the second represents the oil phase, and the third represents S mix (emulsifer: coemulsifer) at a predetermined weightiness ratio as shown in Figure 2 [41,42].

Factors Affecting the Selection of Excipients for Nanoemulsions
Tere are various factors through which choices of excipients get afected which are shown in Figure 3 [35,43].

Methods of Preparation of Nanoemulsion Formulations
NEs can be prepared by two methods: (1) low-energy method and (2) high-energy method (Figure 4).

Low-Energy Methods.
Low-energy emulsifcation techniques use less power to produce nanoemulsion particles and are more energy-efcient since they utilize the systems' intrinsic chemical energy and only require gentle stirring as shown in Figure 3. Te hydrophilic-lipophilic balance of the used oil, the emulsifer-coemulsifer mixture, operational temperature, and the accumulative behavior of drug, oil, emulsifer, coemulsifer/cosolvent, and aqueous phase, were all taken into consideration when developing these methods.
8.1.1.Spontaneous Emulsifcation.Tere are three steps to it: a homogenous organic solution encompassing oil, a lipophilic emulsifer, a water-soluble cosolvent, and hydrophilic emulsifers are frst prepared as the process's initial step.Additionally, a continuous magnetic stirring process is used to produce an o/w nanoemulsion, and the aqueous phase is removed with a reduced evaporation pressure process [40].

Phase Inversion Temperature Method (Self-Nanoemulfcation Method).
It involves the natural bending of the emulsifer, which uses a heating process during emulsifcation that transforms the dispersed phase into the dispersion phase and vice versa.Changes in temperature and composition are two factors that afect spontaneous curvature.In this, phase transitions occur along the emulsifcation path, resulting in the production of fne dispersions through the application of chemical energy.Variations in temperature at constant composition can cause phase transitions.Te efectiveness of this approach depends on how nonionic emulsifers change solubility as a function of temperature [40].

Phase Inverse Composition Method (Self-Nanoemusilfcation Method)
. By gradually adding water to an oil-emulsifer solution while gently stirring and maintaining a steady temperature, it is possible to produce kinetically stable nanoemulsions having droplets size 50 nm.

Scientifca
Nanoemulsion produced by the spontaneous nanoemulsifcation process has high kinetic energy and durable colloidal stability but is not stable thermodynamically [40].
Phase inversion emulsifcation systems can be divided into two classes: transitional phase inversion (TPI) and catastrophic phase inversion (CPI) methods.TPI methods involve phase inversion temperature (PIT) and phase inversion composition (PIC), while CPI methods use the emulsion inversion point (EIP) [3][4][5]9].Catastrophic Phase Inversion (CPI): When the dispersed phase is constantly added, it aggregates with other drops of dispersed phase to produce bicontinuous/lamellar structural phases.A rapid alteration in a system's behavior based on altering circumstances is referred to as a catastrophe.Te coalescence rate is high when the emulsifer is large in the dispersed phase, resulting in rapid phase inversion, which is required for catastrophic phase inversion to take place [5].
Emulsion Inversion Point (EIP) Method: Phase inversion occurs in the EIP technique via CPI processes.Te CPI is brought on by altering the fragmented quantity of the dispersed phase.When the water phase is added to the oilemulsifer mixture, the system starts behaving as a w/o nanoemulsion, the extra quantity of water is added while stirring constantly, water droplets interact with one another, and the phase reversal point is reached, resulting in the creation of bicontinuous or lamellar structures.An intermediary bicontinuous microemulsion is used to amplify the phase inversion process from a w/o to an o/w system.Te  6 Scientifca droplet size produced in a nanoemulsion is determined by the process variables, such as the amount of water added, the stirring rate, and the amount of oil supplied [4].

High-Energy Method.
In order to provide strong disruptive forces for size reduction during high-energy emulsifcation, mechanical equipment is required.Microfuidizers, homogenizers, and ultrasonicators can provide these forces, but they are expensive and produce high working temperatures, which are inappropriate for drugs that are thermolabile.

High-Pressure Homogenization Methods.
Te process produces NEs from a high-pressure homogenizer/piston homogenizer with very fne particle sizes (up to 1 nm).A high-pressure homogenizer forces two liquids (oily phase and aqueous phase) through a tiny inlet hole at an incredibly high pressure to create dispersion [40].

Microfudization.
Microfudization is a unique mixing technique that simultaneously reduces particle size by attrition, impact, hydraulic shear, impingement, severe cavitation, and turbulence.Tis utilizes a microfuidizer device.Using a high-pressure positive displacement pump (500 to 20000 psi), the formulation is driven into the interaction chamber, which is made up of minuscule, repeated "microchannels," producing dispersity and incredibly thin particles in the submicron range.To manufacture homogenous NEs, the procedure is done numerous times to get the required particle size [40].

Piston Pump Homogenizer.
A high-pressure homogenizer/piston homogenizer used in the process generates NEs with extremely small particle sizes (up to 1 nm).To achieve dispersion, an extremely high-pressure homogenizer pushes two liquids (oily phase and aqueous phase) via a minute inlet hole [48].

Ultrasonication
Method.An emulsion of microscale droplets that have been premixed is agitated by ultrasonic waves to produce NEs.Tis technique uses sonotrodes known as sonicator probes to deliver energy.It contains piezoelectric quartz crystal, which responds to an alternating electric voltage by contracting and expanding.Cavitation takes place as the sonicator's tip makes contact with the liquid, causing mechanical vibration.Te collapse of vapor holes in a liquid is known as cavitation.Since emulsion may be made directly using ultrasound, it is typically employed in laboratories to make emulsion in droplets as thin as 0.2 micrometers.[40].Ultrasonication employs the least amount of energy as compared to other high-energy procedures.

Formulation Characterization
It is necessary to evaluate and characterize these multicomponent lipidic formulations via in vitro, ex vivo, and in vivo measures.To characterize and assess the viability of the nanoemulsion formulation process, a variety of techniques have been used.Due to the limitations of each technique, it is challenging to characterize a formulation in its whole, but complete knowledge of the formulation is necessary for its First, a heating-cooling cycle with varied temperature conditions is used to see how this afects the stability of the nanoemulsion.By keeping the formulation for at least 24 hours at each temperature, nanoemulsions are subjected to six cycles between 4 °C and 40 °C.For the following experiment, centrifugation, those preparations that are constant at all these conditions will be chosen.
Te second centrifugation involves spinning the prepared nanoemulsion at 5000 rpm for 30 minutes while observing breaking, creaming, and phase separation.After centrifugation, those nanoemulsions that are stable and have not displayed any signs of instability are subsequently put through a freeze-thaw cycle.
Tird, the study exposes nanoemulsion formulations to three cycles of the freeze-thaw cycle at various temperatures between −21 °and +25 °C.Formulations that pass the test and do not exhibit any signs of instability are thought to have strong stability [49,50].
Dispersibility tests are carried out with the formulation that passed the aforementioned thermodynamic test once these tests are fnished to determine the efectiveness of selfemulsifcation [49,51].9.9.Dispersibility Study.Tis study, which was conducted using a typical USP XXII dissolution apparatus, was done to assess the efectiveness of self-emulsifcation of nanoemulsion formulations.500 ml of the dissolution medium is flled with 2.1 ml of each formulation, and the temperature is kept at 37±0.5 °C.For gentle agitation, a stainless-steel paddle is circulated at 50 rpm.A basic dissolution paddle made of stainless steel revolves at 50 rpm to provide light agitation.Using the grading method presented below [50], the in vitro performance is evaluated visually of the nanoemulsion formulations.
Grade A: Nanoemulsions seem clear or bluish and form quickly within one minute Grade B: Nanoemulsions formed quickly but are to some extent less clear; they have a bluish-white appearance Grade C: Fine milky emulsions form with in less than 20 minutes Grade D: Emulsions have a cloudy appearance in color, appear slightly greasy, and take longer to form (>2 min) Grade E: Large oil globules may be visible on the nanoemulsion's surface, which exhibits either weak or insignifcant emulsifcation  [53].A water-soluble dye will spread evenly when added to an o/w nanoemulsion, but when used with a w/o emulsion, the dye will only persist in the dispersed phase.A microscopic study of the emulsion will reveal this [40].By including a water-soluble dye called eosin yellow into the formulation and observing it under a microscope, Laxmi et al. performed a dye solubilization test on an artemether containing nanoemulsion.Tey found that the oily dispersed phase was left unlabeled although the continuous phase was dye-labeled, confrming that the produced nanoemulsion was an o/w type.9.10.4.Dilutability.Te purpose of the dilutability test is to demonstrate that a dispersion phase can be introduced to a nanoemulsion in greater amounts without negatively impacting its stability.Since w/o nanoemulsions cannot be diluted with water, they undergo an inversion phase and become o/w nanoemulsions.In contrast, O/W nanoemulsions may not undergo the same inversion phase.Only oil can be used to dilute a w/o nanoemulsion [40,53].When Laxmi et al. tested the dilutability of a nanoemulsion by adding water to it, they found no evidence of phase inversion or precipitation, concluding that their formulation was stable [54].9.10.5.Percent Transmittance.Te percent transmittance of a prepared formulation is calculated using a UV spectrophotometer at a specifed wavelength and distilled water as a blank.A nanoemulsion is deemed to be transparent if it's percent transmittance is proven to be greater than 99% [55].
A nanoemulsion of amphotericin B with a percent transmittance of >97% was reported by Harika and Debnath [56].9.10.6.Interfacial Tension.Measuring the interfacial tension allows researchers to better understand how nanoemulsions form and behave.Particularly, the presence of emulsifying agents between the aqueous and oil phases in equilibrium corresponds to phase behavior at incredibly low interfacial tension values.A spinning-drop apparatus is used to evaluate very low interfacial tension.Spinning a drop of lowdensity phase inside a cylinder of high-density phase helps to determine its shape, allowing for the measurement of interfacial tensions [53].

Determination of Encapsulation Efcacy.
A weighed amount of the formulation is ultrasonically determined, i.e., dispersed in an organic solvent to ascertain how much drug is contained within it, and the drug is then extracted into an appropriate bufer.By spectrophotometrically analyzing the extract at λ max the maximum appropriate dilutions against an appropriate blank, the drug content is calculated.Tese equations can be used to calculate the entrapment efciency (EE) and loading efciency (LE) of the drug.Drug LE is defned as drug content in the obtained product (mg)/total product weight (mg)×100 [61], whereas drug EE is defned as drug content in the obtained product (mg)/total drug added (mg) ×100.Drug content could also be assessed using reverse-phase high-performance liquid chromatography (HPLC) [58].9.10.8.Viscosity and Refractive Index Measurement.A rotational viscometer of the Brookfeld type can be used to measure the viscosity of LBFs with diferent compositions at diferent temperatures and shear rates.Te samples to be tested must be submerged in it prior to testing, and a thermo bath must be used to keep the sample temperature at 37 °C.To ensure reproducibility at a specifc temperature, the viscometer used must be properly calibrated to measure the apparent viscosity of the suspension at equilibrium.Abbe's refractometer can be used to calculate the refractive index.It provides information on how isotropic the formulation is [43,59].9.10.9.Particle Size and Polydispersity Index (PDI) Determination.By monitoring variations in scattering light caused by the Brownian movement of particles over time, Malvern Zetasizer is used to determine nanoemulsion particle size and PDI.According to the PCS hypothesis, small particles travel more quickly than large particles, according to the PCS hypothesis.Te solution's submicron particles warp the laser beam.Particle difusion, which is infuenced by particle size, causes signifcant variations in the intensity of laser light scattering around the constant angle mean value.Te size of the particle can be determined Scientifca using a line width distribution histogram generated by an estimated photoelectron time-correlation function.Doubledistilled water is combined with a weighed amount of the formulation to make a homogenous dispersion that must be used right away to gauge the particle size and PDI.Te PDI of a monodisperse system is zero, but the PDI of a polydisperse particle dispersion is one [59].

Morphology Characterization of Nanoemulsion.
As illustrated in fowchart 1, the morphology can be characterized using either an electron microscope or a light scattering approach.In a dynamic light-scattering spectrophotometer, the dynamic light scattering at 90 degrees is measured using a neon laser with a wavelength of 632 nm.
Te gadget has a built-in computer that processes the data.Te more recent technique for particle detection is known as Photon Correlation Spectroscopy (PCS).Some of the commonly used microscopy techniques for morphology characterization are discussed in detail here: (1) Scanning electron microscopy (SEM): Nanoemulsion size, size distribution, and morphology can be determined using SEM data (self-emulsifying powder).However, drying and sorting samples could cause the specimen to shrink and change in appearance [60,61].Additionally, some biomolecule specimens that are nonconductive when scanned by an electron beam have a tendency to charge up and refract the beam, causing inaccuracies in the imaging.To get around this, the sample preparation technique calls for an ultrathin coating of an electrically conductive substance on the molecule [61].In order to scan the attached groups to nanoemulsion surfaces using an electron microscope, a cryogenic freezing technique is frequently required.Furthermore, due to the restricted number of particle samples in the scanning zone, partial assessments of the size distribution of heterogeneous samples are required in SEM [62].(2) Transmission electron microscope (TEM): It is one of the utmost adequate and commonly applied techniques for describing nanoemulsions in electron microscopy.A conceptual resolution to the atomic dimension level (1 nm) and a clear image of nanoemulsions are both provided by TEM [63].An extremely thin sample specimen is subjected to an incoming electron beam, which causes the bombarded electrons to interact with the sample specimen and get distorted into either elastically scattered electrons or unscattered electrons [64].Te distance between the specimen and the objective lens, as well as the distance between the objective lens and its planer image, is the primary determining factor of TEM magnifcation [64].Te high three-dimensional resolution of TEM further improves the structural and morphological characteristics of nanoemulsions, and it can be combined with a variety of analytical techniques.It is fascinating to note that wet TEM can be utilized to assess the particle size, agglomeration, dispersion, and dynamic displacement of nanoemulsions in an aqueous environment [65].(3) Atomic force microscopy (AFM): Te size, form, dispersion, sorption, and aggregation of nanoemulsions are currently being examined using a new technology called AFM.Many scanning modes utilized in AFM research include stagnant mode (also known as a noncontact mode), contact mode, tapping mode (also called intermittent sample contact mode), and dynamic mode [66][67][68].Because it can image biomolecules without apparent damage to diverse intrinsic surfaces, AFM is becoming more and more important.Te foremost asset of AFM is its capacity to image a variability of nanoemulsions in aqueous fuids at the subnanometer scale [69].(4) Dynamic light scattering (DLS): Using radiation scattering technology, the DLS approach is also utilized to describe the physicochemical characteristics of nanoemulsions (self-emulsifying powder), such as biomolecular conformation, aggregation state, and shape [70,71].DLS is based on the idea that for a certain scattering angle, Rayleigh scattering-a transient fuctuation in scattered light's intensity-is created by the Brownian motion of the size of the molecule or particle, and that the smaller the size, the less light is scattered [71].Te scattered lights combined with benefcial and harmful interventions cause the intensity to fuctuate [72].

Zeta Potential Determination (Surface Charges).
Using a Malvern Zetasizer instrument, which measures the zeta potential (ZP) of the nanoemulsion preparation, one can ascertain the surface charge that is present on the particle or globules.Te ZP predicts the stability of the dispersion and how the physicochemical characteristics of the drug, emulsifer, coemulsifer, polymers, vehicle, and other electrolytes present in the formulation will afect its value.Tis measurement of the particle surface charge provides information about the repelling forces between particles, drops, and globules.It also provides information about how these forces are absorbed.Nanoemulsion is diluted for the purpose of evaluating zeta potential value which is determined by the oil globules electrophoretic mobility.ZP should normally increase to a value over 30 mV in order to establish stable NE by preventing the nanodroplets from coalescing and focculating [70].

Fourier Transform Infra-Red Spectroscopy (FTIR).
Te assessment of drug-excipient interactions, cross-linking, polymerization, and drug entrapment in the formulation can all be done using FTIR analysis.Additionally, it is employed for molecular fngerprinting and the identifcation of 10 Scientifca functional groups together with their modes of attachment.At low temperatures, molecules are found in their ground state.Infra-red spectroscopy is based on measuring the energy diferences (delta E) between the ground state and excited state of the molecules.Tese molecules get excited to a higher energy state by absorbing radiant radiation [52].Te most popular method for analyzing spectral bands to reveal the conjugation of nanoemulsion carriers is FTIR spectroscopy [71][72][73].In the present, a developed method known as attenuated total refection (ATR)-FTIR spectroscopy is used to analyze the structure of chemical species at an interface using the efects of total internal refection in light via IR [74,75].ATR-FTIR ofers IR absorption spectra for evaluating things like changes in surface characteristics as well as pinpointing the chemical characteristics of polymer surfaces, among other things [75].9.10.13.In Vitro Drug Release Study.Tis study is done to evaluate the nanoemulsion formulation's in vivo performance.USP dissolution apparatus at 37 ± 0.5 °C and 50 rpm stirring speeds are typically used in this study.Samples are taken out at regular intervals, and an equal amount of dissolution medium is added at each sample withdrawal time.Ten, samples are diluted appropriately, and their absorbance is measured using spectrophotometry at a specifc wavelength.Nanoemulsion or solid nanoparticles containing the drug were dispersed in a bufer solution, introduced into the dialysis bag, and put in a bufercontaining fask.Tese absorbance data are used in combination with the calibration curve to determine the percentage of drug release at various time intervals [59,76].9.10.14.In Vitro Skin Permeation Studies.Permeation tests are conducted both in vitro and ex vivo using the Keshary-Chien difusion cell.Te abdominal skin of mature male rats weighing 250 ± 10 g is commonly used in this study.A portion of rat skin is set in the difusion cells' donor and receiver compartment.Fresh water receiver chambers containing 20% ethanol are continuously swirling at 300 rpm and maintained at a constant temperature of 37 °.
Te formulas are placed in the donor room.At certain intervals, such as 2, 4, 6, and 8 hours, a predetermined volume (0.5 ml) of the receiver compartment's solution was removed for examining gas chromatography.Each time, an equivalent amount of fresh solution was added right away to replace the withdrawn volume.Tree times the same sample is utilized.Cumulative adjustments are used to calculate the total quantity of drugs that entered the rat skin at each point in time, and the fndings are plotted against the passage of time.In a steady state, the slope of the plot is used to calculate drug penetration rates [77].Harwansh et al. used the Franz difusion cell to investigate the transdermal penetration of glycyrrhizin through human cadaver skin.Te standard gel formulation was found to be less permeable to the skin than the nanoemulsion formulation [78].9.10.15.In Vivo Studies.In vivo research can be carried out by employing an animal model that is appropriate for the specifc and chosen activity.Srilatha et al. investigated the antidiabetic activity of glipizide nanoemulsion in a hyperglycemia model in which rats were frst given an intraperitoneal injection of streptozocin solution to induce diabetes.Te formulation was then administered to the diabetic model of rats, and pharmacodynamic parameters were studied.For up to 12 hours, they observed lower blood glucose levels [51].By conducting pharmacokinetic experiments on the nanoemulsion, Chouksey et al. analyzed the in vivo activity of atorvastatin and found that it had a higher bioavailability than the pure drug [79].With the appropriate methods, the full potential of nanoemulsions as a tool for efcient medicine delivery could be realized.Parameters such as quality assurance and quality control should be of the utmost importance with such a precise method of delivery system; as a result, the evaluation tests shall be carried out attentively.9.10.16.Stability Studies.Tis study is performed to estimate the stability of the drug candidate when it is exposed to diferent drug substances, i.e., when it is exposed to diferent environmental factors such as humidity, temperature, and light.According to the references of the ICH (International conference on harmonization), a stability study of the nanoemulsion is carried out after the preparation has been stored for at least 730 days in a freeze-dried or dispersed state.Tese studies are conducted under low temperature (25 °F/60 °RH), freeze (−20 °F), and refrigeration (5 °F) temperature storage conditions.Te essential portion of the nanoemulsion is kept in carefully sealed glass vials, and samples are taken at predetermined intervals.Particle size, polydispersity index, entrapment efcacy, and drug release profles, among other characteristics, were also examined [80].9.10.17.Shelf-Life Determination.Te study of accelerated stability is performed to determine the nanoemulsion's shelf life while the formulation is kept at three distinctive temperatures and humidity (30 °, 40 °, and 50 °RH) for at least 90 days.Te remaining drug amount in the nanoemulsion formulation is evaluated using HPLC (high-performance liquid chromatography) investigation of samples taken at regular intervals (0, 30, 60, and 90 days) under these various settings.As controls, samples taken at the start of time are used [52].Tis establishes the reaction's order, and the reaction rate constant (K) for deterioration is then computed from the slope lines at each high temperature using the following equation.Te logarithm values of K are plotted against the reciprocal of absolute temperature at various raised temperatures using slope � K/2.303 (Arrhenius plot).K at 25 °is calculated from this plot, and the value is then employed in the following equation to determine shelf life: where "shelf life" is well-defned as the amount of time needed for 10% of a medicine to degrade [41].

Application of Nanoemulsion: Encapsulating Drugs for Improving the Bioavailability
Recently, poor drug compounds have drawn attention.Tis section gives an overview of research that has increased the bioavailability of drug compounds by encapsulating them in nanoemulsions.Te research on nanoemulsions created utilizing high-or low-energy techniques is the main emphasis of this review.Nanoemulsion can be produced at low cost in diferent pharmaceutical dosage forms, such as creams, gels, foams, sprays, and aerosols, and it can also be taken orally, topically, intravenously, intrapulmonary, intranasally, and intraocularly.Nanoemulsion is a safe and efective dosage form of subpar medication candidates for increasing bioavailability in the treatment of a variety of conditions, such as hypertension, infammation, and cancer, and lowers the dose-related adverse impact of the drugs.
Tere have already been several research conducted as shown in Table 2 that supports the idea that nanoemulsion is an emerging novel technology for improving the bioavailability of drugs.

Application of Nanoemulsion in Drug Delivery
11.1.Nanoemulsion and Drug Targeting.Te fascinating application that is currently under the development involves using of nanoemulsion formulations for the delivery of controlled and targeted medication [134].Teir submicron size makes it simple to target the tumor's location.Aqueous insoluble drugs have historically been delivered by nanoemulsions, but more recently, attention has been focused on colloidal particles as a carrier for the targeted delivery of diferent anticancer medications, photosensitizers, neutron capture therapy agents, or diagnostic agents.A novel method of treating cancer is the production of magnetic nanoemulsions.Tese can spread into tissue layers of the skin with photosensitizers like Foscan ® , causing hyper- thermia and the subsequent production of free radicals.Photodynamic therapy, which uses this technology, can be utilized to treat cancer [135].

Drug Delivery via Transdermal Nanoemulsions.
Tere has been a lot of interest in this area since it is practical to provide medications through the skin to the systemic circulation for a variety of clinical diseases [136,137].Te parenteral method has the advantage of continuous drugcontrolled distribution over a longer period of time, even when self-administration may not be possible.Te patient can stop taking the medication at any time by simply removing the transdermal patch.Nanoemulsions have a pleasant feeling on the skin thanks to their transparency and fuidity.Te complete absence of gastrointestinal adverse efects such as irritating gastrointestinal and bowel ulcers, which are typically linked to oral delivery, is an added beneft.For a variety of illnesses and disorders, such as cardiovascular problems, Parkinson's disease, Alzheimer's disease, anxiety, and depression, transdermal medicinal treatments have been produced.Te main drawback to this form of administration is the skin's barrier, which prevents the bioactives from penetrating the body efectively.Te stratum corneum, which severely limits their absorption and bioavailability, the sweat ducts, and hair follicles are the three primary routes through which drugs can enter the skin.Te major objective is to improve drug targeting and pharmacokinetics.Te main skin barriers must be broken down for better medication pharmacokinetics and targeting.Additionally, it is important to manage the redistribution of topically applied medications through the cutaneous blood and lymphatic system.Nano-sized emulsions can quickly enter the systemic circulation and pass through the skin's pores, channeling the substance for efcient distribution [138].By oral administration, cafeine has been utilized to treat a variety of cancers.Cafeine nanoemulsions in waterin-oil have been created for transdermal medication delivery.Tese and aqueous cafeine solutions' in vitro skin permeation profles were compared, and the nanoemulsionloaded medicines' permeability parameters signifcantly increased [139].

Drug Delivery via Pulmonary Nanoemulsions.
Very little research has been published in this feld, and the nanoemulsion method has not yet been completely utilized for pulmonary drug administration [140].As an alternative to liposomes as a gene transfer vector, emulsion systems have been developed [141].Other researches on emulsion for gene administration (nonpulmonary route) indicated that the emulsion or DNA combination had a strong afnity than liposomal carriers [142].Genes were administered more efectively using this stable emulsion approach compared with liposomes [143].According to Bivas-Benita et al. [144], cationic submicron emulsions are promising DNA vaccine delivery systems to the lung because they can transfect pulmonary epithelial cells, which may result in crosspriming of antigen-presenting cells and direct activation of dendritic cells, stimulating antigen-specifc T cells.As a result, the nebulization of submicron emulsions will be a new and developing research in the feld of pharmaceutical sciences.However, due to the potential negative efects of oil and Emulsifers on lung alveolar function, more research is required to formulate the inhalable submicron emulsion as a successful route of pulmonary administration (adverse interactions with lung emulsifer).
12 Scientifca   Tis is one of the most common and efcient drug delivery methods, and it is typically used for active ingredients with low bioavailability and limited remedial indices.Because of the ability to dissolve large amounts of hydrophobics, mutual compatibility, and the potential to protect medicines from enzymatic degradation and hydrolysis, nanoemulsions are ideal carriers for parenteral administration.Furthermore, because these emulsions ensure that medications are released continuously and consistently over long periods of time, the injection dosage and their frequency can be reduced throughout the period of drug therapy.In this context, the lack of focculation, creaming, and sedimentation, as well as the high surface area and free energy, provide clear benefts over emulsions with larger particle sizes.Furthermore, because these emulsions ensure that pharmaceuticals are released continuously and under control over long periods of time, the frequency and dosage of injections can be reduced during the course of drug therapy.Te absence of focculation, creaming, and sedimentation, combined with the high surface area and free energy, clearly outperforms emulsions with larger particle sizes in this situation.It was loaded into parenteral emulsions made using the high-energy ultrasonication method to study its pharmacokinetics and anticancer activity.Tis nanoemulsion treatment for colon adenocarcinoma in mice results in the suppression of higher tumors rather than a plain solution of drug treatment, indicating that drug-loaded emulsion may be a useful vehicle for medication transport in treating cancer [145].Tese formulations address a prevalent problem with conventional ophthalmic therapies by being frequently less viscous and easier for patients to administer [146].

Delivery of Intranasal Drugs Using Nanoemulsions.
In addition to oral and parenteral administration routes, intranasal drug delivery systems are now recognized as an efective route for the administration of dosage forms.Te nasal mucosa has been shown to be a therapeutically effective route for systemic medication administration and an efective strategy for circumventing barriers that prevent direct drug entry into the target-oriented site.Tis method was also painless, tolerable, and noninvasive.Due to less enzymatic activity, more immunoactive sites, and permeable epithelium layer, the nasal cavity is one of the most efective places for the delivery of drug [147].Targeting medications for the brain poses several challenges, especially for hydrophilic and large molecular-weight medications.Tis is due to the impermeable properties of the endothelium, which separates the systemic circulation and acts as a bloodbrain barrier [148].Te nasal mucosa's olfactory region serves as a direct link between the nose and the brain, and ailments such as Alzheimer's disease, migraine, depression, schizophrenia, Parkinson's disease, and meningitis are treated with medication-loaded nanoemulsions [149,150].
Tere have been reports of risperidone nanoemulsions being developed for nasal administration [150,151].It is implied that this emulsion works better when taken orally rather than intravenously.Another therapeutic application for intranasal drug delivery systems is vaccine development.
Immunity is produced as a result of mucosal antigen delivery, and the frst intranasal vaccine is now available on the market.One of the potential delivery methods is the use of nanocarriers, which shows considerable excellence in protecting biomolecules, fostering nanocarrier interaction with mucosae, and directing antigens to lymphoid tissues.Te use of nanoemulsion technology in intranasal drug delivery systems is expected to produce signifcant results in treating central nervous system disorders by efectively targeting medications to the brain.

Future Prospective
Since its creation, nanoemulsion has proven to be a versatile and efective new medication delivery technology.Because they have a limited capacity for solubilizing nonpolar active chemicals, nanoemulsions are being proposed for a variety of uses in pharmacies as drug delivery methods.Future applications of nanoemulsion in various therapeutic disciplines or in the creation of cosmetics for the skin or hair are quite bright.Nanoemulsions have a wide range of uses, including medication delivery, where they serve as efective carriers for bioactive and make a variety of administration methods possible.Teir parenteral delivery has been used to meet nutritional needs, manage drug release, deliver vaccines, and target drugs to certain locations.Tere are many benefts and uses for oral medication administration using these vehicles, where the size of the droplets afects how well they are absorbed in the GIT.Te application of nanoemulsions in ocular delivery, where pharmaceutical medicines are better maintained than their corresponding solutions, has also been researched.Other efective administration methods for nanoemulsifed delivery systems Scientifca include pulmonary and transdermal routes.Although there have not been many reports of nanoemulsion uses in other domains, these subjects have a lot of potential, including engineering, agriculture, and the chemical and physical sciences.Te price of making nanoemulsions will go down as new equipment for high-pressure homogenization becomes available and manufacturers begin to compete with one another.Optimized emulsifer systems and more efcient emulsifer utilization will result from the fundamental study into the function of emulsifers in the process of producing nanoemulsions.Te ability to modify nanoemulsions for targeted distribution holds great promise in treating malignancies and in delivering drugs to the brain in the feld of oncology.

Conclusion
Te development and designing of nanotechnology for emulsion systems became a critical parameter for managing and/or improving therapeutic drug bioavailability.Particle size reduced to the nanometric scale exhibits some intriguing physical characteristics, such as optical transparency and abnormal elastic behavior.Nanoemulsions, useful dispersions of deformable nanoscale droplets with a range of fow characteristics and optical properties which range from opaque to nearly transparent, hold great promise in the feld of nanomaterials.Furthermore, nanoemulsions are expected to play a larger role in the commercial sphere because they can often be made with a signifcantly low quantity of emulsifer as compared to nanostructured lyotropic microemulsion systems.Te review paper highlights and gives a brief description of the recent developments in the feld of nanoemulsion carrier formulations which are discovered till date.Nanoemulsions are gaining popularity as drug carrier candidate for enhancing the delivery of pharmaceutical active ingredients because they provide a number of benefts for pharmaceutical delivery.Because they are adaptable to virtually all delivery methods, they have the potential to be used in a broad range of disciplines, including cosmetics, pharmaceuticals, and biotechnology.Nanoemulsion drug delivery systems became an advanced key tool for efective delivery of drugs and reaching a target site.Compared to most conventional dosage forms, they also provide efective bioactive material encapsulation protection and improved delivery.Te potential lies in formulation specialists' inventiveness in overcoming unusual drug delivery issues including permeability and in vivo stability by utilizing the benefts of nanoemulsion carriers.We believe that more research is needed to fully realize the potential of nanoemulsion technology in the delivery of novel phytopharmaceuticals and tiny molecule medications.Tis novel method could be developed to overpower the drug candidates' limitations such as poor solubility, absorption, and miscibility with lipids found in cell membrane lining.Hydrophilic-lipophilic balance S mix : Emulsifer: coemulsifer ratio TPI: Transitional phase inversion CPI: Catastrophic phase inversion PIC: Phase inversion composition EIP: Emulsion inversion point ALTAS: Atmospheric laboratory for applications and science ICI: Imperial Chemical Industries EE: Entrapment efciency LE: Loading efciency LBF: Lipid-based formulation CCB: Calcium channel blocker PDI: Polydispersity index PCS: Photon correlation spectroscopy BCS: Biopharmaceutical classifcation system DLS: Dynamic light scattering SEM: Scanning electron microscopy TEM: Transmission electron microscopy AFM: Atomic force microscopy ZP: Zeta potential FTIR: Fourier transform infra-red spectroscopy ICH: International conference on harmonization.

Figure 3 :
Figure 3: Main factor afecting the choice of excipients for nanoemulsion.

Table 1 :
Various excipients widely used in nanoemulsion formulations.
[25] characteristics are specifcally essential for formulations that are meant to be taken orally.Variations in taste, particularly of active components, are usually caused by alterations in globule size, crystal habit, and subsequent globule size distribution.Te taste, odor, and color of particular ingredient can vary which suggest the chemical incompatibility[43]. weight, and content of the emulsifer.Te medicinal compound's attraction for oil or water, as well as the nature of forced formation, is represented by polarity[25].
[50]re 4: Emulsion formulation consideration and approaches as microemulsion/nanoemulsion, microgel/nanogel, emulsion, and emulgel formation.Scientifca efective commercial exploitation.Conductivity, viscosity, and dielectric constant provide valuable data at the macroscopic level.Te following characteristics commonly defne formulations.9.1.Visual Appearance.A calibrated glass cylinder or transparent glass cylinder can be used to analyze the homogeneity and color of the appearance at equilibrium[43].9.2.Color, Odor, and Taste.9.3.Density.Te specifc gravity or density of nanoemulsion formulation is two crucial parameters.A decrease in the formulation's density is typically a sign that there is trapped air inside its composition.Density at certain temperatures can be determined with high-precision hydrometers.[43].9.4.pH.Te pH value of a particular formulation is tested with a pH meter at specifc temperatures once sedimentation equilibrium has been reached in order to reduce "pH drift," or the buildup of suspended particles on the electrode surface.It is not recommended to add neutral electrolytes to the formulation's outer phase in order to regulate the pH because they afect the suspension's physical stability[43].9.5.Osmolarity Measurements.Nanoemulsion osmolarity is determined using a micro-osmometer using the freezing point method.Tis is done by transferring 100 μl of nanoemulsion into a microtube and taking measurements[49].When Morsi et al. used a pH meter to measure the acetazolamide nanoemulsion's pH, they found that it ranged from 4.9 to 5.5, indicating that it was suitable and nonirritating for use in the eye[50].9.7.Emulsion Droplet Polarity.It is a crucial element in determining the efectiveness of emulsifcation.Te polarization of the oil globules is signifcantly infuenced by the HLB, chain length, degree of unsaturation of the fatty acid, hydrophobic part molecular [40,52]uring conductivity with conductometers, we can determine the emulsion type and whether the microphase is continuous with oil or with water.Tis technique can also identify phase inverse phenomena.Water in the inner phase of the w/o type of nanoemulsion prevents it from conducting, whereas water in the external phase of an o/w type of nanoemulsion makes it highly conductible.Electrical conductance measurements are extremely helpful for identifying the dispersion phase's characteristics and for spotting phase inversion phenomena.Te use of the dielectric constant in determining structural and dynamic characteristics is very important.A conductometer with two electrodes immersed in the nanoemulsion and connected to an electric source is used to measure the conductivity of the nanoemulsion.If the lamp glows during the test, the nanoemulsion is of the o/w type as water conducts the passage of current between connecting electrodes; however, if the lamp does not glow, the nanoemulsion is of w/o type because oil is in the exterior phase and oil does not conduct the current[40,52].
[40].2.Fluorescence Test.Numerous oils show fuorescence when they are radiated with UV light.When an o/w type nanoemulsion under a microscope is exposed to UV light, the fuorescence appears as spots instead of an entire feld while in the case of w/o type, i.e., vice versa[40].9.10.3.Dye Solubilization.A water-soluble dye disperses in o/w globules while remaining soluble disperses in the aqueous phase of w/o globules.Similarly, an oil-soluble dye is dispersed in the w/o globules but is soluble in the o/w globule's oily phase

Table 2 :
A review of nanoemulsion formulation prepared for the treatment of various diseases such as cancer, hypertension, and infammatory.