INTRODUCTION:

One of the possible applications of nanotechnology in medicine is the use of nanocarriers in pharmaceutical drug delivery systems. Various types of nanocarriers are available, such as liposomes, noisome, solid lipid particles, lipoproteins, micelles, microcapsules, dendrimers and nanoemulsion.¹ Among the most recent technology of drug delivery, NEs are acquiring a lot of interests nowadays. NE is an advanced technique of drug delivery system that has been developed, it regarded as promising nanocarrier for various biomedical applications . They are thermodynamically stable, isotropic liquid mixtures of oil, water, surfactant and co-surfactant with mean diameters ranging between 50 and 1000 nm². As well, they offer advantages for providing better delivery of poorly soluble drugs.³

The essential constituent to form NE is oil and water where the spherical droplets represent the dispersed phase, however, the liquid surrounding it constitute the continuous phase.⁴ NEs can be categorized into oil-in-water (O/W) NEs signifying oily phase dispersed in an aqueous phase and water-in-oil (W/O) NEs referring to water droplets dispersed in oily phase. Furthermore, multiple NEs could be fabricated namely, oil-in-water-in-oil (O/W/O) or water-in-oil-in-water (W/O/W). The techniques of NE development can be divided into two major groups, comprising high energy and low energy techniques. Considerable characterization techniques namely, particle size, PDI, surface charge and viscosity would be carried out to provide reference about the criteria of NE that should be established for its appearance, stability and efficiency.⁴ The proper NE falls within a nanoscale that gives rise to its stability; however, destabilization could be happened since the required energy for separating oily phase from aqueous phase is lower than energy needed for emulsification. Subsequently, NEs break down over time as a result of various destabilizing mechanisms such as gravitational separation (creaming or sedimentation), flocculation, coalescence and Ostwald ripening.⁵ So far, the current review article, focus on discussing most applicable research from the recent literatures intended for drug delivery, nutraceutical and cosmeceutical purposes.

Development of Nanoemulsion:

Depending on the amount of energy required for NE preparations, techniques utilized for developing NEs are divided into two main categories as represented in Figure 2, the low-energy and high-energy techniques.⁶ The most commonly used methods for preparing NEs are high-pressure homogenization and microfluidization which are used at laboratory and industrial scale. Other methods are also used for preparation of NE.

Figure 1: A schematic showing the Structure of NE.

Figure 2: Description of NE development techniques.

High Energy Technique:

Generally, applying high-energy techniques for preparing NEs necessitate the presence of certain equipment and mechanical devices to provide sufficient energy required to break up particles and generate small droplets. This powerful energy may be stirring as in micro fluidization, pressure as in case of high-pressure homogenization or wave as present in sonication. In point of fact, this technique requires two sequential phases: (I) disruption of larger particles into the smaller one; (II) surfactant adsorption at the interface for maintaining the steric stabilization.⁷

High-pressure homogenization:

This technique is the most widespread method for preparing NEs. It depends on using high-pressure homogenizer/piston homogenizer to offer NEs of very low particle size. The schematic representation of high- pressure homogenizer is presented in Figure 3. The dispersion of oily phase and aqueous phase is done by driving their mixture in to a small inlet orifice under very high pressure (500 to 5000 psi), by which the product is subjected to strong turbulence and hydraulic shear producing considerably small particles of emulsion. The formed particles show a liquid, lipophilic core separated from the surrounding aqueous phase by a monomolecular layer of phospholipids. This technique is very efficient one. The higher the homogenization cycles the tiny is the particle size acquired. However, it consumes high energy and increase the emulsion temperature during the development.⁸

Figure 3: A schematic representation of high-pressure homogenization technique.

Microfluidization:

Microfluidization is a mixing process done by the use of microfluidizer. Figure 4 showed the schematic representation of microfluidizer. This device requires a high-pressure that drives the product through the interaction chamber, that composed of small channels called microchannel.⁹ The product flows through these microchannel on to an impingement area generating very fine particles of sub- micron range. The process is repeated several times in order to get a uniform NE with the desired particle size. Microfluidizer is said to be more effective than high pressure homogenizer in producing higher quality NEs with smaller particle size.

Figure 4: A schematic representation of Microfluidization technique.

Ultra-sonication:

Ultrasonication technique is of great interest as a result of the efficiency of its energy, easiness of system manipulation and its low production cost. Ultrasound frequency is applied in this method in order to get smaller droplet size. Once the probe of the sonicator introduced into the prepared NE it will stimulate the generation of mechanical vibrations that encourages the formation of microbubbles around the sonication probe. Accordingly, turbulence is generated and resulting in the desired NEs droplet size. The morphology of NE is influenced by the frequency, time and the power of the ultrasound waves.¹⁰

Low Energy Technique:

This technique intended for developing NEs without using any equipment or energy. There is a great interest in the productions of NEs using this way as a result of low cost and ease of application. It relies on the stored chemical energy in the components to be formulated.⁶ This technique requires two liquid phases, a lipophilic and hydrophilic one. The surfactant should be added to the lipophilic phase and solubilized to get a homogeneous liquid at room temperature. Afterward, the hydrophilic part present in the oily phase, which is the surfactant, is solubilized into the aqueous phase to form the nanodroplets. Next, the nanodroplets are stabilized promptly by the amphiphiles. The following techniques are examples of low energy methods used to develop NEs.

Spontaneous emulsification:

It includes the preparation of organic solution composed of oil and lipophilic surfactant with water miscible solvent and hydrophilic surfactant. The organic phase is added to the aqueous phase while mixing on a magnetic stirrer till O/W emulsion is formed. Evaporation of the aqueous phase is done under reduced pressure.¹¹

Phase inversion composition:

In this method, NEs are produced at room temperature without using energy or intensive equipment as in case of high energy method and without solvent like spontaneous emulsification method. The continuous phase components are added slowly to the components of the dispersed phase. Magnetic stirrer is required for mixing oil and surfactant followed by adding water drop wise at room temperature. The formulation of NE is ascribed to interfacial tension, viscosity, phase transition region, the structure and concentration of surfactant.¹²

Phase inversion temperature:

On the contrary to phase inversion composition, this method is a temperature dependent technique which provide flexibility in developing the NE.⁶ Distinctly, oil, water and surfactant are subjected to stirring and heating gradually at room temperature till reach phase inversion temperature. Thereafter, the mixture is allowed to a rapid cooling by putting it into ice bath resulting in the formation of O/W NEs. It is highly noticed that the NE formed by this method is sensitive near the phase inversion temperature thus cosurfactants are usually added in order to stabilize the system.

Solvent evaporation technique:

It comprises preparing a drug solution followed by its emulsification in another liquid that is non-solvent for the drug. Evaporating the solvent gives rise to drug precipitation. For controlling the crystal growth and aggregation of particles, a high shear forces are created via a high-speed stirrer.⁸

Evaluation Parameters of Nanoemulsion:

Physical Properties of Nanoemulsion:

Determination of droplet size and polydispersity index:

Particle size distribution and polydispersity index (PDI) are crucial indicators that help in characterizing the NE quality, stability and uniformity. Particle size could scale the absorption, the rate and extent of drug release.¹³ Droplet size determination of NE can be carried out using a light-scattering and particle size-analyzer counter. It could be also measured by employing Malvern zeta sizer and transmission electron microscopy (TEM). Small particle size prevents coalescence attributing to the high curvature of the particles. In the same way, particles coalescence in NE can be hindered by adding a thick film of surfactant adsorbed over the particle surface¹⁴. Polydispersity index (PDI) indicates the uniformity of droplet size in NE as it manifests the deviation from the average size. Increasing the value of PDI indicates lower uniformity of NE droplet size. Whereas, PDI values of lower than 0.2 is recommendable as it proposes that the NE droplets are dispersed uniformly without any coalescence or aggregation.

Surface charge (Zeta potential):

Zeta potential is one of the significant factors measured to describe the charge on the surface of the particles utilizing an instrument known as Zeta sizer¹⁵. Hence the preparation is put into a zeta cuvette and the data is recorded by mV.¹⁶ Generally, the particles with definite surface charge attract the ions carrying opposite charges and form a hard linkage known as stern layer. The electrical charge on the surface of the droplet affects the interactions between emulsion droplets and in turn influences the stability of NEs. It is well known that when zeta potential of NEs exceeds 30 mV regardless of the positive or negative sign, it gives an indication about NE stability while those with low values of zeta potentials tend to coalescence leading to poor stability.¹⁷

Viscosity determination:

Assessment of viscosity is very fundamental for NE evaluation. It regarded as a pivotal parameter that representing the stability of the preparation. It could be measured using different instruments; the most preferable one is Brookfield viscometer^18,19. Certainly, viscosity is dependent on the compositions and concentration of surfactant, water and oil. The rheological properties of NEs are affected by the type and the shape of the surfactants. Using cosurfactants result in reducing the viscosity as they reduce the interactions between emulsifier and the anionic surfactant. On the contrary, reducing their amounts may result in an increase in interfacial tension between water and oil, producing more viscous preparation. As well, using higher water content during NE preparation will result in lowering the NE viscosity as a consequence.

Morphology:

Microscopy imaging techniques have been utilized for assessing the microstructure characterization of NE. Electron microscopy (EM) is applied for visualizing the microstructure of NEs at a resolution of <5 nm. TEM has been utilized for studying the morphology and structure of the NEs²⁰. The main disadvantage of TEM is that it requires a high-energy electron beam which can damage the structure of the sample materials. This problem could be controlled by using cryogenic preparation (cryo-TEM) and freeze-fracture (FFTEM) techniques.²¹ Scanning electron microscope (SEM) is another way for evaluating microstructure morphology and chemical composition of the NEs in the nanometer to micrometer scale.²² However, the high cost, high vacuum and high sample conductivity considered to be greatest challenges.²¹

Fourier-Transform Infrared Spectroscopy (FTIR):

In order to investigate any chemical interaction between the drug and other excipient used, the infrared (IR) spectrum is performed. Further, it is applied to recognize the functional groups and their attachment and the fingerprint of the molecule.²³ FTIR performed by KBr pellet method in which the NE was placed on the KBr plate and dried in vacuum and the spectra of all samples were recorded between 4000 and 400 cm^-1.

In vitro Drug Release Study:

In vitro release study is performed to evaluate the in vivo performance of drug formulation as it assesses the percentage of drug released from the NE. It is usually investigated on a USP dissolution apparatus in which the drug is dispersed in buffer and then placed into dialysis membrane and put into a flask containing buffer. The study is kept going at 37 ± 0.5°C and allowed to rotate at 50rpm. Sample are withdrawn at specified time intervals and replaced by the same volume of fresh media. Samples are analyzed spectrophotometrically at a particular wavelength. The % of drug release at different time intervals is calculated from the recorded absorbance of the collected sample by means of calibration curve.²⁴

Stability Study:

Stability studies are performed on the formulated NEs for assessing their physical and chemical stabilities under the influence of some environmental factors mainly the temperature and humidity. Samples are stored in sealed glass vials for a specified period of time by keeping them at different storage conditions as per International Conference on Harmonization (ICH) guidelines.¹⁶ Next, the samples are withdrawn and analyzed for their characteristics at the predetermined period of time.²⁵

Nanoemulsion Stabilization:

Physical Instability:

To some extent, the unfavorable interactions occur at the interface between oily and aqueous phase of NE stimulate its instability²⁶. Consequently, NEs break down over time due to several destabilizing parameters including gravitational separation, flocculation, coalescence, phase separation and Ostwald ripening as shown in Figure 5.²⁷

Figure 5: A schematic representation of NE mechanisms of physical instability (Coalescence, flocculation, Ostwald ripening). All lead to creaming and phase separation.

Gravitational separation:

Gravitational separation emerges as a result of the difference in density between aqueous and oily phase which give rise to creaming or sedimentation. In creaming, the particles move upward due to flowability whereas, in sedimentation, the particles tend to settle down at the bottom.²⁸ In respect of density, water being denser than oil thus it has a propensity to descent downward thus O/W NE commonly shows creaming however sedimentation is ordinarily take place in W/O NE.⁵ predominately, large particle size is regarded as a key parameter that generate this condition as the gravity controls the particle movement thus, in most cases, small droplets did not undergo separation. As reported by Rodrigues et al., some NE formulations containing naphthoquinone were unstable exhibiting a significant travelling of oil droplets upward which come up with creaming. Whereas, other formulations with smaller droplets (< 90nm), showed gravitational stability that revealed better physical stability of the formulations. Different stabilizers could be applied as a protection against creaming and sedimentation such as weighting agents which behaves like a hinder for separation. In fact, weighing agents are hydrophobic matters possessing density higher than water such as ester gum, vegetable oil and rosin gum. Thence, adding proper amount of weighting agent can raise the density of these compounds to be in parallel with that of the aqueous phase, reducing the susceptibility for gravitational separation. As well, texture modifiers (thickening and gelling agents) could help in reducing the possibility of gravitational separation through improving the aqueous phase rheological behavior. Various polysaccharides like chitosan, starch, carboxymethyl cellulose, alginates, and pectin are perfect thickening and gelling agents.²⁹

Coalescence and flocculation:

Droplet’s accumulation or aggregation in a specific manner results in either coalescence or flocculation which is indeed difficult to be differentiated from each other.²⁷ In point of fact, this aggregation is less commonly happened in NEs ascribed to their small particle size and the steric stabilization that formed on the surface of the droplet as a result of the adsorbed layer of the emulsifier. Attributable to the attractive interaction between NE particles, droplets may become very adjacent to each other giving a floc or cluster in a process known as flocculation. In contrast, merging these droplets and coming into contact with each other to form a bigger droplet is known as coalescence. Additionally, owing to the fact of small particle size, the effect of the Brownian motion in NE is predominated than gravitational force providing greater stability. Emulsifiers are widely used in NE preparation as a stabilizer in order to get small particles and stable NEs via reducing the interfacial tension. Probably, the emulsifiers act to discourage the collision of the particles and increase the kinetic stability of the NEs.¹³ Given that, incorporating emulsifier into NE preparation above certain level could support its instability attributable to promoting flocculation mechanism.³⁰

Ostwald ripening:

Ostwald ripening is the main instability feature of NE as it characterized by an expansion of the droplet size by the time. It happened when oil particles have limited solubility in the continuous phase and a difference in solubility between small and large droplets is detected which consequently, leads to appearance of a concentration gradient.³¹ As a matter of fact, in order to minimize this process, several methods could be followed like adding one more disperse phase material that is insoluble in the continuous phase. Secondly, certain modulation could be applied like decreasing the interfacial tension of NE that results in reducing of Ostwald ripening.³² Additionally, certain stabilizers namely, ripening inhibitors could be added to the dispersed phase of NE to prevent Ostwald ripening by inhibiting droplet expansion. Ripening inhibitors including essential oils, sunflower oil, coconut oil, corn oil, palm oil and more.

Chemical Instability:

Diverse chemical reactions namely, loss of flavor, fading of color, lipid oxidation and hydrolysis come into being in NEs resulting in disappearance of their appropriate features. The most remarkable sign of NE instability is lipid oxidation because the surface of NE is large enough to be exposed to oxidation.³³ With a view to improve the chemical stability of NE, three strategies could be followed comprising modification of the interfacial characters, adding antioxidants, besides, managing the environmental conditions.³²

Nanoemulsion Applications:

The past decades have seen increasingly rapid advances in the field of nanotechnology. Various investigators have studied the influence of entrapping certain drugs into NE formulations. It has been observed that NE is involved with high percentage in pharmaceutics³⁴, cosmetics³⁵, food industry and others³⁶. Number of researchers has reported considerable importance for using NE preparations over the use of regular formulations. This is actually could be attributed to major characteristics manifested by NE such as reducing the dose and reducing drug resistance.³⁷

NE in pharmaceutical drug delivery:

Fine particle size of NEs helps them to be a suitable strategy and being extensively applied for parenteral delivery in various conditions especially for cancer treatment.³⁸ Over and above, NEs have been shown effectiveness in oral delivery of various drugs, which results in lower required dose compared to the conventional formulations. Besides, abundant drugs demonstrate difficulty for being applied topically when formulated in several dosage forms like gels, creams, ointments and patches as it may result in skin irritation. NEs have confirmed to be efficient as it enhances the drug penetration through lipid bilayers.³⁹

Regulatory Aspects:

As mentioned previously, NEs have found applications in different fields such as food, supplements, cosmetics and pharmaceuticals.⁶ Implementing NEs in such industries requires significant caution as these products would interact with the human body, through various routes of administration. It is necessary to assure safety of these products and confirm that they do not have any adverse reactions on the health.⁶⁵ Adequate selection of the ingredients and method of preparation has a great impact on the physical and chemical stability of the food products. The major hazard associated with NE and has to be considered, is the utilization of surfactants and whether they are safe or not. It is highly recommended to revise the list of generally recognized as safe (GRAS) substances approved by the US Food and drug administration (FDA) prior to incorporating pharmaceuticals, cosmetics or nutraceutical into NEs. FDA encourage the manufacturers for consulting with them to minimize the hazards of unintentional harm to human health, As well as, they issued reports that offered estimation for certain regulatory considerations regarding the safety and efficacy of the products.⁶⁶

CONCLUSION:

NE is extensively applied in pharmaceutical drug delivery systems as a consequence of its properties such as great stability, attractive appearance and high performance. The typical techniques for preparing NEs and methods of characterization were reviewed. It is prospected to lose some of NE features accounted for its acceptability over time however; improving the stability could be managed. NE could successfully ameliorate the efficacy of the pharmaceuticals, as well; they could draw the attention as a potential carrier toward cosmeceuticals and nutraceuticals.

CONFLICT OF INTEREST:

The authors report no conflicts of interest.

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Received on 12.09.2020 Modified on 07.10.2020

Research J. Pharm. and Tech. 2021; 14(7):3938-3946.

DOI: 10.52711/0974-360X.2021.00684

NE composition	Active constituent	Development technique	Application	Therapeutic Efficacy	Ref.
Oily phase (oleic acid), surfactant (Tween 80) and cosurfactant (PEG 400).	Atorvastatin	Pseudo ternary phase diagrams	Cholesterol lowering medication	Developed NE increase drug bioavailability and therefore improves its therapeutic effect.	40
Oily phase (c-T3 vitamin E), surfactant (PEGylated c-T3).	Paclitaxel (PTX)	Solvent evaporation	Anticancer agents	Developed NE was more active against pancreatic tumor cell lines than the based formulation.	41
Oily phase (triacetin), surfactant (Cremophor, tween 20, 80) aqueous phase (butanol)	Cantharidin	Spontaneous emulsification	Anticancer and biopesticide	Optimized NE exhibited effective insecticidal activity	42
Oily phase (Medium-chain triglyceride), Aqueous phase (NaCl solution), Surfactant (Tween 80 and Span 80).	Gemcitabine (GEM)	High and low energy emulsification	Chemotherapeutic drug for various solid tumors	Optimized NE reduced cytotoxicity towards MRC5 when compared to the GEM solution	43
Oily phase (Castor oil), surfactant (Transcutol HP), co-surfactant (PEG400)	5-Fluorouracil	Ultra-sonication	Anticancer	Developed NE provides better treatment of malignancies, promising vehicle for the skin cancer chemoprevention.	44
Oily phase (ethyl oleate), surfactant (Tween 80), cosurfactant (Soluphor P)	Moxifloxacin	Pseudoternary phase diagram by titration technique	Treating of bacterial conjunctivitis	Developed NE can be applied as a safe and effective delivery vehicle for ophthalmic therapy.	45
Oily Phase (Arachis) surfactant (Egg Phosphatidyl choline, soy phosphatidyl choline), co surfactant (cholesterol).	Brucine.	High pressure homogenization	Anticarcenogenic agent.	Developed NE demonstrated anticancer activity against MDA-MB-231 cells.	46

NE composition	Active constituent	Development technique	Application	Therapeutic Efficacy	Ref.
Oily phase (isopropyl myristate, oleic acid). surfactant (Labrasol, Cremophor EL, and Tween 80). co-surfactants (Transcutol HP and propylene glycol).	Coenzyme Q10	Pseudo-ternary phase diagram	Antioxidant, Anti-aging.	Developed NE could enhance solubility and permeability of CoQ10 and improve its anti-wrinkle and anti-aging efficacy.	49
Oily phase (safflower oil, PEG-7 glyceryl cocoate), surfactant (mixture of Ceteareth-20, PEG-40 hydrogenated castor oil and Sorbitan oleate)	Mangifera indica L. kernel extract	high speed homogenization	astringent, vulnerary agent	Developed NE provides anti-acne effect.	50
Oily phase (Castor oil), surfactant (tween 80, xanthan gum).	Kojic monooleate (KMO)	High pressure homogenizer	Treating hyperpigmentation	Developed NE is a promising candidate for a safe cosmetic to prevent hyperpigmentation	51
Oily phase (Tegosoft G20), emulsifier (Tween 80), cosurfactants (ethanol, glycerol, PG)	ceramide IIIB	Phase diagram	Skin dryness	Developed NE exhibited desirable attributes for effective transdermal Delivery	52
Oily phase (Capric Triglyceride), surfactant (Tween 80, span 80)	Polysaccharides	phase inversion composition	Moisturizing agent	Developed NE revealed a promising effect as a moisturizing cosmetic	53
Oily phase (Babacu oil), surfactant (orbitan monoestearate)	Hydroalcoholic extract	Inversion phase temperature	Antioxidant	Developed NE could be used in pharmaceutical or cosmetic formulations	54
Oily phase (Virgin coconut oil, Squalene), Emulsifier (Emulium Kappa)	Kojic Dipalmitate	Emulsion Inversion Point method	Active whitening agent.	Stable NE was developed for whitening purpose	55

NE composition	Active constituent	Development technique	Application	Therapeutic Efficacy	Ref.
Oily phase (Essential oil containing carvacrol), surfactant (polysorbate 80)	Carvacrol	Ultrasonication	human lung adenocarcinoma	Developed NE, it proposed to be a suitable drug for lung cancer therapy after sufficient clinical trials.	58
Oily phase (omega-3 (ω-3) fatty acids), surfactant (Lactoferrinf)	ω-3 PUFAs	high-pressure homogenization	Lower levels of a blood fat and treat heart diseases.	Developed NE reduces the oxidation process and improves the stability of omega-3 as a pharmaceutical and food application.	59
Oily phase (Medium chain triglyceride, Lecithin), surfactant (Tween 80, dextrin)	Turmeric extract	High-speed homogenization and Ultrasonication	antioxidant and anticancer effects	Developed NE can be applied in milk and other colloidal products	60
Oily phase (Nigella sativa oil), surfactant (gum arabic, sodium caseinate, and Tween‐20)	Nigella sativa oil (NSO)	high-pressure homogenization	Used in food applications as functional ingredient	Developed (NSO) NE could be used to fortify ice cream	61
Oily phase (Cinnamon essential oil), surfactant (Tween‐80)	Cinnamon essential oil	Ultrasonication	antioxidant, and antimicrobial activities	Developed NE has higher potential antimicrobial activity than course emulsion to be applied for food applications	62
Oily phase (Linalool), surfactant (Tween‐80)	Linalool	Ultrasonication	Strong antibacterial activity	Developed NE as antibacterial and antibiofilm could be applied in food industry	63
Oily phase (Palm oil), aqueous phase (2% whey protein isolate, WPI)	β-carotene	Microfluidization	Used as food additives and supplements to protect against vitamin A deficiency	Developed NE is the most suitable carrier to increase bioaccessibility and stability of as beta-carotene.	64