INTRODUCTION:

There are three types of emulsions. A comparative presentation of emulsions is given in Table 1. For appropriate combination, an interface is stabilized by surfactants or co-surfactants. Difference between nanoemulsion and micro-emulsion are that the nanoemulsion especially deceitfully they may exhibit excellent kinetic stability and micro-emulsions are thermo dynamically unstable in comparison of nanoemulsion.¹

Nanoemulsions are the mixture of oil and water (immiscible fluids) mixed with the help of surfactant and co- surfactant. Nanoemulsion is emulsion with uniform and they possess the small droplet size having the range of 20-200nm. In 1940, the first nanoemulsion is prepared. Nanoemulsions can be classified into three type of emulsion based on their nano-structure. They are categorized into w/o (water in oil), o/w (oil in water) and bi-continuous types. Nanoemulsions possesses low layer tension in immiscible phase, which offers exceptional characteristics, potential to solubilize, lipophilic, hydrophobic and amphiphilic solutes, which enhance the solubilization and bioavailability of drugs.

Nanoemulsions have emerged as novel vehicles for efficient drug delivery. They can be administered via diverse route such as percutaneous, perioral, topical, transdermal, ocular and parental administration of medicaments.^2,3 Nanoemulsions are transparent and slightly opalescent. They are effective delivery systems for cosmetic products, diagnostics purpose, therapeutic use and biotechnology field.⁷² Addition to this, they also used as a novel delivery system in food industry, natural colors and flavors.⁷³In many cases a co-surfactant or co-solvent is also used in addition to the surfactant, the oil phase and the water phase.⁷⁴. Nanoemulsion is a multiphase colloidal dispersion and is featured by its clarity and stability. It is a heterogeneous planning of at least two immiscible fluids, one of which is scattered consistently as fine beads all through the other.^70,71,78

Classification:

On the basis of composition of water and oil portions nanoemulsion are classified into three types:⁴

Oil in Water Nanoemulsion (o/w): Oil droplets are scatter in water phase or (aqueous phase).

Water in Oil Nanoemulsion (w/o): Water droplets are scatter in the oil phase or (lipophilic).

Bi-continuous Nanoemulsion: Micro area oil and water are interspersed within the system.

Nanoemulsion specifications

Size: 20-200nm with narrow spreading.

Shape: Spherical shape

Stability: They are thermodynamically stable, unbalanced kinetically.

Method of preparation: High and Low energy method.

Polydispersity: Typically, low (< 10-20%).^5,6

Advantages of Nanoemulsion:^3,64,75

· Easy administration

· Thermodynamically stable system (i.e. long life) and therefore the stable settle for emulsification system⁷

· It can be administration by numerous routes, topical, oral blood vessel, parenteral and stratum.²

· Controlled and sustained release drug.

· Reduce patient Changeability.

· Quick and effective penetration of drug moiety.

· Nanoemulsion will distribute each hydrophilic and lipotropic medicine.

· It provides better uptake of oil-soluble supplements in cell culture technology⁷⁵.

Disadvantages of Nanoemulsion:

· It’s exaggerated by temperature associate hydrogen ion concentration.

· Huge concentration of chemical agent co-surfactant needed for stabilizing the nano droplets.

· It is thin solubility and ability for prime melting substance.⁴

· The chemical agent condition is non-toxicant for victimization pharmaceutical presentation.

· These parameters change upon NE delivery to patients.⁷⁶

Components of Nanoemulsion:

Aqueous Phase (water):

The nature of aqueous phase i.e., pH, ionic content of aqueous phase and electrolytes stimulates the droplet size and stability of nanoemulsion, Plain water, simulated gastric fluid (pH 1.2), Ringer's solution, simulated intestinal fluid (pH 6.8) and phosphate buffer saline can be used as aqueous phase for the evaluation of spontaneous Nano emulsification of nanoemulsions. From the above properties of aqueous phase, pH of the aqueous phase can have a dramatic impact on the phase behavior of nanoemulsions when a drug with pH-dependent solubility is loaded in the system^8,9. To understand the composition of nanoemulsion consider the next example Samira khaniet al. designed and evaluated oral nanoemulsion drug delivery system by using drug mebudipine. Nanoemulsion was prepared by using component such as ethyl oleate, polyethylene glycol 400, Tween 80, Span 80, ethanol and deionized water. In this case ethyl oleate used as oil phase, Tween 80 and Span 80 as surfactant, ethanol as cosurfactant and deionized water as aqueous phase¹⁰.

Oil:^11,12

Oil phase or lipophilic phase the most important drug carrier after the water phase or aqueous phase because i t solubilizes lipophilic molecules and its absorption through the lipid layer. Oil phase also having active lipophilic drug delivery because of its unique property of penetration cell wall.

Unsaturated fatty acid: Oleic Acid, Linolenic acid, Linolenic acid

Saturated Fatty acids: Lauric, capric acid, myristic

Fatty acid ester: Oleic acid, ethyl or methyl esters of lauric, myristric.

Surfactant:

For the dispersion of all components interfacial tension must be equal to zero which could be achieved by surfactant where surfactant must be able to reduce the interfacial tension.

For the preparation of water in oil formulation, Surfactants with hydrophobic lipophilic balance (HLB) values3-6 are useful.

For the preparation of oil in water, formulation surfactants with higher hydrophobic lipophilic balance (HLB) values are useful.

Surfactants which having the HLB^13,14value greater than 20 are act as co-surfactant for reduction of concentrations of the surfactants to the acceptable limits and the micro emulsion formation.

Because of ionic surfactants are get affected. Because of this they are being sensitive in stability issues and are generally nor preferable because of toxicity concern. But in case of non-ionic surfactant can produce nontoxic pharmaceutical dosage forms and hence more evident than other type.¹⁵

Co-surfactant:

cosurfactant usually used to enhance the oil-solubilizing capacity of nanoemulsion formulation or to decrease the oil and water interfacial tension. As the figure show small head with green color indicated as co-surfactant which reduce interfacial tension in hydrophobic phase and greater than co-surfactant head are surfactant which forms interfacial film^16,17,18

Pseudo ternary phase diagram^19,20

In order to find out the construction range of components or the existing range of nanoemulsion pseudo ternary phase diagrams can constructed using titration method and an ambient temperature.²¹ Visual observations can be made for transparent and easily flowable nanoemulsions. The physical state of the nanoemulsions are marked on a pseudo ternary phase diagram with one axis representing the aqueous phase, the second one representing oil and third representing a mixture of surfactant and cosurfactant at a fixed weight ratio.²²

Table 1: Examples of ingredients for phase diagrams^23,24,25

Oils	Surfactant	Co-surfactant
Isopropyl myristate (IPM)	Tween 80	Ethanol
Isopropyl palmitate (IPP)	Tween 60	Isopropyl alcohol
Oleic acid, Olive oil	Span 80	Propanol
Soybean oil, Ethyl oleate	Span 60	PEG-400
Cotton seed oil, Glyceryl oleate²⁶	Lecithin	Plural oleique
Triacetin, Epicuron-200, PEG Plural oleique Tetraglycol^27,28	Labrasol	Tetraglycol

Methodology used for nanoemulsions preparation

Method of phase inversion temperature: Phase inversion or phase separation produced by emulsification due to chemical energy. Through keeping composition constant and varying the temperature or keeping temperature constant and varying the composition constant phase transition can be produced.⁴¹

There are two types of emulsion phase inversion as follows:

Transitional Inversion:

Transition inversion can be produced by its changing factor which affects the hydrophobic lipophilic balance of the emulsion.

Catastrophic Inversion:

Catastrophic inversion can be produced by varying the hydrophobic lipophilic balance of the surfactant at constant temperature with the help of mixtures of surfactant^29,30.

PIT or Phase inversion temperature:

Based on the solubility changes of the polyoxyethlene with respect to temperature. When the temperature raises surfactant converts lipophilic due to dehydration of polymer chain.

Ultrasonication method:⁶⁴

Ultra-sonication used to prepare the nanoemulsion. Ultra-sonication is one of the best methods to produce the nanoemulsions because of its reduction of particle size at desired size. Sonication is not suitable for large number of batches due to its compact size. This is the major disadvantage of the sonication method.⁶³ Through this method we can only produce a research level emulsion. First ultra-sonication used in 1960.

High pressure homogenizer:

High-pressure homogenizer used to decrease particle size of emulsion up-to 10-100nm.Themixture passed through to a small inlet, which breaks the molecules into small size as, required for nanoemulsion with the help of high pressure at 500 to 5000 psi. The rate of production of the high-pressure homogenizer is quite low this is the one of major disadvantage. High-pressure homogenizer can use in laboratory research work. After the use of high-pressure homogenizer, sonication is not much required due to its efficient work.

Microfluidization Method:^31,47

In this method, high-pressure positive displacement movement pumps at range 500 psi to 20000 psi are used to flow the emulsion through the interaction chamber. In the chamber there are small channels are fitted called microchannels. When the emulsion flow through impingement area or microchannels resulting fine particles. Hydrophobic phase and lipophilic phase mixture form an uneven emulsion. Microfluidizaion further used to obtain even nanoemulsions

Consideration in nanoemulsion production:³²

· Nanoemulsion should not be in lyotropic (liquid crystal) as “micro-emulsions” phases

· To avoid Oswald foaming development adequate procedure required and the dispersed medium should be insoluble in diffusion medium.

· Flexible interfacial tension should be required to stimulate the nanoemulsion formations.

· The excess amount of surfactant provides adequate area on nano-scale to rapid coating during emulsification inhibiting (coalescence).

Recent application of nanoemulsions through different route of administration:

Nanoemulsions have diverse applications in the pharmaceutical industries field such as personal care and cosmetics, health care, food, agrochemical, drug delivery system in pharmaceutical and material synthesis.

a) Intranasal Drug Delivery System

b) Oral Drug Delivery System

c) Parenteral Drug Delivery System

d) Pulmonary Drug Delivery

e) Cosmetic preparation

f) Topical Delivery

g) Transdermal Drug Delivery System

h) Ocular Delivery System

a) Intranasal Drug Delivery System:

Nanoemulsion containing risperidone for transmission to the brain has been informed. It is inferred that this emulsion is further operative over nasal rather than intravenous route. Several intranasal vaccines are also presented in the market.^33,34,35,36

b) Oral Drug Delivery System:³⁷

Nanoemulsion is ideal in carrying of drugs such as hormones, steroids, antibiotics and diuretics. Primaquine when combined into oral lipid nanoemulsion presented effective Anti-malarial activity against Plasmodium. It also reduced the number of drugs. Lipid nanoemulsion of primaquine enhanced oral bioavailability by liver with drug absorption upper minimum 45% as compared to pure drug.

c) Parenteral Drug Delivery System:⁴⁸

Used for the intravenous route there is strict necessity of formulations droplet size requirement be lower than 1 micrometer due to this nanoemulsion take this advantage. For variety of purpose that is nutrition’s for example: - Fats, Carbohydrates, Vitamins etc. parenteral (or Injectable) administration of nanoemulsion are employed.⁴⁹

d) Pulmonary Drug Delivery:

It is reported that cationic submicron emulsion can be considered as a promising carrier for DNA vaccines to the lung since they are capable to transfect pulmonary epithelial cells, which in turn induces cross preparing of antigen-presenting cells and directly activate dendritic cells, resulting in stimulation of antigen-specific T- cells. Therefore nebulization of submicron emulsions will be a new and coming research area.^50,51

e) Cosmetic preparation:

Nanoemulsions are basically used as moisturizer and creams. Attractive delivery vehicle in the cosmetics as nanoemulsion droplet size is very small, creaming and flocculation is not observed prominent to a more elegant and stable products.^52,53,54,55

f) Topical Preparation Delivery system:

Topical administration having its own multiples benefits over traditional method of drug administration, one of the best reasons is to escape hepatic 1^st pass absorption of the drug and target ability of the drug to infected part of skin or eyes. Nano emulsion can reach a high level of anti-microbial and anti-bacterial activity that has been previously accomplished by general antibiotics.⁵⁶

g) Transdermal Drug Delivery System:

Through the pores of skin Nanoemulsion is able to easily penetrate and then reaches to the systemic circulation thus getting channelized for effective delivery⁵⁷. Comparison of in vitro skin permeation profile between these and aqueous caffeine solutions showed significant increase in permeability parameters for the nanoemulsion loaded drugs.⁵⁸

h) Ocular Delivery System:^77,78

For the treatment of eye diseases, drugs are essentially delivered topically. O/W NEs have been investigated for ocular administration, to dissolve poorly soluble drugs, to increase absorption and to attain prolong release profile.⁷⁷

Characterization ofNanoemulsion:⁴²

Identification test of nanoemulsions:

Dye Solubilization:

When a water-soluble dye mixed in oil in water (o/w) nanoemulsion it takes up color uniformly. If the emulsion is, water in oil than only the disperse phase colored and it will show the inconsistent color. This color can identify with the help of microscope³⁹

Dilutability Test:

Oil in water nanoemulsion is dilute with water (H₂O) and water in oil is not and phase inversion into oil in water nanoemulsion.^40,41

Conductance Measurement:

In o/w Nanoemulsion where the external phase is water and internal phase is oil where o/w is highly conducting whereas w/o are not, since water is the internal or dispersed phase. The electrical conductivity measurements used to determine the nature of the continuous phase and to detect phase inversion phenomena. An extreme increase in conductivity of certain w/o nanoemulsion systems that are optimized at low volume fractions and these types of behavior interprets the indication of a “percolative behavior” or an exchange of ions between droplets before the formation of bi-continuous structures.⁴²

Polydispersity Index:

The average di-meter and poly-dispersity index of samples measured by Photon Correlation Spectroscopy. The measurements performed at Room temperature (25⁰C) using a Helium-Neon laser.³⁶

Interfacial Tension:

The properties of formation of nanoemulsion can study by phase interfacial tension measurements. Phase behavior of nanoemulsion interrelated with ultralow value of interfacial tension. Apparatus used for measurement of ultralow interfacial tension, spinning-drop.³⁷

Viscosity Measurement:

Viscosity of the nanoemulsion measured by viscometer and determines the concentration of components surfactant/co-surfactant, water and oils function of viscosity of nanoemulsion. When the water content increase and lowers the viscosity, whereas surfactant and co-surfactant amount is decrease and increase interfacial tension among water and oil resulting in increased viscosity. Effect of drug release depends upon viscosity whereas adequate viscosity very important for stability of nanoemulsion. Using Brookfield type rotary viscometer, we can measure numerous compositions at different shear rates. For using instrument, sample temperature should be at 37⁰± 2⁰C.³⁸

The apparent pH of the formulation was measured by pH meter.^43,44

Refractive Index⁴⁵

Ratio of the speed of light and phase speed of the wave in a medium defined as refractive index.

n=c/vp

Where n=refractive index, c= Speed of light and vp=phase speed.

Abbe refractometer used at 24±1°C temperature to determine refractive index.

Transmission Electron Microscopy (TEM)⁴⁵

Transmission electron microscopy used to study of the morphology and structure of the nanoemulsion. Combination of field imaging at cumulative magnification and of diffraction modes used to reveal the form and size of nanoemulsion droplet. A drop of the nanoemulsion was directly deposited on the leaky film grid and detected after drying.⁴⁶

In Vivo Bioavailability Studies:

In this evaluation parameter the formulation/preparation is applied to whole live animal. And at definite intervals the blood sample are withdrawn and after that sample is centrifuged. Then by using HPLC plasma is analysed for drug content. The results of in vitro and in vivo studies demonstrate the bioavailability of the drug preparation.^65,66

Stability of nanoemulsion formulation:⁵⁷

Constancy of a dosage form discusses to the chemical and physical honesty of the dosage component and when proper, the capability of the dosage component to keep care against microbiological contamination.^59,60Stability of drug product is one of the major problems related with the development of emulsions, microemulsion and nanoemulsions. Nanoemulsions have been recognized to develop the physical as well as chemical stability of drugs.

Accelerated stability studies can also done. In this case of nanoemulsion formulation should be kept at accelerated temperature and sample quiet at regular intervals which is optimized for drug content by the stability indicating HPLC methods.⁶¹The quantity of drug sorted and enduring in nanoemulsion formulation is determined at each time interval.⁶²

Patent on Nanoemulsion⁵⁷

Though many of them have not reached the market yet, a good number of patents have been received on nanoemulsion formulations. Probably due to the challenges of industrial scale production of nanoemulsions, few patents have been transferred into commercial products. Some patents related to nanoemulsions are presented in Table 4^67,68,69

CONCLUSION:

Nanoemulsion is liquid mixture of water, oil, surfactant and co-surfactant nanoemulsion clear and thermodynamically stable. Nanoemulsion are most usable formulation for control release, increase drug solubility of poorly water-soluble drug, protect liable drug, increase bioavailability and reduce patient variability. Nanoemulsion dosage form may be considered as effective, safe, patient compliance formulation for the delivery of pharmaceutical. Type and concentration of surfactant and co-surfactant, type of oil phase, method uses, stability may be improved, process variable and factor affection of nanoemulsion formulation.

ACKNOWLEDGEMENT:

Author thanks Prof. Syed Waseem Akhtar, Hon. Chancellor and Prof. Aqil Ahmad, Hon. Vice Chancellor for providing excellent research facility in the university. Author also extends their gratitude toward Prof. Syed Misbahul Hasan, Dean for reviewing the manuscript and providing necessary suggestions. The university has provided a manuscript communication number for further communication (IU/RandD/2020-MCN000916).

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Received on 02.05.2020 Modified on 12.06.2020

Research J. Pharm. and Tech. 2021; 14(5):2852-2858.

DOI: 10.52711/0974-360X.2021.00502