INTRODUCTION:

Nanotechnology embraces development of technology on the nanometre scale, typically 0.1-100 nm Size. In the past few years the practice of nanotechnology in pharmaceuticals and medicine has full-fledged. There has been an outpouring of interest in the application of dispersion systems of nanoparticles for a variety of medical and industrial applications in the last few years or so, including within not only the pharmaceutical industry but also in food, agrochemical, cosmetics, and personal care industries¹. The main characteristic of an idyllic drug delivery system are based on the objective of exploiting the therapeutic effect by decreasing the toxicity. The progress of science and technology has allowed drug delivery systems to evolve from simple mixtures and pills to extremely sophisticated systems².

In this particular review we are mainly giving emphasis on a specific nanoparticle dispersion for drug delivery that is nanoemulsions. Nanoemulsion is a heterogeneous system and it consist of two immiscible phase, one phase is oil phase other is aqueous phase, while the droplet is of submicron size range of 5-200nm³. The main components of nanoemulsions are oil phase, aqueous phases and emulsifying agent or blend of surfactants. Bearing in mind the application and the diverse parameters such as toxicity related to oils, route of administration, and solubility of drugs, various types of oils are used which includes not only medium- and long-chain fatty acids but also essential oils for the formulation of nanoemulsions. A high solubility of the drug will lessen the volume of the preparation necessary to deliver the therapeutic agent. Enhanced bioavailability and increased drug loading are main advantages of nanoemulsion². Nanoemulsions have great capability as effective nanomedicines as they can freely solubilize lipophilic drugs, decrease severe adverse effects and can be modified into next generation of smart nanomaterials ⁴. Nanoemulsion is a translucent system compared to ordinary emulsion or sometimes microemulsion⁵. Thermodynamically it is not a stable system, but it can be stabilized by the existence of a surfactants also known as an emulsifying agent or emulgent or emulsifier and co-surfactant⁶. The long term stability has also shown a clear peculiarity between emulsion and nanoemulsions. By using three methods nanoemulsions can be prepared: (1) oil-in-water (O/W) NEs where oil is dispersed in a aqueous phase which is a continuous phase; (2) water-in-oil (W/O) NEs where water is disseminated in an oil which is a continuous phase in this case; and (3) Multiple emulsions which consist of O/W/O or W/O/W. Along with variety of shapes NEs they can be seen as spherical swollen micelles or bicontinuous structures⁷. It gives reproducible plasma drug profile. It can also be used for sustained and targeted drug delivery⁸. Now a days for delivering bioactive food components and drug, formulations based on lipid bases are a good option, which have low oral bioavailability and other formulation problems. Nanoemulsion drug delivery systems are lipid-based formulation system which improve the solubility and bioavailability of drugs which are hydrophobic in nature and bioactive food components⁹. NEs enhance drug absorption due to their nano-size and increased surface area.

Types of nanoemulsions:

Single emulsion:

Single emulsions consist of only one component is dispersed in continuous phase that is either oil is dispersed in water in case of O/W emulsion and waters is dispersed in oil in case of W/O type emulsion. Preparation of these type of emulsions is a simple single step process. Here Surfactant or emulsifying agent is used for stabilizing the two layers by acting as a buffer or a surface stabilizing layer^5,10.

Double Emulsion:

These are either W/O/W or O/W/O emulsions. These type of emulsions are made by two step process. In these type of emulsion two type of emulsions are used one is Hydrophilic and other is hydrophobic. In Oil/water/oil emulsions first oil/water emulsion is prepared which is then dispersed in oil phase. For preparation of primary oil in water emulsion high shear methods are used and for later part shear is reduced to reduce rupturing of droplets^5,10.

Methods of Preparation:

For preparation of nanoemulsions either of two methods can be used namely high energy preparation or low energy preparation method. The main difference between these two preparation methods is energy being transferred during the preparation of emulsion. In high energy method to generate large disruptive forces different mechanical devices being used. Whereas, in low energy method alteration in the physiochemical properties of the system is done to generate nano-sized particles^9,11.

High Energy Preparation Methods:

In high-energy methods, large disrupting forces are provided by the use of mechanical devices such as high pressure homogenizers, microfuidisers and ultrasonicators which produce droplets of micro size. Various parameters like equipment, production conditions, such as temperature and time, as well as the properties and composition of sample affect the drop size in emulsion. High-energy methods require sophisticated equipment and consume large amount of energy, therefore, they are very expensive. Their advantage is that they allow large selection of integral components and allow good control of droplet size. As heat is being transferred during emulsification process, these methods are not valid for thermo labile active ingredients such as retinoid and macromolecules including proteins, enzymes and nucleic acids^5,11,12,13.

Low Energy Preparation Methods:

In case of Low energy methods there is application of internal physical properties of the system such as temperature or composition to produce nanoemulsions^{2, 9}. Different Low energy methods for preparation are as follows

a) Phase Inversion Composition (PIC):

In PIC method at a constant temperature due to a change in the composition of emulsion mixture there’s a change in emulsion mixture phase occurs (i.e., o/w to w/o or vice versa). It involves the addition of oil or water over a mixture of oil and surfactant or water and surfactant respectively^14,15.

b) Spontaneous Emulsification (SE):

This process is low energy nanoemulsion preparation. For this method there is no need of any equipment and process can be carried out at room temperature making it suitable for thermo labile compounds. In this method addition of water to solution of oil and surfactant mixture is done step by step at fixed temperature and gently stirring is carried out to create nanoemulsions of O/W type. The phase transition area, interfacial tension, interfacial and bulk viscosity, and surfactant concentration and structure decides the spontaneity of this process. The disadvantage of this method is less amounts of oil phase and the solvent presence. This method is based on movement of water miscible ingredients such as solvent, surfactant and co-surfactant from an organic phase into the aqueous phase^16,17.

c) Phase Inversion Temperature (PIT):

PIT is a low-energy emulsification method for preparing nanoemulsions. PIT method by changing the temperature it make changes in the optimum curvature of surfactants at constant composition. It has the benefit over SE method in that its composition is without organic solvent which is an integral component of the SE method. The PIT method also has dominance over the PIC method as in PIT the nanoemulsionpolydispersity index (PDI) and droplets have lower diameter. The efficiency of emulsification in PIT method has also been found advanced than that of PIC technique^18,19.

d) Micro Emulsion Dilution:

The other name for this method is self-emulsification method. At a constant temperature a dilution process is used for the formulation of emulsion by this method. The microemulsion of oil-in-water is quickly diluted with large amount of water thereby lowering the surfactant concentration responsible for maintaining thermodynamic stability^20,21.

e) D Phase Emulsification (DPE):

Like other methods of nanoemulsion preparation this method also include water phase, oil phased, and surfactant the significant difference that is seen in this method is the use of alkyl polyol as an extra component to form oil in water nanoemulsion. It requires low surfactant concentration when compared with other methods and there is no strict adherence to HLB scale nor does it require a proper surfactant mixture. There’s also no need of solvent and it consumed less energy compared to the PIC method^11,22.

Stability:

For the evaluation of nanoemulsions, the stability study is a significant standard to be considered. Nanoemulsions are characterized by its high stability than the other dispersed systems²³.

Thermodynamic stability studies:

In these type of stability studies the selected samples are exposed to various thermodynamic stability study tests to admittance of their physical stability²³. The process involved 3 cycles, initially heating and cooling cycles are carried out 6 times, followed by alternately heating and cooling at 40°C and 4°C respectively, this is followed by centrifugation at 3500rpm for 30 min. Each cycle is observed for changes in the formulation due to phase separation²⁴.

Accelerated stability studies:

Accelerated stability studies are performed on optimized formulation. Accelerated stability studies refer to the stability testing under increase temperature condition and humidity. Three batches of the nanoemulsions are taken in glass vials and were kept at a temperature of 30°C, 40°C, and 60° C. at ambient humidity condition²³. The samples are then compared with ICH stability guidelines. Arrhenius equation is basically used for the calculation of half-life and stability related studies^24,25,26. The high colloidal stability can be obtained by achieving small droplet size^27,28. For example if droplets are less than 100 nm in radius, then for overcoming the gravitational force acting upon the droplets the Brownian moment is generally sufficient and it can prevent instability like creaming²⁶. Additionally, flocculation can be prevented by providing a large energetic barrier by long ranged repulsive interactions between surfactant at nano droplet interface and providing more long term stability. As such, nanoemulsions are generally thought to comprise metastable droplets²⁹. As such, nanoemulsions are usually supposed to contain metastable droplets. Still there can be seen instability by various mechanisms such as phase separation, coarsening and creaming due to different choice of materials³⁰. In nano sized emulsions attractive forces which generally lead to instability like flocculation and coalescence are very less compared to the conventional emulsions leading to the better stability towards coalescence and flocculation³¹. Nanoemulsions may become turbid during period of storage, as well as due to different instability mechanisms such as sedimentation, flocculation, and Ostwald ripening and coalescence complete phase separation may occur. Nanoemulsion system are stable as there destabilisation kinetics is very slow and can take several months for their instability³². Due to less particle size of nanoemulsions compared to the conventional macro emulsions the Brownian motion of droplets in nanoemlsion dominate over the gravitational force acting on the droplets and have greater stability of separation under gravitational force. Flocculation and coalescence arise due to the attractive forces among the droplets, which are usually very little in nano-sized emulsion systems. Thus, nanoemulsion also demonstrates much improved stability towards the flocculation and coalescence. Food grade nanoemulsions containing essential oils and short chain triglycerides may subject to another mechanism of instability that is Ostwald ripening³³.

Characterisation of nanoemulsions:

Nanoemulsions display different type physicochemical properties like, droplet size in nanometers, variable viscosity, high transparency, and high stability³¹. These properties are characterized by using different analytical methods such as, viscosity, zeta potential, atomic force microscopy (AFM), small angle neutron scattering (SANS), dynamic light scattering (DLS), and stability. Droplet size effects many properties and play an important role in stability³⁴. Larger molecules with more spherical drops will have a great flow than smaller or distorted droplets which tend to stick together. Polydispersity index is used for the measurement of uniformity of droplet size; if polydispersity index is b0.2 nanoemulsions are generally referred to as ‘monodisperse’. Particle size analysers is used to measure droplet radius using photon correlation spectroscopy (PCS) or laser diffraction. In terms of overall derivable information though PCS has limitations³⁵. It sometimes fails out on smaller populations, which differ considerably from average population. It is also impossible to distinguish between blank droplets (which do not possess any drug molecule) and active droplets containing API, liposomes, surfactant aggregates, micelles, nanoparticles or one colloidal form from other^36,37. In case of Dye Solubilisation when a water soluble dye is solubilized then continuous phase will get coloured in case of O/W emulsion and globules of aqueous phase get coloured in case of W/O emulsion. Similarly when an Oil soluble dye is used dispersed phase get coloured in case of O/W emulsion and continuous phase will get coloured in W/O emulsion. Interfacial tension is another method for the characterisation of nanoemulsions. Various properties of nanoemulsion can be studied by measuring the interfacial tension of nanoemulsions³⁸. Ultra-low interfacial tension of nanoemulsions can be measured by an apparatus called Spinning-drop apparatus. By rotating shape drop of low density phase in cylindrical capillary filled with high density phase the interfacial tension between two phases can be derived³⁹. Characterisation of Refractive Index of nanoemulsion is done by using an Abbes type refractometer. Standard deviation of refractive index is calculated by measuring the refractive index of each sample three times. The characterisation of viscosity of any type of emulsion is important in the point of view of stability. As the viscosity of emulsion increases the stability increases as viscosity prevents coalescence and flocculation, but on other hand the viscosity should be less enough to draw formulation from the container²³. The viscosity of nanoemulsion is measured by using Brookfield viscometer. To study viscosity the spindle size 62 is used at 60rpm and is measured in terms of centipoises. Characterisation of percent drug loading is done by extraction of pre weighed nanoemulsion by dissolving in 25 ml suitable solvent, the spectrophotometric analysis of this extract is done or by using HPLC against standard solution of drug loading is determined⁶. Columns of appropriate porosity drug content is determined by reverse phase HPLC method. In Thermal Conductivity Technique, method named 3 -wire method was developed to measured nanoemulsion by the thermal conductometer. In this method, the temperature of the metal wire is measured in the time domain. O/W nanoemulsion where the external phase is water are highly conducting. Dynamic light scattering measurements are done using a neon laser of wavelength 632nm at 90°⁴⁰. Dynamic light scattering spectrophotometer is used for measurement of particle size and particle size distribution. For evaluation of charge on nanoemulsion surface zeta potential is used⁴¹. It provides clue towards long term stability on emulsion and also gives idea about interaction with target matrix. Zeta potential is directly determined by sing principle of electrophoretic mobility. For long term stability the zeta potential values as a rule of thumb of N +30 mV or b-30 mV are considered optimum⁴². Aggregation and phase separation may occur in emulsions if zeta potential value is too less. For enhancing emulsion stability the need of zeta potential manipulation is there. It is possible to delineate conformational changes occurring in the molecules making up a nanoemulsion with respect to alterations in temperature, drug loading pH, and other processing variables, using a combination of fluorescence quenching, absorption spectroscopy, and zeta potential measurements¹⁰.

Applications of nanoemulsions:

Drug Delivery:

For the delivery of lipophilic drug and biologics like hormones, steroids, antibiotics, cytotoxics, antifungals, and diuretics nanoemulsions are idyllic drug delivery systems²⁴. The ability of nanoemulsions to coat drug allows a platform which helps protecting them against environmental conditions, hydrolytic enzymes or the pH conditions⁶. Parenteral nanoemulsions can be beneficial in delivering drugs with narrow therapeutic index or the less bioavailability^{1, 43, 44}. Parenteral nanoemulsion has a significant application in the treatment of breast and ovarian cancer⁴⁵. Nanoemulsion of a lipophilic anticancer drug Chlorambucil manufactured by the high energy methods like high pressure homogenisatin and ultrasonication can be administered parenterally for the treatment of breast and ovarian cancer. When we consider ocular drug delivery it becomes important to retain drug at site of application, for poorly retaining drugs and drugs which are sensitive, water incompatible or poorly absorbed can be administered with formulating as nanoemulsion¹⁰. The formulation of MTX nanoemulsion in Psoriasis as dermal drug deliverycan inhibit the epidermal cell proliferation and inflammation. The systemic administration of MTX is associated with the liver toxicity and side effects related to the GI tract can be bypassed by formulating MTX nanoemulsion^46,47,48. The loss of skin moisture and elasticity due to skin condition like dermatitis can be regained by the use of ceramide topical nanoemulsion. The emulsifiers present in the nanoemulsions can help in modulating the concentration gradient across skin and can be passed through skin with ease^49,50. This phenomenon can be advantageous in skin drug delivery and efficacy in chemotherapy. Using intravenous route for administration chemotherapeutics can be also delivered as nanoemulsion following transdermal delivery. Etoricoxib gel nanoemulsion is being used for the treatment of rheumatoid arthritis as it can bypass adverse effects caused by oral administration⁵¹. Some Previously published research on nanoemulsion for various routes of drug delivery is shown in Table 1.

Cosmetics:

The low viscosity and transparency of NEs are two of the aesthetic features that have attracted cosmetics companies to employ them. Furthermore, because NEs have small droplets below 200nm, they allow for improved distribution of active ingredient to the skin, which have high-demand quality in cosmetics⁵⁹. In the cosmeceutical trade, NEs are far more practical than macroemulsions since they have no intrinsic creaming, sedimentation, or flocculation⁶⁰. The use of potentially irritating surfactants could be decreased or perhaps eliminated entirely by using high-energy equipment during manufacture^61,62. Nano-gel technology is used to make mini-emulsions, which are ideal for reducing trans-epidermal water loss, improving skin protection, and increasing API penetration. The Kemiranano gel-NE based carrier system is a cosmetic proprietary solution. By employing the phase inversion method, NE formulations were made from hydroalcoholic extracts of Velloziasquamata leaves and stems with high antioxidant activity⁶³.

Vaccines:

Though vaccine delivery by injection bears risk of transmission of various virus and pathogens like HIV and Hepatitis B or C virus, still it is most usual route for vaccination. Vaccine delivery advances suggests the administration of vaccines by skin as it comprises significant components of immune system like dendritic cells and Langerhans cells. Presence of surfactants which can act as penetration enhancers and the components which increase the absorption of lipophilic components are the two main advantages provided by the nanoemulsions. Research has proven that administration of vaccines into the mucosa of nasal part can give immunity to genital mucosa also^64,65,66.

Delivery of herbal bioactives:

Nanotechnology is playing a crucial role in producing numerous nanocarrierswhich will help to enhance the therapeutic effect of the herbal drugs. Use of Herbal medicines have been applied for the treatment of various diseases. The nanosized droplet which offers favourable environment for the uptaking of highly lipophilic herbal bioactive molecules. Drug release from nanoemulsion is depends upon the partitioning of droplets into GIT fluids as well as their motility⁶⁷. Use of nanoemulsion in Topical and transdermal drug delivery systems are alternative as well as promising approaches used for enhancing therapeutic efficacy along with bioavailability of low bioavailable drugs through the skin. Recently, nanoemulsions of numerous herbal bioactive molecules have been investigated to achieve the maximum oral bioavailability and therapeutic efficacy. NEs of these herbal drugs have been studied for improved skin permeability, therapeutic activity and bioavailability⁶⁸. Nanoemulsion techniques used for encapsulation and delivery of herbal bioactive compounds are discussed in Table 2.

Table 1. Previously published research on nanoemulsion for various routes of drug delivery.

Route of administrations	Method of Preparation	API	Purpose	Reference
Oral	Titration method	Letrozole	For improving oral drug delivery in breast cancer	52
Topical	Spontaneous emulsification	Clobitasol propionate and calcipotriol	Topical drug delivery in psoriasis	53
Topical	Titration method	Betamethasone dipropionate	Topical drug delivery in psoriasis	54
Parenteral	Spontaneous emulsification	Thalidomide	Parenteral delivery of Thalidomide	55
Parenteral	Spontaneous emulsification	Carbamazepine	For intravenous delivery.	56
Intranasal	Spontaneous emulsification	Saquinavirmesylate	For brain targeting	57
Intranasal	Aqueous titration	Naringenin	For the Management of Oxidative Stress in Parkinson’s Disease	58

Table 2. Previously published litrature on nanoemulsion for herbal bioactive formulation.

Herbal bioactives	Applications	Biological activities	Route of administrations	Reference
Betulinic acid	Enhanced gastro-intestinal permeability, bioavailability and sustained release action	Hepatoprotection and antioxidant	Oral	69
Ferulic acid	Enhanced skin permeability, sustained release action	UVA protection e fficacy against oxidative stress, antioxidant	Transdermal	70
Glycyrrhizin	Increased percutaneous permeation, sustained release action	Useful in the treatment of dermatitis, eczema, psoriasis, antibacterial and anti-inflammatory	Transdermal	71
Quercetin	Enhanced oral bioavailability, reduced dose, enhanced penetration in blood brain barrier, increased antioxidant activity and 74 times higher drug release, exerted better therapeutic e efficacy, enhanced skin Permeability	Antiobesity, Antioxidant, anticancer, anti-inflammatory, anti-ageing, anti-wrinkle	Oral, intranasal, oral, topical	72-76
Curcumin+ Thymoquinone+ Resveratrol	Improved psoriasis therapy	Anti-psoriatic activity	Topical	77

CONCLUSION:

Recentadvancements in nanoemulsion development shows a great promise in nanomedicine as well as nanocosmeticsand vaccine formulation. NE has achieved success as outstanding vehicle for delivery of APIs to various biological targetssuch as epithelial or mucosal surfaces. With the applications of clinically accepted ingredients and the attainment of injectable formulations such as vaccine adjuvants, the potential of NEs improve not only solubility but also bioavailability and pharmacokinetics of hydrophobic compounds. NEs have anoptimistic future in IV and injectable applications. Nanoemulsions have involvedmajor interest in past few decades for numerous applications due to their unique structures as well as properties. Now days Herbal medicines isgaining popularity as a traditional system of therapy in healthcare system all over the world. Herbal bioactives have become a wide area of research for investigating their several health benefits through application nanotechnology. Nanoemulsions have been used for administering and targeting the herbal bioactives and extracts. Nanoemulsion drug delivery systems successfully overcome the low bioavailability drawback associated with drugs and food components which are hydrophobic, and having high first pass metabolism. Nanoemulsion formulations show numerous advantages for the delivery of drugs, biological or diagnostic agents. They also protect labile drug, increase drug solubility, enhance bioavailability, controlled drug release as well as reduce patient variability.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 06.04.2022 Modified on 22.04.2022

Asian J. Pharm. Tech. 2022; 12(4):329-336.

DOI: 10.52711/2231-5713.2022.00053