Nanoemulsions originally developed as microbiocidal materials by the Michigan Nanotechnology Institute for Medicine and Biological Sciences, also called as ultrafine emulsions (Ref 1) submicron emulsions (Ref 2) and mini emulsions (Ref 3) are non toxic, isotropic mixture of water and oil with mean droplet size less than 25% of wavelength of visible light. Unlike inhomogeneous microemulsions whose repulsive droplets cream at height 1m, the volume fraction of repulsive nanoemulsions remains homogenous for a longer time even when stored in tall containers. However, attractive droplets of nanoemulsion cream as microemulsion (Ref 4). Their entropic driving forces such as Brownian motion are sufficient to overcome de-stabilization due to Ostwald-ripening (Ref 5) and gravitationally driven creaming. They are made of surfactants that are Generally Recognized As Safe (GRAS) by FDA (Ref 6) and the ease of formulating them in various formulations make them ideal server for drug delivery.
Generally nanoemulsions are classified into three with its interface stabilized by surfactant and co-surfactant molecules: 1.droplets of oil dispersed in aqueous phase - oil/water nanoemulsions. 2. Droplets of water dispersed in oil phase - water/oil nanoemulsions and 3. Droplets of oil and water interdispersed - bi-continuous nanoemulsions (Ref 7). Unlike cloudy macro emulsions and white microemulsions that multiply scatter visible light unless the refractive index of continuous phase matches with the dispersed phase, nanoemulsions are optically clear with high free energy and scatter only less visible light in spite of difference in the refractive index (Ref 8), thus serving as a suitable element for optical studies. They utilize only less amount of surfactant however its integrity is maintained consistently for a longer period than for micro/macro emulsions. They have high kinetic stability, enhanced shelf life (Ref 9) and high absorption rate. Their enhanced pharmacological properties and high surface to volume ratio increases the drug penetration (Ref 9), bio-availability (Ref 10) and can be formed in bulk with less input of energy (Ref 7). It reduces the frequency and dosage of drug (Ref 7), thus increases patient compliance. They show resistance to enzymatic degradation and hydrolysis, hence stable. The lipophilic interior helps in encapsulating poorly soluble drugs much better than liposome (Ref 8). The small droplet size (Ref 11) allows for safe intravenous administration. Since they are non irritant, they can also be topically administered. Reduction in the Trans Epidermal Water Loss (TEWL) and increase in the skin penetration leading to optimized concentration of active substances in the targeted region adds to the advantage (Ref 12). In some cases, nanoemulsions may alter the drug permeability in skin which can be modified by permeation enhancers (isopropyl myristate, oleic acid, short chain alkanols) as one of the components of nanoemulsions that is capable of altering the structure of Stratum corneum. The nature of endothelium and presence of Blood Brain Barrier limits the transport of high molecular weight compounds to the brain. Drug loaded nanoemulsions in the olfactory region of nasal mucosa work out well here, thus diseases such as Parkinson disease, Alzheimer can be treated effectively. Risperidone loaded nanoemulsions via nose to brain are reported (Ref 13). Enhanced efficiency is seen when the formulation is given through nasal than intravenous route. Their activity against microbes such as bacteria, viruses (enveloped) and fungi can be utilized in making antimicrobial formulations where cationic nanoemulsions are electrostatically attracted towards anionic pathogen (Ref 14). The release of energy and active substances from the nanoemulsion causes cell death due to alteration in the cell membrane integrity of pathogen. Targeted drug release without damaging healthy ones supports the use of topical antimicrobial formulation. Their ability to deliver proteins, especially recombinant ones, on mucosal layers, is used to deliver vaccines (Ref 15). It adjuvant the proteins applied on the surface of mucosa thus uptake by Antigen Presenting cells is facilitated. This results in IgA and IgG production thus elucidating an immune response. Self Nano Emulsifying Drug Delivery System (SNEDDS) is an emerging technology that show higher transport rate of drug molecules and is proved to be an effective non-invasive delivery system for proteins (Ref 16). Several lyotropic liquid crystalline phases may appear like nanoemulsions but the difference being, the former form equilibrium structures comprising liquid and surfactant that thermodynamically self assemble but the later need an shear being externally applied to overcome surface tension necessary to break the larger droplets to smaller ones thus do not spontaneously form structures. The surfactant used for stabilization may be anionic (soaps, divalent ions), zwitterionic (phospholipids), cationic (amines and quaternary ammonium compounds) or non-ionic (fatty acids, fatty acid esters) (Ref 17). Their selection depends on critical packaging parameter (CPP) and hydrophilic-lipophilic balance (HLB). CPP relates the surfactant's aggregate forming ability to the geometry of the molecule (Ref 18). Generally, water in oil emulsions are formed by low HLB surfactants (HLB<7) whereas oil in water emulsions are formed by high HLB surfactants (HLB>7) (Ref 19). In cases where HLB crosses 20 and where single chain surfactants are unable to reduce the interfacial tension, co-surfactants such as medium chain alcohols are used that can reduce the HLB value and interfacial tension, thus increases the entropy of the system since the fluidity is increased. It provides flexibility in taking different curvature needed for formulating nanoemulsion in different composition. Though hydrogels are used widely for controlled release of drugs, their poor performance on lipophilic drugs limits their usage. Grafting hydrophobic units within the polymer matrix increases the solubility however the loading capability will be retarded. Crosslinked nanoemulsion serves as a better candidate for this purpose (Ref 20). This oil in pregel nanoemulsions has nano oil- droplets stabilized using a suitable surfactant and dispersed in an aqueous gel matrix having monomer and photo initiator. Induction of photo-polymerization results in chemically cross linked hydrogel in continuous phase. However, synthesis and controlling nanoemulsion is not as easy as micro emulsion because of their strong dependence on extreme shear to overcome surface tension which is necessary to break the droplets to nano size, usually exceeds the limit of commercially available mixing devices. Also their solubilising capability is limited when high melting materials is used for making emulsions. However, smartness of nanoemulsion with its remarkable potential in treating pathological conditions and targeted drug delivery dominate pros than its cons, thus help in meeting therapeutic needs of today's world much efficiently.
Preparation of Nanoemulsions
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Nanoemulsions can be prepared with both high energy and low energy method with the former makes use of intense dispersive forces with the aid of mechanical devices capable of disrupting the two phases to nanodroplets (Ref 21) that includes Ultrasonicator (Ref 22), High Pressure Homogenizer (Ref 23), High shear mixer (Ref 24) while the latter makes use of the properties of phase behavior that alters the hydrophilic-lipophilic balance of the system (Ref 25)which includes Phase Inversion Temperature (Ref 26) Self Emulsification (Ref 27) and Phase Transition method.
PREPARATION OF NANOEMULSION
LOW ENERGY METHOD
HIGH ENERGY METHOD
Eg: Self Emulsification, Phase Transition and Phase Invertion Temperature
Eg: Ultrasonicator, High Pressure Homogenizer, High shear mixer
By varying the temperature and composition
Makes use of mechanical devices to create intensely disruptive forces
High Energy Emulsification method
It works on the principle where a vibrating solid surface which may be a bath or a pointed tip that agitates the premixed emulsion at ultrasonic frequencies, typically 20 kHz or larger, and high power, causing extreme shear and cavitation resulting in the formation and collapse of vapor cavities leading to creation of high intense shock waves that flows throughout the solution which ultimately breaks up into extremely small sized droplets (Ref 22). Bath Ultrasonicator makes use of a transducer that converts high power electric energy into ultrasound and is passed through the base of a stainless steel container. Probe Ultrasonicator makes use of piezoelectric sonotrode made of quartz crystals that generate cavitation through mechanical vibration by expanding and contracting in response to voltage applied. Though highly protected electronic circuit aiding to safer aseptic operation, low equipment cost, non dependence of separate rotor-shear as high shear mixer, easy maintenance, treated liquid facing uniform exposure patterns resulting in no bypass of any part of the liquid from the cavitation area favors its usage, this method is not suitable for production in large batches. Since breaking an interface requires a large amount of energy, it is better to prepare coarse emulsion before applying acoustic power. Due to small product throughput, the ultrasound emulsification process is mainly applied in laboratories where emulsion droplet size as low as 0.2 micrometer can be obtained.
High Pressure Homogenizer
Here the fluid is allowed to pass through a minute opening in the homogenizing valve usually a needle seat valve made of zirconium or tungsten carbide or a ball seat valve wherein some cases nozzles are used instead of valves. The applied homogenizing pressure is controlled by the force exerted over the needle or the nozzle thereby creating high shear, acceleration, cavitation and impact causing particles to disperse and disintegrate leading to the formation of extremely small size droplets (~1 nm). The size of the particle depends on the instrumental design, applied pressure and behavioral properties of the fluid (Ref 23). However, with this method, oil in water nanoemulsion with oil phase less than 20% can only be made. Highly viscous solution or liquid with mean droplet size less than 200 nm cannot be prepared by this method. The rate of Ostwald ripening for nanoemulsions prepared by this method was found to be lower than ones prepared by Phase Inversion Temperature, a low energy emulsification method. Extreme heat generation leading to component detoriation, poor productivity and inability for production in large batches limits its usage commercially.
High Shear mixer
These are high performance industrial manufacturing mixers that disperses one phase to continuous phase which would be immiscible when mixed normally. It comprises an electrically driven rotor and a stator, the array of which are commonly called as generators. The velocity of the fluid at the tip of the rotor is greater than at the center thereby creating a velocity gradient resulting in shear. Stator creates an extremely high shear zone when the fluid flows from rotor to the nearby area, the stator at a relatively different velocity thus dispersing the fluid leading to the formation of ultrafine droplets (Ref 24). The particle size depends on the duration of exposure of the fluid in the mixer, diameter of the rotor, distance between rotor and stator, rotational sped of rotor and number of generators present.
Low energy emulsification method
Phase Inversion Temperature
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Here, small sized droplets are obtained by chemical reaction resulting in phase transition that alters the hydrophilic- lipophilic balance of the system. Either the temperature is altered at constant composition or the composition is altered at constant temperature. It is of two types - 1. Transitional Inversion obtained by alteration in the parameters that affect HLB and 2. Catastrophic Inversion obtained by altering the volume of dispersed phase. It was introduced by Shinoda et al based on alteration in the solubility kinetics of polyoxyethylene type surfactant with respect to changes in temperature. With the increase in temperature, the polymer chains dehydrate and the surfactant turns lipophilic. Here the surfactant, oil and water are mixed at room temperature and upon gradual heating, the polyethoxylated surfactant turns hydrophobic. As temperature increases, surfactant becomes completely solubilised in the oil phase and phase invertion from oil in water emulsion to water in oil emulsion occurs. The surfactant monolayer which initially had a positive curvature now will have a negative curvature. Since heating of components is involved, thermo labile drugs like peptides are difficult to incorporate without causing alteration in its stability behavior (Ref 26).
Self Assembling Nano Emulsification (SANE)
This interesting method is expected to meet the demands of present market because of its ability of generating nanoemulsions of extremely small size (~50 nm) without the aid of heat or organic solvent. This can be related to phase transition during emulsification process which involves addition of water into the solution mixture containing surfactant in oil maintained at constant temperature followed by gentle stirring (Ref 27). This involves formation of lamellar crystalline phases or bi-continuous D-type emulsions. However, they are not thermodynamically stable, though they have enhanced colloidal stability for prolonged period, good kinetic stability and high kinetic energy.
It makes use of centrifugal force to analyze the thermodynamic stability of formulations. Stable emulsions will not show any phase separation. Depending on the nature of oil, surfactant and the co-surfactant chosen, the rotation rate and time needed for centrifugation differs. In cases where drug is loaded into NEs, the formulation should be subjected to centrifugation before and after drug loading. Spherical droplets experience a buoyant force Fb = (4πa3/3)ρg where ρ is the mass density difference between continuous phase and dispersed phase, g being centrifuge aided gravity. Viscous drag force Fd = 6πηcav, v being velocity, opposes buoyant force at steady state conditions and v now becomes v = 2a^2ρg/ (9ηc). Small droplets thus takes larger time to cream than larger droplets since velocity is proportional to a^2. Formulations are then subjected to alternating cycles of refrigeration and room temperature conditions not less than a month and all characterization including pH, refractive index, viscosity and size distribution are analyzed during each storage condition. The results are compared by one-way analysis of variance (ANOVA) and Turkey-Krmer multiple comparison test for statistical analysis. An insignificant change in the parameters before and after storage confers physical stability of the emulsion formed.
Analysis of Critical Micellar Concentration (CMC) of surfactant
Surface tension analysis acts as an effective supplementary test for identifying CMC, especially when the desired surfactant is available only in small quantities. It is usually measured by a pre-programmed Tensiometer by Du Noüy ring method at atmospheric pressure with standard deviation not less than ±0.1 mN/m. Surface cleaning and flame drying of platinum ring is necessary for proper output
This is done to analyze the properties of nanoemulsion formed. Since Phase behavioral properties and viscosity are correlated with the interfacial tension, this analysis gains its importance. They are derived by measuring the shape of low density phase by rotating it with high density phase in a cylindrical tube. Surfactant and co-surfactant plays key role in fixing the interfacial tension of formulated emulsions. Interfacial tension between the oil and aqueous phases increases with the decrease in the ratio of surfactant and co-surfactant leading to increased viscosity. Especially when NEs are formulated for drug delivery, low interfacial tension is always preferred. Minimal interfacial tension is achieved when NEs near the temperature of HLB upon formulation using low energy emulsification method. Oil-in-water NEs possess low viscosity than Water-in-oil NEs, thus low interfacial tension favored. Ultra low interfacial tension can be measured using Spinning-Drop apparatus.
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Viscosity of NE formulated at various concentrations is determined at different temperatures and rotations using Brookfield Rotary Viscometer since viscosity plays a key role in stability and drug release kinetics. For this, 37 ± 0.2°C should be maintained by a thermo bath in the spindle area before loading the sample. The spindle type to be used depends on whether the sample is aqueous based (W/O NEs) or oil based (O/W NEs). Usually 0-spindle is used for low viscous formulations. Viscosity decreases with the increase in the concentration of surfactant and decrease in particle size. However, extremely viscous formulations will not retain its stability for prolonged intervals of time.
Particle size analysis
The droplet size and the distribution kinetics of NE formulations can be analyzed by Dynamic Light Scattering (DLS) using Zetasiser at 25°C which works on the principle of Brownian motion. For this, samples are diluted to avoid multiple scattering and are stirred gently for sometime to promote homogeneity prior to analysis. The NE formulations are expected to have size less than 100 nm for uniform drug release kinetics with Poly Dispersity Index (PDI), a measure of homogeneity less than 0.3 for uniform size distribution. Depending on the type of formulation, the type of laser to be used and diffraction angle changes. Further processing of data is done using computer aided software in-built with the instrument. The particle size can also be determined using Laser Diffraction method which depends on volume and is expressed as the volume of spheres formed DN% and average of volume distribution. The Polydispersity is defined by the symmetry of distribution about the median (uniformity) and the width of distribution (span). Narrow size distribution is achieved for smaller span.
Electrical conductivity measurement
It helps to determine the type of NE formed and for analysis of phase behavioral properties. Oil-in-water emulsions highly conduct than water-in-oil ones because of the presence of aqueous exterior. Studies are reported for increase in electrical conductivity at low volume fraction in certain water-in-oil NEs also. Such approach is considered as 'percolative behavior' or ion-exchange between droplets before bi-continuous structure formation.
pH and refractive index
Since human body maintains an acidic pH, the formulated nanoemulsions are expected to have pH<7 when it is made to be employed inside the body. This can be determined using pH meter at room temperature. The refractive index can be measured using Abbes type Refractometer.
SEM and TEM
In order to analyze the structure and morphology at different magnifications, nanoemulsions are subjected to SEM where three dimensional image of the surface morphology of dispersed phase is obtained and TEM to have in-depth analysis at higher resolution. The accelerating voltage depends on the type of sample used. SEM is usually performed at 20 kV whereas TEM is done at 80 kV. Automatic analysis of surface morphology and structure can also be made through Image Analysis Software (e.g., Leica Imaging systems, Cambridge, UK). Computer aided Image Processing software is used to measure the size distribution of TEM micrographs qualitatively.
Ternary- and Pseudo ternary Phase Diagram
Construction is done by varying the ratio of oil and surfactants on a three axis scale with one axis representing the volume of oil, other representing the volume of surfactant and co-surfactant while the third axis represents the aqueous phase (Ref 28). Nanoemulsion region in absence of co-surfactant is determined by the construction of Ternary Phase Diagram. Presence of co-surfactant follows Pseudo Ternary Phase Diagram.
Concentration of drug
Drug is added in excess to small amount of oil, surfactant and co-surfactant which are then mixed in an isothermal shaker. After centrifugation, filter the supernatant using a membrane filter usually of 0.45 μm thickness and are then analyzed using UV spectrophotometer or HPLC at their respective wavelength to determine the drug concentration in each of the three components (oil, surfactant and co-surfactant) at different time intervals. Samples at zero time act as control. To check for the interference of excipients, run the HPLC system separately with pure oil, surfactant and co-surfactant. Construct Arrhenius plot at different temperature between 1/T and log K where K is the degradation rate constant, for graphical analysis of degradation kinetics of drug and shelf life of nanoemulsion. Shelf life (T0.9) of the optimized formulation is determined using the formula
T0.9 = 0.1052 / K
Parameters that affect the stability, structure and morphology of nanoemulsions
Nature of surfactant
Non- ionic surfactants are usually preferred because of its inability to form insoluble salts with calcium, magnesium and ferric ions which forms the component of hard water, non-ionisability thereby avoiding unwanted interactions with ions present in solution, solubility in water and organic solvent and low acute toxicity, thus serves as an ideal candidate in pharmaceutical industry. Increase in the concentration of surfactant increases the stability of formulation. This is due to the hydration layer formation on the surface of hydrophobic tail of the surfactant thereby increases the repulsive forces between particles preventing flocculation and coalescence.
Nature of oil
Not all oils form emulsion. Compatibility between oil and surfactant is necessary for stable emulsion formation which can be determined by varying the surfactant for a particular oil type and analyzing the thermodynamic and physical stability by centrifugation and storage conditions respectively. Increase in the concentration of oil increases the viscosity which in turn affects the stability of the emulsion.
Amount of energy supplied, environmental conditions, presence of microbial contaminants, surface charge, extent of emulsification, mixing ratio of surfactant (Ref 29), order of components (oil, surfactant and co-surfactant) addition, duration of exposure, type of emulsion formed (Ref 30) etc alter the size, stability and texture of nanoemulsion. Formation of small droplets needs supply of high energy. Surface charges of oil should possess enough columbic attraction with the charges of the surfactant to avoid phase separation and confer stability.
Applications of nanoemulsion
COMMERCIAL APPLICATIONS OF NANOEMULSION
Cationic nanoemulsion fuse with anionic charge of pathogens and after sufficient electrostatic attraction between the charges, energy and the active substance trapped inside emulsion is released that alters the lipid bilayer architecture of pathogen resulting in membrane rupture and cell death. Nanoemulsion made of soybean oil showed extensive 1.bactericidal activity against gram positive ones, 2.fungistatic and 3. Antiviral activity for enveloped viruses (Ref 14). Application for human welfare is under progress. Upon emulsification of soybean oil nanoemulsion using tri-n-butyl phosphate and Triton X -100, reduction in the survival rate of Salmonella typhimuriun, Pseudomonas aeruginosa, Staphylococcus aureus and E.coli upto 70% in a minute with zero surveillance rate after 15 minutes of incubation was evidenced. However, undiluted form is relatively toxic than diluted formulations. Nanoemulsions as decontaminating agent against anthrax, Clostridium botulism and ebola was successfully tested by US army in 1999 thus helps in protecting people from bioterrorism. They are proven to be successful on treating gangrene also. The ease of preparing them in various formulations adds to the advantage. Primaquine, an antimalarial drug against Plasmodium vivax and Plasmodium ovale causes tissue related toxicity to gastro intestinal tract at higher doses. When encapsulated into a nanoemulsion, it not only increased the bioavailability but also decreases the plasmodium levels dramatically (Ref 31).
Since particle size of nanoemulsion is very much smaller than the pore size of gravel and rocks, nanoemulsions can be used to recover oil from them which is comparatively difficult for a micro/macro emulsion to perform the same phenomena (Ref 32).The efficiency of oil-in-water NEs in performing Enhance Oil Recovery (EOR) has been reported where Several flooding experiments have been performed to check for the efficacy of nanoemulsion formed form mineral oil and non ionic surfactants (Ref 33, 34). Additional recovery by calculating the material balance is also found to be enhanced for nanoemulsion than for pure oil. Use of nanoemulsion in EOR has opened a new field where enhanced output comes with less input of energy leading to no wastage of time and resources.
Cationic nanoemulsions seemed to solve problems related to dry hair after shampooing for several times. Treated hair found to be non-greasy, shinier with less split ends (Ref 35). Nanoemulsion based body lotions provide more freshness and better skin hydration than commercial body lotions (Ref 24, 36). Reduction in Trans Epidermal Water Loss (TEWL) helps them in serving as an ideal candidate for production of various sun care products, anti-aging and anti-wrinkle creams (Ref 12). The effect of stratum corneum and charges in nanoemulsions on skin properties is investigated (Ref 37). Nanoemulsions containing stratum corneum lipids (NSC), positively (PNSC) and negatively (NNSC) charged along with positively charged nanoemulsions without stratum corneum (PN) are prepared by high energy emulsification method (high pressure homogenizer) using myristic acid and phytosphingosine (PS) as co-surfactants. Carbopol940 is used as thickening agent. Elasticity and humidity of skin are measured for all formulations and it was found that increase in the above measurements was observed with PNSC than NNSC and PN. This indicates the importance of stratum corneum lipids in enhancing the barrier function of skin and positive charge in increasing the efficacy. Topical administration of Dapsone loaded nanoemulsions comprising n-methyl pyrrolidone and isopropyl myristate as oil phase is reported (Ref 38). Higher drug solubility and enhanced nanoemulsion region was seen more for n-methyl pyrrolidone than isopropyl myristate. However, increased epidermal permeation was seen for isopropyl myristate. It followed higuchi model. Both formulations showed good skin permeability and physicochemical stability than pure dapsone. Isopropyl myristate based formulation is used for acne treatment while n-methyl-pyrrolidone based nanoemulsion is used for treating leprosy.
Several drug loaded vehicles show low skin permeation leading to poor efficiency despite their high potency in treating a particular condition. Though substances like permeation enhancers sufficiently overcome this issue, the associated side effects like toxicity, skin irritation limits its use. Nanoemulsions depending on whether the exterior phase is aqueous or oil, they can load both lipophilic and hydrophilic drug. Their small size aids in better permeation, retarded unwanted interactions with the non-targeted region and enhanced efficiency. Lecithin nanoemulsion (LNE) constituting snake oil, glycerol, soybean lecithin and water, formulated by High Energy Emulsification method seemed to have high skin hydration and skin penetration which is confirmed by measuring the dynamic friction co-efficient of skin (Ref 39) Topical administration of EMLA (Eutectic Mixtures of Local Anesthetic), a commercially available nanoemulsion made of prilocaine and lidocaine, found to be a proven sedative for children.
Topical administration of potent anticancer lipid soluble drug Dacarbazine formulated as nanoemulsion with droplet size 131nm showing enhanced reduction in tumor size and growth than micro/macro emulsions on xenograft mouse model is reported (Ref 40). 5 Amino-Levulinic-Acid (ALA), a photosensitizer is formulated as both Oil-in-Water and Water-in-Oil nanoemulsion by High Energy Emulsification method with size less than 260 nm. They showed high drug loading and skin permeation than commercial aqueous ALA formulations with Oil-in-Water predominating than Water-in-Oil ones (Ref 41). Gadolinium loaded nanoemulsion made using soybean oil having HCO-60 and Brij 700 as co-surfactant was intravenously administered to hamsters bearing melanoma for analyzing the effect of neutron capture therapy is reported (Ref 42). It not only increased the concentration of gadolinium in the tumor region but also reduces its accumulation in liver thus surpassing hepatic clearance. Camptothecin, a topoisomerase I inhibitor is encapsulated to nanoemulsions made of coconut oil, perflourocarbons using Phospholipids and Pleuronic F68 as stabilizing agents with particle size 420nm and its cytotoxicity effect is compared with plain Camptothecin which has poor stability, solubility and acute toxicity in ovarian cancer cell lines (Ref 43) Enhanced cell uptake (confirmed by Confocal Laser Scanning Microscopy) with more cytoxicity against cancer cell lines is evidenced. Highly retarded drug release is seen in absence of Ultrasound but controlled and targeted drug release is achieved when Ultrasound is applied. Emulsion made of cremophor oil is found to be more efficient in delivering the photosensitizer at higher concentration in the targeted region than Di-palmityl-Phosphotidyl-choline liposome (Ref 44).
Oil-in-water curcumin nanoemulsions with mean particle size less than 100 nm made by high pressure homogenizer inhibiting the 12-O-tetradecanoylphorbol-13-acetate induced edema in ear of mouse than ones made by high speed homogenizer has been reported (Ref 45). Three different tocopherol isomer (alpha, delta and gamma) containing Anti oxidant Synergy Formulation (ASF) based nanoemulsions are prepared and its efficacy on CD-1 mice induced with auricular inflammation on ear lobe by applying croton oil is analyzed. It was found that Gamma tocopherol containing ASF nanoemulsions not only showed increased bio-availability but also reduction in the levels of TNF- alpha and IL-1 alpha which significantly reduces the auricular inflammation than other formulations (Ref 46). Topical administration of Ibuprofen, a novel NSAID is used to treat Rheumatoid Arthritis (RA). However, its low skin permeability limits its usage. Ibuprofen loaded to Ethoxylated castor oil nanoemulsion is prepared by both traditional and novel method where the former makes use of PEG400 as co-surfactant, 1:1 ratio of span20 and tween80 as surfactant while the latter uses surfactant as L.A.S and labrasol as co-surfactant with its potency on skin permeability analyzed using male wistar rats is reported (Ref 47). Smaller particle size with enhanced skin permeation is seen with both drug loaded nanoemulsions than plain drug with novel NE predominates the ones prepared by traditional method in smaller particle size, effective skin permeability and enhanced nanoemulsion region. Topical administration of nanoemulsion loaded with radio labeled diclofenac showed improved skin permeation properties with retarded skin irritation and allergic reactions thus improving patient's compliance is reported (Ref 48).Their concentration show several folds decrease in plasma, 60 folds increase in muscles and 9 fold increase in joints.
Conclusion and Future perspective
Nanoemulsion serves to be a promising tool and an eye-opener in various fields which includes pharmaceutical, healthcare, food industry etc. Their enhanced physicochemical properties and behavioral kinetics overcome the cons associated with commercially available micro/macro emulsion formulations. Basic researches have to be carried out to take lead to the next level of using many nanoemulsion formulations to meet human needs of today's world in all possible ways.