Overview on Nanoemulsion as a recently developed approach in Drug Nanoformulation
Zainab H. Mahdi*, Nidhal K. Maraie
Department of Pharmaceutics, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq
*Corresponding Author E-mail: zhmpharm@yahoo.com, zhmpharm@uomustansiriyah.edu.iq
ABSTRACT:
A new fashion of medication conveyance framework has been industrialized to hinder main imperfections related to the conformist medication conveyance framework. This review gives an idea of covering the knowledge of modern nanoemulsion. Nanoemulsions are an emulsion of nanodroplet manufactured with low and/or high energy techniques to provide a drug in bestead mode. Nanoemulsions are isotropic thermodynamic stable system consist of two immiscible liquids form a monophasic system using emulsifying agents as surfactant and co-surfactant. These vary in the shape and size of the conventional emulsion droplets of the internal phase, since nanoemulsion has a droplet size range from 20 to 200 nm. This review provides constituent information covering its preparation method, formulation, parameters of evaluation, techniques of characterization and nanoemulsion applications.
KEYWORDS: Cosurfactants, Drug delivery, Emulsifiers, High/low energy techniques, Nanoemulsion.
INTRODUCTION:
Nanoemulsion is colloidal scatterings made of an oil stage, fluid stage, surfactant and co-surfactant at fitting proportions.
Dissimilar to coarse emulsions micronized with outer vitality, the nanoemulsion depends on low interfacial pressure which is accomplished by including a co-surfactant, which prompts unconstrained development of a thermodynamically steady nanoemulsion [3,4]. The main differences between emulsions and nanoemulsion saresummerized in table 1.
Table 1: Differences between emulsion and nanoemulsion
|
Emulsion |
Nanoemulsion |
Microemulsion |
|
Excellent kinetic stability. |
Kinetically unstable. |
They possess some kinetic stability |
|
Thermodynamically unstable and will eventually phase separate. |
Thermodynamically stable and no phase separation occur |
Thermodynamically stable |
|
Emulsions appear cloudy. |
Nanoemulsions are clear or translucent. |
Microemulsionis clear |
|
Methods involved in the preparation of emulsion require a large input of energy. |
Methods of preparation do not require energy input. |
Methods of preparation do not require energy input. |
On the basis of composition of nanoemulsion, there are three nanoemulsion categories can be prepared (a) oil in water nanoemulsions (o/w) where the internal droplets phase (oil) are dispersed in the external phase (water), (b) water in oil nanoemulsions (w/o) where the internal droplets phase (water) are spread in the external phase (oil) as shown in figure 1, and (c) Bi-nonstop nanoemulsions where oil and water microdomains are interdispersed within the system [5].
Fig. 1: O/W and W/O nanoemulsion droplets with diameter size range (20-200 nm) [5]
The nanoemulsion has a wide range of applications (Fig. 2), such as its application in transdermal, oral, parenteral, nasal, targeting, vaccine, pulmonary, ocular, otic and antimicrobial drug delivery systems. Other applications of NE including; cosmetic, disinfectant cleaner (non-toxic), gene delivery, phytopharmaceuticals and others [6,7].
Fig. 2: Biomedical application of nanoemulsion
Nanoemulsion Merits:
1. It gives greater absorption of a drug due to small droplets of nanoemulsion that have a greater surface area.
2. It is nonirritant and non-toxic in nature, if the non-ionic surfactant is used.
3. Lipophilic drugs can be solubilized by nanoemulsion.
4. Water insoluble drugs can be formulated as aqueous dosage forms.
5. It improves drug bioavailability.
6. It delivers the drug through different routes like topical, intranasal and oral. It can be applied in different formulations like foams, creams, liquids,and spray.
7. Quick and sufficient wetting, spreading and penetration of the drug moiety because of low o/w droplets interfacial tension and also the surface tension of all systems is low.
8. It is used in taste masking.
9. It protects drug in the oil phase in o/w nanoemulsion from hydrolysis and oxidation as is not displayed to air and water attack.
10. Both lipophilic and hydrophilic drugs can be loaded in the same nanoemulsion [1].
Nanoemulsion Demerits:
1. The emulsifiers (surfactant and co-surfactant) required to stabilize the internal droplets should be non-toxic.
2. It has restricted solubilizing tendency for substances of high-melting points.
3. The stability of nanoemulsion can be affected by environmental factors (e.g. pH and temperature).
4. Droplet size reduction of nanoemulsion requires special types of instruments and process methods [8].
Constituents of Nanoemulsion:
The major constituents of nanoemulsions are oily phase, emulsifiers (Smix) and aqueous phase (DDW). Oil phase like oleic acid, clove oil, lemon oil, cardamom oil, olive oil and triglycerides (LCT, MCT, SCT). The maximum solubility of a drug in the oil phase determines the oil required for preparing nanoemulsion. The mixture of water with oil produces a basic transient emulsion which will be isolated into two distinct phases upon standing due to droplet coalescence. Emulsifying agents were used in proper concentration to reduce interfacial tension surrounding droplets to stabilize the nanoemulsion [9]. Surfactants may be
(1) Non-ionic surfactants: Examples: Brij 35 (C12E35), sorbitanmonooleate (Span 80).
(2) Zwitterionic surfactants: Example: Phospholipids.
(3) Cationic surfactants: Example: Lecithin, 21 Quaternary ammonium alkyl salts.
(4) Anionic surfactants.
While, cosurfactants like capyrol 90, spans, capmul, transcutol, lauroglycol, propylene glycol, PEG, POE, propylene carbonate, Glycofurol, and so on., may break up a lot of hydrophilic surfactants or the hydrophobic medication into the lipid base. These solvents now and then assume the job of the cosurfactants in the nanoemulsion frameworks [10].
Construction of Phase Diagram:
Construction of the pseudo-ternary or triangular co-ordinate diagrams of water, emulsifiers, and oil are obtained at fixed emulsifier (surfactant: co-surfactant) mixture (Smix) weight ratios (Fig.3). Triangular diagrams are gained by placing nanoemulsion components in glass vials and subjected to water titration with well, stirring at 25º C (room temperature). Formation of the monophasic and biphasic system is proven by the visual investigation. The sample considered biphasic if the turbidity appears after phase separation.The samples considered monophasic if they are transparent, clear and marked as points in the phase diagram. The existent nanoemulsion area is considered under the area containing these points [11,12].
Fig.3: Hypothetical phase regions of nanoemulsion systems. Pseudo-ternary phase diagrams of emulsifiers (at constant weight ratios), water and oil mixtures.
Preparation of Nanoemulsion:
The drug is to be dissolved in the oil phase of the nanoemulsion and the surfactant and a cosurfactant are added after dissolving the drug then the water phases (deionized water) is included at a moderate rate with a slow mixing until the framework is straightforward. The measure of surfactant and cosurfactant to be included and the percent of oil stage that can be consolidated will be resolved with the assistance of the pseudoternary stage graph. Vitality can at last be connected so to accomplish the ideal size range for scattered globules or some other method. It is then being permitted to equilibrate [13].
Techniques for Preparation of Nanoemulsion:
High energy emulsification techniques:
1. High-pressure homogenization:
Piston homogenizer can be used to yield low droplet size nanoemulsions (up to 1 nm) [14].
2. Microfluidization:
Is a high-pressure mixing technique using microfluidizer to supply energy in which the drug forces through the interaction room producing nanosize droplets. The procedure is repeated several times to produce the desireddroplet size nanoemulsion [15].
3. Ultrasonication:
This technique is very reliable for minimizing nanoemulsion droplet size using a sonicator probe to provide energy. When the probe margin approaches, liquid medium, the cavitation and mechanical vibration are produced lead to the lessbubble’s creation. When the outside pressure (atmospheric)increases cause increases the flop pressure of the bubbles of the cavitation (i.e. Becomes more violent than when at atmospheric pressure) [14].
Low energy emulsification techniques:
1. Phase inversion method:
This technique used chemical energy to produce fine dispersion based on phase transition result from changes in the spontaneous curvature of surfactant and can be achieved by changing the emulsion composition and keeping the temperature constant or vice versa [14].
2. Spontaneous Emulsification:
This technique includes three major steps:
i Preparation of uniform andthe homogeneous organic solution contains a surfactant (hydrophilic and lipophilic) and oil in a non-aqueous solvent.
ii The organic solution was dispersed in the water at persistent stirrer until the formation of stable o/w emulsion.
iii Evaporation of the aqueous solvent by reducing the pressure [15].
3. Solvent Evaporation Technique:
It includes the preparation of drug solution, then emulsification of the drug solution in other liquid (non-solvent for the drug) using a high-speed stirrer to avoid crystal growth and particle aggregation. The drug precipitation can be achieved through solvent evaporation [16].
4. Hydrogel Technique:
The drug anti-solvent is miscible with the drug and solvent in contrary to the solvent evaporation technique [17].
Evaluation of Nanoemulsion:
An unfaltering nanoemulsion is depicted by the nonattendance of the internal state, nonappearance of creaming, nonattendance of deterioration by microorganisms, and upkeep of classiness in respect of attendance, shading, scent, and uniformity the various breakdown processes are illustrated in Fig 4. Henceforth the unsteadiness of emulsion can be delegated pursues [18]:
Creaming and flocculation:
Flocculation comprises the association of droplets to frame huge clusters or on the other hand floccules, which get up or drop in the emulsion more quickly than the individual globules. The climbing or sedimentation of dissipated droplets to create a concentrated sheet is identified as creaming. Thusly, creaming due to the flocculation.
Cracking:
The emulsion breaking insinuates a division of the scattered stage (as a layer). While a blended emulsion might be modified by unsettling or shaking, a broke emulsion can't be rectified. Splitting speaks to lasting precariousness. Emulsion splitting might be occurred because of:
(1) Expansion of an emulgent inverse nature,
(2) Emulgent disintegration or precipitation,
(3) Expansion of a typical dissolvable wherein mutually slick and fluid stages are miscible,
(4) Temperature limits,
(5) Creaming,
(6) Microorganisms.
Miscellaneous instability:
Temperature fluctuation or light sight may break down emulsions whenever put away. Consequently, emulsion is typically stuffed in hermetically sealed, hued compartments and put away at a reasonable temperature.
Phase inversion:
It is a physical procedure, including the adjustment in the ratio of emulsion phases from w/o to o/w and the other way around. Stage reversal might be achieved by differing the stage volume proportion, expansion of electrolytes, and temperature changes [19].
Figure 4 clearly demonstrates different processes of physical instability that might occur in nanoemulsions.
Fig.4: Schematic representation of the physical instability processes in the nanoemulsion
Visual Transparency:
Optical straightforwardness for nanoemulsion equation was resolved through optical angle the nanoemulsion recipe is straightforward and clear glass vials under a great light source and saw versus high contrast enlightened foundation [20]. The little bead estimate causes feeble light disperses (progressively straightforward). Moreover, the small droplet size and narrow size distribution contribute to the high kinetic stability of nanoemulsions against aggregation and gravitational separation by Brownian motion [21].
Droplet size, polydispersity index, and zeta potential measurement:
The estimation of the mean bead measure, zeta potential (ʓ - potential; drop surface charge) and polydispersity record (PdI; estimate scope of particles) utilizing dynamic light dispersing strategy (Zetasizer Nano ZS) in which the light dissipating variances were investigated because of the particle’s Brownian movement of nanoemulsion plans [22,23]. It precisely measures estimate in the scope of 0.3 nm to 10 μm.
The droplet size of the nanoemulsions is the net eventual outcome of the controlling system parameters as the kind of essential data and emulsification time other than dependence on centralization of dissipated stage and proportion of Smix.
As demonstrated by the Malvern Zetasizer Nano ZS course of action customer manual, the low estimation of polydispersity record 0.08-0.7 is appealing for uniform flow, high gauge and homogeneity of nano-sized dots inside the status. While PdI regard > 0.7 to under 1 is considered to have a far-reaching flow of globule gauge while PdI identical to 1 is considered so polydisperse and the precedent isn't suitable for estimation by Malvern zetasizer Nano [24,25].
Refractive Index:
The refractive list, (n), of a medium is characterized as the ratio f the speed, (C), of a wave, i.e. light or sound in a reference medium to the stage speed, (VP), of the wave in the medium. n=C/VP It was resolved to utilize an Abbes type refractometer (Nirmal International) at 25 ± 0.5°C [26].
Evaluation of pH:
The evident pH of the plan was estimated by pH meter.
Medication Content:
Medication content was dictated by the turn around stage HPLC strategy utilizing C18 section [27].
Conductivity Test:
The test was used to choose the possibility of the orchestrated nanoemulsion. If the outside ceaseless stage is watery, the nanoemulsions are o/w (very directing) however on the off chance that the inside dispersal stage is fluid, the nanoemulsions are w/o (not driving). Estimating of electrical conductivity (σ) was finished utilizing a conductometer by methods for laying the conductometer test erect in 10 ml of the prepared condition in an estimating glass at room temperature and the mechanical get together will enroll the results in "µs/cm" [28]. Likewise, Zetasizer Nano ZS can be utilized to peruse the conductivity.
Measurement of Transmittance Rate:
The test was connected to observe the transmittance of the readied nanoemulsions. This did by taking cuvette containing 2 ml of every nanoemulsion formula and read the absorbance at a light wavelength (650 nm) utilizing UV spectrophotometer and refined water as the clear. The rate of the transmittance was calculated from the following equation [29];
𝐴 = 2−log 10% 𝑇
Where;
An: absorbance %T: transmittance rate
Weakening Test:
The test was done to observe the physical dependability of nanoemulsions. The watery weakening test was completed by weakening 1 ml of every nanoemulsion recipe to (500, 100, and 50 ml) with refined water at 37º C with consistent mixing at low stirrer and watched outwardly for turbidity, lucidity, and stage partition [30,31]. On the off chance that the emulsion is o/w type, the expansion of progressively consistent stage won't cause splitting or division of that emulsion.
Centrifugation Test:
This test was utilized to observe the physical strength. The centrifugation of every nanoemulsion equation for 30 min (10,000 rpm) was connected to decide nanoemulsion opposition to partition [32,33]. This demonstrates the warm movement of the beads (Brownian movement) surpasses the outside powers, for example, attractive energy or centrifugation [19].
Determination of Nanoemulsion Morphology by (TEM):
The nanoemulsion recipe was additionally described by transmission electron magnifying instrument working at 30 KV. Where a drop of the weakened equation could store on the roundabout film of copper work colored with gold and cast aside to dry. The droplets size and shape were determined by watching the slide under the amplifying instrument [33].
Thermodynamic stability examines:
Amid the thermodynamic dependability of medication stacked nanoemulsions, the accompanying pressure tests can be connected:
1-Heating cooling cycle:
Nanoemulsion definitions were exposed to six cycles between cooler temperature (4° C) and 45° C. Stable plans were then exposed to centrifugation test.
2-Centrifugation:
Nanoemulsions were centrifuged at 3500 rpm,then those that did not demonstrate any stage partition was taken for the stop defrost pressure test.
3-Freeze-defrost cycle:
The plan was exposed to three stops defrost cycles between 21° C and +25°C which held under standard research center conditions. These tests were performed for a time of 3 months. Three bunches of plans were kept at a quickened temperature of 30° C, 40° C, 50° C and 60° Cat surrounding stickiness. The examples were pulled back at normal interims of 0, 1, 2 and 3 months and were investigated for medication content by soundness showing HPLC technique [34,35].
CONCLUSION:
Nanoemulsions offer a few focal points for the conveyance of medications and are hence accepting expanding consideration as medication bearers for enhancing the conveyance of dynamic pharmaceutical fixings. They are pertinent to practically all courses of conveyance and along these lines hold guarantees for various fields, like makeup, therapeutics or biotechnology. This innovation could be created to beat the poor ingestion of some phytopharmaceuticals and poor miscibility of these mixes with the lipid substance of cell layer linings.
ACKNOWLEDGMENTS:
The authors would like to express their gratitude Al-Mustansiriyah University/College of Pharmacy/ Baghdad/Iraq (www.uomustansiriyah.edu.iq (for presenting this work.
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Received on 21.04.2019 Modified on 25.05.2019
Accepted on 18.06.2019 © RJPT All right reserved
Research J. Pharm. and Tech. 2019; 12(11):5554-5560.
DOI: 10.5958/0974-360X.2019.00963.6