INTRODUCTION:

The emulsion is a dispersed system consisting of small droplets well distributed in a vehicle that is immiscible. Macroemulsion (droplet of 1 to 100 μm of diameter) is also known as the conventional emulsion/colloid, the types of emulsions that classified according to their droplets. It is usually unstable with water droplets or floats with virtually the dispersing phase and medium phase, volatile with the absorption of solid particles on the surface [1]. Whereas microemulsion (droplet between 10-100nm) is an isotropic liquid system with more uniform size and excellent physicochemical properties and more stable nanoemulsion (droplet diameter 20-200nm).

Nanoemulgel is known as the formation of hydrogel based on nanoemulsion by adding the integrated nanoemulsion system to the hydrogel matrix, which influences a better penetration of the skin.

Nanoemulsion:

For most medicines, the nanoemulsion method is an ideal drug delivery to optimize effectiveness while reducing toxicity. Researchers have excogitated the simple delivery of drugs in advancing research into eminently refined novel dosage forms.

Nanoemulsion system consists of combining nano ranges of two immiscible liquids (water and oil) to form a homogeneous solution by adding appropriate surfactants/cosurfactants with an acceptable HLB value. This stable, thermodynamic system ranges from 10-100 nm. Figure 1 describes the various compartments of a nanoemulsion that has been stabilized. Nanoemulsion is a promising option for enhancing the penetration of the drug delivery system and targeting poorly soluble drugs by increasing their absorption through the skin, improving drug processing time in the target area and eventually leading to less side effect [2]. The effects of nanoemulsion with globules in an emulsion's nano-scale size do not transmit on the physical properties of the emulsion itself. yet, the bioavailability of therapeutic drugs as a whole was encountered. Research on the bioavailability of lacidipine via transdermal route has been 3.5 times higher than that of an oral course which was thought to be due to the avoidance of the first-pass metabolism.

Also, Nanoemulsion improves drug permeation across the skin, which interacts with researchers' interests. Moreover, the small size of particles, the more medication can be introduced into the mixture, which then enhances the thermodynamics towards the skin. The drug-affinity for partitioning enhances skin permeation.

One of the studies consequently narrates the implications of Nile red (NR) dye loaded in lecithin nanoemulsion was able to penetrate the skin 9.9-fold higher than the NR-loaded general emulsion. Besides that, ingredients used in the formulation consisting of ethyl oleate and propylene glycol, also act as permeation enhancers.

The greatest obstacle upon transdermal drug delivery refers to barrier properties of the stratum corneum a 10 µm to 20µm thick tissue layer with a great composed, structured lipid/protein matrix. A recent study, of topical delivery lipophilic flurbiprofen in nanoemulsion proves an increase in bioavailability by 4.4 times compared to oral administration [3]. Hence, the nanoemulsion as a spontaneous emulsifying method which provides numerous advantages over another carrier such as polymeric nanoparticle and liposomes, including low-cost preparation procedure, high hydrophilic and lipophilic drug loading system to enhance the longer shelf lives upon preserving the therapeutic agents.

Nanoemulgel:

Nanoemulgel, which known as the formation of nanoemulsion based on hydrogel is the addition of the nanoemulsion system intergraded into the hydrogel matrix which influences better skin penetration. This mixture of nanomulgel has attracted the attention of many scientists for the development of numerous drugs that function to treat various kinds of skin disorders.

Emulgel is not a new type of formulation and is already present in the market, as shown in Table 1. On the other hand, Table 2 shows the example of nanoemulgel or microemulgel formulations that have been prepared before.

The formulation of nanoemulgel for the topical delivery system acts as drug reservoirs which, influence the release of drugs from the inner stage to the outer phase and then further onto the skin. These release mechanisms depend on the composition of the network polymer chains and the crosslink density [4]. Besides that, the ability of a drug to permeate the skin and successfully release of the therapeutic agent is influenced by drug affinity to diffuse out from the vehicle and permeate through the barrier.

Nanoemulgel on intact with skin will release the oil droplets from the gel network. The oil droplets then will penetrate the stratum corneum of the skin and directly deliver the drug molecules without a transfer via the hydrophilic phase of nanoemulsions.

Figure 1: Diagram of Stabilized Nanoemulsion.

Advantages of nanoemulgels:

The nanoemulgel offers various advantages over other investigated topical formulations which are:

• Avoid first pass metabolism.

• Easy acceptable for the patient

• Suitably for self-medication.

• Provide local drug delivery.

• Easy termination of medication [5].

• Easily acceptable for the skin environment.

• Proven efficacy for a controlled and sustained drug delivery system.

METHODOLOGY:

A high-pressure homogenization method was used for the formulation of nanoemulgel. There are three steps involved in the formulation of nanoemulgel, which are given fallows.

1. Preparation of Nanoemulsion,

2. Preparation of hydrogel and

3. Finally, nanoemulgel will be produced by the incorporation of Nanoemulsion into the gel with continuous stirring [6].

The production process of nanoemulgel is diagrammatically presented in Fig.2.

Fig.2: Steps of Formulation of Nanoemulgel.

Components of Nanoemulsion:

The main components of Nanoemulsion are as follows:

Oil:

The selection of the oil phase is the most crucial parameter to obtain a stabilized Nanoemulsion so that the maximum amount of drug could solubilize it. Usually, the oil which has maximum solubilizing potential for a selected drug candidate is selected as an oily phase for the formulation of nanoemulsions. This helps to achieve maximum drug loading in the Nanoemulsions. A mixture of oils can also be used to soubise the maximum amount of drug. The different oils used for the nanoemulsion formulation were enlisted in (Table 3).

Table 3: List of oils used in nanoemulsion.

Oils	Botanical Names
Arachis oil (Peanut oil)	Arachis hypogaea
Brahmi oil	Baopa monnieri
Clove oil	Syzygium aromaticum
Linseed oil (Flax seed oil)	Linum usitatissimum
Eucalpytus oil	Eucalyptus globules
Jojoba oil	Buxus chinensis
Peppermint oil	Mentha piperita
Neem oil	Azadirachta oil
Tea tree oil	Melaleuca alternifolia

Surfactant:

Surfactants are vital components used for stabilizing the nanoemulsion system. The anionic, cationic, and nonionic types of surfactants were used in this system [7]. Due to their different chemical nature, proper selection of surfactants (Table 4) becomes a crucial factor in obtaining a stabilized delivery system. For the formation of a stable nanoemulsion, surfactants having decent HLB value are required.

Cosurfactant:

Cosurfactant plays an essential role in reducing the polarity of surfactant to obtain a stabilized nanoemulsion [8]. There are varieties of cosurfactants (Table 5), which acts on surfactant interface, such as short- to medium chain length alcohols (C3-C8). These are also helpful in increasing the penetrability of oil to get a stabilized formulation.

Gelling agents (hydrogels):

The unique physical properties of hydrogels have reflected a particular interest in drug delivery applications. These are the semisolid system with three–a dimensional, cross-linked network of organic and inorganic molecules and inhibition by liquid due to high porosity.

Due to rapid researches in nanotechnology, there is a sudden change that welcomes the new nanogel systems [9]. Table 4 has proven its potential to deliver drugs in a controlled, sustained and targetable manner. They have high drug loading capacity, biocompatibility, and biodegradability, which are the key points to design an effective drug delivery system. (Table 6).

Table 4: List of surfactants used in Nanoemulsion.

Surfactants	Chemical Names
Kolliphor RH 40	Macrogolglycerol hydroxystearate
Ursolic acid	3β-Hydroxy-12-ursen-28-ic acid
Labrafil M 1944 CS	Oleoyl polyoxylglycerides
Lauroglycol FCC	Propylene glycol monolaurate
PEG MW>4000	Carbowax, polyglycol
Plurol Oleique CC 497	Polyglyceryl-3 dioleate
Poloxamer 188	Poly(ethyleneglycol)-block-poly (propylene glycol)- block-poly (ethylene glycol)

Table 5: List of co-surfactants used in nanoemulsion.

Cosurfactants	Molecular Formula	Molecular weight
Transcutol P	C₆H₁₄O₃	134.175 g/mol
Glycerol	C₃H₈O₃	92.09382 g/mol
Propylene glycol	C₃H₈O₂	76.095 g/mol
Ethanol	C₂H₆O	46.068 g/mol
Propanol	C₃H₈O	60.095 g/mol

Table 6: Examples of gelling agents

Name of the gelling agent	Molecular formula	Molecular weight (g/mol)
Poloxamer	C₅H₁₀O₂	102.133
Polyacrylamide	C₃H₅NO	71.077
Hydrin rubber, neoprene	C₄H₅Cl	88.534
HPMC 55	C₃H₇O	59.087
Carbomer 934	C₃H₄O₂	3,000,000

Preparation of nanoemulgel formulation:

Nanoemulsion based gels were prepared by the incorporation of 1g of gelling agent in a sufficient quantity of distilled water.

This gelling agent solution is a place under dark conditions for 25 hours until the complete swelling system obtained.

Then the drug-loaded nanoemulsion is slowly added to the viscous solution of a gelling agent under magnetic stirring.

Aqueous phase:

The nature of aqueous phase mainly influenced the droplet size and the stability of nanoemulsion [10]. The physiological milieu has diverse pH ranges varying from pH 1.2 (pH in the stomach) to 7.4 and greater (pH of blood and intestine). Also, the presence of various ions in the physiological milieu can have a considerable effect on the properties of nanoemulsions.

Methods for preparing stabilized nanoemulsions:

To get clear and stabilized nanoemulsion formulations, proper fabrication procedures should be adopted [11]. The techniques are mandatory in reducing the droplet size to the nanoscale.

Homogenization using high pressure:

For the preparation of stabilized nanoemulsion with particle size 1 nm, the high-pressure homogenizer piston is used by applying several forces, such as cavitation, etc. This process will continue until a desired nanosize formulation was obtained.

Microfluidization:

Microfluidization of the prepared formulation is done by the use of a device known as microfluidizer. The use of high pressure forces the product into microchannels to get a submicron range particle. The process was repeated until a stabilized nanoemulsion was obtained.

Ultrasonication:

In the case of ultrasonication technique, ultrasonic vibrations are used to obtain stabilized nanoemulsion with reduced particle size [12]. In this, cavitation is the preferred mechanism for obtaining desired nanosized formulation.

Phase inversion method:

A stabilized nanoemulsion is obtained using the phase inversion method which, with the aid of the emulsification process, endorses chemical energy for phase transition under constant temperature.

CHARACTERIZATION:

APPEARANCE:

The prepared nanoemulgel formulations were inspected visually for their color, homogeneity, consistency, and pH. The pH values of 1% aqueous solutions of the prepared Gellified Emulsion is measured by a pH meter (Digital pH meter DPH 115 pm).

SPREADABILITY:

Spreadability is determined by the apparatus suggested by Mutimer et al (1956) which is suitably modified in the laboratory and used for the study [13]. It consists of a wooden block, which is provided by a pulley at one end. By this method, spreadability is measured. An excess of nanoemulgel (about 2 gm) under study was placed on this ground slide. The nanoemulgel is sandwiched between this slide and another glass slide having the dimension of the fixed ground slide and provided with the hook. A 1 Kg weight is placed on the top of the two slides for 5 minutes to expel air and to provide a uniform film of the nanoemulgel between the slides. The excess of the nanoemulgel is scrapped off from the edges. The top plate is then subjected to a pull of 80 grams. With the help of string attached to the hook and the time (in seconds) required by the top slide to cover a distance of 7.5 cm is noted. A shorter interval indicates better Spreadability. Spreadability is calculated by using the formula,

S= M.L/T

Where,

S = spreadability,

M = Weight tied to upper slide,

L = Length of glass slides

T = Time taken to separate the slides from each.

RHEOLOGICAL STUDIES:

The measurement of viscosity of the prepared jellified nanoemulsion formulations was done with Brookfield viscometer (Brookfield DV-E viscometer). The jellified nanoemulsion was rotated at 10 (min.) and 100 (max.) rotations per minute with spindle 6. At each speed, the corresponding dial reading was noted16. The viscosity of the formulation was determined.

DRUG CONTENT DETERMINATION:

The drug content in nanoemulgel was measured by a UV spectrophotometer. Ketoconazole content in nanoemulgel was measured by dissolving the Known quantity of nanoemulgel insolvent (methanol) by Sonication. Absorbance is measured after suitable dilution at 226 nm in the UV/VIS spectrophotometer (UV-1700 CE, Shimadzu Corporation Japan). The Drug content of the formulations was determined.

IN- VITRO RELEASE STUDY:

Franz diffusion cell (with effective diffusion area 3.14 cm2 and 15.5 ml cell volume) was used for the drug release studies [14]. Nanoemulgel (200 mg) was applied onto the surface of the egg membrane evenly. The egg membrane is clamped between the donor and the receptor chamber of the diffusion cell. The receptor chamber was filled with freshly prepared PBS (pH 5.5) solution to solubilize the drug. The receptor chamber was stirred by a magnetic stirrer. The samples (1.0 ml aliquots) were collected at a suitable time interval. Samples were analyzed for drug content by UV visible spectrophotometer at 226 nm after appropriate dilutions. Cumulative corrections are made to obtain the total amount of drug release at each time interval. The aggregate amount of drug released across the egg membrane is determined as a function of time.

GLOBULE SIZE AND ITS DISTRIBUTION IN NANOEMULGEL:

Globule size and distribution were determined by Malvern zeta sizer. A 1.0 gm sample was dissolved in purified water and agitated to get homogeneous dispersion. The sample was injected into a photocell of zeta sizer. Mean globule diameter and distribution were obtained.

SCANNING ELECTRON MICROSCOPY:

The morphology of nanoemulsion can be determined by scanning electron microscopy (SEM). SEM gives a three-dimensional image of the globules [15,16]. The samples are examined at suitable accelerating voltage, usually 20 kV, at different magnifications. The functional analysis of surface morphology of the disperse phase in the formulation is obtained through SEM. Image analysis software may be employed to get an automatic analysis result of the shape and surface morphology.

STABILITY STUDIES:

The prepared nanoemulgel formulations were stored away from light in a collapsible tube at 25±2°C, 40±2°C and 4±2°C for three months. After storage, the samples were tested for their physical appearance, pH, rheological behavior, drug release.

EXTRUDABILITY STUDIES (tube test):

This test was used to measure the force required to extrude the material from the tube. The evaluation of extrudability was based upon the quantity of nanoemulgel extruded from the lacquered aluminum collapsible tube on the application of weight in grams required to eject at least 0.5cm ribbon of nanoemulgel in 10 seconds [17]. The better extrudability is depended upon the quantity ejected. The extrudability is than calculated by using the following formula.

Extrudability=Applied weight to extrude nanoemulgel from the tube (in g)/Area (in cm2).

SKIN IRRITATION TEST (Patch test):

The preparation is applied to the properly shaven skin of rat, and undesirable changes in color, change in skin morphology should be checked up to 24 hours. If no irritation occurs, the test is passed.

pH DETERMINATION:

The pH of the prepared formulations is determined by pH using the meter. In this, the formulations are placed in a 250 ml beaker and immersing the pH meter into the formulation and record the readings [18]. The same process was repeated three times with the same wording.

DRUG RELEASE KINETIC STUDY:

To analyze the mechanism of drug release from the topical nanoemulgel, the release date is fitted to the following equations:

Zero-order equation:

Q=K0t

Where Q is the amount of drug released at time t, and K0 is the zero-order release rate.

First-order equation:

In (100-Q) =In 100 – K1t

Where Q is the percentage of drug release at time t, and K1 is the first-order release rate constant.

Higuchi's equation:

Q=K2√t

Where Q is the percentage of drug release at time t, and K2 is the diffusion rate constant.

ACCELERATED STABILITY STUDIES OF GELLIFIED NANOEMULSION:

Stability studies were performed according to ICH guidelines. The formulations were stored in a hot air oven at 37±2°, 45±2° and 60±2° for 3 months [19]. The samples are analyzed for drug content every two weeks by UV‐Visible spectrophotometer. A stability study was carried out by measuring the change in pH of the formulation at a regular interval of time.

CONCLUSION:

Nanoemulsions are non-equilibrium, optically transparent thermodynamically stable, metastable dispersion of nano-sized particles having established surface tension produced by certain shears, consisting of an appropriate oil and a definite mixture of surfactants and co-surfactants and having the capacity to dissolve large quantities of hydrophobic drugs. The nanoemulsion mechanism can be accomplished by means of homogenizers, low energy emulsification and methods for the inversion of phase temperatures. On top of that, there are so many controversies concerning the appropriate method of nanoemulsion preparation and it was later proved that nanoemulsions can be formulated by low-energy emulsification process along with high shear homogenizer method. Nanoemulgel is also known as Hydrogel-Thickened Nanoemulsion (HTN), as the system shows an increase in viscosity compared to the nanoemulsion system. A stable formulation of nanoemulsion is enhanced by nanoemulgel, by decreasing surface and interfacial tension leading to increased viscosity of the aqueous phase.

REFERENCES:

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18. Bhattacharya S, Prajapati BG. Formulation and Optimization of Celecoxib Nanoemulgel. Asian Journal of Pharmaceutical and Clinical Research. 2017; 10(8):355-356.

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Received on 14.03.2020 Modified on 10.04.2020

Res. J. Pharma. Dosage Forms and Tech.2020; 12(2): 125-130.

DOI: 10.5958/0975-4377.2020.00022.1

Voltaren Emulgel^©	Novartis Consumer Health	Active ingredient: 100 g Diclofenac diethylamine corresponding to 1g diclofena sodium, propylene glycol. Base: Fatty emulsion in an aqueous gel to which isopropanol and propylene glycol have been added.
Reumadep Emulgel^©	ErbozetaEnergia Verde	Arnica, Ashwagandha, Myrrh, Ginger, Rosemary, Cloves, Mint.
Emulgel Levorag Monodose^©	THD LAB Farmaceutici
Meloxic Emulgel^©	Provet	Meloxicam
Benzolait AzEmulgel^©	Rordermal	Benzoylperossido 10%
Coolnac Gel Emulgel 1 %^©	Chumchon	Diclofenac Diethylammonium

Author	Year	Formulation
Huabinget al.	2007	Micro emulsion-based hydrogel formulation of ibuprofen.
Mouet al.	2008	Hydrogel-thickened Nano an emulsion system (HTN) of a mixture of camphor, menthol and methyl salicylate.
Gannuet al.	2010	Lacidipine microemulsion-based gel
*Fouad et al.*	2013	Poloxamermicroemulsion-based gel
Khuranaet al.	2013	Nanoemulsion-based gel of meloxicam
*Eid et al.*	2014	Swietenia macrophylla Nanoemulgel.