Introduction

Recent several years, great improvements have been made on the development of novel drug delivery systems (NDDS) for plant actives and extracts. Several plant extracts and phytoconstituents having excellent bioactivity. Herbal medicines are easily available, cheaper, and safer than the synthetic drug. The variety of novel herbal formulations like polymeric nanoparticles, nanocapsules, phytosomes, microemulsion, emulgel, and microsphere has been reported using bioactive and plant extracts. Phytoconstituent based Microemulgel, is a microemulsion and gel combination with the herbal ingredient, with small-sized globule present in an emulsion. The microemulsion concept was introduced in 1940 by hoar and Schulman generated a clear single-phase solution by titrating a milky emulsion with hexanol. The microemulsion is defined as thermodynamically stable, optically isotropic liquid solution which is formed by combining oil, water, and surfactant and Cosurfactants as shown in Figure 1 (Lawrence & Rees, 2012).

Microemulsion consists of delivering a drug dissolved in a mixture of one or more excipient like mono, di, and triglycerides, lipophilic and hydrophilic co-surfactant. Microemulsion content more quantity of emulsifier: These emulsifiers lower the interfacial energy between the oil phase and aqueous phase. The difference between emulsion and microemulsion; emulsion is thermodynamically unstable and both phases will get separated as time passed on. In the case of the microemulsion, the presence of surfactant and cosurfactant reduces interfacial tension by formatting barrier. The microemulsion is formed when entropy changes in that dispersion are greater than the free energy require increasing the surface area between the oil and aqueous phase of dispersion. The change in free energy (G) associated with the process of emulsification ignoring the free energy of mixing can be expressed by McClements (2012).

$\begin{array}{l}∆G=\sum _{}{N}_i\pi r_{i}2\sigma \\ N_{i=}no. of droplet of redius r_i\\ \sigma = interfacial energy\end{array}$

The microemulsion is of two types of emulsion either oil in water and water in oil emulsion. In microemulsion, drug present solubilized form in small-sized droplet which provides a large surface area for absorption. Apart from these, present excipient help to improve bioavailability, lipid enhancing permeability of drug. The surfactant and co-surfactant itself act as a penetration enhancer also.

The nanosized globule of microemulsion (10ηm - 140ηm) use in combination with the gelling agent, these combined dosage forms are referred to as microemulgel. Nanosized emulsion using with gelling agent enhance retention time of formulation dosage form (drug moiety) and permeability. Other topical agents like ointment, cream, lotion have many disadvantages like very sticky, uneasiness to apply, lesser spreading coefficient, need to apply with rubbing and they also have problems with stability. Due to all these issues within the major group of semisolid preparations, the use of transparent gels has useful both in cosmetics and in pharmaceutical preparations. Despite many advantages of gels have a major limitation in the delivery of hydrophobic drugs; to overcome this limitation an emulsion-based approach is being used. A hydrophobic therapeutic moiety can be successfully incorporated and delivered through a gel. The emulsion has two-phase, internal phase, and external phase. Internal phase pass drug moiety to the external phase slowly gets absorb in the skin. Emulsion based gel, the drug get entrapped in a cross-linkage network of gelling agent. In that small drug get entrapped and release in a controlled manner. The stability of emulsion also gets increases as well as increasing penetration ability. Gel matrix influence by type and concentration of polymer is used to prepare, it also affects the release rate of the drug (Phad, Nandgude, & Ganapathy, 2018).

Formulation components

Oil phase

The emulsion is made up of oil phase and water phase hence the selection of oil has great importance in emulgel formulation. The oil phase affects the viscosity, permeability, and stability of the formulation of emulsion. Oil has less hydrophobic property shows better emulsification. If hydrophobicity increases it gives effect on the solubility of a lipophilic drug as shown in Figure 2. Edible oil and vegetable oil show poor capability to dissolve a large amount of lipophilic drug and poor emulsification property. Hence, chemically modified oil, like medium-chain triglyceride or mono- or diglyceride is used as an oil phase for poorly water-soluble drugs. Medium-chain triglycerides are appropriate for encapsulation of drugs with log p-value ranging from 2 to 4. Recent advancements in the formulation that those oils have medicinal value, itself use as an oil phase as well as an active drug ingredient. Some oil also known for their synergistic effect, they used as a penetration enhancer improve permeability drug through the skin. Some of the oil known for its active properties like anti-inflammatory, antimicrobial, antiseptic. Various oils used as oil phase in formulation of emulgel as given in Table 1 (Jäger, Laszczyk, & Scheffler, 2008).

Surfactant

The emulsion is a combination of two immiscible liquid, thermodynamically unstable which is stabilized by using an appropriate emulsifier. The emulsifier used to reduce the interfacial tension between the oil phase and water phase makes stable formulation by avoiding coalescence of nanodroplet emulsifier should be safe, high drug loading capacity, good emulsifying capacity along with better stability. Proper selection of emulsifiers is an important feature due to associated toxicity and a large quantity of surfactants may cause irritation to skin.

HLB values of surfactants show a greater effect on the formulation. If to be obtaining water in oil emulsion formulation, then the HLB value of emulsifier should be 3-8. HLB value 8-12 for oil in water emulsion formation of the stable microemulsion can be obtained by mixing low and high HLB surfactant, the hydrophilic and lipophilic emulsifier are thought to align alongside each other imparting rigidity and strength to the emulsifier film through hydrogen bonding and making microemulsion more stable. In microemulsion, the special attention given to the solubility of oil and drug, surfactant, and co-surfactant.

By adding a surfactant, similar ionic charge present on the surface, they prevent aggregation of the droplet and stabilize microemulsion. Surfactants are divided into 3 classes depending on their ionic nature. cationic surfactant (amine and quaternary ammonium compound, acetyl trimethyl ammonium bromide, lecithin, hexcetyl trimethyl ammonium bromide , dodecyl dimethyl ammonium bromide) non-ionic surfactant capryol 90, labra filcs, labrasol, gelucire 44/14, cremophore RH40, PEG MW >4000, Poloxamer 124,188,softigen 701, tween 80, tween 60.

Anionic surfactant-containing carboxylate group, sodium bis-2-ethylhexylsulfosuccinate, sodium dodecyl sulfate, zwitterionic surfactant (phospholipid). Generally, non-ionic surfactant mostly chosen for the reason that, it gets less affected by pH and changes in ionic strength, biocompatibility,

and safety. Toxicity and skin irritation issue ionic surfactant less preferred. Nowadays, natural surfactants take place because of their less toxicity, biocompatibility, biodegradability. They are amphiphilic in nature affinity for both hydrophilic and hydrophobic. It works on the same mechanism, prevent aggregation by forming repulsive force (Liu, Tian, & Hu, 2012).

Co-surfactant

The only surfactant cannot give transient negative interfacial tension. Co surfactant gives flexibility to the interfacial film by modifying the curvature of oil in water interface which improves oil solubilization. Cosurfactants when combined with surfactants penetrate through surfactant and disturb interfacial film and give required fluidity, provide emulsification by lowering interfacial tension. Surfactant and cosurfactant affect release by partitioning of a therapeutic agent or lipophilic drug in aqueous and oil phase.

The selection of surfactant and co-surfactant also depend upon the transmittance. Transcutol P shows a higher percentage of transmittance and penetration enhancer properties than propylene glycol and Ethanol. The ratio of surfactant and co-surfactant has a great influence on the microemulsion area in the phase diagram. Only surfactant not able to reduce surface tension sufficiently, surfactant, and co-surfactant in equal ratio greatly reduce interfacial tension, give the higher microemulsion area in the phase diagram. But the increase in surfactant in the ration (3:1) may be decreased in the area. 1, 2 propylene glycol, PEG 400, carbitol, absolute ethyl alcohol, propanol, butanol are used as a surfactant in a microemulgel, microemulsion.

Alcohol is generally used as a cosurfactant in the microemulsion. Addition cosurfactant (e.g. Ethyl alcohol) may give positive curvature effect alcohol swells head region so, it becomes more hydrophilic and formed o/w type emulsion. In the case of longer

chain cosurfactant (acetyl alcohol) swelling more, in chain region than the head region and formed w/o type microemulsion (More et al., 2016).

Gelling agent

The gelling agent is used as a thickening agent which increases the consistency of any dosage form. According to the Swedish national encyclopedia, thixotropy is a viscous or gel-like product turning more liquid vigorously for a longer period they get deformed. Generally accepted that thixotropy is the phenomenon of fluid that shows a reversible structural transition (gel- sol-gel) conversion due to time-dependent changes is viscosity induced by temperature, pH, or other components without any changes in the volume of the system. Synthetic, semisynthetic natural gelling agent present in natural gelling agent like guar gum, xanthan gum lead to microbial degradation, hence, synthetic and semisynthetic gelling agent replaces natural agent. Hydroxyl propyl methylcellulose, various grades of carbopol, sodium carboxymethyl cellulose used as a gelling agent. Hydroxyl propyl methyl cellulose is an odorless, tasteless, white to slightly off-white free flowing granular powder.

Synthetic modification of natural polymer is cellulose Carbopol is the polymer of acrylic acid cross-linked with poly alkenyl ethers, or divinyl glycols have particle size about 0.2 to 0.6 µm in diameter. It is insoluble in water and form cross-linkage used for the controlled release of drugs. Gelling agent effect on the release rate of the drug . There is an inverse correlation between the concentration of gelling agents and the amount of drug release. It also depends upon the type of gelling agent used.

The combination of two gelling agent shows better stability, HPMC based Emulgel found to be better than carbopol based emulgel shows improved drug release rate. In this stage, the emulsion will be introduced into the prepared gel at a particular ratio, with continuous mixing to form homogeneity.

Gelling agents in microemulsion formulation is to change its physical state, from liquid to gel which also affects the pharmacokinetic properties of drugs incorporated this Nanocarrier system. Gelling agent prepared by adding gelling agent into aqueous media with continuous stirring at a constant rate at specified condition after swelling addition of emulgel into it. Details of various gelling agents used to develop emulgel of phytocostituents are given in Table 2 (Thakur et al., 2016).

Penetration enhancer

Penetration enhancers help in the permeation of the desired drug through the skin by dropping the impermeability of the skin. These agents interact with skin constituent to induce temporary disrupt skin barrier and lipid barrier, increases skin permeability.

Some properties which are desired in permeation enhancers are the must be pharmacologically inert, non-irritating, nontoxic, no allergic, compatible with drugs and excipients, odorless, tasteless, colorless, and inexpensive and also have good solvent properties. Few Natural Penetration Enhancers (NPE) are summarised in Table 3.

Formulation method of microemulgel

Microemulgel formulated with two steps, first is the formulation of microemulsion by using surfactant and co-surfactant with drug dissolution, followed by the second step that is the formulation of gelling agent and incorporation of microemulsion into these gelling agent.

Microemulsions are isotropic systems, which are difficult to formulate because their formulation is a highly specific process involving spontaneous interaction among constituent molecules. For the preparation of microemulsion basically two methods i.e. low energy and high energy emulsification method.

Low energy emulsification method

Low energy method advantages over high energy methods for the formulation of the microemulsion. The low energy method includes the phase inversion method and the spontaneous method. In the phase inversion method, the mixing of oil, water, and surfactant in a predefined ratio. Constant stirring required at moderate speed with titrating of oil phase with an aqueous phase, so the formation of a nanosized droplet in a continuous phase. The addition of surfactant and co-surfactant affects the emulsification process.

Type of surfactant used determined which type of emulsion formed, the temperature is extremely important in determining the effective head group size of non–ionic surfactant. At low temperatures, they are hydrophilic and form normal oil in the water system. At higher temperatures, they are lipophilic and form water in the oil system. At an intermediate temperature, microemulsion occurs with the water and oil phase form a bicontinuous structure . The spontaneous method is specially used for the thermolabile component. Alternatively, a temperature-dependent spontaneous twist of non-ionic surfactant is used for phase transition during the phase inversion method. The emulsion formed at phase inversion temperature will be reversed on cooling with continuous stirring. This process is also limited to incorporate the thermolabile component, although limitation takes as approach decreased phase inversion temperature by suitable selecting surfactant (Lovelyn & Attama, 2011).

High energy emulsification method:

Apply high shear force energy to rupture the internal phase in the nanosized droplet by high-pressure homogenizers, ultrasonicator. In this method, required to input external energy to develop the formulation. Due to the presence of external energy formulation become unstable (Qian & McClements, 2011).

Evalution for microemulgel

Evaluation for Microemulsion

Droplet size microemulsion

Globule size distribution of microemulsion is determined by using particle size analyzer (Ashara et al., 2016).

Zeta potential measurement

It’s used to measure the charge on droplet. In conventional emulsion, charge on oil droplet is negative due to presence of fatty acid (Ashara et al., 2016).

Viscosity

Viscosity of prepare emulsion measure by Brookfield viscometer (Chincholkar, Nandgude, & Poddar, 2016).

Centrifugation

It is used to evaluate physical stability of microemulsion centrifuge at 5000 rpm for 10 min at ambient temperature and evaluate for creaming and phase separation visually (Chincholkar et al., 2016).

Conductivity measurement

Conductivity measurement gives idea about type of microemulsion if formed, weather it is oil in water or water in oil emulsion visually (Purohit, Nandgude, & Poddar, 2016).

Evaluation for Microemulgel

Physical Examination

Microemulgel were inspected for colour, homogeneity, consistency, texture and pH. pH of microemulgel measured by pH meter by making 1% of aqueous solution of formulated microemulgel (Sathe, Bagade, Nandgude, Kore, & Shete, 2015).

Rheological Studies

Mainly viscosity determine by cone and plate viscometer with spindle 52 at temperature25±1°c using temperature (Sathe et al., 2015).

Syneresis measurement test

Upon standing sometimes gel system get shrinks a bit and little liquid is pressed out. This phenomenon is known as Syneresis. In this test, microemulgel put in a cylindrical plastic tube with a perforated bottom which and covered with filter paper out after some time. In the cylindrical plastic tube liquid which separate from microemulgel will weigh. Percentage of Syneresis calculated as follow: % of Syneresis = Weight of liquid separated from microemulgel / Total Weight of microemulgel before centrifugation x 100

Spreadability measurement

Spreadability measures by slip and drag characteristic. It is determined by such apparatus, which consist of wooden block, pulley at one side end and two same dimensional glass slides. One slide attach to wooden called as ground slide. on ground slide place 1gm of emulgel and above place another glass slide, so emulgel become sandwich between these slide . 1kg wt place on these two slide for 5 minute to expel air out and provided uniform film between slide excess of emulgel scrapped off from edges. Then upper slide subjected to pull a definite weigh with the help of string attached to the hook. Measure time required by top slide to cover a distance of 7.5 cm shorter interval indicate better spreadability (Nandgude et al., 2008).

Extrudability study

Measure force required extruding the material from tube. It is determined by weight required to extrude 0.5 cm ribbon of emulgel in 10 sec from aluminum tube. If tube extruded more quantity it is better extrudability. Extrudability = weight applied to extrude emulgel from tube (gm) / Area (cm²).

Drug content determination

Drug content of gel will be measured by dissolving 1gm of gel in soluble solvent and Sonicate to mix well. Absorbance will be measured after dilution at λ max by using UV spectrometer. Standard plot of drug is prepared in same standard plot by putting the value of absorbance in standard plot equation. Drug content = (concentration × dilution factor ×volume taken) × conversion factor (Nandgude et al., 2008).

In vitro diffusion study

Franz diffusion cell (with effective diffusion area 3.14cm² and 15.5ml cell volume) used for drug release studies with 7.4 phosphate buffer solution. Withdraw specific quantity of sample at specific time interval (Nandgude et al., 2008).

Stability studies

Emulgel stability studies at 5°c, 25°c, 60%, RH, and 40°c/76 RH for a period of 3 month.

Conclusions

To overcome the drawbacks and unwanted side effects of oral and/or parenteral routes, need to explore topical route. To overcome another issues like poor solubility of drug moieties/phytoconstituents in water as well as problem of penetration need of drug delivery systems like microemulgels. Components of microemulgels like oil, emulsifiers and co-emulsifiers are selected based on solubility of it in them, so the problem of solubility would be overcome and deposition of drug moieties at the site will be enhanced which Results in more therapeutic activity and Stability.