A Comprehensive Review on Emulgel: Formulation, Characterization, Applications and Future Perspectives

EMULSION                                                    GEL + EMULSION

RATIONALE OF EMULGEL AS NEW FORMULATION

Emulsions, creams, ointments, lotions, powders, and other kinds of topical drug delivery are used to treat skin-related diseases [6,7]. These formulations have many disadvantages such as sticky nature, stability issues, spread ability which cause patient compliance. To overcome this problem gel or emulgels are formulated in cosmetics and pharmaceuticals preparation because they are less sticky in nature better spread ability and enhance the patient compliance.

Gels are the new class of dosage form in which trapped large amount of aqueous or hydroalcoholic liquid in a colloidal solid particle [8]. Gel shows a significant disadvantage for the delivery of hydrophobic drugs. To cover this limitation, emulgel a noval approach that came into existence. The emulgel are the combination of emulsion and gel base. They are non-greasy, easy to absorb, and better drug penetration. Because the gel base, emulgels give cooling effect and allow the drug reach the skin more effect.

EXAMPLE

There are many examples of emulgels medicines used in pharmaceutical field, such as Diclofenac emulgel, Mefenamic emulgel, etc. Diclofenac is a common pain relief and anti-inflammatory drug (NSAIDS). It is widely used in painful and inflammatory conditions [9].

In some topical preparations isopropyl alcohol is added for better solubility but its prolonged use causes eczema and sensitivity [10]. To avoid this, diclofenac emulgels are made without isopropyl alcohol so they are gentle on the skin [11]. On the other hand, Mefenamic acid is available as in the form of tablet or suspensions [12]. It can also be prepared in the form of an emulgel. In mefenamic acid emulgel, Carbopol 940 is used as the gelling agent, clove oil and mentha oil are added as penetration enhancers to help the drug enter the skin [13].

ADVANTAGES

• Avoid first pass metabolism
• Avoidance of gastrointestinal incompatibility
• Improve the patient compliance
• Easy to spread
• Incorporation of hydrophobic drugs
• Controlled release
• Better loading capacity
• Better stability
• Good for oily skin
• Convenient and easy to apply
• More selective for specific site

DISADVANTAGES

• Skin irritation on contact dermatitis
• Drugs of large particle size are not easy to absorb through the skin
• Chances of allergic reactions occurred.

HOW EMULGEL WORKS:

Emulgel works on the skin more effectively then the simple gel or a conventional emulsion because it combines the both systems. A simple gel mainly contains water and gelling agent, so the simple gel is suitable for hydrophilic drugs but they show poor penetration for the lipophilic drugs and limited drug release through the lipid rich stratum corneum. On the other hand, an emulsion carries lipophilic drugs in its oil phase and hydrophilic drugs in its aqueous phase but it feels greasy, spreads less uniformly, and has lower residence time on the skin, which can reduce patient compliance.

Emulgel overcome these limitations by incorporating an emulsion into a gel base. When applied, the gel components hydrate the stratum corneum and forms a thin, non-greasy film that increases the contact time with the skin, while the emulsion droplets act as reservoirs for the drug. The drug is released in a controlled manner from the emulsion, diffuses through the gel network, and penetrates the skin more efficiently due to hydration and penetration enhancers.

 As a result, emulgel provides better drug penetration, prolonged local action, improved stability, and higher patient acceptability as compared to simple gels and emulsions.

FORMULATION CONSIDERATION

In topical formulation, it is important to make the product safe for the skin. This means it should not be toxic, not cause irritation, not block pore, and not create any allergic reactions. It should also look good, feel smooth, and be compatible with the skin. All these properties mainly depend on the ingredients used in the formulations. Therefore, choosing the right excipients becomes a very important part of making a good emulgel [14-18].

1. Drug:

The absorption of a drug through the skin depends on the drug’s own properties. These physicochemical properties help whether a drug can be successfully made into an emulgel for topical or transdermal use.

A drug that is suitable for emulgel should have:

• A high pKa value
• A short half-life (less than 10 hours)
• Small molecular size
• Molecular weight >500 Daltons
• A partition coefficient between 0.8 and 5
• Low polarity (less water-loving)

Additionally, the drug should not irritate the skin and should have a skin permeability of at least 0.5 × 10⁻³ cm/h [19].

2. Vehicle:

The base or vehicle used in an emulgel significantly influences the drug’s absorption through the skin. A good vehicle should spread evenly on the skin and deposit the drug properly. It should release the drug exactly where it is needed and maintain the drug’s effect in that area for a suitable amount of time. Additionally, the vehicle must be gentle and compatible with the patient’s skin [19].

3. Aqueous medium:

These are serves as the water-based component in the emulsion system. When a gelling agent is added, this watery part helps change the emulsion into an emulgel. Common ingredients used in this aqueous phase are water and alcohols

4. Oils:

Different types of oils are employed in the preparation of emulgels, such as mineral oil, vegetable oils, and fish liver oil, which commonly serves as the oil phase. In oral formulations, non-biodegradable oils like mineral oil and castor oil are frequently used and can produce a local laxative effect. Additionally, vegetable oil such as arachis oil, cottonseed oil, and maize oil are utilized as nutritional supplements [16,17]. The common used oils include: Isopropyl palmitate, Isopropyl myristate, Isopropyl stearate, and liquid paraffin [20].

5. Emulsifiers:

An emulgel is a combination of an emulsion and a gel, formulated by using a suitable gelling agent. Emulsions are thermodynamically unstable system, but their stability can be improved by adding appropriate emulsifying agents. These agents help by lowering the interfacial tension between the phases [21]. The emulsifying agent needs to demonstrate excellent Hydrophilic-Lipophilic Balance (HLB) properties to create stable emulsions. The emulsion becomes water-in-oil when HLB values remain below 8.HLB > 8: makes oil-in-water emulsion [22]

It promotes emulsification and to control stability. Tween- 20,40,80, PEG-40, stearic acid, sodium stearate is commonly used [5].

6. Gelling agent:

These substances help to improve uniformity and can also acts as thickening agents [23]. They are the basic constituent for preparation of emulgel which creates a system thixotropic. These agents help to enhance the texture and overall quality of the dosage form. The type and concentration of the gelling agent play a crucial role in controlling drug release from the emulgel and maintaining its stability. For an example, emulgels made with Hydroxy Propyl Cellulose (HPMC) as the gelling agent have been found to release the drug better than emulgels made with Carbopol polymers [24]. Studies show that increasing the concentration of the gelling agent leads to a reduction in drug release from the emulgel. In other words, more gel makes the drug come out more slowly. While using a combination of different gelling agents together can make the emulgel more stable [17]. Different types of gelling agents are used in emulgel preparation, including natural, semi-synthetic and synthetic ones. The main disadvantage of natural gelling agent is that they can easily break down by the microbes which are responsible to spoil the product. For this reason, semi-synthetic and synthetic gelling agents are commonly preferred in the formulation of emulgels [22].

7. Permeability promoters:

These agents are commonly used to facilitate the passage of the drug through the skin. An appropriate amount of penetration enhancers are used in an emulgel can greatly affect how the drug moves through the skin. Penetration promoters are used in emulgel preparation should be minimally irritating, low in toxicity and possess good penetration ability.

Figure: 1. Basic steps for the preparation of Emulgel

Emulgel preparation is simple and low- cost [25]. There significant steps are explained in fig. 1. Prepare an Emulgel, firstly mix the drug into the formulation [26]. Prepare the gel base first. Then slowly add the prepared emulsion into the gel while stirring continuously [27]. Prepare the emulsion, the aqueous phase is made by mixing purified water with water-loving components. This mixture is heated about 70°C. In this aqueous phase, the emulsifying agents such as Tween is added. This emulsifier helps water and oil mix properly, and forms the stable emulsion [28]. After preparing the aqueous phase, the oil phase is prepared. In this step, a surfactant like span is dissolved in oil [29]. If the drug is hydrophobic in nature, then it is added to this mixture. Heat the oil phase to the same temperature as the water phase. Prepare the gel by mixing polymer with water and stirring well. Adjust the pH to 6-6.5, and then add preservatives to the aqueous phase [30]. Both the phases are heated about 70-80°C. When both phases reach the same temperature, the oil phase is added to the water phase with constant stirring [31]. After cooling at room temperature, mix equal parts of emulsion and gel base to obtain the emulgel [32].

Alternative Methods for The Preparation of Emulgel

Nanoemulsion-Based emulgel

Nanoemulsions are formed by a mixture of oil, water and an emulsifier (in most cases natural and/or biological) in which the oil droplets are in the nano-scale, thus having a droplet size ranging from 20 to 500 nm. The emulsifier (e.g. lecithin) is used to reduce the surface tension between oil and water in order to create small stable droplets of oil in water or vice versa[33]. There are two different forms of nanoemulsions, known as Water-in-Oil (W/O) and Oil-in-Water (O/W). Both provide excellent skin care properties; however Water-in-Oil nanoemulsions are better suited for moisturizing, whilst they have a greasy feel and are less preferred by most. Oil-in-Water nanoemulsions are the most preferred form as they absorb fast into the skin and are easily washed off.

Nanoemulgels are gels filled with nanoemulsions and have potential applications for topical treatments for diseases such as eczema and psoriasis and for acne. The drug delivery of analgesics, anti-inflammatories, and antimicrobials is also a possible application[33].

Nanogels are very small gel particles used for drug delivery and in medical applications. They are safe, easily degrade in the body and can carry a large amount of drug [33].

Nanoemulgels adhere well to skin and can solubilize more drug in their oil phase. This increases the concentration of the drug, which makes it easier to penetrate the skin. They also make patients more comfortable as they are easy to spread, less sticky and more pleasant to use than creams and ointments.

Procedure [34]

Advantages

• Improved bioavailability
• Enhanced drug penetration through skin
• Having high physical stability
• Reduced systemic side effects
• Better Spreadability
• Reduced dose frequency

Disadvantages

• High formulation cost
• Complex formulation process
• Environmental sensitivity

Microemulsion- Based Emulgel Method:

Microemulsions were introduced by Hoar and Schulman in the 1940s. They are clear and stable combinations of oil, water and a surfactant, which is an agent that helps oil and water mix. These systems can improve drug delivery, efficacy and bioavailability. When the surfactant lowers the surface tension between oil and water a microemulsion is formed . The droplets are very small ( 5-200 nm ) . The small size and stability of microemulsions enhance drug penetration into the body and consequently increase the efficacy of the drug [35]. Microemulsion are transparent due to their globule size (less than 25%).

Microemulgel is a combination of microemulsion and gel so it has benefits of both. It is useful to deliver poorly water-soluble (hydrophobic) drugs by first dissolving them in an oil-in-water microemulsion and then mixing this into a gel base. This system enhances drug absorption and penetration leading to increase in bioavailability. The gel also adds stability to the formulation and makes it easy to apply without any mess. Microemulgels are more elegant, non-greasy and easily washed off from the skin as compared to microemulsions alone [35].

Advantages

• Enhanced drug penetration
• Improved bioavailability
• Better stability
• Reduce dosing frequency
• Bypass first- pass metabolism
• Easy application and Spreadability

Disadvantages

• Formulation complexity
• Stability issues after gel incorporation
• Not suitable for all drugs

Comparative Study of Nanoemulgel, Microemulgel, and Emulgel

Conventional emulgels represent an effective approach for topical delivery of hydrophobic drugs; however, their performance is limited by larger droplet size and lower permeation efficiency. Microemulgels and nanoemulgels overcome these limitations through nanoscale droplet systems that provide enhanced solubilization, improved skin penetration, superior stability, controlled drug release, and higher bioavailability. Among these advanced systems, nanoemulgels are particularly advantageous for achieving enhanced therapeutic efficacy and patient compliance in topical drug delivery applications.

Characterization of Emulgel:

1. Visual Properties:

Visual evaluation of the emulgel includes checking its color, texture, homogeneity, and stability against phase separation [1,21 ].

2. pH Determination:

A digital pH meter is used to measure the pH of the prepared emulgel. For this test, 1g of emulgel is mixed with 100ml of distilled water to prepare a 1% w/v solution. The solution is kept for 2 hours to allow proper dispersion. After that, the pH of each formulation is measured. The pH measurement is carried out three times for each formulation, and then the average pH value is calculated [1].

3. Spreadability Study:

Using a Mutimer apparatus (wooden block and pulley), the Spreadability coefficient is measured according to the ease of spreading of the formulation.

Spreadability (S) = M × L/T

Where:

• M = weight tied to the upper slide (g)
•  L = length moved by the glass slide (cm)
• T = time taken to move the distance (seconds)

4. Extrudability:

A 15 g of emulgel is filled into an aluminium tube. The tube is placed properly in the       tube-holding device, and the plunger is adjusted to keep it in position. A pressure of 1kg/cm² is applied to the tube for 30 seconds. After that, the amount of emulgel that came out of the tube is collected and weighed [36].

5. Rheological Study:

Rheological studies evaluate the flow behaviour. viscosity, and consistency of an emulgel    to ensure easy application and stability. A digital rotational viscometer is used to measure the viscosity of the emulgel at 37°C. The emulgel is filled in a beaker, and spindle number III is carefully positioned in the centre without touching the container. The spindle is revolved at 10rpm (minimum) and 100rpm (maximum) and the viscosity values were recorded [37].

6. Size Distribution of emulsion globules:

For analysis, the sample is dissolved in purified water and shaken to achieve uniform dispersion, then injected into the zetasizer cell to determine globule size and distribution  [38,39,40].

7. Drug assay

A known amount of emulgel is taken and dissolved in an appropriate solvent like methanol or ethanol to determine drug content. This mixture is then sonicated to help the drug dissolve completely. After that, the solution is filtered to remove any undissolved particles. The filtered solution is measured at the drug’s maximum wavelength using UV-Visible spectrophotometer. This absorbance value is used to calculate how much drug is present in the emulgel [37,38,39].   

8. Swelling Index:

Swelling index describes how much a gel swells (adsorbs liquid) when it is placed in a solution. Taking 1g sample of gel placed on porous aluminium foil and then kept separately in a 50ml beaker containing 10 ml of 0.1N NaOH. At predetermined time intervals, the sample is taken out of the beaker, allowed to dry for some time, and then reweighed. The swelling index can be measured by following formula:

Swelling index (Sw) % = [(Wt–Wo)/Wo] ×100

Where, (Sw) % =Equilibrium percent swelling; Wo =Original weight of emulgel at zero time after time t and Wt =Weight of swollen emulgel.

9. Drug release assay:

The Franz diffusion cell is used to study how a drug is released from a gel formulation. Approximately 200mg of the emulgel is evenly applied onto the surface of the egg membrane. The membrane is then carefully positioned between the donor and receptor compartments of a diffusion cell. The receptor compartment is filled with phosphate buffer (pH 5.5), which facilitates the dissolution of the drug. Solution in the receptor chamber is continuously stirred using a magnetic stirrer for uniform mixing. The samples are collected specific time intervals 1ml solution is taken from the receptor chamber. These samples are diluted if needed and analysed by using UV- Visible spectrophotometer. The total amount of drug that passes through the egg membrane is measured over time [14].

10. Homogeneity:

 The homogeneity of the formulation was tested by visually examining the emulgel after spreading it as a thin layer on a glass [3].

11. Skin sensitivity test:

The formulation is applied to the properly shaved skin of rats. The treated area is monitored for up to 24 hours to detect any adverse effects, such as alternation in skin color or textur.

Pharmacokinetic Study:

Pharmacokinetic studies are carried out for emulgel formulations that show systemic absorption after transdermal application. Rats are used to evaluate various pharmacokinetic parameters, including maximum plasma concentration (Cmax), time required to reach maximum concentration (Tmax), and the total area under curve (AUC). For this purpose, blood samples are collected from the retro-orbital vein at predetermined time intervals following topical application of the formulation. The collected samples are then subjected to centrifugation at 15,000 rpm for 10 minutes at 4°C in order to separate the plasma. About 100 µl of plasma is then mixed with 1ml of acetonitrile to remove protiens. This mixture is centrifuged again at 15,000 rpm for 5 minutes at 4°C. After this, 20 µl of the clear liquid is collected and analysed using High Performance Liquid Chromatography (HPLC) [38].

Marketed Preparation of Emulgel:

Patents on Emulgel: