INTRODUCTION:

Topical drug delivery can be defined as directly applying a drug-containing formulation to the skin to treat the cutaneous disorder. The TRA drug delivery system is generally used where other routes (like oral, sublingual, rectal, and parental) fail or local skin infection like a fungal infection¹. The prime focus of the transdermal drug delivery system is to bypass first-pass metabolism and inconvenience of intravenous therapy and the varied absorption conditions, like pH changes, the presence of enzymes, and gastric emptying time, are some other advantages of The topical drug delivery system is typically used where the drug utilization process error from the administration. The study is also carried out to avoid the risks and inconvenience of intravenous therapy and the varied absorption conditions, like pH changes, the presence of enzymes, and gastric emptying time.

Transdermal drug delivery is the simplest and easiest route of localized drug delivery anywhere in the body by ophthalmic, rectal, vaginal, and skin routes. These are applied as a broad spectrum of preparations in cosmetic and dermatological cases to the healthy or diseased skin². The formulations are available in different forms, from solid through semisolid to liquid. Many drugs can be administered topically for their action at the application site or systemic effects. Drug absorption is enhanced through the skin if the drug substance is in solution, has a favorable lipid/water partition coefficient, and is a non-electrolyte. The transdermal drug passes through the skin's surface layers, and molecules that penetrate the skin consist of three routes through intact stratum corneum, sweat ducts, and sebaceous follicle. The transdermal drug delivery system such as emulgel (jellified emulsion) is generally used where the other drug administration systems fail to directly treat cutaneous disorders such as fungal infections, acne, psoriasis, etc^3,4.

The rationale of Emulgel as a Transdermal Drug Delivery System:

Many drug products are applied to the skin or mucous membrane that either enhance or restore an essential function of the skin or pharmacologically alter an action in the underlined tissues. Such products are known as topical or dermatological products⁵.

Many broadly used topical agents like ointments, creams, lotions have many disadvantages; they have very sticky, causing discomfort to the patient. Moreover, they also have a low spreading coefficient and need to apply with rubbing, and they exhibit the problem of stability. Due to all these factors, the primary group of semisolid preparations that uses transparent gels has expanded in cosmetics and pharmaceutical preparations.

A gel is a colloid; this is usually 99% wt. The liquid is immobilized through surface tension and a macromolecular network of fibers designed from a small quantity of a gelating substance present. Despite the many advantages of gels, a significant limitation is the delivery of hydrophobic drugs. An emulsion-based approach is being used to overcome this limitation so that even a hydrophobic therapeutic moiety can be efficaciously incorporated and delivered through gels^6,7.

As globules of the drug could penetrate the stratum corneum, a comparatively more extensive surface area could be available for drug action so that less drug dose may provide more pharmacological action^8-10. Moreover, selecting other excipients may assist pharmacological action in one way or another. Emulgel could provide advantages of both emulsion and gel and increase drug deposition over the skin.

Emulsion:

Emulsions are a mixture of two phases or more than two phases of immiscible liquids. The one phase is dispersed into a dispersed medium. Several types as oil in water (O/W), water in oil (W/O), oil in oil (O/O), micro-emulsions, double and multiple emulsions, mixed emulsions, etc., for preparation and stability of the emulsion, the emulsifier is necessary¹¹. Various factors could affect the process of emulsification, such as the nature of oil, emulsifier, the emulsifier concentration used, rpm, and the temperature¹².

Gels:

Gels are constituted by entrapment of large amounts of aqueous or hydroalcoholic liquid in a network of colloidal solid particles, inorganic or organic polymers of natural or synthetic origin. The higher aqueous component permits the more significant dissolution of drugs and permits easy drug migration compared to the ointment or cream base. However, this makes gels poor vehicles for hydrophobic drugs. This limitation of gels can be overcome by making Emulgel⁸.

Emulgel:

Emulsion and gel could be mixed in a preparation called Emulgel¹³, O/W emulsion for lipophilic materials, and W/O for hydrophilic materials¹⁴. Emulgels are easily spreadable, easily removable, emollient, thixotropic, greaseless, non-staining, biofriendly, transparent, and cosmetically acceptable⁸. They also have good cutaneous penetration⁹ and an extended shelf-life¹⁵.

Advantages^16,17

· Avoidance of gastrointestinal incompatibility.

· More selective to a specific site.

· Improve patient compliance.

· Suitability for self-medication.

· Medication quickly stops when needed.

· Convenient and easy to apply.

· Incorporation of hydrophobic drugs

· Better loading capacity

· Better stability

Disadvantages¹⁸

· Skin infuriation.

· Chance of an allergenic reaction.

· The skin permeability is poor for some drugs.

· Drugs of large particle size are not easy to absorb through the skin.

· The occurrence of the bubble during the formulation of emulgel^19,20.

Various ingredients of Emulgel formulation:

Aqueous material:

The aqueous phase of the emulsion generally uses water ²¹.

Oils:

They are responsible for the oily phase of the emulsion. The oil phase has tremendous importance in the gel-based formulation as physicochemical properties of the oil (e.g., molecular volume, polarity, and viscosity). Usually, the oil, which has the maximum solubilizing potential for the selected drug candidate, is preferred as an oily phase for the formulation of emulsion/ microemulsion/nanoemulsion. It helps to attain maximal drug loading. The choice of the oily phase is often a compromise between its tendency to solubilize the drug and capability to when emulsion possesses the property of thixotropic, the processes of penetration into the skin are simplified²¹.

Improve emulsion penetration and stability it is incorporated into the gel. Further, gels for dermatological use have favorable properties, such as emollient^22,23, greaseless, thixotropic, easily removable, non-staining, and compatible with various excipients. The release rate and the stability of the incorporated drug can be affected by the type and concentration of polymer that form the gel. Emulgels are readily accepted by the have patient. It can be perfectly applied to the skin due to its nongreasy nature in comparison to other dermal formulations such as ointments, creams, etc., which are very much thick and require excess rubbing^24-27.

Emulgels may serve as a better option for the topical delivery of poorly water-soluble drugs. It has also proven excellent, and a stable vehicle for poorly water-soluble or hydrophobic drugs^28-30 facilitates the formation of the respective emulsion with desired characteristics. Oil phases which are used in buildout of emulgel are balsam oil³⁰, birch oil³², castor oil^33-36, isopropyl myristate^37-39, myrrh oil⁴⁰, rosehip oil^41,42, and wheat germ oil^42-43.

Table 1: List of oils used in Emulgel

S. No.	Chemical	Quantity	Dosage form	Reference
1	Light liquid paraffin	7-7.5%	Emulsion andEmulgel	61
2	Isopropyl stearate	7-7.5%	Emulsion
3	Isopropyl myristate	7-7.5%	Emulsion
4	Isopropyl palmitate	7-7.5%	Emulsion
5	Propylene glycol	3-5%	Gel

Emulsifiers:

Emulsifiers are used to control the emulsification process and stability. Emulsion stability can be increased by incorporating an appropriate emulsifying agent because these are thermodynamically unstable. Surfactants having HLB values greater than 8, such as the nonionic surfactant (spans, tweens), are used to formulate o/w emulsions, whereas mineral oils such as liquid paraffin have HLB value less than eight and therefore are used in the formulation of water in oil emulsions. In comparison to the individual system of span or tween, mixtures of span-20 and tween-20 results in more excellent stability of the emulsion⁴⁴.

Table 2: List of various Emulsifiers used in Emulgel

S. No	Emulsifiers	Reference
1	Polyethylene glycol stearate-40	46
2	Sorbitan monooleate (Span 20}	47
3	Polyoxyethylene sorbitan monooleate (Tween 80)	48
4	Stearic acid	49
5	Sodium stearate	50

Penetration enhancers:

Penetration enhancers are the substances that assist the absorption of penetrant through the skin by temporarily thinning the impermeability of the skin. Ideally, these materials should be pharmacologically inert, non-irritating, non-toxic, compatible with the excipients and drugs, colorless, odorless, tasteless, inexpensive, and have excellent solvent properties. The enhancers should not guide to the loss of body fluids, electrolytes, and other endogenous materials, and the skin on its removal should instantly regain its barrier properties. Various penetration enhancers used in the emulgel formulation are oleic acid⁵¹, clove oil⁵², and menthol⁵³.

Table 3: List of various Penetration Enhancers used in Emulgel

S. No.	Penetration enhancer	Quantity	Dosage form	Reference
1	Lecithin	5%	Gel	51
2	Cinnamon	8%	Emulgel	51
3	Oleic acid	1%	Gel	51
4	Clove oil	8%	Emulgel	52
5	Menthol	8%	Emulgel	53

Gelling Agents:

Gelling agents form gel bases containing emulsions to form emulgel. These are thickening agents, which expand the consistency of any dosage form by swelling in the aqueous phase and forming a gelly-like structure ⁵⁴.

Incorporating gelling agent into a system makes it thixotropic⁵⁵. HPMC-based Emulgel was superior to Carbopol based Emulgel since it showed a better drug release rate. CMC-based Emulgels for vaginal application showed higher mucoadhesive, increasing drug residence time, and best in-vitro and in-vivo performance. Hydroxyethyl cellulose-based Emulgel showed low mucoadhesion but good drug release profiles and rheological characteristics. Pemulen based Emulgel was meant for buccal administration.

Transdermal drug delivery system:

Nowadays, many drugs are administered orally, but they are not as effective as desired to upgrade such character Transdermal drug delivery system was designed. Drug delivery administered through the skin and attain a systemic effect is called a transdermal drug delivery system⁶³. These dosage forms include drug transport to the reasonable epidermis and potentially dermal tissue of the skin locally therapeutic effect⁶⁴. In contrast, an exceptionally significant drug division is transported in systemic blood circulation. A transdermal dermal patch is a medicated adhesive patch set over the skin to deliver a particular dose of medication with a foreordained release rate to reach the circulation system⁶⁵.

Table 6: Advantages and Disadvantages of Emulgel

S. No.	Advantages of transdermal drug delivery system^66,67	Disadvantages of transdermal drug delivery system^68,69
1	Self-medication is possible	Chances to an allergic reaction.
2	Side effect gets reduced.	High molecular drug levels cannot attain a therapeutic level.
3	Plasma drug concentration becomes maintained.	It is delivered to the ionic drug.
4	Drug duration of action is extendable.
5	GIT incompatibilities get avoided.
6	The number of dosage frequencies was reduced.

Anatomy and physiology of the skin:

Human skin consists of three distinct.

Fig. 2: Physiology of skin different cell layers and appendages.

Epidermis:

The epidermis is an overlaid, squamous, keratinizing epithelium. The complex layer of the epidermis varies in contingent cell size, thickness, and the number of cell layers of the epidermis, which is outer covering from 0.8mm on palms and soles down to 0.06mm on the eyelids. Approximately 90% of epidermal cells are keratinocytes, chest rated in five layers and creates keratin protein, and 8% melanocytes are available. They create melanin yellow or dark-colored colors that provide skin shading and ingests harming UV light. A Langerhans cell grows from red bone marrow and moves to the epidermis, which constitutes a tiny portion of epidermis cells. Markel cells are the slightest several of epidermal cells⁷⁰.

Dermis:

The dermis is a 3-5mm thick layer made out of a lattice of connective tissue, which contains lymph vessels, veins, and nerves. The cutaneous blood supply has a vital capacity in the direction of body temperature. It also gives the skin supplements and oxygen while removing toxins and squander items. Vessels reach inside 0.2mm of the skin surface area pores and skin surface and provide sink situations to most atoms getting into the skin problem. The blood supply in this way continues the dermal centralization of a saturate low, and the following fixation contrast over the dermis gives essential attention inclination to transdermal penetration ⁷¹.

Hypodermis:

The hypodermis or subcutaneous fats tissue underpins the epidermis and dermis. It fills in as a fat storage region. This residue controls temperature gives wholesome help and mechanical security. It conveys chief veins and nerves to the skin and may contain tangible weight organs. For transdermal medication conveyance, sedate needs to infiltrate through all these three layers and venture into the foundational flow, while if there should be an occurrence of topical medication conveyance, entrance through stratum corneum is fundamental. After that, medication maintenance in skin layers is desired⁷².

Table 7: Factors Affecting Topical Absorption of Formulations⁷

S. No.	Physiological Factors	Physiochemical Factors
1	Skin thickness.	Partition coefficient.
2	Skin pH	Molecular weight (<400Dalton).
3	Hydration of skin	Degree of ionization.
4	Inflammation of skin	Effect of vehicles.
5	Lipid content
6	Blood flow
7	The density of hair follicles
8	The density of sweat glands.

Pathway of Transdermal Permeation:

Fig. 3: Diagrammatic flow of pathway of transdermal permeation

Evaluation of emulgel:

Physical appearance:

In physical appearance, check color, consistency, homogeneity, and pH also, pH values of 1% aqueous solutions of the prepared Gellified Emulsion were calculated by a pH meter⁷⁷.

pH:

A digital pH meter measured the pH values of 1% aqueous solutions of the prepared gels. Electrodes were wholly dipped into the semisolid formulations, and pH was noted⁷⁸.

Spreadability:

The emulgel is then sandwiched between the slide and an additional glass slide having the dimension of the fixed ground slide and provided with the hanger. 1Kg wt placed at the top of the slides for 5 min to expel air and provide an even layer of the emulgel among the slides. Excess of the emulgel is scrapped off from the edges. The top plate is then subjected to a pull-off of 80 gms with the help of string attached to the hanger, the time (in seconds) required by the top slide to cover a distance of 7.5 cm be noted. A shorter interval indicates better spreadability⁷⁹.

Spreadability was 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 other.

Swelling Index:

1 gm of the emulgel is taken on a porous aluminum hamper and then placed distinctly in a beaker of 50ml containing 10ml 0.1 N NaOH. Then samples were taken from beakers at different time points and put in a dry place for some time after it reweighed ⁸⁰. The swelling index is calculated as follows:

Wt- Wo

Swelling Index (SW%) = ----------- x100

Where

Wo = Initial weight of emulgel at zero time Wt = Weight of swollen emulgel after time t (SW) % = Percent swelling Index

Drug Content Determination:

Gel formulation (1 gram) was dissolved in a suitable solvent and filtered to obtain a clear solution. The resulting solution absorbance was noted by using UV Visible spectrophotometer. Drug content was determined from the calibration curve for the drug ⁸¹.

Rheological Characterizations:

It has been discussed that a nanoemulgel contains oil, surfactants, and a gelling agent as fabricating components. A minute change in the physicochemical properties of formulation components can significantly affect the rheological properties of a dosage form, such as viscosity and flowability. The change in viscosity can further affect the stability factors, drug release, and other biological functions. Because of these, it is essential to understand the rheological properties of nanoemulgel. Viscosity measurement can be carried out with different kinds of viscometers^82-84.

Globule size and its distribution in emulgel:

The Malvern zeta sizer determines globule size and distribution. A 1.0gm sample is 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 are obtained⁸⁵.

Extrudability:

Here the weight required to extrude 0.5cm ribbon of emulgel in 10 sec from a lacquered collapsible aluminum tube is determined. The test was repeated, and the average values were used for the calculation⁸⁶.

The formula for extrudability calculation Extrudability

= weight applied to extrude emulgel form tube (gm)/Area (cm²)

Viscosity:

Viscosity is characterized using a cone and plate type of Brookfield viscometer (Brook field viscometer RVT) with spindle No.7. The maximum shear rate was 100 RPM, while the minimum was 10 RPM⁸⁷.

In-vitro drug release studies:

In-vitro release behavior from emulgel formulations was investigated using an eggshell membrane. An exciting investigation used egg membrane, like human stratum corneum, consisting mainly of keratin⁸⁸. Using 0.5M, the hydrochloric outer shell of the whole egg was dissolved, resulting in a membrane. After that, the egg contents may be detached, and the membrane washed and refrigerated or soaked in isopropyl myristate under vacuum to impregnate the keratin matrix. The replacement of water in the membrane with this lipid is assumed to increase its likeness to stratum corneum biochemistry. The Keshary-Chien cell was used for release and permeation study. One gram of gel was applied on the 9.8 cm2 surface area of the egg membrane fixed to the lower end of the donor compartment.

The temperature condition of the receptor fluid was maintained at 37˚C and stirred continuously at 100rpm on a magnetic stirrer. Aliquots of 3.0ml were withdrawn and analyzed for the drug content after suitable dilutions using the spectrophotometric method; the fluid volume withdrawn for analysis is replaced quantity of the fresh buffer after every sampling with the same buffer. The cumulative quantity released throughout the egg membrane was calculated and plotted against time⁸⁸.

Zeta potential:

The Zeta potential of emulsions is determined via Zetatrac, measuring the response of charged tiny particles to an electric field. In a stable electric area, particles drift at a stable velocity through the velocity, the rate and Zeta potential are determined. Zetatrac utilizes a high-frequency AC electric field to oscillate the charged tiny particles. The Brownian movement power spectrum is analyzed with the Nanotrac controlled reference approach of particle sizing to determine the Modulated strength Spectrum, a component of the electric spectrum resulting from the oscillating particles ⁸⁹.

Ex-vivo skin permeation and retention studies:

Albino rat 10-12 weeks old weighing 200-250g was used. The excised skin was placed in aluminum foil the dermal aspect of the skin was delicately teased off for any following fats or subcutaneous tissue. The skin was then precisely checked through a magnifying glass to guarantee that specimens were free from any surface inconsistencies, such as small openings or services in part utilized for transdermal permeation studies. The skin was washed with buffer saline solution, and freshly obtained skin was used in all experiments. The ex-vivo skin permeation of the drug from different formulations was studied using the Keshary-Chien cell. The effective permeation area of the diffusion cell was 9.8cm2. The receptor compartment has a volume of 37.5ml. Albino rat skin was sandwiched safely between donor and receptor compartment, with the epidermis site. The donor compartment was maintained at 37±1⁰C with constant stirring.

The emulgel formulation was applied to the selective epidermal surface of the rat skin. At a predetermined time interval of 24hours, 3.0ml of aliquots were withdrawn and replaced with an identical volume of fresh receptor compartment solvent to ensure sink condition. The cumulative percentage of drug diffused across the skin was calculated at each sampling point²⁰.

SUMMARY:

Many formulations are used in a topical drug delivery system, but they also have disadvantages. Most of these disadvantages are overcome by emulgel preparation. The emulgel has proven as the most convenient, better, and effective delivery system through the project. Incorporating the emulsion into gel makes it a dual control release system to solve further problems such as phase separation, creaming associated with emulsion, and stability improvement. The preparation of emulgel is done with three steps; preparation of emulsion, preparation of gel, and incorporation of this two preparation. Every formulation needs a proper evaluation. So, here also there are nearly twenty-five types of evaluation methods, such as Spreadability, Rheological study, In-vitro drug release study, Globule size and its distribution, Extrudability, Viscosity, Zeta potential, etc. Nowadays, the emulgel is widely used. The most commonly used emulgels are Miconaz-H-emulgel, Isofen emulgel, Diclon emulgel, etc.

FUTURE PROSPECTIVE:

During the formulation and development of any new formulation, the most common problems faced from own disadvantages and problems. Because of the hydrophobic nature of many drugs, delivering these to the biological system has been demanding. Ointments, Creams, and lotion are of different types of drug delivery systems applied dermally have excellent emollient effects but retards the release of drugs due to oleaginous bases. Compared to other topical systems, the gel provides quicker drug release because gel provides an aqueous environment to drugs. Hydrophobic drugs can be incorporated into an oily base and delivered to the skin using an emulgel. All such factors of interest of Emulgel over different topical drug delivery systems lead them to be more effective and worthwhile. In the future, these properties will be utilized to convey more topical medications as Emulgel.

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Received on 29.10.2022 Accepted on 18.11.2022

Research J. Topical and Cosmetic Sci. 2023; 14(1):20-28.

DOI: 10.52711/2321-5844.2023.00005

S. no	Gelling agents	The concentration used (%w/w)	Pharmaceutical adaptability	Active pharmaceutical ingredient	References
1	Sodium CMC	3-4%	sterile gels	Benzydamine	56
2	Carbopol-934	1%	controlled release of API incorporated	Chlorphenesin	57
3	Carbopol-940	1%	controlled release of API incorporated	Mefenamic	58
4	HPMC	2.5%	Having good stability, microbial resistance	Chlorphenesin	59
5	Pluronic® F127	1-3%	Good clarity and better solubility in cold water	Piroxicam	60

S. No.	Marketed	API	Manufacturer
1	Voltarol 1.16% emulgel	Diclofenac sodium	Novartis
2	Diclomax Emulgel	Diclofenac sodium	Torrent pharma
3	Miconaz-H-emulgel	Miconazole nitrate, Hydrocortisone	Medical union Pharmaceuticals
4	Dermafeet Emulgel	Urea	Herbitas
5	Isofen Emulgel	Ibuprofen	Beit Jala pharmaceutical
6	Diploma Emulgel	Diclofenac diethylamine	Kuwait Saudi pharmaceutical
7	Dillon Emulgel	Diclofenac diethylamine	Med pharma
8	Cataflam Emulgel	Diclofenac potassium	Novartis
9	Dancing Emulgel	Clindamycin phosphate	Beit Jala pharmaceutical

S. No.	Patent Name	Product	Inventors	Publication Date	Reference
1	WO2006082596A2	Neem oil contraceptive	Kamalinder Kaur Singh, Pratima Arun Tatke, Shruti Dhuru	2006-08-10	73
2	EP 2 055 298 A1	Diclofenac gel Voltaren Emulgel	NOVARTIS AG	2009-05-06	74
3	US20120093882A1	Voveran	Sunilendu Bhushan Roy, Shafiq Sheikh, Jay Kothari, Jitendra Patel	2012-04-19	75
4	WO2008051186A2	Nanoemulsion containing Composition having anti-inflammatory activity	James R Baker Nanobio Corporation	2008-05-02	76