INTRODUCTION:

The topical drug delivery system is generally used where these systems of drug administration fails or in local skin infection like fungal infection. Topical drug delivery system can be defined as direct effects of formulation or drug containing medication to the skin to get localizing effect of drug or directly cure cutaneous disorders. Dermatological products applied to skin are diverse in formulation and range in consistency from liquid to powder but the most popular products are semisolid preparation [2]. Topical drug delivery system has several advantages such as ability to deliver drug more selectively to a specific site, avoidance of gastro-intestinal incompatibility and metabolic degradation associated with oral administration [3]. The release rates of drugs from topical preparations depend directly on the physiochemical properties of the carrier and the drug employed. In topical drug delivery system drug diffuses out of the delivery system, reaches to the site of action and gets absorbed by the skin. Increasing the release rate of the drug from the dosage form might therefore improve percutaneous absorption³.

Emulgel:

As the name suggest, they are the combination of gel and emulsion. Both oil-in-water and water-in-oil type of emulsion used as a vehicle to deliver various drugs to the skin. They also have a high ability to penetrate the skin. The presence of the gelling agent in water phase converts a classical emulsion into an emulgel. Emulgel for dermatological use has several favourable properties such as being thixotropic, greaseless, easily spreadable, easily removable, emollient, non-staining, water-soluble, longer shelf life, bio-friendly, transparent and pleasing appearance.

Molecules can basically penetrate into the skin by three routes: through intact stratum corneum, sweat ducts, or sebaceous follicle. The surface of the stratum corneum presents more than 99% of the total skin surface available for percutaneous drug absorption. Passage through this outermost layer is the rate limiting step for percutaneous absorption⁴.

Rationale of using Emulgel as Drug Delivery System:

Hydrophobic drugs can be easily incorporated into gels using emulsions Most of the hydrophobic drugs cannot be incorporated directly into gel base because solubility act as a barrier and problem arises during the release of the drug. Emulgel helps in the incorporation of hydrophobic drugs into the oil phase and then oily globules are dispersed in aqueous phase resulting in o/w emulsion. And this emulsion can be mixed into gel base. This may be proving better stability and release of drug than simply incorporating drugs into gel base.

· Production feasibility and low preparation cost:

Preparation of emulgels comprises of simpler and short steps which increases the feasibility of the production. There are no specialized instruments needed for the production of emulgels. Moreover materials used are easily available and cheaper. Hence, decreases the production cost of emulgels.

· Controlled release:

Emulgels can be used to prolong the effect of drugs having shorter T1/2.

· Patient compliance:

They are less greasy and easy to apply.

· No intensive sonication:

Production of vesicular molecules needs intensive sonication which may result in drug degradation and leakage. But this problem is not seen during the production of emulgels as no sonication is needed.

· Better loading capacity:

Other novel approaches like niosomes and liposomes are of nano size and due to vesicular structures may result in leakage and result in lesser entrapment efficiency. But gels due to vast network have comparatively better loading capacity.

· Better stability:

Other transdermal preparations are comparatively less stable than emulgels. Like powders are hygroscopic, creams shows phase inversion or breaking and ointment shows rancidity due to oily base.

· Avoidance of first pass metabolism.

· Avoidance of gastrointestinal incompatibility.

· More selective to a specific site.

· Improve patient compliance.

· Suitability for self-medication.

· Providing utilisation of drug with short biological half-life and narrow therapeutic window.

· Ability to easily terminate medication when needed.

· Convenient and easy to apply.

· Incorporation of hydrophobic drugs

Drawbacks of Emulgel:

· Skin irritation on contact dermatitis.

· The possibility of allergenic reactions.

· The poor permeability of some drug through the skin.

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

· The occurrence of the bubble during formation of emulgel.5,6

Factors affecting topical absorption of drug in Emulgel :

Physiological factors:

· Skin thickness.

· Lipid content.

· The density of hair follicles.

· The density of sweat glands.

· Skin pH.

· Blood flow.

· Hydration of skin.

· Inflammation of skin.

Physicochemical factors:

· Partition coefficient.

· The molecular weight (<400 Dalton).

· The degree of ionisation (only unionised drugs gets absorbed well).

· Effect of vehicle

Physiology of Skin:

Fig. 01: Anatomy of Skin

Most of the topical preparations are meant to be applied to the skin. So a basic knowledge of the skin and its physiology function are very important for designing topical dosage form. The skin of an average adult body covers a surface area approximately 2m² and receives about one-third of the blood circulating through the body. An average human skin surface is known to contain, on the average 40-70 hair follicles and 200-300 sweat ducts on every square centimetre of the skin. The pH of the skin varies from 4 to 5.6. Sweat and fatty acid secreted from sebum influence the pH of the skin surface. The skin can be considered to have four distinct layers of tissue.

Non-viable epidermis:

Stratum corneum is the outermost layer of skin, which is the actual physical barrier to the most substance that comes in contact with the skin. The stratum corneum is 10 to 20 cell layer thick over most of the body. Each cell is a flat, plate-like structure-34-44µm long, 25-36µm wide, 0.5 to 0.20µm thick with a surface area of 750 to 1200µm stocked up to each other in brick-like fashion. Stratum corneum consists of lipid (5-15%) including phospholipids, glycosphingolipid, cholesterol sulphate and a neutral lipid, protein (75-85%) which is mainly keratin.⁷

Viable epidermis:

This layer of the skin resides between the stratum corneum and the dermis and has a thickness ranging from 50-100µm. The structures of the cells in the viable epidermis are physicochemically similar to other living tissues. Cells are held together by tonofibrils. The density of this region is not much different than water. The water content is about 90%.

Dermis:

Just beneath the viable epidermis is the dermis. It is a structural fibrin and very few cells are like it can be found histological in normal tissue. Dermis thickness ranges from 2000 to 3000µm and consists of a matrix of loose connective tissue composed of fibrous protein embedded in an amphorphose ground substance.

Subcutaneous connective tissue:

The subcutaneous tissue or hypodermis is not actually considered a true part of the structured connective tissue which is composed of loose textured, white, fibrous connective tissue containing blood and lymph vessels, secretary pores of the sweat gland and cutaneous nerves. Most investigators consider drug is permeating through the skin enter the circulatory system before reaching the hypodermis, although the fatty tissue could serve as a depot of the drug.⁸

Factors to be Considered When choosing a Topical Preparation:

· Effect of the vehicle e.g. An occlusive vehicle enhances penetration of the active ingredient and improves efficacy. The vehicle itself may have a cooling, drying, emollient or protective action.

· Match the type of preparation with the type of lesions. For example, avoid greasy ointments for acute weepy dermatitis.

· Match the type of preparation with the site.(e.g., gel or lotion for hairy areas)

· Irritation or sensitization potential. Generally, ointments and w/o creams are less irritating, while gels are irritating. Ointments do not contain preservatives or emulsifiers if allergy to these agents is a concern⁹.

Emulgel preparation:

Aqueous material:

This forms the aqueous phase of the emulsion. Commonly used agents are water, alcohols.

Oils:

These agents form the oily phase if the emulsion. For externally applied emulsions, mineral oils, either alone or combined with soft or hard paraffin, are widely used both as the vehicle for the drug and for their occlusive and sensory characteristics. Widely used oils in oral preparations are non-biodegradable mineral and castor oils that provide a local laxative effect, and fish liver oils or various fixed oils of vegetable origin (e. g., Arachis, cottonseed, and maize oils) as nutritional supplements.

Table No. 01:

Chemical	Quantity	Dosage form
Light Liquid Paraffin	7.5%	Emulsion and Emulgel
Isopropylmyristate	7-7.5%	Emulsion
Isopropyl stearate	7-7.5%	Emulsion
Isopropyl palmitate	7-7.5%	Emulsion
Propylene glycol	3-5%	Gel

Emulsifiers:

Emulsifying agents are used both to promote emulsification at the time of manufacture and to control stability during a shelf life that can vary from days for extemporaneously prepared emulsions to months or years for commercial preparations. e. g. polyethylene glycol 40 stearate, sorbitan monooleate (span 80), polyoxyethylene sorbitan monooleate (tween 80), stearic acid, sodium stearate.

Gelling agent:

These are the agents used to increase the consistency of any dosage form can also be used as thickening agent.

Permeation enhancers:

These are agents that partition into and interact with skin constituents to induce a temporary and reversible increase in skin permeability.^10,11

Table No. 02:

Gelling agent	Quantity	Dosage form
Carbopol-934	0.5%-2%	Emulgel
Carbopol-940	0.5%-2%	Emulgel
HPMC-2910	2.5%	Emulgel
HPMC	3.5%	Gel
Sodium CMC	1%	Gel

Table No.03:

Penetration enhancer	Quantity	Dosage form
Oleic acid	1%	Gel
Lecithine	5%	Gel
Urea	10%	Gel
Isopropyl myristate	5%	Gel
Linoleic acid	5%	Gel
Clove oil	8%	Emulgel
Menthol	5%	Emulgel
Cinnamon	8%	Emulgel

Preparation of Emulgel:

Emulgel was prepared by the method reported with minor modification. The Gel in formulations were prepared by dispersing Carbopol 934 in purified water with constant stirring at a moderate speed and carbopol 940 in purified water with constant stirring at a moderate speed then the pH are adjusted to 6 to 6.5 using triethanolamine (TEA). The oil phase of the emulsion was prepared by dissolving Span 80 in light liquid paraffin having the drug in ethanol solution while the aqueous phase was prepared by dissolving Tween 80 in purified water. Methyl and Propylparaben was dissolved in propylene glycol and was mixed with the aqueous phase. Both the oily and aqueous phases were separately heated to 70° to 80°C; then the oily phase was added to the aqueous phase with continuous stirring until cooled to room temperature. And add glutaraldehyde in during of mixing of gel and emulsion in ratio 1:1 to obtain the emulgel.¹²

Characterization of Emulgel:

Fourier transforms infrared spectroscopy (FTIR):

The primary objective of this investigation was to identify a stable storage condition for the drug in solid state and identification of compatible excipients for formulation.

Physical examination:

The Prepared emulgel formulations were inspected visually for their colour, homogeneity, consistency and phase separation.

Determination of pH:

pH of the formulation was determined by using digital pH meter. pH meter electrode was washed by distilled water and then dipped into the formulation to measure pH and this process was repeated 3 times.

Measurement of viscosity:

The viscosity of the formulated batches was determined using a Brookfield Viscometer (RVDV-I Prime, Brookfield Engineering Laboratories, USA) with spindle 63. The formulation whose viscosity was to be determined was added to the beaker and was allowed to settle down for 30 min at the assay temperature (25±1 °C) before the measurement was taken. Spindle was lowered perpendicularly into the centre of emulgel taking care that spindle does not touch the bottom of the jar and rotated at a speed of 50rpm for 10 min. The viscosity reading was noted.

Spreadability:

To determine spreadability of the gel formulations, two glass slides of standard dimensions were selected. Formulation whose spreadability was to be determined was placed over one slide and the other slide was placed over its top such that the gel is sandwiched between the two slides. The slides were pressed upon each other so as to displace any air present and the adhering gel was wiped off. The two slides were placed onto a stand such that only the lower slide is held firm by the opposite fangs of the clamp allowing the upper slide to slip off freely by the force of weight tied to it. 20g weight was tied to the upper slide carefully. The time taken by the upper slide to completely detach from the lower slide was noted.

Globule size and its distribution in emulgel:

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

Swelling index:

To determine the swelling index of prepared topical emulgel, 1g of gel is taken on porous aluminium foil and then placed separately in a 50ml beaker containing 10ml 0.1N NaoH. Then samples were removed from beakers at different time intervals and put it on a dry place for some time after it reweighed.

Swelling index is calculated as follows: Swelling Index (SW) % = [(Wt – Wo) / Wo] × 100. Where, (SW) % = Equilibrium percent swelling, Wt = Weight of swollen emulgel after time t, Wo = Original weight of emulgel at zero time.

In vitro drug release study:

The in vitro drug release studies of the Emulgel were carried out on Diffusion cell using egg membrane. This was clamped carefully to one end of the hollow glass tube of dial y sis cell. Emulgel (1g) was applied onto the surface of egg membrane dialysis membrane. The receptor chamber was filled with freshly prepared PBS (pH 7.4) solution to solubilize the drug. The receptor chamber was stirred by a magnetic stirrer. The samples (1ml aliquots) were collected at suitable time interval sample were analysed for drug content by UV-visible spectrophotometer after appropriate dilutions. Cumulative corrections were made to obtain the total amount of drug released at each timeinterval. The cumulative amount of drug release across the egg membrane was determined as a function of time. The cumulative % drug release was calculated using standard calibration curve.

Microbiological assay:

Ditch plate technique was used. It is a technique used for evaluation of bacteriostatic or fungi static activity of a compound. It is mainly applied for semisolid formulations. Previously prepared Sabouraud’s agar dried plates were used. Three grammes of the Gellified emulsion are placed in a ditch cut in the plate. Freshly prepared culture loops are streaked across the agar at a right angle from the ditch to the edge of the plate.

Skin irritation test:

A 0.5g sample of the test article was then applied to each site (two sites per rabbit) by introduction under a double gauze layer to an area of skin approximately 1” x 1” (2.54 x 2.54cm²). The Gellified Emulsion was applied on the skin of a rabbit. Animals were returned to their cages. After a 24 h exposure, the Gellified emulsion is removed. The test sites were wiped with tap water to remove any remaining test article residue.

Stability studies:

The prepared emulgels were packed in aluminium collapsible tubes (5g) and subjected to stability studies at 5°C, 25°C/60% RH, 30°C/65% RH, and 40°C/75% RH for a period of 3 mo. Samples were withdrawn at 15-day time intervals and evaluated for physical appearance, pH, rheological properties, drug content, and drug release profiles.

Drug Content Determination:

Drug concentration in Gellified Emulsion was measured by spectrophotometer. Drug content in Gellified Emulsion was measured by dissolving known quantity of Gellified Emulsion in solvent (methanol) by Sonication. Absorbance was measured after suitable dilution in UV/VIS spectrop hotometer (UV‐1700 CE).

Extrudability Study of Topical Emulgel (Tube Test):

It is a usual empirical test to measure the force required to extrude the material from tube. The method applied for determination of applied shear in the region of the rheogram corresponding to a shear rate exceeding the yield value and exhibiting consequent plug flow. In the present study, the method adopted for evaluating emulgel formulation for extrudability is based upon the quantity in percentage of emulgel and emulgel extruded from lacquered aluminum collapsible tube on application of weight in grams required to extrude at least 0.5 cm ribbon of emulgel in 10 s. More quantity extruded better is extrudability. The measurement of extrudability of each formulation is in triplicate and the average values are presented [52]. The extrudability is than calculated by using the following formula: Extrudability = Applied weight to extrude emulgel from tube (in gm)/Area (in cm2)¹³.

Photo microscopy:

Optimized batch of the emulgel was viewed under light microscope to study the globular structure in gel base. The emulgel was suitably diluted, mounted on glass slide and viewed by light microscope under magnification of 40.

Globule size:

The globule size obtained was determined using Zetasizer (Malvern Instrument 3000HSA, UK). The sample was suitably diluted and the globule size was measured at 25⁰C.

Rheological studies:

The viscosity of the different emulgel formulations is determined at 25⁰C using a cone and plate viscometer with spindle 52 (Brookfield Engineering Laboratories,) and connected to a thermostatically controlled circulating water bath.

Determination of pH:

The pH measurements were done using a digital pH meter (Thermo scientific) which was calibrated with standard buffer solutions. The measurements of pH of each system were replicated three times.

Determination of thixotropic characteristics:

The formulations were subjected to different rates of shear using Gemini 200: Rheometer, at constant temperature (25⁰C). the measuring system employed was the cone and plate system having 40mm diameter and 40 angles. The rheogram was constructed by plotting rate of shear against shear stress.^14,15

Marketed Preparations:

Some preparations of Emulgel are commercially available in markets which are listed as following in Table No. 04.

Table N0.04:

Sr. No.	Drug	Product Name	Manufacturer
01	Miconazole nitrate, Hydrocortisone	Miconaz-H-emulgel	Medical union Pharmaceuticals
02	Diclofenac diethyl ammonium	Voltaren emulgel	Novartis Pharma
03	Metronidazole	Lupigyl gel	Lupin Pharma
04	Benzoyl peroxide	Pernox gel	Cosme Remedies Ltd

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4. Gupta A, Mishra AK, Singh AK., Formulation and evaluation of topical gel of diclofenac sodium using different polymers, Drug Invention Today. 2010; 2:250-253.

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10. http://www.dermweb.com/therapy/common.htm “Principle of Skin Theraphy”.

11. Stanos SP. Topical Agents for the Management of Musculoskeletal Pain. J Pain Symptom Manage. 2007; 33.

12. Mishra AN. Controlled and novel drug delivery. 4^th ed. CBS Publisher and Distributers, Delhi; 1997. p. 107-9.

13. Kullar R, Saini S, Steth N, Rana AC. Emulgel a surrogate approach for topical used hydrophobic drugs. Int J Pharm Biol Sci. 2011;1: 117-28.

14. Lachman L, Lieberman HA. The Theory and Practice of Industrial Pharmacy. 3^rd ed. Varghese Publishing House; 1990. p. 534.

15. Ayub, CA, Gomes ADM, Lima MVC, Vianna- Soares CD, FerreiraLMA. Topical Delivery of Fluconazole: In Vitro Skin Penetration and Permeation Using Emulsions as Dosage Forms Drug. Dev. Ind. Pharm. 2007; 33:273- 280.

Received on 25.09.2020 Modified on 13.11.2020

Res. J. Pharma. Dosage Forms and Tech.2021; 13(1):25-30.

DOI: 10.5958/0975-4377.2021.00006.9