INTRODUCTION:

Emulgel are emulsions, either of the oil-in-water or water in oil type, which are gelled by mixing with a gelling agent. Emulsified gel is stable one and better vehicle for hydrophobic or poorly water soluble drugs ^[1]. They have a high patient acceptability since they possess the advantages Topical drug delivery and antifungal activity of both emulsions and gels. Direct (oil-in-water) systems are used to entrap lipophilic drugs, whereas hydrophilic drugs are encapsulated in the reverse (water-in-oil) systems ^[2]. Therefore, they have been recently used as vehicles to deliver various hydrophobic drugs to the skin.

In the local market, 2 Emulgel are available: Voltaren emulgel (Novartis Pharma, Switzerland), containing diclofenac diethylamine and Miconaz-H emulgel (Medical Union Pharmaceuticals, Egypt), containing miconazole nitrate and hydrocortisone ^[3].

Topical drug administration is a localized drug delivery Topical drug administration is a localized drug delivery system anywhere in the body through ophthalmic, rectal, vaginal and skin as topical routes. Skin is one of the most readily accessible organs on human body for topical administration and is main route of topical drug delivery system. The emulsion gels are hydrogels containing randomly distributed oil microdroplets.^[^4-9]Topical drug delivery systems have been used for centuries for the treatment of local skin disorders, one side the topical applications of the drug offer the potential advantages of delivering the drug directly to the site of action and delivering the drug for extended period of time at the effected site that mainly acts at the related regions^[10-14]. On the other hand, topical delivery system increases the contact time and mean resident time of drug at the applied site leading to an increase in local drug concentration while the pharmacological activity of Emulgel formulations may not change as rapidly as the solution form ^[15]. Several antifungal agents are available on the market in different topical preparations (e.g. creams, ointments, and powders for the purpose of local dermatological therapy)^[^16-18].One of these antifungal agents is Itraconazole, which has both antifungal and antibacterial properties. It is applied locally in mild uncomplicated dermatophyte and other cutaneous infections ^[19-20].

Both oil-in-water and water-in-oil emulsions are extensively used for their therapeutic properties and as vehicles to deliver various drugs to the skin. Emulsions possess a certain degree of elegance and are easily washed off whenever desired. They also have a high ability to penetrate the skin. In addition, the formulator can control the viscosity, appearance, and degree of greasiness of cosmetic or dermatological emulsions. Oil-in-water emulsions are most useful as water washable drug bases and for general cosmetic purposes, while water-in-oil emulsions are employed more widely for the treatment of dry skin and emollient applications. Gels for dermatological use have several favorable properties such as being thixotropic, greaseless, easily spreadable, easily removable, emollient, nonstaining, compatible with several excipients, and water-soluble or miscible. The rheological properties and the breakdown behaviour of gels filled with emulsions droplets can be varied by changing the interactions between oil droplets and gel matrix, the oil content and the oil droplet size.

MATERIALS AND METHODS:

Materials:

Itraconazole was obtaines as a gift sample from Gufic Bioscience Ltd Mumbai, Carbopol 934, Carbopol 940, Light liquid paraffin, Tween 20, Span 20, propylene glycol, methyl paraben and propyl paraben were purchased from lobaie chemicals, Mumbai. Ethanol was procured from Rajarambapu College of Pharmacy, Kasegaon. Double distilled water was used for all experiment. All chemicals were pharmaceutical grade and used without further modification.

Preparation of gellified emulsion Itraconazole:

Gellified Emulsion was prepared. 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 6.5using Tri EthanolAmine (TEA). The oil phase of the emulsion were prepared by dissolving Span 20in light liquid paraffin while the aqueous phase was prepared by dissolving Tween 20 in purified water. Methyl and Propyl paraben was dissolved in propylene glycol whereas drug (Itraconazole)was dissolved in ethanol and both solutions was mixed with the aqueous phase. Both the oily and aqueous phases were separately heated to 70° to 80°C; then the oily phase were added to The aqueous phase with continuous stirring until cooled to room temperature. And add Glutaraldehyde in during of mixing of gel and emulsioin1:1and to obtain the Gellified Emulsion

Emulgel preparation:

Contents	F1	F2	F3	F4	F5
Itraconazole	1	1	1	1	1
Carbopol 940	1	1.5	2	-	-
carbopol 934	1	1.5	2	-	-
Span 20	0.5	0.5	0.5	0.5	0.5
Tween 20	1	1	1	1	1
Liquid paraffin	7.5	7.5	7.5	7.5	7.5
Propylene glycol	5	5	5	5	5
Methyl paraben	0.03	0.03	0.03	0.03	0.03
Propyl paraben	0.02	0.02	0.02	0.02	0.02
Water	q.s	q.s	q.s	q.s	q.s

Contents	F6	F7	F8	F9
Itraconazole	1	1	1	1
Carbopol 940	-	-	-	-
carbopol 934	-	-	-	-
Span 20	0.5	0.5	0.5	0.5
Tween 20	1	1	1	1
Liquid paraffin	7.5	7.5	7.5	7.5
Propylene glycol	5	5	5	5
Methyl paraben	0.03	0.03	0.03	0.03
Propyl paraben	0.02	0.02	0.02	0.02
Water	q.s	q.s	q.s	q.s

Characterization of Emulgel

Physical appearance:

The prepared Itraconazoleemulgel formulations were inspected visually for their color, homogeneity, consistency and pH. The pH values of 1% aqueous solutions of the prepared emulgel were measured by a pH meter (Digital ph meter)

Formulation table	pH
F1	5.80
F2	7.70
F3	6.4
F4	5.65
F5	6.65
F6	6.8
F7	6.4
F8	7.0
F9	6.9

Spreadability:

One of the criteria for an emulgel to meet the ideal quantities is that it should possess good spreadability. It is term expressed to denote the extent of area to which gel readily spread on application to skin or affected part. The therapeutic efficacy of a formulation also depends upon its spreading value. Spreadability is expressed in terms of time in seconds taken by two slides to slip off from emulgel and placed in between the slides under the direction of certain load. It is calculated by using the formula.

Formulation code	Diameter(cm)
F1	4.2
F2	4.7
F3	5.8
F4	4.2
F5	4.5
F6	5.5
F7	4.8
F8	5.0
F9	4.8

Rheological Study:

The viscosity of different emulgel formulation was determined at 250^oC using a brook field viscometer (Brookfield DV-E viscometer). The emulgel were rotated at 10 (min.) and 100 (max.) rotation per minute with spindle 4

Formulation batch	Spindal no	RPM	Viscosity
Formulation batch	Spindal no	RPM	(centipoise)
F1	6	5	88000
F2	5	5	87000
F3	4	10	94000
F4	6	5	91000
F5	6	5	89000
F6	6	5	92000
F7	6	5	93000
F8	6	5	91000
F9	6	5	90000

Drug Content Determination:

Drug concentration in emulgel was measured by UV spectrophotometer. Itroconazole content in emulgel was measured by dissolving Known quantity of emulgel in solvent (methanol) by Sonication. Absorbance was measured after suitable dilution at 226 nm in UV/VIS spectrophotometer (UV-1800, Shimadzu Corporation, Japan).

Formulation code	Drug content %
F1	82.85
F2	85.76
F3	94.97
F4	85.76
F5	91.37
F6	78.57
F7	92.67
F8	90.86
F9	84.86

In Vitro Release Study:

Diffusion cell (with effective diffusion area 3.14 cm2 and 15.5 ml cell volume) was used for the drug release studies. Emulgel (200 mg) was applied onto the surface of egg membrane evenly. The egg membrane was clamped between the donor and the receptor chamber of 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 magnetic stirrer. The samples (1.0 ml aliquots) were collectedat suitable time interval. Samples were analyzed for drug content by UV visible spectrophotometer at 226 nm after appropriate dilutions. Cumulative corrections were made to obtain the total amount of drug release at each time interval .The cumulative amount of drug released across the egg membrane was determined as a function of time.

Time	F1	F2	F3	F4	F5
0	0	0	0	0	0
1	11	13.36	12.29	13.23	11.23
2	12.26	14.28	15.95	16.55	15.45
3	13.63	15.43	24.88	25.11	17.45
4	13.77	17.23	27.38	30.23	19.66
5	14.6	18.31	31.1	31.22	21.45
6	15.62	19.32	31.13	32.44	24.15
7	16.21	21.43	33.81	33.14	29.44
8	17.38	23.35	36.35	35.65	32.63
9	21.22	26.43	39.7	40.36	35.62
10	23.41	29.33	43.61	45.64	38.47
11	27.06	32.21	46.97	47.88	43.49
12	30.61	33.36	56.83	51.42	49.8
13	33.41	36.55	61.77	58.23	53.11
14	35.76	40.22	65.12	62.33	55.87
15	41.01	43.48	77.76	66.54	61.44
16	44.63	48.55	79.33	67.88	63.32
17	47.4	52.33	81.37	71.23	67.99
18	51.45	59.44	84	74.65	69.74
19	55.96	61.22	86.27	78.99	71.44
20	57.7	65.33	87.38	80.12	74.23
21	60.12	67.32	91.13	82.33	77.45

Time	F6	F7	F8	F9
0	0	0	0	0
1	10.23	9.6	12.3	10.36
2	13.32	15.23	19.65	20.64
3	15.3	18.25	20.36	21.33
4	17.45	19.66	24.56	23.54
5	22.32	23.14	26.33	25.88
6	25.46	27.45	29.65	30.21
7	28.45	33.32	31.24	32.69
8	31.26	38.77	34.55	33.14
9	37.45	41.56	39.64	40.55
10	40.45	45.69	43.12	45.64
11	44.12	48.99	48.21	47.98
12	50.16	49.77	53.54	50.12
13	52.36	53.26	56.37	53.11
14	58.79	59.69	59.47	60.21
15	63.79	64.35	63.24	62.36
16	67.96	68.97	65.88	65.55
17	75.88	73.26	69.57	67.99
18	78.46	79.48	70.14	70.45
19	80.23	82.54	72.45	72.36
20	82.31	84.56	72.8	74.65
21	84.13	86.33	74.14	76.98

Skin irritation test:

A 0.5 gm 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 2,54 cm) square. The emulgel re applied on the skin of rabbit. Animals were returned to their cages. After a 24 hour exposure, the emulgel are removed. The test sites were wiped with tap water to remove any remaining test article residue.

Stability studies:

The prepared Itraconazole emulgel formulations were stored away from light in collapsible tube at 25±2°C, 40±2°C and 4±2°C for 3 months. After storage, the samples are tested for their physical appearance, pH, rheological behavior, drug release, skin irritation test and microbiological assay.

Sr no.	Properties	Observation
1	Color (Initial )	White
2	Color (After one month)	White
3	pH (Initial )	6.5
4	pH (After one month)	6.5
5	% drug content	92%

RESULTS:

Physical examination: The prepared Itraconazole emulgel formulations were white viscous creamy preparation with a smooth and homogeneous appearance. The pH values of all prepared formulation ranged from 5.4 to 5.8, which are considered acceptable to avoid the risk of irritation upon application to the skin because adult skin pH is 5.5.

Spreadability:

The values of spreadability indicate that the emulgel is easily spreadable by small amount of shear. Spreadability of F3 was 5.7.cm/sec, indicating spreadability of emulgel containing itroconazole was good as compared to the marketed gel.

Stability studies:

Stability studies of optimized formulation were performed as per ICH guideline (International Conference on Harmonization). It can be observed that the emulgel formulation showed no major alteration in relation to the pH, microbiological study, consistency, skin irritation test and in vitro release study. The formulation shows stability for the period of 3 months. No significant changes in the pH of formulations were observed for 3 months in all storage conditions.

DISCUSSION:

The drug Itraconazole is antifungal drug with wide spectrum of antifungal activity. The physical appearance and melting point of drug were found to be concordant with that mentioned in USP (2002), which shows purity of sample. Solubility of Itraconazole was determined in various aqueous and non aqueous solvents. The drug was found to be freely soluble in methylene chloride, soluble in methanol, sparingly soluble in ethanol, and slightly soluble in PBS (pH 5.5), and insoluble in water. The λmax for drug in PBS (pH 5.5) was 226 nm. The spreadability of formulations ranges from 4.1±0.95g.cm/sec to 5.7±1.17 g.cm/sec. The higher spreadability of emulgel formulation (F3) is 5.7±0.84 g.cm/sec. It may be due to the low concentration of emulsifying agent added in this formulation. The highest viscosity was found in Emulgel F3 it may be due to low level of the liquid paraffin concentration and emulsifying agent concentration. The drug content in emulgel is 78.57± 1.82 % to 94.98 ± 1.20 %. The higher drug content determination in emulgel F3 are 94.98± 1.20 %. The higher drug release observed with formulations F3. This finding may be due to presence of liquid paraffin in its low level and the emulsifying agent in its low level/high level respectively, which lead to an increase in the hydrophilicity of the emulgel, which, in turn, facilitates penetration of the release medium into the emulgel and diffusion of the drug from the emulgel. The percentage inhibition was taken as a measure of antifungal activity of the drug. The emulgel formulations were found to have the same rank order in their antifungal activities as in the in vitro release studies. Thus, the highest activity was observed formula, where the percentage inhibition found to be 47.5 ±1.15 % and 46.6 ± 1.34 % respectively. The Primary Irritation of the emulgel formulation was calculated and found to be nil. The formulations found to be stable for period of 3 months; it can be observed that the emulgel formulation showed no major alteration in relation to the pH consistency, skin irritation test and in vitro release study. The prepared formulation (emulgel) show better release profile than marketed preparation. Emulgel will act as depot of drug which releases drug in sustained manner. Hence the optimized formulation may be used to treat the topical fungal diseases.

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Received on 05.03.2015 Accepted on 10.04.2015

Asian J. Pharm. Tech. 2015; Vol. 5: Issue 2, Pg 91-96

DOI: 10.5958/2231-5713.2015.00014.8