INTRODUCTION:

Allopurinol, a xanthine oxidase inhibitor decreases uric acid production. The Effectiveness of the Xanthine Oxidase Inhibitor Allopurinol in the Treatment of Gout used to treat gout and certain types of kidney stones¹ .It is also used to prevent increased uric acid levels in patients under cancer chemotherapy².Increased uric acid levels may be observed in the patients due to release of uric acid from the dying cancer cells. Allopurinol reduces the amount of uric acid made by the body. Increased uric acid levels can cause gout and kidney problems. Chemically Allopurinol is 1-H-pyrazolo [3,4-d] pyrimidin-4(2H)-one³. It is well absorbed from gastrointestinal tract however its use has been associated with a number of undesirable side effects on the stomach in addition to gastric mucosal damage. Drug delivery through skin is an alternative route which is devoid of the side effects mentioned earlier. The disadvantages associated with topical formulations include stickiness on skin causing uneasiness to the patient when applied. They also have less spreadability and need to apply with rubbing. In order to overcome those limitations, an emulsion based approach was attempted. When gels and emulsions are used in combination, the dosage forms are referred as emulgel.

Emulgelshas several favorable properties such as being thixotropic, greaseless, easily spreadable, easily removable, emollient, non-staining and pleasing appearance⁴. Aim of this work was to develop an emulgel formulation of using allopurinol different concentration of Carbopol 940. Rate of permeation of Allopurinol was enhanced using penetration enhancers like eugenol.

MATERIALS AND METHODS:

Materials:

Allopurinol was procured from Bakul Pharma Pvt. Ltd., Mumbai as gift sample, whereas carbopol 940, propylene glycol and liquid paraffin were purchased from Loba chemicals Mumbai. All other chemicals were used of analytical grade.

Preparation of emulgel:

Different formulations were prepared using varying amount of gelling agent. The gel phase in the formulations was prepared by soaking carbopol 940 in purified water for 24 hours⁵.

After 24 hours it was stirred with a moderate speed by mechanical stirrer and the pH of about 6–6.5 was adjusted with the addition of triethanolamine and the base was kept aside. Aqueous phase of emulsion was prepared by dissolving tween 20 in purified water whereas by dissolving span 20 in light liquid paraffin, eugenol the oil phase of the emulsion was prepared. Methyl paraben was used as stabilizer and was dissolved in propylene glycol. Pure drug Allopurinol was dissolved in dimethyl sulfoxide. Oily and aqueous phases were heated separately to 70–80˚C. When hot, the oily phase was added to the aqueous phase with continuous stirring until it got cooled to room temperature. To formulate the emulgel, the obtained emulsion was mixed with the gel base in 1:1 ratio with gentle stirring. The formulation table is shown as table 1.

Table 1: Formulation Table

Ingredient (%w/w)	F1	F2	F3	F4	F5	F6
Allopurinol	300	300	300	300	300	300
Carbopol 940	0.5	0.5	1	1	1.5	1.5
Liquid paraffin	7.5	7.5	7.5	7.5	7.5	7.5
Tween 20	0.5	0.5	0.5	0.5	0.5	0.5
Span 20	1	1	1	1	1	1
Propylene glycol	5	5	5	5	5	5
Dimethyl sulfoxide	2.5	2.5	2.5	2.5	2.5	2.5
Methyl paraben	0.003	0.003	0.003	0.003	0.003	0.003
Eugenol	8	10	8	10	8	10
Water	q.s.	q.s.	q.s.	q.s.	q.s.	q.s.

Characterization of emulgel:

The formulated emulgels were evaluated for various physicochemical parameters including Physical Appearance, pH measurement, spreadability, extrudability, viscosity, percentage drug content, in-vitro drug diffusion studies and stability studies.

Physical Appearance:

All the prepared emulgel formulations were inspected visually for their colour, homogeneity, consistency, grittiness and phase separation.

Measurement of pH:

The pH of all emulgel formulations was determined by digital pH meter. One gram of gel was dissolved in 100 ml of distilled water and it was placed for two hours. The measurement of pH of each formulation was done in triplicate and average values were noted⁶.

Spreadability:

Spreadability of the formulations was determined by an apparatus suggested by Mutimer et al.⁷The apparatus was suitably modified in laboratory and used for the study. It consists of a wooden block which was provided with a pulley at one end. A rectangular ground glass plate was fixed on the block. An excess of gel (about 2 g) under study was placed on this ground plate. The gel was then sandwiched between this plate and another glass plate having the dimensions of the ground plate and provided with the hook. A 300 g weight was placed on the top of two plates for five minutes to expel air and to provide a uniform film of gel between the plates. Excess of the gel was scrapped off from the edges. The top plate was then subjected to pull 30 g. With the help of a string attached to the hook and the time (in sec) required by the top plate to cover a distance of 10 cm was noted. Shorter the time interval indicates better spreadability.

The Spreadability was determined and it was calculated using the formula:

_{Where S =
Spreadability}

_{m =} Weight tied to the upper slide

_{l = L}ength of the glass slide

_{t =} Time taken in sec..

Extrudability:

Extrudability is the measurement of flow ability of gels from collapsible tube. Comparison among the different formulations can be made regarding the effect of filling under various stress conditions and ease of extrusion. The apparatus used for extrudabiltywas suitably fabricated in laboratory. It consists of a wooden block inclined at an angle of 45⁰fitted with a thin, long metal strip (tin) at one end, while the other end was free. The Aluminum tube containing 20 grams of gel was positioned on inclined surface of wooden block. 1 Kg weight was placed on free end of the Aluminum strip and was just touched for 30 seconds. The quantity of gel extruded from each tube was noted. The results for all the formulations were recorded as extrusion pressure in grams⁸.

Viscosity:

Viscosity of the prepared gels was determined using Brookfield viscometer model (LVDV-II+) with spindle no. CP52 at the temperature of 37⁰ C. The gel sample was filled in the sample holder and the particular spindle immersed into the sample. Then it was allowed to rotate at a particular speed and viscosity of the formulation was measured after 2 minutes^9.

Drug content uniformity:

Drug content uniformity was determined in each of the formulations. About 1 gm of gel was accurately weighed and transferred to 100 ml volumetric flask to which about 70 ml of phosphate buffer pH 7.4 was added, after vigorous shaking the volume made up to 100 ml with phosphate buffer pH 7.4. The content was filtered through a suitable filter paper. An aliquot 1 ml was pipetted out from the filtrate and suitably diluted in phosphate buffer pH 7.4. The content of Meloxicam was determined spectrophotometrically at 227 nm against blank. The blank solution was prepared in the same manner as above, using gels without the drug. The tests were carried out in triplicate¹⁰.

In-vitro drug diffusion studies:

In-vitro drug diffusion studies were carried out using modified Franz diffusion cell. The apparatus consists of a cylindrical glass tube (with 22 mm internal diameter and 76 mm height) which was opened at both the ends. Gel sample (5ml) was spread uniformly on the surface of cellophane membrane (previously soaked in water for overnight) and was fixed to the one end of tube such that the preparation occupies inner circumference of the tube. The whole assembly was fixed in such a way that the lower end of tube containing gel was just touched (1-2 mm deep) the surface of diffusion medium i.e., 100 ml pH 7.4 phosphate buffer contained in 100 ml beaker which was placed in water bath and maintained at 37±2°C. The cellophane membrane acts as a barrier between the gel phase and pH 7.4 phosphate buffer (sink condition). A quantity of 1 ml samples were withdrawn from receptor fluid at the time interval of 1, 2, 3, 4, 5, 6, 7 and 8 hrs. The released drug was estimated by spectrophotometer at 227 nm and 1 ml phosphate buffer pH 7.4 was replaced each time^11,
12.

Stability studies:

Stability studies of selected formulation were performed at room temperature for 1 month and formulation was finally evaluated for appearance, drug content and pH^13,14.

RESULTS AND DISCUSSION:

The formulated emulgels were evaluated for various physicochemical parameters and the results are shown in table 2.

Table 2: Physicochemical parameters of formulated emulgels

Formulation	Appearance	Drug content	Spreadability	Extrudability	pH
F1	White	82.56	19.22	10.23	5.4
F2	White	80.65	20.33	12.35	5.8
F3	Pale Yellow	90.25	21.54	15.65	5.6
F4	White	74.26	19.65	12.48	5.3
F5	White	86.26	20.16	11.98	5.3
F6	Pale Yellow	88.46	18.95	10.33	5.2

Physical appearance:

Formulated emulgel preparations were yellowish white viscous creamy preparations with a smooth homogeneous texture and glossy appearance.

Drug content uniformity:

The drug content of the formulated Emulgel was estimated spectrophotometrically at 227 nm.

The results were in the limits as shown in figure 1.

Figure 1: Graph showing percentage drug contents in all emulgel formulations

Spreadability:

Spreadability test was carried out for all the formulations. The spreadability indicates that the Emulgel is easily spreadable by small amount of shear. Spreadability of the emulgel decreases with the increase in the concentration of the polymer. The spreadability is very much important as it shows the behavior of emulgel when it comes out from the tube. Spreadability of all formulations was found in limits and as shown in figure 2.

Figure 2: Graph showing spreadability of all emulgel formulations

Extrudability The gels were filled into collapsible tubes after formulation. The extrudability of the formulations has been checked and it was found in limits and as shown in figure 3.

Figure 3: Graph showing extrudability of all emulgel formulations

Measurement of pH:

The pH of all emulgel formulations was in the range of 5.8 ± 0.1 to 5.3 ± 0.2, which lies in the normal pH range of the skin and would not produce any skin irritation. There was no significant change in pH values.

Table 3: Cumulative percentage in-vitro drug release from formulated emulgel formulations.

Sr. No.	Time (min.)	F1	F2	F3	F4	F5	F6
1	0	000	000	000	000	000	000
2	30	18.10	16.56	21.92	15.42	17.35	15.97
3	90	22.95	27.22	29.78	20.68	24.26	23.56
4	150	29.14	34.83	40.12	31.75	33.29	36.79
5	210	34.98	39.75	58.75	35.26	42.78	45.36
6	270	40.71	45.26	62.17	40.34	50.26	52.79
7	330	48.14	52.98	79.55	46.23	53.67	66.46
8	390	52.22	64.22	80.65	52.46	67.26	74.49
9	450	66.54	76.25	89.56	62.69	70.98	80.42

In Vitro drug release:

The release of Allopurinol from the emulgel was varied according to concentration of polymer. The release of the drugs from its emulsified gel formulation can be varied in the order F3>F6>F5>F1>F2>F4.The progressive increase in the amount of drug diffusion through memberane from formulation attributed to gradual decrease in the concentration of polymer. It has been concluded that, if we increase the concentration of polymer, the diffusion of drug through the memberane also decreases. The cumulative % drug release profile of all the formulation batches has been shown in table 3 and figure 4.

Figure 4: Graph showing cumulative percentage in-vitro drug release from formulated emulgel formulations.

CONCLUSION:

Topical Emulgels of Allopurinol were formulated and subjected to physicochemical studies i.e. rheological studies, spreading coefficient studies and extrudability test, in vitro release studies. The results demonstrate that the release of the drug is dependent on viscosity of the polymer used. It can be conclusively stated that the Allopurinol emulgel formulation appears to be the promising system for the topical delivery of allopurinol to avoid the disturbances of the conventional routes of administration.

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Received on 07.04.2014 Modified on 20.05.2014

Research J. Pharm. and Tech. 7(7): July 2014 Page 733-736