INTRODUCTION:

Advances in topical drug delivery technology have been rapid because of the sophistication of polymer science that now allows incorporation of polymers in TDDS in adequate quantity. The importance of polymer selection can be appreciated more if one considers the different design criteria that must be fulfilled. The release rate from TDS can be tailored by varying polymer composition, permeability coefficient. Selection of polymeric membrane is very important in designing a variety of membrane permeation controlled TDDS.

Gels are an excellent formulation for several routes of administration such as oral, topical, nasal, vaginal, and rectal. Gel can be clear formulations when all of the particles completely dissolve in the dispersing medium. But this doesn't occur in all gels, and some are therefore turbid. Gels are an intermediate state of matter containing both solid and liquid components.

The solid component comprises a three-dimensional network of interconnected molecules or aggregates which immobilize the liquid continuous phase. Hydrogels have an aqueous continuous phase and organogels have an organic solvent as the liquid continuous medium.^{3, 5, 19}

MATERIALS AND METHOD:

Aceclofenac IP was provided by Rantus Pharmaceutical, Hyderabad. Propylene Glycol, CarboMER 940 were obtained from Research Fine Lab, Mumbai. Triethanolamine, Methanol was obtained from Merck Chemical.

PREPARATION OF GELS:

Carbopol was added in given quantity of ethanol and kept it for 8 hours for adequate swelling of polymer. Aceclofenac was then added in propylene glycol at 65ºC.After that methyl and propyl paraben was added in the solution of propylene glycol, cooled to room temperature added in carbopol base .In another Beaker triethanolamine was mixed with water. This solution was added in above carbopol base with the help of mechanical stirrer by rotating at 600 rpm.^4.8,17

EVALUATION OF GELS:

Organoleptic Characterization:

The formulated gels were inspected visually for colour, presence of any clog and sudden viscosity changes. To evaluate the feel, the formulations were applied on the skin and the feel was experienced organoleptically. The results of organoleptic characterization test were shown in table no:1.

Table 1 : Organoleptic characterization of gels

Formulation

Colour

Clogging

Viscosity change

Feel

F₁

F₂

F₃

F₄

F₅

F₆

Clear

Not Changed

Smooth

Homogeneity test:

A small quantity of each gel was pressed between the thumb and the index finger and the consistency of the gel was noticed (whether homogeneous or not) and if there was any coarse particles appeared or detached. Also, the homogeneity can be detected when a small quantity of the gel was rubbed on the back skin of the hand.

Drug content:

Procedure^{6, 10}

Each formulation (0.5g) was taken in a 50 ml volumetric flask, diluted with ethanol and shaken to dissolve the drug in ethanol. The solution was filtered through Whatman filter paper no. 42, one ml of the above filtrate was pipetted out and diluted to 10 ml with ethanol. The content of the drug was estimated spectrophotometrically by using standard curve plotted at λ_max 276 nm.The results of drug content was shown in table: 2.

Table 2 : Drug content of gels

Sr. No.	Formulations	*Drug content (%)**
Sr. No.	Formulations	1	2	3	Mean ± S. D.
1.	F₁	99.01	98.03	97.81	98.28 ± 0.638
2.	F₂	98.36	95.85	97.05	97.08 ± 1.255
3.	F₃	98.90	98.03	97.16	98.03 ± 0.870
4.	F₄	95.63	96.18	95.85	95.88 ± 0.276
5.	F₅	96.72	97.16	97.81	97.23 ± 0.548
6.	F₆	96.18	97.81	99.12	97.70 ± 1.472

* Mean of three determinations (n=3)

Determination of pH:²⁰

The pH of gel was determined using a pH meter. On the other hand, a solution containing 2.5 g of the gel in 25 ml of the neutralized distilled water was prepared and the pH was measured. The result of pH was shown in table: 3.

Table 3 : pH of gels

Sr. No.	Formulation	pH Mean ± S. D
1.	F₁	7.41 ± 0.020
2.	F₂	7.30 ± 0.046
3.	F₃	7.22 ± 0.023
4.	F₄	7.12 ± 0.023
5.	F₅	7.06 ± 0.030
6.	F₆	6.84 ± 0.021
7.	Marketed	5.86 ± 0.030

* Mean of three determinations (n=3)

Determination of Viscosity:

Viscosity of the gel was determined by using (LV) Brookfield viscometer (Dial type). Spindle no. 4 is used. Viscosity is measured for the fixed time 2 min for 0.3 rpm.

Rheograms:^{12, 14, 18}

For studying rheology of gel, which is very important for the above – mentioned reasons Brookfield viscometer LV dial type was used. For obtaining nature of system and rheograms, both ascending and descending readings were noted down i.e. firstly by increasing shear stress and then by decreasing.Rheograms obtained were plotted by taking RPM on Y – axis and Dial reading on X – axis. The results of Rheograms reading was shown in Fig:1.

Figure No.1

In vitro diffusion study:

Procedure^{7, 9, 11}

To test the pattern of release of drug from formulations, in vitro diffusion studies were carried out. The developed formulations were subjected to in vitro diffusion study through dialysis membrane (HIMEDIA) using Franz diffusion cell. Pieces of dialysis membrane were soaked in medium used for diffusion study for 24 hrs before mounting on a diffusion cell. The receptor compartment was filled with saline phosphate buffer (pH 7.4) and methanol (90:10). Methanol was added in medium to maintained sink condition. The whole assembly was maintained at 37° ± 1° C and receptor solution was stirred with a magnetic stirrer at 600 rpm throughout the experiment. Care was taken that no air bubbles were trapped under the membrane. Aliquots (1 ml) were withdrawn at regular interval of 1 h. for a period of 8 h. and replaced with equal volume of fresh medium equilibrated at 37° ± 1° C. All the samples were suitably diluted with medium and analyzed spectrophotometrically at 274 nm for aceclofenac content. The cumulative quantity of Aceclofenac diffused per unit area of the membrane was calculated for each time interval. The in vitro %cumulative amount of release result was shown in Table: 4 and Fig: 2.

Table 4 : Cumulative % Drug Release Profile of Aceclofenac Gels

Time (Hr)	Formulation Batches
Time (Hr)	F₁	F₂	F₃	F₄	F₅	F₆	M
1	8.10	8.97	10.00	10.34	16.12	17.79	17.76
2	13.58	16.14	16.70	17.04	24.20	25.20	24.44
3	18.16	22.89	23.62	24.11	32.79	33.18	32.34
4	23.40	27.95	33.16	34.00	48.57	44.15	44.00
5	28.41	31.52	39.06	47.93	54.09	54.14	53.11
6	32.20	36.77	49.26	59.48	66.09	65.92	61.21
7	37.29	48.29	54.57	65.08	74.67	76.74	69.93
8	49.14	54.03	63.78	71.13	80.01	85.73	75.01

Fig No.2:

In-vitro permeation profile of Aceclofenac from F_5,F₆and Marketed formulation.

Stability study:^{13, 15}

The gels from the selected and optimized batch F₅and F6 were studied for stability and kept under the accelerated conditions of temperature and moisture (humidity) for the period of 30 days. The gels were studied for stability at 40°C and 75% RH conditions for the period of three months. The results was shown in Table:5.

1. Room Temperature.

2. 40°C ± 2°C at 75 ± 5% RH

Table 5: Stability Study of gel

Formulation		Storage condition
F₆		Room Temp.		40°C ± 2°C at 75 ± 5% RH
F₆		Days		Days
Sr. No.	Parameters	0	30	0	30
1.	Drug content(%)	97.70	97.05	97.70	96.83
2.	Viscosity (Poise)	320	322	320	324
3.	pH	6.84	6.86	6.84	6.89
4.	Flux (ug/cm²/hr)	12.52	12.91	12.52	12.69
5.	Permeability coefficient.	1.252	1.291	1.252	1.269
6.	Spreadability (g.cm/sec)	59.11	58.70	59.11	57.09
7.	Diffusion study(%)	85.73	85.63	85.73	86.7

* % Cumulative amount permeated in 8 hours.

RESULTS AND DISCUSSIONS:

Organoleptic characteristic was important for patient acceptability. Hence each gel was tested for color, clogging, sudden viscosity change, feel.

There was no any coarse particle appeared or detached when each gel formulation was pressed between the thumb and the index finger and also a small quantity of the gel was rubbed on the back skin of the hand.

The consistency of the gel was found to be homogeneous.

Drug content uniformity of all formulations was found to be satisfactory indicating suitability of method adopted for preparing gels. The value of drug content uniformity of gel formulations are given in table which was according to the value mention in BP2005 (95% to 105 %).

According to literature review it was found that the human skin pH is in the range of 4.5 to 7.2. The pH of all the formulated batches was found to be in the range of 6.84 ± 0.021 to 7.41 ± 0.020 and with increase in ethanol concentration in formulation batches the pH was found to be decrease.

According to the viscosity study it was found that viscosity was in the range of40400 to32000 for formulation F₁to F₆respectively. When water is used as dispersion medium the viscosity of formulation increased as seen in formulation batch F_1.

Further it was concluded that when the concentration of ethanol was increase gradually the viscosity was decreased as seen in formulation F_6.

Viscosity of the fixed time 2 min for 0.3 rpm.

Dial reading x factor = viscosity (cps)

Factor = 20M

M = 100

Rheograms obtained were plotted by taking RPM on Y – axis and dial reading on X – axis. From the ascending and descending curve of the rheogram of different formulation it was concluded that the gel exhibits non-Newtonian behavior and plastic flow. This means that substance initially behave like an elastic body and fails to flow when less amount of shear stress was applied. Further increase in shear stress leads to a nonlinear increase in the shear rate which progressively get linearised. The linear portion when extrapolated intersects the x axis at a point called yield value. Therefore, plastic flow resembles Newtonian flow above the yield value. Plastic flow can be adequately expressed in terms of yield value and plasic viscosity.

Drug diffusion was found to be increase with increase in ethanol concentration. From the drug diffusion study it was found that formulation F₅and F₆have greater percent cumulative drug release than the marketed aceclofenac gel.

Samples were evaluated for various criteria after 30 days. Stability study applied for formulation batch F₅and F₆which shows the higher amount of release than marketed. Stability study was done at room temp and 40°C ± 2°C at 75 ± 5% RH. The tests carried out for the stability samples were Drug content, pH, viscosity, spreadability, diffusion study, flux, permeability. The methodology adopted for all the above mentioned studies was similar to procedure discussed previously. The results indicate that no remarkable changes in physical appearance and in vitro diffusion profiles. Negligible changes observed in stability study.

REFERENCES:

1) Slauson D O and Cooper B J, 2006, Mechanisms of Disease: a textbook of comparative general pathology, 3rd ed.2002, Chapter 4: Inflammation and Repair of Tissue, VPM 152 Winter Inflammation and Repair General Pathology (141-143).

2) Block, L. H., 2000. Medicated Topicals. In: Gennaro, A. R., (Ed.), Remington: The Science and Practice of Pharmacy, 20^th edition. Lippincott Williams and Wilkins, Philadelphia, pp 745-747.

3) Zatz, J. L., Kushla, G. P., 1996. Gels. In: H. A., Libermann, M. M., Riger, G. S., Banker, (Ed.), Pharmaceutical Dosage forms: Disperse Systems. Marcel Dekker Inc. New York, Vol 2, 399.

4) Secundum Artem , “Compounding Gel” Volume 4 ,Number 5.

5) http://www.phlojel.com

6) Tripathi KD, 2004, Essential Medical Pharmacology, “Nonsteroidal Antiinflammatory Drug and Antipyretic-Analgesic”, Fifth Edition, Jaypee Brothers Medical Publisher (P) Ltd,167.

7) www.wikipedia.com

8) Ashok k Tiwary, Bharti Sapra and Subheet jain 2007(1), “Innovation in Transdermal Drug Delivery:Formulation and Technique”, Recent Patents on drug Delivery & Formulation,23-36.

9) Misra Ambikanandan, “Transdermal Drug Delivery:Present and Future”, Jul-Aug 2004, The Pharma Review 92-104.

10) Kartin Moser,Katrin Kriwet, Aarti Naik, Yogeshwar N.Kalia, Richard H.Guy 2001, “Passive skin penetration enhancement and its qualification in vitro” European Journal of Pharmaceutics and Biopharmaceutics 52,103-112.

11) Kumar, R., Katare O. P., 2005. Lecithin organogel as a potential phospholipid-structured system for topical drug delivery: A review, AAPS PharmSciTech. 40, 6 (2), E298-E310.

12) Flynn, L. G., 1996. Cutaneous and Transdermal Delivery: Processes and systems of delivery. In: G. S., Banker, C.T., Rhodes, (Ed.), Modern Pharmaceutics, 3^rd edition. Marcel Dekker Inc. New York, 239-298.

13) Florence A. T., 1971, “Webster’s seventh New Collegiate Dictionary”, M. Springfield, pp 242 – 245.

14) Sugibayashi K., Morimoto Y., 1994, Polymers for transdermal drug delivery systems, J. Controlled Release. 29, 177-185.

15) Valenta C., Auner B. G.,2004, The use of polymers for dermal and transdermal delivery. Eur. J. Pharm. Sci., 58, 279-289.

16) Hadgraft. J., Wolff M., Physicochemical and pharmacokinetic parameters affecting percutaneous absorption, In: Gurny R., Teubner A., Eds. Dermal and Transdermal Drug Delivery, Wissenschaftliche verlaasgesellshaft, Stuttgart 161-172.( 1993)

17) Ashok K Tiwary, Bharti Sapra and Subheet jain 2007(1), “Innovation in Transdermal Drug Delivery: Formulation and Technique”, Recent Patents on drug Delivery & Formulation,23-36.

18) Misra Ambikanandan, “Transdermal Drug Delivery:Present and Future”, Jul-Aug 2004, The Pharma Review 92-104.

19) Williams Adrian C., Brian W. Barry 2004, “Penetratio Enhancer”,Advanced Drug Delivery Review 56,603-618.

20) Tripathi KD, 2004, Essential Medical Pharmacology, “Nonsteroidal Antiinflammatory Drug and Antipyretic-Analgesic”, Fifth Edition, Jaypee Brothers Medical Publisher (P) Ltd,155-165.

Received on 01.03.2011 Modified on 02.03.2011

Asian J. Research Chem. 4(5): May, 2011; Page 791-794