INTRODUCTION:

Semisolids preparations constitute a significant proportion of pharmaceutical dosage forms. They serve as carriers for drugs that are topically delivered by way of the skin, cornea, rectal tissue, nasal mucosa, vagina, buccal tissue, urethral membrane, and external ear lining. Because of their peculiar rheological behaviour, semisolids can adhere to the applicationsurface for sufficiently long periods before they are washed off. This property helps prolong drug delivery at the application site. A semisolid dosage form is advantageous in terms ofits ease of application, rapid formulation, and ability to topically deliver a wide variety of drug molecules. Semisolid preparation include ointment, creams, paste and gels.¹ Gels are semisolid systems that consist of either suspensions of small inorganic particles or large organic molecules interpenetrated by a liquid. Gels can be either water based (aqueous gels) or organic solvent based (organogels).²

Oraganogel can be defined as semisolid system which consists of organic liquid phase immobilized into a three-dimensional network composed of self assembled, intertwined gelator fibers. In general, organogels are thermodynamically stable in nature and have been explored as matrices for drug delivery.

The organogels may be regarded as bi-continuous systems consisting of gelators and organic polar solvent, which may or may not contain water-molecules entrapped within the self-assembled structures of the gelator.^3,4

The gelator form self-assembled fibrous structures which get entangled with each other resulting in the formation of a three-dimensional networked structure. The three-dimensional networked structure, hence formed, prevents the flow of external apolar phase. Some common examples of gelators include sterol, sorbitan monostearate, and lecithin and cholesteryl anthraquinone derivatives.⁵ Sorbitan monostearate and sorbitan monopalmitate can gelate a number of organic solvents such as vegetable oils, isopropyl myristate and alkanes (C >5).^6,7,8

Diclofenac Sodium is a potent and most widely used nonsteroidal anti-inflammatory agent because of its strong analgesic, antipyretic and anti-inflammatory activity. Diclofenac Sodium inhibits COX-2 enzyme, however it also inhibits gastric mucosa COX-1 which result into severe damage to gastric mucosa.Several dosage form of diclofenac sodium is available in market, such as oral sustained release preparations, injections and topical formulation. Clinical studies involving comparison between oral and topical NSAID’s efficiency provide evidence which suggest that topical NSAID’s are safe and at least as efficacious as oral NSAID’s in treatment of rheumatic disease.⁹ The topical application allows a higher concentration of drug at site of inflammation, lower or negligible systemic drug levels thus minimizing adverse drug effect. In present study, sorbitan monostearate and sorbitan monopalmitate based organogels are being used to enhance percutaneous absorption of Diclofenac sodium. Diclofenac sodium has a poor permeation into the skin. Inclusion of permeation enhancers like isopropyl myristate, along with Span 60 as a gelator and Tween 80 leads to enhanced percutaneous absorption. Span 40, Span 60 which are being used as a organogelator,are surfactants, thus enhancing diclofenac sodium permeation.

MATERIAL AND METHOD:

Material:

Diclofenac sodium was received as gift sample from Pan India (Indore), Isopropyl myristate, Sorbitan monostearate and Sorbitan monopalmitate were purchased from Loba chemie. All other chemicals/reagents were of analytical grade.

Method:

Preparation of Organogel:

Organogels containing 1% diclofenac sodium were prepared by method reported by Murdan et al.¹⁰Diclofenac sodium was dispersed in isopropyl myristate and was heated to 60⁰C. A mixture of Sorbitan monosterate (Span60) and tween80 was separately heated to 60⁰C (so as to melt Sorbitan monostearate (Span 60) and was added to above solution with constant stirring, solution was then left overnight to cool so as to allow gel formation. On cooling the system beyond the solubility limit of the organogelator, precipitation of organogelator in form of fiber occurs. These fibers then undergo physical interaction to form gelled structure.⁵Addition of polysorbate (tween 80) to the formulation is known to increase the stability of the gel in the solvent used by forming mixed inverse micelles.¹¹ Similarly another set of organogels containing Span40 instead of Span60 were prepared by following similar method. The composition of various organogel is shown in following table

Table 1 Formulation of Organogel

EXCIPIENTS	F1	F2	F3	F4	F5	F6
Drug	1%	1%	1%	1%	1%	1%
Span 60	5%		7.5%		10%
Span 40		5%		7.5%		10%
Tween 80	5%	5%	5%	5%	5%	5%
Isopropyl myristate	q.s 100	q.s 100	q.s 100	q.s 100	q.s 100	q.s 100

Evaluation of Organogel:

Appearance and Homogenity:

The prepared organogel were examined visually for colour, appearance and presence of any clog.

pH:

The pH of the various formulated gels was determined using pH meter. The electrode was immersed in the organogel and pH was recorded. All measurements were made in triplicate using fresh sample each time.

Viscosity:

The viscosity of organogels was determined using Brookfield viscometer (Brookfield viscometer DV E) using spindle 6. The formulation whose viscosity was to be determined was taken in a beaker. Spindle was allowed to move freely in the organogel and reading was recorded. All measurements were made in triplicate using fresh sample each time.

Spreadibilty:

Spreadibility of formulation was determined using spreadibility apparatus which consist of a wooden block and a glass slide. An excess amount of gel was placed between the glass slide and a 100g weight was placed on to the glass slide so as to compress the sample to a uniform thickness. The weight was then removed and weight was placed into the upper pan and time taken to completely separate the two slides was recorded. Spreadibility was then calculated by following formula:¹²

S= M.L/T

Where,

S- Spreadibility in g.cm/s

M- Weight tied to upper slide

L- Length of glass slide

T- Time in seconds

Drug content:

The amount of diclofenac sodium loaded into the organogel was determined by following method:

A specified amount of organogel (1g) was taken and suspended in 100 ml methanol and solution was stirred for 2hrs. Solution was then filtered through filter paper and 1ml of above solution was diluted to 10 ml with methanol. The absorbance was then measured at 282nm using methanol as blank, by UV visible spectrophotometer (Shimadzu Pharma- Spaec 1700). The study was carried out in triplicate.

In vitro drug release:

The in-vitro drug release study was studied using Franz diffusion cell (with effective diffusion area 1.76cm²and 11ml cell volume). Rat abdominal skin was used for drug release study. Male albino rats weighing 75-150g were used for skin sample preparation. A sample of abdominal skin was excised prior to study and was allowed to equilibriate with phosphate buffer (pH 7.4) for 1 hour prior to commencement of study. A section of rat skin of suitable size was clamped between donor and receptor compartment of Franz diffusion cell, such that the corneal layer remains in contact with the applied organogel. Phosphate buffer (pH 7.4) was used as receptor media. The temperature of the cell was maintained at 32⁰C using circulating water jacket. The content of the franz diffusion cell was stirred by means of magnetic stirrer. Organogel was applied on to the corneal layer and samples were withdrawn periodically and replaced with equal amount of fresh media. Samples were analyzed spectrophotometrically at 274 nm.(Shimadzu Pharma- Spaec 1700). Amount permeated per unit area was plotted against time. The slope of the linear portion of the plot gives the flux J(μg/cm²/h).¹³ In vitro drug release was also compared with a marketed preparation.

Skin irritation study:

The irritancy of organogel formulation was determined in male albino rat. The area was shaved before applying the gel. Gel was then applied to the skin. The site was then covered with gauze. After exposure for 24hours the gel was removed and the area was observed for any kind of eryhtema (0-4).¹⁴

RESULT AND DISCUSSION:

Appearance and Homogenity:

Organogels formed were yellowish-white in colour and homogenous in nature. The result is shown in following table

Table 1 Appearance and Homogenity of Organogels

Formulation	Appearance	Homogenity
F1	Yellowish-white	Homogenous
F2	Yellowish-white	Homogenous
F3	Yellowish-white	Homogenous
F4	Yellowish-white	Homogenous
F5	Yellowish-white	Homogenous
F6	Yellowish-white	Homogenous

pH, Viscosity, Spreadibility, Drug content:

The pH of various organogels is shown in table. There is an increase in pH of organogels as concentration of Span60 and Span40 increases in the formulation. The pH of organogel increases in following order:

F2<F1<F4<F3<F6<F5.

The viscosity of various organogels was found to be dependent on the concentration of Span60 and Span40. Organogels based on Span60 showed higher viscosity as comapared to Span40 based organogels. The viscosity of various organogels was found to increase in following order:

F2<F1<F4<F3<F6<F5.

The spreadibility of various organogels is dependent upon its viscosity¹²; an increase in viscosity of the organogels results into a decrease in its spreadibility. This fact is consistent with the above observation as organogels with high viscosity showed low value of spreadibility while organogels with low viscosity showed high value of spreadibility. The spreadibility of various organogels increased in following order

F5<F6<F3<F4<F1<F2.

The %drug content of various organogels is shown in the table. The drug content was highest in formulation F6 (97.54%) followed by F5 while it was least in formulation F4.

Table 2 pH, Viscosity,Spreadibility, %Drug content of various organogel

Formulation	pH	Viscosity (cps)	Spreadibility	%Drug content
F1	6.0±0.3	1985±6.6	19.10±1.35	96.41±0.56
F2	5.9±0.12	1672±9.2	22.3±0.54	95.89±0.71
F3	6.5±0.22	2403±2.3	16.11±1.01	98.46±0.52
F4	6.2±0.14	2068±3.0	18.49±0.92	95.29±0.59
F5	6.8±0.16	2938±5.4	11.23±0.62	96.72±0.42
F6	6.7±0.2	2552±6.0	14.56±1.2	97.54±0.45

Fig 1 pH of various organogels

Fig 2 Viscosity of various organogels

Fig 3 Spreadibilty of various organogels

Fig 4 % Drug content of various organogels

In vitro drug release:

The mechanism for enhanced drug permeation is due to fluidization of stratum corneum by surfactant present in the organogel, further presence of a permeation enhancer like isopropyl myristate assisted permeation of diclofenac sodium across the skin. The cumulative amount of drug permeated per unit area at the end of 6 hr was highest for formulation F3, releasing 279.03 μg/cm² , thus showing a flux value of 48.92 µg/cm²/hr while least from formulation F5 which showed cumulative amount release of 73.92 μg/cm² and flux value was 13.19 µg/cm²/hr. The drug release from various organogel can be ranked as follows F5<F6<F2<F1<F4<F3. It was found that the drug release form the formulation decreased with increase in concentration of organogelator. This can be attributed to formation of network like structure formed due to excessive entagelment of organogelator fibers. The cumulative amount of drug released from formulation F3 was compared to that of the marketed preparation. It was found that the drug release from formulation F3 was comparable to that of the marketed preparation.The cumulative amount of drug permeated per unit area was higher in formulation containing 7.5% Span 60 than formulation containing same percentage (7.5%) of Span 40.

Fig 5 Cumulative amount permeated per unit area Vs Time

Table 3 Flux of various organogels

S.No	FORMULATION	FLUX(µg/cm²/hr)
1.	F1	25.12±1.09
2.	F2	21.60±0.38
3.	F3	48.98±1.14
4.	F4	34.64±0.89
5.	F5	13.19±0.49
6.	F6	17.05±0.57

Skin irritation study:

The skin irritation study conducted on rat did not show any sign of irritation after 24 hours of irritation.

CONCLUSION:

The results of this study indicate that sorbitan monostearate and sorbitan monostearate based organogels can be used for topical delivery. Various pharmaceutical parameters like pH, viscosity, spreadibility and %drug content also indicated that the sorbitan monostearate and sorbitan monopalmitate based organogel can be used as a vehicle for topical delivery of drugs. Skin irritation study also showed non irritant nature of the organogels.

Fig 6 Flux of various organogel

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Received on 21.01.2013 Modified on 10.02.2013

Research J. Pharm. and Tech. 6(4): April 2013; Page 375-378