INTRODUCTION:

Topical delivery can be defined as the application of a drug containing formulation to the skin to directly treat cutaneous disorders (e.g. acne) or the cutaneous manifestations of a general disease (e.g. psoriasis) with the intent of containing the pharmacological or other effect of the drug to the surface of the skin or within the skin. Semi-solid formulation in all their diversity dominates the system for topical delivery. There have been concerns related to the conventional topical dosage forms such as lotions, creams, ointment and powder in terms of drug diffusion or release from the vehicle and delivery through the skin. Creams and lotions often provide poor bioavailability of the drug because they are rapidly cleared from the skin and poorly release the drug from the base. Non-hydrophilic ointments are oleaginous, greasy and are not convenient to patients, and also medicated powders for topical application have short residence time on the skin. Gels are semisolid systems in which the movement of the dispersion medium is restricted by interlacing three dimensional network of particles or solvated macromolecules of dispersed phase.

The increased viscosity caused by interlacing and consequential internal friction is responsible for the semisolid state. Also, a gel may consist of twisted matted strands often tied together by stronger types of Vander Waals Forces to form crystalline and amorphous regions throughout the system.¹

For the topical treatment of dermatological diseases, a wide choice of vehicles ranging from solids to semisolids and liquid preparations are available to clinicians and patients. Within the semisolid preparations transparent gels are widely used in cosmetic pharmaceuticals.^2,3

Out of various semisolid dosage forms, gels are becoming more popular due to ease of application and better percutaneous absorption. Typical three-dimensional structures, characteristics of the gels, come from the links among the polymer chains. Gels can resist the physiological stress caused by the skin flexion, blinking and mucociliary movement, adopting the shape of the applied area and controlling drug release^4-5. Effectiveness of the topical application mainly depends upon its rate and extent of drug release from the base.

Gel are an excellent formulation for several route of administration such as oral, topical, nasal ,gel can be a clear formulation when all of particles are Dissolve in dispersing medium but this cant occur in all gels some are therefore turbid

MATERIALS AND METHODS:

Material:- Diclofenac sodium, was procured from Research fine lab Hyderabad.Mumbai. Methyl paraben,propyl paraben,isopropyl alcohol, mentholwere obtained from Samar chemicals, Nagpur.Triethanolamine fromMerck chemical Mumbai,Propylene glycol Carbopol 940P fromResearch Fine Lab, Mumbai.Hpmc k4m from Merck Chemical Mumbai and marketed gel from Intas PharmaceuticlesLtd,Ahmedabad

Methods:

Formulation of Topical gel containing Diclofenac Sodium was prepared by direct compression technique using varying concentrations of different grades of polymers with carbopol 940 and Hpmc k4m. All the ingredients were accurately weighed and passed. Then, most of the ingredients were buy from summer chemicles, Nagpur

Extraction of Ginger oleoresin: ^6,7,8

Ginger oleoresin is extracted from dried crushed ginger in soxhlet extractor using ethyl ether as a solvent and linseed oil are two key ingredients added to propose formulation for antiinfllamatiory effect.

Two diff procedures are applied to formulate gel 1) formulation of hpmc gel Diclofenac was dissolved in propylene glycol. Menthol was dissolved in Isopropyl alcohol. The whole amount of HPMC was sprinkled on drug solution with slow stirring then methyl paraben and propyl paraben was added. The mixture of drug solution and polymer was kept aside for six hour to seven hour, for adequate swelling of polymer. The oil phase consisting of linseed oil, ginger oleoresin and methyl salicylate was added slowly in above aqueous gel with continuous stirring with overhead stirrer. The gel was packed in aluminium collapsible tube. Ur

2) formulation of carbopol gel Carbopol was added in given quantity of water and kept it for 8 hours for adequate swelling of polymer. Triethanolamine was added for neutralize the above carbopol base for the proper pH adjustment.Diclofenac was then added in propylene glycol at 65⁰C.After that methyl and propyl paraben was added in the solution of propylene glycol, cooled to room temperature and the resultant was added in carbopol base with the help of mechanical stirrer by rotating at 600 rpm.

RESULTS AND DISCUSSION:

The project was undertaken with the aim to design gel formulation for topical delivery of Diclofenac, Linseed oil and Ginger oleoresin .Preliminary studies indicates that Carbopo940, and HPMC, can be used as a gelling agents and methanol as solvent. Different formulations were screened at preliminary level on the basis of drug solubility, drug release, spreadability, excrutability, Rheological behaviour, etc. The formulations have satisfactory Spreadability, Rheological behaviour and their diffusion profile was comparable to marketed gel formulation. The formulations have shown stability over 45 days period at 37⁰C + 2⁰and 45⁰C + 2⁰C /The procured sample of Diclofenac was tested for its identification. The quality of Diclofenac was confirmed by physical characterization, melting point, chemical test and UV-absorption maxima in methanol. The results of these entire tests were in compliance with specification of B.P. 2005. The IR- spectrum obtained for identification of Diclofenac. This was also supported by certificate of analysis supplied by Rantus Pharmaceutical Ltd, Hyderabad. Thus, the Diclofenac used in the entire study was of pure quality. The different formulations using various water and ethanol Proportion were developed. Ethanol, propylene glycol has become recognized as a possible permeation enhancer in the topical drug delivery of drugs and to produce proper viscosity Carbopol 940 and h was used in combination.

FORMULATION AND EVALUATION:

Various batches of gels from F₁ to F₇ were prepared with the help of different ethanol and water proportions taken as vehicle in carbopol 940 base. And Hpmc k4MOut of this formulation batch .

All the formulations were evaluated for the post formulation Organoleptic characteristic, homogeneity, drug content, pH, viscosity, spreadability, In vitro diffusion study, stability study, It was found that, all the formulation were smooth in touch and showed no clogging which indicate good texture of formulation.

All the formulations were evaluated spectrophotometrically for the drug content, the results were found in the acceptable range, indicating the no drug and excipient interaction and also form the uniformity of content.

It was found that the pH of all the formulations is in the range of 6.84 to 7.41 that suits the skin pH (pH 4.5 to 7.2), indicating skin compatibility. This is the primary requirement for a good topical formulation.

Standard calibration curves for Diclofenac were prepared in methanol and in combination of saline phosphate buffer pH 7.4 and methanol (90:10) . It was found that both the standard calibration curve obey the Beer’s- Lambert’s Law within the range of 2 to 20 ug/ml.

Rheological investigation:

With the increase in ethanol concentration viscosity was decrease. Formulation viscosities was found to be in the range of cps (by using spindle no. 4).All formulation showed spreadability in the range of g.cm/sec. This fact reflects higher spreadability was observed with increase in ethanol.

Rheological behavior of the semisolid is essential to achieve spreading, adherence on the skin, removal from containers and release of the drug from the base. Rheograms of formulation shows Non-Newtonian, Plastic flow was observed.

In vitro study:

Effectiveness of topical applications mainly depends upon its rate and extent of drug release from base. All formulations were evaluated for their release patterns from formulation batch and compared with the marketed formulation. Percentage cumulative amount of Diclofenac permeated in 8 hrs from batch F₃, F₇ and marketed formulations were67.06, 73.69;75.01 shows respectively when saline phosphate buffer pH 7.4 and methanol (90: 10) was used as medium for diffusion study.

In nutshell, it was found that F7 formulation have shown near about same cumulative amount of drug permeation than and marketed.

Stability study:

The formulation and manufacture of gel system is not complete without an evaluation of stability test of that system. The chemical integrity of the dispersed active ingredients and the physical characteristics of the gel system needs to be studied together. During stability study, the formulation F3 and F7 were found to be stable and doesn’t showed precipitation, aggregation, phase separation and significant loss of viscosity in thermal cycling test. Both the formulations were also found to be stable at Room Temp and 40°C ± 2°C 5, with respect to drug content, pH, release rate. However, F3 and F7 showed negligble changes in viscosity Indicating overall stability of the formulation F₃ and F₇for 30 days.

CONCLUSION:

· Formulation batch F₇ (2% Diclofenac, 10%PG, 0.15%Methylparaben, 0.05%Propyl Paraben,1.5%Carbopol 940, 67.44%ethanol,16.86%water) had shown higher amount of percent cumulative release as compared to marketed gel(Intas pharmaceutical).

· Spreadiability of formulation F₇was good to cover the painful area.

· In formulation F₇the ethanol in 67.44% concentration had shown the higher penetration enhancer activity which result in higher drug release, flux and permeatability value.

· On the basis of organoleptic characteristic the improved patient acceptability was achieved through formulation F_7.

· The improved patient convenience might thus be obtained by the administration of such a dosage form with minimal blood level fluctuations.

The release penetration enhancer and other materials are cheap, readily available, safe, having wide regulatory acceptance and easy to handle for economic point of view. It may beneficial to adopt such simple technology for the commercial production of Diclofenac gel. The future scope of this study is that formulation should be subjected for long-term stability and in-vivo performance study. And anti-inflammatory activity Table 1: Formulation batches from F1 toF3

Gel with Hydroxy Propyl Methyl Cellulose

Name of Ingredients	Formulation
Name of Ingredients	F1	F2	F3
Diclofenac	1	1	1
Linseed oil	3	3	3
Ginger oleoresin	0.5	1	1.5
Methyl salicylate	10	10	10
Propylene glycol	5	5	5
HPMC	1	1.5	2
Methyl paraben	0.1	0.1	0.1
Propyl paraben	0.03	0.03	0.03
Menthol	5	5	5
Isopropyl alcohol	6.5	6.5	6.5
Water q.s. to make	100	100	100

*All the quantities are in mg.

Table No. 2 Formulation batches from F4 to F7 Gel with carbopol

	Components	F₄	F₅	F₆	F₇
Drug	Diclofenac (%)	2	2	2	2
Excipient	Propylene Glycol (%)	10	10	10	10
	Methyl Paraben(%)	0.15	0.15	0.15	0.15
	Propyl Paraben (%)	0.05	0.05	0.05	0.05
	Carbopol 940 (%)	1.5	1.5	1.5	1.5
	Triethanolamine (%)	2	2	2	2
Vehicle	Ethanol (%)	0	16.86	33.72	67.4
Vehicle	Purified water (%)	74.4	57.28	41.68	9
	oleoresin	1.4	1.4	1.4	1.4
	Linseed oil	8.5	8.5	8.5	8.5

Table No. 3: Organoleptic characterization of formulation batches gels

Formulation

Color

Clogging

Viscosity change

Feel

F₁

F₂

F₃

F₄

F₅

F₆

Clear

Not Changed

Smooth

Table 4: Skin irritation and Appearance test

Formulation	Appearance	Skin irritation
F1	Cream	0
F2	Cream	0
F3	Cream	0
F4	White	0
F5	White	0
F6	White	0
F7	White	0
M1	White	0

Table No. 5 Drug content of formulation batches gels

Sr. No.	Formulations
1.	F₁	97.28
2.	F₂	96.67
3.	F₃	98.18
4.	F₄	98.18
5.	F₅	99.06
6.	F₆	99.69
7	F₇	99.80

Table No.6 pH of gels

Sr. No.	Formulation	PH Mean ± S. D
1.	F₁	7.36±0.012
2.	F₂	7.35± 0.030
3.	F₃	7.29± 0.017
4.	F₄	7.41 ± 0.020
5.	F₅	7.30 ± 0.046
6.	F₆	7.22 ± 0.023
7.	F7	6.84 ± 0.021
8.	Marketed	5.86 ± 0.03

Table 7: Viscosity of various formulation lations at fixed time

S. No.	Formulations	Viscosity
1.	F1	30600
2.	F2	31200
3.	F3	32000
4.	F4	40400
5.	F5	38800
6.	F6	32000
7.	F7	27000

Table8: Viscosity observation of various formulations

Formulations		RPM
Formulations		0.3	0.6	1.5	3	6	12
A1a	Ascending	16.75	21.20	27.70	36.0	49.70	66.80
	Descending	11.50	14.50	21.70	30.70	46.40	66.90
A1b	Ascending	17.20	21.50	30.10	37.70	50.0	67.0
	Descending	11.10	15.20	22.20	31.10	47.0	67.0
A1c	Ascending	18.10	22.70	31.10	38.0	50.60	70.0
	Descending	11.20	16.10	22.70	32.5	47.50	67.50
A2a	Ascending	20.2	28.20	34.40	45.50	62.30	74.40
	Descending	14.90.	18.40	26.80	34.40	52.20	73.20
A2b	Ascending	19.4	24.50	32.60	42.40	61.80	70.70
	Descending	11.20	18.20	25.80	32.40	52.00	69.80
A2c	Ascending	16.30	22.10	29.40	35.0	48.10	65.50
	Descending	11.20	16.10	21.40	30.40	45.50	64.70
A3a	Ascending	14.40	20.70	28.10	35.70	46.20	64.20
	Descending	10.0	15.10	20.70	29.80	41.10	63.10

Table 9: Spreadability of various formulations

Formulations	Time (sec)	Spreadability in time
F1	10	40.68+0.698
F2	10	44.74+0.964
F3	11	47.30+0.964
F4	12	48.46=1.735
F5	13	51.50+1.114
F6	14	52.84+1.206
F7	12	54.99+1.304
Marketed	08	65.71+0.894

Table: 10 Extrudability of various formulations

Formulations	Wt. Required (in gms) to extrude ribbon of 0.5 cm in 10 sec
F1	580
F2	565
F3	560
F4	553
F5	500
F6	475
F7	490
Marketed	502

(F1)

(F2)

(F3)

(F4)

(F5)

(F6)

(F7)

Fig: 1The rheograms of different batches from formulation F₁ to F₇.

Figure 2: Fig: 16 in-vitro permeation profile of Diclofenac from F_1,F₂and Marketed formulation.

Figure 2: Fig: 17 in-vitro permeation profile of Diclofenac from F3 F4and Marketed formulation

Figure 3: Fig:18 in-vitro permeation profile of Diclofenac from F5,F6,F₇and Marketed formulation

Time (Hr)	Formulations
Time (Hr)	F1	F2	F3	F4	F5	F6	F7	Markated
1	14. 36	18.5	8.78	18.37	18.52	15.72	31.40	20.83
2	17. 13	25.19	20.78	22.74	24.96	18.60	36.40	25.80
3	21. 69	31.47	29.07	31.43	31.78	25.33	44.27	36.41
4	28. 01	37.05	37.66	36.18	38.59	30.43	51.37	43.92
5	32.99	43.86	43.47	40.68	42.03	36.71	59.09	49.58
6	41.07	49.57	52.32	46.65	50.98	42.59	67.67	57.71
7	47.04	56.86	60.41	59.09	57.87	50.35	71.34	65.58
8	52.00	62.81	67.06	63.12	60.71	58.70	73.69	75.01