Topical drug delivery system has been the most appropriate and convenient approach over the past two decades. Many conventional semisolid dosage forms such as creams, gels, and lotions found to have problems such as sticky in nature, lesser spreading coefficient, and stability issues.[1] To overcome such issues, a novel, stable topical drug delivery approach can be used to formulate successful drug delivery for hydrophobic drugs. In recent years, the concept of emulgel has gained significant interest in the topical drug delivery system.[2] An emulgel is a combination of emulsion and gel system, which is formulated by mixing emulsion either o/w or w/o with a gelling agent.[3] Emulgel provides several benefits such as better loading capacity, stability, controlled release, improved patient compliance, avoids first pass metabolism, and gastric complications.[4,5] In the present investigation, a model anti-inflammatory drug Diclofenac was chosen since its oral dosage form has demerits such as first pass metabolism, gastric ulcerogenic effects, and metabolic degradation.[6] Diclofenac even though available in conventional gel form since it is a hydrophobic drug formulating it in emulgel makes it more fruitful way to deliver through the skin.[7] Percutaneous absorption of drugs from topical formulation involves the release of the drug from the formulation and permeation through skin to reach the target tissue. The release of the drug from topical preparations depends on the physicochemical properties of the vehicle and the drug employed. In order to enhance drug and skin permeation, methods such as the selection of suitable vehicle, co-administration of a chemical enhancer have been studied. Use of topical agents requires an appreciation of the factors that influence percutaneous absorption. Molecules can penetrate the skin by three routes, through intact stratum corneum, through sweat glands, or through the sebaceous follicle. The surface of the stratum corneum presents more than 99% of the total skin surface available for percutaneous drug absorption1. Passage through this outermost layer is the rate –limiting step for percutaneous absorption. The major steps involved in percutaneous absorption include the establishment of a concentration gradient ,which provides the driving force for drug movement a across the skin ,release of drug from the vehicle (penetration co-efficient);and drug diffusion across the layers of the skin(diffusion co-efficient).preferable characteristic of topical drugs include low molecular mass (600 Daltons),with adequate solubility in oil & water ,and have high partition co-efficient for the topical formulation.
Gels are a relatively newer class of dosage form created by entrapment of large amounts of aqueous or hydro alcoholic liquid in a network of colloidal solid particles.gel formulations generally provide faster drug release compared with ointments and creams. Major drawback of topical dosage form diffusion of drug in the delivery of hydrophobic drugs, and permeation through stratum corneum is for hydrophilic drugs. Therefore, to overcome this limitation emulgels are prepared.
Aim: The present research work was aimed to develop a novel emulgel for Diclofenac to enhance the drug absorption by the topical application, which overcomes the demerits of oral dosage form and conventional gel system of Diclofenac.
Methodology Preparation of Diclofenac emulgel The gel phase and emulsion phase were prepared separately. First, the gel phase was prepared by dispersing the different concentrations of carbopol 934 in distilled water and mixed by a mechanical stirrer. The emulsion phases were prepared by the addition of varying amounts of span 20 in varying quantities of liquid paraffin followed by mechanical stirring. The aqueous phase of emulgel was prepared by incorporating tween 20 in distilled water with continuous stirring, then methyl and propylparaben were added in propylene glycol, and Diclofenac (0.5 g) was dissolved in ethanol, and both the solutions were mixed with water phase of the emulsion. Both the water and oil phases were heated at 70–80°C for 20 min. Later, the oily phase was added to the aqueous phase by gentle stirring and allowed to cool. Finally, the prepared emulsion was mixed with gel base in a 1:1 ratio by manual stirring to get a clear emulgel of Diclofenac. The pH of all the prepared emulgels was adjusted by dropwise addition of Triethanolamine.[8-10] A quantity of 100 g of Diclofenac was prepared for all the six formulations and the formulation composition of Diclofenac emulgels is shown in Table .
Evaluation of emulgels Drug-polymer compatibility by Fourier transforms infrared (FTIR) study This study was carried out by FTIR spectroscopy to verify whether the drug and polymer are compatible with one another or not. It was evaluated by obtaining the IR spectral data of Diclofenac and physical mixture of Diclofenac with carbopol 934 using ATR-Bruker FTIR spectrophotometer. The interaction study was concluded from the interpretation of IR spectra.
Appearance :
All the formulated Diclofenac emulgels were visually inspected for color, clarity, and homogeneity.
Ph:
The pH of all the formulated emulgels was measured by digital pH meter.
Rheological study :
The viscosity of the emulgels was measured by Brookfield viscometer with “T” bar spindle at 5 rpm at a temperature of 25±2°C and the viscosity was recorded in cps.[14]
Spreadability:
An ideal topical gel should possess a sufficient spreading coefficient when applied or rubbed on the skin surface. This was evaluated by placing about 1 g of formulation on a glass slide. Another glass slide of the same length was placed above that, and a mass of 500 g was put on the glass slide so that the gel gets sandwiched between the two glass slides and spreads at a certain distance.[15] The time taken for the gel to travel the distance from the place of its position was noted down. Spreadability was determined by the following formula.
Where, S-Spreadability, g.cm/s
M-Weight put on the upper glass
L-Length of glass slide
T-Time for spreading gel in sec
Swelling index :
It was measured by placing 1 g of formulation in a porous aluminum foil and was placed in a 50 ml beaker containing 10 ml of 0.1 N sodium hydroxide. The samples were removed from beakers at different time intervals and put on the dry place for some time and reweighed.The swelling index of emulgels was calculated using the following formula.
Table 1: Formulation design of Diclofenac emulgels
Ingredients
|
Formulation code
|
AG-1
|
AG-2
|
AG-3
|
AG-4
|
AG-5
|
AG-6
|
Diclofenac
|
0.5 g
|
0.5 g
|
0.5 g
|
0.5 g
|
0.5 g
|
0.5 g
|
Carbopol 934
|
0.50%
|
1%
|
1.50%
|
2%
|
2.50%
|
3%
|
Liquid Paraffin
|
5 ml
|
5 ml
|
8 ml
|
8 ml
|
10 ml
|
10 ml
|
Span 20
|
0.20%
|
0.50%
|
0.20%
|
0.50%
|
0.20%
|
0.50%
|
Tween 20
|
0.20%
|
0.50%
|
0.20%
|
0.50%
|
0.20%
|
0.50%
|
Methylparaben
|
0.20%
|
0.20%
|
0.20%
|
0.20%
|
0.20%
|
0.20%
|
Propylparaben
|
0.20%
|
0.20%
|
0.20%
|
0.20%
|
0.20%
|
0.20%
|
Ethanol
|
5 ml
|
5 ml
|
5 ml
|
5 ml
|
5 ml
|
5 ml
|
Distilled water
|
q.s
|
q.s
|
q.s
|
q.s
|
q.s
|
q.s
|
Triethanolamine
|
q.s to adjust pH
|
q.s to adjust pH
|
q.s to adjust pH
|
q.s to adjust pH
|
q.s to adjust pH
|
q.s to adjust pH
|
Swelling index (SW) % = [(Wt-Wo)]/Wo × 100
Where, (SW) % = Equilibrium percent swelling
Wt = Weight of swollen emulgel after time t,
Wo = Weight of emulgel before swelling at zero time, t.
In vitro Drug release study
Release study of the emulgels was performed using modified Franz diffusion six cell apparatus which has donor and receptor compartment with a linear end for the solution withdrawal. A dialysis membrane, which was soaked overnight in phosphate buffer pH 7.4, was tied on the upper surface of the donor compartment. An amount of 12 ml of freshly prepared phosphate buffer pH 7.4 was put in receptor chamber. The dialysis membrane was sandwiched between the donor and receptor compartment. A magnetic bead was placed inside the receptor compartment by operating at 50 rpm and the apparatus assembly was maintained at 37±0.5°C. 500 mg of emulgel was placed on the dialysis membrane, which was mounted on the donor compartment. Aliquots of 1 ml were withdrawn at time intervals of every 30 min and diluted to 10 ml with phosphate buffer pH 7.4. The study was done for a time period of 6 h. All the solutions were scanned at 275 nm using UV Spectrophotometer. The amount of drug released was estimated, and the percentage cumulative drug release of the emulgels was calculated.
Particle size analysis
This study was done for optimized formulation of Diclofenac emulgel. The procedure involves dilution of 1 g of emulgel with distilled water which was observed under high resolution Biovis Particle Size Analyzer and the average size of the particles were measured in microns.
In vitro skin irritation study
For checking the skin irritation, an in vitro OECD recommended test was used known as Hen’s Embryo Test-Chorioallantoic Membrane (HET-CAM test). In this method, hen eggs which are freshly layed were used and were embroyonated to check the irritation on the developed chick embryo. Three groups were made, each containing three eggs.
Negative control: Here, the eggs were treated with 0.9% NaCl as a standard.
Test group: In this group, eggs were tested with the optimized formulation.
Positive control: In this, eggs were treated with 1% SDS (Sodium dodecyl sulfate) as an irritant for comparison with negative control and test.