ISSN: 0975 -766X CODEN: IJPTFI Available Online …...etodolac pharmacosomes which were compared...
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Vidya Viswanad*et al. /International Journal of Pharmacy & Technology
IJPT| June-2017| Vol. 9 | Issue No.2 | 29665-29680 Page 29665
ISSN: 0975-766X
CODEN: IJPTFI
Available Online through Research Article
www.ijptonline.com FORMULATION AND EVALUATION OF ETODOLAC PHARMACOSOMES: A NOVEL APPROACH
TOWARDS RHEUMATOID ARTHRITIS
Sneha Letha, Shammika P, Vidya Viswanad*
Department of Pharmaceutics, Amrita School of Pharmacy, Amrita University,
Amrita Vishwa Vidyapeetham University, AIMS Health Science Campus Kochi, 682041.
Email: [email protected]
Received on: 25-02-2017 Accepted on: 28-03-2017
Abstract
Aim: To formulate and evaluate etodolac pharmacosomes for the treatment of rheumatoid arthritis.
Methods: A novel etodolac pharmacosomal gel was formulated by thin film hydration technique and characterization
studies were performed. The optimized formulation were studied for entrapment efficiency, in-vitro drug release & skin
permeation study which were compared with pure drug gel. The in-vitro anti- inflammatory tests were also done on
etodolac pharmacosomes which were compared with pure drug gel.
Results: The optimized formulation when studied for in-vitro drug release showed a sustained release of 59.9% for P1G,
58.3% for P4G and 57.5% for P7G compared to 98.6% release of pure drug gel, following drug diffusion as the major
mechanism of release (r2 > 0.9). The in-vitro anti- inflammatory tests also proved significant anti-inflammatory action of
etodolac pharmacosomes as compared to pure drug gel while drug deposition studies indicated a depot action. Complete
Freund’s adjuvant (CFA) induced inflammation in sub-chronic model of inflammation showed marked decrease in
inflammation, as evident from paw edema studies and physical signs of inflammation, probably owing to the depot
action of the formulation.
Conclusion: Etodolac pharmacosomal gel proves to be a better alternative in treatment of rheumatoid arthritis compared
to many marketed formulations.
Keywords: Characterization, Depot, Inflammation, Stability, Sustained.
Introduction
Rheumatoid arthritis is characterized by persistent synovitis, systemic inflammation and auto antibodies [1], which if
untreated may cause permanent joint impairment and increased mortality [2]. Morning stiffness and swelling of soft
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tissues are major symptoms of rheumatoid arthritis and the diagnosis is done by positive rheumatoid factor, increase in
C-reactive protein and decrease of serum haemoglobin [3]. Non-steroidal and steroidal anti-inflammatory drugs are
considered to be the first line drugs used in treatment of rheumatoid arthritis, which aims only in alleviating the pain
associated with inflammation and other inflammatory symptoms providing sufficient time for the slow acting disease
modifying anti-rheumatoid drugs to prevent disease progression [4]. Etodolac is a preferential COX-2 inhibitor, mainly
indicated for rheumatoid arthritis and osteoarthritis. Although studies indicate the disease modifying potential [5] of the
drug in treatment of rheumatoid arthritis, the drug is mainly used for suppressing pain and inflammation. The marketed
formulations of the drug include oral immediate release tablets and capsules and extended release tablets, which on
chronic oral intake may result in hypersensitivity reactions, gastropathy, liver toxicity, prolonged gastric bleeding and
also nephrotoxicity. Despite noteworthy achievements in management of rheumatoid arthritis, currently available drug
delivery systems in rheumatoid systems have limited use, due to safety implications.
Drugs are covalently bound to phospholipids, to form colloidal dispersions of pharmacosomes which is a novel carrier
mediated drug delivery system and offers advantages such as enhanced therapeutic activity, improved bioavailability and
site specific action [4]. They offer better stability, greater drug entrapment and targeted action as compared to other
vesicular systems.
The study mainly focused on the formulation, evaluation and in-vivo anti-inflammatory models assessment of etodolac
pharmacosomal gel for effective transdermal pharmacotherapy in rheumatoid arthritis. The reports suggested that,
etodolac pharmacosomes for transdermal drug delivery. The study deals with its characterization for vesicle size
determination, drug entrapment and chemical interaction.
Materials and Methods
Materials
Etodolac was purchased as a gift sample by Ipca laboratories, Mumbai. Soy lecithin was purchased from Himedia
Laboratories Pvt. Ltd, Mumbai, Complete Freund’s adjuvant was from Sigma Aldrich, USA.
Formulation of Etodolac pharmacosomes
Thin film hydration technique were used to prepared pharmacosomes by using rotary vacuum evaporator [Superfit
Rotavap PBU-6D]. The drug and lecithin were dissolved [6] in a solvent and transferred into a round bottom flask. The
organic solvent was then removed by rotating the mixture in a rotary vacuum evaporator for 45 min at 100 rpm. A thin
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film was formed at the end of 45 min. which was then hydrated using pH 7.4. The optimization of the formulation was
carried out by varying drug: lecithin ratio and solvents namely acetone, dichloromethane and methanol: chloroform (8:2)
as shown in (tab. 1). The obtained pharmacosomal formulations were then sonicated in an ultra-bath sonicator
(Equitron).
Table 1: Composition of Etodolac Pharmacosomal Formulations.
Formulation of Etodolac gel
Pharmacosomal formulations obtained were added to Carbopol 934 (1% w/w), by slow mechanical dispersion using a
mechanical stirrer (Kemi, India) for 1 hour. The gel was finally obtained by addition of triethanolamine. pH was
adjusted. Weighed 100 mg of drug and dissolved in saline phosphate buffer, which was then added to Carbopol 934
(1%w/w) and pure drug gel was finally obtained by the addition of triethanolamine.
Characterization of pharmacosomes
Prepared pharmacosomal formulations were characterized for following parameters
Vesicle size and surface morphology
Dynamic light scattering technique was used to measure the particle size of prepared pharmacosomal formulation with a
zetasizer (Malvern Instruments Ltd). The sample was positioned in quartz cuvette and the size can be measured when the
light scattered at an angle of 900. Morphological characterization were done by using scanning electron microscopy.
Diluted formulations were fixed on a double-sided adhesive carbon taped aluminium stub and then coated with gold and
scanned with the scanning electron microscope [7].
Ingredients P1 P2 P3 P4 P5 P6 P7 P8 P9
Etodolac 100mg 100mg 200mg 100mg 100mg 200mg 100mg 100mg 200mg
Soy lecithin 100mg 200mg 100mg 100mg 200mg 100mg 100mg 200mg 100mg
Acetone 5ml 5ml 5ml - - - - - -
Methanol+
Chloroform
- - - 5ml 5ml 5ml - - -
Dichloromethane - - - - - - 5ml 5ml 5ml
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Surface charge
All the batches of prepared pharmacosomal formulation was dissolved in phosphate buffer pH 7.4, and analyzed using
zeta analyzer (Malvern Instruments Ltd)
Infrared Spectroscopic Analysis
FTIR spectra of the pure etodolac, soy lecithin, etodolac and soy lecithin physical mixture and etodolac – soy lecithin
complex were obtained from FTIR spectrometer (Shimadzu, Kyoto, Japan) in the transmission mode with the wave
number region 3500 – 500 cm-1
for detection of any possible interaction between etodolac and soy lecithin. 1mg sample
powder were mixed with 100 mg KBr [8].
Entrapment Efficiency
The unentrapped drug from Etodolac containing pharmacosome vesicles were separated by centrifuging (High Speed
refrigerated centrifuge, Kemi) at 10,000 rpm at 4°C for 1 hour. The supernatant was diluted with pH7.4. The Etodolac
concentration was assayed spectrophotometrically at 280 nm. The values were expressed as mean standard deviations.
The percentage of drug entrapped in pharmacosomes was calculated by the following equation [9]
Percentage Entrapment Efficiency = [(Ct – Cf) / Ct] x 100 (1)
Where Ct = concentration of total amount of drug added
Cf = concentration of free drug
Percentage yield
The drug loaded pharmacosomes was dried, collected and weighed accurately. The yield of pharmacosomes was
calculated by
% Yield = Total weight of pharmacosomes (mg) X 100 (2)
Total weight of drug + Total weight of excipients
Characterization of Gels
The optimized gel base for pure drug and the pharmacosome loaded gel were evaluated for following parameters.
Physical examination and pH optimization
Visual inspections of the gels were done in order to determine the clarity, consistency, homogeneity and color. PH and
viscosity (Prime Rheometer DV1) determinations were also done.
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Drug content and content uniformity
Pharmacosomal gel containing 100 mg of drug was extracted using methanol for 30 minutes, which is filtered through
membrane filter. From the filtered solution 2.5 ml was pipetted out and made up to 10 ml and the absorbance was
measured at 280nm.
Spreadability: Spreadability was determined by assessing the required time to separate the slide by applying force or
weight over the slide. Spreadability of the formulation was reported in seconds. Spreadability was calculated using the
formula:
S = M x L / T (3)
Where S = spreadability
M = weight to upper slide
L = length of glass slide
T = time taken to separate the slide completely from each other
Extrudability: Extrudability was measured using a closed collapsible tube. The study was done to identify the amount
of drug been extruded within 10 seconds to form a 0.5cm ribbon.
In-vitro studies
Percentage cumulative amount of drug release from cellophane membrane
In order to determine the cumulative drug release, 1gm of formulation was placed in the cellophane membrane dialysis
tubing, both ends of which were sealed and suspended in a beaker having 30 ml phosphate buffer saline pH 7.4
maintained at 37 ± 1°C. The buffer was agitated using a magnetic stirrer at 50 rpm and the samples were withdrawn at
0.5, 1, 2, 4, 6, 8, 10, 14, 18 and 24 h time intervals, and replaced with an equal amount of fresh buffer solution and
analyzed at 280 nm. The percentage drug release was determined by plotting a graph between cumulative percentage
drug releases against time. Various pharmacosomal formulations were evaluated for drug release and were compared
with cumulative drug release pattern of hydro alcoholic solution of drug [10, 11]. Kinetic modelling were assessed to
identify the mechanism followed for the formulated pharmacosomes [12].
Skin permeation and drug deposition study across porcine skin The porcine skin were obtained from animal local
slaughter house and the hair sub cutaneous fatty tissue was removed by using a scalpel, surgical blade & scissors. The
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porcine skin was cut into size and placed in franz diffusion cells (Orchid Scientifics) with a diffusional area of 3.14 cm2.
1g of the formulated pharmacosome was applied on the skin which was placed between the donor and the receptor
compartment containing pH 6.8 (10 ml) maintained at 37 ± 0.5°C and stirred at 500 rpm. 1ml of the test sample were
withdrawn from the receptor compartment at 1, 2, 3, 4, 6, 8, 10, 12, 14 and 24 hr and the same amount of the solution has
been replaced into the receptor compartment and the absorbance was estimated at 280nm. After performing the
permeation studies for 24hrs, the donor compartment was washed 5 times with methanol. The skin was extracted with
methanol as a receptor solution for a further period of 24 hours and drug content was determined spectrophotometrically
at 280 nm. Histopathological study was done with the permeated skin.
Assessment of in-vitro anti-inflammatory activity
Inhibition of Albumin Denaturation
1% aqueous solution of bovine serum albumin was added with the formulated pharmacosomal solution and the pH was
adjusted with 1N HCl. The solution was incubated at 37°C for 20 min and heated to 51°C for 20 min. The sample was
cooled and kept at room temperature for 12 hrs and absorbance was measured at 660 nm [13]. The percentage inhibition
of protein denaturation was calculated as follows:
Percentage Inhibition = (AbsControl – AbsSample) x 100 / AbsControl (4)
Anti-proteinase action
The reaction mixture (2ml) comprises of trypsin (0.06mg), pH 7.4 Tris HCl buffer (1ml, 20mmol) and test sampe (1ml).
The process was performed under after the addition of 0.8% w/v casein (1ml) was added and incubated at 37°C. To arrest
the reaction, the solution was mixed with 70% perchloric acid (2ml) prior to incubation at 37°C. The suspension was
centrifuged and the absorbance was noted at 210 nm against buffer as blank [14]. The experiment was performed in
triplicates. The percentage of proteinase inhibitory action was calculated.
Percentage Inhibition = (AbsControl – AbsSample) x 100 / AbsControl (5)
Heat induced hemolysis
1 ml of the solution consisting of either etodolac pharmacosomal suspension, etodolac solution or standard drug
diclofenac and 1 ml of 10 % v/v human red blood cell suspension were collected in centrifuging tubes and incubated at
56°C for 30 min and centrifuged at 2500 rpm for 5 min and supernatant absorbance was measured at 560 nm. The
experiment was performed in triplicates for all test samples [15, 16].
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Percentage inhibition of hemolysis = (AbsControl – AbsSample) x 100 / AbsControl (6)
In-vivo anti-inflammatory studies
The selected animal model was Wistar albino rats, weighed 190-220 g of either sex in four groups each containing six
rats. Prior to procedure, the animals were fasted overnight. Group I was applied carrier as control and Group II was
applied with diclofenac gel as standard, Group III was applied etodolac gel as test Standard and Group IV was applied
etodolac pharmacosomal formulation as test. Baseline recording of the ankle joint diameter was made by using a vernier
caliper [17-19]. The animals were anesthetized by 0.3 ml of ketamine. Sub plantar injection was administered to induce
0.1 ml CFA mixed with phosphate buffer saline in 1:1 ratio into the right hind paw of the rat for produ
cing inflammation. Drug/ Carrier was administered topically once daily for a period of 14 days. The paw and ankle
thickness (cm) of each group was measured from Day 1 - Day 14 using a vernier caliper.
The severities of inflammation in rats were assessed daily and accurate scoring [19] was made semi qualitatively based
on (tab. 2). Data obtained was used to calculate percentage inflammation at different time points. Also percentage
inhibition of inflammation was calculated for each time point for different treatments.
Swelling % = (Tt - T)/ Tt X 100 (7)
Inhibition % = 1 - % swelling of group treated X 100 (8)
% swelling of control group
Where Tt is thickness at time t, T is initial thickness, at t = 0
Table 2: Scoring parameters for physical signs of inflammation
Score Tenderness Or
PainOn
Movement
Soft Tissue Swelling Warmth Redness
0 Not tender None Cool Normal
1 Tender Probable swelling Probable warmth Mild
2 Tender with wince
response
Definite swelling Definite warmth Moderate
3 Tender with wince
and withdraw
response
Tender swelling Hot Severe
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Stability studies as per ICH guidelines
The optimized formulations were maintained under refrigeration temperature (4±2°C), room temperature (30±2°C) and
at elevated temperature (40±2°C) for 3 months to determine physical and chemical stabilities. The samples were
collected at regular intervals and evaluated for drug entrapment efficiency as mentioned earlier. The formulation was
evaluated visually for any color change, change in consistency and for drug entrapment efficiencies.
Results and Discussion
The formulations were optimized based on vesicle size and zeta potential to form stable pharmacosomes lack of
aggregation, blend and sedimentation. The optimized gel formulations are shown in (fig. 1).
Fig.1. Optimized pharmacosomal gel formation
Vesicle size and zeta potential (ζ)
The method used was found to be suitable in producing vesicles of polydispersity index less than 0.429, indicating the
narrow size distribution of the pharmacosomal formulations. The results showed an increase in vesicle size increases the
concentration of phospholipid as shown in Table 3. Also, ethanol when used as solvent gives the highest size vesicles,
probably due to its high aqueous solubility. Zeta potential for the pharmacosomes was measured for studying the stability
of vesicles. The surface charge was determined by means of a zeta analyzer and was found to be in the range of -8.9
mV - -38.9mV , which provides sufficient stability and also prevents aggregation of vesicles.
Morphological studies
The morphology and surface appearance of pharmacosomes were examined by SEM and optical microscopy. The SEM
micrographs showed the pharmacosomes were somewhat spherical in shape as in (fig. 2).
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Fig.2. SEM of Optimized pharmacosomal gel formation
Drug entrapment efficiency and percentage yield
The entrapment efficiency of etodolac pharmacosomes was found to be greater than other vesicular systems from
literature surveys [20, 21]. Results indicated an increase in entrapment efficiency and percentage yield with an increase
in phospholipid concentration. There was a slight increase in entrapment efficiency when dichloromethane was used as a
solvent as compared to acetone and methanol: chloroform mixture (8:2), possibly due to the lower aqueous solubility of
dichloromethane as compared to other solvents.
Table 3: Drug entrapment efficiency & % yield of Optimized pharmacosomal gel.
Etodolac Formulation Code Entrapment Efficiency
(%)
% Yield
P1 96.6 ± 1.14 91.6 ± 0.6
P2 95.2 ± 1.10 91.1 ± 0.7
P3 92.5 ± 2.18 87.6 ± 1.6
P4 96.6 ± 1.36 92.6 ± 0.9
P5 94.1 ± 2.34 90.4 ± 0.9
P6 91.02 ± 1.8 85.1 ± 1.4
P7 94.8 ± 2.25 94.7 ± 0.4
P8 91.8 ± 1.45 91.2 ± 1.04
P9 90.8 ± 1.92 86.06±1.28
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IR Spectroscopic studies
On comparing the IR spectra of the pure drug etodolac, soy lecithin, etodolac –soy lecithin physical mixture and
etodolac- soy lecithin pharmacosomes complex, clearly indicated significant interaction soy lecithin and etodolac
indicating a bond formation between them as shown in (fig. 3).
Fig.3. FTIR of (a) pure drug etodolac, (b) soy lecithin, etodolac –soy lecithin, (c) physical mixture, and (d)
etodolac- soy lecithin pharmacosomes complex
Evaluation of pharmacosomal gels
The optimized pharmacosomes were evaluated for the following assessment:
Physical appearance
The pharmacosomal gel was found to be smooth, homogenous, transparent and spreadable and free from any grittiness.
pH and viscosity determinations
pH of the optimized formulations were within limits of range of 6.1-6.4 and the viscosity was determined to be between
27,000-28,500
Drug content uniformity
The optimized pharmacosomal gel was found to be satisfactory as there was no percentage deviation from the standard.
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In-vitro drug release studies and kinetic data analysis
The in-vitro release studies indicated a slower drug release from pharmacosomal formulations as compared to pure drug
gel as shown in (fig. 4), probably due to formation of etodolac-phospholipid complex. The pure drug gel showed a 98.6%
release of drug at 24 h compared to 59.9% of P1G, 58.3 % of P4G, 57.5% of P7G. , clearly indicating a sustained release
pattern of the drug from the gel formulation. The decrease in release rate can be attributed to formation of an additional
barrier due to complexation for releasing the drug from vesicle membrane.
Release kinetic studies were done for all the formulations for different kinetic equations (zero-order, first order, Higuchi
and Korsemeyer-peppas ) and the best model was found to be Higuchi model ( r2 > 0.9) , indicating the possible
mechanism of drug release from lipid bilayer by diffusion.
Table 5: Kinetic release data of Optimized pharmacosomal gel.
In-vitro drug permeation and drug deposition studies
Results clearly shows higher permeation rate of pharmacosomal gel formulations across porcine skin indicating
significant interaction between etodolac pharmacosomes and skin. The pharmacosomal gel showed an increased amount
of drug retained in the skin when compared with the pure gel. Hence the pharmacosomal formulations not only enhance
the drug permeation rate but also help in skin localization acting as a depot formulation (Fig. 4 5).
Fig. 4. In-Vitro drug release over cellophane membrane.
Formul
ations
Zero-
order
First-
order
Higuchi
model
Korsemeyer
Peppas
Diffusional
Exponent (N)
P1g 0.5696 0.6471 0.8451 0.8601 1.30
P4g 0.6407 0.7411 0.9485 0.9029 1.32
P7g 0.8887 0.9216 0.9525 0.941 1.2217
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Fig. 5. Percent of drug deposited over porcine skin.
Histopathological studies
The histology of porcine skin kept as control and treated with water, drug solution and optimized gel formulation is
represented in the (fig. 6). The stratum corneum, epidermis and dermis are closely packed when treated with water and
drug solution while clear lipid bilayer disruption can be seen with pharmacosomal gel indicating rapid permeation of the
drug across the skin. Hence it can be said that the pharmacosomal gel alters the lipid fluidity of the stratum corneum and
thereby loosening the tightly packed lipid layer.
Fig.6. Histology of skin treated with (a) normal saline, (b) drug solution, (c) optimized formulation.
In-vitro anti-inflammatory studies
Etodolac pharmacosomal suspension was found to be having significant inhibition of albumin denaturation as compared
to the standard drug diclofenac and etodolac. Denaturation of protein can be attributed to the cause of production of auto
antigens in rheumatoid arthritis. From the results, it suggests the ability of the pharmacosomal gel to regulate the auto-
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antigen production resulting in the inhibition of protein denaturation and hemolysis induction of RBC’s, signifying
membrane stabilization as an additional mechanism of anti-inflammatory effect. This effect can be possibly recognized
to the inhibition of release of lysosomal content of neutrophils at the site of inflammation. The maximum inhibition was
found to be 54.96 % for etodolac pharmacosomes compared to 47.1 % of etodolac and 41.6% % of diclofenac.
Inhibition of proteinase activity is based on the fact that the proteinase activity inherent in leucocytes plays an important
role in the development of tissue damage during inflammatory reactions. A significant level of protection was therefore
provided by the etodolac pharmacosomal formulation as compared to etodolac and diclofenac.
Fig. 7. Comparison study of anti-inflammatory & anti-arthritic actions of different formulations.
In-vivo anti-inflammatory activity in sub chronic model of inflammation
Studies on in vivo anti-inflammatory action were carried out by freund’s adjuvant induced inflammation for 14 days. The
ability of the treatment in inhibiting CFA-induced paw and ankle swelling is an indication of the anti-arthritic potential of
the formulation. CFA, administered subcutaneously in the right paw not only resulted in significant inflammation but
also various cardinal signs of inflammation. The physical markers of inflammation was noted and charted as in the Table
6 based on a scoring system. Results of percentage paw and ankle edema swelling as well as inhibition was calculated
and is shown in (fig. 8 & 9). All the groups except the control group showed marked decrease in inflammation over 14
days. In addition, functional disability accompanied with generalized hardness and darkness of paws was observed with
control group compared to NSAID treated groups. The pharmacosomal gel formulation showed significant decrease in
swelling over other groups and improved physical characteristics.
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Table 6: In-vitro anti-inflammatory studies Optimized pharmacosomal gel
Fig.8. Paw edema studies for (a) control (b) diclofenac gel (c) etodolac gel (d) etodolac pharmacosomal gel.
Fig.9. Percentage Swelling in CFA induced inflammation.
Stability studies
Physical examination of the formulations showed a decrease in viscosity, increased spreadability at elevated
temperatures when compared to room temperature and refrigerated conditions. The results show a decrease in entrapment
efficiency at elevated temperatures as compared to room temperature and refrigerated conditions. Keeping the
pharmacosomal formulations under refrigerated conditions results in better stability of the product.
Formulati
on
Days
Average Score
Day 1 Day 3 Day 7 Day 14
Control 2+2+2+2 3+2+2+2 3+2+2+3 3+3+3+3 9.75
Diclofenac 1+2+1+1 3+2+2+2 2+2+2+2 2+2+2+2 7.5
Etodolac 1+2+1+1 3+2+2+2 2+2+2+2 2+2+2+2 7.5
P7G 1+1+1+1 1+2+2+2 1+2+2+2 1+1+1+3 5.25
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Conclusion
A novel etodolac pharmacosomal gel formulation was designed, synthesized and studied for suitability for transdermal
application. Findings of the study conclusively demonstrate a sustained release mechanism and depot action of the drug.
The current research work focused to reduce dose frequency and to maintain drug concentration at the site for longer
times can be achieved. The entrapment efficiency of the formulation was also found to be higher compared to other
vesicular formulations. The in vitro and in vivo anti-inflammatory studies also indicated superior anti-inflammatory
potential of etodolac pharmacosomal gel formulation compared to pure drug gel and marketed formulation. Etodolac
pharmacosomes showed greater stability when stored under refrigerated conditions and can be suitably used in
pharmacotherapy of rheumatoid arthritis.
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