issn: 0975 -766x coden: ijptfi available online …...etodolac pharmacosomes which were compared...

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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IJPT| June-2017| Vol. 9 | Issue No.1 | 29665-29680 9666

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



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


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.



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


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].



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


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).



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


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.



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


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-



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.


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



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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