FORMULATION AND EVALUATION OF ETODOLAC NIOSOMES BY MODIFIED ETHER INJECTION TECHNIQUE

Objectives: Niosomes are non-ionic surfactant based multilamellar or unilamellar vesicles with aqueous solution of solute that is enclosed by a membrane. Etodolac is an indole acetic acid derivative with half-life of 4 to 7hrs. It is used for the treatment of Rheumatoid arthritis. Whenever used orally, it has many systemic side effects, so it is not preferred orally. The aim of present study was to develop niosomes of Etodolac to avoid all drawbacks associated with it like first pass metabolism and side effects. Methods: In present study four niosomes formulations of Etodolac were successfully developed by modified ether injection technique using different nonionic surfactant i.e. Span 20, Span 40, Tween 20, Tween 40 and cholesterol. Formulations were evaluated for different parameters like particle size, entrapment efficiency, in-vitro release, stability studies. Results: Niosomes formulations of batch N3 shows maximum mean particle diameter i.e. 2.46 μm. The entrapment efficiency of the niosomes was between 66.52-78.32%. The entrapment efficiency was found to be higher with the batch N4 (78.32%). The cumulative percent drug release after 10 hrs of the Etodolac niosomes in between 40.59-78.55%. 68.5% for N1, 50.49% for N2, 40.59 for N3 and 78.55 for N4. Accelerated stability studies for 12 weeks revealed that the Etodolac niosomes formulations of batch N4 were stable at up to 45C. Conclusion: Study concludes that Etodolac can be delivered by niosomes dosage form effectively and all limitations associated with it can be avoided.


INTRODUCTION
The main aim of any novel drug delivery system is to provide a therapeutic amount of drug to reach to the desired site in the body and then maintain the required drug concentration to produce therapeutic effect 1 . Niosome is a class of molecular cluster formed by selfassociation of non-ionic surfactants in an aqueous phase 2 . Niosomes are non-ionic surfactant based multilamellar or unilamellar vesicles in which an aqueous solution of solute is enclosed by a membrane. Niosomes are promising vehicle for drug delivery and being non-ionic; and Niosomes are biodegradable, biocompatible non-immunogenic and exhibit flexibility in their structural characterization. The first niosome formulations were developed and patented by L'Oreal in 1975. Niosomes serve as drug depot in the body which releases the drug in a controlled manner through its bilayer providing sustained release of the enclosed drug 3 .
Etodolac is a nonsteroidal anti-inflammatory drug of COX-2 inhibitor class used for osteoarthritis, rheumatoid arthritis, gout, rheumatoid arthritis and traumatic injury. It produces therapeutic effects by inhibition of prostaglandin synthesis 4 . Due to extensive first pass metabolism it has low bioavailability. Since its terminal half life is 4-7 hrs and hence frequent dosing is required. Frequent oral use of Etodolac leads to serious gastrointestinal disturbance such as ulcer, stomach, or intestinal bleeding and chest pain which may be harmful. Gastrointestinal side effects produced by NSAIDs are either due to direct contact or indirect effect of the drug on the gastrointestinal mucosa. All these associated problems may be avoided by coating of polymer by avoiding release of drug in gastrointestinal tract 5  different parameters to avoid all problems and to improve its oral bioavailability 6 .  11 . ICH (International Conference on Harmonisation) guidelines suggests stability studies for dry niosomes powder meant for reconstitution should be studied for accelerated stability at 75% relative humidity as per international climatic zones and climatic conditions.

RESULTS AND DISCUSSION
A successful attempt was made to formulate four formulations of Etodolac niosomes formulations by modified ether injection technique using nonionic surfactant and cholesterol at different concentrations. The pure drug shows sensitivity to light and moisture. Therefore formulating it into niosomes can solve this problem to a large extent. The mean particle diameter of the Etodolac was between 2.28-2.46 µm for all twelve formulations. Particles of all formulations were smooth, oval and discrete.

Figure 1: Percentage of drug released from Etodolac niosomes
Niosomes formulations of batch N3 shows maximum mean particle diameter i.e. 2.46 µm. The entrapment efficiency of the niosomes was between 66.52-78.32%. The entrapment efficiency was found to be higher with the batch N4 (78.32%), which may have an optimum surfactant cholesterol ratio to provide a high entrapment of Etodolac. The in-vitro permeation of Etodolac from niosomal formulation was studied using locally fabricated diffusion cell. The cumulative percent drug release after 10 hrs of the Etodolac niosomes in between 40.59-78.55%. 68.5% for N1, 50.49% for N2, 40.59 for N3 and 78.55 for N4. The formulation containing tween showed less drug release compared with the preparation containing span. This may be due to the larger size of the vesicles and less lipophilic nature of the Tween, which makes it more difficult for these vesicles to penetrate or fuse with skin whereas, the inclusion of span which is more lipophilic than tween further increased the lipophilicity of the drug leading to better penetration. Rapid drug leakage was observed during the initial phase. However, after that a slow release occurred. This could be because the drug is mainly incorporated between the fatty acid chains in the lipid bilayer of niosomal vesicles which leads to rapid ionization and release upon dispersing niosomes in large buffer (pH 7.4) volumes until reaching equilibrium. Stability studies revealed that the niosomes kept at room temperature (~25°C) and 40°-75% RH showed the maximum stability. The values of drug content and in-vitro studies were close to that of the initial data with only slight variations suggesting that it has an acceptable shelf life. It should be stored in a cool, dry place. Niosomes formulations of Etodolac of batch N4 shows good stability at refrigeration and room temperature in comparison to other.

Figure 2: Stability study of Etodolac niosomes of batch N4 at different temperature CONCLUSION
At present scenario, many researchers are working for transporting the drug molecules to the desired site in the biological systems. The role of the drug delivery system is not only limited to a drug package just meant for convenience and administration but to bring a required change in therapeutic efficacy and safety by carrying the drug molecules to the desired site in the most convenient manner. In present study four Etodolac niosomes formulations were successfully developed by using different surfactants i.e. Span 20, Span 40, Tween 20, Tween 40 by modified ether injection method. Accelerated stability studies for 12 weeks revealed that the Etodolac niosomes formulations of batch N4 were stable at up to 45 0 C. The stability study of the optimized formulation showed satisfactory characteristics without being drastically influenced. Based on particle size morphology, in-vitro release and stability studies, it can be concluded that formulation N4 was an optimum formulation. However, future experiments should explore the suitability of niosomes with wide variety of drugs having designed drawbacks for improved and effective intended therapy. So, that niosomes are