ETODOLAC: A PHARMACOECONOMIC AND CLINICALLY EFFECTIVE NSAID FOR ARTHRITIS
Bhale Shweta*, Saxena Vaishali, Bhandari Govind, Mahajan S.C.
Mahakal Institute of Pharmaceutical studies,
Connective tissue disease include the following state: rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, polyarteritis nodosa, gout, rheumatic fever and osteoarthritis, with the most common forms of which are rheumatoid arthritis, osteoporosis and gout. Rheumatoid arthritis is a chronic, nonsuppurative inflammatory disease of unknown cause affecting primarily peripheral synovial joint. the onset is usually insidious, with immunological reaction playing a major role. Common medications for arthritis include nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs decrease pain, inflammation, and fever by blocking cyclo-oxygenase (COX) enzymes. Understanding of the pharmacology of NSAIDs continues to evolve, but it is now thought that most NSAIDs block three different COX isoenzymes, known as COX-1, COX-2, and COX-3. COX-1 protects the lining of the stomach from acid. COX-2 is found in joint and muscle, and mediates effects on pain and inflammation. By blocking COX-2, NSAIDs reduce pain compared to placebo in patients with arthritis, low back pain, minor injuries, and soft tissue rheumatism. selective NSAIDs or “COX-2 selective NSAIDs” as drugs in the “coxib” class (celecoxib, rofecoxib, valdecoxib, etoricoxib, lumiracoxib). “partially selective NSAIDs” as other drugs shown to have partial in vitro COX-2 selectivity (etodolac, nabumetone, meloxicam).
REFERENCE ID: PHARMATUTOR-ART-1909
Rheumatoid arthritis (RA) is an inflammatory disease. It largely affects synovial joints, which are lined with a specialized tissue called synovium. RA typically affects the small joints of the hands and the feet, and usually both sides equally and symmetrically, although any synovial joint can be affected. It is a systemic disease and so can affect the whole body, including the heart, lungs and eyes.
There are approximately 400,000 people with RA in the UK. The incidence of the condition is low, with around 1.5 men and 3.6 women developing RA per 10,000 people per year. This translates into approximately 12,000 people developing RA per year in the UK. The overall occurrence of RA is two to four times greater in women than men. The peak age of incidence in the UK for both genders is the 70s, but people of all ages can develop the disease. Drug management aims to relieve symptoms, as pain relief is the priority for people with RA, and to modify the disease process.
The total costs of RA in the UK, including indirect costs and work-related disability, have been estimated at between £3.8 and £4.75 billion per year. Clearly this disease is costly to the UK economy and to individuals.
NICE(National Institute for Health and Clinical Excellence) has published five technology appraisals relevant to RA. Two of these are updated in this guideline (‘Anakinra for rheumatoid arthritis’, NICE technology appraisal guidance 72; ; and ‘Guidance on the use of cyclo-oxygenase (Cox) II selective inhibitors, celecoxib, rofecoxib, meloxicam and etodolac for osteoarthritis and rheumatoid arthritis’, NICE technology appraisal guidance 27;.NSAIDs are used for chronic inflammatory conditions such as rheumatoid arthritis and osteoarthritis, posttraumatic conditions (e.g. distortion, contusion), for relieving mild to moderate pain of varied origin, reducing fever, as well as for preventing local inflammation such as gout .8
Etodolac is a member of the pyranocarboxylic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Proprietary name : Lodine ,ramodar, ultradol ,zedolac, . Etodolac is a white crystalline compound, insoluble in water but soluble in alcohols, chloroform, dimethyl sulfoxide, and aqueous polyethylene glycol. TheUV spectra of Etodolac standard in methanol solution are given in Figure (1)The pH dependence solubility was calculated using ACD solubility studies and it is predicated that although the drug exhibits very low solubility at low pH ,its solubility dramatically increases at high pH.The chemical name is (±) 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid. The molecular weight of the base is 287.37. It has a pKa of 4.65 and an n-octanol: water partition coefficient of 11.4 at pH 7.4. The molecular formula for etodolac is C17H21NO3, and it has the following structural formula:
Etodolac is a chiral NSAID that has been marketed as a racemate .S(+) etodolac shows almost all the pharmacological activity ,while R(-) etodolac shows little.Racemic etodolac has been resolved into its individual enanatiomers by forming diastereomers and it is characterized by a melting point .The m.p for S(+) etodolac is 142-143°Cand for R(-) etodolac is 93-96 °C.
The melting point range of etodolac has been reported as 144-150°C
The DSC thermogram is shown in (Fig 1) It measures the heat flow in and out of both sample and reference during a controlled temperature program. The crystalline nature of the pure drug and its thermal behavior was studied by Differential Scanning Calorimetry (DSC). It provides information about the physical properties of the sample as crystalline or amorphous nature and demonstrates a possible interaction between drug and other excipients. and consisted of a single melting endothermic transition ,the endothermic transition was characterized by an onset temperature of 147.1°C ,a temperature maximum of 148.6°C,and an enthalpy of fusion of 118.6.
INFRARED ABSORPTION SPECTROPHOTOMETRY
Examine by infrared absorption spectrophotometry comparing with the spectrum obtained with etodolac.. (Fig 2)11
Spectral region over 2800 cm-1
The bands located in the high frequency region of the spectra of Etodolac are easy to identify and belong to O-H, N H and C–H stretching modes. The characteristic nOH stretching vibration is expected to appear at 3760 cm-1, which is in good agreement with the experimental data. The characteristic nCH stretching vibrations of double ring structure are expected to appear in 2800-3100 cm-1 frequency ranges. The nCH stretching vibrations of the title compound were observed at 2930 and 3004 cm-1 and the corresponding bands are given at 2930 and 3000 cm-1 in the experimental spectrum.11
Spectral region 1750–1000 cm-1
In middle region, the stretching vibration of the C=C band observed at 1736 cm-1 and corresponding band is given at 1745 cm-1 in FTIR spectrum. The H-C–H scissor predicted at 1354 cm-1 is in reasonable agreement with the 1360 cm-1 observed in FTIR. (C–C–H) anglebending mode observed at 1142 and 1197 cm-1 and corresponding band is given at 1150 and 1195 cm-1 in FTIR spectrum.11
Spectral region 1000–650 cm-1
The twisting along with the out of plane ring bend, all of them appear in the frequency range 1000-650 cm-1.The experimental modes 735, 795 and 835 cm-1 matches well with the modes 735, 790 and 829 cm-1 (Due to twisting vibration).11
Spectral region below 650 cm-1
There are some frequencies in lower region due to the torsion modes like 392, 475, 505 and 536 cm-1 having appreciable IR intensity. Furthermore, the study of low frequency vibrations is of great significance, because it gives information on weak intermolecular interactions, which take place in enzyme reactions 11
Formation of coloured complexes between the drug and p-dimethylaminobenzaldehyde reagent (PDAB)in the presence of sulfuric acid and erric chloride ,measurement of the absorbance was carried out at 591.5 nm for etodolac.9
Examine by thin-layer chromatography , using a TLC silica gel GF254 plate R previously activated by heating at 105 °C for 1 h, Place the plate in an unsaturated chamber containing a mixture of hexane:ethyl acetate:acetic acid in the ratio of 60:40:2 V/V .Allow the solution to ascend 1 cm above the line of application on the plate, remove the plate and allow it to dry for at least 30 min. the relative retention( Rf) value obtain is 0.29.6
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