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ETODOLAC: A PHARMACOECONOMIC AND CLINICALLY EFFECTIVE NSAID FOR ARTHRITIS

 

Clinical courses

ABOUT AUTHORS:
Bhale Shweta*, Saxena Vaishali, Bhandari Govind, Mahajan S.C.
Mahakal Institute of Pharmaceutical studies,
Ujjain (m.p)
*bhaleshweta11@gmail.com

ABSTRACT:
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

Introduction:
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

Description
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:

Sterioselectivity
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.

THERMAL BEHAVIOUR
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

UV Spectroscopy
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

Thin-layer chromatography
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

CLINICAL PHARMACOLOGY
Pharmacokinetics

Absorption:  The systemic bioavailability of etodolac tablet  is 100% as compared to solution and at least80% as determined from mass balance studies. Etodolac is well absorbed and had arelative bioavailability of 100% when 200 mg capsules were compared with a solution of etodolac. Based on mass balance studies, the systemic availability of etodolac from either the tablet or capsule formulation is at least 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. Mean (± 1 SD) peak plasma concentrations (Cmax) range from approximately 14 ± 4 to37 ± 9 μg/mL after 200 to 600 mg single doses and are reached in 80 ± 30 minutes. The dose-proportionality based on the area under the plasma concentration-time curve (AUC) is linear following doses up to 600 mg every 12 hours. Peak concentrations are dose proportional for both total and free etodolac following doses up to 400 mg very 12 hours, but following a 600 mg dose, the peak is about 20% higher than predicted on the basis  of lower doses.4

Distribution: The mean apparent volume of distribution (Vd/F) of etodolac is approximately 390 mL/kg. Etodolac ismore than 99% bound to plasma proteins, primarily to albumin. The free fraction is less than 1% and isindependent of etodolac total concentration over the dose range studied. It is not known whether etodolac is excreted in human milk; however, based on its physical-chemical properties, excretion into breast milk is expected. Data from in vitro studies, using peak serum concentrations at reported therapeutic doses in humans, show that the etodolac free fraction is not significantly altered by a cetaminophen, ibuprofen, indomethacin, naproxen, piroxicam, chlorpropamide, glipizide, glyburide, phenytoin, and probenecid.4

Metabolism: Etodolac is extensively metabolized in the liver. The role, if any, of a specific cytochrome P450 systemin the metabolism of etodolac is unknown. Several etodolac metabolites have been identified in human plasma and urine. Other metabolites remain to be identified. The metabolites include 6-, 7-, and 8-hydroxylated-etodolac and etodolac glucuronide. After a single dose of 14C-etodolac, hydroxylated metabolites accounted for less than 10% of total drug in serum. On chronic dosing, hydroxylated etodolac metabolite does not accumulate in the plasma of patients with normal renal function. The extent of accumulation of hydroxylated-etodolac metabolites in patients with renal dysfunction has not been studied. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces.4

Excretion
The mean oral clearance of etodolac following oral dosing is 49 (± 16) mL/h/kg. Approximately 1% of dose is excreted unchanged in the urine with 72% of the dose excreted into urine as parent drug plus metabolite:
— etodolac, unchanged 1%

— etodolacglucuronide 13%

— hydroxylated metabolites (6-, 7-, and 8-OH) 5%

— hydroxylated metabolite glucuronides 20%

— unidentified metabolites 33%

Although renal elimination is a significant pathway of excretion for etodolac metabolites, no dosing adjustment in patients with mild to moderate renal dysfunction is generally necessary. The terminal half-life (t1/2) of etodolac is 6.4 hours (22% CV). In patients with severe renal dysfunction orundergoing hemodialysis, dosing adjustment is not generally necessary.Fecal excretion accounted for 16% of the dose.4

INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of etodolac    and other treatment options before deciding to use etodolac. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

Etodolac ( capsules and tablets) is indicated:

For acute and long-term use in the management of signs and symptoms of the following:
1. Osteoarthritis

2. Rheumatoid arthritis

For the management of acute pain4

Potentially hazardous interactions with other drugs15

  • ACE inhibitors and angiotensin-II antagonists: antagonism of hypotensive effect, increased risk of nephrotoxicity and hyperkalaemia
  • Analgesics: avoid concomitant use of 2 or more NSAIDs, including aspirin (increased side effects); avoid with  ketorolac, increased risk of side effects and haemorrhage
  • Antibacterials: possibly increased risk of convulsions with quinolones
  • Anticoagulants: effects of coumarins enhanced; possibly increased risk of bleeding with heparins and coumarins
  • Antidepressants: increased risk of bleeding with SSRIs and venlafaxine
  • Antidiabetic agents: effects of sulphonylureas enhanced
  • Anti-epileptics: possibly increased phenytoin concentration
  • Antivirals: increased risk of haematological toxicity with zidovudine; concentration possibly increased by ritonavir
  • Ciclosporin: may potentiate nephrotoxicity
  • Cytotoxic agents: reduced excretion of methotrexate; increased risk of bleeding with erlotinib
  • Diuretics: increased risk of nephrotoxicity; antagonism of diuretic effect;hyperkalaemia with potassium-sparing diuretics
  • Lithium: excretion decreased
  • Pentoxifylline: increased risk of bleeding
  • Tacrolimus: increased risk of nephrotoxicity.

HOW SUPPLIED
Lonine (etodolac capsule) is available as:
200 mg capsules (light gray with one wide red band with LONINE 200/white with two narrow redbands)

—in box, plastic or glass bottles of 4-1000 capsules

Store at controlled room temperature 20°-25°C (68°-77°F), protected from moisture. 4

Published Researchs of etodolac

COLON SPECIFIC COMPRESSION COATED TABLETS OF ETODOLAC: The Etodolac colon specific compression coating tablets were successfully prepared by wetgranulation method. The investigation was carried out to develop colon targeted drug delivery system for Etodolac using HPMC,EudragitL100,EudragitS100 as a carriers for effective and safe drug delivery. From invitro drug release studies it was concluded that The maximum drug release was observed from the formulations based on HPMC polymer. Varying the amount of 89.48% affect the drug release.The drug release from HPMC was slower owing to its showing high viscosity in water. Other Polymers (Eudragit L100 and S100) was less permeability of water and their also showing better drug release profile in both dissolution media.14

DEXTRAN-ETODOLAC CONJUGATES: SYNTHESIS, IN VITRO AND IN VIVO EVALUATION:This investigations suggest that the dextran can be employed as carrier to obtain dextran-etodolac conjugates, which may represent potentially useful conjugates for oral administration of etodolac with improved aqueous solubility and remarkably diminished gastrointestinal side effects, while retaining comparable biological activities of the parent drug.17

Polymeric Surfactant Based Etodolac Chewable Tablets: Formulation and In Vivo Evaluation: Formulation of etodolac chewable tablets not only improved its dissolution rate-dependent bioavailability butalso provides a useful tool to improve patient convenience and compliance. Chewable tablets are suitable for administration of large tablets to geriatrics and pediatrics that have difficulty in swallowing solid dosage forms.18

Etodolac Loaded Poly (Lactide-Co-Glycolide) Nanoparticles: Formulation and In Vitro Characterization: nanoparticulate delivery system for etodolac has been designed and evaluated for in vitro properties. it can be concluded that etodolac loaded PLGA nanoparticles of appropriate particle size are obtained by nanoprecipitation technique. High drug loading and yield values were achieved. 21

Development and In Vitro/In Vivo Evaluation of Etodolac Controlled Porosity Osmotic Pump Tablets: In vitro delivery of more than 90% of etodolac over 24 hwith nearly constant zero-order release kinetics was successfully achieved by optimization of the variables influencing the design of controlled porosity osmotic pump tablets of the drug. The rate of drug release from CPOP tablets could be tailored by controlling the osmotic pressure of the core tablet (osmogent type and drug/osmogent ratio), the composition of the coating solution, the membrane weight gain percentages, and the concentration of pore-forming agent. When compared to the immediate-release Napilac® capsules, the best achieved CPOP tablets provided enhanced bioavailability and extended duration of effective etodolac plasma concentration with minimum expected potential for side effects. 22

FORMULATION AND IN-VITRO EVALUATION OF ETODOLAC ENTRAPPED IN MICROSPONGE BASED DRUG DELIVERY SYSTEM: Etodolac was entrapped in the microsponge drug delivery system formed by using ethyl cellulose and eudragit RS 100. Alteration in the release rate of the drug may be due to the entrapment which modifies the release of drug that causes reduction in the severity of the side effects.27

Formulation and Evaluation of Extended Release Etodolac Tablets:The tablets were resulted in more uniform extended drug release. This may be due to Zero-order release kinetics. Extended drug release dosage forms release drug slowly, so that plasma concentrations are maintained at a therapeutic levels for aprolonged period of time usually between 8 to 12 hours.28

CONCLUSION
Clinically effectiveness ofthe Cox-II inhibitors  to that of other NSAIDs in terms of their ability to reduce pain andimprove physical and global function of both OA and RA patients. Thesecond finding of this review was that there is evidence that the four Cox-IIinhibitors are effective in reducing the incidence of GI adverse events of OAand RA patients compared to NSAID therapy. When these two findings areput together, it can be concluded that there is evidence to support the use ofthese four Cox-II inhibitors in preference to NSAIDs for the management of OA and RA.

The cost-effectiveness of Cox-II inhibitors remains inconclusive. Economic models developed by manufacturers generate favourable outcomes for the Cox-II inhibitors versus standard NSAIDs, including cost-savings, for all OA and RA patients, …. (in confidence). There are no published economic evaluations for Cox-II inhibitors in the UK context, other than the one meloxicam study.16

Table-1: Range of Bond lengths and bond angles for Etodolac11

____________________________________________________________

Parameers PM3                                                  Bond Lengths

 

 (C-C)                                                                   1.441-1.554

(C=C)                                                                    1.379

(C-O)                                                                     1.353

(C=O)                                                                    1.219

(C-H)                                                                     1.094-1.108

(O-H)                                                                      0.952

(C-N)                                                                     1.421-1.422

(N-H)                                                                     0.990

Bond Angles

(C-C-C)                                                                  112.12-115.29

(C=C-C)                                                                 121.59

(C-C-H)                                                                  107.98-111.07

(C-O-C)                                                                  117.57

(C-O-H)                                                                  109.89

(C-C=O)                                                                 128.55

(O=C-O)                                                                 115.61

(H-C-H)                                                                  106.27-107.90

(C-C-N)                                                                  126.71

(C-N-C)                                                                  107.12

______________________________________________________

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