Australian Public Assessment Report for Naproxen/esomeprazole
Novel Tocopherol Naproxen Ester Pro Drug
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Transcript of Novel Tocopherol Naproxen Ester Pro Drug
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Design, Synthesis and Anti-inflammatory Activity of Novel -Tocopherol Naproxen
Ester Prodrug
Madan BaralB. Pharm.
School of Health and Allied SciencesPokhara University, PO Box 427, Lekhnath-12, Kaski,
NEPAL
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OVERVIEW Introduction Methodology
• General Procedure of Synthesis• Chemical Analysis• Pharmacokinetic Evaluation
– In Vivo Bioavaibility Study in Rabbit
• Pharmacodynamic Evaluation– Carrageenan Paw Inflammation– Carrageenan Air Pouch Model– Gastric Injury Model
• Statistical Analysis Results and Discussion Conclusion
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Introduction• Naproxen : Non-steroidal anti-inflammatory drugs (NSAIDs) • Therapeutic Uses: Treatment of pain, inflammation and fever, mostly arthritic pain • Side effects : Stomach irritation to ulceration and bleeding• Causes:
– blockage of prostaglandin biosynthesis in the GI tract – direct action of free carboxylic groups in NSAIDs and production of reactive
oxygen species (ROS) is increased in NSAIDs therapy
• Objective : Overcome the oxidative degradation of ROS
• Naproxen esters containing tocopherol was designed and synthesized.
• In vitro and in vivo tests suggested prodrugs exhibited anti-inflammatory activity with a strong and significant reduction in GI lesion.
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Naproxen
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Methodology
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General Procedure of Synthesis of Naproxen Prodrug
Stirring20 min.
Naproxen
DCC
Acetonitrile
Stirring48 Hr.
Tocopherols
Acetonitrie
Triethylamine
Filtrate + Ethylacetate
Susp. Mixture
Distillation Drying ExtractionEster
Prodrug
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Chemical Analysis• 1H NMR • Electron Impact (EI–MS) mass spectra • HPLC separation • Elemental analysis (C, H, N)• Log D calculation using ACD/Labs software • Thinlayer chromatography• Column chromatography
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Chemical and Enzymatic Hydrolysis• Chemical hydrolysis: at 37±0.1 C in buffer phosphate solution at pH 8.0
containing 50% of 2-hydroxypropyl)-β-cyclodextrin (HP-β-CD)
• Enzymatic hydrolysis: initiated by diluting 1:10 (v/v) appropriate amounts of a stock solution of each prodrug in methanol (1 mg/ml) with a preheated buffer phosphate solution at pH 8.0 containing 5% dimethyl-β-cyclodextrin (DM-β-CD) and porcine liver esterase at 37±0.1.
• • Hydrolysis samples are taken and analyzed by HPLC for naproxen, α- or -
tocopherol and the remaining ester prodrug. influence of methanol and DM-β-CD on enzyme activity.
• A new HPLC method was developed to simultaneously analyze the synthesized prodrug and the corresponding tocopherol in hydrolysis studies.
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Reverse Phase column C18 equipped with direct-connect guard column used for further analysis
Methanol 100%
2ml/min
273 nm
Methanol+ 0.05 H3PO4
1 ml/ml
315 nm
Mobile Phase
Flow rate
Detection Limit
• First Method
• Second
Method
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Pharmacokinectic Evaluation• Male New Zealand albino rabbits (Charles River, Calco,Italy) 2-3 kgs
kept under standard laboratory conditions for about 2 weeks
• 3 group of 6 male rabbits
• Cannulated via central ear artery using polyethylene tubing 15 min prior to oral administration of test drugs for the evaluation of oral bioavaibility.
• Blood sample taken were immediately analyzed for the concentration vs. time profile with several different pharmacokinetic parameters
• While the plasma concentration naproxen was determined by HPLC method using indomethacin as internal standard.
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Pharmacodynamic EvaluationCarrageenan Paw Inflammation
• Male Sprague-Dawley rats, six in group taken
• Orally administered with freshly prepared test compounds, VE-α-NPX, VE--NPX, Naproxen or vehicle (5 % Tween 80) were orally administered to each group at 10 mg/kg (Naproxen molar equivalents) 1 hr. prior to the carrageenan injection (50 μl 1% carrageenan in saline) into the right hind paw pad
• Paw volume determined and calculated as % inhibition to access the anti-inflammatory activity
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Carrageenan Air Pouch Model• Male Sprague-Dawley rats, six in group taken
• Air pouch was created by a subcutaneous injection of sterile air into the intrascapular area
• Oral administration of test compounds 1 hour prior to
the carrageenan injection into the pouch
• 4hr later inflammatory exudates collected to determine the prostaglandin E2 (PGE2) levels by immunoassay
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Gastric Injury Model• Freshly prepared test compounds, VE-α-NPX, VE--NPX,
Naproxen or vehicle (5 % Tween 80) were orally administered to rats, six for each group
• Killed 3 hour postdosing and stomachs were removed and examined for visible mucosa damage by an observer unaware of the treatment
• Measure of all hemorrhagic lesions calculated for gastric damage score, which was the sum of the lengths of all lesions in a stomach
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Statistical Analysis
• Analysis of variance (ANOVA)
• Bonferroni-Dunn post hoc pair-wise comparison
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RESULTS
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Chemical Analysis
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Chemical Hydrolysis
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Kinetic Data of Hydrolysis
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Comparison of Plasma Conc. Profile
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Comparative Pharmcokinetic Parameter
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Carrageenan Paw Inflammation Inhibition
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Carrageenan Air Pouch Model
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Gastric Injury Model
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Conclusion• The ester prodrugs of Naproxen VE-α-NPX and
VE--NPX are promising anti-inflammatory agents in the treatment of chronic inflammatory diseases and inflammation- associated disorders due to protective effect against gastric injury.
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Reference
• Spadaro A, Bucolo C, Ronsisvalle G and Pappalardo M (2009); Design, Synthesis and Antiinflammatory Activity of Novel -Tocopherol Naproxen Ester Prodrug, Journal of Pharmaceutical Sciences and Research1(4), 88-95.
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Thank You !!!!!!!!!!!