Propellant Free Pressurized Spray System of Etodolac to Manage Acute Pain Conditions: In Vitro and In Vivo Evaluation.

This study aimed to develop a propellant-free topical spray formulation of Etodolac (BCS-II), a potent NSAID, which could be beneficial in the medical field for the effective treatment of pain and inflammation conditions. The developed novel propellant-free spray formulation is user-friendly, cost-effective, propellant-free, eco-friendly, enhances the penetration of Etodolac through the skin, and has a quick onset of action. Various formulations were developed by adjusting the concentrations of different components, including lecithin, buffering agents, film-forming agents, plasticizers, and permeation enhancers. The prepared propellant-free spray formulations were then extensively characterized and evaluated through various in vitro, ex vivo, and in vivo parameters. The optimized formulation exhibits an average shot weight of 0.24 ± 0.30 ml and an average drug content or content uniformity of 87.3 ± 1.01% per spray. Additionally, the optimized formulation exhibits an evaporation time of 3 ± 0.24 min. The skin permeation study demonstrated that the permeability coefficients of the optimized spray formulation were 21.42 cm/h for rat skin, 13.64 cm/h for mice skin, and 18.97 cm/h for the Strat-M membrane. When assessing its potential for drug deposition using rat skin, mice skin, and the Strat-M membrane, the enhancement ratios for the optimized formulation were 1.88, 2.46, and 1.92, respectively against pure drug solution. The findings from our study suggest that the propellant-free Etodolac spray is a reliable and safe topical formulation. It demonstrates enhanced skin deposition, and improved effectiveness, and is free from any skin irritation concerns.

Application of ionic liquid to enhance the nose-to-brain delivery of etodolac.

The purpose of this study was to enhance the delivery of Etodolac (ETD) to the brain through intranasal administration using an ionic liquid (IL) consisting of ETD and proline ethyl ester. The IL of ETD was prepared by mixing ETD with proline ethyl ester as a counterion in a molar ratio of 1:2.The formation of the IL was confirmed by differential scanning calorimetry (DSC), infrared spectroscopy (IR) and proton nuclear magnetic resonance (1H-NMR).The solubility of ETD in simulated nasal fluids was improved by approximately 200-fold due to the formation of IL. The intranasal administration of ETD-containing IL, which is viscous, increased the nose-to-brain delivery by approximately 7-fold 30 min after an administration of the ETD solution alone. The enhancement of ETD delivery to the brain from the nose was attributed to the enhanced retention of ETD in the nasal mucosal surface due to the viscosity of IL. The induction of prostaglandin E2 in the brain inflammation that was induced by lipopolysaccharides was significantly suppressed by up to 40% in the IL-treated group compared with the drug-untreated group. Therefore, ETD-containing IL were suggested to be useful in designing intranasal formulations for the nasal delivery of ETDs to the brain.

Application of Design of Experiments® Approach-Driven Artificial Intelligence and Machine Learning for Systematic Optimization of Reverse Phase High Performance Liquid Chromatography Method to Analyze Simultaneously Two Drugs (Cyclosporin A and Etodolac) in Solution, Human Plasma, Nanocapsules, and Emulsions.

The objectives of current investigation are (1) to find out wavelength of maximum absorbance (λmax) for combined cyclosporin A and etodolac solution followed by selection of mobile phase suitable for the RP-HPLC method, (2) to define analytical target profile and critical analytical attributes (CAAs) for the analytical quality by design, (3) to screen critical method parameters with the help of full factorial design followed by optimization with face-centered central composite design (CCD) approach-driven artificial neural network (ANN)-linked with the Levenberg-Marquardt (LM) algorithm for finding the RP-HPLC conditions, (4) to perform validation of analytical procedures (trueness, linearity, precision, robustness, specificity and sensitivity) using combined drug solution, and (5) to determine drug entrapment efficiency value in dual drug-loaded nanocapsules/emulsions, percentage recovery value in human plasma spiked with two drugs and solution state stability analysis at different stress conditions for substantiating the double-stage systematically optimized RP-HPLC method conditions. Through isobestic point and scouting step, 205 nm and ACN:H2O mixture (74:26) were selected respectively as the λmax and mobile phase. The ANN topology (3:10:4) indicating the input, hidden and output layers were generated by taking the 20 trials produced from the face-centered CCD model. The ANN-linked LM model produced minimal differences between predicted and observed values of output parameters (or CAAs), low mean squared error and higher correlation coefficient values in comparison to the respective values produced by face-centered CCD model. The optimized RP-HPLC method could be applied to analyze two drugs concurrently in different formulations, human plasma and solution state stability checking.

Investigation of Formulation and Process Parameters of Wet Media Milling to Develop Etodolac Nanosuspensions.

PURPOSE: Etodolac (ETD) is one of the non-steroidal anti-inflammatory drugs which has low aqueous solubility issues. The objective of this study was to develop ETD nanosuspensions to improve its poor aqueous solubility properties while investigating formulation and process parameters of wet media milling method via design of experiment (DoE) approach. METHODS: The critical formulation parameters (CFP) were selected as ETD amount, stabilizer type and ratio as well as critical process parameters (CPP) which were bead size, milling time and milling speed. The two-factorial-23 and The Box-Benkhen Designs were generated to evaluate CFP and CPP, respectively. Particle size (PS), polydispersity index (PDI) and zeta potential (ZP) were analyzed as dependent variables. Characterization, physical stability and solubility studies were performed. RESULTS: Optimum nanosuspensions stabilized by PVP K30 and Poloxamer 188 showed 188.5 ± 1.6 and 279.3 ± 6.1 nm of PS, 0.161 ± 0.049 and 0.345 ± 0.007 PDI, 14.8 ± 0.3 and 16.5 ± 0.4 mV of ZP values, respectively. The thermal properties of ETD did not change after milling and lyophilization process regarding to DSC analysis. Also, the crystalline state of ETD was preserved. The morphology of particle was smooth and spherical on SEM. The dry-nanosuspensions stayed physically stable for six months at room temperature. The solubility of nanosuspensions increased up to 13.0-fold in comparison with micronized ETD. CONCLUSIONS: In conclusion, it is found that the poor solubility issue of ETD can be solved by nanosuspension. DoE approach provided benefits such as reducing number of experiments, saving time and improving final product quality by using wet media milling.

Liquid chromatographic enantioseparation of (RS)-etodolac using (S)-levofloxacin and determination of absolute configuration of the diastereomeric derivatives.

(RS)-Etodolac was isolated from commercial tablets and was purified and characterized to be used as racemic standard. A pair of diastereomeric derivatives was synthesized using (S)-levofloxacin as a chiral derivatizing reagent. The derivatization reaction was carried out under conditions of stirring at room temperature (30°C for 1.5 h) as well as under microwave irradiation; the derivatives obtained by the two methods were compared. Reaction conditions for derivatization were optimized with respect to mole ratio of chiral derivatizing reagent and (RS)-etodolac. No racemization was observed throughout the study. Separation of diastereomeric derivatives was successful using C18 column and a binary mixture of methanol and triethyl ammonium phosphate buffer of pH 4.5 (80:20, v/v) as mobile phase at a flow rate of 1 mL min-1 and UV detection at 223 nm. An efficient approach for recognizing chirality and determining the absolute configuration of the diastereomeric derivatives of (RS)-etodolac is described, which in turn is a measure of the enantiomeric purity of (RS)-etodolac since the diastereomeric derivatives were separated and isolated using preparative thin-layer chromatography.

Mechanistic insights of the controlled release properties of amide adhesive and hydroxyl adhesive.

Although interactions between drugs and acrylate pressure sensitive adhesives (PSAs) containing amide groups were reported in the previous studies, detailed studies elucidating their mechanism of action are still lacking. In the present study, an amide PSA (AACONH2) and a hydroxyl PSA (AAOH, as the control) were synthesized, and their molecular mechanism of controlled drug release was described. Using zolmitriptan (ZOL) and etodolac (ETO) as model drugs, in vitro drug release and skin permeation experiments were performed. Intermolecular interactions between drugs and PSAs were determined by Flory-Huggins model, FT-IR spectroscopic analysis and molecular modeling. In addition, PSA mobility was evaluated using differential scanning calorimetry and rheology study. Release percent of ZOL and ETO from AACONH2 were 43.9 ±â€¯0.3% and 50.0 ±â€¯2.0% respectively, while from AAOH, the release percent of ZOL and ETO were 61.4 ±â€¯1.2% and 81.0 ±â€¯1.2% separately. As a consequence of controlled drug release, skin permeation of both drugs was significantly controlled by AACONH2. It was demonstrated that AACONH2 markedly interacted with drugs, especially with ETO, through hydrogen bonding and weak intermolecular forces (e.g. dipole-dipole and van der waals). PSA mobility of AACONH2 was significantly increased due to drug-PSA interactions. In conclusion, AACONH2 had stronger controlled release properties compared with AAOH, which was mainly caused by the stronger interactions between amide groups and drugs. The amide PSA synthesized in the present study was a potential sustained-release excipient for transdermal drug delivery system.

Synthesis, anticancer activity, and molecular modeling of etodolac-thioether derivatives as potent methionine aminopeptidase (type II) inhibitors.

A series of (R,S)-1-{[5-(substituted)sulfanyl-4-substituted-4H-1,2,4-triazole-3-yl]methyl}-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indoles (5a-v) were designed and synthesized using a five-step synthetic protocol that involves substituted benzyl chlorides and (R,S)-5-[(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)methyl]-4-substituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones in the final step. The synthesized derivatives were evaluated for cytotoxicity and anticancer activity in vitro using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric method against VERO, HEPG2 (human hepatocellular liver carcinoma), SKOV3 (ovarian carcinoma), MCF7 (human breast adenocarcinoma), PC3 and DU145 (prostate carcinoma) cells at 10-5 M (10 µM) for 24 h. Compounds 5d and 5h showed the best biological potency against the SKOV3 cancer cell line (IC50 = 7.22 and 5.10 µM, respectively) and did not display cytotoxicity toward VERO cells compared to etodolac. Compounds 5k, 5s, and 5v showed the most potent biological activity against the PC3 cancer cell line (IC50 = 8.18, 3.10, and 4.00 µM, respectively) and did not display cytotoxicity. Moreover, these compounds were evaluated for caspase-3, -9, and -8 protein expression and activation in the apoptosis pathway for 6, 12, and 24 h, which play a key role in the treatment of cancer. In this study, we also investigated the apoptotic mechanism and molecular modeling of compounds 5k and 5v on the methionine aminopeptidase (type II) enzyme active site in order to get insights into the binding mode and energy.

Removal of Organic Matter and Etodolac from Pharmaceutical Industry Wastewater by PAC Adsorption.

The removal of organic matter and etodolac (an anti-inflammatory pharmaceutical) from a real process wastewater by using powdered activated carbon (PAC) adsorption before and after Fenton oxidation has been studied. The wastewater sample is collected from the final stage of chemical synthesis of a pharmaceutical (etodolac). Fenton oxidation resulted with decrease in chemical oxygen demand (84% removal) and etodolac concentration was reduced to 0.7 mg L-1. Optimum adsorption equilibrium conditions were found as t = 16 hours, and m = 10 g L-1. The Freundlich model showed the best fit for the adsorption of both wastewater with R2 values of 0.89 and 0.99. Lower pseudo-second-order rate constant (k2) (0.067 < 2.62) obtained from the adsorption of raw wastewater with higher organic matter concentration confirms the chemisorption of the adsorbates onto the PAC. Pore surface mass diffusion with R2 value of 0.92 was found as rate-controlling step for adsorption process with Fenton pre-treated wastewater.

Quantitative analysis of anti-inflammatory drugs using FTIR-ATR spectrometry.

Four simple, accurate, sensitive and economic Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopic (ATR-FTIR) methods have been developed for the quantitative estimation of some non-steroidal anti-inflammatory drugs. The first method involves the determination of Etodolac by direct measurement of the absorbance at 1716cm-1. In the second method, the second derivative of the IR spectra of Tolfenamic acid and its reported degradation product (2-chlorobenzoic acid) was used and the amplitudes were measured at 1084.27cm-1 and 1056.02cm-1 for Tolfenamic acid and 2-chlorobenzoic acid, respectively. The third method used the first derivative of the IR spectra of Bumadizone and its reported degradation product, N,N-diphenylhydrazine and the amplitudes were measured at 2874.98cm-1 and 2160.32cm-1 for Bumadizone and N,N-diphenylhydrazine, respectively. The fourth method depends on measuring the amplitude of Diacerein at 1059.18cm-1 and of rhein, its reported degradation product, at 1079.32cm-1 in their first derivative spectra. The four methods were successfully applied on the pharmaceutical formulations by extracting the active constituent in chloroform and the extract was directly measured in liquid phase mode using a specific cell. Moreover, validation of these methods was carried out following International Conference of Harmonisation (ICH) guidelines.

Inclusion Complexation of Etodolac with Hydroxypropyl-beta-cyclodextrin and Auxiliary Agents: Formulation Characterization and Molecular Modeling Studies.

The present investigation was aimed to prepare inclusion complexes of a therapeutically important nonsteroidal anti-inflammatory drug, etodolac (ETD) with hydroxypropyl-beta-cyclodextrin (HP-ß-CD) and to study the effect of l-arginine (l-Arg) as an auxiliary agent on the complexation efficiency of HP-ß-CD to improve aqueous solubility and the dissolution property of ETD. The binary and ternary complexes were prepared by physical mixing, coevaporation, and spray drying methods. The complexes were characterized using differential scanning colorimetry (DSC), Fourier transform-infrared spectroscopy (FT-IR), and powder X-ray diffraction (PXRD) studies. The mechanism of inclusion interaction of guest and host was established through 1H NMR, molecular docking, and molecular dynamics studies. On the basis of preliminary screening studies, l-Arg was found to be the most efficient auxiliary agent for the present research problem. The change in crystallinity of ETD was evident from DSC and PXRD studies which indicated the formation of new solid forms. A remarkable increase in apparent stability constant (Kc) and complexation efficiency (CE) of HP-ß-CD was observed in the presence of l-Arg in ternary complexes with improvement in solubility and dissolution of ETD than binary complexes. However, inclusion complexes of ETD obtained by computational studies is in good correlation with the results obtained through experimental methods. More stable complex formation with l-Arg was confirmed by molecular simulation studies too. Thus, the present study led to the conclusion that the ternary complex of ETD-HP-ß-CD-l-Arg could be an innovative approach to augment the solubility and dissolution behavior of ETD.

Self-Assembling Organogels Based on Pluronic and Lecithin for Sustained Release of Etodolac: In Vitro and In Vivo Correlation.

BACKGROUND: Etodolac, a member of non steroidal anti-inflammatory drugs (NSAIDs), has a poor aqueous solubility. Long term administration of etodolac causes severe gastrointestinal disturbances such as peptic ulcer and bleeding. These disturbances could be overcome by alternative routes such as a topical administration. METHOD: In the present study, pluronic lecithin organogels (PLOs) were prepared by simple mixing of pluronic solution with lecithin solution. Etodolac was loaded into the prepared gels or added during the gel formation. The physicochemical properties of the modified organogels were investigated by different analysis including visual inspection, pH determination, viscosity, spreadability and extrudability. Also, the in vitro release studies of etodolac in the presence of different penetration enhancers were carried out. The anti-inflammatory behavior of the prepared etodolac organogel was investigated using carrageenan induced paw edema test. RESULTS: The results indicated that the prepared organogels showed good physicochemical properties. The organogels, containing a combination of tween 80 and oleic acid as penetration enhancers, showed the highest percentage of drug release. CONCLUSION: All tested organogels showed a significant oedema inhibition compared with oral indomethacin ® and Voltaren® as a topical marketed anti-inflammatory drug. Moreover, the increase of drug concentration from 1% to 5% w/w is accompanied with a longer duration of action up to 12 hrs. Therefore, the formulated organogels are considered as a promising vehicle for controlled topical delivery of etodolac.

HPLC enantioseparation of racemic bupropion, baclofen and etodolac: modification of conventional ligand exchange approach by pre-column formation of chiral ligand exchange complexes.

Separation of racemic mixture of (RS)-bupropion, (RS)-baclofen and (RS)-etodolac, commonly marketed racemic drugs, has been achieved by modifying the conventional ligand exchange approach. The Cu(II) complexes were first prepared with a few l-amino acids, namely, l-proline, l-histidine, l-phenylalanine and l-tryptophan, and to these was introduced a mixture of the enantiomer pair of (RS)-bupropion, or (RS)-baclofen or (RS)-etodolac. As a result, formation of a pair of diastereomeric complexes occurred by 'chiral ligand exchange' via the competition between the chelating l-amino acid and each of the two enantiomers from a given pair. The diastereomeric mixture formed in the pre-column process was loaded onto HPLC column. Thus, both the phases during chromatographic separation process were achiral (i.e. neither the stationary phase had any chiral structural feature of its own nor did the mobile phase have any chiral additive). Separation of diastereomers was successful using a C18 column and a binary mixture of MeCN and TEAP buffer of pH 4.0 (60:40, v/v) as mobile phase at a flow rate of 1 mL/min and UV detection at 230 nm for (RS)-Bup, 220 nm for (RS)-Bac and 223 nm for (RS)-Etd. Baseline separation of the two enantiomers was obtained with a resolution of 6.63 in <15 min. Copyright © 2016 John Wiley & Sons, Ltd.

Lidocaine self-sacrificially improves the skin permeation of the acidic and poorly water-soluble drug etodolac via its transformation into an ionic liquid.

Poor transdermal penetration of active pharmaceutical ingredients (APIs) impairs both bioavailability and therapeutic benefits and is a major challenge in the development of transdermal drug delivery systems. Here, we transformed a poorly water-soluble drug, etodolac, into an ionic liquid in order to improve its hydrophobicity, hydrophilicity and skin permeability. The ionic liquid was prepared by mixing etodolac with lidocaine (1:1, mol/mol). Both the free drug and the transformed ionic liquid were characterized by differential scanning colorimetry (DSC), infrared spectroscopy (IR), and saturation concentration measurements. In addition, in vitro skin-permeation testing was carried out via an ionic liquid-containing patch (Etoreat patch). The lidocaine and etodolac in ionic liquid form led to a relatively lower melting point than either lidocaine or etodolac alone, and this improved the lipophilicity/hydrophilicity of etodolac. In vitro skin-permeation testing demonstrated that the Etoreat patch significantly increased the skin permeation of etodolac (9.3-fold) compared with an etodolac alone patch, although an Etoreat patch did not increase the skin permeation of lidocaine, which was consistent with the results when using a lidocaine alone patch. Lidocaine appeared to self-sacrificially improve the skin permeation of etodolac via its transformation into an ionic liquid. The data suggest that ionic liquids composed of approved drugs may substantially expand the formulation preparation method to meet the challenges of drugs which are characterized by poor rates of transdermal absorption.

Enantioselective analysis of etodolac in human plasma by LC-MS/MS: Application to clinical pharmacokinetics.

Etodolac is a non-steroidal anti-inflammatory drug with preferential inhibition of cyclooxigenase-2 and is widely used in the management of pain in patients with inflammatory arthritis. Etodolac is available as a racemic mixture of (-)-(R)-Etodolac and (+)-(S)-Etodolac; cyclooxigenases inhibition is attributed to (+)-(S)-Etodolac. According to our knowledge, this is the first method for determination of etodolac enantiomers in plasma using LC-MS/MS. Plasma extraction were performed with 25µL of plasma and 1mL of n-hexane:ethyl acetate (95:5); racemic ibuprofen was used as internal standard. Resolution of enantiomers were performed in a Chiralcel(®)OD-H column; deprotonated [M-H](-) and their respective ion products were monitored at transitions of 286>242 for etodolac enantiomers and 205>161 for ibuprofen. The quantitation limit was 3.2ng/mL for both enantiomers in plasma. The method was applied to study the pharmacokinetics of etodolac enantiomers after the administration of a 300 and 400mg dose of racemic drug to a healthy volunteer. Analysis of plasma samples showed higher plasma concentration of (-)-(R)-Etodolacfor both doses (300mg dose: AUC(0-∞)49.80 versus 4.55ugh/mL;400mg dose: AUC(0-∞) 63.90 versus 6.00ugh/mL) with an (R)-(+)/(S)-(-) ratio of approximately 11.

Photochemical fate and eco-genotoxicity assessment of the drug etodolac.

The photochemical behavior of etodolac was investigated under various irradiation conditions. Kinetic data were obtained after irradiation of 10(-4) M aqueous solutions by UVB, UVA and direct exposure to sunlight. The Xenon lamp irradiation was used in order to determine the photodegradation quantum yield under sun-simulated condition (ϕsun). The value was determined to be=0.10±0.01. In order to obtain photoproducts and for mechanistic purposes, experiments were carried out on more concentrated solutions by exposure to sunlight and to UVA and UVB lamps. The drug underwent photooxidative processes following an initial oxygen addition to the double bond of the five membered ring and was mainly converted into a spiro compound and a macrolactam. Ecotoxicity tests were performed on etodolac, its photostable spiro derivative and its sunlight irradiation mixture on two different aquatic trophic levels, plants (algae) and invertebrates (rotifers and crustaceans). Mutagenesis and genotoxicity were detected on bacterial strains. The results showed that only etodolac had long term effects on rotifers although at concentrations far from environmental detection values. A mutagenic and genotoxic potential was found for its derivative.

A novel approach for enantioseparation as applied to (RS)-etodolac from pharmaceutical formulations: LC MS and density functional theory support for confirmation of diastereomers so separated.

In the present studies formation of diastereomers of (RS)-etodolac was confirmed using LC-MS when [M + H](+) or [M](+) were recorded for the diastereomers. The lowest energy optimized structures of two diastereomers were drawn, which confirmed the three-dimensional geometry of the diastereomers. This supports the optimized analytical separation conditions. In addition, separation of diastereomers was successful using a C18 column and a binary mixture of methanol and triethyl ammonium phosphate buffer of pH 4.5 (80:20, v/v) as mobile phase at a flow rate of 1 mL min(-1) and UV detection at 223 nm. The separation method was validated as per International Conference on Harmonization guidelines. (RS)-Etodolac was isolated from commercial tablets and purified and characterized to be used as racemic standard. Three pairs of diastereomers were synthesized using enantiomerically pure amines, namely, (R)-(+)-α-methyl benzyl amine, (S)-(-)-α,4-dimethylbenzylamine and (R)-(-)-1-cyclohexylethylamine. Derivatization reactions were carried out under conditions of stirring at room temperature (30 °C for 2 h) as well as under microwave irradiation (MWI), and the two types of diastereomers were compared. Reaction conditions for derivatization were optimized with respect to mole ratio of chiral derivatizing agent and (RS)-etodolac and MWI time. No racemization was observed throughout the study.

Anti-cancer and anti-hepatitis C virus NS5B polymerase activity of etodolac 1,2,4-triazoles.

Arachidonic acid is an unsaturated fatty acid liberated from phospholipids of cell membranes. NSAIDs are known as targets of cyclooxygenase enzyme (COX-1, COX-2 and COX-3) in arachidonic acid metabolism. This mechanism of COX-2 in carcinogenesis causes cancer. In addition, COX-2 plays a role in the early stages of hepatocarcinogenesis. Hepatitis C virus (HCV) infection is cause of liver cirrhosis and hepatocellular carcinoma (HCC). The aim of our study was to improve effective agents against HCV. A novel series of new etodolac 1,2,4-triazoles derivatives (4a-h) have been synthesized and investigated for their activity against HCV NS5B polymerase. Compound 4a was found to be the most active with IC(50) value of 14.8 µM. In accordance with these results, compound 4a was screened for anti-cancer activity on liver cancer cell lines (Huh7, Mahlavu, HepG2, FOCUS). Compound 4a showed anti-cancer activity against Huh7 human hepatoma cell line with IC(50) value of 4.29 µM. Therefore, compound 4a could be considered as a new anti-cancer and anti-HCV lead compound.

Enantioselective HPLC-DAD method for the determination of etodolac enantiomers in tablets, human plasma and application to comparative pharmacokinetic study of both enantiomers after a single oral dose to twelve healthy volunteers.

An enantioselective high performance liquid chromatographic method with diode array detection (HPLC-DAD) was developed and validated for the determination of etodolac enantiomers in tablets and human plasma. Enantiomeric separation was achieved on a Kromasil Cellucoat chiral column (250 mm × 4.6mm i.d., 5 µm particle size) using a mobile phase consisting of hexane: isopropanol: triflouroacetic acid (90:10:0.1 v/v/v) at a flow rate of 1.0 mL min(-1). The chromatographic system enables the separation of the two enantiomers and the internal standard within a cycle time of 8 min. The resolution between the two enantiomers was 4.25 and the resolution between each enantiomer and the internal standard was more than 2.0. Detection was carried out at 274 nm, and the purity assessment was performed using a photodiode array detector. Solid phase extraction technique using C-18 cartridge was applied to extract the analytes from the plasma samples, and the percentage recovery was more than 95% for the lower quantification limit. The method has been validated with respect to selectivity, linearity, accuracy and precision, robustness, limit of detection and limit of quantification. The validation acceptance criteria were met in all cases. The linearity range for the determination of each enantiomer in human plasma was 0.4-30.0 µg mL(-1) and the limits of quantification of R-etodolac and S-etodolac were 0.20 and 0.19 µg mL(-1), respectively. The validated method was successfully applied to the determination of etodolac enantiomers in tablets and to a comparative pharmacokinetic study of the two enantiomers after the administration of 300 mg single oral dose etodolac racemate tablets to twelve healthy volunteers.

Synthesis, cytotoxicity, and pro-apoptosis activity of etodolac hydrazide derivatives as anticancer agents.

Etodolac hydrazide and a novel series of etodolac hydrazide-hydrazones 3-15 and etodolac 4-thiazolidinones 16-26 were synthesized in this study. The structures of the new compounds were determined by spectral (FT-IR, (1)H NMR, (13)C NMR, HREI-MS) methods. Some selected compounds were determined at one dose toward the full panel of 60 human cancer cell lines by the National Cancer Institute (NCI, Bethesda, USA). 2-(1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetic acid[(4-chlorophenyl)methylene]hydrazide 9 demonstrated the most marked effect on the prostate cancer cell line PC-3, with 58.24% growth inhibition at 10(-5) M (10 µM). Using the MTT colorimetric method, compound 9 was evaluated in vitro against the prostate cell line PC-3 and the rat fibroblast cell line L-929, for cell viability and growth inhibition at different doses. Compound 9 exhibited anticancer activity with an IC(50) value of 54 µM (22.842 µg/mL) against the PC-3 cells and did not display any cytotoxicity toward the L-929 rat fibroblasts, compared to etodolac. In addition, this compound was evaluated for caspase-3 and Bcl-2 activation in the apoptosis pathway, which plays a key role in the treatment of cancer.

Sucrose stearate-enriched lipid matrix tablets of etodolac: modulation of drug release, diffusional modeling and structure elucidation studies.

Etodolac is a non-steroidal anti-inflammatory drug having an elimination half-life of 7 h; oral doses are given every 6-8 h. The aim of current work was the development of controlled-release etodolac lipid matrix tablets. The variables influencing design of these tablets (L1-L28) by the hot fusion method were investigated including; (1) lipid type (stearic acid, cetyl alcohol, cetostearyl alcohol, Imwitor® 900K, Precirol® ATO 5 and Compritol® ATO 888), (2) drug/lipid ratio (1:0.25 and 1:0.50, respectively), (3) filler type (lactose, Avicel® PH101 and their physical mixtures; 2:1, 1:1, and 1:2, respectively), (4) surfactant's HLB (5 and 11), and (5) drug/surfactant ratio (20:1 and 10:1, respectively). Statistical analysis and kinetic modeling of drug release data were evaluated. The inner matrix of the tablet was visualized via scanning electron microscopy (SEM). An inverse correlation was observed between the drug/lipid ratio and the drug release rate. Precirol®- and Compritol®-containing formulae showed more retarded drug release rates. Lactose/Avicel® physical mixture (1:1) was considered as a filler of choice where it minimized the burst effect observed with Avicel®-free formulae. The higher surfactant's HLB, the higher drug release rate. The similarity factor (f(2)) between the drug release profiles revealed similarity within the investigated drug/surfactant ratios. Sucrose stearate D1805®-based matrix (L21) succeeded in delivering more than 90% of etodolac over 12 h, following anomalous (non-Fickian) controlled-release kinetics. SEM micrographs confirmed pore formation, within the latter matrix, upon contact with dissolution medium.