Tamer Baykara et. al., (2002) (20) developed Microsponges containing ketoprofen and Eudragit RS 100 were prepared by quasi-emulsion solvent diffusion method. The effects of different mixing speeds, drug_/polymer ratios, solvent_/polymer ratios on the physical characteristics of the microsponges as well as the in vitro drug release rate from the microsponges were investigated. In vitro dissolution results showed that the release rate of ketoprofen was modified in all formulations.
D'souza J. I. et. al., (2001) ,(21) formulated microspongic delivery system of Benzoyl peroxide was well-established using an emulsion solvent diffusion method by addition of an organic internal phase containing ethyl cellulose, dichloromethane and benzoyl peroxide into a stirred aqueous phase containing polyvinyl alcohol and by suspension polymerization of divinyl benzene and styrene. The prepared microsponges were evaluated for antibacterial activity after dispersing in gel base. Release of drug from the entrapped system is slower when compared with unentrapped BPO.This work was successful in developing drug delivery system with reduced toxicity.
Grimes P. E (2004) (22) formulated MDDS of fluconazole with a proper drug release profile and to bring notable decrease in repeatedly appearing irritation. Polymerisation of styrene and methyl methacrylate by liquid-liquid suspension polymerisation forms microsponges. A gel was prepared using carbopol 940, in which microsponges were dispersed. The release of drug was evaluated using Franz diffusion cell. Average drug release from the gel formulation containing microsponge loaded fluconazole was found to be 67.81 percentage in 12 hours. Drug release from the marketed formulations and the gel formulations containing microsponge loaded fluconazole has followed zero order kinetics (r = 0.9888, 0.973 respectively). Extended drug release has been reported by drug diffusion study. A microsponge containing Fluconazole for topical drug delivery system was very well successful as extended release drug delivery system.
Mine Orlu et. al., (2006) (23) formulated Colon specific drug delivery system containing microsponges loaded flurbiprofen (FLB). Quasi-emulsion solvent diffusion method was used for the preparation of microsponges loaded with FLB and Eudragit RS100. The microsponges were of spherical in shape, and its diameter ranging between 30.7 and 94.5μm and showed high porosity values (61-72%). Structure of microsponges was deformed in case of mechanical tablets that are used for colon specific drug delivery. Release of drug from was observed at 8th hour by invitro studies in case of colon specific compression coated tablets. This is due to the addition of addition of enzymes that corresponds to the proximal colon arrival time.
Netal Amrutiya et. al., (2009) (24) formulated and evaluated microsponge-based topical drug delivery system of mupirocin for sustained release action and to increase drug deposition into the skin. Emulsion solvent diffusion method was used to prepare microsponges of mupirocin. The prepared microsponges were optimised and incorporated into an emulgel base. Mupirocin-loaded formulations were evaluated for in vivo antibacterial activity, ex vivo drug deposition and invitro drug release. Diffusion controlled release pattern was observed through cellulose dialysis membrane. Rat abdominal skin was used for drug deposition studies which exhibited significant retention of drug. The stability and non-irritancy of the formulation to skin was demonstrated by Draize patch test. Mouse surgical wound model infected with S. aureus can be effectively treated with Microsponges-based emulgel formulations that shows prolonged efficacy.
Vikas Jain et. al., (2010) (25) formulated an extended release microsponge drug delivery system containing dicyclomine. Eudragit-based microsponges loaded with dicyclomine were developed using a quasi-emulsion solvent diffusion method. Microsponges were evaluated for shape and surface morphology using scanning electron microscopy.
No chemical interaction was observed during preparation and the stability of drug was not affected in all the formulations. Increase in quantity of polymer resulted in a decrease in the release of the drug. The mechanism of drug release was by Higuchi matrix controlled diffusion kinetics. The drug release was bi-phasic with a first burst effect with 16 - 30 % of the drug was released within the first hour. Prolonged drug release of dicyclomine can be done by this approach. The ideal compressibility of microsponges has been applied to attain effective local action.
J. Milic-Askrabic et. al (1997) (26) prepared Etodolac/β-cyclodextrin (Eto/β-CD) dispersions with a view to study the influence of β-CD on the solubility and dissolution rate of this poorly soluble drug. Two systems were used: physicai mixture of Eto/β-CD and kneading solid dispersion of Eto/β-CD. Physical characterization of the prepared systems was carried out by scanning electron microscopy (SEM), differential scanning calorimetric (DSC), x-ray, and IR studies. The solubility and dissolution rate of Eto were increased with β-CD physical mixture as well us with Eto/β-CD kneading solid dispersion. Enhancement was statistically different among various cyclodextrin dispersions.
N. S. Barakat (2006) (27) developed carrier fusion method to prepare different dispersion of etodolac using Gelucire 44/14 and D-agr-tocopheryl polyethylene glycol 1000 succinate (TPGS). Differential scanning calorimetries (DSC), infrared spectroscopy (IR) were used for physical characterisation of binary systems. USP dissolution apparatus II (paddle method) was used for dissolution studies to know the release rate. Enhanced dissolution rate was observed in all dispersion systems than that of the pure drug. A liquid dispersion system of etodolac (20%) and Gelucire 44/14: TPGS blend (80%), in different ratios, was also prepared. The stability of the capsule formulation was checked at different humidity and temperature conditions as per ICH guidelines. Physical and chemical properties of the dispersion didn't change during a period of storage at room temperature and at 4°C, 0% RH. It was identified that etodolac was chemically stable at all temperature and humidity. Dissolution behavior of etodolac was affected by relative humidity and storage time. The changes in dissolution behavior after storage under conditions of high humidity and temperature might be due to the formation of etodolac microcrystal and to water absorption by the carrier during storage. Moisture-resistant packaging is used for pharmaceutical formulations of this type to obtain acceptable shelf-lives.
Cetin Tas et. al (2007) (28) prepared hydrophilic gel formulations of etodolac were prepared with carboxymethylcellulose sodium. The effect of different terpenes (anethole, carvacrol, and menthol) as an enhancer on the percutaneous absorption of etodolac was also observed. Unjacketed modified horizontal diffusion cells through cellulose membrane and rat skin were used for permeation studies. In vitro studies with cellulose membrane showed that all formulations presented the same drug release profile (p > 0.05). Ex vivo studies with excised rat skin showed that etodolac was released and penetrated into rat skin quickly. Anethole, a hydrophobic terpene, enhanced the absorption of etodolac significantly (p < 0.05). This result is corresponds with the fact that hydrophobic terpenes are effective on the percutaneous absorption of lipophilic drugs. Enhancing the absorption of etodolac cannot be achieved by Menthol and carvacrol. The lipophilicity of the enhancers plays a major role in promoting penetration of etodolac through the skin. Since etodolac creates gastrointestinal (GI) disturbances, including 1% anethole in topical gel formulations of etodolac could be an alternative.
Brunella Cappello et. al (2009) (29) studied the effects of the CDs on the pharmacological and physicochemical properties Etodolac (ET), a practically water-insoluble nonsteroidal anti-inflammatory drug, to individuate a drug formulation with optimized phamacodynamics and pharmacokinetics. 13C-NMR spectroscopy and phase solubility method was used to know the interactions in solution of ET with β-CD, hydroxypropyl-β-CD (HP-β-CD), and γ-CD. Solid binary systems, prepared by physical mixing and freeze-drying, were evaluated by X-ray analysis, differential scanning calorimetry and Fourier transform infrared spectroscopy, and dissolution studies. An in vivo pharmacological investigation (analgesic activity and gastric tolerance studies) was done on freeze-dried ET/CD formulations. Results: 13C-NMR and phase solubility studies demonstrated the ability of CDs to form complex with ET and increase drug solubility. ET/CD interactions at the solid state observed at the molecular level only for freezed-dried samples. Binary systems, containing HP-β-CD and γ -CD, showed a significantly improved dissolution profile of ET. In vivo pharmacological studies showed an improvement of analgesic activity and a reduction of gastrolesivity of ET/CD-tested formulations with respect to ET alone. Conclusions: The formulation of ET with CDs demonstrates relevant pharmaceutical potential in point of decreasing dose and side effects of ET. For industrial applications, HP-β-CD appears to be the best partner for ET, as it is less expensive than γ-CD and gives a higher drug solubilization than β-CD.
Mike Dey et. al (1993) (30) compared by performing the dissolution and bioavailability studies of etodolac capsules, Capsules are exposed to high temperature and relative humidity to those from capsules stored at room temperature (RT). Dissolution of control capsules and stressed were tested by using a USP basket type of apparatus at speed of 100 rpm with 900 ml phosphate buffer(0.05M) of pH 7.5 at 37°C. By applying capsules to stressed conditions, dissolution of etodolac from capsules was evaluated with enzymes (pancreatin, 1%, w/v) by addition to the dissolution medium. Bioavailability of etodolac from capsules when exposed to stressed conditions was compared in both human begins and dogs to capsules stored at Room Temperature( RT) conditions. Capsules having 200 and 300 mg of drug molecule, was exposed to stressed conditions failed the dissolution (without enzymes) specification [not less than 85% released (80% Q) in 30 min]. All capsules met the conditions only upon the addition of enzyme. The rate and extent of absorption of these 200 and 300 mg, etodolac capsules in dogs was same to those from capsules stored at RT conditions. Bioavailability of etodolac from 300 mg capsules, failed the dissolution specification upon exposure to stressed conditions was equivalent to that of control capsules in 24 adult male volunteers. As a result, an in vitro dissolution test with enzymes gives a better indication of stressed capsule performance in vivo.
Yalçın Ozkan et. al (2000) (31) examined the release of etodolac from various molecular weight fractions of polyethylene glycol (PEG) solid dispersions. Different molar ratios of drug/carrier were used to prepare solid dispersions of Etodolac by using solvent and melting methods. The release rate of etodolac from the complexes was determined using dissolution studies by use of USP dissolution apparatus II (paddle method). X-ray diffraction (XRD), infrared spectroscopy (IR) and differential scanning calorimetry (DSC) were used to characterise the physical state and drug:PEG interaction of solid dispersions and physical mixtures . The dissolution rate of etodolac was increased in all of the formulations than that that of the pure drug and physical mixtures. Fastest dissolution profile was observed for the solid dispersion compound prepared in the molar ratio of 1:5 by the solvent method . The physical properties are not affected after 9 months storage in normal conditions.
MA Etman et. Al (32) investigated the solubility of ETO in four different co-solvents; ethanol, propylene glycol, polyethylene glycol 400, and glycerol, three sugars; sucrose, sorbitol, and mannitol, two hydrotropic salts; sodium benzoate and sodium salicylate, and two enhancers; Tween 80 and Brij 58. The order of solubility of ETO by the used co-solvents be is as follows ethanol>PEG 400>PG>glycerol. The increase in temperature from 25 to 37 degree C was accompanied by an increase in drug solubility at higher concentrations of co-solvents and hydrotropic solutions but the effect was insignificant with Tween 80 and Brij 58. The calculated thermodynamic parameters of some of these systems have showed positive entropy and enthalpy and also negative free energy values suggesting high degree of randomness, endothermic dissolution and spontaneity of the solubility process. There was no effect on ETO solubility due to the used sugars and sodium salicylate . Based on the solubility data, a trial has been done to propose a formulation (100mg/3 ml) for parenteral use in an aqueous solvent blend. The formulation was stored for two months and tested for color, turbidity and precipitation. In addition, the formulation didn't show any evidence of visible precipitation upon dilution with normal saline or 5 percent dextrose intravenous fluid except in low dilutions. Finally, the solubilized systems of ETO could be effectively used in the design of other liquid formulations intended for topical and oral administration of the drug.
Savita vyas et. al (2009) (33) utilized a biodegradable polymer dextran has been utilized as a carrier for synthesis of etodolac-dextran conjugates (ED) to improve its aqueous solubility and reduce gastrointestinal side effects. Condensation of activated moiety, i.e. N-acylimidazole derivative of etodolac (EAI), was done with the polysaccharide polymer dextran of different molecular weights (40000, 60000, 110000 and 200000). Formation of ester bonding in the conjugates was confirmed by IR spectral data. Analysis was done by UV-spectrophotometric analysis. Mark-Howink-Sakurada equation was used to determine the molecular weights by measuring viscosity. In vitro hydrolysis of ED was done in aqueous buffers (pH 1.2, 7.4, 9) and in 80% (v/v) human plasma (pH 7.4). At pH 9, a higher rate of etodolac release from ED was observed as compared to aqueous buffer of pH 7.4 and 80% human plasma (pH 7.4), following first-order kinetics. Acute analgesic and antiinflammatory activities were ascertained with the help of acetic acid induced writhing model (mice) and carrageenan-induced rat paw edema model. In comparison to control, E and ED1-ED4 showed highly significant analgesic and anti-inflammatory activities (p < 0.001). Biological evaluation suggested that conjugates (ED1-ED4) pocesses comparable analgesic and antiinflammatory activities with significant reduced ulcerogenicity as compared to their parent drug - Etodolac.
M. Dey et al (2002) (34) formulated sustained-release (SR) formulations, ranging from 200 to 600 mg in strength, have been developed to improve patients convenience and subsequent compliance, when compared with twice daily (b.i.d.) administration of immediate-release capsules. SR formulations were subjected to In vitro dissolution testing and clinical bioavailability studies . Relationship between in vitro dissolution and absorption was evaluated by a pilot bioavailability study.In-vitro drug release and in-vivo plasma concentration-time profiles were modeled by NONLIN which is a computer program. . Target in-vitro release rates were identified Based on the results of the pilot study and the kinetic modeling. Dosage forms exhibiting such in-vitro release profiles were evaluated in a bioavailability and dose proportionality study over the range of 200-600 mg daily doses. The SR formulations were bioequivalent to their respective immediate release doses and also dose-proportional. In-vitro dissolution data helps to predict the in-vivo performance..
Barakat, Nahla S et. al (2009) (35) formulated a self-emulsifying drug delivery system (SEDDS) to enhance the oral bioavailability of a poorly water-soluble drug, etodolac. Optimization of SEDDS was done by testing their ability to self-emulsify when introduced to an aqueous medium under gentle agitation, and by determination of the particle size of the resulting emulsion. An optimized formulation of SEDDS (composed of 20% etodolac, 30% oil Labrafac WL1349, 10% Lauroglycol 90 and 40% Labrasol) was selected for bioavailability assessment in rabbits. The anti-inflammatory effect was determined in rats, which was then compared with powder drug and etodolac suspension in water (50 mg/kg). The peak plasma concentration of 16.4 ± 1.1 μg/ml appeared after 1.3 ± 0.2 h, whereas with powder drug and etodolac suspension the values were 7.5 ± 0.5 and 10.6 ± 0.7 μg/ml at 4.2 ± 0.4 and 2.4 ± 0.2 h, respectively. The AUC0-8 of the etodolac SEDDS formulation was 2.3 times that of the pure drug and 1.4 times that of the suspension form. SEDDS formulation exhibits a 21% increase in paw thickness compared with a 39% increase on oral administration of etodolac suspension after 4 h at the same dose of the drug (20 mg/kg). The result indicates that SEDDS can be effectively to deliver etodolac through oral route and actively other lipophilic drugs.
Salom I L et. Al (1984) (36) Etodolac, a nonsteroidal anti-inflammatory and analgesic drug, was used in a randomized, parallel group, open-label design study, with stool analysis conducted in a blind fashion, to compare its effect in normal men in doses of 400mg (N=11) and 600 mg (N=12) b.i.d (twice daily) on gastrointestinal microbleeding with that of 600mg Ibuprofen, q.i.d (4 times a day) (N=12), 50 mg Indomethacin in the morning, 50 mg at noon, 100 mg h.s (N=9) and 375 mg Naproxen b.i.d (N=9). Etodolac was given about 2.5 and 3.5 times the mean effective dose used for treating patients with rheumatoid arthritis. The other drugs were given at their manufacturers maximum recommended doses. Lead-in placebo was given for 1 week, active drug for 1 week and wash out placebo for 1 week. Fetal blood loss was measured by the 51 Cr tragged red cell method, and was averaged over days 4-7 (base-line), 11-14 (treatments period) and 17-20 (wash out). The signify increase in blood loss for the treatment period for the 400 mg. Etodolac b.i.d group (0.13ml) and 600 mg Etodolac b.i.d (0.10ml) was significantly less (p=0.001) than the corresponding valves for Ibuprofrn (1.14ml), Indomethacin (1.20ml) and Naproxen (0.87 ml). There was no propensity for greater blood loss at higher doses of Etodolac. Etodolac at doses in excess of the mean effective dose in osteoarthritis and rheumatoid arthritis caused significantly less microbleeding in normal male volunteers during the 7-day treatment period than the other drugs, tested and not clinically more than that occuring during baseline placebo.
Gaston G W et. al (1986) (37) single oral doses of Etodolac 50, 100 and 200 mg were compared with Aspirin 650 mg in placebo in a double blind, parallel group study of 189 out patients reporting moderate or severe pain after oral surgery. Over all efficacies of test drgs was evaluated by sum of pain intensity difference (SPID) source and total pain releif (TOTPAR) scores over 0.5-3, 0.5-6,0.5-8, 0.5-12hrs. Etodolac 200mg provided significantly greater analgesia than Aspirin by these measurements over all SPID and all but one TOPAR interval, and was significantly more effective than placebo over all intervals. Etodolac 100mg was superior to Aspirin for SPID 0.5-8 and 0.5-12 hours and superior to placebo for both SPID and TOTPAR over all time intervals. Onset of analgesia for Etodolac 100mg, 200mg and Aspirin was 1hr or less for the mojority of patients in each group; 42% receiving Etodolac 200mg reported onset of analgesia within o.5hr. Duration of analgesia for Etodolac 200mg appeared twice that of Aspirin. A important positive dose-response relationship was obtained for the three doses of Etodolac. A low frequent of side effects was observed in all treatment groups.
Richard A. Jones (1999) (38) Etodolac nonsteroidal anti-inflammatory drug (NSAIDs) which has been used in the treatment of osteoarthritis and Rheumatoid arthritis and a selective COX-2 inhibitor in a wide range of clinically relevant assays in direct comparisons with other NSAIDs. Studies have shown Etodolac to have no overall suppression of gastric or duodenal prostaglandins and endoscopic analysis with Etodolac showed placebo level score in comparision with Ibuprofen, which showed inducement of gastro intestinal tract side effects. This elevated degree of gastric tolerability was further demonstrated by microbleeding studies. The favourable GI tolerability profile of Etodolac has been shown in long-term and large-scale trails and by routine clinical observation. Etodolac is a well recognized selective COX-2 inhibitor that has been shown not to suppress gastric or duodenal prostaglandins, to have minimal hepatic or renal effects and to have favourable GI tolerability in comparision with Ibuprofen.
