Diclofenac Sodium Sustained Release Research Articles

Performance Evaluation of Marketed Brands of Sustained Release Diclofenac Sodium Tablets Using Statistical Approaches

Six commercial brands of sustained release diclofenac sodium tablets have been comparatively studied for physical characteristics, hardness, uniformity of weight, assay and in vitro dissolution tests. Cumulative release greater than 85 % was obtained from all products tested within 8-12 h. Model fitting was done on release data using zero order, first order, Higuchi matrix and Peppas-Korsmeyer model. Some model independent parameters such as t25%, t50%, t90%, dissolution efficiency (DE 480 ) and mean dissolution time (MDT) were computed. Statistical tests such as repeated ANOVA, Friedman test, Friedman ANOVA, Kendall's coefficient of concordance and Tukey-Kramer multiple comparison tests were applied on the range of data obtained from different brands. The results indicated non-significant differences in physical parameters and in vitro drug release, but significant differences were found in hardness, weight variation and drug content. Further, only the second brand complied with theoretical release rate of 8.66 mg/h whereas other brands exhibited higher drug release rates. For all the brands, release was completed within 5-8 h. Keywords : performance evaluation, diclofenac sodium, physical and statistical tests, model dependent parameters, model independent parameters Ethiopian Pharmaceutical Journal Vol. 24 (2) 2006: pp. 91-97

Preparation and evaluation of microcapsules using polymerized rosin as a novel wall forming material

Sustained release diclofenac sodium microcapsules were prepared using polymerized rosin as a novel wall-forming material by a solvent evaporation technique. A novel method developed in our laboratory with the potential for scale-up and production of polymerized rosin microcapsules is detailed. These microcapsules might have application for development of implant/depot systems, primarily due to a sustained/controlled release capability and potential biocompatibility of polymerized rosin. The effect of variables like solvent systems, stirring speed and temperature were previously optimized. The solution system of drug and polymerized rosin dissolved in iso-propyl alcohol and acetone is sprayed with the help of a 0.5 mm nozzle spray gun in liquid paraffin maintained at 60°C in the stirring condition. Varying drug:polymer ratios, namely 1:1, 1:2, 2:1, 1:3 and 3:1, were employed for microcapsule preparation. The prepared microcapsules were evaluated for size, shape, drug content and in vitro drug release. The morphology of microcapsules was characterized by scanning electron microscopy. The microcapsules show sustained release curves at pH 7.4 phosphate buffer for up to 10 h. The data obtained from the dissolution profiles were compared in the light of different kinetics models and the regression coefficients were compared. The in vitro dissolution study confirmed the Higuchi-order release pattern. Particle size and release data analysis from five consecutive batches prepared in the laboratory indicated suitable reproducibility of the proposed solvent evaporation process.

A single-blind, randomized, controlled trial to assess the efficacy and tolerability of rofecoxib, diclofenac sodium, and meloxicam in patients with acute gouty arthritis

Background: Acute attacks of gouty arthritis are characterized by the rapid onset of severe pain, swelling, and erythema of the affected joint. Nonsteroidal anti-inflammatory drugs are considered the drugs of first choice for treating acute gout. Rofecoxib is a specific cyclooxygenase-2 inhibitor, which has demonstrated analgesic efficacy in the setting of acute pain. Whether it is effective in the treatment of acute gouty arthritis remains to be evaluated. Objective: The aim of this study was to assess the efficacy and tolerability of rofecoxib compared with diclofenac sodium sustained release (SR) and meloxicam in the treatment of acute gouty arthritis. Methods: In this single-blind, randomized, controlled, parallel-group study, patients aged ≥18 years with acute gout within 48 hours of onset were randomized to receive oral treatment with 2 tablets of rofecoxib (25 mg), diclofenac (75 mg), or meloxicam (7.5 mg) once daily for 7 days. The primary outcome measures were patients global assessment of response to therapy and investigator assessment of response to therapy on days 3 and 8. Other efficacy measurements included investigator assessment of total inflammatory scores on days 3 and 8 and patient assessment of pain intensity during the first 12 hours of treatment. Results: Sixty-two patients (53 men, 9 women; mean [SD] age, 51.1 [12.1] years) were assigned to receive rofexocib (n = 20), diclofenac (n = 21), or meloxicam (n = 21). For patient global response to therapy on days 3 and 8, rofecoxib was associated with analgesic efficacy in significantly more patients compared with meloxicam (84.2% vs 40.0% of patients [ P = 0.005] and 94.7% vs 60.0% of patients [ P = 0.02], respectively); no significant differences versus diclofenac were found. Similarly, for investigator global assessment of response to therapy, a greater percentage of responders was found in the rofecoxib group compared with the meloxicam group on day 3 (88.9% vs 40.0% of patients [ P = 0.02]), but the difference was not significant on day 8. A greater percentage of responders was found in the rofecoxib group compared with the diclofenac group on day 3 (88.9% vs 47.3% [ P = 0.007]), but the difference was not significant on day 8. Compared with baseline, all regimens showed significant improvement in total inflammatory scores on days 3 and 8 (all P < 0.01). During the first 12 hours after dosing, pain intensity score was significantly reduced with rofecoxib starting at 0.5 hours ( P < 0.05), but not with diclofenac or meloxicam. Clinical adverse events (AEs) were reported in 4 (20.0%), 7 (33.3%), and 6 (28.6%) patients in the rofecoxib, diclofenac, and meloxicam groups, respectively; the most common AEs reported were edema in 1 patient each in the rofecoxib (5.0%) and meloxicam (4.8%) groups and 2 patients (9.5%) in the diclofenac group and abdominal (1 [5.0%], 1 [4.8%], and 2 [9.5%], respectively). No significant differences in tolerability were found among the 3 treatment groups.

In vitro and in vivo comparison of two diclofenac sodium sustained release oral formulations

The aim of this study was to investigate the effect of formulation on the pharmacokinetics of diclofenac in two sustained release formulations (formulation A and Voltaren SR ®) after oral delivery. The dissolution of diclofenac from sustained release formulation was pH-dependent. While drug released from both formulations increased with increased pH, the release kinetics of these two formulations was different. The pharmacokinetic study was conducted in 12 healthy subjects administered with multiple doses of 100 mg of diclofenac in a crossover design. There was a significant difference in area under the plasma concentration–time curve [AUC(0–24)] and C max observed. The formulation with a reduced diffusion exponent with increased kinetic constant results in increased absorption of diclofenac in vivo. This study demonstrated the impact of release mechanism of the formulation on the absorption in vivo.

Statistical optimisation of diclofenac sustained release pellets coated with polymethacrylic films

The objective of the present study was to evaluate three formulation parameters for the application of polymethacrylic films from aqueous dispersions in order to obtain multiparticulate sustained release of diclofenac sodium. Film coating of pellet cores was performed in a laboratory fluid bed apparatus. The chosen independent variables, i.e. the concentration of plasticizer (triethyl citrate), methacrylate polymers ratio (Eudragit RS:Eudragit RL) and the quantity of coating dispersion were optimised with a three-factor, three-level Box-Behnken design. The chosen dependent variables were cumulative percentage values of diclofenac dissolved in 3, 4 and 6 h. Based on the experimental design, different diclofenac release profiles were obtained. Response surface plots were used to relate the dependent and the independent variables. The optimisation procedure generated an optimum of 40% release in 3 h. The levels of plasticizer concentration, quantity of coating dispersion and polymer to polymer ratio (Eudragit RS:Eudragit RL) were 25% w/w, 400 g and 3/1, respectively. The optimised formulation prepared according to computer-determined levels provided a release profile, which was close to the predicted values. We also studied thermal and surface characteristics of the polymethacrylic films to understand the influence of plasticizer concentration on the drug release from the pellets.

Persistent Analgesic Effect of Sustained Release Diclofenac Sodium Preparation on BovineType II Collagen-Induced Arthritis.

As a sustained release preparation of diclofenac sodium (DF-Na), we developed a preparation (SR318B) that was expected to exhibit a persistent analgesic effect by once-daily oral administration. In this study, we investigated the persistence of the analgesic effect of SR318B using female cynomolgus monkeys with arthritis induced by sensitization with bovine type II collagen combined with FreundÕs complete adjuvant. Cynomolgus monkeys in which arthritis was induced to the same severity received oral administration of SR318B (1 mg DF-Na/kg) once daily for 14 days. The mean ellipsoid area of the proximal interphalangeal joints in the monkeys slightly increased before administration on day 3 in the control group. In contrast, the area decreased after day 3 and significantly decreased on day 13 in the SR318B treatment group. The plasma diclofenac (DF) level reached the highest point at 6 hr after administration on day 13, then decreased. The plasma level was lower than the quantification limit 20 hr after administration on both days 0 and 13. In contrast, DF was detected in synovial fluid 24 hr after the initial and final administration. Based on the above findings, SR318B exhibits a persistent analgesic effect on collagen-induced arthritis. While the plasma DF concentration decreased to a level lower than the quantification limit at 20 hr, DF was still detected in the synovial fluid 24 hr after administration. Therefore, the retention of DF in inflammatory regions may play an important role in the analgesic effect.

Analgesic Action of a Sustained Release Preparation of Diclofenac Sodium in a Canine Urate-Induced Gonarthritis.

Using hard capsules (SR318B) developed as a sustained release diclofenac sodium (DF-Na) preparation for once-daily administration, we investigated the persistence of the analgesic effect after oral administration in the canine urate-induced gonarthritis model. In the control group, injection of 2% urate into the knee joint induced gait disorder due to pain 2 hr after administration and thereafter. Gait disorder peaked 6 hr after urate injection, and gradually recovered after 12 hr. In the treatment group, SR318B at 1.0 mg DF-Na/kg body weight was orally administered 6 hr before urate injection, and the walking score significantly decreased 2 hr after urate injection compared with the control group (p < 0.05). Although the analgesic effect was not observed at the peak of urate-induced pain, the walking score significantly decreased 14, 16, and 18 hr after urate injection compared with the control group (p < 0.05). The plasma diclofenac (DF) concentration peaked 6 hr after SR318B administration, and decreased to about 1/3-1/5 12-18 hr after administration (peak of urate-induced pain), and the plasma level was below the quantification limit in three of five animals 24 hr after administration. DF was detected in the synovial fluid 24 hr after administration in all animals and the concentration was 0.03 ± 0.01 μg/ml (mean ± standard error). The above findings showed that the SR318B exhibits a persistent analgesic effect in a canine urate-induced gonarthritis model. Not only DF in the plasma but also the DF that transferred to the synovial fluid may be involved in this persistent analgesic effect.

Sustained Release of Diclofenac from Polymer-Containing Suppository and the Mechanism Involved

Sustained release of diclofenac sodium (DcNa) from suppositories composed of triglycerides and polymer was investigated by dissolution testing through an artificial membrane. DcNa was slowly released from a suppository containing carboxyvinyl polymer (CVP), and the extent of the release decreased with the amount of CVP added. Little effect was noted with the addition of other water-soluble polymers, such as hydroxyethylcellulose (HEC), xanthan gum, and polyvinylalcohol (PVA). When sodium benzoate was used instead of DcNa, a similar result was obtained with the addition of CVP. The result of release rate analysis together with the viscosity and pH in these cases showed that the reduction of solubility and diffusion due to sodium exchange between DcNa and CVP played an important role in the sustained release from the suppository. Also, in comparison with the results when CVP was not used, the plasma concentration profile of diclofenac after the administration of CVP suppository displayed a twofold longer half-life time.

Fluidized-bed spray coated porous hydrogel beads for sustained release of diclofenac sodium

Swellable porous hydrogel beads were loaded with diclofenac sodium and then coated with pseudo-latex ethylcellulose (EC) in a fluidized-bed spray coater. The drug release profile in-vitro can be modified by adding 25% or more triethyl citrate (TEC) or dibutyl sebacate (DBS) as a plasticizer. The plasticized coating film can overcome the swelling stress of the core and function as a barrier for sustained drug release. Adding TEC resulted in a near-zero order kinetics after an initial burst in the release profile, and adding DBS showed a first initial burst, a second stage of linear release, a third stage of slow release. The initial burst is due to the flaws or cracks on the surface of the coated-beads and it can be reduced by increasing the amount of plasticizer or film thickness and also by adjusting the thermal treatment time. A 4- to 6-h treatment at 60°C was found to be the optimal condition to give the smallest initial burst for coating film containing TEC as a plasticizer. Adding hydrophilic hydroxylpropyl methylcellulose (HPMC) could smooth the initial burst and change the release profile to a Fickian-type release, and in this case increasing the thermal treatment time could reduce the release rate. Two kinds of EC-coated beads were tested in-vivo by using rabbits as animal models and showed good sustained release behaviors as the drug concentration in plasma could be maintained above 0.4 μg/ml and lower than 1.5 μg/ml for 24 h.

Comparative study of in-vitro release and bioavailability of sustained release diclofenac sodium from certain hydrophilic polymers and commercial tablets in beagle dogs

Hydrophilic colloids interact with metallic ions to yield crosslinked insoluble salts. Such principle was utilized in the preparation of diclofenac sodium beads from sodium alginate and sodium carboxymethylcellulose. Hard spherical beads of aluminum alginate and aluminum carboxymethylcellulose with a narrow particle size distribution (1.60 ± 0.12 and 3.10 ± 0.20 mm) and low friability (0.5 and 1.4%) respectively were obtained with high yield (80–90%) and a drug content approaching 70–80%. The type and concentration of the polymers as well as the pH of the dissolution medium were found to affect the rate of drug release. Beads prepared from Na-alginate showed a non-significantly (p >; 0.05) faster rate of drug release than that prepared from NaCMC. The higher the polymer concentration, the slower was the rate of drug release. Diclofenac sodium did not release in 0.1 N HC1 (pH 1.2) for 2 h and released in phosphate buffer solution (pH 6.8) from the two formulations studied and from the commercial Voltaren Retard tablet. The two formulations of the beads resulted in a sustained release action of diclofenac sodium for 24 h. They showed Kel values of 0.02 ± 0.01 and 0.3 ± 0.01 h −1 and these correspond to t12 of 34.65 and 27.70 for the Na-alginate and NaCMC beads, respectively. They also showed mean residence time (MRT) values of 9.56 ± 2.5 and 7.86 ± 0.54 h, respectively. They also showed non-significant (p >; 0.05) differences with respect to their plasma levels, Cmax, Tmaxand AUC0 → 24h. The relative bioavailability of the two formulations were 59.01 and 47.96%, respectively, relative to that of the commercial Voltaren Retard tablets of Ciba-Geigy which showed a Kelof 0.044 h −1 corresponding to a t12of 15.75 handMRTof 7.45 ± 1.10 h.

Comparison of the in vitro release characteristics of a wax matrix and a hydrogel sustained release diclofenac sodium tablet

AbstractTwo types of sustained release tablets of diclofenac sodium were formulated, such that one released drug via the pores of a wax matrix (DWM), and the other relied upon the swelling of a hydrogel (DHG). The in vitro release characteristics of these two were compared using USP XXI Dissolution Apparatus I and II as well as an intrinsic dissolution technique at various speeds of rotation. Bnployment of the release exponent ‘n’ as a method of ascertaining the release mode showed that DWM exhibits classic diffusion-controlled release of drug down tortuous pores. This was confirmed by scanning electron microscopy.Release is relatively independent of rotation speed, except when unprotected from abrasion. DHG tablets exhibited near zero-order release, a dynamic equilibrium existing between rate of gel swelling and erosion. This was true up to a point where high rotational speeds upset this equilibrium by increasing erosion. This was confirmed by gel thickness measurements.

Controlled-release indomethacin and sustained-release diclofenac sodium in the treatment of osteoarthritis: A comparative controlled clinical trial in general practice

A double-blind, crossover study was undertaken in general practice to compare the efficacy and tolerability of a new controlled-release indomethacin with sustained-release diclofenac sodium in patients with osteoarthritis. Eighty-four patients were randomly allocated to receive controlled-release indomethacin tablets (75 mg) or sustained-release diclofenac sodium tablets (100 mg) at night for a period of 4 weeks before being crossed-over to receive the alternative treatment for a further 4 weeks. Pain scores for day and night, duration of morning stiffness, requirement for escape analgesia, and treatment preference were similar for both treatments. There was no significant difference between treatments for incidence and severity of side-effects. It was concluded that controlled-release indomethacin tablets (75 mg) given as a single night-time dose were as efficacious and well tolerated as sustained-release diclofenac sodium (100 mg).

Controlled-release indomethacin and sustained-release diclofenac sodium in the treatment of rheumatoid arthritis: A comparative controlled clinical trial

The efficacy and tolerability of a new, controlled-release indomethacin (75 mg) tablet was compared to that of a sustained-release diclofenac sodium (100 mg) tablet in 84 patients with rheumatoid arthritis. The study was designed as a double-blind, double-dummy crossover trial, patients being allocated at random to receive 1 active tablet and 1 placebo tablet of the alternative medication at night for 4 weeks before being crossed over to the alternative treatment for a further 4 weeks. Patient and clinical assessments on entry and at the end of each treatment period showed that pain scores for day and night, duration of morning stiffness, requirement for escape analgesia (paracetamol) and treatment preference were similar for both treatments. Both preparations also significantly improved the degree of joint tenderness compared to baseline (p less than 0.001), as measured by a modified Ritchie Articular Index. Incidence and severity of side-effects were comparable, with a significant improvement in degree of constipation reported for both treatments compared to baseline (p less than 0.05). The incidence and severity of headache was statistically significantly worse (p less than 0.05) for controlled-release indomethacin; however, there was no difference in any other parameter of tolerability. It was concluded that controlled-release indomethacin tablets (75 mg) given as a single night-time dose were as efficacious and well tolerated as sustained-release diclofenac sodium (100 mg).

Effect of Acrylic Polymers on the Physical Parameters and &lt;i&gt;in vitro&lt;/i&gt; Release Kinetics of Diclofenac Sodium Sustained Release Pellets

The aim of the present study is to investigate the effect of Ammonio Methacrylate Copolymer Type A (Eudragit RL 30 D) and Ammonio Methacrylate Copolymer Type B (Eudragit RS 30 D) on the release kinetics study of diclofenac sodium form coated pellets. Eudragit RS 30 D and Eudragit RL 30 D were added into the formulation at 5:1 ratio. Different percent of this polymeric combination was loaded on to the drug-loaded pellets. Loss on drying value as well as bulk density of coated pellets increase along with the increase in polymer level. It was found that the cumulative percent release of drug decreased with the increase of polymer load in all cases. From all formulations it was observed that the release of diclofenac sodium in 0.1N HCl media was very low (maximum 2.87 %) at first 2 hours. Better sustaining effect was found from Eudragit RS 30 D and Eudragit RL 30 D combinations. Drug was released linearly along with time throughout the whole dissolution process in phosphate buffer (pH 6.8) and it was also revealed that, in all cases the release of diclofenac sodium followed zero order kinetics. &#x0D; &#x0D; Key words: Diclofenac sodium, Eudragit RL 30 D, Eudragit RS 30 D, Aqueous coating, Physical parameters, Kinetics of drug release &#x0D; &#x0D; Bangladesh J. Sci. Ind. Res. 42(3), 239-248, 2007

The Effect of Manufacturing Methods and Different Shapes on the Release Pattern of Diclofenac Sodium Matrix Tablet

In the present study sustained release diclofenac sodium matrix tablets were prepared using Kollidon SR polymer. Hydroxypropyl methylcellulose (HPMC 15 cps) and poly ethylene glycol (PEG-600) polymers respectively were used in formulating tablets prepared by direct compression and wet granulation methods. The polymers were used to explore the release pattern of the drug into the dissolution media. The tablets were also prepared in various shapes (caplet oval, round oval and flat oval). A comparatively higher release rate of drug was obtained from the polymer HPMC 15 cps at 10% concentration for directly compressed matrix tablet than those containing 20% of HPMC after a definite period of time. In wet granulation process, 10% PEG-600 containing tablets showed a better release than those containing 20% PEG. The drug release was also found to be sustained in case of wet granulation method than that of the direct compression method. Again the caplet shaped tablets in case of direct compression method showed better release rate of drug than those of the round oval and flat oval shaped tablets. Thus the result of this study shows that the proper selection of the percentage of polymer and the suitable shape of tablet and proper manufacturing method can provide a greater opportunity in designing sustained release dosage forms. Key words: Matrix tablet; release pattern; direct compression; wet granulation; PEG 600; Kollidon SR.DOI: 10.3329/sjps.v2i2.5828Stamford Journal of Pharmaceutical Sciences Vol.2(2) 2009: 76-80