Ibuprofen Sustained Release Research Articles

New solid lipid microparticles for controlled ibuprofen release: Formulation and characterization study

A hot melt dispersion method was used to prepare new sustained release ibuprofen composite microparticles of a solid lipid at ambient temperature, cetyl alcohol. The dispersion of colloidal silicon dioxide nanoparticles (hydrophilic Aerosil ® 200 or hydrophobic Aerosil ® R974) either in the oily phase or in the aqueous phase led to the preparation of large (about 400 μm diameter) surfactant free free-flowing particles. Mapping-scanning electronic microscopy using silicon probe revealed that silicon was in the oily core in all cases. The nature of silica nanoparticles and the way used for their dispersion influenced the internal structure of the composite microparticles and the aggregation of nanoparticles in the core of the microparticles. Hydrophobic Aerosil ® R974 allowed the formation of homogeneous microparticles. Although silica nanoparticles had no influence on thermic profile, crystalline state of ibuprofen and lipid, they had an influence on the kinetics drug release related to the increase of the size of the composite solid lipid microparticles prepared.

Design and study of ibuprofen disintegrating sustained-release tablets comprising coated pellets

One challenge in tableting of sustained-release multiparticulates is maintaining the desired drug release after compaction. The aim of this study was to design sustained-release ibuprofen tablets which upon oral ingestion rapidly disintegrate into sustained-release pellets in which the integrity of the pellet core and/or coat is preserved. First free films composed of Eudragit RS 30D and RL 30D in 4:1 ratio and containing different levels of triethyl citrate (TEC) were prepared and tested to optimize the plasticizer level. Cured Eudragit based pellets with 60% ibuprofen loading which in our previous study showed proper mechanical properties for compression were coated with Eudragit RS 30D/RL 30D (4:1) containing 20% triethyl citrate at different coating levels. The mechanical properties of the coated pellets were tested. Polymer coated pellets were compacted into tablets either alone or with a blend of excipients comprising Avicel, PEG 4000, cross-linked PVP. A 3 2 full factorial design was used to optimize the filler blend composition. Effects of pellet to filler ratio, compression force and granulation of filler on tablet characteristics were investigated. Results of mechanical test showed that the coating of cured pellets had no significant effect on yield point and elastic modulus of the pellets. In the case of 5% coating level sustained release of ibuprofen over a period of 24 h was achieved. The results obtained from tableting procedure showed that by selecting suitable filler blend (60% Avicel, 10% cross-linked PVP and 30% PEG 4000), compression force, and granulation of filler it was possible to prepare sustained-release tablets containing high ratio of coated pellets (even 80%) with desirable strength, disintegration time, and drug release rate. It was observed that compression force, pellet to filler ratio, composition of filler blend and granulation of fillers had no effect on drug release rate from compacted pellets but had significant influence on tablet strength, friability, and disintegration time. SEM graphs and in vitro release profiles for compacted pellets showed no apparent damage to the coated pellets as a result of the compaction process.

Fatality after deliberate ingestion of sustained-release ibuprofen: a case report

IntroductionIbuprofen is a nonsteroidal anti-inflammatory drug available over the counter and on prescription for the management of pain and inflammation. Severe toxicity is rare following deliberate self-poisoning with ibuprofen, and patients are usually either asymptomatic or develop only mild gastrointestinal toxicity. Although there have been nine other reported fatalities, co-existent factors have probably contributed to all of these deaths. We report here a fatality from isolated toxicity following self-poisoning with sustained-release ibuprofen.Case reportA 26-year-old female presented after deliberate ingestion of up to 105 g sustained-release ibuprofen, with a reduced level of consciousness, severe metabolic acidosis and haemodynamic compromise. Despite intensive supportive management, gut decontamination with multidose activated charcoal and correction of the metabolic acidosis with sodium bicarbonate and haemofiltration, the patient did not survive. The ibuprofen concentration ante mortem on presentation in peripheral blood was 760 mg/l and the concentrations post mortem were 518 mg/l in peripheral blood, 74 mg/kg in liver extract and 116 mg/l in the gastric contents.DiscussionMost patients with ibuprofen poisoning are either asymptomatic or have mild gastrointestinal symptoms; severe poisoning with ibuprofen is rare. We report the first death related to isolated sustained-release ibuprofen poisoning.

Effect of Granules Properties on the In-vitro and In-vivo Performance of Ibuprofen Sustained Release Matrix Tablets

The impact of variations in the wet granulation step during the manufacturing process on the in-vitro and in-vivo performance of ibuprofen sustained release matrix tablets was investigated. Two batches were produced under different wet granulation conditions. The granules of the first batch (T1) were characterized by having a lower bulk density (0.56 g/ml), a higher percentage of fines (56.7% w/w) and a smaller geometric mean diameter (dg), 600 µm. While the granules of batch (T2) were characterized by having a more coherent properties, a higher bulk density (0.66 g/ml), a lower percentage of fines (36.9% w/w) and a larger dg, 720 µm. Three large scale production batches (B1, B2, B3) were manufactured similarly to T2 and found to have granules possessing similar properties. In-vitro tests showed that tablets of T1 had a statistically significant higher release rate constant than tablets of either T2, B1 ,B2 or B3. In-vivo tests were done using T1 and T2 tablets. Although T1 and T2 were bioequivalent with respect to Cmax and AUC, T2 exhibited a statistically significant longer sustained release characteristics than T1 (P<0.05).

Use the Correct Statistical Test

To the Editor: Plummer et al. [1] have reported that the addition of sustained release ibuprofen to morphine patient-controlled analgesia "improved efficacy" and, specifically, that "patients receiving ibuprofen reported significantly less pain at rest." This may well be true; however, the paper as presented does not allow us to reach these conclusions. The investigators chose to measure pain by using a four-point ordinal scale (0 = none, 1 = slight, 2 = moderate, 3 = severe, and 4 = unbearable), which is acceptable although probably less satisfactory than the well-established 10-cm Visual Analog Scale. They then analyzed their data inappropriately by using an analysis of variance, a test that is only suitable for normally distributed, continuously variable data. Their Figure 1offers a graphic representation of these inappropriately averaged scores, together with their standard errors of the mean. Simply averaging together ordinal scores like this makes the assumption that a score of "unbearable" is equivalent to two of "moderate" or four of "slight", which is not correct. To correctly analyze their ordinal data, they could have constructed a contingency Table orused the Mann-Whitney U-test. Please, may we see the pain data correctly analyzed using a more suitable test? Does the main conclusion of the paper remain valid or should it be reversed? It would also be helpful to know whether the statistical analysis was performed by the authors themselves or by their sponsors. Was the method of analysis declared in the protocol? If so, how did it escape the attention of the company's statisticians? Should not an elementary statistical error of this magnitude have been detected by the peer review process? J. Robert Sneyd, MD, FRCA Ian G. Kestin, FRCA Department of Anaesthesia; Derriford Hospital; Plymouth PL6 8DH, England

Pain control in the week following laparoscopic surgery: A comparison of sustained-release ibuprofen and paracetamol

Summary. This study compared pain relief and adverse events from sustained-release ibuprofen and paracetamol administered for a week after laparoscopic cholecystectomy. Patients were randomly assigned to receive sustained-release ibuprofen (2 × 800 mg once daily) or paracetamol (2 × 500 mg PRN up to 4 hourly). Oxycodone tablets (5 mg) were available for rescue analgesia. Patients kept a pain diary for 1 week and were assessed by the investigators 24 h after surgery and at the surgical follow-up clinic. Patients receiving ibuprofen (n = 46) reported lower pain scores (scale 0–4, where 0 = no pain and 4 = unbearable pain) than those receiving paracetamol (n = 44) (mean 1.07 vs 1.35) and consumed less oxycodone (mean 0.83 vs 1.67 tablets). Although these differences were not statistically significant (P = 0.057 and P=0.12 respectively), the 95% confidence interval for the difference in mean pain scores was −0.01 to +0.55 indicating that sustained-release ibuprofen was equivalent or superior to paracetamol. Nineteen patients who received ibuprofen reported a total of 33 adverse events compared to 13 patients receiving paracetamol who reported 18 adverse events (P=0.24). Sustained-release ibuprofen is as good as or better than paracetamol for the control of pain after laparoscopic surgery.

Stereospecific formulation and characterization of sustained release ibuprofen microspheres

Ibuprofen microspheres were prepared from the racemate, (+)-S and (+)-R enantiomers using waxes such as ceresine and glyceryl stearate and stereo-specifically characterized. The method of preparation of the microspheres was a hydrophobic congeal able disperse phase encapsulation process and variables such as particle size, wax type, enantiomeric form were evaluated. Dissolution studies were carried out by a modified USP type II method and the samples were analysed by a stereospecific HPLC assay using S-(−)-1(1) naphthyl-ethylamine as the derivatizing agent and fenoprofen as the internal standard. The mean particle sizes of (+)-S and (−)-R enantiomers determined by microscopy/image analysis were 64 and 99 μm respectively while that of the racemate was 48 μm. Differential Scanning Calorimetry (DSC) of ibuprofen and the enantiomers showed endothermic peaks at 72 and 55°C respectively. Thermograms of the physical mixture and microspheres did not show the characteristic ibuprofen peak, indicating a change in crystallinity of the drug. Powder X-ray diffraction patterns of the enantiomers and racemic ibuprofen were found to be dissimilar indicating different crystal properties. The X-ray patterns for the microspheres did not show the characteristic peaks for the drug indicating that ibuprofen may be in solid solution with the waxes. Scanning electron micrographs of the microspheres showed a generally smooth and spongy appearance for the microspheres made of compritol and glyceryl stearate. Microspheres made from the paraffin waxes had rough and hard surface characteristics consistent with the higher melting point of the waxes. Ceresine microspheres made with the enantiomers had a rougher and more porous surface compared to the microspheres made with racemic ibuprofen. Stereospecific release of the racemate from the formulations was found to be sustained (T25 of 4 h), while release from the enantiomers was less sustained (T50 of 2 h). From the S:R ratios and statistical analysis of the data, the release of the enantiomers of ibuprofen from the formulations containing the racemate was found to be non-stereoselective.

Relationship Between Dissolution Rate and Bioavailability of Sustained-Release Ibuprofen Capsules

Dissolution studies of three marketed brands of ibuprofen sustained-release (SR) capsules were conducted on USP XIX dissolution apparatus 1, using buffers simulating the gastrointestinal tract (GIT) pHs. The products showed almost identical drug release pattern in dissolution studies. A single-dose crossover oral bioavailability study revealed statistically significant differences in Cmax, Tmax, AUC and percent bioavailability values among the SR products but no such differences are evident in the t1/2a, Ka, t1/2e, and Ke. Retard quotient values were used to evaluate the sustained-release nature of the products. Statistical moment parameters such as MRT, MAT, and MDT were related with the dissolution parameters. Statistically significant correlations were observed between MRTin vitro and MRTin vivo or MDTin vivo T50% and Tmax; and T90%, and Cmax, or AUC120. The determination of MRTin vitro, T50%, and T90%, may be useful as quality control parameters to which each batch of the ibuprofen SR products could be submitted.

In vitro and in vivo evaluation of a xanthan gum- n-octenylsuccinate starch matrix tablet containing ibuprofen as a model drug

The bioavailability after oral administration of two sustained release ibuprofen formulations using xanthan gum and a combination of n-octenylsuccinate starch (CL490) and xanthan gum has been investigated in healthy human volunteers and compared with a commercial suspension formulation. The ibuprofen-xanthan gum and the ibuprofen-xanthan gum-CL490 matrix tablets were prepared by direct compression. Three different xanthan gum/CL490 ratios (1:1; 1:4 and 1:10) were investigated in vitro. The xanthan gum/CL490 matrix tablets of a 1 4 and a 1 10 ratio both released nearly 100% after 24 h. No difference was observed in the release profiles between the matrix tablets prepared with 1 1 ratio of xanthan gum and CL490 and with pure xanthan gum during the first 8 h of dissolution test. After 8 h, the release rate from the pure xanthan gum matrix increased (nearly 90% after 24 h) while matrix tablet with a 1 1 ratio of xanthan gum and CL490 released 60% after 24 h. A dry core remained after a 24 h dissolution time period for matrix tablets prepared with the 1 1 ratio of xanthan gum and CL490, while the pure xanthan gum matrix had completely eroded. For the in vivo study, a xanthan gum/CL490 (1:1) matrix tablet was compared to a xanthan gum matrix tablet and a conventional suspension formulation. In comparison with the conventional suspension, the oral bioavailability was 86.83% ± 25.80% ( n = 6) and 75.50% ± 17.18% ( n = 6) for the tablets made with xanthan gum and with a combination of xanthan gum and CL490 (ratio 1 1 ), respectively. The combination of a xanthan gum and CL490 seemed to avoid the initial slow absorption phase in vivo that occurred with a pure xanthan gum matrix tablet. The combination of xanthan gum and n-octenylsuccinate starch could offer some advantages in the formulation of sustained release hydrophilic matrix tablets.

Sustained-Release Ibuprofen as an Adjunct to Morphine Patient-Controlled Analgesia

Sustained-Release Ibuprofen as an Adjunct to Morphine Patient-Controlled Analgesia

A double-masked comparison of the efficacy of once-daily sustained-release ibuprofen and once-daily piroxicam for 24-hour control of arthralgia due to osteoarthritis in the elderly

The efficacy and safety of a novel, once-daily, sustained-release (SR) tablet formulation of ibuprofen (2 × 800 mg) and once-daily piroxicam (2 × 10 mg) were compared in 59 elderly patients (age range, 55 to 92 years) with osteoarthritis of the hip and/or knee, in a randomized, double-masked, double-dummy, parallel-group trial over a period of 4 weeks. Approximately twice as many patients were randomized to receive SR ibuprofen (n = 38) as piroxicam (n = 21). Dosing took place daily in the early evening. Goniometric assessment of joint restriction was performed at baseline and at weeks 1, 2, and 4. Patients assessed their joint pain on a visual analog scale (VAS) in the early and late morning, early evening, and at bedtime at baseline and weekly thereafter. No significant differences were identified between treatments in terms of goniometrically assessed joint restriction, and both treatments were equally effective in alleviating arthralgia. Of the patients receiving SR ibuprofen, 76% (29 of 38) judged it to be effective in reducing joint pain, compared with 71% (15 of 21) receiving piroxicam, a nonsignificant difference. Early and late morning VAS pain scores at each of weeks 1 through 4 for the SR ibuprofen-treated group were significantly lower than at baseline, whereas for the piroxicam group, only the early morning pain scores at weeks 3 and 4 were significantly improved. Early evening (predosing) pain scores were significantly reduced versus baseline at week 4 with SR ibuprofen but at none of the early evening assessments in the piroxicam group. This indicated a tendency toward better 24-hour control of pain by SR ibuprofen than by piroxicam. The difference between the incidence of gastrointestinal-related symptoms in patients receiving SR ibuprofen (2 of 38; 5%) versus piroxicam (3 of 21; 14%) was not statistically significant. It was concluded that once-daily SR ibuprofen was at least as effective in relieving arthralgia as piroxicam over a 24-hour period but with a propensity for producing a lower incidence of gastrointestinal disturbances in elderly patients. Ibuprofen SR tablets combined effective control of painful arthralgia attributable to osteoarthritis of the hip and knee, with the acknowledged excellent safety profile of this non-steroidal anti-inflammatory drug.

Efficacy and tolerability of sustained-release ibuprofen in the treatment of patients with chronic back pain

This was a double-blind, parallel-group, multiple-dose study designed to compare the efficacy and tolerability of the sustained-release (SR) formulations of ibuprofen and diclofenac sodium for patients suffering from chronic back pain. The patients were randomly allocated to treatment with either the recommended once-daily dosage of ibuprofen SR (1600 mg) or diclofenac SR (100 mg) for 14 days; 30 patients were treated with ibuprofen and 32 with diclofenac. Clinical assessments of the patients' back condition were made at the beginning and end of the study, and the patients themselves rated their quality of sleep, level of activity, and severity of pain each day. In terms of efficacy, the ibuprofen SR treatment resulted in a trend toward better patient responses for all variables other than quality of sleep and night pain, although differences between the two treatment groups were not statistically significant. There were eight patient withdrawals in the diclofenac SR group (six due to adverse events) compared with four patients in the ibuprofen SR group (only one attributed to adverse events). Overall, 16 diclofenac SR-treated patients reported 24 adverse events, 8 of which were recorded as definitely related to the drug. Four ibuprofen SR-treated patients reported a total of nine adverse events, and only three were considered to be definitely drug related. The difference between the groups in the number of patients reporting adverse events was statistically significant ( P = 0.002). The demonstrated efficacy and superior tolerability of ibuprofen SR provide strong support for the use of this once-daily formulation in the management of patients with chronic back pain.

Preparation and Evaluation of Sustained Release Ibuprofen Beads

AbstractSustained release beads of ibuprofen were prepared by a capillary method using cellulose acetate phthalate, surfactants (Tween 80 and Span 80), and polymers (K 100 M Methocel and K 100 LV Methocel). These beads were formulated into capsule and tablet dosage forms. The beads did not disintegrate in simulated gastric fluid; however, they disintegrated in simulated intestinal fluid. The dissolution profiles of ibuprofen beads and dosage forms of beads (tablets and capsules) were conducted in phosphate buffer (pH 7.2) at 37°C. The beads containing Span 80 and K 100 M Methocel resulted in prolonged drug release. The preparation containing Span 80 and equal quantities of both the polymers (K 100 M Methocel and K 100 LV Methocel), also showed good sustained release properties. The formulations prepared with Tween 80 and K 100 LV Methocel released over 90% of the drug in 2 hours indicating no sustained release properties. The beads in tablet dosage form yielded slower dissolution profiles compared to the beads in capsule form which, in turn, had slower release profiles compared to the beads alone. Release of ibuprofen was much slower from tablets after one year of storage compared to tablets immediately after their manufacture.

Investigation into the duration of action of sustained-release ibuprofen in osteoarthritis and rheumatoid arthritis

The duration of action of sustained-release ibuprofen ('Brufen Retard') was investigated in a 14-day double-blind study involving 14 osteoarthritis and 10 rheumatoid arthritis patients. The recommended once-daily dosage of this preparation (1600 mg taken in the evening) provided effective control of arthritic symptoms for both patient groups, with significant overall improvements in pain and stiffness compared to baseline. Substitution of placebo for a single dose of the active treatment resulted in a trend towards worsening of pain and stiffness in the rheumatoid group; however, the only statistically significant change involved impaired quality of sleep (p = 0.03) during the night after placebo administration, over 24-hours after the previous dose of active medication. In this particular study, symptom control was also clearly achieved for the osteoarthritis patients, as this group showed no deterioration within the same period. The 24-hour clinical action underlying these findings is consistent with ibuprofen plasma profiles obtained with the sustained-release preparation in earlier pharmacokinetic studies. It is likely that the greater sensitivity of rheumatoid patients to withdrawal of a single day's active treatment in this study reflects a more severe inflammatory disease process than that of the osteoarthritis patients.

Effects of disease-modifying anti-rheumatic drugs, steroids and non-steroidal anti-inflammatory drugs on acute-phase proteins in rheumatoid arthritis.

Elevated serum concentrations of acute-phase proteins (APPs) are a characteristic finding of rheumatic diseases, including RA. CRP is the most useful measure of disease activity and is frequently assessed in clinical trials to determine systemic improvement. The effects of different therapies for RA on CRP have been assessed in many studies. The DMARDs such as gold salts, D-penicillamine, sulphasalazine and azathioprine have been shown to reduce serum CRP concentrations significantly in patients with RA. CRP serum concentration is also reduced by the corticosteroids such as prednisone, but addition of pulse therapy with i.v. methylprednisolone had no additive effect compared with DMARDs alone. Many studies have shown that serum CRP concentrations are not reduced by NSAIDs; however, one recent study has demonstrated that CRP concentration was reduced by the NSAIDs flurbiprofen and sustained-release ibuprofen in a subgroup of patients.

Processing factors affecting particle size and in vitro drug release of sustained-release ibuprofen microspheres

Ibuprofen microspheres were prepared using an aqueous dispersion method. The method was adapted so that two processing factors, cooling time and stirring rate, could be altered. The subsequent effects of altering these parameters on the characterisation of the microspheres and the drug release kinetics were investigated. Particle size analysis showed that both stirring rate and cooling time significantly affected the mean particle size although the effects were independent of each other. In vitro release data were fitted to several models, the Higuchi square root of time model (with appropriate limits) giving the best fit for the release data. Increasing the cooling time or decreasing the stirring rate decreased the release of drug from the system. By using this method of manufacture, which allows alteration of processing parameters, it would be relatively straightforward to produce microspheres with tailored in vitro release characteristics.

Controlled study of once-daily, sustained-release ibuprofen in osteoarthritis

This 4-week, double-blind, multinational study compared the efficacy and tolerability of a novel sustained-release formulation of ibuprofen, Brufen Retard® (two 800-mg tablets administered once daily) with conventional-release ibuprofen (one 400-mg tablet administered four times daily) in hospital outpatients with osteoarthritis of the knee. In the 150 patients evaluated, both treatments were effective, producing reductions in day and night pain, joint tenderness/stiffness, and paracetamol consumption, while increasing active and passive knee movement. At week 4, the differences between the treatments were small and not statistically significant. Both treatments were well tolerated and had similar adverse event profiles. Sustained-release ibuprofen provides effective treatment for osteoarthritis while offering the convenience of a once-daily treatment regimen.

The effect of food on gastrointestinal (GI) transit of sustained-release ibuprofen tablets as evaluated by gamma scintigraphy.

The GI transit of radiolabeled sustained-release ibuprofen 800-mg tablets in eight healthy, fed volunteers was monitored using external gamma scintigraphy. Ibuprofen serum concentrations were determined from blood samples drawn over 36 hr following dosing. Sustained-release ibuprofen tablets containing 0.18% of 170Er2O3 (greater than 96% 170Er) in the bulk formulation were manufactured under pilot-scale conditions and were radiolabeled utilizing a neutron activation procedure which converted stable 170Er to radioactive 171Er (t1/2 = 7.5 hr). At the time of dosing, each tablet contained 50 mu Ci of 171Er. Dosage form position were reported at various time intervals. In five subjects the sustained-release tablet remained in the stomach and eroded slowly over 7-12 hr, resulting in gradual increases in small bowel radioactivity. In the remaining three subjects, the intact tablet was ejected from the stomach and a gastric residence time of approximately 4 hr was measured. This is in marked contrast to a previous study conducted in fasted volunteers in which gastric retention time ranged from 10 to 60 min. Differences in GI transit between fed and fasted volunteers had little effect on ibuprofen bioavailability. AUC and Tmax were unaltered and Cmax was increased by 24%, which is in agreement with results from a previous, crossover-design food effect study.

Correlation of serologic indicators of inflammation with effectiveness of nonsteroidal antiinflammatory drug therapy in rheumatoid arthritis

Forty-seven patients with rheumatoid arthritis (mean duration 5.7 years) who were receiving neither disease-modifying drugs nor corticosteroids were enrolled in a 12-week, multicenter study of the relationship between clinical and serologic measures of disease activity in patients taking nonsteroidal antiinflammatory drugs. After a 2-week drug washout period, patients received flurbiprofen (200 mg/day) or sustained-release ibuprofen (2,400 mg/day) for a 10-week trial. Clinical response was assessed biweekly using standard clinical parameters, including 50-foot walk time, tender joint score, duration of morning stiffness, and global assessment of disease activity and pain (by both the patient and the physician). Patients were classified as responders if there was greater than or equal to 30% improvement in at least 3 of the 4 clinical measures of disease activity. Thirty patients completed at least 8 weeks of therapy; there were 12 responders and 18 nonresponders. Of the laboratory parameters examined, the responders, but not the nonresponders, demonstrated significant reductions (from postwashout values) in levels of IgM rheumatoid factor and C-reactive protein (CRP), along with significant increases in the number of circulating lymphocytes and decreases in the number of circulating granulocytes (P less than or equal to 0.05). In contrast, the nonresponders demonstrated either no change or worsening of the laboratory correlates of disease activity. The responders also appeared to have more aggressive disease at baseline, with significantly more painful joints, greater 50-foot walk times, elevated CRP values, and elevated erythrocyte sedimentation rates (P less than or equal to 0.05). These data suggest that there is a subset of rheumatoid arthritis patients in whom clinical improvement with nonsteroidal antiinflammatory drug therapy is associated with significant reductions in IgM rheumatoid factor and CRP levels.

Bimodal release of ibuprofen in a sustained-release formulation: a scintigraphic and pharmacokinetic open study in healthy volunteers under different conditions of food intake

The position of a radiolabelled sustained release ibuprofen formulation containing 800 mg drug and labelled by the addition of 10 mg [ 111In] ion-exchange resin has been followed by gamma scintigraphy in 11 healthy male and female volunteers. The study was conducted first in 5 volunteers who received the tablet with a light breakfast and then as a cross-over study in a separate group of 6 volunteers who had either fasted or ingested a heavy breakfast. Mean times ( ± S.D.) for gastric emptying of the unit were 1.0 ± 0.4 h (fasted, n = 6), 2.0 ± 0.9 h (light breakfast, n = 5) and 8.8 ± 5.9 h (heavy breakfast, n = 4). There were no significant was observed to remain intact until it reached the ascending and transverse colon where it broke into two or three pieces or completely disintegrated. In two subjects, in which the tablet had been administered with a heavy meal, the unit remained in the stomach for more than 15 h. The presence of food markedly altered the pharmacokinetics of the drug which, in fasting subjects, was characterised by a double peak in the plasma concentration time profile. The light breakfast caused a levelling of the two peaks to a plateau lasting from 4 to 13 hours, whereas after the heavy breakfast only the secondary peak was evident. The secondary peak appears to be due to a disintegration of the matrix after 12–14 h coupled with a high absorptive capacity for the drug in the ascending colon. There was no evidence of adhesion of the unit to the gastrointestinal mucosa.