Motrin
Interactions of ibuprofen with cationic polysaccharides in aqueous dispersions and hydrogels. Rheological and diffusional implications.

Rodriguez R, Alvarez-Lorenzo C, Concheiro A.

Departamento de Farmacia y Tecnologia Farmaceutica, Facultad de Farmacia, Universidad de Santiago de Compostela, Santiago de Compostela 15782, Spain.

Non-steroidal antiinflammatory drugs, such as ibuprofen, are amphiphilic substances capable of self-association in aqueous solutions and able to be sorbed onto polymers through hydrophobic and electrostatic bonds. The aim of this work was to analyze the association processes of sodium ibuprofen with cationic celluloses (Celquat H-100 (PQ-4) and SC-230 M (PQ-10)) and cationic guar gums (Ecopol 261-S and 14-S) and their repercussions on the properties of the aqueous dispersions and cross-linked hydrogels. The interaction process was studied in aqueous dispersions through transmittance, surface tension, fluorescence, conductivity, viscosity and oscillatory rheometry measurements. Below cmc, the drug molecules weakly interact with the polymers through hydrophobic and ionic interactions. Around the cmc (4%), a notable decrease in the viscosity, and storage and loss moduli of the dispersions (even precipitation in PQ-10 systems) was observed. An additional increase in drug concentration induced the dispersions to recover their initial properties. Since ibuprofen/polymer cationic groups ratio were in all cases above 1, these observations indicate that drug self-association induces the polymer to coil around the micelles and, as the number of micelles increases (more drug concentration) the polymer chains interact with more of them, uncoiling again to some extent. Polymer (1%) dispersions containing 6% ibuprofen showed drug diffusion coefficients much lower than in water. When a surfactant, sodium dodecylsulfate, was added to these systems the diffusion coefficients decreased even more, suggesting the formation of new associative structures. Chemically cross-linked hydrogels made of these cationic polysaccharides absorb considerable amounts of ibuprofen (up to 15 g/g) and showed a pH-dependent release process. At acidic pH, drug-polymer affinity is maintained, preventing drug release. In contrast, at pH 8 the interactions are broken and the release process is sustained for more than 4h. In summary, ibuprofen interactions with cationic polysaccharides strongly determine the performance of their aqueous dispersions and hydrogels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14659487&dopt=Abstract ibuprofen Motrin



Motrin
Effects of nonsteroidal antiinflammatory drugs on renal plasma flow and glomerular filtration rate in patients with glomerulonephritis.

Stosic Z, Sedlak V, Curic S, Felle D, Budakov P, Tepavcevic P.

Department of Nephrology and Clinical Immunology, Faculty of Medicine, Novi Sad.

We investigated the effects of NSAIDs (Ibuprofen) on renal plasma flow (RPF) and glomerular filtration rate (GFR) in patients with glomerulonephritis. The study included 98 patients (53 men and 45 women) with idiopathic glomerulonephritis. All of the patients received Ibuprofen 1200 mg (3x400) during 7 days. Before and after the treatment with Ibuprofen ERPF (clearance of 131I-Hippuran) and GFR (clearance of 99mTc-DTPA) were determined. In our patients administration of Ibuprofen was associated with a significant reduction in renal plasma flow and glomerular filtration rate. In patients with reduced renal function the decrease in RPF and GFR after Ibuprofen was significantly greater than in patients with normal renal function.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8569600&dopt=Abstract ibuprofen Motrin



Motrin
Effects of age and dose on the pharmacokinetics of ibuprofen in the rat.

Satterwhite JH, Boudinot FD.

Department of Pharmaceutics, College of Pharmacy, University of Georgia, Athens 30602.

The pharmacokinetics of ibuprofen after 2.5 and 25 mg/kg doses were examined in young adult (5 months) and senescent (24 months) male Fischer 344 rats. Plasma concentrations of ibuprofen were determined by HPLC and protein binding was measured by equilibrium dialysis. The cytochrome P-450-mediated metabolism of ibuprofen was investigated in vitro using microsomal protein from rat liver as the source of drug-metabolizing enzymes. Dose had a marked effect on the disposition of ibuprofen, with free plasma clearance (CLfree) decreasing 40% and apparent free steady-state volume of distribution (Vssfree) decreasing 58% as dose increased from 2.5 to 25 mg/kg. These changes reflected saturation of elimination pathways and tissue-binding sites. The binding of ibuprofen to plasma proteins was dependent on drug concentration. Unlike the parameters based on free ibuprofen concentrations, there were no significant changes in total plasma clearance (CL) or steady-state volume of distribution (Vss) due to the nonlinear protein binding. Aging also had a significant effect on ibuprofen pharmacokinetics. Decreases in CLfree and Vssfree of 42 and 51%, respectively, suggested a reduction in metabolic activity and binding of ibuprofen to tissue components in the aged rats. A decrease in plasma protein binding in the old rats was related to decreases in albumin concentration and the number of albumin binding sites. Thus, due to the greater free fraction of ibuprofen in the plasma of aged rats, CL increased significantly, whereas Vss remained unaffected by age when total plasma concentrations were examined. The metabolic capacity exhibited an age-related decline of 42%, whereas the affinity of the metabolic enzymes for ibuprofen was unaffected by age.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1673423&dopt=Abstract ibuprofen Motrin



Motrin
Mechanistic studies on the metabolic chiral inversion of R-ibuprofen in the rat.

Sanins SM, Adams WJ, Kaiser DG, Halstead GW, Hosley J, Barnes H, Baillie TA.

Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.

Deuterium labeling techniques and stereoselective GC/MS methodology have been employed to investigate the mechanism by which R-ibuprofen undergoes metabolic chiral inversion in the rat in vivo. Following oral administration of a mixture of R-ibuprofen (7.5 mg kg-1) and R-[ring-2H4; 2-2H]ibuprofen (R-[2H5]ibuprofen) (7.5 mg kg-1) to male Sprague-Dawley rats, the enantiomeric composition and deuterium excess of the drug were determined in serial plasma samples and in pooled urine collected over 10 hr. The results demonstrate that: (i) R-ibuprofen undergoes extensive inversion of configuration to its S antipode in the rat; (ii) chiral inversion of R-[2H5]ibuprofen yields S-[2H4]ibuprofen in a process that involves quantitative loss of the deuterium atom present originally at C-2; (iii) labeling of R-ibuprofen with deuterium at C-2 does not introduce a measurable kinetic deuterium isotope effect on the chiral inversion reaction; and (iv) metabolism of R-[2H5]ibuprofen leads to the appearance in plasma and urine of molecules of R-ibuprofen labeled with 4 atoms of deuterium. On the basis of these findings, a mechanism is proposed for the chiral inversion reaction that invokes the stereoselective formation of the coenzyme A thioester of R-ibuprofen as a key metabolite; conversion of this species to the corresponding enolate tautomer affords a symmetrical intermediate through which racemization of ibuprofen occurs in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1676645&dopt=Abstract ibuprofen Motrin



Motrin
An evaluation of ibuprofen bioinversion by simulation.

Romero AJ, Rackley RJ, Rhodes CT.

Department of Pharmaceutics, University of Rhode Island, Kingston.

Using a pharmacokinetic model recently proposed to explain ibuprofen disposition in man, plasma concentrations of pure ibuprofen enantiomers were simulated following oral administration of (-)-(R)-ibuprofen, (+)-(S)-ibuprofen, or rac-ibuprofen. Simulated and literature values for AUC's were used to compare S/R ratios for different cases of the model and for different methods of calculating the fraction of R bioinverted to S. Numerical simulation using STELLA confirmed previous results for different cases of bioinversion. Simulated S/R AUC ratios, for administration of the racemate, ranged from 4.0 (presystemic bioinversion) to 1.66 (systemic bioinversion). Literature values for S/R AUC ratios averaged 1.53 +/- 0.2 for administration of the racemate; therefore, systemic bioinversion was concluded to be representative of ibuprofen disposition. Additional simulations of S/R AUC ratios, for administration of (-)-(R)-ibuprofen only, ranged from 1.5 (presystemic bioinversion) to 0.66 (systemic bioinversion). Literature values for S/R AUC ratios averaged 0.50 +/- 0.9 for administration of (-)-(R)-ibuprofen only, which again supported conclusions of systemic bioinversion. Using different equations for estimation of fraction of R inverted to S (FR----S), results based on simulated data were identical; however, FR----S values based on literature data were different. Therefore, assumptions made for different FR----S equations do not appear to be rigorous. Calculations of FR----S, based on literature data, averaged 0.52 overall, indicating bioavailability of (+)-(S)-ibuprofen may be similar for a 150 mg dose of (+)-(S)-ibuprofen compared to a 200 mg dose of racemate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1756097&dopt=Abstract ibuprofen Motrin



Motrin
Influence of different sources on the processing and biopharmaceutical properties of high-dose ibuprofen formulations.

Romero AJ, Lukas G, Rhodes CT.

Department of Pharmaceutics, University of Rhode Island, Kingston 02881.

It is known that depending on the manufacturing and synthetic processes, drugs may exist as different forms. As a result, physicochemical properties, compression characteristics, intrinsic dissolution and bioavailability may vary substantially. The purpose of this study was to investigate the effect of different sources of ibuprofen on the processing of tablets and on their properties. Another emphasis of this work was to rationalize one or several key characteristics of the raw material as directly related to wet granulation parameters and to the behavior of final tablets. Commercially available ibuprofen was obtained from different manufacturers and a preformulation program, including X-ray crystallography, differential scanning calorimetry, scanning electron microscopy, determination of particle size distribution and flowability, was performed to characterize the raw material. Granules were prepared with a planetary mixer and liquid requirements for the end point were obtained by monitoring power consumption. Tablets were manufactured on Stokes rotary and single punch instrumented presses. Data acquisition interfaces produced compression data for each formulation. Granules and final tablets were analyzed for hardness, dissolution profiles and content uniformity. Statistical evaluations using analysis of variance and multiple comparison procedures were performed on the results to determine the significance of the variability between independent parameters. The ibuprofen tested was found to be a unique polymorphic form with some differences in the external crystallinity. The particle size characteristics of the material also allowed a differentiation between sources and although there was no differences in dissolution patterns or content uniformity, particle size was found to account for 50% of the variability in tablet hardness. Two sources of ibuprofen with lower mean particle size showed significant variations in end point liquid requirements resulting in variable tablet crushing strength.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1758891&dopt=Abstract ibuprofen Motrin



Motrin
Effect of low-molecular casein and gelatin on absorption of ibuprofen after oral and rectal administration.

Kimura S, Imai T, Otagiri M.

Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.

Kneaded mixture of ibuprofen with low-molecular gelatin or casein (LM gelatin or LM casein) was prepared, and their in vitro dissolution, release from suppository base and in vivo absorption behaviours were examined. The dissolution rate of ibuprofen from the kneaded mixtures was markedly higher than that of the drug itself. The LM gelatin and LM casein also enhanced the release rate of ibuprofen from suppository base. After oral administration of the kneaded mixture with LM gelatin to beagle dogs, the initial serum concentration was higher than that of the drug alone. On the other hand, LM casein accelerated the absorption of ibuprofen from rectum. However, LM gelatin and LM casein did not affect the bioinversion of R(-)- to S(+)-ibuprofen.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1758897&dopt=Abstract ibuprofen Motrin



Motrin
Effects of metoxibutropate, ibuprofen and guaiacol on the gastrointestinal system.

Fossati A, Vimercati MG, Bozzi M, Passarotti C, Bandi GL, Formenti A.

Research and Development, Formenti Pharmaceutical Co., Origgio, Italy.

In previous studies we have shown that ibuprofen, guaiacol and the guaiacol ester of ibuprofen (I.N.N. metoxibutropate) are able to inhibit in-vitro prostaglandin synthesis. In the present study we have evaluated the effect of ibuprofen, guaiacol and metoxibutropate on the gastrointestinal system. Oral treatment with equimolar increasing doses of the three drugs produced a progressive inhibition of prostaglandin biosynthesis in the intestinal tract, without any effect on the rate of intestinal propulsion. Further studies evaluated the gastric tolerance of a molar dose of ibuprofen causing ulceration in 50% of the animals. After single and repeated administration of guaiacol and of the guaiacol ester of ibuprofen, the percentage of animals with gastric damage was very low and the index of ulceration seemed rather moderate. Our results show that although guaiacol is able to inhibit prostaglandin biosynthesis like a classic NSAID, it does not induce gastric damage. For these reasons it is justified to combine guaiacol with ibuprofen in order to reduce gastric erosions induced by a classic antiinflammatory drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1889963&dopt=Abstract ibuprofen Motrin