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Synthesis, chromatographic resolution and chiroptical properties of carboxyibuprofen stereoisomers: major metabolites of ibuprofen in man.

Tan SC, Baker JA, Stevens N, deBiasi V, Salter C, Chalaux M, Afarinkia K, Hutt AJ.

Department of Pharmacy, King's College London, United Kingdom.

The chromatographic resolution of the four stereoisomers of carboxy-ibuprofen, a major metabolite of ibuprofen in man, was achieved using a Chiralpak AD chiral stationary phase (CSP) (J.T. Baker, Milton, Keynes, UK). The elution order of the stereoisomers was determined to be 2'S,2R;2'R,2R;2'R,2S;2'S,2S by a combination of stereoselective synthesis of diastereoisomeric mixtures and analysis of the two diastereoisomers isolated from human urine following the administration of (S)-ibuprofen. The individual stereoisomers were isolated by semipreparative chiral phase chromatography and characterized by circular dichroism spectroscopy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9094205&dopt=Abstract ibuprofen Motrin



Motrin
Ultralow concentrations of ibuprofen activate cell prostaglandin synthesis.

Sergeeva MG, Gonchar MV, Chistyakov VV, Mevkh AT.

A. N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Russia.

The interest in the prostaglandin (PG) synthesis by animal cells today grows steadily because of the difficulties in obtaining them by any other way. Murine peritoneal macrophages can under certain conditions synthesize large amounts of PGs. The effect of well-known nonsteroidal anti-inflammatory drug ibuprofen on PG synthesis by the cells using a high-performance liquid chromatography (HPLC) method with fluorescence detection of 4-bromomethyl-7-methoxy-coumarin (BrMMC) derivatives was studied. In our case, the main metabolites were PGE2 and PGF2a. The PG synthesis activation effect was shown by ibuprofen concentrations in the 10(-10)-10(-14) M range with the maximum effect of 10(-12)M. In this case, the ibuprofen effect was comparable in value with the effect of well-known cell PG synthesis activator--calcium ionophore A23187. Although the exact mechanism of such an effect is not clear at the moment, at low concentration, ibuprofen itself is able to activate PG synthesis in murine peritoneal macrophages.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9100354&dopt=Abstract ibuprofen Motrin



Motrin
High-performance thin-layer chromatographic determination of ibuprofen in plasma.

Save TK, Parmar DV, Devarajan PV.

Department of Chemical Technology, University of Mumbai, Matunga, India.

A high-performance thin-layer chromatographic (HPTLC) method for quantitation of ibuprofen from plasma is described. The drug was extracted from acidified plasma with hexane-isopropanol (85:15). The mobile phase composition was n-hexane-ethyl acetate-anhydrous acetic acid (75:25:2). Densitometric analysis of ibuprofen was carried out at 222 nm. The calibration curves of ibuprofen in chloroform and in plasma were linear over the range 2-20 micrograms. The mean values of intercept, slope and correlation coefficient were 0.0422 +/- 0.0018. 1.0356 +/- 0.0213 and 0.9976 +/- 0.0013 for standard curves in chloroform and 0.1044 +/- 0.003, 0.8759 +/- 0.0213 and 0.9939 +/- 0.001 for standard curves in plasma, respectively. The limit of detection of ibuprofen from human plasma (assay sensitivity) was 50 ng and no interference was found from endogenous compounds. The recovery of ibuprofen from human plasma using the described extraction procedure was about 85%. The mean relative standard deviations for within-day and between-day analyses were 2.24 and 2.6% for 5 micrograms and 3.67 and 3.2% for 15 micrograms ibuprofen concentration, respectively. The method was utilized to monitor the plasma concentration of ibuprofen post administration of sustained release capsules in human patient volunteers.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9106058&dopt=Abstract ibuprofen Motrin



Motrin
Lipid nanocarriers as drug delivery system for ibuprofen in pain treatment.

Lamprecht A, Saumet JL, Roux J, Benoit JP.

INSERM ERIT-M 0104, Universite d'Angers, France. Alf.Lamprecht pharma.uhp-nancy.fr

Due to their small size, lipid nanocapsules (LNC) might be promising for an injectable as well as for an oral drug delivery system, providing both sufficient drug solubility avoiding vessel embolisation for the intravenous injection and a positive effect of drug absorption after oral administration. Biocompatible ibuprofen LNC were developed in a size range of around 50 nm with a new preparation method. Drug incorporation into LNC was successful to a high degree in all formulations tested (94-98%) and the in vitro drug release in phosphate buffer occurred within 24 h. Pharmacokinetic data were recorded in vivo from rats after intravenous or oral administration, while the antinociceptive efficiency of the LNC formulation was compared with ibuprofen solution by the tail flick test. The AUC and half-life of intravenously injected ibuprofen LNC were found to be 16 and 19%, respectively, higher than a simple drug solution, while the mean residence time was not changed. Oral administration of LNC showed an 18% increase of AUC and a 27% higher mean residence time. The antinociceptive effect was similar for oral administration, drug solution, and LNC at 30 min after administration, and was prolonged up to 4 h in the LNC group. The pain relief after intravenous administration was prolonged when administering LNC formulation for at least 2 h. A drug delivery system for intravenous administration of ibuprofen has been developed which exhibits sustained release properties by either oral or intravenous route and may be interesting in the treatment of postoperative pain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15196644&dopt=Abstract ibuprofen Motrin



Motrin
Chemical, dissolution stability and microscopic evaluation of suspensions of ibuprofen and sustained release ibuprofen-wax microspheres.

Adeyeye CM, Price JC.

Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania, USA.

Chemical stability studies of suspensions of ibuprofen powder and ibuprofen-wax microspheres were performed using an accelerated stability protocol with a modified high performance liquid chromatography (HPLC) procedure. The variables considered were pH, suspending agents and temperature. The study showed little or no chemical degradation in the different suspending agents after storage for three months. Dissolution stability was examined in suspensions of ibuprofen microspheres made from an optimized formulation with 17% drug loading. The storage temperature were 23, 37 and 45 degrees C. Other variables for the dissolution stability studies were suspending agents, wax types, suspending medium pH and microsphere size. Suspensions of ceresine wax microspheres stored at 37 degrees C showed faster drug release than room temperature storage, but suspensions stored at 45 degrees C showed an opposite effect. Microspheres suspended in syrup and stored at 37 degrees C had faster dissolution rates than microspheres suspended in methylcellulose at the same temperature, possibly as a result of an interaction between the syrup and the microsphere constituents. Suspensions of microcrystalline wax microspheres had better dissolution stability than microspheres made from ceresine wax. Higher suspending medium pH resulted in faster release of drug from the suspended microspheres, but particle size did not significantly affect the dissolution stability.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9147285&dopt=Abstract ibuprofen Motrin



Motrin
Lymph distribution of different non-steroidal anti-inflammatory drugs assessed by microsurgical cannulation of the thoracic duct in rat.

Ionac M, Oelkers R, Brune K, Geisslinger G, Bordos D.

2nd Surgical Clinic, University of Medicine and Pharmacy, Timisoara, Romania.

The motility of lymphatic vessels is regulated by arachidonate metabolites and, therefore, can be altered by cyclo-oxygenase blockers such as non-steroidal anti-inflammatory drugs (NSAIDs). In order to investigate the lymphotropic properties of different NSAIDs, pharmacokinetics in plasma and lymph following intragastric administration of three model compounds, namely racemic ibuprofen, tenoxicam and nabumetone, were investigated in rats. Microsurgical cannulation of the thoracic duct allowed cumulative sampling of lymph fluid up to 48 hrs (n = 16). Pharmacokinetic parameters in plasma were determined in a control group (n = 12). Concentrations of R-, S-ibuprofen, tenoxicam, nabumetone and the metabolites OH-ibuprofen, COOH-ibuprofen and 6-methoxy-2-naphthyl-acetic acid (6MNA, metabolite of nabumetone) were monitored in lymph and plasma by HPLC. To quantify the lymphotropic properties of the investigated compounds, a "lymphatic clearance" was defined by dividing the amount recovered in lymph fluid by the corresponding area under the plasma concentration-time curve (AUCP). The "lymphatic clearance" substantially differed between the investigated compounds (mean +/- SD: R-ibuprofen 6.71 +/- 3.15 microliters/min, S-ibuprofen 3.24 +/- 1.20 microliters/min, tenoxicam 8.74 +/- 8.11 microliters/min, nabumetone 46.05 +/- 26.08 microliters/min and 6MNA 6.32 +/- 2.96 microliters/min). The overall recovery of the investigated compounds in lymph did not exceed 5% of the doses given. The known fact that lymphatic drainage is regulated by arachidonate metabolites might suggest that NSAIDs differing in their lymphotropic properties could result in different responses of lymphatic vessels to an inflammatory fluid load.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9167225&dopt=Abstract ibuprofen Motrin



Motrin
Topical administration of racemic ibuprofen.

Millership JS, Collier PS.

School of Pharmacy, Queen's University of Belfast, Northern Ireland.

In vitro experiments to investigate possible stereoselective aspects of the topical administration of ibuprofen have been conducted. Incubation of ibuprofen with rat skin homogenates in the presence of coenzyme A, ATP, and magnesium provided no evidence for the formation of ibuprofenyl coenzyme A (the initial intermediate in the metabolic inversion of [R]- to [S]-ibuprofen). Similar incubation studies gave no indication of a change in the enantiomeric ratios of ibuprofen over the time course of the experiments. Percutaneous penetration studies of ibuprofen gel through porcine skin indicated that the ibuprofen enantiomer levels in the reservoir solutions were consistent with racemic ibuprofen having traversed the skin with no metabolic inversion. These results suggest that, in the models studied, skin metabolism does not result in the chiral inversion of (R)- to (S)-ibuprofen and that the topical administration of ibuprofen will result in the delivery of 50% "isomeric ballast."

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9176998&dopt=Abstract ibuprofen Motrin



Motrin
Stereospecific formulation and characterization of sustained release ibuprofen microspheres.

Janjikhel RK, Adeyeye CM.

Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA.

Ibuprofen microspheres were prepared from the racemate, (+)-S and (-)-R enantiomers using waxes such as ceresine and glyceryl stearate and stereospecifically characterized. The method of preparation of the microspheres was a hydrophobic congealable 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) naphthylethylamine 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 microns respectively while that of the racemate was 48 microns. Differential Scanning Calorimetry (DSC) of ibuprofen and the enantiomers showed endothermic peaks at 72 and 55 degrees 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 recemate 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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9229341&dopt=Abstract ibuprofen Motrin