Some acidic nonsteroidal anti-inflammatory drugs (NSAIDs) are poorly soluble in the stomach. In this study, M-5011, d-2-[4-(3-methyl-2-thienyl) phenyl] propionic acid, was used as a model substance. To increase the dissolution rate of M-5011, a solid dispersion of M-5011 was prepared by the powder mixing method using Eudragit E-100 (aminoacryl methacrylate copolymer) as a carrier. Evaluation by X-ray diffraction and differential scanning calorimetry (DSC) revealed that M-5011 easily formed a solid dispersion with E-100. The dissolution behavior of a physical mixture prepared immediately after mixing and the mixture stored for 14 days at 40 degrees C were examined. It was observed that the former, containing a great deal of E-100, showed a fairly good dissolution behavior, and the latter had a better dissolution rate. The mechanism of the interaction of M-5011 and E-100 was investigated by infrared (IR) spectroscopy and nuclear magnetic resonance (NMR). The interaction was simulated by NMR using a monomer of Eudragit E-100.

01 Jan 1999·Japanese Journal of Pharmacology

Effect of a Novel Non-steroidal Anti-inflammatory Drug (M-5011) on Cytokine Levels in Rats With Monosodium Urate Crystal-Induced Pleurisy

Article

Author: Shizuhiko Aihara ; Takako Saito ; Kazumi Iwata ; Tomohiro Naruse ; Naofumi Murakami

We evaluated the effects of a new non-steroidal anti-inflammatory drug (NSAID), d-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid (M-5011), and indomethacin on the production of arachidonate metabolites and pro-inflammatory cytokines in male Sprague-Dawley rats with monosodium urate crystal (MSU)-induced pleurisy. Levels of tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6 in the pleural exudate were determined by biological assays, while prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and cytokine-induced chemoattractant-1 (CINC-1) levels were quantified by enzyme immunoassays. Orally administered M-5011 (5 mg/kg) decreased the pleural exudate volume at 3 and 4 hr after MSU injection. Indomethacin (10 mg/kg) decreased the volume at 3-5 hr. These drugs reduced the number of leukocytes in the pleural cavity at 6 hr. Both NSAIDs also reduced the content of PGE2 in the exudate without affecting LTB4 levels. Increased productions of both IL-6 and CINC-1 in the exudate were reduced by pretreatment with M-5011 or indomethacin, and TNF levels in the exudate were increased by pretreatment of these drugs. Thus, M-5011 inhibits the production of both IL-6 and CINC-1 at lower doses than those of indomethacin, and the inhibitory effect of M-5011 on CINC-1, but not IL-6, may partly contribute to the inhibition of leukocyte infiltration in rats with MSU-induced pleurisy.

01 Jan 1999·Drug metabolism and disposition: the biological fate of chemicals

In vivo studies on chiral inversion and amino acid conjugation of 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid in rats and dogs.

Article

Author: Kitamura, S ; Tatsumi, K ; Nishikawa, H ; Konishi, T

The relationship between chiral inversion and stereoselective amino acid conjugation of a new nonsteroidal anti-inflammatory agent, R, S-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid (R,S-MTPPA) was investigated in rats and dogs. Only the S-enantiomer was found in plasma after oral administration of S-MTPPA to both species. In contrast, the R- and S-enantiomers were both detected after the dosing of R-MTPPA. In rats, the area under the curve of S-MTPPA in plasma was only 9% of that of R-MTPPA when R-MTPPA was dosed, whereas in dogs it was 2.5 times larger than that of the R-enantiomer. After administration of R-MTPPA, both enantiomers appeared in the urine. In rats, a small amount of S-enantiomer was found in the urine, whereas in the case of dogs the amount of the S-enantiomer was larger than that of the R-enantiomer. It appears that R-MTPPA is chirally inverted to S-MTPPA in both rats and dogs, although the extent of chiral inversion is greater in dogs than in rats. In dogs, the taurine conjugate was detected in plasma, urine and feces as a major metabolite after oral administration of either R- or S-MTPPA. In this case, only S-MTPPA-taurine was detected in the urine after the administration of S-MTPPA, and it was also the main component after administration of R-MTPPA.

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Phase 3	Japan	-	-
Inflammation	Phase 3	-	Maruho Pharmaceutical	-
Osteoporosis, Postmenopausal	Phase 3	Japan	-	-
Pain	Phase 3	Japan	-	-
Pain	Phase 3	-	Maruho Pharmaceutical	-

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