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A conjugate between prednisolone (PD) and chondroitin sulfate (CS) with glycine as a linker was prepared in order to obtain an effective macromolecular prodrug against inflammatory disease, especially rheumatoid arthritis. First, PD was converted to the N-trityl-glycine ester (Tr-GP), and the glycine ester of PD (GP) was obtained by detritylation of Tr-GP. Then, GP and CS were condensed with water-soluble carbodiimide to yield CS-GP. The obtained conjugate had a PD content of 2.24% (w/w). Conversion characteristics were investigated for GP and CS-GP to evaluate their potential as a prodrug. In the stability test of GP, PD was released well in the buffer at pH 6-7.4, but degraded rapidly at pH 8 without sufficient release of PD. As to CS-GP, PD was released more slowly than in GP, and the release rate rose with the increase in the medium pH. PD was released gradually from CS-GP over 24 h at a physiological pH. The conversion profiles of both GP and CS-GP almost followed pseudo-first order kinetics. The calculated conversion rate constants supported the gradual and effective release from CS-GP. The release rate of PD from GP and CS-GP was accelerated by the addition of rat plasma, but the promotion of release from CS-GP was small, suggesting that PD should be released gradually from CS-GP in the systemic circulation. It was demonstrated from the preliminary pharmacological study using rats with adjuvant-induced arthritis that CS-GP had high anti-inflammatory potential against arthritis.

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Chondroitin sulfate-glycyl-prednisolone conjugate (CS-GP) was previously demonstrated to exhibit superior anti-arthritic effects compared to prednisolone (PD) alone. In this study, CS-GP was examined for its pharmacokinetic features and tropism for inflammatory joints using rats with adjuvant-induced arthritis in order to identify the mechanism of the potential enhancement. After intravenous injection (2.5 mg PD eq./ kg), CS-GP yielded an area under the curve (AUC) of the total (free conjugated) drug much higher than that of PD alone. After intravenous administration at the same dose, the drug distribution to the hind paw inflammatory joints was investigated. For PD alone, the PD concentration was 1.2-1.7 µg/g at 1 h and fell to 0.12-0.14 µg/g at 24 h. In contrast, CS-GP maintained the total concentration in the range of 0.55-0.97 µg/g for 1-24 h, and maintained the free PD concentration at 0.06-0.16 µg/g for 1-24 h. Furthermore, at 24 h after intravenous administration (2.5 mg PD eq./kg), CS-GP exhibited a higher total drug concentration in arthritic rats than in healthy rats. These findings suggested that CS-GP may have the ability to target inflammatory joints. As the apparent molecular weight of CS-GP became greater in plasma, it might interact with blood components and cause high plasma retention and good tropism to the inflammatory sites. Enhancement of the anti-inflammatory potential of CS-GP was found to be due to good maintenance of drug levels in the inflamed area.

SC-002 is a novel oral cephalosporin possessing a unique thiadiazolylethenyl moiety at the 3 position. In the present study, it was the most active against gram-positive bacteria among oral cephalosporins such as cefdinir (CFDN), cefpodoxime, cefditoren and cefaclor (CCL). It was equal to or 16 times more active than CFDN against standard and clinical strains. In particular, against clinical isolates of Morganella morganii and Haemophilus influenzae, SC-002 was 8–64 times more active than CFDN. The antibacterial activity of SC-002 against some β-lactam-resistant strains was superior to that of CFDN. The in vivo antibacterial activity of SC-004, a pivaloyloxymethyl ester of SC-002, was 1.2–8 times more protective against systemic infections due to Streptococcus pneumoniae, Escherichia coli and Klebsiella pneumoniae than that of CFDN. The therapeutic effects of SC-004 on experimental respiratory tract infections caused by S. pneumoniae or H. influenzae were superior to those of CFDN and CCL. SC-004 showed higher and longer-lasting blood levels and higher urinary excretion in pharmacokinetics in mice.