Chondroitin Sulfate–Glycyl-Prednisolone Conjugate as Arthritis Targeting System: Localization and Drug Release in Inflammatory Joints

Abstract

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.

Preparation of Chondroitin Sulfate-Glycyl-Prednisolone Conjugate Nanogel and Its Efficacy in Rats with Ulcerative Colitis

“…However, each conjugate dissolved in a mixture of water and an organic solvent such as THF. As reported previously, 20) the CS-GP conjugate, produced under the formulation of CS (120 mg), GP (15 mg), NHS (300 mg), and WSC (500 mg), had a PD content of only 1.4% (w/w) and was water-soluble. On the other hand, conjugates with a PD content of more than 3-4% (w/w) appeared to give a suspension in water, in which the suspension particles showed a submicron size.…”

“…In Vitro Release Release profiles in PBS at 37°C were examined for NG(I) and NG(II). Results were compared with previous findings obtained from CS-GP solution, 20) prepared using CS-GP with a PD content of 1.4% (w/w) (Fig. 4).…”

“…1. 20,29) In the first step, GP was synthesized as an intermediate compound. The Tr-G ester of PD, named Tr-GP, was synthesized as follows.…”

“…This conjugate enhanced the therapeutic efficacy of treatments in animal models of rheumatoid arthritis. 20) Furthermore, CS-GP functioned as a macromolecular prodrug of PD and promoted its localization to inflammatory sites. 21) In those studies, CS-GP with a low drug content of 4% was used and mostly dissolved in saline.…”

Preparation and evaluation of conjugate nanogels of glycyl-prednisolone with natural anionic polysaccharides as anti-arthritic delivery systems

“…As these polymers are highly water-soluble, their conjugates with PD were considered to form the NGs due to the hydrophobicity of PD. As to previously reported CS-GP, the water-soluble type of CS-GP, injected intravenously, was eliminated fairly rapidly from the blood circulation, resulting in the fact that it did not exhibit so prolonged anti-inflammatory effects (Onishi et al, , 2014; though the NG type of CS-GP was not tested. CS itself was reported to undergo a fairly rapid systemic clearance and degradation.…”