New hot-melt extruded drug/polymers for sustained delivery of hydrophilic S-propargyl-cysteine in rheumatoid arthritis

Efficient embedding of highly hydrophilic drugs within poly (D, l-lactic-co-glycolic acid) (PLGA) to realize sustained release was substantially challenging. This study aimed to effectively embedding the hydrophilic low-molecular-weight compound S-propargyl-cysteine (SPRC) within PLGA to provide prolonged maintenance of SPRC both in vitro and in vivo. SPRC-loaded implants (SP-IMs) were prepared by hot melt extrusion (HME). The minor changes in lactide: glycolide (L/G) ratio, molecular weight (M_w), and PLGA endcap, as well as the slight differences in preparation parameters such as mixing methods and the drug-to-PLGA weight ratio, with or without releasing modifier, were also investigated. The findings indicated that embedding SPRC by implantation overcame the escape of SPRC to the external aqueous phase with double emulsion method, thus creating excellent release behavior both in vitro and in vivo. Both the variations in PLGA and the preparation parameters significantly affect the physicochemical characteristics and degradation rates of the PLGA matrix, and consequently, the formulation release behavior both in vitro and in vivo. Different methods of mixing SPRC with PLGA would remarkably affect the SPRC distribution, thus creating varied release profiles. Incorporation of PEG 1500 enhanced SPRC release to offer more steady drug concentration in the whole release period. After subcutaneous administration, the SP-IMs showed more steady drug plasma concentration over the whole release period in comparison with SPRC parental molecule solution. Moreover, the in vivo release behavior was essentially consistent with the in vitro SPRC release profiles. It was concluded that SP-IMs have been successfully designed with high embedding efficiency for sustained release from 1 week to 2 months for the first time and could be promising for the treatment of rheumatoid arthritis (RA).