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In Situ Forming Injectable Hydrogel For Encapsulation Of Nanoiguratimod And Sustained Release Of Therapeutics

Authors Ma Z, Tao C, Sun L, Qi S, Le Y, Wang J, Li C, Liu X, Zhang J, Zhao J

Received 5 May 2019

Accepted for publication 21 October 2019

Published 6 November 2019 Volume 2019:14 Pages 8725—8738


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Mian Wang

Zhenzhen Ma,1,* Cheng Tao,2,* Lin Sun,1 Shengbei Qi,2 Yuan Le,2,3 Jiexin Wang,2–4 Changhong Li,1 Xiangyuan Liu,1 Jianjun Zhang,2 Jinxia Zhao1

1Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100191, People’s Republic of China; 2College of Chemical Engineering, Beijing University of Chemical Technology, Beijing 100029, People’s Republic of China; 3Research Center of the Ministry of Education for High Gravity Engineering and Technology, Beijing University of Chemical Technology, Beijing 100029, People’s Republic of China; 4Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Jianjun Zhang; Jinxia Zhao Email;

Background: Iguratimod (IGUR) is a novel disease-modifying antirheumatic drug used for treating rheumatoid arthritis (RA). To improve its bioavailability and to alleviate gastrointestinal side effects, we changed the formulation into nanoiguratimod-loaded hydrogel (NanoIGUR-loaded hydrogel) composites for sustained release of therapeutics.
Methods: IGUR was first encapsulated in biodegradable polyvinyl alcohol micelle by liquid antisolvent precipitation (LAP) technology, and then loaded into an in situ injectable hyaluronic acid hydrogel, which was cross-linked by PEG (Thiol)2 (HS-PEG-SH) through Michael addition reaction. In vitro, the biological effects (proliferation, migration, and invasion) of NanoIGUR-loaded hydrogel on fibroblast-like synoviocytes (RA-FLS) from RA patients were evaluated. In vivo, the pharmacokinetics of NanoIGUR-loaded hydrogel was assessed and the efficacy of NanoIGUR-loaded hydrogel in treating collagen-induced arthritis (CIA) rats was evaluated.
Results: By the LAP technique, we acquired the amorphous form nanoiguratimod, with an average size of 458 nm, which had higher dissolution rates and higher stability. The release of IGUR from hydrogel composite in PBS was gradual and sustained for up to 72 hrs compared with nanoiguratimod. Different concentrations of NanoIGUR-loaded hydrogel inhibited the proliferation, migration, and invasion of RA-FLS. The pharmacokinetic parameters showed better bioavailability and longer half-life time with NanoIGUR-loaded hydrogel by subcutaneous administration than oral raw iguratimod. Animal experiments confirmed that subcutaneous injection of NanoIGUR-loaded hydrogel (10 mg/kg every 3 days) and oral raw iguratimod (10mg/kg daily) showed similar efficacy in decreasing arthritis index score, pathological score, and expression of inflammatory cytokines.
Conclusion: Overall, we demonstrate that NanoIGUR-loaded hydrogel provides a new route of administration and extends the administration interval. It could be a promising drug-delivery approach in the management of RA.

Keywords: iguratimod, nanoparticles, injectable hydrogel, rheumatoid arthritis, drug sustained-release system

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