Nanocrystals of a potent p38 MAPK inhibitor embedded in microparticles: Therapeutic effects in inflammatory and mechanistic murine models of osteoarthritis

JOURNAL OF CONTROLLED RELEASE

卷:276

Article

Maudens, Pierre¹  Seemayer, Christian Alexander²  Pfefferle, Francois³  Jordan, Olivier¹  Allemann, Eric¹ 

[1] Univ Lausanne, Univ Geneva, Sch Pharmaceut Sci, CH-1211 Geneva 4, Switzerland

[2] Idorsia Pharmaceut Ltd, Dept Clin Sci, CH-4123 Allschwil, Switzerland

[3] Debiopharm Res & Mfg, CH-1920 Martigny, Switzerland

关键词: PH-797804;    Biodegradable microparticles;    Nanocrystals;    Inflammatory and mechanistic mouse models;    Osteoarthritis;    Intra-articular administration;    Extended drug delivery;    p38 alpha/beta MAPK inhibitor;   

DOI  :  10.1016/j.jconrel.2018.03.007

来源: Elsevier

【 摘 要 】

This study aimed to formulate nanocrystal-polymer particles (NPPs) containing the potent p38 alpha/ss MAPK inhibitor PH-797804 (PH-NPPs) and to test their extended-release properties over months in comparison to those of conventional PH microparticles for the intra-articular treatment of inflammatory and mechanistic murine models mirroring aspects of human osteoarthritis (OA). The steps of the study were (i) to formulate PH nanocrystals (wet milling), (ii) to encapsulate a high payload of PH nanocrystals in fluorescent particles (spray drying), (iii) to assess in vitro drug release, (iv) to evaluate PH-NPP toxicity to human OA synoviocytes (MTT test), (v) to investigate the in vivo bioactivity of the particles in mice in an inflammatory antigen-induced arthritis (AIA) model (using histology and RT-qPCR) and (vi) to investigate the in vivo bioactivity of the particles in the OA model obtained by mechanistic surgical destabilization of the medial meniscus (DMM) (using histology, micro-CT, and multiplex ELISA). The PH nanocrystals stabilized with vitamin E TPGS had a monomodal size distribution. The PH-NPPs had a mean diameter of 14.2 mu m and drug loading of similar to 31.5% (w/w), and similar to 20% of the PH was released over 3 months. The NPPs did not exhibit toxicity to cultured human OA synoviocytes at 100xIC(50). Finally, in vivo studies showed good retention of PH-NPPs in the joint and adjacent tissues for up to 2 months, and the PH-NPPs exhibited good functional relevance by significantly reducing inflammation and joint destruction and by inhibiting several biomarkers (e.g., IL-1 ss). In conclusion, local treatment with PH-NPPs, used as an extended-release drug delivery system, improved inflammation and joint degradation in two distinct mouse models, indicating treatment potential for human OA.

【 授权许可】

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