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<p>Mesalamine (MES) remains a first-line therapy for the treatment of inflammatory bowel disease; however, its clinical use is limited by poor aqueous solubility in the colon, high dose requirements, variable pharmacokinetics, pill burden, and patient non-compliance. This study aimed to develop and optimise MES nanocrystals (MES NCs) using a top-down ball milling approach using a stabiliser Hydroxypropyl methylcellulose acetate succinate (HPMC-AS). Thirteen different batches were formulated to assess the effects of speed and time of milling, and polymer concentration on particle size, polydispersity index (PDI), morphology, crystallinity, thermal properties, and dissolution. The B11 batch was evaluated for its biological activity using PMA-differentiated THP 1 cell line treated with LPS using inflammatory markers: IL-4, IL-6, TNFα, and TGF-β. The first reproducibility batches (0.1/400/40; B9-B15) exhibited an intra-batch average particle size of 537.3 ± 139.2&#xa0;nm with a PDI of 0.5 ± 0.1. SEM analysis confirmed a uniform plate-like morphology. PXRD analysis revealed partial peak shifts and broadening, suggesting lattice strain in the milled NCs. Dissolution studies demonstrated pH-dependent release of MES-NCs. FTIR confirmed drug-polymer compatibility. Cytotoxicity testing in PMA-differentiated THP-1 macrophage-like cells showed &gt; 64% cell viability at therapeutic MES NC concentrations up to 2.5&#xa0;µM. Type 2 cytokines (IL-4), typically induced by LPS in the late phase, showed a time-dependent response, further supporting the immunomodulatory effect of MES NCs. The B11 batch significantly increased TGF-β expression compared with the disease group, suggesting activation of regulatory anti-inflammatory pathways with M2 macrophage polarisation.</p> Graphical Abstract <p></p>

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Process Optimisation, Pharmaceutical Characterisation, and in vitro Activity of Mesalamine Nanocrystals in PMA-differentiated THP-1 cell Lines in the Late Inflammatory and Profibrotic Phase

  • 期刊论文

  • 发表日期：

    2026年1月29日

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  • Sonam Sharma,
  • Sakshi Kunjir,
  • Sadhana Dhyagala,
  • Abhishek Sahu,
  • Subramanian Natesan,
  • Rajkumar Malayandi

摘要

Mesalamine (MES) remains a first-line therapy for the treatment of inflammatory bowel disease; however, its clinical use is limited by poor aqueous solubility in the colon, high dose requirements, variable pharmacokinetics, pill burden, and patient non-compliance. This study aimed to develop and optimise MES nanocrystals (MES NCs) using a top-down ball milling approach using a stabiliser Hydroxypropyl methylcellulose acetate succinate (HPMC-AS). Thirteen different batches were formulated to assess the effects of speed and time of milling, and polymer concentration on particle size, polydispersity index (PDI), morphology, crystallinity, thermal properties, and dissolution. The B11 batch was evaluated for its biological activity using PMA-differentiated THP 1 cell line treated with LPS using inflammatory markers: IL-4, IL-6, TNFα, and TGF-β. The first reproducibility batches (0.1/400/40; B9-B15) exhibited an intra-batch average particle size of 537.3 ± 139.2 nm with a PDI of 0.5 ± 0.1. SEM analysis confirmed a uniform plate-like morphology. PXRD analysis revealed partial peak shifts and broadening, suggesting lattice strain in the milled NCs. Dissolution studies demonstrated pH-dependent release of MES-NCs. FTIR confirmed drug-polymer compatibility. Cytotoxicity testing in PMA-differentiated THP-1 macrophage-like cells showed > 64% cell viability at therapeutic MES NC concentrations up to 2.5 µM. Type 2 cytokines (IL-4), typically induced by LPS in the late phase, showed a time-dependent response, further supporting the immunomodulatory effect of MES NCs. The B11 batch significantly increased TGF-β expression compared with the disease group, suggesting activation of regulatory anti-inflammatory pathways with M2 macrophage polarisation.

Graphical Abstract