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<p><i>Ketotifen fumarate</i> is very effective in treating ocular conditions like allergic conjunctivitis. However, its clinical effectiveness is limited by rapid washout, frequent dosing, and poor bioavailability.&#xa0;This study developed a&#xa0;<i>ketotifen fumarate</i>-loaded&#xa0;<i>in situ</i>&#xa0;forming subconjunctival injectable implant (<i>ISFSI</i>) for use in large animal species such as horses and alpacas.&#xa0;<i>ISFSIs</i>&#xa0;were formulated by dispersing&#xa0;<i>ketotifen fumarate</i>&#xa0;in&#xa0;<i>polylactide-co-glycolide</i>&#xa0;(<i>PLGA</i>) combined with different release retarders (<i>Kolliphor</i><sup>®</sup>&#xa0;RH 40,&#xa0;<i>Labrasol</i><sup>®</sup>, and&#xa0;<i>Maisine</i><sup>®)</sup>, then characterized for visual appearance, viscosity, solidification time, and <i>in vitro</i>&#xa0;drug release. The changes in the release medium pH and the solidified ISFSI wet weight were monitored for up to 4&#xa0;weeks. The selected&#xa0;<i>ISFSI</i>, KFM5, was further characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and rheological behavior. The injectability of KFM5 was predicted using the power law for five different syringe and needle dimensions. Cytotoxicity was tested using the Alamar Blue assay and Calcein AM/PI staining on a human corneal epithelial cell line (HCE-T). Results showed that all&#xa0;<i>ISFSI</i>&#xa0;formulations were clear yellowish, with drug recoveries exceeding 95%, varying viscosities, and solidified upon contact with the release medium. KFM5 exhibited a triphasic drug release profile with the lowest burst release (4.91 ± 0.55%) and followed Higuchi kinetics. SEM imaging revealed a "hollow and sponge-like" structure, while DSC confirmed the crystallinity and thermal transitions of&#xa0;<i>ketotifen fumarate</i>&#xa0;within the solidified implant. Rheological analysis indicated shear-thinning fluid behavior with acceptable injection forces. Cytotoxicity assays confirmed &gt; 90% cell viability, confirming biocompatibility in the ocular tissue.</p> Graphical Abstract <p></p>

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Injectable PLGA-based In Situ Forming Subconjunctival Implant for Sustained Ocular Delivery of Ketotifen Fumarate: Formulation, Drug Release, and Biocompatibility Studies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月2日

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  • Nur Mita,
  • Xuejia Kang,
  • Pengyu Chen,
  • Oladiran Fasina,
  • Shenise Howard,
  • Anna-Catherine Bowden,
  • Richard J. McMullen Jr.,
  • Amol Suryawanshi,
  • R. Jayachandra Babu

摘要

Ketotifen fumarate is very effective in treating ocular conditions like allergic conjunctivitis. However, its clinical effectiveness is limited by rapid washout, frequent dosing, and poor bioavailability. This study developed a ketotifen fumarate-loaded in situ forming subconjunctival injectable implant (ISFSI) for use in large animal species such as horses and alpacas. ISFSIs were formulated by dispersing ketotifen fumarate in polylactide-co-glycolide (PLGA) combined with different release retarders (Kolliphor® RH 40, Labrasol®, and Maisine®), then characterized for visual appearance, viscosity, solidification time, and in vitro drug release. The changes in the release medium pH and the solidified ISFSI wet weight were monitored for up to 4 weeks. The selected ISFSI, KFM5, was further characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and rheological behavior. The injectability of KFM5 was predicted using the power law for five different syringe and needle dimensions. Cytotoxicity was tested using the Alamar Blue assay and Calcein AM/PI staining on a human corneal epithelial cell line (HCE-T). Results showed that all ISFSI formulations were clear yellowish, with drug recoveries exceeding 95%, varying viscosities, and solidified upon contact with the release medium. KFM5 exhibited a triphasic drug release profile with the lowest burst release (4.91 ± 0.55%) and followed Higuchi kinetics. SEM imaging revealed a "hollow and sponge-like" structure, while DSC confirmed the crystallinity and thermal transitions of ketotifen fumarate within the solidified implant. Rheological analysis indicated shear-thinning fluid behavior with acceptable injection forces. Cytotoxicity assays confirmed > 90% cell viability, confirming biocompatibility in the ocular tissue.

Graphical Abstract