Therapeutic potential of phosphodiesterase inhibitor-loaded nanomicelles to treat endotoxin-induced anterior uveitis

Abstract

Uveitis is an ocular inflammatory condition that can be infectious or non-infectious, affecting various ocular structures. Corticosteroids and immunomodulators are the current standard of care for treating anterior uveitis, which has side effects such as cataracts and increased intraocular pressure. Therefore, a continuous search is going on to find an alternate strategy (steroid-sparing agent) to treat uveitis with improved safety.

Highlights

• Apremilast-loaded nanomicelles (Aprecel) show sustained drug release of over 24 h.
• In vitro and in vivo safety studies confirm the biocompatibility of the formulation.
• Aprecel has the potential to treat anterior uveitis in endotoxin-induced uveitis model.
• In vivo pharmacokinetics show the improved permeability of Aprecel in aqueous humor.

Apremilast, a phosphodiesterase-4 (PDE-4) inhibitor, has an anti-inflammatory activity, which could regulate the production of inflammatory mediators such as TNF-alpha and nitric oxide by inhibiting the conversion of cyclic adenosine monophosphate to adenosine monophosphate. A dose-inverted therapeutic effect was observed for Apremilast to treat acute anterior uveitis in an endotoxin-induced uveitis rat model. Further, to address the poor solubility and permeability, Apremilast-loaded nanomicelles (Aprecel) were developed and thoroughly characterized. Ocular pharmacokinetics study indicates that the developed nanomicelles facilitated the permeation of Apremilast across the corneal barrier due to increased solubility and residence time.

Also, an in vivo efficacy study shows that the developed Aprecel effectively reduces the cell infiltration and protein levels in the endotoxin-induced uveitis rat model, along with inflammatory cytokines such as TNF-alpha. Therefore, Apremilast-loaded nanomicelles could be used as a potential steroid-sparing alternative to treat acute anterior uveitis with reduced side effects.

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Materials

Apremilast was purchased from Tokyo Chemicals Industry (TCI) India Pvt Ltd, Hyderabad, India. Tocopheryl polyethylene glycol succinate (TPGS) was gifted from PMC Isochem (Vert-le-Petit, France). Lipopolysaccharide (LPS) from E. Coli was purchased from Sigma Aldrich (St. Louis, USA). Dialysis membrane (13 kDa), sodium chloride, potassium chloride, and sodium hydrogen carbonate were purchased from HiMedia (Mumbai, India).

Velmurugan Kailasam, Manisha Malani, Jayabalan Nirmal, Therapeutic potential of phosphodiesterase inhibitor-loaded nanomicelles to treat endotoxin-induced anterior uveitis, International Journal of Pharmaceutics, Volume 684, 2025, 126162, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.126162.

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