TY - JOUR
T1 - Topical tacrolimus nanocapsules eye drops for therapeutic effect enhancement in both anterior and posterior ocular inflammation models
AU - Rebibo, Leslie
AU - Tam, Connie
AU - Sun, Yan
AU - Shoshani, Eve
AU - Badihi, Amit
AU - Nassar, Taher
AU - Benita, Simon
N1 - Publisher Copyright: © 2021 Elsevier B.V.
PY - 2021/5/10
Y1 - 2021/5/10
N2 - Tacrolimus has shown efficacy in eye inflammatory diseases. However, due to the drug lability, its formulation into a stable ophthalmic product remains a challenge. Tacrolimus-loaded nanocapsules (NCs) were designed for ocular instillation. Further, the stability and effects of the formulation were analyzed under different experimental conditions. Physicochemical characterization of the NCs revealed suitable homogeneous size and high encapsulation efficiency. Moreover, the lyophilized formulation was stable at ICH long term and accelerated storage conditions, for at least 18 and 3 months, respectively. The tacrolimus NCs did not elicit any eye irritation in rabbits after single- and multiple-dose applications. Additionally, ex vivo penetration assays on isolated porcine cornea and pharmacokinetics analyses in various rabbit eye compartments demonstrated the superiority of the NCs in retention and permeation into the anterior chamber of the eye compared to the free drug dissolved in oil. Moreover, multiple dose ocular instillation of the NCs in rats allowed high tacrolimus levels in the eye with very low plasma concentrations. Finally, the developed delivery system achieved a significant decrease in four typical inflammatory markers in a murine model of keratitis, an anterior chamber inflammation. Furthermore, these NCs, applied as eye drops, displayed clinical and histological efficacy in the mainly posterior chamber inflammation model of murine, experimental auto-immune uveitis.
AB - Tacrolimus has shown efficacy in eye inflammatory diseases. However, due to the drug lability, its formulation into a stable ophthalmic product remains a challenge. Tacrolimus-loaded nanocapsules (NCs) were designed for ocular instillation. Further, the stability and effects of the formulation were analyzed under different experimental conditions. Physicochemical characterization of the NCs revealed suitable homogeneous size and high encapsulation efficiency. Moreover, the lyophilized formulation was stable at ICH long term and accelerated storage conditions, for at least 18 and 3 months, respectively. The tacrolimus NCs did not elicit any eye irritation in rabbits after single- and multiple-dose applications. Additionally, ex vivo penetration assays on isolated porcine cornea and pharmacokinetics analyses in various rabbit eye compartments demonstrated the superiority of the NCs in retention and permeation into the anterior chamber of the eye compared to the free drug dissolved in oil. Moreover, multiple dose ocular instillation of the NCs in rats allowed high tacrolimus levels in the eye with very low plasma concentrations. Finally, the developed delivery system achieved a significant decrease in four typical inflammatory markers in a murine model of keratitis, an anterior chamber inflammation. Furthermore, these NCs, applied as eye drops, displayed clinical and histological efficacy in the mainly posterior chamber inflammation model of murine, experimental auto-immune uveitis.
KW - Auto-immune uveitis
KW - Keratitis
KW - Nanocapsules
KW - Ocular delivery
KW - Tacrolimus
UR - http://www.scopus.com/inward/record.url?scp=85103695013&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jconrel.2021.03.035
DO - https://doi.org/10.1016/j.jconrel.2021.03.035
M3 - مقالة
C2 - 33798665
SN - 0168-3659
VL - 333
SP - 283
EP - 297
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -