Abstract
Objective: To prepare everolimus nanoformulations and increase their solubility to suit their application in the eye. Methods: The everolimus micelles was prepared by thin film dispersion method using Tween-80 (P80) and polyoxyethylene stearate (P40S) as carriers. In addition, the everolimus nanosuspension was prepared by injection method using poloxamer 407 (P407), hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA) as stabilizers. It was characterized in terms of particle size, PDI and encapsulation efficiency or drug loading. The in vitro release and in vitro rabbit scleral permeability characteristics were investigated, and the pharmacokinetics of anterior chamber drug in rabbit eyes were studied. Results: The average particle size of the micelles was (8.74 ± 0.21) nm, the encapsulation efficiency and drug loading were (90.12 ± 1.18)% and (2.14 ± 0.028)%, while the average particle size of the nanosuspension was (156.47 ± 1.10) nm, and the drug loading was (16.51 ± 0.21)%, respectively. Both in vitro release and rabbit scleral permeation models were consistent with the Higuchi equation. The pharmacokinetic experiments of aqueous humor showed that area under the curve of everolimus nanosuspension was about 3 times higher than that of micelles. Micelles could be achieved in the eye and maintained for a long time. Conclusion: The preparation of everolimus micelles or nanosuspension for eye are suitable for ocular administration and expected to be new dosage form for corneal transplantation immunological rejection or other ocular disease.
Highlights
Everolimus, 4 O-O-(2-hydroxyethyl)-rapamycin, a hydroxy derivative of rapamycin, is a lipophilic 31-membered ring lactone compound isolated from Streptomyces hygroscopicus (Schuler et al, 1997; Kasper et al, 2018)
For corneal transplantation, due to the presence of blood-eye barrier (Thiel et al, 2003), if a systemic administration is used, a large dose of oral administration is required to be effective in the eye, which will undoubtedly increase the risk of side effects such as thrombocytopenia and dyslipidemia which can occur in about 30% of the patients that take the drug (Baspinar et al, 2008; Tedesco-Silva et al, 2019)
The results showed that the HPLC-MS/MS method for the determination of everolimus with good sensitivity and reproducibility was suitable for pharmacokinetic studies
Summary
Everolimus, 4 O-O-(2-hydroxyethyl)-rapamycin, a hydroxy derivative of rapamycin, is a lipophilic 31-membered ring lactone compound isolated from Streptomyces hygroscopicus (Schuler et al, 1997; Kasper et al, 2018). Studies have shown that it can be used in eyes such as autoimmune uveoretinitis, noninfectious uveitis, corneal neovascularization and immune-mediated rejection after corneal transplantation (Li et al, 2008; Cakmak et al, 2016; Blair et al, 2017; Kasper et al, 2018). Immune rejection diseases caused by organ transplantation including corneal transplantation are mostly treated by systemic administration such as oral administration, which is easy to cause systemic immunosuppressive effects and cause serious adverse reactions (Cotovio et al, 2012; Renner et al, 2012; Jebali et al, 2017). The topical preparation of the eye has the advantages of small dosage and mild side effects, so it has become a hot spot for the development of clinical treatment drugs for corneal transplantation (Kauss Hornecker et al, 2015)
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