Abstract
We previously designed ophthalmic formulations (nTRA) containing tranilast nanoparticles (Tra-NPs) with high uptake into ocular tissues. In this study, we used in situ gel (ISG) bases comprising combinations of pluronic F127 (F127) and methylcellulose (MC/F127), pluronic F68 (F68/F127), and Carbopol (Car/F127), and we developed in situ gels incorporating Tra-NPs (Tra-NP-incorporated ISNGs) such as nTRA-F127, nTRA-MC/F127, nTRA-F68/F127, and nTRA-Car/F127. Moreover, we demonstrated the therapeutic effect on conjunctival inflammation using lipopolysaccharide-induced rats. Each Tra-NP-incorporated ISNG was prepared by the bead mill method, the particle size was 40–190 nm, and the tranilast release and diffusion from formulation were nTRA > nTRA-F127 > nTRA-F68/F127 > nTRA-Car/F127 > nTRA-MC/F127. In the Tra-NP-incorporated ISNGs, the tranilast residence time in the lacrimal fluid, cornea, and conjunctiva was prolonged, although the Cmax was attenuated in comparison with nTRA. On the other hand, no significant difference in conjunctival inflammation between non- and nTRA-F127-instilled rats was found; however, the nTRA-F68/F127, nTRA-Car/F127, and nTRA-MC/F127 (combination-ISG) attenuated the vessel leakage, nitric oxide, and tumor necrosis factor-α expression. In particular, nTRA-F68/F127 was significant in preventing the conjunctival inflammation. In conclusion, we found that the combination-ISG base prolonged the residence time of Tra-NPs; however, Tra-NP release from the formulation was attenuated, and the Tmax was delayed longer than that in nTRA. The balance of drug residence and diffusion in lacrimal fluid may be important in providing high ocular bioavailability in formulations containing solid nanoparticles.
Highlights
Pluronic F-127 was provided by Funakoshi Co., Ltd. (Tokyo, Japan), and Tra powder and commercially available Tra eyedrops (CA-TRA) were kindly donated by Kissei Pharmaceutical Co., Ltd. (Nagano, Japan)
We prepared the tranilast nanoparticles (Tra-NPs)-incorporated ISNGs using the pluronic F-127, which is a polymer with thermoresponsive behavior, and other in situ gel (ISG) bases
We found that the increase in viscosity prolonged the pre-corneal residence time of Tra-NPs; it attenuated the delay of Tmax via the NPs release from formulation and showed that this balance was related to the BA in the cornea and conjunctiva
Summary
Eyedrops provide many advantages, such as a noninvasive treatment adherence, compliance, self-administration, and reduced side effects [1,2]. Eyedrops are the most common formulations in the ophthalmic field. A large proportion of eyedrops is lost through nasolacrimal drainage, eye blinking, and binding to the surrounding extraorbital tissues [3,4,5], and the remaining eyedrops are immediately diluted in the lacrimal fluid after instillation. Pre-corneal and pre-conjunctival drug retention is poor, and less than 1–5% of the dose is delivered to the target tissues [1,6,7,8].
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