Objective To prepare naringenin micelles-loaded thermosensitive gel (NMTG), evaluate its biological safety and anti-inflammatory activity, and investigate its therapeutic effects on dry eye disease (DED) induced by benzalkonium chloride (BAC) in rats. Methods Naringenin micelles (NM) were prepared by the thin-film dispersion method. Quality evaluations of the prepared NM included appearance, particle size, ζ potential, transmission electron microscopy, encapsulation efficiency, drug loading and stability. Concentrations of Poloxamer 188 (P188) and Poloxamer 407 (P407) were optimized based on the phase transition temperatures (T_gel and T_{atd gel}) of NMTG before and after dilution with tear fluid. Optimal concentrations of P188 and P407 were dissolved in NM to form NMTG. Biological safety, anti-inflammatory activity, and therapeutic effects on BAC-induced DED rats were investigated. Results Prepared NM was clear and transparent. Transmission electron microscopy showed near-spherical particles with an average particle size of (21.56 ± 0.16) nm, a polydispersity index (PDI) value of 0.053 ± 0.033, and a ζ potential of (-18.63 ± 1.94) mV. Encapsulation efficiency and drug loading were (73.96 ± 0.24)% and (7.34 ± 0.38)%, respectively, and the stability was good within 14 d. The optimal NMTG was achieved with concentrations of 5.29% P188 and 16.24% P407. NMTG demonstrated good biological safety and anti-inflammatory activity. Pharmacological experiments indicated that NMTG showed favorable therapeutic effects on DED rats. Conclusion The successful preparation of NMTG improve the solubility of naringenin, which endow it with good DED therapeutic effects. This will provide support for new indications of naringenin in ocular applications and offer candidate solutions for the development of new naringenin dosage forms.

naringenin  /  micelles  /  thermosensitive gel  /  dry eye disease  /  thin-film dispersion method  /  star-point design-response surface method  /  pharmacodynamics  /  biological safety  /  anti-inflammatory activity