Promoting effects of macrogol 15 hydroxystearate micelles on corneal absorption of terbinafine hydrochloride

Abstract

Background Macrogol 15 hydroxystearate (HS15) is a novel soft non-ionic surfactant and is widely used to solubilize the poorly soluble drugs due to high drug loading and enhancing permeability ability to hydrophobic drug.However, the delivering effects to cornea of HS15 on terbinafine hydrochloride (TH), a insoluble antifungal agents, is unclear. Objective This study was to investigate the promoting corneal absorption effects of HS15 micelles (HNMs) on TH. Methods TH-HNMs was prepared by a co-solvent method.The hydrodynamic droplet size, polydispersity index, and Zeta potential of TH-HNMs were measured by using a Zetasizer.The shape of the micelles was observed under the transmission electron microscope.The high performance liquid chromatography (HPLC) was employed to detect the in vitro cumulative releasing level of TH in the TH-HNMs and drug entrapment efficiency.TH-HNMs was topically administered in eyes of 5 healthy male New Zealand rabbits to evaluate the ocular irritation response.Ninety rabbits were randomized into experimental group and control group, and 50 μl of 0.5% TH-HNMs and 0.5% oily TH were topically administered in the right eyes of the animals in the experimental group and contral group, respectively.The animals were sacrificed 5, 15, 30, 60, 90, 120, 180, 240, 360 minutes after eye dropping by over anesthetization way and the corneas were harvested, and the TH content in the cornea was detected using HPLC.The study protocal was approved by Life Science Ethic Committee of Henen Eye Hospital. Results The average size and polyolis persital index of TH-HNMs were 13.32 nm and 0.046, respectively, and its average Zeta potential was -0.133 mV.The drug entrapment efficiency was 100%.The release level of TH from the micelles presented a pH-dependent manner.The release level of TH was (95.20±3.20)% in the phosphate buffer with pH 5.0 and (0.17±0.01)% in the phosphate buffer with pH 7.4.The ocular irritation score was 2, and no visible damage was found around experimental eyes after instillation of TH-HNMs.The peak content of TH in the rabbit cornea 5 minutes was (20.26±2.26)μg/g in the experimental group, which was significantly higher than (1.40±0.44)μg/g in the control group (t=18.926, P=0.000). The area under the curve (AUC)0-360 min of drug concentration-time curve in the experimental group was 1 292.25 μg/(g·min), which was 15.6 times more than the control group. Conclusions TH-HNMs is an ideal agent with a simple preparing process, high drug entrapment efficiency, small size and low ocular irritation.Compared with oily TH, TH-HNMs can effectively enhance the corneal absorption of TH. Key words: Chemistry, pharmaceuticay; Drug delivery systems/methods; Polyethylene glycols/pharmacokinetics; Micelles; Terbinafine hydrochloride/pharmacokinetics; Macrogol 15 hydroxystearate; Corneal absorption; Rabbit