Cubic and hexagonal liquid crystal gels for ocular delivery with enhanced effect of pilocarpine nitrate on anti-glaucoma treatment

Abstract

The objective of this work was to investigate phytantriol-based liquid crystal (LC) gels including cubic (Q₂) and hexagonal (H₂) phase for ocular delivery of pilocarpine nitrate (PN) to treat glaucoma. The gels were produced by a vortex method and confirmed by crossed polarized light microscopy, small-angle X-ray scattering, and rheological measurements. Moreover, the release behaviors and permeation results of PN from the gels were estimated using in vitro studies. Finally, the anti-glaucoma effect of LC gels was evaluated by in vivo animal experiments. The inner structure of the gels was Pn3m-type Q₂ and H₂ phase, and both of them showed pseudoplastic fluid properties based on characterization techniques. In vitro release profiles suggested that PN could be sustainably released from LC gels within 48 h. Compared with eye drops, Q₂ and H₂ gel produces a 5.25-fold and 6.23-fold increase in the P_app value (p < .05), respectively, leading to a significant enhancement of corneal penetration. Furthermore, a good biocompatibility and longer residence time on precorneal for LC gels confirmed by in vivo animal experiment. Pharmacokinetic studies showed that LC gels could maintain PN concentration in aqueous humor for at least 12 h after administration and remarkably improve the bioavailability of drug. Additionally, in vivo pharmacodynamics studies indicated that LC gels had a more significant intraocular pressure-lowering and miotic effect compared to eye drops. These research findings hinted that LC gels would be a promising pharmaceutical strategy for ocular application to enhance the efficacy of anti-glaucoma.

Keywords: IOP-lowering; Phytantriol; anti-glaucoma; liquid crystal gels; ocular delivery.

Figure 1.

Images of FQ (A) and FH (B) formulations under CPLM (all images were taken at ×100 magnification and the scale bar is 100 μm). SAXS profiles of FQ (C) and FH (D) formulations at 25 ± 0.5 °C, appearance pictures of FQ (a) and FH (b) formulations at room temperature. (E) Schematic illustration of the inner structure of Pn3m-type Q₂ and H₂ phases containing PN molecules.

Figure 2.

(A) Flow curves showing the effect of shear rate sweep on viscosity of the LC gels. (B) Rheological profiles of LC gels were evaluated by strain sweep at 0.01–100%. (C) Viscous and elastic moduli dependence upon oscillation frequency for LC gels. (D) The complex viscosity of LC gels at 37 ± 0.5 °C as a function of angular frequency. (E) The cumulative release profiles of PN from different formulations. The inset panel exhibits the drug release flux graph. (F) Ex vivo transcorneal permeation profiles of PN from LC gels and eye drops using fresh rabbit corneas. Data are reported as mean ± SD of n = 3. *p<.05, statistically significant compared with eye drops. **p<.01, compared with eye drops.

Figure 3.

(A) The lower fornix of the rabbits’ eyes and the anterior surface of the eyeball. (B) Fluorescence photographs of rabbit eyes after application of sodium fluorescein-loaded formulations. Orange and white arrows indicate the release of sodium fluorescein by the gels and the location of the eyeball, respectively.

Figure 4.

Representative histological images of the eye tissues after treated with various formulations for a week (original magnification, ×200). EP: epithelium; ST: stroma; EN: endothelium; ONL: outer nuclear layer; INL: inner nuclear layer; GCL: ganglion cell layer.

Figure 5.

PN concentration in rabbits’ aqueous humor at different time points after administration of LC gels and a commercial PN eye drops (all outcomes are reported as mean ± SD of n = 3). *p<.05, statistically significant compared with eye drops. **p<.01, compared with eye drops.

Figure 6.

(A) Ocular surface was inspected by a slit lamp (a) before establishment of model and (b) after treatment with various formulations. Time-course measurements of (B) pupil diameter and (C) IOP after administration of different PN-loaded formulations in normal rabbits. Time-course measurements of (D) IOP and (E) pupil diameter after administration of different preparations for two weeks in glaucomatous rabbits. *p<.05, statistically significant difference from eye drops. **p<.01, statistically significant compared with eye drops.