Novel vehicle based on cubosomes for ophthalmic delivery of flurbiprofen with low irritancy and high bioavailability

Abstract

Aim: To develop a novel vehicle based on cubosomes as an ophthalmic drug delivery system for flurbiprofen (FB) to reduce ocular irritancy and improve bioavailability.

Methods: FB-loaded cubosomes were prepared using hot and high-pressure homogenization. Cubosomes were then characterized by particle size, zeta potential, encapsulation efficiency, particle morphology, inner cubic structure and in vitro release. Corneal permeation was evaluated using modified Franz-type cells. Ocular irritation was then evaluated using both the Draize method and histological examination. The ocular pharmacokinetics of FB was determined using microdialysis.

Results: The particle size of each cubosome formulation was about 150 nm. A bicontinuous cubic phase of cubic P-type was determined using cryo-transmission electron microscopy (cryo-TEM) observation and small angle X-ray scattering (SAXS) analysis. In vitro corneal permeation study revealed that FB formulated in cubosomes exhibited 2.5-fold (F1) and 2.0-fold (F2) increase in P(app) compared with FB PBS. In the ocular irritation test, irritation scores for each group were less than 2, indicating that all formulations exhibited excellent ocular tolerance. Histological examination revealed that neither the structure nor the integrity of the cornea was visibly affected after incubation with FB cubosomes. The AUC of FB administered as FB cubosome F2 was 486.36+/-38.93 ng.mL(-1).min.microg(-1), which was significantly higher than that of FB Na eye drops (P<0.01). Compared with FB Na eye drops, the T(max) of FB cubosome F2 was about 1.6-fold higher and the MRT was also significantly longer (P<0.001).

Conclusion: This novel low-irritant vehicle based on cubosomes might be a promising system for effective ocular drug delivery.

Figure 1

(A) AFM image and (B) Cryo-TEM image of FB-cubosomes (F1).

Figure 2

Small angle X-ray diffraction profiles of blank cubosome and FB-cubosomes (F1).

Figure 3

In vitro release profiles of FB from FB in PBS, FB-cubosomes F1, and FB-cubosomes F2 in STF (n=3).

Figure 4

In vitro permeation profiles of various FB-formulations (n=3).

Figure 5

Photographs of rabbit eyes in ocular irritation tests.

Figure 6

Histological cross sections of excised rabbit cornea showing epithelium (EP) and stroma (ST), stained with hematoxylin-eosin (scale bar 50 μm) after incubation at 37 °C for 0.5 h. (A) Isotonic phosphate buffer (PBS) pH 7.4; (B) Sodium dodecylsulfate (SDS) solution 0.1% (w/w); (C) FB cubosome F1 (0.2%); (D) FB cubosome F2 (0.02%).

Figure 7

Aqueous humor flurbiprofen concerntration-time profiles following a topical dose in each eye of rabbits. Each point represents the mean±SD (n=3).