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


CONCLUSIONS
This novel low-irritant vehicle based on cubosomes might be a promising system for effective ocular drug delivery.
Han
Shun
S
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Shen
Jin-qiu
JQ
Gan
Yong
Y
Geng
Hai-ming
HM
Zhang
Xin-xin
XX
Zhu
Chun-liu
CL
Gan
Li
L
D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D019540:Area Under Curve; D001682:Biological Availability; D003315:Cornea / Q000378:metabolism*; D016503:Drug Delivery Systems; D005480:Flurbiprofen / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D008297:Male; D017551:Microdialysis; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009883:Ophthalmic Solutions; D010316:Particle Size; D010539:Permeability; D011817:Rabbits
D000894:Anti-Inflammatory Agents, Non-Steroidal; D009883:Ophthalmic Solutions; D005480:Flurbiprofen