Ocular Cubosome Drug Delivery System for Timolol Maleate: Preparation, Characterization, Cytotoxicity, Ex Vivo, and In Vivo Evaluation

Abstract

Glaucoma is an ocular disease featuring increased intraocular pressure (IOP) and its primary treatment strategy is to lower IOP by medication. Current ocular drug delivery in treating glaucoma is confronting a variety of challenges, such as low corneal permeability and bioavailability due to the unique anatomical structure of the human eye. To tackle these challenges, a cubosome drug delivery system for glaucoma treatment was constructed for timolol maleate (TM) in this study. The TM cubosomes (liquid crystalline nanoparticles) were prepared using glycerol monooleate and poloxamer 407 via high-pressure homogenization. These constructed nanoparticles appeared spherical using transmission electron microscopy and had an average particle size of 142 nm, zeta potential of -6.27 mV, and over 85% encapsulation efficiency. Moreover, using polarized light microscopy and small-angle X-ray scattering (SAXS), it was shown that the TM cubosomes have cubic liquid crystalline D-type (Pn3m) structure, which provides good physicochemical stability and high encapsulation efficiency. Ex vivo corneal permeability experiments showed that the total amount of TM cubosomes penetrated was higher than the commercially available eye drops. In addition, in vivo studies revealed that TM cubosomes reduced the IOP in rabbits from 27.8∼39.7 to 21.4∼32.6 mmHg after 1-week administration and had a longer retention time and better lower-IOP effect than the commercial TM eye drops. Furthermore, neither cytotoxicity nor histological impairment in the rabbit corneas was observed. This study suggests that cubosomes are capable of increasing the corneal permeability and bioavailability of TM and have great potential for ocular disease treatment.

Formulation and Characterization of Timolol Maleate-Loaded Nanoparticles Gel by Ionic Gelation Method Using Chitosan and Sodium Alginate

“…However, increasing the concentration of CaCl2 or increasing the concentration of CS shifted the Zeta potential to positive values. These findings were also in accordance with the previously reported data [23].…”

Recent Advances in Topical Nano drug-delivery Systems for the Anterior Ocular Segment

“…The microstructure of the cubosomes is similar to the biological membrane, which leads to enhanced permeation. The ability of cubosome to load is ascribed to lipid bilayer with its high surface area [150,151]. Li et al formulated cubosome of glycerol monoolein and poloxamer 407 loaded with pilocarpine nitrate for glaucoma therapy [152].…”

“…The cubosomes had significantly higher effect on IOP reduction (∼50% IOP reduction) in comparison to the marketed eye drops (∼41%). Similarly, Huang et al formulated cubosomes of glycerol monoolein and poloxamer 407 loaded with timolol maleate [150]. They observed approximately 3.5-times higher cumulative drug permeation across the rabbit corneas in comparison to the marketed eye drops.…”

New technologies of hypotensive drug delivery in glaucoma treatment

“…Многим исследователям представляется перспективным для доставки гипотензивных препаратов использовать комбинации полимеров и коллоидных систем: липосом [22][23][24][25][26], ниосом [27,28], кубосом [29], микроэмульсий [30], наноэмульсий [31][32][33] и наночастиц [34][35][36][37][38][39][40]. За счет медленного высвобождения лекарственных препаратов удается значительно пролонгировать время нахождения активного вещества в глазу.…”