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

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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.

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ACKNOWLEDGEMENTS

We thank Chen Li, Thien Tran, and Maizbha Uddin Ahmed (Monash University) for their critical discussion and manuscript revision and Yanjie Chen, Songfeng Chen, Bingyi Chen, and Kangyan Chen (Sun Yat-sen University) for their experimental assistance. This work is supported by the Science and Technology Foundation, Guangzhou, China (Grant No. 201509030006).

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Authors and Affiliations

  1. School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road Higher Education Mega Center, Guangzhou, Guangdong, 510006, China

    Jiayuan Huang, Tingting Peng, Yanrong Li, Zhengwen Zhan, Youmei Zeng, Ying Huang, Xin Pan & Chuanbin Wu

  2. Research and Development Center of Pharmaceutical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China

    Ying Huang, Xin Pan & Chuanbin Wu

  3. Department of Chemical and Process Engineering, University of Surrey, Guildford, Surrey, GU2 7XH, UK

    Chuan-Yu Wu

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  1. Jiayuan Huang
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Correspondence to Ying Huang or Xin Pan.

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Huang, J., Peng, T., Li, Y. et al. Ocular Cubosome Drug Delivery System for Timolol Maleate: Preparation, Characterization, Cytotoxicity, Ex Vivo, and In Vivo Evaluation. AAPS PharmSciTech 18, 2919–2926 (2017). https://doi.org/10.1208/s12249-017-0763-8

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  • DOI: https://doi.org/10.1208/s12249-017-0763-8

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