Design and optimization of thermosensitive nanoemulsion hydrogel for sustained-release of praziquantel

Abstract

Objective: This work aimed to develop an alternative sustained-release thermosensitive praziquantel-loaded nanoemulsion (PZQ-NE) hydrogel for better schistosomiasis treatment.

Significance: PZQ-NE-dispersed chitosan/glycerol 2-phosphate disodium/HPMC (NE/CS/β-GP/HMPC) hydrogel was successfully prepared to improve bioavailability of PZQ.

Methods: Solubility tests and pseudo-ternary phase diagrams were applied to screen optimal oils, surfactants and co-surfactants of NE. The hydrogels were characterized for gelling time, surface exudates, rheological properties and in vitro drug release. Formulation optimization of NE/CS/β-GP/HMPC hydrogel was conducted by Box–Behnken experimental design combined with response surface methodology. In vitro cytotoxicity of hydrogel was studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide method. The sustained-release property of PZQ in NE and optimized hydrogel was evaluated by pharmacokinetic study in rabbits.

Results: The formulation of PZQ-NE consisted of mass ratio of 12.5% capryol 90 containing PZQ (160 mg/g), 40% cremophor RH 40/tween 20 and transcutol HP (S/CoS = 2:1), 47.5% deionized water. PZQ releasing from NE/CS/β-GP/HMPC hydrogels was best fitted to Higuchi model and governed by diffusion. Rheological investigation evidenced the themosensitive gelation of different hydrogel systems and their gel-like character at 37 °C. The optimized hydrogel formulation consisted of HPMC solution (103.69 mg/g), 3.03% (w/v) chitosan and 14.1% (w/v) β-GP showed no cytotoxicity when the addition of NE was no more than 100 mg/g. Pharmacokinetic parameters indicated that NE/CS/β-GP/HMPC hydrogel can significantly slow down drug elimination, prolong mean residence time and improve bioavailability of PZQ.

Conclusions: NE/CS/β-GP/HMPC hydrogel possessed sustained-release property and could be an alternative antischistosomal drug delivery system with improved therapeutic effect.

Keywords:

• Praziquantel
• nanoemulsion
• hydrogel
• Box–Behnken design
• cytotoxicity
• pharmacokinetics

Acknowledgements

This study was supported by a grant from Key Laboratory of Oriented Veterinary Medicines of the Ministry of Agriculture and Gansu Province, China [No. SYSKF2014KT02]; National Innovative Entrepreneurial Training Plan for University Students of Gansu province, China [No. 20151073001749].

Disclosure statement

The authors report no conflicts of interest.

Novelty statement

The application of nanoemulsion-based technology improved the solubility of antischistosomal drug-praziquantel (PZQ) in thermosensitive hydrogel consisted of PZQ-loaded nanoemulsion (PZQ-NE) and CS/β-GP solution, and the addition of HPMC efficiently reduced the exuded PZQ, resulting in decrease in initial burst release. The new praziquantel delivery system showed sustained-release property in vitro and in vivo, which better adapt to the treatment of schistosomiasis.

Additional information

Funding

This study was supported by a grant from Key Laboratory of Oriented Veterinary Medicines of the Ministry of Agriculture and Gansu Province, China [No. SYSKF2014KT02]; National Innovative Entrepreneurial Training Plan for University Students of Gansu province, China [No. 20151073001749].