Enhanced effect and mechanism of water-in-oil microemulsion as an oral delivery system of hydroxysafflor yellow A

Jianping Qi^1,2, Jie Zhuang¹, Wei Wu², Yi Lu², Yunmei Song³, Zhetao Zhang¹, Jia Jia¹, Qineng Ping^1
1School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; ²School of Pharmacy, Fudan University, Shanghai, People’s Republic of China; ³School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia

Background: A microemulsion is an effective formulation for improving the oral bioavailability of poorly soluble drugs. In this paper, a water-in-oil (w/o) microemulsion was investigated as a system for enhancing the oral bioavailability of Biopharmaceutic Classification System (BCS) III drugs.
Methods: The microemulsion formulation was optimized using a pseudoternary phase diagram, comprising propylene glycol dicaprylocaprate (PG), Cremophor^® RH40, and water (30/46/24 w/w).
Results: The microemulsion increased the oral bioavailability of hydroxysafflor yellow A which was highly water-soluble but very poorly permeable. The relative bioavailability of hydroxysafflor yellow A microemulsion was about 1937% compared with a control solution in bile duct-nonligated rats. However, the microemulsion showed lower enhanced absorption ability in bile duct-ligated rats, and the relative bioavailability was only 181%. In vitro experiments were further employed to study the mechanism of the enhanced effect of the microemulsion. In vitro lipolysis showed that the microemulsion was digested very quickly by pancreatic lipase. About 60% of the microemulsion was digested within 1 hour. Furthermore, the particle size of the microemulsion after digestion was very small (53.3 nm) and the digested microemulsion had high physical stability. An everted gut sac model demonstrated that cumulative transport of the digested microemulsion was significantly higher than that of the diluted microemulsion.
Conclusion: These results suggested that digestion of the microemulsion by pancreatic lipase plays an important role in enhancing oral bioavailability of water-soluble drugs.

Keywords: propylene glycol dicaprylocaprate, microemulsion, hydroxysafflor yellow A, bioavailability, lipolysis