Water-in-oil Microemulsions and Hydrogel Nanoparticles in Water-in-Oil Microemulsions for Local Intestinal Delivery of Peptides and Proteins

Liu, Dongyun

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March 20, 2019

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Liu, Dongyun
- Affiliation: Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics

Abstract

The objectives of the present studies were to develop water-in-oil (W/O) microemulsions (MEs) and hydrogel nanoparticles in W/O MEs for effective local intestinal delivery of peptide and protein drugs. Water-in-oil MEs consisting of Miglyol 812, Capmul MCM, Tween 80 and water were developed and characterized. Selected W/O MEs containing a model peptide, 5-(and-6)-carboxytetramethylrhodamine labeled HIV transactivator protein TAT (TAMRA-TAT), were evaluated both in vitro and in vivo. In vitro enzymatic stability studies showed the half-life (t?1/2?) of TAMRA-TAT in ME was enhanced nearly three-fold compared to that in the water solution when challenged by modified simulated intestinal fluid. In vivo studies in mice showed TAMRA-TAT ME resulted in greater fluorescence intensity in all intestinal sections (duodenum, jejunum, ileum and colon) compared to controls after oral administration. The in vitro and in vivo studies together demonstrated that TAMRA-TAT was better protected in the W/O ME in an enzyme-containing environment, suggesting the W/O MEs developed in this study may serve as a delivery vehicle for local intestinal delivery of peptides or proteins. To further improve the current W/O ME formulations, a thermoreversible gelling polymer Pluronic F127 (PF127) was explored to engineer hydrogel nanoparticles in the W/O MEs. Water-in-oil MEs with 14% PF127 were developed based on viscosity studies and construction of phase diagrams, and then physically characterized at different temperatures. After physical characterization, TAMRA-TAT loaded W/O MEs with 8% and 14% PF127, were evaluated in vitro in enzymatic stability studies. The results showed the t?1/2? of TAMRA-TAT in the W/O ME with 14% PF127 was shorter than that in the W/O ME without PF127. In contrast, the t?1/2? of TAMRA-TAT in the W/O ME with 8% PF127 was almost the same as that in the W/O ME without PF127. This observation was explained by the large increase in droplet diameter, polydispersity index and turbidity of the ME with 14% PF127, which indicated a possible aggregation and precipitation of PF127 from the ME at 37°C. Consequently, the aggregation and precipitation of PF127 might have exposed more TAMRA-TAT associated with it to enzymes, resulting in faster TAMRA-TAT degradation. The formation of hydrogel nanoparticles in the W/O MEs was not completely achieved; further research is necessary to better understand and improve the formulation. In summary, the use of W/O ME systems proposed in this work is an attractive strategy to deliver peptides and proteins orally for the treatment of local intestinal pathologies such as inflammatory bowel diseases.

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