β-Lactoglobulin stabilized lipid nanoparticles enhance oral absorption of insulin by slowing down lipolysis

Lipid-based nanocarriers have staged a remarkable comeback in the oral delivery of proteins and peptides, but delivery efficiency is compromised by lipolysis. β-Lactoglobulin(β-lg) stabilized lipid nanoparticles, including nanoemulsions(NE@β-lg) and nanocapsules(NC@β-lg), were developed to enhance the oral absorption of insulin by slowing down lipolysis due to the protection from β-lg. Cremophor EL stabilized nanoemulsions(NE@Cre-EL) were prepared and set as a control. The lipid nanoparticles produced mild and sustained hypoglycemic effects, amounting to oral bioavailability of 3.0% ± 0.3%, 7.0% ± 1.1%, and7.7% ± 0.8% for NE@Cre-EL, NE@β-lg, and NC@β-lg, respectively. Aggregation-caused quenching(ACQ)probes enabled the identification of intact nanoparticles, which were used to investigate the in vivo and intracellular fates of the lipid nanoparticles. In vitro digestion/lipolysis and ex vivo imaging confirmed delayed lipolysis from β-lg stabilized lipid nanoparticles. NC@β-lg was more resistant to intestinal lipolysis than NE@β-lg due to the Ca^(2+)-induced crosslinking. Live imaging revealed the transepithelial transport of intact nanoparticles and their accumulation in the liver. Cellular studies confirmed the uptake of intact nanoparticles. Slowing down lipolysis via food proteins represents a good strategy to enhance the oral absorption of lipid nanoparticles and thus co-formulated biomacromolecules.

Ionic co-aggregates(ICAs)based oral drug delivery:Solubilization and permeability improvement

Due to the overwhelming percentage of poorly water-soluble drugs,pharmaceutical industry is in urgent need of efficient approaches for solubilization and permeability improvement.Salts consisting of lipophilic fatty acid anions and hydrophilic choline cations are found to be surface active and able to form ionic co-aggregates(ICAs)in water.Choline oleate-based ICAs significantly enhance oral absorption of paclitaxel(PTX)as compared with cremophor EL-based micelles(MCs).Aggregation-caused quenching probes enable tracking of intact ICAs in in vivo transport and cellular interaction.Prolonged intestinal retention of ICAs than MCs implies stronger solubilizing capability in vivo.Ex vivo imaging of major organs and intestinal tracts suggests transepithelial transport of intact ICAs.Cellular studies support the enhanced absorption of PTX and transmembrane transport of intact ICAs.In conclusion,ICAs,consisting of lipophilic ions and hydrophilic counter-ions,are of great potential in delivery of poorly water-soluble drugs by enhancing solubility and permeability.

Green and controllable fabrication of nanocrystals from ionic liquids

Nanocrystals are of great value in delivering poorly soluble drugs as a technique enables enhanced dissolution and bioavailability.The bottom-up technique allows better control of particle properties.However,the commonly used organic solvents are hazardous to environment and operators,and always lead to large particle size and wide size distribution due to failure on controlling the nucleation and crystal growth.The situation is exacerbated in scale-up production.Therefore,in the proof-of-concept study,we evaluated the feasibility of green and controllable fabrication of drug nanocrystals by using biocompatible ionic liquids(ILs)as solvents.Choline based ILs(Ch-ILs)were synthesized via metathesis reactions.Pure paclitaxel nanocrystals of high quality were obtained from Ch-ILs with surface tension higher than 42 m N/m.The sizes were below 250 nm,while the polydispersity indexes were lower than 0.25.Compared with ethanol,choline lactate is superior in controlling the size of the nanocrystals in scale-up production,where the drug concentration was increased by 6 times.The underlying mechanism may be due to the high viscosity and low surface tension of the ILs,which are supposed to benefit homogeneous and burst nucleation.Ch-ILs can be recycled from the process and recovery rate reached 91.1%.Moreover,the applicability of the green technique was validated in a wider range of model drugs and Ch-ILs.In conclusion,ILs are potent solvents in bottom-up technique for green and controllable fabrication of nanocrystals.