Preparation And Preliminary Pharmacokinetic Study Of Borneol-metformin Hydrochloride W/O/W Submicron Emulsions

Objective: Metformin hydrochloride is one of the common drugs for treatment of type2 diabetes in clinical practice.Recently,it has been found that metformin hydrochloride can inhibit the aggregation of amyloid-? protein,reduce the phosphorylation of tau protein in the cell and protect the nerve of the brain.These researches show that as an anti-diabetic drug,metformin hydrochloride can be used as potential drug for the treatment of Alzheimer's disease.However,a handful of metformin hydrochloride can be found in the brain and adverse reactions can be caused in gastrointestinal tract by oral administration.The research demonstrated that borneol could be absorbed quickly via the gastrointestinal tract after oral administration and then the blood brain barrier was opened to improve the other drugs to distribute in the brain.As a novel drug delivery system,W/O/W submicron emulsion has been broadly applied in the field of pharmacy to reduce adverse drug reactions,improve bioavailability and enhance drug targeting.Herein,the shear stirring technology was selected to prepare borneol-metformin hydrochloride W/O submicron emulsion,and then prepare borneol-metformin hydrochloride W/O/W submicron emulsion,in order to reduce adverse drug reactions,prolong the in vivo circulation time and enhance brain targeting.Methods: The borneol-metformin hydrochloride W/O submicron emulsion was prepared by the shear stirring method using isopropyl myristate as oil phase,cremophor EL as surfactant and ethanol as cosurfactant.Then the borneol-metformin hydrochloride W/O/W submicron emulsion was prepared using W/O submicron emulsion as oil phase,tween 80 as surfactant and propylene glycol as cosurfactant.Malvern laser particle size analyzer,transmission electron microscope,differential scanning calorimetry,fourier transform infrared spectroscopy and in vitro release were performed to characterize the particle size,polydispersity index,morphology,crystal form,chemical structure and in vitro release behavior of borneol-metformin hydrochloride W/O/W submicron emulsion.At last,the in vivo pharmacokinetics of borneol-metformin hydrochloride W/O/W submicron emulsion were investigated in rats.Results: The particle size,polydispersity index and encapsulation efficiency of the optimized prescription were 386.5 nm,0.219 and 87.26%,respectively.The results of transmission electron microscope showed that the borneol-metformin hydrochloride W/O/W submicron emulsion were spherical.The differential scanning calorimetry results indicated that metformin hydrochloride in submicron emulsion was in amorphous state.In comparison to metformin hydrochlorid,the borneol-metformin hydrochloride W/O/W submicron emulsion showed slow-release effect and its release behavior fitted with the First-order kinetics.In pharmacokinetic experiments,the AUC,MRT and t1/2 of the borneol-metformin hydrochloride W/O/W submicron emulsion were1.27-fold,2.49-fold and 4.02-fold higher than metformin hydrochloride solution.At0.75 h,2h and 3.2h after oral administration to rats,the drug concentration of the borneol-metformin hydrochloride W/O/W submicron emulsion in brain tissue were2-fold than metformin hydrochloride solution.There is no difference between metformin hydrochloride solution and the metformin hydrochloride W/O/W submicron emulsion.Compared to metformin hydrochloride solution and metformin hydrochloride W/O/W submicron emulsion,the drug targeting index of borneol-metformin hydrochloride W/O/W submicron emulsion was significantly improved.The results indicate that and borneol is succefully modified and significantly improves the distribution of metformin hydrochloride in rats' brain.Conclusion: The borneol-metformin hydrochloride W/O/W submicron emulsion was successfully prepared by the shear stirring method.In comparison with metformin hydrochloride raw drug,the physicochemical properties of metformin hydrochloride in W/O/W submicron emulsion have been changed and the in vivo pharmacokinetic parameters have been improved observably.