Computer Simulation Study Of The Transdermal Mechanism Of Transfersome

Transdermal delivery is an important route of administration,but at the same time the skin is a natural barrier to the effective penetration of most drugs.So accelerating the penetration rate of drugs and enabling the drugs to reach deeper into the skin are key to the development of transdermal drug delivery systems.Transfersome is a kind of flexible liposome for transdermal administration.The key to distinguish it from conventional liposome is its high deformability,so it can penetrate into the tiny channels on the surface of the skin,carrying drugs to the deeper layers of the skin,and even to the blood circulation.Transfersome is a new type of nano-carrier that has attracted much attention in the study field of transdermal drug delivery.However,due to the complexity of this drug delivery system and the limitations of conventional experimental methods,the basic research on transfersome has progressed slowly.Especially,the transdermal penetration mechanism of transfersome is not clear,which result in a lot of difficulties in practical application of transfersomes.In this study,the transdermal penetration mechanism of transfersome was explored by computer simulation,and the active substance of Chinese medicine,pogostone,was selected as the model drug.This study was carried out,on the one hand,to promote the basic research of transfersomes and the application of transfersomes in the field of traditional Chinese medicine,on the other hand,to establish an efficient and economical method for the study of the transdermal penetration mechanism of transfersome,so as to guide the design and evaluation of transfersomes.Based on the above research background and research purposes,this work was organized as follows:(1)Evaluation of transdermal penetration efficacy of pogostone transfersomeIn this part,pogostone transfersomes were prepared by film-ultrasonic dispersion method,and basic characterization parameters of transfersomes were checked.The transdermal penetration efficacy of pogostone transfersomes was examined by in vitro transdermal permeation experiments.Furthermore,a preliminary study of the transdermal penetration mechanism of transfersome was undertaken by force of transmission electron microscopy.The results showed that the steady state skin permeation rate of pogostone transfersomes was four times higher than that of common solution of pogostone,demonstrating that transfersome was indeed able to efficiently mediate transdermal drug delivery.Transfersomes penetrated along the hydrophilic channel in the stratum corneum and could maintain their integrity structure through deformation and self-regulation during the transdermal delivery process.In this section,the transdermal delivery performance of transfersome was confirmed by classical experimental methods,and the transdermal penetration mechanism of transfersome was morphologically revealed,laying a theoretical foundation for the simulation study of this paper.(2)A simulation study of the self-assembly of transfersomeComputer simulations are an attractive means by which to probe the self-assembly and molecular level organization of lipids in nano-vesicle system.In this work,molecular dynamics simulation was used,based on an implicit-solvent version of Martini,nicknamed Dry Martini force field,to demonstrate the ability of the coarse-grained models used for phospholipid,edge activator,and drug to self-assemble,thus validating the Dry Martini force field for use in studies of the lipid vesicle systems.The results showed that the Dry Martini models were able to reproduce the experimentally observed self-assembled structures.Compared with conventional liposomes,the vesicle thickness of the transfersomes decreased by～0.3 nm.Sodium cholate,the edge activator,is embedded in the two-phase interface of the phospholipid bilayer,and can perform 180-degree free inversion to disturb the lateral arrangement of phospholipids.Pogostone,the lipophilic drug,is loaded into the transfersome through package in the non-polar region of vesicle membrane.In this section,a coarse-grained force field with implicit solvent was employed to solve the space limitation of the molecular dynamics simulation.And the molecular level structure of transfersome was grasped.So we can further study the transdermal penetration mechanism of transfersome by these basic research.(3)Simulation exploration of the transdermal penetration mechanism of transfersomeThe most direct link to the transdermal delivery mechanism of transfersome is the deformability of the vesicles,and the most essential link is the flexibility of the membrane.In this part,the pulling dynamics technique was used to simulate the driving transport of vesicles in the skin’s hydrophilic channels.And the physical and chemical properties of the vesicle membranes were analyzed by simulations of vesicle patch.The results show that the deformation energy barrier of transfersome decreases by～1250 kJ mol-1 compared with liposome,which determines the better penetration effect of transfersome through the narrow pore.The deformation energy barrier of liposome loaded with lipophilic drugs are also reduced(～500 kJ mol-1),but the effect is weak.In the bilayer,the presence of edge activator can affect the molecular conformation of phospholipids and trigger changes of the bilayer properties,such as the increase of vibration strength of the phospholipid tail,the enhancement of mobility of the bilayer,the weakening of the orderly lateral arrangement of phospholipids,and so on.However,lipophilic drugs have less interference with membrane flexibility and have a completely different mechanism of action than the edge activator.In addition,there is a concentration saturation effect of the edge activator,that is,when the concentration of the edge activator reaches the concentration of phospholipid phase change,the flexibility of the lipid vesicle membrane does not increase even if the amount of edge activator is increased.In this section,the vesicle deformability and the membrane flexibility were taken as the entry point to illustrate the intrinsic mechanism for the efficient transdermal delivery of transfersome.In this paper,by computer simulations,combined with experiment and theoretical analysis,the transdermal penetration efficacy of transfersome are examined,and a simulation method for studying the lipid vesicle system is established.What’s more,the transdermal penetration mechanism of transfersome is ascertained at the molecular level,grasping the law of the composition of transfersome.The launch of this research has opened up a new path for the study of the action mechanism for complex drug delivery systems and promoted the research process of transfersome.