Research On The Evaluation Methodology Of Transdermal Drug Delivery Performance Based On Molecular Dynamics Simulation

Transfersome is a novel transdermal drug delivery vehicle,with advantages of strong deformability,good transdermal effect,rich variety of entrapped drugs,wide application range,etc.However,due to the limitations of research methods,current transfersome-related research often needs to be based on a large number of exploratory experiments,which will undoubtedly cause great waste of research resources,thereby limiting the development and utilization of transfersome preparations.Therefore,transfersome-related research is urgently needed to develop new and efficient research methods.Molecular dynamics is a new research method derived from the rapid improvement of computing power.It can reveal the objective laws of things from the perspective of interaction between molecules,and has the characteristics of high efficiency,greenness and economy.In this paper,molecular dynamics technology is applied to the evaluation of trandersome’s transdermal drug delivery performance,aiming to establish a rapid evaluation method for transdermal delivery performance of transfersome and accelerate the development and utilization of the transfersome.To this end,efforts are mainly carried out in the following 3 parts according the 3 different aspects of trandersome’s transdermal delivery performance(deformation ability,stability and drug-loading performance):1.Study on evaluation method of transfersome’s deformation ability based on molecular dynamicsDeformation ability is closely related to transdermal effect of transfersome,which is of great significance for evaluating its transdermal delivery performance.In this part.the molecular dynamics simulation was applied to evaluate the deformation ability of transfersome.Two models named "vesicle pore,model and flat patch model was constructed.The microcosmic deformation process of vesicles was analyzed.Parameters including total number of vesicle atoms inside pore(Nin),free energy surface and k,(bending module)were proposed for the evaluation of deformation ability.Then,the deformation ability of transfersome and liposome were compared using this method.The results show that the deformability of the transfersome was much stronger than that of liposome.Because the kc of the lipid bilayer reduced with the introduction of surfactant molecules,which allowed transfersome to maintain morphology intact during a strong deformation process,and could successfully pass through the pore.The results got along well with the penetration mechanism of transfersome and in vitro diffusion experiment,which confirmed the feasibility of molecular dynamics in evaluating the deformation ability of transfersome.It is worth noted that,compared with the classical deformation ability evaluation method(extrusion method).the molecular dynamics evaluation method constructed in this part don’t have to rely on large-scale homogenizer.and has the advantage of high efficiency,green and economy.It can be used as a new evaluation method for the deformation ability of transfersome.2.Study on evaluation method of transfersome’s stability based on molecular dynamicsThe stability of transfersome is one of the main factors limiting its clinical application,which is of great significance for evaluating its transdermal delivery performance.In this part,using nano-liposome fusion as a starting point,molecular dynamics was applied to evaluate the stability of transfersome,and vesicle fusion model was constructed.The effects of model parameters on vesicle fusion were investigated.The micro process of vesicle fusion was analyzed.Two parameters including diffusion coefficient and total length of initial vesicle fusion stage were proposed for the evaluation of vesicle stability.Then,the stability of tansfersome and liposome at three different temperatures were compared using this method.The results showed that the stability of the two vesicles both decreased with the increase of temperature,and the stability of the transfersome at the same temperature was worse than that of the liposome.The results are consistent with the literature reports,which proves the feasibility of the stability evaluation method of molecular dynamics simulation transporter.It is worth mentioning that compared with the conventional stability evaluation methods(observing the change of nanoliposome particle size with time),the transfersome molecular dynamics stability evaluation method constructed in this part greatly shortens the experimental period,and can be used as a new method for the stability evaluation of the transfer.3.Study on evaluation method of transfersome’s　drug-loading properties based on molecular dynamicsDrug-loading properties of transfersome involves many processes,such as drug encapsulation and release,and is another key attribute of transdermal delivery performance.In this part,based on the interaction between lipid bilayer and drug,molecular dynamics simulation was applied to the evaluation of drug-loading properties of transfersomem and umbrella sampling model and drug vesicle interaction model were constructed.Two parameters including free energy and radial distribution density were proposed for the evaluation of drug-loading properties.Then,this method was applied to the prediction of drug-loading location.The results show that with the increase of drug polarity,drug-loading location gradually moved from the middle hydrophobic area to the inner and outer water areas of vesicles.In addition,the differences between transfersome and liposome in the loading of hydrophilic molecules were compared.The results showed that the free energy of hydrophilic molecules passing through the bilayer of transfersome was significantly higher than that of liposome,indicating that the introduction of surfactant molecules was not conducive to the inclusion of hydrophilic drugs.Compared with the classical drug-loading properties evaluation methods(encapsulation efficiency,release rate),the molecular dynamics simulation method constructed in this part can provide micro-level information of the system,which made up for the limitation of the conventional drug loading performance research methods on the research scale.,and could be used as a supplement to the conventional drug loading performance research methods.In summary,this paper applies molecular dynamics simulation to the study of transfersome.It is an exploratory work to construct the molecular dynamics transdermal drug delivery performance evaluation methodology of transfersome from three aspects:deformation ability,stability and drug loading performance,which solves the problem of low efficiency in the early stage of research on transfersome.