Design And Evaluation Of Mucus Penetration Delivery Systems

Enhancing the oral delivery efficiency of biological macromolecular durgs still meets great challenges because multiple barriers exit in the gastrointestinal tract including chemical or enzymatic degradation during oral administration routes,insufficient mucus penetration ability and poor mucous membrane permeability.Among of these,mucus penetration barrier is a key but easily overlooked problem duing oral delivery process.In this study,two trategies including modifying mucus barriers and increasing mucus penetration ability of nanoparticles were applied by screening the potential mucus penetration enhancers and design of hydrophilic high charge density biomimick core-shell nanocomplex to overcome the mucus barrier in oral delivery process.First,taking PLGA nanoparticles as a tool,influence of anionic and nonionic surfactants on mucus barrier and mucus penetration ability of nanoparticles were studied.The movement of PLGA nanoparticles in mucus pretreated by surfactants was tracked by multiple particles tracking method(MPT).The properties of mucus pretreated by surfactants were evaluated by rheology and morphology study.Rat intestinal villus absorption study was used to further evaluate absorption enhancement of nanoparticles.The results showed effective diffusivities of the nanoparticles(Deff)in mucus pretreated by 1%surfactants increased by 2-3 times.In addition to increase the hydrophilicity of mucus microenvironment,mechanism of different surfactants to facilitate the movement of nanoparticles was structure dependent.SDS and Poloxamer increased the mucus permeability by disrupting mucus network in different styles.In contrast,Tween 80 largely retained the original mucus rheology and morphology properties and showed promising potential to facilitate nanoparticles penetration through the mucus barrier with good safety profile.Secondly,taking insulin as a model drug,polycationic chitosan and polyanionic alginates were used as the core-shell forming material,hydrophilic high charge density core-shell nanocomplex was developed by mimicking the virus surface to increase intestinal mucus penetration ability.According to dynamic light scattering(DLS),atomic force microscopy(AFM)and FTIR results,alginate coating layer was successfully formed on the core.The coreshell nanocomplex showed good physical stability and improved about 20%enzymatic stability.In comparison with CS-INS NC,the negatively charged alginate coating layer could improve its mucus penetration ability and alginate with lower molecular weight and G content increased the permeation percentage of the nanocomplex about 4.2 times.The results of multiple particle tracking(MPT)and permeation study in rat intestine also comfirmed the core-shell nanocomplex with good mucus penetrating ability could further increase villi uptake and intestine permeation of nanocomplex.Finally,in order to understand the influence of molecular structure of nanocomplex shell on the mucus penetration ability,the anionic polysaccharides with different molecular structures including hyaluronic acid(HA),chondroitin sulfate(ChS),pectin(Pec)were selected for preparation of mucus penetrating core-shell nanocomplex.The core-shell structure can be successfully formed and comfirmed by DLS,AFM and FTIR study.The mucus penetration study,intestine permeation and villi uptake study showed that the mucus penetration ability of core-shell nanocomplex was affected by molecular structure of shell including ester group,negatively charged groups and monosaccharide structure.The pectin coating layer increased permeation percentage of chitosan nanocomplex by 1.3 times,but no increase of intestine permeation ability was observed.Hyaluronic acid(HA),chondroitin sulfate(ChS)coated nanocomplex increased mucus permeation percentage by 2.8 and 3.3 times respectively,which also showed better intestine permeation ability and villi uptake.Apart from surface charge,the ester group in Pec will increase the possibility of nanocomplex trapped in the mucus.The same N-acetylgalactosamine structure in ChS and HA with mucin linked glycan could reduce the interactions between nanocomplex and mucin and better enhance mucus penetration ability.In this study,modifying the mucus microenvironment by application of mucus penetration enhancers and preparation of hydrophilic,high charge density virus-like core-shell nanocomplex can effectively overcome the mucus barriers during oral delivery.The coating layer molecular structure including ester bonds,negatively charged groups,monosaccharide structure could affect the mucus penetration ability.This study also provides experimental and theoretical basis for the design of efficient oral delivery system for macromolecular drug...