| Objective:Taking the hesperidin delivery system as the research object,the innovative use of TRIZ to analyse the root cause of the problem,find the breakthrough point to solve the problem and give the design idea of the solution;and then explore the key optimization point of the solution through the Qb D-Do E linkage,and characterize and verify the pharmacodynamics test,so as to carry out the design and implementation of solutions to the problem.Methods:（1）To address the problem of low concentration of hesperidin in the lungs during the treatment of acute lung injury,TRIZ tools are used for analytical dismantling（e.g.,functional,causal,and resource analysis）,refinement（e.g.,object-field model and standard solution,scientific effect knowledge base,and contradiction matrix）,and formulation of solutions to design a functional,feasible,and stable technological system for this requirement,i.e.,a novel delivery system of hesperidin for acute lung injury.A novel delivery system of hesperidin for acute lung injury.（2）To establish a method for the determination of the content of HSD-LCNPs,then analyse the CQAs for the preparation of HSD-LCNPs and their influencing factors（i.e.,potential CMAs and CPPs）by using Qb D,and finally,based on the results of the one-way test,to predefine the range of the appropriate levels of the potential CMAs and CPPs for Do E optimisation,so as to provide the basis for the next step of the optimisation of the process.（3）Using the overall normalised value（OD）as the overall evaluation index,the Do E method（Plackett-Burman,hill-climbing test and Box-Behnken design of experiments integrated method）was applied to screen the high-risk CMAs and CPPs of HSD-LCNPs and establish the mathematical relationship between them and the OD value,and at the same time,the optimal process was obtained and verified;and then the optimal process The samples were characterised by physicochemical properties such as Tyndall phenomenon,PLM,FT-IR,TEM,p H,stability and release.（4）The LPS-induced mouse ALI model was constructed by tracheal drip method,and the mice were randomly divided into normal group,model group,blank LCNPs group,HSD suspension group(200 mg·kg-1),low-dose group(100 mg·kg-1),medium-dose group(200 mg·kg-1),and high-dose group(400 mg·kg-1),and the drugs were administered by an air-compressed nebuliser.The therapeutic effects of HSD-LCNPs on ALI mice were evaluated by observing the histopathological morphology of the lungs,wet/dry weight ratio,expression of pro-inflammatory factors（IL-1β,TNF-α）and chemokines（CCL2）in BALF,and the protein concentration and number of WBCs in BALF.Results:（1）Eventually,"III,XV,XXI,XXIV,XXVIII and XXXII"of the 33 conceptual options were adopted,i.e.,the addition of solubilising nanomaterials and other nanomaterials to prepare a liquid crystalline colloidal delivery system for hesperidin,which is then administered by inhalation,injection,tracheal intubation drip and other devices.Hesperidin liquid crystal lipid nanoparticle delivery system has the effects of solubilisation and lung accumulation,which can solve the problem of weak effect of the original delivery system for the treatment of acute lung injury.（2）An HPLC method for the determination of the content of HSD-LCNPs was established,and the methodological investigations were all good or compliant and can be used for subsequent content determination.Qb D was employed to analyse the preparation process of HSD-LCNPs,and the CQAs were screened as encapsulation rate,drug loading,particle size,PDI and zeta potential;the potential CMAs affecting the CQAs were identified as alcohol/water mass fraction,GMO dosage,P407/GMO mass fraction,HSD dosage,and the potential CPPs affecting the CQAs were stirring temperature,stirring time,stirring speed,ultrasonic power,and ultrasonic time,all of which were used as factors for subsequent Do E process optimisation.Then the Do E factors were examined one-way and the level range of each Do E factor was defined.（3）The optimal preparation process of HSD-LCNPs was obtained by applying the Do E integration method.The validation results showed that the measured average OD value was 0.5457±0.0039,which was close to the predicted OD value.Both blank LCNPs and HSD-LCNPs showed milky light and obvious Tyndall effect,and were monorefractive,i.e.isotropic,at all polarisation angles,which was in accordance with the cubic phase liquid crystal properties.The particle size,PDI,zeta potential,encapsulation rate and loading amount of the HSD-LCNPs were reasonable,and the peaks of the distribution plots of the particle size and the zeta potential were symmetrical and well-distributed.The FT-IR analyses demonstrated that the FT-IR analysis showed that HSD was successfully encapsulated or embedded in LCNPs.TEM results showed that the HSD-LCNPs showed a full cubic structure,the sample morphology was complete,and the particle size was uniform.The average p H of the HSD-LCNPs was nearly neutral and consistent with that of the human blood.The stability of the LCNPs was optimal in the case of HSD-LCNPs at 37℃,and was worst in the case of blank LCNPs at 37℃.The stability of the HSD-LCNPs in the ALF was also improved by the use of the HSD-LCNPs at 37℃.The 24 h cumulative release rate of LCNPs in ALF medium was 94.41%±1.60%,which was better than that in MGS medium,and there was no sudden release.The release patterns of this delivery system in both MGS and ALF best fit the Weibull model;and the release mechanisms were both non-Fick diffusion,i.e.,drug diffusion and skeleton dissolution acted synergistically.（4）HSD-LCNPs can effectively reduce the lung histopathological damage in LPS-induced ALI mice,significantly reduce the number of WBCs in the BALF of LPS-induced ALI mice,and at the same time,inhibit the expression levels of pro-inflammatory factors such as IL-1β,TNF-αand chemokines such as CCL2 in the BALF of mice to reduce the pneumonic response,and the higher the dose,the better the effect,and the higher the dose,and the better the effect within reasonable limits.Excipients of LCNPs have no therapeutic effect.Conclusion:In this study,a novel delivery system for hesperidin,HSD-LCNPs,was designed and optimized by the TRIZ-Qb D-Do E integrated innovation method,and its physicochemical characterization and pharmacodynamic tests showed that the design could solve the problem of"low concentration of hesperidin in lungs in the treatment of acute lung injury"and provide a superior intelligent therapeutic solution for patients. |
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