The Design And Evaluation On Ophthalmic Hierarchical Delivery System Of Nanogels For Traditional Chinese Medicine Based On Molecular Docking And 3D Modeling

In the traditional drug delivery system for the posterior segment of the eye,the absorption of drug molecules is hindered by the special anatomical structure and defense barrier of the eye.At the same time,the pathogenesis of diseases of the posterior segment of the eye such as age-related macular degeneration（AMD）is complex and constantly changing.It is difficult to achieve a good therapeutic effect with single drug administration,which eventually leads to uneven drug efficacy.In recent years,in the case that a single drug cannot meet the application of complex diseases,the continuous development of compound nanotechnology is promising to become a safe and effective new ocular drug delivery system.However,how to select an appropriate and effective active ingredient is the primary consideration in the process of designing a drug delivery system.Therefore,this study applied computer screening technology to the optimization of prescription model drugs,and screened 6 effective compounds from many traditional Chinese medicine components.In addition,quantitative understanding of the transport laws of drug molecules in traditional ocular drug delivery systems is crucial for designing effective strategies for the treatment of AMD.Therefore,based on the reasonable application of artificial intelligence technology,a 3D eyeball computing model is constructed to preliminarily predict the bioavailability of the drug on the retina after instillation of the drug into the eye,and provide technical and data support for the construction of a new drug delivery system.1 Selection and evaluation of model drugsMolecular docking was used to screen out 6 active components,including:esculine,quercetin,curcumin,resveratrol,berberine and ligustrazine.At the same time,based on the theory of"combination of components"and the inspiration of clinical compound preparations,the combination of Esculine（ES）and Digitoxin（DIG）was used as the model drug.The COMSOL Multiphysics version 5.3 simulation software was used to preliminarily predict the diffusion and absorption effects of the two in different ocular tissues based on traditional drug delivery methods.Studies have confirmed that the concentration distribution of drugs in the posterior segment of the eye is extremely low and it is difficult to achieve drug efficacy,which provides an opportunity and platform for the subsequent development of new nano-delivery systems.2 Properties of esculine（ES）and digitoxin（DIG）The HPLC quantitative analysis method constructed meets the determination requirements.The ultrafiltration centrifugation method was used to determine the EE and DL of the nanopreparation,and the recovery rate of the ultrafiltration tube was between 95%and 105%.In addition,the results of the oil-water partition coefficients of the drugs indicated that the log Ps of quincetin and digoxigenin were-0.96±0.94 and 2.44±0.26,respectively,which provided the physicochemical parameters of the model drug for subsequent formulation design.3 Construction and characterization of ES-DIG-FNLSolvent evaporation method was used to prepare flexible nanoliposomes,EE and DL were used as evaluation indicators of nanoformulations and the final optimal prescription was determined.The dosage of lecithin was 100 mg,the dosage of cholesterol was 10 mg,the dosage of propylene glycol was 33 mg,the concentration of penetration enhancer Gelucire 44/14 was0.5%,and the dosage ratio of aqueous phase to organic phase was 5:1.The appearance of ES-DIG-FNL was clear and transparent,and the particle shape was round.The particle size was98.34±0.78 nm,PDI was 0.271±0.05.4 Construction and characterization of ES-DIG-FNL-TSGThe temperature-sensitive gel was prepared by the condensation method and the gelling temperature was used as the evaluation to select the excipients.The dosage of P407 was 24%,and the dosage of P188 was 5.5%.The flexible nanoliposomes were loaded into the gel to finally prepare ES-DIG-FNL-TSG.The rheological investigation showed that the phase transition temperatures of ES-DIG-FNL-TSG before and after dilution were 26.2℃and33.9℃.The prepared ES-DIG-FNL-TSG had good mechanical and rheological properties and was suitable for ocular administration.5 In vitro study of ES-DIG-FNL-TSGThe in vitro erosion experiments of ES-DIG-FNL and ES-DIG-FNL-TSG showed that the erosion ability of the gel was only closely related to the gelling excipients.The in vitro release indicated that the drug release behavior was slow release,which conformed to the first-order model.Meanwhile,the results of cytotoxicity and histopathological sections indicated that the nanoformulations were safe and less irritating.6 In vivo study of ES-DIG-FNL-TSGThe pharmacokinetics of microdialysis in the eye was studied and the non-compartmental model was used to calculate the pharmacokinetics.It was clarified that the AUC and C_max of ES in ES-DIG-FNL were increased by 2.58 times and 1.68 times compared with the control solution,respectively（P<0.001）;the C_max of DIG in ES-DIG-FNL increased by 1.40 times（P>0.05）,and the AUC increased by 2.74 times.In ES-DIG-FNL-TSG,the C_max of ES was increased by 1.48 times（P>0.05）,and the AUC was 3.79 times（P<0.001）;the C_max of DIG in ES-DIG-FNL-TSG was 1.54 times（P<0.05）and the AUC was 3.94 times（P<0.001）.In conclusion,ES-DIG-FNL and ES-DIG-FNL-TSG can more effectively improve the problem of difficult absorption in vivo caused by the physicochemical properties of drugs.At the same time,the phase transition advantage of the temperature-sensitive gel solved the problem of short drug retention time due to the special physiological structure of the eye.It is a nanocarrier suitable for ocular drug delivery.Finally,this study constructed a trinity nanogel composite drug delivery system of“gel erosion-nano sustained-drug release”,which improved the ocular bioavailability of ES and DIG.