| There are many disadvantages in the commonly dosage forms of ophthalmic administration.After administration,they are mostly lost due to blinking and elimination of nasolacrimal ducts,resulting in poor bioavailability.Lipid-based and polymer-based ophthalmic nano-delivery systems have been used to improve ocular absorption of drugs.Hence,in this study,QUE and CUR were selected as model drugs by using molecular docking and MD simulation.Afterwards,lipid-based nanoemulsion and polymer-based nanomicelle ocular delivery system were prepared.Furthermore,the in vitro release,cytotoxicity and uptake,ocular irritation,and tear pharmacokinetics were comprehensively studied and evaluated.Additionally,the feasibility of improving the ocular bioavailability of the drugs with two kinds of nano-preparations was studied to provide theoretical and experimental basis for the design of efficient ocular preparations.1 Screening of model drugs based on molecular docking and MD simulationQUE and CUR were virtually selected as model drugs by molecular docking technology.The MD simulation results showed that after QUE and CUR were added into VEGFR2system,the structure of the residues near Lys858 changed greatly.The results indicated Lys858 is the target of action.Cluster analysis of the last 100 ns of MD simulation showed that the binding energy of CUR with VEGFR2 was higher than that of QUE,and the interaction between CUR and VEGFR2 was stronger,which was consistent with the results of molecular docking.2 Study on the physicochemical properties of QUE and CURA high performance liquid chromatography（HPLC）method was used to establish a determination method for the content of QUE and CUR.The methodological investigation results showed that the linearity,precision,reproducibility and recovery all met the requirements of content determination.Moreover,the oil-water partition coefficients of QUE and CUR were 1.39±0.02 and 2.64±0.05,respectively.3 Preparation and characterization of multi-component nanoemulsion of TCMBy investigating the equilibrium solubility of QUE and CUR in different excipients and drawing pseudo ternary phase diagrams,the types and dosage of different excipients were determined as follows:water phase is 17.5 mg,triacetate is 0.9 g,mixed surfactant is 1.6 g,QUE is 9 mg,CUR is 18 mg and m PEG-chitosan is 30 mg.Under this prescription,the EE of QUE and CUR was（98.93±1.11）%and（98.15±2.31）%,and the DL was（3.56±0.14）mg·g-1and（7.07±2.05）mg·g-1,respectively.The particle size（PS）of NE was（14.70±0.66）nm,polydispersity index（PDI）was 0.173±0.02 and zeta potential（ZP）was（34.4±1.37）m V.Furthermore,the microscopic morphology is spherical or spheroidal particles.4 Preparation and characterization of multi-component nanomicelle of TCMNanomicelle was prepared by solvent evaporation method,and the effects of preparation formula on the EE and DL were studied by single factor experiment.The optimal formulation was determined as follows:P407 was 1 mg·m L-1,soluplus was 120 mg,m PEG-CS was 30mg,gelucire 44/14 was 1%（w/v）,QUE was 3 mg and CUR was 6 mg.The EE of QUE and CUR was（97.90±0.44）%and（97.79±0.52）%,and the DL was（1.91±0.02）%and（3.97±0.93）%,respectively.The PS of NM was（94.07±3.16）nm,PDI was 0.194±0.01 and ZP was（17.8±0.71）m V.The microscopic morphology is spherical or spheroidal particles.FT-IR,DSC and XRD results showed that the drugs were encapsulated in the preparation in molecular form.5 In vitro evaluation of multi-component nano-preparations of TCMA method for the determination of the release of QUE and CUR in vitro was established,and the characteristics of drug release in vitro were studied by dynamic dialysis method.The results showed that the in vitro release of QUE and CUR conformed to the First-Order model.Additionally,the drug showed sustained and slow release.6 Study on cell biology of multi-component nano-preparations of TCMCCK-8 method was used to evaluate the toxicity of nano-preparations to human retinal pigment epithelial cells（ARPE-19）.The results showed that the nano-preparations had no effect on cell activity in a certain concentration range.Furthermore,cell uptake results showed that the uptake of C6-NE and m PEG-C6-NE by cells was 1.18-fold and 1.26-fold higher than that of C6-solution,respectively（P<0.01）.The uptake of C6-NM and m PEG-C6-NM by cells was 1.09 and 1.17 times higher than that of C6-solution,respectively（P<0.05）.Compared with the control group,the two kinds of nano-preparations prepared in this experiment could be successfully absorbed by cells.7 In vivo evaluation of multi-component nano-preparations of TCMWith physiological saline as the control group to evaluate the rabbit eye irritation of the nano-preparations.The modified Draize eye irritation test and the histopathological analysis results showed that both nano-preparations had no obvious irritant,which confirmed the safety of the nano-preparations.The pharmacokinetics of nano-preparations was studied with drug solution as control group.The pharmacokinetic parameters of tears showed that the AUC（0-∞）of QUE in QUE-CUR-NE and m PEG-CS-QUE-CUR-NE were 1.43 and 2.01 times higher than that of solution group（P<0.01）,and the AUC（0-∞）of CUR was 1.98 and 2.51 times higher（P<0.01）,respectively.The AUC（0-∞）of QUE in QUE-CUR-NM and m PEG-CS-QUE-CUR-NM was 1.92 and 2.69 times higher than that of solution group（P<0.01）,and the AUC（0-∞）of CUR was 2.83 and 3.59 times higher（P<0.01）,respectively.Therefore,all nano-preparations could prolong the action time of quercetin and curcumin in tears.Therefore,the two kinds of nano-preparations could improve the stability and ocular bioavailability of QUE and CUR in different degrees,and had a certain sustained release effect.Besides,nanomicelle had a more significant effect on improving the ocular absorption of drugs.Therefore,nanomicelle was more suitable as a nanocellular carrier for ocular drug delivery.Meanwhile,nanomicelle also had certain advantages due to their large drug loading capacity,good stability and low irritation.Additionally,compared with ordinary nano-preparations,nano-preparations modified by m PEG-CS had a more significant effect on improving the ocular bioavailability of drugs QUE and CUR,which provided a reference for the ocular delivery system of hydrophobic drugs. |
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