| Resveratrol is an active substance with a variety of biological activities such as anti-inflammatory and antioxidant,and has broad prospects for industrial application in the field of oral and transdermal delivery.There are problems such as low solubility,poor stability,and low bioavailability of resveratrol,which seriously affect its practical application.The encapsulation of resveratrol in lipid nanocarriers can effectively improve the water solubility and loading capacity,however,its poor stability,poor compatibility,and poor controlled slow release can not be completely solved.In order to solve the above problems,this paper based on resveratrol lipid carriers using secondary wrapping technology,successfully constructed lipid nanocarrier-hydrogel composite system,conducted structural characterization,performance evaluation,and initially explored the anti-inflammatory and in vitro antioxidant mechanism of the composite system,laying a good foundation for its industrial application.In this paper,lipid nanocarrier-hydrogel composite systems loaded with resveratrol were prepared for oral and transdermal delivery applications,respectively,and the main research contents of this study are as follows.（1）First,resveratrol-loaded NLC-chitosan hydrogel beads（System 1）were prepared for the application of resveratrol-loaded nanostructured lipid carriers（NLC）in transdermal delivery.It was shown that the highest encapsulation efficiency of resveratrol（95.7±1.36%）was achieved at chitosan concentration of 5.0%,sodium tripolyphosphate concentration of 0.5%and cross-linking time of 30 min.The results of DLS,SEM,XRD,DSC,and FTIR indicated that the chitosan hydrogel beads did not significantly affect the mean particle size,morphology and internal structure of resveratrol-loaded NLC,which were only physically mixed.The results of stability studies showed that chitosan hydrogel beads significantly improved the high temperature stability of resveratrol-loaded NLC.In vitro antioxidant studies showed that the in vitro antioxidant activity was concentration-dependent,and its own antioxidant properties were not affected by the secondary coating.The results of in vitro release studies showed that the System 1 exhibited a sustained effect on the release of resveratrol.Compared with free resveratrol,System 1 not only significantly increased the transdermal permeation and intradermal distribution of resveratrol,but also significantly inhibited inflammatory mediators and inflammatory factors.However,in comparison,resveratrol-loaded NLC-chitosan hydrogel beads exhibited better anti-inflammatory effects and also promoted the release of anti-inflammatory factors.（2）Secondly,for the application of resveratrol-loaded Pickering emulsion in oral delivery,Ca2+/K+double crosslinking was used to prepare resveratrol-loaded Pickering emulsion sodium alginate/κ-carrageenan hydrogel beads（System 2）.It was demonstrated that proper adjustment of the ratio of salt concentration(Ca2+and K+)in the cross-linking solution could improve the encapsulation efficiency,swelling resistance,and hardness of the hydrogel beads.SEM studies indicated that the hydrogel beads were spherical and the Pickering emulsion was encapsulated in the hydrogel beads.FTIR studies showed that the hydrogel beads were formed by physical cross-linking.XRD suggested that resveratrol in System 2 was in a molecularly dispersed or dissolved state.In addition,System 2 improved the photostability and thermal stability of resveratrol without affecting its antioxidant capacity.In vitro digestion studies showed that the hydrogel beads prepared with suitable salt concentration ratios were able to control the release of resveratrol and the bioavailability of resveratrol was enhanced.The cellular uptake study results demonstrated that for the same concentration of resveratrol,the uptake of resveratrol in hydrogel beads by Caco-2 cells was significantly higher than that of free resveratrol at the same concentration within 24 h.Moreover,System 2 could significantly increase the permeation of resveratrol in the Caco-2 monolayer cell model.（3）Further,in order to further broaden the application scope of resveratrol-loaded Pickering emulsion in the field of oral delivery,resveratrol-loaded Pickering emulsion sodium alginate/pectin hydrogel beads（System 3）were prepared.The hydrogel beads were prepared by cross-linking sodium alginate and pectin in different mass ratios（9:1,8:2,7:3,6:4 and 5:5）and Ca2+.The encapsulation efficiency and loading capacity of resveratrol could be improved by adjusting the ratio of sodium alginate and pectin.SEM studies showed that the hydrogel beads were spherical and the Pickering emulsion was uniformly distributed in the polymer network.FTIR studies indicated that the hydrogel beads were formed by physical cross-linking.XRD studies showed that resveratrol was present in the hydrogel beads in an amorphous form.In addition,the stability studies and antioxidant studies showed that the hydrogel beads could provide protection to resveratrol from degradation under light and high temperature while maintaining the antioxidant capacity.Importantly,at suitable sodium alginate/pectin ratios,hydrogel beads significantly reduced the release of free fatty acids during in vitro digestion.In addition,compared with free resveratrol,the hydrogel beads still had strong antioxidant capacity after simulated gastrointestinal digestion,inhibiting lipid peroxidation,with significantly lower intracellular malondialdehyde（MDA）content and significantly higher antioxidant enzyme activity,exerting better protective activity against cellular oxidative stress.（4）Finally,the resveratrol liposome temperature-sensitive gel（System 4）for intravaginal use was prepared using the gelling temperature as an indicator,a single-factor investigation of the blank gel matrix,and optimization of the preparation process.The study showed that the system has good centrifugation,dilution,and resting stability.In vitro antioxidant studies showed that its antioxidant activity was superior to that of commonly used commercially available commercial products.In vivo retention studies showed that the gel should be used with minimal activity to prolong its residence time in the body.In vitro release studies showed that this system has a moderate release effect on the release of resveratrol.Compared to free resveratrol,this system not only significantly increased the transdermal permeation of resveratrol but also the intradermal distribution of resveratrol.Anti-oxidative damage repair studies showed that resveratrol liposome temperature-sensitive gel could repair the oxidative damage caused by H2O2 to L929 cells.At present,the system has been successfully industrialized and applied.In summary,the application of lipid nanocarrier-hydrogel composite system can improve the stability and transdermal permeation of resveratrol,further control the release and digestion rate of resveratrol,improve the anti-inflammatory activity and antioxidant activity,thus achieving the purpose of improving bioavailability.It is promising to solve the bottleneck of resveratrol,lipid nanocarriers,and hydrogels for application.It broadens the ideas for the development of novel carrier systems and their application in the fields of oral delivery and transdermal delivery. |
