Treatment And Evaluation Of Oral Intelligent Gel Drug Delivery Systems For The Ulcerative Colitis

The main disadvantage of oral treatment of ulcerative colitis（UC）is the non-specific distribution of drugs during the long-term treatment,therefore,in the long-term treatment,the drugs did not really work,and the patients did not get a fundamental treatment.It is well known that curcumin（Cur）is effective as an anti-inflammatory drug,however,it is limited due to its low bioavailability in the treatment of UC.This work explores three oral intelligent hydrogel delivery systems for the treatment of UC.First,through the combination of polyvinyl alcohol（PVA）and sodium alginate（SA）,an interpenetrating network hydrogel based on SA and PVA was prepared by means of freeze-thaw and Ca²⁺crosslinking methods.The results showed that compared with pure SA hydrogel or pure PVA hydrogel,the water absorption and degradation ability of PVA-SA complex hydrogels were significantly improved.Moreover,hydrogels showed significant p H sensitivity ability and sustained drug release for almost 24 h in simulated intestinal fluid.On the basis of aforementioned research,in order to improve the colon targeted-effect of the hydrogel delivery system,a p H sensitive hyaluronic acid/gelatin（HA/GE）composite hydrogel delivery system was prepared.The system loaded Carboxymethyl chitosan（CC）microspheres containing Cur for the treatment of UC.The composition and structure of the composite system were adjusted and optimized.The physicochemical properties of the composite system were studied by infrared spectroscopy,X-ray diffraction and swelling experiment.In vitro,the drug release rate was 65%for about 50 h.In vivo pharmacokinetic studies showed that high levels of Cur in colon tissue were maintained for more than 24 h.The anti-inflammatory effect was evaluated by evaluating the histopathological changes through hematoxylin and eosin（H&E）,myeloperoxidase（MPO）and immunofluorescence staining.In addition,compared with the control group,the formulation effectively inhibited the levels of pro-inflammatory cytokines such as interleukin-6（IL-6）and tumor necrosis factor-α（TNF-α）secreted by macrophages.Pharmacodynamic experiments showed that,the CUR@gels group had the best therapeutic effect on colitis in mice.Therefore,the composite gel delivery system has the potential for effective delivery of Cur in the treatment of colitis.Finally,in order to further enhance the colon targeted-delivery effect,the p H sensitive bilayer microgel delivery system（CUR@gels）containing with Cur microspheres in the inner core which derived from polyvinyl alcohol（PVA）and guar gum（GG）,followed by outer-membrane formation with SA and surface functionalization using chitosan（CS）.Cur was used as a treatment drug to achieve the goal of sustained release for a long time.The internal morphology of the bilayer microgel was observed by scanning electron microscope.The physicochemical properties of the hydrogel were characterized by IR and X-ray diffraction.The release behavior of the double microgels was tested.The final drug release rate was84.6%over 34 h.Pharmacokinetic experiments showed that after oral administration of CUR@gels,the Cur levels in serum,stomach,small intestine and colon can be maintained for a long time,and the clearance rate（CL）of the CUR@gels group was significantly lower than that of CUR group.The pharmacodynamic experiments in vivo showed that,CUR@gels can effectively reduce the inflammation symptoms of weight loss and colon shortening in mice.The experimental results show that the Cur loaded bilayer microgel system can effectively treat colitis induced by DSS and has potential application prospects.In summary,three gel systems have been prepared.The release and targeting ability of the model drugs can be effectively achieved through the selection of matrix materials and the design of hydrogel structure.The potential of two gel formulations in the treatment of UC has been further investigated.Both in vivo and in vitro experiments show that both can effectively reduce the level of proinflammatory cytokines in the colon and play an effective role in anti-inflammatory treatment.Therefore,oral hydrogel has advantages in targeted for colon site,as well as sustained and controlled release of anti-inflammatory drugs in UC treatment.This study provides a theoretical basis for the development and application of oral UC drugs.