Studies On Synthesis Of Colon- Specific Prodrugs Of Andrographolide And Their Release Behaviors

Ulcerative colitis is a common digestive system disease,which is difficult to cure.The incidences of ulcerative colitis are increasing in recent years.However,most of the therapeutic drugs,which are currently used topically to treat ulcerative colitis,are not satisfactory because of their remarkable side-effects and poor long-term effects.So safe and effective medication for the treatment of ulcerative colitis are lacking.Andrographolide is one of the main active ingredients of andrographis.It possesses a wide range of bioactivities such as antiviral,antibacterial,anti-inflammatory and anti-tumor activity.Varieties of andrographolide derivatives have been proved effectively in the treatment of inflammatory bowel disease in clinic.However,the study on gastrointestinal absorption of the active ingredients of andrographis revealed that,the low bioavailability of andrographolide may make people difficult to obtaining a satisfactory curative effect.In this study,the enzyme-controlled oral colon-specific drug delivery system was taken as model,and the andrographolide was grafted to dextran to synthesis a series of polymer prodrugs which with different structures and molecular weights.The release behaviors of the prodrugs were studied in vivo.Specific work includes the following aspects:(1)First of all,dehydroandrographolide monosuccinate(SDA)and dehydro-andrographolide succinate(DDA)were synthesized and their reaction conditions was investigated to find out a optimum technological conditions.The optimum technological conditions for synthetize SDA is DA:succinic anhydride:DMAP=1:1:0.7,and for DDA is DA:succinic anhydride:DMAP=1:4:6.(2)The effects of condensation agent,mole ratio,reaction time for coupling conditions were studied to determine the optimum technological conditions:the molar ratio of the synthesis of SDA-DEX is 1:5:5:2.5(SDA:EDCI:NHS:DEX),reacted for 6 days at room temperature.A series of chain-like and reticular molecule prodrugs with different molecular weights were synthesized.The structure of the prodrugs were were characterized by ~1H-NMR,IR and UV,and the measuring method of drug loading was established.The DDA-DEX drug loading dosage of DDA-DEX was about 5-6%,while the SDA-DEX drug loading can reach 7-9%.The molecular weight of DEX has little impact on the drug loading dosage of the prodrugs.(3)SDA-DEX-7W and DDA-DEX-7W were taken for research objects to investigate the release behaviors in vivo of prodrugs with the molecule structure of chain-like or reticular.The results showed that,prodrugs with the molecule structure of chain-like or reticular showed good colon targeting property and sustained-release effect.After oral administration of the prodrugs,the percentage of DA content in caecum and colon were much higer than that of control group.However,chain-like structure prodrugs release more drug than reticular prodrugs.So,the chain-linke structure prodrugs showed a better effect on oral colon-specific drug delivery than reticular.(4)The drug release behaviors of prodrugs with different molecular weights were examined.The results showed that the increase of molecular weight and reticular molecule structure could hinder the release of DA in caecum and colon site.SDA-DEX-1W has the most excellent capability on oral colon-specific drug delivery as andrographolide prodrugs.