| Oral colon-specific drug delivery system(OCDDS)has gained much interest during the past decade.Two important therapeutic applications which can be found for OCDDS are the treatment of local disorders of the colon and the delivery of protein and peptide drugs via the oral route.In recent years,the ulcerous colonitis (UC)incidence rises continuously,and was classified as one of the difficult and complicated cases by World Health Organization(WHO).The investigations of etiopathogenisis,pathogenesis and therapeutic medicine are constantly warm spots in this territory,which draw more attentions from medicine vocation of home and abroad.Compared with western medicine,Chinese medicine has better curative effects,less adverse reactions and lower recurrence rate,but the laggard dosage forms restrict its function.Thus the research on oral colon-specific target delivery system for ulcerous colonitis in TCM is very important and urgent.Folium syringae is one species of Oleaceae families,mainly contained syringa oblata lindl,syringa vulgaris L and syringa diatata Nakai.This plant distributes mainly in the temperate zone of northeast area and Northern China,as a well known ornamental and horticultural plant.The taste of leaves of this plant is bitter strongly, and whose nature character is cold.As one of traditional Chinese folk herbS,it has been used to antibiosis,diminish inflammation and cholagogue.Recently,the pharmacological functions of Folium syringae have been studied by many scholars, the result indicated that it has marked broad-spectnun antiseptic and antiviral curative effects,and had been listed in Drug Standards of Heilongjiang.The main preparations of Folium syringae are Yanlixiao capsules and tablets,which had been listed in Drug standard of Ministry of Public Health to treat chordapsus,upper respiratory infection, acute icterohepatitis and bacillary,dysentery.The active fraction of Folium syringae is an effective drug for the treatment of inflammatory bowel disease.Following oral administration of conventional preparations,the active components would be extensively absorbed from the upper gastro-intestinal tract,with little of the drug reaching the colon.However the active components are thought to exert a mainly local action.Therefore the active components of Yanlixiao preparations should be designed to release the drug in the terminal ileum and colon,providing a low systemic absorption and reducing the incidence of systemic side effects.The objective of our study was to develop a colon-specific drug delivery system.In this thesis,the active fraction of Folium syringae was selected as the model drug to prepare a colon-specific delivery system for pH-dependent and time-contolled coated tablets with acrylic resin water dispersion coating technique to treat chronic ulcerative colitis because of the high content,more extensive basic researches and good curative effects.The indexes i(?)cluding chemical composition and biological activity,were adopted to study the extracting technology of active fraction of medicinal materials in preparation.The qualitative and quantitative analysis methods were developed to control the inherent quality of the preparation.Based on these results,the pH-dependent and time-contolled coated tablets delivery to the colon was investigated.With the enrichment degree of syringae as an index,the analytical method of HPLC was developed,AB-8 macroporous resin was selected as the purification medium,and the optimal conditions of the enrichment process were investigated.The active fraction of Folium syringae was ext(?)acted with water,precipitated with 70% alcohol and purified with AB-8 macropore resin.The optimal conditions showed that the extract of Folium syringae was taken into AB-8 resin column,the resin was washed by 4 times of distilled water to get rid of impurity and 5 times of 50%ethanol to elute syringae,and the average content(?)as 47.56%.The result indicated that this extraction and purification methods was economic and efficient,and provided a way to research new medicine delivery system.Yanlixiao colon-specific targeting coated tablets were prepared by a sugar coater,with multi-layer coating technology,using HPMC as sealing-coat layer, Eudragit L30D-55/S100 as enteric-dissolved layer,and Eudragit RL30D/RS30D as sustained-release layer,using triethyl citrate as plasticizer and talc powder as antisticking agent.An optimal prescription was obtained by orthogonal design.The drug dissolusion rate in vitro was studied in simulating gastrointestinal circumstances. The result of orthogonal experiment showed that combination of Eudragit L30D-55/S100 was 1:5,coating weight was 5%;combination of Eudragit RL30D/RS was 1:1.5,coating weight was 2%,were the optimal formulation.There was no drug released in 0.1moL·L-1hydrochloric acid solution for 2 hours.In pH6.8 phosphate buffer,dissolution rate was less than 10%for 3 hours.In pH7.5 phosphate buffer,the coated tablets showed sustained-release behavior,about 70%of the drug would be released to colon region for 12 hours.The accumulated dissolution rate was over 80%.A simple,rapid and sensitive high-performance liquid chromatographic method for the simultaneous determination of syringopicroside in plasma.The calibration curve for syringopicroside was linear between 0.524μg·mL-1～52.4μg·mL-1.The pharmacokinetics of syringopicroside in six healthy rabbits was Studied with the naked tablets as a reference preparation.The results indicated that the systemic absorption of the colon-specific coated tablets was significantly Lower than that of the core tablets(p＜0.001).For the core tablets and the colon-specific coated tablets,the AUC0-36of syringopicroside were 75.306 mg/L·h and 202.383 mg/L·h respectively. The lag time of in vivo absorption for syringopicroside was 4.619h,which was identical with that of in vitro release.Thus it is demonstrated that the colon-specific coated tablets reduce the systemic absorption of syringopicroside and release drug into the ileum and colon.In this subject,the ulcerative colitis(UC)rat models were induced by TNBS. The colon pathological changes of every group were observed under light microscope by HE stain.Apoptosis in the colon tissue was observed and detected with TUNEL method.The expressing proteins of Fas,Bcl-2,Bax,Caspase-3 and NF-κBp65 in the colon tissue were observed and detected by immunohistochemistry method.The experiment adopted toβ—actin as house-keeping gene,got the standard curve,and established a real-time PCR method to detect Fas,Bcl-2,Caspase-3 and NF-κBp65 gene transcriptions,in order to research the molecular biology mechanism and treatment effect of the active fraction of Folium syringae on molecular level,and make a progress for treatment UC with TCM.
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