Preparation And Preliminary Study Of Targeted Pellets Of 5-Fu/Lv Combined With Drugs

Purpose:The study focuses on the preparation and preliminary study of 5-Fu/Lv?5-Fluorouracil/Calcium folinate?combined colon targeted pellets.It explores that using oral replaces injection of the two drugs alternated with each other frequently in the clinical to improve the bioavailability and toxicity.Methods:The study prepared 5-Fu sustained-release colon targeted pellets and Lv immediate-released colon pellets,respectively.In the first part,the ultraviolet measurement method?3-27?g/mL?and a high performance liquid measurement method?3-27?g/mL?of 5-Fu were established;5-Fu-GC-SA-NPs prepared by GC?galactosylated chitosan?and the ion-crosslinking were determined the optimal prescription with single factor;5-Fu pellets and 5-Fu-NPs sustained-release pellets prepared by the extrusion-spheronization was determined the optimal prescription with the single factor and the orthogonal design;the HPMC coated sustained-release pellets,the adherent pellets coated with GC,and the colon-soluble pellets coated with Eudragit S100 prepared by a fluidized bed coating was determine the optimal prescription with the single factor.The method of preliminary evaluation for pellets in vitro and in vivo were as follows:release in vitro was used to investigate the time-delay type and pH-targeting properties of the pellets,the chute rinse was used to investigate the adhesiveness,the in vivo imaging ang pharmacokinetics was used to investigate the targeting in vivo.In the second part,the ultraviolet measurement?3-27?g/mL?of Lv was established to determine the preparation of Lv immediate release pellets,and the prescription and process optimization of them were determined with the single factor;Then,the colon-soluble Lv pellets coated with Eudragit S 100 and the colon targeting were investigated.The absorption of the drug in the colon was examined by the single-pass intestinal perfusion?SPIP?of 5-Fu,5-Fu-NPs and Lv.Results:Methodological studies showed that 5-Fu and Lv were not interfered by excipients in the measurement range and the precision,recovery and standard curve meet the requirements.In the first part,the optimal prescription of 5-Fu-GC-SA-NPs was as follows:GC concentration was 1.6 mg/mL?15 mL?,SA concentration was 2.0 mg/mL?25 mL?,5-Fu amount was 90 mg and CaCl2 volume was 70 mg;The best prescription of the 5-Fu pellets was as follows:5-Fu:MCC:CMS-Na:Lactose:Water=3:21:2:6:35;The optimum process of the 5-Fu pellets was as follows:the extrusion speed was 23r/min,the rounding time was 4 min and the rounding speed was 600 r/min;The best prescription of the 5-Fu-NPs pellets was MCC:CMS-Na:MCC:Lactose:H₂O=13:1:3:17 and the optimum process is the same as the drug-containing pellets;The optimal weight gain of the HPMC-coated slow-release pellets was 8%,which achieved a predetermined sustained-release effect;The best weight gain of the GC-adhered coated pellets was 3%,which achieved better adhesion;The best weight gain of the colon dissolving coated pellets was 110%,which achieved release rarely in the stomach and small intestine but release in the colon;There was the good effect about colon targeting of the pellets based on vivo imaging and pharmacokinetic.In the second part,it was determined that Lv immediate release pellets were prepared by coating 1 mg/mL Lv solution.The optimal weight gain of colon coating was 130%,which achieved colon targeting in vitro.The results of the single-pass intestinal perfusion?SPIP?showed that the absorption of Lv was more better than 5-Fu and 5-Fu-NPs in the colon and 5-Fu-NPs was more batter than 5-Fu.Conclusion:The 5-Fu/Lv combined colon targeting pellets was prepared by the combination of nano-preparations and pellets.The preliminary studies presented it achieved multi-targeting of the colon and the interval release between 5-Fu and Lv.And it is feasible that using oral replaces injection of the two drugs alternated with each other frequently in the clinical.The mode of administration can reduce the toxicity greatly and improve the efficacy.