Preparation And Preliminary Study Of 5-Fu And Lv Mesoporous Silica Colon-Targeted Pellets

Purpose:Colon cancer is one of the more common intestinal malignancies.5-fu/lv intravenous injection is mainly used in clinic,but the side effects are great.In this study,5-FU@MSN-NH₂/GCcolon-targetedsustained-releasepelletsand LV@MSN-COOH/GC colon-targeted immediate-release pellets were prepared by5-FU@MSN-NH₂/GC and LV@MSN-COOH/GC with galectin-3 mediated endocytosis.It not only prevents the release of the drug in the intestines such as the stomach and small intestine,but also makes the pellets release when they arrives at the colon site,and can makes LV releases first and 5-FU later.Enhance the effect of5-FU and reduce systemic toxicity.Method:Firstly,the method for detecting the content and in vitro release of 5-FU and LV in pellets was established,and the methodological investigation was carried out.Then,microcrystalline cellulose?MCC?,lactose and carboxymethyl starch sodium?CMS-Na?were used as excipients and the drug-loading pellet core was prepared by extrusion spheronization using 5-FU@MSN-NH₂/GC and LV@MSN-COOH/GC as main drugs.The particle size distribution and release were used as the evaluation index,the ratio of lactose to CMS-Na,the percentage of lactose and CMS-Na,and the total amount of 5-FU@MSN-NH₂/GC or LV@MSN-COOH/GC were used as the prescription factors.Three levels were selected,and the optimized prescription for preparing the pellet core was determined by L9?3³?orthogonal test;Taking the particle size distribution and roundness?length to length ratio?as the index,the extrusion speed,the spheronization speed and the spheronization time were selected as the process factors,and the optimization process of the pellet core was determined by the L9?3³?orthogonal test.Secondly,the method for detecting the content and in vitro release of 5-FU and LV in coated pellets was established,and the methodological investigation was carried out.By aqueous bed bottom spray coating method,ethyl cellulose aqueous dispersion?Surelease,Su Lisi?as a sustained release layer and acrylic resin S100?Eudragit S100?aqueous solution containing plasticizer triethyl citrate?TEC?as the enteric layer to prepare pH Time-dependent 5-FU colon-localized sustained-release pellets and pH-dependent LV colon-targeted immediate-release pellets.The"time-delay"of pellets and the"cumulative release"of pellets in media were used as evaluation indexes,the sustained-release coating material,the sustained-release coating layer weight gain,the sustained-release coating layer plasticizing temperature,the sustained-release coating layer plasticizing time,the content of TEC in enteric coating liquid,the weight gain of enteric coating,the plasticizing temperature of enteric coating layer,and the plasticizing time of enteric coating layer were investigated to obtain optimized conditions.Finally,the method of detecting the content of 5-FU and LV in plasma was established,and the methodological investigation was carried out.The results of blood concentration and combined with the results of in vivo imaging were used to preliminarily determine the translocation of pellets in vivo.Result:Ultraviolet spectrophotometry for the determination of 5-FU and LV content and in vitro release method is simple,precise,high recovery and specificity.Prescription composition:the ratio of lactose to CMS-Na is 3:1,lactose and CMS-Na account for 25%of the total,5-FU@MSN-NH₂/GC or LV@MSN-COOH/GC accounts for 20%of the total.The technology:extrusion speed is 23Hz,spheronization speed is600r/min,spheronization time is 3min.The prepared pellets have good powder properties and the release rate meets the requirements.The drug loading rate of5-FU@MSN-NH₂/GC pellets is 4.431±0.027%,and the average drug loading rate of LV@MSN-COOH/GC pellets is 4.385.±0.027%.The high-performance liquid phase method was used to determine the content of5-FU and LV in coated pellets in vitro with high precision,high recovery rate and strong specificity.The coating technology of the sustained-release layer:inlet air temperature is 50°C,material temperature is 35°C,fan frequency is 35 Hz,peristaltic pump speed is0.8-1.0 mL/min.Surelease was selected as the sustained-release coating layer material and the coating weight gain was 40%,the plasticizing temperature is 40°C,and the plasticizing time was 2 h;The enteric layer coating process:inlet air temperature is40°C,material temperature is 30°C,The fan frequency is 35 Hz,the peristaltic pump speed is 1 mL/min,and the atomization pressure is 0.06-0.1 MPa.In the coating of the enteric layer,the plasticizer is used in an amount of 10%of the polymer,the coating weight gain is 40%,and the plasticizing temperature is 40°C,and the plasticizing time is 12 h.The drug-loading rate of the final 5-FU colon-targeted sustained-release pellets was 2.111±0.023%.The drug loading rate of LV colon-positioned pellets was 2.973±0.018%,which was almost not released in the solution of pH 1.2 and pH 6.8,and the drug was released at a faster rate in the solution reaching pH 7.4.The high-phase liquid phase method was used to determine the content of 5-FU and LV in plasma.The method has high sensitivity,good precision,high recovery rate and strong specificity.The results of blood concentration combined with in vivo imaging showed that 5-FU and LV uncoated pellets were released immediately after entering the rat body,and the drug was detected in plasma at 0.25 h,reaching the maximum concentration at 1 h,and the maximum concentration is 2.309?g/mL and2.116?g/mL respectively.The enteric coated sustained-release pellets were not released in the stomach and small intestine after entering the rat body.The drug was detected in 5-10 h,and the maximum concentration was 0.248?g/mL at 8 h.The enteric coated immediate release pellets were not released in the stomach and small intestine,and the drug was detected at 5 h,and reached a maximum concentration of0.426?g/mL at 6.5 h.Conclusion:By optimizing the formulation and process,the pellets prepared by the extrusion-spheronization method have good roundness and concentrated particle size distribution.The fluidized bed coated pellets were tightly coated.Animal experiments show that 5-FU@MSN-NH₂/GC enteric coated sustained-release pellets are almost non-released in the stomach and small intestine,and the coating layer gradually dissolves at the end of the small intestine and ileocecal region,and release drug slowly;LV@The MSN-COOH/GC enteric coated pellets are almost non-released in the stomach and small intestine,and the coating layer gradually dissolves at the end of the small intestine and the ileocecal region,and release drug rapidly.It can be seen that the design requirements for LV release first and 5-FU release later are basically realized.It not only improves the effect of oral colon localization of 5-FU,but also reduces the systemic absorption of the drug,achieving the purpose of the experiment.