Study On Adhesion Behavior And Pharmacodynamics Of Starch-based Oral Colon Targeted Bioadhesive Drug Delivery System

Oral colon targeted bioadhesive drug delivery system combined the advanta ges of bothoral colon targeted drug delivery system and bioadhesion drug delivery system. It not only canprevent drugs from a variety of enzymes and the acidic environment in the human digestivetract which can result in the negatively effects on drugs, but also avoid the first pass effect of theliver and extend the delivery time. Thus, this drug delivery system can highly improve the drugbioavailability. Therefore, oral colon targeted bioadhesive drug delivery system is suitable asthe oral delivery carriers for protein drugs because it can control the release and improve theabsorption of drug by prolonging the release time and targeting to the desire site for the drugsand the research of the carriers for this drug delivery system has become the front ier andhotspot of modern pharmaceutical research field.The early studies have shown that acetate starch has a good colonic targeting performanceand can obtain a good colon bioadhesive performance by combining with Con A. Film coatedpellets drug delivery systems used acetate starch-Con A as the carriers had the good colonictargeting performance and release properties in in-vitro experiments. On these bases of ourearly research, the preparation process of starch-based oral colon-targeting bioadhesive filmcoated pellets drug delivery systems were further optimized. Using extrusion-spheronizationand bottom-spray fluidized bed coating methods, the optimized process parameters were asfollows: extrusion temperature of6-12℃, extrusion speed of30-40r/min; spheronization speedof500-600r/min, spheronization time of5-10min; the inlet air temperature30-35°C,atomization pressure range of0.125-0.2MPa, fluidized pressure range of0.1-0.15MPa. Thestarch-based oral colon-targeting bioadhesive film coated pellets drug delivery systemsconstructed in these optimized conditions showed better targeting and releasing properties invitro.At the cellular level, the adhesion behavior between plant lectin and cells was investigatedusing multi-function fluorescent microplate reader. The specific adhesion behavior between thedifferent lectin such as Con A、LCA、PSA、PNA、PVE、UEA、DBA、GNA and thedifferent epithelial cells of human digestive tract such as MGC803, Hic, Caco-2was examined and the external factors which affected the adhesion behavior were estimated. The resultsindicated that Con A had good specific adhesion to the Caco-2colonic epithelial cells and canbe used as ligands for the carrier of oral colon targeted bioadhesive drug delivery systems. Theconcentration of the plant lectin, incubation time, incubation temperature and the pH ofincubation environment had a significant impact on the adhesion behavior between the Con Aand the Caco-2cells. Meanwhile, the adhesion forms of Con A on the Caco-2cells underdifferent temperatures were observed by laser confocal microscopy. The results showed that atlow temperatures, Con A was uniformLy distributed on the cell surface and at37°C, Con A wasspecifically aggregated in the surface of the cells, indicating that this specific adhesion isrelated to the receptor location on the surface of the Caco-2cells and the support of the energygenerated by the cell metabolism.Furthermore, the pharmacodynamics of the starch-based oral colon targeted bioadhesivedrug delivery system was evaluated through animal experiments. After treatment with the oraladministration of the starch-based oral colon targeted bioadhesive insulin delivery system to thetype2diabetic rat model, the results showed that this drug delivery system had goodhypoglycemic effect and prolonged the insulin releasing time in vivo which can reach to60hours. The starch-based oral colon targeting bioadhesive insulin delivery system with50IU/kgcan achieve a similar hypoglycemic effect as compared with that of the insulin injectiondelivery system with35IU/kg. This research showed that the oral administration of insulin canbe successfully realized through the starch-based oralcolon targeting bioadhesive drug deliverysystem. In addition, a better pharmacodynamic evaluation system complete oral insulindelivery system also established.These researches and results not only provide guidance and basic data for the clinicalapplication of the starch-based oral colon targeted bioadhesive carrier material and itscorresponding drug delivery systems but also promoted the development of oral colon targeteddrug delivery systems and bioadhesive drug delivery systems.