Study On The Manufacture And Vitro Release Of Oral Colon-specific Ketoprofen Pellets

This project chose insoluble ketoprofen as a model drug. Bacteria-triggered colon specific drug delivery pellets were prepared by enzyme-controlled colon specific drug delivery principle.The aim was as following:improve the characteristic of colon specific drug delivery, increase local drug concentration of colon and bioavailability, reduce drug adverse reaction in gastrointestinal tract and raise patients' compliance.1. In this study, HPLC was developed for in vitro assay during the study of content of ketoprofen pellets. And UV spectrophotometry was developed for in vitro assay during the study of drug-loading rate, entrapment rate and release of ketoprofen pellets. And the technology investigation was carried out to these analytical method. The results indicate that the two analytical method were both accurate and can be used as in vitro assay of ketoprofen.2. Three kinds of free films (chitosan-pectin free films, pectin-zinc free films,chitosan-pectin-zinc films) were respectively prepared with chitosan, pectin and pectin-zinc as film materials. One principle was polyelectrolyte formed from electrostatic interaction between polyainons and polycations.The other principle was insoluble pectin-zinc formed from pectin and zinc ions. The drug releasing barrier role in gastrointestinal tract which was created by different composition polysaccharides carrier materials and colon-targeted releasing characteristics were initially evaluated by inspecting the affection to free films' physicochemical properties (appearance, expansibility,permeability, vapor permeability) from prescription composition and mediator environment. The results reveal that the films-forming effect of free films which was prepared as the optimization of prescription and its permeability were well.Besides, the chitosan-pectin-zinc films was superiority in expansibility and permeability than the others. When in presence of enzyme the permeability coefficient is bigger than in absence of enzyme. This project provides a simple method to choose colon-targeted carrier materials.3. Ketoprofen pectin-calcium colon releasing pellets were prepared with calcium chloride cross linking agent by the principle that pectin and calcium ions can form insoluble pectin-calcium. We inspected the affection of prescription composition to pellets' compactibility,drug-loading rate and entrapment rate, optimized the prescription, and determined vitro releasing rate to optimizing prescription by imitating pH environment in gastrointestinal tract.The results indicate that the pellets' compactibility prepared by optimizing prescription is not very good, the accumulated releasing rate is less than 10% in artificial gastric juice for 2 hours, while it is about 90% in artificial intestinal juice for 4 hours. The prepared pellets can control drug releasing in the upper gastrointestinal tract in some extent. If we improved its intensity, controlled its releasing in intestine section, we would expect that the aim of colon specific drug delivery can be achieved.4. Pectin and zinc ions can generate pectin-zinc which can control the releasing of drug before its releasing at colon. We prepared Ketoprofen pectin-zinc colon releasing pellets with zinc acetate as a cross linking agent instead of calcium chloride.We inspected the affection of prescription composition to pellets' compactibility,drug-loading rate and entrapment rate, optimized its prescription and determined vitro releasing rate to optimizing prescription by imitating pH environment in gastrointestinal tract. The results indicate that the compactibility of Ketoprofen pectin-zinc pellets is better than pectin-calcium pellets, the accumulated releasing rate is less than 10% in artificial gastric juice for 2 hours, while it is more than 80% in artificial intestinal juice for 4 hours, but the releasing dose of pectin-zinc during the first 2 hours is less than the pectin-calcium pellets' in artificial intestinal juice. The prepared pellets can control drug releasing in the upper gastrointestinal tract in some extent. Compared with pectin-calcium pellets, the compactibility of pectin-zinc pellets is obviously improved. We still need to improve the control of drug releasing in intestine section to achieve colon specific drug delivery.5.To improve colon-targeted drug delivery, this project used chitosan. Polyelectrolyte between chitosan and pectin made the pectin free carboxy which can be crossed by zinc ions and chitosan together, and forming more strengthen gel net structure to control the releasing of drug before its releasing at colon. We prepared Ketoprofen chitosan-pectin zinc colon-targeted pellets by this principle. We inspected the affection of prescription composition to pellets' compactibility,drug-loading rate and entrapment rate, optimized its prescription and determined vitro releasing rate to optimizing prescription by imitating pH environment in gastrointestinal tract. And for the prepared pellets, we inspected the affection of prescription composition to pellets' vitro release. The results indicate that the compactibility of Ketoprofen chitosan -pectin zinc colon-targeted pellet was very good and the inlet of chitosan lower the pH sensitivity of the pellets as well as increase the intensity. The accumulated releasing rate of Ketoprofen chitosan-pectin zinc colon-targeted pellet can be effectually controlled nearly 40% in artificial intestinal juice for 8 hours.