Study On Duodenum-specific Drug Delivery System

Duodenal ulcer (DU) is a kind of chronic disease commonly found in digestive system with the symptoms of repeated pain in the superior belly, periodically and regularly. It is believed as a defection occurred in the duodenal mucous membrane, usually followed by bleeding, perforation, and duodenal cancer. Up to now, there is no a single drug which can effectively deal with DU. Therefore, program about triple treatment or quadruple treatment was widely used in DU clinical therapy, which centered by drug eradicating the helicobacter pylori (Hp).The aim of our study is to establish a kind of duodenum-specific drug delivery system. Due to the special environmental pH of the ulcer duodenum, we synthesized pH sensitive polymer HPMCT as a coating agent that dissolve at around pH 4. On the basis of it, berberine hydrochloride tablets coated with pH sensitive film was prepared. Therefore, the drug release in duodenum can be controlled by the pH sensitivity of the HPMCT layer. Model drug-berberine hydrochloride as an antibacterial drug with broad spectrum has been proved effective to peptic ulcer.HPMCT was synthesized and the pharmaceutical propertieswere investigated . In addition, we conducted systemic investigation on the formulation screening about the core and film, preparing method, release method in vitro and quality evaluation .The in vitro drug release experiment proved that, the purpose of duodenum-specific drug delivery system was achieved initially.To obtain pH-sensitive HPMCT (Hydroxypropyl methycellulose trimellitate) polymer, Hydroxypropyl methycellulose(HPMC) as a base polymer was modified with trimellitic anhydride at various degree of substitution . The structure of this polymer was characterized by FT-IR and its pharmaceutical properties such as film forming, dissolution behavior, pH-sensitive values, water vapor permeability of the free film, tensile strength, and Tg were investigated. It proved that the material has high pH sensitivity. Change the reaction conditions such as ratio of HPMC/TMA or the amount of catalyst, we can obtain HPMC derivatives that have slightly different pH sensitive point. The experiment showed that HPMCT has good film forming property and can be used as an ideal pharmaceutical coating material.Considering characteristics of berberine hydrochloride and the purpose of our project, we improve formulation and preparing method of tablet core on the basis of some formulations. The tablet core was prepared by wettinggranulation compression. After the excipients were selected, basic formulation formed, including pregelatinized starch as fillers, PVPK30 as adhesives, CMS-Na as disintegrants. According to the regulations in Chinese Pharmacopoeia (2000), the determination method was set up for the dissolution rate, buffer solution and gastric fluid as dissolution medium respectively. Fast-released tablet was obtained using one factor screening test.Based on the preliminary study about the concentration of coating solution and coating technology, berberine hydrochloride tablet core was coated by 2% HPMCT solution in a mixer of acetone/ethanol (1/1, v/v) using trundle pan coating method. Orthogonal project was employed to optimize the coating prescriptions which based on the study of mono-factor experiment, with the dissolution rate in buffer solution and gastric fluid respectively, the amount of water vapor permeability of film as index. This part adopted grade to evaluate influence factors and levels synthetically according to results. The optimized prescription include 20% Tweens 80 as bore maker, 10% dibutyl phthalate as plasticizer and 2% Coating amount. The in vitro release experiment of coated tablet demonstrates that the optimized coating formulation meet the requirements of our research. The results indicate coated tablet has advantages over conventional sugarcoating tablets in DU-specific drugdelivery.The dissolution condition test in vitro drug release experiment indicates, the release behavior employing paddle method similar to that of the rotating basket method. However, different rate of the rotating basket method will have effect on drug release to some extent.According to characteristics of berberine hydrochloride and coated tablet, referring to Chinese Pharmacopoeia (2000), a series of quality evaluation approaches which included discrimination, in vitro drug release and drug content determination were established.This research successfully developed a kind of coated tablet in which the drug can be released in specific site by use of pH sensitive polymer HPMCT. The results studied will be a good foundation of comprehensive development of novel enteric agents for diverse forms. At the same time, the study provides the method and idea for developing duodenum-specific drug release system. Furthermore, it is of significance to protect unstable or stimulated drug to release in the upper intestine and to maintain the stability of the drug.