| Colon-specific delivery of 5-Aminosalicylic acid(5-ASA) and salicylic acid(SA) can effectively treat inflammatory bowel disease, rheumatic disease and colorectal cancer. There have been many ways to achieve colon-specific delivery of these drugs, among which, polymeric drugs are new trials, although accompanying with the shortcomings of low drug loading percent, slow drug release rate and/or limited degradation of the carrier polymer. Polyanhydride is a kind of biodegradable material, and also a bioadhesive kind. When applied in the bioadhesive drug delivery systems, it can significantly lengthen the system's drug delivery duration in the soft mucosal tissue, especially the bowel. The topic of this thesis is to introduce the two drugs mentioned above into the molecular backbone of polyanhydride to obtain polymeric prodrugs with high drug loading, relatively quick drug release, complete biodegradation of the carrier polymer and bioadhesive characteristics. With these polymer prodrugs, we can predict the bioadhesive colon-specific delivery of 5-Aminosalicylic acid and salicylic acid. The thesis mainly covers several parts as illustrated below:1. 5-ASA was reacted with adipic anhydride and the diacid monomer carboxybutylformamidosalicylic acid (CBFS) was obtained. CBFS was melt polycondensationed at different temperatures, thus poly[(5-carboxybutylformamido)acetylsalicylic]anhydrides -P(CBFAS) series prodrugs with bioactive 5-ASA contained in the polymer backbone were synthesized. Their chemical structures were proved to be the same as that predicted with IR and !H-NMR etc. Their molecular weights were estimated by VPO. The polymer drugs have loaded 50.2% of 5-ASA. which is much higher than that of normal polymer drugs (<20%).2. PCBFAS series poly anhydrides are biodegradable polymer drugs, which can release 5-ASA and 5-acetylaminosaliylic acid (5-Acetyl-ASA) under simulatedgastrointestinal conditions, HPLC was used to determine the amount of 5-ASA and 5-Acetyl-ASA released. The results show that the release rate of 5-ASA and 5-Acetyl-ASA is influenced by polymeric molecular weight, pH value of degradation media and rat cecal contents, for example in the phosphate buffer system (PBS, pH value 6.5) and at the time point of 13h, PCBFAS2 (Mn4870) has 4.2% of ASA(sum of 5-ASA and 5-Acetyl-ASA ) released, while PCBFASi(Mnl0770) has only 2.5% of that; the total release of ASA of PCBFAS, at 35h at pH2.0 is 1.4%, while that at 13h at pH8.0 has exceeded 5%, while that at 13h and pHS.O with 5% cecal contents is 13.6%. From the results it can be seen that the drug release rate of PCBFAS in the upper gastrointestinal tract is very slow while that in the distal part of the tract is relatively much fast, which indicating the polymers' potential in colon-specific delivery of 5-ASA.3.Two SA molecules were reacted with adipyl cloride to get drug contained diacid monomer- bi(o-carboxyphenyl)adipate(BOCA). BOCA was melt copolymerized with end hydroxy group carboxylated polyethylene glycol(PEG) with different ratio and PEG molecular weight, thus poly[bi(o-carboxyphenyl)adipate-PEG]anhydrides-P(BOCA-PEG) series polymer drugs were obtained. Their structures and characteristics were determined by IR, ]H-NMR, DSC, GPC and static contact angle meter, etc. As PEG200 content increases from 5% to 35%, the SA content keeps higher than 43.5%, with some even up to 71.3%.4. P(BOCA:PEG) series polyanhydrides are biodegradable polymer drugs, which can release SA under simulated gastrointestinal conditions. HPLC was used to measure the amount of SA released, the results show the release rate of SA was influenced by polymer structure and external conditions: for example, at pH8.0 and 10h, P(BOCA-PEG200) with 5% PEG content released 1.5% SA, while that with 35%PEG was 12.4%; in PBS 8.0 containing 5% rat cecal contents and at 15h, P(BOCA-PEG200)(80:20) with Mw 2727 released 13.4% SA, while that with Mw 4956 released 8.3% SA; while that with Mw 4956 at PBS8.0 without rat cecalcontents and at 15h had only released 4.2% SA, but a... |
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