Chitosan as a pore former in coated beads for colon specific drug delivery

描述（由申请人提供）：长期目标是提供从小分子到大分子的活性物质的结肠特异性递送。药物递送至结肠在克罗恩病和溃疡性结肠炎的局部治疗中至关重要。这些无法预防的疾病影响到每10，000人中的7人。最有效的治疗是口服5-氨基水杨酸（5-阿萨）和糖皮质激素。治疗工作受到阻碍，因为这些药物，甚至5-阿萨前药，从小肠吸收，导致全身浓度高到足以引起副作用，较低剂量到达结肠。拟议的研究检查壳聚糖作为其乙酸盐在Aquacoat。将包衣应用于含5-ASA的挤出和球形化的珠粒，以（i）限制小肠条件下的药物释放和（ii）实现药物内容物的剩余部分的结肠递送。壳聚糖将水合但不溶解于小肠液中，这是本研究与在包衣珠中使用聚合物的其他研究相比的独特特征。壳聚糖的水合促进结肠递送，因为水合壳聚糖在结肠中对酶催化降解敏感，但在上胃肠道中不敏感。乙基纤维素，Aquacoat.中的聚合物和主要成分，没有显示出对结肠酶降解的敏感性。初步研究表明，可以使用流化床包衣机将含有壳聚糖的粗糙光滑的包衣应用于含药物的珠粒，并且当在模拟肠液中研究药物释放时，该包衣基于壳聚糖类型和珠粒上的包衣水平修改药物释放滞后时间和释放速率。脱乙酰化的分子量和程度决定了壳聚糖的类型及其在大鼠盲肠和结肠酶存在下对降解的敏感性。选择大鼠酶是因为它们在类型和水平上应该与人类结肠中发现的酶相似。所提出的研究探讨了壳聚糖类型、其在包衣中的含量以及珠粒上的包衣水平对珠粒坚固性和药物释放曲线的影响。将通过测量在含有大鼠盲肠和结肠酶的介质中的药物释放来评估在6小时内在小肠液中表现出小于10%释放的产物在结肠特异性递送中的成功。如果这些微珠在模拟结肠环境的介质中在12小时内释放剩余药物，则认为它们是成功的。该项目为将来研究结肠特异性递送其他活性物质，如抗癌剂，治疗肽和蛋白质奠定了基础。 公共卫生相关性：克罗恩病和溃疡性结肠炎的治疗努力受到阻碍，因为糖皮质激素、5-氨基水杨酸（5-阿萨）、甚至5-阿萨的前药形式从上胃肠道吸收，全身浓度足够高，使得患者经历由此产生的副作用。由于较低量的药物到达需要药物作用的结肠，因此必须施用较高剂量以在结肠处实现治疗药物水平。如果该项目的目标得以实现，则可以施用较低剂量，具有更有效的治疗和更低的全身副作用发生率的治疗益处。

DESCRIPTION (provided by applicant): Long term objectives are to provide colon specific delivery for actives ranging from small molecules to macromolecules. Drug delivery to the colon is critical in the local treatment of Crohn's disease and ulcerative colitis. These unpreventable conditions affect 7 of every 10,000 people. The most effective treatment is oral 5-aminosalicylic acid (5-ASA) and glucocorticosteroids. Therapeutic efforts are hampered because these drugs, and even 5-ASA prodrugs, are absorbed from the small intestine, resulting in systemic concentrations high enough to cause side effects, with lower doses reaching the colon. The proposed studies examine chitosan as its acetate salt in an Aquacoat. coating applied to 5-ASA-containing extruded and spheronized beads to (i) limit drug release under small intestine conditions and (ii) achieve colon delivery of the remainder of the drug content. Chitosan will hydrate but not dissolve in small intestine fluid, a unique feature to this study in comparison to other studies utilizing a polymer in a coated bead. Hydration of chitosan facilitates colon delivery because hydrated chitosan is susceptible to enzyme-catalyzed degradation in the colon, but not in the upper gastrointestinal tract. Ethylcellulose, the polymer and primary component in Aquacoat., has not revealed a sensitivity to degradation by colon enzymes. Preliminary studies indicate that a rugged, smooth coat containing chitosan can be applied using a fluid bed coater to drug-containing beads and that this coat modifies both the drug release lag time and release rate based on chitosan type and the coating level on the beads when drug release is studied in simulated intestinal fluid. The molecular weight and degree of deacetylation determine the type of chitosan and its susceptibility to degradation in the presence of rat cecum and colon enzymes. Rat enzymes were chosen because they should be similar in type and levels to those found in the human colon. The proposed studies explore the effects of chitosan type, its content in the coat, and the level of coat on the beads on bead ruggedness and the drug release profile. The products that exhibit less than 10% release in small intestine fluid in 6 h will be assessed for success in colon specific delivery by measuring drug release in media containing rat cecum and colon enzymes. Those beads assessed will be considered successful if they release the remainder of the drug in less than 12 h in this media that mimics the colon environment. This project lays the foundation for future studies on colon specific delivery of other actives, such as anticancer agents, and therapeutic peptides and proteins. Public Health Relevance: Therapeutic efforts in the treatment of Crohn's disease and ulcerative colitis are hampered because glucocorticoids, 5-aminosalicylic acid (5-ASA), and even prodrug versions of 5-ASA are absorbed from the upper gastrointestinal tract, with systemic concentrations high enough that the patient experiences the resultant side effects. Since lowered amounts of drug reach the colon where drug action is desired, a higher dose must be administered to accomplish a therapeutic drug level at the colon. If the goals of this project are achieved, then lower doses can be administered with the therapeutic benefits of more effective treatment and far lower incidences of systemic side effects.