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

描述（由申请人提供）：长期目标是为从小分子到大分子的活性物质提供结肠特异性递送。给药到结肠是克罗恩病和溃疡性结肠炎局部治疗的关键。这些无法预防的疾病影响着每1万人中的7人。最有效的治疗方法是口服5-氨基水杨酸（5-ASA）和糖皮质激素。治疗工作受到阻碍，因为这些药物，甚至5-ASA前药，都是从小肠吸收的，导致全身浓度高到足以引起副作用，而到达结肠的剂量较低。本研究考察了壳聚糖在水膜中的醋酸盐作用。涂覆在含有5- asa的挤压球状珠上，以(i)限制药物在小肠条件下的释放，（ii）实现剩余药物含量的结肠递送。壳聚糖会水化，但不会溶解在小肠液中，这是本研究与其他使用聚合物涂层珠的研究相比的独特之处。壳聚糖的水化有助于结肠输送，因为水化壳聚糖在结肠中容易被酶催化降解，而在上胃肠道中则不容易。乙基纤维素，聚合物和水衣的主要成分。目前还没有发现对结肠酶降解的敏感性。初步研究表明，在模拟肠液中研究药物释放时，可以用流化床包衣机在含药微球表面涂上一层凹凸不平、光滑的壳聚糖包衣，并根据壳聚糖类型和包衣水平改变药物的释放滞后时间和释放速度。分子量和去乙酰化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的降解敏感性。选择大鼠的酶是因为它们在类型和水平上应该与人类结肠中的酶相似。研究了壳聚糖类型、壳聚糖在包被中的含量、壳聚糖在包被上的水平对包被韧性和药物释放特性的影响。通过测量药物在含有大鼠盲肠和结肠酶的介质中的释放量，评估6小时内在小肠液中释放量小于10%的产品是否成功用于结肠特异性递送。如果这些被评估的微球在模拟结肠环境的培养基中在不到12小时内释放出药物的剩余部分，则被认为是成功的。该项目为未来研究其他活性物质，如抗癌药物、治疗肽和蛋白质的结肠特异性递送奠定了基础。

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.