Colon-Specific Drug Delivery System Based on Cyclodextrin Conjugate

以α-、β-和γ-环糊精（α-、β-和γ-CyD）为模型药物，通过酯键或酰胺键将β-联苯乙酸（BPAA）选择性地偶联到α-、β-和γ-环糊精的伯羟基之一上（BPAA/α-、β-和γ-CyD偶联物）。并对其体内外释药、口服吸收及大鼠模型释药效果进行了研究，以评价其作为结肠定位给药系统的可行性。1）NMR和质谱分析结果表明，BPAA被选择性地引入到CyDs的一个伯羟基上。α-和β-CyD偶联物的水溶性分别约为BPAA的100倍和10倍，而BPAA的水溶性分别约为BPAA的100倍和10倍。的β-CyD缀合物降低到约十分之一。该酯缀合物在大鼠盲肠和结肠内容物中选择性地释放BPAA，而它们在大鼠的其他生物体液中是稳定的。2）口服给药α-和-γ-CyD酯缀合物后约3小时，BPAA的血清水平增加，伴随着血清水平的显著增加，而β-CyD和酰胺缀合物导致血清水平几乎没有增加。3）与β-CyD复合物相比，评价γ-CyD酯缀合物的抑制作用，采用角叉菜胶诱导的大鼠足急性水肿模型。在β-CyD复合物的情况下，由于复合物的快速溶解，观察到快速的荧光反应。与此形成鲜明对比的是，γ-CyD偶联物需要相当长的滞后时间才能表现出药物递送，因为BPAA是在到达盲肠和结肠之后产生的。

An antiinflammatory 4-biphenylylacetic acid (BPAA), as a model drug, was selectively conjugated onto one of the primary hydroxyl groups of alpha-, beta- and gamma-cyclodextrins (alpha-, beta- and gamma-CyDs) though an ester or amide linkage, (BPAA/alpha-, beta- and gamma-CyD conjugates). and their in-vitro and in- vivo drug release, oral absorption behavior, and antiinflammatory effect in rat model were investigate to evaluate them as a colon-specific drug delivery system. The results obtained were summarized as follows :1) The NMR and mass spectroscopic results indicate that the BPAA moiety was introduced selectively onto one of the primary hydroxyl groups of CyDs. The aqueous solubilities of the alpha- and beta-CyD conjugates were about 100 and 10 times respectively, that of BPAA, whereas that. of the beta-CyD conjugate decreased to about one-tenth. The ester conjugates released BPAA selectively in rat cecal and colonic contents, whereas they were stable in other biological fluids of rats.2) The serum levels of BPAA increased about 3 hours after oral administration of the alpha-and -gamma-CyD ester conjugates to rats, accompanying a marked increase in the serum levels, whereas the beta-CyD and the amide conjugates resulted in little increase of the serum levels.3) The antiinflammatory effect of the gamma-CyD ester conjugate was evaluated, in comparison with that of the beta-CyD complex, using the model of carageenan-induced acute edema in rat paw. In the case of the beta-CyD complex a rapid antiinflammatory response was observed, because of the fast dissolution of the complex. In sharp contrast, the gamma-CyD conjugate needed a fairly long lag time to exhibit, the drug delivery, because BPAA was produced after it had reached the cecum and colon.The present conjugate approach provides a versatile means for construction of not only colon-specific delivery system but also delay-release system of certain drugs.