吲哚美辛-5-氟尿嘧啶甲酯干乳液：5-氟尿嘧啶的一种潜在口服递药系统。

School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, PR China.

Drug Dev Ind Pharm. 2010 Jun;36(6):647-56. doi: 10.3109/03639040903410318.

OBJECTIVE

To produce a combined effect of indomethacin (IDM) and 5-fluorouracil (5FU) for cancer therapy, the side effects of IDM on the gastrointestinal (GI) tract were reduced and the oral adsorption of 5FU was improved. Indomethacin-5-fluorouracil-methyl ester (IFM) dry emulsion was prepared and evaluated as a potential oral delivery system for 5FU.

METHODS

IFM was synthesized by formation of an ester between IDM and 5FU intermediate and then characterized by structure, melting point, solubility, apparent partition coefficient, and incubation with GI tract contents and plasma. Gum acacia and sodium carboxymethyl cellulose (CMC-Na) were applied as the adsorbent and solid carrier to prepare IFM dry emulsion. IFM dry emulsion was then characterized by reconstitution in water and in situ intestinal perfusion experiment.

RESULTS

Physicochemical properties of the new synthesized compound confirmed the formation of IFM. Incubation of IFM in the contents of the GI tract and plasma revealed that IFM was not relatively stable in GI contents during the time period of transit through the GI tract, whereas it was very unstable in plasma and released 5FU rapidly. The IFM dry emulsion could be easily reconstituted in water, and the mean particle size was 2.416 microm. The absorption rate constant (K) for IFM with concentration of 2, 5, and 10 microg/mL in the in situ perfusion experiment were 0.473, 0.423, and 0.433/h, respectively, demonstrating passive diffusion of IFM across the biological membranes.

CONCLUSION

This study indicates that the IFM dry emulsion may represent a potentially useful oral delivery system for 5FU.

目的

为了产生吲哚美辛（IDM）和 5-氟尿嘧啶（5FU）联合治疗癌症的效果，降低 IDM 对胃肠道（GI）的副作用，并提高 5FU 的口服吸附。制备吲哚美辛-5-氟尿嘧啶-甲酯（IFM）干乳液，并将其评估为 5FU 的潜在口服给药系统。

方法

IFM 是通过 IDM 和 5FU 中间体之间形成酯而合成的，然后通过结构、熔点、溶解度、表观分配系数以及与 GI 内容物和血浆孵育进行表征。胶阿拉伯树胶和羧甲基纤维素钠（CMC-Na）用作吸附剂和固体载体来制备 IFM 干乳液。然后通过在水中重构成形和原位肠灌注实验来表征 IFM 干乳液。

结果

新合成化合物的物理化学性质证实了 IFM 的形成。IFM 在 GI 内容物和血浆中的孵育表明，IFM 在通过 GI 道的过程中在 GI 内容物中相对不稳定，而在血浆中非常不稳定并且迅速释放 5FU。IFM 干乳液可轻松在水中重构成形，平均粒径为 2.416 微米。在原位灌注实验中，浓度为 2、5 和 10μg/mL 的 IFM 的吸收速率常数（K）分别为 0.473、0.423 和 0.433/h，表明 IFM 是通过生物膜的被动扩散。