WR-2721口服肠溶生物降解微囊的制备研究

Development of biodegradable enteric microcapsules of WR-2721 for oral delivery

目的通过制备WR-2721口服肠溶生物降解微囊,从而改善其口服利用度。方法以高分子可生物降解的丙烯酸树脂Eudragit L 100-55为囊材,用喷雾干燥技术制备微囊;利用横移激光散射图案在介质中的分布测量微粒直径、形状及粒径分布;微囊体外溶出度实验及体内血液及各组织分布使用高效液相色谱法(HPLC)测定含量;小鼠口服微囊1 h后全身照射6 Gy的γ射线观察30 d存活率实验。结果 3批微囊90%的直径在(2.8±0.24)μm,微囊表面光滑、圆球形,得囊率为80%;体外24 h释放率分别为(95.35±2.13)%(37℃)和(89.68±3.17)%(4℃),且37℃的释放率高于4℃;30 d存活率实验WR-2721微囊组为80%、WR-2721口服组为50%、辐射对照组为0%、空白对照组和腹腔注射组为100%。结论 WR-2721口服微囊有显著的辐射防护作用。

Objective Amifostine （WR-2721） is the first FDA-approved cyto-protective agent, which is prescribed to reduce certain side-effects during chemotherapy of ovarian, non-small cell lung cancer, and in the radiation treatment for head-and-neck cancer patients. However, due to the fact that intravenous infusion of the drug was the main route of medication and assimilation was low if taken orally, its wide application was therefore affected clinically. For this reason, we intended to develop biodegradable enteric micro- capsules of WR-2721 for oral delivery, so as to improve the bioavailability of the drug. Methods The preparation of the microcapsule was made by using the high-molecular and biodegradable Eudragit L100-55 as its capsule material and by the spray drying technique. The diameter, shape, particle size distribution and yield rate of the capsules were measured by transversal distribution measurement of laser light scattering pattern in medium particle diameter. High performance liquid chromatography （HPLC） was used to detect in vitro release of the drug and the drug amount remaining in the microeapsule at a specific sampling time. One hour after medication, radio- protective efficacy of the new drug formulation was determined by 30-day mice survival rate with whole-body exposure to 6Gy. Results The diameter of 90% microcapsules of the 3 batches was （2.8 ± 0.24） μm. The shape of the microcapsule was spherical with a smooth surface, and the yield rate was 80%. In vitro release rate in 24 h was respectively [ （95.35 ±2.13）% ] at 37 ℃ and [ （89.68± 3. 17）% ] at 4℃, with the release rate at 37℃ being higher than that at 4℃. The 30-day survival rate for the WR-2721 microcapsule group was 80%, the rate for the WR-2721 oral group was 50%, the rate for the radiation group was 0%, and the rates for the blank control group and the abdominal injection group were as high as 100%. Conclusion As compared with the oral WR-2721 group, the WR-2721 micr0capsule had significant radio-protective effect.