DL-Lactide/Glycolide Copolymer Nanosphere To Improve Oral Delivery Of Tacrolimus

DL-丙交酯/乙交酯共聚物纳米球改善他克莫司的口服给药

• 批准号: 15591355
• 负责人: UNO Takeji
• 金额: $ 1.86万
• 依托单位: Jichi Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591355/
• 关键词: DL-lactide; glycolide copolymer nanospheres; tacrolimus; sustained release drug delivery system; ポリ乳酸-グリコール酸共重合体; ラット心移植; 経口剤; 局所免疫抑制; ポリ乳酸グリコール酸共重合体; 薬物担体; ラット小腸移植

Objective : To develop DL-lactide/glycolide copolymer nanospheres (PLGA nanoshere) system to improve tacrolimus absorption and prolomg the physiological and immunosuppressive activity following oral administration.Methods : We prepared PLGA nanosphere. LEW/SsN rats were given PLGA nanosphere at a dose of 4.8 mg/kg (n=5) tacrolimus contents, by a single oral administration to achieve sustained release over a long period. LEW/SsN rats were given PLGA nanosphere by a single oral administration at a dose of 4.8 mg/kg (n=5) tacrolimus contents to clarify the main site of PLGA nanosphere uptake in the organs. In the rat heart transplantation model, the recipients were given PLGA nanosphere at a dose of 4.8 mg/kg (n=5) tacrolimus contents by a single oral administration every other day for 2 weeks on the first day after operation compared with conventional formation every day for 2 weeks. Overall survival days of grafts were compared.Results : The value of AUC and t_<1/2β>(half life of elimination phase) in the PLGA nanosphere was significantly higher (p<0.01) than in the conventional formulation. There were no significant differences in tacrolimus levels of organs between PLGA nanosphere and conventional formulation. However, there were no significant differences in graft survival between PLGA nanosphere, every other day and conventional formulation, every day.Conclusion : PLGA nanosphere revealed a continuous flat concentration profile for 2 days after a single oral administration in the current study. This finding may suggest that it is possible to administer PLGA nanosphere one time per 2 days.

目的：建立dl -丙交酯/甘油酯共聚物纳米微球（PLGA纳米微球）体系，以改善口服他克莫司的吸收，延长其生理和免疫抑制活性。方法：制备PLGA纳米球。给LEW/SsN大鼠以4.8 mg/kg （n=5）他克莫司含量的PLGA纳米球单次口服，达到长期缓释。采用单次口服他克莫司4.8 mg/kg （n=5）的剂量给药LEW/SsN大鼠，以明确PLGA纳米球在器官中的主要摄取部位。在大鼠心脏移植模型中，术后第一天给予他克莫司含量4.8 mg/kg （n=5）的PLGA纳米球单次口服，每隔一天给药，连续2周。比较移植物的总存活时间。结果：PLGA纳米球的AUC和t_<1/2β>（消除相半衰期）均显著高于常规配方（p<0.01）。PLGA纳米球与常规制剂在器官组织中他克莫司水平无显著差异。然而，每隔一天的PLGA纳米球与每天的常规配方在移植物存活率上没有显著差异。结论：在本研究中，PLGA纳米球在单次口服后2天内呈现连续的平坦浓度分布。这一发现可能表明，每2天给药一次PLGA纳米球是可能的。

项目成果

Miyamoto, Y, Uno T, Yamamoto H, et al.: "Pharmacokinetic and Immunosuppressive Effects of Tacrolimus- Loaded Biodegradable Microspheres"Liver Transplantation. 10・3. 392-396 (2004)

Miyamoto, Y, Uno T, Yamamoto H, et al.：“负载他克莫司的可生物降解微球的药代动力学和免疫抑制作用”10・3 (2004)。