The cornerstone of this study was to formulate and optimize fumaryl diketopiperazine (FDKP) microspheres of insulin-load (INS@FDKP-MPs) with the aid of Box-Behnken design (BBD) to enhance insulin bioavailability. The property characterization of INS@FDKP-MPs was studied and the stability study was confirmed by evaluating the effect on sample appearance, insulin and related protein content, hygroscopicity. At the same time, the pharmacodynamics of INS@FDKP-MPs was evaluated by testing the concentration of blood glucose of the diabetic model rats under different conditions. The optimized formulation of INS@FDKP-MPs drug loading microspheres is 2.37 h of stirring time, 4.64 of pH value and 23.11% of the drug ratio. Under this condition, the results of optimized formulation showed the average microspheres size of 1.69 nm, the drug loading rate of 10.95%. The size of microspheres is all below 3 m and the pulmonary deposition rate in stage 3 and stage 4 is more than twice that of other stages. The results of stability confirmed that INS@FDKP-MPs had good stability within three months. Futhermore, pharmacodynamics results indicated that inhaled insulin (Tmin 60 to 90 min) could rapidly be absorbed into the systemic circulation compared to subcutaneous injection (Tmin 120 min); Inhaled insulin can continuously reduce blood glucose concentration within 120 minutes, which is significantly faster than subcutaneous injection (180 minutes). That is stand for reducing the possibility of hypoglycemia. Through Pulmonary Administration, INS@FDKP-MPs can be efficiently and effectively absorbed into the systemic circulation with good pharmacodynamics and the ability to lower blood glucose levels.

中文翻译：

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用于糖尿病大鼠模型中蛋白质肺部递送的Fumaryl Diketopiperazine微球平台设计。

这项研究的基础是借助Box-Behnken设计（BBD）来提高胰岛素的生物利用度，从而配制和优化胰岛素负载的富马酰基二酮哌嗪（FDKP）微球体（INS @ FDKP-MPs）。研究了INS @ FDKP-MPs的性质表征，并通过评估其对样品外观，胰岛素和相关蛋白含量，吸湿性的影响来确认稳定性研究。同时，通过测试糖尿病模型大鼠在不同条件下的血糖浓度来评估INS @ FDKP-MPs的药效学。INS @ FDKP-MPs载药微球的优化配方为搅拌时间为2.37 h，pH值为4.64，药物比例为23.11％。在这种条件下，优化配方的结果显示平均微球尺寸为1.69 nm，载药率为10。95％。微球的大小均在3 m以下，第3阶段和第4阶段的肺部沉积速率是其他阶段的两倍以上。稳定性结果证实INS @ FDKP-MPs在三个月内具有良好的稳定性。此外，药效学结果表明，与皮下注射（Tmin 120分钟）相比，吸入胰岛素（Tmin 60至90分钟）可以迅速吸收到体循环中。吸入胰岛素可以在120分钟内连续降低血糖浓度，这比皮下注射（180分钟）要快得多。这代表着降低低血糖的可能性。通过肺部给药，INS @ FDKP-MPs可以被有效地吸收到全身循环中，并具有良好的药效学和降低血糖水平的能力。微球的大小均在3 m以下，第3阶段和第4阶段的肺部沉积速率是其他阶段的两倍以上。稳定性结果证实INS @ FDKP-MPs在三个月内具有良好的稳定性。此外，药效学结果表明，与皮下注射（Tmin 120分钟）相比，吸入胰岛素（Tmin 60至90分钟）可以迅速吸收到体循环中。吸入胰岛素可以在120分钟内连续降低血糖浓度，这比皮下注射（180分钟）要快得多。这代表着降低低血糖的可能性。通过肺部给药，INS @ FDKP-MPs可以被有效地吸收到全身循环中，并具有良好的药效学和降低血糖水平的能力。微球的大小均在3 m以下，第3阶段和第4阶段的肺部沉积速率是其他阶段的两倍以上。稳定性结果证实INS @ FDKP-MPs在三个月内具有良好的稳定性。此外，药效学结果表明，与皮下注射（Tmin 120分钟）相比，吸入胰岛素（Tmin 60至90分钟）可以迅速吸收到体循环中。吸入胰岛素可以在120分钟内连续降低血糖浓度，这比皮下注射（180分钟）要快得多。这代表着降低低血糖的可能性。通过肺部给药，INS @ FDKP-MPs可以被有效地吸收到全身循环中，并具有良好的药效学和降低血糖水平的能力。