Steiner S, Pfützner A, Wilson B R, Harzer O, Heinemann L, Rave K
Pharmaceutical Discovery Corporation, Elmsford, NY, USA.
Exp Clin Endocrinol Diabetes. 2002 Jan;110(1):17-21. doi: 10.1055/s-2002-19989.
Summary.Technosphere/Insulin (TI) is a formulation of regular human insulin and Technosphere, a new drug delivery system for pulmonary administration. The formulation is designed for efficient transport of insulin across the intact respiratory epithelium into the systemic circulation. We have investigated the pharmacodynamic and pharmacokinetic properties of Technosphere/Insulin in five healthy, non-smoking volunteers. In an open, randomized, three-way crossover study, subjects received 5 IU regular human insulin (HI) intravenously, 10 IU HI subcutaneously; and 100 IU TI via inhalation using a small commercially available asthma inhaler. The time action profiles of all three insulin formulations were assessed by the euglycemic glucose clamp technique on three different study days. Glucose infusion rates were monitored from 2 h before until 6 h after insulin administration. Other study measures were serum insulin, serum C-peptide concentrations, and safety parameters. The inhalation of TI was well tolerated. The time to peak action was significantly shorter with both i.v. injection and inhalation, as compared to s.c. (14 +/- 6 min and 39 +/- 36 min vs. 163 +/- 25 min; p < 0.0002 and p < 0.007 (mean +/- SD)). The metabolic effect during the first 3 h after insulin administration was higher with inhaled TI than with HI s.c. (AUC0-180 for glucose infusion rate: 1.94 +/- 0.77 mg/kg * min vs. 1.15 +/- 0.50 mg/kg * min; p < 0.04). Relative and absolute bioavailability for the first 3 h were 26 +/- 12% and 15 +/- 5% respectively (6 h: 16 +/- 8 and 16 +/- 6%). We conclude that inhalation of TI leads to a rapid onset of metabolic action resembling the effect observed with i.v. administration of regular HI. Despite the use of a common asthma inhaler, bioavailability over the three hour prandial period was substantially greater than with other reported pulmonary systems. Therefore, inhalation of Technosphere/Insulin may become a suitable and attractive alternative for prandial insulin delivery, especially for patients with type 2 diabetes mellitus.
摘要。技术球/胰岛素（TI）是普通重组人胰岛素与技术球（一种用于肺部给药的新型药物递送系统）的制剂。该制剂旨在使胰岛素有效穿过完整的呼吸道上皮进入体循环。我们在5名健康、不吸烟的志愿者中研究了技术球/胰岛素的药效学和药代动力学特性。在一项开放、随机、三交叉研究中，受试者分别接受静脉注射5IU普通重组人胰岛素（HI）、皮下注射10IU HI以及使用市售小型哮喘吸入器吸入100IU TI。在三个不同研究日通过正常血糖葡萄糖钳夹技术评估了所有三种胰岛素制剂的时间-作用曲线。在胰岛素给药前2小时直至给药后6小时监测葡萄糖输注速率。其他研究指标包括血清胰岛素、血清C肽浓度以及安全性参数。吸入TI耐受性良好。与皮下注射相比静脉注射和吸入后的达峰时间均显著缩短（分别为14±6分钟和39±36分钟，而皮下注射为163±25分钟；p<0.0002和p<0.007（均值±标准差））。胰岛素给药后最初3小时内吸入TI的代谢效应高于皮下注射HI（葡萄糖输注速率的AUC0 - 180：1.94±0.77mg/kg·分钟对1.15±0.50mg/kg·分钟；p<0.04）。最初3小时的相对和绝对生物利用度分别为26±12%和15±5%（6小时时分别为16±8%和16±6%）。我们得出结论，吸入TI导致代谢作用迅速起效，类似于静脉注射普通HI所观察到的效果。尽管使用了普通哮喘吸入器，但在三个小时进餐期的生物利用度显著高于其他报道过的肺部给药系统。因此，吸入技术球/胰岛素可能成为餐时胰岛素给药合适且有吸引力的替代方法，尤其适用于2型糖尿病患者。
