Technosphere^TM/Insulin - proof of concept study with a new insulin formulation for pulmonary delivery

Summary

Technosphere^TM/Insulin (TI) is a formulation of regular human insulin and Technosphere^TM, 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^TM/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. (AUC_0-180 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^TM/Insulin may become a suitable and attractive alternative for prandial insulin delivery, especially for patients with type 2 diabetes mellitus.

Technosphere - Pulmonary insulin - Prandial insulin delivery

References

• 1 Anderson J H, Koivisto V A. Clinical studies on insulin lispro.  Drugs of Today. 1998;  34 37-50
• 2 Brunner G A, Balent B, Ellmerer M, Schaupp L, Siebenhofer A, Jendle J H, Okikawa J, Pieber T R. Dose-response relation of liquid aerosol inhaled insulin in type 1 diabetic patients.  Diabetologia. 2001;  44 305-308
• 3 Cefalu W T, Skyler S S, Kourides I A, Landschulz W H, Balagta C C, Cheng S L, Gelfand R A. Inhaled human insulin treatment in patients with Type 2 diabetes mellitus.  Ann Intern Med. 2001;  134 203-207
• 4 Fishman R S, Guinta D, Chambers F, Quintana R, Shapiro D. Insulin administration via the AeroDose TM inhaler: comparison to subcutaneously injected insulin.  Diabetes. 49 ((Suppl 1)) 2000;  A9
• 5 Heinemann L, Traut T, Heise T. Time-action profile of inhaled insulin.  Diabetic Med. 1997;  14 63-72
• 6 Heinemann L, Pfützner A, Heise T. Alternative routes of administration as an approach to improve insulin therapy: Update on dermal, oral, nasal, and pulmonary insulin delivery.  Curr Pharm Des. 2001;  7 1327-1351
• 7 Heise T, Rave K, Bott S, Sha S, Willavize S A, Carroll R S, Gruber S, Lee J D, Heinemann L. Time-action profile of an inhaled insulin preparation in comparison to insulin lispro and regular insulin.  Diabetes. 49 ((Suppl 1)) 2000;  A10
• 8 Hilsted J, Madsbad S, Hvidberg A, Rasmussen M H, Krarup T, Ipsen H, Hansen B, Pedersen M, Djurup R, Oxenbull B. Intranasal insulin therapy: the clinical realities.  Diabetologia. 1995;  38 680-684
• 9 Köhler D, Schlüter K J, Kerp L, Matthys H. Nicht radioaktives Verfahren zur Messung der Lungenpermeabilität: Inhalation von Insulin.  Atemwegs und Lungenkrankheiten. 1987;  13 230-232
• 10 Laube B L, Georgopoulos A, Adams G KI. Preliminary study of the efficacy of insulin aerosol delivered by oral inhalation in diabetic patients.  JAMA. 1993;  269 2106-2109
• 11 Laube B L, Benedict G W, Dobs A S. Time to peak insulin level, relative bioavailability, and effect of site of deposition of nebulized insulin in patients with noninsulin-dependent diabetes mellitus.  J Aerosol Med. 1998;  11 153-173
• 12 Lian H, Steiner S S, Sofia R D, Woodhead J H, Wolf H H, White H S, Shen G S, Rhodes C A, McCabe R T. A self-complementary, self-assembling microsphere system: application for intravenous delivery of the antiepileptic and neuroprotectant compound felbamate.  J Pharm Sci. 2000;  89 867-875
• 13 Olsen C L, Liu G, Charles A. Novel routes of insulin delivery. In: Marshall SM, Home PD (eds) The Diabetes Annual Elsevier, Amsterdam, London, New York, Tokyo 1994: 243-276
• 14 Pohl R, Muggenburg B A, Wilson B R, Woods R J, Burell B E, Steiner S S. A dog model as predictor of the temporal properties of pulmonary Technosphere/Insulin in humans.  2000;  Resp Drug Delivery. VII 463-465
• 15 Skyler J S, Cefalu W T, Kourides I A, Landschulz W H, Balagtas C C, Cheng S L, Gelfand R A. Efficacy of inhaled human insulin in Type 1 diabetes mellitus: a randomized proof of concept study.  Lancet. 2001;  357 331-335
• 16 Wigley F W, Londono J H, Wood S H, Shipp J C, Waldman R H. Insulin across respiratory mucosae by aerosol delivery.  Diabetes. 1971;  20 552-556