AIR System

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The AIR system uses a semi-disposable inhaler to deliver a dry-powder insulin particle that is characterized by large size but low density keeping the aerodynamic diameter small. Currently under development are the 2 and 6 unit capsules which contain 0.9 and 2.6mg/capsule of insulin, respectively. The inhaler is approximately the size of a cell phone and utilizes breath actuated technology to deliver the dose (Fig. 4) (34,35). The insulin capsule is placed in the inhaler where it is punctured by the device (34). The inhalation of air through the device provides enough energy to make the capsule spin, forming an aerosol for inhalation.

When compared to SC insulin lispro in healthy subjects, the AIR system seems to be comparable in terms of pharmacokinetic and pharmacodynamic parameters (35). Subjects who were given doses of 2.6, 5.2, and 7.8 mg, the onset of action were 13, 13, and 15 min, respectively (Fig. 5). This was found to be a significantly faster onset compared to SC insulin lispro. Peak serum concentrations were reached in 45, 30, and 45 min for the 2.6, 5.2, and 7.8 mg doses, respectively. Mean AUC values were similar between the inhaled AIR system and SC insulin lispro. Cmax values were similar for the 7.8 mg dose compared to 18 units of SC insulin lispro, however, the 2.6 and 5.2 mg had lower Cmax values compared to the 6 and 12 units of SC insulin lispro,

Figure 3 Insulin pharmacokinetics in smokers and asthmatics using the AERx® system.
tem inhaler.

0 60 120 180 240 300 360 420 480 540 600 0 60 120 180 240 300 360 420 480 540 600

(B) Time after dose (min) (D) Time after dose (min)

Figure 5 Pharmacokinetic and glucodynamic results after inhalation of insulin using the AIR product and SC lispro injection. (A) Mean serum insulin concentration of three doses of inhaled insulin. (B) Mean serum insulin concentration of three different SC lispro doses. (C) Plots of glucose infusion rates of three different doses of inhaled insulin. (D) Plots of glucose infusion rates of three different SC lispro doses.

0 60 120 180 240 300 360 420 480 540 600 0 60 120 180 240 300 360 420 480 540 600

(B) Time after dose (min) (D) Time after dose (min)

Figure 5 Pharmacokinetic and glucodynamic results after inhalation of insulin using the AIR product and SC lispro injection. (A) Mean serum insulin concentration of three doses of inhaled insulin. (B) Mean serum insulin concentration of three different SC lispro doses. (C) Plots of glucose infusion rates of three different doses of inhaled insulin. (D) Plots of glucose infusion rates of three different SC lispro doses.

respectively. Higher doses extends the duration of action. In subjects who received the 7.8 mg dose, the duration of action was 8 h compared to subjects who received the 2.6 and 5.2 mg dose whose duration of action was 6-7 h. Intrasubject variability of the inhaled product is similar to SC insulin lispro (35). A major difference between the Exubera product and the AIR product is the capsule dose equivalency. Unlike Exubera, 3 inhalations of 2 unit AIR capsules are equivalent to one inhalation of a 6-unit capsule.

One study evaluated the pharmacokinetics and glucodynamics of the AIR system in patient with COPD (36). The mean AUC and metabolic effect were reduced in patients with COPD compared to healthy subjects. Moreover, the intrasubject variability was greater in patients with chronic bronchitis. More extensive studies are needed in this population to further investigate the safety profile.

Technosphere™/InsuNn

The Technosphere/Insulin technology is unique in that it captures and stabilizes peptides in small particles (37). A small organic molecule, 3,6-bis

[N-fumaryl-N-(n-butyl)amino-2,5-diketopiperazine] self-assembles in a mild acidic environment into microspheres of approximately 2 ^m (Fig. 6) (38). Peptides in the reaction solution, such as insulin, are trapped in the microspheres during self assembly. The particles are then dried and suitable for pulmonary delivery. In the neutral pH of the deep lungs, the microspheres dissolve and facilitate the absorption of the insulin into the systemic circulation. The carrier molecules are excreted as ammonium salts in the urine within hours (37). The Technosphere/Insulin is provided in gelatin capsules that contain 50 IU of dry powder regular human insulin (38). In studies evaluating Technosphere/Insulin technology a specifically developed breath-powered unit dose dry powder inhaler was utilized (37). The inhaler does not require any external energy and subjects were instructed to take three deep breaths per capsule. Delivery of the drug is dependant on the breath effort of the patients (38).

In a pilot study of five healthy subjects, a euglycemic clamp technique was used to evaluate the biologic efficacy and pharmacokinetic properties of the Technosphere/Insulin technology (38). Subjects were randomized to one of three groups inhaled 100 IU of Technosphere/Insulin, 10 units of SC regular insulin and 5 units of intravenous (IV) regular insulin (Fig. 7). Technosphere/Insulin showed an onset of action similar to that of IV regular insulin (13 vs. 9min) and much quicker than that of SC regular insulin (121 min). Insulin concentrations with the Technosphere/Insulin technology returned to baseline after 3 h. In a following dose ranging study, subjects were randomized to receive 25, 50, and 100 IU of Technosphere/ Insulin. This study found that there is a linear dose dependant increase in metabolic activity and systemic insulin uptake. Technosphere/Insulin

Figure 6 Scanning electron micrograph of precipitated Technosphere particles. Mean particle size = 2-3 ^m.
Figure 7 Serum insulin concentrations after administration of 5 IU of insulin IV, 10 IU of insulin SC, and 100 IU of Technosphere /Insulin in five healthy volunteers in a euglycemic clamp study.

technology differs from the other inhaled technologies in that the onset is faster, although they have not been directly compared.

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