Insulin Inhalation.

The inhalation of insulin into the lungs offers a new method of insulin treatment delivery for people with diabetes. The same features that make the lung so well suited for gas exchange also make it an ideal organ for absorption of small molecules into the bloodstream. The pulmonary alveolar surface area of the lung is 130 m2, the size of a tennis court, and the pulmonary capillary surface area is nearly as large at 115 m2. With each breath, air flows into nearly 300 million alveoli. Moreover, the alveolar lining cell is just 1 to 2 mcm from the pulmonary capillary lumen, a distance that favors rapid uptake into the bloodstream. Absorption of a molecule across the alveolar-capillary interface is inversely related to its molecular mass. Small peptides, such as insulin (approximately 6000 Daltons) are readily absorbed across the very thin, vesiculated, permeable membrane. Molecules that make it to the alveolar level have longer residence time there, because mucociliary mechanisms at this level are minimal. There are several factors affecting lower respiratory deposition of an aerosol or dry powder formulation. One of these is particle size. Particles greater than 5 mcm in diameter impact and are deposited in the pharynx and large airways. Particles 1 to 3 mcm generally reach the lower airways and alveoli. Particle velocity also affects deposition. Flow rates > 35 L/min or < 10 L/min will favor upper airway impaction, while flow rates of 15 to 25 L/min are ideal for lower airway deposition. Even under the best of circumstances, however, only the minority of an aerosol or dry powder usually makes it deep into the lungs Inhaled Human Insulin There are several forms of inhaled insulin, either approved or in development. The only inhaled insulin that is approved is Exubera® (insulin human [rDNA origin]) Inhalation Powder. Other forms in development include AERx (NovoNordisk), AIR (Lilly), Spiro (Dura), Technosphere Insulin (MannKind), and Aerodose (Aerogen). Some are not powder but aerosol. Their excipients and medication delivery systems also differ. Exubera is a dry powder insulin contained in small blisters of 1 mg and 3 mg potency. After the blister is inserted into the base of the inhaler, a vacuum is established by cocking the lever at the base, allowing aerosolization of the powder. The aerosolized particles are then inhaled.[21] Each actuation of the Exubera inhaler produces 200 mL of a homogeneous powder. This powder contains human (rDNA origin) insulin, and the excipients sodium citrate, glycine, sodium hydroxide (to maintain pH), and mannitol. None of these are known to be immunogenic. Mannitol has been clinically used as an agent in bronchoprovocation testing, but its concentration in Exubera is lower than the lowest dose used in such testing. There are several forms of inhaled insulin, either approved or in development. The only inhaled insulin that is approved is Exubera® (insulin human [rDNA origin]) Inhalation Powder. Other forms in development include AERx (NovoNordisk), AIR (Lilly), Spiro (Dura), Technosphere Insulin (MannKind), and Aerodose (Aerogen). Some are not powder but aerosol. Their excipients and medication delivery systems also differ. There are several forms of inhaled insulin, either approved or in development. The only inhaled insulin that is approved is Exubera® (insulin human [rDNA origin]) Inhalation Powder. Other forms in development include AERx (NovoNordisk), AIR (Lilly), Spiro (Dura), Technosphere Insulin (MannKind), and Aerodose (Aerogen). Some are not powder but aerosol. Their excipients and medication delivery systems also differ. Exubera is a dry powder insulin contained in small blisters of 1 mg and 3 mg potency. After the blister is inserted into the base of the inhaler, a vacuum is established by cocking the lever at the base, allowing aerosolization of the powder. The aerosolized particles are then inhaled.[21] Each actuation of the Exubera inhaler produces 200 mL of a homogeneous powder. This powder contains human (rDNA origin) insulin, and the excipients sodium citrate, glycine, sodium hydroxide (to maintain pH), and mannitol. None of these are known to be immunogenic. Mannitol has been clinically used as an agent in bronchoprovocation testing, but its concentration in Exubera is lower than the lowest dose used in such testing. The dose of Exubera that reaches the alveolar level is the “fine particle dose,” which consists of particles 3.3 mcm in diameter or smaller. The “fill mass” is the amount of insulin plus excipient in the individual insulin blister. In the case of a 1-mg Exubera blister, there is 0.7 mg of excipient and 1 mg of insulin; on actuation of the inhaler, 0.53 mg of insulin is emitted, of which 0.4 mg is less than 3.3 mcm in diameter. Thus, of the 1-mg insulin in the blister, 0.4 mg or 40% is deposited at the alveolar level. A 3-mg Exubera blister creates a 1.0 mg fine particle dose; hence, 33% is deposited in the alveoli. This explains why 3 1-mg blisters deliver more insulin (1.2 mg) than 1 3-mg blister, which delivers only 1 mg to the alveoli.[21] Most of the insulin that reaches the distal lung is absorbed. There is no evidence of insulin accumulation in the alveoli. The insulin that is not absorbed undergoes metabolic degradation or slow mucociliary clearance Smoking. Insulin absorption studies have looked at the maximum concentration of serum insulin after a dose of insulin (Cmax) as well as the area under the serum insulin vs. time curve (AUC) following that dose. Such studies have shown that active smoking increases absorption of inhaled insulin 2- to 5-fold. The mechanism by which smoking affects inhaled insulin absorption is still unknown. The absorption of subcutaneous insulin is not affected by smoking.[22] Cessation of smoking is accompanied by a reduction in absorption of inhaled insulin toward normal in as little as days. After a week of abstinence from smoking, inhaled insulin absorption decreases toward normal by as much as 50%. Resumption of smoking for just 3 days increases absorption of the peptide toward levels seen during chronic smoking.[22] Because of the wide variations in absorption of inhaled insulin observed with smoking, cigarette smoking within the past 6 months has been a contraindication to inhaled insulin use in Phase 2 and 3 studies, and remains a contraindication to use of inhaled insulin.[21] Passive smoking has been examined experimentally, in a study in which subjects were exposed to smoke in a smoking chamber for 2 hours at concentrations mimicking those found in a smoky bar. Contrary to active smoking, passive smoking appears to decrease inhaled insulin absorption by as much as 20% to 30%.[23] It is not clear how long this effect lasts after subjects are removed from the smoky environment. It is likewise unclear why passive smoking and active smoking have opposite effects on the absorption of inhaled insulin. Asthma, Chronic Obstructive Pulmonary Disease, and Their Treatment. Studies have shown that insulin absorption, as measured by area under the curve (AUC) and maximum concentration (Cmax), is 20% to 50% lower in mild to moderate asthmatics than in normals.[23] In contradistinction to asthmatics, a small cohort of patients with chronic bronchitis and emphysema having a predicted baseline forced expiratory volume in 1 second (FEV1) of 35% to 40% were tested and found to have rates of absorption for inhaled insulin that were 2-fold higher than those of subjects without chronic obstructive pulmonary disease (COPD).[23] Although both asthma and COPD are characterized by small airway inflammation, it is not known why inhaled insulin absorption is affected in opposite ways by these disorders. In patients with mild (FEV180% or more) or moderate (FEV180% or less) asthma, the administration of albuterol 30 minutes before taking inhaled insulin resulted in a 25% to 50% increase in systemic insulin absorption compared with administration of inhaled insulin alone. (Data on file) Inhaled fluticasone appears to have no effect on inhaled insulin absorption, but other medications used for asthma and COPD have not been systematically This slide summarizes how respiratory factors affect inhaled insulin absorption. Other Factors Affecting Absorption. In clinical studies of Exubera, episodes of viral upper respiratory infection, laryngitis, and acute bronchitis had no discernible effect in either direction on inhaled insulin absorption. There were not enough cases of pneumonia in phase 2/3 studies to be able to comment on the effects of a more severe infection on inhaled Respiratory Tract Effects of Inhaled Insulin Symptoms, Adverse Events. Respiratory safety of inhaled insulin has been a concern for several reasons: 1. It is a novel drug substance with novel excipients that is being inhaled. 2. Its administration is chronic. 3. Insulin is a polypeptide with potential for immune response in the lung. 4. Insulin has growth-promoting properties. Consequently, respiratory side effects have been looked at closely in phase 2/3 studies. In some studies, cough has been reported in 22% to 30% of patients with diabetes on Exubera compared with 4% to 10% of patients with diabetes on comparator treatment. (Data on file) The cough tended to occur within seconds to minutes after Exubera inhalation, and was generally rated as mild. The cough was rarely productive and rarely occurred at night. Cough prevalence was greatest in the first month of use, then decreased by 20% to 40% over the next 3 months, and remained constant thereafter. In clinical studies, only 1.2% of patients discontinued Exubera because of cough. Patients who cough while on Exubera do not, on average, have any change in pulmonary function tests (PFTs) that distinguishes them from those who do not cough. Finally, such patients destined to cough cannot be reliably determined beforehand—they have the same mean pretreatment FEV1 as those patients who do not cough. Shown here are respiratory adverse events reported in >1% of patients receiving inhaled insulin or a comparator drug (oral medications or subcutaneous insulin) in phase 2/3 studies.[21] Dyspnea has been reported by 4% of patients on Exubera and by 1% to 3% of patients on comparator agents. Nearly all cases were reported as mild or moderate; discontinuation of Exubera due to dyspnea was uncommon (0.4%). In clinical studies, patients with dyspnea were more likely to have a reduction in their pulmonary function, whether they were treated with Exubera or a comparator drug. Additionally, on occasion, the cause of dyspnea was another disease process, unrelated to either the Exubera or the comparator treatment. Chest pain has been reported in 4.7% of patients on Exubera and in 3.2% of patients treated with subcutaneous insulin or oral antidiabetes medications. Of these patients, 90% rated the pain as mild or moderate. There were no differences in the incidence of angina (1%) and myocardial infarction (1%) between those patients treated with Exubera versus other agents. Other symptoms reported more often in Exubera-treated patients than in comparator-treated patients include: 1. Increased sputum in 3% to 4% (vs. 1% of comparator patients) 2. Epistaxis in 1.2% (vs. 0.4-0.8%) 3. Voice alteration in 1.3% of patients with type 2 diabetes (vs. 0-0.3%) 4. Dry mouth in 2.4% (vs. 0.8%)[21] Effects on Pulmonary Function. More than 43,000 PFTs have been performed in over 4600 adult subjects taking inhaled insulin. Spirometry, with measurement of FEV1 and forced vital capacity (FVC), has been used to look for the effects of inhaled insulin on airflow and airway function. Lung volumes, and especially carbon monoxide diffusing capacity of the lung (DLCO), have been used to look for any effect of inhaled insulin on pulmonary

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