Insulin, inhaled

Oral Inhalation Insulin Recombinant human Exubera Pfizer 1 mg = 10-20 0.5-1.5 6 1 mg, 3 mg blister packs... 

Allergic reactions to insulin include erythema, pruritus, and indurations,22 which usually are transient. For the more troublesome reactions, treatment options include dexamethasone, desensitization, or change in delivery system (i.e., insulin pump or inhaled insulin). 

JS Patton, J Bukar, S Nagarajan. Inhaled insulin. Advanced Drug Deliv Rev 35 235-247, 1999. 

Virtually all therapeutic proteins must enter the blood in order to promote a therapeutic effect. Such products must usually be administered parenterally. However, research continues on the development of non-parenteral routes which may prove more convenient, less costly and obtain improved patient compliance. Alternative potential delivery routes include transdermal, nasal, oral and bucal approaches, although most progress to date has been recorded with pulmonary-based delivery systems (Chapter 4). An inhaled insulin product ( Exubera , Chapters 4 and 11) was approved in 2006 for the treatment of type I and II diabetes. 

Pulmonary delivery currently represents the most promising alternative to parenteral delivery systems for biopharmaceuticals. Delivery via the pulmonary route moved from concept to reality in 2006 with the approval of Exubera, an inhalable insulin product (Chapter 11). Although the lung is not particularly permeable to solutes of low molecular mass (e.g. sucrose or urea), macromolecules can be absorbed into the blood via the lungs surprisingly well. In fact, pulmonary... 

Patton, J.S., Bukar, J.G., and Eldon, M.A. 2004. Clinical pharmacokinetics and pharmacodynamics of inhaled insulin. Clinical Pharmacokinetics 43(12), 781-801. 

Quattrin, T. 2004. Inhaled insulin recent advances in the therapy of type 1 and 2 diabetes. Expert Opinion on Pharmacotherapy. 5(12), 2597-2604. 

Scherbaum, W. 2005. Inhaled insulin clinical efficacy. Diabetes Obesity and Metabolism 7(Suppl. 1), S1-S13. 

Becker RHA, Sha S, Frick AD, Fountaine RJ (2006) The effect of smoking cessation and subsequent resumption on absorption of inhaled insulin. Diabetes Care 29 277-282. 

Wise S, Chien J, Yeo K, Richardson C (2006) Smoking enhances absorption of insulin but reduces glucodynamic effects in individuals using the Lilly-Dura inhaled insulin system. Diabet Med 23 510-515. 

In January 2006, the FDA approved the inhalable insulin Exubera for type I and type II diabetes. Details are presented in Exhibit 4.14. 

Exubera is an inhaled insulin. It represents a major step forward since the first insulin injection was approved in the 1920s. The insulin particles are formulated to a certain micron size for deep lung delivery. An inhaler is used to achieve the delivery. The large surface area of the thin alveolar walls in the lungs allows for fast absorption of the insulin into the bloodstream. 

Inhalation Administration Aerosol particles of drug can be inhaled into the lungs. Because of the large surface area of the alveoli, absorption is rapid and effective. As the lungs are richly supplied with capillaries, distribution of inhalational drugs is very quick (refer to Exhibit 4.14 on inhalable insulin). 

Exubera (see also Exhibit 4.14) Exubera is an inhalable insulin for the treatment of type I and II diabetes. Each dose consists of 1 or 3 mg insulin in a powder formulation with sodium citrate (dehydrate), mannitol, glycine, and sodium hydroxide. 

Ipratropium Atrovent HFA, Atrovent Nasal) [Bronchodilotor/ Anticholinergic] Uses Bronchospasm w/ COPD, rhinitis, rhinorrhea Action Synthetic anticholinergic similar to atropine antagonizes acetylcholine receptors, inhibits mucous gland secretions Dose Adults Feds >12 y. Nebuliza-tion 500 meg in 2.5-3.0 mL NS Feds. Nebulization 125-250 meg in 2.5-3.0 mL NS Caution [B, +/-] w/ inhal insulin Contra Allergy to soya lecithin/related foods Disp HFAmet-dose inhal 18 meg/dose inhal soln 0.02% nasal spray 0.03,... 

Although no biopharmaceutical product delivered to the bloodstream via the pulmonary route has been approved to date, several companies continue to pursue active research and development programmes in the area. Amongst the leading product candidates is Exubera , an inhalable dry powder insulin formulation currently being evaluated by Pfizer and Aventis Pharma in Phase III clinical studies. The inhaled insulin is actually more rapidly absorbed than if administered subcutaneously and appears to achieve equivalent glycaemic control. While promising, final approval or otherwise of this product also depends upon additional safety studies which are currently under way. 

Skyler JS, Weinstock RS, Pasdn P, Yale JF, Barrett E, Gerich JE, Gerstein HC (2005) Use of inhaled insulin in a basal/bolus insulin regimen in type 1 diabetic subjects A 16-month randomized, comparative trial. Diab Care 28(7) 1630-1635... 

Inhaled insulin has been studied in 72 patients in an open, parallel-group, randomized trial for 12 weeks 35 used inhaled insulin (206). The inhaled insulin was given... 

The dose of inhaled insulin is about 10 times higher than the subcutaneous dose that produces the same hypoglycemic effect. In an open, randomized, crossover study subcutaneous insulin was compared with a 10 times higher dose of inhaled insulin in 15 non-smoking patients with type 2 diabetes (262). The peak action of inhaled insulin was earlier. Apart from that, the effects were similar. There were no differences in FEVi at baseline or at 4 or 8 hours after treatment. Absorption of inhaled insulin is significantly higher in smokers (263). In non-diabetics, absorption is reduced in asthma (264). Inhaled insulin may increase the titer of insulin antibodies (265). 

Non-invasive insulin delivery is still experimental. The various methods (transdermal, nasal, lungs, oral) have been reviewed, with special attention to the various techniques and administration of inhaled insulin, which seems the most promising alternative to injection (266,267). 

Insulin-binding IgG antibodies are found in about 75% of patients with type 2 diabetes using inhaled insulin (270). This is more than one would expect from the use of subcutaneous insulin. The antibodies appear to plateau after 1 year. There are no obvious clinical effects. 

In an open study of 107 patients with type 2 diabetes using the AERx insulin diabetes management system (n = 54) or subcutaneous insulin (n — 53), the number of people with insulin antibodies increased from 6% to 35% in those who used the AERx insulin diabetes management system (271). The number of patients with antibodies remained stable at about 10% in those who used subcutaneous insulin. There were no obvious clinical consequences. Similar results were found in a study of patients with type 1 diabetes 29% of those who used inhaled insulin compared with 3% of those who used subcutaneous insulin (272). 

The risk of hypoglycemia with inhaled insulin has been reported to be similar to that with subcutaneous insulin (273). In an open study of 107 patients with type 2 diabetes, mean age 58 years, using liquid insulin aerosol droplets + subcutaneous NPH insulin (n = 54) compared with Actrapid + NPH (n — 53) for 24 weeks, there were three major episodes of hypoglycemia in two patients using inhaled insulin and none in the other group (268). 

Of 335 patients with type 1 diabetes randomized to receive preprandial inhaled insulin as a dry powder formulation via an aerosol delivery system (Exubera) plus bedtime subcutaneous Ultralente insulin, or to continue NPH and regular insulins subcutaneously, 170 received inhaled insulin (mean age 33 years) (272). Six discontinued inhaled insulin, one because of mild cough, two because of hypoglycemia, and three because of insufficient responses. The risk of hypoglycemia was slightly lower in those who used inhaled insulin, at 8.6 events per month compared with 9.0 events per month in the conventional insulin group. 

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