Exubera Inhalative Insulin

Barnett AH. Exubera inhaled insulin a review. Int J Clin Pract 2004 5 394-401. 

Insulin Diabetes Human (416 type-1 diabetic patients) Inhalation (Exubera ) Inhaled insulin effective, well-tolerated and well-accepted [60]... 

Pfizer Exubera Inhaled insulin powder Approved... 

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

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... 

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. 

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. 

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. 

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. 

Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 1 diabetes. Diabetes Care 2004 27 2622-7. 

Odegard PS, Capoccia KL. Inhaled insulin Exubera. Ann Pharmacother 2005 39 843-53. 

Fineberg SE, Kawabata T, Finco-Kent D, Liu C, Krasner A. Antibody response to inhaled insulin in patients with type 1 or type 2 diabetes. An analysis of initial phase II and III inhaled insulin (Exubera) trials and a two year extension trial. J Clin Endocrinol Metab 2005 90 3287-94. 

A.E. Mehta, J.L. Milburn, K.S. Hershon, J.L. Chiasson, and S.R. Levin. 2004. Efficacy and safety of inhaled insulin (exubera) compared with subcutaneous insulin therapy in patients with type 2 diabetes results of a 6-month, randomized, comparative trial. Diabetes Care 27 2356-2362. 

Since the first introduction of insulin to treat diabetic patients in 1923, much effort has been made to seek alternative convenient and painless routes for insulin administration instead of daily injections. In this respect the pulmonary route has received the most attention, and substantial evidence has shown inhaled insulin to be an effective, well-tolerated, noninvasive alternative route [53-56]. Insulin therapy is required for patients with type 1 diabetes. Although some patients with type 2 diabetes can control their disease with oral antidiabetics, many will eventually also require insulin. Thus, inhaled insulin shows promise for type 2 diabetic patients [54, 56]. There are two principal inhalation systems for insulin, namely aqueous solution and dry powder. The dry powder form (Exubera ) has been approved by FDA and the European Medicines Agency (EMEA) in January 2006. 

New formulations for inhaled insulin are currently under development by several companies, and are at various stages of clinical trials. Among these, AERx is in advanced Phase III trials [59], while Exubera has been approved in the USA and Europe. The clinical pharmacokinetics and pharmacodynamics of inhaled insulin were recently reviewed by Eldon et al. [59]. 

Rosenstock, J., Cappelleri, J. C., Bolinder, B., and Gerber, R. A. (2004), Patient satisfaction and glycemic control after 1 year with inhaled insulin (exubera) in patients with type 1 or type 2 diabetes, Diabetes Care, 27,1318-1323. 

Therapeutic peptides and proteins are far more stable in the solid state compared to the liquid state. Delicate proteins often significantly degrade within hours when held at room temperature in the liquid state. All FDA approved therapeutic proteins for human use are injectable products, except Exubera the first inhaleable insulin. A recent survey has shown that 12 of the 30 commercial products are available only as dry powder and 28 of the 30 require refrigeration (49). Not having to refrigerate a pharmaceutical product greatly increases convenience and significantly reduces transportation and distribution costs, this is particularly true for vaccines, where an alternative to break the so called distribution cold chain is badly needed in third world countries. 

A third area to consider is the generation of an enhanced product that adds value to the original finished dosage form. Product enhancements include, for example, other forms of dehvery (e.g., transder-mal, nasal, inhalable, etc.) or new formulations. Examples among the biopharmaceuticals are the development of inhaled insulins, e.g., Exubera currently in phase III clinical trials developed by Nektar Therapeutics, Pfizer, and Aventis (admittedly, this work is not driven by a potential generic threat, but primarily by the enormous market potential of an insuhn that does not have to be injected) (see also Part VI, Chapter 2). 

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