Insulin inhalable product

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... 

Anonymous (2006), First inhaled insulin product approved, FDA Consum., 40,28-29. 

A new trend in the delivery of medicines is to employ a device component. This may be an implantable pump for insulin, a metallic stent coated with a drug, or unit capable of rapidly vaporizing a discrete dose for inhalation. Such products are regulated by the FDA as "combination" products and may be reviewed by multiple Centers within the Agency, which may require additional levels of documentation to support the product design. 

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. 

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). 

Systemic absorption of pulmonary-deUvered peptides and proteins has been the objective of many investigations [2]. The most successful work in this field is the development of insulin formulations for inhalation.These dosage forms might, in the near future, become a suitable alternative for the current subcutaneous injection of insulin that is used to obtain meal-time glucose control [3]. In spite of the strict requirements regarding dose variability for insulin, the pulmonary products under development seem to be as safe as the subcutaneous injections. 

---