title: Inhaled insulin-intrapulmonary, intranasal, and other routes of administration: mechanisms of action.
abstract: BACKGROUND
  After discovery of insulin as a hypoglycemic agent in 1921 various routes of administration to control blood glucose were attempted. These included subcutaneous, oral, rectal, sublingual, buccal, transdermal, vaginal, intramuscular, intrapulmonary and intranasal delivery systems. While each delivery system controlled hyperglycemia the subcutaneous route was given priority until 2006 when the Federal Drug Administration (FDA) approved the first commercially available pulmonary inhaled insulin.
  
  
  METHODS
  A review of major publications dealing with intrapulmonary administration of insulin was made to understand the physiological basis for its use, its efficacy in controlling hyperglycemia, its side effects and a comparison of its efficacy with other delivery methods.
  
  
  RESULTS
  The large surface area of the lung, its good vascularization, capacity for solute exchange and ultra thin membranes of alveolar epithelia are unique features that facilitate pulmonary insulin delivery. Large lung surface area ( approximately 75 m(2)) and thin alveolar epithelium ( approximately 0.1-0.5 microm) permit rapid drug absorption. First pass metabolism avoids gastrointestinal tract metabolism. Lung drug delivery depends upon a complex of factors including size, shape, density, charge and pH of delivery entity, velocity of entry, quality of aerosol deposition, character of alveoli, binding characteristics of aerosol on the alveolar surface, quality of alveolar capillary bed and its subsequent vascular tree. Many studies were performed to optimize each of these factors using several delivery systems to enhance pulmonary absorption. Availability was about 80% of subcutaneous administration with peak activity within 40-60 min of administration. Intranasal insulin delivery faces a smaller surface area ( approximately 180 cm(2)) with quite different absorption characteristics in nasal epithelium and its associated vasculature. Absorption depends upon many factors including composition and character of nasal mucus. Absorption of intranasal insulin resulted in a faster absorption time course than with subcutaneous insulin.
  
  
  CONCLUSIONS
  After many studies the FDA approved Pfizer's product, Exubera, for intrapulmonary insulin delivery. While the system was effective its expense and putative side effects caused the drug company to withdraw the drug from the marketplace. Attempts by other pharmaceutical companies to use intrapulmonary insulin delivery are presently being made as well as some minor attempts to use intranasal delivery systems.
authors.affiliation: Center for Molecular Nutrition and Sensory Disorders, The Taste and Smell Clinic, Washington, DC, USA. rihenkin@earthlink.net
authors.forename: R I
authors.initials: RI
authors.lastname: Henkin
mesh_terms: D000042:Absorption; D000280:Administration, Inhalation; D000281:Administration, Intranasal; D000336:Aerosols / Q000737:chemistry; D004333:Drug Administration Routes; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000378:metabolism; D007328:Insulin / Q000008:administration & dosage* / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D009297:Nasal Mucosa / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000336:Aerosols; D007004:Hypoglycemic Agents; D007328:Insulin