Table 1—

Potential noninvasive insulin delivery options

• Jet injectors
 Deliver high pressure stream of insulin
 May benefit selected cases (e.g., severe lipoatrophy); suggested that use be advocated only for those who develop problems with other injection routes
• Transdermal
  Electrical current used to enhance transdermal insulin delivery; proof-of-principle from animal studies; human studies needed
 Low-frequency ultrasound
  Use of low-frequency sound wave to augment delivery of insulin and other macromolecules across human skin
  Composite phosphatidylcholine-based vesicles with similar permeability to water, although 1,000 times larger
  Transdermal delivery of insulin with bioefficiency ≥50% of the subcutaneous dose
  Administration over a 40-cm2 skin area may supply sufficient basal insulin to a typical type 1 diabetic patient
• Intranasal
 Nasal administration of certain proteins (e.g., oxytocin, desmopressin, and calcitonin) is now well established
 Permeability enhancers are generally required to augment insulin bioavailability; insulin bioavailability is typically in the range of 8–15% with enhancers
 Nasal irritation is common (e.g., with lecithin, bile salts, or laureth-9 as enhancers).
 Nasal tolerance and high rates of treatment failure are major limitations
 Recent clinical studies have shown more promising results (e.g., with gelified nasal insulin)
• Oral
  Oral enteric insulin delivery has limited bioavailability
  Insulin is too large and hydrophillic to readily cross the intestinal mucosa
  Polypeptides undergo extensive enzymatic and chemical degardation
  Only around 0.5% of a dose of oral insulin reaches the systemic circulation
  Several methods used to promote bioavailability
  Ongoing phase I and II clinical trials with new formulation suggest a bioavailability of ∼5%, which may result in an acceptable  glucose-lowering effect
  Liquid aerosol insulin is sprayed into the buccal cavity without entering the airways
  A liquid formulation of human recombinant insulin with added enhancers, stabilizers, and a non-chlorofluorocarbon propellant delivered via a metered dose inhaler in clinical trials
  Efficacy studies are preliminary and safety reports are scarce
• Pulmonary
 High permeability and large surface area provide a favorable anatomy for protein/drug uptake
 Very rapid absorption of insulin after inhalation mimics time-activity profile of fast-acting insulin; appropriate for premeal delivery
 Appears comparable to subcutaneous insulin on glycemic parameters for both type 1 and type 2 diabetic patients
 Several pulmonary insulin delivery systems are in development and in phase III testing (see Fig. 1)