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
 Iontophoresis
  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
 Transfersomes
  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
 Enteric
  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
 Buccal
  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)