Inhaled Insulin: A Breath of Fresh Air? A Review of Inhaled Insulin
Introduction
Improvements in subcutaneous insulin have allowed for more physiologic regimens since its discovery in the 1920s. The development of rapid-acting insulin analogues has improved pharmacokinetic and pharmacodynamic properties of insulin formulations. However, these formulations continue to fall short of physiologic needs to control postprandial hyperglycemia, with delayed onset of action and prolonged effects leading to excessive hyperglycemia after eating and delayed hypoglycemia.1 The importance of tight glycemic control has been shown to prevent and/or delay long-term complications of diabetes.2 The success of insulin therapy, however, depends on its physiologic properties as well as on its proper use. Barriers to patient use of subcutaneous insulin include anticipated pain, anxiety, inconvenience, fear of hypoglycemia, and concern about weight gain.3 Evidence suggests that patients may be reluctant to start insulin when prescribed or to delay starting treatment.4 In one study of patients with type 2 diabetes (T2DM), 28% of subjects reported they were unwilling to start insulin, 45% reported resistance to insulin therapy due to restrictions on daily life (eg, harder to travel, eat out), and 43% of patients reported fear of hypoglycemia.5 Practical issues can also occur (eg, lipodystrophy, lipohypertrophy) from several years of recurrent injections.
It has been >90 years since the first therapeutic use of insulin by Banting and Best. Since that time, researchers have been searching for alternate modes of insulin delivery, including transdermal, ocular, oral, buccal, nasal, rectal, vaginal, and uterine delivery systems. Reports of pulmonary delivery of aerosolized insulin was first shown in the 1920s to decrease blood glucose levels.6 However, these methods have historically failed as insulin delivery systems, primarily due to low bioavailability. For example, oral bioavailability of insulin is limited due to extensive enzymatic and chemical degradation in the gastrointestinal tract and inability to cross intestinal mucosa due to the large hydrophilic nature.7, 8 Currently, several alternative methods of delivery are under investigation. Potential improvements include improved absorption of transdermal insulin-using iontophoresis (electrical currents), low-frequency ultrasound, and transfersomes (lipid vesicles) and increasing bioavailability of oral insulin such as stabilizing degradation and using microspheres to enhance absorption. The use of buccal insulin has also been proposed to overcome some of the aforementioned issues with oral insulin.9
Therefore, there is a need not only for alternative modes of insulin delivery but for a more physiologic, rapid-on/rapid-off, prandial insulin to improve glycemic control and reduce hypoglycemia. The present review focuses on the past and present data regarding the safety and effectiveness of inhaled insulin products as prandial insulin.
Section snippets
Materials and Methods
A systematic search was conducted in MEDLINE and the ClinicalTrials.gov registry (through May 2014) to find English-language studies and review articles of prior and current inhaled insulin products. The following search terms were used: diabetes, glycemic control, inhaled, inhalation, insulin, pulmonary, Exubera®, and Technosphere® insulin. We searched for additional publications in citation sections of the recovered articles. The US Food and Drug Administration (FDA) Website was also reviewed
Pulmonary Delivery of Insulin
Of the alternative modes of delivery investigated thus far, pulmonary delivery of insulin has shown the most promise, perhaps due to advantageous characteristics for medication delivery. Pulmonary delivery of insulin has been shown to have a ~4- to 40-fold increase in bioavailability compared with nasal, rectal, buccal, and conjunctival formulations.10 The lung is highly vascularized with ~500 million alveoli, providing an extremely large surface area (50–140 m2).7 The thin alveolar-capillary
Conclusions
A major unmet need in T1DM is the lack of rapid-on/rapid-off insulin leading to improved postprandial hyperglycemia and reduced delayed hypoglycemia. For the T2DM population requiring insulin therapy, there is not only patient resistance but also clinical inertia on the health care professional’s part to starting insulin. The development of an insulin formulation that has improved pharmacokinetics and pharmacodynamics compared with fast-acting analogues and the needle-less route of
Conflicts of interest
Tricia Santos Cavaiola have indicated that they have no other conflicts of interest regarding the content of this article. Steven Edelman is on the medical advisory boards and speakers bureau for Sanofi, NovoNordisk and Lilly
Acknowledgments
All authors contributed equally.
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2021, Molecular MetabolismCitation Excerpt :So intractable seemed this molecular dilemma that alternative, more efficient routes of delivery were explored, including portal injection [126–128] and inhaled insulin [129–132], in each case seeking to exploit extensive peritoneal or pulmonary absorptive surfaces. Such engineering efforts are continuing, as exemplified by implanted intraperitoneal pumps [133,134] and inhalation devices for insulin powders [130]. Irrespective of technology, the central therapeutic goal was avoidance of immediate post-prandial hyperglycemia (from a delay in insulin action) and late post-prandial hypoglycemia (from a prolonged tail of insulin action).