Inhaled Insulin for Diabetes Mellitus

Tarun K. Mandal


Am J Health Syst Pharm. 2005;62(13):1359-1364. 

In This Article

Abstract and Introduction

Purpose: Pharmacokinetic and safety data related to the use of inhaled insulin for the management of diabetes mellitus are discussed. The various pulmonary insulin delivery systems under development are also reviewed.
Summary: Several pharmaceutical companies are developing pulmonary insulin delivery systems. These products fall into two main groups: solution and drug powder formulations, which are delivered through different patented inhaler systems. Exubera, a rapid-acting insulin in powder form, has been studied extensively in patients with type 1 and type 2 diabetes mellitus. The AERx Insulin Diabetes Management System delivers a liquid form of human insulin. Preliminary data indicate that patients converting from insulin injections to this system showed higher compliance to therapy, demonstrated by improved glycemic control. Other pulmonary insulin delivery systems, including ProMaxx, AIR, Spiros, and Technosphere, are also under investigation. In humans, inhaled regular insulin is more rapidly absorbed than insulin from the subcutaneous injection site. The efficiency of inhaled insulin is lower than that of subcutaneous injection because pulmonary delivery of insulin involves some loss of drug within the inhaler or mouth during inhalation. A concern of many clinicians is the possibility of long-term effects from the intraalveolar deposition of insulin within the lung, since insulin is known to have growth-promoting properties. The longterm safety of these products has not been established.
Conclusion: Several inhaled insulin products are under development. If these products receive marketing approval, the pulmonary delivery of insulin may offer patients with diabetes an alternative to repeated insulin injections.

Patients with type 1 diabetes mellitus require insulin therapy for glycemic control from the time of diagnosis.[1] Depending on the severity of the disease, patients often require three or more insulin injections daily to control blood glucose levels. Unlike type 1 diabetes mellitus, type 2 diabetes mellitus is often managed by noninsulin therapy, including oral hypoglycemic drugs, diet changes, and daily exercise. However, as the disease progresses, most patients with type 2 diabetes eventually require daily insulin injections.

In the history of medicine there are few events more dramatic than the discovery of insulin. In the early 1900s, several attempts were made to treat diabetic patients with pancreas extract. Fredrick G. Banting, a young Canadian surgeon, and his colleague Charles H. Best were the first to successfully extract the hormone in 1921 and subsequently injected it into a 14-year-old patient.[2] A wide range of injectable insulin products are available on the market and differ significantly in their pharmacokinetic profiles.[3] Some of these products (fast-acting insulin analogs) have a short duration of action (3–5 hours), and others (slow-acting protamine zinc insulin) have a longer duration of action (24–36 hours).

Insulin is a 5700 molecular weight protein that has been a candidate for noninvasive delivery since its initial use for the management of diabetes. However, efforts to develop commercially viable methods of noninvasive insulin delivery, particularly oral and nasal formulations, have not been successful. The major problem with these approaches has been biology: both the nasal and gastrointestinal epithelia are functionally impermeable to insulin.[4] After more than two decades of unsuccessful intensive work on nasal and oral protein and peptide delivery, the lung, which is naturally permeable to some proteins, is now receiving close scrutiny as a port of entry for injectable drugs such as insulin.

The pulmonary route has been used for decades to administer drug to the lungs for the treatment of asthma and other local respiratory diseases. This route has received in creasing attention for the treatment of systemic diseases.[5] The onset of action following the pulmonary administration of some drugs is very fast and comparable to i.v. administration. For example, Davidson et al.[6] reported that the time for inhaled testosterone to reach maximum concentration was less than two minutes in postmenopausal women. The lungs are an attractive site for the systemic delivery of protein and peptide drugs because they offer a larger surface area (70 m2) for systemic absorption of drugs when compared with other nontraditional routes of systemic drug delivery, such as the buccal, sublingual, nasal, rectal, and vaginal cavities. The pulmonary delivery of insulin could reduce the number of insulin injections required daily for millions of patients with diabetes, which should lead to improved compliance and long-term outcomes.

The objectives of this review are to discuss factors affecting the pulmonary delivery of insulin, provide an overview of pulmonary insulin delivery systems in development, and discuss the pharmacokinetics and safety of inhaled insulin. Patient acceptance and compliance will also be discussed. A thorough review of the results of several clinical trials using pulmonary insulin products has been published elsewhere by Agu et al.[7]