Credit: Prof. Th. Premchand Singh, Professor, Department of Medicine, Regional Institute of Medical Sciences, Imphal, India.
Abstract:
Inhaled insulin is a novel therapeutic option among the insulin delivery devices in the management of diabetes mellitus. It may ultimately replace the need for multiple daily subcutaneous injections of insulin. Subcutaneous insulin in all forms either pen devices or Subcutaneous Insulin Infusion (Insulin pump) is painful, inconvenient and does not achieve the recommended glycaemic goal. Insulin delivery through pulmonary route is rapidly absorbed comparable to subcutaneous injection of two faster acting insulin analogues, insulin lispro and insulin aspart with a much longer duration of action lasting four to six hours. Studies have shown that availability of inhaled insulin as a potential treatment option increases patients’ willingness to add or change to insulin therapy.
Introduction
Subcutaneous injection has been the only route of delivering insulin to patients with diabetes mellitus for the past 85 years, since its discovery by Fredrick G. Banting, Charles H. Best in 1921[1]. Subcutaneous injection is not only painful and inconvenient and not readily accepted by the diabetic patients. At the same time it does not achieve recommended glycaemic control, even with the newer analogue insulins, insulin aspart and insulin lispro. Alternative routes of insulin administration have been studied including dermal, oral, nasal and pulmonary routes. The dream of an “insulin tablet” has not been materialized due to the presence of peptidases in the gastrointestinal tract and rapid degradation of insulin by liver through “first pass metabolism”. Pulmonary application of insulin has become a viable alternative route of insulin administration which has been found comparable or even better than the subcutaneous injection of rapid acting insulin analogues.
Pulmonary route for drug administration:
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 also received increasing attention for the treatment of systemic diseases [2] . The lung has inherent advantages for insulin administration because of the vast (50-140 m2, ~500 millions of alveoli) and well-perfused absorptive surface (~5 L blood/min, pulmonary capillary blood volume ~0.25 L) and a thin alveolar-capillary barrier[3]. These conditions allow a fast absorption of peptides into the bloodstream and a rapid onset of action after inhalation, thereby, the lung represents a highly permeable ‘port of entry’ into the blood for insulin macromolecules[4].
Insulin administration through pulmonary route:
Insulin in a given aerosol whether in powder or liquid forms, is unevenly distributed in the lung among particles with various sizes and deposition properties. Thus, the inhalation of insulin cannot be expected to yield 100% of the applied dose. Several studies with inhaled insulin showed a relative bioavailability and biopotency of less than 20%. The reasons for the loss of 90% of insulin during inhalation are not fully understood(5), but the following factors may be considered:
1. Part of the insulin remains in the drug container after inhalation,
2. Some of the insulin adheres to the inner surfaces of the inhaler,
3. Larger particles of insulin get deposited in the mouth, throat and bronchial tree
4. Smaller particles are exhaled without being deposited in the lung alveoli, and
5. Some of the insulin deposited in the alveoli is degraded by macrophages and peptidases.
It is observed that inhaled insulin is more rapidly absorbed, peak concentrations achieved in 49 to 65 minutes compared to the subcutaneous injection of regular insulin whose peak concentrations are achieved in 119 minutes[6]. The time to reach maximum insulin concentration in blood following inhalation (tmax) is comparable to that of subcutaneous injection with the two fast-acting DNA recombinant insulin analogues, insulin lispro and insulin aspart. The duration of action of inhaled insulin lasts four to six hours which is slightly longer than that following subcutaneous administration of insulin lispro or insulin aspart lasting three to five hours but is shorter than that of subcutaneous administration of regular insulin which lasts four to eight hours [7]. This suggests that rapid glycemic control at mealtimes may be achieved with inhaled insulin, similar to that of fast-acting recombinant insulin analogues. Thus patients may be able to inhale a dose 5–10 minutes before a meal to achieve adequate glycemic control rather than the 20–30 minutes necessary with subcutaneous regular insulin injections. Inhaled insulin should be used in combination with a once-daily injection of long-acting insulin because of the shorter duration of action with pulmonary insulin delivery .
A number of insulin delivery systems through pulmonary route are studied and these fall into two main groups: solution and drug powder formulations, which are delivered through different inhaler systems. Exubera, a rapid-acting insulin in powder form, has been studied extensively in patients with type 1 and type 2 diabetes mellitus and now accepted by FDA, US. The AERx Insulin Diabetes Management System delivers a liquid form of human insulin. Other pulmonary insulin delivery systems, including ProMaxx, AIR, Spiros, and Technosphere, are also under study.
Potential risks associated with the inhalation of insulin:
A potential long term risk from the intraalveolar deposition of insulin within the lungs has always been considered, since insulin is known to have growth-promoting properties[8,9]. The high concentration of insulin can stimulate proliferation of local cells via a cross-reaction with Insulin like Growth Factor -1 (IGF-1) receptors or act as a tumour promoter. This is specially so in subjects exposed to carcinogens such as smokers. However, clinical data have not indicated increased cellular proliferation or growth promotion in patients receiving orally inhaled insulin. Wollmer and his colleagues has not observed any substantial change in lung function in patients with type 2 diabetes receiving inhaled regular insulin via the AERx iDMS, in combination with NPH insulin at bedtime[10].
A rise in insulin antibody levels has also been observed with inhaled insulin. The increase is higher in patients with type 1 than with type 2 diabetes specially in the first few months of treatment. However, detailed analysis of clinical data from the patients in these studies showed no correlation of antibody levels with increased glycated haemoglobin, insulin doses, or hypoglycaemia rates. Thus, the appearance of insulin binding antibodies appears not to be correlated to indices of metabolic control and clinical safety.(11).
Acceptability of inhaled insulin:
Results of numerous clinical trials with inhaled insulin have shown a high degree of patient compliance and acceptance(12, 13,14,15). Freemantle et al.[15] examined the impact of the availability of inhaled insulin on patient acceptance. The study was conducted in seven countries with patients with type 2 diabetes The results of this study suggest that the availability of inhaled insulin as a potential treatment may increase patients’ willingness to add or change to insulin therapy.
Conclusions
With the availability of a pulmonary insulin application it can be predicted that the pre-prandial inhalation of insulin will become the first practically applicable alternative to subcutaneous injections in the near future. The clinical-experimental studies show that the pharmacodynamic effects of inhaled insulin are as good as or even better than subcutaneous injection of regular insulin including the new insulin analogues, insulin lispro and insulin aspart, in controlling postprandial hyperglycaemia.
The critical questions regarding the long-term consequences of the inhalation of insulin like changes in lung-function, lung safety and the development of insulin-antibodies, appear to be answered by appropriate long-term studies. This is a topic which requires careful evaluation in view of the potential long-term exposure of patients with diabetes.
References:
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14. Cappelleri JC, Cefalu WT, Rosenstock J et al. Treatment satisfaction in type 2 diabetes: a comparison between an inhaled insulin regimen and a subcutaneous insulin regimen. Clin Ther. 2002; 24:552-64.
15. Freemantle N, Blonde L, Bolinder B et al. Inhaled insulin (Exubera) leads to a greater potential acceptance of insulin therapy in patients with uncontrolled type 2 diabetes. Diabetes. 2004; 53:1950. Abstract.34-37
Correspondence Address:
Prof. Th. Premchand Singh. Department of Medicine, Regional Institute of Medical Sciences, Imphal – 795004, Manipur. Email: premthangjam@gmail.com. Phone: +91 9436038030