Oral insulin and buccal insulin: a critical reappraisal

Abstract

Despite the availability of modern insulin injection devices with needles that are so sharp and thin that practically no injection pain takes place, it is still the dream of patients with diabetes to, for example, swallow a tablet with insulin. This is not associated with any pain and would allow more discretion. Therefore, availability of oral insulin would not only ease insulin therapy, it would certainly increase compliance. However, despite numerous attempts to develop such a "tablet" in the past 85 years, still no oral insulin is commercially available. Buccal insulin is currently in the last stages of clinical development by one company and might become available in the United States and Europe in the coming years (it is already on the market in some other countries). The aim of this review is to critically describe the different approaches that are currently under development. Optimal coverage of prandial insulin requirements is the aim with both routes of insulin administration (at least with most approaches). The speed of onset of metabolic effect seen with some oral insulin approaches is rapid, but absorption appears to be lower when the tablet is taken immediately prior to a meal. With all approaches, considerable amounts of insulin have to be applied in order to induce therapeutically relevant increases in the metabolic effect because of the low relative biopotency of buccal insulin. Unfortunately, the number of publications about clinical-experimental and clinical studies is surprisingly low. In addition, there is no study published in which the variability of the metabolic effect induced (with and without a meal) was studied adequately. In summary, after the failure of inhaled insulin, oral insulin and buccal insulin are hot candidates to come to the market as the next alternative routes of insulin administration.

Figure 1.

Factors having an impact on insulin absorption after oral application of insulin.

Figure 2.

Glucose infusion rates necessary to keep blood glucose constant after swallowing a capsule with 300 U of an oral insulin formulation (Emisphere) in a glucose clamp setting in a patient with type 2 diabetes.

Figure 3.

(A) Blood glucose excursions and (B) serum insulin levels after a test meal in four patients with type 2 diabetes with 300 IU oral insulin or placebo.

Figure 4.

Primary structure of the conjugated oral insulin IN-105.

Figure 5.

Increase in mean plasma insulin levels and subsequent decrease of plasma glucose in 11 healthy subjects after oral administration of 5 mg IN-105 at t = 0 min.

Figure 6.

Increase in mean plasma glucose levels of 14 healthy subjects after a meal. On the different study days, IN-105 was applied with a different time interval prior to the start of the meal.

Figure 7.

Area under the postprandial blood glucose profiles of six patients with type 2 diabetes while escalating doses of oral HDV-I were applied. SEM, standard error of the mean.

Figure 8.

Scatter plot of the mean daily seven-point blood glucose values for subjects in the three different treatment groups on days 1, 4, 7, and 11. Each point on the graph is the mean of 11 subjects for the injection groups and 8 subjects for the oral treatment group.

Figure 9.

Changes in blood glucose (measured by a blood glucose meter) and plasma insulin in one healthy subject after swallowing a capsule with 216 U insulin and excipients at t = 0 min that promote insulin uptake.

Figure 10.

Mean GIR and serum insulin levels over 360 min following administration of SC insulin and buccal insulin in three different doses (+placebo spray) in healthy subjects t = 0 min.