A new non-invasive method for treating insulin-reaction: intranasal lyophylized glucagon

Abstract

The main therapeutic indication for glucagon is the treatment of hypoglycaemia in insulin overdosed Type 1 (insulin-dependent) diabetic patients. We have previously shown that an intranasal spray of 7.5 mg glucagon with deoxycholic acid as surfactant was able to correct an i.v. insulin-induced hypoglycaemia in diabetic patients. However, bioavailability and stability needed to be improved before intranasal glucagon could be introduced into clinical practice. This has now been achieved with a freeze-dried mixture of glucagon (1 mg) and glycocholic acid (1 mg) as a surfactant. Kinetics and efficacy have been controlled by (1) comparing subcutaneous and intranasal glucagon in 12 healthy non-hypoglycaemic subjects; (2) testing intranasal glucagon in six Type 1 diabetic patients in whom hypoglycaemia was induced by an i.v. bolus of insulin and (3) comparing subcutaneous and intranasal glucagon in six Type 1 diabetic patients in whom hypoglycaemia was induced by adding extra subcutaneous regular insulin to their usual morning dosage. Our results show that 1 mg of intranasal glucagon is as effective as 1 mg of subcutaneous glucagon in terms of the rise in blood glucose. Differences in kinetics between the subcutaneous and the intranasal routes may be observed: intranasal glucagon initiates the blood glucose rise earlier than does the subcutaneous form but the effect of the latter is more sustained. Glycocholic acid appears to be a perfectly tolerated agent in acute conditions. The use of intranasal lyophylized glucagon, for the reversal of hypoglycaemia in Type 1 diabetes, seems to be a clinically relevant alternative to its parenteral equivalent and should now be ready to be introduced in the market.

Intranasal glucagon treatment relieves hypoglycaemia in children with Type 1 (insulin-dependent) diabetes mellitus

“…As previously reported in studies of children [11,14] and adults [13], glucagon treatment is accompanied by the late development of marked nausea. In this study we found that almost all the children developed nausea 90-120 rain after the s.c. injection of glucagon.…”

“…Like others [13,22], we found that the peak of i. n. glucagon concentration occurred earlier following i.n. administration and that it fell more rapidly than that following s. c. glucagon administration.…”

“…They showed that the treatment was effective and induced a significant rise in blood glucose concentration. Slama et al [13] presented another study, comparing intranasal (i. n.) and subcutaneously (s. c.) administered glucagon in adult diabetic patients with insulin-induced hypoglycaemia. They concluded that i.n.…”

Glucagon for hypoglycemic episodes in insulin-treated diabetic patients: a systematic review and meta-analysis with a comparison of glucagon with dextrose and of different glucagon formulations

“…Measure of efficacy was the number/percentage of patients/subjects not responding to glucagon according to criteria pre-defined by the authors of each paper. All the data are tabulated in Tables 1 and 2. Sixteen studies fulfilled the inclusion criteria [33,42,44,[50][51][52][53][54][55][56][57][58][59][60][61][62]. Details of data source and searches, study selection, data extraction and quality assessment, data synthesis, ER emergency room, SH severe hypoglycemia, IV intravenous, IM intramuscular; AEs adverse events, FDA food and drugs administration, EMS emergency medical services, and NEMSIS national emergency medical services information system and analysis have already been published [12].…”

Intranasal Glucagon

“…22 Studies performed later showed that glucagon solutions and powders were similarly effective, provided a promoter was present (sodium glycocholate, 9-lauryl ether, deoxycholic acid, didecanoyl phosphatidylcholine [DDPC] with alpha-cyclodextrine, sodium caprate, microcrystalline cellulose). [23][24][25][26] Eventually, several authors showed the ability of IN glucagon to resolve hypoglycemia in normal volunteers and in diabetic patients, adults, and children. [25][26][27][28][29][30][31][32] These studies, which encompass almost 300 study subjects, demonstrate that glucagon is well-suited for IN administration.…”