Needle-free nasal delivery of glucagon for treatment of diabetes-related severe hypoglycemia: toxicology of polypropylene resin used in delivery device

Reno, Frederick E.; Edwards, Craig; Jensen, Morten Bendix; Török-Bathó, Magdolna; Esdaile, David J.; Piché, Claude A.; Triest, Myriam; Carballo, D. Calero

doi:10.3109/15569527.2015.1089884

Cited by 6 publications

(5 citation statements)

References 21 publications

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“…The project has been continued by Eli Lilly, a U.S. pharmaceutical company that obtained registration for IN glucagon as a powder (with beta-cyclodextrin plus dodecyl-phospho-choline as the promoter) [ 69 , 70 ] for severe hypoglycemia in adult and adolescent insulin users in US, Canada, and Europe in 2019. As shown in Table 1 , the recommended dose of IN glucagon (Baqsimi) is 3 mg.…”

Section: Introductionmentioning

confidence: 99%

New Fast Acting Glucagon for Recovery from Hypoglycemia, a Life-Threatening Situation: Nasal Powder and Injected Stable Solutions

Sala

Pontiroli

2021

IJMS

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The goal of diabetes care is to achieve and maintain good glycemic control over time, so as to prevent or delay the development of micro- and macrovascular complications in type 1 (T1D) and type 2 diabetes (T2D). However, numerous barriers hinder the achievement of this goal, first of all the frequent episodes of hypoglycemia typical in patients treated with insulin as T1D patients, or sulphonylureas as T2D patients. The prevention strategy and treatment of hypoglycemia are important for the well-being of patients with diabetes. Hypoglycemia is strongly associated with an increased risk of cardiovascular disease in diabetic patients, due probably to the release of inflammatory markers and prothrombotic effects triggered by hypoglycemia. Treatment of hypoglycemia is traditionally based on administration of carbohydrates or of glucagon via intramuscular (IM) or subcutaneous injection (SC). The injection of traditional glucagon is cumbersome, such that glucagon is an under-utilized drug. In 1983, it was shown for the first time that intranasal (IN) glucagon increases blood glucose levels in healthy volunteers, and in 1989-1992 that IN glucagon is similar to IM glucagon in resolving hypoglycemia in normal volunteers and in patients with diabetes, both adults and children. IN glucagon was developed in 2010 and continued in 2015; in 2019 IN glucagon obtained approval in the US, Canada, and Europe for severe hypoglycemia in children and adults. In the 2010s, two ready-to-use injectable formulations, a stable non-aqueous glucagon solution and the glucagon analog dasiglucagon, were developed, showing an efficacy similar to traditional glucagon, and approved in the US in 2020 and in 2021, respectively, for severe hypoglycemia in adults and in children. Fast-acting glucagon (nasal administration and injected solutions) appears to represent a major breakthrough in the treatment of severe hypoglycemia in insulin-treated patients with diabetes, both adults and children. It is anticipated that the availability of fast-acting glucagon will expand the use of glucagon, improve overall metabolic control, and prevent hypoglycemia-related complications, in particular cardiovascular complications and cognitive impairment.

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Section: Introductionmentioning

confidence: 99%

New Fast Acting Glucagon for Recovery from Hypoglycemia, a Life-Threatening Situation: Nasal Powder and Injected Stable Solutions

Sala

Pontiroli

2021

IJMS

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“…This preparation and administration procedure can be inconvenient, intimidating, and is more susceptible to potential dosing errors, especially when administered by people who are not trained in reconstitution and injection techniques in emergency situations. Recently, nasal delivery of glucagon powder has been investigated for treating diabetes-related severe hypoglycemia [1,2]. It consisted of a dry powder spray formulation of synthetic glucagon in a single-use device.…”

Section: Introductionmentioning

confidence: 99%

Excipient Interactions in Glucagon Dry Powder Inhaler Formulation for Pulmonary Delivery

et al. 2019

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Purpose: This study describes the development and characterization of glucagon dry powder inhaler (DPI) formulation for pulmonary delivery. Lactose monohydrate, as a carrier, and L-leucine and magnesium stearate (MgSt) were used as dispersibility enhancers for this formulation. Methods: Using Fourier-transform infrared (FTIR) spectroscopy, Differential Scanning Calorimetry (DSC), and Raman confocal microscopy, the interactions between glucagon and all excipients were characterized. The fine particle fractions (FPFs) of glucagon in different formulations were determined by a twin stage impinger (TSI) using a 2.5% glucagon mixture, and the glucagon concentration was measured by a validated LC-MS/MS method. Results: The FPF of the glucagon was 6.4%, which increased six-fold from the formulations with excipients. The highest FPF (36%) was observed for the formulation containing MgSt and large carrier lactose. The FTIR, Raman, and DSC data showed remarkable physical interactions of glucagon with leucine and a minor interaction with lactose; however, there were no interactions with MgSt alone or mixed with lactose. Conclusion: Due to the interaction between L-leucine and glucagon, leucine was not a suitable excipient for glucagon formulation. In contrast, the use of lactose and MgSt could be considered to prepare an efficient DPI formulation for the pulmonary delivery of glucagon.

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“…This evaluation may start early during product development, even to drive the selection of the optimal device for the subsequent clinical trials. For instance, in vitro cytotoxicity and in vivo skin sensitization and irritation tests were carried out on the polypropylene resin used for the delivery device of the glucagon nasal powder (Reno et al, 2016).…”

Section: Delivery Devices For Nasal Powder Insufflationmentioning

confidence: 99%

Opportunity and challenges of nasal powders: Drug formulation and delivery

Fasiolo

Manniello

Tratta

et al. 2018

European Journal of Pharmaceutical Sciences

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In the field of nasal drug delivery, among the preparations defined by the European Pharmacopoeia, nasal powders facilitate the formulation of poorly water-soluble active compounds. They often display a simple composition in excipients (if any), allow for the administration of larger drug doses and enhance drug diffusion and absorption across the mucosa, improving bioavailability compared to nasal liquids. Despite the positive features, however, nasal products in this form still struggle to enter the market: the few available on the market are Onzetra Xsail® (sumatriptan) for migraine relief and, for the treatment of rhinitis, Rhinocort® Turbuhaler® (budesonide), Teijin Rhinocort® (beclomethasone dipropionate) and Erizas® (dexamethasone cipecilate). Hence, this review tries to understand why nasal powder formulations are still less common than liquid ones by analyzing whether this depends on the lack of (i) real evidence of superior therapeutic benefit of powders, (ii) therapeutic and/or commercial interest, (iii) efficient manufacturing methods or (iv) availability of suitable and affordable delivery devices. To this purpose, the reader's attention will be guided through nasal powder formulation strategies and manufacturing techniques, eventually giving up-to-date evidences of therapeutic efficacy in vivo. Advancements in the technology of insufflation devices will also be provided as nasal drug products are typical drug-device combinations.

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Needle-free nasal delivery of glucagon for treatment of diabetes-related severe hypoglycemia: toxicology of polypropylene resin used in delivery device

Cited by 6 publications

References 21 publications

New Fast Acting Glucagon for Recovery from Hypoglycemia, a Life-Threatening Situation: Nasal Powder and Injected Stable Solutions

New Fast Acting Glucagon for Recovery from Hypoglycemia, a Life-Threatening Situation: Nasal Powder and Injected Stable Solutions

Excipient Interactions in Glucagon Dry Powder Inhaler Formulation for Pulmonary Delivery

Opportunity and challenges of nasal powders: Drug formulation and delivery

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