Cyclodextrins have not been popular excipients for nasal or pulmonary drug delivery so far. This can change soon, with the appearance of a new product from Lilly, called Baqsimi. Baqsimi contains beta cyclodextrin (BCD) as an inactive ingredient. FDA approved the product last summer, and EMA approved the product in the end of 2019.
Baqsimi is a glucagon nasal powder and a medical device containing a single dose of 3 mg glucagon per device (Figure 1). It is a hyperglycemic agent and intended to use in emergency situations for the treatment of severe hypoglycemic reactions in insulin-treated patients with diabetes mellitus. Until now the emergency treatment for severe hypoglycemia was an intramuscular glucagon injection. The nasal product was developed by a company called Locemia; Lilly aquired the formulation in 2015 when the development was in Phase III .
Figure 1. Baqsimi
The first appearance of this formulation in a scientific journal was in 2015, when Reno et al reported their results on the toxicology studies in animal models . They tested the product in rats, dogs and rabbits and concluded that large overdoses of the product (containing 10% (w/v) glucagon) resulted in only mild to moderate reversible histological changes to the nasal mucosa in some animals. Recently, Pontiroli and Tagliabue showed the benefits of the intranasal glucagon in comparison to the intramuscular glucagon in a review article .
According to the EMA product information , Baqsimi contains 3 mg glucagon, and the rest is BCD and dedecylphosphocholine. BCD could help in improving the stability, solubility and bioavailability of glucagon.
This recent approval of Baqsimi is important, since before there was only one other intranasal formulation on the market containing a cyclodextrin. Aerodiol from Servier contained Estradiol and randomly methylated beta cyclodextrin (RAMEB). The nasal spray was launched in Ireland for menopausal syndrome, although, it is not on the market anymore.
According to the European Medicines Agency , methylated cyclodextrins (RAMEB, DIMEB) can have a direct action on the mucosal membranes and improve the nasal permeability. While hydroxypropyl beta cyclodextrin (HPBCD) does not have a direct effect on the mucosal membranes, it can solubilize various APIs and HPBCD is well tolerated by the nasal mucosa in solutions up to 10%. Sulfobutylether beta cyclodextrin (SBECD) should be also compatible with nasal delivery. RAMEB can be applied in solutions up to 10% too. This 2014 document only suggest the use of BCD in maximum 1.5% solutions, due to their low aqueous solubility. Now this should be updated that BCD can be used in solid intranasal formulations as well.
There is still a great potential for cyclodextrins in intranasal and pulmonary drug delivery of poorly soluble, unstable drugs. Hopefully we will see more products containing cyclodextrins appear on the market in the future.
 “Lilly Acquires Phase III Intranasal Glucagon from Locemia Solutions” (2015) https://investor.lilly.com/news-releases/news-release-details/lilly-acquires-phase-iii-intranasal-glucagon-locemia-solutions
 Frederick Reno; Patrick Normand; Kevin McInally, Sherwin Silo; Patricia Stotland; Myriam Triest; Dolores Carballo and Claude Piché (2015) “A novel nasal powder formulation of glucagon: toxicology studies in animal models”. BMC Pharmacology & Toxicology 16:29; DOI:10.1186/s40360-015-0026-9
 Antonio E. Pontiroli, Elena Tagliabue (2019) “Therapeutic Use of Intranasal Glucagon: Resolution of Hypoglycemia”. International Journal of Molecular Sciences 20. p3646; DOI:10.3390/ijms20153646
 Baqsimi product information, Annex 1; https://www.ema.europa.eu/en/documents/product-information/baqsimi-epar-product-information_en.pdf
 European Medicines Agency, “Background review for cyclodextrin used as excipients; https://www.ema.europa.eu/en/documents/report/background-review-cyclodextrins-used-excipients-context-revision-guideline-excipients-label-package_en.pdf