Nasal Absorption of Dihydroergotamine from Liquid and Powder Formulations in Rabbits

Nasal drug delivery is an interesting route of administration for dihydroergotamine in migraine therapy. The currently available formulation contains dihydroergotamine at 4mg/mL. For a nasal dose of 2mg, a volume of 0.5mL has to be administered, which sometimes leads to spillage of the formulation. The aim of the present study was to develop a nasal spray with a dihydroergotamine concentration of 10mg/mL. To increase the solubility and stability of dihydroergotamine, randomly methylated β-cyclodextrin was used. Liquid formulations and lyophilized powders of dihydroergotamine and randomly methylated β-cyclodextrin were prepared. The liquid and powder formulations were compared by determining their pharmacokinetics and absolute bioavailability after nasal administration in rabbits. Nasal sprays were significantly more effective than drops in increasing the nasal bioavailability of dihydroergotamine, but the amount of randomly methylated β-cyclodextrin in liquid sprays did not significantly alter the nasal absorption. For powder formulations, the dihydroergotamine absorption was dependent on the amount of methylated β-cyclodextrin and powder volume, and the nasal bioavailability from the optimal powder was slightly, but not significantly, higher than that for liquids. In conclusion, the formulations investigated are a substantial improvement of the current commercial formulation, not only because the spray volume of the liquid spray can be reduced 2.5 times, but also because of the increased stability of liquid and powder sprays with randomly methylated-β-cyclodextrin.