Bioavailability of intranasal formulations of dihydroergotamine

Objective: A comparison of the pharmacokinetic properties of two novel intranasal preparations of dihydroergotamine mesilate (DHEM) with a commercially available intranasal preparation. Methods: Two intranasal formulations of DHEM in combination with randomly methylated β-cyclodextrin (RAMEB) were prepared. Subsequently, in an open, randomised, crossover study in nine healthy volunteers, the following medication was administered: 2 mg DHEM/2% RAMEB nasal spray (=two puffs of 100 μl); 2 mg DHEM/4 mg RAMEB nasal powder; 2 mg Diergo nasal spray (= four puffs of 125 μl); 0.5 mg DHEM i.m., and 2 mg DHEM solution p.o. Results: No statistically significant differences were found in maximum plasma concentration (C(max)), time to reach C(max) (t(max)), area under plasma concentration-time curve (AUC(0-8 h)), Frel((t = 8h)) and C(max)/AUC((t = 8h)) for the three intranasal preparations. The relative bioavailabilities of the DHEM/RAMEB nasal spray, the DHEM/RAMEB nasal powder and the commercially available DHEM nasal spray were 25%, 19% and 21%, respectively, in comparison with i.m. administration. The relative bioavailability after oral administration was 8%. Conclusion: The pharmacokinetic properties of the novel intranasal preparations are not significantly different from the commercially available nasal spray. Advantages of the DHEM/RAMEB nasal spray are (1) less complicated handling, (2) reduction of the number of puffs and (3) a preference by the volunteers.