Cyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal spray

The cyclodextrin solubilization of three benzodiazepines, i.e. alprazolam, midazolam and triazolam, was investigated. The cyclodextrin solubilization was enhanced through ring-opening of the benzodiazepine rings and ionizatio n of the ring-open forms. Additional enhancement was obtained through inter action of a water-soluble polymer with the cyclodextrin complexes. The ring -opening was pH-dependent and completely reversible, the ring-open forms do minating at low pH but the ring-closed forms at physiologic pH. The ring-cl osed forms were rapidly regenerated upon elevation of pH. In freshly collec ted human serum in vitro at 37 degreesC, the half-life for the first-order rate constant for the ring-closing reaction was estimated to be less than 2 min for both alprazolam and midazolam. Midazolam (17 mg/ml) was solubilize d in aqueous pH 4.3 nasal formulation containing 14% (w/v) sulfobutylether beta -cydodextrin, 0.1% (w/v) hydroxypropyl methylcellulose, preservatives and buffer salts. Six healthy volunteers received 0.06 mg/kg midazolam intr anasally and 2 mg intravenously, and blood samples were collected up to 360 min after the administration. Midazolam was absorbed rapidly reaching maxi mum serum concentrations of 54.3 +/- 5.0 ng/ml at 15 +/- 2 min. The elimina tion half-life of midazolam was 2.2 +/- 0.3 h and the absolute availability was 73 +/- 7%. All mean values +/- SEM. (C) 2001 Elsevier Science B.V. All rights reserved.