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dc.contributor.authorLoftsson, T
dc.contributor.authorGudmundsdottir, H
dc.contributor.authorSigurjonsdottir, J F
dc.contributor.authorSigurdsson, H H
dc.contributor.authorSigfusson, S D
dc.contributor.authorMasson, M
dc.contributor.authorStefansson, E
dc.date.accessioned2009-09-29T14:40:45Z
dc.date.available2009-09-29T14:40:45Z
dc.date.issued2001-01-05
dc.date.submitted2009-09-29
dc.identifier.citationInt J Pharm. 2001, 212(1):29-40en
dc.identifier.issn0378-5173
dc.identifier.pmid11165818
dc.identifier.doi10.1016/S0378-5173(00)00580-9
dc.identifier.urihttp://hdl.handle.net/2336/82993
dc.descriptionTo access publisher full text version of this article. Please click on the hyperlink in Additional Links fielden
dc.description.abstractThe 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 ionization of the ring-open forms. Additional enhancement was obtained through interaction of a water-soluble polymer with the cyclodextrin complexes. The ring-opening was pH-dependent and completely reversible, the ring-open forms dominating at low pH but the ring-closed forms at physiologic pH. The ring-closed forms were rapidly regenerated upon elevation of pH. In freshly collected human serum in vitro at 37 degrees C, 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 solubilized in aqueous pH 4.3 nasal formulation containing 14% (w/v) sulfobutylether beta-cyclodextrin, 0.1% (w/v) hydroxypropyl methylcellulose, preservatives and buffer salts. Six healthy volunteers received 0.06 mg/kg midazolam intranasally and 2 mg intravenously, and blood samples were collected up to 360 min after the administration. Midazolam was absorbed rapidly reaching maximum serum concentrations of 54.3+/-5.0 ng/ml at 15+/-2 min. The elimination half-life of midazolam was 2.2+/-0.3 h and the absolute availability was 73+/-7%. All mean values+/-SEM.
dc.language.isoenen
dc.publisherElsevier/North-Holland Biomedical Pressen
dc.relation.urlhttp://dx.doi.org/10.1016/S0378-5173(00)00580-9en
dc.subject.meshAdministration, Intranasalen
dc.subject.meshAdulten
dc.subject.meshAnimalsen
dc.subject.meshAnti-Anxiety Agentsen
dc.subject.meshChemistry, Pharmaceuticalen
dc.subject.meshCyclodextrinsen
dc.subject.meshFemaleen
dc.subject.meshHumansen
dc.subject.meshHydrogen-Ion Concentrationen
dc.subject.meshMaleen
dc.subject.meshMidazolamen
dc.subject.meshSolubilityen
dc.titleCyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal sprayen
dc.typeArticleen
dc.contributor.departmentFaculty of Pharmacy, University of Iceland, P.O. Box 7210, IS-127, Reykjavik, Iceland. thorstlo@hi.isen
dc.identifier.journalInternational journal of pharmaceuticsen
html.description.abstractThe 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 ionization of the ring-open forms. Additional enhancement was obtained through interaction of a water-soluble polymer with the cyclodextrin complexes. The ring-opening was pH-dependent and completely reversible, the ring-open forms dominating at low pH but the ring-closed forms at physiologic pH. The ring-closed forms were rapidly regenerated upon elevation of pH. In freshly collected human serum in vitro at 37 degrees C, 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 solubilized in aqueous pH 4.3 nasal formulation containing 14% (w/v) sulfobutylether beta-cyclodextrin, 0.1% (w/v) hydroxypropyl methylcellulose, preservatives and buffer salts. Six healthy volunteers received 0.06 mg/kg midazolam intranasally and 2 mg intravenously, and blood samples were collected up to 360 min after the administration. Midazolam was absorbed rapidly reaching maximum serum concentrations of 54.3+/-5.0 ng/ml at 15+/-2 min. The elimination half-life of midazolam was 2.2+/-0.3 h and the absolute availability was 73+/-7%. All mean values+/-SEM.


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