title: Benefits of methylated cyclodextrins in the development of midazolam pharmaceutical formulations.
abstract: Midazolam (MDZ) is a benzodiazepine commonly administered in preanesthesia of children by oral or by sublingual routes. To mask its bitter taste and enhance its aqueous solubility, we already developed a 0.2% (w/v) MDZ oral solution containing γ-cyclodextrin (γ-CD), which proves to be better accepted by children in pediatrics at University Hospital of Amiens. To improve the MDZ solubility, its closed form proportion in acidobasic equilibrium and its chemical stability, nuclear magnetic resonance, liquid chromatography-electrospray-high-resolution mass spectrometry, and tandem mass spectrometry methods were used to highlight the advantages of using partially methylated CD (2,6 di-O-methyl-β-cyclodextrin) and randomized methylated-β-cyclodextrin (RAMEB). The formation of 1:1 inclusion complex offered an improvement of the MDZ solubility and an increase of the closed and pharmacologically active form with a 33% gain when compared with the aqueous solution without CD. It was also demonstrated that RAMEB had a protecting effect on the MDZ degradation because it was found in almost 95% of remaining MDZ solution after 3 months at 40°C.
authors.affiliation: Plateforme Analytique, Institut de Chimie de Picardie FR3085 Université de Picardie Jules Verne, Amiens 80039, France.
authors.forename: David
authors.initials: D
authors.lastname: Mathiron
authors.forename: Frédéric
authors.initials: F
authors.lastname: Marçon
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Dubaele
authors.forename: Dominique
authors.initials: D
authors.lastname: Cailleu
authors.forename: Serge
authors.initials: S
authors.lastname: Pilard
authors.forename: Florence
authors.initials: F
authors.lastname: Djedaïni-Pilard
mesh_terms: D000759:Adjuvants, Anesthesia / Q000008:administration & dosage* / Q000737:chemistry; D002648:Child; D002851:Chromatography, High Pressure Liquid; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008874:Midazolam / Q000008:administration & dosage* / Q000737:chemistry; D012995:Solubility; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D000759:Adjuvants, Anesthesia; D004337:Drug Carriers; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D008874:Midazolam