Benefits of methylated cyclodextrins in the development of midazolam pharmaceutical formulations

Authors

  • David Mathiron,

    1. Plateforme Analytique, Institut de Chimie de Picardie FR3085 Université de Picardie Jules Verne, Amiens 80039, France
    2. Laboratoire des Glucides FRE3517, Institut de Chimie de Picardie FR3085 Université de Picardie Jules Verne, Amiens 80039, France
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  • Frédéric Marçon,

    1. Pharmacie Centrale, Centre Hospitalier Universitaire, place Victor Pauchet, Amiens 80054, France
    2. Laboratoire des Glucides FRE3517, Institut de Chimie de Picardie FR3085 Université de Picardie Jules Verne, Amiens 80039, France
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  • Jean-marc Dubaele,

    1. Pharmacie Centrale, Centre Hospitalier Universitaire, place Victor Pauchet, Amiens 80054, France
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  • Dominique Cailleu,

    1. Plateforme Analytique, Institut de Chimie de Picardie FR3085 Université de Picardie Jules Verne, Amiens 80039, France
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  • Serge Pilard,

    1. Plateforme Analytique, Institut de Chimie de Picardie FR3085 Université de Picardie Jules Verne, Amiens 80039, France
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  • Florence DjedaÏni-pilard

    Corresponding author
    1. Laboratoire des Glucides FRE3517, Institut de Chimie de Picardie FR3085 Université de Picardie Jules Verne, Amiens 80039, France
    • Laboratoire des Glucides FRE3517, Institut de Chimie de Picardie FR3085 Université de Picardie Jules Verne, Amiens 80039, France. Telephone: +33-3-22-82-75-62; Fax: +33-3-22-82-75-60
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  • Dedicated in memory of Frédéric Aubry

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. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2102–2111, 2013

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