Tolerability of Midazolam to treat acute agitation in elderly demented patients: A systematic review.

WHAT IS KNOWN AND OBJECTIVE: Behavioural disorders are difficult to manage in elderly demented patients because of the lack of appropriate drugs or difficulties surrounding the route of administration. The tolerability of Midazolam is well described in the emergency management of agitation for young patients, when administered intramuscularly or intravenously. However, very little data are available on the use of oral Midazolam for this indication and in the elderly population. METHODS: A literature review was conducted, and studies were included if involving adults, receiving Midazolam, alone or in combination, whatever the route, dosage or indication and if they reported adverse events related to the use of Midazolam. RESULTS AND DISCUSSION: Forty-one articles were included. Eleven different adverse events were identified from the studies. Hypotension and desaturation were the two most frequent adverse events reported. Adverse reactions appear to be more common in older patients but also when Midazolam was used in combination with other drugs. The frequency of these adverse effects was lower than those reported for neuroleptic drugs. WHAT IS NEW AND CONCLUSION: The oral route appears to be appropriate to provide a rapid and well-tolerated response. Further studies will be needed to confirm the good tolerance of oral Midazolam in the management of acute agitation in elderly demented patients.

Benefits of methylated cyclodextrins in the development of midazolam pharmaceutical formulations.

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-ß-cyclodextrin) and randomized methylated-ß-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.

Development and formulation of a 0.2% oral solution of midazolam containing gamma-cyclodextrin.

In absence of dedicated children formulation, intravenous formulations of midazolam, which exhibit strong bitterness, are occasionally used for oral or sublingual administration. In order to improve the quality and the acceptance by children of a midazolam anesthesia premedication, a new 0.2% (w/v) aqueous solution for oral administration has been prepared. The final formulation was obtained by the adjunction of a sweetener (sucralose), an aroma (orange aroma) and gamma-cyclodextrin to a citric acid solution of midazolam. The gamma-cyclodextrin forms an inclusion complex with the hydrophobic midazolam as evidenced using nuclear magnetic resonance spectroscopy (stoichiometry 1:1, K=283 M(-1)). A sterile filtration method was selected for the formulation microbial preservation using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS). Finally, a routine high performance liquid chromatography (HPLC) method is proposed for the quantitative determination of global midazolam amount in the pharmaceutical preparation.