Pharmaceutical compositions comprising midazolam in a high concentration

Abstract

Compositions of midazolam, a benzodiazapine, in concentrations of 35-100 mg / ml are disclosed for the treatment of anxiety, epilepsy and epileptic seizures, invasive surgical procedures and diagnostic procedures and sedation. These compositions are particularly characterized by a solubilizer such an propylene glycol. Preferably, the compositions are aqueous solutions for intranasal administration.

Description

FIELD OF THE INVENTION [0001] The present invention relates to the administration of benzodiazepines such as midazolam. In particular, the invention provides improved midazolam compositions for intranasal administration comprising high concentrations of midazolam. DISCUSSION OF THE PRIOR ART [0002] Midazolam is a potent benzodiazepine derivative with sedative, anxiolytic, hypnotic, amnesic, anticonvulsant and muscle relaxant pharmacological properties. Because of the basicity of this molecule, it is possible to prepare salts (e.g., with hydrochloric, maleic and lactic acid) which are soluble in water. From these salts, stable aqueous solutions with a pH of 3.5 can be made for intravenous and intramuscular injections of midazolam (Smith et al., 1981; Gerecke, 1983; Persson et al., 1988). Following administration by injection, midazolam is characterized by a fast onset of action as well as short duration of action, due to its rapid metabolic inactivation by liver enzymes. Midazolam is...

AI Technical Summary

Benefits of technology

[0027] In light of the foregoing, it is clear that there is the need for a midazolam formulation which is specifically formulated for intranasal administration, in order to overcome all of the various disadvantages associated with the known formulations which are administered intranasally. It is therefore an aim of the present invention to provide a formulation with a high enough midazolam concentration to allow adequate doses of midazolam to be efficiently and comfortably administered via the intranasal route in a small volume. The formulation should also cause as little irritation as possible and have as high a bioavailability as possible. Finally, the formulation should have a similar or reduced ciliostatic effect in vitro experiments, compared to the known nasal formulations.

Problems solved by technology

However, this mode of administration is not suitable for midazolam, as orally delivered midazolam is extensively degraded by first-pass elimination and has also been found to be a substrate for the intestinal drug efflux transporter (Allonen et al., 1981; Crevoisier et al., 1983; Tolle-Sander et al., 2003).

Other disadvantages associated with the oral administration of midazolam are the slow onset of action and the observed low peak plasma concentrations.

These disadvantages are also observed when midazolam is administered rectally (Saint-Maurice et al., 1986; Malinovsky et al., 1993, 1995).

However, this mode of administration has a number of obvious disadvantages which make it unattractive.

For example, injections are painful and not well accepted by the patients, particularly not by young children.

Often there is a difficulty in siting a butterfly needle or cannula, causing the child to cry, become very restless, or to pull the leads off”.

The nasal administration of such large volumes of solution also accounts for a number of unpleasant side-effects sometimes experienced by patients, including lacrimation, burning sensations, irritation in the nose and throat, and general discomfort (Lugo et al., 1993; Burstein et al., 1997; Kogan 2002).

In addition, treatment failure can occur due to the inadequate technique of delivering unphysiologically large volumes of the midazolam solution (Scheepers et al., 2000).

A further problem is clearly the loss of a large proportion of the composition and of the midazolam, which leads to inconsistent and unpredictable amounts of midazolam being absorbed.

It is therefore clear that the use of commercially available midazolam injection solutions for intranasal midazolam administration is inefficient and unpleasant for the patients, due to the necessary large volumes applied.

This can lead to reduced nasal bioavailability and ineffective plasma peak concentrations of midazolam and therefore to an insufficient therapeutic efficacy.

However, nasal administration of a total volume of 200 μl of this formulation will not achieve therapeutically effective midazolam plasma levels in humans, because the midazolam concentration in this formulation is far too low.

A further disadvantage associated with this formulation is that the preservative mixture of 0.02% benzalkonium chloride / 0.1% EDTA inhibits the ciliary movement in vitro and is classified as ciliostatic (Merkus et al., 2001).

More importantly, the midazolam concentration of this nasal formulation is too low to provide adequate therapeutic efficacy of the drug.

It is evident from these studies that the volume of the formulation used to administer a dose of 5 and 10 mg via the nose is very large (two and four nasal sprays), and this is probably the cause of many of these adverse side effects.

These adverse effects could prohibit the use of this formulation in clinical practice.