Delivery of sedative-hypnotics through an inhalation route

Details Delivery of sedative-hypnotics through an inhalation route Delivery of sedative-hypnotics through an inhalation route

2002-05-17

2004-04-06

Hartley, Michael G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Effervescent or pressurized fluid containing

Organic pressurized fluid

C424S043000, C424S046000, C424S450000, C514S923000, C128S200140, C128S200240

Reexamination Certificate

active

06716415

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the delivery of sedative-hypnotics through an inhalation route. Specifically, it relates to aerosols containing sedative-hypnotics that are used in inhalation therapy.
BACKGROUND OF THE INVENTION
There are a number of compositions currently marketed as sedative-hypnotics. The compositions contain at least one active ingredient that provides for observed therapeutic effects. Among the active ingredients given in sedative-hypnotic compositions are zolpidem, zaleplon, and zopiclone.
It is desirable to provide a new route of administration for sedative-hypnotics that rapidly produces peak plasma concentrations of the compound. The provision of such a route is an object of the present invention.
SUMMARY OF THE INVENTION
The present invention relates to the delivery of sedative-hypnotics through an inhalation route. Specifically, it relates to aerosols containing sedative-hypnotics that are used in inhalation therapy.
In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of a sedative-hypnotic. Preferably, the particles comprise at least 10 percent by weight of a sedative hypnotic. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent by weight of a sedative hypnotic.
Typically, the aerosol has a mass of at least 10 &mgr;g. Preferably, the aerosol has a mass of at least 100 &mgr;g. More preferably, the aerosol has a mass of at least 200 &mgr;g.
Typically, the particles comprise less than 10 percent by weight of sedative-hypnotic degradation products. Preferably, the particles comprise less than 5 percent by weight of sedative-hypnotic degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of sedative-hypnotic degradation products.
Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.
Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.
Typically, the aerosol has an inhalable aerosol particle density greater than 10
6
particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 10
7
particles/mL or 10
8
particles/mL.
Typically, the aerosol particles have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).
Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0. Preferably, the geometric standard deviation is less than 2.5. More preferably, the geometric standard deviation is less than 2.2.
Typically, the aerosol is formed by heating a composition containing a sedative-hypnotic to form a vapor and subsequently allowing the vapor to condense into an aerosol.
In another composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of zaleplon, zolpidem or zopiclone. Preferably, the particles comprise at least 10 percent by weight of zaleplon, zolpidem or zopiclone. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent by weight of zaleplon, zolpidem or zopiclone.
Typically, the aerosol has a mass of at least 10 &mgr;g. Preferably, the aerosol has a mass of at least 100 &mgr;g. More preferably, the aerosol has a mass of at least 200 &mgr;g.
Typically, the particles comprise less than 10 percent by weight of zaleplon, zolpidem or zopiclone degradation products. Preferably, the particles comprise less than 5 percent by weight of zaleplon, zolpidem or zopiclone degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of zaleplon, zolpidem or zopiclone degradation products.
Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.
Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.
Typically, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 40 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 20 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 10 mg/L.
Typically, the aerosol has an inhalable aerosol particle density greater than 10
6
particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 10
7
particles/mL or 10
8
particles/mL.
Typically, the aerosol particles have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).
Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0. Preferably, the geometric standard deviation is less than 2.5. More preferably, the geometric standard deviation is less than 2.2.
Typically, the aerosol is formed by heating a composition containing zaleplon, zolpidem or zopiclone to form a vapor and subsequently allowing the vapor to condense into an aerosol.
In a method aspect of the present invention, one of a sedative-hypnotic is delivered to a mammal through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises at least 5 percent by weight of a sedative-hypnotic, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal. Preferably, the composition that is heated comprises at least 10 percent by weight of a sedative-hypnotic. More preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of a sedative-hypnotic.
Typically, the particles comprise at least 5 percent by weight of a sedative-hypnotic. Preferably, the particles comprise at least 10 percent by weight of a sedative-hypnotic. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of a sedative-hypnotic.
Typically, the condensation aerosol has a mass of at least 10 &mgr;g. Preferably, the aerosol has a mass of at least 100 &mgr;g. More preferably, the aerosol has a mass of at least 200 &mgr;g.
Typically, the particles comprise less

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