The present invention relates to the delivery of muscle relaxants through an inhalation route. Specifically, it relates to aerosols containing muscle relaxants that are used in inhalation therapy. In a method aspect of the present invention, a muscle relaxant is delivered to a patient through an inhalation route. The method comprises: a) heating a coating of a muscle relaxant, on a solid support, to form a vapor; and, b) passing air through the heated vapor to produce aerosol particles having less than 5% muscle relaxant degradation products. In a kit aspect of the present invention, a kit for delivering a muscle relaxant through an inhalation route is provided which comprises: a) a coating of a muscle relaxant and b) a device for dispensing said coating a muscle relaxant as a condensation aerosol.

SUMMARY OF THE INVENTION

The present invention relates to the delivery of muscle relaxants through an inhalation route. Specifically, it relates to aerosols containing muscle relaxants 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 muscle relaxant. Preferably, the particles comprise at least 10 percent by weight of a muscle relaxant. 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 muscle relaxant.

Typically, the aerosol has a mass of at least 10 .mu.g. Preferably, the aerosol has a mass of at least 100 .mu.g. More preferably, the aerosol has a mass of at least 200 .mu.g.

Typically, the particles comprise less than 10 percent by weight of muscle relaxant degradation products. Preferably, the particles comprise less than 5 percent by weight of muscle relaxant degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of muscle relaxant 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.sup.6 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 10.sup.7 particles/mL or 10.sup.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 2.1.

Typically, the aerosol is formed by heating a composition containing a muscle relaxant 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 quinine, chlorzoxazone, carisprodol or cyclobenzaprine. Preferably, the particles comprise at least 10 percent by weight of quinine, chlorzoxazone, carisprodol or cyclobenzaprine. 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 quinine, chlorzoxazone, carisprodol or cyclobenzaprine.

Typically, the aerosol has a mass of at least 10 .mu.g. Preferably, the aerosol has a mass of at least 100 .mu.g. More preferably, the aerosol has a mass of at least 200 .mu.g.

Typically, the particles comprise less than 10 percent by weight of quinine, chlorzoxazone, carisprodol or cyclobenzaprine degradation products. Preferably, the particles comprise less than 5 percent by weight of quinine, chlorzoxazone, carisprodol or cyclobenzaprine degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of quinine, chlorzoxazone, carisprodol or cyclobenzaprine 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, where the aerosol comprises quinine, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 500 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 400 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 50 mg/L and 300 mg/L.

Typically, where the aerosol comprises chlorzoxazone, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 400 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 300 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 50 mg/L and 200 mg/L.

Typically, where the aerosol comprises carisprodol, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 500 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 400 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 50 mg/L and 200 mg/L.

Typically, where the aerosol comprises cyclobenzaprine, the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 20 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 15 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 10 mg/L.

Typically, the aerosol has an inhalable aerosol particle density greater than 10.sup.6 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 10.sup.7 particles/mL or 10.sup.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). In certain embodiments the particles have an MMAD of from about 0.2 to about 3 microns.

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 2.1.

Typically, the aerosol is formed by heating a composition containing quinine, chlorzoxazone, carisprodol or cyclobenzaprine to form a vapor and subsequently allowing the vapor to condense into an aerosol.

In a method aspect of the present invention, a muscle relaxant 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 muscle relaxant, 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 muscle relaxant. 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 muscle relaxant.

Typically, the particles comprise at least 5 percent by weight of a muscle relaxant. Preferably, the particles comprise at least 10 percent by weight of a muscle relaxant. 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 muscle relaxant.

Typically, the aerosol has a mass of at least 10 .mu.g. Preferably, the aerosol has a mass of at least 100 .mu.g. More preferably, the aerosol has a mass of at least 200 .mu.g.

Typically, the particles comprise less than 10 percent by weight of muscle relaxant degradation products. Preferably, the particles comprise less than 5 percent by weight of muscle relaxant degradation products. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of muscle relaxant 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, the particles of the delivered condensation aerosol 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 2.1.

Typically, the delivered aerosol has an inhalable aerosol particle density greater than 10.sup.6 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 10.sup.7 particles/mL or 10.sup.8 particles/mL.

Typically, the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 10.sup.8 particles per second. Preferably, the aerosol is formed at a rate greater than 10.sup.9 inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 10.sup.10 inhalable particles per second.

Typically, the delivered condensation aerosol is formed at a rate greater than 0.5 mg/second. Preferably, the aerosol is formed at a rate greater than 0.75 mg/second. More preferably, the aerosol is formed at a rate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

Typically, the delivered condensation aerosol results in a peak plasma concentration of a muscle relaxant in the mammal in less than 1 h. Preferably, the peak plasma concentration is reached in less than 0.5 h. More preferably, the peak plasma concentration is reached in less than 0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

In another method aspect of the present invention, one of quinine, chlorzoxazone, carisprodol or cyclobenzaprine 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 quinine, chlorzoxazone, carisprodol or cyclobenzaprine, 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 quinine, chlorzoxazone, carisprodol or cyclobenzaprine. 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 quinine, chlorzoxazone, carisprodol or cyclobenzaprine.

Typically, the particles comprise at least 5 percent by weight of quinine, chlorzoxazone, carisprodol or cyclobenzaprine. Preferably, the particles comprise at least 10 percent by weight of quinine, chlorzoxazone, carisprodol or cyclobenzaprine. 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 quinine, chlorzoxazone, carisprodol or cyclobenzaprine.

Typically, the aerosol has a mass of at least 10 .mu.g. Preferably, the aerosol has a mass of at least 100 .mu.g. More preferably, the aerosol has a mass of at least 200 .mu.g.

Typically, the particles comprise less than 10 percent by weight of quinine, chlorzoxazone, carisprodol or cyclobenzaprine degradation products. Preferably, the particles comprise less than 5 percent by weight of quinine, chlorzoxazone, carisprodol or cyclobenzaprine degradation products. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of quinine, chlorzoxazone, carisprodol or cyclobenzaprine 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, the particles of the delivered condensation aerosol 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 2.1.

Typically, where the aerosol comprises quinine, the delivered aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 500 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 400 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 50 mg/L and 300 mg/L.

Typically, where the aerosol comprises chlorzoxazone, the delivered aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 400 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 300 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 50 mg/L and 200 mg/L.

Typically, where the aerosol comprises carisprodol, the delivered aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 500 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 400 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 50 mg/L and 300 mg/L.

Typically, where the aerosol comprises cyclobenzaprine, the delivered aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 20 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 15 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 10 mg/L.

Typically, the delivered aerosol has an inhalable aerosol particle density greater than 10.sup.6 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 10.sup.7 particles/mL or 10.sup.8 particles/mL.

Typically, the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 10.sup.8 particles per second. Preferably, the aerosol is formed at a rate greater than 10.sup.9 inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 10.sup.10 inhalable particles per second.

Typically, the delivered condensation aerosol is formed at a rate greater than 0.5 mg/second. Preferably, the aerosol is formed at a rate greater than 0.75 mg/second. More preferably, the aerosol is formed at a rate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

Typically, where the condensation aerosol comprises quinine, between 50 mg and 500 mg of quinine are delivered to the mammal in a single inspiration. Preferably, between 100 mg and 450 mg of quinine are delivered to the mammal in a single inspiration. More preferably, between 100 mg and 400 mg of quinine are delivered in a single inspiration.

Typically, where the condensation aerosol comprises chlorzoxazone, between 50 mg and 400 mg of chlorzoxazone are delivered to the mammal in a single inspiration. Preferably, between 100 mg and 350 mg of chlorzoxazone are delivered to the mammal in a single inspiration. More preferably, between 100 mg and 300 mg of chlorzoxazone are delivered in a single inspiration.

Typically, where the condensation aerosol comprises carisprodol, between 70 mg and 500 mg of carisprodol are delivered to the mammal in a single inspiration. Preferably, between 150 mg and 450 mg of carisprodol are delivered to the mammal in a single inspiration. More preferably, between 150 mg and 400 mg of carisprodol are delivered in a single inspiration.

Typically, where the condensation aerosol comprises cyclobenzaprine, between 2 mg and 25 mg of cyclobenzaprine are delivered to the mammal in a single inspiration. Preferably, between 5 mg and 20 mg of cyclobenzaprine are delivered to the mammal in a single inspiration. More preferably, between 5 mg and 15 mg of cyclobenzaprine are delivered to the mammal in a single inspiration.

Typically, the delivered condensation aerosol results in a peak plasma concentration of quinine, chlorzoxazone, carisprodol or cyclobenzaprine in the mammal in less than 1 h. Preferably, the peak plasma concentration is reached in less than 0.5 h. More preferably, the peak plasma concentration is reached in less than 0.2, 0.1, 0.05, 0.02, 0.01 h, or 0.005 h (arterial measurement).

Typically, the delivered condensation aerosol is used to treat musculoskeletal pain.

In a kit aspect of the present invention, a kit for delivering a muscle relaxant through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of a muscle relaxant; and, b) a device that forms a muscle relaxant aerosol from the composition, for inhalation by the mammal. 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 muscle relaxant.

Typically, the device contained in the kit comprises: a) an element for heating the muscle relaxant composition to form a vapor; b) an element allowing the vapor to cool to form an aerosol; and, c) an element permitting the mammal to inhale the aerosol.

In another kit aspect of the present invention, a kit for delivering quinine, chlorzoxazone, carisprodol or cyclobenzaprine through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of quinine, chlorzoxazone, carisprodol or cyclobenzaprine; and, b) a device that forms an quinine, chlorzoxazone, carisprodol or cyclobenzaprine aerosol from the composition, for inhalation by the mammal. 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 quinine, chlorzoxazone, carisprodol or cyclobenzaprine.

Typically, the device contained in the kit comprises: a) an element for heating the quinine, chlorzoxazone, carisprodol or cyclobenzaprine composition to form a vapor; b) an element allowing the vapor to cool to form an aerosol; and, c) an element permitting the mammal to inhale the aerosol.

 

Claim 1 of 34 Claims

1. A condensation aerosol for delivery of a drug selected from the group consisting of quinine, chlorzoxazone, carisprodol and cyclobenzaprine, wherein the condensation aerosol is formed by heating a thin layer containing the drug, on a solid support, to produce a vapor of the drug, and condensing the vapor to form a condensation aerosol characterized by less than 10% drug degradation products by weight, and an MMAD of less than 5 microns.

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