Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2002-05-20
2004-05-25
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000, C424S043000, C128S200140, C128S200240, C128S200250
Reexamination Certificate
active
06740307
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the delivery of beta-blockers through an inhalation route. Specifically, it relates to aerosols containing atenolol, pindolol, esmolol, propranolol, or metoprolol that are used in inhalation therapy.
BACKGROUND OF THE INVENTION
There are a number of compositions currently marketed for the treatment of hypertension. The compositions contain at least one active ingredient that provides for observed therapeutic effects. Among the active ingredients given in such antihypertensive compositions are atenolol, pindolol, esmolol, propranolol, and metoprolol.
It is desirable to provide a new route of administration for atenolol, pindolol, esmolol, propranolol, or metoprolol that rapidly produces peak plasma concentrations of the compounds. 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 beta-blockers through an inhalation route. Specifically, it relates to aerosols containing atenolol, pindolol, esmolol, propranolol, or metoprolol that are used in inhalation therapy. In certain cases the beta-blockers are &bgr;1 selective.
In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of atenolol, pindolol, esmolol, propranolol, or metoprolol. Preferably, the particles comprise at least 10 percent by weight of atenolol, pindolol, esmolol, propranolol, or metoprolol. 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 atenolol, pindolol, esmolol, propranolol, or metoprolol.
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;.
Typically, the particles comprise less than 10 percent by weight of atenolol, pindolol, esmolol, propranolol, or metoprolol degradation products. Preferably, the particles comprise less than 5 percent by weight of atenolol, pindolol, esmolol, propranolol, or metoprolol degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of atenolol, pindolol, esmolol, propranolol, or metoprolol.
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 atenolol, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 20 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 10 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 5 mg/L.
Typically, where the aerosol comprises pindolol, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 20 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 10 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 5 mg/L.
Typically, where the aerosol comprises esmolol, the aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 100 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 8 mg/L and 75 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 12 mg/L and 50 mg/L.
Typically, where the aerosol comprises propranolol, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 50 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 40 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 20 mg/L.
Typically, where the aerosol comprises metoprolol, the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 30 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 25 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 3 mg/L and 20 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 atenolol, pindolol, esmolol, propranolol, or metoprolol to form a vapor and subsequently allowing the vapor to condense into an aerosol.
In a method aspect of the present invention, one of atenolol, pindolol, esmolol, propranolol, or metoprolol 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 atenolol, pindolol, esmolol, propranolol, or metoprolol, 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 atenolol, pindolol, esmolol, propranolol, or metoprolol. 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 atenolol, pindolol, esmolol, propranolol, or metoprolol.
Typically, the particles comprise at least 5 percent by weight of atenolol, pindolol, esmolol, propranolol, or metoprolol. Preferably, the particles comprise at least 10 percent by weight of atenolol, pindolol, esmolol, propranolol, or metoprolol. 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 atenolol, pindolol, esmolol, propranolol, or metoprolol.
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 than 10 percent by weight of atenolol, pindolol, esmolol, propranolol, or metoprolol degradation products. Preferably, the particles comprise less than 5 percent by weight of atenolol, pindolol, esmolol, propranolol, or metoprolol degradation products. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of atenolol, pindolol, esmolol, propranolol, or metoprolol 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
Rabinowitz Joshua D.
Zaffaroni Alejandro C.
Alexza Molecular Delivery Corporation
Haghighatian Mina
Hartley Michael G.
Stracker Elaine C.
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