Pulse drug nebulization systems, formulations therefore, and methods of use

Abstract

Liquid nebulizer apparatus, systems, and formulation compositions, as well as systems for the nebulized, aerosol delivery of such compositions, for the administration and insufflation of medicinal aerosols into the pulmonary system of a mammal are described. The nebulizing apparatus and system can effectively aerosolize a variety of viscosities of medicinal liquid drug carriers, including those made up of oil, water, or emulsions of oil and water. Drugs dissolved or suspended in the compositions and formulations described and adapted for use herein are not damages or denatured by the nebulization process when the nebulizer described is used. Further, the nebulization system itself can be adapted for use with both mechanically assisted pulmonary ventilation systems as well as hand-held inhalers and nose/mouth face masks for use in pulmonary drug delivery.

1 . A nebulization system comprising:
 a nozzle;   an outer gas-delivery tube; and   an inner microchannel delivery tube having a central fluid channel;   wherein the outer delivery tube is concentrically configured around the inner delivery tube, such concentric configuration forming an annular intermediate space between the two tubes, and   wherein the intermediate air space between the two tubes is the free air opening value, the value of which is the internal diameter of the outer gas-delivery tube minus the total inside diameter of the inner microchannel delivery tube.   
     
     
         2 . The nebulization system of  claim 1 , wherein the nozzle has an air volume to nebulized droplet volume ratio less than about 60,000:1. 
     
     
         3 . The nebulization system of  claim 1 , wherein the value of the intermediate air space between the two tubes ranges from about 0.00000259 in 2  to about 0.001 in 2 . 
     
     
         4 . The nebulization system of  claim 1 , wherein the outer gas delivery tube has an inner diameter ranging from about 0.01 inches to about 0.05 inches. 
     
     
         5 . The nebulization system of  claim 1 , wherein the inner microchannel delivery tube has an outer diameter ranging from about 0.01 inches to about 0.04 inches. 
     
     
         6 . The nebulization system of  claim 1 , wherein the system is capable of producing aerosol droplets of compositions comprising a fatty acid or lipids having particle sizes ranging from about 2 μm to about 12 μm. 
     
     
         7 . A pulmonary drug delivery system capable of nebulizing a composition comprising a water-insoluble or substantially water-insoluble drug and a fatty acid or lipid, the system comprising:
 a reservoir for containing the drug composition;   a reservoir for containing a propellant gas;   a mechanical control valve capable of regulating the flow of the propellant gas and the drug composition; and   a nebulizing nozzle adapted to receive both the drug composition and the propellant gas;   wherein the nebulizing nozzle can produce aerosol droplets having a particle size ranging from about 2 μm to about 12 μm in median mass aerodynamic size.   
     
     
         8 . The pulmonary drug delivery system of  claim 7 , further comprising an assembly fitted into the air stream of a mammalian patient. 
     
     
         9 . The pulmonary drug delivery system of  claim 7 , wherein the nebulizing nozzle can produce aerosol droplets having a particle size ranging from about 2 μm to about 5 μm. 
     
     
         10 . A non-aqueous medicinal aerosol composition, comprising:
 a therapeutically effective amount of a pulmonary medicament or a derivative, metabolite, solvate, hydrate, prodrug, or polymorph thereof;   a lipid or fatty acid; and   a fluid propellant carrier.   
     
     
         11 . The composition of  claim 10 , wherein the pulmonary medicament is gamma-tocopherol. 
     
     
         12 . The medicament of  claim 11 , wherein the gamma-tocopherol is in either the d-, l-, or dl-conformation, or a combination thereof. 
     
     
         13 . The composition of  claim 10 , wherein the therapeutically effective amount of the pulmonary medicament ranges from about 1% (w/w) to about 99% (w/w). 
     
     
         14 . The composition of  claim 10 , wherein the lipid or fatty acid is present in an amount ranging from about 1% (w/w) to about 99% (w/w). 
     
     
         15 . The composition of  claim 10 , further comprising an antioxidant for use in the preparation of a medicament for the treatment of disease or disorder of the pulmonary system, including but not limited to acute lung injury. 
     
     
         16 . The composition of  claim 15 , wherein the antioxidant is a vitamin selected form the group consisting of Vitamin E, Vitamin C, riboflavin, niacin, vitamin K3, ascorbic acid, coenzyme-Q and β-carotene. 
     
     
         17 . The composition of  claim 10 , wherein the fatty acid is selected from the group consisting of flax seed oil, sunflower oil, saffron oil, and canola oil. 
     
     
         18 . The composition of  claim 10 , further comprising a surfactant. 
     
     
         19 . The medicinal composition of  claim 10 , wherein the therapeutically effective amount ranges from about 1 mg/kg/d to about 1,000 mg/kg/d. 
     
     
         20 . A drug nebulizing apparatus adapted for pulmonary inhalation and delivery of aerosolized medicaments into a mammalian patient, the apparatus comprising:
 a reservoir containing a drug formulation; and   a nebulizing nozzle adapted to be fit to a breathing circuit and further attached to a face mask;   wherein the nebulizing nozzle produces aerosolized droplets sized for pulmonary, inhaled drug delivery of the drug formulation.   
     
     
         21 . The drug nebulizing apparatus of  claim 19 , wherein the drug formulation is in the form of a mixture, a solution, a suspension, or an emulsion. 
     
     
         22 . The drug nebulizing apparatus of  claim 19 , wherein the face mask is capable of being fit to the patient's nose, mouth, or both the nose and the mouth. 
     
     
         23 . The drug nebulizing apparatus of  claim 19 , wherein the droplets range in size from about 2 μm to about 10 μm. 
     
     
         24 . The drug nebulizing apparatus of  claim 22 , wherein the droplets range in size from about 2 μm to about 5 μm. 
     
     
         25 . The drug nebulizing apparatus of  claim 19 , wherein the nebulizing nozzle comprises a fluid micro-tube with an air delivery tube capable of nebulizing a fluid from the micro-tube into droplets into droplets sized for inhaled drug delivery.