Compositions, methods & systems for respiratory delivery of two or more active agents

Abstract

Compositions, methods and systems are provided for pulmonary or nasal delivery of two or more active agents via a metered dose inhaler. In one embodiment, the compositions include a suspension medium, active agent particles, and suspending particles, in which the active agent particles and suspending particles form a co-suspension within the suspension medium.

1 .- 61 . (canceled) 
     
     
         62 . A method for treating a pulmonary disease or disorder in a patient, comprising:
 providing a metered dose inhaler comprising a pharmaceutical composition, wherein the pharmaceutical composition comprises:
 a suspension medium comprising a pharmaceutically acceptable propellant; 
 a plurality of respirable active agent particles comprising a corticosteroid or a pharmaceutically acceptable salt thereof, and a short-acting beta agonist or a pharmaceutically acceptable salt thereof; and 
 a plurality of respirable suspending particles comprising phospholipid particles, wherein the phospholipid particles comprise perforated microstructures; 
 and wherein the plurality of suspending particles and the plurality of active agent particles are co-suspended in the suspension medium at a weight ratio of total mass of suspending particles to total mass of active agent particles that ranges from above 1:1 and up to 200:1; and 
   administering the pharmaceutical composition to the patient by actuating the metered dose inhaler, wherein the administration comprises delivering a therapeutically effective amount of the active agents to the patient.   
     
     
         63 . The method of  claim 62 , wherein the corticosteroid is selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, mometasone, prednisone, and triamcinolone. 
     
     
         64 . The method of  claim 62 , wherein the short-acting beta agonist is selected from bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline (isoproterenol), levosalbutamol, orciprenaline (metaproterenol), pirbuterol, procaterol, rimiterol, albuterol (salbutamol), terbutaline, tulobuterol, reproterol, and epinephrine. 
     
     
         65 . The method of  claim 62 , wherein the respirable active agent particles are present in micronized form. 
     
     
         66 . The method of  claim 64 , wherein:
 the albuterol or the pharmaceutically acceptable salt thereof is present in crystalline or substantially crystalline form;   the phospholipid particles comprise 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and calcium chloride;   the ratio of the total mass of the suspending particles to the total mass of the active agent particles is between 10 and 200;   the suspending particles exhibit a volume median optical diameter between 0.2 μm and 50 μm; and   at least 90% of the respirable active agent particles by volume exhibit an optical diameter of 7 μm or less.   
     
     
         67 . The method of  claim 66 , wherein the pharmaceutical composition provides a delivered dose of budesonide of between about 30 μg and about 240 μg, or between about 30 μg and about 120 μg, or between about 30 μg and about 50 μg per actuation of the metered dose inhaler. 
     
     
         68 . The method of  claim 67 , wherein the pulmonary disease or disorder is selected from asthma, chronic obstructive pulmonary disease (COPD), exacerbation of airways hyper reactivity consequent to other drug therapy, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension, and pulmonary inflammation and obstruction associated with cystic fibrosis. 
     
     
         69 . The method of  claim 68 , wherein the pulmonary disease or disorder is asthma or COPD. 
     
     
         70 . A pharmaceutical composition deliverable from a metered dose inhaler, the pharmaceutical composition comprising:
 a suspension medium comprising a pharmaceutically acceptable propellant;   a plurality of respirable active agent particles comprising a corticosteroid or a pharmaceutically acceptable salt thereof, and a short-acting beta agonist or a pharmaceutically acceptable salt thereof; and   a plurality of respirable suspending particles comprising phospholipid particles, wherein the phospholipid particles comprise perforated microstructures, and the total mass of the plurality of suspending particles exceeds the total mass of the respirable active agent particles.   
     
     
         71 . The pharmaceutical composition of  claim 70 , wherein the corticosteroid is selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, mometasone, prednisone, and triamcinolone. 
     
     
         72 . The pharmaceutical composition of  claim 71 , wherein the short-acting beta agonist is selected from bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline (isoproterenol), levosalbutamol, orciprenaline (metaproterenol), pirbuterol, procaterol, rimiterol, albuterol (salbutamol), terbutaline, tulobuterol, reproterol, and epinephrine. 
     
     
         73 . The pharmaceutical composition of  claim 72 , wherein the plurality of suspending particles and the plurality of active agent particles are co-suspended in the suspension medium at a weight ratio of total mass of suspending particles to total mass of active agent particles that ranges from above 1:1 and up to 200:1. 
     
     
         74 . The pharmaceutical composition of  claim 73 , wherein the suspending particles exhibit a mass median aerodynamic diameter (MMAD) between 10 μm and 500 nm. 
     
     
         75 . The pharmaceutical composition of  claim 73 , wherein the respirable active agent particles comprise budesonide or a pharmaceutically acceptable salt thereof, and albuterol or a pharmaceutically acceptable salt thereof. 
     
     
         76 . The pharmaceutical composition of  claim 75 , wherein the respirable active agent particles are present in micronized form. 
     
     
         77 . The pharmaceutical composition of  claim 76 , wherein the albuterol or the pharmaceutically acceptable salt thereof is present in crystalline or substantially crystalline form. 
     
     
         78 . The pharmaceutical composition of  claim 77 , wherein the phospholipid particles comprise 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and calcium chloride. 
     
     
         79 . The pharmaceutical composition of  claim 78 , wherein the ratio of the total mass of the suspending particles to the total mass of the active agent particles is between 10 and 200. 
     
     
         80 . The pharmaceutical composition of  claim 79 , wherein the suspending particles exhibit a volume median optical diameter between 0.2 μm and 50 μm. 
     
     
         81 . The pharmaceutical composition of  claim 80 , wherein at least 90% of the respirable active agent particles by volume exhibit an optical diameter of 7 μm or less.