Compositions for pulmonary delivery of long-acting muscarinic antagonists and associated methods and systems

Abstract

Compositions, methods and systems are provided for pulmonary delivery of long-acting muscarinic antagonists and long-acting β 2 adrenergic receptor agonists via a metered dose inhaler. In particular embodiments, 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 .- 92 . (canceled) 
     
     
         93 . A pharmaceutical composition deliverable from a metered dose inhaler, comprising:
 a suspension medium comprising a pharmaceutically acceptable propellant;   a plurality of active agent particles comprising an active agent selected from a long-acting muscarinic antagonist (LAMA) active agent and a long-acting β 2  adrenergic receptor agonist (LABA) active agent; and   a plurality of respirable suspending particles, wherein the respirable suspending particles are substantially insoluble in the suspension medium and comprise a phospholipid;   and wherein the ratio of the total mass of the respirable suspending particles to the total mass of the active agent particles is from greater than 1:1 up to 200:1.   
     
     
         94 . The pharmaceutical composition according to  claim 93 , wherein the suspending particles comprise perforated microstructures. 
     
     
         95 . The pharmaceutical composition according to  claim 94 , wherein the perforated microstructures are prepared using a spray drying process. 
     
     
         96 . The pharmaceutical composition according to  claim 95 , wherein the perforated microstructures comprise a spray dried emulsion of perfluorooctyl bromide, DSPC, and calcium chloride in water. 
     
     
         97 . The pharmaceutical composition according to  claim 93 , wherein the suspending particles exhibit an MMAD selected from between about 10 μm and about 500 nm, between about 5 μm and about 750 nm, between about and 1 μm and about 3 μm. 
     
     
         98 . The pharmaceutical composition according to  claim 93 , wherein the suspending particles exhibit a volume median optical diameter selected from between about 0.2 μm and about 50 μm, between about 0.5 μm and about 15 μm, between about 1.5 μm and about 10 μm, and between about 2 μm and about 5 μm. 
     
     
         99 . The pharmaceutical composition according to  claim 93 , wherein the propellant comprises a propellant selected from an HFA propellant, a PFC propellant and combinations thereof, and wherein the propellant is substantially free of additional constituents. 
     
     
         100 . The pharmaceutical composition according to  claim 93 , wherein a ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from above about 1.5, up to about 5, up to about 10, up to about 15, up to about 17, up to about 20, up to about 30, up to about 40, up to about 50, up to about 60, up to about 75, up to about 100, up to about 150, and up to about 200. 
     
     
         101 . The pharmaceutical composition according to  claim 93 , wherein the active agent particles comprise crystalline active agent. 
     
     
         102 . The pharmaceutical composition according to  claim 93 , wherein the active agent particles comprise micronized, crystalline active agent. 
     
     
         103 . The pharmaceutical composition according to  claim 93 , wherein the active agent included in the active agent particles is a LAMA active agent selected from glycopyrrolate, dexpirronium, tiotropium, trospium, aclidinium, and darotropium, and any pharmaceutically acceptable salts, esters, isomers, or solvates thereof. 
     
     
         104 . The pharmaceutical composition according to  claim 103 , wherein the active agent particles comprise glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof. 
     
     
         105 . The pharmaceutical composition according to  claim 104 , wherein the active agent particles comprise crystalline glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof. 
     
     
         106 . The pharmaceutical composition according to  claim 104 , wherein the active agent particles comprise micronized, crystalline glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof. 
     
     
         107 . The pharmaceutical composition according to  claim 104 , wherein the glycopyrrolate active agent particles are included in the suspension medium at a concentration sufficient to provide a delivered dose of glycopyrrolate per actuation of the metered dose inhaler of no more than 10 μg. 
     
     
         108 . The pharmaceutical composition of  claim 107 , wherein the glycopyrrolate active agent particles comprise a pharmaceutically acceptable salt of glycopyrrolate selected from fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl-acetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate, and benzenesulfonate salts. 
     
     
         109 . The pharmaceutical composition of  claim 108 , wherein the pharmaceutically acceptable salt of glycopyrrolate is selected from fluoride, chloride, bromide, and iodide salts. 
     
     
         110 . The pharmaceutical composition of  claim 109 , wherein the pharmaceutically acceptable salt of glycopyrrolate is 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide. 
     
     
         111 . A pharmaceutical composition according to  claim 93 , wherein the active agent included in the active agent particles is a LABA active agent selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived β2 agonists, and any pharmaceutically acceptable salts, esters, isomers or solvates thereof. 
     
     
         112 . The pharmaceutical composition according to  claim 111 , wherein the active agent particles comprise formoterol, including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof. 
     
     
         113 . The pharmaceutical composition according to  claim 111 , wherein the active agent particles comprise crystalline formoterol, including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof. 
     
     
         114 . The pharmaceutical composition according to  claim 111 , wherein the active agent particles comprise micronized, crystalline formoterol, including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof. 
     
     
         115 . The pharmaceutical composition according to  claim 111 , wherein the formoterol active agent particles are included in the suspension medium at a concentration sufficient to provide a delivered dose of formoterol per actuation of the metered dose inhaler of no more than 5 μg. 
     
     
         116 . The pharmaceutical composition according to  claim 115 , wherein the formoterol active agent comprise a pharmaceutically acceptable salt of formoterol selected from hydrochloric, hydrobromic, sulfuric, phosphoric, fumaric, maleic, acetic, lactic, citric, tartaric, ascorbic, succinic, glutaric, gluconic, tricarballylic, oleic, benzoic, p-methoxybenzoic, salicylic, o- and p-hydroxybenzoic, p-chlorobenzoic, methanesulfonic, p-toluenesulfonic, and 3-hydroxy-2-naphthalene carboxylic acid salts. 
     
     
         117 . The pharmaceutical composition according to  claim 116 , wherein the pharmaceutically acceptable salt of formoterol is formoterol fumarate. 
     
     
         118 . A method for treating a pulmonary disease or disorder in a patient, the method comprising administering a therapeutically effective amount of a pharmaceutical composition from a metered dose inhaler, the pharmaceutical composition comprising:
 a suspension medium comprising a pharmaceutically acceptable propellant;   a plurality of active agent particles comprising an active agent selected from a LAMA active agent and a LABA active agent; and   a plurality of respirable suspending particles, wherein the respirable suspending particles are substantially insoluble in the suspension medium and comprise a phospholipid;   and wherein the ratio of the total mass of the respirable suspending particles to the total mass of the active agent particles is from greater than 1:1 up to 200:1.   
     
     
         119 . The method of  claim 118 , wherein the active agent particles comprise crystalline active agent. 
     
     
         120 . The method of  claim 118 , wherein the active agent particles comprise micronized, crystalline active agent. 
     
     
         121 . The method of  claim 118 , wherein the active agent comprises a LAMA active agent selected from glycopyrrolate, dexpirronium, tiotropium, trospium, aclidinium, and darotropium, and any pharmaceutically acceptable salts, esters, isomers, or solvates thereof. 
     
     
         122 . The method of  claim 118 , wherein the active agent comprises a LABA active agent selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived β 2  agonists, and any pharmaceutically acceptable salts, esters, isomers, or solvates thereof. 
     
     
         123 . The method of  claim 118 , wherein the pulmonary disease or disorder is selected from at least one of asthma, COPD, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension, pulmonary inflammation associated with cystic fibrosis, and pulmonary obstruction associated with cystic fibrosis. 
     
     
         124 . The method of  claim 121 , wherein said administering the pharmaceutical composition comprises administering a delivered dose of glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof, of no more than 150 μg. 
     
     
         125 . The method of  claim 124 , wherein the glycopyrrolate or pharmaceutically acceptable salt, ester, isomer, or solvate thereof, comprises crystalline glycopyrrolate. 
     
     
         126 . The method of  claim 124 , wherein the glycopyrrolate or pharmaceutically acceptable salt, ester, isomer, or solvate thereof, comprises micronized, crystalline glycopyrrolate. 
     
     
         127 . The pharmaceutical composition of  claim 124 , wherein the glycopyrrolate active agent particles comprise a pharmaceutically acceptable salt of glycopyrrolate and the pharmaceutically acceptable salt of glycopyrrolate is 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide. 
     
     
         128 . The method according to  claim 124 , wherein said administering results in a clinically significant increase in inspiratory capacity (IC) in the patient. 
     
     
         129 . The method of  claim 121 , wherein said administering the pharmaceutical composition comprises administering a delivered dose of glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof, of no more than 80 μg, and said administering results in an increase in FEV 1  of at least 150 mL within 0.5 hours, or less. 
     
     
         130 . The method according to  claim 122 , wherein said administering of the pharmaceutical composition comprises delivering a dose of 10 μg, or less, of formoterol, including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof, per actuation of the metered dose inhaler. 
     
     
         131 . The method of  claim 130 , wherein the formoterol, or pharmaceutically acceptable salt, ester, isomer, or solvate thereof, comprises crystalline formoterol. 
     
     
         132 . The method of  claim 130 , wherein the formoterol, or pharmaceutically acceptable salt, ester, isomer, or solvate thereof, comprises micronized, crystalline formoterol. 
     
     
         133 . The pharmaceutical composition of  claim 130 , wherein the active agent particles comprise a pharmaceutically acceptable salt of formoterol and the pharmaceutically acceptable salt of formoterol is formoterol fumarate. 
     
     
         134 . The method according to  claim 122 , wherein said administering of the pharmaceutical composition comprises delivering a dose of 10 μg, or less, of formoterol, including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof, per actuation of the metered dose inhaler, and said administering of the pharmaceutical composition results in a clinically significant increase in FEV 1  in the patient.