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 pharmaceutical composition deliverable from a metered dose inhaler, the composition comprising:
 a suspension medium comprising a pharmaceutically acceptable propellant;   one or more species of respirable active agent particles comprising two or more active agents; and   a plurality of respirable suspending particles different than the active agent particles and comprising a particulate phospholipid material that is substantially insoluble in the suspension medium, wherein the active agent particles and suspending particles are included in the suspension medium at a weight ratio of total mass of the suspending particles to total mass of the one or more species of active agent particles that ranges from above 1:1 and up to 200:1.   
     
     
         63 . The pharmaceutical composition of  claim 62 , wherein the two or more active agents are selected from short-acting beta agonist, long-acting and ultra long-acting β 2  adrenergic receptor agonist (LABA), corticosteroid, anti-inflammatory, anti-tussive, bronchodilator, muscarinic antagonist, and long-acting muscarinic antagonist (LAMA) active agents, including any pharmaceutically acceptable salts, esters, or isomers thereof 
     
     
         64 . The pharmaceutical composition of  claim 63 , wherein the one or more species of respirable active agent particles comprises two or more different species of respirable active agent particles, each of the two or more different species of respirable active agent particles comprises a different active agent, and the different active agents are selected from (a) a short-acting beta agonist active agent selected from bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline (isoproterenol), levosalbutamol, orciprenaline (metaproterenol), pirbuterol, procaterol, rimiterol, salbutamol (albuterol), terbutaline, tulobuterol, reproterol, ipratropium, and epinephrine, including any pharmaceutically acceptable salts, esters, or isomers thereof; (b) a LAMA active agent selected from glycopyrrolate, dexipirronium, tiotropium, trospium, aclidinium, and darotropium, including any pharmaceutically acceptable salts, esters, or isomers thereof; (c) a LABA active agent selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived β 2  agonists, including any pharmaceutically acceptable salts, esters, or isomers thereof; and (d) a corticosteroid active agent selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone, and triamcinolone, including any pharmaceutically acceptable salts, esters, or isomers thereof. 
     
     
         65 . The pharmaceutical composition of  claim 64 , wherein the composition comprises:
 a first species of respirable active agent particles comprising a LAMA active agent selected from glycopyrrolate, dexipirronium, tiotropium, trospium, aclidinium, and darotropium, including any pharmaceutically acceptable salts, esters, or isomers thereof; and   a second species of respirable active agent particles comprising a LABA active agent selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived β 2  agonists, including any pharmaceutically acceptable salts, esters, or isomers thereof.   
     
     
         66 . The pharmaceutical composition of  claim 65 , wherein the LAMA active agent comprises glycopyrrolate, including any pharmaceutically acceptable salts, esters, or isomers thereof and the LABA active agent comprises formoterol, including any pharmaceutically acceptable salts, esters, or isomers thereof. 
     
     
         67 . The pharmaceutical composition of  claim 64 , wherein the composition comprises:
 a first species of respirable active agent particles comprising a LAMA active agent selected from glycopyrrolate, dexipirronium, tiotropium, trospium, aclidinium, and darotropium, including any pharmaceutically acceptable salts, esters, or isomers thereof; and   a second species of respirable active agent particles comprising a corticosteroid active agent selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone, and triamcinolone, including any pharmaceutically acceptable salts, esters, or isomers thereof.   
     
     
         68 . The pharmaceutical composition of  claim 67 , wherein the LAMA active agent comprises glycopyrrolate, including any pharmaceutically acceptable salts, esters, or isomers thereof, and the corticosteroid active agent comprises budesonide, including any pharmaceutically acceptable salts, esters, or isomers thereof. 
     
     
         69 . The pharmaceutical composition of  claim 64 , wherein the composition comprises:
 a first species of respirable active agent particles comprising a LABA active agent selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived β 2  agonists, including any pharmaceutically acceptable salts, esters, or isomers thereof; and   a second species of respirable active agent particles comprising a corticosteroid active agent selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone, and triamcinolone, including any pharmaceutically acceptable salts, esters, or isomers thereof.   
     
     
         70 . The pharmaceutical composition of  claim 69 , wherein the LABA active agent comprises formoterol, including any pharmaceutically acceptable salts, esters, or isomers thereof, and the corticosteroid active agent comprises budesonide, including any pharmaceutically acceptable salts, esters, or isomers thereof. 
     
     
         71 . The pharmaceutical composition of  claim 64 , wherein the composition comprises:
 a first species of respirable active agent particles comprising a short-acting beta agonist active agent selected from bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline (isoproterenol), levosalbutamol, orciprenaline (metaproterenol), pirbuterol, procaterol, rimiterol, salbutamol (albuterol), terbutaline, tulobuterol, reproterol, ipratropium, and epinephrine, including any pharmaceutically acceptable salts, esters, or isomers thereof; and   a second species of respirable active agent particles comprising a corticosteroid active agent selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone, and triamcinolone, including any pharmaceutically acceptable salts, esters, or isomers thereof.   
     
     
         72 . The pharmaceutical composition of  claim 71 , wherein the short-acting beta agonist active agent comprises salbutamol (albuterol), including any pharmaceutically acceptable salts, esters, or isomers thereof, and the corticosteroid active agent comprises budesonide, including any pharmaceutically acceptable salts, esters, or isomers thereof. 
     
     
         73 . The pharmaceutical composition of  claim 64 , wherein the one or more species of respirable active agent particles comprises three or more different species of respirable active agent particles, each of the three or more different species of respirable active agent particles comprises a different active agent, and the different active agents are selected from (a) a LAMA active agent selected from glycopyrrolate, dexipirronium, tiotropium, trospium, aclidinium, and darotropium, including any pharmaceutically acceptable salts, esters, or isomers thereof; (b) a LABA active agent selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived β 2  agonists, including any pharmaceutically acceptable salts, esters, or isomers thereof; and (c) a corticosteroid active agent selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone, and triamcinolone, including any pharmaceutically acceptable salts, esters, or isomers thereof. 
     
     
         74 . The pharmaceutical composition of  claim 73 , wherein (a) the LAMA active agent comprises glycopyrrolate, including any pharmaceutically acceptable salts, esters, or isomers thereof; and (b) the LABA active agent comprises formoterol, including any pharmaceutically acceptable salts, esters, or isomers thereof; and (c) the corticosteroid active agent comprises budesonide, including any pharmaceutically acceptable salts, esters, or isomers thereof. 
     
     
         75 . The pharmaceutical composition of  claim 62 , wherein the one or more species of respirable active agent particles are substantially insoluble in the propellant. 
     
     
         76 . The pharmaceutical composition of  claim 62 , wherein the respirable suspending particles comprise perforated microstructures. 
     
     
         77 . The pharmaceutical composition of  claim 76 , wherein the respirable suspending particles comprise DSPC. 
     
     
         78 . The pharmaceutical composition of  claim 62 , wherein the respirable suspending particles included in the suspension medium at a concentration selected from between about 1 mg/mL and about 15 mg/mL, between about 3 mg/mL and about 10 mg/mL, between about 5 mg/mL and about 8 mg/mL, and about 6 mg/mL. 
     
     
         79 . The pharmaceutical composition of  claim 62 , wherein the weight ratio of total mass of the respirable suspending particles to total mass of the one or more species of respirable active agent particles is selected from above about 1.5:1, up to about 5:1, up to about 10:1, up to about 15:1, up to about 17:1, up to about 20:1, up to about 30:1, up to about 40:1, up to about 50:1, up to about 60:1, up to about 75:1, up to about 100:1, up to about 150:1, and up to about 200:1. 
     
     
         80 . The pharmaceutical composition of  claim 62 , wherein the weight ratio of total mass of the respirable suspending particles to total mass of the one or more species of respirable active agent particles is selected from the ranges of between about 3:1 and about 15:1 and between about 2:1 and about 8:1. 
     
     
         81 . The pharmaceutical composition of  claim 62 , wherein the weight ratio of total mass of the respirable suspending particles to total mass of the one or more species of respirable active agent particles is selected from the ranges of between about 10:1 and about 200:1, between about 60:1 and about 200:1, between about 15:1 and about 60:1, and between about 15:1 and about 170:1. 
     
     
         82 . The pharmaceutical composition of  claim 66  or  claim 74 , wherein the glycopyrrolate and the formoterol, or pharmaceutically acceptable salts, esters, or isomers thereof, are crystalline. 
     
     
         83 . The pharmaceutical composition of  claim 66  or  claim 74 , wherein the pharmaceutically acceptable salt of glycopyrrolate is 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. 
     
     
         84 . The pharmaceutical composition of  claim 83 , wherein the pharmaceutically acceptable salt of glycopyrrolate is selected from fluoride, chloride, bromide, and iodide salts. 
     
     
         85 . The pharmaceutical composition of  claim 84 , wherein the pharmaceutically acceptable salt of glycopyrrolate is 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide. 
     
     
         86 . The pharmaceutical composition of  claim 66  or  claim 74 , wherein the pharmaceutically acceptable salt of formoterol is 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. 
     
     
         87 . The pharmaceutical composition of  claim 86 , wherein the pharmaceutically acceptable salt, ester, or isomer of formoterol is formoterol fumarate. 
     
     
         88 . The pharmaceutical composition of  claim 75 , wherein the propellant is selected from an HFA propellant, a PFC propellant, and combinations thereof. 
     
     
         89 . The pharmaceutical composition of  claim 66  or  claim 74 , wherein the respirable active agent particles are included in the composition in an amount sufficient to provide a delivered dose of formoterol, or pharmaceutically acceptable salt, ester, or isomer thereof, selected from up to about 30 μg, up to about 10 μg, up to about 5 μg, up to about 2.5 μg, up to about 2 μg, or up to about 1.5 μg per actuation of the metered dose inhaler. 
     
     
         90 . The pharmaceutical composition of  claim 66  or  claim 74 , wherein the respirable active agent particles are included in the composition in an amount sufficient to provide a delivered dose of glycopyrrolate, or pharmaceutically acceptable salt, ester, or isomer thereof, selected from up to about 100 μg, up to about 80 μg, up to about 40 μg, up to about 20 μg, or up to about 10 μg per actuation of the metered dose inhaler. 
     
     
         91 . The pharmaceutical composition of  claim 72  or  claim 74 , wherein the respirable active agent particles are included in the composition in an amount sufficient to provide a delivered dose of budesonide, or pharmaceutically acceptable salt, ester, or isomer thereof, selected from up to about 240 μg, up to about 120 μg, or up to about 50 μg per actuation of the metered dose inhaler.