Compositions for pulmonary delivery of long-acting b2 adrenergic receptor agonists 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 . 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 plurality of active agent particles associate with the plurality of suspending particles to form a co-suspension.   
     
     
         2 . A method for treating a pulmonary disease or disorder in a patient, the method comprising:
 providing metered dose inhaler comprising a pharmaceutically acceptable co-suspension, the co-suspension 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 plurality of active agent particles associate with the plurality of suspending particles; and 
   administering the co-suspension to the patient by actuating the metered dose inhaler, wherein said administering of the co-suspension composition comprises delivering a therapeutically effective amount of the LAMA or LABA active agent to the patient.   
     
     
         3 . A method for respiratory delivery of a LAMA or LABA active agent to a patient, the method comprising;
 providing metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension 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 plurality of active agent particles associate with the plurality of suspending particles; and 
   actuating the metered dose inhaler to provide respiratory delivery of the LAMA or LABA active agent to the patient.   
     
     
         4 . A pharmaceutical composition according to  claim 1 , 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 β 2  agonists, and any pharmaceutically acceptable salts, esters, isomers or solvates thereof. 
     
     
         5 . The pharmaceutical composition according to  claim 4 , wherein the active agent particles comprise formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. 
     
     
         6 . The pharmaceutical composition according to  claim 5 , wherein the active agent particles comprise crystalline formoterol. 
     
     
         7 . The pharmaceutical composition according to  claim 5 , wherein the formoterol active agent particles are included in the composition at a concentration sufficient to provide a delivered dose of formoterol selected from between about 1 μg and about 30 μg, between about 0.5 μg and about 10 μg, between about 2 μg and 5 μg, between about 2 μg and about 10 μg, between about 5 μg and about 10 μg, and between 3 μg and about 30 μg per actuation of the metered dose inhaler. 
     
     
         8 . The pharmaceutical composition according to  claim 5 , wherein the formoterol active agent particles are included in the composition at a concentration sufficient to provide a delivered dose of formoterol 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. 
     
     
         9 . The pharmaceutical composition according to  claim 5 , wherein the concentration of formoterol included in the co-suspension is selected from between about 0.01 mg/ml and about 1 mg/ml, between about 0.01 mg/ml and about 0.5 mg/ml, and between about 0.03 mg/ml and about 0.4 mg/ml. 
     
     
         10 . The pharmaceutical composition according to  claim 5 , wherein at least 90% of the formoterol active agent particles by volume exhibit an optical diameter of 5 μm or less. 
     
     
         11 . The pharmaceutical composition according to  claim 5 , wherein at least 50% of the formoterol active agent particles by volume exhibit an optical diameter of 2 μm or less. 
     
     
         12 . The pharmaceutical composition according to  claim 4 , wherein the suspending particles comprise perforated microstructures. 
     
     
         13 . The pharmaceutical composition according to  claim 12 , wherein the perforated microstructures are prepared using a spray drying process. 
     
     
         14 . The pharmaceutical composition according to  claim 13 , wherein the perforated microstructures comprise a spray dried emulsion of perfluorooctyl bromide, DSPC and calcium chloride in water. 
     
     
         15 . The pharmaceutical composition according to  claim 4 , wherein the suspending particles comprise an excipient selected from at least one of lipids, phospholipids, nonionic detergents, polymers, nonionic block copolymers, surfactants, non-ionic surfactants, biocompatible fluorinated surfactants, carbohydrates, amino acids, organic salts, peptides, proteins, alditols, and combinations thereof. 
     
     
         16 . The pharmaceutical composition according to  claim 4 , 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, and 1 μm and about 3 μm. 
     
     
         17 . The pharmaceutical composition according to  claim 4 , 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. 
     
     
         18 . The pharmaceutical composition according to  claim 4 , 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. 
     
     
         19 . The pharmaceutical composition according to  claim 4 , wherein a total mass of the suspending particles exceeds a total mass of the active agent particles. 
     
     
         20 . The pharmaceutical composition according to  claim 19 , 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. 
     
     
         21 . The pharmaceutical composition according to  claim 19 , wherein a ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1. 
     
     
         22 . The pharmaceutical composition according to  claim 4 , wherein the suspending particles remain associated with the active agent particles even when subjected to buoyancy forces amplified by centrifugation at an acceleration selected from accelerations of at least 1 g, at least 10 g, at least 50 g, and at least 100 g. 
     
     
         23 . The method of  claim 2 , wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising a plurality of active agent particles comprising a LABA active agent. 
     
     
         24 . The method of  claim 23 , wherein the LABA active agent is 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. 
     
     
         25 . The method of  claim 24 , 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 vasoconstriction, pulmonary inflammation associated with cystic fibrosis, and pulmonary obstruction associated with cystic fibrosis. 
     
     
         26 . The method of  claim 24 , wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising a plurality of active agent particles comprising formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. 
     
     
         27 . The method of  claim 26 , wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising a plurality of active agent particles comprising formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, and the concentration of formoterol included in the co-suspension is selected from between about 0.01 mg/ml and about 1 mg/ml, between about 0.01 mg/ml and about 0.5 mg/ml, and between about 0.03 mg/ml and about 0.4 mg/ml. 
     
     
         28 . The method of  claim 24 , wherein administering the pharmaceutical composition comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in FEV 1  in the patient within 1 hour, or less. 
     
     
         29 . The method of  claim 24 , wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in FEV 1  in the patient within 0.5 hours, or less. 
     
     
         30 . The method of  claim 24 , wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in an increase of FEV 1  of 150 ml or greater within a period of time selected from 0.5 hours, or less, 1 hour, or less, and 1.5 hours, or less. 
     
     
         31 . The method of  claim 24 , wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in FEV 1  in the patient within 0.5 hours, or less, and providing a clinically significant increase in FEV 1  for a time period selected from up to 4 hours, up to 6 hours, and up to 8 hours, or more. 
     
     
         32 . The method of  claim 28 , wherein administering the pharmaceutically acceptable co-suspension comprises administering to the patient a dose of LABA active agent selected from between about 1 μg and about 50 μg, between about 1 μg and about 30 μg, between about 2 μg and 5 μg, between about 2 μg and about 10 μg, between about 5 μg and about 10 μg, and between 3 μg and about 30 μg per actuation. 
     
     
         33 . The method of  claim 28 , wherein administering the pharmaceutically acceptable co-suspension comprises administering to the patient a dose of formoterol or a pharmaceutically acceptable salt, ester, isomer or solvate 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, and up to about 1.5 μg per actuation. 
     
     
         34 . The method of  claim 24 , wherein administering the pharmaceutical composition comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in inspiratory capacity. 
     
     
         35 . The method of  claim 3 , wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising a plurality of active agent particles comprising a LABA active agent. 
     
     
         36 . The method of  claim 35 , wherein the LABA active agent is 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. 
     
     
         37 . The method of  claim 36 , wherein the LABA active agent is formoterol, including pharmaceutically acceptable salts, esters, isomers or solvates thereof. 
     
     
         38 . The method of  claim 36 , wherein actuating the metered dose inhaler to provide respiratory delivery of the LABA active agent comprises delivering the LABA active agent to the patient at a DDU selected from a DDU of ±30%, or better, a DDU of ±25%, or better, and a DDU of ±20%, or better, throughout emptying of the canister. 
     
     
         39 . The method of  claim 36 , wherein actuating the metered dose inhaler to provide respiratory delivery of the LABA active agent comprises delivering the LABA active agent at an initial fine particle fraction and the initial fine particle fraction delivered from the metered dose inhaler is substantially maintained, such that, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 80% of the initial fine particle fraction. 
     
     
         40 . The method of  claim 39 , wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 90% of the initial fine particle fraction. 
     
     
         41 . The method of  claim 40 , wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine particle fraction. 
     
     
         42 . A metered dose inhaler for delivery of a LAMA or a LABA active agent, the metered dose inhaler comprising:
 a canister containing a pharmaceutically acceptable co-suspension 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 plurality of active agent particles associate with the plurality of suspending particles; 
   wherein the LAMA or LABA active agent included in the pharmaceutically acceptable co-suspension is chemically stable over a period of at least 18 months when stored at 5° C.   
     
     
         43 . The metered dose inhaler according to  claim 42 , wherein the LAMA or LABA active agent included in the pharmaceutically acceptable co-suspension is 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. 
     
     
         44 . The metered dose inhaler according to  claim 43  wherein the LABA active agent is formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. 
     
     
         45 . The metered dose inhaler according to  claim 44 , wherein a rate of formation of N-(2-hydroxy-5-(1-(2-hydroxy-5-(1-hydroxy-2-(1-(4-methoxyphenyl)propan-2-ylamino)ethyl)phenylamino)-2-(1-(4-methoxyphenyl)propan-2-ylamino)ethyl)phenyl)acetamide within the pharmaceutically acceptable co-suspension is not greater than about 0.15%, after the canister is subjected to a temperature of 40° C. and a relative humidity of 75% for a period of one month. 
     
     
         46 . The metered dose inhaler according to  claim 44 , wherein a rate of formation of N-(2-hydroxy-5-(1-(2-hydroxy-5-(1-hydroxy-2-(1-(4-methoxyphenyl)propan-2-ylamino)ethyl)phenylamino)-2-(1-(4-methoxyphenyl)propan-2-ylamino)ethyl)phenyl)acetamide within the pharmaceutically acceptable co-suspension is not greater than about 0.5%, after the canister is subjected to a temperature of 40° C. and a relative humidity of 75% for a period of one month. 
     
     
         47 . A pharmaceutical composition deliverable from a metered dose inhaler, comprising:
 a suspension medium comprising a pharmaceutically acceptable HFA propellant;   a plurality of active agent particles comprising formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, said active agent particles are included in the suspension medium at a concentration sufficient to provide a delivered dose of formoterol of between about 2 μg and about 10 μg per actuation of the metered dose inhaler; and   a plurality of respirable suspending particles comprising perforated microstructures exhibiting a volume median optical diameter of between about 1.5 μm and about 10 μm, said perforated microstructures associate with the plurality of active agent particles to form a co-suspension.   
     
     
         48 . The pharmaceutical composition according to  claim 47 , wherein a ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1. 
     
     
         49 . A method for respiratory delivery of LABA active agent to a patient, the method comprising;
 providing a metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprising:
 a suspension medium comprising a pharmaceutically acceptable HFA propellant; 
 a plurality of active agent particles comprising formoterol, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and 
 a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles; and 
   actuating the metered dose inhaler to provide respiratory delivery of formoterol to the patient at a DDU of ±20%, or better, throughout emptying of the canister.   
     
     
         50 . The method of  claim 49 , wherein actuating the metered dose inhaler to provide respiratory delivery of formoterol to the patient comprises delivering the formoterol at an initial fine particle fraction and the initial fine particle fraction delivered from the metered dose inhaler is substantially maintained, such that, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 80% of the initial fine particle fraction. 
     
     
         51 . The method of  claim 50 , wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 90% of the initial fine particle fraction. 
     
     
         52 . The method of  claim 51 , wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine particle fraction. 
     
     
         53 . A method for treating a pulmonary disease or disorder in a patient, the method comprising:
 providing metered dose inhaler comprising a pharmaceutically acceptable co-suspension, the co-suspension comprising:
 a suspension medium comprising a pharmaceutically acceptable HFA propellant; 
 a plurality of active agent particles comprising formoterol, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and 
 a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles; and 
   administering the co-suspension to the patient by actuating the metered dose inhaler, wherein said administering of the co-suspension composition comprises delivering a dose of 10 μg, or less, of formoterol per actuation of the metered dose inhaler and results in a clinically significant increase in FEV 1  in the patient.   
     
     
         54 . The method of  claim 53 , 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 vasoconstriction, pulmonary inflammation associated with cystic fibrosis, and pulmonary obstruction associated with cystic fibrosis.