Aerosol delivery systems, compositions and methods

Abstract

An aerosol preparation assembly includes an entrainment chamber defining an entrainment volume. The entrainment chamber includes a gas inlet port, an aerosol inlet port and an outlet port. The entrainment chamber is configured such that a velocity of a flow of a gas within the entrainment volume is less than a velocity of the flow of the gas within the gas inlet port. The entrainment chamber is configured such that at least a portion of inlet aerosol is entrained into the flow of the gas within the entrainment volume to produce an entrained aerosol flow at the outlet port. The particle selection chamber is configured to receive the entrained aerosol flow and produce an outlet aerosol flow. The particle selection chamber and nozzle are collectively configured such that a volumetric median diameter of the outlet aerosol flow is less than a volumetric median diameter of the inlet aerosol.

What is claimed is: 
     
         1 . An aerosol suspension of liquid particles comprising an active agent and a buffering agent; wherein the aerosol particles have a volume median diameter (VMD) from about 0.5 μm to about 2.5 μm and there are not more than about 10% aerosol particles larger than 4 μm based on volume normalized amounts; and the aerosol particles produce a deposition efficiency of greater than about 3% on lung airway surfaces via transnasal administration and maintain the physiological pH of lung airway surfaces upon delivery. 
     
     
         2 . The aerosol suspension of  claim 1 , wherein the aerosol particles have a VMD from about 1 μm to about 2 μm; or about 1.2 μm to about 1.6 μm; or about 1.4 μm. 
     
     
         3 . The aerosol suspension of  claim 1 , wherein there are not more than about 5%, or 2.5%, or 1% aerosol particles larger than 4 μm based on volume normalized amounts. 
     
     
         4 . The aerosol suspension of  claim 1 , wherein the aerosol particles produce a deposition efficiency of greater than about 10%, or greater than about 15%, or greater than about 20%, or greater than about 25%, or greater than about 30%, or greater than about 35%, or greater than about 40%, or greater than about 45%, or greater than about 50%, or greater than about 55%, or greater than about 60%, or greater than about 65%, or greater than about 70%, or greater than about 75%, or up to about 80%. 
     
     
         5 . The aerosol suspension of  claim 1 , wherein the aerosol particles produce a deposition rate of less than about 10 mg/min, or less than about 3 mg/min, or less than about 2 mg/min, or less than about 1 mg/min of the active agent on lung airway surfaces. 
     
     
         6 . The aerosol suspension of  claim 1 , wherein the active agent is selected from the group consisting of osmolytes, secretagogues, sodium channel blockers, mucus modifying agents (mucolytics) such as Pulmozyme and NAC, anti-infective agents including type II antibiotics such as meropenem, anti-virals such as ribavirin, anti-inflammatory agents, bronchodilators including beta-agonists and muscarinic receptor antagonists, steroids such as beclamethasone, budesonide, ciclesonide, flunisolide, fluticasone and mometasone, triamcinolone, anti-fungal agents such as amphotericin, intraconazol and voriconazol, anti-rejection drugs such as cyclosporine, tacrolimus and sirolimus, siRNAs, microRNAs, microRNA mimics, surfactants, therapeutic proteins and antibodies, gene therapy vectors, aptamers, endothelin-receptor antagonists, alpha-1-antitrypsin, prostacyclins, vaccines, and combinations thereof. 
     
     
         7 . The aerosol suspension of  claim 1 , wherein the active agent is hypotonic saline, isotonic saline, or hypertonic saline. 
     
     
         8 . The aerosol suspension of  claim 7 , wherein the active agent is hypertonic saline having a concentration ranging of about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% by weight (grams/mL). 
     
     
         9 . The aerosol suspension of  claim 1 , wherein the buffering agent is a compound comprising an anionic component which is able to maintain a pH from about 6.8 to about 7.6, or from about 6.9 to about 7.5, or from about 7.0 to about 7.4. 
     
     
         10 . The aerosol suspension of  claim 9 , wherein the anionic component comprises carbonate or bicarbonate. 
     
     
         11 . A method of transnasally administering to either lungs of a subject in need thereof an effective amount of an aerosol suspension of liquid particles which comprises an active agent and a buffering agent; wherein
 the aerosol particles have a volume median diameter (VMD) from about 0.5 μm to about 2.5 μm and there are not more than about 10% aerosol particles larger than 4 μm based on volume normalized amounts; and   the aerosol particles produce a deposition efficiency of greater than about 3% on lung airway surfaces and maintain the physiological pH of lung airway surfaces upon delivery.   
     
     
         12 . A method of treating a disease or condition associated with either lungs of a subject comprising transnasally administering an effective amount of an aerosol suspension of liquid particles which comprises an active agent and a buffering agent; wherein
 the aerosol particles have a volume median diameter (VMD) from about 0.5 μm to about 2.5 μm and there are not more than about 10% aerosol particles larger than 4 μm based on volume normalized amounts; and   the aerosol particles produce a deposition efficiency of greater than about 3% on lung airway surfaces and maintain the physiological pH of lung airway surfaces upon delivery.   
     
     
         13 . The method of  claim 11  or  12 , wherein the active agent is deposited on lung airway surfaces as compared to nasal airway surfaces at a weight ratio of at least 2:1, 3:1, or 4:1. 
     
     
         14 . The method of  claim 11  or  12 , wherein the active agent is deposited on lung airway surfaces as compared to the combination of oropharynx and gastrointestinal deposition at a weight ratio of at least 2:1, 3:1, or 4:1. 
     
     
         15 . The method of  claim 11  or  12 , wherein the administration is carried out over a period of more than about 1 hour, or up to about 4 hours, or up to about 6 hours, or up to about 8 hours, or up to about 10 hours, or up to 12 hours, or up to 14 hours, or up to 16 hours, or up to 18 hours, or up to 20 hours, or up to 22 hours, or up to 24 hours. 
     
     
         16 . The method of  claim 11  or  12 , wherein the aerosol suspension is administered at an airflow of from about 1 to about 2 Liters per minute to about 3 or about 4 Liters per minute. 
     
     
         17 . The method of  claim 11  or  12 , wherein the aerosol suspension is administered by a nebulizer having a nasal cannula. 
     
     
         18 . The method of  claim 11  or  12 , wherein the aerosol particles have a VMD from about 1 μm to about 2 μm; or about 1.2 μm to about 1.6 μm; or about 1.4 μm. 
     
     
         19 . The method of  claim 11  or  12 , wherein there are not more than about 5%, or 2.5%, or 1% aerosol particles larger than 4 μm based on volume normalized amounts. 
     
     
         20 . The method of  claim 11  or  12 , wherein the aerosol particles produce a deposition efficiency of greater than about 10%, or greater than about 15%, or greater than about 20%, or greater than about 25%, or greater than about 30%, or greater than about 35%, or greater than about 40%, or greater than about 45%, or greater than about 50%, or greater than about 55%, or greater than about 60%, or greater than about 65%, or greater than about 70%, or greater than about 75%, or up to about 80%. 
     
     
         21 . The method of  claim 11  or  12 , wherein the aerosol particles produce a deposition rate of less than about 10 mg/min, or less than about 3 mg/min, or less than about 2 mg/min, or less than about 1 mg/min of the active agent on lung airway surfaces. 
     
     
         22 . The method of  claim 12 , wherein the disease or condition is cystic fibrosis (CF), chronic bronchitis, emphysema, non-CF bronchiectasis, RSV infection, RSV infection induced bronchiolitis, rhinovirus infection, sinus-related disorders such as rhinitis and sinusitis, chronic obstructive pulmonary disease, aspiration pneumonitis, ventilator-associated pneumonia, hospital-acquired or nosocomial pneumonia, sleep apnea, healthcare-associated pneumonia, asthma, and/or a bacterial infection, viral infection or a fungal infection of the lungs. 
     
     
         23 . A system for treating a disease or condition associated with either lungs of a subject comprising:
 a) a pharmaceutical formulation comprising a hypertonic saline solution and a bicarbonate buffering agent; and   b) an aerosol delivery device configured to generate an aerosol comprising the pharmaceutical formulation, the aerosol delivery device including an entrainment chamber and a particle selection chamber;   wherein the aerosol has a volume median diameter (VMD) from about 0.5 μm to about 2.5 μm and there are not more than about 10% aerosol larger than 4 μm based on volume normalized amounts; and the aerosol produces a deposition efficiency of greater than about 3% on lung airway surfaces via transnasal administration and maintains the physiological pH of lung airway surfaces upon delivery.   
     
     
         24 . An apparatus comprising:
 an entrainment chamber defining an entrainment volume, the entrainment chamber including a gas inlet port, an aerosol inlet port and an outlet port, the gas inlet port configured to fluidically couple a gas source to the entrainment volume, the entrainment chamber configured such that a velocity of a flow of a gas within the entrainment volume is less than a velocity of the flow of the gas within the gas inlet port, the aerosol inlet port configured to receive an inlet aerosol produced by an aerosol generator, the entrainment chamber configured such that at least a portion of the inlet aerosol is entrained into the flow of the gas within the entrainment volume to produce an entrained aerosol flow at the outlet port;   a nozzle in fluidic communication with the outlet port of the entrainment chamber, the nozzle configured to accelerate the entrained aerosol flow; and   a particle selection chamber including a cannula coupling port configured to be coupled to a nasal cannula, the particle selection chamber configured to receive the entrained aerosol flow from the nozzle and produce an outlet aerosol flow, the particle selection chamber and nozzle collectively configured such that a volumetric median diameter of the outlet aerosol flow is less than a volumetric median diameter of the inlet aerosol.   
     
     
         25 . The apparatus of  claim 24 , wherein the inlet port of the entrainment chamber has an expansion ratio entering the entrainment volume of at least two. 
     
     
         26 . The apparatus of  claim 24 , wherein the nozzle is monolithically constructed with at least one of the entrainment chamber or the particle selection chamber. 
     
     
         27 . The apparatus of  claim 24 , wherein the entrainment chamber and the particle selection chamber are monolithically constructed. 
     
     
         28 . The apparatus of  claim 24 , wherein the particle selection chamber defines a tortuous path within the selection volume to produce the outlet aerosol flow. 
     
     
         29 . The apparatus of  claim 24 , wherein the particle selection chamber includes a baffle, the nozzle and the baffle configured such that a portion of the entrained aerosol particles impinges on the baffle. 
     
     
         30 . The apparatus of  claim 24 , wherein:
 the entrainment chamber defines a first recirculation port configured to receive a rained out portion of the inlet aerosol, the first recirculation port fluidically coupled to the aerosol generator, and   the particle selection chamber defines a second recirculation port configured to receive a rained out portion of the entrained aerosol flow, the second recirculation port fluidically coupled to the aerosol generator.   
     
     
         31 . The apparatus of  claim 24 , wherein the particle selection chamber and the nozzle are collectively configured such that the volumetric median diameter of the outlet aerosol flow is substantially independent of the volumetric median diameter of the inlet aerosol. 
     
     
         32 . The apparatus of  claim 24 , wherein the particle selection chamber and the nozzle are collectively configured such that the volumetric median diameter of the outlet aerosol flow is between approximately one micron and approximately two microns when the volumetric median diameter of the inlet aerosol is within a range of between approximately two microns and approximately seven microns. 
     
     
         33 . The apparatus of  claim 24 , wherein the particle selection chamber and nozzle are collectively configured such that the volumetric median diameter of the outlet aerosol flow is between approximately one micron and approximately two microns. 
     
     
         34 . The apparatus of  claim 24 , wherein the cannula coupling port includes a cannula nozzle and a coupling portion, an effective flow area of a flow path defined by an inner wall of the cannula nozzle being substantially the same as an effective flow area of a flow path defined by an inner wall of the nasal cannula, the coupling portion configured to be coupled to the nasal cannula such that the inner wall of the cannula nozzle and the inner wall of the nasal cannula form a substantially continuous surface. 
     
     
         35 . The apparatus of  claim 24 , further comprising:
 the gas source, the gas source configured to produce the flow of a gas within the entrainment volume having a periodic variation in flow rate.   
     
     
         36 . The apparatus of  claim 24 , further comprising:
 a cartridge in fluid communication with the aerosol generator, the cartridge containing a medicament from which the inlet aerosol is produced by the aerosol generator.   
     
     
         37 . The apparatus of  claim 36 , wherein the medicament includes hypertonic saline. 
     
     
         38 . An apparatus comprising:
 an entrainment chamber defining an entrainment volume, the entrainment chamber including a gas inlet port, an aerosol inlet port and an outlet port, the gas inlet port configured to fluidically couple a gas source to the entrainment volume, the aerosol inlet port configured to receive an inlet aerosol produced by an aerosol generator, the entrainment chamber configured such that at least a portion of the inlet aerosol is entrained into a flow of a gas within the entrainment volume to produce an entrained aerosol flow at the outlet port; and   a particle selection chamber including a cannula coupling port configured to be coupled to a nasal cannula, the particle selection chamber configured to receive the entrained aerosol flow from the outlet port of the entrainment chamber and produce an outlet aerosol flow, the particle selection chamber configured to extract a portion of the entrained aerosol from the entrained aerosol flow such that a volumetric median diameter of the outlet aerosol flow is less than a volumetric median diameter of the inlet aerosol,   the cannula coupling port including a cannula nozzle and a coupling portion, the coupling portion configured to be coupled to the nasal cannula such that an inner wall of the cannula nozzle and an inner wall of the nasal cannula form a substantially continuous surface.   
     
     
         39 . The apparatus of  claim 38 , further comprising:
 a nozzle fluidically coupled to the outlet port of the entrainment chamber, the nozzle configured to accelerate the entrained aerosol flow between the entrainment chamber and the particle selection chamber,   the particle selection chamber including a baffle, the nozzle and the baffle configured such that a portion of the entrained aerosol in the entrained aerosol flow impinges on the baffle.   
     
     
         40 . The apparatus of  claim 38 , wherein:
 the entrainment chamber defines a first recirculation port configured to receive a rained out portion of the inlet aerosol, the first recirculation port fluidically coupled to the aerosol generator, and   the particle selection chamber defines a second recirculation port configured to receive a rained out portion of the entrained aerosol flow, the second recirculation port fluidically coupled to the aerosol generator.   
     
     
         41 . An apparatus comprising:
 an entrainment chamber defining an entrainment volume, the entrainment chamber including a gas inlet port, an aerosol inlet port, an outlet port and a first recirculation port, the gas inlet port configured to fluidically couple a gas source to the entrainment volume, the aerosol inlet port configured to receive an inlet aerosol produced by an aerosol generator, the entrainment chamber configured such that a first portion of the inlet aerosol is entrained into a flow of a gas within the entrainment volume to produce an entrained aerosol flow at the outlet port and a second portion of the inlet aerosol is collected within the entrainment chamber, the first recirculation port configured to receive the second portion of the inlet aerosol, the first recirculation port fluidically coupled to the aerosol generator via a first recirculation pathway that excludes the entrainment chamber; and   a particle selection chamber including a cannula coupling port configured to be coupled to a nasal cannula, the particle selection chamber configured to receive the entrained aerosol flow from the outlet port of the entrainment chamber and produce an outlet aerosol flow, the particle selection chamber configured to extract a portion of the entrained aerosol from the entrained aerosol flow such that a volumetric median diameter of the outlet aerosol flow is less than a volumetric median diameter of the inlet aerosol, the second recirculation port configured to receive the extracted portion of the entrained aerosol, the second recirculation port fluidically coupled to the aerosol generator via a second recirculation pathway that excludes the entrainment chamber   
     
     
         42 . The apparatus of  claim 41 , wherein:
 the outlet port includes a nozzle configured to accelerate the entrained aerosol flow between the entrainment chamber and the particle selection chamber; and   the particle selection chamber includes a baffle, the nozzle and the baffle configured such that at least a portion of the extracted portion of the entrained aerosol flow impinges on the baffle.   
     
     
         43 . The apparatus of  claim 41 , wherein the cannula coupling port includes a cannula nozzle and a coupling portion, the coupling portion configured to be coupled to the nasal cannula such that an inner wall of the cannula nozzle and an inner wall of the nasal cannula form a substantially continuous surface. 
     
     
         44 . The apparatus of  claim 41 , further comprising:
 a cartridge in fluid communication with the aerosol generator, the cartridge containing a medicament from which the inlet aerosol is produced by the aerosol generator.   
     
     
         45 . The apparatus of  claim 41 , wherein the medicament includes hypertonic saline. 
     
     
         46 . An apparatus, comprising:
 a medicament container containing a liquid medicament;   an interface member coupled to the medicament container, the interface member configured to be removably coupled to an inlet opening defined by an aerosol generator; and   a valve configured to limit flow of the liquid medicament from the medicament container into a reservoir of the aerosol generator.   
     
     
         47 . The apparatus of  claim 46 , wherein the liquid medicament includes hypertonic saline. 
     
     
         48 . The apparatus of  claim 46 , wherein the interface member is constructed from a deformable material configured to form a substantially fluid-tight seal with aerosol generator when coupled to the aerosol generator, the valve defining a gas flow path from the reservoir of the aerosol generator. 
     
     
         49 . The apparatus of  claim 46 , wherein the aerosol generator is a nebulizer. 
     
     
         50 . The apparatus of  claim 46 , further comprising a filter disposed between the valve and the reservoir of the aerosol generator. 
     
     
         51 . The apparatus of  claim 46 , wherein the valve is configured to limit the static pressure exerted by the liquid medicament within the medicament container on a surface of the aerosol generator. 
     
     
         52 . The apparatus of  claim 51 , wherein the aerosol generator is a nebulizer, the surface being a vibrating mesh.