# US 9,433,588 B2 · Delivery of submicrometer and nanometer aerosols to the lungs using hygroscopic excipients or dual stream nasal delivery

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- Number: US 9,433,588 B2
- Document ID: US9433588B2
- Status: Granted
- Kind: B2
- Application number: 13/503,927
- Filed: 2010-11-09
- Published: 2012-10-04
- Granted: 2016-09-06
- Earliest claimed: 2009-11-09
- Assignees: Virginia Commonwealth Univeristy
- Applicants: Philip Worth Longest; Michael Hindle
- Inventors: Philip Worth Longest; Michael Hindle
- Web page: https://patentgrep.com/patent/US9433588B2

## CPC

- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 9/008: {comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]}
- A61K 9/12: Aerosols; Foams {(A61K9/0043, A61K9/0056, A61K9/006, A61K9/0073 take precedence; spray-films A61K9/7015)}
- A61K 9/5115: {Inorganic compounds}
- A61K 9/5123: {Organic compounds, e.g. fats, sugars}
- A61K 31/58: containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048})
- A61M 11/001: {Particle size control}
- A61M 15/009: {using medicine packages with incorporated spraying means, e.g. aerosol cans (pocket atomiser of the injector type A61M11/08)}
- A61M 15/08: Inhaling devices inserted into the nose
- A61M 16/0057: {Pumps therefor}
- A61M 16/0666: {Nasal cannulas or tubing (devices for improving normal breathing through the nose A61F5/08; nose filters A62B23/06; outside holding devices A61M25/02)}
- A61M 16/0875: {Connecting tubes}
- A61M 16/109: {the humidifying liquid or the beneficial agent}
- A61M 16/147: {the respiratory gas not passing through the liquid container}
- A61M 16/16: Devices to humidify the respiration air {(A61M16/1045 takes precedence)}
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 23/00: Anaesthetics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/24: Antidepressants
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61M 11/00: Sprayers or atomisers specially adapted for therapeutic purposes (in general B05B; {aerosol containers B65D83/14})
- A61M 11/005: {using ultrasonics (spraying or atomising liquids using ultrasonic vibrations in general B05B17/06)}
- A61M 15/00: Inhalators {(drug delivery in endotracheal tubes A61M16/04)}
- A61M 16/12: by mixing different gases
- A61M 16/20: Valves specially adapted to medical respiratory devices
- A61M 2202/0208: Oxygen
- A61M 2202/064: Powder
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Pharmaceutically engineered aerosols (e.g. submicrometer and nano-particles and droplets) containing a hygroscopic growth excipient or agent are employed to improve the delivery of respiratory aerosols to the lung. Inclusion of the hygroscopic agent results in near zero depositional loss in the nose-mouth-throat regions and near 100% deposition of the aerosol in the lung. Targeting of the aerosol to specific lung depths is also possible. In addition, methods and apparatuses for delivering aerosols to the lung are provided. The aerosol is delivered to one nostril of a patient while a relatively high humidity gaseous carrier is delivered to the other nostril, resulting in post-nasopharyngeal growth of the aerosol to a size that promotes deposition in the lung.

## Claims

### Claim 1

A method of targeted delivery of an active agent to a region of the respiratory system of a patient in need thereof, comprising
providing said active agent to said patient as individually aerosolized submicrometer particles or droplets which combine both
i) said active agent; and
ii) at least one hygroscopic excipient with a hygroscopic parameter iexρex/Mex of at least 7 kmol/m3;
wherein said active agent and said at least one hygroscopic excipient are present in said individually aerosolized submicrometer particles or droplets in amounts sufficient to cause a predetermined amount of hygroscopic growth of said individually aerosolized submicrometer particles or droplets during passage through airways having natural airway humidity levels of said patient
wherein said individually aerosolized submicrometer particles or droplets have a growth coefficient iexρex/Mex·vfex+iaaρaa/Maa·vfaa of at least 2.8;
where
iex is the molecular dissociation constant of said at least one hygroscopic excipient,
iaa is the molecular dissociation constant of said active agent,
ρex is the density of said at least one hygroscopic excipient,
ρaa is the density of said active agent,
Mex is the molar mass of said at least one hygroscopic excipient,
Maa is the molar mass of said active agent,
vfex is the solute volume fraction of said at least one hygroscopic excipient, and
vfaa is the solute volume fraction of said active agent;
wherein said individually aerosolized submicrometer particles or droplets are at least 250 nm in size;
wherein submicrometer refers to size according to mass median aerodynamic diameter (MMAD);
and wherein said predetermined amount of hygroscopic growth caused by said amounts of said active agent and said at least one hygroscopic excipient results in said individually aerosolized submicrometer particles or droplets growing to an aerodynamic diameter which reaches or surpasses 2 μm in size.

### Claim 2 (depends on 1)

The method of claim 1, wherein said active agent is a medicament.

### Claim 3 (depends on 1)

The method of claim 1, wherein said active agent is a peptide.

### Claim 4 (depends on 1)

The method of claim 1, wherein said active agent is selected from the group consisting of agents for the treatment of asthma, agents for the treatment of respiratory disorders, anesthesia agents, nucleic acid molecules, anti-pain agents, anti-inflammation agents, anti-depressants, mood altering drugs, anti-viral agents, anti-bacterial agents, anti-fungal agents, anti-cancer agents, hormones, benzodiazepines and calcitonin.

### Claim 5 (depends on 1)

The method of claim 1, wherein said predetermined amount of hygroscopic growth is sufficient to cause targeted deposition of said individually aerosolized submicrometer particles or droplets in a region of said respiratory system of said patient selected from the group consisting of: nasal cavity, trachea, lung, alveolar airways, tracheobronchial airways, upper tracheobronchial airways, lower tracheobronchial airways, and lower tracheobronchial-alveolar airways.

### Claim 6 (depends on 1)

The method of claim 1, wherein said region of said respiratory system is the nasal cavity.

### Claim 7 (depends on 1)

The method of claim 1, wherein said region of said respiratory system is the trachea.

### Claim 8 (depends on 1)

The method of claim 1, wherein said region of said respiratory system is the lung.

### Claim 9 (depends on 1)

The method of claim 1, wherein said region of said respiratory system is the alveolar airways.

### Claim 10 (depends on 1)

The method of claim 1, wherein said region of said respiratory system is the tracheobronchial airways.

### Claim 11 (depends on 1)

The method of claim 1, wherein said region of said respiratory system is the lower tracheobronchial-alveolar airways.