WO2006076265A2 - Procede et dispositif de reduction de la contamination - Google Patents

Procede et dispositif de reduction de la contamination Download PDF

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Publication number
WO2006076265A2
WO2006076265A2 PCT/US2006/000618 US2006000618W WO2006076265A2 WO 2006076265 A2 WO2006076265 A2 WO 2006076265A2 US 2006000618 W US2006000618 W US 2006000618W WO 2006076265 A2 WO2006076265 A2 WO 2006076265A2
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WO
WIPO (PCT)
Prior art keywords
particle
mouthpiece
filter
particles
particle counter
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Application number
PCT/US2006/000618
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English (en)
Other versions
WO2006076265A3 (fr
Inventor
David A. Edwards
Mark J. Gabrielson
Robert William Clarke
Wesley Hugh Dehaan
Matthew Frederick Brande
Jonathan Chun-Wah Man
Original Assignee
Pulmatrix, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority claimed from PCT/US2005/006903 external-priority patent/WO2005084638A2/fr
Application filed by Pulmatrix, Inc. filed Critical Pulmatrix, Inc.
Priority to CA002601080A priority Critical patent/CA2601080A1/fr
Priority to AU2006205108A priority patent/AU2006205108B2/en
Priority to JP2007550530A priority patent/JP5075638B2/ja
Priority to EP06717779A priority patent/EP1850749A2/fr
Publication of WO2006076265A2 publication Critical patent/WO2006076265A2/fr
Publication of WO2006076265A3 publication Critical patent/WO2006076265A3/fr
Priority to US11/827,031 priority patent/US8627821B2/en

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/497—Physical analysis of biological material of gaseous biological material, e.g. breath
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
    • A61B5/097—Devices for facilitating collection of breath or for directing breath into or through measuring devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
    • A61B5/0816—Measuring devices for examining respiratory frequency
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
    • A61B5/087—Measuring breath flow
    • A61B5/0878—Measuring breath flow using temperature sensing means
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/02—Investigating particle size or size distribution
    • G01N15/0205—Investigating particle size or size distribution by optical means

Definitions

  • the present invention is in the field of methods, formulations and devices to decrease particle exhalation and contamination in various environments, and is particularly useful in cleanrooms. Background of the Invention
  • a cleanroom is a controlled environment where products are manufactured. It is a room in which the concentration of airborne particles is controlled to specified limits. Eliminating sub-micron airborne contamination is really a process of control. These contaminants are generated by people, process, facilities and equipment. They must be continually removed from the air. The level to which these particles need to be removed depends upon the standards required. The most frequently used standard is the Federal Standard 209E. The 209E is a document that establishes standard classes of air cleanliness for airborne particulate levels in cleanrooms and clean zones. Strict rules and procedures are followed to prevent contamination of the product.
  • Cleanrooms are planned and manufactured using strict protocol and methods. They are frequently found in electronics, pharmaceutical, biopharmaceutical, medical device industries and other critical manufacturing environments.
  • Typical office building ail- contains from 500,000 to 1,000,000 particles (0.5 microns or larger) per cubic foot of air.
  • a Class 100 cleanroom is designed to never allow more than 100 particles (0.5 microns or larger) per cubic foot of air.
  • Class 1000 and Class 10,000 cleanrooms are designed to limit particles to 1000 and 10,000 respectively.
  • a human hair is about 75-100 microns in diameter.
  • a particle 200 times smaller (0.5 micron) than the human hair can cause major disaster in a cleanroom. Contamination can lead to expensive downtime and increased production costs. Once a cleanroom is built, it must be maintained and cleaned to the same high standards.
  • Contamination is a process or act that causes materials or surfaces to be soiled with contaminating substances.
  • surface contaminants There are two broad categories of surface contaminants: film type and particulates. These contaminants can produce a "killer defect" in a miniature circuit. Film contaminants of only 10 nm (nanometers) can drastically reduce coating adhesion on a wafer or chip. It is widely accepted that particles of 0.5 microns or larger are the target. However, some industries are now targeting smaller particles.
  • a partial list of contaminants is provided below. Any of these can be the source for killing a circuit. Preventing these contaminants from entering the cleanroom environment is a major objective. It has been found that many of these contaminants are generated from five basic sources: facilities, people, tools, fluids and the product being manufactured. 1. Facilities: Walls, floors and ceilings; Paint and coatings; Construction material (sheet rock, saw dust etc.); Air conditioning debris; Room air and vapors; Spills and leaks
  • Fluids Particulates floating in air; Bacteria, organics and moisture; Floor finishes or coatings; Cleaning chemicals; Plasticizers (outgasses); Deionized water
  • HEPA High Efficiency Particulate Air filters. These filters are extremely important for maintaining contamination control. They filter particles as small as 0.3 microns with a 99.97% minimum particle-collective efficiency. Cleanrooms are designed to achieve and maintain an airflow in which essentially the entire body of air within a confined area moves with uniform velocity along parallel flow lines. This air flow is called laminar flow. The more restriction of air flow the more turbulence. Turbulence can cause particle movement. In addition to the HEPA filters commonly used in cleanrooms, there are a number of other filtration mechanisms used to remove particles from gases and liquids. These filters are essential for providing effective contamination control. Cleaning is also an essential element of contamination control. The requirements for cleanroom garments will vary from location to location.
  • the device (10) contains a mouthpiece (12), a filter (14), a low resistance one-way valve (16), a particle counter (20) and a computer (30).
  • the device also contains a gas flow meter (22).
  • the data obtained using the device can be used to determine if a formulation for reducing particle exhalation is needed. This device is particularly useful prior to and/or following entry in a cleanroom to ensure that the cleanroom standards are maintained.
  • the device can also be used to identify animals and humans who have an enhanced propensity to exhale aerosols (referred to herein as "over producers", “super-producers”, or “superspreaders”).
  • Formulations to reduce particle production are also described herein.
  • the formulation is administered in an amount sufficient to alter biophysical properties in the mucosal linings of the body. When applied to mucosal lining fluids, the formulation alters the physical properties such as the gel characteristics at the air/liquid interface, surface elasticity, surface viscosity, surface tension and bulk viscoelasticity of the mucosal lining.
  • the formulation is administered in an effective amount to minimize ambient contamination due to particle formation during breathing, coughing, sneezing, or talking, which is particularly important in the cleanroom applications.
  • the formulation for administration is a non-surfactant solution.
  • the formulations are conductive formulations containing conductive agents, such as salts, ionic surfactants, or other substances that are in an ionized state or easily ionized in an aqueous or organic solvent environment.
  • conductive agents such as salts, ionic surfactants, or other substances that are in an ionized state or easily ionized in an aqueous or organic solvent environment.
  • active agents such as antivirals, antimicrobials, antiinflammatories, proteins or peptides, may be included with the formulation.
  • Figure 1 is a schematic of a diagnostic instrument for the measurement of particles produced and exhaled by a person.
  • Figure 2 is a schematic of a diagnostic instrument for the measurement of particles produced and exhaled by a person with associated breathing rate.
  • Figure 6A is a graph of total particles exhaled (greater than 0.3 microns) over time (minutes) showing data obtained from sham treated animals.
  • Figure 6B is a graph of mean percent (%) baseline particle counts over time (minutes) showing data obtained from animals treated with nebulized saline for 1.8 minutes (- ⁇ -), 6.0 minutes (-A-), 12.0 minutes (-G-), and sham (- ⁇ -).
  • Figure 7 is a graph of time following completion of administration of formulation for reduction of particle production (hours) versus average particle counts greater than 0.3 ⁇ m produced relative to baseline (% counts/liter).
  • Lung mucociliary clearance is the primary mechanism by which the airways are kept clean from particles present in the liquid film that coats them.
  • the conducting airways are lined with ciliated epithelium that beat to drive a layer of mucus towards the larynx, clearing the airways from the lowest ciliated region in 24 hours.
  • the fluid coating consists of water, sugars, proteins, glycoproteins, and lipids. It is generated in the airway epithelium and the submucosal glands, and the thickness of the layer ranges from several microns in the trachea to approximately 1 micron in the distal airways in humans, rat, and guinea pig.
  • a second important mechanism for keeping the lungs clean is via momentum transfer from the air flowing through the lungs to the mucus coating. Coughing increases this momentum transfer and is used by the body to aid the removal of excess mucus. It becomes important when mucus cannot be adequately removed by ciliary beating alone, as occurs in mucus hypersecretion associated with many disease states. Air speeds as high as 200 m/s can be generated during a forceful cough. The onset of unstable sinusoidal disturbances at the mucus layer has been observed at such air speeds. This disturbance results in enhanced momentum transfer from the air to the mucus and consequently accelerates the rate of mucus clearance from the lungs.
  • the first and second objections can be achieved using a device such as that described herein which measures the size and number of particles produced on an individual basis. Particle production can be measured at rest or during various activities. This allows for determination if a formulation for reducing particle exhalation should be administered to an individual and/or for selection of individuals with the minimal particle production for use in cleanroom environments.
  • the third objective can be achieved by administering a formulation for decreasing particle production, such as formulation containing a substances that are easily ionized in an aqueous or organic solvent environment (also referred to herein as "conductive agents"), as described herein.
  • a formulation for decreasing particle production such as formulation containing a substances that are easily ionized in an aqueous or organic solvent environment (also referred to herein as "conductive agents"), as described herein.
  • the formulation is administered to one or more individuals using a device which provides an aerosol that sprays a fine mist of the formulation into the pulmonary and/or nasal region of an individual, thereby decreasing the output of particles. Individuals may be treated prior to entering, and/or after entering, the cleanroom.
  • I. Diagnostic Device for Determining Particle Production rate and size range
  • the analysis of this data can be used to determine if a formulation for reducing particle exhalation is needed.
  • This device is particularly useful prior to entry in a cleaniOom or while a user is working in a cleanroom to ensure that the cleanroom standards are maintained.
  • the device can also be used to identify animals and humans who have an enhanced propensity to exhale aerosols (referred to herein as "over producers", “super-producers”, or “super spreaders").
  • the assessment of exhaled particle numbers is done at a respiratory flow rate of about 10 to about 120 liters per minutes (LPM).
  • a diagnostic instrument ( 10) for the measurement of particles produced and exhaled by a person is illustrated in Figures 1 and 2. As shown in Figure 1, the device (10) contains a mouthpiece (12).
  • the outlet (13) of the mouthpiece (12) is attached to a filter (14) and a low resistance one-way valve (16) via a branched connector (18), such as a wye or tee connector.
  • the one-way valve (16) is typically located inside a tube (19) which forms one half of the connector (18) or is attached directly to one end of the connector (18).
  • the tube (19) is attached to a particle counter (20).
  • the particle counter (20) is connected to the computer (30) in a manner that allows data to be provided to the computer (30).
  • the data from the particle counter (20) is sent to a computer (30), to allow a user to read, analyze and interpret the data.
  • the device is portable and, optionally, operates on batteries.
  • the mouthpiece (12) is designed to allow the user to place his lips around the outside of the mouthpiece and thereby form a seal between his lips and the mouthpiece.
  • the mouthpiece is in the form of a nasal prongs and a seal is fo ⁇ ned between the user's nostrils and the prongs.
  • the mouthpiece is in the form of a mask, which covers the user's mouth and nose. In this embodiment, a seal is formed between the user's face and the mask.
  • the mouthpiece is in the form of a mask which only covers the user's nose.
  • the mouthpiece is disposable.
  • the filter (14) is typically a high efficiency (>99.97% at 0.3 ⁇ m), low pressure drop ( ⁇ 2.5 cm H 2 O at 60 L/min) filter, optionally the filter has a bacterial/viral removal efficiency of >99.99%.
  • the filter is selected to remove at least particles having sizes in the range to be measured by the particle counter (20), preferably the filter removes particles having a sizes even smaller that the range to be measured by the particle counter.
  • the filter is designed to remove particles of greater than or equal to 0.1 micrometer in diameter.
  • a series of two or more filters (14) may be included between the mouthpiece and the ambient air in order to prevent the contamination of the upstream system between users.
  • one or more of the filters may be replaced with a bank of filters in parallel in order to minimize flow resistance.
  • the mouthpiece (12), filter (14), connector (18), and one-way valve (16) are all disposable.
  • the mouthpiece (12), filter (14), connector (18), and/or one-way valve (16) are formed from biodegradable materials.
  • the particle counter (20) must have sufficient sensitivity to accurately count sub-micron sized particles and may be designed and assembled as described.
  • the measurement of particle number and particle size can be done by electrical mobility analysis, impaction, electrostatic impaction, infrared spectroscopy, laser diffraction, or light scattering.
  • Examples of currently available particle counters for the measurement of particle number and size include: Scanning Mobility Particle Sizer (SMPS) (TSI, Shoreview MN), Andersen cascade inipactor or Next generation pharmaceutical impactor (Copley Scientific, Nottingham UK), Electrical low pressure impactor (ELPI) (Dekati, Tampere Finland) and Helos (Sympatec, Clausthal, Gennany).
  • SMPS Scanning Mobility Particle Sizer
  • ELPI Electrical low pressure impactor
  • Helos Sympatec, Clausthal, Gennany
  • the particle counter is an optical particle counter, most preferably one which operated by light scattering using a LASER or laser diode light source.
  • the optical particle counter has a range of at least 0.3 to 5 ⁇ m and preferably from 0.1 to 25 ⁇ m. It differentiates its measurement range into at least 2 channels and preferably at least 4 channels. It operates at a steady sample flow rate of at least 0.1 cubic foot per minute and preferably of at least 1 cubic foot per minute which may be generated and controlled as part of the particle counter or as separate vacuum pump and flow regulator components (not shown in figure).
  • optical particle counters that may be appropriate for this preferred embodiment include model CI-450, CI-500, CI-550 of Ultimate 100 (Climet Instruments, Redlands CA) and models Lasair II, Airnet 310 (Particle Measuring Systems, Boulder CO)
  • the particle counter (20) is connected to the computer (30) in a manner that allows data from the particle counter (20) to be sent to the computer (30).
  • the particle counter (20) is also connected to the computer (30) in a manner that allows control commands to be sent from the computer (30) to the particle counter (20).
  • the computer may be a microprocessor internal or external to the particle counter.
  • the device (10) contains a gas flow meter (22).
  • the gas flow meter (22) should have a low flow resistance so as not to influence the user's respiration rate such as a pneumotachometer or pneumotachograph of type Fleisch or Lilly.
  • the gas flow meter may measure flow by measuring the temperature change or heat transfer from an electrically heated wire (e.g. a hot wire anemometer), or by counting the number of revolutions per unit of time of a small turbine (e.g a turbine flow meter), or by measuring the differential pressure across or the bypass flow rate through a bypass around a flow restriction, such as a laminar flow element. The volume displacement is then computed by integrating flow with respect to time.
  • Pneumotachometers are commonly used to measure the flow rate of different gases during respiration. Air is passed through a short tube (e.g. a Fleisch tube) that contains a mesh which presents a small resistance to the air flow (not shown in figure). The resulting pressure drop across the mesh is proportional to the flow rate. The pressure drop is very small, usually around a few mmH 2 0.
  • a differential pressure transducer (24) is normally used to measure the pressure drop across the flow meter (e.g. Fleisch tube), in order to enhance detection of such small drops in pressure.
  • the differential pressure transducer is connected to a signal conditioner (26) which amplifies the signal and sends it to data acquisition software in the computer (30).
  • the differential pressure transducer (24) is a Validyne DP45-14 differential pressure transducer.
  • the signal conditioner (26) is a Validyne CD 15 sine wave carrier demodulator.
  • the pneumotachometer may be used in lung function analysis, or during artificial ventilation of the lungs.
  • the flow meter (22) is a low flow rate mass flow meter measuring the bypass flow around a flow restriction, such as a laminar flow element.
  • the laminar flow element (not shown in figure) consists of a series of parallel tubes sized such that the flow through the tubes is in the laminar flow regime for respirable flow rates, preferably for flow rates between +130 and -70 L/min, where positive flow represents the flow direction during exhalation.
  • the low flow meter provides digital output at a frequency greater than 5Hz.
  • the Sensirion model ASF1430 is the Sensirion model ASF1430.
  • the device (10) includes comiections for performing further exhaled breath analysis simultaneously or in series with particle size and count measurements. For example, exhaled breath condensate may be collected in standard devices such as R-tubes or exhaled air may be passed through culture media filters for further analysis via connections (not shown in figure) located along the tube (19) leading to the optical particle counter (20).
  • Bioaerosol particles are formed by instabilities in the endogenous surfactant layer in the airways.
  • the formulations described herein are effective to alter the biophysical properties of the mucosal lining. These properties include, for example, increasing gelation at the mucus surface, the surface tension of the mucosal lining, the surface elasticity of the mucosal lining, and the bulk viscoelasticity of the mucosal lining.
  • the formulations described herein are effective to decrease particle exhalation, by preventing or reducing exhaled particle formation from the oropharynx or nasal cavities.
  • the endogenous surfactant layer may be altered by simply diluting the endogenous surfactant pool via either delivery of isotonic saline (though not in such a large amount as to cause a subject to expectorate) or a hypertonic saline solution that causes the cells lining the lung's airways to dilute further the endogenous surfactant layer via production of water.
  • Preferred formulations for altering the biophysical properties of the lung's lining fluid are formulations containing certain charge concentrations and mobility, and thus liquid conductivity.
  • the formulations include aqueous solutions or suspensions that are conductive (also referred to herein as the "conductive formulation(s)").
  • Suitable conductive formulations typically have conductivity values of greater than 5,000 ⁇ S/cm, preferably greater than 10,000 ⁇ S/cm, and more preferably greater than 20,000 ⁇ S/cm. These formulations are particularly useful when administered to a patient to suppress particle exhalation.
  • Solution conductivity is a product of the ionic strength, concentration, and mobility (the latter two contribute to the conductivity of the formulation as a whole).
  • any form of the ionic components can be used. These conductive materials may alter the mucosal lining properties by acting, for example, as a cross-linking agent within the mucus.
  • the ionic components in the formulations described herein may interact with the strongly linked anionic glycoproteins within normal tracheobronchial mucus. These interactions may influence the state of the air/liquid surface of the airway lining fluid and transiently the nature of the physical entanglements due to covalent and noncovalent interactions, including hydrogen bonding, hydrophobic, and electrostatic interactions (Dawson, M., Wirtz, D., Hanes, J. (2003) The Journal of Biological Chemistry. Vol. 278, No. 50, pp. 50393- 50401).
  • the formulation includes mucoactive or mucolytic agents, such as MUC5AC and MUC5B mucins, DNA, N-acetylcysteine (NAC), cysteine, nacystelyn, dornase alfa, gelsolin, heparin, heparin sulfate, P2Y2 agonists (e.g. UTP, INS365), and nedocromil sodium.
  • mucoactive or mucolytic agents such as MUC5AC and MUC5B mucins, DNA, N-acetylcysteine (NAC), cysteine, nacystelyn, dornase alfa, gelsolin, heparin, heparin sulfate, P2Y2 agonists (e.g. UTP, INS365), and nedocromil sodium.
  • mucoactive or mucolytic agents such as MUC5AC and MUC5B mucins, DNA, N-acet
  • the formulations contain substances that are easily ionized in an aqueous or organic solvent environment (also referred to herein as "conductive agents"), such as salts, ionic surfactants, charged amino acids, charged proteins or peptides, or charged materials (cationic, anionic, or zwitterionic).
  • conductive agents such as salts, ionic surfactants, charged amino acids, charged proteins or peptides, or charged materials (cationic, anionic, or zwitterionic).
  • Suitable salts include any salt form of the elements sodium, potassium, magnesium, calcium, aluminum, silicon, scandium, titanium, vanadium, chromium, cobalt, nickel, copper, manganese, zinc, tin, and similar elements.
  • Examples include sodium chloride, sodium acetate, sodium bicarbonate, sodium carbonate, sodium sulfate, sodium stearate, sodium ascorbate, sodium benzoate, sodium biphosphate, sodium phosphate, sodium bisulfite, sodium citrate, sodium borate, sodium gluconate, calcium chloride, calcium carbonate, calcium acetate, calcium phosphate, calcium alginite, calcium stearate, calcium sorbate, calcium sulfate, calcium gluconate, magnesium carbonate, magnesium sulfate, magnesium stearate, magnesium trisilicate, potassium bicarbonate, potassium chloride, potassium citrate, potassium borate, potassium bisulfite, potassium biphosphate, potassium alginate, potassium benzoate, magnesium chloride, cupric sulfate, chromium chloride, stannous chloride, and sodium metasilicate and similar salts.
  • Suitable ionic surfactants include sodium dodecyl sulfate (SDS) (also known as sodium lauryl sulfate (SLS)), magnesium lauryl sulfate, Polysorbate 20, Polysorbate 80, and similar surfactants.
  • SDS sodium dodecyl sulfate
  • Suitable charged amino acids include L-Lysine, L-Arginine, Histidine, Aspartate, Glutamate, Glycine, Cysteine, Tyrosine.
  • Suitable charge proteins or peptides include proteins and peptides containing the charged amino acids, Calmodulin (CaM), and Troponin C.
  • Charged phospholipids such as 1 ,2-dioleoyl-sn- glycero-3-ethylphosphocholine triflate (EDOPC) and alkyl phosphocholine trimesters, can be used.
  • the preferred formulations are formulations containing salts, such as saline (0.15 M NaCl or 0.9%) solution, CaCl 2 solution, CaCl 2 in saline solution, or saline solution containing ionic surfactants, such as SDS or SLS.
  • the formulation contains saline solution and CaCl 2 .
  • Suitable concentration ranges of the salt or other conductive/charged compounds can vary from about 0.01% to about 20% (weight of conductive or charged compound/total weight of formulation), preferably between 0.1% to about 10% (weight of conductive or charged compound/total weight of formulation), most preferably between 0.1 to 7% (weight of conductive or charged compound/total weight of formulation).
  • Saline solutions have long been delivered chronically to the lungs with small amounts of therapeutically active agents, such as beta agonists, corticosteroids, or antibiotics.
  • therapeutically active agents such as beta agonists, corticosteroids, or antibiotics.
  • beta agonists such as beta agonists, corticosteroids, or antibiotics.
  • VENTOLIN ' Inhalation
  • GSK is an albuterol sulfate solution used in the chronic treatment of asthma and exercise-induced bronchospasm symptoms.
  • a VENTOLIN ® solution for nebulization is prepared (by the patient) by mixing 1.25-2.5nig of albuterol sulfate (in 0.25-0.5mL of aqueous solution) into sterile normal saline to achieve a total volume of 3mL. No adverse effects are thought to be associated with the delivery of saline to the lungs by VENTOLIN nebulization, even though nebulization times can range from 5-15 minutes. Saline is also delivered in more significant amounts to induce expectoration. Often these saline solutions are hypertonic (sodium chloride concentrations greater than 0.9%, often as high as 5%) and generally they are delivered for up to 20 minutes.
  • Osmotically active materials including binary salts, such as sodium chloride, or any other kinds of salts, or sugars, such as mannitol.
  • Osmotically active materials normally owing to their ionization and possibly size, do not easily permeate cell membranes and therefore exert an osmotic pressure on contiguous cells. Such osmotic pressure is essential to the physical environment of cellular material, and regulation of this pressure occurs by cell pumping of water into or out of the cell. Solutions delivered to the lungs that are isotonic normally do not create an imbalance in osmotic pressure in the lung fluid and therefore simply dilute the natural endogenous lung fluid with water and salt. Solutions of high osmotic content (i.e. hypertonic solutions) create an imbalance of osmotic pressure, with greater pressure in the lung fluid, causing cells to pump water into the lung fluid and therefore further dilute lung surfactant composition.
  • binary salts such as sodium chloride
  • sugars such as mannitol.
  • the formulations disclosed herein can be used by any route for delivery of a variety of organic or inorganic molecules, especially small molecule drugs, such as antivirals and antibacterial drugs including antibiotics, antihistamines, bronchodilators, cough suppressants, antiinflammatories, vaccines, adjuvants and expectorants.
  • small molecule drugs such as antivirals and antibacterial drugs including antibiotics, antihistamines, bronchodilators, cough suppressants, antiinflammatories, vaccines, adjuvants and expectorants.
  • macromolecules include proteins and large peptides, polysaccharides and oligosaccharides, and DNA and RNA nucleic acid molecules and their analogs having therapeutic, prophylactic or diagnostic activities.
  • Nucleic acid molecules include genes, antisense molecules that bind to complementary DNA to inhibit transcription, and ribozymes. Preferred agents are antiviral, steroid, bronchodilators, antibiotics, mucus production inhibitors and vaccines.
  • the concentration of the active agent ranges from about 0.01% to about 20% by weight. In a more preferred embodiment, the concentration of active agent ranges from between 0.9% to about 10%.
  • the formulation may be delivered in a solution, a suspension, a spray, a mist, a foam, a gel, a vapor, droplets, particles, or a dry powder form (for example, using a metered dose inhaler including HFA propellant, a metered dose inhaler with non-HFA propellant, a nebulizer, a pressurized can, or a continuous sprayer).
  • Carriers can be divided into those for administration via solutions or suspensions (liquid formulations) and those for administration via particles (dry powder formulations).
  • the formulation is typically in the fo ⁇ n of solution, suspension or dry powder.
  • the formulation is aerosolized.
  • the formulation can be generated via any aerosol generators, such as dry powder inhaler (DPI), nebulizers or pressurized metered dose inhalers (pMDI).
  • DPI dry powder inhaler
  • pMDI pressurized metered dose inhalers
  • aerosol refers to any preparation of a fine mist of particles, typically less than 10 microns in diameter.
  • the preferred mean diameter for aqueous formulation aerosol particles is about 5 microns, for example between 0.1 and 30 microns, more preferably between 0.5 and 20 microns and most preferably between 0.5 and 10 microns.
  • the formulation may be administered as a solid that dissolves following administration to the mouth and/or adheres to the mucosal surface, or a liquid.
  • a preferred aerosol solution for altering physical properties of the lung's lining fluid is isotonic saline.
  • the aerosol can consist just of a solution, such as an aqueous solution, most preferably a saline solution.
  • the aerosol may consist of an aqueous suspension or dry particles.
  • Aerosols for the delivery of therapeutic agents to the respiratory tract have been developed. See, for example, Adjei, A. and Garren, J. P harm. Res., 7: 565-569 (1990); and Zanen, P. and Lamm, J.-W. J Int. J. Pharm., 114: 111-115 (1995). These are typically formed by atomizing a liquid formulation, such as a solution or suspension, under pressure through a nebulizer or through the use of a metered dose inhaler ("MDI"). In the preferred embodiment, the liquid formulations are aqueous solutions or suspensions. 3. Dry Powder Formulations
  • the geometry of the ainvays is a major barrier for drug dispersal within the lungs.
  • the lungs are designed to entrap particles of foreign matter that are breathed in, such as dust.
  • Impaction occurs when particles are unable to stay within the air stream, particularly at airway branches. They are adsorbed onto the mucus layer covering bronchial walls and cleaned out by mucocilliary action. Impaction mostly occurs with particles over 5 ⁇ m in diameter.
  • Smaller particles ⁇ 5 ⁇ m can stay within the air stream and be transported deep into the lungs. Sedimentation often occurs in the lower respiratory system where airflow is slower. Very small particles ( ⁇ 0.6 ⁇ m) can deposit by Brownian motion. This regime is undesirable because deposition cannot be targeted to the alveoli (N. Worakul & J.R.
  • the preferred mean diameter for aerodynamically light particles for inhalation is at least about 5 microns, for example between about 5 and 30 microns, most preferably between 3 and 7 microns in diameter.
  • the particles may be fabricated with the appropriate material, surface roughness, diameter and tap density for localized delivery to selected regions of the respiratory tract such as the deep lung or upper airways. For example, higher density or larger particles may be used for upper airway delivery.
  • a mixture of different sized particles, provided with the same or different therapeutic agent may be administered to target different regions of the lung in one administration.
  • the phrase "aerodynamically light particles” refers to particles having a mean or tap density less than about 0.4 g/cm 3 .
  • the tap density of particles of a dry powder may be obtained by the standard USP tap density measurement. Tap density is a standard measure of the envelope mass density.
  • the envelope mass density of an isotropic particle is defined as the mass of the particle divided by the minimum sphere envelope volume in which it can be enclosed. Additional features contributing to low tap density include irregular surface texture and porous structure.
  • Dry powder formulations with large particle size have improved flowability characteristics, such as less aggregation (Visser, J., Powder Technology 58: 1-10 (1989)), easier aerosolization, and potentially less phagocytosis. Rudt, S. and R. H. Muller, J. Controlled Release, 22: 263- 272 (1992); Tabata, Y., and Y. Ikada, J. Biomed. Mater. Res., 22: 837-858 (1988). Dry powder aerosols for inhalation therapy are generally produced with mean diameters primarily in the range of less than 5 microns, although a preferred range is between one and ten microns in aerodynamic diameter. Ganderton, D., J.
  • Particles can contain conductive agent(s), alone, or in combination with drug, antiviral, antibacterial, antimicrobial, surfactant, proteins, peptides, polymer, or combinations thereof.
  • Representative surfactants include L- ⁇ . -phosphatidylcholine dipalmitoyl ("DPPC"), diphosphatidyl glycerol (DPPG), l,2-Dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS), 1 5 2-Dipalmitoyl-sn-glycero-3-phosphocholine (DSPC), 1 ,2-Distearoyl-sn- glycero-3-phosphoethanolamine (DSPE), l-palmitoyl-2- oleoylphosphatidylcholine (POPC), fatty alcohols, polyoxyethylene-9-lauryl ether, surface active fatty acids, sorbitan trioleate (Span 85), glycocholate, surfactin, poloxomers,
  • Polymers may be tailored to optimize particle characteristics including: i) interactions between the agent to be delivered and the polymer to provide stabilization of the agent and retention of activity upon delivery; ii) rate of polymer degradation and thus drug release profile; iii) surface characteristics and targeting capabilities via chemical modification; and iv) particle porosity.
  • Polymeric particles may be prepared using single and double emulsion, solvent evaporation, spray drying, solvent extraction, phase separation, simple and complex coacervation, interfacial polymerization, and other methods well known to those of ordinary skill in the art. Particles may be made using methods for making microspheres or microcapsules known in the art.
  • the preferred methods of manufacture are by spray drying and freeze drying, which entails using a solution containing the conductive/charged materials, spraying the solution onto a substrate to form droplets of the desired size, and removing the solvent.
  • the conductive formulation contains a suitable conductivity for increasing the viscoelasticity of the mucosal membrane at the site of administration of the formulation to suppress or reduce the formation of bioaerosol particles formation during breathing, coughing, sneezing, and/or talking.
  • the formulation is administered to one or more individuals in an effective amount to reduce particle production.
  • the formulation is administered to a person prior to entry in a cleanroom or while a person is working in a cleanroom to ensure that the cleanroom standards are maintained. If animals or humans have been identified as having an enhanced propensity to exhale aerosols (i.e.
  • the formulation may be administered to reduce particle production, to prevent or reduce spread of infections, or to prevent or reduce uptake of pathogens by the human or animal.
  • the respiratory tract is the structure involved in the exchange of gases between the atmosphere and the blood stream.
  • the lungs are branching structures ultimately ending with the alveoli where the exchange of gases occurs.
  • the alveolar surface area is the largest in the respiratory system and is where drug absorption occurs.
  • the alveoli are covered by a thin epithelium without cilia or a mucus blanket and secrete surfactant phospholipids. J.S. Patton & R.M. Platz. 1992. Adv. Drug Del. Rev. 8:179- 196
  • the respiratory tract encompasses the upper airways, including the oropharynx and larynx, followed by the lower airways, which include the trachea followed by bifurcations into the bronchi and bronchioli.
  • the upper and lower airways are called the conducting airways.
  • the terminal bronchioli then divide into respiratory bronchioli which lead to the ultimate respiratory zone, the alveoli or deep lung.
  • the deep lung, or alveoli is the primary target of inhaled therapeutic aerosols for systemic drug delivery.
  • the formulations are typically administered to an individual to deliver an effective amount to alter physical properties such as surface tension and viscosity of endogenous fluid in the upper airways, thereby enhancing delivery to the lungs and/or suppressing coughing and/or improving clearance from the lungs.
  • Effectiveness can be measured using a diagnostic device as described herein. For example, saline can be administered in a volume of 1 gram to a normal adult. Exhalation of particles is then measured. Delivery is then optimized to minimize dose and particle number.
  • Formulations can be administered using a metered dose inhaler ("MDI"), a nebulizer, an aerosolizer, or using a dry powder inhaler. Suitable devices are commercially available and described in the literature.
  • Aerosol dosage, formulations and delivery systems may be selected for a particular therapeutic application, as described, for example, in Gonda, I. "Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract," in Critical Reviews in Therapeutic Drug Carrier Systems, 6:273-313, 1990; and in Moren, "Aerosol dosage forms and formulations,” in: Aerosols in Medicine, Principles, Diagnosis and Therapy, Moren, et al., Eds. Esevier, Amsterdam, 1985.
  • Delivery is achieved by one of several methods, for example, using a metered dose inhaler including HFA propellant, a metered dose inhaler with non-HFA propellant, a nebulizer, a pressurized can, or a continuous sprayer.
  • a metered dose inhaler including HFA propellant, a metered dose inhaler with non-HFA propellant, a nebulizer, a pressurized can, or a continuous sprayer.
  • the patient can mix a dried powder of pre-suspended therapeutic with solvent and then nebulize it. It may be more appropriate to use a pre-nebulized solution, regulating the dosage administered and avoiding possible loss of suspension. After nebulization, it may be possible to pressurize the aerosol and have it administered through a metered dose inhaler (MDI).
  • MDI metered dose inhaler
  • Nebulizers create a fine mist from a solution or suspension, which is inhaled by the patient.
  • An MDI typically includes a pressurized canister having a meter valve, wherein the canister is filled with the solution or suspension and a propellant.
  • the solvent itself may function as the propellant, or the composition may be combined with a propellant, such as FREON® (E. I. Du Pont De Nemours and Co. Corp.).
  • FREON® E. I. Du Pont De Nemours and Co. Corp.
  • the composition is a fine mist when released from the canister due to the release in pressure.
  • the propellant and solvent may wholly or partially evaporate due to the decrease in pressure.
  • the formulation is in the form of salt or osmotically active material particles which are dispersed on or in an inert substrate, which is placed over the nose and/or mouth and the formulation particles inhaled.
  • the inert substrate is preferably a biodegradable or disposable woven or non-woven fabric and more preferably the fabric is formed of a cellulosic-type material.
  • tissues currently sold which contain lotion to minimize irritation following frequent use.
  • These formulations can be packaged and sold individually or in packages similar to tissue or baby wipe packages, which are easily adapted for use with a liquid solution or suspension.
  • the formulation is administered to one or more individuals using a device which provides an aerosol that sprays a fine mist of the formulation into the pulmonary and/or nasal region of an individual, thereby decreasing the output of particles.
  • the formulation may be administered to humans or animals by creating an aqueous environment in which the humans and animals move or remain for sufficient periods of time to sufficiently hydrate the lungs. This atmosphere might be created by use of a nebulizer or even a humidifier. Preferably the nebulizer or humidifier administers a conductive formulation. Individuals may be treated prior to entering, and/or after entering, a cleanroom. IV. Methods of using the Diagnostic Device
  • the user places his lips around the mouthpiece (12).
  • the user seals his airways off from the ambient air preferably via a nose clip and by sealing his lips to a mouthpiece.
  • a mask is used as the mouthpiece, the user places the mask over Ms mouth and/or nose.
  • nose prongs are used as the mouthpiece, the user places the nose prongs in his nose.
  • the mouthpiece is in the form of a mask, the user places the mask over his nose and/or mouth, and thereby seals off his airways from the ambient air. Then the user inhales.
  • Inspired air enters the system through the filter (14) which removes particles in the predetermined measured range.
  • Exhaled air passes through the low resistance one-way valve (16) and into the particle counter (20).
  • the one-way valve (16) helps to prevent the transmission of exhaled pathogens from one user to the next.
  • the expired air travels to the particle counter (20), which measures the number of particles and size of particles.
  • the particle counter (20) samples at a fixed flow rate preferably greater than the peak exhaled flow rate so that at all points in time the mean flow direction through the filter (14) is into the system, preventing the loss of exhaled particles into the filter (14).
  • the particle counter samples at flow rates greater than 28 L/min.
  • the particle counter (20) then provides the data from the particle counter (20) to the computer (30).
  • the user is provided with a visual feedback of his breathing pattern and cues to maintain a prescribed breathing pattern, for example tidal breathing.
  • the particle counter (20) can be controlled either remotely from a PC or locally such as from a touch screen interface with data measurement and analysis performed locally at the optical particle counter or remotely at a personal computer.
  • a controller (not shown in figure) for the generation and control of the sample flow rate may be internal or external to the optical particle counter.
  • the inhalation, exhalation, and measurement steps may be repeated multiple times.
  • the computer calculates the mean particle size, the average particle distribution, and mean rate of particle production. If it is necessary to decrease the number and size of particles exhaled by the user, a formulation for decreasing particle exhalation as described herein, is administered to the user.
  • the diagnostic instrument (10) is designed to measure particles produced and exhaled by a person with associated breathing rate.
  • the inspired air enters the system through a low flow resistance flow meter (22) which characterizes the breathing pattern of the user and the particle counter flow rate together. Air then enters the filter (14) which removes particles in the measured range. Exhaled air passes through a low resistance one way valve (16), through the tube (18) and into the particle counter (20), as described above.
  • the data from the flow meter, differential pressure transducer, and or signal conditioner is sent to the computer for calculation and analysis.
  • a formulation may be administered to the user in an effective amount to reduce particle production.
  • the formulation may be administered prior to entry or following entry into a cleanroom.
  • Example 1 In Vitro Simulation A simulated cough machine system was designed similar to that described by King Am. J. Respir. Crit. Care Med. 156(1): 173-7 (1997).
  • An air-tight 6.25-liter Plexiglas tank equipped with a digital pressure gauge and pressure relief valve was constructed to serve as the capacitance function of the lungs.
  • a compressed air cylinder with regulator and air filter was connected to the inlet.
  • an Asco two-way normally-closed solenoid valve (8210G94) with a sufficient Cv flow factor was connected for gas release.
  • the solenoid valve was wired using a typical 120V, 60Hz light switch. Connected to the outflow of the solenoid valve was a Fleisch no.
  • Locust bean gum (LBG) (Fluka BioChemika) solutions were crosslinked with sodium tetraborate (Na 2 B 4 O 7 ) (J.T.Baker).
  • LBG at 2% wt/vol was dissolved in boiling Milli-Q distilled water.
  • a concentrated sodium tetraborate solution was prepared in Milli-Q distilled water.
  • small amounts of sodium tetraborate solution were added and the mixture was slowly rotated for 1 minute.
  • the still watery mucus simulant was then pipetted onto the model trachea creating simulant depth based on simple trough geometry. Mucus simulant layers were allowed 30 minutes to crosslink prior to initiation of "cough" experiments.
  • Nebulized solutions were delivered to the mucus simulant via a PARI LC Jet nebulizer and Proneb Ultra compressor.
  • Formulations included normal isotonic 0.9% saline (VWR) and 100 mg/mL of synthetic phospholipids 1 ,2-Dipalmitoyl-sn-glycero-3-phosphocholine/l -Palmitoyl-2- oleoyl-sn-glycero-3-phosphoglycerol (DPPC/POPG) (Genzyme) 7/3 wt% suspended in isotonic saline.
  • VWR normal isotonic 0.9% saline
  • DPPC/POPG synthetic phospholipids 1 ,2-Dipalmitoyl-sn-glycero-3-phosphocholine/l -Palmitoyl-2- oleoyl-sn-glycero-3-phosphoglycerol
  • a Sympatec HELOS/KF laser diffraction particle sizer was used to size the created mucus simulant bioaerosols.
  • the Fraunhoffer method for sizing diffracted particles was used.
  • the HELOS was equipped with an R2 submicron window module enabling a measuring range of 0.25-87.5 ⁇ m.
  • the end of the model trachea was adjusted to be no more than 3 cms from the laser beam.
  • the bottom of the model trachea was aligned with the 2.2 mm laser beam using support jacks and levels. Dispersed bioaerosols were collected after passing through the diffraction beam using a vacuum connected to an inertial cyclone followed by a HEPA filter.
  • Bioaerosol particle concentration following three coughs was measured over time ( Figures 3 A, 3B and 3C) in the case of an undisturbed mucus simulant, and in the cases of saline delivery ( Figures 3 A, 3B and 3C) and surfactant delivery (not shown).
  • bioaerosol particle size remains constant over time with a median size of about 400 nanometers.
  • Example 2 Reduction of Exhaled Aerosol Particles in Human Study A proof of concept study of exhaled aerosol particle production was performed using 12 healthy subjects. The objectives of the study were (1) to determine the nature of exhaled bioaerosol particles (size distribution and number); (2) to validate the utility of a device that is sensitive enough to accurately count the exhaled particles; (3) to assess the baseline count of particles exhaled from the healthy lung; and (4) to measure the effect of two exogenously administered treatment aerosols on exhaled particle count suppression. Experiments were performed with different particle detectors to determine average particles per liter and average particle size for healthy human subjects. Following the inspiration of particle-free air, healthy subjects breathe out as little as 1-5 particles per liter, with an average size of 200-400 nm in diameter.
  • Exclusion criteria were presence or a history of significant pulmonary disease (e.g. asthma, COPD, cystic fibrosis), cardiovascular disease, acute or chronic infection of the respiratory tract, and pregnant or lactating females.
  • pulmonary disease e.g. asthma, COPD, cystic fibrosis
  • cardiovascular disease e.g. chronic pulmonary disease
  • acute or chronic infection of the respiratory tract e.g. asthma, COPD, cystic fibrosis
  • FIG 4A shows substantial inter-subject variability.
  • the data shown are measurements made prior to administration of one of the test aerosols. This baseline expired particle result points to the existence of "super producers'" of exhaled aerosols. In this study "super-producers" were defined as subjects exhaling more than 1 ,000 particles/liter at baseline measurement.
  • Figure 4B shows the individual particle counts for subjects receiving Formulation 1. The data indicate that a simple formulation of exogenously applied aerosol can suppress exhaled particle counts.
  • Figure 5 A shows the effect of prototype formulation 1 on the two "super-producers" found at baseline in this group. These data indicate that the prototype formulation may exert a more pronounced effect on super- producers.
  • Figure 5B summarizes the percent change (versus baseline) of the cumulative exhaled particle counts for the "super-producers" identified in the two treatment groups.
  • the exposure matrix for the animals included in the study is found in Table 3.
  • the dosing occurred over a 57 day period, with at least a 7 day interval between dosages.
  • Each animal (n 7) received each dose at least once during the duration of dosing, with the exception of the omission of one 6.0 minute dose (see animal no. 1736) and one 12.0 minute dose (see animal no. 1735). These two were excluded due to unexpected problems with the ventilator and/or anesthesia equipment.
  • Figure 6A show the particle count over time for each animal after it received a sham dosage. Each timepoint typically represents the mean of at least three particle count determinations.
  • the data in Figure 6A shows that certain individual animals inherently produce more particles than others ("superspreaders"). Additionally, the data show that throughout the assessment period, quiescently breathing anesthetized animals maintain a relatively stable exhaled particle output (see e.g. Animal nos. 1731, 1735, 1738, 1739, and 1741).
  • Figure 6B represents the mean percent change in exhaled particle counts over time following each treatment. Each data point represents the mean of six to seven measurements from the treatment group. AU animals had returned to baseline by 180 minutes post treatment.
  • Example 4 Reduction of Exhaled Aerosol Particles in Human Study
  • particle counts were measured using a device similar to that illustrated in Figure 2 prior and subsequent to treatment with a formulation for reducing the number of exhaled particles.
  • Treatment involved a six minute inhalation from a Pari LC+ jet nebulizer of a formulation containing 1.29% CaCl 2 by weight in 0.9% NaCl solution.
  • Exhaled particles were measured prior to treatment and at timepoints 10 minutes, 1, 2, 4, and 6 hours after treatment completion.
  • Total count rate of particles greater than 0.3 ⁇ m in diameter during a 3 minute test immediately following a 2 minute washout of ambient particles from the lungs was measured using a device similar to that illustrated in figure 2.
  • the device contained a Climet CI-500B optical particle counter. This device accurately measured particles in the range of 300-2500 nm. A series of filters eliminated all background particle noise.
  • Figure 7 shows the effect of the inhaled treatment on the count rate of particles greater than 0.3 ⁇ m particles produced.
  • the mean count rate was seen to decrease from the baseline count rate prior to treatment for all timepoints up to 6 hours after treatment.
  • Example 5 Characterization of Exhaled Aerosol Particles in Human Study
  • particle size distribution and number of particles produced during tidal breathing were measured in 580 adults and in 97 children using a measurement system similar to that illustrated in Figure 2.
  • the measurement system included a Fleisch pneumotachometer (model no. 1, Phipps and Bird, Richmond VA) for measuring the patient flow rate during the test and an optical particle counter (Climet Model CI-500B, Climet Instruments Company, Redlands, CA) for measuring particle counts and size distribution over the range of 0.3-25 ⁇ m. Following a 2 minute washout period of breathing particle free air, the particle count rate was measured during a 3 minute test interval.

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Abstract

L'invention concerne des procédés et des dispositifs qui permettent de déterminer le taux de production des particules et la distribution granulométrique des particules produites chez un sujet. Ce dispositif (10) comprend un embout buccal (12), un filtre (14), un clapet de non-retour à faible résolution (16), un compteur de particules (20) et un ordinateur (30). Ce dispositif peut éventuellement comprendre un débitmètre de gaz (22). Les données obtenues au moyen de ce dispositif peuvent servir à déterminer si une formulation de réduction de l'exhalation de particules doit être administrée à l'individu. Ce dispositif est particulièrement utilisé avant et/ou après l'entrée en salle blanche pour respecter les normes de salle blanche. Ce dispositif peut également servir à identifier les animaux et les humains qui ont tendance à exhaler beaucoup d'aérosols (appelés ici surproducteurs, ou superproducteurs, ou superpropagateurs). L'invention concerne en outre des formulations de réduction de la production de particules. La formulation est administrée en quantité suffisante pour modifier les propriétés biophysiques des muqueuses. Après application sur les fluides des muqueuses, la formulation modifie les propriétés physiques telles que les caractéristiques de gel dans l'interface air/liquide, l'élasticité de surface, la viscosité de surface, la tension de surface et la viscosité massive des muqueuses. La formulation est administrée en quantité suffisante pour réduire au minimum la contamination ambiante due à la formation de particules en cas de respiration, de toux, d'éternuement, de parole, ce qui constitue un point très important dans des applications dans des salles blanche. Dans un premier mode de réalisation, la formulation à administrer est une solution non tensioactive. Dans un autre mode de réalisation, les formulations sont conductrices et contiennent des agents conducteurs, tels que sels, tensioactifs ioniques, ou autres substances ionisées ou facilement ionisées dans un environnement solvant aqueux ou organique. De préférence, la formulation est administrée sous forme d'aérosol.
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Cited By (11)

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Publication number Priority date Publication date Assignee Title
US8627821B2 (en) 2005-01-10 2014-01-14 Pulmatrix, Inc. Method and device for decreasing contamination
WO2009045163A1 (fr) * 2007-10-02 2009-04-09 Anna-Carin Olin Récupération et mesure de particules exhalées
JP2010540959A (ja) * 2007-10-02 2010-12-24 オリン，アナ−キャリン 呼気粒子の捕集及び測定
US9976944B2 (en) 2007-10-02 2018-05-22 Pexa Ab Collection and measurement of exhaled particles
US10568541B2 (en) 2008-12-01 2020-02-25 TricornTech Taiwan Breath analysis systems and methods for asthma, tuberculosis and lung cancer diagnostics and disease management
US11690528B2 (en) 2008-12-01 2023-07-04 TricornTech Taiwan Breath analysis system and methods for asthma, tuberculosis and lung cancer diagnostics and disease management
EP2709442A2 (fr) * 2011-05-19 2014-03-26 C-Lock Inc. Vaccin et applications relevant du domaine de la santé pour système de surveillance de la respiration des ruminants
EP2709442A4 (fr) * 2011-05-19 2014-06-11 Lock Inc C Vaccin et applications relevant du domaine de la santé pour système de surveillance de la respiration des ruminants
EP2811902A1 (fr) * 2012-02-08 2014-12-17 Lundin, Stefan Dispositif et procédé d'analyse non invasive de particules au cours de la ventilation médicale
US11547322B2 (en) 2012-02-08 2023-01-10 Lundin Stefan Device and method for non-invasive analysis of particles during medical ventilation
US10806770B2 (en) 2014-10-31 2020-10-20 Monash University Powder formulation

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