WO2007120644A2 - Diagnostic device for determining particle production - Google Patents
Diagnostic device for determining particle production Download PDFInfo
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- WO2007120644A2 WO2007120644A2 PCT/US2007/008815 US2007008815W WO2007120644A2 WO 2007120644 A2 WO2007120644 A2 WO 2007120644A2 US 2007008815 W US2007008815 W US 2007008815W WO 2007120644 A2 WO2007120644 A2 WO 2007120644A2
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- WIPO (PCT)
- Prior art keywords
- particle
- mouthpiece
- filter
- particles
- computer
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Classifications
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- 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
- G01N15/06—Investigating concentration of particle suspensions
-
- 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
Definitions
- the present invention is in the field of devices and methods to measure and decrease particle exhalation and contamination in various environments, and is particularly useful in cleanrooms.
- 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.
- the 209E is a document that establishes standard classes of air cleanliness for airborne particulate levels in cleanrooms and clean zones.
- Class 2 is equivalent to 209 Class 10.
- 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 air 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
- 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
- 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.
- 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 2.
- People Skin flakes and oil; Cosmetics and perfume; Spittle; Clothing debris (lint, fibers etc.); Hair
- 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.
- 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. Gloves, face masks and head covers are standard in nearly every cleanroom environment. Smocks are being used more and more. Jump suits are required in very clean environments. Care must be taken when selecting and using commodity items in cleanrooms. Wipers, cleanroom paper and pencils and other supplies that service the cleanroom should be carefully screened and selected. Review of the local cleanroom requirements for approving and taking these items into the cleanroom is essential. In fact, many cleanroom managers will have approval lists of these types of items.
- 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 cleanroorn 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”).
- the invention provides a diagnostic device comprising a disposable kit (50) and a main housing (60).
- the disposable kit (50) can be functionally connected to the main housing (60) to provide for airflow between an individual and the main housing (60).
- the disposable kit (50) is connected to the main housing (60) with one or more connecting tubes (7OA and 70B) exterior to the main housing (60).
- the disposable kit (50) comprises a mouthpiece (12), a filter (14), a connector (18), and a one-way valve (16).
- the components of the disposable kit (50) are optionally formed from biodegradable materials.
- the mouthpiece (12) of the disposable kit allows for creation of a sealed passage between the airway of an individual and the diagnostic device.
- the mouthpiece (12) can be made of a flexible material (e.g., rubber and/or plastic) for purpose of creating a firm seal.
- the filter (14) of the disposable kit (50) is typically a high-efficiency, low pressure drop filter, optionally with a bacterial/viral removal efficiency of greater than 99.99%.
- the main housing (60) of the diagnostic device comprises a particle counter (20), and optionally comprises a computer (30), gas flow meter (22), display (64), and/or vacuum pump (62).
- the invention provides a diagnostic device for measuring particle exhalation in an individual, comprising a disposable kit and a main housing, the disposable kit comprising a mouthpiece, a two-way filter, and a low resistance one-way valve; the main housing comprising a particle counter and a computer, and wherein the mouthpiece has an outlet connected to the filter and to the one-way valve, the filter exposed to the ambient environment at one end and connected to the mouthpiece at the other end, and the disposable kit connected to the main housing via two connecting tubes.
- the filter is capable of removing particles having a size greater than or equal to 0.1 microns in diameter.
- the mouthpiece is a mouthpiece designed for a user to place his lips around, nasal prongs, a mask that is capable of covering a user's mouth and nose, or a mask that is capable of covering a user's nose.
- the mouthpiece may comprise a curved flange and two protrusions, wherein the mouthpiece is designed for a user to place the flange between his lips and teeth to form a seal when the user bites down on the protrusions.
- the filter may be a combination of two or more filters
- the particle counter may be an electrical mobility particle counter, an impaction particle counter, an electrostatic impaction particle counter, an infrared spectroscopy particle counter, a laser diffraction particle counter, a light scattering particle counter, or an optical particle counter.
- the particle counter is preferrably connected to the computer in a manner that allows control commands to be sent from the computer to the particle counter.
- the computer can be a microprocessor internal or external to the particle counter.
- the device further may comprise a gas flow meter connected to the filter and located between the filter and the ambient environment, prefrrably a Fleisch-type or Lilly-type pneumotachometer.
- the gas flow meter can operate by measuring the differential pressure across or the bypass flow rate through a bypass around a laminar flow element, or the device may further comprise a differential pressure transducer that is capable of measuring the pressure drop across the flow meter, and a signal conditioner connected to the differential pressure transducer and capable of amplifying the signal and sending the signal to the computer.
- the invention provides a method for using such a diagnostic device to measure the rate and size of particle exhalation in an individual by placing the mouthpiece in or over the individual's mouth or nose, inhaling air through the mouthpiece, wherein the air is pulled through the filter prior to inhalation, exhaling through the mouthpiece and into the one-way valve, measuring the number of particles and size of particles using the particle counter, and providing the data from the particle counter to the computer.
- the air is pulled through the gas flow meter during inhalation prior to being pulled through the filter.
- Data may be provided from the signal conditioner to the computer prior to exhalation through the mouthpiece.
- the steps of inhaling, exhaling, measuring, and providing data are often repeated multiple times and the mean particle size, average particle distribution, and mean rate of particle production are calculated.
- the method further can comprise inhaling a formulation that, when administered to the mucosal lining of a human or other animal, alters the surface viscoelastic properties of the mucosal lining, surface tension of the mucosal lining, or bulk viscosity of the mucosal lining, and then repeating the steps of placing the mouthpiece over the individual's mouth or nose, inhaling air through the mouthpiece, exhaling through the mouthpiece, measuring number and size of particles using the particle counter, providing the data from the particle counter to the computer, and calculating mean particle size, average particle distribution, and mean rate of particle production.
- 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.
- FIGs 3 A and 3B are illustrations of the preferred embodiment of the diagnostic instrument.
- the lid is transparent.
- the lid has been removed.
- Figures 4A and 4B are illustrations of a preferred embodiment of the disposable kit.
- Figure 4A is a space-filled illustration.
- Figure 4B is a side-view
- Figures 5A and 5B are illustrations of a preferred embodiment of the mouthpiece.
- Figure 5A is a front elevational view.
- Figure 5B is a side view.
- Figures 6A and 6B are illustrations of a preferred embodiment of the components attached to the bottom of the main housing.
- Figure 6 A is a space-filed view.
- Figure 6B is a top view.
- Figures 7 A and 7B are illustrations of a preferred embodiment of the lid of the main housing.
- Figure 7 A is a view of the outside of the lid.
- Figure 7B is a side view.
- Figures 8A, 8B, and 8C are illustrations of a preferred embodiment of the flow meter.
- Figure 8A is a space-filed view.
- Figures 8B and 8C are a side views.
- Figure 12A is a graph of total particles exhaled (greater than 0.3 microns) over time (minutes) showing data obtained from sham treated animals.
- Figure 12B 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 (- ⁇ -), and sham (- ⁇ -).
- Figure 13 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).
- 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 1-3.
- the device (10) contains at least two main components: (1) a disposable kit (50) and a main housing (60).
- the disposable kit (50) is connected to the main housing (60) with one or more connecting tubes (7OA and 70B) exterior to the main housing.
- the instrument (10) is portable and, optionally, operates on batteries.
- the disposable kit (50) is illustrated in Figures 4A and 4B.
- the disposable kit contains: a mouthpiece (12), a filter (14), a connector (18), and a one-way valve (16).
- the mouthpiece (12), filter (14), connector (18), and oneway valve (16) are all disposable.
- the mouthpiece (12), filter (14), connector (18), and/or one-way valve (16) are formed from biodegradable materials.
- 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) oris attached directly to one end of the connector (18).
- the disposable kit is attached to the main housing (60) using one or more connecting tubes. In the embodiment illustrated by figure 3, two connecting tubes are used (7OA and 70B).
- Mouthpiece Any suitable mouthpiece may be used. A preferred mouthpiece is illustrated in figures 4 A, 4B, 5 A, and 5B.
- the preferred mouthpiece is made of a flexible material, such as plastic, rubber, silicon (e.g., silicone rubber, polyvinyl chloride or thermoplastic rubber) or similar flexible material, and has a curved flange (40).
- a flexible material such as plastic, rubber, silicon (e.g., silicone rubber, polyvinyl chloride or thermoplastic rubber) or similar flexible material
- the curved flange (40) is placed between the user's lips and teeth to form a seal.
- the mouthpiece (12) has at least 2 protrusions (42 A and 42 B) attached to the each of the opposite sides of the curved flange (40) and designed to fit between the user's top and bottom teeth to hold the mouthpiece in place when in use.
- the protrusions (42 A and 42B) also function to set a gap between the top and bottom rows of teeth, ensuring that the user's mouth remains open throughout the use of the diagnostic device. It is preferred that the thickness of the protrusions is greater than 4 mm, most preferably between 6 and 15 mm.
- the curved flange (40) contains an opening (43) in the center of the flange. The flange is connected to a tube (44) through the opening (43). The opening (43) is located at the end (45) of the tube (44) proximal to the flange (40).
- the mouthpiece outlet (13) is located at the end (47) of the tube (44) that is distal to the flange (40).
- 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 formed between the user's nostrils and the prongs.
- the mouthpiece may also be in the form of a mask, which covers the user's mouth and nose, with a seal 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. ii.
- 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 (12) 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 instrument contains two filters in series.
- the first filter (14) is external to the main housing and is part of the disposable kit (50).
- the second filter is internal to the main housing.
- FIGs 6A, 6B, 7A, and 7B A preferred embodiment of the main housing (60) is illustrated in Figures 6A, 6B, 7A, and 7B.
- the main housing (60) contains a particle counter (20), a computer (30) and a vacuum pump (62), and a display (64).
- the particle counter (20) and the vacuum pump (62) are attached to the bottom (68) of the main housing (60).
- the computer (30) is attached to the lid (66) of the main housing (60); and the display (64) is on the outside face of the lid (66).
- 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 particle counter (20) is connected to vacuum pump (62).
- the main housing contains the particle counter (20), but the computer (30), display (64) and/or vacuum pump (62) are exterior to the main housing.
- 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 impactor or Next generation pharmaceutical impactor (Copley Scientific, Nottingham UK), Electrical low pressure impactor (ELPI) (Dekati, Tampere Finland) and Helos (Sympatec, Clausthal, Germany).
- SMPS Scanning Mobility Particle Sizer
- ELPI Electrical low pressure impactor
- Helos Sympatec, Clausthal, Germany
- 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 normally has a range of at least 0.3 to 5 ⁇ m and preferably from 0.1 to 25 ⁇ m, and differentiates its measurement range into at least 2 channels and preferably at least 4 channels.
- the optical particle carrier can operate 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 (62) and flow regulator components.
- 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 computer includes a display which may be physically separated from the central processing and data storage units and more preferably the display incorporates touch screen capabilities.
- the main housing (60) contains the particle counter (20) and the computer (30 ui. Flow Meter
- the device (10) may contain 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 may then be 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 mmHaO.
- 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).
- One differential pressure transducer (24) useful in the invention is a Validyne DP45-14 differential pressure transducer. If this is used, the preferred signal conditioner (26) is a Validyne CDl 5 sine wave carrier demodulator.
- the pneumotachometer may be used in lung function analysis, or during artificial ventilation of the lungs.
- the preferred flow meter contains a by-pass tube (82, a low flow rate flow meter (84), and a laminar flow element (86).
- Flow meter (22) is normally a low flow rate mass flow meter measuring the bypass flow around a flow restriction, such as a laminar flow element (86).
- the laminar flow element (86) 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 4-130 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.
- this type of flow meter is the Sensirion model ASF1430.
- the device (10) often includes connections for performing further exhaled breath analysis simultaneously or in series with particle size and count measurements.
- 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).
- 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, for use in certain embodiments of the instant invention, are effective to alter the biophysical properties of the mucosal lining.
- saline solution a saline solution
- aqueous saline solution containing other materials such as osmotically active materials, conductive materials, and/or surfactants.
- Concentration ranges of the salt or other osmotically active material range from about 0.01% to about 10% by weight, preferably between 0.9% to about 10%.
- a preferred aerosol solution for altering physical properties of the mucosal lining is isotonic saline.
- compositions of the invention 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 l ⁇ -dioleoyl-sn-glycero-S-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, CaCU 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).
- VENTOLIN ® Inhalation Solution 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 1.25-2.5mg of albuterol sulfate (in 0.25-0.5mL of aqueous solution) into sterile normal saline to achieve a total volume of 3mL.
- saline 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.
- 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.
- 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, anti-infiammatories, 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%.
- a conductive formulation can be administered that 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 may be 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.
- 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.
- 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 may be 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.
- 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 his 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.
- the user places the curved flange (40) between his lips and teeth to form a seal.
- the user bites down on the two protrusions (42A and 42 B) to hold the mouthpiece in place when in use and to keep his mouth open during use.
- 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). Preferably the particle counter samples at flow rates greater than 28 L/min.
- the particle counter (20) then provides the data 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 (see Figure 7 A, element 64) with data measurement and analysis performed locally at the main housing or remotely at a personal computer.
- a controller for the generation and control of the sample flow rate may be internal or external to the main housing.
- 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, such as described in PCT/US2006/000618, filed January 10, 2006, 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.
- a simulated cough machine system was designed similar to that described by King Am. J. Respir. Crit. Care Med. 156(l):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.
- 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.
- An acrylic model trachea was designed 30 cm long with interior width and height of 1.6 cm.
- the model trachea formed a rectangular shaped tube with a separate top to fit, allowing for easy access to the mucus simulant layer.
- a gasket and C-clamps were used to create an air-tight seal.
- a rectangular cross- section was chosen to enable uniform mucus simulant height and to avoid problems associated with round tubes and gravity drainage.
- the cross-sectional area of the model trachea was also physiologically relevant. The end of the model trachea remained open to the atmosphere.
- 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 l ⁇ -Dipalmitoyl-sn-glycero-S-phosphocholine/l-Palmitoyl-l-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 l ⁇ -Dipalmitoyl-sn-glycero-S-phosphocholine/l-Palmitoyl-l-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. Before each run, the laser was referenced for 5 s to ambient conditions.
- Sympatec WINDOX software was used to create cumulative and density distribution graphs versus log particle size by volume.
- a typical cough profile consisting of a biphasic burst of air, was passed over the 1.5 mm layer of mucus simulant.
- the initial flow or air possessed a flow rate of about 12 L/s for 30-50 ms.
- the second phase lasted 200-500 ms and then rapidly decayed.
- Bioaerosol particle concentration following three coughs was measured over time ( Figures 9 A, 9B and 9C) in the case of an undisturbed mucus simulant, and in the cases of saline delivery ( Figures 9A, 9B and 9C) and surfactant delivery (not shown).
- bioaerosol particle size remains constant over time with a median size of about 400 nanometers.
- 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.
- Inclusion criteria were good health, age 18- 65 years, normal lung function (FEVi predicted > 80%), informed consent and capability to perform the measurements. 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. One individual was not able to complete the entire dosing regimen and therefore was excluded from the data analysis.
- pulmonary disease e.g. asthma, COPD, cystic fibrosis
- cardiovascular disease e.g. asthma, COPD, cystic fibrosis
- acute or chronic infection of the respiratory tract e.g. asthma, COPD, cystic fibrosis
- FIG. 1OA 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 1 IA 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 1 IB summarizes the percent change (versus baseline) of the cumulative exhaled particle counts for the "super-producers" identified in the two treatment groups.
- Results from this study demonstrate that exhaled particles can be accurately measured using a laser-detection system, that these particles are predominantly less than 1 micron in diameter, and that the number of these particles varies substantially from subject to subject.
- "Super-producing" subjects respond most markedly to delivery of an aerosol that modifies the physical properties of the surface of the lining fluid of the lungs. Such super-producers might bear significant responsibility for pathogen shedding and transmission in a population of infected patients.
- 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 12A 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 12A 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 12B 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. The data suggest that the 6.0 minute treatment period provides an adequate dose to prevent the exhalation of particles for at least 150 minutes post-treatment. The other treatments appear to be either too short or too long to provide an effective, lasting suppression of aerosol exhalation.
- Figure 13 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-
Abstract
Description
Claims
Priority Applications (5)
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AU2007238854A AU2007238854A1 (en) | 2006-04-12 | 2007-04-11 | Diagnostic device for determining particle production |
CA002649442A CA2649442A1 (en) | 2006-04-12 | 2007-04-11 | Diagnostic device for determining particle production |
EP07755177A EP2010295A2 (en) | 2006-04-12 | 2007-04-11 | Diagnostic device for determining particle production |
JP2009505428A JP2009533681A (en) | 2006-04-12 | 2007-04-11 | Diagnostic device for measuring particle formation |
US11/827,031 US8627821B2 (en) | 2005-01-10 | 2007-07-10 | Method and device for decreasing contamination |
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US74472906P | 2006-04-12 | 2006-04-12 | |
US60/744,729 | 2006-04-12 |
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PCT/US2006/000618 Continuation-In-Part WO2006076265A2 (en) | 2005-01-10 | 2006-01-10 | Method and device for decreasing contamination |
US11/827,031 Continuation-In-Part US8627821B2 (en) | 2005-01-10 | 2007-07-10 | Method and device for decreasing contamination |
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WO2007120644A2 true WO2007120644A2 (en) | 2007-10-25 |
WO2007120644A3 WO2007120644A3 (en) | 2008-11-13 |
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PCT/US2007/008815 WO2007120644A2 (en) | 2005-01-10 | 2007-04-11 | Diagnostic device for determining particle production |
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EP (1) | EP2010295A2 (en) |
JP (1) | JP2009533681A (en) |
CN (1) | CN101466436A (en) |
AU (1) | AU2007238854A1 (en) |
CA (1) | CA2649442A1 (en) |
WO (1) | WO2007120644A2 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2970858A4 (en) * | 2013-03-12 | 2016-11-16 | Deton Corp | System for breath sample collection and analysis |
US9617582B2 (en) | 2012-09-04 | 2017-04-11 | University Of Maryland College Park | Human exhaled aerosol droplet biomarker system and method |
US9988691B2 (en) | 2010-07-06 | 2018-06-05 | Deton Corp. | System for airborne bacterial sample collection and analysis |
US10502665B2 (en) | 2016-04-18 | 2019-12-10 | University Of Maryland, College Park | Aerosol collection system and method |
US10806770B2 (en) | 2014-10-31 | 2020-10-20 | Monash University | Powder formulation |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2701352A1 (en) * | 2007-10-02 | 2009-04-09 | Ann-Charlotte Almstrand | Collection and measurement of exhaled particles |
SE541748C2 (en) * | 2017-07-10 | 2019-12-10 | Pexa Ab | System for collecting exhaled particles |
WO2020007858A1 (en) * | 2018-07-04 | 2020-01-09 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Device and method for determining an aerosol delivery |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5038792A (en) * | 1988-06-29 | 1991-08-13 | Mault James R | Oxygen consumption meter |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5178155A (en) * | 1988-06-29 | 1993-01-12 | Mault James R | Respiratory calorimeter with bidirectional flow monitors for calculating of oxygen consumption and carbon dioxide production |
ATE191839T1 (en) * | 1991-06-27 | 2000-05-15 | James R Mault | MEASURING DEVICE FOR OXYGEN ABSORPTION |
KR100236717B1 (en) * | 1997-12-24 | 2000-01-15 | 윤종용 | Particle formation analyzer of smock for clean room and method for it |
JP3558574B2 (en) * | 1999-12-24 | 2004-08-25 | 日本電信電話株式会社 | Pollen sorting method and device, and pollen scattering number measuring method and device |
US20040077093A1 (en) * | 2002-07-12 | 2004-04-22 | Baxter International Inc. | Method and apparatus for the detection of the presence of a bacteria in the gastrointestinal tract of a subject |
JP5075638B2 (en) * | 2005-01-10 | 2012-11-21 | プルマトリックス,インコーポレイティッド | Method and apparatus for reducing contamination |
-
2007
- 2007-04-11 CN CNA2007800216502A patent/CN101466436A/en active Pending
- 2007-04-11 JP JP2009505428A patent/JP2009533681A/en active Pending
- 2007-04-11 WO PCT/US2007/008815 patent/WO2007120644A2/en active Application Filing
- 2007-04-11 CA CA002649442A patent/CA2649442A1/en not_active Abandoned
- 2007-04-11 EP EP07755177A patent/EP2010295A2/en not_active Withdrawn
- 2007-04-11 AU AU2007238854A patent/AU2007238854A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5038792A (en) * | 1988-06-29 | 1991-08-13 | Mault James R | Oxygen consumption meter |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9988691B2 (en) | 2010-07-06 | 2018-06-05 | Deton Corp. | System for airborne bacterial sample collection and analysis |
US9617582B2 (en) | 2012-09-04 | 2017-04-11 | University Of Maryland College Park | Human exhaled aerosol droplet biomarker system and method |
US10393753B2 (en) | 2012-09-04 | 2019-08-27 | University Of Maryland, College Park | Human exhaled aerosol droplet biomarker system and method |
EP2970858A4 (en) * | 2013-03-12 | 2016-11-16 | Deton Corp | System for breath sample collection and analysis |
US10080857B2 (en) | 2013-03-12 | 2018-09-25 | Deton Corp. | System for breath sample collection and analysis |
US10806770B2 (en) | 2014-10-31 | 2020-10-20 | Monash University | Powder formulation |
US10502665B2 (en) | 2016-04-18 | 2019-12-10 | University Of Maryland, College Park | Aerosol collection system and method |
Also Published As
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CN101466436A (en) | 2009-06-24 |
WO2007120644A3 (en) | 2008-11-13 |
CA2649442A1 (en) | 2007-10-25 |
JP2009533681A (en) | 2009-09-17 |
AU2007238854A1 (en) | 2007-10-25 |
EP2010295A2 (en) | 2009-01-07 |
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