HK1131581A - Diagnostic device for determining particle production - Google Patents

Abstract

Methods and devices to determine rate of particle production and the size range for the particles produced for an individual are described herein. 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). Optionally, 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').

Description

Diagnostic device for determining particle production

Technical Field

The present invention is in the field of devices and methods for measuring and reducing particle exhalation and contamination in various environments, and is particularly useful in clean rooms.

Background

Clean rooms (cleanrooms) are regulated product manufacturing environments. Which is the space where the airborne particle concentration is controlled to a certain limit. The removal of sub-micron airborne contamination is in fact a controlled process. These contaminants are generated by people, processes, facilities and equipment. It must be continuously removed from the air. The extent to which such particles must be removed depends on the desired criteria. The most commonly used Standard is Federal Standard 209E. This 209E is a file that sets a standard classification of air cleanliness for airborne particle volumes in clean rooms and clean zones. Strict rules and procedures were followed to prevent contamination of the product.

The table below shows the most recent clean room classification. Note that ISO class 2 is equivalent to class10 of 209.

Table 1: airborne particulate cleanliness rating

The only way to control pollution is to control the overall environment. Air flow rate and direction, pressurization, temperature, humidity and specific filtration all need to be closely controlled. These particle sources need to be controlled or eliminated if possible. Clean rooms are designed and built using strict procedures and methods. It is often found in the electronics, pharmaceutical, biopharmaceutical, medical device industries and other important manufacturing environments.

Differences from a typical office building are seen as long as rapid monitoring of the air is undertaken in the clean room. Typical office building air contains 500,000 to 1,000,000 particles (0.5 microns or more)/cubic feet of air. Class100 (Class100) cleanrooms are designed to not exceed 100 particles (0.5 microns or more) of air per cubic foot. The class 1000 and class10,000 are designed to limit the number of particles to 1000 and 10,000, respectively.

Human hair is about 75 to 100 microns in diameter. Particles 200 times smaller (0.5 micron) than human hair can cause a catastrophic failure in a clean room. Contamination can result in costly downtime and increased production costs. Once a clean room is established, it must be maintained and cleaned to the same high standards.

Contamination is a process or action that causes a material or surface to become contaminated with contaminating substances. There are two main classes of surface contaminants: film type and fine particle type. These contaminants can create "killer defects" in the microcircuit. Only 10nm (nanometers) of film contamination can significantly reduce coating adhesion on the wafer or chip. Particles of 0.5 microns or larger are widely accepted as targets. However, some industries now target smaller particles.

A partial list of contaminants is provided below. Any of these may be a source of damage to the loop. The prevention of these contaminants from entering the clean room environment is a major goal. Many of these contaminants have been found to be produced from five basic sources: facilities, people, tools, fluids, and products manufactured.

1. Facilities: walls, floors and ceilings; paints and coatings; building materials (plaster cement plywood, sawdust, etc.); air conditioning debris; room air and steam; spillage and leakage.

2. Human: dandruff and oils; cosmetics and perfumes; spittle; clothing debris (lint, fibers, etc.); hair.

3. The tool produces: grinding and abrading the particles; lubricants and projectiles; vibrating; brooms, mops and rags.

4. Fluid: fine particles floating in the air; bacteria, organic matter and moisture; floor finishes (floor finishes) or paints; a cleaning chemical; plasticizers (degassing); deionized water.

5. The product produced was: a silicon wafer; quartz chips; the dust in the clean room is remained; aluminum particles.

Existing methods and devices for reducing pollution include HEPA (high efficiency fine air) filters. Such filters are important to maintain contamination control. These filters filter out particles as small as 0.3 microns with a minimum particle collection efficiency of 99.97%. The clean room is designed to achieve and maintain an air flow in which the entire air moves at a uniform velocity mainly along parallel flow lines in a confined area. Such air flow is called laminar flow. The more restrictive the air flow, the more turbulent (turbulence) is generated. Turbulence can cause the particles to move. In addition to HEPA filters, which are commonly used in clean rooms, there are many other filtration devices used to remove particles from gases and liquids. Such filters are necessary to provide effective contamination control. Cleaning is also an element of pollution control. The requirements for clean room clothing vary from place to place. In almost every clean room environment, gloves, face masks and headgear are standard equipment. Work clothes are used more and more often. Jump suits (jump suits) are required in a highly dustless environment. Care is taken in selecting and using the commodity in a clean room. Wipes, dust-free paper and pencils, as well as other supplies used in clean rooms, should be carefully screened and selected. Consulting a local cleanroom may be necessary to grant and carry such items into the cleanroom. In fact, many cleanroom managers have licensed lists of these types of items.

When a person is in a clean room, both physical and psychological concerns are needed. Physical behaviors such as fast movement and play can increase pollution. Psychological concerns such as room temperature, humidity, claustrophobia, odor and workplace attitude are important. The pollution mode of people comprises scurf, grease, sweat and hair caused by the regeneration process of human bodies; behaviors include rate of movement, sneezing and coughing; attitude in working habits and conversation among workers. The main source of contamination in the clean room was found to be as shown in table 2 below. Table 2 lists typical activities of a person and the corresponding rates and particle production (number of particles produced per minute). These particles are 0.3 microns and larger.

Table 2: typical activity and particle production rate

Human movement	Particle (0.3 micron and larger) production rate (particles/minute)
		Without movement (standing or sitting)	100,000
About 2mph of walking	5,000,000
		About 3.5mph when walking	7,000,000
About 5mph when walking	10,000,000

Toy alarm

100,000,000

It is a further object of the present invention to provide a device for measuring the number and size of particles exhaled, particularly for use in determining whether a formulation that reduces particle exhalation is desired.

It is an object of the present invention to provide a method of measuring exhaled particles of an individual using a device.

Disclosure of Invention

Methods and devices for determining a rate of particle production and a size range of particles produced by an individual are described herein. The device (10) comprises: a mouthpiece (12), a filter (14), a low resistance one-way valve (16), a particle counter (20) and a computer (30). Optionally, the apparatus may also include a gas flow meter (22). Data obtained using the device can be used to determine whether a formulation that reduces particle exhalation is desired. The device may be used in particular before and/or after entering a clean room (clean room) to ensure that the clean room standards are maintained. The device is also used to identify animals and humans (referred to herein as "overproducers", "superproducers" or "superspreaders") that have an increased propensity to exhale airborne particles (aerosol).

The present invention provides a diagnostic device comprising: a disposable set (50) and a main housing (60). The disposable set (50) is functionally connectable to the main housing (60) to provide a flow of air between the individual and the main housing (60). In some embodiments, the disposable set (50) is connected to the main housing (60) via one or more connecting tubes (70A and 70B) external to the main housing (60). The disposable set (50) includes a mouthpiece (12), a filter (14), a connector (18), and a one-way valve (16). The components of the disposable set (50) may optionally be made from biodegradable materials. A mouthpiece (12) of the disposable set allows a sealed passage to be established between the airway of the individual and the diagnostic device. The mouthpiece (12) may be made of a flexible material (e.g., rubber and/or plastic) to establish a secure seal. The filter (14) of the disposable cartridge (50) is typically a high efficiency, low pressure drop filter, optionally having a bacteria/virus removal efficiency of greater than 99.99%. The main housing (60) of the diagnostic device includes a particle counter (20), and optionally a computer (30), a gas flow meter (22), a display (64), and/or a vacuum pump (62).

The invention provides a diagnostic device for measuring particle exhalation of an individual, comprising a disposable kit and a main box, wherein the disposable kit comprises a mouthpiece, a two-way filter and a low-resistance one-way valve, the main box comprises a particle counter and a computer, and wherein the mouthpiece has an outlet connected to the filter and to the one-way valve, one end of the filter is exposed to the surrounding environment and the other end is connected to the mouthpiece, and the disposable kit is connected to the main box via two connecting pipes.

Preferably, the filter is capable of removing particles having a size greater than or equal to 0.1 micron in diameter. In another embodiment, the mouthpiece is a mouthpiece (mouthpiece), a nasal cannula (nasal proging), a mask (mask) that covers the mouth and nose of the user, or a mask that covers the nose of the user designed to allow the user to place their lips around. The mouthpiece may include a curved flange and two projections, wherein the mouthpiece is designed to allow the user to place the flange between their lips and teeth to form a seal when the user bites on the projections.

The filter may be a combination of two or more filters, and the particle counter may be an electro-migration (electrical) particle counter, an impact particle counter, an electrostatic impact 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 preferably connected to the computer in a manner that allows control instructions to be transmitted from the computer to the particle counter.

The computer may be a microprocessor internal or external to the particle counter. The apparatus may further comprise a gas flow meter, preferably a Fleisch-type or Lilly-type gas flow meter (pneumotachmeter), connected to the filter and located between the filter and the ambient environment. The gas flow meter may operate by measuring a differential pressure across the bypass around the laminar flow unit or measuring a bypass flow rate through the bypass around the laminar flow unit, or the apparatus may further comprise a differential pressure sensor (transducer) capable of measuring a pressure drop across the flow meter, and a signal conditioner connected to the differential pressure sensor and capable of amplifying a signal and transmitting the signal to a computer.

In one aspect, the invention provides a method of measuring the rate and size of particle exhalation in a subject using such a diagnostic device, comprising: placing a mouthpiece in or on the mouth or nose of the individual; drawing air through the mouthpiece, wherein the air is drawn through a filter prior to the drawing; exhaling through the mouthpiece and into a one-way valve; measuring the number of particles and the size of the particles using a particle counter; and supplying data from the particle counter to a computer. During inspiration, air is drawn through the gas meter before it is drawn through the filter. Data may be supplied to the computer from the signal conditioner prior to exhalation through the mouthpiece. The steps of inhaling, exhaling, measuring and providing data are typically repeated a plurality of times and the average particle size, average particle distribution and average rate of particle generation are calculated. The method may further comprise inhaling a formulation which, when administered to a mucosal lining of a human or other animal, alters the surface viscoelastic properties of the mucosal lining, the surface tension of the mucosal lining or the bulk viscosity (bulkviscosensitivity) of the mucosal lining, and then repeating the steps of placing a mouthpiece over the mouth or nose of the individual, inhaling air through the mouthpiece, exhaling through the mouthpiece, measuring the number and size of particles using a particle counter, supplying data from the particle counter to a computer, and calculating the average particle size, average particle distribution and average rate of particle generation.

Drawings

Fig. 1 is a diagram of a diagnostic instrument for measuring particles produced and exhaled by a person.

Fig. 2 is a diagram of a diagnostic instrument for measuring particles produced and exhaled by a person having an associated breathing rate.

FIGS. 3A and 3B are explanatory views of a preferred embodiment of the diagnostic apparatus. In fig. 3A, the cover is transparent. In fig. 3B, the cover has been removed.

Fig. 4A and 4B are illustrations of a preferred embodiment of a disposable set. Fig. 4A is an explanatory diagram of filling the space. Fig. 4B is a side view.

Fig. 5A and 5B are explanatory views of a preferred embodiment of the mouthpiece. Fig. 5A is a front view. Fig. 5B is a side view.

Fig. 6A and 6B are explanatory views of a preferred embodiment of the components attached to the bottom of the main body case. Fig. 6A is a diagram of filling up a space. Fig. 6B is a top view.

Fig. 7A and 7B are explanatory views of a preferred embodiment of the lid of the main body. Fig. 7A is a view of the exterior of the lid. Fig. 7B is a side view.

Fig. 8A, 8B, and 8C are explanatory diagrams of a preferred embodiment of the flow meter. Fig. 8A is a diagram of filling up a space. Fig. 8B and 8C are side views.

Fig. 9A, 9B and 9C are graphs illustrating the particle concentration after three coughs for those without mucoadhesive and measured at t 0 min (fig. 9A), t 30 min (fig. 9B) and t 60 min (fig. 9C) after saline delivery.

Fig. 10A is a bar graph of basal line particle counts (greater than 150nm) exhaled by an individual (n ═ 11) when inhaling particle-free air; and fig. 10B is a graph of particle counts (greater than 150nm) exhaled by an individual (n-11) after saline (approximately 1 gram) was administered as an aerosol (aerosol) to the lungs for a period of time (minutes).

Figure 11A is a graph of particle counts (greater than 150nm) for individuals with pre-treatment baseline exhalation values greater than 1000 particles/liter (when inhaling particle-free air) after administration of an isotonic saline solution (about 1 gram solution) as an aerosol to the lungs for a period of time (minutes); and figure 11B is a graph of particle counts (greater than 150nm) exhaled after aerosol administration of phospholipid-containing isotonic saline solution (approximately 1 gram solution) to the lungs for a period of time (minutes) for individuals with a baseline exhalation value greater than 1000 particles/liter (when inhaling air without particles) prior to treatment (n ═ 2).

Figure 12A is a graph of the total number of exhaled particles (greater than 0.3 microns) over time (minutes), showing data obtained from sham-treated animals. FIG. 12B is a plot of mean percent (%) baseline particle counts over time (minutes) showing data obtained from animals treated with nebulized saline solution for 1.8 minutes (- ■ -), 6.0 minutes (-. tangle-solidup. -), 12.0 minutes (- □ -), and sham treated animals (-. diamond-solid. -).

Fig. 13 is a graph of the average particle count (% count/liter) generated over 0.3 μm after completion of administration of the reduced particle generation formulation (hours) versus the baseline.

Detailed Description

From the above discussion of clean rooms it is clear that the following would be highly advantageous: (1) determining the individual's particle production rate and the size range of the particles produced, (2) predicting those persons will produce the greatest degree of contamination, and (3) minimizing contamination from breathing, coughing, movement, etc.

These objects are achieved by an apparatus for measuring the size and number of particles produced on an individual basis, such as described herein. Particle production can be measured during rest or various activities. This allows us to determine whether a formulation that reduces particle exhalation should be administered to an individual and/or select an individual that produces minimal particle production to work in a clean room environment.

Diagnostic device for determining particle production

Animals or humans are diagnosed to determine the rate of particle production during exhalation and the size range of the particles produced. Analysis of this data can be used to determine whether a formulation that reduces particle exhalation is desired. The device is particularly useful prior to entering the cleanroom or when the user is working in the cleanroom to ensure that cleanroom standards are maintained. The device may also be used to identify animals and humans (referred to herein as "overproducers", "superproducers" or "superspreaders") that have an increased propensity to exhale airborne particles (aerosol). This can be achieved by screening for a number of factors, including: exhaled and inhaled air measurements, an assessment of the number of exhaled particles, an assessment of exhaled particle size, a tidal volume (tidal volume) and respiratory frequency during sampling, and an assessment of viral and bacterial infectivity. The number of exhaled particles was evaluated at a respiratory flow rate of about 10 to 120 Liters Per Minute (LPM).

A diagnostic instrument (10) for measuring particles generated and exhaled by a person is illustrated in fig. 1 to 3. As shown in fig. 3, the device (10) contains at least two main components: (1) a disposable set (50) and a main housing (60). In a preferred embodiment, the disposable set (50) is connected to the main housing (60) via one or more connecting tubes (70A and 70B) external to the main housing (60). In one embodiment, the instrument (10) is portable and optionally battery operated.

A. Disposable set

A disposable kit (50) is illustrated in fig. 4A and 4B. The disposable set (50) contains: a mouthpiece (12), a filter (14), a connector (18) and a one-way valve (16). In a preferred embodiment, the mouthpiece (12), filter (14), connector (18) and one-way valve (16) are all disposable. Optionally, the mouthpiece (12), filter (14), connector (18) and one-way valve (16) are formed from biodegradable materials.

The outlet (13) of the mouthpiece (12) is attached to the filter (14) and low resistance one way valve (16) via a branched connection (18), such as a Y-or T-connection. The one-way valve (16) is usually located inside a tube (19) forming half of the connector (18) or attached directly at one end of the connector (18).

As shown in fig. 3, the disposable set is attached to the main housing (60) using one or more connecting tubes. In the example illustrated in fig. 3, two connection pipes (70A and 70B) are used.

i. Mouthpiece

Any suitable mouthpiece may be used. Preferred mouthpiece is illustrated in fig. 4A, 4B, 5A and 5B. As shown in fig. 5A and 5B, the preferred mouthpiece is made of a flexible material, such as plastic, rubber, silicone-containing material (e.g., silicone rubber, polyvinyl chloride, or thermoplastic rubber), or similar flexible material, and has a curved flange (40). When in use, the curved flange (40) is placed between the lips and teeth of the user to form a seal. The mouthpiece (12) has at least two projections (42A and 42B) attached to each of opposite sides of the curved flange (40) and designed to fit between the upper and lower teeth of a user to hold the mouthpiece in place in use. When in use, the projections (42A and 42B) also function to create a gap between the upper and lower rows of teeth to ensure that the mouth of the user remains open during the entire use of the diagnostic device. The thickness of the protrusion is preferably greater than 4mm, most preferably between 6mm and 15 mm. The bent flange (40) has an opening (43) in the center of the flange. The flange is connected to a pipe (44) via an 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) distal to the flange (40). As illustrated in fig. 1 and 2, the mouthpiece (12) is designed to allow the user to hold their lips against the exterior of the mouthpiece, thereby forming a seal between their lips and the mouthpiece. Another option is for the mouthpiece to be in the form of a nasal cannula and for a seal to be formed between the user's nares and the cannula. The mouthpiece may also be in the form of a mask which covers the mouth and nose of the user and forms a seal between the user's face and the mask. Yet another option is for the mouthpiece to be in the form of a mask that covers only the nose of the user. Preferably, the mouthpiece is disposable.

ii, a filter

The filter (14) is typically highly efficient (at 0.3 μm,>99.97%), low pressure drop (at 60 liters/min,<2.5cm H₂o) a filter, optionally having>99.99% bacteria/virus removal efficiency. The filter is chosen to remove particles having at least a size within the range measurable by the particle counter (20), preferably even smaller than the range measurable by the particle counter (20). The filter is preferably designed to remove particles greater than or equal to 0.1 microns in diameter. A series of 2 or more filters (14) may be included between the mouthpiece (12) and the ambient air to prevent contamination of the upstream system between users. In this embodiment, 1 or more filters can be replaced with 1 set of filters parallel to each other to minimize flow resistance. In the preferred embodiment illustrated in FIG. 3, the instrument contains 2 filters in series. The first filter (14) is external to the main housing and is part of a disposable cartridge (50). The second filter is inside the main tank.

B. Main box

A preferred embodiment of the main body (60) is illustrated in fig. 6A, 6B, 7A and 7B. Preferably, the main housing (60) contains a particle counter (20), a computer (30) and a vacuum pump (62), and a display (64). As shown in fig. 6A and 6B, the particle counter (20) and the vacuum pump (62) are attached to the bottom (68) of the main tank (60). As shown in fig. 7B, the computer (30) is attached to the cover (66) of the main case (60); and a display (64) on an outer surface of the cover (66).

The particle counter (20) is connected to the computer (30) in a manner that allows data to be supplied to the computer (30). Data from the particle counter (20) is transmitted to a computer (30) to allow the user to read, analyze and interpret the data. As illustrated in fig. 6A and 6B, the particle counter (20) is connected to a vacuum pump (62). The other option is as follows: the main housing contains the particle counter (20), but the computer (30), display (64) and/or vacuum pump (62) are external to the main housing.

i. Particle counter

The particle counter (20) must have sufficient sensitivity to accurately calculate sub-micron sized particles and can be designed and combined as described. The measurement of the number of particles and the size of the particles can be performed by electromigration analysis, impact, electrostatic impact, infrared spectroscopy, laser diffraction or light scattering. Examples of particle counters currently available for measuring particle number and size include: scanning Mobility Particle Sizer (SMPS) (TSI, shore MN), anderson cascade impactor (Andersen cascade impactor) or Next generation pharmaceutical impactor (co-generation Scientific, not-mingham UK), Electric Low Pressure Impactor (ELPI) (Dekati, tarphere Finland) and Helos (Sympatec, claustral, germany). In a preferred embodiment, the particle counter is an optical particle counter, preferably by a light scattering operator using a laser or laser dipole light source. The optical particle counter typically has a range of at least 0.3 to 5 μm, preferably from 0.1 to 25 μm, and its measurement range is divided into at least 2 bands (channels), preferably at least 4 bands. The optical particle counter may be operated with a constant sample flow velocity of at least 0.1 cubic feet per minute, preferably at least 1 cubic feet per minute, which may be generated and controlled by a vacuum pump (62) and flow regulating components that are part of the particle counter or separate. Existing optical Particle counters that may be used in the preferred embodiment include the types CI-450, CI-500, and CI-550 of Ultimate 100 (Climet Instruments, Redlands CA), as well as the types LasairII, Airnet 310 (Particle measurement Systems, Boulder CO).

ii computer

The particle counter (20) is connected to the computer (30) in a manner that allows data to be transmitted from the particle counter (20) to the computer (30). Optionally, the particle counter (20) may also be connected to the computer (30) in a manner that allows control instructions to be transmitted from the computer (30) to the particle counter (20). The computer may be a microprocessor internal or external to the particle counter (20). Preferably, the computer includes a display that is physically separable from the central processing unit and the data storage unit, and preferably the display incorporates touch screen functionality. As shown in FIGS. 3A and 3B, in a preferred embodiment, the main housing (60) contains a particle counter (20) and a computer (30).

iii flow meter

As illustrated in fig. 2, the apparatus (10) may contain a gas flow meter (22). The gas flow meter (22) should have a low flow resistance so as not to affect the user's breathing rate, such as a Fleisch-type or Lilly-type gas flow meter (pneumotachograph) or pneumotach (pneumotachograph). The other option is as follows: the gas meter may measure the flow by measuring temperature changes or heat transfer from a hot wire (e.g. hot wire anemometer), or by counting the revolutions per unit time of a small turbine (e.g. turbine meter), or by measuring the pressure difference across a bypass around a flow restriction (such as a laminar flow unit) or the bypass flow rate through the bypass. The volume displacement is then calculated by integrating the flow rate over time.

Gas flow meters are often used to measure the flow rate of different gases during a breath. Passing the air through a short tube with a screen (e.g. Fleisch tube) which presents a small resistance to the air flow (not shown in the figures)Out). The resulting pressure drop across the screen is proportional to the flow rate. The pressure drop is extremely small, typically in the order of mmH₂And O. Differential pressure sensors (24) are typically used to measure the pressure drop across a flow meter (e.g., a Flickey tube) to enhance the detection of such small drops in pressure. Preferably the differential pressure sensor is connected to a signal conditioner (26), which signal conditioner (26) amplifies the signal and transmits it to data acquisition software in a computer (30). One differential pressure sensor (24) useful in the present invention is the Validyne DP45-14 differential pressure sensor. If the differential pressure sensor is used, the preferred signal conditioner (26) is a Validyne CD15 sine wave carrier demodulator. The gas flow rate meter may be used in lung function analysis or in artificial ventilation of the lungs.

As shown in fig. 8A to 8C, the preferred flow meter contains a bypass tube (82), a low flow rate flow meter (84), and a laminar flow unit (86). The flow meter (22) is typically a low flow rate mass flow meter that measures bypass flow around a flow restriction such as a laminar flow cell (86). The laminar flow unit (86) is comprised of a series of parallel tubes sized to enable flow through the tubes to be in a laminar range for respirable flow rates, preferably for flow rates between +130 and-70 liters/minute (where positive flow represents the direction of flow during exhalation). In a preferred embodiment, the low flow meter provides a digital output at a frequency greater than 5 Hz. An example of this type of flow meter is the Sensirion ASF1430 type.

C. Accessories

The apparatus (10) often includes connections for further breath analysis, either simultaneously with or in series with the measurement of particle size and count. For example, exhaled breath condensate may be collected in standard devices such as R-tubes or exhaled air passed through a media filter for further analysis via a connection fitting (not shown in the figures) located along the tubing (19) leading to the optical particle counter (20).

Formulations for reducing particle production

Biological airborne particles are formed by the destabilization of the endogenous surfactant layer in the airways. The formulations described herein, when used in certain embodiments of the invention, are effective in altering the biophysical properties of the mucosal lining.

It has been found that the physical properties of endogenous surfactant fluids in the lung can be altered by administration of saline solutions as well as by administration of saline solutions containing other substances, such as osmotically active substances, electrically conductive substances and/or surfactants. The concentration of the salt or other osmotically active substance ranges from about 0.01% to about 10% by weight, preferably between 0.9% and about 10%. A preferred aerosol solution for altering the physical properties of the mucosal lining is isotonic saline.

Certain formulations of the present invention contain a material (also referred to herein as a "conductive agent") that is readily ionized in an aqueous or organic solvent environment, such as a salt, an ionic surfactant, a charged amino acid, a charged protein or peptide, or a charged material (cationic, anionic, or zwitterionic). Suitable salts include salt forms of the elements sodium, potassium, magnesium, calcium, aluminum, silicon, scandium, titanium, vanadium, chromium, cobalt, nickel, copper, magnesium, zinc, tin, and the like. Examples of such salts include: sodium chloride, sodium acetate, sodium bicarbonate, sodium carbonate, sodium sulfate, sodium stearate, sodium ascorbate, sodium benzoate, sodium hydrogen phosphate, sodium bisulfite, sodium citrate, sodium borate, sodium gluconate, calcium chloride, calcium carbonate, calcium acetate, calcium phosphate, calcium alginate, 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 sulfite, potassium hydrogen phosphate, potassium alginate, potassium benzoate, magnesium chloride, copper sulfate, chromium chloride, stannous chloride, and sodium metasilicate, and the like. Suitable ionic surfactants include Sodium Dodecyl Sulfate (SDS), also known as Sodium Lauryl Sulfate (SLS), magnesium lauryl sulfate, polyoxyethylene sorbitan monooleate 20(Polysorbate 20), polyoxyethylene sorbitan monooleate 80(Polysorbate 80), and similar surfactants. Suitable charged amino acids include: l-lysine, L-arginine, histidine, aspartic acid, glutamic acid, glycine, cystine and tyrosine. Suitable charged proteins or peptides include those containing the charged amino acids, Calmodulin (CaM) and troponin c (troponin c). Charged phospholipids such as 1, 2-dioleoyl-semisynthetic-glycero-3-ethyllecithin triflate (EDOPC) and alkyl lecithin triesters may be used.

Preferred formulations are salt-containing formulations, such as saline (0.15M NaCl or 0.9%) solution, CaCl₂Solution of CaCl₂Or a saline solution containing an ionic surfactant (such as SDS or SLS). In some embodiments, the formulation solution comprises a saline solution and CaCl₂. Suitable concentrations of the salt or other conducting/charged compound may range from about 0.01% to about 20% (weight of conducting or charged compound/total weight of formulation), preferably between 0.1% to about 10% (weight of conducting or charged compound/total weight of formulation), most preferably between 0.1% to 7% (weight of conducting or charged compound/total weight of formulation).

Saline solutions, along with small amounts of therapeutically active agents such as beta-agonists, corticosteroids (corticosterioids), or antibiotics, have long been delivered to the lungs. For example, the above-mentioned materials can be used,inhalation solutions (GSK) are salbutamol sulfate solutions for the long-term treatment of asthma and exercise induced bronchospasm symptoms. For sprayingThe solution was prepared by mixing 1.25 to 2.5mg of salbutamol sulphate (in 0.25 to 0.5ml of aqueous solution) into sterile saline to bring the total volume to 3 ml. Without adverse reaction is thought to pass through with salt waterThe delivery of the spray to the lungs is relevant even if the spray time is 5 to 15 minutes. Can also deliver larger amount of salt solutionTo induce sputum excretion. These saline solutions are often hypertonic (sodium chloride concentration greater than 0.9%, often up to 5%) and are typically delivered for up to 20 minutes.

The formulations disclosed herein may be used via any route of delivery of a variety of organic or inorganic molecules, especially small molecule drugs such as antiviral and antibacterial drugs including antibiotics, antihistamines, bronchodilators, antitussives, anti-inflammatory agents, vaccines, adjuvants and expectorants. Examples of macromolecules include proteins and large peptides, polysaccharides and oligosaccharides, and DNA and RNA nucleic acid molecules and analogs thereof having therapeutic, prophylactic or diagnostic activity. The nucleic acid molecule includes: genes, antisense molecules that bind to complementary DNA to inhibit transcription, and ribozymes (ribozymes). Preferred agents are antivirals, steroids, bronchodilators, antibiotics, mucus production inhibitors and vaccines.

In a preferred embodiment, the concentration of the active agent ranges from about 0.01% to about 20% by weight. In a more preferred embodiment, the concentration of the active agent is in the range of 0.9% to about 10%.

Administration of the formulation to the respiratory tract

A. Administration of conductive formulations to reduce the amount of exhaled particles

Conductive formulations containing appropriate conductivity can be administered to increase the viscoelasticity of the mucosa at the site of administration of the formulation to suppress or reduce the production of biological airborne particles during respiration, coughing, sneezing and/or conversation. Preferably the formulation is administered to 1 or more subjects in an effective amount to reduce particle production. The formulation may be administered to a person prior to the person entering the cleanroom or while the person is working in the cleanroom to ensure that cleanroom standards are maintained. If a human or animal has been identified as having an increased propensity to exhale airborne aerosols (i.e., an "overproducer," "overproducer," or "superdistributor"), the formulation may be administered to reduce particle production, prevent or reduce the spread of infection, or prevent or reduce the uptake of pathogenic bacteria by the human or animal.

B. Administered to the respiratory tract

The respiratory tract is a structure that involves the exchange of gases between the atmosphere and the blood stream. The lung is a branched structure that ends in an alveolus, where gas exchange occurs. The alveolar surface area is the largest in the respiratory system and where drug absorption occurs. Alveoli are covered by thin epithelium without cilia or mucous blankets (muco blanket) and secrete surface active phospholipids. J.s.pattern & 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, which in turn branches into bronchi and bronchioles. The upper and lower airways are also known as transfer airways. The terminal bronchioles then divide into respiratory bronchioles, which lead to the final respiratory zone, alveoli or deep lung. The deep lung or alveoli are the primary target for inhaled therapeutic aerosols for systemic drug delivery.

The formulations are typically administered to a subject to deliver an effective amount to alter physical properties such as surface tension and viscosity of endogenous fluids in the upper airway, thereby increasing transport to the lung and/or suppressing cough and/or improving clearance from the lung. Effectiveness can be measured using the diagnostic devices described herein. For example, 1 gram quantities of saline solution may be administered to a normal adult. The exhalation of the particles is then measured. Delivery is then optimized to minimize dose and particle count.

The formulations are administered using a metered dose inhaler (MDP), a nebulizer (nebulizer), an aerosol (aerosolizer), or using a dry powder inhaler. Suitable devices are commercially available and are described in the literature.

The aerosol dose, formulation and delivery system may be selected for a particular therapeutic application, as described in the following documents: "Aerosol delivery of Therapeutic and diagnostic agents to the respiratory tract", clinical Reviews in Therapeutic Drug Carrier Systems, 6: 273, 313, 1990; and Moren, "aerosol formulations and formulations," Aerosols in medicine, Principles, Diagnosis and Therapy, Moren, et al, eds.

Delivery is achieved by one of several methods, such as using metered dose inhalers that include HFA propellants, metered dose inhalers that do not contain HFA propellants, nebulizers, pressurized canisters, or continuous nebulizers. For example, a patient may mix a dry powder of the therapeutic agent with a solvent prior to suspension and then aerosolize it. It is most appropriate to use the solution before nebulization, to adjust the dose administered and to avoid possible losses of suspension. After nebulization, the aerosol can be pressurized and administered via a Metered Dose Inhaler (MDI). Nebulizers produce a fine mist from a solution or suspension that is inhaled by the patient. The device described in U.S. patent No. 5,709,202 to Lloyd et al may be used. MDIs typically comprise a pressurized canister with a metering valve, wherein the pressurized canister is filled with a solution or suspension and a propellant. The solvent may itself function as a propellant, or the composition may be combined with a propellant such as(e.i. du PontDe Nemours and co.corp.) combinations. The composition is a fine mist when released from the can due to release under pressure. The propellant and solvent may evaporate completely or partially due to the pressure drop.

The other option is as follows: the formulation is in the form of particles of a salt or osmotically active material dispersed on or in an inert substrate, wherein the substrate is placed over the nose and/or mouth and the inhaled particles of the formulation. The inert substrate is preferably a microbially degradable or disposable woven or nonwoven fabric, more preferably the fabric is formed from a cellulosic material. An example of this is toilet paper which is currently marketed and contains a lotion to minimize irritation after frequent use. These formulations can be packaged and sold individually or in packages similar to toilet paper or baby wet wipes packages, which are readily combined with liquid solutions or suspensions.

The formulation can be administered to 1 or more subjects using a device that provides an aerosol that administers a fine mist of the formulation to the pulmonary and/or nasal regions of the subject, thereby reducing the output of particles. The formulation can be administered to humans or animals by establishing an aqueous environment that allows the human or animal to move or to remain in position long enough to adequately hydrate the lungs. The aeration (atmosphere) can be established by using an atomizer or even a humidifier. The conductive formulation is preferably administered with an atomizer or humidifier. The individual is processed before entering the cleanroom and/or after entering the cleanroom.

Method of using a diagnostic device

When using the device illustrated in figures 1 and 2, the user places their lips around the mouthpiece (12). The user preferably seals his airway from ambient air by sealing the mouthpiece via the nose clip and by closing the mouthpiece with his lips. If a mask is used as the mouthpiece, the user places the mask over their mouth and/or nose. If a nasal cannula is used as the mouthpiece, the user places the nasal cannula in the nose. If the mouthpiece is in the form of a mask, the user places the mask over their nose and/or mouth, thereby sealing their airways from the ingress of ambient air.

When using the device illustrated in fig. 3-8, the user places the curved flange (40) between his lips and teeth to form a seal. The user bites on the two projections (42A and 42B) to hold the mouthpiece in place during use and to keep its mouth open during use.

When the user inhales, inhaled air enters the system via the filter (14), wherein the filter (14) removes particles within a predetermined measurement range. Exhaled air passes through a low resistance one-way valve (16) into a particle counter (20). The one-way valve (16) helps to prevent transmission of exhaled pathogens from one user to the next.

The exhaled air travels to a particle counter (20) which measures the number of particles and the size of the particles. The particle counter (20) samples at a fixed flow rate, preferably greater than the peak exhalation flow rate, so that the average flow direction through the filter (14) at all points in time is into the system to prevent exhaled particles from escaping into the filter (14). Preferably the particle counter samples at a flow rate greater than 28 liters/minute. The particle counter (20) then provides the data to the computer (30). In one embodiment, visual feedback is provided to the user of his breathing pattern, prompting the user to maintain a specified breathing pattern, such as tidal breathing (tidal breathing). The particle counter (20) may be remotely controlled, either by a Personal Computer (PC) or locally, such as by a touch screen interface (FIG. 7A, element 64), where data measurement and analysis is performed locally in the main housing or remotely at the PC. The 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 then calculates the average particle size, the average particle distribution, and the average rate of particle generation. If it is necessary to reduce the number and size of particles exhaled by the user, a formulation for reducing particle exhalation, such as described in PCT/US2006/000618, filed on.1/10.2006, is administered to the user.

Optionally, the diagnostic instrument (10) is designed to measure particles produced and exhaled by a person having an associated respiration rate. In the embodiment illustrated in fig. 2, the inhaled air enters the system via a low flow resistance flow meter (22) that simultaneously identifies the user's breathing pattern and the particle counter flow rate. The air then enters a filter (14), which filter (14) removes particles within the measurement range. Exhaled air passes through a low resistance one-way valve (16), through a tube (18), and into the particle counter (20). Data from the flow meter, differential pressure sensor and/or signal conditioner is transmitted to a computer for calculation and analysis.

Depending on the rate of particle generation and the size of the particles generated (as determined using data obtained from a diagnostic device), the formulation may be administered to the user in an effective amount to reduce particle generation. The formulation can be administered before or after entering the cleanroom.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The publications cited herein and the materials cited by these publications are specifically incorporated by reference.

The invention will be further understood by reference to the following non-limiting examples.

Examples

Example 1: in vitro simulation

Design and King am.j.respir.crit.care med.156 (1): 173-7(1997) a similar simulated cough machine system. A6.25 liter airtight plastic glass (Plexiglas) tank equipped with a digital pressure gauge and a pressure reducing valve (pressure relief) was constructed to function as a lung volume. To pressurize the tank, a compressed air cylinder with a regulator and air filter is connected to the inlet. At the outlet of the cell, an Asco two-way normally closed solenoid valve (8210G94) with sufficient Cv flow factor was connected for the release of gas. The solenoid valve is wired and a typical 120V, 60Hz lamp switch is used. The output of the solenoid valve is connected to a fletch 4 gas flow meter which produces the Poiseuille flow required to check the "cough" mode (profile). The outlet of the fleshy tube was connected to the 1/4 inch-hour NPT inlet of the model trachea. The pressure drop across the Flickey tube was measured with a Validyne DP45-14 differential pressure transducer. The signal to the data acquisition software was amplified using a Validyne CD15 sinusoidal carrier demodulator. Weak polymer gels with rheological properties similar to tracheobronchial mucus such as kit al Nurs res.31 (6): 324-9 (1982). The Locust Bean Gum (LBG) (Fluka BioChemika) solution was crosslinked with sodium tetraborate (Na)₂B₄O₇) (j.t.baker). LBG was dissolved at 2% w/v in boiling Milli-Q distilled water. Concentrated sodium tetraborate solution was prepared with Milli-Q distilled water. After cooling the LBG solution to room temperature, a small amount of sodium tetraborate solution was added and the mixture was slowly rotated for 1 minute. A still watery mucus simulant aspirate is then instilled into the model trachea, establishing a simulated depth according to simple tunnel geometry (simple troughgeometry). The mucus-mimicking layer was allowed to cross-link for 30 minutes before the "cough" experiment was initiated.At this time t is measured at 0 minutes, followed by 30 minutes and 60 minutes. The final concentration of sodium tetraborate is 1 to 3 mM. The acrylic model gas tube was designed to be 30cm long and 1.6cm high inside. The model balloon is formed as a rectangular tube with a split top to ease access to the mucus simulation layer. A gasket and C-clamp were used to create a gas tight seal. The rectangular cross-section is selected to provide a uniform height of the mucus simulant and to avoid problems associated with round tubes and gravity drainage. The cross-sectional area of the model trachea also simulates physiological conditions. The terminal end of the model trachea remains open to the atmosphere. Nebulized solution was delivered to the mucus simulant via a PARI LC jet nebulizer and a Proneb Ultra compressor. The formulation included 0.9% isotonic saline (VWR) and 100mg/mL 7/3% by weight synthetic phospholipid 1, 2-dipalmitoyl-semisynthetic-glycero-3-lecithin/1-palmitoyl-2-oleoyl-semisynthetic-glycero-3-lecithin (DPPC/POPG) (Genzyme) suspended in isotonic saline. A 3mL volume of the selected formulation was drawn into the nebulizer and nebulized until the nebulizer splashed the formulation into the mucus-simulating layer via an open-ended, but clamped, model tracheal tube (sputter). The model gas tube was then attached to the exit of the fleshy tube prior to the experiment (t ═ 0 minutes). And experiments were performed at t 30 minutes and t 60 minutes (after dosing).

The dimensions of the produced mucus simulant biological air aerosols were analyzed using a Sympat ec HELOS/KF laser diffraction particle size analyzer. The size of the diffracted particles was analyzed using the Fraunhoffer method. The HELOS was equipped with an R2 submicron window module capable of measuring in the range of 0.25 to 87.5 microns. Prior to the "cough" experiment, the terminal end of the model trachea was adjusted to not more than 3cm from the laser beam. The bottom of the model trachea was aligned with a 2.2mm laser beam using support jacks and a level. The dispersed biological air aerosols are collected by vacuum following HEPA filter connection to inertial cyclone after diffraction beam. The laser was positioned under ambient conditions for 5 seconds prior to each run. In the light gathering (C)_opt) Starting measurement after specific excitation conditions of ≧ 0.2% and at C_optStop for 2 seconds after ≦ 0.2%. Building cumulative distribution map and density distribution map pair body by using Sympatec WINDOX softwareProduct calculated logarithmic particle size.

A typical cough pattern consisting of a bi-directional pulse of air (biphasic burst) was passed through a 1.5mm mucus-simulating layer. The initial stream or air has a flow rate of about 12 liters/second for a total of 30 to 50 milliseconds. The second phase lasts 200 to 500 milliseconds and then decreases rapidly.

Concentration of suspended particles of biological air after three coughs measured over time in the absence of interferent mucus simulants (fig. 9A, 9B and 9C) and in saline delivery (fig. 9A, 9B and 9C) and surfactant delivery. In the absence of interference, the biological airborne particle size remains constant over time, with a median size of about 400 nanometers. After addition of saline solution, the bio-airborne particle size increased from 1 micron (t ═ 0) (fig. 9A) to about 60 microns (t ═ 30 minutes) (fig. 9B), and then decreased to 30 microns (t ═ 60 minutes) (fig. 9C).

These in vitro results show that saline solution delivered to the mucus layer causes a substantial increase in particle size upon mucus breakdown, possibly due to an increase in surface tension. As the results in vivo show, larger sized droplets are less able to exit the mouth. Therefore, the delivery of the solution significantly reduces the number of exhaled particles.

Example 2: reduction of exhaled air suspended particles in human studies

A proof-of-concept study on the generation of exhaled air suspended particles was performed using 12 healthy individuals. The goal of the study was (1) to determine the properties (size distribution and number) of exhaled biological air-borne particles; (2) use of a device that proves to be sensitive enough to accurately count exhaled particles; (3) evaluating a baseline count of particles exhaled from a healthy lung; and (4) measuring the effect of two therapeutic aerosols administered externally on the suppressed exhaled particle count. Experiments were performed with different particle detectors for healthy subjects to determine the average particle number per liter and the average particle size. Healthy individuals exhale as few as 1 to 5 particles per liter after inhaling particle-free air, with an average size of 200 to 400nm in diameter. The number of particles varies significantly between individuals, so that some exhale up to 30,000 particles per liter, again predominantly sub-micron particle size. Devices with sensitivity sufficient to accurately calculate sub-micron sized particles are designed and assembled. The laser assembly of the apparatus was calibrated according to the manufacturing procedure (Climet Instruments Company, Redlands, Calif.). The device accurately measures particles in the range of 150 to 500nm with a sensitivity of 1 particle/liter. A series of filters removes all background particle noise.

Under compliance with IRB licensing procedures, 12 healthy individuals enrolled to receive the study. The inclusion criteria were: good health, age 18 to 65 years, normal lung function (predicted FEV)₁>80%), informed consent (expressed present), and the ability to make this measurement. Exclusion criteria: there is significant lung disease (e.g., asthma, COPD, fibrocysts), cardiovascular disease, acute or chronic infections of the respiratory tract and pregnant or lactating women, or a history of such disease. 1 individual failed to complete the entire course of administration, so was excluded from the data analysis.

After completion of the physical examination, subjects were arbitrarily divided into two groups: the one initially received prototype (prototype) formulation 1 and the one received prototype formulation 2. Baseline exhaled particle production was measured after 2 minutes of "washout" of the device. The evaluation was carried out over a period of 2 minutes, and counts per minute were derived from the average over 2 minutes. After baseline measurements, the prototype formulation was dosed for 6 minutes using a commercially available water atomizer (Pari Respiratory Equipment, Stamberg, Germany). Formulation 1 consisted of an isotonic saline solution. Formulation 2 consisted of a combination of phospholipids suspended in an isotonic saline carrier. Following administration, exhaled particle counts were assessed 5 minutes, 30 minutes, 1 hour, 2 hours, and 3 hours after the single administration.

As shown in fig. 10A, substantial inter-individual differences were found in baseline particle counts. The data shown are measurements taken prior to administration of one of the test aerosols. This baseline exhalation particle result indicates the presence of a "super producer" of exhaled air aerosols. In this study, "super-producers" were defined as individuals that exhaled more than 1,000 particles per liter when measured on the baseline. Figure 10B shows the individual particle counts for the individuals receiving formulation 1. The data show that a simple formulation with externally administered aerosol can suppress exhaled particle counts.

Figure 11 shows the effect of prototype formulation 1 on two "super producers" found in the group of base lines. These data show that the prototype formulation exerts a more significant impact on the super producer.

Similar results were found for delivery of formulation 2. Fig. 11B summarizes the percent change in cumulative exhaled particle counts (relative to the baseline) for the "super producers" identified by the two treatment groups. The results from this study demonstrate that exhaled particles can be accurately measured by using a laser-detection system, these particles are predominantly those less than 1 micron in diameter, and the number of such particles varies substantially from individual to individual. The "super-producer" individuals responded most significantly to the delivery of aerosols that modified the physical properties of the fluid surface lining the lungs. These overproducers may be responsible for the spread of pathogenic bacteria and for infections in the infected population. These data also demonstrate that it is feasible to suppress aerosol exhalation by a relatively simple and safe aerosol formulation administered from the outside.

Example 3: study of Large animals

7 Holstein bulls were anesthetized, intubated and screened for baseline particle exhalation by optical laser counting. Animals were then either not treated (sham treated group) or treated with a nebulized aerosol of saline at one of three doses (1.8 min, 6.0 min, or 12.0 min). During the administration of the sham dose, the animals were treated in the same manner as when the dose of isotonic saline solution was administered. One animal was dosed daily and nebulizer dosing was randomized throughout the exposure period (dosing schedule see table 3). All doses received by each animal during the study were recorded. Following administration of each dose, exhaled particle counts were monitored at separate time points (0, 15, 30, 45, 60, 90, 120) during 180 minutes.

The exposure pattern (exposure matrix) of the animals included in this study is shown in table 3. The dosing period amounted to 57 days, with at least 7 days between doses. Each animal (n-7) received each dose at least once during the dosing period, with the exception of one 6.0 minute dose (see animal 1736) and one 12.0 minute dose (see animal 1735). The exclusion of these two doses is an unpredictable problem due to the ventilator and/or anesthesia equipment.

Table 3: administration to large animals

Results

Fig. 12A shows the particle counts over time for each animal after the animals received a sham dose. Each time point typically represents the average of at least three particle count measurements. The data in fig. 12A shows that some individual animals produced more particles than others on a congenital basis ("superscatterers"). In addition, the data shows that statically-breathed anesthetized animals maintain a fairly stable exhaled particle output throughout the evaluation period (see, e.g., animal numbers 1731, 1735, 1738, 1739, and 1741).

Figure 12B represents the average percent change in exhaled particle count over time after each treatment. Each data point represents the average of 6 to 7 measurements from the treatment population. All animals returned to baseline 180 minutes after treatment. This data suggests that a dose sufficient to prevent particle exhalation for at least 150 minutes following treatment was provided during the 6.0 minute treatment period. Other treatments appear to be either too short or too long to provide effective and sustained compression of the exhalation of airborne particles.

Example 4: reduction of exhaled air suspended particles in human studies

In a study of 4 healthy adults, a formulation similar to that used to reduce the number of exhaled particles was used before and after treatment with the formulationThe apparatus illustrated in fig. 2 measures particle counts. The treatment involved removing 1.29% by weight CaCl from a 0.9% NaCl solution₂The Pari LC + jet nebulizer of the formulation of (1) was inhaled for 6 minutes. Exhaled particles were measured before treatment and at time points of 10 minutes and 1, 2, 4 and 6 hours after completion of treatment. The total count rate (total count rate) of particles having a diameter greater than 0.3 μm during a 3 minute test period immediately after 2 minutes of washout of surrounding particles from the lung was measured with a device similar to that illustrated in figure 2. The device had a Climet CI-500B optical particle counter. The device accurately measures particles in the range of 300 to 2500 nm. A series of filters removes all background particle noise.

Figure 13 shows the effect of the inhalation process on the particle count rate of the resulting particles greater than 0.3 μm. The average count rate was seen to decline from the baseline count rate before treatment at all time points up to 6 hours after treatment.

Example 5: characterization of exhaled air-borne particles in human studies

In two separate studies, the particle size distribution and number of particles generated during tidal breathing were measured in 580 adults and 97 children using a measurement system similar to that illustrated in fig. 2.

For both studies, the measurement system included: a fletch-type gas flow meter (Model 1, philips and Bird, Richmond VA) for measuring patient flow rate and an optical particle counter (Climet Model CI-500B, Climet Instruments Company, redlords, CA) for measuring particle count and size distribution in the range of 0.3 to 25 μm during the experiment. After a 2 minute wash-out (breathing air without particles) time, the particle count rate during the 3 minute test was measured.

Similar to the smaller study of example 2, a large inter-individual difference in the number of exhaled particles was seen in both studies. In the adult study, 26% of the population was classified as "super producers", producing greater than 10,000 particles per minute and 94% of the particles measured in the study. The number of counts per minute ranges up to almost 5 orders of magnitude (order of magnitude).

In the study of exhaled particle production by children, 12% of the population was classified as "super producers" under the same criteria and accounted for 86% of the total number of particles produced. Particle counts per minute range is also almost of the order of 5.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention disclosed herein. Such equivalents are intended to be encompassed by the following claims.

Claims (19)

1. A diagnostic device for measuring the exhalation of particles from an individual, comprising a disposable set and a main housing,

the disposable set includes a mouthpiece, a two-way filter and a low resistance one-way valve,

the main box body comprises a particle counter and a computer, and

wherein the mouthpiece has an outlet connected to the filter and the one-way valve,

one end of the filter is exposed to the ambient environment and the other end is connected to the mouthpiece, an

The disposable set is connected to the main tank via two connecting pipes.

2. The device of claim 1, wherein the filter is capable of removing particles having a size greater than or equal to 0.1 microns in diameter.

3. The device of claim 1, wherein the mouthpiece is selected from the group consisting of a mouthpiece designed to allow a user to place their lips around the mouthpiece, a nasal cannula, a mask capable of covering the mouth and nose of the user, and a mask capable of covering the nose of the user.

4. The device of claim 3, wherein the mouthpiece includes a curved flange and two projections, wherein the mouthpiece is designed to allow a user to position the flange between their lips and teeth to form a seal when the user bites on the projections.

5. The device of claim 1, wherein the filter is a combination of two or more filters.

6. The apparatus of claim 1, wherein the particle counter is selected from the group consisting of electromigration, ballistic, electrostatic ballistic, infrared spectroscopy, laser diffraction, and light scattering particle counters.

7. The apparatus of claim 1, wherein the particle counter is an optical particle counter.

8. The apparatus of claim 1, wherein the particle counter is connected to the computer in a manner that allows control instructions to be transmitted from the computer to the particle counter.

9. The apparatus of claim 1, wherein the computer is a microprocessor internal or external to the particle counter.

10. The apparatus of claim 1, further comprising a gas flow meter coupled to the filter and positioned between the filter and the ambient environment.

11. The apparatus of claim 10, wherein the gas flow meter is a fleshy-type gas flow meter or a leigh-type gas flow meter.

12. The apparatus of claim 10, wherein the gas flow meter operates by measuring a pressure differential across a bypass around the laminar flow unit or measuring a bypass flow rate through the bypass around the laminar flow unit.

13. The device of claim 10, further comprising:

a differential pressure sensor capable of measuring a pressure drop across the flow meter, an

A signal conditioner connected to the differential pressure sensor and capable of amplifying a signal and transmitting the signal to the computer.

14. A method of measuring the rate and size of particle exhalation by a subject using the diagnostic device of claim 1, comprising:

(i) placing a mouthpiece in or on the mouth or nose of the individual,

(ii) drawing through air via the mouthpiece, wherein the air is drawn through the filter prior to the drawing,

(iii) the one-way valve is used for breathing out and breathing in through the mouthpiece,

(iv) measuring the number of particles and the size of the particles using the particle counter, and

(v) data from the particle counter is provided to the computer.

15. The method of claim 14, wherein during step (ii), air is drawn through a gas flow meter before being drawn through the filter.

16. The method of claim 14, further comprising providing data from the signal conditioner to a computer prior to step (iii).

17. The method of claim 14, wherein steps (ii) through (v) are repeated a plurality of times.

18. The method of claim 17, further comprising (vi) calculating average particle size, average particle distribution, and average rate of particle production.

19. The method of claim 18, further comprising: (vii) inhalation formulation which, when administered to a mucosal lining of a human or other animal, alters the surface viscoelastic properties of the mucosal lining, the surface tension of the mucosal lining or the bulk viscosity of the mucosal lining; and then repeating steps (i) to (vi).