CN101137325A - Method and device for decreasing contamination - Google Patents

Abstract

The present invention is described herein as a method and apparatus for determining particle production rate and particle size in an individual. The equipment (10) includes: mouthpiece (12), filter (14), low-resistance one-way valve (16), particle counter (20) and computer (30). Optionally, the device also has a gas flow meter (22). Data obtained using the device can be used to decide whether a formulation to reduce particle shedding should be administered to an individual. This equipment is particularly useful before and/or after entering a cleanroom to ensure that cleanroom standards are maintained. The apparatus can also be used to identify animals and humans prone to increased exhaled airborne particulates (referred to herein as "overproducers", "superproducers", or "superdispersors"). The invention herein also describes formulations that reduce particle production. An amount of the formulation sufficient to alter the biophysical properties in the mucosal lining of a human is administered. When applied to mucosal lining fluids, the formulations alter physical properties such as: the colloidal character of the mucosal lining at the air/liquid interface, surface elasticity, surface viscosity, surface tension, and bulk viscoelasticity. It is especially important in clean room applications that a sufficient amount of the formulation is administered to reduce ambient contamination from particles when breathing, coughing, sneezing or talking. In a specific embodiment, the formulation for administration is a non-surfactant solution. In one embodiment, the formulation is a conductive formulation containing a conductive agent such as a salt, an ionic surfactant, or another substance that is in an ionic state or that readily ionizes in an aqueous or organic solvent environment. Preferably the formulation is applied as a spray.

Description

Methods and equipment for reducing pollution

【Technical field】

The present invention is in the field of methods, formulations and apparatus for reducing particle emissions and contamination in various environments, and in particular for use in cleanrooms.

【Background technique】

A cleanroom is a controlled environment in which a product is manufactured. A clean room is a space where the concentration of airborne particles is controlled within a specific range. The reduction of sub-micron airborne pollution is a regulatory process. These contaminations can be generated by people, processes, facilities and equipment. These pollutants must be continuously removed from the air. The degree to which particles need to be removed depends on the desired criteria. The most commonly used standard is Federal Standard 209E. 209E is a document for establishing air cleanliness standard classification for the level of airborne particles in the clean room or clean zone (clean zone). Follow strict rules and procedures to avoid product contamination.

The table below shows the most recent cleanroom classifications. Note: ISO class 2 is equivalent to 209 class 10.

Table 1: Cleanliness level of airborne particles

Grading number number (N) Maxinmm concentration limits (particles/m ³ of air) for particles equal to and larger than the sizes listed below 0.1 microns 0.2 microns O.3 micron 0.5 micron 1 micron 5 microns ISO 1 10 2 ISO 2 100 twenty four 10 4 ISO 3 1,000 237 102 35 8 ISO 4 10,000 2,370 1,020 352 83 ISO 5 100,000 23,700 10,200 3,520 832 29 ISO 6 1,000,000 237,000 102,000 35,200 8,320 293 ISO 7 352,000 83,200 2,930 ISO 8 3,520,000 832,000 29,300 ISO 9 35,200,000 8,320,000 293,000

The only way to control pollution is to control the entire environment. The speed and direction of air flow, pressure transmission, temperature, humidity and special filtration must be strictly controlled. Whenever possible, there is also a need to control or reduce the source of these particulates. Use strict procedures and methods to plan and manufacture clean rooms. It is commonly found in the electronics, pharmaceutical, biopharmaceutical, medical device industries, and other stringent manufacturing environments.

It only takes a quick air monitor in a clean room to compare it to a typical office building to see the difference. The air in a typical office building contains 500,000 to 1,000,000 particles (0.5 micron (micron) or larger) per cubic foot of air. A Class 100 cleanroom is designed to never allow more than 100 particles (0.5 microns or larger) per cubic foot of air. Class 1000 and Class 10,000 cleanrooms are designed to limit particles to 1,000 and 10,000 particles, respectively.

A human hair is about 75 to 100 microns in diameter. Particles 200 times smaller than a human hair (0.5 micron) can cause major disasters in a clean room. Contamination can cause expensive downtime and increase product costs. Once a cleanroom is established, it must be maintained and cleaned to an equally high standard.

Contamination is the process or action that results in the soiling of a substance or surface with a polluting substance. There are two broad classifications of surface contamination: film types and particulate matter. These contaminants can create "fatal flaws" in microcircuits. Film contamination of as little as 10nm (nanometer) can drastically reduce the adhesion of coatings on wafers or wafers. Particles 0.5 micron or larger are widely accepted targets. However, some industries are now targeting even smaller particles.

Some of the pollutants are listed below. Any of these can be a source of strangling circuits. Avoiding the entry of these contaminants into the cleanroom environment is the main goal. Many of these contaminants have been found to come from five basic sources: facilities, people, tools, fluids, and manufactured products.

1. Facility: Walls, floors and ceilings; coatings and coverings; building materials (plasterboard, sawdust, etc.); debris from air cleaning regulators; room air and steam; spills and leaks.

2. People: skin debris and oil; cosmetics and perfume; saliva; clothing debris (threads, fibers, etc.); hair.

3. Tool production: friction and wear particles; lubricants and radiation; vibration; brooms, mops and dust collectors.

4. Fluids: particles floating in the air; organisms and moisture; floor paint or coatings; cleaning chemicals; plasticizers (heating to remove gases); deionized water.

5. Product development: silicon wafers; quartz fragments; clean room fragments; aluminum particles.

Current methods and devices for reducing pollution include HEPA (High Efficiency Particulate Air) filters. These filters are very important in maintaining contamination control. It has a minimum particle-collective efficiency of 99.97% to filter particles as small as 0.3 microns. Cleanrooms are designed to achieve and maintain airflow, which is substantially the bulk of air moving along parallel flow lines at a uniform velocity in a confined area. This air flow is called laminar flow. The more restrictions there are on the airflow, the more turbulence there is. Turbulence causes particle movement. In addition to HEPA filters commonly used in clean rooms, there are several other filtration structures used to remove particles from gases and liquids. These filters generally provide effective contamination control. Cleanliness is also an essential element in pollution control. Clothing requirements in a cleanroom will vary from location to location. Gloves, face shields and hoods are standard equipment in nearly every cleanroom environment. Workwear is increasingly used. Coveralls are required in very clean environments. Everyday items must be carefully selected and used in a clean room. Wipes, cleanroom paper and pencils and other cleanroom supplies must be carefully screened and selected. Inspection of the local clean room is necessary to agree and accept the rules for the entry of these items into the clean room. In fact, many cleanroom supervisors will have an agreed list of such items.

When a person is in a clean room, there are two considerations, physical and psychological. Physical actions such as quick movements and playfulness can increase pollution. Psychological considerations such as room temperature, humidity, claustrophobia, odors and workplace attitudes are all important. The methods of human pollution include skin debris, oil, sweat and hair caused by the process of human regeneration; behaviors including speed of movement, sneezing and coughing; work habits and attitudes and communication between workers. Humans are the main source of contamination in cleanrooms, as shown in Table 2 below. Table 2 lists typical human activities and the corresponding velocity or particle production (number of particles produced per minute). Particles are 0.3 microns and larger.

Table 2: Typical activities and particle production rates

human activity Particle (0.3 micron or larger) production speed (particles/min) immobility (standing or sitting) 100,000 Walk about 2mph 5,000,000 Walk about 3.5mph 7,000,000 Walk about 5mph 10,000,000 play around 100,000,000

It is an object of the present invention to provide an apparatus and method for reducing pollution in an environment such as a clean room.

It is a further object of the present invention to provide methods for reducing or limiting the airborne transmission of viruses and bacteria in environments such as clean rooms.

A still further object of the present invention is to make an apparatus for measuring the number of emitted particles and the particle size to determine whether a formulation for reducing particle emission is required.

【Content of invention】

Cross reference to related applications

This application claims priority to U.S.S.N. 60/642,643 filed January 10, 2005, International Application PCT/US2005/006903 filed March 3, 2005, and U.S.S.N 60/682,356 filed May 18, 2005 .

Methods and apparatus for determining the particle production rate and the particle size range produced on an individual are described herein. The equipment (10) includes: 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 has a gas flow meter (22). Data obtained using this device can be used to determine the need for formulations to reduce particle emissions. Data obtained from the use of this equipment can be used to determine if formulations to reduce particle emissions are required. This equipment is especially useful before and/or after entering a cleanroom to ensure cleanroom standards are maintained. The device can also be used to identify animals and humans prone to increased exhaled airborne particulates (referred to herein as "overproducers", "superproducers", or "superdispersors").

Formulations that reduce particle production are also described herein. An effective amount of the formulation sufficient to alter the biophysical properties in the mucosal lining of a human is administered. When applied to mucosal lining fluids, the formulations alter physical properties such as: the colloidal character of the mucosal lining at the air/liquid interface, surface elasticity, surface viscosity, surface tension, and bulk viscoelasticity. Administration of an effective amount of the formulation to reduce ambient contamination from particles upon breathing, coughing, sneezing or talking is especially important in clean room applications. In a specific embodiment, the formulation for administration is a non-surfactant solution. In one embodiment, the formulation is a conductive formulation containing a conductive agent such as a salt, an ionic surfactant, or another substance that is in an ionic state or that readily ionizes in an aqueous or organic solvent environment. One or more active agents (eg, antiviral substances, antimicrobial substances, anti-inflammatory substances, proteins or peptides) may be included in the formulation.

【Detailed ways】

Pulmonary mucociliary clearance is the primary mechanism by which the airways are kept clean, freeing particles from being present in the liquid film that covers the airways. Conducting airways are lined with ciliated epithelium that flaps and directs a layer of mucus toward the larynx, clearing the airways from the lowest ciliated region for 24 hours. The liquid coating consists of water, sugars, proteins, glycoproteins and lipids. In humans, rats and guinea pigs, a fluid lining develops on the airway epithelium and submucosal glands, and the thickness of this layer ranges from a few micrometers in the trachea to about 1 micrometer in the terminal airways.

A second important mechanism for maintaining lung cleanliness is the transfer of power through the flow of air through the lungs to the mucus coating. Coughing increases this power transfer and is also used by the body to help remove excess mucus. Coughing becomes important when mucus is not adequately removed by ciliary flapping alone, which also occurs in many disease states associated with hypersecretion of mucus. Air velocities of up to 200 meters per second (m/s) can be generated in a powerful cough. At this air velocity, an unstable sinusoidal disturbance at the onset of the mucus layer has been observed. This disturbance results in increased power transfer from air to mucus, thus accelerating the rate at which mucus is cleared from the lungs. Experiments have shown that this disturbance is initiated when the air velocity exceeds some important values, which are functions of film thickness, surface tension, and viscosity (M. Gad-El-Hak, R. F. Blackweler, J. J. Riley. J. Fluid Mech. (1984) 140:257-280). Theoretical predictions and experiments with mucus-like membranes show that the critical velocity of the initiation wave disturbance in the lungs is in the range of 5 to 30 m/s.

From the above discussion of cleanrooms it is clear to (1) measure particle production rates and particle size ranges produced by individuals, (2) predict who will generate the most contamination, and (3) reduce the number of particles produced by breathing, coughing Pollution from , movement, etc. will be very beneficial.

The first and second objectives can be achieved using equipment, as described herein, that measures the size and number of particles produced on an individual basis. Particle production can be measured at rest or during various activities. This enables a decision as to whether a particle emission-reducing formulation should be administered to an individual, and/or allows selection of an individual with minimal particle generation in a clean room environment.

The third objective can be achieved by administering formulations that reduce particle production, eg, formulations containing substances that readily ionize in aqueous or organic solvent environments (also referred to herein as "conductors"), as described herein. In one embodiment, the formulation is administered to one or more individuals using a device that provides an aerosol that sprays a fine mist of the formulation into the lung area and/or nasal area of the individual, thereby reducing particle production . Individuals can be treated before entering the clean room and/or after entering the clean room.

I. DIAGNOSTIC EQUIPMENT FOR DETERMINING PARTICLE GENERATION (VELOCITY AND SIZE RANGE)

Diagnosis of animals or humans during exhalation to measure particle production rate and size range of particles produced. Analysis of this data can be used to determine the need for formulations that reduce particle emissions. This device is especially useful before entering the cleanroom or while the user is working in the cleanroom to ensure cleanroom standards are maintained. The device can also be used to identify animals and humans prone to increased exhaled airborne particulates (referred to herein as "overproducers", "superproducers", or "superdispersors"). This can be accomplished by screening for a number of factors including measurements of exhaled and inspiratory breath, estimates of exhaled particle counts, estimates of exhaled particle size, estimates of tidal volume and respiratory rate at the time of sampling, and estimates of viral and bacterial infectivity. Estimation of exhaled particle counts is done at a respiratory flow rate (LPM) of about 10 to about 120 liters per minute.

A diagnostic instrument (10) for measuring particles produced and exhaled by humans is illustrated in Figures 1 and 2. As shown in Figure 1, the device (10) contains a mouthpiece (12). The outlet (13) of the mouthpiece (12) is attached to the filter (14) and the low-resistance one-way valve (16) through a branch connecting pipe (18), such as a Y-shaped connecting pipe or a T-shaped connecting pipe. The one-way valve (16) is typically located in a tube (19) which forms one half of the connecting tube (18) or is directly attached to one end of the connecting tube (18). At the end remote from the outlet (13) of the mouthpiece, a tube (19) is attached to a particle counter (20). The particle counter (20) is connected to the computer (30) in such a manner that data can be supplied to the computer (30). Data from the particle counter (20) is sent to a computer (30) allowing the user to read, analyze and interpret the data. In one embodiment, the device is portable and optionally battery operated.

Any suitable mouthpiece can be used. In a specific embodiment, as illustrated in Figures 1 and 2, the mouthpiece (12) is designed so that the user can place his lips around the outside of the mouthpiece, thus creating a gap between his lips and the mouthpiece. A seal is formed between the mouths. In another embodiment, the mouthpiece is in the form of a nasal cannula forming a seal between the user's nostril and the cannula. In another embodiment, the mouthpiece is in the form of a mask covering the user's mouth and nose. In this particular embodiment, a seal is formed between the user's face and the mask. In another embodiment, the mouthpiece covers only the user's nose in the form of a mask. The mouthpiece is preferably disposable.

The filter (14) is typically a high efficiency (>99.97% at 0.3 micron (μm)), low pressure drop (<2.5 centimeter (cm) _H2O at 60 liters/minute) filter, optionally with >99.99% bacteria/virus removal efficiency. The filter is selected to remove particles having at least a particle size within the measurable range of the particle counter (20), preferably the filter removes particles of a size even smaller than the measurable range of the particle counter. Preferably the filter is designed to remove particles with a diameter greater than or equal to 0.1 microns. In one embodiment, two or more filters (14) (not shown) in succession may be included between the mouthpiece and the ambient air to avoid contamination of the upstream system between users. In this particular embodiment, one or more filters may be replaced by a set of parallel filters to reduce flow resistance.

In a preferred embodiment, the mouthpiece (12), the filter (14), the connecting pipe (18) and the one-way valve (16) are all disposable. Optionally, the mouthpiece (12), the filter (14), the connecting pipe (18) and/or the one-way valve (16) are all formed of biodegradable substances.

The particle counter (20) must be sensitive enough to correctly count sub-micron sized particles and can be designed and assembled as described. The measurement of particle number and particle size can be done by electrical mobility analysis, impact, electrostatic impact, infrared spectroscopy, laser diffraction or light scattering. Examples of particle counters currently available to measure particle count and size include: scanning mobility particle sizer (SMPS) (TSI, Shoreview MN), Andersen cascade impactor or new generation Next generation pharmaceutical impactor (Copley Scientific, Nottingham UK), electrical low pressure impactor (ELPI) (Dekati, Tampere Finland) and laser particle size analyzer (Helos) (Sympatec, Clausthal, Germany). In a preferred embodiment, the particle counter is an optical particle counter, preferably the particle counter operates with light scattering using a laser or laser diode light source. In this preferred embodiment, the optical particle counter has a range of at least 0.3 to 5 micrometers ([mu]m) and preferably from 0.1 to 25 micrometers ([mu]m). Optical particle counting differentiation has a measurement range of at least 2 wavebands and preferably at least 4 wavebands. The optical particle counter operates at a steady sample flow rate of at least 0.1 cubic feet per minute, and preferably at least 1 cubic foot per minute, which can be manufactured and controlled as part of the particle counter or as a separate vacuum pump and flow regulator components (not shown in the figure). Currently available optical particle counters suitable for this preferred embodiment include Ultimate 100 models CI-450, CI-500, CI-550 (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 such a manner that data from the particle counter (20) is transmitted to the computer (30). If necessary, the particle counter (20) is also connected to the computer (30) in such a way that control instructions are transmitted from the computer (30) to the particle counter (20). The computer can be an internal or external microprocessor connected to the particle counter.

In a specific embodiment, as illustrated in FIG. 2, the device (10) includes a gas flow meter (22). The gas flow meter (22) has low resistance and does not affect the breathing speed of the user, for example: a Fleisch or Lilly barometric flow meter (pneumotachometer) or a pneumotachometer (pneumotachograph). Alternatively, the gas flowmeter is used to measure the temperature change or heat transfer from an electric heating wire (such as a hot wire anemometer), or to count the number of cycles per unit time of a small turbine (such as a turbine flowmeter), or to measure Flow is measured by differential pressure in a restricted bypass or by-pass velocity through a bypass, such as a laminar flow element. Volume displacement is then calculated as time combined with flow.

Barometric flow meters are commonly used to measure the flow rate of different gases during breathing. The air is passed through short tubes (eg Fleisch tubes) containing meshes that provide little resistance to air flow (shown in the figure). The pressure drop across the mesh is proportional to the flow rate. The pressure drop is very small, usually on the order of a few _mmH2O . A differential pressure transducer (24) is commonly used to measure the pressure drop across a flow meter (eg Fleisch tube) to facilitate detection of this small pressure drop. Preferably the differential pressure converter is connected to a signal conditioner (26) that amplifies the signal and sends it to the computer (30) for data acquisition software. In a preferred specific embodiment, the differential pressure converter (24) is a Validyne DP45-14 differential pressure converter. In a preferred embodiment, the signal conditioner (26) is a Validyne CD15 sine wave carrier demodulator. Barometric flow meters can be used for lung function analysis, or for respiratory resuscitation of the lungs.

In a preferred embodiment, the flow meter (22) is a low velocity mass flow meter measuring bypass flow around a restriction, eg a laminar flow element. In this particular embodiment, the laminar flow element (not shown in the figure) consists of a set of parallel tubes sized such that the flow through the tubes supplies a breathable flow rate under a laminar flow regime, between +130 And -70 liters/minute is better, its positive flow represents the flow direction when distributing. In a preferred embodiment, the low flow meter provides a digital output with a frequency greater than 5 hertz (Hz). An example of such a flow meter is Sensirion model ASF1430.

In another embodiment, the device (10) comprises connections to perform further breath analysis simultaneously or measure particle size and count continuously. Example: Exhaled breath concentrate can be collected with standard equipment such as an R-tube or exhaled air can be passed through a media filter through a connector (not shown) located along the tube (19) for further analysis , leading to the optical particle counter (20).

II. Formulations to Reduce Particle Production

Biological airborne particles are formed as a result of destabilization of the endogenous interfacial layer within the airways. The formulations described herein are effective in altering the biophysical properties of the mucosal lining. Such properties include, for example, increased mucus surface gelation, mucosal lining surface tension, mucosal lining surface elasticity, and mucosal lining bulk viscoelasticity. The formulations described herein are effective in reducing particle shedding by avoiding or reducing the formation of exhaled particles from the oropharynx or nasal cavity. This can be achieved simply by administering isotonic saline (but not in such quantities as to cause the individual to cough up) or hypertonic saline to cause the cellular lining of the lung's airways to further dilute the endogenous surfactant layer by producing water Dilution of the endogenous interfacial pool changes the endogenous interfacial layer.

It has been found that the physical properties of the endogenous surfactant fluid in the lungs can be altered by the administration of saline solutions, as can administration of saline solutions containing other substances such as osmotically active substances, 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% to about 10% by weight. A preferred spray solution for modifying the physical properties of the mucosal lining is isotonic saline.

conductivity formulation

Preferred formulations to alter the biophysical properties of the lung lining fluid are those that contain certain charge concentrations and mobility, and thus are fluid conductive. In a preferred embodiment, the formulation comprises a conductive aqueous solution or suspension (also referred to herein as "conductive formulation"). Suitable conductivity formulations typically have conductance values greater than 5,000 μS (microseconds)/cm, preferably greater than 10,000 μS/cm, and more preferably greater than 20,000 μS/cm. These formulations are particularly useful for administration to patients to inhibit particle shedding. Solution conductivity is a product of ionic strength, concentration, and fluidity (the latter two collectively provide formulation conductivity). Either form of the ionic component (anionic, cationic or zwitterionic) can be used. These conductive substances modify the properties of the mucosal lining by, for example, acting as cross-linking agents in mucus. The ionic components of the formulations described herein can interact with strongly bound anionic glycoproteins in normal tracheal branch mucus. This interaction is due to covalent or non-covalent interactions, including hydrogen bonding, hydrophobic and electrostatic interactions (Dawson, M., Wirtz, D., Hanes, J. (2003) TheJournal of Biological Chemistry.Vol.278, No.50, pp 50393-50401) affect the state of the airway lining fluid-air/liquid surface, and briefly affect the nature of physical entanglements.

Optionally, formulations include mucoactive or mucolytic agents, such as: MUC5AC and MUC5B mucins, DNA, N-acetylcysteine (NAC), cysteine, nylides Nacystelyn, dornase alfa, gelsolin, heparin, heparin sulfate, P2Y2 agonists (eg, UTP, INS365), and sodium nitrate (Nedocromil sodium).

i. Conductive agent

Formulations containing substances (also referred to herein as "conductors") that readily ionize in an aqueous or organic solvent environment, such as: salts, ionic surfactants, charged amino acids, charged proteins or peptides, or charged substances (cations, anions or zwitterions). Suitable salts include the elements: sodium, potassium, magnesium, calcium, aluminum, silicon, scandium, titanium, vanadium, chromium, cobalt, nickel, copper, manganese, zinc, tin, and any salt form of the like elements. Examples include sodium chloride, sodium acetate, sodium bicarbonate, sodium carbonate, sodium sulfate, sodium stearate, sodium ascorbate, sodium benzoate, sodium dihydrogen phosphate, sodium phosphate, sodium bisulfite, sodium citrate , Sodium Tetraborate, Sodium Gluconate, Calcium Chloride, Calcium Carbonate, Calcium Acetate, Calcium Phosphate, Calcium Alginate, Calcium Stearate, Calcium Dienoate, Calcium Sulfate, Calcium Gluconate, Magnesium Carbonate, Magnesium sulfate, Magnesium stearate, Trisilicate, Potassium bicarbonate, Potassium chloride, Potassium citrate, Potassium borate, Potassium bisulfite, Potassium hydrogen phosphate, Potassium alginate, Potassium benzoate, Magnesium chloride, Copper sulfate, Chromium chloride, tin(II) chloride, and sodium metasilicate and similar salts. Suitable ionic surfactants include sodium lauryl sulfate (SDS) (also known as sodium lauryl sulfate (SLS)), magnesium lauryl sulfate, polysorbate 20 (polysorbate 20), polysorbate 80, and similar to surfactants. Suitable charged amino acids include L-lysine, L-arginine, histidine, aspartic acid, glutamic acid, glycine, cysteine, tyrosine. Suitable charged proteins or peptides include proteins and peptides containing charged amino acids, Calmodulin (CaM) and Troponin C. Charged phospholipids can be used, for example: 1,2-dioleyl-sn-glycerol-3-ethylphosphocholine trifluoromethanesulfonate (EDOPC) and alkylphosphocholine triesters.

Preferred formulations are saline formulations such as: saline (0.15 molar (M) NaCl or 0.9%) solution, _CaCl solution, _CaCl in saline solution, or saline solution containing ionic surfactants, For example: SDS or SLS. In a preferred embodiment, the formulation contains saline solution and _CaCl2 . Suitable concentration ranges for saline or other conductive/charged compounds may vary from about 0.01% to about 20% (weight conductive or charged compound/total formulation weight), preferably between 0.1% to about 10% Between (weight of conductive or charged compound/total weight of formulation), optimally between 0.1% and 7% (weight of conductive or charged compound/total weight of formulation).

吸入性溶液(GSK)为硫酸沙丁胺醇(albuterol sulfate)溶液用于长期治疗气喘(asthma)及运动引发的支气管痉挛症状。制备雾化的

溶液(由病人准备)为混合1.25至2.5毫克(mg)的硫酸沙丁胺醇(在0.25至0.5毫升(mL)的水溶液)与无菌正规盐水达到总体积3毫升(mL)。无严重副作用与

雾化施用盐水到肺部有关，即使雾化时间可为5至15分钟。亦可施用更大量的盐水以引发吐出。通常此类的盐水为高张(氯化钠浓度大于0.9％，通常为5％)，且一般施用达20分钟。Saline solutions and small amounts of therapeutically active agents (eg, beta agonists, corticoids, or antibiotics) have been administered chronically to the lungs over time. For example:

Inhalation solution (GSK) is albuterol sulfate solution for long-term treatment of symptoms of asthma and exercise-induced bronchospasm. Preparation of atomized

The solution (prepared by the patient) was to mix 1.25 to 2.5 milligrams (mg) of albuterol sulfate (in 0.25 to 0.5 milliliters (mL) of water) with sterile regular saline to achieve a total volume of 3 milliliters (mL). No serious side effects and

Nebulized administration of saline into the lungs is relevant, even though the nebulization time can be 5 to 15 minutes. Larger volumes of saline can also be administered to induce vomiting. Typically such saline is hypertonic (sodium chloride concentration greater than 0.9%, usually 5%), and is typically administered for up to 20 minutes.

B. Osmotically Active Substances

Many substances are osmotically active, including binary salts such as sodium chloride or any other kind of salt, or sugars such as mannitol. Because of their ionization and possible size, osmotically active substances normally do not readily penetrate cell membranes and thus exert osmotic pressure on adjacent cells. This osmotic pressure is necessary to the physical environment of the cellular material and regulation of this pressure moves water in and out of the cell by the cell. Solutions administered into the lungs are isotonic and normally do not create an osmotic imbalance in the pulmonary fluid, so only the natural endogenous lung fluid is diluted with water and saline. Solutions with high osmolarity (ie, hypertonic solutions) create an unbalanced osmotic pressure with greater pressure in the lung fluid, causing the cells to pump water into the lung fluid, thus further diluting the lung surfactant complex.

C. Active ingredient

The formulations disclosed herein can be used in any route for the administration of various organic or inorganic molecules, especially small molecule drugs, such as: antiviral and antibacterial drugs, including antibiotics, antihistamines, bronchodilators, cough suppressants, Anti-inflammatory agents, vaccines, adjuvants and expectorants. Examples of macromolecules include proteins and large peptides, polysaccharides and oligosaccharides, DNA and RNA nucleic acid molecules and their analogs having therapeutic, prophylactic or diagnostic activity. Nucleic acid molecules include genes, antisense molecules that bind to complementary DNA to inhibit transcription, and ribozymes. Preferred agents are antivirals, steroids, bronchodilators, antibiotics, mucus production inhibitors, and vaccines.

In preferred embodiments, the concentration of active agent is between about 0.01% and about 20% by weight. In a more preferred embodiment, the concentration of the active agent is between 0.9% and about 10% by weight.

D. Carriers and Sprays for Application

Formulations can be administered as solutions, suspensions, sprays, mists, foams, colloids, vapors, drops, granules or dry powders (e.g. metered dose inhalers with HFA propellants, metered dose inhalers without HFA propellants, nebulizers , pressure tank or continuous sprayer). Carriers can be divided into administration by solution or suspension (liquid formulations) and administration by particles (dry powder formulations).

Dosage Forms for Administration to Different Mucosal Surfaces

For administration to the mucosal surfaces of the respiratory tract, formulations are typically in the form of solutions, suspensions or dry powders. Nebulized formulations are preferred. Formulations can be delivered by any aerosol maker, eg a dry powder inhaler (DPI), nebulizer or pressurized metered dose inhaler (pMDI). The term "spray" as used herein refers to any formulation having finely divided spray particles, typically less than 10 microns in diameter. Aqueous formulation spray particles preferably have an average diameter of about 5 microns, for example between 0.1 and 30 microns, preferably between 0.5 and 20 microns and more preferably between 0.5 and 10 microns .

For application to the oral mucosa, including the buccal mucosa, formulations may be administered as a solid, which dissolves and/or adheres to the mucosal surface upon application to the mouth, or as a liquid.

A preferred nebulizer solution to alter the physical properties of the lung lining fluid is isotonic saline. Sprays may consist of only one solution, eg an aqueous solution, preferably a saline solution. Alternatively, sprays may consist of suspended aqueous solutions or dry particles.

liquid formulation

Sprays have been developed to administer therapeutic agents to the respiratory tract. See, eg, Adjei, A. and Garren, J. Pharm. Res., 7:565-569 (1990); and Zanen, P. and Lamm, J.-W.J. Int. J. Pharm., 114:111 -115 (1995). These are typically formed by nebulizing liquid formulations, eg solutions or suspensions, under pressure via a nebuliser or using a metered dose inhaler ("MDI"). In preferred embodiments, the liquid formulations are aqueous solutions or suspensions.

dry powder formulation

The shape of the airways is a major barrier to drug diffusion in the lungs. The lungs are designed to catch particles such as dust when foreign matter is inhaled. There are three basic deposition mechanisms: inertial impact (impaction), sedimentation (sedimentation), and Brownian motion (Brownianmotion) (JMPadfield.1987.In: D.Ganderton & T.Jones eds.Drug Delivery to the Respiratory Tract, Ellis Harwood, Chicherster, UK). Inertial impact occurs when particles are unable to stay in the airflow, especially in airway branches. It is adsorbed to the mucus layer covering the bronchial walls and cleared by mucociliary movements. Inertial impact mostly occurs when the particle diameter is larger than 5 microns (μm). Smaller particles (<5 micrometers (μm)) can remain in the airstream and be transported deep into the lungs. Subsidence usually occurs in the lower part of the respiratory system, where the airflow is slower. Very small particles (<0.6 microns) can be deposited due to Brownian motion. This mechanism is less desirable because the target of deposition is not the alveoli (N. Worakul & JR Robinson. 2002. In: Polymeric Biomaterials, ^{2 nd} ed. S. Dumitriu ed. Marcel Dekker. New York).

Aerodynamically light particles for inhalation preferably have an average diameter of at least about 5 microns, eg, between about 5 and 30 microns, most preferably between 3 and 7 microns. For targeted administration to selected areas of the respiratory tract, such as the deep lungs or the upper airways, particles can be manufactured with a suitable substance, surface roughness, diameter and tap density. For example: higher density or larger particles can be used for upper airway administration. Similarly, mixtures of different sized particles of the same or different therapeutic agents can be provided to different target areas of the lung in one administration.

As used herein, the term "aerodynamic photoparticles" refers to particles having an average or compactness of less than about 0.4 g/cm- ³ . The compactness of dry powder particles can be measured by the standard USP compactness. Tightness is a standard measure of envelope mass density. The shell mass density of an isotropic particle is defined as the mass of the particle divided by the shell volume of the smallest enclosable sphere. Features of low density include irregular surface texture and pore-like structure.

Dry powder formulations ("DPFs") of large particle size have enhanced flow characteristics, such as: less aggregation (Visser, J., Power Technology 58: 1-10 (1989)), easier aerosolization (aerosolization) and Potentially less phagocytosis. Rudt, S. and R.H. Muller, J. Controlled Release, 33:263-272 (1992): Tabata, Y., and Y. Ikada, J. Biomed. Mater. Res., 22:837-858 (1988). Dry powder aerosols for inhalation therapy generally have a mean diameter mainly in the range of less than 5 microns, with an aerodynamic diameter preferably in the range between 1 and 10 microns. Ganderton, D., J. Biopharmaceutical Science, 3:101-105 (1992); Gonda, I. "Physico-Chemical Principle in Aerosol Delivery" in Topics in Pharmaceutical Sciences 1991, Crommelin, D.J. and K.K. Midha, Eds., Medpharm Scientific Publishers, Stuttgart, pp. 95-115 (1992). Large "carrier" particles (without medicament) are applied with the treatment spray, helping to achieve effective gasification, among other possible benefits. French, D.L., Edwards, D.A. and Niven, R.W., J. Aerosol Sci., 27:769-783 (1996). Particles with decomposition and release times ranging from seconds to months can be designed and fabricated with methods established in this field.

Particles may contain transduction agents alone, or in combination with pharmaceutical agents, antiviral agents, antibacterial agents, antimicrobial agents, surfactants, proteins, peptides, polymers, or combinations thereof. Representative surfactants include L-alpha-phosphatidylcholinedipalmitoyl ("DPPC"), diphosphatidyl glycerol (DPPG), 1,2-dipalmityl-sn-glycerol- 3-phospho-L-serine (DPPS), 1,2-dipalmitate-sn-glycero-3-phosphocholine (DSPC), 1,2-distearate-sn-glycero-3-phospho Ethanolamine (DSPE), 1-palmitoyl-2-oleoylphosphatidylcholine (POPC), fatty alcohol, polyoxyethylene-9-lauryl ether, surface-active fatty acid, sorbitan trioleate ) (Span 85), glycocholate, surfactin, poloxamer, sorbitol fatty acid ester, tyloxapol, phospholipids and alkylated sugars. The polymers can be modified to optimize particle characteristics including: i) the interaction between the formulation being administered and the polymer providing formulation stability and maintenance of activity upon administration; ii) the rate of polymer breakdown and thus the rate of release of the agent. overview; iii) surface characteristics and targeting capabilities by chemical modification; and iv) particle porosity. The particles can be polymerized using single and double emulsions, solvent evaporation, spray drying, solvent extraction, phase separation, simple and complex coacervation, interfacial polymerization, and other methods well known to those skilled in the art. Particles can be produced using methods known in the art for producing microspheres or microcapsules. The method of manufacture is preferably by spray drying and freeze drying, which must use a conductive/charged material, spray the solution onto the substrate to form droplets of the desired size, and remove the solvent.

III. Administration of Formulations to the Respiratory Tract

Administer conductive formulations to reduce exhaled particle volume

In a preferred embodiment, the conductive formulation contains appropriate conductivity to increase the viscoelasticity of the mucous membrane at the site of application of the formulation to inhibit or reduce biological Formation of suspended particles. Preferably, an effective amount of the formulation is administered to one or more individuals to reduce particle production. The formulation is preferably applied before humans enter the clean room or while humans are working in the clean room to ensure that clean room standards are maintained. If an animal or human is identified as having a tendency to increase exhaled airborne particulates (referred to herein as an "overproducer," "superproducer," or "superspreader"), the formulation can be administered to reduce particle production to avoid or To reduce the spread of infection in humans or animals, or to avoid or reduce the ingestion of pathogens.

B. Administration to the respiratory tract

The airways are structures involved in the exchange of gases between the atmosphere and the bloodstream. The lungs are a branching structure terminating in the alveoli, where gas exchange occurs. The alveolar surface area is the largest area in the respiratory system and is where drug absorption occurs. The alveoli are covered by a thin epithelium without a ciliated or mucus covering and secrete surfactant phospholipids. J.S. Patton & R.M. Platz. 1992. Adv. Drug Del. Rev. 8:179-196.

The respiratory tract consists of the upper airway, including the oropharynx and larynx, followed by the lower airway, which consists of the trachea with branches into the bronchi and bronchioles. The upper and lower airways are called the guiding airways. The terminal bronchioles then divide into respiratory bronchioles leading to the final respiratory zone, alveoli, or deep lung. The deep lungs or alveoli are the primary target for systemically administered inhaled therapeutic aerosols. Formulations are typically administered to an individual to deliver an effective amount to alter physical properties such as surface tension and viscosity of endogenous fluids within the upper airways, thereby enhancing delivery to the lungs and/or suppressing cough and/or enhancing pulmonary clearance. Performance can be measured using the diagnostic equipment described herein. For example: 1 gram volume of saline can be administered to a normal adult. Exhaled particles are then measured. Administration can thus be optimized to the minimum dose and number of particles.

Formulations may be administered using a metered dose inhaler ("MDI"), a nebulizer, an aerosolizer, or using a dry powder inhaler. Suitable equipment is commercially available and described in the literature.

Spray doses, formulations and delivery systems can be selected to meet specific therapeutic applications, e.g. as described in Gonda, 1990, I. Published in Critical Reviews in Therapeutic

Drug Carrier Systems, 6:273-313 "Aerosols for Delivery of Therapeutic and Diagnostic Agents to the Respiratory Tract"; and in Moren "Aerosol Dosage Forms and Formulations" in Aerosols in Medicine, Principles, Diagnosis and Therapy, Moren, et al. , Eds. Esevier, Amsterdam, 1985.

(E.I.Du Pont DeNemours及Co.Crop.)。当从罐子释放出来时，因以压力释放，组合为细致喷雾。因压力减少，推进剂与溶液可完全地或部分地蒸发。Administration can be achieved by one of several methods, eg, using a metered dose inhaler with HFA propellant, a metered dose inhaler without HFA propellant, a nebulizer, a pressure can, or a continuous nebulizer. The patient can mix the pre-suspended dry powder of the treatment with a solvent and then nebulize it. It is more appropriate to use preformed sprayable solutions, which allow adjustment of the application dose and avoid possible loss of the suspension. After nebulization, the spray may be pressurized and administered by metered dose inhaler (MDI). Nebulizers create a fine mist from a solution or suspension to be inhaled by the patient. The apparatus described in US Patent 5,709,202 to Lloyd et al. can be used. MDI typically includes a pressurized tank containing a metering valve, wherein the tank is filled with a solution or suspension and a propellant. The solution itself can act as a propellant, or combinations can be combined with propellants such as:

(EI Du Pont DeNemours and Co. Crop.). When released from the can, it combines into a fine spray due to pressure release. Due to the pressure reduction, the propellant and solution can be completely or partially evaporated.

In an alternative embodiment, the formulation is in the form of a salt or in the form of particles of an osmotically active substance dispersed on or in an inert substance which is placed on the nose and/or mouth and the particles of the formulation are inhaled . The inert material is preferably biodegradable or disposable disposable woven or non-woven fabric, and the fabric is more preferably formed of fibrous materials. An example is the currently marketed tissue (tissue), which contains a lotion to reduce irritation after frequent use. These formulations can be packaged and sold individually or in kits, similar to a kit of tissues or baby wipes, which are readily adapted for use with liquid solutions or suspensions.

In one embodiment, the formulation is administered to one or more individuals using a device that provides an aerosol that sprays a fine mist of the formulation into the lungs and/or nasal area of the individual, thereby reducing particle output. The formulation can be administered to a human or animal by creating an aqueous environment in which the human or animal moves or remains for a sufficient time to adequately hydrate the lungs. Create this atmosphere by using a mister or even a humidifier. A nebulizer or humidifier is preferred for applying conductive formulations. The individual can be treated before the individual enters the clean room and/or after entering the clean room.

IV. Methods of using diagnostic equipment

When using the device as shown in Figures 1 and 2, the user places their lips around the mouthpiece (12). The user seals their airway from the surrounding air, preferably by means of a nose clip and seals their lips over the mouthpiece. If using a mask as a mouthpiece, the user places the mask over their mouth and/or nose. If using a nasal cannula as a 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 his nose and/or mouth, thus sealing the airway from the surrounding air. The user then inhales. Inhaled air entering the system is passed through a filter (14) which removes particles within a predetermined measurement range. Exhaled air passes through the low resistance one-way valve (16) and enters the particle counter (20). The one-phase valve (16) helps to avoid the transmission of exhaled pathogens from a user to the next user.

The exhaled air is passed to the particle counter (20) to measure the particle number and particle size. The particle counter (20) samples at a fixed flow rate, preferably greater than the peak exhalation flow rate, so that at all time points, the average flow direction through the filter (14) enters the system, avoiding loss of exhaled particles entering the filter (14). The particle counter preferably samples at a flow rate greater than 28 liters/minute. The particle counter (20) then provides data from the particle counter (20) to the computer (30). In one embodiment, visual feedback of the user's breathing pattern and cues to maintain a prescribed breathing pattern, such as tidal breathing, are provided. The particle counter (20) can be remotely controlled by a PC or on-site, for example: from an optical particle counter with a touch screen interface for on-site data measurement and analysis or a personal computer with a touch screen for remote data measurement and analysis interface. A controller (not shown) for generation and control of the sample flow rate and the optical particle counter can be internally or externally connected. Inhalation, exhalation and measurement steps can be repeated several times. The computer then calculates the average particle size, average particle distribution, and average rate of particle production. If it is necessary to reduce the number and size of particles exhaled by the user, the particle emission reducing formulations described herein can be administered to the user.

Optionally, the diagnostic instrument (10) is designed to measure particles produced and exhaled by a human with a relevant breathing rate. In this embodiment, as shown in Figure 2, intake air enters the system through a low flow resistance flow meter (22), which together characterizes the user's breathing pattern and particle counting flow rate. The air then enters the filter (14) to remove particles within the measuring range. As described above, exhaled air passes through the low resistance one-way valve (16), through the tube (18) and into the particle counter (20). Data from flow meters, differential pressure transducers and/or signal conditioners are sent to a computer for calculation and analysis.

Based on the rate of particle production and the size of the particles produced, as determined from data obtained using diagnostic equipment, an effective amount of the formulation can be administered to a user to reduce particle production. The formulations can be applied before entering the clean room or after entering the clean room. The invention may be further understood by reference to the following non-limiting examples.

Example

Example 1: In vitro simulation

The simulated cough machine system was designed similarly as described by King Am J. Respir. Crit. Care Med. 156(1):173-7 (1997). Construct an air-tight 6.5 liter Plexiglas tank with additional digital pressure measuring instrument and pressure relief valve as the capacitive function of the lungs. The tank is pressurized and a compressed air cylinder with regulator and air filter is connected to the inlet. At the inlet of the tank, an Asco two-way normal closed solenoid valve (8210G94) with sufficient Cv flow coefficient was connected for gas release. Reinforced solenoid valve with typical 120V, 60Hz light switch wire. The outlet connected to the solenoid valve was a Fleisch no. 4 pneumotachometer, which created the required Poiseuille flow detection "cough" profile. The outlet of the Fleisch tube was connected to the 1/4'' NPT inlet to the model trachea. The Validyne DP45-14 Differential Pressure Transducer measures the pressure drop across the Fleisch tube. Use Validyne CD15 sine wave carrier demodulator to amplify the signal to the data acquisition software. A thin polymeric gel having rheological properties similar to tracheal and bronchial mucus was prepared as described by King et al. Nurs Res. 31(6):324-9 (1982). A solution of locust bean gum (LBG) (Fluka BioChemika) was cross-linked with sodium tetraborate (Na ₂ B ₄ O ₇ ) (JT Baker). 2% w/v LBG was dissolved in boiling Milli-Q distilled water. Concentrated sodium tetraborate solutions were prepared in Milli-Q distilled water. After the LBG solution was cooled to room temperature, a small amount of sodium tetraborate solution was added and the mixture was stirred slowly for 1 minute. The still watery mucus simulant was then pipetted onto a model trachea that created simulated depths based on simple trough geometry. The mucus-mimicking layer was cross-linked 30 min before the "cough" experiment started. At the point of t = 0 min, time points were measured, followed by t = 30 min and t = 60 min. Sodium tetraborate final concentrations ranged from 1 to 3 millimolar (mM). The acrylic model trachea was designed to be 30 cm long with an internal width and height of 1.6 cm. The model trachea is formed as a rectangular tube with an individual mounting top allowing easy access to the mucus simulation layer. Use the gasket and C-clamp to create an airtight seal. Choosing a rectangular section allows for a uniform height of the slime simulation and avoids problems associated with round pipes and gravity drainage. The cross-sectional area of the model trachea is also physiologically relevant. Keep the end of the model trachea open to the atmosphere. The misty solution was applied to the mucus simulation by PARI LC Jet nebulizer and Proneb Ultra compressor. The formulation consisted of normal isotonic 0.9% saline (VWR) and 100 mg/mL of synthetic phospholipids 1,2-dipalmitate-sn-glycerol-3-phosphocholine/epalmitate-2-oleyl-sn-glycerol - 3-Phosphoglycerol (DPPC/POPG) (Genzyme) 7/3% by weight suspended in isotonic saline. With a pipette 3 milliliters (mL) of the selected formulation was transferred to the nebulizer and nebulized until the nebulizer sprayed out the open end and the clamped model trachea troughed on the mucus simulated layer. The model trachea was then attached to the outlet of the Fleisch tube before t=0 min experiment. The t=30 min and t=60 min (post-dose) experiments were also performed.

The created mucus-mimicking biological aerosols were estimated using a Sympatec HELOS/KF laser diffraction particle sizer. Diffraction particles were estimated using the Fraunhoffer method. HELOS is equipped with R2 sub-micron window module (window module) to make the measurement range from 0.25 to 87.5 microns (μm). Before the "cough" experiment, the end of the model trachea was adjusted so that it was no more than 3 centimeters (cm) away from the laser light. Likewise, using a support jack and level, align the bottom of the model trachea with the 2.2 millimeter (mm) laser beam. Dispersed biological aerosols after passing through the diffracted light were collected using a vacuum unit connected to an inert cyclone followed by a HEPA filter. Before each operation, laser for 5 seconds (s) according to the surrounding conditions. After the specific inducing condition of optical concentration (C _opt. ) ≥ 0.2%, the measurement is started, and when C _opt. ≤ 0.2%, stop for 2s. Use Sympatec WINDOX software to create progressive and density profiles versus logarithmic particle sizes by volume. Typical cough profile, consisting of a bidirectional pulse of air passing through a 1.5 millimeter (mm) simulated layer of mucus. The initial flow or air has a flow rate of about 12 L/s for 30 to 50 ms. The second stage lasts for 200 to 500 meters, after which there is a rapid decline.

Biosuspended particle concentrations were measured over time after three coughs in the absence of perturbed mucus simulants, in saline (Fig. 3A, 3B, and 3C), and in the case of surfactant administration (not shown) (Fig. Triple A, Triple B and Triple C). In the absence of disturbance, the biosuspended particle size remains constant over time to an intermediate size of about 400 nm. With the addition of saline, the particle size of biosuspended particles increased from 1 micron (t=0) (Fig. 3A) to about 60 microns (t=30 min) (Fig. minutes) (Fig. 3C).

These in vitro results show that application of saline to the mucus layer resulted in fragmentation with a substantial increase in particle size, possibly due to increased surface tension. As shown by the in vivo results, large size droplets were less able to exit the oral cavity. Therefore, the solution was administered to significantly reduce the amount of exhaled particles. Example 2: Reduction of Exhaled Airborne Particulates in Human Studies

A proof of concept study of exhaled aerosol particle generation was performed using 12 healthy individuals. The objectives of the study were (1) to determine the properties (size distribution and number) of exhaled bioaerosols; (2) to demonstrate the utility of the device sensitive enough to correctly count exhaled particles; (3) to estimate baseline counts of exhaled particles from healthy lungs; and (4) measuring the effect of two exogenously administered treatment sprays on inhibition of exhaled particle counts. Experiments were performed with different particle detectors to determine the average number of particles per liter and the average particle size in healthy human subjects. After inhaling particle-free air, healthy individuals exhale as few as 1 to 5 particles per liter with an average size of 200 to 400 nanometers (nm) in diameter. Significant inter-individual variation occurs in particle numbers, with some individuals exhaling as many as 30,000 particles per liter, notably sub-micron particle sizes. Design and assemble equipment with sufficient sensitivity to correctly count sub-micron sized particles. The laser components in the equipment were calibrated according to the manufacturer's procedures (Climet Instruments Company, Redlands, CA). Particles in the range of 150 to 500 nm are correctly measured with a device having a sensitivity of 1 particle/liter. A set of filters removes all background particle noise.

After obtaining protocol IRB approval, 12 healthy individuals were recruited into the study. Inclusion criteria were good health, age 18 to 25 years, normal lung function (predicted FEV _1- >80%), giving consent and ability to perform measurements. Exclusion criteria were the presence or history of significant pulmonary disease (eg, asthma, COPD, cystic fibrosis), cardiovascular disease, acute or chronic respiratory infection, and women who were pregnant or breastfeeding. An individual who was unable to complete the entire dosing regimen was excluded from data analysis.

After a complete physical examination, the subjects were randomly divided into two groups: those who initially received prototype formulation 1 and those who received prototype formulation 2. After a 2 minute "wash" period of the device, a baseline of exhaled particle production was measured. Estimates were made over a 2-minute period as counts per minute derived from a two-minute average. Following the baseline measurement, the prototype formulation was applied during 6 minutes using a commercially available aqueous nebulizer (Pari Respiratory Equipment, Starnberg, Germany). Formulation 1 consisted of isotonic saline solution. Formulation 2 consisted of a composition of phospholipids suspended in an isotonic saline vehicle. Following administration, exhaled particle counts were assessed at 5 minutes, 30 minutes, 1 hour, 2 hours, and 3 hours after a single administration.

As shown in Figure 4A, substantial intra-individual variability can be derived from baseline particle counts. The data shown are measurements taken prior to application of one of the test sprays. This baseline exhaled particle result points to the existence of a "super-producer" of exhaled aerosols. In this study, a "superproducer" was defined as an individual who exhaled more than 1,000 particles/liter at baseline. Figure 4B shows individual particle counts for individuals receiving Formulation 1. This data shows that a simple formulation of exogenously applied spray can suppress the total number of exhaled particles.

Figure 5A shows the effect of Prototype Formulation 1 on the baseline discovery of two "super-producers" in this cohort. These data show that the prototype formulation can exert a more pronounced effect on the supermaker.

Similar results were also found for the administration of Formulation 2. Figure 5B summarizes the percent change in cumulative exhaled particle counts (vs. baseline) for identified "superproducers" in the two treatment cohorts.

The results from this study demonstrate that exhaled particles, which are significantly less than 1 micron in diameter, can be correctly measured using a laser detection system, and that the number of these particles varies substantially from one individual to another. "Ultrafabricated" individuals respond remarkably well to the administration of a spray that modifies the physical properties of the fluid surface lining the lungs. Among infected patient populations, this super-producer may bear significant responsibility for the shedding and transmission of pathogens. These data may also demonstrate the utility of suppressing the emission of suspended particles with a relatively simple and safe extrinsic application of spray formulations.

Example 3: Large animal studies

Seven Holstein steers were anesthetized, intubated and screened, and the baseline particle emission was measured by optical laser counting. Animals were then either untreated (sham) or treated with one of three doses (1.8 minutes, 6.0 minutes or 12 minutes) via a saline aerosolized spray. In the case of sham dosing, animals were treated in the same manner as they were dosed with isotonic saline solution. One animal was dosed daily and by random nebulizer throughout the exposure period (see Table 3 for dosing schedule). Each selected animal received all doses during the study. Exhaled particle counts were monitored for 180 minutes at discrete time points (0, 15, 30, 45, 60, 90, 120) after each dose was administered.

The exposure matrix for animals used in this study can be found in Table 3. During the 57-day dosing period, there was an interval of at least 7 days between dosing. During the dosing period, each animal (n=7) received at least one of each dose except one 6-minute dose (see animal no. 1736) and one 12-minute dose (see animal no. 1735). These two were ruled out due to unexpected problems with ventilators and/or anesthesia equipment.

Table 3: Dosing regimens for large animals

Administration animal number fake drug 1.8 minutes 6.0 minutes 12.0 minutes 1731 Day 17 3rd day Day 10 Day 25 1732 Day 7 Day 21 Day 1 Day 14 1735 Day 18 Day 11 Day 4 Not implemented 1736 Day 23 Day 2 Not implemented Day 9 1738 Day 8 Day 15 Day 36 Day 25 1739 Day 20 Day 38 Day 30 Day 45 1741 Day 50 Day 35 Day 57 Day 42

result

Figure 6A shows particle counts per animal over time after animals received sham dosing. Each time point typically represents the average of at least 3 particle count determinations. The data in Figure 6A show that some individual animals inherently produce more particles than others (super-dispersers). In addition, the data showed that animals with inactive respiratory anesthesia maintained a fairly constant exhaled particle output throughout the evaluation period (see eg, Animal Nos. 1731, 1735, 1738, 1739, and 1741).

Figure 6B shows the mean percent change in exhaled particle counts over time after each treatment. Each data point shows the mean of 6 to 7 measurements in the treatment cohort. All animals returned to baseline 180 minutes after treatment. The data suggest that the 6 minute treatment period provided sufficient dosing to avoid particle shedding for at least 150 minutes after treatment. Other treatments were shown to be either too short or too long to provide effective long-lasting suppression of suspended particulates.

Example 4: Human study reduces exhaled suspended particles

In a study of 4 healthy adults, particle counts were measured using an apparatus similar to that illustrated in Figure 2, followed by treatment with a formulation that reduced the number of exhaled particles. This treatment involved inhalation for 6 minutes from a Pari LC+jet nebulizer containing a formulation of 1.29 wt% _CaCl2 in 0.9% NaCl solution. Exhaled particles were measured before treatment and at time points 10 minutes, 1, 2, 4 and 6 hours after treatment. During the 3 min test period, the ratio of total particle counts greater than 0.3 μm in diameter was measured using equipment similar to that illustrated in Figure 2, immediately followed by a 2 min peripulmonary particle washout. The equipment contains a Climet CI-500B optical particle counter. This device correctly measures particles in the range of 300 to 2500nm. A set of filters removes all background particle noise.

Figure 7 shows the effect of inhalation therapy on particle count ratios producing particles greater than 0.3 microns (μm). A decrease in mean count rate from baseline count rate can be seen for all time points from pre-treatment to post-treatment up to 6 hours.

Example 5: Characterization of Exhaled Suspended Particles in Human Research

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

In both studies, the measurement system consisted of a Fleisch barometric flow meter (Model No. 1, Phipps and Bird, Richmond VA) to measure patient flow velocity during the test and a particle count and particle Distributed optical particle counter (Climet Model CI-500B, Climet Instruments Company, Redlands, CA). Particle count ratios were measured at 3-minute test intervals following a 2-minute flush of breathing particle-free air.

Similar to the smaller study in Example 2, large inter-individual variability in exhaled particle counts was seen in both studies. In the adult study, 26% of the population were classified as "super-producers," producing greater than 10,000 particles per minute and accounting for 94% of the particles measured in the study. The number of counts per minute ranged over nearly 5 units of intensity.

In a study of exhaled particle production in children, 12% of the population was classified as "super-producers" by the same criteria and accounted for 86% of the total particles produced. Particle counts per minute also range over nearly 5 units of intensity.

【Description of drawings】

Figure 1 is a diagram of a diagnostic instrument used to measure particles produced and exhaled by humans.

Figure 2 is a diagram of a diagnostic instrument used to measure particles produced and exhaled by a human with associated respiration rates.

Figure 3A, Figure 3B and Figure 3C illustrate that with three coughs at t=0 minutes (Figure 3A), t=30 minutes (Figure 3B), and t=60 minutes (Figure 3C), the simulated Particle concentrations measured in clean mucus and after delivery with salt.

Figure 4A is a graph of baseline particle counts (greater than 150 nanometers (nm)) exhaled by individuals (n=11) while inhaling particle-free air; and Figure 4B is a graph of saline (approximately 1 gram (g)) spray Plot of exhaled particle counts (greater than 150 nanometers (nm)) by individuals (n=11) after administration to the lungs over time (minutes).

Figure 5A is a graph of individuals (n=2) with a baseline emission greater than 1000 particles/liter (when inhaling particle-free air) before treatment in an isotonic saline solution (approximately 1 gram (g) solution) administered as a spray to the lungs. After the first part, the graph of exhaled particle count (greater than 150 nanometers (nm)) over time (minutes); and the fifth graph B is the individual with baseline emission greater than 1000 particles/liter (when inhaling particle-free air) before treatment (n=2) Exhaled particle counts (greater than 150 nanometers (nm)) over time (minutes) after phospholipid-containing isotonic saline solution (approximately 1 gram (g) solution) was administered to the lungs by aerosol Graph.

Figure 6A is a graph of total exhaled particle counts (greater than 0.3 microns) over time (minutes), showing data from sham-treated animals. Figure 6B is a graph of mean percentage (%) baseline particle counts over time (minutes), showing results from 1.8 minutes (-■-), 6.0 minutes (-▲-), 12.0 minutes (-□ -), and data obtained from sham-treated (-◆-) animals.

Figure 7 is a graph of time (hours) after completion of application of formulations with reduced particle production versus mean particle counts (% counts/liter) produced relative to baseline greater than 0.3 micrometers (μm).

[Description of component symbols]

10 Equipment 12 Mouthpieces

14 filter 16 low resistance one-way valve

20 particle counters 30 computers

22 gas flow meter

Claims (27)

1. one kind in order to measure the diagnostic device that particle distributes in the individuality, comprising:

Blow gun,

Two-way filter,

The lower resistance check valve,

Particle counter and

Computer,

The outlet of wherein said blow gun is connected with check valve with filter,

One end of wherein said filter is exposed in the surrounding, and the other end is connected with blow gun,

Wherein said check valve is arranged in pipe,

Wherein said pipe is connected with particle counter away from an end of blow gun outlet, and

Wherein said particle counter is connected with computer in the mode that allows data from particle counter to be sent to computer.

2. equipment as claimed in claim 1, wherein said filter can remove diameter more than or equal to 0.1 micron particle.

3. equipment as claimed in claim 1, wherein said blow gun are selected from the face shield through design makes user its lip can be positioned over blow gun, nasal cannula around the blow gun, the mouth and the face shield of nose that can cover user maybe can cover the nose of user.

4. equipment as claimed in claim 1, wherein said filter are the combinations of two or more filter.

5. equipment as claimed in claim 1, wherein said blow gun, described filter, described pipe and described check valve are disposable.

6. equipment as claimed in claim 1, wherein said particle counter are selected from electromobility particle counter (electrical mobility particle counter), impact (impaction) particle counter, electrostatic impact particle counter, infrared spectrum (infrared spectroscopy) particle counter, laser diffraction (laser diffraction) particle counter or light diffusing particles enumerator.

7. equipment as claimed in claim 1, described particle counter is an optical particle counter.

8. equipment as claimed in claim 1, wherein said particle counter is connected with computer in the mode that allows control instruction to be sent to particle counter from computer.

9. equipment as claimed in claim 1, described computer are inside or the external microprocessors that is connected with particle counter.

10. equipment as claimed in claim 1 further comprises with filter and is connected and the gas flowmeter between filter and surrounding.

11. equipment as claimed in claim 10, wherein said gas flow are counted Fleisch vapour-pressure type current meter (pneumotachometer) or Lilly vapour-pressure type current meter.

12. equipment as claimed in claim 10, the operation of wherein said gas flowmeter are by measuring the pressure reduction by laminar flow element or measuring by the bypass flow velocity around the bypass pipe of laminar flow element and undertaken.

13. equipment as claimed in claim 10 further comprises:

Differential pressure conditioner, wherein said differential pressure conditioner can measure by the differential pressure of effusion meter and

The signal actuator, wherein said signal actuator is connected with differential pressure conditioner, and it can amplify signal and signal is sent to computer.

14. one kind is used diagnostic device to measure particle distributes in the individuality the speed and the method for size, wherein said equipment comprises:

Blow gun,

Two-way filter,

The lower resistance check valve,

Particle counter and

Computer,

The outlet of wherein said blow gun is connected with filter and check valve,

One end of wherein said filter is exposed in the surrounding, and the other end is connected with blow gun,

Wherein said check valve is arranged in pipe,

Wherein said pipe is connected with described particle counter away from an end of blow gun outlet, and

Wherein, described particle counter is connected with computer,

This method comprises:

(i) blow gun is placed individual mouth or nose or place individual mouth go up or nose on,

(ii) suck air by blow gun, wherein air got by the filter extraction before sucking,

(iii) distribute and enter check valve by blow gun,

(iv) use particle counter measuring population and particle size, and

(v) will be provided to computer from the data of particle counter.

15. method as claimed in claim 14, wherein said equipment further comprises:

Gas flowmeter, this gas flowmeter are connected with filter and between filter and surrounding,

Differential pressure conditioner, wherein said differential pressure conditioner can measure by the differential pressure of effusion meter and

Signal actuator, wherein said signal actuator are connected with differential pressure conditioner and can amplify signal and signal is sent to computer.

16. method as claimed in claim 14, wherein step (ii) in, described air extracted by gas flowmeter earlier before extracting by filter.

17. method as claimed in claim 15 further comprises, step (iii) before, will be provided to computer from the data of signal actuator.

18. method as claimed in claim 14, wherein repeat number time step is (ii) to (v).

19. method as claimed in claim 18 further comprises and (vi) calculates the Mean Speed that average particle size, averaged particles distribution and particle produce.

20. method as claimed in claim 19, further comprise and (vii) suck composite, when composite is applied to the mucosal lining of the mankind or other animals, change surperficial viscous-elastic behaviour, the surface tension of mucosal lining or the bulk viscosity of mucosal lining of mucosal lining, subsequently again repeating step (i) to (vi).

21. the wherein said composite of method as claimed in claim 20 comprises charging cpd.

22. method as claimed in claim 21, wherein said charging cpd are selected from salt, ionic surface active agent, charged aminoacid, charged protein or peptide, or its combination.

23. method as claimed in claim 20, wherein said composite are aqueous, non-surface-active agent composite.

24. method as claimed in claim 20, wherein said composite are spray form.

25. method as claimed in claim 24, wherein said composite are saline (saline).

26. wherein entering the preceding step (i) of carrying out of dust free room (cleanroom) to (v) as each described method in the claim 14 to 25.

27. as each described method in the claim 14 to 25, wherein in step (i) before, user enters dust free room.

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