Design of aerosol systems and interfaces for delivering clinically and economically viable inhalation doses in neonatal CPAP devices.

Abstract

To provide an aerosol system to deliver clinically and economically feasible inhaled dose with a neonatal CPAP device.SOLUTION: A method of delivering an aerosolized agent to an infant includes interfacing an aerosolization device with an airway of an infant and aerosolizing, using the aerosolization device, a volume of surfactant into particles having a mass mean aerodynamic diameter (MMAD) of less than about 3 μm at a rate of at least 0.1 ml / min. The surfactant is aerosolized within about 1 to 8 cm from a patient interface. Aerosol is generated for up to approximately 80% or each inspiration. The method also includes delivering the aerosolized surfactant to the infant's airway.SELECTED DRAWING: Figure 9

Description

Technical Field

[0001] The present invention relates to the design of an aerosol system and an interface for delivering clinically and economically achievable inhalation doses in a neonatal CPAP device.

Background Art

[0002] Delivery of surfactants to infants, especially premature infants, is invasive and often causes acute side effects. Therefore, it is desirable to be able to deliver surfactants non-invasively.

Summary of the Invention

Problems to be Solved by the Invention

[0003] However, it is difficult to deliver surfactants effectively and efficiently by conventional non-invasive methods. For example, in conventional methods, aerosolized drugs are often delivered continuously. That is, the drug is aerosolized even between the patient's breaths, so it is very inefficient. Furthermore, in conventional methods, the particle size of the aerosol is often larger than desired for delivery to the lungs (usually the mass median aerodynamic diameter (MMAD) is about 4 - 7 μm), because it is difficult to generate aerosolized surfactant particles of a small diameter at a sufficiently high output flow rate to enable lung delivery. Embodiments of the present invention solve these and other problems.

Means for Solving the Problems

[0004] Embodiments of the present invention provide an aerosolization system and method for delivering drugs to infants, especially premature infants. In some embodiments, a method for effectively and efficiently delivering a drug to an infant's nostrils is provided. In some embodiments, aerosol droplets of a fine drug that can penetrate the lungs are provided. In some embodiments, a significantly higher drug delivery efficiency than conventional non-invasive methods is achieved.

[0005] In one embodiment, a method for delivering an aerosolized drug to an infant is provided. This method comprises connecting an aerosolizer to the infant's airway and using the aerosolizer to aerosolize a certain amount of drug into particles with an aerodynamic median particle size (MMAD) of less than approximately 3 μm at a flow rate of at least 0.1 ml / min. The drug may be aerosolized within approximately 2 to 8 cm from the patient interface. This method may also include delivering the aerosolized drug to the infant's airway.

[0006] In another embodiment, an aerosolization system is provided. This aerosolization system comprises an aerosolizing device having an aerosol generator positioned at a first end of an aerosol chamber. The aerosol generator has a containment configured to receive a certain amount of liquid surfactant to be aerosolized by the aerosol generator. The aerosol generator is configured to aerosolize the above amount of liquid agent into particles with an aerodynamic median particle size (MMAD) of less than about 3 μm at a flow rate of at least 0.1 ml / min. The aerosolizing device comprises a patient interface positioned within about 2 cm and 8 cm from the aerosol generator, and a breathing adapter configured to connect the aerosolization system to a breathing system having an inspiratory rim and an expiratory rim. The breathing adapter has at least one barrier defining at least one vent passage communicating with the aerosol chamber. The at least one barrier is configured to divert a first portion of the airflow from the inspiratory rim to the expiratory rim and a second portion of the airflow to the aerosol chamber through at least one vent passage. The second portion of the airflow is the respiratory flow and is smaller than the first portion. The aerosol chamber may be configured to mix the respiratory flow with the aerosolized agent from the aerosolizing device. In some embodiments, the aerosolizing system includes at least one respiratory sensor configured to detect the infant's inhalation and a control device configured to synchronize the aerosolization of the above-mentioned amount of surfactant with the detected inhalation.

[0007] In one embodiment, an aerosolization system is provided. This system comprises a breathing system having an inspiratory rim and an expiratory rim. The system also comprises an aerosolization device having an aerosol chamber having a first end and a second end, and an aerosol generator positioned at the first end of the aerosol chamber. The aerosol generator has a containment configured to receive a certain amount of liquid drug to be aerosolized by the aerosol generator. The aerosol generator is configured to aerosolize the amount of drug into particles with an aerodynamic median particle size (MMAD) of less than about 3 μm at a flow rate of at least 0.1 ml / min. The aerosolization device may also have a patient interface positioned near the second end of the aerosol chamber and a breathing adapter configured to connect the aerosolization system to the breathing system. The system also has at least one breathing sensor configured to detect patient inspiration and a control device configured to operate the aerosol generator to aerosolize the amount of drug in synchronization with the detected inspiration.

[0008] In some embodiments, the patient interface is located within approximately 1–8 cm of the aerosol generator. In some embodiments, the breathing adapter includes a flow diversion mechanism configured to divert a portion of the airflow from the breathing system to an aerosol chamber through at least one vent. The aerosol chamber may be configured to mix a portion of the airflow with an aerosolized drug supplied from the aerosol generator. In some embodiments, a portion of the airflow is the respiratory flow, less than the amount of air that continues to advance to the expiratory rim of the breathing system. In some embodiments, the flow diversion mechanism has at least one barrier defining at least one vent. The at least one barrier may be configured to divert a portion of the airflow to the aerosol chamber through at least one vent, and to divert another portion of the airflow from the inspiratory rim toward the expiratory rim. In some embodiments, the at least one barrier includes a first barrier defining a first vent and a second barrier defining a second vent. In some embodiments, a first vent is provided at the lateral end of the first barrier, and a second vent is provided beyond the leading edge of the second barrier, with the lateral end and leading edge extending in different directions from each other so that the respiratory flow moves in multiple directions and passes through the first and second barriers.

[0009] In some embodiments, the system further includes a conduit configured to deliver the above-mentioned amount of liquid drug from the containment to an aerosol generator. In some embodiments, the tip of the conduit has a diameter and is positioned at a distance of less than or equal to the diameter from the mesh. In some embodiments, the synchronization of aerosolization of the above-mentioned amount of drug includes aerosolizing a portion of the above-mentioned amount of drug in at least the first 50-80% portion of each of a series of consecutive inhalations, such that exhaust air is supplied in at least the last 20% portion of each of a series of consecutive inhalations. In some embodiments, at least the respiratory sensor has a respiratory sensor capsule connected to the patient's abdomen. In some embodiments, the control device is detachable from the aerosolizer. In some embodiments, the aerosolizer is configured to perform aerosolization and deliver aerosolized particles of the drug when the patient interface is oriented in a downward, lateral, and upward position, respectively. In some embodiments, the system further includes a supply line configured to supply the above-mentioned amount of drug from a supply source to the containment. In some embodiments, the patient interface includes nasal prongs or a nasal mask. In some embodiments, the agent includes a surfactant.

[0010] Another embodiment provides a method for delivering an aerosolized drug to an infant. This method comprises detecting the infant's inhalation using one or more respiratory sensors, and, based on the detected inhalation, aerosolizing a certain amount of drug into particles with an aerodynamic median particle size (MMAD) of less than approximately 3 μm at a flow rate of at least 0.1 ml / min using an aerosolizer. The drug is aerosolized within approximately 1–8 cm of the patient interface.

[0011] In some embodiments, aerosolizing the above-mentioned amount of drug includes delivering the above-mentioned amount of drug from a containment to a mesh of an aerosolizing device and vibrating the mesh to aerosolize the above-mentioned amount of drug. In some embodiments, the above-mentioned amount of drug is delivered from the containment to the mesh via a conduit having a tip having a diameter. The tip of the conduit may be positioned at a distance from the mesh of less than or equal to the diameter. In some embodiments, aerosolizing the above-mentioned amount of drug includes aerosolizing a portion of the above-mentioned amount of drug in at least a portion of the first 80% of each of a series of consecutive inhalations, such that exhaust air is supplied in at least a portion of the last 20% of each of a series of consecutive inhalations. In some embodiments, one or more respiratory sensors include a respiratory sensor capsule connected to the patient's abdomen. In some embodiments, this method further includes delivering the aerosolized drug to the infant's airway via a patient interface. In some embodiments, the patient interface includes nasal prongs or a nasal mask.

[0012] In some embodiments, the method includes connecting an aerosolizer to a respiratory system and diverting a portion of the airflow from the respiratory system to a chamber in the aerosolizer through at least one vent. This chamber is configured to mix a portion of the airflow with the aerosolized drug. In some embodiments, a portion of the airflow is the respiratory flow and is less than the amount of air that continues to advance to the expiratory rim of the respiratory system. In some embodiments, a portion of the airflow is diverted using at least one barrier defining at least one vent. The at least one barrier is configured to divert a portion of the airflow to the aerosol chamber through at least one vent, and to divert another portion of the airflow from the inspiratory rim toward the expiratory rim. In some embodiments, the at least one barrier includes a first barrier defining a first vent and a second barrier defining a second vent. In some embodiments, a first vent is provided at the lateral end of the first barrier, and a second vent is provided beyond the leading edge of the second barrier, with the lateral end and leading edge extending in different directions from each other so that the respiratory flow moves in multiple directions and passes through the first and second barriers.

[0013] In another embodiment, a method for initializing an aerosolization system is provided. This method includes connecting the aerosolization device to a control unit, a respiratory sensor, a drug source, and a respiratory system; inputting user access authentication to the control unit; and inputting patient-related information and medication information to the control unit. This method also includes connecting the respiratory sensor to the patient; priming the aerosolization device; and connecting the patient interface to the patient's airway.

[0014] In some embodiments, the method further includes executing an activation sequence that repeats multiple audible alarms, visual alarms, or both audible and video alarms. In some embodiments, access authentication includes one or more of user identifiers, passwords, possession authentication, and biometric authentication. In some embodiments, the respiratory sensor is attached to the patient's abdomen. In some embodiments, the method further includes confirming the detection of respiration after connecting the respiratory sensor to the patient. In some embodiments, the drug source has a vented vial access device (VVAD) connected to a fluid supply line. In some embodiments, connecting the aerosolizer to the control device, respiratory sensor, drug source, and respiratory system includes connecting a fluid supply line between the drug source and the aerosolizer. In some embodiments, priming the aerosolizer includes aerosolizing a portion of the drug before connecting the patient interface to the patient's airway. In some embodiments, the method further includes connecting the patient interface to the aerosolizer. In some embodiments, the patient interface is secured to the patient via one or both of at least one strap and a foamed plastic pad configured to rest on the patient's head. In some embodiments, the method includes delivering an aerosolized dose of the drug to the patient via a patient interface. In some embodiments, the method further includes ensuring that the timing of dose delivery is synchronized with detected inhalation. [Brief explanation of the drawing]

[0015] [Figure 1] An isometric view of an aerosolization apparatus according to an embodiment. [Figure 1A] Cross-sectional view of the aerosolization apparatus shown in Figure 1. [Figure 2] Figure 1 shows the flow pattern through the aerosolization apparatus. [Figure 3] An isometric view of an aerosolization apparatus according to an embodiment. [Figure 3A] Cross-sectional view of the atomization device of FIG. 3. [Figure 4A] Diagram showing the flow pattern through the atomization device of FIG. 3. [Figure 4B] Diagram showing the flow pattern through the atomization device of FIG. 3. [Figure 5A] Diagram showing the flow pattern through the atomization device of FIG. 3 from a low-flow breathing system. [Figure 5B] Diagram showing the flow pattern through the atomization device of FIG. 3 from a low-flow breathing system. [Figure 6] Isometric view of the atomization device according to an embodiment. [Figure 6A] Cross-sectional view of the atomization device of FIG. 6. [Figure 6B] Cross-sectional view of the atomization device of FIG. 6. [Figure 6C] Cross-sectional view of the atomization device of FIG. 6. [Figure 6D] Diagram showing the flow pattern through the atomization device of FIG. 6. [[ID=*31]] [Figure 7] Diagram showing the atomization device of FIG. 6 connected to a fluid supply line and a breathing system. [Figure 8] Diagram showing an atomization device connected to a drug supply source. [Figure 9] Diagram showing the atomization device of FIG. 8 connected to a drug supply source and a control device. [Figure 10] Diagram showing the control device of FIG. 9. [Figure 11] Diagram showing the vial holder of the control device of FIG. 9. [Figure 12] Diagram showing the drug supply source of FIG. 9. [Figure 13] Diagram showing the function of the control device of FIG. 9. [Figure 14A] Diagram showing the process of using the atomization system of FIGS. 9 - 13. [Figure 14B] Diagram showing the process of using the atomization system of FIGS. 9 - 13. [Figure 14C] Diagram showing the process of using the atomization system of FIGS. 9 - 13. Note: There seems to be a formatting issue with line 32 where the tag is [Figure 7] instead of [Figure 7] as it should be according to the pattern. I've translated it as is. If this is a mistake, the correct tag should be used for an accurate translation. [Figure 14D] Figures 9-13 illustrate the process using the aerosolization system. [Figure 14E] Figures 9-13 illustrate the process using the aerosolization system. [Figure 14F] Figures 9-13 illustrate the process using the aerosolization system. [Figure 14G] Figures 9-13 illustrate the process using the aerosolization system. [Figure 14H] Figures 9-13 illustrate the process using the aerosolization system. [Figure 14I] Figures 9-13 illustrate the process using the aerosolization system. [Figure 15] A diagram showing an aerosolization device according to an embodiment, connected to an infant. [Figure 16] A diagram showing a respiratory sensor capsule connected to the abdomen of an infant. [Figure 17] A diagram showing an aerosolization system for delivering surfactants to an infant, according to an embodiment. [Figure 18] A flowchart illustrating the process of delivering aerosolized drugs to patients. [Figure 19] A flowchart illustrating the process for initializing an aerosolization system. [Figure 20] A bar graph showing the release dose rate using the aerosolization system according to the embodiment. [Figure 21] A bar graph showing the discharge dose rate according to respiratory rate and flow rate using the aerosolization system according to the embodiment. [Figure 22] A graph showing deposition rate and particle size. [Figure 23] A graph showing deposition rate and particle size. [Figure 24] A graph showing the effectiveness of inhalation detection using flow sensors and respiratory sensor capsules. [Figure 25] A graph showing the survival rate when surfactants are not injected, according to one study. [Figure 26]A graph showing the particle size distribution of impactors, according to one study. [Figure 27] A graph showing the particle size distribution of impactors, according to one study. [Figure 28] A graph showing the particle size distribution of impactors, according to one study. [Figure 29] A graph showing the powder mass distribution at different CPAP settings, based on a study. [Figure 30] A graph showing the powder mass distribution at different CPAP settings, based on a study. [Figure 31] A graph showing the powder mass distribution at different CPAP settings, based on a study. [Modes for carrying out the invention]

[0016] The descriptions of embodiments below are not intended to limit the scope, applicability, or configuration of the disclosure. The descriptions of embodiments below are intended to provide those skilled in the art with an explanation that enables the implementation of the embodiments. Various modifications can be made to the function and arrangement of the elements without departing from the spirit and scope of the disclosure.

[0017] In the aerosolization system and method according to embodiments of the present invention, the aerosolized drug and respiratory gas are mixed in an aerosolization chamber isolated from the direct flow of the respiratory system, such that a small amount of the respiratory gas enters the aerosolization chamber, while the majority of the respiratory flow bypasses the aerosolization chamber and passes through the expiratory rim of the respiratory system. This design ensures a constant drug delivery rate regardless of the flow rate from the respiratory system. Furthermore, embodiments of the present invention provide an add-on aerosolization configuration that can be connected to existing respiratory systems and can be adapted to deliver a stable dose of aerosolized drug to the patient's airway. The aerosolization system described herein is also configured to allow the control device to predict the patient's inspiration by including one or more respiratory sensors, such as one or more flow sensors (e.g., electrical flow sensors), radar sensors (e.g., UWB (ultra-wideband) radar sensors for measuring chest displacement), CO2 sensors, high-speed temperature sensors, acoustic sensors, impedance plethysmography sensors, respiratory inductance plethysmography sensors, and pressure sensors. This allows the drug to be aerosolized during or immediately before the patient's inspiration.

[0018] Embodiments of the present invention provide an aerosolization system that isolates an aerosolized drug from the main respiratory gas flow in order to avoid the loss or dilution of aerosols generated in the inspiratory phase. Such isolation can be achieved by using a barrier and / or other wall designed to redirect the main flow from inlet to outlet rather than pushing the gas into the patient interface.

[0019] Embodiments of the present invention also generate and deliver surfactant aerosols only during the inspiratory cycle (inhalation). Generally used devices deliver aerosols continuously. However, since infants can only inhale aerosols during inhalation, the aerosols are lost and wasted during exhalation (up to two-thirds of the respiratory cycle) as they bypass the airways. By limiting aerosol generation to inhalation only and delivering the aerosols near the nostrils, the proportion of surfactant deposited in the lungs can be maximized.

[0020] Embodiments of the present invention also generate aerosols near the patient interface to increase the amount of aerosol delivered to the patient. Conventional nebulizers are placed at one point on the inspiratory tube of a ventilator or nCPAP circuit, and aerosols are generated in a continuous gas flow. As a result, the aerosol is significantly diluted during delivery, and much of it is lost in the continuous gas flow. Generally, the flow rate of this gas flow is higher than the inspiratory flow in question. In contrast, the aerosolizing device of the present invention generates aerosols directly toward the patient interface (nasal prongs, etc.), diverting most of the gas flow from the nCPAP circuit from the atomized aerosol, thereby significantly suppressing aerosol loss in the continuous gas flow of the circuit. Embodiments also enable a reduction in administration time by using an aerosol generator that releases aerosol surfactant at a flow rate of 0.3 mL / min or more with undiluted surfactant, which is higher than the flow rates previously observed in other mesh nebulizers. Although the delivery of surfactants is mainly described, other types of drugs may be used with the aerosolizing system of the present invention to deliver aerosolized drugs to the patient's lungs.

[0021] In some embodiments, the aerosolization system described herein comprises a reusable device control unit and a disposable aerosolizer, used only once per patient, having a drug delivery circuit and / or respiratory sensor. Such an aerosolizer functions as a standalone drug delivery device integrated into various ventilators (such as CPAP machines) and, in some embodiments, is not designed to connect to a hospital network or the internet. For example, the control unit may be a reusable component for use by multiple patients, comprising a flat-panel touchscreen display, electronics, and software. For example, three main functions of the control unit are detecting inspiration via a respiratory sensor placed on the patient's abdomen (e.g., designed for use by only one patient), delivering a suspension to the aerosolizer via an integrated delivery mechanism, and generating an aerosol during inspiration toward the nCPAP interface. These functions may be performed in sync with the infant's inspiratory cycle. The flat-panel touchscreen is configured to allow the user to set and monitor delivery parameters, alarms, and system diagnostics using a graphical user interface (GUI). Visual and auditory alarms may be incorporated into the control unit. A pod may be used to transmit signals from the respiratory sensor to the control unit, and to transmit signals for generating aerosols in synchronization with the detected respiration. The containment, which is the source of the pharmaceutical, may be a pharmaceutical vial containing the drug.

[0022] In some embodiments, a disposable aerosolizer, used only once per patient, comprises a vented vial access device (VVAD) provided to the user in individual packaging to facilitate access to the drug containment, and a drug delivery tube. The drug delivery tube has a Luer connector (connected to the VVAD) and a tube that delivers the drug suspension from the Luer to the aerosol generator of the aerosolizer. The aerosol generator of the aerosolizer may also feature a customized PDAP (photodefined perforated plate) vibrating mesh that stands out for its performance in small droplet size and high output flow rate. The PDAP mesh has an innovative structure in which up to 20 times more pores are formed in smaller diameters than conventional meshes. The aerosol generator is designed to deliver aerosol near the airway of an infant and to connect to a conventional nCPAP system.

[0023] The reusable control unit features a built-in touchscreen with a processor that monitors delivery parameters, alarms (visual and auditory), and system diagnostics. The control unit and pod work together via a respiratory sensor. One end of the respiratory sensor is attached to the infant's abdomen, and the other end is connected to the pod. The control unit activates the drug delivery mechanism, delivering the drug to the nebulizer and generating aerosols synchronized with the infant's breathing cycle.

[0024] The freeze-dried surfactant is reduced within the glass vial it came in to form a saline / surfactant suspension. The vial is connected to a drug delivery circuit, including a drug delivery tube, via a vented vial access device. The vented vial access device pierces the vial's septum, allowing air to enter the vial and uniformly emptying the suspension. An integrated volumetric drug delivery mechanism delivers the surfactant suspension through the drug delivery tube to an integrated nebulizer (with a unique vibrating mesh) in the drug delivery circuit interface. Nasal prongs are used for the interface. The interface is connected to the infant's clinical nCPAP circuit and is placed in the infant, replacing a previously placed interface. Subsequently, the aerosol is delivered in sync with the infant's inhalation, in response to a respiratory sensor.

[0025] Although the primary focus is on the use of surfactants, the methods and apparatus of this disclosure can be used with any liquid drug. For example, drugs such as bronchodilators, anti-infectives, antivirals, anti-inflammatory mucokinetics, siRNA, and PFOBs can be used in accordance with this disclosure, but are not limited to these.

[0026] Figure 1 shows one embodiment of an aerosolization system. The aerosolizer 100 is located on the first side of the aerosol chamber 102, and the patient interface 104 is located on the opposite side, the second side of the aerosolization chamber 102. The aerosolizer 100 is a sprayer or any other device configured to aerosolize a dose of liquid medication. Such devices are described in U.S. Patent No. 5,758,637, U.S. Patent No. 6,235,177, U.S. Patent Publication No. 2015 / 0336115, and U.S. Patent Publication No. 2016 / 0130715, the full contents of which are incorporated herein by reference. The aerosolizer 100 has a containment section configured to receive and / or contain a certain amount of liquid medication to be aerosolized. In some embodiments, the containment section is a "substantial containment section" in the form of a conduit extending to connect a fluid supply line to the mesh of the aerosolizer 100. For example, the conduit is sized to accommodate only about 10-15 mcl of the drug that accumulates in the conduit between each aerosolization step. The primary containment may be in the form of a vial containing the drug, and the drug is supplied to the mesh via the conduit or substantial containment with each breath through a supply mechanism and supply line. In some embodiments, the patient interface is a nasal prong, endotracheal tube, nasal cannula / mask, tracheostomy tube, etc.

[0027] The system has a breathing adapter 106 configured to function in connection with a breathing system such as a ventilator, humidifier, CPAP (continuous positive airway pressure) device, nCPAP system, and / or a combination thereof. For example, the breathing adapter 106 has an inlet 108, such as an inlet barrier configured to connect to the inspiratory rim of the breathing system. For example, the inlet 108 is an inlet barrier configured to connect to a Flexitrunk® midline interface manufactured by Fisher & Paykel Healthcare and to direct the respiratory flow to an aerosolization chamber 102. The inlet 108 is connected to the aerosol chamber 102, for example, via a fluid path 110. In some embodiments, the inlet 108 is designed to redirect gas from the breathing system to the aerosolization chamber without increasing resistance or work of breathing for the patient. This is achieved by providing a fluid path 110 having a cross-sectional area of ​​about 80% or more of the inner cross-sectional diameter of the patient interface 104.

[0028] Figure 1A shows a cross-sectional view of the aerosolization system of Figure 1. As shown, the aerosol generator 112 of the aerosolization device 100 is located at the first end of the aerosol chamber 102 so that the drug aerosolized by the aerosol generator 112 is introduced into the aerosolization chamber 102. The aerosol generator 112 has a mesh configured to produce aerosol particles. Conventional aerosol devices typically produce aerosols with an average droplet diameter in the range of 4 to 5 microns. However, for drug delivery through the nostrils via the narrow airways of the airways of premature infants, aerosol droplets generally need to be less than 3 microns in diameter. Aerosol droplets larger than this diameter are prone to depositing in the nostrils and delivery tubes. If the droplets are significantly smaller than 1 micron, they may not deposit in the lungs and may be coughed up. In this case, the efficiency of drug delivery to the lungs is reduced. Embodiments of the present invention use a mesh pore size designed to produce droplets having an average diameter between 2 and 3 microns. For example, in some embodiments, the aerosol generator 112 includes a PDAP (photoforming perforated plate) mesh configured to generate small-diameter aerosol particles, such as less than 3 μm. Such meshes are disclosed in the aforementioned U.S. Patent Publication No. 2016 / 0130715. By positioning the aerosol generator 112 near the patient interface 104, aerosolized drugs released during the inspiratory cycle are preferentially aspirated, minimizing interruptions to the continuous or biased flow through the respiratory system circuit. In the illustrated aerosol chamber 102, the first end is smaller than the second end. The barrier forming the inlet 108 is designed to draw a portion of the respiratory flow from the inspiratory rim of the respiratory system into the aerosol chamber 102 via a fluid path 110 near the first end. The fluid path 110 communicates with the inspiratory rim at the junction of the inspiratory rim and / or the inlet 108 at an angle of 90 degrees or less with respect to the respiratory flow within the rim and / or the upstream side of the inspiratory rim. This configuration allows the aerosolization chamber to be isolated from the direct respiratory flow. For example, the respiratory flow is intermittently introduced into the aerosol chamber 102 only when the patient is inhaling.

[0029] Figure 2 shows the flow pattern through the aerosolization system. Figure 2 shows the inspiratory rim 200 of the breathing system that supplies the respiratory airflow. A portion of this respiratory airflow is drawn into the inlet 108 and introduced into the aerosol chamber 102 and patient interface 104 via the fluid pathway 110. For example, when a patient inhales, the inhalation creates negative pressure in the aerosolization chamber, drawing a certain volume of respiratory airflow through the fluid pathway 110. Excess respiratory airflow and / or exhaled gas is expelled through the exhalation rim 202 of the breathing system.

[0030] The aerosolization systems shown in Figures 1, 1A, and 2 can increase and stabilize inhaled doses compared to conventional aerosolization systems across the gas flow rate ranges used in various nCPAP systems. For example, the aerosolization systems described herein increase inhaled doses in high-flow nCPAP systems (higher than 6 L / min) from approximately 6% (conventional systems) to approximately 40-50%, while reducing variability in low-flow systems (0.5 L / min) that also achieve approximately 40-50% inhaled doses.

[0031] Figure 3 shows another embodiment of an aerosolizer for supplying a patient with a stable dose of aerosolized medication. This aerosolizer has an aerosol generator 300 located at a first end of an aerosol chamber 302, and a patient interface 304 located at the opposite, second end of the aerosol chamber 302. The aerosol generator 300 may be a sprayer having a vibrating mesh that can be selectively vibrated using a piezoelectric actuator. In some embodiments, the aerosol generator 300 has a containment section configured to receive and / or contain a certain amount of liquid medication to be aerosolized. The aerosol generator 300 is connected to a medication supply line 306 configured to deliver a certain amount of liquid medication to the containment section via a pump (not shown), etc. The aerosolizer may have a cable 308 connected to a power source, but in some embodiments, the aerosolizer is battery-powered.

[0032] In some embodiments, the aerosolizer has an inlet 310 and an outlet 312 connected to the inspiratory and expiratory rims of a ventilating system, respectively. Examples of usable ventilating systems include, but are not limited to, ventilators, humidifiers, CPAP devices, and / or combinations thereof. In some embodiments, the inlet 310 and outlet 312 are a single unit forming a breathing gas flow path, while in other embodiments, the inlet 310 and outlet 312 are separate components connected to each other. The inlet 310 and / or outlet 312 are configured to receive the ends of the gas conduits of the breathing system. For example, the airflow barriers at the inlet and / or outlet correspond to the unidirectional circuit of a standard nCPAP circuit. Thus, the barriers can minimize interruptions to the airflow from the inlet to the outlet, resulting in reduced turbulence within the aerosol chamber 302.

[0033] As shown in Figure 3A, the aerosolizer also has a fluid channel 314 connecting the aerosol chamber 302 to the inlet 310 and / or outlet 312. As shown, the fluid channel 314 delivers breathing gas to the upper part of the aerosol chamber 302 near the aerosol generator 300, but in some embodiments, it may deliver to other locations such as the inner portion of the aerosol chamber 302 and / or a portion closer to the patient interface 304. The fluid channel 314 intersects the inlet 310 and / or outlet 312 upstream of the inlet 310 and / or outlet 312, and / or with respect to the flow channels formed within the inlet 310 and / or outlet 312, such that the angle between the fluid channel 314 and the flow channels formed within the inlet 310 and / or outlet 312 does not exceed 90 degrees. In other words, the gas fluid channel 314 extends perpendicular to the inlet 310 and / or outlet 312, or extends in a direction at least partially opposite to the airflow through the inlet 31 and / or outlet 312. By positioning the fluid channel 314 in this manner, the aerosol chamber 302 can be isolated from the continuous flow of respiratory gas from the inlet 310 (inspiratory rim) to the outlet 312 (expiratory rim). This results in several benefits. Firstly, isolating the aerosol chamber 302 from the continuous flow prevents the aerosolized drug from being "blown away" or diluted by the gas flow. Secondly, isolation allows the aerosolized drug to be pre-filled into the aerosol chamber 302 immediately before a respiratory event, and also allows for the retention of any remaining drug from the previous breath.

[0034] In some embodiments, a portion of the breathing gas is drawn into an aerosol chamber 302 through a fluid channel 314 to mix with an aerosolized drug. The portion of breathing gas drawn into the aerosol chamber 302 is drawn in by the negative pressure created by the patient's inhalation at the patient interface 304.

[0035] The aerosol chamber 302 has an internal shape suitable for delivering the mist to the patient interface 304 while minimizing impact. Specifically, the aerosol chamber 302 is designed so that the aerosol generator 300 is located on the opposite side of the patient interface 304. Furthermore, the aerosol chamber 302 is designed to have a generally funnel-shaped contour, tapering (linearly or nonlinearly) from a wide section to a narrow section near the patient interface 304, thereby reducing the impact on the aerosol emitted from the aerosol generator 300. This design also allows for miniaturization of the aerosol chamber 302.

[0036] Figures 4A and 4B show the flow path of the respiratory flow supplied from the high-flow breathing system and passing through the aerosolizer in Figures 3 and 3A. While the patient is inhaling at a flow rate of 1 L / min, the inspiratory flow passes through the inlet 310 at a flow rate of 8 L / min. The pressure at the expiratory rim connected to the outlet 312 is 490.32 Pa (5 cmH2O). A portion of the respiratory gas is drawn into the aerosol chamber 302 through the fluid flow path 314 when the patient inhales through the patient interface 304.

[0037] Figures 5A and 5B show the path of the respiratory flow supplied from the low-flow breathing system and passing through the aerosolizer in Figures 3 and 3A. While the patient is inhaling at a flow rate of 1 L / min, the inspiratory flow flows through the inlet 310 at a flow rate of 2 L / min. The pressure at the expiratory rim connected to the outlet 312 is 490.32 Pa (5 cmH2O). Similar to the high-flow embodiment, a portion of the respiratory gas is drawn into the aerosol chamber 302 through the fluid channel 314 when the patient inhales through the patient interface 304. As shown in Figure 5B, the portion of the respiratory flow drawn into the aerosol chamber 302 is introduced into the patient's airway via the patient interface 304.

[0038] Figures 6-6D show another embodiment of the aerosolizing device 600. The aerosol generator 612 (Figures 6A-6D) is located on the first side of the aerosol chamber 602, similar to those described above, and the patient interface 604 is located on the opposite side, the second side of the aerosol chamber 602. The aerosol generator 612 has a containment section configured to receive and / or contain a certain amount of liquid drug to be aerosolized. For example, in some embodiments, the aerosolizing device 600 has at least one drug supply port 614 configured to connect to a drug supply line (not shown) used to deliver the liquid drug to the aerosol generator 612 (or the containment section, if any). In some embodiments, the containment section is formed as an elongated conduit extending between the drug supply port 614 and the aerosol generator 612. In some embodiments, the patient interface 604 is a nasal prong, endotracheal tube, nasal cannula / mask, tracheostomy tube, etc. The aerosolizer 600 also has at least one power connection port 640. As shown in the figure, the power connection port 640 is a port that allows a power cable to be connected to the aerosolizer 600 to supply power and / or control commands to the aerosol generator 612.

[0039] The device has a breathing adapter 606 configured to function in connection with a breathing system such as a ventilator, humidifier, CPAP (continuous positive airway pressure) device, nCPAP system, and / or a combination thereof. For example, the breathing adapter 606 has an inlet 608, such as an inlet barrier, configured to connect to the inspiratory rim 650 of the breathing system. The breathing adapter 606 also has an outlet 616, such as an outlet barrier, configured to connect to the expiratory rim 652 of the breathing system. For example, as shown in the figure, the inlet 608 and / or outlet 616 are configured to be inserted into and held (e.g., held by friction fitting and / or other fixing mechanisms) within the conduits of the inspiratory rim 650 and / or expiratory rim 652, respectively. In other embodiments, the inlet 608 and / or outlet 616 are configured to be larger than the conduits of the breathing system so that the conduits of the inspiratory rim 650 and / or expiratory rim 652 are inserted into and held (held by fixing mechanisms such as friction fitting) within the inlet 608 and outlet 616, respectively. Other methods may be used to connect the inlet 608 and / or outlet 616 to the respiratory system. Furthermore, the same method does not need to be used for connecting the inlet 608 and outlet 616.

[0040] Figure 6A shows a cross-sectional view of the aerosolization system of Figure 6. As shown, the aerosol generator 612 of the aerosolization apparatus 600 is positioned at the first end 618 of the aerosolization chamber 602 so that the drug aerosolized by the aerosol generator 612 is introduced into the aerosol chamber 602. For example, the drug is delivered to the aerosol generator 612 via a drug supply port 614 which communicates with a containment. In some embodiments, the containment is a "substantial containment" in the form of a conduit 632 that delivers the drug to the surface of the aerosol generator 612. The conduit 632, which is the substantial containment, is connected to a drug source such as a vial via a fluid line connected to the drug supply port 614. The diameter of the tip 634 located at the most distal end of the conduit 632 is less than or equal to the distance between the tip 634 and the proximal end surface of the mesh of the aerosol generator 612. This configuration ensures that droplets of liquid drug discharged from tip 634 are formed to a size that allows them to contact and move across the mesh of the aerosol generator 612. Surface tension ensures that the liquid remains on the surface of the mesh and spreads, resulting in the aerosolization of all or nearly all of the liquid. Therefore, the aerosolizer 600 can operate in any orientation, allowing treatment to be performed whether the patient (such as an infant) is lying on their side, on their back, or on their stomach. For example, in some embodiments, the tip of the drug supply port 614 is positioned at a distance of approximately 5 to 40 microns from the surface of the aerosol generator 612, and the tip 364 has a diameter less than or equal to this distance. As shown in the figure, the aerosol generator 612 is positioned near the patient interface 604, and the aerosol chamber 602 is the only component positioned between the aerosol generator 612 and the patient interface 604. By positioning the aerosol generator 612 near the patient interface 604 in this manner, aerosolized drugs released during the inspiratory cycle are preferentially aspirated, minimizing interruptions to the continuous or biased flow passing through the respiratory system circuit. The aerosol chamber 602 is formed such that the first end 618 is smaller than the second end 620, thereby reducing the impact on the aerosol leaving the aerosolizer 600.

[0041] The inlet 608 is formed by a barrier configured to draw a portion of the respiratory flow from the inspiratory rim 650 of the respiratory system into the aerosol chamber 602 via a fluid path near the first end. The fluid path is described in detail later with reference to Figures 6B and 6C. In some embodiments, the inlet 608 is designed to redirect gas from the respiratory system to the aerosol chamber 602 without substantially increasing, or at least significantly increasing, the resistance to the patient or the work of breathing (e.g., inspiratory pressure). This is achieved by providing a fluid path within the respiratory adapter 606 having multiple barriers. These barriers guide a portion of the air flowing from the inspiratory rim (only the amount necessary for inspiration) into the aerosol chamber 602, while significantly reducing turbulence in the airflow drawn into the aerosolizer 600. As a result, a more layered flow can be generated within the aerosol chamber 602.

[0042] Figures 6B and 6C show the aerosolizer 600 in a divided state. Although shown in the figures as two separable components, the aerosolizer 600 may consist of any number of components that are connected to one another (e.g., by connecting / engaging functions). Alternatively, it may consist of a single component formed by molding, 3D printing and / or other known or unknown manufacturing methods. As shown in Figure 6B, the portion of the aerosolizer 600 having a fluid path has multiple barriers. In the illustrated embodiment, the aerosolizer 600 has a first barrier 622 that directs a large amount of flow from the inhalation rim 650 to the exhalation rim 652, while allowing some of the flow from the inhalation rim 650 to enter the aerosol chamber 602. For example, the barrier 622 is generally U-shaped, with one or both ends open to form a vent 624 between the barrier 622 and the side wall of the housing of the aerosolizer 600. This vent 624 allows a small amount of air to pass over the end of the barrier 622. Meanwhile, the main body of the barrier 622 prevents other air from passing through it and instead directs air toward the exhalation rim 652. In this embodiment, a U-shaped barrier 622 is used, but it may be modified to other shapes to suit specific applications.

[0043] The aerosolizer 602 has a second barrier 626 positioned near the first barrier 622. As shown in the figure, the second barrier 626 is a generally U-shaped wall oriented in the opposite direction to the first barrier 622 (however, the second barrier 626 may be configured in a different shape and orientation, and may be a second barrier 622 that extends generally linearly across the entire width of the interior of the aerosolizer 600, or may be a second barrier 626 that is curved and oriented in the same direction as the first barrier 622). In some embodiments, the first barrier 622 and the second barrier 626 are formed as a single member that shares, for example, an inner portion, while in other embodiments, the barriers are provided as separate components. As shown in the figure, the second barrier 626 extends to reach both side walls of the housing, but a gap is left between the leading edge of the second barrier 626 and the top of the housing of the aerosolizer 602, forming a path for air to enter the aerosolizing chamber 602. Therefore, as shown in the figure, when the patient inhales through the patient interface 604, some of the gas supplied by the inspiratory rim 650 is drawn in through the vents 624 at one or more ends of the barrier 622. The drawn-in air is pushed upward and flows over the second barrier 624, forming a generally layered flow within the aerosol chamber 602. However, in some embodiments, instead of directing the airflow towards the top of the housing, the second barrier 626 is configured to direct the air towards the bottom of the housing or towards a central opening formed between the upper and lower barriers. To generate some airflow of respiratory gas during patient inspiration while isolating the aerosol chamber 602 from the direct airflow of respiratory gas in the respiratory system, any number of barriers and / or other flow diversion mechanisms (including valves) of any design can be used.

[0044] Figure 6C shows another part of the aerosolizer 600 connected to the first part. This part of the aerosolizer 600 forms a seat 628 for receiving the aerosol generator 612, the drug supply port 614, and / or other related components. There is also an engaging function 630 for receiving and securing the barrier 622 in place. For example, the engaging function 630 defines a groove or passage of a size and shape that can receive the upper edge of the barrier 622. This connection ensures that the barrier 622 extends over the entire range from the bottom to the top of the housing of the aerosolizer 600. As a result, while directing most of the airflow towards the outlet 616, it is possible to ensure that only the airflow passing through the vents 624 at each end of the barrier 622 can pass over the barrier 622.

[0045] Figure 6D shows the flow pattern of the airflow drawn from the inspiratory rim 650 through the inlet 608 into the aerosolizer 600. For example, as the air from the inspiratory rim 650 (passing through a humidifier, etc.) passes through the breathing adapter 606, the barrier 622 redirects most of the air towards the expiratory rim 652 through the outlet 616. As described above, since the barrier 622 forms one or more vents 624, a portion of the airflow from the inspiratory rim 650 is drawn inward each time the patient inhales. This portion of air drawn in through the vents reaches a second barrier 626. Due to the presence of the second barrier 626, the air drawn over the end of the barrier 622 moves upward and flows over the second barrier 626 into the aerosolizing chamber 602. As shown, the air is introduced into the aerosol chamber 602 near the first end 618 in the vicinity of the aerosol generator 612. In other embodiments, the airflow is introduced into the aerosol chamber 602 at a different location. In one example, air is introduced near the side wall of the aerosol chamber 602 using a barrier similar to barrier 622. As shown, air is introduced into the aerosolizing chamber 602 near the first end 618 in the vicinity of the aerosol generator 612. In other embodiments, the airflow is introduced into the aerosolizing chamber 602 at a different location. In one example, air is introduced near the side wall of the aerosolizing chamber 602 using a barrier similar to barrier 622. Other barrier designs and / or locations may be used to introduce air into the aerosolizing chamber 602 while isolating it from the direct flow within the respiratory system. Furthermore, in some embodiments, other mechanisms can be used to direct the air flowing from the respiratory system into the aerosolizing chamber 602 each time the patient inhales. For example, in some embodiments, one or more one-way valves are incorporated between the aerosolizing chamber 602 and the inspiratory rim 650 and / or expiratory rim 652. One or more valves isolate the aerosolization chamber 602 from the respiratory system by sealing or other means until the patient inhales. When inhalation occurs, one or more valves open, allowing a small amount of respiratory flow into the aerosolization chamber 602.

[0046] By providing a series of barriers that allow small amounts of air to flow from the inspiratory rim 650 into the aerosol chamber 602, embodiments of the present invention suppress turbulence in the air drawn into the aerosol chamber 602, making it more layered. As a result, the drug is more easily deposited in the lungs. The barriers can be designed so that the gas / air flow rate drawn through the barriers is the same as or near that of an infant's inspiratory flow (much lower than the gas passing through the inspiratory rim 650). Although two barriers are used in the illustrated embodiment, other numbers and arrangements of barriers can also suppress turbulence in the airflow from the inspiratory rim 650 before introducing the airflow into the aerosol chamber 602 without significantly increasing the suction force required to draw air into the patient's airway. While a U-shaped barrier is used in the above example, other barrier designs may be used that limit the amount of airflow drawn into the aerosol chamber 602 with each inspiration and reduce the amount of turbulence within this airflow. This configuration also suppresses dilution of the aerosolized drug by the air supplied by the inspiratory rim 650.

[0047] Figure 7 shows the aerosolizer 600 of Figures 6-6D connected to both the fluid supply line 700 and the respiratory system 702. As shown in the figure, the first end of the fluid supply line 700 is connected to the drug supply port 614. For example, in some embodiments, the drug supply port 614 has a tip that protrudes outward from the body of the aerosolizer 600. By attaching the opening of the fluid supply line 700 to the tip, the fluid from the fluid supply line 700 passes through the drug supply port 614 into the housing and / or conduit 634 and is then delivered to the aerosol generator 602. The second end of the fluid supply line 700 (not shown) is connected to a fluid source such as a vial of liquid drug (or other type of container).

[0048] The breathing adapter 606 is connected to the breathing system 702. As shown in the figure, the inlet 608 is connected to the inspiratory rim 650 of the breathing system 702, but the outlet 616 and expiratory rim 652 are not visible in this figure. Air and / or other breathing gases are delivered from the inspiratory rim 650 to the breathing adapter 606, where one or more flow diversion mechanisms, such as valves or barriers, divert a portion of the airflow to the aerosol chamber 602 via a fluid path. The majority of the remaining airflow in the breathing system 702 is directed to the expiratory rim 652 by the breathing adapter 606.

[0049] The sprayer cable 704 is connected to the power connection unit 640. The sprayer cable 704 is configured to supply power to the aerosol generator 602 and to provide operating commands (such as commands to control the timing and duration of operation of the aerosol generator 602). For example, a control device (not shown) is connected to the aerosolization device 600 via the sprayer cable. The control device monitors the patient's respiratory cycle using one or more respiratory sensors. Based on this information, the control device sends signals via the sprayer cable 704 (or other communication link) to activate the pump to deliver liquid to the aerosol generator 612 and to activate the aerosol generator 612 to aerosolize the drug.

[0050] Figure 8 shows another embodiment of the aerosolizer 800. The aerosolizer 800 is similar to the aerosolizer 600 described above. As shown in the figure, the aerosolizer 800 is connected to a drug source 802. The drug source 802 is any container that holds a certain amount of drug. In the example shown in the figure, the drug source 802 is a vial and is connected to the drug port of the aerosolizer via a Luer connector 804 and the entire length of a fluid supply line 806. The aerosolizer 800 is also connected to a sprayer cable 808 which can be connected to a control device (not shown). The sprayer cable 808 terminates in a pod 810 for connecting the aerosolizer 800 and / or a respiratory sensor to the control device.

[0051] Figure 9 shows an aerosolizer 800 connected to a drug source 802 and a control device 812. The control device is configured to deliver liquid drug to the aerosolizer 800 via a fluid supply line 806 and to operate the aerosolizer 800. In some embodiments, the control device 812 operates the aerosolizer 800 in response to detected patient inspiration. For example, the control device 812 is connected to a respiratory sensor 814 that can detect the start, duration, and / or end of patient inspiration. In some embodiments, the respiratory sensor 814 is a Graseby-like sensor positioned against the patient's torso (abdomen and / or chest) to detect the patient's respiratory cycle. In this case, for example, the control device 812 receives a signal from the respiratory sensor 814 indicating that the patient has begun to inhale. The control device 812 then sends a command to supply a certain amount of liquid drug to the aerosol generator of the aerosolizer 800 and to operate the aerosol generator to aerosolize the liquid drug during inspiration.

[0052] In some embodiments, the respiratory sensor 814 and / or the aerosolizer 800 are directly connected to the control unit 812. In other embodiments, the respiratory sensor 814 and / or the aerosolizer 800 are connected to the control unit 812 using a pod 810 and / or other adapters. For example, in some embodiments, a connector such as a slip lure is inserted into a port on the pod 810 to connect the respiratory sensor to the pod. In this embodiment, the respiratory sensor 814 is attached to the patient's abdomen by adhesive or the like to initiate sensing of the inspiratory cycle.

[0053] Figure 10 shows the control device 812. The control device 812 has a user interface 818, such as a display screen. In some embodiments, the user interface 818 is a touchscreen. The control device 812 is equipped with one or more input devices, such as buttons, dials, keypads, and touchscreens, which allow the user to operate the control device 812 to adjust settings such as dose levels. The control device 812 has a number of ports 820 for connecting the control device 812 to peripheral units such as the aerosolizer 800 and / or respiratory sensor 814. In some embodiments, the control device 812 has one or more indicators 824, such as LEDs, configured to warn the user of the status of various functions. For example, the indicators 824 notify the user whether the aerosolizer 800 and / or respiratory sensor 814 are properly connected, whether the power supply 832 of the control device 812 is operating (i.e., connected, and / or charging or fully charged in the case of a battery), or whether a system fault has been detected. In some embodiments, the indicators 824 are integrated into the user interface 818. The housing 822 of the control device 812 has a holder 826 configured to safely receive the drug source 802, as clearly shown in Figure 11. In this embodiment, the drug source 802 is a vial fixed upside down within the holder 826, and the entire amount of the drug source 802 is configured to be delivered from the drug source 802 to the aerosolizer 802 by means of flowing out or pressurizing.

[0054] Figure 12 shows the drug source 802. In this example, the drug source 802 is a vial to which a VVAD (Vial Access Device with Vent) 828 is attached. The VVAD 828 has a removable cap 830, and when the cap 830 is attached to the VVAD 828, the opening of the VVAD 828 is sealed. The VVAD 828 also has a filter 832, which functions to minimize aerosols in the vial and fluid supply line 806, suppress surface contamination, and equalize the vial pressure. When in use, the cap 830 is removed and a port (not shown) is attached to a Luer connector, connecting the drug source 802 to the fluid supply line 806.

[0055] In some embodiments, the aerosolizing apparatus described herein comprises an aerosol generator that can be connected to various mechanical ventilation systems. The aerosol generator receives a liquid drug from a fluid source via a fluid delivery conduit. During operation, the fluid from the fluid source is delivered by a pump through the fluid delivery conduit to the aerosol generator, where the fluid is aerosolized in the aerosol generator before and / or during the patient's inspiration. In some embodiments, the fluid delivery conduit is primed with fluid before treatment (e.g., the fluid is pre-delivered to the aerosol generator) to ensure rapid delivery. The pump is controlled by a control device that controls the fluid delivery time and dosage.

[0056] The control unit comprises one or more processors that execute instructions stored in one or more memories to drive the operation of the pump and aerosol generator. For example, the memory stores instructions indicating the amount of fluid delivered to the aerosol generator in a single dose for each operation of the aerosol generator, the amount of fluid delivered over a specific period or number of times, etc. The stored instructions are based on the patient's body size, age, sex, type of drug, fluid additives, desired amount of aerosol, etc. The memory also stores instructions for operating the aerosol generator. As shown in the figure, the control unit is connected to the aerosol generator by a cable (i.e., an electrical cable), but in some embodiments, the control unit is connected to the aerosol generator wirelessly. The cable transmits signals to operate a piezoelectric actuator (or other actuator) in the aerosol generator. When the piezoelectric actuator operates, the vibrating member vibrates, aerosolizing the fluid and delivering it to the patient (i.e., delivered by inhalation). Thus, the memory stores instructions for controlling the start timing, stop timing, vibration frequency, or frequency of the piezoelectric actuator.

[0057] The aerosolization systems described herein can enhance therapeutic effects by adjusting the timing of aerosol generation. For example, an aerosol delivery system may begin aerosolizing the drug before the patient inhales. In this case, the aerosol delivery system can utilize the increased airflow at the start of inhalation. As a result, the inhaled air carries the drug further into the patient's lungs, thus facilitating drug delivery to the patient. Alternatively, the aerosol delivery system may begin aerosolizing the drug as soon as inhalation is detected (e.g., during spontaneous breathing).

[0058] Aerosol delivery systems can use one or more respiratory sensors to determine the timing and duration of a patient's inspiration and adjust drug delivery accordingly. These respiratory sensors communicate with a control device via wired and / or wireless connections. In some embodiments, aerosol delivery systems can achieve redundancy and / or more accurate monitoring of a patient's respiratory cycle by using a combination of multiple respiratory sensors. In one example, an aerosol delivery system uses a flow sensor in combination with a radar sensor to monitor both airflow and chest movement. In another example, an aerosol delivery system uses a flow sensor, a radar sensor, and a plethysmography sensor to monitor the respiratory cycle. Any number and / or any combination of respiratory sensors can be used for any application to monitor a patient's respiratory cycle.

[0059] In some embodiments, a flow sensor is connected to a gas delivery conduit to sense changes in airflow during inspiration (e.g., forced breathing, assisted breathing, or spontaneous breathing). In some embodiments, a flow sensor is also connected to a gas return conduit to detect the start and end of exhalation. In yet another embodiment, the aerosol delivery system has flow sensors connected to both the gas delivery conduit and the gas return conduit. When a control device receives data from the flow sensors, it monitors the breathing pattern to predict when the patient will breathe. By being able to predict the start of inspiration, the aerosol delivery system can prepare aerosolized medication for immediate inhalation. More specifically, the aerosol delivery system can pre-position the fluid on the vibrating member of the aerosol generator, thus aerosolizing the fluid before inspiration. Because flow detection is not a delayed-changing indicator, the flow sensor can quickly detect irregular or spontaneous inspiration and perform aerosol delivery (e.g., less than 10 milliseconds from the start of inspiration).

[0060] To predict patient inspiration, the control system first tracks the patient's breathing pattern and / or ventilation cycle (if the patient is undergoing forced ventilation) using one or more respiratory sensors and / or flow sensors. The control system then uses the tracked data to predict when the next inspiration will begin. This allows the control system to instruct the pump to deliver fluid from the fluid source to the aerosol generator 16 before inspiration. Furthermore, the control system signals the aerosol generator to begin aerosolizing the fluid at an appropriate time, such as before and / or during the predicted inspiration (e.g., within a predetermined period of + / - 0.5 seconds). Thus, the aerosol is ready for the patient at the start of inspiration. The aerosol delivery system can not only predict the respiratory cycle and generate aerosol for the patient, but can also use respiratory sensors to detect spontaneous / irregular breathing that is not part of the normal pattern. Once spontaneous breathing is detected, the aerosol delivery system immediately delivers fluid to the aerosol generator for delivery to the patient.

[0061] Figure 13 shows an example of the function of the control unit 812. As shown in plot A, the control unit 812 receives a signal from the respiratory sensor 814 indicating that the patient has begun to inhale. The control unit 812 then sends a command to begin delivery of a certain amount of drug to the aerosol generator, which operates to aerosolize the liquid drug, as shown in plots B-D. In some embodiments, the control unit 812 is programmed to aerosolize the drug only in the first part of the inhalation, with the last part of the inhalation drawing in chase air to facilitate the aerosolized drug reaching deep into the lungs. For example, as shown in several plots, the control unit 812 aerosolizes the drug only in the first 80% of each inhalation, with the last 20% of each inhalation allowing chase air to be drawn into the patient's airway. Of course, other aerosolization patterns may be used. For example, drug aerosolization occurs during the first 50% to 90% of each inhalation (more commonly between 60% and 80%, and even more commonly between 70% and 80%). For more than 80% of the time, the amount of aerosol exhaled before reaching the lower airway increases in the upper airway. Therefore, in the last 10% to 50% of the inhalation (more commonly around 20% to 40%, and even more commonly between 20% and 30%), the expelled air is drawn into the patient's airway.

[0062] Figures 14A-14K show the setup process for using the aerosolization system shown in Figures 8-13. At startup, the control unit 812 is powered on (e.g., switched on) to initiate the startup sequence. In some embodiments, the startup sequence includes a power-on self-test, in which various audible and visual alarms are repeatedly sounded on the alarm display at the top of the control unit. System backup alarms may also be sounded as a test. As shown in Figure 14A, the user (e.g., a healthcare professional) must log in to the control unit 812 via the user interface 818. For example, when starting to use the aerosolization system, the user must enter a username, password, possession authentication (e.g., magnetic stripe card and / or digital key or authentication using radio communication protocols), and biometric authentication (e.g., fingerprint scan, facial scan, retinal scan, voice scan). After logging in, the user must enter patient information regarding the timing, amount, and / or other factors related to the patient's treatment. For example, as shown in Figure 14B, the user must enter a patient identifier (name, identification number, etc.), patient weight, dosage type (high / low, etc.), quantity, and / or other details about the patient. Once all the necessary patient information has been entered, a confirmation screen is displayed to the user before proceeding, allowing the user to verify that the patient and medication information is accurate. If the patient and medication information is correct, the user confirms and proceeds with the setup process. If either the patient or medication information is incorrect, the user must re-enter the incorrect information before proceeding.

[0063] Next, as shown in Figure 14C, instructions for using the aerosolization system are displayed to the user. Here, the user interface 818 instructs the user to connect the pod 810 to the control unit 812 of the aerosolization system. For example, the user inserts the connector of the pod 810 into one of the ports 820 of the control unit 812. In some embodiments, the user interface 818 displays a notification indicating that the pod 810 is properly connected to the control unit 812. In some embodiments, the control unit 812 and / or a stand (not shown) supporting the control unit 812 by means of fixing or other means has a basket and / or other support structure to support the excess portion of the cable extending from the pod 810. Other instructions may also be displayed to assist the user in setting up the aerosolization system. In another example, as shown in Figure 14D, the user interface 818 instructs the user to connect a respiratory sensor 814 (such as a respiratory sensor capsule) to both the pod 810 and the patient, and then to confirm the patient's inhalation. As shown in the figure, in some embodiments, the respiratory sensor is connected to the pod by inserting a connector such as a slip lure into the port of the pod 810. In this embodiment, the respiratory sensor 814 is attached to the patient's abdomen by adhesive or the like to begin sensing the inspiratory cycle. For example, the patient's skin is wiped with a wet wipe to protect the skin from adhesive and then dried. Next, the respiratory sensor 814 is positioned on the flank and / or lower abdomen and secured in place with tape. No tape is applied to the tube of the respiratory sensor 814. The user interface 818 prompts the user to confirm that the control device 812 has received the respiratory signal and that it is properly displayed on the user interface 818.

[0064] As shown in Figure 14E, instructions are displayed to the user on how to set up the drug supply line 806 and sprayer cable 808 of the aerosolization system. For example, the user attaches the VVAD 828 to the drug vial (drug source 802) and aligns the filter 832 with the confirmation window on the vial's label. At this time, the vial is held upright and the perforated portion (not shown) of the VVAD 828 is passed through the septum (not shown) of the vial until the VVAD 828 clicks into place and locks in place. A supply mechanism (pump, etc., not shown) on the side of the housing of the control device 812 is opened, the fluid supply line 806 is inserted into the supply mechanism, and then it is closed. The vial is positioned horizontally and connected to the fluid supply line 806. The Luer end of the VVAD 828 is placed in the Luer holder portion of the holder 826 and rotated upward so that the confirmation window faces outward and is inserted into the metal clip. Next, the sprayer cable 808 is connected to the pod 810. The aerosolizer 800 is also connected to a respiratory system such as a ventilator. Once all the various components are connected, the aerosolizer 800 is primed.

[0065] Figure 14F shows the priming of the pump. Priming is performed by selecting the priming function from the user interface 818 of the control unit 812. After priming is complete, an aerosol check is performed as shown in Figure 14G. Next, the user operates the user interface 818 to start aerosol generation. The user then confirms that the aerosolization system is functioning correctly by observing that an aerosol is being generated and released from the patient interface (if attached) or the opening of the aerosolizer 800. If an aerosol is observed, the user continues the setup. If no aerosol is observed, the user repeats the priming and aerosol check procedure. Before or after the aerosol check is complete, the user interface 818 instructs the user to connect the patient interface (e.g., nasal prongs) to the aerosolizer 800. The user selects a patient interface of the appropriate size and presses it into the aerosolizer 800. In some embodiments, the connection between the patient interface and the aerosolizer 800 is trapezoidal. In this shape, it is easier for the user to properly position the patient interface in the correct orientation, but other shapes are also possible. As shown in Figure 14H, the aerosolizer 800 is connected to the infant. For example, nasal prongs (or other patient interface) are connected to the infant's airway. In some embodiments, the aerosolizer 800 is secured to the infant's airway and head using one or more straps and / or other restraints so that the aerosolizer stays in place even if the infant moves. In some embodiments, the aerosolizer 800 is secured to the infant's head by one or more straps attached to a hat worn by the infant. In addition, a foamed resin pad is attached to the aerosolizer 800 and extends between the aerosolizer 800 and the infant's head (positioned laterally away from the portion of the aerosolizer 800 that contains the aerosol generator).The foamed resin pad consists of multiple peelable foamed resin layers, and the distance between the aerosolizer 800 and the infant's head can be adjusted by peeling and / or otherwise removing the layers. Often, the foamed resin pad has a curved surface designed to match or substantially match the contour of the infant's head. Once positioned, the foamed resin pad (and any straps) functions to maintain the aerosolizer 800 in the correct position and orientation relative to the infant, regardless of the infant's movement or orientation (supine, lateral, or prone). Once the aerosolizing system is connected to the infant, the user initiates medication administration by operating the user interface 818, as shown in Figure 14I. For example, the user verifies patient data and total dose and confirms that the number of drug vials matches the pharmacy calculations and dispensing documents provided by the pharmacist. After data verification, the user operates the control unit 812 to initiate the medication administration procedure. Once the medication administration procedure is initiated, data such as respiratory cycle, dose display, spray rate, and remaining drug amount in drug source 802 are displayed. The user interface 818 also instructs the user to ensure that the aerosol is synchronized with the infant's breathing pattern.

[0066] In some embodiments, if the vial is empty, the control unit 812 stops dispensing medication. Often, a low-priority alarm is activated when the amount of medication in the vial reaches a threshold amount (e.g., 5%, 10%, 15%, 20%). If a predetermined time elapses without the low-priority alarm being acknowledged by the user, a medium-priority alarm is activated, and a “Vial Warning” message is displayed on the user interface 818 and / or by one of the indicators 820. In some embodiments, when the vial becomes empty, the control unit 812 automatically pauses and a medium-level alarm is activated. If a predetermined time elapses without the user acknowledging this alarm, a high-priority alarm is activated. The user is instructed to “replace the vial and resume dispensing from the medication delivery screen.” Once the empty vial is replaced with a new medication vial, dispensing can be resumed. When dispensing is complete, the user confirms the end of dispensing and operates the control unit 812 to return to a normal CPAP or other breathing circuit.

[0067] In some embodiments, low-priority alarms are visual only and are displayed as textual information on the user interface 818. In some embodiments, medium-priority alarms include visual and audible elements, combining a corresponding colored alarm display (e.g., yellow) with corresponding audio and textual information. In some embodiments, high-priority alarms include visual and audible elements, combining a corresponding colored display box (e.g., red) on the user interface 818 with textual information on the user interface 818. In some embodiments, alarms are triggered if: respiration is not detected; effective continuous respiration is not detected (effective continuous respiration consisting of three consecutive effective respirations is not detected; each respiration is determined to be effective if the inspiratory time is 100 milliseconds or longer; it is determined to be an invalid continuous respiration if it includes at least one invalid respiration; it is determined to be an invalid respiration if the inspiratory time is less than 100 milliseconds); the nebulizer cable is detached from the pod during medication administration; or the conditions are wet / dry. An alarm will sound if any of the following events are not detected (for example, if the tube is twisted and the drug is not being delivered to the aerosol generator, if no drug is being sprayed and the entire amount of drug is being released from the vent, if no drug is being sprayed from the vent, or if drug is being sprayed from the vent); if the remaining amount of drug in the vial is below the threshold amount (including empty); if the pod cable is disconnected from the pod during drug administration; if the pod cable is disconnected from the pod when no drug is being administered; if a pod communication failure is detected; if an internal pod failure is detected; if a system error is detected; if the drug delivery mechanism fails; if the main power is cut off and the system is operating in battery mode; if the battery charge is below the threshold level (including empty); and / or if the power-on self-test fails.

[0068] Figure 15 shows the aerosolizer 1500 connected to an infant. The aerosolizer 1500 is similar to those described herein and has an aerosol generator positioned near the infant's airway and has a barrier to minimize flow through the direct connection area between the patient and the aerosol generator during aerosol generation. Furthermore, the aerosolizer 1500 has a PDAP mesh or similar mesh capable of performing aerosolization of particles with an MMAD of less than about 3 μm (more preferably less than about 2 μm) at high flow rates (about 0.1 ml / min to 1.5 ml / min). The aerosolizer 1500 has a power / control port for connecting one or more control devices (similar to control device 812) that send power and operating commands to the aerosol generator.

[0069] The aerosolizer 1500 has one or more straps or other restraints 1502 for securing the aerosolizer 1500 to the infant's head and airway. Furthermore, the aerosolizer 1500 has a foamed plastic pad 1504 designed to maintain the aerosolizer 1500 in the appropriate position and orientation relative to the infant, regardless of the infant's movement or orientation (supine, lateral, or prone). The foamed plastic pad 1504 consists of multiple peelable foamed plastic layers, and the distance between the aerosolizer 1500 and the infant's head can be adjusted by peeling and / or removing the layers. Often, the foamed plastic pad 1504 has a curved surface designed to match or substantially match the contour of the infant's head. The aerosolizer 1500 is formed from a lightweight material (such as medical-grade foamed plastic) that allows the infant to move around without moving the aerosolizer 1500 from its proper position.

[0070] Figure 16 shows a respiratory sensor capsule 1600 (similar to respiratory sensor 814) connected to the infant's abdomen. As shown in the figure, the respiratory sensor capsule 1600 is attached to the infant's abdomen with tape or the like and is used to detect the start and / or end of the infant's inspiratory cycle. Detection uses changes in the volume of the sensor capsule 1600 in response to abdominal movement associated with breathing. Using data from one or more inspiratory cycles, a control device (not shown) monitors the inflow and outflow of the capsule in response to changes in the abdominal sensor volume and maximizes the delivery efficiency of the surfactant by delivering the aerosolized surfactant in sync with the infant's breathing.

[0071] Figure 17 shows another embodiment of the aerosolization system 1700 for effectively and efficiently delivering surfactants to an infant. As shown in the figure, a control device 1702 (similar to control device 812) is used to power and control the aerosolizer 1704. Furthermore, the control device 1702 is configured to control the delivery mode of the aerosolizer 1704. For example, the control device 1702 is configured to alternate between a timed mode in which treatment is performed over a set period of time and a continuous mode in which aerosolized surfactant is delivered indefinitely based on the infant's inhalation pattern. The system 1700 also has an additional control device 1706 for healthcare professionals to set aerosol delivery conditions. For example, the additional control device 1706 can be used to set the flow rate to initiate aerosol delivery, the inhalation time for aerosol delivery, and / or other conditions to adjust the timing, amount, duration, etc., of the administration of the aerosolized drug. Although the control device 1702 and the additional control device 1206 are described as different components, in some embodiments, the operation of the system 1700 is controlled using a single control device (or more control devices).

[0072] System 1700 also includes one or more flow sensors and / or other respiratory sensors 1708. As shown in the figure, the flow sensor 1708 is connected to the inspiratory rim 1710 of the respiratory system 1712, for example, upstream and / or downstream of any humidifier 1714. The respiratory sensor 1708 is used to detect infant inhalation. In other embodiments, the respiratory sensor 1708 is a respiratory sensor capsule connected to the infant's abdomen. The respiratory sensor 1708 is electronically connected to one or both of the control devices 1702 or 1706, which initiate the operation of the aerosolizer 1704 (similar to any of the aerosolizers described herein) based on the inhalation data. The control devices 1702 and 1706 are electronically connected to the aerosolizer 1704, which sends both power and operation commands to the aerosolizer 1704. In some embodiments, the aerosolizer 1704 has a PDAP mesh 1716 that generates aerosolized surfactant with an MMAD of less than approximately 3 μm (preferably less than approximately 2 μm) at a flow rate of at least 0.1 ml / min. When used in combination with control devices 1702, 1706 and a respiratory sensor 1708, such an aerosolizer 1704 enables 1) the generation and delivery of sufficiently small aerosol particles, 2) the delivery of aerosols in sync with respiration, and 3) the placement of the aerosol generator near the infant's airway and obstruction of continuous gas flow to minimize flow through the direct connection area between the patient and the aerosol generator during aerosol generation (clearly illustrated in Figures 6-6D). As a result, lung delivery efficiency is significantly improved, achieving efficiencies of approximately 25% to 60%, and more commonly, approximately 40% to 60%.

[0073] Figure 18 is a flowchart of process 1800 for delivering an aerosolized surfactant to an infant. Process 1800 can be performed using any of the aerosolizers, processors and / or respiratory sensors described herein. Process 1800 begins in block 1802 with detecting the infant's inhalation using one or more respiratory sensors. For example, the respiratory sensors are attached to the infant's abdomen. The respiratory sensors detect the expansion of the infant's abdomen accompanying inhalation. In response to the detected inhalation, in block 1804, the control device causes the aerosolizer to aerosolize a certain amount of surfactant into particles with an aerodynamic median particle size (MMAD) of less than about 3 μm at a flow rate of at least 0.1 ml / min. The surfactant is aerosolized within about 1–8 cm of the patient interface. In some embodiments, aerosolizing the above amount of surfactant includes delivering the above amount of surfactant from the containment to the mesh of the aerosolizer and vibrating the mesh to aerosolize the above amount of surfactant. In some embodiments, the above-mentioned amount of surfactant is delivered from the containment to the mesh via a conduit having a tip having a diameter. The tip of the conduit is positioned at a distance from the mesh of the aerosol generator that is less than or equal to the above-mentioned diameter. Therefore, the agent released from the tip comes into contact with the surface of the mesh and rises up, so that the aerosolizer can operate effectively in any orientation. In some embodiments, when the above-mentioned amount of surfactant is aerosolized, a portion of the above-mentioned amount of surfactant is aerosolized in at least a portion of the first 80% of each of a series of consecutive inhalations, such that expulsion air is supplied in at least a portion of the last 20% of each of the series of consecutive inhalations. In block 1806, the aerosolized surfactant is delivered to the infant's airway via a patient interface such as nasal prongs.

[0074] In some embodiments, process 1800 includes connecting an aerosolizer to a breathing system and diverting a portion of the airflow from the breathing system to a chamber in the aerosolizer through at least one vent. This chamber is configured to mix a portion of the airflow with an aerosolized surfactant. In some embodiments, a portion of the airflow is a breathing flow, less than the amount of air that continues to advance to the expiratory rim of the breathing system. In some embodiments, a portion of the airflow is diverted by at least one barrier defining at least one vent. The at least one barrier may be configured to divert a portion of the airflow to the aerosol chamber through at least one vent, and to divert another portion of the airflow from the inspiratory rim toward the expiratory rim. In some embodiments, two barriers are used. A first barrier defines a first vent, and a second barrier defines a second vent. The first ventilation passage is located at the lateral end of the first barrier, and the second ventilation passage is located beyond the leading edge of the second barrier. The lateral end and leading edge extend in different directions from each other so that the respiratory flow moves in multiple directions and passes through the first and second barriers.

[0075] Figure 19 is a flowchart of process 1900 for initializing the aerosolization system. Process 1900 can be performed using any of the aerosolizers, processors, and / or respiratory sensors described herein. Process 1900 begins in block 1902 with connecting the aerosolizer to a control unit, respiratory sensor, drug source, and respiratory system. Here, a sprayer cable is connected between the aerosolizer and the control unit (may be via a pod or other adapter), the inspiratory rim of the respiratory system is connected to the inlet of the aerosolizer, the expiratory rim of the respiratory system is connected to the outlet of the aerosolizer, the cable of the respiratory sensor is connected to the control unit (may be via a pod or other adapter), and / or the aerosolizer is connected to the drug source. In some embodiments, when connecting the aerosolizer to the drug source, a fluid supply line is connected between the drug source and the aerosolizer. In some embodiments, the drug source is a vented vial access device (VVAD) connected to the fluid supply line.

[0076] In block 1904, user access authentication is entered into the control unit, allowing only authorized users to administer medication using the aerosolization system. Access authentication may be one or more of the following: user identifier, password, possession authentication, and biometric authentication. In block 1906, patient-related information and medication information are entered into the control unit. This includes information such as patient identifier, patient weight, and dose level. In block 1908, a respiratory sensor is connected to the patient. For example, the sensor is attached to the patient's abdomen. In some embodiments, respiratory detection is configured after the respiratory sensor is connected to the patient. In block 1910, the aerosolization device is primed. For example, a portion of the medication is aerosolized before connecting the patient interface to the patient's airway to verify that the device functions correctly. In block 1912, the aerosolization device is connected to the patient's airway. For example, nasal prongs are inserted into the infant's nostrils. In some embodiments, the patient interface needs to be secured to the aerosolization device before connecting the device to the patient. In some embodiments, one or more straps and / or foam pads are positioned and / or secured around the infant to fix the aerosolizing device in place. Once fixed in place, the user may initiate the delivery of the dose to the infant and / or check the user interface of the control device to confirm that the delivery of the aerosolized dose is synchronized with the infant's inhalation.

[0077] In some embodiments, process 1900 includes performing a startup sequence when the control unit is powered on. The startup sequence involves the repeated activation of multiple audible alarms, visual alarms, or both audible and video alarms to verify that the control unit is functioning correctly before use.

[0078] (Examples) In vitro experiments were conducted using the aerosolization apparatus according to the present invention to determine the effective release dose of the drug. Simulations of infant inhalation were performed using a modified sinusoidal small animal ventilator from Harvard Apparatus connected to a patient adapter (nasal prongs in this example) of the aerosolization apparatus similar to those shown in Figures 6-6D, and a lung simulator from Ingmar. The simulations were performed using two different sizes of nasal prongs: large nasal prongs (5560) and small nasal prongs (4030). As shown in the bar graph in Figure 20, the release dose increases with increasing prong size. In particular, the release dose for large nasal prongs (5560) was 68% to 72%, while the release dose for small nasal prongs (4030) was approximately 35% to 37%.

[0079] The airflow was set to 6 LPM (liters / minute), 8 LPM, and 10 LPM, and the respiratory rates were 60 BPM (breaths / minute), 80 BPM, 100 BPM, and 120 BPM. Next, the release dose rate was measured for each combination of airflow and respiratory rate. As shown in Figure 21, the delivery efficiency was affected by the gas flow, and as the flow rate increased, the delivery efficiency decreased slightly. For example, at low flow rates (6 LPM), the release dose with a large nasal prong (5560) was approximately 50% to 60% across the entire range of respiratory rates tested. On the other hand, at high flow rates (10 LPM), the release dose ranged from approximately 42% to 47%. As the respiratory rate increased, the difference in efficiency with increasing flow rates became smaller. For example, the range of release dose rates at 60 BPM was approximately 44% to 60%, while the range at 120 BPM was approximately 42% to 51%. Based on these results, the aerosol generators described herein were found to enable uniform drug inhalation doses across the entire range of clinically reasonable respiratory rates (60–120 BPM) and CPAP flow rates commonly used in bubble CPAP and ventilated CPAP systems (6–10 LPM).

[0080] Furthermore, embodiments of the present invention provide systems and methods for non-invasively delivering surfactants (or other agents) to infants, particularly premature infants. To achieve effective and efficient administration of drug aerosols to premature infants, the following combination of attributes is necessary: ​​1) sufficiently small aerosol particles; 2) aerosol delivery synchronized with respiration; and 3) positioning the aerosol generator in the vicinity of the infant's airway (within approximately 1-8 cm) and obstructing continuous gas flow to minimize flow through the direct connection area between the patient and the aerosol generator during aerosol generation. By satisfying these conditions, surfactant delivery rates higher than 40% and up to approximately 60% can be achieved, which is a significant improvement over conventional efficiencies of less than 10%.

[0081] Considering the respiratory physiological functions of premature infants, nasal delivery methods, such as nasal prongs that can be inserted into the infant's nasal cavity, are necessary for the non-invasive and appropriate delivery of aerosolized surfactants to infants. Such delivery methods are desirable for delivering aerosol particles smaller than approximately 2 μm. Larger particles often collide within the interface of the aerosolizer and / or the airway before dispersing in the infant's lungs. This is also shown in Figures 22 and 23. These figures show particle deposition rates in neonates at various particle sizes (using MMAD and geometric standard deviation (GSD) of 2.2). Neonatal 1 was a 4-month-old premature infant, and Neonatal 2 was a 28-week-old premature infant. Figure 22 shows that lung deposition increases with decreasing particle size (Figure 22 shows only the results for Neonatal 1), and lung deposition exceeds 40% when particle size is smaller than 2 μm. In particular, for particles larger than 2 μm, nasal deposition is typically around 50%–70%, and this portion consists of particles that are not delivered to the infant's lungs. Figure 23 shows a comparison of lung and nasal deposition rates in two neonates using aerosols with MMADs of 3 μm and 2 μm. In both neonates, improved lung deposition was observed with the MMAD 2 μm aerosol, with deposition rates of slightly less than 40% in neonate 1 and slightly less than 60% in neonate 2. These results indicate that smaller aerosol particles are necessary to maximize delivery efficiency.

[0082] Conventional nasal delivery methods typically use particles with an MMAD of 4-7 μm, resulting in a geometric standard deviation of approximately 2.0 or greater. This is because many surfactants are viscous, making it extremely difficult to aerosolize undiluted surfactants into small particles at an effective flow rate using conventional jet sprayers, special jet sprayers, mesh sprayers, heated capillary generators, etc. The collision rate of such conventional delivery methods reduces the effective amount of aerosol in a single dose by up to 80%. Only 40-60% of the remaining aerosol (the portion consisting of particles smaller than approximately 2 μm) reaches the lower airways of the lungs, resulting in an overall efficiency of approximately 10% of the initial dose released from the aerosol generator.

[0083] In some embodiments of the present invention, a system and method are provided for generating sufficiently small aerosol particles using an aerosolizing apparatus such as the apparatus described above with reference to Figures 1-8. In particular, in some embodiments, an aerosolizing apparatus equipped with an aerosol generator that utilizes the functionality of a PDAP mesh (such as that disclosed in U.S. Patent Publication No. 2016 / 0130715) is used to uniformly generate aerosolized surfactant particles of less than approximately 3 μm (more preferably about 1.5 μm to about 2.5 μm) at an output flow rate of about 0.1 ml / min to 0.6 ml / min. Embodiments of the present invention utilize the capabilities of such aerosol generator to sufficiently reduce particle size and effectively and efficiently deliver the surfactant to the lungs. For example, even aerosols with an MMAD of less than 3 μm can achieve a transnasal lung delivery efficiency of about 40-60% of the nominal dose of the surfactant.

[0084] As mentioned earlier, synchronizing aerosol delivery with the infant's inhalation is also effective in maximizing delivery efficiency. Synchronization prevents the surfactant from being wasted by aerosolization during exhalation or between breaths. For example, the inhalation-to-exhalation ratio of infants is often about 1:1 to 1:3. Therefore, aerosolized surfactants are usually only inhaled for about 25-50% of the time. In conventional systems, aerosols are often carried by a gas flow of about 6-10 LPM from a bubble CPAP. This flow rate exceeds the infant's maximum inspiratory flow rate, resulting in up to half of the aerosolized drug being wasted.

[0085] In some embodiments of the present invention, the aerosol generator is operated in conjunction with the infant's breathing. As previously mentioned, this is done by tracking the patient's breathing pattern and / or ventilation cycle using one or more respiratory sensors and / or flow sensors. Based on this information, the control device predicts when the next inspiration will begin and synchronizes the timing of the fluid supply from the fluid source to the aerosol generator and / or the operation of the aerosol generator with the infant's inspiration. In some embodiments, inspiration is detected using a respiratory sensor capsule attached to the infant's abdomen. The respiratory sensor capsule detects abdominal movement associated with inspiration, which occurs immediately before the inspiration itself begins. For this reason, the respiratory sensor capsule is particularly effective in determining inspiration timing to synchronize aerosol generation.

[0086] Figure 24 shows the effectiveness of the respiratory sensor capsule in inhalation detection. In this example, individual flow sensors were connected to the infant's airway, and the respiratory sensor capsule was fixed to the infant's abdomen. The infant weighed 1500g and had a respiratory rate of 70 BPM. As can be seen from the graph in Figure 24, the sensor signal from the respiratory sensor capsule detected each inhalation and exhalation detected by the flow sensors, and the respiratory sensor capsule detected the onset of inhalation slightly before the flow sensors. This time can be used by the control device to activate the aerosol generator. These results confirm that the use of the respiratory sensor capsule is particularly effective in synchronizing respiration and aerosol generation. Also from Figure 24, it can be seen that although these inhalations occur over a period of 5 seconds, inhalation accounts for only about one-third of that time. Therefore, if aerosol delivery is not synchronized with respiration, more than two-thirds of the aerosolized surfactant will be wasted.

[0087] In some embodiments, the aerosolizing apparatus described herein comprises an aerosol generator that can be connected to various mechanical ventilation systems. The aerosol generator receives a liquid drug from a fluid source via a fluid delivery conduit. During operation, the fluid from the fluid source is delivered by a pump through the fluid delivery conduit to the aerosol generator, where the fluid is aerosolized in the aerosol generator before and / or during the patient's inspiration. In some embodiments, the fluid delivery conduit is primed with fluid before treatment (e.g., the fluid is pre-delivered to the aerosol generator) to ensure rapid delivery. The pump is controlled by a control device that controls the fluid delivery time and dosage.

[0088] The control unit comprises one or more processors that execute instructions stored in one or more memories to drive the operation of the pump and aerosol generator. For example, the memory stores instructions indicating the amount of fluid delivered to the aerosol generator in a single dose for each operation of the aerosol generator, the amount of fluid delivered over a specific period or number of times, etc. The stored instructions are based on the patient's body size, age, sex, type of drug, fluid additives, desired amount of aerosol, etc. The memory also stores instructions for operating the aerosol generator. As shown in the figure, the control unit is connected to the aerosol generator by a cable (i.e., an electrical cable), but in some embodiments, the control unit is connected to the aerosol generator wirelessly. The cable transmits signals to operate a piezoelectric actuator (or other actuator) in the aerosol generator. When the piezoelectric actuator operates, the vibrating member vibrates, aerosolizing the fluid and delivering it to the patient (i.e., delivered by inhalation). Thus, the memory stores instructions for controlling the start timing, stop timing, vibration frequency, or frequency of the piezoelectric actuator.

[0089] The aerosolization systems described herein can enhance therapeutic effects by adjusting the timing of aerosol generation. For example, an aerosol delivery system may begin aerosolizing the drug before the patient inhales. In this case, the aerosol delivery system can utilize the increased airflow at the start of inhalation. As a result, the inhaled air carries the drug further into the patient's lungs, thus facilitating drug delivery to the patient. Alternatively, the aerosol delivery system may begin aerosolizing the drug as soon as inhalation is detected (e.g., during spontaneous breathing).

[0090] Aerosol delivery systems can use one or more respiratory sensors to determine the timing and duration of a patient's inspiration and adjust drug delivery accordingly. These respiratory sensors communicate with a control device via wired and / or wireless connections. In some embodiments, aerosol delivery systems can achieve redundancy and / or more accurate monitoring of a patient's respiratory cycle by using a combination of multiple respiratory sensors. In one example, an aerosol delivery system uses a flow sensor in combination with a radar sensor to monitor both airflow and chest movement. In another example, an aerosol delivery system uses a flow sensor, a radar sensor, and a plethysmography sensor to monitor the respiratory cycle. Any number and / or any combination of respiratory sensors can be used for any application to monitor a patient's respiratory cycle.

[0091] In some embodiments, a flow sensor is connected to a gas delivery conduit to sense changes in airflow during inspiration (e.g., forced breathing, assisted breathing, or spontaneous breathing). In some embodiments, a flow sensor is also connected to a gas return conduit to detect the start and end of exhalation. In yet another embodiment, the aerosol delivery system has flow sensors connected to both the gas delivery conduit and the gas return conduit. When a control device receives data from the flow sensors, it monitors the breathing pattern to predict when the patient will breathe. By being able to predict the start of inspiration, the aerosol delivery system can prepare aerosolized medication for immediate inhalation. More specifically, the aerosol delivery system can pre-position the fluid on the vibrating member of the aerosol generator, thus aerosolizing the fluid before inspiration. Because flow detection is not a delayed-changing indicator, the flow sensor can quickly detect irregular or spontaneous inspiration and perform aerosol delivery (e.g., less than 10 milliseconds from the start of inspiration).

[0092] To predict patient inspiration, the system first tracks the patient's breathing pattern and / or ventilation cycle (if the patient is undergoing forced ventilation) using one or more respiratory sensors and / or flow sensors. The control system then uses the tracked data to predict when the next inspiration will begin. This allows the control system to instruct the pump to deliver fluid from the fluid source to the aerosol generator before inspiration. Furthermore, the control system signals the aerosol generator to begin aerosolizing the fluid at an appropriate time, such as before and / or during the predicted inspiration (e.g., within a predetermined period of + / - 0.5 seconds). Thus, the aerosol is ready for the patient at the start of inspiration. The aerosol delivery system can not only predict the respiratory cycle and generate aerosol for the patient, but can also use respiratory sensors to detect spontaneous / irregular breathing that is not part of the normal pattern. Once spontaneous breathing is detected, the aerosol delivery system immediately delivers fluid to the aerosol generator for delivery to the patient.

[0093] (Example 1) A two-part study was conducted to evaluate the safety and tolerability of inhaled surfactant administration during nCPAP treatment in premature infants at risk of respiratory distress syndrome (RDS) exacerbation. In Part 1 (10 infants), patients were treated with a single dose, and in Part 2, patients were treated with multiple doses. A total of 31 premature infants requiring nCPAP (device-assisted CPAP) were enrolled in this study. Infants were first stabilized with nCPAP / nIMV (nasal intermittent forced ventilation) by adjusting CPAP and inspired oxygen concentration (FiO2) as appropriate to maintain clinical blood gas (CBG) and oxygen saturation (SpO2) according to clinical guidelines. After the infant's condition stabilized, AeroFact was administered via nCPAP within 2 hours of birth.

[0094] AeroFact was administered as a single dose to the infant, containing an aerosol equivalent to a 108 mg / kg infusion dose (resulting in a 50% delivery efficiency relative to a nominal dose of 216 mg / kg). Oxygenation and ventilation parameters were monitored according to the plan until an effect was observed (as defined in the plan). The infant continued to receive nCPAP after administration. Clinical observation, respiratory support indicators, and premature comorbidities of the infant were monitored until discharge from the neonatal intensive care unit (NICU).

[0095] Following the successful completion of Part 1 and approval by the Independent Data Safety Monitoring Committee (DSMB), registration for Part 2 of the study was permitted. Part two of the study was conducted with a different group of premature infants who were also receiving nCPAP and were at risk of RDS exacerbation.

[0096] An aerosolized dose of SF-RI1 at a nominal dose of 216 mg / kg was initially administered. Oxygenation and ventilation parameters were monitored according to the protocol, and aerosol delivery was stopped when the intended dose was reached.

[0097] Infants continued to receive nCPAP. AeroFact was re-administered (nominal dose 216 mg / kg) if the respiratory severity score (RSS: mean airway pressure × inspired oxygen concentration), which maintained an SpO2 level of 90% to 95% (measured with a pulse oximeter), was ≥ 2.0, and at least (1) 2 hours had passed since the end of the first dose, and (2) 4 hours had passed since the end of the second or third dose. Additional doses of AeroFact were permitted up to a maximum of three times within 96 hours.

[0098] Ten patients were enrolled in Part 1 of the study, and 21 patients in Part 2, comprising both the intention-to-treat (ITT) analysis population and the safety analysis population. There were 30 patients in the historical control group in Part 1 and 63 patients in Part 2.

[0099] In accordance with the plan, all 10 patients (100%) in Part 1 received one dose of the study drug. In Part 2, 13 patients (61.9%) received one dose of the study drug, 4 patients (19%) received two doses, and 4 patients (19%) received three doses. No patients received four doses of the study drug.

[0100] The incidence of one or more adverse events (AEs) in AeroFact patients was 7 (70%) in Part 1 and 13 (61.9%) in Part 2. No AEs were assessed by the principal investigator as being related to the investigational drug, device, or procedure, and no AEs led to early discontinuation of the investigational drug or patient study.

[0101] The incidence of adverse events (AEs) related to drug tolerance during the first 24 hours was generally low. The number of patients with immature comorbidities was 6 (60%) in Part 1 of the study and 20 (66.7%) in the historical control group of Part 1. In Part 2 of the study, the number was 12 (57.14%) and 31 (49.21%) in the historical control group of Part 2. The incidence of immature comorbidities and AEs after administration was generally low and comparable between patients treated with AeroFact and the historical control group.

[0102] (Conclusion) AeroFact administration, up to four times within 96 hours of birth, was found to be safe and well-tolerated in patients with a gestational age between 26 weeks 2 days and 30 weeks 4 days, and weighing between 640 and 1664 grams.

[0103] In the second part of the study, the need for salvage therapy with surfactant bolus injection was lower than in the corresponding historical control group. As shown in the graph in Figure 25, five AeroFact patients (25%) in the second part required salvage therapy with surfactant bolus injection, compared to 27 patients (45%) in the corresponding historical control group. In other words, the relative risk of AeroFact treatment was 0.56, indicating that AeroFact treatment was more effective.

[0104] This study showed that the incidence of post-administration immature comorbidities and adverse events (AEs) was lower in patients treated with the aerosolization system shown in Figure 17 compared to the historical control group, and there was no inter-patient variability. No therapeutic adverse events (TEAEs) were determined to be related to the study drug, device, or procedure. Between days 1 and 4 of the study, following the drug regimen, one instance of moderate nasal congestion occurred in Part 1, and five instances of moderate nasal congestion and one instance of severe nasal congestion occurred in Part 2. One patient in Part 1 and one patient in Part 2 experienced a fatal serious adverse event (SAE) (sepsis as demonstrated by culture). These were not related to the study drug, device, or procedure, and did not occur during the treatment period. The incidence of AEs related to drug tolerance during the first 24 hours was generally low. Regarding the incidence of AEs, administration using only the aerosolization system shown in Figure 17 was comparable to administration combining the aerosolization device with bolus injection of the surfactant.

[0105] (Example 2) An active test lung was driven by a ventilator to activate an AF2b device respiratory sensor (similar to the sensor in Figure 16) and simulate the breathing pattern of an infant. A training / test lung (Michigan Instruments) was driven using a ventilator (Pulmonetic Systems). The training / test lung was driven on the adult side with the test lung balloon attached to the air circuit using a T-piece to represent the subtle abdominal movements during neonatal respiration. An AF2b respiratory sensor (normally attached to an infant) was attached to the lung balloon. Small movements of the balloon during the inspiratory / expiratory cycle triggered the sensor to activate the device's respiratory function. The adult training / test lung was mechanically coupled to an infant training / test lung used to simulate the actual breathing of an infant. Various infant breathing patterns could be simulated by adjusting the ventilator settings. Infant respiratory parameters were confirmed using a gas flow analyzer (IMT Analytics). Table 1 summarizes the parameters for the active lung / ventilator test.

[0106] [Table 1]

[0107] Aerodynamic particle size measurement using a next-generation impactor. Next, the United States Pharmacopeia (USP) <1601> Next-generation impactor (NGI) tests were performed according to the following procedure. NGIs were cooled in a refrigerator at 4–8°C for at least 90 minutes before use and sampled at a flow rate of 15 L / min. Approximately 0.5 mL of AlveoFact® formulation was used for each NGI run. During the test, the NGIs were placed in a cooling chamber (maintained at 5°C), and ambient air was drawn in using an AF2b device located outside the cooling chamber. The nebulizer (without nasal prongs) shown in Figures 6–6D was attached to the introduction port of the NGI using a T-piece with an adapter. The inspiratory and expiratory rims were open, and the open end of the T-piece was closed. NGI samples were weighed by the gravimetric method of AS00006.

[0108] (Exam Overview)

[0109] [Table 2]

[0110] (result) The results confirmed that the aerodynamic particle size was equivalent across all tested ventilator settings (low, medium, and high). As shown in Table 3 below, the average MMAD and GSD (for the three ventilators) for the low, medium, and high settings were 2.3 μm and 1.5 μm, respectively.

[0111] [Table 3]

[0112] As can be seen from Figures 26-28, the aerodynamic particle size distribution was similar for each test sprayer, regardless of the ventilator settings. Furthermore, uniform results were obtained across all CPAP settings (low, medium, and high).

[0113] Furthermore, Tables 4-6 and Figures 29-31 show the NGI mass values ​​for each stage. The stage cutoff diameter indicates the maximum diameter of particles that can pass through each stage of the NGI, and the particle mass refers to the mass that passes through each stage in each CPAP setting.

[0114] [Table 4]

[0115] [Table 5]

[0116] [Table 6]

[0117] (Conclusion) The results above indicate that the aerodynamic particle size of AlveoFact® generated by the AF2b PDAP® device is unaffected by the simulated spontaneous breathing settings. Specifically, regardless of the CPAP setting, aerosol particles were less than 3 μm, more specifically 2.0–2.5 μm, with a very small geometric standard deviation (GSD) of 1.5–1.6. The fine particle fraction, consisting of particles smaller than 3.3 μm, was approximately 83% across all CPAP settings. Furthermore, this study confirmed stable particle delivery across the entire range of CPAP settings.

[0118] Furthermore, Tables 4-6 and Figures 29-31 show the NGI mass values ​​for each stage. This data indicates that the powder mass was uniform across various CPAP settings at each stage of the impactor.

[0119] Furthermore, at a CPAP flow rate of 6 LPM and delivery at 344.738 kPA (50 psi), the aerosol droplet size was uniform throughout the entire dose. The test setup is shown in Table 7 below.

[0120] [Table 7]

[0121] As shown in Table 8 below, the MMAD generated in each aerosolizer was remarkably uniform from the start of administration to the completion of the maximum dose (four 108 mg vials), with MMAD being less than 3.0 μm (2.5–3.0 μm) and GSD being 1.4–1.5 in each aerosolizer. This indicates that no mesh pore expansion occurred due to the use of the mesh, and that the PDAP mesh was capable of generating aerosol particles with MMAD less than approximately 3.0 μm over a lifetime exceeding the upper limit of the permissible number of administrations of the surfactant.

[0122] [Table 8]

[0123] Table 9 shows the test parameters for testing suction dose efficiency with different nasal prong diameters.

[0124] [Table 9]

[0125] As shown in Table 10 below, the delivery dose across various sizes of nasal prongs was uniform, ranging from 42% to 57% (significantly exceeding the delivery dose of approximately 6% for conventional devices). The average dose-depletion (DD) for small, medium, and large prongs was 51%, 45%, and 50%, respectively. These results confirm that prong size does not significantly affect the DD.

[0126] [Table 10]

[0127] Table 11 shows the test settings for determining the effectiveness of the aerosolizer when delivering aerosolized drugs in various orientations. The aerosolizer was tested at 0° (supine infant), 90° (lateral infant), and 180° (prone infant), and the delivery dose was measured for each orientation.

[0128] [Table 11]

[0129] Table 12 shows the results of the orientation test. These results indicate that the DD (death load) was not affected by orientation at either the 0° (supine) or 90° (lateral) administration positions, with average values ​​of 69% and 70% respectively. At the 180° (prone) position, the AF2b device was able to maintain respiration-initiated aerosolization for the entire 0.5 mL dose across all three devices, with an average DD of 46%. These results demonstrate that the system can reliably generate aerosols in all tested orientations.

[0130] [Table 12]

[0131] The methods, systems, and apparatus described above are examples. Some embodiments are described as processes shown as flow diagrams or block diagrams. In each process, multiple operations may be described as sequential processes, but many operations may be executed in parallel or simultaneously. The order of operations is also changeable. Processes may include additional steps not shown in the diagrams. Furthermore, embodiments of the methods are implemented by hardware, software, firmware, middleware, microcode, hardware description languages, or any combination thereof. When implemented in software, firmware, middleware, or microcode, the program code or code segments for performing the relevant tasks are stored in a computer-readable medium such as a storage medium. The relevant tasks are executed by a processor.

[0132] The systems and devices described above are for illustrative purposes only. In various embodiments, various procedures or components may be omitted, substituted, or added as needed. Features described in relation to a particular embodiment can be combined with various other embodiments. Different aspects and elements of the embodiments can also be combined in a similar manner. Furthermore, since technology is constantly evolving, many elements are merely illustrative and should not be construed as limiting the scope of the invention.

[0133] Certain details are described in the specification for the purpose of a complete understanding of the embodiments. However, embodiments can be implemented without including these specific details. For example, to avoid obscurity in the description of embodiments, well-known structures and techniques are described without unnecessary details. Such descriptions are intended to be illustrative of embodiments only and do not limit the scope, applicability, or configuration of the invention. The above description of embodiments provides those skilled in the art with an explanation for enabling embodiments of the invention. Various modifications can be made to the function and arrangement of the elements without departing from the spirit and scope of the invention.

[0134] The methods, systems, apparatus, graphs, and tables described above are examples. In various configurations, various procedures or components may be omitted, substituted, or added as needed. For example, in alternative configurations, the methods may be performed in a different order than those described, and various steps may be added, omitted, and / or combined. Also, the functions described for a particular configuration can be combined in various other configurations. Different aspects and elements of the configurations can also be combined in a similar manner. Furthermore, since technology is constantly evolving, many of the elements are merely illustrative and do not limit the scope of this disclosure or the claims. In addition, the methods described herein may yield different results with different types of context-aware classifiers.

[0135] While exemplary and currently preferred embodiments of the disclosed systems, methods, and machine-readable media are described in detail herein, the concepts of the present invention can be embodied and used in various other ways, and unless limited by the prior art, the appended claims shall be construed to include such modifications.

[0136] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as they are commonly or conventionally understood. In this specification, “one” means one or more (i.e., at least one) objects. For example, “one element” means one or more elements. “Approximately” and / or “about” as used herein in reference to measurable values ​​such as quantity, duration, etc., means a variation of ±20%, ±10%, ±5%, or +0.1% from a specified value. Such variations are considered appropriate in the sense of the systems, apparatus, circuits, methods, and other implementations described herein. “Approximately” as used herein in reference to measurable values ​​such as quantity, duration, physical attributes (such as frequency), etc., means a variation of ±20%, ±10%, ±5%, or +0.1% from a specified value. Such variations are considered appropriate in the sense of the systems, apparatus, circuits, methods, and other implementations described herein. In the enumeration of items beginning with “at least one” or “one or more” as described herein, including in the claims, the “and” indicates that the enumerated items can be combined in any way. For example, “at least one of A, B, and C” includes any combination of A, B, C, AB, AC, BC, and / or ABC (i.e., A, B, and C). Also, if multiple uses of item A, B, or C are possible, multiple uses of A, B, and / or C are considered part of the intended combination. For example, “at least one of A, B, and C” also includes AA, AAB, AAA, BB, etc.

[0137] In the embodiments described above, various modifications, alternative structures, and equivalents may be used without departing from the spirit of the invention. For example, the elements described above may be merely components of a larger system, and other rules may take precedence over the application of the invention or modify the application of the invention. Furthermore, several steps can be performed before, during, or after considering the elements described above. Therefore, the above description should not be construed as limiting the scope of the invention.

[0138] The terms “equipped,” “having,” “possessing,” “including,” “consisting of,” and “provided,” as used herein and in the following claims, indicate the presence of a described function, integer, component, or process, but do not preclude the presence or addition of one or more other functions, integers, components, processes, actions, or groups. [Example 1] An aerosolization system, A breathing system having an inspiratory limb and an expiratory limb, Aerosolization device, an aerosol chamber having a first end and a second end, an aerosol generator located at the first end of the aerosol chamber, The aerosol generator has a containment section configured to receive a certain amount of liquid drug to be aerosolized by the aerosol generator, The aerosol generator is configured to aerosolize the aforementioned amount of drug into particles with an aerodynamic median particle diameter (MMAD) of less than approximately 3 μm at a flow rate of at least 0.1 ml / min, A patient interface positioned near the second end of the aerosol chamber, an aerosolizing device having a breathing adapter configured to connect the aerosolizing system to the breathing system, A respiratory sensor configured to detect patient inspiration, An aerosolization system comprising: a control device configured to operate the aerosol generator to aerosolize the aforementioned amount of drug in synchronization with detected inhalation; and a control device configured to operate the aerosol generator to aerosolize the aforementioned amount of drug in synchronization with detected inhalation. [Example 2] The aerosolization system according to Example 1, wherein the patient interface is located within approximately 1 to 8 cm of the aerosol generator. [Example 3] The breathing adapter is equipped with a flow diversion mechanism configured to divert a portion of the airflow from the breathing system to the aerosol chamber through at least one air passage, The aerosolization system according to Example 1, wherein the aerosol chamber is configured to mix a portion of the airflow with the aerosolized agent supplied from the aerosol generator. [Example 4] The aerosolization system according to Example 3, wherein a portion of the airflow is a respiratory flow, and is less than the amount of air that continues to advance into the exhalation rim of the respiratory system. [Example 5] The flow separation mechanism has at least one barrier defining the at least one ventilation passage, The aerosolization system according to Example 3, wherein the at least one barrier is configured to divert a portion of the airflow to the aerosol chamber through the at least one vent and to divert another portion of the airflow from the inspiratory rim toward the expiratory rim. [Example 6] The aerosolization system according to Example 5, wherein the at least one barrier includes a first barrier defining a first air passage and a second barrier defining a second air passage. [Example 7] The first ventilation passage is provided at the lateral end of the first barrier, The second ventilation passage is provided at a position beyond the leading edge of the second barrier, The aerosolization system according to Example 6, wherein the lateral end and the tip edge extend in different directions from each other so that the respiratory flow moves in multiple directions and passes through the first and second barriers. [Example 8] The aerosolization system according to Example 1, wherein the aerosolization device further comprises a conduit configured to deliver the amount of liquid agent from the containment to the aerosol generator. [Example 9] The tip of the conduit has a diameter, The aerosolization system according to Example 8, wherein the tip of the conduit is positioned at a distance from the mesh that is less than or equal to the diameter. [Example 10] The aerosolization system according to Example 1, wherein the synchronization of aerosolization of the amount of drug includes aerosolizing a portion of the amount of drug in at least the first 50-80% portion of each of the consecutive inhalations such that exhaust air is supplied in at least the last 20% portion of each of the consecutive inhalations. [Example 11] The aerosolization system according to Example 1, wherein at least the respiratory sensor includes a respiratory sensor capsule connected to the patient's abdomen. [Example 12] The aerosolization system according to Example 1, wherein the control device is detachable from the aerosolization apparatus. [Example 13] The aerosolization system according to Example 1, wherein the aerosolizing device is configured to perform aerosolization and deliver aerosolized particles of the drug when the patient interface is oriented in a downward, sideways, and upward position, respectively. [Example 14] The aerosolization system according to Example 1, further comprising a supply line configured to supply the amount of drug from a supply source to the containment. [Example 15] The aerosolization system according to Example 1, wherein the patient interface includes nasal prongs or a nasal mask. [Example 16] The aerosolization system according to Example 1, wherein the agent contains a surfactant. [Example 17] A method for delivering an aerosolized drug to an infant, Detecting infant inhalation using one or more respiratory sensors, Based on the detected inhalation, the process involves using an aerosolizer to aerate a certain amount of the drug into particles with an aerodynamic median particle size (MMAD) of less than approximately 3 μm at a flow rate of at least 0.1 ml / min. A method by which the drug is aerosolized within approximately 1 to 8 cm of the patient interface. [Example 18] Aerosolizing the amount of the drug is The aforementioned amount of drug is delivered from the containment unit to the mesh of the aerosolizing device, A method for delivering an aerosolized drug to an infant according to Example 17, comprising vibrating the mesh to aerosolize the amount of drug. [Example 19] The amount of drug is delivered from the containment to the mesh via a conduit having a diameter tip, A method for delivering an aerosolized drug to an infant according to Example 18, wherein the tip of the conduit is positioned at a distance from the mesh that is less than or equal to the diameter. [Example 20] A method for delivering an aerosolized drug to an infant according to Example 17, wherein the aerosolization of the drug is performed such that aerosolization of the drug is performed in at least a portion of the first 80% of each of the successive inhalations, such that expulsion air is supplied in at least a portion of the last 20% of each of the successive inhalations. [Example 21] A method for delivering an aerosolized drug to an infant according to Example 17, wherein the one or more respiratory sensors include a respiratory sensor capsule connected to the patient's abdomen. [Example 22] Connecting the aerosolizing device to a respiratory system, The further includes diverting a portion of the airflow from the breathing system to the chamber of the aerosolizing device through at least one vent, A method for delivering an aerosolized drug to an infant according to Example 17, wherein the chamber is configured to mix a portion of the airflow with the aerosolized drug. [Example 23] A method for delivering an aerosolized drug according to Example 22 to an infant, wherein a portion of the airflow is respiratory flow and is less than the amount of air that continues to advance into the exhalation rim of the respiratory system. [Example 24] A portion of the airflow is diverted using at least one barrier that defines the at least one air passage. A method for delivering an aerosolized drug to an infant according to Example 22, wherein the at least one barrier is configured to divert a portion of the airflow to the aerosol chamber through the at least one vent and to divert another portion of the airflow from the inspiratory rim toward the expiratory rim. [Example 25] A method for delivering an aerosolized drug to an infant according to Example 24, wherein the at least one barrier includes a first barrier defining a first air passage and a second barrier defining a second air passage. [Example 26] The first ventilation passage is provided at the lateral end of the first barrier, The second ventilation passage is provided at a position beyond the leading edge of the second barrier, A method for delivering an aerosolized drug to an infant according to Example 25, wherein the lateral end and the tip edge extend in different directions from each other so that the respiratory flow moves in multiple directions and passes through the first and second barriers. [Example 27] A method for delivering the aerosolized drug described in Example 17 to an infant, wherein the patient interface includes nasal prongs or a nasal mask. [Example 28] A method for delivering an aerosolized drug to an infant according to Example 17, further comprising delivering the aerosolized drug to the infant's airway via a patient interface. [Example 29] A method for initializing an aerosolization system, The aerosolization device is connected to the control unit, respiratory sensor, drug source, and respiratory system. Inputting the user's access authentication to the control device, The control device is used to input patient-related information and medication information, Connecting the aforementioned respiratory sensor to the patient, The aerosolization apparatus is primed, A method comprising connecting a patient interface to the patient's airway. [Example 30] A method for initializing the aerosolization system described in Example 29, further comprising performing an activation sequence that repeats multiple audio alarms, visual alarms, or both audio and video alarms. [Example 31] A method for initializing the aerosolization system described in Example 29, wherein the access authentication includes one or more of a user identifier, password, possession authentication, and biometric authentication. [Example 32] A method for initializing the aerosolization system according to Example 29, wherein the respiratory sensor is attached to the patient's abdomen. [Example 33] A method for initializing the aerosolization system according to Example 29, further comprising confirming the detection of respiration after connecting the respiratory sensor to a patient. [Example 34] A method for initializing the aerosolization system according to Example 29, wherein the drug source has a vented vial access device (VVAD) connected to a fluid supply line. [Example 35] A method for initializing the aerosolization system according to Example 29, wherein connecting the aerosolizer to the control device, respiratory sensor, drug source and respiratory system includes connecting a fluid supply line between the drug source and the aerosolizer. [Example 36] A method for initializing the aerosolization system according to Example 29, wherein priming the aerosolization device includes aerosolizing a portion of the drug before connecting the patient interface to the patient's airway. [Example 37] A method for initializing the aerosolization system according to Example 29, further comprising connecting the patient interface to the aerosolization device. [Example 38] A method for initializing the aerosolization system according to Example 29, wherein the patient interface is secured to the patient via at least one strap and or both of a foamed resin pad configured to rest on the patient's head. [Example 39] A method for initializing the aerosolization system according to Example 29, further comprising delivering an aerosolized dose of the drug to a patient via the patient interface. [Example 40] A method for initializing the aerosolization system according to Example 39, further comprising confirming that the timing of the delivery of the dose is synchronized with the detected inhalation.

Claims

1. Aerosolization system, A breathing system having an inspiratory limb and an expiratory limb, Aerosolization device, an aerosol chamber having a first end and a second end, an aerosol generator located at the first end of the aerosol chamber, The aerosol generator comprises a containment section configured to receive a certain amount of liquid drug to be aerosolized by the aerosol generator, and a vibrating mesh of a photoforming perforated plate. The aerosol generator is configured to deliver the aforementioned amount of drug from the containment section to the mesh and vibrate the mesh to aerosolize particles with an aerodynamic median particle diameter (MMAD) of less than approximately 3 μm at a flow rate of at least 0.1 ml / min, A patient interface positioned near the second end of the aerosol chamber, The system includes a breathing adapter configured to connect the aerosolization system to the breathing system, The breathing adapter has a flow diversion mechanism configured to divert a portion of the airflow from the breathing system to the aerosol chamber via a first air passage and a second air passage, The flow separation mechanism includes a first barrier defining the first ventilation passage and a second barrier defining the second ventilation passage. The first barrier and the second barrier are configured to divert a portion of the airflow to the aerosol chamber through the first and second ventilation passages, The first barrier is configured to divert another portion of the airflow from the inhalation rim toward the exhalation rim, The second barrier is positioned between the first barrier and the aerosol chamber such that a portion of the airflow flows through the first vent toward the second barrier and then flows into the aerosol chamber through the second vent. An aerosolizing apparatus comprising an aerosol chamber configured to mix a portion of the airflow with an aerosolized agent supplied from an aerosol generator, A respiratory sensor configured to detect the patient's inhalation, An aerosolization system comprising: a control device configured to operate the aerosol generator to aerosolize the aforementioned amount of drug in synchronization with detected inhalation; and a control device configured to operate the aerosol generator to aerosolize the aforementioned amount of drug in synchronization with detected inhalation.

2. The patient interface is located within approximately 1 cm to 8 cm of the aerosol generator. The aerosolization system according to claim 1.

3. A portion of the aforementioned airflow is a respiratory flow, and is less than the amount of air that continues to advance into the exhalation rim of the respiratory system. The aerosolization system according to claim 1.

4. The aerosol chamber has a first end and a second end in the axial direction, The first barrier has two transverse ends in the transverse direction that are aligned along the airflow direction from the intake rim to the expiratory rim, The second barrier has an axial leading edge that is positioned to direct a portion of the airflow toward the first end of the aerosol chamber, The first ventilation passage is provided at least one of the two lateral ends of the first barrier, The second ventilation passage is provided at a position beyond the leading edge of the second barrier, At least one of the two lateral ends extends along the axial direction, and the tip edge extends along the lateral direction, such that a portion of the airflow moves in multiple directions and passes through the first and second barriers. The aerosolization system according to claim 1.

5. The aerosolizing device further includes a conduit configured to deliver the aforementioned amount of liquid drug from the containment unit to the aerosol generator. The aerosolization system according to claim 1.

6. The tip of the aforementioned conduit has a diameter, The distance between the tip of the conduit and the vibrable mesh of the aerosol generator is less than or equal to the diameter. The aerosolization system according to claim 5.

7. The synchronization of the aerosolization of the aforementioned amount of drug includes aerosolizing a portion of the aforementioned amount of drug in at least the first 50-80% portion of each of the consecutive inhalations, such that exhaust air is supplied in at least the last 20% portion of each of the consecutive inhalations. The aerosolization system according to claim 1.

8. The at least respiratory sensor includes a respiratory sensor capsule connected to the patient's abdomen, The aerosolization system according to claim 1.

9. The control device is removable from the aerosolizing apparatus. The aerosolization system according to claim 1.

10. The aerosolizing device is configured to perform aerosolization and deliver aerosolized particles of the drug when the patient interface is oriented in a downward, sideways, and upward position, respectively. The aerosolization system according to claim 1.

11. The system further includes a supply line configured to supply the aforementioned amount of drug from a supply source to the storage unit. The aerosolization system according to claim 1.

12. The patient interface includes nasal prongs or a nasal mask. The aerosolization system according to claim 1.

13. The aforementioned drug contains a surfactant. The aerosolization system according to claim 1.

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