Design of an aerosol system and interface for clinically and economically feasible delivery of inhaled doses in a neonatal CPAP device

Abstract

A method for delivering aerosolized surfactant to an infant includes docking a nebulizing device with the airway of the infant, using the nebulizing device to nebulize a quantity 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 nebulized within about 1 to 8 cm of a patient interface. An aerosol is generated at up to about 80% or each inhalation. The method also includes delivering the nebulized surfactant to the airway of the infant.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 852,862, filed on May 24, 2019, entitled "Design of an Aerosol System and Interface for Clinically and Economically Viable Delivery of Inhaled Doses in a Neonatal CPAP Device," and U.S. Provisional Application No. 62 / 852,867, filed on May 24, 2019, entitled "Design of an Aerosol Chamber and Interface for Optimizing Inhaled Doses in a Neonatal CPAP Device," the entire contents of which are incorporated herein by reference.

[0003] This application is related to U.S. application No. 15 / 933,205, entitled “Aerosol Delivery Device,” filed on March 22, 2018, U.S. application No. 15 / 933,217, entitled “Improved Aerosol Delivery System and Method,” filed on March 22, 2018, U.S. application No. 15 / 933,219, entitled “Aerosol Delivery System and Method,” filed on March 22, 2018, U.S. application No. 62 / 475,618, entitled “Improved Aerosol Delivery System and Method,” filed on March 23, 2017, U.S. application No. 62 / 475,635, entitled “Aerosol Delivery Device,” filed on March 23, 2017, and U.S. application No. 62 / 475,603, entitled “Aerosol Delivery System and Method,” filed on March 23, 2017, the entire contents of which are incorporated herein by reference. Background Art

[0004] The delivery of surfactants to infants, particularly premature infants, can be invasive and is often associated with acute side effects. Therefore, there is a need to provide non-invasive delivery of surfactants. However, it is difficult to effectively and efficiently deliver surfactants using conventional non-invasive techniques. For example, conventional techniques typically rely on constant delivery of aerosolized medications, which is very inefficient because the medication is aerosolized even between the patient's breaths. In addition, conventional techniques typically involve aerosolized particles that are larger than required for pulmonary delivery (typically about 4-7 μm mass mean aerodynamic diameter (MMAD)), because it is difficult to produce aerosolized particles that are small enough for surfactant at a sufficiently high output rate to make pulmonary delivery feasible. Embodiments of the present invention address these and other problems. Summary of the invention

[0005] Embodiments of the present invention provide a nebulization system and method for delivering drugs to infants, particularly premature infants. Embodiments provide techniques for effectively and efficiently delivering drugs to infants' nostrils. Embodiments also provide sufficiently fine aerosol droplets of drugs that penetrate into the lungs. Embodiments provide significantly higher drug delivery efficiency than traditional non-invasive techniques.

[0006] In one embodiment, a method for delivering aerosolized medication to an infant is provided. The method may include docking a nebulizer device with the airway of the infant, and using the nebulizer device to nebulize a certain amount of medication into particles with a mass mean aerodynamic diameter (MMAD) of less than about 3 μm at a rate of at least 0.1 ml / min. The medication may be nebulized within about 2 to 8 cm from the patient interface. The method may also include delivering the nebulized medication to the airway of the infant.

[0007] In another embodiment, a nebulization system is provided. The nebulization system may include a nebulization device having an aerosol generator positioned at a first end of an aerosol chamber. The aerosol generator may include a reservoir configured to receive a certain amount of liquid surfactant to be nebulized by the aerosol generator. The aerosol generator may be configured to nebulize a certain amount of medicine into particles with a mass average aerodynamic particle size (MMAD) less than about 3 μm at a rate of at least 0.1 ml / min. The nebulization device may include a patient interface positioned within about 2 cm to 8 cm from the aerosol generator and a respiratory adapter configured to connect the nebulization system to a respiratory system, and the respiratory system may include an inspiratory limb and an expiratory limb. The respiratory adapter may include at least one baffle, which may define at least one airway in fluid communication with the aerosol chamber. At least one baffle may be configured to divert a first portion of the airflow from the inspiratory limb to the expiratory limb via at least one airway, and divert a second portion of the airflow to the aerosol chamber. The second portion of the airflow may be a respiratory flow and may be smaller than the first portion. The aerosol chamber may be configured to mix the respiratory flow with the aerosolized medication from the aerosolizing device. In some embodiments, the aerosolizing system may further include at least one respiratory sensor configured to detect inhalation of the infant, and a controller configured to synchronize aerosolization of an amount of surfactant with the detected inhalation.

[0008] In one embodiment, a nebulization system is provided. The system may include a respiratory system including an inspiratory limb and an expiratory limb. The system may also include a nebulization device including 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 may include a reservoir configured to receive a certain amount of liquid medicine to be aerosolized by the aerosol generator. The aerosol generator may be configured to aerosolize a certain amount of medicine into particles with a mass average aerodynamic particle size (MMAD) less than about 3 μm at a rate of at least 0.1 ml / min. The nebulization device may include a patient interface positioned adjacent to the second end of the aerosol chamber; and a respiratory adapter configured to connect the nebulization system to the respiratory system. The system may also include at least one respiratory sensor configured to detect the patient's inhalation, and a controller configured to actuate the aerosol generator to aerosolize a certain amount of medicine synchronously with the detected inhalation.

[0009] In some embodiments, the patient interface may be positioned between about 1 cm and 8 cm from the aerosol generator. In some embodiments, the respiratory adapter may include a steering mechanism configured to divert a portion of the airflow from the respiratory system to the aerosol chamber via at least one airway. The aerosol chamber may be configured to mix the portion of the airflow with the aerosolized drug from the aerosol generator. In some embodiments, the portion of the airflow may be a respiratory flow and less than the amount of air that continues to reach the expiratory branch of the respiratory system. In some embodiments, the steering mechanism may include at least one baffle defining at least one airway. At least one baffle may be configured to divert the portion of the airflow to the aerosol chamber via at least one airway and divert an additional portion of the airflow from the inspiratory branch to the expiratory branch. In some embodiments, at least one baffle includes a first baffle defining a first airway and a second baffle defining a second airway. In some embodiments, the first airway may be disposed at a side end of the first baffle, the second airway is disposed outside the distal edge of the second baffle, and the side end and the distal edge may extend in different directions so that the respiratory flow moves through the first baffle and the second baffle in multiple directions.

[0010] In some embodiments, the system may further include a conduit configured to deliver a certain amount of liquid medicine from the reservoir to the aerosol generator. In some embodiments, the distal tip of the conduit has a diameter and the distal tip of the conduit is positioned at a distance less than or equal to the diameter from the net. In some embodiments, the synchronization of atomizing a certain amount of medicine may include atomizing a portion of a certain amount of medicine within at least a portion of the first 50%-80% of each of the continuous multiple inhalations, so that chase air is provided within at least a portion of the last 20% of each of the continuous multiple inhalations. In some embodiments, at least one respiratory sensor may include a respiratory sensor capsule docked with the patient's abdomen. In some embodiments, the controller may be removed from the atomizing device. In some embodiments, the atomizing device may be configured to atomize and deliver atomized particles of medicine in each of the downward position, the lateral position, and the upward position when the patient interface is oriented. In some embodiments, the system also includes a supply line configured to supply a certain amount of medicine from a source to the reservoir. In some embodiments, the patient interface includes a nasal plug or a nasal mask. In some embodiments, the drug includes a surfactant.

[0011] In another embodiment, a method for delivering aerosolized medication to an infant is provided. The method may include detecting an inhalation of the infant using one or more respiratory sensors and based on the detected inhalation, aerosolizing a certain amount of medication 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 using a nebulizing device. The medication may be aerosolized within about 1 to 8 cm from a patient interface.

[0012] In some embodiments, aerosolizing a certain amount of medicine may include delivering a certain amount of medicine from a reservoir to a mesh of an aerosolizing device; and vibrating the mesh to aerosolize the certain amount of medicine. In some embodiments, a certain amount of medicine may be delivered from a reservoir to the mesh via a catheter having a distal-most tip, the distal-most tip having a diameter. The distal-most tip of the catheter may be positioned at a distance from the mesh that is less than or equal to the diameter. In some embodiments, aerosolizing a certain amount of medicine may include aerosolizing a portion of a certain amount of medicine within at least a portion of the first 80% of each of the consecutive multiple inhalations, so that chase air is provided within at least a portion of the last 20% of each of the consecutive multiple inhalations. In some embodiments, one or more respiratory sensors may include a respiratory sensor capsule that docks with the patient's abdomen. In some embodiments, the method also includes delivering the aerosolized medicine to the infant's airway via a patient interface. In some embodiments, the patient interface includes a nasal prong or a nasal mask.

[0013] In some embodiments, the method may further include connecting the nebulizer to the respiratory system; and diverting a portion of the airflow from the respiratory system to the chamber of the nebulizer via at least one airway. The chamber may be configured to mix the portion of the airflow with the nebulized drug. In some embodiments, the portion of the airflow may be a respiratory flow and is less than the amount of air that continues to reach the expiratory branch of the respiratory system. In some embodiments, at least one baffle defining at least one airway may be used to divert the portion of the airflow. At least one baffle may be configured to divert the portion of the airflow into the aerosol chamber via at least one airway and divert an additional portion of the airflow from the inspiratory branch to the expiratory branch. In some embodiments, at least one baffle may include a first baffle defining a first airway and a second baffle defining a second airway. In some embodiments, the first airway is disposed at a side end of the first baffle, the second airway is disposed outside the distal edge of the second baffle, and the side end and the distal edge extend in different directions so that the airflow moves through the first baffle and the second baffle in multiple directions.

[0014] In another embodiment, a method of initializing a nebulizer system is provided. The method may include connecting a nebulizer device to a controller, a respiratory sensor, a source of medication, and a respiratory system; inputting a user's access credentials into the controller; and inputting patient-related information and dosage information into the controller. The method may also include connecting a respiratory sensor to a patient; priming the nebulizer device; and docking a patient interface with a patient's airway.

[0015] In some embodiments, the method may also include executing a startup sequence that cycles through multiple auditory alarms, visual alarms, or both auditory and visual alarms. In some embodiments, access credentials include one or more of a user identifier, a password, a credential based on possession, and a biometric credential. In some embodiments, a respiratory sensor may be adhered to the patient's abdomen. In some embodiments, the method also includes confirming the detection of breathing after connecting the respiratory sensor to the patient. In some embodiments, the drug source includes a ventilation vial access device (VVAD) connected to a fluid supply line. In some embodiments, connecting the atomizer to the controller, the respiratory sensor, the drug source, and the respiratory system includes connecting the fluid supply line between the drug source and the atomizer. In some embodiments, priming the atomizer may include atomizing a portion of the drug before docking the patient interface with the patient's airway. In some embodiments, the method may also include connecting the patient interface to the atomizer. In some embodiments, the patient interface is fixed to the patient via at least one strip and one or two of the foam pads configured to rest against the patient's head. In some embodiments, the method may include delivering a dose of atomized drug to the patient via the patient interface. In some embodiments, the method may also include confirming that the timing of the delivery dose is synchronized with the detected inhalation. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 is an isometric view of an atomization device according to an embodiment.

[0017] Figure 1A yes Figure 1 Cross-sectional view of the atomization device.

[0018] Figure 2 Shown by Figure 1 Flow pattern in the atomizer.

[0019] Figure 3 is an isometric view of an atomization device according to an embodiment.

[0020] Figure 3A yes Figure 3 Cross-sectional view of the atomization device.

[0021] Figure 4A Shown by Figure 3 Flow pattern in the atomizer.

[0022] Figure 4B Shown by Figure 3 Flow pattern in the atomizer.

[0023] Figure 5A Shown from a low flow breathing system Figure 3 Flow pattern in the atomizer.

[0024] Figure 5B Shown from a low flow breathing system Figure 3 Flow pattern in the atomizer.

[0025] Figure 6 is an isometric view of an atomization device according to an embodiment.

[0026] Fig. 6A yes Figure 6 Cross-sectional view of the atomization device.

[0027] Figure 6B yes Figure 6 Cross-sectional view of the atomization device.

[0028] Figure 6C yes Figure 6 Cross-sectional view of the atomization device.

[0029] Fig.6D Shown by Figure 6 Flow pattern in the atomizer.

[0030] Figure 7 Shown is the connection with the fluid supply line and breathing system Figure 6 Atomization device in.

[0031] Figure 8 The nebulizer device is shown connected to a source of medication.

[0032] Fig. 9 Shown is a diagram of a device connected to a drug source and a controller. Figure 8 Atomization device in.

[0033] Fig.10 Show Fig. 9 Controller in .

[0034] Fig.11 Show Fig. 9 Vial holder for mid controller.

[0035] Fig.12 Show Fig. 9 Sources of drugs.

[0036] Fig.13 Show Fig. 9 Function of the controller.

[0037] Figures 14A-14I Show use Figure 9-13 The process of the atomization system.

[0038] Fig.15 The nebulizing device is shown docked with an infant according to an embodiment.

[0039] Fig.16 A breathing sensor capsule is shown docked to an infant's abdomen.

[0040] Fig.17 An atomization system for delivering surfactant to an infant is shown according to an embodiment.

[0041] Fig.18 is a flow chart of the process of delivering aerosolized medication to a patient.

[0042] Fig.19 is a flow chart of the process of initializing the atomization system.

[0043] Fig. 20 is a bar graph showing emitted dose rate using a fogging system according to an embodiment.

[0044] Fig.21 is a bar graph showing emitted dose rate as a function of breathing rate and flow rate using a nebulization system according to an embodiment.

[0045] Fig. 22 is a graph showing deposition rate versus particle size.

[0046] Fig.23 is a graph showing deposition rate versus particle size.

[0047] Fig.24 is a graph showing the effectiveness of inhalation detection using a flow sensor and a breath sensor capsule.

[0048] Fig.25 is a graph showing the survival rate without instilled surfactant according to the study.

[0049] Fig.26 is a graph showing the particle size distribution according to the studied impactor.

[0050] Fig. 27 is a graph showing the particle size distribution according to the studied impactor.

[0051] Fig.28 is a graph showing the particle size distribution according to the studied impactor.

[0052] Fig.29 is a graph of powder mass distribution across different CPAP settings based on research.

[0053] Fig.30 is a graph of powder mass distribution across different CPAP settings based on research.

[0054] Fig.31 is a graph of powder mass distribution across different CPAP settings based on research. DETAILED DESCRIPTION

[0055] The following description provides only embodiments and is not intended to limit the scope, applicability or configuration of the present invention. On the contrary, the subsequent description of the embodiments will provide an enabling description of the embodiments to those skilled in the art. It should be understood that various changes may be made in the functions and arrangements of the elements without departing from the spirit and scope of the present invention.

[0056] Embodiments of the present invention provide atomization systems and methods, wherein atomized medicine and respiratory gas are mixed in atomization chamber isolated from the direct current of the respiratory system, so that a small part of the respiratory gas enters the atomization chamber, and most of the respiratory flow bypasses the chamber and passes through the expiratory limb of the respiratory system. Such design considerations ensure that the drug delivery rate is consistent, regardless of the flow rate of the respiratory system. In addition, embodiments of the present invention provide improved atomization solutions, which can be connected to an existing respiratory system to transform the existing system so that it can deliver a reliable dose of atomized medicine to the patient's airway. In addition, the atomization system provided herein may include one or more respiratory sensors that enable the controller to predict the patient's inhalation, such as one or more flow sensors (e.g., current flow sensors), radar sensors (e.g., ultra-wideband (UWB) radar sensors for measuring chest displacement), CO2 sensors, high-speed temperature sensors, acoustic sensors, impedance plethysmography sensors, respiratory inductance plethysmography sensors, pressure sensors, etc., so as to allow atomization of medicine during patient inhalation or atomization of medicine immediately before patient inhalation.

[0057] Embodiments of the present invention provide a nebulization system that isolates aerosolized medication from the main respiratory airflow to avoid interference and dilution of the aerosol produced during the inspiration phase. This isolation can be achieved using baffles and / or other barriers designed to redirect the main flow from the inlet to the outlet without flushing gas through the patient interface.

[0058] Embodiments of the present invention also generate and deliver surfactant aerosol only during the inhalation cycle (inhalation). Conventional devices deliver the aerosol continuously. However, infants can only inhale the aerosol during inhalation, so during exhalation (up to two-thirds of the respiratory cycle) the aerosol bypasses the airway and is lost and wasted. By limiting the generation of the aerosol to occur only during inhalation and delivering the aerosol proximal to the nostrils, the highest percentage of surfactant is ensured to be deposited in the lungs.

[0059] Embodiments of the present invention also generate aerosols near the patient interface to help increase the amount of aerosol delivered to the patient. Conventional nebulizers are placed somewhere in the inspiratory tube of a ventilator or nCPAP circuit, where aerosols are generated in a continuous airflow. This greatly dilutes the aerosol being delivered and loses a lot in the continuous airflow, which usually exceeds the inspiratory flow of the subject. In contrast, the atomizing device of the present invention directly generates aerosols at the patient interface (such as a stuffy nose) and diverts a large amount of airflow from the nCPAP circuit to stay away from the aerosol plume, thereby significantly reducing aerosol losses in the continuous airflow of the circuit. The embodiment also uses an aerosol generator that emits aerosol surfactants and undiluted surfactants at a rate of 0.3 ml / min or more, which is faster than the use of other mesh nebulizers previously reported, thereby reducing the administration time. Although mainly discussed with respect to the delivery of surfactants, it should be understood that other forms of drugs can be used with the atomizing system of the present invention to deliver aerosolized drugs to the lungs of patients.

[0060] In some embodiments, the atomization system described herein may include a reusable device controller and a disposable single-patient single-use atomization device, which includes a drug delivery circuit and / or a respiratory sensor. This atomization device is used as an independent drug delivery device, which is integrated with various ventilation devices (such as CPAP devices), and in some embodiments, it is not designed to be connected to a hospital network or the Internet. For example, the controller can be a multi-patient, reusable component with a flat-panel touch screen display, electronic components and software. The controller may have three core functions: to detect inspiration via a respiratory sensor (which can be designed for use by a single patient) that can be attached to the patient's abdomen, to advance the suspension to the atomization device via an integrated feeding mechanism, and to generate an aerosol at the nCPAP interface during inhalation. These functions can occur synchronously with the infant's inhalation cycle. The flat-panel touch screen utilizes a graphical user interface (GUI) to allow the user to set and monitor delivery parameters, alarms and system diagnostics. Visual and audible alarms can be integrated into the controller. The cabin (pod) can be used to transmit signals from the respiratory sensor to the controller, and transmit signals to synchronize the generation of aerosols with detected breathing. The reservoir from which the drug product is dispensed may be a vial in which the drug is provided.

[0061] In some embodiments, a disposable single-patient single-use nebulizer device includes a ventilation vial access device (VVAD) that facilitates access to a drug reservoir and is provided to the user in a separate package; and a drug feed tube that includes a Luer connector (to the VVAD) and a tubing that delivers the drug suspension from the Luer connector to the aerosol generator of the nebulizer device. The nebulizer device may also include an aerosol generator that can use a custom light-defined aperture plate (PDAP) vibrating mesh, which is unique in that it provides small droplet sizes and higher output rates. This is due to the innovative architecture of the PDAP mesh, which provides up to 20 times more holes with a smaller diameter than traditional meshes. The aerosol generator is designed to distribute aerosols to the proximal side of the infant's airway and connect to a traditional nCPAP system.

[0062] The reusable controller is equipped with a built-in touch screen with a processor that monitors delivery parameters, alarms (visual and audible), and system diagnostics. The controller and capsule work in conjunction to detect inspiration via a breathing sensor that is attached to the infant's abdomen at one end and inserted into the capsule at the other end. The controller activates the drug feed mechanism, which drives drug delivery to the nebulizer to synchronize aerosol generation with the infant's inspiratory cycle.

[0063] The lyophilized surfactant is reconstituted in its original glass vial to produce a saline / surfactant suspension. The vial is connected to a drug delivery circuit including a drug feed tubing by piercing the vial septum to allow air to vent into the vial, thereby allowing the suspension to be emptied in a consistent manner. An integrated volumetric drug feed mechanism propels the surfactant suspension through the drug feed tubing and delivers it to a nebulizer (proprietary vibrating mesh) integrated into the drug delivery circuit interface. The interface uses a nasal prong. The interface is attached to the infant's clinical nCPAP circuit and placed on the infant, replacing the previous interface. The aerosol is then delivered in sync with the infant's inspiration triggered by a respiratory sensor.

[0064] Although discussed primarily in the context of surfactants, it should be understood that the methods and devices of the present invention can be used with any liquid medication. For example, drugs such as, but not limited to, bronchodilators, anti-infectives, anti-virals, anti-inflammatory drugs, mucus regulators, siRNA, PFOB, etc. can be utilized in accordance with the present invention.

[0065] Go to Figure 1, an embodiment of a nebulization system is provided. Here, the nebulization device 100 is positioned on a first side of the aerosol chamber 102, wherein the patient interface 104 is positioned on a second side opposite to the nebulization chamber 102. The nebulization device 100 can be a sprayer or any other device configured to atomize a certain dose of liquid medicine. Such devices are described in U.S. Patent 5,758,637, U.S. Patent 6,235,177, U.S. Patent Publication 2015 / 0336115 and U.S. Patent Publication 2016 / 0130715, all of which are incorporated herein by reference. The nebulization device 100 may include a reservoir configured to receive and / or hold a certain amount of liquid medicine to be atomized. In some embodiments, the reservoir can be a "virtual reservoir" in the form of a catheter, which is connected and extended between a fluid feed line and a net of the nebulization device 100. For example, the size of the catheter can be set to only hold between about 10-15mcl, and the material that can be collected in the catheter between atomization. The primary reservoir may be in the form of a vial containing medication that, via a feeding mechanism and feeding line, may provide medication to the mesh via a catheter or dummy reservoir on a breath-by-breath basis. In some embodiments, the patient interface may include nasal prongs, endotracheal tubes, nasal cannula / mask, tracheostomy tube, and the like.

[0066] The system includes a respiratory adapter 106 configured to interface with an artificial respiration system, such as a ventilator, a humidifier, a continuous positive airway pressure (CPAP) machine, an nCPAP system, and / or a combination thereof. For example, the respiratory adapter 106 may include an inlet 108, such as an inlet baffle, configured to couple with an inspiratory limb of the respiratory system. For example, the inlet 108 may be an inlet baffle configured to couple with a FlexiTrunk manufactured by Fisher & Paykel Healthcare. TM The midline interface is connected and directs the respiratory flow into the nebulizer chamber 102. The inlet 108 can be connected to the aerosol chamber 102, such as via a fluid path 110. In some embodiments, the inlet 108 is designed to redirect the gas from the respiratory system to the nebulizer chamber without increasing the patient's breathing resistance or breathing work. This can be achieved by providing a fluid path 110 with a cross-sectional area of ​​about 80% or more relative to the internal cross-sectional diameter of the patient interface 104.

[0067] Figure 1A Show Figure 11. A cross-sectional view of a nebulization system in FIG. Here, the aerosol generator 112 of the nebulizer 100 is shown as being positioned at the first end of the aerosol chamber 102 so that any medicine atomized by the aerosol generator 112 is introduced into the nebulizer chamber 102. The aerosol generator 112 may include a net configured to generate aerosol particles. Conventional aerosol devices typically produce aerosols with an average droplet diameter in the range of 4 to 5 microns. However, the aerosol droplet size required for delivering drugs through the small airways of the respiratory tract of premature infants from the nostrils is typically less than 3 microns in diameter. Aerosol droplets larger than this size are easily deposited in the nostrils and the delivery tubing. If the droplets are much smaller than 1 micron, the droplets may not be deposited in the lungs and may be exhaled. This reduces the dose delivery rate to the lungs. Embodiments of the present invention utilize a mesh size designed to produce droplets with a median diameter between 2 and 3 microns. For example, in some embodiments, the aerosol generator 112 may include a light-defined aperture plate (PDAP) mesh configured to generate small aerosol particle sizes, such as less than 3 μm. Such a mesh is disclosed in U.S. Patent Publication 2016 / 0130715, which is previously incorporated by reference. Placing the aerosol generator 112 proximal to the patient interface 104 allows the aerosolized drug emitted during the inhalation cycle to be preferentially inhaled, while minimally interfering with the continuous flow or bias flow through the respiratory system circuit. Here, the aerosol chamber 102 is shown as a first end smaller than the second end. The inlet 108 is formed by a baffle, which is designed to draw a portion of the respiratory flow from the respiratory system inspiratory branch into the aerosol chamber 102 via a fluid path 110 at a position close to the first end. The fluid path 110 is connected to the inspiratory branch fluid so that the fluid path 110 has an angle of no more than 90 degrees on the upstream side of the inspiratory branch relative to the respiratory flow through the branch and / or at the junction between the branch and the inlet 108. This positioning helps to isolate the nebulization chamber from the direct respiratory flow.For example, the respiratory flow is intermittently introduced into the aerosol chamber 102, which only occurs during the patient's inhalation.

[0068] Figure 2 Flow patterns through the nebulization system are shown in FIG, which shows an inspiratory limb 200 of the respiratory system supplying a respiratory gas flow. A portion of this respiratory gas flow can be drawn into the inlet 108 and introduced into the aerosol chamber 102 and the patient interface 104 via the fluid path 110. For example, when the patient inhales, the inhalation creates a vacuum in the nebulization chamber, which draws in a certain amount of respiratory gas flow through the fluid path 110. Excess respiratory gas flow and / or exhaled gas can be exhausted through the expiratory limb 202 of the respiratory system.

[0069] Figure 1 , 1AThe nebulizer system of and 2 provides a higher and more consistent inhaled dose than conventional nebulizer systems over a range of airflows used with various nCPAP systems. For example, the nebulizer system described herein increases the inhaled dose from about 6% (as shown in conventional systems) to between about 40-50% with higher flow nCPAP systems (>6 L / min) and reduces the variability of low flow systems (0.5 L / min), which also delivers an inhaled dose between about 40-50%.

[0070] Figure 3 Another embodiment of the atomizing device for providing a consistent dose of atomized medicine to a patient is described. The atomizing device may include an aerosol generator 300 positioned at the first end of the aerosol chamber 302, wherein the patient interface 304 is positioned at the second end relative to the aerosol chamber 302. The aerosol generator 300 may be a sprayer with a vibrating net, and the vibrating net can be selectively vibrated using a piezoelectric actuator. In certain embodiments, the aerosol generator 300 may include a reservoir configured to receive and / or hold a certain amount of liquid medicine to be atomized. The aerosol generator 300 may be connected to a medicine feed line 306, which is configured to be such as via a pump (not shown) that a certain amount of liquid medicine is delivered to the reservoir. The atomizing device may also include a cable 308 connected to a power source, but in certain embodiments, the atomizing device may also be battery powered.

[0071] In some embodiments, the atomizing device may include an inlet 310 and an outlet 312, which may be connected to the inspiratory branch and the expiratory branch of the artificial respiration system, respectively. Potential artificial respiration systems include, but are not limited to, ventilators, humidifiers, CPAP machines, and / or combinations thereof. In some embodiments, the inlet 310 and the outlet 312 may be a single unit forming a flow path for the respiratory gas, while in other embodiments, the inlet 310 and the outlet 312 may be separate components connected together. The inlet 310 and / or the outlet 312 may be configured to receive the end of a gas conduit of a respiratory system. For example, the inlet and / or outlet airflow baffles may support a one-way loop of a standard nCPAP circuit. This enables the baffle to minimize interference with the airflow from the inlet to the outlet, thereby generating less interference with the aerosol chamber 302.

[0072] like Figure 3A310 and / or the outlet 312. As shown in FIG. 314 , the atomizing device further includes a fluid flow path 314 connecting the aerosol chamber 302 with the inlet 310 and / or the outlet 312. As shown here, the fluid flow path 314 can deliver the breathing gas to the top portion of the aerosol chamber 302 adjacent to the aerosol generator 300, however, in some embodiments, other locations are also contemplated, such as a middle portion of the aerosol chamber 302 and / or a portion adjacent to the patient interface 304. The fluid flow path 314 can intersect the inlet 310 and / or the outlet 312, such that the fluid flow path 314 forms an angle of no more than 90 degrees with the upstream side of the inlet 310 and / or the outlet 312 and / or the flow path formed within the inlet 310 and / or the outlet 312, such that the gas flow path 314 is orthogonal to the inlet 310 and / or the outlet 312 or extends in a direction at least partially opposite to the air flow through the inlet 310 and / or the outlet 312. This positioning of the fluid flow path 314 helps to isolate the aerosol chamber 302 from the continuous flow of respiratory gases from the inlet 310 (inspiratory limb) to the outlet 312 (expiratory limb). This provides several benefits. First, isolating the aerosol chamber 302 from the continuous flow prevents the aerosolized drug from being "carried away" or diluted by the airflow. Second, the isolation allows the aerosol chamber 302 to be preloaded with aerosolized drug immediately before a respiratory event, while also being able to preserve any drug left over from the previous breath.

[0073] In some embodiments, a portion of the breathing gas may be drawn into aerosol chamber 302 through fluid flow path 314 to mix with the aerosolized medication. The portion of the breathing gas drawn into aerosol chamber 302 may be drawn in via the vacuum created when the patient inhales at patient interface 304.

[0074] The aerosol chamber 302 has an optimized internal geometry to direct the plume toward the patient interface 304 with minimal impact. Specifically, the aerosol chamber 302 is designed so that the aerosol generator 300 is positioned opposite the patient interface 304. In addition, the aerosol chamber 302 is designed to have a generally funnel-shaped profile, which helps reduce impact when the aerosol leaves the aerosol generator 300 by providing a wider portion that tapers (linearly or nonlinearly) to a narrow portion adjacent to the patient interface 304. This design also helps to minimize the size of the aerosol chamber 302.

[0075] Figure 4A and 4B Depicts respiratory flow from a high flow breathing system through Figure 3 and 3A310. The inspiratory flow flows through the inlet 310 at a rate of 8 liters / minute, while the patient inhales at a rate of 1 liter / minute. The pressure at the expiratory branch connected to the outlet 312 is 5 cm H2O. When the patient inhales through the patient interface 304, a portion of the respiratory gas is drawn into the aerosol chamber 302 through the fluid flow path 314.

[0076] Figure 5A and 5B Depicts the flow of air from a low flow breathing system through Figure 3 and 3A The inspiratory flow flows through the inlet 310 at a rate of 2 liters / minute, while the patient inhales at a rate of 1 liter / minute. The pressure at the expiratory branch connected to the outlet 312 is 5 cmH2O. Similar to the high flow embodiment, when the patient inhales through the patient interface 304, a portion of the respiratory gas is drawn into the aerosol chamber 302 through the fluid flow path 314. Figure 5B As seen in FIG, the portion of the respiratory flow that is drawn into the aerosol chamber 302 is introduced into the patient's airway via the patient interface 304 .

[0077] Figure 6-6D Another embodiment of a nebulizing device 600 is shown. Here, similar to those described above, an aerosol generator 612 ( Figures 6A-6D The aerosol generator 612 may include a reservoir configured to receive and / or hold a certain amount of liquid medicine to be atomized. For example, in some embodiments, the atomizing device 600 may include at least one drug supply port 614, which is configured to be connected to a drug supply line (not shown) for delivering liquid medicine to the aerosol generator 612 (such as to the reservoir, if any). In some embodiments, the reservoir may be in the form of an elongated conduit extending between the drug supply port 614 and the aerosol generator 612. In some embodiments, the patient interface 604 may include a nasal plug, an endotracheal cannula, a nasal cannula / mask, a tracheostomy tube, etc. The atomizing device 600 may also include at least one power connection 640. As shown, the power connection 640 is a port that allows a power cable to be connected to the atomizing device 600 to provide power and / or control commands to the aerosol generator 612.

[0078] The device includes a respiratory adapter 606 configured to interface with an artificial respiration system, such as a ventilator, a humidifier, a continuous positive airway pressure (CPAP) machine, an nCPAP system, and / or a combination thereof. For example, the respiratory adapter 606 may include an inlet 608, such as an inlet baffle, configured to be connected to an inspiratory branch 650 of the respiratory system. The respiratory adapter 606 may also include an outlet 616, such as an outlet baffle, configured to interface with an expiratory branch 652 of the respiratory system. For example, as shown, the inlet 608 and / or the outlet 616 may be configured to be inserted and retained (such as using friction fit and / or other fixing mechanisms) in the conduits of the inspiratory branch 650 and the expiratory branch 652, respectively. In other embodiments, the inlet 608 and / or the outlet 616 may be configured to be larger than the conduits of the respiratory system, so that the conduits of the inspiratory branch 650 and / or the expiratory branch 652 can be inserted and retained (such as using friction fit and / or other fixing mechanisms) in the inlet 608 and the outlet 616, respectively. It should be appreciated that other techniques for interfacing inlet 608 and / or outlet 616 with the respiratory system may be utilized, and that inlet 608 and outlet 616 need not be interfaced using the same technique.

[0079] Fig. 6A Shows Figure 6600 is a cross-sectional view of an atomization system. Here, the aerosol generator 612 of the atomization device 600 is shown as being positioned at the first end of the atomization chamber 602, so that any medicine atomized by the aerosol generator 612 is introduced into the aerosol chamber 602. For example, the medicine can be delivered to the aerosol generator 612 via a medicine supply port 614 communicated with the reservoir. In some embodiments, the reservoir can be a "virtual reservoir" in the form of a conduit 632, which delivers the medicine to the surface of the aerosol generator 612. Virtual reservoir, the conduit 632 can be connected to a source of medicine, such as a vial, via a fluid line connected to the medicine supply port 614. The most distal tip 634 of the conduit 632 can have a diameter less than or equal to the distance between the proximal surface of the net of the tip 634 and the aerosol generator 612. This size design ensures that the liquid drug droplets ejected from the tip 634 are large enough to contact and transfer to the net of the aerosol generator 612. Surface tension ensures that liquid stays on the surface of the net and unfolds along the surface of the net, so that all or substantially all liquids are atomized. This allows atomizing device 600 to operate in any orientation, thereby allowing patients (such as infants) to treat when lying on their sides, lying on their backs or lying prone. For example, in some embodiments, the tip of drug supply port 614 can be positioned between about 5 to 40 microns from the surface of aerosol generator 612, and tip 364 has a diameter less than or equal to the distance. As shown in the figure, aerosol generator 612 is placed adjacent to patient interface 604, because the only component that separates aerosol generator 612 from patient interface 604 is aerosol chamber 602. This placement of aerosol generator 612 adjacent to patient interface 604 allows the atomized medicine emitted by the inhalation cycle to be preferentially inhaled, wherein the interference with the continuous flow or bias flow through the respiratory system circuit is minimal. Here, aerosol chamber 602 is shown as first end 618 less than second end 620, which helps to reduce the impact when aerosol leaves atomizing device 600.

[0080] The inlet 608 may be formed by a baffle designed to pass through a fluid path (which will be in contact with the fluid path) at a position close to the first end. Figure 6B and 6C 600 ) draws a portion of the respiratory flow from the respiratory system inspiratory limb 650 into the aerosol chamber 602. In some embodiments, the inlet 608 can be designed to redirect the gas from the respiratory system to the aerosol chamber 602 without substantially increasing the patient's respiratory resistance or respiratory work (e.g., inspiratory pressure), or at least not to any significant extent. This can be accomplished by providing a fluid path in the respiratory adapter 606 that includes a plurality of baffles that direct a portion of the air of the inspiratory limb (just enough for inhalation) into the aerosol chamber 602 in a manner that significantly reduces the turbulence of the airflow drawn into the atomizing device 600, thereby creating more laminar flow within the aerosol chamber 602.

[0081] Figure 6B and 6C Two halves of atomizing device 600 are shown. Although shown as two separable components, it should be understood that atomizing device 600 may include any number of components that can be coupled together (such as using connecting / mating features) and / or may be formed from a single component that can be formed by known molding, 3D printing, and / or other known and unknown manufacturing techniques. Figure 6B As shown, a portion of the atomizing device 600 includes a fluid flow path having a plurality of baffles. In the illustrated embodiment, the atomizing device 600 includes a first baffle 622, which directs a large amount of flow of the inspiratory branch 650 to the expiratory branch 652, while allowing a portion of the inspiratory branch 650 to turn and enter the aerosol chamber 602. For example, the baffle 622 may generally be U-shaped, with one or both ends open to form an airway 624 between the baffle 622 and the side wall of the atomizing device 600 housing, the airway 624 allowing a small amount of air to flow through the end of the baffle 622, while the body of the baffle 622 prevents the remaining air from passing through the baffle 622, and instead directs the air to the expiratory branch 652. It should be understood that although a U-shaped baffle 622 is used in the present embodiment, other shapes may also be used to meet the needs of a particular application.

[0082] Atomizing device 602 may include a second baffle 626 positioned adjacent to baffle 622. As shown, second baffle 626 is in the form of a generally U-shaped barrier, oriented in the opposite direction to baffle 622 (however, other shapes and orientations of second baffle 626 are also possible, such as a second baffle 626 extending across the internal width of atomizing device 600 in a generally linear manner and / or a second baffle 626 bent or otherwise oriented in the same direction as baffle 622). In some embodiments, first baffle 622 and second baffle 626 may be a single component, such as realized by sharing a middle portion, while other embodiments utilize baffles that are separate components. As shown, second baffle 626 extends all the way to the side wall of the housing, but leaves a gap between the distal edge of second baffle 626 and the top of atomizing device 602 housing, which provides a path for air to enter atomizing chamber 602. Thus, as shown, when the patient inhales at the patient interface 604, a portion of the gas supplied by the inspiratory branch 650 is drawn through the airway 624 on one or more ends of the baffle 622, where the air is pushed upward over the second baffle 624 and forms a generally laminar flow within the aerosol chamber 602. However, it should be understood that in some embodiments, the second baffle 626 may direct air to the bottom of the housing and / or to a central opening formed between the top and bottom of the baffle, rather than directing the airflow toward the top of the housing. Any number of designs of baffles and / or other steering mechanisms (including valves) may be used to help isolate the aerosol chamber 602 from the respiratory gas flow of the respiratory system while providing some flow of the respiratory gas during the patient's inhalation.

[0083] Figure 6C Another part of atomizing device 600 docking with the first part is shown. This part of atomizing device 600 defines a seat 628 for receiving aerosol generator 612, drug supply port 614 and / or other related components. A mating feature 630 may also be provided, which receives baffle 622 and fixes it in place. For example, mating feature 630 may define a groove or channel with a size and shape that is set to receive the top edge of baffle 622. This connection ensures that baffle 622 can extend from the bottom surface of atomizing device 600 housing to the top surface of housing, which ensures that only the airflow passing through airway 624 on either end of baffle 622 exceeds baffle 622, while most of the airflow is directed to outlet 616.

[0084] Fig.6D The flow pattern of the airflow drawn from the inspiratory limb 650 via the inlet 608 into the nebulizing device 600 is shown. For example, air from the inspiratory limb 650 (which may pass through a humidifier) ​​may pass through the respiratory adapter 606, where the baffle 622 redirects most of the air into the expiratory limb 652 via the outlet 616. As described above, the baffle 622 provides one or more airways 624 that allow a portion of the airflow of the inspiratory limb 650 to be drawn inward each time the patient inhales. This portion of air is inhaled through the airway, where it encounters the second baffle 626. The second baffle 626 pushes the air drawn through the end of the baffle 622 upward, where the air flows over the second baffle 626 and into the nebulizing chamber 602. As shown here, the air is introduced into the aerosol chamber 602 at a location near the first end 618 of the adjacent aerosol generator 612. In other embodiments, the airflow may be introduced into the aerosol chamber 602 at other locations. As just one example, a baffle similar to baffle 622 may be used to introduce air near the sidewall of the aerosol chamber 602. As shown here, air is introduced into the atomizing chamber 602 at a position near the first end 618 of the adjacent aerosol generator 612. In other embodiments, the airflow may be introduced into the atomizing chamber 602 at other positions. As just one example, a baffle similar to baffle 622 may be used to introduce air near the sidewall of the atomizing chamber 602. It should be understood that other designs and / or positions of baffles may be used to introduce air into the atomizing chamber 602 while isolating the atomizing chamber 602 from the direct current in the respiratory system. In addition, some embodiments may utilize other mechanisms to divert some air from the respiratory system to the atomizing chamber 602 during each inhalation of the patient. For example, some embodiments may incorporate one or more one-way valves, which are arranged between the atomizing chamber 602 and the inspiratory limb 650 and / or the expiratory limb 652. The one or more valves seal and / or otherwise isolate the nebulizing chamber 602 from the respiratory system until the patient inhales, at which time the one or more valves open and allow a small amount of breath to flow into the nebulizing chamber 602 .

[0085] By using a series of baffles that direct a small amount of air from the inspiratory branch 650 to the aerosol chamber 602, embodiments of the present invention ensure that the air drawn into the aerosol chamber 602 has less turbulence and more laminar flow, which provides better deposition of the drug in the lungs. The baffles can be designed so that the gas / air drawn beyond the baffles is at or close to the inspiratory flow of the infant (which is much lower than the gas passing through the inspiratory branch 650). It should be understood that, although two baffles are used in the illustrated embodiment, before the airflow is introduced into the aerosol chamber 602, other numbers and arrangements of baffles can be used to reduce the turbulence in the airflow from the inspiratory branch 650 without significantly increasing the amount of inspiratory force required to draw air into the patient's airway. In addition, although U-shaped baffles are shown, it should be understood that other baffle designs that both limit the amount of airflow drawn into the aerosol chamber 602 during each inhalation and reduce the amount of turbulence in such airflow can also be used. This also helps to reduce the dilution of the atomized drug in the air supplied by the inspiratory branch 650.

[0086] Figure 7 Shows Figure 6-6D The atomizing device 600 in the embodiment of the present invention is in a state of being connected to both the fluid supply line 700 and the respiratory system 702. As shown, 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 includes a tip protruding outward from the atomizing device 600 body. The opening of the fluid supply line 700 can be assembled above the tip, thereby allowing the fluid from the fluid supply line 700 to enter the reservoir and / or conduit 634 through the drug supply port 614 for subsequent delivery to the aerosol generator 602. The second end (not shown) of the fluid supply line 700 can be connected to a fluid source, such as a vial (or other type of container) of a liquid drug.

[0087] The breathing adapter 606 can be coupled to the breathing system 702. As shown here, the inlet 608 is coupled to the inspiratory limb 650 of the breathing system 702, while the outlet 616 and the expiratory limb 652 are blocked. Air and / or other respiratory gases can pass from the inspiratory limb 650 to the breathing adapter 606, where one or more diverting mechanisms, such as valves, baffles, etc., can divert a portion of the airflow into the aerosol chamber 602 via the fluid path, while the remaining larger portion of the airflow of the breathing system 702 is directed by the breathing adapter 606 through the expiratory limb 652.

[0088] The nebulizer cable 704 is connected to the power connection 640. The nebulizer cable 704 is configured to deliver power to the aerosol generator 602, and provide operating commands (such as commands to control when to actuate the aerosol generator 602 and how long to actuate). For example, a controller (not shown) can be connected to the atomizing device 600 via the nebulizer cable. The controller can use one or more respiratory sensors to monitor the patient's respiratory cycle. Based on this information, the controller can use the nebulizer cable 704 (or other communication link) to send a signal that activates the pump to deliver liquid to the aerosol generator 612 and actuate the aerosol generator 612 to atomize the medicine.

[0089] Figure 8 Another embodiment of atomizing device 800 is shown. Atomizing device 800 may be similar to atomizing device 600 described above. As shown, atomizing device 800 is connected to a drug source 802. Drug source 802 may be any container that holds a certain amount of drug. As shown, drug source 802 is a vial connected to atomizing device drug port via Luer connection 804 and the length of fluid supply line 806. Also connected to atomizing device 800 is a sprayer cable 808 that may be connected to a controller (not shown). Sprayer cable 808 terminates in a cabin 810 that may be used to connect atomizing device 800 and / or a respiratory sensor to a controller.

[0090] Fig. 9 A nebulizer 800 connected to a drug source 802 and a controller 812 is shown. The controller may be configured to deliver liquid medicine to the nebulizer 800 via a fluid supply line 806 and actuate the nebulizer 800. In some embodiments, the controller 812 may actuate the nebulizer 800 based on the detected patient inhalation. For example, the controller 812 may be connected to a breathing sensor 814, which may detect the start, duration and / or end of the patient's inhalation. In some embodiments, the breathing sensor 814 may be a sensor similar to a Graseby sensor, which may be positioned against the patient's trunk (abdomen and / or chest) to detect the patient's breathing cycle. As such an example, the controller 812 may receive a signal from the breathing sensor 814, which indicates that the patient begins to inhale. The controller 812 may then send a command, which causes a certain amount of liquid medicine to be supplied to the aerosol generator of the nebulizer 800 and causes the aerosol generator to be activated during inhalation to atomize the liquid medicine.

[0091] In some embodiments, the breathing sensor 814 and / or the nebulizing device 800 may be directly coupled to the controller 812. In other embodiments, the capsule 810 and / or other adapters may be used to connect the breathing sensor 814 and / or the nebulizing device 800 to the controller 812. For example, in some embodiments, connecting the breathing sensor to the capsule includes inserting a connection such as a sliding luer connection into a port of the capsule 810. In this embodiment, the breathing sensor 814 may be adhered and / or otherwise attached to the patient's abdomen to begin sensing the inhalation cycle.

[0092] Fig.10 Controller 812 is shown. Controller 812 includes a user interface 818, such as a display screen. In some embodiments, user interface 818 can be a touch screen. Controller 812 may include one or more input devices, such as buttons, dials, keypads, touch screens, etc., which allow users to interact with controller 812 to adjust settings, such as dosage levels, etc. Controller 812 may also include multiple ports 820, which can be used to connect controller 812 to peripheral units, such as atomizing device 800 and / or respiratory sensor 814. In some embodiments, controller 812 may include one or more indicators 824, such as LEDs, which are configured to warn the user of the status of various features. For example, indicator 824 may notify the user whether atomizing device 800 and / or respiratory sensor 814 are properly connected, whether the power supply 832 of controller 812 is valid (i.e., whether the battery (if present) is charged or charged), whether any fault in the system has been detected, etc. In some embodiments, indicator 824 may be integrated into user interface 818. The housing 822 of the controller 812 may include a holder 826 configured to securely receive the drug source 802, such as Fig.11 In this embodiment, the drug source 802 is a vial secured in an inverted orientation within the holder 826, thereby allowing the entire contents of the drug source 802 to be drained, pumped and / or otherwise delivered from the drug source 802 to the atomizing device 802.

[0093] Fig.12 A source of medication 802 is shown. Here, the source of medication 802 is in the form of a vial with a vented vial access device (VVAD) 828 attached. The VVAD 828 may include a removable cap 830 that seals the opening of the VVAD 828 when attached to the VVAD 828. The VVAD 828 may also include a filter 832 that helps minimize aerosols within the vial and fluid supply line 806, minimize surface contamination, and offset vial pressure. In use, the cap 830 may be removed and a port (not shown) may be attached to a Luer connector to connect the source of medication 802 to the fluid supply line 806.

[0094] In certain embodiments, atomizing device as herein described comprises an aerosol generator that can be connected to various artificial respiration systems.Aerosol generator can receive liquid medicine from fluid source by fluid delivery conduit.In operation, pump the fluid pump from fluid source by fluid delivery conduit to aerosol generator, there, before patient inhales and / or patient inhales atomizing fluid simultaneously.In certain embodiments, can be before treatment with fluid perfusion fluid delivery conduit to ensure fast delivery (for example, fluid is preloaded in aerosol generator).Pump can be controlled by controller, and controller arranges time for delivery and dosage of fluid.

[0095] The controller includes one or more processors, which execute instructions stored on one or more memories to drive the operation of pumps and aerosol generators. For example, the memory may include instructions, which indicate the amount of fluid to be pumped to the aerosol generator in each dose of each actuation of the aerosol generator, how much fluid to be pumped in a specific time period, etc. The stored instructions may be based on the patient's body shape, the patient's age, the patient's gender, the type of medicine, fluid additives, the desired aerosol amount, etc. The memory also includes instructions for activating the aerosol generator. As shown in the figure, the controller is connected to the aerosol generator with a cable (i.e., cable), but in some embodiments, the controller may also be wirelessly connected to the aerosol generator. The cable carries a signal, which activates the piezoelectric (or other) actuator inside the aerosol generator. When the piezoelectric actuator operates, it vibrates the vibrating member, and then atomizes the fluid to be delivered to the patient (i.e., by inhalation). Therefore, the memory may include instructions for controlling when the piezoelectric actuator starts, stops, and vibrates at a frequency, etc.

[0096] The atomization system described herein can improve the therapeutic efficacy by timing the generation of aerosol. For example, the aerosol delivery system can start atomizing the drug before the patient inhales. In this way, the aerosol delivery system utilizes increased airflow at the beginning of inhalation. When the inhaled air brings the drug deeper into the patient's lungs, this increases the drug delivery to the patient. The aerosol delivery system can also atomize the drug once inhalation is detected (e.g., for spontaneous breathing).

[0097] The aerosol delivery system coordinates the delivery of the medication using one or more respiratory sensors to determine when the patient inhales and for how long. These respiratory sensors can communicate with the controller via a wired connection and / or a wireless connection. In some embodiments, the aerosol delivery system can use a combination of respiratory sensors to provide redundancy and / or more accurate monitoring of the patient's respiratory cycle. As just one example, an aerosol delivery system can use a flow sensor in combination with a radar sensor to monitor both airflow and chest movement. As another example, an aerosol delivery system can use a flow sensor, a radar sensor, and a plethysmographic sensor to monitor the respiratory cycle. It should be understood that in a given application, any number and / or any combination of respiratory sensors can be used to monitor the patient's respiratory cycle.

[0098] In some embodiments, a flow sensor is connected to the gas delivery conduit to sense changes in airflow during inhalation (e.g., forced, assisted, or spontaneous breathing). In some embodiments, the flow sensor may also be connected to the gas return conduit to detect the start and end of exhalation. In other embodiments, the aerosol delivery system may include a flow sensor that is connected to the gas delivery conduit and the gas return conduit. When the controller receives data from the flow sensor, the controller may monitor the breathing pattern to predict when the patient will breathe. The ability to predict when inhalation begins enables the aerosol delivery system to prepare aerosolized medicine for immediate inhalation. More specifically, the aerosol delivery system can preload the fluid on a vibrating member in the aerosol generator so that the fluid can be atomized before inhalation. Since flow detection is not a hysteresis indicator, the flow sensor can quickly detect unusual or spontaneous inhalation of aerosol delivery (e.g., less than 10 milliseconds from the start of inhalation).

[0099] Predicting the patient's inhalation can be started by tracking the patient's breathing pattern and / or ventilation cycle using one or more breathing and / or flow sensors (if the patient is on mandatory ventilation). The controller then uses the tracked data to predict when the subsequent inhalation will begin. This allows the controller to instruct the pump to deliver fluid from the fluid source to the aerosol generator 16 before inhalation. The controller can also signal the aerosol generator to start atomizing the fluid at the appropriate time, such as before and / or during the predicted inhalation, within a predetermined time period (e.g., + / - 0.5 seconds). In this way, an aerosol is prepared for the patient when the inhalation begins. Although the aerosol delivery system is able to predict the breathing cycle to generate an aerosol for the patient, the aerosol delivery system is also able to use a breathing sensor to identify spontaneous / irregular breathing that is part of an abnormal pattern. Once spontaneous breathing is identified, the aerosol delivery system can immediately pump the fluid to the aerosol generator for delivery to the patient.

[0100] Fig.13An example of the function of controller 812 is shown. As shown in Figure A, controller 812 receives a signal from respiratory sensor 814, which indicates that the patient has started to inhale. Then, controller 812 sends a command to start delivering a certain amount of medicine to the aerosol generator, which is activated to atomize liquid medicine, as shown in Figures B to D. In some embodiments, controller 812 can be programmed to atomize medicine only in the first part of the inhalation, thereby allowing the last part of the inhalation to inhale chase air (chase air) to help deliver the atomized medicine to the deep lung. For example, as shown in various charts, controller 812 causes medicine atomization only in the first 80% of each inhalation, thereby allowing the last 20% of each inhalation to draw chase air into the patient's airway. It should be understood that other atomization modes can be used. For example, the atomization of medicine can be completed in the first 50% to 90% of each inhalation (more commonly between 60% and 80%, even more commonly between 70% and 80%). More than 80% of the time is associated with more aerosol in the upper airway that is exhaled before reaching the lower airway. This allows the final 10% to 50% (more typically between about 20% to 40%, and even more typically between 20% and 30%) of the inspiration to be used to draw chase air into the patient's airway.

[0101] Figure 14A-1 4K shows the use of Figure 8-13 To begin, the controller 812 may be powered on (such as by turning on a switch), thereby allowing the controller 812 to begin a startup sequence. In some embodiments, the startup sequence may include a power-on self-test of any audible alarm range and / or an alarm display on the top of the controller that cycles through a visual alarm range. A backup alarm for the system may also sound as a test. Fig.14A As shown, a user (such as a medical professional) may need to log into the controller 812 using the user interface 818. For example, the user may need to enter credentials, such as a username, a password, occupancy-based credentials (such as a magnetic stripe card and / or a digital key or credentials provided using a radio frequency communication protocol), biometric credentials (fingerprint scan, facial scan, retinal scan, voice scan, etc.), etc. to begin using the nebulizer system. Once logged in, the user may need to provide patient information, which may be related to scheduling, volume, and / or other factors related to the patient's treatment. For example, Fig. 14BAs shown, the user must enter a patient identifier (such as name, identification number, etc.), the patient's weight, dosage type (high / low, etc.) and / or amount, and / or other details related to the patient. After entering all necessary patient information, a confirmation screen may be presented to the user, allowing the user to review and confirm the accuracy of the patient and dosing information before continuing. If the patient and dosing information are correct, the user may confirm and continue the setup process. If any of the patient or dosing information is incorrect, the user may re-enter the incorrect information before continuing.

[0102] The user may then be presented with information on using Fig. 14C Here, the user interface 818 instructs the user to connect the pod 810 to the controller 812 of the nebulizer system. For example, the user may insert the connector of the pod 810 into one of the ports 820 of the controller 812. In some embodiments, the user interface 818 may display a notification when the pod 810 is properly connected to the controller 812. In some embodiments, the controller 812 and / or a stand (not shown) to which the controller 812 may be attached and / or otherwise supported may include a basket and / or other support structure that may be used to hold any excess cables from the pod 810. Other instructions may be presented to help the user set up the nebulizer system for use. As another example, in Fig.14D In the embodiment, user interface 818 can instruct the user to connect the breathing sensor 814 (such as, breathing sensor capsule) to both cabin 810 and patient, and then confirm the patient's inhalation. As shown in the figure, in some embodiments, the breathing sensor is connected to the cabin and includes inserting a connection such as a sliding luer into the port of cabin 810. In the present embodiment, the breathing sensor 814 can adhere to and / or otherwise be attached to the abdomen of the patient to begin sensing the inhalation cycle. For example, a sticky barrier wipe can be used to prepare the patient's skin and make the skin dry. Then, the breathing sensor 814 can be placed on the flank and / or lower abdomen and fixed in place with adhesive tape, wherein the piping of the breathing sensor 814 does not have adhesive tape. The user interface 818 can prompt the user to confirm that the breathing signal is received by the controller 812 and is correctly displayed on the user interface 818.

[0103] like Fig.14EAs shown, instructions on how to set up the drug feed line 806 and sprayer cable 808 of the atomization system can be presented to the user. For example, the user can attach the VVAD 828 to the drug vial (drug source 802), wherein the filter 832 is aligned with the observation window on the vial label. This can be done by keeping the vial upright and placing the perforator (not shown) of the VVAD 828 through the diaphragm (not shown) of the vial until the VVAD 828 clicks and locks in place. The feed mechanism (e.g., pump, not shown) can be opened, such as on one side of the controller 812 housing, and the fluid supply line 806 is inserted into the feed mechanism, which is then closed. The vial can be placed in a horizontal orientation and connected to the fluid supply line 806. The Luer end of the VVAD 828 can be placed in the Luer holder portion of the holder 826 and pivoted upward to a metal clip with an observation window facing outward. The sprayer cable 808 can then be connected to the cabin 810. The nebulizing device 800 may also be coupled to a respiratory system, such as a ventilator. Once the various components are connected, the nebulizing device 800 may be primed.

[0104] Fig.14F Prime the pump. This can be done by selecting the prime function using the user interface 818 of the controller 812. Once primed, an aerosol check can be performed, such as Figure 14G As shown. The user can then interact with the user interface 818 to begin initiating aerosol generation. The user can then observe the aerosol generated and emitted from the patient interface (if attached) or from the opening in the nebulizer device 800 to ensure that the nebulizer system is operating correctly. If an aerosol is observed, the user can continue with the setup. If no aerosol is observed, the user can repeat the priming and aerosol check steps. Before or after completing the aerosol check, the user interface 818 may prompt the user to connect a patient interface (such as a nasal plug) to the nebulizer device 800. The user can select the appropriate size of the patient interface and press the patient interface onto the nebulizer device 800. In some embodiments, the connection between the patient interface and the nebulizer device 800 can be trapezoidal. This shape can help the user properly align the patient interface in the correct orientation, however other shapes can also be used. As Fig.14HAs shown, atomizing device 800 can be connected to an infant. For example, a nasal plug (or other patient interface) can be docked with the infant's airway. In certain embodiments, one or more strips and / or other restraints can be used to fix atomizing device 800 to the infant's airway and head to ensure that if the infant moves, the atomizing device remains in place. In certain embodiments, atomizing device 800 can be fixed to the infant's head using one or more strips, and the strips can be fixed to the soft hat that the infant wears. In addition, a foam pad can be attached to atomizing device 800, and the foam pad can extend between atomizing device 800 (a part of aerosol generator with atomizing device 800 is laterally spaced apart) and the infant's head. The foam pad can include multiple layers of peelable foam, thereby allowing the layer to be peeled off and / or otherwise removed to adjust the distance between atomizing device 800 and the infant's head. Typically, the foam pad can include a curved surface designed to match or substantially match the infant's head profile. Once in place, the foam pad (along with any straps) helps maintain the nebulizing device 800 in the proper position and orientation with respect to the infant, regardless of the infant's movement or orientation (supine, side, prone). Once the nebulizing system is connected to the infant, the user can interact with the user interface 818 to begin administering medication to the infant, such as Fig.14I As shown. For example, the user can confirm the patient data and the total dose, as well as verify that the number of drug vials matches the pharmacist's pharmacy calculation and dispensing form. Once the data is confirmed, the user can interact with the controller 812 to start the drug administration procedure. Once the drug administration procedure is started, data such as breathing cycle, dose indication, atomization rate, and the amount of drug remaining in the drug source 802 are displayed. The user interface 818 can also prompt the user to confirm that the aerosol is synchronized with the infant's breathing pattern.

[0105] In some embodiments, when the vial is empty, the controller 812 interrupts the drug administration. Typically, a low priority alarm may be activated when a threshold amount of drug remaining in the vial is reached (such as less than 5%, 10%, 15%, 20%, etc.). After a set period of time, if the user does not acknowledge the low priority alarm, a medium priority alarm is activated and a "vial alarm" may be displayed on the user interface 818 and / or generated on one of the indicators 820. In some embodiments, when the vial is empty, the controller 812 automatically pauses and activates a medium alarm. If the user does not acknowledge the alarm after a predetermined time, a high priority alarm is activated. The user may be prompted to "Change vial, restart drug administration from the drug delivery screen." The empty vial can be exchanged for a new drug vial and drug administration can continue. Once drug administration is completed, the user can confirm the end of drug administration and interact with the controller 812 to return to a normal CPAP or other breathing circuit.

[0106] In some embodiments, a low priority alarm is visual only and is annunciated only by text on the user interface 818. In some embodiments, a medium priority alarm has both a visual and an audible component, combining an associated colored alarm display (such as yellow) with associated audio and text. In some embodiments, a high priority alarm has both a visual and an audible component, combining an associated colored display box (such as red) on the user interface 818 with text on the user interface 818. In some embodiments, an alarm may be provided for one or more of the following non-limiting events: if no breath is detected, if no valid breath sequence is detected (which may occur when no valid breath sequence is detected, where a valid breath sequence consists of three consecutive valid breaths, where a valid breath is determined to be an inspiratory period ≥ 100 milliseconds in duration, and an invalid breath sequence consists of at least one invalid breath, and an invalid breath is determined to be an inspiratory period < 100 milliseconds in duration), if the nebulizer cable is disconnected from the chamber during drug administration, if no wet / dry event is detected (such as due to a condition that prevents drug administration), if a nebulizer cable is disconnected from the chamber during drug administration, if a wet / dry event is detected (such as due to a condition that prevents drug administration), if a nebulizer cable is disconnected from the chamber, if a nebulizer cable is disconnected from the chamber during drug administration, if a nebulizer cable is disconnected from the chamber ... kinks in the tubing entering the aerosol generator, not aerosolized and all drug is coming out of the vent, aerosolized and no drug is coming out of the vent, aerosolized and drug is coming out of the vent), if the remaining amount in the vial is at or less than a threshold amount (including empty), if the capsule cable is disconnected from the capsule during drug administration, if the capsule cable is disconnected from the capsule when not administering, if a communication failure with the capsule is detected, if an internal fault in the capsule is detected, if a system error is detected, if the drug feed mechanism fails, if the mains is disconnected and operating in battery mode, if the battery is at or below a threshold charge level (including empty), and / or if the self-test power-up fails.

[0107] Fig.15 A nebulizer 1500 is shown docked with an infant. Here, the nebulizer 1500 may be similar to those described herein and place the aerosol generator proximal to the infant's airway, including a baffle that minimizes flow through the aerosol generator / interface area adjacent to the patient during aerosol generation. The nebulizer 1500 may also include a PDAP mesh or similar mesh that is capable of aerosolizing particles less than about 3 μm (more preferably less than about 2 μm) MMAD at a high flow rate (between about 0.1 ml / min and 1.5 ml / min). The nebulizer 1500 may also include a power / control port that allows connection of one or more controllers (similar to controller 812) to provide power and / or operating commands to the aerosol generator.

[0108] Atomizing device 1500 may also include one or more straps or other restraints 1502 that enable atomizing device 1500 to be fixed with the baby's head and airway. In addition, atomizing device 1500 may include foam pad 1504, which is designed to help atomizing device 1500 to be maintained at the appropriate position and orientation about the baby, regardless of the movement or orientation (supine, side, prone) of the baby. Foam pad 1504 may include multi-layer peelable foam, thereby allowing the layer to be peeled off and / or otherwise removed to adjust the distance between atomizing device 1500 and the baby's head. Typically, foam pad 1504 may include a curved surface that is designed to match or substantially matches the baby's head profile. Atomizing device 1500 may be made of sufficiently light material (such as, medical grade plastic foam), which allows the baby to move around and not cause atomizing device 1500 to move out of the correct position.

[0109] Fig.16 A breathing sensor capsule 1600 (similar to breathing sensor 814) is shown docked with the abdomen of a patient. As shown, the breathing sensor capsule 1600 is taped and / or otherwise adhered to the abdomen of an infant and is subsequently used to detect the beginning and / or end of an infant's inspiratory cycle. This is accomplished by using 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 controller (not shown) can monitor the flow rate in and out of the capsule associated with volume changes in the abdominal sensor and synchronize the delivery of aerosolized surfactant with the infant's inhalation to help maximize the efficiency of the surfactant delivery.

[0110] Fig.17 Another embodiment of a nebulization system 1700 for delivering surfactant to an infant in an effective and efficient manner is shown. As shown, a controller 1702 (which may be similar to controller 812) is used to provide power and control to a nebulization device 1704. Controller 1702 may also be configured to control the delivery mode of nebulization device 1704. For example, controller 1702 may be configured to alternate between a timing mode or a continuous mode, in which treatment is given within a set time period; in a continuous mode, the delivery of nebulized surfactant is performed indefinitely based on the infant's inhalation pattern. System 1700 may also include an additional controller 1706 that allows medical personnel to set aerosol delivery criteria. For example, additional controller 1706 may enable a flow rate that triggers aerosol delivery, an inhalation time for delivering aerosols, and / or other criteria for controlling the timing, dosage, and / or duration of a nebulized dose. Although described with respect to different component controllers 1702 and additional controllers 1206, it should be understood that in some embodiments, a single controller (or multiple controllers) may be used to control the operation of system 1700.

[0111] The system 1700 may also include one or more flow sensors and / or other respiratory sensors 1708. As shown, the flow sensor 1708 may be coupled to the inspiratory limb 1710 of the respiratory system 1712, such as before and / or after the optional humidifier 1714. The respiratory sensor 1708 may be used to detect the inhalation of the infant. In other embodiments, the respiratory sensor 1708 may be a respiratory sensor capsule that docks with the infant's abdomen. The respiratory sensor 1708 may be electrically coupled to one or both of the controllers 1702 or 1706 so that the inhalation data may be used to trigger the activation of the nebulizer 1704 (which may be similar to any of the nebulizers described herein). The controllers 1702 and 1706 may be electrically coupled to the nebulizer 1704 to provide both power and operating commands to the nebulizer 1704. In some embodiments, the nebulizer 1704 may include a PDAP mesh 1716 that produces a nebulized surfactant of less than about 3 μm (preferably less than about 2 μm) MMAD at a rate of at least 0.1 ml / min. This nebulizing device 1704, when used in conjunction with controllers 1702, 1706 and respiratory sensor 1708, allows for 1) generation and delivery of sufficiently small aerosol particles, 2) delivery of the aerosol in sync with respiration, and 3) placement of the aerosol generator proximal to the infant's airway, wherein continuous airflow is controlled to minimize flow through the aerosol generator / interface area proximal to the patient during aerosol generation (e.g., Figure 6-6D best shown), thereby being able to greatly increase the delivery efficiency to the lungs to between about 25% and 60%, more typically between about 40% and 60%.

[0112] Fig.181800 is a flow chart of a process 1800 for delivering aerosolized surfactant to an infant. The process 1800 may be performed using any of the aerosolizing devices, processors, and / or respiratory sensors described herein. The process 1800 may be started at box 1802 by detecting an infant's inhalation using one or more respiratory sensors. For example, the respiratory sensor may be attached to the infant's abdomen. The respiratory sensor may detect the expansion of the infant's abdomen associated with inhalation. At box 1804, based on the detected inhalation, the controller may cause the aerosolizing device to aerosolize a certain amount of surfactant into particles less than about 3 μm mass average aerodynamic particle diameter (MMAD) at a rate of at least 0.1 ml / min. The surfactant may be aerosolized within about 1 to 8 cm from the patient interface. In some embodiments, aerosolizing a certain amount of surfactant may include delivering a certain amount of surfactant from a reservoir to a net of the aerosolizing device; and vibrating the net to aerosolize a certain amount of surfactant. In some embodiments, a certain amount of surfactant may be delivered from a reservoir to a net via a catheter having a distal tip having a certain diameter. The distal tip of the catheter may be positioned at a distance less than or equal to the diameter of the net of the aerosol generator. This ensures that any drug ejected from the tip contacts the surface of the mesh and wicks along it, thereby enabling the nebulizer to operate effectively in any orientation. In some embodiments, nebulizing a quantity of surfactant involves nebulizing a portion of the quantity of surfactant within at least a portion of the first 80% of each of the consecutive multiple inhalations, such that chase air is provided within at least a portion of the last 20% of each of the consecutive multiple inhalations. At block 1806, the nebulized surfactant may be delivered to the infant's airway via a patient interface, such as a nasal prong.

[0113] In some embodiments, the process 1800 may also include coupling the nebulizing device to the respiratory system; and diverting a portion of the airflow of the respiratory system to a chamber of the nebulizing device via at least one airway. The chamber is configured to mix the portion of the airflow with the nebulized surfactant. In some embodiments, the portion of the airflow is a respiratory flow and is less than the amount of air that continues to reach the expiratory limb of the respiratory system. In some embodiments, the portion of the airflow is diverted using at least one baffle defining at least one airway. At least one baffle may be configured to divert the portion of the airflow to the aerosol chamber via at least one airway and divert the airflow of an additional portion of the inspiratory limb to the expiratory limb. In some embodiments, two baffles are used. The first baffle may define a first airway, and the second baffle may define a second airway. The first airway is disposed at a side end of the first baffle, and the second airway is disposed at a position beyond a distal edge of the second baffle, wherein the side end and the distal edge extend in different directions so that the respiratory flow moves through the first baffle and the second baffle in multiple directions.

[0114] Fig.19It is a flow chart for initializing the process 1900 of atomizing system.Process 1900 can be performed using any one of atomizing device, processor and / or respiratory sensor as described herein.Process 1900 starts at frame 1902 by connecting atomizing device and controller, respiratory sensor, drug source and respiratory system.This may involve connecting the nebulizer cable between atomizing device and controller (can be carried out via cabin or other adapters), connecting the inlet of the inspiratory branch of respiratory system and atomizing device, connecting the outlet of the expiratory branch of respiratory system and atomizing device, connecting the cable of respiratory sensor and controller (can be via cabin or other adapters) and / or connecting atomizing device and drug source.In certain embodiments, connecting atomizing device and drug source may include connecting the fluid supply line between drug source and atomizing device.In certain embodiments, drug source is the ventilation bottle access device (VVAD) connected with fluid supply line.

[0115] At box 1904, the user's access credentials are entered into the controller to ensure that only authorized users can access the atomization system and the ability to administer medication. The access credentials may include one or more of a user identifier, a password, a possession-based credential, and a biometric credential. Information and dosage information related to the patient may be entered into the controller at box 1906. This may include information such as a patient identifier, patient weight, dosage level, etc. At box 1908, a respiratory sensor may be connected to the patient. This may involve adhering the sensor to the patient's abdomen. In some embodiments, the detection of breathing may be configured after the respiratory sensor is connected to the patient. At box 1910, the atomization device may be irrigated. This may include atomizing a portion of the drug before docking the patient interface with the patient's airway to ensure that the device operates correctly. At box 1912, the atomization device may be docked with the patient's airway. For example, a nasal plug may be inserted into the baby's nostrils. In some embodiments, the patient interface may need to be fixed to the atomization device before the device is docked with the patient. In some embodiments, one or more strips and / or foam pads may be positioned and / or fixed around the baby to fix the atomization device in place. Once secured in place, the user may begin delivering a dose to the infant and / or may review the user interface of the controller to confirm that delivery of the aerosolized dose is synchronized with the infant's inhalation.

[0116] In some embodiments, process 1900 may also include executing a startup sequence when the controller is powered on. The startup sequence may cycle through a plurality of audible alarms, visual alarms, or both audible and visual alarms to ensure that the controller is operating correctly before use.

[0117] Example

[0118] In vitro experiments were conducted using the atomization device according to the present invention to determine the effective emission dose of the drug. Figure 6-6DThe patient adapter of the nebulizer device shown (here, in the form of a nasal prong) is docked with a modified Harvard Apparatus Sine Small Animal Ventilator and an Enigma Lung Simulator to perform simulated infant inhalation. Two different sizes of nasal prongs (a larger nasal prong (5560) and a smaller nasal prong (4030)) are used to perform the simulation. Fig. 20 As shown in the bar graph, the larger the plug size, the higher the emitted dose. Notably, the larger nasal plug (5560) resulted in an emitted dose between 68% and 72%, while the smaller nasal plug (4030) resulted in an emitted dose between about 35% and 37%.

[0119] The airflow was then set to 6 liters per minute (LPM), 8 LPM, and 10 LPM, with a respiratory rate of 60 breaths per minute (BPM), 80 BPM, 100 BPM, and 120 BPM. The emitted dose rate was then measured at each combination of air flow rate and respiratory rate. Fig.21 As shown, airflow has an effect on delivery efficiency, where a larger flow rate results in a slightly lower delivery efficiency. For example, at a lower flow rate (6LPM), a larger nasal plug (5560) produces an emission dose of about 50% to about 50% at the extreme end of the tested respiratory rate, while at a higher flow rate (10LPM), the emission dose ranges from about 42% to about 47%. It is worth noting that as the respiratory rate increases, the efficiency differences associated with the greater flow rate become less obvious. For example, the emission dose rate at 60BPM ranges from about 44% to about 60%, while the emission dose rate at 120BPM ranges from about 42% to about 51%. Based on these results, it is determined that the aerosol generator described herein is capable of achieving consistent drug inhalation doses within a clinically relevant range of respiratory rates (60 to 120BPM) and CPAP flows (6 to 10LPM) commonly used with bubble and ventilation CPAP systems.

[0120] Embodiments of the present invention also provide systems and methods for delivering surfactants (or other drugs) to infants, particularly premature infants, in a non-invasive manner. In order to achieve effective and efficient delivery of medical aerosols to premature infants, a combination of the following properties is required: 1) sufficiently small aerosol particles, 2) aerosol delivery synchronized with breathing, and 3) placing the aerosol generator proximal to the infant's airway (within about 1 to 8 cm), wherein the continuous airflow is controlled to minimize the flow through the aerosol generator / interface area adjacent to the patient during aerosol generation. By meeting these conditions, surfactant delivery rates of more than 40% and even up to about 60% can be achieved, which provides a significant improvement over traditional effectiveness rates of less than 10%.

[0121] Due to the respiratory physiology of premature infants, in order to properly deliver the nebulized surfactant to the infant in a non-invasive manner, it is necessary to utilize nasal delivery techniques, such as nasal prongs that can be inserted into the infant's nasal passages. Using such delivery techniques, it is desirable to deliver aerosol particles smaller than about 2 μm, since particles larger than this value are typically dislodged from the nebulizer device interface and / or airways prior to being dispersed in the infant's lungs. Fig. 22 and 23 , which demonstrates the particle deposition rates for various particle sizes (using MMAD and a GSD of 2.2) for neonates, Neonate 1 being 4 months old and Neonate 2 being a 28 week premature neonate. Fig. 22 It is shown that as the particle size decreases, lung deposition increases ( Fig. 22 Results are shown only for neonates 1), with lung deposition exceeding 40% as particle size drops below 2 μm. Of note, nasal deposition is typically between about 50% and 70% for particles larger than 2 μm, representing particles that are not delivered to the infant's lungs. Fig.23 The lung and nose deposition rates for two newborns using MMAD 3 μm and MMAD 2 μm aerosols are shown. Here, improved lung deposition was observed for the MMAD 2 μm aerosol for both newborns, with a deposition rate of just under 40% for newborn 1 and just under 60% for newborn 2. These results suggest that smaller aerosol particles are needed to maximize delivery efficiency.

[0122] Traditional nasal delivery technology usually utilizes particles of 4 to 7 μm MMAD, wherein the geometric standard deviation is about 2.0 or higher. This is due to the viscosity of most surfactants, which makes it difficult to effectively atomize undiluted surfactants into particles of sufficiently small size with a sufficiently high atomization rate using traditional jet nebulizers, professional jet nebulizers, mesh nebulizers, heated capillary generators, etc. Traditional delivery technology has seen the impact rate that reduces the available mass of aerosol in a given dose by up to 80%. Then, only 40 to 60% of the remaining aerosol (the part consisting of less than about 2 μm particles) will reach the lower airway of the lungs, resulting in a total effective rate of about 10% of the initial emission dose from the aerosol generator.

[0123] Embodiments of the present invention provide for using an atomizing device (such as Figures 1 to 8Those described above) to generate systems and methods for sufficiently small aerosol particles. In particular, embodiments utilize a nebulizing device including an aerosol generator that utilizes the ability of a PDAP mesh to consistently generate aerosolized surfactants less than about 3 μm (more preferably in the range of about 1.5 μm to about 2.5 μm) at an output rate between about 0.1 ml / min and 0.6 ml / min (such as disclosed in U.S. Patent Publication No. 2016 / 0130715, previously incorporated by reference). By utilizing the capabilities of such an aerosol generator, embodiments of the present invention are able to provide particle sizes small enough to effectively and efficiently deliver surfactants to the lungs. For example, even with an aerosol of less than 3 μm MMAD, a nasal to lung efficiency of approximately 40 to 60% of the nominal dose of surfactant can be achieved.

[0124] As mentioned above, in order to fully maximize the delivery efficiency, it is also useful to synchronize the delivery of the aerosol with the infant's inhalation. This helps to ensure that the surfactant is not wasted when it is aerosolized during exhalation and / or between breaths. For example, infants typically have an inhalation: exhalation ratio ranging from about 1:1 to about 1:3. Therefore, the aerosolized surfactant is typically inhaled only about 25 to 50% of the time. In traditional systems, the aerosol is typically carried by an airflow with bubble CPAP between about 6 and 10 LPM, which exceeds the peak inspiratory flow of the infant and wastes up to half of the aerosolized drug.

[0125] Embodiments of the present invention may link the activation of the aerosol generator to the breathing of the infant. As described above, this may be accomplished using one or more respiratory and / or flow sensors to track the patient's breathing pattern and / or ventilation cycle. The controller then uses this information to predict when subsequent inhalation will begin and the time to deliver fluid from the fluid source to the aerosol generator and / or to synchronize the activation of the aerosol generator with the infant's inhalation. In some embodiments, detection of inhalation may be accomplished using a respiratory sensor capsule attached to the infant's abdomen. The respiratory sensor capsule may detect abdominal movements associated with inhalation, which typically occur before the inhalation itself occurs, making the respiratory sensor capsule particularly useful in determining the inhalation timing for synchronized aerosol generation.

[0126] Fig.24 Demonstration of the effectiveness of the respiratory sensor capsule in detecting inhalation. Here, a separate flow sensor interfaces with the infant's airway and the respiratory sensor capsule affixed to the infant's abdomen. The infant weighs 1,500 grams and has a respiratory rate of 70 BPM. Fig.24The graph in shows the sensor signal detected by the breath sensor capsule at each inhalation and exhalation detected by the flow sensor, where the breath sensor capsule detects the start of inhalation slightly earlier than the flow sensor, which gives the controller time to activate the aerosol generator. These results confirm that the use of the breath sensor capsule may be particularly useful for synchronizing breathing and aerosol generation. Fig.24 It was also shown that this particular set of inhalations was within a 5 second period, and that inhalation only took about 1 / 3 of that period. Thus, without synchronous breathing and aerosol delivery, more than 2 / 3 of the nebulized surfactant dose would be wasted.

[0127] In certain embodiments, atomizing device as herein described comprises an aerosol generator that can be connected to various artificial respiration systems.Aerosol generator can receive liquid medicine from fluid source by fluid delivery conduit.In operation, fluid from fluid source is advanced to aerosol generator by fluid delivery conduit with pump, and there, before patient inhales and / or simultaneously atomizes fluid.In certain embodiments, fluid delivery conduit can be filled with fluid before treatment to ensure fast delivery (for example, fluid is preloaded in aerosol generator).Pump can be controlled by controller, and controller arranges time for delivery and dosage of fluid.

[0128] The controller includes one or more processors, which execute instructions stored on one or more memories to drive the operation of pumps and aerosol generators. For example, the memory may include instructions, which indicate the amount of fluid to be pumped to the aerosol generator in each dose of each actuation of the aerosol generator, how much fluid to be pumped in a specific time period, etc. The stored instructions may be based on patient size, patient age, patient gender, drug type, fluid additives, desired aerosol amount, etc. The memory also includes instructions for activating the aerosol generator. As shown in the figure, the controller is connected to the aerosol generator with a cable (i.e., cable), but in some embodiments, the controller may also be wirelessly connected to the aerosol generator. The cable carries a signal, which activates the piezoelectric (or other) actuator inside the aerosol generator. When the piezoelectric actuator operates, it vibrates the vibrating member, and the vibrating member subsequently atomizes the fluid to be delivered to the patient (i.e., by inhalation). Therefore, the memory may include instructions for controlling when the piezoelectric actuator starts, stops, and vibrates at a frequency, etc.

[0129] The atomization system described herein can improve the therapeutic efficacy by timing the generation of aerosol. For example, the aerosol delivery system can start atomizing the drug before the patient inhales. In this way, the aerosol delivery system utilizes increased airflow at the beginning of inhalation. When the inhaled air brings the drug deeper into the patient's lungs, this increases the drug delivery to the patient. The aerosol delivery system can also atomize the drug once inhalation is detected (e.g., for spontaneous breathing).

[0130] The aerosol delivery system coordinates the delivery of the medication using one or more respiratory sensors to determine when the patient inhales and for how long. These respiratory sensors can communicate with the controller via a wired connection and / or a wireless connection. In some embodiments, the aerosol delivery system can use a combination of respiratory sensors to provide redundancy and / or more accurate monitoring of the patient's respiratory cycle. As just one example, an aerosol delivery system can use a flow sensor in combination with a radar sensor to monitor both airflow and chest movement. As another example, an aerosol delivery system can use a flow sensor, a radar sensor, and a plethysmographic sensor to monitor the respiratory cycle. It should be understood that any number and / or any combination of respiratory sensors can be used in a given application to monitor the patient's respiratory cycle.

[0131] In some embodiments, a flow sensor is connected to the gas delivery conduit to sense changes in airflow during inhalation (e.g., forced, assisted, or spontaneous breathing). In some embodiments, the flow sensor may also be connected to the gas return conduit to detect the start and end of exhalation. And in other embodiments, the aerosol delivery system may include a flow sensor that is connected to the gas delivery conduit and the gas return conduit. When the controller receives data from the flow sensor, the controller can monitor the breathing pattern to predict when the patient will breathe. The ability to predict when inhalation begins enables the aerosol delivery system to prepare aerosolized medicine for immediate inhalation. More specifically, the aerosol delivery system can preload the fluid on a vibrating member in the aerosol generator so that the fluid can be atomized before inhalation. Since flow detection is not a hysteresis indicator, the flow sensor can quickly detect unusual or spontaneous inhalation for aerosol delivery (e.g., less than 10 milliseconds from the start of inhalation).

[0132] The patient's inhalation (if the patient is forced to ventilate) can be predicted by using one or more breathing and / or flow sensors to track the patient's breathing pattern and / or ventilation cycle. Then, the controller uses the tracked data to predict when the subsequent inhalation will begin. This allows the controller to instruct the pump to deliver the fluid from the fluid source to the aerosol generator before inhalation. The controller can also signal the aerosol generator to start atomizing the fluid at the appropriate time, such as within a predetermined time period (e.g., + / - 0.5 seconds) before and / or during the predicted inhalation. In this way, the aerosol is prepared for the patient when the inhalation begins. Although the aerosol delivery system is able to predict the breathing cycle to generate an aerosol for the patient, the aerosol delivery system is also able to use a breathing sensor to identify spontaneous / irregular breathing that is part of an abnormal pattern. Once spontaneous breathing is identified, the aerosol delivery system can immediately pump the fluid to the aerosol generator for delivery to the patient.

[0133] Example 1

[0134] A two-part trial was conducted to determine the safety and tolerability of doses of inhaled surfactant in preterm infants at risk for worsening RDS while receiving nCPAP. The first part (10 infants) involved treating patients with a single dose and the second part involved multiple doses. A total of 31 preterm infants requiring nCPAP (machine CPAP) were enrolled in the study. Infants were initially stabilized on nCPAP / nIMV by adjusting CPAP and FiO2 as needed to maintain clinical blood gases (CBG) and oxygen saturation (SpO2) according to clinical guidelines. Once the infant was stabilized, AeroFact was administered via nCPAP within two hours of birth.

[0135] The AeroFact dosing strategy was to administer a single aerosol dose to the infant, which was equivalent to an instillation dose of 108 mg / kg (allowing for a 50% delivery efficiency derived from a nominal dose of 216 mg / kg). Oxygenation and ventilation parameters were monitored as outlined in the protocol until an effect (as defined by the protocol) was observed. Following dose administration, the infant continued on nCPAP. The infant's clinical observations, respiratory support index, and comorbidities of prematurity were monitored until discharge from the neonatal intensive care unit (NICU).

[0136] After successful completion of Part I and recommendation by the independent Data Safety Monitoring Board (DSMB), sites were allowed to begin participation in Part II of the study.

[0137] The second part of the study was conducted in a separate group of premature infants, also using nCPAP and at risk for worsening RDS.

[0138] An initial nominal dose of 216 mg / kg of nebulized SF-RI 1 was administered. Oxygenation and ventilation parameters were monitored as outlined in the protocol, and delivery of the aerosol was stopped when the expected dose was completed.

[0139] Infants will continue on nCPAP. Re-administration of AeroFact (nominal dose of 216 mg / kg) will occur if a respiratory severity score (RSS; mean airway pressure x inspired oxygen fraction) of ≥ 2.0 is maintained with SpO2 between 90% and 95% (as measured by pulse oximetry) and (1) at least 2 hours have passed since the end of the first dose and (2) at least 4 hours have passed since the end of either the second or third dose. Up to 3 additional doses of AeroFact are allowed within 96 hours.

[0140] Ten (10) patients participated in Part I and 21 patients participated in Part II of the study and included both the ITT and safety populations. The historical control group had 30 and 63 patients for Part I and Part II, respectively.

[0141] According to the protocol, all 10 patients (100%) received 1 dose of study drug in Part 1. In Part 2, 13 patients (61.9%) received 1 dose of study drug, 4 patients (19%) received 2 doses of study drug, 4 patients (19%) received 3 doses of study drug, and no patient received 4 doses of study drug.

[0142] The incidence of AeroFact patients experiencing 1 or more AEs was 7 (70%) in Part 1 and 13 (61.9%) in Part 2. There were no AEs assessed by the investigator as related to study drug, device, or procedure, and no AEs led to premature discontinuation of study drug or premature discontinuation of the patient from the study.

[0143] In general, the incidence of AEs related to dosing tolerance within the first 24 hours was low.

[0144] The number of patients with any complication of preterm birth in the first part of the study was 6 (60%) compared to 20 (66.7%) in the historical controls in the first part, and 12 (57.14%) in the second part of the study compared to 31 (49.21%) in the historical controls. In general, the incidence of post-dose complications of preterm birth and AEs was low and consistent between patients treated with AeroFact and historical controls.

[0145] in conclusion

[0146] Administration of up to 4 doses of AeroFact within 96 hours of birth was shown to be safe and well tolerated in patients with a gestational age range of 26 2 / 7 weeks to 30 4 / 7 weeks and a body weight between 640 and 1,664 grams.

[0147] The need for rescue therapy with surfactant bolus instillations was lower in the second part of the study compared with matched historical controls; 5 AeroFact patients (25%) required rescue with surfactant bolus instillations in the second part, compared with 27 patients (45%) in the matched historical control group. Fig.25 ; this corresponds to a relative risk of 0.56 in favor of AeroFact treatment.

[0148] Based on this study, it was concluded that the use of Fig.17The incidence of post-dose complications of preterm birth and adverse events (AEs) was low and consistent in patients treated with the nebulizer system compared to historical controls. There were no treatment-emergent adverse events (TEAEs) that were assessed as related to study drug, device, or procedure. During Days 1 to 4 of the study, following the dosing protocol, 1 case of moderate nasal congestion occurred in Part 1, while 5 cases of moderate nasal congestion and 1 case 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) (culture-confirmed sepsis) that was not related to study drug, device, or procedure and did not occur during treatment. In general, the incidence of AEs associated with dosing tolerability within the first 24 hours was low. Use only Fig.17 The incidence of AEs with the nebulizer system was comparable to that with the nebulizer system with a bolus surfactant.

[0149] Example 2

[0150] The active test lung is driven by the ventilator to provide a trigger for the AF2b device breathing sensor (similar to Fig.16 The training / test lung is a device that is used to simulate the breathing pattern of an infant. A mechanical ventilator (Pulmonetic Systems) is used to drive the training / test lung (Michigan Instruments, Inc.). The training / test lung is driven by a test lung balloon attached to the air circuit using a T-piece on the adult side to provide a representation of the subtle abdominal movements of a newborn during breathing. The AF2b respiratory sensor (which is usually attached to an infant) is attached to the lung balloon. A small deflection of the balloon during the inspiration / expiration cycle triggers the sensor to perform respiratory actuation of the device. The adult training / test lung is mechanically linked to the infant training / test lung, which is then used to simulate the actual breathing of the infant. By adjusting the settings of the ventilator, different infant breathing patterns can be simulated. An airflow analyzer (IMT Analytics) is used to confirm infant breathing parameters. Table 1 summarizes the parameters of the active lung / ventilator test.

[0151] Table 1. Active lung / ventilator test setup

[0152]

[0153] Aerodynamic particle size measurement by next generation impactor.

[0154] Next Generation Impactor (NGI) Testing According to USP <1601> The NGI was performed using NGI that had been chilled in a refrigerator at 4 to 8°C for >90 minutes prior to use and sampling at a flow rate of 15 L / min. Each NGI run used approximately 0.5 mL of AlveoFact TMDuring the test, the NGI was kept in a cooling room (maintained at 5°C) while ambient air was inhaled outside the cooling room using the AF2b device. Figures 6 to 6D The described nebulizer (without the nasal prong) was attached to the NGI sensing port using a T-piece with an adapter. The inspiratory and expiratory limbs were left open, while the open end of the T-piece was blocked. Gravimetric analysis of the NGI samples was performed according to AS00006.

[0155] Research Overview

[0156] Table 2. Test overview

[0157]

[0158] result

[0159] The results show that the aerodynamic particle size for all tested ventilator settings (low, medium and high) is comparable for all three tested nebulizers. The mass mean aerodynamic particle diameter MMAD and GSD (three nebulizers) for the low, medium and high settings are 2.3 μm and 1.5, respectively, as shown in Table 3 below.

[0160] Table 3. Summary of results

[0161]

[0162] The results further prove that Figure 26-28 The aerodynamic particle size distribution was comparable regardless of the ventilator setting for each of the nebulizers tested, showing consistent results across each CPAP setting (low, medium, high).

[0163] In addition, in Tables 4 to 6 and Figures 29 to 31 The step-wise NGI mass values ​​are shown in . The stage cut-off diameter indicates the maximum particle size that can pass through each stage of the NGI, with the mass of particles passing through each stage at each CPAP setting.

[0164] Table 4. Summary of NGI stage quality for nebulizer 189972-0046

[0165]

[0166] Table 5. Summary of NGI stage quality for nebulizer 189970-0087

[0167]

[0168] Table 6. Summary of NGI stage quality for nebulizer 189970-0071

[0169]

[0170] in conclusion

[0171] Based on the results, from AF2b PDAP TM Device generated The aerodynamic particle size of the aerosol was shown to be independent of the simulated spontaneous breathing setting. Specifically, regardless of the CPAP setting, the aerosol particles were smaller than 3 μm, more specifically, in the range between 2.0 and 2.5 μm, with a very small geometric standard deviation (GSD) of 1.5 to 1.6. The fine particle fraction of particles smaller than 3.3 μm across all CPAP settings was approximately 83%. This study further illustrates that consistent particle delivery was provided across a range of CPAP settings.

[0172] In addition, in Tables 4 to 6 and Figures 29 to 31 The stepwise NGI mass values ​​are shown in . This data demonstrates that for each impactor stage, the powder mass is consistent across various CPAP settings.

[0173] The testing also showed that the aerosol droplet size was consistent across full dose delivery at a CPAP flow rate of 6 LPM at 50 psi. The test setup is described in Table 7 below.

[0174] Table 7. DIR90-178 / 152 - Aerosol Droplet Size (Medium Nasal Congestion)

[0175]

[0176] Table 8 below shows that the MMAD produced by each nebulizer is very consistent from the beginning of the dose to the end of the maximum dose (4 bottles of 108 mg), with the MMAD for each nebulizer being below 3.0 μm (between 2.5 and 3.0 μm) and the GSD being between 1.4 and 1.5. This shows that the use of the mesh does not lead to the enlargement of the mesh, thereby ensuring that the PDAP mesh is able to generate aerosolized particles with MMAD less than about 3.0 μm under the condition of covering the life of the maximum allowed dose of the surfactant.

[0177] Table 8: NGI results for DIR90-178 / 152 aerosol droplet size

[0178]

[0179] Table 9 indicates the test parameters used to test the inhalation dose efficiency with different sized nasal prong diameters.

[0180] Table 9. DIR90-178 / 004 - Nasal plug adapter

[0181]

[0182] As shown in the results of Table 10 below, the delivered doses of various nasal plug sizes were consistent, ranging from 42% to 57% (which greatly exceeds the delivered dose of about 6% of conventional devices). The results show that the average DD for small, medium, and large nasal plugs was 51%, 45%, and 50%, respectively. This indicates that the size of the nasal plug has no significant effect on the DD.

[0183] Table 10: Delivered dose results for DIR90-178 / 004 nasal adapter testing

[0184]

[0185] 1 % Calculated

[0186] Table 11 provides the test setup used to determine the effectiveness of the nebulizer in delivering a nebulized dose in various orientations. The nebulizer was tested at 0° (infant supine), 90° (infant sideways), and 180° (infant prone), with the delivered dose measured at each orientation.

[0187] Table 11. DIR90-178 / 002 - Orientation (Medium Nasal Congestion)

[0188]

[0189] Table 12 provides the results of the orientation testing. The results show that there was no orientation effect on DD for the two dosing positions, 0° (supine) and 90° (side-lying), with mean values ​​of 69% and 70%, respectively. In the 180° (prone) position, the AF2b device was able to maintain breath-actuated nebulization for the entire 0.5 mL dose for all three devices with a mean DD of 46%. Both results indicate that the system reliably generated aerosols in all tested orientations.

[0190] Table 12: Delivered dose results for DIR90-178 / 002 directional testing

[0191]

[0192] 1 % are calculated based on a nominal 0.5 mL dose of SF-RI 1 (empirically determined to contain 25.5 mg of SF-RI 1 dry contents).

[0193] The methods, systems, and devices discussed above are examples. Some embodiments are described as processes depicted as flow charts or block diagrams. Although each may describe the operations as sequential processes, many operations may also be performed in parallel or simultaneously. In addition, the order of the operations may be rearranged. The process may have additional steps not included in the figure. Moreover, embodiments of the method may be implemented by hardware, software, firmware, middleware, microcode, hardware description language, and / or any combination thereof. When implemented in software, firmware, middleware, or microcode, program code or code segments for performing associated tasks may be stored in a machine-readable medium, such as a storage medium. A processor may perform associated tasks.

[0194] It should be noted that the systems and devices discussed above are intended to be examples only. It must be emphasized that various embodiments may omit, replace, or add various programs or components as appropriate. In addition, the features described with respect to certain embodiments may be combined in various other embodiments. Different aspects and elements of the embodiments may be combined in a similar manner. In addition, it should be emphasized that technology is developing, and therefore, many elements are examples and should not be interpreted as limiting the scope of the invention.

[0195] Specific details are given in the above description to provide a thorough understanding of the embodiments. However, it will be appreciated by those skilled in the art that embodiments may be practiced without these specific details. For example, known structures and techniques are shown without unnecessary details to avoid blurring the embodiments. This description provides only example embodiments and is not intended to limit the scope, applicability or configuration of the present invention. On the contrary, the above description of the embodiments will provide an enabling description for implementing embodiments of the present invention for those skilled in the art. Various changes may be made in the functions and arrangements of the elements without departing from the spirit and scope of the present invention.

[0196] The methods, systems, devices, figures and tables discussed above are examples. Various configurations may omit, replace or add various programs or components as appropriate. For example, in alternative configurations, the methods may be performed in a different order than described, and / or the various stages may be added, omitted and / or combined. In addition, the features described with respect to certain configurations may be combined in various other configurations. Different aspects and elements of the configurations may be combined in a similar manner. In addition, the technology is developing, and therefore many of the elements are examples and do not limit the scope of the invention or the claims. In addition, the technology discussed herein may provide different results with different types of context-aware classifiers.

[0197] Although illustrative and presently preferred embodiments of the disclosed systems, methods, and machine-readable media have been described in detail herein, it should be understood that the concepts of the present invention may be otherwise differently embodied and employed, and the appended claims are intended to be interpreted to include such variations unless limited by prior art.

[0198] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly or conventionally understood. As used herein, the articles "a" and "an" refer to one or more than one (i.e., one or at least one) of the grammatical objects of an object. As an example, "an element" can represent one element or more than one element. As used herein, "about" and / or "approximately" include changes of ±20% or ±10%, ±5% or +0.1% with the specified value when referring to measurable values, such as amount, duration in time, etc., because such changes are applicable to the background of systems, devices, circuits, methods and other embodiments described herein. As used herein, "substantially" also includes changes of ±20% or ±10%, ±5% or +0.1% with the specified value when referring to measurable values, such as amount, duration in time, physical properties (such as, frequency), etc., because such changes are applicable to the background of systems, devices, circuits, methods and other embodiments described herein. As used herein, including in the claims, "and" used in the list of items beginning with "at least one" or "one or more" indicates that any combination of the listed items can be used. For example, a list of "at least one of A, B, and C" includes any of the combinations A or B or C or AB or AC or BC and / or ABC (i.e., A and B and C). Furthermore, to the extent that items A, B, or C may appear or be used more than once, multiple uses of A, B, and / or C may form part of the contemplated combinations. For example, a list of "at least one of A, B, and C" may also include AA, AAB, AAA, BB, etc.

[0199] Several embodiments have been described, and those skilled in the art will recognize that various modifications, alternative configurations, and equivalents may be used without departing from the essence of the present invention. For example, the above elements may be merely components of a larger system, wherein other rules may take precedence over the application of the present invention or otherwise modify the application of the present invention. In addition, many steps may be taken before, during, or after considering the above elements. Accordingly, the above description should not be considered to limit the scope of the present invention.

[0200] Furthermore, when used in this specification and claims, the words “comprises,” “comprising,” “including,” and “containing” are intended to specify the presence of stated features, integers, components, or steps, but do not preclude the presence or addition of one or more other features, integers, components, steps, actions, or groups.

Claims

1. An atomization system, comprising: A respiratory system with an inspiratory limb and an expiratory limb; Atomizing device, the atomizing device comprising: an aerosol chamber having a first end and a second end; an aerosol generator positioned at said first end of said aerosol chamber, wherein: The aerosol generator includes a reservoir configured to receive a quantity of liquid medicament to be aerosolized by the aerosol generator; and The aerosol generator is configured to aerosolize the amount of the drug into particles having a mass mean aerodynamic diameter (MMAD) of less than 3 μm at a rate of at least 0.1 ml / min; a patient interface positioned adjacent the second end of the aerosol chamber; and a breathing adapter configured to couple the nebulizing system to the breathing system, the breathing adapter having an inlet and an outlet, wherein a fluid flow path is configured to deliver gas from the breathing adapter via the inlet to a location of the aerosol chamber adjacent both the first end and the aerosol generator; the respiratory adapter comprising a diverting mechanism configured to divert a portion of airflow from the respiratory system into the aerosol chamber via the inlet; and The aerosol chamber is configured to mix the portion of the airflow with the aerosolized medicament from the aerosol generator; at least one breath sensor configured to detect inhalation of the patient; and A controller configured to actuate the aerosol generator to aerosolize the quantity of medicament in synchronization with the detected inhalation.

2. The atomization system according to claim 1, wherein: The patient interface is positioned between 1 cm and 8 cm from the aerosol generator.

3. The atomization system according to claim 1, wherein: The respiratory adapter includes a diverting mechanism configured to divert a portion of airflow from the respiratory system into the aerosol chamber via at least one airway; and The aerosol chamber is configured to mix the portion of the airflow with aerosolized medicament from the aerosol generator.

4. The atomization system according to claim 3, wherein: The portion of the air flow is the respiratory flow and is less than the amount of air that continues to the expiratory limb of the respiratory system.

5. The atomization system according to claim 4, wherein: The steering mechanism includes at least one baffle defining the at least one air passage; and The at least one baffle is configured to divert the portion of the airflow into the aerosol chamber via the at least one airway and to divert an additional portion of the airflow from the inspiratory limb to the expiratory limb.

6. The atomization system according to claim 5, wherein: The at least one baffle includes a first baffle defining a first air passage and a second baffle defining a second air passage.

7. The atomization system according to claim 6, wherein: The first air channel is arranged at a side end of the first baffle; The second air channel is disposed outside a distal edge of the second baffle; and The side ends and the distal edge extend in different directions such that the respiratory flow moves past the first baffle and the second baffle in multiple directions.

8. The atomization system according to claim 1, wherein: The nebulizing device also includes a conduit configured to deliver the quantity of liquid drug from the reservoir to the aerosol generator.

9. The atomization system according to claim 8, wherein: The aerosol generator includes a mesh configured to generate aerosol particles; The distal-most tip of the catheter has a diameter; and The distal-most tip of the catheter is positioned at a distance from the mesh that is less than or equal to the diameter.

10. The atomization system according to claim 1, wherein: Synchronizing the aerosolizing of the amount of medication includes aerosolizing a portion of the amount of medication within at least a portion of the first 50%-80% of each of the consecutive multiple inhalations so that chase air is provided within at least a portion of the last 20% of each of the consecutive multiple inhalations.

11. The atomization system according to claim 1, wherein: The at least one respiratory sensor includes a respiratory sensor capsule that interfaces with the patient's abdomen.

12. The atomization system of claim 1, wherein: The controller is removable from the atomizing device.

13. The atomization system of claim 1, wherein: The atomizing device is configured to atomize and deliver aerosolized particles of the medicament when the patient interface is oriented in each of a downward position, a sideways position, and an upward position.

14. The atomization system according to claim 1, further comprising: A supply line is configured to supply the quantity of drug from a source to the reservoir.

15. The atomization system of claim 1, wherein: The patient interface comprises nasal prongs or a nasal mask.

16. The atomization system of claim 1, wherein: The drug includes a surfactant.

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