Designing an aerosol system and interface to deliver a clinically and economically feasible inhaled dose in neonatal CPAP devices

Abstract

A method for delivering an aerosolized medication to an infant comprises connecting an aerosolization device to the infant's airway and using the aerosolization device to aerosolize a quantity of surfactant into particles having a mass median aerodynamic diameter (MMAD) of less than about 3 μm at a flow rate of at least 0.1 ml / min. The surfactant is aerosolized within about 1-8 cm of the patient interface. Aerosols are generated with up to about 80% or each inspiration. The method also includes delivering the aerosolized surfactant to the infant's airway.

Description

[Technical Field]

[0001] The present invention relates to the design of an aerosol system and interface for delivering a clinically and economically feasible inhaled dose in a neonatal CPAP device. [Background technology]

[0002] The delivery of surfactants to infants, especially premature infants, is invasive and often causes acute side effects, so it would be desirable to be able to deliver surfactants non-invasively. Summary of the Invention [Problem to be solved by the invention]

[0003] However, it is difficult to effectively and efficiently deliver surfactants using conventional noninvasive methods. For example, conventional methods often deliver aerosolized drug continuously, meaning that the drug is aerosolized between patient breaths, making them highly inefficient. Furthermore, conventional methods often produce aerosols with particle sizes larger than desired for pulmonary delivery (typically about 4-7 μm mass median aerodynamic diameter (MMAD)) because it is difficult to generate small aerosolized surfactant particles at sufficiently high output flow rates to make pulmonary delivery feasible. Embodiments of the present invention solve these and other problems. [Means for solving the problem]

[0004] Embodiments of the present invention provide aerosolization systems and methods for delivering medication to infants, particularly premature infants. In some embodiments, methods are provided for effectively and efficiently delivering medication to an infant's nostrils. In some embodiments, fine aerosol droplets of medication are provided that can penetrate the lungs. In some embodiments, significantly higher medication delivery efficiencies are achieved than conventional non-invasive methods.

[0005] In one embodiment, a method of delivering aerosolized medication to an infant is provided. The method comprises connecting an aerosolization device to the infant's airways and using the aerosolization device to aerosolize a dose of medication into particles having a mass median aerodynamic diameter (MMAD) of less than about 3 μm at a flow rate of at least 0.1 ml / min. The medication may be aerosolized within about 2-8 cm of the patient interface. The method may also include delivering the aerosolized medication to the infant's airways.

[0006] In another embodiment, an aerosolization system is provided. The aerosolization system includes an aerosolization device having an aerosol generator disposed at a first end of an aerosol chamber. The aerosol generator has a reservoir configured to receive a quantity of liquid surfactant to be aerosolized by the aerosol generator. The aerosol generator is configured to aerosolize the quantity of liquid medicament into particles having a mass median aerodynamic diameter (MMAD) of less than about 3 μm at a flow rate of at least 0.1 ml / min. The aerosolization device includes a patient interface disposed within about 2 cm and 8 cm of the aerosol generator, and a respiratory adapter configured to connect the aerosolization system to a respiratory system having an inspiratory limb and an expiratory limb. The respiratory adapter includes at least one barrier defining at least one airway communicating with the aerosol chamber. The at least one barrier is configured to divert a first portion of the airflow from the inspiratory limb to the expiratory limb and to divert a second portion of the airflow to the aerosol chamber via the at least one airway. The second portion of the airflow is a respiratory flow and is smaller than the first portion. The aerosol chamber may be configured to mix the respiratory flow with the aerosolized medicament from the aerosolization device. In some embodiments, the aerosolization system includes at least one respiratory sensor configured to detect the infant's inspiration and a controller configured to synchronize the aerosolization of the quantity of surfactant with the detected inspiration.

[0007] In one embodiment, an aerosolization system is provided. The system includes a respiratory system having an inspiratory limb and an expiratory limb. The system also includes an aerosolization device having an aerosol chamber having a first end and a second end, and an aerosol generator disposed at the first end of the aerosol chamber. The aerosol generator has a reservoir configured to receive a quantity of liquid medicament to be aerosolized by the aerosol generator. The aerosol generator is configured to aerosolize the quantity of medicament into particles having a mass median aerodynamic diameter (MMAD) of less than about 3 μm at a flow rate of at least 0.1 ml / min. The aerosolization device may include a patient interface disposed near the second end of the aerosol chamber and a respiratory adapter configured to couple the aerosolization system to the respiratory system. The system also includes at least one respiratory sensor configured to detect a patient's inspiration and a controller configured to operate the aerosol generator to aerosolize the quantity of medicament in synchronization with the detected inspiration.

[0008] In some embodiments, the patient interface is positioned within approximately 1-8 cm of the aerosol generator. In some embodiments, the respiratory adapter includes a flow diverting 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 aerosolized medicament provided by the aerosol generator. In some embodiments, the portion of the airflow is a respiratory flow, less than the amount of air that continues to the expiratory limb of the respiratory system. In some embodiments, the flow diverting mechanism includes at least one barrier defining the at least one airway. The at least one barrier may be configured to divert a portion of the airflow to the aerosol chamber via the at least one airway and to divert another portion of the airflow from the inspiratory limb toward the expiratory limb. In some embodiments, the at least one barrier includes a first barrier defining a first airway and a second barrier defining a second airway. In some embodiments, a first airway is located at a lateral end of the first barrier and a second airway is located beyond the distal edge of the second barrier, the lateral end and distal edge extending in different directions from one another so that respiratory flow travels in multiple directions past the first and second barriers.

[0009] In some embodiments, the system further comprises a conduit configured to deliver the quantity of liquid medicament from the reservoir to the aerosol generator. In some embodiments, the tip of the conduit has a diameter, and the tip of the conduit is positioned a distance equal to or less than the diameter from the mesh. In some embodiments, synchronizing the aerosolization of the quantity of medicament comprises aerosolizing a portion of the quantity of medicament during at least a portion of the first 50-80% of each of a plurality of consecutive inspirations, such that purge air is provided during at least a portion of the last 20% of each of the plurality of consecutive inspirations. In some embodiments, at least the respiratory sensor comprises a respiratory sensor capsule connected to the patient's abdomen. In some embodiments, the controller is detachable from the aerosolization device. In some embodiments, the aerosolization device is configured to aerosolize and deliver aerosolized particles of medicament when the patient interface is oriented in each of the face-down, side-lying, and face-up positions. In some embodiments, the system further comprises a supply line configured to deliver the quantity of medicament from a supply source to the reservoir. In some embodiments, the patient interface comprises nasal prongs or a nasal mask. In some embodiments, the agent comprises a surfactant.

[0010] In another embodiment, a method of delivering aerosolized medication to an infant is provided. The method comprises detecting an inhalation of the infant using one or more breath sensors, and, based on the detected inhalation, aerosolizing a quantity of medication with an aerosolization device into particles having a mass median aerodynamic diameter (MMAD) of less than about 3 μm at a flow rate of at least 0.1 ml / min. The medication is aerosolized within about 1-8 cm of the patient interface.

[0011] In some embodiments, aerosolizing the quantity of medicament includes delivering the quantity of medicament from a reservoir to a mesh of an aerosolization device and vibrating the mesh to aerosolize the quantity of medicament. In some embodiments, the quantity of medicament is delivered from the reservoir to the mesh through a conduit with a tip having a diameter. The tip of the conduit may be positioned a distance from the mesh that is equal to or less than the diameter. In some embodiments, aerosolizing the quantity of medicament includes aerosolizing a portion of the quantity of medicament in at least a portion of the first 80% of each of a plurality of consecutive inspirations, such that purge air is provided in at least a portion of the last 20% of each of a plurality of consecutive inspirations. In some embodiments, the one or more respiratory sensors include a respiratory sensor capsule connected to the patient's abdomen. In some embodiments, the method further includes delivering the aerosolized medicament to the infant's airway via a patient interface. In some embodiments, the patient interface includes nasal prongs or a nasal mask.

[0012] In some embodiments, the method includes connecting an aerosolization device to a respiratory system and diverting a portion of an airflow from the respiratory system to a chamber of the aerosolization device via at least one airway. The chamber is configured to mix the portion of the airflow with the aerosolized medicament. In some embodiments, the portion of the airflow is a respiratory flow, and is less than the amount of air that continues to the expiratory limb of the respiratory system. In some embodiments, the portion of the airflow is diverted using at least one barrier defining at least one airway. The at least one barrier is configured to divert a portion of the airflow to the aerosol chamber via the at least one airway and to divert another portion of the airflow from the inspiratory limb toward the expiratory limb. In some embodiments, the at least one barrier includes a first barrier defining a first airway and a second barrier defining a second airway. In some embodiments, a first airway is located at a lateral end of the first barrier and a second airway is located beyond the distal edge of the second barrier, the lateral end and distal edge extending in different directions from one another so that respiratory flow travels in multiple directions past the first and second barriers.

[0013] In another embodiment, a method for initializing an aerosolization system is provided. The method includes connecting the aerosolization device to a controller, a respiratory sensor, a medication source, and a respiratory system, entering user access credentials into the controller, and entering patient-related information and medication information into the controller. The method also includes connecting the respiratory sensor to the patient, priming the aerosolization device, and connecting a patient interface to the patient's airway.

[0014] In some embodiments, the method further includes executing a wake-up sequence that cycles through multiple audio alarms, visual alarms, or both audio and video alarms. In some embodiments, the access authentication includes one or more of a user identifier, a password, property authentication, and biometric authentication. In some embodiments, the respiratory sensor is adhered to the patient's abdomen. In some embodiments, the method further includes confirming breath detection after connecting the respiratory sensor to the patient. In some embodiments, the drug source includes a vented vial access device (VVAD) coupled to a fluid supply line. In some embodiments, connecting the aerosolization device to the controller, the respiratory sensor, the drug source, and the respiratory system includes connecting a fluid supply line between the drug source and the aerosolization device. In some embodiments, priming the aerosolization device includes aerosolizing a portion of the drug before connecting the patient interface to the patient's airway. In some embodiments, the method further includes coupling the patient interface to the aerosolization device. In some embodiments, the patient interface is secured to the patient via one or both of at least one strap and a foam pad configured to rest on the patient's head. In some embodiments, the method includes delivering an aerosolized dose of medication to the patient via a patient interface. In some embodiments, the method further includes verifying that the timing of delivery of the dose is synchronized with the detected inspiration. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 is an isometric view of an aerosolization device according to an embodiment. [Figure 1A] FIG. 2 is a cross-sectional view of the aerosolization device of FIG. 1. [Figure 2] FIG. 2 illustrates the flow pattern through the aerosolization device of FIG. 1. [Figure 3] FIG. 1 is an isometric view of an aerosolization device according to an embodiment. [Figure 3A] FIG. 4 is a cross-sectional view of the aerosolization device of FIG. 3. [Figure 4A] FIG. 4 illustrates the flow pattern through the aerosolization device of FIG. 3. [Figure 4B] FIG. 4 illustrates the flow pattern through the aerosolization device of FIG. 3. [Figure 5A] 4 illustrates the flow pattern from a low-flow breathing system through the aerosolization device of FIG. 3. [Figure 5B] 4 illustrates the flow pattern from a low-flow breathing system through the aerosolization device of FIG. 3. [Figure 6] FIG. 1 is an isometric view of an aerosolization device according to an embodiment. [Figure 6A] 7 is a cross-sectional view of the aerosolization device of FIG. 6. [Figure 6B] 7 is a cross-sectional view of the aerosolization device of FIG. 6. [Figure 6C] 7 is a cross-sectional view of the aerosolization device of FIG. 6. [Figure 6D] FIG. 7 illustrates the flow pattern through the aerosolization device of FIG. 6. [Figure 7] 7 shows the aerosolization device of FIG. 6 connected to a fluid supply line and a breathing system. [Figure 8] FIG. 1 shows an aerosolization device connected to a drug supply source. [Figure 9] 9 shows the aerosolization device of FIG. 8 connected to a drug source and a control device. [Figure 10] FIG. 10 is a diagram showing the control device of FIG. 9. [Figure 11] FIG. 10 is a diagram showing a vial holder of the control device of FIG. 9. [Figure 12] FIG. 10 is a diagram showing the drug supply source of FIG. 9. [Figure 13] FIG. 10 is a diagram showing the functions of the control device in FIG. 9. [Figure 14A] FIG. 14 illustrates a process for using the aerosolization system of FIGS. [Figure 14B] FIG. 14 illustrates a process for using the aerosolization system of FIGS. [Figure 14C] FIG. 14 illustrates a process for using the aerosolization system of FIGS. [Figure 14D] FIG. 14 illustrates a process for using the aerosolization system of FIGS. [Figure 14E] FIG. 14 illustrates a process for using the aerosolization system of FIGS. [Figure 14F] FIG. 14 illustrates a process for using the aerosolization system of FIGS. [Figure 14G] FIG. 14 illustrates a process for using the aerosolization system of FIGS. [Figure 14H] FIG. 14 illustrates a process for using the aerosolization system of FIGS. [Figure 14I] FIG. 14 illustrates a process for using the aerosolization system of FIGS. [Figure 15] 1 illustrates an aerosolization device according to an embodiment connected to an infant. [Figure 16] FIG. 1 shows a respiratory sensor capsule connected to an infant's abdomen. [Figure 17] 1 illustrates an aerosolization system for delivering surfactant to an infant, according to an embodiment. [Figure 18] 1 is a flow chart illustrating a process for delivering aerosolized medication to a patient. [Figure 19] 1 is a flow chart illustrating a process for initializing an aerosolization system. [Figure 20] 10 is a bar graph illustrating emitted dose rates using an aerosolization system according to an embodiment. [Figure 21] 10 is a bar graph showing emitted dose rate as a function of respiratory rate and flow rate using an aerosolization system according to an embodiment. [Figure 22] Graph showing deposition rate and particle size. [Figure 23] Graph showing deposition rate and particle size. [Figure 24] Graph showing the effectiveness of inspiration detection using a flow sensor and a breath sensor capsule. [Figure 25] A graph from one study showing survival rates without surfactant injection. [Figure 26]A graph showing the particle size distribution of impactors from one study. [Figure 27] A graph showing the particle size distribution of impactors from one study. [Figure 28] A graph showing the particle size distribution of impactors from one study. [Figure 29] Graph showing powder mass distribution at different CPAP settings from one study. [Figure 30] Graph showing powder mass distribution at different CPAP settings from one study. [Figure 31] Graph showing powder mass distribution at different CPAP settings from one study. DETAILED DESCRIPTION OF THE INVENTION

[0016] The following description of the embodiments is not intended to limit the scope, applicability, or configuration of the present disclosure. The description of the embodiments is intended to provide those skilled in the art with an enabling description for practicing the embodiments. Various changes may be made in the function and arrangement of elements without departing from the spirit and scope of the present disclosure.

[0017] In an aerosolization system and method according to embodiments of the present invention, aerosolized medication and respiratory gas are mixed in an aerosolization chamber isolated from the direct respiratory flow, such that a small portion of the respiratory gas enters the aerosolization chamber, while the majority of the respiratory flow bypasses the aerosolization chamber and passes through the expiratory limb of the respiratory system. This design maintains a consistent medication delivery rate regardless of the flow rate from the respiratory system. Furthermore, embodiments of the present invention provide a retrofit aerosolization configuration that can be interfaced with existing respiratory systems and adapted to deliver a stable dose of aerosolized medication to the patient's airway. The aerosolization systems described herein are also configured to include one or more respiratory sensors, such as one or more flow sensors (e.g., electrical flow sensors), radar sensors (e.g., ultra-wideband (UWB) radar sensors measuring chest displacement), CO2 sensors, high-speed temperature sensors, acoustic sensors, impedance plethysmography sensors, respiratory inductance plethysmography sensors, and pressure sensors, to enable the controller to predict patient inspiration. This allows medication aerosolization to occur during or immediately prior to patient inspiration.

[0018] In embodiments of the present invention, an aerosolization system is provided that isolates the aerosolized medication from the main respiratory gas flow to avoid loss or dilution of the aerosol generated during the inspiratory phase. Such isolation can be achieved by using barriers and / or other walls designed to redirect the main flow from the inlet to the outlet rather than forcing the gas through the patient interface.

[0019] Embodiments of the present invention also generate and deliver surfactant aerosol only during the inspiratory cycle (inhalation). Commonly used devices administer aerosol continuously. However, because infants can only inhale aerosol during inspiration, aerosol bypasses the airways during exhalation (up to two-thirds of the breathing cycle) and is lost or wasted. By limiting aerosol generation to only during inspiration and delivering the aerosol near the nostrils, the highest percentage of surfactant is deposited in the lungs.

[0020] Embodiments of the present invention also generate aerosol near the patient interface to increase the amount of aerosol delivered to the patient. Conventional nebulizers are placed in a single location on the inspiratory tube of a ventilator or nCPAP circuit and generate aerosol in the continuous gas flow. As a result, the aerosol is significantly diluted during delivery and is lost in the continuous gas flow, which typically has a higher flow rate than the subject's inspiratory flow. In contrast, the aerosolization device of the present invention generates aerosol directly toward the patient interface (e.g., nasal prongs), diverting a significant portion of the gas flow from the nCPAP circuit away from the nebulized aerosol, thereby significantly reducing aerosol loss in the circuit's continuous gas flow. Embodiments also enable shorter administration times by using an aerosol generator that emits aerosol surfactant at flow rates of 0.3 mL / min or more for undiluted surfactant, exceeding flow rates previously observed with other mesh nebulizers. While surfactant delivery is primarily described, other types of drugs may be utilized with the aerosolization system of the present invention to deliver aerosolized drugs to the patient's lungs.

[0021] In some embodiments, the aerosolization systems described herein include a reusable device controller and a disposable aerosolization device with drug delivery circuitry and / or a breath sensor for single-use with a single patient. Such aerosolization devices function as stand-alone drug delivery devices integrated into various respiratory devices (e.g., CPAP devices) and, in some embodiments, are not designed to connect to a hospital network or the Internet. For example, the controller may be a reusable component for use with multiple patients, including a flat-panel touchscreen display, electronics, and software. For example, the controller's three primary functions are detecting inspiration via a breath sensor placed on the patient's abdomen (e.g., designed for single-patient use only), delivering suspension to the aerosolization device via an integrated delivery mechanism, and generating aerosol during inspiration toward the nCPAP interface. These functions may be performed in synchronization with the infant's inspiration cycle. The flat-panel touchscreen is configured to allow the user to configure and monitor delivery parameters, alarms, and system diagnostics using a graphical user interface (GUI). The controller may also incorporate visual and audible alarms. The pod may be used to communicate a signal from the breath sensor to a controller to synchronize the generation of the aerosol with the detected breath. The medication source reservoir may be a medicine vial containing the medication.

[0022] In some embodiments, a disposable aerosolization device for single-use per patient includes a vented vial access device (VVAD) that allows easy access to the drug reservoir and is provided to the user in an individual package, and a drug supply tube. The drug supply tube has a luer connector (connected to the VVAD) and a tube that delivers the drug suspension from the luer to the aerosol generator of the aerosolization device. The aerosol generator of the aerosolization device may also include a customized PDAP (photo-defined perforated plate) vibrating mesh that is distinguished by its small droplet size and high output flow rate. The PDAP mesh has an innovative structure that contains up to 20 times more pores with smaller diameters than conventional meshes. The aerosol generator is designed to deliver aerosol near an infant's airway and to be connected to a conventional nCPAP system.

[0023] The reusable control unit features a built-in touchscreen with a processor that monitors delivery parameters, alarms (visual and audible), and system diagnostics. The control unit and pod work in conjunction via a breath sensor, one end of which is attached to the infant's abdomen and the other end of which is connected to the pod. The control unit activates a drug delivery mechanism that delivers medication to the nebulizer, synchronizing aerosol generation with the infant's inspiratory cycle.

[0024] The lyophilized surfactant is reconstituted in its original glass vial to form a saline / surfactant suspension. The vial is connected to a drug delivery circuit, including a drug delivery tube, via a vented vial access device. The vented vial access device pierces the vial's septum, allowing air to enter the vial and uniformly emptying the suspension. An integrated volumetric drug delivery mechanism delivers the surfactant suspension through the drug delivery tube to a unique vibrating mesh nebulizer integrated into the drug delivery circuit interface. The interface uses nasal prongs. The interface is connected to the infant's clinical nCPAP circuit and placed on the infant, replacing the previously placed interface. The aerosol is then delivered in synchronization with the infant's inspiration, in response to a respiratory sensor.

[0025] Although primarily described with respect to surfactants, the methods and devices of the present disclosure can be used with any liquid medication, including, but not limited to, bronchodilators, anti-infectives, anti-virals, anti-inflammatory mucokinetics, siRNA, PFOB, and the like, which can be used in accordance with the present disclosure.

[0026] FIG. 1 illustrates one embodiment of an aerosolization system. An aerosolization device 100 is disposed on a first side of an aerosol chamber 102, and a patient interface 104 is disposed on an opposite, second side of the aerosolization chamber 102. The aerosolization device 100 is a nebulizer or any other device configured to aerosolize a dose of a liquid medicament. Such devices are described in U.S. Pat. Nos. 5,758,637, 6,235,177, 2015 / 0336115, and 2016 / 0130715, the entire contents of which are incorporated herein by reference. The aerosolization device 100 includes a reservoir configured to receive and / or contain a quantity of a liquid medicament to be aerosolized. In some embodiments, the reservoir is a "virtual reservoir" in the form of a conduit extending to connect a fluid supply line to the mesh of the aerosolization device 100. For example, the conduit is sized to accommodate only about 10-15 mcl, which accumulates within the conduit between each aerosolization step. The primary containment may be in the form of a vial containing medication, and the medication is delivered to the mesh through the conduit or virtual containment with each breath via a delivery mechanism and delivery line. In some embodiments, the patient interface is a nasal prong, an endotracheal tube, a nasal cannula / mask, a tracheostomy tube, or the like.

[0027] The system includes a respiratory adapter 106 configured to interface with a respiratory system, such as a ventilator, a humidifier, a CPAP (Continuous Positive Airway Pressure) machine, an nCPAP system, and / or a combination thereof. For example, the respiratory adapter 106 includes an inlet 108, such as an inlet barrier, configured to couple to the inspiratory limb of the respiratory system. For example, the inlet 108 is an inlet barrier configured to interface with a Flexitrunk® midline interface manufactured by Fisher & Paykel Healthcare and direct respiratory flow toward the aerosolization chamber 102. The inlet 108 is coupled to the aerosol chamber 102, for example, via a fluid pathway 110. In some embodiments, the inlet 108 is designed to redirect gases from the respiratory system to the aerosolization chamber without increasing resistance or work of breathing for the patient. This is accomplished by providing a fluid pathway 110 with a cross-sectional area that is approximately 80% or greater than the inner cross-sectional diameter of the patient interface 104.

[0028] FIG. 1A shows a cross-sectional view of the aerosolization system of FIG. 1. As shown, the aerosol generator 112 of the aerosolization device 100 is positioned at a first end of the aerosol chamber 102 so that the aerosolized medication is introduced into the aerosolization chamber 102. The aerosol generator 112 has a mesh configured to generate aerosol particles. Conventional aerosol devices typically generate aerosols with an average droplet diameter in the range of 4 to 5 microns. However, to deliver medication through the nostrils through the narrow airways of premature infants, aerosol droplets generally need to be less than 3 microns in diameter. Aerosol droplets larger than this diameter are likely to deposit in the nostrils and delivery tubes. If the droplets are significantly smaller than 1 micron, they may not deposit in the lungs and may be exhaled, resulting in reduced pulmonary delivery efficiency. Embodiments of the present invention use a mesh pore size designed to generate droplets with an average diameter between 2 and 3 microns. For example, in some embodiments, the aerosol generator 112 comprises a PDAP (photoformed perforated plate) mesh configured to generate small aerosol particles, such as particles less than 3 μm in diameter. Such a mesh is disclosed in the aforementioned U.S. Patent Publication No. 2016 / 0130715. By locating the aerosol generator 112 near the patient interface 104, aerosolized medicament released during the inspiratory cycle is preferentially inhaled, minimizing disruption of the continuous or bias flow through the respiratory system circuit. In the illustrated aerosol chamber 102, the first end is smaller than the second end. The barrier defining the inlet 108 is designed to draw a portion of the respiratory flow from the inspiratory limb of the respiratory system into the aerosol chamber 102 near the first end via a fluid pathway 110. The fluid pathway 110 is connected to the inspiratory limb at a junction between the inspiratory limb and the inlet 108 at an angle of 90 degrees or less relative to the respiratory flow within the limb and / or the upstream side of the inspiratory limb. Such an arrangement allows the aerosolization chamber to be isolated from the direct respiratory flow, e.g., the respiratory flow is introduced intermittently into the aerosol chamber 102 only when the patient inhales.

[0029] Figure 2 illustrates the flow pattern through the aerosolization system. It shows the inspiratory limb 200 of the breathing system, which provides the respiratory airflow. A portion of this respiratory airflow is drawn into the inlet 108 and introduced into the aerosol chamber 102 and patient interface 104 via fluid path 110. For example, when the patient inhales, a volume of respiratory airflow is drawn in via fluid path 110 because the inspiration creates negative pressure within the aerosolization chamber. Excess respiratory airflow and / or exhaled gas is exhausted through the expiratory limb 202 of the breathing system.

[0030] 1, 1A, and 2 can increase and stabilize the inhaled dose compared to conventional aerosolization systems across the range of gas flow rates used in various nCPAP systems. For example, the aerosolization systems described herein increase the inhaled dose in high-flow nCPAP systems (greater than 6 L / min) from about 6% (conventional systems) to about 40-50%, with reduced variability compared to low-flow systems (0.5 L / min) that also achieve about 40-50% inhaled dose.

[0031] FIG. 3 illustrates another embodiment of an aerosolization device for delivering a stable dose of aerosolized medication to a patient. The aerosolization device includes an aerosol generator 300 disposed at a first end of an aerosol chamber 302, with a patient interface 304 disposed at the opposite, second end of the aerosol chamber 302. The aerosol generator 300 may be a nebulizer having a vibrating mesh that can be selectively vibrated using a piezoelectric actuator. In some embodiments, the aerosol generator 300 includes a reservoir configured to receive and / or contain a quantity of liquid medication to be aerosolized. The aerosol generator 300 is coupled to a medication supply line 306 configured to deliver the quantity of liquid medication to the reservoir, such as via a pump (not shown). The aerosolization device may include a cable 308 connected to a power source, although in some embodiments, the aerosolization device is battery-powered.

[0032] In some embodiments, the aerosolization device has an inlet 310 and an outlet 312 that are coupled to the inspiratory and expiratory limbs, respectively, of a respiratory system. Examples of usable respiratory systems include, but are not limited to, a ventilator, a humidifier, a CPAP device, and / or combinations thereof. In some embodiments, the inlet 310 and the outlet 312 are a single unit that forms a respiratory gas flow path, while in other embodiments, the inlet 310 and the outlet 312 are separate components coupled to each other. The inlet 310 and / or the outlet 312 are configured to receive the ends of gas conduits of the respiratory system. For example, the airflow barriers at the inlet and / or outlet correspond to the one-way circuit of a standard nCPAP circuit. Therefore, the barriers can minimize interruption of the airflow from the inlet to the outlet, thereby reducing turbulence within the aerosol chamber 302.

[0033] 3A , the aerosolization device also includes a fluid flow path 314 connecting the aerosol chamber 302 to the inlet 310 and / or outlet 312. As shown, the fluid flow path 314 delivers respiratory gas to an upper portion of the aerosol chamber 302 near the aerosol generator 300, although in some embodiments, the fluid flow path 314 may deliver the respiratory gas to another location, such as an interior portion of the aerosol chamber 302 and / or a portion closer to the patient interface 304. The fluid flow path 314 intersects the inlet 310 and / or outlet 312 upstream of the inlet 310 and / or outlet 312 and / or at an angle of no more than 90 degrees relative to the flow path formed within the inlet 310 and / or outlet 312. That is, the gas fluid flow path 314 extends perpendicular to the inlet 310 and / or outlet 312 or in a direction at least partially opposite the flow of air through the inlet 310 and / or outlet 312. Locating fluid flow path 314 in this manner allows aerosol chamber 302 to be isolated from the continuous flow of respiratory gases that flows from inlet 310 (inspiratory limb) to outlet 312 (expiratory limb). This results in several benefits. First, isolating aerosol chamber 302 from the continuous flow prevents aerosolized medication from being "swept away" or diluted by the gas flow. Second, isolation allows aerosol chamber 302 to be pre-loaded with aerosolized medication immediately prior to a respiratory event, while also preserving any remaining medication from a previous breath.

[0034] In some embodiments, a portion of the respiratory gas is drawn through the fluid flow path 314 into the aerosol chamber 302 for mixing with the aerosolized medication. The portion of the respiratory gas drawn into the aerosol chamber 302 is drawn by the negative pressure created by the patient's inspiration at the patient interface 304.

[0035] The aerosol chamber 302 has an internal geometry suitable for delivering nebulized material to the patient interface 304 while minimizing shock. Specifically, the aerosol chamber 302 is designed so that the aerosol generator 300 is positioned opposite the patient interface 304. Furthermore, the aerosol chamber 302 is designed with a generally funnel-shaped profile, tapering (linearly or non-linearly) from a wide portion to a narrow portion near the patient interface 304, thereby reducing shock to the aerosol exiting the aerosol generator 300. Such a design also allows for a compact aerosol chamber 302.

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

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

[0038] 6-6D illustrate another embodiment of an aerosolization device 600. Similar to those described above, an aerosol generator 612 (FIGS. 6A-6D) is disposed on a first side of an aerosol chamber 602, and a patient interface 604 is disposed on an opposite, second side of the aerosol chamber 602. The aerosol generator 612 includes a reservoir configured to receive and / or contain a quantity of liquid medicament to be aerosolized. For example, in some embodiments, the aerosolization device 600 includes at least one drug supply port 614 configured to couple with a drug supply line (not shown) used to deliver the liquid medicament to the aerosol generator 612 (e.g., the reservoir, if present). In some embodiments, the reservoir is formed as an elongated conduit extending between the drug supply port 614 and the aerosol generator 612. In some embodiments, the patient interface 604 is a nasal prong, an endotracheal tube, a nasal cannula / mask, a tracheostomy tube, or the like. Aerosolization device 600 also has at least one power connection 640. As shown, power connection 640 is a port that allows a power cable to be connected to aerosolization device 600 to provide power and / or control commands to aerosol generator 612.

[0039] The device includes a respiratory adapter 606 configured to interface with a respiratory system, such as a ventilator, a humidifier, a CPAP (Continuous Positive Airway Pressure) machine, an nCPAP system, and / or a combination thereof. For example, the respiratory adapter 606 includes an inlet 608, such as an inlet barrier, configured to couple to an inspiratory limb 650 of the respiratory system. The respiratory adapter 606 also includes an outlet 616, such as an outlet barrier, configured to connect to an expiratory limb 652 of the respiratory system. For example, as shown, the inlet 608 and / or outlet 616 are configured to be inserted into and retained (e.g., by a friction fit and / or other securing mechanism) within the conduits of the inspiratory limb 650 and expiratory limb 652, respectively. In other embodiments, the inlet 608 and / or outlet 616 are configured to be larger than the conduits of the respiratory system, such that the conduits of the inspiratory limb 650 and / or expiratory limb 652 can be inserted into and retained (e.g., by a friction fit or other securing mechanism) within the inlet 608 and outlet 616, respectively. Other techniques for connecting the inlet 608 and / or outlet 616 to the breathing system may be used, and the inlet 608 and outlet 616 do not have to be connected using the same technique.

[0040] FIG. 6A shows a cross-sectional view of the aerosolization system of FIG. 6. As shown, the aerosol generator 612 of the aerosolization device 600 is disposed at a first end 618 of the aerosolization chamber 602 so that the aerosolized drug is introduced into the aerosol chamber 602. For example, the drug is delivered to the aerosol generator 612 via a drug supply port 614 that is in communication with the reservoir. In some embodiments, the reservoir is a "virtual reservoir" in the form of a conduit 632 that delivers the drug to the surface of the aerosol generator 612. The virtual reservoir, conduit 632, is connected to a drug source, such as a vial, via a fluid line connected to the drug supply port 614. The diameter of the distal-most tip 634 of the conduit 632 is equal to or less than the distance between the tip 634 and the proximal surface of the mesh of the aerosol generator 612. These dimensions ensure that droplets of liquid medicament expelled from tip 634 are large enough to contact and move against the mesh of aerosol generator 612. Surface tension ensures that the liquid remains on the surface of the mesh and spreads, resulting in total or near-total aerosolization of the liquid. This allows aerosolization device 600 to operate in any orientation, allowing treatment of patients (e.g., infants) while lying on their side, back, or stomach. For example, in some embodiments, the tip of drug delivery port 614 is positioned approximately 5-40 microns from the surface of aerosol generator 612, and tip 364 has a diameter equal to or less than this distance. As shown, aerosol generator 612 is positioned adjacent to patient interface 604, with aerosol chamber 602 being the only component positioned between aerosol generator 612 and patient interface 604. By locating the aerosol generator 612 in this proximity to the patient interface 604, aerosolized medication released during the inspiratory cycle is preferentially inhaled, minimizing disruption of the continuous or bias flow through the breathing system circuit. The aerosol chamber 602 is shaped so that the first end 618 is smaller than the second end 620, thereby reducing impact on the aerosol exiting the aerosolization device 600.

[0041] The inlet 608 is formed by a barrier configured to draw a portion of the respiratory flow from the inspiratory rim 650 of the respiratory system near the first end through a fluid pathway into the aerosol chamber 602. The fluid pathways are described in more detail below with reference to FIGS. 6B and 6C. In some embodiments, the inlet 608 is designed to redirect gases from the respiratory system into the aerosol chamber 602 without substantially increasing, or at least not significantly increasing, the patient's resistance or work of breathing (e.g., inspiratory pressure). This is achieved by providing a fluid pathway within the respiratory adapter 606 with multiple barriers. These barriers direct a portion of the air flowing from the inspiratory rim (only that needed for inspiration) into the aerosol chamber 602 while significantly reducing turbulence in the airflow drawn into the aerosolization device 600. This results in a more laminar flow within the aerosol chamber 602.

[0042] 6B and 6C show the aerosolization device 600 in two separate pieces. While depicted as two separable components, the aerosolization device 600 may be comprised of any number of components connected to each other (e.g., connected by connecting / engaging features, etc.). Alternatively, the aerosolization device 600 may be comprised of a single component formed by molding, 3D printing, and / or other known or unknown manufacturing techniques. As shown in FIG. 6B, the portion of the aerosolization device 600 containing the fluid path includes multiple barriers. In the illustrated embodiment, the aerosolization device 600 includes a first barrier 622 that directs a large amount of flow from the inhalation rim 650 to the exhalation rim 652 while allowing a portion of the flow from the inhalation rim 650 to enter the aerosol chamber 602. For example, the barrier 622 is generally U-shaped and open at one or both ends to form a vent path 624 between the barrier 622 and the sidewall of the housing of the aerosolization device 600. The air passage 624 allows a small amount of air to pass over the edge of the barrier 622, while the main body of the barrier 622 is configured to prevent any other air from passing through the barrier 622, instead directing the air towards the exhalation rim 652. While a U-shaped barrier 622 is used in this embodiment, other shapes may be used to suit a particular application.

[0043] The aerosolization device 602 includes a second barrier 626 positioned near the barrier 622. As shown, the second barrier 626 is a generally U-shaped wall oriented in the opposite direction from the barrier 622 (although the second barrier 626 may be configured in other shapes and orientations, such as a generally straight second barrier 622 extending across the entire width of the interior of the aerosolization device 600, or a curved second barrier 626 oriented in the same direction as the barrier 622). In some embodiments, the first barrier 622 and the second barrier 626 are formed as a single member, e.g., sharing an interior portion, while in other embodiments, separate barriers are provided. As shown, the second barrier 626 extends to both side walls of the housing, but a gap is provided between the leading edge of the second barrier 626 and the top of the housing of the aerosolization device 602, providing a path for air to enter the aerosolization chamber 602. Thus, as shown, when the patient inhales through the patient interface 604, a portion of the gas delivered by the inhalation rim 650 is drawn through the air passages 624 at one or more ends of the barrier 622. The drawn air is forced upward and flows over the second barrier 624, creating a generally laminar flow within the aerosol chamber 602. However, in some embodiments, rather than directing the airflow toward the top of the housing, the second barrier 626 is configured to direct the air toward the bottom of the housing or toward a central opening formed between the upper and lower barriers. Any number of barrier and / or flow diverting mechanisms (including valves) can be used to isolate the aerosol chamber 602 from the direct flow of respiratory gas from the breathing system while still allowing some flow of respiratory gas during patient inspiration.

[0044] FIG. 6C shows another portion of the aerosolization device 600 connected to the first portion. This portion of the aerosolization device 600 forms a seat 628 for receiving the aerosol generator 612, the drug delivery port 614, and / or other associated components. An engagement feature 630 is also provided to receive and secure the barrier 622 in place. For example, the engagement feature 630 defines a groove or passage sized and shaped to receive the top edge of the barrier 622. This connection ensures that the barrier 622 extends the entire length of the aerosolization device 600 housing, from the bottom to the top of the housing. This ensures that only airflow through the air passages 624 at each end of the barrier 622 passes over the barrier 622, while directing the majority of the airflow toward the outlet 616.

[0045] 6D illustrates the flow pattern of airflow drawn from the inhalation rim 650 through the inlet 608 into the aerosolization device 600. For example, as air from the inhalation rim 650 (which may have passed through a humidifier, etc.) passes through the respiratory adapter 606, the barrier 622 redirects a majority of the air through the outlet 616 to the exhalation rim 652. As described above, because the barrier 622 defines one or more air passages 624, a portion of the airflow from the inhalation rim 650 is drawn inward each time the patient inhales. This portion of air drawn through the air passages reaches the second barrier 626. Due to the presence of the second barrier 626, air drawn over the end of the barrier 622 travels upward and flows over the second barrier 626 into the aerosolization chamber 602. As illustrated, air is introduced into the aerosol chamber 602 near the first end 618, near the aerosol generator 612. In other embodiments, the airflow is introduced into the aerosol chamber 602 at other locations. In one example, the air is introduced near the sidewall of the aerosol chamber 602 using a barrier similar to barrier 622. As shown, the air is introduced into the aerosolization chamber 602 near the first end 618 near the aerosol generator 612. In other embodiments, the airflow is introduced into the aerosolization chamber 602 at other locations. In one example, the air is introduced near the sidewall of the aerosolization chamber 602 using a barrier similar to barrier 622. However, other barrier designs and / or locations may be used to introduce air into the aerosolization chamber 602 while isolating it from the direct flow within the respiratory system. Additionally, in some embodiments, other mechanisms may be utilized to direct air flowing from the respiratory system into the aerosolization chamber 602 each time the patient inhales. For example, in some embodiments, one or more one-way valves are incorporated between the aerosolization chamber 602 and the inspiratory limb 650 and / or the expiratory limb 652. The valve(s) seal or otherwise isolate the aerosolization chamber 602 from the respiratory system until the patient inhales, at which point the valve(s) open to allow a small amount of respiratory flow into the aerosolization chamber 602.

[0046] By providing a series of barriers that allow a small amount of air to enter the aerosol chamber 602 from the inhalation rim 650, embodiments of the present invention reduce turbulence and make the air drawn into the aerosol chamber 602 more stratified, thereby facilitating medication deposition in the lungs. The barriers can be designed so that the gas / air flow rate drawn through them is at or near the infant's inspiratory flow rate (which is much lower than the gas passing through the inhalation rim 650). Note that while two barriers are used in the illustrated embodiment, other numbers and arrangements of barriers can reduce turbulence in the airflow from the inhalation rim 650 before it enters the aerosol chamber 602 without significantly increasing the suction required to draw air into the patient's airway. While the above example uses U-shaped barriers, other barrier designs can be used that limit the amount of air drawn into the aerosol chamber 602 with each inspiration and reduce the amount of turbulence within this airflow. This configuration can also reduce dilution of the aerosolized medication with the air delivered by the inhalation rim 650.

[0047] FIG. 7 illustrates the aerosolization device 600 of FIGS. 6-6D connected to both a fluid supply line 700 and a breathing system 702. As shown, a first end of the fluid supply line 700 is connected to a drug supply port 614. For example, in some embodiments, the drug supply port 614 has a tip that protrudes outward from the body of the aerosolization device 600. By attaching the opening of the fluid supply line 700 to the tip, fluid from the fluid supply line 700 passes through the drug supply port 614, enters the reservoir and / or conduit 634, and is then delivered to the aerosol generator 602. A second end (not shown) of the fluid supply line 700 is connected to a fluid source, such as a vial (or other type of container) of liquid drug.

[0048] The respiratory adapter 606 is coupled to the respiratory system 702. As shown, the inlet 608 is coupled to the inspiratory limb 650 of the respiratory system 702, while the outlet 616 and expiratory limb 652 are not visible in this view. Air and / or other respiratory gases are channeled from the inspiratory limb 650 to the respiratory adapter 606, and one or more diverting mechanisms, such as valves or barriers, divert a portion of the airflow through a fluid pathway to the aerosol chamber 602. A substantial portion of the remaining airflow of the respiratory system 702 is directed by the respiratory adapter 606 to the expiratory limb 652.

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

[0050] FIG. 8 illustrates another embodiment of an aerosolization device 800. The aerosolization device 800 is similar to the aerosolization device 600 described above. As shown, the aerosolization device 800 is coupled to a drug source 802. The drug source 802 is any container that holds a quantity of drug. In the illustrated example, the drug source 802 is a vial, which is coupled to the drug port of the aerosolization device via a luer connection 804 and an entire length of fluid supply line 806. The aerosolization device 800 also has coupled to it a nebulizer cable 808 that can be connected to a controller (not shown). The nebulizer cable 808 terminates in a pod 810 for coupling the aerosolization device 800 and / or the breath sensor to the controller.

[0051] FIG. 9 shows aerosolization device 800 connected to a drug source 802 and a controller 812. The controller is configured to deliver liquid drug to aerosolization device 800 via fluid supply line 806 and activate aerosolization device 800. In some embodiments, controller 812 activates aerosolization device 800 in response to detected patient inspiration. For example, controller 812 is coupled to a respiration sensor 814 that can detect the onset, duration, and / or end of a patient's inspiration. In some embodiments, respiration sensor 814 is a sensor similar to a Graseby sensor that is placed against the patient's torso (abdomen and / or chest) to detect the patient's respiratory cycle. In this case, for example, controller 812 receives a signal from respiration sensor 814 indicating that the patient is beginning to inhale. Controller 812 then sends a command to provide a quantity of liquid drug to an aerosol generator of aerosolization device 800 and activates the aerosol generator to aerosolize the liquid drug during inspiration.

[0052] In some embodiments, the respiratory sensor 814 and / or aerosolization device 800 are directly coupled to the controller 812. In other embodiments, the pod 810 and / or other adapter is used to connect the respiratory sensor 814 and / or aerosolization device 800 to the controller 812. For example, in some embodiments, a fitting such as a slip luer is inserted into a port on the pod 810 to connect the respiratory sensor to the pod. In this embodiment, the respiratory sensor 814 is attached, such as by adhesive, to the patient's abdomen to begin sensing the inspiratory cycle.

[0053] FIG. 10 illustrates a controller 812. The controller 812 includes a user interface 818, such as a display screen. In some embodiments, the user interface 818 is a touchscreen. The controller 812 includes one or more input devices, such as buttons, dials, a keypad, a touchscreen, etc., that allow a user to interact with the controller 812 and adjust settings, such as the dose level. The controller 812 includes multiple ports 820 for connecting the controller 812 to peripheral units, such as the aerosolization device 800 and / or the breath sensor 814. In some embodiments, the controller 812 includes one or more indicators 824, such as LEDs, configured to alert the user to the status of various functions. For example, the indicators 824 may inform the user as to whether the aerosolization device 800 and / or the breath sensor 814 are properly connected, whether the power source 832 of the controller 812 is operational (i.e., connected and / or, in the case of a battery, charging or fully charged), whether a system fault has been detected, etc. In some embodiments, the indicators 824 are integrated into the user interface 818. The housing 822 of the control device 812 includes a holder 826 configured to securely receive the drug source 802, as best seen in Figure 11. In this embodiment, the drug source 802 is a vial secured upside down within the holder 826, and is configured to deliver the entire amount of drug source 802 from the drug source 802 to the aerosolization device 802 by means such as spilling or squeezing.

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

[0055] In some embodiments, the aerosolization devices described herein include an aerosol generator that can be coupled to various ventilator systems. The aerosol generator receives a liquid medicament from a fluid source via a fluid delivery conduit. In operation, fluid from the fluid source is delivered by a pump through the fluid delivery conduit to the aerosol generator, where the fluid is aerosolized before and / or during a patient's inspiration. In some embodiments, the fluid delivery conduit is primed with fluid prior to treatment (e.g., pre-fed with fluid to the aerosol generator) for rapid delivery. The pump is controlled by a controller that controls the duration and dosage of the fluid delivery.

[0056] The controller includes one or more processors that execute instructions stored in one or more memories to drive the operation of the pump and aerosol generator. For example, the memory may store instructions indicating the amount of fluid to be delivered to the aerosol generator per dose, the amount of fluid to be delivered over a specific period or number of times, etc. The stored instructions may be based on the patient's size, age, sex, type of medication, fluid additives, desired volume of aerosol, etc. The memory also stores instructions for operating the aerosol generator. As shown, the controller is coupled to the aerosol generator by a cable (i.e., an electrical cable), although in some embodiments, the controller is wirelessly connected to the aerosol generator. The cable carries signals that activate a piezoelectric actuator (or other actuator) within the aerosol generator. Operation of the piezoelectric actuator causes a vibrating member to vibrate, thereby aerosolizing the fluid and delivering it to the patient (i.e., delivering it with inspiration). Thus, the memory stores instructions for controlling the start and stop timing, oscillation frequency, or vibrational frequency of the piezoelectric actuator.

[0057] The aerosolization systems described herein can enhance therapeutic efficacy by timing aerosol generation. For example, the aerosol delivery system can begin aerosolizing the medication before the patient inhales. In this case, the aerosol delivery system can take advantage of the increased airflow at the beginning of inspiration. As a result, the inhaled air carries the medication further into the patient's lungs, thereby facilitating delivery of the medication to the patient. Alternatively, the aerosol delivery system may aerosolize the medication as soon as inspiration is detected (e.g., during spontaneous breathing).

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

[0059] In some embodiments, a flow sensor is coupled to the gas delivery conduit to sense changes in airflow during inspiration (e.g., forced breathing, assisted breathing, or spontaneous breathing). In some embodiments, a flow sensor is also coupled to the gas return conduit to detect the start and end of exhalation. In yet another embodiment, an aerosol delivery system has flow sensors coupled to the gas delivery conduit and the gas return conduit. Once the controller receives data from the flow sensor, the controller monitors breathing patterns to predict when the patient will breathe. Being able to predict the start of inspiration allows the aerosol delivery system to have the aerosolized medicament ready for immediate inhalation. More specifically, the aerosol delivery system can pre-position fluid on the vibrating member of the aerosol generator so that the fluid can be aerosolized before inspiration. Because flow detection is not a delayed indicator, the flow sensor can quickly detect irregular or spontaneous inspiration and deliver aerosol (e.g., within 10 milliseconds of the start of inspiration).

[0060] To predict a patient's inspiration, one or more respiratory and / or flow sensors are used to track the patient's breathing pattern and / or ventilation cycle (if the patient is undergoing mandatory ventilation). The tracked data is then used by the controller to predict when the next inspiration will begin. This allows the controller to instruct the pump to deliver fluid from the fluid source to the aerosol generator 16 before inspiration. The controller then signals the aerosol generator to begin aerosolizing the fluid at the appropriate time, such as within a predetermined period (e.g., + / - 0.5 seconds) before and / or during the anticipated inspiration. In this way, the aerosol is ready for the patient at the start of inspiration. The aerosol delivery system can predict the respiratory cycle and generate aerosol for the patient, and can also use respiratory sensors to identify spontaneous / irregular breathing that is not part of a normal pattern. If spontaneous breathing is identified, the aerosol delivery system immediately sends fluid to the aerosol generator for delivery to the patient.

[0061] FIG. 13 illustrates an example of the functionality of the controller 812. As shown in plot A, the controller 812 receives a signal from the breath sensor 814 indicating that the patient has begun inhaling. The controller 812 then sends a command to initiate delivery of a quantity of medication to the aerosol generator, which operates to aerosolize the liquid medication, as shown in plots B-D. In some embodiments, the controller 812 is programmed to aerosolize the medication only during the first portion of the inspiration, with the last portion of the inspiration drawing in chase air to facilitate delivery of the aerosolized medication to the deep lung. For example, as shown in multiple plots, the controller 812 aerosolizes the medication only within the first 80% of each inspiration, with chase air being drawn into the patient's airways during the last 20% of each inspiration. Of course, other aerosolization patterns may be used. For example, aerosolization of medication occurs during the first 50% to 90% of each inspiration (more typically between 60% and 80%, and even more typically between 70% and 80%). Beyond 80%, more aerosol is exhaled in the upper airways before reaching the lower airways. This allows expulsion air to be drawn into the patient's airways during the last 10% to 50% of inspiration (more typically about 20% to 40%, and even more typically about 20% to 30%).

[0062] 14A-14K illustrate the setup process for using the aerosolization system shown in FIGS. 8-13. During startup, the controller 812 is powered on (e.g., switched on), causing the controller 812 to begin a startup sequence. In some embodiments, the startup sequence includes a power-on self-test of various audible alarms and / or an alarm indicator on the top of the controller that cycles through various visual alarms. A system backup alarm may also be sounded as a test. As shown in FIG. 14A, a user (e.g., a healthcare professional) must log in to the controller 812 via the user interface 818. For example, when first using the aerosolization system, the user must enter credentials such as a username, password, property authentication (e.g., a magnetic stripe card and / or a digital key or authentication using a radio wave communication protocol), biometric authentication (e.g., a fingerprint scan, face scan, retina scan, voice scan), etc. After logging in, the user must enter patient information, such as timing, dosage, and / or other factors related to the patient's treatment. For example, as shown in FIG. 14B, the user must enter a patient identifier (e.g., name, identification number), patient weight, dose type (high / low, etc.) and amount, and / or other details about the patient. Once all required patient information has been entered, a confirmation screen is displayed to the user, allowing the user to verify the accuracy of the patient and medication information before proceeding. If the patient and medication information is correct, the user confirms and proceeds with the setup process. If either the patient or medication information is incorrect, the user must re-enter the incorrect information before proceeding.

[0063] Next, instructions for using the aerosolization system are displayed to the user, as shown in FIG. 14C . Here, the user interface 818 instructs the user to connect the pod 810 to the aerosolization system's controller 812. For example, the user inserts the pod 810's connector into one of the ports 820 of the controller 812. In some embodiments, the user interface 818 displays a notification that the pod 810 has been properly connected to the controller 812. In some embodiments, the controller 812 and / or a stand (not shown) that supports the controller 812 includes a basket and / or other support structure to support excess cable extending from the pod 810. Other instructions may be displayed to assist the user in setting up the aerosolization system for use. In another example, as shown in FIG. 14D , the user interface 818 instructs the user to connect the respiratory sensor 814 (e.g., a respiratory sensor capsule) to both the pod 810 and the patient, and then to check that the patient is inhaling. As shown in the figures, in some embodiments, connecting the respiratory sensor to the pod is done by inserting a connector, such as a slip luer, into a port on the pod 810. In this embodiment, the respiratory sensor 814 is attached, such as by adhesive, to the patient's abdomen to begin sensing the inspiratory cycle. For example, the patient's skin is wiped with a wet wipe to protect the skin from the adhesive and then allowed to dry. The respiratory sensor 814 is then placed on the flank and / or lower abdomen and taped into place. The tubing of the respiratory sensor 814 is not taped. The user interface 818 prompts the user to confirm that the controller 812 is receiving the respiratory signal and that it is properly displayed on the user interface 818.

[0064] As shown in FIG. 14E, instructions are displayed to the user on how to set up the drug supply line 806 and nebulizer cable 808 of the aerosolization system. For example, the user attaches the VVAD 828 to a drug vial (drug source 802) and aligns the filter 832 with the identification window on the vial's label. The user then holds the vial upright and pierces the VVAD 828's perforation (not shown) through the vial's septum (not shown) until the VVAD 828 clicks and locks into place. A supply mechanism (such as a pump, not shown), such as the side of the housing of the control device 812, is opened, and the fluid supply line 806 is inserted into the mechanism, which is then closed. The vial is positioned horizontally and coupled to the fluid supply line 806. The luer end of the VVAD 828 is placed in the luer holder portion of the holder 826 and rotated upward and inserted into the metal clip, with the identification window facing outward. The nebulizer cable 808 is then connected to the pod 810. The aerosolization device 800 is also connected to a breathing system, such as a ventilator. Once the various components are connected, the aerosolization device 800 is primed.

[0065] FIG. 14F illustrates priming of the pump. Priming is performed by selecting the priming function from the user interface 818 of the control device 812. Once priming is complete, an aerosol check is performed, as shown in FIG. 14G. The user then operates the user interface 818 to initiate aerosol generation. The user then confirms that the aerosolization system is functioning properly by observing aerosol generation and release from the patient interface (if attached) or the opening in the aerosolization device 800. If aerosol is observed, the user continues with setup. If aerosol is not observed, the user repeats the priming and aerosol check procedure. Before or after the aerosol check is complete, the user interface 818 prompts the user to connect a patient interface (e.g., nasal prongs) to the aerosolization device 800. The user selects an appropriately sized patient interface and presses the patient interface onto the aerosolization device 800. In some embodiments, the connection between the patient interface and the aerosolization device 800 is trapezoidal. This configuration facilitates proper alignment of the patient interface by the user, although other configurations are possible. As shown in FIG. 14H, aerosolization device 800 is connected to the infant. For example, nasal prongs (or other patient interface) are connected to the infant's airway. In some embodiments, one or more straps and / or other restraints are used to secure aerosolization device 800 to the infant's airway and head so that the aerosolization device remains in place even if the infant moves. In some embodiments, aerosolization device 800 is secured to the infant's head by one or more straps secured to a hat worn by the infant. Additionally, a foam pad is attached to aerosolization device 800, extending between aerosolization device 800 and the infant's head (positioned laterally away from the portion of aerosolization device 800 containing the aerosol generator).The foam pad is comprised of multiple peelable foam layers that can be peeled and / or otherwise removed to adjust the distance between the aerosolization device 800 and the infant's head. Often, the foam pad has a curved surface designed to conform or substantially conform to the contours of the infant's head. Once in place, the foam pad (and any optional straps) function to maintain the aerosolization device 800 in the proper position and orientation relative to the infant, regardless of the infant's movements or position (e.g., supine, side, or prone). Once the aerosolization system is connected to the infant, the user interacts with the user interface 818, as shown in FIG. 14I, to initiate medication delivery to the infant. For example, the user may verify the patient data and total dose, and confirm that the number of medication vials matches the pharmacy calculation and dispensing documentation provided by the pharmacist. After verifying the data, the user interacts with the control device 812 to begin the medication delivery procedure. Once the medication delivery procedure begins, data such as the respiratory cycle, dose indication, nebulization rate, and the amount of medication remaining in the medication source 802 are displayed. The user interface 818 also prompts the user to ensure that the aerosol is synchronized with the infant's breathing pattern.

[0066] In some embodiments, if the vial is empty, the controller 812 stops dosing. Often, a low-priority alarm is activated when a threshold amount of medication in the vial (e.g., 5%, 10%, 15%, 20%, etc.) is reached. If the low-priority alarm remains unacknowledged by the user for a predetermined period of time, a medium-priority alarm is activated and a "Vial Alert" is displayed on the user interface 818 and / or by one of the indicators 820. In some embodiments, if the vial is empty, the controller 812 automatically pauses and activates a medium-priority alarm. If the alarm remains unacknowledged for a predetermined period of time, a high-priority alarm is activated. The user is instructed to "replace the vial and resume dosing from the medication delivery screen." Once the empty vial is replaced with a new medication vial, dosing can continue. Once dosing is complete, the user acknowledges the end of dosing and operates the controller 812 to return to a normal CPAP or other breathing circuit.

[0067] In some embodiments, a low priority alarm is a visual alarm only and is displayed with text information only on the user interface 818. In some embodiments, a medium priority alarm includes visual and audio elements, and is displayed with a corresponding color alarm indicator (e.g., yellow) combined with corresponding audio and text information. In some embodiments, a high priority alarm includes visual and audio elements, and is displayed with a corresponding color display box (e.g., red) on the user interface 818 combined with text information on the user interface 818. In some embodiments, an alarm is generated when no breath is detected, when a valid continuous breath is not detected (when a valid continuous breath consisting of three consecutive valid breaths is not detected. Each breath is considered a valid breath if its inspiration time is 100 milliseconds or more. A breath containing at least one invalid breath is considered an invalid continuous breath. A breath is considered an invalid breath if its inspiration time is less than 100 milliseconds), when the nebulizer cable becomes detached from the pod during medication administration, or when a wet / dry condition occurs. An alarm may be activated when a drug discharge event is not detected (e.g., tubing is kinked and no medication is being delivered to the aerosol generator; no nebulization is occurring and all medication is being released through the vent; nebulization is occurring with no medication coming out of the vent; nebulization is occurring with medication coming out of the vent); the amount of medication remaining in the vial is below a threshold amount (including empty); the pod cable becomes disconnected from the pod while a dose is being dispensed; the pod cable becomes disconnected from the pod when no medication is being dispensed; a pod communication failure is detected; an internal pod failure is detected; a system error is detected; the medication delivery mechanism has failed; the main power is disconnected and the device is operating in battery mode; the battery charge is below a threshold level (including empty); and / or the power-on self-test fails.

[0068] FIG. 15 shows an aerosolization device 1500 connected to an infant. The aerosolization device 1500 is similar to those described herein, having an aerosol generator positioned near the infant's airway and a barrier to minimize flow through the direct connection between the patient and the aerosol generator during aerosol generation. Additionally, the aerosolization device 1500 includes a PDAP mesh or similar mesh capable of aerosolizing particles with an MMAD of less than about 3 μm (more preferably less than about 2 μm) at high flow rates (approximately 0.1 ml / min to 1.5 ml / min). The aerosolization device 1500 includes a power / control port for connecting one or more controllers (similar to controller 812) that provide power and operational commands to the aerosol generator.

[0069] The aerosolization device 1500 includes one or more straps or other restraints 1502 for securing the aerosolization device 1500 to the infant's head and airway. Additionally, the aerosolization device 1500 includes a foam pad 1504 designed to maintain the aerosolization device 1500 in the proper position and orientation relative to the infant, regardless of the infant's movements or position (e.g., supine, side, or prone). The foam pad 1504 is made of multiple peelable foam layers, allowing the distance between the aerosolization device 1500 and the infant's head to be adjusted by peeling and / or otherwise removing layers. Often, the foam pad 1504 has a curved surface designed to conform to or substantially conform to the contours of the infant's head. The aerosolization device 1500 is formed from a lightweight material (e.g., medical-grade foam plastic) that allows the infant to move around without displacing the aerosolization device 1500 from its proper position.

[0070] FIG. 16 shows a breath sensor capsule 1600 (similar to breath sensor 814) connected to the infant's abdomen. As shown, breath sensor capsule 1600 is attached to the infant's abdomen with tape or the like and is used to detect the start and / or end of the infant's inspiration cycle by using the change in volume of sensor capsule 1600 in response to abdominal movement associated with breathing. Using data from one or more inspiration cycles, a controller (not shown) monitors flow into and out of the capsule as the abdominal sensor volume changes, and delivers aerosolized surfactant in sync with the infant's breathing, thereby maximizing surfactant delivery efficiency.

[0071] FIG. 17 illustrates another embodiment of an aerosolization system 1700 that effectively and efficiently delivers surfactant to an infant. As shown, a controller 1702 (similar to controller 812) is used to power and control the aerosolization device 1704. Additionally, the controller 1702 is configured to control the delivery mode of the aerosolization device 1704. For example, the controller 1702 may be configured to alternate between a timed mode, in which treatment is administered for a set period of time, and a continuous mode, in which aerosolized surfactant is delivered indefinitely based on the infant's inspiration pattern. The system 1700 also includes an additional controller 1706 that allows a healthcare professional to set the aerosol delivery conditions. For example, the additional controller 1706 may set the flow rate at which aerosol delivery begins, the inspiration time at which aerosol delivery occurs, and / or other conditions to adjust the timing, amount, and duration of administration of the aerosolized medication. Note that although controller 1702 and additional controller 1206 are described as separate components, in some embodiments a single controller (or more controllers) is used to control the operation of system 1700.

[0072] System 1700 also includes one or more flow and / or other respiratory sensors 1708. As shown, flow sensor 1708 is coupled to an inspiratory limb 1710 of respiratory system 1712, for example, upstream and / or downstream of optional humidifier 1714. The respiratory sensor 1708 is used to detect the infant's inhalation. In another embodiment, respiratory sensor 1708 is a respiratory sensor capsule that is connected to the infant's abdomen. The respiratory sensor 1708 is electronically coupled to one or both of controllers 1702 or 1706, which initiate operation of aerosolization device 1704 (similar to any of the aerosolization devices described herein) based on the inhalation data. Controllers 1702 and 1706 are electronically coupled to aerosolization device 1704 to provide both power and operational commands to aerosolization device 1704. In some embodiments, the aerosolization device 1704 includes a PDAP mesh 1716 that generates aerosolized surfactant with an MMAD of less than about 3 μm (preferably less than about 2 μm) at a flow rate of at least 0.1 ml / min. Used in conjunction with the controllers 1702, 1706, and the respiratory sensor 1708, this aerosolization device 1704 allows for: 1) the generation and delivery of sufficiently small aerosol particles; 2) the delivery of the aerosol synchronized with breathing; and 3) placement of the aerosol generator near the infant's airway while preventing continuous gas flow and minimizing flow through the direct connection between the patient and the aerosol generator during aerosol generation (as clearly illustrated in FIGS. 6-6D). As a result, pulmonary delivery efficiency is significantly improved, achieving efficiencies of about 25%-60%, more typically about 40%-60%.

[0073] FIG. 18 is a flowchart illustrating a process 1800 for delivering aerosolized surfactant to an infant. Process 1800 can be performed using any of the aerosolization devices, processors, and / or breath sensors described herein. Process 1800 begins, at block 1802, with detecting the infant's intake of air using one or more breath sensors. For example, a breath sensor is attached to the infant's abdomen. The breath sensor detects the infant's abdominal expansion associated with intake of air. In response to the detected intake of air, at block 1804, the controller causes the aerosolization device to aerosolize a quantity of surfactant into particles having a mass median aerodynamic diameter (MMAD) of less than about 3 μm at a flow rate of at least 0.1 ml / min. The surfactant is aerosolized within about 1-8 cm of the patient interface. In some embodiments, aerosolizing the quantity of surfactant includes delivering the quantity of surfactant from a reservoir to a mesh of the aerosolization device and vibrating the mesh to aerosolize the quantity of surfactant. In some embodiments, the quantity of surfactant is delivered from the reservoir to the mesh through a conduit with a tip having a diameter. The tip of the conduit is positioned at a distance equal to or less than the diameter from the mesh of the aerosol generator. This allows the aerosolization device to operate effectively in any orientation, as the drug released from the tip will contact and climb up the surface of the mesh. In some embodiments, when the quantity of surfactant is aerosolized, a portion of the quantity of surfactant is aerosolized in at least a portion of the first 80% of each of multiple consecutive inspirations, such that sweeping air is provided in at least a portion of the last 20% of each of multiple consecutive inspirations. At block 1806, the aerosolized surfactant is delivered to the infant's airway via a patient interface, such as nasal prongs.

[0074] In some embodiments, the process 1800 includes coupling an aerosolization device to a respiratory system and diverting a portion of the airflow from the respiratory system to a chamber of the aerosolization device via at least one airway. The chamber is configured to mix the portion of the airflow with the aerosolized surfactant. In some embodiments, the portion of the airflow is a respiratory flow, which is less than the amount of air that continues to the expiratory limb of the respiratory system. In some embodiments, the portion of the airflow is diverted by at least one barrier defining at least one airway. The at least one barrier may be configured to divert a portion of the airflow to the aerosol chamber via the at least one airway and to divert another portion of the airflow from the inspiratory limb toward the expiratory limb. In some embodiments, two barriers are used. A first barrier defines a first airway, and a second barrier defines a second airway. A first airway is located at a lateral end of the first barrier and a second airway is located beyond a distal edge of the second barrier, the lateral ends and the distal edge extending in different directions from one another to allow respiratory flow to travel in multiple directions past the first and second barriers.

[0075] FIG. 19 is a flowchart illustrating a process 1900 for initializing an aerosolization system. Process 1900 can be performed using any of the aerosolization devices, processors, and / or breath sensors described herein. Process 1900 begins at block 1902 by connecting the aerosolization device to a controller, a breath sensor, a drug source, and a breathing system. Here, an atomizer cable is coupled between the aerosolization device and the controller (possibly via a pod or other adapter), the inspiratory limb of the breathing system is coupled to an inlet of the aerosolization device, the expiratory limb of the breathing system is coupled to an outlet of the aerosolization device, the breath sensor cable is coupled to the controller (possibly via a pod or other adapter), and / or the aerosolization device is coupled to a drug source. In some embodiments, when the aerosolization device is coupled to a drug source, a fluid supply line is coupled between the drug source and the aerosolization device. In some embodiments, the drug source is a vented vial access device (VVAD) coupled to a fluid supply line.

[0076] At block 1904, user access credentials are entered into the control device, allowing only authorized users to use the aerosolization system to administer medication. The access credentials may be, for example, one or more of a user identifier, a password, property authentication, and biometric authentication. At block 1906, patient-related and medication information is entered into the control device. This may include information such as a patient identifier, patient weight, and dosage level. At block 1908, a respiratory sensor is connected to the patient. For example, the sensor may be attached to the patient's abdomen. In some embodiments, breath detection is configured after connecting the respiratory sensor to the patient. At lock 1910, the aerosolization device is primed. For example, a portion of the medication may be aerosolized to ensure proper device function before connecting the patient interface to the patient's airway. At block 1912, the aerosolization device is connected to the patient's airway. For example, nasal prongs may be inserted into the infant's nostrils. In some embodiments, the patient interface must be secured to the aerosolization device before connecting the device to the patient. In some embodiments, one or more straps and / or foam pads are placed and / or secured around the infant to secure the aerosolization device in place. Once secured in place, the user may begin delivering the dose to the infant and / or may check the user interface of the control device to ensure that delivery of the aerosolized dose is synchronized with the infant's inspiration.

[0077] In some embodiments, the process 1900 includes executing a start-up sequence upon powering up the control device, which may include multiple audio, visual, or both audio and video alarms to verify that the control device is functioning properly before use.

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

[0079] Airflow was set at 6 LPM (liters per minute), 8 LPM, and 10 LPM, and respiratory rates were 60 BPM (breaths per minute), 80 BPM, 100 BPM, and 120 BPM. The emitted dose rate was then measured for each combination of airflow rate and respiratory rate. As shown in Figure 21, delivery efficiency was affected by gas flow, with delivery efficiency decreasing slightly as flow rate increased. For example, at low flow rates (6 LPM), the emitted dose using the large nasal prongs (5560) ranged from approximately 50% to approximately 60% across the entire range of respiratory rates tested. Meanwhile, at high flow rates (10 LPM), the emitted dose ranged from approximately 42% to approximately 47%. As respiratory rate increased, the difference in efficiency with increasing flow rate became smaller. For example, at 60 BPM, the emitted dose rate ranged from approximately 44% to approximately 60%, while at 120 BPM, the emitted dose rate ranged from approximately 42% to approximately 51%. Based on these results, the aerosol generator described herein was found to enable uniform inhaled drug doses across the entire clinically relevant range of respiratory rates (60-120 BPM) and CPAP flow rates (6-10 LPM) commonly used in bubble CPAP and ventilated CPAP systems.

[0080] Additionally, embodiments of the present invention provide systems and methods for non-invasively delivering surfactant (or other drugs) to infants, particularly preterm infants. Achieving effective and efficient drug aerosol administration to preterm infants requires a combination of the following attributes: 1) sufficiently small aerosol particles; 2) aerosol delivery synchronized with breathing; and 3) placement of the aerosol generator in close proximity to the infant's airway (within approximately 1-8 cm) while preventing continuous gas flow and minimizing flow through the direct connection between the patient and the aerosol generator during aerosol generation. By meeting these conditions, surfactant delivery efficiencies of greater than 40%, and up to approximately 60%, are achievable, a significant improvement over conventional efficiencies of less than 10%.

[0081] Given the respiratory physiology of preterm infants, nasal delivery methods, such as nasal prongs that can be inserted into the infant's nasal passages, are necessary to ensure adequate noninvasive delivery of aerosolized surfactant to infants. It is desirable to deliver aerosolized particles smaller than approximately 2 μm using such delivery methods. Larger particles often impinge within the aerosolization device interface and / or on the airways before dispersing in the infant's lungs. This is also illustrated in Figures 22 and 23, which show particle deposition rates for various particle sizes (using a MMAD and a geometric standard deviation (GSD) of 2.2) in neonates. Neonate 1 was 4 months old, and Neonate 2 was 28 weeks preterm. Figure 22 shows that lung deposition increases with decreasing particle size (Figure 22 only shows the results for Neonate 1), with lung deposition exceeding 40% for particle sizes smaller than 2 μm. Notably, for particles larger than 2 μm, nasal deposition is typically approximately 50%–70%, representing particles that do not reach the infant's lungs. Figure 23 shows a comparison of lung and nasal deposition rates for both neonates using aerosols with 3 μm and 2 μm MMAD. For both neonates, improved lung deposition was observed with the 2 μm MMAD aerosol, with deposition rates of just under 40% for neonate 1 and just under 60% for neonate 2. These results demonstrate the need for small aerosol particles to maximize delivery efficiency.

[0082] Conventional nasal delivery methods typically use particles with an MMAD of 4–7 μm, with a geometric standard deviation of approximately 2.0 or greater. This is due to the viscous nature of many surfactants, making it extremely difficult to aerosolize undiluted surfactants into small particles at effective flow rates using conventional jet nebulizers, specialized jet nebulizers, mesh nebulizers, heated capillary generators, and other methods. The impaction rate of these conventional delivery methods can result in up to 80% of the effective aerosol volume in a single dose being lost. Only 40–60% of the remaining aerosol (composed of particles smaller than approximately 2 μm) reaches the lower airways of the lungs, resulting in an overall efficiency of approximately 10% of the initial dose emitted by the aerosol generator.

[0083] Some embodiments of the present invention provide systems and methods for generating sufficiently small aerosol particles using an aerosolization device, such as the device described above with reference to Figures 1-8. In particular, some embodiments use an aerosolization device with an aerosol generator that utilizes the capabilities of a PDAP mesh (such as that disclosed in U.S. Patent Publication No. 2016 / 0130715, supra) to uniformly generate aerosolized surfactant particles of less than about 3 μm (more preferably, about 1.5 μm to about 2.5 μm) at an output flow rate of about 0.1 ml / min to 0.6 ml / min. By leveraging the capabilities of such an aerosol generator, embodiments of the present invention achieve sufficiently small particle sizes to effectively and efficiently deliver surfactant to the lungs. For example, even with aerosols with an MMAD of less than 3 μm, nasal pulmonary delivery efficiencies of about 40-60% of the nominal surfactant dose can be achieved.

[0084] As mentioned above, to maximize delivery efficiency, it is also effective to synchronize aerosol delivery with the infant's inspiration. This synchronization avoids wasting surfactant during expiration and between breaths. For example, infants often have an inspiration-to-expiration ratio of approximately 1:1 to approximately 1:3. Therefore, aerosolized surfactant is typically only inspired approximately 25–50% of the time. In conventional systems, the aerosol is often delivered by a bubble CPAP gas flow of approximately 6–10 LPM. This flow rate exceeds the infant's maximum inspiratory flow, resulting in waste of up to half of the aerosolized medication.

[0085] In some embodiments of the present invention, the aerosol generator is synchronized with the infant's breathing. As previously described, this is accomplished by tracking the patient's breathing pattern and / or ventilation cycle using one or more respiratory and / or flow sensors. Based on this information, the controller predicts when the next inspiration will begin and synchronizes the timing of fluid delivery from the fluid source to the aerosol generator and / or activation of the aerosol generator approximately with the infant's inspiration. In some embodiments, inspiration is detected using a respiratory sensor capsule attached to the infant's abdomen. The respiratory sensor capsule detects abdominal movement associated with inspiration, which occurs immediately before the inspiration itself. This makes the respiratory sensor capsule particularly useful for determining inspiration timing in order to synchronize aerosol generation.

[0086] Figure 24 demonstrates the effectiveness of the breath sensor capsule in detecting inspiration. In this example, a separate flow sensor was connected to the infant's airway, and the breath sensor capsule was secured to the infant's abdomen. The infant weighed 1500 g and had a respiratory rate of 70 BPM. As can be seen from the graph in Figure 24, the sensor signal from the breath sensor capsule detected each inspiration and expiration detected by the flow sensor, and the breath sensor capsule detected the start of inspiration slightly before the flow sensor. This time can be used by the control device to activate the aerosol generator. These results confirm that the use of the breath sensor capsule is particularly effective in synchronizing breathing and aerosol generation. Figure 24 also shows that, although these inspirations occurred over a 5-second period, inspiration only took up approximately one-third of that time. Therefore, if aerosol delivery is not synchronized with breathing, more than two-thirds of the aerosolized surfactant would be wasted.

[0087] In some embodiments, the aerosolization devices described herein include an aerosol generator that can be coupled to various ventilator systems. The aerosol generator receives a liquid medicament from a fluid source via a fluid delivery conduit. In operation, fluid from the fluid source is delivered by a pump through the fluid delivery conduit to the aerosol generator, where the fluid is aerosolized before and / or during a patient's inspiration. In some embodiments, the fluid delivery conduit is primed with fluid prior to treatment (e.g., pre-fed with fluid to the aerosol generator) for rapid delivery. The pump is controlled by a controller that controls the duration and dosage of the fluid delivery.

[0088] The controller includes one or more processors that execute instructions stored in one or more memories to drive the operation of the pump and aerosol generator. For example, the memory may store instructions indicating the amount of fluid to be delivered to the aerosol generator per dose, the amount of fluid to be delivered over a specific period or number of times, etc. The stored instructions may be based on the patient's size, age, sex, type of medication, fluid additives, desired volume of aerosol, etc. The memory also stores instructions for operating the aerosol generator. As shown, the controller is coupled to the aerosol generator by a cable (i.e., an electrical cable), although in some embodiments, the controller is wirelessly connected to the aerosol generator. The cable carries signals that activate a piezoelectric actuator (or other actuator) within the aerosol generator. Operation of the piezoelectric actuator causes a vibrating member to vibrate, thereby aerosolizing the fluid and delivering it to the patient (i.e., delivering it with inspiration). Thus, the memory stores instructions for controlling the start and stop timing, oscillation frequency, or vibrational frequency of the piezoelectric actuator.

[0089] The aerosolization systems described herein can enhance therapeutic efficacy by timing aerosol generation. For example, the aerosol delivery system can begin aerosolizing the medication before the patient inhales. In this case, the aerosol delivery system can take advantage of the increased airflow at the beginning of inspiration. As a result, the inhaled air carries the medication further into the patient's lungs, thereby facilitating delivery of the medication to the patient. Alternatively, the aerosol delivery system may aerosolize the medication as soon as inspiration is detected (e.g., during spontaneous breathing).

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

[0091] In some embodiments, a flow sensor is coupled to the gas delivery conduit to sense changes in airflow during inspiration (e.g., forced breathing, assisted breathing, or spontaneous breathing). In some embodiments, a flow sensor is also coupled to the gas return conduit to detect the start and end of exhalation. In yet another embodiment, an aerosol delivery system has flow sensors coupled to the gas delivery conduit and the gas return conduit. Once the controller receives data from the flow sensor, the controller monitors breathing patterns to predict when the patient will breathe. Being able to predict the start of inspiration allows the aerosol delivery system to have the aerosolized medicament ready for immediate inhalation. More specifically, the aerosol delivery system can pre-position fluid on the vibrating member of the aerosol generator so that the fluid can be aerosolized before inspiration. Because flow detection is not a delayed indicator, the flow sensor can quickly detect irregular or spontaneous inspiration and deliver aerosol (e.g., within 10 milliseconds of the start of inspiration).

[0092] To predict a patient's inspiration, one or more respiratory and / or flow sensors are used to track the patient's breathing pattern and / or ventilation cycle (if the patient is undergoing mandatory ventilation). The tracked data is then used by the controller to predict when the next inspiration will begin. This allows the controller to instruct the pump to deliver fluid from the fluid source to the aerosol generator before inspiration. The controller then signals the aerosol generator to begin aerosolizing the fluid at the appropriate time, such as within a predetermined period (e.g., + / - 0.5 seconds) before and / or during the anticipated inspiration. In this way, the aerosol is ready for the patient at the start of inspiration. The aerosol delivery system can predict the respiratory cycle and generate aerosol for the patient, and can also use respiratory sensors to identify spontaneous / irregular breathing that is not part of a normal pattern. If spontaneous breathing is identified, the aerosol delivery system immediately sends fluid to the aerosol generator for delivery to the patient.

[0093] Example 1 A two-part study was conducted to evaluate the safety and tolerability of inhaled surfactant administered during nCPAP therapy in preterm infants at risk for developing respiratory distress syndrome (RDS). In Part 1 (10 infants), patients were treated with a single dose, and in Part 2, multiple doses were administered. A total of 31 preterm infants requiring nCPAP (device-assisted CPAP) were enrolled in this study. Infants were initially stabilized with nCPAP / nIMV (nasal intermittent mandatory ventilation) with CPAP and fraction of inspired oxygen (FiO2) adjusted accordingly to maintain clinical blood gas (CBG) and oxygen saturation (SpO2) according to clinical guidelines. After stabilization, AeroFact was administered with nCPAP within 2 hours of birth.

[0094] AeroFact was administered to infants via a single aerosol dose equivalent to an infused dose of 108 mg / kg (50% delivery efficiency for a nominal dose of 216 mg / kg). Oxygenation and ventilation parameters were monitored according to protocol until efficacy was observed (as defined in the protocol). Infants continued to receive nCPAP after administration. Clinical observations, indicators of respiratory support, and infant comorbidities of prematurity were monitored until discharge from the neonatal intensive care unit (NICU).

[0095] Following successful completion of Part 1 and acceptance by the independent Data Safety Monitoring Board (DSMB), Part 2 of the study was permitted to begin enrollment. The second part of the study was carried out in another group of preterm infants who were also receiving nCPAP and who were at risk for worsening RDS.

[0096] A nominal dose of 216 mg / kg of aerosolized SF-RI1 was administered initially. Oxygenation and ventilation parameters were monitored as specified in the protocol, and aerosol delivery was stopped once the intended dose was reached.

[0097] The infants continued to receive nCPAP. The respiratory severity score (RSS: mean airway pressure × fraction of inspired oxygen) was calculated to maintain SpO2 between 90% and 95% (measured by pulse oximetry). ≧ A re-administration of AeroFact (nominal dose 216 mg / kg) was permitted if the patient's serotonin level was 2.0 and at least (1) 2 hours had elapsed since the completion of the first dose and (2) 4 hours had elapsed since the completion of the second or third dose. Up to three additional doses of AeroFact were permitted within a 96-hour period.

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

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

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

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

[0102] (Conclusion) AeroFact, administered up to four times within the first 96 hours of life, was found to be safe and well tolerated in patients with gestational ages ranging from 26 weeks 2 days to 30 weeks 4 days and weighing between 640 and 1664 grams.

[0103] In the second part of the study, the need for rescue therapy with surfactant bolus injections was lower than in the matched historical control group. As shown in the graph in Figure 25, five (25%) AeroFact patients in Part 2 required rescue therapy with surfactant bolus injections, compared with 27 (45%) patients in the matched historical control group. Thus, the relative risk for AeroFact treatment was 0.56, favoring AeroFact treatment.

[0104] This study found that the incidence of post-administration premature comorbidities and adverse events (AEs) was lower and more consistent among patients treated using the aerosolization system (Figure 17) compared with the historical control group. No treatment-emergent adverse events (TEAEs) were determined to be related to the study drug, device, or procedure. Between days 1 and 4 of the study, according to the dosing protocol, one moderate nasal congestion occurred in Part 1, five moderate nasal congestion events, and one severe nasal congestion event occurred in Part 2. One patient in Part 1 and one patient in Part 2 experienced a fatal serious adverse event (SAE) (culture-proven sepsis). These events were not related to the study drug, device, or procedure, and did not occur during the treatment period. The incidence of AEs related to drug tolerance within the first 24 hours was generally low. The incidence of AEs was comparable between dosing using the aerosolization system (Figure 17) alone and dosing using the aerosolization device in combination with surfactant bolus injection.

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

[0106] [Table 1]

[0107] Aerodynamic particle size measurement with the next generation impactor. Next, the United States Pharmacopeia (USP) <1601> Next Generation Impactor (NGI) testing was performed according to the method described in [1]. The NGI was cooled in a refrigerator at 4-8°C for at least 90 minutes before use and sampled at a flow rate of 15 L / min. Approximately 0.5 mL of AlveoFact® formulation was used for each NGI run. During testing, the NGI was placed in a cooling chamber (maintained at 5°C), and ambient air was aspirated using an AF2b device located outside the cooling chamber. The nebulizer (without nasal prongs) shown in Figures 6-6D was attached to the inlet port of the NGI using a T-piece with an adapter. The inspiratory and expiratory limbs were open, and the open end of the T-piece was closed. NGI samples were weighed gravimetrically according to AS00006.

[0108] (Test Overview)

[0109] [Table 2]

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

[0111] [Table 3]

[0112] As can be seen from Figures 26-28, the aerodynamic particle size distribution was comparable for each test nebulizer, regardless of ventilator setting, and was consistent across all CPAP settings (low, medium, and high).

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

[0114] [Table 4]

[0115] [Table 5]

[0116] [Table 6]

[0117] (Conclusion) These results demonstrate that the aerodynamic particle size of AlveoFact® produced by the AF2b PDAP™ device is not affected by the simulated spontaneous breathing settings. Specifically, regardless of CPAP setting, aerosol particles were less than 3 μm, more specifically, between 2.0 and 2.5 μm, with very small geometric standard deviations (GSDs) of 1.5 to 1.6. The fine particle fraction of particles less than 3.3 μm was approximately 83% across all CPAP settings. Furthermore, this study confirmed consistent particle delivery across the range of CPAP settings.

[0118] Additionally, NGI mass values ​​per stage are also shown in Tables 4-6 and Figures 29-31. This data shows that powder mass was uniform across the various CPAP settings at each stage of the impactor.

[0119] Additionally, aerosol droplet size was uniform across the entire dose delivered at a CPAP flow rate of 6 LPM and 50 psi. The test setup is shown in Table 7 below.

[0120] [Table 7]

[0121] As shown in Table 8 below, the MMAD produced by each aerosolization device was very uniform from the start of dosing to the completion of the maximum dose (four 108 mg vials), with an MMAD of 3.0 μm or less (2.5-3.0 μm) and a GSD of 1.4-1.5 for each aerosolization device. This indicates that the mesh pores did not expand due to use, and demonstrates that the PDAP mesh is capable of producing aerosol particles with an MMAD of approximately 3.0 μm or less for a lifetime exceeding the maximum number of surfactant doses allowed.

[0122] [Table 8]

[0123] Table 9 shows the test parameters for testing the aspiration dose efficiency of different sized nasal prong diameters.

[0124] [Table 9]

[0125] As shown in Table 10 below, the delivered dose for various nasal prong sizes was uniform, ranging from 42% to 57% (which significantly exceeds the approximately 6% delivered dose for conventional devices). The average DD for small, medium, and large prongs was 51, 45, and 50%, respectively. This result confirms that prong size does not significantly affect DD.

[0126] [Table 10]

[0127] Table 11 shows the test setup to determine the effectiveness of the aerosolization device in delivering aerosolized medication in various orientations. The aerosolization device was tested at 0° (infant lying supine), 90° (infant lying on its side), and 180° (infant lying prone), and the delivered dose was measured at each orientation.

[0128] [Table 11]

[0129] Table 12 shows the results of the orientation tests. The results show that DD is not affected by orientation in either administration position, averaging 69% and 70% for the 0° (supine) and 90° (side) administration positions, respectively. In the 180° (prone) position, the AF2b device was able to sustain breath-triggered aerosolization across the entire 0.5 mL dose for all three devices, with an average DD of 46%. These results demonstrate that the system was capable of reliably producing aerosols in all orientations tested.

[0130] [Table 12]

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

[0132] The above-described systems and devices are intended to be merely illustrative. Various procedures or components may be omitted, substituted, or added as desired in various embodiments. Also, features described with respect to particular embodiments may be combined in various other embodiments. Different aspects and elements of the embodiments may also be combined in a similar manner. Also, because technology is constantly evolving, many of the elements are illustrative only and should not be construed as limiting the scope of the invention.

[0133] Specific details are described in the specification for a thorough understanding of the embodiments. However, the embodiments may be practiced without these specific details. For example, well-known structures and techniques have been described without unnecessary detail to avoid obscuring the description of the embodiments. Such description is intended only to illustrate the embodiments and does not limit the scope, applicability, or configuration of the invention. The above description of the embodiments provides those skilled in the art with an enabling description for practicing the embodiments of the invention. Various changes can be made in the function and arrangement of elements without departing from the spirit and scope of the invention.

[0134] The above methods, systems, devices, graphs, and tables are examples. In various configurations, various procedures or components may be omitted, substituted, or added as needed. For example, in alternative configurations, methods may be performed in a different order than described, or various steps may be added, omitted, and / or combined. Additionally, functionality described with respect to particular configurations may be combined in various other configurations. Different aspects and elements of the configurations may also be combined in a similar manner. Additionally, because technology is constantly evolving, many of the elements are merely examples and do not limit the scope of the present disclosure or the claims. Furthermore, the techniques described herein may produce different results with different types of context-aware classifiers.

[0135] While exemplary and presently preferred embodiments of the disclosed systems, methods, and machine-readable media have been described in detail herein, the inventive concepts may be variously embodied and used in other ways, and the appended claims are intended to include such variations except insofar as limited by the prior art.

[0136] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly or conventionally understood. As used herein, "one" refers to one or more (i.e., at least one) of an object. For example, "an element" means one element or multiple elements. As used herein with reference to a measurable value, such as an amount, duration, or the like, "about" and / or "approximately" refers to a variation of ±20%, ±10%, ±5%, or +0.1% from the specified value. Such variations are deemed appropriate within the context of the systems, devices, circuits, methods, and other implementations described herein. As used herein with reference to a measurable value, such as an amount, duration, physical attribute (such as frequency), or the like, refers to a variation of ±20%, ±10%, ±5%, or +0.1% from the specified value. Such variations are deemed appropriate within the context of the systems, devices, circuits, methods, and other implementations described herein. As used herein, including in the claims, when a list of items begins with "at least one" or "one or more," the use of "and" indicates that the listed items can be combined in any combination. For example, a list of "at least one of A, B, and C" includes any combination of A, B, C, AB, AC, BC, and / or ABC (i.e., A, B, and C). Also, when multiple performances or uses of items A, B, or C are possible, the multiple uses of A, B, and / or C are considered to be part of the intended combination. For example, a list of "at least one of A, B, and C" also includes AA, AAB, AAA, BB, etc.

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

[0138] The terms "comprises," "comprises," "have," "having," "including," "consisting of," and "provided," when used in this specification and the following claims, indicate the presence of stated features, integers, components or steps, but do not exclude the presence or addition of one or more other features, integers, components, steps, acts or groups. Example 1: An aerosolization system comprising: a breathing system having an inspiratory limb and an expiratory limb; 1. An aerosolization device comprising: an aerosol chamber having a first end and a second end; an aerosol generator disposed at a first end of the aerosol chamber, the aerosol generator having a reservoir configured to receive a quantity of liquid medicament to be aerosolized by the aerosol generator; an aerosol generator configured to aerosolize the dose of medicament into particles having a mass median aerodynamic diameter (MMAD) of less than about 3 μm at a flow rate of at least 0.1 ml / min; a patient interface disposed near a second end of the aerosol chamber; and a respiratory adapter configured to connect the aerosolization system to the respiratory system; and at least one respiratory sensor configured to detect inspiration of the patient; a controller configured to operate the aerosol generator to aerosolize the dose of medicament in synchronization with detected inspiration. [Example 2] An aerosolization system as described in Example 1, wherein the patient interface is positioned within approximately 1 to 8 cm of the aerosol generator. [Example 3] The breathing adapter includes a diversion mechanism configured to divert a portion of airflow from the breathing system to the aerosol chamber via at least one airway; The aerosolization system of Example 1, wherein the aerosol chamber is configured to mix a portion of the airflow with aerosolized medicament provided from the aerosol generator. [Example 4] An aerosolization system as described in Example 3, wherein a portion of the airflow is a respiratory flow and is less than the amount of air that continues to the expiratory limb of the respiratory system. [Example 5] The flow dividing mechanism has at least one barrier defining the at least one air passage, The aerosolization system of Example 3, wherein the at least one barrier is configured to divert a portion of the airflow to the aerosol chamber through the at least one air passage and to divert another portion of the airflow from the inhalation limb toward the exhalation limb. [Example 6] An aerosolization system as described in Example 5, wherein the at least one barrier includes a first barrier defining a first air passage and a second barrier defining a second air passage. [Example 7] The first ventilation channel is provided at a lateral end of the first barrier, the second ventilation passage is provided at a position beyond the leading edge of the second barrier; An aerosolization system as described in Example 6, wherein the lateral ends and the distal edge extend in different directions from each other so that the respiratory flow moves in multiple directions past the first and second barriers. [Example 8] An aerosolization system as described in Example 1, wherein the aerosolization device further comprises a conduit configured to deliver the quantity of liquid medicament from the storage portion to the aerosol generator. [Example 9] The tip of the conduit has a diameter, The aerosolization system of Example 8, wherein the tip of the conduit is positioned at a distance from the mesh that is less than or equal to the diameter of the mesh. [Example 10] An aerosolization system as described in Example 1, wherein synchronizing the aerosolization of the dose of drug includes aerosolizing a portion of the dose of drug in at least a portion of the first 50-80% of each of the consecutive inspirations, such that purge air is provided in at least a portion of the last 20% of each of the consecutive inspirations. [Example 11] An aerosolization system as described in Example 1, wherein the at least one respiratory sensor includes a respiratory sensor capsule connected to the patient's abdomen. [Example 12] An aerosolization system as described in Example 1, wherein the control device is removable from the aerosolization device. [Example 13] An aerosolization system as described in Example 1, wherein the aerosolization device is configured to perform aerosolization and deliver aerosolized particles of the medication when the patient interface is oriented in each of a downward position, a sideways position, and an upward position. [Example 14] An aerosolization system as described in Example 1, further comprising a supply line configured to supply the amount of drug from a supply source to the storage portion. [Example 15] The aerosolization system of Example 1, wherein the patient interface comprises nasal prongs or a nasal mask. [Example 16] The aerosolization system described in Example 1, wherein the drug comprises a surfactant. Example 17: A method for delivering an aerosolized medication to an infant, comprising: detecting an infant's inhalation using one or more respiratory sensors; aerosolizing, based on the detected inspiration, a quantity of medicament with an aerosolization device into particles having a mass median aerodynamic diameter (MMAD) of less than about 3 μm at a flow rate of at least 0.1 ml / min; The method wherein the medication is aerosolized within about 1 to 8 cm of the patient interface. [Example 18] Aerosolizing the amount of drug delivering the dose of medicament from a reservoir to a mesh of the aerosolization device; vibrating the mesh to aerosolize the quantity of drug. [Example 19] The amount of drug is delivered from the reservoir to the mesh via a conduit having a tip with a diameter; The method of delivering an aerosolized medication to an infant described in Example 18, wherein the tip of the conduit is positioned at a distance from the mesh that is less than or equal to the diameter of the mesh. [Example 20] A method of delivering aerosolized medication to an infant as described in Example 17, wherein aerosolizing the quantity of medication includes aerosolizing a portion of the quantity of medication in at least a portion of the first 80% of each of the consecutive inspirations, such that expulsion air is provided in at least a portion of the last 20% of each of the consecutive inspirations. [Example 21] A method of delivering aerosolized medication to an infant as described in Example 17, wherein the one or more respiratory sensors include a respiratory sensor capsule connected to the patient's abdomen. [Example 22] connecting the aerosolization device to a breathing system; diverting a portion of the airflow from the respiratory system to a chamber of the aerosolization device via at least one airway; 18. The method of delivering an aerosolized medication to an infant of Example 17, wherein the chamber is configured to mix a portion of the airflow with the aerosolized medication. [Example 23] A method of delivering aerosolized medication to an infant as described in Example 22, wherein a portion of the airflow is a respiratory flow and is less than the amount of air that continues to the expiratory limb of the respiratory system. [Example 24] A portion of the airflow is diverted using at least one barrier defining the at least one air passage; 23. The method of delivering aerosolized medication to an infant described in Example 22, wherein the at least one barrier is configured to divert a portion of the airflow to the aerosol chamber through the at least one airway and to divert another portion of the airflow from the inspiratory limb toward the expiratory limb. [Example 25] A method of delivering aerosolized medication to an infant as described in Example 24, wherein the at least one barrier includes a first barrier defining a first airway and a second barrier defining a second airway. [Example 26] The first ventilation channel is provided at a lateral end of the first barrier, the second ventilation passage is provided at a position beyond the leading edge of the second barrier; The method of delivering aerosolized medication to an infant described in Example 25, wherein the lateral ends and the distal edge extend in different directions from each other so that the respiratory flow moves in multiple directions past the first barrier and the second barrier. [Example 27] The method of delivering aerosolized medication to an infant described in Example 17, wherein the patient interface comprises nasal prongs or a nasal mask. [Example 28] A method of delivering an aerosolized medication to an infant described in Example 17, further comprising delivering the aerosolized medication to the infant's airway via a patient interface. Example 29: A method for initializing an aerosolization system, comprising: connecting the aerosolization device to a controller, a breath sensor, a drug source, and a breathing system; entering user access credentials into said control device; inputting patient-related information and medication information into said control device; connecting the respiratory sensor to a patient; priming the aerosolization device; connecting a patient interface to the patient's airway. [Example 30] A method for initializing the aerosolization system described in Example 29, further comprising executing a wake-up sequence that cycles through multiple audio alarms, visual alarms, or both audio and video alarms. [Example 31] A method for initializing an aerosolization system described in Example 29, wherein the access authentication includes one or more of a user identifier, a password, property authentication, and biometric authentication. [Example 32] A method for initially setting up the aerosolization system described in Example 29, wherein the respiratory sensor is adhered to the abdomen of the patient. [Example 33] A method for initializing the aerosolization system described in Example 29, further comprising confirming detection of breath after connecting the breath sensor to the patient. [Example 34] A method for initializing the aerosolization system described in Example 29, wherein the drug source has a vented vial access device (VVAD) connected to a fluid supply line. [Example 35] A method for initializing the aerosolization system described in Example 29, wherein connecting the aerosolization device to the control device, respiratory sensor, drug source and respiratory system includes connecting a fluid supply line between the drug source and the aerosolization device. [Example 36] A method for initializing an aerosolization system described in Example 29, wherein priming the aerosolization device includes aerosolizing a portion of the medication before connecting the patient interface to the patient's airway. [Example 37] A method for initializing the aerosolization system described in Example 29, further comprising connecting the patient interface to the aerosolization device. [Example 38] A method for initially setting up the aerosolization system described in Example 29, wherein the patient interface is secured to the patient via one or both of at least one strap and a foam pad configured to be placed on the patient's head. [Example 39] A method for initializing the aerosolization system described in Example 29, further comprising delivering an aerosolized dose of medication to a patient via the patient interface. [Example 40] A method for initializing the aerosolization system described in Example 39, further comprising verifying that the timing of delivery of the dose is synchronized with detected inspiration.

Claims

1. 1. An aerosolization system comprising: a breathing system having an inspiratory limb and an expiratory limb; 1. An aerosolization device comprising: an aerosol chamber having a first end and a second end; an aerosol generator disposed at the first end of the aerosol chamber, the aerosol generator having a reservoir configured to receive a quantity of liquid medicament to be aerosolized by the aerosol generator, and a vibrating mesh of a photoforming perforated plate; an aerosol generator configured to deliver the quantity of medicament from the reservoir to the mesh and vibrate the mesh to aerosolize the medicament into particles having a mass median aerodynamic diameter (MMAD) of less than about 3 μm at a flow rate of at least 0.1 ml / min; a patient interface disposed near a second end of the aerosol chamber; and an aerosolization device comprising: a respiratory adapter configured to connect the aerosolization system to the respiratory system, the respiratory adapter including an inlet and an outlet, a fluid flow path configured to deliver gas from the respiratory adapter toward both the first end of the aerosol chamber and the aerosol generator, the respiratory adapter including a flow diverter mechanism configured to divert a portion of the airflow from the respiratory system to the aerosol chamber, the aerosol chamber configured to mix the portion of the airflow with aerosolized medicament from the aerosol generator; at least one respiratory sensor configured to detect inspiration of the patient; a controller configured to operate the aerosol generator to aerosolize the dose of medicament in synchronization with detected inspiration.

2. 10. The aerosolization system of claim 1, wherein the patient interface is positioned within about 1-8 cm of the aerosol generator.

3. 10. The aerosolization system of claim 1, wherein a portion of the airflow is a respiratory flow and is less than the amount of air that continues to the expiratory limb of the breathing system.

4. the flow diverter structure having at least one barrier defining the at least one air passage; 2. The aerosolization system of claim 1, wherein the at least one barrier is configured to divert a portion of the airflow to the aerosol chamber through the at least one air passage and to divert another portion of the airflow from the inhalation limb toward the exhalation limb.

5. the at least one barrier includes a first barrier defining a first air passageway and a second barrier defining a second air passageway; the first ventilation passage is provided at a lateral end of the first barrier; the second ventilation passage is provided at a position beyond the leading edge of the second barrier; 5. The aerosolization system of claim 4, wherein the lateral ends and the distal edge extend in different directions so that respiratory flow moves in multiple directions past the first and second barriers.

6. 10. The aerosolization system of claim 1, wherein the aerosolization device further comprises a conduit configured to deliver the quantity of liquid medicament from the reservoir to the aerosol generator.

7. the tip of the conduit has a diameter; 7. The aerosolization system of claim 6, wherein the tip of the conduit is positioned at a distance from the mesh that is equal to or less than the diameter of the mesh.

8. 10. The aerosolization system of claim 1, wherein synchronizing the aerosolization of the dose of medicament comprises aerosolizing a portion of the dose of medicament during at least a portion of the first 50-80% of each of the consecutive inspirations, such that purge air is provided during at least a portion of the last 20% of each of the consecutive inspirations.

9. 10. The aerosolization system of claim 1, wherein the at least one respiratory sensor comprises a respiratory sensor capsule connected to the patient's abdomen.

10. 10. The aerosolization system of claim 1, wherein the control device is removable from the aerosolization device.

11. 10. The aerosolization system of claim 1, wherein the aerosolization device is configured to perform aerosolization and deliver aerosolized particles of the medicament when the patient interface is oriented in each of a face-down position, a sideways position, and a face-up position.

12. 10. The aerosolization system of claim 1, further comprising a supply line configured to supply the dose of medicament from a supply source to the reservoir.

13. 10. The aerosolization system of claim 1, wherein the patient interface comprises nasal prongs or a nasal mask.

14. 10. The aerosolization system of claim 1, wherein the agent comprises a surfactant.

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