Design of aerosol system and interface to deliver clinically and economically feasible inhaled dose with neonatal CPAP device

Abstract

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

Description

[Technical field]

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

[0002] Delivery of surfactant to infants, especially premature infants, is invasive and often causes acute side effects, therefore it is desirable to be able to deliver surfactant 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 non-invasive methods. For example, conventional methods often deliver aerosolized drug continuously, i.e., the drug is aerosolized between patient breaths, which is 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. These and other problems are solved by embodiments of the present invention. [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 the nostrils of an infant. In some embodiments, fine aerosol droplets of medication are provided that can penetrate the lungs. In some embodiments, significantly higher efficiency of medication delivery is achieved than conventional non-invasive methods.

[0005] In one embodiment, a method of delivering an aerosolized medication to an infant is provided. The method comprises connecting an aerosolization device to the infant's airways and aerosolizing a quantity of medication with the 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 may be aerosolized within about 2-8 cm of the patient interface. The method may 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 couple the aerosolization system to a respiratory system having an inhalation limb and an expiratory limb. The respiratory adapter has at least one barrier defining at least one airway in communication with the aerosol chamber. The at least one barrier is configured to divert a first portion of the airflow from the inhalation 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 an intake of an infant and a controller configured to synchronize the aerosolization of the quantity of surfactant with the detected intake.

[0007] In one embodiment, an aerosolization system is provided. The system includes a respiratory system having an inhalation limb and an exhalation 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 container 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 inhalation, and a controller configured to operate the aerosol generator to aerosolize the quantity of medicament in synchrony with the detected inhalation.

[0008] In some embodiments, the patient interface is located within about 1-8 cm of the aerosol generator. In some embodiments, the respiratory adapter includes a diversion mechanism configured to divert a portion of the airflow from the respiratory system to the aerosol chamber via at least one airway. The aerosol chamber may be configured to mix the portion of the airflow with the aerosolized medicament provided by the aerosol generator. 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 diversion mechanism includes 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, 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 air passage is provided at a lateral end of the first barrier and a second air passage is provided beyond a distal edge of the second barrier, the lateral end and distal edge extending in different directions from one another such 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 located at 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 in at least a portion of the first 50-80% of each of a plurality of consecutive inspirations such that sweeping air is provided in at least a portion of the last 20% of each of a 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 the 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 supply the quantity of medicament from a 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 an aerosolized medication to an infant is provided, the method comprising: detecting an intake of the infant using one or more breath sensors; and, based on the detected intake, 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 via a conduit with a tip having a diameter. The tip of the conduit may be located at a distance equal to or less than the diameter from the mesh. In some embodiments, aerosolizing the quantity of medicament includes aerosolizing a portion of the quantity of medicament in at least a portion of a first 80% of each of a plurality of successive inspirations such that sweeping air is provided in at least a portion of a last 20% of each of a plurality of successive 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 breathing system and diverting a portion of an airflow from the breathing system to a chamber of the aerosolization device through 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 breathing 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 through the at least one airway and to divert another portion of the airflow from the inhalation 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 air passage is provided at a lateral end of the first barrier and a second air passage is provided beyond a distal edge of the second barrier, the lateral end and distal edge extending in different directions from one another such that respiratory flow travels in multiple directions past the first and second barriers.

[0013] In another embodiment, a method of initializing an aerosolization system is provided. The method includes connecting an aerosolization device to a controller, a respiratory sensor, a drug source, and a respiratory system, entering user access credentials into the controller, and entering patient-related and medication information into the controller. The method also includes connecting a 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 breath sensor is adhered to the patient's abdomen. In some embodiments, the method further includes verifying detection of a breath after connecting the breath sensor to the patient. In some embodiments, the drug source has a vented vial access device (VVAD) coupled to a fluid supply line. In some embodiments, connecting the aerosolization device to the controller, the breath 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 at least one strap and / or 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 description of the drawings]

[0015] [Figure 1] 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. [Diagram 2] FIG. 2 illustrates the flow pattern through the aerosolization device of FIG. 1. [Diagram 3] 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. [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] FIG. 4 illustrates the flow pattern from a low-flow breathing system through the aerosolization device of FIG. 3. [Figure 5B] FIG. 4 illustrates the flow pattern from a low-flow breathing system through the aerosolization device of FIG. 3. [Figure 6] 1 is an isometric view of an aerosolization device according to an embodiment. [Figure 6A] FIG. 7 is a cross-sectional view of the aerosolization device of FIG. [Figure 6B] FIG. 7 is a cross-sectional view of the aerosolization device of FIG. [Figure 6C] FIG. 7 is a cross-sectional view of the aerosolization device of FIG. [Figure 6D] FIG. 7 illustrates the flow pattern through the aerosolization device of FIG. 6. [Figure 7] FIG. 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. [Figure 11] FIG. 10 shows a vial holder of the control device of FIG. 9. [Figure 12] FIG. 10 illustrates the drug supply source of FIG. [Figure 13] FIG. 10 is a diagram showing the function of the control device in FIG. [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] FIG. 1 illustrates an aerosolization device according to an embodiment connected to an infant. [Figure 16] FIG. 13 shows a respiratory sensor capsule connected to an infant's abdomen. [Figure 17] FIG. 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] 1 is a bar graph illustrating emitted dose rate using an aerosolization system according to an embodiment. [Figure 21] 11 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. [Diagram 23] Graph showing deposition rate and particle size. [Figure 24] 13 is a graph showing the effectiveness of inhalation detection using a flow sensor and a breath sensor capsule. [Diagram 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] A graph showing powder mass distribution at different CPAP settings from a study. [Diagram 30] A graph showing powder mass distribution at different CPAP settings from a study. [Diagram 31] A graph showing powder mass distribution at different CPAP settings from a study. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The following description of the embodiments is not intended to limit the scope, applicability, or configuration of the present disclosure. The following description of the embodiments is intended to provide those skilled in the art with an enabling description for implementing 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 the aerosolization system and method according to the embodiments of the present invention, the aerosolized drug and the respiratory gas are mixed in an aerosolization chamber isolated from the direct flow of the respiratory system, such that a small amount of the respiratory gas enters the aerosolization chamber, while the majority of the respiratory flow bypasses the aerosolization chamber and passes through the expiratory limb of the respiratory system. Such a design keeps the delivery rate of the drug constant regardless of the flow rate from the respiratory system. Furthermore, the embodiments of the present invention provide a retrofit aerosolization configuration that can be interfaced with an existing respiratory system and can adapt the existing system to deliver a stable dose of aerosolized drug to the patient's airway. The aerosolization system described herein is also configured to include one or more respiratory sensors, such as one or more flow sensors (such as an electrical flow sensor), radar sensors (such as an ultra-wideband (UWB) radar sensor measuring chest displacement), CO2 sensors, high-speed temperature sensors, acoustic sensors, impedance plethysmography sensors, respiratory inductance plethysmography sensors, pressure sensors, etc., to allow the controller to predict the patient's inspiration. Thus, the aerosolization of the drug can be performed during or just before the patient's inspiration.

[0018] In an embodiment of the present invention, an aerosolization system is provided that isolates the aerosolized drug from the main respiratory gas flow to avoid loss or dilution of the aerosol generated during the inhalation 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] The present invention also generates and delivers surfactant aerosol only during the inspiration cycle (inhalation). Commonly used devices administer aerosol continuously. However, because infants can only inhale aerosol during inspiration, aerosol is lost and wasted during expiration (up to two-thirds of the breathing cycle) as it bypasses the airways. By limiting aerosol generation only during inspiration and delivering the aerosol close to the nostrils, the highest percentage of surfactant is deposited in the lungs.

[0020] The present invention also generates aerosols near the patient interface to increase the amount of aerosol delivered to the patient. Conventional nebulizers are placed at one point on the inspiratory tube of a ventilator or nCPAP circuit and generate aerosols in the continuous gas flow. As a result, the aerosol is significantly diluted during delivery and much of it 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 aerosols directly toward the patient interface (such as nasal prongs) and diverts a large portion of the gas flow from the nCPAP circuit away from the nebulized aerosol, thereby significantly reducing aerosol loss in the continuous gas flow of the circuit. The present invention also enables reduced administration times by using an aerosol generator that releases aerosol surfactant at flow rates that exceed those previously observed with other mesh nebulizers, which are 0.3 mL / min or more for undiluted surfactant. It is noted that 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 system described herein includes a reusable device controller and a disposable aerosolization device having a drug delivery circuit and / or a breath sensor, which is used only once for a single patient. Such an aerosolization device functions as a stand-alone drug delivery device integrated into various artificial respiratory devices (such as CPAP devices) and, in some embodiments, is not designed to connect to a hospital network or the Internet. For example, the controller may be a reusable component for use by multiple patients, with a flat panel touch screen display, electronics and software. For example, the three main functions of the controller are to detect inspiration via a breath sensor placed on the patient's abdomen (e.g., designed for use only with a single patient), to deliver suspension to the aerosolization device via an integrated delivery mechanism, and to generate aerosol during inspiration to the nCPAP interface. These functions may be performed in synchrony with the infant's inspiration cycle. The flat panel touch screen is configured to allow the user to set and monitor delivery parameters, alarms and system diagnostics using a GUI (Graphical User Interface). The controller may 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 drug source container may be a medicine vial containing the medication.

[0022] In some embodiments, a disposable aerosolization device for single-use with a single 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 includes 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 stands out for its small droplet size and high output flow rate performance. The PDAP mesh has an innovative structure that has up to 20 times more holes with smaller diameters than conventional meshes. The aerosol generator is designed to supply aerosol near the infant's airway and connect to a conventional nCPAP system.

[0023] The reusable controller has an integrated touch screen with a processor that monitors delivery parameters, alarms (visual and audible), and system diagnostics. The controller and pod work in tandem 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 controller activates a drug delivery mechanism that delivers drug to the nebulizer for breath-synchronized aerosol generation in sync with the infant's inspiration cycle.

[0024] The lyophilized surfactant is reconstituted in the glass vial it came in, resulting in 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 septum of the vial, 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 nebulizer (a proprietary vibrating mesh) 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 the use of surfactants, the methods and devices of the present disclosure can be used with any liquid drug, including, but not limited to, bronchodilators, anti-infectives, anti-virals, anti-inflammatory mucokinetics, siRNA, PFOB, and the like, that 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. No. 5,758,637, U.S. Pat. No. 6,235,177, U.S. Patent Publication No. 2015 / 0336115, and U.S. Patent Publication No. 2016 / 0130715, the entire contents of which are incorporated herein by reference. The aerosolization device 100 has 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 and a 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 the medication, and the medication is delivered to the mesh via 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 tracheotomy 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 an inspiratory limb of the respiratory system. For example, the inlet 108 is an inlet barrier configured to couple with a Flexitrunk® midline interface manufactured by Fisher & Paykel Healthcare and direct respiratory flow to 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 gas 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 having a cross-sectional area of ​​about 80% or greater relative to 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 disposed at a first end of the aerosol chamber 102 such that the aerosolized drug by the aerosol generator 112 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 size in the range of 4-5 microns. However, to deliver drug through the nostrils through the narrow airways of a premature infant's airway, the aerosol droplets generally need to be smaller 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, the droplets may not deposit in the lungs and may be exhaled. In this case, the efficiency of dosing to the lungs is reduced. An embodiment of the present invention uses a mesh hole size designed to generate droplets having an average diameter between 2-3 microns. For example, in some embodiments, the aerosol generator 112 comprises a mesh of a photoformed perforated plate (PDAP) configured to generate aerosol particles of small diameter, such as less than 3 μm. Such a mesh is disclosed in the aforementioned U.S. Patent Publication No. 2016 / 0130715. By locating the aerosol generator 112 close to the patient interface 104, the aerosolized medicament released during the inhalation cycle is preferentially drawn in, minimizing interruption 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 forming the inlet 108 is designed to draw a portion of the respiratory flow from the inhalation limb of the respiratory system into the aerosol chamber 102 near the first end via the fluid path 110. The fluid path 110 is in communication with the inhalation limb at a junction of the inhalation limb and at an angle of 90 degrees or less with respect to the respiratory flow in the limb and / or the upstream side of the inhalation limb. Such an arrangement allows for isolating the aerosolization chamber from the direct respiratory flow, e.g., the respiratory flow is introduced intermittently into the aerosol chamber 102 only when the patient inhales.

[0029] The flow pattern through the aerosolization system is shown in Figure 2. It shows the inhalation 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 the 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 inhalation creates a negative pressure in the aerosolization chamber. Excess respiratory airflow and / or exhaled gas is exhausted via the exhalation limb 202 of the breathing system.

[0030] The aerosolization systems of Figures 1, 1A and 2 can increase and stabilize the inhaled dose over conventional aerosolization systems over 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 over 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 steady dose of aerosolized medicament to a patient. The aerosolization device has an aerosol generator 300 disposed at a first end of an aerosol chamber 302, and a patient interface 304 disposed at an opposite, second end of the aerosol chamber 302. The aerosol generator 300 may be a nebulizer having a vibrating mesh that is selectively vibrable using a piezoelectric actuator. In some embodiments, the aerosol generator 300 has a reservoir configured to receive and / or contain a quantity of liquid medicament to be aerosolized. The aerosol generator 300 is coupled to a medicament supply line 306 configured to deliver a quantity of liquid medicament to the reservoir, such as via a pump (not shown). The aerosolization device may have 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 inhalation and exhalation limbs, respectively, of a respiratory system. Examples of respiratory systems that can be used 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 flow path for respiratory gas, while in other embodiments, the inlet 310 and the outlet 312 are separate components that are coupled to each other. The inlet 310 and / or the outlet 312 are configured to receive the end of a gas conduit of the respiratory system. For example, the airflow barriers of the inlet and / or the outlet correspond to the one-way circuit of a standard nCPAP circuit. Thus, the barriers can minimize interruption of the airflow from the inlet to the outlet, thereby suppressing turbulence in the aerosol chamber 302.

[0033] 3A, the aerosolization device also has 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, but in some embodiments may deliver to another location, such as an inner 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 at an angle of no more than 90 degrees relative to the flow path formed in 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 extends at least partially in a direction opposite to the flow of air through the inlet 310 and / or outlet 312. Such a location of the fluid flow path 314 allows the aerosol chamber 302 to be isolated from the continuous flow of respiratory gases that flows from the inlet 310 (inhalation limb) to the outlet 312 (exhalation limb). This results in several benefits. First, isolating the aerosol chamber 302 from the continuous flow prevents the aerosolized drug from being "blown away" or diluted by the gas flow. Second, isolation allows the aerosol chamber 302 to be pre-loaded with aerosolized drug immediately prior to a respiratory event while also maintaining any drug remaining 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 medicament. The portion of the respiratory gas drawn into the aerosol chamber 302 is drawn by 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 mist to the patient interface 304 while minimizing shock. Specifically, the aerosol chamber 302 is designed such that the aerosol generator 300 is located opposite the patient interface 304. Additionally, 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 adjacent the patient interface 304, thereby reducing shock on 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 from a high flow breathing system through the aerosolization device of Figures 3 and 3A. While the patient is inhaling at a rate of 1 L / min, the inspiratory flow flows through the inlet 310 at a rate of 8 L / min. The pressure at the expiratory limb connecting to the outlet 312 is 490.32 Pa (5 cmH2O). A portion of the respiratory gas is drawn through the fluid flow path 314 into the aerosol chamber 302 as the patient inhales through the patient interface 304.

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

[0038] 6-6D show another embodiment of the aerosolization device 600. The aerosol generator 612 (FIGS. 6A-6D) is disposed on a first side of the aerosol chamber 602, similar to that described above, and the patient interface 604 is disposed on an opposite, second side of the aerosol chamber 602. The aerosol generator 612 has a receptacle configured to receive and / or contain a quantity of liquid medicament to be aerosolized. For example, in some embodiments, the aerosolization device 600 has 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 receptacle, if any). In some embodiments, the receptacle 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 tracheotomy tube, or the like. The aerosolization device 600 also has at least one power connection 640. As shown, the power connection 640 is a port that allows a power cable to be connected to the aerosolization device 600 to provide power and / or control commands to the 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, a nCPAP system, and / or combinations thereof. For example, the respiratory adapter 606 includes an inlet 608, such as an inlet barrier, configured to couple to an inhalation 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 and retained (e.g., retained by a friction fit and / or other securing mechanism) within the conduits of the inhalation 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 inhalation limb 650 and / or expiratory limb 652 are inserted and retained (e.g., retained by a friction fit and / or other securing mechanism) within the inlet 608 and outlet 616, respectively. Other techniques may be used to connect the inlet 608 and / or outlet 616 to the breathing system, 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 such that the drug aerosolized by the aerosol generator 612 is introduced into the aerosol chamber 602. For example, the drug is delivered to the aerosol generator 612 via a drug supply port 614 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 over the mesh of aerosol generator 612. Surface tension ensures that the liquid stays on and spreads over the surface of the mesh, resulting in total or near total aerosolization of the liquid. This allows aerosolization device 600 to operate in any orientation, allowing treatment of a patient (such as an infant) on their side, back, or stomach. For example, in some embodiments, the tip of drug delivery port 614 is located 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 located adjacent to patient interface 604, and aerosol chamber 602 is the only component located between aerosol generator 612 and patient interface 604. By locating the aerosol generator 612 in this manner adjacent the patient interface 604, aerosolized medicament released during the inspiratory cycle is preferentially inhaled, minimizing interruption of the continuous or bias flow through the respiratory system circuit. The aerosol chamber 602 is shaped such 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 inhalation rim 650 of the respiratory system near the first end through a fluid path into the aerosol chamber 602. The fluid paths are described in more detail below with reference to FIGS. 6B and 6C. In some embodiments, the inlet 608 is designed to redirect gas from the respiratory system to the aerosol chamber 602 without substantially increasing, or at least not significantly increasing, the resistance or work of breathing (e.g., inhalation pressure) for the patient. This is achieved by providing a fluid path in the respiratory adapter 606 with multiple barriers. These barriers direct a portion of the air flowing from the inhalation rim (only as much as is needed for inspiration) into the aerosol chamber 602 while significantly reducing the turbulence of the airflow drawn into the aerosolization device 600. As a result, a more laminar flow can be generated in the aerosol chamber 602.

[0042] 6B and 6C show the aerosolization device 600 in a two-part state. Although shown as two separable components in the figures, the aerosolization device 600 may be composed of any number of components that are connected together (e.g., connected by connecting / engaging features, etc.). Alternatively, the aerosolization device 600 may be composed of a single component formed by molding, 3D printing, and / or other known or unknown manufacturing techniques. As shown in FIG. 6B, a plurality of barriers are formed in the portion of the aerosolization device 600 that has a fluid path. In the illustrated embodiment, the aerosolization device 600 has a first barrier 622 that directs a large amount of flow from the inhalation rim 650 to the exhalation rim 652 while allowing 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 an air passage 624 between the barrier 622 and the side wall of the housing of the aerosolization device 600. The air passage 624 allows a small amount of air to pass past the end of the barrier 622. Meanwhile, the 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. Although 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 has a second barrier 626 disposed near the barrier 622. As shown, the second barrier 626 is a generally U-shaped wall oriented in the opposite direction to the barrier 622 (although the second barrier 626 may be configured in other shapes and orientations, such as the second barrier 622 being generally linear across the entire width of the interior of the aerosolization device 600, or the second barrier 626 being curved and 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, such as sharing an inner portion, while in other embodiments, separate barrier components are provided. As shown, the second barrier 626 extends to both side walls of the housing, but there is a gap between the leading edge of the second barrier 626 and the top of the housing of the aerosolization device 602 to provide 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, forming a generally laminar flow within the aerosol chamber 602. However, in some embodiments, rather than directing the airflow towards the top of the housing, the second barrier 626 is configured to direct the air towards the bottom of the housing and towards a central opening formed between the upper and lower barriers. Any number of designs of barriers and / or other flow diverting mechanisms (including valves) can be used to isolate the aerosol chamber 602 from the direct flow of respiratory gases from the respiratory system while still allowing some flow of respiratory gases to occur 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 all the way from the bottom surface of the housing of the aerosolization device 600 to the top surface of the housing. As a result, only airflow through the air passages 624 at each end of the barrier 622 can pass over the barrier 622 while directing the majority of the airflow towards 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 (passing through a humidifier, etc.) passes through the breathing adapter 606, the barrier 622 redirects a majority of the air through the outlet 616 to the exhalation rim 652. As described above, due to the barrier 622 forming one or more airways 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 airway reaches the second barrier 626. Due to the presence of the second barrier 626, the 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 proximate 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 at a location near the first end 618 proximate 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 the aerosolization chamber 602 from the direct flow in the breathing system. Additionally, in some embodiments, other mechanisms may be utilized to direct the air flowing from the breathing system into the aerosolization chamber 602 each time the patient takes a breath. For example, in some embodiments, one or more one-way valves are incorporated between the aerosolization chamber 602 and the inhalation rim 650 and / or exhalation rim 652. The valve or valves seal or otherwise isolate the aerosolization chamber 602 from the respiratory system until the patient inhales, at which point the valve or valves 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 flow from the inhalation rim 650 into the aerosol chamber 602, embodiments of the present invention reduce turbulence and make the air drawn into the aerosol chamber 602 more stratified, which in turn facilitates deposition of the medication in the lungs. The barriers can be designed so that the flow rate of gas / air drawn through the barriers is the same as or close to the infant's inhalation flow (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 introducing the airflow into 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 airflow drawn into the aerosol chamber 602 per inspiration while also reducing the amount of turbulence in this airflow. This configuration can also reduce dilution of the aerosolized medication with the air provided by the inhalation rim 650.

[0047] FIG. 7 illustrates the aerosolization device 600 of FIGS. 6-6D in connection with 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 an opening of the fluid supply line 700 to the tip, fluid from the fluid supply line 700 passes through the drug supply port 614 and into 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 inhalation limb 650 of the respiratory system 702, while the outlet 616 and the exhalation limb 652 are not visible in this view. Air and / or other respiratory gases are delivered from the inhalation 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. The majority of the remaining airflow of the respiratory system 702 is directed by the respiratory adapter 606 to the exhalation 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 provide operational commands (such as commands to control the timing and length 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 a signal 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 a device 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 a drug port of the aerosolization device via a luer connection 804 and a length of fluid supply line 806. Also coupled to the aerosolization device 800 is 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 a breath sensor to a controller.

[0051] FIG. 9 shows the aerosolization device 800 connected to a drug source 802 and a controller 812. The controller is configured to deliver liquid drug to the aerosolization device 800 via a fluid supply line 806 and to operate the aerosolization device 800. In some embodiments, the controller 812 operates the aerosolization device 800 in response to a detected patient inhalation. For example, the controller 812 is coupled to a respiratory sensor 814 that can detect the start, duration and / or end of a patient's inhalation. In some embodiments, the respiratory 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, the controller 812 receives a signal from the respiratory sensor 814 indicating that the patient is beginning to inhale. The controller 812 then sends a command to provide a quantity of liquid drug to an aerosol generator of the aerosolization device 800 and to operate the aerosol generator to aerosolize the liquid drug during inhalation.

[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 adapters are 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 initiate sensing of the inhalation cycle.

[0053] FIG. 10 illustrates a controller 812. The controller 812 has a user interface 818, such as a display screen. In some embodiments, the user interface 818 is a touch screen. The controller 812 includes one or more input devices, such as buttons, dials, a keypad, a touch screen, etc., that allow a user to operate the controller 812 to adjust settings, such as a dose level. The controller 812 has a number of 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 has one or more indicators 824, such as LEDs, configured to alert a user of the status of various functions. For example, the indicators 824 inform the user whether the aerosolization device 800 and / or the breath sensor 814 are properly connected, whether the power source 832 of the controller 812 is working (i.e., connected and / or charging or fully charged in the case of a battery), whether a fault has been detected in the system, 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 flowing or squeezing.

[0054] 12 illustrates 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 device described herein includes an aerosol generator that can be coupled to various artificial ventilation systems. The aerosol generator receives 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 (e.g., pre-delivered to the aerosol generator) prior to treatment to expedite delivery. The pump is controlled by a controller that controls the delivery time and dosage of the fluid.

[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 the aerosol generator. For example, the memory stores instructions indicating the amount of fluid to be delivered to the aerosol generator in one dose per operation of the aerosol generator, the amount of fluid to be delivered over a particular period or number of times, etc. The stored instructions are based on the patient's body size, the patient's age, the patient's sex, the type of medication, the fluid additive, the desired amount of aerosol, etc. The memory also stores instructions for operating the aerosol generator. As shown in the figures, 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 a signal to activate a piezoelectric actuator (or other actuator) in the aerosol generator. When the piezoelectric actuator is activated, it vibrates a vibrating member to aerosolize the fluid and send it to the patient (i.e., delivered by inspiration). Thus, the memory stores instructions for controlling when to start and stop the piezoelectric actuator, and the vibration frequency or number of vibrations.

[0057] The aerosolization system described herein can enhance therapeutic efficacy by timing the generation of aerosols. For example, the aerosol delivery system can begin aerosolizing the medicament 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 medicament further into the patient's lungs, enhancing delivery of the medicament to the patient. The aerosol delivery system can also aerosolize the medicament 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 respiratory cycle. Any number and / or combination of respiratory sensors can be used for any application in monitoring the patient's respiratory cycle.

[0059] In some embodiments, the flow sensor is coupled to the gas delivery conduit to sense changes in airflow during inspiration (e.g., forced, assisted, or spontaneous breathing). In some embodiments, a flow sensor is also coupled to the gas return conduit to detect the start and end of expiration. In yet another embodiment, the aerosol delivery system has flow sensors coupled to the gas delivery conduit and the gas return conduit. When 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 the 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 for aerosol delivery (e.g., less than 10 milliseconds from the start of inspiration).

[0060] To predict a patient's inspiration, first, one or more breath 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 prior to 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) prior to and / or during the predicted inspiration. In this way, the aerosol is ready for the patient at the beginning of inspiration. The aerosol delivery system can predict the breathing cycle to generate aerosol for the patient, and can also use breath sensors to identify spontaneous / irregular breathing that is not part of the normal pattern. If spontaneous breathing is identified, the aerosol delivery system immediately delivers 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 to inhale. 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, and the last portion of the inspiration draws in chase air to help the aerosolized medication reach the deep lungs. For example, as shown in multiple plots, the controller 812 aerosolizes the medication only within the first 80% of each inspiration, and the last 20% of each inspiration draws in chase air into the patient's airways. Of course, other aerosolization patterns may be used. For example, aerosolization of the drug occurs during the first 50%-90% (more typically between 60%-80%, and even more typically between 70%-80%) of each inspiration. Beyond 80% of the time, more aerosol is exhaled in the upper airways before reaching the lower airways. This causes the last 10%-50% (more typically about 20%-40%, and even more typically about 20%-30%) of inspiration to draw expelled air into the patient's airways.

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

[0063] Next, instructions for use of 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 controller 812 of the aerosolization system. For example, the user inserts the connector of the pod 810 into one of the ports 820 of the controller 812. In some embodiments, the user interface 818 displays a notification that the pod 810 is properly connected to the controller 812. In some embodiments, the controller 812 and / or a stand (not shown) that supports the controller 812 in a fixed or other manner includes a basket and / or other support structure that supports the 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 a breath sensor 814 (such as a breath sensor capsule) to both the pod 810 and the patient, and then check that the patient is inhaling. As shown, in some embodiments, connecting the respiratory sensor to the pod is done by inserting a fitting, 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 inhalation 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 in place. No tape is attached to the tubing of the respiratory sensor 814. The user interface 818 prompts the user to confirm that the controller 812 has received the respiratory signal and is properly displayed on the user interface 818.

[0064] As shown in FIG. 14E, the user is shown instructions on how to set up the drug supply line 806 and the 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 piercing portion (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 supply mechanism, which is then closed. The vial is placed horizontally and coupled to the fluid supply line 806. The luer end of the VVAD 828 is placed into the luer holder portion of the holder 826 and rotated upward and inserted into the metal clip, with the identification window facing outward. The aerosolizer 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 have been connected, the aerosolization device 800 is primed.

[0065] FIG. 14F illustrates priming of the pump. Priming is performed by selecting a 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 start aerosol generation. The user then verifies that the aerosolization system is functioning properly by observing that aerosol is generated and released from the patient interface (if attached) or the opening of the aerosolization device 800. If aerosol is observed, the user continues with the setup. If aerosol is not observed, the user repeats the priming and aerosol check procedure. Before or after the aerosol check is completed, the user interface 818 prompts the user to connect a patient interface (such as nasal prongs) to the aerosolization device 800. The user selects an appropriate size 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 shape helps the user to properly align the patient interface in the correct orientation, although other shapes are possible. As shown in FIG. 14H, the 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, the aerosolization device 800 is secured to the infant's airway and head using one or more straps and / or other restraints so that the aerosolization device remains in place even if the infant moves. In some embodiments, the 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 the aerosolization device 800 and extends between the aerosolization device 800 and the infant's head (positioned laterally away from the portion of the aerosolization device 800 having the aerosol generator).The foam pad is made of multiple peelable foam layers, and the distance between the aerosolization device 800 and the baby's head can be adjusted by peeling and / or otherwise removing the layers. Often, the foam pad has a curved surface designed to match or substantially match the contours of the baby's head. Once in place, the foam pad (and any straps) function to maintain the aerosolization device 800 in the proper position and orientation with respect to the baby, regardless of the baby's movements or orientation (supine, side, prone). Once the aerosolization system is connected to the baby, the user operates the user interface 818 as shown in FIG. 14I to begin administering medication to the baby. For example, the user confirms the patient data and total dose, and verifies that the number of vials of medication matches the pharmacy calculations and dispensing paperwork provided by the pharmacist. After verifying the data, the user operates the control device 812 to begin the medication procedure. Once the medication procedure is started, data such as the breathing 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 (5%, 10%, 15%, 20%, etc.) is reached. If the low priority alarm is not acknowledged by the user for a predetermined 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 a medium alarm is activated. If the alarm is not acknowledged by the user for a predetermined time, a high priority alarm is activated. The user is instructed to "replace vial and resume dosing from the medication delivery screen." The empty vial is replaced with a new medication vial and 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, the low priority alarm is a visual alarm only and is displayed with text information only on the user interface 818. In some embodiments, the medium priority alarm includes visual and audio elements and is combined with a corresponding color alarm indication (e.g., yellow) and corresponding audio and text information. In some embodiments, the high priority alarm includes visual and audio elements and is combined with a corresponding color display box (e.g., red) on the user interface 818 and text information on the user interface 818. In some embodiments, the alarm is generated when no breath is detected, no valid consecutive breath is detected (when no valid consecutive breaths consisting of three consecutive valid breaths are detected. Each breath is determined to be a valid breath if it has an inspiration time of 100 milliseconds or more. Each breath is determined to be an invalid consecutive breath if it contains at least one invalid breath. An invalid breath is determined to be an invalid breath if the inspiration time is less than 100 milliseconds), the nebulizer cable becomes detached from the pod during medication administration, a wet / dry condition (wet / dry) An alarm may be activated when, but is not limited to, a drug discharge event is not detected (e.g., tubing is kinked and drug is not being delivered to the aerosol generator, no aerosol is being emitted and all drug is coming out of the vent, aerosol is being aerosolized with no drug coming out of the vent, aerosol is being aerosolized with drug coming out of the vent), the amount of drug remaining in the vial is below a threshold amount (including empty), the pod cable becomes disconnected from the pod while a drug is being dispensed, the pod cable becomes disconnected from the pod when no drug is being dispensed, a pod communication failure is detected, an internal pod failure is detected, a system error is detected, the drug delivery mechanism has failed, main power has been 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 that minimizes flow through the area of ​​direct connection between the patient and the aerosol generator during aerosol generation. Additionally, the aerosolization device 1500 has a PDAP mesh or similar mesh capable of aerosolizing particles with a MMAD of less than about 3 μm (more preferably less than about 2 μm) at high flow rates (about 0.1 ml / min to 1.5 ml / min). The aerosolization device 1500 has 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 has one or more straps or other restraints 1502 for securing the aerosolization device 1500 against the infant's head and airways. Additionally, the aerosolization device 1500 has 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 orientation (back, side, stomach). The foam pad 1504 is made of multiple peelable foam layers, and the distance between the aerosolization device 1500 and the infant's head can be adjusted by peeling and / or otherwise removing layers. In many cases, the foam pad 1504 has a curved surface designed to match or substantially match the contours of the infant's head. The aerosolization device 1500 is made of a lightweight material (such as medical grade foam plastic) that allows the infant to move around without moving 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 abdomen of the infant. As shown, the 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 using the change in volume of the sensor capsule 1600 in response to abdominal movement associated with breathing. Using data from one or more inspiration cycles, a controller (not shown) monitors the flow into and out of the capsule associated with the abdominal sensor volume change and maximizes surfactant delivery efficiency by delivering aerosolized surfactant in sync with the infant's breathing.

[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 is 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 for a medical professional to set aerosol delivery conditions. For example, the additional controller 1706 can set the flow rate at which aerosol delivery begins, the inspiration time at which aerosol delivery occurs, and / or other conditions to regulate the timing, amount, duration, etc., 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] The system 1700 also has one or more flow and / or other respiratory sensors 1708. As shown, the flow sensor 1708 is coupled to the inhalation limb 1710 of the respiratory system 1712, for example, upstream and / or downstream of an optional humidifier 1714. The respiratory sensor 1708 is used to detect the infant's inhalation. In other embodiments, the 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 the controllers 1702 or 1706, which initiate operation of the aerosolization device 1704 (similar to any of the aerosolization devices described herein) based on the inhalation data. The controllers 1702 and 1706 are electronically coupled to the aerosolization device 1704 to provide both power and operational commands to the aerosolization device 1704. In some embodiments, the aerosolization device 1704 has a PDAP mesh 1716 that produces aerosolized surfactant with a MMAD of less than about 3 μm, preferably less than about 2 μm, at a flow rate of at least 0.1 ml / min. Such an aerosolization device 1704, in combination with the controllers 1702, 1706 and the breath sensor 1708, allows 1) the generation and delivery of aerosol particles small enough, 2) the delivery of the aerosol in synchrony with breathing, and 3) the placement of the aerosol generator in close proximity to the infant's airways while preventing continuous gas flow to minimize flow through the direct connection area between the patient and the aerosol generator during aerosol generation (as clearly shown in FIGS. 6-6D). As a result, the efficiency of delivery to the lungs is significantly improved, achieving efficiencies of about 25%-60%, more typically about 40%-60%.

[0073] FIG. 18 is a flow chart illustrating a process 1800 for delivering an 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 an intake of the infant using one or more breath sensors. For example, a breath sensor is attached to the infant's abdomen. The breath sensor detects an expansion of the infant's abdomen associated with the 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 via 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, such that the drug released from the tip will contact and creep up the surface of the mesh, allowing the aerosolization device to operate effectively in any orientation. 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 a number of successive inspirations, such that sweeping air is provided in at least a portion of the last 20% of each of a number of successive 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 breathing system and diverting a portion of the airflow from the breathing system to a chamber of the aerosolization device through 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 and is less than the amount of air that continues to the expiratory limb of the breathing 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 through the at least one airway and to divert another portion of the airflow from the inhalation 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 disposed at a lateral end of the first barrier and a second airway is disposed beyond a distal edge of the second barrier, the lateral ends and the distal edge extending in different directions such that respiratory flow travels in multiple directions past the first and second barriers.

[0075] FIG. 19 is a flow chart illustrating a process 1900 for initializing an aerosolization system. The process 1900 can be performed using any of the aerosolization devices, processors, and / or breath sensors described herein. The process 1900 begins at block 1902 with connecting the aerosolization device to a controller, a breath sensor, a drug source, and a breathing system. Here, a nebulizer cable is coupled between the aerosolization device and the controller (may be via a pod or other adapter), an inhalation limb of the breathing system is coupled to an inlet of the aerosolization device, an exhalation limb of the breathing system is coupled to an outlet of the aerosolization device, a breath sensor cable is coupled to the controller (may be 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] In block 1904, user access credentials are entered into the control device such that only authorized users can 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. In block 1906, patient-related and medication information is entered into the control device. This may include information such as a patient identifier, the patient's weight, and dose level. In block 1908, a breath sensor is connected to the patient. For example, the sensor is attached to the patient's abdomen. In some embodiments, breath detection is configured after connecting the breath sensor to the patient. In lock 1910, the aerosolization device is primed. For example, a portion of the medication is aerosolized to ensure the device is functioning properly before connecting the patient interface to the patient's airway. In block 1912, the aerosolization device is connected to the patient's airway. For example, nasal prongs are inserted into the infant's nostrils. In some embodiments, the patient interface needs to be secured to the aerosolization device before connecting the device to the patient. In some embodiments, one or more straps and / or foam pads are placed and / or secured around the infant to secure the aerosolization device in place. Once in place, the user may begin delivery of 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 performing a start-up sequence upon powering up the control device, which may include multiple repeated audio, visual, or both audio and video alarms to ensure the control device is functioning properly prior to use.

[0078] (Example) In vitro experiments were performed 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 sine wave small animal ventilator from Harvard Apparatus connected to the patient adapter (in this example, nasal prongs) of an aerosolization device similar to that of Figs. 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 of Fig. 20, the larger the prong size, the greater the emitted dose. Notably, 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 FIG. 21, the delivery efficiency was affected by gas flow, with the delivery efficiency decreasing slightly as the flow rate increased. For example, at low flow rates (6 LPM), the emitted dose with the large nasal prongs (5560) ranged from about 50% to about 60% over the entire range of respiratory rates tested. Meanwhile, at high flow rates (10 LPM), the emitted dose ranged from about 42% to about 47%. As the respiratory rate increased, the difference in efficiency with increasing flow rates became smaller. For example, the emitted dose rate ranged from about 44% to about 60% at 60 BPM, while the emitted dose rate ranged from about 42% to about 51% at 120 BPM. Based on these results, the aerosol generator described herein was found to enable uniform inhaled drug doses across the entire range of clinically relevant 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-invasive delivery of surfactant (or other drugs) to infants, particularly preterm infants. To achieve effective and efficient administration of drug aerosols to preterm infants, a combination of the following attributes is required: 1) sufficiently small aerosol particles; 2) aerosol delivery synchronized with breathing; and 3) placement of the aerosol generator in close proximity (within about 1-8 cm) of the infant's airway while preventing continuous gas flow to minimize flow through the direct connection area between the patient and the aerosol generator during aerosol generation. By meeting these conditions, surfactant delivery rates of greater than 40% and up to about 60% are achievable, which is a significant improvement over conventional efficiencies of less than 10%.

[0081] Given the respiratory physiology of preterm infants, a non-invasive, adequate delivery of aerosolized surfactant to infants requires the use of a nasal delivery method, such as nasal prongs that can be inserted into the infant's nasal passages. It is desirable to deliver aerosolized particles smaller than about 2 μm by such a delivery method. Larger particles often impinge within the aerosolization device interface and / or on the airways before dispersing in the infant's lungs. This is also shown in Figures 22 and 23, which show the particle deposition rates for various particle sizes (using 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 shows only 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 usually about 50%-70%, which represents particles that are not delivered to 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. Enhanced lung deposition was observed for both neonates with aerosols with 2 μm MMAD, with deposition rates of just under 40% in neonate 1 and just under 60% in neonate 2. These results indicate that small aerosol particles are required to maximize delivery efficiency.

[0082] Conventional nasal delivery methods typically use particles with MMADs between 4 and 7 μm, with a geometric standard deviation of about 2.0 or greater. This is because many surfactants are viscous, and it is very difficult for conventional jet nebulizers, special jet nebulizers, mesh nebulizers, heated capillary generators, etc. to aerosolize undiluted surfactants into small particles at flow rates that can achieve efficacy. The impaction rate of such conventional delivery methods reduces the effective amount of aerosol by up to 80% in a single dose. Only 40-60% of the remaining aerosol (composed of particles smaller than about 2 μm) reaches the lower airways of the lungs, resulting in an overall efficiency of about 10% of the initial dose emitted by the aerosol generator.

[0083] In some embodiments of the present invention, systems and methods are provided for generating sufficiently small aerosol particles using an aerosolization device, such as the device described above with reference to Figures 1-8. In particular, in some embodiments, 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) is used to uniformly generate aerosolized surfactant at 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. Embodiments of the present invention utilize the capabilities of such an aerosol generator to achieve a particle size sufficiently small to effectively and efficiently deliver the surfactant to the lungs. For example, aerosols with an MMAD of less than 3 μm can achieve a pulmonary delivery efficiency of about 40-60% of the nominal dose of surfactant via the nose.

[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 by aerosolization during expiration and between breaths. For example, infants often have an inspiration:expiration ratio of about 1:1 to about 1:3. Thus, aerosolized surfactant is typically only inspired about 25-50% of the time. In conventional systems, the aerosol is often carried by a gas flow of about 6-10 LPM for bubble CPAP. This flow rate exceeds the infant's maximum inspiratory flow rate, so up to half of the aerosolized medication is wasted.

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

[0086] FIG. 24 shows 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 fixed 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 FIG. 24, the sensor signal from the breath sensor capsule detected each inspiration and expiration detected by the flow sensor, which detected the start of inspiration slightly before the flow sensor. This time can be used by the controller 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. Also, from FIG. 24, it can be seen that although these inspirations occurred over a period of 5 seconds, inspiration only took up about one-third of that time. Thus, more than two-thirds of the aerosolized surfactant would be wasted if the delivery of the aerosol was not synchronized with breathing.

[0087] In some embodiments, the aerosolization device described herein includes an aerosol generator that can be coupled to various artificial ventilation systems. The aerosol generator receives 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 (e.g., pre-delivered to the aerosol generator) prior to treatment to expedite delivery. The pump is controlled by a controller that controls the delivery time and dosage of the fluid.

[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 the aerosol generator. For example, the memory stores instructions indicating the amount of fluid to be delivered to the aerosol generator in one dose per operation of the aerosol generator, the amount of fluid to be delivered over a particular period or number of times, etc. The stored instructions are based on the patient's body size, the patient's age, the patient's sex, the type of medication, the fluid additive, the desired amount of aerosol, etc. The memory also stores instructions for operating the aerosol generator. As shown in the figures, 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 a signal to activate a piezoelectric actuator (or other actuator) in the aerosol generator. When the piezoelectric actuator is activated, it vibrates a vibrating member to aerosolize the fluid and send it to the patient (i.e., delivered by inspiration). Thus, the memory stores instructions for controlling when to start and stop the piezoelectric actuator, and the vibration frequency or number of vibrations.

[0089] The aerosolization system described herein can enhance therapeutic efficacy by timing the generation of aerosols. For example, the aerosol delivery system can begin aerosolizing the medicament 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 medicament further into the patient's lungs, enhancing delivery of the medicament to the patient. The aerosol delivery system can also aerosolize the medicament 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 respiratory cycle. Any number and / or combination of respiratory sensors can be used for any application in monitoring the patient's respiratory cycle.

[0091] In some embodiments, the flow sensor is coupled to the gas delivery conduit to sense changes in airflow during inspiration (e.g., forced, assisted, or spontaneous breathing). In some embodiments, a flow sensor is also coupled to the gas return conduit to detect the start and end of expiration. In yet another embodiment, the aerosol delivery system has flow sensors coupled to the gas delivery conduit and the gas return conduit. When 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 the 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 for aerosol delivery (e.g., less than 10 milliseconds from the start of inspiration).

[0092] To predict a patient's inspiration, first, one or more breath 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 the 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 predicted inspiration. In this way, the aerosol is ready for the patient at the beginning of the inspiration. The aerosol delivery system can predict the breathing cycle to generate aerosol for the patient, and can also use breath sensors to check for spontaneous / irregular breathing that is not part of the normal pattern. If spontaneous breathing is confirmed, the aerosol delivery system immediately delivers fluid to the aerosol generator for delivery to the patient.

[0093] Example 1 A two-part study was conducted to evaluate the safety and tolerability of inhaled surfactant administered during nCPAP 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 (machine-based CPAP) were enrolled in the study. Infants were first stabilized with nCPAP / nIMV (nasal intermittent mandatory ventilation) with appropriate adjustments in CPAP and fraction of inspired oxygen (FiO2) to maintain clinical blood gases (CBG) and oxygen saturation (SpO2) according to clinical guidelines. After infants were stabilized, AeroFact was administered with nCPAP within 2 hours of birth.

[0094] AeroFact was administered to infants by single administration of aerosol equivalent to an injected 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 (protocol-defined efficacy). Infants continued to receive nCPAP after dosing. 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] Aerosolized SF-RI1 was administered initially at a nominal dose of 216 mg / kg. Oxygenation and ventilation parameters were monitored as specified in the protocol, and aerosol delivery was stopped when the intended dosage was reached.

[0097] Infants continued to receive nCPAP. AeroFact was administered again (nominal dose 216 mg / kg) if the respiratory severity score (RSS: mean airway pressure × fraction of inspired oxygen) to maintain SpO2 at 90%-95% (measured by pulse oximetry) was ≥ 2.0 and at least (1) 2 hours had elapsed since the end of the first dose and (2) 4 hours had elapsed since the end of the second or third dose. Up to three additional doses of AeroFact were permitted within 96 hours.

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

[0099] Per 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 who experienced 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 study drug, device, or procedure, and no AEs led to premature discontinuation of study drug or patient from the study.

[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 treatment 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 1,664 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 patients (45%) in the matched historical control group. Thus, the relative risk for AeroFact treatment was 0.56, favoring AeroFact treatment.

[0104] From this study, the incidence of post-administration premature comorbidities and adverse events (AEs) was lower and less variable between patients in patients treated using the aerosolization system of FIG. 17 compared to 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 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 resistance during the first 24 hours was generally low. The incidence of AEs was comparable between dosing using the aerosolization system of FIG. 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 cycles trigger the sensor to react and actuate the breath of the device. The adult training / test lung was mechanically linked to an infant training / test lung used to simulate an infant's actual breathing. By adjusting the ventilator settings, various infant breathing patterns could be simulated. A gas flow analyzer (IMT Analytics) was used to verify the infant's breathing parameters. Table 1 summarizes the parameters of the active lung / ventilator test.

[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. NGIs were cooled in a refrigerator at 4-8 °C for >90 min 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 with an AF2b device outside the cooling chamber. The nebulizer (without nasal prongs) shown in Figures 6-6D was attached to the introduction port of the NGI using a T-piece with an adapter. The inspiratory and expiratory 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 for the three nebulizers tested for all ventilator settings tested (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 diameter of particles that can pass through each stage of the NGI, and the particle mass refers to the mass that passes through each stage at each CPAP setting.

[0114] [Table 4]

[0115] [Table 5]

[0116] [Table 6]

[0117] (Conclusion) The above results indicate 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 settings, 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, the study confirmed that consistent particle delivery occurred across the range of CPAP settings.

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

[0119] Additionally, aerosol droplet size was consistent 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 no enlargement of the mesh pores occurred with the use of the mesh, and demonstrates that the PDAP mesh is capable of producing aerosol particles with an MMAD of approximately less than 3.0 μm for a lifetime that exceeds the upper limit of the number of allowable doses of the surfactant.

[0122] [Table 8]

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

[0124] [Table 9]

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

[0126] [Table 10]

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

[0128] [Table 11]

[0129] Table 12 shows the results of the orientation testing. The results show that the DD is not affected by orientation in any of the administration positions, 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 over the entire 0.5 mL dose volume for all three devices, with an average DD of 46%. These results show that the system was able to reliably produce aerosols in all orientations tested.

[0130] [Table 12]

[0131] The above methods, systems and devices are examples. Some embodiments are described as processes shown as flow diagrams or block diagrams. In each process, although operations may be described as sequential processes, many operations may be performed in parallel or simultaneously. Also, the order of operations may be changed. A process may include additional steps not included in the figures. Furthermore, the 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. In various embodiments, various procedures or components can be omitted, substituted, or added, as appropriate. Also, features described with respect to certain embodiments can be combined in various other embodiments. Different aspects and elements of the embodiments can 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] For a thorough understanding of the embodiments, certain details are described in the specification. However, the embodiments can be practiced without including these specific details. For example, unnecessary details of well-known structures and techniques are omitted 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 present invention. The above description of the embodiments provides a person skilled in the art with an enabling description for implementing the embodiments of the present invention. Various changes can be made in the function and arrangement of elements without departing from the spirit and scope of the present invention.

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

[0135] Although exemplary and presently preferred embodiments of the disclosed system, method and machine-readable medium 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 modifications 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. "About" and / or "approximately" as used herein with reference to a measurable value, such as an amount, duration, etc., means a variation of ±20%, ±10%, ±5%, or +0.1% from the specified value. Such variations are deemed appropriate in the context of the systems, devices, circuits, methods, and other implementations described herein. "Approximately" as used herein with reference to a measurable value, such as an amount, duration, physical attribute (such as frequency), etc., means a variation of ±20%, ±10%, ±5%, or +0.1% from the specified value. Such variations are deemed appropriate in the context of the systems, devices, circuits, methods, and other implementations described herein. In the present specification, including the claims, when a list of items begins with "at least one" or "one or more," "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 and 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 embodiments, various modifications, alternative structures and equivalents can be used without departing from the spirit of the present invention. For example, the above elements may be merely 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 elements. Therefore, the above description should not be interpreted 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 claims that follow, 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.

Claims

1. 1. An aerosolization system comprising: a breathing system having an inhalation rim and an expiratory rim; 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 adjacent a second end of the aerosol chamber; 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; and a controller configured to operate the aerosol generator to aerosolize the quantity of medicament in synchronization with a 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. 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 air passage; 10. The aerosolization system of claim 1, wherein the aerosol chamber is configured to mix a portion of the airflow with aerosolized medicament provided from the aerosol generator.

4. 4. The aerosolization system of claim 3, wherein 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.

5. the flow diverter structure having at least one barrier defining the at least one air passage; 4. The aerosolization system of claim 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.

6. 6. The aerosolization system of claim 5, wherein the at least one barrier includes a first barrier defining a first ventilation passageway and a second barrier defining a second ventilation passageway.

7. the first vent is provided at a lateral end of the first barrier; the second vent is located beyond a distal edge of the second barrier; 7. The aerosolization system of claim 6, wherein the lateral ends and the distal edge extend in different directions such that the respiratory flow moves in multiple directions past the first and second barriers.

8. 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.

9. the tip of the conduit has a diameter; 9. The aerosolization system of claim 8, wherein the tip of the conduit is positioned at a distance from the mesh that is less than or equal to the diameter.

10. 2. The aerosolization system of claim 1, wherein synchronizing the aerosolization of the dose of medicament includes aerosolizing a portion of the dose in at least a portion of the first 50-80% of each of the successive multiple inspirations such that purge air is provided in at least a portion of the last 20% of each of the successive multiple inspirations.

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

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

13. 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 an upward position.

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

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

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

17. 1. A method of delivering an aerosolized medication to an infant, comprising: detecting an intake of air by the infant using one or more respiratory sensors; aerosolizing 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 based on the detected inspiration; The method wherein the medicament is aerosolized within about 1-8 cm of the patient interface.

18. aerosolizing said quantity of medicament, delivering the quantity of medicament from a reservoir to a mesh of the aerosolization device; and vibrating the mesh to aerosolize the quantity of medication.

19. the quantity of drug is delivered from the reservoir to the mesh via a conduit having a tip with a diameter; 20. The method of claim 18, wherein the tip of the conduit is positioned a distance from the mesh that is less than or equal to the diameter of the mesh.

20. 20. The method of delivering aerosolized medication to an infant as described in claim 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 a plurality of successive inspirations such that sweeping air is provided in at least a portion of the last 20% of each of a plurality of successive inspirations.

21. 20. The method of delivering aerosolized medication to an infant of claim 17, wherein the one or more breath sensors include a breath sensor capsule connected to the patient's abdomen.

22. connecting the aerosolization device to a breathing system; diverting a portion of the airflow from the breathing system to a chamber of the aerosolization device via at least one airway; 20. The method of claim 17, wherein the chamber is configured to mix a portion of the airflow with the aerosolized medication.

23. 23. A method of delivering aerosolized medication to an infant as described in claim 22, wherein 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.

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 as described in claim 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 inhalation limb toward the exhalation limb.

25. 25. The method of delivering aerosolized medication to an infant as described in claim 24, wherein the at least one barrier includes a first barrier defining a first airway and a second barrier defining a second airway.

26. the first vent is provided at a lateral end of the first barrier; the second vent is located beyond a distal edge of the second barrier; 26. The method of delivering aerosolized medication to an infant as described in claim 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 and second barriers.

27. 20. The method of delivering aerosolized medication to an infant of claim 17, wherein the patient interface comprises nasal prongs or a nasal mask.

28. 20. The method of delivering aerosolized medication to an infant of claim 17, further comprising delivering the aerosolized medication to the infant's airway via a patient interface.

29. 1. 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; inputting 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.

30. 30. The method of initializing an aerosolization system of claim 29, further comprising executing a wake-up sequence that cycles through multiple audio alarms, visual alarms, or both audio and video alarms.

31. 30. The method of initializing an aerosolization system of claim 29, wherein the access authentication includes one or more of a user identifier, a password, property authentication, and biometric authentication.

32. 30. The method of initializing an aerosolization system of claim 29, wherein the breath sensor is adhered to the patient's abdomen.

33. 30. The method of initializing an aerosolization system of claim 29, further comprising verifying detection of a breath after connecting the breath sensor to a patient.

34. 30. The method of initializing an aerosolization system of claim 29, wherein the drug source comprises a vented vial access device (VVAD) connected to a fluid supply line.

35. 30. The method of initializing an aerosolization system of claim 29, wherein connecting the aerosolization device to the control device, breath sensor, drug source and breathing system includes connecting a fluid supply line between the drug source and the aerosolization device.

36. 30. The method of initializing an aerosolization system of claim 29, wherein priming the aerosolization device comprises aerosolizing a portion of the medicament prior to connecting the patient interface to the patient's airway.

37. 30. The method of initializing an aerosolization system of claim 29, further comprising coupling the patient interface to the aerosolization device.

38. 30. The method of initially setting up an aerosolization system of claim 29, wherein the patient interface is secured to the patient via at least one strap and / or a foam pad configured to rest on the patient's head.

39. 30. The method of initializing an aerosolization system of claim 29, further comprising delivering an aerosolized dose of medicament to a patient via the patient interface.

40. 40. The method of initializing an aerosolization system of claim 39, further comprising verifying that timing of delivery of the dose is synchronized with detected inspiration.

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