Aerosol chamber and interface design to optimize inhaled dose in neonatal CPAP devices

Abstract

The aerosolization system includes a breathing system having an inspiratory limb and an expiratory limb. The system includes an aerosol chamber connected to the inspiratory limb via a fluid passageway. The fluid passageway is positioned to isolate the aerosol chamber from a continuous flow of air passing through the breathing system. The system includes a patient interface positioned at a first location on the aerosol chamber and an aerosolization device positioned at a second location on the aerosol chamber opposite the first location. The aerosolization device has a reservoir that receives a quantity of liquid medicament to be aerosolized by the aerosolization device. The aerosol chamber mixes the aerosolized medicament provided by the aerosolization device with the respiratory flow received from the breathing system via the fluid passageway.

Description

[Technical Field]

[0001] The present invention relates to the design of an aerosol chamber and interface to optimize the inhaled dose in a neonatal CPAP device. [Background technology]

[0002] A conventional interface for nasal CPAP consists of a gas inlet from the inspiratory limb and an outlet to the expiratory limb, with the patient interface consisting of nasal prongs or a nasal mask. For example, in conventional systems, aerosol is introduced through a secondary port before entering the inspiratory limb, and the aerosol flow is delivered to the patient interface through a separate conduit. This approach requires continuous aerosol generation and gas flow. Summary of the Invention [Problem to be solved by the invention]

[0003] When an aerosol generator is placed between the gas flow and the patient interface, drug delivery can vary significantly depending on the gas flow rate of the breathing system. For example, at low system gas flow rates (below 0.5 L / min), the inhaled dose is 30–45% or more, whereas at high system gas flow rates (greater than 6 L / min), the inhaled dose is reduced to less than 6%. A more stable drug delivery system is desirable. [Means for solving the problem]

[0004] In an aerosolization system and method according to an embodiment of the present invention, aerosolized medication and respiratory gas are mixed in an aerosolization chamber before being introduced into the patient's airway. The aerosolization chamber is isolated from the main flow path of the breathing system. In other words, within the aerosolization chamber, respiratory gas exists intermittently and is drawn in only by the patient's inspiration, rather than being continuously pushed into the aerosolization chamber by the breathing system. This design reduces fluctuations due to flow rate, thereby maintaining consistent medication delivery.

[0005] In one aspect, an aerosolization system is provided. The aerosolization system includes a breathing system having an inspiratory limb and an expiratory limb. The system also includes an inlet connected to the inspiratory limb of the breathing system. The system further includes an aerosol chamber connected to the inlet via a fluid passageway. The fluid passageway is positioned to isolate the aerosol chamber from a continuous flow of air passing through the breathing system. The system further includes a patient interface disposed at a first end of the aerosol chamber and an aerosolization device disposed at a second end of the aerosol chamber opposite the first end. The aerosolization device includes a housing configured to communicate the medicament with a mesh of the aerosol generator and / or to receive a quantity of liquid medicament to be aerosolized by the aerosolization device. The aerosol chamber is configured to mix the aerosolized medicament from the aerosolization device with the respiratory flow received from the breathing system via the fluid passageway.

[0006] In another aspect, the aerosolization system includes an aerosol chamber and an aerosolization device disposed at a first end of the aerosol chamber. The aerosolization device has a reservoir configured to receive a quantity of liquid medicament to be aerosolized by the aerosolization device. The system further includes an inlet, an outlet, and a fluid passageway connecting the aerosol passageway with one of the inlet and the outlet. The fluid passageway may be positioned to isolate the aerosol chamber from a continuous flow from the inlet to the outlet. The aerosol chamber may be configured to mix a respiratory flow received from a respiratory system via the fluid passageway with the aerosolized medicament from the aerosolization device.

[0007] In another aspect, a method for delivering aerosolized medicament to a patient is provided. The method includes providing an aerosolization system. The aerosolization system includes a breathing system having an inspiratory limb and an expiratory limb, an inlet connected to the inspiratory limb of the breathing system, and an outlet connected to the expiratory limb of the breathing system. The outlet is in communication with the inlet. The aerosolization system may include an aerosol chamber connected to one of the inlet or the outlet via a fluid passage. The fluid passage may be positioned to isolate the aerosol chamber from a continuous flow from the inlet to the outlet. The aerosolization system may further include a patient interface disposed at a first end of the aerosol chamber and an aerosolization device disposed at a second end of the aerosol chamber opposite the first end. The aerosolization device may have a reservoir configured to receive a quantity of liquid medicament to be aerosolized by the aerosolization device. The aerosol chamber may be configured to mix the aerosolized medicament from the aerosolization device with a respiratory flow received from the breathing system via the fluid passage.

[0008] The method may include connecting a patient interface to the patient's airway and channeling a respiratory flow from the respiratory system through the inlet and the outlet, aerosolizing a quantity of liquid medicament in an aerosolization chamber using an aerosolization device, mixing the aerosolized medicament with a portion of the respiratory flow drawn into the aerosolization chamber, and delivering the mixture of aerosolized medicament and the respiratory flow to the patient via the patient interface.

[0009] In one embodiment, an aerosolization device is provided. The device may include 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 is configured to aerosolize a 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 device may include a patient interface disposed near the second end of the aerosol chamber, and a respiratory adapter configured to couple the aerosolization device to a respiratory system and to divert a portion of the respiratory system airflow to the aerosol chamber via a fluid passageway. The aerosol chamber may be configured to mix the portion of the airflow with aerosolized surfactant provided by the aerosol generator for subsequent delivery to the patient via the patient interface. In some embodiments, the aerosol generator includes a reservoir configured to receive a quantity of liquid surfactant to be aerosolized by the aerosol generator. In some embodiments, the respiratory adapter includes a flow diverting mechanism configured to divert a portion of the airflow from the breathing system to the aerosol chamber through a fluid passageway. In some embodiments, the portion of the airflow is a respiratory flow, which is less than the amount of air that continues to the expiratory limb of the breathing system. In some embodiments, the flow diverting mechanism includes at least one barrier defining a fluid passageway. The at least one barrier may be configured to divert a portion of the airflow to the aerosol chamber through the fluid passageway and to divert another portion of the airflow from the inspiratory limb toward the expiratory limb. In some embodiments, the at least one barrier includes a first barrier defining a first airway and a second barrier defining a second airway. In some embodiments, a first airway is located at a lateral end of the first barrier and a second airway is located beyond the distal edge of the second barrier, the lateral end and distal edge extending in different directions from one another so that respiratory flow travels in multiple directions past the first and second barriers.

[0010] In some embodiments, the device further comprises a conduit configured to deliver the dose of medicament to the aerosol generator. The tip of the conduit has a diameter. The tip of the conduit may be positioned a distance equal to or less than the diameter from the mesh. In some embodiments, the aerosol chamber is generally funnel-shaped, with a first end comprising a wider portion of the aerosol chamber and a second end comprising a narrower portion of the aerosol chamber. In some embodiments, the patient interface comprises nasal prongs. In some embodiments, a fluid path defined by the fluid passage forms an angle of 90 degrees or less with respect to an upstream side of a flow path through the respiratory system. In some embodiments, the respiratory adapter has an inlet configured to connect with an inspiratory limb of the respiratory system and an outlet configured to connect with an expiratory limb of the respiratory system. In some embodiments, the fluid passage is positioned such that respiratory flow does not enter the aerosol chamber between breaths of the patient. In some embodiments, the device further comprises a fluid supply line coupled to the aerosolization device and a pump configured to deliver the dose of medicament to the housing of the aerosolization device through the fluid supply line. In some embodiments, the agent comprises a surfactant.

[0011] In another embodiment, the aerosolization device includes an aerosol chamber and an aerosolization generator disposed at a first end of the aerosol chamber. The aerosolization generator may be configured to aerosolize a 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. The device may further include a patient interface disposed at a second end of the aerosol chamber opposite the first end, an inlet configured to connect to an inspiratory limb of a respiratory system, an outlet configured to connect to an expiratory limb of the respiratory system, and a fluid passageway connecting the aerosol passageway to at least one of the inlet and the outlet. The fluid passageway may be positioned to isolate the aerosol chamber from a continuous flow from the inlet to the outlet. The aerosol chamber may be configured to mix a respiratory flow received from the respiratory system via the fluid passageway with the aerosolized medicament from the aerosolization device.

[0012] In some embodiments, the aerosol chamber is generally funnel-shaped, with a first end comprising a wider portion of the aerosol chamber and a second end comprising a narrower portion of the aerosol chamber. In some embodiments, the patient interface comprises nasal prongs or a nasal mask. In some embodiments, the fluid path defined by the fluid passage forms an acute angle with respect to the upstream side of at least one of the inlet and outlet to which the fluid passage is coupled. In some embodiments, the inlet and outlet are configured to direct the flow of gas from the inspiratory limb to the expiratory limb to prevent respiratory flow from entering the aerosol chamber between breaths of the patient. In some embodiments, the device further comprises a fluid supply line coupled to the aerosolization device and a pump configured to deliver a quantity of liquid medicament through the fluid supply line to the conduit of the aerosolization device. In some embodiments, the inlet and outlet are integrally formed.

[0013] In another embodiment, a method for delivering aerosolized medicament to a patient is provided. The method includes providing an aerosolization device having an aerosol chamber, a respiratory adapter, an aerosol generator disposed at a first end of the aerosol chamber opposite the first end, and a patient interface disposed at a second end of the aerosol chamber. The method may further include connecting the patient interface to the patient's airway, connecting the respiratory adapter to a respiratory system, and diverting a portion of the respiratory system's airflow to the aerosol chamber using the respiratory adapter when the patient inhales. The method may further include providing a quantity of liquid medicament to the aerosol generator, aerosolizing the quantity of liquid medicament in the aerosolization chamber using the aerosol generator to produce 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 that mix with the airflow introduced into the aerosolization chamber, and delivering the mixture of the aerosolized medicament and the airflow to the patient via the patient interface.

[0014] In some embodiments, the method includes sensing a patient's inhalation using one or more breath sensors. In some embodiments, aerosolization of the quantity of liquid medicament is initiated based on the sensed patient inhalation. In some embodiments, the aerosol chamber is generally funnel-shaped, with a first end comprising a wide portion of the aerosol chamber and a second end comprising a narrow portion of the aerosol chamber. In some embodiments, negative pressure created by the patient's inhalation at the patient interface draws airflow into the aerosol chamber. In some embodiments, the respiratory adapter has an inlet and an outlet, and the aerosol chamber is coupled to at least one of the inlet or the outlet via a fluid passageway. The fluid passageway may be positioned to isolate the aerosol chamber from a continuous flow from the inlet to the outlet. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 is an isometric view of an aerosolization device according to an embodiment. [Figure 1A] FIG. 2 is a cross-sectional view of the aerosolization device of FIG. 1. [Figure 2] FIG. 2 illustrates the flow pattern through the aerosolization device of FIG. 1. [Figure 3] FIG. 1 is an isometric view of an aerosolization device according to an embodiment. [Figure 3A] FIG. 4 is a cross-sectional view of the aerosolization device of FIG. 3. [Figure 4A] FIG. 4 illustrates the flow pattern through the aerosolization device of FIG. 3. [Figure 4B] FIG. 4 illustrates the flow pattern through the aerosolization device of FIG. 3. [Figure 5A] 4 illustrates the flow pattern from a low-flow breathing system through the aerosolization device of FIG. 3. [Figure 5B] 4 illustrates the flow pattern from a low-flow breathing system through the aerosolization device of FIG. 3. [Figure 6] FIG. 1 is an isometric view of an aerosolization device according to an embodiment. [Figure 6A] 7 is a cross-sectional view of the aerosolization device of FIG. 6. [Figure 6B] 7 is a cross-sectional view of the aerosolization device of FIG. 6. [Figure 6C] 7 is a cross-sectional view of the aerosolization device of FIG. 6. [Figure 6D] FIG. 7 illustrates the flow pattern through the aerosolization device of FIG. 6. [Figure 7] 7 shows the aerosolization device of FIG. 6 connected to a fluid supply line and a breathing system. [Figure 8] FIG. 1 shows an aerosolization device connected to a drug supply source. [Figure 9] 9 shows the aerosolization device of FIG. 8 connected to a drug source and a control device. [Figure 10] FIG. 10 is a diagram showing the control device of FIG. 9. [Figure 11] FIG. 10 is a diagram showing a vial holder of the control device of FIG. 9. [Figure 12] FIG. 10 is a diagram showing the drug supply source of FIG. 9. [Figure 13]FIG. 10 is a diagram showing the functions of the control device in FIG. 9. [Figure 14] 1 is a flow chart illustrating a process for delivering aerosolized medication to a patient. [Figure 15] 10 is a bar graph illustrating emitted dose rates using an aerosolization device according to an embodiment. [Figure 16] 10 is a bar graph showing emitted dose rate as a function of respiratory rate and flow rate using an aerosolization device according to an embodiment. DETAILED DESCRIPTION OF THE INVENTION

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0062] FIG. 14 is a flowchart illustrating a process 900 for delivering an aerosolized medication to a patient. Process 900 begins with providing an aerosolization device at block 902. For example, the aerosolization device may be similar to devices described herein. For example, the aerosolization device may include an aerosol chamber, a respiratory adapter, an aerosol generator disposed at a first end of the aerosol chamber opposite the first end, and a patient interface disposed at a second end of the aerosol chamber. Process 900 continues at block 904, connecting the patient interface to the patient's airway. In some embodiments, the patient interface includes nasal prongs inserted into the patient's nares. In some embodiments, the nasal prongs are removably secured to the aerosolization device so that different sizes of prongs can be attached to the aerosolization device to accommodate patients of different sizes. At block 906, the respiratory adapter is connected to a breathing system. For example, the breathing adapter may have an inlet connected to an inspiratory limb of the breathing system and an outlet connected to an expiratory limb of the breathing system.

[0063] Once the aerosolization device is connected to the patient and respiratory system, in block 908, a portion of the respiratory system airflow is diverted to the aerosol chamber via the respiratory adapter in conjunction with the patient's inspiration. For example, the respiratory adapter may have one or more barriers configured to direct a majority of the airflow through the respiratory system toward the expiratory limb while directing a small amount of airflow into the aerosol chamber via the fluid passageway. In block 910, a quantity of liquid medicament is provided to the aerosol generator. In block 912, the aerosol generator is used to aerosolize the quantity of liquid medicament in the aerosolization chamber, generating 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 generated particles are mixed with the airflow introduced into the aerosol chamber. For example, the liquid medicament is provided to a mesh, such as a PDAP mesh, which vibrates to aerosolize the liquid medicament. In block 914, the aerosolized medicament and airflow mixture is delivered to the patient via the patient interface.

[0064] In some embodiments, the process includes sensing a patient's inspiration using one or more breath sensors. In such embodiments, aerosolization of a quantity of liquid medication occurs when the patient's inspiration is sensed. For example, the breath sensor can detect inspiration. A controller (such as controller 812) receives the indication of inspiration and sends a command to the aerosol generator to begin delivering the quantity of medication. This activates the aerosol generator to aerosolize the liquid medication. In some embodiments, controller 812 is programmed to aerosolize the medication only during the initial portion of inspiration and to draw in sweeping air during the final portion of inspiration to facilitate delivery of the aerosolized medication to the deep lung. (Example) In vitro experiments were conducted using an aerosolization device according to the present invention to determine the effective emitted dose of a drug. A test lung (Ingmar) and / or a modified small animal ventilator (Harvard Apparatus) was connected to the distal end of a collection filter connected to a patient adapter (in this example, nasal prongs) of an aerosolization device similar to that shown in Figures 6-6D, to simulate infant inspiration (volume, flow rate, and inspiratory:expiratory ratio). Simulations were performed using two different sizes of nasal prongs: large (5560) and small (4030). As shown in the bar graph in Figure 15, the emitted dose increased with increasing prong size. Specifically, the emitted dose for the large nasal prongs (5560) was 68% to 72%, while the emitted dose for the small nasal prongs (4030) was approximately 35% to 37%.

[0065] Airflow was set at 6 LPM (liters per minute), 8 LPM, and 10 LPM, and respiratory rates were 60 BPM (breaths per minute), 80 BPM, 100 BPM, and 120 BPM. The emitted dose rate was then measured for each combination of airflow rate and respiratory rate. As shown in Figure 16, delivery efficiency was affected by gas flow, with delivery efficiency decreasing slightly as flow rate increased. For example, at low flow rates (6 LPM), the emitted dose using the large nasal prongs (5560) ranged from approximately 50% to approximately 60% across the entire range of respiratory rates tested. Meanwhile, at high flow rates (10 LPM), the emitted dose ranged from approximately 42% to approximately 47%. As respiratory rate increased, the difference in efficiency with increasing flow rate became smaller. For example, the emitted dose rate ranged from approximately 44% to approximately 60% at 60 BPM, but from approximately 42% to approximately 51% at 120 BPM. Based on these results, the aerosol generator described herein was found to enable uniform inhaled drug doses across the entire clinically relevant range of respiratory rates (60-120 BPM) and CPAP flow rates (6-10 LPM) commonly used in bubble CPAP and ventilated CPAP systems.

[0066] The above methods, systems, and devices are examples. Some embodiments are described as processes depicted as flow diagrams or block diagrams. In each process, while multiple operations may be described as sequential processes, many operations may be performed in parallel or simultaneously. The order of operations may also be changed. A process may include additional steps not shown in the diagrams. Furthermore, method embodiments may be implemented by hardware, software, firmware, middleware, microcode, hardware description languages, or any combination thereof. When implemented in software, firmware, middleware, or microcode, program code or code segments for performing the associated tasks are stored in a computer-readable medium, such as a storage medium. The associated tasks are performed by a processor.

[0067] The above-described systems and devices are intended to be merely illustrative. Various procedures or components may be omitted, substituted, or added as desired in various embodiments. Also, features described with respect to particular embodiments may be combined in various other embodiments. Different aspects and elements of the embodiments may also be combined in a similar manner. Also, because technology is constantly evolving, many of the elements are illustrative only and should not be construed as limiting the scope of the invention.

[0068] Specific details are described in the specification for a thorough understanding of the embodiments. However, the embodiments may be practiced without these specific details. For example, well-known structures and techniques have been described without unnecessary detail to avoid obscuring the description of the embodiments. Such description is intended only to illustrate the embodiments and does not limit the scope, applicability, or configuration of the invention. The above description of the embodiments provides those skilled in the art with an enabling description for practicing the embodiments of the invention. Various changes can be made in the function and arrangement of elements without departing from the spirit and scope of the invention.

[0069] The above methods, systems, devices, graphs, and tables are examples. In various configurations, various procedures or components may be omitted, substituted, or added as needed. For example, in alternative configurations, methods may be performed in a different order than described, or various steps may be added, omitted, and / or combined. Additionally, functionality described with respect to particular configurations may be combined in various other configurations. Different aspects and elements of the configurations may also be combined in a similar manner. Additionally, because technology is constantly evolving, many of the elements are merely examples and do not limit the scope of the present disclosure or the claims. Furthermore, the techniques described herein may produce different results with different types of context-aware classifiers.

[0070] While exemplary and presently preferred embodiments of the disclosed systems, methods, and machine-readable media have been described in detail herein, the inventive concepts may be variously embodied and used in other ways, and the appended claims are intended to include such variations except insofar as limited by the prior art.

[0071] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly or conventionally understood. As used herein, "one" refers to one or more (i.e., at least one) of an object. For example, "an element" means one element or multiple elements. As used herein with reference to a measurable value, such as an amount, duration, or the like, "about" and / or "approximately" refers to a variation of ±20%, ±10%, ±5%, or +0.1% from the specified value. Such variations are deemed appropriate within the context of the systems, devices, circuits, methods, and other implementations described herein. As used herein with reference to a measurable value, such as an amount, duration, physical attribute (such as frequency), or the like, refers to a variation of ±20%, ±10%, ±5%, or +0.1% from the specified value. Such variations are deemed appropriate within the context of the systems, devices, circuits, methods, and other implementations described herein. As used herein, including in the claims, when a list of items begins with "at least one" or "one or more," the use of "and" indicates that the listed items can be combined in any combination. For example, a list of "at least one of A, B, and C" includes any combination of A, B, C, AB, AC, BC, and / or ABC (i.e., A, B, and C). Also, when multiple performances or uses of items A, B, or C are possible, the multiple uses of A, B, and / or C are considered to be part of the intended combination. For example, a list of "at least one of A, B, and C" also includes AA, AAB, AAA, BB, etc.

[0072] In the above-described embodiments, various modifications, alternative structures, and equivalents may be used without departing from the spirit of the present invention. For example, the above-described elements may merely be components of a larger system, and other rules may take precedence over or modify the application of the present invention. Also, some steps may be performed before, during, or after considering the above-described elements. Therefore, the above description should not be construed as limiting the scope of the present invention.

[0073] The terms "comprises," "comprises," "have," "having," "including," "consisting of," and "provided," when used in this specification and the following claims, indicate the presence of stated features, integers, components or steps, but do not exclude the presence or addition of one or more other features, integers, components, steps, acts or groups.

Claims

1. 1. An aerosolization device comprising: an aerosol chamber having first and second axial ends and defined by an axially extending peripheral wall; an aerosol generator disposed at the first end of the aerosol chamber, the aerosol generator configured to aerosolize a 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; a patient interface positioned near the second end of the aerosol chamber opposite the aerosol generator; and a breathing adapter configured to couple the aerosolization device to a breathing system and to divert a portion of the airflow of the breathing system to the aerosol chamber via a fluid passageway; the fluid passage is connected to the aerosol chamber at a portion of the peripheral wall adjacent the first end, thereby being arranged to deliver a portion of the airflow to the aerosol chamber; the aerosol chamber configured to mix a portion of the airflow with aerosolized surfactant provided by the aerosol generator for subsequent delivery to the patient via the patient interface.

2. 10. The aerosolization device of claim 1, wherein the aerosol generator comprises a reservoir configured to receive a quantity of liquid surfactant to be aerosolized by the aerosol generator.

3. 10. The aerosolization device of claim 1, wherein the breathing adapter includes a flow diverter mechanism configured to divert a portion of the airflow from the breathing system to the aerosol chamber via a fluid passageway.

4. 4. The aerosolization device 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 fluid passageway; 4. The aerosolization device of claim 3, wherein the at least one barrier is configured to divert a portion of the airflow to the aerosol chamber through the fluid passage and to divert another portion of the airflow from the inhalation limb toward the exhalation limb.

6. 6. The aerosolization device of claim 5, wherein the at least one barrier comprises a first barrier defining a first airway and a second barrier defining a second airway.

7. the first ventilation passage is provided at a lateral end of the first barrier; the second ventilation passage is provided at a position beyond the leading edge of the second barrier; 7. The aerosolization device of claim 6, wherein the lateral ends and the leading edge extend in different directions such that a portion of the airflow moves in multiple directions past the first and second barriers.

8. a conduit configured to deliver the dose of medicament to the aerosol generator; the distal end of the conduit has a diameter; 2. The aerosolization device of claim 1, wherein the tip of the conduit is positioned at a distance from the mesh that is equal to or less than the diameter of the mesh.

9. 10. The aerosolization device of claim 1, wherein the aerosol chamber is generally funnel-shaped such that the first end comprises a wide portion of the aerosol chamber and the second end comprises a narrow portion of the aerosol chamber.

10. 10. The aerosolization device of claim 1, wherein the patient interface comprises nasal prongs.

11. 10. The aerosolization device of claim 1, wherein the fluid path defined by the fluid passage forms an angle of 90 degrees or less with respect to an upstream side of a flow path through the respiratory system.

12. The breathing adapter: an inlet configured to connect with an intake rim of the breathing system; 10. The aerosolization device of claim 1, further comprising an outlet configured to connect to an expiratory limb of the breathing system.

13. 13. The aerosolization device of claim 12, wherein the fluid passage is positioned such that the airflow does not enter the aerosol chamber between breaths of a patient.

14. a fluid supply line connected to the aerosolization device; 10. The aerosolization device of claim 1, further comprising a pump configured to deliver the dose of medicament through the fluid supply line to a reservoir of the aerosolization device.

15. 10. The aerosolization device of claim 1, wherein the agent comprises a surfactant.

16. 1. An aerosolization device comprising: an aerosol chamber having first and second axial ends and defined by an axially extending peripheral wall; an aerosolization generator disposed at the first end of the aerosol chamber, the aerosolization generator configured to aerosolize a 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; a patient interface disposed at the second end of the aerosol chamber opposite the first end, the patient interface being disposed opposite the aerosolization generator; an inlet configured to couple to an intake rim of a breathing system; an outlet configured to couple to an expiratory limb of the breathing system; a fluid passageway connecting the aerosol chamber with at least one of the inlet and the outlet; the fluid passage is connected to the aerosol chamber at a portion of the peripheral wall adjacent the first end, thereby being arranged to deliver a portion of the respiratory flow to the aerosol chamber; the fluid passage is positioned to isolate the aerosol chamber from a continuous flow of fluid from the inlet to the outlet; The aerosolization device, wherein the aerosol chamber is configured to mix the respiratory flow received from the respiratory system via the fluid passage with aerosolized medicament from the aerosolization device.

17. 17. The aerosolization device of claim 16, wherein the aerosol chamber is generally funnel-shaped such that the first end comprises a wide portion of the aerosol chamber and the second end comprises a narrow portion of the aerosol chamber.

18. 17. The aerosolization device of claim 16, wherein the patient interface comprises nasal prongs or a nasal mask.

19. 17. The aerosolization device of claim 16, wherein the fluid path defined by the fluid passage forms an acute angle with respect to the upstream side of at least one of the inlet and outlet to which the fluid passage is connected.

20. 17. The aerosolization device of claim 16, wherein the inlet and outlet are configured to direct the flow of gas from the inhalation limb to the exhalation limb so that the respiratory flow does not enter the aerosol chamber between breaths of a patient.

21. a fluid supply line connected to the aerosolization device; 17. The aerosolization device of claim 16, further comprising: a pump configured to deliver a quantity of liquid medicament through the fluid supply line to a conduit of the aerosolization device.

22. 17. The aerosolization device of claim 16, wherein the inlet and outlet are integrally formed.

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