Administration of the aerosol to the patient

Abstract

The aerosol generating device (162) herein comprises an air inlet (164) configured to receive a portion of breathing air (166) from a ventilation circuit (160) to be provided to an aerosol generating element (170), the aerosol generating element (170) configured to generate aerosol particles and introduce the aerosol particles into an aerosol flow (114), and an aerosol conduit (172) configured to provide the aerosol flow (114) containing the aerosol particles to a patient (116) through a conducting element. In particular, the device (162) is designed to provide a high aerosol concentration to the patient (116), particularly premature infants, newborns, children, and adults. Also disclosed is a processing device (120) configured to control an apparatus (110) for administering an aerosol (112) to a patient (116) by controlling the aerosol flow (114) to the patient (116) triggered at a time point that hastened at least one of the onset or cessation of breathing of the patient (116).

Description

[Technical Field]

[0001] The present invention relates to an apparatus and method for administering an aerosol to a patient, an aerosol generating device configured to generate an aerosol stream, a method for generating an aerosol stream, and a processing device configured to control an apparatus for administering an aerosol to a patient. In particular, the apparatus and method can be designed to provide a defined aerosol concentration, preferably a high aerosol concentration, to a patient, in particular, but not limited to, a premature infant, a newborn, a child, or an adult. Further applications are also possible. [Background technology]

[0002] Pulmonary diseases such as asthma or chronic obstructive pulmonary disease (COPD) are usually treated by inhalation of the corresponding aerosol. Furthermore, efforts are being made to deliver surfactant in the form of an aerosol during mechanical ventilation to premature infants suffering from surfactant deficiency, especially since this form of treatment is non-invasive and therefore less harmful to the infant, in contrast to the standard treatment using invasive instillation of surfactant suspensions.

[0003] Aerosols can be continuously generated and administered to patients without synchronized aerosol release. However, a portion of the continuously delivered aerosolized drug may be lost and therefore may not provide any medical benefit. As further demonstrated by Longest, PW, Azimi, M., and Hindle, M., Optimal Delivery of Aerosols to Infants During Mechanical Ventilation, Journal of Aerosol Medicine and Pulmonary Drug Delivery 2014, 27, 371-385, doi:10.1089 / jamp.2013.1077, only aerosols delivered during the first half of the inhalation phase reach the periphery of the alveoli. Furthermore, local pulmonary drug requirements for surfactant inhalation applications can significantly exceed those for other inhalation applications of aerosols for pulmonary diseases.

[0004] Therefore, breath-triggered drug release is of great interest. When a breath is detected, the aerosol should be released accordingly, i.e., over a defined period of time, such as a short or long aerosol bolus. However, known approaches for breath detection and aerosol release during respiratory assistance or independent breathing have various problems and drawbacks.

[0005] Known respiratory monitoring devices function via a flow or pressure sensor configured to determine the inhalation flow at the patient interface. As a result, the release of the medication may occur only after a delay, i.e., not immediately after the start of inhalation. Accordingly, a pressurized metered-dose inhaler may be integrated into the ventilation circuit in combination with a spacer. However, the medication is only released via effective actuation of the inhaler by the patient or a further person. Alternatively, an aerosol generating device may be coupled to the ventilation circuit by using an adapter.

[0006] Triggering of aerosol release can be based on detecting a pressure change in the ventilator tube caused by breathing, after which aerosol generation is activated or deactivated. However, the drug is only released after a corresponding pressure change is recorded, so drug release occurs with a delay. Alternatively, drug release can be controlled by using pressure measurements at the mouthpiece, and the evaluation algorithm can take into account the averaging of consecutive breaths.

[0007] U.S. Patent No. 10,987,474 B2 discloses an aerosol delivery system including an aerosol generator that aerosolizes a fluid for delivery to a patient when the patient inhales. The aerosol delivery system includes a pump coupled to the aerosol generator for pumping fluid to the aerosol generator, and a breath sensor that emits a signal when the patient breathes. A controller is coupled to the aerosol generator, the pump, and the breath sensor. In operation, the controller receives a signal from the breath sensor and, in response to the signal, controls the flow of fluid to the aerosol generator to control the aerosol generator to begin aerosolizing the fluid before the patient inhales.

[0008] U.S. Patent Application Publication No. 2021 / 0283345(A1) discloses an aerosol delivery system having an aerosol generator that aerosolizes a fluid for delivery to a patient when the patient inhales. The aerosol delivery system includes a pump coupled to the aerosol generator to pump fluid to the aerosol generator and a breath sensor that emits a signal when the patient breathes. A controller is coupled to the aerosol generator, the pump, and the breath sensor. In operation, the controller receives a signal from the breath sensor and, in response to the signal, controls the flow of fluid to the aerosol generator to control the aerosol generator to begin aerosolizing the fluid before the patient inhales.

[0009] WO 2020 / 243107 A1 and U.S. Patent Application Publication No. 2020 / 368457 A1 disclose a method for delivering an aerosolized surfactant to an infant, the method comprising: connecting an aerosolization device to the infant's airway; and using the aerosolization device to aerosolize a volume of surfactant into particles having a mean aerodynamic diameter of less than about 3 μm at a rate of at least 0.1 mL / min. The surfactant is aerosolized within a range of about 1 to 8 cm from the patient interface. Aerosols are generated for up to about 80% of each inspiration. The method also includes delivering the aerosolized surfactant to the infant's airway.

[0010] WO2019 / 115771A1 discloses a nebulizer system including a nebulizer for an assisted breathing device. The nebulizer includes a body having a first connection for connecting the nebulizer to the assisted breathing device and a second connection for connecting the nebulizer to a patient, particularly a neonate, forming a flow path from the first connection to the second connection, and a spraying device for spraying a liquid. The spraying device is disposed between the first and second connections within the flow path. The nebulizer is configured to be fitted to an oral and / or nasal communication element such as nasal prongs, a nasal mask, a face mask, or a mouthpiece. The invention also relates to a holding system for holding the nebulizer or nebulizer system.

[0011] WO2020 / 079055A1 discloses methods, devices, and compositions for use in inhalation treatment of newborns, infants, or children suffering from diseases, optionally pulmonary diseases such as asthma, whereby a large amount of inhaled medication is directed to the small airways in the periphery of the lungs of newborns, infants, and children using a slow, controlled flow rate and a preset inhalation volume. A novel inhalation device adapted for use with newborns, infants, and children and to provide said slow, controlled flow rate in a simplified jet nebulizer setting is disclosed, along with a kit comprising the device.

[0012] However, most known techniques are usually based on inadequate predictions since premature infants exhibit irregular breathing, and therefore do not allow optimal generation and release of aerosols. Due to the inherent dead space, such devices are often not suitable for use in premature infants.

[0013] U.S. Patent Application Publication No. 2019 / 0247595(A1) discloses a system for breath-controlled application of a powdered aerosol during artificial or assisted ventilation of a patient, the system including an interface for contacting the patient's respiratory system, a unit for generating a respiratory airflow, at least one inspiratory line through which the airflow is conducted to the interface, an aerosol generator, at least one aerosol line through which the generated aerosol is conducted from the aerosol generator to the interface, and a breath sensor for detecting a patient's breath signal. A valve in the at least one aerosol line is controlled based on the detected breath signal. An intermediate reservoir for the generated powdered aerosol is disposed between the valve and the aerosol generator. The airflow has a first pressure equal to or greater than ambient pressure, and the aerosol has a second pressure equal to or greater than the first pressure.

[0014] WO 2012 / 020004 A1 discloses a device for connecting the airway of a patient undergoing ventilation assistance to a source of respiratory gas and an aerosol, the device comprising a contact component adapted to be positioned in contact with the patient's airway, the contact component comprising one or two tubes, each of the one or two tubes including a lumen capable of delivering respiratory gas and aerosol to the patient's airway, a mixing lumen in fluid communication with one or more of the lumens of the one or two tubes and having a longitudinal axis extending substantially perpendicular to one or more longitudinal axes of the one or more lumens, and a port arranged to allow an aerosol to be introduced into the mixing lumen and to allow the aerosol and the respiratory gas to mix within the mixing lumen.

[0015] Wiegandt, F.C., Biegger, D., Fast, J.F., Matusiak, G., Mazela, J., Ortmaier, T., Doll, T., Dietzel, A., Bohnhorst, B., and Pohlmann, G., "Detection of Breathing Movements of Preterm Neonates by Recording Their Abdominal Movements with a Time-of-Flight Camera," Pharmaceutics 2021, 13, doi:10.3390 / pharmaceutics13050721, describes the need to detect the onset of patient inspiration for breath-triggered delivery of aerosolized medication. Respiratory sensors, especially invasive ones, cannot be tested on preterm neonates without significant effort due to clinical and ethical obstacles. Therefore, physiological models are highly desirable to validate these sensors. To develop such a system, abdominal movement data from preterm neonates is needed. We used a time-of-flight camera to record time sequences of abdominal movements in five preterm neonates and successfully extracted various breathing patterns and parameters. Several characteristic breathing patterns, such as labored breathing, sighs, apneas, and whimpering, were identified from the movement data. Respiratory parameters, such as inspiration and expiration duration, and respiratory rate and movement over time, were also extracted. We demonstrated that respiratory parameters in preterm neonates can be determined noncontact. Therefore, such a system can be used for breath detection to provide trigger signals for breath-triggered drug release systems.

[0016] Koch, E., Dietzel, A., "Skin-attachable flexible sensor array for respiratory monitoring," Sensors and Actuators A: Physical 2016, 250, 138-144, doi:10.1016 / j.sna.2016.09.020, describes a 6 × 6 sensor array for curvature sensing in the form of a thin, flexible polyimide foil. The sensor foil is attached directly to the skin and used to monitor respiration in preterm infants by measuring body deformation caused by respiration. The sensor signal will be used in the future not only to trigger respiratory devices but also to provide time-dependent body surface reconstruction as a diagnostic tool. One single sensor element consists of four gold strain gauges in a Wheatstone bridge configuration. To suppress the sensor response to foil stretching and increase bending sensitivity, a double-sided sensor designed with strain gauges on both sides of the thin foil was introduced, achieving 170% higher sensitivity than a single-sided sensor design. Differently oriented double-sided sensor elements are arranged in an alternating pattern across the array, allowing for complete and unambiguous determination of the curvature vector using plausibility considerations based on signals from adjacent elements. Summary of the Invention [Problem to be solved by the invention]

[0017] It is therefore an object of the present invention to provide an apparatus and method for administering an aerosol to a patient, an aerosol generating device configured to generate an aerosol stream, a method for generating an aerosol stream, and a processing device configured to control an apparatus for administering an aerosol to a patient, which at least partially avoid the problems and drawbacks of known approaches.

[0018] It is particularly desirable that the devices and methods be capable of administering a significant portion of the pharmaceutical formulation contained by the aerosol to a patient, particularly, but not limited to, a premature infant, a neonate, a child, or an adult, to ensure that the anticipated amount of pharmaceutical formulation is actually provided to the patient at the desired concentration and is not diluted and / or dispersed elsewhere. It is further desirable to reduce, or preferably avoid, delays in administering the pharmaceutical formulation to the patient. It is further desirable to be able to administer the pharmaceutical formulation to one or more predefined targets within the central or peripheral regions of the lung. [Means for solving the problem]

[0019] This problem is solved by an apparatus and method for administering an aerosol to a patient, an aerosol generating device configured to generate an aerosol flow, a method for generating an aerosol flow, and a processing device configured to control an apparatus for administering an aerosol to a patient, which have the features of the independent claims. Preferred embodiments, which can be implemented separately or in any combination, are disclosed in the dependent claims and in the description as a whole.

[0020] In a first aspect, the present invention provides an aerosol generation device configured to generate an aerosol stream, comprising: an air inlet configured to receive a portion of breathing air from the ventilation circuit to be provided to the aerosol generating element; - an aerosol generating element configured to generate aerosol particles and introduce the aerosol particles into the aerosol stream; an aerosol tube configured to provide an aerosol stream containing aerosol particles to a patient through a conducting element; The present invention relates to an aerosol generating device comprising:

[0021] Herein, the conducting element may preferably comprise at least one of a patient interface or an aerosol valve, as disclosed in more detail below. However, the use of a tube may also be feasible. In addition, the aerosol generating device may comprise at least one further element, in particular at least one of a pressure regulating element or a breathing filter, as disclosed elsewhere herein. However, the use of at least one different further element is also conceivable.

[0022] When used generally, the term "aerosol" refers to an aerosolizable material containing solid or liquid particles of a substance suspended in the gas phase; these particles may be or include, in particular, particles of a pharmaceutical agent, such as, but not limited to, a pulmonary surfactant. To convert the particles to this state, the aerosolizable material, i.e., powder or solution, is processed in an aerosol-generating element, in particular by using a powder generator or nebulizer, in particular a vibrating mesh or ultrasound, to entrain the solid or liquid particles into a gas stream of a carrier gas, such as a respiratory gas. In this state, the particles are preferably dispersed throughout the volume of the carrier gas, in particular in a uniform, finely dispersed form. As a result, the aerosol is provided as an "aerosol stream," with the solid or liquid aerosol particles carried or carried by the carrier gas stream. Furthermore, the term "administer" or any grammatical variant thereof refers to the process of providing a controlled application of respiratory gas and the aerosol contained thereby by delivering a predefined amount of pharmaceutical agent, in particular a humidified aerosol, to a patient over a period of time. As used herein, the term "respiratory gas" refers to a composition suitable for artificial ventilation of a patient, in particular a gas mixture comprising air or oxygen-enriched air.

[0023] Furthermore, the term "mechanical ventilation circuit" refers to a device configured to ventilate respiratory gas provided by a ventilator to a patient and returned from the patient to the ventilator, thereby isolating the patient's respiratory system. As further used herein, the term "patient" refers to a human being of any age, including, in particular, a premature infant, a newborn, a child, or an adult. Furthermore, the term "mechanical ventilation" relates to a process of achieving respiratory gas movement, in particular through alternating steps of inhalation and exhalation. In contrast to a healthy breathing patient who is able to perform breathing without additional support, a patient receiving mechanical ventilation or positive pressure ventilation requires that respiratory gas be provided at least partially from a ventilator via a mechanical ventilation circuit. As used herein, the term "patient interface" refers to a device configured to provide a connection between the mechanical ventilation circuit and the patient's respiratory system; therefore, the patient interface is generally positioned adjacent to the patient. To this end, the patient interface can be integrated into or attached to the mechanical ventilation circuit, which can generally include a ventilator and a tube adapted to guide gas from the ventilator back to the patient interface. In particular, a mouthpiece, breathing mask, nasal cannula, nasal prongs, or tracheostomy tube may be part of the patient interface or may be attachable to the patient interface, although further arrangements may also be feasible.

[0024] According to the present invention, the aerosol generating device comprises an air inlet configured to receive a portion of breathing air from a breathing circuit to be provided to an aerosol generating element further included by the aerosol generating device. Herein, the aerosol generating element is configured to generate aerosol particles and introduce the aerosol particles into a carrier gas. Herein, the term "aerosol generating element" refers to an element designated to convert an aerosolizable material, i.e., a powder or a solution, into an aerosol, in particular by using a powder generator or a nebulizer, in particular a vibrating mesh or ultrasound, to entrain solid or liquid particles into a gas flow of a carrier gas, such as a breathing gas. To this end, the aerosol generating element can preferably be selected from at least one of a nebulizer or a powder generator. Furthermore, the aerosol generating device comprises an aerosol tube configured to provide an aerosol flow containing aerosol particles to a patient through a conducting element, which can preferably comprise at least one of a patient interface or an aerosol valve.

[0025] In certain embodiments, the aerosol generating device may further comprise a pressure regulating element. As used herein, the term "pressure regulating element" refers to an element configured to regulate pressure, in particular to provide additional pressure in the aerosol flow. Preferably, the pressure regulating element may be selected from at least one of a ventilator, a fan, a pump, a mechanical element, or an electromechanical element configured for this purpose. In particular, the additional pressure may be used to improve the way the aerosol flow is guided to the patient through the conducting element, which may preferably comprise at least one of a patient interface or an aerosol valve. Preferably, the pressure that may prevail in the aerosol tube when the aerosol is administered to the patient, in particular when the aerosol valve is in the open position, may exceed the additional pressure that may prevail at the air inlet by at least 0.1 mbar, preferably at least 0.05 mbar, more preferably at least 0.02 mbar, and in particular at least 0.01 mbar.

[0026] In a further preferred embodiment, the pressure regulating element can be further configured to limit the additional pressure in the aerosol generating device to an additional peak pressure. Herein, the additional peak pressure can be a maximum of 20 mbar or 10 mbar, preferably 5 mbar, more preferably 2 mbar, and particularly 1 mbar or less. Limiting the additional peak pressure in the patient interface when the aerosol is administered to the patient, particularly when the aerosol valve is in the open position, can contribute to avoiding damage to the patient due to excessive pressure. In this further preferred embodiment, a flow rate of 0.01 L / min to 3 L / min, averaging approximately 1 L / min, can be preferably generated by the pressure regulating element. Herein, a flow rate of 0.01 L / min to 3 L / min, averaging approximately 1 L / min, lower than the flow rate in the artificial ventilation circuit, enables the direct delivery of a substantially undiluted, high aerosol concentration to the patient.

[0027] In further particular embodiments, the aerosol generating device may additionally comprise a breathing filter that may be positioned upstream relative to the aerosol generating element. When used generally, the term "breathing filter" refers to a filtering element configured to remove at least one interfering substance from breathing air to be provided to the aerosol generating element.

[0028] The aerosol generating device according to the present invention is used in a bypass configuration for a breathing circuit. When used generally, the term "bypass" refers to a flow configuration in which a portion of the flow is removed from the main flow and reintroduced into the main flow after a separate treatment. Here, a portion of the breathing air is removed from the ventilation circuit, enriched with aerosol, and reintroduced into the ventilation circuit, and the aerosol-enriched breathing air is administered to the patient. Therefore, the aerosol generating device according to the present invention differs from the aerosol generator disclosed in U.S. Pat. No. 10,987,474 (B2), which does not mention the bypass configuration according to the present invention. The aerosol generating device according to the present invention offers the advantage that the bypass configuration is configured to deliver a high, substantially undiluted aerosol concentration directly to the patient interface, preferably via a mouthpiece, breathing mask, nasal cannula, nasal prongs, or tracheostomy tube, to the patient.

[0029] As a further advantage, the aerosol generating device according to the present invention is not integrated into the patient interface, but rather the aerosol flow is supplied directly to the patient interface, independent of the respiratory airflow of the ventilation circuit. This arrangement minimizes the overall weight of the patient interface, thereby reducing or avoiding injury to the nose and / or mouth of premature infants, newborns, and children. Additionally, in contrast to aerosolization directly within the patient interface, as disclosed in WO 2020 / 243107 A1, WO 2020 / 079055 A1, or WO 2019 / 115771 A1, supplying the aerosol flow directly to the patient interface does not create additional dead space. Conversely, the dead space volume according to the present invention corresponds only to the volume of the patient interface, in particular the mouthpiece, breathing mask, nasal cannula, nasal prongs, or tracheostomy tube.

[0030] The use of a particularly advantageous pressure regulating element allows a priori limiting of the maximum pressure entering the patient interface, thus preventing patient injury. In addition, by controlling the strength of the bypass arrangement flow rate according to the pressure regulating element, the aerosol concentration can be varied, so that a higher aerosol concentration can be achieved by using a lower flow rate. In addition, there is no need to precisely record and control the pressure and flow rate, compared to known devices in which air is delivered from a compressed air network. As a result of these advantages, the aerosol generating device according to the invention can be used for both liquid and powdered medicinal products to be administered to patients of all ages, including premature infants, newborns, children, or adults.

[0031] In particular, the aerosol generating device according to the present invention can be configured to operate independently of the ventilatory system and / or ventilatory circuit, particularly independent of any parameters used to control the ventilatory system and / or ventilatory circuit. As a result, the aerosol generating device can be adapted to deliver a controlled aerosol flow to a patient without relying on or synchronizing with the ventilatory system's operating settings or cycle, thereby ensuring consistent and effective aerosol delivery regardless of the ventilatory system's state or operating mode. Furthermore, the aerosol generating device can be configured to variably adjust the aerosol concentration in response to changes in flow rate, facilitated by a pressure regulating element configured to regulate additional pressure in the aerosol flow for delivery through the conducting element to the patient. Furthermore, the aerosol generating device can be designed to operate without the need for an external pressure sensor or control unit, particularly by utilizing a bypass arrangement to contain pressure from the ventilatory circuit and a pressure regulating element to minimize this pressure buildup, thereby enabling efficient aerosol delivery without the complexity of additional pressure monitoring or control components.

[0032] In a further aspect, the present invention provides a method for generating an aerosol stream, comprising: (i) receiving a portion of breathing air from the ventilation circuit to be provided to the aerosol generating element; (ii) generating aerosol particles and introducing the aerosol particles into an aerosol stream; (iii) providing an aerosol stream containing the aerosol particles through a conducting element to a patient; The present invention relates to a method, comprising:

[0033] In particularly preferred embodiments, the aerosol stream containing the aerosol particles can be provided directly to the patient interface, and in further preferred embodiments, additional pressure can be provided in the aerosol stream to guide it through a conducting element to the patient, which can preferably comprise at least one of the patient interface or the aerosol valve.

[0034] For further details on how to generate an aerosol stream, please refer to the aerosol generation devices configured to generate an aerosol stream described elsewhere herein.

[0035] In a further aspect, the present invention provides a processing device configured to control an apparatus for administering an aerosol to a patient, the controlling of the apparatus comprising: - receiving input data related to a breathing pattern of a patient, the breathing pattern including information regarding a time course of at least one of rise or deflation of at least one of the patient's chest or abdomen; - determining at least one time point from the breathing pattern; - controlling the aerosol flow to the patient triggered at least one time; carried out by The at least one time point relates to a processing device that advances at least one of the onset or cessation of the patient's breathing.

[0036] As used herein, the term "apparatus" refers to a device comprising multiple elements, each of which cooperates with at least one further element to administer an aerosol to a patient. In particular, the apparatus can be implemented as a single device that can comprise at least all elements required for this purpose. Alternatively, at least two elements of the apparatus can be located at different locations, and each element can comprise or cooperate with a communication element configured for communication between the at least two elements of the apparatus. By way of example, the different locations can be within the same room, building, town, or country, or can be distributed across at least two continents. Further examples are possible.

[0037] As used herein, the term "processing" or any grammatical variant thereof refers to applying at least one algorithm to data received by at least one input file such that the desired control of the device for administering aerosol to the patient is provided by at least one output file including at least one command for controlling an aerosol valve configured to provide the aerosol flow to the patient. In particular, with respect to the present invention, the term "data" refers to at least one piece of information contained by at least one file, specifically at least one input file or at least one output file. In particular, with respect to the present invention, the at least one piece of information contained by the at least one input file relates to a patient's breathing pattern, and the at least one piece of information contained by the at least one output file relates to at least one command for controlling the aerosol flow to the patient, which is triggered at least at one time point. As used herein, the at least one algorithm may be configured to determine data for the at least one output file from data provided by the at least one input file according to a predefined scheme, and may also apply artificial intelligence, specifically at least one machine learning algorithm, as described in more detail below.

[0038] When used in its entirety, the term "processing device" refers to a specific type of device designated to determine data for at least one output file from data provided by at least one input file, where the at least one input file can be provided to the processing device preferably by using at least one input interface, and the at least one output file can be provided by the processing device preferably by using at least one output interface. Specifically, the processing device may comprise at least one of an integrated circuit, particularly an application-specific integrated circuit (ASIC), or a digital processing device, particularly at least one of a digital signal processor (DSP), a field-programmable gate array (FPGA), a microcontroller, a microcomputer, a computer, or a mobile communication device, particularly a notebook, tablet, smartphone, or personal digital assistant. Further components, particularly at least one of a pre-processing element or a data storage element, may also be executable. The processing device may preferably be designed to execute at least one computer program, particularly at least one line of computer program code, configured to execute at least one algorithm for determining data for at least one output file, and the processing of data may be performed in at least one of a serial or parallel manner.

[0039] According to the present invention, a processing device is configured to control an apparatus for administering an aerosol to a patient by first receiving input data related to the patient's breathing pattern. When used generally, the term "receive" or any grammatical variant thereof refers to the process of acquiring at least one piece of information, particularly at least one input file. In particular, with respect to the present invention, the at least one input file contains data related to the patient's breathing pattern. Furthermore, when used generally, the term "breathing pattern" refers to the time course of changes in at least one body part of the patient related to the patient's breathing due to the patient's breathing. Herein, each breathing pattern can be identified by a first time point related to the onset of the patient's breathing and a second time point related to the cessation of the patient's breathing, where the first and second time points alternate, thereby defining a breathing cycle. In many cases, a breathing pattern has a regular pattern that repeats after each breathing cycle, and typically, each breathing cycle can have approximately the same duration. However, alternatively or in addition, a breathing pattern can also include at least one irregular feature related to the patient's breathing. However, there may be differences in duration between successive breathing patterns, particularly in premature infants or critically ill adults. Advantageously, the present invention operates independently of whether the breathing pattern is a regular pattern or not, as will be explained in more detail below.

[0040] Additionally, the processing device is configured to determine at least one time point from the breathing pattern. When used generally, the term "determine" or any grammatical variations thereof refers to a process that generates a representative result, typically referred to as "data." In particular with respect to the present invention, the data generated by the processing device corresponds to at least one output file that includes at least one information related to at least one command configured to control an aerosol flow to the patient, the at least one command being triggered at at least one time point. To this end, the at least one command corresponds to at least one information directed to varying the flow rate of the aerosol flow, in particular to one of initiating, increasing, maintaining, decreasing, or terminating the volume of the aerosol flow. As will be explained in more detail below, an aerosol valve configured to provide the aerosol flow to the patient can be controlled for this purpose, although other procedures, such as varying the gas flow of a carrier gas, could in principle also be performed.

[0041] Further, the processing device is configured to control the aerosol flow to the patient when triggered at least at one time. When used generally, the term "control" or any grammatical variant thereof refers to a process of adjusting at least one characteristic of an object or condition by using at least one command. Further, when used generally, the term "trigger" or any grammatical variant thereof refers to a signal configured to initiate a change in an object or condition. In the context of the present invention, the aerosol flow to the patient is controlled such that the rate of the aerosol flow changes when a signal is provided by at least one command determined by the processing device from input data.

[0042] According to the present invention, the breathing pattern includes information regarding the time course of at least one of the rise and contraction of at least one of the patient's chest or abdomen. As is generally known, the patient's chest and abdomen undergo alternating rise and contraction, particularly as the patient breathes, thereby defining a breathing cycle. When used generally, the term "rise" refers to the rise of the abdominal wall and / or rib cage, and the term "contraction" refers to the fall of the abdominal wall and / or rib cage, whereby the abdominal wall and / or rib cage resume their previous position. As noted above, breathing cycles can be regular or irregular, and the present invention has particular advantages because it allows for control of aerosol flow to a patient independently of whether the breathing pattern is regular or irregular.

[0043] Furthermore, controlling the aerosol flow to the patient includes triggering the aerosol flow at at least one time point, i.e., at least one of a first time point related to the onset of the patient's breathing or a second time point related to the cessation of the patient's breathing, with triggering the aerosol flow at the first time point generally being preferable to triggering the aerosol flow at the second time point. Specifically, according to the present invention, the at least one time point advances at least one of the onset or cessation of the patient's breathing, which may correspond, in particular, to the onset or cessation of the aerosol flow through at least one of the patient's nose or mouth. Consequently, the first time point is related to the onset of the patient's breathing as determined from a rise in at least one of the patient's chest or abdomen, but nevertheless advances the onset of the patient's breathing as indicated by the onset and subsequent increase in the volume of the aerosol flow through at least one of the patient's nose or mouth. Similarly, the second time point is related to the cessation of the patient's breathing as determined from a contraction in at least one of the patient's chest or abdomen, but nevertheless advances the cessation of the patient's breathing as indicated by a drop in the volume of the aerosol flow through at least one of the patient's nose or mouth. In particular, at least one time point may advance the start or stop of the patient's breathing by a time interval of 1 millisecond, preferably 50 milliseconds, more preferably 100 milliseconds, to 1 second, preferably 500 milliseconds, more preferably 200 milliseconds, respectively, although different values ​​may be feasible depending on the particular patient.

[0044] In other words, the aerosol flow to the patient can be preferably triggered by at least one command determined by the processing device from input data including information about the rise or contraction of at least one of the patient's chest or abdomen, thereby preferably hastening at least one of the start or cessation of the patient's breathing. Input data corresponding to the patient's chest or abdomen movement has been found to be particularly suitable for determining at least one time point at which the trigger for the aerosol flow to the patient is released. Because the patient's nose and mouth movements are synchronized with the patient's breathing, the patient's chest or abdomen movement precedes the above-mentioned time interval and can therefore be used, for purposes of the present invention, to administer to the patient a pharmaceutical formulation contained by the aerosol, in particular to ensure that a predominant amount, preferably a complete amount, of the pharmaceutical formulation can actually be provided to the patient at the desired concentration and is not diluted or dispersed elsewhere.

[0045] This advantage contrasts particularly with known prior art, where up to 90% or more by volume of the pharmaceutical may actually be dispersed elsewhere away from the patient, typically resulting in high dilution of the pharmaceutical during administration to the patient. Conversely, advancing the triggering of the aerosol by a small time interval relative to the onset or cessation of the patient's breathing, respectively, has the particular advantageous effect of introducing the pharmaceutical contained in the aerosol into the respiratory gas at a time that ensures that a predominant amount, preferably the complete amount, of the introduced pharmaceutical can actually be received by at least one predefined target in the patient's respiratory tract, particularly at least one central or peripheral region of the lungs. Furthermore, respiratory-triggered release of the pharmaceutical near the patient can further reduce or preferably avoid delays in administering the pharmaceutical to the patient. In this way, optimal respiratory-triggered release of the pharmaceutical can be achieved, particularly by providing a batch of aerosol to at least one of the patient's nose or mouth before the onset of the inhalation flow. Such a type of "pre-trigger" is provided by the present invention, since it enables detecting the onset of the inhalation flow before measuring the onset of the inhalation flow. Similar results can also be achieved for respiratory flow arrest using the present invention. Additionally, the use of input data of the type generated specifically for this purpose ensures that this effect is independent of whether the patient's breathing pattern is regular or not. As a result, the present invention can be used, among other things, to treat and cure premature infants or critically ill adults who typically exhibit irregular breathing patterns.

[0046] In a further aspect, the present invention relates to a device for administering an aerosol to a patient. Thus, the device comprises: - an aerosol valve configured to provide an aerosol stream to the patient; - at least one of the following: an aerosol generating device configured to generate an aerosol stream as disclosed herein, or a processing device configured to control an apparatus for administering an aerosol to a patient as further disclosed herein with at least one of Equipped with.

[0047] Thus, an apparatus for administering an aerosol to a patient comprises an aerosol valve configured to provide an aerosol stream to the patient, as well as the aerosol generation device and processing device described above and in more detail below, where the aerosol generation device comprises an aerosol generating element configured to generate aerosol particles and introduce the aerosol particles into the aerosol stream, and the processing device is configured to control the aerosol flow through the aerosol valve by triggering the aerosol valve at least one time, whereby the aerosol stream designated to be provided to the patient is regulated as disclosed herein. Alternatively, an apparatus according to the present invention can comprise an aerosol valve and aerosol generation device disclosed herein and a prior art processing device, or as a further alternative, can comprise an aerosol valve and a processing device disclosed herein and a prior art aerosol generation device.

[0048] When used generally, the term "aerosol valve" refers to a device configured to control the volume of an aerosol flow, particularly to be provided to at least one of the patient's nose or mouth. As described above, the aerosol valve can be controlled by at least one command including at least one piece of information directed to varying the flow rate of the aerosol flow, particularly to initiating, increasing, maintaining, decreasing, or terminating the volume of the aerosol flow. For this purpose, a pneumatic device addressable by at least one command can be used, although further embodiments may be feasible. In a preferred embodiment, the aerosol valve can be integrated into a patient interface, which, as described above, is configured to provide a connection between the artificial ventilation circuit and the patient's ventilator. Alternatively, the aerosol valve can be located upstream relative to the patient interface. Further alternatives are also contemplated.

[0049] In a preferred embodiment of the present invention, the apparatus for administering an aerosol to a patient may further comprise a breath detection device. As used herein, the term "breath detection device" refers to a device configured to determine input data related to a patient's breathing pattern and to transmit the input data related to the patient's breathing pattern to a processing device as disclosed herein. In particular with respect to the present invention, the breath detection device may be configured to determine at least one of a rise or a contraction of at least one of the patient's chest or abdomen related to the patient's breathing. In certain embodiments, the breath detection device comprises at least: - a detection element configured to register at least one of a rise or a deflation of at least one of the patient's chest or abdomen; - a processing element configured to determine input data related to the patient's breathing pattern from at least one of a rise or a deflation of at least one of the patient's chest or abdomen; - a communication interface configured to transmit input data to a processing device; Additional components are also contemplated.

[0050] As used herein, the term "sensing element" refers to a device or portion thereof configured to record and measure at least one physical characteristic related to the movement of a body part. As used herein, the sensing element may operate in contact with the patient's body, or alternatively or additionally, may operate contactlessly. In particular, the sensing element may be a respiration detection sensor selected from at least one of a strain gauge element, a time-of-flight camera, an electrical impedance tomography sensor, a respiratory induction plethysmography sensor, a millimeter wave sensor, a radar sensor, or a thermal sensor. However, it may also be feasible to use different types of sensing elements.

[0051] As further used herein, the term "processing element" refers to a further device or part thereof configured to determine at least one piece of data. Herein, the processing element and the communication interface may preferably constitute a single device, and the detection element may constitute a separate device. Embodiments may also be possible in which the processing element, the detection element, and the communication interface may form an integrated device. In the context of the present invention, the processing element may be configured to receive measurement data from the detection element, in particular related to at least one rise or contraction of at least one of the patient's chest or abdomen, from which input data related to the patient's breathing pattern may be determined.

[0052] As further used herein, the term "communication interface" refers to a transmission channel designated to transmit data from a first location to a second location, particularly different from the first location. Preferably, the communication interface may be a unidirectional interface configured to transfer data in a single direction, such as from a processing element to a processing device. Alternatively, the communication interface may be a bidirectional interface configured to transfer data in one of two directions, such as from a processing element to a processing device or vice versa, and particularly to further transmit at least one command from the processing device to the processing element, where the at least one command may be selected from starting or ending a measurement or starting or ending a data transmission. For data transmission purposes, the communication interface may comprise at least one wired or wireless element, and the wireless element may be configured to operate by using a wireless communication protocol such as Wi-Fi or Bluetooth, although further types of communication interfaces may also be feasible. In certain embodiments, the communication may be or include the transmission or exchange of encrypted data, particularly for the protection of personal data.

[0053] For details regarding apparatus for administering an aerosol to a patient, see the descriptions of processing devices and exemplary embodiments elsewhere herein.

[0054] In a further aspect, a method of administering an aerosol to a patient is provided, the method comprising: a) receiving input data related to a patient's breathing pattern, the breathing pattern including information regarding a time course of at least one of rise or deflation of at least one of the patient's chest or abdomen; b) determining at least one time point from the breathing pattern; c) controlling the aerosol flow to the patient triggered at least one time point; Including, At least one of the points in time advances at least one of the onset or cessation of the patient's breathing.

[0055] The steps a) through c) shown herein can be performed in the order presented, and preferably all of the steps shown can be performed at least partially simultaneously. Additionally, additional method steps can also be performed, whether or not described herein.

[0056] The method for administering an aerosol to a patient disclosed herein can preferably be a computer-implemented method. When used generally, the term "computer-implemented method" refers to a method involving at least one programmable device, particularly selected from mobile communication devices. However, other types of programmable devices, etc., can also be implemented. Herein, the at least one programmable device can, in particular, comprise a processing device disclosed herein or have access to a processing device disclosed herein, and at least one feature of the method is implemented by using at least one computer program. For this purpose, the computer program can be provided on the at least one programmable device, or the at least one programmable device can have access to the computer program via a network, such as a local network or the Internet, which can be located on a remote server or in the cloud.

[0057] According to step a), input data relating to a patient's breathing pattern is received, the breathing pattern including information regarding the time course of at least one of rise or deflation of at least one of the patient's chest or abdomen.

[0058] According to step b), at least one time point is determined from the breathing pattern, as described in more detail elsewhere herein.

[0059] According to step c), the aerosol flow to the patient is controlled by triggering the aerosol flow at least one time point, the at least one time point predating at least one of the onset or cessation of the patient's breathing.

[0060] For details on how to administer an aerosol to a patient, please see the descriptions of processing devices, apparatus for administering an aerosol to a patient, and exemplary embodiments elsewhere herein.

[0061] The apparatus, devices, and methods according to the present invention offer various advantages over known apparatus, devices, and methods. The processing device and corresponding method are particularly configured to use the respiratory motion signal contained by the breathing pattern in a largely raw, minimally analyzed form. This advantage eliminates the need for predictive analysis. In contrast to the disclosures of U.S. Pat. No. 10,987,474 B2, WO 2020 / 243107 A1, and U.S. Patent Application Publication No. 2020 / 368457 A1, among others, no prior analysis of the breathing pattern is required to predict the patient's breathing. Therefore, there is no need to rely on predictive algorithms. The processing device and corresponding method do not use algorithms for pattern recognition and / or prediction of respiratory events over the time course of breathing. Instead, real-time signals related to the patient's chest and / or abdominal movement, i.e., rise or fall, are used to indicate the start or stop of the patient's breathing. This advantage results in immediate, rapid aerosol delivery. The aerosol flow can respond without delay to real-time changes in the respiratory cycle. Furthermore, this arrangement reduces complexity, particularly because no sophisticated pattern recognition or prediction algorithms are required. These advantages provide increased accuracy and efficiency for drug delivery during natural breathing cycles as well as irregular breathing patterns. The aerosol flow can be precisely synchronized with each breath, making it suitable for patients with irregular breathing patterns. This results in precise delivery of the aerosol flow to the patient by ensuring accurate drug delivery, particularly at the beginning of inhalation, maximizing efficacy, and minimizing waste. In contrast, known predictive models, such as those disclosed in U.S. Pat. No. 10,987,474 (B2), WO 2020 / 243107 A1, and U.S. Patent Application Publication No. 2020 / 368457 A1, are prone to errors when applied to irregular breathing. The present invention overcomes these drawbacks by using a direct measurement approach.Furthermore, in contrast to using prior art mesh systems that require a lead time to aerosolize the medication, the aerosol generating device according to the present invention can continuously create and deliver an aerosol stream to an aerosol valve that can open immediately upon the start of a breath, thereby making the aerosol stream immediately available to the patient. Similarly, the aerosol valve can close immediately upon the cessation of breath, thereby immediately terminating the aerosol stream, thereby reducing waste.

[0062] A further advantage of the apparatus, device, and method according to the present invention is that different regions of the lungs can be reached depending on the release time. If the aerosol can be administered to the patient immediately after the start of inhalation, the peripheral regions of the lungs can be primarily treated. If the aerosol can be administered shortly before the end of inhalation, the central regions of the lungs can be primarily treated. In addition, as in the case of pulsed delivery of medical gases, bolus delivery can also be used to specifically treat well-ventilated or poorly-ventilated regions of the lungs. This allows for time-efficient, targeted inhalation therapy, which can contribute to reducing the dose of medicinal drug administered and therefore reducing side effects.

[0063] In this specification, the terms "have," "comprise," or "include," or any grammatical variations thereof, are used non-exclusively. Thus, these terms can refer both to a situation in which, apart from the features introduced by these terms, no further features are present in the entity described in this context, and to a situation in which one or more further features are present. As an example, the expressions "A has B," "A comprises B," and "A includes B" can refer both to a situation in which, apart from B, no other elements are present in A (i.e., a situation in which A consists solely and exclusively of B), and to a situation in which, apart from B, one or more further elements are present in entity A, such as element C, elements C and D, or further elements.

[0064] As used further in this specification, the terms "preferably," "more preferably," "particularly," "more particularly," or similar terms are used in conjunction with optional features without limiting alternative possibilities. Features introduced by these terms are therefore optional features and are not intended to limit the scope of the claims in any way. The present invention can be implemented by using alternative features, as would be understood by a person skilled in the art. Similarly, features introduced by "in one embodiment of the present invention" or similar expressions are intended to be optional features, without any limitations on alternative embodiments of the invention, on the scope of the invention, or on the possibility of combining the features thus introduced with other features of the invention.

[0065] Further optional features and embodiments of the present invention are disclosed in more detail in the following description of preferred embodiments, preferably in conjunction with the dependent claims. Here, as will be understood by those skilled in the art, each optional feature can be implemented separately as well as in any feasible combination. It is emphasized that the scope of the present invention is not limited by the preferred embodiments. The embodiments are illustrated diagrammatically in the figures, where identical reference numbers in these figures refer to identical or functionally equivalent elements. [Brief explanation of the drawings]

[0066] [Figure 1] 1 is a schematic diagram of a preferred embodiment of an exemplary device for administering an aerosol to a patient according to the present invention. [Figure 2A] FIG. 10 is a diagram illustrating a comparison between the time course of a first signal generated by using a strain gauge element during the expiratory phase and the time course of a second signal generated by using a flow sensor. [Figure 2B] FIG. 10 is a diagram illustrating a comparison between the time course of a first signal generated by using a strain gauge element during the inhalation phase and the time course of a second signal generated by using a flow sensor. [Figure 3] FIG. 10 is a schematic diagram illustrating respiratory phases of a premature infant extracted from abdominal movement data recorded by a time-of-flight camera. [Figure 4] FIG. 1 shows a schematic comparison of the dose efficiency of the formulations relative to the emitted dose in different studies. DETAILED DESCRIPTION OF THE INVENTION

[0067] 1 schematically illustrates a preferred embodiment of an exemplary apparatus 110 for administering an aerosol 112, particularly in the form of an aerosol stream 114, to a patient 116. It is emphasized here that, although the exemplary embodiment of apparatus 110 illustrated schematically in FIG. 1 comprises both a processing device 120 and an aerosol generation device 162, it is also feasible to use only the processing device 120 or the aerosol generation device 162. In particular, apparatus 110 is designed to provide an aerosol stream 114 having a defined aerosol concentration, preferably a high aerosol concentration, to a patient 116, which may in particular be a premature infant, a newborn, a child, or a critically ill adult. However, further applications of apparatus 110 are also feasible.

[0068] 1 includes a notebook 118 that is or includes a processing device 120 configured to control the apparatus 110 to administer the aerosol 112, preferably in the form of an aerosol stream 114, to the patient 116. Alternatively, the processing device 120 can be or be included in a different kind of mobile communication device, in particular a tablet, a smartphone, or a personal digital assistant. As a further alternative, at least one of an integrated circuit, in particular an application specific integrated circuit (ASIC), or a digital processing device, in particular at least one of a digital signal processor (DSP), a field programmable gate array (FPGA), a microcontroller, a microcomputer, or a computer, can be used as the processing device 120.

[0069] The processing device 120 is designed to determine data for the at least one output file 122 from data provided by at least one input file 124, where the at least one input file 124 may be provided to the processing device 120 by using an input interface 126 and the at least one output file 122 may be provided by the processing device 120 by using an output interface 128. The processing device 120 shown in Figure 1 is further designed to execute at least one computer program, in particular at least one line of computer program code, configured to execute at least one algorithm 130 for determining data for the at least one output file 122, where processing of the data may be performed by using the at least one algorithm 130 in a serial and / or parallel manner.

[0070] To this end, the processing device 120 is configured to receive at least one input file 124 containing input data relating to the breathing pattern of the patient 116. In this exemplary embodiment, the breathing pattern includes information regarding the time course of the rise 132 and contraction 134 of the chest 136 or abdomen 138 of the patient 116. In this manner, information regarding the rise and fall of the abdominal wall and rib cage of the patient 116 can be obtained, from which the breathing pattern can be derived. Generally, the breathing pattern can be regular or, particularly in the case of premature infants or critically ill adults, irregular, and the present invention has particular advantages since it is possible to control the aerosol flow 114 to the patient 116 independently of whether the breathing pattern is regular or not.

[0071] 1 further comprises a respiration detection device 140 configured to determine at least one input file 124 containing input data related to the breathing pattern of the patient 116 and to transmit the at least one input file 124 to the processing device 120 by using the input interface 126. With particular regard to the present invention, the respiration detection device 140, in this exemplary embodiment, is configured to determine both rise 132 and contraction 134 of the chest 136 and / or abdomen 138 of the patient 116 related to the breathing of the patient 116.

[0072] 1 , breath detection device 140, in this exemplary embodiment, includes a detection element 142 configured to record both rise 132 and contraction 134 of chest 136 and / or abdomen 138 of patient 116. Generally, detection element 142 can operate in contact with the body of patient 116, or alternatively, or in addition, can operate contactlessly. As shown in FIG. 1 , detection element 142 is or includes a time-of-flight camera 144 configured to contactlessly record and measure at least one physical property related to movement of chest 136 and / or abdomen 138 of patient 116. Alternatively, different types of breath detection sensors can be used as detection element 142, in particular contact-providing elements such as strain gauge elements, or different contactless elements such as electrical impedance tomography sensors, respiratory induction plethysmography sensors, millimeter wave sensors, radar sensors, or thermal sensors.

[0073] 1, the breath detection device 140 further comprises a notebook 118, which additionally has a processing element 146 configured to determine at least one input file 124 including input data related to the breathing pattern of the patient 116, and a communication interface 148 configured to transmit the at least one input file 124 including input data related to the breathing pattern of the patient 116 to an input interface 126 included by the processing device 120. In the exemplary embodiment of FIG. 1, both the processing element 146 and the communication interface 148 are included by the notebook 118, while the detection element 142 is implemented as a separate device. However, other embodiments are also possible, particularly embodiments in which the detection element 142, the processing element 146, and the communication interface 148 can form an integrated device (not shown here). For the purpose of data transmission, the communication interface 148 may comprise at least one of a wired element or a wireless element, the wireless element being configured to operate by using a wireless communication protocol such as Wi-Fi or Bluetooth, and may also be capable of transmitting or exchanging encrypted data, in particular for the protection of personal data.

[0074] Communications interface 148 may be or comprise a unidirectional interface configured to transmit data in a single direction from processing elements 146 contained by processing device 120 to input interface 126. Alternatively, communications interface 148 may be a bidirectional interface configured to transfer data in one of two directions, such as from processing elements 146 to input interface 126 or vice versa, and in particular to further transmit at least one command from processing device 120 to processing element 146, where the at least one command may be for starting or ending a measurement or for starting or ending a data transmission.

[0075] Further, the processing device 120 is configured to determine at least one time point from the breathing pattern and control the aerosol flow 114 to the patient 116 triggered at the at least one time point, the at least one time point advancing the start and / or cessation of the patient's breathing, respectively. In particular, the at least one time point can advancing the start or cessation of the aerosol flow 114 through the nose 150 or mouth 152 of the patient 116, respectively. More particularly, the at least one time point can advancing the start or cessation of the patient's breathing, respectively, by a time interval of 1 millisecond, preferably 50 milliseconds, more preferably 100 milliseconds, to 1 second, preferably 500 milliseconds, more preferably 200 milliseconds, although different values ​​may be feasible depending on the particular patient 116. In this regard, the aerosol flow 114 to the patient 116 is triggered by at least one command contained in at least one output file 122 determined by the processing device 120 by using at least one algorithm 130, and the at least one output file 122 contains at least one command that is transferred to an aerosol valve 154 configured to provide the aerosol flow 114 to the patient 116 by using an output interface 128.

[0076] It has been found that by using at least one input file 124 containing input data relating to the breathing pattern of the patient 116 determined by using information regarding the rise 132 and / or contraction 134 of the chest 136 and / or abdomen 138 of the patient 116, it is possible to use the processing device 120 to predict at least one time point at which the trigger for the aerosol flow 114 to the patient 116 can reasonably be released. In contrast to the flow movement through the nose 150 and mouth 152 of the patient 116, which is synchronized with the breathing of the patient 116, the movement of the chest 136 and / or abdomen 138 of the patient 116 precedes the movement by the aforementioned time interval and can therefore be used for purposes of the present invention, particularly to administer the pharmaceutical agent contained by the aerosol 112 to the patient 116. In this way, it can be ensured that a dominant amount, preferably the complete amount, of the pharmaceutical agent can actually be provided to the patient 116 and not dispersed elsewhere, such as to undesired parts of the device 110 or around the device 110. By using at least one input file 124, it can be further ensured that this effect is independent of whether the patient's breathing pattern is regular or not.

[0077] Further in accordance with the present invention, the device 110 further comprises an aerosol valve 154 configured to provide the aerosol flow 114 to the patient 116. To this end, the aerosol valve 154 is configured to control the volume of the aerosol flow 114 provided to the nose 150 or to the mouth 152 of the patient 116, such as by using a pair of nasal prongs 156. As described above, the aerosol valve 154 can be controlled by at least one command including at least one command directed to varying the flow rate of the aerosol flow 114, in particular to initiating, increasing, maintaining, decreasing, or terminating the volume of the aerosol flow 114. In the exemplary embodiment of FIG. 1, the aerosol valve 154 is integrated into a patient interface 158 configured to provide a connection between the artificial ventilation circuit 160 and the patient's respiratory system. Alternatively (not shown here), the aerosol valve 154 can be located in a different position, such as upstream, relative to the patient interface 158.

[0078] 1 , the exemplary embodiment of the apparatus 110 comprises an aerosol generating device 162 configured to generate an aerosol flow 114 to be provided to the patient 116, particularly preferably directly to the patient interface 158. In particular, the aerosol generating device 162 shown in FIG. 1 comprises an air inlet 164 configured to receive a portion of breathing air 166 from the artificial ventilation circuit 160 via a junction 167, where the breathing air 166 is provided to a breathing filter 168 configured to remove at least one interfering substance from the breathing air 166 before being provided to an aerosol generating element 170 further comprised by the aerosol generating device 162. Herein, the aerosol generating element 170 may be configured, among other things, to generate aerosol particles and introduce the aerosol particles into the aerosol flow 114. For this purpose, the aerosol generating element 170 can be designed to convert an aerosolizable material, i.e., a powder or a solution, into the desired aerosol 112, in particular by using a powder generator or a nebulizer, in particular a vibrating mesh or ultrasound, to entrain solid or liquid particles into a gas flow, which may include breathing air 166 and a carrier gas, such as a breathing gas. Herein, the aerosol generating element 170 can preferably be selected from a nebulizer and / or a powder generator. As further shown in FIG. 1 , the aerosol generating device 162 further comprises an aerosol tube 172 configured to provide the aerosol 112 containing the aerosol particles to the patient 116 through a conducting element, in particular the aerosol valve 154 and / or the patient interface 158. However, using a tube (not shown here) can also be feasible.

[0079] In the particular embodiment shown in FIG. 1 , the aerosol generation device 162 further comprises a pressure regulating element 174 configured to provide additional pressure in the aerosol flow 114. In particular, the additional pressure can be used to improve the way the aerosol flow 114 is guided to the patient 116 through the conducting elements, in particular the aerosol valve 154 and / or the patient interface 158. Preferably, when the aerosol 112 is administered to the patient 116, in particular when the aerosol valve 154 is in the open position, the pressure prevailing in the aerosol conduit 172 can exceed the additional pressure prevailing in the air inlet 164 by at least 0.1 mbar, preferably at least 0.05 mbar, more preferably at least 0.02 mbar, in particular at least 0.01 mbar. Preferably, the pressure regulating element 174 can further be configured to limit the additional pressure in the aerosol generation device to an additional peak pressure, which can be at most 20 mbar or 10 mbar, preferably 5 mbar, more preferably 2 mbar, in particular 1 mbar, or even less. Limiting additional peak pressures within the patient interface 158 when the aerosol 112 is administered to the patient 116, particularly when the aerosol valve 154 is in the open position, can help prevent damage to the patient 116 from excessive pressure. In this manner, a flow rate of 0.01 L / min to 3 L / min, averaging approximately 1 L / min, can be generated by the pressure regulating element 174. Herein, a lower flow rate of 0.01 L / min to 3 L / min, averaging approximately 1 L / min, compared to the flow rate within the ventilation circuit 160, enables delivery of a high, substantially undiluted aerosol concentration directly to the patient 116.

[0080] If the aerosol flow 114 were injected directly into the ventilation circuit 160 according to the prior art, this would result in a strong dilution of the aerosol concentration. For example, using a respiratory airflow of 7 L / min, an aerosol output of 4.5 mg / min from a prior art aerosol generator, and a homogeneous distribution of aerosol particles would achieve an aerosol concentration of 0.75 mg / L in the respiratory gas. In contrast, according to the present invention, this dilution effect can be avoided by using a small partial flow that is removed from the respiratory gas upstream of the patient interface 158, enriched with aerosol, and delivered directly into the patient interface 158. If the aerosol delivery flow is reduced, the aerosol concentration increases. For example, by using a low delivery flow of only 1 L / min independent of the respiratory airflow in the ventilation system, the aerosol can be delivered to the patient interface 158, resulting in an aerosol concentration of 4.5 mg / L in the respiratory gas, thus six times higher than in the prior art. As a result, the dose inhaled by the patient per unit of time can be significantly increased. Additionally, as discussed above, the efficiency of aerosol deposition in the lungs can be further increased by using a respiratory-gated drug delivery device.

[0081] FIG. 2 schematically illustrates a comparison between a first time course 180 of a first signal generated by using a strain gauge element and a second time course 182 of a second signal generated by using a flow sensor during the exhalation phase (FIG. 2A) and the inhalation phase (FIG. 2B), respectively. Here, the x-axis indicates time t in seconds (s), the left y-axis indicates respiratory flow f measured by using the flow sensor in L / min, and the right y-axis indicates the average signal S generated by the strain gauge element in volts. The respective switches from exhalation to inhalation and vice versa are indicated by circles 184, 184', 184", ... for the flow sensor and by vertical dashed lines 186, 186', 186", ... for the strain gauge element. Breathing was paused twice to allow accurate representation of the onset of inhalation and exhalation, respectively, as indicated by horizontal line 188. The transition from inhalation to exhalation is indicated by a zero crossing on the y-axis for the flow sensor and by an extreme value or a sudden increase or decrease in the slope for the strain gauge element, respectively. As shown in FIG. 2, maximum inhalation is followed by maximum abdominal stretch, resulting in maximum stretch and therefore maximum positive tension on the strain gauge element. Similarly, maximum exhalation is followed by minimum abdominal stretch, resulting in minimum stretch and therefore maximum negative stress on the strain gauge element. As shown in FIG. 2, the strain gauge element is able to detect inhalation or exhalation, respectively, for a time interval of approximately 200 ms to 300 ms before the flow sensor. This time interval allows the strain gauge element to detect the upcoming inhalation or exhalation earlier than the flow sensor, thereby enabling earlier triggering of the aerosol 112 relative to the onset or cessation of breathing of the patient 116, respectively, thereby providing the beneficial effects described elsewhere herein.

[0082] Figure 3 shows a schematic representation of the respiratory phases 190 of a premature infant extracted from abdominal movement data recorded by the time-of-flight camera 144. Here, the distance d in meters m from the time-of-flight camera 144 to the premature infant's abdomen 138 is shown versus time t in seconds s. The maxima and minima shown in Figure 3 represent the transitions from inhalation to exhalation and vice versa.

[0083] 4 shows a schematic comparison of the dose efficiency (eff) of the formulation in % relative to the emitted dose in various tests 192, 194, 196. In the first test 192, a standard patient interface according to the prior art was used, in the second test 194, an aerosol generating device 162 in a bypass configuration without the aerosol valve 154 disclosed herein was used, and in the third test 196, an apparatus 110 according to the present invention was used that includes an aerosol generating device 162 by using the aerosol valve 154 disclosed herein.

[0084] For this purpose, 0.9% saline by volume was aerosolized using a mesh nebulizer and delivered to each test stand according to tests 192, 194, and 196 described above as follows. When using the standard patient interface used in the first test 192, the aerosol was coupled into the ventilation circuit 160 by using a Y-connector. In the second test 194, when the aerosol generating device 162 was used in bypass configuration without the aerosol valve 154, aerosol 112 was delivered directly into the patient interface 158 at a flow rate of approximately 1 L / min. The ventilation circuit 160 was operated in continuous positive airway pressure (CPAP) mode with a positive end-expiratory pressure (PEEP) of 5 mbar and a respiratory airflow of 6 L / min. To determine the amount of aerosol 112 delivered, advanced testing equipment disclosed in WO 2020 / 007858 A1 was used. This testing equipment allows for the use of different breathing rates (30-80 breaths / min), tidal volumes (2-40 ml), and inhaled volumes (0.25-0.75 ml). For the second test 194, a frequency of 51 breaths / min, a tidal volume of 12.3 ml, and an inhaled volume of 0.39 ml were used as simulated breathing parameters. In a third test 196, the device 110 according to the invention was used, and the same conditions were applied as in the second test 194, but the aerosol valve 154 was used, which was opened in a triggered mode at the start of the simulated inspiration and closed at the start of the simulated expiration. For this purpose, the aerosol valve 154 was closed or opened by using a pneumatic device.

[0085] 4, the dose efficiencies achieved in the first test 192 were 10.3%, in the second test 194 24.7% (non-triggered release), and in the third test 196 41.5% (triggered release). As a result, applying a non-triggered release by using the aerosol generating device 162 is approximately 2.5 times more efficient than using a standard patient interface. Furthermore, using a breath-triggered release in combination with the aerosol generating device 162 is approximately 1.7 times more efficient than a non-triggered release and approximately 4.2 times more efficient than using a standard patient interface.

[0086] Furthermore, aerosol measurements were performed under realistic clinical conditions to compare the aerosol generating device 162 according to the present invention with a conventional standard inhalation clinical (SoC) system. A test bed based on the disclosure of WO 2020 / 007858 A1 was used to simulate the respiratory parameters of premature infants. This test bed allows for different respiratory rates (30-80 breaths / min), tidal volumes (2-40 ml), and inspiratory volumes (0.25-0.75 ml). A respiratory rate of 50 breaths / min, a tidal volume of 8 ml, and an inspiratory-to-expiratory ratio of 1:1.5 were used as respiratory parameters. A Babylog® 8000 plus ventilator (Dragerwerk AG und Co. KGaA, Lübeck, Germany) was used to operate the ventilator circuit 160 in continuous positive airway pressure mode, applying a positive end-expiratory pressure of 5 mbar and a respiratory airflow of 6 L / min. A 3 ml solution containing equal amounts of budesonide (0.125 mg / ml) and saline (0.9%) was nebulized using an Aerogen Solo mesh nebulizer, manufactured by Aerogen Ltd., Galway, Ireland.

[0087] The aerosol is - via a prior art SoC system, Flexitrunk™, manufactured by Fisher & Paykel Healthcare Limited, Panmure, Auckland, New Zealand, where the aerosol is delivered directly into the ventilation circuit; or via an aerosol generating device 162 according to the invention, which delivers the aerosol directly into the patient interface 158 at a flow rate of about 1 L / min; Delivered to the test stand.

[0088] As experimentally demonstrated, the measured inhaled dose obtained using the prior art SoC system was 3.0%, compared to 9.7% using the aerosol-generating device 162 according to the present invention. As a result, the use of the aerosol-generating device 162 according to the present invention advantageously makes it possible to achieve a significant increase in inhalation efficiency of 3.2 times compared to the prior art SoC system. [Explanation of symbols]

[0089] 110 Equipment 112 Aerosols 114 Aerosol flow 116 patients 118 Notebooks 120 Processing Device 122 Output File 124 input files 126 input interfaces 128 output interfaces 130 Algorithms 132 rise 134 Contraction 136 Chest 138 Abdomen 140 Breath detection device 142 detection elements 144 Time-of-Flight Camera 146 processing elements 148 Communication Interface 150 nose 152 mouths 154 Aerosol Valve 156 Nasal Prongs 158 Patient Interface 160 Artificial respiration circuit 162 Aerosol generating device 164 Air inlet 166 Breathing Air 167 Joint 168 Breathing Filter 170 Aerosol-generating factors 172 Aerosol Tube 174 Pressure Regulating Element 180 First Time Course 182 Second Time Course 184, 184', ... yen 186, 186", ... vertical dashed lines 188 horizontal lines 190 Respiratory phase 192 First Test 194 Second Test 196 Third Test

Claims

1. an aerosol generation device (162) configured to generate an aerosol stream (114), an air inlet (164) configured to receive a portion of breathing air (166) from the ventilation circuit (160) to be provided to the aerosol generating element (170); - the aerosol generation element (170) configured to generate aerosol particles and introduce the aerosol particles into the aerosol flow (114); an aerosol conduit (172) configured to provide the aerosol flow (114) containing the aerosol particles to a patient (116) through a conducting element; An aerosol generating device (162).

2. 10. The aerosol generating device (162) of claim 1, wherein the aerosol generating element (170) is selected from at least one of a nebulizer or a powder generator.

3. 3. The aerosol generating device (162) of claim 1 or 2, wherein the conducting element comprises at least one of an aerosol valve (154) or a patient interface (158).

4. 4. An aerosol generating device (162) according to any one of claims 1 to 3, wherein the air inlet (164) is configured to receive a portion of the breathing air from the artificial ventilation circuit (160) via a junction (167).

5. 5. The aerosol generation device (162) of claim 1, further comprising a pressure regulating element (174) configured to provide additional pressure in the aerosol flow (114) to guide the aerosol flow (114) through the conducting element to the patient (116).

6. 6. The aerosol generating device (162) of claim 5, wherein when the aerosol (112) is administered to the patient (116), the pressure prevailing in the aerosol tube (172) exceeds the further pressure prevailing in the air inlet (164) by at least 0.01 mbar.

7. 7. The aerosol generation device (162) of claim 5 or 6, wherein the pressure regulating element (174) is further configured to limit the additional pressure in the aerosol generation device (162) to an additional peak pressure.

8. 8. The aerosol generating device (162) of claim 1, further comprising a breathing filter (168) upstream of the aerosol generating element (170), the breathing filter (168) configured to remove at least one interfering substance from the breathing air (166) to be provided to the aerosol generating element (170).

9. A processing device (120) configured to control an apparatus (110) for administering an aerosol (112) to a patient (116), wherein controlling the apparatus (110) comprises: - receiving input data relating to a breathing pattern of a patient (116), the breathing pattern including information regarding the time course of at least one of a rise (132) or a deflation (134) of at least one of a chest (136) or an abdomen (138) of the patient (116); - determining at least one time point from said breathing pattern; - controlling the aerosol flow (114) to the patient (116) triggered at the at least one time point; carried out by The at least one time point advances at least one of the start or cessation of breathing of the patient (116), a processing device (120).

10. 10. The processing device (120) of claim 9, wherein the start and stop of the breathing of the patient (116) corresponds to the start or stop of the aerosol flow (114) through at least one of the nose (150) or mouth (152) of the patient (116).

11. 11. The processing device (120) of claim 9 or 10, wherein the at least one time point advances at least one of the start or the stop of the breathing of the patient (116) by a time interval between 1 millisecond and 1 second.

12. 1. A device (110) for administering an aerosol (112) to a patient (116), comprising: an aerosol valve (154) configured to provide an aerosol flow (114) to the patient (116); - at least one of the following: an aerosol generating device (162) configured to generate the aerosol flow (114) according to any one of claims 1 to 8 directed to said aerosol generating device (162), or A processing device (120) configured to control the apparatus (110) for administering the aerosol (112) to the patient (116) according to any one of claims 9 to 11 directed to the processing device (120). with at least one of An apparatus (110) comprising:

13. 13. The apparatus (110) of claim 12, further comprising a respiration detection device (140), the respiration detection device (140) configured to determine at least one of the rise (132) or the contraction (134) of the at least one of the chest (136) or the abdomen (138) of the patient (116) related to the respiration of the patient (116).

14. The breath detection device (140) a detection element (142) configured to record at least one of the rise (132) or the contraction (134) of the at least one of the chest (136) or the abdomen (138) of the patient (116); a processing element (146) configured to determine the input data related to the breathing pattern of the patient (116) from the at least one of the rise (132) or the deflation (134) of the at least one of the chest (136) or the abdomen (138) of the patient (116); a communication interface (148) configured to transmit the input data to the processing device (120); 14. The device (110) of claim 13, comprising:

15. 15. The device of claim 14, wherein the detection element is a respiration detection sensor selected from at least one of a time-of-flight camera, a strain gauge element, an electrical impedance tomography sensor, a respiratory induction plethysmography sensor, a millimeter wave sensor, a radar sensor, or a thermal sensor.

16. A method for generating an aerosol stream (114), comprising: (i) receiving a portion of breathing air (166) from the ventilation circuit (160) to be provided to the aerosol generating element (170); (ii) generating aerosol particles and introducing the aerosol particles into an aerosol stream (114); (iii) providing the aerosol flow (114) containing the aerosol particles through a conducting element to the patient (116); A method comprising:

17. 17. The method of claim 16, wherein the aerosol flow (114) containing the aerosol particles is provided to the patient (116) via at least one of an aerosol valve (154) or a patient interface (158).

18. 18. The method of claim 16 or 17, wherein additional pressure is provided in the aerosol flow (114) to guide the aerosol flow (114) through the conducting element to the patient (116).

19. A method for administering an aerosol (112) to a patient (116), comprising: a) receiving input data relating to a breathing pattern of a patient (116), the breathing pattern including information regarding the time course of at least one of a rise (132) or a deflation (134) of at least one of a chest (136) or an abdomen (138) of the patient (116); b) determining at least one time point from said breathing pattern; c) controlling the aerosol flow (114) to the patient (116) triggered at the at least one time point; Including, The method, wherein the at least one time point advances at least one of the onset or cessation of breathing of the patient (116).

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