Administration of aerosol to patient

Abstract

The present invention relates to an aerosol generating device (162) configured to generate an aerosol flow (114) to a patient (116), and a treatment device (120) configured to control an apparatus (110) for administering an aerosol to a patient (116). Here, the aerosol generating device (162) comprises: an air inlet (164) configured to receive a portion of breathing gas (166) from the ventilation circuit (160) to be provided to the aerosol generating element (170); an aerosol generating element (170) configured to generate aerosol particles and to introduce the aerosol particles into an aerosol stream (114); and an aerosol tube (172) configured to provide an aerosol flow (114) comprising aerosol particles to a patient (116) through the conducting element. In particular, the device (162) is designed to provide high aerosol concentrations to patients (116), in particular preterm infants, neonates, children and adults. Also disclosed is a treatment device (120) configured to control an apparatus (110) for administering an aerosol (112) to a patient (116) by controlling an aerosol flow (114) to the patient (116) triggered at at least one point in time earlier than a start or pause of respiration of the patient (116).

Description

Field of the Invention

[0001] The present invention relates to a device and method for administering an aerosol to a patient, an aerosol generating device configured to generate an aerosol stream, a method of generating an aerosol stream, and a processing device configured to control a device for administering an aerosol to a patient. In particular, the device and method can be designed to provide a prescribed aerosol concentration, preferably a high aerosol concentration, to a patient (especially but not limited to premature infants, neonates, children or adults). Further applications are possible.

[0002] Related Art

[0003] Lung diseases such as asthma or chronic obstructive pulmonary disease (COPD) are typically treated by inhaling the corresponding aerosol. In addition, efforts have been made to deliver surfactant in the form of an aerosol during ventilation of premature infants suffering from surfactant deficiency, especially since this form of treatment is non-invasive and thus less harmful to premature infants compared to the standard therapy using invasive instillation of surfactant suspension.

[0004] An aerosol can be continuously generated and administered to a patient without releasing the aerosol in synchronization with respiration. However, a portion of the continuously delivered nebulized drug may be lost and thus may not show any medical benefit. It is further demonstrated in Longest, P.W.; Azimi, M.; 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 that only the aerosol delivered in the first half of the inhalation phase can reach the perialveolar region. In addition, the drug requirements for inhaled surfactant for local lung use may be significantly higher than those for other inhaled aerosols for lung diseases.

[0005] Therefore, breath-triggered drug release has attracted great interest. When respiration is detected, the aerosol must be released accordingly, i.e., within a prescribed time, a short or long aerosol jet is released, for example. However, currently known methods for detecting respiration during respiratory support or during independent respiration, and methods for aerosol release, have various problems and drawbacks.

[0006] Known respiratory monitoring devices work by volume flow or pressure sensors, which are configured to determine the inhalation flow at the patient interface. Therefore, drug release can only be produced with a delay, i.e., it cannot be released directly at the beginning of inhalation. Thus, a pressurized metered-dose inhaler can be integrated into the ventilation circuit in combination with a spacer. However, the drug formulation can only be released by actively driving the inhaler by the patient or someone else. Alternatively, an adapter can be used to couple an aerosol generating device to the ventilation circuit.

[0007] Aerosol release can be triggered based on the detection of pressure changes in the breathing tube caused by breathing, and then the generation of the aerosol is activated or stopped. However, the drug is only released after the corresponding pressure change occurs, and there is a delay in this change. Alternatively, drug release can be controlled by measuring the pressure at the mouthpiece, where the evaluation algorithm can consider the average value of consecutive breaths.

[0008] US10987474B2 discloses an aerosol delivery system that includes an aerosol generator that atomizes a fluid for delivery to a patient when the patient inhales. The aerosol delivery system includes a pump coupled to the aerosol generator that pumps the fluid to the aerosol generator, and a respiration sensor that emits a signal during the patient's respiration. A controller is coupled to the aerosol generator, the pump, and the respiration sensor. In operation, the controller receives a signal from the respiration sensor, controls the flow rate of the fluid flowing to the aerosol generator in response to the signal, and controls the aerosol generator to start atomizing the fluid before the patient inhales.

[0009] US2021 / 0283345A1 discloses an aerosol delivery system that has an aerosol generator that atomizes a fluid for delivery to a patient when the patient inhales. The aerosol delivery system includes a pump coupled to the aerosol generator that pumps the fluid to the aerosol generator, and a respiration sensor that emits a signal during the patient's respiration. A controller is coupled to the aerosol generator, the pump, and the respiration sensor. In operation, the controller receives a signal from the respiration sensor, controls the flow rate of the fluid flowing to the aerosol generator in response to the signal, and controls the aerosol generator to start atomizing the fluid before the patient inhales.

[0010] WO2020 / 243107A1 and US2020 / 368457A1 disclose a method for delivering aerosolized surfactant to an infant, which includes connecting an atomizing device to the airway of the infant and using the atomizing device to atomize a certain volume of surfactant at a rate of at least 0.1 mL / min into particles with a mass median aerodynamic diameter of less than about 3 μm. The surfactant is atomized within a range of about 1 cm - 8 cm from the patient interface. Up to about 80% of the aerosol is generated with each inhalation. The method further includes delivering the aerosolized surfactant to the airway of the infant.

[0011] WO2019 / 115771A1 discloses an atomizer system, including an atomizer for an assisted breathing device. The atomizer includes a body having a first connector for connecting the atomizer to the assisted breathing device and a second connector for connecting the atomizer to a patient (especially a neonate), wherein the body forms a flow channel from the first connector to the second connector, and an atomizing device for atomizing a fluid. The atomizing device is arranged in the flow channel between the first connector and the second connector. The atomizer is configured to accommodate an oral and / or nasal connection element, such as a nasal cannula, nasal mask, face mask or mouthpiece. In addition, the invention relates to a holding system for holding the atomizer or the atomizer system.

[0012] WO2020 / 079055A1 discloses methods, devices and compositions for inhalation therapy of neonates, infants or children suffering from a disease (optionally a lung disease such as asthma), by which a large amount of inhaled drug is directed to the small airways of the peripheral lungs of neonates, infants and children using a slow, controlled flow rate and a preset inhalation volume. The invention discloses a novel inhalation device, which is suitable for neonates, infants and children and is adapted to provide the slow, controlled flow rate through the disclosed simplified jet atomizer arrangement and a kit including the device.

[0013] However, most known methods are based on predictions that are usually inappropriate, because premature infants exhibit irregular breathing, so the aerosol cannot be generated and released in an optimal manner. Due to the inherent dead space volume, such devices are generally not suitable for premature infants.

[0014] US2019 / 0247595A1 discloses a system for administering a powder aerosol in a respiration-controlled manner when a patient is undergoing artificial respiration or assisted respiration, which includes an interface in contact with the patient's respiratory tract; a unit for generating a respiratory inflow; at least one inhalation line through which the air flow is directed to the interface; an aerosol generator; at least one aerosol line through which the generated aerosol is directed from the aerosol generator to the interface, and a respiration sensor for detecting the patient's respiration signal. A valve in at least one aerosol line is controlled based on the detected respiration signal. An intermediate memory for storing the generated powder aerosol is arranged between the valve and the aerosol generator. The air flow has a first pressure higher than or equal to the ambient pressure, and the aerosol has a second pressure higher than or equal to the first pressure.

[0015] WO2012 / 020004A1 discloses a device for connecting the airway of a patient receiving ventilation support to a respiratory gas source and an aerosol source. The device includes a contact assembly adapted to contact the patient's airway and comprising: one or two tubes, each tube including a lumen through which respiratory gas and aerosol can be delivered to the patient's airway, a mixing lumen fluidly connected to the lumen of the one or two tubes and having a longitudinal axis extending substantially perpendicular to the longitudinal axis of the lumen, and a port through which aerosol can be introduced into the mixing lumen and which is arranged such that the aerosol and the respiratory gas can be mixed in the mixing lumen.

[0016] Wiegandt, F.C.; Biegger, D.; Fast, J.F.; Matusiak, G.; Mazela, J.; Ortmaier, T.; Doll, T.; Dietzel, A.; Bohnhorst, B.; Pohlmann, G., Detecting the respiratory movements of premature neonates by recording their abdominal movements using a time-of-flight camera, Pharmaceutics 2021, 13, doi:10.3390 / pharmaceuticsl3050721 describes the need to detect the onset of inhalation of a patient in order to deliver aerosolized drugs in a breath-triggered manner. Due to clinical and ethical barriers, respiratory sensors (especially invasive respiratory sensors) can only be tested on premature neonates with great effort. Therefore, there is a great need for physiological models to validate these sensors. To develop such a system, abdominal movement data of premature neonates are needed. The authors recorded the time series of abdominal movements of five premature neonates using a time-of-flight camera and successfully extracted various respiratory patterns and respiratory parameters. Several characteristic respiratory patterns, such as forced breathing, sighing, apnea, and crying, were identified from the movement data. Respiratory parameters, such as the duration of inhalation and exhalation, as well as the respiratory frequency and respiratory movement over time, were also extracted. They demonstrated that the respiratory parameters of premature neonates can be determined without contact. Therefore, such a system can be used for respiratory detection and provide a trigger signal for a breath-triggered drug release system.

[0017] Koch, E.; Dietzel, A. A 6x6 sensor array for curvature sensing, described in Sensors and Actuators A: Physical 2016, 250, 138-144, doi:10.1016 / j.sna.2016.09.020, is in the form of a thin flexible polyimide foil. The sensor foil measures body deformations caused by breathing by being directly attached to the skin and is used for respiratory monitoring of premature infants. In the future, the sensor signals can not only be used to trigger respiratory devices but also serve as a diagnostic tool to provide time-related body surface reconstruction. A single sensor element consists of four gold strain gauges in a Wheatstone bridge configuration. To suppress the sensor's response to foil stretching and increase the bending sensitivity, they introduced a double-sided sensor design with strain gauges mounted on both surfaces of the thin foil, which results in a 170% higher sensitivity than the single-sided sensor design. The double-sided sensor elements with different orientations are arranged on the array in an alternating pattern, allowing the complete and unambiguous determination of the bending vector using rational considerations based on signals from adjacent elements.

[0018] Problem to be solved

[0019] Accordingly, it is 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 of 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 disadvantages of currently known methods.

[0020] Particularly preferably, the apparatus and method are capable of administering most of the pharmaceutical formulation contained in the aerosol to a patient (especially but not limited to premature infants, neonates, children, or adults), specifically to ensure that the desired concentration of the pharmaceutical formulation in the expected amount can actually be provided to the patient and is not diluted and / or distributed elsewhere. It is further preferable to reduce or preferably avoid a delay in administering the pharmaceutical formulation to the patient. It is still further preferable to be able to administer the pharmaceutical formulation to one or more predetermined targets in the central or peripheral regions of the lungs. Summary of the invention

[0021] 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 stream, a method of generating an aerosol stream, and a processing device configured to control an apparatus for administering an aerosol to a patient, having the features of the independent claims. The dependent claims and the entire specification disclose preferred embodiments, which can be implemented individually or in any combination. In a first aspect, the present invention relates to an aerosol generating device configured to generate an aerosol stream, comprising:

[0022] - An air inlet configured to receive a portion of the breathing gas from a ventilation circuit for supply to an aerosol generating element;

[0023] - An aerosol generating element configured to generate aerosol particles and introduce the aerosol particles into an aerosol stream; and

[0024] - An aerosol tube configured to supply an aerosol stream including aerosol particles to a patient via a conducting element.

[0025] Here, the conducting element may preferably include at least one of a patient interface or an aerosol valve, as disclosed in more detail below. However, it may also be feasible to use a tube. Additionally, the aerosol generating device may include at least one further element, particularly at least one of a pressure regulating element or a breathing filter as disclosed elsewhere herein. However, it is also conceivable to use at least one different further element.

[0026] As used herein, the term "aerosol" refers to an atomizable substance that includes solid or liquid particles of a substance suspended in a gas phase, where the particles may in particular be a pharmaceutical formulation or particles containing a pharmaceutical formulation (such as, but not limited to, pulmonary surfactant). To convert the particles into this state, the atomizable material (i.e., powder or fluid solution) is processed in the aerosol generating element, particularly by using a powder generator or an atomizer, especially a vibrating mesh or ultrasonic, so as to entrain the solid or liquid particles into an air stream of a carrier gas (such as breathing gas). In this state, the particles are preferably distributed throughout the volume of the carrier gas, particularly in a uniform and finely dispersed form. Accordingly, the aerosol is provided in the form of an "aerosol stream", in which the solid or liquid aerosol particles are carried or delivered by the carrier gas stream. Further, the term "administer" or any of its grammatical variants refers to the process of providing a controlled application of the breathing gas and the aerosol contained therein, particularly by delivering a predetermined amount of the pharmaceutical formulation contained in the humidified aerosol to the patient during each time period. The term "breathing gas" as used herein refers to a gas mixture containing components suitable for patient ventilation, particularly air or oxygen-enriched air.

[0027] Furthermore, the term "ventilation circuit" refers to a device configured to ventilate breathing gas provided by a ventilator to a patient and return it from the patient to the ventilator, and thus does not include the patient's respiratory tract. As further used herein, the term "patient" refers to humans of any age, particularly including premature infants, neonates, children or adults. Furthermore, the term "ventilation" relates to the process of accomplishing the movement of breathing gas, particularly by alternating inhalation and exhalation steps. Compared to a healthy breathing patient who can breathe without any additional assistance, a patient receiving mechanical ventilation or positive pressure ventilation requires breathing gas that is at least partially provided by a ventilator through a ventilation circuit. The term "patient interface" as used herein refers to a device configured to provide a connection between the ventilation circuit and the patient's respiratory tract, and thus this device is typically located near the patient. To this end, the patient interface can be integrated into or attached to the ventilation circuit, which typically can include a ventilator and a tube adapted to direct gas from the ventilator to the patient interface and back. In particular, a mouthpiece, a breathing mask, a nasal cannula, nasal plugs or an endotracheal tube can be part of or attachable to the patient interface. However, further arrangements may also be feasible.

[0028] According to the invention, an aerosol generating device comprises an air inlet configured to receive a portion of the breathing gas from the ventilation circuit to be provided to an aerosol generating element also included in the aerosol generating device. Here, the aerosol generating element is configured to generate aerosol particles and introduce them into a carrier gas. The term "aerosol generating element" as used herein refers to an element designed to convert an aerosolizable material (i.e., a powder or a fluid solution) into an aerosol, particularly by using a powder generator or a nebulizer, especially a vibrating mesh or ultrasound, so as to entrain solid or liquid particles into a gas stream of a carrier gas (e.g., 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 stream comprising aerosol particles to the patient through a conducting element, which can preferably include at least one of a patient interface or an aerosol valve.

[0029] In a specific embodiment, the aerosol generating device may further include a pressure regulating element. As used herein, the term "pressure regulating element" refers to an element configured to regulate pressure, particularly to provide additional pressure within the aerosol stream. 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 can be used to improve the way the aerosol stream is directed to the patient through a conduction element (which preferably may include at least one of a patient interface or an aerosol valve). Preferably, when the aerosol is administered to the patient, particularly when the aerosol valve is in the open position, the pressure that may exist at the aerosol tube may be at least 0.1 mbar, preferably at least 0.05 mbar, more preferably at least 0.02 mbar, especially at least 0.01 mbar higher than another pressure that may exist at the air inlet.

[0030] In a further preferred embodiment, the pressure regulating element may also be configured to limit the additional pressure within the aerosol generating device to an additional peak pressure. Here, the additional peak pressure may take a value of up to 20 mbar or 10 mbar, preferably 5 mbar, more preferably 2 mbar, especially 1 mbar or lower. Limiting the additional peak pressure in the patient interface can help avoid harm to the patient caused by excessive pressure when the aerosol is administered to the patient, particularly when the aerosol valve is in the open position. In this further preferred embodiment, a volumetric flow rate of 0.01 L / min - 3 L / min, with an average of approximately 1 L / min, may preferably be generated by the pressure regulating element. Here, the low volumetric flow rate of 0.01 L / min - 3 L / min, with an average of approximately 1 L / min, compared to the volumetric flow rate in the ventilation circuit, can deliver a high-concentration, almost undiluted aerosol directly to the patient.

[0031] In other specific embodiments, the aerosol generating device may further include a respiratory filter that may be located upstream of the aerosol generating element. The term "respiratory filter" as used herein refers to a filtering element configured to remove at least one interfering substance from the respiratory gas to be provided to the aerosol generating element.

[0032] The aerosol generating device according to the present invention is used in a bypass arrangement of a ventilation circuit. The term "bypass" herein refers to a flow arrangement in which a portion of the flow is removed from the main flow and reintroduced into the main flow after separate treatment. Here, a portion of the breathing gas is removed from the ventilation circuit, enriched with the aerosol, and reintroduced into the ventilation circuit to deliver the aerosol-rich breathing gas to the patient. Thus, the aerosol generating device according to the present invention is different from the aerosol generator disclosed in US10987474B2, which does not mention the bypass arrangement according to the present invention. The aerosol generating device according to the present invention has the following advantages: The bypass device is configured to directly deliver a high concentration, almost undiluted aerosol into the patient's body interface and is preferably connected to the patient through a mouthpiece, a breathing mask, a nasal cannula, a nasal plug or an endotracheal tube.

[0033] As a further advantage, the aerosol generating device according to the present invention may not be integrated into the patient interface; instead, the aerosol stream is directly supplied to the patient interface, independent of the breathing gas flow of the ventilation circuit. This arrangement minimizes the overall weight of the patient interface. Thus, damage to the nasal cavity and / or oral cavity of premature infants, neonates, and children can be reduced or avoided. In addition, different from atomization directly within the patient interface as disclosed in, for example, WO2020 / 243107A1, WO2020 / 079055A1 or WO2019 / 115771A1, directly supplying the aerosol stream to the patient interface does not create an additional dead space volume. Instead, the dead space volume according to the present invention only corresponds to the volume of the patient interface, particularly corresponding to the volume of the mouthpiece, the breathing mask, the nasal cannula, the nasal plug or the endotracheal tube.

[0034] Particularly advantageously, the maximum pressure when entering the patient interface can be pre-limited by using a pressure regulating element, thereby precluding patient injury. In addition, the aerosol concentration can be changed by controlling the intensity of the volume flow rate of the bypass arrangement (depending on the pressure regulating element), so that a higher aerosol concentration can be achieved by using a lower volume flow rate. In addition, compared with known devices that supply air from a compressed air network, precise recording and control of pressure and volume flow rate are not required. Due to these advantages, the aerosol generating device according to the present invention can be used to provide liquid and powder drugs to patients of any age, including premature infants, neonates, children or adults.

[0035] In particular, the aerosol generating device according to the present invention can be configured to operate independently of a ventilation system and / or a ventilation circuit, especially independently of any parameters for controlling the ventilation system and / or the ventilation circuit. Thus, the aerosol generating device can be adapted to deliver a controlled aerosol flow to a patient without relying on or synchronizing with the operating settings or cycles of the ventilation system, thereby ensuring consistent and effective delivery of the aerosol regardless of the state or operating mode of the ventilation system. Additionally, the aerosol generating device can be configured to variably adjust the aerosol concentration in response to changes in the volumetric flow rate facilitated by a pressure regulating element, which is configured to regulate an additional pressure within the aerosol flow for delivery to the patient via a conducting element. Further, the aerosol generating device can be designed to operate without an external pressure sensor or control unit, especially by utilizing a bypass arrangement to control the pressure from the ventilation circuit and the pressure regulating element to minimally increase the pressure, thereby enabling efficient aerosol delivery without complex additional pressure monitoring or control components.

[0036] In another aspect, the present invention relates to a method of generating an aerosol flow, the method comprising the steps of:

[0037] (i) receiving a portion of the breathing gas from the ventilation circuit to be provided to the aerosol generating element;

[0038] (ii) generating aerosol particles and introducing the aerosol particles into the aerosol flow; and

[0039] (iii) providing the aerosol flow containing the aerosol particles to the patient via a conducting element.

[0040] In a particularly preferred embodiment, the aerosol flow containing the aerosol particles can be provided directly to the patient interface. In a further preferred embodiment, an additional pressure can be provided within the aerosol flow to direct the aerosol flow through the conducting element to the patient, which can preferably include at least one of a patient interface or an aerosol valve.

[0041] For more details regarding the method of generating an aerosol flow, reference can be made to the aerosol generating device configured to generate an aerosol flow described elsewhere herein.

[0042] In another aspect, the present invention relates to a processing device configured to control a device for administering an aerosol to a patient by:

[0043] - receiving input data related to the breathing pattern of the patient, wherein the breathing pattern includes information about the time course of at least one of the bulging or contraction of at least one of the patient's chest or abdomen;

[0044] - determining at least one time point based on the breathing pattern; and

[0045] - Control an aerosol flow to a patient triggered at at least one time point, where the at least one time point is earlier than at least one of the start or pause of the patient's breathing.

[0046] As used herein, the term "device" refers to an apparatus comprising a plurality of elements, where each element cooperates with at least one other element to administer an aerosol to a patient. In particular, the device can be embodied as a single device that can include at least all the elements required for this purpose. Alternatively, at least two elements of the device can be placed at different locations, where each element can include or cooperate with a communication element configured to communicate between at least two elements of the device. For example, the different locations can be in the same room, building, town or country, or distributed across at least two continents. More examples can also be envisioned.

[0047] As used herein, the term "processing" or any of its grammatical variants refers to applying at least one algorithm to data received from at least one input file such that the required control of a device for administering an aerosol to a patient is provided by at least one output file, which includes at least one command for controlling an aerosol valve configured to provide an aerosol flow to the patient. In particular for the present invention, the term "data" refers to at least one piece of information contained in at least one file, particularly at least one input file or at least one output file. Specifically, for the present invention, at least one piece of information included in at least one input file is related to the breathing pattern of the patient, while at least one piece of information included in at least one output file is related to at least one command for controlling the provision of an aerosol flow to the patient triggered at at least one time point. Here, at least one algorithm can be configured to determine the data of at least one output file from the data provided by at least one input file according to a predetermined scheme, where, as described in more detail below, artificial intelligence, particularly at least one machine learning algorithm, can also be applied.

[0048] In this document, the term "processing device" refers to a specific type of device that is designated to determine data for at least one output file from data provided by at least one input file, where preferably, at least one input file can be provided to the processing device by using at least one input interface, and where preferably, at least one output file can be provided by the processing device by using at least one output interface. Specifically, the processing device can include at least one integrated circuit, in particular an application-specific integrated circuit (ASIC), or a digital processing device, in particular a digital signal processor (DSP), a field-programmable gate array (FPGA), a microcontroller, a microcomputer, a computer, or a mobile communication device (in particular a laptop, a tablet, a smartphone, or a personal digital assistant). Other components can also be employed, in particular at least one preprocessing element or data storage element. Preferably, the processing device can be designed to execute at least one computer program, in particular at least a string of computer program code, which is configured to execute at least one algorithm for determining data for at least one output file, where the processing of the data can be performed in at least one of a sequential or parallel manner.

[0049] According to the present invention, the processing device is configured to first control a device for administering an aerosol to a patient by receiving input data related to the patient's breathing pattern. In this document, the term "receiving" or any of its grammatical variants refers to the process of obtaining at least one piece of information (in particular as at least one input file). Specifically, and particularly for the present invention, the at least one input file includes data related to the patient's breathing pattern. Further, the term "breathing pattern" relates to the time course of changes in at least one body part of the patient that are caused by and related to the patient's breathing. Here, each breathing pattern can be identified by a first time point related to the start of the patient's breathing and a second time point related to the patient's apnea, where the first time point and the second time point occur in an alternating manner, thus defining the breathing cycle. In many cases, the breathing pattern has a regular pattern that repeats after each breathing cycle, where typically each breathing cycle can have a substantially the same duration. However, alternatively or additionally, the breathing pattern can also include at least one irregular feature of the patient's breathing. However, especially in premature infants or critically ill adults, the duration of consecutive breathing patterns can vary. Advantageously, as described in more detail below, the operation of the present invention is independent of whether the breathing pattern is a regular pattern.

[0050] In addition, the processing device is configured to determine at least one time point based on a breathing pattern. In the present context, the term "determine" or any of its grammatical variants refers to a process that yields a representative result (commonly referred to as "data"). In particular, for the present invention, the data generated by the processing device corresponds to at least one output file that includes at least one piece of information related to at least one command, the at least one command being configured to control an aerosol flow directed to a patient that is triggered at at least one time point. To this end, the at least one command corresponds to at least one piece of information that is used to change the flow rate of the aerosol flow, in particular one of starting, increasing, maintaining, decreasing, or terminating the volume of the aerosol flow. As described in more detail below, an aerosol valve configured to provide an aerosol flow to a patient can be controlled for this purpose, although other procedures (such as changing the gas flow of a carrier gas) are also feasible in principle.

[0051] In addition, the processing device is configured to control an aerosol flow directed to a patient that is triggered at at least one time point. In the present context, the term "control" or any of its grammatical variants refers to a process of using at least one command to adjust at least one property of an object or a state. Further, the term "trigger" or any of its grammatical variants refers to a signal that is configured to start changing an object or a state. For the present invention, the aerosol flow directed to a patient is controlled in such a way that the flow rate of the aerosol flow is changed according to a signal provided by at least one command determined by the processing device based on input data.

[0052] According to the present invention, the breathing pattern includes information about the time course of at least one of the elevation or contraction of at least one of the patient's chest or abdomen. It is well known that the patient's chest and abdomen alternately undergo elevation and contraction, in particular due to the patient's breathing, thereby defining a breathing cycle. In the present context, the term "elevation" refers to the upward movement of the abdominal wall and / or the thoracic cage, while the term "contraction" refers to the downward movement of the abdominal wall and / or the thoracic cage, thereby returning them to their previous positions. As described above, the breathing cycle can be regular or irregular, and the present invention has particular advantages because it can control the aerosol flow directed to a patient regardless of whether the breathing pattern is regular.

[0053] In addition, the aerosol flow directed to the patient includes triggering the aerosol flow at at least one time point (i.e., at least one of a first time point associated with the start of the patient's breathing or a second time point associated with the patient's pause in breathing), wherein triggering the aerosol flow at the first time point may generally be preferred over triggering the aerosol flow at the second time point. In particular, according to the present invention, the at least one time point is earlier than at least one of the start or pause of the patient's breathing, wherein the start and pause of the patient's breathing may particularly correspond to the start or pause of the aerosol flow through at least one of the patient's nose or mouth. Thus, although the first time point determined by the elevation of at least one of the patient's chest or abdomen is related to the start of the patient's breathing, it is earlier than the start of the patient's breathing, as indicated by the start and subsequent increase in the volume of the aerosol flow through at least one of the patient's nose or mouth. Similarly, although the second time point determined by the contraction of at least one of the patient's chest or abdomen is related to the pause in the patient's breathing, it is earlier than the pause in the patient's breathing, as indicated by at least the decrease and subsequent reduction in the volume of the aerosol flow through the patient's nose or mouth. Specifically, the at least one time point may be respectively earlier than the start or pause of the patient's breathing by a time interval of 1 ms (preferably 50 ms, more preferably 100 ms) to 1 s (preferably 500 ms, more preferably 200 ms); however, depending on the specific patient, different values are also feasible.

[0054] In other words, preferably, the aerosol flow directed to the patient can be triggered by at least one command determined by the processing device based on the input data, the input data including information about the elevation or contraction of at least one of the patient's chest or abdomen, so as to be earlier than the start or pause of the patient's breathing in an advantageous manner. It has been found that the input data corresponding to the movement of the patient's chest or abdomen is particularly suitable for determining at least one time point for triggering the release of the aerosol flow to the patient. Although the movement of the patient's nose and mouth is synchronized with the patient's breathing, the movement of the patient's chest or abdomen is earlier than the breathing by the time interval as described above, and thus can be used for the purposes of the present invention, especially for administering the pharmaceutical preparation contained in the aerosol to the patient, in particular to ensure that a large amount, preferably all of the pharmaceutical preparation can be actually provided to the patient at the desired concentration, and the pharmaceutical preparation is not diluted or distributed elsewhere.

[0055] This advantage stands in sharp contrast to the known prior art, according to which up to 90 vol% or more of the pharmaceutical formulation may actually be distributed elsewhere than in the patient, and the pharmaceutical formulation is typically highly diluted when administered to the patient. In contrast, triggering the aerosol a short time interval prior to the start or pause of the patient's respiration can produce particularly advantageous effects, namely that the pharmaceutical formulation comprised in the aerosol is introduced into the respiratory gas at a time point where it can be ensured that the major amount (preferably the entire amount) of the introduced pharmaceutical formulation can actually be received by the respiratory tract of the patient, in particular can reach at least one of the central or peripheral regions in the lungs. Furthermore, by the proximity to the patient and the respiration-triggered release of the pharmaceutical formulation, a delay in the administration of the pharmaceutical formulation to the patient can also be reduced or preferably avoided. In this way, an optimal respiration-triggered release of the pharmaceutical formulation can be achieved, in particular by providing a puff of aerosol to at least one of the patient's nose or mouth prior to the start of the inhalation flow. The present invention provides such "pre-triggering" as it is capable of detecting the start of the inhalation flow prior to measuring the start of the respiratory flow. Similar results can also be obtained with the present invention for the pause of the respiratory flow. Furthermore, using input data of the type specifically generated for this purpose according to the present invention ensures that this effect is independent of whether the patient's respiration pattern is a regular pattern. Thus, the present invention can in particular be used for treating and curing premature infants or severely ill adults, who typically exhibit an irregular respiration pattern.

[0056] On the other hand, the present invention relates to a device for administering an aerosol to a patient. Accordingly, the device comprises:

[0057] - an aerosol valve, which is configured to provide an aerosol stream to the patient;

[0058] - and at least one of the following devices:

[0059] o an aerosol generation device, which is configured to generate an aerosol stream as disclosed herein;

[0060] o a processing device, which is configured to control the device for administering an aerosol to a patient as further disclosed herein.

[0061] Accordingly, a device for administering an aerosol to a patient includes an aerosol valve configured to provide an aerosol stream to the patient. In addition, it includes an aerosol generating device and a processing device, as described in more detail above and below. The aerosol generating device includes an aerosol generating element configured to generate aerosol particles and introduce them into the aerosol stream. The processing device is configured to control the aerosol stream through the aerosol valve by triggering the aerosol valve at at least one time point, thereby adjusting the specified aerosol stream provided to the patient in the manner disclosed herein. As an alternative, the device according to the invention may include an aerosol valve and an aerosol generating device as disclosed herein, and a processing device of the prior art. Or, as another alternative, it may include an aerosol valve and a processing device as disclosed herein, and an aerosol generating device of the prior art.

[0062] As used herein, the term "aerosol valve" refers to a device configured to control the volume of an aerosol stream, particularly for at least one of the nose or mouth of a patient. As described above, the aerosol valve can be controlled by at least one command, which includes at least one piece of information for changing the flow rate of the aerosol stream, particularly one of starting, increasing, maintaining, decreasing, or terminating the volume of the aerosol stream. For this purpose, a pneumatic device that can be addressed by at least one command can be used; however, other embodiments are also feasible. In a preferred embodiment, the aerosol valve can be integrated into the patient interface, which, as described above, is configured to provide a connection between the ventilation circuit and the patient's respiratory tract. Alternatively, the aerosol valve can be located upstream of the patient interface. Other alternatives are also conceivable.

[0063] In a preferred embodiment of the invention, the device for administering an aerosol to a patient may further include a respiration detection device. As used herein, the term "respiration detection device" is a device configured to determine input data related to the patient's breathing pattern and to transmit the input data related to the patient's breathing pattern to the processing device disclosed herein. Specifically, for the present invention, the respiration detection device can be configured to determine at least one of the elevation or contraction of at least one of the patient's chest or abdomen related to the patient's breathing. In a specific embodiment, the respiration detection device may at least include:

[0064] - a detection element configured to record at least one of the elevation or contraction of at least one of the patient's chest or abdomen;

[0065] - a processing element configured to determine input data related to the patient's breathing pattern based on at least one of the elevation or contraction of at least one of the patient's chest or abdomen; and

[0066] - a communication interface configured to transmit the input data to the processing device.

[0067] Other components can be envisaged.

[0068] In this document, the term "detection element" refers to a device or a part thereof configured to record and measure at least one physical property related to the movement of a body part. Here, the detection element can operate in contact with the patient's body, or alternatively or additionally, operate in a non-contact manner. Specifically, the detection element can 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 inductive plethysmography sensor, a millimeter wave sensor, a radar sensor, or a thermal sensor. However, it may also be feasible to use different types of detection elements.

[0069] Also in this document, the term "processing element" refers to another device or a part thereof configured to determine at least one piece of data. Here, the processing element and the communication interface can preferably form a single device, while the detection element can form a separate device. It may also be feasible that the processing element, the detection element, and the communication interface form an integrated device. For the purposes of the present invention, the processing element can in particular be configured to receive measurement data from the detection element regarding at least one of the bulging or contraction of at least one of the patient's chest or abdomen, based on which input data related to the patient's respiration pattern can be determined.

[0070] Also in this document, the term "communication interface" refers to a transmission channel for transmitting data from a first location to a second location, specifically, the second location is different from the first location. Preferably, the communication interface can be a unidirectional interface configured to forward data in a single direction, such as from the processing element to the processing device. Alternatively, the communication interface can be a bidirectional interface configured to forward data in one of two directions, such as from the processing element to the processing device, or vice versa, especially for further transmitting at least one command from the processing device to the processing element, where the at least one command can be selected from starting or ending the measurement, or starting or ending the data transmission. For data transmission, the communication interface can include at least one of a wired element or a wireless element, where the wireless element can be configured to operate by using a wireless communication protocol (such as Wi-Fi or Bluetooth); however, other types of communication interfaces are also feasible. In a specific embodiment, the communication can be (or include) an encrypted data transmission or an encrypted data exchange, especially for protecting personal data.

[0071] For details regarding the device for administering an aerosol to a patient, reference can be made to the description of the processing device and the exemplary embodiments elsewhere in this document.

[0072] On the other hand, a method for administering an aerosol to a patient is proposed, where the method includes steps a)-c):

[0073] a) Receive input data related to a patient's breathing pattern, wherein the breathing pattern includes information about the time course of at least one of the elevation or contraction of at least one of the patient's chest or abdomen;

[0074] b) Determine at least one time point based on the breathing pattern; and

[0075] c) Control an aerosol flow to the patient triggered at the at least one time point, wherein the at least one time point is earlier than at least one of the start or pause of the patient's breathing.

[0076] Here, the steps a)-c) shown may be performed in the order provided, wherein, preferably, all the steps shown may be performed at least partially simultaneously. Additionally, additional method steps may be performed (whether or not described herein).

[0077] The method of administering an aerosol to a patient disclosed herein may preferably be a computer-implemented method. Herein, the term "computer-implemented method" refers to a method involving at least one programmable device (especially selected from mobile communication devices). However, other types of programmable devices are also feasible, for example. Here, the at least one programmable device may particularly include a processing device as disclosed or a device accessible to the processing device, wherein at least one feature of the method is performed by using at least one computer program. To this end, the computer program may be provided for the at least one programmable device, or the at least one programmable device may access the computer program via a network (such as an internal network or the Internet), and the computer program may be located on a remote server or in the cloud.

[0078] According to step a), receive input data related to a patient's breathing pattern, wherein the breathing pattern includes information about the time course of at least one of the elevation or contraction of at least one of the patient's chest or abdomen.

[0079] According to step b), determine at least one time point based on the breathing pattern, as described in more detail elsewhere herein.

[0080] According to step c), control the aerosol flow to the patient by triggering the aerosol flow at the at least one time point, wherein the at least one time point is earlier than at least one of the start or pause of the patient's breathing.

[0081] For details regarding the method of administering an aerosol to a patient, reference may be made to the description of the processing device, the device for administering an aerosol to a patient, and the exemplary embodiments elsewhere herein.

[0082] The devices, equipment and methods according to the present invention offer several advantages over known devices, equipment and methods. The processing device and the corresponding method are particularly configured to use the breathing movement signals included in the breathing pattern, which are mostly raw and have a very low level of analysis. This advantage eliminates the need for predictive analysis. In particular, contrary to the disclosures in US10987474B2, WO2020 / 243107A1 and US2020 / 368457A1, it is not necessary to pre-analyze the breathing pattern to predict the patient's breathing. Therefore, there is no need to rely on predictive algorithms. The processing device and the corresponding method do not use any algorithms for pattern recognition and / or predicting breathing events in the breathing time course. Instead, real-time signals related to the movement (i.e., elevation or contraction) of the patient's chest and / or abdomen are used to indicate the start or pause of the patient's breathing. The advantage is that immediate and sensitive aerosol delivery can be obtained. The aerosol flow can respond without delay to real-time changes in the breathing cycle. In addition, this arrangement exhibits a reduction in complexity, especially since it does not require complex pattern recognition or predictive algorithms. These advantages improve the accuracy and efficiency of drug delivery during natural breathing cycles and irregular breathing patterns. The aerosol flow can be precisely synchronized with each breath, making it suitable for patients with irregular breathing patterns. In this way, the aerosol flow can be precisely delivered to the patient, especially by ensuring accurate drug delivery at the beginning of inhalation, maximizing the therapeutic effect and minimizing waste. In contrast, known predictive models (such as the models disclosed in US10987474B2, WO2020 / 243107A1 and US2020 / 368457A1) are prone to errors when applied to irregular breathing, while the present invention overcomes these drawbacks by using direct measurement methods. In addition, compared with the need for a certain preparation time to atomize drugs using the prior art grid system, the aerosol generating device according to the present invention can continuously generate an aerosol flow and deliver it to the aerosol valve, where the aerosol valve can be directly opened at the beginning of breathing, enabling the patient to immediately obtain the aerosol flow. Similarly, the aerosol valve can be directly closed during a breathing pause, causing the aerosol flow to terminate immediately, thereby reducing waste.

[0083] Another advantage of the devices, equipment and methods according to the present invention is that different regions of the lungs can be reached by the release time. If the aerosol can be directly administered to the patient at the beginning of inhalation, the peripheral regions of the lungs can be mainly treated. If the aerosol is administered at the end of inhalation, the central regions of the lungs can be mainly treated. In addition, bolus delivery can be used to specifically treat well-ventilated or poorly-ventilated regions of the lungs, as in the case of pulsed delivery of medical gases. Therefore, time-efficient and targeted inhalation therapy can be achieved, which helps to reduce the dose of the administered drug and thus reduce side effects.

[0084] In this text, the terms "comprising", "including", or "containing" or any grammatical variants thereof are used in a non-exclusive manner. Thus, these terms may refer to a situation where there are no other features in the entity described in this context apart from the features introduced by these terms, as well as a situation where there is one or more other features. For example, the expressions "A comprises B", "A includes B", and "A contains B" can either refer to a situation where there are no other elements in A apart from B (i.e., the situation where A consists solely and exclusively of B), or a situation where there is one or more other elements in A apart from B, such as element C, elements C and D, or even other elements.

[0085] Additionally, in this text, terms such as "preferably", "more preferably", "specially", "more specially", or similar terms are used in conjunction with optional features without restricting alternative possibilities. Thus, the features introduced by these terms are optional features and are not intended to limit the scope of the claims in any way. Those skilled in the art will recognize that the present invention can be implemented by using alternative features. Similarly, features introduced by "in an embodiment of the present invention" or similar expressions are intended to be optional features, without restricting alternative embodiments of the present invention, without restricting the scope of the present invention, and without restricting the possibility of combining the features introduced in this way with other features of the present invention. Brief Description of the Drawings

[0087] Other optional features and embodiments of the present invention will be disclosed in more detail in the subsequent description of the preferred embodiments, preferably in combination with the dependent claims. Among them, each optional feature can be implemented independently or in any feasible combination, as recognized by those skilled in the art. It should be noted that the scope of the present invention is not limited by the preferred embodiments. These embodiments are schematically depicted in the drawings. Among them, the same reference numerals in these drawings refer to the same or functionally equivalent elements.

[0088] In the drawings:

[0089] Figure 1 A preferred embodiment of an exemplary device for administering an aerosol to a patient according to the present invention is schematically shown;

[0090] Figure 2 schematically shows the comparison between the time course of the first signal generated using a strain gauge element and the time course of the second signal generated using a fluid sensor during the exhalation phase ( Figure 2A ) and the inhalation phase ( Figure 2B );

[0091] Figure 3 The respiratory phases of a premature infant extracted from abdominal movement data recorded using a time-of-flight camera are schematically shown; and

[0092] Figure 4 Schematically shows a comparison of the dose efficiency of pharmaceutical formulations for various tests on the emitted dose.

[0093] Detailed description of the embodiments

[0094] Figure 1 Schematically shows a preferred embodiment of an exemplary device 110 for administering an aerosol 112 (in particular in the form of an aerosol stream 114) to a patient 116. It should be noted here that, as Figure 1 shown, the exemplary embodiment of the device 110 includes a processing device 120 and an aerosol generating device 162. However, it is also feasible to use only the processing device 120 or the aerosol generating device 162. Specifically, the device 110 is designed to provide an aerosol stream 114 with a defined aerosol concentration (preferably a high aerosol concentration) to the patient 116, and the patient 116 can in particular be a premature infant, a newborn, a child or a critically ill adult. However, other applications of the device 110 are also feasible.

[0095] In addition, as Figure 1 shown, the exemplary device 110 includes a laptop computer 118, which is (or includes) the processing device 120, and the processing device 120 is configured to control the device 110 to administer the aerosol 112 (preferably in the form of an aerosol stream 114) to the patient 116. As an alternative, the processing device 120 can be a different type of mobile communication device, or consist of different types of mobile communication devices, in particular a tablet computer, a smart phone or a personal digital assistant. As another 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.

[0096] The processing device 120 is used to determine the data of at least one output file 122 according to the data provided by at least one input file 124, wherein at least one input file 124 can be provided to the processing device 120 by using an input interface 126, and at least one output file 122 can be provided by the processing device 120 by using an output interface 128. As Figure 1 shown, the processing device 120 is also designed to execute at least one computer program, in particular at least a string of computer program code, and is configured to execute at least one algorithm 130 for determining the data of at least one output file 122, wherein the data processing can be executed by using at least one algorithm 130 in a sequential and / or parallel manner.

[0097] To this end, the processing device 120 is configured to receive at least one input file 124 comprising input data related to the breathing pattern of the patient 116. The breathing pattern in this exemplary embodiment includes information about the time course of the elevation 132 and contraction 134 of the chest 136 or abdomen 138 of the patient 116. In this way, information about the rise and fall of the abdominal wall and chest cage of the patient 116 can be obtained from which the breathing pattern can be derived. Generally speaking, the breathing pattern can be a regular breathing pattern or, especially for premature infants or critically ill adults, an irregular breathing pattern, where the present invention has a particular advantage in that it allows control of the aerosol flow 114 flowing to the patient 116 regardless of whether the breathing pattern is regular or not.

[0098] As Figure 1 The exemplary device 110 shown also includes a breathing detection device 140, which is configured to determine at least one input file 124 comprising 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 using the input interface 126. Specifically, for the present invention, in this exemplary embodiment, the breathing detection device 140 is configured to determine the elevation 132 and contraction 134 of the chest 136 and / or abdomen 138 of the patient 116 related to his breathing.

[0099] As Figure 1 As further shown, the breathing detection device 140 includes a detection element 142, which in this exemplary embodiment is configured to record the elevation 132 and contraction 134 of the chest 136 and / or abdomen 138 of the patient 116. Generally, the detection element 142 can operate in contact with the body of the patient 116 or, alternatively or additionally, in a non-contact manner. As shown in the figure, the detection element 142 is (or includes) a time-of-flight camera 144, which is configured to record and measure at least one physical property related to the movement of the chest 136 and / or abdomen 138 of the patient 116 in a non-contact manner. As an alternative, different types of breathing detection sensors can be used as the detection element 142, especially contact elements such as strain gauge elements, or different non-contact elements such as electrical impedance tomography sensors, respiratory inductive plethysmography sensors, millimeter wave sensors, radar sensors or thermal sensors.

[0100] As Figure 1Further shown, the respiratory detection device 140 further includes a laptop computer 118, which also has a processing element 146 and a communication interface 148. The processing element 146 is configured to determine at least one input file 124 including input data related to the breathing pattern of the patient 116, and the communication interface 148 is configured to transmit at least one input file 124 including input data related to the breathing pattern of the patient 116 to the input interface 126 included in the processing device 120. In Figure 1 In an exemplary embodiment, both the processing element 146 and the communication interface 148 are included in the laptop computer 118, while the detection element 142 is embodied as a separate device. However, other embodiments are also feasible, especially embodiments in which the detection element 142, the processing element 146, and the communication interface 148 form an integrated device (not shown here). For data transmission, the communication interface 148 may include at least one wired or wireless element, which is configured to operate by using a wireless communication protocol (such as Wi-Fi or Bluetooth), and encrypted data transmission or encrypted data exchange (especially for protecting personal data) is also feasible.

[0101] The communication interface 148 may be (or include) a unidirectional interface, which is configured to unidirectionally transmit data from the processing element 146 to the input interface 126 included in the processing device 120. Alternatively, the communication interface 148 may be a bidirectional interface, which is configured to forward data in one of two directions, for example, from the processing element 146 to the input interface 126, or vice versa, especially for further transmitting at least one command from the processing device 120 to the processing element 146, where the at least one command may be used to start or complete a measurement, or start or complete data transmission.

[0102] In addition, the treatment device 120 is configured to determine at least one time point from the breathing pattern and is used to control the aerosol flow 114 flowing to the patient 116 triggered at the at least one time point, where the at least one time point is respectively earlier than the start and / or pause of the patient's breathing. In particular, the at least one time point can be respectively the start or pause of the aerosol flow 114 through the nose 150 or mouth 152 of the patient 116. More particularly, the at least one time point can be respectively earlier than the start or pause of the patient 116's breathing by a time interval of 1 ms (preferably 50 ms, more preferably 100 ms) to 1 s (preferably 500 ms, more preferably 200 ms); however, different values are also feasible according to the specific patient 116. In this regard, the aerosol flow 114 provided to the patient 116 is triggered by at least one command included in at least one output file 122 determined by the treatment device 120 using at least one algorithm 130, where the at least one output file 122 includes at least one command forwarded to the aerosol valve 154 through the output interface 128, and the aerosol valve 154 is configured to provide the aerosol flow 114 to the patient 116.

[0103] It has been found that using at least one input file 124 including input data related to the breathing pattern of the patient 116 (determined by using information on the bulges 132 and / or contractions 134 of the chest 136 and / or abdomen 138 of the patient 116) enables the treatment device 120 to predict at least one time point at which the release of the aerosol flow 114 to the patient 116 can be reasonably triggered. Contrary to the flow movement through the nose 150 and mouth 152 of the patient 116 (synchronized with the breathing of the patient 116), the movement of the chest 136 and / or abdomen 138 of the patient 116 is earlier by the time interval as described above, and thus, this can be used for the purposes of the present invention, especially for administering the pharmaceutical preparation contained in the aerosol 112 to the patient 116. In this way, it can be ensured that most (preferably all) of the pharmaceutical preparation can be actually provided to the patient 116 without being distributed elsewhere, such as to parts of the device 110 that are not needed or to the surrounding environment of the device 110. By using at least one input file 124, it can also be ensured that this effect is independent of whether the patient's breathing pattern is regular.

[0104] Further in accordance with the present invention, the device 110 further includes an aerosol valve 154 which is configured to provide an aerosol stream 114 to the patient 116. To this end, the aerosol valve 154 is configured to control the volume of the aerosol stream 114 which is particularly provided to the nose 150 of the patient 116 (e.g. by using a pair of nasal plugs 156) or to the mouth 152 of the patient 116. As described above, the aerosol valve 154 can be controlled by at least one command which includes at least one piece of information for changing the flow rate of the aerosol stream 114, particularly one of starting, increasing, maintaining, decreasing or terminating the volume of the aerosol stream 114. In Figure 1 an exemplary embodiment, the aerosol valve 154 is integrated into the patient interface 158 which is configured to provide a connection between the ventilation circuit 160 and the patient's respiratory tract. As an alternative (not shown here), the aerosol valve 154 can be located at a different position, such as upstream of the patient interface 158.

[0105] As Figure 1 further shown, an exemplary embodiment of the device 110 includes an aerosol generating device 162 which is configured to generate an aerosol stream 114 to be provided to the patient 116 (particularly preferably directly to the patient interface 158). Specifically, as shown in the figure, the aerosol generating device 162 includes an air inlet 164 which is configured to receive a portion of the respiratory gas 166 from the ventilation circuit 160 through a connector 167, where the air inlet 164 is provided to a respiratory filter 168 which is configured to remove at least one interfering substance from the respiratory gas 166 before providing the respiratory gas 166 to the aerosol generating element 170 (also included by the aerosol generating device 162). Here, the aerosol generating element 170 can particularly be configured to generate aerosol particles and introduce the aerosol particles into the aerosol stream 114. To this end, the aerosol generating element 170 can be used to convert an aerosolizable material (i.e. powder or fluid solution) into the desired aerosol 112, particularly by using a powder generator or a nebulizer (especially vibrating mesh or ultrasonic) in order to entrain solid or liquid particles into an air stream which may include the respiratory gas 166 and a carrier gas (e.g. respiratory gas). Here, the aerosol generating element 170 can preferably be selected from nebulizers and / or powder generators. As Figure 1 further shown, the aerosol generating device 162 further includes an aerosol tube 172 which is configured to provide the aerosol 112 containing aerosol particles to the patient 116 through a conducting element (particularly the aerosol valve 154 and / or the patient interface 158). However, it may also be feasible to use a tube (not shown here).

[0106] In as Figure 1In the specific embodiment shown, the aerosol generating device 162 further includes a pressure regulating element 174 configured to provide additional pressure within the aerosol stream 114. Specifically, the additional pressure can be used to improve the manner in which the aerosol stream 114 is directed to the patient 116 through the conduction elements, particularly the aerosol valve 154 and / or the patient interface 158. Preferably, when the aerosol 112 is administered to the patient 116, particularly when the aerosol valve 154 is in the open position, the pressure at the aerosol tube 172 can exceed the pressure at the air inlet 164 by at least 0.1 mbar, preferably at least 0.05 mbar, more preferably at least 0.02 mbar, and especially at least 0.01 mbar. Preferably, the pressure regulating element 174 can also be configured to limit the additional pressure within the aerosol generating device to an additional peak pressure, where the additional peak pressure can be set to a maximum of 20 mbar or 10 mbar, preferably 5 mbar, more preferably 2 mbar, and especially 1 mbar or less. Limiting the additional peak pressure in 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 avoid harm to the patient 116 due to excessive pressure. In this way, a volume flow rate of 0.01 L / min - 3 L / min, with an average of approximately 1 L / min, can be generated by the pressure regulating element 174. Here, compared to the volume flow rate in the ventilation circuit 160, the low volume flow rate of 0.01 L / min - 3 L / min, with an average of approximately 1 L / min, can deliver a high concentration, almost undiluted aerosol directly to the patient 116.

[0107] If the aerosol stream 114 is directly injected into the ventilation circuit 160 according to the prior art, this will result in a significant dilution of the aerosol concentration. For example, using a respiratory gas flow rate of 7 L / min, an aerosol output of 4.5 mg / min from a prior art aerosol generator, and uniformly distributed aerosol particles, an aerosol concentration of 0.75 mg / L in the respiratory gas will be achieved. In contrast, according to the present invention, by using a small portion of the stream that is removed from the respiratory gas upstream of the patient interface 158 and is rich in aerosol and directly supplied to the patient interface 158, the aforementioned dilution effect can be avoided. If the aerosol delivery flow rate is reduced, the aerosol concentration will increase. For example, an aerosol can be delivered to the patient interface 158 using a low delivery flow rate of only 1 L / min, which is independent of the respiratory gas flow rate in the ventilation system and may result in an aerosol concentration of 4.5 mg / L in the respiratory gas, thus six times higher than the prior art. Therefore, the dose inhaled by the patient per unit time can be significantly increased. By additionally using a respiratory synchronized drug delivery device as described above, the efficiency of aerosol deposition in the lungs can be further improved.

[0108] Figure 2 schematically shows, respectively, during the exhalation phase (Figure 2A ) and the inhalation phase ( Figure 2B ) during the first time course 180 of the first signal generated using the strain gauge element and the second time course 182 of the second signal generated using the flow sensor. Here, the x-axis represents time t (in seconds s), the left y-axis represents the respiratory flow f measured using the flow sensor (in L / min), and the right y-axis represents the average signal S generated by the strain gauge element (in volts). The switching of the flow sensor from exhalation to inhalation or from inhalation to exhalation is indicated by circles 184, 184’, 184” ……, while the strain gauge element is indicated by vertical dotted lines 186, 186’, 186” ……. As shown by the horizontal line 188, the breathing stops twice so that the start of inhalation and exhalation can be accurately represented separately. The change from inhalation to exhalation is represented respectively by the zero crossing of the y-axis of the flow sensor and by the extreme value of the strain gauge element, or a sudden increase or decrease in the slope. As shown in Figure 2, after maximum inhalation, the abdomen stretches to the maximum extent, causing the strain gauge element to stretch to the maximum extent, thereby generating the maximum positive tension. Similarly, after maximum exhalation, the abdominal stretch is minimal, causing the strain gauge element to stretch minimally, thereby generating the maximum negative stress. As shown in Figure 2, the strain gauge element can detect inhalation or exhalation separately at a time interval approximately 200 ms - 300 ms earlier than the flow sensor. Through this time interval, the strain gauge element can detect the upcoming inhalation or exhalation earlier than the flow sensor, thereby allowing the aerosol 112 to be triggered earlier respectively compared to the start or pause of the patient 116's breathing, thereby producing the beneficial effects described elsewhere in this article.

[0109] Figure 3 Schematically shows the respiratory phases 190 of a premature infant extracted from the abdominal movement data recorded using the time-of-flight camera 144. Here, a graph of the relationship between the distance d (in meters m) from the time-of-flight camera 144 to the abdomen 138 of the premature infant and time t (in seconds s) is plotted. Figure 3 The maximum and minimum values shown represent the transition from inhalation to exhalation and vice versa.

[0110] Figure 4 Schematically shows the comparison of the dose efficiency eff of various test drug formulations 192, 194, 196 relative to the emitted dose (expressed as %). 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 arrangement was used (the aerosol valve 154 disclosed in this article was not used); while in the third test 196, a device 110 according to the present invention was used, which includes an aerosol generating device 162 using the aerosol valve 154 disclosed in this article.

[0111] To this end, a 0.9 vol.% saline solution was atomized using a mesh nebulizer and delivered to the corresponding test benches according to Tests 192, 194, 196 described above, as follows:

[0112] - When using a standard patient interface in the first Test 192, the aerosol was coupled to the ventilation circuit 160 using a Y-shaped connector;

[0113] - When using the aerosol generating device 162 in the bypass arrangement without using the aerosol valve 154 in the second Test 194, the aerosol 112 was directly delivered to 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, using 5 mbar of positive end-expiratory pressure (PEEP) and a respiratory gas flow rate of 6 L / min. To determine the delivery amount of the aerosol 112, an advanced test device disclosed in WO2020 / 007858A1 was used. This test device allows the use of different respiratory frequencies (30 breaths / min - 80 breaths / min), tidal volumes (2 ml - 40 ml), and inspiratory fractions (0.25 - 0.75). For the second Test 194, a frequency of 51 breaths / min, a tidal volume of 12.3 ml, and an inspiratory fraction of 0.39 were used as simulated respiratory parameters; and

[0114] - When using the device 110 according to the present invention in the third Test 196, the conditions applied were the same as in the second Test 194, except that the aerosol valve 154 was used and opened in a trigger operation mode at the start of simulated inhalation and closed at the start of simulated exhalation. To this end, a pneumatic device was used to close or open the aerosol valve 154.

[0115] According to Figure 4 the results shown, the value of the dose efficiency eff in the first Test 192 was 10.3%, the dose efficiency eff in the second Test 194 was 24.7% (non-triggered release), and the dose efficiency eff in the third Test 196 was 41.5% (triggered release). Therefore, applying non-triggered release using the aerosol generating device 162 was approximately 2.5 times more efficient than using a standard patient interface. In addition, using respiratory-triggered release in combination with the aerosol generating device 162 was approximately 1.7 times more efficient than non-triggered release and approximately 4.2 times more efficient than using a standard patient interface.

[0116] In addition, aerosol measurements were carried out under realistic clinical conditions in order to compare the aerosol generating device 162 according to the invention with a standard inhalation clinical (SoC) system of the prior art. A test bench based on the disclosure of WO2020 / 007858A1 was used to simulate the breathing parameters of premature infants. This test bench allows the use of different breathing frequencies (30 breaths / min - 80 breaths / min), tidal volumes (2 ml - 40 ml) and inspiratory fractions (0.25 - 0.75). The breathing parameters were set to a breathing frequency of 50 breaths / min, a tidal volume of 8 ml, and an inhalation to exhalation ratio of 1:1.5. The 8000plus from Dragerwerk AG und Co. KGaA, Lübeck, Germany was used to operate the ventilation circuit 160 in continuous positive airway pressure mode, applying an end-expiratory positive pressure of 5 mbar and a breathing gas flow rate of 6 L / min. A mesh nebulizer from Aerogen Solo, Aerogen Ltd., Galway, Ireland was used to nebulize 3 ml aliquots of budesonide (0.125 mg / ml) and saline (0.9%) solution.

[0117] The aerosol was delivered to the test bench:

[0118] - via an existing technology SoC system, FlexitrunkTM, Fisher & Paykel Healthcare Limited, Panmure, Auckland, New Zealand, which delivered the aerosol directly into the ventilation circuit; or

[0119] - via the aerosol generating device 162 according to the invention, where the aerosol was delivered directly into the patient interface 158 at a flow rate of approximately 1 L / min.

[0120] As demonstrated by the experiments, the measured inhaled dose obtained using the existing technology SoC system was 3.0%, while the measured inhaled dose obtained using the aerosol generating device 162 according to the invention was 9.7%. Thus, it is advantageous that the use of the aerosol generating device 162 according to the invention can achieve a significant increase in inhalation efficiency, which is 3.2 times higher than that of the existing technology SoC system.

[0121] List of drawing numbers

[0122] 110 Device

[0123] 112 Aerosol

[0124] 114 Aerosol flow

[0125] 116 Patient

[0126] 118 Laptop

[0127] 120 Processing device

[0128] 122 Output file

[0129] 124 Input file

[0130] 126 Input interface

[0131] 128 Output interface

[0132] 130 Algorithm

[0133] 132 Bulge

[0134] 134 Shrinkage

[0135] 136 Chest

[0136] 138 Abdomen

[0137] 140 Respiration detection device

[0138] 142 Detection element

[0139] 144 Time-of-flight camera

[0140] 146 Processing element

[0141] 148 Communication interface

[0142] 150 Nose

[0143] 152 Mouth

[0144] 154 Aerosol valve

[0145] 156 Nasal plug

[0146] 158 Patient interface

[0147] 160 Ventilation circuit

[0148] 162 Aerosol generation device

[0149] 164 Air inlet

[0150] 166 Respiratory gas

[0151] 167 Connector

[0152] 168 Respiratory filter

[0153] 170 Aerosol generation element

[0154] 172 Aerosol tube

[0155] 174 Pressure regulating element

[0156] 180 First time process

[0157] 182 Second time process

[0158] 184, 184’, …… circles

[0159] 186, 186’, …… vertical dotted lines

[0160] 188 Horizontal line

[0161] 190 Respiratory phase

[0162] 192 First test

[0163] 194 Second test

[0164] 196 Third test

Claims

1. An aerosol generating device (162) configured to generate an aerosol stream (114), comprising: - an air inlet (164) configured to receive a portion of the breathing gas (166) from a ventilation circuit (160) to be supplied to an aerosol generating element (170); - an aerosol generating element (170) configured to generate aerosol particles and introduce the aerosol particles into the aerosol stream (114); and - an aerosol tube (172) configured to supply the aerosol stream (114) comprising the aerosol particles to a patient (116) via a conducting element.

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

3. The aerosol generating device (162) according to any one of the preceding claims, wherein the conducting element comprises at least one of an aerosol valve (154) or a patient interface (158).

4. The aerosol generating device (162) according to any one of the preceding claims, wherein the air inlet (164) is configured to receive the portion of the breathing gas from the ventilation circuit (160) via a connector (167).

5. The aerosol generating device (162) according to any one of the preceding claims, wherein the aerosol generating device (162) further comprises a pressure regulating element (174) configured to provide additional pressure within the aerosol stream (114) to direct the aerosol stream (114) through the conducting element to the patient (116).

6. The aerosol generating device (162) according to claim 5, wherein when the aerosol (112) is administered to the patient (116), the pressure at the aerosol tube (172) is at least 0.01 mbar higher than the pressure at the air inlet (164).

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

8. The aerosol generating device (162) according to any one of the preceding claims, wherein the aerosol generating device (162) further comprises a breathing filter (168) located upstream of the aerosol generating element (170), wherein the breathing filter (168) is configured to remove at least one interfering substance from the breathing gas (166) to be supplied to the aerosol generating element (170).

9. A treatment device (120) configured to control a device (110) for administering an aerosol (112) to a patient (116) by: - receiving input data related to the breathing pattern of the patient (116), wherein the breathing pattern comprises information about the time course of at least one of the bulges (132) or contractions (134) of at least one of the chest (136) or abdomen (138) of the patient (116); - Determine at least one time point according to the breathing pattern; and - Control the aerosol flow (114) flowing to the patient (116) triggered at the at least one time point, wherein the at least one time point is earlier than at least one of the start or pause of the patient's (116) breathing.

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

11. The processing device (120) according to claim 9 or 10, wherein the at least one time point is earlier than at least one of the start or pause of the patient's (116) breathing by a time interval of 1 ms to 1 s.

12. 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); and - At least one of the following devices: An aerosol generating device (162) configured to generate the aerosol flow (114) described in any one of the foregoing claims related to the aerosol generating device (162); or A processing device (120) configured to control the device (110) for administering an aerosol (112) to a patient (116) described in any one of the foregoing claims related to the processing device (120).

13. The device (110) according to claim 12, further comprising a respiration detection device (140), wherein the respiration detection device (140) is configured to determine at least one of the bulges (132) or contractions (134) of at least one of the patient's (116) chest (136) or abdomen (138) related to the patient's (116) breathing.

14. The device (110) according to claim 13, wherein the respiration detection device (140) comprises: - A detection element (142) configured to record at least one of the bulges (132) or contractions (134) of at least one of the patient's (116) chest (136) or abdomen (138); - A processing element (146) configured to determine input data related to the patient's (116) breathing pattern based on at least one of the bulges (132) or contractions (134) of at least one of the patient's (116) chest (136) or abdomen (138); and - A communication interface (148) configured to transmit the input data to the processing device (120).

15. The device (110) according to claim 14, wherein the detection element (142) is a respiration detection sensor selected from at least one of the following: a time-of-flight camera (144), a strain gauge element, an electrical impedance tomography sensor, a respiratory inductive plethysmography sensor, a millimeter wave sensor, a radar sensor, or a thermal sensor.

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

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

18. The method according to claim 16 or 17, wherein an additional pressure is provided within the aerosol stream (114) to direct the aerosol stream (114) through the conducting element to the patient (116).

19. A method of administering an aerosol (112) to a patient (116), the method comprising the steps of: a) receiving input data related to the breathing pattern of the patient (116), wherein the breathing pattern includes information about the time course of at least one of the elevation (132) or contraction (134) of at least one of the patient's (116) chest (136) or abdomen (138); b) determining at least one time point based on the breathing pattern; and c) controlling the aerosol stream (114) flowing to the patient (116) triggered at the at least one time point, wherein the at least one time point is earlier than at least one of the start or pause of the patient's (116) breathing.

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