A nebulizer device and method suitable for multiple body positions

Abstract

The present application relates to a kind of atomizer suitable for multi-position, including the inertial sensor and signal processor arranged on atomizer, the inertial sensor, signal processor are connected with the drive circuit of atomizer;The signal processor is based on the attitude signal collected by the inertial sensor, it is handled into the regulation and control signal that atomizer can directly respond, the drive circuit real-time adjustment the output of atomizer, the atomizer also includes atomizing cup, multiple bifurcation cotton core is provided in the atomizing cup, the end of the multiple bifurcation cotton core is divided into multiple unequal length branch, distribution in space different direction.The present application also relates to the calibration method of the atomizer.The atomizer of the present application can automatically identify user body position change (such as sitting, lying, side lying), dynamically adjust atomization output parameter, ensure that in any body position can realize the maximization atomization efficiency and treatment effect of current state, significantly improve the bioavailability of atomized drug.

Description

Technical Field

[0001] This invention relates to the field of nebulizers, and in particular to a nebulizer and method suitable for multiple body positions. Background Technology

[0002] Nebulized drug delivery allows medication to be delivered directly to the lungs or airway lesions via the respiratory tract (nasal cavity, trachea, bronchi, alveoli) in aerosol form. Clinically, it is used to treat respiratory diseases such as cough, asthma, chronic obstructive pulmonary disease (COPD), and lung infections, reducing systemic exposure, significantly improving treatment efficacy, and minimizing side effects. The alveoli have a large surface area (approximately 70 square meters) and are rich in capillaries. Drugs deposited in the lungs via the respiratory tract passively diffuse and are rapidly absorbed into the bloodstream. Compared to oral medications, nebulized drug delivery offers significant technological advantages in terms of dosage, onset time, patient compliance, and convenience.

[0003] Nebulizers are essential devices for nebulized drug delivery. Common clinical nebulizers include compressor type, ultrasonic type, vibrating sieve type, and vibrating screen type. Their driving principle is basically the same: the actuator made of piezoelectric material vibrates at high frequency under the action of the driving signal, and the liquid drug is processed into an aerosol through compression, ultrasonic vibration, or any combination of atomizing plates with a special structure array on the surface of the actuator.

[0004] Gravitational settling and inertial impaction affect user posture and thus the deposition and distribution of aerosols within the user's body. Gravitational settling is related to aerosol particle size, while inertial impaction can be described by inertial parameters, as shown in the following equation.

[0005]

[0006] in, For droplet density, The initial diameter of the droplet. This refers to the inhalation flow rate.

[0007] The density of atomized droplets in a single atomizer is closely related to its initial diameter. Intake flow rate is the main influencing factor for the deposition of liquid aerosols through inertial collisions.

[0008] Existing studies have shown that after drugs are aerosolized by nebulizers and enter the respiratory tract, the deposition location of inhaled drugs is closely related to the inspiratory airflow velocity, aerosol particle size, and even the user's posture. Generally speaking, drugs with a particle size of 1-5 μm tend to deposit in the alveoli, while those >5 μm tend to deposit in the upper respiratory tract.

[0009] Existing nebulizers mostly rely on a fixed nebulization volume to deliver drug aerosols, failing to consider changes in user posture during actual use. This leads to differences in airflow and drug deposition in the respiratory tract under different body positions, affecting therapeutic efficacy. Nebulizers that adapt to user positions and postures remain an unmet clinical need, and how to adjust the nebulization volume according to changes in user position to ensure optimal nebulization inhalation is a pressing technical problem. Therefore, this paper designs a system that can achieve optimal nebulization inhalation in different body positions, adapting to different user postures to effectively improve nebulization delivery, and enhance therapeutic efficacy, ease of use, and user compliance. Summary of the Invention

[0010] The purpose of this invention is to provide an atomizer suitable for multiple postures, including an inertial sensor and a signal processor arranged on the atomizer, characterized in that...

[0011] The inertial sensor and signal processor are connected to the drive circuit of the atomizer;

[0012] The signal processor processes the attitude signal collected by the inertial sensor into a control signal that the atomizer can directly respond to, and the drive circuit adjusts the output of the atomizer in real time.

[0013] The atomizer also includes an atomizing cup, in which a multi-branched cotton wick is provided. The end of the multi-branched cotton wick is divided into multiple branches of unequal length, distributed in different directions in space.

[0014] In a preferred embodiment of the present invention, the atomizing cup is one.

[0015] In a preferred embodiment of the present invention, the inertial sensor integrates a three-axis gyroscope and a three-axis accelerometer to work together to detect the attitude of the atomizer in real time.

[0016] In a preferred embodiment of the present invention, the inertial sensor integrates one triaxial gyroscope and one triaxial accelerometer.

[0017] In a preferred embodiment of the present invention, the detection signals from the three-axis gyroscope and the three-axis accelerometer are filtered and sent to the signal processor to obtain the Euler angles (pitch, roll, yaw) of the atomizer attitude.

[0018] In a preferred embodiment of the present invention, the filtering process includes any one or a combination of Kalman filtering, complementary filtering, etc.

[0019] In a preferred embodiment of the present invention, the signal processor first calculates the detection signal into a quaternion, converts it into Euler angles, and then outputs it as a corresponding unit vector (a, b, c).

[0020] In a preferred embodiment of the present invention, the optimal output atomization amount corresponding to the current atomizer posture is obtained based on a pre-stored optimal relationship algorithm between atomizer posture and atomization output amount. The driving circuit generates a corresponding driving signal in response to the optimal output atomization amount and adjusts the atomization amount to the optimal value in real time.

[0021] In a preferred embodiment of the present invention, the optimal relationship algorithm is: ,in, For the optimal atomization output, a, b, and c are the magnitudes of the unit vectors corresponding to Euler angles, i.e., (a, b, c); in the algorithm, the z-axis of the Euler angle reference coordinate system is vertically upward; the x-axis is horizontally forward; and the y-axis is horizontally to the left.

[0022] In a preferred embodiment of the present invention, the driving circuit adjusts the atomization output to the optimal level by adjusting the duty cycle in the driving signal based on the optimal output atomization amount.

[0023] In a preferred embodiment of the present invention, the atomizer uses piezoelectric ceramic as an actuator, and the driving signal drives the actuator at the self-excited frequency of the actuator to form atomized aerosol with stable particle size.

[0024] In a preferred embodiment of the present invention, a conical microporous structure array is further included, which is fixed to one side of the atomizing liquid surface of the actuator.

[0025] Another object of the present invention is to provide an attitude adaptive calibration method for an atomizer as described above, comprising the following steps:

[0026] (1) Establish the reference coordinate system of the inertial sensor and set the initial position of the atomizer;

[0027] (2) Based on the initial position, a human mouth and throat model was used to calibrate the atomized inhalation volume under different flow rates at different postures, in order to determine the deposition ratio. To characterize, among which, The mass of the droplets deposited in the human mouth and throat model. This represents the total mass of droplets collected at each location;

[0028] (3) Using three mutually orthogonal postures as a reference, determine the optimal atomization amount under the three postures;

[0029] (4) Based on the data measured in steps (2) and (3), numerical fitting is performed to determine the optimal atomization algorithm under the attitude after rotating by any Euler angle relative to the reference coordinate system.

[0030] In a preferred embodiment of the present invention, the correction method includes the following steps:

[0031] (1) Establish the world coordinate system as the reference coordinate system with the positive Z-axis pointing vertically upward, the positive X-axis pointing horizontally forward, and the positive Y-axis pointing horizontally to the left;

[0032] (2) In an upright sitting position, the actuator plane of the atomizer is parallel to the YZ plane;

[0033] (3) The optimal atomization amount was determined by selecting three postures: sitting (1,0,0), lateral (0,1,0), and supine (0,0,1). The optimal atomization amounts for the three postures were 0.242 g / min, 0.213 g / min, and 0.196 g / min, respectively.

[0034] (4) The algorithm for the optimal atomization amount is based on the unit vector (a, b, c) corresponding to the Euler angles of any attitude detected by the inertial sensor.

[0035] .

[0036] The present invention uses LC-MS / MS to detect the drug concentration of salbutamol in the plasma of experimental animals (see Table 1).

[0037] Table 1

[0038]

[0039] This invention uses Analyst 1.6.2 software to collect, integrate, calculate and process chromatographic peaks; with the ratio of the peak area of ​​the analyte to the internal standard as the ordinate (y) and the concentration as the abscissa (x), a weighted least squares method (W=1 / x2) is used to perform regression calculation, and the regression equation is: y=ax+b.

[0040] In this invention, when analyzing drug concentrations in samples, a standard curve is established for each analytical batch (Run) to calculate the concentration of the analyte in the quality control and unknown samples of that analytical batch. The ratio of the peak area of ​​the analyte in the sample to the peak area of ​​the internal standard is substituted into the corresponding standard curve to calculate the concentration of each analyte.

[0041] This invention calculates the average value, standard deviation, and CV of the data, and processes and plots the data. The concentration unit is ng·mL. -1 The original data is rounded to 3 decimal places, the calculated average and SD values ​​are rounded to 4 decimal places, and the CV values ​​are rounded to 2 decimal places.

[0042] This invention uses a non-compartmental model of WinNonlin 6.3 to calculate pharmacokinetic parameters, and analyzes key pharmacokinetic parameters such as AUC and C. max t 1 / 2 and T max Statistical analysis was then performed.

[0043] Unless otherwise stated, when this invention relates to percentages between liquids, the percentage is volume / volume percentage; when this invention relates to percentages between liquids and solids, the percentage is volume / weight percentage; when this invention relates to percentages between solids and liquids, the percentage is weight / volume percentage; the remainder is weight / weight percentage.

[0044] Compared with the prior art, the present invention has the following beneficial technical effects and significant advantages:

[0045] 1. The nebulizer of this invention features multi-position adaptive nebulization, ensuring stable and efficient drug delivery. Traditional nebulizers rely on gravity for liquid supply, which often leads to unstable supply or nebulization interruption due to liquid level shift in tilted or lateral positions. This invention introduces a multi-branched cotton wick structure within the drug cup, utilizing its capillary action to achieve continuous liquid supply independent of gravity. This design ensures that the cotton wick remains in contact with the drug even when the nebulizer nozzle is facing upwards or the liquid level is extremely low, providing reliable "anti-gravity" nebulization capability and solving the problem of intermittent supply caused by changes in body position. This structure not only significantly improves the stability of the nebulization process and the continuity of aerosol output but also optimizes the aerosol particle size distribution, increasing the proportion of inhalable particles. In vitro deposition experiments show that cotton wick-assisted liquid supply can increase the effective amount of fine particles by approximately 5%, directly enhancing the drug delivery efficiency in the lungs.

[0046] 2. The nebulizer of this invention integrates a high-precision inertial sensor, which can automatically identify changes in the user's body position (such as sitting, lying down, or side-lying). By intelligently comparing and calculating the real-time sensed body position vector with a preset benchmark body position model (such as sitting or lying flat), the system can dynamically adjust the nebulization output parameters to ensure that the nebulization efficiency and therapeutic effect can be maximized in any body position. This significantly improves the treatment compliance and experience of users (especially the elderly, bedridden individuals, infants, and other groups whose body positions are not easily fixed) and significantly reduces drug residues.

[0047] 3. The nebulizer of this invention significantly improves the bioavailability of nebulized drugs, validating clinical equivalence and superiority. While achieving convenience and stability, this invention demonstrates significant advantages in core pharmacodynamic indicators. Experiments have confirmed that, while achieving pharmacokinetic exposure characteristics comparable to commercially available products, the relative bioavailability (F%) of this nebulizer is significantly higher than that of the commercially available control product by approximately 1.6 times. This proves that this invention meets the standards for the feasibility and reliability of inhaled drug delivery, and further demonstrates significantly superior performance compared to existing technologies in terms of drug deposition efficiency in the lungs and inhalable fraction. Attached Figure Description

[0048] Figure 1The atomization drive control unit of Example 1 includes a medicine cup 1, a wire 2, a controller 3, a drive board 4, an inertial sensor 5, and an atomizing plate 6;

[0049] Figure 2 Block diagram of the driving circuit of this invention;

[0050] Figure 3 The multi-branched cotton core structure of the present invention;

[0051] Figure 4 Schematic diagram of the atomizing plate 6 of the atomizer in Example 1;

[0052] Figure 5 Comparison of deposition ratio of the atomizer of the present invention under different postures;

[0053] Figure 6 A schematic diagram illustrating the use of the atomizer of this invention. Detailed Implementation

[0054] The preferred embodiments of the present invention will be described below with reference to the accompanying drawings. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.

[0055] Example 1 Attitude-adaptive atomizer drive control unit based on vibrating screen-type atomizer modification

[0056] Figure 1 This is a schematic diagram of the drive control unit of the atomizer of the present invention, which consists of an atomizing cup 1, a drive board 4, a battery 3, an inertial sensor 5, a power supply, and wires 2.

[0057] The actuator for the atomizing plate 6 is located on the inner wall of the atomizing cup 1; the drive plate 4 is located below the atomizing cup 1, and the drive plate 4 is connected to the inertial sensor 5 and the signal processor, as well as... Figure 2 The driving circuit is shown. The driving board 4 is connected to the battery 3 via wire 2; the driving board 4 is connected to the atomizing plate 6 via wire 2; the inertial sensor 5 consists of a gyroscope sensor, an accelerometer sensor, and a digital motion processor.

[0058] The atomizing cup (1) is equipped with such Figure 3 The multi-branched cotton wick shown has multiple branches of unequal length at its end, distributed in different directions in space. When the user is in different positions, the liquid medicine naturally accumulates at the lowest point of the cup, and there is always one branch that can contact the liquid surface. The cotton wick fully contacts the actuator with the liquid medicine at the lowest point of the atomizing cup 1 in a wetting manner, thereby generating drug aerosol output.

[0059] The gyroscope calculates the user's exact position to complete the attitude navigation task. Taking a three-axis gyroscope as an example, the gyroscope angles of the three axes are integrated to obtain attitude data of rotation angles in three directions. Because of actual errors and noise, gyroscope integration cannot yield completely accurate attitude data; therefore, an accelerometer sensor is used for auxiliary correction. The correction steps include...

[0060] Step 1, Calibrate data (zero drift). The accelerometer sensor is installed on the device at an initial angle, which is set to 0 degrees. Subtract this initial data from each data point to obtain a relative angle.

[0061] Step 2: Convert the measured values ​​to the corresponding units. Dividing the raw data by its sensitivity within that range will give you the actual physical unit. The physical unit for acceleration is g, and the physical unit for angular velocity is ° / s.

[0062] Step 3, filtering and data fusion. There are three common methods: complementary filtering, Kalman filtering, and hardware DMP quaternion calculation. (1) Complementary filtering: because the accelerometer has high-frequency noise and the gyroscope has low-frequency noise, complementary filtering is required to obtain a more reliable angle value. (2) Kalman filtering: using the linear system state equation, the algorithm estimates the system state optimally through the system input and output observation data. Since the observation data includes noise and interference in the system, the optimal estimation can also be regarded as a filtering process. (3) Hardware DMP quaternion calculation: DMP directly converts the original data into quaternion output and uses the Euler angle conversion algorithm to obtain yaw, roll, and pitch. The attitude navigation of the gyroscope and the correction of the accelerometer sensor can be completed by the digital motion processor built into the inertial sensor 5, outputting the attitude detection signal and transmitting it to the signal processor. Of course, it is understandable that the signals detected by the gyroscope and accelerometer can also be directly sent to the signal processor, which will perform the calculation to obtain the attitude information required for subsequent adjustment of the atomization output.

[0063] The signal processor calculates the optimal output atomization amount corresponding to the current atomizer posture based on the attitude information sensed by the inertial sensor, based on the pre-stored optimal relationship algorithm of atomizer posture and optimal atomization amount. The drive circuit responds to the output of the signal processor, adjusts the drive signal, and adjusts the atomization amount to the optimal value in real time.

[0064] In a specific application, the z-axis of the Euler angle reference coordinate system is set vertically upward; the x-axis is horizontally forward; and the y-axis is horizontally to the left. With a reference resting inspiratory volume of 15 L / min, the optimal nebulization mass flow rate for each body position can be determined. Taking the nebulizer of Embodiment 1 of this invention as an example, its nebulization output in a seated position is 0.323 g / min. Measurements show that the inspiratory flow rate with the lowest upper respiratory tract deposition ratio, i.e., the highest intrapulmonary delivery efficiency, is 20 L / min (see...). Figure 5 The optimal nebulization amount for this body position can then be calculated as follows:

[0065] Seated posture, 0.323 / 20×15 = 0.242 g / min

[0066] Similarly, it can be calculated that:

[0067] In the lateral decubitus position, 0.426 / 30×15 = 0.213 g / min

[0068] Supine position, 0.392 / 30×15 = 0.196 g / min

[0069] The optimal nebulization rate was found to be 0.213 g / min in the lateral decubitus position and 0.196 g / min in the supine position.

[0070] After fitting, the optimal relation algorithm is obtained as follows: ,in, For the optimal atomization output, a, b, and c are the amplitudes of the unit vector corresponding to the Euler angles, i.e., (a b c ).

[0071] The above values ​​indicate that, assuming the user's inspiratory flow rate is unknown and they are in a typical resting state (15 L / min), in order to ensure that the lung deposition rate is close to the optimal level, the system should adjust the nebulization output to 0.242 g / min, 0.213 g / min and 0.196 g / min for sitting, lateral, and supine positions, respectively.

[0072] Finally, the optimal atomization amount under the three body positions was unified into a vector model, with the sitting posture direction as the x-axis (0.242). ), with the y-axis at lateral position (0.213). ), lying supine with the z-axis at 0.196 ).

[0073] The optimal atomization amount is unified into a vector model (0.242). 0.213 0.196 The value was obtained at a rated atomization output of 0.323 g / min. For a rated output of... For any atomizer with a concentration of g / min, its optimal atomization quantity unified vector model is (0. 242). 0.213 0.196 )× / 0.323.

[0074] Algorithm for finding the optimal relationship. ,in, denoted as the rated output of the atomizer, where a, b, and c are the unit vectors (a, b, c) corresponding to Euler angles.

[0075] The nebulizer cup 1 is a closed chamber containing the drug solution to be nebulized. It has a nebulizing plate 6 on its side, which can convert the drug solution into micron-sized droplets under the drive of an electrical signal.

[0076] The wire 2 and the signal connection component are used to realize the electrical connection and signal transmission between the above components, and to power the entire system through the power supply unit of the battery 3.

[0077] The actuator for the atomizing plate 6 includes a metal substrate, a ring-shaped piezoelectric ceramic, and electrodes (such as...). Figure 4 (As shown). The atomizing plate employs a piezoelectric micro-vibration structure with a conical micropore structure on its surface that has a larger opening towards the liquid surface. Under stable driving conditions at a self-excited frequency (typically 116–117 kHz) and with a constant voltage, it achieves uniform jetting of liquid towards the air side, forming atomized aerosol with stable particle size. Combined with the designed drive plate, the median diameter (MMD) of the atomized aerosol is 4.267 μm, satisfying an atomization rate ≥0.2 ml / min, a particle size distribution with ≥50% of particles smaller than 5 μm, and good drug delivery uniformity and dispersibility.

[0078] The signal processor adjusts the drive signal generated by the drive circuit based on the body position data obtained by the inertial sensor 5. For example, by adjusting the duty cycle and frequency of the PWM signal, the drive circuit controls the drive signal adjusted in real time to drive the actuator to generate high-frequency vibration, so that the drug solution to be atomized in the atomizing cup 1 is atomized into an aerosol and sprayed out based on the adaptive adjustment of the atomization amount based on attitude perception.

[0079] In a preferred embodiment of the present invention, the controller serving as the signal processor is an Arduino development board.

[0080] In a preferred embodiment of the present invention, the controller includes a core processing unit responsible for receiving body position data, determining posture, calculating the optimal atomization amount, and adjusting the output of the drive circuit accordingly.

[0081] In a preferred embodiment of the present invention, the driving circuit includes a piezoelectric waveform generator, a voltage pull-down circuit, an operational amplifier circuit, and a power amplifier circuit. The voltage waveform generator responds to a signal processor, which adjusts the driving signal in real time based on the attitude, and after amplification, drives the actuator to vibrate at high frequency, causing the solution contained in the atomizing cup 1 to be atomized and sprayed out.

[0082] In a preferred embodiment of the present invention, the driving circuit is used to generate the high-frequency driving signal (such as voltage or pulse waveform) required by the atomizing plate, and its output parameters (such as duty cycle and voltage amplitude) can be dynamically adjusted by the controller.

[0083] In a preferred embodiment of this invention, the inertial sensor 5 is a six-axis or nine-axis IMU (including a three-axis accelerometer and a three-axis gyroscope), such as the typical MPU6050, used to collect the attitude information of the atomizer body in space, including the direction angle, acceleration vector, etc., and can calculate the azimuth angle in real time. The signal processor adjusts the drive circuit based on the azimuth angle.

[0084] In a preferred embodiment of the present invention, the inertial sensor 5 is used to monitor the user's body position and acquire the user's body position data to determine the user's current body position orientation; the inertial sensor is used to collect the user's current spatial orientation information, and after receiving the information, the controller derives the target atomization mass flow rate corresponding to the body position through the built-in optimal atomization amount calculation model, and sends a control signal to the drive circuit to adjust the drive duty cycle of the atomizing plate.

[0085] Figure 1 The nebulizer drive control unit shown can be designed as an integrated unit, encapsulating the nebulizer cup, inertial sensor, control circuitry, and battery within the same housing, and secured to the user's mouth via the mouthpiece. Because the device rotates naturally with the head posture, the inertial sensor reliably acquires the direction of the airway. If the device uses a separate structure, such as a separate drive control unit from the nebulizer cup, the inertial sensor must be installed in a location that rotates synchronously with the user's posture, such as the mouthpiece, mask, or nebulizer cup interface, to ensure accurate acquisition of body position information.

[0086] It is understood that the atomization drive control unit in this embodiment can be integrated with any atomizer to realize the attitude adaptation function of the atomizer, and its actuator can also be replaced with other sol-excitation methods, which does not constitute a substantial limitation on the present invention.

[0087] Example 2 This invention relates to a calibration method for multi-position nebulizers.

[0088] Based on the experimental device of the nebulizer drive control unit in Example 1, a commonly used human mouth and throat model is used to simulate the respiratory system structure of the real human body, and the deposition distribution of atomized aerosol in the human body is tested.

[0089] The human mouth and throat model used for calibration is made of highly transparent resin and is divided into left and right halves to facilitate the removal of any deposited droplets with deionized water after the experiment. During the experiment, the left and right halves of the model are clamped tightly with clamps to ensure structural airtightness and prevent droplets from escaping through the gaps. Any suitable human mouth and throat model in this field can be selected for the experiment, including two different scenarios:

[0090] 1) For general users, a respiratory tract model based on population averages is used. This model represents the oral and laryngeal structure of a normal adult and can provide standard nebulization effects for most users. This model can simulate droplet deposition distribution under different body positions and measure the optimal nebulization volume under different positions.

[0091] 2) Special users (e.g., specific users or users with special needs) can have their own customized airway models created based on their CT scan data. By processing the CT data and performing 3D reconstruction, a user-specific oral-oral model is formed to more accurately simulate the user's airflow path and drug deposition effect. This method can provide more personalized nebulization therapy and optimize it for the user's specific situation, thereby achieving customized services.

[0092] The atomization control device is connected to the human mouth and throat model so that the liquid mist aerosol atomized by the atomization control device enters the human mouth and throat model under the suction of the vacuum pump. The filtration device includes a bubble absorption tube, a slag discharge filter, and a filter membrane filter unit to capture droplets escaping from the human mouth and throat model. The vacuum pump is configured to draw the liquid mist aerosol into the experimental device at a constant suction flow rate (controlled by a flow meter).

[0093] Any suitable filtration device in the art can be selected. An appropriate water level is maintained in the bubble absorption tube to prevent excessive droplet splashing due to high flow velocity. A sludge-removing filter is placed between the bubble absorption tube and the membrane filter unit to perform secondary filtration on the airflow exiting the bubble absorption tube, capturing droplets in the airflow. The membrane filter unit is placed after the sludge-removing filter to perform deep filtration of the airflow, completely capturing residual atomized droplets and improving experimental accuracy.

[0094] The vacuum pump can be any suitable vacuum pump in the art, without limitation. A rotor flow meter can be further installed upstream of the vacuum pump to adjust the experimental flow rate. The flow rate for this experiment is set to 2-120 L / min.

[0095] An analytical balance is configured to measure the mass of the atomization control device before and after atomization. By dividing the mass difference of the atomization control device before and after atomization by the atomization time, the device can easily calculate the atomization amount of the atomization control device under different body positions. The analytical balance can be any suitable weight sensor in the art, without limitation. The analytical balance is a high-precision balance. The analytical balance is positioned at the bottom of the atomization control device to effectively measure the weight change of the atomization control device before and after atomization.

[0096] Based on the above experimental setup, the steps for calibrating the attitude-adaptive atomizer are as follows.

[0097] (1) Preparation for nebulized inhalation experiment: Place the nebulizing solution in the nebulizer cup; wherein, the nebulizer cup is a chamber for holding the nebulized solution, and the chamber may be any suitable closed chamber in the art. The nebulizing solution may be any suitable drug solution in the art, for example, but not limited to, a 0.9% sodium chloride aqueous solution. In some embodiments, the nebulized liquid in the cup contains a drug portion and a fluorescent substance portion for determining the deposition amount;

[0098] (2) Experimental setup: Establish the reference coordinate system of the inertial sensor and set the initial position of the atomizer. Based on the initial position, use the above-mentioned human mouth and throat model to calibrate the atomized inhalation volume under different flow rates at different postures, with the deposition ratio... To characterize, among which, The mass of the droplets deposited in the human mouth and throat model. This represents the total mass of droplets collected at each location;

[0099] (3) Using three mutually orthogonal postures as a reference, determine the optimal atomization amount under the three postures;

[0100] (4) Based on the data measured in steps (2) and (3), numerical fitting is performed to determine the optimal atomization amount algorithm under the attitude after rotating arbitrarily by Euler angle relative to the reference coordinate system.

[0101] In practice, three orthogonal postures are used: the human oral-throat model is tested in supine, sitting, and lateral positions. A 0.9% w / v NaCl and 0.1% w / v fluorescein aqueous solution is used as the test solution. The inspiratory flow rate is 2-60 L / min, and the test solution is placed in a medicine cup. The vacuum pump is started, and the inspiratory flow rate is adjusted to a given flow rate. After the airflow stabilizes, the nebulization control device is turned on, and the solution is atomized and sprayed out at a certain rate. Under the suction of the vacuum pump, the liquid aerosol enters the real human oral-throat model and deposits. Subsequently, the aerosols not deposited in the oral-throat area are captured by a three-stage filtration device. At each flow rate, nebulization is continued for a certain period of time. Some of the drug is deposited in the human upper respiratory tract model, and some is captured by the rear collection unit after passing through the upper respiratory tract. The captured drug can be considered delivered to the lungs.

[0102] After each atomization inhalation experiment, each part of the system is ultrasonically cleaned, and the absorbance of the wash liquid after volume adjustment is measured with an instrument. The mass of fluorescent droplets deposited in each part of the system is determined according to the solution concentration and volume, and the deposition ratio is determined according to formula (1).

[0103] (1)

[0104] in, The mass of the droplets deposited in the human mouth and throat model. This represents the total mass of droplets collected at each location. Deposition ratio data for each operating condition were repeated three times, and the results were averaged to minimize experimental error. Experiments were conducted at different body positions and different inhalation flow rates, covering sufficient inhalation flow rate conditions within the range of 2-60 L / min. In the experiments, deposition atomization was measured at the following constant inhalation flow rates: 10 L / min, 20 L / min, 30 L / min, 40 L / min, and 50 L / min, obtaining the following results: Figure 5 The deposition ratio-inspired flow rate relationship is shown. It can be observed that as the inspired flow rate gradually increases from a low level (e.g., 10 L / min), the deposition ratio first decreases and then increases. The deposition ratio (DF) at the inflection point is recorded. min And inhalation flow rate. Combined with the rated atomization rate of the atomizer during the experiment. g / min can be used to obtain the optimal nebulization rate per unit inspiratory flow rate under this body position. g / (L·min) 2 ), where i=x,y,z correspond to sitting, side-lying and supine positions, respectively.

[0105]

[0106] By comparing experimental data, the lowest drug deposition ratio was observed when the user was in a supine position and the inspiratory flow rate was 30 L / min. At this point, the optimal nebulization rate per unit inspiratory flow rate could be calculated, maximizing drug utilization. A pressure sensor detects the negative pressure generated by the mouthpiece during user inhalation, and the inspiratory flow rate is determined by the pressure difference. Combined with body position, the cloud platform calculates a more suitable nebulization plan for the user.

[0107] Assuming an inspiratory flow rate of 15 L / min for an adult in three different body positions, the optimal nebulization rate in a given body position is: g / min. The optimal atomization rate for achieving the lowest deposition ratio under different body positions using the atomization control device is recorded in Table 2 below.

[0108] Table 2

[0109] body position Sitting Side-lying Lie flat on your back (or supine) Required atomization rate (g / min) 0.242 0.213 0.196

[0110] The attitude data in steps (2) and (4) is automatically calculated by the inertial sensor. The specific process is as follows: the gyroscope angles of the three axes are integrated to obtain the attitude data of the rotation angles in the three directions. Due to the existence of error noise, the gyroscope integration cannot obtain a completely accurate attitude. Therefore, an accelerometer sensor is used for auxiliary correction. The correction method includes the following steps:

[0111] S-1, Calibration data (zero drift): The accelerometer sensor is installed on the device at an initial angle, which is set to 0 degrees. Subtract this initial data from each data point to obtain a relative angle.

[0112] S-2, convert the measured value to the corresponding unit. Dividing the original data by its sensitivity within that range yields the actual physical unit. The physical unit for acceleration is g, and the physical unit for angular velocity is ° / s;

[0113] S-3, filtering and data fusion, there are three common methods: complementary filtering, Kalman filtering, and hardware DMP quaternion calculation. (1) Complementary filtering: because the accelerometer has high-frequency noise and the gyroscope has low-frequency noise, complementary filtering is required to obtain a more reliable angle value. (2) Kalman filtering: using the linear system state equation, the algorithm estimates the system state optimally through the system input and output observation data. Since the observation data includes noise and interference in the system, the optimal estimation can also be regarded as a filtering process. (3) Hardware DMP quaternion calculation: DMP directly converts the original data into quaternion output, and uses the Euler angle conversion algorithm to obtain yaw, roll and pitch. The attitude navigation of the gyroscope and the correction of the accelerometer sensor can be completed by the digital motion processor built into the inertial sensor 5, outputting the attitude detection signal and transmitting it to the signal processor. Of course, it is understandable that the signals detected by the gyroscope and accelerometer can also be directly sent to the signal processor, which will perform the calculation to obtain the attitude information required for subsequent adjustment of the atomization output.

[0114] The optimal atomized inhalation volume under different postures was determined through the above experiments. g / min, based on numerical fitting, to determine the optimal nebulized inhalation volume. The algorithm relating g / min and attitude is pre-set in the signal processor so that the drive signal can be adjusted in real time during use, ensuring that the atomizer always operates in the optimal atomization output state.

[0115] Taking the positive Z-axis of the world coordinate system as vertically upward, the positive X-axis as horizontally forward, and the positive Y-axis as horizontally to the left as an example, in an upright sitting posture, the actuator plane of the atomizer is parallel to the YZ plane; selecting three orthogonal postures: sitting (1,0,0), side-lying (0,1,0), and supine (0,0,1), g / min=0.323g / min, and the optimal atomization rates for the three attitudes are 0.242g / min, 0.213g / min, and 0.196g / min, respectively;

[0116] The algorithm for determining the optimal atomization amount m based on the unit vector (a, b, c) corresponding to the Euler angles of any attitude detected by the inertial sensor is as follows:

[0117] .

[0118] Experimental Example 1 This invention relates to the pharmacokinetic study of an attitude-adaptive nebulizer for drug nebulization inhalation.

[0119] Twelve male SD rats weighing 200±20g (purchased from Beijing Huafukang Biotechnology Co., Ltd.) were selected and administered salbutamol sulfate solution via nebulization. The animals were randomly divided into an experimental group (administered via nebulizer as described in Example 1) and a control group (administered via handheld nebulizer M105), with six animals in each group. The dosage of salbutamol sulfate was 2.5 mg / kg, the nebulized solution was 2 mL, and the nebulization frequency was 0.5 mL / min.

[0120] At 5 min, 20 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 12 h and 24 h after nebulization, the drug concentration of salbutamol in the plasma samples of the test animals was detected using the method of the present invention, and its pharmacokinetic parameters were calculated using the method of the present invention.

[0121] The results showed that both the experimental and control groups rapidly reached peak concentrations within 0.1–0.5 hours after administration, demonstrating good pulmonary absorption characteristics; the t1 / 2 and MRT showed no significant difference, indicating that the drug's metabolism and clearance processes in vivo were consistent. The AUC of salbutamol sulfate in the experimental group was [not specified]. 0–t The AUC of salbutamol sulfate was used as the control group. 0–t The atomizer of the present invention has a significantly superior atomization performance compared to the prior art, which is 1.6 times that of the present invention.

[0122] The nebulizer of this invention significantly improves the deposition efficiency and inhalable fraction of nebulized drugs, and achieves pharmacokinetic exposure and absorption characteristics comparable to those of commercially available nebulizers, verifying its feasibility and reliability for inhalation drug delivery.

[0123] Experimental Example 2 The posture-adaptive nebulizer of this invention is used for nebulized drug delivery to users.

[0124] like Figure 6 As shown, when the atomizer of Example 1 is worn on the user's mouth, the unit direction vector of the user's body position measured by the inertial sensor is (0.6, 0, 0.8). Based on this, the optimal atomization amount for the user in this direction is calculated as follows: The atomizer will automatically adjust and provide the user with the optimal amount of vapor.

[0125] When the user changes position, the inertial sensor re-detects the unit direction vector of the user's position, recalculates the optimal atomization amount for the user in that direction, and the atomizer adjusts accordingly to provide the optimal atomization amount to the user.

[0126] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An atomizer suitable for multiple postures, comprising an inertial sensor and a signal processor arranged on the atomizer, characterized in that, The inertial sensor and signal processor are connected to the drive circuit of the atomizer; The signal processor processes the attitude signal collected by the inertial sensor into a control signal that the atomizer can directly respond to, and the drive circuit adjusts the output of the atomizer to the optimal atomization output in real time. The atomizer also includes an atomizing cup, in which a multi-branched cotton wick is provided. The end of the multi-branched cotton wick is divided into multiple branches of unequal length, distributed in different directions in space.

2. The atomizer as described in claim 1, characterized in that, The inertial sensor integrates a three-axis gyroscope and a three-axis accelerometer to detect the atomizer's attitude in real time.

3. The atomizer according to any one of claims 1-2, characterized in that, The signal processor first calculates the detection signal into a quaternion, then converts it into Euler angles, and finally outputs it as a corresponding unit vector (a, b, c).

4. The atomizer according to any one of claims 1-3, characterized in that, Based on the pre-stored optimal relationship algorithm between atomizer posture and atomization output, the optimal atomization output corresponding to the current atomizer posture is obtained. The drive circuit responds to the optimal atomization output to generate a corresponding drive signal and adjusts the atomization output to the optimal value in real time.

5. The atomizer as described in claim 4, characterized in that, For rated output For an atomizer with a flow rate of 0.323 g / min, the optimal relationship algorithm is as follows: ,in, For the optimal atomization output, a, b, and c are the magnitudes of the unit vectors corresponding to Euler angles, i.e., (a, b, c); in the algorithm, the z-axis of the Euler angle reference coordinate system is vertically upward; the x-axis is horizontally forward; and the y-axis is horizontally to the left.

6. The atomizer according to any one of claims 1-5, characterized in that, The atomizer uses piezoelectric ceramic as an actuator, and the driving signal drives the actuator at the self-excited frequency of the actuator to form atomized aerosol with stable particle size.

7. The atomizer as described in claim 6, characterized in that, It also includes a tapered microporous structure array fixed to one side of the atomizing liquid surface of the actuator.

8. A method for attitude adaptive calibration of an atomizer as described in any one of claims 1-7, comprising the following steps, (1) Establish the reference coordinate system of the inertial sensor and set the initial position of the atomizer; (2) Based on the initial position, a human mouth and throat model was used to calibrate the atomized inhalation volume under different flow rates at different postures, in order to determine the deposition ratio. To characterize, among which, The mass of the droplets deposited in the human mouth and throat model. This represents the total mass of droplets collected at each location; (3) Using three mutually orthogonal postures as a reference, determine the optimal atomization amount under the three postures; (4) Based on the data measured in steps (2) and (3), numerical fitting is performed to determine the optimal atomization algorithm under the attitude after rotating by any Euler angle relative to the reference coordinate system.

9. The method as described in claim 8, characterized in that, The algorithm for finding the optimal atomization amount is as follows: ,in, denoted as the rated output of the atomizer, where a, b, and c are the unit vectors (a, b, c) corresponding to Euler angles.

10. The method as described in any one of claims 8-9, characterized in that, The positive Z-axis of the world coordinate system, which serves as the reference coordinate system, is vertically upward, the positive X-axis is horizontally forward, and the positive Y-axis is horizontally to the left. When sitting upright, the actuator plane of the atomizer is parallel to the YZ plane; Three positions were selected: seated (1,0,0), lateral (0,1,0), and supine (0,0,1). The optimal atomization volume and the atomizer were determined. =0.323g / min, and the optimal atomization rates for the three attitudes are 0.242g / min, 0.213g / min, and 0.196g / min, respectively; The algorithm for determining the optimal atomization amount m based on the unit vector (a, b, c) corresponding to the Euler angles of any attitude detected by the inertial sensor is as follows: .

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