Respiratory tract deposition distribution testing device for inhalation preparation

Abstract

The utility model relates to the technical field of respiratory medicine physiological research, and discloses a respiratory tract deposition distribution testing device for inhalation preparations, which comprises a respiratory tract model unit, a head model and a respiratory tract model unit, the respiratory tract model unit comprises a sealed container, a pulmonary trachea model and a head model, and the air inlet end of the pulmonary trachea model extends to the outside of the sealed container; the head model is connected with the air inlet end of the pulmonary trachea model; the breathing machine system comprises a breathing machine, a connecting pipeline and a medicine feeding device, and the end, away from the breathing machine, of the connecting pipeline is connected to the mouth and / or the nose of the head model; and the air bag unit comprises a filtering assembly and an air bag assembly, the filtering assembly is connected with the sealed container, and the air bag assembly comprises an air bag which adaptively expands and contracts when the breathing machine system works. Under the condition that a breathing machine system assists ventilation, the respiratory tract model adapts to running parameters of the breathing machine, the function that a real bionic breathing machine assists human body breathing is achieved, and the deposition result of drug particles in the respiratory tract is accurately simulated.

Description

Technical Field

[0001] This utility model relates to the field of respiratory medical physiological research technology, and in particular to a respiratory tract deposition distribution testing device for inhaled preparations. Background Technology

[0002] Inhalation is a drug delivery route that uses a combination of drug delivery devices to treat respiratory or systemic diseases. The effectiveness of inhaled formulations is influenced by various factors, including the device, the drug itself, and patient compliance. Therefore, in vitro evaluation of inhaled products is necessary in preclinical pharmaceutical studies. According to regulations and guidelines issued by the US FDA, European EMA, and CDE, cascade impactors are the primary method for testing the aerodynamic particle size of inhaled formulations. Aerosol particles with an aerodynamic particle size in the range of 1-5 μm can be inhaled and deposited in the lower respiratory tract. The Chinese Pharmacopoeia 0951 specifies aerodynamic testing devices for fine particles in inhaled formulations, including two-stage impactors, multi-stage impactors, and next-generation impactors (NGI).

[0003] While cascade impactor testing methods can obtain the aerodynamic particle size distribution of nebulized drugs, they cannot determine the drug deposition distribution of inhaled formulations within the respiratory tract. Because of the lack of accurate inhaled drug deposition distribution data, satisfactory in vivo and in vitro consistency evaluation results cannot be obtained. Furthermore, cascade impactors cannot simulate the use of a nebulizer connected to a ventilator, neglecting the influence of various key factors on drug delivery during nebulization. In vitro testing methods for cascade impactors require a constant flow rate, and current technologies cannot simulate the actual respiratory curves during real-world drug administration.

[0004] Furthermore, aerodynamic distribution results are generally used as a tool for formulation management evaluation in preclinical pharmaceutical studies, and currently, no direct relationship has been established between these results and clinical research results. For example, in the consistency evaluation of generic drugs, consistent in vitro test results of cascade impactors do not guarantee consistent in vivo results. Therefore, in the development of new drugs and generic drugs, existing methods, such as cascade impactors, cannot accurately guide the conduct of clinical trials.

[0005] Most inhaled medications are delivered through inhalation, atomizing the drug and allowing it to enter the respiratory tract via the mouth. In intensive care unit (ICU) applications, nebulizers need to be connected to a ventilator, atomizing the medication before it enters the patient's airway via the ventilator's airway. This delivery method differs from other inhaled medications, as the atomization process is affected by factors such as the nebulizer, ventilator operating parameters, tubing structure, intubation structure, mask structure, and mouthpiece structure. Especially for antibacterial drugs administered via ventilator, there are currently no approved clinical products in China. There is an urgent need for in vitro evaluation platforms and methods to support the research, development, and commercialization of these drugs, and to provide a powerful tool for new drug review. Current artificial lung model testing equipment and methods are not systematic and do not cover testing protocols for inhaled medications used under ventilator systems, making it impossible to accurately evaluate their respiratory tract deposition distribution. Utility Model Content

[0006] The purpose of this section is to outline embodiments of the present invention. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents, and such simplifications or omissions shall not be construed as limiting the scope of the present invention.

[0007] Given that existing artificial lung model testing equipment and methods cannot directly connect artificial lung models to ventilators and optimize the use of ventilator system functions, this utility model is proposed.

[0008] Therefore, the purpose of this invention is to provide a respiratory tract deposition distribution testing device for inhaled preparations, especially when connected to a ventilator system. Its purpose is to solve the problem that existing testing methods such as cascade impactors and artificial lungs are difficult to use in conjunction with ventilator systems for in vitro respiratory tract deposition testing of inhaled liquid preparations.

[0009] To solve the above-mentioned technical problems, this utility model provides the following technical solution: a respiratory tract deposition distribution testing device for inhaled preparations, comprising:

[0010] A respiratory tract model unit includes a sealed container, a tracheal model and a head model disposed within the sealed container, wherein the air inlet of the tracheal model extends to the outside of the sealed container, and the air outlet of the head model is connected to the air inlet of the tracheal model.

[0011] A ventilator system, comprising a ventilator, a connecting tubing connected to the ventilator, and a drug delivery device disposed on the connecting tubing, wherein one end of the connecting tubing away from the ventilator is connected to the mouth and / or nose of the head model.

[0012] An airbag unit includes a filter assembly and an airbag assembly connected to the filter assembly, the end of the filter assembly remote from the airbag assembly being connected to the sealed container, and the airbag assembly including an airbag that adaptively inflates and contracts during operation of the ventilator system.

[0013] Optionally, the filtration assembly includes at least one filter membrane for allowing gas to pass through while blocking the drug to be tested.

[0014] Optionally, the airbag assembly further includes a clamping plate, the clamping plate having a hollow portion for mounting the airbag, and the air inlet end of the airbag being connected to the filter assembly.

[0015] Optionally, the drug delivery device is an atomizing device.

[0016] Optionally, the tracheal model includes a main trachea, a left trachea and a right trachea connected to the main trachea, with one end of the main trachea extending outside the sealed container and connected to the head model.

[0017] Optionally, the tracheal model is located inside the sealed container.

[0018] Optionally, the sealed container includes a sealed box and a sealing gasket and a sealing cap that match the opening of the sealed box;

[0019] The sealing box has a connection hole on its side wall, which is connected to the filter assembly.

[0020] Optionally, the tracheal model is supported within the sealed container by a support frame.

[0021] Optionally, the number of the sealed containers is 2, used to accommodate the left trachea and the right trachea respectively;

[0022] Each of the sealed containers is provided with a connection port for connecting the filter assembly. The end of the filter assembly away from the sealed container is connected to an air outlet branch pipe. The ends of the two air outlet branch pipes away from the filter assembly are both connected to a main pipe, which is connected to the airbag assembly.

[0023] The beneficial effects of this utility model are:

[0024] 1. The present invention can mimic the human respiratory function, and realize the function of a biomimetic ventilator assisting human lung breathing under the assisted ventilation conditions of a ventilator system.

[0025] 2. Compared with existing cascade impactor equipment and testing methods, this solution features a realistically modeled respiratory tract physiological structure, including the mouth, pharynx, larynx, trachea, and bronchi. The environment closely resembles real-world clinical scenarios, accurately mimicking drug particle deposition in the respiratory tract. It provides data on the drug deposition distribution within the biomimetic respiratory tract of inhaled formulations within the ventilator system. The results closely approximate the actual human drug administration process, making it suitable for evaluating the efficacy, pharmacokinetics, and safety of new drugs, as well as for generic drug consistency evaluation and inhalation device performance assessment. It provides laboratories, medical institutions, and pharmaceutical companies with accurate and reliable in vitro testing results, replacing human trials. For example, in special populations or under extreme conditions, it can shorten drug development cycles, increase the likelihood of successful research and development, and save development costs.

[0026] 3. Compared with existing cascade impactor equipment and testing methods, this scheme broadens the application scope of existing methods. This scheme can be used to study the full-process parameters of deposition distribution in the human respiratory tract under different drug administration conditions, such as drug, formulation, concentration, tidal volume, inspiratory-to-expiratory ratio, and different nebulizers, such as dry powder inhalers, pressure metered-dose inhalers, soft fog inhalers, jet nebulizers, screen nebulizers, ultrasonic nebulizers, etc., providing key guidance for the balance optimization of multiple parameters in the process of new drug development and future application.

[0027] 4. The deposition distribution in specific locations of the respiratory tract obtained by this test can be directly used to evaluate the delivery effect of drugs that target specific locations of the respiratory tract for treatment, such as drugs that need to be delivered to deep lung locations to treat diseases. Attached Figure Description

[0028] To more clearly illustrate the technical solutions of the embodiments of this utility model, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this utility model. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Among them:

[0029] Figure 1 This is a schematic diagram of the overall structure of the respiratory tract deposition distribution testing device for inhaled preparations according to this utility model.

[0030] Figure 2 This is a schematic diagram of the connection structure between the respiratory tract model unit and the airbag unit of the respiratory tract deposition distribution testing device for inhaled preparations according to this utility model.

[0031] Figure 3 This is a schematic diagram of a scenario where a breathing mask is connected during the respiratory tract deposition distribution test of an inhaled preparation according to this invention.

[0032] Figure 4This is a schematic diagram of the internal structure of the respiratory tract model unit of the respiratory tract deposition distribution testing device for inhaled preparations according to this utility model.

[0033] Figure 5 This is a schematic diagram of the filter assembly structure of the respiratory tract deposition distribution testing device for inhaled preparations according to the present invention.

[0034] Figure 6 This is a schematic diagram of a scenario where the present invention is used to test the respiratory tract deposition distribution of inhaled preparations with endotracheal intubation.

[0035] Figure 7 This is a schematic diagram of the airflow direction during the simulated inhalation process when the respiratory tract deposition distribution test of the present invention is used for inhaled preparations.

[0036] Figure 8 This is a schematic diagram of the airflow during the simulated exhalation process for testing the respiratory tract deposition distribution of inhaled formulations according to this invention.

[0037] Figure 9 This is a schematic diagram of a respiratory tract deposition distribution testing device for inhaled preparations according to another embodiment of the present invention.

[0038] Figure 10 This is a schematic diagram of a scenario where a breathing mask is connected during testing of the simplified testing device of this utility model.

[0039] Figure 11 This is a schematic diagram illustrating a scenario where the simplified testing device of this utility model is connected via endotracheal intubation.

[0040] Figure 12 This is a flowchart of the respiratory tract deposition distribution test method for inhaled formulations according to the present invention.

[0041] Figure 13 This is a schematic diagram of the aerodynamic particle size distribution of fine particles in Comparative Example 1.

[0042] Figure 14 This is a schematic diagram showing the deposition and distribution of the drug at various locations in the respiratory tract in Embodiment 1 of this utility model.

[0043] Figure 15 This is a schematic diagram showing the deposition and distribution of the drug at various locations in the respiratory tract in Embodiment 2 of this utility model.

[0044] Figure 16 This is a schematic diagram showing the deposition and distribution of the drug at various locations in the respiratory tract in Example 3 of this utility model. Detailed Implementation

[0045] To make the above-mentioned objectives, features and advantages of this utility model more apparent and understandable, the specific embodiments of this utility model will be described in detail below with reference to the accompanying drawings.

[0046] Many specific details are set forth in the following description in order to provide a full understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein. Those skilled in the art can make similar extensions without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0047] Secondly, the term "an embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that excludes other embodiments.

[0048] Secondly, this utility model is described in detail with reference to the schematic diagrams. When describing the embodiments of this utility model, for ease of explanation, the cross-sectional views illustrating the device structure may be partially enlarged, not adhering to the usual scale. Furthermore, the schematic diagrams are merely examples and should not limit the scope of protection of this utility model. In addition, actual manufacturing should include the three-dimensional spatial dimensions of length, width, and depth.

[0049] Figure 1 This is a schematic diagram of the overall structure of the respiratory tract deposition distribution testing device for inhaled preparations according to this utility model. Figure 2 This is a schematic diagram of the connection structure between the respiratory tract model unit and the airbag unit of the respiratory tract deposition distribution testing device for inhaled preparations according to this utility model. Figure 3 This is a schematic diagram of a scenario where a breathing mask is connected during the respiratory tract deposition distribution test of an inhaled preparation according to this invention. Figure 4 This is a schematic diagram of the internal structure of the respiratory tract model unit in the respiratory tract deposition distribution testing device for inhaled formulations according to this utility model. This application provides a respiratory tract deposition distribution testing device for inhaled formulations, such as... Figure 1 As shown, in one embodiment, the respiratory tract deposition distribution testing device includes a respiratory tract model unit 100, a ventilator system 300, and an airbag unit 200.

[0050] like Figure 2As shown, the respiratory tract model unit 100 includes a sealed container 101, a tracheal model 102 disposed within the sealed container 101, and a head model 103. The air inlet of the tracheal model 102 extends to the outside of the sealed container 101, and the air outlet of the head model 103 is connected to the air inlet of the tracheal model 102. Both the tracheal model 102 and the head model 103 are modeled based on real CT data and can be independent whole models or composed of segments; the specific configuration is not specifically limited. The tracheal model 102 is manufactured to mimic the bronchial hierarchy of a real human lung trachea. The structure of the tracheal model is a real human structure or a simplified version of a real human structure, thus facilitating biomimetic testing outside the human body. For example, the bronchial hierarchy of the tracheal model 102 ranges from 1 to 12 (considering both scientific validity and feasibility), and the head model 103 includes oral and nasal structures. The sealed container 101 is designed to resemble the human thoracic cavity and is used to encapsulate the tracheal model 102.

[0051] like Figure 3 As shown, the ventilator system 300 includes a ventilator 301, a connecting tubing connected to the ventilator 301, and a drug delivery device disposed on the connecting tubing. One end of the connecting tubing, away from the ventilator 301, is connected to the mouth and / or nose of the head model 103. For example, the end of the connecting tubing is connected to a mask, which covers the mouth and nose, or the end of the connecting tubing is inserted into the mouth or nose via a cannula. In this embodiment, the drug delivery device is a nebulizer W. In other embodiments, the drug delivery device can be other types of devices, such as liquid or solid drug delivery devices, etc., and is not limited here. The ventilator system 300 is used to realize the exhalation and inhalation process of the bionic human body and to deliver the test drug to the bionic respiratory tract model.

[0052] like Figure 4 As shown, the airbag unit 200 includes a filter assembly 201 and an airbag assembly 202 connected to the filter assembly 201. The end of the filter assembly 201 away from the airbag assembly 202 is connected to a sealed container 101. The airbag assembly 202 includes an airbag 202b that adaptively inflates and contracts during operation of the ventilator system 300. The filter assembly 201 filters test reagents contained in the gas inhaled or exhaled from the sealed container 101, allowing for continuous inhalation and exhalation. The airbag assembly 202 temporarily stores the filtered gas.

[0053] The respiratory tract deposition distribution testing device of this embodiment is equipped with an airbag unit 200 connected to the respiratory tract model unit 100. The airbag 202b of the airbag unit 200 can expand or contract adaptively in coordination with the operation of the ventilator 301 to realize the biomimetic human breathing function. This allows the respiratory tract model unit 100 to adapt to the operation of the ventilator 301 and simulate the usage scenario of the human body connected to the ventilator 301, thus realizing the function of the biomimetic ventilator assisting human lung breathing.

[0054] Furthermore, the deposited drug collected at the sealed container 101 and filter assembly 201 can be used to measure the drug in the deep lung region, and the deposited drug collected at the head model 103 can be used to measure the drug in the mouth, pharynx, and larynx region. Combined with the drug deposition measurement in the tracheal model, the drug distribution test in various regions of the respiratory tract can be realized, thereby improving the accuracy of respiratory drug distribution test. It is particularly suitable for tests that require understanding the drug deposition in the deep lung region.

[0055] It should be noted that the connecting tubing is a standard component of the ventilator, such as... Figure 3 As shown, it generally includes an inspiratory tubing 302 connected to the air supply end of the ventilator 301 and an expiratory tubing 303 connected to the air exhaust end of the ventilator 301. The ends of both the inspiratory tubing 302 and the expiratory tubing 303 away from the ventilator 301 are connected to an endotracheal tube 305 via a Y-tube 304. The end of the endotracheal tube 305 away from the Y-tube 304 is connected to a breathing mask 306. A filter 301a is also connected to the air exhaust end of the ventilator 301. A humidifier 302a and a nebulizer W are connected to the inspiratory tubing 302. The endotracheal tube 305 can be inserted into the oral or nasal structure of the head model 103 and is connected to the air intake end of the tracheal model 102. The breathing mask 306 is worn on the outside of the mouth and nose of the head model 103. The nebulizer W is connected to the end of the inhalation tubing 302 or the end of the Y-tube 304. The nebulizer W contains the prepared inhalation preparation, which is then nebulized and enters the tracheal model 102 with the airflow.

[0056] Figure 6 This is a schematic diagram illustrating a scenario where an endotracheal tube is connected during the respiratory tract deposition distribution test of an inhaled formulation, according to this invention. Figure 6 As shown, in another embodiment, one end of the endotracheal tube 305 is not equipped with a breathing mask 306, but is directly inserted into the oral cavity or nasal cavity of the head model 103.

[0057] The ventilator system 300 can be assembled using commercially available standard components. The ventilator 301 has two ports: an air supply port and an air exhaust port. The air supply port supplies air to the inspiratory tubing 302, Y-tube 304, endotracheal tube 305, and breathing mask 306; and the air exhaust port draws air from the expiratory tubing 303, Y-tube 304, endotracheal tube 305, and breathing mask 306. It should be noted that both the endotracheal tube 305 and the breathing mask 306 can be independently connected to the head model 103 for testing the distribution of respiratory tract deposits.

[0058] In one embodiment, the filter assembly 201 includes at least one filter membrane 201c-1, which allows gas to pass through while blocking the drug to be tested, so that the drug to be tested cannot enter the airbag 202b, thereby avoiding affecting the normal operation of the airbag.

[0059] like Figure 5 In the illustrated embodiment, the filter assembly 201 includes a first connecting cover 201a, a second connecting cover 201b, and a filter element 201c disposed between the first connecting cover 201a and the second connecting cover 201b. The first connecting cover 201a includes a first connecting pipe 201a-1 and a cap 201a-2 connected to the first connecting pipe 201a-1, with the two maintaining communication between their chambers. The second connecting cover 201b includes a second connecting pipe 201b-1 and a cover plate 201b-2 connected to the second connecting pipe 201b-1, with the chamber of the second connecting pipe 201b-1 extending through the cover plate 201b-2. The cover plate 201b-2 can be fitted and confined within the chamber of the cap 201a-2, forming an accommodating space M for placing the filter element 201c.

[0060] The inner wall of the cap 201a-2 is provided with a spiral limiting groove X, and the outer wall of the cover plate 201b-2 is provided with a connecting slider H; the connecting slider H can slide and be limited within the limiting groove X.

[0061] Specifically, the first connecting cover 201a and the second connecting cover 201b can be combined and connected. In the first connecting cover 201a, one end of the first connecting tube 201a-1 is connected into the connecting hole L and the connection is sealed. The cap 201a-2 is connected to the first connecting tube 201a-1, and the end of the cap 201a-2 away from the first connecting tube 201a-1 has a cavity. The cover plate 201b-2 is fitted and connected in the cavity, and one end of the second connecting tube 201b-1 is connected into the airbag 202b of the airbag assembly 202. It should be noted that there are various ways in which the cover plate 201b-2 is fitted and connected in the cavity, such as threaded engagement, engagement of protrusion and groove, snap-fit ​​structure, etc.

[0062] This solution uses the mating structure of a protrusion and a groove as an example for illustration. Figure 5As shown, at least two sets of spiral-shaped limiting grooves X are symmetrically or evenly arranged on the inner side wall of the cavity of the cap 201a-1. The opening of the limiting groove X is located at the end of the side wall of the cap 201a-1, while the other end of the limiting groove X is a transverse groove, which can be used for transverse fitting and limiting. Connecting sliders H corresponding to the number of limiting grooves X are provided on the circumferential side wall of the cover plate 201b-2. When the cover plate 201b-2 is placed into the cavity of the cap 201a-1, the connecting sliders H can enter along the opening of the limiting groove X and slide along the spiral-shaped limiting groove X, eventually sliding into the transverse groove, thus confining the cover plate 201b-2 within the cap 201a-1. At the same time, the chamber of the cap 201a-1 will contain the filter element 201c. The chamber space shrinks as the cover plate 201b-2 is screwed in. When the cover plate 201b-2 is in the final position, the chamber of the cap 201a-1 will form a receiving space M for placing the filter element 201c.

[0063] Furthermore, the filter element 201c includes a filter membrane 201c-1 and a sealing ring 201c-2 disposed on the outer ring of the filter membrane 201c-1. In addition, the filter element 201c also includes a support filter screen 201c-3, which is symmetrically distributed on both sides of the filter membrane 201c-1. The size of the filter element 201c is defined by the size of the accommodating space M. The filter membrane 201c-1 is preferably made of one or more of the following materials: glass fiber, nylon, polypropylene (PP), polytetrafluoroethylene (PTFE), mixed cellulose (MCE), and cellulose acetate (CA). The sealing ring 201c-2 is used to maintain the airtightness of the accommodating space M, ensuring that gas passing through the first connecting pipe 201a-1 and the second connecting pipe 201b-1 must pass through the filter membrane 201c-1. The purpose of providing support filters 201c-3 on both sides of the filter membrane 201c-1 is to protect the filter membrane 201c-1 and prevent it from malfunctioning if damaged. It should be noted that in this filter element 201c, the support filters 201c-3 may not be provided on both sides of the filter membrane 201c-1, or they may be replaced by other devices with the same filtration function.

[0064] Furthermore, the airbag assembly 202 also includes a clamping plate 202a, which has a hollow portion for mounting the airbag 202b. The air inlet end of the airbag 202b is connected to the filter assembly. Specifically, the air inlet end of the airbag 202b extends outside the clamping plate 202a and is connected to the end of the second connecting pipe 202b-1 away from the cover plate 201b-2. The airbag 202b is installed in the clamping cavity of the clamping plate 202a, both of which have elastic deformation capabilities. The inner cavity of the airbag 202b is kept in communication with the sealed container 101 through the filter assembly 201.

[0065] When subjected to positive air pressure from the ventilator system (i.e., simulating the human inhalation process), the air bag 202b inflates; when subjected to reverse air pressure (i.e., during exhalation), the air bag 202b deflates and contracts. It should be noted that the volume of the air bag assembly 202 can be selected, preferably 0.5L, 1L, 2L, or 3L. Furthermore, the air bag assembly 202 can be replaced with any device or apparatus capable of providing load to the ventilator system 300 and adjusting airway resistance and compliance. For example, the sealing container 101 can be made of an elastic material, allowing for volume adjustment like a human chest cavity. Further, the shape of the sealing container 101 can be selected, for example, as a single square, spherical, or lung-lobe-like shape, sealing the entire tracheal model 102. Alternatively, it can be a separate square, spherical, or lung-lobe-like shape, sealing each part of the tracheal model 102 individually.

[0066] In one embodiment, the tracheal model 102 includes a main trachea section 102a, a left tracheal section 102b connected to the main trachea section 102a, and a right tracheal section 102c. One end of the main tracheal section 102a extends outside the sealed container 101 and is connected to the head model 103. The tracheal model 102 is located inside the sealed container 101. The sealed container 101 includes a sealed box 101a, a sealing gasket 101b matching the opening of the sealed box 101a, and a sealing cap 101c. A connection hole L is provided on the side wall of the sealed box 101a (see...). Figure 2 The connecting hole L is connected to the filter assembly 201. The tracheal model 102 is supported inside the sealed container 101 by the support frame Z. The air inlet of the tracheal model 102 extends outside the sealed box 101a and is connected to the head model 103 or directly to the endotracheal tube 305 of the ventilator system 300. The exhaust of the tracheal model 102 is located inside the sealed box 101a. In one embodiment, the sealed box 101a adopts a square box structure. This box structure is modular, that is, the top of the box is open and equipped with a sealing cover 101c. Furthermore, in order to maintain good sealing, a sealing gasket 101b is added at the connection between the box and the cover. The advantage of the modular box structure is that the volume of the sealed box 101a can be adjusted, and the tracheal model 102 inside the sealed box 101a can be easily adjusted, such as the number of bronchial stages, the size of the bronchial tubes, the installation position, etc. The connection hole L on the side wall of the sealed box 101a is used to install the airbag unit 200.

[0067] Based on the aforementioned testing apparatus, it is essential to ensure a secure seal between the ventilator system 300 and the airway model unit 100 after connection before the deposition distribution of the inhaled formulation in the airway can be measured. When connected using an endotracheal tube 305, the end of the endotracheal tube 305 must pass through the oral cavity structure of the head model 103 and enter the main trachea of ​​the tracheal model 102. The balloon of the endotracheal tube 305, after inflation, should form a tight seal with the inner surface of the tracheal model 102. Similarly, the end of the endotracheal tube 305 must pass through the nasopharyngeal structure of the head model 103 and enter the main trachea of ​​the tracheal model 102. The balloon of the endotracheal tube 305, after inflation, should form a tight seal with the inner surface of the tracheal model 102. When connected using a breathing mask 306, the breathing mask 306 must be worn outside the oral and nasal structures of the head model 103, ensuring good contact between the mask edge and the head model 103 to maintain a seal.

[0068] Figure 7 This is a schematic diagram illustrating the airflow direction during the simulated inhalation process when testing the respiratory tract deposition distribution of inhaled formulations according to this invention. Figure 7 As shown, after the ventilator system 100 is connected to the test device, when simulating inhalation, the air supply end of the ventilator 301 blows air into the respiratory tract model unit 100, while the exhaust end is closed; the airflow passes through the nebulizer W and carries the atomized drug particles into the respiratory tract model unit 100, where they are deposited at various locations; the undeposited drug particles are filtered and deposited by the filter assembly 201, and the gas finally enters the cuff assembly 202, causing the cuff assembly 202 to expand elastically and generate load and airway resistance in the entire tubing system. The ventilator 301 detects the pressure generated and can automatically adjust the inhalation state according to parameters such as tidal volume and inspiratory pressure.

[0069] Figure 8 This is a schematic diagram illustrating the airflow during a simulated exhalation process for testing the respiratory tract deposition distribution of inhaled formulations according to this invention. When simulating exhalation, combined with the attached... Figure 8 When the air supply end of the ventilator 301 is closed and the exhaust end is opened, the air bag assembly 202 elastically contracts, and the gas inside the air bag 202b is compressed and discharged from the test system through the exhaust end of the respiratory tract model unit 100 and the ventilator system 300.

[0070] During one cycle of inhalation and exhalation, nebulized drug particles are deposited in various parts of the ventilator system 300, nebulizer W, respiratory tract model unit 100, and filter assembly 201, simulating the drug delivery process of the ventilator system 300; the deposition results can be further analyzed to obtain the drug deposition distribution in the respiratory tract.

[0071] Figure 9This is a schematic diagram of a respiratory tract deposition distribution testing device for inhaled formulations according to another embodiment of the present invention. Figure 9 As shown, in another embodiment, there are two sealed containers 101, one for the left trachea and one for the right trachea. Each sealed container 101 has a connection port for connecting a filter assembly 201. The end of the filter assembly 201 furthest from the sealed container 101 is connected to an outlet bronchus 104. The ends of both outlet bronchus 104 furthest from the filter assembly 201 are connected to a main pipe 105, which is connected to an airbag assembly 202. The respiratory model 100 in this embodiment is closer to a real lung, and because the two sealed containers 101 are each connected to a filter assembly 201, the deposited drug collected at the two filter assemblies 201 can better distinguish the drug distribution in the left and right lungs, providing corresponding data support for situations requiring information on the deep lung delivery volume in the left and right lungs.

[0072] Furthermore, this testing device can be simplified by omitting the sealed container 101 and the tracheal model 102, and directly connecting the filter assembly 201 to the output end of the head model 103. The testing process for this simplified device is the same as that for the complete testing device, and the test results can simulate the amount of drug delivered into the body (head model 103) by the nebulizer W. This testing process requires less work, and the results can be used for comparative experiments, providing valuable reference. It should be noted that when this simplified testing device is connected to the ventilator system 300, it can also be connected to the head model 103 using an endotracheal tube 305 and a breathing mask 306, as shown in the attached diagram. Figure 10 and Figure 11 As shown in the image.

[0073] Figure 12 This is a flowchart of the respiratory tract deposition distribution testing method for inhaled formulations according to the present invention. This application also provides a respiratory tract deposition distribution testing method for inhaled formulations, implemented using the respiratory tract deposition distribution testing device for inhaled formulations described in any of the above embodiments, such as... Figure 12 As shown, in one embodiment, the respiratory tract deposition distribution testing method includes the following steps:

[0074] Step S100: Start the ventilator 301 with preset ventilator parameters and run it for several cycles;

[0075] Step S200: Continue running the ventilator 301 and start the nebulizer W with preset nebulization parameters. The nebulizer W contains the drug to be tested.

[0076] Step S300: After the atomizer W has been in operation for a preset time, turn off the atomizer W.

[0077] Step S400: After turning off the nebulizer W, control the ventilator 301 to run for several cycles, and then turn off the ventilator 301.

[0078] Step S500: Separate the respiratory tract model unit 100, the filter component 201, and the air bag 202b.

[0079] In step S600, the amount of drug deposited in the respiratory model unit 100, the filter component 201 and the air bag 202b is measured to obtain the deposition distribution results.

[0080] The test medication in the nebulizer W is pre-prepared. Specifically, the medication should be loaded into the nebulizer W according to the product instructions or technical requirements. For example, the solution formulation for preparing the inhaled medication can be any one of the following two:

[0081] Prescription 1: Dissolve polymyxin B sulfate (calculated as matrix) in distilled or sterile water to obtain the test drug with a concentration of 10 mg / mL.

[0082] Prescription 2: Dissolve polymyxin B sulfate (calculated as matrix) in distilled or sterile water to obtain the test drug at a concentration of 5 mg / mL.

[0083] The working time of nebulizer W should be sufficient to guarantee the amount of active substance required for quantitative analysis. If the amount of active substance deposited in the respiratory model unit 100 is insufficient for quantitative analysis, the working time of nebulizer W can be extended; if the amount of active substance deposited in the respiratory model unit 100 is large, it will accumulate on the inner surface of the model to form droplets and flow, in which case the working time of nebulizer W can be shortened.

[0084] When determining the amount of deposited drug, the analytical methods specified under each product item are used to determine the amount of deposited drug in the components collected at each location, and the deposition distribution at each location is calculated.

[0085] Comparative Example 1

[0086] The method for determining the aerodynamic properties of fine particles of inhaled drugs is as follows:

[0087] Equipment and apparatus: A cascade impactor with 7 stages and 1 micropore collector (MOC) is used to collect the amount of drug deposited at different stages, and then high performance liquid chromatography is used to determine the collected drug.

[0088] Test conditions and parameters: The assembled impactor and L-shaped connecting pipe were kept at a constant temperature (5℃) in a constant temperature cooling cabinet. After the test was completed under the driving airflow, the test was carried out under a constant temperature in the cooling cabinet. The atomization time of the atomizing device was 3 minutes.

[0089] The determination was performed in accordance with the provisions of General Chapter 0951 of the 2020 edition of the Chinese Pharmacopoeia, Part IV, on the determination of the aerodynamic properties of fine particles in inhaled preparations.

[0090] The atomization of fine particles using a Gentec atomizer was performed, and the results are shown in Table 1 and 2. Figure 13 .

[0091] Table 1. Results of fine particle aerodynamic characteristics tested using a cascade impactor for Formula 1.

[0092] Atomization time, min 3 Delivered dose, mg 13.2(±0.3) Drug delivery dose per minute, mg / min 4.39(±0.11) FPD (fine mist amount less than 5μm), mg 7.54(±0.59) FPF (percentage of fine mist particles smaller than 5μm), % 57.2(±3.0) MMAD (median particle size), mm 4.44(±0.24) GSD (Geometric Standard Deviation) 1.85(±0.04) R 1(±0.01)

[0093] Example 1:

[0094] The respiratory model unit 100 using the aforementioned sealed container 101 was equipped with a Gentec piezoelectric nebulizer, model GUN-300-A adult type. Referring to the indications and recommended doses of polymyxin B via airway nebulization in the "Multidisciplinary Expert Consensus on the Rational Clinical Use of Polymyxin Antibiotics in China," the recommended dose of polymyxin B sulfate is 250,000–500,000 U. It was nebulized using a standard device and dissolved in 5 mL of distilled water (i.e., 5 mL of prescription 1 drug). During testing, the ventilator 301 was run 10 times in both steps S100 and S400, and the preset operating time of the Gentec nebulizer in step S300 was 11 minutes.

[0095] The respiratory tract model uses an Asian adult male model. The head model 103 includes the mouth and throat. The bronchial hierarchy of the lung and trachea model 102 is 5-7 levels, including the main trachea, main bronchus, right upper bronchus, right middle bronchus, right lower bronchus, left upper bronchus, and left lower bronchus.

[0096] The endotracheal intubation ventilation mode in the ventilator system was as follows: Mode A / C (assisted / controlled ventilation); Tidal volume: 500 mL; Respiratory rate: 15 bpm; Inspiratory time: 1.3 s; Positive end-expiratory pressure: 3 cmH2O. The deposition distribution of the nebulized drug in the respiratory tract was measured, and the results are shown in Table 2. Figure 14 .

[0097] Table 2 shows the results of testing the deposition and distribution characteristics of drug formulation 1 in the respiratory tract using the test scheme of this utility model.

[0098] Atomization time, min 11 Delivered dose (dose delivered to the respiratory tract), mg 8.00(±0.66) The drug delivery dose to the respiratory tract per minute, mg / min 0.73(±0.06) Deep lung delivery, mg 3.42(±0.43) Deep lung delivery as a percentage of total delivered dose, % 42.8(±2.3)

[0099] In summary, the aerodynamic characteristics of the fine particles of the nebulized drug (Formula 1) obtained by the cascade impactor test are compared with the deposition distribution characteristics in the biomimetic respiratory tract of this scheme.

[0100] This protocol provides the specific deposition distribution of nebulized medication within the ventilator system components and airway when the patient is supported by a ventilator system (300). Cascade impactor testing cannot assess the impact of airway system tubing, endotracheal intubation, and respiratory masks on drug delivery in actual clinical settings.

[0101] Furthermore, the deposition distribution at specific locations in the respiratory tract obtained through this test can be directly used to evaluate the delivery efficacy of drugs targeting specific respiratory therapeutic sites, such as drugs that need to be delivered to deep lung locations to treat diseases. These results cannot be directly obtained through cascade impactor testing.

[0102] Example 2

[0103] The only difference between this embodiment and Embodiment 1 is that a Gentec nebulizer was used to nebulize 10 mL of Prescription 2 medication, with a total nebulization time of 20 min. The results are shown in Table 3 and... Figure 15 .

[0104] Table 3 shows the results of testing the deposition and distribution characteristics of drug formulation 2 in the respiratory tract using the test scheme of this utility model.

[0105]

[0106]

[0107] Example 3

[0108] The only difference between this embodiment and Embodiment 1 is that the tidal volume in the ventilator parameters is 250 mL. The deposition distribution of the nebulized drug in the respiratory tract was measured, and the results are shown in Table 4. Figure 16 .

[0109] Table 4 shows the results of testing the deposition and distribution characteristics of drug formulation 1 in the respiratory tract using the test scheme of this utility model.

[0110] Atomization time, min 11 Delivered dose (dose delivered to the respiratory tract), mg 7.61(±0.6) Drug delivery dose to the respiratory tract per minute, mg / min 0.69(±0.06) Deep lung delivery, mg 4.13(±0.28) Deep lung delivery as a percentage of total delivered dose, % 54.2(±3.8)

[0111] Comparing the results of Example 1 and Example 2, using the same ventilator system parameters but different prescription drug concentrations, this invention can test the effect of different prescription drug concentrations on drug distribution within the respiratory tract. The test results are shown in Tables 2 and 3. Figure 14 and 15 .

[0112] Comparing the results of Examples 1 and 3, using the same prescription but different ventilator system parameters, this invention can test the effect of different ventilator system parameters on drug distribution in the respiratory tract. The test results are shown in Tables 2 and 4. Figure 14 and 16 .

[0113] It should be noted that the drug doses delivered to the respiratory tract in Tables 2 to 4 are based on the drug deposits collected from the mouth and throat area of ​​the head model 103, the trachea model 102, the sealed container 101, and the filter assembly 201. The deep lung delivery volume refers to the drug deposits in the sealed container 101 and the filter assembly 201.

[0114] It should be noted that the above embodiments are only used to illustrate the technical solution of this utility model and are not intended to limit it. Although this utility model has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solution of this utility model without departing from the spirit and scope of the technical solution of this utility model, and all such modifications or substitutions should be covered within the scope of the claims of this utility model.

Claims

1. A respiratory tract deposition distribution test device for an inhaled formulation, characterised in that, include: A respiratory tract model unit (100) includes a sealed container (101), a tracheal model (102) disposed within the sealed container (101), and a head model (103). The air inlet of the tracheal model (102) extends to the outside of the sealed container (101), and the air outlet of the head model (103) is connected to the air inlet of the tracheal model (102). A ventilator system (300) includes a ventilator (301), a connecting tubing connected to the ventilator (301), and a drug delivery device disposed on the connecting tubing, wherein one end of the connecting tubing away from the ventilator (301) is connected to the mouth and / or nose of the head model (103). An airbag unit (200) includes a filter assembly (201) and an airbag assembly (202) connected to the filter assembly (201), wherein one end of the filter assembly (201) remote from the airbag assembly (202) is connected to the sealed container (101), and the airbag assembly (202) includes an airbag (202b) that adaptively inflates and contracts when the ventilator system (300) is in operation.

2. A test device for respiratory tract deposition profile of inhaled formulations according to claim 1, characterized in that, The filter assembly (201) includes at least one filter membrane (201c-1) for passing gas and blocking the drug to be tested.

3. A test device for respiratory tract deposition profile of inhaled formulations according to claim 1, characterized in that, The airbag assembly (202) further includes a clamping plate (202a), which has a hollow portion for mounting the airbag (202b), and the air inlet end of the airbag (202b) is connected to the filter assembly.

4. A test device for respiratory tract deposition profile of inhaled formulations according to claim 1, characterized in that, The drug delivery device is an atomizing device.

5. A test device for respiratory tract deposition profile of an inhaled formulation according to any one of claims 1 to 4, wherein, The tracheal model (102) includes a main tracheal section (102a), a left tracheal section (102b) and a right tracheal section (102c) connected to the main tracheal section (102a), and one end of the main tracheal section extends out of the sealed container (101) and is connected to the head model (103).

6. The respiratory tract deposition distribution testing device for inhaled formulations according to claim 5, characterized in that, The tracheal model (102) is located inside the sealed container (101).

7. A test device for respiratory tract deposition profile of inhaled formulations according to claim 6, characterized in that, The sealed container (101) includes a sealed box (101a), a sealing gasket (101b) and a sealing cap (101c) that match the opening of the sealed box (101a); The sealing box (101a) has a connection hole (L) on its side wall, which is connected to the filter assembly (201).

8. A test device for respiratory tract deposition profile of inhaled formulations according to claim 6, characterized in that, The tracheal model (102) is supported within the sealed container (101) by a support frame (Z).

9. A test device for respiratory tract deposition profile of inhaled formulations according to claim 5, characterized in that, The number of the sealed containers (101) is 2, which are used to accommodate the left tracheal section (102b) and the right tracheal section (102c) respectively; Each of the sealed containers (101) is provided with a connection port for connecting the filter assembly (201). The end of the filter assembly (201) away from the sealed container (101) is connected to an air outlet branch pipe (104). The ends of the two air outlet branch pipes (104) away from the filter assembly (201) are connected to a main pipe (105). The main pipe (105) is connected to the airbag assembly (202).

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