Respiratory tract deposition distribution testing device and method for inhalation preparation

Abstract

The invention relates to the technical field of respiratory medicine physiological research, and discloses a respiratory tract deposition distribution testing device and method for an inhalation preparation, the testing device comprises a respiratory tract model unit, the respiratory tract model unit comprises a sealed container, a pulmonary trachea model and a head model, the air inlet end of the pulmonary trachea model extends to the outside of the sealed container, and the air outlet end of the head 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 the running parameters of the breathing machine, the function of assisting human body breathing of the bionic real breathing machine is achieved, and the deposition result of the bionic drug particles in the respiratory tract is accurately achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of respiratory medical physiology research, and particularly to a respiratory tract deposition distribution test device and a test method for inhalation preparations. Background Art

[0002] Inhalation administration is a drug delivery route for delivering drugs to treat respiratory or systemic diseases through a combination of a drug device. Inhalation preparations are affected by various factors such as the device, the preparation drug, and patient compliance. Therefore, in preclinical pharmaceutical research, it is necessary to conduct in vitro evaluation of inhalation preparation products. According to relevant regulations and guiding principles issued by the US FDA, the European EMA, and the CDE, the cascade impactor is the main method for testing in vitro indicators of inhalation preparations, that is, the aerodynamic particle size test. Only when the aerodynamic particle size is in the range of 1-5 μm can aerosol particles be inhaled and deposited in the lower respiratory tract. The Chinese Pharmacopoeia 0951 stipulates the test device for the aerodynamic properties of fine particles of inhalation preparations, including a two-stage impactor, a multi-stage impactor, and a new generation impactor (NGI).

[0003] The cascade impactor test method can obtain the aerodynamic particle size distribution results of the atomized drug, but cannot obtain the drug deposition distribution results of the inhalation preparation in the respiratory tract. Because there is no accurate inhalation drug deposition distribution result, a good in vivo and in vitro consistency evaluation result cannot be obtained. Moreover, the cascade impactor cannot simulate the use process of connecting the atomizing device to a ventilator, ignoring the influence of various main factors on drug delivery during the atomization process. The cascade impactor in vitro test method must use a constant flow rate, and the prior art cannot simulate the real breathing curve during the real drug administration process.

[0004] Moreover, the aerodynamic distribution results are generally used as a tool for preparation management evaluation in preclinical pharmaceutical research, and currently there is no direct relationship established between its results and clinical research results. For example, for the consistency evaluation of generic drugs, consistent in vitro test results of the cascade impactor do not guarantee consistent in vivo results. Therefore, in the development process of new drugs and generic drugs, existing methods, such as the cascade impactor, cannot accurately guide the conduct of clinical trials.

[0005] Most inhalation preparations atomize drugs through inhalation and enter the respiratory tract through the oral cavity. In the application in the intensive care unit (ICU), the atomization device needs to be connected to a ventilator for use. After the drug is atomized by the atomization device, it enters the patient's respiratory tract through the ventilator air circuit. This administration method is different from the use methods of other inhalation preparations, and its atomization process is affected by factors such as the atomization device, ventilator operating parameters, pipeline structure, intubation structure, mask structure, and mouthpiece structure. Especially for drugs used for antibacterial treatment through ventilator administration, there are no approved products for clinical use in China. There is an urgent need for a test platform and method for in vitro evaluation to assist the research and development and transformation of such drugs, and to provide a powerful tool for new drug review. Currently, the existing artificial lung model test equipment and methods are not systematic, do not involve the test scheme for inhalation preparations used under the ventilator system, and cannot accurately evaluate their respiratory tract deposition distribution. Summary of the Invention

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

[0007] In view of the problem that the existing artificial lung model test equipment and methods cannot directly connect the artificial lung model to the ventilator and realize the optimized use of the ventilator system function, the present invention is proposed.

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

[0009] To solve the above technical problems, the present invention provides the following technical solutions: A test device for the respiratory tract deposition distribution of inhalation preparations, comprising:

[0010] A respiratory tract model unit, which includes a sealed container, a lung trachea model and a head model arranged in the sealed container. The air inlet end of the lung trachea model extends to the outside of the sealed container, and the air outlet end of the head model is connected to the air inlet end of the lung trachea model;

[0011] A ventilator system, which includes a ventilator, a connecting pipeline connected to the ventilator, and a drug administration device arranged on the connecting pipeline. The end of the connecting pipeline away from the ventilator is connected to the mouth and / or nose of the head model;

[0012] An airbag unit, comprising a filtering component and an airbag component connected to the filtering component, one end of the filtering component away from the airbag component is connected to the sealed container, and the airbag component includes an airbag that expands and contracts adaptively when the ventilator system operates.

[0013] Optionally, the filtering component includes at least one layer of filter membrane, and the filter membrane is used to pass gas and block the drug to be tested.

[0014] Optionally, the airbag component further includes a splint, the splint is provided with a hollow part for installing the airbag, and the air inlet end of the airbag is connected to the filtering component.

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

[0016] Optionally, the lung trachea model includes a main trachea part, a left lung trachea part and a right lung trachea part connected to the main trachea part, and one end of the main trachea part extends outside the sealed container and is connected to the head model.

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

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

[0019] A connection hole is provided on the side wall of the sealed box, and the connection hole is connected to the filtering component.

[0020] Optionally, the lung trachea model is supported in the sealed container by a support frame.

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

[0022] Each of the sealed containers is provided with a connection port for connecting the filtering component. One end of the filtering component away from the sealed container is connected with an outlet branch pipe, and one ends of the two outlet branch pipes away from the filtering component are both connected to a main pipe, and the main pipe is connected to the airbag component.

[0023] Another object of the present invention is to provide a respiratory deposition distribution test method implemented by using the respiratory deposition distribution test device for inhalation preparations as described in any one of the above, including the following steps:

[0024] Start the ventilator with preset ventilator parameters and run several cycles;

[0025] Continue to run the ventilator and start the nebulizer with preset nebulization parameters. The nebulizer contains the drug to be tested;

[0026] Turn off the atomizer after it has been operating for a preset time;

[0027] After turning off the atomizer, control the ventilator to run for several cycles and then turn off the ventilator;

[0028] Separate the respiratory tract model unit, the filter component and the airbag;

[0029] Measure the amount of the deposited drug in the respiratory tract model unit, the filter component and the airbag to obtain a deposition distribution result.

[0030] Advantages of the present invention:

[0031] 1. The solution of the present invention can mimic the respiratory function of the human body, realizing that under the condition of assisted ventilation of the ventilator system, the respiratory tract model adapts to the operating parameters of the ventilator, and realizing the function of the bionic ventilator assisting the human lung to breathe.

[0032] 2. Compared with the existing cascade impactor equipment and testing methods, this solution has a physiological structure of the actual size of the respiratory tract model, including structures such as the mouth, pharynx, larynx, trachea and bronchi; the environment can be close to the actual clinical use scenario, and can accurately mimic the deposition result of drug particles in the respiratory tract; the regional deposition distribution of the drug in the bionic respiratory tract in the ventilator system can be obtained; the result is close to the actual human drug administration process, and can be used for the efficacy, pharmacokinetics and safety evaluation of new drugs and the consistency evaluation of generic drugs, as well as the efficacy evaluation of inhalation devices; it can provide accurate and reliable in vitro test results for laboratories, medical institutions, pharmaceutical companies, etc., replacing human experiments, for example, in special populations or extreme conditions, shortening the drug development cycle, increasing the possibility of R & D success, and saving development costs.

[0033] 3. Compared with the existing cascade impactor equipment and testing methods, this solution broadens the application scope of the existing methods. This solution can be used for the research of the whole process parameters of the deposition distribution in the human respiratory tract under different drug administration conditions, such as drugs, formulations, concentrations, tidal volumes, inhalation-exhalation ratios, different atomization devices, such as dry powder inhalers, pressurized metered-dose inhalers, soft mist inhalers, jet atomizers, mesh atomizers, ultrasonic atomizers, etc. large-scale parameters, providing key guidance for multiple parameters in the balance optimization during the development and future application of new drugs.

[0034] 4. The deposition distribution of the specific parts of the respiratory tract obtained by testing this solution can be directly used to evaluate the delivery effect of drugs targeting the treatment position of the respiratory tract, such as drugs that need to be delivered to the deep lung position to treat diseases. Description of the Drawings

[0035] To more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings. Among them:

[0036] Figure 1 It is a schematic diagram of the overall structure of the respiratory tract deposition distribution test device for inhalation preparations of the present invention.

[0037] Figure 2 It is a schematic diagram of the connection structure of the respiratory tract model unit and the airbag unit of the respiratory tract deposition distribution test device for inhalation preparations of the present invention.

[0038] Figure 3 It is a schematic diagram of the connection scenario with a breathing mask during the respiratory tract deposition distribution test for inhalation preparations of the present invention.

[0039] Figure 4 It is a schematic diagram of the internal structure of the respiratory tract model unit of the respiratory tract deposition distribution test device for inhalation preparations of the present invention.

[0040] Figure 5 It is a schematic diagram of the structure of the filter component of the respiratory tract deposition distribution test device for inhalation preparations of the present invention.

[0041] Figure 6 It is a schematic diagram of the connection scenario with a tracheal intubation during the respiratory tract deposition distribution test for inhalation preparations of the present invention.

[0042] Figure 7 It is a schematic diagram of the air flow direction during the simulated inhalation process in the respiratory tract deposition distribution test for inhalation preparations of the present invention.

[0043] Figure 8 It is a schematic diagram of the air flow during the simulated exhalation process in the respiratory tract deposition distribution test for inhalation preparations of the present invention.

[0044] Figure 9 It is a schematic diagram of the structure of the respiratory tract deposition distribution test device for inhalation preparations of another embodiment of the present invention.

[0045] Figure 10 It is a schematic diagram of the connection scenario with a breathing mask during the test of the simplified test device of the present invention.

[0046] Figure 11 It is a schematic diagram of the connection scenario with a tracheal intubation during the test of the simplified test device of the present invention.

[0047] Figure 12 It is a flowchart of the respiratory tract deposition distribution test method for inhalation preparations of the present invention.

[0048] Figure 13 Schematic diagram of the aerodynamic particle size distribution of the fine particles of Comparative Example 1.

[0049] Figure 14 Schematic diagram of the deposition distribution results of the drug of Example 1 of the present invention at various positions in the respiratory tract.

[0050] Figure 15 Schematic diagram of the deposition distribution results of the drug of Example 2 of the present invention at various positions in the respiratory tract.

[0051] Figure 16 Schematic diagram of the deposition distribution results of the drug of Example 3 of the present invention at various positions in the respiratory tract. Detailed implementation manners

[0052] In order to make the above objects, features and advantages of the present invention more obvious and understandable, the following will describe the detailed implementation manners of the present invention with reference to the accompanying drawings of the specification.

[0053] In the following description, many specific details are set forth in order to fully understand the present invention. However, the present invention can also be implemented in other ways different from those described herein. Those skilled in the art can make similar extensions without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0054] Secondly, the so-called "one embodiment" or "embodiment" herein refers to a specific feature, structure or characteristic that can be included in at least one implementation manner 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 separate or alternative embodiment that excludes other embodiments.

[0055] Furthermore, the present invention is described in detail with reference to the schematic diagrams. When detailing the embodiments of the present invention, for the sake of convenience of explanation, the cross-sectional views showing the device structure will be enlarged locally out of the general scale, and the schematic diagrams are only examples and should not limit the scope of protection of the present invention herein. In addition, in actual production, three-dimensional spatial dimensions including length, width and depth should be included.

[0056] Figure 1 Schematic diagram of the overall structure of the respiratory tract deposition distribution test device for the inhalation preparation of the present invention. Figure 2 Schematic diagram of the connection structure between the respiratory tract model unit and the airbag unit of the respiratory tract deposition distribution test device for the inhalation preparation of the present invention. Figure 3 Schematic diagram of the connection scenario with a breathing mask during the respiratory tract deposition distribution test for the inhalation preparation of the present invention. Figure 4This is a schematic diagram of the internal structure of the respiratory tract model unit of the respiratory tract deposition distribution test device for the inhalation preparation of the present invention. The present application provides a respiratory tract deposition distribution test device for inhalation preparations. As Figure 1 shown, in one embodiment, the respiratory tract deposition distribution test device includes a respiratory tract model unit 100, a ventilator system 300, and an airbag unit 200.

[0057] As Figure 2 shown, the respiratory tract model unit 100 includes a sealed container 101, a lung trachea model 102 and a head model 103 arranged in the sealed container 101. The intake end of the lung trachea model 102 extends to the outside of the sealed container 101, and the outlet end of the head model 103 is connected to the intake end of the lung trachea model 102. Both the lung trachea model 102 and the head model 103 are modeled based on real CT data, and can be independent integral models or segmented and combined. The specific composition form is not specifically limited. The lung trachea model 102 is manufactured according to the bronchial hierarchy range of the real human lung trachea. The structure of the lung trachea model is the real human structure or simplified based on the real human structure, so as to facilitate the bionic test outside the human body. For example, the bronchial hierarchy range of the lung trachea model 102 is from 1 to 12 levels (taking into account scientificity and feasibility), and the head model 103 has an oral structure and a nasal structure. The sealed container 101 is set with reference to the human chest cavity and is used to encapsulate the lung trachea model 102.

[0058] As Figure 3 shown, the ventilator system 300 includes a ventilator 301, a connecting pipeline connected to the ventilator 301, and a drug delivery device arranged on the connecting pipeline. The end of the connecting pipeline far from the ventilator 301 is connected to the mouth and / or nose of the head model 103. For example, the end of the connecting pipeline is connected to a mask that covers the mouth and nose, or the end of the connecting pipeline is inserted into the mouth or nose through a cannula. In this embodiment, the drug delivery device is an atomizer W. In other embodiments, the drug delivery device can also be other types of devices, such as liquid or solid drug delivery devices, etc., which are not limited here. The ventilator system 300 is used to realize the exhalation and inhalation processes of the bionic human body and send the test drug into the bionic respiratory tract model.

[0059] As Figure 4 shown, the airbag unit 200 includes a filtering component 201 and an airbag component 202 connected to the filtering component 201. The end of the filtering component 201 far from the airbag component 202 is connected to the sealed container 101. The airbag component 202 includes an airbag 202b that expands and contracts adaptively when the ventilator system 300 works. The filtering component 201 is used to filter the test drug contained in the gas inhaled or discharged from the sealed container 101, so that the inhalation process and the exhalation process can be carried out continuously. The airbag component 202 is used to temporarily store the filtered gas.

[0060] The respiratory deposition distribution testing device of this embodiment is provided with an airbag unit 200 connected to the respiratory model unit 100. The airbag 202b of the airbag unit 200 can adaptively expand or contract in coordination with the operation of the ventilator 301, thereby realizing the respiratory function of the bionic human body, so that the respiratory model unit 100 can adapt to the operation of the ventilator 301, and can simulate the use scenario of the human body connected to the ventilator 301, thereby realizing the function of the bionic ventilator to assist the human lung breathing.

[0061] Furthermore, by collecting the deposited drugs in the sealed container 101 and the filter component 201, the drug in the deep lung region can be measured. By collecting the deposited drugs in the head model 103, the drug in the mouth, pharynx and throat region can be measured. Combined with the drug deposition measurement in the lung trachea model, the drug distribution test in various areas of the respiratory tract can be achieved, thereby improving the accuracy of the respiratory tract drug distribution test, which is particularly suitable for tests that require understanding of the drug deposition situation in the deep lung position.

[0062] It should be noted that the connecting pipe is a common component of the ventilator, such as Figure 3 As shown, it can generally include an inhalation line 302 connected to the air supply end of the ventilator 301 and an exhalation line 303 connected to the exhaust end of the ventilator 301. The ends of the inhalation line 302 and the exhalation line 303 away from the ventilator 301 are connected to the endotracheal tube 305 through a Y-shaped tube 304, and the end of the endotracheal tube 305 away from the Y-shaped tube 304 is connected to a breathing mask 306. The exhaust end of the ventilator 301 is also connected to a filter 301a. A humidifier 302a and a nebulizer W are connected to the inhalation line 302. The endotracheal tube 305 can be inserted into the oral cavity structure or nasal cavity structure of the head model 103, and is connected to the air inlet end of the lung trachea 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 pipeline 302 or the end of the Y-tube 304. The nebulizer W contains the prepared inhalation preparation, which enters the lung trachea model 102 along with the airflow after being atomized.

[0063] Figure 6 This is a schematic diagram of the scene of connecting the endotracheal tube when testing the respiratory tract deposition distribution of the inhalation preparation of the present invention. Figure 6 As shown, in another embodiment, one end of the endotracheal tube 305 is not provided with a breathing mask 306, but is directly inserted into the oral cavity or nasal cavity of the head model 103.

[0064] The ventilator system 300 can be assembled using commercially available standard components. Among them, the ventilator 301 has two ports, an air supply end and an exhaust end. The ventilator 301 supplies air from the air supply end to the inhalation tube 302, the Y-shaped tube 304, the tracheal intubation 305, and the breathing mask 306; and extracts air from the exhalation tube 303, the Y-shaped tube 304, the tracheal intubation 305, and the breathing mask 306 through the exhaust end. It should be noted that both the tracheal intubation 305 and the breathing mask 306 can be independently connected to the head model 103 for testing the deposition distribution in the respiratory tract.

[0065] In one embodiment, the filter assembly 201 includes at least one layer of filter membrane 201c-1, and the filter membrane 201c-1 is used to pass gas and block the drug to be tested, so that the drug to be tested cannot enter the airbag 202b, to avoid affecting the normal operation of the airbag.

[0066] As Figure 5 In the illustrated embodiment, the filter assembly 201 includes a first connection cover 201a, a second connection cover 201b, and a filter element 201c disposed between the first connection cover 201a and the second connection cover 201b. The first connection cover 201a includes a first connection tube 201a-1 and a cap 201a-2 connected to the first connection tube 201a-1, and the two maintain a communicating chamber. The second connection cover 201b includes a second connection tube 201b-1 and a cover plate 201b-2 connected to the second connection tube 201b-1, and the chamber of the second connection tube 20b-1 penetrates the cover plate 201b-2. The cover plate 201b-2 can be fitted and limited within the chamber of the cap 201a-2, and a receiving space M for placing the filter element 201c is formed.

[0067] A spiral limiting groove X is provided on the inner cavity side wall of the cap 201a-2, and a connecting slider H is provided on the outer side wall of the cover plate 201b-2; the connecting slider H can be fitted and slid and limited within the limiting groove X.

[0068] Specifically, the first connection cover 201a and the second connection cover 201b can be combined and connected. In the first connection cover 201a, one end of its first connection tube 201a-1 is inserted into the connection hole L and the connection is sealed; the cap 201a-2 is in communication with the first connection tube 201a-1, and the end of the cap 201a-2 away from the first connection tube 201a-1 has a chamber; the cover plate 201b-2 is fitted and connected within the chamber, and one end of the second connection tube 201b-1 is inserted into the airbag 202b of the airbag assembly 202; it should be noted that there are various ways for the cover plate 201b-2 to be fitted and connected within the chamber, such as screw fit, convex block and chute fit, snap structure, etc.

[0069] This solution will be described by taking the cooperation structure of the convex block and the chute as an example. As Figure 5As shown in the figure, on the inner side wall of the cavity of the cap 201a-1, there are symmetrically or evenly arranged no less than two sets of spiral limiting grooves X, and the notch 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. On the circumferential side wall of the cover plate 201b-2, there are connecting sliders H corresponding to the number of the limiting grooves X. When the cover plate 201b-2 is placed into the cavity of the cap 201a-1, the connecting slider H can enter along the notch of the limiting groove X and slide along the spiral limiting groove X, and finally slide into the transverse groove, and the cover plate 201b-2 is limited within the cap 201a-1. At the same time, a filter element 201c is placed in the cavity of the cap 201a-1, and the cavity space shrinks as the cover plate 201b-2 is screwed in. When the cover plate 201b-2 is in the final position, a receiving space M for placing the filter element 201c is formed in the cavity of the cap 201a-1.

[0070] Furthermore, the filter element 201c includes a filter membrane 201c-1 and a sealing ring 201c-2 arranged on the outer ring of the filter membrane 201c-1. In addition, the filter element 201c further includes a supporting filter mesh 201c-3, and the supporting filter meshes 201c-3 are symmetrically distributed on both sides of the filter membrane 201c-1. Among them, the size of the filter element 201c is limited by the size of the receiving space M. The material of the filter membrane 201c-1 is preferably one or more of glass fiber, nylon, polypropylene (PP), polytetrafluoroethylene (PTFE), mixed cellulose (MCE), and cellulose acetate (CA). The sealing ring 201c-2 is used to maintain the sealing of the receiving space M, so that the 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 arranging the supporting filter meshes 201c-3 on both sides of the filter membrane 201c-1 is to protect the filter membrane 201c-1 and prevent the filter membrane 201c-1 from failing after being damaged. It should be noted that in this filter element 201c, the supporting filter meshes 201c-3 may not be arranged on both sides of the filter membrane 201c-1, or replaced by other devices with the same filtering function.

[0071] Furthermore, the airbag assembly 202 further includes a clamping plate 202a, and the clamping plate 202a is provided with a hollow part for installing the airbag 202b, and the air inlet end of the airbag 202b is connected to the filtering assembly. Specifically, the air inlet end of the airbag 202b extends outside the clamping plate 202a and is connected to one end of the second connecting pipe 202b-1 away from the cover plate 201b-2. Among them, the airbag 202b is installed in the clamping cavity of the clamping plate 202a, and both of them have the ability of elastic deformation. The inner cavity of the airbag 202b is kept in communication with the sealed container 101 through the filtering assembly 201.

[0072] When under the positive air pressure of the ventilator system (i.e., simulating the human inhalation process), the airbag 202b intakes air and expands; when under the reverse air pressure (i.e., exhalation process), the airbag 202b exhausts air and contracts. It should be noted that the volume of the airbag assembly 202 can be selected, and the preferred volumes are 0.5L, 1L, 2L, and 3L. In addition, the airbag assembly 202 can be replaced, and any device or component that can provide a load for the ventilator system 300 and achieve the adjustment of airway resistance and compliance is acceptable. For example, the sealed container 101 can be made of an elastic material so that its volume can be adjusted like the human chest cavity. Further, the shape of the sealed container 101 can be selected. For example, it can be a whole square, a spherical-like shape, or a lung lobe-like shape, and the lung trachea model 102 is sealed as a whole. Or it can be a split square, a spherical-like shape, or a lung lobe-like shape, and each part of the lung trachea model 102 is separately sealed.

[0073] In one embodiment, the lung trachea model 102 includes a main trachea part 102a, a left lung trachea part 102b connected to the main trachea part 102a, and a right lung trachea part 102c. One end of the main trachea part 102a extends outside the sealed container 101 and is connected to the head model 103. The lung trachea 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 cover 101c. A connection hole L (see Figure 2 ) is provided on the side wall of the sealed box 101a, and the connection hole L is connected to the filtering component 201. The lung trachea model 102 is supported inside the sealed container 101 by a support frame Z. The intake end of the lung trachea model 102 extends outside the sealed box 101a and is connected to the head model 103 or directly connected to the tracheal intubation 305 of the ventilator system 300. The exhaust end of the lung trachea model 102 is located inside the sealed box 101a. In one embodiment, the sealed box 101a adopts a square box structure, and this box structure is a combined type, that is, the top of the box is open and is equipped with a sealing cover 101c. Further, to maintain good sealing performance, a sealing gasket 101b is added at the connection between the box body and the box cover. The advantage of the combined box structure is that the volume of the sealed box 101a can be adjusted, and at the same time, it is convenient to adjust the lung trachea model 102 inside the sealed box 101a, such as the number of bronchi in the lung trachea, the size of the bronchi, 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.

[0074] Based on the above test device, it is necessary to ensure the integrity of the seal between the ventilator system 300 and the respiratory tract model unit 100 after connection, and then the deposition distribution of the inhalation preparation in the respiratory tract can be measured. When connecting with the tracheal intubation 305, the end of the tracheal intubation 305 needs to enter the main trachea position of the lung trachea model 102 through the oral structure of the head model 103. After the balloon of the tracheal intubation 305 expands, it is in close contact with the inner surface of the lung trachea model 102 to form a seal; the end of the tracheal intubation 305 needs to enter the main trachea part of the lung trachea model 102 through the nasopharyngeal structure of the head model 103. After the balloon of the tracheal intubation 305 expands, it is in close contact with the inner surface of the lung trachea model 102 to form a seal. When connecting with the breathing mask 306, the breathing mask 306 needs to be worn outside the oral structure and nasal structure of the head model 103, and the contact between the mask edge and the head model 103 should be kept good to maintain the seal.

[0075] Figure 7 This is a schematic diagram of the air flow direction during the simulated inhalation process for the respiratory tract deposition distribution test of the inhalation preparation of the present invention. As Figure 7 shown, after the ventilator system 100 is connected to the test device, when simulating the inhalation state, the air supply end of the ventilator 301 blows air into the respiratory tract model unit 100, and at the same time the exhaust end is closed; the air flow passes through the nebulizer W and carries the atomized drug particles into the respiratory tract model unit 100 and deposits at various positions; the undeposited drug particles are filtered and deposited by the filter assembly 201, and the gas finally enters the airbag assembly 202, causing the airbag assembly 202 to expand elastically and generating load and airway resistance in the entire pipeline system. The ventilator 301 detects the pressure generated by it and can automatically adjust the inhalation state according to parameters such as tidal volume and inspiratory-expiratory pressure.

[0076] Figure 8 This is a schematic diagram of the air flow during the simulated exhalation process for the respiratory tract deposition distribution test of the inhalation preparation of the present invention. When simulating the exhalation state, combined with the attached Figure 8 , the air supply end of the ventilator 301 is closed, and at the same time the exhaust end is opened. The airbag assembly 202 contracts elastically, and the gas in the airbag 202b is compressed and discharged out of the test system through the respiratory tract model unit 100 and the exhaust end of the ventilator system 300.

[0077] During one cycle of inhalation and exhalation, the atomized drug particles are deposited in various parts of the ventilator system 300, the nebulizing device W, the respiratory tract model unit 100, and the filter assembly 201, simulating the drug delivery process of the ventilator system 300 for inhaled drugs; the deposition results can be further analyzed to obtain the deposition distribution of the drug in the respiratory tract.

[0078] Figure 9 This is a schematic structural diagram of the test device for the respiratory tract deposition distribution test of the inhalation preparation according to another embodiment of the present invention. AsFigure 9 As shown, in another embodiment, the number of sealed containers 101 is 2, which are respectively used to accommodate the left lung tracheal part and the right lung tracheal part. Each sealed container 101 is provided with a connection port for connecting the filtration component 201. One end of the filtration component 201 away from the sealed container 101 is connected with an outlet branch pipe 104, and one ends of the two outlet branch pipes 104 away from the filtration component 201 are both connected to the main pipe 105, and the main pipe 105 is connected with the airbag component 202. The respiratory tract model 100 of this embodiment is closer to the real lung. And because the two sealed containers 101 are respectively connected with the filtration components 201, the deposited drugs collected at the two filtration components 201 can better distinguish the drug distribution conditions of the left lung and the right lung, and can provide corresponding data support for the situation where it is necessary to understand the deep lung delivery amounts of the left lung and the right lung respectively.

[0079] Furthermore, this test device can also be simplified, that is, the sealed container 101 and the lung trachea model 102 are omitted, and the filtration component 201 is directly connected to the output end of the head model 103. The test process of this simplified device can be the same as that of the complete test device, and its test result can simulate the amount of drug delivered into the body (head model 103) by the nebulizer W. This test process has a small workload and this result can be used for comparative tests and has reference significance. It should be noted that when this simplified test device is connected to the ventilator system 300, the tracheal intubation 305 and the breathing mask 306 can also be respectively used to connect with the head model 103, as shown in the appendix Figure 10 and Figure 11 shown.

[0080] Figure 12 This is a flowchart of the respiratory tract deposition distribution test method for inhalation preparations of the present invention. The present application also provides a respiratory tract deposition distribution test method for inhalation preparations, which is implemented by using the respiratory tract deposition distribution test device of any of the above embodiments, as shown in Figure 12 shown. In one embodiment, the respiratory tract deposition distribution test method includes the following steps:

[0081] Step S100, start the ventilator 301 with preset ventilator parameters and run for several cycles;

[0082] Step S200, continue to run the ventilator 301 and start the nebulizer W with preset atomization parameters. The nebulizer W contains the drug to be tested;

[0083] Step S300, turn off the nebulizer W after the nebulizer W works for a preset time;

[0084] Step S400, after turning off the nebulizer W, control the ventilator 301 to run for several cycles, and then turn off the ventilator 301;

[0085] Step S500, separate the respiratory tract model unit 100, the filtering component 201 and the airbag 202b;

[0086] Step S600, measure the amount of the deposited drug in the respiratory tract model unit 100, the filtering component 201 and the airbag 202b to obtain the deposition distribution result.

[0087] The drug to be tested in the nebulizer W is pre-prepared. Specifically, load the drug into the nebulizer W according to the product instruction manual or product technical requirements. For example, choose any one of the following two solution formulations for preparing the inhaled drug solution:

[0088] Prescription 1: Dissolve polymyxin B sulfate (calculated based on the matrix) in distilled water or sterile water to obtain a drug to be tested with a concentration of 10 mg / mL.

[0089] Prescription 2: Dissolve polymyxin B sulfate (calculated based on the matrix) in distilled water or sterile water to obtain a drug to be tested with a concentration of 5 mg / mL.

[0090] The working time of the nebulizer W should ensure the amount of the active substance required for quantitative analysis. If the amount of the active substance deposited in the respiratory tract model unit 100 cannot meet the requirements of quantitative analysis, the working time of the nebulizer W can be extended; if the amount of the active substance deposited in the respiratory tract model unit 100 is relatively large and droplets are formed and flow on the inner surface of the model, the working time of the nebulizer W can be shortened.

[0091] When measuring the amount of the deposited drug, use the analysis method specified in each variety item to measure the amount of the deposited drug in the components at each position, and calculate the deposition distribution at each position.

[0092] Comparative Example 1

[0093] The method for measuring the aerodynamic characteristics of the fine particles of the inhaled drug is as follows:

[0094] Equipment device: Use a cascade impactor with 7 stages and 1 micro-orifice collector (MOC) to collect the drug deposition amounts at different levels of the drug, and then use high performance liquid chromatography to measure the collected drug.

[0095] Test conditions and parameters: Keep the assembled impactor and the L-shaped connecting pipe at a constant temperature in a constant temperature (5°C) cooling cabinet. After the test is completed under the driving air flow, keep the constant temperature state in the cooling cabinet for testing. The atomization time of the atomization device is 3 min.

[0096] Measure according to the method for measuring the aerodynamic characteristics of the fine particles of the inhalation preparation in General Chapter 0951 of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition.

[0097] Atomize using a Gentec nebulizer and detect the aerodynamic characteristics of fine particles in its atomization prescription 1. The results are shown in Table 1 and Figure 13 .

[0098] Table 1 Results of the aerodynamic characteristics of fine particles tested by a cascade impactor for Prescription 1

[0099] Atomization time, min 3 Delivered dose, mg 13.2(±0.3) Drug delivered dose per minute, mg / min 4.39(±0.11) FPD (fine particle dose < 5μm), mg 7.54(±0.59) FPF (fine particle fraction < 5μm), % 57.2(±3.0) MMAD (mass median aerodynamic diameter), mm 4.44(±0.24) GSD (geometric standard deviation) 1.85(±0.04) R 1(±0.01)

[0100] Example 1:

[0101] For the respiratory tract model unit 100 with the above-mentioned one sealed container 101, the selected nebulizer W is: Gentec piezoelectric nebulizer generator, model GUN-300-A adult type. Referring to the indications and recommended doses of polymyxin antibiotics for aerosol inhalation in the airway in the "Multi-disciplinary Expert Consensus on the Rational Clinical Application of Polymyxin Antibiotics in China", the recommended dose of polymyxin B sulfate is 250,000 - 500,000 U, atomized with a conventional device and dissolved in 5 mL of distilled water (i.e., 5 mL of Prescription 1 drug). During the test, the ventilator 301 in steps S100 and S400 both ran in cycles 10 times, and the preset working time of the Gentec nebulizer in step S300 was 11 min.

[0102] The respiratory tract model uses an Asian adult male model. The head model 103 includes the oral and laryngeal parts. The bronchial hierarchy of the lung 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.

[0103] In the ventilator system, the tracheal intubation ventilation method, and the ventilator parameters are: mode A / C (assist / control ventilation); tidal volume: 500 mL; respiratory rate: 15 bpm; inspiratory time: 1.3 s; positive end-expiratory pressure: 3 cmH2O. Detect the deposition distribution of its atomized drug in the respiratory tract. The results are shown in Table 2 and Figure 14 .

[0104] Table 2 Results of the deposition distribution characteristics of Prescription 1 drug in the respiratory tract tested by the test scheme of the present invention

[0105] Atomization time, min 11 Drug delivered to the respiratory tract dose, mg 8.00(±0.66) Drug delivered to the respiratory tract dose per minute, mg / min 0.73(±0.06) Deep lung delivery amount, mg 3.42(±0.43) Proportion of deep lung delivery in total delivered dose, % 42.8(±2.3)

[0106] In summary, compare the aerodynamic characteristics of fine particles of the atomized drug (Prescription 1) obtained by cascade impactor testing and the deposition distribution characteristics results in the bionic respiratory tract of this scheme.

[0107] This scheme can provide the specific deposition distribution of the atomized drug at various positions in the ventilator system components and the respiratory tract under the support of the ventilator system 300 for patients. Cascade impactor testing cannot evaluate the influence of the respiratory tract system pipeline, tracheal intubation, breathing mask, etc. on drug delivery in actual clinical practice.

[0108] Furthermore, the deposition distribution of specific respiratory tract locations obtained by this method can be directly used to evaluate the delivery effect of drugs with targeted respiratory tract treatment locations, such as drugs that need to be delivered to deep lung locations to treat diseases. These results cannot be directly obtained by cascade impactor testing.

[0109] Example 2

[0110] The difference between this example and Example 1 is that a total of 10 mL of prescription 2 drug was atomized using a Gentec atomizer, and the total atomization time was 20 min. The results are shown in Tables 3 and Figure 15 .

[0111] Table 3 Results of the deposition and distribution characteristics of the drug in the respiratory tract of prescription 2 tested using the test scheme of the present invention

[0112] Atomization time, min 20 Drug delivered to the respiratory tract dose, mg 39.2(±3.6) Drug delivered to the respiratory tract dose per minute, mg / min 1.96(±0.18) Deep lung delivery amount, mg 31.3(±2.6) Proportion of deep lung delivery in total delivered dose, % 79.9(±7.1)

[0113] Example 3

[0114] 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 atomized drug in the respiratory tract was detected, and the results are shown in Tables 4 and Figure 16 .

[0115] Table 4 Results of the deposition and distribution characteristics of the drug in the respiratory tract of prescription 1 tested using the test scheme of the present invention

[0116] Atomization time, min 11 Drug delivered to the respiratory tract dose, mg 7.61(±0.6) Drug delivered to the respiratory tract dose per minute, mg / min 0.69(±0.06) Deep lung delivery amount, mg 4.13(±0.28) Proportion of deep lung delivery in total delivered dose, % 54.2(±3.8)

[0117] Comparing the results of Example 1 and Example 2, using the same ventilator system parameters and different prescription drug concentrations, the scheme of the present invention can test the influence of different prescription drug concentrations on the distribution of drugs in the respiratory tract. The test results are shown in Tables 2 and 3. Figure 14 and 15 .

[0118] Comparing the results of Example 1 and Example 3, using the same prescription and different ventilator system parameters, the scheme of the present invention can test the influence of different ventilator system parameters on the distribution of drugs in the respiratory tract. The test results are shown in Tables 2 and 4. Figure 14 and 16 .

[0119] It should be noted that the drug doses delivered to the respiratory tract in Tables 2 to 4 are obtained by collecting the deposited drugs in the oral and throat areas of the head model 103, the lung and trachea model 102, the sealed container 101 and the filter component 201, and the deep lung delivery amount refers to the deposited drugs in the sealed container 101 and the filter component 201.

[0120] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention, and they should all be covered within the scope of the claims of the present invention.

Claims

1. A respiratory deposition distribution test device for inhalation preparations, characterized in that, Comprising: A respiratory tract model unit (100), which includes a sealed container (101), a lung trachea model (102) and a head model (103) arranged in the sealed container (101). The intake end of the lung trachea model (102) extends to the outside of the sealed container (101), and the outlet end of the head model (103) is connected to the intake end of the lung trachea model (102); A ventilator system (300), which includes a ventilator (301), a connecting pipeline connected to the ventilator (301), and a drug administration device arranged on the connecting pipeline. The end of the connecting pipeline away from the ventilator (301) is connected to the mouth and / or nose of the head model (103); An airbag unit (200), which includes a filtering component (201) and an airbag component (202) connected to the filtering component (201). The end of the filtering component (201) away from the airbag component (202) is connected to the sealed container (101), and the airbag component (202) includes an airbag (202b) that expands and contracts adaptively when the ventilator system (300) operates.

2. The respiratory tract deposition distribution testing device for inhalation preparations according to claim 1, wherein, The filtering component (201) includes at least one layer of filter membrane (201c-1), and the filter membrane (201c-1) is used to pass gas and block the drug to be tested.

3. The respiratory tract deposition distribution test device for inhalation preparations according to claim 1, characterized in that The airbag component (202) further includes a splint (202a), and the splint (202a) is provided with a hollow part for installing the airbag (202b), and the intake end of the airbag (202b) is connected to the filtering component.

4. The respiratory tract deposition distribution testing device for inhalation preparations according to claim 1, characterized in that, The drug administration device is an atomizing device.

5. The respiratory tract deposition distribution testing device for inhalation preparations according to any one of claims 1-4, characterized in that, The lung trachea model (102) includes a main trachea part (102a), a left lung trachea part (102b) and a right lung trachea part (102c) connected to the main trachea part (102a). One end of the main trachea part extends to the outside of the sealed container (101) and is connected to the head model (103).

6. The respiratory tract deposition distribution testing device for inhalation preparations according to claim 5, wherein, The lung trachea model (102) is located in the sealed container (101).

7. The respiratory tract deposition distribution testing device for inhalation preparations according to claim 6, characterized in that, The sealed container (101) includes a sealed box (101a), a sealing gasket (101b) and a sealing cover (101c) that match the opening part of the sealed box (101a); A connection hole (L) is arranged on the side wall of the sealed box (101a), and the connection hole (L) is connected to the filtering component (201).

8. The respiratory tract deposition distribution test device for inhalation preparations according to claim 6, wherein, The lung trachea model (102) is supported in the sealed container (101) through a support frame (Z).

9. The respiratory tract deposition distribution testing device for inhalation preparations according to claim 5, characterized in that The number of the sealed containers (101) is 2, which are respectively used to accommodate the left lung trachea part (102b) and the right lung trachea part (102c); Each sealed container (101) is provided with a connection port for connecting the filtering component (201). The end of the filtering component (201) away from the sealed container (101) is connected with an outlet branch pipe (104). The ends of the two outlet branch pipes (104) away from the filtering component (201) are both connected to a main pipe (105), and the main pipe (105) is connected to the airbag component (202).

10. A method for testing respiratory deposition distribution implemented by using the respiratory deposition distribution testing device for inhalation preparations according to any one of claims 1 to 9, characterized in that Including the following steps: Start the ventilator (301) with preset ventilator parameters and run several cycles; Continue to run the ventilator (301) and start the nebulizer (W) with preset nebulization parameters. The nebulizer (W) contains the drug to be tested; Turn off the nebulizer (W) after it has been working for a preset time; After turning off the nebulizer (W), control the ventilator (301) to run several cycles, and then turn off the ventilator (301); Separate the respiratory tract model unit (100), the filter component (201), and the airbag (202b); Measure the amount of the drug deposited in the respiratory tract model unit (100), the filter component (201), and the airbag (202b) to obtain the deposition distribution result.

Images