Delivery particle collecting device for in-vitro research and evaluation of inhalation preparation

Abstract

The invention belongs to the field of medicine product manufacturing, relates to manufacturing and quality control of inhalation preparation medicine products, and provides a drug delivery particle collecting device used in inhalation preparation in-vitro research and evaluation. By optimizing the structure of the device, the provided drug delivery particle collecting device is not only suitable for collecting and measuring the traditional delivery dosage, but also especially suitable for applying the delivered drug particles to in-vitro dissolution evaluation; the medicine particles collected by the device provided by the invention can still keep extremely high dissolution curve similarity under different medicine deposition amounts (the similarity factor f2 of the optimal device can reach 90.6). On the basis, the influence of the medicine deposition amount on the dissolution rate can be avoided, and the product quality of the inhaled preparation medicine can be evaluated more objectively, so that the product research and development and quality control of the inhaled preparation new medicine or the imitated medicine can be smoothly promoted.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical product manufacturing, relates to the manufacturing and quality control of inhalation preparation pharmaceutical products, and particularly relates to a drug delivery particle collection device used in in vitro research and evaluation of inhalation preparations. Background Art

[0002] Unlike oral solid preparations, the pharmacopoeia currently does not specify the dissolution determination method for inhalation preparations. Although there is still controversy as to whether the critical quality attributes (CQA) of inhalation preparations need to be evaluated by dissolution, with the rise of generic inhalation preparation research, especially for some complex inhalation preparations (such as powder inhalers containing excipients, suspension aerosols or nebulized inhalation suspensions, etc.), the dissolution method has become an important in vitro research method for in vitro-in vivo correlation (IVIVC) research; and, since the particle size of the active pharmaceutical ingredient (API) in an inhalation preparation is usually related to its dissolution rate, the dissolution method is also commonly used to: 1) evaluate whether the API particle size in the reference preparation and the homemade preparation is consistent; 2) evaluate the particle size change of the API during the production process or stability placement (storage) of the inhalation preparation.

[0003] In addition, inhalation preparations are usually drug-device combined products. When administering the drug, a device is required to deliver the drug into the human body, and the dissolution assay needs to detect the drug delivered by the device (i.e., the delivered dose of the inhaled drug). However, establishing a stable and repeatable sample collection method is one of the difficulties in the dissolution assay of inhalation preparations. According to the purpose of the dissolution study, in the in vitro and in vivo correlation (IVIVC) study, it is necessary to further divide the delivered dose into several parts according to the particle size and collect them separately. The collection of this part of the dissolution sample usually requires the use of a cascade impactor, such as the Anderson cascade impactor (ACI) or the next generation cascade impactor (NGI), combined with a specially designed collection device.

[0004] For example, patent document US11499904B2 uses a collection plate with circular holes and a sealing assembly to collect drug particles at each level of NGI and perform dissolution measurement. However, the collection method in this patent cannot make the drug particles evenly deposited and distributed on the filter membrane. Moreover, as the amount of drug deposition increases, the aggregation between drug particles becomes more serious, which will slow down the dissolution rate of the drug during dissolution testing. For example, patent document CN108027303B and patent application document CN114829898A disclose that a specially designed external collecting device can be used in conjunction with NGI to realize the collection and dissolution determination of drug particles in the layer group (such as layer 2 and below) of NGI. Although these patents solve the problem that drug particles cannot be evenly deposited and distributed on the filter membrane, the method described in patent document CN108027303B requires modification of the nozzle structure of the NGI device, and requires special tools to remove the external collecting device from the NGI device, which increases the difficulty of operation and reduces the sample collection efficiency. The external collecting device described in patent application document CN114829898A has many structural components and requires a special locking device for sealing connection. The purpose of this design is to facilitate the removal of the filter membrane that has collected drug particles from the device.

[0005] At the same time, another purpose of the dissolution determination study is to collect the entire delivered dose of the inhaled drug for the research on the quality of the preparation, but there is no relevant patent report at present; at the same time, the delivered dose of the inhaled preparation is one of the CQA of this type of preparation. It has been tried to use the pharmacopoeia method to detect the delivery dose uniformity device (DUSA) to collect dissolution samples, and the filter membrane that collected the drug was subjected to dissolution testing. The results showed that the dissolution rate of the drug slowed down with the increase of the amount of drug collected on the filter membrane. This phenomenon is also often reported in the literature on the dissolution method of inhaled drugs. The reason may be that the drug particles form aggregates on the filter membrane with the airflow instead of being evenly dispersed on the filter membrane. With the increase of the deposition amount (such as the increase of the number of aerosols or the extension of the collection time of the nebulizer), the aggregation of drug particles becomes more serious, resulting in inconsistent contact between drug particles distributed at different positions and the dissolution medium, thereby affecting the dissolution rate of the drug. On the one hand, compared with other dosage forms, the delivered dose of inhalation preparations itself fluctuates greatly. Even if only the same dosage units are collected during dissolution sampling, this introduces the influence of drug deposition fluctuations on dissolution rate in the dissolution test, which may mask the dissolution difference caused by the change (difference) in the API particle size in the preparation itself. On the other hand, the devices used to collect the delivered doses of aerosols, powder sprays and nebulizers in inhalation preparations in the pharmacopoeia are different, and the filter membrane diameters are also different, which increases the difficulty of operation during dissolution sampling, and the dissolution results of different preparations of the same active pharmaceutical ingredient (API) cannot be compared.

[0006] Aerodynamic particle size distribution (APSD) is also one of the CQAs of inhalation preparations, and NGI devices are often used for this inspection item. Although using a full-level NGI device to detect APSD can provide more detailed hierarchical distribution data and important characteristic data such as mass median aerodynamic particle size (MMAD) and geometric standard deviation (GSD), the testing process is time-consuming and labor-intensive, and requires high skills and proficiency from the operator. In view of this, the IPAC-RS organization proposed a simplified impactor test (AIM) for NGI devices and recommended it to regulatory agencies for quality control (QC) testing of inhalation preparations; although this method has not yet become a pharmacopoeia method, literature has reported that the results of full-level NGI device testing and AIM testing are comparable. Currently, there are commercial AIM solutions for NGI devices (such as Copley's collection kit, and NGI equipped with this collection kit is also called Reduced NGI). However, compared with conventional testing of NGI devices, AIM requires separating the NGI device's cover with an embedded interstage airway from the sealing component with a nozzle before and after each test, and installing the collection kit (filter membrane support base, filter membrane and retaining ring) into (or removing it from) the nozzle corresponding to the particle size range to be examined, which increases the complexity of the operation. Summary of the invention

[0007] The object of the present invention is to provide a drug delivery particle collection device used in in vitro research and evaluation of inhalation preparations, which can achieve that the drug particles delivered by the drug delivery device are uniformly deposited on the filter membrane along with the airflow in the collection device, so that the fluctuation of the deposition amount of the drug on the filter membrane will not affect the dissolution rate of the drug during dissolution detection.

[0008] A delivery particle collection device for in vitro research and evaluation of inhalation preparations comprises an inlet mechanism, a middle airway and a filter membrane support base which are connected in sequence. When the present invention is in use, the inlet mechanism is used to connect the middle airway with the mouthpiece of the drug delivery device. When assembled, the inlet mechanism is installed at the upper end of the middle airway, and the middle airway is installed at the upper end of the filter membrane support base. A curved surface structure airway is provided in the middle airway, and an airflow channel connected to the middle airway is provided in the filter membrane support base. The airway wall of the curved surface structure airway is a smoothly transitioned curved surface. The airflow channel can be in any shape such as a straight cylinder, a funnel, or a curved surface. A filter membrane support net for installing the filter membrane is also provided at the air inlet end of the airflow channel. The filter membrane support net can be an integrated structure with the filter membrane support base, or it can be a separately provided component. When the membrane support net is a separate component, the membrane support net can be directly pressed between the middle airway and the membrane support base when the middle airway and the membrane support base are assembled; and in order to facilitate the installation of the membrane support net, a circular step for the membrane support net to be installed can also be set at the air inlet end of the airflow channel or the outlet end of the curved structure airway. The membrane support net is directly installed on the circular step when it is installed, and when the middle airway and the membrane support base are assembled, the membrane support net is pressed and fixed on the circular step. Of course, in order to facilitate the precise installation of the membrane support net, the circular step can also be replaced by other structures, such as the matching structure of the card block and the card slot. In the present invention, by designing the curved structure airway into a curved shape, it is beneficial for the drug to be evenly deposited on the filter membrane along with the airflow.

[0009] Furthermore, the diameter of the curved surface structure airway first gradually increases from top to bottom, and then gradually decreases, that is, the maximum diameter of the curved surface structure airway is located in the middle of the curved surface structure airway.

[0010] Furthermore, the diameter of the air inlet end of the curved structure airway is larger than the diameter of the air outlet end of the curved structure airway. The air inlet end of the curved structure airway is the end connected to the inside of the inlet mechanism, and the outlet end of the curved structure airway is the end connected to the airflow channel.

[0011] Furthermore, the axial length of the curved surface structure airway is 55 to 85 mm. Preferably, the axial length of the curved surface structure airway is 65 to 85 mm. Preferably, the length of the curved surface structure airway is 65 mm.

[0012] Furthermore, the axial distance from the maximum diameter of the middle part of the curved structure airway to the air inlet end of the curved structure airway is 12-14 mm, preferably 13-13.7 mm, and more preferably, the axial distance from the maximum diameter of the middle part of the curved structure airway to the airway entrance is 13 mm.

[0013] Furthermore, the maximum diameter of the middle part of the curved surface structure airway is 52 mm, and the diameter of the air inlet end of the curved surface structure airway is 50 mm.

[0014] Furthermore, the diameter of the airway outlet of the curved structure is equal to the diameter of the air inlet of the airflow channel, both of which are preferably 35 mm, so that the medicine can smoothly enter the airflow channel after being deposited on the filter membrane, avoiding backflow of the airflow after passing through the filter membrane.

[0015] Furthermore, in order to facilitate the assembly and disassembly of the inlet mechanism, the filter membrane support base and the middle airway, the middle airway and the inlet mechanism, as well as the middle airway and the filter membrane support base are detachably connected; preferably, the middle airway and the inlet mechanism, as well as the middle airway and the filter membrane support base are threaded or snap-connected, and the specific connection method between the middle airway and the inlet mechanism, as well as the middle airway and the filter membrane support base can be selected according to actual conditions.

[0016] Furthermore, in order to ensure the sealing between the inlet mechanism and the middle airway, and between the middle airway and the filter membrane support base, a sealing ring and / or a sealing gasket are also installed between the middle airway and the inlet mechanism, and between the middle airway and the filter membrane support base; specifically, only a sealing ring can be installed between the inlet mechanism and the middle airway, and between the middle airway and the filter membrane support base, and only a sealing gasket can be installed between the inlet mechanism and the middle airway, and between the middle airway and the filter membrane support base, and between the inlet mechanism and the middle airway, and between the middle airway and the filter membrane support base The sealing ring and the sealing gasket are installed at the same time. Of course, the sealing ring can also be installed between the inlet mechanism and the middle air duct, and the sealing gasket can be installed between the middle air duct and the filter membrane support base. The sealing ring and the sealing gasket can also be installed between the inlet mechanism and the middle air duct, and the sealing ring can be installed between the middle air duct and the filter membrane support base. That is, under the premise of ensuring the sealing between the inlet mechanism and the middle air duct, and between the middle air duct and the filter membrane support base, the installation method of the sealing ring and the sealing gasket between the middle air duct and the inlet mechanism, and between the middle air duct and the filter membrane support base is not fixed. The sealing ring and the sealing gasket are both made of rubber, and the sealing ring is an O-ring. When the inlet mechanism, the middle air duct and the filter membrane support base are assembled, the sealing ring and / or the sealing gasket are pressed and installed on the end face of the inlet mechanism or the end face of the middle air duct or the end face of the filter membrane support base. When the inlet mechanism, the middle air duct and the filter membrane support base are assembled, the gaps between the inlet mechanism and the middle air duct, and between the middle air duct and the filter membrane support base are closed by the sealing ring and / or the sealing gasket to avoid leakage in the gaps between the inlet mechanism and the middle air duct, and between the middle air duct and the filter membrane support base.

[0017] Furthermore, the filter membrane support base is also provided with a connecting mechanism that cooperates with the DUSA device base, so that after the assembly of the present invention is completed, the present invention can be directly connected to the DUSA device base through the filter membrane support base, and then further simply connected to the vacuum pump through the DUSA device base for rapid use.

[0018] Furthermore, a connector for connecting to a vacuum pump is provided at the bottom outlet of the filter membrane base, so that the filter membrane support base can be directly and simply connected to the vacuum pump for rapid use.

[0019] Furthermore, the connecting mechanism is a limit locking groove provided on the outer wall of the filter membrane support base, and the limit locking groove is adapted to the clamping block on the DUSA device base, which not only enables the filter membrane support base and the DUSA device base to be quickly clamped through the limit locking groove and the clamping block during assembly, thereby achieving a quick connection between the filter membrane support base and the DUSA device base, but also enables the filter membrane support base and the DUSA device base to be quickly separated when disassembly is required, making the present invention more convenient to use.

[0020] Furthermore, the limiting locking groove is located on the outer wall of the filter membrane support base, the limiting locking groove is L-shaped, the lower end of the vertical section of the limiting locking groove is flush with the lower end surface of the filter membrane support base, and the horizontal section of the limiting locking groove extends along the circumferential direction of the filter membrane support base, so that the lower end of the vertical section of the limiting locking groove is open. When it is necessary to assemble the membrane filter support base and the DUSA device base, the membrane filter support base is gradually inserted into the DUSA device base. During the process of inserting the membrane filter support base into the DUSA device base, the clamping block on the DUSA device base is gradually inserted into the vertical section of the limit locking groove. When the membrane filter support base is fully inserted into the DUSA device base, the clamping block on the DUSA device base enters the horizontal section of the limit locking groove. At this time, the membrane filter support base and the DUSA device base produce relative movement, so that the clamping block on the DUSA device base gradually enters the end of the horizontal section of the limit locking groove, so that when the membrane filter support base and the DUSA device base move along the axial direction, the clamping block on the DUSA device base cannot be separated from the limit locking groove, thereby locking the membrane filter support base and the DUSA device base, thereby realizing the assembly of the membrane filter support base and the DUSA device base. When it is necessary to separate the filter membrane support base from the DUSA device base, the filter membrane support base or the DUSA device base is rotated in the reverse direction, and then the filter membrane support base is pulled out from the DUSA device base.

[0021] Furthermore, the inlet mechanism includes a nozzle adapter and a standard interface which are interconnected. The standard interface is in the shape of a cap, and the outer wall of the standard interface is in the shape of a stepped shaft. The nozzle adapter is sleeved on the standard interface. The large-diameter end cover of the standard interface is arranged on the middle airway, and the standard interface is connected to the middle airway.

[0022] Furthermore, the inlet mechanism further includes an elbow joint, the standard interface and the middle airway are connected via the elbow joint, the inner diameter of the outlet end of the elbow joint is equal to the inner diameter of the air inlet end of the middle airway, and the inner diameter of the air inlet end of the elbow joint is equal to the inner diameter of the outlet end of the standard interface. Preferably, the standard interface and the elbow joint can be designed as an integrated molding, and of course, the standard interface and the elbow joint can also be designed as a split structure.

[0023] Furthermore, since different specific drug varieties have corresponding structural forms of drug delivery devices that are different, multiple nozzle adapters are required to match them during the test process. There are more than two types of nozzle adapters, and different types of nozzle adapters have different nozzle adaptation structures corresponding to delivery devices of different types of inhalation preparations. Multiple different types of nozzle adapters share a standard interface, which facilitates the collection of delivery doses of aerosols, powder aerosols and nebulized inhalers in inhalation preparations for dissolution testing.

[0024] Furthermore, the inlet mechanism can also be an NGI perforated collection plate that cooperates with the NGI device. When the collection plate is installed on the middle airway, the present invention can be used as a collection device for drug particles in a specific particle size range through the NGI perforated collection plate in conjunction with the NGI device, so that the drugs collected on the filter membrane can be used for AIM detection of the NGI device.

[0025] When the present invention is used in conjunction with an NGI device, by adopting an NGI perforated collection plate instead of a standard interface, drug particles in a specific particle size range of an inhalation preparation can be collected for simplified impactor detection of the NGI device, thereby realizing the collection of drug particles in the layer group (layer 3 and below, layer 4 and below, or layer 5 and below) of the NGI device. These drugs collected on the filter membrane are mainly used to study the drug deposition amount in a specific particle size range.

[0026] Furthermore, in order to minimize the contact area between the membrane support net and the filter membrane during installation, the membrane support net includes a cross frame and a ring, there are one or more rings, the center of the ring coincides with the center of the cross frame, the ring is installed on the cross frame, and the extended end of the cross frame is fixed to the membrane support base, so that the membrane support net can support the filter membrane while avoiding the formation of drug particle aggregation due to the airflow preferentially passing through the non-contact area.

[0027] The beneficial effects of the present invention are:

[0028] 1. The present invention can achieve uniform deposition of drug particles delivered by the drug delivery device on the filter membrane along with the airflow in the collection device through structural optimization, so that fluctuations in the deposition amount of the drug on the filter membrane will not affect the dissolution rate of the drug during dissolution testing.

[0029] 2. In the present invention, by setting the interior of the middle airway into a curved structure airway, and connecting the filter membrane support base for installing the filter membrane at the lower end of the middle airway, when the present invention and the DUSA device collect pharmaceutical sample particles under the same conditions, the pharmaceutical sample particles collected by the DUSA device are visible as dark red small particles on the filter membrane, while the pharmaceutical sample particles collected by the present invention are basically invisible as dark red small particles on the filter membrane. That is, when the pharmaceutical sample particles are collected by the present invention, the aggregation between sample particles is significantly reduced, and the sample is more evenly distributed on the filter membrane. At the same time, after comparison, the dissolution rate of the drug particles collected by the DUSA device for 1 press and 2 presses was significantly slowed down with the increase of the drug deposition amount on the filter membrane in the DUSA device, and the similarity factor between the two was 60.9. The fluctuation of the drug deposition amount on the filter membrane in the present invention did not affect its dissolution rate, and the similarity factor between the two was significantly increased to 90.6, which was significantly improved compared with the dissolution result f2 of the DUSA device. In addition, the present invention also maintained a good recovery rate of 101.4%.

[0030] 3. The present invention adopts a modular design. By switching the nozzle adapters and module components for different inhalation dosage forms, the delivered dose of aerosols, powder aerosols and nebulized inhalers in the inhalation preparations can be easily collected and used for dissolution testing without having to switch between the collection devices specified in the pharmacopoeia corresponding to the dosage forms. Different detection purposes can be achieved and the diameter of the filter membrane for collecting the drug is guaranteed to be consistent. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The accompanying drawings illustrate exemplary embodiments of the present invention and together with the description serve to explain the principles of the present invention. These drawings are included to provide a further understanding of the present invention and are incorporated in and constitute a part of this specification.

[0032] Figure 1 It is a schematic diagram of the structure of device A (DUSA device);

[0033] Figure 2 Schematic diagram of the structure of device B (straight tube M), in which a is an exploded view, b is a cross-sectional view of each component, and c is a cross-sectional view in an assembled state;

[0034] Figure 3 Schematic diagram of the structure of device C (straight cylinder L + membrane support), in which a is an exploded view, b is a cross-sectional view of each component, and c is a cross-sectional view in an assembled state;

[0035] Figure 4 Schematic diagram of the structure of device D (funnel), in which a is an exploded view, b is a cross-sectional view of each component, and c is a cross-sectional view in an assembled state;

[0036] Figure 5Schematic diagram of the structure of device E (funnel + membrane support), in which a is an exploded view, b is a cross-sectional view of each component, and c is a cross-sectional view in an assembled state;

[0037] Figure 6 Schematic diagram of the structure of device F1 (curved surface S + membrane support), in which a is an exploded view, b is a cross-sectional view of each component, and c is a cross-sectional view in an assembled state;

[0038] Figure 7 Schematic diagram of the structure of device F2 (curved surface M + membrane support), in which a is an exploded view, b is a cross-sectional view of each component, and c is a cross-sectional view in an assembled state;

[0039] Figure 8 Schematic diagram of the structure of device F3 (curved surface L + membrane support), in which a is an exploded view, b is a cross-sectional view of each component, and c is a cross-sectional view in an assembled state;

[0040] Fig. 9 Schematic diagram of the structure of device G1 (curved surface S+membrane support+bend joint), in which a is an exploded view, b is a cross-sectional view of each component, and c is a cross-sectional view in an assembled state;

[0041] Fig.10 Schematic diagram of the structure of device G2 (curved surface M+membrane support+bend joint), in which a is an exploded view, b is a cross-sectional view of each component, and c is a cross-sectional view in an assembled state;

[0042] Fig.11 Schematic diagram of the structure of device G3 (curved surface L+membrane support+bend joint), in which a is an exploded view, b is a cross-sectional view of each component, and c is a cross-sectional view in an assembled state;

[0043] Fig.12 It is a schematic diagram of the structure of the device H (curved surface M+membrane support+NGI perforated collecting plate), in which a is an exploded view, b is a cross-sectional view of each component, and c is a cross-sectional view in the assembled state;

[0044] Reference numerals in the figure: 1-nozzle adapter, 11-shoulder reduction, 2-standard interface, 3-middle airway, 31-straight structure airway, 31'-curved structure airway, 4-sealing ring, 5-DUSA device base, 51-clamping block, 6-filter membrane support base, 61-filter membrane support net, 62-limiting locking groove, 63-air flow channel, 7-sealing pad, 8-elbow joint, 9-NGI perforated collection tray.

[0045] Fig.13 1 is a comparison diagram of the collection filter membrane distribution of the curcumin inhalation aerosol in test example A, a is the collection filter membrane of device A (DUSA device), and b is the collection filter membrane of device F2 (curved surface M+membrane support);

[0046] Fig.14These are the in vitro dissolution curves of the collected drug particles of the fluticasone propionate inhalation aerosol in test example B, a is the in vitro dissolution curve of 1 press and 2 presses collected by device A (DUSA device), and b is the in vitro dissolution curve of 1 press and 2 presses collected by device F2 (curved surface M+membrane support).

[0047] Fig.15 These are the in vitro dissolution curves of the collected drug particles of the salmeterol and fluticasone inhalation powder in test example C, a is the in vitro dissolution curve of 1 press and 2 presses collected by device A (DUSA device), and b is the in vitro dissolution curve of 1 press and 2 presses collected by device G2 (curved surface M+membrane support+bend joint). DETAILED DESCRIPTION

[0048] The present invention will be further described in detail below in conjunction with the accompanying drawings and implementations. It is to be understood that the specific implementations described herein are only used to explain the relevant content, rather than to limit the present invention. It is also necessary to explain that, for ease of description, only the parts related to the present invention are shown in the accompanying drawings.

[0049] It should be noted that, in the absence of conflict, the embodiments and features of the embodiments of the present invention can be combined with each other. The present invention will be described in detail below with reference to the accompanying drawings and in combination with the embodiments.

[0050] Unless otherwise specified, the abbreviations used in the present invention are generally understood in accordance with the industry.

[0051] The following abbreviations appearing in the present invention have the following meanings:

[0052] IVIVC: In vitro-In vivo Correlation

[0053] API: Active Pharmaceutical Ingredient

[0054] ACI: Andersen Cascade Impactor, Anderson Cascade Impactor

[0055] NGI: Next Generation Impactor

[0056] APSD: Aerodynamic Particle Size Distribution, aerodynamic particle size distribution

[0057] CQA: Critical Quality Attributes

[0058] DUSA: Dosage Unit Sampling Apparatus

[0059] MMAD: Mass Median Aerodynamic Distribution, mass median aerodynamic diameter

[0060] GSD: Geometric Standard Deviation, geometric standard deviation

[0061] QC: Quality Control

[0062] AIM: Abbreviated Impactor Measurement, simplifies impactor detection

[0063] MOC: Micro-Orifice Collector, micro-orifice collector.

[0064] 1. Examples of the collection device involved in the present invention

[0065] 1. Device A - DUSA device:

[0066] This device is included in the chapter 0111 on inhalation preparations in the Pharmacopoeia of the People's Republic of China, Part IV, 2020 Edition. Figure 1 As shown, it includes a base with a stainless steel mesh for placing a filter membrane, a sample collection tube with two sealing end caps, and a nozzle adapter.

[0067] The DUSA device is used to collect and measure the "uniformity of delivered dose" of "inhaled aerosol" (the dose released from the outside of the device is the delivered dose, and the degree of difference between the delivered dose measured multiple times and the average value is the uniformity of delivered dose). Specifically, after the two ends of the DUSA device are connected to a vacuum pump, the inhaled aerosol to be tested is started and the drug is collected by pressing and ejecting, the filter membrane is removed and dissolved and cleaned with an appropriate solvent, the cleaning liquid is combined and diluted to a certain volume, and the drug content in the cleaning liquid is determined by an analytical method. This is repeated multiple times to calculate and determine the uniformity of delivered dose.

[0068] The DUSA device is designed to collect the total amount of drugs delivered by aerosol, and the collected drugs need to be dissolved in a good solvent before further testing. Therefore, it only needs to intercept and enrich all the drugs, and does not pay attention to the influence of the particle size of the particles delivered by aerosol. It has been verified and confirmed by the present invention that the drug particles collected by the DUSA device are seriously aggregated. Although this particle aggregation does not affect the measurement of the consistency of the total amount delivered for the purpose of the pharmacopoeia, if it is used for in vitro dissolution evaluation for in vitro research evaluation, its dissolution rate will significantly slow down with the increase of drug deposition, and it cannot correctly reflect the influence of different particle sizes of the delivered drugs on in vitro dissolution. This situation will be further illustrated in the test examples of the present invention later.

[0069] In view of the shortcomings of the DUSA device, the present invention has made structural optimization to form the following exemplary improved devices. These different improved devices have different effects in collecting drug particles required for in vitro dissolution evaluation, which will be exemplified in the subsequent test examples for verification and comparison:

[0070] 2. Device B: Straight M

[0071] like Figure 2 As shown, the improved example device B is adapted for inhalation of aerosols, including a mouthpiece adapter 1, a standard interface 2 and a middle airway 3 connected in sequence. The air inlet end of the mouthpiece adapter 1 is designed to be adapted to a metered dose inhalation aerosol (MDI), and in particular, the air inlet end of the mouthpiece adapter 1 is designed with a yielding shoulder 11 that fits the side wall of the metered dose inhalation aerosol (MDI). The mouthpiece adapter 1 is sleeved on the standard interface 2, and the sleeve connection form allows an air gap between the two. A threaded connection is adopted between the standard interface 2 and the middle airway 3, and a sealing ring 4 is provided at the threaded connection, and the sealing ring 4 is an O-ring. The interior of the middle airway 3 is provided with a straight cylinder structure airway 31 with an inner diameter of 35 mm (abbreviated as "straight cylinder M", and the straight cylinder structure airway with an inner diameter of 50 mm of the device C is simply recorded as "straight cylinder L" for distinction). A limit locking groove 62 is also provided on the outer wall of the middle airway 3 to cooperate with the DUSA device base 5.

[0072] When the device B is used, similar to the use of the DUSA device, a 55mm circular filter membrane is placed in the DUSA device base 5, and then the middle airway 3 and the DUSA device base 5 are locked together through the limiting locking groove 62. At this time, the circular filter membrane is pressed and fixed in the DUSA device base 5 by the middle airway 3.

[0073] 3. Device C: Straight tube L + membrane support

[0074] like Figure 3As shown, the improved example device C is a further optimization based on the device B, which attempts to improve the collection effect of drug particles by expanding the diameter of the straight-tube structure airway 31 of the middle airway 3.

[0075] Except for the differences described below, the rest of the structure of device C is consistent with that of device B.

[0076] The device C has a newly designed middle air channel 3, and a straight cylinder structure air channel 31 (abbreviated as "straight cylinder L") with an inner diameter of 50 mm is provided inside the middle air channel 3.

[0077] The air inlet end of the middle airway 3 of the device C is threadedly connected to the standard interface 2, and the outlet end of the middle airway 3 is also threadedly connected to the filter membrane support base 6 (abbreviated as "membrane support"). The inside of the filter membrane support base 6 is provided with an air flow channel 63, and the diameter of the air inlet end of the air flow channel 63 is equal to the diameter of the outlet end of the middle airway 3, both of which are 55mm. The diameter of the outlet end of the air flow channel 63 is equal to the channel in the DUSA device base 5, both of which are 35mm, and the middle part of the air flow channel 63 has a smooth transition. The air inlet end of the air flow channel 63 of the filter membrane support base 6 is also provided with a filter membrane support net 61, and the diameter of the filter membrane support net 61 is 50mm. The threaded connection between the middle airway 3 and the filter membrane support base 6 is provided with a sealing ring 4 and a sealing gasket 7, the sealing ring 4 is an O-ring, and the sealing gasket 7 is a silicone sealing gasket. The outer wall of the filter membrane support base 6 is also provided with a limit locking groove 62 that is connected with the clamping block 51 on the DUSA device base 5. Since the device C is connected to the DUSA device base 5 through the filter membrane support base 6, there is no need to design a limiting locking groove 62 on the outer side wall of the middle airway 3 of the device C.

[0078] When the device C is used, the middle airway 3 and the filter membrane support base 6 are disassembled, the filter membrane is placed on the filter membrane support net 61, and then the middle airway 3 and the filter membrane support base 6 are reassembled, and the filter membrane is pressed and fixed on the filter membrane support net 61 by the middle airway 3.

[0079] 4. Device D: Funnel

[0080] like Figure 4 As shown, the improved example device D is a further optimization based on the device B, which attempts to improve the collection effect of drug particles by changing the airway structure shape of the middle airway 3.

[0081] Except for the differences described below, the rest of the structure of device D is consistent with that of device B.

[0082] A funnel-shaped airway (abbreviated as "funnel") is provided inside the middle airway 3 of the device D. The diameter of the outlet end of the funnel-shaped airway is equal to the channel in the DUSA device base 5, both of which are 35 mm, and the diameter of the air inlet end of the funnel-shaped airway is 50 mm. The diameter of the funnel-shaped airway gradually decreases from top to bottom, presenting a funnel shape.

[0083] When the device D is used, similar to the use of the DUSA device, a 55mm circular filter membrane is placed in the DUSA device base 5, and then the middle airway 3 and the DUSA device base 5 are locked together through the limit locking groove 62. At this time, the circular filter membrane is pressed and fixed in the DUSA device base 5 by the middle airway 3.

[0084] 5. Device E: Funnel + membrane support

[0085] like Figure 5 As shown, the improved example device E is a further optimization based on the device D, which attempts to improve the collection effect of drug particles by further adding a filter membrane support base 6 on the basis of changing the airway structure shape of the middle airway 3.

[0086] Except for the differences described below, the rest of the structure of device E is consistent with that of device D.

[0087] The air inlet end of the middle airway 3 of the device E is threadedly connected to the standard interface 2, and the outlet end of the middle airway 3 is also threadedly connected to the filter membrane support base 6 (abbreviated as "membrane support"). The inside of the filter membrane support base 6 is provided with an air flow channel 63, and the outlet end diameter of the air flow channel 63 is equal to the channel in the DUSA device base 5, both of which are 35mm. The air inlet end of the air flow channel 63 of the filter membrane support base 6 is also provided with a filter membrane support net 61. The threaded connection between the middle airway 3 and the filter membrane support base 6 is provided with a sealing ring 4 and a sealing gasket 7, the sealing ring 4 is an O-ring, and the sealing gasket 7 is a silicone sealing gasket. The outer wall of the filter membrane support base 6 is also provided with a limit locking groove 62 that is connected to the DUSA device base 5. Since the device E is connected to the DUSA device base 5 through the filter membrane support base 6, there is no need to design a limit locking groove 62 on the outer wall of the middle airway 3 of the device E.

[0088] When the device E is used, the middle airway 3 and the filter membrane support base 6 are disassembled, the filter membrane is placed on the filter membrane support net 61, and then the middle airway 3 and the filter membrane support base 6 are reassembled, and the filter membrane is pressed and fixed on the filter membrane support net 61 by the middle airway 3.

[0089] 6. Device F: curved surface + membrane support

[0090] like Figures 6 to 8As shown, the improved example device F is a further optimization based on the device E, which attempts to improve the collection effect of drug particles by further changing the airway structure shape of the middle airway 3.

[0091] Except for the differences described below, the rest of the structure of device F is consistent with that of device E.

[0092] A curved surface structured air duct 31' is provided inside the middle air duct 3 of the device F. The outlet diameter of the curved surface structured air duct 31' is equal to the inlet diameter of the air flow channel 63 and the channel in the DUSA device base 5, both of which are 35 mm. The diameter of the curved surface structured air duct 31' gradually increases and then gradually decreases from top to bottom, with a smooth transition.

[0093] Device F is designed with three different specific devices based on different specific dimensions of the middle airway 3, as follows:

[0094] Device F1: curved surface S+membrane support: the axial length of the middle air channel 3 is 55 mm, the diameter of the air inlet end of the curved surface structure air channel 31' is 50 mm, the diameter of the maximum diameter of the middle part of the curved surface structure air channel 31' is 52 mm, and the distance between the maximum diameter of the middle part of the curved surface structure air channel 31' and the axial line of the air inlet end of the curved surface structure air channel 31' is 12.5 mm (the middle air channel 3 designed with this size is simply referred to as "curved surface S");

[0095] Device F2: curved surface M+membrane support: the axial length of the middle air channel 3 is 65 mm, the diameter of the air inlet end of the curved surface structure air channel 31' is 50 mm, the diameter of the maximum diameter of the middle part of the curved surface structure air channel 31' is 52 mm, and the distance between the maximum diameter of the middle part of the curved surface structure air channel 31' and the axial line of the air inlet end of the curved surface structure air channel 31' is 13 mm (the middle air channel 3 designed with this size is simply referred to as "curved surface M");

[0096] Device F3: curved surface L+membrane support: the axial length of the middle air channel 3 is 85mm, the diameter of the air inlet end of the curved surface structure air channel 31' is 50mm, the maximum diameter of the middle part of the curved surface structure air channel 31' is 52mm, and the maximum diameter of the middle part of the curved surface structure air channel 31' is 13.7mm away from the axial line of the air inlet end of the curved surface structure air channel 31' (the middle air channel 3 designed with this size is simply recorded as "curved surface L").

[0097] 7. Device G: curved surface + membrane support + elbow joint

[0098] like Figures 9-11 As shown, the improved example device G is a further optimization based on the device F, which attempts to improve the drug particle collection effect of the powder inhalation dosage form product by adding a bent joint 8.

[0099] Except for the differences described below, the rest of the structure of device G is consistent with that of device F.

[0100] The standard interface 2 of the device G is connected to the middle airway 3 by an elbow joint 8. The outlet end of the elbow joint 8 is threadedly connected to the middle airway 3, and a sealing ring 4 is provided at the threaded connection between the elbow joint 8 and the middle airway 3. The sealing ring 4 is an O-ring; the air inlet end of the elbow joint 8 is connected to the standard interface 2, and the elbow joint 8 and the standard interface 2 are integrally formed.

[0101] In addition to the above differences from device F, device G is also designed with three types corresponding to device F1: curved surface S + membrane support, device F2: curved surface M + membrane support, device F3: curved surface L + membrane support according to the different axial lengths of the middle airway 3, namely, device G1: curved surface S + membrane support + bent joint, device G2: curved surface M + membrane support + bent joint, device G3: curved surface L + membrane support + bent joint.

[0102] 8. Device H: curved surface M + membrane support + NGI perforated collection tray

[0103] like Fig.12 As shown, the improved example device H is a further optimization based on the device F2, which replaces the standard interface 2 in the collection device with an NGI perforated collection plate 9 that cooperates with the NGI device, so that the collection device H can be used in conjunction with the NGI device to achieve the collection of drug particles in a specific particle size range, and then conduct an in vitro dissolution evaluation of the drug particles in the specific particle size range of the inhalation preparation to be tested.

[0104] Except for the differences described below, the rest of the structure of device H is consistent with that of device F2.

[0105] Device H discards the nozzle adapter 1 and the standard interface 2 in the original device F2 and replaces them with an NGI perforated collection tray 9. The overall structure of the NGI perforated collection tray 9 is consistent with the shape of the detachable collection tray in the NGI device. The NGI perforated collection tray 9 is also provided with a through hole corresponding to and connected to the middle airway 3. The NGI perforated collection tray 9 is threadedly connected to the middle airway 3. The threaded connection between the NGI perforated collection tray 9 and the middle airway 3 is provided with a sealing ring 4, which is an O-type sealing ring.

[0106] The following is a summary of the structural differences between device A to device H, as shown in the following table:

[0107]

[0108]

[0109] The test results of the above devices A to H are as follows:

[0110] 2. Test Example A: Distribution of Collection Filters for Curcumin Inhalation Aerosol

[0111] 1. Test collection device:

[0112] Device A (DUSA device), device F2 (curved surface M + membrane support).

[0113] 2. Test drugs:

[0114] Homemade curcumin inhalation aerosol (1 g of curcumin was moistened with ethanol, 20 g of propellant HFA-134a was added, sealed in an aluminum can, and assembled with a driver).

[0115] 3. Test method:

[0116] Disassemble the collection device, insert the circular filter membrane, and reassemble the collection device. Screw the outlet end of the collection device into the DUSA device base 5 through the limit locking groove 62 to connect and fix. Connect the port 5 of the DUSA device base to a vacuum pump (LCP5, Copley). Connect the air inlet end of the collection device to a flow meter (DFM4, Copley), turn on and adjust the vacuum pump so that it can extract air from the collection device at a flow rate of 30L / min (±5%).

[0117] Remove the flow meter, insert the aluminum can of curcumin inhalation aerosol into the driver, and connect the driver nozzle to the air inlet of the collection device. Press the driver once, press for 2 seconds and then release. After releasing, the vacuum pump continues to run for 5 seconds and then shuts down. Disassemble the collection device and take out the filter membrane. Observe the distribution of curcumin drug particles collected by different test collection devices on the filter membrane. The results are as follows: Fig.13 shown.

[0118] 4. Test results:

[0119] See also Fig.13 , device A (DUSA device) was used to collect the curcumin inhalation aerosol, which was distributed on the filter membrane as follows Fig.13 As shown in a, dark red small particles (shown as uneven darker black small particles in the decolorized grayscale photo) are distributed on the filter membrane. Under the same conditions, the curcumin inhalation aerosol was collected using device F2 (curved surface M + membrane support), and its distribution on the filter membrane is as follows Fig.13As shown in b, the dark red small particles on the filter membrane (shown as uneven darker black small particles in the decolorized grayscale photo) are basically invisible. It is proved that when the device F2 (curved surface M + membrane support) is used to collect samples, the aggregation between sample particles is significantly reduced compared with the device A (DUSA device), and the sample is more evenly distributed on the filter membrane. The occurrence of particle aggregation has an important impact on the drug dissolution rate during the in vitro dissolution evaluation of the sample. The serious aggregation of the collected drug particles in the device A (DUSA device) will lead to the non-objective and inaccurate test results of its in vitro drug dissolution rate, and it is difficult to examine the effect of the properties of the sample drug particles themselves on the in vitro dissolution. This is also confirmed in the subsequent in vitro dissolution test examples.

[0120] 3. Test Example B: In vitro dissolution of collected drug particles from fluticasone propionate inhalation aerosol

[0121] 1. Test collection device:

[0122] Device A, device B, device C, device D, device E, device F1, device F2, device F3 and device G1.

[0123] 2. Test drugs:

[0124] Fluticasone propionate inhalation aerosol, trade name "Fluticasone", 125μg / press, manufacturer: GlaxoSmithKline.

[0125] 3. Test method:

[0126] Disassemble the collection device, insert the circular filter membrane, and reassemble the collection device. Screw the outlet end of the collection device into the DUSA device base 5 through the limit locking groove 62 to connect and fix. Connect the port 5 of the DUSA device base to a vacuum pump (LCP5, Copley). Connect the air inlet end of the collection device to a flow meter (DFM4, Copley), turn on and adjust the vacuum pump so that it can extract air from the collection device at a flow rate of 30L / min (±5%).

[0127] Remove the flow meter, insert the aerosol aluminum can into the driver, and connect the driver nozzle to the air inlet of the collection device. Press the driver once, press for 2 seconds and then release. After releasing, the vacuum pump continues to run for 5 seconds and then shuts down. Disassemble the collection device and take out the filter membrane. At this time, the filter membrane collects and carries 1 sample for subsequent dissolution testing.

[0128] Replace the circular filter membrane with a new one and repeat the above operation. After collecting 1 press, keep the vacuum pump running, take out the aerosol aluminum can, shake it for 5 seconds, and collect another 1 press in the same way. Disassemble the collection device and take out the filter membrane. At this time, the filter membrane collects and carries 2 presses of sample for subsequent dissolution testing.

[0129] Detection of in vitro dissolution similarity factor: Take the filter membrane carrying 1 or 2 presses of sample, transfer it to a glass slide dissolution kit with PTFE mesh (Copley), and put it into a dissolution cup with 900 mL of dissolution medium (abbreviated as "dissolution medium") containing 0.5% (w / v) Tween 80 at pH 7.4 phosphate buffered saline (PBS) according to USP5 paddle-disk method. The temperature of the dissolution medium is maintained at 37°C and the paddle speed is maintained at 75 rpm. Dissolution samples are collected at different time points using a dissolution automatic sampling system (agilent), and the content of fluticasone propionate in the dissolution samples is detected by HPLC. The amount of fluticasone propionate dissolved at each time point is converted into dissolution rate, and the similarity factor (f2) between the dissolution curves corresponding to the dissolution samples collected for 1 press and 2 presses is calculated.

[0130] In vitro dissolution recovery rate detection: Take the filter membrane of each collection device carrying 2 samples, directly use the diluent to elute and detect the amount of collected drug. And use the drug deposition amount on the filter membrane of device A (DUSA device) as a comparison basis to calculate the collection recovery rate of other collection devices (collection recovery rate = drug deposition amount of other devices / drug deposition amount of device A × 100%).

[0131] 4. Test results:

[0132] See also Fig.14 , Fig.14 a shows the dissolution curves of drug particles collected by device A (DUSA device) at 1 press and 2 press. It can be seen that the dissolution rate slows down significantly with the increase of drug deposition on the filter membrane. The similarity factor between the two is 60.9. Fig.14 b shows the comparison of the dissolution curves of the drug particles collected at 1 press and 2 press using device F2 (curved surface M + membrane support). It can be seen that the fluctuation of the amount of drug deposited on the filter membrane does not affect its dissolution rate, and the similarity factor between the two is significantly increased to 90.6.

[0133] The similarity factor and recovery rate test results of all test collection devices are statistically analyzed, as shown in the following table:

[0134]

[0135] Through the above table and Fig.14 , we can know that:

[0136] 1) Comparison of devices A, B, and C: When the middle airway 3 of the straight cylinder structure airway 31 is used, whether it is relatively small in diameter (device B) or relatively large in diameter (device C), whether it is directly connected to the DUSA device base 5 (device B) or connected to the DUSA device base 5 through the filter membrane support base 6 (device C), when used as a delivery particle collection device, the dissolution result f2 is not significantly improved compared with the DUSA device (device A), and is at a poor level.

[0137] 2) Comparison of devices A, D, and E: When the middle airway 3 of the funnel-shaped structure is directly connected to the DUSA device base 5 (device D), the dissolution result f2 of the DUSA device (device A) is slightly improved, but not obvious. When the middle airway 3 of the funnel-shaped structure is connected to the DUSA device base 5 through the filter membrane support base 6 (device E), the dissolution result f2 of the DUSA device (device A) is significantly improved.

[0138] 3) Comparison of devices A, F1, F2, and F3: When the middle airway 3 with a curved airway 31' is connected to the DUSA device base 5 through a filter membrane support base 6 (device F), the collection devices of different sizes of the middle airway 3 (devices F1, F2, and F3) have achieved significant improvements in the dissolution result f2 relative to the DUSA device (device A). In particular, the dissolution result f2 of the collection devices (devices F2 and F3) of the middle airway 3 of a specific size is further significantly improved to the 90 level, but with the further increase in the length of the middle airway 3 (device F3), its recovery rate gradually begins to decline. But surprisingly, the collection device (device F2) of the middle airway 3 of a specific size not only significantly improves the dissolution result f2 to 90.6, but also maintains a good recovery rate of 101.4%. Therefore, the collection device (device F2) of the middle airway 3 of this specific size is the most preferred.

[0139] 4) Comparison of devices A, F1, and G1: Although the dissolution result f2 of the device G1 was improved to some extent compared with the DUSA device (device A), the dissolution result f2 and recovery rate of the device G1 were significantly reduced compared with the device F1, revealing that for the "inhalation aerosol" dosage form, there is no need to use the structural design of adding the bend joint 8.

[0140] 5) Based on the comparison of the distribution of the drug on the filter membrane of the collection device A (DUSA device) and the collection device F2 (curved surface M + membrane support) in test example A, it can be inferred that the delivered drug particles can be uniformly deposited on the filter membrane through the improved collection device (especially device F2), reducing the effect of aggregation between particles on the drug dissolution rate. Within the range of drug deposition investigated, the effect of fluctuations in the amount of drug deposition on the filter membrane on its dissolution is eliminated, so that the dissolution results can better reflect the differences in the properties of the drug itself (such as particle size, excipients, process and storage conditions, etc.), and can make an objective evaluation of the product quality of inhalation preparations.

[0141] IV. Test Example C: In vitro dissolution of collected drug particles of salmeterol-fluticasone inhalation powder

[0142] 1. Test collection device:

[0143] Device A, device F2, device G1, device G2 and device G3.

[0144] 2. Test drugs:

[0145] Salmeterol and fluticasone inhalation powder, trade name "Seretide", 50μg / 250μg per bubble, manufacturer: GlaxoSmithKline.

[0146] 3. Test method:

[0147] Disassemble the collection device, insert the circular filter membrane, and reassemble the collection device. Screw the outlet end of the collection device into the DUSA device base 5 through the limit locking groove 62 to connect and fix. Connect the port 5 of the DUSA device base to a vacuum pump (HCP5, Copley). Connect the air inlet end of the collection device to a flow meter (DFM4, Copley), turn on the vacuum pump and open the flow control valve (BAC2100, Copley) to adjust the flow rate so that it can be drawn from the collection device at a flow rate of 60L / min (±5%), and confirm that the P3 / P2 value should not be greater than 0.5.

[0148] Remove the flow meter, connect the Seretide dosing device to the air inlet of the collection device, turn the paddle of the Seretide dosing device to open a blister, set the flow control valve to aspiration time of 2s, and after aspiration of the opened blister, disassemble the collection device and take out the filter membrane. At this time, the filter membrane collects and carries 1 bubble of sample for subsequent dissolution testing.

[0149] Replace the circular filter membrane with a new one and repeat the above operation. After collecting 1 bubble, turn the paddle of the Seretide drug delivery device again to open another blister. Set the flow control valve to draw for 2 seconds. After the blister is drawn, disassemble the collection device and take out the filter membrane. At this time, the filter membrane collects and carries 2 bubble samples for subsequent dissolution testing.

[0150] Detection of in vitro dissolution similarity factor: Take the filter membrane carrying 1 or 2 bubble samples, transfer it to a glass sheet dissolution kit with a PTFE mesh (Copley), and put it into a dissolution cup with 900mL dissolution medium according to the USP5 paddle-disc method. The dissolution medium temperature is maintained at 37°C and the paddle speed is maintained at 75rpm. The dissolution samples are collected at different time points using a dissolution automatic sampling system (agilent), and the content of fluticasone propionate in the dissolution samples is detected by HPLC. The amount of fluticasone propionate dissolved at each time point is converted into a dissolution rate, and the similarity factor (f2) between the dissolution curves corresponding to the dissolution samples of collecting 1 bubble and collecting 2 bubbles is calculated.

[0151] In vitro dissolution recovery rate detection: Take the filter membrane of each collection device carrying 2 bubbles of samples, directly use the diluent to elute and detect the amount of collected drug. And use the drug deposition amount of the filter membrane of device A (DUSA device) as a comparison basis to calculate the collection recovery rate of other collection devices (= drug deposition amount of other devices / drug deposition amount of device A×100%).

[0152] 4. Test results:

[0153] The similarity factor and recovery rate test results of all test collection devices are statistically analyzed, as shown in the following table: From the above table, we can see that:

[0154] 1) In addition to the active ingredient particles, there are a large number of excipient carrier particles with relatively large particle sizes in powder inhalers. In addition, passive products such as Seretide do not have the power to deliver the powder outward, and external suction is required to release the powder from the product device. The complex preparation and device product technology of powder inhalers exacerbates the difficulty in in vitro dissolution evaluation. For example, in this test example, the similarity factor f2 of device A (DUSA device) for powder inhalers is only 54.7, which is less than 60.9 for aerosols. However, even so, the results of devices F2, G1, G2, and G3 still show that the airway with a curved surface structure still achieved a significantly improved in vitro dissolution f2.

[0155] 2) Test Example B has confirmed that the device F2 has a special unexpected advantage in the collection of delivered particles of inhaled aerosols and the subsequent in vitro dissolution evaluation test. This test example further demonstrates that the device F2 can also be used for the collection of delivered particles of dry powder inhalers (i.e. inhaled powder aerosols) and in vitro dissolution evaluation tests. The in vitro dissolution f2 can reach 72.2, and the recovery rate of 98.8% is also at a high level.

[0156] 3) Comparison between apparatus F2 and G2: After adding elbow 8, the dissolution result f2 of apparatus G2 was significantly improved to 83.2 compared with apparatus F2, but the recovery rate decreased, which is presumably due to the deposition of drug particles at the newly added elbow 8. Even so, when the main purpose of the investigation is to study the effect of drug particle size distribution on in vitro dissolution or to evaluate it, apparatus G2 with better in vitro dissolution result f2 can still be selected under an acceptable recovery rate.

[0157] 4) Comparison of devices G1, G2, and G3: There are obvious differences in the dissolution results f2 of the collection devices (devices G1, G2, and G3) of the middle airway 3 of different sizes. The middle airway 3 of devices G2 and G3 has a better in vitro dissolution result f2 advantage, especially the device G2 of the middle airway 3 of a specific size has the best in vitro dissolution f2. Therefore, device G2 is preferred as the delivery particle collection device for powder inhalers, and is further used for in vitro dissolution detection and evaluation after delivery particle collection.

[0158] V. Test Example D: In vitro dissolution of collected drug particles of fluticasone propionate suspension for aerosol inhalation

[0159] 1. Test collection device:

[0160] Device F2.

[0161] 2. Test drugs:

[0162] Fluticasone propionate nebulized inhalation suspension, trade name "Fluticasone", 2mL / 0.5mg, manufacturer: GlaxoSmithKline.

[0163] 3. Test method:

[0164] Disassemble the collection device, insert the circular filter membrane, and reassemble the collection device. Screw the outlet end of the collection device into the DUSA device base 5 through the limit locking groove to connect and fix. Connect the port 5 of the DUSA device base to a vacuum pump (LCP5, Copley). Connect the air inlet end of the collection device to a flow meter (DFM4, Copley), turn on the vacuum pump and adjust the flow rate so that it can extract air from the collection device at a flow rate of 15L / min (±5%).

[0165] Remove the flow meter and connect the nebulizer (PARI BOY) nozzle to the air inlet of the collection device. Take a tube of fluticasone propionate suspension for nebulized inhalation, shake it evenly, and pour it into the nebulizer cup. Turn on the nebulizer compressed air pump and count for 120 seconds before turning it off. Keep the vacuum pump running for 10 seconds before turning it off. Disassemble the collection device and take out the filter membrane. At this time, the filter membrane collects and carries 1 sample for subsequent dissolution testing.

[0166] Replace the circular filter membrane with a new one and repeat the above operation. After collecting one tube, keep the vacuum pump running, replace the clean nebulizer cup, take another new fluticasone propionate suspension for nebulized inhalation and add it to the clean nebulizer cup. Collect another tube in the same way, disassemble the collection device and take out the filter membrane. At this time, the filter membrane collects and carries 2 samples for subsequent dissolution testing.

[0167] Detection of in vitro dissolution similarity factor: Take the filter membrane carrying 1 or 2 samples, transfer it to the glass sheet dissolution kit with PTFE mesh (Copley), and put it into the dissolution cup with 900mL dissolution medium according to the USP5 paddle disk method. The dissolution medium temperature is maintained at 37°C and the paddle speed is maintained at 75rpm. The dissolution samples are collected at different time points using the dissolution automatic sampling system (agilent), and the content of fluticasone propionate in the dissolution samples is detected by HPLC. The amount of fluticasone propionate dissolved at each time point is converted into the dissolution rate, and the similarity factor (f2) between the dissolution curves corresponding to the dissolution samples of collecting 1 bubble and collecting 2 bubbles is calculated.

[0168] 4. Test results:

[0169] The test result of the in vitro dissolution similarity factor was 79.1, indicating that the device F2 is also suitable for the collection of delivery particles of aerosol inhalation suspension preparations, and is further suitable for in vitro dissolution testing and evaluation after the delivery particles are collected.

[0170] VI. Test Example E: Deposition of collected drug particles in a specific particle size range of budegfolate inhalation aerosol

[0171] 1. Test collection device:

[0172] 1) NGI device,

[0173] 2) NGI device combination device H.

[0174] 2. Test drugs:

[0175] Budeglobate inhalation aerosol, trade name "Bezeril", 160μg / 7.2μg / 4.8μg per press, manufacturer: AstraZeneca.

[0176] 3. Test method:

[0177] When the test collection device is "1) NGI device", the collection disk of the NGI device is used as the collection membrane of the drug particles. At this time, the NGI device is directly assembled and used as the collection device.

[0178] When the test device is "2) NGI device combined with device H", a circular filter membrane is used as a collection membrane for drug particles. At this time, the NGI perforated collection plate 9 of device H needs to replace the corresponding collection plate in the NGI device of the particle size range to be collected, and the NGI perforated collection plate 9 of device H is installed on the bottom bracket of the NGI device. At this time, device H and the NGI device are assembled as a collection device.

[0179] Insert an artificial throat into the air inlet end of the collecting device (i.e., the air inlet end of the NGI cascade impactor), and connect the other end of the artificial throat to a flow meter (DFM4, Copley). Connect a vacuum pump (LCP5, Copley) to the outlet end of the collecting device ("When the collecting device is '1) NGI device', the outlet end is the outlet end of the NGI cascade impactor"; "When the collecting device is '2) NGI device combination device H', the outlet end of device H is screwed into the DUSA device base 5 through the limit locking groove and connected and fixed as the outlet end"). Turn on and adjust the vacuum pump so that it can extract air from the collecting device at a flow rate of 30L / min (±5%).

[0180] Remove the flowmeter, insert the aerosol aluminum can into the driver, and connect the driver closely to the artificial throat through a suitable nozzle adapter. Press the driver once, press for 2 seconds and then release. After release, the vacuum pump continues to run for 5 seconds and then shuts down. Disassemble the collection device and take out the collection membrane. Add an appropriate amount of diluent, elute and collect the drugs in each collection membrane and dilute to an appropriate volume. Use HPLC to detect the content of budesonide in each collection membrane and calculate the sum of the drug deposition corresponding to a specific level, that is, the drug deposition of the level group.

[0181] 4. Test results:

[0182] The results of drug particle deposition in different particle size ranges of all test collection devices are statistically analyzed, as shown in the following table:

[0183] Note: a The deposition amount is expressed as Mean±SD (n=3), which is the deposition amount averaged to 1 press at different collection times, where the deposition amount of the NGI device is the sum of the deposition amounts corresponding to each level from the corresponding level to the MOC, and the deposition amount of the device H is the drug deposition amount on the filter membrane of the device H installed in the collection cup corresponding to the corresponding level; b The ratio is the ratio of the average deposition amount of the device H to the average deposition amount of the NGI device.

[0184] From the table above, we can see that there is no significant difference in the deposition of drug particles of different particle size ranges between the device H and the NGI device for the three batches of inhaled aerosols, and the deposition ratio is between 103.0%-104.9% (particle size less than 6.40μm) and 112.7%-116.8% (particle size less than 2.30μm). The results show that there is a good correlation between the drug deposition amount of a specific layer cutoff particle size corresponding to the device H and the layer cumulative deposition amount corresponding to the same cutoff particle size of the NGI device. The drug deposition amount of the collection device can replace the drug cumulative deposition amount corresponding to each layer of the NGI device for AIM detection.

[0185] In the description of this specification, the description with reference to the terms "one embodiment / method", "some embodiments / methods", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment / method or example are included in at least one embodiment / method or example of the present application. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment / method or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments / methods or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments / methods or examples described in this specification and the features of the different embodiments / methods or examples, unless they are contradictory.

[0186] In addition, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In the description of this application, the meaning of "plurality" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined.

[0187] It should be understood by those skilled in the art that the above embodiments are only for the purpose of clearly illustrating the present invention, and are not intended to limit the scope of the present invention. For those skilled in the art, other changes or modifications may be made based on the above disclosure, and these changes or modifications are still within the scope of the present invention.

Claims

1. A delivery particle collection device for in vitro evaluation of inhalation preparations, characterized in that: The invention comprises an inlet mechanism, a middle airway (3) and a filter membrane support base (6) which are connected in sequence, wherein a curved surface structure airway (31') is provided in the middle airway (3), an air flow channel (63) connected to the middle airway (3) is provided in the filter membrane support base (6), and a filter membrane support net (61) for installing the filter membrane is also provided at the air inlet end of the air flow channel (63).

2. The delivery particle collection device according to claim 1, characterized in that The diameter of the curved surface structure airway (31') first gradually increases from top to bottom, and then gradually decreases.

3. The delivery particle collection device according to claim 2, characterized in that: The diameter of the air inlet end of the curved surface structure air duct (31') is greater than the diameter of the outlet end of the curved surface structure air duct (31'); preferably, the axial length of the curved surface structure air duct (31') is 55 to 85 mm, preferably 65 to 85 mm, and more preferably 65 mm; preferably, the axial distance from the maximum diameter of the middle part of the curved surface structure air duct (31') to the air inlet end of the curved surface structure air duct (31') is 12 to 14 mm, preferably 13 to 13.7 mm, and more preferably 13 mm.

4. The delivery particle collection device according to claim 2, characterized in that: The maximum diameter of the middle part of the curved surface structure air channel (31') is 52 mm, and the diameter of the air inlet end of the curved surface structure air channel (31') can be 50 mm.

5. The delivery particle collection device according to claim 2, characterized in that: The diameter of the outlet end of the curved surface structure air channel (31') is equal to the diameter of the air inlet end of the air flow channel (61), and both are preferably 35 mm.

6. The delivery particle collection device according to any one of claims 1 to 5, characterized in that: The middle air duct (3) and the inlet mechanism, and the middle air duct (3) and the filter membrane support base (6) are detachably connected; preferably, the middle air duct (3) and the inlet mechanism, and the middle air duct (3) and the filter membrane support base (6) are threadedly connected or snap-fitted; preferably, a sealing ring (4) and / or a sealing gasket (7) are also installed between the middle air duct (3) and the inlet mechanism, and between the middle air duct (3) and the filter membrane support base (6).

7. The delivery particle collection device according to any one of claims 1 to 5, characterized in that: The filter membrane support base (6) is also provided with a connection mechanism that cooperates with the DUSA device base (5); preferably, the bottom outlet end of the filter membrane support base (6) is provided with a connector for connecting to a vacuum pump.

8. The delivery particle collection device according to claim 7, characterized in that: The connecting mechanism is a limiting locking groove (62) provided on the outer wall of the filter membrane support base (6); preferably, the limiting locking groove (62) is L-shaped, the lower end of the vertical section of the limiting locking groove (62) is flush with the lower end surface of the filter membrane support base (6), and the horizontal section of the limiting locking groove (62) extends along the circumferential direction of the filter membrane support base (6).

9. The delivery particle collection device according to any one of claims 1 to 5, characterized in that: The inlet mechanism comprises a nozzle adapter (1) and a standard interface (2) which are interconnected, the nozzle adapter (1) being sleeved on the standard interface (2), and the standard interface (2) being interconnected with the middle airway (3); preferably, the inlet mechanism further comprises a bend joint (8), and the standard interface (2) is interconnected with the middle airway (3) via the bend joint (8); preferably, the standard interface (2) and the bend joint (8) are optionally integrally formed; preferably, the nozzle adapter (1) is of two or more types, and different types of nozzle adapters (1) have different nozzle matching structures corresponding to delivery devices of different types of inhalation preparation drugs, and a plurality of different types of nozzle adapters (1) share one standard interface (2).

10. The delivery particle collection device according to any one of claims 1 to 5, characterized in that: The inlet mechanism is an NGI perforated collection plate (9) matched with the NGI device; preferably, the filter membrane support net (61) includes a cross frame and a ring, the ring is installed on the cross frame, and the extended end of the cross frame is fixed to the filter membrane support base (6).

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