Testing device and testing method for inhaled liquid preparation

Abstract

The invention belongs to the technical field of medicine testing, and particularly relates to a testing device and method for inhaling a liquid preparation, and the testing device comprises a testing device atomizer which is used for atomizing the liquid preparation; the breathing simulator is used for simulating breathing and inhaling the atomized liquid preparation; the filtering and intercepting device is used for intercepting the atomized liquid preparation, a filter membrane is arranged in the filtering and intercepting device, one end of the filtering and intercepting device is communicated with an atomization outlet of the atomizer, and the other end of the filtering and intercepting device is communicated with an inlet of the respiration simulator; and the pumping device is used for extracting the liquid preparation in the filter membrane. According to the invention, the delivery rate and the total delivery amount of the inhaled liquid preparation can be accurately measured.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical testing technology, specifically relating to a testing device and testing method for inhaled liquid formulations. Background Technology

[0002] Inhaled liquid formulations are one of the most common types of medications on the market. Among them, nebulized inhaled formulations are a special type of inhaled liquid formulation, requiring the use of a nebulizer. According to the "Technical Requirements for Pharmaceutical Research of Chemical Drug Inhaled Liquid Formulations" issued by the Center for Drug Evaluation (CDE), nebulized inhaled formulations need to undergo in vitro consistency evaluation to ensure that the generic drug achieves the same respiratory dosage as the original or reference formulation.

[0003] Delivery rate and total delivery volume are important evaluation parameters for in vitro consistency assessment. Currently, delivery rate and total delivery volume are determined using a respiratory simulator to simulate human breathing. A jet nebulizer is used, with its outlet connected to the respiratory simulator via a dedicated interface. A drug collection device is placed in the middle of the connection path. The nebulizer's compressor provides a continuous and stable high-velocity compressed air flow. This compressed air impacts the liquid in the nebulizer cup, shattering the liquid into numerous drug droplets. Simultaneously, the respiratory simulator simulates human breathing; during inhalation, outside air is drawn into the simulator, and as the airflow passes through the nebulizer, the aerosol is carried by the airflow through the drug collection device and remains on the filter membrane. The filter membrane after sample collection is eluted by rinsing with solvent and then repeatedly eluted by manual squeezing. After collecting the eluent, the content of the inhaled formulation sample is measured. Due to the porous nature of the filter membrane material and the strong adsorption effect of drug particles, incomplete extrusion or excessive loss often occurs during repeated manual extrusion, leading to measurement errors. Some active pharmaceutical ingredients (APIs) may still irreversibly remain in the deep structure of the filter membrane and cannot be effectively recovered, resulting in low measurement efficiency and seriously affecting the accuracy and reliability of product quality assessment. Summary of the Invention

[0004] In view of the technical problems mentioned in the background art regarding the measurement error and low measurement efficiency of existing methods for testing the delivery rate and total delivery of inhaled liquid formulations, the present invention provides a testing device and testing method for inhaled liquid formulations, which can accurately determine the delivery rate and total delivery of inhaled liquid formulations.

[0005] Technical solution of the present invention:

[0006] A testing device for inhaling liquid formulations, comprising:

[0007] Nebulizers are used to atomize liquid preparations;

[0008] Breathing simulator, used to simulate breathing and inhaling nebulized liquid preparations;

[0009] A filtration and retention device is used to retain the liquid preparation after atomization. The filtration and retention device is equipped with a filter membrane. One end of the filtration and retention device is connected to the atomization outlet of the nebulizer, and the other end is connected to the inlet of the breathing simulator.

[0010] A pressure extraction device is used to extract liquid formulations from a filter membrane.

[0011] Furthermore, the atomizer includes a main unit, a connecting tube, an atomizing cup, and a mouthpiece connected in sequence. The main unit is used to generate compressed air, and the atomizing cup is used to hold liquid reagents.

[0012] Furthermore, the filtration and retention device includes a filter membrane position and a breathing connector, the nebulizer connector is connected to a mouthpiece, and the breathing connector is connected to a breathing simulator.

[0013] A test method for inhaled liquid formulations includes the following steps:

[0014] Step 1: Install the first filter membrane in the filtration and retention device, connect the filtration and retention device to the nebulizer and breathing simulator, take a certain amount of the test preparation and put it into the nebulizer, set the breathing mode and turn on the nebulizer to perform nebulization.

[0015] Step 2: Nebulize for the predetermined time, stop the breathing simulator and nebulizer, take out the first filter membrane, place it in a container, add wetting liquid and sonicate, after sonication, place the first filter membrane in the suction device, extract the wetting liquid and squeeze the first filter membrane, and the resulting solution is added to the container to obtain the first mixture.

[0016] Step 3: Install the second filter membrane in the filtration and retention device, set the breathing mode and turn on the nebulizer to nebulize until the inhaled liquid preparation is completely nebulized. Remove the second filter membrane and process it according to the operating steps in Step 2.

[0017] A second mixture was obtained;

[0018] Step 4: Measure the API content of the inhaled liquid formulation in the three mixtures using liquid chromatography, and calculate the delivery rate, total delivery amount, and recovery rate of the inhaled liquid formulation.

[0019] Furthermore, the breathing mode in step one includes an adult mode and a child mode. The adult mode has a tidal volume of 500 ml, a respiratory rate of 15 cycles / minute, a sinusoidal respiratory waveform, and an inspiratory-to-expiratory ratio of 1:1. The child mode has a tidal volume of 155 ml, a respiratory rate of 25 cycles / minute, a sinusoidal respiratory waveform, and an inspiratory-to-expiratory ratio of 1:2.

[0020] Furthermore, in step two, the atomization time is 1 minute, the wetting solution is sodium dihydrogen phosphate solution, the ultrasonic time is 10-20 minutes, and the number of pumping cycles is 10-15.

[0021] Furthermore, in step three, the atomization time is 10-20 minutes, the ultrasonic time is 10-20 minutes, and the number of pumping cycles is 10-15.

[0022] Furthermore, the chromatographic conditions in step four are as follows:

[0023] Filler: Octylsilane-bonded silica gel;

[0024] Mobile phase A: 0.025 mol / L sodium dihydrogen phosphate solution, wherein the sodium dihydrogen phosphate solution contains 0.05% triethylamine and has a pH of 3;

[0025] Mobile phase B: a mixed solution of acetonitrile and methanol with a volume ratio of 65:35;

[0026] The flow rate was 1.0 ml per minute; the column temperature was 30℃; the detection wavelength was 273 nm; the injection volume was 50 μl; and the run time was 15 min.

[0027] Furthermore, in step four...

[0028] The delivery rate is calculated as follows: Delivery rate = Amount of API detected in the first mixture / Atomization time;

[0029] The formula for calculating the total delivery volume is: Total delivery volume = Amount of API detected in the first mixture + Amount of API detected in the second mixture;

[0030] The recovery rate is calculated as follows: Recovery rate = (Amount of API detected in the first mixture + Amount of API detected in the second mixture + Amount of API detected in the third mixture) / Nebulized drug dosage.

[0031] The beneficial effects of this invention are:

[0032] This invention provides a testing device and method for inhaled liquid formulations. By using a breathing simulator, a nebulizer, a filtration device, and a pumping device, the delivery rate and total volume of the inhaled liquid formulation can be accurately calculated. This invention significantly improves testing accuracy by adjusting test parameters and adding a pumping device. Attached Figure Description

[0033] Figure 1 This is a schematic diagram of the test device used for inhaling liquid formulations in the experimental examples of the present invention.

[0034] Explanation of the labels in the diagram:

[0035] 1. Nebulizer main unit; 2. Connecting tube; 3. Nebulizer cup; 4. Mouthpiece; 5. Filter membrane position; 6. Breathing connector; 7. Breathing simulator; 8. Pumping device. Detailed Implementation

[0036] The specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings. It should be noted that the technical features or combinations of technical features described in the following embodiments should not be considered in isolation, but can be combined with each other to achieve better technical effects.

[0037] Example

[0038] A testing device for inhaling liquid preparations includes a nebulizer for nebulizing the liquid preparation; a breathing simulator 7; a filtration and retention device for retaining the nebulized liquid preparation, wherein the filtration and retention device has a filter membrane, one end of the filtration and retention device is connected to the nebulization outlet of the nebulizer, and the other end is connected to the test port of the breathing simulator 7; and a pressure extraction device 8 for extracting the liquid preparation from the filter membrane.

[0039] In this embodiment, the nebulizer includes a nebulizer host 1, a connecting tube 2, a nebulizing cup 3, and a mouthpiece 4 connected in sequence. The host is used to generate compressed air to atomize the liquid to be tested. The connecting tube 2 is used to connect the host and the nebulizing cup 3. The nebulizing cup 3 is used to hold the liquid reagent to be tested. The mouthpiece is used to connect the nebulizing cup 3 and the filter trap.

[0040] The filtration and retention device includes a filter membrane position 5 and a breathing connector 6. The nebulizer connector is connected to the mouthpiece 4, and the breathing connector 6 is connected to the breathing simulator 7.

[0041] In this embodiment, the suction device 8 is a medical syringe.

[0042] A test method for inhaled liquid formulations includes the following steps:

[0043] Step 1: Install the first filter membrane in the filtration and retention device, connect the filtration and retention device to the nebulizer and breathing simulator 7, take a certain amount of the test preparation and put it into the nebulizer, set the breathing mode and turn on the nebulizer to perform nebulization.

[0044] Specifically, a first filter membrane is installed in the filtration and retention device and connected to the upper interface of the breathing simulator 7. The nebulizer main unit 1, connecting tube 2, and nebulizer cup 3 are connected in sequence. The mouthpiece 4 is connected to the filtration and retention device with the filter membrane installed. 3ml of inhaled liquid preparation is placed into the nebulizer cup 3, and a breathing mode is selected to simulate breathing. The breathing modes include an adult mode and a child mode. The adult mode is set as follows: tidal volume 500ml, respiratory rate 15 cycles / minute, sinusoidal breathing waveform, and I / O ratio 1:1. The child mode is set as follows: tidal volume 155ml, respiratory rate 25 cycles / minute, sinusoidal breathing waveform, and I / O ratio 1:2. After setting, the nebulizer is turned on to nebulize and collect the nebulized liquid.

[0045] Step 2: After nebulizing for the predetermined time, stop the breathing simulator 7 and the nebulizer, take out the first filter membrane, place it in a container, add the wetting liquid, and sonicate it. After sonication, place the first filter membrane in the suction device 8, extract the wetting liquid, squeeze the first filter membrane, and combine the resulting solution into the container to obtain the first mixture.

[0046] Specifically, after nebulization for 1 minute, stop the breathing simulator 7 and the nebulizer. Remove the first filter membrane and place it in a beaker. Add 10 ml of wetting solution to wet the filter membrane and sonicate for 10 minutes to extract. Place the extract in a 20 ml volumetric flask. Then place the first filter membrane in the suction device 8, wet the filter membrane with 10 ml of wetting solution, and squeeze the filter membrane in small amounts several times. The resulting filtrate is added to a 20 ml volumetric flask and diluted to volume to obtain the first mixture.

[0047] Step 3: Install a second filter membrane in the filtration and retention device, set the breathing mode and turn on the nebulizer to nebulize until the inhaled liquid preparation is completely nebulized, remove the second filter membrane, process the second filter membrane according to the operation steps in Step 2, and obtain the second mixture.

[0048] Specifically, a second filter membrane is installed in the filtration and retention device. The breathing mode is set, and the nebulizer is turned on for nebulization until the inhaled liquid preparation is completely nebulized. The second filter membrane is then removed and placed in a beaker. 10 ml of wetting solution is added to rinse the filtration and retention device, mouthpiece 4, and adapter into the beaker. The second filter membrane is then sonicated for 10 minutes and extracted. The extract is transferred to a 20 ml volumetric flask. The second filter membrane is placed in the suction device 8, and 10 ml of wetting solution is used to wet the second filter membrane, squeezing it repeatedly in small amounts. The resulting filtrate is added to the 20 ml volumetric flask and diluted to volume to obtain the second mixture. Finally, the nebulizer cup 3 is rinsed repeatedly with the wetting solution and the volumetric flask is diluted to volume to obtain the third mixture.

[0049] Step 4: Measure the API content of the inhaled liquid formulation in the three mixtures using liquid chromatography, and calculate the delivery rate, total delivery amount, and recovery rate of the inhaled liquid formulation.

[0050] Specifically, the content of the inhaled liquid formulation in the three-component mixture was measured using liquid chromatography (LC). The LC conditions were as follows: octylsilane-bonded silica gel (Hypersil BDS C8, 4.6 × 150 mm, 3 μm) was used as the stationary phase; mobile phase A was 0.025 mol / L sodium dihydrogen phosphate solution (containing 0.05% triethylamine, adjusted to pH 3.0 with 10% phosphoric acid solution); mobile phase B was acetonitrile-methanol (65:35); and isocratic elution was performed using mobile phase A-mobile phase B (95:5); the flow rate was 1.0 mL / min; the column temperature was 30 °C; the detection wavelength was 273 nm; the injection volume was 50 μL; and the run time was 15 min.

[0051] For system suitability solution preparation, accurately weigh 2.5 mg of impurity J reference standard into a 100 ml volumetric flask, dissolve and dilute to the mark with solvent, and shake well to prepare impurity J stock solution. Accurately transfer 1.0 ml of impurity J stock solution into a 50 ml volumetric flask, and dilute with the reference standard solution to prepare a solution containing approximately 0.16 mg salbutamol and 0.5 μg impurity J per ml.

[0052] Accurately weigh 19 mg of salbutamol sulfate reference standard and place it in a 100 ml volumetric flask. Dissolve and dilute with solvent to prepare a solution containing approximately 0.16 mg of salbutamol per ml. Prepare two parallel solutions.

[0053] The delivery rate is calculated as follows: Delivery rate = Amount of API detected in the first mixture / Nebulization time

[0054] The formula for calculating the total delivery volume is: Total delivery volume = Amount of API detected in the first mixture + Amount of API detected in the second mixture

[0055] The recovery rate is calculated as follows: Recovery rate = (Amount of API detected in the first mixture + Amount of API detected in the second mixture + Amount of API detected in the third mixture) / Nebulized drug dose, where the nebulized drug dose is the amount of API in the inhaled liquid formulation added to the nebulizer cup in step one.

[0056] Comparative Example

[0057] The difference between this comparative example and the embodiment is that no pressure device was used. In the test method, only ultrasound was used on the first and second filter membranes. Specifically, steps two and three are as follows: After nebulization for 1 minute, the breathing simulator and nebulizer were stopped. The first filter membrane was removed and placed in a beaker. 10 ml of wetting solution was added to wet the filter membrane, and ultrasound was used for 10 minutes for extraction. The extract was placed in a 20 ml volumetric flask and diluted to volume to obtain the first mixture. The second filter membrane was installed in the filtration trap. The breathing mode was set, and the nebulizer was turned on for nebulization until the inhaled liquid preparation was completely nebulized. The second filter membrane was removed and placed in a beaker. 10 ml of wetting solution was added to rinse the filtration trap, mouthpiece, and adapter into the beaker. The second filter membrane was then wetted, ultrasound was used for 10 minutes, and extraction was performed. The extract was placed in a 20 ml volumetric flask and diluted to volume to obtain the second mixture. Finally, the nebulizer cup was rinsed with wetting solution in small amounts several times and the mixture was diluted to volume in a 20 ml volumetric flask to obtain the third mixture.

[0058] The test results for delivery rate, total delivery volume, and recovery rate for the examples and comparative examples are shown in the table below:

[0059] Delivery rate (mg / min) Total delivery amount (mg) Recovery rate (%) Example 0.2142 1.3188 95.7 Comparative Example 0.1342 1.0156 83.7

[0060] Experimental Results Analysis: The results show that the test device and method of this invention achieve a recovery rate of 95.7% for the tested inhaled liquid formulation, significantly higher than the ultrasonic collection method used in existing technologies. Furthermore, it is more accurate in terms of delivery rate and total delivery volume compared to the comparative method, enabling better product quality assessment.

[0061] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered exemplary and not restrictive in all respects. Furthermore, it should be understood that although this specification describes embodiments, it does not encompass only one technical solution. This descriptive method is merely for clarity, and those skilled in the art should consider the specification as a whole. The technical solutions in the embodiments can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A test device for inhalation of a liquid formulation, characterised in that: The utility model relates to a kind of inhalation test device, comprising Atomizer for atomizing liquid preparation; Respiratory simulator for simulating breathing inhaling atomized liquid preparation; Filtering and retaining device for retaining atomized liquid preparation, the filtering and retaining device is equipped with filter membrane, one end of the filtering and retaining device is communicated with the atomization outlet of atomizer, the other end is communicated with the inlet of respiratory simulator; Suction and pressure device for extracting liquid preparation in filter membrane.

2. A test device for inhalation of a liquid formulation according to claim 1 characterised in that, The atomizer comprises atomizer main machine, connecting pipe, atomization cup and mouthpiece connected in sequence, the atomizer main machine is used to generate compressed air, and the atomization cup is used to place liquid reagent.

3. A test device for inhalation of a liquid formulation according to claim 2, characterised in that, The filtering and retaining device comprises atomization joint, filter membrane site and respiratory joint, the filter membrane site is located between atomization joint and respiratory joint, the atomization joint is connected with mouthpiece, and the respiratory joint is communicated with respiratory simulator.

4. A test method for inhalation of a liquid formulation, characterized by, The utility model relates to a kind of inhalation test device, comprising Step one, first filter membrane is installed in filtering and retaining device, filtering and retaining device is connected with atomizer and respiratory simulator, quantitative preparation to be measured is placed in atomizer, breathing mode is set, and atomizer is started to atomize simultaneously; Step two, atomize to predetermined time, stop respiratory simulator and atomizer, first filter membrane is taken out, is placed in container, is added with infiltration liquid after ultrasonic, after ultrasonic, first filter membrane is placed in suction and pressure device, is extracted after infiltration liquid, and first filter membrane is squeezed, the obtained solution is added in container to obtain first mixed solution; Step three, second filter membrane is installed in filtering and retaining device, breathing mode is set, and atomizer is started to atomize simultaneously, until inhaling liquid preparation is completely atomized, second filter membrane is taken out, and second filter membrane is handled according to the operation steps in step two, to obtain second mixed solution, and third mixed solution is obtained by flushing atomizer with infiltration liquid; Step four, the content API of three mixed solutions in inhaling liquid preparation is measured by liquid chromatograph, and the delivery rate, total delivery amount and recovery rate of inhaling liquid preparation are calculated.

5. A test method for inhalation of a liquid formulation as claimed in claim 4, characterized in that, The breathing mode in step one includes adult mode and child mode, the adult mode is tidal volume 500ml, breathing frequency 15 cycles / min, breathing waveform sinusoidal, and inspiration-expiration ratio 1:1;The child mode is tidal volume 155ml, breathing frequency 25 cycles / min, breathing waveform sinusoidal, and inspiration-expiration ratio 1:

2.

6. The test method for inhalation of a liquid formulation as claimed in claim 4, wherein, The atomization time in step two is 1min, the infiltration liquid is sodium dihydrogen phosphate solution, the ultrasonic time is 10-20min, and the suction and pressure frequency is 10-15 times.

7. The test method for inhalation of a liquid formulation as claimed in claim 4, wherein, The atomization time in step three is 10-20min, the ultrasonic time is 10-20min, and the suction and pressure frequency is 10-15 times.

8. The test method for inhalation of a liquid formulation as claimed in claim 4, wherein, The chromatographic conditions in step four are as follows: Filler: octylsilane bonded silica gel; Mobile phase A: 0.025mol / L sodium dihydrogen phosphate solution containing 0.05% triethylamine, pH 3; Mobile phase B: acetonitrile-methanol mixed solution with a volume ratio of 65:35; Flow rate: 1.0ml / min;column temperature: 30℃;detection wavelength: 273nm;injection volume: 50μl;running time: 15min.

9. A test method for inhalation of a liquid formulation as claimed in claim 8, characterized in that, The calculation formula of delivery rate in step four is: delivery rate = the amount of detected API in first mixed solution / atomization time. The calculation formula of the total delivery amount is: total delivery amount = the amount of API detected in the first mixed solution + the amount of API detected in the second mixed solution; The calculation formula of the recovery rate is: recovery rate = (the amount of API detected in the first mixed solution + the amount of API detected in the second mixed solution + the amount of API detected in the third mixed solution) / the amount of atomized medicament.

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