Hydrogen sulfide rapid detection device and method for clinical use of inhaled acetylcysteine solution

Abstract

The application discloses a kind of inhaled acetylcysteine solution clinical use hydrogen sulfide rapid detection device and method, the device includes gas detector, atomizer and atomizing cup, the atomizer is connected by first pipeline seal the detection end of gas detector, the first pipeline is sealed by sealing membrane with atomizing cup is set.The method mainly includes obtaining the concentration of the gas detector in the preset time within the preset time period, the preset time period includes multiple detection times, the time interval between each detection time is equal;With detection time as abscissa, concentration as ordinate, draw curve, calculate the total amount of hydrogen sulfide gas detection curve area.The different time values of hydrogen sulfide can reflect the release characteristics of the drug in clinical use, and the total amount of hydrogen sulfide calculated according to the formula can reflect the situation of hydrogen sulfide in the preparation, which can provide technical guidance for the clinical use of inhaled acetylcysteine solution.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of hydrogen sulfide detection, in particular to a hydrogen sulfide rapid detection device and method for clinical use of inhaled acetylcysteine solution. BACKGROUND

[0002] Acetylcysteine is a classic expectorant drug, and inhaled acetylcysteine solution is its inhalation dosage form. Inhaled acetylcysteine solution is unstable under high temperature and high pressure conditions, and hydrogen sulfide, a toxic gas impurity formed by the easy loss or oxidation of the free thiol group in its structure, seriously affects the safety of the use of the product. At present, only the British Pharmacopoeia has collected the hydrogen sulfide detection standard of acetylcysteine injection, and its method is consistent with the manual detection method of the drug registration standard of some enterprises in China. The Chinese Pharmacopoeia has not yet collected this product. Previous studies have shown that the manual detection method is limited by the sampling method and device, and there is a certain difference in the detection results of hydrogen sulfide. In the experiment, the experimental device is as shown in Figure 1 The sampling time is controlled within 10s, and the detection amount of hydrogen sulfide is the highest; with the increase of sample transfer and shaking time, the detection amount of hydrogen sulfide gradually decreases. Compared with the direct sampling result after shaking for 60s, the detection amount of hydrogen sulfide is reduced by about half.

[0003] The adverse reactions in the clinic are coughing, bronchospasm, nausea, vomiting, etc., which may be caused by the oxidation of the drug during production or storage, resulting in the loss of free thiol group to form hydrogen sulfide. And this product is an inhalation preparation, which is delivered into the respiratory system of the patient through the atomization device to play a role, and at the same time, hydrogen sulfide also enters the body. Therefore, it is very necessary to detect hydrogen sulfide in the clinical use of the drug.

[0004] Hydrogen sulfide is a neurotoxicant, and the hydrogen sulfide component or residue in the drug will cause adverse reactions in the human body, seriously affecting the quality of the drug. How to accurately and quickly detect the content of hydrogen sulfide is very important for drug quality evaluation. SUMMARY

[0005] In order to solve the above technical problems, the technical scheme adopted by the present application is as follows:

[0006] According to the first aspect of the present application, a hydrogen sulfide rapid detection device for clinical use of inhaled acetylcysteine solution is provided, which comprises a gas detector, an atomizer and an atomization cup, the atomizer is sealedly connected with the detection end of the gas detector through a first pipeline, and the atomization cup is sealedly arranged on the first pipeline through a sealing film.

[0007] Further, the atomizer is a compressed air type atomizer.

[0008] According to a second aspect of the present application, there is provided a method for rapid detection of hydrogen sulfide in clinical use of inhaled acetylcysteine solution, based on the device as described above, the method comprising:

[0009] feeding a sample into the atomization cup;

[0010] opening the atomizer and the gas detector, and the sample is fed into the gas detector after being atomized by the atomizer;

[0011] acquiring the concentration of the gas detector in a preset time period, the preset time period comprising a plurality of detection times, and the time intervals between the detection times being equal;

[0012] plotting a curve with the detection times as the abscissa and the concentrations as the ordinate, and calculating the total amount of hydrogen sulfide gas detection as the area of the curve.

[0013] Further, feeding a sample into the atomization cup comprises:

[0014] collecting the sample by a syringe;

[0015] breaking the sealing film arranged on the sample inlet of the atomization cup without damaging the sealing film;

[0016] feeding the sample into the atomization cup through the sample inlet of the atomization cup by the syringe;

[0017] sealing the sample inlet of the atomization cup by the sealing film.

[0018] Further, the volume of the sample collected by the syringe is 2-4 ml.

[0019] Further, the preset time is 1-20 min.

[0020] Further, the preset time is 10 min.

[0021] Further, the time intervals between the detection times are 0.1-2 s.

[0022] Further, the time intervals between the detection times are 1 s.

[0023] Further, the total amount of hydrogen sulfide gas detection is calculated by the following formula (1) and formula (2):

[0024] S(1~N)=∑1 / 2(y i +y i+1 )×(x i+1 +x i )*v (1)

[0025] Z 总= S (1-N) / 0.3 (2)

[0026] In the formula, S (1-N) is the hydrogen sulfide area and in N seconds; ∑ is the summation symbol, y i is the amount of hydrogen sulfide detected in 1 second, in ppm; y i+1 is the amount of hydrogen sulfide detected in the next 1 second, in ppm; x i+1 is the next 1 second; x i is 1 second; v is the flow rate, in ml / min; Z 总 is the total amount of hydrogen sulfide in each sample, in ppm.

[0027] Compared with the prior art, the present application has at least the following beneficial effects: the values of hydrogen sulfide detected at different times can reflect the release characteristics of the drug in clinical use, the total amount of hydrogen sulfide calculated according to the formula can relatively reflect the hydrogen sulfide in the preparation, and can provide technical guidance for the clinical use of inhaled acetylcysteine solution. BRIEF DESCRIPTION OF DRAWINGS

[0028] In the drawings, which are not necessarily drawn to scale, like reference numerals can describe similar parts throughout the various views. Like reference numerals with an alphabetical suffix have different meanings, and like reference numerals with a different alphabetical suffix can represent similar parts unless otherwise specified. The drawings, together with the description, afford the best explanation of the disclosed embodiments. The same reference numbers in different drawings can identify the same or similar elements. Such embodiments are illustrative rather than restrictive and are intended to provide examples of the present devices and methods. In all cases, the present disclosure can also include other embodiments.

[0029] Figure 1 A structural schematic diagram of an experimental device for detecting hydrogen sulfide for the clinical use of inhaled acetylcysteine solution according to one of the prior art is shown;

[0030] Figure 2 A structural schematic diagram of a rapid detection device for hydrogen sulfide for the clinical use of inhaled acetylcysteine solution according to an embodiment of the present application is shown;

[0031] Figure 3 A flowchart of a rapid detection method for hydrogen sulfide for the clinical use of inhaled acetylcysteine solution according to an embodiment of the present application is shown;

[0032] Figure 4 A flowchart of feeding a sample into the atomizing cup according to an embodiment of the present application is shown;

[0033] Figure 5 A sample gas detector result curve according to an embodiment of the present application is shown;

[0034] Figure 6 The detection result curve of two inspectors according to the embodiment of the application is shown;

[0035] Figure 7 The physical diagram of two atomizers of different brands according to the embodiment of the application is shown;

[0036] Figure 8 The detection result curve of two atomizers according to the embodiment of the application is shown;

[0037] Figure 9a The physical diagram of one style of atomizing cup according to the embodiment of the application is shown;

[0038] Figure 9b The physical diagram of another style of atomizing cup according to the embodiment of the application is shown;

[0039] Figure 10 The detection curve of different atomizing cups according to the embodiment of the application is shown;

[0040] Figure 11 The detection result of sample hydrogen sulfide according to the embodiment of the application is shown, wherein A: the detection curve of three batches of samples of Warner, B: the detection curve of three batches of samples of Stada, C: the detection curve of three batches of samples of Zanbang, and D: the detection result comparison of total hydrogen sulfide of three batches of samples of three enterprises. DETAILED DESCRIPTION

[0041] The following part of the embodiments is only for better illustrating the application, but the application is not limited to the application in the embodiments. Therefore, the skilled in the art can make non-essential improvements and adjustments to the embodiments according to the above description, and apply them to other embodiments, which are still within the protection scope of the application.

[0042] The embodiment of the application provides a hydrogen sulfide rapid detection device for clinical use of inhaled acetylcysteine solution, as shown in the figure, the device comprises a gas detector 100, an atomizer 200 and an atomizing cup 300, the atomizer 200 is sealedly connected with the detection end of the gas detector 100 through a first pipeline 400, and the atomizing cup 300 is sealedly arranged on the first pipeline 200 through a sealing film 500. Figure 2 It should be noted that the gas detector 100, the atomizer 200 and the atomizing cup 300 described herein can all use existing corresponding instruments and equipment, for example, the atomizer 200 is a compressed air type atomizer, and two structures thereof can refer to the figures shown in

[0043] Figure 7 Figure 9a and Figure 9b

[0044] ​​​The embodiment temporarily stores a certain volume of sample in the atomizing cup 300, wherein the sample is an inhaled acetylcysteine solution, and gradually introduces the sample atomized by the atomizer 200 into the detector 100, and determines the total amount of hydrogen sulfide gas detected corresponding to the current volume of sample according to the concentration monitored by the detector 100 at different monitoring times, wherein the concentration monitored by the detector 100 at different monitoring times can reflect the release characteristics of the drug in clinical use, and the total amount of hydrogen sulfide calculated according to the formula can reflect the hydrogen sulfide in the preparation, thereby providing technical guidance for the clinical use of the inhaled acetylcysteine solution.

[0045] The embodiment of the present application also provides a hydrogen sulfide rapid detection method for clinical use of an inhaled acetylcysteine solution, which is based on the device as described above, as shown in the figure, and the method comprises the following steps. Figure 3

[0046] Step S100: introducing a sample into the atomizing cup.

[0047] Step S200: opening the atomizer and the gas detector, and introducing the sample into the gas detector after atomization by the atomizer.

[0048] Step S300: obtaining the concentration of the gas detector in a preset time period, wherein the preset time period comprises a plurality of detection times, and the time intervals between the detection times are equal.

[0049] Step S400: taking the detection time as the abscissa and the concentration as the ordinate to draw a curve, and calculating the area of the curve as the total amount of hydrogen sulfide gas detection.

[0050] In some embodiments, as shown in the figure, introducing a sample into the atomizing cup comprises the following steps. Figure 4

[0051] Step S101: collecting the sample by using a syringe.

[0052] Step S102: breaking the sealing film arranged on the sample inlet of the atomizing cup without damaging the sealing film.

[0053] Step S103: introducing the sample into the atomizing cup through the sample inlet of the atomizing cup by using the syringe.

[0054] Step S104: sealing the sample inlet of the atomizing cup by using the sealing film.

[0055] In some embodiments, the volume of the sample collected by the syringe is 2-4 ml.

[0056] In some embodiments, the preset time is 1-20 min. ​​

[0057] In some embodiments, the preset time is 10 min.

[0058] In some embodiments, the time interval between each detection time is 0.1-2 s.

[0059] In some embodiments, the time interval between each detection time is 1 s.

[0060] In some embodiments, the total amount of hydrogen sulfide gas detection is calculated by the following formula (1) and formula (2):

[0061] S(1~N) =∑1 / 2(y i +y i+1 ) ×(x i+1 +x i )*v (1)

[0062] Z 总 = S(1~N) / 0.3 (2)

[0063] In the formula, S(1~N) is the area of hydrogen sulfide in N seconds; ∑ is the summation symbol, y i is the amount of hydrogen sulfide detected in 1 second, with the unit of ppm; y i+1 is the amount of hydrogen sulfide detected in the next 1 second, with the unit of ppm; x i+1 is the next 1 second; x i is 1 second; v is the flow rate, with the unit of ml / min; Z 总 is the total amount of hydrogen sulfide in each sample, with the unit of ppm.

[0064] The embodiments of the present application will be further illustrated below in combination with specific experimental data to further illustrate the feasibility and progressiveness of the present application.

[0065] Experimental apparatus and consumables: gas detector, RAE, USA; compressed air atomizer, Jiangsu Yuke Medical Equipment Co., Ltd.; compressed air atomizer, Shanghai Haier Medical Technology Co., Ltd.; atomization cup, specification 2-8 ml, medical device product. The detection device is developed by assembling the above three instruments, as shown in Figure 2 Sealing film, PARAFILM.

[0066] Samples: 3 batches of acetylcysteine solution products for inhalation from Zambon, Hainan Sida, and Warner-Lambert, Italy, respectively, a total of 9 batches of samples.

[0067] Clinical use of acetylcysteine solution inhalation hydrogen sulfide rapid detection method: the position of the nebulizer cup and hydrogen sulfide gas detector is sealed with sealing film, and the sample is sealed with sealing film at the sample opening position (the sample is ampoule packaged). The sample is taken out with a 10 ml syringe, about 3.0 ml, and the sample inlet of the nebulizer cup is immediately sealed with sealing film. After sealing, open the nebulizer, and count 10 minutes. The hydrogen sulfide gas detector reads a value every 1s, and the unit is ppm. The total number of values is 600 in 10 minutes. The detection time is taken as the abscissa, and the concentration (ppm) is taken as the ordinate to draw a curve. The area of the curve is the total amount of hydrogen sulfide gas detection (μg).

[0068] The total amount of hydrogen sulfide gas detection is calculated by the following formula (1) and formula (2):

[0069] S(1~N) = ∑1 / 2(y i +y i+1 ) × (x i+1 +x i )*v (1)

[0070] Z 总 = S(1~N) / 0.3 (2)

[0071] In the formula, S(1~N) is the area sum of hydrogen sulfide in N seconds; ∑ is the summation symbol, y i is the amount of hydrogen sulfide detected in 1 second, with the unit of ppm; y i+1 is the amount of hydrogen sulfide detected in the next 1 second, with the unit of ppm; x i+1 is the next 1 second; x i is 1 second; v is the flow rate, with the unit of ml / min; Z 总 is the total amount of hydrogen sulfide in each sample, with the unit of ppm.

[0072] The specificity, precision and durability of the clinical use of acetylcysteine solution inhalation hydrogen sulfide rapid detection method were verified.

[0073] Specificity:

[0074] ①Take 3 ml of sterile water and add it to the nebulizer cup. Seal the sample inlet of the nebulizer cup with sealing film. After sealing, open the nebulizer and gas detector, and count 10 minutes. The gas detector measures the results as 0 ppm, with no curve fluctuation.

[0075] ②Connect the gas detector sample inlet to the N2 bottle outlet, open the gas detector, and count 10 minutes. Record the detection results, which are all 0 ppm, with no curve fluctuation.

[0076] Precision:

[0077] ①Repeatability

[0078] Take Warner large sample 1 batch, according to the above experimental method operation, repeat 6 times experiment, record the test results, as Figure 4 The results of the gas detector showed consistent curves. The concentration of hydrogen sulfide in the sample reached 100 ppm, the high explosion value of the instrument, at about 30 s. Then it quickly dropped to less than 5 ppm within 60 s, and to less than 1 ppm at 140 s. The value of hydrogen sulfide remained at about 0.3 ppm thereafter. The total amount of hydrogen sulfide and RSD% of six repeated experiments are shown in Table 1. The total amount of hydrogen sulfide in the sample was calculated according to the formula in the experimental method. As can be seen from Table 1, the total amount of hydrogen sulfide in the sample was 13.3 ppm, and the total amount of hydrogen sulfide within 60 s was 11.0 ppm. The total amount of hydrogen sulfide detected within the first 60 s accounted for more than 78% of the total amount of hydrogen sulfide in the sample. The RSD% of the total amount of hydrogen sulfide in the sample detected in six experiments was 5.7%, indicating good repeatability of the method.

[0079] Table 1 Reproducibility test results

[0080]

[0081]

[0082] ②Intermediate precision

[0083] Warner large sample 1 batch, two inspectors made three times respectively, the results as Figure 5 From the result curve, it can be seen that the detection results of the two inspectors can completely coincide, and the RSD of the results is 2.0%.

[0084] Table 2 Detection results of different inspectors

[0085]

[0086] Durability:

[0087] ①Different atomizers

[0088] Two brands of atomizers were selected, namely Yujie and Haier as Figure 6 , which belong to medical equipment products, and the flow rate is 0.2 ml / min, as Figure 7 shown, the result curves of the two atomizers detecting the same sample coincide to a large extent, and the specific detection results are shown in Table 3, and the RSD% is 4.2%.

[0089] Table 3 Detection results of two atomizers

[0090]

[0091] ②Different atomizing cups

[0092] Two different styles of nebulization cups with the same range (2-8 ml) were selected, and the styles of the nebulization cups were as shown in Figure 8 The hydrogen sulfide detection results of the two different styles of nebulization cups are shown in FIG. 9, and the results can be completely overlapped, with an RSD% of 0.2%.

[0093] Table 4: Detection results of different nebulization cups

[0094]

[0095] The summary of the verification results is shown in Table 5.

[0096] Table 5: Summary of verification results

[0097]

[0098] The samples of three batches from each of Warner Big, Zambon, and Stada were detected according to the above method, and the results are shown in Figure 10 The detection curves of the samples of Warner Big, Zambon, and Stada are consistent, and the value of hydrogen sulfide rapidly increases from a low value to a high value within 60 s, quickly decreases to a low value, and then remains at a low value until the end of the timing. The total amount of hydrogen sulfide inhaled in the acetylcysteine solution calculated according to the formula is shown in Figure 11 The total amount of hydrogen sulfide of Warner Big and Zambon is not significantly different among the three batches, and the total amount of hydrogen sulfide of Stada is significantly different from the other two. By analyzing the production processes of the three enterprises, it is found that Warner Big and Zambon adopt terminal sterilization production mode, and Stada adopts aseptic production mode without terminal sterilization. It has been reported in literature that high temperature can cause the thiol group of acetylcysteine to fall off, generating hydrogen sulfide. Therefore, the values of hydrogen sulfide detected at different times by the method can reflect the release characteristics of the drug in clinical use, and the total amount of hydrogen sulfide calculated according to the formula can reflect the situation of hydrogen sulfide in the preparation, which can provide technical guidance for the clinical use of the drug.

[0099] The above description is intended to be illustrative and not restrictive. For example, the above examples (or one or more aspects thereof) can be used in combination with each other. Other embodiments can be used as well by those having ordinary skill in the art upon the reading and comprehension of the above description. In addition, in the above detailed description, various features can be grouped together in one or more embodiments for simplicity. This should not be interpreted as a requirement that the features are necessarily grouped together in one or more embodiments. Rather, the subject matter of the present application can be less than all of the features of a particular disclosed embodiment. Accordingly, the following claims are hereby incorporated into the detailed description as examples or embodiments, wherein each claim is independently a separate embodiment, and these embodiments can be combined with each other in various combinations or permutations. The scope of the present application should be determined with reference to the appended claims and all of their full scope of equivalents.

Claims

1. A method for rapid detection of hydrogen sulfide in clinical use of inhaled acetylcysteine solution, characterized by, The application discloses a device for rapidly detecting hydrogen sulfide based on clinical use of inhaled acetylcysteine solution, which comprises a gas detector, an atomizer and an atomizing cup. The method comprises: feeding a sample into the atomizing cup; opening the atomizer and the gas detector, and atomizing the sample through the atomizer and then feeding the sample into the gas detector; acquiring the concentration of the gas detector in a preset time period within a preset time, wherein the preset time period comprises a plurality of detection times, and the time intervals between the detection times are equal; plotting a curve with the detection time as the horizontal coordinate and the concentration as the vertical coordinate, and calculating the total amount of hydrogen sulfide gas detection as the area of the curve; the total amount of hydrogen sulfide gas detection is calculated through the following formula (1) and formula (2): where S(1-N) is the area under the curve for hydrogen sulfide from 1 to N seconds; ∑ is the summation symbol; y i is the amount of hydrogen sulfide detected in 1 second, in ppm; y i+1 is the amount of hydrogen sulfide detected in the next 1 second, in ppm; x i+1 is the next 1 second; x i is 1 second; v is the flow rate, in ml / min; Z 总 is the total amount of hydrogen sulfide in each sample, in ppm.

2. The method for rapid detection of hydrogen sulfide in clinical use of inhaled acetylcysteine solution according to claim 1, characterized in that, the atomizer is a compressed air atomizer.

3. The method for rapid detection of hydrogen sulfide in clinical use of inhaled acetylcysteine solution according to claim 1, characterized in that, The feeding of the sample into the atomizing cup comprises: collecting the sample through a syringe; breaking the sealing film arranged on the sample inlet of the atomizing cup without damaging the sealing film; feeding the sample into the atomizing cup through the sample inlet of the atomizing cup through the syringe; sealing the sample inlet of the atomizing cup by using the sealing film.

4. The method for rapid detection of hydrogen sulfide in clinical use of inhaled acetylcysteine solution according to claim 3, characterized in that, The volume of the sample collected through the syringe is 2-4 ml.

5. The method for rapid detection of hydrogen sulfide in clinical use of inhaled acetylcysteine solution according to claim 1, characterized in that, The preset time is 1-20 min.

6. The method for rapid detection of hydrogen sulfide in clinical use of inhaled acetylcysteine solution according to claim 5, characterized in that, The preset time is 10 min.

7. The method for rapid detection of hydrogen sulfide in clinical use of inhaled acetylcysteine solution according to claim 1, characterized in that, The time interval between the detection times is 0.1-2 s.

8. The method for rapid detection of hydrogen sulfide in clinical use of inhaled acetylcysteine solution according to claim 7, characterized in that, The time interval between the detection times is 1 s.

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