Method for detecting granularity of raw materials in suspension for fluticasone propionate aerosol inhalation

Abstract

The invention discloses a method for detecting the granularity of raw materials in a suspension for fluticasone propionate aerosol inhalation, which comprises the following steps: heating the suspension for fluticasone propionate aerosol inhalation to be detected, and dissolving auxiliary materials to obtain a solution only containing the raw materials; adding the obtained solution into a heat-insulating dispersing agent, and dispersing again to prepare a sample suspension; and detecting the granularity of the fluticasone propionate in the obtained sample suspension by adopting a laser diffraction method. The invention provides a method suitable for detecting the granularity of raw materials in a suspension for fluticasone propionate aerosol inhalation, the suspension for fluticasone propionate aerosol inhalation is subjected to water bath heating, so that auxiliary materials are dissolved, it is guaranteed that only the fluticasone propionate raw material exists in a sample, the problem of interference of the auxiliary materials in detection of the granularity of the raw materials is avoided, and the detection accuracy of the granularity of the raw materials is improved. The accurate detection of the particle size distribution of the fluticasone propionate raw material in the suspension is realized.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical quality control, and particularly relates to a method for detecting the particle size of a raw material in a suspension of fluticasone propionate for inhalation. BACKGROUND

[0002] The statements herein are provided only to enhance understanding of the present application and are not necessarily intended to constitute the prior art.

[0003] The suspension of fluticasone propionate for inhalation is an important drug for treating respiratory diseases such as asthma, and the particle size of the raw material directly affects the lung deposition efficiency and curative effect, so controlling the particle size of the drug is a research focus of the in vitro quality evaluation of inhalation preparations.

[0004] The methods for measuring the particle size distribution of inhalants mainly include a microscope method, a Raman spectroscopy method, a laser diffraction method, a time of flight (TOF) method for measuring the aerodynamic particle size distribution, and a cascade impaction method. The laser diffraction method is a new means for measuring the particle size of drugs, can realize multiple measurements of samples in a short time, and has a wide measurement range. The particle size distribution information of the drug can be obtained according to D10, D50 and D90 (respectively representing the aerodynamic particle size of the API under 10%, 50% and 90% cumulative fraction).

[0005] In the prescription of the suspension of fluticasone propionate for inhalation, polysorbate 20 and lauryl sorbitan are used as surfactants, and the following problems exist when the particle size is detected: 1. Interference of excipients: Polysorbate 20 and lauryl sorbitan in the prescription are easy to form micelles or adsorption layers with fluticasone propionate, resulting in signal distortion during laser particle size detection, and the measured particle size is the particle size of the mixture of the excipients polysorbate 20 and lauryl sorbitan and the fluticasone propionate raw material, so the accurate particle size distribution of the fluticasone propionate raw material in the suspension cannot be obtained.

[0006] 2. Limitation of dispersion medium: The existing methods mostly use water or organic solvents, but fluticasone propionate is easy to dissolve or not easy to disperse in organic solvents, and the interference of excipients in the water dispersion system is significant.

[0007] To solve the above problems, various organic solvents were tried, but none of them could be used as a suitable dispersant. Some could not meet the requirements of both dissolving polysorbate 20 and laurilsorbate and not dissolving fluticasone propionate raw materials; some could not form a uniform suspension. Patent CN117760917 mentions a particle size detection method for an inhaled beclometasone dipropionate suspension, which uses ethyl acetate extraction to separate the raw materials and excipients in the beclometasone dipropionate suspension to be tested. While the beclometasone dipropionate is not dissolved, the water-insoluble excipients in the suspension to be tested are extracted out, so that only beclometasone dipropionate raw materials and water are left in the raffinate phase, facilitating the detection of beclometasone dipropionate particle size in the later stage. However, fluticasone propionate will dissolve in ethyl acetate, so this method is not suitable for detecting the particle size of fluticasone propionate in the suspension for nebulization and inhalation.

[0008] Therefore, there is an urgent need to develop a particle size detection method for the suspension for nebulization and inhalation of fluticasone propionate to accurately determine the particle size of the raw material in the suspension for nebulization and inhalation of fluticasone propionate, which is of great significance to the quality control of the suspension for nebulization and inhalation of fluticasone propionate. SUMMARY

[0009] In view of the deficiencies of the prior art, the purpose of the present application is to provide a method for detecting the particle size of raw materials in a suspension for nebulization and inhalation of fluticasone propionate.

[0010] To achieve the above-mentioned purpose, the present application provides the following technical solution: A method for detecting the particle size of raw materials in a suspension for nebulization and inhalation of fluticasone propionate, comprising the following steps: S1, heating the suspension for nebulization and inhalation of fluticasone propionate to be tested to dissolve the excipients, obtaining a solution in which only the raw materials are not dissolved; S2, adding the solution obtained in S1 to a dispersion agent under heat preservation, and dispersing again to prepare a sample suspension; S3, detecting the particle size of fluticasone propionate in the sample suspension obtained in S2 by laser diffraction method.

[0011] In the suspension for nebulization and inhalation of fluticasone propionate, both the raw materials and the excipients are not dissolved, and the excipients play a suspending role, making the whole system in a suspended state. When the excipients are present, the solution can be seen to be opaque and opaque like frosted glass. In the treatment method provided by the present application, in step S1, the excipients are dissolved by heating, and after the excipients are dissolved, the solution becomes colorless and transparent. At this time, the raw materials lose the assistance of the suspending agent and sink to the bottom of the solution, obtaining a solution in which only the raw materials are not dissolved.

[0012] In step S2 of the present application, the re-dispersing into a suspension means that the settled raw material is suspended again by adding into a dispersing agent to form a new suspension, and in the obtained sample suspension, the raw material is in a suspended state and the excipient is in a dissolved state.

[0013] It has been proved in the embodiments of the present application that polysorbate 20 or laurilsorbate has been dissolved at 60-80℃, and as long as the temperature is kept at 60-80℃, the polysorbate 20 or laurilsorbate can be prevented from being precipitated.

[0014] In the detection method provided by the present application, the excipient is dissolved by heating the fluticasone propionate nebulized suspension at a suitable temperature, so that only the fluticasone propionate raw material is not dissolved in the sample in the subsequent re-dispersing step, and the influence of the excipient on the detection of the particle size of the raw material is avoided.

[0015] Preferably, in step S1, a water bath heating method is used, and the water bath heating temperature is 70-90℃; in step S2, the dispersing agent is kept at a temperature of 60-80℃.

[0016] Preferably, in step S2, the dispersing agent is a mixed solution of cetyltrimethylammonium bromide and sodium hexametaphosphate; and the mass ratio of cetyltrimethylammonium bromide to sodium hexametaphosphate in the dispersing agent is 1:2-2:1.

[0017] Preferably, in step S2, the dispersing agent is a mixed solution of cetyltrimethylammonium bromide solution and sodium hexametaphosphate solution; and the concentrations of cetyltrimethylammonium bromide solution and sodium hexametaphosphate solution in the dispersing agent are 0.05%-0.2% w / v, respectively.

[0018] Preferably, the volume ratio of cetyltrimethylammonium bromide solution to sodium hexametaphosphate solution in the dispersing agent is 1:2-2:1.

[0019] Further preferably, the concentrations of cetyltrimethylammonium bromide solution and sodium hexametaphosphate solution in the dispersing agent are both 0.1%, and the volume ratio is 1:1.

[0020] Preferably, in step S2, the specific preparation steps of the sample suspension are as follows: adding the solution in which only the raw material is not dissolved into the dispersing agent kept at 60-80℃, and ultrasonicating to form a sample suspension.

[0021] In the present application, the heated sample is added into the dispersing agent kept at a temperature, and ultrasonicated to form a uniform suspension again, so as to prevent the problems of inaccurate detection results and poor repeatability caused by uneven dispersion of the raw material in the sample. Preferably, the ultrasonic power is 150-220W, and the ultrasonic time is 1-4min; further preferably, the ultrasonic power is 160-190W.

[0022] Preferably, the laser diffraction method in step S3 uses a Malvern laser particle size analyzer, the analysis mode is general mode, and the particle type is non-spherical. The Malvern laser particle size analyzer can accurately detect in the range of 0.1 to 3500 microns, which can meet the detection needs of the particle size in the suspension.

[0023] Preferably, the test parameters of the laser particle size analyzer in step S3 include: obscuration of 2% to 15%, refractive index of 1.50 to 1.60, and absorption rate of 0.01 to 0.1; stirring rate of 700 to 900 rpm, background measurement time of 5 to 15 seconds, and sample measurement time of 5 to 15 seconds.

[0024] Further preferably, the test parameters of the laser particle size analyzer in step S3 include: obscuration of 4% to 10%, refractive index of 1.53, and absorption rate of 0.1; stirring rate of 800 rpm, background measurement time of 10 seconds, and sample measurement time of 10 seconds.

[0025] Further preferably, the suspension for nebulized inhalation of fluticasone propionate contains at least one of polysorbate 20 or laurilsorbate.

[0026] Compared with the prior art, the present application has the following beneficial effects: 1. The present application provides a method for detecting the particle size of fluticasone propionate in a suspension for nebulized inhalation, which heats the suspension for nebulized inhalation of fluticasone propionate in a water bath to dissolve the excipients, ensuring that only the fluticasone propionate raw material is insoluble in the sample, avoiding the interference of the excipients in the raw material particle size detection, and realizing accurate detection of the particle size distribution of fluticasone propionate in the suspension. 2. The present application overcomes the problem that the solubility of organic solvents in the raw material and excipients cannot meet the particle size detection requirements in the particle size detection of fluticasone propionate in a suspension for nebulized inhalation, and the best detection conditions are obtained through the exploration of temperature, ultrasonic power, reagent concentration and ratio. 3. The detection method of the present application is simple to operate and has good reproducibility, which solves the problem that the prior art cannot overcome in the particle size test of fluticasone propionate in a suspension for nebulized inhalation, and provides a reliable technical means for product quality control. BRIEF DESCRIPTION OF DRAWINGS

[0027] The drawings accompanying the specification of the present application serve to provide a further understanding of the present application, and the illustrative embodiments of the present application and their descriptions serve to explain the present application, and do not constitute an improper limitation on the present application.

[0028] Figure 1Particle size distribution graph of the fluticasone propionate suspension for inhalation in Example 3 using 0.1% (w / v) cetyltrimethylammonium bromide solution: 0.1% (w / v) sodium hexametaphosphate solution = 1:1 as dispersant; Figure 2 Superimposed particle size distribution graph of three times of detection of the fluticasone propionate suspension for inhalation in Example 4 at a dispersant holding temperature of 40℃; Figure 3 Particle size change of fluticasone propionate in the fluticasone propionate suspension for inhalation under different ultrasonic powers in Example 5; wherein, from bottom to top, the three lines represent the particle size results of D10, D50 and D90 under different ultrasonic powers.

[0029] Figure 4 Superimposed particle size distribution graph of three times of detection of fluticasone propionate in the fluticasone propionate suspension for inhalation of YF24050703 batch in Example 6. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical scheme and advantages of the present application more clear, the present application is described by the following specific examples, but is not limited to this. The following description is a better embodiment of the present application, which is only used to describe the present application, and cannot be understood as a limitation of the present application. It should be pointed out that any modification, equivalent replacement and improvement made within the spirit and principle of the present application should be included in the protection scope of the present application.

[0031] In some embodiments of the present application, a detection method of the particle size of the raw material in the fluticasone propionate suspension for inhalation is provided, which comprises the following steps: S1, heating the fluticasone propionate suspension for inhalation to be detected to dissolve the auxiliary material, so as to obtain a solution in which only the raw material is not dissolved; S2, adding the solution obtained in S1 into a heated dispersant to disperse again to prepare a sample suspension; S3, detecting the particle size of fluticasone propionate in the sample suspension obtained in S2 by laser diffraction method.

[0032] In some embodiments of the present application, in step S1, the water bath heating method is used, and the water bath heating temperature is 70-90℃; in step S2, the holding temperature of the dispersant is 60-80℃.

[0033] In some embodiments of the present application, the dispersant in step S2 is a mixed solution of cetyltrimethylammonium bromide and sodium hexametaphosphate; and the mass ratio of cetyltrimethylammonium bromide to sodium hexametaphosphate in the dispersant is 1:2-2:1.

[0034] In some embodiments of the present invention, the dispersant in step S2 is a mixed solution of hexadecyltrimethylammonium bromide solution and sodium hexametaphosphate solution; the concentrations of hexadecyltrimethylammonium bromide solution and sodium hexametaphosphate solution in the dispersant are 0.05%~0.2% w / v, respectively; and the volume ratio of hexadecyltrimethylammonium bromide solution to sodium hexametaphosphate solution in the dispersant is 1:2~2:1.

[0035] In some embodiments of the present invention, the specific preparation steps of the sample suspension in step S2 are as follows: adding only the undissolved raw material solution to a dispersant kept at 60~80°C, and sonicating it to suspend it, thereby obtaining the sample suspension.

[0036] In some embodiments of the present invention, the ultrasonic power is 150~220W and the ultrasonic time is 1~4min.

[0037] In some embodiments of the present invention, the test parameters of the laser particle size analyzer in step S3 include: shading degree of 2%~15%, refractive index of 1.50~1.60, absorptivity of 0.01~0.1; stirring speed of 700~900 rpm, background measurement time of 5s~15s, and sample measurement time of 5~15s.

[0038] In some embodiments of the present invention, the fluticasone propionate nebulized inhalation suspension contains at least one of polysorbate 20 or lauryl sorbitan as an excipient.

[0039] In some embodiments of the present invention, the raw material particle size D 10 For any value within the range of 0.5, 0.6, 0.7, 0.8, 0.9, 1.1, 1.2, or 0.5~1.2 μm, D 50 For any value within the range of 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5 or 1.4~2.5 μm, D 90 It can be any value within the range of 2.5, 3.0, 3.5, 4.0, 5.0 or 2.5~5.0 μm.

[0040] In this embodiment, the instrument parameters for the particle size testing method are set as follows: Injector system name: Hydro SV; Refractive index: 1.53; Absorption rate: 0.1; Background measurement time: 10s; Sample measurement time: 10s; Light blocking rate range: 4%-10%; Speed: 800 rpm; Analysis model: General; Result type: Volume distribution.

[0041] The particle size of the different batches of raw materials used in the following examples is shown in Table 1: Table 1

[0042] Example 1: Method for determining the particle size of raw materials in fluticasone propionate nebulized inhalation suspension 1. Preparation of reagents: Preparation of 0.1% hexadecyltrimethylammonium bromide solution: Weigh 1g of hexadecyltrimethylammonium bromide into 1000mL of water, stir thoroughly to dissolve, and keep warm at 70℃.

[0043] Preparation of 0.1% sodium hexametaphosphate solution: Weigh 1g of sodium hexametaphosphate into 1000mL of water, stir thoroughly to dissolve, and keep warm at 70℃.

[0044] 2. Preparation of sample suspension Take the fluticasone propionate nebulization suspension, heat it in an 80°C water bath to dissolve the excipients, and after the solution becomes clear, add it to a dispersant (0.1% (w / v) hexadecyltrimethylammonium bromide solution: 0.1% (w / v) sodium hexametaphosphate solution = 1:1) kept at 70°C, and sonicate it to suspend it. The ultrasonic power is 175W to obtain the sample suspension.

[0045] 3. Sample Measurement After the instrument background test is completed, the sample suspension is slowly added to the sample cell of the injector for testing. The results are shown in Table 2: Table 2

[0046] The particle size of fluticasone propionate in the product obtained by this method is almost the same as that of the raw material, which shows that this method can accurately detect the particle size of the raw material in the fluticasone propionate nebulized inhalation suspension.

[0047] Example 2: Comparison of excipient solubility in fluticasone propionate nebulized suspension under different temperature conditions The fluticasone propionate nebulized suspension was heated in a water bath at temperatures of 40°C, 50°C, 60°C, 70°C, 80°C, and 90°C respectively. The dissolution of excipients in the fluticasone propionate nebulized suspension under different temperature conditions was compared. Other conditions were the same as in Example 1.

[0048] The results are shown in Table 3: Table 3

[0049] In the table above, "solution clarification" refers to the dissolution of excipients and the settling of raw materials, at which point the solution is clear because there are no excipients present.

[0050] As shown in the table above, when the water bath temperature is low, the excipients cannot be completely dissolved, and a clear and transparent solution cannot be obtained. When the water bath temperature is above 60°C, the excipients in the suspension can be completely dissolved, and the time required to dissolve the excipients decreases as the temperature increases. In conjunction with this invention, considering the upper limit of the water bath heating temperature and the heating time, a water bath heating temperature of 70~90°C is selected.

[0051] Example 3: Different dispersants were used for particle size analysis of raw materials in sample suspensions. Fluticasone propionate nebulization suspension prepared from raw material batch YF2209915 was heated in an 80°C water bath to dissolve the excipients. After the solution became clear, it was added to a dispersant kept at 70°C and sonicated to suspend the suspension. The ultrasonic power was 175W to obtain the sample suspension. Three samples were prepared in the same way.

[0052] In the above operations, the following dispersants were used: 0.05% (w / v) hexadecyltrimethylammonium bromide solution: 0.2% (w / v) sodium hexametaphosphate solution = 2:1, 0.1% (w / v) hexadecyltrimethylammonium bromide solution: 0.1% (w / v) sodium hexametaphosphate solution = 2:1, 0.1% (w / v) hexadecyltrimethylammonium bromide solution: 0.1% (w / v) sodium hexametaphosphate solution = 1:1, 0.1% (w / v) hexadecyltrimethylammonium bromide solution: 0.1% (w / v) sodium hexametaphosphate solution = 1:2, and 0.2% (w / v) hexadecyltrimethylammonium bromide solution: 0.2% (w / v) sodium hexametaphosphate solution = 1:1. The effect of different dispersants on the sample suspension was investigated, and the results are shown in Table 4. Table 4

[0053] From the data in Table 4 and Figure 1It can be seen that using 0.05% (w / v) hexadecyltrimethylammonium bromide solution : 0.2% (w / v) sodium hexametaphosphate solution = 2:1, 0.1% (w / v) hexadecyltrimethylammonium bromide solution : 0.1% (w / v) sodium hexametaphosphate solution = 2:1, 0.1% (w / v) hexadecyltrimethylammonium bromide solution : 0.1% (w / v) sodium hexametaphosphate solution = 1:1, and 0.1% (w / v) hexadecyltrimethylammonium bromide solution : 0.1% (w / v) sodium hexametaphosphate solution = 1:1, 0.1% (w / v) hexadecyltrimethylammonium bromide solution : 0.1% (w / v) sodium hexametaphosphate solution = ... Using 0.2% (w / v) sodium hexametaphosphate solution at a ratio of 1:2 and 0.2% (w / v) hexadecyltrimethylammonium bromide solution at a ratio of 1:1 as dispersants, the RSD was less than 10%, meeting the limit requirements. Further analysis of the data showed that the concentrations and ratios of the hexadecyltrimethylammonium bromide solution and sodium hexametaphosphate solution had varying degrees of impact on the particle size distribution. Adjusting their concentrations and ratios improved the RSD of the particle size distribution, especially the D... 10 and D 90 The RSD of the results showed that the particle size results had the best repeatability and corresponded to the particle size results of the raw materials used when using a 0.1% (w / v) hexadecyltrimethylammonium bromide solution: 0.1% (w / v) sodium hexametaphosphate solution = 2:1 or 0.1% (w / v) hexadecyltrimethylammonium bromide solution: 0.1% (w / v) sodium hexametaphosphate solution = 1:1.

[0054] Example 4: Detection of raw material particle size in sample suspensions under different dispersant incubation temperatures. Fluticasone propionate nebulization suspension prepared from raw material batch YF2209915 was heated in an 80°C water bath to dissolve the excipients. After the solution became clear, it was added to a dispersant (0.1% (w / v) hexadecyltrimethylammonium bromide solution: 0.1% (w / v) sodium hexametaphosphate solution = 1:1) kept at 40°C. The suspension was then sonicated at a power of 175W to obtain the sample suspension. Three samples were prepared using the same method.

[0055] As mentioned above, the dispersant was kept at water temperatures of 50℃, 60℃, 70℃, 80℃, and 90℃ respectively to investigate the effect of different holding temperatures on the preparation of sample suspensions. The results are shown in Table 5 and... Figure 2 As shown: Table 5

[0056] As shown in Table 5, when using 40℃ and 50℃ as the holding temperature for the dispersant, the particle size test results of the sample suspension could not be stably reproduced. When using 60℃, 70℃, and 80℃ as the holding temperature for the dispersant, the particle size test results of the sample suspension showed good reproducibility, with RSDs all less than 10%, meeting the limit requirements. At 90℃, the particle size decreased slightly, suggesting that the raw material partially dissolved in the dispersant at 90℃. Based on this invention, a holding temperature of 60~80℃ was selected, preferably 70℃. Figure 2 It can be seen that when 40℃ is used as the holding temperature for the dispersant, the particle size distribution map shows huge differences when the test is repeated three times. This indicates that the excipients have not completely dissolved at this temperature, which seriously interferes with the particle size test results.

[0057] Example 5: Detection of raw material particle size in sample suspension under different ultrasonic powers Fluticasone propionate nebulization suspension prepared from raw material batch YF2209915 was heated in an 80°C water bath to dissolve the excipients. After the solution became clear, it was added to a dispersant (0.1% (w / v) hexadecyltrimethylammonium bromide solution: 0.1% (w / v) sodium hexametaphosphate solution = 1:1) kept at 70°C. The suspension was then sonicated at a power of 175W to obtain a sample suspension. The particle size was then tested using the method described in this patent.

[0058] As mentioned above, ultrasonic powers of 50W, 100W, 160W, 175W, and 190W were used to investigate the effect of different ultrasonic powers on the preparation of sample suspensions. The results are shown in Table 6 and... Figure 3 As shown: Table 6

[0059] From Table 6 and Figure 3 It can be seen that at ultrasonic powers of 50W and 100W, the particle size distribution results are significantly larger, indicating that the sample is not sufficiently dispersed at these power levels. At ultrasonic powers of 150-220W, the particle size distribution results are basically consistent, indicating that the sample is not broken and is well dispersed. Based on this invention, an ultrasonic power of 150-220W can be considered the recommended power, with 160-190W being optimal.

[0060] Example 6: Accuracy and Reproducibility Test Three batches of fluticasone propionate nebulization suspensions were prepared using raw materials of different particle sizes. Each batch of fluticasone propionate nebulization suspension was heated in an 80°C water bath to dissolve the excipients. After the solution became clear, it was added to a dispersant (0.1% (w / v) hexadecyltrimethylammonium bromide solution: 0.1% (w / v) sodium hexametaphosphate solution = 1:1) kept at 70°C. The suspension was then sonicated at 175W to obtain the sample suspension. Particle size was determined according to the method described in this invention. The results are shown in Table 7 and... Figure 4 As shown: Table 7

[0061] From Table 7 and Figure 4 It can be seen that, using the method described in this application, the RSD of three batches of fluticasone propionate nebulized inhalation suspension prepared using raw materials of different particle sizes was less than 10%, which meets the limit requirements. The method of the present invention has good accuracy and reproducibility. Figure 4 The image in the middle is a superimposed graph of three tests on batch YF24050703. It can be seen that the repeatability is good and the particle size distribution curves of the three tests basically overlap.

[0062] Comparative Example 1: Comparison of the dispersion effects of other dispersants Water, 0.05%–0.3% Triton X-100 aqueous solution, 0.01%–0.5% Tween 80 aqueous solution, methanol, isooctane, ethyl acetate, 0.1% (w / v) hexadecyltrimethylammonium bromide solution, and 0.1% sodium hexametaphosphate solution were used as dispersants. The above dispersants were kept at 70°C, and the state of each solution was observed. An attempt was made to disperse the fluticasone propionate suspension (with excipients dissolved by heating) using 175W ultrasonic power, with other conditions the same as in Example 1. The results are shown in Table 8. Table 8

[0063] As shown in the table above, when the above dispersants were kept at 70°C and the test fluticasone propionate suspension (with excipients dissolved by heating) was attempted to be dispersed, water, methanol, and isooctane could not form a uniform suspension when used directly as dispersants. Ethyl acetate dissolved the fluticasone propionate raw material and could not be used as a dispersant. Dispersants with Triton X-100 and Tween 80 as surfactants dissolved at 70°C, and the surfactants lost their function. 0.1% (w / v) hexadecyltrimethylammonium bromide solution and 0.1% (w / v) sodium hexametaphosphate solution still had some suspending effect at 70°C, but both had different degrees of defects. It is proposed to investigate the effect of mixing the two at different concentrations and ratios as dispersants.

[0064] Comparative Example 2: Comparison of the dispersion effects of other dispersants The suspension effects of different concentrations and ratios of hexadecyltrimethylammonium bromide solution and sodium hexametaphosphate solution were compared, with other conditions being the same as in Example 1.

[0065] The dispersion effects of 0.05%, 0.1%, and 0.2% (w / v) hexadecyltrimethylammonium bromide solutions with 0.05%, 0.1%, and 0.2% (w / v) sodium hexametaphosphate solutions in different proportions were investigated, and the results are shown in Table 9. Table 9

[0066] As shown in Table 9, when the concentrations of both hexadecyltrimethylammonium bromide solution and sodium hexametaphosphate solution are low, some raw materials will precipitate regardless of the mixing ratio, and a uniform suspension cannot be formed. When the concentrations of both hexadecyltrimethylammonium bromide solution and sodium hexametaphosphate solution are high (above 0.1%), a uniform suspension can be formed regardless of the mixing ratio, and the stability is good. When the concentration of hexadecyltrimethylammonium bromide solution is low and the concentration of sodium hexametaphosphate solution is high, the proportion of hexadecyltrimethylammonium bromide solution needs to be increased to form a uniform suspension. When the concentration of hexadecyltrimethylammonium bromide solution is high and the concentration of sodium hexametaphosphate solution is low, a uniform suspension can be formed, and increasing the proportion of sodium hexametaphosphate solution can improve the stability.

[0067] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for detecting the particle size of raw materials in a fluticasone propionate nebulized inhalation suspension, characterized in that, Includes the following steps: S1, the fluticasone propionate to be tested is nebulized and inhaled, and the suspension is heated to dissolve the excipients, resulting in a solution in which only the raw material remains undissolved; S2, add the solution obtained in S1 to the heat-insulating dispersant, and disperse again to prepare a sample suspension; S3, the particle size of fluticasone propionate in the sample suspension obtained in S2 was determined by laser diffraction.

2. The method for detecting the particle size of raw materials in the fluticasone propionate nebulized inhalation suspension according to claim 1, characterized in that, In step S1, a water bath heating method is used, and the water bath heating temperature is 70~90℃; in step S2, the dispersant is kept at a temperature of 60~80℃.

3. The method for detecting the particle size of raw materials in the fluticasone propionate nebulized inhalation suspension according to claim 1, characterized in that, The dispersant in step S2 is a mixed solution of hexadecyltrimethylammonium bromide and sodium hexametaphosphate; the mass ratio of hexadecyltrimethylammonium bromide to sodium hexametaphosphate in the dispersant is 1:2 to 2:

1.

4. The method for detecting the particle size of raw materials in the fluticasone propionate nebulized inhalation suspension according to claim 1, characterized in that, The dispersant mentioned in step S2 is a mixed solution of hexadecyltrimethylammonium bromide solution and sodium hexametaphosphate solution; the concentrations of hexadecyltrimethylammonium bromide solution and sodium hexametaphosphate solution are 0.05%~0.2% w / v, respectively.

5. The method for detecting the particle size of raw materials in the fluticasone propionate nebulized inhalation suspension according to claim 4, characterized in that, The volume ratio of hexadecyltrimethylammonium bromide solution to sodium hexametaphosphate solution in the dispersant is 1:2 to 2:

1.

6. The method for detecting the particle size of raw materials in the fluticasone propionate nebulized inhalation suspension according to claim 1, characterized in that, The specific preparation steps of the sample suspension in step S2 are as follows: add the solution containing only undissolved raw materials to a dispersant kept at 60~80℃, and sonicate to suspend it, thus obtaining the sample suspension.

7. The method for detecting the particle size of raw materials in the fluticasone propionate nebulized inhalation suspension according to claim 6, characterized in that, The ultrasonic power is 150~220W, and the ultrasonic time is 1~4min; the ultrasonic power is further preferably 160~190W.

8. The method for detecting the particle size of raw materials in the fluticasone propionate nebulized inhalation suspension according to claim 1, characterized in that, The instrument used in step S3 for the laser diffraction method is a Malvern laser particle size analyzer, the analysis mode is general mode, and the particle type is non-spherical.

9. The method for detecting the particle size of raw materials in the fluticasone propionate nebulized inhalation suspension according to claim 8, characterized in that, The test parameters of the laser particle size analyzer in step S3 include: shading degree of 2%~15%, refractive index of 1.50~1.60, absorptivity of 0.01~0.1; stirring speed of 700~900 rpm, background measurement time of 5s~15s, and sample measurement time of 5~15s.

10. The method for detecting the particle size of raw materials in the fluticasone propionate nebulized inhalation suspension according to claim 1, characterized in that, The fluticasone propionate nebulized suspension contains at least one of polysorbate 20 or lauryl sorbitan as an excipient.

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