Study On Environmental Factors Affecting The Characteristics Of Inhaled Aerosol Preparations

The delivery dose（DD）is the dose released from the device when the inhaled preparation is used.It is a dose that directly enters the patient’s mouth.It is closely related to the clinical basis of the doctor and the actual effect of the patient’s use.2020Chinese Pharmacopoeia The inhaled formulation general public notice has required that the delivered dose should be indicated on the label.The difference in the aerodynamic particle size distribution（APSD）of inhaled preparations will affect the particle deposition site in the respiratory tract,there by affecting the effective deposition rate of drug particles in the lungs.DD and APSD are generally considered to be the main indicators of the effectiveness of inhaled preparations in vitro.In the test of cascade impact method to study the delivery efficiency of inhaled preparations,the effects of the above equipment parameters have been thoroughly explored,but there are many environmental factors that will affect its delivery efficiency.In order to achieve better results under actual conditions of use,external factors affecting the ejection and delivery of inhaled formulation drugs must also be considered.This article investigates the characteristics of drug formulations of ambient temperature,humidity,and sample temperature by examining the delivered dose and aerodynamic particle size distribution of solution-based and suspension-type metered dose inhaler（MDI）under different measurement conditions.The effect of this will provide basis for determining the formulation of the formulation,determining the drug labeling and guiding the clinical use.In this paper,different types of suspension budesonide,SFH11402 inhalation aerosol and solution ipratropium bromide inhalation aerosol are used as model drugs.Firstly,the environmental conditions for solution and mixed Based on the effect of drug delivery dose of suspension aerosol,on this basis,when using different fine particle measurement devices（two-stage glass impactor TI and new generation cascade impactor NGI）,the environmental conditions(including ambient temperature and humidity and The effect of sample test temperature on the percentage of microparticle dose and aerodynamic particle size distribution test results of drug particles,and the results were statistically analyzed:p<0.05 is a significant difference,p<0.01 is a very significant difference.The specific content and results are as follows:（1）Effect of environmental conditions on three MDI delivery doses.Respectively at ambient temperature（18℃,22-25℃,32℃）,ambient humidity（RH30%±5%,RH50%±5%,RH80%±5%）,sample tank temperature（5℃,22-25℃,40℃）conditions,using the DUSA tube method to test the delivery dose of three kinds of MDI,the results show that each environmental factor has no significant effect on the two types of MDI delivery dose,the results have no statistical difference（p>0.05）.（2）The impact of environmental conditions on the use of two stage impactors（TSI）to test the MDI fine particles.The FPF%measured under ambient temperature（18-32℃）and ambient humidity（30-80%）has no significant difference.The canister temperature has a significant effect on the fine particle fraction measured by TI.Compared with the high temperature（40℃）,the FPF of the three MDIs measured at a low temperature（5℃）is reduced by 40.39%（BUD）,40.16%（SFH11402）and 37.82%（IPT）respectively;Compared with room temperature（22-25℃）,the FPF of the three MDIs measured at low temperature（5℃）decreased by37.04%（BUD）,34.72%（SFH11402）,28.36%（IPT）respectively,the results have a very significant difference（p<0.01）;there is no significant difference between the sample at room temperature and high temperature.（3）The influence of environmental conditions on the aerodynamic particle size distribution of MDI using the New Generation Impactor（NGI）.There is no significant difference in FPF%measured at ambient temperature（18-32℃）,but MMAD and GSD increase at 18℃;.Ambient humidity has a significant effect on the measured FPF%and MMAD of the aerosol.Compared with the low humidity of 30%,the FPF of the three MDIs measured at high humidity of 80%was reduced by 17.94%（BUD）,21.22%（SFH11402）,12.74%（IPT）;Compared with 50%of medium humidity,the FPF of the three MDIs measured under high humidity 80%conditions were reduced by 13.69%（BUD）,18.64%（SFH11402）,9.03%（IPT）,（p<0.05）,and MMAD increased significantly under high humidity conditions（p<0.05）,the deposition of drug particles in various parts changed;There was no significant difference between the results of RH30%and RH50%.The canister temperature also has a significant effect on the fine particle fraction and MMAD of MDI measured by NGI:Compared with the high temperature（40℃）,the FPF of the tank temperature measured at low temperature（5℃）is reduced by 21.86%（BUD）,29.51%（SFH11402）,26.85%（IPT）;Compared with room temperature（22-25℃）,the FPF measured at a low temperature（5℃）of the tank body is reduced by22.80%（BUD）and 28.76%respectively（SFH11402）,26.55%（IPT）,compared with room temperature（22-25℃）and high temperature（40℃）MMAD increased significantly,the results have a very significant difference（p<0.01）;There is no significant difference between the sample normal temperature and high temperature.（4）Multiple linear regression analysis of various factors affecting the diameter distribution of mdi for NGI determination.The multiple linear regression equation of SFH11402 aerosol FPF%（Y）using sample data fitting independent variables ambient temperature（X₁）,ambient humidity（X₂）,sample temperature（X₃）:Y^{^}=38.830+0.029X₁—0.170X₂+0.297X₃,R²=0.763.The determination coefficient indicates that the effect of this equation is better.The canister temperature had the greatest effect on the fumarate formoterol FPF%,followed by the environmental humidity,and the ambient temperature had basically no effect.Conclusion:The study found that environmental conditions have different degrees of influence on the in vitro aerodynamic particle size distribution determination of inhaled aerosols.The temperature and humidity of the environment and the temperature of the canister should be considered in the process of in vitro evaluation and determination of aerosol particle size and distribution of inhaled preparations.At the same time,it is suggested that MDI stored at low temperature should be returned to room temperature before use.