Method for evaluating influence of storage conditions on efficacy of posaconazole enteric-coated tablets

Abstract

The invention relates to a method for evaluating the influence of storage conditions on the drug effect of posaconazole enteric-coated tablets, which is applied to the field of drug detection, by simulating the actual seasonal environment, firstly, drugs are respectively stored in the four-season simulation environment of spring, summer, autumn and winter, and through regular drug effect testing, the influence of the four-season environment temperature on the drug effect of the drugs is effectively evaluated; according to the evaluation result, the maximum continuous taking quantity of a doctor for a patient during single medicine preparation in each season can be strictly stipulated in actual application, so that the actual treatment effect of the medicine is not greatly different from the expected treatment effect due to long-term storage factors, and meanwhile, the treatment effect of the medicine is greatly improved. The method comprises the following steps of: respectively carrying out spring-to-summer, summer-to-autumn, autumn-to-winter and winter-to-spring environment replacement on medicines after passing through a four-season simulation environment for one month, and then effectively evaluating the influence of actual season replacement on the medicines through a medicine effect test, so as to further stipulate the maximum quantity of medicines which are allowed to be prepared by a doctor at a single time at the tail sound of each season; furthermore, the drug treatment effect is consistent with the expected treatment effect.

Description

Technical Field

[0001] The present invention relates to an evaluation method, and in particular to an evaluation method for the effect of storage conditions on the efficacy of posaconazole enteric-coated tablets, which is applied to the field of drug detection. Background Art

[0002] Posaconazole is an antifungal drug, commonly available in enteric-coated tablets and oral suspension. The stability and effectiveness of enteric-coated posaconazole tablets may change under different storage conditions. Temperature, humidity, light and other factors can affect the chemical composition and physical structure of the tablets, thereby affecting their efficacy.

[0003] The Chinese patent CN111103368B specification discloses a method for predicting the shelf life of esomeprazole enteric-coated tablets, using the impurity content with a relative retention time of 0.35 in the high-performance liquid chromatogram of esomeprazole enteric-coated tablets obtained by the related substance detection method in the 2015 edition of the Pharmacopoeia as an indicator, analyzing the indicator content in different temperature and humidity environments, obtaining a curve of impurity content changing with time under the corresponding temperature T and humidity RH conditions and the shelf life t, performing linear regression on 1 / T and RH with ln1 / t, and using the humidity-corrected Arrhenius equation to predict the shelf life of esomeprazole enteric-coated tablets at a specific storage temperature and humidity. The shelf life prediction equation established by the present invention has a short test cycle, good repeatability, and reliable prediction results.

[0004] The specification of Chinese patent CN112877397B discloses a method for evaluating the efficacy of antimicrobial drugs against intracellular bacterial infection and its application. The method comprises: obtaining an antimicrobial drug efficacy index ρ value based on changes in the cell infection percentage NIC and the total amount of intracellular bacterial invasion NIB before and after antimicrobial drug treatment; evaluating the efficacy of the antimicrobial drug according to the antimicrobial drug efficacy index ρ value, and the closer the ρ value is to 1, the better the efficacy is. The method adopts different soft and hard substrates established by polyacrylamide hydrogel, and takes host cells into consideration, which is closer to the infection situation in the host body, and is more conducive to simulating the mechanical microenvironment of cells in the host body when they are infected by pathogens. It is simple and intuitive and closer to the in vivo drug treatment model.

[0005] The existing means of evaluating the effect of storage conditions on drug efficacy mostly involves placing the drug under different environmental conditions such as temperature, humidity or light, and testing the effect of a single environmental variable on the drug efficacy (e.g., setting different temperatures to test the effect of the drug under different temperature conditions, or setting different light conditions to test the effect of the drug under different light conditions, etc.). However, in actual situations, after the drug is purchased by the patient, it is generally at room temperature. Moreover, due to the different temperatures in the four seasons, the efficacy of the drug will change to varying degrees after it is purchased, which will have different degrees of impact on the patient's treatment effect. Therefore, the existing means of testing the effect of a single environmental variable on drug efficacy is quite different from the actual storage conditions, and it is difficult to effectively evaluate the storage quality of the drug in the actual environment. Summary of the invention

[0006] In view of the above-mentioned prior art, the technical problem to be solved by the present invention is that the existing means of evaluating the impact of storage conditions on drug efficacy mostly test the impact of a single environmental variable on drug efficacy. This method is quite different from the actual storage conditions and it is difficult to effectively evaluate the storage quality of drugs in the actual environment.

[0007] In order to solve the above problems, the present invention provides a method for evaluating the effect of storage conditions on the efficacy of posaconazole enteric-coated tablets, comprising the following steps:

[0008] S1. Select a batch of posaconazole enteric-coated tablets that are of qualified quality and packaged in the same batch, simulate the temperature change of the pharmacy, and store the drugs in the simulated environment of the pharmacy for 1-2 months;

[0009] S2. Seasonal test: The drugs are randomly and evenly grouped to obtain one group of control drugs and four groups of test drugs. The control drugs are still stored in the simulated environment of the pharmacy. The four groups of test drugs are placed in the simulated environments of spring, summer, autumn and winter, respectively. The simulated environment in spring is 15-25°C and the relative humidity is 40% to 60%, the simulated environment in summer is 25-35°C and the relative humidity is 60% to 80%, the simulated environment in autumn is 10-20°C and the relative humidity is 30% to 50%, and the simulated environment in winter is 0-10°C and the relative humidity is 20% to 40%;

[0010] In the following 1-3 months, at the end of each month, the same number of samples were randomly taken from the five groups of drugs for efficacy testing to evaluate the effects of different seasonal environments on the efficacy of drugs after storage;

[0011] S3, seasonal change test: at the end of the first month in step S2, randomly take out a portion of the four groups of test drugs, and then simulate the actual seasonal change, and change the storage conditions of the four groups of test drugs to simulate the environment from spring to summer, from summer to autumn, from autumn to winter, and from winter to spring, that is, the test drugs taken out from the spring simulated environment are placed in the summer simulated environment, the test drugs taken out from the summer simulated environment are placed in the autumn simulated environment, and so on;

[0012] In the following 1-3 months, at the end of each month, the same number of samples were randomly taken from the five groups of drugs for efficacy testing to evaluate the impact of actual seasonal changes on drug efficacy;

[0013] S4. Accelerated replacement test: Select another batch of qualified and packaged posaconazole enteric-coated tablets, randomly divide them into four groups, and place them in simulated environments of spring, summer, autumn and winter respectively. The simulation standard of the environment is the same as that of step S2. Then, within 1-2 months, regularly perform the four-season cycle operation of spring to summer, summer to autumn, autumn to winter, and winter to spring on the four groups of drugs to accelerate drug aging. At the same time, every half a month, randomly take out the same number of samples from the four groups of drugs for efficacy testing, and compare them with the drug efficacy in step S1 to evaluate the impact of accelerated environmental replacement on drug efficacy.

[0014] As a further supplement to the present application, the efficacy testing methods in step S2, step S3 and step S4 all use high performance liquid chromatography analysis to determine the content changes of active ingredients in the tablets.

[0015] A method for evaluating the effect of storage conditions on the efficacy of posaconazole enteric-coated tablets, further comprising the following steps:

[0016] Cross-validation test: perform step S1, then randomly divide the drugs obtained in step S1 into two groups, and place the two groups of drugs in simulated environments of summer and winter, respectively. The simulation standard of the environment is the same as that of step S2. During the storage process, the temperature of the simulated environment in summer is regularly adjusted to a high temperature peak value of 38-40°C and maintained for a short time, and the temperature of the simulated environment in winter is regularly adjusted to a low temperature valley value of -5 to 0°C and maintained for a short time;

[0017] Within 1-3 months, at the end of each month, the same number of samples are randomly taken out from the two groups of drugs for efficacy testing, and compared with the efficacy of the drugs in step S2, so as to further evaluate the impact of the extreme environment in the four seasons on the efficacy of the drugs in accordance with the actual situation.

[0018] As another improvement of the present application, a four-season zoning simulator is used to test drugs in step S2, step S3 and step S4, and the four-season zoning simulator includes a seasonal simulation test chamber, a test bench is provided inside the seasonal simulation test chamber, the upper end of the test bench is fixedly connected to the output end of the motor, and the fixed end of the motor is fixedly connected to the upper inner wall of the seasonal simulation test chamber, upper and lower sides of the test bench are respectively provided with an upper spacer ring and a lower spacer ring, the ends of the upper and lower spacer rings away from the test bench are respectively fixedly connected to the upper and lower inner walls of the seasonal simulation test chamber, a plurality of partitions are fixedly connected between the upper and lower spacer rings, and the side ends of the partitions are fixedly connected to the inner wall of the seasonal simulation test chamber.

[0019] As another improved supplement of the present application, multiple partitions divide the space composed of the upper partition ring, the lower partition ring, the test bench and the seasonal simulation test chamber into multiple environmental simulation areas, and the multiple environmental simulation areas serve as simulation areas for the four seasons of spring, summer, autumn and winter.

[0020] As another improvement supplement to the present application, the outer ring diameter of the test bench is larger than the outer ring diameters of the upper spacer ring and the lower spacer ring, a rotating groove is provided on the partition, the test bench is rotatably connected to the inside of the rotating groove, a sealing mesh is fixedly connected to the inner wall of the rotating groove, and the sealing mesh is in contact with the outer surface of the test bench.

[0021] As another improved supplement of the present application, the test bench includes a cylindrical table, and a plurality of evenly distributed medicine grooves are opened at the side ends of the cylindrical table. The medicine grooves are used to store posaconazole enteric-coated tablets to be tested, and the inner walls of the medicine grooves are fixedly connected with temperature and humidity sensors.

[0022] As another improved supplement of the present application, a mesh door plate is inserted at the edge opening of the medicine groove, a card slot is opened on the lower inner wall of the medicine groove, and a card strip is fixedly connected to the lower end of the mesh door plate, and the card strip is inserted inside the card slot.

[0023] As another improved supplement of the present application, the upper end of the seasonal simulation test chamber is fixedly connected to a humidity controlling chamber, the outer end of the humidity controlling chamber is fixedly connected to a humidity inlet pipe and a plurality of humidity controlling pipes with valves, the plurality of humidity controlling pipes penetrate the upper end of the seasonal simulation test chamber and are respectively connected to a plurality of environmental simulation areas, the upper end of the humidity controlling chamber is fixedly connected to a temperature controlling chamber, the outer end of the temperature controlling chamber is fixedly connected to a temperature inlet pipe and a plurality of temperature controlling pipes with valves, the plurality of temperature controlling pipes penetrate the upper end of the seasonal simulation test chamber and are respectively connected to a plurality of environmental simulation areas.

[0024] As another improved supplement of the present application, a plurality of operation openings are opened at the side end of the seasonal simulation test chamber, and chamber doors are hinged at the edge ends of the operation openings, and the plurality of chamber doors respectively correspond to a plurality of environmental simulation areas.

[0025] To summarize, the present application simulates the actual seasonal environment, first stores the drugs in the simulated environment of spring, summer, autumn and winter, and regularly takes out the drugs for efficacy testing, so as to effectively evaluate the effect of the environmental temperature of the four seasons on the efficacy of the drugs. According to the evaluation results, the maximum number of continuous doses that doctors are allowed to prescribe to patients in each season can be strictly stipulated, so that the actual therapeutic effect of the drugs is not likely to differ greatly from the expected therapeutic effect due to long-term storage factors. At the same time, the drugs that have experienced the simulated environment of the four seasons for one month are replaced by the environment from spring to summer, summer to autumn, autumn to winter, and winter to spring respectively. Through the drug test results, the impact of the actual seasonal changes on the drug efficacy is effectively evaluated, thereby further stipulating the maximum number of drugs that doctors are allowed to prescribe to patients at a time at the end of each season, so that the drug treatment effect is also consistent with the expected treatment effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The method flow of the first and second implementation methods of this application Figure 1 ;

[0027] Figure 2 The method flow of the first and second implementation methods of this application Figure 2 ;

[0028] Figure 3 The three-dimensional four-season partition simulator of the second embodiment of the present application Figure 1 ;

[0029] Figure 4 This is a partially disassembled stereoscopic image of the four-season zone simulator according to the second embodiment of the present application;

[0030] Figure 5 A three-dimensional diagram of the internal structure of the seasonal simulation test chamber according to the second embodiment of the present application;

[0031] Figure 6 The third embodiment of the test bench of the present application is a three-dimensional Figure 1 ;

[0032] Figure 7 The third embodiment of the test bench of the present application is a three-dimensional Figure 2 ;

[0033] Figure 8 The three-dimensional four-season partition simulator of the second embodiment of the present application Figure 2 .

[0034] Description of the numbers in the figure:

[0035] 1 Seasonal simulation test chamber, 2 chamber door, 31 temperature control chamber, 32 temperature control pipe, 33 temperature inlet pipe, 41 humidity control chamber, 42 humidity control pipe, 43 humidity inlet pipe, 51 upper spacer ring, 52 lower spacer ring, 6 test bench, 61 columnar table, 6101 medicine trough, 6102 card slot, 62 mesh door plate, 63 card strip, 64 temperature and humidity sensor, 7 motor, 8 partition, 801 rotating trough, 9 sealing mesh. DETAILED DESCRIPTION

[0036] The following describes two implementation modes of the present application in detail with reference to the accompanying drawings.

[0037] The first implementation method:

[0038] The present invention provides a method for evaluating the effect of storage conditions on the efficacy of posaconazole enteric-coated tablets. Figure 1 , including the following steps:

[0039] S1. Select a batch of posaconazole enteric-coated tablets that are of qualified quality and packaged in the same batch, simulate the temperature change of the pharmacy, and store the drugs in the simulated environment of the pharmacy for 1-2 months;

[0040] After the drugs are transported to the medical institution and before they reach the patients, they are generally stored in the pharmacy or medicine warehouse of the medical institution. The storage environment of the pharmacy and the medicine warehouse is similar, generally controlled at a temperature between 15-25°C and a humidity between 45% and 60%. Therefore, in step S1, the pharmacy simulation environment can adopt the above-mentioned temperature and humidity standards to simulate the early storage conditions of the drugs in full accordance with the actual situation.

[0041] S2. Seasonal test: The drugs are randomly and evenly grouped to obtain one group of control drugs and four groups of test drugs. The control drugs are still stored in the pharmacy simulation environment, and the four groups of test drugs are placed in the simulation environments of spring, summer, autumn and winter, respectively, wherein: the spring simulation environment is a temperature of 15-25°C and a relative humidity of 40% to 60%, the summer simulation environment is a temperature of 25-35°C and a relative humidity of 60% to 80%, the autumn simulation environment is a temperature of 10-20°C and a relative humidity of 30% to 50%, and the winter simulation environment is a temperature of 0-10°C and a relative humidity of 20% to 40% (since the temperature and humidity in the actual environment are generally not kept constant, in this embodiment, the temperature and humidity in each simulation environment do not need to be kept constant, and can be kept within the set range);

[0042] In the following 1-3 months, at the end of each month, the same number of samples were randomly taken from the five groups of drugs for efficacy testing to evaluate the effects of different seasonal environments on the efficacy of drugs after storage;

[0043] After the drugs are purchased by the patients, they are generally stored at room temperature. Therefore, in step S2, according to the actual situation, the four groups of test drugs after step S1 are stored in the simulated environments of spring, summer, autumn and winter respectively. During the storage process, the drugs are taken out regularly for efficacy testing, and the test results are compared with the efficacy of the control drugs that continue to be stored in the simulated environment of the pharmacy, so as to effectively evaluate the effect of the ambient temperature of the four seasons on the efficacy of the drugs. In addition, according to the evaluation results, the maximum number of consecutive doses that the doctor is allowed to prescribe for the patient in each season can be strictly stipulated, so that the actual therapeutic effect of the drugs on the patients is not likely to differ greatly from the expected therapeutic effect due to the long-term storage factor;

[0044] For example: if it is found during the efficacy test that the content of active ingredients in the test drug after storage for 2 months in a simulated summer environment has not decreased significantly, but the content of active ingredients in the test drug after storage for 3 months has decreased significantly, then in actual application, it can be stipulated that the maximum continuous use time for which doctors are allowed to prescribe posaconazole enteric-coated tablets to patients in the summer shall not exceed 2 months, thereby effectively ensuring that the therapeutic effect of posaconazole enteric-coated tablets on patients is consistent with the expected therapeutic effect (supplementary note: the "significant decrease in the content of active ingredients" recorded in this application only represents the change in the effective cost content of the drug, and has nothing to do with the usability and effectiveness of the drug, that is, this statement does not mean that the drug cannot be used, nor does it mean that the drug has lost its therapeutic effect).

[0045] S3, seasonal change test: at the end of the first month in step S2, randomly take out a portion of the four groups of test drugs, and then simulate the actual seasonal change, and change the storage conditions of the four groups of test drugs to simulate the environment from spring to summer, from summer to autumn, from autumn to winter, and from winter to spring, that is, the test drugs taken out from the spring simulated environment are placed in the summer simulated environment, the test drugs taken out from the summer simulated environment are placed in the autumn simulated environment, and so on;

[0046] In the following 1-3 months, at the end of each month, the same number of samples were randomly taken from the five groups of drugs for efficacy testing to evaluate the impact of actual seasonal changes on drug efficacy;

[0047] In actual situations, after the patients purchase drugs that need to be taken continuously for a long time, if the number of drugs is large, some drugs also experience seasonal changes. The change of seasons replaces the change of temperature and humidity. Such changes in temperature and humidity are also likely to cause the loss or deterioration of the active ingredients of the drugs. Therefore, in step S3, the drugs that have experienced the simulated environment of spring, summer, autumn and winter for one month are subjected to seasonal environment changes. Subsequently, during the storage process, the drugs are taken out regularly for efficacy testing, and the test results are compared with the efficacy of the test drugs in step S2, so as to effectively evaluate the impact of the actual seasonal changes on the efficacy of the drugs. In addition, according to the evaluation results, strict regulations can be made on the maximum number of continuous medications that doctors are allowed to prescribe to patients at the end of each season, so that the actual therapeutic effect of the drugs on the patients is not likely to differ greatly from the expected therapeutic effect due to seasonal changes and environmental changes.

[0048] For example: if it is found during the efficacy test that: at the end of the first month in step S3, the active ingredients of the test drug that was converted from the summer simulation environment to the autumn simulation environment decreased significantly, while the active ingredients of the test drug that continued to be stored in the summer simulation environment in step S2 and the test drug that was always stored in the autumn simulation environment did not decrease significantly, then it indicates that the change of seasonal environment has a certain impact on the efficacy of the drug. At this time, in actual application, it can be stipulated that the maximum continuous use time of posaconazole enteric-coated tablets that doctors are allowed to prescribe to patients at the end of summer (such as during the last month of summer) shall not exceed 1 month, so that it is not easy for patients to continue taking the medicine until the end of the first month of autumn, thereby effectively ensuring that the therapeutic effect of posaconazole enteric-coated tablets on patients is consistent with the expected therapeutic effect.

[0049] S4, accelerated replacement test: another batch of posaconazole enteric-coated tablets that are qualified and packaged are selected, randomly divided into four groups, and placed in simulated environments of spring, summer, autumn, and winter, respectively. The simulation standard of the environment is the same as that of step S2, and then within 1-2 months, the four groups of drugs are regularly subjected to the four-season cycle operation of spring to summer, summer to autumn, autumn to winter, and winter to spring to accelerate drug aging. At the same time, every half a month, the same number of samples are randomly taken out from the four groups of drugs for efficacy testing, and compared with the drug efficacy in step S1 to evaluate the impact of the accelerated environmental replacement on the drug efficacy;

[0050] Since the drug will go through inevitable processes such as transportation, handling, and replacement of storage space after production, the environmental conditions of the drug after production will change irregularly. The above-mentioned replacement accelerated test can simulate the variability of the drug storage environment in actual conditions to a certain extent. Through regular testing of the drug, the impact of the variability of the storage environment on the drug efficacy can be effectively evaluated, and then whether the drug has a certain weakening of efficacy after experiencing environmental changes such as transportation can be evaluated. In addition, due to the use of four-season environmental simulation, the evaluation results can also be used to determine the best storage efficacy period of the drug in the actual environment to a certain extent. For example, when the test drug is tested to have a content of the active ingredient of the drug below the standard range after experiencing two four-season cycles, it indicates that in actual conditions, without considering the impact of other conditions on the drug, the best storage efficacy period of the drug under four-season room temperature storage conditions is less than 2 years (supplementary note: This is a preliminary evaluation of the best storage efficacy period of the drug in this application, and does not represent the best storage efficacy period finally determined. Since the test results can only be used as preliminary evaluation results, there are certain differences from the actual situation, so those skilled in the art can conduct selective tests as needed).

[0051] The efficacy testing methods in step S2, step S3 and step S4 all use high performance liquid chromatography analysis to determine the content change of the active ingredient in the tablets. High performance liquid chromatography analysis is a chromatographic process based on classical liquid chromatography and using liquid under high pressure as the mobile phase. It is an efficient and rapid analytical separation technology.

[0052] In order to further match the actual storage conditions, the present embodiment may also carry out the following cross-validation test process, as follows:

[0053] First, perform step S1, and then randomly divide the drugs obtained in step S1 into two groups. The two groups of drugs are placed in simulated environments in summer and winter, respectively. The simulation standard of the environment is the same as that in step S2. During the storage process, the temperature of the simulated environment in summer is regularly adjusted to a high temperature peak value of 38-40°C and maintained for a short time. The temperature of the simulated environment in winter is regularly adjusted to a low temperature valley value of -5 to 0°C and maintained for a short time (e.g., it can be adjusted every half a month for 12-24 hours. After the maintenance time, the simulated environment is readjusted to the environmental simulation standard in step S2);

[0054] Within 1-3 months, at the end of each month, the same number of samples are randomly taken out from the two groups of drugs for efficacy testing, and compared with the efficacy of the drugs in step S2, so as to further evaluate the impact of the extreme environment existing in the four seasons on the efficacy of the drugs in accordance with the actual situation, so as to further regulate the maximum number of consecutive doses that doctors are allowed to prescribe for patients at a time during the corresponding season in actual application.

[0055] Second implementation method:

[0056] Based on Implementation 1, this implementation provides a four-season partition simulator that is compatible with the test process in Implementation 1, which can effectively reduce the environmental adjustment, drug transfer and other processes during the test process, and effectively improve the simplicity of drug testing, as follows:

[0057] In step S2, step S3 and step S4, the drug can be tested using the four-season partition simulator. Figure 3 and Figure 4 The four-season zone simulator includes a seasonal simulation test chamber 1, wherein a test bench 6 is provided inside the seasonal simulation test chamber 1, an upper end of the test bench 6 is fixedly connected to an output end of a motor 7, and a fixed end of the motor 7 is fixedly connected to an upper inner wall of the seasonal simulation test chamber 1, an upper partition ring 51 and a lower partition ring 52 are respectively provided on upper and lower sides of the test bench 6, an end of the upper partition ring 51 and the lower partition ring 52 away from the test bench 6 are respectively fixedly connected to the upper and lower inner walls of the seasonal simulation test chamber 1, a plurality of partitions 8 are fixedly connected between the upper partition ring 51 and the lower partition ring 52, a side end of the partition 8 is fixedly connected to the inner wall of the seasonal simulation test chamber 1, and a plurality of partitions 8 divide the space composed of the upper partition ring 51, the lower partition ring 52, the test bench 6 and the seasonal simulation test chamber 1 into four environmental simulation areas, and the four environmental simulation areas are respectively used as simulation areas for the four seasons of spring, summer, autumn and winter.

[0058] Combination Figure 4 and Figure 6 As shown, the outer ring diameter of the test bench 6 is larger than the outer ring diameters of the upper spacer ring 51 and the lower spacer ring 52, a rotating groove 801 is opened on the partition 8, the test bench 6 is rotatably connected to the inside of the rotating groove 801, and the inner wall of the rotating groove 801 is fixedly connected to a sealing mesh 9, which is in contact with the outer surface of the test bench 6, and the two are in a surface contact sealing state, and the lower end of the upper spacer ring 51 and the upper end of the test bench 6, the upper end of the lower spacer ring 52 and the lower end of the test bench 6, and the upper and lower inner walls of the rotating groove 801 and the test bench 6 are also in a surface contact sealing state, so that the spring, summer, autumn and winter four seasons simulation areas formed by division are all relatively sealed space areas, and multiple structures related to the space area (including the seasonal simulation test chamber 1, the test bench 6, the upper spacer ring 51, the lower spacer ring 52, the partition 8 and the sealing mesh 9) are all made of thermal insulation materials to reduce heat exchange between each other and with the outside world, so that the four simulation areas can effectively maintain their own temperature and humidity environment, thereby effectively reducing the frequency of environmental adjustment of each area.

[0059] See also Figure 4 and Figure 5The test bench 6 includes a columnar table 61, and four evenly distributed medicine slots 6101 are opened at the side end of the columnar table 61. The medicine slots 6101 are used to store the posaconazole enteric-coated tablets to be tested, and the inner wall of the medicine slot 6101 is fixedly connected with a temperature and humidity sensor 64. When in use, the four medicine slots 6101 are respectively located in four simulation areas of spring, summer, autumn and winter, so that the medicines inside are stored in the corresponding seasonal environment. The temperature and humidity sensor 64 is used to monitor the temperature and humidity in the corresponding simulation area in real time, so as to adjust it in time when the simulation environment does not meet the environmental standards of the corresponding season. A mesh door plate 62 is inserted at the edge opening of the medicine slot 6101, and a card slot 6102 is opened on the lower inner wall of the medicine slot 6101. The mesh door plate The lower end of 62 is fixedly connected with a card strip 63, and the card strip 63 is inserted into the inside of the card slot 6102. The mesh door plate 62 protects the medicine in the medicine slot 6101 without affecting the airflow communication between the medicine slot 6101 and the simulation area to which it belongs, so that when the test bench 6 is rotated to change the drug storage environment, the drug is not easily removed from the medicine slot 6101. The outer circle diameter of the mesh door plate 62 is connected with the outer circle diameter of the columnar table 61, and the upper end of the mesh door plate 62 is flush with the upper end of the columnar table 61, so that the test bench 6 is in a complete cylindrical structure, which is convenient for rotation inside the rotating slot 801. At the same time, during the rotation process, the test bench 6 and the sealing mesh 9 and the rotating slot 801 continue to maintain a surface contact sealing state.

[0060] Combination Figure 3 and Figure 8 As shown, the upper end of the seasonal simulation test chamber 1 is fixedly connected with a humidity control chamber 41, and the outer end of the humidity control chamber 41 is fixedly connected with a humidity inlet pipe 43 and a plurality of humidity control pipes 42 with valves, and the plurality of humidity control pipes 42 pass through the upper end of the seasonal simulation test chamber 1 and are respectively connected with a plurality of environmental simulation areas, and the upper end of the humidity control chamber 41 is fixedly connected with a temperature control chamber 31, and the outer end of the temperature control chamber 31 is fixedly connected with a temperature inlet pipe 33 and a plurality of temperature control pipes 32 with valves, and the plurality of temperature control pipes 32 pass through the upper end of the seasonal simulation test chamber 1 and are respectively connected with a plurality of environmental simulation areas. When the temperature and humidity in the simulation area of ​​the seasonal simulation test chamber 1 do not meet the set environmental standards, the above structure facilitates the temperature and humidity adjustment of the simulation area;

[0061] For example, when the temperature in the spring simulation environment area is lower than the set range of 15-25°C, the valves on the temperature regulating pipe 32 and the humidity regulating pipe 42 connected to the spring simulation environment area are opened, and then dry warm gas is slowly input into the temperature inlet pipe 33. The gas enters the spring simulation environment area through the temperature regulating pipe 32, causing the internal temperature to gradually rise. At the same time, the original gas in the area is discharged to the outside through the humidity regulating pipe 42, the humidity regulating chamber 41 and the humidity inlet pipe 43 in turn. When the temperature and humidity sensor 64 located in the spring simulation environment area detects that the temperature has returned to the range of 15-25°C, the input of warm gas is stopped, and the valves on the temperature regulating pipe 32 and the humidity regulating pipe 42 are closed.

[0062] A plurality of operation ports are provided at the side end of the seasonal simulation test chamber 1, and a chamber door 2 is hinged at the edge end of the operation port. The plurality of chamber doors 2 respectively correspond to a plurality of environmental simulation areas. By opening the chamber door 2, drugs can be conveniently placed in and taken out through the operation port.

[0063] Combination Figure 5 , Figure 6 and Figure 7 As shown, when performing step S2 in implementation mode 1, the medicine is placed in the medicine tank 6101, and storage simulations of the four seasons of spring, summer, autumn and winter are performed in four simulation areas, respectively, and spring-summer, summer-autumn, autumn-winter, and winter-spring are adjacent to each other;

[0064] When performing step S3, it is only necessary to drive the test bench 6 to rotate by the motor 7, so that the medicine trough 6101 and the medicine located in the spring simulation area are rotated to the summer simulation area. At the same time, the medicine trough 6101 and the medicine in the summer, autumn and winter simulation environments are respectively rotated to the autumn, winter and spring simulation environments, so as to realize the rapid replacement of the drug storage environment, that is, to realize the seasonal change operation. Moreover, when the medicine trough 6101 rotates to the inner side of the rotating trough 801, when the same medicine trough 6101 is located in two adjacent simulation areas at the same time, the sealing mesh 9 closes the mesh door plate 62, and the horizontal length of the sealing mesh 9 is greater than the horizontal length of the mesh door plate 62, so that the medicine trough 6101 is not likely to be in communication with the two simulation areas at the same time, and thus the airflow is not likely to be in communication between the two adjacent areas, thereby effectively maintaining the temperature and humidity stability in each area.

[0065] When performing step S4, the drug replacement acceleration test process is also achieved by periodically rotating the test bench 6. Therefore, the four-season partition simulator is applied in implementation mode 1. Compared with the test method of directly adjusting the ambient temperature and humidity in the prior art, this implementation mode provides a more efficient and quick experimental process, and effectively reduces the energy consumption problem caused by large-scale and multi-frequency individual adjustment of each environmental simulation condition.

[0066] In view of current practical needs, the above-mentioned implementation mode adopted in this application is not limited to the scope of protection. Various changes made within the knowledge scope of technical personnel in this field without departing from the concept of this application still fall within the scope of protection of the present invention.

Claims

1. A method for evaluating the effect of storage conditions on the efficacy of posaconazole enteric-coated tablets, characterized in that: The following steps are involved: S1. Select a batch of posaconazole enteric-coated tablets that are of qualified quality and packaged in the same batch, simulate the temperature change of the pharmacy, and store the drugs in the simulated environment of the pharmacy for 1-2 months; S2. Seasonal test: The drugs are randomly and evenly grouped to obtain one group of control drugs and four groups of test drugs. The control drugs are still stored in the simulated environment of the pharmacy. The four groups of test drugs are placed in the simulated environments of spring, summer, autumn and winter, respectively. The simulated environment in spring is 15-25°C and the relative humidity is 40% to 60%, the simulated environment in summer is 25-35°C and the relative humidity is 60% to 80%, the simulated environment in autumn is 10-20°C and the relative humidity is 30% to 50%, and the simulated environment in winter is 0-10°C and the relative humidity is 20% to 40%; In the following 1-3 months, at the end of each month, the same number of samples were randomly taken from the five groups of drugs for efficacy testing to evaluate the effects of different seasonal environments on the efficacy of drugs after storage; S3, seasonal change test: at the end of the first month in step S2, randomly take out a portion of the four groups of test drugs, and then simulate the actual seasonal change, and change the storage conditions of the four groups of test drugs to simulate the environment from spring to summer, from summer to autumn, from autumn to winter, and from winter to spring, that is, the test drugs taken out from the spring simulated environment are placed in the summer simulated environment, the test drugs taken out from the summer simulated environment are placed in the autumn simulated environment, and so on; In the following 1-3 months, at the end of each month, the same number of samples were randomly taken from the five groups of drugs for efficacy testing to evaluate the impact of actual seasonal changes on drug efficacy; S4. Accelerated replacement test: Select another batch of qualified and packaged posaconazole enteric-coated tablets, randomly divide them into four groups, and place them in simulated environments of spring, summer, autumn and winter respectively. The simulation standard of the environment is the same as that of step S2. Then, within 1-2 months, regularly perform the four-season cycle operation of spring to summer, summer to autumn, autumn to winter, and winter to spring on the four groups of drugs to accelerate drug aging. At the same time, every half a month, randomly take out the same number of samples from the four groups of drugs for efficacy testing, and compare them with the drug efficacy in step S1 to evaluate the impact of accelerated environmental replacement on drug efficacy.

2. The method for evaluating the effect of storage conditions on the efficacy of posaconazole enteric-coated tablets according to claim 1, characterized in that: The efficacy testing methods described in step S2, step S3 and step S4 all use high performance liquid chromatography analysis to determine the content change of the active ingredient in the tablets.

3. The method for evaluating the effect of storage conditions on the efficacy of posaconazole enteric-coated tablets according to claim 1, characterized in that: The following steps are also included: Cross-validation test: perform step S1, then randomly divide the drugs obtained in step S1 into two groups, and place the two groups of drugs in simulated environments of summer and winter, respectively. The simulation standard of the environment is the same as that of step S2. During the storage process, the temperature of the simulated environment in summer is regularly adjusted to a high temperature peak value of 38-40°C and maintained for a short time, and the temperature of the simulated environment in winter is regularly adjusted to a low temperature valley value of -5 to 0°C and maintained for a short time; Within 1-3 months, at the end of each month, the same number of samples are randomly taken out from the two groups of drugs for efficacy testing, and compared with the efficacy of the drugs in step S2, so as to further evaluate the impact of the extreme environment in the four seasons on the efficacy of the drugs in accordance with the actual situation.

4. The method for evaluating the effect of storage conditions on the efficacy of posaconazole enteric-coated tablets according to claim 1, characterized in that: In step S2, step S3 and step S4, a four-season zone simulator is used to test the drug. The four-season zone simulator includes a seasonal simulation test chamber (1). A test bench (6) is provided inside the seasonal simulation test chamber (1). The upper end of the test bench (6) is fixedly connected to the output end of the motor (7), and the fixed end of the motor (7) is fixedly connected to the upper inner wall of the seasonal simulation test chamber (1). The upper and lower sides of the test bench (6) are respectively provided with an upper spacer ring (51) and a lower spacer ring (52). The ends of the upper spacer ring (51) and the lower spacer ring (52) away from the test bench (6) are respectively fixedly connected to the upper and lower inner walls of the seasonal simulation test chamber (1). A plurality of partitions (8) are fixedly connected between the upper spacer ring (51) and the lower spacer ring (52), and the side ends of the partitions (8) are fixedly connected to the inner wall of the seasonal simulation test chamber (1).

5. The method for evaluating the effect of storage conditions on the efficacy of posaconazole enteric-coated tablets according to claim 4, characterized in that: The plurality of partitions (8) divide the space formed by the upper partition ring (51), the lower partition ring (52), the test bench (6) and the seasonal simulation test chamber (1) into a plurality of environmental simulation areas, and the plurality of environmental simulation areas serve as simulation areas for the four seasons of spring, summer, autumn and winter, respectively.

6. The method for evaluating the effect of storage conditions on the efficacy of posaconazole enteric-coated tablets according to claim 4, characterized in that: The outer ring diameter of the test bench (6) is larger than the outer ring diameters of the upper spacer ring (51) and the lower spacer ring (52); a rotation groove (801) is provided on the partition plate (8); the test bench (6) is rotatably connected to the inside of the rotation groove (801); a sealing mesh (9) is fixedly connected to the inner wall of the rotation groove (801); and the sealing mesh (9) is in contact with the outer surface of the test bench (6).

7. The method for evaluating the effect of storage conditions on the efficacy of posaconazole enteric-coated tablets according to claim 4, characterized in that: The test bench (6) comprises a columnar table (61), a side end of which is provided with a plurality of evenly distributed medicine slots (6101), the medicine slots (6101) being used to store posaconazole enteric-coated tablets to be tested, and an inner wall of the medicine slot (6101) being fixedly connected with a temperature and humidity sensor (64).

8. The method for evaluating the effect of storage conditions on the efficacy of posaconazole enteric-coated tablets according to claim 7, characterized in that: A mesh door plate (62) is inserted into the edge opening of the medicine groove (6101), a card slot (6102) is opened on the lower inner wall of the medicine groove (6101), a card strip (63) is fixedly connected to the lower end of the mesh door plate (62), and the card strip (63) is inserted into the inside of the card slot (6102).

9. The method for evaluating the effect of storage conditions on the efficacy of posaconazole enteric-coated tablets according to claim 5, characterized in that: The upper end of the seasonal simulation test chamber (1) is fixedly connected to a humidity control chamber (41); the outer end of the humidity control chamber (41) is fixedly connected to a humidity inlet pipe (43) and a plurality of humidity control pipes (42) with valves; the plurality of humidity control pipes (42) penetrate the upper end of the seasonal simulation test chamber (1) and are respectively connected to a plurality of environmental simulation areas; the upper end of the humidity control chamber (41) is fixedly connected to a temperature control chamber (31); the outer end of the temperature control chamber (31) is fixedly connected to a temperature inlet pipe (33) and a plurality of temperature control pipes (32) with valves; the plurality of temperature control pipes (32) penetrate the upper end of the seasonal simulation test chamber (1) and are respectively connected to a plurality of environmental simulation areas.

10. The method for evaluating the effect of storage conditions on the efficacy of posaconazole enteric-coated tablets according to claim 5, characterized in that: The side end of the seasonal simulation test chamber (1) is provided with a plurality of operation openings, the edge end of the operation opening is hinged with a chamber door (2), and the plurality of chamber doors (2) respectively correspond to a plurality of environmental simulation areas.

Images