A method for detecting the release rate of mesalazine enteric-coated sustained-release tablets

Abstract

The invention relates to a release rate detection method of mesalazine enteric-coated sustained-release tablets in the field of drug analysis. During the detection process, the release medium and the mesalazine enteric-coated sustained-release tablets in a small intestine simulation unit are squeezed by a driven ring and a peristaltic unit, thereby simulating the effect of gastrointestinal peristalsis on the small intestine simulation unit. The driven ring itself rotates under the drive of a power tooth, thereby simulating a comprehensive gastrointestinal peristalsis effect on the small intestine simulation unit. At the same time, under the drive of an electric slider, the peristaltic outer ring and the driven ring as a whole can move along the direction of the small intestine simulation unit, and a comprehensive peristaltic simulation is performed on the small intestine simulation unit. Through the reasonable design of the release rate detection device, the real environment of gastrointestinal peristalsis can be more realistically simulated. At the same time, according to the detection needs, in the process of simulating gastrointestinal peristalsis, the intensity of the peristalsis can change periodically to increase the simulation effect.

Description

Technical Field

[0001] The invention relates to a method for detecting the release rate of a mesalazine enteric-coated sustained-release tablet, in particular to a method for detecting the release rate of a mesalazine enteric-coated sustained-release tablet applied in the field of drug analysis. Background Art

[0002] The main ingredient of Mesalazine Enteric-coated Sustained-release Tablets is mesalazine, a drug used to treat inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis). The enteric-coated sustained-release tablet form is designed to protect the drug from being destroyed in the gastric acid environment and release the drug when it reaches the small intestine or colon.

[0003] The invention patent CN201811625887.8 specification discloses a method for determining related substances of mesalazine enteric-coated sustained-release tablets. The specification reveals the relationship between the impurities of mesalazine and the release rate of mesalazine enteric-coated sustained-release tablets. It can quickly detect mesalazine-related substances to improve the safety of the product. The method is scientific, reliable, and can control the related substances of mesalazine.

[0004] The invention patent CN202180087181.4 specification discloses a gastrointestinal simulation system and method, the gastrointestinal simulation system also includes a fluid delivery system for delivering fluid to and from the at least two consecutive compartments, the method also includes introducing and dissolving a substance in a fluid simulating a physiological fluid of the gastrointestinal tract present in a first compartment, delivering the fluid from the first compartment to the inner container, ensuring that the dissolved substance flows from the inner container by permeating through a semipermeable membrane or a dialysis membrane, and removing the fluid from the outer container.

[0005] In the existing technology, there are two main methods for drug testing: clinical testing and experimental testing. Before clinical testing, a large number of instrument experiments and biological experiments such as mice are usually required to ensure the safety of the drug to the greatest extent. During the existing testing process of sustained-release tablets, a stirring device is usually introduced to simulate gastrointestinal peristalsis. Although it can restore the movement of human organs to a certain extent, it is difficult to meet the simulation requirements. 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 it is difficult for existing experimental detection instruments to simulate the peristalsis of the stomach and intestines and it is difficult to meet the simulation requirements.

[0007] In order to solve the above problems, the present invention provides a method for detecting the release rate of mesalazine enteric-coated sustained-release tablets, comprising the following steps:

[0008] S1. Preparation for testing. According to the requirements of the release test of mesalazine enteric-coated sustained-release tablets, release media for the stomach, small intestine and colon are prepared respectively, wherein the stomach release medium is 1000 mL of hydrochloric acid solution with a pH of 1.2, the small intestine release medium is 1000 mL of phosphate buffer with a pH of 6.8, and the colon release medium is 1000 mL of phosphate buffer with a pH of 7.5. Meanwhile, a series of standard mesalazine solutions with known concentrations are prepared. The absorbance of the standard mesalazine solution is measured at a wavelength of 254 nm using a UV / Vis spectrophotometer, and a concentration standard curve of the corresponding mesalazine solution is drawn. According to the expected release of mesalazine enteric-coated sustained-release tablets recorded in the pharmacopoeia of mesalazine enteric-coated sustained-release tablets, a detection standard curve is established, and the detection standard curve is thickened to form a standard band, and the width of the standard band is 3% of the maximum absorbance in the standard mesalazine solution of known concentration;

[0009] S2. Gastric simulation test: two 1.2g intact mesalazine enteric-coated sustained-release tablets together with the gastric release medium are placed in the release test equipment, and the gastric simulation test is performed at 37.5±0.5℃. During the test, the release test equipment will continue to imitate the peristalsis of the stomach, and the gastric release medium and the dissolved mesalazine enteric-coated sustained-release tablets will form a gastric simulation liquid. After 2 hours, 10ml of the gastric simulation liquid is taken and filtered with glass fiber filter paper to separate the mesalazine enteric-coated sustained-release tablets and the gastric filtrate. The concentration of mesalazine is determined by the gastric filtrate, and the test data is summarized and uploaded;

[0010] S3, small intestine simulation test, the mesalazine enteric-coated sustained-release tablets after step S2 are cleaned with distilled water, and after the surface moisture is adsorbed, they are put into the release test equipment together with the small intestine release medium, and the small intestine simulation test is carried out at 37.5±0.5°C. During the test, the release test equipment will continue to imitate the peristalsis of the small intestine, and the small intestine release medium and the dissolved mesalazine enteric-coated sustained-release tablets will form a small intestine simulation liquid. At 1h and 2h in the step test process, 10ml of the small intestine simulation liquid is taken respectively, and 10ml of the small intestine release medium is added to the release test equipment immediately after the sample is taken out, and the sample is filtered with glass fiber filter paper to separate the mesalazine enteric-coated sustained-release tablets and the small intestine filtrate, and the concentration of mesalazine is determined by the small intestine filtrate, and the test data is summarized and uploaded;

[0011] S4, colon simulation, the mesalazine enteric-coated sustained-release tablets after step S3 are cleaned with distilled water, and after the surface moisture is adsorbed, they are put into the release test device together with the colon release medium, and the colon simulation test is performed at 37.5±0.5°C. During the test, the release test device will continue to imitate the peristalsis of the colon, and the colon release medium and the dissolved mesalazine enteric-coated sustained-release tablets form a colon simulation liquid. At 2h, 4h, 6h and 8h in the step test process, 10ml of the colon simulation liquid is taken respectively, and 10ml of the colon release medium is added to the release test device immediately after the sample is taken out, and the sample is filtered with glass fiber filter paper, and the concentration of mesalazine is determined by the colon simulation liquid obtained by filtration, and the test data is summarized and uploaded;

[0012] S5. Data analysis: summarize the data obtained from the tests in step S2, step S3 and step S4, and establish a release curve that matches the standard band based on the cumulative release percentage at each time point in the experimental process. When the portion of the release curve outside the standard band exceeds 5% of itself, the current test sample is judged to be unqualified, and when the portion of the release curve outside the standard band is less than 5% of itself, the current test sample is judged to be qualified.

[0013] In the above-mentioned release rate detection method of mesalazine enteric-coated sustained-release tablets, the release of mesalazine enteric-coated sustained-release tablets in the stomach, small intestine and colon can be simulated, and a corresponding data verification method can be established to increase the accuracy of the detection.

[0014] As a further improvement of the present application, in steps S2, S3 and S4, the release degree detection equipment used needs to be cleaned or replaced with a new one to reduce the system error caused by the equipment.

[0015] As a further improvement of the present application, pancreatic lipase, trypsin, amylase and intestinal flora need to be added to the small intestine release medium and the colon release medium to simulate the corresponding intestinal environment.

[0016] As a further improvement of the present application, the release degree detection device includes a base, and a small intestine simulation unit and an electric slide are respectively provided on the upper side of the base, and the electric slide is located on the upper side of the small intestine simulation unit, and the two ends of the small intestine simulation unit are respectively plugged with fixed plugs, and the ends of the two fixed plugs away from the small intestine simulation unit both penetrate the base and are threadedly connected with fixed nuts;

[0017] An electric slider is slidably connected in the electric slide groove, and a peristaltic outer ring is fixedly connected to the lower end of the electric slider. The peristaltic outer ring is sleeved on the outside of the small intestine simulation unit. The peristaltic outer ring includes a ring body. A transmission groove, a connecting groove and a power groove are opened on the upper half of the ring body. The connecting groove connects the transmission groove and the power groove. A power tooth is rotatably connected in the transmission groove. A motor is rotatably connected in the power groove. The power output end of the motor passes through the connecting groove and is fixedly connected to the power tooth. Sealing covers 1 and 2 matching the same are fixedly connected to the openings of the transmission groove and the power groove respectively. A rotating groove is opened on the inner wall of the ring body. A driven ring is rotatably connected in the rotating groove. The driven ring is meshed with the power tooth. The inner wall of the driven ring is connected to the peristaltic unit. The peristaltic outer ring and the driven ring can move along the direction of the small intestine simulation unit as a whole to perform a comprehensive peristaltic simulation of the small intestine simulation unit.

[0018] As a further improvement and supplement to the present application, the small intestine simulation unit includes an insulating elastic shell, which is made of insulating material. The outer wall of the insulating elastic shell is fixedly connected to an external tarsal frame. The insulating elastic shell made of insulating material can heat the stomach release medium, small intestine release medium and colon release medium to the detection temperature and then add them into the insulating elastic shell to ensure the detection temperature, while the external tarsal frame can effectively protect the insulating elastic shell, so that the insulating elastic shell is not prone to excessive deformation.

[0019] As a further improvement and supplement to the present application, buffering and shock-absorbing materials are connected between the sealing cover 2 and the power slot and the motor, and the shock-absorbing materials are fixedly connected to the sealing cover 2 and the power slot respectively, so as to reduce the vibration and noise generated by the operation of the motor and increase the overall stability of the peristaltic outer ring.

[0020] As a further improvement and supplement to the present application, an installation cavity is excavated in the driven ring, an elastic airbag is fixedly connected in the installation cavity, the elastic airbag is fixedly connected to the peristaltic unit, the end of the peristaltic unit away from the elastic airbag passes through the driven ring and extends to the outside of the installation cavity, the peristaltic unit includes a movable ring, the end of the movable ring close to the elastic airbag is fixedly connected to an electric heating network, the end of the movable ring away from the electric heating network is fixedly connected to a plurality of simulation protrusions, in the process of simulating gastrointestinal peristalsis, the electric heating network is started, and the heat generated will cause the elastic airbag to expand, thereby exerting pressure on the movable ring, causing the movable ring to deform, so that the peristaltic unit can simulate gastrointestinal peristalsis of different degrees, and at the same time, the power of the electric heating network can be controlled and changed periodically, so that in the process of simulating gastrointestinal peristalsis, the intensity of the peristalsis will change periodically, thereby increasing the simulation effect.

[0021] In summary, in the present application, the release medium and mesalazine enteric-coated sustained-release tablets located in the small intestine simulation unit will be squeezed by the driven ring and the peristaltic unit during the detection process, thereby simulating the effect of gastrointestinal peristalsis on the small intestine simulation unit, and the driven ring itself will rotate under the drive of the power teeth, thereby simulating a comprehensive gastrointestinal peristalsis effect on the small intestine simulation unit. At the same time, driven by the electric slider, the peristaltic outer ring and the driven ring as a whole can move along the direction of the small intestine simulation unit, thereby performing a comprehensive peristaltic simulation of the small intestine simulation unit.

[0022] Through the reasonable design of the release degree detection equipment, the real environment of gastrointestinal peristalsis can be simulated more realistically. At the same time, according to the detection needs, the intensity of peristalsis can be changed periodically during the simulation of gastrointestinal peristalsis to enhance the simulation effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is a flow chart of a method for detecting the release rate of mesalazine enteric-coated sustained-release tablets according to the first embodiment of the present application;

[0024] Figure 2 This is a schematic structural diagram of a small intestine simulation device according to a first embodiment of the present application;

[0025] Figure 3 A front view of a small intestine simulation device according to a first embodiment of the present application;

[0026] Figure 4 A front cross-sectional view of a small intestine simulation device according to a first embodiment of the present application;

[0027] Figure 5 for Figure 4 The structural diagram at A in the middle;

[0028] Figure 6 This is a schematic diagram of the structure of the peristaltic outer ring of the first embodiment of the present application;

[0029] Figure 7 This is a side cross-sectional view of the peristaltic outer ring of the first embodiment of the present application;

[0030] Figure 8 This is a schematic structural diagram of a driven ring according to a first embodiment of the present application;

[0031] Fig. 9 A side cross-sectional view of a driven ring according to a first embodiment of the present application;

[0032] Fig.10 This is a schematic diagram of the structure of the peristaltic unit of the first embodiment of the present application.

[0033] Description of the numbers in the figure:

[0034] 1 base, 2 fixing nut, 3 small intestine simulation unit, 301 insulating elastic shell, 302 outer tarsal frame, 4 fixing plug, 5 electric slide, 6 electric slider, 7 peristaltic outer ring, 701 ring body, 702 transmission groove, 703 connecting groove, 704 power groove, 705 rotating groove, 8 power teeth, 9 electric motor, 10 driven ring, 11 sealing cover 1, 12 sealing cover 2, 13 elastic airbag, 14 peristaltic unit, 1401 movable ring, 1402 electric heating network, 1403 simulation convex point. DETAILED DESCRIPTION

[0035] Two implementation modes of the present application are described in detail below with reference to the accompanying drawings.

[0036] The first implementation method:

[0037] Figure 1 A method for detecting the release rate of mesalazine enteric-coated sustained-release tablets is shown, comprising the following steps:

[0038] S1. Preparation for testing. According to the needs of the release test of mesalazine enteric-coated sustained-release tablets, release media for the stomach, small intestine and colon are prepared respectively, wherein the stomach release medium is 1000 mL of hydrochloric acid solution with a pH of 1.2, the small intestine release medium is 1000 mL of phosphate buffer with a pH of 6.8, and the colon release medium is 1000 mL of phosphate buffer with a pH of 7.5. Meanwhile, a series of standard mesalazine solutions with known concentrations are prepared. The absorbance of the standard mesalazine solution is measured at a wavelength of 254 nm by a UV / Vis spectrophotometer, and a concentration standard curve of the corresponding mesalazine solution is drawn. According to the expected release of mesalazine enteric-coated sustained-release tablets recorded in the pharmacopoeia of mesalazine enteric-coated sustained-release tablets, a test standard curve is established, and the test standard curve is bolded to form a standard band. The width of the standard band is 3% of the maximum absorbance in the standard mesalazine solution of known concentration. The smaller the width, the more accurate the test and the higher the safety factor.

[0039] S2. Gastric simulation test: two 1.2g intact mesalazine enteric-coated sustained-release tablets together with the gastric release medium are placed in the release test equipment, and the gastric simulation test is performed at 37.5±0.5℃. During the test, the release test equipment will continue to imitate the peristalsis of the stomach, and the gastric release medium and the dissolved mesalazine enteric-coated sustained-release tablets will form a gastric simulation liquid. After 2 hours, 10ml of the gastric simulation liquid is taken and filtered with glass fiber filter paper to separate the mesalazine enteric-coated sustained-release tablets and the gastric filtrate. The concentration of mesalazine is determined by the gastric filtrate, and the test data is summarized and uploaded;

[0040] S3, small intestine simulation test, the mesalazine enteric-coated sustained-release tablets after step S2 are cleaned with distilled water, and after the surface moisture is adsorbed, they are put into the release test equipment together with the small intestine release medium, and the small intestine simulation test is carried out at 37.5±0.5°C. During the test, the release test equipment will continue to imitate the peristalsis of the small intestine, and the small intestine release medium and the dissolved mesalazine enteric-coated sustained-release tablets will form a small intestine simulation liquid. At 1h and 2h in the step test process, 10ml of the small intestine simulation liquid is taken respectively, and 10ml of the small intestine release medium is added to the release test equipment immediately after the sample is taken out, and the sample is filtered with glass fiber filter paper to separate the mesalazine enteric-coated sustained-release tablets and the small intestine filtrate, and the concentration of mesalazine is determined by the small intestine filtrate, and the test data is summarized and uploaded;

[0041] S4, colon simulation, the mesalazine enteric-coated sustained-release tablets after step S3 are cleaned with distilled water, and after the surface moisture is adsorbed, they are put into the release test device together with the colon release medium, and the colon simulation test is performed at 37.5±0.5°C. During the test, the release test device will continue to imitate the peristalsis of the colon, and the colon release medium and the dissolved mesalazine enteric-coated sustained-release tablets form a colon simulation liquid. At 2h, 4h, 6h and 8h in the step test process, 10ml of the colon simulation liquid is taken respectively, and 10ml of the colon release medium is added to the release test device immediately after the sample is taken out, and the sample is filtered with glass fiber filter paper, and the concentration of mesalazine is determined by the colon simulation liquid obtained by filtration, and the test data is summarized and uploaded;

[0042] S5. Data analysis: summarize the data obtained from the tests in step S2, step S3 and step S4, and establish a release curve that matches the standard band based on the cumulative release percentage at each time point in the experimental process. When the portion of the release curve outside the standard band exceeds 5% of itself, the current test sample is judged to be unqualified, and when the portion of the release curve outside the standard band is less than 5% of itself, the current test sample is judged to be qualified.

[0043] In steps S2, S3 and S4, the release degree detection equipment used needs to be cleaned or replaced with a new one to reduce the system error caused by the equipment.

[0044] Pancreatic lipase, trypsin, amylase and intestinal flora need to be added to the small intestine release medium and colon release medium to simulate the corresponding intestinal environment.

[0045] See also Figure 2-7The release degree detection device comprises a base 1, a small intestine simulation unit 3 and an electric slide 5 are respectively provided on the upper side of the base 1, and the electric slide 5 is located on the upper side of the small intestine simulation unit 3, and fixing plugs 4 are respectively inserted at both ends of the small intestine simulation unit 3, and the ends of the two fixing plugs 4 away from the small intestine simulation unit 3 both penetrate the base 1 and are threadedly connected with fixing nuts 2, wherein the mesalazine enteric-coated sustained-release tablets, the gastric release medium, the small intestine release medium and the colon release medium are respectively placed in the small intestine simulation units 3 of different release degree detection devices;

[0046] An electric slider 6 is slidably connected in the electric slide groove 5, and a peristaltic outer ring 7 is fixedly connected to the lower end of the electric slider 6. The peristaltic outer ring 7 is sleeved on the outside of the small intestine simulation unit 3. The peristaltic outer ring 7 includes a ring body 701. A transmission groove 702, a connecting groove 703 and a power groove 704 are opened on the upper half of the ring body 701. The connecting groove 703 connects the transmission groove 702 and the power groove 704. A power tooth 8 is rotatably connected in the transmission groove 702. A motor 9 is rotatably connected in the power groove 704. The power output end of the motor 9 passes through the connecting groove 703 and is fixedly connected to the power tooth 8. The openings of the transmission groove 702 and the power groove 704 are respectively fixedly connected with a sealing cover 11 and a sealing cover 2 12 matching themselves. A rotating groove 705 is opened on the inner wall of the ring body 701. A driven ring 10 is rotatably connected in the rotating groove 705. The driven ring 10 is meshed with the power tooth 8, and the inner wall of the driven ring 10 is connected to the peristaltic unit 14.

[0047] In particular, the specific shape of the small intestine simulation unit 3 in the present application can be reasonably designed by technical personnel in the field. For the convenience of display, the present application only shows it in the shape of an intestine in the drawings of the specification. At the same time, it is a common technology for technical personnel in the field to open and close a material intake port on the small intestine simulation unit 3. Therefore, in the present application, the corresponding structure is not disclosed in detail, and technical personnel in the field can make a reasonable design based on the existing technology.

[0048] During the detection process, the release medium and mesalazine enteric-coated sustained-release tablets located in the small intestine simulation unit 3 will be squeezed by the driven ring 10 and the peristaltic unit 14, thereby simulating the effect of gastrointestinal peristalsis on the small intestine simulation unit 3, and the driven ring 10 itself will rotate under the drive of the power teeth 8, thereby simulating a comprehensive gastrointestinal peristalsis effect on the small intestine simulation unit 3. At the same time, driven by the electric slider 6, the peristaltic outer ring 7 and the driven ring 10 as a whole can move along the direction of the small intestine simulation unit 3 to perform a comprehensive peristaltic simulation of the small intestine simulation unit 3.

[0049] The small intestine simulation unit 3 includes an insulating elastic shell 301, which is made of insulating material. The outer wall of the insulating elastic shell 301 is fixedly connected with an external tarsal frame 302. The insulating elastic shell 301 made of insulating material can heat the stomach release medium, the small intestine release medium and the colon release medium to the detection temperature and then add them into the insulating elastic shell 301 to ensure the detection temperature, while the external tarsal frame 302 can effectively protect the insulating elastic shell 301, so that the insulating elastic shell 301 is not prone to excessive deformation.

[0050] Buffering and shock-absorbing materials are connected between the sealing cover 12 and the inner wall of the power groove 704 and the motor 9, and the shock-absorbing materials are fixedly connected to the sealing cover 12 and the power groove 704 respectively, so as to reduce the vibration and noise generated by the operation of the motor 9 and increase the overall stability of the peristaltic outer ring 7.

[0051] See also Figure 5-10 A mounting cavity is excavated in the driven ring 10, in which an elastic airbag 13 is fixedly connected, the elastic airbag 13 is fixedly connected to the peristaltic unit 14, and one end of the peristaltic unit 14 away from the elastic airbag 13 passes through the driven ring 10 and extends to the outside of the mounting cavity. The peristaltic unit 14 includes a movable ring 1401, and one end of the movable ring 1401 close to the elastic airbag 13 is fixedly connected to an electric heating network 1402, and one end of the movable ring 1401 away from the electric heating network 1402 is fixedly connected to a plurality of simulation bumps 1403. In the process of simulating gastrointestinal peristalsis, the electric heating network 1402 is started, and the heat generated will cause the elastic airbag 13 to expand, thereby compressing the movable ring 1401, causing the movable ring 1401 to deform, so that the peristaltic unit 14 can simulate gastrointestinal peristalsis of different degrees. At the same time, the power of the electric heating network 1402 can be controlled and changed periodically, so that in the process of simulating gastrointestinal peristalsis, the intensity of the peristalsis will change periodically, thereby increasing the simulation effect.

[0052] The second implementation method:

[0053] A method for detecting the release rate of mesalazine enteric-coated sustained-release tablets, wherein the clinical trial method comprises:

[0054] Healthy subjects were given 2.4 g or 4.8 g of mesalamine enteric-coated sustained-release tablets once daily for 14 days, and it was found that the total absorption of mesalamine was approximately 21% to 22% of the administered dose.

[0055] Gamma-scintigraphy showed that a single dose of 1.2 g of mesalamine enteric-coated sustained-release tablets (1 tablet) passed intact through the upper gastrointestinal tract of fasting healthy subjects. Scintigraphic images showed traces of radiolabeled tracer in the colon, indicating that mesalamine had been distributed through this region of the gastrointestinal tract.

[0056] In a single-dose study, healthy subjects were given 1.2g, 2.4g, and 4.8g of mesalazine enteric-coated sustained-release tablets in the fasting state. The plasma concentration of mesalazine could be detected 2 hours after the study dose, and the average plasma concentration reached the maximum value at 9-12 hours. According to the area under the plasma concentration-time curve (AUC), the systemic exposure of mesalazine was slightly higher than the dose ratio between the doses of 1.2g and 4.8g of mesalazine enteric-coated sustained-release tablets. The maximum plasma concentration (C max ) increased roughly in proportion to the dose, with the maximum plasma concentration (C max ) increased at a less-than-dose ratio, with the dose-normalized value at the 4.8 g dose averaging 74% of the 2.4 g dose based on the geometric mean, as shown in the following table:

[0057]

[0058] Among them, except T max and T lag Except for , the other parameters are arithmetic means;

[0059] Where N is the number of subjects, and the parameter contains The data outside the brackets are medians, and the data inside the brackets are the minimum, maximum, and T lag is the drug lag time, T max It refers to the time point when the blood drug concentration reaches the peak after a single dose.

[0060] A single administration of 4.8 g of mesalazine enteric-coated extended-release tablets with a high-fat meal resulted in further delayed absorption, with plasma concentrations of mesalazine being detectable 4 hours after administration. However, a high-fat meal increased the systemic exposure of mesalazine compared with the results in the fasting state (mean C max In controlled clinical trials, mesalazine enteric-coated extended-release tablets were taken with meals.

[0061] In the pharmacokinetic study of single and multiple doses of mesalazine enteric-coated sustained-release tablets, 28 healthy subjects in each dose group received 2.4g or 4.8g once daily, taken with a standard meal, and the plasma concentration of mesalazine could be detected 4 hours after a single dose, reaching a peak at 8 hours, and usually reaching steady state 2 days after administration. The average AUC at steady state was only slightly higher (1.1-1.4 times) than the predicted value of single-dose pharmacokinetics.

[0062] The only major metabolite of mesalamine (5-aminosalicylic acid) is N-acetyl-5-aminosalicylic acid. Its formation is caused by the activity of N-acetyltransferase (NAT) in the liver and intestinal mucosal cells, mainly NAT-1.

[0063] Mesalazine is metabolized to N-acetyl-5-aminosalicylic acid (acetylated) and is excreted mainly through the kidneys; the parent drug is also excreted in small amounts through the urine. Of the approximately 21% to 22% of the absorbed dose, less than 8% is excreted in the urine as the prototype after 24 hours, while N-acetyl-5-aminosalicylic acid is more than 13%. After a single dose, the average renal clearance (CL) of adults is R ) ranged from 1.8L / h to 2.9L / h, and ranged from 5.5L / h to 6.4L / h after multiple administrations for 14 days. After administration of 2.4g and 4.8g of mesalamine enteric-coated sustained-release tablets, the apparent terminal half-life of mesalamine and its major metabolites averaged 7-9 hours and 8-12 hours, respectively. Based on the estimated creatinine clearance, the systemic exposure of adult subjects was negatively correlated with renal function.

[0064] Through the experimental testing of the first embodiment and the clinical testing of the second embodiment, a complete release rate detection method for mesalazine enteric-coated sustained-release tablets is constructed. In particular, during the experimental testing process, through the reasonable design of the release rate detection equipment, the real environment of gastrointestinal motility can be more realistically simulated. At the same time, according to the testing needs, the intensity of the motility can be changed periodically during the simulation of gastrointestinal motility to increase the simulation effect.

[0065] 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 detecting the release rate of mesalazine enteric-coated sustained-release tablets, characterized in that: The following steps are involved: S1. Preparation for testing. According to the requirements of the release test of mesalazine enteric-coated sustained-release tablets, release media for the stomach, small intestine and colon are prepared respectively, wherein the stomach release medium is 1000 mL of hydrochloric acid solution with a pH of 1.2, the small intestine release medium is 1000 mL of phosphate buffer with a pH of 6.8, and the colon release medium is 1000 mL of phosphate buffer with a pH of 7.

5. Meanwhile, a series of standard mesalazine solutions with known concentrations are prepared. The absorbance of the standard mesalazine solution is measured at a wavelength of 254 nm using a UV / Vis spectrophotometer, and a concentration standard curve of the corresponding mesalazine solution is drawn. According to the expected release of mesalazine enteric-coated sustained-release tablets recorded in the pharmacopoeia of mesalazine enteric-coated sustained-release tablets, a detection standard curve is established, and the detection standard curve is thickened to form a standard band, and the width of the standard band is 3% of the maximum absorbance in the standard mesalazine solution of known concentration; S2. Gastric simulation test: two 1.2g intact mesalazine enteric-coated sustained-release tablets together with the gastric release medium are placed in the release test equipment, and the gastric simulation test is performed at 37.5±0.5℃. During the test, the release test equipment will continue to imitate the peristalsis of the stomach, and the gastric release medium and the dissolved mesalazine enteric-coated sustained-release tablets will form a gastric simulation liquid. After 2 hours, 10ml of the gastric simulation liquid is taken and filtered with glass fiber filter paper to separate the mesalazine enteric-coated sustained-release tablets and the gastric filtrate. The concentration of mesalazine is determined by the gastric filtrate, and the test data is summarized and uploaded; S3, small intestine simulation test, the mesalazine enteric-coated sustained-release tablets after step S2 are cleaned with distilled water, and after the surface moisture is adsorbed, they are put into the release test equipment together with the small intestine release medium, and the small intestine simulation test is carried out at 37.5±0.5°C. During the test, the release test equipment will continue to imitate the peristalsis of the small intestine, and the small intestine release medium and the dissolved mesalazine enteric-coated sustained-release tablets will form a small intestine simulation liquid. At 1h and 2h in the step test process, 10ml of the small intestine simulation liquid is taken respectively, and 10ml of the small intestine release medium is added to the release test equipment immediately after the sample is taken out, and the sample is filtered with glass fiber filter paper to separate the mesalazine enteric-coated sustained-release tablets and the small intestine filtrate, and the concentration of mesalazine is determined by the small intestine filtrate, and the test data is summarized and uploaded; S4, colon simulation, the mesalazine enteric-coated sustained-release tablets after step S3 are cleaned with distilled water, and after the surface moisture is adsorbed, they are put into the release test device together with the colon release medium, and the colon simulation test is performed at 37.5±0.5°C. During the test, the release test device will continue to imitate the peristalsis of the colon, and the colon release medium and the dissolved mesalazine enteric-coated sustained-release tablets form a colon simulation liquid. At 2h, 4h, 6h and 8h in the step test process, 10ml of the colon simulation liquid is taken respectively, and 10ml of the colon release medium is added to the release test device immediately after the sample is taken out, and the sample is filtered with glass fiber filter paper, and the concentration of mesalazine is determined by the colon simulation liquid obtained by filtration, and the test data is summarized and uploaded; S5. Data analysis: summarize the data obtained from the tests in step S2, step S3 and step S4, and establish a release curve that matches the standard band based on the cumulative release percentage at each time point in the experimental process. When the portion of the release curve outside the standard band exceeds 5% of itself, the current test sample is judged to be unqualified, and when the portion of the release curve outside the standard band is less than 5% of itself, the current test sample is judged to be qualified.

2. A method for detecting the release rate of mesalazine enteric-coated sustained-release tablets according to claim 1, characterized in that: In the steps S2, S3 and S4, the release degree detection equipment used needs to be cleaned or replaced with a new one.

3. A method for detecting the release rate of mesalazine enteric-coated sustained-release tablets according to claim 1, characterized in that: Pancreatic lipase, trypsin, amylase and intestinal flora need to be added to the small intestine release medium and the colon release medium to simulate the corresponding intestinal environment.

4. A method for detecting the release rate of mesalazine enteric-coated sustained-release tablets according to claim 1, characterized in that: The release degree detection device comprises a base (1), a small intestine simulation unit (3) and an electric slide (5) are respectively provided on the upper side of the base (1), and the electric slide (5) is located on the upper side of the small intestine simulation unit (3), and fixing plugs (4) are respectively inserted at both ends of the small intestine simulation unit (3), and the ends of the two fixing plugs (4) away from the small intestine simulation unit (3) both penetrate the base (1) and are threadedly connected with fixing nuts (2); The electric slide groove (5) is slidably connected with an electric slider (6), and the lower end of the electric slider (6) is fixedly connected with a peristaltic outer ring (7), and the peristaltic outer ring (7) is sleeved on the outer side of the small intestine simulation unit (3). The peristaltic outer ring (7) includes a ring body (701), and the upper half of the ring body (701) is provided with a transmission groove (702), a connecting groove (703) and a power groove (704), and the connecting groove (703) is connected to the transmission groove (702) and the power groove (704), and the transmission groove (702) is rotatably connected with a power tooth (8), and the power groove (70 4) is rotatably connected to an electric motor (9), the power output end of the electric motor (9) passes through the connecting groove (703) and is fixedly connected to the power tooth (8), the openings of the transmission groove (702) and the power groove (704) are respectively fixedly connected to a sealing cover 1 (11) and a sealing cover 2 (12) that match the transmission groove (702) and the power groove (704), a rotating groove (705) is cut on the inner wall of the ring body (701), a driven ring (10) is rotatably connected in the rotating groove (705), the driven ring (10) is meshed with the power tooth (8), and the inner wall of the driven ring (10) is connected to a peristaltic unit (14).

5. A method for detecting the release rate of mesalazine enteric-coated sustained-release tablets according to claim 4, characterized in that: The small intestine simulation unit (3) comprises a heat-insulating elastic shell (301), the heat-insulating elastic shell (301) is made of a heat-insulating material, and the outer wall of the heat-insulating elastic shell (301) is fixedly connected to an outer tarsal frame (302).

6. A method for detecting the release rate of mesalazine enteric-coated sustained-release tablets according to claim 4, characterized in that: Buffering and shock-absorbing materials are connected between the second sealing cover (12) and the inner wall of the power groove (704) and the motor (9), and the shock-absorbing materials are fixedly connected to the second sealing cover (12) and the power groove (704) respectively.

7. A method for detecting the release rate of mesalazine enteric-coated sustained-release tablets according to claim 4, characterized in that: The driven ring (10) has an installation cavity bored inside, an elastic airbag (13) is fixedly connected inside the installation cavity, the elastic airbag (13) is fixedly connected to a peristaltic unit (14), one end of the peristaltic unit (14) away from the elastic airbag (13) passes through the driven ring (10) and extends to the outside of the installation cavity, the peristaltic unit (14) comprises a movable ring (1401), one end of the movable ring (1401) close to the elastic airbag (13) is fixedly connected to an electric heating network (1402), and one end of the movable ring (1401) away from the electric heating network (1402) is fixedly connected to a plurality of simulated protrusions (1403).

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