Dissolution test system and test method

Abstract

The invention discloses a dissolution test system, which is used for testing the dissolution condition of a medicament in a solvent or the combination condition of the medicament and a solute in the solvent in a shaking table oscillation state, and comprises a dissolution bottle for accommodating the solvent; the connecting rod is fixedly connected with the dissolution bottle and comprises a bottom end, and the bottom end extends into the dissolution bottle in the axial direction of the dissolution bottle; the mesh basket is connected with the bottom end of the connecting rod, is suspended in the dissolution bottle and is used for accommodating medicaments; and the dissolution bottle is placed on the shaking table. The in-vivo release of the medicament can be more accurately simulated, the adhesion phenomenon of the medicament and the bottom of the dissolution bottle is reduced, the nonuniform dispersion of the medicament is avoided, the accuracy and the reliability of the in-vitro experiment result of the medicament are improved, and the uniformity and the repeatability of the experiment are improved. The invention also discloses a dissolution test method which is used for testing the dissolution condition of a medicament in a solvent in a shaking table oscillation state. The invention also discloses a phosphate binding force testing method, which is used for testing the phosphate binding force of a medicament in a solvent in a shaking table oscillation state.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical testing and relates to a dissolution testing system and a testing method. Background Art

[0002] Oral solid dosage forms play an important role in drug development and production, and their quality is directly related to the safety and effectiveness of drugs. In order to ensure the good release and absorption of oral solid dosage forms in the body, in vitro dissolution testing has become a key link in evaluating drug quality.

[0003] In in vitro dissolution experiments, the shaking table method is considered to have a high degree of simulation because it can simulate the natural movement of the human gastrointestinal tract. Compared with other equipment, the shaking table method can more realistically reflect the behavior of drugs in the gastrointestinal tract. Therefore, drug regulatory agencies recommend the use of the shaking table method for in vitro evaluation of some drugs.

[0004] The existing experimental technology usually puts the solid medicine directly into the dissolution bottle, and then puts it into the shaking table for in vitro dissolution experiment. This experimental device is simple and easy to operate, and can meet the needs of in vitro dissolution experimental research of oral solid medicines to a certain extent. However, when the solid medicine is heavy, the shaking table method has certain problems. The solid medicine tends to sink to the bottom quickly after entering the conical bottle, causing the shell of the solid medicine to adhere to the bottom of the dissolution bottle. The degree of adhesion is random, which affects the parallelism of the test results.

[0005] The prior art conducts dissolution testing by directly placing the drug into a dissolution bottle and placing it on a shaker for dissolution testing. However, the problem of how to more accurately simulate the release of the drug in the body, improve the accuracy and reliability of the in vitro test results of the drug, and improve the uniformity and repeatability of the experiment has not been effectively solved. Summary of the invention

[0006] The purpose of the present invention is to solve how to more accurately simulate the release of drugs in vivo, improve the accuracy and reliability of the results of in vitro experiments of pharmaceutical agents (for example, dissolution tests, combination of pharmaceutical agents with in vivo elements), and improve the uniformity and repeatability of experiments.

[0007] In a first aspect, the present invention provides a dissolution testing system for testing the dissolution of a drug in a solvent or the binding of a drug with a solute in the solvent under shaking of a shaking table, comprising:

[0008] A dissolution bottle, used to contain a solvent;

[0009] A connecting rod, fixedly connected to the dissolution bottle, comprises a bottom end, and the bottom end extends into the dissolution bottle along the axial direction of the dissolution bottle;

[0010] The net basket is connected to the bottom end of the connecting rod and is suspended in the dissolution bottle to contain the medicine;

[0011] Shaker, the dissolution bottle is placed on the shaker.

[0012] The above technical solution can more accurately simulate the release of drugs in the body, reduce the adhesion of drugs to the bottom of the dissolution bottle, avoid uneven dispersion of drugs, improve the accuracy and reliability of in vitro drug test results, and improve the uniformity and repeatability of the experiment.

[0013] According to another specific embodiment of the present invention, the connecting rod comprises:

[0014] The rod body comprises an external thread extending along the axial direction of the rod body;

[0015] A fixing piece is fixedly connected to the dissolution bottle, and the fixing piece is sleeved on the outer periphery of the rod body and is threadedly connected to the rod body;

[0016] The rod body and the fixing piece move relative to each other in the axial direction through thread transmission, thereby adjusting the length of the rod body extending into the dissolution bottle.

[0017] According to another specific embodiment of the present invention, the dissolution testing system further comprises:

[0018] The height setter has one end fixedly connected to the bottom of the net basket and the other end abutting against the bottom of the dissolution bottle, and is used to fix the distance between the bottom of the net basket and the bottom of the dissolution bottle.

[0019] According to another specific embodiment of the present invention, the length of the height determiner along the axial direction is adjustable, and the adjustment range of the length is 2mm-50mm.

[0020] According to another specific embodiment of the present invention, it includes height setters with different axial length specifications, and the length of the height setters with different axial length specifications along the axial direction is 2mm-50mm.

[0021] According to another specific embodiment of the present invention, the bottom end of the connecting rod is detachably connected to the basket.

[0022] According to another specific embodiment of the present invention, the bottom end of the connecting rod is connected to the basket via a buckle.

[0023] According to another specific embodiment of the present invention, the connecting rod and the basket are integrally formed.

[0024] According to another specific embodiment of the present invention, the mesh number of the net basket is 10 meshes to 200 meshes.

[0025] According to another specific embodiment of the present invention, the connecting rod is made of stainless steel or plastic, in particular, polytetrafluoroethylene (PTFE) or perfluoroalkoxy polymer (PFA).

[0026] In a second aspect, the present invention further provides a dissolution testing method, using the above-mentioned dissolution testing system, comprising:

[0027] placing the solvent in the dissolution bottle;

[0028] Place the potion in the mesh basket;

[0029] Extend the connecting rod connected to the net basket into the dissolution bottle to allow the medicine to be immersed in the solvent;

[0030] Place the dissolution bottle on a shaker, dissolve the drug in the solvent while the shaker is shaking, and test the dissolution of the drug.

[0031] The above technical solution can more accurately simulate the release of drugs in vivo, improve the accuracy and reliability of in vitro experimental results, and improve the uniformity and repeatability of experiments.

[0032] In a third aspect, the present invention further provides a method for testing phosphate binding capacity, using the above-mentioned dissolution test system to test the phosphate binding capacity of the agent in the solvent, wherein the solute in the solvent is phosphate, and the testing method comprises:

[0033] The dissolution bottle is filled with a solvent, and the concentration of the solute in the solvent is concentration C1;

[0034] The medicine is placed in a mesh basket, and a connecting rod connected to the mesh basket is extended into a dissolution bottle to allow the medicine to be immersed in the solvent; the dissolution bottle is placed on a shaker, and the medicine and the phosphate in the solvent are combined under the shaking state of the shaker; and the concentration C2 of the solute in the solvent is detected;

[0035] The phosphate binding capacity of the agent in the solvent is calculated based on the difference between the concentration C1 and the concentration C2.

[0036] The above technical solution can simulate the phosphate binding capacity of the drug after it is fully disintegrated in the body, improve the accuracy and reliability of the in vitro test results of the drug, and improve the uniformity and repeatability of the experiment.

[0037] According to another specific embodiment of the present invention, the phosphate comprises potassium dihydrogen phosphate and / or sodium dihydrogen phosphate. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 A schematic diagram showing a partial cross-sectional structure of a dissolution test system in an embodiment of the present invention Figure 1 ;

[0039] Figure 2 A schematic diagram showing a partial cross-sectional structure of a dissolution test system in an embodiment of the present invention Figure 2 ;

[0040] Figure 3A schematic diagram of a half-section structure of a mesh basket according to an embodiment of the present invention is shown;

[0041] Figure 4 The structure of the dissolution test system in the embodiment of the present invention is shown as follows: Figure 1 .

[0042] Explanation of symbols

[0043] 1 connecting rod, 11 fixing part, 12 rod body, 2 basket, 3 height setting device, 4 shaking table, 5 dissolution bottle, 10 dissolution test system. DETAILED DESCRIPTION

[0044] The following specific embodiments illustrate the implementation of the present invention, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. Although the description of the present invention will be introduced in conjunction with the preferred embodiment, this does not mean that the features of this invention are limited to this implementation. On the contrary, the purpose of introducing the invention in conjunction with the implementation is to cover other options or modifications that may extend based on the claims of the present invention. In order to provide a deep understanding of the present invention, the following description will include many specific details. The present invention can also be implemented without using these details. In addition, in order to avoid confusion or blurring the focus of the present invention, some specific details will be omitted in the description. It should be noted that the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.

[0045] It should be noted that in this specification, similar reference numerals and letters denote similar items in the following drawings, and therefore, once an item is defined in one drawing, it does not need to be further defined and explained in the subsequent drawings.

[0046] To make the objectives, technical solutions and advantages of the present invention more clear, the embodiments of the present invention will be further described in detail below with reference to the accompanying drawings.

[0047] The shaking table method is used in the field of dissolution testing because it can simulate the natural movement of the human gastrointestinal tract. When the solid medicine is heavy, the shaking table method has certain problems. The solid medicine tends to sink to the bottom quickly after entering the conical flask, causing the outer shell of the solid medicine to adhere to the bottom of the dissolution bottle. The degree of adhesion is random, which affects the parallelism and accuracy of the test results. The inventor thought of designing a mesh basket structure suspended in the dissolution bottle in the shaking table, placing the medicine in the mesh basket, and then testing the dissolution of the medicine in the solvent under the shaking table oscillation state, that is, it can avoid the phenomenon of medicine adhesion caused by directly placing the medicine in the dissolution bottle and using the shaking table method to test, which affects the accuracy of the dissolution test.

[0048] Based on the above principles, in a first aspect, the present invention provides a dissolution testing system 10, such as Figure 4As shown, it is used to test the dissolution of the drug in the solvent or the combination with the solute in the solvent under the shaking state of the shaker, including:

[0049] A dissolution bottle 5, used for containing a solvent;

[0050] A connecting rod 1 is fixedly connected to the dissolution bottle 5 and includes a bottom end, and the bottom end extends into the dissolution bottle 5 along the axial direction of the dissolution bottle 5;

[0051] The net basket 2 is connected to the bottom end of the connecting rod 1 and is suspended in the dissolution bottle 5 to contain the medicine;

[0052] A shaking table 4 and a dissolution bottle 5 are placed on the shaking table.

[0053] The above technical solution can more accurately simulate the release of the drug in the body, reduce the adhesion of the drug to the bottom of the dissolution bottle 5, avoid uneven dispersion of the drug, improve the accuracy and reliability of the in vitro test results of the drug, and improve the uniformity and repeatability of the experiment. The drug is fully dissolved in the basket 2 of the present invention mainly by the oscillation of the shaking table 4, without applying additional power (for example, electric power) for stirring or rotation, which more accurately simulates the scene of drug release in the human body, and avoids the uneven flow state of the solvent liquid caused by the high-speed circular rotation of the basket 2 during the dissolution test, and avoids the shear force generated during the rotation affecting the dissolution or binding behavior of certain drugs.

[0054] Specifically, the connecting rod 1 is suspended in the dissolution bottle 5, one end of the connecting rod 1 is fixedly connected to the bottle mouth of the dissolution bottle 5, and the other end is fixedly connected to the net basket 2. The drug to be tested is placed inside the net basket 2, and the net basket 2 is fixedly connected to the bottom of the connecting rod 1. The net basket 2 is suspended in the dissolution bottle 5, and the solvent in the dissolution bottle 5 immerses the drug to be tested. The drugs include solid preparations such as capsules and tablets, and semi-solid preparations.

[0055] Further, the dissolution bottle 5 is a triangular flask or a conical flask. There can be one or more dissolution bottles 5, and the dissolution bottles 5 are placed in the shaking table 4 to perform the dissolution test.

[0056] According to another specific embodiment of the present invention, Figure 1 Shown and Figure 4 The connecting rod 1 includes: a rod body 12, including an external thread extending in the axial direction of the rod body 12; a fixing member 11; fixedly connected to the dissolution bottle 5, the fixing member 11 is sleeved on the outer periphery of the rod body 12, and is threadedly connected to the rod body 12. The rod body 12 and the fixing member 11 move relative to each other in the axial direction through thread transmission, thereby adjusting the length of the rod body 12 extending into the dissolution bottle 5. By adopting the above technical solution, the length of the rod body 12 extending into the dissolution bottle 5 can be adjusted, which is convenient for adapting to different dissolution test experimental conditions.

[0057] In this embodiment, refer to Figure 1 and Figure 4 The rod body 12 rotates relative to the fixing member 11 to adjust the length of the rod body 12 extending into the dissolution bottle 5. In addition, the rod body 12 and the fixing member 11 do not rotate relative to the dissolution bottle 5, that is, the rod body 12 is fixed to the dissolution bottle 5 by the fixing member 11. When performing the dissolution test, the rod body 12 and the fixing member 11 do not rotate, and the oscillation of the shaking table 4 promotes the dissolution of the drug in the solvent.

[0058] Specifically, continue to refer to Figure 1 The fixing member 11 has a through hole penetrating the fixing member 11, and the through hole is an internal threaded hole. The end of the rod body 12 connected to the fixing member 11 has an external thread extending along the axis of the rod body 12. By rotating the fixing member 11, the thread is driven to change the relative position of the rod body 12 and the fixing member 11, so that the rod body 12 and the fixing member 11 move relative to each other in the axial direction of the rod body 12, thereby adjusting the length of the rod body 12 extending into the dissolution bottle. The rod body 12 is fixedly connected to the basket 2.

[0059] Further, the length of the rod body 12 can be matched according to the size of different dissolution bottles, for example, the length of the rod body ranges from 5 to 30 cm. Preferably, the length of the rod body 12 is 12 to 15 cm, and the length of the rod body 12 can be changed between 12 and 15 cm by changing the relative position of the rod body 12 and the fixing member 11.

[0060] According to another specific embodiment of the present invention, Figure 2 and Figure 4 As shown, the dissolution test system also includes: a height setter 3, one end of which is fixedly connected to the bottom of the basket 2, and the other end is abutted against the bottom of the dissolution bottle 5, so as to fix the distance between the bottom of the basket 2 and the bottom of the dissolution bottle 5. The connecting rod 1 includes a rod body 12 and a fixing member 11, one end of the basket 2 is fixedly connected to the rod body 12 of the connecting rod 1, and the other end of the basket 2 is fixedly connected to the height setter 3. The length of the rod body 12 extending into the dissolution bottle 5 can be adjusted by screw drive, the height setter 3 is fixedly connected to the basket 2, and the length of the rod body 12 extending into the dissolution bottle 5 is changed by rotating the fixing member 11, and the height setter 3 is abutted against the bottom of the dissolution bottle 5, so that the position of the basket 2 in the dissolution bottle 5 is fixed, that is, the bottom of the basket 2 is at an equal distance from the bottom of the dissolution bottle 5. The above technical solution is adopted to make the depth of each dose of the dissolution test experiment immersed in the solvent equal, so as to ensure the consistency of the dissolution test.

[0061] According to another specific embodiment of the present invention, the length of the height setter 3 in the axial direction is adjustable, and the adjustment range of the length is 2mm-50mm. For example, when there are multiple dissolution bottles 5 and corresponding baskets 2 and connecting rods 1 for parallel experiments, multiple height setters 3 are adjusted to the same height to perform dissolution tests. For another example, when testing the effects of different immersion depths on the dissolution test, the height setters 3 are adjusted to different heights to perform dissolution tests. With the above technical solution, the length of the height setter 3 in the axial direction is adjustable, and can match and adapt to different dissolution test experimental conditions.

[0062] According to another specific embodiment of the present invention, a height setting device 3 with different axial length specifications is included, and the length of the height setting device 3 with different axial length specifications along the axial direction is 2mm-50mm. For example, a plurality of height setting devices 3 with different axial lengths can be used in the dissolution test to match different dissolution test condition requirements. The above technical solution can adapt to different dissolution test experimental conditions.

[0063] In the above embodiments, the height setting device 3 may also be a plurality of identical height setting devices 3 , so as to be used in conjunction with a plurality of identical dissolution bottles 5 , connecting rods 1 and baskets 2 to conduct parallel experiments.

[0064] According to another specific embodiment of the present invention, the bottom end of the connecting rod 1 is detachably connected to the basket 2. The above technical solution is convenient for cleaning and maintenance, and for replacing damaged parts.

[0065] According to another specific embodiment of the present invention, the bottom end of the connecting rod 1 is connected to the net basket 2 by a buckle. Specifically, the connection is made by the buckle at the bottom of the connecting rod 1 and / or the buckle at the top of the net basket 2. With the above technical solution, the net basket 2 can be quickly disassembled and installed, which can reduce the experimental preparation time and improve the experimental efficiency.

[0066] Optionally, a sealing ring is provided between the connecting rod 1 and the basket 2 to increase the tightness and stability of the connection.

[0067] In the above embodiments, the top and / or bottom and / or side of the basket 2 are provided with openings to facilitate the placement of medicines.

[0068] According to another specific embodiment of the present invention, the connecting rod 1 and the basket 2 are integrally formed. With the above technical solution, the dissolution test device has a stable structure, and the integrally formed design makes the structure of the connecting rod 1 and the basket 2 more solid and not easy to deform, thereby maintaining stable performance during long-term use or repeated experiments.

[0069] Figure 3Schematic diagram of the half-section structure of the basket 2 in the embodiment of the present invention. In the present embodiment, the basket 2 is a cylinder. When the basket 2 is a cylinder, the diameter range of the basket 2 is 1-100 mm, and the diameter range of the basket 2 is preferably 6 mm-35 mm. The length range of the basket 2 along the axial direction is 1-100 mm, and the length range of the basket 2 along the axial direction is preferably 6 mm-45 mm. The shape of the basket 2 is a cylinder or a prism. The shape of the basket 2 can also be other shapes such as a sphere and a polyhedron. The material of the basket 2 is stainless steel, titanium alloy or nickel alloy.

[0070] According to another specific embodiment of the present invention, the mesh number of the basket 2 is 2 meshes to 200 meshes. Further, the mesh number of the basket 2 is preferably 5 meshes to 50 meshes. Further, the mesh number of the basket 2 is preferably 10 meshes to 20 meshes. The above technical solution is used to adapt to dissolution test experiments under different conditions.

[0071] According to another specific embodiment of the present invention, the material of the connecting rod 1 is stainless steel or plastic, in particular polytetrafluoroethylene (PTFE) or perfluoroalkoxy polymer (PFA). With the above technical solution, the connecting rod 1 is corrosion-resistant, not easy to dissolve, and stable in use.

[0072] In a second aspect, the present invention further provides a dissolution testing method, using the above-mentioned dissolution testing system, comprising:

[0073] Place the solvent in dissolution bottle 5;

[0074] Place the medicine in the basket 2;

[0075] The connecting rod 1 connected to the basket 2 is extended into the dissolution bottle 5 to allow the medicine to be immersed in the solvent;

[0076] The dissolution bottle 5 is placed on the shaking table 4, and the medicine is dissolved in the solvent under the shaking state of the shaking table 4, and the dissolution of the medicine is tested.

[0077] The above technical solution can more accurately simulate the release of drugs in vivo, improve the accuracy and reliability of in vitro drug test results, and improve the uniformity and repeatability of the experiment.

[0078] Specifically, the solvent is placed in the dissolution bottle 5, and the dissolution bottle 5 is placed in the shaking table 4, and preheated under the conditions of a preset temperature and a preset speed. Among them, the preset temperature and the preset speed are set according to the conditions such as the medicine, the type of solvent, and the measured value. For example, in some specific embodiments, the preset temperature is 37°C and the preset speed is 100r / min. The preset temperature and the preset speed can be adjusted according to actual needs. The medicine is loaded into the basket 2, the basket 2 is fixedly connected to the connecting rod 1, the connecting rod 1 is extended into the dissolution bottle 5, the length of the rod body 12 extending into the dissolution bottle 5 is adjusted, and the connecting rod 1 is fixed to the bottle mouth of the dissolution bottle 5. The medicine is soaked in the solvent, and the dissolution bottle 5 is placed on the shaking table to perform a dissolution test at a preset temperature and a preset speed. Because the basket 2 is meshed, the contact area between the basket 2 and the medicine is small, and the medicine slowly falls into the dissolution bottle when it disintegrates rapidly, avoiding the adhesion between the medicine shell and the bottom of the dissolution bottle 5. It is realized that the release or reaction of drugs in the human body is simulated under the oscillation state of the shaking table 4.

[0079] In a third aspect, the present invention further provides a method for testing phosphate binding capacity, which is used to test the phosphate binding capacity of a drug in a solvent, wherein the solute in the solvent is phosphate and the solvent is a phosphate buffer, and the testing method comprises:

[0080] The dissolution bottle is filled with a solvent, and the concentration of the solute in the solvent is concentration C1;

[0081] The medicine is placed in the mesh basket 2, and the connecting rod 1 connected to the mesh basket 2 is extended into the dissolution bottle 5 to allow the medicine to be immersed in the solvent;

[0082] The dissolution bottle 5 is placed on the shaking table 4, and the drug and the phosphate in the solvent are combined under the shaking state of the shaking table 4;

[0083] Detect the concentration of solute in the solvent C2;

[0084] The phosphate binding capacity of the agent in the solvent is calculated based on the difference between the concentration C1 and the concentration C2.

[0085] The above technical solution can simulate the phosphate binding capacity of the drug after it is fully disintegrated in the body, improve the accuracy and reliability of the in vitro test results of the drug, and improve the uniformity and repeatability of the experiment.

[0086] According to another specific embodiment of the present invention, the phosphate comprises potassium dihydrogen phosphate and / or sodium dihydrogen phosphate.

[0087] A more specific example is described below for testing the phosphate binding capacity of the agent in the solvent.

[0088] Examples 1-6 use the dissolution test system of the present invention, wherein the mesh basket 2 is 10 meshes and the medicine is a capsule. Examples 7-12 use the dissolution test system of the present invention, wherein the mesh basket 2 is 20 meshes and the medicine is a capsule. Comparative Examples 1-6 directly add the medicine to the dissolution bottle 5 and place it on a shaker, wherein the medicine is a capsule. Control Groups 1-6 directly add the medicine to the dissolution bottle 5 and place it on a shaker, wherein the medicine is the contents of the capsule.

[0089] Reagents and materials: purified water, potassium dihydrogen phosphate, sodium chloride, N,N-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), sodium hydroxide, 36%-38% hydrochloric acid, 10.0 mg / mL phosphorus standard solution.

[0090] Instruments and equipment: inductively coupled plasma optical emission spectrometer (ICP-OES), water bath shaker, pH meter, thermometer, tachometer, centrifuge, electronic balance, ultrapure water meter, and the dissolution test system of the present invention.

[0091] ICP-OES instrument parameters: plasma gas flow rate: 15 L / min; auxiliary gas flow rate: 0.5 L / min; nebulizer flow rate: 0.85 L / min; RF power: 1400 W; observation distance: 15.0; plasma observation: radial; sample flow rate: 1.50 mL / min; wavelength: 213.617 nm; delay time: 40 s; number of repetitions: 3 times.

[0092] Solution preparation:

[0093] 6% Hydrochloric acid solution (w / v): Transfer 80 mL of 36%-38% hydrochloric acid to a 500 mL volumetric flask, dilute to volume with pure water and mix.

[0094] 1N Sodium Hydroxide Solution: Weigh approximately 4.0 g (accurate to 0.01 g) of sodium hydroxide into a 100 mL beaker, dissolve it in pure water and transfer it to a 100 mL volumetric flask. Make up to volume with pure water and mix well.

[0095] pH 2.0 buffer: weigh about 96.0 g (accurate to 0.01 g) BES and 20.88 g (accurate to 0.01 g) NaCl into a suitable container and dissolve in 4500 mL pure water. Use 6% HCl solution and / or 1N NaOH solution to adjust the pH to 2.00 ± 0.03.

[0096] Diluent: Transfer 200 mL of pH 2.0 buffer and 1800 mL of pure water into a 2 L bottle and mix well.

[0097] Solvent (15 mM KH2PO4 solution at pH 2.0): weigh about 8.16 g (accurate to 0.01 g) of KH2PO4 into a suitable container, dissolve in 4000 mL of pH 2.0 buffer, sonicate for about 30 minutes to completely dissolve the KH2PO4, and mix. Use 6% HCl solution and / or 1N NaOH solution to adjust the pH to 2.00 ± 0.03.

[0098] Linear solution: dilute the 10.0 mg / mL phosphorus standard solution with diluent to prepare a series of linear solutions ranging from 10 to 50 μg / mL.

[0099] Blank: Transfer 200 mL of pH 2.0 buffer and 1800 mL of pure water into a 2 L bottle and mix well.

[0100] Standard solution 1: Dilute 10.0 mg / mL phosphorus standard solution to 30 μg / mL with diluent.

[0101] Standard solution 2: Dilute the 10.0 mg / mL phosphorus standard solution to 30 μg / mL with diluent.

[0102] Control solution (1.5mM KH2PO4 solution): Transfer 2.0mL of solvent into a 20mL volumetric flask, dilute to volume with pure water and mix well. Prepare two portions in parallel. Used to ensure the stability of the ICP-OES instrument.

[0103] The operating steps of Example 1-6 are as follows: accurately transfer 300mL of solvent to a 500mL dissolution bottle 5, place it in a water bath shaker 4, and preheat it at 37°C and 100 rpm for half an hour. Take 1 capsule and put it into a 10-mesh basket 2, fix the basket 2 and the connecting rod 1, put it into the dissolution bottle 5, fix the connecting rod 1 to the dissolution bottle 5, place it in a water bath shaker 4, and perform a dissolution test at 37°C and 100 rpm for 24 hours, that is, cultivate it for 24 hours. After the dissolution test is completed, take out the dissolution bottle 5, shake it lightly to mix the solution, pour out 2 portions of about 10mL of the suspension and centrifuge them, filter and collect the remaining filtrate. Transfer 2.0mL of the filtrate to a 20mL volumetric flask, dilute to volume with pure water and mix.

[0104] The operating steps of Examples 7-12 are as follows: accurately transfer 300 mL of solvent to a 500 mL dissolution bottle 5, place it in a water bath shaker 4, and preheat it at 37°C and 100 rpm for half an hour. Take 1 capsule and put it into a 20-mesh basket 2, fix the basket 2 and the connecting rod 1, put it into the dissolution bottle 5, fix the connecting rod 1 to the dissolution bottle 5, place it in a water bath shaker 4, and perform a dissolution test at 37°C and 100 rpm for 24 hours, that is, cultivate it for 24 hours. After the dissolution test is completed, take out the dissolution bottle 5, shake it lightly to mix the solution, pour out 2 portions of about 10 mL of the suspension and centrifuge them, filter and collect the remaining filtrate. Transfer 2.0 mL of the filtrate to a 20 mL volumetric flask, dilute to volume with pure water and mix.

[0105] The operating steps of comparative examples 1-6 are as follows: accurately transfer 300 mL of solvent to a 500 mL dissolution bottle 5, place it in a water bath shaker 4, and preheat it at 37°C and 100 rpm for half an hour. Take 1 capsule and put it into the dissolution bottle, plug the bottle stopper, place it in a water bath shaker 4, and perform a dissolution test at 37°C and 100 rpm for 24 hours, i.e., cultivate it for 24 hours. After the dissolution test, take out the dissolution bottle 5, shake it lightly to mix the solution, pour out 2 portions of about 10 mL of the suspension, centrifuge it, filter and collect the remaining filtrate. Transfer 2.0 mL of the filtrate to a 20 mL volumetric flask, dilute to volume with pure water and mix it.

[0106] Control group 1-6 operation steps: accurately transfer 300mL of solvent to 500mL dissolution bottle 5, place it in a water bath shaker 4, and preheat it at 37°C and 100 rpm for half an hour. Take 1 capsule, open the capsule shell, put the capsule contents into the dissolution bottle, plug the bottle stopper, place it in a water bath shaker 4, and perform the dissolution test at 37°C and 100 rpm for 24 hours, that is, incubate for 24 hours. After the dissolution test, take out the dissolution bottle 5, shake it lightly to mix the solution, pour out 2 portions of about 10mL of the suspension, centrifuge, filter and collect the remaining filtrate. Transfer 2.0mL of the filtrate to a 20mL volumetric flask, dilute to volume with pure water and mix.

[0107] A phosphorus standard curve was established, and the phosphorus concentrations in Examples 1-12, Comparative Examples 1-6, and Control Groups 1-6 were measured according to the phosphorus standard curve.

[0108]

[0109] Where W is the phosphate binding capacity (mg / g), measured in labeled amount. C0 is the concentration of phosphorus in the dilution solvent (μg / mL), spl is the concentration of phosphorus in the sample solution (μg / mL), Mw(P) is the relative atomic mass of phosphorus, Mw(PO4 3- ) is the relative molecular mass of phosphate. LC is the labeled amount, 700 mg.

[0110] The experimental results are shown in Table 1.

[0111] Table 1 Phosphate binding capacity and relative standard deviation of the examples, comparative examples and control group

[0112]

[0113] As can be seen from Table 1, Examples 1-6 use the dissolution test system and phosphate binding test method of the present invention, wherein the mesh basket 2 is 10 meshes, and the average value of the phosphate binding of the agent is measured to be 267 mg / g, and the relative standard deviation is 1.1%. Examples 7-12 use the dissolution test system and phosphate binding test method of the present invention, wherein the mesh basket 2 is 20 meshes, and the average value of the phosphate binding of the agent is measured to be 271 mg / g, and the relative standard deviation is 0.9%. The relative standard deviations (Relative Standard Deviation, RSD) are all less than 2%. This shows that the dissolution test system and phosphate binding test method of the present invention have good parallelism, and the test results for phosphate binding are stable.

[0114] Comparative Examples 1-6 directly add the agent to the dissolution bottle and place it on the shaker 4 for testing. The average value of the phosphate binding capacity of the agent is 247 mg / g, and the relative standard deviation is 7.6%, indicating that the consistency of directly adding the agent to the dissolution bottle 5 and placing it on the shaker 4 for testing is poor. And the phosphate binding capacity of comparative example 6 is 209 mg / g, which is much lower than the average phosphate binding capacity of 264 mg / g of the control group. This indicates that the capsules in the comparative example are unevenly dispersed and the results are inaccurate. Compared with directly placing the capsules in the dissolution bottle on the shaker, the dissolution test system and phosphate binding test method of the present invention have a small relative standard deviation, better consistency, and more accurate test results. The dissolution test system and test method of the present invention are particularly suitable for the detection of phosphate binding capacity.

[0115] The average value of phosphate binding capacity of Examples 1-6 is 267 mg / g, the average value of phosphate binding capacity of Examples 7-12 is 271 mg / g, and the average value of phosphate binding capacity of Control Group 1-6 is 264 mg / g. Control Group 1-6 is a group in which the capsule shell is removed and only the capsule contents are added, which can reflect the experimental results of the capsule contents without the influence of the capsule shell and can be used as a control for the real results. The average values ​​of phosphate binding capacity of Examples 1-6, Examples 7-12 and Control Group 1-6 are not much different, indicating that the device of the present invention can fully combine the drug with phosphate, so that the medicament reflects the real efficacy results.

[0116] Although the present invention has been illustrated and described with reference to certain preferred embodiments of the present invention, it should be understood by those skilled in the art that the above is a further detailed description of the present invention in conjunction with specific embodiments, and it cannot be determined that the specific implementation of the present invention is limited to these descriptions. Those skilled in the art may make various changes in form and details, including making several simple deductions or substitutions, without departing from the spirit and scope of the present invention.

Claims

1. A dissolution testing system, characterized in that: Used to test the dissolution of the drug in the solvent or the combination with the solute in the solvent under shaking, including: A dissolution bottle, used to contain a solvent; A connecting rod, fixedly connected to the dissolution bottle, comprises a bottom end, and the bottom end extends into the dissolution bottle along the axial direction of the dissolution bottle; A net basket connected to the bottom end of the connecting rod, suspended in the dissolution bottle, and used to contain medicine; A shaking table, on which the dissolution bottle is placed.

2. The dissolution testing system according to claim 1, characterized in that: The connecting rod comprises: A rod body, comprising an external thread extending along the axial direction of the rod body; A fixing piece, fixedly connected to the dissolution bottle, the fixing piece is sleeved on the outer circumference of the rod body and is threadedly connected to the rod body; The rod body and the fixing member move relatively along the axial direction through thread transmission, so as to adjust the length of the rod body extending into the dissolution bottle.

3. The dissolution testing system according to claim 2, characterized in that: Also includes: A height fixer, one end of which is fixedly connected to the bottom of the net basket and the other end of which abuts against the bottom of the dissolution bottle, is used to fix the distance between the bottom of the net basket and the bottom of the dissolution bottle.

4. The dissolution testing system according to claim 3, characterized in that: The length of the height determiner along the axial direction is adjustable, and the adjustment range of the length is 2mm-50mm.

5. The dissolution testing system according to claim 3, characterized in that: It comprises height setters with different axial length specifications, wherein the length of the height setters with different axial length specifications along the axial direction is 2mm-50mm.

6. The dissolution testing system according to claim 1, characterized in that: The bottom end of the connecting rod is detachably connected to the net basket.

7. The dissolution testing system according to claim 1, characterized in that: The bottom end of the connecting rod is connected to the net basket via a buckle.

8. The dissolution testing system according to claim 1, characterized in that: The connecting rod and the net basket are integrally formed.

9. The dissolution testing system according to claim 1, characterized in that: The mesh number of the net basket is 10 to 200 meshes.

10. The dissolution testing system according to claim 1, characterized in that: The connecting rod is made of polytetrafluoroethylene (PTFE), perfluoroalkoxy polymer (PFA), stainless steel or plastic.

11. A dissolution test method, characterized in that: A dissolution testing system according to any one of claims 1 to 10, comprising: placing the solvent in the dissolution bottle; placing the medicine in the mesh basket; Extending the connecting rod connected to the net basket into the dissolution bottle to allow the medicine to be soaked in the solvent; The dissolution bottle is placed on the shaker, and the medicine is dissolved in the solvent under the shaking state of the shaker, and the dissolution of the medicine is tested.

12. A method for testing phosphate binding capacity, characterized in that: The dissolution test system according to any one of claims 1 to 10 is used to test the phosphate binding capacity of the agent in the solvent, wherein the solute in the solvent is phosphate, and the phosphate binding capacity test method comprises: The dissolution bottle is filled with the solvent, and the concentration of the solute in the solvent is concentration C1; Placing the medicine in the mesh basket, extending the connecting rod connected to the mesh basket into the dissolution bottle, so that the medicine is immersed in the solvent; Placing the dissolution bottle on the shaker, and combining the agent with the phosphate in the solvent under the shaking state of the shaker; Detecting the concentration C2 of the solute in the solvent; The phosphate binding capacity of the agent in the solvent is calculated according to the difference between the concentration C1 and the concentration C2.

13. The method for testing phosphate binding capacity according to claim 12, wherein: The phosphate comprises potassium dihydrogen phosphate and / or sodium dihydrogen phosphate.

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