Dissolution test net

Abstract

A dissolution test device comprising a vessel specified in a dissolution test method of the Japanese Pharmacopoeia, the US Pharmacopoeia or the EU Pharmacopoeia, or, comprising a vessel used in a dissolution test and a paddle formed from a stirring vane and a rotary shaft, wherein a net is disposed at a position below the bottom of the stirring vane and above the bottom surface of the vessel, and a suspension agent or solid agent is loaded or placed on the net, whereby a drug is dissolved from the agent and variations in the dissolution rate of the drug between a plurality of the same agents can be reduced.　

Description

[Technical field]

[0001] The present invention relates to a dissolution test apparatus for suspensions or solid preparations, comprising a vessel specified in the dissolution test methods of the Japanese Pharmacopoeia, the United States Pharmacopoeia, or the European Pharmacopoeia, or a vessel used in dissolution tests, and a paddle consisting of an agitating blade and a rotating shaft, the dissolution test apparatus comprising a net for use in dissolution tests that is arranged below the lowest part of the agitating blade and above the bottom of the vessel, more specifically, a net arranged 5 to 35 mm below the lowest part of the agitating blade or a net arranged 1 to 30 mm above the bottom of the vessel, a vessel in which the net is arranged, and a dissolution test apparatus comprising a vessel in which the net is arranged, and a paddle having an agitating blade and a rotating shaft. [Background technology]

[0002] A common method for evaluating the dissolution of drugs from tablets, capsules, etc. is the dissolution test method prescribed in the Japanese Pharmacopoeia (commonly known as the "Pharmacopoeia"). This dissolution test method includes the first method (rotating basket method), in which a test liquid is placed in a dissolution test container (hereinafter sometimes called a "vessel") of a dissolution test apparatus, a basket containing a drug product is rotated in the test liquid, and the dissolution rate is measured, and the second method (paddle method), in which a test liquid is placed in a vessel, the drug product is placed in the test liquid, and the dissolution rate is measured by rotating the stirring blades of a paddle in the test liquid. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Laid-Open No. 2-264862 [Patent Document 2] JP 2004-233332 A [Patent Document 3] JP 2008-32482 A [Non-patent literature]

[0004] [Non-Patent Document 1] Biopharmaceutics Modeling and Simulations Theory, Practice, Methods and applications (by Kiyohiko Sugano) Summary of the Invention [Problem to be solved by the invention]

[0005] When performing a dissolution test using the above-mentioned second method (paddle method), the rotation speed of the impeller of the dissolution tester is often set to 50 to 75 rpm. However, according to Non-Patent Document 1, when reproducing the dissolution properties in the digestive tract, the rotation speed of the impeller is 10 to 30 rpm, which is lower than the above rotation speed. Thus, when the rotation speed of the impeller is low, 1) the dissolution rate of the drug from the formulation is low and 2) there is a large variation in the dissolution rate when measuring the dissolution rate of multiple identical formulations when the rotation speed of the impeller is high.

[0006] In tablets and capsules containing poorly soluble drugs, the drug dissolution rate is low and when measuring the dissolution rate of multiple identical preparations, the cause of the large variation in dissolution rate was investigated. As a result, it was found that the cause was the so-called coning phenomenon, in which poorly soluble drugs and insoluble additives contained in the preparation are deposited on the bottom of the vessel of the dissolution tester.

[0007] Various patent applications have been filed for dissolution testers (Patent Document 1). In addition, patent applications have been filed for devices that perform disintegration tests on orally disintegrating tablets under conditions closer to those in vivo (Patent Documents 2 and 3). However, these documents do not mention or suggest any devices or tools that take into account dissolution in the digestive tract, or how to prevent coning. [Means for solving the problem]

[0008] In view of the above circumstances, the inventors conducted extensive research and found that, when a mesh is placed in the vessel of a dissolution test apparatus and a suspension, solid preparation or the like is poured or placed on the mesh, the drug is continuously dissolved from the preparation even when the stirring blade of the dissolution test apparatus is rotated at a low speed, and further, when multiple dissolution tests are performed on the same preparation, the variation in the dissolution rate is small.

[0009] That is, (1) A mesh for use in dissolution testing of suspensions or solid preparations, which is placed below the lowest part of the agitator and above the bottom of the vessel in a dissolution test apparatus equipped with a vessel specified in the dissolution test method of the Japanese Pharmacopoeia, the United States Pharmacopoeia, or the European Pharmacopoeia, or a vessel used in dissolution testing, and a paddle consisting of an agitator and a rotating shaft; (2) The net according to (1) above, wherein the net is disposed at a position 5 to 35 mm below the lowest part of the stirring blade; (3) The net according to (1) above, wherein the net is disposed at a position 1 to 30 mm above the bottom surface of the vessel. (4) A net according to (2) or (3) above, wherein the net is disposed at a position 5 to 35 mm below the lowest part of the stirring blade and 1 to 30 mm above the bottom surface of the vessel. (5) A net according to any one of (1) to (4) above, wherein the shape of the net is circular and the diameter of the net is 10 to 95 mm. (6) A net according to any one of (1) to (5) above, having an opening of 2 to 200 mesh. (7) A net according to any one of (1) to (6) above, having an edge at the end of the net. (8) A net according to any one of (1) to (7) above, wherein the net is provided with legs. (9) A mesh according to any one of (1) to (8) above for preventing coning of a suspension or solid preparation in a dissolution test. (10) A mesh for use in a dissolution test of a suspension or solid preparation, which is disposed below the lowest part of the agitator and above the bottom of the vessel in a dissolution test apparatus equipped with a vessel specified in the dissolution test method of the Japanese Pharmacopoeia, the United States Pharmacopoeia, or the European Pharmacopoeia, or a vessel used in a dissolution test, and a paddle consisting of an agitator and a rotating shaft, and which is circular in shape, has a diameter of 10 to 95 mm, and has an opening size of 2 to 200 mesh, and is used to prevent coning of a suspension or solid preparation in a dissolution test; (11) A vessel in which the net according to any one of (1) to (10) above is disposed. (12) A dissolution test apparatus comprising the vessel of (11) above and a paddle having an agitator and a rotating shaft. (13) A dissolution test apparatus comprising the vessel of (11) above, and a paddle having a stirring blade and a rotating shaft whose length can be adjusted. (14) A method for conducting a dissolution test by placing or placing a suspension or solid preparation on the mesh according to any one of (1) to (10) above. (15) A method for conducting a dissolution test by placing or casting a suspension or solid preparation in a sinker on the net described in any one of (1) to (10) above. (16) The method according to (14) or (15) above, in which a suspension or a solid preparation is placed on or on the mesh according to any one of (1) to (10) above, and the paddle rotation speed is set to 10 to 75 rpm. (17) The method according to any one of (14) to (16) above, in which a suspension or a solid preparation is placed on or on the mesh according to any one of (1) to (10) above, the paddle rotation speed is set to 10 to 75 rpm, and the CV% of the dissolution rate is within 20%. The present invention relates to the Effect of the Invention

[0010] Even if an oral preparation containing a poorly soluble drug, particularly a solid preparation such as a suspension or a tablet or capsule, is placed on the net of the present invention and a dissolution test is performed by rotating the impeller at a low speed by the paddle method in accordance with the behavior of the digestive tract, the preparation hardly accumulates (cones) in the vessel of the dissolution tester. Therefore, even if a suspension or a solid preparation such as a tablet or capsule is placed on the net of the present invention and the impeller is rotated at a low speed by the paddle method, when a dissolution test is performed on multiple identical preparations, the variation in dissolution rate between the preparations can be reduced. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 shows the net of the present invention placed in the vessel of a dissolution test apparatus. [Diagram 2] A diagram of the edged net of the present invention. [Diagram 3] FIG. 1 shows a mesh screen with edges according to the present invention placed in a vessel of a dissolution test apparatus. [Figure 4] A diagram of a net with legs according to the present invention. [Diagram 5] FIG. 1 shows a mesh with legs according to the present invention placed in a vessel of a dissolution test device. [Figure 6] Dissolution behavior of Lipitor tablets 10mg [Figure 7] Dissolution behavior of Baxo Capsule 20 [Figure 8] Dissolution behavior of Celecoxib tablets 100mg [Figure 9] Predicted PK profile of Celecoxib 100mg tablets [Figure 10] Dissolution behavior of Tegretol tablets 200mg [Figure 11] Predicted PK of Tegretol tablets 200mg BEST MODE FOR CARRYING OUT THEINVENTION

[0012] Hereinafter, an embodiment of the present invention will be described in detail. The mesh of the present invention is a mesh for use in a dissolution test, which is arranged below the lowest part of the stirring blade of the dissolution test apparatus used in the dissolution test method and above the inner bottom surface of the vessel, although it does not conform to the Japanese Pharmacopoeia, the United States Pharmacopoeia, or the European Pharmacopoeia (hereinafter sometimes referred to as "dissolution test apparatus") or the Japanese Pharmacopoeia. The mesh of the present invention may be any mesh with openings, and may be a mesh conforming to the JIS standard, or a plate-like mesh with openings, such as a punched plate or punched metal. A punched plate or punched metal is a plate made of metal or the like, which is processed by punching holes with a die of a punching press. Note that there may be an error of about ±2 mm in the arrangement position, diameter, thickness, etc. of the mesh described below.

[0013] The net of the present invention is placed in a vessel, and the net is placed almost parallel to the stirring blades of the paddle of the dissolution test apparatus used in the "dissolution test method" described in the Japanese Pharmacopoeia, as shown in FIG. 1. The vessel may be any container used in the "dissolution test method" described in the Japanese Pharmacopoeia. That is, the vessel is cylindrical with a circular cross section and a semispherical bottom, has a volume of about 1 L, a height of 160 to 210 mm, an inner diameter of 98 to 106 mm, and has a chime at the top of the container. The vessel may be covered with a lid to prevent the test solution from evaporating. The vessel may be made of any material that is not corroded by the test solution, such as glass or plastic.

[0014] The net of the present invention is placed in a vessel, but the net can be used in vessels that do not comply with the dissolution test apparatus used in the "Dissolution Test Method" described in the Japanese Pharmacopoeia. For example, the vessel has a circular cross section and a cylindrical shape with a semispherical bottom, a volume of about 100 ml to 500 ml, an inner diameter of 30 to 120 mm, and a height of 80 to 250 mm. For example, there are vessels with an inner diameter of 41.0 mm and a height of 108.00 mm, vessels with an inner diameter of 41.0 mm and a height of 203.0 mm, vessels with an inner diameter of 41.0 mm and a height of 176.3 mm, and vessels with an inner diameter of 101.0 mm and a height of 99.5 mm. The top of the container has a chime. The vessel can be covered with a lid to prevent the test solution from evaporating. The vessel may be made of any material that is not corroded by the test solution, such as glass or plastic.

[0015] The shape of the net of the present invention may be any shape that fits into the space of the vessel, and is basically circular, but may be other shapes such as triangular, rectangular, pentagonal, hexagonal, octagonal, decagonal, star-shaped, etc.

[0016] The net of the present invention may be placed at a position below the lowest part of the agitator blade of the dissolution test apparatus, and is usually placed at a position 5 to 35 mm below the lowest part of the agitator blade, preferably 7.5 to 32.5 mm below the lowest part of the agitator blade, and more preferably 7.5 to 30 mm below the lowest part of the agitator blade.

[0017] The mesh of the present invention used in a dissolution test apparatus in the dissolution test method described in the Japanese Pharmacopoeia, the United States Pharmacopoeia, or the European Pharmacopoeia is usually placed at a position 5 to 35 mm below the lowest point of the stirring blade, preferably 10 to 32.5 mm below the lowest point of the stirring blade, more preferably 15 to 30 mm below the lowest point of the stirring blade, and particularly preferably about 25 mm below the lowest point of the stirring blade. If the position of the mesh is smaller than this point from the lowest point of the stirring blade, there is a risk that the stirring blade and the preparation will come into contact, and if the position of the mesh is larger than this point from the lowest point of the stirring blade, there is a possibility that an appropriate stirring force will not reach the preparation.

[0018] The net of the present invention may be placed above the inner bottom surface of the vessel of the dissolution test apparatus, and is usually placed at a position 1 to 30 mm above the bottom surface of the vessel, preferably 1 to 27.5 mm above the bottom surface of the vessel, and more preferably 1 to 25 mm above the inner bottom surface of the vessel.

[0019] The mesh of the present invention used in the dissolution test apparatus in the dissolution test method described in the Japanese Pharmacopoeia, the United States Pharmacopoeia, or the European Pharmacopoeia may be placed above the inner bottom surface of the vessel of the dissolution test apparatus, and is usually placed 5 to 30 mm above the bottom surface of the vessel, preferably 10 to 27.5 mm above the bottom surface of the vessel, more preferably 15 to 25 mm above the inner bottom surface of the vessel, and particularly preferably about 16 mm above the inner bottom surface of the vessel of the dissolution test apparatus. If the position of the mesh is smaller than this from the inner bottom surface of the vessel, there is almost no space between the inner bottom surface of the vessel and the mesh, and compounds and additives may accumulate at the bottom of the vessel, and if it is larger than this from the bottom surface of the vessel, there is a possibility that an appropriate stirring force will not reach the bottom surface of the vessel.

[0020] The mesh of the present invention may be placed below the lowest part of the agitator impeller of the dissolution test apparatus and above the inner bottom surface of the vessel, but is usually placed 5 to 35 mm below the lowest part of the agitator impeller and 1 to 30 mm above the inner bottom surface of the vessel, preferably 7.5 to 32.5 mm below the lowest part of the agitator impeller and 1 to 27.5 mm above the inner bottom surface of the vessel, and more preferably 7.5 to 30 mm below the lowest part of the agitator impeller and 1 to 25 mm above the inner bottom surface of the vessel.

[0021] The mesh of the present invention used in a dissolution test apparatus in a dissolution test method described in the Japanese Pharmacopoeia, the United States Pharmacopoeia, or the European Pharmacopoeia is usually placed at a position 5 to 35 mm below the lowest part of the agitating impeller and 5 to 30 mm above the inner bottom surface of the vessel, preferably at a position 10 to 32.5 mm below the lowest part of the agitating impeller and 10 to 27.5 mm above the inner bottom surface of the vessel, more preferably at a position 15 to 30 mm below the lowest part of the agitating impeller and 15 to 25 mm above the inner bottom surface of the vessel, and particularly preferably at a position about 25 mm below the lowest part of the agitating impeller and 16 mm above the inner bottom surface of the vessel.

[0022] When the shape of the net of the present invention is circular, the diameter of the net may be any diameter that allows it to be placed in a vessel, and is usually 10 to 95 mm, preferably 12.5 to 90 mm, and more preferably 15 to 85 mm.

[0023] When the mesh used in the dissolution test apparatus in the dissolution test method described in the Japanese Pharmacopoeia, the United States Pharmacopoeia, or the European Pharmacopoeia is circular, the diameter of the mesh is usually 40 to 95 mm, preferably 45 to 90 mm, and more preferably 50 to 85 mm. If the diameter of the mesh is smaller than this, there is almost no space between the inner bottom surface of the vessel and the mesh, and compounds and additives may accumulate at the bottom of the vessel, and if the diameter is larger than this, it may not be possible to place the mesh inside the vessel.

[0024] The mesh size of the mesh of the present invention is usually 2 to 200 mesh, preferably 5 to 100 mesh, more preferably 10 to 60 mesh according to the JIS standard. In addition, in the case of a punched plate or punched metal, the mesh size is 0.07 to 12.0 mm, preferably 0.14 to 4.6 mm, more preferably 0.25 to 2.3 mm. If the mesh size of the mesh, punched plate, or punched metal is larger than this, the formulation itself may pass through, and if it is smaller than this, compounds, additives, etc. in the disintegrated formulation may accumulate on the mesh.

[0025] The thickness of the net of the present invention is sufficient if the net can withstand water pressure since the net is placed on the bottom surface, and is usually 0.04 to 2 mm, preferably 0.08 to 2 mm, and more preferably 0.1 to 1.2 mm. If the thickness of the net is smaller than this range, the net cannot withstand the water pressure or the weight of the formulation and may deform, whereas if the thickness is larger than this range, the weight becomes too heavy and may damage the vessel.

[0026] When the shape of the net of the present invention is circular, the net generally has a diameter of 10 to 95 mm and a mesh size of 2 to 200 mesh, preferably a diameter of 12.5 to 90 mm and a mesh size of 5 to 100 mesh, and more preferably a diameter of 15 to 85 mm and a mesh size of 10 to 60 mesh. By using such a net structure, there is little risk that compounds and additives in the disintegrated formulation will accumulate on the net.

[0027] The mesh of the present invention is a mesh used in a dissolution test apparatus in the dissolution test method described in the Japanese Pharmacopoeia, the United States Pharmacopoeia, or the European Pharmacopoeia, and when the shape of the mesh is circular, the diameter of the mesh is usually 40 to 95 mm, and the mesh size of the mesh is 2 to 200 mesh, preferably the diameter of the mesh is 45 to 90 mm, the mesh size of the mesh is 5 to 100 mesh, and more preferably the diameter of the mesh is 50 to 85 mm, and the mesh size of the mesh is 10 to 60 mesh. By using such a mesh structure, there is little risk that compounds or additives in the disintegrated formulation will be deposited on the mesh, and there is also little variation in dissolution rate between formulations.

[0028] The net of the present invention is a net for use in a dissolution test of a suspension or solid preparation, which is disposed below the lowest part of the stirring blade and above the bottom of the vessel in a dissolution test apparatus equipped with a vessel specified in the dissolution test method of the Japanese Pharmacopoeia, the United States Pharmacopoeia, or the European Pharmacopoeia, or a vessel used in a dissolution test, and a paddle consisting of a stirring blade and a rotating shaft. Furthermore, when the shape of the net is circular, the diameter of the net is 10 to 95 mm, and the opening size of the net is 2 to 200 mesh, preferably the diameter of the net is 12.5 to 90 mm, the opening size of the net is 5 to 100 mesh, and more preferably the diameter of the net is 50 to 85 mm, and the opening size of the net is 10 to 60 mesh. By using such a structure of the net, there is little risk that compounds or additives in the disintegrated preparation will be deposited on the net, and there is little variation in the dissolution rate between preparations.

[0029] When the shape of the net of the present invention is circular, the diameter of the net is usually 10 to 95 mm, the size of the opening of the net is 2 to 200 mesh, and the thickness of the net is 0.04 to 2 mm, preferably the diameter of the net is 12.5 to 90 mm, the size of the opening of the net is 5 to 100 mesh, and the thickness of the net is 0.08 to 2 mm, and more preferably the diameter of the net is 15 to 85 mm, the size of the opening of the net is 10 to 60 mesh, and the thickness of the net is 0.1 to 1.2 mm. By using such a net structure, there is little risk that compounds or additives in the disintegrated preparation will be deposited on the net, and there is also little variation in the dissolution rate between preparations.

[0030] The mesh of the present invention is a mesh used in a dissolution test apparatus in the dissolution test method described in the Japanese Pharmacopoeia, the United States Pharmacopoeia, or the European Pharmacopoeia, and when the shape of the mesh is circular, the diameter of the mesh is usually 40 to 95 mm, the size of the opening of the mesh is 2 to 200 mesh, and the thickness of the mesh is 0.04 to 2 mm, preferably the diameter of the mesh is 45 to 90 mm, the size of the opening of the mesh is 5 to 100 mesh, and the thickness of the mesh is 0.08 to 2 mm, and more preferably the diameter of the mesh is 50 to 85 mm, the size of the opening of the mesh is 10 to 60 mesh, and the thickness of the mesh is 0.1 to 1.2 mm. By using such a mesh structure, there is little risk that compounds or additives in the disintegrated formulation will be deposited on the mesh, and there is little variation in the dissolution rate between formulations.

[0031] The mesh of the present invention is a mesh for use in a dissolution test of a suspension or solid preparation, which is disposed below the lowest part of the stirring blade and above the bottom of the vessel in a dissolution test apparatus equipped with a vessel specified in the dissolution test method of the Japanese Pharmacopoeia, the United States Pharmacopoeia, or the European Pharmacopoeia, or a vessel used in a dissolution test, and a paddle consisting of a stirring blade and a rotating shaft. When the shape of the mesh is circular, the diameter of the mesh is 10 to 95 mm, the opening size of the mesh is 2 to 200 mesh, and the thickness of the mesh is 0.04 to 2 mm, preferably the diameter of the mesh is 12.5 to 90 mm, the opening size of the mesh is 5 to 100 mesh, and the thickness of the mesh is 0.08 to 2 mm, and more preferably the diameter of the mesh of the present invention is 50 to 85 mm, the opening size of the mesh is 10 to 60 mesh, and the thickness of the mesh is 0.1 to 1.2 mm. By using such a net structure, there is little risk that compounds or additives in the disintegrated preparation will accumulate on the net, and there is also little variation in dissolution rate between preparations.

[0032] The material of the net of the present invention is to be placed in the elution test container containing the elution test liquid, so it is sufficient that it is chemically inactive and does not interfere with the analysis.Specific examples of the material of the net include metals such as aluminum, stainless steel (SUS), and iron, and plastics such as polyethylene, polypropylene, and fluororesin.

[0033] The net of the present invention may have a rim without mesh openings at the end of the net as shown in FIG. 2 in order to increase the strength of the net, ensure the safety of the operator, or to fix the net in a fixed position when placed in a vessel. The rim has a width of 1 to 10 mm, preferably 1 to 9 mm, and more preferably 1 to 8 mm. In this case, the outer diameter of the net including the mesh openings and the rim is usually 40 to 95 mm, preferably 45 to 90 mm, and more preferably 50 to 85 mm, and the inner diameter of the mesh openings is usually 30 to 94 mm, preferably 36 to 88 mm, and more preferably 42 to 82 mm. The net with the rim can be placed in the vessel of the dissolution tester as shown in FIG. 3.

[0034] The material for the edges of the net of the present invention may be metals such as aluminum, stainless steel (SUS), iron, etc., or inactive resins such as polyethylene, polypropylene, fluororesin, Teflon (registered trademark), etc., so as to not corrode in water or damage the glass of a vessel, etc.

[0035] The edge of the net of the present invention that comes into contact with the vessel can be rounded to fit the R of the vessel. The edge of the net can be provided with a step to stably fix the net. The height of the step may be any height that allows the net to be stably fixed, and is usually 0.1 to 10 mm, preferably 0.2 to 7 mm, and more preferably 0.2 to 6 mm.

[0036] In order to fix the net of the present invention in a fixed position, legs may be attached to the net as shown in Fig. 4. When legs are attached to the net, the number of legs may be any number that allows the net to be fixed, and 3 to 6 legs may be sufficient for a net to be placed in a dissolution tester used in the dissolution test method of the Japanese Pharmacopoeia. The height of the legs may be any height that allows the net to be stably fixed, and is usually 0.1 to 10 mm, preferably 0.2 to 7 mm, and more preferably 0.2 to 6 mm. The net provided with legs can be placed in the vessel of the dissolution tester as shown in Fig. 5.

[0037] When the mesh of the present invention is not used, coning of the components contained in the suspension or solid preparation may occur when the suspension or solid preparation is placed in a vessel containing a test liquid, but when the mesh of the present invention is used, coning of the components contained in the suspension or solid preparation hardly occurs. Coning is a phenomenon in which disintegrated products of the preparation, such as poorly soluble or insoluble substances, are locally deposited on the bottom of the vessel.

[0038] The present invention is a net for dissolution testing of oral preparations, particularly solid preparations, and the dissolution test uses a dissolution test apparatus described in the Japanese Pharmacopoeia Dissolution Test Method. That is, the dissolution test apparatus is an apparatus including a vessel, a motor, a rotating shaft, and a paddle having an agitating blade, which is a container made of glass or a transparent, chemically inert material with a lid. The vessel can be placed in a thermostatic water bath of an appropriate size or placed in a thermostatic jacket or the like and heated. The thermostatic water bath or thermostatic jacket can be adjusted so that the temperature inside the container during the test is 37±0.5°C and the liquid inside the thermostatic water bath moves smoothly. Other than the smooth rotation of the paddle, there should be no shaking or vibration caused by the surrounding environment in which the apparatus is installed or by the apparatus itself.

[0039] The stirring unit of the dissolution test apparatus may be any stirring unit used in the "Dissolution Test Method" described in the Japanese Pharmacopoeia. A paddle having a stirring blade and a rotating shaft can be used as the stirring unit. The vertical axis of the stirring blade should pass through the center of the rotating shaft, and the lower chord of the stirring blade should be on the same plane as the lower end of the rotating shaft.

[0040] The stirring blade of the dissolution test apparatus may be any stirring blade used in the "Dissolution Test Method" described in the Japanese Pharmacopoeia.

[0041] The rotating shaft of the dissolution test apparatus may be any rotating shaft used in the "Dissolution Test Method" described in the Japanese Pharmacopoeia. The rotating shaft should rotate smoothly and should not cause any shaking or vibration that may affect the dissolution results. The rotating shaft may be a rotating shaft whose length can be adjusted. For example, the length of the rotating shaft can be adjusted in stages by using a movable rotating shaft with a screw or a positioning attachment.

[0042] The impeller and shaft shall be one unit made of metal or other chemically inert and robust material. Detachable paddles may be used provided that the impeller and shaft can be held firmly in place during testing. The impeller and shaft may be coated with a suitable coating to make them chemically inert.

[0043] The dissolution test apparatus complies with the dissolution test apparatus used in the dissolution test methods listed in not only the Japanese Pharmacopoeia but also the United States Pharmacopoeia or the European Pharmacopoeia.

[0044] When the mesh of the present invention is used to measure the dissolution rate of a drug in a suspension or solid preparation, the suspension or solid preparation is placed or placed on the mesh of the present invention placed in a vessel, and a dissolution test is performed. A suspension is a suspension or syrup as specified in the Japanese Pharmacopoeia, which is a liquid in which an active ingredient is finely and homogeneously suspended, or a viscous liquid or solid preparation containing sugar or a sweetener. A solid preparation is a solid preparation, which is a tablet, capsule, granule, pill, etc. as specified in the Japanese Pharmacopoeia.

[0045] A sample for dissolution testing of a suspension or solid preparation is placed or thrown on a net placed in a dissolution test vessel before the rotation of the agitator blades begins. In this case, "putting" means putting a suspension on the net, and "placing" means placing a solid preparation on the net. Even if a suspension or solid preparation is put or placed on the net of the present invention, the solid preparation may float. In this case, a suspension or solid preparation in a sinker may be put or placed on the net of the present invention placed in a vessel, and a dissolution test may be performed. This makes it possible to prevent the solid preparation from floating. A sinker is a small, non-tight container made of a chemically inert material, such as a wire wound several times in a spiral shape.

[0046] The suspension or solid preparation may be any of the suspensions, syrups, tablets, capsules, granules, pills, etc. specified in the Japanese Pharmacopoeia, but the effect of the net of the present invention is particularly evident in suspensions or solid preparations containing a poorly soluble drug and an insoluble additive.

[0047] The drug may be in any form, such as a solid, powder, crystal, oil, or solution, as long as it can be manufactured as a suspension or solid preparation. For example, one or more components selected from the group consisting of tonics, antipyretics, analgesics, and anti-inflammatory drugs, psychotropic drugs, antianxiety drugs, antidepressants, hypnotics, sedatives, antispasmodics, central nervous system drugs, brain metabolism improvers, brain circulation improvers, antiepileptic drugs, sympathetic stimulants, gastrointestinal drugs, antacids, antiulcer drugs, antitussives and expectorants, antiemetics, respiratory stimulants, bronchodilators, antiallergic drugs, dental and oral medicines, antihistamines, cardiac stimulants, arrhythmia drugs, diuretics, blood pressure lowering drugs, vasoconstrictors, coronary vasodilators, peripheral vasodilators, hyperlipidemic drugs, choleretic drugs, antibiotics, chemotherapy drugs, diabetes drugs, osteoporosis drugs, antirheumatic drugs, skeletal muscle relaxants, antispasmodics, hormone drugs, alkaloid narcotics, sulfa drugs, gout drugs, blood coagulation inhibitors, anti-cancer drugs, and Alzheimer's disease drugs may be used.

[0048] When a suspension or solid preparation is placed or poured onto the net of the present invention and the paddle of the dissolution test apparatus is rotated in accordance with the behavior of the digestive tract, i.e., even when the paddle rotation speed is set to 10 to 75 rpm, or in some cases 10 to 50 rpm, or in some cases 10 to 30 rpm, the drug dissolves from the suspension or solid preparation, and the drug dissolves continuously from the early stage of the dissolution test.

[0049] When a suspension or solid preparation is placed on the mesh of the present invention and the paddle of the dissolution tester is rotated in accordance with the behavior of the digestive tract, that is, even when the paddle rotation speed is set to 10 to 75 rpm, in some cases 10 to 50 rpm, and in some cases 10 to 30 rpm, the drug is dissolved from the suspension or solid preparation. In particular, when the same preparation is repeatedly subjected to dissolution tests, the use of the mesh of the present invention can reduce the variation in dissolution behavior compared to the case where it is not used, and the CV% of the dissolution rate can be kept within 20%. CV% is an abbreviation for Coefficient of Variation, and is generally used as an index of data variation, and can be calculated by the following formula. CV% = (standard deviation / average value) x 100

[0050] When a suspension or solid preparation is placed on the mesh of the present invention, and the paddle of a dissolution tester is rotated in accordance with the behavior of the digestive tract, and the predicted blood concentration from digestive tract absorption calculated using the results of the dissolution test is compared with the actual measured blood concentration, the predicted and actual values ​​are almost equivalent, and the mesh of the present invention can be used to predict the blood concentration from digestive tract absorption from a dissolution test. Methods for predicting the blood concentration from in vivo digestive tract absorption from in vitro dissolution results include a method using commercially available human PK prediction software. EXAMPLES

[0051] The present invention will be described in detail below with reference to Examples, Comparative Examples and Reference Examples, but the present invention is not limited thereto. 1. Dissolution test of Lipitor tablets 10mg (active ingredient: atorvastatin calcium) 1) Dissolution test method (paddle method, dissolution test method 2) A mesh (diameter: 72 mm, outer diameter: 72 mm, inner diameter: 60 mm, thickness: 0.37 mm) for use in the dissolution test was placed in a vessel (cylindrical with a semispherical bottom, volume: 1 L, height: about 170 mm, inner diameter: about 100 mm) of a dissolution test apparatus (manufactured by Toyama Sangyo Co., Ltd.) described in the 17th Edition Japanese Pharmacopoeia Dissolution Test Method, 25 mm below the lowest part of the stirring blade and 16 mm above the bottom of the vessel. Then, 900 mL of fasting artificial small intestinal fluid (FaSSIF) (pH about 6.5) was placed in the vessel, the water temperature was set to 37 ± 0.5 ° C, and a Lipitor tablet 10 mg (manufactured by Astellas Pharma Inc.) was placed on the mesh, and a dissolution test was performed under the following conditions. This dissolution test was repeated three times. (Dissolution test conditions) Test method: Japanese Pharmacopoeia Method 2 (Paddle method) -Stirring speed of the impeller: 30 rpm -Test liquid collection time: 0, 5, 10, 15, 20, 30, 45, 60, 75, 90, 120 (min) The dissolution tests were a dissolution test with the net of the present invention placed (Example 1), a dissolution test without the net of the present invention placed (Comparative Example 1), and a dissolution test by the rotating basket method described below (Comparative Example 2). 2) Dissolution test method (rotating basket method, dissolution test method 1) Test method: Japanese Pharmacopoeia Method 1 (rotating basket method) -Stirring speed of the impeller: 40 rpm -Test liquid collection time: 0, 5, 10, 15, 20, 30, 45, 60, 75, 90, 120 (min) 3) Analysis method The sample solution and the standard solution were analyzed by liquid chromatography under the following analytical conditions to measure the compounds. (Analysis conditions) Column: AQUITY UPLC CSH C18, 1.7 μm 2.1×50 mm (Waters) Column temperature: 40℃ Mobile phase flow rate: 0.4 mL / min Detector: UV detector (measurement wavelength: 246 nm) Mobile phase A: 50 mM ammonium formate in water Mobile phase B: Acetonitrile Mobile phase ratio: Mobile phase A / Mobile phase B=40 / 60

[0052] (Experimental Results) The changes in the average value and standard deviation of the dissolution rate for three replicates are shown in Figure 6, and the average value, standard deviation, and CV% of the dissolution rate are shown in Table 1.

[0053] [Table 1] The dissolution behavior of the formulations of Comparative Examples 1 and 2 was lower than that of the formulation of Example 1. In addition, the standard deviation and CV (%) of the dissolution rate of the formulations of Comparative Examples 1 and 2 were larger than that of the formulation of Example 1, revealing a large variation in the dissolution rate. After the test was completed, the formulation of Example 1 did not have coning, but the formulation of Comparative Example 1 had coning at the bottom of the dissolution test container, and the formulation of Comparative Example 2 had coning in the basket.

[0054] 2. Dissolution test of Baxo Capsule 20 (active ingredient: piroxicam) 1) Dissolution test method (paddle method, dissolution test method 2) A mesh (diameter: 72 mm, outer diameter: 72 mm, inner diameter: 60 mm, thickness: 0.37 mm) for use in the dissolution test was placed in a vessel (cylindrical with a semispherical bottom, volume: 1 L, height: about 170 mm, inner diameter: about 100 mm) of a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) described in the 17th Edition Japanese Pharmacopoeia Dissolution Test Method, 25 mm below the lowest part of the stirring blade and 16 mm above the bottom of the vessel. Then, 900 mL of fasting artificial small intestinal fluid (FaSSIF) (pH about 6.5) was placed in the vessel, the water temperature was set to 37±0.5°C, and a BAXO Capsule 20 (manufactured by Fujifilm Toyama Chemical Co., Ltd.) was placed on the mesh. The conditions of the dissolution test were as in Example 1, Comparative Examples 1 and 2. The dissolution test was repeated three times. The dissolution tests were a dissolution test with the net of the present invention placed (Example 2), a dissolution test without the net of the present invention placed (Comparative Example 3), and a dissolution test by the rotating basket method described below (Comparative Example 4). 2) Analysis method The sample solution and the standard solution were analyzed by liquid chromatography under the following analytical conditions to measure the compounds. (Analysis conditions) Column: AQUITY UPLC CSH C18, 1.7 μm 2.1×50 mm (Waters) Column temperature: 40℃ Mobile phase flow rate: 0.4mL / min Detector: UV detector (measurement wavelength: 254 nm) Mobile phase A: 50 mM ammonium formate in water Mobile phase B: Acetonitrile Mobile phase ratio: Mobile phase A / Mobile phase B=40 / 60

[0055] (Experimental Results) The changes in the average value and standard deviation of the dissolution rate for three replicates are shown in Figure 7, and the average value, standard deviation, and CV% of the dissolution rate are shown in Table 2.

[0056] [Table 2] The dissolution behavior in the early stage of the dissolution test of the formulations of Comparative Examples 3 and 4 was lower than that of the formulation of Example 2. In addition, the standard deviation and CV (%) of the dissolution rate in the early stage of the dissolution test of the formulations of Comparative Examples 3 and 4 were larger than those of Example 2, revealing a large variability in the dissolution rate in the early stage of the dissolution test. During the test, the granules in the capsule of Example 2 were present without being covered with a capsule shell, whereas the granules in the capsules of Comparative Examples 3 and 4 were covered with a capsule shell.

[0057] 3. Dissolution test of Celecoxib tablets 100mg (active ingredient: celecoxib) 1) Dissolution test method (paddle method, dissolution test method 2) A mesh (diameter: 72 mm, outer diameter: 72 mm, inner diameter: 60 mm, thickness: 0.37 mm) for use in the dissolution test was placed in a vessel (cylindrical with a semispherical bottom, volume: 1 L, height: about 170 mm, inner diameter: about 100 mm) of a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) described in the 17th Edition Japanese Pharmacopoeia Dissolution Test Method, 25 mm below the lowest part of the stirring blade and 16 mm above the bottom of the vessel. Then, 900 mL of fasting artificial small intestinal fluid (FaSSIF) (pH about 6.5) was placed in the vessel, the water temperature was set to 37±0.5°C, and 100 mg of Celecox tablets (manufactured by Astellas Pharma Inc.) were placed on the mesh. The conditions for the dissolution test were as in Example 1. The dissolution test was repeated three times. The dissolution test was conducted with the net of the present invention placed (Example 3) and without the net of the present invention placed (Comparative Example 5). 2) Analysis method The sample solution and the standard solution were analyzed by liquid chromatography under the following analytical conditions to measure the compounds. (Analysis conditions) Column: AQUITY UPLC CSH C18, 1.7 μm 2.1×50 mm (Waters) Column temperature: 40℃ Mobile phase flow rate: 0.4mL / min Detector: UV detector (measurement wavelength: 249 nm) Mobile phase A: 50 mM ammonium formate in water Mobile phase B: Acetonitrile Mobile phase ratio: Mobile phase A / Mobile phase B=40:60 3) PK prediction study PK prediction software GastroPlus (trademark) 9.6 (SimulationPlus) was used, and the parameters shown in Tables 3 and 4 were input. As a control, a prediction curve was also calculated for the case where the dissolution test data was not input and the drug was administered as a solution formulation.

[0058] [Table 3]

[0059] [Table 4]

[0060] (Experimental Results) 1) Dissolution test The changes in the average value and standard deviation of the dissolution rate for three replicates are shown in FIG. 8, and the average value, standard deviation, and CV% of the dissolution rate are shown in Table 5.

[0061] [Table 5] The initial dissolution behavior of the formulation of Comparative Example 5 in the dissolution test was lower than that of the formulation of Example 3. In addition, the standard deviation and CV (%) of the dissolution rate in the dissolution test of the formulation of Comparative Example 5 were larger than those of the formulation of Example 3, revealing a large variation in the dissolution rate in the dissolution test. After the test was completed, the formulation of Example 3 did not have coning, but the formulation of Comparative Example 5 had coning on the bottom of the dissolution test container. 2) PK prediction study FIG. 9 shows a graph of the blood kinetics based on the PK prediction of the formulation of Example 3, and Table 6 shows the PE (%, prediction error relative to actual measurement) of the predicted PK. In FIG. 9 and Table 6, "with dissolution process" refers to a prediction made by inputting data obtained by performing a dissolution test using the dissolution test net of the present invention, and "without dissolution process" refers to a prediction made without inputting dissolution data and assuming that the drug was administered as a solution formulation. When the absolute value of PE is 20 or less, the predicted value and the actual measurement value are in good agreement. When the dissolution test was performed using the net of the present invention and the predicted value of the blood concentration was compared with the actual measurement value of the blood concentration, it was revealed that the absolute value of PE was 20 or less for both Cmax and AUC, and the predicted value and the actual measurement value were in good agreement. On the other hand, the absolute value of PE for Cmax predicted without using the results of the dissolution test was 20 or more, and it was revealed that the actual measurement value and the predicted value did not match.

[0062] [Table 6]

[0063] 4. Dissolution test of Tegretol tablets 200mg (active ingredient: carbamazepine) 1) Dissolution test method (paddle method, dissolution test method 2) A mesh (diameter: 72 mm, outer diameter: 72 mm, inner diameter: 60 mm, thickness: 0.37 mm) for use in the dissolution test was placed in a vessel (cylindrical with a semispherical bottom, volume: 1 L, height: about 170 mm, inner diameter: about 100 mm) of a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) described in the 17th Edition Japanese Pharmacopoeia Dissolution Test Method, 25 mm below the lowest part of the stirring blade and 16 mm above the bottom of the vessel. Then, 900 mL of fasting artificial small intestinal fluid (FaSSIF) (pH about 6.5) was placed in the vessel, the water temperature was set to 37±0.5°C, and 200 mg of Tegretol tablets (manufactured by Mitsubishi Tanabe Pharma Co., Ltd.) were placed on the mesh. The conditions of the dissolution test were as in Example 1. The dissolution test was repeated three times. The dissolution test was conducted with the net of the present invention placed (Example 4) and without the net of the present invention placed (Comparative Example 6). 2) Analysis method The sample solution and the standard solution were analyzed by liquid chromatography under the following analytical conditions to measure the compounds. (Analysis conditions) Column: AQUITY UPLC CSH C18, 1.7 μm 2.1×50 mm (Waters) Column temperature: 40℃ Mobile phase flow rate: 0.4 mL / min Detector: UV detector (measurement wavelength: 286 nm) Mobile phase A: 50 mM ammonium formate in water Mobile phase B: Acetonitrile Mobile phase ratio: Mobile phase A / Mobile phase B=70:30 3) PK prediction study PK prediction software GastroPlus (trademark) 9.6 (SimulationPlus) was used, and the parameters shown in Tables 7 and 8 were input. As a control, a prediction curve was also calculated for the case where the dissolution test data was not input and the drug was administered as a solution formulation.

[0064] [Table 7]

[0065] [Table 8]

[0066] (Experimental Results) 1) Dissolution test The changes in the average value and standard deviation of the dissolution rate for three replicates are shown in FIG. 10, and the average value, standard deviation and CV% of the dissolution rate are shown in Table 9.

[0067] [Table 9] The initial dissolution behavior of the formulation of Comparative Example 6 in the dissolution test was lower than that of the formulation of Example 4. The standard deviation and CV (%) of the dissolution rate in the dissolution test of the formulation of Comparative Example 6 were larger than those of the formulation of Example 4, revealing a large variation in the dissolution rate in the dissolution test. After the test was completed, the formulation of Example 4 did not have coning, but the formulation of Comparative Example 6 had coning on the bottom of the dissolution test container. 2) PK prediction study FIG. 11 shows a graph of the blood concentration by PK prediction for the formulation of Example 4, and Table 10 shows the PE (%, prediction error relative to actual measurement) of the predicted PK value. In FIG. 11 and Table 10, "with dissolution process" refers to a prediction made by inputting data obtained by performing a dissolution test using the dissolution test net of the present invention, and "without dissolution process" refers to a prediction made without inputting dissolution data and assuming that the drug was administered as a solution formulation. When the absolute value of PE is 20 or less, the predicted value and the actual measurement value are in good agreement. When a dissolution test was performed using the net of the present invention and the predicted value of the blood concentration was compared with the actual measurement value of the blood concentration, the absolute value of PE was 20 or less for both Cmax and AUC, and it was clear that the predicted value and the actual measurement value were in good agreement. On the other hand, the absolute value of PE for Cmax predicted without using the results of the dissolution test was 20 or more, and it was clear that the actual measurement value and the predicted value did not match.

[0068] [Table 10] [Industrial Applicability]

[0069] When the net of the present invention is placed in the vessel of a dissolution tester and a suspension or solid preparation is put or placed on the net, it has been found that the drug dissolves from the preparation in accordance with the dissolution properties in the digestive tract even at a low paddle rotation speed. In addition, even when the dissolution rates of multiple identical preparations are measured, there is almost no variation in the dissolution rates. The net of the present invention, the vessel in which the net is placed, and the dissolution tester can be used to measure the dissolution rate of a drug from a preparation containing a poorly water-soluble drug or an insoluble additive in the digestive tract.

Claims

1. A method of using a mesh for dissolution testing of a suspension or solid preparation, the mesh having a diameter of 10 to 95 mm and a mesh size of 2 to 200 mesh, in a dissolution test apparatus equipped with a vessel or a vessel used in dissolution testing specified in the dissolution test methods of the Japanese Pharmacopoeia, the United States Pharmacopoeia, or the European Pharmacopoeia, and a paddle consisting of an agitator and a rotating shaft, the mesh is placed below the bottom of the agitator blade and above the bottom of the vessel, and a suspension or solid preparation is poured or placed on the mesh.

2. 2. The method for using a net according to claim 1, wherein the net is disposed at a position 5 to 35 mm below the lowest part of the stirring blade.

3. 2. The method of claim 1, wherein the net is disposed at a position 1 to 30 mm above the bottom surface of the vessel.

4. 4. The method for using a net according to claim 2 or 3, wherein the net is disposed at a position 5 to 35 mm below the lowest part of the stirring blades and 1 to 30 mm above the bottom surface of the vessel.

5. A method of using a net described in any one of claims 1 to 4, comprising using a net having edges at the ends.

6. A method of using a net described in any one of claims 1 to 5, comprising using a net having legs.

7. Use of the mesh according to any one of claims 1 to 6 for preventing coning of a suspension or solid preparation in a dissolution test.

8. A method of using a net described in any one of claims 1 to 7, comprising pouring or placing a suspension or solid preparation in a sinker onto the net.

9. A method for dissolution testing of a suspension or solid preparation, comprising: in a dissolution test apparatus equipped with a vessel or a vessel used in a dissolution test specified in the dissolution test methods of the Japanese Pharmacopoeia, the United States Pharmacopoeia, or the European Pharmacopoeia, and a paddle consisting of an agitator and a rotating shaft, a mesh is placed below the lowest part of the agitator and above the bottom of the vessel, and the suspension or solid preparation is poured or placed on the mesh, the diameter of the mesh being 10 to 95 mm and the mesh openings being 2 to 200 mesh.

10. The method described in claim 9, wherein the paddle rotation speed is 10 to 75 rpm.

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