Apparatus and method for evaluating the gastric emptying dynamics of orally ingested components.

Abstract

The present invention provides an apparatus and method that can accurately evaluate the elimination dynamics of preparations, drugs, or food from the stomach. [Solution] A gastric emptying dynamics evaluation device comprising a cylindrical upper part having an inlet A and a drain port A for a test liquid, a plurality of cylindrical fluid actuators having a fluid inlet B connected to the drain port A, a flow path for the fluid flowing in from the fluid inlet B to pass through, and an opening / closing part provided in the flow path for opening and closing the flow path, and a lower part having a drain port B, and control means for controlling the opening and closing of the opening / closing part, wherein the plurality of cylindrical fluid actuators are connected in series, and a method for evaluating gastric emptying dynamics, wherein after introducing a test liquid into the fluid inlet A of the upper part of the evaluation device, the test liquid is moved by opening and closing the opening / closing parts of the plurality of cylindrical fluid actuators in the lower part of the device in phase with each cylindrical fluid actuator, and the test liquid is discharged from the drain port B in the lower part of the device, and the amount or properties of the discharged test liquid are measured.

Description

Technical Field

[0001] The present invention relates to an apparatus and method for accurately evaluating the gastric excretion dynamics (excretion profile) of orally ingested components such as drugs and food components administered orally.

Background Art

[0002] Orally ingested drugs and food components are sent from the esophagus to the stomach, and after being sterilized and digested by gastric acid and pepsin in the stomach, they are sent to the small intestine, which is the main absorption site. In the case of oral solid preparations such as tablets and capsules, after administration, the degree and rate of disintegration of the preparation and elution of the drug in the stomach have a great influence on the subsequent absorption of the drug from the small intestine. Therefore, accurately evaluating the behavior of orally administered preparations in the stomach and the excretion profile to the small intestine is extremely important for analyzing the absorption dynamics of drugs.

[0003] A bioequivalence test (hereinafter sometimes referred to as a "BE (Bioequivalence) test") to show that two preparations containing the same drug are biologically equivalent and the same therapeutic effect can be expected after administration is carried out at the time of approval of a generic drug or a formulation change during a clinical trial of a new drug, and is a particularly important process in the development of generic drugs. In order to show that a test preparation, which is a newly prepared preparation, is biologically equivalent to a standard preparation, which is an existing preparation, that is, to meet the BE test, for oral preparations, the blood concentration of the drug after formulation administration is measured over time, and the maximum blood concentration (Cmax) calculated from the change in the blood concentration of the drug and the difference between formulations in the area under the blood concentration-time curve (AUC) are required to be within a certain range. Cmax is an index of the absorption rate of the drug, and AUC is an index of the absorption amount of the drug.

[0004] In Japan, drug-enhancing (BE) studies for oral formulations first involve in vitro verification of drug dissolution from both the test formulation and the reference formulation. If the dissolution is deemed similar, then clinical trials in humans are conducted. Methods for verifying drug dissolution from formulations before human BE studies include the paddle method, rotating basket method, and flow-through cell method, as specified in the 18th edition of the Japanese Pharmacopoeia. The paddle method involves placing the test drug in a container filled with a test solution simulating gastric or intestinal fluid, and measuring the concentration of the drug eluted from the formulation into the test solution over time while agitating the test solution by rotating a paddle. The rotating basket method involves placing the formulation in a basket inside a container filled with a test solution simulating gastric or intestinal fluid, and measuring the concentration of the drug eluted from the formulation into the test solution over time while rotating the container. The flow-through cell method involves placing the test formulation on glass beads or a holder installed in a cell, and measuring the concentration of the drug eluted from the formulation into the test solution over time while introducing a test solution simulating gastric or intestinal fluid from the bottom of the cell at a predetermined flow rate.

[0005] The gastrointestinal tract moves orally ingested preparations by peristalsis, mixing them with gastrointestinal fluids. However, in the dissolution tests described above, the preparation is brought into contact with the test solution by rotating a paddle or container, or by flowing the test solution. Therefore, it is difficult to say that the above dissolution tests reflect the actual physiological state of the gastrointestinal tract, and it is not possible to accurately predict the dissolution of drugs from the preparation in the actual gastrointestinal tract, and consequently, the changes in blood concentration.

[0006] The process by which orally administered solid dosage forms are absorbed into the bloodstream begins with the form being absorbed into the stomach. There, the form is disintegrated and the drug is released. The form then moves from the stomach to the small intestine, releasing the drug as it goes. The released drug then dissolves and is absorbed into the solution in the stomach and small intestine as it moves through the intestines. Generally, very little drug is absorbed from the stomach, so absorption begins once the drug reaches the small intestine. Since pharmacokinetics in the blood are strongly dependent on the gastric elimination of the formulation or drug, there is a need for an in vitro system that can accurately evaluate the gastric elimination of the formulation or drug.

[0007] In BE trials and clinical trials of new drugs, the test drug is administered orally under fasting conditions, regardless of post-marketing dosage. This is because administering the drug under fasting conditions allows for easier detection of pharmacokinetic differences, as it is unaffected by food. In Europe and the United States, for drugs taken after meals after marketing, both fasting and post-meal administration trials are conducted. In Japan, the BE trial guidelines are currently being revised, and it is expected that human equivalence trials will be required not only under fasting conditions but also after meals in the future.

[0008] As shown in Figure 1, the stomach consists of the fundus, body, and pyloric antrum. When fasting, approximately 10-50 mL of gastric juice and saliva accumulates in the pyloric antrum, and the fundus and body are smaller than shown in Figure 1. Even when fasting, the stomach moves autonomously, repeating a cycle of 90-120 minutes consisting of a weak resting period, a moderately strong contraction period, and a strong contraction period. This contraction propagates from the cardia towards the pylorus. After eating, the fundus and body of the stomach expand, and the gastric volume becomes approximately 1.5 to 2.5 liters. For about 30 minutes after eating, stomach contractions are minimal, followed by regular, weak contractions, and finally strong contractions that send the contents into the duodenum. Both during fasting and after eating, the frequency and strength of stomach wall contractions vary depending on the area of ​​the stomach.

[0009] Conventionally, various in vitro devices have been developed for the purpose of predicting the behavior of pharmaceuticals and foods in the gastrointestinal tract in vivo. For example, Non-Patent Document 1 discloses a simulated intestinal tract in which valves that open and close with air pressure are arranged at regular intervals inside a tube that mimics the small intestine. This simulated intestinal tract is designed so that the corresponding part of the tube can be closed by injecting liquid into the valves. After introducing simulated intestinal fluid and a test substance into the tube, the valves are sequentially closed to mimic the movement of the small intestine as it expels its contents. However, while the entire wall of the actual small intestine is involved in contraction, this artificial intestinal tract only partially contracts the tube, and therefore cannot be said to accurately mimic the movement of the small intestine.

[0010] Furthermore, Non-Patent Document 2 discloses a device comprising a simulated gastric tube consisting of the gastric fundus, gastric body, and pyloric antrum, and three covering tubes that cover the entire portions corresponding to the gastric fundus, gastric body, and pyloric antrum, respectively. This device attempts to mimic the movement of the stomach, which agitates and propels its contents, by contracting the entire gastric fundus, gastric body, and pyloric antrum of the simulated gastric tube using the pressure of water injected into the three covering tubes. However, in the actual stomach, propagating contractions occur, and in particular, the pyloric antrum exhibits peristaltic movement due to continuous contractions. Therefore, this device cannot be said to accurately mimic the movement of the stomach.

[0011] In addition, various devices that mimic the movement of the digestive tract have been proposed, but all of these devices primarily assume the movement of the digestive tract during feeding. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Wright, ND, Kong, F., Williams, BS, & Fortner, L. (2016). A human duodenum model (HDM) tostudy transport and digestion of intestinal contents. Journal of Food Engineering, 171, 129-136. [Non-Patent Document 2] Bellmann, S., Lelieveld, J., Gorissen, T., Minekus, M., & Havenaar, R. (2016). Developmentofanadvancedinvitromodelofthestomach andits evaluation versus human gastricphysiology. FoodResearch International, 88, 191-198. [Overview of the project] [Problems that the invention aims to solve]

[0013] The present invention aims to provide an apparatus and method that can accurately evaluate the elimination dynamics of a pharmaceutical preparation or drug from the stomach. In particular, the present invention aims to provide an apparatus and method that can accurately evaluate the elimination dynamics of a pharmaceutical preparation or drug from the stomach in a fasted state. [Means for solving the problem]

[0014] The inventors have conducted extensive research to solve the above problems, A cylindrical upper part of the device having an inlet A and a drainage port A for the test liquid (meaning a liquid whose effluent dynamics are to be evaluated; for example, a mixture of a test substance, test preparation, test drug and a simulated gastric juice containing it), A plurality of cylindrical fluid actuators having a fluid inlet B connected to the drain port A, a flow path through which the test liquid flowing in from the fluid inlet B passes, and an opening / closing part provided within the flow path for opening and closing the flow path, and the lower part of the device having the drain port B, and The system has control means for controlling the opening and closing of the opening / closing section, We have found that by using a gastric emptying dynamics evaluation device in which a plurality of cylindrical fluid actuators are connected in series (meaning that the drainage portion of the test fluid of one cylindrical fluid actuator is connected to the inflow portion of the test fluid of another cylindrical fluid actuator), it is possible to control the opening and closing movements of the opening and closing parts within the plurality of cylindrical fluid actuators (for example, the expansion and contraction of a bag made of a flexible membrane), thereby mimicking the peristaltic movement of the pyloric antrum of the stomach, and accurately reproducing the emptying dynamics of a preparation or drug from the stomach of a fasted person.

[0015] The present invention was completed based on the above findings and provides the following [1] to [5]. [1] The upper part of the cylindrical device having an inlet A and a drain port A for the liquid to be tested, A fluid inlet B connected to the drain port A, a fluid passage through which the fluid flowing in from the fluid inlet B passes, and a plurality of cylindrical fluid actuators having opening and closing parts provided within the fluid passage for opening and closing the fluid passage, and the lower part of the device having the drain port B, and The system has control means for controlling the opening and closing of the opening / closing section, A device for evaluating gastric emptying dynamics, comprising a plurality of cylindrical fluid actuators connected in series. [2] The gastric emptying dynamics evaluation device according to [1], characterized by having three or more cylindrical fluid actuators. [3] The gastric emptying dynamics evaluation device according to [1] or [2], characterized in that the opening and closing section consists of a bag formed from a flexible membrane provided on the inner wall of the cylindrical fluid actuator, and the opening and closing of the flow path is performed by the expansion and contraction of the bag due to the inflow and discharge of fluid into the bag. [4] The gastric emptying dynamics evaluation device according to any one of [1] to [3], wherein the upper part of the device has a plurality of cylindrical fluid actuators having a fluid flow path and an opening / closing part for opening and closing the flow path, and a control means for controlling the opening and closing of the opening / closing part. [5] A method for evaluating gastric emptying dynamics, in which the liquid to be tested is introduced into the fluid inlet A at the top of the gastric emptying dynamics evaluation apparatus described in any of [1] to [4] above, and the liquid to be tested is moved by opening and closing the opening and closing parts of a plurality of cylindrical fluid actuators located at the bottom of the apparatus, or at the top and bottom of the apparatus, with a phase difference between each cylindrical fluid actuator, and the liquid to be discharged from the drain port B at the bottom of the apparatus, and the amount or properties of the discharged liquid to be tested is measured.

[0016] The tubular fluid actuator is a tubular body that has a fluid passage inside and has a function of controlling the flow of the fluid by varying the volume inside the tubular body under external control. Here, controlling the flow of the fluid means, for example, controlling the direction, speed, and pressure of the fluid flow. In the gastric emptying dynamics evaluation apparatus of the present invention, the fluid is a test solution, and the opening / closing part has a function of controlling the flow of the fluid, i.e., the test solution, and by this function, the test solution in the passage is moved in one direction at a predetermined speed and pressure. External control is performed, for example, by varying the volume in the passage by an electric signal, or by injecting air or other fluid from the outside into the opening / closing part.

Advantages of the Invention

[0017] The apparatus of the present invention can accurately reproduce the peristaltic movement of the pyloric vestibule of the stomach by controlling the opening and closing of a plurality of tubular fluid actuators having opening / closing parts with a phase shift. In particular, when the opening / closing part is formed of a bag body formed from a flexible film provided on the inner wall of the tubular fluid actuator, and the opening and closing of the flow path are performed by the inflow and discharge of fluid into the bag body, by controlling the degree of expansion and contraction of the bag body caused by the inflow and discharge of fluid with a phase shift, the peristaltic movement of the pyloric vestibule of the stomach can be reproduced more accurately. As shown in the results of the examples, the discharge dynamics of the liquid from the apparatus of the present invention are extremely similar to the discharge dynamics of the contents from the human stomach. Therefore, if a test solution (for example, a formulation and simulated gastric fluid) is placed in this apparatus and the expansion and contraction operations of a plurality of tubular fluid actuators are appropriately performed, the migration pattern of the formulation or drug into the small intestine can be accurately reproduced, and as a result, the pharmacokinetics in the blood (especially, AUC and Cmax) can be accurately predicted. The peristaltic movement of the stomach varies depending on the age, health condition, drug administered, treatment received, etc. of the patient. According to the apparatus of the present invention, by controlling the frequency of the opening and closing operations of the tubular fluid actuators, the operation interval between each tubular fluid actuator, the opening and closing width, etc., the gastric emptying dynamics suitable for the evaluation subject can be reproduced.

[0018] Thus, by using the device of the present invention, it is possible to sufficiently verify the excretion dynamics of the formulation or drug from the stomach after oral administration to humans before human BE tests or clinical tests of new formulations. Therefore, unnecessary clinical tests can be avoided, or the number of subjects in clinical tests can be reduced, or the success rate of clinical tests can be increased.

[0019] In addition, when the device of the present invention has an opening / closing part not only in the lower part of the device (the part simulating the pyloric vestibule) but also in the upper part of the device (the part simulating the fundus and body of the stomach), by injecting the test liquid until it reaches the upper part of the device, the peristaltic movement of the stomach after eating can be accurately reproduced. Further, by controlling the frequency of the opening / closing operation of the cylindrical fluid actuator in the upper part of the device, the operation interval between each cylindrical fluid actuator, the opening / closing width, etc., it is possible to reproduce the gastric excretion dynamics after eating suitable for the evaluation subject.

Brief Description of the Drawings

[0020] [[ID=I3]] [Figure 1] It is a schematic diagram of the structure of the stomach. [Figure 2-1] It is a schematic cross-sectional view of one embodiment of the device of the present invention. [Figure 2-2] It is a photograph showing one embodiment of the device of the present invention in perspective. [Figure 2-3] It is a schematic cross-sectional view of one embodiment of the cylindrical fluid actuator constituting the device of the present invention. [Figure 3] It is a diagram showing the operation program of the three opening / closing parts of the device in FIG. 2. [Figure 4] It is a graph comparing the change over time in the amount of gastric solution after administering 150 mL of water into the human stomach and the change over time in the amount of solution in the cylindrical fluid actuator in the lower part of the device of the present invention when 150 mL of water is put into the cylindrical fluid actuator and the opening / closing operation is performed. [Figure 5]This graph shows the change in the liquid volume in the cylindrical fluid actuator at the bottom of the apparatus of the present invention over time when 150 mL of water is placed in the cylindrical fluid actuator and at the same time a liquid simulating the secretion of gastric juice and saliva (simulated gastric fluid) is injected at a rate of 1.5 mL / min (left figure) or 3.0 mL / min (right figure). [Figure 6] This graph compares the time-dependent changes in drug concentration, predicted from the time-dependent changes in the liquid volume in the cylindrical fluid actuator at the bottom of the apparatus of the present invention, with the time-dependent changes in drug concentration in the stomach after drug administration to a human. [Modes for carrying out the invention]

[0021] The present invention will be described in detail below. (1) Device for evaluating the gastric emptying dynamics of orally ingested components The present invention is a gastric emptying dynamics evaluation device comprising a cylindrical or bag-shaped upper part having an inlet A and a drain port A, and a lower part having a plurality of cylindrical fluid actuators connected in series, each having a liquid inlet B connected to the drain port A of the upper part of the device, a flow path for passing fluid flowing in from the fluid inlet B, and a drain port B, and having the flow path inside, wherein each cylindrical fluid actuator has an opening / closing part inside for opening and closing the flow path, and control means for controlling the opening and closing of the opening / closing part.

[0022] Figure 2-1 is a schematic cross-sectional view of an example of the gastric emptying dynamics evaluation device of the present invention, cut in a plane including the flow direction of the fluid (test liquid); Figure 2-2 is a photograph of the device's appearance when installed on its base; and Figure 2-3 is a schematic cross-sectional view of an example of a cylindrical fluid actuator of the device, cut in a plane perpendicular to the flow direction of the fluid (test liquid).

[0023] In Figure 2-1, 1 is the top of the device, 2 is the bottom of the device, 3 is inlet A, 4 is drain port A, 5 is fluid inlet B, and 6 is drain port B. The arrows in the figure indicate the flow of the fluid (test liquid) inside the device. In Figure 2-2, 1 is the upper part of the device, 2 is the lower part of the device, and 20 is the mounting means for the device. As shown in Figure 2-1, the drain port A4 and the fluid inlet B5 are connected. The fluid (test liquid) is added to the upper part 1 of the device from the inlet A3, flows into the lower part 2 of the device from the fluid inlet B5, passes through the lower part 2 of the device, and is discharged outside the device from the drain port B6.

[0024] In Figure 2-1, 7 is a cylindrical fluid actuator located at the bottom of the device, and 8 is a cylindrical fluid actuator located at the top of the device, both connected to control means 9 and control means 10, respectively. Multiple (two or more) cylindrical fluid actuators located at the bottom and top of the device are connected in series, but cylindrical fluid actuators are not required to be located at the top of the device. In the example shown in the figure, three cylindrical fluid actuators 7 are located at the bottom 2 of the device, connected in series so that the fluid (test liquid) passes through their opening and closing parts. Here, being connected in series means that the fluid inlet portion of one cylindrical fluid actuator is connected to the fluid outlet portion of an adjacent cylindrical fluid actuator. The same applies to the cylindrical fluid actuator 8 described below. Also in the example shown in the figure, three cylindrical fluid actuators 8 are located at the bottom 1 of the device, connected in series so that the fluid (test liquid) passes through their opening and closing parts.

[0025] In Figure 2-3, the cross-sections of both the cylindrical fluid actuator 7 and the cylindrical fluid actuator 8 are schematically shown. In the example cylindrical fluid actuator in the figure, the opening and closing part consists of a bag-like body formed from a flexible membrane (e.g., rubber membrane, plastic membrane) provided on the inner wall. In Figure 2-3, 11 is the opening and closing part, and 12 is the bag-like body. The opening and closing of the flow path is performed by the expansion and contraction of the bag-like body due to the inflow and outflow of fluid (e.g., air, water) into and out of the bag-like body 12. In the example in Figure 2-3, each cylindrical fluid actuator has six bag-like bodies 12. Figures 2-3(a), (b), and (c) show the state where the bag-like body is expanded and the opening and closing part is closed, the state where the bag-like body is slightly contracted and the opening and closing part is partially open, and the state where the bag-like body is almost contracted and the opening and closing part is fully open, respectively.

[0026] The control means are not particularly limited as long as they can control the opening and closing of the opening / closing part of the cylindrical fluid actuator according to a predetermined program. In the example shown in the figure, the control means 9 and 10 are means for controlling the inflow and outflow of fluid (e.g., air, water) into the bag 12 according to a predetermined program.

[0027] The lower part of the device corresponds to the pyloric antrum of the stomach. By opening and closing the opening and closing parts of multiple cylindrical fluid actuators installed there with a phase (time) difference, it is possible to simulate the peristaltic movement of the pyloric antrum of the stomach. The number of cylindrical fluid actuators installed in the lower part of the device can be two or more, three or more, four or more, or five or more. The more cylindrical fluid actuators installed, the closer the movement will be to that of a human stomach. However, as the number increases, control tends to become more difficult, so for example, it can be limited to 10 or fewer. The upper part of the device corresponds to the stomach fundus and stomach body, and by opening and closing the opening and closing parts of multiple cylindrical fluid actuators installed there with a phase (time) difference, it is possible to simulate the peristaltic movement of the stomach fundus and stomach body. The number of cylindrical fluid actuators installed on the upper part of the device can be two or more, three or more, four or more, or five or more, and can also be, for example, ten or fewer.

[0028] The inner diameter of each cylindrical fluid actuator at the bottom of the device is typically 5 to 60 mm, preferably 20 to 50 mm, and more preferably 20 to 30 mm. If the cross-section of the cylindrical fluid actuator is not circular, it should be made to have a cross-sectional area equivalent to that of the circular case. The length of each cylindrical fluid actuator at the bottom of the device in the longitudinal direction (direction of fluid flow) is usually 20 to 90 mm, preferably 50 to 80 mm, and more preferably 60 to 70 mm. The opening diameter of the drainage port B, which corresponds to the pylorus, is usually 0.5 to 10 mm, preferably 1 to 5 mm, and more preferably 1 to 2 mm. If the opening is not circular, the opening area should be made equivalent to that of the circular case. Furthermore, the inner diameter of each cylindrical fluid actuator at the top of the device is usually 5 to 60 mm, preferably 20 to 50 mm, and more preferably 20 to 30 mm. If the cross-section of the cylindrical fluid actuator is not circular, it should be made to have a cross-sectional area equivalent to that of the circular case. The length of each cylindrical fluid actuator at the top of the device in the longitudinal direction (fluid flow direction) is usually 10 to 50 mm, preferably 20 to 40 mm, and more preferably 20 to 30 mm.

[0029] (2) Method for evaluating the gastric emptying dynamics of orally ingested components The present invention provides a method for evaluating the gastric emptying dynamics of orally ingested components using the apparatus of the present invention described above.

[0030] The apparatus of the present invention can be used with the cylindrical fluid actuator at the bottom of the apparatus, corresponding to the pyloric antrum, tilted upward from the liquid inlet side to the drainage port side at an angle of 0 to 20 degrees relative to the horizontal, particularly 0 to 10 degrees, and especially 4 to 6 degrees upward (as shown in the photograph in Figure 2-2). Within this range, the dynamics of human gastric emptying can be accurately reproduced. Furthermore, the apparatus also reproduces the state of the human stomach by ensuring that a volume of fluid equivalent to that of a human stomach is always present in the cylindrical fluid actuator. Furthermore, the upper part of the device, which corresponds to the gastric fundus and the main body of the stomach, should be used tilted upwards from the lower side of the device toward the inlet side at an angle of 20 to 90 degrees relative to the horizontal, particularly 40 to 70 degrees, and especially 50 to 60 degrees. Within this range, the dynamics of human gastric emptying can be accurately reproduced.

[0031] The evaluation method of the present invention is applied to the measurement of gastric emptying dynamics of orally ingested components as they pass through the stomach and are sent to the intestines. The orally ingested component can be not only a drug, but also a preparation containing a drug (test substance). The preparation may be a solid preparation such as tablets, powders, granules, pills, or capsules (soft capsules, hard capsules); or a liquid preparation such as a liquid preparation, elixir, suspension, emulsion, lemonade, or syrup. Furthermore, food components, food preparations (so-called supplements), and general foods can also be evaluated. The formulation should be introduced into the inlet A at the top of the apparatus of the present invention in a single dose. The amount of drugs, food components, and general food products to be introduced should be determined according to the purpose of the test.

[0032] In the evaluation method of the present invention, first, the liquid to be tested is introduced into the inlet A at the top of the evaluation device. The following explanation will take the case where the test solution consists of simulated gastric fluid and the test substance as an example. The simulated gastric fluid and the test substance may be added simultaneously, or the test substance may be added after the simulated gastric fluid. Depending on the volume of simulated gastric fluid, it may flow out of drain port B before the start of the test. In that case, drain port B can be kept closed until the start of the test.

[0033] The pH of human gastric fluid is approximately 1-3 during fasting and approximately 2-6 after eating. Therefore, the pH of simulated gastric fluid should be set to approximately 1-3 when evaluating fasting dynamics and approximately 2-6 when evaluating feeding dynamics. For example, the pH can be adjusted by using a buffer such as acetate buffer. Furthermore, when conducting tests simulating patients with hypoacidity or other conditions where the pH of gastric fluid is higher than that of healthy individuals, the pH can be adjusted to match that of the assumed patient's gastric fluid using phosphate buffer or similar solutions. Furthermore, the simulated gastric fluid may contain digestive enzymes such as pepsin and sodium chloride, which can be used to approximate the simulated gastric fluid to that of human stomachs. When evaluating only the rate of gastric emptying, a liquid with a significantly different composition and pH from actual gastric fluid, such as water, can be used as the test solution to simulate gastric fluid.

[0034] In studies evaluating fasting-induced pharmacokinetics, the initial volume of simulated gastric fluid should be 10-250 mL, particularly 50-200 mL. The volume of gastric fluid in a fasted adult human is approximately 10-50 mL, and since solid dosage forms are often taken with water (150-200 mL of water in clinical trials), this volume range allows for evaluation that accurately reflects the movement of contents within the human stomach. In tests evaluating post-feeding dynamics, the volume of simulated gastric fluid at the start of the test should be 500-2000 mL, and more specifically, 600-1200 mL.

[0035] After the test substance is introduced into the simulated gastric fluid, the peristaltic motion is simulated by opening and closing the opening and closing parts of multiple cylindrical fluid actuators. If the opening and closing parts consist of bags, the peristaltic motion is simulated by the expansion and contraction of the bags. By suctioning fluid from inside the bags of the opening and closing parts, the bags are contracted and the flow path is opened. By injecting fluid into the bags of the opening and closing parts, the bags are expanded and the opening of the flow path is closed. The order of contraction and expansion can be set according to the assumed subject, but in order to simulate the sequential movement of contents from the cardia to the pylorus of the human stomach, it is preferable to contract and then expand the bags in the cylindrical fluid actuators closest to the inlet in order.

[0036] When sequentially contracting and expanding bags in adjacent cylindrical fluid actuators, the time between the start of contraction or expansion of one bag and the start of contraction or expansion of the next bag should be set according to the expected subject. However, for the lower part of the device corresponding to the pyloric antrum and the upper part of the device corresponding to the gastric fundus and gastric body, it is usually 60 seconds or less, more preferably 30 seconds or less, more preferably 10 seconds or less, more preferably 5 seconds or less, and especially preferably 0 seconds (simultaneous start of contraction or expansion of bags in adjacent cylindrical fluid actuators). Within this range, the peristaltic movement of the human stomach can be accurately reproduced.

[0037] The frequency of the opening and closing motion, consisting of contraction and expansion, should be set according to the expected subject. In the lower part of the device, corresponding to the pyloric antrum, it is usually 1 to 5 times / minute, with some variations being 1 to 3 times / minute and others 2 to 3 times / minute. In the upper part of the device, corresponding to the gastric fundus and gastric body, it is usually 1 to 5 times / minute, with some variations being 2 to 4 times / minute and others 2 to 3 times / minute.

[0038] The opening and closing range (or, in the case of a bag, the range of contraction and expansion) should be set according to the expected subject, but normally, the lower part of the device corresponding to the pyloric antrum and the upper part of the device corresponding to the gastric fundus and gastric body should be closed until the opening area is 80% or less of the area when fully open, more preferably 50% or less, more preferably 10% or less, and especially 0% (completely closed). Alternatively, the opening area should be 10% or more of the area when fully open, more preferably 50% or more, more preferably 80% or more, and especially 100% (completely open).

[0039] The human stomach secretes saliva and gastric acid at a flow rate of approximately 0.5–4 mL / min during fasting and 5–15 mL / min during feeding. Therefore, in the fasting test, simulated gastric fluid should be introduced into the device at a flow rate of 0.5–4 mL / min, specifically 1–3 mL / min and 1.5–3 mL / min, from the start of the test. In the post-feeding test, simulated gastric fluid should be introduced into the device at a flow rate of 5–15 mL / min, specifically 5–12 mL / min and 5–10 mL / min, from the start of the test.

[0040] Depending on the evaluation objective, the volume of liquid in the cylindrical fluid actuator, the concentration of the test substance in the cylindrical fluid actuator, the volume of liquid discharged from drain port B, and / or the concentration of the target substance in the drained liquid should be measured (especially measured over time). [Examples]

[0041] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. Device for evaluating the gastric emptying dynamics of orally ingested components As described above, Figures 2-1 and 2-2 (photograph) show an example of the gastric emptying dynamics evaluation device of the present invention.

[0042] Pump operating program Figure 3 shows the operating programs for the bag of the cylindrical fluid actuator 7 of the gastric emptying dynamics evaluation device shown in Figure 2. Figures 3(1), (2), and (3) correspond to the three cylindrical fluid actuators that make up the cylindrical fluid actuator 7. The cylindrical fluid actuators (1), (2), and (3) are connected in series from the fluid inlet B5 side. Figure 3 shows, from top to bottom, the operating programs for the bag of the cylindrical fluid actuator (1), the operating program for the cylindrical fluid actuator (2), and the operating program for the cylindrical fluid actuator (3). The operating program shows the "injection" and "suction" (amount) of air into the bag on the vertical axis, and the elapsed time since the start of the test on the horizontal axis. Here, "injection" is the action of injecting air into the bag to inflate it and closing the opening, while "suction" is the action of sucking air out of the bag to deflate it and opening it.

[0043] Using (3) as an example, we will specifically explain the operation shown in Figure 3. Before the test begins, 22 mL of air is injected into the bag using a pump that injects and sucks air into the bag, and the opening is completely closed before starting the test. Ten seconds after the start of the test, 15 mL of air was aspirated from the bag over 6 seconds, leaving the opening at (15 / 22). (The period from the start of the test to the above is referred to as Step 1.) The time during which the pump is not operated and neither injection nor aspiration is performed is called the "delay time." One second after the suction was completed, the pump was activated to inject 15 mL of air into the bag over 6 seconds, and the opening was completely closed. (After completing Step 1, the above steps constitute Step 2.) Twenty seconds after the injection was complete, the pump was activated to aspirate 7.5 mL of air from the bag over 3 seconds, opening the opening to (7.5 / 22). (After completing Step 2, the above steps constitute Step 3.) After suction was complete, 7.5 mL of air was injected into the bag over 3 seconds, and the opening was completely closed. (This is Step 4.) After Step 4 is complete, repeat the process from Step 1.

[0044] The cylindrical fluid actuators (2) and (3) operate in the same manner as the cylindrical fluid actuator (1) described above, except that the delay time is changed as shown in Figure 3. Then, the operation of Steps 1 to 4 was repeated for the cylindrical fluid actuators (1), (2), and (3) for the test period of 30 minutes. As shown in Figure 3, the two operations consisting of expansion and contraction of the bag were performed over 11 seconds and 20 seconds, respectively (average opening and closing frequency was 3.9 times / minute). The start interval of the bag operation of the adjacent cylindrical fluid actuator was 3 seconds for the first operation and 0 seconds for the second operation. The opening and closing width was 68 (15 / 22)% of the opening area for the first operation and 34 (7.5 / 22)% for the second operation.

[0045] Evaluation of changes in fluid volume over time within a gastric model (No. 1) Before the start of the test, 30 mL of water, simulating the volume of gastric juice during fasting, was added to the stomach model. 22 mL of air was injected into the bags of all cylindrical fluid actuators using a pump. Simultaneously with the start of the inflation and deflation movement of the cylindrical fluid actuator bags (Figure 3), 150 mL of water, simulating the water taken during clinical trials, was added to the stomach model. During the test, water simulating saliva and gastric juice flowing into the stomach was added to the stomach model at a constant flow rate of 1.5 mL / min or 3.0 mL / min. The amount of drainage was measured over a 30-minute period to evaluate the volume of water in the stomach model. Three tests were conducted, and the average value was calculated. Furthermore, healthy individuals (males, 20-40 years old) were fasted for at least 12 hours prior to the experiment, and then 150 mL of atenolol solution was administered into their stomachs. The changes in the concentration of atenolol in the stomach were then measured. Since atenolol is not absorbed from the stomach, the changes in the volume of fluid in the stomach were calculated from the changes in the gastric concentration of atenolol. The results are shown in Figure 4. The change in the amount of water in the cylindrical fluid actuator of the present invention over time was in close agreement with the change in the amount of fluid in the human stomach over time.

[0046] Evaluation of changes in fluid volume over time within a gastric model (No. 2) Using the apparatus shown in Figure 2, the same test as in "Evaluation of changes in fluid volume over time in a stomach model (No. 1)" was performed. A control test was also conducted, in which the same operation was performed except that the expansion and contraction of the bag body of the cylindrical fluid actuator was not performed (the opening and closing part inside the cylindrical fluid actuator was in the open position). In each case, the test with the opening and closing part of the cylindrical fluid actuator was operated three times, and the test without the opening and closing part of the cylindrical fluid actuator (control test) was performed once. The results are shown in Figure 5. When the opening and closing operation of the opening and closing section within the cylindrical fluid actuator was not performed, a larger amount of water remained in the cylindrical fluid actuator than when the opening and closing operation was performed, which did not correspond to the change in the amount of fluid in the human stomach over time shown in Figure 4. Figure 6 shows the amount of drug remaining in the cylindrical fluid actuator (percentage of administered dose (remaining rate)) calculated based on the time course of the amount of water remaining in the cylindrical fluid actuator shown in Figure 5, assuming that the drug was completely dissolved in the cylindrical fluid actuator. The time course of the drug remaining rate in the cylindrical fluid actuator was in close agreement with the time course of the drug remaining rate in the stomach measured in humans.

[0047] Estimation of changes in drug concentration over time within a gastric model. Based on the results of "Evaluation of changes in fluid volume over time in a gastric model (No. 2)," we estimated the changes in drug concentration over time in a cylindrical fluid actuator after adding water and atenolol to the cylindrical fluid actuator of the gastric model. Furthermore, healthy human subjects (males, 20-40 years old) were fasted for more than 12 hours prior to the test, and then 150 mL of atenolol solution was administered into their stomachs. The changes in atenolol concentration in the stomach were then measured. The results are shown in Figure 6. The estimated change in drug concentration over time in the cylindrical fluid actuator of the present invention was in close agreement with the change in drug concentration over time in the stomach of human subjects. [Industrial applicability]

[0048] Because the device of the present invention accurately mimics the movement of the human stomach, it can accurately reproduce the gastric emptying dynamics of pharmaceuticals, drugs, and foods, and as a result, accurately predict the blood kinetics of pharmaceutical or food components. This reduces the burden of human blood enzyme (BE) testing, which is performed when developing generic drugs or making design changes to pharmaceutical formulations. [Explanation of Symbols]

[0049] 1. Top of the device 2. Lower part of the device 3 Inlet A 4. Drain port A 5. Fluid inlet B 6. Drain port B 7. Cylindrical fluid actuator (located at the bottom of the device) 8. A cylindrical fluid actuator (located on the top of the device) 9.10. Control Means 11. Opening / Closing Section 12. Bag body 20. Installation means of the device

Claims

1. The upper part of the cylindrical device has an inlet A and a drain port A for the liquid to be tested, A plurality of cylindrical fluid actuators having a fluid inlet B connected to the drain port A, a flow path for the fluid flowing in from the fluid inlet B to pass through, and an opening / closing part provided within the flow path for opening and closing the flow path, and the lower part of the device having the drain port B, The system has control means for controlling the opening and closing of the opening / closing section, A device for evaluating gastric emptying dynamics, comprising a plurality of cylindrical fluid actuators connected in series.

2. The gastric emptying dynamics evaluation device according to claim 1, characterized in that it has three or more cylindrical fluid actuators.

3. The gastric emptying dynamics evaluation device according to claim 1 or 2, characterized in that the opening and closing section is provided on the inner wall of the cylindrical fluid actuator and consists of a bag made of a flexible membrane, and the opening and closing of the flow path is performed by the expansion and contraction of the bag due to the inflow and discharge of fluid into the bag.

4. The gastric emptying dynamics evaluation device according to claim 1 or 2, wherein the upper part of the device has a plurality of cylindrical fluid actuators having a fluid flow path and an opening / closing part for opening and closing the flow path, and a control means for controlling the opening and closing of the opening / closing part.

5. A method for evaluating gastric emptying dynamics, comprising introducing a test liquid into a fluid inlet A at the top of the gastric emptying dynamics evaluation apparatus according to claim 1 or 2, moving the test liquid by opening and closing the opening and closing parts of a plurality of cylindrical fluid actuators at the bottom of the apparatus in a phase-shifted manner between each cylindrical fluid actuator, discharging it from a drain port B at the bottom of the apparatus, and measuring the amount or properties of the discharged test liquid.

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