JP2012145573A - Classification method of candidate agent for clinical drug interaction testing - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method of testing in vitro for selecting an agent on which clinic drug interaction testing should be carried out, from absorbents for oral administration and drugs for combination administration.SOLUTION: The above problem is a classification method, for clinical drug interaction testing, of absorbents for oral administration and combination agents to be administered in combination, and can be solved by a classification method of combination agents which is characterized by comprising a step (1) of measuring the elution speed of a combination agent in a dosage form for oral administration; a step (2) of measuring the absorption speed of the combination agent with an absorbent for oral administration; and a step (3) of carrying out elution speed determination and absorption speed determination and of classifying the combination agent according to combination of those determinations.

Description

  The present invention relates to a method for classifying candidate drugs for clinical drug interaction tests. According to the present invention, the drug interaction of a drug that may be used in combination with an adsorbent for oral administration can be determined.

Patients with deficient renal or hepatic functions cause encephalopathy such as uremia and disturbance of consciousness because harmful toxic substances accumulate in the body, such as in the blood, due to their organ dysfunction. Since the number of these patients tends to increase year by year, the development of organ substitute devices or therapeutic agents having a function of removing toxic substances from the body in place of these defective organs has become an important issue. At present, the removal method of toxic substances by hemodialysis is most popular as an artificial kidney. However, such a hemodialysis artificial kidney requires a special engineer from the viewpoint of safety management in order to use a special device, and the physical, mental and economic burden on the patient due to blood removal from the body is high. However, it is not always satisfactory.
In recent years, adsorbents for oral administration that can be taken orally and can treat renal or liver dysfunction have attracted attention as means for solving these drawbacks.

On the other hand, patients with kidney disease may cause complications such as hypertension, hypotension, arteriosclerosis, renal anemia, renal osteodystrophy, abnormal Ca / P metabolism, vascular complications, and infections. Many. It is also known that patients with liver disease also develop complications such as hepatic encephalopathy, esophageal varices, and diabetes. Therefore, patients with kidney disease and liver disease are often administered in combination with the therapeutic agent for the above-mentioned complications in addition to the adsorbent for oral administration.
However, since the adsorbent for oral administration is an adsorbent, when used in combination with another therapeutic agent, the therapeutic agent is adsorbed, and as a result, the effect of the combined therapeutic agent may be diminished. That is, it is considered that an adsorbent for oral administration and a therapeutic agent for complications of kidney disease or liver disease cause drug interaction in vivo.
Regarding the combination of drugs that may cause such drug interaction, in 2001, the Ministry of Health and Welfare provided a guideline “About a method for examining drug interaction” (Non-patent Document 1). Among them, it is described that it is desirable to study drug interactions in healthy volunteers using concomitant drugs that are expected to have drug interactions.
Drug interactions have also been investigated for therapeutic agents used in combination with orally administered adsorbents. For example, for losartan, which is a therapeutic agent for hypertension, the maximum plasma concentration of losartan (Cmax) and the drug blood concentration-time curve are obtained by administering an adsorbent for oral administration 1 hour after the administration of losartan. It has been reported that there is no significant effect on the lower area (AUC) (Non-patent Document 3). In addition, with respect to amlodipine, which is a therapeutic agent for hypertension, it has been reported that administration of an adsorbent for oral administration 1.5 hours after administration of amlodipine does not affect AUC (Non-Patent Document). 4) As for aspirin, which is a therapeutic agent for angina pectoris, it is disclosed that administration of an adsorbent for oral administration one hour after administration of aspirin eliminates the effect on Cmax and AUC (non- Patent Document 5).
However, it is difficult to conduct an in vivo clinical drug interaction test for all orally administered drugs and adsorbents for oral administration. Therefore, the development of an in vitro test method for selecting a drug to be subjected to a clinical drug interaction test has been expected.

Medicinal Proceedings No. 813 “Methods for Examining Drug Interactions” June 4, 2001, p. 17-18 “Pharmaceutical Journal (Yakugaku ZASSHI)” 2007, Vol. 127, p. 2051-2055 “Journal of Clinical Pharmacology” (USA) 2006, 46, p. 310-320 “Journal of Clinical Pharmacology” (USA) 2007, Vol. 47, p. 904-908 “Japan Journal of Hospital Pharmacology”, 1998, Vol. 24, p. 383-388

Regarding drug interactions between adsorbents for oral administration and other drugs, in vitro study of drug interactions between α-glucosidase inhibitor miglitol used for the treatment of diabetic patients and adsorbent for oral administration It is reported in Patent Document 2. However, Non-Patent Document 2 merely measures the adsorption rate of miglitol to an adsorbent for oral administration, and does not sufficiently reflect clinical drug interaction tests.
Accordingly, an object of the present invention is to provide an in vitro test method for selecting a drug to be subjected to a clinical drug interaction test from drugs administered in combination with an adsorbent for oral administration. is there. Another object of the present invention is to provide an in vitro drug interaction test with a drug administered in combination with an adsorbent for oral administration. Yet another object of the present invention is to provide a method for classifying concomitant drugs as a preliminary test for clinical drug interaction studies.

As a result of intensive research on in vitro drug interaction tests between an adsorbent for oral administration and a drug administered in combination, the present inventor has surprisingly measured the elution rate of the combined drug and used for oral administration. It was found that the results of the in vitro drug interaction test combined with the measurement of the adsorption rate of the concomitant drug by the adsorbent are highly correlated with the clinical drug interaction test.
The present invention is based on these findings.

Therefore, the present invention
[1] Classification method for clinical drug interaction test of concomitant drugs that may be co-administered with adsorbent for oral administration, (1) Elution of concomitant drug in dosage form for oral administration A step of measuring the rate, (2) a step of measuring the adsorption rate of the concomitant drug by the adsorbent for oral administration, and (3) a determination of the elution rate and a determination of the adsorbing rate, and the combination of these determinations A method for classifying a concomitant drug, comprising the step of classifying
[2] (1) The determination of the elution rate is to determine a concomitant drug into two or more groups based on the elution rate, and the determination of the adsorption rate is determined to be two or more groups based on the adsorption rate (2) The determination of the elution rate is performed by quantifying the elution rate, and the determination of the adsorption rate is performed by quantifying the adsorption rate. [1 ], The method for classifying concomitant drugs according to
[3] A continuous test method in which the step (1) and the step (2) are continuously performed, wherein the step (1) puts the combined drug in the dosage form for oral administration into a dissolution tester, This is a step of measuring the dissolution rate, and in step (2), when the interval time elapses, the adsorbent for oral administration is introduced into the dissolution tester, and the adsorption rate of the concomitant drug by the adsorbent for oral administration is measured. A method for classifying a concomitant drug according to [1] or [2],
[4] An independent test method in which the step (1) and the step (2) are discontinuously performed, and the step (1) inputs the combined drug in a dosage form for oral administration into a dissolution tester. The dissolution rate is measured, wherein the step (2) is performed by introducing an adsorbent for oral administration into an elution tester filled with a solution in which the concomitant drug is dissolved, and using the adsorbent for oral administration. The method for classifying a concomitant drug according to [1] or [2], which is a step of measuring the adsorption rate of the concomitant drug,
[5] The elution rate is determined by determining at least one elution rate between 5% and 95% at any one determination time between 1/6 and the total elapsed time of the input interval time. Select as a value, and determine the concomitant drugs into two or more groups according to the elution determination value,
The determination of the adsorption rate is performed by using the adsorption rate when the amount of drug elution immediately before the oral administration adsorbent is added is 100, and any one determination between 5 and 180 minutes after the oral administration adsorbent is input. In time, any one or more of the adsorption rates between 5 and 95% are selected as the adsorption determination value, and the combination drug is determined into two or more groups based on the adsorption determination value. [3] Classification method of the combination drug as described,
[6] The elution rate is any one or more elution rates between 5% and 95% at any one determination time between 5 and 90 minutes after the introduction of the concomitant drug. And determining the concomitant drug into two or more groups based on the elution determination value, and the determination of the adsorption rate is any one determination between 5 and 180 minutes after the adsorbent for oral administration is added. In the time, any one adsorption rate between 5% and 95% is selected as an adsorption determination value, and the combination drug is determined into two or more groups based on the adsorption determination value. Classification method of concomitant drugs,
[7] When n elution judgment values are selected, the combination drug is judged as the group (n + 1), scored in descending order from the higher elution rate group to the lower group, and m adsorption judgment values are selected. The concomitant drugs are determined as the group (m + 1), scored in descending order from the group with the lowest adsorption rate to the group with the higher adsorption rate, and the concomitant drugs are classified according to the score obtained by adding the elution rate score and the adsorption rate score [5] Or a method for classifying a concomitant drug according to [6],
[8] The classification step (3) is a step of determining the maximum blood concentration arrival time, and classifying the combination drug by a combination of determination of elution rate, determination of adsorption rate, and determination of maximum blood concentration arrival time. A method for classifying a concomitant drug according to any one of [1] to [7],
[9] In determining the maximum blood concentration arrival time, one or more times are selected as the maximum blood concentration arrival time determination value, and two or more concomitant drugs are selected according to the maximum blood concentration arrival time determination value. [10] The determination method of the concomitant drug according to [8] and [10] determination of the maximum blood concentration arrival time as one or more times as the maximum blood concentration arrival time determination value The combination drug is determined into two or more groups based on the maximum blood concentration arrival time determination value, and when one of the maximum blood concentration arrival time determination values is selected, the combination drug is (l + 1) The number of points was determined in descending order from the group with the shortest time to reach the highest blood concentration to the longest group, and the points for the elution rate, the points for the adsorption rate, and the points for the time to reach the highest blood concentration were added. By concomitant drugs Classification method of the combination drug according to the classifying [9],
About.
The present invention also provides:
[11] The method includes the steps of (1) measuring the dissolution rate of a concomitant drug in a dosage form for oral administration, and (2) measuring the adsorption rate of the concomitant drug by an adsorbent for oral administration. , Drug interaction test methods for concomitant drugs that may be co-administered with adsorbents for oral administration,
[12] (3) A step of determining the elution rate obtained in the step (1) and the adsorption rate obtained in the step (2), and classifying the combination drug according to the combination of the determinations. The drug interaction test method according to [11], further comprising:
[13] A continuous test method in which the step (1) and the step (2) are continuously performed, wherein the step (1) throws the combined drug in the dosage form for oral administration into a dissolution tester, This is a step of measuring the dissolution rate, and in step (2), when the interval time elapses, the adsorbent for oral administration is introduced into the dissolution tester, and the adsorption rate of the concomitant drug by the adsorbent for oral administration is measured. A drug interaction test method according to [11] or [12],
[14] An independent test method in which the step (1) and the step (2) are discontinuously performed, and the step (1) inputs the combined drug in a dosage form for oral administration into a dissolution tester The dissolution rate is measured, wherein the step (2) is performed by introducing an adsorbent for oral administration into an elution tester filled with a solution in which the concomitant drug is dissolved, and using the adsorbent for oral administration. The drug interaction test method according to [11] or [12], which is a step of measuring the adsorption rate of the concomitant drug,
About.
In the drug interaction test of the present invention, the classification step (3) in the method for classifying a concomitant drug can be used without limitation. That is, the classification step (3) described in [1] to [10] can be used in the drug interaction test of the present invention.

In particular, the classification method of the present invention is a classification method for clinical drug interaction test of a concomitant drug that may be administered in combination with an adsorbent for oral administration, and (1) an agent for oral administration Measuring the elution rate of the combined drug in the form, (2) measuring the adsorption rate of the combined drug by the orally administered adsorbent, and (3) determining the elution rate and determining the adsorption rate. A group with a fast elution rate and a slow adsorption rate; a group with a fast elution rate and a fast adsorption rate; a group with a slow elution rate and a slow adsorption rate; and a group with a slow elution rate and a fast adsorption rate A method of classifying the concomitant drug, comprising the step of classifying into any one of the groups.
In a preferred embodiment of the method for classifying a concomitant drug of the present invention, a continuous test method in which the step (1) and the step (2) are continuously performed, wherein the step (1) is the dosage form for oral administration. In the dissolution tester, and the dissolution rate is measured. In the step (2), when the interval time has elapsed, the adsorbent for oral administration is introduced into the dissolution tester, This is a step of measuring the adsorption rate of the concomitant drug by the adsorbent.
In a further preferred aspect of the method for classifying a concomitant drug of the present invention, the elution rate is determined at any one (arbitrary) determination time between 1/6 of the input interval time and the total elapsed time. Select any one (arbitrary) elution rate between 20% and 80% as the judgment value, and when the elution rate of the concomitant drug is greater than or equal to the elution judgment value, the elution rate is fast and less than the elution judgment value. In some cases, it is determined that the elution rate is slow, and the determination of the adsorption rate uses the adsorption rate when the amount of drug elution immediately before the oral administration adsorbent is input is 100, and 5 to 5 At any one (arbitrary) determination time of 180 minutes, any one (arbitrary) adsorption rate between 20 and 80% is selected as the adsorption determination value, and the adsorption rate of the concomitant drug is determined as the adsorption rate. If it is above the judgment value, the adsorption speed is fast, Determining if less than the determination value and slow adsorption rate.
In a further preferred aspect of the method for classifying a concomitant drug of the present invention, the elution determination value is an elution rate of 50% when ½ of the input interval time has elapsed, and the elution rate of the concomitant drug is 50% or more. When the elution rate is fast and less than 50%, it is determined that the elution rate is slow, and the adsorption determination value is 30% when the adsorbent for oral administration has been introduced for 15 minutes, and the adsorption rate of the concomitant drug is 30. If it is at least%, the adsorption rate is fast, and if it is less than 30%, the adsorption rate is judged to be slow.

In another preferred embodiment of the method for classifying a concomitant drug of the present invention, the method is an independent test method in which the step (1) and the step (2) are discontinuously performed, and the step (1) is for oral administration. In the dissolution tester, and the dissolution rate is measured. The step (2) is used for oral administration in a dissolution tester filled with a solution in which the combined drug is dissolved. In this step, an adsorbent is added and the adsorption rate of the concomitant drug by the oral adsorbent is measured.
In a further preferred aspect of the method for classifying a concomitant drug of the present invention, the elution rate is determined as an elution determination value at any one (arbitrary) determination time between 5 and 90 minutes after the introduction of the concomitant drug. Select any one (arbitrary) elution rate between 20% and 80%, and if the elution rate of the concomitant drug is greater than or equal to the elution judgment value, the elution rate is fast and less than the elution judgment value It is determined that the elution rate is slow, and the determination of the adsorption rate is 20 to 80% as an adsorption determination value at any one (arbitrary) determination time between 5 and 180 minutes after charging the adsorbent for oral administration. When any one (optional) adsorption rate is selected and the adsorption rate of the concomitant drug is greater than or equal to the adsorption determination value, the adsorption rate is fast, and when it is less than the adsorption decision value, the adsorption rate is slow judge.
In a further preferred aspect of the method for classifying a concomitant drug according to the present invention, the elution determination value is 50% after 30 minutes from the introduction of the concomitant drug, and the dissolution rate of the concomitant drug is 50% or more. When the elution rate is fast and less than 50%, it is determined that the elution rate is slow. The adsorption determination value is 50% when the adsorbent for oral administration has been introduced for 15 minutes, and the adsorption rate of the concomitant drug is 50. If it is equal to or greater than%, the adsorption speed is fast, and if it is less than 50%, the adsorption speed is determined to be slow.

In another preferred embodiment of the method for classifying a concomitant drug of the present invention, the step (3) comprises a step of dissolving the concomitant drug in a group having a high elution rate, a slow adsorption rate, and a short time to reach the maximum blood concentration; Group with high speed, slow adsorption rate, and long time to reach maximum blood concentration; group with fast elution rate, fast adsorption rate, and short time to reach maximum blood concentration; fast dissolution rate, fast adsorption rate A group with a long time to reach the maximum blood concentration; a group with a slow elution rate, a slow adsorption rate, and a short time to reach a maximum blood concentration; a slow elution rate, a slow adsorption rate, and a time to reach the maximum blood concentration Any of the following: a group having a long elution rate, a high adsorption rate, and a short time for reaching the maximum blood concentration; and a group having a slow elution rate, a high adsorption rate, and a long time for reaching the maximum blood concentration. To classify A.
In a further preferred aspect of the method for classifying a concomitant drug of the present invention, when the maximum blood concentration attainment time is 1 hour or less, it is determined that the maximum blood concentration attainment time is short, and the case in which the maximum blood concentration attainment time exceeds 1 hour is the maximum. It is determined that the time to reach the blood concentration is long.

  According to the method for classifying a concomitant drug of the present invention, it is possible to determine the drug interaction between the adsorbent for oral administration and the concomitant drug in vitro, and the clinical drug interaction test is greatly performed. Can be reduced. That is, the results of the method for classifying concomitant drugs of the present invention and the results of clinical drug interaction tests are highly correlated. Therefore, it is possible to greatly reduce the time and cost required for developing a new drug for an adsorbent for oral administration.

It is a graph which shows the test result of losartan, glimepiride, warfarin, and metoprolol by the continuous test method at the time of using the porous spherical carbonaceous material obtained by manufacture example 1 which is one embodiment of this invention. The test results of losartan, glimepiride, warfarin, metoprolol, acetylsalicylic acid, and amlodipine by a continuous test method using the porous spherical carbonaceous material obtained in Production Example 2, which is one embodiment of the present invention, are shown. It is a graph. It is a graph which shows the measurement result of the elution rate of losartan, glimepiride, warfarin, and metoprolol by the independent test method at the time of using the porous spherical carbonaceous material obtained by manufacture example 1 which is one embodiment of this invention. is there. It is a graph which shows the measurement result of the adsorption rate of losartan, glimepiride, warfarin, and metoprolol by the independent test method at the time of using the porous spherical carbonaceous material obtained by manufacture example 1 which is one embodiment of this invention. is there. Measurement of dissolution rate of losartan, glimepiride, warfarin, metoprolol, acetylsalicylic acid, and amlodipine by an independent test method using the porous spherical carbonaceous material obtained in Production Example 2, which is one embodiment of the present invention It is a graph which shows a result. Measurement of adsorption rates of losartan, glimepiride, warfarin, metoprolol, acetylsalicylic acid, and amlodipine by an independent test method using the porous spherical carbonaceous material obtained in Production Example 2, which is one embodiment of the present invention It is a graph which shows a result.

[1] Method for classifying concomitant drugs The method for classifying concomitant drugs of the present invention is not limited. The purpose is to determine whether or not to conduct an interaction test, or to determine the priority order for conducting an in vivo clinical drug interaction test.

The adsorbent for oral administration used in the method of the present invention is not particularly limited as long as it is an adsorbent for oral administration used for medical purposes. For example, a spherical adsorbent charcoal that is a therapeutic agent for chronic renal failure (for example, Kuremedin (Kureha), Spherical Adsorbed Charcoal “Mylan” (Mylan Pharmaceutical) or Cucal (Nichiko), Adsorbents for the Treatment of Hypercholesterolemia (eg, Cholestyramine (Sanofi-Aventis) Colestimide (Mitsubishi Tanabe Pharma) ), Adsorbents for the treatment of hyperphosphatemia (eg, sevelamer hydrochloride (Chugai Pharmaceutical)), and adsorbents for the treatment of hyperkalemia associated with acute and chronic renal failure (eg, calcium calcium sulfonate (fuso) Chemical), or sodium polystyrene sulfonate (Torii Pharmaceutical).
In particular, patients with chronic renal failure who receive spherical adsorbed charcoal may have various complications. Therefore, there are many drugs that may be administered in combination with spherical adsorbent charcoal, and there are many concomitant drugs that require clinical drug interaction tests in vivo with spherical adsorbent charcoal.
The spherical adsorption charcoal is made of spherical activated carbon, and the average particle diameter is not particularly limited, but is preferably 0.02-1 mm, more preferably 0.03-0.90 mm, and 0.05-0. 80 mm is more preferable. Further, the range of the particle diameter (diameter) of the spherical activated carbon is preferably 0.01 to 2 mm, more preferably 0.02 to 1.5 mm, and further preferably 0.03 to 1 mm. preferable.
“Spherical activated carbon” means that the specific surface area is 100 m ² / g or more, but the specific surface area of the spherical activated carbon used in the present invention is preferably 500 m ² / g or more, more preferably 700 m ² / g or more, 1300 m ² / g or more is more preferred, 1650 m ² / g or more is particularly preferable.
Hereinafter, as a typical example of an adsorbent for oral administration, description will be made using spherical adsorbent charcoal.

  The concomitant drug classified by the classification method of the present invention is not limited as long as it can be administered in combination with an adsorbent for oral administration. Mention may be made of drugs that have a narrow therapeutic window and may affect the safety and efficacy of the concomitant drugs due to drug interactions even if the opportunities for concomitant use are small. For example, as a drug frequently used in combination with a spherical adsorbent charcoal (for example, cremedin), which is a therapeutic drug for chronic renal failure, a therapeutic drug for a complication of kidney disease can be mentioned. Examples of complications of kidney disease include hypertension, hypotension, arteriosclerosis, renal anemia, renal osteodystrophy, abnormal Ca / P metabolism, vascular complications, and infections. The drugs include losartan (hypertension), warfarin (thromboembolism), metoprolol (essential hypertension (mild to moderate)), temocapril (hypertension), imidapril (hypertension), olmesartan (hypertension), candesartan (Hypertension), amlodipine (hypertension), furosemide (hypertension), betaxolol (essential hypertension (mild to moderate)), allopurinol (hyperuricemia), ferrous sodium citrate (iron deficiency anemia) ), Or aspirin (angina).

  In addition, the spherical adsorbed charcoal (eg, cremedin) can be used as a therapeutic agent for liver disease, and as a drug frequently used in combination with the spherical adsorbed charcoal (eg, cremedin), complications of liver disease Can be mentioned. Complications of liver disease can include hepatic encephalopathy, esophageal varices, and diabetes, and therapies include glimepiride (insulin-independent diabetes), voglibose (diabetes), or pioglitazone (insulin-independent) Type diabetes).

Many drugs that are administered in combination with an adsorbent for oral administration require clinical drug interaction testing. In a clinical drug interaction test, an orally administered adsorbent and a concomitant drug are administered to a subject simultaneously or after a certain interval. Then, the pharmacokinetic parameters of the concomitant drug, for example, the maximum plasma concentration (Cmax), the area under the drug blood concentration-time curve (AUC) and the maximum concentration arrival time (Tmax) were measured, and the control group to which only the concomitant drug was administered And the presence or absence of drug interaction between the orally administered adsorbent and the concomitant drug.
Of the concomitant drugs, losartan was administered in an oral adsorbent 1 hour after administration of losartan by a drug interaction test of healthy individuals described in Non-Patent Document 3, whereby Cmax of losartan, And it has been confirmed that there is no significant effect on AUC. As for amlodipine, which is a therapeutic drug for hypertension, as described in Non-Patent Document 4, AUC is affected by administering an adsorbent for oral administration 1.5 hours after administration of amlodipine. As for aspirin, which is reported to have no angina and is a therapeutic agent for angina pectoris, as described in Non-Patent Document 5, an adsorbent for oral administration should be administered 1 hour after administration of aspirin. Thus, it is disclosed that Cmax and AUC are not affected.

The classification method of a concomitant drug of the present invention is a classification method for clinical drug interaction test of a concomitant drug that may be administered in combination with an adsorbent for oral administration, which is (1) for oral administration. A step of measuring the elution rate of the concomitant drug in the dosage form (hereinafter referred to as elution rate measuring step (1) or simply referred to as step (1)), and (2) a step of measuring the adsorption rate of the concomitant drug by the orally administered adsorbent. (Hereinafter referred to as adsorption rate measuring step (2) or simply referred to as step (2)), and (3) determining elution rate and determining adsorption rate, and classifying concomitant drugs according to the combination of these determinations (Hereinafter referred to as a classification step (3)).
In the present specification, the determination of “determination of elution rate” means determination of whether the elution rate is fast or slow, that is, whether the elution rate is fast or slow. “Adsorption speed determination” means determination of whether the adsorption speed is fast or slow, that is, whether the adsorption speed is fast or slow.
Further, as a specific aspect of the present invention, (1) a step of measuring the elution rate of a concomitant drug in a dosage form for oral administration, (2) a step of measuring the adsorption rate of the concomitant drug by an adsorbent for oral administration, And (3) The elution rate is determined and the adsorption rate is determined, and the concomitant drug is dissolved in a group with a high elution rate and a slow adsorption rate; a group with a high elution rate and a high adsorption rate; a slow elution rate And a group that is classified into any one of a group having a low adsorption rate; and a group having a low elution rate and a high adsorption rate.
The classification method of the present invention can also be performed by a continuous test method in which the elution rate measuring step (1) and the adsorption rate measuring step (2) are performed continuously, and the elution rate measuring step (1) and The adsorption rate measurement step (2) and the independent test method can be performed separately, but the continuous test method is preferred because it reflects the state of clinical drug interaction tests. Hereinafter, the continuous test method will be described, and then the independent test method will be described.

《Continuous test method》
When the classification method of the present invention is performed by a continuous test method, the elution rate and the adsorption rate are continuously measured with one tester. The tester used for the continuous test method is not limited as long as the dissolution rate and adsorption rate can be measured. That is, it is not particularly limited as long as it can sample the test solution in which the drug is eluted and the test solution in which the drug is adsorbed by the adsorbent for oral administration over time. For example, use a dissolution tester. Can do. The dissolution tester is used for dissolution test, which is a general test method listed in JP. The dissolution test includes the first method (rotating basket method) or the second method (paddle method), but the dissolution tester used in the present invention preferably has a paddle used in the second method. The liquid can be easily sampled over time.

(Elution rate measurement process (1))
In the elution rate measurement step (1) in the continuous test method, the elution rate of the concomitant drug in the dosage form for oral administration is measured. In the measurement of the dissolution rate, it is possible to use a compound of an active ingredient contained in a concomitant drug, but in the present invention, in order to reflect the state of a clinical drug interaction test, it is actually administered to a human in clinical practice. The combined drug in the dosage form for oral administration is used, and it is put into, for example, a dissolution tester, and the dissolution rate is measured. The dose of the concomitant drug can be appropriately determined, but it is preferable to use a single dose of the concomitant drug.
In addition, the elution rate measurement method is not particularly limited, for example, by sampling the test solution at regular time intervals, measuring the elution amount of the eluted concomitant drug, and determining the dissolution rate of the injected drug, It can be calculated by the following formula.

Dissolution rate = {(elution amount of concomitant drug after a certain time) / (dose of concomitant drug)} × 100

  The test solution used in step (1) is not particularly limited as long as it can be used for the dissolution test. For example, the dissolution test first solution, dissolution test second solution, purified water, or pH is adjusted. Adjusted McIlvine buffer and phosphate buffer can be used, but since the drug interaction between the adsorbent for oral administration and the concomitant drug is likely to occur in the intestinal tract, the second dissolution test solution is used. It is preferable to use it. However, when using a concomitant drug that cannot be dissolved in the second dissolution test solution, a test solution that can dissolve the concomitant drug to be tested can be used as appropriate.

  As the test solution, a test solution that has been degassed may be used, or a test solution that is not degassed may be used. Therefore, it is preferable to use a degassed test solution. The deaeration method is not particularly limited, and for example, a vacuum suction filtration method or a helium replacement method can be used. In the case of the vacuum suction filtration method, the test solution is heated to 41 ° C. and immediately filtered using a filter having a pore diameter of 0.45 μm while stirring with an aspirator. While stirring under reduced pressure, suction is further performed for 5 minutes and used as a test solution.

  The volume of the test solution can also be appropriately selected according to the concentration of the test device used and the concomitant drug, and is not particularly limited. For example, when using the dissolution test device, the volume of the test solution is 500 mL to 1000 mL per vessel. A volume can be used, for example, testing can be performed at a volume of 900 mL / vessel.

  The temperature of the test solution is not particularly limited, but is preferably 20 ° C. to 40 ° C., and particularly preferably 37 ° C. ± 0.5 ° C. close to human body temperature.

  Although it is possible to perform the test without stirring the test solution, it is preferable to perform stirring in order to make the dispersed state of the concomitant drug uniform. The stirring method is not particularly limited, but a paddle can be used when the dissolution tester is used. Although the rotation speed of a paddle is not specifically limited, it can carry out at 10-200 rotations / minute, Preferably it is 20-100 rotations / minute, More preferably, it is 30-70 rotations / minute, More preferably, 40- 60 revolutions / minute. This is because if the number of rotations is too small, the state of dispersion of the concomitant drug will be poor, and if the number of rotations is too large, the in vivo state will not be reflected and the dissolution rate of the concomitant drug will be too fast.

(Adsorption rate measurement process (2))
In the adsorption rate measurement step (2) in the continuous test method, the adsorption rate of the concomitant drug by the adsorbent for oral administration is measured. That is, in the continuous test method, the adsorbent for oral administration is introduced into the dissolution tester when the input interval time elapses, and the adsorption rate is measured.
In this specification, the input interval time is the time from when the concomitant drug is introduced into the dissolution tester to when the adsorbent for oral administration is introduced, and the interval between administration of the concomitant drug and the adsorbent for oral administration to the living body. However, it is preferably 0 minute to 3 hours, more preferably 30 minutes to 2 hours, and further preferably 45 minutes to 1.5 hours.
Also in clinical drug interaction tests, taking into account the interval between administration of the concomitant drug and the adsorbent for oral administration to the living body, the administration interval for administering the drug for oral administration after the concomitant drug is administered Time is determined. In the classification method of the present invention, the input interval time is preferably the same as the administration interval time of the clinical drug interaction test in order to reflect the state of the clinical drug interaction test.

In order to reflect the state of clinical drug interaction tests, the oral adsorbent used in the adsorption rate measurement step (2) is an oral dosage form that is actually administered to humans. Use. Specifically, an adsorbent for oral administration such as a fine granule, a capsule, or a tablet can be used. The dose of the adsorbent for oral administration can be determined as appropriate, but it is preferable to use a single dose of the adsorbent for oral administration.
The method for measuring the adsorption rate is not particularly limited. For example, the test solution is sampled at regular intervals, the residual amount (elution amount) of the concomitant drug is measured, and the adsorption rate of the concomitant drug is obtained. Can be calculated.
The adsorption rate in the continuous method is an adsorption rate when the elution amount of the concomitant drug immediately before the adsorbent for oral administration is set to 100, and can be expressed by the following equation.

Adsorption rate in continuous method = {(eluting amount of concomitant drug just before the adsorbent for oral administration)-(residual amount of concomitant drug after a certain time (eluting amount))} / (combination just before the adsorbent for oral administration) Drug elution amount) x 100

Therefore, in the continuous test method, when 100% of the concomitant drug is not eluted during the administration interval time, in the adsorption rate measurement step (2), the concomitant drug is eluted and the concomitant drug by the adsorbent for oral administration is used. Adsorption proceeds simultaneously. From this point, the continuous test method reflects the state of clinical drug interaction tests.

  The type of the test solution used in the step (2), the volume of the test solution, the temperature of the test solution, and the stirring of the test solution are not particularly limited and can be appropriately determined. It is preferable to perform the test continuously under conditions.

(Classification process (3))
In the classification step (3) in the continuous test method, the elution rate is determined from the measurement result of the elution rate measurement step (1), and the adsorption rate is determined from the measurement result of the adsorption rate measurement step (2). The concomitant drugs are classified based on the determination result.
The elution rate of the concomitant drug can be determined depending on whether the elution rate of the concomitant drug is fast or slow. For example, the elution rate of the concomitant drug can be determined by whether the elution rate of the concomitant drug is greater or less than a certain elution determination value (elution rate) in a certain elution determination time after the combination drug is introduced.

The elution determination time and elution determination value can be appropriately determined within a certain range. For example, the dissolution determination time is determined by selecting at least one time between the input interval times (the time from when the concomitant drug is input to the dissolution tester to when the adsorbent for oral administration is input). be able to. The elution determination time is not particularly limited as long as it is between the input interval times, but immediately after the concomitant drug is put into the dissolution tester, it is appropriate as the time for measuring the dissolution rate of the concomitant drug. is not. Therefore, the elution determination time is preferably any one of 1/12 passages to the total elapsed time of the charging interval time, more preferably any one of 2/12 passages to 10/12 hours of the charging interval time, Any one of 4/12 to 8/12 hours elapsed is more preferable, and for example, a time that is 1/2 elapsed input time can be used.
In the present invention, it is also possible to classify concomitant drugs by combining determinations at two or more elution determination times.

The elution judgment value is not particularly limited as long as it is any one between 0% and less than 100%, but for example, the elution judgment value is in the range of 5 to 95%. Any one of the above elution rates is preferable, an elution rate in the range of 20 to 80% is more preferable, an elution rate in the range of 30 to 70% is more preferable, and an elution rate in the range of 40 to 60% is still more preferable. An elution rate of 50% can be used as an elution determination value.
The determination of the elution rate of the concomitant drug is, for example, when the elution rate of the tested concomitant drug is greater than or equal to the selected elution determination value, it is determined that the elution rate is fast and is less than the elution determination value. It can be determined that the elution rate is slow.

  In addition, the determination of the elution rate may be to determine a concomitant drug into two or more groups based on the elution rate. For example, one elution determination value may be selected and, as described above, determination may be made into two groups of “elution speed is fast” and “elution speed is low”. Further, two or more elution determination values may be selected and determined to be three or more groups. For example, a first high elution judgment value (for example, 60%) and a second low elution judgment value (for example, 40%) are selected. If the elution rate is less than the first elution determination value and greater than or equal to the second elution determination value, the elution rate is determined to be intermediate, and if it is less than the second elution determination value, the elution rate is determined to be slow. can do. It is also possible to select three or more elution determination values and make the same determination.

  Furthermore, it is also possible to determine n by selecting n elution determination values, determining the concomitant drugs to (n + 1) groups, and scoring them in descending order from a group with a high elution rate to a group with a low elution rate. For example, when two elution determination values are selected, the three groups are determined as described above. Here, it can be determined by scoring “high elution rate” as 3 points, “elution rate intermediate” as 2 points, and “slow elution rate” as 1 point.

  The selection of elution determination time and elution determination value is not limited, but may be performed after measuring a plurality of drugs. For example, 10 types of concomitant drugs can be measured, and the elution determination time and elution determination value can be selected according to the distribution of elution rates of these concomitant drugs. One object of the present invention is to provide an in vitro test method for selecting a drug to be subjected to a clinical drug interaction test from drugs administered in combination with an adsorbent for oral administration. It is. Therefore, in order to select a drug to be subjected to a clinical drug interaction test from many drugs, it is preferable to determine the rank of those drugs. Therefore, in order to select the elution determination time and elution determination value for appropriately classifying the concomitant drug, it is also preferable to select the elution determination time and elution determination value after measuring a plurality of drugs.

  The determination of the adsorption rate of the concomitant drug can be made based on whether the adsorption rate of the concomitant drug by the orally administered adsorbent is fast or slow. For example, the rate of adsorption of a concomitant drug by an orally administered adsorbent is greater than the constant adsorbent judgment value (elution rate) at a certain adsorption judgment time after injection of the orally administered adsorbent. Judgment can be made according to whether there are few.

The adsorption determination time and the adsorption determination value can be appropriately determined within a certain range. For example, the adsorption determination time can be determined by selecting at least one time after charging the orally administered adsorbent. The adsorption determination time is not particularly limited as long as it is after the injection of the oral administration adsorbent, but immediately after the oral administration adsorbent is introduced into the dissolution tester, The time for measuring the adsorption rate of the concomitant drug is not appropriate. Therefore, the adsorption determination time is preferably any one of 5 to 180 minutes after the adsorbent for oral administration is added, preferably any one of 10 to 120 minutes, or any of 15 to 60 minutes. One is more preferable, and for example, the time when 15 minutes have passed after the adsorbent for oral administration has elapsed can be used.
In the present invention, it is also possible to classify concomitant drugs by combining determinations at two or more adsorption determination times.

The adsorption determination value is not particularly limited as long as it is any one between 0% and less than 100%, but for example, the adsorption determination value is in the range of 5 to 95%. Any one of the adsorption rates is preferred, an elution rate in the range of 20-80% is more preferred, an adsorption rate in the range of 30-70% is more preferred, an adsorption rate in the range of 40-60% is still more preferred, An adsorption rate of 50% can be used as the adsorption determination value.
Then, the determination of the adsorption rate of the concomitant drug is determined when the adsorption rate of the tested concomitant drug is equal to or higher than the selected adsorption determination value, and the adsorption rate is determined to be fast and less than the adsorption determination value. Is determined that the adsorption speed is slow.

  Further, the determination of the adsorption rate may be to determine the concomitant drug into two or more groups based on the adsorption rate. For example, one adsorption determination value may be selected and, as described above, the determination may be made into two groups of “fast adsorption speed” and “slow adsorption speed”. Further, two or more suction determination values may be selected and determined to be three or more groups. For example, a first high adsorption determination value (for example, 60%) and a second low adsorption determination value (for example, 40%) are selected. "If the adsorption rate is less than the first adsorption determination value and greater than or equal to the second elution determination value, the adsorption rate is determined to be intermediate", and if it is less than the second adsorption determination value, the adsorption rate is determined to be slow. can do. It is also possible to select three or more suction determination values and make the same determination.

  Furthermore, it is also possible to select m adsorption determination values, determine the concomitant drugs to the group (m + 1), and determine by scoring in descending order from a group having a low adsorption rate to a group having a high adsorption rate. For example, when two adsorption determination values are selected, the three groups are determined as described above. Here, the “adsorption speed is fast” can be determined by scoring 1 point, the “adsorption speed is intermediate” by 2 points, and the “adsorption speed is slow” by 3 points.

  The adsorption determination time and the adsorption determination value are not limited, but are preferably changed depending on the adsorbent for oral administration. This is because the speed of adsorption may vary depending on the adsorbent for oral administration.

  Further, the selection of the adsorption determination time and the adsorption determination value is not limited, but may be performed after measuring a plurality of drugs. For example, 10 types of concomitant drugs can be measured, and the adsorption determination time and the adsorption determination value can be selected based on the distribution of the adsorption rates of these concomitant drugs. One object of the present invention is to provide an in vitro test method for selecting a drug to be subjected to a clinical drug interaction test from drugs administered in combination with an adsorbent for oral administration. It is. Therefore, in order to select a drug to be subjected to a clinical drug interaction test from many drugs, it is preferable to determine the rank of those drugs. Therefore, in order to select the adsorption determination time and the adsorption determination value for appropriately classifying the combination drug, it is preferable to select the elution determination time and the elution determination value after measuring a plurality of drugs.

According to the classification method of the present invention, for example, a concomitant drug that may be administered in combination with an adsorbent for oral administration is a group in which the concomitant drug has a high elution rate and a low adsorption rate; a high elution rate and a high adsorption rate. The group can be classified into any one of a fast group; a group having a slow elution rate and a slow adsorption rate; and a group having a slow elution rate and a fast adsorption rate.
When the elution judgment value is 50% after elapse of ½ of the input interval time and the adsorption judgment value is 30% after 15 minutes of the adsorbent injection for oral administration, it is carried out in Examples 1-4. Furthermore, the concomitant drugs losartan, glimepiride, warfarin, and metoprolol for the porous spherical carbonaceous material obtained in Production Example 1 can be classified as shown in Table 1.

  In Group A, since the elution rate of the concomitant drug is fast and the adsorption rate of the concomitant drug is slow, clinical drug interaction is unlikely to occur. On the other hand, in Group D, the elution rate of the concomitant drug is slow, and the adsorbing rate of the concomitant drug is fast, so clinical drug interaction is likely to occur. Groups B and C are considered to be intermediate between group A and group D. The classification method of the present invention and the results of the drug interaction test of losartan described in Non-Patent Document 3 are well correlated. Therefore, the classification method of the present invention is a drug used in combination with an adsorbent for oral administration. It is possible to determine the drug interaction.

  The porous spherical carbonaceous material obtained in Production Example 2 of Examples 5 to 10 showed a tendency that the adsorption rate was slower than that of the porous spherical carbonaceous material obtained in Production Example 1. In order to classify the six types of concomitant drugs, two elution judgment values of 60% and 40% after elapse of half of the input interval time are selected, and 3 items with 60% or more, 40% or more A score of less than 60% was determined as 2 points, and a score of less than 40% was determined as 1 point. Further, the adsorption determination value was determined to be 30% after 30 minutes from the introduction of the adsorbent for oral administration, with an adsorption rate of less than 30% being 2 points and 30% or more being 1 point. The concomitant drugs losartan, glimepiride, warfarin, metoprolol, acetylsalicylic acid, and amlodipine can be classified as shown in Table 2.

Furthermore, in the method for classifying a concomitant drug of the present invention, the determination of the elution rate in the classification step (3) may be performed by quantifying the elution rate, and the determination of the adsorption rate may be performed by determining the adsorption rate. It may be determined numerically. Specifically, the elution rate during a specific elution determination time (for example, after the lapse of half of the input interval time) is used for the elution rate determination, and the specific adsorption determination time (for example, for oral administration) is used for the determination of the adsorption rate. The concomitant drugs can be classified by adding the elution rate and the residual rate using the residual rate (after 30 minutes after the adsorbent is charged). The reason why the residual rate is used for the determination of the adsorption rate is that the higher the residual rate of the concomitant drug, the lower the drug interaction.
Table 3 shows the results of categorizing the drugs of Examples 5 to 10 by adding the dissolution rate after 1/2 passage of the charging interval time and the residual rate after 30 minutes of charging of the adsorbent for oral administration.

  The classification method of the present invention and the clinical drug interaction test results of losartan, acetylsalicylic acid, and amlodipine described in Non-Patent Documents 3 to 5 are well correlated. It is possible to determine the drug interaction between the adsorbent for administration and the drug used in combination.

《Independent test method》
When the classification method of the present invention is performed by an independent test method, the elution rate and the adsorption rate are individually measured. Therefore, the elution rate measurement step (1) and the adsorption rate measurement step (2) can be performed simultaneously in parallel.
The tester used for the separation test method is not limited as long as the elution rate and the adsorption rate can be measured. The same test is performed in the elution rate measurement step (1) and the adsorption rate measurement step (2). A different tester may be used. Specifically, there is no particular limitation as long as the test solution in which the drug is eluted and the test solution in which the drug is adsorbed by the adsorbent for oral administration can be sampled over time. For example, the continuous test The dissolution tester described in the method can be used. As described above, the dissolution tester is used for the dissolution test, which is a general test method listed in JP, and preferably has a paddle used for the second method (paddle method), and samples the test solution over time. Can be easily performed.

(Elution rate measurement process (1))
The elution rate measurement step (1) in the independent test method can be performed under the same conditions as the elution rate measurement step (1) in the continuous test method. That is, it is possible to use conditions such as the type of test solution, the volume of the test solution, the temperature of the test solution, and the stirring method of the test solution described in the dissolution rate measurement step (1) of the continuous test method.
In addition, the elution rate measurement method is not particularly limited, for example, by sampling the test solution at regular time intervals, measuring the elution amount of the eluted concomitant drug, and determining the dissolution rate of the injected drug, It can be calculated by the following formula.

Dissolution rate = {(elution amount of concomitant drug after a certain time) / (dose of concomitant drug)} × 100

In the independent test method, it is not necessary to perform the adsorption rate measurement step (2) using the same tester after the elution rate measurement step (1). Therefore, since there is no limitation on the time interval between the introduction of the concomitant drug into the dissolution tester and the adsorbent for oral administration, the test solution should be used until the dissolution rate of the added concomitant drug reaches 100%. It is also possible to sample and measure the dissolution rate of the concomitant drug.

(Adsorption rate measurement process (2))
In the adsorption rate measurement step (2) in the independent test method, the adsorption rate of the concomitant drug by the orally administered adsorbent is measured. In the independent test method, an adsorbent for oral administration is introduced into a test device previously filled with a solution in which the concomitant drug is dissolved, and the adsorption rate of the concomitant drug by the adsorbent for oral administration is measured.
As the concomitant drug to be dissolved, it is possible to use only the compound of the active ingredient contained in the concomitant drug. It is preferable to use a combined drug in a dosage form for oral administration. This is because when the dosage form for oral administration is used, since the excipient and the like are dissolved in the test solution, the effect of the excipient and the like is also taken into consideration in the adsorption rate. The dissolution amount of the concomitant drug can be determined as appropriate, but it is preferable to use a single dose of the concomitant drug.
Similarly, in order to reflect the state of clinical drug interaction tests, an oral administration adsorbent in a dosage form that is actually administered clinically to humans is used for the oral administration adsorbent. Specifically, adsorbents for oral administration such as powders, granules, capsules or tablets can be used. The dose of the adsorbent for oral administration can be determined as appropriate, but it is preferable to use a single dose of the adsorbent for oral administration.

In the independent test method, the method for measuring the adsorption rate is not particularly limited, for example, by sampling the test solution at regular intervals, measuring the residual amount of the concomitant drug, and determining the adsorption rate of the concomitant drug, Can be calculated.
The adsorption rate in the independent test method is an adsorption rate when the amount of the combined drug dissolved is 100, and can be represented by the following formula.

Adsorption rate in independent test method = {(dissolved amount of concomitant drug) − (residual amount of concomitant drug after a certain time)} / (dissolved amount of concomitant drug) × 100

  The type of test liquid used in step (2), the volume of the test liquid, the temperature of the test liquid, and the stirring of the test liquid are not particularly limited and can be determined as appropriate, but the conditions in the continuous test method are as follows. Can be used.

(Classification process (3))
In the classification step (3) in the independent test method, the elution rate is determined from the measurement result of the elution rate measurement step (1), and the adsorption rate is determined from the measurement result of the adsorption rate measurement step (2). The concomitant drugs are classified based on the determination result.
The elution rate of the concomitant drug can be determined depending on whether the elution rate of the concomitant drug is fast or slow. For example, the elution rate of the concomitant drug can be determined by whether the elution rate of the concomitant drug is greater or less than a constant elution determination value (elution rate) at a constant elution determination time after the concomitant drug is charged.

The elution determination time and elution determination value can be appropriately determined within a certain range. For example, the elution determination time can be determined by selecting at least one time after introduction of the concomitant drug. The elution determination time is not particularly limited as long as it is the time after the concomitant drug is charged, but immediately after the concomitant drug is charged into the dissolution tester, the time for measuring the dissolution rate of the concomitant drug is: Not appropriate. Therefore, the elution determination time is preferably any one of 5 to 90 minutes after the concomitant drug is added, preferably any one of 10 to 60 minutes, and further any one of 15 to 45 minutes. Preferably, for example, the time when 30 minutes have elapsed for the introduction of the concomitant drug can be used.
In the present invention, it is also possible to classify concomitant drugs by combining determinations at two or more elution determination times.

The elution determination value is not particularly limited as long as it is any one between 0% and less than 100%, but elution rate close to 0% or 100% The value is not appropriate. Therefore, the elution determination value is preferably any one of elution rates in the range of 5 to 95%, more preferably elution rates in the range of 20 to 80%, more preferably elution rates in the range of 30 to 70%, 40 An elution rate in the range of ˜60% is more preferable. For example, an elution rate of 50% can be used as the elution determination value.
The determination of the elution rate of the concomitant drug is, for example, when the elution rate of the tested concomitant drug is greater than or equal to the selected elution determination value, it is determined that the elution rate is fast and is less than the elution determination value. The case is determined to have a slow elution rate.

  In addition, the determination of the elution rate may be to determine a concomitant drug into two or more groups based on the elution rate. For example, one elution determination value may be selected and, as described above, determination may be made into two groups of “elution speed is fast” and “elution speed is low”. Further, two or more elution determination values may be selected and determined to be three or more groups. For example, a first high elution judgment value (for example, 60%) and a second low elution judgment value (for example, 40%) are selected. If the elution rate is less than the first elution determination value and greater than or equal to the second elution determination value, the elution rate is determined to be intermediate, and if it is less than the second elution determination value, the elution rate is determined to be slow. can do. It is also possible to select three or more elution determination values and make the same determination.

  Furthermore, it is also possible to determine n by selecting n elution determination values, determining the concomitant drugs to (n + 1) groups, and scoring them in descending order from a group with a high elution rate to a group with a low elution rate. For example, when two elution determination values are selected, the three groups are determined as described above. Here, it can be determined by scoring “high elution rate” as 3 points, “elution rate intermediate” as 2 points, and “slow elution rate” as 1 point.

  The determination of the adsorption rate of the concomitant drug can be made based on whether the adsorption rate of the concomitant drug by the orally administered adsorbent is fast or slow. For example, the rate of adsorption of a concomitant drug by an orally administered adsorbent is greater than the constant adsorbent judgment value (elution rate) at a certain adsorption judgment time after injection of the orally administered adsorbent. Judgment can be made according to whether there are few.

The adsorption determination time and the adsorption determination value can be appropriately determined within a certain range. For example, the adsorption determination time can be determined by selecting at least one time after charging the orally administered adsorbent. The adsorption determination time is not particularly limited as long as it is after the injection of the oral administration adsorbent, but immediately after the oral administration adsorbent is introduced into the dissolution tester, The time for measuring the adsorption rate of the concomitant drug is not appropriate. Therefore, the adsorption determination time is preferably any one of 5 to 180 minutes after the adsorbent for oral administration is added, preferably any one of 10 to 120 minutes, or any of 15 to 60 minutes. One is more preferable, and for example, the time when 15 minutes have passed after the adsorbent for oral administration has elapsed can be used.
In the present invention, it is also possible to classify concomitant drugs by combining determinations at two or more adsorption determination times.

The adsorption determination value is not particularly limited as long as it is any one between 0% and less than 100% elution rate, but an adsorption rate close to 0% or 100% is an adsorption determination. The value is not appropriate. Therefore, the adsorption determination value is preferably any one of the adsorption rates in the range of 20 to 80%, more preferably the adsorption rate in the range of 30 to 70%, and still more preferably the adsorption rate in the range of 40 to 60%. An adsorption rate of 50% can be used as the adsorption determination value.
Then, the determination of the adsorption rate of the concomitant drug is determined when the adsorption rate of the tested concomitant drug is equal to or higher than the selected adsorption determination value, and the adsorption rate is determined to be fast and less than the adsorption determination value. Is determined that the adsorption speed is slow.

  Further, the determination of the adsorption rate may be to determine the concomitant drug into two or more groups based on the adsorption rate. For example, one adsorption determination value may be selected and, as described above, the determination may be made into two groups of “fast adsorption speed” and “slow adsorption speed”. Further, two or more suction determination values may be selected and determined to be three or more groups. For example, a first high adsorption determination value (for example, 60%) and a second low adsorption determination value (for example, 40%) are selected. "If the adsorption rate is less than the first adsorption determination value and greater than or equal to the second elution determination value, the adsorption rate is determined to be intermediate", and if it is less than the second adsorption determination value, the adsorption rate is determined to be slow. can do. It is also possible to select three or more suction determination values and make the same determination.

  Furthermore, it is also possible to select m adsorption determination values, determine the concomitant drug to the group (m + 1), and determine by scoring in descending order from the group with the lowest adsorption rate to the higher group. For example, when two adsorption determination values are selected, the three groups are determined as described above. Here, the “adsorption speed is fast” can be determined by scoring 1 point, the “adsorption speed is intermediate” by 2 points, and the “adsorption speed is slow” by 3 points.

According to the classification method of the present invention, for example, a concomitant drug that may be administered in combination with an adsorbent for oral administration is classified into any one of groups A to D as in the case of the classification by the continuous test method. The
Production performed in Examples 11 to 14 when the elution determination value was 50% after 30 minutes from the introduction of the combined drug and the adsorption determination value was 50% after 15 minutes from the adsorbent for oral administration. The concomitant drugs losartan, glimepiride, warfarin, and metoprolol for the porous spherical carbonaceous material obtained in Example 1 can be classified as shown in Table 4.

  The classification method of the present invention and the results of the clinical drug interaction test of losartan described in Non-Patent Document 3 are well correlated. Therefore, the classification method of the present invention is used in combination with an adsorbent for oral administration. It is possible to determine the drug interaction of a given drug.

  In Examples 15 to 20, two elution determination values of 60% and 40% after 30 minutes from the introduction of the concomitant drug are selected, and 3 for 60% or more and 2 for 40% or more and less than 60%. A score of less than 40% was determined as 1 point. Further, the adsorption determination value was determined to be 30% after 30 minutes from the introduction of the adsorbent for oral administration, with an adsorption rate of less than 30% being 2 points and 30% or more being 1 point. The concomitant drugs losartan, glimepiride, warfarin, metoprolol, acetylsalicylic acid, and amlodipine can be classified as shown in Table 5.

  The classification method of the present invention and the clinical drug interaction test results of losartan, acetylsalicylic acid, and amlodipine described in Non-Patent Documents 3 to 5 are well correlated. It is possible to determine the drug interaction between the adsorbent for administration and the drug used in combination.

(Importance of elution rate and adsorption rate)
In the classification method of the present invention, the dissolution rate of the concomitant drug and the adsorption rate of the concomitant drug are both important, but when the dissolution rate of the concomitant drug is very fast, the adsorbent for oral administration is used after the administration interval time. It may be absorbed into the living body before contact. Therefore, the high elution rate of the concomitant drug is important in order not to cause drug interaction. In the classification method of the present invention, for example, among the concomitant drugs classified into group A or group B, those having a particularly fast dissolution rate of the concomitant drug are considered to hardly cause drug interaction. Conversely, among the concomitant drugs classified into Group C or Group D, those having a particularly slow elution rate of the concomitant drug are considered to be highly likely to cause drug interaction even if the adsorption rate is slow.

In the classification step (3) in the classification method of the present invention, in addition to the determination of the elution rate and the determination of the adsorption rate, the determination of the maximum blood concentration arrival time (Tmax) of the determination drug, It is also possible to classify them finely.
In the present specification, “determination of time to reach maximum blood concentration” means determination of whether the time to reach maximum blood concentration is long or short, that is, to determine whether the time to reach maximum blood concentration is long or short. .
The time to reach the maximum blood concentration means “time until the blood concentration reaches the maximum after administration of the drug”, and is often measured by a pharmacokinetic test in a drug trial. According to the “drug blood concentration-time curve” in the pharmacokinetic test (the horizontal axis is the elapsed time and the vertical axis is the blood drug concentration), the blood drug concentration reaches the maximum value Cmax between time 0 and Tmax. It rises and then declines. When the maximum blood concentration attainment time is short, absorption of the concomitant drug is fast in vivo, and it is considered that drug interaction between the orally administered adsorbent and the concomitant drug is unlikely to occur.

The determination of the maximum blood concentration attainment time of the concomitant drug can be performed depending on whether the maximum blood concentration attainment time is short or long. For example, the determination of the maximum blood concentration arrival time is determined by whether the maximum blood concentration arrival time of the concomitant drug is shorter or longer than a certain maximum blood concentration arrival time (hereinafter referred to as the maximum blood concentration arrival time determination value). can do. That is, when the maximum blood concentration arrival time determination value is less than or equal to the maximum blood concentration arrival time determination value, it is determined that the maximum blood concentration arrival time is short, and when the maximum blood concentration arrival time determination value is exceeded, it is determined that the maximum blood concentration arrival time is long .
The maximum blood concentration arrival time determination value can be determined as appropriate, but is not particularly limited, but is preferably 0.5 to 1.5 hours, and 0.7 to 1.3 hours. Preferably, 0.8 to 1.2 hours are preferable, for example, 1 hour. The maximum blood concentration arrival time of the drug is often indicated in a range from the lowest value to the highest value. In such a case, for example, a median value (median) can be used.

  In addition, the determination of the maximum blood concentration arrival time may be made by determining the concomitant drugs into two or more groups based on the maximum blood concentration arrival time. For example, one highest blood concentration arrival time determination value is selected, and as described above, two values, “the highest blood concentration arrival time determination value is long” and “the highest blood concentration arrival time determination value is short”. It may be determined as a group. Further, two or more maximum blood concentration arrival time determination values may be selected and determined to be three or more groups. For example, a first short maximum blood concentration arrival time determination value (for example, 0.5 hour) and a second long adsorption determination value (for example, 1 hour) are selected and less than the first maximum blood concentration arrival time determination value Is determined as `` the maximum blood concentration arrival time judgment value is short '', and when it is greater than or equal to the first highest blood concentration arrival time judgment value and less than the second highest blood concentration arrival time judgment value, The medium concentration arrival time is determined to be “intermediate”, and the case where the medium concentration arrival time is equal to or greater than the second maximum blood concentration arrival time determination value can be determined to be “the maximum blood concentration arrival time is long”. It is also possible to select three or more maximum blood concentration arrival time determination values and make the same determination.

  In addition, the number of determination values for reaching the highest blood concentration time is selected, the concomitant drugs are determined as the group (l + 1), and the scores are scored in descending order from the shortest group to the longest blood concentration arrival time determination value. It is also possible to determine by. For example, when two maximum blood concentration arrival time determination values are selected, the three groups are determined as described above. Here, “Short time to reach maximum blood concentration” is scored as 3 points, “Maximum blood concentration time to reach in middle” is scored as 2 points, and “High blood concentration attainment time judgment value is long” is scored as 1 point. It can be judged by.

  By combining the determination of the maximum blood concentration arrival time with the determination of the elution rate in the previous period and the determination of the adsorption rate, it is possible to further classify the concomitant drugs. For example, when 1 determination value of the maximum blood concentration arrival time is selected, the concomitant drug is determined to be the group (l + 1), and is scored in descending order from the shortest group to the longest blood concentration arrival time. Concomitant drugs can be classified based on the points obtained by adding the points of the rate, the adsorption rate, and the maximum blood concentration arrival time.

The time to reach the maximum blood concentration of the concomitant drug used in the examples described below is as follows.
Losartan: 0.7-1.3 hours (median: 1.0)
Glimepiride: 0.72-1.33 hours (median: 1.04)
Warfarin: 0.5-1.0 hours (median: 0.75)
Metoprolol (sustained-release tablet); 3.7 hours acetylsalicylic acid; 0.39 hours amlodipine; 5.5 hours The porous spherical carbonaceous materials obtained in Production Example 1 of 4 can be classified as shown in Table 6.

  It is considered that the shorter the maximum blood concentration time (Tmax) is, the faster the drug is absorbed from the digestive tract. That is, there is a high possibility that the contact time with the adsorbent for oral administration in the digestive tract is also shortened. Therefore, for example, when comparing warfarin classified into group B1 and glimepiride classified into group B2 in Table 6, warfarin with a short Tmax is less likely to cause drug interaction.

  In addition, for the porous spherical carbonaceous material obtained in Production Example 2 of Examples 5 to 10, two maximum blood concentration arrival time determination values of 1 hour and 2 hours are selected and less than 1 hour 3 points, 1 hour or more and less than 2 hours as 2 points, 2 hours or more as 1 point. The results are shown in Table 7.

  As described in Non-Patent Documents 3 to 5, losartan and aspirin (acetylsalicylic acid) are administered at 1 hour after their administration, by administering an oral adsorbent, so that the maximum plasma concentration (Cmax) And the area under the drug blood concentration-time curve (AUC) is not significantly affected. Amlodipine does not affect AUC by administering an oral adsorbent 1.5 hours after its administration. These in vivo drug interaction tests and the classifications in Table 7 are well correlated, and the concomitant drugs can be classified appropriately.

  Furthermore, the method for classifying a concomitant drug of the present invention can be used as an in vitro screening method for conducting a clinical drug interaction test of a concomitant drug administered in combination with an adsorbent for oral administration. In addition, since the method for classifying a concomitant drug of the present invention has a high correlation with a clinical drug interaction test as shown in the examples described later, it can also be used as an in vitro drug interaction test. .

  Furthermore, the elution rate measurement step (1) and the adsorption rate measurement step (2) in the classification method of the present invention are performed, and the elution rate and adsorption rate of the concomitant drug are measured. It can be used as an evaluation method as a candidate compound. That is, the candidate compound can be evaluated from the elution rate and the adsorption rate even when the group (A) to the group (D) are not clearly classified by the classification step (3).

[2] Drug interaction test method The drug interaction test method of the present invention includes (1) a step of measuring the dissolution rate of a concomitant drug in a dosage form for oral administration, and (2) a concomitant drug using an adsorbent for oral administration. It is a drug interaction test method for a concomitant drug that may be administered in combination with an adsorbent for oral administration, comprising the step of measuring the adsorption rate of the drug. The elution rate measurement step (1) and the adsorption rate measurement step (2) are the “elution rate measurement step (1)” and “adsorption rate measurement step (2) described in the column“ [1] Method for classifying concomitant drugs ”. ) "Can be used without limitation.
For example, the drug interaction test method of the present invention may be performed by the “elution rate measurement step (1)” and the “adsorption rate measurement step (2)” of the continuous test method, or the “elution rate measurement step of the independent test method”. You may perform by (1) "and" adsorption rate measurement process (2). "

  The drug interaction test method of the present invention is not intended for volunteers in clinical practice but can be easily performed in vitro. In the present invention, based on the results obtained in the elution rate measurement step (1) and the adsorption rate measurement step (2), for example, a doctor, a pharmacist, a pharmaceutical research and development person, or a clinical trial person The drug interaction can be preliminarily determined. That is, it is possible to perform a drug interaction test method using a specific classification method without particularly classifying the concomitant drug.

  The drug interaction test method of the present invention comprises (3) determination of the dissolution rate obtained in the step (1) and determination of the adsorption rate obtained in the step (2). The method may further include a step of classifying the combination drug according to the combination. In the classification step (3), the “classification step (3)” described in the column “[1] Method for classifying concomitant drugs” can be used without limitation. For example, the drug interaction test method of the present invention may be performed by the “classification step (3)” of the continuous test method or the “classification step (3)” of the independent test method.

  EXAMPLES Hereinafter, the present invention will be specifically described by way of examples, but these do not limit the scope of the present invention.

<< Production Example 1: Production of Porous Spherical Carbonaceous Material >>
A porous spherical carbonaceous material (surface-modified spherical activated carbon) was obtained in the same manner as described in Example 1 of JP-A-2005-314416. The specific operation is as follows.
220 g of deionized water and 58 g of methylcellulose were placed in a 1 L separable flask, and 105 g of styrene, purity of 57% divinylbenzene (57% divinylbenzene and 43% ethylvinylbenzene) 184 g, 2,2′-azobis After adding 1.68 g of (2,4-dimethylvaleronitrile) and 63 g of 1-butanol as a porogen, the system was replaced with nitrogen gas, and this two-phase system was stirred at 200 rpm and heated to 55 ° C. And then kept for 20 hours. The obtained resin was filtered and dried on a rotary evaporator. Then, 1-butanol was removed from the resin by distillation using a vacuum dryer, and then dried under reduced pressure at 90 ° C. for 12 hours. A spherical particle having an average particle size of 180 μm was obtained. A porous synthetic resin was obtained. The specific surface area of the porous synthetic resin was about 90 m ² / g.
100 g of the obtained spherical porous synthetic resin was charged into a reaction tube with a mesh dish and subjected to infusibilization treatment in a vertical tubular furnace. The infusibilizing condition is that a spherical porous oxide resin is obtained by flowing dry air from the lower part of the reaction tube to the upper part at 3 L / min, raising the temperature to 260 ° C. at 5 ° C./h, and holding at 260 ° C. for 4 hours. Got. After heat treatment of spherical porous oxidized resin at 600 ° C. for 1 hour in a nitrogen atmosphere, activation treatment was performed at 820 ° C. for 10 hours in a nitrogen gas atmosphere containing 64.5 vol% of water vapor using a fluidized bed. Obtained. The obtained spherical activated carbon was further oxidized in a fluidized bed at 470 ° C. for 3 hours and 15 minutes in a mixed gas atmosphere of nitrogen and oxygen having an oxygen concentration of 18.5 vol%, and then in a fluidized bed under a nitrogen gas atmosphere 900 Reduction treatment was carried out at 17 ° C. for 17 minutes to obtain surface-modified spherical activated carbon.
The main characteristics of the obtained surface-modified spherical activated carbon are as follows.
Specific surface area = 1763 m ² / g (BET method);
Pore volume = 0.05 mL / g
(Pore volume in the range of 20 to 15000 nm pore diameter determined by mercury porosimetry);
Average particle size = 111 μm (Dv50);
Total acidic groups = 0.59 meq / g;
Total basic group = 0.61 meq / g;
Bulk density = 0.50 g / cm ³ ;

<< Production Example 2: Production of Porous Spherical Carbonaceous Material >>
A porous spherical carbonaceous material was obtained in the same manner as described in Example 1 of Japanese Patent No. 3522708 (Japanese Patent Laid-Open No. 2002-308785). The specific operation is as follows.
68 kg of petroleum-based pitch (softening point = 210 ° C .; quinoline insoluble content = 1 wt% or less; H / C atomic ratio = 0.63) and 32 kg of naphthalene are charged into a pressure-resistant container having an internal volume of 300 L with a stirring blade. After melt mixing at 180 ° C., the mixture was cooled to 80 to 90 ° C. and extruded to obtain a string-like molded body. Next, the string-like molded body was crushed so that the ratio of diameter to length was about 1-2.
The crushed material was put into an aqueous solution in which 0.23% by weight of polyvinyl alcohol (degree of saponification = 88%) was dissolved and heated to 93 ° C., and spheroidized by stirring and dispersing. Was replaced by water and cooled at 20 ° C. for 3 hours to solidify the pitch and precipitate naphthalene crystals to obtain a spherical pitch formed body slurry.
After most of the water was removed by filtration, naphthalene in the pitch formed body was extracted and removed with about 6 times the weight of n-hexane of the spherical pitch formed body. The porous spherical pitch obtained in this way was heated to 235 ° C. through heated air using a fluidized bed, and then oxidized by holding at 235 ° C. for 1 hour, so that it was infusible to heat. A porous spherical oxide pitch was obtained.
Subsequently, the porous spherical oxidized pitch was activated at 900 ° C. for 170 minutes in a nitrogen gas atmosphere containing 50 vol% of water vapor using a fluidized bed to obtain porous spherical activated carbon. Then, oxidation treatment is performed at 470 ° C. for 3 hours and 15 minutes in a mixed gas atmosphere of nitrogen and oxygen having an oxygen concentration of 18.5 vol%, and then reduction treatment is performed at 900 ° C. for 17 minutes in a fluidized bed under a nitrogen gas atmosphere. A porous spherical carbonaceous material was obtained.
The main characteristics of the obtained carbonaceous material are as follows.
Specific surface area = 1300 m ² / g (BET method);
Pore volume = 0.08 mL / g
(Pore volume in the range of 20 to 15000 nm pore diameter determined by mercury porosimetry);
Average particle size = 350 μm;
Total acidic groups = 0.67 meq / g;
Total basic groups = 0.54 meq / g;

In Examples 1 to 10, the classification of concomitant drugs by a continuous test method was examined.
Example 1
In this example, with respect to losartan used for the treatment of hypertension, classification of candidate compounds for drug interaction tests was examined by a continuous test method using the porous spherical carbonaceous material obtained in Production Example 1. Losartan potassium tablets were put into a dissolution tester, the dissolution rate was measured, and after 1 hour, the adsorption rate for oral administration was measured by loading the adsorbent for oral administration.
First, 17.00 g of potassium dihydrogen phosphate and 17.75 g of anhydrous disodium hydrogen phosphate were dissolved in purified water to prepare 5000 mL of pH 6.8 phosphate buffer. The resulting pH 6.8 phosphate buffer solution (5000 mL) and purified water (5000 mL) were mixed to prepare a second solution for dissolution test.
This was used as a test solution, and the test solution was heated to 41 ° C. while stirring with a stirrer, and immediately filtered with a membrane filter (Durapore ™) while stirring with suction. Mixed. Immediately after the deaeration, 900 mL of the test solution was immediately placed in a vessel of a dissolution tester (Varian 705 DS: manufactured by VARIAN) and left until the temperature of the test solution reached 37 ° C. ± 0.5 ° C. After confirming that the temperature of the test solution reached 37 ° C. ± 0.5 ° C., put a losartan potassium tablet (Neurotan ™ tablet 100 mg; Ariyu Pharmaceutical Co., Ltd.) into the vessel of the dissolution tester and paddle The number of revolutions was set to 50 revolutions per minute. The time at which stirring with the paddle was started was set as the test start (0 hour). About 10 mL of the test solution was sampled at each time point of 0.25, 0.5, and 1 hour from the start of the test, and the membrane filter (Millex ( (Trademark) -HV). The first 5 mL was discarded, the remaining filtrate was collected, and the dissolution amount of the tablets was measured.

  After sampling for 1 hour, 2.0 g of the porous spherical carbonaceous material obtained in Production Example 1 was added as an adsorbent for oral administration, and after 0.25, 0.5, 1, 2, and 3 hours. At each time point (1.25, 1.5, 2, 3, and 4 hours after the start of the test, respectively), about 10 mL of the test solution is similarly sampled, and the membrane filter (Millex ™ -HV ). The first 5 mL was discarded, the remaining filtrate was collected, and the amount of losartan remaining in the test solution was measured. This test was performed at n = 3.

The elution amount and residual amount of losartan were quantified by absorbance measurement. About the obtained sample, the light absorbency in wavelength 277.6nm was measured. As a control, the second solution for dissolution test was used. As a self-recording spectrophotometer, UV-2400PC (Shimadzu Corporation) was used.
The dissolution rate (residual rate) was calculated by the following calculation formula.

Elution rate (residual rate) (%) = {(elution amount of concomitant drug) / (dose of concomitant drug)} × 100

Adsorption rate in continuous method = {(eluting amount of concomitant drug just before the adsorbent for oral administration)-(residual amount of concomitant drug after a certain time (eluting amount))} / (combination just before the adsorbent for oral administration) Drug elution amount) x 100

The results are shown in FIG.

Example 2
In this example, regarding the glimepiride used for the treatment of non-insulin-dependent diabetes, the classification of candidate compounds for drug interaction tests was examined by the continuous test method using the porous spherical carbonaceous material obtained in Production Example 1. did.
Other than using glimepiride formulation (Amalil ™ 3 mg tablet; sanofi-aventis KK) instead of losartan potassium tablet, and using pH 8.0 phosphate buffer instead of second dissolution test Repeated the operation of Example 1 and measured the elution amount and adsorption amount of glimepiride.
The pH 8.0 phosphate buffer was prepared as follows. 27.218 g of potassium dihydrogen phosphate for pH standard solution was weighed, purified water was added to make 1 L, and a potassium dihydrogen phosphate test solution (0.2 mol / L) was prepared. Moreover, 8.0 g of sodium hydroxide was weighed and purified water was added to make 1 L, which was a sodium hydroxide solution (0.2 mol / L). To 50 mL of potassium dihydrogen phosphate test solution, 46.1 mL of sodium hydroxide solution and purified water were added to make 200 mL. A 0.2 mol / L sodium hydroxide solution was added to adjust the pH to 8.00 to obtain a pH 8.0 phosphate buffer. Since glimepiride is a poorly soluble compound and cannot be dissolved in the second dissolution test solution at a set concentration, a pH 8.0 phosphate buffer solution that has been confirmed to dissolve was used as a solvent. For dissolution, ultrasonic treatment and stirring for a certain period of time were performed.

The elution amount and adsorption amount of glimepiride were quantified by HPLC (Shimadzu Corporation) by dispensing a part of the sample into a vial. The concentration (mg / L) of glimepiride in the sample solution was automatically analyzed based on the peak area of the standard solution using LCsolution software. The measured value was output with 3 digits after the decimal point.
The analysis conditions of HPLC are as follows.

Analysis condition column: CAPCELL PAK C18 UG120 5 μm 4.6 mm ID × 150 mm (Shiseido)
Mobile phase: Mobile phase for analysis of glimepiride Column temperature: Constant temperature flow around 35 ° C Flow rate: 0.85 mL / min
Detection: UV 228 nm
Injection volume: 50 μL
Analysis time: 15 minutes (The peak retention time of glimepiride is about 10 minutes)
Sample cooler temperature: constant temperature around 25 ° C Number of injections: once per measurement sample (injected in the order of standard solution and sample solution)
Mobile phase for analysis of glimepiride: Dissolve 0.5 g of sodium dihydrogen phosphate dihydrate in 500 mL of distilled water, add 500 mL of acetonitrile, add diluted phosphoric acid (1 → 5) to adjust the pH to 3.5. Using. Degassed for 10 minutes using an ultrasonic cleaner.
The results are shown in FIG.

Example 3
In this example, with regard to warfarin used for the treatment of thromboembolism, classification of candidate compounds for drug interaction tests was examined by a continuous test method using the porous spherical carbonaceous material obtained in Production Example 1.
The procedure of Example 1 was repeated except that warfarin potassium tablets (Warfarin tablets 5 mg; Eisai Co., Ltd.) were used in place of the losartan potassium tablets, and the amount of warfarin eluted and adsorbed were measured.
The elution amount and adsorption amount of warfarin were quantified by HPLC by dispensing a part of the sample into a vial. The concentration (mg / L) of warfarin in the sample solution was automatically analyzed based on the peak area of the standard solution using LCsolution software. The measured value was output with 3 digits after the decimal point.
The analysis conditions of HPLC are as follows.

Analysis condition column: CAPCELL PAK CN UG120 5 μm 4.6 mm ID x 250 mm (Shiseido)
Mobile phase: Mobile phase column for warfarin analysis Column temperature: Constant temperature flow around 40 ° C: 2.1 mL / min
Detection: UV 280 nm
Injection volume: 50 μL
Analysis time: 15 minutes (peak retention time of warfarin is about 10 minutes)
Sample cooler temperature: Constant temperature around 4 ° C Number of injections: Once per sample (standard solution and sample solution were injected in this order)
As the mobile phase for warfarin analysis, distilled water, acetonitrile and acetic acid were mixed at a volume ratio of 68: 32: 1 and then deaerated for 10 minutes using an ultrasonic cleaner.
The results are shown in FIG.

Example 4
In this example, metoprolol used for the treatment of essential hypertension (mild to moderate) is a candidate for drug interaction test by a continuous test method using the porous spherical carbonaceous material obtained in Production Example 1. The classification of the compounds was examined.
The procedure of Example 1 was repeated except that metoprolol tartrate sustained-release tablets (Ropressol (trademark) SR tablets 120 mg; Novartis Pharma Co., Ltd.) were used instead of losartan potassium tablets, and the elution amount and adsorption amount of metoprolol Was measured.
The elution amount and adsorption amount of metoprolol were quantified by absorbance measurement. About the obtained sample, the light absorbency in wavelength 232.5nm was measured. As a control, the second solution for dissolution test was used. The results are shown in FIG.

Example 5
In this example, with respect to losartan used for the treatment of hypertension, classification of candidate compounds for drug interaction tests was examined by a continuous test method using the porous spherical carbonaceous material obtained in Production Example 2.
The procedure of Example 1 was repeated except that the porous spherical carbonaceous material obtained in Production Example 2 was used as the spherical activated carbon, and Neurotan (trademark) tablet 50 mg; MSD Co., Ltd. was used as the losartan potassium tablet. Thus, the elution amount and adsorption amount of losartan were measured.
Note that the elution amount and adsorption amount of losartan were quantified by UPLC (Waters) by dispensing a part of the sample into a vial. The concentration (mg / L) of losartan in the sample solution was automatically analyzed based on the peak area of the standard solution using Empor2 software. The measured value was output with 3 digits after the decimal point.
The UPLC analysis conditions are as follows.

Analysis condition column: ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm Column (Waters)
Mobile phase: A (water: acetonitrile: trifluoroacetic acid = 95: 5: 0.05 mixed solution)
B (water: acetonitrile: trifluoroacetic acid = 20: 80: 0.05 mixed solution)
(The product was degassed for 10 minutes using an ultrasonic cleaner.)
Column temperature: Constant temperature around 40 ° C Flow rate: 0.5 mL / min
Detection: UV 270 nm
Injection volume: 8 μL
Analysis time: 8 minutes (Losartan peak retention time is approximately 2.5 minutes)
The gradient conditions were as follows.

サンプルクーラー温度：4℃付近の一定温度
注入回数：1測定検体につき1回
（標準溶液、試料溶液の順に注入した。）
結果を図２及び表１２に示す。

Sample cooler temperature: Constant temperature around 4 ° C Number of injections: Once per sample (standard solution and sample solution were injected in this order)
The results are shown in FIG.

Example 6
In this example, regarding the glimepiride used for the treatment of non-insulin-dependent diabetes, the classification of candidate compounds for drug interaction tests was examined by the continuous test method using the porous spherical carbonaceous material obtained in Production Example 2. did.
Except that the porous spherical carbonaceous material obtained in Production Example 2 was used as the spherical activated carbon, and that the test solution was as shown below, the procedure of Example 2 was repeated, and the elution amount and adsorption amount of glimepiride Was measured.
By adding a solution obtained by dissolving 5.25 g of citric acid monohydrate in 1000 mL of purified water to 1000 mL of 0.05 mol / L disodium hydrogen phosphate test solution and adjusting the pH to 7.5, pH 7.5 hydrogen phosphate Disodium citrate buffer was prepared.
The pH 7.5 disodium hydrogen phosphate / citrate buffer was heated to 41 ° C. while stirring with a stirrer, and immediately filtered with a membrane filter (Durapore ™) while stirring under suction. Mix under vacuum for 5 minutes. Immediately after the deaeration, 890 mL of a pH 7.5 disodium hydrogen phosphate / citrate buffer solution was placed in the vessel of the dissolution tester, and 10 mL of acetonitrile was accurately added thereto. This was used as a test solution and allowed to stand at 37 ° C. ± 0.5 ° C.
The elution amount and adsorption amount of glimepiride were determined by dispensing a part of the sample into a vial, and the concentration (mg / L) of glimepiride in the sample solution quantified by HPLC was determined using the LCsolution software. What was automatically analyzed based on the peak height was adopted. The measured value was output with 3 digits after the decimal point.
The analysis conditions of HPLC are as follows.

Analysis condition column: CAPCELL PAK C18 UG120 5 μm 4.6 mm ID × 150 mm (Shiseido)
Mobile phase: Mobile phase for analysis of glimepiride Column temperature: Constant temperature flow around 25 ° C: 0.99 mL / min
Detection: UV 228 nm
Injection volume: 50 μL
Analysis time: 15 minutes (The peak retention time of glimepiride is about 10 minutes)
Sample cooler temperature: constant temperature around 25 ° C Number of injections: once per measurement sample (injected in the order of standard solution and sample solution)
Mobile phase for analysis of glimepiride: Dissolve 0.5 g of sodium dihydrogen phosphate dihydrate in 500 mL of distilled water, add 500 mL of acetonitrile, add diluted phosphoric acid (1 → 5) to adjust the pH to 3.5. Using. Degassed for 10 minutes using an ultrasonic cleaner.
The results are shown in FIG.

Example 7
In this example, with regard to warfarin used for the treatment of thromboembolism, classification of candidate compounds for drug interaction tests was examined by a continuous test method using the porous spherical carbonaceous material obtained in Production Example 2.
The procedure of Example 3 was repeated except that the porous spherical carbonaceous material obtained in Production Example 2 was used as the spherical activated carbon, and the amount of warfarin eluted and adsorbed were measured.
The elution amount and adsorption amount of warfarin were quantified by UPLC by dispensing a part of the sample into a vial. The concentration (mg / L) of warfarin in the sample solution was automatically analyzed based on the peak area of the standard solution using the software of Empor2. The measured value was output with 3 digits after the decimal point.
The UPLC analysis conditions are as follows.

Analysis condition column: ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm Column (Waters)
Mobile phase: A (water: acetonitrile: trifluoroacetic acid = 95: 5: 0.05 mixed solution)
B (water: acetonitrile: trifluoroacetic acid = 20: 80: 0.05 mixed solution)
(The product was degassed for 10 minutes using an ultrasonic cleaner.)
Column temperature: Constant temperature around 40 ° C Flow rate: 0.5 mL / min
Detection: UV 282 nm
Injection volume: 8 μL
Analysis time: 8 minutes (Warfarin peak retention time is approximately 3.3 minutes)
The gradient conditions were as follows.

サンプルクーラー温度：4℃付近の一定温度
注入回数：1測定検体につき1回
（標準溶液、試料溶液の順に注入した。）
結果を図２及び表１２に示す。

Sample cooler temperature: Constant temperature around 4 ° C Number of injections: Once per sample (standard solution and sample solution were injected in this order)
The results are shown in FIG.

Example 8
In this example, metoprolol used for the treatment of essential hypertension (mild to moderate) is a candidate for drug interaction test by a continuous test method using the porous spherical carbonaceous material obtained in Production Example 2. The classification of the compounds was examined.
The procedure of Example 4 was repeated except that the porous spherical carbonaceous material obtained in Production Example 2 was used as the spherical activated carbon, and the elution amount and adsorption amount of metoprolol were measured.
The elution amount and adsorption amount of metoprolol were quantified by UPLC by dispensing a part of the sample into a vial. As the concentration (mg / L) of metoprolol in the sample solution, one automatically analyzed based on the peak area of the standard solution using Emper2 software was adopted. The measured value was output with 3 digits after the decimal point.
The UPLC analysis conditions are as follows.

Analysis condition column: ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm Column (Waters)
Mobile phase: A (water: acetonitrile: trifluoroacetic acid = 95: 5: 0.05 mixed solution)
B (water: acetonitrile: trifluoroacetic acid = 20: 80: 0.05 mixed solution)
(The product was degassed for 10 minutes using an ultrasonic cleaner.)
Column temperature: Constant temperature around 40 ° C Flow rate: 0.5 mL / min
Detection: UV 275 nm
Injection volume: 8 μL
Analysis time: 8 minutes (metoprolol peak retention time is about 1.7 minutes)
The gradient conditions were as follows.

サンプルクーラー温度：4℃付近の一定温度
注入回数：1測定検体につき1回
（標準溶液、試料溶液の順に注入した。）
結果を図２及び表１２に示す。

Sample cooler temperature: Constant temperature around 4 ° C Number of injections: Once per sample (standard solution and sample solution were injected in this order)
The results are shown in FIG.

Example 9
In this example, for acetylsalicylic acid used for the treatment of angina pectoris, the classification of candidate compounds for drug interaction tests was examined by a continuous test method using the porous spherical carbonaceous material obtained in Production Example 2. .
Example 1 except that an aspirin tablet (Bafarin Combination Tablets A81; Lion Co., Ltd.) was used instead of the losartan potassium tablet, and the porous spherical carbonaceous material obtained in Production Example 2 was used as a spherical activated carbon. These procedures were repeated to measure the elution amount and adsorption amount of acetylsalicylic acid.
In addition, the elution amount and adsorption amount of acetylsalicylic acid were quantified by HPLC by dispensing a part of the sample into a vial. The concentration (mg / L) of acetylsalicylic acid in the sample solution was automatically analyzed based on the peak area of the standard solution using LCsolution software. The measured value was output with 3 digits after the decimal point.
The analysis conditions of HPLC are as follows.

Analysis condition column: Inertsil ODS-3 3 μm 2.1 mm x 100 mm (GL Sciences Inc.)
Mobile phase: mobile phase for acetylsalicylic acid analysis Column temperature: constant temperature flow around 45 ° C: 0.3 mL / min
Detection: UV 274 nm
Injection volume: 10 μL
Analysis time: 10 minutes (Acetylsalicylic acid peak retention time is about 3.2 minutes)
Sample cooler temperature: Constant temperature around 4 ° C Number of injections: Once per sample (standard solution and sample solution were injected in this order)
Acetylsalicylic acid analysis mobile phase: 5 mL of phosphoric acid was accurately collected, and distilled water was added to make 1000 mL (0.5 Vol% phosphoric acid solution). A 0.5 Vol% phosphoric acid solution and methanol were mixed at a ratio of 6: 4, and then degassed for 10 minutes using an ultrasonic cleaner.
The results are shown in FIG.

Example 10
In this example, for amlodipine used for the treatment of hypertension, classification of candidate compounds for drug interaction tests was examined by a continuous test method using the porous spherical carbonaceous material obtained in Production Example 2.
Other than using amlodipine besylate tablets (Norbasque (trademark) tablets 5 mg; Pfizer Co., Ltd.) instead of losartan potassium tablets, and using the porous spherical carbonaceous material obtained in Production Example 2 as spherical activated carbon The procedure of Example 1 was repeated to measure the amlodipine elution amount and adsorption amount. However, the sampled test solution was centrifuged at 3500 rpm for 5 minutes, and the supernatant was collected as a sample solution.
In addition, the elution amount and adsorption amount of amlodipine were mixed with an equal amount of the sample solution and the following mobile phase for amlodipine analysis, and a part thereof was dispensed into a vial and quantified by HPLC. The amlodipine concentration (mg / L) in the sample solution was automatically analyzed based on the peak area of the standard solution using LCsolution software. The measured value was output with 3 digits after the decimal point.
The analysis conditions of HPLC are as follows.

Analysis condition column: CAPCELL PAK C18 UG120 5 μm 4.6 mm ID × 150 mm (Shiseido)
Mobile phase: Amlodipine analysis mobile phase Column temperature: Constant temperature flow around 40 ° C Flow rate: 1.5 mL / min
Detection: UV 237 nm
Injection volume: 50 μL
Analysis time: 10 minutes (Amlodipine peak retention time is approximately 5.1 minutes)
Sample cooler temperature: Constant temperature around 4 ° C Number of injections: Once per sample (standard solution and sample solution were injected in this order)
Amlodipine mobile phase for analysis: 7.0 mL of triethylamine was added to 900 mL of distilled water, and the pH was adjusted to 3.0 ± 0.1 using phosphoric acid. Distilled water was added to this to make exactly 1000 mL (Buffer A). Methanol, acetonitrile, and Buffer A were mixed at a volume ratio of 7: 3: 10, and then degassed for 10 minutes using an ultrasonic cleaner.
The results are shown in FIG.

<Classification>
The elution judgment value was 50% after 30 minutes of the time between injections (30 minutes), and the adsorption judgment value was 30% after 15 minutes of oral administration. Losartan of Example 1 performed on the porous spherical carbonaceous material obtained in Production Example 1 was classified into Group A having a high elution rate and a low adsorption rate. Glimepiride of Example 2 and warfarin of Example 3 were classified into Group B, which has a high elution rate and a high adsorption rate. Moreover, the metoprolol of Example 4 was classified into Group D, which has a low elution rate and a high adsorption rate.

  Further, in the classification method performed on the porous spherical carbonaceous material obtained in Production Example 2, two elution determination values were selected and scored for classification. The first elution judgment value is 60% after elapse of ½ of the input interval time, the second elution judgment value is 40% after ½ of the input interval time, and the elution rate is 60% or more. 3 points, 40% or more and less than 60% were 2 points, and less than 40% were 1 point. Also, the adsorption determination value was 30% after 30 minutes from the introduction of the adsorbent for oral administration, with 2 points less than 30% and 1 point 30% or more. Losartan of Example 5, Warfarin of Example 7, and Acetylsalicylic acid of Example 9 were classified into Group A of 5 points. Moreover, the glimepiride of Example 6 and the amlodipine of Example 10 were classified into the 4-group B. The metoprolol of Example 8 was classified into 3 points group C.

In Examples 11 to 20, classification of concomitant drugs by independent test methods was examined.
Example 11
In this example, with respect to losartan used for the treatment of hypertension, classification of candidate compounds for drug interaction test was examined by an independent test method using the porous spherical carbonaceous material obtained in Production Example 1. Losartan potassium tablets were put into a dissolution tester and the dissolution rate was measured. Moreover, the adsorption | suction speed | velocity | rate by the adsorption agent for oral administration of a losartan was measured by throwing into the dissolution tester the solution which melt | dissolved the potassium losartan, and the adsorption agent for oral administration.
The elution rate was measured as follows.
The second dissolution test solution (hereinafter referred to as test solution) was heated to 41 ° C. while stirring with a stirrer, and immediately filtered with a membrane filter (Durapore ™) while stirring under suction. Mix under vacuum for 5 minutes. Immediately after the deaeration, 900 mL of the test solution was immediately placed in the vessel of the dissolution tester and left until the temperature of the test solution reached 37 ° C. ± 0.5 ° C. After confirming that the temperature of the test solution reached 37 ° C. ± 0.5 ° C., put a losartan potassium tablet (Neurotan ™ tablet 100 mg; Ariyu Pharmaceutical Co., Ltd.) into the vessel of the dissolution tester and paddle The number of revolutions was set to 50 revolutions per minute. The time point at which stirring with the paddle was started was set as the test start (0 hour). About 10 mL of the test solution was sampled at each time point of 0.25, 0.5, 1, 2, and 3 hours from the start of the test. Filtered through a filter (Millex ™ -HV). The first 5 mL was discarded, the remaining filtrate was collected, and the dissolution amount of the tablets was measured. This test was performed at n = 2.

The adsorption rate was measured as follows.
About 111.1 mg of losartan potassium (manufactured by AK Scientific) was weighed and the second solution of dissolution test was added to make exactly 1000 mL to prepare an 111.1 mg / L losartan potassium solution.
The test solution was heated to 41 ° C. while stirring with a stirrer, immediately filtered with a membrane filter (Durapore ™) while stirring under suction, and further mixed under reduced pressure for 5 minutes. Immediately after the deaeration, 900 mL of the losartan potassium solution was immediately put into the vessel of the dissolution tester and allowed to stand until the temperature of the test solution reached 37 ° C. ± 0.5 ° C. After confirming that the temperature of the test solution reached 37 ° C. ± 0.5 ° C., 2.0 g of the porous spherical carbonaceous material obtained in Production Example 1 was adsorbed into the vessel of the dissolution tester for oral administration. The paddle was rotated at a rate of 50 revolutions per minute. When the porous spherical carbonaceous material is added, the test is started (0 hour), and approximately 10 mL of the test solution is sampled at each time point of 0.25, 0.5, 1, 2, and 3 hours from the start of the test. And filtered through a membrane filter (Millex ™ -HV). The first 5 mL was discarded, the remaining filtrate was collected, and the amount of losartan remaining in the test solution was measured. This test was performed at n = 3.

Losartan elution amount and adsorption amount were quantified by absorbance measurement in the same manner as in Example 1.

Elution rate (residual rate) (%) = {(elution amount of concomitant drug) / (dose of concomitant drug)} × 100

Adsorption rate in independent test method = {(dissolved amount of concomitant drug) − (residual amount of concomitant drug after a certain time)} / (dissolved amount of concomitant drug) × 100

The results are shown in FIGS. 3 and 4 and Tables 13 and 14.

Example 12
In this example, regarding the glimepiride used for the treatment of non-insulin-dependent diabetes, the classification of candidate compounds for drug interaction tests was examined by the independent test method using the porous spherical carbonaceous material obtained in Production Example 1. did. The glimepiride preparation was put into a dissolution tester and the dissolution rate was measured. Moreover, the adsorption | suction speed | velocity | rate by the adsorbent for oral administration of glimepiride was measured by throwing into the dissolution tester the solution which melt | dissolved glimepiride, and the adsorbent for oral administration.
Instead of losartan potassium tablets, glimepiride preparation (Amalil ™ 3 mg tablets; sanofi-aventis Co., Ltd.) was used, glimepiride (Sigma Aldrich Japan Co., Ltd.) was used instead of losartan potassium, and dissolution test The procedure of Example 11 was repeated except that the pH 8.0 phosphate buffer was used instead of the second solution, and the elution amount and adsorption amount of glimepiride were measured.
The glimepiride solution was dissolved by weighing about 3.3 mg of glimepiride (Sigma Aldrich Japan Co., Ltd.), adding an appropriate amount of pH 8.0 phosphate buffer and sonicating, and stirring for 1 hour or more. After confirming that it was visually dissolved, a pH 8.0 phosphate buffer solution was added to make exactly 1000 mL, and a 3.3 mg / L glimepiride solution was obtained.
The elution amount and adsorption amount of glimepiride were measured by HPLC as in Example 2.
The results are shown in FIGS. 3 and 4 and Tables 13 and 14.

Example 13
In this example, with regard to warfarin used for the treatment of thromboembolism, classification of candidate compounds for drug interaction tests was examined by an independent test method using the porous spherical carbonaceous material obtained in Production Example 1. Warfarin potassium tablets were put into a dissolution tester and the dissolution rate was measured. Separately, a solution of warfarin sodium dissolved in an elution tester and an adsorbent for oral administration were used to measure the adsorption rate of warfarin by the adsorbent for oral administration.
Example except that warfarin potassium tablet (Warfarin tablet 5 mg; Eisai Co., Ltd.) was used instead of losartan potassium tablet, and warfarin sodium (Tokyo Chemical Industry Co., Ltd.) was used instead of losartan potassium. The procedure of 11 was repeated, and the amount of warfarin eluted and the amount adsorbed were measured.
The warfarin solution weighed about 5.3 mg of warfarin sodium (Tokyo Kasei Kogyo Co., Ltd.) and added the second solution of dissolution test to make exactly 1000 mL, to obtain a 5.3 mg / L warfarin sodium solution. The molecular weight of potassium was corrected, and the content of warfarin (free body) in 1 tablet of 5 mg warfarin tablet and the amount of warfarin (free body) in 1 vessel (900 mL) in this experiment were set to be the same amount. (Warfarin potassium: molecular weight 346.4183, warfarin: molecular weight 308.332794, warfarin sodium: molecular weight 330.30976769)
The amount of warfarin eluted and adsorbed was quantified by HPLC as in Example 3.
The results are shown in FIGS. 3 and 4 and Tables 13 and 14.

Example 14
In this example, metoprolol used for the treatment of essential hypertension (mild to moderate) is a candidate for drug interaction test by an independent test method using the porous spherical carbonaceous material obtained in Production Example 1. The classification of the compounds was examined. Metoprolol tartrate sustained-release tablets were placed in a dissolution tester and the dissolution rate was measured. Separately, a solution of metoprolol tartrate (isomer mixture) (Wako Pure Chemical Industries, Ltd.) dissolved in an elution tester and an adsorbent for oral administration are used. The adsorption rate was measured.
The procedure of Example 11 was repeated except that metoprolol tartrate sustained-release tablets (Ropressol (trademark) SR tablets 120 mg; Novartis Pharma Co., Ltd.) were used instead of losartan potassium tablets, and the elution amount and adsorption amount of metoprolol Was measured.
The metoprolol tartrate solution weighed about 133.3 mg of metoprolol tartrate, added the second dissolution test solution to make exactly 1000 mL, and prepared a 133.3 mg / L metoprolol tartrate solution.
The elution amount and adsorption amount of metoprolol were quantified by absorbance measurement in the same manner as in Example 4.
The results are shown in FIGS. 3 and 4 and Tables 13 and 14.

Example 15
In this example, with respect to losartan used for the treatment of hypertension, the classification of candidate compounds for drug interaction tests was examined by an independent test method using the porous spherical carbonaceous material obtained in Production Example 2. Losartan potassium tablets were put into a dissolution tester and the dissolution rate was measured. Moreover, the adsorption | suction speed | velocity | rate by the adsorption agent for oral administration of a losartan was measured by throwing into the dissolution tester the solution which melt | dissolved the potassium losartan, and the adsorption agent for oral administration.
The procedure of Example 11 was repeated except that the porous spherical carbonaceous material obtained in Production Example 2 was used as the spherical activated carbon, and Neurotan (trademark) tablet 50 mg; MSD Co., Ltd. was used as the losartan potassium tablet. Thus, the elution amount and adsorption amount of losartan were measured.
Losartan potassium solution weighed 55.6 mg of losartan potassium and added the second dissolution test solution to make exactly 1000 mL, resulting in a 55.6 mg / L losartan potassium solution.
Losartan elution amount and adsorption amount were measured by UPLC in the same manner as in Example 5.
The results are shown in FIGS. 5 and 6 and Tables 15 and 16.

Example 16
In this example, for glimepiride used for treatment of non-insulin-dependent diabetes, the classification of candidate compounds for drug interaction tests was examined by an independent test method using the porous spherical carbonaceous material obtained in Production Example 2. did. The glimepiride preparation was put into a dissolution tester and the dissolution rate was measured. Moreover, the adsorption | suction speed | velocity | rate by the adsorbent for oral administration of glimepiride was measured by throwing into the dissolution tester the solution which melt | dissolved glimepiride, and the adsorbent for oral administration.
Except that the porous spherical carbonaceous material obtained in Production Example 2 was used as the spherical activated carbon, and that the test solution was as shown below, the procedure of Example 12 was repeated, and the elution amount and adsorption amount of glimepiride Was measured.
A test solution for measuring the dissolution rate of the glimepiride preparation was prepared in the same manner as in Example 6. Moreover, the glimepiride solution was prepared by the following method. A solution of 3.0 mg of glimepiride and made exactly 10 mL by adding acetonitrile was used as an acetonitrile solution. After putting 890 mL of pH 7.5 disodium hydrogen phosphate citrate buffer into the vessel of the dissolution tester in the same manner as in Example 6, accurately measure 10 mL of this acetonitrile solution and add it to the vessel. A 3.3 mg / L glimepiride solution was prepared.
The elution amount and adsorption amount of glimepiride were measured by HPLC as in Example 6.
The results are shown in FIGS. 5 and 6 and Tables 15 and 16.

Example 17
In this example, with regard to warfarin used for the treatment of thromboembolism, classification of candidate compounds for drug interaction tests was examined by an independent test method using the porous spherical carbonaceous material obtained in Production Example 2. Warfarin potassium tablets were put into a dissolution tester and the dissolution rate was measured. Separately, a solution of warfarin sodium dissolved in an elution tester and an adsorbent for oral administration were used to measure the adsorption rate of warfarin by the adsorbent for oral administration.
Except that the porous spherical carbonaceous material obtained in Production Example 2 was used as the spherical activated carbon, the procedure of Example 13 was repeated to measure the amount of warfarin eluted and adsorbed.
The elution amount and adsorption amount of warfarin were measured by UPLC as in Example 7.
The results are shown in FIGS. 5 and 6 and Tables 15 and 16.

Example 18
In this example, metoprolol used for the treatment of essential hypertension (mild to moderate) is a candidate for drug interaction test by an independent test method using the porous spherical carbonaceous material obtained in Production Example 2. The classification of the compounds was examined. Metoprolol tartrate tablets were put into a dissolution tester and the dissolution rate was measured. Separately, a solution of metoprolol tartrate dissolved in a dissolution tester and an adsorbent for oral administration were used to measure the adsorption rate of metoprolol by the adsorbent for oral administration.
The procedure of Example 14 was repeated except that the porous spherical carbonaceous material obtained in Production Example 2 was used as the spherical activated carbon, and the elution amount and adsorption amount of metoprolol were measured.
The elution amount and adsorption amount of metoprolol were measured by UPLC as in Example 8.
The results are shown in FIGS. 5 and 6 and Tables 15 and 16.

Example 19
In this example, for acetylsalicylic acid used for the treatment of angina pectoris, the classification of candidate compounds for drug interaction tests was examined by an independent test method using the porous spherical carbonaceous material obtained in Production Example 2. . Aspirin tablets were put into a dissolution tester and the dissolution rate was measured. Separately, a solution in which acetylsalicylic acid was dissolved in an elution tester and an adsorbent for oral administration were added to measure the adsorption rate of acetylsalicylic acid by the adsorbent for oral administration.
The amount of acetylsalicylic acid eluted by repeating the procedure of Example 11 except that an aspirin tablet was used instead of the losartan potassium tablet, and the porous spherical carbonaceous material obtained in Production Example 2 was used as a spherical activated carbon. And the amount of adsorption was measured.
About 90 mg of acetylsalicylic acid solution weighed about 90 mg of acetylsalicylic acid, and added the second solution of dissolution test to make exactly 1000 mL to prepare a 90 mg / L acetylsalicylic acid solution.
The elution amount and adsorption amount of acetylsalicylic acid were measured by HPLC in the same manner as in Example 9.
The results are shown in FIGS. 5 and 6 and Tables 15 and 16.

Example 20
In this example, for amlodipine used for the treatment of hypertension, the classification of candidate compounds for drug interaction tests was examined by an independent test method using the porous spherical carbonaceous material obtained in Production Example 2. Amlodipine besylate tablets were put into a dissolution tester and the dissolution rate was measured. Separately, a solution of amlodipine besylate dissolved in an elution tester and an adsorbent for oral administration were used to measure the adsorption rate of amlodipine by the adsorbent for oral administration.
Example 11 The amount of elution and the amount of adsorption were measured. However, the sampled test solution was centrifuged at 3500 rpm for 5 minutes, and the supernatant was recovered and used as a sample solution.
The amlodipine solution weighed about 7.7 mg of amlodipine, and added the second solution of dissolution test to make exactly 1000 mL to prepare a 5.56 mg / L amlodipine solution. Correct the molecular weight of besylate so that the content of amlodipine (free form) in 1 tablet of Norvasc (registered) tablets 5 mg is the same as the amount of amlodipine (free form) in 1 vessel (900 mL) in this experiment. Set. (Amlodipine besylate: molecular weight 567.05094, amlodipine: molecular weight 408.8759)
The amount of amlodipine eluted and adsorbed was measured by HPLC as in Example 10.
The results are shown in FIGS. 5 and 6 and Tables 15 and 16.

<Classification>
The elution judgment value was set to 50% after 30 minutes from the introduction of the concomitant drug, and the adsorption judgment value was taken to be 50% after 15 minutes from the introduction of the adsorbent for oral administration. Losartan of Example 11 performed on the porous spherical carbonaceous material obtained in Production Example 1 was classified into Group A, which has a high elution rate and a low adsorption rate. The glimepiride of Example 12 and the warfarin of Example 13 were classified into Group B, which has a high elution rate and a high adsorption rate. Moreover, the metoprolol of Example 14 was classified into Group D, which has a low elution rate and a high adsorption rate.

  In addition, in the classification method performed on the porous spherical carbonaceous material obtained in Production Example 2, two elution judgment values of elution rate 60% and 40% after 30 minutes of the combined drug injection are selected, and 60% or more 3 points, 2 points for 40% or more and less than 60%, and 1 point for less than 40%. Also, the adsorption determination value was 30% after 30 minutes from the introduction of the adsorbent for oral administration, with 2 points less than 30% and 1 point 30% or more. Losartan of Example 15 and glimepiride of Example 16 were classified into Group A of 5 points. The warfarin of Example 17 and the acetylsalicylic acid of Example 19 were classified into Group B of 4 points. Moreover, the amlodipine of Example 20 was classified into 3 points of group C. In addition, the metoprolol of Example 18 was classified into two point group D.

  The classification method of the present invention can determine the drug interaction between the adsorbent for oral administration and the drug used in combination in vitro, and can greatly reduce the implementation of clinical drug interaction tests. it can. That is, it is possible to greatly reduce the time and cost required to develop a new drug for an adsorbent for oral administration. Furthermore, it is useful as a drug interaction test in vitro.

Claims (14)

A classification method for clinical drug interaction studies of concomitant drugs that may be co-administered with an adsorbent for oral administration,
(1) a step of measuring the dissolution rate of a concomitant drug in a dosage form for oral administration;
(2) measuring the adsorption rate of the concomitant drug by the orally administered adsorbent, and (3) determining the elution rate and determining the adsorbing rate, and classifying the concomitant drug according to the combination of these determinations,
A method for classifying a concomitant drug, comprising: (1) The determination of the elution rate is to determine a concomitant drug into two or more groups based on the elution rate, and the determination of the adsorption rate is to determine two or more groups based on the adsorption rate. Or (2) The determination of the elution rate is performed by quantifying the elution rate, and the determination of the adsorption rate is performed by quantifying the adsorption rate.
The method for classifying a concomitant drug according to claim 1. A continuous test method in which the step (1) and the step (2) are continuously performed,
The step (1) is a step in which a concomitant drug in the dosage form for oral administration is put into a dissolution tester and the dissolution rate is measured, and the dissolution test is performed when the injection interval time has elapsed. The method for classifying a concomitant drug according to claim 1 or 2, wherein the adsorbent for oral administration is charged into a vessel and the adsorption rate of the concomitant drug by the adsorbent for oral administration is measured. An independent test method in which the step (1) and the step (2) are performed discontinuously,
The step (1) is a step in which the combined drug in a dosage form for oral administration is put into a dissolution tester and the dissolution rate is measured, and the step (2) is filled with a solution in which the combined drug is dissolved. The method for classifying a concomitant drug according to claim 1 or 2, wherein the adsorbent for oral administration is loaded into the dissolution tester and the adsorption rate of the concomitant drug by the adsorbent for oral administration is measured. In the determination of the elution rate, one or more elution rates between 5 and 95% are selected as elution determination values in any one determination time between 1/6 elapse of the input interval time and the total elapse time. The combination drug is determined into two or more groups based on the elution determination value.
Then, the determination of the adsorption rate is performed by using the adsorption rate when the amount of drug elution immediately before the adsorbent for oral administration is set to 100, and any one determination between 5 and 180 minutes after the adsorbent for oral administration is charged In time, any one or more adsorption rate between 5 to 95% is selected as the adsorption determination value, and the combination drug is determined into two or more groups by the adsorption determination value.
The method for classifying a concomitant drug according to claim 3. In the determination of the elution rate, any one or more elution rates between 5 and 95% are selected as elution determination values in any one determination time between 5 and 90 minutes after the concomitant drug is introduced. , To determine the concomitant drugs into two or more groups based on the elution determination value,
The determination of the adsorption rate selects any one adsorption rate between 5% and 95% as an adsorption determination value in any one determination time between 5 and 180 minutes after charging the adsorbent for oral administration. The combination drug is determined into two or more groups based on the adsorption determination value.
The method for classifying a concomitant drug according to claim 4.   When n elution judgment values are selected, the concomitant drug is judged to be (n + 1) groups, scored in descending order from the group with the highest elution rate to the lower group, and when m adsorption judgment values are selected, the concomitant drug 7 or (m + 1) is determined, points are assigned in descending order from a group having a low adsorption rate to a group having a high adsorption rate, and the concomitant drugs are classified based on the points obtained by adding the points of the dissolution rate and the points of the adsorption rate. Classification method of concomitant drugs described in 1.   The classification step (3) is a step of determining the maximum blood concentration arrival time and classifying the combination drug by a combination of determination of elution rate, determination of adsorption rate and determination of maximum blood concentration arrival time. Item 8. The method for classifying a concomitant drug according to any one of Items 1-7.   In determining the maximum blood concentration arrival time, one or more times are selected as the maximum blood concentration arrival time determination value, and the combination drug is determined into two or more groups based on the maximum blood concentration arrival time determination value. The method for classifying a concomitant drug according to claim 8, wherein   In determining the maximum blood concentration arrival time, one or more times are selected as the maximum blood concentration arrival time determination value, and the combination drug is determined into two or more groups based on the maximum blood concentration arrival time determination value. In the case of selecting one of the above-mentioned maximum blood concentration arrival time judgment values, the concomitant drug is determined to be the group (l + 1), and scored in descending order from the shortest to the longest blood concentration reaching group. 10. The method for classifying a concomitant drug according to claim 9, wherein the concomitant drug is classified based on a score obtained by adding the score of the elution rate, the score of the adsorption rate, and the score of the time to reach the maximum blood concentration. (1) a step of measuring the dissolution rate of the concomitant drug in the dosage form for oral administration, and (2) a step of measuring the adsorption rate of the concomitant drug by the adsorbent for oral administration.
A drug interaction test method for a concomitant drug that may be administered in combination with an adsorbent for oral administration, comprising: (3) The determination of the elution rate obtained in the step (1) and the determination of the adsorption rate obtained in the step (2) are further performed, and the method further includes the step of classifying the concomitant drugs according to the combination of the determinations. The drug interaction test method according to claim 11. A continuous test method in which the step (1) and the step (2) are continuously performed,
The step (1) is a step in which a concomitant drug in the dosage form for oral administration is put into a dissolution tester and the dissolution rate is measured. The drug interaction test method according to claim 11 or 12, which is a step of introducing an adsorbent for oral administration into a vessel and measuring the adsorption rate of the concomitant drug by the adsorbent for oral administration. An independent test method in which the step (1) and the step (2) are performed discontinuously,
The step (1) is a step in which the combined drug in a dosage form for oral administration is put into a dissolution tester and the dissolution rate is measured, and the step (2) is filled with a solution in which the combined drug is dissolved. The drug interaction test method according to claim 11 or 12, which is a step of introducing an oral administration adsorbent into the dissolution tester and measuring the adsorption rate of the concomitant drug by the oral administration adsorbent.

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