Safer medicine and application thereof

Abstract

The invention provides a safer medicine and application thereof, and provides a safer medicine composition without sudden cardiac death toxicity and application thereof. The safer medicine provided by the invention is a compound preparation containing the 5-hydroxytryptamine receptor antagonist and diltiazem, and can effectively avoid the possibility of corresponding arrhythmia and sudden cardiac death caused by ventricular depolarization and repolarization disorder caused by the 5-hydroxytryptamine receptor antagonist ondansetron. The invention also provides application of diltiazem in preparation of medicines for improving cardiac electrical activity and a corresponding treatment method.

Description

[0001] This application is a divisional application with application number 2022112054079, application date September 30, 2022, and patent name "A safer drug and its application". Technical Field

[0002] The present application belongs to the field of western medicine. Specifically, the present application relates to a safer drug and its application, and in particular to a new compound drug containing ondansetron and diltiazem and its application, which can effectively prevent ondansetron from causing arrhythmia or sudden cardiac death. Background Art

[0003] Ondansetron, English name Ondansetron, chemical name is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4-one, chemical formula is C 18 H 19 N 3 O is a highly selective 5-hydroxytryptamine (5-HT3) receptor antagonist with high strength and selectivity, which can control vomiting caused by the stimulation of receptors in the small intestine and CTZ. At the same time, ondansetron can also enhance gastric emptying at antiemetic doses, which helps to relieve nausea; it also has an antianxiety effect on the central nervous system, which helps to inhibit the excitement of the vomiting center. Ondansetron is currently a first-line antiemetic drug used at home and abroad. It is widely used clinically to prevent or treat nausea and vomiting caused by chemotherapy drugs (such as cisplatin, doxorubicin, etc.), radiotherapy, surgery or anesthesia.

[0004] The QT interval is a key part of the surface electrocardiogram, and disturbances in cardiac electrical activity are associated with a potentially fatal arrhythmia, torsade de pointes (TdP), and sudden cardiac death. For every 10 ms increase in the patient's QT interval, the risk of progression to TdP increases by 5%-7%. It is generally believed that when the absolute QT interval is >500 ms, the risk increases significantly and necessary intervention measures should be considered.

[0005] In patients treated with ondansetron, there have been reports of transient electrocardiographic changes including cardiac electrical activity disturbances. In addition, in post-marketing case reports, patients treated with ondansetron have experienced torsades de pointes (the FDA issued a special warning on this in 2012). Randomized, double-blind, cross-controlled clinical trials from the United States have confirmed that cardiac electrical activity disturbances caused by ondansetron are dose-dependent, especially for a single intravenous dose of 32 mg. After baseline correction, the maximum mean difference in cardiac electrical activity disturbances was 20 ms compared with placebo, while the maximum mean difference was 6 ms at a lower dose (8 mg) of intravenous injection. Patients with high-risk factors for cardiac electrical activity disturbances (suffering from congenital cardiac electrical activity disorder syndrome, congestive heart failure, bradyarrhythmias, or concurrent use of drugs that can cause ventricular depolarization and repolarization disturbances) are more likely to induce severe arrhythmias or even sudden death when using ondansetron. Therefore, it is generally required that a single intravenous dose of ondansetron should not exceed 16 mg. GlaxoSmithKline and other companies have also revised the ondansetron drug instructions, deleting the 32mg single intravenous dose. Figure 1 , Fig.11 ) presents ondansetron adverse events and the FDA’s response.

[0006] like Figure 1 As shown, according to statistics from the eHealthMe website based on medical big data and artificial intelligence algorithms, as of July 19, 2022, 83,849 people reported side effects while using ondansetron, of which 3,448 (4.11%) died. A. shows the number of people who reported side effects from taking ondansetron each year; B. shows the number of people who died each year. Summary of the invention

[0007] Although the adjusted dosage recommendation can reduce the probability of ondansetron causing arrhythmias to a certain extent, it does not fundamentally avoid this possibility. Patients using this drug, especially those at high risk of congenital long QT syndrome or other underlying diseases, still have considerable risks.

[0008] In view of the above problems, the applicant used the pluripotent stem cell cardiac electrophysiology research and development platform to design a new antiemetic drug that eliminates the cardiac toxic side effects of fatal arrhythmias, and found that diltiazem can effectively avoid the disorder of cardiac electrical activity caused by ondansetron, thereby reducing the possibility of arrhythmias, sudden cardiac death and other problems. On the one hand, the present application provides a new safe antiemetic drug (improved new drug) with reduced cardiac electrical activity disorder, which includes a 5-hydroxytryptamine receptor antagonist and diltiazem.

[0009] Furthermore, the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

[0010] Furthermore, the 5-hydroxytryptamine receptor antagonist is ondansetron.

[0011] Furthermore, the novel safe drug is a compound preparation.

[0012] Furthermore, the mass ratio of the serotonin receptor antagonist to diltiazem in the novel safe drug is 180:1 to 1:4.

[0013] Furthermore, the mass ratio of the serotonin receptor antagonist to diltiazem in the novel safe drug is 35:1 to 5:1.

[0014] Furthermore, the mass ratio of the serotonin receptor antagonist to diltiazem in the novel safe drug is 24:1 to 12:1.

[0015] Furthermore, the new safe drug (improved new drug) can be an oral preparation or injection, a local application preparation, a spray, etc.; oral preparations include capsules, oral liquids, tablets; injections include injections and powder injections.

[0016] On the other hand, the present application provides the use of diltiazem in preparing a medicament for reducing cardiac electrical activity disorder.

[0017] Furthermore, the cardiac electrical activity disorder is a cardiac electrical activity disorder caused by 5-hydroxytryptamine receptor antagonism.

[0018] Furthermore, the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

[0019] Furthermore, the 5-hydroxytryptamine receptor antagonist is ondansetron.

[0020] Furthermore, the drug is an oral preparation or an injection, a local application preparation, a spray, etc.; oral preparations include capsules, oral liquids, and tablets; injections include injections and powder injections.

[0021] Further, the administration dose of diltiazem is 1-60 mg for a single oral formulation or 0.0002-0.35 mg / kg for injection.

[0022] Further, the administration dose of diltiazem is 1-30 mg for a single oral preparation or 0.0005-0.15 mg / kg for injection.

[0023] Furthermore, the blood concentration of diltiazem in the compound preparation after entering the human body is 0.4 μg / L-300 μg / L.

[0024] Furthermore, the blood concentration of diltiazem in the compound preparation after entering the human body is 2 μg / L-130 μg / L.

[0025] Furthermore, the blood concentration of diltiazem in the compound preparation after entering the human body is 4 μg / L-50 μg / L.

[0026] In another aspect, the present application provides a method for reducing cardiac electrical activity disturbances, comprising administering diltiazem to a subject at risk of, or having symptoms of, cardiac electrical activity disturbances.

[0027] Furthermore, the subject is a human.

[0028] Furthermore, the subject is a female.

[0029] Furthermore, the cardiac electrical activity disorder is a cardiac electrical activity disorder caused by 5-hydroxytryptamine receptor antagonism.

[0030] Furthermore, the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

[0031] Furthermore, the 5-hydroxytryptamine receptor antagonist is ondansetron.

[0032] Further, the administration dose of diltiazem is 1-60 mg for a single oral preparation or 0.0002-0.35 mg / kg for injection.

[0033] Further, the administration dose of diltiazem is 1-30 mg for a single oral preparation or 0.0005-0.15 mg / kg for injection.

[0034] Furthermore, the frequency and duration of administration of diltiazem is once to six times a day, for 1-14 consecutive days.

[0035] Furthermore, the frequency and duration of administration of diltiazem is once to four times a day, for 1-7 consecutive days.

[0036] The English name of ondansetron in this application is Ondansetron, the corresponding CAS number is 99614-02-5, and the molecular formula is C 18 H 19 N 3 O; the English name of diltiazem in this application is Diltiazem, the corresponding CAS number is 42399-41-7, and the molecular formula is C 22 H 26 N 2 O 4 S; The above-mentioned numbers, names and various hydrochlorides or other salts, other aliases and trade names of products on the market, including but not limited to Hexinshuang, Hebaoshuang, Tianerxin, Debaoxing, etc. can be used interchangeably to represent the same drug.

[0037] In the present application, 5-hydroxytryptamine and 5-HT represent the same meaning and can be used interchangeably.

[0038] Ondansetron and diltiazem in the present application can be prepared in the same pharmaceutical composition; can also be provided in the form of two drugs in the same package; can also be packaged separately and used in combination when used; various feasible combination forms known in the art are applicable to the present invention.

[0039] The dosage forms applicable in the present application include, but are not limited to, oral preparations and injections. The compound preparations, ondansetron preparations and diltiazem preparations of the present application can be applicable to any specific dosage forms acceptable clinically, including, but not limited to, tablets, capsules, oral liquids, injections, powder injections, topical preparations, sprays, etc. When the ondansetron preparation and the diltiazem preparation are provided separately in the same package or in various packages, the dosage forms of the two may be the same or different.

[0040] Depending on the dosage form prepared / administered, various pharmaceutically acceptable excipients may be selected in the preparation, including but not limited to coating materials, solvents, solubilizers, adhesives, stabilizers, antioxidants, pH adjusters, and flavoring agents. Those skilled in the art may select these excipient ingredients based on common knowledge in pharmacy.

[0041] In addition to the above-mentioned auxiliary ingredients, the preparation of the present application may also include, or be provided separately, or other known drugs or therapies for inhibiting vomiting may be administered simultaneously when implementing the method of the present application, including but not limited to other 5-HT receptor antagonists, NK-1 receptor antagonists, dopamine receptor blockers, glucocorticoids, etc., such as granisetron, dolasetron, ramosetron, tropisetron, palonosetron, aprepitant, metoclopramide, dexamethasone, etc.; and other drugs or therapies for reducing cardiac electrical activity disorders, including but not limited to beta-blockers, sympathetic nerve blockers, such as propranolol, phenytoin sodium, reserpine, epinephrine, atropine, verapamil, sympathetic ganglionectomy, etc.

[0042] Beneficial effects:

[0043] 1. It avoids the disturbance of cardiac electrical activity caused by ondansetron, thereby reducing the possibility of arrhythmia, tachycardia, sudden cardiac death and other problems.

[0044] 2. Retain the efficacy of ondansetron in preventing and treating vomiting.

[0045] 3. For high-risk groups with congenital long QT syndrome or other underlying diseases, patients taking other drugs that cause cardiac electrical activity disorders, or patients with electrolyte imbalance (hypokalemia, hypocalcemia, hypomagnesemia), liver and kidney function decline, heart failure, left ventricular hypertrophy, myocardial infarction and other heart diseases that form a state prone to arrhythmias, the drug or method of this application can be used more safely than ondansetron alone.

[0046] 4. Diltiazem has a certain effect of improving myocardial blood supply and has a cardioprotective effect. Compound preparations containing diltiazem are more suitable for middle-aged and elderly people or patients with heart disease.

[0047] 5. Women have a higher risk of drug-induced TdP than men, and the present invention provides more significant protection for the female patient group. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 According to statistics from the eHealthMe website based on medical big data and artificial intelligence algorithms, as of July 19, 2022, 83,849 people reported side effects while using ondansetron, of which 3,448 (4.11%) died. A. shows the number of people who reported side effects from taking ondansetron each year; B. shows the number of people who died each year.

[0049] Figure 2 Schematic diagram of an electrocardiogram (ECG). A is a normal electrocardiogram of a healthy human individual. B is a schematic diagram of an electrocardiogram with disordered cardiac electrical activity.

[0050] Figure 3 The electrocardiogram showed torsade de pointes (TdP).

[0051] Figure 4 Multi-electrode array (MEA) was used to record the field potential characteristics (FP) of induced pluripotent stem cell differentiated cardiomyocytes (hiPSC-CMs); A: a representative normal MEA signal recording of hiPSC-CMs field potential electrical signals; B: a representative arrhythmia MEA signal recording of hiPSC-CMs field potential electrical signals, which can detect arrhythmia events; C: MEA signal traces can be analyzed to obtain field potential parameters: field potential duration (FPD), beating period and corrected field potential duration (FPDc).

[0052] Figure 5Diltiazem (modified new drug group) can effectively reverse the cardiac electrical activity disorder of myocardial cells caused by ondansetron, thereby preventing the development of related arrhythmias and avoiding the occurrence of sudden cardiac death caused by drug side effects. A shows that the use of ondansetron alone can significantly increase FPDc compared with the control group, while the combination of ondansetron and diltiazem (modified new drug group) did not significantly change FPDc compared with the control group. B uses the original field potential recording diagram to show that the use of ondansetron alone can significantly increase FPDc compared with the control group, while the combination of ondansetron and diltiazem (modified new drug group) did not significantly change FPDc compared with the control group. FPDc (the rate corrected field potential duration) is the duration of the heart rate corrected field potential, which is equivalent to the QT interval in the electrocardiogram. In this figure, the concentration of ondansetron in the modified new drug is 120μg / L and the concentration of diltiazem is 8.29μg / L.

[0053] Figure 6 This is the effect of combining other drugs with ondansetron in the process of finding an effective combination. A indicates that atenolol cannot reverse the toxicity of ondansetron. B indicates that diazoxide cannot reverse the toxicity of ondansetron. In this figure, the concentration of ondansetron is 120μg / L, the concentration of atenolol is 4.79mg / L, and the concentration of diazoxide is 6.92mg / L.

[0054] Figure 7 This is the effect of combining other concentrations with ondansetron in the process of finding an effective combination concentration. A. Indicates that the concentration of diltiazem in the improved new drug other ratio-1 is too low to reverse the toxicity of ondansetron. B. Indicates that when the concentration of diltiazem in the improved new drug other ratio-2 is too high, it will over-reverse the toxicity of ondansetron. In this figure, the ondansetron concentration is 120μg / L, the diltiazem concentration in the improved new drug other ratio-1 is 8.29μg / L, and the diltiazem concentration in the improved new drug other ratio-2 is 24.87μg / L.

[0055] Figure 8 The computer-simulated in vitro arrhythmogenic model showed that the action potential duration of the ondansetron group was longer than that of the negative control group. There was no significant difference between the modified new drug group and the negative control group. This shows that the modified new drug group can effectively avoid the changes in myocardial action potential caused by the ondansetron group.

[0056] Fig. 9 The incidence of arrhythmias in human myocardial cells under the action of different drugs and concentrations. A. Shows the percentage of arrhythmias in myocardial cells under the action of different concentrations of ondansetron. B. Shows the percentage of arrhythmias in myocardial cells induced by high-dose ondansetron and its corresponding improved new drug. C. Shows the percentage of arrhythmias in myocardial cells induced by 10-fold high-dose ondansetron and its corresponding improved new drug.

[0057] Fig.10 In the influencing factor test, the effects of light avoidance, high temperature, and light on the improved new drug formulation and each component were observed. Among them, API-1 is ondansetron and API-2 is diltiazem. A. It shows that single-prescription API-1 and API-1 in the compound are relatively stable at high temperature and light avoidance. B. It shows that single-prescription API-1 is unstable under light, and API-1 in the compound is stable under light, so single-prescription API-1 needs to be stored away from light. This shows that under high temperature conditions, API-2 has no effect on the stability of API-1. Under light conditions, API-2 has a stabilizing effect on API-1, but light still has a significant degradation trend, and it needs to be stored away from light. C. It shows that single-prescription API-2 and API-2 in the compound are unstable at high temperature and stable under light avoidance. Under high temperature and light avoidance conditions, API-1 has basically no significant effect on the stability of API-2. D. It shows that under light conditions, the compound API-2 is more stable than single-prescription API-2. This shows that API-2 is unstable under high temperature and light, and the compound is unstable under high temperature and light, and needs to be stored at low temperature and away from light.

[0058] Fig.11 The FDA's response to different doses of ondansetron is shown in Figure 2.

[0059] Fig.12 The stability of API-1 (ondansetron) at 2-8℃ and 25℃ is shown, and there is no significant change in related substances; API-2 (diltiazem) is relatively stable under 2-8℃ storage conditions, and mainly produces degradation impurity API-2F at 25℃. Impurity API-2F is a metabolite in the body, so it is very safe. It is predicted that the compound will have good stability under light-proof and low-temperature (2-8℃) storage conditions, and the quality meets the requirements (no new safety issues will arise due to impurities). DETAILED DESCRIPTION

[0060] Example 1 Drug Screening

[0061] Normal people, cardiac electrical activity disorder and Tdp electrocardiogram and reference Figure 2 and Figure 3 shown.

[0062] Based on induced pluripotent stem cell technology, combined with the latest international electrophysiology, pharmacology and other high-tech, we have established a pluripotent stem cell cardiac electrophysiology research and development platform that focuses on the world's advanced precision drug screening and development, thereby designing a new antiemetic drug that eliminates the cardiac toxic side effects of fatal arrhythmias. The platform can record and analyze parameters such as heart rate, QT, QTc, beating period, etc.; analyze the changes in heart rate, QT, QTc, beating period and other parameters caused by drugs.

[0063] Use the stem cell cardiac electrophysiology platform to screen drug combination solutions. The basic process is:

[0064] (1) Cardiomyocytes differentiated from human induced stem cells were thawed and seeded on Multi-Electrode Array (MEA) cell culture plates, and the cell culture medium was replaced daily.

[0065] (2) After about 4-8 days, the heart cell electrical signals are recorded. The heart cell electrical signals before the addition of drugs are recorded, as well as the heart cell electrical signals after the addition of ondansetron and diltiazem.

[0066] (3) Compare the differences in electrical signals under the action of different drugs, analyze the data, and make graphical comparisons.

[0067] Figure 4 The multi-electrode array (MEA) was used to record the field potential (FP) of cardiomyocytes differentiated from induced pluripotent stem cells (hiPSC-CMs).

[0068] Example 2 Effect of the compound medicine of this application

[0069] The hiPSC-CMs were thawed and seeded on the Multiple Electride Array (MEA) plate with the base solution of the hiPSC-CMs. The culture medium of the hiPSC-CMs was replaced, and then the cell culture medium was changed every day until the addition of drugs and the recording was completed. The myocardial cells were planted on the MEA plate for 4-8 days, and the electrical signals of the heart cells can be recorded. The baseline baseline recorded the electrical signals of the heart cells before the addition of drugs, and the electrical signal data of the heart cells were recorded after the addition of ondansetron, and then the drugs such as diltiazem were added to record the electrical signal data of the heart cells. The recorded electrical signal data were exported to Excel after analysis, and then the graphs were analyzed using Graph Pad.

[0070] Figure 5It shows that diltiazem (modified new drug group) can effectively reverse the cardiac electrical activity disorder of myocardial cells caused by ondansetron, thereby preventing the development of related arrhythmias and avoiding the occurrence of sudden cardiac death caused by drug side effects. A shows that the use of ondansetron alone can significantly increase FPDc compared with the control group, while the combination of ondansetron and diltiazem (modified new drug group) did not significantly change FPDc compared with the control group. B uses the original field potential recording diagram to show that the use of ondansetron alone can significantly increase FPDc compared with the control group, while the combination of ondansetron and diltiazem (modified new drug group) did not significantly change FPDc compared with the control group. FPDc (the rate corrected field potential duration) is the duration of the heart rate corrected field potential, which is equivalent to the QT interval in the electrocardiogram. In this figure, the concentration of ondansetron in the modified new drug is 120μg / L and the concentration of diltiazem is 8.12μg / L.

[0071] Figure 6 This figure shows the effects of several other drugs combined with ondansetron. A indicates that atenolol cannot eliminate the toxicity of ondansetron. B indicates that diazoxide cannot eliminate the toxicity of ondansetron. In this figure, the ondansetron concentration is 120μg / L, the atenolol concentration is 4.79mg / L, and the diazoxide concentration is 6.92mg / L.

[0072] Figure 7 This is the effect of combining other concentrations with ondansetron in the process of finding an effective combination concentration. A. Indicates that the concentration of diltiazem in the improved new drug other ratio-1 is too low to reverse the toxicity of ondansetron. B. Indicates that when the concentration of diltiazem in the improved new drug other ratio-2 is too high, it will over-reverse the toxicity of ondansetron. In this figure, the ondansetron concentration is 120μg / L, the diltiazem concentration in the improved new drug other ratio-1 is 8.29μg / L, and the diltiazem concentration in the improved new drug other ratio-2 is 24.87μg / L.

[0073] Figure 8 The computer-simulated in vitro arrhythmogenic model showed that the action potential duration of the ondansetron group was longer than that of the negative control group. There was no significant difference between the modified new drug group and the negative control group. This shows that the modified new drug group can effectively avoid the changes in myocardial action potential caused by the ondansetron group.

[0074] Fig. 9 The incidence of arrhythmias in human myocardial cells under the action of different drugs and concentrations. A. Shows the percentage of arrhythmias in myocardial cells under the action of different concentrations of ondansetron. B. Shows the percentage of arrhythmias in myocardial cells induced by high-dose ondansetron and its corresponding improved new drug. C. Shows the percentage of arrhythmias in myocardial cells induced by 10-fold high-dose ondansetron and its corresponding improved new drug.

[0075] Fig.10 In the influencing factor test, the effects of light avoidance, high temperature, and light on the improved new drug formulation and each component were observed. Among them, API-1 is ondansetron and API-2 is diltiazem. A. It shows that single-prescription API-1 and API-1 in the compound are relatively stable at high temperature and light avoidance. B. It shows that single-prescription API-1 is unstable under light, and API-1 in the compound is stable under light, so single-prescription API-1 needs to be stored away from light. This shows that under high temperature conditions, API-2 has no effect on the stability of API-1. Under light conditions, API-2 has a stabilizing effect on API-1, but light still has a significant degradation trend, and it needs to be stored away from light. C. It shows that single-prescription API-2 and API-2 in the compound are unstable at high temperature and stable under light avoidance. Under high temperature and light avoidance conditions, API-1 has basically no significant effect on the stability of API-2. D. It shows that under light conditions, the compound API-2 is more stable than single-prescription API-2. This shows that API-2 is unstable under high temperature and light, and the compound is unstable under high temperature and light, and needs to be stored at low temperature and away from light.

[0076] Fig.11 The FDA's response to different doses of ondansetron is shown in Figure 2.

[0077] Fig.12 Laboratory optimal formulation stability test.

Claims

1. A safer drug, characterized in that The safer drugs include serotonin receptor antagonists and diltiazem.

2. The safer drug according to claim 1, wherein the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

3. The safer drug according to claim 2, wherein the serotonin receptor antagonist is ondansetron.

4. The safer drug according to any one of claims 1 to 3, which is a compound preparation.

5. The safer drug according to claim 4, wherein the mass ratio of the serotonin receptor antagonist to diltiazem in the compound preparation is 180:1 to 1:4; preferably 35:1 to 5:1; further preferably 24:1 to 12:

1.

6. The safer drug according to any one of claims 1 to 5, wherein the compound preparation is an oral preparation or an injection, a topical preparation, or a spray; the oral preparation includes capsules, oral liquids, and tablets; the injection includes injections and powder injections.

7. The safer drug according to claim 6, wherein the concentration of diltiazem in the compound preparation after entering the human body is 0.4 μg / L-300 μg / L in blood.

8. The safer drug according to claim 7, wherein the blood concentration of diltiazem in the compound preparation after entering the human body is 2 μg / L-130 μg / L.

9. The safer drug according to claim 8, wherein the blood concentration of diltiazem in the compound preparation after entering the human body is 4 μg / L-50 μg / L.

10. Use of diltiazem in the preparation of a drug for reducing the possibility of drug-induced cardiac arrhythmia and sudden death.

11. The use according to claim 10, wherein the cardiac arrhythmia and sudden death are cardiac electrical activity disorders caused by 5-hydroxytryptamine receptor antagonism.

12. The use according to claim 11, wherein the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

13. The use according to claim 12, wherein the 5-hydroxytryptamine receptor antagonist is ondansetron.

14. The use according to any one of claims 10-13, wherein the drug is an oral preparation or an injection, a local application preparation, or a spray; the oral preparation includes capsules, oral liquids, and tablets; the injection includes injections and powder injections.

15. The use according to any one of claims 10 to 14, wherein the dosage of diltiazem is 1-60 mg for a single oral preparation or 0.0002-0.35 mg / kg for injection.

16. The use according to claim 15, wherein the dosage of diltiazem is 1-30 mg for a single oral preparation or 0.0005-0.15 mg / kg for injection.

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