Safer drug and use thereof

Abstract

Provided are a safer drug and the use thereof. Provided are a pharmaceutical composition which is safer and which does not have toxicity leading to sudden cardiac death, and the use thereof. The provided safer drug is a compound formulation containing a 5-hydroxytryptamine receptor antagonist and diltiazem, and can effectively avoid the possibility of cardiac arrhythmia and sudden cardiac death due to ventricular depolarization and repolarization disorders caused by the 5-hydroxytryptamine receptor antagonist ondansetron. Further provided are the use of diltiazem in preparing a drug for improving electrical activity of the heart and a corresponding therapeutic method.

Description

A safer drug and its application Technical field:

[0001] 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 technology:

[0002] Ondansetron, English name Ondansetron, chemical name is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, chemical formula is C 18 H 19 N3O is a highly selective 5-hydroxytryptamine (5-HT3) receptor antagonist with high potency and selectivity, capable of controlling vomiting caused by stimulation of receptors in the small intestine and CTZ. Furthermore, at antiemetic doses, ondansetron can enhance gastric emptying, helping to alleviate nausea. It also has an anxiolytic effect on the central nervous system, helping to suppress activation of the vomiting center. Ondansetron is currently a first-line antiemetic drug used both domestically and internationally, and is widely used clinically to prevent or treat nausea and vomiting caused by chemotherapy drugs (such as cisplatin and doxorubicin), radiotherapy, surgery, or post-anesthesia.

[0003] The QT interval is a key part of the surface electrocardiogram (ECG), 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 a patient's QT interval, the risk of developing 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.

[0004] Transient electrocardiographic changes, including disturbances in cardiac electrical activity, have been reported in patients treated with ondansetron. Furthermore, postmarketing case reports have linked to the development of torsades de pointes in patients treated with ondansetron (a specific FDA alert was issued in 2012). Randomized, double-blind, crossover clinical trials in the United States have demonstrated that ondansetron-induced disturbances in cardiac electrical activity are dose-dependent. Specifically, a single intravenous dose of 32 mg resulted in a maximum mean difference of 20 milliseconds in cardiac electrical activity compared with placebo after baseline adjustment, while the maximum mean difference was 6 milliseconds at a lower intravenous dose (8 mg). Patients at high risk for cardiac electrical activity disturbances (congenital cardiac electrical activity disorder syndrome, congestive heart failure, bradyarrhythmias, or concomitant use of medications that can disrupt ventricular depolarization and repolarization) are more susceptible to severe arrhythmias and even sudden death when treated with ondansetron. Therefore, a single intravenous dose of ondansetron should generally not exceed 16 mg. Companies like GlaxoSmithKline have also revised their ondansetron product labeling, removing the 32mg single intravenous dose. The following figures and tables (Figures 1 and 11) illustrate ondansetron adverse events and the FDA's response.

[0005] As shown in Figure 1, according to statistics from the eHealthMe website, which uses medical big data and artificial intelligence algorithms, as of July 19, 2022, 83,849 people reported experiencing side effects while using ondansetron, of whom 3,448 (4.11%) died. Figure 1A shows the number of people who reported experiencing side effects while taking ondansetron each year; Figure 1B shows the number of deaths each year.

[0006] Summary of the Invention

[0007] Although the adjusted dosage recommendations can reduce the probability of ondansetron-induced arrhythmias to a certain extent, they do not fundamentally eliminate this possibility. Patients using this drug, especially those at high risk with congenital long QT syndrome or other underlying diseases, still face considerable risks.

[0008] To address the above-mentioned issues, the applicant used a 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. It was found that diltiazem can effectively avoid the disturbance of cardiac electrical activity caused by ondansetron, thereby reducing the possibility of arrhythmias, sudden cardiac death and other problems.

[0009] In one aspect, the present application provides a novel and safe antiemetic drug (improved new drug) with reduced cardiac electrical activity disturbance, which comprises a 5-hydroxytryptamine receptor antagonist and diltiazem.

[0010] Furthermore, the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

[0011] Furthermore, the 5-hydroxytryptamine receptor antagonist is ondansetron.

[0012] Furthermore, the novel safe drug is a compound preparation.

[0013] Furthermore, the mass ratio of the serotonin receptor antagonist to diltiazem in the novel safe drug is 180:1 to 1:4.

[0014] Furthermore, the mass ratio of the serotonin receptor antagonist to diltiazem in the novel safe drug is 35:1 to 5:1.

[0015] Furthermore, the mass ratio of the serotonin receptor antagonist to diltiazem in the novel safe drug is 24:1 to 12:1.

[0016] Furthermore, the novel safe drug (improved new drug) may be an oral preparation or an injection, a topical preparation, a spray, etc.; oral preparations include capsules, oral liquids, and tablets; and injections include injections and powder injections.

[0017] On the other hand, the present application provides the use of diltiazem in preparing a medicament for reducing cardiac electrical activity disorder.

[0018] Furthermore, the cardiac electrical activity disorder is a cardiac electrical activity disorder caused by a 5-hydroxytryptamine receptor antagonist.

[0019] Furthermore, the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

[0020] Furthermore, the 5-hydroxytryptamine receptor antagonist is ondansetron.

[0021] Furthermore, the drug is an oral preparation or injection, a topical preparation, a spray, etc.; oral preparations include capsules, oral liquids, and tablets; injections include injections and powder injections.

[0022] Furthermore, the dosage of diltiazem is 1-60 mg for a single oral formulation or 0.0002-0.35 mg / kg for an injection.

[0023] Furthermore, the dosage of diltiazem is 1-30 mg for a single oral preparation or 0.0005-0.15 mg / kg for injection.

[0024] Furthermore, the blood concentration of diltiazem in the compound preparation after entering the human body is 0.4 μg / L-300 μg / L.

[0025] Furthermore, the blood concentration of diltiazem in the compound preparation after entering the human body is 2 μg / L-130 μg / L.

[0026] Furthermore, the blood concentration of diltiazem in the compound preparation after entering the human body is 4 μg / L-50 μg / L.

[0027] In another aspect, the present application provides a method for reducing cardiac electrical activity disturbances, comprising administering diltiazem to a subject at risk for or experiencing symptoms of cardiac electrical activity disturbances.

[0028] Furthermore, the subject is a human.

[0029] Furthermore, the subject is a female.

[0030] Furthermore, the cardiac electrical activity disorder is a cardiac electrical activity disorder caused by a 5-hydroxytryptamine receptor antagonist.

[0031] Furthermore, the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

[0032] Furthermore, the 5-hydroxytryptamine receptor antagonist is ondansetron.

[0033] Furthermore, the dosage of diltiazem is 1-60 mg for a single oral formulation or 0.0002-0.35 mg / kg for an injection.

[0034] Furthermore, the dosage of diltiazem is 1-30 mg for a single oral preparation or 0.0005-0.15 mg / kg for injection.

[0035] Furthermore, the frequency and duration of administration of diltiazem is once to six times a day, for 1-14 consecutive days.

[0036] Furthermore, the frequency and duration of administration of diltiazem is once to four times a day, for 1-7 consecutive days.

[0037] On the other hand, the present application relates to the use of diltiazem in the preparation of a drug for reducing the possibility of drug-induced cardiac arrhythmia and sudden death.

[0038] Furthermore, the cardiac arrhythmia and sudden death are disturbances of cardiac electrical activity caused by 5-hydroxytryptamine receptor antagonists.

[0039] Furthermore, the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

[0040] Furthermore, the 5-hydroxytryptamine receptor antagonist is ondansetron.

[0041] Furthermore, the drug is an oral preparation or an injection, a topical preparation, or a spray; oral preparations include capsules, oral liquids, and tablets; and injections include injections and powder injections.

[0042] Furthermore, the dosage of diltiazem is 1-60 mg for a single oral preparation or 0.0002-0.35 mg / kg for an injection.

[0043] Furthermore, the dosage of diltiazem is 1-30 mg for a single oral preparation or 0.0005-0.15 mg / kg for an injection.

[0044] In another aspect, the present application also relates to a method for reducing the risk of cardiac arrhythmias and sudden death, wherein the method comprises administering diltiazem to a subject at risk for or experiencing symptoms of a disturbance in the electrical activity of the heart.

[0045] Furthermore, the subject is a human.

[0046] Furthermore, the subject is a female.

[0047] Furthermore, the cardiac electrical activity disorder is a cardiac electrical activity disorder caused by a 5-hydroxytryptamine receptor antagonist.

[0048] Furthermore, the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

[0049] Furthermore, the 5-hydroxytryptamine receptor antagonist is ondansetron.

[0050] Furthermore, the dosage of diltiazem is 1-60 mg for a single oral preparation or 0.0002-0.35 mg / kg for an injection.

[0051] Furthermore, the dosage of diltiazem is 1-30 mg for a single oral preparation or 0.0005-0.15 mg / kg for an injection.

[0052] Furthermore, the frequency and duration of administration of diltiazem is once to six times a day, for 1-14 consecutive days.

[0053] Furthermore, the frequency and duration of administration of diltiazem are once to four times a day, for 1-7 consecutive days.

[0054] Furthermore, the blood concentration of diltiazem after entering the human body is 0.4μg / L–300μg / L.

[0055] Furthermore, the blood concentration of diltiazem after entering the human body is 2μg / L–130μg / L.

[0056] Furthermore, the blood concentration of diltiazem after entering the human body is 4μg / L–50μg / L.

[0057] 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 N3O; 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 N2O4S; the above-mentioned numbers, names, 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.

[0058] In this application, 5-hydroxytryptamine and 5-HT represent the same meaning and can be used interchangeably.

[0059] Ondansetron and diltiazem in the present application can be prepared in the same pharmaceutical composition; can also be provided as two drugs in the same package; can also be packaged separately and used in combination; various feasible combination forms known in the art are applicable to the present application.

[0060] Applicable dosage forms in this application include, but are not limited to, oral preparations and injections. The compound preparation, ondansetron preparation, and diltiazem preparation of this application may be applied to any clinically acceptable specific dosage form, including, but not limited to, tablets, capsules, oral solutions, injections, powder injections, topical preparations, sprays, etc. When the ondansetron preparation and the diltiazem preparation are provided in the same package or separately in different packages, the dosage forms of the two may be the same or different.

[0061] Depending on the dosage form to be 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 pharmaceutical knowledge.

[0062] In addition to the above-mentioned excipient components, the preparation of the present application may also include other pharmaceutically acceptable excipients. The preparation of the present application is provided alone, or when implementing the method of the present application, other known drugs or therapies for suppressing vomiting may also be administered simultaneously, 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, sympathectomy, etc. Beneficial effects:

[0063] 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.

[0064] 2. Preserve the efficacy of ondansetron in preventing and treating vomiting.

[0065] 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.

[0066] 4. Diltiazem has a certain effect on improving myocardial blood flow and has a cardioprotective effect. Combination preparations containing diltiazem are more suitable for middle-aged and elderly patients or those with heart disease.

[0067] 5. Women have a higher risk of developing drug-induced TdP than men. This application provides more significant protection for the female patient group. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 shows statistics from the eHealthMe website, which uses medical big data and artificial intelligence algorithms. As of July 19, 2022, 83,849 people reported experiencing side effects while using ondansetron, of whom 3,448 (4.11%) died. Figure 1A shows the number of people who reported experiencing side effects while taking ondansetron each year; Figure 1B shows the number of deaths each year.

[0069] Figure 2 is a schematic diagram of an electrocardiogram (ECG). Figure 2A is a normal ECG of a healthy human individual. Figure 2B is a schematic diagram of an ECG with disordered cardiac electrical activity.

[0070] Figure 3 shows an electrocardiogram showing torsades de pointes (TdP).

[0071] Figure 4 shows the field potential characteristics (FP) of induced pluripotent stem cell differentiated cardiomyocytes (hiPSC-CMs) recorded by a multi-electrode array (MEA); Figure 4A: A representative normal MEA signal recording of the hiPSC-CMs field potential electrical signal; Figure 4B: A representative arrhythmia MEA signal recording of the hiPSC-CMs field potential electrical signal, which can detect arrhythmia events; Figure 4C: The MEA signal trace can be analyzed to obtain field potential parameters: field potential duration (FPD), beating period and corrected field potential duration (FPDc).

[0072] [Corrected 21.03.2024 in accordance with Rule 91] Figure 5 shows that diltiazem (modified new drug group) can effectively reverse the cardiac electrical activity disturbances induced by ondansetron, thereby preventing the development of related arrhythmias and, in turn, avoiding the occurrence of sudden cardiac death due to drug side effects. Figures 5A and 5B demonstrate that ondansetron alone significantly increased FPDc compared to the control group, while the combination of ondansetron and diltiazem (modified new drug group) did not significantly change FPDc compared to the control group. Figure 5C, using raw field potential recordings, demonstrates that ondansetron alone significantly increased FPDc compared to the control group, while the combination of ondansetron and diltiazem (modified new drug group) did not significantly change FPDc compared to the control group. FPDc (the rate-corrected field potential duration) is the duration of the rate-corrected field potential, equivalent to the QT interval in an electrocardiogram. In this figure, the concentration of ondansetron in the improved new drug is 120 μg / L and the concentration of diltiazem is 8.29 μg / L.

[0073] Figure 6 shows the effects of other drugs combined with ondansetron during the search for effective combinations. Figure 6A shows that atenolol was unable to reverse ondansetron toxicity. Figure 6B shows that diazoxide was unable to reverse ondansetron toxicity. In this figure, the ondansetron concentration was 120 μg / L, the atenolol concentration was 4.79 mg / L, and the diazoxide concentration was 6.92 mg / L.

[0074] Figure 7 shows the effects of combining ondansetron with other concentrations during the search for effective concentration combinations. Figure 7A shows that the diltiazem concentration in the modified new drug, Other Ratio-1, was too low to reverse ondansetron toxicity. Figure 7B shows that the diltiazem concentration in the modified new drug, Other Ratio-2, was too high to reverse ondansetron toxicity. In this figure, the ondansetron concentration was 120 μg / L, the diltiazem concentration in the modified new drug, Other Ratio-1, was 8.29 μg / L, and the diltiazem concentration in the modified new drug, Other Ratio-2, was 24.87 μg / L.

[0075] Figure 8 shows a computer-simulated in vitro arrhythmogenic model showing that the action potential duration in the ondansetron group was longer than that in the negative control group. There was no significant difference between the modified new drug group and the negative control group. This suggests that the modified new drug group effectively prevented the myocardial action potential changes induced by the ondansetron group.

[0076] Figure 9 shows the incidence of arrhythmias in human cardiomyocytes treated with different drugs and concentrations. Figure 9A shows the percentage of cardiomyocytes experiencing arrhythmias at different ondansetron concentrations. Figure 9B shows the percentage of cardiomyocytes experiencing arrhythmias induced by high-dose ondansetron and its corresponding improved new drug. Figure 9C shows the percentage of cardiomyocytes experiencing arrhythmias induced by 10-fold higher-dose ondansetron and its corresponding improved new drug.

[0077] Figure 10 shows the effects of light protection, high temperature, and light on the modified new drug formulation and its components in an influencing factor experiment. API-1 is ondansetron, and API-2 is diltiazem. Figure 10A shows that both API-1 alone and the compound are relatively stable under high temperature and light protection. Figure 10B shows that API-1 alone is unstable under light, while API-1 in the compound is stable under light, necessitating that API-1 alone be stored away from light. This indicates that API-2 has no effect on the stability of API-1 under high temperature. While API-2 does stabilize API-1 under light, it still shows a significant tendency to degrade under light, necessitating storage away from light. Figure 10C shows that both API-2 alone and the compound are unstable under high temperature but stable under light protection. API-1 has little significant effect on the stability of API-2 under high temperature and light protection. Figure 10D shows that the compound is more stable than API-2 alone under light conditions. This indicates that API-2 is unstable at high temperature and light, and the compound is unstable at high temperature and light, and needs to be stored at low temperature and away from light.

[0078] Figure 11 shows the FDA's response to different doses of ondansetron.

[0079] Figure 12 shows the stability of API-1 (ondansetron) at 2-8°C and 25°C, showing no significant changes in related substances. API-2 (diltiazem) is relatively stable when stored at 2-8°C, but primarily produces the degradation impurity API-2F at 25°C. Impurity API-2F is a metabolite in vivo, thus providing a high safety profile. The compound is predicted to be stable and meet quality requirements when stored in the dark and at low temperatures (2-8°C), with no new safety concerns arising from impurities. DETAILED DESCRIPTION

[0080] Example 1 Drug Screening

[0081] The electrocardiograms of normal individuals, individuals with cardiac electrical activity disorders, and Tdp are shown in Figures 2 and 3.

[0082] Leveraging induced pluripotent stem cell technology, combined with the latest international electrophysiology and pharmacology technologies, we have established a pluripotent stem cell cardiac electrophysiology research and development platform focused on world-leading precision drug screening and development. This platform has resulted in the design of novel antiemetic drugs that eliminate the cardiac toxicity associated with fatal arrhythmias. The platform can record and analyze parameters such as heart rate, QT, QTc, and beating period, and analyze drug-induced changes in these parameters.

[0083] Use the stem cell cardiac electrophysiology platform to screen drug combination strategies. The basic process is:

[0084] (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.

[0085] (2) After approximately 4-8 days, begin recording cardiac cell electrical signals. Record the baseline cardiac cell electrical signals before drug addition, as well as the cardiac cell electrical signal data after the addition of drugs such as ondansetron and diltiazem.

[0086] (3) Compare the differences in electrical signals under the action of different drugs, analyze the data, and make graphical comparisons.

[0087] FIG4 shows the field potential (FP) characteristics of induced pluripotent stem cell differentiated cardiomyocytes (hiPSC-CMs) recorded by a multi-electrode array (MEA).

[0088] Example 2 Effect of the compound medicine of this application

[0089] Human induced pluripotent stem cell-differentiated cardiomyocytes (hiPSC-CMs) are thawed and seeded onto Multiple Electride Array (MEA) plates coated with a substrate containing human induced pluripotent stem cell-differentiated cardiomyocytes. The culture medium used to maintain the differentiated cardiomyocytes is replaced daily until drug addition and recording is complete. Cardiomyocyte electrical signals can be recorded 4-8 days after the cardiomyocytes are seeded on the MEA plates. A baseline is recorded for cardiac cell electrical signals before drug addition. After ondansetron is added, cardiac cell electrical signal data is recorded. Then, drugs such as diltiazem are added and cardiac cell electrical signal data is recorded. The recorded electrical signal data is analyzed and exported to Excel, where they are then graphically analyzed using Graph Pad.

[0090] [Corrected 21.03.2024 in accordance with Rule 91] Figure 5 shows that diltiazem (modified new drug group) can effectively reverse the cardiac electrical activity disturbances induced by ondansetron, thereby preventing the development of related arrhythmias and, in turn, avoiding the occurrence of sudden cardiac death due to drug side effects. Figures 5A and 5B demonstrate that ondansetron alone significantly increased FPDc compared to the control group, while the combination of ondansetron and diltiazem (modified new drug group) did not significantly change FPDc compared to the control group. Figure 5C, using raw field potential recordings, demonstrates that ondansetron alone significantly increased FPDc compared to the control group, while the combination of ondansetron and diltiazem (modified new drug group) did not significantly change FPDc compared to the control group. FPDc (the rate-corrected field potential duration) is the duration of the rate-corrected field potential, equivalent to the QT interval in an electrocardiogram. In this figure, the concentration of ondansetron in the improved new drug is 120 μg / L and the concentration of diltiazem is 8.12 μg / L.

[0091] Figure 6 shows the effects of combining several other drugs with ondansetron. Figure 6A shows that atenolol was unable to eliminate ondansetron toxicity. Figure 6B shows that diazoxide was unable to eliminate ondansetron toxicity. In this figure, the ondansetron concentration was 120 μg / L, the atenolol concentration was 4.79 mg / L, and the diazoxide concentration was 6.92 mg / L.

[0092] Figure 7 shows the effects of combining ondansetron with other concentrations during the search for effective concentration combinations. Figure 7A shows that the diltiazem concentration in the modified new drug, Other Ratio-1, was too low to reverse ondansetron toxicity. Figure 7B shows that the diltiazem concentration in the modified new drug, Other Ratio-2, was too high to reverse ondansetron toxicity. In this figure, the ondansetron concentration was 120 μg / L, the diltiazem concentration in the modified new drug, Other Ratio-1, was 8.29 μg / L, and the diltiazem concentration in the modified new drug, Other Ratio-2, was 24.87 μg / L.

[0093] Figure 8 shows a computer-simulated in vitro arrhythmogenic model showing that the action potential duration in the ondansetron group was longer than that in the negative control group. There was no significant difference between the modified new drug group and the negative control group. This suggests that the modified new drug group effectively prevented the myocardial action potential changes induced by the ondansetron group.

[0094] Figure 9 shows the incidence of arrhythmias in human cardiomyocytes treated with different drugs and concentrations. Figure 9A shows the percentage of cardiomyocytes experiencing arrhythmias at different ondansetron concentrations. Figure 9B shows the percentage of cardiomyocytes experiencing arrhythmias induced by high-dose ondansetron and its corresponding improved new drug. Figure 9C shows the percentage of cardiomyocytes experiencing arrhythmias induced by 10-fold higher-dose ondansetron and its corresponding improved new drug.

[0095] Figure 10 shows the effects of light protection, high temperature, and light on the modified new drug formulation and its components in an influencing factor experiment. API-1 is ondansetron, and API-2 is diltiazem. Figure 10A shows that both API-1 alone and the compound are relatively stable under high temperature and light protection. Figure 10B shows that API-1 alone is unstable under light, while API-1 in the compound is stable under light, necessitating that API-1 alone be stored away from light. This indicates that API-2 has no effect on the stability of API-1 under high temperature. While API-2 does stabilize API-1 under light, it still shows a significant tendency to degrade under light, necessitating storage away from light. Figure 10C shows that both API-2 alone and the compound are unstable under high temperature but stable under light protection. API-1 has little significant effect on the stability of API-2 under high temperature and light protection. Figure 10D shows that the compound is more stable than API-2 alone under light conditions. This indicates that API-2 is unstable at high temperature and light, and the compound is unstable at high temperature and light, and needs to be stored at low temperature and away from light.

[0096] Figure 11 shows the FDA's response to different doses of ondansetron.

[0097] Figure 12 Laboratory optimal formulation stability test.

Claims

1. A safer drug comprising a serotonin receptor antagonist and diltiazem.

2. The safer drug according to claim 1, wherein the serotonin receptor antagonist is a serotonin 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; and more 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; oral preparations include capsules, oral liquids, and tablets; and injections include injections and powder injections.

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

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 antagonists.

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 serotonin receptor antagonist is ondansetron.

14. The use according to any one of claims 10 to 13, wherein the drug is an oral preparation or an injection, a topical preparation, or a spray; oral preparations include capsules, oral liquids, and tablets; and injections include 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.

17. A method for reducing the risk of cardiac arrhythmias and sudden death, characterized in that The method comprises administering diltiazem to a subject at risk for or experiencing symptoms of a disturbance in the electrical activity of the heart.

18. The method of claim 17, wherein the subject is a human.

19. The method of claim 18, wherein the subject is female.

20. The method according to any one of claims 17 to 19, wherein the cardiac electrical activity disorder is cardiac electrical activity disorder caused by a 5-hydroxytryptamine receptor antagonist.

21. The method of claim 20, wherein the serotonin receptor antagonist is a serotonin 3 receptor antagonist.

22. The method of claim 21, wherein the serotonin receptor antagonist is ondansetron.

23. The method according to any one of claims 17 to 22, wherein the dosage of diltiazem administered is 1 to 60 mg for a single oral formulation or 0.0002 to 0.35 mg / kg for injection.

24. The method of claim 23, wherein the dosage of diltiazem administered is 1-30 mg for a single oral formulation or 0.0005-0.15 mg / kg for injection.

25. The method according to any one of claims 17 to 22, wherein the frequency and duration of administration of diltiazem is from once to six times a day for 1 to 14 consecutive days.

26. The method of claim 25, wherein the frequency and duration of administration of diltiazem is from once to four times a day for 1-7 consecutive days.

27. The method according to claim 17, wherein the blood concentration of diltiazem after entering the human body is 0.4 μg / L-300 μg / L.

28. The method according to claim 27, wherein the blood concentration of diltiazem after entering the human body is 2 μg / L-130 μg / L.

29. The method according to claim 28, wherein the blood concentration of diltiazem after entering the human body is 4 μg / L-50 μg / L.

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